Ferri's clinical advisor 2021 9780323713344, 0323713343

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CLINICAL DISORDERS CARDIOVASCULAR DISEASES SECTION Acute coronary syndromes I Aneurysm, abdominal aorta I Angina pectoris I Aortic coarctation I Aortic dissection I Aortic regurgitation I Aortic stenosis I Arrhythmogenic right ventricular cardiomyopathy I Atrial enlargement, left atrium II Atrial fibrillation I Atrial flutter I Atrial myxoma I Atrial septal defect I Atrium enlargement, right atrium II Atrioventricular dissociation I Bicuspid aortic valve I Branch bundle block I Bradycardia III Brugada syndrome I Calcifications, cardiac on x-ray II Calcifications, valvular on x-ray II Cardiac death, sudden II Cardiac tamponade I Cardiac tumors II Cardioembolism II Cardiomegaly on chest x-ray III Cardiomyopathy, chemical-induced I Cardiomyopathy, dilated I Cardiomyopathy, hypertrophic I Cardiomyopathy, ischemic, surgical management III Cardiomyopathy, restrictive I Cardiorenal syndrome I Carotid sinus syndrome I I Cervical artery dissection Chronic urticaria I I Cirrhotic cardiomyopathy Congestive heart failure I Congestive heart failure and cardiomyopathy II I Connective tissue disease–associated vasculitis Coronary artery disease I Cor pulmonale I Cyanosis II Early repolarization syndrome I Ejection sound or click II Giant cell myocarditis I Heart block, second-degree I Heart failure, acute I, II Heart failure, pregnancy II I HIV-associated cardiomyopathy Hypercholesterolemia I Hyperlipoproteinemia, primary I Hypertension I Hypertension, in children II Hypotension III Intraventricular conduction defect (IVCD) I Junctional rhythm I Long QT syndrome I Mesenteric arterial embolism, associated II factors Mitral regurgitation I Mitral stenosis I Mitral valve prolapse I Multifocal atrial tachycardia I Murmur, diastolic III Murmur, systolic III Myocardial infarction I Myocarditis I Orthostatic hypotension I Palpitations III Paroxysmal supraventricular tachycardia I Patent ductus arteriosus I Pericardial effusion, malignant III Pericarditis I Pleural effusion, malignant III Pleural effusions, malignancy-associated II Postural hypotension, nonneurologic causes II Premature ventricular contractions and II ventricular tachycardia Pulmonary edema I Pulmonary edema, non-cardiogenic II Pulseless electrical activity I Renal artery stenosis I Rib notching on x-ray II Short QT syndrome I Sick sinus syndrome I Syncope I Tachycardia III Tachycardia, narrow complex III Tachycardia, wide complex III Takayasu's arteritis I Takotsubo cardiomyopathy I Thrombotic microangiopathies, diagnosis III Torsades des pointes I Valvular heart disease II Venous ulcers I Ventricular septal defect I

Ventricular fibrillation Ventricular tachycardia Wolff-Parkinson-White syndrome DERMATOLOGY Acne vulgaris Actinic keratosis Alopecia Angioedema Angular cheilitis Atopic dermatitis Balanitis Basal cell carcinoma Bedbug bite Calcifications, cutaneous Candidiasis, cutaneous Contact dermatitis Cutaneous infections, athletes Cutaneous occlusion syndromes Cyanosis, algorithm Dermatitis herpetiformis Discoid lupus Eosinophilic dermatoses Epidermolysis bullosa (EB) Erosions, genitalia Erysipelas Erythema elevatum diutinum Erythema multiforme Erythroderma Eyelid neoplasm Fifth disease (parvovirus infection) Finger lesions, inflammatory Flushing Folliculitis Foot dermatitis Genital lesions or ulcers Granuloma, algorithm Granuloma annulare Granulomatous dermatitides Hand-foot-mouth disease Herpes simplex Herpes zoster Hidradenitis suppurativa Hyperhydrosis Hyperpigmentation IgA vasculitis Impetigo Jaundice, neonatal, algorithm Kaposi sarcoma Leg ulcer Lichen planus Lichen sclerosus Lichen simplex chronicus Malar eruption Mastocytosis Melanoma Melanonychia Molluscum contagiosum Mucormycosis Myositis Nail dystrophy Neurofibromatosis Onycholysis Oral hairy leukoplakia Panniculitis Papulosquamous disorders, pediatric patient Paronychia Pediculosis Pemphigus vulgaris Photosensitivity Pinworms Pityriasis rosea Porphyrias Premature graying, scalp hair Pruritus, generalized, clinical algorithm Pruritus vulvae Psoriasis Purpura, nonpalpable Purpura, non-purpuric disorders simulating purpura Purpura, palpable Purpura, palpable, clinical algorithm Reactive erythema, pediatric patient Rocky Mountain spotted fever Rosacea Roseola Scabies Scarlet fever Scleroderma (systemic sclerosis) Skin blisters Stevens-Johnson syndrome Tinea capitis Tinea corporis Tinea cruris Tinea pedis Tinea versicolor Varicella Venous insufficiency, chronic Venous ulcers

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Verrucous lesions Vitiligo Warts ENDOCRINOLOGY Adrenal incidentaloma Adrenal insufficiency Adrenal mass, clinical algorithm Adrenocortical hyperfunction Adrenocortical hypofunction Aldosteronism Androgen excess, reproductive-age woman Anhydrosis Bone density, decreased, generalized Bone density, decreased, localized Bone mass, low Breast, nipple discharge evaluation Calcifications, abdominal, nonvisceral on x-ray Calcifications, adrenal gland on x-ray Calcifications, genital tract, female on x-ray Calcium stones Cushing's disease and syndrome Delayed puberty Diabetes insipidus Diabetes mellitus Diabetic foot Diabetic gastroparesis Diabetic ketoacidosis Diabetic nephropathy Erectile dysfunction Exocrine pancreatic insufficiency (EPI) Flushing Foot lesion, ulcerating Galactorrhea Genitourinary syndrome of menopause (GSM) Goiter evaluation and management Graves disease Gynecomastia Hirsutism Hot flashes Hypercalcemia, clinical algorithm Hypercalcemia, laboratory differential diagnosis Hypercalcemia, malignancy-induced Hyperlipoproteinemia, primary Hyperosmolar hyperclycemic syndrome Hyperostosis, cortical bone Hyperparathyroidism Hyperthyroidism Hypoaldosteronism Hypocalcemia, laboratory differential diagnosis Hypoglycemia Hypogonadism Hypoparathyroidism Hypopituitarism Hypothyroidism Infertility Menopause Metabolic syndrome Osteoporosis Osteoporosis, secondary causes Paget disease of the bone Pancreatic islet cell tumors Paraneoplastic syndromes Pheochromocytoma Pituitary adenoma Pituitary region tumors Polycystic ovary syndrome Primary ovarian insufficiency Prolactinoma Pseudohermaphroditism Sexual dysfunction Sexual precocity, female breast development Sexual precocity, female pubic hair development Sexual precocity, male Short stature Syndrome of inappropriate antidiuresis Thyroid nodule Thyroid, painful, clinical algorithm Thyroiditis Thyromegaly ENVIRONMENTAL MEDICINE Amebiasis Babesiosis Bite wounds Bites and stings, arachnids Bites and stings, insect Bites, snake Botulism Burns Contact dermatitis Diarrhea, acute Drowning Ehrlichiosis Electrical injury Envenomation, marine Food poisoning, bacterial Frostbite Giardiasis

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Heat exhaustion and heat stroke High-altitude sickness Hypothermia Lyme disease Malaria Microsporidosis Mushroom poisoning Radiation exposure Rocky Mountain spotted fever Salmonellosis Shigellosis Southern tick-associated rash illness (STARI) Tapeworm infestation Vaccinations for international travel Zika virus GASTROENTEROLOGY Abdominal compartment syndrome Abdominal pain, chronic lower Abdominal pain, nonsurgical causes Achalasia Acute colonoic pseudo-obstruction Acute liver failure Acute lower gastrointestinal bleeding Acute mesenteric ischemia Alcoholic hepatitis Anal abscess and fistula Anorectal fistula Anorectal stricture Anorexia Aphthous ulcers Appendicitis Ascariasis Ascites Autoimmune hepatitis Bacterial overgrowth, small intestine Barrett esophagus Bile duct, dilated Bleeding, gastrointestinal, algorithm Bleeding, rectal Bleeding, variceal Budd-Chiari syndrome Calcifications, liver on x-ray Calcifications, pancreas on x-ray Calcifications, spleen on x-ray Celiac disease Cholangiocarcinoma Cholangitis Cholecystitis Choledocholithiasis Cholelithiasis Chronic pancreatitis Cirrhosis Cirrhosis, primary biliary Cirrhotic cardiomyopathy Colic, acute abdominal Colorectal cancer Colostridium difficile infection Constipation, adult patient Constipation Crohn disease Cryptosporidium infection Delayed passage of meconium Diarrhea, acute Diarrhea, acute watery and bloody Diarrhea, chronic Diarrhea, chronic, in patients with HIV infection, algorithm Diarrhea, infectious Diarrhea, non-infectious Diarrhea, persistent Diverticular disease (diverticulosis, ­diverticulitis) Drug-induced liver injury Dyspepsia Dyspepsia, nonulcerative Dysphagia, oropharyngeal Echinococcosis Eosinophilic esophagitis Epigastric pain Esophageal tumors Esophageal varices Esophagitis Familial adenomatous polyps and Gardner syndrome Fetal alcohol spectrum disorder Food poisoning, bacterial Functional gallbladder disorder Gallbladder carcinoma Gastric cancer Gastric dilatation Gastric emptying, delayed Gastritis Gastroenteritis Gastroesophageal reflux disease Giardiasis Gilbert disease Glossitis Glossodynia

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Helicobacter pylori infection Hematemesis Hemochromatosis Hemoperitoneum Hemoptysis Hepatic encephalopathy Hepatitis A Hepatitis, acute Hepatitis B Hepatitis B prophylaxis Hepatitis C Hepatitis D Hepatitis E Hepatitis, viral Hepatomegaly, algorithm Hepatomegaly, by shape of liver Hepatopulmonary syndrome Hepatorenal syndrome Hookworm Hypergastrinemia Hypersplenism, associated conditions Hypoglycemia Incontinence, fecal Inguinal hernia Irritable bowel syndrome Ischemia, colon Ischemic colitis Ischemic hepatitis Jaundice, classification Jaundice in the adult patient Jaundice, neonatal Jaundice, neonatal, algorithm Lactose intolerance Large bowel obstruction Large bowel stricture Levator ani syndrome Liver abscess Liver disease, pregnancy Liver lesions, benign Liver transplantation Lynch syndrome Malabsorption Malabsorption algorithm Mallory-Weiss tear Microscopic colitis Nonalcoholic fatty liver disease Non-celiac disease gluten sensitivity Nutrition assessment and intervention in cancer patient Odynophagia Pancreas transplantation Pancreatic calcifications Pancreatic cancer (exocrine) Pancreatitis, drug-induced Peptic ulcer disease Perianal pain Peritonitis, secondary Peutz-Jeghers syndrome and other polyposis syndromes Pinworms Pneumatosis intestinalis in neonate and older child Portal hypertension Portal vein thrombosis Primary sclerosing cholangitis Rectal mass, palpable Retropharyngeal abscess Shigellosis Short bowel syndrome Small bowel masses Small bowel obstruction Small bowel intestinal bacterial overgrowth Small intestine ulceration Spontaneous bacterial peritonitis Subphrenic abscess Tapeworm infestation Toxic megacolon Traveler's diarrhea Ulcerative colitis Vitamin deficiency (hypovitaminosis) GYNECOLOGY AND OBSTETRICS Abruptio placentae Abnormal uterine bleeding Acute fatty liver of pregnancy Acute pelvic pain in women Adnexal masses Amniotic fluid alpha-fetoprotein elevation Bartholin gland abscess Bleeding, early pregnancy Bleeding neonate Bleeding, vaginal Bone mineral density, increased Breast cancer Breastfeeding difficulties Breast, nipple discharge evaluation Breast, radiologic evaluation Breast, routine screen or palpable mass evaluation Cervical cancer Cervical dysplasia

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Cervicitis Chlamydia genital infections Condyloma acuminatum Contraception Cystitis, acute Delayed passage of meconium Dysmenorrhea Dyspareunia Dysuria and/or urethral/vaginal discharge Eclampsia Ectopic pregnancy Endometrial cancer Endometriosis Endometritis Erosions, genitalia Fallopian tube cancer Fertility preservation in women Fibrocystic breast disease Genital lesions or ulcers, algorithm Genitopelvic pain/penetration syndrome Gonococcal urethritis Gonorrhea Groin masses Heart failure, pregnancy Heavy menstrual bleeding Hereditary breast and ovarian cancer syndrome Herpes simplex Hot flashes Hyperemesis gravidarum Hypoactive sexual desire disorder Hypogonadism Immunizations during pregnancy Incontinence (urinary) Infertility Mastitis Mastodynia Meigs syndrome Menopause Molar pregnancy Nipple lesions Nongonococcal urethritis Ovarian cancer Ovarian neoplasm, benign Paget's disease of the breast Pelvic abscess Pelvic congestion syndrome Pelvic inflammatory disease Pelvic mass, algorithm Pelvic organ prolapse (uterine prolapse) Pelvic pain, causes in women Pelvic pain, reproductive-age woman Perirectal abscess Placenta previa Polycystic ovary syndrome Postpartum depression Postpartum hemorrhage Preeclampsia Premature rupture of membranes Premenstrual syndrome Preterm labor Primary ovarian insufficiency Pruritus, pregnant patient Pruritus vulvae Rh incompatibility Sexual assault Sexual dysfunction Sexual dysfunction in women Spontaneous abortion Syphilis Thrombocytopenia, in pregnancy Toxic shock syndrome Urinary tract infection Uterine fibroids Uterine malignancy Vaginal bleeding during pregnancy Vaginal discharge, algorithm Vaginal fistulas Vaginal cancer Vaginal prolapse Vaginitis, estrogen-deficient Vaginitis, fungal Vaginitis, prepubescent Vaginitis, Trichomonas Vaginosis, bacterial

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HEMATOLOGY/ONCOLOGY Acute lymphoblastic leukemia Acute myeloid leukemia Anemia, algorithm Anemia, aplastic Anemia, aplastic due to drugs and chemicals Anemia, autoimmune hemolytic Anemia, hypochromic Anemia, inflammatory Anemia in newborn Anemia, iron deficiency Anemia, macrocytic Anemia, microcytic Anemia, pernicious

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Anemia with reticulocytosis Anorexia-cachexia syndrome associated with malignancy Antiphospholipid antibody syndrome Astrocytoma Atypical lymphocytosis, heterophil negative, infectious causes Basal cell carcinoma Bladder cancer Bleeding, congenital disorder Bleeding neonate Bleeding time (modified Ivy method) Bone marrow failure syndromes, inherited Bone tumor, primary malignant Brain metastases Brain neoplasm Brain neoplasm, benign Brain neoplasm, glioblastoma Breast cancer Cancer of unknown primary site Cervical cancer Chemotherapy-induced nausea and vomiting Cholangiocarcinoma Chronic lymphocytic leukemia Chronic myeloid leukemia Chylothorax Cobalamin deficiency Colorectal cancer Conjunctival neoplasm Cryoglobulinemia Deep vein thrombosis Disseminated intravascular coagulation Endometrial cancer Erythrocytosis Erythrocytosis, acquired Esophageal tumors Eyelid neoplasm Fallopian tube cancer Fetal alcohol spectrum disorder Fever and neutropenia, pediatric patient Fever, non-infectious causes Folate deficiency Gallbladder carcinoma Gastric cancer Graft-versus-host disease (GVHD) Groin masses Head and neck squamous cell carcinoma Hemolysis, mechanical Hemolytic-uremic syndrome Hemophilia Hemoptysis Heparin-induced thrombocytopenia Hepatocellular carcinoma Hereditary breast and ovarian cancer syndrome Hodgkin lymphoma Hypercalcemia, malignancy-induced Hypercoagulable state Hypercoagulable state, associated disorders Hypersplenism Hypersplenism, associated conditions Immune thrombocytopenic purpura Intraocular neoplasm Iron overload Kaposi sarcoma Lead poisoning Liver lesions, benign Lung cancer, occupational causes Lung neoplasms, primary Lymphadenopathy, generalized, algorithm Lymphocytes Lymphocytosis, atypical Macrothrombocytopenia, inherited Medical marijuana Meigs syndrome Melanoma Meningioma Mesothelioma, malignant Microangiopathic hemolytic anemia Monoclonal gammopathy of renal significance (MGRS) Monoclonal gammopathy of undetermined significance Monocytosis Mononucleosis, monospot negative Multiple endocrine neoplasia Multiple myeloma Myelodysplastic syndrome Nasopharyngeal carcinoma Neutropenia Neutropenia with decreased marrow reserve Neutrophilia Non-Hodgkin lymphoma Nutrition assessment and intervention in cancer patient Ovarian cancer Ovarian neoplasm, benign Paget's disease of the breast Pancreatic cancer (exocrine) Pancreatic islet cell tumors

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Pancytopenia Paraneoplastic neurologic syndromes Pericardial effusion, malignant Pheochromocytoma Pigmenturia Pituitary adenoma Pituitary region tumors Pleural effusion, malignant Pleural effusions, malignancy-associated Polycythemia Polycythemia, algorithm Polycythemia, relative versus absolute Polycythemia vera Postthrombotic syndrome Prolactinoma Prostate cancer Pulmonary infiltrates, immunocompromised host Purpura, nonpalpable Purpura, non-purpuric disorders simulating purpura Purpura, palpable Renal cell adenocarcinoma Reticulocyte count Retinoblastoma Rh incompatibility Salivary gland neoplasms Sickle cell disease Spine tumor Splenomegaly, algorithm Splenomegaly and hepatomegaly Splenomegaly, children Squamous cell carcinoma Superior vena cava syndrome Testicular cancer Thalassemias Thrombocytopenia, differential diagnosis Thrombocytopenia, inherited disorders Thrombocytopenia, in pregnancy Thrombocytosis Thrombosis or thrombotic diathesis Thrombotic thrombocytopenic purpura Thyroid carcinoma Transfusion reaction, hemolytic Tumor lysis syndrome Tumor markers elevation Upper extremity deep vein thrombosis Uterine malignancy Vaginal cancer Von Willebrand disease Waldenström macroglobulinemia INFECTIOUS DISEASES Acquired immunodeficiency syndrome Acute bronchitis Amebiasis Anaerobic infections Anal abscess and fistula Ascariasis Aspergillosis Aspiration, oral contents Aspiration pneumonia Atypical lymphocytosis, heterophil negative, infectious causes Babesiosis Bacterial overgrowth, small intestine Bacterial pneumonia Balanitis Bartholin gland abscess Bedbug bite Bite wounds Botulism Brain abscess Breast abscess Candidiasis, cutaneous Candidiasis, invasive Cat-scratch disease Cavernous sinus thrombosis Cellulitis Cervicitis Childhood and adolescent immunizations Chlamydia genital infections Cholangitis Cholecystitis Clostridium difficile infection Colorado tick fever Condyloma acuminatum Conjunctivitis Cryptococcosis Cryptosporidium infection Cysticercosis Cytomegalovirus infection Diarrhea, infectious Ear pain Echinococcosis Ehrlichiosis Empyema Encephalitis, acute viral Endocarditis, infective Endocarditis prophylaxis

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Endometritis Epididymitis Epidural abscess Epiglottitis Epstein-Barr virus infection Erysipelas Esophagitis Fever and infection in high-risk patient without obvious source Fever and neutropenia, pediatric patient Fever in the returning traveler Fever of undetermined origin Fifth disease (parvovirus infection) Folliculitis Food poisoning, bacterial Foot lesion, ulcerating Genital lesions or ulcers Giardiasis Gonococcal urethritis Granulomatous dermatitides Groin masses Hand-foot-mouth disease Helicobacter pylori infection Hepatitis A Hepatitis, acute Hepatitis B Hepatitis C Hepatitis D Hepatitis E Hepatitis, viral Herpes simplex Herpes simplex keratitis Herpes zoster HIV-associated cardiomyopathy Histoplasmosis HIV cognitive dysfunction HIV: Recommended immunization schedule for HIV-infected children Hookworm Human immunodeficiency virus Impetigo Immunization schedule, childhood, accelerated if necessary for travel Immunization schedule, childhood and adolescence Immunization schedule, contraindications and precautions Immunization schedule, HIV-infected children Immunizations for adults Immunizations during pregnancy Immunizations for immunocompromised infants and children Immunizing agents and immunization schedules for health-care workers Influenza Ischemic hepatitis Kaposi sarcoma Laryngitis Laryngotracheobronchitis Legionnaires' disease Lemierre syndrome Listeriosis Liver abscess Lung abscess Lyme disease Lymphangitis Lymphocytosis, atypical Malaria Mastoiditis Mediastinitis Mediastinitis, acute Meningitis, bacterial Meningitis, viral Meningitis, recurrent Mesenteric adenitis Methicillin resistant Staphylococcus aureus (MRSA) Microsporidiosis Middle East respiratory syndrome Molluscum contagiosum Mononucleosis Mononucleosis, monospot negative Mucormycosis Multidrug-resistant gram-negative rods (MRD-GNRs) Mumps Necrotizing fasciitis Necrotizing pneumonias Nongonococcal urethritis Orchitis Osteomyelitis Otitis externa Otitis media Paronychia Pediculosis Pelvic abscess Pelvic inflammatory disease Perirectal abscess Peritonitis, secondary Pertussis

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Pharyngitis/tonsillitis Pinworms Pneumonia, mycoplasma Pneumonia, pnuemocystis jiroveci Pneumonia, viral Prostatitis Pyelonephritis Reactive arthritis Renal abscess Rocky Mountain spotted fever Roseola Salmonellosis Scabies Scarlet fever Sepsis Septic arthritis Shigellosis Sialadenitis Sinusitis Sore throat Southern tick-associated rash illness (STARI) Spinal epidural abscess Spontaneous bacterial peritonitis Stomatitis Stye (hordeolum) Syphilis Tapeworm infestation Thrombophlebitis, superficial Tinea corporis Tinea cruris Tinea unguium Tinea versicolor Toxoplasmosis Tuberculosis, miliary Tuberculosis, pulmonary Urinary tract infection Urosepsis Vaccinations for international travel Vaccinations, recommendations for persons with medical conditions Vaginitis, fungal Vaginitis, Trichomonas Vancomycin resistant Enterococcus (VRE) Varicella Viral bronchiolitis Zika virus MISCELLANEOUS Abdominal wall masses Anaphylaxis Anorexia Cyanosis Deep vein thrombosis Dehydration correction, pediatric patient Delayed passage of meconium Drowning Familial Mediterranean Fever Fever, non-infectious causes Food allergies Graft-versus-host disease (GVHD) Groin lump Hallucinogenic overdose Iliac fossa pain, left sided Iliac fossa pain, right sided Lactic acidosis Malignant hyperthermia Mediastinitis Mediastinal compartments, anatomy and pathology Medical marijuana Methanol and ethylene glycol poisoning Opioid overdose Opioid use disorder Paralytic shellfish poisoning Paraneoplastic syndromes Pleurisy Postthrombotic syndrome Sarcoma Shift work disorder Sore throat Statin-induced muscle syndromes Substance use disorder Synthetic cannabinoids Tracheobronchial narrowing on x-ray Upper extremity deep vein thrombosis Vitamin D deficiency Vitamin deficiency (hypovitaminosis) NEPHROLOGY Acid-base homeostasis Acidosis, metabolic, algorithm Acute glomerulonephritis Acute kidney injury Acute tubular necrosis Acute urinary retention (AUR) Alkalosis, metabolic, algorithm Autosomal dominant polycystic kidney disease AV malformations, cerebral Calcium-alkali syndrome

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Calcium stones Cardiorenal syndrome Chronic kidney disease Contrast-associated acute kidney injury Dehydration correction, pediatric patient Edema, generalized, algorithm End-stage kidney disease Glomerulonephritis, rapidly progressive Glomerulopathies, thrombotic, microangiopathic Glomerulosclerosis, focal segmental Goodpasture syndrome Hematuria, in children Hemolytic-uremic syndrome Hepatorenal syndrome Hydronephrosis Hypercalcemia, algorithm Hyperkalemia Hypermagnesemia, algorithm Hypernatremia, algorithm Hyperuricemia Hypocalcemia, laboratory differential diagnosis Hypokalemia, algorithm Hypokalemia, differential diagnosis Hypokalemic periodic paralysis Hypomagnesemia Hypomagnesemia, algorithm Hypomagnesemia, differential diagnosis Hyponatremia Hypoparathyroidism Hypophosphatemia, algorithm IgA nephropathy Interstitial nephritis Kidney enlargement, unilateral Microscopic polyangiits Monoclonal gammopathy of renal significance (MGRS) Nephrocalcinosis Nephrotic syndrome Oliguria, algorithm Pigmenturia Pyelonephritis Relapsing polychondritis Renal abscess Renal artery stenosis Renal cell adenocarcinoma Renal cystic disorders Renal disease, ischemic management Renal failure, acute, pigment-induced Renal mass Renal parenchymal disease, chronic Renal tubular acidosis Renal vein thrombosis Rhabdomyolysis Scombroid poisoning Statin-induced muscle syndromes Tension-type headache Tumor lysis syndrome Uric acid stones Urinary retention Urine color abnormalities Urolithiasis NEUROLOGY Absence seizures Acoustic neuroma Alzheimer's disease Amaurosis fugax Amblyopia Amyotrophic lateral sclerosis Anisocoria Anoxic brain injury Antibody-mediated autoimmune encephalitis Astrocytoma Ataxia, acute or recurrent Ataxia, cerebellar, adult onset Ataxia, cerebellar, children Ataxia, chronic or progressive Ataxia, progressive Autistic spectrum disorders AV malformations, cerebral Ballism Bell palsy Benign paroxysmal positional vertigo Blindness, monocular, transient Brain neoplasm Brain neoplasm, benign Brain neoplasm, glioblastoma Carotid artery stenosis Carpal tunnel syndrome Cerebral infarction secondary to inherited disorders Cerebrospinal fluid (CSF) Charcot-Marie-Tooth disease Chronic inflammatory demyelinating polyneuropathy Chronic traumatic encephalopathy (CTE) Cluster headache Complex regional pain syndrome Concussion

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Convulsive disorder, pediatric age Daytime sleepiness Delirium Delirium, agitated Delirium, dialysis patient Dementia, algorithm Dementia with Lewy bodies Diabetic polyneuropathy Dilated pupil Diplopia, monocular Diplopia, vertical Dissociative disorders Dizziness Dystonia Elbow pain Encephalomyelitis, nonviral causes Encephalopathy Epidural abscess Epidural hematoma Esotropia Essential tremor Febrile seizures Focal seizures Footdrop Frontotemporal dementia Generalized tonic-clonic seizures Guillain-Barré syndrome Hallucinogenic overdose Headache, acute Headache, chronic Hearing loss, algorithm Hereditary neuropathy HIV cognitive dysfunction Horner syndrome Huntington chorea Hydrocephalus, normal pressure Inclusion body myositis Inflammatory myopathies Intracerebral hemorrhage, nonhypertensive causes Labyrinthitis Leg movement when standing, involuntary Leptomeningeal lesions Memory loss symptoms, elderly patients Meniere disease Meningioma Mental status changes and coma Migraine headache Mild cognitive impairment Mononeuropathies, isolated Motion sickness Multiple sclerosis Muscle disease Muscle weakness, algorithm Muscular dystrophy Myasthenia gravis Myelin disorders Myoclonus Myotonia Narcolepsy Neurocognitive disorders Neuromuscular junction dysfunction Neuronopathies, sensory (ganglionopathies) Neuropathic bladder Neuropathic pain Neuropathies, peripheral, asymmetrical proximal/distal Neuropathies with facial nerve involvement New onset seizures Nystagmus, monocular Opsoclonus Optic atrophy Optic neuritis Osteosclerosis, diffuse Paraneoplastic neurologic syndromes Paraparesis, acute or subacute Paraparesis, chronic progressive Parkinsonism-plus syndromes Parkinson disease Periodic limb movement disorder Polyneuropathies, demyelinating Polyneuropathies, distal, sensorimotor Postconcussive syndrome Postherpetic neuralgia Primary angiitis of the central nervous system Ramsay Hunt syndrome Restless legs syndrome Sciatica Seizures, mimics Shaken baby syndrome Smell disturbance Spasticity Spinal cord compression Spinal cord compression, epidural Spinal cord dysfunction, non-traumatic Spinal cord ischemic syndromes Spinal stenosis Status epilepticus Stroke, acute ischemic

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2021 Ferri’s

CLINICAL ADVISOR

FRED F. FERRI, MD, FACP Clinical Professor Department of Medicine Warren Alpert Medical School Brown University Providence, Rhode Island

Elsevier 1600 John F. Kennedy Blvd. Ste 1800 Philadelphia, PA 19103-2899 FERRI'S CLINICAL ADVISOR 2021 Copyright © 2021 by Elsevier, Inc. All rights reserved.

ISBN: 978-0-323-71333-7

No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher's permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions. This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein).

Notice Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds or experiments described herein. Because of rapid advances in the medical sciences, in particular, independent verification of diagnoses and drug dosages should be made. To the fullest extent of the law, no responsibility is assumed by Elsevier, authors, editors or contributors for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. ISBN: 978-0-323-71333-7

Publisher: Sarah Barth Senior Content Development Specialist: Mary Hegeler Publishing Services Manager: Catherine Jackson Senior Project Manager: Kate Mannix Design Direction: Bridget Hoette Printed in the United States Last digit is the print number: 9 8 7 6 5 4 3 2 1

Section Editors Manuel F. DaSilva, MD Director, Medical Student Education Department of Orthopedic Surgery Warren Alpert Medical School of Brown University Providence, Rhode Island

Gregory L. Fricchione, MD Associate Chief of Psychiatry Director, Benson Henry Institute for Mind Body Medicine Director, Pierce Division of Global Psychiatry Massachusetts General Hospital Mind Body Medical Institute Professor of Psychiatry Harvard Medical School Boston, Massachusetts

Fred F. Ferri, MD, FACP Clinical Professor Department of Medicine Warren Alpert Medical School of Brown University Providence, Rhode Island

Corey Elam Goldsmith, MD Assistant Professor of Neurology Neurology Residency Program Director Baylor College of Medicine Chief of Neurology Outpatient Clinics Ben Taub Hospital—Harris Health System Houston, Texas

Glenn G. Fort, MD, MPH, FACP, FIDSA Clinical Associate Professor of Medicine Warren Alpert Medical School of Brown University; Chief, Infectious Diseases Our Lady of Fatima Hospital and Landmark Medical Center Providence, Rhode Island

Joseph S. Kass, MD, JD, FAAN Associate Dean of Student Affairs Professor of Neurology, Psychiatry, and Medical Ethics Director, Alzheimer’s Disease and Memory Disorders Center Baylor College of Medicine Ben Taub General Hospital Houston, Texas

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iv

Section Editors Bharti Rathore, MD Program Director, Hematology/ Oncology Fellowship Roger Williams Medical Center Providence, Rhode Island; Assistant Professor of Medicine Boston University School of Medicine Boston, Massachusetts

Iris L. Tong, MD Associate Professor Department of Medicine Warren Alpert Medical School of Brown University; Attending Physician Women’s Primary Care Women’s Medicine Collaborative Providence, Rhode Island

Daphne ScaramangasPlumley, MD Rheumatologist Attune Health Cedars-Sinai Medical Center Beverly Hills, California

John Wylie, MD, FACC Director, Cardiac Electrophysiology Steward Health Care System; Associate Professor of Medicine Tufts University School of Medicine Boston, Massachusetts

Anthony Sciscione, DO Professor of Obstetrics and Gynecology Jefferson Medical College Philadelphia, Pennsylvania; Residency Program Director Director of Maternal-Fetal Medicine Department of Obstetrics and Gynecology Christiana Care Health System Newark, Delaware

Jerry Yee, MD Clinical Professor of Medicine Department of Internal Medicine Wayne State University School of Medicine; Division Head, Nephrology and Hypertension Henry Ford Hospital Detroit, Michigan

Contributors Alexandra Abrams-Downey, MD Professor of Medicine Icahn School of Medicine at Mount Sinai New York, New York

Maria Andrievskaya, MD Nephrology Fellow Henry Ford Hospital Detroit, Michigan

W. Peyton Adkins, MD Resident Physician Emergency Medicine University of Tennessee Health Science Center Memphis, Tennessee

Kathryn Taylor Anilowski, MS, PT, CLT-LANA Physical Therapist Saratoga Springs, New York

Maxwell Eyram Afari, MD Advanced Heart Failure and Transplant Cardiologist Department of Cardiovascular Medicine Maine Medical Center Portland, Maine Sandeep Agarwal, MD Associate Professor of Medicine Division of Nephrology and Hypertension Drexel University College of Medicine Philadelphia, Pennsylvania Mhd Hussam Al Jandali, MD Nephrology Fellow Department of Internal Medicine, Nephrology Henry Ford Health System Detroit, Michigan Maad M. Alhudairy, MD, MAS Resident Physician Internal Medicine St. Elizabeth’s Medical Center Tufts University School of Medicine Boston, Massachusetts Tanya Ali, MD Clinical Assistant Professor of Medicine Warren Alpert Medical School of Brown University Providence, Rhode Island Stephanie Michelle Allen, MS Baylor College of Medicine Houston, Texas Ihab Alomari, MD Interventional Cardiologist Assistant Professor of Medicine University of California, Irvine Orange, California Rasha B. Alqadi, MD Rheumatologist Providence Sacred Heart Medical Center and Children’s Hospital Spokane, Washington Jordan Anderson, MD Rhode Island Hospital Departments of Neurology and Psychiatry Providence, Rhode Island

Anngene Anthony, MD, MPH, FAAFP Teaching Faculty Family Medicine Hackensack Meridian Health Mountainside Medical Center Montclair, New Jersey Joe Aoun, MD Cardiovascular Medicine Fellow Houston Methodist DeBakey Heart and Vascular Center Houston, Texas Erick A. Argueta, MD Department of Internal Medicine Warren Alpert Medical School of Brown University Providence, Rhode Island Pinar Arikan, MD Resident Physician Internal Medicine Warren Alpert Medical School of Brown University Providence, Rhode Island Zuhal Arzomand, MD Rheumatology Fellow Warren Alpert Medical School of Brown University Providence, Rhode Island Daniel K. Asiedu, MD, PhD, FACP Staff Physician Internal Medicine Coastal Medical, Inc. Lincoln, Rhode Island Sudeep K. Aulakh, MD Director, Ambulatory Education, Baystate Internal Medicine Residency Assistant Professor University of Massachusetts Medical School—Baystate Baystate Health Springfield, Massachusetts Rupali Avasare, MD Physician Nephrology and Hypertension Department Oregon Health and Science University Portland, Oregon Sarah Aziz, DO Candidate Rowan University School of Osteopathic Medicine Stratford, New Jersey

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Contributors Tania B. Babar, MD Electrophysiologist Division of Electrophysiology Charleston Area Medical Center Charleston, West Virginia

Vicky H. Bhagat, MD, MPH Gastroenterology Fellow Robert Wood Johnson University Hospital New Brunswick, New Jersey

Emelia Argyropoulos Bachman, MD Assistant Professor of Clinical Obstetrics and Gynecology Division of Reproductive Endocrinology and Infertility Hospital of the University of Pennsylvania Philadelphia, Pennsylvania

Harikrashna B. Bhatt, MD Assistant Professor of Medicine Warren Alpert Medical School of Brown University Chief of Endocrinology Providence VA Medical Center Providence, Rhode Island

T. Caroline Bank, MD Resident Physician Obstetrics and Gynecology Christiana Care Health System Newark, Delaware

Danish Bhatti, MD Assistant Professor Department of Neurological Sciences University of Nebraska Medical Center Omaha, Nebraska

Trace Barrett, MD Cardiovascular Disease Fellow University of Vermont Medical Center Burlington, Vermont

Jiaying Bi, MA Center for Health Profession Studies University of Delaware City Newark, Delaware

Ailin Barseghian, MD Assistant Clinical Professor Department of Internal Medicine Division of Cardiology University of California, Irvine Orange, California

Courtney Clark Bilodeau, MD, FACP Assistant Clinical Professor of Obstetric Medicine Warren Alpert Medical School of Brown University Attending Physician, Women’s Medicine Collaborative Providence, Rhode Island

Craig L. Basman, MD Structural Heart Disease Fellow Department of Cardiothoracic Surgery Lenox Hill Hospital Northwell Health New York, New York Lee Baumgarten, MD Resident Physician Vattikuti Urology Institute Henry Ford Health System Detroit, Michigan Jennifer Bell, MD St. Elizabeth’s Medical Center Tufts University School of Medicine Boston, Massachusetts Deanna Benner, MSN, APRN Nurse Practitioner Christiana Care Health System Obstetrics and Gynecology Newark, Delaware Michael Bergen, MD Resident Physician Department of Orthopedic Surgery Brown University/Rhode Island Hospital Providence, Rhode Island Arnaldo A. Berges, MD Director, Division of Inpatient Psychiatry Rhode Island Hospital Assistant Clinical Professor Warren Alpert Medical School of Brown University Providence, Rhode Island

Stefani Bissonette, MD Resident Physician Obstetrics and Gynecology Christiana Care Health System Newark, Delaware Ghamar Bitar, MD Resident Physician Obstetrics and Gynecology Christiana Care Health System Newark, Delaware Craig Blakeney, MD Emergency Medicine Physician Department of Emergency Medicine University of Tennessee Health Science Center Memphis, Tennessee Brad Blankenhorn, MD Assistant Professor Department of Orthopedic Surgery Brown University/Rhode Island Hospital Providence, Rhode Island Christopher P. Blomberg, DO Cardiovascular Medicine Southern Maine Health Care Maine Health Biddeford, Maine Steven L. Bokshan, MD Orthopedics Warren Alpert Medical School of Brown University Providence, Rhode Island Alex F. Borchert, MD Vattikuti Urology Institute Henry Ford Hospital Health System Detroit, Michigan

Contributors Christina M. Bortz, MD Attending Physician Assistant Professor of Medicine Clinical Educator Department of Internal Medicine Warren Alpert Medical School of Brown University Providence, Rhode Island Alexandra Boske, MD Director of Inpatient Neurology Stroke Program Director Saint David’s Round Rock Medical Center Round Rock, Texas Tara C. Bouton, MD, MPH, TM Research Fellow Division of Infectious Diseases Miriam Hospital Warren Alpert Medical School of Brown University Providence, Rhode Island

Alexandra Buffie, MD Baylor College of Medicine Houston, Texas Christine Burke, MD Resident Physician Obstetrics and Gynecology Christiana Care Health System Newark, Delaware Ryan J. W. Burris, MD Cardiology Fellow Department of Medicine/Cardiology University of California, Irvine Orange, California D. Brandon Burtis, DO Assistant Professor of Neurology University of Florida Gainesville, Florida

Lynn A. Bowlby, MD Medical Director, Duke Outpatient Clinic Department of General Internal Medicine Duke University Medical Center Durham, North Carolina

Kate Cahill, MD Assistant Professor of Medicine, Clinician Educator Division of Internal Medicine Warren Alpert Medical School of Brown University Providence, Rhode Island

Amanda Box, MD, MS Resident Physician Emergency Medicine University of Tennessee Memphis, Tennessee

Rebecca Cangemi, MD Resident Physician Department of Internal Medicine Rhode Island Hospital/Lifespan, Brown University Providence, Rhode Island

Mark F. Brady, MD, MPH, MMSc Assistant Professor Department of Emergency Medicine University of Tennessee Health Science Center Memphis, Tennessee

Caleb Cantrell, BS MD Candidate (2021) University of Tennessee Health Science Center Memphis, Tennessee

Russell E. Bratman, MD Fellow Department of Endocrinology Warren Alpert Medical School of Brown University Providence, Rhode Island Keith Brennan, MD Geriatric Medicine Stony Brook University Stony Brook, New York Gavin Brown, MD General Neurologist Laureate Medical Group, Northside Hospital Atlanta, Georgia Neal Bucher, MD University of Toledo College of Medicine and Life Sciences Toledo, Ohio Jennifer Buckley, MD Clinical Instructor of Family Medicine Warren Alpert Medical School of Brown University Providence, Rhode Island Family Medicine Memorial Hospital of Rhode Island Pawtucket, Rhode Island Kent Memorial Hospital Warwick, Rhode Island

Andrew Caraganis, MD Internal Medicine Boston University School of Medicine Roger Williams Medical Center Providence, Rhode Island Ashlie Sewdass Carter, MD Resident Physician Obstetrics and Gynecology Christiana Care Health System Newark, Delaware Valerie Carter, MD Assistant Professor Internal Medicine Hospital Medicine/Division of General Internal Medicine Froedtert & the Medical College of Wisconsin Milwaukee, Wisconsin Ana Castaneda-Guarderas, MD Assistant Professor Emergency Medicine Department University of Tennessee Regional One Physicians Memphis, Tennessee

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Contributors Jorge J. Castillo, MD Associate Professor Division of Hematologic Malignancies Dana-Farber Cancer Institute Harvard Medical School Boston, Massachusetts Andreea M. Catana, MD Department of Gastroenterology and Hepatology Beth Israel Deaconess Medical Center Boston, Massachusetts Carolina S. Cerezo, MD, FAAP Medical Director Division of Pediatric Gastroenterology, Nutrition and Liver Diseases Hasbro Children’s/Rhode Island Hospital Associate Professor Department of Pediatrics Warren Alpert Medical School of Brown University Providence, Rhode Island Joshua Chalkely, DO, MS Department of Neurology University of Kentucky Medical Center Lexington, Kentucky Paul D. Chamberlain, MD Department of Neurology Baylor College of Medicine Houston, Texas Philip A. Chan, MD, MS Associate Professor Department of Medicine Warren Alpert Medical School of Brown University Providence, Rhode Island Anjulika Chawla, MD Associate Medical Director, Bluebird Bio Attending Physician Division of Pediatric Hematology Hasbro Children’s Hospital Associate Professor Warren Alpert Medical School of Brown University Providence, Rhode Island Dhruti P. Chen, MD Fellow Division of Nephrology and Hypertension University of North Carolina UNC Kidney Center Chapel Hill, North Carolina Vicky Cheng, MD Assistant Professor Warren Alpert Medical School of Brown University Department of Endocrinology Providence, Rhode Island Roxana Chis, MD Division of Gastroenterology University of Toronto Toronto, Ontario, Canada

Sarah L. Chisholm, MD Resident Physician Department of Obstetrics and Gynecology University of Colorado Hospital Denver, Colorado Chandrika Chitturi, MD Attending Staff Division of Nephrology and Hypertension Henry Ford Hospital Detroit, Michigan George Cholankeril, MD Transplant Hepatology University of Tennessee Health Science Center Memphis, Tennessee Rosann Cholankeril, MD Boston University School of Medicine Roger Williams Medical Center Providence, Rhode Island Seth Clark, MD, MPH Addiction Medicine Fellow Warren Alpert Medical School of Brown University Rhode Island Hospital Providence, Rhode Island Brian Clyne, MD Interim Chair, Assistant Professor Department of Emergency Medicine Warren Alpert Medical School of Brown University Providence, Rhode Island Debbie L. Cohen, MD Professor of Medicine Renal Electrolyte and Hypertension Division University of Pennsylvania Philadelphia, Pennsylvania Lisa Cohen, PharmD Associate Professor of Pharmacy University of Rhode Island Kingston, Rhode Island Zachary Cohn, MD Fellow Department of Hematology and Oncology University of Massachusetts Worcester, Massachusetts Soontharee Congrete, MD Fellow Pulmonary and Critical Care Medicine University of Connecticut Farmington, Connecticut River Cook, MD University of Kansas Medical Center Wichita, Kansas Eddie L. Copelin II, MD, MHA Internal Medicine Boston University School of Medicine Roger Williams Medical Center Providence, Rhode Island

Contributors James Earl Corley III, MD Resident Physician Emergency Medicine University of Tennessee Health Science Center Memphis, Tennessee Rebecca Craine, MSEd, CCC-SLP Speech Language Pathologist Bradley Children’s Hospital East Providence, Rhode Island Meagan S. Cramer, MD Fellow Oregon Health and Science University Obstetrics and Gynecology Portland, Oregon Patricia Cristofaro, MD Assistant Professor Department of Infectious Diseases Warren Alpert Medical School of Brown University Providence, Rhode Island Tess Crouss, MD Fellow Female Pelvic Medicine and Reconstructive Surgery Cooper University Health Care Camden, New Jersey Joanne Szczygiel Cunha, MD Assistant Professor of Medicine Division of Rheumatology Warren Alpert Medical School of Brown University Providence, Rhode Island Karlene Cunningham, PhD Clinical Assistant Professor Department of Psychiatry and Behavioral Medicine Brody School of Medicine at East Carolina University Greenville, North Carolina Alicia J. Curtin, PhD Assistant Professor Division of Geriatrics Warren Alpert Medical School of Brown University Providence, Rhode Island Ganary Dabiri, MD, PhD Staff Dermatologist Roger Williams Medical Center Providence, Rhode Island Lynn Dado, MD Primary Care Physician Internal Medicine Henry Ford Medical Center Detroit, Michigan Deepan S. Dalal, MD, MPH Assistant Professor Medicine, Rheumatology Warren Alpert Medical School of Brown University and School of Public Health Department of Health Services, Policy, and Practice Rhode Island Hospital Providence, Rhode Island

Kristin Dalphon, PA Physician Assistant New York University School of Medicine New York, New York Kristy L. Dalrymple, PhD Director of Adult Psychology Rhode Island and The Miriam Hospitals Associate Professor, Clinician Educator Warren Alpert Medical School of Brown University Providence, Rhode Island Gerard H. Daly, MD, MSc Vascular/Structural Fellow Cardiovascular Medicine St. Elizabeth’s Medical Center Boston, Massachusetts Shivang U. Danak, MD St. George’s University Detroit, Michigan Rituparna Das, MD Assistant Professor Neurology Baylor College of Medicine Houston, Texas Manuel F. DaSilva, MD Director, Medical Student Education Department of Orthopedic Surgery Warren Alpert Medical School of Brown University Providence, Rhode Island Catherine D’Avanzato, PhD Psychologist Rhode Island Hospital Clinical Assistant Professor Warren Alpert Medical School of Brown University Providence, Rhode Island Steven F. DeFroda, MD, MEng Department of Orthopaedic Surgery Warren Alpert Medical School of Brown University Providence, Rhode Island Alexandra Degenhardt, MD, MMSc Director Multiple Sclerosis Center Pen Bay Medical Center Rockport, Maine Ashwini U. Dhokte, MD Resident Physician Christiana Care Hospital Newark, Delaware Joseph A. Diaz, MD, MPH Associate Dean for Diversity and Multicultural Affairs Associate Professor of Medicine Associate Professor of Medical Science Warren Alpert Medical School of Brown University Providence, Rhode Island

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Contributors Allison Dillon, MD Resident Physician Obstetrics and Gynecology Christiana Care Health System Newark, Delaware

Pamela Ellsworth, MD Chief, Division of Pediatric Urology Professor of Urology Nemours Children’s Hospital Orlando, Florida

Thomas H. Dohlman, MD Cornea Service, Massachusetts Eye and Ear Infirmary Harvard Medical School Boston, Massachusetts

Alan Epstein, MD Roger Williams Medical Center Providence, Rhode Island

Stephen Dolter, MD Pediatric Hospitalist Children’s Hospital and Medical Center Pediatric Hospital Medicine Omaha, Nebraska David J. Domenichini, MD Clinical Instructor Endocrinology and Metabolism Hartford Hospital University of Connecticut Health Center West Hartford, Connecticut Kathleen Doo, MD Sleep Medicine Fellow New York University New York, New York James H. Dove, MD Resident Department of Orthopedic Surgery Warren Alpert Medical School of Brown University Providence, Rhode Island Andrew P. Duker, MD Associate Professor Movement Disorders Division Director, Department of Neurology and Rehabilitation Medicine University of Cincinnati College of Medicine Cincinnati, Ohio Shashank Dwivedi, MD Resident Physician Department of Orthopaedic Surgery Warren Alpert Medical School of Brown University Rhode Island Hospital Providence, Rhode Island Evlyn Eickhoff, MD Resident Physician Department of Medicine, Division of Nephrology University of New Mexico Health Science Center Albuquerque, New Mexico Christine Eisenhower, PharmD Clinical Assistant Professor Pharmacy Practice University of Rhode Island College of Pharmacy Kingston, Rhode Island Amani A. Elghafri, MD, MSc, Med Ed Resident Physician Department of Internal Medicine University of California San Francisco Fresno, California

Patricio Sebastian Espinosa, MD, MPH Associate Professor Department of Neurology Department of Clinical Biomedical Science Charles E. Schmidt College of Medicine, Florida Atlantic University Boca Raton, Florida Danyelle Evans, MD Baylor College of Medicine Houston, Texas Mark D. Faber, MD Senior Staff Nephrologist Associate Professor Wayne State University School of Medicine Henry Ford Hospital Detroit, Michigan Matthew J. Fagan, MD, FACOC Attending Physician Director of Undergraduate Medical Education Obstetrics and Gynecology Christiana Care Health System Newark, Delaware Ronan Farrell, MD Gastroenterology Fellow Department of Gastroenterology and Hepatology Warren Alpert Medical School of Brown University Providence, Rhode Island Timothy W. Farrell, MD, AGSF Associate Professor of Medicine Adjunct Associate Professor of Family Medicine Director, University of Utah Health Interprofessional Education Program Physician Investigator, VA Salt Lake City Geriatric Research, Education, and Clinical Center University of Utah School of Medicine Salt Lake City, Utah Kevin Fay, MD Fellow Renal Electrolyte and Hypertension Department University of Pennsylvania Philadelphia, Pennsylvania Mariam Fayek, MD Clinical Assistant Professor Department of Medicine Attending Physician Warren Alpert Medical School of Brown University Center for Women’s Gastrointestinal Health Women and Infants Hospital Providence, Rhode Island

Contributors Jason D. Ferreira, MD Gastroenterologist University Gastroenterology, LLC Providence, Rhode Island Fred F. Ferri, MD Clinical Professor Department of Medicine Warren Alpert Medical School of Brown University Providence, Rhode Island Heather Ferri, DO Department of Medicine Warren Alpert Medical School of Brown University Rhode Island Hospital Providence, Rhode Island Barry Fine, MD, PhD Assistant Professor of Medicine Division of Cardiology Columbia University Vagelos College of Physicians and Surgeons New York, New York Staci A. Fischer, MD Field Director of Education and Training Clinical Learning Environment Review Program Accreditation Council for Graduate Medical Education Chicago, Illinois Tamara G. Fong, MD, PhD Assistant Professor of Neurology Harvard Medical School Staff Neurologist Beth Israel Deaconess Medical Center Assistant Scientist Aging Brain Center, Institute for Aging Research, Hebrew SeniorLife Boston, Massachusetts Yaneve Fonge, MD Resident Physician Obstetrics and Gynecology Christiana Care Health Systems Newark, Delaware Michelle Forcier, MD, MPH Professor of Pediatrics Warren Alpert Medical School of Brown University Providence, Rhode Island Frank G. Fort, MD, FACS, RPHS Medical Director Capital Region Vein Centre Schenectady, New York Glenn G. Fort, MD, MPH Clinical Associate Professor of Medicine Division of Infectious Disease Warren Alpert Medical School of Brown University Providence, Rhode Island Justin F. Fraser, MD Assistant Professor of Cerebrovascular Endovascular, and Skull Base Surgery Department of Neurosurgery University of Kentucky Lexington, Kentucky

Gregory L. Fricchione, MD Associate Chief of Psychiatry Director, Benson Henry Institute for Mind Body Medicine Director, Pierce Division of Global Psychiatry Massachusetts General Hospital Mind Body Medical Institute Professor of Psychiatry Harvard Medical School Boston, Massachusetts Michael Friedman, MD Clinical Associate Professor Department of Psychiatry and Human Behavior and Department of Neurology Warren Alpert Medical School of Brown University Providence, Rhode Island Daniel R. Frisch, MD Electrophysiology Section, Division of Cardiology Thomas Jefferson University Hospital Philadelphia, Pennsylvania Anthony Gallo, MD Director of ECT Service Rhode Island Hospital Clinical Assistant Professor Warren Alpert Medical School of Brown University Providence, Rhode Island Mostafa Ghanim, MD Fellow Cardiology MercyOne North Iowa Medical Center Mason City, Iowa Irene M. Ghobrial, MD Professor of Medicine Harvard Medical School Dana Farber Cancer Institute Boston, Massachusetts Katarzyna Gilek-Seibert, MD, RhMUS Director, Rheumatology Division and Fellowship Training Program Boston University Affiliated Roger Williams Medical Center Providence, Rhode Island Richard Gillerman, MD, PhD Chief Medical Information Officer Clinical Assistant Professor of Surgery Department of Anesthesia Warren Alpert Medical School of Brown University Providence, Rhode Island Andrew Gillis-Smith, MD Fellow Hematology/Oncology UMass Memorial Medical Center Worcester, Massachusetts Dimitri Gitelmaker, MD Resident Physician Internal Medicine Roger Williams Medical Center Boston University School of Medicine Providence, Rhode Island Alla Goldburt, MD Assistant Clinical Professor Family Medicine Warren Alpert Medical School of Brown University Providence, Rhode Island

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Contributors Danielle Goldfarb, MD Neurologist/Psychiatrist Banner Alzheimer’s Institute Phoenix, Arizona Jesse Goldman, MD, FASH Professor of Medicine Drexel University College of Medicine Philadelphia, Pennsylvania Corey Goldsmith, MD Assistant Professor of Neurology Neurology Residency Program Director Baylor College of Medicine Chief of Neurology Outpatient Clinics Ben Taub Hospital, Harris Health System Houston, Texas Maheswara Satya Gangadhara Rao Golla, MD Department of Cardiovascular Medicine Steward Family Hospital, St. Elizabeth’s Medical Center Brighton, Massachusetts Caroline Golski, MD Resident Physician General Psychiatry Warren Alpert Medical School of Brown University Providence, Rhode Island Helen B. Gomez, MD Resident Physician Obstetrics and Gynecology Christiana Care Health System Newark, Delaware Avi D. Goodman, MD Orthopedic Trauma Fellow Department of Orthopedics Warren Alpert Medical School of Brown University Providence, Rhode Island Paul Gordon, MD Clinical Assistant Professor of Medicine Division of Cardiology Warren Alpert Medical School of Brown University Providence, Rhode Island John A. Gray, MD, PhD Assistant Professor Department of Neurology Center for Neuroscience University of California, Davis Davis, California Simon Gringut, MD Cardiac Electrophysiology Fellow Yale New Haven Hospital New Haven, Connecticut Lauren Grocott, BA Clinical Research Assistant Rhode Island Hospital Providence, Rhode Island Stephen L. Grupke, MD, MS Assistant Professor Department of Neurosurgery University of Kentucky Lexington, Kentucky

Juan Guerra, DO Attending Physician Clinical Adjunct Faculty Department of Emergency Medicine University of Tennessee Health Science Center Memphis, Tennessee Patan Gultawatvichai, MD Assistant Professor Hematology–Oncology University of Massachusetts Medical School Worcester, Massachusetts David Guo, MD Associate Urologist Kaiser Permanente Hospital Santa Clara, California Priya Sarin Gupta, MD, MPH Adolescent Medicine Fellow Division of General Pediatrics and Adolescent Medicine Johns Hopkins Hospital Baltimore, Maryland Nawaz K. A. Hack, MD Assistant Professor of Neurology F. Edward Hébert School of Medicine Uniformed Services University of the Health Sciences Bethesda, Maryland Moti Haim, MD Director, Cardiac Electrophysiology and Pacing Soroka Medical Center Ben Gurion University of the Negev Be’er-Sheva, Israel Sajeev Handa, MD, SFHM Chief, Hospital Medicine Lifespan Physician Group Rhode Island, Miriam, and Newport Hospitals Clinical Assistant Professor of Medicine and Neurology Warren Alpert Medical School of Brown University Providence, Rhode Island M. Owais Hanif, MD Senior Nephrology Fellow Hahnemann Hospital Philadelphia, Pennsylvania Nikolas Harbord, MD Division Chief, Nephrology and Hypertension Mount Sinai Beth Israel Assistant Professor Icahn School of Medicine at Mount Sinai New York, New York Sonali Harchandani, MD Fellow Hematology/Oncology University of Massachusetts Medical School Worcester, Massachusetts Erica Hardy, MD, MMS Director of Women’s Infectious Disease Division of Infectious Disease and Obstetric Medicine Women and Infants Hospital Providence, Rhode Island

Contributors Colin J. Harrington, MD Director of Consultation-Liaison Psychiatry and Neuropsychiatry Education Director of Psychosomatic Medicine Fellowship Co-Director of CNS-Psychiatry Clerkship Rhode Island Hospital Warren Alpert Medical School of Brown University Providence, Rhode Island

R. Scott Hoffman, MD Ophthalmology Doctors Eye Institute Assistant Clinical Professor Department of Ophthalmology University of Louisville Louisville, Kentucky

Taylor Harrison, MD Assistant Professor of Neurology Emory University Atlanta, Georgia

Dawn Hogan, MD Clinical Assistant Professor of Family Medicine Warren Alpert Medical School of Brown University Providence, Rhode Island

Brian Hawkins, MD Otolaryngologist Louisville, Kentucky

N. Wilson Holland, MD Associate Professor of Medicine Division of Geriatrics and Gerontology Emory University School of Medicine Acting Designated Learning Officer Atlanta Veterans Administration Medical Center Atlanta, Georgia

Don Hayes, Jr., MD, MS, MEd Professor Departments of Pediatrics, Internal Medicine, Surgery, Epidemiology The Ohio State University Columbus, Ohio Shruti Hegde, MD Fellow Cardiovascular Medicine St. Elizabeth’s Medical Center Brighton, Massachusetts Rachel Wright Heinle, MD, FACOG Attending Physician Obstetrics and Gynecology Christiana Care Health System Newark, Delaware Dwayne R. Heitmiller, MD, FAPM Attending Physician Consultation-Liaison Division Abbott Northwestern Hospital Minneapolis, Minnesota Jyothsna I. Herek, MD Senior Staff Physician Department of Nephrology and Hypertension Henry Ford Hospital Detroit, Michigan Margaret R. Hines, MD Clinical Fellow Female Pelvic Medicine and Reconstructive Surgery Baylor Scott and White Health Temple, Texas Ashley Hodges, MD Resident Physician Obstetrics and Gynecology Christiana Care Health System Newark, Delaware Pamela E. Hoffman, MD Assistant Director, Hasbro Psychiatric Emergency Services Assistant Professor, Clinician Educator Department of Psychiatry and Human Behavior Warren Alpert Medical School of Brown University Providence, Rhode Island

Siri M. Holton, MD Resident Physician Obstetrics and Gynecology Christiana Care Health System Newark, Delaware Anne L. Hume, PharmD Professor of Pharmacy Department of Pharmacy Practice University of Rhode Island Kingston, Rhode Island Zilla Hussain, MD Gastroenterologist Lifespan Physicians Group Department of Hepatology and Gastroenterology Providence, Rhode Island Donny V. Huynh, MD Staff Physician McLeod Oncology and Hematology at Seacoast McLeod Regional Medical Center Little River, South Carolina Terri Q. Huynh, MD, MSCR Associate Fellowship Program Director Minimally Invasive Gynecologic Surgery Christiana Care Health System Newark, Delaware Sarah Hyder, MD Assistant Professor of Medicine Associate Program Director, GI Fellowship Department of Gastroenterology Warren Alpert Medical School of Brown University Lifespan Physician Group Providence, Rhode Island Dina A. Ibrahim, MD Kent Hospital Warren Alpert Medical School of Brown University Providence, Rhode Island Caitlin Ingraham, MD Resident Physician Obstetrics and Gynecology Christiana Care Health System Newark, Delaware

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Contributors Nicholas J. Inman, MD University of Tennessee Health Science Center Memphis, Tennessee Louis Insalaco, MD Surgeon Massachusetts Eye and Ear Infirmary Department of Otolaryngology, Head and Neck Surgery Boston, Massachusetts Ashley A. Jacobson, MD Resident Physician Department of Emergency Medicine Mayo Clinic Rochester, Minnesota Koyal Jain, MD Assistant Professor of Medicine Division of Nephrology and Hypertension University of North Carolina, Chapel Hill Chapel Hill, North Carolina Vanita D. Jain, MD Clinical Assistant Professor Obstetrics and Gynecology Sidney Kimmel College of Medicine Thomas Jefferson University Philadelphia, Pennsylvania Medical Director, Perinatal Special Care Unit and Clinic Christiana Care Health System Newark, Delaware Fariha Jamal, MD Assistant Professor of Neurology Baylor College of Medicine Michael. E. DeBakey VA Medical Center Houston, Texas Sehrish Jamot, MD Gastroenterology/Hepatology Fellow Chief Gastroenterology Fellow Warren Alpert Medical School of Brown University Lifespan Physician Group Providence, Rhode Island Robert H. Janigian, Jr., MD Clinical Associate Professor of Surgery Department of Surgery/Ophthalmology Warren Alpert Medical School of Brown University Providence, Rhode Island Noelle Marie Javier, MD Assistant Professor of Medicine Brookdale Department of Geriatrics and Palliative Care Icahn School of Medicine at Mount Sinai New York, New York Michael Johl, MD Cardiology Fellow Department of Cardiology University of California, Irvine Orange, California Christina M. Johnson, MD Minimally Invasive Gynecologic Surgeon Department of Obstetrics and Gynecology Beth Israel Lahey Health Burlington, Massachusetts

Michael P. Johnson, MD Internist, Medical Attending Rhode Island and Miriam Hospitals Providence, Rhode Island Angad Jolly, PhD Baylor College of Medicine Houston, Texas Rebecca Jonas, MD Resident Physician Department of Internal Medicine Lenox Hill Hospital New York, New York Kimberly Jones, MD Associate Professor of Child Neurology Department of Neurology University of Kentucky Lexington, Kentucky Shyam Joshi, MD Assistant Professor of Medicine Section of Allergy and Immunology Oregon Health Sciences University Portland, Oregon Siddharth Kapoor, MD Assistant Professor of Neurology Director, Headache Medicine Program Director, Fellowship in Headache Medicine Department of Neurology University of Kentucky College of Medicine Lexington, Kentucky Vanji Karthikeyan, MD Nephrologist Department of Nephrology and Hypertension Henry Ford Hospital Detroit, Michigan Joseph S. Kass, MD, JD, FAAN Associate Dean of Student Affairs Professor of Neurology, Psychiatry, and Medical Ethics Director, Alzheimer’s Disease and Memory Disorders Center Baylor College of Medicine Ben Taub General Hospital Houston, Texas Emily R. Katz, MD Associate Professor, Clinician Educator Department of Psychiatry and Human Behavior Department of Pediatrics Warren Alpert Medical School of Brown University Director, Child and Adolescent Psychiatry Consultation-Liaison Service Hasbro Children’s Hospital Providence, Rhode Island Ali Kazim, MD Chief of Psychiatry Phoenix VA Health Care System Clinical Professor of Psychiatry University of Arizona Medical College Phoenix, Arizona

Contributors Sudad Kazzaz, MD Baylor College of Medicine Houston, Texas Sachin Kedar, MBBS, MD Associate Professor Neurological Sciences, Ophthalmology and Visual Sciences University of Nebraska Medical School and Truhlsen Eye Institute Omaha, Nebraska A. Basit Khan, MD Resident Physician Neurosurgery Baylor College of Medicine Houston, Texas Bilal Shahzad Khan, MD Internal Medicine Fellow Hypertension and Nephrology Henry Ford Hospital Detroit, Michigan Rizwan Khan, MD Cardiology Fellow St. Elizabeth’s Medical Center Boston, Massachusetts Sarthak Khare, MD Medicine Resident and Cardiology Fellow St. Elizabeth’s Medical Center Department of Medicine Boston, Massachusetts Hussain R. Khawaja, MD Assistant Professor of Medicine, Clinician Educator Warren Alpert Medical School of Brown University Division of General Internal Medicine Rhode Island Hospital Providence, Rhode Island Byung Kim, MD Department of Hematology Oncology Harold Alfond Center for Cancer Care Augusta, Maine Robert M. Kirchner, MD Cardiology Fellow Warren Alpert Medical School of Brown University Providence, Rhode Island Robert Kohn, MD Department of Psychiatry and Human Behavior Warren Alpert Medical School of Brown University Providence, Rhode Island Erna Milunka Kojic, MD Professor Division of Infectious Diseases Icahn School of Medicine at Mount Sinai New York, New York Aravind Rao Kokkirala, MD, FACC Warren Alpert Medical School of Brown University Providence, Rhode Island Yuval Konstantino, MD Cardiology Clinical Cardiac Electrophysiology Soroka University Medical Center Be’er-Sheva, Israel

Nelson Kopyt, DO Chief of Nephrology Lehigh Valley Hospital Allentown, Pennsylvania Clinical Professor of Medicine Morsani College of Medicine Tampa, Florida Lindsay R. Kosinski, MD Resident Physician Warren Alpert Medical School of Brown University Rhode Island Hospital Providence, Rhode Island Katherine Kostroun, MD Baylor College of Medicine Houston, Texas Ioannis Koulouridis, MD, MS Cardiology Fellow St. Elizabeth’s Medical Center Boston, Massachusetts Timothy R. Kreider, MD, PhD Assistant Professor Department of Psychiatry Donald and Barbara Zucker School of Medicine at Hofstra/Northwell Hempstead, New York Prashanth Krishnamohan, MBBS, MD Neurocritical Care Stanford University Palo Alto, California Mohit Kukreja, MD Clinical Fellow Shoulder and Elbow Surgery Warren Alpert Medical School of Brown University Providence, Rhode Island Lalathaksha Kumbar, MD Senior Staff Physician Division of Nephrology and Hypertension Henry Ford Hospital Detroit, Michigan David I. Kurss, MD, FACOG, NCMP Attending Physician, Clinical Assistant Professor Obstetrics and Gynecology State University of New York School of Medicine Buffalo, New York Sebastian G. Kurz, MD Associate Professor Department of Internal Medicine Division of Pulmonary, Critical Care and Sleep Medicine Mount Sinai Hospital New York, New York Michael Kutschke, MD Resident Physician Department of Orthopedic Surgery Warren Alpert Medical School of Brown University Providence, Rhode Island Peter LaCamera, MD Assistant Professor of Medicine Tufts University School of Medicine Boston, Massachusetts

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Contributors Ann S. LaCasce, MD, MMSc Associate Professor of Medicine Medical Oncology Harvard Medical School Boston, Massachusetts Ashley Lakin, DO, MA Assistant Professor of Family Medicine (Clinical) Warren Alpert Medical School of Brown University Providence, Rhode Island Jayanth Lakshmikanth, MD Fellow Nephrology and Critical Care Henry Ford Hospital System Detroit, Michigan Uyen T. Lam, MD Noninvasive Cardiology St. Elizabeth’s Medical Center Tufts University School of Medicine Boston, Massachusetts Jhenette Lauder, MD Maternal-Fetal Medicine Fellow Obstetrics and Gynecology University of Utah Salt Lake City, Utah Nykia Leach, BA Clinical Research Assistant Rhode Island Hospital Providence, Rhode Island David A. Leavitt, MD Associate Director of Endourology Director of Laser Surgery Senior Staff Vattikuti Urology Institute Henry Ford Hospital Health System Detroit, Michigan Kachiu C. Lee, MD, MPH Department of Dermatology Warren Alpert Medical School of Brown University Providence, Rhode Island Nicholas J. Lemme, MD Resident Physician Department of Orthopedics Warren Alpert Medical School of Brown University Rhode Island Hospital Providence, Rhode Island Beth Leopold, MD Resident Physician Obstetrics and Gynecology Christiana Care Health System Newark, Delaware Jian Li, MD, PhD Clinical Assistant Professor Internal Medicine, Hypertension and Nephrology Wayne State University School of Medicine Henry Ford Hospital Detroit, Michigan Suqing Li, MD Gastroenterology Fellow University of Toronto Toronto, Ontario, Canada

Donita Dillon Lightner, MD Assistant Professor of Pediatric Neurology University of Kentucky Lexington, Kentucky Stanley Linder, DO Nephrology and Critical Care Fellow Henry Ford Hospital Detroit, Michigan Kito Lord, MD, MBA Assistant Professor Department of Emergency Medicine University of Tennessee Health Science Center Memphis, Tennessee Elizabeth A. Lowenhaupt, MD Associate Professor, Clinician Educator Department of Psychiatry and Human Behavior Warren Alpert Medical School of Brown University Providence, Rhode Island Curtis Lee Lowery III, MD, PhD Resident Physician Emergency Medicine University of Tennessee Health Science Center Memphis, Tennessee David J. Lucier Jr., MD, MBA, MPH Director of Quality and Patient Safety, Hospital Medicine Division of General Internal Medicine Massachusetts General Hospital Boston, Massachusetts Michelle C. Maciag, MD Fellow Allergy and Clinical Immunology Boston Children’s Hospital Harvard Medical School Boston, Massachusetts Susanna R. Magee, MD, MPH Assistant Professor Department of Family Medicine Warren Alpert Medical School of Brown University Providence, Rhode Island Marta Majczak, MD Attending Psychiatrist Bradley Hospital East Providence, Rhode Island Shefali Majmudar, DO Rheumatologist Jackson Medical Center Miami, Florida Gretchen Makai, MD Clinical Assistant Professor Obstetrics and Gynecology Sidney Kimmel Medical College, Thomas Jefferson University Philadelphia, Pennsylvania; Director, Division of Minimally Invasive Gynecologic Surgery Christiana Care Health System Newark, Delaware Pieusha Malhotra, MD, MPH Assistant Professor Division of Allergy, Immunology, and Rheumatology Rutgers New Jersey School of Medicine Newark, New Jersey

Contributors Eishita Manjrekar, PhD Postdoctoral Fellow Rhode Island Hospital Warren Alpert Medical School of Brown University Providence, Rhode Island Abigail K. Mansfield, PhD Assistant Professor Warren Alpert Medical School of Brown University Providence, Rhode Island Stephen E. Marcaccio, MD Department of Orthopaedic Surgery Rhode Island Hospital Warren Alpert Medical School of Brown University Providence, Rhode Island

Jorge Mercado, MD Assistant Professor of Medicine Assistant Chief of Pulmonary and Critical Care Medicine Director of Pulmonary Section NYU School of Medicine New York, New York Scott J. Merrill, MD Resident Physician Obstetrics and Gynecology Christiana Care Health System Newark, Delaware Jennifer B. Merriman, MD Delaware Center for Maternal-Fetal Medicine of Christiana Care Newark, Delaware

Lauren J. Maskin, MD Pediatric Hospitalist Division of Pediatric Hospital Medicine Children’s Hospital and Medical Center Omaha, Nebraska

Rory Merritt, MD, MEHP Emergency Medicine Warren Alpert Medical School of Brown University/Lifespan Rhode Island Hospital and Miriam Hospital Providence, Rhode Island

Robert Matera, MD Resident Physician Internal Medicine Warren Alpert Medical School of Brown University Providence, Rhode Island

Brittany N. Mertz, PA-C, MMSc-PA Physician Assistant Wesley Chapel, Florida

Kelly L. Matson, PharmD, BCPPS Clinical Professor Department of Pharmacy Practice University of Rhode Island Kingston, Rhode Island Maitreyi Mazumdar, MD, MPH, MSc Assistant Professor of Neurology Harvard Medical School Staff Physician Department of Neurology Boston Children’s Hospital Boston, Massachusetts Nadine Mbuyi, MD Assistant Professor of Medicine Division of Rheumatology George Washington University School of Medicine and Health Sciences Washington, DC Russell J. McCulloh, MD Associate Professor Pediatrics and Internal Medicine University of Nebraska Medical Center Children’s Hospital and Medical Center Omaha, Nebraska Christopher McDonald, MD Resident Physician Orthopedic Surgery Rhode Island Hospital Warren Alpert Medical School of Brown University Providence, Rhode Island Barbara McGuirk, MD Director of Surgery Reproductive Associates of Delaware Newark, Delaware

Robin Metcalfe-Klaw, MD Obstetrics and Gynecology Christiana Care Health System Newark, Delaware Gaetane Michaud, MD Professor of Medicine and Cardiothoracic Surgery NYU Langone Health New York, New York Taro Minami, MD Associate Professor of Medicine, Clinician Educator Warren Alpert Medical School of Brown University Providence, Rhode Island Hassan M. Minhas, MD Clinical Assistant Professor Department of Law and Psychiatry Yale University New Haven, Connecticut; Medical Director, Outpatient Autism Services Hospital for Special Care New Britain, Connecticut Jared D. Minkel, PhD Assistant Professor Psychiatry and Human Behavior Warren Alpert Medical School of Brown University Providence, Rhode Island Farhan A. Mirza, MD Resident Physician Neurosurgery University of Kentucky Lexington, Kentucky Hetal D. Mistry, MD Resident Physician Internal Medicine Warren Alpert Medical School of Brown University Providence, Rhode Island

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Contributors Jacob Modest, MD Resident Physician Orthopedic Surgery Warren Alpert Medical School of Brown University Rhode Island Hospital Providence, Rhode Island Marc Monachese, MD Division of Gastroenterology University of Toronto Toronto, Ontario, Canada Eveline Mordehai, MD Resident Physician Anesthesia Warren Alpert Medical School of Brown University Providence, Rhode Island Theresa A. Morgan, PhD Clinical Assistant Professor Psychiatry and Human Behavior Warren Alpert Medical School of Brown University Providence, Rhode Island Aleem I. Mughal, MD Cardiac Electrophysiologist Heart Center of North Texas Fort Worth, Texas

Adrienne B. Neithardt, MD Reproductive Associates of Delaware Newark, Delaware Peter Nguyen, MD Interventional Cardiology Fellow University of California, Irvine Orange, California Samantha Ni, MD Resident Physician Emergency Department University of Tennessee Health Science Center Memphis, Tennessee Melissa Nothnagle, MD, MSc Chief of Family Medicine Natividad Hospital Salinas, California James E. Novak, MD, PhD Division of Nephrology and Hypertension Henry Ford Hospital Detroit, Michigan Chloe Mander Nunneley, MD Baylor College of Medicine Houston, Texas

Marjan Mujib, MD Cardiology Fellow Department of Medicine, Division of Cardiology Warren Alpert Medical School of Brown University Providence, Rhode Island

Emily E. Nuss, MD Resident Physician Obstetrics and Gynecology Christiana Care Health System Wilmington, Delaware

Shiva Kumar R. Mukkamalla, MD, MPH Attending Physician Internal Medicine/Hematology and Medical Oncology Presbyterian Healthcare Services Rio Rancho, New Mexico

Gail M. O’Brien, MD Physician Internal Medicine/Obesity Medicine Lahey Hospital Primary Care Burlington, Massachusetts

Vivek Murthy, MD Assistant Professor of Medicine Albert Einstein College of Medicine Montefiore Medical Center Bronx, New York

Ryan M. O’Donnell, MD Resident Physician Orthopedic Surgery Warren Alpert Medical School of Brown University Rhode Island Hospital Providence, Rhode Island

Omar Nadeem, MD Instructor in Medicine Department of Hematologic Malignancies, Medical Oncology Harvard Medical School Dana Farber Cancer Institute Boston, Massachusetts Catherine E. Najem, MD Section of Rheumatology Lewis Katz School of Medicine at Temple University Philadelphia, Pennsylvania Hussain Mohammad H. Naseri, MD Physician, Hematology/Oncology Ohio Valley Medical Center Wheeling, West Virginia Uzma Nasir, MD Assistant Professor Clinical Anesthesia and Pain Management SUNY at Stony Brook University Hospital, VA Hospital Northport, New York

Adam J. Olszewski, MD Assistant Professor of Medicine Warren Alpert Medical School of Brown University Providence, Rhode Island Lindsay M. Orchowski, PhD Associate Professor (Research) Department of Psychiatry and Human Behavior Warren Alpert Medical School of Brown University Providence, Rhode Island Sebastian Orman, MD Resident Physician Orthopaedic Surgery Warren Alpert Medical School of Brown University/Lifespan Providence, Rhode Island Brett D. Owens, MD Surgeon, Orthopedic Sports Medicine Complex Shoulder and Knee Specialist Warren Alpert Medical School of Brown University Providence, Rhode Island

Contributors Paolo G. Pace, MASc, MD Resident Physician Internal Medicine Roger Williams Medical Center Providence, Rhode Island Argyro Papafilippaki, MD, FACC Cardiology Fellow St. Elizabeth’s Medical Center Department of Medicine Boston, Massachusetts Lisa Pappas-Taffer, MD Assistant Professor Dermatology University of Pennsylvania Philadelphia, Pennsylvania Marco Pares, BS (MD Candidate) Baylor College of Medicine Houston, Texas Anshul Parulkar, MD Resident Physician Internal Medicine Rhode Island Hospital Warren Alpert Medical School of Brown University Providence, Rhode Island Birju B. Patel, MD Assistant Professor of Medicine Division of Geriatrics and Gerontology Emory University School of Medicine Atlanta Veterans Affairs Medical Center Atlanta, Georgia Devan D. Patel, MD Resident Physician Warren Alpert Medical School of Brown University Rhode Island Hospital Providence, Rhode Island Nima R. Patel, MD, MS Program Director, TriHealth OB/GYN Residency Division of Minimally Invasive Surgery TriHealth/Good Samaritan Hospital Cincinnati, Ohio Pranav M. Patel, MD, FACC, FAHA, FSCAI Professor of Medicine and Biomedical Engineering Chief, Division of Cardiology University of California, Irvine Irvine, California Saagar N. Patel, MD Baylor College of Medicine Houston, Texas Shivani K. Patel, MD Physician Department of Internal Medicine/Rheumatology St. Jude Medical Center Fullerton, California Shyam A. Patel, MD Resident Physician Warren Alpert Medical School of Brown University Rhode Island Hospital Providence, Rhode Island

Brett Patrick, MD University of Tennessee Health Science Center Memphis, Tennessee Grace Rebecca Paul, MBBS, MD Assistant Professor of Pediatrics Division of Pulmonary and Sleep Medicine Nationwide Children’s Hospital Columbus, Ohio E. Scott Paxton, MD Assistant Professor Orthopedic Surgery Warren Alpert Medical School of Brown University Providence, Rhode Island Mark Perazella, MD Professor Department of Internal Medicine and Section of Nephrology Yale University School of Medicine New Haven, Connecticut Lily Pham, MD Resident Physician Neurology Baylor College of Medicine Houston, Texas Long Pham, MD Rheumatology Fellow Cedars-Sinai Medical Center Los Angeles, California Katharine A. Phillips, MD Professor of Psychiatry DeWitt Wallace Senior Scholar Weill Cornell Medical College Attending Psychiatrist New York-Presbyterian Hospital New York, New York; Adjunct Professor of Psychiatry and Human Behavior Warren Alpert Medical School of Brown University Providence, Rhode Island Christopher Pickett, MD Associate Professor of Medicine University of Connecticut Farmington, Connecticut Justin Pinkston, MD East Tennessee State University Quillen College of Medicine Department of Emergency Medicine Johnson City, Tennessee Wendy A. Plante, PhD Staff Psychologist Director of Outpatient Services Division of Child and Adolescent Psychiatry Hasbro Children’s Hospital/Rhode Island Hospital Clinical Associate Professor of Psychiatry and Human Behavior Warren Alpert Medical School of Brown University Providence, Rhode Island Kevin V. Plumley, MD, MPH Physician Internal Medicine Kaiser Permanente Los Angeles, California

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Contributors Michael Pohlen, MD Baylor College of Medicine Houston, Texas Sharon S. Hartman Polensek, MD, PhD Assistant Professor of Neurology Center for Dizziness and Balance Disorders Emory University Atlanta, Georgia Kittika Poonsombudlert, MD Resident Physician Internal Medicine University of Hawaii Honolulu, Hawaii Donn Posner, PhD Adjunct Clinical Associate Professor Psychiatry and Behavioral Sciences Stanford University School of Medicine Palo Alto Veterans Institute for Research Veterans Affairs Palo Alto Health Care System Palo Alto, California Rohini Prashar, MD Nephrologist Department of Nephrology and Hypertension Henry Ford Hospital Detroit, Michigan Amanda Pressman, MD Assistant Professor of Medicine Department of Gastroenterology Warren Alpert Medical School of Brown University Providence, Rhode Island Adam J. Prince, MD Resident Physician Internal Medicine Lennox Hill Hospital New York, New York Imrana Qawi, MD Assistant Professor of Medicine Pulmonary/Critical Care Tufts Medical Center Boston, Massachusetts Reema Qureshi, MD Fellow Department of Cardiology Rhode Island Hospital Warren Alpert Medical School of Brown University Providence, Rhode Island Nora Rader, MD University of South Carolina School of Medicine, Greenville Greenville, South Carolina Jeremy E. Raducha, MD Resident Physician Orthopedic Surgery Warren Alpert Medical School of Brown University Providence, Rhode Island Samaan Rafeq, MD Pulmonologist NYU Langone Health New York, New York

Neha Rana, MD Physician Obstetrics and Gynecology Hospital of the University of Pennsylvania Philadelphia, Pennsylvania Gina Ranieri, DO Resident Physician Obstetrics and Gynecology Christiana Care Health System Newark, Delaware Bharti Rathore, MD Program Director, Hematology/Oncology Fellowship Roger Williams Medical Center Providence, Rhode Island Assistant Professor of Medicine Boston University School of Medicine Boston, Massachusetts Ritesh Rathore, MD Associate Professor Boston University School of Medicine Director, Hematology/Oncology Roger Williams Medical Center Providence, Rhode Island Neha P. Raukar, MD, MS Associate Professor Emergency Medicine Mayo Clinic Rochester, Minnesota John L. Reagan, MD Assistant Professor Internal Medicine, Hematology/Oncology Warren Alpert Medical School of Brown University Providence, Rhode Island Bharathi V. Reddy, MD Associate Professor of Medicine Section of Nephrology University of Chicago Chicago, Illinois Chakravarthy Reddy, MD Associate Professor Pulmonary and Critical Care University of Utah Salt Lake City, Utah Snigdha T. Reddy, MD Division of Nephrology and Hypertension Henry Ford Hospital Detroit, Michigan Anthony M. Reginato, PhD, MD Director, Division of Rheumatology Associate Professor of Medicine Warren Alpert Medical School of Brown University Providence, Rhode Island Michael S. Reich, MD Resident Physician Emergency Medicine University of Tennessee Health Science Center Memphis, Tennessee

Contributors James P. Reichart, MD Associate Program Director Division of Nephrology Lehigh Valley Health Network Allentown, Pennsylvania

Todd F. Roberts, MD, FRCPC Medical Director, Leukemia, Blood and Marrow Transplant Program Medical Director, Immunotherapy Program Roger Williams Medical Center Providence, Rhode Island

Daniel Brian Carlin Reid, MD, MPH Resident Physician Warren Alpert Medical School of Brown University Rhode Island Hospital Providence, Rhode Island

Gregory Rochu, MD, MPH Assistant Professor of Medicine Division of Geriatrics and Palliative Medicine Warren Alpert Medical School of Brown University Providence, Rhode Island

Victor I. Reus, MD Distinguished Professor of Psychiatry University of California San Francisco School of Medicine University of California San Francisco Weill Institute for Neurosciences Langley Porter Psychiatric Institute San Francisco, California

Emily Rosenfeld, MD, MPH Resident Physician Obstetrics and Gynecology Christiana Care Health Systems Newark, Delaware

Candice Reyes, MD, RhMSUS Associate Clinical Professor of Medicine Department of Rheumatology University of California San Francisco Fresno, California Harlan G. Rich, MD, FACP, AGAF Associate Professor of Medicine and Medical Science Warren Alpert Medical School of Brown University Director of Endoscopy Rhode Island Hospital Clinical Director of the Division of Gastroenterology Brown Medicine/Brown Physicians, Inc. Providence, Rhode Island Rocco J. Richards, MD Roger Williams Medical Center Department of Internal Medicine Boston University School of Medicine Boston, Massachusetts Nathan Riddell, MD Interventional Cardiology Fellow Department of Cardiovascular Medicine St. Elizabeth’s Medical Center Boston, Massachusetts Giulia Righi, PhD Staff Psychologist Bradley Hospital East Providence, Rhode Island Assistant Professor (Research) Warren Alpert Medical School of Brown University Providence, Rhode Island Alvaro M. Rivera, MD Internal Medicine Roger Williams Medical Center Providence, Rhode Island Nicole A. Roberts, MD Assistant Professor Obstetrics and Gynecology University of South Florida Tampa, Florida

Julie L. Roth, MD Director of Women’s Neurology Department of Neurology Rhode Island Hospital Providence, Rhode Island Steven Rougas, MD, MS, FACEP Director, Doctoring Program Assistant Professor of Emergency Medicine and Medical Science Warren Alpert Medical School of Brown University Providence, Rhode Island Breton Roussel, MD Chief Resident Department of General Internal Medicine Warren Alpert Medical School of Brown University Providence, Rhode Island Amity Rubeor, DO, CAQSM Assistant Professor Department of Family Medicine Warren Alpert Medical School of Brown University Providence, Rhode Island Kelly Ruhstaller, MD Christiana Care Health Systems Newark, Delaware Javeryah Safi, MD Clinical Associate Department of Pulmonary and Critical Care Medicine Tufts University Boston, Massachusetts Emily Saks, MD, MSSCE Physician Female Pelvic Medicine and Reconstructive Surgery Christiana Care Health System Newark, Delaware Milagros Samaniego-Picota, MD Section Head and Medical Director, Kidney Pancreas Transplantation Transplant Institute and Division of Nephrology and Hypertension Henry Ford Health System Detroit, Michigan

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Contributors Radhika Sampat, DO Instructor Department of Neurology, Neuromuscular Division Emory University School of Medicine Atlanta, Georgia Hemant K. Satpathy, MD Fellow Division of Maternal Fetal Medicine Department of Obstetrics and Gynecology Emory University Atlanta, Georgia Ruby K. Satpathy, MD Fellow Cardiology Department of Internal Medicine Creighton University Omaha, Nebraska Syeda M. Sayeed, MD Attending Physician Department of Rheumatology South Coast Health Fall River, Massachusetts Daphne Scaramangas-Plumley, MD Rheumatologist Attune Health Cedars-Sinai Medical Center Beverly Hills, California Aaron Schaffner, MD Physician Emergency Medicine University of Tennessee Health Science Center Memphis, Tennessee Paul J. Scheel, Jr., MD Nephrologist CEO, Washington University Physicians Associate Vice Chancellor of Clinical Affairs Washington University, St. Louis Barnes-Jewish Hospital St. Louis, Missouri Bradley Schlussel, MD Rheumatologist Department of Rheumatology Greenwich Hospital Northeast Medical Group—Yale New Haven Health Greenwich, Connecticut Heiko Schmitt, MD, PhD Associate Professor of Medicine Department of Cardiology Co-Director Cardiac Electrophysiology Director Anticoagulation Clinic UConn Health Farmington, Connecticut Anthony Sciscione, DO Professor of Obstetrics and Gynecology Jefferson Medical College Philadelphia, Pennsylvania; Residency Program Director Director of Maternal-Fetal Medicine Department of Obstetrics and Gynecology Christiana Care Health System Newark, Delaware

Christina D. Scully, MD Consultation-Liaison Psychiatry Attending Providence, Rhode Island Peter J. Sell, DO Associate Professor Department of Pediatrics University of Massachusetts Medical School Worcester, Massachusetts Steven M. Sepe, MD, PhD Chair, Department of Medicine Roger Williams Medical Center Clinical Professor of Medicine Assistant Dean of Clinical Affairs Boston University School of Medicine Boston, Massachusetts Hesham Shaban, MD Senior Staff Division of Nephrology Henry Ford Hospital System Detroit, Michigan Ankur Shah, MD Assistant Professor of Medicine Division of Nephrology Warren Alpert Medical School of Brown University Providence, Rhode Island Kalpit N. Shah, MD Fellow Orthopedic Trauma Department of Orthopedic Surgery Warren Alpert Medical School of Brown University Rhode Island Hospital Providence, Rhode Island Shivani Shah, MD Obstetrician/Gynecologist Geisinger Health System Wilkes-Barre, Pennsylvania Esseim Sharma, MD Fellow Cardiology Warren Alpert Medical School of Brown University Providence, Rhode Island Yuvraj Sharma, MD Senior Staff Physician Department of Nephrology and Hypertension Henry Ford Hospital Detroit, Michigan Lydia Sharp, MD Assistant Professor Department of Neurology Baylor College of Medicine Houston, Texas Charles Fox Sherrod IV, MD Resident Physician Internal Medicine Warren Alpert Medical School of Brown University Providence, Rhode Island

Contributors Jessica E. Shill, MD Senior Staff Physician Division of Endocrinology, Diabetes and Bone and Mineral Disorders Henry Ford Health System Clinical Associate Professor of Medicine Wayne State University School of Medicine Detroit, Michigan Philip A. Shlossman, MD Associate Director, Maternal and Fetal Medicine Obstetrics and Gynecology Christiana Hospital Newark, Delaware Asha Shrestha, MD Rheumatologist Department of Rheumatology St. Joseph Healthcare Bangor, Maine

Irina A. Skylar-Scott, MD Resident Physician Neurology Harvard Medical School Boston, Massachusetts John Sladky, MD Staff Neurologist Associate Program Director Wilford Hall Medical Center San Antonio, Texas Brett Slingsby, MD Child Abuse Pediatrician Lawrence A. Aubin Sr. Child Protection Center Assistant Professor of Pediatrics Warren Alpert Medical School of Brown University Providence, Rhode Island

Jordan Shull, MD University of Texas Health Science Center at Houston McGovern Medical School Houston, Texas

Jeanette G. Smith, MD Assistant Professor Department of Medicine Warren Alpert Medical School of Brown University Providence, Rhode Island

Khawja A. Siddiqui, MD Resident Physician Neurology Baylor College of Medicine Houston, Texas

Jonathan H. Smith, MD Assistant Professor Neurology University of Kentucky Lexington, Kentucky

Lisa Sieczkowski, MD Pediatric Hospitalist Children’s Hospital and Medical Center Pediatric Hospital Medicine Omaha, Nebraska

Matthew J. Smith, MD Physical Medicine and Rehabilitation Warren Alpert Medical School of Brown University Rhode Island Hospital Providence, Rhode Island

Mark Sigman, MD Professor of Surgery, Urology Professor of Pathology and Laboratory Medicine Warren Alpert Medical School of Brown University Providence, Rhode Island

U. Shivraj Sohur, MD, PhD Assistant Professor Neurology Harvard Medical School Boston, Massachusetts

James Simon, MD Assistant Professor Lerner College of Medicine Cleveland, Ohio

Vivek Soi, MD Assistant Professor Internal Medicine, Nephrology Henry Ford Health System Detroit, Michigan

Harinder P. Singh, MD Clinical Associate Department of Pulmonary and Critical Care Medicine St. Elizabeth Medical Center Tufts University Boston, Massachusetts Divya Singhal, MD Medical Director Oklahoma City VA Medical Center Residents’ Longitudinal Clinic Vice Chair, Women’s Issues in Neurology American Academy of Neurology Assistant Professor of Neurology University of Oklahoma Epileptologist, Department of Neurology/Rehabilitation Services Oklahoma City, Oklahoma Lauren Sittard, PharmD Candidate Department of Pharmacy Practice University of Rhode Island Kingston, Rhode Island

Rebecca Soinski, MD Attending Rheumatology Physician Women’s Medicine Collaborative Lifespan Physician Group Providence, Rhode Island Maria E. Soler, MD, MPH, MBA Director, Education Division and Obstetric Triage Obstetrics and Gynecology Christiana Care Health System Newark, Delaware Sandeep Soman, MD Associate Division Head Nephrology and Hypertension Henry Ford Hospital Detroit, Michigan

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Contributors Akshay Sood, MD Chief Resident Vattikuti Urology Institute Henry Ford Hospital Health System Detroit, Michigan C. John Sperati, MD, MHS Associate Professor of Medicine Johns Hopkins University School of Medicine Division of Nephrology Baltimore, Maryland Johannes Steiner, MD Assistant Professor Cardiology Oregon Health and Science University Portland, Oregon Ella Stern, MD Resident Physician Obstetrics and Gynecology Christiana Care Health System Newark, Delaware Philip Stockwell, MD Assistant Professor of Medicine Division of Cardiology Warren Alpert Medical School of Brown University Providence, Rhode Island Padmaja Sudhakar, MBBS Assistant Professor Neurology University of Kentucky Lexington, Kentucky Jaspreet S. Suri, MD Department of Hepatology Beth Israel Deaconess Medical Center Boston, Massachusetts Elizabeth Sushereba, MSN, CNM Senior Midwife Obstetrics and Gynecology Christiana Care Health System Newark, Delaware Arun Swaminathan, MBBS Resident Physician Neurology University of Kentucky College of Medicine University of Kentucky Hospital Lexington, Kentucky Joseph Sweeney, MD, FACP, FRCPath Professor Laboratory Medicine and Pathology Warren Alpert Medical School of Brown University Providence, Rhode Island Wajih A. Syed, MD Cardiologist Kaiser Permanente Roseville, California Maher Tabba, MD, FACP, FCCP Associate Professor of Medicine and Surgery Department of Pulmonary, Critical Care and Sleep Medicine Tufts Medical Center Boston, Massachusetts

Dominick Tammaro, MD Associate Professor Internal Medicine Warren Alpert Medical School of Brown University Rhode Island Hospital Providence, Rhode Island Alan Taylor, MD Assistant Professor Emergency Medicine University of Tennessee Health Science Center Memphis, Tennessee Tahir Tellioglu, MD Assistant Professor Psychiatry and Human Behavior Warren Alpert Medical School of Brown University; Medical Co-Director, Lifespan Recovery Center Providence, Rhode Island Edward J. Testa, MD Resident Physician Orthopedic Surgery Warren Alpert Medical School of Brown University Providence, Rhode Island Jigisha P. Thakkar, MD Chief Resident Neurology University of Kentucky Lexington, Kentucky Anthony G. Thomas, DO, FACP Clinical Assistant Professor of Medicine Hematology and Oncology Warren Alpert Medical School of Brown University Providence, Rhode Island Andrew P. Thome, Jr., MD Resident Physician Orthopedic Surgery Warren Alpert Medical School of Brown University Rhode Island Hospital Providence, Rhode Island Erin Tibbetts, PharmD Clinical Pharmacist Division of Pharmacy and Medical Intensive Care Boston Children’s Hospital Boston, Massachusetts Alexandra Meyer Tien, MD Clinical Assistant Professor Family Medicine Warren Alpert Medical School of Brown University Providence, Rhode Island David Robbins Tien, MD Clinical Associate Professor Surgery, Ophthalmology Warren Alpert Medical School of Brown University Providence, Rhode Island Helen Toma, MD, MSPH Resident Physician Obstetrics and Gynecology Christiana Care Health System Newark, Delaware

Contributors Iris L. Tong, MD Associate Professor Department of Medicine Warren Alpert Medical School of Brown University Attending Physician Women’s Primary Care Women’s Medicine Collaborative Providence, Rhode Island Brett L. Tooley, MD Resident Physician Emergency Medicine University of Tennessee Health Science Center Memphis, Tennessee Steven P. Treon, MD Director, Bing Center for Waldenström’s Macroglobulinemia Dana Farber Cancer Institute Boston, Massachusetts Thomas M. Triplett, MD Assistant Professor Department of Emergency Medicine University of Tennessee Health Science Center Memphis, Tennessee Hiresh D. Trivedi, MD Fellow Gastroenterology and Hepatology Beth Israel Deaconess Medical Center Harvard Medical School Boston, Massachusetts Vrinda Trivedi, MBBS Fellow Cardiovascular Diseases Warren Alpert Medical School of Brown University Providence, Rhode Island Margaret Tryforos, MD Team C Leader Family Medicine Care New England Primary Care Medical Group Kent Hospital Pawtucket, Rhode Island Hisashi Tsukada, MD, PhD Instructor in Surgery Harvard Medical School Boston, Massachusetts Joseph R. Tucci, MD, FACP, FACE Professor of Medicine Boston University School of Medicine Director, Division of Endocrinology Roger Williams Medical Center Boston University School of Medicine Providence, Rhode Island Sara Moradi Tuchayi, MD Dermatology Massachusetts General Hospital Boston, Massachusetts Melissa H. Tukey, MD, MS Department of Pulmonary and Critical Care Kaiser Oakland Medical Center Oakland, California

Junior Uduman, MD Medical Director, Acute Dialysis Division of Nephrology and Hypertension Henry Ford Hospital Detroit, Michigan Sean H. Uiterwyk, MD Clinical Assistant Professor Community and Family Medicine Geisel School of Medicine at Dartmouth Hanover, New Hampshire Nicole J. Ullrich, MD, PhD Associate Professor of Neurology Harvard Medical School; Director of Neurologic Neuro-oncology Boston Children’s Hospital Boston, Massachusetts Leo Ungar, MD Fellow Cardiology University of California, Irvine Orange, California Bryant Uy, MPH, PA-C Physician Assistant Attune Health Beverly Hills, California Babak Vakili, MD Vice-Chair, Gynecologic Surgery Department of Obstetrics and Gynecology Urogynecology Christiana Care Health System Newark, Delaware Emily Van Kirk, MD Internal Medicine Roger Williams Medical Center Providence, Rhode Island Jennifer E. Vaughan, MD Fellow Neurology and Rehabilitation Medicine University of Cincinnati College of Medicine Cincinnati, Ohio Emil Stefan Vutescu, MD Resident Physician Orthopedics Warren Alpert Medical School of Brown University Providence, Rhode Island Brent T. Wagner, MD Professor of Medicine University of New Mexico Health Science Center; Director, Kidney Institute of New Mexico Albuquerque, New Mexico J. Richard Walker III, MD, MS, FACEP Interim Chair and Program Director Department of Emergency Medicine University of Tennessee Health Science Center Memphis, Tennessee

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Contributors Ray Walther, MD Methodist University Hospital Memphis, Tennessee Connie Wang, PharmD Tufts University Boston, Massachusetts Danielle Wang, MD Fellow Rheumatology Cedars-Sinai Medical Center Los Angeles, California Jozal Waroich, MD Resident Physician Internal Medicine Warren Alpert Medical School of Brown University Providence, Rhode Island Emma H. Weiss, MD Baylor College of Medicine Houston, Texas Mary-Beth Welesko, MS, APRN-BC, WCC Nurse Practitioner Division of Geriatrics and Palliative Medicine Care New England Medical Group Warwick, Rhode Island Adrienne Werth, MD Resident Physician Obstetrics and Gynecology Christiana Care Health System Newark, Delaware Matthew J. White, DO Fellow Rheumatology Roger Williams Medical Center Providence, Rhode Island Paul White, MD Physician School of Medicine University of North Carolina Chapel Hill, North Carolina Estelle H. Whitney, MD Generalist Physician Obstetrics and Gynecology Christiana Care Health System Newark, Delaware Matthew P. Wicklund, MD Professor Department of Neurology Penn State College of Medicine; Vice-Chair for Education Department of Neurology Milton S. Hershey Medical Center Hershey, Pennsylvania Jeffrey P. Wincze, PhD Department of Psychiatry Rhode Island Hospital Providence, Rhode Island

John P. Wincze, PhD Clinical Professor Emeritus Department of Psychiatry and Human Behavior Warren Alpert Medical School of Brown University Providence, Rhode Island Marlene Fishman Wolpert, MPH, CIC, FAPIC Independent Consultant and Long-Term Care Infection Preventionist Miriam Hospital Lifespan Laboratories Outreach Department Providence, Rhode Island Tzu-Ching (Teddy) Wu, MD, MPH Assistant Professor of Neurology University of Texas Medical School at Houston Director of Telemedicine Mischer Neuroscience Institute Houston, Texas John Wylie, MD, FACC Director, Cardiac Electrophysiology Steward Health Care System; Associate Professor of Medicine Tufts University School of Medicine Boston, Massachusetts Nicole B. Yang, MD Instructor in Medicine Harvard Medical School Division of Rheumatology Brigham and Women’s Hospital Boston, Massachusetts Jerry Yee, MD Clinical Professor of Medicine Department of Internal Medicine Wayne State University School of Medicine; Division Head, Nephrology and Hypertension Henry Ford Hospital Detroit, Michigan Gemini Yesodharan, MD Fellow Cardiology Steward Family Hospital, St. Elizabeth’s Medical Center Brighton, Massachusetts Agustin G. Yip, MD, PhD Associate Medical Director Short Term Unit McLean Hospital Belmont, Massachusetts John Q. Young, MD, MPP, PhD Professor and Vice Chair for Education Department of Psychiatry Donald and Barbara Zucker School of Medicine at Hofstra/Northwell Hempstead, New York Matthew H. H. Young, MD, JD Resident Physician Obstetrics and Gynecology Christiana Health Care System Newark, Delaware Reem Yusufani, MD Fellow Nephrology and Hypertension Henry Ford Hospital Detroit, Michigan

Contributors Caroline Zahm, MD Fellow Cardiology St. Elizabeth’s Medical Center Boston, Massachusetts Evan Zeitler, MD Fellow Adult Nephrology Division of Nephrology and Hypertension University of North Carolina at Chapel Hill Chapel Hill, North Carolina Talia Zenlea, MD Assistant Professor of Medicine Division of Gastroenterology University of Toronto Women’s College Hospital Toronto, Ontario, Canada

Mark Zimmerman, MD Director, Outpatient Psychiatry and Partial Hospital Program Rhode Island Hospital Professor Department of Psychiatry and Human Behavior Warren Alpert Medical School of Brown University Providence, Rhode Island Aline N. Zouk, MD Fellow New York University School of Medicine New York, New York

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To my sons, Dr. Vito F. Ferri and Dr. Christopher A. Ferri, and my daughter-in-law, Dr. Heather A. Ferri, for their help and constant support, and to my wife, Christina, for her patience during manuscript preparation. A special thanks to all the readers who have personally commented on the merits of this book and through their suggestions have helped make this product a bestseller in the medical field.

Fred F. Ferri, MD, FACP Clinical Professor Department of Medicine Warren Alpert Medical School of Brown University Providence, Rhode Island

Preface This book is intended to be a clear and concise reference for physicians and allied health professionals. Its user-friendly format is designed to provide a fast and efficient way to identify important clinical information and to offer practical guidance in patient management. The book is divided into five sections and an appendix, each with emphasis on clinical information. The tremendous success of the previous editions and the enthusiastic comments from numerous colleagues have brought about several positive changes over time. Each section has been significantly expanded from prior editions, bringing the total number of medical topics covered in this book to more than 1200. Hundreds of new illustrations, tables, and boxes have been added to this edition to enhance recollection of clinically important facts. The expedited claims submission and reimbursement ICD-10CM codes are included in all topics. Section I describes in detail 988 medical disorders and diseases— including 25 new topics this edition—arranged alphabetically and presented in outline format for ease of retrieval. Topics with an accompanying algorithm are identified with an ALG icon. Similarly, those topics with an accompanying online Patient Teaching Guide (PTG) are identified with a PTG symbol. Throughout the text, key quick-access information is consistently highlighted, with clinical photographs to further illustrate selected medical conditions, and relevant ICD-10CM codes listed. Most references focus on current peer-reviewed journal articles rather than outdated textbooks and old review articles. Topics in Section I use the following structured approach: 1. Basic Information (Definition, Synonyms, ICD-10CM Codes, Epidemiology & Demographics, Physical Findings & Clinical Presentation, Etiology) 2. Diagnosis (Differential Diagnosis, Workup, Laboratory Tests, Imaging Studies) 3. Treatment (Nonpharmacologic Therapy, Acute General Rx, Chronic Rx, Disposition, Referral) 4. Pearls & Considerations (Comments, Suggested Readings) Section II includes the differential diagnosis, etiology, and classification of signs and symptoms. This practical section allows the user investigating a physical complaint or abnormal laboratory value to follow a “workup” leading to a diagnosis. The physician can then easily look up the presumptive diagnosis in Section I for information specific to that illness. Section III includes more than 150 clinical algorithms to guide and expedite the patient’s workup and therapy. For the 2021 edition, we have continued to update algorithms and colorize online versions for improved readability. Physicians describe this section as particularly valuable in today’s managed-care environment. Section IV includes normal laboratory values and interpretation of results of commonly ordered laboratory tests. By providing interpretation of

abnormal results, this section facilitates the diagnosis of medical disorders and further adds to the comprehensive “one-stop” nature of our text. New illustrations and tables have been added for this edition. Section V focuses on preventive medicine. Information here includes screening recommendations for major diseases and disorders, patient counseling, and immunization and chemoprophylaxis recommendations. The Appendix is divided into nine major sections. Appendix I contains extensive information on complementary and alternative medicine (CAM), now expanded to include Common Herbs in Integrated Medicine, as well as Herbal Activities Against Pain and Chronic Diseases. With this material, we aim to lessen the current scarcity of exposure of allopathic and osteopathic physicians to the diversity of CAM therapies. Appendix II focuses on nutrition, with an emphasis on dietary supplements, vitamins, and minerals. Appendix III deals with diagnosis and treatment of acute poisoning. Appendix IV is a guide on impairment and disability evaluation. Appendix V focuses on the protection of travelers. Appendix VI addresses Physician Quality Reporting System (PQRS) measures. Appendix VII—available in the online version of Ferri’s Clinical Advisor— is a repository of practical patient instruction sheets, organized alphabetically and covers the majority of topics in this book. These guides can be easily customized and printed and serve as valuable tools for improving physician-patient communication, patient satisfaction, and ultimately quality of care. Appendix VIII and IX are both new to this edition and offer guidance related to palliative care and preoperative evaluation, respectively. I believe that we have produced a state-of-the-art information system with significant differences from existing texts. The information offered in all five sections and patient education guides could be sold separately based on their content, yet are available under a single cover, offering the reader tremendous value. I hope that the Clinical Advisor’s user-friendly approach, numerous unique features, and yearly updates will make this book a valuable medical reference, not only to primary care physicians but also to physicians in other specialties, medical students, and allied health professionals. Fred F. Ferri, MD, FACP Clinical Professor Department of Medicine Warren Alpert Medical School of Brown University Providence, Rhode Island Note: Comments from readers are always appreciated and can be forwarded directly to Dr. Ferri at [email protected].

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Ferri’s Clinical Advisor 2021—How to Use This Book

 ouse icon: Indicates content with additional references, figures, or tables M available at ExpertConsult.com. PTG icon: Indicates an accompanying Patient Teaching Guide available at PTG ExpertConsult.com. Many additional PTGs are available online that are not connected to topics in Section I. ALG ALG icon: Indicates a topic with an accompanying algorithm.

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Abdominal Aortic Aneurysm BASIC INFORMATION

ICD-10CM CODES I71.4 Abdominal aortic aneurysm, without rupture I71.3 Abdominal aortic aneurysm, ruptured

EPIDEMIOLOGY & DEMOGRAPHICS • Approximately 15,000 deaths/yr in the United States are attributed to AAA. • AAA is predominantly a disease of older adults, affecting men more than women (4:1). • The prevalence rate ranges from 4% to 9% in men in developed countries. • Clinically important AAAs ≥4 cm are present in 1% of men between age 55 and 64; and the prevalence rate increases by 2% to 4% per decade thereafter. • The peak incidence is among men approximately 70 yr old. • The frequency is much higher in smokers than in nonsmokers (8:1); and the risk decreases with smoking cessation. • Risk factors for AAA are similar to those for other atherosclerotic cardiovascular diseases. They include age, Caucasian race, smoking, male gender, family history, hypertension, hyperlipidemia, peripheral vascular disease, and aneurysm of other large vessels. • AAA is two to four times more common in first-degree male relatives of known AAA patients. • A decreased risk of AAA is associated with female gender, non-Caucasian race, and diabetes. • Rupture of the AAA occurs in 1% to 3% of men age 65 or older. 1. Rupture is the 10th leading cause of death in men older than age 55. 2. Mortality from rupture is 70% to 95%. 3. Risk factors for rupture include cardiac or renal transplants, severe obstructive lung disease, uncontrolled blood pressure, female sex, and ongoing tobacco use. • A recent decline in incidence and prevalence of AAA and related mortality has been attributed to reductions in tobacco use. However, AAA are at least 9× more common than thoracic aortic aneurysms.

NATURAL HISTORY • AAAs tend to develop in the infrarenal aorta and to expand, on average, at a rate of 0.2 to 0.5 cm per yr. • The risk of aneurysmal rupture is largely influenced by aneurysm size, rate of expansion, and sex. Other factors associated with increased risk for rupture include continued smoking, uncontrolled hypertension, and increased wall stress. • Higher tension in the abdominal aorta (together with histopathologic changes such as accumulation of foam cells, cholesterol crystals, and matrix metalloproteinases) renders the abdominal aortic wall more susceptible to dilation and subsequent rupture. • The 5-yr rupture rate of asymptomatic AAAs is 25% to 40% for aneurysms >5.0 cm in diameter, 1% to 7% for AAAs 4.0 to 5.0 cm, and nearly 0% for AAAs 5.5 cm; this size also demonstrates a faster rate of expansion (>0.5 cm over 6 months) and is more likely to be found in those who continue to smoke and in females. • Mortality rate after rupture can be as high as 90% because most patients do not reach the hospital in time for surgical repair. Of those who reach the hospital, the mortality rate is still 50%, compared with the 1% to 4% mortality rate for elective repair of a nonruptured AAA.

SCREENING AND MONITORING • The USPSTF recommends one-time screening for AAA by ultrasonography in men ages 65 to 75 who have a history of smoking, and in those 60 yr of age or older with a history of AAA in a parent or sibling. These populations have been shown to have a higher prevalence of AAA, and selectively screening this group has been shown to decrease AAAspecific mortality. • The USPSTF has found little benefit in repeat screening in men with a negative ultrasound and has determined that men over the age of 75 are unlikely to benefit from screening. It was also concluded that the current evidence is insufficient to assess the balance of the harms and benefits of screening for AAA in women ages 65 to 75 who have ever smoked. • The Society for Vascular Surgery Guidelines recommend monitoring by ultrasound or CT scan should be performed every 6 months for patients with AAAs measuring 5.0 to 5.4 cm in diameter, every 12 months for AAAs measuring 4.0 to 4.9 cm in diameter, and every 3 yr for AAAs 3.0 to 3.9 cm in diameter.

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Diseases and Disorders

DEFINITION An abdominal aortic aneurysm (AAA) is a focal full-thickness dilation of the abdominal aortic artery to at least 1.5 times the diameter measured at the level of the renal arteries, or exceeding the normal diameter of the abdominal aorta by 50%. The normal diameter at the renal arteries is 2 cm (range 1.4 to 3.0 cm), and a diameter 3 cm or larger is generally considered aneurysmal.

ETIOLOGY • Exact etiology is unknown and is likely multifactorial. 1. Degenerative: a.  Alterations in vascular wall biology leading to a loss of vascular structural proteins and wall strength. b. The most common association is atherosclerosis. It is uncertain whether atherosclerosis causes or results from AAAs. c. Tobacco use: >90% of people who develop an AAA have smoked at some point in their lives. 2. Inherited: Familial clusters are common. High familial prevalence rate is notable in male individuals. The nature of the genetic disorder is unclear but may be linked to alpha-1-antitrypsin deficiency or X-linked mutation. Connective tissue disorders, such as Marfan syndrome and Ehlers-Danlos syndrome, have also been strongly associated with AAA. 3.  Inflammatory: AAA is a progressive inflammatory disease of the artery walls. Activated B lymphocytes promote AAA by producing immunoglobulins, cytokines, and matrix metalloproteinases (MMPs), resulting in the activation of macrophages, mast cells (MCs), and complement pathways that lead to the degradation of collagen and matrix proteins and to aortic wall remodeling. 4. Infection, mycotic: Syphilis, Salmonella.

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PHYSICAL FINDINGS & CLINICAL PRESENTATION • Most aneurysms are asymptomatic and incidentally discovered on imaging studies; however, symptomatic aneurysms are at an increased risk for rupture. • Physical examination has a sensitivity of 76% for detecting AAAs >5 cm and only 29% for AAAs 3.0 to 3.9 cm. The accuracy of the physical examination is markedly diminished by obese body habitus. • Symptomatic patients may present with abdominal, back, flank, or groin pain. • A pulsatile epigastric mass that may or may not be tender may be present • Abdominal bruits can be present in case of renal or visceral arterial stenosis. • Common iliac arteries can be aneurysmal and palpable in the lower abdominal quadrants. In addition, prominent femoral and popliteal pulses warrant an abdominal ultrasound and lower extremity ultrasound. • Early satiety, nausea, and vomiting may be caused by compression of adjacent bowel. • Venous thrombosis or insufficiency may occur from iliocaval venous compression. • Thromboembolization can cause lower extremity pain and discoloration. • Ureteral obstruction and hydronephrosis can cause flank and groin pain and lead to obstructive renal failure. • Rupture classically presents as a triad of abdominal or back pain, hypotension, and a pulsatile abdominal mass in 50% of patients. • Acute blood loss may lead to myocardial infarction; arteriovenous fistulas may present as heart failure; aortoenteric fistulas may present as hematemesis or melena associated with abdominal and back pain.

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Abdominal Aortic Aneurysm Symptoms of AAA: pulsatile mass; abdominal pain radiating to back, flank, groin; peripheral emboli; flank and/or groin pain; melena thought to be due to aortoenteric fistula; syncope; flank mass or discoloration; lower-extremity paralysis

RA

cm

IN LK

Vital signs, intravenous access via 2 large-bore catheters, oxygen, complete blood count, serum chemistry panel, liver function panel, type and cross-match for 6 units of blood, urinalysis, prothrombin/partial thromboplastin time, electrocardiogram, portable chest radiograph

Stable, but concern for AAA

Unstable: low BP, tachycardia, ill-appearing

NS fluid boluses and un–cross-matched PRBCs; caution for too aggressive fluid resuscitation that may prevent local clot formation; be wary of potential of dilutional coagulopathy; aim for SBP 90-100 mm Hg; keep patient warm and consider level one infuser

Spiral CT (fastest and easiest); MRI; angiography

Bedside US

Aorta well visualized and no sign of aneurysm

Stabilized and no clear aneurysm or doubt as to diagnosis

Surgery consultation

An

CIA IIA EIA

FIG. 3  Three-dimensional computed tomography image illustrates the presence of an infrarenal abdominal aortic aneurysm. An, Aneurysm; CIA, common iliac artery; EIA, external iliac artery; IIA, internal iliac artery; IN, infrarenal neck; LK, left kidney; RA, renal artery; RK, right kidney. (From Townsend CM et  al [eds]: Sabiston textbook of surgery, ed 17, Philadelphia, 2004, Saunders.)

DIAGNOSIS AAA

Surgery consultation for operative repair

Consider spiral CT Consider alternative diagnosis: musculoskeletal back pain, diverticulitis, cholecystitis, appendicitis, renal colic, pancreatitis, intestinal ischemia, bowel obstruction, myocardial infarction; epidural abscess or vertebral osteomyelitis, aortic dissection, cauda equina

FIG. 1  Algorithm for the diagnosis and treatment of abdominal aortic aneurysms (AAAs). BP, Blood pressure; CT, computed tomography; MRI, magnetic resonance imaging; NS, normal saline; PRBCs, packed red blood cells; SBP, systolic blood pressure; US, ultrasonography. (From Adams JG et al: Emergency medicine, clinical essentials, ed 2, Philadelphia, 2013, Elsevier.)

EPI

3.33cm 3.85cm

RK

FIG. 2  Transverse image of an abdominal aortic aneurysm. Note the measurements of 3.33 × 3.85 cm. The inferior vena cava is seen to the patient’s right of the aorta, and the vertebral body is seen below the two vessels. Note also that there appears to be an echogenic flap within the aorta, possibly representing an aortic dissection. (From Adams JG et al: Emergency medicine, clinical essentials, ed 2, Philadelphia, 2013, Elsevier.)

DIFFERENTIAL DIAGNOSIS Almost 75% of patients with AAA are asymptomatic, and the condition is discovered on routine examination or serendipitously when ordering studies for other symptoms. Diagnosis of AAA should be considered in the differential of the following symptoms: abdominal pain, back pain, and/or pulsatile abdominal mass. The differential diagnosis includes peptic ulcer disease, mesenteric ischemia, renal calculi, pyelonephritis, and diverticulitis. LABORATORY TESTS Not routinely indicated. For suspected infected or inflammatory aneurysms, WBC, ESR/CRP, and blood cultures can be considered. An elevated d-dimer may indicate a thrombus within the aneurysm. Fig. 1 describes an algorithm for the diagnosis and treatment of abdominal aortic aneurysms. IMAGING STUDIES • Abdominal ultrasound (Fig. 2) has nearly 100% sensitivity and specificity in identifying an aneurysm and estimating the size to within 0.3 to 0.4 cm. It is not accurate in estimating the extension to the renal arteries or the iliac arteries. • Computed tomography (CT) (Fig. 3) scan is recommended for preoperative aneurysm imaging and estimates the size of the AAA to within 0.3 mm. There are no false-negative results, and the scan can identify extension to renal vessels with more precision than ultrasound. It is the imaging modality of choice for symptomatic AAA. Intravenous contrast is not required to establish a diagnosis of ruptured AAA. CT can also detect the integrity of the wall (Fig. 4) and exclude rupture.

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Abdominal Aortic Aneurysm costs, in comparison with CTA. In numerous prospective studies and meta-analyses, the detection and characterization of endoleaks with CEUS is comparable to that of CTA imaging.

TREATMENT NONPHARMACOLOGIC THERAPY • Despite lack of data substantiating reduction in expansion rate through treatment of cardiac risk factors, nonpharmacologic treatment continues to focus on risk factor modification (most importantly smoking cessation, diet, and exercise). Of note, moderate exercise does not increase the rate of aneurysm expansion or the risk of rupture. • Serial studies have shown that expansion rates are faster in current smokers than in former smokers. Patients with known AAA or a family history of aneurysms should be advised to stop smoking and be offered smoking cessation interventions. • Definitive treatment depends on the size of the aneurysm (see “Chronic Rx”). ACUTE GENERAL Rx • Acute symptomatic or ruptured AAA can be treated with open surgical repair (OSR) or EVAR. The choice is determined by anatomic considerations, operative risks, and availability of regular patient follow-up for EVAR.

L T

FIG. 4  Aneurysm of the abdominal aorta. A large aortic aneurysm is evident. The aorta exceeds 5 cm in diameter. A large amount of thrombus (T) partially surrounds the contrastenhanced patent lumen (L). Note the atherosclerotic calcification (arrowhead) in the wall of the aneurysm.

A

FIG. 6  Completion digital subtraction angiogram following endovascular aneurysm repair. (From Fillit HM: Brocklehurst’s textbook of geriatric medicine and gerontology, ed 8, Philadelphia, 2017, Elsevier.)

B

FIG. 5  A, Conventional catheter angiography with bilateral marked catheters in place demonstrates a large, lobulated, infrarenal aortic aneurysm (arrowhead) with a 4-cm proximal neck suitable for endovascular repair. B, An image after endovascular repair demonstrates complete exclusion of the aneurysm (arrowhead) with no endoleak and preservation of the renal and hypogastric arteries. (From Soto JA, Lucey BC: Emergency radiology: the requisites, ed 2, Philadelphia, 2017, Elsevier.)

• Emergent open repair has been the traditional method of treatment. However, multiple trials have shown lower mortality and shorter hospital stay with EVAR. More centers are increasingly using endovascular repair for patients who fit certain anatomic and physiologic criteria. • A recent Cochrane meta-analysis involving pooled data for four trials comparing EVAR versus open repair for ruptured abdominal aortic aneurysm failed to show a difference in 30-day mortality between EVAR versus open repair. There was a higher incidence of reintervention for patients undergoing EVAR, although interventions to deal with procedural complications were generally less invasive and involved catheter-based approaches. • The major limitations for EVAR include anatomical issues such as tortuosity or small caliber iliac arteries and inability to follow up patients to exclude late failure of stent-grafts and development of endoleaks.

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Diseases and Disorders

• Magnetic resonance angiography (MRA) may also be used and is at least as accurate as CT. • Plain radiographs may show the outline of an aneurysm in calcified aortas. This is an insensitive test for diagnosing AAA. • Diagnostic aortography has essentially been replaced by other noninvasive imaging modalities such as CT or MR angiography. Intraoperative angiography is still used for determining treatment options and postprocedure efficacy (Fig. 5). • Endovascular aneurysm repair (EVAR) needs close and lifelong imaging surveillance of the aneurysm site for the timely detection of possible complications, including endoleaks, graft migration, fractures, graft infection, and enlargement of aneurysm sac size with eventual rupture. The rate of complications after EVAR is approximately 30% with 2% to 3% of these requiring reintervention. Contrastenhanced computed tomography (CTA) is considered the gold standard in EVAR followup (Fig. 6), but it is accompanied with radiation burden and renal injury because of the use of contrast media. In the past 2 decades, several studies have shown the role of contrast-enhanced ultrasonography (CEUS) in post-EVAR surveillance, with very good diagnostic performance, absence of renal impairment, and no radiation, accompanied by low

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CHRONIC Rx • Blood pressure and fasting lipids should be monitored and controlled as recommended for patients with atherosclerotic disease. Statins are associated with decreased mortality after successful AAA repair, and are recommended for those with known AAA to reduce the progression of atherosclerosis and overall cardiovascular risk. • The most commonly used predictor of rupture is the maximum diameter of the AAA. • Long-term beta-blocker therapy has slowed the rate of aortic dilation and decreased the incidence of aortic complications in patients with Marfan syndrome. Several studies have also suggested that beta-blocker therapy may reduce the rate of expansion and risk of rupture; however, conclusive evidence is lacking. • A recent multicenter study of 5362 patients with AAA found no significant association between AAA progression and the use of statins, beta-blockers, angiotensin-converting enzyme inhibitors, or angiotensin II receptor blockers. • Antibiotics such as doxycycline and roxithromycin have been shown to limit the expansion of small AAAs. • AAA repair to eliminate the risk for rupture should be performed for patients with infrarenal or juxtarenal AAA of approximately 5.5 cm or larger in diameter. Repair in females can be considered at diameters larger than 5 cm. Additionally, AAAs with a rate of enlargement greater than 0.5 cm over 6 months should be considered for repair. All patients who are symptomatic should undergo repair, regardless of size. Timing of repair in symptomatic unruptured AAA is still under debate. • There is no clear advantage to early repair (open or endovascular) for small asymptomatic AAAs (less than 5.5 cm). • Percutaneous, endovascular, stent-anchored grafts placed with the patient under local anesthesia have provided an alternative approach for patients with favorable anatomy.

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Abdominal Aortic Aneurysm In patients who have undergone EVAR, longterm surveillance is required to assess for an endoleak, stent migration, change in aneurysm size, and need for re-intervention. • EVAR with proximally fenestrated grafts is an alternative to open repair in the management of juxtarenal aortic aneurysms and short-neck abdominal aortic aneurysms (the “neck” is the distance from the lowest main renal artery to the beginning of the aneurysm). Contemporary literature shows it is a safe and efficacious treatment, particularly for those deemed surgically high risk. • Randomized trials and meta-analyses comparing EVAR with OSR have shown that EVAR is associated with lower 30-day mortality and MI rates, shorter hospital stays, and better health-related quality of life up to 12 months postoperatively. However, EVAR also has increased rates of graft-related complications and is more costly. Additionally, a recent meta-analysis showed that 5 to 9 yr postoperatively, EVAR is associated with higher all-cause mortality, reintervention, and secondary rupture rates compared with OSR. Over >10 yr, EVAR is associated with higher reintervention and secondary rupture rates. • Based on current data, less than 2% of endovascular repairs require open conversion, and approximately half of all early endoleaks resolve spontaneously within a period of 30 days. • Open surgical repair of AAAs is the preferred approach for patients with a long life expectancy. • Endovascular AAA repair is the preferred approach for most patients with a reasonable life expectancy and suitable anatomy. • For patients with limited life expectancy, elective AAA repair is not recommended. • Surveillance for endovascular AAA repair has typically involved use of periodic CT scans, but abdominal ultrasound is gaining widespread adoption for postprocedure monitoring. Surveillance is recommended to occur 1 and 12 months postoperatively and then annually thereafter.

• In high-risk patients undergoing AAA repair, specifically those with coronary artery disease or those with more than one clinical risk factor based on the American Heart Association (AHA) guidelines, preoperative administration of beta-blockers titrated to a goal heart rate of 60 have been shown to decrease incidence of death from cardiac causes or nonfatal myocardial infarctions. Beta-blockers initiated within 24 hours of the procedure have not shown an advantage; however beta-blockers the patient is already taking should be continued. • Patients with chronic obstructive pulmonary disease (COPD) are at higher risk for major clinical complications, particularly if the COPD is suboptimally managed or if it is present in conjunction with cardiac or renal disease. Smoking cessation for 2 months before surgery has also been shown to decrease pulmonary morbidity. • Renal dysfunction is a strong predictor of mortality, showing up to as high as 41% mortality in those with impaired renal function compared with 6% in those without renal dysfunction.

REFERRAL • Vascular surgical referral should be made in asymptomatic patients with AAAs that are approximately 4.5 cm. • In patients with an expansion rate of 0.5 cm over 6 months, it is reasonable to offer repair, although small studies have shown that using expansion as a criterion for surgical referral is of unclear benefit. • It is important to optimize any comorbid conditions before surgical referral.

 EARLS & P CONSIDERATIONS • Repairing asymptomatic AAAs smaller than 5.5 cm has not been shown to improve survival because the risk of rupture is lower than the risk of surgery.

• The results from multiple trials to date demonstrate no advantage to immediate repair for small AAA (4.0 to 5.5 cm), regardless of whether open or endovascular repair is used and, at least for open repair, regardless of patient age and AAA diameter. Thus, neither immediate open nor immediate endovascular repair of small AAAs is supported by the currently available evidence. • Five-yr survival remains poor after elective AAA repair despite advances in shortterm outcomes and is associated with AAA diameter and patient age at the time of surgery. Research in this field should attempt to improve the life expectancy of patients with repaired AAA and to optimize patient selection.

COMMENTS • Most AAAs are infrarenal. This is thought to be due in part to decreased lamellar structural proteins in the vascular wall below the renal arteries leading to decreased vascular wall strength. • Surgical risk is increased in patients with coexisting coronary artery disease, pulmonary disease, or chronic renal failure. Evaluation for ischemia and aggressive perioperative hemodynamic monitoring help identify high-risk patients and decrease postoperative complications. • It is estimated that AAAs at 5 cm expand at a rate of 0.3 to 0.5 cm/yr. SUGGESTED READINGS Available at ExpertConsult.com RELATED CONTENT Abdominal Aortic Aneurysm (Patient Information) AUTHORS: Ryan J.W. Burris, MD, and Pranav M. Patel, MD, FACC, FAHA, FSCAI

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Abdominal Aortic Aneurysm SUGGESTED READINGS Badger S et al: Endovascular treatment for ruptured abdominal aortic aneurysm, Cochrane Database Syst Rev 5:CD005261, 2017. Brewster DC et al: Guidelines for the treatment of abdominal aortic aneurysms, Report of a subcommittee of the Joint Council of the American Association for Vascular Surgery and Society for Vascular Surgery, J Vasc Surg 37:11061117, 2003. Cantisani V et al: EVAR: benefits of CEUS for monitoring stent-graft status, Eur J Radiol 84(9):1658-1665, 2015. De Bruin JL et al: Long-term outcome of open or endovascular repair of abdominal aortic aneurysm, N Engl J Med 362:1863-1871, 2010. Filardo G et al: Surgery for small asymptomatic abdominal aortic aneurysms, Cochrane Database Syst Rev 8(2):CD001835, 2015. IMPROVE Trial Investigations: Comparative clinical effectiveness and cost effectiveness of endovascular strategies vs. open repair for ruptured abdominal aortic aneurysms. Three year results of the IMPROVE randomized trial, BMJ 359:148-159, 2017. Jackson RS et al: Comparison of long-term survival after open vs endovascular repair of intact abdominal aortic aneurysm among Medicare beneficiaries, JAMA 307(15):1621-1628, 2012. Kayssi A et  al: Health-related quality-of-life outcomes after open versus endovascular abdominal aortic aneurysm repair, J Vasc Surg 62(2):491-498, 2015. Kent KC: Abdominal aortic aneurysms, N Engl J Med 371:2101-2108, 2014. Kent KC et al: Analysis of risk factors for abdominal aortic aneurysm in a cohort of more than 3 million individuals, J Vasc Surg 52:539-548, 2010. Kouvelos G et al: Late open conversion after endovascular abdominal aortic aneurysm repair, J Vasc Surg 61(5):1350-1356, 2015. Lederle FA et  al: Long-term comparison of endovascular and open repair of abdominal aortic aneurysm, N Engl J Med 367:1988-1997, 2012. Lederle FA, Noorbaloochi S, Nugent S, et al: Multicentre study of abdominal aortic aneurysm measurement and enlargement, Br J Surg 102:1480-1487, 2015. Lederle FA et al: Open versus endovascular repair of abdominal aortic aneurysm, NEJM 380:2126-2135, 2019. Lefevre ML: Screening for abdominal aortic aneurysm: US Preventive Services Task Force Recommendation Statement, Ann Intern Med 161:281-290, 2014. Li B et al: A systematic review and meta-analysis of the long-term outcomes of endovascular versus open repair of abdominal aortic aneurysm, J Vasc Surg 70(3):954-969, 2019.

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Mohan PP, Hamblin MH: Comparison of endovascular and open repair of ruptured abdominal aortic aneurysm in the United States in the past decade, Cardiovasc Intervent Radiol 37(2):337-342, 2013. Norman PE et al: Understanding the effects of tobacco smoke on the pathogenesis of aortic aneurysm, Arterioscler Thromb Vasc Biol 33(1473), 2013. Ou J et al: A systematic review of fenestrated endovascular repair for juxtarenal and short-neck aortic aneurysm: evidence so far, Ann Vasc Surg 29(8):16801688, 2015. Paravastu SCV et al: Endovascular repair of abdominal aortic aneurysm, Cochrane Database Syst Rev 1:CD004178, 2014. RESCAN Collaborators et  al: Surveillance intervals for small abdominal aortic aneurysms: a meta-analysis, JAMA 309(8):806-813, 2013. Rooke TW et al: 2011 ACCF/AHA Focused update of the guideline for the management of patients with peripheral artery disease (updating the 2005 guideline), J Am Coll Cardiol 58(19):2020-2045, 2011. Sweeting MJ, et al: Ruptured Aneurysm Trialists, Ruptured Aneurysm Trials: the importance of longer-term outcomes and meta-analysis for 1-year mortality, Eur J Vasc Endovasc Surg 50(3):297-302, 2015. Takayama T, Yamanouchi D: Aneurysmal disease: the abdominal aorta, Surg Clin N Am 93:877, 2013. The United Kingdom EVAR Trial Investigators: Endovascular repair of aortic aneurysm in patients physically ineligible for open repair, N Engl J Med 362:18721880, 2010. The United Kingdom EVAR Trial Investigators: Endovascular versus open repair of abdominal aortic aneurysm, N Engl J Med 362:1863-1871, 2010. Thomas DM et al: Open versus endovascular repair of abdominal aortic aneurysm in the elective and emergent setting in a pooled population of 37,781 patients: a systematic review and meta-analysis, ISRN Cardiol 149243(2014), 2014. Wanhainen A et al: European Society for Vascular Surgery (ESVS) 2019 Clinical Practice Guidelines on the Management of Abdominal Aorto-iliac Artery Aneurysms, Eur J Vasc Endovasc Surg 57(1):8-93, 2019. Zhang L, Wang Y: B lymphocytes in abdominal aortic aneurysms, Atherosclerosis 242(1):311-317, 2015.

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Abdominal Compartment Syndrome BASIC INFORMATION DEFINITION Abdominal compartment syndrome (ACS) is defined by the presence of organ dysfunction as a result of increased abdominal pressure or intraabdominal hypertension. The increased abdominal pressure reduces blood flow to internal organs, which can lead to multiple system failure and death if not promptly recognized and treated. ICD-10CM CODE M79.A3 Nontraumatic compartment ­syndrome of abdomen

EPIDEMIOLOGY & DEMOGRAPHICS INCIDENCE: Very few studies have examined the incidence of ACS outside of trauma patients,

among whom it ranges from 1% to 14%, depending on the population and type of trauma studied. The incidence is the highest among critically ill patients. RISK FACTORS: The biggest risk factor for developing ACS is critical illness stemming from a wide array of medical and surgical conditions (Table E1). In particular, any illness that requires a patient to undergo large volume intravenous fluid resuscitation can be associated with ACS; the third-spacing of fluid can lead to increased intraabdominal pressures secondary to tissue edema. Due to large volume fluid resuscitation, ACS is commonly seen in severe burns, trauma, post-surgical patients, and sepsis. Other conditions associated with ACS include intraabdominal and retroperitoneal pathologies such as significant bowel distention, liver transplantation, massive ascites, ruptured abdominal aortic aneurysm with resulting hemoperitoneum, pancreatitis, and abdominal surgery (Table E2).

TABLE E1  Causes of Intraabdominal Hypertension and Abdominal Compartment Syndrome Increased Abdominal Contents

Decreased Abdominal Volume

Ascites Hemoperitoneum

Reduction of large long-standing hernia Direct closure of large, long-standing abdominal wall defect

Abdominal packs Peritonitis Retroperitoneal edema (pancreatitis) Large pelvic, retroperitoneal hematoma Intestinal obstruction Ileus Gastric distention (esophageal ventilation) Abdominal aortic aneurysm Severe constipation Large abdominal tumor (chronic) Morbid obesity (chronic) Pregnancy (chronic)

Retroperitoneal edema (pancreatitis) Large pelvic, retroperitoneal hematoma

PHYSICAL FINDINGS & CLINICAL PRESENTATION • The most striking physical examination finding is often massive abdominal distention. • Difficulty maintaining respiratory support and decreased urine output are also typical hallmarks. • Other common findings include those associated with poor perfusion states and hypotension such as skin mottling, cool extremities, and obtundation. Patients will often have abdominal tenderness, signs of volume overload such as edema and elevated jugular venous pressures, and may present with acute respiratory decompensation. ETIOLOGY ACS can affect nearly every organ system. High intraabdominal pressures are associated with increased intracranial pressures, which can precipitate cerebral ischemia. Elevated abdominal pressures can cause cardiac compression by decreasing ventricular compliance and contractility as well as impairing inferior vena cava venous return, leading to increased central venous and pulmonary pressures. Due to elevation of the diaphragm, patients will often have reduced tidal volumes and lower chest wall compliance, which can lead to atelectasis, pneumonia, hypoxemia, and hypercarbia. Mechanically ventilated patients will also require increased airway pressures that can lead to barotrauma. In addition, renal vein compression and renal artery vasoconstriction lead to decreased urine output. Reduced mesenteric blood flow can lead to intestinal ischemia and lactic acidosis.

DIAGNOSIS

From Vincent JL et al: Textbook of critical care, ed 6, Philadelphia, 2011, Saunders.

TABLE E2  Independent Predictors of Postinjury Primary and Secondary Abdominal Compartment Syndrome ED Model

ICU Model

Independent Predictors

Independent Predictors

Primary ACS

To OR 20 mm Hg, but patients may have ACS with pressures of >10 mm Hg and above. Oliguria tends to develop at a pressure of 15 mm Hg, and anuria occurs around 30 mm Hg. Intraabdominal pressures can also be estimated using intragastric, intracolonic, and inferior vena cava approaches (Table E3).

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Abdominal Compartment Syndrome

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TABLE E3  Classification of Abdominal Compartment Syndrome Basis of Classification Time frame Relation to peritoneal cavity Etiology

Subcategories Acute Chronic Primary Secondary Trauma Burn Postoperative Pancreatitis Bowel obstruction Ileus Abdominal aortic aneurysm Oncologic Gynecologic

FIG. E1  Open abdomen management of abdominal compartment syndrome. The sterile saline bag was sewn to the skin edges. Closed suction drains were placed to limit fluid accumulation, and occlusive dressing was applied to cover the abdominal wall. (Courtesy Brian J. Kimbrell, MD, In Vincent JL et al: Textbook of critical care, ed 7, Philadelphia, 2017, Elsevier.)

From Vincent JL et al: Textbook of critical care, ed 6, Philadelphia, 2011, Saunders.

LABORATORY TESTS Laboratory testing is generally not helpful for the diagnosis of ACS. The presence of lactic acidosis suggests bowel ischemia, which portends a poorer prognosis. IMAGING STUDIES Imaging alone has no diagnostic value in ACS, but chest imaging can be helpful to evaluate for diaphragmatic elevation and evidence of pulmonary complications (atelectasis, volume overload, pneumonia, etc.). Abdominal computed tomography imaging will sometimes show renal displacement, inferior vena cava compression, abdominal wall thickening, or bowel injury related to ischemia but should not be relied on to make the diagnosis of ACS.

TREATMENT Supportive care and, when appropriate, surgical abdominal decompression are the mainstays of ACS treatment.

NONPHARMACOLOGIC THERAPY • Supportive care, often with hemodynamic and ventilatory support, as well as techniques to improve abdominal wall compliance, are the foundations of ACS management. • Severe burns to the abdomen leading to ACS will require surgical escharotomy to improve abdominal wall compliance. • Patients with tense ascites leading to ACS will require large volume paracentesis to decrease intraabdominal pressures. • Patients should be positioned supine if possible as any elevation of the head will increase abdominal pressures. • Rectal and nasogastric decompression is required if ACS is due to massive bowel distention.

FIG. E2  Open abdomen management of abdominal compartment syndrome using a vacuumassisted closure (VAC) system. The bowel is covered with omentum if possible. Nonadherent dressing is layered under a VAC sponge, or a smaller pore sponge is used against the viscera. Negative pressure is applied to the wound closure to drain fluid, facilitate closure, and prevent evisceration. (Courtesy Brian J. Kimbrell, MD, In Vincent JL et al: Textbook of critical care, ed 7, Philadelphia, 2017, Elsevier.)

• Proper sedation and pain control can decrease intraabdominal pressures, and some patients may require ventilatory support and chemical paralysis to maximize abdominal wall relaxation. • Mechanical ventilation is often difficult due to the high pressures that need to be generated to overcome the increased intraabdominal pressures. Often a combination of low tidal volumes, permissive hypercapnia, chemical paralysis, and high positive end-expiratory pressure are required to ensure adequate ventilatory support. • Although there is little data to support its use, the administration of colloid may be superior to crystalloid if the patient requires further volume resuscitation. The administration of intravenous fluids will transiently increase renal blood flow, leading to increased urine output and improved organ perfusion and cardiac output. Pressors may also have a role to maintain perfusion pressures, but all of these measures are temporizing and supportive until definitive action through surgical decompression is performed.

• The threshold to perform surgical decompression for ACS has yet to be established; however, data suggest that early decompression prior to the development of ACS may lead to better outcomes. If appropriate, consensus dictates that surgical decompression should be performed on all patients with intraabdominal pressure >25 mm Hg; however, some surgeons are more aggressive and will consider decompression with pressures of 15 to 25 mm Hg in the right clinical setting. Surgical decompression (Fig. E1, Fig. E2) by incising vertically through the linea alba can be performed at the bedside in emergent situations and most surgeons will then keep the abdomen open through the use of a temporary abdominal closure device that retains heat/fluid and prevents evisceration until the time is appropriate to attempt to close the abdomen again.

ACUTE GENERAL Rx There are no direct pharmacologic agents that treat ACS other than pressors, sedatives, pain medications, and paralytics required for

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Abdominal Compartment Syndrome s­upportive care as described above. Despite underlying volume overload, diuretics have no role in therapy. Definitive management is surgical decompression.

DISPOSITION Close inpatient monitoring, preferably in an intensive care setting, is indicated as mortality can be extremely high (>40%) with ACS. REFERRAL Patients with ACS often require admission to an intensive care setting with surgical consultation in case decompression is required.

 EARLS & P CONSIDERATIONS COMMENTS • ACS is seen in critically ill medical and surgical patients, and its diagnosis requires both the presence of intraabdominal hypertension and end organ dysfunction. • ACS is truly a systemic illness that can lead to multisystem organ failure and is therefore associated with a high mortality. • Definitive diagnosis of ACS requires measurement of intraabdominal pressure, which

6.e4 is most frequently estimated using bladder pressure as a surrogate. • Supportive care, including hemodynamic support with colloids, pressors, and ventilatory support, is often required, but surgical decompression is the only definitive treatment. • Surgical decompression is indicated for intraabdominal pressures >25 mm Hg; however, precise thresholds have not been established, and earlier decompression may lead to better outcomes. AUTHOR: Jason D. Ferreira, MD

SUGGESTED READINGS Maluso P et al: Abdominal compartment hypertension and abdominal compartment syndrome, Crit Care Clin 32:213-222, 2016. Roberts DJ et al: Increased pressure within the abdominal compartment: intraabdominal hypertension and the abdominal compartment syndrome, Curr Opin Crit Care 22:174-185, 2016. Rogers WK et al: Intraabdominal hypertension, abdominal compartment syndrome and the open abdomen, Chest 153(1):238-259, 2018. Van Damme L et al: Effect of decompressive laparotomy on organ function in patient with abdominal compartment syndrome: a systematic review and ­meta-analysis, Crit Care 22(1):179, 2018.

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ALG BASIC INFORMATION

SYNONYMS Abnormal uterine bleeding (AUB) Dysfunctional uterine bleeding ICD-10CM CODES N92.5 Other specified irregular menstruation N92.0 Excessive and frequent menstruation with regular cycle N91.5 Oligomenorrhea, unspecified N92.1 Excessive and frequent menstruation with irregular cycle N94.6 Dysmenorrhea, unspecified

EPIDEMIOLOGY & DEMOGRAPHICS • Most cases of AUB result from uterine pathology (the PALM portion of the acronym). • Up to 20% of women presenting with heavy menstrual bleeding will be found to have a coagulopathy. PHYSICAL FINDINGS & CLINICAL PRESENTATION • Physical findings depend on the etiology. For example, an enlarged/irregular uterine contour may suggest fibroids, or a polyp may be seen on the cervix during a speculum examination. • The clinical presentation is also variable. Although many patients complain of the abnormality of their cycles, some will present with symptoms of anemia, with AUB being elicited only with a careful history. Patients may note recent weight gain or on examination, may have other findings (as noted later) suggestive of the etiology for their bleeding. • Thorough physical and pelvic examination to exclude the other causes of abnormal bleeding: 1. Includes thyroid, breast, liver (e.g., presence or absence of ecchymotic lesions) 2. Patient habitus: Obese and hirsute (polycystic ovarian disease) or thin (think eating disorders or excessive exercise) 3. Presence or absence of vulvar, vaginal, or cervical lesions, uterine (fibroid) or ovarian tumors, urethral caruncles or diverticula, hemorrhoids, anal fissures, colorectal lesions

TABLE 1  Definitions of Abnormal Uterine Bleeding Term

Description

Oligomenorrhea Polymenorrhea Hypermenorrhea (menorrhagia) Metrorrhagia Menometrorrhagia Withdrawal bleeding

Bleeding at intervals greater than 35 days Bleeding at intervals less than 21 days Excessive flow or bleeding with normal intervals Bleeding between menses Excessive flow or duration with periods and between periods Bleeding after the withdrawal of hormones

Crum CP et al: Diagnostic gynecologic and obstetric pathology, ed 3, Philadelphia, 2018, Elsevier.

TABLE 2  Causes of Abnormal Uterine Bleeding Age (Years)

Causes (In Order of Decreasing Frequency)

Prepubertal Adolescence

Precocious puberty (hypothalamic, pituitary, ovarian) • Disorders in the hypothalamic-pituitary axis (transient) • Disorders in folliculogenesis (transient) • Sexually transmitted infections, undiscovered pregnancy • Hematologic disorders (von Willebrand factors VII, XI) • Oral contraceptive pill-related • Postpregnancy • Benign organic lesions (polyps, leiomyomata, endometritis) • Anovulatory cycle • Anovulatory or altered cycle • Benign organic lesions (polyps, adenomyosis, leiomyomata, or endometritis) • Neoplasia • Hormone replacement therapy • Benign organic lesions (polyps, adenomyosis, leiomyomata, endometritis) • Atrophy • Neoplasia

Third and fourth decades Fifth decade Sixth decade

Crum CP et al: Diagnostic gynecologic and obstetric pathology, ed 3, Philadelphia, 2018, Elsevier.

4.  Bimanual pelvic examination: Normalsized or enlarged uterus, regular or irregular contour

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ETIOLOGY • Table 2 describes many of the various causes of AUB. The causes of AUB in the fourth and fifth decade are summarized in Table 3. • Endocrinopathies, including hyperprolactinemia and thyroid disorders, may also contribute to heavy or irregular menstrual bleeding.

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • PALM–COEIN: 1. Polyps (AUB-P) 2. Adenomyosis (AUB-A) 3. Leiomyoma (AUB-L) 4. Malignancy/hyperplasia (AUB-M) 5.  Coagulopathy (AUB-C; most commonly von Willebrand disease) 6. Ovulatory dysfunction (AUB-O; most commonly polycystic ovarian syndrome) 7. Endometrial (AUB-E) 8.  Iatrogenic (AUB-I; e.g., anticoagulants, hormonal contraception, and some herbal remedies) 9. Not yet classified (AUB-N) • Anatomic nonuterine causes: 1. Cervical neoplasia, cervicitis 2.  Vaginal neoplasia, adhesions, trauma, foreign body, atrophic vaginitis, infections, condyloma 3. Vulvar trauma, infections, neoplasia, condyloma, dystrophy, varices 4. Urinary tract: Urethral caruncle, diverticulum, hematuria 5. Gastrointestinal tract: Hemorrhoids, anal fissure, colorectal lesions • Systemic diseases/effects: 1.  Exogenous hormone intake: Hormone replacement therapy

Diseases and Disorders

DEFINITION Abnormal uterine bleeding (AUB) describes uterine bleeding that is abnormal in regularity, quantity, frequency, or duration, in the nonpregnant person. Historically, AUB was described as in Table 1. The term “dysfunctional uterine bleeding” was applied when no clear etiology could be identified. These terms have fallen out of favor. In 2011, the FIGO Working Group on Menstrual Disorders released a classification system intended to simplify these definitions. It is known by the acronym PALM-COEIN, described later. Today, AUB is described according to these criteria. A normal menstrual cycle is typically described as lasting 21 to 35 days with 5 days of bleeding per cycle. Total blood loss for normal menses is thought to be less than 80 ml.

Abnormal Uterine Bleeding

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TABLE 3  Causes of Abnormal Uterine Bleeding in the Fourth and Fifth Decades Cause

Differential Diagnosis

Anovulation

• Endometrial polyp • Basalis • Basalis/lower uterine segment • Tangentially sectioned functionalis • Atypical polypoid adenomyoma • Adenomyomatous polyp • Intraendometrial leiomyoma • Adenosarcoma • Late menstrual endometrium • Postpartum/postabortal endometrium • Cervical tissue (plasma cells) • Menstrual endometrium • Lymphoproliferative disorder • Progestin/tamoxifen therapy • Endometrial polyp • Stromal neoplasm

Endometrial polyp

Chronic endometritis

Submucosal leiomyoma

Crum CP et al: Diagnostic gynecologic and obstetric pathology, ed 3, Philadelphia, 2018, Elsevier.

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2. Medications 3. Coagulopathies: Von Willebrand disease, thrombocytopenia, hepatic failure 4. Endocrinopathies: Thyroid disorder, hyperprolactinemia, diabetes mellitus 5.  Renal diseases: Generally causing acquired coagulopathy 6.  Impaired nutritional status: Anorexia/­ bulimia • Section II describes a differential diagnosis of vaginal bleeding abnormalities.

WORKUP • Detailed history: 1. Age of menarche 2.  Prior menstrual characteristics (newly abnormal or always so) 3. Severity of bleeding 4. Surgical and medical history suggestive of other causes/contributors • Thorough physical examination, including a pelvic examination (bimanual and speculum) to exclude causes mentioned above • Includes thyroid, breast, liver (e.g., presence or absence of goiter, galactorrhea, or ecchymotic lesions) 1. Patient habitus: Obese and hirsute (polycystic ovarian disease) or thin (think eating disorders or excessive exercise) 2. Presence or absence of vulvar, vaginal, or cervical lesions, uterine (fibroid) or ovarian tumors, urethral caruncles or diverticula, hemorrhoids, anal fissures, or colorectal lesions LABORATORY TESTS (AS INDICATED BY HISTORY AND PHYSICAL) • Complete blood count with platelets to evaluate for possible iron-deficiency anemia or thrombocytopenia • Prothrombin/INR and partial thromboplastin (or PFA-100 assay) if coagulopathy is suspected • von Willebrand panel, particularly in women with heavy bleeding since menarche if initial testing suggests coagulopathy • Serum or urine human chorionic gonadotropin • Chemistry profile, including liver function tests • Thyroid profile • Pap smear if not up to date • Cultures for gonorrhea and chlamydia • Serum gonadotropins and prolactin • Serum androgens • Endometrial biopsy or dilation and curettage, especially in patients over 45, or in younger patients with a long-standing history of anovulatory bleeding with fewer than three menstrual cycles per yr or with a high risk of endometrial neoplasia with prolonged unopposed estrogen exposure • Stool testing for occult blood • Urinalysis for hematuria IMAGING STUDIES • Pelvic ultrasound, including measurement of endometrial thickness in the postmenopausal woman and assessment of myometrial or endometrial defects. This is considered first line.

ALG

• Fluid contrast ultrasound (also called saline sonogram, sonohysterogram, saline infusion sonogram, etc.) may be indicated if the endometrium appears thickened or irregular. It distends the uterine cavity so that “filling defects” of the endometrium can be assessed for possible endometrial polyp, uterine fibroid, or neoplasm. • Hysteroscopy may be performed to assess intracavitary fibroids or polyps. • Magnetic resonance imaging may help better characterize large fibroids or uterine pathology but is rarely needed.

TREATMENT NONPHARMACOLOGIC THERAPY • Increase iron intake in the form of pills and a diet rich in iron to combat anemia. • Initiate lifestyle changes, including weight loss, exercise, and low-carb diet, if indicated. ACUTE GENERAL Rx • Progestins: 1. Medroxyprogesterone acetate (oral), 10 to 20 mg daily for 15 days 2. Megestrol acetate, 40 to 120 mg daily in divided doses for 15 days 3. Oral contraceptives: One tablet tid for 5 to 7 days; patient should then continue on oral contraceptives daily • Estrogens: 1. Conjugated estrogen 25 mg IV q4h until bleeding is under control (in cases of severe or life-threatening bleeding); maximum 24 hr 2.  For prolonged bleeding that is not life threatening: Premarin 1.25 mg (Estrace 2 mg) q4h for 24 hr, followed by Provera to bring on withdrawal bleeding; then sequential regimen of estrogen and progestin (Premarin 1.25 mg qd for 24 days, Provera 10 mg for last 10 days) or oral contraceptives CHRONIC Rx • Progestins: 1.  Medroxyprogesterone acetate 10 mg daily for 12 days, then cyclically to induce monthly withdrawal bleeding 2. Norethindrone 2.5 to 10 mg qd for 12 days each mo or 0.35 mg daily (marketed as the “mini-pill”) 3. Depo-Provera 150 mg IM every 3 mo 4. Oral contraceptives, one tablet qd either cyclically or continuously using only active pills 5. Levonorgestrel-releasing intrauterine device (Mirena has an FDA indication for heavy menstrual bleeding) • Letrozole or clomiphene citrate: Not typically a treatment for abnormal bleeding but may help patients with anovulatory bleeding who want to become pregnant. Progesterone withdrawal may be counterproductive in patients wishing to start an ovulation induction regimen. Pregnancy rates are lower when patients undergo withdrawal compared to when random ovulation induction start

is used. Letrozole is superior to clomiphene citrate in ovulation induction in women with PCOS. Human menopausal gonadotropin (HMG) can be used for women who do not ovulate with oral agents or who have hypothalamic dysfunction. • Others: 1. Anti-prostaglandins (ibuprofen or naproxen sodium can reduce bleeding by 40%). 2. Danazol (rarely used due to side-effect profile). 3. Gonadotropin-releasing hormone (GnRH) analogues; often used to reduce bleeding and ameliorate anemia and in preparation for a surgical procedure. 4.  Tranexamic acid (Lysteda) is an antifibrinolytic agent FDA approved for cyclic heavy menstrual bleeding. Dosage in normal renal function is 3900 mg daily (650 mg tablets, 2 tablets tid) for up to five days during menses. 5. Endometrial tamponade with Foley catheter. • Surgical treatment: 1. Dilation and curettage and operative hysteroscopy 2. Endometrial ablation 3. Uterine artery embolization 4. Hysterectomy

DISPOSITION Cyclical treatment on birth control pills or Provera for several cycles, then discontinue pill and watch patient for onset of regular menses. If the patient does not want to conceive, continued cycle management with a hormonal contraceptive is commonly used. REFERRAL To gynecologist in case of failure of treatment

PEARLS & CONSIDERATIONS • Always get a pregnancy test. • If a young patient presents at menarche with bleeding severe enough to warrant emergency evaluation, there is a higher risk of a bleeding disorder, such as von Willebrand disease. • Endometrial sampling is indicated in patients over 45 yr of age with new AUB.

COMMENTS Patient education material may be obtained from the American College of Obstetricians and Gynecologists, 409 12th Street SW, Washington, DC 20024-2188; phone 202-638-5577. SUGGESTED READING Available at ExpertConsult.com RELATED CONTENT Abnormal Uterine Bleeding (Patient Information) Endometrial Cancer (Related Key Topic) Heavy Menstrual Bleeding (Menorrhagia) (Related Key Topic) Uterine Fibroids (Related Key Topic) AUTHOR: Nicole A. Roberts, MD

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Abnormal Uterine Bleeding

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SUGGESTED READING Munro MG et al: FIGO classification system (PALM-COEIN) for causes of abnormal uterine bleeding in nongravid women of reproductive age, Int J Gynaecol Obstet 113:3-13, 2011.

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  Abruptio Placentae BASIC INFORMATION

SYNONYM Premature separation of placenta ICD-10CM CODES O45.8X9 Other premature separation of placenta, unspecified trimester O45.8X1 Other premature separation of placenta, first trimester O45.8X2 Other premature separation of placenta, second trimester O45.8X3 Other premature separation of placenta, third trimester O45.91 Premature separation of placenta, unspecified, first trimester O45.92 Premature separation of placenta, unspecified, second trimester O45.93 Premature separation of placenta, unspecified, third trimester

EPIDEMIOLOGY & DEMOGRAPHICS INCIDENCE (IN U.S.): 9.6 per 1000 births; 80% occur before the onset of labor. RISK FACTORS: Hypertension (greatest association), trauma, polyhydramnios, multifetal

Partial separation (concealed hemorrhage)

Partial separation (apparent hemorrhage)

PHYSICAL FINDINGS & CLINICAL PRESENTATION • Triad of uterine bleeding (concealed or per vagina), hypertonic uterine contractions or signs of preterm labor, and evidence of fetal compromise exists. • More than 80% of cases have external bleeding; 20% of cases have no bleeding but have indirect evidence of abruption, such as failed tocolysis for preterm labor. • Tetanic uterine contractions are found in only 17%. ETIOLOGY • Primary etiology: Unknown • Hypertension: Found in 40% to 50% of grade III abruptions • Rapid decompression of uterine cavity, as can occur in polyhydramnios or multifetal gestation • Blunt external trauma (motor vehicle accident, spousal abuse)

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • Placenta previa • Cervical or vaginal trauma • Labor • Cervical cancer • Rupture of membranes • The differential diagnosis of vaginal bleeding in pregnancy is described in Section III WORKUP • Placental abruption is primarily a clinical diagnosis that is supported by laboratory, radiographic (Fig. 2), and pathologic studies. • Initial assessment should evaluate for the source of bleeding, ruling out placenta previa that may contraindicate any type of vaginal examination (e.g., pelvic speculum examination). • Continuous fetal heart monitoring is indicated for all viable gestations (60% incidence of

Complete separation (concealed hemorrhage)

FIG. 1  Classification of placental abruption. (From Magowan BA: Clinical obstetrics & gynecology, ed 4, 2019, Elsevier.)

fetal distress in labor); may show early signs of maternal hypovolemia (late decelerations or fetal tachycardia) before overt maternal vital sign changes. • Actual amount of blood loss is often greater than initially perceived because of the possibility of concealed retroplacental bleeding and apparent “normal” vital signs. The relative hypervolemia of pregnancy initially protects the patient until late in the course of bleeding, when abrupt and sudden cardiovascular collapse can occur.

LABORATORY TESTS • Baseline serum hemoglobin helps quantify blood loss and establish baseline values for serial comparisons during expectant management. • Coagulation profile: Platelets, fibrinogen, prothrombin, and partial thromboplastin time. Diffuse intravascular coagulation can develop with severe abruption. If fibrinogen is 8 hr after ingestion

REFERRAL Psychiatric referral is recommended after intentional ingestions. RELATED CONTENT Acetaminophen Overdose (Patient Information) AUTHOR: Rory Merritt, MD, MEHP

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Acetaminophen Poisoning

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TABLE E1  Four Stages of Acetaminophen Poisoning Stage 1 (0-24 hr)

Asymptomatic

Stage 2 (24-72 hr) Stage 3 (72-96 hr)

Onset of hepatotoxicity Maximal hepatotoxicity

Stage 4 (4 days to 2 wk)

Recovery phase

Patients are initially asymptomatic, with normal vital signs and no physical findings. Laboratory results are normal. Nonspecific complaints of nausea, vomiting, and malaise may start to develop near the end of this stage. Right upper quadrant abdominal pain may develop. Levels of AST, the most sensitive indicator of hepatotoxicity, and ALT begin to rise. Later, INR values may begin to rise and renal function to deteriorate. The patient exhibits clinical and laboratory manifestations of hepatic necrosis: Varying degrees of hepatic encephalopathy, jaundice, renal failure, coagulation defects, and myocardial abnormalities. AST and ALT levels peak, the INR value rises, blood urea nitrogen and creatinine levels rise, and pH drops. Death may occur, typically 3-5 days after overdose. Death from fulminant hepatic failure may be characterized by cerebral edema, sepsis, multisystem organ failure, hemorrhage, and acute respiratory distress syndrome. Patients who survive stage 3 undergo complete regeneration of the liver. Laboratory abnormalities typically return to normal 5-7 days after overdose.

ALT, Alanine transaminase; AST, aspartate transaminase; INR, international normalized ratio. From Adams J (ed), Barton E et al (associate eds): Emergency medicine: clinical essentials, ed 2, Philadelphia, 2013, Saunders.

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Acetaminophen Poisoning

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Acute APAP ingestion (irrespective of coingestant)

Presents to ED 4 hours but 5 cm) breaks in the 20-mm Hg IBC Frequent Failed Peristalsis 30% of absent swallows

Normal

FIG. 1  Algorithm for applying the Chicago Classification of esophageal motor disorders. CFV, Contractile front velocity; DCI, distal contractile interval; DL, distal latency; EGJ, esophagogastric junction; IBC, isobar contour; IRP, integrated relaxation pressure (see Table 2 for more details). (From Feldman M et al: Sleisenger and Fortran’s gastrointestinal and liver disease, ed 10, Philadelphia, 2016, Elsevier.)

TABLE 2  Chicago Classification of Esophageal Motility Disorders Diagnosis Achalasia Type I Type II Type III EGJ outflow obstruction Motility Disorders Distal esophageal spasm Hypercontractile esophagus (jackhammer esophagus) Absent peristalsis Peristaltic Abnormality Weak peristalsis Frequent failed peristalsis Rapid peristalsis Hypertensive peristalsis (nutcracker esophagus) Normal

Diagnostic Criteria 100% failed peristalsis, mean IRP >10 mm Hg No esophageal contraction and panesophageal pressurization with ≥20% of swallows; mean IRP >10 mm Hg Premature contractions with ≥20% of swallows, mean IRP ≥17 mm Hg Mean IRP ≥15 mm Hg; mix of normal, weak, rapid, hypertensive, failed peristalsis or panesophageal pressurization (Patterns not observed in normal individuals) Mean IRP 8000 mm Hg⋅s⋅cm Mean IRP ≤10 mm Hg, 100% failed peristalsis (Defined by exceeding statistical limits of normal) Mean IRP 30%, but 4.5 s Mean DCI >5000 mm Hg⋅s⋅cm, but not meeting criteria for hypercontractile esophagus Not achieving any of the above diagnostic criteria

DCI, Distal contractile interval; DL, distal latency; EGJ, esophagogastric junction; IRP, integrated relaxation pressure. From Feldman M, Friedman LS, Brandt LJ: Sleisenger and Fortran’s gastrointestinal and liver disease, ed 10, Philadelphia, 2016, Saunders.

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ALG TREATMENT NONPHARMACOLOGIC THERAPY • The goals of therapy are to decrease LES pressure to relieve the functional obstruction, relieve symptoms, and prevent progression to a dilated esophagus, sometimes referred to as a megaesophagus. Treatment does not improve esophageal peristalsis. Achalasia is treatable but incurable. • Pneumatic dilation (PD) to disrupt the LES muscle fibers may benefit 65% to 90% of patients. Multiple sessions may be required, and most protocols use a graded dilation approach, starting with a 30-mm balloon, and repeating if required with a 35-mm or 40-mm balloon. Some studies suggest this may be more effective in females, older patients, and particularly HRM type II patients. Esophageal rupture or perforation is a rare complication (2% to 4%) that may be managed conservatively in some stable patients with a small perforation. • Surgical: Laparoscopic, or less commonly, open Heller esophagomyotomy (HM) is effective (90%). Approximately 35% of patients undergoing surgery will develop reflux disease. As a result, some surgeons will perform a “loose” or partial antireflux repair (fundoplication) as part of the surgical procedure. Some studies suggest this may be more effective in men and younger patients. An observational study has suggested that those who have had prior endoscopic treatment before myotomy may not do as well as those who have a primary myotomy. • A large European study suggested that in experienced hands, patients may expect similar medium-term outcomes from myotomy and balloon dilation. A meta-analysis suggests better long-term durability of myotomy. Balloon dilation may be the more cost-effective treatment. A small percentage (20% to 30%) of patients undergoing either therapy may require re-treatment within 5 to 7 yr. • Endoscopic submucosal myotomy (per-oral endoscopic myotomy [POEM]) has a high success rate comparable to laparoscopic HM (particularly in HRM type III patients in whom a longer myotomy, tailored to the length of the diseased segment, improves outcome), few adverse events (which can include pneumomediastinum, pneumothorax, pneumoperitoneum, pleural effusion, pneumonia, and bleeding), and exceedingly rare mortality. Because no antireflux procedure is performed, there is a modest risk (up to 53%) of developing pathologic reflux. It should only be performed at high-volume centers. A randomized multicenter study showed a higher treatment success rate for POEM at 2 years when compared with pneumatic dilation. • FLIP and timed barium esophagogram may help determine response to therapy.

• Esophagectomy has been performed in patients with end-stage achalasia with a dilated, often sigmoid-shaped or megaesophagus, who have failed myotomy or pneumatic dilation.

ACUTE GENERAL Rx • Medications may be useful for short-term symptom relief and in patients with refractory chest pain. They should only be considered in patients unable to receive, or who are scheduled for, more definitive procedures. LES pressure may be lowered by up to 50% through sublingual use of long-acting nitrates (e.g., isosorbide dinitrate 5 to 20 mg) or calcium channel blockers (e.g., nifedipine 10 to 30 mg). Side effects are common and duration of relief tends to be short. Sildenafil was shown to be effective in a few small, short-term studies, but it is generally not recommended. • Botulinum toxin injection will benefit up to 85% of patients by inhibiting acetylcholine release from cholinergic nerve endings, blocking the unopposed cholinergic stimulation of the LES, but having no impact on the myogenic tone. Up to half of these patients will require repeat injections by 6 months. A few studies have suggested that repeated injections may have diminished efficacy and can lead to fibrosis, which may complicate subsequent attempts at surgical therapy. • Many patients will require proton pump inhibitor therapy for gastroesophageal reflux after effective disruption of the LES.

15

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Diseases and Disorders

• An acutely tapered contrast column (“bird’s beak”; Fig. E2) • Dilation of the distal esophagus (smooth muscle portion) • Esophageal air-fluid level with evidence of poor esophageal emptying • Late-stage changes include tortuosity, angulation, dilated megaesophagus, retained food, and secretions Manometry is considered the “gold standard” test to confirm the diagnosis. • In classic achalasia (type I achalasia), conventional manometric abnormalities include low-amplitude disorganized contractions/ aperistalsis, incomplete or absent LES relaxation (with residual pressure >10 mm Hg) after swallow, and high resting LES pressure. • A subset of patients with “vigorous achalasia” may have high-amplitude, long-duration, simultaneous esophageal contractions. This term is now thought to be imprecise because of a newer classification of the disease. • High-resolution manometry (HRM), or highresolution esophageal pressure topography (HREPT), has defined subsets of patients with achalasia who may have different responses to medical or surgical therapies and prognoses. Unlike type I achalasia, type II achalasia shows panesophageal pressurization to greater than 30 mm Hg with ≥20% of test swallows, and type III achalasia shows spastic, lumen-obliterating contractions of the distal esophagus with ≥20% of swallows. This technique uses the integrated relaxation pressure (IRP) >15 mm Hg to define better the failure of esophagogastric junction relaxation. HRM also utilizes the distal contraction integral (DCI) to define hypercontractile vs. weak swallows vs. failed peristalsis. The distal latency (DL) defines premature contractions, seen with diffuse esophageal spasm and type III achalasia. • HREPT has also defined an achalasia variant described as esophagogastric junction outflow obstruction, where the IRP is >15 mm Hg, but peristalsis is present. Some are associated with secondary causes; a small percentage may progress to achalasia; and, in many, the natural history is unclear and response to therapy is variable. • Direct visualization by endoscopy, including careful visualization of the esophagogastric junction and cardia, should be performed to exclude other causes of dysphagia, including “functional esophagogastric junction obstruction,” strictures, secondary causes of achalasia (including infiltrating cancers), and pseudoachalasia. • Functional luminal imaging probe (FLIP) technology is a new technique that can measure compliance and distensibility across the esophagogastric junction and may demonstrate both impaired LES relaxation and response to achalasia therapy.

Achalasia

I

PEARLS & CONSIDERATIONS COMMENTS • Medication has a limited role in treatment. • Botulinum toxin is transiently effective in improving symptoms. • Pneumatic dilation, surgical myotomy, and POEM provide more durable long-term responses and are the treatment of choice for most patients. Botulinum toxin should be considered primarily in patients too elderly or ill to be considered for these other therapies. • Patients with achalasia may be at long-term risk of squamous cell carcinoma of the esophagus and non–reflux-associated esophagitis. Treated patients may be at long-term risk for reflux esophagitis, Barrett esophagus, and adenocarcinoma. Endoscopic surveillance is not routinely recommended in these patients. SUGGESTED READINGS Available at ExpertConsult.com RELATED CONTENT Achalasia (Patient Information) Dysphagia (Related Key Topic) AUTHOR: Harlan G. Rich, MD, FACP, AGAF

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Achalasia

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FIG. E2  Classic appearance of achalasia of the esophagus. The dilated esophagus ends in a narrow segment. (From Hoekelman R [ed]: Primary pediatric care, ed 3, St Louis, 1997, Mosby.)

SUGGESTED READINGS Boeckxstaens GE et al: Pneumatic dilatation versus laparoscopic Heller’s myotomy for idiopathic achalasia, N Engl J Med 364:1807-1816, 2011. Bredenoord AJ et  al: Chicago classification criteria of esophageal motility disorders defined in high resolution esophageal pressure topography, Neurogastroenterol Motil 24(Suppl 1):57-65, 2012. Furuzawa-Carballeda J et al: Achalasia—an autoimmune inflammatory disease: a cross-sectional study, J Immunol Res 2015:729217, 2015. Inoue Het al et al: Per-oral endoscopic myotomy: a series of 500 patients, J Am Coll Surg 221:256, 2015. Kahrilas PJ et al: The spectrum of achalasia: lessons from studies of pathophysiology and high-resolution manometry, Gastroenterology 145:954, 2013. Kahrilas PJ et al: Treatments for achalasia in 2017: how to choose among them, Curr Opin Gastroenterol 33(4):270-276, 2017. Kane ED et al: Myotomy length informed by high-resolution esophageal manometry (HREM) results in improved per-oral endoscopic myotomy (POEM) outcomes for type III achalasia, Surg Endosc, 2018 Jul 27, https://doi. org/10.1007/s00464-018-6356-0. [Epub ahead of print]. Katzka DA et al: Review article: an analysis of the efficacy, perforation rates and methods used in pneumatic dilation for achalasia, Aliment Pharmacol Ther 34:832, 2011. Ponds FA: Effect of peroral endoscopic myotomy vs pneumatic dilation on symptom severity and treatment outcomes among treatment-naive patients with achalasia: a randomized clinical trial, JAMA 322(2):134-144, 2019. Richter JE: Achalasia—an update, J Neurogastroenterol Motil 16:232-242, 2010. Roman S et  al: The Chicago classification of motility disorders: an update, Gastrointest Endosc Clin N Am 24:545, 2014. Vaezi MF et  al: Achalasia: from diagnosis to management, Ann NY Acad Sci 1381(1):34-44, 2016, https://doi.org/10.1111/nyas.13176. Werner YB et al: Endoscopic or surgical myotomy in patients with idiopathic achalasia, N Engl J Med 381:2219-2229, 2019.

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15.e2

Achilles Tendon Rupture  BASIC INFORMATION DEFINITION Achilles tendon rupture is a disruption of the continuity of the Achilles tendon that either occurs as a result of forced dorsiflexion of the foot in plantar flexion or forced plantar flexion against resistance. ICD-10CM CODES S86.0 Unspecified injury of Achilles tendon S86.012 Achilles tendon rupture left S86.011 Achilles tendon rupture right M66.871 Non traumatic Achilles tendon rupture right M66.872 Non traumatic Achilles tendon rupture left

EPIDEMIOLOGY & DEMOGRAPHICS INCIDENCE: In the general population, Achilles tendon ruptures occur in 18 per 100,000 individuals per year and are the most common large tendon ruptures, accounting for 20% to 35% of all large tendon injuries in the human body. They can often be missed and initially diagnosed as an ankle sprain. PEAK INCIDENCE: 30- to 40-year-old males PREDOMINANT AGE: 30- to 55-years-old RISK FACTORS: General risk factors include recreational athletes, stop-and-go sports (e.g., basketball, tennis, and soccer), preexisting Achilles tendinopathy, increase in duration or intensity of running, advanced age, male gender, and poor running mechanics. Fluoroquinolone antibiotics have been associated with Achilles tendon ruptures, with an incidence of 12 per 100,000. This is more likely to occur in first-time users of fluoroquinolones and usually occurs within the first 90 days of therapy. Additionally, corticosteroid use has been implicated in Achilles tendon rupture. CLINICAL PRESENTATION A classic presentation for acute Achilles tendon rupture is a middle-aged male who participates in strenuous activities involving sudden pivoting on a foot or rapid deceleration as in recreational sports. A popping sensation of the tendon may be described by some patients, followed by an acute onset of severe pain in the calf and lower leg. Patients who also attempt new strenuous activities without proper training and stretching or who typically lead a sedentary lifestyle are more likely to experience Achilles tendinopathy, including ruptures. It is important to note that pain is not always an initial presenting symptom. PHYSICAL FINDINGS A palpable defect in the posterior distal third of the Achilles tendon may be appreciated with palpation. Depending on the severity of the rupture, pain, ecchymosis and diffuse edema may be noted. The patient may present with an antalgic gait and the inability to perform a single heel raise on the injured limb secondary

to weakened plantar flexion power. Additionally, the patient may not be able to plantarflex against resistance. Having them lie prone with their legs off the examination table may show their injured side to be more dorsiflexed compared to the contralateral side and squeezing the affected calf will not produce plantarflexion of the foot.

ETIOLOGY/MECHANISM OF INJURY Indirect trauma is most often associated with Achilles tendon ruptures, which typically fall under three categories: mechanical, vascular, and poor tissue quality. • Mechanical: Involves variations of a rapid loading process on an already tensed tendon such as a sudden dorsiflexion of the ankle with the knee extended while an eccentric load is applied. • Vascular: Located 2 to 6 cm proximal to the Achilles tendon insertion is a known area of hypo vascularity. • Poor tissue quality: Tendonitis, which is inflammation that occurs within the tendon after an acute injury, and tendinosis, which is a degeneration process from repetitive tears related to chronic injuries, are known to weaken the tendon before it is ruptured. This often occurs in the form of repetitive microtrauma from improper training techniques.

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • Achilles tendinopathy (tendinosis tendonitis) • Retrocalcaneal bursitis • Ankle sprain • Calcaneal avulsion fracture • Partial rupture of gastrocnemius • Plantaris rupture • Os trigonum syndrome • Calcaneal apophysitis

vs.

WORKUP A thorough history and physical examination, along with a high clinical suspicion, is key to distinguishing Achilles tendon ruptures from other Achilles tendinopathies. The clinical history in most presentations is very specific, and the physical examination is usually diagnostic. The following is a list of specific clinical tests and imaging modalities. • Thompson test (Fig. E1): Also known as the “calf squeeze test,” it is an accurate means of detecting Achilles tendon ruptures. The patient is placed in a prone position with the knee flexed. While squeezing the gastrocnemius, the clinician evaluates for the presence or absence of ankle plantar flexion. If ankle plantar flexion is absent, the test is said to be positive and indicative of Achilles tendon rupture. • Matles test (knee flexion test): The test is an additional physical examination finding utilized to assess Achilles tendon ruptures. The patient is placed in the prone position

with the knees flexed at 90 degrees. If the injured foot falls in an increased dorsiflexed position instead of a resting plantar flexed position when compared to the contralateral limb, the test of the injured limb is positive for Achilles tendon rupture.

IMAGING STUDIES • Ultrasound imaging may be used to assess Achilles tendinopathy and is considered by some the first-line imaging modality. Ultrasound provides clinicians with a practical means of evaluating Achilles tendinopathy and ruptures at the bedside. • MRI (Fig. E2) is often utilized to further evaluate Achilles tendinopathy, especially ruptures. Discontinuity of the Achilles tendon can be seen on T2-weighted images, where the signal in the tendon is increased at the area of rupture and the tendon diameter is increased. MRI provides greater anatomic detail as well as greater accuracy in detecting partial Achilles tendon tears. MRI has proved to be superior to ultrasound in defining ruptures histologically.

TREATMENT Initial treatment should consist of the RICE protocol (rest, ice, compression to reduce swelling, and elevation). Adequate analgesics for at-home use can include acetaminophen and/ or nonsteroidal antiinflammatory drugs. The patient should also be placed into a posterior slab splint with the foot in resting equinus (held at its natural plantarflexed position). The typical course of immobilization of the injured limb ranges from a minimum of 8 to 12 weeks. Over the past few years there has been a trend in nonoperative management of Achilles tendon ruptures that include accelerated protocol to rehabilitation. These accelerated protocols have been shown to improve outcomes of nonoperative Achilles tendon management. These protocols have the patient non–weight bearing in a posterior splint or short leg cast in equinus with crutches for 2 weeks. A controlled ankle motion walker with special sequential heel wedges then follows this for the next 4 weeks of non–weight bearing with crutches. After 4 to 6 weeks the patient may return to regular shoe gear, with a heel wedge modification for an additional 2 months. During this period, it is recommended that patients start resistance exercises, proprioception and gait retraining, and sport retraining.

SURGICAL TREATMENT If surgical intervention is warranted, it should be done within 4 weeks of the initial injury, although within 7 to 14 days of injury is ideal. Proper timing of surgical repair is imperative to postsurgical recovery. The inflammatory phase of wound healing occurs within the first 7 to 14 days following an acute Achilles tendon rupture. During this phase, vascularity to the injured tendon increases, aiding in postoperative healing.

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Achilles Tendon Rupture

15.e3

NORMAL

RUPTURED ACHILLES TENDON Palpation of tendon Palpable gap

No palpable gap

Calf squeeze test

Ankle plantarflexes

No movement

Knee flexion test (Matles test)

Ankle >90°

Ankle 80 portends a high risk of death at initial presentation of a STEMI.

Diseases and Disorders

Class

I

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32

Acute Coronary Syndrome Symptoms concerning for ACS5

A – High risk for STEMI B – High risk for UA/NSTEMI C – Intermediate risk D – Low risk E – Very low risk

History Physical examination 12-lead ECG A STEMI or new LBBB

PCI

B

C

D

E

• CP/anginal equivalent4 with h/o CAD, CRI, PVD, age ≥70, or high clinical suspicion • ST ∆s ≥0.5 mm; resolve when asymptomatic • ST depression ≥1 mm in 2 leads • T wave inversion ≥2 mm in 2 leads • Positive cardiac markers

• Age >55 M; >65 F, typical angina1 or intermediate suspicion • No new significant ECG changes6 • Normal cardiac markers

• Atypical chest pain, low clinical suspicion • No new significant ECG changes6 • Normal cardiac markers

Clearly noncoronary

Admit to heart ED

• Cardiac markers/ECG at 0/90/180 min2 • Repeat ECG with recurrent/persistent symptoms

PCP follow-up

• Cardiac markers/ECG at 0/90/180 min2 • Repeat ECG with recurrent/persistent symptoms

• Cardiac markers/ECG at 0 min/4 hr/8 hr2 • Repeat ECG with recurrent/persistent symptoms

Active CP or CP in past 2 hours

No

• Admit to heart ED OR • Discharge with PCP follow-up for outpatient stress test

Yes • Medical management • Admit to Cardiology

Abnormal

• Medical management • Admit to Cardiology

Normal

Rest myocardial perfusion imaging with Tc 99m9

• Arrange stress test • Collaborate with Cardiology • See stress test algorithm

Results normal?

Yes

PCP follow-up with outpatient stress test

No

• Medical management • Admit to Cardiology 5ACS:

DEFINITIONS: 1Typical angina:

(1) Substernal chest pain or discomfort that is (2) provoked by exertion or emotional stress and (3) relieved by rest and/or nitroglycerin 2Cardiac marker timing: Based on symptom onset; in cases of uncertainty

assume symptom onset at ED arrival

3ECG normal: No significant ST depression/T wave inversions, BBB, LVH

with repolarization, conduction defect, digoxin effect

4Anginal equivalent:

• Any symptoms that the physician feels may represent ACS • Exertional dyspnea—most common anginal equivalent symptom

• STE-ACS—1 mm ST elevation in 2 leads • NSTE-ACS – NSTEMI—positive cardiac biomarkers – Unstable angina—ischemia with negative biomarkers

6New significant ECG changes:

• ST ∆s ≥0.5 mm; resolve when asymptomatic • ST depression ≥1 mm in 2 leads • T wave inversion ≥2 mm in 2 leads

7Regadenoson is preferred agent for chemical nuclear stress test.

Technetium Tc-99m tetrofosmin is the preferred tracer.

FIG. 1  Evaluation of patients for acute coronary syndrome (ACS). CAD, Coronary artery disease; CP, chest pain; CRI, chronic renal insufficiency; ECG, electrocardiogram; ED, emergency department; h/o, history of; LBBB, left bundle branch block; NSTE, non–ST-segment elevation; NSTEMI, non–ST-segment elevation myocardial infarction; PCP, primary care physician; PVD, peripheral vascular disease; STE, ST-segment elevation; STEMI, ST-segment elevation myocardial infarction; UA, unstable angina. (From Adams JG et al: Emergency medicine, clinical essentials, ed 2, Philadelphia, 2013, Elsevier.)

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Acute Coronary Syndrome mal initial treatment, signs or s­ymptoms of heart failure, new or worsening mitral regurgitation, hemodynamic instability, sustained ventricular tachycardia or ventricular fibrillation

FIG. 4  Right coronary artery after successful percutaneous coronary artery stenting during ST-elevation myocardial infarction.

3. D  elayed invasive (25 to 72 hours): None of the immediate or early characteristics but renal insufficiency, left ventricular ejection fraction of 140 or temporal change in troponin

33

I

TABLE 3  Summary of Recommendations for Standard Medical Therapy in the Early Hospital Care Phase of Management of Patients with Non–ST-Elevation Acute Coronary Syndromes (NSTE-ACS) Recommendations

COR

LOE

I

C

I I III: Harm

C B B

IIb III: Harm

B B

I

A

I

C

I IIa III: Harm

C C B

I

B

I

C

I I III: Harm

C C B

I IIa

A C

Oxygen Administer supplemental oxygen only with oxygen saturation 0.24 sec, or second- or third-degree atrioventricular block without a cardiac ­pacemaker. Administer oral nondihydropyridine calcium antagonists with recurrent ischemia after use of beta blocker and nitrates in the absence of contraindications. CCBs are recommended for ischemic symptoms when beta blockers are not successful, are contraindicated, or cause unacceptable side effects.* Long-acting CCBs and nitrates are recommended for patients with coronary artery spasm. Immediate-release nifedipine is contraindicated in the absence of a beta-blocker. Cholesterol Management Initiate or continue high-intensity statin therapy in patients with no contraindications. Obtain a fasting lipid profile, preferably within 24 hr.

*Short-acting dihydropyridine calcium channel antagonists should be avoided. COR, Class of recommendation; HF, heart failure; IV, intravenous; LOE, level of evidence; LV, left ventricular; MACE, major adverse cardiovascular events; N/A, not available; NSAIDs, nonsteroidal antiinflammatory drugs; NTG, nitroglycerin. From Amsterdam EA et al: 2014 AHA/ACC guideline for the management of patients with non–ST-elevation acute coronary syndromes: A report of the American College of Cardiology/American Heart Association task force on practice guidelines. J Am Coll Cardiol 64:e139-228, 2014 in Zipes DP: Braunwald’s heart disease, a textbook of cardiovascular medicine, ed 11, Philadelphia, 2019, Elsevier.

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34

Acute Coronary Syndrome of ACS. This consists of administering antiplatelet and anticoagulant agents (Table 5). • Antiplatelet agents (Table 6) inhibit platelet activation and aggregation. Aspirin is a cyclooxygenase inhibitor that blocks platelet aggregation and should be administered to all ACS patients without contraindications. • All patients with ACS should receive fulldose non–enteric-coated chewable aspirin of 162 to 325 mg to establish a high blood level for its antiplatelet effects. Thereafter, daily dose of 81mg should be continued indefinitely. • Clopidogrel is a thienopyridine agent that inhibits platelet activation and aggregation. It should be administered in all ACS patients, with the timing dependent on the clinical scenario and management strategy. It requires a loading dose of 300 to 600 mg followed by 75 mg daily. It should be discontinued at least 5 days before CABG. If a patient is unable to take aspirin in the setting of hypersensitivity or major gastrointestinal

intolerance, a loading dose of clopidogrel followed by daily maintenance should be started. • Other antiplatelet agents that can be substituted instead of clopidogrel include prasugrel and ticagrelor. Ticagrelor has a half-life of 12 hours with a more rapid onset and more consistent onset of action. There was a reduction in death from vascular causes, MI, and stroke in patients with NSTE-ACS over clopidogrel. This benefit is limited to patients taking aspirin 75 to 100 mg per day. Prasugrel is not recommended in patients with NSTE-ACS. Multiple studies have demonstrated an increase in bleeding in patients taking Prasugrel, in particular those with a history of cerebrovascular events. Cangrelor is an IV ADP-P2Y12 receptor antagonist that may be used initially as a load in the emergency department before an invasive strategy, given its initial action and quick platelet recovery time. As a rule, all ACS patients should have two antiplatelet agents initiated and should be continued up to 12 mo

regardless of ischemia-guided vs. invasive strategy. • GP IIB/III a inhibitors (Table 7) may be considered as an intravenous antiplatelet therapy in addition to aspirin for medium- or high-risk patients with NSTE-ACS in whom an invasive strategy is planned (Class IIb). Eptifibatide and tirofiban are preferred agents over abciximab for NSTEACS patients; however, for STEMI patients undergoing primary PCI, IV abciximab has the same Class IIa indication as tirofiban and eptifibatide. • Anticoagulant agents should be administered to all ACS patients, irrespective of initial treatment strategy. Options include either unfractionated heparin (UFH), or ­low-molecular-weight heparin (enoxaparin), or factor Xa inhibitors such as fondaparinux, or direct thrombin inhibitors such as bivalirudin (Table 8). • For STEMI, fondaparinux can be used for anticoagulation. It has been shown to decrease bleeding complications as compared with either UFH or LMWH. However, it should not

TABLE 4  Summary of Recommendations for Antithrombotic Therapy Recommendations

Dosing, special considerations

COR

LOE

162-325 mg 81-325 mg/day*

I I

A A

75 mg

I

B

I

B

300- or 600-mg loading dose, then 75 mg/day 180-mg loading dose, then 90 mg twice daily N/A

I

B

N/A

IIa

B

Preferred options are eptifibatide or tirofiban

IIb

B

1 mg/kg SC every 12 hr (reduce dose to 1 mg/kg/day SC in patients with CrCl females; European ancestry slightly > African ancestry

PHYSICAL FINDINGS & CLINICAL PRESENTATION Symptoms/exam findings: • Complications of bone marrow failure: 1. Thrombocytopenia-associated bleeding 2. Fatigue and shortness of breath associated with anemia 3. Infection associated with neutropenia • Complications of leukocytosis (hyperleukocytic leukemia, WBC >100,000/mcl): 1.  Retinal hemorrhage with visual symptoms 2. Headache and intracranial bleeding 3.  Respiratory symptoms from pulmonary involvement • Systemic symptoms: 1. Fatigue, fever (usually infectious, rarely tumor), bone pain (more common in ALL) • Hemorrhagic complications of disseminated intravascular coagulation (DIC), especially with acute promyelocytic leukemia (APML) • Physical exam will reflect consequences of cytopenias (bruising from thrombocytopenia, pallor from anemia). Enlarged lymph nodes and enlarged liver and spleen are rare. Exam is often normal • Rarely disease will present as skin lesions (leukemia cutis) or mass lesions (granulocytic sarcoma) • Gum hypertrophy and organ/skin involvement is more common in monocytic leukemia ETIOLOGY • Environmental/exposure related: Benzene (best documented), organic solvents (including gasoline), cigarette smoking (≥20 pack-yr 1.34 relative risk), obesity, best documented in women • Hereditary disorders: Numerous, including Fanconi anemia, Bloom syndrome, Schwachman Diamond syndrome, Diamond Blackfan anemia, among others • Therapy related: 1. Alkylator (e.g., melphalan, busulfan, cisplatin) related: Typical latency 5 to 7 yr, associated with chromosome 5 and 7 abnormalities 2. Topoisomerase II inhibitor (e.g. etoposide, doxorubicin): Typical latency 1 to 3 yr, associated with 11q23 (mixed lineage leukemia [MLL] gene) rearrangements • Radiation exposures (therapeutic—generally low risk), occupational • A ntecedent hematologic disorders: Myelodysplasia, myeloproliferative disorders, aplastic anemia

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • Disorders that can present with circulating blasts or cells with blastlike appearance: 1. Acute myeloid leukemia/acute lymphocytic leukemia 2.  Myelodysplasia (up to 20% circulating blasts, if ≥20% = AML)



3. Primary myelofibrosis 4. Chronic myeloid leukemia 5. Blastoid variant of mantle cell lymphoma 6. Prolymphocytic leukemia 7. Blastic plasmacytoid dendritic cell neoplasm 8. Atypical lymphocytes of Epstein-Barr and cytomegalovirus infection may have blastlike appearance

WORKUP The diagnostic workup consists of a morphologic assessment, immunophenotyping by flow cytometry, assessment of karyotype, and a panel of gene mutations (Fig. 1). LABORATORY TESTS • Complete blood counts and blood smear evaluation. Note that morphologic evaluation of blasts may suggest myeloid or lymphoid origin, but flow cytometry or cytochemistries (often faster) are needed to confirm. Auer rods are seen in blasts of myeloid origin. • LDH is commonly elevated. Other biochemistries to assess organ function (creatinine, liver enzymes) and spontaneous tumor lysis syndrome (uric acid, potassium, phosphate, calcium). • Coagulation studies to assess DIC. DIC is always present in APML, but can be present in all forms of acute leukemia, especially acute monocytic leukemia. • HLA typing for possible bone marrow transplant and platelet support. • Cytochemical stains: 1.  Myeloperoxidase can be performed in minutes, + in myeloid origin leukemia. 2. Alpha naphthyl acetate esterase (“nonspecific esterase”) stains mainly monocytic cells. • Flow cytometry on blood and/or bone marrow (see Table E1). • Cytogenetic studies, ideally on bone marrow, but can be done on peripheral blood. Fluorescence in situ hybridization (FISH) is often used as an adjunct to conventional chromosome analysis. • Next Generation Sequencing (NGS) by PCR to detect specific prognostic gene mutations • Molecular studies to further stratify risk and prognosis, which may affect treatment choices (see Tables E2, 3, and 4). Directing this workup should be done with combined hematology and laboratory expertise and typically will consist of studies for fmsrelated tyrosine kinase gene (FLT3) mutations, nucleophosmin gene (NPM) mutations, and CCAAT/enhancer binding protein α gene (CEBPA) mutations. Wider molecular panels are increasingly common because of the increasing numbers of potential markers and the potential availability of targeted therapies for FLT3 mutated disease and those with isocitrate dehydrogenase mutations, among others. TP53 mutation, mutated RUNX1, and mutated ASXL1 have recently been added to the NCCN poor-risk category for AML in 2018. Table E5 summarizes common recurrent mutations in adult acute myeloid leukemia.

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ALG

Acute Myeloid Leukemia

≥20% Blasts in marrow and/or blood

OR

3% of blasts and/or presence of Auer Rods is diagnostic for AML. Absence of any of these features does not rule out AML.

Morphology cytochemistry immunohistochemistry

Stage/Lineage

IF

Marker

Precursor

CD34, CD38, CD117, CD133, HLA-DR

Granulocytic

CD13, CD15, CD16, CD33, CD65, cMPO

Monocytic

NSE, CD11c, CD14, CD64, lysozyme, CD4, CD11b, CD36, NG2 homologue

Megakaryocytic Erythroid

CD41(gp IIb/IIIa), CD61(gp IIIa), CD42 (gp1b) CD235a (glycophorin A)

Karyotyping

AML with recurrent cytogenetic abnormalities as defined by WHO 2008

Gene mutation analysis

Testing for FLT3, NPM1, CEBPA (KIT in CBF AML)

Additional features

Morphology: Absence or presence of dysplasia History: Previous exposure to chemotherapy ± radiation antecedent hematologic disorder (AHD)

Diseases and Disorders

Immunophenotyping

61

t(8;21)(q22;q22) inv(16)(p13;q22) t(16;16)(p13;q22) t(15;17)(q23;q12) 11q23 (MLL)

I

FIG. 1  Workup of acute myeloid leukemia. The diagnostic workup consists of a morphologic assessment, immunophenotyping by flow cytometry, assessment of the karyotype, and a panel of gene mutations. Whereas morphologic assessment by itself is often not sufficient to render a diagnosis, flow cytometry will confirm the lineage assignment (myeloid vs. lymphoid) and stage of differentiation in more than 95% of cases. In the remainder, either no lineage-specific antigens are expressed (acute undifferentiated leukemia) or antigens of more than one lineage are present (mixed-phenotype acute leukemia). In the latter scenario, antigens of several lineages can be found on one (biphenotypic) or separate populations of blasts (bilineal). Karyotyping and gene mutation analysis may add diagnostic information in morphologically ambiguous situations but is otherwise of more interest in determining prognosis. Additional information (exposure to previous chemotherapy and/or radiation therapy, history of an antecedent hematologic disorder, dysplasia) forms the basis for the 2008 revision of the WHO classification of AML. AHD, Antecedent hematologic disorder; AML, acute myeloid leukemia; ANLL, acute nonlymphocytic leukemia; CBF, core-binding factor; MPO, myeloperoxidase; WHO, World Health Organization. (From Hoffman R et al: Hematology, basic principles and practice, ed 7, Philadelphia, 2018, Elsevier.)

TABLE 3  European LeukemiaNet AML Risk Classification Genetic Group

Subsets

Favorable

t(8;21)(q22;q22); RUNX1-RUNX1T1 inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11 Mutated NPM1 without FLT3-ITD (normal karyotype) Mutated CEBPA (normal karyotype) Mutated NPM1 and FLT3-ITD (normal karyotype) Wild-type NPM1 and FLT3-ITD (normal karyotype) Wild-type NPM1 without FLT3-ITD (normal karyotype) t(9;11)(p22;q23); MLLT3-MLL Cytogenetic abnormalities not classified as favorable or adverseb inv(3)(q21q26.2) or t(3;3)(q21;q26.2); RPN1-EVI1 t(6;9)(p23;q34); DEK-NUP214 t(v;11)(v;q23); MLL rearranged −5 or del(5q); −7; abnl(17p); complex karyotypec

Intermediate-Ia

Intermediate-II Adverse

aIncludes

all AMLs with normal karyotype except for those included in the favorable subgroup; most of these cases are associated with poor prognosis. bFor most abnormalities, adequate numbers have not been studied to draw firm conclusions regarding their prognostic significance. cThree or more chromosome abnormalities in the absence of one of the WHO designated recurring translocations or inversions, that is, t(15;17), t(8;21), inv(16) or t(16;16), t(9;11), t(v;11)(v;q23), t(6;9), inv(3), or t(3;3). From Hoffman R et al: Hematology, basic principles and practice, ed 7, Philadelphia, 2018, Elsevier.

• Formal diagnosis of acute nonlymphocytic leukemia is established if the marrow or peripheral blood blast percentage is ≥20%, unless t(8;21), inv(16), t(16;16) or t(15;17) are present, in which case the percentage of blasts may be lower.

1.  Myeloperoxidase (MPO) staining of 3% of blasts establishes myeloid lineage, but MPO may be negative in some AML cases diagnosed by flow cytometry. 2. Specific criteria exist for diagnosing other forms of ANLL, mainly to distinguish it

from myelodysplasia. The WHO AML classification is outlined in Table 6. 3. Bone marrow findings are described in Fig. E2. IMAGING STUDIES • Imaging studies are typically directed to evaluating specific complaints. • E chocardiogram or multigated acquisition scan is usually performed to verify that cardiac function is adequate to tolerate anthracycline (usually daunorubicin) therapy, with left ventricular ejection fraction (LVEF) of >50% typically considered acceptable.

TREATMENT ACUTE GENERAL Rx • The general approach to AML is summarized in Fig. 3. Therapy of AML typically has three components: 1. Immediate therapy to correct metabolic, infectious, or hyperleukocytic emergencies (if needed). Therapy for AML is always urgent but not always an emergency. However, treatment for APML should be considered a medical emergency to prevent catastrophic bleeding. 2.  Induction therapy, which is therapy of active disease intended to obtain remis-

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62

Acute Myeloid Leukemia

ALG

TABLE 4  Allogeneic Transplantation Guidelines for Adult Acute Myeloid Leukemia Based on Commonly Assessed Cytogenetic and Molecular Markers AML Category

Prognostic Impact

Allogeneic Transplantation

Notes

AML-CR1: Younger Adults Good-risk disease APL CBF-AML without mKIT

Favorable Favorable

No No

APL is treatable by chemotherapy. t(8;21) AML with high WBC count at diagnosis may have worse prognosis.

CBF-AML with mKIT

Intermediate

Possible: MRD, MUD Uncertain: MMUD, UCB, haplo

Intermediate-Risk Disease CN-AML with CEBPA CN-AML with mutant NPM1 but not FLT-3-ITD

Favorable Favorable

No Possible: MRD

CN-AML with FLT-3-ITD

Unfavorablea

Other intermediate-risk disease

Intermediate or Unfavorable

Yes: MRD, MUD Possibleb: MMUD, UCB, haplo Yes: MRD Likely acceptablea: MUD Possibleb: MMUD, UCB, haplo

Poor-Risk Disease Monosomal karyotype absent

Unfavorable

Monosomal karyotype present

Very unfavorable

Abnormal 17(p)

Very unfavorable

AML-CR1: Older adults

Unfavorable

AML-CR1: t-AML, AML/MDS

Unfavorable

AML-CR2

Very unfavorable

AML not in remission

Very unfavorable

Yes: MRD, MUD Likely acceptableb: MMUD, UCB, haplo Yes: MRD, MUD Acceptableb: MMUD, UCB, haplo Yes: MRD, MUD Acceptableb: MMUD, UCB, haplo Yes: MRD, MUD Likely acceptableb: MMUD, UCB, haplo Yes: MRD, MUD Acceptableb: MMUD, UCB, haplo Yes: MRD, MUD Acceptableb: MMUD, UCB, haplo Yes: MRD, MUD Uncertain: MMUD, UCB, haplo

Benefit likely restricted to DM-CEBPA Emerging data suggests allogeneic HSCT benefit for this category, with reduced relapse and improved DFS in patients >40 yr. Unfavorable risk may be restricted to AML with FLT-3-ITD allelic ratio >0.51 Likely considerable underlying clinical heterogeneity. Molecular risk profiling may further delineate risk in this category.

Molecular risk profiling may supersede clinical classification of secondary AML, especially in older patients.

For selected patients: Good performance status, little comorbidity, lower leukemic burden; CIBMTR risk score may be useful.

AML, Acute myeloid leukemia; APL, acute promyelocytic leukemia; CBF, core binding factor; CIBMTR, Center for International Blood and Marrow Transplant Research; CN, cytogenetically normal; CR1, first complete remission; CR2, second complete remission; haplo, haploidentical; MDS, myelodysplastic syndrome; MMUD, mismatched unrelated donor; MRD, matched related donor; MUD, matched unrelated donor; t-AML, therapy-related AML; UCB, umbilical cord blood; WBC, white blood cell. aIf no sibling donor available. bIf no timely matched donor available. From Hoffman R et al: Hematology, basic principles and practice, ed 7, Philadelphia, 2018, Elsevier.

sion and restore normal bone marrow function. Remission is defined as blasts 1000/mcl, platelets >100,000/mcl, and transfusion independence. Complete remission with incomplete marrow recovery (CRi) indicates absence of leukemic blasts in the marrow but persistent cytopenias. 3.  Consolidation therapy, typically some form of intensive chemotherapy or stem cell transplant therapy intended to prevent relapse. 4. Hyperleukocytic symptoms are typically seen with WBC >100,000/ml. Leukapheresis requires catheter placement and pheresis but spares tumor lysis. Rapid cytoreduction with chemotherapy (hydroxyurea 3 to 6 g orally or cytarabine) is often adequate and easier but risks tumor lysis. Optimal management is therefore individualized. 5. Tumor lysis syndrome (TLS) is associated with a rise in uric acid, potassium,





and serum phosphate, the last causing a reciprocal fall in calcium. The metabolic changes may result in renal failure, cardiac dysrhythmias, muscle spasms (due to low calcium), seizures, and death (a more detailed discussion is in the section on acute lymphocytic leukemia). 6. The mainstays of therapy for AML are medications dating from the 1970s— daunorubicin and cytarabine—with few medications having meaningful impact on therapy in the last four decades. In 2017, the U.S. FDA approved four new agents, including three targeted agents, for treatment of AML. The role of these agents and their relation to standard therapy is outlined below. 7. Induction chemotherapy typically consists of daunorubicin 60 or 90 mg/m2 IV for 3 days and cytarabine (Ara-C) 100 or 200 mg/m2/day as continuous infusion for 7 days (“7+3”). Success rates are 60% to 80% and have been better in





recent trials. Other agents that are used include etoposide, idarubicin, fludarabine, and cladribine. Bone marrow examination is usually performed at day 14 of therapy to assess the response. 8. Gemtuzumab ozogamicin (GO, Mylotarg) is an antibody-drug conjugate binding an anti-CD33 antibody to the chemotherapeutic agent calicheamicin that was approved in 2017 for therapy of newly diagnosed CD33+ AML. In newly diagnosed AML, the use of low-dose GO when added to standard 7+3 induction had a success rate of 81%, with 2-yr relapse-free survival improving from 22.7% to 50.3% compared with standard therapy alone. The benefit was seen in favorable and intermediate-risk patients. 9. Midostaurin was also approved in 2017 for treatment of newly diagnosed AML with mutations in the fms-related tyrosine kinase 3 (FLT3) gene in combination with standard induction therapy. Four-yr

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Acute Myeloid Leukemia

Acute myeloid leukemia

APL No CBF AML

• Age • Performance status • Comorbidities • Karyotype • Genotype

No Other AML

A Yes

• ATRA plus arsenic trioxide(± anthracycline) • ATRA plus anthracycline

Yes

• High-dose cytarabine -FLAG ± anthracycline or gemtuzumab

Age ≤60 yrs

• Cytarabine/anthracycline-based

Diseases and Disorders

Age >60 yrs • Low-dose cytarabine • Hypomethylating agents • Cytarabine/anthracycline-based • Clinical study

FIG. 3  General approach to acute myeloid leukemia therapy. AML, Acute myeloid leukemia; APL, acute promyelocytic leukemia; ATRA, all-trans retinoic acid; CBF, core binding factor; FLAG, fludarabine, cytarabine (ara-C), and granulocyte colony-stimulating factor. (From Hoffman R et  al: Hematology, basic principles and practice, ed 7, Philadelphia, 2018, Elsevier.)

overall survival was 51.4% in FLT3positive patients receiving midostaurin vs. 44.3% in the placebo arm, with improved durability of remissions in patients achieving remission. The optimal use of these therapies requires rapid access to genetic data at the time of diagnosis. Also approved in 2017 was CPX-351, a liposomal formulation of cytarabine and daunorubicin encapsulated in a 5:1 ratio, for patients with AML related to previous therapy (t-AML) or with AML with myelodysplasia-related change (AML-MRC). In a trial of t-AML and AML evolving from myelodysplasia or with WHO-defined myelodysplasiarelated cytogenetic changes in patients ages 60 to 75 yr, CPX-351 improved survival to 9.56 mo vs. 5.95 mo with standard 7+3 induction. 10. Gilteritinib was FDA approved in 2018 for treatment of adult patients who have relapsed or refractory acute myeloid leukemia with a FLT3 mutation. Approval was based on an interim analysis of a trial, which included 138 adult patients with relapsed or refractory AML having a FLT3 ITD, D835, or I836 mutation. Gilteritinib was given orally at a dose of 120 mg daily until unacceptable toxicity or lack of clinical benefit. After a median follow-up of 4.6 mo, 21% of patients achieved complete remission (CR) or CR with partial hematologic recovery (CRh). 11. In 2018, the FDA granted accelerated approval to Venetoclax, a BCL-2 inhibitor, in combination with azacitidine or decitabine or low-dose cytarabine for the treatment of newly-diagnosed acute myeloid leukemia in adults who are age 75 yr or older, or who have comorbidities that preclude the use of intensive induction chemotherapy. The recom-

63

mended Venetoclax dose depends upon the combination regimen. • Consolidation therapy is controversial. For patients managed with chemotherapy, cytarabine 3 g/m2 for six doses is commonly used (day 1, 3, 5), but intermediate doses (1000 to 1500 mg/m2) for six doses appear equally effective and less toxic. Doses above 1000 mg/m2 are poorly tolerated in patients over 60 yr because of cerebellar toxicity. Renal insufficiency also increases the risk of cerebellar toxicity from Ara-C, which can be severe. 1. For favorable risk disease, consolidation with chemotherapy alone with two to four cycles of intermediate/high-dose cytarabine is typically given, with long-term survival of 60% to 70%. 2.  For intermediate-risk and unfavorablerisk disease, first-remission allogeneic stem cell marrow transplant is often recommended if a donor is available. If not, chemotherapy consolidation chemotherapy is offered, although the optimal therapy and schedule, especially for unfavorable disease, is uncertain. 3. In the trial of GO as initial therapy, GO was also used in consolidation with high-dose cytarabine and daunorubicin. 4. The role of autologous bone marrow transplant is controversial, with some evidence of decreased relapse rates after chemotherapy but no clear benefit in overall survival. 5.  Allogeneic bone marrow transplant is offered to patients with relapsed disease if a second remission can be obtained in good risk patients. It is offered to high-risk and intermediate-risk patients in first remission if a donor is available. In 2018, most patients will be able to find a donor from either a matched related donor, matched unrelated donor,

I

mismatched unrelated donor, haploidentical donor, or cord blood donor. The Center for International Blood and Marrow Transplant Research (CIBMTR) has published data for 12,309 patients receiving an HLA-matched sibling transplant and 15,632 patients receiving a matched unrelated donor for AML between 2002 and 2012. Their disease status at the time of transplant and the donor type were found to be the best predictors of posttransplant survival. The 3-yr probabilities of survival after HLA-matched sibling transplant in this cohort was 58% ±1%, 50% ± 1%, and 24% ± 1% for patients with early, intermediate, and advanced disease, respectively. The probabilities of survival after an unrelated donor transplant were 49% ± 1%, 47% ± 1%, and 22% ± 1% for patient with early, intermediate, and advanced disease, respectively. 6. Enasidenib, a selective inhibitor of mutated isocitrate dehydrogenase 2 (IDH-2), was approved by the FDA in 2017 for relapsed or refractory AML with IDH-2 mutations. IDH-2 mutations are found in about 12% of AML patients. At a dose of 100 mg orally, the response rate was 40.3%, with 19.3% achieving remission, some durable. Differentiation syndrome can be seen with enasidenib, similar to therapy for APML. 7. Ivosidenib, a selective inhibitor of isocitrate dehydrogenase-1 (IDH-1) mutation, was approved by the FDA in 2018 as the first treatment of adult patients with relapsed/refractory acute myeloid leukemia with an IDH-1 mutation. Approval was based on results from a phase 1, open-label, single-arm, multicenter, dose-escalation, expansion trial of adult patients in this population. The primary end point was combined complete remis-

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Acute Myeloid Leukemia

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TABLE 6  Classification of Acute Myeloid Leukemia According to the Revised World Health Organization Classification (2016) Category

Subtype/Definition*

AML with recurrent cytogenetic abnormalities

t(8;21)(q22;q22); RUNX1-RUNX1T1† inv(16)(p13.1q22); CBFB-MYH11† t(16;16)(p13.1q22); CBFB-MYH11† t(15;17)(q22;q12); PML-RARA† (= acute promyelocytic leukemia) t(9;11)(p22;q23); MLLT3-KMT2A t(6;9)(p23;q34); DEK-NUP214 inv(3)(q21q26.2); GATA2, MECOM t(3;3)(q21;q26.2); RPN1-EVI1 t(1;22)(p13q13); RBM15-MKL1 (megakaryoblastic) with mutated NPM1 with biallelic mutations of CEBPA Morphologic features of MDS, or prior history of MDS or MDS/MPN, or MDS-related karyotype, and none of the recurrent genetic abnormalities above Late complications of cytotoxic chemotherapy (alkylating agents, topoisomerase II inhibitors) and/or ionizing radiation therapy† AML with minimal differentiation AML without maturation AML with maturation Acute myelomonocytic leukemia Acute monoblastic/monocytic leukemia Pure erythroid leukemia Acute megakaryoblastic leukemia Acute basophilic leukemia Acute panmyelosis with myelofibrosis

AML with MDS-related changes Therapy-related myeloid neoplasms AML, not otherwise specified

Myeloid Sarcoma Myeloid proliferations related to Down Transient abnormal myelopoiesis syndrome Myeloid leukemia associated with Down syndrome Blastic Plasmacytoid Dendritic Cell Neoplasm Acute leukemia of ambiguous lineage Acute undifferentiated leukemia Mixed-phenotype acute leukemia with: t(9;22)(q34;q11.2); BCRABL1 t(v;11q23); KMT2A rearranged Mixed-phenotype acute leukemia, B/myeloid, NOS Mixed-phenotype acute leukemia, T/myeloid, NOS Provisional entities AML with mutated NPM1 AML with mutated CEBPA NK-cell lymphoblastic leukemia/lymphoma AML, Acute myeloid leukemia; MDS, myelodysplastic syndrome; MPN, myeloproliferative neoplasm; NK, natural killer; NOS, not otherwise specified. For AML with recurrent genetic abnormalities, specific genes rearranged follow the chromosome rearrangement. In 2016, the MLL gene has been renamed KMT2A. *Diagnosis of AML regardless of percentage of blasts. †Excluded are patients with AML who have transformed from MPN.

sion and complete remission with partial hematologic improvement; the combined rate was 32.8%, and the median duration of remission was 8.2 mo. 8. Relapses after bone marrow transplant can sometimes be managed with donor lymphocyte infusions, adjustment of immune suppression, and chemotherapy (often low intensity). In general, outcomes are poor with posttransplant relapses. • Treatment of older patients (>60 yr) is problematic, with cure rates of 10% to 15%. Older patients do worse because they are more likely to have high-risk features and less likely to tolerate therapy. Several models have been devised to identify variables that predict which patients may do well with conventional therapy versus those who will not (Table 7). Options for these patients include: 1. Standard induction therapy is reasonable for patients likely to tolerate it. Even in the absence of cure, quality of life is often excellent in remission. More recent studies

suggest that the early death rate (within 30 days of diagnosis) was lower for patients in their 70s and 80s receiving standard induction. There is no standardized approach to evaluating fitness for therapy; one algorithm is at www.aml-score.org/. 2. Hypomethylating agents—decitabine and azacytidine—may be considered in patients unlikely to tolerate induction therapy. Azacytidine (75 mg/m2 daily for 7 days every 28 days) and decitabine (20 mg/m2 for 5 days every 28 days) are considered in older patients who are not considered appropriate for induction chemotherapy. Both are outpatient regimens, and decitabine especially is very well tolerated. Recent data with azacytidine suggest benefit in about 20% to 30% lasting 14 to 16 mo in responders, with equivalent results in low blast count (20% to 30% in the bone marrow) vs. higher blast count disease. 3. Single-agent gemtuzumab ozogamicin is an option for treatment of CD33+ AML in

patients considered unfit for induction. The benefit compared to best supportive care (BSC) was mainly seen in patients with CD33 expression of greater than 80% and favorable/intermediate cytogenetics (1 yr survival 22% and 37% respectively, BSC 10,000/mcl were considered high risk, patients with WBC 40,000 were considered low risk, and all others were considered intermediate

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TABLE 7  Prognostic Models in Older Patients with Acute Myeloid Leukemia Outcome

Unfavorable Characteristics

Study Alliance Leukemia

Survival Disease-free survival

UK Medical Research Council

Survival

Acute Leukemia French Association

Survival

MD Anderson Cancer Center

Remission rate Induction mortality Survival

Hematopoietic Cell Transplantation Comorbidity Index

Early mortality Survival

CD34 expression >10% WBC >20 × 109/L Age >65 yr LDH >700 U/L NPM1 status wild-typea Adverse cytogenetic group Elevated WBCb Poor performance statusb Older ageb Secondary AML High-risk cytogenetics ± Age ≥75 yr Performance status ≥2 WBC ≥50 × 109/L Age ≥75 yr Secondary AMLc AHD duration ≥6c (12) mo Treatment outside LAFR Unfavorable cytogenetics WBC ≥25 × 109/Lc Hemoglobin ≤8 g/dlc Creatinine >1.3 mg/dl Performance status >2 LDH >600 U/Ld Dyspnea Coronary artery disease, CHF, MI, or EF 35 kg/m2

AHD, Antecedent hematologic disorder; AML, acute myeloid leukemia; BMI, body mass index; CHF, congestive heart failure; EF, ejection fraction; LAFR, laminar air flow room (isolation floor); LDH, lactate dehydrogenase; MI, myocardial infarction; WBC, white blood cell count. aFavorable and high-risk groups were defined solely by cytogenetic aberrations. Above factors served to further divide the intermediate risk group into good intermediate versus adverse intermediate. bAs continuous variables. cOnly significant for prediction of remission. dOnly significant for prediction of survival. From Hoffman R et al: Hematology, basic principles and practice, ed 7, Philadelphia, 2018, Elsevier.

risk. In current protocols, high-risk patients receive some form of intensified therapy. • APML is a medical emergency because of the high risk of bleeding complications. 1. All patients with APML have DIC, caused by overexpression of annexin II, (which increases generation of plasmin, degrading fibrin), elastases (which degrade fibrinogen and fibrinolytic inhibitors), and increased endothelial tissue plasminogen activator release. 2. Early death due to hemorrhage is seen in 5% to 17% of newly diagnosed APML patients, usually intracranial or pulmonary. Risk factors include elevated WBC, increased age, and elevated creatinine. 3. Retinoic acid rapidly stabilizes the coagulopathy of APML; consideration should be given to starting this immediately for suspected cases. 4. Cryoprecipitate (usual dose 10 bags) to raise the fibrinogen level to 150 mg/ dl and platelet transfusion to raise the count to >50,000mcl should be given as needed. 5. Unfractionated heparin may paradoxically stop bleeding in APML by inhibiting DIC,

but is rarely used in the retinoic acid treatment era. • Diagnosis of APML. 1. Rapid diagnosis is essential due to treatment implications. 2. Diagnosis by classic APML blast morphology and clinical syndrome (especially DIC with low fibrinogen) is sufficient to justify starting treatment with retinoic acid pending confirmation with molecular studies. Immediate therapy with retinoic acid will rapidly stabilize the coagulopathy and help prevent catastrophic bleeding. 3. Polymerase chain reaction for PML/RARa. 4. FISH for t(15;17) or variants. 5. Flow cytometry is typically distinct with lack of HLA-DR and CD34; CD13, CD33 and CD64 are usually positive. • Therapy of APML. 1. Emergency measures to stabilize coagulopathy as outlined previously. 2. Patients with WBC ≤10,000 (low/intermediate risk) are treated with retinoic acid and arsenic trioxide (“differentiation therapy”).

A

Diseases and Disorders

Study

3. Therapy of high-risk patients is less well standardized but has included intensification with cytarabine, anthracyclines, and gemtuzumab ozogamicin. A recent trial using arsenic and retinoic acid with GO demonstrated 100% 4-yr survival in highrisk patients after 30 days, emphasizing the importance of preventing early deaths in APML. 4. Maintenance therapy for 2 yr is given in some APML protocols. 5.  Patients with high-risk disease receive central nervous system prophylaxis with intrathecal chemotherapy. 6. Treatment of relapsed disease typically consists of autologous bone marrow transplant after obtaining second remission. • Differentiation syndrome (DS) is a potentially fatal complication of therapy with retinoic acid and arsenic trioxide. It is associated with fever, interstitial pulmonary infiltrates, peripheral edema, pleural and pericardial effusions and renal failure; it is commonly associated with rising WBC seen in patients on differentiation therapy. 1. Therapy for suspected differentiation syndrome is dexamethasone 10 mg/m2 every 12 hr. Cytoreductive therapy (hydroxyurea, idarubicin) and stopping retinoic acid and arsenic are appropriate for inadequate response to dexamethasone. 2. Prophylaxis for differentiation syndrome with dexamethasone 2.5 mg/m2 every 12 hr has been suggested for WBC >5000 or creatinine >1.4 mg/dl. Hydroxyurea is used to keep the WBC below 10,000/mcl in some protocols.

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PEARLS & CONSIDERATIONS • The diagnosis of acute myeloid leukemia or variants is often, but not always, a medical emergency requiring rapid clinical and laboratory assessment by appropriate expertise. • APML is a distinct clinical entity that has a high cure rate with current protocols, but which requires intensive supportive care at the time of diagnosis.

SUGGESTED READINGS Available at ExpertConsult.com RELATED CONTENT Acute Myelogenous Leukemia Information)

(Patient

AUTHOR: Todd F. Roberts, MD, FRCP(C)

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TABLE E1  Flow Cytometry Markers Used For Diagnosis of ANLL Precursor stage Granulocytic (myeloid) markers Monocytic markers Megakaryocytic markers Erythroid markers

CD34, CD38, CD117, CD133, HLA-DR CD13, CD15 CD16, CD33, CD65, cytoplasmic myeloperoxidase CD11c, CD14, CD64, CD4, CD11b, CD36, NG2 homologue CD41 (glycoprotein IIb/IIIa), CD61 (glycoprotein IIIa), CD42 glycoprotein 1b CD235 (glycophorin A)

ANLL, Acute nonlymphocytic leukemia. Adapted from Doehner H et al: Diagnosis and management of acute myeloid leukemia in adults, recommendations from an international expert panel, on behalf of the European Leukemia Net, Blood 115: 453-474, 2010.

TABLE E2  Significance of Molecular Abnormalities in Cytogenetically Normal Patients With AML Molecular Profile

Patients

4-yr Overall Survival

Mutant CEBPA Mutant NPM, without FLT-3 ITD FLT-3 ITD present FLT-3 ITD absent, wild type NPM, wild type CEBPA (triple negative leukemia)

67 150 164 69

62% 60% 24% 33%

AML, Acute myeloid leukemia; CEBPA, CCAAT/enhancer binding protein α gene; FLT-3 ITD, FMS-related tyrosine kinase gene internal tandem duplication; NPM, nucleophosmin gene. Improved prognosis in patients with CEBPA mutations is limited to patients who lack FLT-3 ITD and have biallelic mutations. CEBPA mutations are seen in approximately 6% to 10% of AML cases, NPM mutations in 25% to 35% (more common in cytogenetically normal cases) and FLT-3 ITD in approximately 20% to 30% of cases. The updated 2018 NCCN guidelines for AML risk stratification contain favorable, intermediate, and poor risk categories. Molecular abnormalities now included in this updated version in addition to NPM1, FLT3-ITD, and biallelic CEBPA mutation include TP53 mutation, mutated RUNX1, and mutated ASXL1. Molecular abnormalities validation and prognostication is a rapidly evolving field, and risk stratification should be modified on the continuous evaluation of research data. See the NCCN Guidelines Version 3.2018 AML Risk stratification for specific details. Data from Schlenk RF et al: N Engl J Med 358: 1909-18, 2008, and Green CL et al: J Clin Oncol 28: 2739-47, 2010.

B

A

C

FIG. E2  Acute myeloid leukemia with t(8;21)(q22;q22), (AML/ETO). A, Low-power, Wright-stained bone marrow aspirate smear showing increased blasts associated with differentiating myeloid cells. B, Details illustrating some of the features associated with the leukemia. They include blasts with long thin Auer rods (top left), immature cells with abnormal eosinophilic globules (top and bottom, second from left), abnormal salmoncolored granulation in the maturing cells, sometimes associated with a basophilic periphery (top and bottom, fourth from left), and slightly abnormal features in the mature neutrophils (far right). Pseudo–Chédiak-Higashi granules were not seen in this case. C, Biopsy shows the significant degree of maturation that is sometimes seen. In some cases the blast count is less than 20%, but the diagnosis of acute myeloid leukemia still can be made with the cytogenetic finding of t(8;21). (From Hoffman R et al: Hematology, basic principles and practice, ed 5, Philadelphia, 2009, Churchill Livingstone.)

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TABLE E5  Common Recurrent Mutations in Adult Acute Myeloid Leukemia Gene Class

Gene

Frequency % of Patients

Clinical Significance

NPM1 Tumor suppressor

NPM1 TP53

25-30 8

DNA methylation

DNMT3A TET2

18-22 7-25

IDH1 IDH2 FLT3-ITD

7-14 8-19 20

KIT NRAS RUNX1

4 to 5 cm in size and hemorrhagic in nature) • Ovarian torsion • Degenerating or torsed uterine fibroid • Mittelschmerz pain • Tubo-ovarian abscess • Endometriosis • Dysmenorrhea • Hematometra/Hematocolpos EARLY PREGNANCY/POSTPARTUM-RELATED CAUSES: • Miscarriage • Ectopic pregnancy (especially with ruptured ectopic) • Postpartum endometritis NONOBSTETRIC OR GYNECOLOGIC CAUSES: • Appendicitis • Urinary tract infection • Nephrolithiasis • Diverticulitis • Colitis • Bowel obstruction • Mesenteric lymphadenitis • Inflammatory bowel disease • Meckel diverticulum • Constipation • Hernia • Gastroenteritis • Musculoskeletal dysfunction • Trauma WORKUP The workup of acute pelvic pain begins with a thorough history and physical examination, then targeted imaging and laboratory studies are ordered to further the diagnosis. The pelvic examination includes vaginal speculum examination, as well as bimanual and rectovaginal pelvic examinations. During the speculum examination the patient is evaluated for any active vaginal bleeding, any vaginal or cervical discharge, and any vulvar or vaginal lesions and masses. • Testing for gonorrhea and chlamydia should be collected via nucleic acid probe. • The bimanual and rectovaginal examinations help elucidate the size and contour of the uterus, the presence of any adnexal masses or tenderness, and whether the patient has cervical motion tenderness. LABORATORY TESTS • Erythrocyte sedimentation rate (ESR) • First and foremost, one must determine the pregnancy status of the patient. The most common pregnancy-related causes of acute pelvic pain are ectopic pregnancy (approximately 1 in 7000 spontaneously conceived

pregnancies and 1 in 100 pregnancies conceived via artificial reproduction) and spontaneous or threatened miscarriage. In both of these cases, the Rh status of the patient must be determined and RhoGAM administered if she is Rh negative • Pregnancy testing via urine or serum • Urinalysis will assist with the diagnosis of both acute cystitis and nephrolithiasis and urine culture should be ordered as well when appropriate. Nucleic acid probes for gonorrhea and chlamydia are very sensitive and specific tests and should be collected on any patient with pelvic pain. CBC and ESR can be utilized in the patient with suspected gastrointestinal disease, appendicitis, and pelvic infection of any kind to help determine the severity of disease

IMAGING STUDIES • Pelvic ultrasound is the primary imaging modality for acute pelvic pain in women that is suspected to be of gynecologic origin. Ultrasound can be used to diagnose intrauterine and ectopic pregnancy (Fig. 1), uterine fibroids, adnexal masses, nephrolithiasis, and even appendicitis, thus assisting with the diagnosis of the vast majority of the differential diagnosis of acute pelvic pain in women. However, there are limitations to the test, such as the level of expertise of the individual sonographer and patient body habitus interfering with the quality of the images. • In the case of the patient with nonfocal symptoms or an inconclusive ultrasound, computed tomography (CT) of the abdomen and pelvis can be performed. CT is highly useful in the patient with early pelvic inflammatory disease (PID) or tubo-ovarian abscess, as well as in the nonpregnant patient with appendicitis or other gastrointestinal pathology not seen on ultrasound. • Magnetic resonance imaging (MRI) also plays a role when CT is unable to discern whether a mass in the pelvis is of uterine or adnexal origin such as with a degenerating fibroid or when one must further characterize an ovarian mass. MRI is also extremely helpful in the pregnant patient who presents with many signs and symptoms of appendicitis but has an inconclusive ultrasound result. Pediatric patients are also excellent candidates for MRI when ultrasound is inconclusive. Lower levels of ionizing radiation and its excellent diagnostic capabilities make it a very useful test in this population.

TREATMENT NONPHARMACOLOGIC THERAPY • The underlying cause of acute pelvic pain cannot always be diagnosed with history, exam, laboratory, and imaging studies alone. In many cases, diagnostic laparoscopy is necessary to complete the diagnosis. In fact, even when the diagnosis seems sure, laparoscopy can reveal an entirely different finding as was illustrated in one study where

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Acute Pelvic Pain in Women g­astroenterology, general surgery, or musculoskeletal medicine—for further workup and management of their now chronic pelvic pain. Referral should also be considered when the underlying cause of pain cannot be found.

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A

PEARLS & CONSIDERATIONS

just over half of women clinically diagnosed with appendicitis actually had the disease. • The practitioner should not hesitate to take the patient with unstable vital signs and suspected intraabdominal bleeding or findings suggestive of ruptured appendix to the operating room. When one’s clinical suspicion is quite high for such diagnoses, laboratory data and imaging studies should be forgone to expedite getting the patient the surgical interventions she needs.

ACUTE GENERAL Rx The initial treatment of the woman with acute pelvic pain must be tailored to the underlying cause. However, as the workup is in progress, her pain must be managed. Although narcotic pain medications are sometimes initially necessary to control pain, NSAIDs are the traditional first-line pharmacotherapy for the patient with pelvic pain of an inflammatory nature. Such medications are highly useful in cases

of ­ endometriosis, dysmenorrhea, nonsurgical cases of ovarian masses and ruptured ovarian cysts, spontaneous miscarriage, nephrolithiasis, musculoskeletal dysfunction, and PID/ tubo-ovarian abscess. Heat and ice can also be employed as needed for additional symptomatic relief in the appropriate patient.

CHRONIC Rx Once a diagnosis is made, treatment is based on the underlying cause of the pain. Most patients are managed on a combination of NSAID and narcotic pain medications for a short course until the pathology has resolved or after any surgical interventions. Antibiotic therapy is routinely included in the case of an infectious cause. REFERRAL Patients with pain lasting greater than 3 to 6 months should be seen by a specialist in the appropriate field—gynecology,

Diseases and Disorders

FIG. 1  A sonographic image of a 23-year-old patient with a ruptured ectopic pregnancy. The free fluid containing echogenic debris representing blood is seen in the cul-de-sac (arrow). (From Soto JA, Lucey BC: Emergency radiology, the requisites, ed 2, Philadelphia, 2017, Elsevier.)

A solid knowledge of the differential diagnosis of acute pelvic pain in women and a thorough history and physical examination will lead the practitioner to the underlying cause in the vast majority of cases. But all women who present with acute pelvic pain MUST have a pregnancy test as a part of their initial workup. If imaging is needed, pelvic ultrasound is an excellent tool and should be utilized first before CT and MRI in most cases.

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SUGGESTED READINGS Available at ExpertConsult.com RELATED CONTENT Appendicitis (Related Key Topic) Crohn Disease (Related Key Topic) Diverticular Disease (Diverticulosis, Diverticulitis, Diverticular Hemorrhage) (Related Key Topic) Ectopic Pregnancy (Related Key Topic) Endometriosis (Related Key Topic) Endometritis (Related Key Topic) Pelvic Inflammatory Disease (Related Key Topic) Spontaneous Abortion (Related Key Topic) Ulcerative Colitis (Related Key Topic) Urinary Tract Infection (Related Key Topic) Urolithiasis (Nephrolithiasis) (Related Key Topic) Uterine Fibroids (Related Key Topic) AUTHORS: Anthony Sciscione, DO, and Ghamar Bitar, MD

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SUGGESTED READINGS Kreisel K et  al: Prevalence of pelvic inflammatory disease in sexually experienced women of reproductive age—United States, 2013–2014, CDC MMWR 66:3, 2017. Accessed at www.cdc.gov/mmwr/volumes/66/wr/mm6603a3. htm. Kruszka PS, Kruszka SJ: Evaluation of acute pelvic pain in women, Am Fam Physician 82(2), 2010. Potter AW, Chandrasekhar CA: US and CT evaluation of acute pelvic pain of gynecologic origin in nonpregnant premenopausal patients, RadioGraphics 28(6), 2008. Special Issue. Vandermeer FQ, Wong-You-Cheong JJ: Imaging of acute pelvic pain, Clin Obstet Gynecol 52(1), 2009.

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Acute Respiratory Distress Syndrome BASIC INFORMATION DEFINITION Acute respiratory distress syndrome (ARDS) is a form of noncardiogenic pulmonary edema that results from acute damage to the alveoli. It is characterized by acute diffuse infiltrative lung lesions with resulting interstitial and alveolar edema, severe hypoxemia, and respiratory failure. The cardinal feature of ARDS, refractory hypoxemia, is caused by formation of protein-rich alveolar edema after damage to the integrity of the lung’s alveolar-capillary barrier. The definition of ARDS based on the American– European Consensus Conference (AECC) from 1994 included the following components: 1. The syndrome must present acutely 2. A ratio of Pao2 to Fio2 ≤200 regardless of the level of positive end expiratory pressure (PEEP) 3.  The detection of bilateral pulmonary infiltrates on frontal chest radiograph 4. Absence of congestive heart failure (pulmonary artery wedge pressure [PAWP] ≤18 mm Hg or no clinical evidence of elevated left atrial pressure on the basis of chest radiograph or other clinical data) The Berlin definition of ARDS (Table 1) adopted in 2011 addresses some of the limitations of the AECC definition and establishes the following criteria for ARDS: • Timing: Within 1 week of a known clinical insult or new or worsening respiratory symptoms • Chest imaging (chest x-ray or computed tomography [CT] scan): Bilateral opacities,

not fully explained by effusions, lobar/lung collapse, or nodules • Origin of edema: Respiratory failure not fully explained by cardiac failure or fluid overload. Need objective assessment (e.g., echocardiography) to exclude hydrostatic edema if no risk factor present • Oxygenation (if altitude is higher than 1000 m, the correction factor should be calculated as follows: [Pao2/Fio2 × {barometric pressure/760}] • Mild: 200 mm Hg 30% of cases) • Trauma (>20% of cases) • Pneumonia (aspiration of gastric contents and sepsis together account for more than 85% of cases of ARDS in recent clinical trials) • Multiple transfusions, blood products • Drugs (e.g., overdose of morphine, methadone, heroin; reaction to nitrofurantoin) • Noxious inhalation (e.g., chlorine gas, high O2 concentration) • Post-resuscitation • Cardiopulmonary bypass • Burns • Pancreatitis • A history of chronic alcohol abuse significantly increases the risk of developing ARDS in critically ill patients • Table 2 describes risk factors associated with development of ARDS

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • Congestive heart failure • Interstitial lung disease (acute interstitial pneumonia, nonspecific interstitial pneumonia [NSIP], cryptogenic organizing pneumonia [COP], acute eosinophilic pneumonia, hypersensitivity pneumonia, pulmonary alveolar proteinosis) • Connective tissue diseases, such as polymyositis • Diffuse alveolar hemorrhage • Lymphangitic carcinomatosis from T-cell or B-cell lymphomas • Drug-induced lung diseases (amiodarone, bleomycin) WORKUP The search for an underlying cause should focus on treatable causes (e.g., infections such as sepsis or pneumonia)

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Acute Respiratory Distress Syndrome

69

A

B

C

FIG. 1  Acute respiratory distress syndrome. X-ray of a young man who had sustained severe trauma and blood loss in a road traffic accident; the lungs cover a period of 5 days from a relatively normal x-ray (A), to bilateral infiltrates (B), to bilateral “whiteout” (C), accompanied by severe hypoxemia. A Swan-Ganz catheter for measurement of pulmonary artery “wedge” pressure (as a reflection of left atrial pressure) can be seen in situ on the x-ray in C. The patient died shortly after the last film. (From Souhami RL, Moxham J: Textbook of medicine, ed 4, London, 2002, Churchill Livingstone.)

• Arterial blood gases (ABGs) • Hemodynamic monitoring • Bronchoalveolar lavage (selected patients)

LABORATORY TESTS • ABGs: 1.  Initially: Varying degrees of hypoxemia, generally resistant to supplemental oxygen 2. Respiratory alkalosis, decreased Pco2 3. Widened alveolar-arterial gradient 4. Hypercapnia as the disease progresses • Bronchoalveolar lavage: 1. The most prominent finding is an increased number of polymorphonucleocytes. 2. The presence of eosinophilia has therapeutic implications because these patients respond to corticosteroids. • Blood and urine cultures • Blood work: 1.  Increased or reduced white blood cell count with left shift if concomitant infectious process 2. Normal or mildly elevated B-type natriuretic peptide level 3.  Increased lactate level if concomitant sepsis or septic shock IMAGING STUDIES Chest radiograph (Fig. 1). • The initial chest radiograph might be normal in the initial hours after the precipitating event. • Bilateral interstitial infiltrates are usually seen within 24 hr; they often are more prominent in the bases and periphery. • CT scan of chest: Bilateral diffuse, dense consolidations with air bronchograms.

TREATMENT NONPHARMACOLOGIC THERAPY Treatment of ARDS is supportive. Hemodynamic monitoring: • Can be used for the initial evaluation of ARDS (in ruling out cardiogenic pulmonary edema) and its subsequent management. However,

a pulmonary catheter is not indicated in the routine management of ARDS and trials have shown that clinical management involving the early use of pulmonary artery catheters in patients with ARDS did not significantly affect mortality and morbidity rates and may result in more complications as compared with a central venous catheter. • Although no dynamic profile is diagnostic of ARDS, the presence of pulmonary edema, a high cardiac output, and a low pulmonary capillary wedge pressure (PCWP) is characteristic of ARDS. • It is important to remember that partially treated intravascular volume overload and flash pulmonary edema can have the hemodynamic features of ARDS; filling pressures can also be elevated by increased intrathoracic pressures or with fluid administration; cardiac function can be depressed by acidosis, hypoxemia, or other factors associated with sepsis. Ventilatory support: • Noninvasive positive-pressure ventilation (NIPPV) (i.e., BiPAP) should only be used in selected cases in patients with hypoxic respiratory failure. A recent randomized control study showed that high-flow oxygen by nasal cannula reduced ventilator-free days and mortality compared with NIPPV in patients with hypoxemic respiratory failure without hypercapnia. Either modality should not delay intubation and mechanical ventilation initiation in patients with rapidly progressing clinical deterioration. • Mechanical ventilation is generally necessary to maintain adequate gas exchange (Table 3). General recommendations for ventilator settings in ARDS are described in Table 4. A low tidal volume and low plateau pressure ventilator strategy are recommended to avoid ventilator-induced injury. Assist-control is generally preferred initially with the following ventilator settings: 1. Fio2 1.0 (until a lower value can be used to achieve adequate oxygenation). When possible, minimize oxygen toxicity by maintaining Fio2 at 90 85-90 45-55 2-5 40-60 45-50 50-60 15-20 30-35 25-30 5-8 4-6 1-2

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Anaphylaxis 1st line Epinephrine 0.3−0.5 mg repeated as needed Fluid boluses if hemoconcentration or hypotensive Avoidance/elimination of causal agent O2 for SpO2 93%−95% Airway protection (difficult airway procedures) Methylprednisolone 1 mg/kg/day for 72 h max (+ antihistaminics) 2nd line (persisting shock) Methylene blue Vasopressin Angiotensin ? Glucagon

FIG. E1  Management of a patient with severe anaphylaxis. O2, Oxygen; SpO2, oxygen saturation measured by pulse oximetry. (From Parrillo JE, Dellinger RP: Critical care medicine, principles of diagnosis and management in the adult, ed 5, Philadelphia, 2019, Elsevier.)

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ALG BASIC INFORMATION DEFINITION Aplastic anemia (AA) refers to a bone marrow failure syndrome characterized by immune-mediated bone marrow destruction and peripheral blood pancytopenia. Severe aplastic anemia (SAA) is defined by the presence of two of the following criteria: Neutrophil counts 90%). • During the 2001 bioterrorism attacks, the case fatality rate was lower at 45%. The decrease was linked to improvement in critical care management, drainage of effusions, and antimicrobial therapy. • The case fatality rate for cutaneous anthrax when left untreated is less than 1%. • The case fatality rate for gastrointestinal anthrax is estimated to be 25% to 60%. • Even with treatment, the mortality rate for injectional anthrax is 34%. REFERRAL Consultation with an infectious disease specialist is recommended in all cases of anthrax. Local and state authorities should also be notified of suspected cases of anthrax.

PEARLS & CONSIDERATIONS COMMENTS • Postexposure prophylaxis: If the exposure to B. anthracis is confirmed and anthrax vaccine is available, three doses of the vaccine should be given at 0, 2, and 4 wk, and antibiotics should be continued throughout the 4-wk period. If vaccine is not available, antibiotics should be continued for 60 days. • Preexposure vaccination is limited to groups at risk for repeated exposures to B. anthracis spores, such as bioterrorism level B laboratories and workers who will be making repeated entries into known B. anthracis spore-contaminated areas. • The U.S. anthrax vaccine is an inactivated cell-free product licensed to be given in a six-dose series. SUGGESTED READING Adalja AA et al: Clinical management of potential bioterrorism-related conditions, N Engl J Med 372:954-962, 2015.

RELATED CONTENT Anthrax (Patient Information) AUTHOR: Samaan Rafeq, MD

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Anthrax

132.e6

Activate local triage teamt

Clinical finding of inhalation/other systemic anthrax warranting admission?§

No

•PEP¶ •Anthrax fact sheets •Follow-up instructions

Yes

Meningitis? No

Yes or cannot be excluded

Yes Dual antimicrobial therapy with good CNS penetration •Bactericidal •Protein synthesis inhibitor (Select from Figure E6)

Dual antimicrobial therapy •Bactericidal •Protein synthesis inhibitor

Administer antitoxin

No

Shortage of recommended antimicrobials?

No Triple antimicrobial therapy (Figure E5)

Shortage of antitoxins?** (Box E3) Yes

Monitor/reassess††

No

Severe sepsis? (Box E1) Yes

Improved?

Yes

No

Action/treatment Decision point Major decision point/action addressed in guidelines

Administer antitoxin (if not previously administered)

Observe/step-down to single agent antimicrobial when clinically stable§§

Abbreviations: CNS = central nervous system; IOM = Institutes of Medicine. * Possible triggers indicating a shift in standards of care. † As outlined in the IOM 2012 Crisis Standards of care. § Admission criteria for nonsystemically ill patients may depend on local and regional bed space. ¶ Clinicians may choose to administer a second oral antimicrobial for patients with nonspecific symptoms of anthrax who do not meet criteria for hospitalization. Close follow-up is recommended. ** Patients with meningitis or in whom meningitis cannot be excluded should be treated aggressively and receive antitoxin even if an antitoxin shortage exists. †† Drainage of effusions improves survival. Clinicians experienced with management of effusions should assess for significant fluid collections and drain as possible under the current standard of care. §§ Patients with meningitis or in whom meningitis cannot be excluded should receive a minimum of 14 days of IV antimicrobials before stepping down to single agent.

FIG. E4  Crisis standards of care* framework for medical countermeasure prioritization among hospitalized persons with known or potential exposure to anthrax. (From Centers for Disease Control and Prevention: Clinical framework and medical countermeasure use during an anthrax mass-casualty incident, MMWR 64[RR04]:1-28, 2015.)

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Bactericidal agent* (fluoroquinolone)

Bactericidal agent* ( -lactam)

Protein synthesis inhibitor*

Ciprofloxacin

Meropenem

Linezolid

or

or

or

PLUS

Levofloxacin

PLUS

Imipenem

Clindamycin

or

or

or

Moxifloxacin

Doripenem

Rifampin† or Chloramphenicol

OR

Alternatives for penicillin-susceptible strains Penicillin G or Ampicillin

* Preferred drugs are indicated in boldface. Alternative drugs are listed in order of preference for treatment for patients who cannot take first-line treatment or if first-line treatment is unavailable. † Rifampin is not a protein synthesis inhibitor. However, it may be used in combination with other antimicrobial drugs on the basis of its in vitro synergy.

FIG. E5  Intravenous treatment for systemic anthrax with suspected, possible, or confirmed meningitis. (Adapted from Hendricks KA et al: Centers for Disease Control and Prevention expert panel meetings on prevention and treatment of anthrax in adults, Emerg Infect Dis 20[2], 2014. Available at https://doi.org/10.3201 /eid2002.130687.) Bactericidal agent* Alternatives for penicillin-susceptible strains

Ciprofloxacint or Levofloxacint or

Protein synthesis inhibitor*

Clindamycint or

Penicillin Gt OR

or Ampicillint

PLUS

Linezolidt or

Moxifloxacint

Doxycycline

or

or

Meropenemt

Rifampin§

or Imipenemt or Doripenemt or Vancomycin

* Preferred drugs are indicated in boldface. Alternative drugs are listed in order of preference for treatment for patients who cannot take first-line treatment or if first-line treatment is unavailable. † Antimicrobials with good central nervous system penetration. § Rifampin is not a protein synthesis inhibitor. However, it may be used in combination with other antimicrobial drugs on the basis of its in vitro synergy.

FIG. E6  Intravenous treatment for systemic anthrax when meningitis has been excluded. (Adapted from Hendricks KA et al: Centers for Disease Control and Prevention expert panel meetings on prevention and treatment of anthrax in adults, Emerg Infect Dis 20[2], 2014. Available at https://doi.org/10.3201/eid2002.130687.)

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BOX E1  Diagnostic Criteria for Sepsis and Severe Sepsis* Sepsis—documented or suspected infection plus one or more of the following: General variables • Fever (>38.3° C) • Hypothermia (core temperature 90/min or >2 SD above normal value for age • Tachypnea • Altered mental status • Significant edema or positive fluid balance (>20 ml/kg over 24 hr) • Hyperglycemia (plasma glucose >140 mg/dl or 7.7 mmol/L) in the absence of diabetes Inflammatory variables • Leukocytosis (WBC count >12 × 103/μL) • Leukopenia (WBC count 2 SD above normal value • Plasma procalcitonin >2 SD above normal value Hemodynamic variables • Arterial hypotension (SBP 60 s) • Ileus (absent bowel sounds) • Thrombocytopenia (platelet count 4 mg/dl or >70 μmol/L) Tissue perfusion variables • Hyperlactatemia (>1 mmol/L) • Decreased capillary refill or mottling Severe sepsis—documented or suspected infection resulting in tissue hypoperfusion or organ dysfunction documented by one or more of the following: • Sepsis-induced hypotension • Lactate above upper normal limits of laboratory • Urine output 2 hours despite adequate fluid resuscitation • Acute lung injury with PaO2/FiO2 2 mg/dl (34.2 μmol/L) • Platelet count 1.5) *Diagnostic criteria for sepsis in the pediatric population are signs and symptoms of inflammation plus infection with hyperthermia or hypothermia (rectal temperature >38.5° or 40 MPL, GPL, or >99th percentile on two or more occasions at least 12 wk apart, or 3. Anti-β2-glycoprotein-I antibodies present in serum or plasma at >99th percentile on two or more occasions at least 12 wk apart • Screening tests: 1.  Partial thromboplastin time (PTT): Elevated, activated partial thromboplastin time prolongation indicating either the presence of a clotting factor deficiency, or the presence of an inhibitor such as a lupus anticoagulant. 2. Mixing study: Elevated. Normal plasma is incubated with the patient’s plasma. In cases of clotting factor deficiencies, the PTT will correct. If an inhibitor is present as in the case with APS, the PTT will not correct. 3. Dilute Russell viper venom time: Elevated. Laboratory clotting requires the addition of phospholipids and calcium to plasma samples. Antiphospholipid antibodies bind the phospholipids in the test tube, thereby preventing clot formation. The addition of Russell viper venom to plasma results in immediate activation of Factor X (common pathway). Therefore, it will not be prolonged in intrinsic or extrinsic factor deficiencies but will be prolonged in the presence of an antiphospholipid antibody. 4. The Lupus Anticoagulant screen is the addition of Russell viper venom to plasma. In the Lupus Anticoagulant confirmatory testing, massive doses of phospholipids are added to saturate the antiphospholipid antibody, thereby correcting the prolonged PTT. • Initial testing for presence of aPL: 1. Anticardiolipin (aCL) ELISA antibodies (IgG or IgM), or 2. Lupus anticoagulant activity found, or 3. Anti-beta2-glycoprotein (anti-β2GPI) ELISA antibodies (IgG or IgM). • Confirmatory aPL testing (Table 5): Repeat testing after 12 wk is required to confirm the persistence of a positive aCL, anti-β2GPI, or LA test because transient aPL elevations can occur.

LABORATORY TESTS Diagnostic evaluation of aPLs is indicated in: • Patient with underlying SLE or collagenvascular disease with thrombosis. • Patient with recurrent, familial, or juvenile deep vein thrombosis (DVT) or thrombosis in an unusual location (mesenteric or cerebral).

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Antiphospholipid Antibody Syndrome BOX 1  Preliminary Criteria for Classification of Antiphospholipid Syndrome

ELISA, Enzyme-linked immunosorbent assay; Ig, immunoglobulin. From Hochberg MC: Rheumatology, ed 7, Philadelphia, 2019, Elsevier.

TABLE 4  Assays Used to Confirm Diagnosis of Antiphospholipid Syndrome Assay

Methodology

“Criteria” aPL Assays aCL Anti-β2-GPI LAC “Noncriteria” aPL Assays Assays to detect antibodies to other phospholipids (i.e., phosphatidylserine, phosphatidylinositol, phosphatidic acid, phosphatidylglycerol, phosphatidylethanolamine, phosphatidylcholine) Annexin A5 resistance assay Assays to detect antibodies to prothrombin or prothrombin/phosphatidylserine Assays to detect antibodies to clotting proteins (i.e., protein C, protein S)

ELISA ELISA Clotting/functional assays ELISA Clotting/mechanistic assay ELISA ELISA

aCL, Anticardiolipin; aPL, antiphospholipid antibody; ELISA, enzyme-linked immunosorbent assay; β2 GPI, β2 -glycoprotein I; LAC, lupus anticoagulant. From Hochberg MC et al: Rheumatology, ed 5, St Louis, 2011, Mosby.

• O ne or more unexplained thrombotic events. Do not test those at low risk, e.g., elderly patients with other thrombotic risk factors. • One or more specific pregnancy events. • Unexplained thrombocytopenia or microangiopathic hemolytic anemia. • Patients with an unexplained elevation in PTT, or less commonly, in PT/INR.

TREATMENT ACUTE Rx • Initial anticoagulation with heparin or lowmolecular-weight heparin (LMWH), before transitioning to a vitamin K antagonist (VKA) such as warfarin, is recommended. DOACs

PRIMARY PREVENTION • Although other cardiovascular risk factors, such as hypertension and hyperlipidemia, should be controlled, aspirin use for primary prevention remains controversial. • Adding low-dose warfarin to aspirin for primary prevention seems to confer no benefit. • Hydroxychloroquine may be useful in those patients with SLE and aPL; it has been shown to reduce the incidence of thrombotic complications in this population. • Modifiable risk factors for thrombosis, such as smoking and immobility, should also be addressed when possible. • For pregnant women with a positive test for aPL antibodies without a history of DVT or pregnancy morbidity, decision to treat with low-dose subcutaneous UFH or LMWH and/or low-dose aspirin, or to manage with surveillance should be made on an individual basis as there is no clear consensus data.

A

Diseases and Disorders

Clinical criteria Vascular thrombosis One or more clinical events of arterial, venous, or small-vessel thrombosis in any tissue or organ. Thrombosis must be confirmed by Doppler ultrasonography, other imaging, or histopathologic analysis, with the exception of superficial venous thrombosis. The histopathologic study does not have to demonstrate significant evidence of inflammation of the blood vessel. Pregnancy morbidity • One or more unexplained deaths of morphologically normal fetuses at 10 or more wk of gestation, with a normal fetal morphology confirmed by ultrasound or direct examination of the fetus. • One or more premature births of a morphologically normal newborn at 34 wk of gestation or before caused by • Severe preeclampsia or eclampsia defined according to current standards, or • Recognized placental insufficiency • Three or more consecutive spontaneous abortions without explanation before 10 wk of gestation, excluding those associated with hormonal or anatomic alterations in the mother or chromosomal alterations inherited from either parent. Laboratory criteria The presence of at least one of the following test results: • Lupus anticoagulant in the plasma on two or more separate occasions within a period of 12 wk, detected according to the guidelines of the International Society of Thrombosis and Haemostasis (Scientific Subcommittee on lupus anticoagulant/ phospholipid-dependent antibodies). • IgG or IgM anticardiolipin antibodies in plasma or serum in medium-high titers (more than 40 GPL or MPL units, respectively) on two or more separate occasions within a period of 12 wk, as measured by standardized ELISA. • IgG or IgM anti–β2-glycoprotein I antibodies in the serum or plasma (in titer above the 99th percentile) on two or more separate occasions within a period of 12 wk, as measured by standardized ELISA according to recommended procedures.

are not recommended due to recent studies which have shown increased risk of recurrent thromboembolism, particularly in patients with high-risk APS (positivity for all three antiphospholipid antibodies) for patients on rivaroxaban compared to warfarin. • Standard intensity (INR 2.0 to 3.0) anticoagulation with warfarin is preferred in venous thrombosis, as prior randomized trials failed to show a decrease in recurrent thromboses with high-intensity anticoagulation (INR 3.0 to 4.0). Task-force reports have not reached a consensus regarding intensity of anticoagulation in secondary thromboprophylaxis of arterial events. • Unfractionated heparin (UFH) is preferred if quick reversibility is needed.

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I

SECONDARY PREVENTION • For men and nonpregnant women, long-term anticoagulation with warfarin, or with UFH or LMWH if warfarin is contraindicated, should be used. • Modifiable risk factors for thrombosis should be reduced when possible. • For pregnant women with previously diagnosed APS: 1. Warfarin should be discontinued before pregnancy due to its teratogenic effects. 2. For women with APS without prior thrombosis but with pregnancy morbidities of either unexplained fetal death at ≥10 wks’ gestation or ≥3 unexplained spontaneous abortions before 10 wks’ gestation, aspirin 81 mg in combination with subcutaneous UFH or LMWH is recommended to improve pregnancy outcomes. 3. For women with APS without prior thrombosis but with pregnancy morbidity of ≥1 premature births before 34 wks’ gestation secondary to eclampsia, preeclampsia, or severe placental insufficiency, aspirin 81 mg is recommended to improve pregnancy outcomes.

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136

Antiphospholipid Antibody Syndrome TABLE 5  Current Assays Used to Confirm the Diagnosis of Antiphospholipid Syndrome Assay

Method

Criteria aPL assays Anticardiolipin Anti–β2-glycoprotein I Lupus anticoagulant Noncriteria aPL assays Assays to detect antibodies to other phospholipids (e.g., phosphatidylserine, phosphatidylinositol, phosphatidic acid, phosphatidylglycerol, phosphatidylethanolamine, phosphatidylcholine) Annexin A5 resistance assay Assays to detect antibodies to prothrombin or prothrombin/phosphatidylserine Assays to detect antibodies to clotting proteins (e.g., protein C, protein S)

ELISA ELISA Clotting or functional assays ELISA Clotting or mechanistic assay ELISA ELISA

aPL, Antiphospholipid antibody; ELISA, enzyme-linked immunosorbent assay. From Hochberg MC: Rheumatology, ed 7, Philadelphia, 2019, Elsevier.

4. For pregnant women with APS and prior thrombosis, aspirin in combination with subcutaneous UFH or LMWH should be used. 5. Pregnant patients taking LMWH should be transitioned to unfractionated heparin before delivery for ease of reversibility. 6. Hypertension and hyperlipidemia, if present, should be controlled.

FOR CATASTROPHIC ANTIPHOSPHOLIPID ANTIBODY SYNDROME (CAPS) • The combination of anticoagulation with heparin products, high-dose corticosteroids, and supportive care, including debriding necrotic tissue and treating underlying infections is the mainstay of therapy. • Patients may be transitioned to oral anticoagulation with warfarin once clinically stable. • Plasma exchange with or without IVIG has been shown to improve mortality; however, the decision to use IVIG should be made on an individual basis (e.g., avoid in patients in whom anticoagulation has been discontinued). • Eculizumab (monoclonal antibody against complement protein C5) and rituximab (monoclonal antibody against CD20) have been used successfully in refractory cases. • Immunosuppressant therapy with cyclophosphamide should be considered in patients with CAPS and SLE as it has been demonstrated to decrease mortality in this group. CHRONIC Rx • Anticoagulation with VKAs, such as warfarin, remains the standard of care. The

potential role of new oral anticoagulants in APS remains uncertain. Trials involving rivaroxaban did not show non-inferiority to dose adjusted VKAs for thrombotic APS, and in fact showed a non-statistically significant near doubling of the risk for recurrent thrombosis.1 • Duration of treatment is unknown and should be determined on an individual basis. However, in the absence of any contraindication to anticoagulation, indefinite therapy is recommended, as the lifelong recurrence rate reached nearly 30% in some studies. • Immunosuppressive agents such as corticosteroids and cyclophosphamide have not been shown to be effective for chronic treatment of APS. • Limited data suggest that hydroxychloroquine may be effective in patients with APS and SLE, although efficacy in primary APS remains unproven. • Recurrent thrombosis can occur even in the setting of “therapeutic” anticoagulation, and multiple assays have been studied to monitor the adequacy of anticoagulation in APS. • In cases of recurrent thrombosis, hydroxychloroquine and statins (antiinflammatory and antithrombotic activity) may be considered as adjuvant therapies. • Table 6 summarizes alternative therapies for antiphospholipid syndrome.

1Ordi-Ros

J et al: Rivaroxaban versus vitamin K antagonist in antiphospholipid syndrome: a randomized noninferiority trial, Ann Intern Med 171(10):685694, 2019.

DISPOSITION • APS patients have a 20% to 70% risk for recurrent thrombosis. Positivity in more than one aPL assay is associated with increased thrombotic risk. • Initial arterial thrombosis tends to be followed by arterial events, and initial venous thrombosis tends to be followed by venous events. • Incidence of developing catastrophic APS is approximately 1.0% among APS patients. REFERRAL Referrals to hematology, rheumatology, and/ or obstetric medicine should be placed when diagnosis is made.

PEARLS & CONSIDERATIONS COMMENTS • Cerebral features of SLE may be more related to thrombosis than inflammation and may respond better to anticoagulants than immunosuppression. • False-positive lupus anticoagulant (LAC) tests have been reported in patients taking direct oral anticoagulants and heparin. For this reason, thrombophilia testing should be delayed until 2 to 4 wk after completion of anticoagulation. PREVENTION Prophylaxis for asymptomatic patients with positive aPL tests without previous thrombosis: • No routine prophylaxis is recommended. • Questionable whether low-dose aspirin is effective. • Antithrombotic prophylaxis for major surgery, prolonged immobilization, and pregnancy is appropriate. • Avoid combination oral contraceptive pills in women with positive aPL tests. SUGGESTED READINGS Available at ExpertConsult.com RELATED CONTENT Antiphospholipid Antibody Syndrome (Patient Information) Deep Vein Thrombosis (Related Key Topic) Hypercoagulable State (Related Key Topic) Pulmonary Embolism (Related Key Topic) AUTHORS: Jozal Waroich, MD, and John L. Reagan, MD

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Antiphospholipid Antibody Syndrome TABLE 6  Alternative Therapies for Antiphospholipid Syndrome Target effect (in vitro and/or animal studies)

Results of human studies

Hydroxychloroquine

aPL-induced platelet activation Inhibition of aPL-mediated thrombosis in mice Protection of aPL-induced displacement of annexin A5 from phospholipin bilayers Reversal of aPL-induced endothelial cell activation and TF upregulation Abrogation of enhanced thrombus formation in mice Blocking of B-cell activating factor, which can prevent disease onset in APS mouse model

Decreases thrombotic risk in SLE Increases survival in SLE Protective against thrombosis in aPL+ individuals Decreases aPL and/or LAC in SLE patients Decrease proinflammatory and prothrombotic markers in APS Contraindicated in pregnancy

Statins Rituximab

Potential immunomodulatory approaches

Experimental Tx

Anticomplement peptides Inhibition of TF Inhibition of nuclear factor κB Inhibition of p38 MAPK Inhibition of TLR-4 Inhibition of TNF-α, or IL-6 Inhibition of apo ER2 Inhibition of mTORC Peptides mimicking domains of β2-GPI or β2-GPI receptor blockers Other biologics (Belimumab, Abatacept) Autologous hematopoietic stem cell transplantation

Effective for aPL-related cytopenias Effective for catastrophic APS Increases response in APS (off-label use) RITAPS trial: Effective for some noncriteria manifestations of APS Experimental studies (MBB2: A single-chain fragment variable recognizing β2-GP1) No human data

A

Diseases and Disorders

Treatment

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Limited data; appears to be effective and safe in APS patients

aPL, Antiphospholipid antibody; APS, antiphospholipid syndrome; β2-GPI, β2-glycoprotein I; IL-6, interleukin-6; LAC, lupus anticoagulant; MAPK, mitogen-activated protein kinase; mTORC, mammalian target of rapamycin complex; RITAPS, rituximab in antiphospholipid syndrome; SLE, systemic lupus erythematosus; TF, tissue factor; TLR, Toll-like receptor; TNF, tumor necrosis factor. Modified from Hochberg MC: Rheumatology, ed 7, Philadelphia, 2019, Elsevier.

BOX 2  Mechanisms of Thrombosis in Antiphospholipid Syndrome • Interaction between antiphospholipid antibodies and cells (endothelial cells, monocytes, platelets) • Activation of cell signaling pathways • Transcription of procoagulant factors (tissue factor) and adhesion molecules • Complement activation • Impaired nitric oxide production • Antiphospholipid antibody inactivation of fibrinolysis • Heightened release and decreased degradation of NETs NET, Neutrophil extracellular trap.

BOX 3  Mechanisms of Pregnancy Loss in Antiphospholipid Syndrome • Intraplacental thrombosis • Impaired trophoblastic invasion and hormone production • Activation of the complement system • Defective placentation due to interference of anti–β2-GPI with trophoblast growth and differentiation • Displacement of annexin A5 by IgG antiphospholipid antibody–β2-GPI complexes β2-GPI, β2-Glycoprotein I; Ig, immunoglobulin.

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Antiphospholipid Antibody Syndrome

137.e1

SUGGESTED READINGS Andrade D et  al: 15th International Congress on Antiphospholipid Antibodies Task Force on Antiphospholipid Syndrome treatment trends report. In Erkan D, Lockshin MD, editors: Antiphospholipid Syndrome, New York, Springer, pp 317-338, 2017. Carmi O et al: Diagnosis and management of catastrophic antiphospholipid syndrome, Expert Rev Hematol 10:365-374, 2017. Cervera R et al: Morbidity and mortality in the antiphospholipid syndrome during a 10-year period: a multicentre prospective study of 1000 patients, Ann Rheum Dis 74:1011-1018, 2015. Dufrost V et al: Increased risk of thrombosis in antiphospholipid syndrome patients treated with direct oral anticoagulants. Results from an international patient-level data meta-analysis, Autoimmun Rev 17:1011-1021, 2018. Kearon C et al: Antiphospholipid antibodies and recurrent thrombosis after a first unprovoked venous thromboembolism, Blood 131:2151-2160, 2018. Pengo V et al: Rivaroxaban vs warfarin in high-risk patients with antiphospholipid syndrome, Blood 132:1365-1371, 2018. Tektonidou M et al: EULAR recommendations for the management of antiphospholipid syndrome in adults, Ann Rheum Dis 78:1296-1304, 2019.

FIG. E1  Cutaneous thrombosis in antiphospholipid antibody syndrome. (From James WD et al: Andrews’ diseases of the skin, ed 12, Philadelphia, 2016, WB Saunders.)

A

B

FIG. E2  Antiphospholipid syndrome. The clinical presentations of this disorder are protean and include those shown here. A, Broad bands of livedo around the knees in a patient with anticardiolipin antibodies. Physiologic livedo has a finer patterning and less obvious lesions. B, Digital infarcts, a nonspecific feature of several vascular occlusion disorders. (From White GM, Cox NH [eds]: Diseases of the skin, a color atlas and text, ed 2, St Louis, 2006, Mosby.)

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138

Anxiety (Generalized Anxiety Disorder) BASIC INFORMATION DEFINITION Generalized anxiety disorder (GAD) is most likely to present in combination with other psychiatric and medical conditions. Individuals with GAD commonly present with excessive and disproportionately high levels of anxiety, fear, or worry for most days over at least a 6-mo period in a number of areas. The worrying must be greater than would be expected given the situation, and it must cause significant interference in functioning. The subjective anxiety must be accompanied by at least three somatic symptoms in adults and one in children (e.g., restlessness, irritability, sleep disturbance, muscle tension, difficulty concentrating, or fatigue). GAD cannot be diagnosed if it occurs only in the context of an active mood disorder, such as depression, or if the anxiety is better explained by another active anxiety disorder, such as PTSD or panic disorder. SYNONYMS Anxiety neurosis (former name for a subset of anxiety disorders) Chronic anxiety GAD ICD-10CM CODE F41.1 Generalized anxiety disorder300.02 DSM-5 CODE 300.02

EPIDEMIOLOGY & DEMOGRAPHICS INCIDENCE (IN U.S.): 6% to 9% per yr in adult primary care clinics; 1-yr incident rate per 100 persons/yr of 1.12 PEAK INCIDENCE: Peak incidence tends to occur later relative to other anxiety disorders, such as phobias; cumulative incidence of 4.3% by age 34 in a German community sample. PREVALENCE (IN U.S.): In general population: Lifetime morbid risk of 9%; 12-month prevalence of 2.9%; lifetime prevalence in the National Comorbidity Survey-Replication was 5.7%. • In primary care setting: 3% (the most common anxiety disorder in this setting) PREDOMINANT SEX: Women are more frequently affected (2:1 ratio) but may present for treatment less often (3:2 female:male). PREDOMINANT AGE: • 30% report onset before age 11 • 50% have onset before age 18 • Median age of onset: 30 yr GENETICS: Concordance rates in dizygotic twins and monozygotic twins are not different (0% to 5%) PHYSICAL FINDINGS & CLINICAL PRESENTATION • Report of being “anxious” all of their lives • Excessive worry, usually regarding family, finances, work, or health • Sleep disturbance, particularly early insomnia

• Muscle tension (typically in the muscles of neck and shoulders) or headache • Difficulty concentrating • Daytime fatigue • Gastrointestinal symptoms compatible with irritable bowel syndrome (one third of patients) • Physical symptoms are the usual reason for seeking medical attention • Comorbid psychiatric illness (e.g., dysthymia or major depression) and substance abuse (e.g., alcohol abuse) are frequent

ETIOLOGY • Hypotheses include models based on neurotransmitters (catecholamines, indolamines) and developmental psychology (e.g., behavioral inhibition, neuroticism, and harm avoidance) • Prevalence increased with a family history, increase in stress, history of physical or emotional trauma, and medical illness

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • Wide range of psychiatric and medical conditions: 1.  Cardiovascular and pulmonary disease, such as cardiac arrhythmias or COPD 2. Hyperthyroidism, hypoglycemia 3. Substance abuse (e.g., cocaine, amphetamines, and PCP) or withdrawal (e.g., alcohol or benzodiazepines) 4. Other anxiety disorders (e.g., social anxiety disorder), mood disorder 5. Intrusive thoughts in obsessive-compulsive disorder or illness anxiety disorder WORKUP • Screening tests may enhance detection. A screening tool often used in primary care is the GAD-2. It asks, “During the past month, have you been bothered a lot by: (1) Nerves or feeling anxious or on edge? (2) Worrying about a lot of different things?” The response to each question is given a score of 0 (not at all), 1 (several days), 2 (more than half of the days), 3 (nearly every day). A score of ≥3 has a sensitivity of 86% and a specificity of 83% for detecting GAD. A simple 7-item in-office case finding instrument, the GAD-7, includes additional questions to assess symptom severity and can be used to monitor symptoms. • Physical examination: Additional laboratory and radiologic workup depending on presenting symptoms. • Iatrogenic cause should be suspected if anxiety follows recent changes in medication.

TREATMENT NONPHARMACOLOGIC THERAPY • Cognitive-behavioral therapy • Acceptance and commitment therapy • R elaxation training and meditative approaches • Biofeedback • Psychodynamic psychotherapy

PHARMACOLOGIC THERAPY • Selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs) • Azapirones (e.g., buspirone) • Benzodiazepines (less favored) ACUTE GENERAL Rx • Acute treatment is rarely indicated because GAD is a chronic condition. • If patients are in acute distress, the possibility of another cause, including another anxiety disorder such as panic disorder, should be considered. • Caution in prescribing benzodiazepines because of the propensity for misuse and dependence. If used, the patient should be educated about the options and the risks. CHRONIC Rx • SSRIs and SNRIs (e.g., venlafaxine and duloxetine) are effective typical first-line treatment. Particularly useful if comorbid depression present. • Buspirone can be effective with minimal potential for tolerance or abuse. May be less effective in patients with previous benzodiazepine exposure and may require a high-dose titration. • Benzodiazepines can be effective under close supervision; however, they have fallen out of favor as a first-line treatment given their potential for functional impairment, abuse, and dependence. • Sedating antidepressants, such as mirtazapine, may also be useful for initial insomnia secondary to anxious ruminations. DISPOSITION • GAD is chronic with periodic exacerbations. • Treatment is given to reduce level of symptoms and improve functioning. Suicide risk is higher than in the general population. REFERRAL • For refractory symptoms • For comorbid psychiatric conditions

PEARLS & CONSIDERATIONS Since GAD is a risk factor for major depression, screening and early intervention for GAD (especially in women) may sometimes be helpful in reducing vulnerability to a mood disorder later in life.

SUGGESTED READINGS Available at ExpertConsult.com RELATED CONTENT Anxiety (Patient Information) Panic Disorder, with or without Agoraphobia (Related Key Topic) Social Anxiety Disorder (Related Key Topic) AUTHOR: Kristy L. Dalrymple, PhD

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138.e1

SUGGESTED READINGS Altunoz U et al: Clinical characteristics of generalized anxiety disorder: older vs. young adults, Nordic J Psychiatry 72:97-102, 2018. Curtiss J, Klemanski DH: Taxonicity and network structure of generalized anxiety disorder and major depressive disorder: an admixture analysis and complex network analysis, J Affect Disord 199:99-105, 2016. Goodwin H et al: Generalized anxiety disorder, worry and attention to threat: a systematic review, Clin Psychol Rev 54:107-122, 2017. McEvoy PM et al: Group metacognitive therapy for repetitive negative thinking in primary and non-primary generalized anxiety disorder: an effectiveness trial, J Affect Disord 175:124-132, 2015. Mennin DS et al: A randomized controlled trial of emotion regulation therapy for generalized anxiety disorder with and without co-occurring depression, J Consult Clin Psychol 86:268-281, 2018. Romero-Sanchiz P et al: Differences in clinical intrusive thoughts between obsessive-compulsive disorder, generalized anxiety disorder, and hypochondria, Clin Psychol Psychother 24:O1464-O1473, 2017.

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138.e2

Aortic Coarctation BASIC INFORMATION DEFINITION Coarctation of the aorta is a narrowing of the aorta that occurs near the ligamentum arteriosum just distal to the origin of the left subclavian artery. It causes an outflow obstruction proximal to the site of the stenosis, which leads to left ventricular pressure overload, hypertrophy, and potentially heart failure. The stenosis can be discrete or long and may have collateral vessels. It is commonly associated with other cardiac abnormalities such as a bicuspid aortic valve, patent ductus arteriosus, or ventricular septal defect. SYNONYMS Postductal coarctation of the aorta Preductal coarctation of the aorta Congenital hypoplasia of aortic arch Coarctation of the aorta ICD-10CM CODE Q25.1 Aortic coarctation

EPIDEMIOLOGY & DEMOGRAPHICS Aortic coarctation has a prevalence of approximately 4 per 10,000 live births and accounts for 4% to 6% of all congenital heart defects. It affects predominantly males, with a male to female ratio of 1.5:1. GENETICS: Although most cases are sporadic and no specific genetic mutations have been identified, there have been case reports of coarctation occurring in families. Its association with a number of other conditions, such as WilliamsBeuren and Sturge-Weber syndromes, also suggests a genetic predisposition. Most notably, up to 30% of patients with Turner syndrome also have coarctation of the aorta, and 5% to 15% of girls with coarctation have Turner syndrome. RISK FACTORS: The cause for aortic coarctation among most patients is unknown. Genetic mutation and environmental causes are possibilities. It also can be acquired through inflammatory conditions such as Takayasu arteritis or severe atherosclerosis. CLINICAL PRESENTATION & PHYSICAL FINDINGS • Clinical presentation: 1. The clinical manifestations of coarctation of the aorta depend on the age of discovery, severity of the aortic narrowing, and adequacy of collateral circulation. 2.  Neonates with severe coarctation may present with heart failure and/or shock when the ductus arteriosus closes. Neonates without severe aortic coarctation or with a persistent patent ductus arteriosus may be asymptomatic. Heart failure rarely occurs beyond the neonatal period. 3. Beyond infancy, most patients are asymptomatic. Symptoms arise from severe hypertension, which may lead to epistaxis, headache, heart failure symptoms, or aortic dissection. Claudication of the lower extremities may also occur with physical exertion.

• Physical exam findings: 1.  “Brachial-femoral” delay characterized by diminished or delayed femoral pulses compared to the brachial pulses 2. Upper extremity systolic hypertension 3. Low or unobtainable blood pressure in the lower extremities 4. Systolic ejection murmur at the left upper sternal border and left subscapular region 5. A continuous murmur heard best posteriorly over the thoracic spine may be heard if there are large collaterals 6. Systolic murmurs may be heard if there are coexisting cardiac defects (i.e., systolic ejection murmur with bicuspid aortic valve)

ETIOLOGY • The exact pathogenesis is unknown. The two main theories for potential mechanisms are reduced antegrade intrauterine flow leading to underdevelopment of the fetal aortic arch and abnormal extension of tissue from the ductus arteriosus into the wall of the fetal thoracic aorta. • In aortic coarctation, the arterial wall of the aorta has several pathologic abnormalities. There are cystic medial necrosis, increased stiffness and less distensibility, and increased collagen and less smooth muscle mass in the prestenotic segment.

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • Hypoplastic left heart syndrome • Interrupted aortic arch • Pseudocoarctation • Left ventricular outflow tract obstruction, including subaortic and supravalvular aortic stenosis • Prior surgical ligation • Critical aortic valve stenosis • Obstructive peripheral arterial disease • Aortic dissection WORKUP • Bilateral arm and leg blood pressures should be measured to search for a differential pressure. • For patients with suspected aortic coarctation, the physical exam should include simultaneous palpation of the brachial and femoral pulses to assess for “brachial-femoral delay,” which is characteristic of significant aortic coarctation. • An electrocardiogram may show left ventricular hypertrophy, ST-T wave abnormalities, and RV conduction delay. • Transthoracic echocardiogram, including suprasternal notch acoustic windows, should be performed. • Every patient with coarctation should have at least one cardiovascular MRI or CT scan for a complete evaluation of the thoracic aorta and intracranial vessels. • Cardiac catheterization is indicated when associated coronary artery disease is suspected or for therapeutic intervention of the coarctation. LABORATORY TESTS No specific laboratory tests are needed for coarctation of the aorta.

IMAGING STUDIES • Box E1 summarizes important findings in the imaging evaluation of coarctation of the aorta. Anomalies associated with aortic coarctation are described in Box E2. • Chest x-ray (Fig. E1): 1. Posterior rib notching of ribs 3 to 8 is due to bony erosion by large collateral arteries. 2. The “3” sign is formed by indentation of the aortic wall at the site of the coarctation with pre- and postcoarctation dilation. • Echocardiography: 1. Generally, echocardiography can establish the diagnosis and severity of coarctation of the aorta, but it is less useful for postoperative patients or for adult patients who may have less favorable acoustic windows compared with children. 2.  Aortic narrowing is visualized in the suprasternal notch view. 3. Color flow imaging and pulsed Doppler localize the area of coarctation. 4. Continuous wave Doppler estimates the severity of coarctation. The presence of collaterals may diminish the gradient across the coarctation; the gradient may be less severe than expected for the degree of the obstruction. 5.  Associated cardiac defects, chamber sizes, and left ventricular function can be evaluated. • Magnetic resonance imaging and computed tomography: 1. Per the ACC/AHA adult congenital heart disease guidelines, every adult patient with coarctation should have at least one cardiovascular MRI (Fig. E2, Fig. E3) or CT (Fig. E4) or a complete evaluation of the thoracic aorta. 2. The modalities have very high diagnostic accuracy (>95%) in detecting coarctation of the aorta and its associated abnormalities. 3. Both provide a large field of view and allow simultaneous visualization of the ascending aorta, aortic arch, descending aorta, aortic valve, and collaterals. 4. CT and MRI are indicated for serial follow up imaging after surgical repair to assess for aortic dilatation or aneurysm formation. 5. MRI is preferred to CT to decrease the lifetime exposure to radiation. • Cardiac catheterization: 1. Cardiac catheterization (Fig. E5) may be used to assess the peak gradient across the coarctation but is usually performed in conjunction with a therapeutic intervention (balloon angioplasty or stent placement).

TREATMENT ACUTE GENERAL Rx • Infants with critical coarctation are at risk for heart failure and death once the ductus arteriosus closes. Treatments include: 1. Continuous intravenous infusion of prostaglandin E1 to keep the ductus arteriosus patent

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138.e3

BOX E1  Imaging Evaluation of Coarctation of the Aorta Patency of the Ductus Arteriosus Closed Patent Flow from aorta to pulmonary artery (typically postductal coarctation) Flow from pulmonary artery to aorta (preductal coarctation or pulmonary hypertension) Collateral Pathways Scarce (typical of patients under 2 yr of age) Abundant Bridging the coarctated segment Internal mammary to intercostal to distal aorta Circumscapular pathways to distal aorta Other Arch Anomalies and Stenoses Arch interruption Double aortic arch with stenosis in either or both arches Coarctation proximal to left subclavian artery Takayasu aortitis, rubella, Williams syndrome, neurofibromatosis, mucopolysaccharidosis, and other causes of stenoses not in the aortic isthmus Subclavian Artery Anomalies Atresia or stenosis of the left subclavian artery Aberrant retroesophageal right subclavian artery Proximal to the coarctation Distal to the coarctation Origin of both subclavian arteries distal to the coarctation Associated Lesions Cardiac, such as ventricular septal defect or bicuspid aortic valve Aneurysms: In aorta adjacent to coarctation In the ductus In the intercostal arteries In the circle of Willis Boxt LM, Abbara S: Cardiac imaging: the requisites, ed 4, Philadelphia, 2016, Elsevier.

BOX E2  Anomalies Associated with Aortic Coarctation Common Bicuspid aortic valve with stenosis and regurgitation Patent ductus arteriosus Ventricular septal defects Turner syndrome Rare: Transposition of the great arteries Double-outlet right ventricle Shone syndrome (parachute mitral valve, supramitral ring, aortic valve stenosis, and aortic coarctation) Boxt LM, Abbara S: Cardiac imaging: the requisites, ed 4, Philadelphia, 2016, Elsevier.

2. Dopamine and/or dobutamine to increase contractility for those with heart failure 3. Surgical repair once the patient is stabilized

CHRONIC Rx • Systemic hypertension should be treated with angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, or beta-blockers. • All patients with aortic coarctation should have long-term follow up with a congenital heart disease specialist. • After repair, a CT or MRI of the repair site should be obtained at 1 yr postoperatively and then every 5 yr or less depending on anatomy to detect long-term complications. NONPHARMACOLOGIC THERAPY Aortic coarctation can be repaired surgically or percutaneously by balloon angioplasty and/

or stent placement. The choice of intervention is made on an individual basis based on aortic morphology and should be determined by a multidisciplinary team including cardiologists, interventionalists, and cardiac surgeons who are experienced in treating patients with congenital heart disease. • Repair should be performed in infancy or early childhood to prevent the common complications of unrepaired coarctation, including systemic hypertension, accelerated coronary artery disease, stroke, heart failure, and aortic dissection. • The indications for intervention according to the ACC/AHA guidelines for the management of adults with congenital heart disease are: 1.  Peak-to-peak coarctation gradient ≥20 mm Hg (Level of evidence C). 2. Peak-to-peak coarctation gradient 22 mm. 5. There is ongoing debate about a possible beneficial role of TEVAR for uncomplicated type B dissections. Data suggest that 30% of uncomplicated type B dissections will progress to an aneurysm.

ACUTE GENERAL Rx • Admit to ICU for monitoring. • Target systolic blood pressure 100 to 120 mm Hg; heart rate 4.5 cm ≥5.0 cm >4.5 cm 4.0-4.5 cm 4.5-5.0 cm >2.5 cm/m2

*Lower thresholds for intervention may be considered according to body surface area in patients of small stature or in the case of rapid growth of the aorta. Age, body size, rapid growth, family history, risk of surgery, and patient and physician wishes may influence aortic size threshold. †Family history of aortic dissection or aortic growth rate of 0.5 cm or more per yr or if the patient is at low surgical risk (3 mm/yr), or severe aortic or mitral regurgitation. If pregnancy desired, consider prophylactic aortic surgery for aortic diameter of 4.0 to 4.5 cm. §It is reasonable to consider surgical repair of the aorta in adults with Loeys-Dietz syndrome or a confirmed TGFBR1 or TGFBR2 mutation with aortic diameter of 4.2 cm or more by transesophageal echocardiogram or 4.4 to 4.6 or more by CT or MRI. Aortic surgery at smaller diameters may be recommended when there are severe craniofacial features, rapid growth, or a family history of aortic dissection. ¶Surgical thresholds vary depending on the specific gene mutation involved. TAA caused by ACTA2, SMAD3, and MYLK may lead to aortic dissection at relatively small aortic diameters. From Zipes DP: Braunwald’s heart disease, a textbook of cardiovascular medicine, ed 11, Philadelphia, 2019, Elsevier.

TABLE 6  Indications for Thoracic Endovascular Aortic Repair for Type B Aortic Dissection* Rupture Impending rupture Malperfusion Hemorrhagic pleural effusion Refractory pain Refractory hypertension Aneurysmal dilation (>55 mm) Rapid increase in diameter Recurrent symptoms *Or open surgical repair if anatomy is unsuitable for TEVAR. From Zipes DP: Braunwald’s heart disease, a textbook of cardiovascular medicine, ed 11, Philadelphia, 2019, Elsevier.

CHRONIC Rx • Chronic aortic dissection (>2 wk) managed with aggressive blood pressure control; target 20 mm Hg over the brachial systolic pressure (Hill sign); a 40 to 60 mm difference represents moderate AR and >60 mm difference, severe AR • Findings more of historical than practical interest, which are neither sensitive nor specific, include: 1. Mueller sign—Systolic pulsations of the uvula 2. Becker sign—Visible pulsations of the retinal arteries and pupils 3.  Mayne sign—More than a 15 mm Hg decrease in diastolic blood pressure with arm elevation from the value obtained with the arm in the standard position 4.  Rosenbach sign—Systolic pulsations of the liver 5.  Gerhard sign—Systolic pulsations of the spleen

Aortic Regurgitation

I

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • Patent ductus arteriosus, pulmonary regurgitation, and other valvular abnormalities. • The differential diagnosis of cardiac murmurs is described in Sections II and III. WORKUP • Echocardiogram, chest radiograph, electrocardiogram (ECG), cardiac magnetic resonance (CMR) imaging, and cardiac catheterization (selected patients). • Medical history and physical examination focused on dyspnea on exertion, syncope, chest pain, and CHF IMAGING STUDIES • Chest radiography: 1. Left ventricular hypertrophy (LVH) (chronic AR) 2. Aortic dilation 3.  Normal cardiac silhouette with pulmonary edema: Possible in patients with acute AR

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Aortic Regurgitation

ALG

TABLE 2  Stages of Chronic Aortic Regurgitation Stage

Definition

Valve Anatomy

Valve Hemodynamics

Hemodynamic Consequences

Symptoms

A

At risk of AR

AR severity none or trace

None

None

B

Progressive AR

Bicuspid aortic valve (or other congenital valve anomaly) Aortic valve sclerosis Diseases of the aortic sinuses or ascending aorta History of rheumatic fever or known rheumatic heart disease IE Mild to moderate calcification of a trileaflet valve bicuspid aortic valve (or other congenital valve anomaly) Dilated aortic sinuses Rheumatic valve changes Previous IE

Normal LV systolic function Normal LV volume or mild LV dilation

None

C

Asymptomatic severe AR

Calcific aortic valve disease Bicuspid valve (or other congenital abnormality) Dilated aortic sinuses or ascending aorta Rheumatic valve changes IE with abnormal leaflet closure or perforation

Mild AR: Jet width 60 ml per/beat). • CMR is indicated (class 1) in patients with moderate or severe AR and suboptimal echocardiographic images for the assessment of AR severity as well as LV systolic function and volumes.

• Cardiac catheterization is indicated in selected patients to assess the degree of left ventricular dysfunction and AR when echocardiographic parameters are inconclusive, and to determine if there is coexistent coronary artery disease. • Serial evaluation of the size and morphology of the aortic sinuses and ascending aorta by echocardiography, CMR, or CT angiography is recommended in patients with a bicuspid

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ALG AV and an aortic diameter >4.0 cm, with the examination interval determined by the degree and rate of progression of aortic dilation and by family history. Patients with an aortic diameter >4.5 cm should be evaluated annually (Class 1).

TABLE 3  American College of Cardiology/American Heart Association Guidelines for Aortic Valve Replacement (AVR) for Chronic Aortic Regurgitation (AR) Indication

Loe

I

AVR for symptomatic patients with severe AR regardless of LV systolic function (stage D). AVR for asymptomatic patients with chronic severe AR and LV systolic dysfunction (LVEF 50 mm). AVR is reasonable in patients with moderate AR (stage B) who are undergoing other cardiac surgery. AVR may be considered for asymptomatic patients with severe AR and normal LV systolic function (stage C1, LVEF ≥50%) but severe LV dilation (LVEDD >65 mm) if surgical risk is low.*

B

CHRONIC Rx Management depends on whether patients are symptomatic and candidates for valve surgery. ACC/AHA guidelines for aortic valve replacement for chronic aortic regurgitation are summarized in Table 3. • Symptomatic patients with severe AR who are candidates for valve surgery should proceed with valve replacement after medical optimization of heart failure. When surgery is contraindicated, TAVR is currently under assessment for treatment of native AR. • Asymptomatic patients with severe AR and systolic dysfunction who are not surgical candidates should receive ACE/ARBs. • Other medical treatments for AR are based on limited studies. Beta-blocker use is controversial but has been associated with a higher survival rate in severe AR. Vasodilatory therapies (nifedipine and enalapril) have failed to show benefit in reducing the need for

IIb

B C B C C

*Particularly in the setting of progressive LV enlargement. LOE, Level of evidence; LV, left ventricular; LVEDD, LV end-diastolic dimension; LVEF, LV ejection fraction; LVESD, LV end-systolic dimension. From Zipes DP et al: Braunwald’s heart disease, a textbook of cardiovascular disease, ed 11, Philadelphia, 2019, Elsevier.

or delaying AV replacement in asymptomatic, severe AR with normal systolic function, but ACE/ARB therapy may indeed benefit moderate to severe AR. Long-term vasodilator therapy with ACE inhibitors or nifedipine may be used in patients who have concomitant hypertension. There is no current definitive indication of medical therapy with afterload reduction for aortic regurgitation other than hypertension control. • Beta-blockers in combination with ACE inhibitors are reasonable in patients with symptomatic severe AR or LV dysfunction when surgery cannot be performed because of concomitant comorbidities. In a retrospective cohort study of 756 patients with chronic AR, beta-blocker therapy was associated with decreased mortality. Patients treated with beta-blockers were more likely to be taking ACE inhibitors and dihydropyridine calcium channel blockers as well (53% vs. 40%). In the same study, patients treated with betablockers and undergoing AVR were also noted to have a mortality benefit. • Diuretics and sodium restriction for CHF. • Comparable efficacy of losartan and atenolol was shown in curbing aortic root dilatation growth in children and young adults (6 mo to 25 yr) with Marfan syndrome with similar outcomes of aortic regurgitation severity, surgery, aortic dissection, and death at 3 yr. Fig. 3 describes a management strategy for patients with chronic severe AR.

Diseases and Disorders

ACUTE GENERAL Rx • Emergent AV replacement (preferred) or repair for acute, severe AR • Intraaortic balloon pump is contraindicated • Afterload reduction: Angiotensin-converting enzyme (ACE) inhibitors and vasodilators (i.e., nitroprusside) in acute AR; diuretics for pulmonary edema • Avoid beta-blockers that can prolong diastole • Emergent surgical referral for cardiogenic shock

IIa

145

A

Class

TREATMENT NONPHARMACOLOGIC THERAPY • Avoidance of competitive sports and heavy weight lifting if: severe AR, patient is symptomatic, ejection fraction 50%, but with left ventricular dilation: 1. Echocardiographic end-systolic dimension >50 mm (Class IIa level of evidence) or; 2. Echocardiographic end-diastolic dimension >65 mm with low surgical risk (Class IIb) SUGGESTED READINGS Available at ExpertConsult.com RELATED CONTENT Aortic Insufficiency (Patient Information) AUTHORS: Sarthak Khare, MD, and Argyro Papafilippaki, MD, FACC

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Aortic Regurgitation

ALG Class I Aortic regurgitation

Class IIa Class IIb

Severe AR (stages C and D) Vena contracta >0.6 cm Holodiastolic aortic flow reversal Rvol ≥ 60 mL/beat RF ≥ 50% ERO ≥0.3 cm2 LV dilation

Progressive AR (stage B) Vena contracta ≤ 0.6 cm Rvol 1 yr of age or mebendazole 500 mg PO × 1 dose for persons >1 yr of age (not available as 500 mg in the U.S.) • Cure rate with these agents is 95% to 100%, but they are contraindicated in pregnancy. • Side effects: GI discomfort, headache, and rarely leukopenia • Alternative agent or for use in pregnancy: Pyrantel pamoate (Antiminth) 1. Given at a dose of 11 mg/kg PO (maximum dose of 1 g/day) 2. Considered safe for use in pregnant women • Other alternative agents: 1. Ivermectin: 150 to 200 mcg/kg orally once 2. Nitazoxanide: Ages 2 to 3 yrs: 100 mg/5 ml bid × 3 days, and ages 4 to 11 yrs: 200 mg/10 ml bid × 3 days. Cure rates in heavy worm burden are only 50% to 80% 3. Piperazine citrate: No longer first-line agent due to toxicity but still used in cases of intestinal or biliary obstruction, as drug paralyzes the worm, helping its expulsion. Dose: 50 to 75 mg/kg once daily up to maximum of 3.5 g for 2 days 4. Levamisole: 2.5 mg/kg once orally is recommended by the WHO as alternative therapy, but not available in the U.S. • Complete obstruction should be managed surgically. DISPOSITION Overall prognosis is good. Patients should be reevaluated in 2 to 3 mo. Reinfection is common. REFERRAL • To gastroenterologist in cases of visualized pancreaticobiliary tract or appendiceal obstruction

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Ascariasis • To surgeon in cases of complete obstruction or suspected secondary complication (e.g., perforation or volvulus)

PEARLS & CONSIDERATIONS

• Given the known transmission of the parasite, routine hand washing with soap and proper disposal of human waste would significantly decrease the prevalence of this disease. • Other protective measures to avoid ingestion of worm eggs: 1. Peel or cook food. 2. Boil drinking water. 3. Do not place small children directly on soil.

SUGGESTED READINGS Available at ExpertConsult.com

RELATED CONTENT Ascariasis (Patient Information) AUTHOR: Glenn G. Fort, MD, MPH

A

Diseases and Disorders

COMMENTS • Hepatic abscess, containing both viable and dead worms, complicating Ascarisinduced biliary duct disease has been documented.

159

I

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Ascariasis

159.e1

SUGGESTED READINGS Das AK: Hepatic and biliary ascariasis, J Glob Infect Dis 6:65-72, 2014. Dold C, Holland CV: Ascaris and ascariasis, Microbes Infect 13:632-637, 2011. Jourdan PM et al: Soil-transmitted helminths in infections, Lancet 391:252-265, 2018. Lamberton PH, Jourdan PM: Human ascariasis: diagnostic update, Curr Trop Med Rep 2:189-200, 2015.

TABLE E1  Features of Major Intestinal Nematodes Direct Personto-Person Transmission

Geographic Distribution

Duration of Infection

Location of Adult Worm(s)

No

Warm, humid areas; temperate zones in warmer months

1-2 yr

Free in lumen of small bowel, primarily jejunum

Ingestion of infective eggs

No

1-3 yr

Necator americanus, Ancylostoma duodenale (hookworm)

Penetration of skin by filariform larvae

No

Warm, humid areas; temperate zones in warmer months Warm, humid areas; temperate zones in warmer months

Anchored in superficial mucosa of cecum and colon Attached to mucosa of mid to upper portion of small bowel

Strongyloides stercoralis

Penetration of skin or bowel mucosa by filariform larvae Ingestion of infective eggs

Yes

Primarily warm, humid areas but can be worldwide

Lifetime of host

Embedded in mucosa of duodenum, jejunum

Yes

Worldwide

1 mo

Free in lumen of cecum, appendix, adjacent colon

Nematode

Transmission

Ascaris lumbricoides

Ingestion of infective eggs

Trichuris trichiura (whipworm)

Enterobius vermicularis (pinworm)

3-5 yr (Necator); 1 yr (Ancylostoma)

Treatment* Albendazole Mebendazole Pyrantel Ivermectin Levamisole Piperazine Albendazole Mebendazole Albendazole Mebendazole Levamisole Pyrantel Ivermectin† Albendazole Thiabendazole Albendazole Mebendazole Pyrantel Ivermectin Levamisole Piperazine

*Nitazoxanide has been shown to be effective in the treatment of ascariasis, trichuriasis, and enterobiasis in several trials in Mexico. Tribendimidine, which is licensed in China, was shown to be efficacious against Ascaris spp. and had moderate efficacy against Strongyloides spp. in a randomized trial. †Drug of choice. From Bennett et al: Mandell, Douglas, and Bennett’s principles and practice of infectious diseases, ed 8, Philadelphia, 2015, WB Saunders.

FIG. E1  Ascaris lumbricoides ovum in feces. The ovum measures 50 to 70 mm × 40 to 50 mm and is elliptical. The rough albuminous coat gives it a mammillated appearance. (From Cohen J, Powderly WG: Infectious diseases, ed 2, St Louis, 2004, Mosby.)

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Ascites BASIC INFORMATION DEFINITIONS Ascites refers to a pathologic accumulation of fluid in the peritoneal cavity, most commonly caused by liver cirrhosis. • Diuretic-resistant ascites: Ascites that cannot be mobilized or the early recurrence of which cannot be prevented because of lack of response to dietary sodium restriction and maximal doses of diuretics. • Diuretic-intractable ascites: Ascites that cannot be mobilized or the early recurrence of which cannot be prevented because of the development of diuretic-induced complications that precludes the use of effective doses of diuretics. SYNONYMS Peritoneal cavity fluid Hydroperitoneum Hydroperitonia Hydrops abdominis ICD-10CM CODES R18 Ascites C78.6 Malignant ascites K70.11 Alcoholic hepatitis with ascites K70.31 Alcoholic cirrhosis of liver with ascites K71.51 Toxic liver disease with chronic active hepatitis with ascites R18.8 Other ascites

EPIDEMIOLOGY & DEMOGRAPHICS Ascites is the most common complication of cirrhosis and signifies decompensation of chronic liver disease. Ascites occurs at a rate of 7% to 10% annually in cirrhotic patients. Ascites occurs in ∼60% of individuals with cirrhosis within 10 yr of diagnosis. Cirrhosis is the cause of 85% of cases of ascites. CLINICAL PRESENTATION & PHYSICAL FINDINGS • Important information to elicit within history: 1. History of viral hepatitis 2. Alcoholism 3. Intravenous drug use, intranasal cocaine use 4. Sexual history (i.e., men who have sex with men) 5. History of transfusions, tattoos, piercings, imprisonment 6. Travel history and time spent in endemic regions for hepatitis 7.  Symptoms suggestive of peritoneal malignancy (e.g., weight loss, pain, palpable masses, rectal/vaginal bleeding) 8.  Other liver disease symptoms (e.g., increasing abdominal girth, jaundice, pruritus, confusion, pedal edema) 9. Cardiac symptoms (e.g., pedal edema, shortness of breath, orthopnea, chest pain)

10.  Hypothyroid disease (fatigue, weight gain, constipation) 11. History of ascites, prior treatment, LVP requirements and frequency • Important physical exam findings: 1. Protuberant abdomen (Fig. E1) 2. Bulging flanks (can be present in obesity) 3.  Flank dullness to percussion (requires ∼1500 ml of fluid) 4. Fluid wave on abdominal exam 5. Lower extremity edema 6. Shifting dullness on abdominal exam 7. Physical signs associated with liver cirrhosis: Spider angiomas, jaundice, loss of body hair, skeletal muscle wasting (sarcopenia), Dupuytren contracture, bruising, palmar erythema, gynecomastia, testicular atrophy, rectal varices, and caput medusae

ETIOLOGY Pathophysiology of ascites (Fig. E2): Increased hepatic resistance to portal flow leads to portal hypertension. A portal pressure >12 mm Hg appears to be required for fluid retention. The splanchnic vessels respond by increased secretion of nitric oxide, causing splanchnic artery vasodilation. Vasodilation appears also to be mediated by the translocation of enteric bacteria and bacterial products. Early in the disease increased plasma volume and increased cardiac output compensate for this vasodilation. However, as the disease progresses the effective arterial blood volume decreases, causing sodium and fluid retention through activation of the renin-angiotensin system. Over time activation of the sympathetic system causes renal vascular perfusion to decrease and may lead to hepatorenal syndrome. The change in capillary pressure causes increased permeability and retention of fluid in the abdomen.

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • Chronic parenchymal liver disease, leading to portal hypertension • Acute liver failure • Noncirrhotic portal hypertension (e.g., portal vein clot) • Peritoneal carcinomatosis • Cardiac disease (e.g., heart failure, constrictive pericarditis) • Hepatic venous outflow obstruction (e.g., Budd-Chiari syndrome, IVC webs) • Protein losing enteropathy • Peritoneal tuberculosis • Nephrotic syndrome • Pancreatitis LABORATORY TESTS • Initial evaluation should always include: 1. Diagnostic paracentesis. Laboratory tests on this fluid should include a cell count and differential, cytology, albumin, total protein, culture, and Gram stain. A serumascites albumin gradient (SAAG) should

be calculated in all patients. The SAAG is measured by subtracting the level of albumin in the ascitic fluid from a ­concurrent serum albumin measurement: SAAG = serum albumin – ascites albumin a. If the SAAG is greater than 1.1, the cause of ascites can be attributed to portal hypertension (from Cirrhosis, Budd-Chiari syndrome) or heart failure. b. If SAAG is less than 1.1, a non-portal hypertension etiology of ascites must be sought. Optional tests on paracentesis fluid include amylase, LDH, acid-fast bacilli, and glucose levels. c. Total ascitic fluid protein assess the risk of spontaneous bacterial peritonitis (SBP). Patients with protein concentration 80% FEV1/FVC 75%-80% FEV1/FVC 2 days/wk or multiple times on ≤2 days/wk ≥2×/mo Some limitation >2 days/wk

Throughout the day ≥2×/wk Extremely limited Several times per day

>80% predicted/personal best

60%-80% predicted/per80% predicted 75%-80% 2 days/wk but not daily 1-2×/mo >2 days/wk but not daily

Daily 3-4×/mo Daily

Throughout the day >1×/wk Several times per day

None

Minor limitation

Some limitation

Extremely limited

≥2 exacerbations in 6 mo requiring oral systemic corticosteroids, or ≥4 wheezing episodes/1 yr lasting >1 day AND risk factors for persistent asthma. Consider severity and interval since last exacerbation. Frequency and severity may fluctuate over time. Exacerbations of any severity may occur in patients in any severity category. Step 1 Step 2 Step 3 and consider short course of oral systemic corticosteroids In 2-6 wk, depending on severity, evaluate level of asthma control that is achieved. If no clear benefit is observed in 4-6 wk, consider adjusting therapy or alternative diagnoses. 0-1 per yr

The stepwise approach is meant to assist, not replace, the clinical decision-making required to meet individual patient needs. Level of severity is determined by assessment of both impairment and risk. Assess impairment domain by patient’s/caregiver’s recall of previous 2-4 wk. Symptom assessment for longer periods should reflect a global assessment such as inquiring whether the patient’s asthma is better or worse since the last visit. Assign severity to the most severe category in which any feature occurs. At present, there are inadequate data to correspond frequencies of exacerbations with different levels of asthma severity. For treatment purposes, patients who had ≥2 exacerbations requiring oral systemic corticosteroids in the past six months, or ≥4 wheezing episodes in the past year, and who have risk factors for persistent asthma may be considered the same as patients who have persistent asthma, even in the absence of impairment levels consistent with persistent asthma. To access the complete Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma, go to www.nhlbi.nih.gov/guidelines/asthma/asthgdln.pdf. EIB, Exercise-induced bronchospasm. From National Asthma Education and Prevention Program: Expert panel report 3: guidelines for diagnosis and management of asthma, National Institutes of Health, National Heart, Lung, and Blood Institute, August 2007, NIH publication 08-4051.

TABLE 9  Assessing Asthma Control and Adjusting Therapy in Children 0-4 Yr of Age CLASSIFICATION OF ASTHMA CONTROL (0-4 YR OF AGE) Components of Control Impairment

Risk

Symptoms Nighttime awakenings Interference with normal activity Short-acting beta2-agonist use for symptom control (not prevention of EIB) Exacerbations requiring oral systemic corticosteroids Treatment-related adverse effects

Recommended Action for Treatment

Well Controlled

Not Well Controlled

Very Poorly Controlled

≤2 days/wk ≤13/mo None ≤2 days/wk

>2 days/wk >1×/mo Some limitation >2 days/wk

Throughout the day >1×/wk Extremely limited Several times per day

0-1 per yr

2-3 per yr

>3 per yr

Medication side effects can vary in intensity from none to very troublesome and worrisome. The level of intensity does not correlate to specific levels of control but should be considered in the overall assessment of risk. Maintain current step. Step up 1 step. Consider short course of oral sysRegular follow-up every 1-6 Reevaluate in 2-6 wk. temic corticosteroids. mo. If no clear benefit in 4-6 Step up 1-2 steps. Consider step down if well conwk, consider alternative Reevaluate in 2 wk. trolled for at least 3 mo. diagnoses or adjusting If no clear benefit in 4-6 wk, contherapy. sider alternative diagnoses or For side effects, conadjusting therapy. sider alternative treatment For side effects, consider alternaoptions. tive treatment options.

The stepwise approach is meant to assist, not replace, the clinical decision-making required to meet individual patient needs. The level of control is based on the most severe impairment or risk category. Assess impairment domain by caregiver’s recall of previous 2 to 4 wk. Symptom assessment for longer periods should reflect a global assessment such as inquiring whether the patient’s asthma is better or worse since the last visit. At present, there are inadequate data to correspond frequencies of exacerbations with different levels of asthma control. In general, more frequent and intense exacerbations (e.g., requiring urgent, unscheduled care, hospitalization, or ICU admission) indicate poorer disease control. For treatment purposes, patients who had ≥2 exacerbations requiring oral systemic corticosteroids in the past year may be considered the same as patients who have not-well-controlled asthma, even in the absence of impairment levels consistent with not-well-controlled asthma. Before step up in therapy: • Review adherence to medications, inhaler technique, and environmental control. • If an alternative treatment option was used in a step, discontinue it and use preferred treatment for that step. EIB, Exercise-induced bronchospasm; ICU, intensive care unit. From National Asthma Education and Prevention Program: Expert panel report 3: guidelines for diagnosis and management of asthma, National Institutes of Health, National Heart, Lung, and Blood Institute, August 2007, NIH publication 08-4051.

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Asthma TABLE 10  Stepwise Approach for Managing Asthma in Children 0-4 Yr Intermittent Asthma

A

Persistent Asthma: Daily Medication Consult with asthma specialist if step 3 care or higher is required. Consider consultation at step 2.

Step 2

Step 3 Preferred: Medium-dose ICS

Step 4 Preferred: Medium-dose ICS either LABA or montelukast

Step 5 Preferred: High-dose ICS either LABA or montelukast

Step 6 Preferred: High-dose ICS either LABA or montelukast Oral systemic corticosteroid

Alternative: Cromolyn or montelukast

Step up if needed (first, check adherence, inhaler technique, and environmental control) Assess control Step down if possible

Preferred: SABA prn

(and asthma is well controlled at least 3 months)

Patient Education and Environmental Control at Each Step

Diseases and Disorders

Preferred: Low-dose ICS

Step 1

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Quick-Relief Medication for All Patients • SABA as needed for symptoms. Intensity of treatment depends on severity of symptoms. • With viral respiratory infection: SABA q 4-6 hours up to 24 hours (longer with physician consult). Consider short course of oral systemic corticosteroids if exacerbation is severe or patient has history of previous severe exacerbations. • Caution: Frequent use of SABA may indicate the need to step up treatment. See text for recommendations on initiating daily long-term-control therapy. The stepwise approach is meant to assist, not replace, the clinical decision-making required to meet individual patient needs. If alternative treatment is used and response is inadequate, discontinue it and use the preferred treatment before stepping up. If clear benefit is not observed within 4 to 6 wk and patient/family medication technique and adherence are satisfactory, consider adjusting therapy or alternative diagnosis. Studies on children 0 to 4 yr are limited. Step 2 preferred therapy is based on Evidence A. All other recommendations are based on expert opinion and extrapolation from studies in other children. This information is directly abstracted from the 2007 NAEPP Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma and is not intended to promote or endorse any of the listed products. ICS, Inhaled corticosteroid; LABA, inhaled long-acting beta2-agonist; prn, as necessary; SABA, inhaled short-acting beta2-agonist. From National Asthma Education and Prevention Program: Expert panel report 3: guidelines for diagnosis and management of asthma, National Institutes of Health, National Heart, Lung, and Blood Institute, August 2007, NIH publication 08-4051.

• In the future, treatments tailored to asthma phenotypes may improve asthma outcomes. Treatment of status asthmaticus is as follows: • Oxygen generally started at 2 to 4 L/min by nasal cannula or Venti-Mask at 40% Fio2; further adjustments are made according to oxygen saturations. • Bronchodilators: Initiate treatment with highdose SABA plus ipratropium bromide administered by means of a nebulizer every 20 min. Use of a metered-dose inhaler with valved holding chamber may be acceptable for patients with mild-to-moderate exacerbations. • Albuterol nebulizer solution (0.63 mg/3 ml, 1.25 mg/3 ml, 2.5 mg/3 ml, or 5.0 mg/ml): 2.5 to 5 mg every 20 min over the first hr, then 2.5 to 10 mg every 1 to 4 hr as needed or 10 to 15 mg/hr continuously. Other useful medications are levalbuterol nebulizer solution (0.31 mg/3 ml, 0.63 mg/3 ml, 1.25 mg/3 ml) and ipratropium nebulizer solution (0.25/ ml [0.025%]). • Corticosteroids: 1. Early administration is advised, particularly in patients using steroids at home. 2. Patients may be started on systemic corticosteroids; methylprednisolone, prednisone, or prednisolone may be used. Dose

range is from 40-80 mg/day in one or two divided doses, generally given until peak expiratory flow reaches 70% of predicted value. 3. Generally for corticosteroid courses 92% Use heated cascade humidifier to avoid dry air–induced bronchoconstriction

Transient drop in O2 tension with beta-adrenergic therapy Avoid hyperoxia (may be associated with hypercarbia)

Albuterol: 2.5-5 mg (0.5-1 ml of 0.5% solution in 5 ml of normal saline) by nebulizer every 20 min for 3 doses total (for optimal delivery, dilute aerosols to a minimum of 3 ml at gas flow of 6-8 L/min), followed by 2.5-10 mg q1-4h as needed, or 10-15 mg/h continuously; titration based on response and severity of symptoms Albuterol MDI, delivered with a spacer (each spacer dose takes 1-2 min; 90 μg/puff), 4-8 puffs every 20 min for 4 h, then q4h as needed Albuterol: 5-7.5 mg by jet nebulizer (each treatment takes 15-20 min) Levalbuterol (0.63 mg/3 ml and 1.25 mg/3 ml nebulizer): 1.252.5 mg every 20 min for 3 doses total, then 1.25-5 mg q1-4h as needed, or 5-7.5 mg/h continuous nebulization Levalbuterol MDI (45 μg/puff): 4-8 puffs every 20 min for 4 h, followed by q1-4h as needed Subcutaneous epinephrine dose for adults: 0.3-0.5 ml of a 1:1000 dilution (1 mg/ml), depending on age and weight; repeat every 20 min for 3 doses total Subcutaneous terbutaline, 0.25 mg; repeat every 20 min for 3 doses total

Beta2-selective agonists are the cornerstone of therapy Continuous nebulization used for a majority of severely ill patients In study of continuous vs. intermittent therapy in severe exacerbations (excluding life-threatening asthma), no difference noted in pulmonary function improvement or need for hospitalization Lower frequency of side effects with continuous treatment Watch for hypokalemia, tremors, tachycardia, and lactic acidosis Oral or parenteral route: Loss of beta2-selectivity MDI: 4 puffs of albuterol (0.36 mg) = 2.5 mg of albuterol nebulization Levalbuterol 0.63 mg = racemic albuterol 1.25 mg for efficacy and side effects Intubated patients: Nebulizers are less efficient in delivering doses to lower airways (6-10%) than MDIs (11%)

Ipratropium bromide: 0.5 mg by nebulizer (0.25 mg/ml) every 20 min for 3 doses, then q2-4h as needed Ipratropium MDI (0.018 mg/puff): 4-8 puffs per treatment every 20 min for up to 3 h Combinations: Albuterol (2.5 mg/3 ml) + ipratropium (0.5 mg/3 ml): 3 ml every 20 min for 3 doses total, then as needed MDI delivering albuterol 90 μg + ipratropium 18 μg: 8 puffs every 20 min for up to 3 h 40-80 mg/day in 1 or 2 divided doses until peak expiratory flow reaches 70% of predicted or personal best FEV1 or PEFR 90%. • Counseling points for women with average risk interested in contralateral prophylactic mastectomy (CPM) are summarized in Box 3. • Selective estrogen receptor modulators (SERM) reduce the incidence of hormone receptor-positive invasive breast cancer by 50%. • Ovarian failure is a common toxic effect of chemotherapy. Administration of the gonadotropin-releasing hormone (GnRH) agonist Goserelin appears to protect against ovarian failure, reducing the risk of early menopause and improving prospects for fertility.

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Breast Cancer

ALG

TABLE 10  Breast Cancer Screening Recommendations by Organization Organization

When to Initiate Screening

Frequency of Screening

When to Stop Screening

American Academy of Family Physicians (AAFP) American Cancer Society (ACS)

Follow U.S. Preventive Services Task Force (USPSTF) recommendations Opportunity to begin screening at ages 40-44 Regular screening starting at age 45 Annual screening starting at age 40

Follow USPSTF recommendations

Follow USPSTF recommendations

Annually from age 45-54 Biennially starting at age 55 with opportunity to continue annually Annually

Continue screening mammography as long as overall health is good and life expectancy is 10 yr or longer Not specified

Individualized for women ages 40-49 Regular screening starting at age 50 Annual screening starting at age 40

Biennially

National Comprehensive Cancer Network (NCCN)

Annual screening starting at age 40

Annually

U.S. Preventive Services Task Force (USPSTF)

Individualized for women ages 40-49 Regular screening beginning at age 50

Biennially

Age 75 yr or older Women of any age with life expectancy 37 wk. Success rates range from 16% to 100%. Adequate uterine relaxation is essential. Use of terbutaline and/or epidural anesthesia improves success rates. Data are not adequate to establish absolute or relative contraindications; must individualize. Contraindicated if vaginal delivery is not appropriate. In general, contraindicated with active placental abruption, placenta previa, certain fetal anomalies, version of a first breech presenting multiple gestation, or nonreassuring fetal status. Other relative contraindications: Perform with caution with low-lying placenta, prior uterine incision, and preterm gestation. Informed consent includes risks of abruption, cord prolapse, rupture of membranes, stillbirth, and hemorrhage (37 wk (proceed with caution in preterm delivery of the breech fetus; consider Maternal-Fetal Medicine consultation in these situations) • Estimated fetal weight, 2500 to 4000 g— recognizing inherent error in estimated fetal weight approximations; actual fetal weight may be substantially smaller or larger (proceed with caution in fetuses weighing 15002500 g; consider Maternal-Fetal Medicine consultation in these situations) • Adequate pelvis • Flexed fetal head

• Frank or complete breech preferred if planning induction, although in active spontaneous unplanned labor, footling breech can be delivered safely if no cord prolapse • No known fetal anomalies • Normal amniotic fluid index (consider at minimum presence of mean vertical pocket >2 cm) • Bedside availability of anesthesia and capability for immediate cesarean section (consider epidural placement; consider delivery in operating room in the event of need for emergent cesarean section) • Informed consent • Obstetrician trained in vaginal breech delivery

SUGGESTIONS FOR WHEN TO CONSIDER A PLANNED CESAREAN SECTION FOR BREECH • Estimated fetal weight 4000 g • Footling presentation (20% risk of cord prolapse, usually late in course of labor) • Inadequate pelvis • Hyperextended fetal head (21% risk of spinal cord injury) • Nonreassuring fetal status • Abnormal progress of labor • Lack of trained obstetrician RELATED CONTENT Breech Birth (Patient Information) Preterm Labor (Related Key Topic) AUTHOR: Vanita D. Jain, MD

SUGGESTED READINGS American College of Obstetricians and Gynecologists: ACOG practice bulletin number 161, External cephalic version, February 2016. American College of Obstetricians and Gynecologists: ACOG Committee Opinion Number 745. Mode of Term Singleton Breech Delivery. Replaces Committee Opinion Number 340 July 2006. Interim update August 2018. American College of Obstetricians and Gynecologists: ACOG & SMFM Joint Obstetric Care Consensus Statement. Safe Prevention of the Primary Cesarean Delivery Number 1, reaffirmed 2019. American College of Obstetricians and Gynecologists: ACOG Patient Education Pamphlet AP079. If your baby is breech, February 2019. Hofmeyr GJ et al: Planned caesarean section for term breech delivery, Cochrane Database Syst Rev 7:CD000166, 2015.

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Bronchiectasis BASIC INFORMATION

ICD-10CM CODES J47.0 Bronchiectasis with acute lower respiratory infection J47.1 Bronchiectasis with (acute) exacerbation J47.9 Bronchiectasis, uncomplicated Q33.4 Congenital bronchiectasis

EPIDEMIOLOGY & DEMOGRAPHICS • The exact prevalence of bronchiectasis is unknown. • Cystic fibrosis is responsible for nearly 50% of all cases of bronchiectasis. • Acquired primary bronchiectasis is uncommon because of rapid diagnosis of pulmonary infections and frequent use of antibiotics. • Effective childhood immunizations have led to a significant decrease in the incidence of bronchiectasis resulting from pertussis. • Declining incidence of pulmonary tuberculosis has also resulted in a decline in bronchiectasis without apparent causes. • In developed countries, an increasing proportion of patients with an identifiable cause of bronchiectasis is being seen. • Data on morbidity and mortality from bronchiectasis are limited because patients with the highest morbidity typically are not adequately represented in randomized controlled studies. PHYSICAL FINDINGS & CLINICAL PRESENTATION • Moist crackles at lung bases • Chronic cough, typically with expectoration of large amount of purulent sputum • Fever, night sweats, generalized malaise, weight loss • Hemoptysis • Halitosis, skin pallor • Clubbing (infrequent) ETIOLOGY • Cystic fibrosis • Lung infections (pneumonia, lung abscess, TB, nontubercular mycobacterial infections, fungal infections, viral infections) • Impaired host defense (panhypogammaglobulinemia, primary ciliary dyskinesia/ Kartagener syndrome, AIDS, chemotherapy) • Localized airway obstruction (congenital structural defects, foreign bodies, neoplasms) • Inflammation (inflammatory pneumonitis, granulomatous lung disease, allergic aspergillosis) • Rheumatoid arthritis, ulcerative colitis, and so on

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • TB • Asthma • Chronic bronchitis or chronic rhinosinusitis • Interstitial fibrosis • Chronic lung abscess • Foreign body aspiration • Cystic fibrosis • Lung carcinoma • GERD LABORATORY TESTS • Sputum for Gram stain, culture and sensitivity, and acid-fast bacteria • Complete blood count with differential (leukocytosis with left shift, anemia) • Serum protein electrophoresis to evaluate for hypogammaglobulinemia • Antibody test for aspergillosis • Testing for allergic bronchopulmonary aspergillosis • Serum immunoglobulins (total IgG, IgA, IgM) • Sweat test in patients with suspected cystic fibrosis • Pulmonary function tests: Mild to moderate airflow obstruction • Serum anti-Pseudomonas aeruginosa (PA) IgG antibody testing is highly accurate to detect chronic PA colonization in bronchiectasis patients IMAGING STUDIES • Chest x-ray (Fig. E1 and Fig. E2): Hyperinflation, crowded lung markings, small cystic spaces at the base of the lungs. • High-resolution CT scan of the chest (Figs. E3 to E6) has become the best tool to detect cystic lesions and exclude underlying obstruction from neoplasm with a sensitivity and specificity exceeding 90%. The CT study should be a noncontrast study with the use of 1- to 1.5-mm window every 1 cm with acquisition time of 1 sec. Typical findings on CT include enlarged internal bronchial diameter, bronchi appearing larger than accompanying artery, lack of tapering of an airway toward periphery, ballooned cysts at the end of bronchus, and varicose constrictions along airways. • Bronchoscopy may be helpful to evaluate hemoptysis, rule out obstructive lesions, remove mucus plugs, and also obtain microbiologic data on respiratory pathogens. • Table 1 summarizes diagnostic studies for the classification and management of patients with bronchiectasis.

TREATMENT NONPHARMACOLOGIC THERAPY • Postural drainage (reclining prone on a bed with the head down on the side) and chest percussion with use of inflatable vests/high-frequency

chest wall oscillation or mechanical vibrators applied to the chest may enhance removal of respiratory secretions. • Adequate hydration. • Supplemental oxygen for hypoxemia. • Inhaled hypertonic saline in conjunction with chest physiotherapy improves airway clearance.

ACUTE GENERAL Rx • Antibiotic therapy is based on the results of sputum, Gram stain, and culture and sensitivity; in patients with inadequate or inconclusive results, empiric therapy with amoxicillin/ clavulanate 500 to 875 mg q12h, TMP-SMX q12h, doxycycline 100 mg bid, a fluoroquinolone, or cefuroxime 250 mg bid for 14 to 21 days is recommended. • There is strong consideration for intravenous antibiotics in patients who require hospitalizations for acute exacerbation with signs of respiratory distress. • Bronchodilators are useful in patients with demonstrable airflow obstruction.

B

Diseases and Disorders

DEFINITION Bronchiectasis is an irreversible pathologic dilatation of the bronchi or bronchioles resulting from a variety of causes through an interplay of host factors (either anatomic or immune defense abnormality), respiratory pathogens, and environmental factors. Radiographically, it is often divided into cylindrical, varicose, and cystic varieties, although these variants have no significant etiologic or prognostic relevance.

• Congenital disorders such as tracheobronchomegaly (Mounier Kuhn syndrome), cartilage deficiency (Williams-Campbell syndrome)

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CHRONIC Rx • Avoidance of tobacco. • Maintenance of proper nutrition and hydration. • Prompt identification and treatment of infections. • Pneumococcal vaccination and annual influenza vaccination. • In patients with cystic fibrosis, using rhDNase and aerosolized antipseudomonal antibiotics should be considered. This should not be offered to patients with non–cystic fibrosis related bronchiectasis. • Specific immunoglobulin replacement in patients with selective immunoglobulin deficiency. • Adults with bronchiectasis with a new isolation of P. aeruginosa should be offered eradication antibiotic treatment. This should not be offered to adults with bronchiectasis following new isolation of pathogens other than P. aeruginosa. • Inhaled corticosteroids should not be offered to adults with isolated bronchiectasis. However, the diagnosis of bronchiectasis should not affect the use of inhaled corticosteroid in patients with comorbid asthma of chronic obstructive pulmonary disease. • Long-term antibiotics should be offered for adults with bronchiectasis who have three or more exacerbations per yr. • Long-term mucoactive treatment (≥3 mo) should be considered in patients who have difficulty in expectorating sputum and poor quality of life and where standard airway clearance techniques such as chest physiotherapy have failed to control symptoms. • Bronchodilators should be used before physiotherapy, including inhaled mucoactive drugs, as well as before inhaled antibiotics, as this increases tolerability and optimizes delivery of medications in diseased areas of the lungs.

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Bronchiectasis TABLE 1  Diagnostic Studies for the Classification and Management of Patients with Bronchiectasis Test

Comments

Routine, Universal Studies Computed tomogIf bronchiectasis (BXSIS) is suspected, CTLS is the definitive test. Thin-section, high-resolution images may help detect subtle airway dilation raphy lung scan before bronchial walls are grossly thickened. Contrast is generally not helpful and may, in fact, compromise the overall resolution of the study. (CTLS) CTLS may also identify esophageal abnormalities. Pulmonary funcFor patients with significant bronchiectasis, comprehensive PFTs, including spirometry, bronchodilator responsiveness, lung volumes, and diffusion tion tests (PFTs) capacity, are important studies that aid in management and prognosis. PFTs may also provide useful hints regarding predisposing conditions. Complete blood Anemia may reflect effects of chronic infection or blood loss (consider inflammatory bowel disorders). count Leukocytosis may mark severity of infection. Eosinophilia may suggest ABPA/M. ESR, C-reactive Nonspecific markers of inflammation; very high levels may suggest underlying connective tissue disease or vasculitis. protein Routine sputum Antibiotic therapy in bronchiectasis should generally be directed against specific pathogens and guided by in vitro susceptibility. The presence of culture mucoid strains of Pseudomonas aeruginosa and Staphylococcus aureus may raise suspicions for CF. Stenotrophomonas maltophilia, Alcaligenes xylosoxidans, and Burkholderia cepacia are gram-negative bacilli that may prove problematic pathogens in patients with long-standing bronchiectasis. Isolation of B. cepacia and Helicobacter pylori requires special laboratory techniques. Mycobacterial spuEnvironmental mycobacteria such as Mycobacterium avium complex, M. chelonae, and M. abscessus appear to be increasingly common in contum culture temporary bronchiectasis. May be commensal but often are pathogenic. Fungal sputum In patients with an asthmatic component, the presence of Aspergillus species (or other molds including Pseudallescheria or penicillium) may be culture suggestive of etiology. CT scan of sinuses Many patients with bronchiectasis also suffer chronic rhinosinusitis. The presence of extensive sinus involvement suggests possible CF, immunoglobulin deficiencies, or ciliary disorders. Also, optimal management often entails aggressive sinus care. Specific, Directed Studies Sweat chloride, CF For bronchiectasis patients with bilateral disease, recurrent sinusitis, and no other identified risk factor, mild variants of CF appear to be relatively genotyping, and common. Sweat chloride is regarded as the primary screening test for CF, but a considerable portion of adults with CF have borderline or nornasal potential mal results. Nasal potential difference may be useful for identifying CF in equivocal cases. differences Alpha1-antitrypsin AAT anomalies appear to be a substantial risk factor for bronchiectasis, especially with white females. Abnormal proteinase inhibitor (Pi) pheno(AAT) levels and types, even heterozygous patterns such as MS, appear to confer risk even with normal levels of AAT. Repletion of AAT may enhance resistance phenotype to lower respiratory tract infections. Immunoglobulin Deficiencies of IgG or IgA may promote bronchiectasis; IgG subclass deficiencies may also be a factor. Elevated levels of IgE may suggest ABPA/M (Ig) levels or Job syndrome. Hyper-IgM may be associated, as well, with chronic infections. Ciliary morphology For individuals with suggestive stories, a nasal ciliated epithelium biopsy with transmission electron microscopy may identify primary ciliary dyskior function nesia. Other studies including ex vivo ciliary activity, the saccharine test, or spermatozoa analysis may aid in this diagnosis. Nasal nitric oxide Patients with documented PCD have significantly lower levels of NNO than normal or patients with CF. Although not universally available, such testing (NNO) levels may prove highly useful in identifying PCD. Paradoxically, exhaled NO levels have been elevated in bronchiectasis of diverse etiologies except CF. Barium swallow The BaS may detect disturbed deglutition, esophageal diverticula, obstructing lesions (tumors or strictures), hypomotility, achalasia, hiatal hernias, or (BaS) lower esophageal sphincter (LES) incompetence with reflux. The absence of reflux on a BaS, however, does not exclude this problem (see pH probe). pH probe For patients suspected of gastroesophageal reflux, an 18- to 24-hour study with a transnasal pH probe may identify, quantitate, and characterize reflux. Medications that inhibit acid production must be stopped before such tests. Esophageal For patients being considered for surgical repair of the LES, manometry should be performed to determine that the esophagus generates sufficient manometry pressure to propel food and liquids through the tightened sphincter. Tailored hypophaTH is useful in detecting abnormalities of the initial phase of swallowing, deglutition. Persons particularly prone to problems include those with prior ryngography strokes, Parkinson disease, bulbar disorders including postpolio syndrome, and those with prior laryngeal or pharyngeal surgery. Note that some (TH) patients have gross aspiration without clinical manifestations (choking, coughing); this may occur in individuals with none of the above risk factors. Less Common, Exotic Studies Collagen vascular Various CVDs may contribute to the risk for bronchiectasis, including RA, ankylosing spondylitis, and systemic lupus erythematosus. Thus, for disease (CVD) patients with compatible histories or physical findings, assays for rheumatoid factor, HLA-B27, and ANA may provide insight into predisposing serologies conditions. CVD serologies may also suggest the diagnosis of Sjögren syndrome, particularly SSA/Ro and/or SSB/La. Schirmer test For patients with histories suggestive of “sicca syndrome” (dry eyes, dry mouth, oral ulcers), a positive Schirmer test may indicate the presence of either primary or secondary (associated with a CVD) Sjögren syndrome. ABPA/M, Allergic bronchopulmonary aspergillosis/other mycoses; ANA, antinuclear antibody; CF, cystic fibrosis; ESR, erythrocyte sedimentation rate; HLA, human leukocyte antigen; MS, multiple sclerosis; NO, nitric oxide; PCD, primary ciliary dyskinesia; RA, rheumatoid arthritis. From Mason RJ: Murray & Nadel’s textbook of respiratory medicine, ed 5, Philadelphia, 2010, Saunders.

DISPOSITION • Prognosis is variable with severity of the disease and underlying etiology of bronchiectasis. • In overlap syndrome of bronchiectasis with rheumatoid arthritis, worse outcomes occurred compared with other bronchiectasis etiologies. REFERRAL • Surgical referral for partial lung resection in patients with localized, severe disease unresponsive to medical therapy or in patients

with massive hemoptysis. Surgical resection of localized bronchiectasis is safe and improves quality of life. • Lung transplantation for bronchiectasis accounts for about 2% to 3% of all lung transplant candidates (The Registry of the International Society for Heart and Lung Transplantation).

RELATED CONTENT Bronchiectasis (Patient Information) AUTHORS: Aline N. Zouk, MD, and Samaan Rafeq, MD

SUGGESTED READINGS Available at ExpertConsult.com

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Bronchiectasis

FIG. E1  Bronchiectasis. Multiple ring shadows, many containing air-fluid levels, are present throughout the lower zones of this patient with cystic bronchiectasis. (From Grant LA: Grainger & Allison’s diagnostic radiology essentials, ed 2, 2019, Elsevier.)

268.e1

FIG. E2  Bronchiectasis. Targeted image of a right lower lung base shows tramlines and ring opacities. (From Grant LA: Grainger & Allison’s diagnostic radiology essentials, ed 2, 2019, Elsevier.) FIG. E3  Bronchiectasis. CT demonstrating dilated subsegmental bronchi. The bronchi are larger than the accompanying vessels with some demonstrating the “signet ring” sign (arrows). Plugging of peripheral smaller bronchi is also evident (curved arrow). (From Grant LA: Grainger & Allison’s diagnostic radiology essentials, ed 2, 2019, Elsevier.)

FIG. E4  Cystic bronchiectasis. CT demonstrates multiple ring shadows due to irregularly dilated bronchi. (From Grant LA: Grainger & Allison’s diagnostic radiology essentials, ed 2, 2019, Elsevier.)

FIG. E5  Cylindrical bronchiectasis. The bronchi fail to taper and have irregular thickened walls. (From Grant LA: Grainger & Allison’s diagnostic radiology essentials, ed 2, 2019, Elsevier.)

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Bronchiectasis

268.e2

FIG. E6  ABPA. HRCT demonstrating mucoid impactions within segmental and subsegmental dilated bronchi in the upper lobes. Small centrilobular linear branching opacities are seen in the periphery of the right upper lobe. (From Grant LA: Grainger & Allison’s diagnostic radiology essentials, ed 2, 2019, Elsevier.)

SUGGESTED READINGS Aksamit TR et  al: Adult patients with bronchiectasis: a first look at the US Bronchiectasis Research Registry, Chest 151:982, 2017. Polverino E et al: European Respiratory Society guidelines for the management of adult bronchiectasis, Eur Respir J 50:1700629, 2017.

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Brucellosis BASIC INFORMATION DEFINITION Brucellosis is a zoonotic infection caused by one of four species of Brucella. It commonly presents as a nondescript febrile illness. It is the most common zoonosis worldwide. SYNONYMS Malta fever, undulant fever Bang disease ICD-10CM CODE A23.9 Brucellosis, unspecified

EPIDEMIOLOGY & DEMOGRAPHICS INCIDENCE (IN U.S.): About 100 to 200 cases/yr (may be underreported) (Fig. E1), predominantly B. melitensis. The number of cases is increasing worldwide due to travel and globalization. PREDOMINANT SEX: Male PREDOMINANT AGE: Adult CONGENITAL INFECTION: Recent evidence suggests a high rate of spontaneous abortions in untreated pregnant women during the first and second trimesters. NEONATAL INFECTION: Can occur if mother is infected during pregnancy. PHYSICAL FINDINGS & CLINICAL PRESENTATION • Incubation period is 1 wk to 3 mo. • Patients may be asymptomatic or have nonspecific symptoms such as fever, sweats, malaise, weight loss, depression, arthralgia, and arthritis. • Fever is the most common finding (Fig. E2). • Hepatomegaly, splenomegaly, or lymphadenopathy is possible. • Localized disease includes endocarditis, meningitis, spondylitis, sacroiliitis, and osteomyelitis (especially vertebral). • Chronic hepatosplenic suppurative brucellosis (CHSB) presents with hepatic or splenic abscesses. This form is thought to be a reactivation and can occur years after the acute infection. • Table E1 describes a clinical classification of human brucellosis. ETIOLOGY • Caused by infection with Brucella species: 1. Most commonly B. melitensis but also B. suis, B. abortus, or B. canis. 2. A small, gram-negative coccobacillus. • Acquired through ingestion of organisms (unpasteurized goat’s or cow’s milk, cheese, or ice cream) or breaks in the skin or by inhalation. • Most cases occur after exposure to animals (sheep, goats, swine, cattle, or dogs) or animal products (i.e., milk, cheese, hides, tissue). • Most cases (in the U.S.) occur in men with occupational exposure to animals (e.g., farmers, ranchers, laboratory workers, veterinarians, abattoir workers). Accidental animal vaccine exposure warrants evaluation for a full therapeutic antibiotic regimen.

• Laboratory workers, especially those in microbiology, are also at increased risk. Guidelines for postexposure prophylaxis are available from MMWR Surveill Summ 57:39, 2009.

268.e3

• Serum agglutination test (see the following).

LABORATORY TESTS • WBC count: Normal or low. • Serology: 1. Serum agglutination test (SAT) to detect antibodies to B. abortus, B. melitensis, and B. suis. An elevated initial titer of ≥1:160 or demonstration of a fourfold increase from acute to convalescent titers is considered diagnostic. Positive test results warrant confirmatory testing with specific Brucella agglutination tests. 2. Specific antibody test to identify antibodies to B. canis. 3. False-negative SAT possibly resulting from a prozone effect. 4. PCR (polymerase chain reaction) for Brucella spp. specific 16S rRNA or DNA sequences are increasingly used for the

DIAGNOSIS DIFFERENTIAL DIAGNOSIS Many febrile conditions without localizing manifestations (i.e., tuberculosis, endocarditis, typhoid fever, malaria, autoimmune diseases) WORKUP • Cultures of blood, bone marrow, or other tissue (e.g., lymph node, liver) should be sent and held for 4 wk because Brucella spp. grow slowly in vitro. • Granulomas on biopsy are suggestive of diagnosis.

2 2

3

1

26 9

4

1 2

4 3 1

1 3

4

1

1 1

1 2 2

21

2

2 9

1 DC 4 NYC AS CNMI GU PR VI

2 0

≥1

FIG. E1  Brucellosis. Number of reported cases—United States and U.S. territories, 2010. (From Centers for Disease Control and Prevention: Summary of notifiable diseases—United States, 2010, MMWR Morb Mortal Wkly Rep 59:1-111, 2012.)

FIG. E2  Brucellosis. Several small noncaseating granulomas are present in the bone marrow of a patient with an unexplained febrile disease. He was not aware of exposure to Brucella in over 30 yr (HANDE, ×40, Brucella suis isolated from blood cultures). (From Scott MA et  al: Infectious disease pathology. Silverberg SG [ed]: Principles and practice of surgical pathology and cytopathology, ed 4, Philadelphia, 2006, Churchill Livingstone, p 101.)

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Brucellosis

268.e4

TABLE E1  Clinical Classification of Human Brucellosis

Classification

Duration of Symptoms Before Diagnosis

Major Symptoms and Signs

Diagnosis

Comments

Subclinical

—

Asymptomatic

Acute and subacute

Up to 2-3 mo and 3 mo to 1 yr

Localized

Occurs with acute or chronic untreated disease 2-3 mo after initial episode

Malaise, chills, sweats, fatigue, headache, anorexia, arthralgias, fever, splenomegaly, lymphadenopathy, hepatomegaly Related to involved organs

Positive (low titer) serology, negative cultures Positive serology, positive blood or bone marrow cultures Positive serology, positive cultures in specific tissues

Occurs in abattoir workers, farmers, and veterinarians Presentation can be mild, selflimited (B. abortus) or fulminant with severe complications (B. melitensis) Bone or joint, genitourinary, hepatosplenic involvement most common

Positive serology, positive cultures

May be extremely difficult to distinguish relapse from reinfection

Low titer or negative serology, negative cultures

Most controversial classification; localized disease may be associated

Relapsing Chronic

>1 yr

Same as acute illness but may have higher fever and more fatigue, weakness, chills, and sweats Nonspecific presentation but neuropsychiatric symptoms and lowgrade fever most common

From Goldman L, Schafer AI: Goldman’s Cecil medicine, ed 24, Philadelphia, 2012, Saunders.

diagnosis of brucellosis from blood, tissue samples, and bone marrow.

IMAGING STUDIES • Radiographs to show splenic or hepatic calcifications in chronic disease • Bone scan, MRI, and radiographs of the spine to suggest osteomyelitis • Ultrasound or CT scan of the abdomen to show an enlarged liver or spleen • Echocardiogram to reveal vegetations in endocarditis

TREATMENT NONPHARMACOLOGIC THERAPY • Drainage of abscesses • Valve replacement for endocarditis ACUTE GENERAL Rx Combination antibiotics required: • Major options: 1. Doxycycline 100 mg PO bid for 6 wk plus rifampin plus gentamycin 5 mg/kg qd for 7 days.

• Alternative therapies: 1. Doxycycline 100 mg PO bid plus rifampin 600 to 900 mg PO qd for 6 wk plus streptomycin. 2. Sulfamethoxazole 800 mg/trimethoprim 160 mg one DS tablet PO qid, ciprofloxacin 500 mg bid for 6 wk along with doxycycline or rifampin as an alternative regimen. 3. Courses 60 ms and VERP (ventricular effective refractory period) 2.5 g/dl, coagulopathy (usually international normalized ratio [INR] >1.5), variceal bleeding, encephalopathy within 8 wk of onset of jaundice, renal failure. Biopsy, if performed, would reveal hepatic necrosis. Early recognition and treatment are essential for survival; a slow decrease in ALT is associated with poor survival. 2. Subacute/chronic (60%): Vague abdominal discomfort, gradual progression to caudate lobe hypertrophy with atrophy of the rest of the liver, portal hypertension with or without cirrhosis and its sequelae, transudative ascites, lower-extremity edema, esophageal varices, splenomegaly, coagulopathy, mild to moderate elevation in aminotransferases, bilirubin and alkaline phosphatase, hepatorenal syndrome, hepatopulmonary syndrome, and rarely, encephalopathy; biopsy, if performed, could reveal minimal hepatic necrosis. 3. Asymptomatic (up to 20%): Usually discovered incidentally by abnormal liver function tests or imaging attained for other reasons.

ETIOLOGY: Approximately 80% to 87% of patients have one prothrombotic risk factor, and approximately 50% have multiple. • Primary myeloproliferative diseases: Up to 53% of BCS patients have a primary myeloproliferative disease and polycythemia vera is responsible for 10% to 40% of these cases. 1.  Essential thrombocythemia and idiopathic myelofibrosis are less common causes. 2.  JAK2 mutations are implicated in cases of idiopathic BCS (identified in 25% to 60% of cases). • Hypercoagulable states (inherited and acquired) often coexist with other causes. 1. Anticardiolipin antibodies (up to 25%) 2. Hyperhomocysteinemia (22%) 3.  Paroxysmal nocturnal hemoglobinuria (5% to 19%) 4. Factor V Leiden (25%) 5. Factor II gene mutation (5%) • Protein C, protein S, and antithrombin III deficiency are difficult to interpret because the presence of liver disease may confound results. However, they account for 4.0%, 3.0%, and 3.0% of BCS, respectively.

• Heterozygosity for G20210A prothrombin gene mutation, methylenetetrahydrofolate reductase (MTHFR) mutation, Tet methylcytosine dioxygenase 2 mutation, and calreticulin mutation may be seen in BCS. • Pregnancy and oral contraceptive pills are also predisposing factors to develop BCS. • Malignancy causing external compression or invasion of vascular structures (up to 10% of cases). 1.  Most commonly due to hepatocellular carcinoma but also can be due to neoplasms of the kidney, adrenal gland, pancreas, stomach, lung and sarcomas of the right atrium, inferior vena cava, and hepatic veins. • Rare but reported: Sickle cell anemia, infections with liver abscess, hydatid cyst (echinococcosis), schistosomiasis, sarcoidosis, Behçet disease, membranous webs of IVC or hepatic veins (more common in Africa and South Asia, can be congenital or acquired secondary to underlying myeloproliferative disorder), abdominal trauma, liver torsion, granulomatous venulitis, ulcerative colitis, celiac disease, systemic lupus erythematous, minimal change nephrotic syndrome, neurofibromatosis, α-1 antitrypsin deficiency, hypereosinophilic syndrome, idiopathic (10% to 25%).

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • Hepatitis from ischemia, viral infection, toxin, alcohol • Cholecystitis • Hepatic veno-occlusive disease (sinusoidal obstruction syndrome) • Congestive hepatopathy, also known as cardiac cirrhosis, from tricuspid regurgitation, right atrial myxoma, constrictive pericarditis • Cirrhosis from any etiology LABORATORY TESTS • Assessment of liver injury and function: Serum aminotransferases, alkaline phosphatase, prothrombin time (PT), albumin, bilirubin. • Exclusion of another form of liver disease: Viral hepatitis panel, autoantibodies (antinuclear antibody, anti–smooth muscle antibody, anti-mitochondrial antibody), iron studies, ceruloplasmin, and α-1 antitrypsin. • Ascites protein content ≥2.5 g/dl and serum ascites albumin gradient >1.1 g/dl are suggestive of transudative ascites from BCS or cardiac ascites. • Evaluation for underlying myeloproliferative disorder and hypercoagulable state: CBC, bone marrow biopsy, tests for hypercoagulable states (Factor V Leiden, prothrombin gene G20210A mutation, protein C, protein S, antithrombin deficiencies, antiphospholipid syndrome, and paroxysmal nocturnal hemoglobinuria). Protein C, protein S, and antithrombin deficiencies may be difficult to

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Budd-Chiari Syndrome

ALG interpret in the setting of liver dysfunction, but levels 70, nonscarring, no mucosal involvement, absence of bullous lesions on head and neck) plus evidence of linear IgG and/or C3 deposits along basement membrane on DIF microscopy 2. Skin biopsy: Evidence of IgG anti-basement membrane autoantibodies on indirect immunofluorescence (IIF) microscopy 3. Skin biopsy: Evidence of anti-BP180 IgG and/ or anti-BP230 IgG autoantibodies on enzymelinked immunosorbent assay (ELISA)

DIFFERENTIAL DIAGNOSIS • Bullous arthropod bites • Linear IgA bullous dermatosis • Dermatitis herpetiformis • Anti-laminin gamma-1 (anti-p200) pemphigoid • Brunsting-Perry pemphigoid • Bullous systemic lupus erythematosus • Mucous membrane or cicatricial pemphigoid • Epidermolysis bullosa acquisita • Pemphigoid gestationis • Bullous erythema multiforme • Generalized fixed drug eruption • Impetigo • Porphyria cutanea tarda • Bullous lichen planus • Pemphigus vulgaris • Paraneoplastic pemphigus • Table E1 compares some of these immunobullous diseases LABORATORY TESTS • Histology of lesional skin

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Bullous Pemphigoid

274.e6

TABLE E1  Immunobullous Skin Diseases Immunobullous Disease

Clinical Presentation

Pemphigus Dermatoses Pemphigus vulgaris Flaccid bullae on noninflamed skin, crusting, positive Nikolsky sign;† commonly affects scalp, chest, intertriginous areas, and oral mucosa Pemphigus foliaceous Superficial bullae, erosions, and scale with crusting, positive Nikolsky sign† Paraneoplastic Flaccid bullae, lichenoid or pemphigus erythema multiformelike, usually involves mucosa, often extensively includes esophageal and respiratory areas IgA pemphigus Flaccid bullae, similar to pemphigus vulgaris Pemphigoid Dermatoses Bullous pemphigoid Tense bullae, often on urticarial base, prominent pruritus Mucous membrane or Tense bullae and erosions, cicatricial scarring sequelae pemphigoid Pemphigoid gestationis Epidermolysis bullosa acquisita Linear IgA bullous dermatosis and chronic bullous disease of childhood Dermatitis herpetiformis

Bullous lupus erythematosus§

Tense bullae, similar to bullous pemphigoid; onset during or immediately after pregnancy Tense bullae; commonly occurs in areas of trauma and in oral mucosa Tense bullae, similar to bullous pemphigoid; oral involvement common in adult disease Small bullae on extensor surfaces (elbows and knees); markedly pruritic; associated with intestinal gluten sensitivity Tense bullae, photodistributed

Serum Autoantibodies

Targeted Protein or Structure

Tissue Immunofluorescence*

IgG epithelial cell surface; correlates with disease activity

Desmoglein 3 and desmoglein 1 of the desmosome

Epidermal IgG and C3 cell surface staining

IgG epithelial cell surface; correlates with disease activity IgG epithelial cell surface and basement membrane zone (staining on rodent bladder epithelium is characteristic); correlates with disease activity

Desmoglein 1 of the desmosome

Epidermal IgG and C3 cell surface staining

Desmoglein 3, desmoplakin 1, desmoplakin 2, BPAG1, envoplakin, periplakin, other proteins of the desmosome and hemidesmosome Desmocollin 1 of the desmosome

Epidermal IgG and C3 cell surface and basement membrane zone staining

Linear basement membrane zone IgG and C3

Complement fixing, basement membrane zone, epidermal

BPAG2, BPAG1, hemidesmosome, lamina lucida BPAG2, laminin 332 (previously known as laminin 5 or epiligrin), hemidesmosome, lamina lucida BPAG2, BPAG1, hemidesmosome, lamina lucida

IgG basement membrane zone, dermal‡

Type VII collagen, anchoring fibrils

IgA basement membrane zone, epidermal (rarely dermal)

97-kD portion of BPAG2, hemidesmosome, lamina lucida Epidermal transglutaminase

Linear basement membrane zone IgG and C3; may show linear IgA and IgM Linear basement membrane zone IgA

IgA epithelial cell surface; correlates with disease activity IgG basement membrane zone, epidermal IgG basement membrane zone, epidermal

IgA endomysial and transglutaminase antibodies; correlates with disease activity and compliance with gluten-free diet IgG basement membrane zone, dermal

Type VII collagen, anchoring fibrils

Epidermal IgA cell surface staining

Linear basement membrane zone IgG and C3

Linear basement membrane zone C3

Granular basement membrane zone IgA with stippling in dermal papillae Linear basement membrane zone IgG; may show granular IgM and C3 basement membrane zone as in lupus band

BPAG1, 230-kD bullous pemphigoid antigen 1; BPAG2, 180-kD bullous pemphigoid antigen 2; C3, complement component 3, cell surface, intercellular substance; Ig, immunoglobulin. *In all suspected immunobullous disease, the biopsy for diagnosis should be obtained from perilesional tissue because immunoreactants may not be present in lesional tissue; perilesional skin is the area immediately adjacent to but not involving a lesion. Serum studies are also essential to differentiate diseases. †The Nikolsky sign is the formation of a new blister or extension of a blister from shearing pressure applied on normal-appearing skin or at the edge of an existing blister. ‡Dermal and epidermal refer to localization of antibodies on human split skin by indirect immunofluorescence of serum. From Adkinson NF et al: Middleton’s allergy principles and practice, ed 8, Philadelphia, 2014, Saunders.

1.  Light microscopy: Subepidermal bullae with eosinophils and/or neutrophils with associated eosinophil and/or neutrophil dermal infiltrate 2. Direct immunofluorescence (DIF) microscopy (gold standard): Linear IgG and or C3 deposits along dermoepidermal junction

• Immune serological tests. note: Only confirmatory with DIF microscopy findings 1. Indirect immunofluorescence (IIF): Circulating IgG anti-basement antibodies using 1 mol/L NaCl-separated normal skin as substrate 2. ELISA: Test for anti-BP180 IgG; if negative, test for anti-BP230 IgG

TREATMENT Bullous pemphigoid may be a self-limited disease, but its course may last from months to yrs. Treatment is based on the degree of disease involvement and the rate of disease

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Bullous Pemphigoid 274.e7 progression; however, there is no general consensus on how to determine disease severity. A European guideline defines severity by percent skin involvement, with less than 10% defined as mild, between 10% and 30% defined as moderate, and greater than 30% defined as severe.

NONPHARMACOLOGIC THERAPY • Mild soaps with emollients to wet skin after bathing • Use of nonadherent dressings in the case of extensive erosive lesions to prevent bacterial superinfection, minimize pain, and promote healing • Only drain larger blisters and leave the blister roof intact as a natural dressing; remove fluttering skin only in broken blisters • Avoid mechanical trauma to the skin

immunosuppressive therapy, including azathioprine, dapsone, doxycycline, methotrexate, and mycophenolate mofetil • Initial doses greater than 1.0 mg/kg of prednisolone show little added benefit

TREATMENT-RESISTANT THERAPY • Intravenous immunoglobulin therapy 2 g/kg per cycle (4- to 6-week intervals) • Immunoadsorption or plasmapheresis • Rituximab (anti-CD20) 1000 mg IV on day 1 then day 14 or 375 mg/m2 IV administered four times at weekly intervals

TETRACYCLINES • Doxycycline 100 mg twice daily is similar in effectiveness to oral prednisolone, with decreased side effects compared with oral steroids. • Tetracycline 500 mg four times daily plus nicotinamide 500 mg three times daily had similar effectiveness as prednisone 40 to 80 mg daily.

SYSTEMIC CONSOLIDATION THERAPY • Once disease control is achieved with oral steroids, begin tapering corticosteroids by 25% at 7- to 14-day intervals; if induction dose is less than 20 mg/day, taper over 2- to 4-week intervals. • If relapse occurs, return to dose given two reduction intervals prior; can resume taper after 14 days of disease control. • May add or switch to adjuvant agents as needed. • Disease control is defined as no new lesion formation concurrent with healing of existing lesions. • Relapse is defined as greater than three new lesions per month or one lesion greater than 10 cm that does not heal spontaneously in one week or progression of the existing lesions or reemergence of daily pruritus.

SYSTEMIC STEROID INDUCTION THERAPY • Prednisolone (or equivalent) 0.5 mg/kg per day, which can be combined with adjuvant

DISPOSITION In the United States, mortality rates are estimated at between 11% to 23% after 1 yr. Standardized mortality ratios range from 1.90 to

STAGE-SPECIFIC THERAPY • Mild: Topical class I steroids daily • Moderate: Class I topical steroids daily; systemic therapy may be added as needed • Severe: Class I topical steroids daily in combination with systemic immunosuppressants • Intralesional triamcinolone acetonide to isolated lesions • Oral antihistamines to control pruritus

SUGGESTED READINGS Bagci IS et al: Bullous pemphigoid, Autoimmun Rev 16(5):445-455, 2017. Baican A et al: Pemphigus vulgaris is the most common autoimmune bullous disease in Northwestern Romania, Int J Dermatol 49(7):768-774, 2010. Baum S et al: Diagnosis and classification of autoimmune blistering diseases, Autoimmun Rev 13(4–5):482-489, 2014. Bene J et al: Bullous pemphigoid and dipeptidyl peptidase IV inhibitors: a casenoncase study in the French Pharmacovigilance Database, Br J Dermatol 175(2):296-301, 2016. Binitha MP et al: Localized bullous pemphigoid on sites of radiotherapy and lymphedema in the same patient, Indian Dermatol Online J 5(Suppl 2):S101S103, 2014. Brick KE et  al: Incidence of bullous pemphigoid and mortality of patients with bullous pemphigoid in Olmsted County, Minnesota, 1960 through 2009, J Am Acad Dermatol 71(1):92-99, 2014. Cortes B et al: Autoimmune bullous disease Swiss study G: mortality of bullous pemphigoid in Switzerland: a prospective study, Br J Dermatol 165(2):368374, 2011. de la Fuente S et al: Postvaccination bullous pemphigoid in infancy: report of three new cases and literature review, Pediatr Dermatol 30(6):741-744, 2013. Di Zenzo G et al: Bullous pemphigoid: from the clinic to the bench, Clin Dermatol 30(1):3-16, 2012.

6.6. BP is a chronic disease; exacerbations and relapses are not uncommon, even in successfully treated individuals. A recent prospective study reported a 45% relapse rate of the evaluable patients at 12 months, with the majority of relapses occurring in the first 6 months after cessation of therapy. In this study, an ELISA titer score three times higher than the normal cutoff value at time of therapy cessation was the main predicting factor for BP relapse within the next yr. Dementia and initial extensive disease may be two additional independent risk factors associated with relapse during the first yr of therapy.

REFERRAL Dermatology

PEARLS & CONSIDERATIONS COMMENTS • Pruritus can be the presenting complaint and can precede the appearance of any skin lesions. • Bullous pemphigoid should be high on the differential in patients over 70 yr old with tense bullae. • Extremely pruritic urticarial plaques can precede onset of tense bullae by months. • Doxycycline 100 mg twice daily is equally effective to oral prednisolone. RELATED CONTENT Bullous Pemphigoid (Patient Information) AUTHORS: Sara Moradi Tuchayi, MD, and Kachiu C. Lee, MD, MPH

Eming R et al: S2k guidelines for the treatment of pemphigus vulgaris/foliaceus and bullous pemphigoid, J Dtsch Dermatol Ges 13(8):833-844, 2015. Feliciani C et al: Management of bullous pemphigoid: the European Dermatology Forum consensus in collaboration with the European Academy Of Dermatology And Venereology, Br J Dermatol 172(4):867-877, 2015. Fichel F et al: Clinical and immunologic factors associated with bullous pemphigoid relapse during the first year of treatment: a multicenter, prospective study, JAMA Dermatol 150(1):25-33, 2014. Isohashi F et al: A case of bullous pemphigoid exacerbated by irradiation after breast conservative radiotherapy, Jpn J Clin Oncol 41(6):811-813, 2011. Joly P et al: Incidence and mortality of bullous pemphigoid in France, J Invest Dermatol 132(8):1998-2004, 2012. Lai YC, Yew YW, Lambert WC: Bullous pemphigoid and its association with neurological diseases: a systematic review and meta-analysis, J Eur Acad Dermatol Venereol 30(12):2007-2015, 2016. Olsha O, Lijoretzky G, Grenader T: Bullous pemphigoid following adjuvant radiotherapy for breast cancer, Breast J 17(2):204-205, 2011. Sears A et al: Bullous pemphigoid induced by radiotherapy recurring on rechallenge, Clin Exp Dermatol 37(8):916-917, 2012. Williams HC et al: Doxycycline versus prednisolone as an initial treatment strategy for bullous pemphigoid: a pragmatic, non-inferiority, randomised controlled trial, Lancet 389(10079):1630-1638, 2017.

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Bundle Branch Block BASIC INFORMATION

R

I AVN

HB

R

I AVN

LB 2

D LA LPD

RB II

L

SYNONYMS • Fascicular block • Aberrancy • Conduction disturbance • Conduction delay • Conduction defect

1

F

HB

RB III

II

L

LB 1

2

D LA LPD III

F

FIG. 1  Diagrammatic representation of fascicular blocks in the left ventricle. Left, Interruption of the left anterior fascicle or division (here labeled LAD) results in an initial inferior (1) followed by a dominant superior (2) direction of activation. Right, Interruption of the left posterior fascicle or division (here labeled LPD) results in an initial superior (1) followed by a dominant inferior (2) direction of activation. AVN, Atrioventricular node; HB, His bundle; LB, left bundle; RB, right bundle. (Courtesy Dr. C. Fisch.) (From Mann DL et al: Braunwald’s heart disease, ed 10, Philadelphia, 2015, Elsevier.)

TABLE 1  Common Diagnostic Criteria for Fascicular Blocks Left Anterior Fascicular Block Frontal plane mean QRS axis between −45 and −90 degrees qR pattern in lead aVLQRS duration 50 msec in V1 aVF, Augmented vector foot; aVL, augmented vector left. From Mann DL et al: Braunwald’s heart disease, ed 10, Philadelphia, 2015, Elsevier.

ICD-10CM CODES Bundle branch block (fascicular block): I44.4 Anterior I44.5 Posterior I44.60 Hemiblock (hemifascicular block) I44.7 Left I45.10 Right I45.2 Bilateral (bifascicular)

EPIDEMIOLOGY & DEMOGRAPHICS INCIDENCE: The cumulative incidence of any type of bundle branch block increases with age (1.5% at age 50, 18% at age 80) PEAK INCIDENCE: Cumulative incidence of 18% at age 80 for any type of bundle branch block PREVALENCE: The estimated prevalence in the general population for any type of bundle branch block ranges between 0.2% and 3.4% and increases with age. • Complete LBBB: 0.4% men age 50, 5.7% men age 80, 1.1% women age 50 to 80 • Complete RBBB: 0.2% men before age 30, 0.8% men age 50, 1.3% men age 80, 1.3% women age 50 to 80, 2.3% in men and women age 60 • Incomplete RBBB: 13.5% age 20, 3.4% age 50 PREDOMINANT SEX AND AGE: More common in men, incidence increases with age GENETICS: Most cases of bundle branch block are not hereditary. The Brugada syndrome is an autosomal dominant genetic disorder with pseudo-RBBB but is not a true bundle branch block (see section on Brugada Syndrome). The hereditary bundle branch defect is an autosomal dominant genetic disease that has been described in Lebanon and was mapped to the long arm of chromosome 19. RISK FACTORS: Male gender, elder age, structural heart disease, cardiomyopathy, hypertension

B

Diseases and Disorders

DEFINITION • Delayed conduction in the His-Purkinje system that meets criteria for right bundle branch block (RBBB), left bundle branch block (LBBB), or hemifascicular block. The latter can be either left anterior fascicular block (LAFB) or left posterior fascicular block (LPFB). Bifascicular block is a combination of RBBB and either LAFB or LPFB. All of these are categories of bundle branch block. Any delayed conduction that does not meet these criteria is not considered bundle branch block but rather categorized as intraventricular conduction delay (IVCD) (see also topic “Intraventricular Conduction Delay”). Repolarization abnormalities may be seen in multiple leads with LBBB and in leads V1-V3 in RBBB. These include T wave inversions and ST segment depression in the opposite direction from the QRS

complex. Fig.  1 illustrates a diagrammatic representation of fascicular blocks in the left ventricle. Table 1 and Table 2 summarize common diagnostic criteria for fascicular blocks and bundle branch blocks. • The bundle branch block can be persistent or intermittent. The latter is predominantly rate-related, usually RBBB, during tachycardia or acute shortening of the R-R interval, which is common during atrial fibrillation. Bradycardia-dependent aberrancy can also be seen. Alternating bundle branch block between RBBB and LBBB is a sign of conduction system disease and will often progress to complete heart block.

275

I

PHYSICAL FINDINGS & CLINICAL PRESENTATION • RBBB can cause wide splitting of the second heart sound (S2). Either LBBB or RBBB can cause continuous splitting of S2 during respiration. • Isolated bundle branch block does not cause symptoms. Nevertheless, it is usually a result of heart disease, either in the conduction system or the surrounding cardiac tissues, and its existence can aggravate the clinical picture of the causal entity. • In patients with heart failure, the presence of LBBB can cause ventricular dyssynchrony and worsen heart failure. LBBB or RBBB, when coexistent with coronary artery disease, diabetes, or heart failure, are markers for increased mortality. • RBBB can be seen in pulmonary hypertension or acute pulmonary embolism, generally in entities that increase the right ventricular afterload. The presence of bundle branch block can be associated with other conduction defects such as second or third degree AV block.

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276

Bundle Branch Block ETIOLOGY • Bundle branch block can be a result of disease in the His-Purkinje conduction system but can also result from disease or fibrosis surrounding the conduction system (i.e., myocardial infarction), antiarrhythmic drugs, or hyperkalemia. Selected causes of bundle branch block are the following: intracardiac catheter manipulation, myocardial ischemia or infarction, myocarditis, cardiomyopathy, and Lenegre or Lev disease. RBBB in particular is associated with pulmonary hypertension and pulmonary embolism, whereas LBBB can be caused by an anterior myocardial infarction. • Rate-related branch block in normal hearts is usually seen in tachycardia or in atrial fibrillation where a long R-R interval is followed by a shorter one. This is due to Ashman phenomenon, where a long cycle length interval causes prolongation in the refractory period resulting in bundle branch block on the subsequent early beat. This is a common property of all cardiac tissues but more evident in the conduction system. The rate-related bundle block is usually RBBB since the right bundle has a longer refractory period than the left bundle for the same heart rate. Another phenomenon is bradycardia-dependent aberrancy. This may be due to automaticity in a bundle branch block during diastole leading to BBB on a subsequent beat. Other explanations include vagal tone inhibition or phase 4 block. In phase 4 block, the cells have depleted sodium reserves resulting in low resting membrane potentials that impose difficulty in cell excitability resulting in conduction block. • In patients with LBBB, detailed mapping has demonstrated that the site of block is in the proximal left conduction system in 64% of cases.

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • Refer to Table 3. • An accessory pathway can cause an appearance of RBBB or LBBB. If lead V1 is placed

higher than the fourth intercostal space or more right than the parasternal area, the EKG can resemble incomplete RBBB. • An inferior myocardial infarction can resemble left anterior fascicular block, but in the inferior myocardial infarction, the inferior leads (II, III, aVF) will have qR instead of QS morphology. Left posterior fascicular block can resemble lateral myocardial infarction, right ventricular hypertrophy, dextrocardia, or lateral accessory pathway. Accelerated idioventricular rhythm can resemble LBBB or RBBB, depending on the origin of the ventricular pacemaker site.

WORKUP • Resting, ambulatory, and exercise electrocardiogram • Investigation of coexistent comorbidities such as heart failure, myocardial infarction, and cardiomyopathies • Acute LBBB should prompt investigation for anterior myocardial infarction (Fig. 2) whereas acute RBBB for pulmonary hypertension, or pulmonary embolism (Fig. 3) • Figs. 2 and 3 illustrate diagnostic evaluations for bundle branch block. LABORATORY TESTS • Standard laboratory testing appropriate for age, gender, and metabolic abnormalities • Electrolyte abnormalities and especially hyperkalemia should be excluded

is appropriate for patients with cardiac syncope or coexisting third degree, or Mobitz type II second degree AV block, when not due to a reversible cause.

ACUTE GENERAL Rx In acutely established bundle branch block, investigate the cause. In acute LBBB, anterior myocardial infarction should be investigated whereas in acute RBBB investigation should target pulmonary embolism. CHRONIC Rx Optimization of potential coexisting comorbidities such as coronary artery disease, heart failure, hyperkalemia, diabetes DISPOSITION There is no specific disposition plan for isolated bundle branch block. Entities such as myocardial ischemia or infarction, myocarditis, and cardiomyopathy should be investigated prior to disposition in a new bundle branch block with associated symptoms. Pulmonary embolism should also be investigated in a new RBBB with suspecting symptoms. REFERRAL In selected patients at risk for sudden cardiac death such as Brugada syndrome, or in cases of new bundle branch block associated with acute symptoms, referral is indicated.

PEARLS & CONSIDERATIONS

IMAGING STUDIES Electrocardiogram (Figs. 4 and 5)

TREATMENT • Treat the underlying cause (Tables 4 and 5) • In asymptomatic patients with an isolated bundle branch block, no therapy is required

NONPHARMACOLOGIC THERAPY Cardiac resynchronization therapy (CRT) with biventricular or His-bundle devices can benefit selected patients with LBBB and depressed EF, if heart failure is present. Permanent pacemaker

COMMENTS Acute LBBB can be caused by anterior myocardial infarction. Acute RBBB can be due to pulmonary embolism. Bundle branch block is a normal variant, especially in young individuals. History and physical exam are needed to identify associated cardiac abnormalities. In patients with heart failure, and depressed ejection fraction, cardiac resynchronization is beneficial in the presence of LBBB but not in the presence of RBBB.

TABLE 3  Differential Diagnosis of Bundle Branch Block Right Bundle Branch Block

Left Bundle Branch Block

Incomplete

Complete

Incomplete

Complete

QRS Axis QRS Duration I

Normal 120 msec Deep S

Normal or left 130 msec Tall R wave, no q wave, no S wave Tall R wave, no q wave, no S wave

II, III, aVF Precordial Leads

rSR' in V1-V2, qRs in V5-V6

RsR' in V1-V2, deep S in V5-V6

aVR

rsR'

No q wave in V5-V6

QS or rS in V1-V2, tall R wave and no q wave or S wave in V5-V6

Hemifascicular Block Left Anterior Fascicular Block

Left Posterior Fascicular Block

Left and >–45° +90° 90%), moderately emetic (>30% to 90%), low emetic (10% to 30%), and minimally emetic (0% to 10%). • With certain chemotherapy regimens, CINV will occur in the majority of patients. However, patients’ tolerance may vary, and symptoms may occur in as low as 10% of patients. • Symptoms may be dose dependent (the higher the dose, the greater the risk for symptoms). • CINV is more likely to affect female and younger patients. • Patients expecting CINV before receiving therapy (anticipatory emesis) are at greater risk of experiencing symptoms. • Patients with a history of alcohol consumption are at lower risk. • Patients with a history of motion sickness are at greater risk. INCIDENCE: The highest incidence of CINV is before or during the first cycle of chemotherapy. GENETICS: Some rapid metabolizers of certain 5-HT3 receptor antagonists and polymorphisms in the 5-HT3 receptor confer greater risk for CINV.

alternative diagnosis; physical examination findings such as increased blood pressure, abdominal tenderness, or focal neurologic deficits may suggest symptoms caused by cancer progression or other acute illness such as infection.

PHYSICAL FINDINGS & CLINICAL PRESENTATION • Symptoms may include anxiety and lightheadedness. • The most common physical findings are increased pulse rate and abnormal blood pressure (elevated if the person is highly anxious, reduced if the patient is dehydrated). • Symptoms such as diarrhea, fever, headache, and abdominal pain may suggest an

PATHOPHYSIOLOGY The pathophysiology of nausea and vomiting is illustrated in Fig. E1. CINV is likely the result of chemotherapy acting in two places: Directly in the gastrointestinal tract and in the vomiting center of the brain. In both areas, nausea and vomiting are mediated by the actions of certain neurotransmitters, with serotonin, dopamine, and neurokinin-1 being the most important.

TABLE 1  Emetogenic Potential of Commonly Used Oral Antineoplastic Agents Risk

Frequency of Emesis (%; Without Prophylaxis)

High

>90

Moderate

30-90

Low

10-30

Minimal

3 mo for more than 2 successive yrs. These terms are no longer included in the formal definition of COPD, although they are still used clinically. Although emphysema and chronic bronchitis are commonly associated with COPD, neither is required to make the diagnosis. An overlap syndrome known as ACOS (asthma-COPD overlap syndrome), characterized by persistent airflow limitation with several features associated with asthma and several features associated with COPD, has been gaining recognition and may have treatment and mortality implications (Global Initiative for Chronic Obstructive Lung Disease [GOLD] and Global Initiative for Asthma [GINA] consensus statement). SYNONYMS COPD Emphysema Chronic bronchitis ICD-10CM CODES J42 Chronic bronchitis, unspecified chronic bronchitis type J44.9 Chronic obstructive pulmonary disease, unspecified COPD type J44.0 Chronic obstructive pulmonary disease with acute lower respiratory infection J44.1 Chronic obstructive pulmonary disease with acute exacerbation J43.0 Unilateral emphysema J43.1 Panlobular emphysema J43.2 Centrilobular emphysema J43.8 Other emphysema J43.9 Pulmonary emphysema, unspecified emphysema type

chemical vapors, irritants, and fumes; 80% to 90% is due to cigarette smoking. • COPD is the third leading cause of death in the U.S. • Highest incidence is in males >40 yr. • 16 million office visits, 500,000 hospitalizations, 126,000 deaths annually, and >$18 billion in direct health care costs annually can be attributed to COPD. • Patients with COPD living in isolated rural areas of the U.S. are at greater risk for COPD exacerbation-related mortality than those living in urban areas, independent of hospital rurality and volume.

PHYSICAL FINDINGS & CLINICAL PRESENTATION • Patients with COPD have historically been classically subdivided in two major groups based on their phenotype: 1.  Blue bloaters are patients with chronic bronchitis; the name is derived from the bluish tinge of the skin (as a result of chronic hypoxemia and hypercapnia) and from the frequent presence of peripheral edema (from cor pulmonale); chronic cough with production of large amounts of sputum is characteristic. 2.  Pink puffers are patients with emphysema; they have a cachectic appearance but pink skin color (adequate oxygen saturation); shortness of breath is manifested by pursed-lip breathing and use of accessory muscles of respiration. • COPD may present with combinations of the following signs and symptoms: 1. Cyanosis, chronic cough (usually productive but may be intermittent and may be unproductive), tachypnea, tachycardia. 2.  Dyspnea (persistent, progressive), pursed-lip breathing with use of accessory muscles for respiration, decreased breath sounds, wheezing. 3. Chronic sputum production. 4. Chest wall abnormalities (hyperinflation, “barrel chest,” protruding abdomen). 5. Flattening of diaphragm. TABLE 1 Systemic Manifestations and Comorbidities of COPD Cardiovascular

Hypercoagulability

Systemic

EPIDEMIOLOGY & DEMOGRAPHICS • COPD affects 14% of U.S. adults aged 40 to 79 yr. • Between 10% and 20% of COPD in the U.S. is due to occupational or other exposure to

Lung cancer

Infarction Arrhythmia Congestive heart failure Aortic aneurysm Stroke Pulmonary embolism Deep vein thrombosis Atrophy Weight loss Osteoporosis Skin wrinkling Anemia Fluid retention Depression

From Mason RJ: Murray & Nadel’s textbook of respiratory medicine, ed 5, Philadelphia, 2010, WB Saunders.

• Systemic manifestations and comorbidities of COPD are described in Table 1. • Acute exacerbation of COPD is mainly a clinical diagnosis and generally manifests with worsening dyspnea, increase in sputum purulence, and increase in sputum volume. Respiratory symptom status, however, is not a reliable indicator of the presence of airflow obstruction. Individuals with normal spirometry values may report respiratory symptoms, whereas individuals who have severe to very severe airflow obstruction by spirometry may report no symptoms. Individuals with sedentary lifestyles may underestimate their symptoms and careful history taking is important to elicit symptoms suggestive of COPD.

ETIOLOGY • Tobacco exposure (Fig. E1) • Occupational exposure to pulmonary toxins (e.g., dust, noxious gases, vapors, fumes, cadmium, coal, silica); the industries with the highest exposure risk are plastics, leather, rubber, and textiles • Atmospheric pollution • Alpha-1-antitrypsin deficiency (rare; 27 kg/m2 and those who train 90% for the identification of concussion. • Consider the Buffalo Concussion Treadmill Test, which identifies physiologic dysfunction in concussion, rules out other diagnoses, and can quantify a safe level of activity in concussion recovery. IMAGING STUDIES • CT imaging is not universally indicated and should be considered on an individual basis. It is indicated in any athlete with a rapidly changing or focal neurologic exam or with a suspected intracranial bleed. • Consider following PECARN guidelines.

TREATMENT ACUTE GENERAL Rx • Removal from game • Physical rest

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Concussion after a concussion. Each case should be individually considered.

TABLE 2  Graduated Return to Play Protocol Functional Exercise at Each Stage of Rehabilitation

1 . No activity 2. Light aerobic exercise

Complete physical and cognitive rest Walking, swimming, or stationary cycling, keeping intensity 18 yr) • Adaptive behavior or subcultural delinquency • Underlying neurological disorder (rare) WORKUP Diagnosis is made based on history, including individual and family interviews as well as collateral data from additional sources (e.g., parents, teachers, other medical providers, therapists). LABORATORY TESTS Consider urine toxicology for possible substance use comorbidity.

IMAGING STUDIES None indicated; however, both structural and functional differences have been noted in certain areas of the brain in individuals with CD.

TREATMENT Initial treatment of CD should include psychosocial and environmental interventions aimed at decreasing the frequency and severity of delinquent behaviors. If the interventions listed here are not effective or if serious concerns exist regarding safety or impairment in functioning, pharmacologic interventions targeting specific symptoms (e.g., aggression) or comorbid disorders (e.g., ADHD, anxiety disorders, or mood disorders) may help. There are currently no medications approved by the FDA for the treatment of CD.

NONPHARMACOLOGIC THERAPY • Parent management training. • Cognitive problem-solving skills training (including elements of social skills, conflict resolution, anger management, impulse control, and vocational training). • Multisystemic therapy (MST). • Social skills training. • Individual psychotherapy. • Family psychotherapy. • Higher levels of care such as a hospital or acute residential setting may be required for stabilization if acute safety concerns develop in the context of CD, such as severe aggression. • Legal involvement or out-of-home-placements may be necessary to monitor safety of both the patient and the community. PHARMACOLOGIC THERAPY Medication may be considered as an adjunct to behavioral treatment or in cases in which comorbidity is a factor. There is some evidence for symptom improvement with trials of several classes of psychotropic medications—including stimulants, mood stabilizers, atypical antipsychotics, antidepressants, and alpha-2 agonists—all of which seem to target aggressive symptoms in particular; medication, however, should never be used alone or as first-line treatment for CD. DISPOSITION • Approximately half of those with early onset of CD persist with antisocial behaviors into adulthood. There is no reliable way to predict which 50% will persist. • Approximately half of those with early onset of CD do not develop antisocial personality disorder in adulthood. This subgroup is at higher risk for depression, anxiety, and social isolation as adults. • Approximately 85% of those with adolescent onset of CD do not demonstrate lifetime persistent violence, convictions, and incarcerations. However, adult prognosis may often include substance use and crimes that go largely undetected.

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Conduct Disorder  EARLS & P CONSIDERATIONS COMMENTS • Treatment noncompliance is common (expect 30% treatment noncompliance rate).

397.e3 • Consider community-based resources (including unique strengths of patient and family) and recruit multiple multidisciplinary team members to create the most effective possible treatment plan. AUTHORS: Hassan M. Minhas, MD, and Elizabeth A. Lowenhaupt, MD

SUGGESTED READINGS Erskine H et  al: Long-term outcomes of attention-deficit/hyperactivity disorder and conduct disorder: a systematic review and meta-analysis, J Am Acad Child Adolesc Psychiatry 55(10):841-850, 2016. Jolla NJ et al: Attention deficit hyperactivity disorder and arrest history: differential association of clinical characteristics by sex, Int J Law Psychiatry 58: 150-156, 2018. Noordermeer S et al: A systematic review and meta-analysis of neuroimaging in oppositional defiant disorder (ODD) and conduct disorder (CD) taking attention-deficit hyperactivity disorder (ADHD) into account, Neuropsychol Rev 26:44-72, 2016. Sun X et al: MAOA genotype influences neural response during an inhibitory task in adolescents with conduct disorder, Eur Child Adolesc Psychiatry 27(9): 1159-1169, 2018.

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398

Condyloma Acuminatum  BASIC INFORMATION DEFINITION Condyloma acuminatum, also known as anogenital warts, is a sexually transmitted viral disease of the penis, vulva, vagina, cervix, perineum, and perianal area caused by the human papillomavirus (HPV). More than 100 subtypes of the HPV virus have been identified, yet 90% of genital warts are caused by HPV types 6 or 11. SYNONYMS Genital warts Venereal warts Anogenital warts ICD-10CM CODE A63.0 Anogenital (venereal) warts

EPIDEMIOLOGY & DEMOGRAPHICS • The estimated prevalence rate of HPV anogenital infection in the U.S. adult population is 10% to 20% among unvaccinated individuals • Seen mostly in young adults, with peak age of onset of 16 to 25 yr • A sexually transmitted disease spread by skin-to-skin contact • Highly contagious, with 75% of sexually active adults in the United States having been infected with at least one genital HPV type at some time • Virus shed from both macroscopic and microscopic lesions • Average incubation time is 2 mo (range, 1 to 8 mo) • Predisposing conditions: Diabetes, pregnancy, local trauma, and immunosuppression (e.g., transplant recipients, those with HIV infection) PHYSICAL FINDINGS & CLINICAL PRESENTATION • Usually found in genital area but can be present elsewhere on the body (larynx, oropharynx, trachea, and extremities) • Lesions usually in similar positions on both sides of perineum • Initial lesions are pedunculated, soft papules about 2 to 3 mm in diameter, 10 to 20 mm long; may occur as single papule or in clusters • Size of lesions varies from pinhead to large cauliflower-like masses (Fig. E1) • Usually asymptomatic, but if infected can cause pain, odor, or bleeding • Vulvar condyloma more common than vaginal and cervical • Four morphologic types: Condylomatous, keratotic, papular, and flat warts • Intra-anal warts are observed predominantly in persons who have had receptive anal intercourse ETIOLOGY • HPV is a group of nonenveloped, doublestranded DNA viruses belonging to the family Papillomaviridae.

• HPV DNA types 6 and 11 usually found in exophytic warts and have no malignant potential. 90% of genital warts are caused by HPV 6 and 11. • HPV types 16 and 18 usually found in flat warts and are associated with increased risk of malignancy. • Recurrence associated with persisting viral infection of adjacent normal skin in 25% to 50% of cases.

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • Molluscum contagiosum • Seborrhea keratosis • Fordyce spots • Lichen planus • Lichen nitidus • Condylomata lata of syphilis • Malignancy • Abnormal anatomic variants or skin tags around labia minora and introitus • Dysplastic warts • Table 1 summarizes treatment options for anal warts WORKUP • Colposcopic examination of lower genital tract from cervix to perianal skin with 3% to 5% acetic acid • Biopsy of vulvar lesions that lack the classic appearance of warts and that become ulcerated or do not respond to treatment • Biopsy of flat, white, or ulcerated cervical lesions LABORATORY TESTS • HPV tests are available to detect oncogenic types of HPV infection and are used in the context of cervical cancer screening and management or follow-up of abnormal cervical cytology or histology • Cervical cultures for Neisseria gonorrhoeae and Chlamydia • Serologic test for syphilis • HIV testing offered • Wet mount or DNA testing for trichomoniasis, Candida albicans, and Gardnerella vaginalis (if patient has abnormal vaginal discharge)

TREATMENT NONPHARMACOLOGIC THERAPY • Cryotherapy with liquid nitrogen • Surgical removal ACUTE GENERAL Rx Factors that influence selection of treatment include wart size, wart number, anatomic site of wart, wart morphology, patient preference, cost of treatment, convenience, adverse effects, and provider experience. Keratolytic agents: • Podophyllin (Podofilox 0.5% solution or gel) 1.  Acts by poisoning mitotic spindle and causing intense vasospasm

2. Applied by patient directly to lesion weekly and washed off in 6 hours 3. Used in minimal vulvar or anal disease 4. Applied cautiously to nonkeratinized epithelial surfaces 5. Contraindicated in pregnancy 6. Discontinued if lesions do not disappear in 6 wk; switch to other treatment • Sinecatechins 15% ointment (green tea flavonoid extracts) 1. Acts by upregulating apoptosis-associated genes 2. Applied by patient three time daily (0.5 cm strand of ointment to each wart) 3. Should not be continued longer than 16 wk • Trichloroacetic acid (30% to 80% solution) 1. Acts by destruction of the warty lesions through precipitation of surface proteins 2.  Applied weekly to lesion by a trained clinician 3.  Indicated for vulvar, anal, and vaginal lesions; can be used for cervical lesions 4. Less painful and irritating to normal tissue than podophyllin • 5-Fluorouracil 1. Acts by causing necrosis and sloughing of growing tissue 2. Can be used intravaginally or for vulvar, anal, or urethral lesions 3. Better tolerated; 3 g (two thirds of vaginal applicator) applied weekly for 12 wk 4. Possible vaginal ulceration and erythema 5. Patient’s vagina examined after four to six applications 6. 80% cure rate Physical agents: • Cryotherapy with liquid nitrogen or cryoprobe 1.  Acts by causing tissue damage by formation of ice crystals, leading to disruption of cell membranes and cell death 2. Can be used weekly for 3 to 6 wk 3. 62% to 79% cure rate 4. Not suitable for large warts • Laser therapy 1. Done by physician with necessary expertise and equipment 2. Painful; requires anesthesia • Electrocautery or excision 1. For recurrent, very large lesions 2. Local anesthesia needed Immunotherapy: • Interferon A 1. Injected intralesionally at a dose of 3 million U/m2 three times weekly for 8 wk 2. Side effects: Fever, chills, malaise, headache • Imiquimod 5% cream: Immunomodulatory drug that increases the immune response to warts 1. Applied by patient at night, 3× per wk; wash off after 6 to 10 hours 2. Usage for 16 wk maximum 3. Increases wart clearance after 3 mo • 40% to 77% cure rate • Interferon, topical: Increases wart clearance at 4 wk

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Condyloma Acuminatum TABLE 1  Treatment Options for Anal Warts Success Rate

Comments

Podophyllin

20%-50%

Trichloroacetic or dichloroacetic acid

75%

Cryotherapy

75%

Topical 5-fluorouracil

50%-75%

Imiquimod

75% in women 33% in men 60%-90%

May need repeat applications Skin irritation can occur Not used in the anal canal Poorly absorbed by keratinized lesions (most chronic warts are keratinized) Can be used in the anal canal Care is required to control the size of the slough Can be used in the anal canal Care is required to limit the size of the wound Fumes from the therapy can contain active HPV* Probably better used after surgical excision to decrease the frequency of recurrence Cannot be used in the anal canal; works better in women than in men Fumes from the cautery may contain HPV* May need to be done in more than one session to avoid excising or burning excessive anoderm if a thick carpet of lesions is present Injected into the base of up to 5 warts 3 times a wk for 3-8 wk Approved by the FDA for refractory condyloma Promising treatment involving subcutaneous injections Fusion protein that combines immune-stimulating properties and a target antigen from HPV Reserved for giant cavitating condyloma (Buschke-Löwenstein lesions) Used as a last resort, usually when bleeding or tissue invasion cannot be controlled

Surgical excision (usually combined with cautery) Intralesional interferon-α

>70%

HspE7

Experimental

External-beam radiation therapy

Variable

*The risk of HPV transmission from such fumes is unknown. FDA, Food and Drug Administration; HPV, human papillomavirus. From Feldman M, Friedman LS, Brandt LJ: Sleisenger and Fortran’s gastrointestinal and liver disease, ed 10, Philadelphia, 2016, Elsevier.

DISPOSITION • M ost genital warts resolve without therapy. • Follow-up exam every 6 to 12 mo as needed. • Referral to a specialist experienced in the treatment of anogenital warts (e.g., dermatologist, urologist, or colorectal surgeon) is appropriate for patients who are immunosuppressed or who have treatment-refractory anogenital warts. • Patients with large, bulky perianal or genital warts that may require extensive surgical

removal should be referred to a colorectal surgeon or urologist.

PREVENTION • Male and female condoms should be used consistently and correctly to lower the risks of acquiring and transmitting HPV. However, because HPV can infect areas not covered by a condom, condoms will not fully protect against HPV. • New guidelines for the routine vaccination of young adolescents (females and males)

C

Diseases and Disorders

Treatment

ages 9 to 14 are two doses of the HPV vaccine given at a 6- to 12-mo interval, which offers the same protection as the three-dose vaccination. • Young women from ages 15 to 26 should receive three doses of the HPV vaccine (the 9vHPV, 4vHPV, and 2vHPV are approved for females). • Young males from ages 15 to 21 should receive three doses of the HPV vaccine. The age limit for male HPV vaccination may be extended up to age 26 (only the 4vHPV and 9vHPV vaccines are approved for males). For men who have sex with men (including young men who identify as gay and bisexual), for young transgender adults, and for young adults who are immunocompromised (secondary to HIV, chronic steroid usage, or prior history of transplant), HPV vaccination is recommended up to age 26. Three-dose HPV vaccination series are administered as IM injections over a 6-mo period, with the second and third doses given 1 to 2 and 6 mo after the first dose, respectively. The same vaccine type should be used for the entire three-dosage series. • 4vHPV (Gardasil) vaccinates against types 6, 11, 16, and 18, which account for 66% of all cervical cancers. • 2vHPV (Cervarix) vaccinates against types 16 and 18 (licensed for females only). • 9vHPV (Gardasil 9) vaccine is available for preventing infection against HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58. It offers protection against five additional types of HPV accounting for 15% of cervical cancers not covered by Gardasil or Cervarix. • HPV vaccines are not recommended for use in pregnant women.

399

I

SUGGESTED READING Available at ExpertConsult.com RELATED CONTENT Genital Warts (Patient Information) Warts (Related Key Topic) AUTHORS: Helen B. Gomez, MD, and Rachel Wright Heinle, MD, FACOG

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Condyloma Acuminatum

399.e1

SUGGESTED READING Workowski KA, Bolan GA: Centers for Disease Control and Prevention: Sexually transmitted diseases treatment guidelines 2015, MMWR Recomm Rep 64(RR03):1-137, 2015.

A

B

C

FIG. E1  Condyloma acuminatum. A, Scattered, flesh-colored or hyperpigmented, smooth or verrucous papules or erythematous macules along the shaft of the penis, scrotum, and perianal area are characteristic. The term bowenoid papulosis is used when the histologic picture of a lesion resembles Bowen disease. B, Perianal condyloma acuminatum. The viral particles causing perianal condyloma may have originated from warts elsewhere on the body and been transmitted via the patient’s own hands, or they may have been contracted during anal sex. C, Condyloma acuminatum. Multiple lesions on the shaft of the penis. (From White GM, Cox NH [eds]: Diseases of the skin: a color atlas and text, ed 2, St Louis, 2006, Mosby.)

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399.e2

Congenital Adrenal Hyperplasia BASIC INFORMATION DEFINITION Congenital adrenal hyperplasia (CAH) is a spectrum of disorders resulting from a deficiency or complete lack of one of the enzymes in the cortisol synthesis pathway. These autosomal recessive genetic disorders are usually characterized by cortisol deficiency and virilization, with or without salt wasting. SYNONYMS CAH 21-Hydroxylase deficiency (equivalent to CYP21A2 deficiency) 11β-Hydroxylase deficiency 3β-Hydroxysteroid dehydrogenase deficiency 17-Hydroxylase deficiency Lipoid adrenal hyperplasia Adrenal virilism Adrenogenital syndrome Virilizing adrenal hyperplasia ICD-10CM CODE E25.0 Congenital adrenogenital disorders associated with enzyme deficiency

EPIDEMIOLOGY & DEMOGRAPHICS • About 95% of cases of CAH are caused by 21-hydroxylase deficiency, of which twothirds are the salt-wasting form. Table E1 summarizes genotype-phenotype correlations in congenital adrenal hyperplasia owing to 21-hydroxylase deficiency. • Autosomal recessive inheritance. • The “classic” form presents in childhood, and the “nonclassic” form is the mild, late-onset form. • Incidence is estimated at about 1:10,000 to 1:20,000 live births (Hispanic > American Indian > white > black > Asian). • Most common cause of ambiguous genitalia in 46,XX females.

CLINICAL PRESENTATION “Classic” salt-wasting form (impaired cortisol and aldosterone synthesis): • Adrenal crisis in first weeks of life with vomiting, poor weight gain, lethargy, dehydration, hyponatremia, hyperkalemia, and elevated plasma renin. • Females are born with ambiguous genitalia (Fig. E1) that often leads to diagnosis before adrenal crisis occurs. • Males may have greater penile size and smaller testes than expected during childhood. Males may also develop adrenal rests, or ectopic islands of adrenal cortical tissue in the testes, in childhood and may experience infertility as adults. • If patients survive infancy, their overall life expectancy is not compromised. • Both males and females may exhibit rapid growth in childhood due to early epiphyseal closure, which then results in short stature in adulthood. • Precocious puberty is common in both males and females. “Classic” non–salt-wasting or simple virilizing form (impaired cortisol synthesis only): • Females present with ambiguous genitalia at birth. • The normal appearance of male genitalia in the simple virilizing form makes this a difficult diagnosis in male infants. • Characterized by precocious puberty, short stature, and testicular adrenal rests, as in the salt-wasting form. “Nonclassic” or mild, late-onset form (varying degrees of androgen excess): • Usually presents in adolescence or adulthood and is not detected on newborn screening • Often asymptomatic but can be associated with mild virilization • PCOS-like symptoms occur in women (hirsutism, oligomenorrhea, acne, infertility, insulin resistance, and abnormal menses) • Associated with infertility in males

ETIOLOGY In 21-hydroxylase deficiency, the pathways for aldosterone production (from the conversion of progesterone to deoxycorticosterone) and cortisol production (from the conversion of 17-hydroxyprogesterone to 11-deoxycortisol) by the cP450 enzyme 21-hydroxylase are interrupted. The production of ACTH is thus stimulated by a negative feedback mechanism, leading to adrenal hyperplasia and mineralocorticoid deficiency as the intermediaries in aldosterone and cortisol synthesis are shunted to the androgen biosynthesis pathway. A recombination event between the active CYP21A2 gene on chromosome 6p21.3 and the CYP21A1 pseudogene is thought to create the deficient 21-hydroxylase enzyme.

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • Precocious puberty • Polycystic ovarian syndrome (PCOS) • Androgen resistance syndromes • Pseudohermaphroditism • Mixed gonadal dysgenesis • Testicular carcinoma • Leydig cell tumors • Adrenocortical carcinoma • Addison disease • Pituitary adenoma LABORATORY TESTS • Prenatal: Chorionic villus sampling for history; genetic testing or measurement of 17-hydroxyprogesterone if family history. • Serum 17-hydroxyprogesterone level, which is included in the newborn screen in all states, is the first-line test for suspected CAH. • Adrenocorticotropin (ACTH) stimulation test is the next step to confirm the diagnosis and identify type of CAH. • Additional tests that may be useful include plasma renin activity, aldosterone level, and electrolytes.

TABLE E1  Genotype-Phenotype Correlations in Congenital Adrenal Hyperplasia Owing to 21-Hydroxylase Deficiency Mutation Group

A

B

C

Enzymatic activity, % normal CYP21 mutations (phenotype generally corresponds to the least affected allele)

1–2% I172N

20–50% P30L V281L P453S

Severity Aldosterone synthesis Age at diagnosis (without newborn screening)

Nil Gene deletion Exon 3 del 8 bp Exon 6 cluster Q318X R356W Intron 2 splice* Salt wasting Low Infancy

Nonclassic Normal Childhood to adulthood, or asymptomatic

Virilization Incidence

Severe 1/20,000

Simple virilizing Normal Infancy (females) Childhood (males) Moderate to severe 1/50,000

None to mild 1/500

*This mutation is associated with both salt wasting and simple virilizing disease. From Kliegman, RM: Nelson textbook of pediatrics, ed 21, Philadelphia, 2020, Elsevier.

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Congenital Adrenal Hyperplasia IMAGING STUDIES • Abdominal ultrasound (Fig. E2) to evaluate adrenal glands can accelerate diagnosis. • Ultrasound to identify a uterus in cases of ambiguous genitalia. • Ultrasound is preferred to rule out testicular adrenal rest tumors (found in classic and nonclassic forms) and should be done beginning in adolescence.

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TREATMENT NONPHARMACOLOGIC THERAPY • Surgical correction of ambiguous genitalia may be necessary. • Monitoring: Serum 17-hydroxyprogesterone and androstenedione, renin, electrolytes,

A

blood pressure, bone age and density, Tanner staging, growth velocity, weight. • Bilateral laparoscopic adrenalectomy with lifelong glucocorticoid and mineralocorticoid replacement (controversial). • Gene therapy (hypothetical). • Psychological counseling.

CHRONIC Rx • Glucocorticoids to partially suppress adrenal androgen secretion. During periods of physiologic stress, they may need to be doubled or tripled. 1. In children, hydrocortisone is preferred because of its short half-life, which minimizes the risk of iatrogenic short stature. After patients are fully grown, long-acting glucocorticoids can be used. 2. Adolescents and adults: Dexamethasone 0.25 to 0.75 mg PO QHS (also used to treat adrenal rests) or prednisone 5 to 7.5 mg/day in two divided doses. • Mineralocorticoids (e.g., fludrocortisone) to normalize electrolytes and plasma renin activity. 1. In infants, salt supplementation is also required. • Treatment of simple virilizing form: Similar to salt-wasting form, but mineralocorticoid replacement is unnecessary. • Treatment of nonclassic form: 1. In adolescent and adult women: Oral contraceptives, glucocorticoids, and/or antiandrogens. 2. In children and adult males, usually no treatment is necessary. 3. Prenatal glucocorticoid treatment is controversial but may decrease virilization in female fetuses.

PEARLS & CONSIDERATIONS

B FIG. E1  Congenital adrenal hyperplasia. This newborn has ambiguous genitalia. Note the marked clitoral enlargement (resembling a penis), the rugated and partially fused labia majora (A), and the common opening between the vagina and the urethra (urogenital sinus) (B). (Courtesy Marleta Reynolds, MD. From Paller AS, Mancini AJ: Hurwitz clinical pediatric dermatology, a textbook of skin disorders of childhood and adolescence, ed 5, Philadelphia, 2016, Elsevier.)

A

COMMENTS • Consider the diagnosis of classic salt-wasting CAH in infants with failure to thrive. • There is believed to be an increased prevalence of CAH in patients diagnosed with adrenal “incidentalomas”—adrenal gland lesions detected unexpectedly on imaging, usually by MRI or CT scanning.

B

FIG. E2  Congenital adrenal hyperplasia in a patient with male pseudohermaphroditism. Sagittal US of the (A) right and (B) left adrenal glands demonstrates masslike enlargement. (From Grant LA: Grainger & Allison’s diagnostic radiology essentials, ed 2, 2019, Elsevier.)

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Congenital Adrenal Hyperplasia • Cushing syndrome may result from overtreatment of CAH with glucocorticoids. • Patients with CAH may have gender dysphoria and sexual dysfunction. • T able E2 summarizes diagnosis and treatment of CAH.

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PREVENTION • Prenatal: Early CVS sampling. Use of dexamethasone 20 to 25 mg/kg daily beginning at 5- to 8-wk gestation for female fetuses only is controversial because long-term studies are unavailable

• Neonatal screening • Genetic counseling AUTHOR: Fred F. Ferri, MD

TABLE E2  Diagnosis and Treatment of Congenital Adrenal Hyperplasia Disorder

Affected Gene and Chromosome

21-Hydroxylase deficiency, classic form

CYP21 6p21.3

Signs and Symptoms

Laboratory Findings

Therapeutic Measures

Glucocorticoid deficiency

↓ Cortisol, ↑ACTH ↑↑ Baseline and ­ACTH-stimulated 17-hydroxy-progesterone Hyponatremia, hyperkalemia ↑ Plasma renin

Glucocorticoid (hydrocortisone) replacement

Mineralocorticoid deficiency (salt-wasting crisis)

21-Hydroxylase deficiency, nonclassic form

CYP21 6p21.3

11β-Hydroxylase deficiency

CYP11B1 8q24.3

3β-Hydroxysteroid dehydrogenase deficiency, classic form

HSD3B2 1p13.1

Ambiguous genitalia in females Postnatal virilization in males and females May be asymptomatic; precocious adrenarche, hirsutism, acne, menstrual irregularity, infertility Glucocorticoid deficiency

Ambiguous genitalia in females Postnatal virilization in males and females Hypertension Glucocorticoid deficiency

Mineralocorticoid deficiency (salt-wasting crisis)

17α-Hydroxylase/17,20lyase deficiency

CYP17 10q24.3

↑ Serum androgens ↑ Serum androgens ↑ Baseline and ACTH-stimulated ­17-hydroxyprogesterone ↑ Serum androgens ↓ Cortisol, ↑ ACTH ↑↑ Baseline and ACTHstimulated 11-deoxycortisol and deoxycorticosterone ↑ Serum androgens ↑ Serum androgens ↓ Plasma renin, hypokalemia ↓ Cortisol, ↑ ACTH ↑↑ Baseline and ACTHstimulated Δ5 steroids (pregnenolone, 17-hydroxy-pregnenolone, DHEA) Hyponatremia, hyperkalemia ↑ Plasma renin

Ambiguous genitalia in females and males

↑ DHEA, ↓ androstenedione, testosterone, and estradiol

Precocious adrenarche, ­disordered puberty Cortisol deficiency ­(corticosterone is an adequate glucocorticoid)

↑ DHEA, ↓ ­androstenedione, testosterone, and estradiol ↓ Cortisol, ↑ ACTH ↑ DOC, corticosterone Low 17α-hydroxylated steroids; poor response to ACTH ↓ Serum androgens; poor response to hCG

Ambiguous genitalia in males

Sexual infantilism Hypertension

↓ Serum androgens or estrogens ↓ Plasma renin; hypokalemia

Mineralocorticoid (fludrocortisone) replacement; sodium chloride supplementation Vaginoplasty and clitoral recession Suppression with glucocorticoids Suppression with glucocorticoids

Glucocorticoid (hydrocortisone) replacement

Vaginoplasty and clitoral recession Suppression with glucocorticoids Suppression with glucocorticoids Glucocorticoid (hydrocortisone) replacement

Mineralocorticoid (fludrocortisone) replacement; sodium chloride supplementation Surgical correction of genitals and sex hormone replacement as necessary, consonant with sex of rearing Suppression with glucocorticoids Glucocorticoid (hydrocortisone) administration

Orchidopexy or removal of intraabdominal testes; sex hormone replacement consonant with sex of rearing Sex hormone replacement consonant with sex of rearing Suppression with glucocorticoids Continued

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Congenital Adrenal Hyperplasia

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TABLE E2  Diagnosis and Treatment of Congenital Adrenal Hyperplasia—cont’d Disorder

Affected Gene and Chromosome

Congenital lipoid adrenal hyperplasia

STAR 8p11.2

Signs and Symptoms

Laboratory Findings

Therapeutic Measures

Glucocorticoid deficiency

↑ ACTH Low levels of all steroid hormones, with decreased or absent response to ACTH Hyponatremia, hyperkalemia ↓ Aldosterone, ↑ plasma renin

Glucocorticoid (hydrocortisone) replacement

Mineralocorticoid deficiency (salt-wasting crisis)

P450 oxidoreductase ­deficiency

POR 7q11.3

Ambiguous genitalia in males

Decreased or absent response to hCG in males

Poor pubertal development or premature ovarian failure in females Glucocorticoid deficiency

↑ FSH, ↑ LH, ↓ estradiol (after puberty)

Ambiguous genitalia in males and females Maternal virilization Antley-Bixler syndrome

↓ Cortisol, ↑ ACTH ↑ Pregnenolone, ↑ progesterone ↑ Serum androgens prenatally, ↓ androgens and estrogens at puberty

Mineralocorticoid (fludrocortisone) replacement; sodium chloride supplementation Orchidopexy or removal of intraabdominal testes; sex hormone replacement consonant with sex of rearing Estrogen replacement Glucocorticoid (hydrocortisone) replacement Surgical correction of genitals and sex hormone replacement as necessary, consonant with sex of rearing

Decreased ratio of estrogens to androgens

↓, Decreased; ↑, increased; ↑↑, markedly increased; ACTH, adrenocorticotropic hormone; DHEA, dehydroepiandrosterone; DOC, 11-deoxycorticosterone; FSH, follicle-stimulating hormone; hCG, human chorionic gonadotropin; LH, luteinizing hormone. From Kliegman, RM: Nelson textbook of pediatrics, ed 21, Philadelphia, 2020, Elsevier.

SUGGESTED READINGS Falhammar H et al: Clinical outcomes in the management of congenital adrenal hyperplasia, Endocrine 41(3):355-373, 2012. Pezzuti IL et al: A three-year follow-up of congenital adrenal hyperplasia newborn screening, J Pediatr (Rio J) 90(3):300-307, 2014. Speiser PW et al: Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: an Endocrine Society clinical practice guideline, J Clin Endocrinol Metab 95:4133-4160, 2010.

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Conjunctivitis  BASIC INFORMATION DEFINITION The term conjunctivitis refers to an inflammation of the conjunctiva resulting from a variety of causes, including allergies and bacterial, viral, and chlamydial infections. SYNONYMS “Red eye” Pink eye Acute conjunctivitis Subacute conjunctivitis Chronic conjunctivitis Purulent conjunctivitis Pseudomembranous conjunctivitis Papillary conjunctivitis Follicular conjunctivitis Newborn conjunctivitis ICD-10CM CODES H10.9 Unspecified conjunctivitis B30 Viral conjunctivitis H10.0 Mucopurulent conjunctivitis H10.1 Acute atopic conjunctivitis H10.4 Chronic conjunctivitis

EPIDEMIOLOGY & DEMOGRAPHICS INCIDENCE (IN U.S.): 1.6% to 12% in newborns PREVALENCE (IN U.S.): • Allergic conjunctivitis (Fig. E1), the most common form of ocular allergy, is usually associated with allergic rhinitis and may be seasonal or perennial. • Bacterial or viral conjunctivitis is often seasonal and can be extremely contagious. PREDOMINANT AGE: Occurs at any age. Most cases in adults are due to viral infection. Children are more prone to develop bacterial conjunctivitis than viral forms. PEAK INCIDENCE: More common in the spring and fall, when viral infections and pollens increase. PHYSICAL FINDINGS & CLINICAL PRESENTATION • Infection and chemosis of conjunctivae with discharge. Gluing of the eyelids and no itching is more indicative of a bacterial cause (Fig. E2). • Cornea is clear or can be involved (certain bacteria, such as Neisseria, can rapidly develop into corneal infection). • Vision is often normal but can be blurred. Mucus and watering can cause fluctuating vision. • Fig. E3 illustrates the difference between papillary and follicular conjunctivitis. ETIOLOGY • B acterial: Haemophilus influenzae, Streptococcus pneumoniae, and Moraxella catarrhalis in children; Staphylococcus

species in adults. Gram-negative infections are more common in contact lens wearers. Gonococcal ophthalmia neonatorum is caused by Neisseria gonorrhoeae acquired by exposure of the neonatal conjunctivae to infected cervicovaginal secretions during delivery • Viral: Most common overall cause of infectious conjunctivitis • Chlamydial • Allergic • Traumatic (chemical or toxin exposure) • Chronic eyelid inflammation (blepharitis)

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • Acute glaucoma (fixed pupil with headache may indicate acute angle closure) • Corneal lesions • Acute iritis (with pain and photophobia, blurred vision) • Episcleritis • Scleritis (more severe pain, local globe tenderness, and no drainage) • Canalicular obstruction (eye watering, inflammation near the tear punctum) • Table 1 compares allergic diseases of the eye; histologic and laboratory manifestations of allergic ocular disease are described in Table 2 WORKUP • History and physical examination • Visual acuity and eye examination • Reports of itching, pain, and visual changes LABORATORY TESTS Cultures are useful if not successfully treated with antibiotics; initial culture is usually not necessary, since normal conjunctival flora interferes with helpful culture results.

TREATMENT NONPHARMACOLOGIC THERAPY • Warm compresses if infective conjunctivitis • Cold compresses if irritative or allergic conjunctivitis • Contact lenses should be taken out until an infection is completely resolved. Nondisposable lenses should be cleaned thoroughly as recommended by the manufacturer, and a new lens case should be used. Disposable contact lenses should be thrown away ACUTE GENERAL Rx • The majority of cases of bacterial conjunctivitis are self-limiting, and no treatment is necessary in uncomplicated cases.1 1 Azari

AA, Barney NP: Conjunctivitis, a systematic review of diagnosis and treatment, JAMA 310(16):1721-1729, 2013.

Antibiotic drops (e.g., levofloxacin, ofloxacin, ciprofloxacin, tobramycin, gentamicin ophthalmic solution, 1 or 2 drops q2 to 4h) are indicated for complicated bacterial conjunctivitis, in conjunctivitis caused by gonorrhea or chlamydia, and in bacterial conjunctivitis in contact lens wearers. • Caution: Be careful with ophthalmic corticosteroid treatment and avoid unless sure of diagnosis; corticosteroids can exacerbate infections and have been associated with increased intraocular pressure and cataract formation. • An oral antihistamine (e.g., cetirizine, loratadine, desloratadine, or fexofenadine) is effective in relieving itching. • Mast cell stabilizers (e.g., ketotifen, olopatadine, azelastine bid) are effective for allergic conjunctivitis. Others include Elestat, Optivar, and Patanol. • Bepotastine, alcaftadine, azelastine, epinastine, and ketotifen are H1-antihistamines and mast cell stabilizers effective for topical treatment of itching associated with allergic conjunctivitis. The topical NSAID ketorolac (0.5%, 1 drop qd) is also useful in allergic conjunctivitis. Table 3 describes topical ophthalmic medications for allergic conjunctivitis. • Antihistamine/decongestant combinations such as pheniramine/naphazoline (Visine A), available over the counter, are more effective than either agent alone but have a short duration and can result in rebound vasodilatation with prolonged use. Others include Naphcon-A, Albalon-A, and Opcon-A.

CHRONIC Rx • Depends on cause. • If allergic, nonsteroidals such as ketorolac and bromfenac ophthalmic solution; mast cell stabilizers such as Patanol and Zaditor (ketotifen) are useful for improving ocular itching in patients with allergic conjunctivitis. • If an infection, use antibiotic drops (see “Acute General Rx”). • Dry eyes need artificial tears, topical cyclosporine, or lacrimal duct plugs when indicated. • Chronic and recurrent conjunctivitis often occurs with blepharitis. Daily warm compresses and lid scrub treatment may help relieve symptoms. DISPOSITION Follow carefully for the first 2 wk to ensure secondary complications do not occur. Otitis media can develop in 25% of children with H. influenzae conjunctivitis. Bacterial keratitis occurs in 30/1000 contact lens wearers. REFERRAL To ophthalmologist if symptoms are refractory to initial treatment. Indications for urgent referral are severe eye pain or headache, photophobia, decreased vision, and contact lens use.

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Conjunctivitis TABLE 1  Allergic Diseases of the Eye Clinical Parameters

Signs and Symptoms

Seasonal allergic conjunctivitis (SAC)

Occurs in sensitized individuals Both females and males affected Bilateral involvement Seasonal allergens Self-limiting

Ocular itching Tearing (watery discharge) Chemosis, redness Often associated with rhinitis Not sight-threatening

Perennial allergic ­conjunctivitis (PAC)

Occurs in sensitized individuals Both females and males affected Bilateral involvement Year-round allergens Self-limiting Occurs in sensitized individuals Peak incidence: 20-50 yr of age Both females and males affected Bilateral involvement Seasonal or perennial allergens Atopic dermatitis Chronic symptoms Occurs in some sensitized individuals Peak incidence: 3-20 yr of age Males predominate (in 3:1 ratio) Bilateral involvement Warm, dry climate Seasonal/perennial allergens Chronic symptoms Sensitization not necessary Both females and males affected Bilateral involvement Prosthetic and contact lens exposure Occurs anytime Chronic symptoms Nonseasonal occurrence

Ocular itching Tearing (watery discharge) Chemosis, redness Often associated with rhinitis Not sight-threatening Severe ocular itching Red, flaking periocular skin Mucoid discharge, photophobia Corneal erosions Scarring of conjunctiva Cataract (anterior subcapsular) Sight-threatening Severe ocular itching Severe photophobia Thick, ropy discharge Cobblestone papillae Corneal ulceration and scarring Sight-threatening

Atopic keratoconjunctivitis (AKC)

Vernal keratoconjunctivitis (VKC)

Giant papillary conjunctivitis (GPC)

Differential Diagnosis

C

Infective conjunctivitis Preservative toxicity (any eye drop with preservative) Medicamentosa Dry eye Perennial allergic conjunctivitis Vernal keratoconjunctivitis (VKC) Atopic keratoconjunctivitis (AKC) Infective conjunctivitis Preservative toxicity Dry eye SAC/AKC/VKC Contact dermatitis Infective conjunctivitis Blepharitis Pemphigoid VKC/SAC/PAC/GPC

Diseases and Disorders

Disease

401

I

Infective conjunctivitis Blepharitis AKC/SAC/PAC/GPC

Mild ocular itching Mild mucoid discharge Giant papillae Contact lens intolerance Foreign body sensation Protein buildup on contact lens Not sight-threatening

Infective conjunctivitis Preservative toxicity SAC/PAC/AKC/VKC

From Adkinson NF et al: Middleton’s allergy principles and practice, ed 8, Philadelphia, 2014, Saunders.

TABLE 2  Histopathologic and Laboratory Manifestations of Allergic Ocular Disease Disease

Histopathologic Features

Laboratory Manifestations

Seasonal/perennial allergic conjunctivitis

Mast cell/eosinophil infiltration in conjunctival epithelium and substantia propria Mast cell activation Upregulation of ICAM-1 on epithelial cells

Atopic keratoconjunctivitis

Increased mast cells, eosinophils in conjunctival epithelium and substantia propria Epithelial cell/goblet cell hypertrophy Increased CD4/CD8 ratio in conjunctival epithelium and substantia propria Increased collagen Increased mast cells, eosinophils in conjunctival epithelium and substantia propria Eosinophil major basic protein deposition in conjunctiva CD4+ clones from conjunctiva found to have helper function for local production of IgE antibody Increased collagen Increased ICAM-1 on corneal epithelium Giant papillae Conjunctival thickening Mast cells in epithelium

Increased in tears: Specific IgE antibody Histamine Tryptase TNF-α Increased specific IgE antibody in tears Depressed cell-mediated immunity Increased IgE antibody and eosinophils in blood Eosinophils found in conjunctival scrapings

Vernal keratoconjunctivitis

Giant papillary conjunctivitis

Increased specific IgE/IgG antibody in tears Elevated ­histamine and tryptase in tears Reduced serum histaminase activity Increased serum levels of nerve growth factor and ­substance P No increased histamine in tears Increased tryptase in tears

ICAM-1, Intercellular adhesion molecule 1; IgE, immunoglobulin E; IgG, immunoglobulin G; TNF-α, tumor necrosis factor-α. From Adkinson NF et al: Middleton’s allergy principles and practice, ed 8, Philadelphia, 2014, Saunders.

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402

Conjunctivitis TABLE 3  Topical Ophthalmic Medications for Allergic Conjunctivitis Drug and Trade Names

Mechanism of Action and Dosing

Azelastine hydrochloride 0.05% Optivar

Antihistamine Children ≥3 yr: 1 gtt bid

Not for treatment of contact lens–related irritation; the preservative may be absorbed by soft contact lenses. Wait at least 10  min after administration before inserting soft contact lenses.

Emedastine difumarate 0.05% Emadine

Antihistamine Children ≥3 yr: 1 gtt qid

Soft contact lenses should not be worn if the eye is red. Wait at least 10  min after administration before inserting soft contact lenses.

Levocabastine hydrochloride 0.05% Livostin

Antihistamine Children ≥12 yr: 1 gtt bid-qid up to 2 wk

Not for use in patients wearing soft contact lenses during treatment.

Pheniramine maleate

Antihistamine/vasoconstrictor

Avoid prolonged use (>3-4 days) to avoid rebound symptoms. Not for use with contact lenses.

0.3% Naphazoline hydrochloride

Children >6 yr: 1-2 gtt qid

Cautions and Adverse Events

0.025% Naphcon-A, Opcon-A Cromolyn sodium 4% Crolom, Opticrom

Mast cell stabilizer Children >4 yr: 1-2 gtt q4-6h

Can be used to treat giant papillary conjunctivitis and vernal keratitis. Not for use with contact lenses.

Lodoxamide tromethamine 0.1% Alomide

Mast cell stabilizer Children ≥2 yr: 1-2 gtt qid up to 3 mo

Can be used to treat vernal keratoconjunctivitis. Not for use in patients wearing soft contact lenses during treatment.

Nedocromil sodium 2% Alocril

Mast cell stabilizer Children ≥3 yr: 1-2 gtt bid

Avoid wearing contact lenses while exhibiting the signs and symptoms of allergic conjunctivitis.

Pemirolast potassium 0.1% Alamast

Mast cell stabilizer Children >3 yr: 1-2 gtt qid

Not for treatment of contact lens–related irritation; the preservative may be absorbed by soft contact lenses. Wait at least 10  min after administration before inserting soft contact lenses.

Epinastine hydrochloride 0.05% Elestat

Antihistamine/mast cell stabilizer Children ≥3 yr: 1 gtt bid

Contact lenses should be removed before use. Wait at least 15  min after administration before inserting soft contact lenses. Not for the treatment of contact lens irritation.

Ketotifen fumarate 0.025% Zaditor

Antihistamine/mast cell stabilizer Children ≥3 yr: 1 gtt bid q8-12h

Not for treatment of contact lens–related irritation; the preservative may be absorbed by soft contact lenses. Wait at least 10  min after administration before inserting soft contact lenses.

Olopatadine hydrochloride 0.1%, 0.2%, 0.7% Patanol Pataday Pazeo

Antihistamine/mast cell stabilizer Children ≥3 yr: 1 gtt bid (8 hr apart) Children ≥2 yr: 1 gtt qd

Not for treatment of contact lens–related irritation; the preservative may be absorbed by soft contact lenses. Wait at least 10  min after administration before inserting soft contact lenses.

Alcaftadine, 0.25% Lastacaft

Antihistamine/mast cell stabilizer Children >2 yr: 1 gtt bid q8-12h

Contact lenses should be removed before application; may be inserted after 10  min. Not for the treatment of contact lens irritation.

Bepotastine besilate 1.5% Bepreve

Antihistamine/mast cell stabilizer Children >2 yr: 1 gtt bid q8-12h

Contact lenses should be removed before application, may be inserted after 10  min. Not for the treatment of contact lens irritation.

Ketorolac tromethamine 0.5% Acular

NSAID Children ≥3 yr: 1 gtt qid

Fluorometholone 0.1%, 0.25% suspension (0.1%, 0.25%) and ointment (0.1%) FML, FML Forte, Flarex

Fluorinated corticosteroid Children ≥2 yr, 1 gtt into conjunctival sac of affected eye(s) bid-qid. During initial 24-48 hr, dosage may be increased to 1 gtt q4h. Ointment (∼1.3 cm in length) into conjunctival sac of affected eye(s) 1-3 times daily. May be applied q4h during initial 24-48 hr of therapy.

Avoid with aspirin or NSAID sensitivity. Use ocular product with caution in patients with complicated ocular surgeries, corneal denervation or epithelial defects, ocular surface diseases (e.g., dry eye syndrome), repeated ocular surgeries within a short period, diabetes mellitus, or rheumatoid arthritis; these patients may be at risk for corneal adverse events that may be sight-threatening. Do not use while wearing contact lenses. If improvement does not occur after 2 days, patient should be reevaluated. Patient should remove soft contact lenses before administering (contains benzalkonium chloride) and delay reinsertion of lenses for ≥15  min after administration. Close monitoring for development of glaucoma and cataracts.

bid, Two times daily; gtt, drops; NSAID, nonsteroidal antiinflammatory drug; q4-6h, every 4-6 h; qd, every day; qid, four times daily. From Kliegman RM: Nelson textbook of pediatrics, ed 21, Philadelphia, 2020, Elsevier.

PEARLS & CONSIDERATIONS COMMENTS • Red eyes are not simply conjunctivitis when the patient has significant pain or loss of sight. However, it is usually safe

to treat pain-free eyes and the normalseeing red eye with lid hygiene and topical treatment. • Use caution with patients wearing soft contact lenses, infants, and the elderly. • Do not use steroids indiscriminately; use only when the diagnosis is certain.

• Bacterial conjunctivitis is generally self-limiting. More than 60% of persons will improve with placebo within 2 to 5 days.

RELATED CONTENT Conjunctivitis (Patient Information) AUTHOR: R. Scott Hoffman, MD

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Conjunctivitis

402.e1

FIG. E1  Allergic conjunctivitis. Arrow indicates area of chemosis in the conjunctivitis. (From Adkinson NF Jr et  al [eds]: Middleton’s allergy principles and practice, ed 7, vol 2, Philadelphia, 2008, Mosby.)

FIG. E2  Bacterial conjunctivitis. Purulent discharge and conjunctiva hyperemia suggest bacterial conjunctivitis. Viral conjunctivitis produces watery discharge, foreign body sensation, preauricular lymphadenopathy, and conjunctival follicles seen on slit lamp examination. (Reproduced with permission from the American Academy of Ophthalmology. From Goldman L, Schafer AI: Goldman’s Cecil medicine, ed 24, Philadelphia, 2012, Saunders.)

Limbus

Periphery of globe

Papillary conjunctivitis

Follicular conjunctivitis

FIG. E3  Conjunctivitis: Papillary versus follicular. The erythema of conjunctivitis (shaded dark gray) is most intense on the inside surface of the eyelids (tarsal conjunctiva) and peripherally on the globe (near the fornices), whereas the erythema is less intense centrally near the limbus. In more severe conjunctivitis, the entire conjunctival surface (both tarsal and bulbar) is red. This pattern of erythema contrasts with iritis, which causes more intense erythema centrally around the limbus, a finding called circumlimbal flush or ciliary flush. In patients with conjunctivitis, the clinician should inspect the everted upper or lower lids, noting whether the inner membrane has its normal smooth surface or instead has small, uneven projections, which are characterized as either papillae or follicles. In this example, the clinician has used his thumb to gently evert the lower lid for inspection. Papillae (left bottom) are contiguous red vascular bumps; the center of each papilla contains a blood vessel. They are red on the surface and pale at the base. Papillae are often so tiny that the conjunctiva acquires a velvety appearance, and only magnification reveals their true nature. Other times, papillae may become large and produce a cobblestone appearance. Follicles (right bottom) are discrete 1- to 2-mm-diameter white bumps consisting of aggregates of lymphoid tissue; the center of each is avascular. They are pale on the surface and red at the base. (From McGee S: Evidence-based physical diagnosis, ed 4, Philadelphia, 2018, Elsevier.)

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402.e2

Connective Tissue Disease–Associated Vasculitis BASIC INFORMATION DEFINITION Vasculitis is defined by inflammatory leukocytes and subsequent necrosis of blood vessel walls that can eventually lead to tissue ischemia. When vasculitis is associated with a connective tissue disease (CTD), it is defined as a secondary vasculitis. The connective tissue diseases that most commonly cause vasculitis include rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and Sjögren syndrome (SS). Vasculitis rarely occurs in the setting of other connective tissue diseases, including systemic sclerosis (SSc), relapsing polychondritis, primary antiphospholipid syndrome, inflammatory myopathies, and mixed connective tissue disease. Vasculitis is typically classified into large, medium, and small vessel vasculitis. When associated with a connective tissue disease, any type of vasculitis can occur; however, small vessel vasculitis is most common. SYNONYMS Connective tissue disorder–associated vasculitis CTD ICD-1OCM CODE M35.9 Systemic involvement of connective tissue, unspecified EPIDEMIOLOGY & DEMOGRAPHICS • Rheumatoid vasculitis: Estimated to occur in 1% to 5% of patients with RA, with no racial or ethnic predominance. Incidence is decreasing. • Lupus-associated vasculitis: Estimates of the prevalence range from 11% to 36%. • Sjögren-associated vasculitis: Cutaneous vasculitis occurs in approximately 10% of patients with primary Sjögren; systemic vasculitis is rare. • Other CTD: Rare, but well described. PHYSICAL FINDINGS & CLINICAL PRESENTATION GENERAL:

• Constitutional symptoms—fatigue, myalgias, weight loss, fever • Skin manifestations—nail fold lesions (splinter hemorrhages), palpable purpura, leg ulcers, panniculitis, digital gangrene, livedo

reticularis, urticaria, Janeway lesions, Osler nodes • Neurologic manifestations—mononeuritis multiplex, distal symmetric sensorimotor neuropathy, transverse myelitis • Ocular manifestations—episcleritis, scleritis, ulcerative keratitis • Cardiac manifestations—arrhythmias, pericarditis, aortitis • Gastrointestinal manifestations—pancreatitis, peritonitis, colitis • Pulmonary manifestations—pneumonitis, alveolar hemorrhage • Renal manifestations—glomerulonephritis note: Any

organ may be involved because vasculitis can disrupt the corresponding vasculature (an example would be kidney injury due to destructive inflammation of the renal vasculature). MOST COMMON SYNDROMES:

• Rheumatoid vasculitis: 1. The most common clinical presentation of rheumatoid vasculitis includes skin lesions and peripheral neuropathy. 2. Although a diagnosis of RA is needed to develop a secondary vasculitis, occasionally the vasculitic symptoms are the first manifestation of RA. 3. Most patients with rheumatoid vasculitis have long-standing uncontrolled erosive RA, with rheumatoid nodules and high levels of rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP). 4. The diagnosis of rheumatoid vasculitis is usually confirmed by obtaining a biopsy of the clinically involved organ. • Lupus-associated vasculitis: 1. Skin lesions are the most common manifestation. 2.  T he most common types of skin lesions are palpable purpura, petechiae, papulonodular lesions, livedo reticularis, panniculitis, and splinter hemorrhages. • Sjögren-associated vasculitis: 1. Vasculitis is one of the most common extraglandular manifestations of Sjögren syndrome. 2. The most common skin lesions are palpable purpura, which most often represents a leukocytoclastic vasculitis. 3. It can be quite difficult to tell the difference between vasculitis secondary to Sjögren disease and a concomitant primary vasculitis.

Sjögren disease has been associated with several other primary vasculitides, including ANCA-associated vasculitis and polyarteritis nodosa. Should also assess for cryoglobulinemia.

ETIOLOGY The vasculitis usually reflects the pathophysiology of the underlying connective tissue disease.

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • Infection • Hypercoagulable states (thrombotic thrombocytopenic purpura, hemolytic–uremic syndrome) • Malignancy (leukemia, lymphoma) • Primary vasculitides WORKUP The diagnosis usually requires multiple modalities, including a full history and physical, as well as laboratory testing, imaging, and sometimes a biopsy of skin or other involved organ. In order to have a connective tissue disease–associated vasculitis, one must meet diagnostic criteria for an underlying connective tissue disease. LABORATORY TESTS • Erythrocyte sedimentation rate/c-reactive protein • CBC with diff. and platelets • Albumin • Complement studies • Blood urea nitrogen and creatinine • Urinalysis • Antinuclear antibodies, RF, anti-CCP antibodies • Double-stranded DNA (dsDNA) (if patient has a history suggesting SLE) • Antineutrophil cytoplasmic antibodies (ANCA) that include ANCA-specific antibodies (antiproteinase-3 and antimyeloperoxidase antibodies) IMAGING AND OTHER STUDIES • Imaging may be helpful depending on the clinical manifestations of the disease. For instance, in aortitis or renal artery vasculitis, an angiogram, computed tomography angiography, or magnetic resonance angiography may be useful.

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Connective Tissue Disease–Associated Vasculitis • Biopsy of the affected site may be very useful. Skin, nerve, muscle, and kidney biopsies, depending on the affected organ system, will usually help to arrive at a final diagnosis and rule out vasculitis mimics.

TREATMENT Initial treatment is aimed at the underlying connective tissue disease. Additional immunosuppressive therapy may be needed depending on the severity of the vasculitis.

CHRONIC Rx May need extended immunosuppressive therapy to prevent relapse

REFERRAL Rheumatology

 EARLS & P CONSIDERATIONS COMMENTS Patients with a history of CTD who present with new cutaneous lesions or systemic symptoms should be evaluated for vasculitis. Conversely, in patients who present with vasculitis, consideration should be given to the possibility of underlying CTD. It is important not to confuse vasculitis with vasculopathy. The latter is a noninflammatory

402.e3

vascular process that is integral to the pathophysiology of some CTDs, such as SLE and SSc.

RELATED CONTENT Rheumatoid Arthritis (Related Key Topic) Sjögren Syndrome (Related Key Topic) Systemic Lupus Erythematosus (Related Key Topic) Vasculitis, Systemic (Related Key Topic) AUTHOR: Bradley Schlussel, MD

SUGGESTED READINGS Barile-Fabris L et al: Vasculitis in systemic lupus erythematosus, Curr Rheumatol Rep 16(9):440, 2014. Cozzani E et  al: Vasculitis associated with connective tissue diseases, G Ital Dermatol Venereol 150:221-232, 2015. Makol A et al: Rheumatoid vasculitis an update, Curr Opin in Rheum 27(1):63-70, 2015. Scofield R: Vasculitis in Sjögren’s syndrome, Curr Rheumatol Rep 13(6):482-488, 2011.

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ALG BASIC INFORMATION

ICD-10CM CODES K59.0 Constipation K59.00 Unspecified K59.01 Slow-transit constipation K59.02 Outlet dysfunction constipation K59.03 Drug-induced constipation K59.04 Chronic idiopathic constipation K59.09 Other constipation K59.8 Other specified functional intestinal disorders K59.9 Functional intestinal disorder, unspecified

EPIDEMIOLOGY & DEMOGRAPHICS PREVALENCE: • 12% to 19% of adults all ages • Chronic constipation increases with age • 33.5% of adults 60 to 101 yr of age • Approximately 26% of men and 34% of women >65 have constipation RISK FACTORS: More prevalent in women, nonwhites, patients with low income, patients older than 60 yr, patients who perform little physical activity, patients with low education level, or those with underlying medical condition predisposing them to constipation (e.g., Parkinson disease) PHYSICAL FINDINGS & CLINICAL PRESENTATION • A thorough history is paramount for evaluation. The duration of constipation, change in bowel movements, medication history, or any other concurrent medical history is important to inform your diagnosis. • Clinical presentation varies for every patient, as their personal definition of constipation may differ from medical lexicon. • Constipation can be accompanied by an increased frequency of liquid stools (overflow diarrhea), typically caused by stool impaction. • Must rule out alarm features such as hematochezia, weight loss of greater than 10 lbs, a family history of colon cancer or inflammatory bowel disease, anemia, positive fecal occult blood tests, or acute onset of constipation. • Physical examination must include a digital rectal exam. • Rectal examination will rule out etiologies that can result in constipation. Pain on examination, asymmetric anal opening, impaired sphincter function, masses, strictures, or the presence and character of stool (soft, hard, impacted) can help determine the etiology. • Clinical clues to an evacuation disorder are summarized in Box 1.

DIAGNOSIS BASED ON ROME IV CRITERIA • Symptoms present for at least 3 mo out of the previous 6 mo. • Loose stools are rarely present without the use of laxatives. • Criteria for irritable bowel syndrome (IBS) are not met.

• Presence of two or more of the following specific symptoms: 1. Straining during more than 25% of defecations 2. Lumpy or hard stools in more than 25% of defecations 3. Sensation of incomplete evacuation for more than 25% of defecations 4. Sensation of anorectal obstruction/blockage for more than 25% of defecations 5. Manual maneuvers to facilitate more than 25% of defecations (e.g., digital evacuation, support of the pelvic floor) 6. Fewer than three spontaneous bowel movements per wk • See Fig. 1 for an algorithmic approach to the diagnosis of constipation.

DIFFERENTIAL DIAGNOSIS • First delineate between functional constipation vs. secondary causes. • Secondary causes of constipation include medications, diabetes, hyperparathyroidism, hypothyroidism, lead poisoning, uremia, Parkinson disease, multiple sclerosis, scleroderma, lupus, and malignancy. • Functional constipation must be differentiated from irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), appendicitis, ileus, and Ogilvie syndrome.

403

C

Diseases and Disorders

DEFINITION Decreased stool frequency (fewer than three bowel movements [BM] per wk) with complaints of excessive straining, lower abdominal fullness, hard stools, feeling of incomplete evacuation, commonly associated with hardened feces or another underlying disorder. Rome IV criteria (see “Diagnosis”) are used to classify patients.

ETIOLOGY • Characterized as idiopathic vs. secondary causes of constipation. • Secondary causes include neurologic, metabolic, or endocrine disturbances; psychiatric disorders; gastrointestinal (GI) malignancies; and medication-induced constipation. • Types of anorectal dysfunction causing rectal outlet delay in older people are summarized in Table 1. • Medication-induced constipation is very common; frequent offenders include: 1. Anticholinergics 2. Iron supplements 3. Antacids 4. Opiates 5. Antihypertensive medications (especially calcium channel blockers) 6. Serotonin antagonists 7. Ganglionic blockers

Constipation

I

BOX 1  Clinical Clues to an Evacuation Disorder History Prolonged straining to expel stool Assumption of unusual postures on the toilet to facilitate stool expulsion Support of the perineum, digitation of rectum, or application of pressure to the posterior vaginal wall to facilitate rectal emptying Inability to expel enema fluid Constipation after subtotal colectomy for constipation Rectal Examination (with patient in left lateral position) Inspection Anus “pulled” forward during attempts to simulate strain during defecation Anal verge descends 4 cm (or beyond ischial tuberosities) during attempts to simulate straining at defecation. The perineum balloons down during straining; rectal mucosa partially prolapses through anal canal. Palpation High anal sphincter tone at rest precludes easy entry of the examining finger (in absence of a painful perianal condition [e.g., anal fissure]). Anal sphincter pressure during voluntary squeeze only minimally higher than anal pressure at rest. The perineum and examining finger descend 4 cm during simulated straining at defecation. The puborectalis muscle is tender to palpation through the rectal wall posteriorly, or palpation reproduces pain. Palpable mucosal prolapse during straining. “Defect” in anterior wall of the rectum, suggestive of rectocele. Anorectal Manometry and Balloon Expulsion (with patient in left lateral position) Elevated resting anal sphincter pressure Delay in balloon expulsion test (normal values for women 50%) and low-risk criteria on noninvasive testing. 3. Coronary angiography is not recommended to assess risk in patients who are at low risk according to clinical criteria and who have not undergone noninvasive risk testing. 4. Coronary angiography is not recommended to assess risk in asymptomatic patients with no evidence of ischemia on noninvasive testing.

B

IIa (good supportive evidence)

III (no benefit)

B C C C C B B C C

ACCF/AHA, American College of Cardiology Foundation/American Heart Association; EF, ejection fraction; LV, left ventricle; SIHD, stable ischemic heart disease. From Zipes DP: Braunwald’s heart disease, a textbook of cardiovascular medicine, ed 11, Philadelphia, 2019, Elsevier.

BOX 1  Noninvasive Risk Stratification High risk (>3% annual mortality rate) 1. Severe resting left ventricular dysfunction (LVEF twice normal Cholestasis with inflammation; symptoms of hepatitis; raised -serum ALT and AP levels

Phenytoin, warfarin, heparins

Dose-dependent hepatotoxicity Other cytopathic toxicity, acute steatosis Acute hepatitis

Chronic hepatitis

Granulomatous hepatitis Cholestasis without hepatitis Cholestatic hepatitis

Cholestasis with bile duct injury Chronic cholestasis Vanishing bile duct syndrome (VBDS) Sclerosing cholangitis Steatohepatitis Fibrosis and cirrhosis Vascular disorders Tumors

Bile duct lesions and cholestatic hepatitis; clinical features of cholangitis Duration >3 mo Paucity of small bile ducts; resembles PBC but AMA negative Strictures of large bile ducts Steatosis, focal necrosis, Mallory hyaline, pericellular fibrosis, cirrhosis; chronic liver disease, portal hypertension Fibrosis, nodular regeneration (other features [e.g., interface hepatitis, steatohepatitis, paucity of bile ducts, cholestasis] depend on etiology) Sinusoidal obstruction syndrome, nodular regenerative hyperplasia, others Hepatocellular carcinoma, adenoma, angiosarcoma, others

Rifampin, HIV protease inhibitors Acetaminophen, nicotinic acid, amodiaquine, hycanthone Valproic acid, didanosine, HAART agents, fialuridine, l-asparaginase, some herbal medicines Isoniazid, dantrolene, nitrofurantoin, halothane, ­sulfonamides, phenytoin, disulfiram, acebutolol, ­etretinate, ketoconazole, terbinafine, troglitazone Nitrofurantoin, etretinate, diclofenac, minocycline, ­nefazodone Allopurinol, carbamazepine, hydralazine, quinidine, quinine Oral contraceptives, androgens Chlorpromazine, tricyclic antidepressants, erythromycins, amoxicillin–clavulanic acid, cyproterone acetate Chlorpromazine, flucloxacillin, dextropropoxyphene

Chlorpromazine, flucloxacillin, trimethoprim/sulfamethoxazole Intraarterial floxuridine, intralesional scolicidals Perhexiline, amiodarone, tamoxifen Methotrexate, cyproterone acetate; also see VBDS, chronic hepatitis, steatohepatitis Many Many

ALT, Alanine aminotransferase; AMA, antimitochondrial antibody; AP, alkaline phosphatase; GGTP, gamma-glutamyl transpeptidase; HAART, highly active antiretroviral therapy; HIV, human immunodeficiency virus; PBC, primary biliary cirrhosis. From Feldman M et al (eds): Sleisenger and Fordtran’s gastrointestinal and liver disease, ed 10, Philadelphia, 2016, Elsevier.

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482.e12

Drug-Induced Liver Injury TABLE E3  Comparative Features of Causes of Acute Postoperative Liver Injury Feature

Haloalkane Anesthetic Toxicity

Ischemic Hepatitis

Postoperative Cholestasis

Incidence Latency Fever, rash, eosinophilia Serum ALT/AST (×ULN) Jaundice Histology

Rare 2-15 days Present 25-200× Common Zone 3 necrosis

Common A few days Absent Minimal or normal Common (direct hyperbilirubinemia) Bile plugs, cholestasis

Mortality Recovery time Risk Factors  Age  Gender  Body weight  Hypotension

High Up to 12 wk

Not uncommon Within 24 hours Absent Can exceed 200× (AST≫ALT) Rare Coagulative necrosis, sinusoidal congestion Varies with diagnosis 10-12 days with supportive care

Adults, age >40 yr F > M 2:1 Obese May or may not be present

Any F=M Any Documented in 50%

Any F=M Any Absent

Not from liver disease Variable, may be prolonged

ALT, Alanine aminotransferase; AST, aspartate aminotransferase; F, Female; M, male; ULN, upper limit of normal. From Feldman M et al (eds): Sleisenger and Fordtran’s gastrointestinal and liver disease, ed 10, Philadelphia, 2016, Elsevier.

TABLE E4  Hepatotoxic Herbal Remedies, Dietary Supplements, and Weight Loss Products Hepatotoxic Component

Remedy

Popular Uses

Source

Ayurvedic herbal medicine

Multiple

Multiple

Barakol

Anxiolytic

Cassia siamea

Black cohosh “Bush tea”

Menopausal symptoms Fever

Uncertain Pyrrolizidine alkaloids

Cascara Chaparral leaf (greasewood, creosote bush) Chaso/onshido

Laxative “Liver tonic,” burn salve, weight loss Weight loss

Cimicifuga racemosa Senecio, Heliotropium, Crotalaria spp. Cascara sagrada Larrea tridentate

Reversible hepatitis or ­cholestasis Hepatitis (causality uncertain) SOS

Anthracene glycoside Nordihydroguaiaretic acid

Cholestatic hepatitis Acute and chronic hepatitis, FHF

—

N-nitro-fenfluramine

Acute hepatitis, FHF

Lycopodium serratum

Levo-tetrahydropalmatine

Ephedra spp. Polygonum multiflorum Thumb (fleeceflower root) Scutellaria root

Ephedrine Anthraquinone

Sho-saido-to

Weight loss Anti-aging, neuroprotection, laxative Multiple

Acute or chronic hepatitis or ­cholestasis, steatosis Severe hepatitis, FHF Acute hepatitis or cholestasis

Comfrey Germander

Herbal tea Weight loss, fever

Pyrrolizidine alkaloid Diterpenoids, epoxides

Greater celandine Green tea leaf extract Herbalife

Isoquinoline alkaloids Catechins Various; ephedra

Hydroxycut

Gallstones, IBS Multiple Nutritional supplement, weight loss Weight loss

Symphytum spp. Teucrium chamaedrys, T. capitatum, T. polium Chelidonium majus Camellia sinensis —

Hepatocellular necrosis, cholestasis, steatosis, granulomas Acute SOS, cirrhosis Acute and chronic hepatitis, FHF, autoimmune injury Cholestatic hepatitis, fibrosis Hepatitis (causality questioned) Severe hepatitis, FHF

Uncertain

Acute hepatitis, FHF

Impila Kava Kombucha Limbrel (Flavocoxid)

Multiple Anxiolytic Weight loss Osteoarthritis

Camellia sinensis, among other constituents Callilepis laureola Piper methysticum Lichen alkaloid Plant bioflavonoids

Potassium atractylate Kava lactone, pipermethystine Usnic acid Baicalin, epicatechin

LipoKinetix

Weight loss

Lichen alkaloid

Usnic acid

Hepatic necrosis Acute hepatitis, cholestasis, FHF Acute hepatitis Acute mixed hepatocellularcholestatic injury Acute hepatitis, jaundice, FHF

Chinese medicines (traditional) Jin bu huan Sleep aid, analgesic Ma huang Shou-wu-pian

Uncertain (may contain heavy metal contaminants) Uncertain

Diterpenoids

Type of Liver Injury Hepatitis

Continued

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Drug-Induced Liver Injury 482.e13 TABLE E4  Hepatotoxic Herbal Remedies, Dietary Supplements, and Weight Loss Products—cont’d Remedy

Popular Uses

Source

Hepatotoxic Component

Mistletoe

Asthma, infertility

Viscus album

Uncertain

Oil of cloves Pennyroyal (squaw mint oil)

Dental pain Abortifacient

Eugenol Pulegone, monoterpenes

Prostata Sassafras Senna

Prostatism Herbal tea Laxative

Various foods, oils Hedeoma pulegioides, Mentha pulegium Multiple Sassafras albidum Cassia angustifolia

Skullcap Valerian

Anxiolytic Sedative

Scutellaria Valeriana officinalis

Uncertain Safrole Sennoside alkaloids; anthrone Diterpenoids Uncertain

Type of Liver Injury Hepatitis (in combination with skullcap) Zonal necrosis Severe hepatocellular necrosis Chronic cholestasis HCC (in animals) Acute hepatitis Hepatitis Elevated liver enzymes

FHF, Fulminant hepatic failure; HCC, hepatocellular carcinoma; IBS, irritable bowel syndrome; SOS, sinusoidal obstruction syndrome. From Feldman M et al (eds): Sleisenger and Fordtran’s gastrointestinal and liver disease, ed 10, Philadelphia, 2016, Elsevier.

BOX E1  Clinicopathologic Spectrum of Chemical Hepatotoxins Acute Injury Necrosis Carbon tetrachloride and other haloalkanes Cocaine, “ecstasy,” phencyclidine Haloaromatics, nitroaromatics, nitroaliphatics Hydrochlorofluorocarbons Phosphorus, iron, copper salts, inorganic arsenic Microvesicular Steatosis Boric acid Chlordecone Cocaine Dimethylformamide Hydrazine Hypoglycin Thallium Toluene, xylene Cholestasis Alpha-naphthylisocyanate Aniline—rapeseed oil Dinitrophenol Methylenedianiline Paraquat Subacute Injury Necrosis Trinitrotoluene Sinusoidal Obstruction Syndrome Pyrrolizidine alkaloids, arsenic, thorium dioxide Toxic Cirrhosis Hexachlorobenzene, polychlorinated biphenyls Tetrachloroethane Peliosis Hepatis Dioxin Chronic Injury Cirrhosis Chlor aliphatics, trinitrotoluene, arsenic, pyrrolizidine alkaloids Hepatoportal Sclerosis Arsenic, vinyl chloride Neoplasia Hepatocellular Carcinoma Arsenic, aflatoxins, thorium dioxide Angiosarcoma Vinyl chloride, thorium dioxide, arsenic Hemangioendothelioma Arsenic From Feldman M et al (eds): Sleisenger and Fordtran’s gastrointestinal and liver disease, ed 10, Philadelphia, 2016, Elsevier.

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482.e14

Drug-Induced Liver Injury TABLE E5  Drug-Induced Chronic Hepatitis: Causative Agents, Risk Factors, Clinicopathologic Features, and Outcomes Causative Agent* Risk Factors

Clinicopathologic Features

Outcomes

Nitrofurantoin

Age >40 yr; 90% of cases in women; continued ingestion after onset

Mortality rate 10%

Methyldopa

Diclofenac

Age >50 yr; 80% of cases in women; repeated courses, continued ingestion in sensitized patient Age >65 yr; most cases in women

Clinical features of chronic hepatitis, liver failure; some cases with features of cholestasis; 20% with pneumonitis; hyperglobulinemia usual, ANA, SMA Jaundice, diarrhea, liver failure; hyperglobulinemia, ANA, SMA positive; protracted course

Minocycline

Young women; prolonged use of drug

Clinical features of chronic hepatitis, liver failure; hyperglobulinemia, ANAs, SMA Often part of drug-induced systemic lupus erythematosus syndrome (arthritis, rash, rarely nephritis); hyperglobulinemia, ANAs

Isoniazid

Age >50 yr; continued drug ingestion after onset; duration of therapy Age >30 yr; dose, duration of therapy Age >50 yr; two-thirds in women

Response to glucocorticoids in a few cases Cases may be severe, with a fatal outcome or need for liver transplantation; glucocorticoid treatment may be indicated High mortality rate or need for liver transplantation High mortality rate Response to glucocorticoids in two reported cases Rapid normalization of liver biochemical test levels after the drug is stopped

Dantrolene Etretinate Acetaminophen

Regular intake at moderate doses (2-6 g/ day); alcohol, fasting, other drugs

Severe and fatal cases with cirrhosis; no immune phenomena Jaundice, liver failure; no immune phenomena Jaundice, weight loss, liver failure; deterioration after stopping drug No features of chronic liver disease, no autoimmune phenomena; these are cases of chronic toxicity

High mortality rate

*Several other agents, including sulfonamides, aspirin, halothane, cimetidine, methotrexate, trazodone, fluoxetine, fenofibrate, and germander, have been mentioned as associated with chronic hepatitis, but evidence of causation is not robust. In the past, causes included oxyphenisatin and tienilic acid, which are no longer available. ANA, Antinuclear antibody; SMA, smooth muscle antibody. From Feldman M et al (eds): Sleisenger and Fordtran’s gastrointestinal and liver disease, ed 10, Philadelphia, 2016, Elsevier.

TABLE E6  Drug-Induced Acute Hepatitis: Immunoallergic Reaction vs. Metabolic Idiosyncrasy Characteristic

Immunoallergic Reaction

Metabolic Idiosyncrasy

Frequency Gender predilection Latent period to onset of hepatitis Relationship to the dose

1 yr Usually none, but drugs with daily doses >50 mg/day are overrepresented in cases of DILI Alcohol; occasionally other drugs (e.g., isoniazid with rifampin) Variable; occasionally slow improvement or deterioration (e.g., troglitazone) Usual (in two thirds of cases), abnormal liver biochemical test levels in 2-21 days Infrequent, less prominent Rare

33%-67% of cases Usual, pronounced Often present Nitrofurantoin, phenytoin, methyldopa, sulfonamides, etretinate, minocycline

40 yr, no gender predilection

No reported fatality, rapid recovery

Phenylbutazone

1:5000 exposed

No age or gender predilection

Allopurinol

Rare (40 yr of age. Gender is not an independent risk factor. GENETICS: Limited studies have shown that there may be a racial difference in the incidence of DILD. RISK FACTORS: Age, sex, ethnicity, drug dose, oxygen, drug interaction, radiation, presence of underlying lung disease. PHYSICAL FINDINGS & CLINICAL PRESENTATION • Presentation is similar to other parenchymal lung diseases including shortness of

breath, dry cough, fever, general malaise, and fatigue. • No pathognomonic clinical, laboratory, physical, radiographic, or histologic findings. DILD is considered a diagnosis of exclusion. • Lung examination findings are nonspecific and include dry crackles, Velcro rales, and inspiratory squeaks. In advanced stages, clubbing can be seen.

ETIOLOGY • Mechanism varies by offending drug and is not fully understood in some cases. Both direct cytotoxic effects and immune mechanisms of action may be involved independently or in combination. Table E1 summarizes the histiologic pattern of drug-induced lung disease. • Two possible routes of exposure have been identified: Inhalation vs. vasculature system. • Initial exposure leading to acute toxicity may progress to chronic inflammation and fibrotic changes, which interfere with gas exchange. • Amiodarone is a well-known cause of DILD and is usually associated with DILD at higher doses of administration (≥400 mg daily) in 5% to 15% of patients. The mechanism of lung damage is unknown. Chronic interstitial pneumonitis is the most common manifestation of amiodarone pulmonary toxicity, but there are reports of confluent lesions occurring as a result of amiodarone pneumonitis. Many of these lesions are bronchiolitis obliterans. CT scan of the lung (Fig. E1) can further define these lesions. • Lung toxicity can occur after weeks to months of both low- and high-dose methotrexate administration. Hypersensitivity pneumonitis is its most common manifestation of lung toxicity. The mechanism by which it occurs is unknown.

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • Acute respiratory distress syndrome • Alveolar proteinosis • Congestive heart failure • Diffuse lung diseases • Hypersensitivity pneumonitis • Lung malignancy • Pulmonary infections • Pulmonary vasculitis syndromes • Radiation pneumonitis • Respiratory failure secondary to hypoxia • Occupational lung diseases: 1. Asbestosis 2. Berylliosis 3. Chemical worker’s lung 4. Coal worker’s pneumoconiosis 5. Farmer’s lung 6. Silicosis 7. Nitrous dioxide toxicity (i.e., silo filler’s disease) 8. Tobacco worker’s lung WORKUP • DILD is suspected after exclusion of other etiologies in patients with recent exposure to offending drug. • Tables E2 and E3 list medications associated with pulmonary toxicities. • Fig. E2 illustrates various radiographic presentations of DILD. LABORATORY TESTS • CBC may show increased eosinophils. • Arterial blood gas (ABG) may show hypoxemia. IMAGING STUDIES • Chest x-ray (Fig. E3) • CT scan (Fig. E4) • Other studies include pulmonary function tests (PTFs), flexible bronchoscopy with bronchoalveolar lavage (BAL), open lung biopsy

TABLE E1  Histological Pattern of Drug-Induced Lung Disease Diffuse Alveolar Damage

Organizing Pneumonia

Diffuse Alveolar Hemorrhage

Interstitial Pneumonia

Amiodarone

Anticoagulants Amphotericin B

Amiodarone

Amiodarone Bleomycin Cyclophosphamide

Bleomycin Cyclophosphamide Methotrexate

Cyclophosphamide Cytosine arabinoside (ara-c)

Carmustine Chlorambucil Cyclophosphamide Methotrexate Nitrofurantoin

Gold salts Penicillamine

Penicillamine Mitomycin Melphalan Gold salts

Eosinophilic Pneumonia Nitrofurantoin Nonsteroidal antiinflammatory drugs Paraaminosalicylic acid Penicillamine Sulfasalazine

Methotrexate Nitrofurantoin Sulfasalazine

From Grant LA: Grainger & Allison’s diagnostic radiology essentials, ed 2, 2019, Elsevier.

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Drug-Induced Parenchymal Lung Disease (DILD) A

482.e17

A

R

R 20mm

A

20mm

B

W/L: -400/1800 HF

W/L: -400/1800 HF

A

R 20mm

C W/L: -400/2000 HF

FIG. E1  Radiologic examples of drug-induced parenchymal lung disease (DILD). A, Cryptogenic organizing pneumonia. B, Nonspecific interstitial pneumonia. C, Usual interstitial pneumonia. (From Schwaiblmair MM et al: Drug induced interstitial lung disease, Open Respir Med J 6:63-74, 2012.)

TREATMENT There is no specific recognized treatment of DILD other than removal of offending agent.

NONPHARMACOLOGIC THERAPY Removal of offending agent. Supportive measures including smoking cessation, control of underlying lung disease, and prompt treatment of concomitant respiratory infection.

ACUTE GENERAL Rx Glucocorticoids have been used with rapid improvement in gas exchange and reversal in radiographic abnormalities.

DISPOSITION Most patients can be treated in the community setting. Transfer to a tertiary center is indicated when diagnosis is unclear.

CHRONIC Rx None

REFERRAL For workup and diagnosis, early involvement of a pulmonary specialist is advised.

COMPLEMENTARY & ALTERNATIVE MEDICINE Lung transplantation in cases of severe irreversible fibrosis

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TABLE E2  Drugs Associated with the Development of Interstitial Lung Disease Antimicrobial Agents • Aspirin • Etanercept • Gold • Infliximab • Methotrexate • Nonsteroidal antiinflammatory drugs • Penicillamine

Antiinflammatory Agents • Amphotericin B • Isoniazid • Nitrofurantoin • Sulfasalazine

Biological Agents • Adalimumab • Alemtuzumab • Bevacizumab • Cetuximab • Rituximab • Trastuzumab • Tumor necrosis factor (TNF)-α blockers

Cardiovascular Agents • ACE inhibitors • Amiodarone • Anticoagulants

• β-Blockers • Flecainide • Hydrochlorothiazide • Procainamide • Statins • Tocainide

Chemotherapeutic Agents • Azathioprine • BCNU • Bleomycin • Bortezomib • Busulfan • Carmustine • Chlorambucil • Colony-stimulating factors • Cyclophosphamide • Cytarabine • Deferoxamine • Docetaxel • Doxorubicin • Erlotinib • Etoposide • Fludarabine • Flutamide • Gefitinib

• Gemcitabine • Hydroxyurea • Imatinib • Interferons • Lomustine • Melphalan • Methotrexate • Methyl-CCNU • Mitomycin-C • Nitrosoureas • Paclitaxel • Procarbazine • Thalidomide • Vinblastine • Zinostatin

Miscellaneous • Bromocriptine • Carbamazepine • Cabergoline • Methysergide • Penicillamine • Phenytoin • Sirolimus • Talc

ACE, Angiotensin-converting enzyme; BCNU, bischloroethyl nitrosourea (carmustine); CCNU, chloroethyl cyclohexyl nitrosourea (lomustine). From Schwaiblmair M et al: Drug induced interstitial lung disease, Open Respir Med J 6:63-74, 2012.

 EARLS & P CONSIDERATIONS COMMENTS • DILD can manifest as noncardiogenic pulmonary edema (NCPE)/capillary leak syndrome, hypersensitivity reaction, cryptogenic pulmonary edema, or interstitial pneumonitis. Almost all histopathologic subtypes of ILD may be observed.

• PFT findings are usually consistent with restrictive lung disease, demonstrating reduced total lung capacity (TLC) as well as reduced diffusion capacity of the lung (DLCO). • BAL findings are nonspecific but may be helpful in the right context. Low CD4+ to CD8+ ratio suggests DILD. Elevated eosinophils (>40%) can be seen in patients with DILD.

PREVENTION • When prescribing drugs known to cause DILD, close observation is in order.

• A voidance of administration.

unnecessary

drug

RELATED CONTENT Acute Respiratory Distress Syndrome (ARDS) (Related Key Content) Interstitial Lung Disease (Related Key Content) AUTHORS: Javeryah Safi, MD, and Samaan Rafeq, MD

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TABLE E3  Pharmacologic Action of Selected Chemotherapeutic Agents with Associated Pulmonary Toxicities Antibiotic-Derived Agents

• Bleomycin • Mitomycin C Alkylating Agents • Busulfan • Cyclophosphamide • Chlorambucil • Melphalan Antimetabolites • Methotrexate • 6-Mercaptopurine • Azathioprine • Cytosine arabinoside • Gemcitabine • Fludarabine Nitrosoureas • Bischloroethyl nitrosourea (BCNU) • Chloroethyl cyclohexyl nitrosourea (CCNU) • Methyl-CCNU Podophyllotoxins • Etoposide • Paclitaxel • Docetaxel Novel Antitumor Agents • All-trans retinoic acid (ATRA) • Gefitinib • Imatinib mesylate • Irinotecan Immune Modulatory Agents Used in Malignancy • Interferons • Interleukin-2 • Tumor necrosis factor α • Nivolumab • Pembrolizumab Other Miscellaneous Chemotherapy Agents • Procarbazine • Zinostatin • Vinblastine

FIG. E2  A computed tomography scan of bleomycin pneumonitis showing a nodular pattern (arrows). The histologic features of this form of bleomycin-induced lung injury are typical of bronchiolitis obliterans with organizing pneumonitis. (From Mason RJ et al: Murray & Nadel’s textbook of respiratory medicine, ed 5, Philadelphia, 2010, WB Saunders.)

From Mason RJ et al: Murray & Nadel’s textbook of respiratory medicine, ed 5, Philadelphia, 2010, WB Saunders.

FIG. E3  A chest radiograph of a 44-yr-old woman showing acute noncardiogenic pulmonary edema that resulted from cytosine arabinoside–induced pulmonary disease. Histologic examination typically demonstrates intense intra-alveolar proteinaceous material forming hyaline membranes but little other reaction. (From Mason RJ et al: Murray & Nadel’s textbook of respiratory medicine, ed 5, Philadelphia, 2010, WB Saunders.)

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FIG. E4  A chest computed tomography (CT) scan showing confluent pulmonary masses (arrows) from amiodarone pneumonitis. Note that the masses are appreciably denser than the surrounding soft tissue in the chest wall in this CT scan obtained without contrast. (From Mason RJ et al: Murray & Nadel’s textbook of respiratory medicine, ed 5, Philadelphia, 2010, WB Saunders.)

SUGGESTED READING Schwaiblmair: Drug induced interstitial lung disease, Open Respir Med J 6:63-74, 2012.

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Drug Use Disorder BASIC INFORMATION

SYNONYMS Substance use disorder Substance abuse Addiction ICD-10CM CODES F19.129 Other psychoactive substance abuse, unspecified F10-F19 Defined by specific substance Z71.51 Drug abuse counseling and surveillance of drug abuser The new term substance use disorder in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) combines the categories of substance abuse and substance dependence into a single disorder measured on a continuum from mild to severe. DSM-5 CODE Depends on specific drug of abuse

EPIDEMIOLOGY & DEMOGRAPHICS INCIDENCE (IN U.S.): Alcohol or drug dependence: 5% to 10% of population. PREVALENCE (IN U.S.): Approximately 15% of patients in primary care practice have an atrisk pattern of drug and/or alcohol use; lifetime prevalence of any alcohol use disorder: 30%; prescription drug misuse is on the rise with 5% past-yr prevalence. Almost 9% of the U.S. population greater than age 12 has used an illicit drug in the past month (2011 National Survey on Drug Use and Health). PREDOMINANT SEX: Males > females

• Genetic model: Genetic predisposition is often a factor in dependency and certain addictive behaviors. • Social model: Person–environment interactions (i.e., socialization, imitation of observable behavior, and the influence of modeling) shape addictive behavior.

PHYSICAL FINDINGS & CLINICAL PRESENTATION • Polysubstance use and comorbidity with psychiatric disorders are common. • History often reveals recurring behavioral problems, such as relationship, work, or legal problems; violence and traumatic injuries; and anxiety, depression, insomnia, and cognitive and memory dysfunction. • Repeated requests for early refills of controlled substances and obtaining prescriptions from multiple providers should raise concern for prescription drug use disorder (Table 2). • Physical findings may include injection marks (Fig. E1), nasal lesions or recurrent epistaxis, poor dentition, scars or bruises from falls or trauma, and poor nutritional status; signs/symptoms of intoxication or withdrawal are highly suggestive of substance use disorder.

WORKUP • A thorough history is crucial for diagnosis. • The physician’s history-taking style and techniques strongly affect patient’s willingness to report use and participate in future treatment activities. • A structured, nonjudgmental approach is generally preferable: 1. Ask about quantity and frequency of alcohol or drug use. For example, the National Institute on Alcohol Abuse and Alcoholism (NIAAA) declares that problem drinking is defined as more than two drinks per day for men and more than one drink per day for women or anyone older than 65 yr. 2. Use a short screening instrument such as the CAGE questionnaire (“1. Have you ever felt you need to Cut down on your alcohol or drug use? 2. Have people Annoyed you by criticizing your alcohol or drug use? 3. Have you ever felt Guilty about alcohol or drug use? 4. Have you ever felt you need to drink first thing in the morning [Eye opener] to stop shakiness?”). • Problematic behavior during intoxication or withdrawal is diagnostic.

ETIOLOGY Several models of addiction have been proposed: • Disease model: Addiction is a mental illness, which occurs as a result of the impairment of healthy neurochemical or behavioral processes.

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • Psychiatric disorders such as depression, mania, psychosis, and anxiety disorders may coexist or occur as a consequence of substance use. • Rule out seizure disorder and underlying illness.

I

TABLE 2  “Red Flags” for Abuse Behavior and Opioid Addiction

1. The substance is often taken in larger amounts over a longer period than intended 2. Unsuccessful efforts to cut down 3. A great deal of time spent obtaining the substance or recovering from its effects 4. Craving 5. Social, occupational, or recreational 6. Recurrent despite hazards 7. Tolerance or withdrawal

Potential Abuse/Addiction Behaviors* 1. Patient displays an overwhelming focus on opioid issues during clinic visits that occupies a significant proportion of the clinic visit and impedes progress with other pain issues or medical problems. 2. Patient has a pattern of early refills (three or more) or escalating drug use in the absence of acute change or progression of his or her medical condition. 3. Patient generates multiple telephone calls or unscheduled visits to request more opioids, early refills, or problems associated with the opioid prescription that often creates a disturbance of the clinic staff. 4. There is a pattern of prescription problems with reports of medications lost, spilled, or stolen. 5. Patient has supplemental sources of opioids from multiple providers, emergency departments, or illegal sources. Additional “Red Flag” Abuse Behavior 1. Selling prescribed medications 2. Prescription forgery 3. Stealing another patient’s medications 4. Injecting or snorting oral medication 5. Concurrent use of illicit drug(s) 6. Appearing intoxicated or oversedated 7. Insisting on obtaining a specific opioid medication

Reprinted from Goldman L, Bennett JC (eds): Cecil textbook of medicine, ed 22, Philadelphia, 2004, Saunders.

*Adapted from Chabal criteria for opioid abuse. From Hochberg MC et al: Rheumatology, ed 5, St Louis, 2011, Mosby.

TABLE 1  Key Features of Substance Abuse

D

Diseases and Disorders

DEFINITION Drug use disorder is a recurring pattern of harmful use of a substance despite adverse consequences to work, school, relationships, the legal system, or physical health. This may occur concurrently with or independently from substance dependence, in which the impairment or distress is more pervasive and often (though not necessarily) includes physical dependence and withdrawal symptoms (Table 1).

PREDOMINANT AGE: • Problematic use of substances may begin in early life (8 to 10 yr). • Mean age of onset of problem drinking is approximately 25 yr for men and 30 yr for women. PEAK INCIDENCE: For most substances: Age 15 to 30 yr DURATION OF CONDITION: • Men: Average >20 yr of heavy drinking • Women: Average 15 yr of heavy drinking • In general, substance use disorders are chronic and relapsing and often progressive GENETICS: There is evidence of nonspecific genetic factors. Addiction may result in part from underlying, inherited abnormalities in brain structure that impair behavior control and encourage impulsive behavior.

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Drug Use Disorder • Because self-report of substance use and its consequences can be unreliable, obtaining corroborating information, such as from family members, past detoxifications, or drug rehabilitations, is often helpful. • Adolescent drug use disorder detection and treatment is extremely challenging. Stages of adolescent substance use are described in Table E3. An assessment for evaluating the seriousness of adolescent drug use disorder is described in Table E4.

LABORATORY TESTS • Blood alcohol content (BAC) measured on the breath is practical to define intoxication and provides a rough measure of impairment. In general, two standard drinks may cause BAC 0.08% or higher, which is considered legally impaired. • Obtain toxicology screen in urine or blood samples. • Biologic markers such as elevated mean corpuscular volume (MCV), γ-glutamyltransferase (GGT), liver function tests (AST and ALT; AST:ALT ratio of 2:1 or greater is suggestive of alcoholic liver disease), and carbohydrate deficient transferrin (CDT) may also be used to diagnose and monitor. IMAGING STUDIES Not helpful in routine diagnosis and management of substance abuse, but possibly useful in the management of sequelae of substance abuse (e.g., brain imaging to evaluate the alcohol abuse– associated increased risk of subdural hematomas or increased evidence of cerebral atrophy).

TREATMENT NONPHARMACOLOGIC THERAPY • First assess readiness for change; if precontemplative or contemplative, counsel about risks of use and benefits of abstinence; a motivational interviewing approach has been shown to be effective. • Nonpharmacologic strategies have the greatest documented efficacy: Advice, feedback, goal setting, problem solving, and additional contacts for further assistance. • Opiate contracts, prohibiting a patient from getting early refills or obtaining opiates from multiple prescribers, should be considered for all patients with chronic pain receiving opioid painkillers, especially for patients with a history of substance abuse or medication abuse. • Relapse prevention facilitated by avoidance of trigger stimuli or by uncoupling trigger stimuli from substance ingestion. • Self-help and 12-step support groups such as Alcoholics Anonymous and Narcotics Anonymous are helpful in achieving and maintaining sobriety. • Residential or inpatient treatment programs should be a consideration for any individual with continued or escalating use despite outpatient treatment. ACUTE GENERAL Rx • Detoxification is an important first step. Seizure risk is greatest within the first 48

hours of alcohol abstinence. Detoxification goals are to facilitate withdrawal and initiate abstinence safely, prevent withdrawal seizures and reduce symptoms, and refer the patient to ongoing treatment. • Benzodiazepines are effective in acute alcohol withdrawal for the management of symptoms as well as the prevention of seizures. One strategy is to give the patient a loading dose of a long-acting benzodiazepine (e.g., 20 mg of diazepam) and then continue the benzodiazepine as scheduled while tapering down the dose gradually. An example would be chlordiazepoxide 25 to 50 mg every 6 hours on day 1, 25 to 50 mg every 8 hours on day 2, 25 to 50 mg every 12 hours on day 3, and 25 to 50 mg at hour of sleep on day 4 and day 5 and then discontinue. An alternative “symptom-driven” strategy is to follow the patient closely with serial assessments, such as the Clinical Institute Withdrawal Assessment for Alcohol (CIWA) scale, and to dose with 1 to 2 mg of lorazepam as needed to treat specified withdrawal symptoms. • The prophylactic administration of thiamine and folic acid (first intravenously or intramuscularly followed by supplemental oral doses) in alcohol withdrawal is recommended before starting any carbohydrate-containing fluids or food to prevent Wernicke-Korsakoff syndrome (alcoholic encephalopathy and psychosis). Magnesium appears to be effective in the treatment of alcohol withdrawal–related cardiac arrhythmias, but not other symptoms of alcohol withdrawal. • Beta-blockers and clonidine generally should be avoided in alcohol withdrawal; they may mask markers of the severity of the withdrawal (blood pressure and pulse rate). • Unlike withdrawal from alcohol or benzodiazepines, opioid withdrawal is not life threatening. • Clonidine alleviates the discomfort of opiate withdrawal. Clonidine tablets, 0.1 mg q4-6h as needed, can be used while monitoring patient’s blood pressure. Clonidine transdermal patch, 0.1 mg/24 hr, can be used to treat autonomic hyperactivity symptoms; however, it has a very slow onset and may take 2 to 3 days to achieve therapeutic levels. Antidiarrheals, ibuprofen, and dicyclomine can be used as adjuncts to treat opiate withdrawal symptoms. • Methadone taper is an effective approach for detoxification in opioid dependence. • Buprenorphine is a partial μ-opioid receptor agonist that may be used for detoxification and maintenance in treatment of opioid dependence (see dosing in next section).

LONG-TERM Rx • Naltrexone helps reduce craving for alcohol. Naltrexone 50 mg once daily for 12 wk can be a useful adjunct to substance abuse counseling or rehabilitation programs. Randomized treatment studies are equivocal for long-term outcomes. Naltrexone reduces relapse and the intensity or

frequency of any drinking that does occur. It can be hepatotoxic and is contraindicated in opiate users. Intramuscular naltrexone (380 mg monthly) may be considered if adherence is an issue. • Acamprosate also helps reduce craving for alcohol. Acamprosate 666 mg three times daily may be an effective adjunct to counseling. A recent meta-analysis showed overall benefit with increase in the number of abstinent days. • Disulfiram provokes acetaldehyde accumulation after alcohol ingestion, producing a toxic state manifested by nausea, headache, flushing, and respiratory distress. Studies have shown limited efficacy mostly due to noncompliance. • Topiramate may be an alternative treatment for alcoholism. In a 12-wk randomized trial topiramate up to 300 mg daily significantly reduced the number of heavy drinking days. • Methadone maintenance for opiate addiction is effective and involves once-daily dosing of methadone in a controlled setting via methadone clinics. • Buprenorphine is as effective as low-dose methadone and may be prescribed by physicians who have completed approved training. For induction, initiate 12 to 24 hr after short-acting opioid use and 24 to 48 hr after long-acting opioid use. Use buprenorphine/naloxone (Suboxone) tablets in most patients, since buprenorphine-only tablets have risk of abuse. Maximum first-day dosage is 4 to 8 mg of buprenorphine. Titrate buprenorphine dose up to 12 mg on day 2 for signs of withdrawal. Then adjust dosage in frequent outpatient visits (weekly) to minimum needed for maintenance (up to 32 mg daily). • Naltrexone (oral or injectable) may also be used for maintenance in opioid dependence treatment, though evidence of effectiveness is limited. • Always combine pharmacotherapy with counseling. There is good evidence that this combination improves outcome. • Treatment of comorbid psychiatric disorders improves outcomes. • Intervention may be used to break through denial of a person with a serious addictive disorder to help the person acknowledge that he or she suffers from a disorder and agree to treatment.

STIMULANT ABUSE: COCAINE AND METHAMPHETAMINE COCAINE: Health effects of cocaine use include: • Constricted blood vessels • Dilated pupils • Nausea • Raised body temperature and blood pressure • Fast or irregular heartbeat • Tremors and muscle twitches • Restlessness Long-term effects of cocaine use include vulnerability to HIV and hepatitis C infections; malnourishment because cocaine decreases appetite; and movement disorders, including Parkinson disease, irritability and restlessness from cocaine

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• Rapid and/or irregular heartbeat • Increased blood pressure and body temperature Injecting methamphetamine increases risk of contracting HIV and hepatitis B and C. Methamphetamine use can also alter judgment and decision making leading to risky behaviors, such as unprotected sex, which also increases risk for infection. Methamphetamine may worsen the progression of HIV/AIDS and its consequences. Long-term methamphetamine use has many other negative consequences, including: • Extreme weight loss • Addiction • Severe dental problems ("meth mouth") • Intense itching, leading to skin sores from scratching • Anxiety • Changes in brain structure and function • Confusion • Memory loss • Sleeping problems • Violent behavior • Delusions • Hallucinations There are no approved medications for methamphetamine treatment, although medications are used for symptoms such as psychotic symptoms. Behavior therapies such as CBT and contingency management or motivational incentives as noted above for cocaine treatment are also used for methamphetamine treatment.

DISPOSITION • Substance abuse is a chronic relapsing illness, so relapses are best approached as part of the course of the illness, as opposed to treatment failure. • The goal of treatment is always abstinence, but success of treatment is measured by return of function, increasing duration between relapses, and prevention of sequelae of use. REFERRAL Physicians should refer patients who do not make progress on changing substance use

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patterns to addiction specialists and/or specialized substance abuse programs. Patients with comorbid psychiatric illness should be referred for mental health care.

D

PEARLS & CONSIDERATIONS • The opioid crisis, which has led to an epidemic of overdose deaths in the U.S., was partially fueled by the use of oral narcotics in the treatment of chronic pain and this has prompted a revision of chronic pain management with strict guidelines for the use of opiate medications for this condition. • Fentanyl involvement in opioid overdose deaths rose from 14.3% in 2010 to 46% in 2016 (National Vital Statistics System data). Fentanyl is now involved in more deaths than prescription opioids (40% in 2016) or heroin (36.6% in 2016). In many deaths, more than one drug is involved, and combining fentanyl with heroin may enhance its lethality. • Acute withdrawal from alcohol can become life threatening. • Withdrawal from opioids can resemble a severe case of the flu. • A brief intervention (providing information and advising the patient to reduce consumption of alcohol) by the primary care doctor has been demonstrated in randomized trials to reduce drinking in at-risk patients. • Treatment rates for alcohol use disorders remain low despite available effective treatments.

Diseases and Disorders

binges, and severe paranoia and perceptual changes such as auditory hallucinations. Cocaine abuse can cause cardiomyopathy, myocardial infarction and arrhythmias, and cerebrovascular accidents and lower the threshold for seizures. During cocaine withdrawal patients can experience: • Depression • Agitation • Intense cravings • Need for higher doses • Apathy • Exhaustion • Long periods of sleep Behavioral therapy may be used to treat cocaine addiction. Examples include: • Cognitive-behavioral therapy (CBT) • Contingency management or motivational incentives—providing rewards to patients who remain substance free • Therapeutic communities • Community-based recovery groups, such as 12-step programs Most pharmacotherapies have been ineffective for treating cocaine use disorder. Bupropion, psychostimulants, and topiramate may improve abstinence. While no government-approved medicines are currently available to treat cocaine addiction, researchers are testing some treatments that have been used to treat other disorders, including: • Disulfiram (used to treat alcoholism) • Modafinil (used to treat narcolepsy—a disorder characterized by uncontrollable episodes of deep sleep) • Lorcaserin (used to treat obesity) • Buprenorphine (used to treat opioid addiction) Observational studies suggest that cannabidiol may reduce problems related with crack-cocaine addiction, such as withdrawal symptoms, craving, impulsivity, and paranoia. METHAMPHETAMINE: Even small amounts of methamphetamine can result in many of the same health effects as those of other stimulants, such as cocaine or amphetamines. These include: • Increased wakefulness and physical activity • Decreased appetite • Faster breathing

Drug Use Disorder

I

SUGGESTED READINGS Available at ExpertConsult.com RELATED CONTENT Drug Use Disorder (Patient Information) Alcohol Use Disorder (Related Key Topic) Opioid Use Disorder (Related Key Topic) AUTHOR: Tahir Tellioglu, MD

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SUGGESTED READINGS www.drugabuse.gov/publications/finder/t/160/drugfacts. www.drugabuse.gov/publications/infofacts/. Commonly Abused Drug Charts, www.drugabuse.gov/drugs-abuse/commonlyabused-drugs-charts. Center for Substance Abuse Treatment: U.S. Department of Health and Human Services. www.csat.samhsa.gov. Ersche KD et al: Abnormal brain structure implicated in stimulant drug addiction, Science 335:601, 2012. Fleury MJ et al: Remission from substance use disorders: a systematic review and meta-analysis, Drug Alcohol Depend 168:293-306, 2016. McNeely J et  al: Performance of the tobacco, alcohol, prescription medication, and other substance Use (TAPS) tool for substance use screening in primary care patients, Ann Intern Med 165:690-699, 2016. Pace CA et al: In the clinic: substance use disorders, Ann Int Med, 2016. Schuckit MA: Treatment of opioid-use disorders, N Engl J Med 375(4):357-368, 2016.

FIG. E1  Tracks secondary to intravenous heroin abuse. (Marx JA et al: Rosen’s emergency medicine, ed 8, Philadelphia, 2014, Saunders.)

TABLE E3  Stages of Adolescent Substance Abuse Stage

Description

1

Potential for abuse Decreased impulse control Need for immediate gratification Available drugs, alcohol, inhalants Need for peer acceptance Experimentation: Learning the euphoria Use of inhalants, tobacco, marijuana, and alcohol with friends Few, if any, consequences Use may increase to weekends regularly Little change in behavior Regular use: Seeking the euphoria Use of other drugs, e.g., stimulants, LSD, sedatives Behavioral changes and some consequences Increased frequency of use; use alone Buying or stealing drugs Regular use: Preoccupation with the “high” Daily use of drugs Loss of control Multiple consequences and risk-taking Estrangement from family and “straight” friends Burnout: Use of drugs to feel normal Polysubstance use/cross-addiction Guilt, withdrawal, shame, remorse, depression Physical and mental deterioration Increased risk-taking, self-destructive, suicidal

2

3

4

5

LSD, Lysergic acid diethylamide. From Kliegman RM et al: Nelson textbook of pediatrics, ed 19, Philadelphia, 2011, Saunders.

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TABLE E4  Assessing the Seriousness of Adolescent Drug Use Disorder Variable

0

+1

Age (yr) Sex Family history of drug use disorder Setting of drug use Affect before drug use School performance Use before driving History of accidents Time of week Time of day Type of drug

>15 Male

12 beats/min and a rise in hydrogen breath excretion have a sensitivity of 94% and specificity >92%. An increase of >3% in the 30-min hematocrit is also suggestive of a positive test. A nadir blood glucose leg Prominent bulbar signs Female Developmental regression following a period of normal development Stereotypic hand movements Acquired microcephaly Epilepsy Ataxia Dementia, psychiatric symptoms Parkinsonism Stereotyped movements Premonitory urge, suppressible Infantile encephalopathy, hypotonia Oculogyric crises, ptosis Autonomic symptoms Less diurnal fluctuation than DRD

Alternating hemiplegia of childhood

Aromatic amino acid decarboxylase deficiency (AADC) ARX gene mutation (X-linked) Benign paroxysmal torticollis of infancy Complex regional pain syndrome Dopa-responsive dystonia (DRD) Drug-induced dystonia Dystonia-deafness optic neuropathy syndrome DYT1 dystonia Glutaric aciduria type 1 GM1 gangliosidosis type 3

Huntington disease (HD) Kernicterus

CT, Computed tomography; MRI, magnetic resonance imaging. From Kliegman RM et al: Nelson textbook of pediatrics, ed 19, Philadelphia, 2011, Saunders.

Lesch-Nyhan syndrome (X-linked)

Myoclonus dystonia Neuroacanthocytosis Neurodegeneration with brain iron accumulation Niemann-Pick type C

Rapid onset dystonia parkinsonism (DYT12)

Spinocerebellar ataxia 17 (SCA17) Tics Tyrosine hydroxylase deficiency

Dystonia tern), physical examination to determine associated features (weakness, myoclonus, tremor) and to determine pattern of dystonia—focal (single body region), segmental (two or more body contiguous body regions), multifocal (two or more noncontiguous body regions), generalized (involving the trunk and at least two other sites), or hemidystonia (involving more regions but restricted to one body side).

LABORATORY TESTS • Usually not helpful for diagnosis • Serum ceruloplasmin if Wilson disease is suspected • Genetic testing (DYT gene mutations, inborn errors of metabolism, or mitochondrial disease) if indicated, based on family history • Comprehensive toxicology screen indicated if causative drugs suspected (dopamineblocking agents) and history unavailable IMAGING STUDIES • Primary dystonias are generally not associated with structural CNS abnormalities. CT scan or MRI of brain if a CNS lesion is suspected as a cause of secondary dystonia. • Electrophysiologic testing can provide diagnostic support for the diagnosis, but dystonia is a clinical diagnosis.

TREATMENT NONPHARMACOLOGIC THERAPY • Heat, massage, physical therapy to relieve pain.

492.e4 • Splints to prevent contractures. • “Sensory trick” (geste antagoniste) involves lightly touching the affected body part; this can relieve the discomfort of dystonia.

ACUTE GENERAL Rx • For acute dystonic reactions to phenothiazines/butyrophenones, use diphenhydramine 50 mg IV or benztropine 2 mg IV. • For patients presenting with subacute or chronic dystonia, a trial of L-dopa can be useful in distinguishing dopa-responsive dystonia from other causes. CHRONIC Rx • For treatment of drug-induced dystonia, slowly withdraw offending agents (antiemetics, antipsychotics most commonly). • For generalized dystonia, a trial of carbidopa/ levodopa may be beneficial and diagnostic of dopa-responsive dystonia. • Trihexyphenidyl and tetrabenazine are the mainstays of medical treatment for generalized dystonias not responsive to dopa. • Diazepam, clonazepam, or baclofen may be helpful as adjunctive agents. • Injections of botulinum toxin into the affected muscles are the standard treatment for focal or multifocal dystonias but cannot be used for generalized dystonia. The mechanism of action involves blockage of the neuromuscular junction acetylcholine transmission. • Surgical procedures, most commonly deep brain stimulation of the internal globus pallidus, may be helpful for severe, refractory cases.

SUGGESTED READING Albanese A et al: Phenomenology and classification of dystonia: a consensus update, Mov Disord 28:863, 2013. Fox MD, Alterman RL: Brain stimulation for torsion dystonia, JAMA Neurol 72(6):713, 2015. Simpson DM et al: Practice guideline update summary: botulinum neurotoxin for the treatment of blepharospasm, cervical dystonia, adult spasticity, and headache: report of the guideline development subcommittee of the American Academy of Neurology, Neurology 86(19):1818, 2016. Epub 2016 Apr 18.

• Intrathecal baclofen can be useful for spastic or truncal dystonia.

DISPOSITION Spontaneous remission of focal cervical dystonia can occur, but dystonia is generally progressive, and pharmacologic therapy is often ineffective. REFERRAL • Neurology (movement disorders) and/or neurosurgery for severe or refractory cases. • Physical therapy for maintaining flexibility.

PEARLS & CONSIDERATIONS COMMENTS • Avoid triggers/exacerbating factors. • Early physical therapy and splinting to prevent contractures. • Consider botulinum toxin injections early in the course. • Consider deep brain stimulation surgery for severe or refractory dystonia and for focal dystonias. RELATED CONTENT Blepharospasm (Related Key Topic) Torticollis (Related Key Topic) AUTHOR: Julie L. Roth, MD

Early Repolarization Syndrome EPIDEMIOLOGY & DEMOGRAPHICS INCIDENCE: The clinical entity “early repolarization pattern” is commonly asymptomatic; therefore, the true incidence of the pattern is difficult to definitively establish. In one comparison of patients with idiopathic ventricular fibrillation (VF) vs. young athletes vs. age-matched controls, the presence of ERP, defined as J point elevation >1.0 mm, in idiopathic VF patients was 31.1% in any lead, 17.8% in inferior leads, 11.1% in leads I and aVL, and 6.7% in leads V4 to V6. For comparison, the incidence in agematched controls was 8.9% in any lead, 6.5% in inferior leads, 0% in leads I and aVL, and 4.9% in leads V4 to V6. PREDOMINANT SEX: J point elevation >1 mm was documented significantly higher in males vs. females. GENETICS: The mode of transmission and the genetic basis of the syndrome are unclear. An autosomal dominant pattern of inheritance of the KCNJ8 gene, which has been associated with sporadic cases, has been shown. The prognostic value of the inheritance pattern is not known. RISK FACTORS: Male sex, younger age, lower systolic blood pressure, higher Sokolow-Lyon index, and lower Cornell voltage have been shown to be associated with the presence of the early repolarization pattern. The early repolariza-

BASIC INFORMATION DEFINITION An early repolarization pattern (ERP) in a QRS complex with a duration 20 wk of gestation or 9.6 mg/ dl, stop infusion. Respiratory and cardiac arrest occur at extremely high magnesium levels. Antidote for toxicity is calcium gluconate 10 ml of 10% solution. Phenytoin has been used as an alternative in patients in whom magnesium sulfate is contraindicated (e.g., heart block, myasthenia gravis). • Give sodium amobarbital 250 mg IV over 3 min for persistent seizures not responsive to magnesium sulfate. • Treat BP >160 mm Hg systolic or BP >110 mm Hg diastolic with either hydralazine 5 to 10 mg IV, then 10 mg, then 10 mg every 20 minutes to a maximum of 20 mg; or labetalol hydrochloride 20, 40, 80 mg IV, escalating the dose every 10 minutes to maximum total dose of 300 mg; or nifedipine 10 - 20 mg orally every 20 minutes can be used for acute blood pressure control, if no IV access, to a total dose of 180 mg/day. If maximum dose of one medication is reached, add an additional medication to reach goal of BP 140 to 150/90 to 100 mm Hg. • Evaluate patient for delivery.

CHRONIC Rx • The first priority is stabilization of the mother in terms of adequate oxygenation, hemodynamics, and laboratory abnormalities, such as associated coagulopathies. • Cervical status and gestational age should be assessed. If unfavorable cervix and 35 yr, multiple lifetime sexual partners, DES exposure in utero PHYSICAL FINDINGS & CLINICAL PRESENTATION: • Abdominal tenderness: 95% • Adnexal tenderness: 87% to 99% • Peritoneal signs: 71% to 76% • Amenorrhea or abnormal vaginal bleeding: 75% • Adnexal mass: 33% to 53% • Enlarged uterus: 6% to 30% • Shock: 2% to 17% • Shoulder pain: 10% • Tissue passage: 6% to 7% ETIOLOGY • Anatomic obstruction to zygote passage • Abnormalities in tubal motility • Transperitoneal migration of the zygote

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • Corpus luteum cyst • Rupture or torsion of ovarian cyst • Threatened or incomplete abortion • Pelvic inflammatory disease • Appendicitis • Gastroenteritis

WORKUP • The classic presentation of EP includes the triad of abnormal vaginal bleeding, pelvic pain, and an adnexal mass. Fig. 1 describes a diagnostic approach to suspected EP. Fig. 2 (top) describes potential sites of ectopic implantations. Consider in all women with abdominopelvic pain and a positive pregnancy test. • Transvaginal ultrasound (Fig. 2 [bottom]). • Quantitative serum human chorionic gonadotropin level. • Type and screen if presents with vaginal bleeding; give Rhogam if Rh-negative status on initial presentation of vaginal bleeding with positive pregnancy test. • Laparoscopy in equivocal situations and possibly for treatment. LABORATORY TESTS • Quantitative human chorionic gonadotropin (qhCG): Check on initial presentation. qhCG allows one to interpret initial ultrasound. If qhCG >6000 mIU/ml, should see intrauterine pregnancy (IUP) on abdominal scan; qhCG >1500 mIU/ml for transvaginal scan. The ability to visualize an early pregnancy is dependent on the gestational age and expertise of the ultrasonographer; therefore, some may use up to qhCG >3500 mIU/ml as the discriminatory threshold for transvaginal ultrasonography. • Approximately 25% to 50% of women with an EP present with a pregnancy of unknown location, meaning that the initial ultrasound does not show a pregnancy in the uterus or the fallopian tube. Therefore, serial measurement of qhCG, typically obtained every 2 days, can help distinguish between an IUP, resolving miscarriage, or EP. • The expected rate of qhCG increase varies by the initial starting hCG. For an initial hCG level 3000 mIU/ml. • Dropping hematocrit may be associated with tubal rupture or possible abnormal intrauterine pregnancy. IMAGING STUDIES • Ultrasound: Presence of an intrauterine yolk sac makes EP extremely unlikely. However, if the patient used assisted reproductive technologies, a heterotopic pregnancy (an EP with concurrent IUP) is a possibility. A repeat ultrasonographic examination within 7 days after presentation may identify the location of a pregnancy that was not identified on initial ultrasonographic examination. • Findings on ultrasound in EP include: 1. Empty uterus (i.e., no yolk sac or fetal pole; a pseudosac in uterus may appear similar to a gestational sac)

2.  Adnexal mass (typically separate from adjacent ovary, commonly seen with “ring of fire” appearance) 3.  Enlarged hysterotomy scar, may bulge beyond contour of the uterus 4. Fluid in cul-de-sac 5. Yolk sac and/or fetal pole in tube 6. Fetal cardiac activity in adnexa

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TREATMENT NONPHARMACOLOGIC THERAPY Surgery performed via laparoscopy is preferred; however, laparotomy is appropriate if patient is very unstable or if visualization of the pelvis is poor at the time of laparoscopy. • Salpingostomy, or resecting EP with conservation of tube, has the potential benefit of higher rates of subsequent IUP; however, recent randomized controlled trials suggest there is no difference in fecundity rate between salpingostomy and salpingectomy. The procedure requires postoperative serial monitoring of qhCG. • Salpingectomy, or removal of affected fallopian tube, is considered the standard surgical procedure and is preferred in the following circumstances: 1. Ruptured tube 2. Future fertility not desired 3. Recurrent EP in the same tube 4. Uncontrolled hemorrhage • Direct injection of chemotherapy into the EP by laparoscopy, transvaginal ultrasound, or hysteroscopy. Direct injection of methotrexate, and possibly KCl if there is active cardiac activity, may be performed when the pregnancy is in a location where there is high morbidity, such as the cervix, cesarean section scar, or cornu. • Cervical and cesarean scar pregnancies may be managed with a combination of methotrexate administration, laparoscopic and/or hysteroscopic techniques, uterine artery embolization, laparotomy, and possible hysterectomy. ACUTE GENERAL Rx • Medical management with methotrexate, a folic acid antagonist, is a safe alternative if the patient is stable. Check the methotrexate safety labs prior to administration (CBC, creatinine, LFTs). • Contraindications: 1. Hemodynamically unstable; ruptured EP 2.  Patient unable to comply with follow-up 3. Medical contraindication to methotrexate including the following: Hepatic or renal disease, thrombocytopenia, leukopenia, or significant anemia 4. Breastfeeding, preexisting blood dyscrasias, known sensitivity to methotrexate, active pulmonary disease, chronic liver disease, alcoholism, laboratory evidence of immunodeficiency, renal disease, and peptic ulcer disease 5. Intrauterine gestation

Diseases and Disorders

SYNONYMS Tubal pregnancy (97%) Interstitial (cornual) pregnancy (1% to 2%) Ovarian pregnancy (1% to 3%) Abdominal pregnancy (0.03% to 1%) Cervical pregnancy (0.5%) Cesarean scar pregnancy (6% of women with prior cesarean)

• Dysfunctional uterine bleeding • Degenerating uterine fibroids • Endometriosis

Ectopic Pregnancy

I

496

Ectopic Pregnancy

ALG Positive urinary pregnancy test

Transvaginal ultrasound scan

Pregnancy of unknown location (PUL)

Haemodynamically stable Pain free

Haemodynamically stable Pain

Expectant management

Serum human chorionic gonadotrophin (hCG)

Serum hCG levels at 0 and 48 hours

Consider laparoscopy

Haemodynamically unstable Pain

Consider laparoscopy or laparotomy

Initial level 1500 IU/L

>66% increase in serum hCG 0–48 hours

5000 mIU/ml (more likely to require multidose regimen) 3. Presence of cardiac activity in the fetus • Most common regimen is methotrexate 50 mg/m2 of body surface area and is administered on day 1. May require second dose or surgical intervention if qhCG increases or plateaus (80 or fourfold increase in titer to antigen IMAGING STUDIES • Chest radiograph examination to show interstitial pneumonitis (unusual) • MRI of the brain in cases of encephalitis

TREATMENT ACUTE GENERAL Rx • Immediate therapy to limit extent of acute illness and complication • Doxycycline: 100 mg twice a day for 7 to 14 days is therapy of choice for adults and children >8 yr (4 mg/kg/day in 2 divided doses) • Doxycycline is now recommended as well for children aged 50 countries

Paroxetine Sertraline

50-200 mg

Fluoxetine

20-40 mg

Citalopram

20-40 mg

On demand, 1-3 hr before intercourse Once daily or 4-5 hours prior to sexual activity Once daily or 4-5 hours prior to sexual activity Once daily or 4-5 hours prior to sexual activity Once daily

Clomipramine

12.5-50 mg

Once daily

12.5-50 mg

On demand, 3-4 hr before intercourse On demand, 3-4 hr before intercourse On demand, 20-30 min before intercourse

Tramadol

25-50 mg

Topical lignocaine/prilocaine Alprostadil

Patient titrated

PDE5 inhibitors

Sildenafil 25-100 mg Tadalafil 10-20 mg Vardenafil 10-20 mg

5-20 μg

Patient administered intracavernous injection 5 min before intercourse On demand, 30-50 min before intercourse

High

Lifelong PE Acquired PE

High

Lifelong PE Acquired PE

High

Lifelong PE Acquired PE Lifelong PE Acquired PE Lifelong PE Acquired PE Lifelong PE Acquired PE Lifelong PE Acquired PE

High

Lifelong PE Acquired PE Lifelong and acquired PE in men with normal erectile function Lifelong and acquired PE in men with ED

ED, Erectile dysfunction; PDE5, phosphodiesterase type 5; SSRI, selective serotonin reuptake inhibitor. From Wein AJ et al: Campbell-Walsh urology, ed 11, Philadelphia, 2016, Elsevier.

High High Potential risk for opiate addiction

Low High

Risk for priapism and corporal fibrosis

Very low

Very low

? Improved efficacy if combined with SSRI

Moderate

Ejaculation and Orgasm Disorders

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PE-like EJAC. DYS. Patient/partner history

No Natural variable PE

Yes

Treatment Reassurance Education Behavioral therapy

Premature ejaculation (PE) Yes Manage primary cause

PE secondary to ED or other sexual dysfunction

Yes

No

Lifelong PE

Acquired PE

Treatment Behavioral therapy SSRI pharmacotherapy Combination treatment

Patient preference

Treatment SSRI pharmacotherapy Behavioral therapy Combination treatment

Attempt graduated withdrawal of drug therapy after 6-8 wk

FIG. E2  Algorithm for the office management of premature ejaculation (PE). ED, Erectile dysfunction; EJAC DYS, ejaculation dysfunction; SSRI, selective serotonin reuptake inhibitor. (From Wein AJ et al: Campbell-Walsh urology, ed 11, Philadelphia, 2016, Elsevier.)

ALG BASIC INFORMATION DEFINITION Elder abuse consists of actions that cause harm committed by someone in a trust relationship whether in the community or institutional ­setting. • Physical abuse: Inflicting physical pain or injury • Sexual abuse: Inflicting nonconsensual sexual activity • Psychological abuse: Inflicting mental anguish, including intimidation, humiliation, or threats • Financial abuse: Improper use of resources, property, or assets without the person’s consent • Neglect: Abandonment, failure to fulfill a care-taking obligation, including provision of food, safe shelter, physical health and mental health care, or basic custodial care • Box E1 summarizes definitions of types of abuse, with examples of behavior and effects SYNONYMS Battered elder syndrome Elder mistreatment Domestic violence in the elderly Diogenes syndrome Intimate partner violence (IPV) Adult abuse, neglect, and maltreatment cover a range of diagnostic codes depending on whether the issue is confirmed or suspected and whether the problem is neglect, physical, psychological, or sexual. The DSM-5 includes these codes under other conditions that may be a focus of clinical attention. Core Codes: ICD-10CM CODES T74 and T76 Abuse, neglect, and other maltreatment T74.0 and T76.0 Neglect or abandonment T74.1 and T76.1 Physical abuse T74.2 and T76.2 Sexual abuse T74.3 and T76.3 Psychological abuse T74.9 and T76.9 Unspecified adult maltreatment DSM-5 CODES Depends on specific diagnosis

EPIDEMIOLOGY & DEMOGRAPHICS INCIDENCE: As many as 5,000,000 elders are abused annually in the U.S. PEAK INCIDENCE: >75 yr; more recent studies now suggest 10% of the body surface): 1. Located over the entry and exit sites (Fig. E1) 2. Most common entry sites are the hands (Fig. E2) and skull 3. Most common exit sites are the heels 4. “Kissing burns” over the flexor creases 5.  Oral burns are common in children; bleeding from the labial artery may present 7 to 10 days after the injury 6. Charring at the contact site (Figs. E3 and E4) • Asystole or ventricular fibrillation may be the initial cardiac rhythm • Bone fractures and periosteal burns • Compartment syndrome from severe muscle tissue damage • Headaches, memory disturbances • Weakness and paresthesias • Otologic injury, conductive hearing loss from tympanic membrane rupture or ossicular disruption • Rhabdomyolysis and myoglobin-induced acute tubular necrosis • Vascular injury from coagulation of small vessels or compartment syndrome

Lightning

Energy level

30 million volts, Usually much 50,000 Å lower* Brief, instanta- Seconds neous Flashover, orifice Deep, internal Superficial, Deep, major minor injury Rare myoglobin- Myoglobinuric uria or hemo- renal failglobinuria ure common Rarely if ever Common, necessary early, and extensive Explosive thun- Falls, being der effect thrown

Time of exposure Pathway Burns Renal

Fasciotomy Blunt injury

WORKUP Physical examination may not reveal the extent of damage that has occurred. Detailed testing to determine the extent of internal organ damage is indicated. In lightning injuries, male victims may have scrotal (on the undersurface of the scrotum) and penile burns, which may often be overlooked. Hemorrhage behind the eardrum with or without perforation is not uncommon. An otoscopic examination is indicated in all lightning-strike victims.

High Voltage

*Range is 500 V up to millions of volts in transmission lines. From Auerbach P: Wilderness medicine, expert consult. Premium Edition—Enhanced Online Features and Print, Philadelphia, 2012, Saunders.

ETIOLOGY • Electricity causes tissue injury by converting electrical energy into heat or by blunt trauma from being thrown from the electrical source or from continuous muscle contraction (tetany). • The effects of electricity are determined by seven factors: (1) type of current, (2) amount of current, (3) pathway of current, (4) duration, (5) area of contact, (6) resistance of the body, and (7) voltage. • Tissue damage is greater with higher voltage and longer duration of contact. • Direct current (DC) contact causes a single muscle contraction, throwing the patient away from the source. Alternating current (AC) contact precipitates a tetanic contraction, not allowing the patient to withdraw from the source and prolonging the duration of contact. AC contact is more ominous than DC contact. • Electrical injuries are arbitrarily divided into high-voltage (>1000 volts) and low-voltage (100 × 106 >200,000 Instantaneous Mostly DC Arrest: Asystole

Respiratory effect

Respiratory arrest: Direct CNS injury

1000 Variable Brief DC or AC Arrest: Ventricular fibrillation Respiratory arrest: Indirect trauma or tetanic contractions of respiratory muscles Contraction:DC—single AC—tetanic Early and delayed brain injury, coma, seizures, blindness, deafness, aphasia, cerebral vein thrombosis, late spinal cord deficits, cataracts Common: Superficial (less) and deep (most)

Usually superficial, can be full thickness

Very common Muscle contraction, fall Moderate (about 5%-15%)

Common Fall (uncommon)

From Cameron JL, Cameron AM: Current surgical therapy, ed 12, Philadelphia, 2017, Elsevier.

Burns TABLE E3  Examples of Late Electrical Injury Organ Tissue Dysfunction Tissue

Late Effects

Heart

Patchy cardiac tissue necrosis (myocardium, nodal tissue, conduction pathways, coronary arteries), late arrhythmias are rare Cognitive deficits, spinal cord and peripheral nerve dysfunction, cataracts Weakness, arthropathy, nonspecific myopathy and fibrosis, limitation of joint function Venous thrombosis, arterial rupture

Central nervous system Muscle

Vascular

From Cameron JL, Cameron AM: Current surgical therapy, ed 12, Philadelphia, 2017, Elsevier.

502.e10

Rhabdomyolysis Blunt injury Mortality (early)

Contraction: Tetanic Paresthesias, transient neuropathy

Low

AC, Alternating current; CNS, central nervous system; DC, direct current. From Cameron JL, Cameron AM: Current surgical therapy, ed 12, Philadelphia, 2017, Elsevier.

BOX E2  Mechanisms of Lightning Injury Electrothermal Effects • Direct strike • Contact potential • Side flash, sometimes called “splash” (1 to 3 may include surface arcs over the body surface) • Step voltage (also termed “Earth potential rise” or “ground current”): 1. Transmitted through the ground

2. Surface arcing • Upward streamer current (also called “fifth mechanism”) Blunt Force Trauma Effects • Barotrauma • Concussive injury • Musculoskeletal injury from muscle contraction, falls

From Auerbach P: Wilderness medicine, expert consult. Premium Edition—Enhanced Online Features and Print, Philadelphia, 2012, Saunders, Elsevier.

TREATMENT NONPHARMACOLOGIC THERAPY • At the scene: Ensure the electrical power source of injury is turned off before approaching patients • Basic and advanced cardiac life support with cervical spine precautions. Prolonged cardiopulmonary resuscitation should be undertaken regardless of the initial cardiac rhythm • Cardiac monitoring • Oxygen • Tetanus prophylaxis

ACUTE GENERAL Rx • IV fluids to maintain urine output of 50 to 100 ml/hr (IV hydration should be reassessed with central nervous system expert in patients at risk of developing cerebral edema). • Alkalinization of the urine (sodium bicarbonate 50 mEq in 1 L of normal saline) in patients with or at risk of myoglobinuria. • Furosemide 20 to 40 mg PO or IV and/or mannitol 12.5 g/kg/hr may be used to force diuresis. • S eizures are treated in the standard fashion. • Treat burns with sulfadiazine silver dressings.

• Table E5 summarizes critical care management of the electrical injury patient in the first hour.

CHRONIC Rx • Hospitalization is indicated in patients with high-voltage injuries, extensive burns, central nervous system symptoms, myonecrosis (creatine kinase level more than twice normal, high serum myoglobin levels, or myoglobinuria), new cardiac arrhythmia or ECG changes, or any internal organ damage. • Ophthalmology consultation at the followup to screen for cataract formation (occurs

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Electrical and Lightning Injury

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TABLE E5  Critical Care Management of the Electrical Injury Patient (First Hour) Concern

Action

Goal

Airway (PRIORITY) Assess for:

1 . Manual airway support as needed (e.g., clear airway, bag valve mask) 2. Intubate early; diffuse edema and multisystem organ dysfunction may progress quickly (surgical airway may be necessary) 3. Clinically confirm placement with examination and end-tidal CO2 monitor (radiologic confirmation of ETT placement ASAP); well-secure ETT in place 4. Immediate C/T/L/S spine immobilization 5. Initiate pulse oximetry

• Secure airway

Breathing Assess for:

1 . Treat pneumothorax immediately 2. Initiate mechanical ventilation if needed 3. Correct hypoxia with supplemental O2 (start with 100% FiO2) 4. Check ABG 5. CXR (confirm tube placement, identify injury) 6. Consider early bronchoscopy to assess for inhalation injury if flame exposure is involved 7. Early escharotomy if needed

• Avoid hypoxia • SaO2 >92% • pCO2 35-45 mm Hg • Plateau pressure 1.0 cc/kg/hr) • SvO2 60-65 mm Hg • Lactic acid 25). d. Available over the counter without a prescription for all ages. Providing a prescription may decrease the cost of the medication, especially for Medicaid recipients. 3. Combined estrogen/progestin contraceptive pills: a. Least effective method with highest incidence of side effects. b. Two doses, 12 hours apart, of 100 to 120 mcg ethinyl estradiol and 0.5 to 0.6 mg of levonorgestrel (or 1.0 to 1.2 mg of norgestrel) per dose. c. Prescription is required, but if patient uses combined oral contraceptives, she may have the product on hand. d. The Emergency Contraception website provides instructions for using available combined oral contraceptive pills for EC. (See http://ec.princeton.e du/questions/dose.html#dose.) • Side effects: 1. Nausea: Combined estrogen-progestin EC will cause nausea in 50% of women and vomiting in 20%. Side effects resolve within 1 to 2 days. Antiemetics such as

502.e13

meclizine 25 mg orally are recommended 1 hour before taking combined estrogenprogestin EC. It can be used on an asneeded basis with the other EC methods. 2. Irregular bleeding: Many patients may experience irregular bleeding from 1 wk to 1 mo after EC. Irregular bleeding is typically self-limited. 3. Other side effects include, but are not limited to, headache, fatigue, cramping, and breast tenderness. • Contraindications: 1. Few contraindications to EC exist other than hypersensitivity to the product. EC pills will not affect an established pregnancy. 2. There are no other evidence-based medical contraindications to the use of EC pills. The benefits of EC in preventing pregnancy generally outweigh the theoretical risks for women with contraindications to long-term use of combined hormonal contraception, such as thromboembolic disease, smoking after age 35 yr, heart disease, or liver disease. Non–estrogencontaining EC is preferable for all women because of better efficacy but particularly for those with any of these conditions or who are breastfeeding.

CHRONIC Rx Because EC pills are less effective than other forms of contraception, they are not recommended as an ongoing method of contraception. The copper IUD is highly effective for EC and can be kept in place to prevent pregnancy for up to 12 yr. DISPOSITION After using EC, most women will have their menses within 1 to 2 wk of the expected date. If a woman’s next expected menses are delayed by more than 3 wk, a pregnancy test should be performed.

PEARLS & CONSIDERATIONS COMMENTS • The copper IUD is the most effective form of EC and is the only method that provides users with long-term contraception. • All forms of EC pills reduce the risk of pregnancy up to 5 days after unprotected intercourse, with ulipristal acetate being the most

TABLE E1  Emergency Contraceptive Pills Available in the United States Emergency Contraception Pills Brand

Dose

Dose

Ella Plan B One-Step Next Choice One Dose My Way Levonorgestrel 0.75 mg

1 pill 1 pill 1 pill 1 pill 2 pills

30 mg ulipristal acetate 1.5 mg levonorgestrel 1.5 mg levonorgestrel 1.5 mg levonorgestrel 1.5 mg levonorgestrel

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 Emergency Contraception effective pill. Delayed ovulation can result in a later-cycle pregnancy, so patients should use a barrier method for 2 wk following EC pill use. • The copper IUD is highly effective regardless of BMI. EC pills are less effective in overweight and obese women, but the weight at which they lose efficacy is unclear and may vary between women. Therefore, regardless of BMI, all EC methods should be offered to all women with appropriate counseling that some forms may be less effective with higher BMI. Ulipristal acetate is more effective than levonorgestrel, particularly in overweight and obese women. • A pregnancy test is not necessary before administering EC pills because the

medications will not harm an existing pregnancy. • Advanced prescription of EC pills at routine visits may increase timely use of EC and does not decrease the use of more reliable means of contraception. Health care providers who speak with the pharmacist directly are more likely to ensure timely distribution of EC pills to their patients. • Levonorgestrel EC is available in the U.S. without a prescription or proof of age.

PREVENTION • Women should be counseled about contraceptive options and the availability of EC before it is needed.

502.e14 • Patients should begin an effective method of birth control immediately after using EC. Hormonal contraceptives can be started the day after EC is administered. Abstinence or a barrier method should be used for 2 wk. • EC should be offered to all women after sexual assault.

PATIENT & FAMILY EDUCATION EC website: http://ec.princeton.edu/index.html RELATED CONTENT Contraception (Related Key Topic) AUTHORS: Emelia Argyropoulos Bachman, MD, Jennifer Buckley, MD, and Melissa Nothnagle, MD, MSc

SUGGESTED READING Batur P: Emergency contraception: separating fact from fiction, Cleve Clin J Med 79:771-776, 2012. Brache V et  al: Ulipristal acetate prevents ovulation more effectively than levonorgestrel: analysis of pooled data from three randomized trials of emergency contraception regimens, Contraception 88(5):611-618, 2013. Cheng L et  al: Interventions for emergency contraception, Cochrane Database Syst Rev 8:CD001324, 2012. Raymond EG et  al: Clinical practice. Emergency contraception, N Engl J Med 372:1342-1348, 2015.

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Empyema BASIC INFORMATION DEFINITION An accumulation of pus in the pleural space, most often caused by bacterial infection. SYNONYMS Infected pleuritis Infected pleural effusion Purulent pleural effusion

EPIDEMIOLOGY & DEMOGRAPHICS • Empyema is most commonly a complication of bacterial pneumonia, especially in association with pneumococcal or anaerobic infection (40% to 60% of cases of empyema) • Occurs as a complication of thoracic surgery (0.5 or pleural fluid to serum LDH >0.6. Characteristically, empyema fluid is grossly purulent with visible organisms on Gram stain with glucose 65 yr of age. • Rabies may occur months after contact with the rabid animal, and the exposure (especially bat rabies) may have been seemingly insignificant and even inapparent. • Experimental therapies are worthy of consideration for some forms of viral encephalitis (e.g., immune plasma, ribavirin, interferons), and expert consultation should be obtained early on for possible treatment interventions with promising experimental therapies.

SUGGESTED READINGS Available at ExpertConsult.com RELATED CONTENT Herpes Encephalitis (Patient Information) Rabies (Related Key Topic) West Nile Virus Infection (Related Key Topic) AUTHOR: Glenn G. Fort, MD, MPH

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Encephalitis, Acute Viral

506.e1

TABLE E1  Encephalitis (with a Focus on Immunocompetent Patients and Pathogens in the United States) Etiology Viruses Adenovirus Eastern equine encephalitis virus Enteroviruses (include coxsackieviruses and enterovirus 71)

Association with Encephalitis

Epidemiology Sporadic; children and immunocompromised persons at greatest risk Atlantic and Gulf U.S. states

Respiratory symptoms common

Viral culture or PCR from respiratory site, CSF, or brain tissue

Subclinical to fulminant; 50%70% mortality

Serology

Most common cause of encephalitis in pediatric population

Highest incidence in late summer and early fall but can occur year round; large outbreaks of enterovirus 71 infection in Asia have occurred. During acute infection

Aseptic meningitis most common but also encephalitis; hand, foot, and mouth rash may be present; enterovirus 71 can cause rhombencephalitis

CSF PCR single best test but not always sensitive; to increase sensitivity of detection add serum/plasma, throat PCR, or culture.

Infectious mononucleosis during acute infection, cerebellar ataxia, sensory distortion (“Alice-in-Wonderland” syndrome) Nonspecific

Serology and CSF PCR. Beware of PCR false-positive results (detection of low levels may represent latent infection) and false-negative results (not all cases are CSF positive). Contact local health department or Special Pathogens Branch at CDC. CSF PCR

Relatively common

Hendra virus

Less common

Endemic in Australia; associated with equine exposure

Hepatitis C

Mostly anecdotal data; unclear neurotropic potential; neurologic symptoms may be related to vasculitis Proven neurotropic potential; rare

Hepatitis C–seropositive patients

Herpes simplex virus (HSV) types 1 and 2

Relatively common

HSV type 1 accounts for 5%-10% of encephalitis; typically a reactivation disease, HSV type 2 occurs in neonates.

Human herpesvirus–6

Unknown, especially owing to difficult interpretation of CSF PCR false-positive results Anecdotal evidence only

Young children (≤2 yr) or immunocompromised patients, particularly bone-marrowtransplant recipients Newly described; almost exclusively in children Children 50 yr Vaccine-preventable; transmitted via tick or ingestion of unpasteurized milk; endemic to Asia, Europe, and areas of former Soviet Union Primarily associated with vaccination Central and South America; sometimes in U.S. border states (Texas, Arizona)

Tremors, seizures, paresis, urinary symptoms, SIADH variably present

Serology (cross reacts with other flaviviruses)

Weakness ranging from mild paresis to acute flaccid paralysis

Serology

Vaccinia rash (localized or disseminated) Myalgias, pharyngitis, upper respiratory tract infection variably present

CSF antibodies, serum IgM (natural infection) Serology, viral cultures (blood, oropharynx), CSF antibody

Vesicular rash (disseminated or dermatome), cerebellar ataxia, large vessel vasculitis Nonspecific

DFA or PCR of skin lesions, CSF PCR, serum IgM (acute infection) Serology

Weakness and acute flaccid paralysis, tremors, myoclonus, parkinsonian features; MRI shows basal ganglia and thalamic lesions.

CSF IgM, serum IgM/IgG, paired serology (cross reactivity with West Nile virus and SLE)

Epidemiology

Measles virus

Less common in countries where vaccine is routinely used

Vaccine preventable; measles inclusion body encephalitis onset 1-6 mo after infection; SSPE can manifest >5 yr after infection.

Mumps virus

Less common

Murray Valley encephalitis virus Nipah virus

Less common

Parainfluenza 1-4

Unknown neurotropic potential; anecdotal evidence Anecdotal evidence only Less common

Vaccine preventable; used to be leading cause of encephalitis-meningitis, now rarely seen Highest incidence in Aboriginal children in Australia and New Guinea Epidemics in Southeast Asia; contact with pigs Worldwide

Parvovirus B19 Powassan virus

Less common

Rabies virus

Uncommon in developed countries; relatively common in Africa, Asia, South America

Rotavirus

Correlation with seizures in young child but unclear association with encephalitis Less common in countries where vaccine is routinely used Relatively common

Rubella virus St. Louis encephalitis virus

Sporadic cases Tick-borne; endemic to New England, Canada Vaccine preventable; most common vector is bat (bites often unrecognized); dogs important source in developing countries; worldwide distribution Typically children; winter; vaccine preventable

Tick-borne encephalitis virus

Relatively common in affected geographic areas

Vaccinia

Less common

Venezuelan equine encephalitis virus Varicella zoster virus

Less common

Relatively common

Acute infection (chickenpox) or reactivation (shingles)

Western equine encephalitis virus West Nile virus

Less common

Onset in summer and early fall; western U.S. and Canada, Central and South America Mosquito-borne; emerging cause of epidemic encephalitis in U.S., Europe; endemic in Middle East; highest incidence in adults >50 yr; documented transmission through organ and blood

Relatively common

Serology, throat swab PCR, CSF culture, or PCR

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Encephalitis, Acute Viral

506.e3

TABLE E1  Encephalitis (with a Focus on Immunocompetent Patients and Pathogens in the United States)—cont’d Etiology Bacteria Bartonella henselae and other Bartonella spp.

Association with Encephalitis

Epidemiology

Relatively common

Often occurs after scratch or bite from kitten

Borrelia burgdorferi

Less common

Tick-borne infection; in U.S. and mostly in New England and eastern Mid-Atlantic states

Chlamydia spp.

Anecdotal evidence only

Coxiella burnetti

Less common

Ehrlichia/ Anaplasma

Relatively common

Mycoplasma pneumoniae

One of most frequently identified agents in case series but mostly anecdotal evidence

Associated with C. psittaci and Chlamydophila pneumoniae Animal exposures, particularly placenta and amniotic fluid Tick-borne bacteria causing human monocytic and human granulocytic ehrlichiosis (HME, HGE), respectively; HME endemic to southern and central U.S.; HGE endemic to northeastern U.S. and Midwest Worldwide distribution

Mycobacterium tuberculosis

Relatively common

Most common in developing countries; disease of very young and very old or immunocompromised

Rickettsia rickettsii

Relatively common in affected geographic areas

Treponema pallidum

Rare (especially in pediatrics)

Tick-borne infection in North America; highest incidence in southeast and south central U.S. Sexually transmitted disease; meningoencephalitis in early disseminated disease; progressive dementia in late disease

Tropheryma whippelii

Rare (especially in pediatrics)

Protozoa Acanthamoeba spp.

Clinical and Laboratory Hallmarks

Recommended Tests and “Pitfalls”

Encephalopathy with seizures (often status epilepticus); peripheral lymphadenopathy; CSF is usually paucicellular. Facial nerve palsy (often bilateral), meningitis, radiculitis; may be associated with or follow erythema migrans rash. Often with associated respiratory symptoms Flulike symptoms

Serology (acute usually diagnostic), PCR of lymph node; CSF PCR rarely positive

Acute onset of fever and HA; rash seen in 55 yr, 10% to 40% of hospitalized elderly, and 60% of nursing home patients >75 yr; 100,000 to 200,000 cases annually with anoxic encephalopathy RISK FACTORS: Advanced age; cancer; AIDS; terminal illness; bone marrow transplant; postoperative state; poor nutritional status; acute or chronic cardiac, pulmonary, renal, or hepatic dysfunction; history of previous insult to the brain; epilepsy; drug abuse; alcoholism; overtreatment and undertreatment of pain; use of anticholinergics, benzodiazepines, narcotics, barbiturates, and neuroleptics PHYSICAL FINDINGS & CLINICAL PRESENTATION • Common to all encephalopathies is a fluctuating level of arousal, poor attention, and disorientation. Table 1 summarizes stages of encephalopathy in chronic liver disease. • Some patients may appear agitated and others lethargic.

ETIOLOGY The final common pathway of all causes of encephalopathy is widespread neuronal dysfunction from either a structural or functional cause. Many conditions are reversible and carry a good prognosis if treated in a timely manner. • Organ failure (e.g., hepatic encephalopathy [Fig. 1], hypoxia, hypercapnia, uremia) • Infection: Systemic (e.g., urinary tract, pneumonia, sepsis) or involving the central nervous system (e.g., meningitis, encephalitis) • Toxin ingestion or withdrawal: Special consideration should be paid to alcohol, benzodiazepines, anticholinergics, neuroleptics, antibiotics (such as fluoroquinolones), and recreational drugs • Metabolic disturbance: Hyperosmolar states, hypernatremia, hyponatremia, hyperglycemia, hypoglycemia, hypercalcemia, hypophosphatemia, acidosis, alkalosis, inborn errors of metabolism

• Endocrinopathy: Hyperthyroidism, hypothyroidism, Cushing syndrome, adrenal insufficiency, pituitary failure • Neoplasm: Tumors of the central nervous system, primary or metastatic; effects of distant tumors (e.g., paraneoplastic limbic encephalitis) • Nutritional deficiency, mostly in alcoholics and chronically ill patients, such as vitamin B1 deficiency (Wernicke encephalopathy) • Seizures: Postictal state, nonconvulsive status epilepticus, complex partial seizures, absence seizures • Trauma: Concussion, contusion, subdural hematoma, epidural hematoma, diffuse axonal injury • Vascular: Ischemic and hemorrhagic strokes, vasculitis, venous thrombosis • Post-anoxic encephalopathy • Psychiatric disease: Acute psychosis, depression with psychiatric features • Acute demyelinating disease: Acute disseminating encephalomyelitis, tumefactive multiple sclerosis • Other autoimmune diseases: Autoimmune encephalitis (e.g., anti-NMDA receptor encephalitis), lupus cerebritis, cerebral vasculitis (primary angiitis of the central nervous system or a secondary cerebral vasculitis) • Other: Posterior reversible encephalopathy syndrome (PRES), hypertensive encephalopathy, postoperative status, sleep deprivation

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Diseases and Disorders

ICD-10CM CODES G93.40 Encephalopathy, unspecified G93.41 Metabolic encephalopathy G93.49 Other encephalopathy G92 Toxic encephalopathy E51.2 Wernicke encephalopathy G04.30 Acute necrotizing hemorrhagic encephalopathy, unspecified G04.31 Postinfectious acute necrotizing hemorrhagic encephalopathy G04.32 Postimmunization acute necrotizing hemorrhagic encephalopathy G04.39 Other acute necrotizing hemorrhagic encephalopathy G93.49 Other encephalopathy I67.4 Hypertensive encephalopathy I67.83 Posterior reversible encephalopathy syndrome J10.81 Influenza due to other identified influenza virus with encephalopathy J11.81 Influenza due to unidentified influenza virus with encephalopathy P91.60 Hypoxic ischemic encephalopathy [HIE], unspecified P91.61 Mild hypoxic ischemic encephalopathy [HIE] P91.62 Moderate hypoxic ischemic encephalopathy [HIE] P91.63 Severe hypoxic ischemic encephalopathy [HIE]

• Delusions (fixed false beliefs) and hallucinations are common. • Asterixis (negative myoclonus) is common. • Other physical findings, such as fever, ascites, jaundice, or tachycardia, may vary depending on the underlying cause of encephalopathy. • Because toxins and metabolic disturbances are common causes of encephalopathy, the history should focus on exposure to toxins, especially medications, and symptoms suggesting a concurrent illness such as a urinary tract infection, pneumonia, sepsis, meningitis, or encephalitis. Clinical events precipitating hepatic encephalopathy in patients with cirrhosis are summarized in Box 1.

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DIAGNOSIS DIFFERENTIAL DIAGNOSIS Differential diagnosis for encephalopathy is broad. It is typically helpful to distinguish toxic/metabolic causes from primary neurologic causes.

TABLE 1  Stages of Encephalopathy in Chronic Liver Disease (West Haven Criteria) Stage

Clinical Signs

Stage I Stage II

Mental slowness, euphoria or anxiety, shortened attention span, impaired calculating ability Lethargy or apathy, inappropriate behavior, personality change, more obvious problems with ­calculations Lethargic, somnolent, marked confusion and disorientation, but responds to verbal stimuli Coma, patient may or may not respond to noxious stimuli

Stage III Stage IV

Patients with chronic liver disease rarely, if ever, demonstrate cerebral edema, regardless of the stage of encephalopathy. From Vincent JL, Abraham E, Moore FA et al: Textbook of critical care, ed 7, Philadelphia, 2017, Elsevier.

BOX 1  Clinical Events Precipitating Hepatic Encephalopathy in Patients with Cirrhosis Gastrointestinal hemorrhage Infection (including spontaneous bacterial peritonitis) Sepsis Dehydration Imbalance of electrolytes or acid-base Renal failure Drugs, toxins, medications (especially sedative-hypnotics or narcotics) Illicit substances Alcohol Dietary indiscretion (excessive protein intake) From Vincent JL, Abraham E, Moore FA et al: Textbook of critical care, ed 7, Philadelphia, 2017, Elsevier.

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Encephalopathy Cirrhosis and portal hypertension

Inflammation, bacterial translocation, and vasoactive mediators

Splanchnic and peripheral vasodilatation

Hepatocyte dysfunction

Portosystemic shunting

↑ Blood NH3 levels

Brain edema Astrocyte swelling (↑ Glu and Gln) Neurotransmitter and receptor alterations (↑ GABA) Altered brain glucose metabolism

Increased permeability of blood-brain barrier

Hepatic encephalopathy

FIG. 1  Proposed pathophysiology of hepatic encephalopathy. GABA, Gamma-aminobutyric acid; Gln, glutamine; Glu, glutamate; NH3, ammonia. (From Feldman M et al [eds]: Sleisenger and Fordtran’s gastrointestinal and liver disease, ed 10, Philadelphia, 2016, Saunders.)

• Dementia: Distinguished from encephalopathy by a history of slowly progressive cognitive decline over time (fluctuating cognitive function is rare except in Dementia with Lewy Bodies) • Hypersomnia • Aphasia: Distinguished from encephalopathy by virtue of its representing a specific disorder of language rather than a global disturbance of cognitive function • Depression • Psychosis: Some overlap with encephalopathy because delusions and hallucinations may be common to both • Mania • Vegetative state from cerebral injury; these patients appear awake (eyes are open) but there is no content to their consciousness • Akinetic mutism: These patients do not talk and do not move; there is little fluctuation in their state, and there is no asterixis or other focal deficit • Locked-in syndrome: May be distinguished from encephalopathy by the presence of fixed neurologic deficits (e.g., paralysis of all four limbs); however, the patient is aware of his or her environment

WORKUP The best tool in the evaluation of encephalopathy is a good history and physical exam, which

will help tailor the remainder of the diagnostic workup. Interview family members and other providers to identify preceding events, medication changes, and medical history. Evaluate focal deficits.

LABORATORY TESTS • Comprehensive metabolic panel, amylase, lipase, ammonia, TSH, B12 • Complete blood count with differential • Drug screen and alcohol level (must order ethylene glycol separately if suspected) • Lumbar puncture if meningitis, encephalitis, autoimmune process, or subarachnoid hemorrhage with negative imaging is suspected • HIV, RPR • Urinalysis and microscopy, urine culture, blood cultures • Arterial blood gases IMAGING STUDIES The following imaging and diagnostic studies may be indicated depending on history and physical examination: • Chest radiograph to rule out pneumonia • Head CT to rule out intracranial hemorrhage, hydrocephalus, tumors • Brain MRI with and without contrast and with diffusion-weighted images for suspected encephalitis, tumors, acute strokes, or acute autoimmune processes

• Magnetic resonance angiography/venography for strokes, arterial dissection, venous thrombosis • Conventional angiography for CNS vasculitis and aneurysms • EEG: Evaluate for subclinical status epilepticus

TREATMENT The encephalopathy itself is a symptom of these underlying problems. In general, it is best to avoid treating the symptom of encephalopathy with antipsychotics or sedatives. The best approach is to treat the underlying toxic or metabolic disturbance. • Thiamine supplementation. • Glucose for hypoglycemia. • Antibiotics in cases of infections (choose an agent with good CNS penetration in cases of primary CNS infections; to prevent exacerbation of underlying problem, ensure also that the agent is not associated with causing encephalopathy, if possible). • Insulin in hyperglycemic conditions (e.g., diabetic ketoacidosis, hyperosmolar nonketosis, and sepsis). • Correct electrolyte disturbances properly. • Treat organ failure and its sequelae; for example, implement appropriate therapy for hyperammonemia and uremia. • Ensure hemodynamic stability (blood pressure and heart rate). • Eliminate medications that can cause or exacerbate encephalopathy: Anticholinergic drugs, benzodiazepines and other sedativehypnotics, neuroleptics, and narcotics. • Consider acute intoxication with, or withdrawal from, drugs or alcohol and treat withdrawal appropriately. • Consider serotonin syndrome and neuroleptic malignant syndrome in the appropriate clinical setting.

SUGGESTED READINGS Available at ExpertConsult.com RELATED CONTENT Delirium (Related Key Topic) Encephalitis, Acute Viral (Related Key Topic) Hepatic Encephalopathy (Related Key Topic) AUTHORS: Chloe Mander Nunneley, MD, Joseph S. Kass, MD, JD, FAAN, and Joshua Chalkely, DO, MS

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Encephalopathy

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SUGGESTED READINGS Agrawal A et al: Secondary prophylaxis of hepatic encephalopathy in cirrhosis: an open-label, randomized controlled trial of lactulose, probiotics, and no therapy, Am J Gastroenterol 107:1043, 2012. Bass N et  al: Rifaximin treatment in hepatic encephalopathy, N Engl J Med 362:1071-1081, 2010. Riordan SM, Williams R: Gut flora and hepatic encephalopathy in patients with cirrhosis, N Engl J Med 362:1140-1141, 2010.

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Encopresis BASIC INFORMATION DEFINITION/DIAGNOSTIC CRITERIA (DSM-5; ROME IV) • Reverted passage of feces into inappropriate places (e.g., clothing, floor), whether involuntary or intentional • At least one such event occurs each month for at least 3 mo • The behavior is not attributable to the physiologic effects of a substance (e.g., laxatives) or another medical condition except through a mechanism involving constipation In May 2016, Rome Foundation published the revised criteria for anorectal disorders. Encopresis is no longer named as a subclassification of functional anorectal disorders. Fecal incontinence (FI) and nonretentive fecal incontinence (NFI) are now the terms used. FI is defined as recurrent uncontrolled passage of fecal material in an individual with a developmental age of at least 4 yr for at least 3 mo. Diagnostic criteria for NFI include at least a 1-mo history of the following symptoms in a child with a developmental age older than 4 yr: 1. Defecation into places inappropriate to the sociocultural context; 2. No evidence of fecal retention; 3. After appropriate medical evaluation, the fecal incontinence cannot be explained by another medical condition. SYNONYMS Stool/fecal incontinence; soiling ICD-10CM CODES R15.9 Fecal incontinence F98.1 Encopresis not due to a substance or known physiological condition; fecal incontinence (non-retentive) not due to an organic medical etiology DSM-5 CODE 307.7 Encopresis with or without constipation and overflow incontinence

EPIDEMIOLOGY & DEMOGRAPHICS PEAK INCIDENCE: Preschool age (though also occurs during school age and adolescence) PREVALENCE (IN U.S.): 1.5% to 7.5% of children 4 to 12 yr old PREDOMINANT SEX: More often in males (estimates range from 1.9:1 to 9:1) PHYSICAL FINDINGS & CLINICAL PRESENTATION • Most children are toilet-trained for stool by age 4. Constipation and withholding of stool are significant factors in 80% to 90% of cases (“retentive encopresis” or FI). In 10% to 20%, constipation is not a factor (NFI). • When constipation is longstanding, soft or liquid stool may flow around the retained feces, resulting in overflow incontinence. This may occur several times per day and may mistakenly be construed as diarrhea.

• Children may report a lack of awareness of stool passage when longstanding constipation/impaction has resulted in loss of rectal tone and sensation. Furthermore, some children habituate to the odor. • In NFI, physical examination is normal. Abdominal radiograph does not reveal fecal loading.

ETIOLOGY • Approximately 96% of children have bowel movements between three times daily to once every other day. When bowel movements are less frequent, stool becomes drier and harder and much more uncomfortable or painful to pass. Children may avoid the discomfort or pain by avoiding elimination, resulting in worsening constipation and overflow incontinence. • Constipation may begin gradually as a result of a decrease in elimination frequency, or more acutely after an illness or changes in diet. • Toilet training practices that increase anxiety may also play a role in stool retention, the development of constipation, and eventual encopresis.

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • Hirschsprung disease • Endocrine disease (hypothyroidism) • Cerebral palsy • Myelomeningocele • Pseudoobstruction • Anorectal lesions (rectal stenosis) • Malformations • Trauma • Rectal prolapse • Celiac disease • Hypothyroidism • Medications WORKUP • History: Frequency of elimination, character of the stool, associated pain, and presence of enuresis (with which it is frequently associated). • Evaluate for other developmental or psychiatric problems. • Common physical findings in retentive encopresis: Abdominal fecal mass, stool impacted rectum, loose anal sphincter, fecal material in the perianal area, anal tags or fissures. • Perform a complete neurologic examination to exclude sensory-neural or spinal cord abnormalities. LABORATORY TESTS • Consider thyroid function tests, celiac screening tests, electrolytes, calcium, urinalysis, and urine culture. • If concerned about the possibility of Hirschsprung disease, obtain rectal biopsy or anorectal manometry.

IMAGING STUDIES Abdominal radiograph to determine presence of fecal impaction; MRI of spine to assess for neural tube defects or tethered cord

TREATMENT ACUTE GENERAL Rx • Disimpaction is a necessary first step, by oral or rectal route (or combination). • For oral disimpaction, polyethylene glycol, magnesium citrate, or high doses of mineral oil are effective (avoid use of mineral oil in patients at risk for aspiration). • Adding stimulant laxatives such as senna or bisacodyl can make oral disimpaction more effective. • For rectal disimpaction, phosphate, saline, or mineral oil enemas are effective. • When medical workup determines that constipation is not present (nonretentive encopresis/NFI), consider implementing toilettraining routines or referral to behavioral health provider. CHRONIC Rx • Prevent recurrence of constipation with oral stool softeners (e.g., polyethylene glycol or lactulose) or stool lubricants (mineral oil). • In immediate post disimpaction period (1 mo after acute treatment), stimulant laxatives may be needed because bowel tone remains low; taper use as quickly as possible to avoid dependence. • Family documentation of stool passage, including location and amount, on a chart or calendar helps inform medication changes and best times for toilet sitting. • Praise and other small incentives for positive toileting routines and taking medication can help to maintain good bowel habits. Balanced diet and increased fiber intake/supplementation may also help. • Formal behavioral treatment (education, reinforcement of treatment adherence and exercises to improve anal sphincter control) increases treatment success. Biofeedback to improve sphincter function is advocated by some, with 1-yr results comparable to behavioral treatment. Adjunctive Internetbased interventions that incorporate behavioral therapy and medical management are also beginning to show promise. DISPOSITION Encopresis may be self-limited or relatively brief in duration; may require prolonged maintenance therapy. Relapses are common. REFERRAL Behavioral family therapy should be considered for patients who do not respond to medical treatment within a few months or who have significant contributing psychiatric or family factors.

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Encopresis  EARLS & P CONSIDERATIONS • It is crucial to educate parents and children about constipation and encopresis and to defuse negative interactions. • Emphasize that this can require prolonged maintenance therapy and that relapses are common.

508.e3 RELATED CONTENT Encopresis (Patient Information) AUTHORS: Carolina S. Cerezo, MD, FAAP, and Wendy A. Plante, PhD

SUGGESTED READINGS Hyams JS et al: Childhood functional gastrointestinal disorders: child/adolescent, Gastroenterology 150:1456-1468, 2016. Tabbers MM et al: Evaluation and treatment of functional constipation in infants and children: evidence based recommendations from ESPGHAN and NASPGHAN, J Pediatr Gastroenterol Nutr 58(2):258-274, 2014.

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ALG BASIC INFORMATION

SYNONYMS Bacterial endocarditis Subacute bacterial endocarditis (SBE) Endocarditis ICD-10CM CODES I33.0 Acute and subacute infective ­endocarditis I33.9 Acute endocarditis, unspecified

EPIDEMIOLOGY & DEMOGRAPHICS INCIDENCE (IN U.S.): Yearly incidence is 15 cases/100,000 persons and is increasing due to medical interventions in the elderly and an increase in implanted cardiac devices. PEAK INCIDENCE: Females: Often 1:800 • Evidence for endocardial involvement • TTE (TEE in prosthetic valve) showing oscillating intracardiac mass on a valve or supporting structures, in the path of regurgitant jet or on implanted material, in the absence of an alternative anatomic explanation, or • Abscess, or • New partial dehiscence of prosthetic valve. Minor Criteria • Predisposition (e.g., prosthetic valve, intravenous drug use). • Fever: 38° C (100.4° F). • Vascular phenomena. • Immunologic phenomena. • Microbiologic evidence: Positive blood culture but not meeting major criteria. Ig, Immunoglobulin; TEE, transesophageal echocardiogram; TTE, transthoracic echocardiogram. *Adapted from Li JS et al: Proposed modifications to the Duke criteria for the diagnosis of infective endocarditis, Clin Infect Dis 30:633-638, 2000. From Ballinger A: Kumar & Clark’s essentials of clinical medicine, ed 6, Edinburgh, 2012, WB Saunders.

PREDOMINANT SEX: Male < female PREDOMINANT AGE: 45 to 65 yr

ENDOCARDITIS TRENDS From 1998 through 2013 the population of patients with prosthetic valve endocarditis increased from 2% to 13.8%, as did cardiac device-related endocarditis, from 1.3% to 4.1%, whereas native valve endocarditis decreased from 74.5% to 68.4%. PHYSICAL FINDINGS & CLINICAL PRESENTATION • Clinical manifestations of infective endocarditis are described in Table 1 and Table 2. • Fever may be variable in presentation; may be high, hectic, or absent. • Fever, chills, fatigue, and rigors occur in 25% to 80% of patients. • Heart murmur may be absent in right-sided endocarditis. • Embolic phenomenon with peripheral manifestations is found in 50% of patients. • Skin manifestations include petechiae, Osler nodes (Fig. E1), splinter hemorrhages, Janeway lesions (Fig. E2). • Splenomegaly is more common with subacute course. ETIOLOGY Staphylococcal infection is now the leading cause of native or prosthetic valve infection. Variation in incidence may occur that is influenced by the patient’s risk for developing infection. Table 3 summarizes the microbiology of infective endocarditis. Risk factors include hemodialysis (8%), IV drug use (10%), mitral regurgitation (43%), aortic regurgitation (26%), and rheumatic heart disease (3.3%).

TABLE 1  Symptoms in Infective Endocarditis Symptom

Patients Affected (%)

Fever Chills Weakness Malaise Sweats Anorexia Headache Dyspnea Cough Weight loss Myalgia/arthralgia Stroke Confusion/delirium Nausea/vomiting Edema Chest pain Abdominal pain Hemoptysis Back pain

80-95 40-70 40-50 20-40 20-40 20-40 20-40 20-40 20-30 20-30 10-30 10-20 10-20 10-20 5-15 5-15 5-15 5-10 5-10

From Zipes DP: Braunwald’s heart disease, a textbook of cardiovascular medicine, ed 11, Philadelphia, 2019, Elsevier.

ACUTE ENDOCARDITIS: • Staphylococcus aureus (MSSA and MRSA) • Staphylococcus lugdunensis • Streptococcus pneumoniae • Streptococcal species and groups A through G • Haemophilus influenzae SUBACUTE ENDOCARDITIS: • Viridans streptococci (alpha-hemolytic) including nutritionally variant species:

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Diseases and Disorders

DEFINITION Infective endocarditis is an infection of the endocardial surface of the heart or mural endocardium. Box 1 describes the modified Duke criteria for the diagnosis of infective endocarditis. ACUTE ENDOCARDITIS: Usually caused by Staphylococcus aureus, Streptococcus pyogenes, S. pneumoniae, and Neisseria organisms; classic clinical presentation of high fever, positive blood cultures, vascular and immunologic phenomenon SUBACUTE ENDOCARDITIS: Usually caused by viridans streptococci in the presence of valvular pathology; less toxic, often indolent presentation with lower fevers, night sweats, fatigue ENDOCARDITIS IN INJECTION DRUG USERS: Often involving S. aureus or Pseudomonas aeruginosa with variation that may be geographically influenced; tricuspid or multiple valvular involvement; high mortality rate of 50% to 60% PROSTHETIC VALVE ENDOCARDITIS (EARLY): Usually caused by S. aureus (leading cause of PVE) within 2 mo of valve replacement; other organisms include S. epidermidis, gram-negative bacilli, diphtheroids, Candida organisms PROSTHETIC VALVE ENDOCARDITIS (LATE): Typically develops >60 days after valvular replacement; involved organisms similar to early prosthetic valve endocarditis, including viridans streptococci, enterococci, and group D streptococci NOSOCOMIAL ENDOCARDITIS: Secondary to intravenous catheters, TPN lines, pacemakers; coagulase-negative staphylococci, S. aureus, and streptococci most common Non-HACEK gram-negative bacillus endocarditis is not primarily a disease of injection drug users. More than half of all cases are associated with health care contact

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Endocarditis, Infective TABLE 2  Physical Findings in Infective Endocarditis Finding Fever Heart murmur New murmur Changing murmur Central neurologic abnormality Splenomegaly Petechiae/conjunctival hemorrhage Splinter hemorrhages Janeway lesions Osler nodes Retinal lesion or Roth spot

Patients Affected (%) 80-90 75-85 10-50 5-20 20-40 10-40 10-40 5-15 5-10 3-10 2-10

From Zipes DP: Braunwald’s heart disease, a textbook of cardiovascular medicine, ed 11, Philadelphia, 2019, Elsevier.

1.  Abiotrophia spp and Granulicatella spp; • S. bovis (now called S. gallollyticus) • Enterococci • S. aureus ENDOCARDITIS IN INJECTION DRUG USERS: • S. aureus • P. aeruginosa • Candida spp. • Enterococci PROSTHETIC VALVE ENDOCARDITIS (EARLY): • S. epidermidis • S. aureus • Gram-negative bacilli • Group D streptococci PROSTHETIC VALVE ENDOCARDITIS (LATE): • S. epidermidis • Viridans streptococci • S. aureus • Enterococci and group D streptococci NOSOCOMIAL ENDOCARDITIS: • Coagulase-negative staphylococci • S. aureus • Streptococci: Viridans, group B, enterococcus HACEK ORGANISMS: • Fastidious gram-negative bacilli • H. parainfluenzae • H. aphrophilus • A. actinomycetemcomitans • Cardiobacterium hominis • Eikenella corrodens • Kingella kingae Other unusual pathogens: • Q fever: Coxiella burnetii • Bartonella henselae (etiologic agent of cat scratch disease) • Tropheryma whippelii (Whipple disease)

RISK FACTORS • Poor dental hygiene • Long-term hemodialysis • Diabetes mellitus • HIV infection • Mitral valve prolapse

ALG DIAGNOSIS DIFFERENTIAL DIAGNOSIS • Brain abscess • FUO • Pericarditis • Meningitis • Rheumatic fever • Osteomyelitis • Salmonella • TB • Bacteremia • Pericarditis • Glomerulonephritis WORKUP Physical examination to evaluate for the previous physical findings followed by laboratory testing (see “Laboratory Tests”). Fig. 3 describes a diagnostic evaluation of suspected endocarditis. The modified Duke criteria for diagnosis of endocarditis defines “major criteria” as persistently positive blood cultures of organisms typical of endocarditis or endocardial involvement (new valvular regurgitation or positive echocardiogram). “Minor criteria” are defined as presence of predisposing condition or injection drug use, fever, embolic vascular pneumonia (e.g., glomerulonephritis, rheumatoid factor), or positive blood cultures not meeting major criteria. Definite endocarditis is two major criteria or one major criteria and three minor criteria or five minor criteria or presence of organisms by culture or histologic examination of a vegetation. LABORATORY TESTS • Blood cultures: Three sets in first 24 hr. Table 4 describes causes of culture-negative endocarditis. • More culturing if patient has received prior antibiotic • CBC (anemia possibly present, subacute) • WBC (leukocytosis is higher in acute endocarditis) • ESR and C-reactive protein (elevated) • Positive rheumatoid factor (subacute endocarditis) • Proteinuria, hematuria, RBC casts • Serologies or PCR for more unusual pathogens (B. henselae, C. burnetii, etc.) IMAGING STUDIES • Echocardiogram: Two-dimensional. Transtho­ racic echocardiography (TTE) (Fig. E4) is noninvasive and more easily available but has less-than-optimal sensitivity (50% to 80%) for endocarditis. • Transesophageal echocardiography (TEE): More sensitive in detecting vegetations and preferred diagnostic modality. It is especially helpful with prosthetic valves or in detecting perivalvular disease (Fig. E5). Echocardiographic features that suggest potential need for surgical intervention are summarized in Table 5. • Electrocardiogram: Look for cardiac conduction abnormalities, injury pattern, or evidence

of pericarditis—any such new findings are suggestive of myocardial abscess.

TREATMENT Initial IV antibiotic therapy (before culture results) is aimed at the most likely organism. The American Heart Association has developed guidelines based on the most frequently encountered bacteria. Tables 6 through 10 summarize treatment recommendations. • Native valve endocarditis caused by penicillin-susceptible S. viridians, S. gallolyticus (previously called S. bovis), and other streptococci (MIC of penicillin ≤0.12 mcg/ml): Pen G 12 to 18 million U IV q24h continuous or divided q4h for 4 wk or ceftriaxone 2 g IV or IM q day for 4 wk for penicillin-allergic patients. Vancomycin at 30 mg/kg per 24 hr in two equally divided doses assuming normal kidney function, for 4 wk. • Native valve endocarditis caused by strains of viridians streptococci and S. gallolyticus (S. bovis) relatively resistant to penicillin (MIC >0.12 mcg/ml): Pen G: 24 million units per 24 hr IV either continuously or in 4 or 6 equally divided doses for 4 wk or ceftriaxone 2 g per 24 hr IV or IM for 4 wk plus gentamicin 3 mg/kg per 24 hr IV or IM in one dose or in 2 to 3 equally divided doses for 2 wk or monotherapy with vancomycin 30 mg/kg per 24 hr IV in 2 equally divided doses for 4 wk not to exceed 2 g per 24 hr unless concentrations in serum too low. • Native valve endocarditis due to Staphylococcus: 1.  MSSA: Nafcillin (or oxacillin) 12 per 24 hr IV in 4 or 6 equally divided doses for 6 wk plus optional addition of gentamicin 3 mg/kg per 24 hr IV or IM in 2 or 3 equally divided doses for 3 to 5 days or cefazolin 6 g per 24 hr IV in 3 equally divided doses for 6 wk, plus optional addition of gentamicin 3 mg/kg per 24 hr IV or IM in 2 or 3 equally divided doses for 3 to 5 days. A newer antibiotic daptomycin has an indication for right-sided endocarditis with MSSA at 6 mg/kg IV q24h. 2.  MRSA: Vancomycin 30 mg/kg per 24 hr in 2 equally divided doses for 6 wk; not to exceed 2 g per 24 hr unless concentrations in serum are low. • For culture-negative native valve endocarditis one of the following regimens is suggested: Ampicillin-sulbactam: 12 g per 24 hr IV in 4 equally divided doses for 4 to 6 wk plus gentamicin 3 mg/kg per 24 hr IV or IM in 3 equally divided doses for 4 to 6 wk or vancomycin 30 mg/kg per 24 hr IV in 2 equally divided doses for 4 to 6 wk; not to exceed 2 g per 24 hr unless concentrations in serum low plus gentamicin 3 mg/kg per 24 hr IV or IM in 3 equally divided doses for 4 to 6 wk plus ciprofloxacin 1000 mg per 24 hr orally or 800 mg per 24 hr IV in 2 equally divided doses for 4 to 6 wk. • For treatment of native valve endocarditis due to HACEK organisms: Ceftriaxone 2 g per 24

High suspicion for IE from history and physical findings

E

Perform ABCs of resuscitation and initiate stabilization procedures

Obtain CBC, serum chemistries, liver function tests, coagulation panel, ESR, C-reactive protein, type and hold/cross, troponin, blood culture, urinalysis, ECG, chest radiograph

Simultaneously

Attempt to diagnose and treat underlying IE

Diseases and Disorders

Treat presenting disease processes (e.g., CHF, CVA, complete heart block)

Assess acuity of IE presentation Acute/unstable IE presentation

I

Subacute/stable IE presentation

Administer stabilizing treatment

Native valve, low risk for IE by history, no focal infection evident

Prosthetic valve, high-risk history such as injection drug use, concomitant infectious illness (pneumonia, meningitis, abscess)

Obtain two or three sets of blood cultures from separate sites within 5 to 20 min

Obtain at least three sets of blood cultures from separate sites at least 30 min apart over 3 to 6 hours; may delay time course further based on clinical need

Order at least three sets of blood cultures from separate sites at least 30 min apart over 3 to 6 hours; may accelerate time course based on clinical need

1. Promptly initiate empiric antibiotics (see text) 2. Obtain echocardiogram* 3. Admit to appropriate hospital unit (monitored bed, ICU, operating room)

1. Order echocardiogram* 2. Hold antibiotics pending blood culture results 3. Admit to monitored medicine service 4. Consider discharge if patient is very stable with close follow-up care

1. Order echocardiogram* 2. Begin empiric antibiotics (see text) 3. Admit to monitored medicine service (discharge/not recommended)

Inpatient workup Obtain echocardiogram*

Positive for vegetation

No vegetation noted

Start empiric antibiotics if not already started (see text)

1. Await blood culture results 2. Look for alternative diagnosis 3. Repeat echocardiogram*

Echo positive for vegetation

Blood culture positive

Start or adjust antibiotics based on organism and sensitivities

Echocardiogram and blood cultures both negative

Alternative diagnosis established

1. Consider “culture negative” organisms 2. Consider alternative diagnosis 3. Continue to pursue IE as diagnosis

FIG. 3  Diagnostic algorithm for the emergency department management of patients in whom infective endocarditis (IE) is suspected. *Echocardiography can be performed via either the transthoracic (TTE) or transesophageal (TEE) technique. TEE is more invasive but is more sensitive for detecting vegetations and complications of IE, such as perivalvular abscesses; it is recommended for prosthetic valves; for situations in which optimal visualization by TTE will be difficult, such as emphysema and morbid obesity; for high suspicion of IE but normal TTE findings; and for high suspicion of a complication of IE, such as perivalvular abscess. Normal findings with either technique do not exclude IE if clinical suspicion is high. Echocardiograms can be repeated in an attempt to identify problems such as vegetations and abscesses that may not be noted initially. ABCs, Airway, breathing, and circulation; CBC, complete blood count; CHF, congestive heart failure; CVA, cerebrovascular accident; ECG, electrocardiogram; ESR, erythrocyte sedimentation rate; ICU, intensive care unit. (From Adams JG et al: Emergency medicine, clinical essentials, ed 2, Philadelphia, 2013, Elsevier.)

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Endocarditis, Infective

ALG

TABLE 3  Microbiology of Infective Endocarditis (IE) Native Valve

Prosthetic Valve

Health Care-Associated IE (%)

ORGANISM Staphylococcus aureus Coagulase-negative staphylococci Enterococcus species Viridans group streptococci Streptococcus gallolyticus* HACEK Fungi Other Negative blood culture

CommunityAcquired IE (%) (n = 1201)

Nosocomial (n = 370)

Nonnosocomial (n = 254)

Intravenous Drug Users with IE (%) (n = 237)

Early IE (%) (n = 140)

Late IE (%) (n = 390)

21

45

42

68

34

19

6

12

15

3

28

20

10

14

16

5

10

13

26

10

6

10

1

11

10

3

3

1

1

7

3 0 13 11

0 2 7 7

0 2 10 6

0 1 7 5

0 6 6 14

2 3 15 10

*Formerly Streptococcus bovis. HACEK, Haemophilus spp., Aggregatibacter spp., Cardiobacterium hominis, Eikenella corrodens, and Kingella spp. From Zipes DP: Braunwald’s Heart Disease, A textbook of Cardiovascular Medicine, ed 11, Philadelphia, 2019, Elsevier.

TABLE 4  Causes of Culture-Negative Endocarditis Organism

Epidemiology and Exposures

Diagnostic Approaches

Aspergillus and other noncandidal fungi Bartonella spp.

Prosthetic valve

Lysis-centrifugation technique; also culture and histopathologic examination of any emboli Most common cause of culture-negative IE in U.S.; serologic testing (may crossreact with Chlamydia spp.); PCR assay of valve or emboli is best test; lysiscentrifugation technique may be useful Blood cultures ultimately become positive in 80% of cases with extended incubation time of 4-6 wk; lysis-centrifugation technique may expedite growth; serologic tests are available Serologic tests available but exhibit cross-reactivity with Bartonella; monoclonal antibody direct stains on tissue may be useful; PCR assay now available Serologic tests (high titers of antibody to both phase 1 and phase 2 antigens); also PCR assay on blood or valve tissue Although traditionally a cause of culture-negative IE, HACEK species are now routinely isolated from most liquid broth continuous monitoring blood culture systems without prolonged incubation times Serology available; periodic subcultures onto buffered charcoal yeast extract medium; lysis-centrifugation technique; PCR assay available Supplemented culture media or growth as satellite colonies around Staphylococcus aureus streak; antimicrobial susceptibility testing often requires processing specialized microbiology laboratory Histologic examination of valve with periodic acid–Schiff stain; valve cultures may be done using fibroblast cell lines; PCR assay on vegetation material

Brucella spp.

B. henselae: Exposure to cats or cat fleas B. quintana: Louse infestation; homelessness, ­alcohol abuse Ingestion of unpasteurized milk or dairy products; livestock contact

Chlamydia psittaci

Bird exposure

Coxiella burnetii (Q fever) HACEK spp.

Global distribution; exposure to unpasteurized milk or agricultural areas Periodontal disease or preceding dental work

Legionella spp.

Contaminated water distribution systems; prosthetic valves Slow and indolent course

Nutritionally variant streptococci Tropheryma whipplei (Whipple disease)

Typical signs and symptoms include diarrhea, weight loss, arthralgias, abdominal pain, lymphadenopathy, central nervous system involvement; IE may be present without systemic symptoms

HACEK, Haemophilus spp., Aggregatibacter spp., Cardiobacterium hominis, Eikenella corrodens, and Kingella spp.; IE, infective endocarditis; PCR, polymerase chain reaction. From Bennett JE et al: Mandell, Douglas, and Bennett’s principles and practice of infectious diseases, ed 8, Philadelphia, 2015, WB Saunders.

hr IV or IM in 1 dose for 4 wk or ampicillinsulbactam 12 g per 24 hr IV in 4 equally divided doses for 4 wk or ciprofloxacin 1000 mg per 24 hr orally or 800 mg per 24 hr IV in 2 equally divided doses for 4 wk. • Patients with prosthetic valves endocarditis: • Methicillin-susceptible strains: Nafcillin or oxacillin 12 g per 24 hr IV in 6 equally divided

doses for at least 6 wk plus rifampin 900 mg per 24 hr IV or orally in 3 equally divided doses for at least 6 wk plus gentamicin 3 mg/kg IV or IM in 2 or 3 equally divided doses for 2 wk. • Methicillin-resistant strains: Vancomycin 30 mg/kg per 24 hr in two equally divided doses for at least 6 wk plus rifampin 900 mg per 24 hr IV or orally in three equally divided doses

for at least 6 wk plus gentamicin 3 mg/kg per 24 hr IV or IM in two or three equally divided doses for 2 wk. Antibiotic therapy after identification of the organism should be guided by susceptibility testing, preferably by formal testing by MIC (minimum inhibitory concentration).

TABLE 5  Echocardiographic Features That Suggest Potential Need for Surgical Intervention Vegetation Persistent vegetation after systemic embolization Anterior mitral valve leaflet vegetation, particularly if it is highly mobile with size >10 mm* One or more embolic events during the first 2 wk of antimicrobial therapy* Increase in vegetation size despite appropriate antimicrobial therapy*† Valvular Dysfunction Acute aortic or mitral insufficiency with signs of ventricular failure† Heart failure unresponsive to medical therapy† Valve perforation or rupture† Perivalvular Extension Valvular dehiscence, rupture, or fistula† New heart block†‡ Large abscess or extension of abscess despite appropriate antimicrobial therapy†

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may be required because of risk of embolization. may be required because of heart failure or failure of medical therapy. ‡Echocardiography should not be the primary modality used to detect or monitor heart block. From Zipes DP: Braunwald’s Heart Disease, A textbook of Cardiovascular Medicine, ed 11, Philadelphia, 2019, Elsevier. †Surgery

TABLE 6  Therapy of Native Valve Endocarditis Caused by Highly Penicillin-Susceptible Viridans Group Streptococci and Streptococcus gallolyticus Duration (wk)

Class

LOE

Comments

12-18 million U/24 hr IV either continuously or in four or six equally divided doses

4

IIa

B

Preferred in most patients >65 years of age or patients with impairment of 8th cranial nerve function or renal function

2 g/24 hr IV/IM in one dose 12-18 million U/24 hr IV either continuously or in six equally divided doses

4 2

IIa IIa

B B

2 g/24 hr IV/IM in one dose

2

IIa

B

3 mg/kg/24 hr IV/IM in one dose

2

30 mg/kg/24 hr IV in two equally divided doses, not to exceed 2 g/24 hr unless concentrations in serum are inappropriately low

4

IIa

B

Regimen

Dosage* and Route

Aqueous crystalline penicillin G sodium or Ceftriaxone sodium Aqueous crystalline penicillin G sodium or Ceftriaxone sodium plus Gentamicin sulfate† Vancomycin ­hydrochloride§

2-wk regimen not intended for patients with known cardiac or extracardiac abscess or for those with creatinine clearance of 38° C (after first 24 hours) • Symptoms of abdominal pain, fevers, chills, purulent or foul-smelling lochia, heavier vaginal bleeding • On physical exam, tachycardia, localized uterine or parametrial tenderness, purulent or malodorous lochia; physical examination revealing uterine or parametrial tenderness ETIOLOGY Endometritis is usually polymicrobial including aerobic and anaerobic organisms: Group A or B streptococci, Staphylococcus aureus and Bacteroides species, Neisseria gonorrhoeae, Chlamydia trachomatis, enterococci, Gardnerella vaginalis, Escherichia coli, and Mycoplasma. Table E1 summarizes categories of endometritis and common pathogens.

TABLE E1 Endometritis Category

Pathogen

Purpura sepsis Chronic (or acute and chronic) ­plasmacytic endometritis (CPE) Granulomatous endometritis

Staphylococcus, clostridia Chlamydia, gonorrhea, enteric organisms

Xanthogranulomatous endometritis Lymphocytic endometritis Reactive endometritis Endometrial polyp Submucosal leiomyoma Intrauterine device (IUD) Ablation related

Tuberculosis, herpes simplex virus (HSV) infection, cytomegalovirus (CMV) infection, idiopathic Unknown

From Crum CP et al: Diagnostic gynecologic and obstetric pathology, ed 3, Philadelphia, 2018, Elsevier.

• Consider CT imaging if concern for intraabdominal abscess. Postpartum endometritis is overall a clinical diagnosis and based on documented fever (>38.0° C), with leukocytosis (WBC >15,000), abdominal pain, uterine tenderness, and purulent, malodorous vaginal discharge, with no other clear source of infection

FIG. E1  Endometritis. Patient with uterine tenderness and fever 7 days after classic cesarean section for premature rupture of membranes, chorioamnionitis, and fundic presentation at 27 wks’ gestational age. Sagittal transvaginal ultrasonography shows increased vascularity within the endometrium, which can be seen with endometritis. Linear echogenic foci within the anterior myometrium likely represent air and suture material in the vertical uterine incision. Patient’s symptoms resolved with antibiotics. (From Fielding JR et al: Gynecologic imaging, Philadelphia, 2011, Saunders.)

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • Chorioamnionitis (intrapartum intra-amniotic infection) • Pelvic inflammatory disease • Sepsis • Urinary tract infection or pyelonephritis • Wound infection or abscess • Septic pelvic thrombophlebitis WORKUP Laboratory Tests: • Complete blood count with differential • If concerned for systemic infection, consider blood cultures or urine cultures • Consider lactate if concerned for sepsis IMAGING STUDIES • Ultrasound (Fig. E1) may be useful if retained products are considered a possible source of infection.

TREATMENT ACUTE GENERAL Rx IV regimens: • Clindamycin and gentamicin +/- ampicillin (considered “gold standard”) • Clindamycin and aztreonam • Extended-spectrum penicillins: Piperacillintazobactam, ampicillin-sulbactam, ticarcillin-clavulanate • Cephalosporins: Cefoxitin, cefotetan, cefotaxime • Metronidazole, ampicillin, and gentamicin • Carbapenems: Imipenem-cilastatin, meropenem, ertapenem • Vancomycin: Consider adding to above regimens Regimen should be continued for at least 24 to 48 hr after substantial clinical improvement. If response is not adequate (Table E2), broaden your differential and consider other sources of infection. DISPOSITION With appropriate antibiotic therapy, 95% to 98% cure rate. Patient can be discharged once 24 hours afebrile, and oral antibiotics are not typically indicated or recommended. REFERRAL For patients who do not respond within 48 to 72 hr of appropriate antibiotic therapy, obtain an infectious disease consultation or gynecologic consultation. AUTHORS: Siri M. Holton, MD, and Rachel Wright Heinle, MD, FACOG

Endometritis

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TABLE E2  Identified Causes of Poor Response to Antibiotic Therapy in Patients with Endometritis Cause Infected mass, including abscess, hematoma, septic pelvic thrombophlebitis, pelvic cellulitis, retained placenta Resistant organisms, commonly enterococci, in a patient receiving clindamycin-aminoglycoside or a cephalosporin Additional cause, including catheter phlebitis, inadequate dose of antibiotics No cause evident but response to empirical change in antibiotic therapy From Gorbach SL: Infectious diseases, ed 2, Philadelphia, 1998, Saunders.

Approximate Prevalence (%) 40-50 20 10 20-30

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End-Stage Kidney Disease BASIC INFORMATION DEFINITION End-stage kidney disease (ESKD) refers to chronic kidney disease (CKD) that is treated with renal replacement therapy (RRT), i.e., dialytic therapy or kidney transplantation. SYNONYMS End-stage renal disease ESKD Dialysis dependency Renal replacement therapy Chronic irreversible renal failure ICD-10CM CODES N18.6 End-stage renal disease Z99.2 Dependence on renal dialysis Z94.0 Kidney transplant status

EPIDEMIOLOGY & DEMOGRAPHICS INCIDENCE: According to the U.S. Renal Data System (USRDS), there were 124,675 incident cases of ESKD in the U.S. in 2016. • 87.3% of incident individuals began RRT with hemodialysis (HD) • 9.7% of incident individuals began RRT peritoneal dialysis (PD) • 2.8% of incident individuals began RRT with a preemptive kidney transplant • There has been an increase in incident PD cases more recently • There is a significant cost difference among modalities, with average Medicare spending for HD at $90,971 per patient-yr versus PD at $76,177 per patient-yr The incidence of ESKD differs among countries; the highest incidences are noted in Taiwan, the U.S., and the Jalisco region of Mexico. PREVALENCE: According to the USRDS, there were 726,331 prevalent cases of ESKD in 2016. The number of prevalent cases has increased by approximately 20,000/yr. • 63.1% of all prevalent ESKD patients in the U.S. were treated by HD. • 7.0% of all prevalent ESKD patients were treated by PD. • 29.6% of all prevalent ESKD patients had a functioning kidney transplant. ESKD prevalence varies greatly by country, with Hong Kong, the Jalisco region of Mexico, and Guatemala having >50% PD utilization. Home HD use is highest in New Zealand and Australia. PREDOMINANT SEX AND AGE: The incidence and prevalence of ESKD increases with age, but individuals can experience ESKD at any age. Older patients are more likely to be dialyzed with HD than PD. Males constitute 59% of prevalent ESKD patients. GENETICS: Genome-wide association studies (GWAS) have shown several genes that are associated with the development of CKD and progression to ESKD. The APOL1 gene is most strongly implicated. Single-nucleotide polymor-

phisms of the following genes are associated with greater risk for the development of ESKD: UMOD, PRKAG2, ANXA9, DAB2, and SHROOM3. RISK FACTORS: Risk factors for the development of ESKD include proteinuria, higher body mass index, diabetes mellitus, high blood pressure, higher serum creatinine, male gender, lower educational status, and African American descent.

PHYSICAL FINDINGS & CLINICAL PRESENTATION Clinical presentations of uremia are myriad. Signs and symptoms may include hypertension, edema, uremic frost, asterixis, ankle clonus, altered mentation, pallor, and pericardial friction rub. Classic uremic symptoms include anorexia, dysgeusia, aversion to meat, nausea or vomiting, hiccups, pruritus, weight loss, reversal of sleep cycles, and loss of energy. ETIOLOGY The most common causes of ESKD in the U.S. are, in order of frequency, diabetes, hypertension, glomerulonephritis, and cystic diseases.

DIAGNOSIS WORKUP The diagnosis of ESKD is made in the setting of CKD, manifested by an elevated creatinine concentration and decrease of the glomerular filtration rate, typically 100 ng/ml) and transferrin saturation (>20%). Patients who do not meet these parameters are managed with intravenous iron or a trial of oral iron. Intravenous iron may be administered without a trial of oral iron. In patients who are iron repleted, erythropoiesisstimulating agents are used to increase hemoglobin. Large randomized controlled trials demonstrate an association between increased cancer death and stroke with attainment of hemoglobin levels >11g/dl. The target hemoglobin range for a dialysis patient is 9 to 11 g/dl. • Patients with ESKD are at risk for several different metabolic bone diseases. 1. Secondary hyperparathyroidism of renal origin, which is aggravated by metabolic acidosis. The intact PTH level is characteristically elevated in these individuals (>600 pg/ml). 2.  Adynamic bone disease, which occurs more frequently in individuals with diabetes. Typically, the intact PTH level is low (5 yr of age). The diagnosis is made if voiding occurs at least twice a wk for 3 mo. Primary enuresis refers to enuresis without a period of continence, whereas secondary enuresis occurs after a 6-mo period of normal bladder control. SYNONYMS Urinary incontinence Bedwetting Nocturia ICD-10CM CODES N39.44 Nocturnal enuresis F98.0 Enuresis not due to a substance or known physiological condition DSM-5 CODES 307.6

EPIDEMIOLOGY & DEMOGRAPHICS PEAK INCIDENCE: Ages 5 to 10 yr. 5 to 7 million children in the U.S. have enuresis. PREVALENCE (IN U.S.): • Age 5 yr: 7% of males and 3% of females • Age 10 yr: 3% of males and 2% of females • Ages 15 and older: 1% of males and females PREDOMINANT SEX: Twice as many males as females at all ages PREDOMINANT AGE: Highest prevalence at age 5 with a steady decrease thereafter at a rate of approximately 12% to 15% per yr GENETICS: • Approximately 75% of children with enuresis have a first-degree relative with enuresis. • Almost twice as common in monozygotic than dizygotic twins. RISK FACTORS: • Developmental delays • Behavior problems and attention deficit hyperactivity disorder (ADHD) • Younger age • Male • Positive family history PHYSICAL FINDINGS & CLINICAL PRESENTATION Three enuresis subtypes are defined in DSM-5: 1. Nocturnal only (also known as monosymptomatic enuresis): Occurs in each sleep stage in proportion to the time spent in the particular stage. May occur during transition from deep sleep to rapid eye movement (REM) and is without other lower urinary tract symptoms. 2. Diurnal only (also referred to as nonmonosymptomatic or urinary incontinence): More frequent in girls and rarely after age 9 yr; voiding occurs in early afternoon on school days. Within this subtype, individuals have “urge incontinence” with sudden symptoms

of urgency and detrusor instability or “voiding postponement” where individuals ignore urges until the point of incontinence. 3. Combined nocturnal and diurnal.

ETIOLOGY • Enuresis often correlates with other maturational delays, particularly language, motor skills, and social development. • May be related to toilet training issues, stress (secondary enuresis), inability to concentrate urine, altered smooth muscle physiology, small bladder capacity, or dysfunction of the arousal system. • Diurnal enuresis associated with a higher rate of urinary tract infections.

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • The pathophysiology of primary enuresis involves the inability to awaken from sleep in response to full bladder, or a decreased functional capacity of the bladder with possible excessive nighttime urine production. • May be associated with encopresis and sleep disorders such as sleep terrors; much less likely to be a primary psychological disorder. • Organic causes of enuresis include diabetes mellitus, diabetes insipidus, bladder outlet obstruction, small bladder capacity, detrusor instability, urethral valves, meatal stenosis, cerebral palsy, spina bifida, pelvic mass, impacted stool, sedating medications, nocturnal seizures, urinary tract infections, kidney disease, hyperthyroidism, pinworms, and obstructive sleep apnea. WORKUP • History and physical examination to rule out anatomic abnormalities, look for signs of obstructive sleep apnea. Fluid intake, voiding diaries, and stooling histories may be useful. Family history of enuresis, particularly for nocturnal enuresis. • Children frequently experience shame, so gentleness and care must be exercised when questioning or examining the child. • Observation of voiding is useful to assess for weak stream. LABORATORY TESTS • Urinalysis with specific gravity and urine culture if white cells or nitrites to rule out infection • Serum studies to rule out diabetes, electrolyte abnormalities, or renal dysfunction IMAGING STUDIES • In complicated cases, or if there is evidence of obstructive sleep apnea, sleep studies may be useful. • If an anatomic abnormality is suspected, urologic imaging, including voiding cystourethrogram and renal sonogram is

possibly indicated: An abdominal x-ray may demonstrate stool retention; MRI of the spine if evidence of abnormalities of lower spine or perineum is found on examination.

TREATMENT NONPHARMACOLOGIC THERAPY Behavioral treatment: • Scheduled voiding to reduce the frequency of enuretic episodes. • Motivational therapy including sticker or star charts to reward child for dry nights. • Alarm and pad technique: 66% response rate (compared with 4% of control participants), although about half relapse. • Punishment for enuresis is not effective. ACUTE GENERAL Rx Education and motivational therapy CHRONIC Rx • Alarm pad is first-line treatment. • Desmopressin (DDAVP) administered orally at bedtime significantly reduces the incidence of bedwetting with complete response in 30% of patients and another 40% with dramatic reduction in symptoms. Relapse rate is as high as 70% after discontinuation. Of note, the intranasal preparation is associated with a greater risk for water intoxication and is not recommended. • Tricyclic antidepressants (imipramine): Efficacy supported by randomized control trials. Use with care in children, given the side effect profile. • Serotonin reuptake inhibitors: Lack of adequate trials is notable. • Indomethacin suppositories may reduce normal prostaglandin inhibitory effects on antidiuretic hormone. COMPLEMENTARY & ALTERNATIVE MEDICINE Weak or limited evidence for complementary treatment interventions, including psychotherapy, hypnosis, chiropractic care, acupuncture, and medicinal herbs DISPOSITION • After age 5 yr, the rate of spontaneous remissions is approximately 12% to 15% per yr. • The disorder usually resolves by adolescence. However, effective treatment spares considerable misery. • Fewer than 1% will have enuresis as adults. REFERRAL • If coexisting, a psychiatric condition complicates the course of treatment. • Referral to a pediatric urologist is indicated for primary enuresis refractory to therapy and for selected secondary causes (e.g., urinary tract malformations, neurologic disorders).

Enuresis  EARLS & P CONSIDERATIONS Illness, hospitalization, and family stressors may precipitate recurrent enuresis after a period of dryness.

525.e3 PATIENT & FAMILY EDUCATION • American Academy of Pediatrics: www. healthychildren.org/English/ages-stages/ toddler/toilet-training/Pages/default.aspx • Kidshealth: http://kidshealth.org/parent/gene ral/sleep/enuresis.html

SUGGESTED READINGS Baird DC, Seehusen DA, Bode DV: Enuresis in children: a case-based approach, Am Fam Physician 90(8):560-568, 2014. Joinson C: Childhood incontinence: risk factors and impact, Nurs Times 112(20):1516, 2016.

RELATED CONTENT Bedwetting (Patient Information) AUTHOR: Marta Majczak, MD

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Eosinophilic Esophagitis (EoE) BASIC INFORMATION DEFINITION Eosinophilic esophagitis is a chronic, antigenand immune-mediated disease, which requires these inclusion criteria after secondary causes of esophageal eosinophilia are excluded: 1. Inflammation secondary to eosinophilic infiltration within the esophagus (confirmed with at least 15 eosinophils per high power field (HPF) detected on biopsy of mucosa taken at mid and distal esophagus) 2. Symptoms related to esophageal dysfunction Mucosal eosinophilia is isolated to the esophagus and persists after a proton pump inhibitor (PPI) trial SYNONYMS Esophageal eosinophilia EoE EE ICD-10CM CODE K20.0 Eosinophilic esophagitis

EPIDEMIOLOGY & DEMOGRAPHICS INCIDENCE (IN U.S.): One to 20 new cases per 100,000 inhabitants per yr, increased from last year PREVALENCE: Between 13 and 49 cases per 100,000 inhabitants PREDOMINANT SEX: Male predominance (ratio ∼3:1) PREDOMINANT AGE: Peak of disease activity at age 35 to 39 PEAK INCIDENCE: Older children; in adults, ages 30 to 50 GENETICS: • Association between thymic stromal lymphopoietin (TSL) gene mutation and risk for EoE • Higher risk in those with homozygous pattern for the mutation • TSL gene found on Yp11.3 chromosome • Association with polymorphism on eotaxin-3 (CCL-26) RISK FACTORS/ETIOLOGY: Genetic, host immune, and environmental PHYSICAL FINDINGS & CLINICAL PRESENTATION • Adults: Dysphagia to solid foods, food impaction, heartburn, noncardiac chest pain, increased time to consume meals, concurrent allergic disease (asthma, eczema, rhinitis, atopic dermatitis, seasonal/food allergies) • Children: Vomiting, regurgitation, nausea, epigastric/abdominal pain, chest pain, water brash, globus, decreased appetite, gagging, choking, refusal of food, possible atopy • Often associated with asthma, rhinitis, dermatitis, and other atopic conditions

microabscesses, linear furrows, esophageal narrowing with stricture, mucosal tearing, and esophageal trachealization (Fig. 2), esophageal rings, felinization of esophagus. Felinization of the esophagus is a radiologic term used to describe 1 to 2 mm transverse folds found circumferentially along the entire lumen of the esophagus that appear transiently on EGD and barium studies, possibly attributed to thickened and contracted muscularis mucosae

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • Gastroesophageal reflux disease • PPI-responsive esophageal eosinophilia (PPIREE)—see “Acute General Rx” • Celiac disease • Eosinophilic gastroenteritis • Crohn disease • Hypereosinophilic syndrome • Achalasia • Vasculitis/pemphigus/connective tissue diseases • Infectious (fungal/viral) • Graft-versus-host disease • Pemphigus • Connective tissue disease

LABORATORY TESTS • Forty percent to 50% have elevated peripheral eosinophilia • Fifty percent to 60% have elevated serum immunoglobulin E (IgE) levels IMAGING STUDIES Esophagram can reveal rings and strictures.

WORKUP • Esophagogastroduodenoscopy (EGD) with at least two to four biopsies from distal and mid/ proximal esophagus after a PPI trial • Confirmation: Persistence of symptoms and ≥15 eosinophils/HPF on pathology (Fig. 1) although esophagus is normal in ∼5% to 10% of patients • Other histological findings can include basal zone hyperplasia, dilated intracellular spaces, and subepithelial fibrosis. • Endoscopic findings can include white mucosal papules, which represent eosinophilic

TREATMENT NONPHARMACOLOGIC THERAPY Three strategies of dietary therapy: • Empiric six-food elimination diet (eliminates milk, soy, egg, wheat, nuts, and seafood) For patients with response, foods can be reintroduced one at a time for 6 wk • Total elimination of all food allergens with elemental or amino acid–based formula

* FIG. 1  H&E staining of an esophageal specimen from a patient with eosinophilic esophagitis. Arrows point to eosinophils, including some at the surface. Arrowhead points to dilated intercellular spaces. Asterisk marks the lamina propria, showing inflammation and fibrosis. Green arrow points to elongated papillae. There is also marked basal layer hyperplasia, with the basal layer reaching almost to the luminal surface. H&E, hematoxylin and eosin. (From Feldman M et al Sleisenger and Fordtran’s gastrointestinal and liver disease, ed 10, Philadelphia, 2016, Elsevier.)

FIG. 2  Endoscopic view of eosinophilic esophagitis with furrowing and exudates. (From Feldman M et al: Sleisenger and Fordtran’s gastrointestinal and liver disease, ed 10, Philadelphia, 2016, Elsevier.)

Eosinophilic Esophagitis (EoE) • Targeted elimination diet guided by allergy testing, typically skin prick testing or patch testing • Dilation if stricture is present and/or patient is refractory to therapy with the goal of creating a tear in the mucosa

DISPOSITION Follow-up by gastroenterologist is important to gauge progression or regression of disease.

CHRONIC Rx • If patient is responsive to PPI therapy, EoE has been excluded and patient can be continued on PPI therapy with surveillance of symptoms. • If patient is responsive to aerosolized topical steroids and/or dietary modification, continue steroids at lowest dose and/or continue dietary elimination. • If lack of response to initial therapy: 1. Assess compliance. 2. Restrict diet further. 3. Increase steroid dose or consider alternative steroid. 4. Switch from dietary modification to steroid therapy and vice versa. 5. Consider second-line agents or clinical trials. 6.  Reevaluate diagnosis and secondary causes of esophageal eosinophilia (see “Differential Diagnosis” earlier). • Chronic histologic and symptomatic surveillance is recommended. • If dysphagia persists, endoscopic dilation is recommended for amelioration of symptoms.

COMMENTS • EoE can be confused with PPI-REE, and patients should undergo a PPI trial before confirmation of EoE and utilization of topical steroids, step-up elimination diet, or esophageal dilation. • Endoscopic surveillance of disease with or without symptoms is important. • While esophageal dilation is the mainstay of therapy in patients with esophageal strictures, narrowing of esophagus, and esophageal rings, dilation will not reduce the risk of recurrence as eosinophilic burden is unaffected.





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REFERRAL Referrals to gastroenterologists, allergists, and dieticians allow for a multidisciplinary approach to diagnosis and management of EoE.

PEARLS & CONSIDERATIONS

SUGGESTED READINGS Available at ExpertConsult.com RELATED CONTENT Gastroesophageal Reflux Disease (Related Key Topic) AUTHOR: Zilla Hussain, MD

Diseases and Disorders

ACUTE GENERAL Rx • An 8-wk trial of PPI therapy to exclude PPIresponsive esophageal eosinophilia should be initiated after an initial EGD with biopsy based on clinical symptoms with subsequent EGD (with biopsies). 1. If eosinophilia persists on biopsy despite PPI use, diagnosis is EoE 2. If eosinophilia is reduced on repeat biopsies, patient is considered to have proton pump inhibitor-responsive esophageal eosinophilia (PPI-REE), not EoE • An EGD (with biopsies) should be performed initially if a critical stricture is present (e.g., patient presents with food impaction). • If EoE is confirmed, patient should be tried on aerosolized topical glucocorticoids (fluticasone or budesonide) and/or dietary elimination. 1. Topical steroids shown to be most effective: a. Swallowed fluticasone 880 to 1760 mcg/day in a divided dose bid (adult dosing) (1) Delivered by meter-dosed inhaler without a spacer. (2)  Medication is sprayed into the patient’s mouth and then swallowed. (3) Patient should not inhale when the medication is being delivered. (4) Patient should not eat or drink for 30 to 60 min following administration.

b.  Swallowed budesonide 2 mg daily, typically in divided doses (1) Administered using a nebulizer: Patient then instructed to swallow accumulated liquid (2) Administered as viscous slurry: Mixing 1 mg/2 ml nebulizer ampules with sucralose (5 1-g packets per 1 mg of budesonide) (3)  Patient should not eat or drink for 30 to 60 min after taking the budesonide suspension



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Eosinophilic Esophagitis (EoE) SUGGESTED READINGS Dellon ES: Epidemiology of eosinophilic esophagitis, Gastroenterol Clin North Am 43(2):201-218, 2014. Dellon ES et al: Prevalence of eosinophilic esophagitis in the United States, Clin Gastroenterol Hepatol 12(4):589-596, 2014. Dellon ES, Liacouras CA: Advances in clinical management of eosinophilic esophagitis, Gastroenterol 147(6):1238-1254, 2014. Dellon ES et al: Efficacy of budesonide vs fluticasone for initial treatment of eosinophilic esophagitis in a randomized controlled trial, Gastroenterology 157(1):65-73.e5, 2019. Kavitt RT et al: Diagnosis and treatment of eosinophilic esophagitis in adults, AJM 129(9):924-934, 2016. Lucendo AJ et al: Guidelines on eosinophilic esophagitis: evidence-based statements and recommendations for diagnosis and management in children and adults, United Eur Gastroenterol J 5:335-358, 2017. Merves J et al: Eosinophilic esophagitis, Ann Allergy Asthma Immunol 112(5):397403, 2014. Souza RF: Eosinophilic esophagitis: what if elimination diet does not work? Digestive Disease Week 2, 2018. Washington, D.C.

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Eosinophilic Fasciitis BASIC INFORMATION DEFINITION Eosinophilic fasciitis (EF) is a rare inflammatory disease of the skin and subcutaneous tissue characterized by erythema, edema, and eosinophilia in peripheral blood that was first described by Lawrence Shulman in 1974. This condition starts with acute onset of symmetrical erythema, edema, and induration of the trunk or an extremity and later may progress to sclerosis of the dermis and subcutaneous fascia leading to contractures. SYNONYMS Shulman syndrome Diffuse fasciitis with eosinophilia ICD-10CM CODE M35.4 Diffuse (eosinophilic) fasciitis

EPIDEMIOLOGY & DEMOGRAPHICS • Exact incidence of EF is unknown. • Women are 1.3 to 2.1 times as likely as men to be affected. • Mean age of onset: 47 to 57 yr. PHYSICAL FINDINGS & CLINICAL PRESENTATION • Early stage: 1. Acute onset of limb (typically symmetrical) or trunk erythema and edema 2. Peripheral eosinophilia • Late stage: 1. Indurated collagenous thickening of the subcutaneous fascia 2. Peripheral eosinophilia often absent • Cutaneous: Peau d’orange, Groove sign (visible indentation of superficial vein; Fig. E1) 1.  Face, hands, and feet are typically spared • M usculoskeletal: Limited joint mobility (joint contractures in 50% to 60% of patients)

• Neuropathies: Cranial and peripheral neuropathies (carpal tunnel syndrome, mononeuritis multiplex) • Constitutional: Myalgia, muscle weakness, fatigue, weight loss • Hematologic: Up to 10% of EF cases have been associated with hematologic disorders such as aplastic anemia, myeloproliferative disorders, lymphoma, leukemia, and multiple myeloma • Patients with EF often lack visceral involvement or history of Raynaud phenomenon

ETIOLOGY The etiology is unknown. A proposed mechanism of disease is a nonspecific immune-mediated inflammation of the fascia triggered by stress (exercise, trauma), exposures (medications, radiation therapy, burns), infection (Borrelia burgdorferi), autoimmune disease, or hematologic disorder. Most cases are considered idiopathic.

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • Localized scleroderma: Morphea, linear • Systemic scleroderma • Scleroderma-like disorders: Nephrogenic systemic fibrosis, scleromyxedema, scleredema • Hypereosinophilic syndrome • Deep vein thrombosis • Cellulitis • Graft-versus-host disease WORKUP • Diagnosis by histopathology with fascial thickening and fibrosis is considered gold standard. • Universally accepted, validated diagnostic criteria are lacking. • Proposed diagnostic criteria (two major or one major and two minor) by Pinal-Fernandez et al (2014): 1.  Major: a. Swelling, induration, and thickening of the skin and subcutaneous tissue that is symmetrical or nonsymmetrical,

diffuse (extremities, trunk, and abdomen), or localized (extremities) b. Fascial thickening with accumulation of lymphocytes and macrophages with or without eosinophilic infiltration (determined by full-thickness wedge biopsy of clinically affected skin) 2. Minor: a. Eosinophilia >0.5 × 109/L b. Hypergammaglobulinemia >1.5 g/L c. Muscle weakness and/or elevated aldolase levels d. Groove sign and/or peau d’orange e. H yperintense fascia on MR T2-weighted images • Exclusion criteria: Diagnosis of systemic sclerosis

LABORATORY TESTS • Peripheral eosinophilia in 64% to 86% of cases in early stage • Elevated erythrocyte sedimentation rate and/ or elevated aldolase usually correlates with disease activity • Creatinine kinase usually normal • Hypergammaglobulinemia (35%) of unclear significance IMAGING STUDIES • Consider MRI during initial work-up: 1. Noninvasive 2. Identifies presence of fascia edema and inflammation 3. Can guide appropriate site for biopsy or be used if biopsy nondiagnostic • Consider PET-CT (though limited data based on case reports)

TREATMENT ACUTE GENERAL Rx • Given the rarity of EF, no randomized controlled trials have been performed to date. • Corticosteroids (prednisone 0.5 to 1 mg/kg/d) are considered mainstay of treatment. • Based on a recent retrospective review from 2016 of the largest cohort of EF patients to date, complete response is more likely with combination of corticosteroids and methotrexate compared to other treatment combinations, corticosteroid therapy, or treatment without corticosteroids. • Other potential agents based on case reports include mycophenolate mofetil (MMF), intravenous immunoglobulin (IVIG), cyclosporine, azathioprine, infliximab, rituximab, and sirolimus as well as UVA phototherapy or extracorporeal photochemotherapy. CHRONIC Rx • Treatment duration is unknown. Patients are monitored for clinical response, and medications are decreased/discontinued accordingly. • Patients with incomplete response may require increased doses of corticosteroids.

FIG. E1  The “groove sign” of eosinophilic fasciitis. (From Hochberg MC: Rheumatology, ed 7, Philadelphia, 2019, Elsevier.)

Eosinophilic Fasciitis DISPOSITION • Improved outcomes with early treatment. • Long-term prognosis is unknown but is generally good. • Relapse can occur after cessation of steroids. REFERRAL Dermatology should be consulted for full skin-tomuscle biopsy. May require surgical evaluation to reduce contracture and maintain function.

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PEARLS & CONSIDERATIONS COMMENTS • Physical therapy is a crucial, but often overlooked, part of managing EF. • Patients should be started on prophylaxis for opportunistic infections when on long-term corticosteroids or immunosuppression.

SUGGESTED READINGS Fett N et  al: Eosinophilic fasciitis: current concepts, Clin Dermatol 36:487-497, 2018. Jinnin M et al: Diagnostic criteria, severity classification and guidelines of eosinophilic fasciitis, J Dermatol 45:881-890, 2018. Mazori D et al: Eosinophilic fasciitis: an updated review on diagnosis and treatment, Curr Rheumatolog Rep 19:74, 2017. Pinal-Fernandez I et  al: Diagnosis and classification of eosinophilic fasciitis, Autoimmun Rev 13:379-382, 2014. Wright NA et al: Epidemiology and treatment of eosinophilic fasciitis: an analysis of 63 patients from 3 tertiary care centers, JAMA Dermatol 152:97-99, 2016.

AUTHORS: Alexandra Abrams-Downey, MD, and Erna Milunka Kojic, MD

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Eosinophilic Granulomatosis with Polyangiitis BASIC INFORMATION DEFINITION Eosinophilic granulomatosis with polyangiitis (EGPA), formerly known as Churg-Strauss syndrome (CSS) and also as allergic granulomatosis and angiitis, refers to a multisystem granulomatous vasculitis characterized by severe asthma, chronic rhinosinusitis, and hypereosinophilia. Classification criteria and definition for EGPA are described in Table E1. SYNONYMS Allergic angiitis Allergic granulomatosis Allergic granulomatosis and angiitis Churg-Strauss syndrome (CSS) EGPA ICD-10CM CODES M31.30 Wegener granulomatosis without renal involvement

EPIDEMIOLOGY & DEMOGRAPHICS • Overall incidence of 2.4 cases per 1 million persons in the U.S. Among patients with asthma, the annual incidence of EPGA is estimated to average 34.6 per 1 million patients. • Usually occurs at a mean age of 40 yr, and is uncommon in those ≥65 yr. It is rare in children but presents in an aggressive form with cardiopulmonary involvement when it does occur. • No gender predominance. • Rarest of the ANCA-associated vasculitis but most common of the p-ANCA vasculitides. • Cardiac or GI involvement and age ≥65 yr are indicators of worse prognosis. • With treatment, 1-yr survival rate is approximately 90%, and 5-yr survival is 62%. PHYSICAL FINDINGS & CLINICAL PRESENTATION The clinical picture of EPGA typically consists of three partially overlapping phases, which may or may not be sequential: • Prodromal phase: 1. Severe adult-onset asthma, with or without allergic rhinitis, atopic dermatitis, sinusitis, headache, cough, and wheezing

2. P recedes development of systemic vasculitis by several yrs • Eosinophilic/tissue infiltration phase: 1. Peripheral eosinophilia and eosinophilic infiltration of the lungs, myocardium, and GI tract, with or without granulomas 2. Signs and symptoms of cough, fever, anorexia, weight loss, sweats, malaise, nausea, vomiting, abdominal pain, and diarrhea 3. Forty percent of EGPA patients present with asthma, pulmonary opacities, and hypereosinophilia in this phase • Systemic vasculitic phase: 1. Development of necrotizing vasculitis that is clinically apparent primarily in peripheral nerves, skin, and kidneys, although any organ can be affected 2. Signs and symptoms include fever, fatigue, weight loss • Skin involvement is common and seen in >50% of patients. It can be divided into three categories: 1.  Erythematous maculopapules (can resemble erythema multiforme) 2. Hemorrhagic lesions (associated with wheals) 3. Cutaneous and subcutaneous nodules on extensor surfaces

ETIOLOGY Etiology unknown but believed to be an autoimmune-mediated process (see “Comments”)

DIAGNOSIS • Clinical findings and biopsy showing eosinophilic vasculitis. • The American College of Rheumatology (ACR) has established the criteria for EGPA diagnosis in patients without vasculitis (Table E1). The presence of any four or more of the six criteria yields a sensitivity of 85% and a specificity of 99.7%. For patients with vasculitis, the presence of asthma and eosinophilia is 90% sensitive and 99% specific for EGPA.

DIFFERENTIAL DIAGNOSIS • Polyarteritis nodosa (PAN) • Granulomatosis with polyangiitis and microscopic polyangiitis (GPA, formerly known as Wegener granulomatosis)

TABLE E1  Classification Criteria and Definition for Churg-Strauss Syndrome Diagnosis Criteria American College of Rheumatology (Preferred; Requires 4 of 6) Asthma Eosinophilia (>10% total WBC count) Neuropathy (mono- or polyneuropathy) Pulmonary infiltrates (migratory or transitory) Paranasal sinus abnormality (pain, tenderness, or radiologic abnormality) Extravascular eosinophils (in a biopsy containing an artery, arteriole, or venule)

Lanham (Requires All 3) Asthma Eosinophilia (>10% WBC count or >1.5 × 109) Systemic vasculitis affecting at least two or more extrapulmonary sites

WBC, White blood cell. From Hochberg MC, et al: Rheumatology, ed 5, St. Louis, 2011, Mosby.

• Goodpasture syndrome • Loeffler syndrome • Hypereosinophilia syndrome • Rheumatoid arthritis • Leukocytoclastic vasculitis Although similar and at times grouped with patients with PAN or GPA, EGPA differs in that: • EGPA vasculitis involves small-sized arteries, veins, and venules. • EGPA, unlike PAN, predominantly involves the lung. • Kidney involvement is much less common in EGPA than in GPA. Pulmonary lesions in GPA usually involve the upper respiratory tract rather than the peripheral lung parenchyma in EGPA. • EGPA shows necrotizing vasculitis along with eosinophilic granulomas.

LABORATORY TESTS • Complete blood count with differential: Eosinophilia >10% is an American College of Rheumatology (ACR) diagnostic criterion. • Blood urea nitrogen and creatinine may be mildly elevated, suggesting renal involvement. • Urinalysis may show mild hematuria and proteinuria. • 24-hour urine for protein; >1 g/day is a poor prognostic factor. • Perinuclear antineutrophilic cytoplasmic antibody (P-ANCA) is found in 40% to 60% of patients. Negative ANCA does not rule out EGPA. • Antiproteinase 3 (PR3) antibody positivity. • IgE is commonly elevated. • Elevation of aspartate aminotransferase, alanine aminotransferase, and creatinine phosphokinase may indicate liver or muscle (skeletal or cardiac) involvement. • Rheumatoid factor may be positive. • Biopsy helps confirm the diagnosis. Surgical lung biopsy is the gold standard. Transbronchial biopsy is rarely helpful. Necrotizing vasculitis and extravascular necrotizing granulomas, usually with eosinophilic infiltrates, are suggestive of EGPA. The presence of eosinophils in extravascular tissues is most specific for EGPA. IMAGING STUDIES • Chest radiograph is abnormal in eosinophilic and vasculitic phases: Asymmetrical bilateral patchy migratory infiltrates, interstitial lung disease, small pleural effusions, or nodular infiltrates (Fig. E1). • Lung lesions in EGPA are noncavitating, as opposed to those in GPA. • Paranasal sinus films may reveal sinus opacification, which is an ACR diagnostic criterion. • Angiography is sometimes done in patients with mesenteric ischemia or renal involvement.

TREATMENT NONPHARMACOLOGIC THERAPY Oxygen therapy in severe asthmatic exacerbations

Eosinophilic Granulomatosis with Polyangiitis

527.e5 REFERRAL • A pulmonary referral for diagnosis and management is appropriate. • Patients should be followed up closely by rheumatology. Patients usually need longterm immunosuppressive medications.

PEARLS & CONSIDERATIONS

FIG. E1  Allergic angiitis and granulomatosis. Posteroanterior chest radiograph demonstrates peripheral air space consolidation in the right lung and a nodule (arrow) in the left upper lobe in this asthmatic patient. (From McLoud TC [ed]: Thoracic radiology: the requisites, St Louis, 1998, Mosby.)

PHARMACOLOGIC THERAPY The following five factors suggest poor prognosis (five-factor score) and determine the aggressiveness of the immune suppressive therapy: 1. Proteinuria >1 g/day 2. Creatinine >1.58 mg/dl 3. Cardiovascular involvement 4. GI tract involvement 5. CNS involvement ACUTE GENERAL Rx • Corticosteroids are the treatment of choice if no poor prognostic factors are present. Prednisone 0.5 to 1.5 mg/kg/day is the starting dose and is continued for 6 to 12 wk and then tapered to 10 mg/day at 1 yr as clinical disease resolves. Response to steroids may be dramatic. Patients with extensive disease may require IV corticosteroids. • A drop in the patient’s eosinophil count and the ESR indicates a response to treatment. P-ANCA does not reliably correspond with disease activity. • For severe disease, cyclophosphamide is used in combination with corticosteroids. CHRONIC Rx • In patients with one or more poor prognostic factors, immunosuppressant agents (cyclophosphamide 1 to 2 mg/kg/day) are used with corticosteroids as first-line therapy. The ideal duration of cyclophosphamide ranges from 6 to 12 mo.

• In patients who do not respond to corticosteroid treatment or in EGPA relapse, cyclophosphamide therapy is indicated as a second-line therapy. • Azathioprine (2 mg/kg/day) or high-dose IV immunoglobulin has shown benefit in patients with severe disease and in patients unresponsive to corticosteroids. • Corticosteroids, in combination with interferon-alpha, have also been used in refractory cases but may be difficult to tolerate. • Patients with persistent symptoms of asthma will require long-term corticosteroids even if vasculitis is no longer present. • Maintenance therapy using methotrexate (15 to 25 mg/wk) or azathioprine (2 mg/kg/day) is an alternative to cyclophosphamide.

DISPOSITION • Clinical remission is obtained in more than 90% of patients after treatment. Relapse is common on cessation of therapy (∼26%). • Five-yr survival rate with treatment is between 60% and 90% and decreases to 50% at 7 yr. Asthma generally remains persistent, and ischemic damage to peripheral nerves can be permanent. • The 5-yr survival rate of untreated EPGA is 25%. • Death usually occurs from progressive refractory vasculitis, myocardial involvement (∼50% of deaths), or severe GI involvement (mesenteric ischemia, pancreatitis).

SUGGESTED READINGS Baldini C et al: Clinical manifestations and treatment of Churg-Strauss syndrome, Rheum Dis Clin North Am 36(3):527-543, 2010. Comarmond C et al: Eosinophilic granulomatosis with polyangiitis (ChurgStrauss), Arthritis Rheum 65(1):270-281, 2013.

COMMENTS • EGPA is distinguished from other vasculitides by the nearly universal presence of adultonset asthma that typically precedes all other symptoms. Family history is often negative for allergies or asthma. • Vasculitis may not present until several yrs after the prodromal phase. • Up to 77% of patients in the prodromal phase of EGPA require oral steroids for asthma control. • Patients often have constitutional symptoms of weight loss, fever, and malaise before specific organ involvement is clinically evident. • Peripheral nerve involvement from vasculitis of the vasa vasorum commonly manifests as mononeuritis multiplex. Patients may present with sudden foot or wrist drop, along with sensory deficits in the distribution of one or more distal nerves. • Most patients with GI involvement are symptomatic. Gastroenteritis, acute abdomen, cholecystitis, hemorrhage, bowel perforation, and mesenteric ischemia have all been reported in patients with EGPA. • Most patients with EGPA respond to corticosteroid treatment and do not require cytotoxic therapy. • Symptoms of GPA typically appear as oral corticosteroids are being decreased or discontinued for the treatment of asthma and not triggered by leukotriene receptor-1 antagonists, as previously reported. • Compared with GPA, patients more often present with history of atopy, asthma, or allergic rhinitis. When present, eosinophilia in EGPA is often >1000 eosinophils/mm3 compared with GPA, in which eosinophilia is much milder (500 cells/ml The disease has been characterized by a staging system. Patients do not necessarily proceed from one stage to another. Stage I Stage II Stage III Stage IV Stage V

Acute phase Remission Exacerbation Glucocorticoiddependent ABPA End-stage (fibrotic) ABPA

• Treatment: Systemic corticosteroids are the mainstay of treatment. Antifungals may provide additional benefit in modulating airway fungal burden and are recommended for use in patients with relapse or glucocorticoiddependent disease. • Development of bronchiectasis portends a worse prognosis. • Response to therapy and activity of disease may be monitored by measuring IgE levels, which typically will decrease by 35% to 50% when a patient is in remission. TROPICAL PULMONARY EOSINOPHILIA: • Onset of asthma, fever, paroxysmal cough and bronchospasm, marked peripheral blood eosinophilia • Basilar reticulonodular and interstitial infiltrates • High serum IgE levels • Presumed etiology: Filariasis (Wuchereria bancrofti and Brugia malayi) • Treatment is with diethylcarbamazine EOSINOPHILIC GRANULOMATOSIS WITH POLYANGIITIS (EGPA): • Formerly known as Churg-Strauss syndrome. • Eosinophilic granulomatous inflammation and necrotizing vasculitis of small- to medium-size vessels that involves many organ systems in the setting of asthma. • Patients present with signs of asthma and atopy including cough, dyspnea, wheezing, sinusitis, and allergic rhinitis; other symptoms depend on other organs involved. • Labs reveal peripheral blood eosinophilia, elevated IgE. • 40% of patients will have a positive ANCA (p-ANCA more common than c-ANCA). • Imaging may show patchy opacities, consolidation, or nodules. • Pulmonary function test may reveal airflow obstruction. • Organ systems involved include lungs, heart, skin, peripheral nervous system, GI tract, and kidneys.

Eosinophilic Pneumonias • Pathogenesis is not clearly known. • Untreated mortality is high, but remission is common with treatment. • Treatment includes steroids and other immunosuppressive agents. HYPEREOSINOPHILIC SYNDROME: • A disease of persistently elevated peripheral eosinophils (>6 mo) of unknown etiology with tissue hypereosinophilia, resulting in end organ damage. • Can involve multiple organs, including the heart, lungs, nervous system, and GI tract. • Cardiac disease can be severe, including valvular disease and myocardial fibrosis. • Presentation often depends on the organ systems involved but can include fever, cough, weight loss, wheezing, or CNS abnormalities. • In addition to the idiopathic form, may have a myeloproliferative etiology. • Lungs are affected in 25% of patients. • Chest imaging may show opacities, consolidation, or lymphadenopathy. • Diagnosis of exclusion. • Check echocardiogram. • Treat with steroids if symptomatic or evidence of end-organ dysfunction (particularly cardiac disease). • Patients with myeloproliferative disease associated hypereosinophilic syndrome with FIP1L1-PDGFRA fusion gene mutations typically have an aggressive course and are treated with imatinib. DRUG- OR TOXIN-INDUCED EOSINOPHILIC PNEUMONIA: • Can have several different clinical presentations, including simple pulmonary eosinophilia, chronic eosinophilic pneumonia, acute eosinophilic pneumonia, or drug reaction with eosinophilia and systemic symptoms (DRESS). • Described causes of drug- or toxin-induced EP: Most commonly associated with antibiotics and NSAIDs. Others include amiodarone, bleomycin, captopril, iodine, methotrexate, venlafaxine, sulfa-containing drugs, illicit drugs, dust exposure, and so on. • Consider DRESS when pulmonary symptoms are also associated with skin eruption and fevers. • Imaging findings are nonspecific and can include bilateral infiltrates. • Diagnostic evaluation often includes BAL to exclude infection or other lung disease. • Laboratory evaluation rarely diagnostic. • Treatment includes removal of the offending agent and sometimes steroids.

DIAGNOSIS • Diagnosis varies depending on specific cause of pneumonia. • Usually involves chest radiograph (Fig. E1), CT, peripheral eosinophil count, BAL, and possibly lung biopsy.

DIFFERENTIAL DIAGNOSIS • Bacterial pneumonia • Tuberculosis

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FIG. E1  Chest radiograph shows pattern of peripheral pulmonary infiltrates characteristic of chronic eosinophilic pneumonia. (From Weinberger SE: Principles of pulmonary medicine, ed 7, Philadelphia, 2019, Elsevier.)

• Fungal pneumonia • Parasitic infection (Ascaris, Strongyloides) • Idiopathic pulmonary fibrosis • Bronchiolitis obliterans and organizing pneumonia • Hypersensitivity pneumonitis • Radiation pneumonitis • Bronchogenic carcinoma • Rheumatoid lung disease • Sarcoidosis

• Steroids may be helpful in many cases; doses and length of treatment depend on etiology of symptoms and response to treatment. • There have been recent case reports of successful use of omalizumab (Xolair) as a steroid-sparing agent in the treatment of chronic eosinophilic pneumonia, although this practice is not well examined in the literature to date. • Supportive respiratory care.

WORKUP Physical examination, laboratory tests, imaging, bronchoscopy

DISPOSITION Depends on etiology. Prognosis is good if offending agent can be removed or an infectious etiology treated. Glucocorticoids have a good effect, but relapse often recurs with tapering in chronic idiopathic cases.

LABORATORY TESTS • WBC counts are often normal • Often peripheral blood eosinophilia • Elevated eosinophil count on BAL • Consider ANCA, stool O+P, parasite serologies, IgE, Aspergillus precipitins, rheumatologic serologies as appropriate based on history and examination IMAGING STUDIES Chest radiograph may show a variety of infiltrates depending on the cause of EP. CT demonstrates a more characteristic pattern and distribution of parenchymal opacities than chest radiography.

TREATMENT • Varies depending on the cause. • Remove offending agent or treat with appropriate antibiotic.

REFERRAL To pulmonologist if a BAL or lung biopsy is needed to establish the diagnosis

PEARLS & CONSIDERATIONS • History (including travel) and physical examination are most important. Temporal association of eosinophilia and pulmonary abnormalities is an important diagnostic clue. • Coccidioidomycosis and Aspergillus can present as eosinophilic lung disease and are important to recognize because steroid therapy can produce progressive infection. • Aspergillus from respiratory specimens does not always indicate true infection and may be colonization.

Eosinophilic Pneumonias • Blood eosinophilia >1 × 109 eosinophils/L or BAL >25% is helpful in narrowing diagnosis. • Integrating the clinical, radiologic, and pathologic findings facilitates the initial and differential diagnoses of various eosinophilic lung diseases.

RELATED CONTENT Aspergillosis (Related Key Topic) Drug-Induced Parenchymal Lung Disease (Related Key Topic)

SUGGESTED READINGS Cottin V et al: Eosinophilic lung diseases, Immunol Allergy Clin North Am 32:557, 2012. Kaya H et  al: Omalizumab as a steroid-sparing agent in chronic eosinophilic pneumonia, Chest 142(2):513, 2012. Simon HU et al: Refining the definition of hypereosinophilic syndrome, J Allergy Clin Immunol 126:45-49, 2010. Wechsler ME et al: Novel targeted therapies for eosinophilic disorders, J Allergy Clin Immunol 130:563-567, 2012.

527.e8 Eosinophilic Granulomatosis with Polyangiitis (Related Key Topic) Hypereosinophilic Syndrome (Related Key Topic) AUTHOR: Melissa H. Tukey, MD, MS

Epicondylitis BASIC INFORMATION

RESISTED WRIST EXTENSION TEST

DEFINITION Epicondylitis is an overuse injury of the common extensor tendon origin at the lateral epicondyle (tennis elbow) and common flexor tendon origin at the medial epicondyle (golfer elbow). The term epicondylitis is a misnomer because the tendon, rather than the epicondyle, is primarily involved in this degenerative process, and histologic changes are characterized by angiofibroblastic hyperplasia, rather than inflammatory changes. SYNONYMS Tennis elbow (lateral epicondylitis) Golfer elbow (medial epicondylitis) Elbow tendinosis Elbow tendinopathy Epicondylalgia Elbow tendinitis ICD-10CM CODES M77.00 Medial epicondylitis, unspecified elbow M77.10 Lateral epicondylitis, unspecified elbow M77.01 Medial epicondylitis, right elbow M77.02 Medial epicondylitis, left elbow M77.11 Lateral epicondylitis, right elbow M77.12 Lateral epicondylitis, left elbow M77.0 Medial epicondylitis M77.1 Lateral epicondylitis

EPIDEMIOLOGY & DEMOGRAPHICS PREVALENCE • 1% to 3% of the general population. 1. 90% of cases of tennis elbow are not related to playing tennis. Recreational tennis players who play >2 h/d have two to four times greater risk of developing epicondylitis compared with the general population. 2.  Smoking, obesity, repetitive movement for more than 2 h daily, and forceful activity are risk factors in the general population. • The lateral side is involved more often than the medial. PREDOMINANT AGE AND SEX: • Affects middle-aged women more often than men. • More common in individuals 40 to 60 yr old. PHYSICAL FINDINGS & CLINICAL PRESENTATION • Main symptom is pain in lateral or medial elbow. 1. Pain is typically related to activity. 2. Physical examination maneuver to provoke pain: Wrist extension against resistance tests for lateral epicondylitis and wrist flexion against resistance for medial epicondylitis. Local tenderness is experienced over the affected epicondyle (Figs. E1 and E2).

FIG. E1  Resisted wrist and long finger extension. Patients with lateral epicondylitis normally experience increased pain as this test is performed. (From Hochberg MC: Rheumatology, ed 7, Philadelphia, 2019, Elsevier.)

RESISTED WRIST FLEXION TEST

FIG. E2  Resisted wrist flexion with the elbow in extension. This normally increases medial elbow pain in patients with medial epicondylitis. (From Hochberg MC: Rheumatology, ed 7, Philadelphia, 2019, Elsevier.)

ETIOLOGY • Epicondylitis is thought to be secondary to repetitive microtrauma, leading to degeneration, tendinosis, and possibly tendon tear, which results in a robust angiogenic and fibroblastic response. • The pathology is defined by a disorganization of normal collagen by invading fibroblasts in association with an immature vascular reparative response and the absence of inflammatory cells, which is termed angiofibroblastic tendinosis. • Although classic inflammatory changes are not present, cytokines have been shown to play a role in the cause of epicondylitis. GENETICS Patients with BstUI and DpnII variants of the COL5A1 gene are at increased risk for development of lateral epicondylitis.

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • Intraarticular elbow pathology (osteoarthritis, osteochondritis dissecans, loose body) • Radial tunnel syndrome (compression of the posterior interosseous nerve) • Cubital tunnel syndrome (compression of the median nerve) • Medial collateral ligament instability • Valgus extension overload • Ulnar neuritis • Tumors • Avascular necrosis • Thoracic outlet syndrome • Cervical radiculopathy IMAGING STUDIES • Plain radiography is useful for chronic cases to evaluate for osteoarthritis, exostosis, or other bony abnormalities.

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Epicondylitis • Ultrasound may show tendinosis as hypoechoic swelling of the involved tendon, possible hyperechoic calcification, and bony abnormality. Power or color Doppler signal is variable. • MRI is the gold standard in detecting epicondylitis. MRI is the most sensitive test, showing tendon thickening and high T2 signal intensity.

TREATMENT • Rest, activity modification, and overuse prevention. • Athletes may benefit from technique modifications. • Ice packs and heat may be beneficial. • N onsteroidal antiinflammatory drugs (NSAIDs) can be used topically or orally but usually provide only short-term relief. • Local steroid/lidocaine injection (Fig. E3) can be considered, but recent trials have called into question the long-term efficacy of corticosteroid injections for epicondylitis. • Wrist brace or splint. • Physical therapy with isometric strengthening exercises. Tendon fenestration (tenotomy or dry needling) has been deployed in ultrasound-guided treatment of lateral

527.e10 epicondylitis with some success. A recent small study reports short-term benefit of Kinesiotaping and extracorporeal shock wave therapy (ESWT) in treatment of lateral epicondylitis. • Acupuncture has been found to be beneficial in some cases. • Local injection of platelet-rich plasma has been investigated to a limited extent for use in the treatment of lateral epicondylitis with some evidence of improvement in pain and function. • Autologous blood and prolotherapy are also currently used in clinical practice. • Injection of botulinum toxin A at the myotendinous junction has been found to be helpful in a small randomized controlled trial. • Patients with refractory symptoms after 6 mo of nonoperative management may benefit from surgical intervention.

DISPOSITION • Epicondylitis is self-limited in most cases. Resolution of symptoms may take months to years. • Prognosis is worse in the following situations: 1. The dominant hand is involved. 2. Patient experiences high physical strain at work.

3. Duration of symptoms is more than 3 mo. 4. P atient experiences severe pain at presentation and concomitant neck pain.

REFERRAL If symptoms do not respond to a 6-mo trial of conservative therapy, surgical referral is appropriate.

P  EARLS & CONSIDERATIONS • The lateral epicondyle may be harder to localize than bony medial epicondyle. • The diagnosis can frequently be made with physical examination and history alone. • The majority of cases are self-resolving.

RELATED CONTENT Golfer Elbow (Patient Information) Tennis Elbow (Patient Information) AUTHORS: Manuel F. DaSilva, MD, and Nicholas J. Lemme, MD

SUGGESTED READINGS

FIG. E3  Injection for right tennis elbow (lateral epicondylar syndrome). (From Hochberg MC: Rheumatology, ed 7, Philadelphia, 2019, Elsevier.)

Eraslan L et al: Does Kinesiotaping improve pain and functionality in patients with newly diagnosed lateral epicondylitis? Knee Surg Sports Traumatol Arthrosc 2017. Keijsers R et al: Tennis elbow, Shoulder elbow 11(5):L384-L392, 2019. Riff AJ et al: Open vs percutaneous vs arthroscopic surgical treatment of lateral epicondylitis: an updated systematic review, Am J Orthop 47(6), 2018. Shergill R, Choudur HN: Ultrasound-guided interventions in lateral epicondylitis, J Clin Rheumatol 2018. Shiri R et al: Lateral and medial epicondylitis: role of occupational factors, Best Pract Res Clin Rheumatol 25:43-57, 2011. Tosti R et al: Lateral epicondylitis of the elbow, Am J Med 126(4):357, 2013. e1-e6. Vaquero-Picado A et al: Lateral epicondylitis of the elbow, EFFORT Open Rev 1(11):391-397, 2017. Von Hofwegen C et al: Epicondylitis in the athlete’s elbow, Clin Sports Med 29(4):577-597, 2010. Walz DM et al: Epicondylitis: pathogenesis, imaging, and treatment, Radiographics 30:167, 2010.

ALG BASIC INFORMATION DEFINITION Epidermolysis bullosa (EB) is a rare disorder presenting in adults with the development of blisters on the hands, feet, elbows, knees, and other body regions after mild trauma. It represents a group of genetic disorders characterized by mechanically fragile skin with a propensity to develop blisters and/or erosions. There are four major types: dystrophic (DEB), junctional (JEB), simplex (EBS), and Kindler syndrome. They differ in the ultrastructural site within which cutaneous blisters form. Kindler syndrome is an extremely rare form characterized by trauma-induced blistering, photosensitivity, progressive poikiloderma, cutaneous atrophy, and mucosal inflammation. Characteristics of major forms of EBS, basal are summarized in Table E1. The characteristics of the major forms of JEB are described in Table E2. SYNONYMS EB Kindler syndrome

Epidermolysis Bullosa

TABLE E1  Characteristics of Major Forms of Epidermolysis Bullosa Simplex, Basal Type

Clinical Manifestations

EBS, localized (formerly Weber-Cockayne)

Easy blistering on palms and soles May be focal keratoderma of palms and soles in adults 25% show oral mucosal erosions Rarely show reticulated pigmentation, especially on arms and trunk and punctate keratoderma (EBS with mottled pigmentation) Generalized blistering Variable mucosal involvement Focal keratoderma of palms and soles Nail involvement in 20% Improves with advancing age Most severe in neonate, infant; improves beyond childhood Large, generalized blisters; later, smaller (herpetiform) blisters Mucosal blistering, including esophageal Nails thickened, shed but regrow May have natal teeth Reticulated hyperpigmentation, especially on arms and trunk Punctate keratoses and keratoderma

EBS, generalized, ­intermediate (formerly Koebner)

EBS, generalized, severe (formerly Dowling-Meara)

EBS with mottled pigmentation

ICD-10CM CODES L12.30 Acquired epidermolysis bullosa, unspecified Q81.2 Epidermolysis bullosa dystrophica Q81.0 Epidermolysis bullosa simplex

EBS, Epidermolysis bullosa simplex. From Paller AS, Mancini AJ (eds): Hurwitz clinical pediatric dermatology, ed 5, Philadelphia, 2016, Elsevier, Table 13.2, p. 319, in Kliegman RM: Nelson textbook of pediatrics, ed 21, Philadelphia, 2020, Elsevier.

Q81.9 Epidermolysis bullosa, unspecified

Type

Clinical Manifestations

JEB, generalized severe (formerly Herlitz)

50% of patients die by 2 yr old Blisters heal with atrophic scarring but no milia Periungual and fingerpad blistering, erythema Blistering of oral and esophageal mucosae Laryngeal and airway involvement with early hoarseness Later, perioral granulation tissue with sparing of lips Anonychia Dental enamel hypoplasia, excessive caries Growth retardation Anemia Less severe, but similar manifestations to Herlitz type, including dental, nail, and laryngeal involvement Granulation tissue is rare Perinasal cicatrization Less mucosal involvement Alopecia Anemia, but not as severe as JEB, generalized severe Localized blisters without residual scarring or granulation tissue Minimal mucosal involvement Dental and nail abnormalities as in JEB, generalized severe Usually lethal in neonatal period Generalized blistering, leading to atrophic scarring May be born with large areas of cutis aplasia No granulation tissue Nail dystrophy or anonychia Pyloric atresia, genitourinary malformations Rudimentary ears Dental enamel hypoplasia (survivors) Variable anemia, growth retardation, mucosal blistering

EPIDEMIOLOGY & DEMOGRAPHICS PREVALENCE AND INCIDENCE: The estimated overall prevalence and incidence of EB in the U.S. are 11.1 per 1 million population and 19.6 per 1 million live births, respectively. The approximate prevalences and incidences, respectively, of the major types of EB are as follows: EB simplex, 6.0 and 7.9; junctional EB, 0.5 and 2.7; dominant dystrophic EB, 1.5 and 2.1; and recessive dystrophic EB, 1.4 and 3.0. GENETICS: The most common forms of EB simplex (EBS) are transmitted in an autosomal dominant manner. Table E3 summarizes the various clinical phenotypes and inheritance. PHYSICAL FINDINGS & CLINICAL PRESENTATION EB is marked by development of painful blisters on the hands, feet (Fig. E1), elbows, and knees after mild trauma. Extensive blistering (Fig. E2) may occur. EB may also be complicated by atrophic scarring, milia formation, and nail dystrophy. Fig. E3 illustrates helpful cutaneous findings in patients with EB. Table E4 summarizes major extracutaneous complications of EB. ETIOLOGY T his is an inherited disorder (see Table E3).

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • Bullous pemphigoid • Pemphigus vulgaris • Linear IgA bullous dermatosis

TABLE E2  Characteristics of Major Forms of Junctional Epidermolysis Bullosa

JEB, generalized, ­intermediate (formerly non-Herlitz)

JEB, localized

JEB, generalized with pyloric atresia

JEB, Junctional epidermolysis bullosa. From Paller AS, Mancini AJ (eds): Hurwitz clinical pediatric dermatology, ed 5, Philadelphia, 2016, Elsevier, Table 13.4, p. 321, in Kliegman RM: Nelson textbook of pediatrics, ed 21, Philadelphia, 2020, Elsevier.

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TABLE E3  Epidermolysis Bullosa: Simplex, Junctional, and Dystrophic Subtypes and Kindler Syndrome Entities with a lighter background represent rare variants. EPIDERMOLYSIS BULLOSA: SIMPLEX, JUNCTIONAL AND DYSTROPHIC SUBTYPES AND KINDLER SYNDROME Subtype

Inheritance

Defective protein(s)

Acral peeling skin syndrome

AR

Transglutaminase 5

EB superficialis

Unknown

Unknown

Acantholytic EBS

AR

Desmoplakin; plakoglobin

Desmoplakin deficiency (skin fragility–woolly hair syndrome)

AR

Desmoplakin

Plakoglobin deficiency

AR

Plakoglobin

Plakophilin deficiency (skin fragility–ectodermal dysplasia syndrome)

AR

Plakophilin 1

AD

Keratins 5 and 14

AD

Keratin 5

EBS, AR-KRT14

AR

Keratin 14

EBS due to KLHL24

AD

Kelch-like protein 24

EBS with muscular dystrophy

AR AR

Plectin Plectin; α6β4 integrin

Suprabasal intraepidermal cleavage

Skin fragility syndromes

Basal intraepidermal cleavage EBS, localized (formerly Weber–Cockayne) EBS, generalized severe (formerly Dowling–Meara) EBS, generalized intermediate EBS with mottled pigmentation EBS, migratory circinate

EBS with pyloric atresia EBS-Ogna

AD

Plectin

EBS, AR-BP230 deficiency

AR

Bullous pemphigoid antigen 1 (BP230)

EBS, AR-exophilin 5 deficiency

AR

Exophilin 5

JEB, generalized severe (formerly Herlitz)

AR

Laminin 332

JEB, generalized intermediate

AR* AR

Laminin 332; collagen XVII α6β4 integrin

AR AR

Collagen XVII α3 integrin subunit

Intra-lamina lucida cleavage

JEB with pyloric atresia JEB, late onset JEB with respiratory and renal involvement JEB, localized

AR

Collagen XVII; α6β4 integrin

JEB, inversa

AR

Laminin 332

JEB-laryngo-onycho-cutaneous syndrome

AR

Laminin α3 chain (an isoform)

AD

Collagen VII

Sublamina densa cleavage DDEB, generalized Other DDEB variants: acral, pretibial, pruriginosa, nails only DDEB, bullous dermolysis of the newborn RDEB, generalized severe (formerly Hallopeau–Siemens)

AR

RDEB, generalized intermediate RDEB, inversa Other RDEB variants: localized, pretibial, pruriginosa, centripetalis RDEB, bullous dermolysis of the newborn Mixed cleavage planes Kindler syndrome

AR

Kindlin-1

*One case with AD inheritance has been reported. AD, Autosomal dominant; AR, autosomal recessive; DDEB, dominant dystrophic EB; EB, epidermolysis bullosa; EBS, epidermolysis bullosa simplex; JEB, junctional epidermolysis bullosa; RDEB, ­recessive dystrophic EB. From Bolognia J: Dermatology, ed 4, Philadelphia, 2018, Elsevier.

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A

B FIG. E1  Localized epidermolysis bullosa simplex. A and B, Bullae arising on the toes and plantar surfaces at sites of lateral or rotary traction. The majority of blisters occur in acral sites. (A, From Bolognia J: Dermatology, ed 4, Philadelphia, 2018, Elsevier. B, Courtesy Julie V. Schaffer, MD)

• Porphyria cutanea tarda • Chemical burn • Thermal burn • Blisters due to trauma (friction blisters) • Cicatricial pemphigoid

WORKUP An approach to the laboratory diagnosis of EB is illustrated in Fig. E4. LABORATORY TESTS Skin biopsy and serum for direct and indirect immunofluorescence can detect skin basement membrane–specific autoantibodies.

TREATMENT ACUTE GENERAL Rx • Nutritional support, avoidance of trauma

• Topical antibiotics, sterile dressing • Dressings frequently used in patients with EB are described in Table E5 • Systemic corticosteroids • Dapsone • Azathioprine • Colchicine • Cyclosporine

CHRONIC Rx The management of long-term complications of EB is summarized in Table E6. REFERRAL Dermatology in all cases

PEARLS & CONSIDERATIONS COMMENTS Workup for inflammatory bowel disease and ELISA for type VII collagen-specific autoantibodies should also be considered. AUTHOR: Fred F. Ferri, MD

SUGGESTED READING Fine JD, Mellerio JE: Epidermolysis bullosa. In Bolognia JL et al: Dermatology, ed 4, Philadelphia, 2018, Elsevier, pp. 538-553.

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B FIG. E2  Generalized intermediate epidermolysis bullosa simplex. Extensive blistering on the buttocks (A) and blistering in association with focal keratoderma on the soles (B) of a 2-yr-old girl. (From Bolognia J: Dermatology, ed 4, Philadelphia, 2018, Elsevier; Courtesy, Julie V. Schaffer, MD)

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HELPFUL CUTANEOUS FINDINGS IN PATIENTS WITH EB

Distinguishing cutaneous findings in patients with EB

Primary involvement of the palms and soles

Primary involvement of axillae and groin

Grouped or “herpetiform” blisters, sometimes in a figurate array

Reticulated hyperpigmentation

Excessive or exuberant granulation tissue, e.g., periorificial, axillae, neck, upper back

Confluent palmoplantar keratoderma

Prurigo-like nodules coalescing into linear plaques on the shins

EBS, localized

JEB, inversa subtype; recessive dystrophic EB, inversa subtype

EBS, generalized severe

EBS with mottled pigmentation

JEB, generalized severe

EBS, generalized severe

DEB, pruriginosa

FIG. E3  Helpful cutaneous findings in patients with epidermolysis bullosa (EB). DEB, Dystrophic EB; EBS, EB simplex; JEB, junctional EB. (From Bolognia J: Dermatology, ed 4, Philadelphia, 2018, Elsevier.)

TABLE E4  Major Extracutaneous Complications of Epidermolysis Bullosa EB Subtype(s) Most Commonly Affected Complications

≥50% of Patients

Eyes Corneal blisters, ulcers, and scarring RDEB-gen/sev Ectropion formation Oral Cavity and Upper Airway (Excluding Blisters) Microstomia RDEB-gen/sev Enamel hypoplasia JEB (all subtypes) Excessive caries and premature loss of teeth RDEB gen/sev, JEB-gen/sev Tracheolaryngeal stenosis JEB-gen/sev Gastrointestinal Tract Esophageal strictures RDEB-gen/sev, RDEB-inv Pyloric atresia JEB-PA, EBS-PA Malnutrition/failure to thrive RDEB-gen/sev, JEB-gen/sev Severe constipation RDEB-gen/sev GERD RDEB Colitis Genitourinary Tract Urethral meatal stenosis Chronic renal failure* Hydroureter and hydronephrosis Nephrotic syndrome JEB-resp/renal Heart Dilated cardiomyopathy Musculoskeletal System Pseudosyndactyly RDEB-gen/sev Osteoporosis or osteopenia RDEB-gen/sev Muscular dystrophy EBS-MD Bone Marrow Severe multifactorial anemia RDEB-gen/sev, JEB-gen/sev

RDEB-gen/intermed, RDEB-inv, JEB-gen/intermed JEB-gen/sev; Kindler JEB-gen/sev, RDEB-inv

JEB-gen/intermed RDEB-gen/intermed, Kindler > JEB-gen/sev JEB-gen/intermed JEB-gen/sev, EBS-gen/sev JEB, EBS-gen/sev Kindler, RDEB-gen/sev RDEB-gen/sev, JEB-gen/sev, Kindler RDEB-gen/sev JEB-PA, JEB-gen/sev JEB-gen/sev RDEB-gen/sev > JEB, RDEB-gen/intermed RDEB-gen/intermed, Kindler RDEB-gen/sev, JEB-gen/sev

*Causes include renal amyloidosis and glomerulonephritis. EB, Epidermolysis bullosa; EBS, EB simplex; gen/intermed, generalized intermediate; gen/sev, generalized severe; GERD, gastroesophageal reflux disease; inv, inversa; JEB, junctional EB; MD, muscular dystrophy; PA, pyloric atresia; RDEB, recessive dystrophic EB; resp/renal, respiratory and renal involvement. From Bolognia J: Dermatology, ed 4, Philadelphia, 2018, Elsevier.

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APPROACH TO THE LABORATORY DIAGNOSIS OF EPIDERMOLYSIS BULLOSA (EB)

Approach to the laboratory diagnosis of epidermolysis bullosa (EB)

Immunofluorescence antigen mapping (IFM) and/or transmission electron microscopy (TEM) of biopsy specimen(s) from a fresh induced blister • Preferred sites: Upper inner arm just above elbow or a non-acral blister-prone area • Apply firm pressure on intact skin with pencil eraser and rotate 180° in each direction 3 to 10+ times • Perform 3 to 4 mm punch biopsy at blister edge

Next-generation sequencing panel with all known EB genes

*

IFM using anti-BM monoclonal antibodies • Place sample in Michel/Zeus medium

TEM • Place sample in glutaraldehyde

Determine plane of cleavage • Relative to antigens identified in a primary screening antibody panel, e.g., against laminin 2 chain and collagen types IV, VII and XVII

Assess for abnormal expression or distribution of BM proteins • Targeted secondary antibody panel • Decreased antigen expression is most often seen in recessive forms of EB: Antigen Selected EB subtypes with absent/markedly reduced staining Plectin EBS with muscular dystrophy 64 integrin JEB with pyloric atresia Laminin 332 JEB-generalized severe Type XVII collagen JEB-generalized intermediate Type VII collagen RDEB-generalized severe Kindlin-1 Kindler syndrome (findings vary) • Often relatively normal staining in dominant forms of EB, e.g., keratin 5/14 in EBS and type VII collagen in DDEB • In active DDEB-bullous dermolysis of the newborn, collagen VII staining is granular within basal keratinocytes but reduced/absent within the BM Consider genetic analysis guided by results • Required for DNA-based prenatal/preimplantation testing

*May be more difficult to induce blisters in patients with localized EBS or DDEB FIG. E4  Approach to the laboratory diagnosis of epidermolysis bullosa (EB). BM, Basement membrane; DDEB, dominant dystrophic EB; DNA, deoxyribonucleic acid; EBS, EB simplex; JEB, junctional EB; RDEB, recessive dystrophic EB. (From Bolognia J: Dermatology, ed 4, Philadelphia, 2018, Elsevier.)

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TABLE E5  Dressings Frequently Used in Patients with Epidermolysis Bullosa Dressing Type

Use

Examples®,™

Soft silicone dressings (“low-tack”)

• Suitable as primary or secondary dressings in many types of EB • May have a foam backing for mechanical protection or to wick exudate away from the wound • Suitable for primary contact • Provide moisture to drier wounds to facilitate healing • May provide relief from pain or itch • Useful to absorb moderate amounts of wound exudate • Useful to absorb heavy amounts of wound exudate • Clinically infected or highly colonized wounds • Avoid prolonged use due to risk of silver absorption • Clinically infected or highly colonized wounds

Mepitel, Mepilex, Mepilex Transfer, Mepilex Border

Nonadherent lipido-colloid dressings Hydrogel dressings Foam dressings Absorptive dressings Silver-containing dressings Other antimicrobial dressings

UrgoTul Flexigel, Curagel, ActiFormCool Mepilex, Allevyn Eclypse, Sorbion Sana UrgoTul SSD, Mepilex AG PolyMem, Cutimed Sorbact, Activon Tulle, Suprasorb X + PHMB

EB, Epidermolysis bullosa. From Bolognia J: Dermatology, ed 4, Philadelphia, 2018, Elsevier.

TABLE E6  Management of Long-Term Complications of Epidermolysis Bullosa Complication

Prevention and Monitoring/Detection

Management

• Diligent oral hygiene • Antiseptic and fluoride mouthwashes • Periodic evaluation and cleaning by a dentist

• Restorative dentistry

Oral and Gastrointestinal Excessive caries Microstomia Oral ulceration Esophageal strictures

• Evaluate dysphagia with contrast studies

Gastroesophageal reflux disease Constipation

• Ensure adequate fluid intake and dietary fiber

• Physical therapy • “Mouth expanding” devices • Topical antiseptics, topical NSAIDs, barrier preparations (e.g., sucralfate suspension) • Dietary modification (soft foods/purées, caloric supplementation) • Fluoroscopically guided balloon dilatation; repeated procedures are often required • In severe and recalcitrant cases, surgical options include colonic interposition • Proton pump inhibitors, H2 blockers, prokinetic agents (e.g., metoclopramide, domperidone [not available in the U.S.]) • Osmotic laxatives (e.g., containing polyethylene glycol), mineral oil • Avoid suppositories and enemas

Nutritional Growth retardation/inadequate intake to meet nutritional needs

• Monitor height, weight, and body mass index • Periodically assess serum zinc, selenium, iron, vitamin D, and carnitine levels (e.g., yearly) • Oral supplements to optimize intake of calories, protein, vitamins, and minerals

• Consider gastrostomy feedings

• Monitor CBC and measures of iron stores

• Iron supplementation (oral or IV) • Consider erythropoietin or darbepoetin alpha • Consider blood transfusion if hemoglobin ≤7-8 g/dl and/or symptomatic

• Consider annual ultrasound of the urinary tract and urodynamic studies (especially for JEB)

• Dilatation procedures as needed to treat obstruction • Avoid unnecessary instrumentation

• Blood urea nitrogen and serum electrolyte levels, urinalysis, and blood pressure evaluation every 6 mo in RDEB patients • Adequately treat streptococcal infections

• Hemodialysis or peritoneal dialysis if renal failure develops

• Annual DEXA scan and spinal radiographs beginning at age 5 yr in RDEB and JEB patients • Calcium and vitamin D supplementation • Cushioned splints on hands/forearms and individual wrapping of fingers in RDEB patients

• Consider IV bisphosphonate therapy

Hematologic Anemia due to iron deficiency and chronic inflammation

Genitourinary and Renal Urinary outflow obstruction (e.g., urethral or ureteral strictures) Renal disease (e.g., ­hydronephrosis, postinfectious glomerulonephritis, renal ­amyloidosis, IgA nephropathy)

Musculoskeletal Osteopenia and osteoporosis Pseudosyndactyly of hands/feet

• Surgery to release contractures and webbing Continued

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TABLE E6  Management of Long-Term Complications of Epidermolysis Bullosa—cont’d Complication

Prevention and Monitoring/Detection

Management

• Periodic total-body skin examinations; for RDEB patients, approximately every 3-6 mo beginning at age 10 yr and every 3 mo after age 16 yr • Biopsy or monitor nonhealing ulcers • Consider taking serial photographs

• Excision ± skin grafting (sometimes amputation); consider MRI to assess extent of local disease • Consider staging with CT, PET-CT, sentinel lymph node biopsy

• Periodic ophthalmologic evaluation for patients with eye involvement • Lubricating eye drops

• Surgical procedures, e.g., division of symblepharon, amniotic membrane transplantation

• Consider annual echocardiography beginning in late childhood for RDEB patients

• Medical management • Supplement selenium and carnitine if deficient

• Consider family counseling, support groups • Consider psychological counseling, support groups

• Psychological/family counseling • Psychiatric evaluation, antidepressant therapy

Oncologic Cutaneous squamous cell ­carcinoma

Ocular Chronic complications include corneal scarring, symblepharon, ectropion

Cardiac Dilated cardiomyopathy

Psychological and Psychiatric Disrupted family unit (e.g., via divorce) Depression and suicidal ideation/ attempts

CBC, Complete blood count; CT, computed tomography; DEXA, dual-energy x-ray absorptiometry; EB, epidermolysis bullosa; Ig, immunoglobulin; IV, intravenous; JEB, junctional EB; MRI, magnetic resonance imaging; NSAID, nonsteroidal antiinflammatory drug; PET-CT, positron emission tomography and computed tomography; RDEB, recessive dystrophic EB. Modified from Bolognia J: Dermatology, ed 4, Philadelphia, 2018, Elsevier.

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Epididymitis BASIC INFORMATION DEFINITION • Epididymitis is an inflammatory reaction of the epididymis caused by either an infectious agent or local trauma. In most cases of acute epididymitis, the testis is also involved (orchitis). • Epididymitis is considered chronic if lasting ≥6 wk. Chronic epididymitis has been subcategorized into inflammatory chronic epididymitis, obstructive chronic epididymitis, and chronic epididymalgia. SYNONYMS Nonspecific bacterial epididymitis Sexually transmitted epididymitis ICD-10CM CODES N45.1 Epididymitis A54.00 Gonococcal infection of lower genitourinary tract, unspecified

EPIDEMIOLOGY & DEMOGRAPHICS INCIDENCE (IN U.S.): Cause of >600,000 visits to physicians per yr PEAK INCIDENCE: Sexually active yrs PREDOMINANT SEX: Exclusive to males PREDOMINANT AGE: All ages affected but usually in sexually active men or older males CONGENITAL: Congenital urologic structural disorders possibly predisposing to infections PHYSICAL FINDINGS & CLINICAL PRESENTATION • Tender swelling of the scrotum with erythema, usually unilateral testicular pain and tenderness • Dysuria and/or urethral discharge • Fever and signs of systemic illness (less common) • Pain and redness on scrotal examination • Hydrocele or even epididymo-orchitis, especially late • Chronic draining scrotal sinuses with a “beadlike” enlargement of the vas deferens in tuberculous disease ETIOLOGY • In young, sexually active men (35 yr of age) or those with underlying urologic disease: 1. Gram-negative aerobic rods are predominant (i.e., Escherichia coli). 2. Similar organisms are found in men following invasive urologic procedures. 3. Gram-positive cocci are rarely seen in these groups. 4. Mycobacteria may also be a cause of epididymitis. • Acute epididymitis caused by sexually transmitted enteric organisms (e.g., Escherichia coli) also occurs among men who are the insertive partner during anal intercourse. • Young, prepubertal boys may present with epididymitis caused by coliform bacteria;

almost always a complication of underlying urologic disease such as reflux. • In AIDS patients, CMV and Salmonella epididymitis have been described. CMV may have a negative urine culture. Toxoplasmosis and Cryptococcus should also be considered as a cause of epididymitis in AIDS patients. • Chronic infectious epididymitis is most frequently seen in conditions associated with granulomatous reaction; mycobacterium tuberculosis is the most common granulomatous disease affecting the epididymis.

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • Orchitis • Testicular torsion, trauma, or tumor • Epididymal cyst • Hydrocele • Varicocele • Spermatocele • Testicular torsion should be considered in all cases (Table E1). WORKUP • Consideration of a full assessment of the urologic tract in patients with bacterial infection, especially if recurrent • If discharge is present, cultures and Gram stain smear of urethral exudate. Gram stain should demonstrate ≥5 WBC per oil immersion field • In sexually active men: Gonococcal cultures of the throat and rectum possibly of value • If testicular torsion a consideration: Radionuclear imaging • Examination of first void uncentrifuged urine for leukocytes if the urethral Gram stain is negative. Positive leukocyte esterase test on first-void urine or microscopic examination of first-void urine sediment will demonstrate ≥10 WBC per high power field. A culture and Gram-stained smear of this urine specimen should be obtained along with nucleic acid amplification testing (NAAT) from urine samples for gonorrhea and chlamydia • Imaging with sonogram (Fig. E1) LABORATORY TESTS • All suspected cases of acute epididymitis should be tested for C. trachomatis and for N. gonorrhoeae by NAAT. Urine is the preferred specimen for NAAT testing. • Urinalysis and urine culture if dysuria is present or if urinary tract infection is suspected. • HIV testing and counseling. • PPD placed and chest x-ray viewed if TB suspected (rare cases). • Rarely, biopsy to ensure the diagnosis of tuberculous epididymitis.

TREATMENT ACUTE GENERAL Rx • Ice packs and scrotal elevation for relief of pain • Analgesia with acetaminophen with or without codeine or NSAIDs

• Antibiotics to cover suspected pathogens. Empiric therapy is indicated before laboratory test results are available • Recommended regimens are ceftriaxone 250 mg IM in a single dose plus doxycycline 100 mg bid for 10 days. For acute epididymitis most likely caused by enteric organisms, treatment options are levofloxacin 500 mg qd × 10 days or ofloxacin 300 mg bid × 10 days. Add ceftriaxone 250 mg IM single dose to levofloxacin or ofloxacin in men who practice insertive anal sex and are suspected to have chlamydia and gonorrhea and enteric organisms • Best treatment for older men with gramnegative bacteriuria: Ofloxacin 300 mg PO bid for 10 days or levofloxacin 500 mg PO qd for 10 days • Pseudomonas covered by ciprofloxacin PO or IV or cefepime (2 g IV q8h) • Consider ampicillin-sulbactam, third-generation cephalosporin, ticarcillin-clavulanate, or piperacillin-tazobactam in toxic-appearing patients • Surgical aspiration of local abscesses or even open surgical drainage • Diabetics: Especially prone to develop more extensive scrotal infections, including Fournier gangrene • Reinforcement of compliance with antibiotics to avoid partial treatment

CHRONIC Rx • Repair of underlying structural defects is considered especially if infections are severe or recur. • Surgical repair of reflux in young boys should be undertaken promptly and at a young age when possible. • Sex partners of patient should be referred for evaluation and treatment. REFERRAL • If abscess or chronic structural problems suspected • If another diagnosis, such as testicular torsion, is suspected

PEARLS & CONSIDERATIONS • Recurrent epididymitis in sexually active men is usually related to failure to simultaneously treat sexual partners for STDs. • Recurrent epididymitis in nonsexually active men is generally related to structural-anatomic defects in the genitourinary system or relapsing disease from inadequate initial treatment or antimicrobial resistance. • Tuberculous epididymitis fails to respond to seemingly adequate antimicrobial therapy even without characteristic radiographic changes on chest films.

RELATED CONTENT Epididymitis (Patient Information) Orchitis (Related Key Topic) Testicular Torsion (Related Key Topic) AUTHORS: Philip A. Chan, MD, MS, and Glenn G. Fort, MD, MPH

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TABLE E1  Differentiation among Causes of the Acute Scrotum Feature

Testicular Torsion

Appendix Torsion

Epididymitis

Age Onset Location of pain Systemic symptoms Cremasteric reflex Pyuria Ultrasound findings

female PEAK INCIDENCE: Peak incidence is among adolescents and young adults. It is rarely found in patients older than 50 to 60 yr old. GENETICS: There is a role for genetics in spontaneous (nontraumatic) EDH caused by coagulopathies and vascular malformations. RISK FACTORS: Head trauma, especially in cases involving skull fracture PHYSICAL FINDINGS & CLINICAL PRESENTATION • History of head trauma is present. • Signs and symptoms vary depending on severity. • Symptoms: Altered mental status, nuchal rigidity, headache, vomiting, drowsiness, confusion, aphasia, photophobia, and paralysis. • Signs: Transient loss of consciousness, followed by a “lucid interval” in 47% of cases, in which the patient is free of any neurologic signs or symptoms. This is followed by clinical deterioration including vomiting, lethargy, confusion, or seizures. Other signs may include focal neurologic deficits such as paralysis of limbs, unequal pupils, and coma. Signs of increased intracranial pressure could be found including the Cushing reflex of hypertension, bradycardia, and respiratory distress. External signs of skull ­fracture— lacerations, ecchymoses, cerebrospinal fluid (CSF) rhinorrhea or otorrhea—may be observed. Skull fractures can be found in 75% to 95% of EDH patients. • Coma or stupor with ipsilateral cranial nerve III palsy and contralateral hemiparesis may indicate transtentorial (uncal) herniation.

ETIOLOGY • Traumatic: Commonly caused by arterial injury (the middle meningeal artery) from a temporal bone fracture (Fig. 1) but may also be injury of the anterior meningeal artery, a dural arteriovenous (AV) fistula at the vertex, or from venous bleeding • Nontraumatic: Caused by an infection/eroding abscess, coagulopathy, hemorrhagic tumors, vascular malformations, postsurgical procedures, and in special populations (e.g., pregnant women, patients receiving hemodialysis)

DIAGNOSIS DIFFERENTIAL DIAGNOSIS In the setting of head trauma: Subdural hematoma, subarachnoid hemorrhage, cerebral contusion, brain laceration, diffuse brain swelling WORKUP • Imaging is the mainstay of diagnosis. • Serial head CT is the test most commonly used due to its simplicity, widespread use, and availability. Typical appearance is a “lens shaped,” or “lentiform” hyperdensity (Fig. 2). Box 1 describes CT findings of EDH. • Note: Head CT is not conclusive in 8% of cases possibly due to severe anemia, early scanning (before blood has time to accumulate), and severe hypotension. • Brain MRI: More sensitive. Indicated in situations in which there is a strong clinical suspicion but no evidence of EDH on head CT (Fig. 3). • Angiography: Rarely necessary but may be used to evaluate an underlying vascular lesion. • Note: Lumbar puncture (LP) is contraindicated in EDH due to risk of brain stem herniation. LABORATORY TESTS • Laboratory tests are helpful as adjunct to diagnosis but are not the mainstay of diagnosis or treatment. Anterior meningeal artery

Dura

Posterior meningeal artery

• CBC may be helpful to evaluate for anemia, although in an acute onset of bleeding hemoglobin levels can be normal. • Other tests: Renal functions, electrolytes, liver functions, INR may be helpful depending on the case scenario.

TREATMENT Acute symptomatic EDH is a neurologic emergency that requires surgical treatment to prevent permanent brain injury.

NONPHARMACOLOGIC THERAPY • Immediate surgical decompression, ideally within 1 to 2 hr after traumatic event

FIG. 2  Head computed tomography showing two epidural hematomas in a 23-year-old involved in a motor vehicle accident. Note air bubbles that are a result of linear fracture in the left temporal bone (short arrow).

Epidural hematoma Dura

Compression of cranial nerve III causing ipsilateral pupillary dilation Shift of brainstem

Epidural hematoma

B A

Middle meningeal artery Herniation of uncus of temporal lobe medial to tentorium cerebelli

C Compression of corticospinal and associated pathways

FIG. 1  Epidural hematoma is typically caused by trauma resulting in laceration of the middle meningeal artery. A, The middle meningeal artery. The typical traumatic epidural hematoma is caused by a laceration of this vessel. B and C, A linear fracture of the squamous portion of the temporal bone has torn the middle meningeal artery, which has resulted in an epidural hematoma. (From Rothrock JC: Neurosurgery. In Rothrock JC [ed.]: Alexander’s care of the patient in surgery, ed 13, Philadelphia, 2007, Elsevier.)

Epidural Hematoma BOX 1  Computed Tomography (CT) Findings of Epidural Hematoma • • • • • • • • •

 T appearance: variable white to gray on brain windows C Location: peripheral to brain, variable but usually temporal region Shape: biconvex disc or lens Pearl: does not cross suture lines White swirl sign means active bleeding Significance: may cause mass effect and herniation Look for midline shift Look for effacement of ventricles and sulci Surgical indications: 15-mm thickness or 5-mm midline shift

FIG. 3  Epidural hematoma on magnetic resonance image. Coronal T2-weighted images show hypointense biconvex extraaxial collection in the left temporal region.

• Craniotomy and hematoma evacuation is the treatment of choice. When indicated, identify and ligate the bleeding vessel. • Burr hole evacuation: This involves drilling a hole in the skull to evacuate the hematoma. It is a lifesaving procedure that is indicated if surgical expertise is limited.

ACUTE GENERAL Rx • Cardiopulmonary resuscitation and assessment for disability. • Medical resuscitation maneuvers: Head elevation, hyperventilation, monitoring of vital signs and avoidance of hypotension and hyperthermia, sedation if necessary. • Medications: Osmotic diuresis with IV mannitol, cerebrosedating medications, antiepileptics may be used to treat or, in some situations, prevent seizures. The patient should also be started on a proton pump inhibitor to decrease risks of developing an upper gastrointestinal bleed. • R eversing anticoagulation should be weighed in terms of advantages versus disadvantages. • n ote: Glucocorticoid therapy is not indicated following head injury and may be related to increased mortality. • Evaluation for surgery: The best available evidence points toward advantages of decompression procedures. Nonoperative treatment may only be indicated if the patient has no symptoms, no focal neurologic deficit, no coma (Glasgow coma score >8), and EDH volume is less than 30 ml by CT scan, with clot thickness 4 yr and living with an index case, give close family contacts of the patient (including adults) rifampin 20 mg/kg/day for 4 days (up to 600 mg/day) for prophylaxis. • Role of epinephrine or corticosteroids in the management of epiglottitis is not firmly established. DISPOSITION Invasive H. influenzae infections and epiglottitis are reportable illnesses; this may be particularly important in recognizing an outbreak in a day care center with unvaccinated children. REFERRAL • Close cooperation between the pediatrician or internist, anesthesiologist, and otorhinolaryngologist, especially when epiglottis is visualized and when the patient requires endotracheal intubation. • Best managed in a critical care setting or ICU.

 EARLS & P CONSIDERATIONS The incidence of epiglottitis has diminished markedly since the introduction of the protein conjugate vaccine against H. influenzae serotype B into routine childhood immunization. The mortality rate now in children is about 1% but still remains at about 7% in adults.

Ph

E

SUGGESTED READING Available at ExpertConsult.com T

FIG. 1  Epiglottitis. A lateral soft tissue view of the neck shows a ballooned pharynx (Ph) with swollen epiglottis (E) in the shape of a large thumbprint (arrows). T, Trachea. (From Mettler FA [ed]: Primary care radiology, Philadelphia, 2000, Saunders.)

RELATED CONTENT Epiglottitis (Patient Information) AUTHOR: Glenn G. Fort, MD, MPH

Epiglottitis

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SUGGESTED READING Chen C et al: Acute epiglottitis in the immunocompromised host: case report and review of the literature, Open Forum Infect Dis 5:ofy038, 2018. Westerhuis B, Bietz MG, Lindemann J: Acute epiglottitis in adults: an underrecognized and life-threatening condition, S.D Med 66(8):309-311, 2013.

TABLE E1  Comparison of Croup, Epiglottitis, and Bacterial Tracheitis Croup

Epiglottitis

Bacterial Tracheitis

Peak age

6 mo-3 yr

3-5 yr but seen throughout childhood

Pathologic features

Subglottic inflammation, edema

5-7 yr but can be seen throughout childhood Inflammation and edema of the epiglottis, aryepiglottic folds

Organisms

Parainfluenza virus, RSV, adenovirus

Clinical features

Onset follows URI prodrome consisting of croupy cough, hoarse voice, low-grade fever, inspiratory stridor Steeple sign on PA view of the neck, or normal

Laboratory and radiographic findings Management

Steroids uncommon, aerosolized epinephrine

PA, Posteroanterior; RSV, respiratory syncytial virus; URI, upper respiratory infection. From Marx JA et al: Rosen’s emergency medicine, ed 8, Philadelphia, 2014, Saunders.

Group A beta-hemolytic streptococcus, Staphylococcus aureus, Streptococcus pneumoniae, Haemophilus influenzae Rapid progression of high fever, toxicity, drooling, stridor Thumbprint sign on lateral aspect of the neck, thickened aryepiglottic folds, loss of air in the vallecula Intubation, antibiotics

Bacterial superinfection with inflammation of the tracheal mucosa, copious mucopurulent secretions obstructing the trachea Staphylococcus aureus or mixed flora Several-day prodrome of crouplike illness progressing to toxicity, inspiratory and expiratory stridor, marked distress Normal upper airway structures, shaggy tracheal air column Intubation common, antibiotics rare, intubation

Epiglottitis

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Initial clinical assessment (do not examine epiglottis)

Epiglottitis unlikely

Epiglottitis likely

Mobilize team (anesthesia, pediatrics, pulmonary, surgery, ENT); minimize agitation; give oxygen and racemic epinephrine

Clinical assessment (do not examine epiglottis)

Angioedema, foreign body unlikely

Angioedema, foreign body likely

Mild to moderate distress

Manage

Severe distress

Examine hypopharynx with caution

Epiglottitis unlikely

Epiglottitis excluded

Epiglottitis likely

Manage as viral croup To operating room for examination under anesthesia

Epiglottitis confirmed

Artificial airway then antibiotics, cultures, etc.

Moderate to severe distress

Mild to moderate distress

Humidification Racemic epinephrine Consider intubation under controlled conditions with persistent cyanosis or rapid progression

Humidification

Individualized disposition

Pediatric intensive care unit

FIG. E2  Optimal assessment and management of upper airway obstruction caused by epiglottitis or severe croup. Care must be individualized to reflect resources and logistic issues within a given institution. ENT, Ear, nose, throat. (From Barkin RM et al: Emergency pediatrics, St Louis, 1999, Mosby.)

Epiploic Appendagitis BASIC INFORMATION DEFINITION Epiploic appendagitis is an ischemic infarction of an epiploic appendage caused by the torsion or spontaneous thrombosis of the epiploic appendage central draining vein. Epiploic appendages are fat-containing, peritoneum-bounded sites containing blood vessels that extend from the serosa of the colon. They vary in size from 5 mm to 5 cm and occur throughout the colon but are most numerous in the sigmoid colon. Epiploic appendagitis is usually a benign self-limited condition but can mimic other causes of acute abdomen such as diverticulitis or acute appendicitis. SYNONYMS Appendicitis epiploica Epiplopericolitis Hemorrhagic epiploitis Appendagitis ICD-10CM CODE K55.0 Acute vascular disorders of the intestine

EPIDEMIOLOGY & DEMOGRAPHICS INCIDENCE: Reported in 2% to 7% of patients suspected of diverticulitis and 0.3% to 1% of patients suspected of appendicitis PEAK INCIDENCE: Reported age range of 12 to 82 yr with a peak incidence in the fifth decade of life PREDOMINANT SEX AND AGE: Four times higher in men than women RISK FACTORS: Obesity and strenuous exercise PHYSICAL FINDINGS & CLINICAL PRESENTATION • Patients present with acute or subacute onset of lower abdominal pain.

• Pain is left sided in 60% to 80% of cases and is nonmigratory, but worsens with cough and abdominal stretching. • Less frequent are nausea and vomiting, lowgrade fever, diarrhea, and bloating. • Patients do not appear acutely ill, rebound tenderness is not common, and a mass is only palpable in 10% to 30% of patients.

ETIOLOGY • Epiploic appendage: Small, fat-filled, serosacovered sacs, attached on the external surface of the colon by vascular stalks, from cecum to rectosigmoid junction. There are about 50 to 100 of these, they measure 1 to 2 cm thick and 2 to 5 cm long, and they may serve as a protective and defensive mechanism • Primary epiploic appendagitis: Ischemic infarction of an epiploic appendage either by torsion or spontaneous thrombosis of the epiploic appendage central draining vein, causing vascular occlusion and focal inflammation • Secondary epiploic appendagitis: Inflammation of the epiploic appendage is caused by an external process such as diverticulitis, appendicitis, pancreatitis, or cholecystitis

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • Appendicitis • Diverticulitis • Ovarian torsion, ovarian cyst rupture, ectopic pregnancy • Secondary epiploic appendagitis: Pancreatitis, and cholecystitis are predisposing conditions WORKUP • Physical exam, bloodwork, and radiology

LABORATORY TESTS Complete blood count, erythrocyte sedimentation rate, C-reactive may be normal or mildly elevated IMAGING STUDIES • Abdominal CT: Characteristic finding of round or ovoid lesions of fatty density measuring 1.5 to 3 cm in diameter with a hyperattenuating rim (Fig. E1) and ill-defined fat stranding are seen in mesenteric fat adjacent to the colon. At times the thrombosed vein can be seen as a high attenuated dot within the appendage. • Abdominal ultrasound: At the site of maximum tenderness, a noncompressible hyperechoic small ovoid or round solid mass of adipose tissue is identified between the colon and abdominal wall.

TREATMENT PHARMACOLOGIC THERAPY • Ibuprofen: 600 mg PO q8h for 4 to 6 days • Opiates for pain for 4 to 6 days if needed ACUTE GENERAL Rx Epiploic appendagitis is usually a self-limited, benign condition lasting 3 to 14 days. DISPOSITION • Patients usually do not require hospitalization or antibiotics. • Recurrence rates are low. REFERRAL Surgery is only required for patients who do not improve or who have a complication such as abscess or bowel obstruction.

PEARLS & CONSIDERATIONS • It is important to consider this entity in patients with abdominal pain because the correct diagnosis could avoid unnecessary use of further diagnostic studies, antibiotic therapy, and even surgical therapy. • Although symptoms of epiploic appendagitis generally resolve within 2 weeks, CT findings may persist for 6 months.

RELATED TOPICS Appendicitis (Related Key Topic) Diverticular Disease (Diverticulosis, Diverticulitis, Diverticular Hemorrhage) (Related Key Topic) AUTHOR: Glenn G. Fort, MD, MPH

FIG. E1  Epiploic appendagitis. Axial computed tomography shows a pericolonic focus of inflammation enveloping a focus of fat (arrowhead). This finding is characteristic of epiploic appendagitis. (From Webb WR, et al.: Fundamentals of body CT, ed 4, Philadelphia, 2015, Saunders.)

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Episcleritis   BASIC INFORMATION DEFINITION Episcleritis is an inflammation of the episclera, the thin layer of vascular elastic tissue between the sclera and conjunctiva. ICD-10CM CODE H15.1 Episcleritis

EPIDEMIOLOGY & DEMOGRAPHICS INCIDENCE (IN U.S.): Relatively rare in an ophthalmologic practice PEAK INCIDENCE: Most common in middle and old age PREDOMINANT SEX: None PREDOMINANT AGE: 40s PHYSICAL FINDINGS & CLINICAL PRESENTATION • Red, vascular injection of conjunctiva with engorged and enlarged blood vessels beneath the conjunctiva (Fig. E1) • Pain in area of inflammation that is usually localized (severe pain suggests deeper inflammation; see Scleritis) • Can be diffuse or nodular inflammation ETIOLOGY Associated with collagen-vascular diseases, vasculitis, trauma; usually idiopathic

A

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • Acute glaucoma. • Conjunctivitis and blepharoconjunctivitis. • Scleritis. • Subconjunctival hemorrhage. • Congenital or lymphoid masses. • The differential diagnosis of “red eye” is described in Section II. • Table E1 compares immunologic diseases of the eye. WORKUP Eye examination, general check-up for collagenvascular disease or other autoimmune diseases LABORATORY TESTS Studies for collagen-vascular disease (e.g., antinuclear antibody, erythrocyte sedimentation rate, rheumatoid factor)

TREATMENT NONPHARMACOLOGIC THERAPY Warm compresses ACUTE GENERAL Rx • Topical steroids, 1% prednisolone if no glaucoma; nonsteroidal eye drops if there is a tendency for glaucoma. • N onsteroidal antiinflammatory drugs (NSAIDs): Treat underlying systemic disease.

CHRONIC Rx NSAID eye drops (diclofenac eye drops, ketorolac ophthalmic solution) DISPOSITION Close follow-up needed REFERRAL To ophthalmologist if patient unresponsive to treatment after a few days

PEARLS & CONSIDERATIONS COMMENTS • Can rarely be associated with collagenvascular disease. • Episcleritis has a tendency to recur. • May occur with systemic autoimmune disease. Workup for autoimmune disease is often negative, more likely with scleritis (50%). Ask about other symptoms to find autoimmune disorders, helps to guide workups. • Episcleritis is a benign and self-limiting condition; loss of vision only occurs with steroidinduced cataracts. Prolonged topical steroid treatment is worse than the condition itself. RELATED CONTENT Episcleritis (Patient Information) Scleritis (Related Key Topic) AUTHOR: R. Scott Hoffman, MD

B

FIG. E1  A, Diffuse episcleritis with maximal vascular congestion in the superficial episcleral plexus. B, Scleritis with congestion of the deep vascular plexus. (Fig. A, Courtesy of P Watson. Fig. B, In Bowling B: Kanski’s clinical ophthalmology, a systemic approach, ed 8, Philadelphia, 2016, Elsevier.)

Episcleritis

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TABLE E1  Immunologic Diseases of the Eye Clinical Parameters

Ocular cicatricial pemphigoid

Systemic pemphigoid Females predominate Peak incidence: 60-70 yr of age

Severe conjunctival redness Chronic conjunctivitis Mucous discharge Conjunctival scarring Inturning eyelids and eyelashes Breakdown of corneal and conjunctival epithelium Sight threatening

Mild: Dapsone Severe: Systemic steroids Immunosuppressive drugs

Peripheral ulcerative keratitis

Mild: Both females and males affected Any age Example: Associated with staphylococcal blepharitis Necrotizing: Mooren ulcer Both females and males affected Adults Unilateral involvement (worldwide) Bilateral involvement (males of African descent) History of infectious ocular disease History of rheumatic disease

Mild: Topical steroids and antibiotics Necrotizing: Topical steroids Systemic steroids and other immunosuppressive drugs Surgical intervention

Episcleritis

Females predominate Peak incidence: 40 yr of age

Mild: Pain Photophobia Tearing Redness Peripheral infiltrate on ocular examination Not sight-threatening Necrotizing: Pain Photophobia Tearing Redness Perilimbal ulceration Sight-threatening Conjunctival redness Diffuse or nodular Minimal pain Not sight threatening

Scleritis

Females predominate Peak incidence: 40 yr of age; rare in children Anterior scleritis: diffuse, nodular, necrotizing Posterior scleritis: Scleritis associated with systemic disease, rarely with ocular infection (40%)

Uveitis

Associated with systemic and infectious disease (40%) All ages Occurrence rates: Anterior uveitis: 70% Intermediate uveitis: 20% Posterior uveitis: 10%

NSAIDs, Nonsteroidal antiinflammatory drugs. From Adkinson NF et al: Middleton’s allergy principles and practice, ed 8, Philadelphia, 2014, Saunders.

Signs/Symptoms

Treatment

Disease

Anterior scleritis: Deep, boring pain Diffuse ocular redness Raised nodules Scleral ulceration Necrotizing scleritis: Sight threatening Posterior scleritis: Pain with eye movement Sight threatening Anterior: Redness Pain Photophobia Anterior chamber cells and fibrin Pupil miotic Intermediate: Bilateral involvement Mildly hazy/blurry vision Posterior: Photophobia Pain Sight threatening

Cool compress Treat associated blepharitis Artificial tears Topical NSAIDs Topical steroids Topical steroids ineffective Periocular steroid injection ­acceptable Oral NSAIDs, systemic steroids, immunosuppressive drugs

Anterior: Topical steroids Intermediate: Periocular steroids Systemic steroids Posterior: Systemic steroids Immunosuppressive drugs

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Epistaxis BASIC INFORMATION DEFINITION Epistaxis is defined as bleeding from the nose or nasal hemorrhage and is classified as either anterior or posterior. SYNONYM Nosebleed ICD-10CM CODE R04.0 Epistaxis

EPIDEMIOLOGY & DEMOGRAPHICS • Epistaxis accounts for one of every 200 emergency department visits in the U.S. annually. • It increases in frequency after age 20 yr and reaches the highest levels among the elderly population. • More than 80% of cases of epistaxis are anterior in origin (Little area) and occur from Kiesselbach plexus. • Only 5% of patients with epistaxis have posterior bleeds. PHYSICAL FINDINGS & CLINICAL PRESENTATION • Nosebleed • Hypotension and hemodynamic instability with acute, severe epistaxis ETIOLOGY • Approximately 90% of epistaxis events are idiopathic. • Common identifiable causes are: 1. Cold, dry environment 2. Trauma (nose picking, accidents, and physical altercations) 3. Structural deformities (septal deviations or spurs, chronic perforations) 4. Inflammatory (rhinosinusitis, nasal polyposis) 5. Allergies 6. Foreign bodies in the nasal cavity 7. Tumors (juvenile angiofibroma) 8. Irritants 9. Hypertension 10. C oagulopathy (hemophilia, von Willebrand disease, thrombocytopenia) 11. Osler-Weber-Rendu disease 12. Renal failure 13. Drugs: Aspirin, nonsteroidal antiinflammatory drugs, warfarin, alcohol, sildenafil, and tadalafil 14. Blood vessel disorders (connective tissue disease, hereditary hemorrhagic telangiectasia) 15. Pseudoaneurysm and aneurysm of the internal carotid artery might present as epistaxis

IMAGING STUDIES Radiographic studies are usually not helpful.

DIAGNOSIS A good attempt should be made to directly visualize the source of bleeding to confirm the diagnosis and determine the best treatment. Fig. E1 illustrates anatomical sites for epistaxis.

DIFFERENTIAL DIAGNOSIS Pseudoepistaxis must be ruled out. Common extranasal sites of bleeding that can simulate epistaxis include: • Pulmonary hemoptysis • Bleeding esophageal varices • Tumor bleeding from the pharynx, larynx, or trachea WORKUP The workup should include laboratory blood testing to exclude obvious causes. Type and cross in anticipation of transfusion if the bleeding is severe. LABORATORY TESTS • Hemoglobin and hematocrit • Platelet count • Blood urea nitrogen and creatinine • Coagulation studies (prothrombin time and partial thromboplastin time) • Type and crossmatching of blood products

TREATMENT NONPHARMACOLOGIC THERAPY • Digital compression or pinching of the lower soft cartilaginous part of the nose for 10 min is the method of choice. • Use cotton or tissue plug. • The patient should be sitting and leaning forward, breathing through the mouth, allowing blood to flow out of the nostrils as opposed to bending backward, which would allow the blood to flow down the throat. • Application of cold compresses to the bridge of the nose to cause a vasoconstrictive effect; the patient may also suck on ice to achieve this effect. ACUTE GENERAL Rx Anterior epistaxis: • Local vasoconstriction is performed by moistening a cotton pledget with either: 1. 4% lidocaine with 1:1000 epinephrine 2. 4% lidocaine with 1% phenylephrine (Neo-Synephrine) 3. 4% lidocaine with 0.05% oxymetazoline (Afrin)

Internal carotid artery Ophthalmic artery Anterior ethmoidal artery

Posterior ethmoidal artery

Little’s area

Septal branch

Superior labial artery

Greater palatine artery

Facial artery

Branches of sphenopalatine artery

Maxillary artery

External carotid artery

FIG. E1  Anatomical sites for epistaxis. (From McLarnon CM, Carrie S: Epistaxis, Surgery (Oxford) 30(11):584-589, 2012.)

Epistaxis 4. 4 % cocaine or cocaine 25% in paraffin base ointment and inserting the pledget into the nasal cavity with bayonet forceps • Cauterization with silver nitrate or trichloroacetic acid is performed once hemostasis is achieved. • Anterior nasal packing is needed when local measures are unsuccessful. Nasal packing is performed under local anesthesia and is done by inserting Vaseline gauze strips in layers from the floor of the nasal cavity to the front entrance of the nasal orifice. Enough pressure is placed to tamponade the epistaxis. • Other commercially available nasal packing uses sponge packs that expand when exposed to blood or moisture and can be used for anterior epistaxis. Posterior epistaxis: • Posterior nasal packing: 1. Commercially available nasal sponge packing can be applied 2. Rolled gauze technique • Foley catheter balloon insertion into the nasopharynx can be tried in patients with posterior epistaxis. Newer agents in the treatment of epistaxis: • Quick clot hemostatic agent, available OTC. When it comes in contact with blood in and around a wound, it absorbs the smaller water molecules from the blood to promote rapid clotting • FloSeal hemostatic matrix, a combination of human thrombin, gelatin matrix, and calcium chloride, which are mixed together and placed at bleeding site • Recombinant factor VIIa, generally reserved for uncontrolled epistaxis

CHRONIC Rx • If acute treatment fails to stop the bleeding or the site of bleeding cannot be located, electrocautery or endoscopic cauterization can be used.

532.e7 • Electrocautery is performed after suitable anesthesia, such as application of a topical anesthetic followed by local anesthetic injection. Only one side of the nasal septum should be cauterized at a time because perforation can result from bilateral cauterization. • Arterial ligation or embolization has been used in refractory posterior epistaxis. • For cases involving irritated or inflamed mucosa, a conservative regimen of triamcinolone 0.025%, Nemdyn, Nasalate, or equivalent cream should be applied once a week, combined with nightly application of a small quantity of petroleum jelly to the septum before bedtime.

DISPOSITION • Most cases of anterior epistaxis from Kiesselbach plexus can be stopped by nasal compression and local vasoconstriction or cauterization. • Nasal packing with gauze or sponge can control 90% of anterior epistaxis. • Anterior and posterior packs are removed in 2 to 3 days. Hospital admission should be considered in patients who cannot be expected to return for prompt follow-up because prolonged packing increases the risk of pressure necrosis, toxic shock syndrome, sinus infections, and other complications. • Although rare, epistaxis can lead to death by aspiration of blood, hemodynamic compromise from rapid excessive blood loss, or toxic shock syndrome. REFERRAL • If epistaxis cannot be controlled, an earnose-throat (ENT) specialist should be called for assistance. • ENT specialist should be consulted in any patient with posterior epistaxis requiring posterior packing.

 EARLS & P CONSIDERATIONS COMMENTS • Silver nitrate cauterization, if done on both sides of the nasal septum, can lead to septal perforation and should be discouraged. • If anterior nasal packing is done, broad-spectrum antibiotics (e.g., amoxicillin-clavulanate 250 mg PO tid or trimethoprim-sulfamethoxazole 1 tablet PO bid) are used until the anterior packs are removed. Although it is customary to place patients on antibiotics to prevent sinusitis from obstruction, there is no proof that this is effective. • Complications of nasal packing include: 1. Aspiration 2. Dislodged packing 3. Infection 4. Nasal trauma • Traditional risk factors for epistaxis, including nasal perforation, nasal septum deviation, rhinitis, sinusitis, and upper respiratory tract infection, do not increase the risk of recurrent epistaxis. Significant risk factors for recurrent epistaxis include congestive heart failure, diabetes mellitus, hypertension, and a history of angina. Warfarin use also increases risk of recurrence, independent of INR. Aspirin and clopidogrel do not increase the risk of recurrent epistaxis.1 RELATED CONTENT Nosebleeds (Patient Information) AUTHOR: Tanya Ali, MD

1Abrich

V et al: Risk factors for recurrent spontaneous epistaxis, Mayo Clin Proc 89(12):1636-1643, 2014.

Epstein-Barr Virus Infection BASIC INFORMATION DEFINITION Epstein-Barr virus infection refers to a disease caused by Epstein-Barr virus (EBV), a human herpesvirus. SYNONYMS Infectious mononucleosis (IM) Kissing disease

EPIDEMIOLOGY & DEMOGRAPHICS INCIDENCE (IN U.S.): 5 cases/100,000 persons per yr of IM PREDOMINANT SEX: Neither, although peak incidence occurs about 2 yr earlier in women PREDOMINANT AGE: • Clinical evidence of IM: Occurs most commonly at ages 15 to 24 yr • EBV infection: Occurs earlier in life in lower socioeconomic groups PHYSICAL FINDINGS & CLINICAL PRESENTATION • Most EBV infections either are asymptomatic or cause a nonspecific viral illness. • Incubation period is 1 to 2 mo, possibly followed by a prodrome of anorexia, low-grade fever, malaise, headache, and chills; after several days, clinical triad of pharyngitis, moderate to high fever, and adenopathy may appear, accompanied by fatigue and malaise. • Pharyngitis is usually the most severe symptom; white or necrotic exudates are common. • Symmetrical lymphadenopathy is most prominent in the posterior more than anterior cervical region but may be diffuse. • Splenomegaly (50% of cases) is possible, most commonly during the second week of illness. • Maculopapular or morbilliform rash is uncommon but will often occur in patients who receive ampicillin (Fig. E1). Patients may have palatal petechiae, periorbital, or palpebral edema. Mucocutaneous oral hairy leukoplakia (OHL), which is associated with intense EBV replication and the action of

ETIOLOGY • EBV is a ubiquitous virus. • Infection during childhood is much less likely to cause significant illness. • Frequency of IM in late adolescence is attributed to the onset of social contact between the sexes. • Close personal contact is usually necessary for transmission, although EBV is occasionally transmitted by blood transfusion; transfer

via saliva while kissing may be responsible for many cases.

E

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • Heterophile-negative IM caused by cytomegalovirus (CMV) • Although clinical presentation similar, CMV more frequently follows transfusion • Bacterial and viral causes of pharyngitis • Toxoplasmosis • Acute retroviral syndrome of HIV • Lymphoma • Lyme disease WORKUP Heterophile antibody and CBC with blood smear. Table 2 describes frequently determined EBVspecific antibodies. LABORATORY TESTS • Increased WBC common, with a relative lymphocytosis of more than 50% and neutropenia identified. • Hallmark of IM: Atypical lymphocytes of more than 10% (not pathognomonic) are found. • Mild thrombocytopenia is present. • Falling hematocrit signals the possibility of splenic rupture or immune hemolytic anemia. • Elevated hepatocellular enzymes and cryoglobulins are found in most cases. • Heterophile antibody: 1. As measured by the monospot test, may be positive at presentation or may appear later in the course of illness. Its accuracy is 71% to 90% but has a 25% falsenegative rate in the first week of illness. 2. A negative test should be repeated in 1 wk if clinical suspicion is high. 3. A false-positive test has been reported with primary HIV infection. • Viral capsid antigen (VCA) IgG and IgM are rarely used for diagnosis, but better value in children because heterophile antibody is negative in most children younger than 8 yr.

TABLE 1  Epstein-Barr Virus (EBV)-Associated Malignancies Malignancy

EBV Frequency (%)

Hodgkin disease Non-Hodgkin lymphomas Burkitt lymphoma Diffuse large B-cell lymphoma and CD30+ Ki-1+ anaplastic large cell lymphoma Lymphomatoid granulomatosis T-cell–rich B-cell lymphoma Angioimmunoblastic lymphoma T-cell, NK-cell, and T/NK-cell lymphomas Nasopharyngeal carcinoma Gastric adenocarcinoma Pyothorax-associated lymphoma Leiomyosarcoma in immunocompromised patients

∼40 20-95 10-35 80-95 20 >80 30-90 >95 5-10 >95 >95

NK cell, Natural killer cell; T cell, T lymphocyte cell. From Hoffman R et al: Hematology: basic principles and practice, ed 5, Philadelphia, 2009, Churchill Livingstone.

Diseases and Disorders

ICD-10CM CODES B27.80 Other infectious mononucleosis without complication B27.81 Other infectious mononucleosis with polyneuropathy B27.82 Other infectious mononucleosis with meningitis B27.89 Other infectious mononucleosis with other complication B27.90 Infectious mononucleosis, unspecified without complication B27.91 Infectious mononucleosis, unspecified with polyneuropathy B27.92 Infectious mononucleosis, unspecified with meningitis B27.99 Infectious mononucleosis, unspecified with other complication

EBV-encoded proteins such as latent membrane protein-1, may occur. • Possible IM presentation: Fever and adenopathy without pharyngitis. • Nausea, vomiting, and anorexia are frequent in patients with IM, probably reflecting mild hepatitis encountered in 90% of infected individuals. • Although complications such as spleen rupture, airway obstruction, and malignancy may be severe and fatal, they are uncommon and tend to resolve completely. • Hematologic involvement includes hemolytic or aplastic anemia, thrombocytopenia, thrombotic thrombocytopenic purpura/hemolytic-uremic syndrome, and disseminated intravascular coagulation (DIC). Pneumonia, myocarditis, pancreatitis, mesenteric adenitis, myositis, and glomerulonephritis may occur as well. Nervous system involvement includes Guillain-Barré syndrome, facial nerve palsy, meningoencephalitis, aseptic meningitis, transverse myelitis, peripheral neuritis, and optic neuritis. • IM is usually a self-limited illness. Acute symptoms resolve in 1 to 2 wk, but symptoms of malaise and fatigue often persist for months. • EBV is related to lymphoproliferative syndromes in transplant recipients and in AIDS patients. • Increasing evidence showing an association between EBV infection and African Burkitt, B-cell or T-cell lymphoma, and nasopharyngeal carcinoma. Table 1 describes EBVassociated malignancies.

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Epstein-Barr Virus Infection TABLE 2  Frequently Determined EBV-Specific Antibodies Antibody Specificity

Positive in IM (%)

Time of Appearance in IM

Persistence

Comments

Viral Capsid Antigen VCA-IgM

100

At clinical presentation

4-8 weeks

VCA-IgG Early Antigen Anti-D

100

At clinical presentation

Lifelong

Highly sensitive and specific; of major diagnostic utility Useful for documentation of past EBV infection

70

Peaks 3-4 weeks after onset

3-6 months

Anti-R

Low

EBNA

100

2 weeks to several months after onset 3-4 weeks after onset

2 months to >3 yr Lifelong

Correlates with disease severity; seen in NPC patients Occasionally seen with unusually severe cases; seen in African Burkitt lymphoma patients Presence excludes primary EBV infection

EBNA, EBV nuclear antigen; EBV, Epstein-Barr virus; Ig, immunoglobulin; IM, infectious mononucleosis; NPC, nasopharyngeal carcinoma; VCA, viral capsid antigen. Adapted from Schooley RT: Epstein-Barr virus (infectious mononucleosis). In Mandell GL et al (eds): Principles and practice of infectious diseases, Philadelphia, 2010, Churchill Livingstone.

• PCR DNA for CMV is the test of choice in transplant recipients who develop lympho­ proliferative syndromes.

IMAGING STUDIES Chest radiograph examination: • May rarely show infiltrates • Possible elevated left hemidiaphragm with splenic rupture

TREATMENT NONPHARMACOLOGIC THERAPY • Supportive including rest • Splenectomy if rupture occurs • Transfusions for severe anemia or thrombocytopenia ACUTE GENERAL Rx • Pharmacologic therapy is not indicated in uncomplicated illness. • Avoid aspirin due to the risk of Reye syndrome. • Avoid ampicillin and amoxicillin as their use can frequently precipitate a nonallergic rash. Azithromycin has also been implicated. • Use of steroids is suggested in patients who have severe thrombocytopenia, hemolytic

anemia, impending airway obstruction resulting from enlarged tonsils, or fulminant liver failure. Prednisone 60 to 80 mg PO qd for 3 days, then tapered over 1 to 2 wk. • Although it may reduce initial viral shedding, there is little evidence to support the use of antiviral agents such as acyclovir in the management of IM.

CHRONIC Rx An extremely rare, chronic form of IM with persistent fevers and fatigue has been described and should be differentiated from chronic fatigue syndrome, which is not related to EBV. DISPOSITION Eventual resolution of all symptoms REFERRAL If more than mild illness

PEARLS & CONSIDERATIONS • Epstein-Barr infection will occur in 95% of the world population at some point in life. • It is felt the antibiotic-induced rash in IM is a transient virus-mediated immune alteration

that sets the stage for loss of antigenic tolerance and the development of a reversible, delayed-type hypersensitivity reaction to the antibiotic

COMMENTS Avoidance of contact sports during the first month of illness because splenic rupture can occur even in the absence of clinically detectable splenomegaly in 0.1% to 0.5% of patients. SUGGESTED READINGS Available at ExpertConsult.com RELATED CONTENT Epstein-Barr Virus Infection (Patient Information) Mononucleosis (Related Key Topic) AUTHOR: Glenn G. Fort, MD, MPH

Epstein-Barr Virus Infection SUGGESTED READINGS Shepard RJ: Exercise and the athlete with infectious mononucleosis, Clin J Sport Med 27:168-178, 2017. Thompson DF, Ramos CL: Antibiotic-induced rash in patients with infectious mononucleosis, Ann Pharmacother 51:154-162, 2017. Womack J, Jimenez M: Common questions about infectious mononucleosis, Am Fam Physician 91(6):372-376, 2015.

FIG. E1  Patient with infectious mononucleosis and ampicillin-induced rash. Maculopapular rash extends over the trunk and extremities. Rash frequently has a violaceous hue and is often accompanied by pruritus. (Bennett JE et  al: Mandell, Douglas, and Bennett’s principles and practice of infectious diseases, ed 8, Philadelphia, 2015, Saunders.)

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ALG BASIC INFORMATION DEFINITION Erectile dysfunction (ED) is the persistent inability to achieve or sustain a penile erection of adequate rigidity to make sexual penetration possible or satisfactory.

ICD-10CM CODES N48.4 Impotence of organic origin F52.2 Failure of genital response F52.9 Unspecified sexual dysfunction, not caused by organic disorder or disease N52.01 Erectile dysfunction due to arterial insufficiency N52.02 Corporo-venous occlusive erectile dysfunction N52.03 Combined arterial insufficiency and corporo-venous occlusive erectile dysfunction N52.1 Erectile dysfunction due to diseases classified elsewhere N52.2 Drug-induced erectile dysfunction N52.31 Erectile dysfunction following radical prostatectomy N52.32 Erectile dysfunction following radical cystectomy N52.33 Erectile dysfunction following urethral surgery N52.34 Erectile dysfunction following simple prostatectomy N52.39 Other post-surgical erectile dysfunction N52.8 Other male erectile dysfunction N52.9 Male erectile dysfunction, unspecified DSM-5 CODE 302.72 Failure of genital response

EPIDEMIOLOGY & DEMOGRAPHICS PREVALENCE (IN U.S.): • Increases with age and presence of specific medical comorbidities • Approximately 8% in the 20s to 30s, 18% in the 50s, 25% in the 60s, 37% in the 70s, 80% in the 80s PREDOMINANT SEX: By definition, only in males PREDOMINANT AGE: Increases with age RISK FACTORS: Age, coronary artery disease, peripheral vascular disease, hypertension, hypogonadism, diabetes mellitus, hypercholesterolemia, prostate surgery, neurologic injury, numerous medications, alcohol, smoking or drug abuse, obesity, obstructive sleep apnea, systemic sclerosis; psychological: performance anxiety ETIOLOGY • A classification of male erectile dysfunction is described in Box 1. • Most cases involving men older than 50 yr are caused by organic problems related to

• Vascular disease: History of hypertension (HTN), peripheral vascular disease, ischemic heart disease, diabetes, smoking. In approximately 40% of men >50 yr, the primary cause of ED is related to atherosclerotic disease, diabetes mellitus (DM), neuropathy, or vascular disease. • Obesity and metabolic syndrome. • Medication side effects: Antihypertensives such as thiazides and clonidine, guanethidine or methyldopa (consider change to ACE inhibitors and calcium channel blockers with lower reported incidence of ED); antiandrogens such as spironolactone, finasteride, ketoconazole; cimetidine (but not ranitidine or famotidine); antidepressants such as selective serotonin reuptake inhibitors [SSRIs]; and antipsychotics. Table 1 summarizes drug-induced erectile dysfunction and suggested alternatives.

BOX 1  Classification of Male Erectile Dysfunction Organic I. Vasculogenic A. Arteriogenic B. Cavernosal C. Mixed II. Neurogenic III. Anatomic IV. Endocrinologic Psychogenic I. Generalized A. Generalized unresponsiveness 1. Primary lack of sexual arousability 2. Aging-related decline in sexual arousability B. Generalized inhibition 1. Chronic disorder of sexual intimacy II. Situational A. Partner-related 1. Lack of arousability in specific relationship 2. Lack of arousability owing to sexual object preference 3. High central inhibition owing to partner conflict or threat B. Performance-related 1. Associated with other sexual dysfunction (e.g., rapid ejaculation) 2. Situational performance anxiety (e.g., fear of failure) C. Psychological distress or adjustment related 1. Associated with negative mood state (e.g., depression) or major life stress (e.g., death of partner) From Wein AJ et al: Campbell-Walsh urology, ed 11, Philadelphia, 2016, Elsevier.

TABLE 1  Drug-Induced Erectile Dysfunction and Suggested Alternatives Class

Known to Cause Erectile Dysfunction

Antihypertensives

Thiazide diuretics General β blockers

Psychotropics

Antipsychotics Antidepressants Anxiolytics Androgen receptor antagonists Luteinizing hormone–releasing hormone agonists 5α-Reductase inhibitors

Antiandrogen

Opiates Antiretroviral agents Tobacco Alcohol

Large amount

Suggested Alternatives α-Blockers Calcium channel blockers Specific β-blockers Angiotensin-converting enzyme inhibitors Angiotensin II receptor antagonists Anxiolytic (buspirone); antidepressant (bupropion)

Quit smoking Small amount

From Wein AJ et al: Campbell-Walsh urology, ed 11, Philadelphia, 2016, Elsevier.

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E

Diseases and Disorders

SYNONYMS ED Impotence Male erectile disorder Sexual dysfunction (a nonspecific term)

neurologic, hormonal, or vascular abnormalities or prescription or recreational drugs. In organic ED, nocturnal penile tumescence is generally diminished or absent, and ED is also experienced during private masturbation and across partners. • Psychogenic ED results from mental stress, depression, a stressful partner relationship, a partner’s sexual and mental health problems, and performance anxiety. Performance anxiety is extremely common and is characterized by a focus on the performance outcome of sex (i.e., obtaining and maintaining an erection) rather than a focus on the process and enjoyment of sex. Psychogenic ED is characterized by normal nocturnal penile tumescence and/or erections associated with erotic material or other partners, and by otherwise negative medical test results.

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Erectile Dysfunction

ALG

• Excessive alcohol and nicotine use. • Recreational drugs, including cocaine, heroin, amphetamines, and marijuana. These may increase libido but impair performance. • Hormonal dysfunction such as testosterone deficiency (decreases libido and erection), hypothyroidism or hyperthyroidism, hyper­ prolactinemia, and adrenal insufficiency. • Neurogenic causes including spinal cord lesions, cortical lesions, and peripheral neuropathies. • Trauma or pelvic surgeries such as radical prostatectomy or cystectomy.

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • A useful tool to diagnose/evaluate ED severity is the Sexual Health Inventory for Men (SHIM). • Distinguish psychogenic and organic contributions to ED. • Evaluate for underlying etiology of organic ED and comorbid psychiatric condition. WORKUP • Clinical history should include time course (abrupt onset may correlate with reversible cause such as medications, psychosocial stress, psychiatric complaint, trauma; nonsustained erection may be secondary to anxiety or vascular steal syndrome), cause (psychogenic vs. organic), and change in libido. Box 2 describes symptoms suggesting neurologic sexual impairment. • Report of spontaneous nocturnal or morning erections indicate intact neurologic reflexes and penile blood flow. • Decreased libido may indicate endocrinologic or psychogenic cause. • If possible, interview partner regarding partner’s sexual function, relationship satisfaction, and mental health history. • Medical and social history should address cardiac disease symptoms and risk factors (HTN, DM, hyperlipidemia, smoking, and substance abuse), pelvic surgery, medications, and mental health. Coronary artery calcium score (CAC) is best indicator of subclinical coronary artery disease. BOX 2  Symptoms Suggesting Neurologic Sexual Impairment

• Physical examination to check blood pressure, visual field defects to evaluate for pituitary tumors; femoral and peripheral pulses, femoral bruits; gynecomastia; neuronal damage (genital sensation, cremasteric reflex); direct penile damage (e.g., plaque formation such as Peyronie disease); prostate examination; or testicular atrophy and other secondary sexual characteristics. Signs of neurologic sexual impairment are summarized in Box 3.

LABORATORY TESTS Screen for diabetes mellitus with fasting glucose. Consider lipid panel, thyroid-stimulating hormone, morning serum testosterone (free and total). If decreased testosterone, check prolactin, folliclestimulating hormone, and luteinizing hormone. IMAGING STUDIES Imaging studies are rarely performed except in situations of pelvic trauma or surgery. OTHER STUDIES • Nocturnal penile tumescence testing is very specific for distinguishing psychogenic versus organic causes. • Neurogenic etiologies examined by the cremasteric reflex (inner-thigh touch elicits scrotal contraction), the bulbocavernosus reflex, or the pudendal-evoked response. • Intracorporeal injection of prostaglandin E1 to distinguish vascular and nonvascular etiologies (erection is achieved in patients with normal vascular systems). If no erection with direct injection of vasoactive substance, consider duplex ultrasound of penile vasculature. • In patients without an obvious cause of ED, consider screening for cardiovascular disease prior to starting treatment.

TREATMENT (FIG. 1) NONPHARMACOLOGIC THERAPY • Various psychotherapeutic approaches: Cognitive-behavioral therapy preferred; success rates decrease with advancing age and duration of symptoms. BOX 3  Signs of Neurologic Sexual Impairment

Continual erectile dysfunction Absence of morning erections No erection or orgasm during masturbation or sex with different partners Related somatic complaints Sensory loss in genitals, pelvis, or legs Urinary incontinence Certain neurologic conditions Spinal cord injury Diabetic neuropathy Multiple sclerosis Herniated intervertebral disk Use of many medications

Signs of spinal cord injury Paraparesis or quadriparesis Leg spasticity Urinary incontinence Signs of autonomic nervous system injury Orthostatic hypotension or lightheadedness Anhidrosis in groin and legs Urinary incontinence Retrograde ejaculation Signs of peripheral nervous system injury Loss of sensation in the genitals, “saddle area,” and legs Paresis and areflexia in legs Scrotal, cremasteric, and anal reflex loss

From Kaufman DM et al: Kaufman’s clinical neurology for psychiatrists, ed 8, Philadelphia, 2017, Elsevier.

From Kaufman DM et al: Kaufman’s clinical neurology for psychiatrists, ed 8, Philadelphia, 2017, Elsevier.

• Psychosexual therapy is first line for psychogenic ED. Psychosexual therapy may be used as for adjunctive therapy in ED from any cause to address contributing, performance anxiety, social, and relationship issues. • Performance anxiety is best addressed by sensate focus in which a couple is asked to refrain from sexual penetration but enjoy erotic touching. • Mechanical vacuum devices (function by drawing blood into corpus cavernosum) are 70% to 90% effective but are difficult to use and subject to noncompliance. • Incorporate vascular risk factor reduction including counsel on diet, exercise, smoking cessation, ETOH intake and screening/treatment for HTN, insulin resistance, and hypercholesterolemia as appropriate. Trials have shown that lifestyle modification and pharmacotherapy for cardiovascular risk factors are effective in improving sexual function in men with ED.

ACUTE GENERAL Rx • First-line treatment: In setting of sexual stimulation, four selective phosphodiesterase type 5 (PDE5) inhibitors (Table 2) prolong nitric oxide–induced vasodilation by increase of intracavernosal cyclic guanosine monophosphate levels. Sildenafil (Viagra) and vardenafil (Levitra, Staxyn) can be taken 30 to 60 min before sexual activity, and both are effective for about 4 hr. Avanafil (Stendra) can be taken 15 to 30 min before sexual activity and is effective for about 6 hr. Tadalafil (Cialis) can be taken several hours before sexual activity (although 50% respond within 30 min) and lasts up to 36 hr. All four PDE5 inhibitors have similar efficacy and tolerability, but tadalafil has a longer duration of action and is less affected by high-fat meals and alcohol. Counsel patients to avoid high-fat meals and excessive alcohol when taking PDE5 inhibitors, as they may impede effectiveness. • With PDE5 inhibitors, avoid concomitant use of nitrates (absolute contraindication), drugs that inhibit or induce cytochrome P450 CYP3A4, and drugs that prolong the QT interval. Caution in men on alpha-adrenergic blocker therapy because of concern for hypotension; start the lowest dose of PDE5 inhibitor. Caution in men who have had myocardial infarction in the past 6 mo, resting hypotension or uncontrolled hypertension, unstable angina, positive exercise stress test or poor exercise tolerance. Counsel on side effects of headache, flushing, dyspepsia, nasal congestion, changes in color perception (including blue vision for sildenafil and vardenafil but not tadalafil), sudden hearing loss, and priapism (rare). Nonarteritic anterior ischemic optic neuropathy is also a rare association with sildenafil and tadalafil. Consider counseling on safe sexual practices when prescribing PDE5 inhibitors. • Second-line treatment if PDE5 inhibitors fail: Self-injection with intraurethral alprostadil (prostaglandin E1 [medicated urethral suppository]) applied into meatus of penis before intercourse; or intracavernosal injections of vasodilators (e.g., papaverine or prostaglandin E1). Consider combining intraurethral

ALG alprostadil with PDE5 inhibitor. Relatively high success with self-injection, but attrition is high (Table E3). • Second-line treatment alternative: Vacuum constriction pump; has variable satisfaction rate.

Psychosexual counseling of the couple

DISPOSITION • Psychogenic-acquired ED will remit spontaneously in 15% to 30% of cases. • Lifelong ED is usually a chronic and unremitting condition.

Optimize medical management of comorbid conditions

Evaluate cardiovascular risk and potential contraindications to PDE5I use

No contraindications to PDE5I use

PDE5I use contraindicated

Initiate PDE5I therapy

Satisfactory clinical response

Unsatisfactory clinical response

• Evaluate: appropriate use, compliance, couple relationship, AEs, or fear of AEs • Escalate dose to maximal allowed or maximal tolerable dose

Recommend second-line therapies: vacuum constriction device, intraurethral alprostadil, or intracavernosal alprostadil

Satisfactory clinical response

Penile implant

FIG. 1  An algorithmic approach to the treatment of erectile dysfunction in men. AE, Adverse effects; PDE5I, phosphodiesterase 5 inhibitor. (From Melmed S et al: Williams textbook of endocrinology, ed 12, Philadelphia, 2011, WB Saunders.)

PEARLS & CONSIDERATIONS • ED is commonly evaluated and treated by primary care physician; refer to urologist if oral therapy fails or surgery is required. • PDE5 inhibitors are treatment of choice for most causes of ED. Main contraindications are nitrate use and decompensated cardiac disease. Caution in patients on alpha-adrenergic blockers and with blood pressures at extreme ends (significant hypotension or hypertension). • For optimal response, patients should be appropriately informed of proper use, precautions, and adverse effects of PDE5 inhibitors. Try six to eight times at optimal doses before declaring PDE5 inhibitors a failure. Consider switching among the four PDE5 inhibitors if one fails. • Men with ED are at increased risk of coronary, cerebrovascular, and peripheral vascular diseases. Screen for cardiovascular risk factors in these patients.

RELATED CONTENT Erectile Dysfunction (Patient Information) Ejaculation and Orgasm Disorders (Related Key Topic) Hypogonadism, Male (Related Key Topic) AUTHOR: John P. Wincze, PhD

TABLE 2  Comparison of Four Phosphodiesterase Type 5 Inhibitors Currently Available in the United States

Cmax (ng/ml) Tmax (hr) Onset of action (min) Half-life (hr) Bioavailability Fatty food Recommended dosage Side effects Headache, dyspepsia, facial flushing Backache, myalgia Blurred/blue vision Precaution with antiarrhythmics Contraindication with nitrates

E

REFERRAL • Refer if psychotherapy, sexual focused therapy, or invasive organic treatment required • Refer to urology if PDE5 inhibitors fail or sudden onset occurs after penile trauma

SUGGESTED READINGS Available at ExpertConsult.com

Unsatisfactory clinical response

Unsatisfactory response Periodic medical follow-up

• Situational ED may remit with changes in social environment and reducing performance anxiety.

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Sildenafil

Vardenafil

Tadalafil

Avanafil

450 0.8 15-60 3-5 40% Reduced absorption 25, 50, 100 mg

20.9 0.7-0.9 15-60 4-5 15% Reduced absorption 5, 10, 20 mg

378 2 15-120 17.5 Not tested No effect 5, 10, 20 mg

2153 0.3-0.5 15-60 3-5 30% Reduced absorption 50, 100, 200 mg

Yes

Yes

Yes

Yes

Rare Yes No

Rare Rare Yes

Yes Rare No

Rare No No

Yes

Yes

Yes

Yes

Cmax, Maximal plasma concentration; half-life, time required for elimination of one half of the medication from plasma; Tmax, time required to attain Cmax. From Wein AJ et al: Campbell-Walsh urology, ed 11, Philadelphia, 2016, Elsevier.

Diseases and Disorders

CHRONIC Rx • Psychosexual therapy is helpful as an adjunctive treatment. • Psychogenic impotence: PDE5 inhibitors are effective in patients with depression because tissues, nerves, hormones, and vasculature are normal. PDE5 inhibitors are also effective as a way of providing positive experiences and building sexual confidence. Full psychological evaluation is recommended before starting treatment.

• For men not responding to other approaches: Surgical implantation of penile prosthesis may be considered. Full psychological evaluation is recommended to evaluate the possibility of unrealistic expectations or partner problems contributing to ED. • Testosterone therapy in men with low testosterone (i.e., hypogonadal); evaluate for prostate cancer before prescribing testosterone. • Aerobic exercise may improve ED along with pharmacologic treatment.

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Erectile Dysfunction SUGGESTED READINGS Chung JH et al: Safety and efficacy of once daily administration of 50 mg mirodenafil in patients with erectile dysfunction: a multicenter, double-blind, placebo controlled trial, J Urol 189:1006-1013, 2013. Gupta BP et al: The effect of lifestyle modification and cardiovascular risk factor reduction on erectile dysfunction, Arch Intern Med 171(20):1797-1803, 2011. Rew KT, Heidelbaugh JJ: Erectile dysfunction, Am Fam Phys 94(10):820-827, 2016. Shah N et al: Cardiovascular disease prevention in men with vascular erectile dysfunction: the view of the preventive cardiologist, Am J Med 129:251-259, 2016. Wincze JP, Weisberg RB: Sexual dysfunction: a guide for assessment and treatment, ed 3, NY, 2015, Guilford Press.

TABLE E3  Guidelines for Intracavernosal Therapy 1. Do not prescribe intracavernosal therapy to men who have psychiatric disorders, hypercoagulable states, or sickle cell disease; who are receiving anticoagulant therapy; or who are unable to comprehend the risks or take appropriate action should complications occur. 2. Designate a physician or a urologist to be available to handle emergencies related to complications of intracavernosal injections, such as prolonged erection and priapism. 3. Instruct the patient in the injection technique, the risks of intracavernosal therapy, and the steps to be taken in the event of prolonged erection or priapism. 4. Administer the first injection in the office, and observe the blood pressure and heart rate response. This provides an excellent opportunity for educating the patient, observing adverse effects, and determining whether the patient will respond to intracavernosal therapy. 5. Start with a low dose of alprostadil and titrate the dose based on the erectile response and the duration of erection. Adjust the dose of alprostadil to achieve an erection that is sufficient for sexual intercourse but does not last more than 30 min. 6. If the erection does not abate in 30 min, the patient should be instructed to take a tablet of pseudoephedrine or terbutaline (Brethine) or an intracavernosal injection of phenylephrine. If this is not effective, the patient should call the designated physician or urologist and go to the emergency department. From Melmed S et al: Williams textbook of endocrinology, ed 12, Philadelphia, 2011, WB Saunders, Elsevier.

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Erysipelas  BASIC INFORMATION DEFINITION Erysipelas is a type of cellulitis caused by infection of the superficial layers of the skin and cutaneous lymphatics. Erysipelas is characterized by redness, induration, lymphangitis, lymphadenopathy, and a sharply demarcated, raised border. SYNONYM St. Anthony’s fire ICD-10CM CODE A46 Erysipelas

EPIDEMIOLOGY & DEMOGRAPHICS PREDOMINANT AGE: Occurs most often in the young or old RISK FACTORS: Patients with impaired lymphatic or venous drainage (mastectomy, saphenous vein harvesting) and immunocompromised patients. Athlete’s foot is a common portal of entry. RECURRENCE RATE: Relatively common PHYSICAL FINDINGS & CLINICAL PRESENTATION • Distinctive red, warm, tender skin lesion with induration and a sharply defined, advancing, raised border (Fig. E1). • Most common sites are lower extremities and face. • Systemic signs of infection (fever) are often present. • Vesicles or bullae may develop. • After several days, lesions may appear ecchymotic. • After 7 to 10 days, desquamation of affected area may occur.

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • Other types of cellulitis • Necrotizing fasciitis • Deep vein thrombosis • Stasis dermatitis • Erythema nodosum • Contact dermatitis • Erythema migrans (Lyme disease) • Insect bite • Herpes zoster • Erysipeloid • Acute gout • Pseudogout WORKUP History, physical examination, and laboratory evaluation LABORATORY TESTS Diagnosis is usually made by characteristic clinical setting and appearance. • Complete blood count: White blood cell count often elevated • Blood cultures positive in 5% of patients. Septic, or there is a history of animal bites for immersion injury and are not routinely indicated unless the host is immunocompromised • Gram stain and culture of any drainage from skin lesions has low yield • Culture of aspirated fluid from leading edge of skin lesion has low yield IMAGING STUDIES • Not routinely indicated • Duplex ultrasound for patients suspected of having deep vein thrombosis • CT scan or MRI for patients with suspected necrotizing fasciitis

TREATMENT

ETIOLOGY • Usually group A β-hemolytic streptococci (GABHS) • Less often group B, C, or G streptococci • Rarely Staphylococcus aureus

NONPHARMACOLOGIC THERAPY • Elevation of the affected limb • Warm compresses

COMPLICATIONS • Abscess • Necrotizing fasciitis • Thrombophlebitis • Gangrene • Metastatic infection

ACUTE GENERAL Rx Typical erysipelas of extremity in nondiabetic patient: • P O: Penicillin V 500 mg q6h. Use clindamycin in patients who are allergic to penicillin.

• IV: Penicillin G (aqueous) 1 to 2 million units q6h. Use vancomycin 15 mg/kg IV q12h in penicillin-allergic patients. Facial erysipelas (include coverage for Staphylococcus aureus): • PO dicloxacillin 500 mg q6h • IV nafcillin or oxacillin 2 g q4h • IV vancomycin 1 g q12h • Daptomycin 4 mg/kg IV q24h • Linezolid 600 mg IV q12h

DISPOSITION Prognosis is good with antibiotic treatment but recurrence is common. REFERRAL For surgical debridement for patients with necrotizing fasciitis or for drainage of abscess

PEARLS & CONSIDERATIONS • Consider early surgical referral when necrotizing fasciitis suspected. Consider skin biopsy when not responding to appropriate antibiotics. • Look for tinea pedis as portal of entry in erysipelas of lower extremities, and treat if present.

SUGGESTED READING Available at ExpertConsult.com RELATED CONTENT Erysipelas (Patient Information) Cellulitis (Related Key Topic) AUTHOR: Gail M. O’Brien, MD

Erysipelas SUGGESTED READING Smith E et  al: Which outcomes are reported in cellulitis trials? Br J Dermatol 178(5):1028-1034, 2018.

A

B FIG. E1  A and B, Erysipelas. (From James WD et  al: Andrews’ diseases of the skin, ed 12, Philadelphia, 2016, Elsevier.)

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Erythema Elevatum Diutinum BASIC INFORMATION DEFINITION Erythema elevatum diutinum (EED) is a chronic form of leukocytoclastic vasculitis consisting of violaceous, red-brown, or yellowish papules, plaques, or nodules that favor the extensor surfaces. EED may occur in association with infections, hematologic abnormalities, autoimmune diseases, or other conditions. SYNONYM EED ICD-10CM CODE L951 Erythema elevatum diutinum

EPIDEMIOLOGY & DEMOGRAPHICS • EED is a rare disease. • It most frequently affects young and middleaged adults between the ages of 30 and 60 yr. • There is no known sex or racial predilection. ASSOCIATED FACTORS • Infections: HIV infection, beta-hemolytic streptococcal infections, hepatitis, and tuberculosis. • Hematologic disorders: Plasma cell dyscrasias (particularly IgA monoclonal gammopathies), myelodysplasia, myeloproliferative disorders, B-cell lymphoma, and hairy cell leukemia. EED may appear yrs after the diagnosis of the hematologic disease. • Autoimmune disease: Inflammatory bowel disease, rheumatoid arthritis, celiac disease, relapsing polychondritis, lupus erythematosus, granulomatous polyangiitis, and dermatomyositis. • Other sporadic reports of disease associations include breast carcinoma and dermatitis herpetiformis. PHYSICAL FINDINGS & CLINICAL PRESENTATION • EED most commonly manifests as a bilateral eruption of violaceous, red-brown, or yellowish papules, plaques, or nodules. • Early EED tends to be soft and erythematous. • Older lesions are often more firm secondary to fibrosis. • EED is most frequently found on acral skin and periarticular skin. • The extensor surfaces of the elbows (Fig. E1), knees, ankles, hands, and fingers (Fig. E2) are commonly involved. • Less frequently involved sites include the face, retroauricular area, trunk, axillae, buttocks, and genitalia. • Nodular lesions progressing to bulky masses appear to be more common in patients with EED associated with human immunodeficiency virus (HIV) infection. • Additional reported presentations of EED include annular plaques with raised borders, verrucous plaques on the soles, and vesicobullous presentations.

• The cutaneous manifestations of EED may be asymptomatic or associated with a burning or stinging sensation or pruritus (especially in early stages). • Extracutaneous symptoms include arthralgia, fever, or other constitutional symptoms. • Ocular abnormalities such as peripheral keratitis, nodular scleritis, panuveitis, and blindness also have been reported.

ETIOLOGY • The pathogenesis of EED is not well understood. • It appears to be a form of immune complex– mediated vasculitis. • The cutaneous findings may result from the deposition of immune complexes in small blood vessels in the skin, leading to complement activation, neutrophilic infiltration, and the release of destructive enzymes. • Direct immunofluorescence studies reveal perivascular deposition of complement, IgG, IgM, IgA, and fibrin in EED. • In vitro studies suggest that activation of cytokines such as interleukin-8 contributes to selective recruitment of leukocytes to affected skin. • Antineutrophil cytoplasmic antibodies (ANCA) may also be pathogenic in EED.

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • Granuloma faciale • Sweet syndrome • Rheumatoid neutrophilic dermatitis • Palisaded neutrophilic and granulomatous dermatitis • Rheumatoid nodules • Multicentric reticulohistiocytosis • Sarcoidosis • Leprosy

WORKUP/LABORATORY TESTS/ IMAGING STUDIES • Complete blood count, comprehensive metabolic panel • Human immunodeficiency virus (HIV) test • Immunofixation electrophoresis • Streptozyme test • Hepatitis B and C serology • Antinuclear antibody (ANA) • Antineutrophil cytoplasmic antibodies • Anti-nDNA antibody, antiphospholipid antibodies • Chest radiograph, urinalysis • Specific testing for other infections or autoimmune diseases should be based upon the presence of suggestive signs, symptoms, or patient history

TREATMENT NONPHARMACOLOGIC THERAPY Local surgical excision can be beneficial for localized fibrotic nodules of EED. ACUTE GENERAL Rx Dapsone (with or without glucocorticoids) is the medical treatment of choice for EED. CHRONIC Rx Dapsone, colchicine, methotrexate, tetracycline DISPOSITION • EED usually has a prolonged course, characterized by fluctuating periods of exacerbation and stability. • The disease may resolve spontaneously after 5 to 10 yr; however, persistence up to 40 yr has occurred. • EED does not progress to systemic vasculitis. • Recurrence is common after cessation of dapsone.

PEARLS & CONSIDERATIONS • EED is a rare form of leukocytoclastic vasculitis consisting of violaceous, red-brown, or yellowish papules, plaques, or nodules that favor the extensor surfaces. • It may occur in association with infections, hematologic disorders, or autoimmune diseases. • The diagnosis of EED is made based upon correlation of the clinical and histologic findings. • Treatments for EED have included local medications, systemic medications, and surgery. • In addition, the associated underlying disease (when present) should be treated. • Erythema elevatum diutinum exhibits a prolonged relapsing-remitting course.

FIG. E1  Erythema elevatum diutinum. Nodules typically form over the extensor surfaces of the knuckles and other joints. (Firestein GS et al: Kelley’s textbook of rheumatology, Philadelphia, 2013, WB Saunders.)

REFERRAL Ophthalmology, dermatology, rheumatology AUTHOR: Catherine E. Najem, MD

Erythema Elevatum Diutinum

FIG. E2  Erythema elevatum diutinum. (From Hochberg MC: Rheumatology, ed 7, Philadelphia, 2019, Elsevier.)

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Erythema Multiforme BASIC INFORMATION DEFINITION Erythema multiforme is an inflammatory disease characterized by eruption of annular, maculopapular lesions with dark raised, erythematous, or vesiculobullous center surrounded by a pale zone. It is believed to be caused by immune complex formation and subsequent deposition in the skin and mucous membranes. It is considered a hypersensitivity reaction to infection or drugs. SYNONYM EM ICD-10CM CODES L51.0 Nonbullous erythema multiforme L51.8 Other erythema multiforme L51.9 Erythema multiforme, unspecified

EPIDEMIOLOGY & DEMOGRAPHICS PREDOMINANT AGE: 20 to 40 yr RISK FACTORS: Often associated with herpes simplex and other infectious agents, drugs, or connective tissue diseases PHYSICAL FINDINGS & CLINICAL PRESENTATION • Prodromal symptoms are mild or absent. Itching or burning at the site of eruption may occur. • Symmetric skin lesions (Fig. E1) with a classic “target” appearance (caused by the centrifugal spread of red maculopapules to circumference of 1 to 3 cm with a purpuric, cyanotic, or vesicular center) are present (Fig. E2). The papules may enlarge into plaques measuring a few centimeters in diameter with a dark or red central portion (Fig. E3). Target lesions may not be apparent for several days and generally heal in 1 to 2 wk without scarring. • EM lesions are most common on the face, back of the hands and feet, and extensor aspect of the forearms and legs (EM minor). Trunk involvement can occur in severe cases (EM major).

• Urticarial papules, vesicles, and bullae may also be present and generally indicate EM major. • EM major bullae and erosions may also be present in the oral cavity. The most common sites are the lips and buccal mucosa.

ETIOLOGY • Immune complex formation and subsequent deposition in the cutaneous microvasculature may play a role in the pathogenesis of erythema multiforme. • The majority of cases follow outbreaks of herpes simplex virus 1 and 2. • Mycoplasma pneumoniae, fungal infections, medications (bupropion, sulfonamides, penicillins, nonsteroidal antiinflammatory drugs, barbiturates, phenothiazines, hydantoins). • In >50% of patients no specific cause is identified.

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • Chronic urticaria • Pityriasis rosea • Contact dermatitis • Pemphigus vulgaris • Lichen planus • Serum sickness • Drug eruption • Granuloma annulare • Polymorphic light eruption • Viral exanthema • Stevens-Johnson syndrome (SJS) • Toxic epidermal necrolysis (TEN) • Bullous pemphigoid • Viral exanthems • Leukocytoclastic vasculitis • Lupus erythematosus • Secondary syphilis WORKUP • Medical history with emphasis on drug ingestion. • Laboratory evaluation in patients with suspected collagen-vascular diseases. • Skin biopsy when diagnosis is unclear.

LABORATORY TESTS • Complete blood count with differential, elevated ESR • Antinuclear antibody • Serology for Mycoplasma pneumoniae, HSV1, HSV-2 • Biopsy for atypical cases • Direct immunofluorescence if suspecting bullous diseases

TREATMENT NONPHARMACOLOGIC THERAPY • Mild cases generally do not require treatment; lesions resolve spontaneously within 1 mo. • Potential drug precipitants should be removed. ACUTE GENERAL Rx • Treatment of associated diseases (e.g., valacyclovir or famciclovir for herpes simplex, erythromycin for Mycoplasma infection). • Dapsone, antimalarials, or azathioprine for severe or resistant cases. • Prednisone 40 to 80 mg/day for 1 to 3 wk is effective for decreasing inflammation and pain and may be tried in patients with many target lesions; however, the role of systemic steroids remains controversial. • Levamisole, an immunomodulator, may be effective in the treatment of patients with chronic or recurrent oral lesions (dose is 150 mg/day for 3 consecutive days used alone or in combination with prednisone). • IV immunoglobulins in severe cases. • Antimicrobial therapy is indicated if M. pneumoniae is the trigger of EM. DISPOSITION The rash generally evolves over a 2-wk period and resolves within 3 to 4 wk without scarring. A severe bullous form can occur (see entry for “Stevens-Johnson Syndrome”). REFERRAL Hospital admission in patients with suspected Stevens-Johnson syndrome

 EARLS & P CONSIDERATIONS COMMENTS The risk of recurrence of erythema multiforme exceeds 30%. Recurrence may be treated with valacyclovir 500 to 1000 mg/day, famciclovir 125 to 250 mg/day, or acyclovir 400 mg bid. Dapsone, antimalarials, azathioprine, or cyclosporine use is reserved for cases resistant to antivirals. RELATED CONTENT Erythema Multiforme (Patient Information) Stevens-Johnson Syndrome (Related Key Topic) AUTHOR: Fred F. Ferri, MD

FIG. E1  Erythema multiforme (EM). Round erythematous swollen plaques and target lesions on the palms. This girl developed EM in association with her systemic lupus erythematosus. (From Paller AS, Mancini AJ: Hurwitz clinical pediatric dermatology: a textbook of skin disorders of childhood and adolescence, ed 5, Philadelphia, 2016, Elsevier.)

Erythema Multiforme

FIG. E2  Erythema multiforme. Classic target lesions and marginated wheals with central vesicles are characteristic. (From Paller AS, Mancini, AJ: Hurwitz clinical pediatric dermatology: a textbook of skin disorders of childhood and adolescence, ed 5, Philadelphia, 2016, Elsevier.)

FIG. E3  Erythema multiforme. Extensive target lesions on the thighs of a 12-yr-old girl. The recurrent reaction was suppressed by administration of oral acyclovir. (From Paller AS, Mancini AJ: Hurwitz clinical pediatric dermatology: a textbook of skin disorders of childhood and adolescence, ed 5, Philadelphia, 2016, Elsevier.)

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  Erythema Nodosum BASIC INFORMATION DEFINITION Erythema nodosum (EN) is an acute, tender, erythematous, nodular skin eruption resulting from inflammation of subcutaneous fat, often associated with bruising. It is the most common form of panniculitis.

ICD-10CM CODE L52 Erythema nodosum

EPIDEMIOLOGY & DEMOGRAPHICS INCIDENCE: It is the most common form of panniculitis. Two to three cases/100,000 persons per yr. PREDOMINANT SEX: Female:male ratio of 3 to 4:1 PREDOMINANT AGE: 25 to 40 yr PHYSICAL FINDINGS & CLINICAL PRESENTATION • Prodromal symptoms of fatigue, malaise, upper respiratory infection symptoms may precede eruption by 1 to 2 wk. • Acute onset of tender nodules typically located on the shins and occasionally seen on the thighs and forearms (Fig. E1). • The nodules are usually 1/8 to 1 inch in diameter but can be as large as 4 inches; they begin as light red lesions, then become darker and often ecchymotic. The nodules heal within 8 wk without ulceration. • Associated findings: 1. Fever (60%) 2. Lymphadenopathy (10% of body mass predicts poor outcome • Hoarseness: Suggests recurrent laryngeal nerve involvement • Odynophagia and halitosis: Unusual symptoms • Cervical adenopathy: Usually involving supraclavicular lymph nodes • Dry cough: Suggests tracheal involvement • Aspiration pneumonia: Caused by fistula between the esophagus and trachea • Iron deficiency anemia: Related to chronic GI blood loss • Massive hemoptysis or hematemesis from the invasion of vascular structures • Advanced disease spreads to lymph nodes, liver, lungs, peritoneum, and pleura • Hypercalcemia: Associated with squamous cell carcinoma from secretion of a parathyroid-like tumor peptide Clinical findings: • 50% to 60% of patients present with the inoperative stage of their disease (locally advanced, regional, or metastatic). ETIOLOGY The pathogenesis of esophageal cancers is attributable to chronic recurrent oxidative damage from any of the following etiologic agents, which cause inflammation, and esophagitis, increased cell turnover, and, ultimately, initiation of the carcinogenic process.

ETIOLOGIC AGENTS: Squamous cell carcinoma • Excess alcohol consumption is strongly associated with squamous cell esophageal cancer in the United States; hard liquor is associated with a higher incidence than wine or beer. • Tobacco and alcohol synergistically increase risk for squamous cell cancer • Other ingested carcinogens: 1. Nitrates (converted to nitrites): South Asia, China 2. Smoked opiates: Northern Iran 3. Fungal toxins in pickled vegetables 4. Betel nut chewing • Mucosal damage: 1. Long-term exposure to extremely hot tea (>70 °C [158 °F]) 2. Lye ingestion • Radiation-induced strictures • Achalasia: Incidence of esophageal cancer is seven times greater in this population • Host susceptibility as a result of precancerous lesions: 1.  Plummer-Vinson syndrome (PatersonKelly): Glossitis with iron deficiency 2. Congenital hyperkeratosis and pitting of palms and soles (tylosis) • Human papillomavirus infection (particularly types 16 and 18) has been variably detected in squamous cell carcinoma of the esophagus, sometimes associated with p53 tumor suppressor gene mutations • Questionable relationship with prolonged bisphosphonate use (≥10 prescriptions, or use >3 yr) • Possible association with celiac sprue or dietary deficiencies of molybdenum, selenium, zinc, vitamin A ADENOCARCINOMA: The incidence of adenocarcinoma is continually rising, whereas that of squamous cell carcinoma is unchanged. • Smoking increases the risk of developing adenocarcinoma, particularly in patients with Barrett. • Obesity, hiatal hernia, and diets lacking in fresh fruit and vegetables and high in fat (particularly from red meat and processed foods). • Chronic GERD leading to Barrett metaplasia and adenocarcinoma via immune cell infiltration and production of inflammatory mediators and reactive oxygen species. The annual rate of transformation from Barrett to adenocarcinoma is 90% of pancreatic glandular function is loss

• Edema (as a result of protein malnutrition and hypoalbuminemia) • Fat-soluble vitamins deficiencies (rare): 1. Vitamin A (impaired night vision) 2.  Vitamin D (osteoporosis, metabolic bone disease, hyperparathyroidism, hypocalcemia) 3. Vitamin E (neuropathy, anemia) 4. Vitamin K (ecchymosis)

ETIOLOGY (TABLE 1) EPI usually results from CP in adults or CF in children. Pancreatic exocrine insufficiency is also a common occurrence in patients recovering from severe acute pancreatitis, with the severity of symptoms correlating with the degree of pancreatic necrosis. Causative factors can generally be classified into pancreatic and extrapancreatic conditions.

DIAGNOSIS The diagnosis of EPI is challenging because patients often present with nonspecific signs and symptoms, and reliable diagnostic tests are lacking.

DIFFERENTIAL DIAGNOSIS With the exception of voluminous and foulsmelling stools, the following conditions may present in a manner similar to EPI: • Celiac disease • IBS • Inflammatory bowel disease • SIBO • Short bowel syndrome WORKUP • A complete history, physical examination, and laboratory evaluation are essential to making the diagnosis and excluding other common causes of diarrhea and weight loss. • Complete electrolyte panel to detect hypokalemia, hypocalcemia (in setting of vitamin D deficiency), hypomagnesemia, and metabolic acidosis from malabsorption and gastrointestinal losses. • Complete blood count (CBC) may reveal anemia from iron, vitamin B12, or folate deficiencies. • Prolonged prothrombin times may be elevated because of vitamin K malabsorption.

• Alternative causes of maldigestion should be investigated, such as infection with Giardia lamblia, celiac serology, liver disease, and SIBO tests.

LABORATORY TESTS Direct and indirect pancreatic function tests are available to diagnose EPI. • Indirect: Measures the level of pancreatic enzymes or the consequences of exocrine insufficiency. Used to monitor the effectiveness of pancreatic enzyme replacement therapy (PERT). 1.  Fecal fat quantification: Considered the gold standard for evaluating fat digestion. However, it does not distinguish between maldigestion and malabsorption. 2.  Fecal elastase-1 (FE-1): The most sensitive and specific test of pancreatic function. This enzyme is minimally degraded during intestinal transit. The test measures enzymatic production of FE-1 and can be used to screen for moderate-to-severe EPI with high sensitivity. FE-1 levels >200 μg/g are normal, levels of 100 to 200 μg/g are considered mild, and levels F; with predominant physical symptoms F > M by a ratio of 3:1. Munchausen syndrome M > F, and Munchausen by proxy mostly younger females PREDOMINANT AGE: 30 to 40 yr of age PEAK INCIDENCE: Approximately 30 to 40 yrs of age GENETICS: No genetic predisposition known PHYSICAL FINDINGS & CLINICAL PRESENTATION • Patient is inconsistent or intentionally misleading and resistant to allowing providers to obtain outside records.

• Clinical picture is atypical for the natural history of disease (e.g., an infection that does not respond to multiple courses of appropriate antibiotics). • Tests, consultations, and medical and surgical treatments done to no avail and often contradicting history provided by the patient. • Presentation may be acute and dramatic and in excess of what might be expected. • The patient may predict deterioration or report exacerbation just before scheduled discharge. • Opposition to psychiatric consultation.

ETIOLOGY • A history of significant childhood illness; traumatic experiences such as having witnessed violence and physical, emotional, or sexual abuse can predispose. • Personality disorders and psychodynamic factors often play a significant role in the development and maintenance of this disorder.

DIAGNOSIS This is a diagnosis of exclusion. It requires demonstrating that the individual is taking surreptitious actions to misinterpret, simulate, or cause signs or symptoms of illness or injury in the absence of any obvious external reward. Early diagnosis is helpful to prevent extensive and unnecessary testing, which can cause iatrogenic injury. There may be direct observation of fabrication, the presence of signs or symptoms that contradict laboratory testing, nonphysiologic response to treatment, physical evidence of fabrication (e.g., syringes at the bedside), recurrent patterns of illness exacerbation, or failure to follow the expected natural history of disease. Box E1 describes clues that increase the likelihood of subtle forms of factitious disease.

DIFFERENTIAL DIAGNOSIS • Primary medical condition • Somatic symptoms disorder: Not intentionally produced • Conversion disorder

• Conditions in which self-injurious behavior is common such as borderline personality disorder. The goal is self-injury and not to attain the sick role • Malingering: Clear secondary gain with conscious motivation (e.g., financial gain or avoidance of unwanted duties)

WORKUP • Dictated by the presenting complaints. A reasonable index of suspicion when presentation is not consistent with known pathology. • Methods that have been used to bolster or confirm a suspicion of self-induced or factitious disease are summarized in Box E2. LABORATORY TESTS • L aboratory testing often reveals inconsistencies. • Laboratory abnormalities may reflect the underlying factitious behavior (e.g., hypokalemia in an individual surreptitiously taking furosemide or a clean urine sample obtained by straight catheterization in someone complaining of hematuria).

TREATMENT NONPHARMACOLOGIC THERAPY Two approaches may be considered: • Nonpunitive constructive confrontation by the primary physician and a psychiatrist in collaboration. A supportive stance should be maintained and an offer for ongoing support and follow-up made. Box E3 summarizes consensus opinions on the treatment of factitious disease. • Avoid overt confrontation with patient but provide him or her with a face-saving way to recover. For example, a therapeutic double bind would involve saying, “There are two possibilities here: one is that you have a medical problem that should respond to the next intervention we do, or two, you have a factitious disorder. The outcome will give us the answer.” Features of supportive confrontation are described in Box E4. • Munchausen syndrome is the most severe variant and may be virtually impossible to treat except to avoid further invasive and iatrogenic intervention.

BOX E1  Clues That Increase the Likelihood of Subtle Forms of Factitious Disease Predominantly women Previous experience in the medical field, which provides an unusual grasp of terminology and access to medical supplies Multiple surgeries, multiple procedures Inexplicable laboratory test results Inconsistency and implausibility of certain aspects of the history Visits to three or more medical centers previously for the same symptoms, or to a nationally known referral center such as the Mayo Clinic or Cleveland Clinic, despite residing far away History of substance abuse or prior psychiatric disorder Vagueness in regard to details of past history and/or reluctance to allow release of previous medical records From Feldman M, Friedman LS, Brandt LJ: Sleisenger and Fordtran’s gastrointestinal and liver disease, ed 10, Philadelphia, 2016, Elsevier.

Factitious Disorder (Including Munchausen Syndrome) BOX E2  Methods That Have Been Used to Bolster or Confirm a Suspicion of Self-Induced or Factitious Disease Review old medical records and discuss case with previous doctors and family members if appropriate. Identify discrepancies and inconsistencies, and estimate influence of gain derived from the sick role. Inquire about psychosomatic illness, previous psychiatric treatment, suicide attempts, stress in the patient’s life, childhood abuse, marital/sexual problems, eating disorders, and so on. A forensic consultant with access to multiple records can be uniquely helpful in identifying conflicting stories. Review previous biopsy slides, looking for foreign body material in wounds, melanosis coli, and other clues, as appropriate for the patient’s symptoms. Obtain a psychiatric evaluation to help determine whether the patient has a personality disorder or psychiatric disease, absence of which would argue against factitious disease. Psychiatrists should not attempt initially to discover the underlying unconscious motivation that may have impelled the patient to assume the sick role. If symptoms and signs may be explained by surreptitious ingestion of medications and poisons, obtain appropriate medication and toxicology screens. Consider obtaining a urine test for diuretics even in the absence of renal or electrolyte disorders. Evaluate results of such screens in light of the sensitivity and specificity of the tests employed. Test biological fluids collected under direct observation and compare results with fluids collected privately by the patient. For example, compare fecal material obtained at “unprepped” sigmoidoscopy with fecal material submitted by the patient. Have nursing staff observe the patient to detect tampering behavior. Search the patient’s personal belongings. Conduct covert videotape surveillance, especially in suspected Munchausen syndrome by proxy. From Feldman M, Friedman LS, Brandt LJ: Sleisenger and Fordtran’s gastrointestinal and liver disease, ed 10, Philadelphia, 2016, Elsevier.

BOX E3  Consensus Opinions on the Treatment of Factitious Disease Achievement of insight should not be the principal early goal of treatment, because it can weaken the patient’s defenses. One person should have primary responsibility for patient management. There should be a comprehensive psychiatric evaluation of the patient, including assessment for suicide risk. All members of a multidisciplinary team should be aware of the psychiatric assessment and treatment plan. The treatment plan should be individualized. Comorbid illness should be treated appropriately. If confrontational techniques are used, they should be nonpunitive and supportive. From Feldman M et al: Sleisenger and Fordtran’s gastrointestinal and liver disease, ed 10, Philadelphia, 2016, Elsevier.

BOX E4  Features of Supportive Confrontation Tell the patient what you suspect without outright accusation. Support the diagnosis of factitious disease with facts. Provide empathetic and face-saving comments.* Avoid probing to uncover the patient’s underlying feelings and motivations.† Assure the patient that the physician will not release the diagnosis to others without the patient’s permission unless required to do so by law.‡ Ensure that the staff demonstrates continued acceptance of the patient. Encourage psychiatric help, but do not force the issue. *“Maybe you didn't know what you were taking—this medication could cause you to be sick”; “Maybe you took it in your sleep”; “What you did was a cry for help, and we understand”; “We realize you must be in great distress”; “We want to continue to take care of you.” †This is done to minimize disruption of essential emotional defenses. ‡Later it may be decided to break this promise in patients with potentially fatal factitious disease, such as patients who are creating sepsis by injecting contaminated material into their bodies. This promise should only be broken after consultation and consensus opinion has been obtained by an ethics committee, legal personnel, and others, as described in the text. From Feldman M et al: Sleisenger and Fordtran’s gastrointestinal and liver disease, ed 10, Philadelphia, 2016, Elsevier.

ACUTE GENERAL Rx • Treatment of comorbid psychiatric disorders may be helpful with medications and/or psychotherapy, which may ameliorate the factitious behavior. • Multidisciplinary staff meetings can be useful to ventilate feelings and develop cohesive treatment plans. CHRONIC Rx • Attempt to engage the patient in some form of psychotherapy or at least a harm-reduction strategy. • Establishment of a central reporting register has been proposed to aid development of evidence-based guidelines.

DISPOSITION • After being confronted with their behavior, patients may cease factitious behavior, but they may also seek other physicians or hospitals, as in the Munchausen variant. • Some patients may enter psychotherapy, particularly when they have been given a face-saving approach with avoidance of a humiliating confrontation. REFERRAL Always obtain psychiatric referral. Risk management attorneys and hospital ethicists may contribute to challenging decision making in these patients.

PEARLS & CONSIDERATIONS • Think of factitious disorders whenever there is an unexplained medical course that continues to repeat itself despite appropriate treatment. • Patients may have a history of working in the health care field. • Gratuitous, self-aggrandizing deception may be noted. AUTHORS: Christina D. Scully, MD, and Dwayne R. Heitmiller, MD, FAPM

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Factitious Disorder (Including Munchausen Syndrome) SUGGESTED READINGS Bass C et al: Factitious disorders and malingering: challenges for clinical assessment and management, Lancet 383:1422–1432, 2014. Diagnostic and statistical manual of mental disorders, ed 5, Washington, DC, 2013, American Psychiatric Publishing. Hamilton J et al: Somatoform, factitious, and related diagnoses in the national hospital discharge survey: addressing the proposed DSM-5 revision, Psychosomatics 54(2):142–148, 2013. Kanaan RA et al: Factitious disorders in neurology: an analysis of reported cases, Psychosomatics 51(1):47–54, 2010. Kinns H et al: Munchausen syndrome and factitious disorder: the role of the laboratory in its detection and diagnosis, Ann Clin Biochem 50:194–203, 2013.

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ALG BASIC INFORMATION DEFINITION Failure to thrive (FTT) describes a delay in growth and development among children. FTT is a cluster of symptoms rather than a specific disease. CLINICALLY The term (FTT) is often used for infants and children with weight below the 5th percentile for sex and corrected age. SYNONYMS Pediatric undernutrition Faltering growth Weight faltering Growth failure FTT ICD-10CM CODE R62.51 Failure to thrive (child)

EPIDEMIOLOGY & DEMOGRAPHICS INCIDENCE: FTT is a common problem, though its incidence in the community is unclear. A total of 1% to 5% of inpatient pediatric admissions are for evaluation of FTT. PREDOMINANT SEX AND AGE: FTT most commonly occurs among children ages 6 to 12 mo, with 80% presenting before 18 mo of age. Most FTT patients present before 3 yr of age. Males and females are equally affected. RISK FACTORS: Poverty is the single greatest risk factor. Nonmedical: Poverty, food insecurity, social isolation, neglect, and physical or emotional abuse. Medical: Intrauterine growth restriction (IUGR), prematurity, medical conditions leading to inadequate food intake, food malabsorption, or increased metabolic demand. PHYSICAL FINDINGS & CLINICAL PRESENTATION Children have blunted growth in height, weight, head circumference, or any combination of these. Children may have pallid, dry, or cracked skin, sparse hair growth, poorly developed musculature, lack of subcutaneous fat, swollen abdomen, or evidence of vitamin deficiencies. ETIOLOGY FTT is the result of inadequate nutrition, which may be due to a wide range of medical or psychosocial causes. FTT can be thought of as stemming from inadequate nutritional intake, malabsorption of nutrients, or increased caloric expenditure, though the actual cause is commonly multifactorial.

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • Inadequate nutritional intake: Food insecurity, poor parent knowledge of child’s needs, formula dilution, excessive juice, breastfeeding

Failure to Thrive (Pediatric)

difficulties, neglect, behavioral feeding problem, oromotor dysfunction, developmental delay, emesis, gastroesophageal reflux, volvulus, increased intracranial pressure, genetic disease (trisomy 13, 18, 21), and psychiatric conditions • Malabsorption: Cystic fibrosis, celiac disease, eosinophilic esophagitis, food protein insensitivity or intolerance, and inflammatory bowel disease • Increased metabolic demand: Insulin resistance, congenital infection, other infection, genetic syndrome, hyperthyroidism, chronic disease, and malignancy

WORKUP • Evaluation should include the child’s eating habits, caloric intake, parent-child interactions, psychosocial history, past medical history, medications, family history to include parent stature and weight, review of systems, and physical exam. Fig. E1 illustrates an algorithm for management of a child with FTT. • Height, weight, and weight-to-length measurements are most sensitive, whereas head circumference and body mass index (BMI) may be useful. Common FTT criteria for children younger than 2 yr are below, but clinical judgment should be used because normal causes and biologic variants may exist. 1. Length, weight, or BMI below the 3rd or 5th percentile on more than one consecutive visit

2. Weight that drops below two major percentile lines 3. Weight less than 80% of the ideal weight for age 4. Weight-to-length below the 5th percentile or weight-for-length less than 70% to 79% of the median 5. Weight velocity below the 3rd or 5th percentile 6. Weight less than 70% of the 50th percentile; may require hospitalization • Obtain caliper measurements of skinfold thickness and midarm muscle circumference. • Observation of a meal being taken to assess potential feeding difficulties. • A 3-day food diary is helpful, as well as consultation by a nutritionist, to calculate the child’s intake of energy, protein, vitamins, and minerals. • Assess stool frequency, consistency, quantity, as well as fat, blood, or mucus content. • Routine hospitalization for FTT evaluation is not recommended. Rarely, hospitalization for observed feedings and further workup is warranted.

LABORATORY TESTS • Laboratory tests should be based on medical history and physical exam findings and should consider the risk for refeeding syndrome and other medical complications. • Consider CBC with red blood cell indices, complete chemistry panel including phosphorus, thyroid function, urinalysis, HIV

Diagnosis of FTT

Predominant organic etiology identified

No predominant organic etiology identified

Assess prior growth pattern, parental heightgrowth variant

No

Specific management

Dietary assessment and management

Yes Reassurance and periodic monitoring

Good response

Continue treatment until resolution

Good response Poor response and/or evidence of feeding difficulty

Socioeconomic assessment and parental interaction

Feeding team evaluation and intervention

Poor response

Continue management

Further testing and intervention including supplemental feeding and home-based intervention

FIG. E1 Algorithm for management of a child with failure to thrive (FTT). (Shashidhar H, Tolia V: Failure to thrive. In Wyllie R, Hyams JS [eds], Pediatric gastrointestinal and liver disease, ed 4, Philadelphia, 2011, Elsevier, pp 136-145.e3.)

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Failure to Thrive (Pediatric) testing, C-reactive protein or erythrocyte sedimentation rate, celiac screening, stool examination for fats or reducing substances, or sweat chloride testing. If clinically indicated, growth hormone level and genetic sequencing can be checked.

IMAGING STUDIES Imaging tests are not routinely performed but may be warranted depending on underlying medical cause.

TREATMENT Identification and management of underlying causes should be implemented. In cases in which there is no underlying medical condition, providing nutrition repletion will, by definition, correct FTT. A multidisciplinary team (including, but not limited to, social workers, occupational/ speech therapists, nutritionists/dietitians, nurses, advanced practice nurses, and pediatricians) should be used.

NONPHARMACOLOGIC THERAPY • Add calorie-dense foods or increase the number of feedings. • Enteral feeding, percutaneous endoscopic gastrostomy (PEG), and nasogastric feeding tubes can be used to accelerate weight gain, and results should be seen within 2 to 7 days. Caloric intake should be titrated up to goal over 5 to 7 days. Caloric goals by age group: 0 to 6 mo: 108 kcal/kg/day, 6 to 12 mo: 98 kcal/kg/day, and 1 to 3 yr: 102 kcal/kg/day. • Swift restoration of nutrition can lead to life-threatening refeeding syndrome, where shifts in electrolyte balance (low phosphate, magnesium, potassium), fluid balance (edema), hypoglycemia, gastroparesis or

ALG

ileus, impaired heart function or arrhythmia, and sudden death can occur. Calories must therefore be titrated slowly to goal with close monitoring. • Treat underlying medical conditions, including mental health disorders. • Assist with family psychosocial stressors. • Follow up closely, including home nursing visits. • In cases where economic, psychosocial, or parental issues are suspected and the child’s growth is not maintained, state and federal legislation regarding reporting to child protection services must be followed.

ACUTE GENERAL Rx Multivitamins including iron and zinc CHRONIC Rx Nutrient repletion with the goal of accelerated growth should be continued for 4 to 9 months DISPOSITION Children with FTT commonly remain small in height and weight. Studies consistently find that children with FTT are more prone to long-term cognitive, learning, and behavioral abnormalities. REFERRAL • Indicated based on the cause of FTT • Hospitalization should be considered in cases of FTT in which a child is less than 70% of predicted weight for length, where outpatient management has failed, when a suspicion of abuse or neglect exists, where signs of traumatic injury are present, where serious impairment of the child’s caregiver is evident, or for close observation and treatment for refeeding syndrome.

SUGGESTED READINGS Cole SZ, Lanham JS: Failure to thrive: an update, Am Fam Physician 83(7):829834, 2011. Harper NS: Neglect: failure to thrive and obesity, Pediatr Clin North Am 61(5):937957, 2014. Homan GJ: Failure to thrive: a practical guide, Am Fam Physician 94(4):295-299, 2016. Jaffe AC: Failure to thrive: current clinical concepts, Pediatr Rev 32(3):100-108, 2011. King C, Davis T: Nutritional treatment of infants and children with faltering growth, Eur J Clin Nutr 64(Suppl 1):S11-S13, 2010. Rogol AD, Hayden GF: Etiologies and early diagnosis of short stature and growth failure in children and adolescents, J Pediatr 164(Suppl 5):S1-S14, 2014. Shields B et al: Weight faltering and failure to thrive in infancy and early childhood, Br Med J 325:e5931, 2012.

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PEARLS & CONSIDERATIONS COMMENTS • FTT is a common childhood symptom encountered in the outpatient and inpatient pediatric populations, is caused by undernutrition, and is associated with inadequate nutritional intake, malabsorption, or increased metabolic demand. • A thorough multidisciplinary approach to assessment, diagnosis, and management should be used to manage nutrient status and any underlying cause(s). • Child height/length, weight, and weight-forlength measurements with comparison to standard growth curves are useful in the identification of potential cases of FTT. • FTT treatment should include restoration of nutrition along with treatment of the underlying cause(s), including psychosocial factors. • Although FTT can usually be managed effectively in the outpatient setting, specific indications for inpatient treatment should be considered. PREVENTION Nutritional counseling and anticipatory guidance should be provided at each well-child visit. Growth parameters should be measured during serial clinical assessments and compared with growth standards. Enlist dietitians and visiting nurses to provide support to families with children at high risk of FTT. AUTHOR: Fred F. Ferri, MD

Fallopian Tube Cancer BASIC INFORMATION DEFINITION A “primary” fallopian tube tumor is defined as a tumor that is restricted to or mainly affects the fallopian tube. SYNONYMS Fallopian tube cancers, serous tubal intraepithelial carcinomas ICD-10CM CODES C57.00 Malignant neoplasm of unspecified fallopian tube C57.01 Malignant neoplasm of right fallopian tube C57.02 Malignant neoplasm of left fallopian tube

EPIDEMIOLOGY & DEMOGRAPHICS INCIDENCE: Primary fallopian tube tumors make up 0.3% to 1.1% of all gynecologic cancers. Highest incidence in white, non-Hispanic women aged 60 to 79 yr. GENETICS: Patients with BRCA mutations have a 0% to 12% incidence of serous tubal intraepithelial carcinomas (STIC). Women with hereditary nonpolyposis colorectal cancer also have a higher risk of STIC than the general population. PHYSICAL FINDINGS & CLINICAL PRESENTATION Physical exam findings are similar to those of ovarian and primary peritoneal cancers.

Patients can have abdominal bloating, early satiety, abdominal distention, and weight loss. However, many early fallopian tube cancers are detected at time of risk-reducing bilateral salpingoophorectomy.

IMAGING STUDIES • Pelvic ultrasonography • CT abdomen/pelvis

ETIOLOGY Etiology is unknown at this time. STIC is believed to be the precursor lesion to high-grade serous carcinomas (HGSC) of the ovary.

See Table E1.

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • Ovarian cancer • Primary peritoneal cancer WORKUP LABORATORY TESTS: • Complete blood count, basic metabolic panel • CA125 • Pathology: 1. Until recently, grossly positive tubal mass was required to assign the tumor origin to the fallopian tube. 2. Fimbrial carcinoma is unlikely to cause tubal dilation. 3. More recently the SEE-FIM protocol for pathologic evaluation of fallopian tubes has been used to better evaluate the potential for primary fallopian tube cancers. 4. SEE-FIM involves sectioning and extensively examining the fimbriated end. Fimbrial carcinoma is unlikely to cause tubal dilation. 5. Fimbrial carcinomas contain TP53 mutations.

STAGING

TREATMENT Approach mirrors treatment for ovarian cancers

NONPHARMACOLOGIC THERAPY Surgery: Generally, total hysterectomy with removal of both tube and ovaries is the first-line treatment with goal of complete resection of all visible tumors; pelvic and para-aortic lymph node resection is often also performed. ACUTE GENERAL Rx Medications to control nausea and vomiting, constipation associated with tumor burden CHRONIC Rx • Adjuvant chemotherapy: 1. Usually with platinum-based combination chemotherapy regimens, usually platinum-taxane combination • Radiotherapy is no longer recommended DISPOSITION SURVIVAL: • 5-yr survival is about 65% or higher. • Stage of disease at time of diagnosis is the most important prognostic indicator. • Overall survival is 30% to 50%. AUTHORS: Emily E. Nuss, MD, Beth Leopold, MD, and Anthony Sciscione, DO

TABLE E1  International Federation of Gynecology and Obstetrics Staging • Stage 0. Carcinoma in situ (limited to tubal mucosa) • Stage I. Growth limited to the fallopian tubes 1. Stage IA. Growth limited to one tube with extension into submucosa and/or muscularis, but not penetrating the serosal surface. No malignant calls in ascites or peritoneal washings. 2. Stage IB. Growth limited to both tubes with extension into submucosa and/or muscularis but not penetrating the serosal surface. No malignant calls in ascites or peritoneal washings. 3. Stage 1C. Tumor either stage IA or IB with tumor extension through or onto the tubal serosa OR with ascites containing malignant cells OR with positive peritoneal washings. • Stage II. Growth involving one or both fallopian tubes with pelvic extension. 1. Stage IIA. Extension and/or metastasis to the uterus and/or ovaries 2. Stage IIB. Extension to other pelvic tissues 3. Stage IIC. Tumor either stage IIA or IIB AND with ascites containing malignant cells OR with positive peritoneal washing • Stage III. Tumor involving one or both fallopian tubes with peritoneal implants outside of the pelvis, involvement of the small bowel, omentum, or liver surface, and/or positive retroperitoneal or inguinal nodes. Peritoneal implants are studs of tumors implanted in the abdominal wall 1. Stage IIIA. Tumor grossly limited to the true pelvis with negative nodes, but with histologically confirmed microscopic seeding of abdominal peritoneal surfaces (small bowel, omentum, or liver surface) 2. Stage IIIB. Tumor involving one or both tubes with histologically confirmed implants visualized on the abdominal peritoneal surfaces (small bowel, omentum, liver surface), none exceeding 2 cm in diameter. Lymph nodes negative for tumor 3. Stage IIIC. Abdominal implants greater than 2 cm in diameter and/or positive retroperitoneal or inguinal nodes • Stage IV. Growth invading one or both fallopian tubes with distant metastases, including parenchymal liver metastases. Parenchymal liver disease refers to cancer inside the liver; it differs from disease on the liver surface, which may qualify as stage III disease. Fluid on the lungs (pleural effusion) may classify as stage IV disease, but only if cancer cells are found to be present in the fluid

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Falls in the Elderly

ALG

BASIC INFORMATION DEFINITION A fall is an “event which results in a person coming to rest inadvertently on the ground and other than a consequence of the following: loss of consciousness, sudden onset of paralysis, or epileptic seizure.” SYNONYMS Syncope Collapse ICD-10CM CODES E880-E888.9 Accidental fall R29.6 Repeated falls

EPIDEMIOLOGY & DEMOGRAPHICS INCIDENCE: • Trauma is the fifth leading cause of death in persons >65 yr of age, and falls are responsible for 70% of accidental deaths in persons ≥75 yr. • The incidence of falls among communitydwelling older adults is 30% to 40%. Two thirds of falls in the community are preventable; 6% to 7% of these falls result in fracture. • The incidence of falls for nursing home and hospitalized older adults is three times the rate of community-dwelling older adults. Over 50% of nursing home residents fall during their stay. • 20% to 30% of older adults who fall suffer significant injury leading to immobility, dependence, and an increased risk of early death. HEALTH CARE COST: In 2006, patients ≥65 had over 2.1 million visits to the ED for injurious falls, which was 10.5% of all ED visits among the elderly and 29.6% of these visits required hospital admission. In those that were admitted, the mean length of stay was 5.5 days with a mean cost of $10,800. The aggregate hospital cost for those requiring admission in 2006 was $6.8 billion. (Source: Healthcare Cost and Utilization Project.) PREDOMINANT SEX & AGE: • Fall-related mortality is highest among older white men followed by white women, African American men, and African American women. • The incidence rates of falls increase with advancing age. • Older adults ≥85 yr are 10 to 15 times more likely to have a fracture compared with those aged 60 to 65 yr. RISK FACTORS: Four groups of risk factors for falls have been identified (Table 1): • Intrinsic factors inherent in the older adult who falls. • Extrinsic factors circumstantial to the older adult who falls. • Falls in nursing homes. • Situational or the activity in which the older adult is engaged in when a fall occurs.

CLINICAL PRESENTATION • Older adults who fall may present with minor soft tissue injuries, such as lacerations or bruising, hip fracture, or head trauma; however, most falls are not reported unless an injury has occurred. • If an older adult presents for medical attention for a fall or reports recurrent falls in the past year or difficulties in walking or balance, a multifactorial fall risk assessment should be completed. • The multifactorial fall risk assessment should include: 1. Focused history: A detailed history of events and circumstances surrounding fall, relevant risk factors including review of medications, acute and chronic medical problems (e.g., osteoporosis, urinary incontinence, and cardiovascular disease), and whether the fall was witnessed 2. Physical examination: a. Vital signs including orthostatics. b. Cardiovascular examination assessing for arrhythmias, carotid bruits, or new murmurs.









c. N  eurologic examination including vision assessment, evaluation of lower-extremity strength, peripheral nerves, proprioception, and testing of cortical, extrapyramidal, and cerebellar function. d. Gait and balance assessment: Multiple screening tools are available for fall risk screening and balance assessment (Tables 2 and 3). “Get up and go test” is a rapid assessment that will quickly tell you if the patient needs rehabilitation and what to work on. (Ask patient to stand from a seated position without use of hands, walk 10 feet forward, turn around, and return to chair and sit). e. Musculoskeletal exam with attention to joints of lower extremity, feet, and footwear. 3. Functional assessment including the older adult’s activities of daily living skills, use of adaptive equipment, and fear of falling 4. Environmental assessment of home safety

TABLE 1  Risk Factors for Falls in the Elderly Intrinsic Aging Age-related decline in vestibular function might lead to loss of balance, dizziness, and falls. Aging of the vision system (e.g., glaucoma, cataracts, retinopathy) may result in decreased visual acuity, inability to discriminate dark/light, and decreased spatial perception. Cardiac Cardiac arrhythmias, carotid sinus hypersensitivity, neurocardiogenic syncope. Neurologic Parkinson disease, normal pressure hydrocephalus (NPH), sensory neuropathy, dementia/impaired cognition, cervical myelopathy, senile gait disorder, prior stroke. (One third of the elderly have abnormal position sense.) Musculoskeletal Lower extremity weakness, impaired knee extension and ankle plantar flexion strength contribute to abnormalities in gait velocity and step length, deconditioning, arthritis, foot abnormalities (such as bunions, calluses, or nail abnormalities). Vascular Vertebrobasilar insufficiency, postural hypotension, postprandial hypotension. Metabolic Hypoglycemia, hypothyroidism, hyponatremia. Psychiatric Depression. Medications Use of more than four medications may be associated with an increased risk of falls. Medications that may increase fall risk include benzodiazepines, sleeping medications, neuroleptics, antidepressants, anticonvulsants, class I antiarrhythmics, and antihypertensives.

Extrinsic Environmental Environmental hazards cause >50% of falls in the elderly (cords, furniture, small objects, ill-fitting shoes, slippery surfaces, loose rugs, uneven steps, optical patterns on escalators). Majority occurs with mild-moderate activity (walking, stepping up/down, changing position); 70% occur at home and 10% on stairs (descending > ascending). Nursing Home Falls 20% have a cardiovascular cause (hypotension: drug induced, postprandial, postural, or bradycardia) 5% are the result of an acute illness such as PNA, febrile illness, UTI, CHF. 3% are from an overwhelming intrinsic event such as syncope, seizure, stroke, psychoactive drugs. Situational Tripping over obstacles, carrying heavy items, descending/ascending stairs, rapid turning, reaching overhead, climbing ladders, ill-fitting shoes, lack of assistive devices. CHF, Congestive heart failure; PNA, pneumonia; UTI, urinary tract infection.

Falls in the Elderly

ALG TABLE 2  Scales Used for Fall Risk Screening and Balance Assessment

F

Setting Instrument

Items

Multifactorial Reports STRATIFY Morse Fall Scale FROP-Com

Functional Mobility Berg Balance test Functional reach Performance-oriented mobility and balance Timed up and go Dynamic gait index Functional mobility tests Physiologic profile assessment

Five items—history of falls, agitation, visual impairment, frequent toileting, able to stand but needs assistance with moving Six items—history of falls, secondary diagnoses, parenteral therapy, use of ambulation aids, gait, mental status 13 risk factors in 26 items—fall and fall injury history, medications, medical conditions, sensory loss, feet, cognitive status, toileting, nutrition, environment, function, behavior, balance, gait; total score, 0 to 60; fall risk high with score >24 Among persons who can stand without assistance—poor balance or two of three the following: Fall history, nursing home residence, urinary incontinence Among persons who cannot stand without assistance—one of three of the following: fall history, hostel residence, use of nine or more medications 14 tasks scored 0 to 4; total range 0 to 56; fall risk increases as score decreases Distance reached in inches without moving the feet; fall risk 6 sec increased fall risk Performance in five domains: Sway, reaction time, strength, proprioception, contrast sensitivity; total score 0 to >3; fall risk increased with score ≥2

Acute

Chronic

X

X

X

X

X X

X X X

X X

X

X X X X

X X X

FROP-Com, Falls Risk for Older People in the Community; STRATIFY, St. Thomas Risk Assessment Tool in Falling elderly inpatients. From Fillit HM et al: Brocklehurst’s textbook of geriatric medicine and gerontology, ed 8, Philadelphia, 2017, Elsevier.

TABLE 3  Clinical Assessment Based on Components of Postural Control Organ System

Impairment

Clinical Evaluation

Potential Cause

Eye

Vision chart Confrontation, perimetry Stereo or depth testing

Presbyopia, macular degeneration, cataracts Glaucoma, posterior circulation stroke Monocular vision

Self-report—inability to dilate pupil in low light

Aging, miotic agents for glaucoma

Vestibular apparatus

Decreased acuity Reduced visual fields Decreased depth perception Decreased dark adaptation Otoliths Semicircular canals

Benign positional vertigo Meniere disease, vestibular hypofunction

Peripheral nerve

Peripheral neuropathy

Circulation

Reduced cerebral perfusion Orthostatic hypotension Reduced attention

Ability to detect true vertical, Hallpike maneuver Ability to detect position during rotation with eyes closed, nystagmus, visual acuity during head motion Light touch, filaments, two-point discrimination, vibratory sense Low blood pressure, altered level of consciousness, light-headedness Positional change in blood pressure Ability to perform dual tasks like timed up and go with cup of water, executive function tasks Timed tapping, timed finger to nose test, trails A test (connect the dots) Absent or slowed righting reflexes

Brain

Psychomotor slowing Altered postural reflexes Muscle

Reduced strength

Manual muscle testing, strength-based functional performance (chair rise, squat)

Musculoskeletal pain

Loss of flexibility Bone and joint deficits Disturbance of spinal cord, roots, nerves

Contractures, decreased range of motion Weight-bearing pain Leg and back pain with activity

From Fillit HM et al: Brocklehurst’s textbook of geriatric medicine and gerontology, ed 8, Philadelphia, 2017, Elsevier.

Diabetes, peripheral vascular disease, vitamin B12 deficiency Medications, arrhythmias, postprandial hypotension Medications, autonomic dysfunction, dehydration Mild cognitive impairment, dementia, medications Medications, degenerative and vascular brain diseases Parkinson disease, other extrapyramidal and degenerative brain diseases Generalized—inactivity, sarcopenia, vitamin D deficiency, myopathies Focal deficits, spinal cord and peripheral motor nerve conditions Arthritis, inactivity Arthritis, fractures, periarticular conditions, foot problems Spinal stenosis, radiculopathies, peripheral neuropathies

Diseases and Disorders

Fall risk for residential care

Community

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ETIOLOGY • Falls are a multifactorial syndrome resulting from the cumulative effects of impaired gait and balance, aging, polypharmacy, depression, cognitive impairment, acute medical illness, or environmental factors (Fig. E1). • Most falls among community-dwelling older adults are due to environmental factors, whereas falls among nursing home residents are a result of confusion, gait impairment, or postural hypotension.

DIAGNOSIS DIFFERENTIAL DIAGNOSIS Falls are often a nonspecific symptom of an acute illness (such as delirium, urinary tract infection, acute anemia, or pneumonia) or an exacerbation of a chronic disease (chronic heart failure [CHF] or chronic obstructive pulmonary disease [COPD]). The mnemonic “DELIRIUMS” can be used to assess the differential diagnosis in acute delirium. (Drugs, Emotional [depression], Low PaO2 [CHF, COPD], Infection, Retention [urinary, fecal], Ictal status, Under nutrition/hydration, Metabolic, Subdural/ Sensory [all neurologic causes] workup). WORKUP • Older adults presenting with a noninjurious fall need a detailed history and physical exam to identify acute medical illnesses and potential modifiable risk factors. Laboratory and neuroimaging studies may be necessary if the history and physical exam indicate a specific problem. ECG and Holter monitoring may be considered if cardiac arrhythmia is suspected. • See Fig. E1. LABORATORY TESTS CBC, stool guaiac, blood chemistries, thyroid function, liver function, vitamin B12 level, folate level, erythrocyte sedimentation rate, vitamin D level, drug levels, and urinalysis depending on physical/historical findings. IMAGING STUDIES • CT or MRI of the brain or cervical spine films in the presence of neurologic or gait impairment. • Chest x-ray if pulmonary pathology (pneumonia, pulmonary edema) is suspected. • Consider ECG, echocardiography, or Holter monitor if suspicious for structural cardiac abnormality or syncope.

TREATMENT NONPHARMACOLOGIC THERAPY • Physical therapy evaluation for gait and balance training, evaluation of appropriate

assisted devices (e.g., cane, walker), the use of fall prevention equipment (e.g., low beds, bed alarms). • Home safety assessment: Studies show that 50% of recurrent fallers fell doing the same activity that caused them to fall the first time. This can be prevented by creating a home safety evaluation checklist (preferably done by family member to improve compliance) or arranging for a home safety inspection by a visiting nurse or occupational therapist. • Minimization or discontinuation of certain medications associated with falls (psychotropics). • Customized exercise program to improve strength, gait, and balance. • Evaluation of proper footwear, hard sole, and low heel height.

ACUTE GENERAL Rx Hospitalization may be necessary for treatment of hip fracture, subdural hematoma, lacerations, or trauma as well as the treatment of underlying cause of the fall such as infection, metabolic disturbances, cardiovascular (e.g., carotid sinus hypersensitivity, vasovagal syndrome, bradyarrhythmias, and tachyarrhythmias) or neurologic abnormality. CHRONIC Rx • Screen and treat for osteoporosis as low bone density increases the risk of hip or other fractures. • Optimize treatment of chronic illnesses such as CHF, COPD, osteoarthritis, Parkinson disease, dementia, postural hypotension, and visual problems. • Vitamin D supplementation of at least 800 IU per day. Epidemiological studies reveal that compared with usual care, short-term intervention with oral nutritional supplementation and dietetic counseling significantly decrease falls in malnourished older adults. • Table 4 summarizes the management of impairments that contribute to instability and falls. COMPLEMENTARY & ALTERNATIVE MEDICINE T’ai chi has been shown to reduce the risk of falls in community-dwelling study participants. DISPOSITION Falls increase the older adult’s risk of hospitalization, institutionalization, and mortality. REFERRAL • Referral may be appropriate to cardiologist, ophthalmologist, neurologist, or podiatrist depending on the presence of a specific condition. • Consider referral to physical therapist for gait and balance training, evaluation for assisted device, or strengthening program.

 EARLS & P CONSIDERATIONS COMMENTS • Fear of falling may lead to restriction of activities, social isolation, and dependence. • Older adults with four or more risk factors have a 78% chance of falling. • Mortality from falls has increased by 42% over the past decade. PREVENTION The U.S. Preventive Services Task Force recommends exercise or physical therapy and vitamin D supplementation to prevent falls in community-dwelling adults aged ≥65 who are at increased risk for falls. It does not recommend automatically performing an in-depth multifactorial risk assessment in conjunction with comprehensive management of identified risks to prevent falls in community-dwelling adults aged 65 or older because the likelihood of benefit is small. In determining whether this service is appropriate in individual cases, patients and clinicians should consider the balance of benefits and harms on the basis of the circumstances of prior falls, comorbid medical conditions, and patient values. SCREENING The “get up and go test” is a quick assessment of balance and gait. A more in-depth screening tool for falls is the Tinetti gait and balance assessment, which evaluates normal and adaptive ability to maintain balance when rising from a chair, standing with eyes closed, turning, and receiving a sternal nudge. It also evaluates several components of gait (step height, postural sway, path deviation). The test is scored on the patient’s ability to perform specific tasks. Scoring is done on a 3-point scale with a range of 0 to 2. Individual scores are combined to form three measures: an overall gait assessment score (maximum score = 12), an overall balance assessment score (maximum score = 16), and a gait and balance score (maximum score = 28). In general, patients who score below 19 are at high risk for falls, and those who score 19 to 24 are at risk for falls. PATIENT & FAMILY EDUCATION Providing education and information for the patient and caregiver regarding fall prevention strategies in addition to multifactorial risk reduction strategies SUGGESTED READINGS Available at ExpertConsult.com AUTHORS: Sean H. Uiterwyk, MD, Alicia J. Curtin, PhD, and Keith Brennan, MD

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Falls in the Elderly

TABLE 4  Management of Impairments That Contribute to Instability and Falls Organ System

Impairment

Medical Management

Restorative Services

Eye

Decreased acuity Reduced visual fields

Corrective lenses Prisms in spectacles

Loss of depth perception Poor dark adaptation

Cataract removal, if indicated

Low vision rehabilitation Low vision rehabilitation, teach to scan using head rotation Teach to use shadows to detect depth

Peripheral nerve

Benign paroxysmal positional vertigo (BPPV) Meniere disease Neuropathy

Central circulation

Reduced brain perfusion Orthostatic hypotension

Brain

Effector muscle

Reduced attention Psychomotor slowing Abnormal righting reflexes Weakness

Cautious use of meclizine, diuretics; rarely, surgery Footwear to protect foot and maximize sensation Treatment varies by cause Arrhythmias—medications to control rate and rhythm, pacemakers Postprandial hypotension—frequent small meals Treatment varies by cause Adjust offending medications Autonomic neuropathy—salt loading, fluorinated corticosteroids Dehydration—hydration, reduce diuretic dose Medication adjustment Medication adjustment Antiparkinsonian medication helps bradykinesia more than balance Reduced activity—treat contributing causes (e.g., CHF, anemia, COPD, arthritis) Focal motor deficit due to spinal stenosis—sometimes surgery Myopathy—adjust offending medications, possibly steroids for myositis

Musculoskeletal

Decreased range of m motion

Pain

Bone and joint

Analgesics, injections

Spinal cord, roots, nerves

Injections, surgery, analgesics

CHF, Congestive heart failure; COPD, chronic obstructive pulmonary disease. From Fillit HM et al: Brocklehurst’s textbook of geriatric medicine and gerontology, ed 8, Philadelphia, 2017, Elsevier.

Lighting

Lighting to accent shadows, contrast Lighting

Vestibular rehabilitation Vestibular rehabilitation Assistive devices for haptic enhancement

Hand holds, railings

Compression hose, calf muscle contractions

Practice dual tasks Practice movement speed Assistive devices, practice getting up after a fall Strength-training exercises

Protective clothing Raise chair height

Orthotics, exercise, assistive devices Active and passive range of motion exercise, orthotics Physical modalities (e.g., heat, massage, assistive devices, orthoses, adaptive equipment) Orthoses, assistive devices

F

Diseases and Disorders

Vestibular system

Switching to glaucoma medications that do not cause miosis Epley maneuver

Environmental Modifications

553

Place items within easy reach Place items within easy reach

I

Falls in the Elderly

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Prevention of Falls in Older Persons Living in the Community 1 Older person encounters healthcare provider [A] 2

Sidebar: Screening for Fall(s) Questions Screen for fall(s) or risk for falling (See questions in sidebar) [B] 3

1. Two or more falls in prior 12 months? 2. Presents with acute fall? 3. Difficulty with walking or balance?

Answers positive to any of the screening questions? (See sidebar) [C]

Yes

No 4

Does the person report a single fall in the past 12 months? [D]

7

Yes 5

No

Evaluate gait and balance [E] 6

Are abnormalities in gait or unsteadiness identified?

Yes

No

1. Obtain relevant medical history, physical examination, cognitive and functional assessment 2. Determine multifactorial fall risk: a. History of falls b. Medications c. Gait, balance, and mobility d. Visual acuity e. Other neurologic impairments f. Muscle strength g. Heart rate and rhythm h. Postural hypotension i. Feet and footwear j. Environmental hazards [F]

8

Any indication for additional intervention?

Yes 9

No

10 Reassess periodically

Initiate multifactorial/multicomponent intervention to address identified risk(s) and prevent falls: 1. 2. 3. 4. 5. 6. 7. 8. 9.

Minimize medications Provide individually tailored exercise program Treat vision impairment (including cataract) Manage postural hypotension Manage heart rate and rhythm abnormalities Supplement vitamin D Manage foot and footwear problems Modify the home environment Provide education and information

FIG. E1  Guideline for the prevention of falls in older persons living in the community. (From Panel on Prevention of Falls in Older Persons, American Geriatrics Society and British Geriatrics Society: Summary of the Updated American Geriatrics Society/British Geriatrics Society clinical practice guideline for prevention of falls in older persons, J Am Geriatr Soc 59:148-157, 2011.)

Falls in the Elderly SUGGESTED READINGS Centers for Disease Control and Prevention: Home & recreational safety: falls— older adults. Available from: www.cdc.gov/homeandrecreationalsafety/falls/i ndex.html. Greenhouse AH et  al: Falls among the elderly. In Albert ML, Knoefel JE, (eds): Clinical neurology of aging, ed 2, Oxford University Press: New York. Michael YL et al: Primary care-relevant interventions to prevent falling in older patients: a systematic evidence review for the U.S. Preventive Services Task Force, Ann Intern Med 153:815-825, 2010. Moncada LV: Management of falls in older persons: a prescription for prevention, Am Fam Phys 84(11):1267-1276, 2011. Moyer VA: Prevention of falls in community-dwelling older adults: U.S. Preventive Services Task Force recommendation statement, Ann Intern Med 157:197204, 2012. Neelemaat F et al: Short-term oral nutritional intervention with protein and vitamin D decreases falls in malnourished older adults, J Am Geriatr Soc 60(4):691699, 2012. Panel on Prevention of Falls in Older Persons: American Geriatrics Society and British Geriatrics Society: summary of the Updated American Geriatrics Society/British Geriatrics Society clinical practice guideline for prevention of falls in older persons, J Am Geriatr Soc 59:148-157, 2011. Phelan EA, Ritchey K: In the clinic: fall prevention in community-dwelling older adults, Ann Int Med, 2018. Ungar A et  al: Etiology of syncope and unexplained falls in elderly adults with dementia: syncope and dementia (SYD) study, J Am Geriatr Soc 64:15671573, 2016. U.S. Preventive Services Task Force: Prevention of falls in community-dwelling older adults. www.uspreventiveservicestaskforce.org/uspstf11/fallspreventio n/fallsprevrs.htm.

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Familial Adenomatous Polyposis and Gardner Syndrome BASIC INFORMATION DEFINITION Familial adenomatous polyposis (FAP) is a highly penetrant, autosomal-dominant condition characterized by hundreds of colorectal adenomatous polyps that inevitably progress to cancer (Fig. E1). Gardner syndrome is a subset of FAP, with prominent extraintestinal manifestations including dental abnormalities, soft tissue lesions, desmoid tumors, and osteomas. ICD-10CM CODES D12.2 Benign neoplasm of ascending colon D12.3 Benign neoplasm of transverse colon D12.4 Benign neoplasm of descending colon D12.5 Benign neoplasm of sigmoid colon D12.6 Benign neoplasm of colon, unspecified

EPIDEMIOLOGY & DEMOGRAPHICS • FAP occurs in approximately 1 in 10,000 births worldwide. • FAP accounts for pleuritis > pericarditis Monoarthritis > exerciseinduced myalgia

Abdominal pain, but rarely ­serositis Arthralgia > ­oligoarticular arthritis > myalgia

Erythematous patches and edematous plaques (often annular or serpiginous); later ecchymotic in appearance; rarely oral ulcers Migrate distally on an extremity with underlying myalgia; may be more widespread Peritonitis > pleuritis, pericarditis

AD NLRP3 (CIAS1); NLRP12 1q44 Cryopyrin; monarch-1 Minutes – 3 days Cold-induced urticarial papules and plaques

Rare

Rare

Arthralgia > myalgia

Epiphyseal and patellar overgrowth, arthritis, deforming arthropathy

Ocular findings

Uncommon

Uncommon

Conjunctivitis

Neurologic ­findings

Rarely aseptic meningitis

Headache

Abdominal pain, but rarely serositis Myalgia (“lancinating limb pain”), arthralgia > large-joint ­oligoarticular arthritis Conjunctivitis, episcleritis, optic disc edema Sensorineural hearing loss; headache

Other clinical findings

Acute scrotal swelling; ­splenomegaly

Cervical LAN, HSM

Scrotal pain; splenomegaly, occasional LAN

Amyloidosis

Most common in M694V ­homozygotes Neutrophils

Rare

∼15% of cases

∼25% of cases

Uncommon

Conjunctivitis, uveitis, optic disc edema, blindness Sensorineural hearing loss; aseptic meningitis, seizures LAN, HSM; dysmorphic facies—frontal bossing, protruding eyes Late complication

Neutrophils and/ or lymphocytes; mild vasculitis common LCV/HSP

Lymphocytes, monocytes, and a few neutrophils

Neutrophils and/ or lymphocytes (sparse)

Neutrophils (perivascular)

Neutrophils (perivascular + periadnexal)

Ethnicity

Musculoskeletal findings

Dermal infiltrate in typical skin lesions Cutaneous vasculitis

LCV/HSP (5%10%), PAN (∼1%)

Migratory myalgia > arthralgia > monoarthritis

Periorbital edema, conjunctivitis, rarely uveitis Headache

Lymphocytic small vessel (rare)

Headache

NOMID (CINCA)

1q44 Cryopyrin Continuous + flares Urticarial papules and plaques; occasional oral ulcers

Familial Mediterranean Fever (FMF)

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TABLE E1  Hereditary Periodic Fever Syndromes—cont’d Hereditary Periodic Fever Syndromes Cryopyrin-associated periodic syndromes (CAPS) FMF

HIDS

TRAPS*

Laboratory abnormalities§

Low C5a inhibitor in serosal fluids

Low serum soluble TNF ­receptor-1 (100 IU/ml) and IgA1; mevalonate in urine during attacks; low lymphocyte mevalonate kinase Corticosteroids for acute attacks; anakinra; TNF inhibitors (e.g., etanercept); simvastatin

Corticosteroids; TNF inhibitors (e.g., etanercept)

MWS

Corticosteroids; IL-1/IL-1R antagonists: rilonacept, canakinumab, anakinra

FCAS† (1 and 2)

IL-1/IL-1R antagonists

NOMID (CINCA)

IL-1/IL-1R antagonists

AD, Autosomal dominant; AR, autosomal recessive; CINCA, chronic infantile neurologic, cutaneous, and articular syndrome; FCAS, familial cold autoinflammatory syndrome; FMF, familial Mediterranean fever; HIDS, hyperimmunoglobulinemia D with periodic fever syndrome; HSM, hepatosplenomegaly; HSP; Henoch-Schönlein purpura; Ig, immunoglobulin; IL, interleukin; LAN, lymphadenopathy; LCV, leukocytoclastic vasculitis; MWS, Muckle–Wells syndrome; NOMID, neonatal-onset multisystem inflammatory disease; NSAID, nonsteroidal antiinflammatory drug; PAN, polyarteritis nodosa; TNF, tumor necrosis factor; TRAPS, TNF receptor-associated periodic syndrome. *Includes familial Hibernian fever. †Also referred to as familial cold urticaria. ‡Allelic with mevalonic aciduria, which is characterized by dysmorphology, psychomotor retardation, and progressive cerebellar ataxia as well as periodic fevers and other features of HIDS. §Genetic analysis can be performed to confirm the diagnosis. ‖IgD levels are occasionally normal; elevated IgD may also be observed in FMF and TRAPS. Courtesy, Julie V Schaffer, M.D. In Bolognia J: Dermatology, ed 4, Philadelphia, 2018, Elsevier.

IMAGING STUDIES During an acute attack, depending on manifestations such as peritonitis, pleuritis, or arthritis, may see air-fluid levels, pleural effusions, and/ or synovial effusions.

TREATMENT The main goals of treatment are to (1) prevent acute attacks and (2) prevent the development of amyloidosis.

ACUTE GENERAL AND CHRONIC Rx • Supportive care during acute episodes with IVF, NSAIDs, pain control. • To prevent attacks first-line Rx is colchicine, 0.6 to 1.8 mg daily. 1. If colchicine unresponsive, possibility of noncompliance, or reconsider diagnosis. 2. Should continue colchicine in pregnant FMF patients, and it is safe to breastfeed.

• If truly colchicine unresponsive, IL-1 inhibition (anakinra, rilonacept, canakinumab) is second-line; 5% to 10% of patients are colchicine resistant. There are also successful reports of using thalidomide, TNF inhibitors, and tocilizumab.

DISPOSITION Since the usage of colchicine, most treated patients are asymptomatic and do not commonly see development of AA amyloidosis. REFERRAL Rheumatology

PEARLS & CONSIDERATIONS COMMENTS • Most patients have disease onset before age 20, and attacks typically last 1 to 3 days.

Colchicine is the standard of care for prophylaxis of attacks and prevention of amyloidosis. Should continue treatment with colchicine during pregnancy. Should question diagnosis if there is no response to colchicine. Type AA amyloidosis is the most frequent complication of FMF, with the kidneys being the most affected organ. • Contrary to expectations, the incidence of cancer in patients with FMF is significantly lower than the general population.

PREVENTION Should consider referring all first-degree relatives of FMF patients for genetic testing, whether or not they have symptoms. PATIENT & FAMILY EDUCATION https://rarediseases.info.nih.gov/diseases/6421 /disease AUTHOR: Daphne Scaramangas-Plumley, MD

Familial Mediterranean Fever (FMF) SUGGESTED READINGS Brenner R et al: Familial Mediterranean fever and incidence of cancer: an analysis of 8,534 Israeli patients with 258,803 persons-years, Arthritis Rheumatol 70:127-133, 2018. De Benedetti S et al: Canakinumab for the treatment of autoinflammatory recurrent fever syndromes, NEJM 378(20):1908-1919, 2018. Ozen S et  al: EULAR recommendations for the management of familial Mediterranean fever, Ann Rheum Dis 75:644-651, 2016. Padeh S, Berkun Y: Familial Mediterranean fever, Curr Opin Rheumatol 28:523529, 2016.

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Fatty Liver of Pregnancy, Acute  BASIC INFORMATION DEFINITION Acute fatty liver of pregnancy (AFLP) is characterized histologically by microvesicular fatty cytoplasmic infiltration of hepatocytes with minimal hepatocellular necrosis. SYNONYMS Acute fatty metamorphosis Acute yellow atrophy AFLP Acute fatty liver of pregnancy ICD-10CM CODES O26.611 Liver and biliary tract disorders in pregnancy, first trimester O26.612 Liver and biliary tract disorders in pregnancy, second trimester O26.613 Liver and biliary tract disorders in pregnancy, third trimester O26.619 Liver and biliary tract disorders in pregnancy, unspecified trimester

EPIDEMIOLOGY & DEMOGRAPHICS INCIDENCE: • Rare: 1 in 10,000 to 1 in 20,000 pregnancies • Equal frequencies in all races and at all maternal ages AVERAGE GESTATIONAL AGE: 37 wk (range 28 to 42 wk) • 20% present postnatally RISK FACTORS: • Primiparity • Multiple gestation • Male fetus • History of type 2 diabetes mellitus • Preeclampsia GENETICS: Some with a familial deficiency of long-chain 3-hydroxyacyl-coenzyme A dehydrogenase (LCHAD) PHYSICAL FINDINGS & CLINICAL PRESENTATION • Initial manifestations: 1. Nausea and vomiting (70%) 2. Pain in right upper quadrant or epigastrium (50% to 80%) 3. Malaise and anorexia • Jaundice often in 1 to 2 wk • Hypoglycemia • Late manifestations: 1. Fulminant hepatic failure 2. Encephalopathy 3. Renal failure 4. Pancreatitis 5. Gastrointestinal and uterine bleeding 6. Disseminated intravascular coagulation (10%) 7. Seizures 8. Coma • Liver: 1. Usually small 2.  Normal or enlarged in preeclampsia, eclampsia, HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets), and acute hepatitis

3. C  oexistent preeclampsia in up to 46% of patients

ETIOLOGY • Fetal long-chain L-3 hydroxyacyl-CoA dehydrogenase deficiency (LCHAD) deficiency results in transplacental passage of excess fetal fatty acids and subsequent accumulation in the maternal liver. • Postulated that inhibition of mitochondrial oxidation of fatty acids may lead to microvesicular fatty infiltration of liver. • Fatty metamorphosis of preeclamptic liver disease believed to be of different etiology.

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • Acute gastroenteritis • Preeclampsia or eclampsia with liver involvement • HELLP syndrome • Acute viral hepatitis • Fulminant hepatitis • Drug-induced hepatitis caused by halothane, phenytoin, methyldopa, isoniazid, hydrochlorothiazide, or tetracycline • Intrahepatic cholestasis of pregnancy • Gallbladder disease • Reye syndrome • Hemolytic-uremic syndrome • Budd-Chiari syndrome • Systemic lupus erythematosus WORKUP • A clinical diagnosis is based predominantly on physical and laboratory findings (Swansea criteria). • Most definitive diagnosis is through liver biopsy with oil red O staining and electron microscopy. • Liver biopsy is reserved for atypical cases only and only after any existing coagulopathy is corrected with fresh frozen plasma because of concerns for excessive bleeding. LABORATORY TESTS Tests to determine the following: • Hypoglycemia (often profound 90% of cases; Fig. E1): Africa (including Egypt), areas of Central and South America, the Pacific Islands, and the Caribbean Basin. • B. malayi: Restricted to India, Malaysia, and other parts of Southeast Asia.

• B. timori: Confined to the Indonesian archipelago. After bite of an infected mosquito: 1. Filarial larvae move into lymphatic vessels and nodes and mature into adult male (2- to 4-cm) and female (4- to 10-cm) worms (Fig. E2). Wolbachia bacteria are needed for filarial development. • After fertilization, the female nematode produces 10,000 or more microfilariae that enter into the bloodstream via the lymphatics. • Nocturnal periodicity, an increased presence of microfilariae in the circulation during the night when mosquitos are active, is important for diagnosis by blood smear. • Humans are the definitive hosts. Acute and chronic inflammatory and granulomatous changes in the lymphatic channels: • Result from complex interaction of adult worms and host’s immune systems

FIG. E1  Microfilaria of Wuchereria bancrofti in peripheral blood. (Courtesy Division of Parasitic Diseases and Malaria, Centers for Disease Control and Prevention. From Wein AJ et al: Campbell-Walsh urology, ed 11, Philadelphia, 2016, Elsevier.)

Microfilariae mature in mosquito thoracic muscle to become infective larvae

MOSQUITO

HUMAN

Microfilariae shed by female in lymphatics enter bloodstream

Adults develop in lymphatic channels

FIBROSIS AND INFLAMMATION CAUSED BY ADULTS IN LYMPHATICS

ELEPHANTIASIS

FIG. E2  Lifecycle of lymphatic filariasis. (From Souhami RL, Moxham J: Textbook of medicine, ed 4, London, 2002, Churchill Livingstone.)

Filariasis • Eventually lead to fibrosis and obstruction • Most likely to develop into obstructive lymphatic disease with recurrent exposure over many yrs, with approximately 30% of those infected going on to develop lymphedema/ hydrocele

DIAGNOSIS DIFFERENTIAL DIAGNOSIS Milroy disease, postoperative scarring, and lymphedema of malignancy WORKUP Diagnosis is suspected in individuals who have resided in endemic areas for at least 3 to 6 mo or more and complain of recurrent episodes of lymphangitis, lymphadenitis, scrotal edema, or thrombophlebitis, with or without fever. LABORATORY TESTS • Demonstration of microfilariae on a blood smear via Giemsa or Wright Stain for definitive diagnosis. Samples drawn at night, especially between 10 pm and 2 am, have the greatest yield. • Occasionally, microfilaremia in chylous urine or hydrocele fluid. • Prominent eosinophilia only during periods of acute lymphangitis or lymphadenitis. • Serologic tests for antibody, including enzyme-linked immunosorbent assay and indirect fluorescent antibody (often unable to distinguish among the various forms of filariasis or between acute and remote infection). • Immunoassays (e.g., circulating filaria antigen [CFA]): More successful in antigen detection in patients who are microfilaremic than in those who are amicrofilaremic. IMAGING STUDIES • Chest radiography: Reticular nodular infiltrates (tropical pulmonary eosinophilia syndrome).

569.e7 • In men proven to be microfilaremic, scrotal ultrasonography to aid in the detection of adult worms and “filarial dance sign” may be seen.

TREATMENT NONPHARMACOLOGIC THERAPY • Standard of care for elephantiasis: 1. Elevation of the affected limb 2. Use of elastic stockings 3. Local foot care • General wound care for chronic ulcers and prevention of secondary infection • Surgical intervention may be necessary for hydrocele ACUTE GENERAL Rx • Diethylcarbamazine citrate (DEC) to reduce microfilaremia by 90%. 1. Effect on adult worms, especially those of the Wuchereria species, less certain. 2. Given in an oral dose of 6 mg/kg PO qd in 3 divided doses × 14 days or 6 mg/kg/ day as single PO dose daily × 14 days plus doxycycline 200 mg/day × 6 wk (to decrease number of Wolbachia and number of microfilaria). 3. DEC should not be used if coinfection with Loa loa or onchocerciasis is suspected, because of severe adverse reactions, including blindness and death. • Ivermectin alone or in combination with DEC to decrease microfilaremia. Ivermectin kills the microfilariae but does not kill adult worms. • Side effects of these drugs include severe hypotensive reactions with dizziness, headache, fever, and vomiting, especially in patients with high microfilarial loads. • World Health Organization (WHO) recommendation: DEC given as a single dose, alone or (preferably) in combination with ivermectin as treatment in endemic areas.

SUGGESTED READINGS Fox LM: Lymphatic filariasis. In CDC Yellow book 2018: health information for international travel, New York, 2017, Oxford University Press. Molyneux DH: Tropical lymphedemas—control and prevention, N Engl J Med 366:1169-1171, 2012.

• Antibacterial agents (a penicillin or cephalosporin) may be indicated to treat coexisting bacterial soft tissue infection (cellulitis or lymphangiitis), which frequently complicates filariasis of the lower extremities. • Doxycycline for 1 to 2 mo may decrease the number of adult worms and improve lymphatic pathology. • A recent trial revealed that a single dose of a three-drug regimen of ivermectin, diethylcarbamazine, and albendazole results in a greater clearance of microfilariae than a single dose of a two-drug regimen of diethylcarbamazine plus albendazole.1

CHRONIC Rx • Surgical drainage of hydroceles • No satisfactory therapy for patients with chyluria DISPOSITION Rarely fatal, but the psychological impact of limb and scrotal deformities associated with elephantiasis is substantial REFERRAL To a surgeon for management of hydrocele; to a lymphedema therapist when appropriate PREVENTION Individuals who intend to travel or reside in endemic areas should be advised to institute preventive measures such as the use of netting and insect repellents containing DEET, especially at night when mosquitos transmitting disease are most active. AUTHORS: Tara C. Bouton, MD, MPH, TM, Philip A. Chan, MD, MS, and Glenn G. Fort, MD, MPH

1 King

CL et al: A trial of a triple-drug treatment for lymphatic filariasis, N Engl J Med 379:1807-1810, 2018.

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Focal Seizures  BASIC INFORMATION DEFINITION Focal seizures are characterized by focal cortical discharges that provoke seizure symptoms related to the area of the brain involved. Focal aware seizures (previously known as simple partial seizures) do not cause impairment of consciousness. However, focal aware seizures can evolve into focal impaired awareness (previously known as complex partial) and/or tonic clonic seizures. In the revised International League Against Epilepsy (ILAE) classification of seizures, the name “partial seizures” has been replaced with “focal seizures.” SYNONYMS Simple partial seizures Seizures, partial Partial seizures ICD-10CM CODES G40.0 Localization-related (focal) (partial) idiopathic epilepsy and epileptic syndromes with seizures of localized onset G40. Localization-related (focal) (partial) 109 symptomatic epilepsy and epileptic syndromes with simple partial seizures, not intractable, without status epilepticus

EPIDEMIOLOGY & DEMOGRAPHICS INCIDENCE: 30 to 50 cases per 100,000 person per yr PREVALENCE: 5 to 8 cases per 1000 persons PREDOMINANT SEX AND AGE: No gender preference PHYSICAL FINDINGS & CLINICAL PRESENTATION • Patients with focal seizures usually have normal physical and neurologic examinations unless secondary due to a structural abnormality such as a stroke, where the patient will have a neurologic exam consistent with the area of CNS structural damage. • During focal seizures the patients are conscious, but they may have an alteration of awareness. However, if there is spread of the epileptic focus causing secondary generalization, the patient will then lose consciousness and evolve into a generalized tonic clonic seizure. Clues to this progression include a subjective aura before the onset of convulsion, unilateral shaking, and head turning to one side (versive head turning). • Patients with focal seizures can experience postictal weakness/paralysis that usually resolves within 24 hr (Todd paralysis). However, focal neurologic deficits may also be indicative of a new structural brain lesion. • Manifestations of focal impaired awareness seizures may include automatisms (semipurposeful behaviors) such as fumbling of fingers or lip smacking.

ETIOLOGY • Seizures in general are a cardinal sign of cortical neurologic injury. • The etiology of focal seizures can be either genetic or due to a neurologic injury. • Frequent causes of focal seizures are tumors, stroke, CNS infections (neurocysticercosis among others), arteriovenous malformations (AVMs), cavernous malformations, traumatic brain injury, cortical dysplasia, and structural abnormalities.

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • Transient ischemic attack • Movement disorders • Psychogenic nonepileptic spells • Migraines • The differential diagnosis of nonepileptic events is summarized in Table 1. Table 2 summarizes clinical characteristics that help distinguish epileptic from nonepileptic events WORKUP EEG. Ambulatory EEG and/or video EEG recommended for patients with diagnostic uncertainty LABORATORY TESTS Routine blood workup (CBC, CMP, glucose, electrolytes) may be considered in appropriate clinical situations. IMAGING STUDIES • In the acute setting, a CT scan of the head is high yield to rule out space-occupying lesions. • MRI of the brain with a defined epilepsy protocol should be performed in all patients with recurrent seizures.

TREATMENT • Almost all antiepileptic drugs are approved for focal seizures, either in monotherapy or in adjunct. Carbamazepine traditionally has

been the standard initial drug treatment for focal seizures. However, newer antiepileptic drugs have better side effect profiles. • Lamotrigine, levetiracetam, and oxcarbazepine are effective and well-tolerated antiepileptic drugs for treating focal seizures. • Eslicarbazepine is indicated for the treatment of focal-onset seizures as monotherapy or adjunctive therapy. The recommended initial dose of eslicarbazepine is 400 mg once daily. Increase the dose in weekly increments of 200 mg, based on clinical response and tolerability, to a recommended maintenance dose of 800 to 1600 mg once daily. • Lacosamide is indicated as monotherapy or adjunctive therapy in patients with focalonset seizures. The initial recommended dose is 50 mg twice daily; increase at weekly intervals by 50 mg twice daily, up to a recommended maintenance dose of 100 to 200 mg twice daily. • Patients who continue to have seizures despite a trial of two antiepileptic drugs and adequate doses should be referred for evaluation for epilepsy surgery. Surgical treatments (e.g., temporal lobectomy in mesial temporal sclerosis) may be indicated in refractory cases of focal seizures.

GENERAL Rx • After a first unprovoked seizure with normal examination, imaging, and EEG, no treatment may be necessary, although patients may elect to undergo treatment. • According to a recent joint American Academy of Neurology and American Epilepsy Society evidence-based guideline on the management of a first unprovoked seizure in adults, there is strong evidence that the risk of a second seizure is highest in the first 2 yr and ranges from 21% to 45%. This risk is higher for patients with prior brain insults such a traumatic brain injury or stroke or those with epileptiform abnormalities on EEG. Significant brain imaging abnormalities and nocturnal seizures also indicate a more elevated risk of recurrent seizures. Chronic treatment with antiepileptic drugs is indicated for more than

TABLE 1  Differential Diagnosis of Nonepileptic Events General Medical Conditions • Transient ischemic attack (TIA) • Complicated migraine • Syncope • Hypoglycemia • Parasomnia (e.g., rapid eye movement [REM], behavior disorder, or night terrors) • Narcolepsy • Myoclonus (from metabolic disturbance) Psychiatric Causes • Conversion disorder • Somatic symptom disorder • Dissociative disorder • Panic disorder (simulating focal seizures) Volitional Deception • Factitious disorder (goal is to maintain the sick role) • Malingering (goal is to obtain secondary gain, e.g., disability income) From Stern TA et al: Massachusetts General Hospital handbook of general hospital psychiatry, ed 7, Philadelphia, 2018, Elsevier.

Focal Seizures TABLE 2  Clinical Characteristics That Help Distinguish Epileptic from Nonepileptic Events

Onset Duration Perception

Nonepileptic Seizures/Events

Sudden onset and offset Often 16 hr): Some toxin-mediated, some invasive. • Toxin-producing organisms include: 1.  C. botulinum: Should be considered when a diarrheal illness coincides with or precedes paralysis; severity of illness related to the quantity of toxin ingested; characteristic cranial nerve palsies progressing to a descending paralysis; fever usually absent; usually associated with homecanned foods. 2. Enterotoxigenic E. coli (ETEC): Most common cause of travelers’ diarrhea; after

1- to 2-day incubation period, abdominal cramps and copious diarrhea occur; vomiting and fever uncommon; usually resolves after 3 to 4 days; vehicle usually unbottled water or contaminated salad or ice. 3. Enterohemorrhagic E. coli (EHEC): Can cause severe abdominal cramps and watery diarrhea, which may eventually become bloody; bacteria (strain O157:H7) are noninvasive; no fever; illness may be complicated by hemolytic-uremic syndrome; associated with contaminated beef (especially hamburger), unpasteurized milk or juice. Table 3 summarizes the various strains of diarrheagenic E. coli. 4. V. cholerae: Varies from a mild, selflimited illness to life-threatening cholera; diarrhea, nausea, and vomiting, abdominal cramps, and muscle cramps; no fever; severe cases may progress to shock and death within hours of onset; survivors usually have resolution of symptoms in 1 wk; U.S. cases are either imported or result from ingestion of imported food. • Invasive organisms include: 1.  Salmonella: Associated most often with nontyphoidal strains; incubation period generally 12 to 48 hr; nausea, vomiting, diarrhea, and abdominal cramps typical; fever possible; outbreaks of gastroenteritis related to contaminated poultry, meat, and dairy products. 2. Shigella: Asymptomatic infection possible, but some with fever and watery diarrhea that may progress to bloody diarrhea and dysentery; with mild illness, usually self-limited, resolves in a few days; with severe illness, may develop complications; transmission usually from person to person but can occur via contaminated food or water. 3.  C. jejuni: The most common foodborne bacterial pathogen; incubation period is about 1 day, then a prodrome of fever, headache, and myalgias; intestinal phase marked by diarrhea associated with fever, malaise, and abdominal pain; diarrhea mild to profuse and bloody; usually resolves in about 7 days, but relapse is possible; associated with undercooked meats and poultry, unpasteurized dairy products, and drinking from freshwater streams. 4. Y. enterocolitica and Y. pseudotuberculosis: Infrequent causes of enteritis

TABLE 1  Pathogenic Mechanisms in Bacterial Foodborne Disease Preformed Toxin

Toxin Production in Vivo

Tissue Invasion

Toxin Production and/or Tissue Invasion

Staphylococcus aureus Bacillus cereus (short incubation) Clostridium botulinum

Clostridium perfringens B. cereus (long incubation) C. botulinum (infant botulism) Enterotoxigenic Escherichia coli Vibrio cholerae O1 or O139 V. cholerae non-O1 Shiga toxin–producing E. coli

Campylobacter jejuni Salmonella Shigella Invasive E. coli

Vibrio parahaemolyticus Yersinia enterocolitica

From Mandell GL et al: Principles and practice of infectious diseases, ed 6, Philadelphia, 2005, Churchill Livingstone.

Food Poisoning, Bacterial TABLE 2  Foodborne Disease Agents and Clinical Presentation Usual Incubation Periods Causative Agent

F

Clinical Illness Fever

Diarrhea

Vomiting

Chemical or toxin

Rare

Occasional

Common

Staphylococcus aureus enterotoxin Bacillus cereus emetic toxin

Rare

Occasional

Profuse

Rare

Occasional

Profuse

6-24 h

Rare

Typical

Occasional

Rare

Typical

Occasional

12-72 h

Clostridium perfringens enterotoxin B. cereus enterotoxin Clostridium botulinum

Constipation more common

16-96 h

Shigella

Clinical sydrome compatible with botulism Common

Nontyphoidal Salmonella Enteroinvasive E. coli (EIEC)

Common Common

Enteropathogenic E. coli (EPEC) Enterotoxigenic E. coli (ETEC) Vibrio parahaemolyticus; V. cholerae enterotoxin Caliciviruses (noroviruses) Rotavirus

1-10 days

Occasional

Occasional

Typical, often bloody Typical Typical, may be bloody Typical

Rare Occasional

Typical Typical

Rare Occasional

Occasional

Typical

Common

Yersinia

Uncommon

Uncommon

2-10 days

Campylobacter jejuni

Common

1-11 days

Cryptosporidium

Occasional

Typical, severe abdominal pain Typical, often bloody Common

Cyclospora

Occasional

Common

Occasional

Giardia intestinalis

Occasional

Common

Occasional

2 days-wks

Bacillus anthracis

Common

Typical

Frequent

1-7 days

E. coli O157:H7 and other Shiga toxin–producing E. coli Salmonella typhi

Uncommon

Typical

Frequent

Common

Uncommon

Brucella spp.

Common

Diarrhea or constipation Common

1-4 wk

Giardia lamblia

Rare

Common

Rare

2 days-8 wk

Trichinella spiralis

Common

Common

Common

3-60 days, usually 7-14 7-21 days

Epidemiologic and Laboratory Diagnosis Demonstration of toxin or chemical from food or epidemiologic incrimination of food Isolation of organisms in food (>105/g)/vomitus/ stool; detection of enterotoxin in food Isolation of organisms in food (>105/g)/vomitus/ stool Isolation of organisms or toxin from food (105/g) or stools of ill persons, epidemiologic incrimination of food; detection of enterotoxin in food

Occasional Occasional

Isolation of organism or toxin from food (105/g) or stools; demonstration of toxin in serum or food Isolation of organism from clinical specimens from two or more ill persons; isolation of organism from epidemiologically implicated food

Occasional

Uncommon

Antigen detection (enzyme immunoassay) in stool; immune electron microscopy of stool; detection of viral RNA in stool or vomitus by PCR Isolation of organisms from food or clinical specimens of ill persons Isolation of organisms from food or clinical specimens of ill persons Demonstration of oocysts in stool or in small bowel biopsy of ill persons; demonstration of organism in epidemiologically implicated food Demonstration of parasite in stool or in small bowel biopsy of ill persons; demonstration of organism in epidemiologically implicated food Demonstration of parasite in stool or in small bowel biopsy of ill persons; demonstration of organism in epidemiologically implicated food Isolation of organism from blood or contaminated meat Isolation of organism from food or stool or identification of toxin in stools of ill persons

Occasional

Rare

Isolation of organisms from food or clinical specimens of ill persons Isolation of organisms from blood or bone marrow culture of ill persons; fourfold increase in standard agglutination titer overall several wks or single titer 1:160 in person with compatible clinical syndrome Stool for ova and parasite examination enzyme immunoassay Serology, muscle biopsy

PCR, Polymerase chain reaction; RNA, ribonucleic acid. From Cherry JD et al: Feigin and Cherry’s Pediatric infectious diseases, ed 8, Philadelphia, 2019, Elsevier.

in the United States; children affected more often than adults; fever, diarrhea, and abdominal pain lasting 1 to 3 wk; some with mesenteric adenitis that mimics acute appendicitis; contaminated food or water is usually responsible.

5.  V. parahaemolyticus: In the United States, most outbreaks in coastal states or on cruise ships during the summer months; incubation period usually >1 day, followed by explosive watery diarrhea in the majority of cases; nausea, vomiting, abdominal cramps, and headache also

common; fever less common; usually resolves by 1 wk; related to ingestion of seafood. 6. Enteroinvasive E. coli (EIEC): A rare cause of disease in the United States; high ­incidence of fever and bloody diarrhea; may resemble bacillary dysentery.

Diseases and Disorders

5 min-6 h (usually 60 days are generally safe to eat.) • Do not eat home-canned foods that were not known to be adequately heat processed during canning.

Recommendations for Persons at High Risk, Such as Pregnant Women and People With Weakened Immune Systems, in Addition to the Recommendations Listed Above

Measures to Prevent a Variety of Bacterial Infections • Do not eat uncooked sprouts. • Do not drink prepackaged juice or juice-containing beverages that have not been processed to reduce or eliminate microbial contamination (e.g., by pasteurization). Listeriosis Prevention Measures • Do not eat soft cheeses, such as feta, Brie, and Camembert; blue-veined cheeses; and Mexican-style cheeses, such as queso blanco, queso fresco, and panela, unless the package has a label that clearly states that the cheese is made from pasteurized milk. • Do not eat refrigerated pâtés or meat spreads. Canned or shelf-stable pâtés and meat spreads are safe to eat. • Do not eat refrigerated smoked seafood unless it is contained in a cooked dish, such as a casserole. Refrigerated smoked seafood, such as salmon, trout, whitefish, cod, tuna, and mackerel, is most often labeled as “nova-style,” “lox,” “kippered,” “smoked,” or “jerky.” The fish is found in the refrigerator section or sold at delicatessen counters of grocery stores and delicatessens. Canned or shelf-stable smoked seafood is safe to eat. • Do not eat hot dogs, luncheon meats, or delicatessen meats unless they are reheated until steaming hot. • Avoid getting fluid from hot dog packages on other foods, utensils, and food preparation surfaces, and wash hands after handling hot dogs, luncheon meats, and delicatessen meats. Salmonellosis Prevention Measures • Choose pasteurized eggs. Vibriosis, Toxoplasmosis, and Norovirus Prevention Measures • Do not eat raw or lightly steamed oysters, clams, or other raw shellfish (especially important for patients with liver disease). More food safety information can be found at www.foodsafety.gov/keep/index.html. *Poultry: 165°F (73.9°C); ground meats: 160°F (71.1°C); intact cuts of beef, pork, ham, veal, and lamb: 145°F (62.8°C) and allow to rest for at least 3 minutes before eating; fish and shellfish: 145°F (62.8°C); egg dishes: 160°F (71.1°C). From Bennett JE, Dolin R, Blaser MJ: Mandell, Douglas, and Bennett’s principles and practice of infectious diseases, ed 8, Philadelphia, 2015, Saunders.

Food Poisoning, Bacterial SUGGESTED READINGS Braden CR, Tauxe RV: Emerging trends in foodborne diseases, Infect Dis Clin North Am 27:517-533, 2013. Donnenberg MS, Narayanan S: How to diagnose a foodborne illness, Infect Dis Clinics North Am 27:535-554, 2013. DuPont HL: Acute infectious diarrhea in immunocompetent adults, N Engl J Med 370:1532-1540, 2014. Kalyoussef S, Feja KN: Foodborne illnesses, Adv Pediatr 61:287-312, 2014. Switaj TL, Winter KJ, Christensen SR: Diagnosis and management of foodborne illness, Am Fam Physician 92:358-365, 2015.

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Friedreich Ataxia BASIC INFORMATION DEFINITION Friedreich ataxia is the most common hereditary neurodegenerative ataxic disorder. It results in degeneration of the dorsal root ganglia, posterior columns, spinocerebellar and corticospinal tracts, and large sensory peripheral neurons. ICD-10CM CODE G11.1 Early-onset cerebellar ataxia

EPIDEMIOLOGY & DEMOGRAPHICS INCIDENCE (IN U.S.): Estimated at 1 in 30,000 Caucasians PEAK INCIDENCE: 8 to 15 yr PREVALENCE (IN U.S.): 2 to 4 per 100,000. Carrier rate 1:120 to 1:160; lower prevalence in people of Asian or African descent PREDOMINANT SEX: Males and females affected equally GENETICS: Autosomal recessive; 96% of affected patients are homozygous and 4% are compound heterozygous (two different mutations). Trinucleotide repeat expansion accounts for 94% to 98% of cases, whereas point mutations account for 2% to 6% of cases. PHYSICAL FINDINGS & CLINICAL PRESENTATION • Onset of progressive appendicular and gait ataxia, with absent muscle stretch reflexes in the lower extremities • With disease progression (within 5 yr): Dysarthria, distal loss of position and vibration sense, pyramidal leg weakness, areflexia in all four limbs, and extensor plantar responses • Common findings: Progressive scoliosis, distal atrophy, pes cavus, and cardiomyopathy (symmetric concentric hypertrophic form in most cases) • Insulin-requiring diabetes mellitus may occur in 10% of patients with glucose intolerance occurring in an additional 10% to 20%

WORKUP • Specific gene testing for the expanded GAA trinucleotide repeat (only required test). Other tests, listed below, support the diagnosis but are not specific like genetic testing. • Diagnostic criteria include electrophysiologic evidence for a generalized axonal sensory or sensorimotor neuropathy. • ECG may show widespread T-wave inversion and evidence of left ventricular hypertrophy. ECG abnormalities are present in 65% of patients. • Sural nerve biopsy shows loss of large myelinated fibers. LABORATORY TESTS • Genetic testing • Electromyography or nerve conduction study • ECG and echocardiogram • Peripheral blood smear for acanthocytes • Lipid profile • 2-hour glucose tolerance test • Vitamin E levels (if necessary) IMAGING STUDIES MRI of the spinal cord may demonstrate spinal cord atrophy with essentially normal cerebrum, brainstem, and cerebellum (Fig. E1).

NONPHARMACOLOGIC THERAPY • Surgical correction of scoliosis and foot deformities in selected patients • Prosthetic devices as required (e.g., anklefoot orthosis for footdrop) • Physical therapy • Communication devices for patients with severe dysarthria ACUTE GENERAL Rx None established. • An antioxidant, idebenone (short-chain analogue of coenzyme Q10), administered orally at 5 to 20 mg/kg/day with or without vitamin E has demonstrated inconsistent effects on neurologic, cardiac, and psychosocial outcome measures in clinical trials. • Further research with various antioxidants and iron chelators is ongoing. An open-label pilot study of antioxidants (coenzyme Q10, 400 mg/day, and vitamin E, 2100 U/day) in a small cohort demonstrated slowing in progression of generalized ataxia and kinetic dysfunction and significant improvement in cardiac function with unaltered deterioration in posture, gait, and hand dexterity. CHRONIC Rx Chronic management of congestive heart failure is required. Cardiac arrhythmias will warrant pacemaker implantation. DISPOSITION • Loss of ambulation typically occurs within 15 yr of symptom onset, and 95% are wheelchair bound by age 45 yr. • Life expectancy is reduced, particularly if heart disease is present.

A

ETIOLOGY • Genetic: Frataxin gene is localized to the centromeric region of chromosome 9q13. • Normal sequence has 6 to 27 repeats; abnormal sequence has 120 to 1700 GAA repeats. • Frataxin deficiency leads to impaired mitochondrial iron homeostasis.

REFERRAL • Neurologist for evaluation and diagnosis • Genetic counseling (recommended if available) • Cardiologist to manage cardiomyopathy and electrophysiologic abnormalities

PEARLS & CONSIDERATIONS Friedreich ataxia should be considered in all preadolescent and adolescent children presenting with progressive ataxia. Early recognition of cardiac failure and arrhythmias and institution of appropriate therapy helps prolong survival.

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • Charcot-Marie-Tooth disease type 2 • Abetalipoproteinemia • Severe vitamin E deficiency with malabsorption • Early-onset cerebellar ataxia with retained reflexes • Autosomal-dominant cerebellar ataxia (spinocerebellar ataxia)

TREATMENT

B FIG. E1  T1 magnetic resonance image of the brain (midsagittal section) and spinal cord (axial slice at level of the dens) showing severe shrinkage of the cervical cord, but the cerebellum and brain stem are of normal size. (From Goetz CG: Textbook of clinical neurology, Philadelphia, 1999, Saunders.)

RELATED CONTENT Friedreich Ataxia (Patient Information) AUTHORS: Joseph S. Kass, MD, JD, FAAN, and Fariha Jamal, MD

Frontotemporal Dementia BASIC INFORMATION

SYNONYMS • FTD • FTLD • Frontotemporal lobar degeneration (FTLD) is the term used for the neuropathologic findings seen in the different FTD syndromes. • Pick disease: This term was historically used to refer to FTD. However, it is now strictly a neuropathologic diagnosis for patients found to have Pick bodies at autopsy, as very few diagnoses of FTD are associated with these neuropathologic findings. ICD-10CM CODES G31.0 Frontotemporal dementia G31.01 Pick disease G31.09 Other frontotemporal dementia

EPIDEMIOLOGY & DEMOGRAPHICS The current data on epidemiology of FTD are variable due to misdiagnosis and underreporting. The following data are estimations obtained through systematic reviews. INCIDENCE: The estimated annual incidence is 2.7 to 4.1 per 100,000 persons.

Some patients meet criteria for both FTD and amyotrophic lateral sclerosis. • Although behavioral changes can also occur in the other FTD syndromes SD and PNFA, these two primarily have language deficits that precede the behavioral changes. 1. SD is characterized by a gradual loss of the knowledge of words, objects, and concepts, with preservation of speech fluency and syntax. 2. PNFA is characterized by effortful, nonfluent speech, word-finding difficulties, and agrammatism, with preservation of single-word comprehension.

PHYSICAL FINDINGS & CLINICAL PRESENTATION • The early stage of bvFTD is characterized by changes in behavior and personality. Patients display a lack of insight into these changes, and family members may initially think they are suffering a midlife crisis or a new-onset psychiatric disorder. Therefore, careful history-taking is required. • Behavioral changes include disinhibition, impulsivity, distractibility, violation of social norms (such as offensive, insensitive, or inappropriate sexual remarks; inappropriate behaviors; inappropriately explicit or personal conversations; or encroachment on the personal space of others), as well as increased irritability and impulsive criminal behavior (such as shoplifting or violating traffic laws). • Patients also display decreased ability to empathize with others, insensitivity to the needs and emotions of their loved ones, and distance/detachment in their personal relationships. • Apathy and inertia are also common symptoms, with possible development of immobility as the disorder progresses. • Other associated symptoms that may develop are changes in language and speech (verbal aspontaneity, stereotyped phrases, mutism in late stages), repetitive motor movements, or hyperphagia. • Physical exam findings for bvFTD can include upper and/or lower motor neuron signs, dysarthria, dysphagia, and pseudobulbar affect.

DIAGNOSIS Diagnosis of bvFTD is primarily clinical, with neuroimaging and pathology/genetics required for further confirmation. In 2011, the International Behavioral Variant FTD Consortium (FTDC) developed revised criteria for the diagnosis of bvFTD (Table 3). • In summary, six core symptoms that can be seen in bvFTD were identified. The presence of any three is sufficient to diagnose possible bvFTD. • Diagnosis of probable bvFTD requires meeting the following three conditions: (1) patient has diagnosed possible bvFTD, (2) significant functional decline, and (3) frontal and/ or anterior temporal atrophy/hypoperfusion seen on imaging. • Diagnosis of definitive bvFTD can be made only when the patient has possible or probable bvFTD, plus either (1) pathologic evidence of FTLD on biopsy or postmortem, or (2) presence of a known causal genetic mutation.

DIFFERENTIAL DIAGNOSIS • Other neurodegenerative disorders, including Alzheimer disease (AD), idiopathic Parkinson disease, dementia with Lewy bodies, corticobasal syndrome, progressive supranuclear palsy, and chronic traumatic encephalopathy

TABLE 1  Clinical, Genetic, and Pathologic Correlations in Frontotemporal Lobar Degeneration Clinical Presentation

% of FTLD

bvFTD

57%

Comorbidities Associated Genes Parkinsonism C9orf72 GRN MAPT VCP CHMP2B

nfvPPA

24% C9orf72 GRN MAPT

svPPA

++ + + +/− +/−

19%

+ ++ +

Neuropathologic Subtypes

MND

IBM PDB

FTLD-tau

FTLD-TDP

+

+

+/−

++

++

+ + +

++

+/− + + + +/−

Type B > A Type A

FTLD-FUS FTLD-UPS FTLD-ni +

+/−

+/−

+/−

+ +/− +/− +/−

+

Type D + ++

+ Type A

+/−

+ +/−

++ (Type C)

Rarely genetic Number of plus signs (+) signifies relative frequency of the observation; +/− indicates rare observation. bv, Behavioral variant; FTLD, frontotemporal lobar degeneration; FUS, fused in sarcoma; IBM, inclusion body myopathy; MND, motor neuron disease; nfv, agrammatic or nonfluent variant; ni, no inclusions; PDB, Paget disease of the bone; PPA, primary progressive aphasia; sv, semantic variant; TDP, TAR DNA-binding protein; UPS, ubiquitin-proteasome system. From Fillit HM: Brocklehurst’s textbook of geriatric medicine and gerontology, ed 8, Philadelphia, 2017, Elsevier.

F

Diseases and Disorders

DEFINITION Frontotemporal dementia (FTD) is an umbrella term that encompasses three distinct syndromes: behavioral variant FTD (bvFTD), semantic dementia (SD), and progressive nonfluent aphasia (PNFA). All three syndromes are marked by frontal and/or temporal lobe atrophy; however, they manifest with different clinical presentations. The most common subtype is bvFTD, which is marked by changes in behavior and personality with disinhibition and the breaking of social norms. SD is characterized by a loss of word comprehension and meaning, and PNFA presents with agrammatic, nonfluent speech.

PREVALENCE: The estimated point prevalence is 15 to 22 per 100,000 persons. PREDOMINANT SEX AND AGE: There is a nearly equal distribution by sex, and the average age of presentation is 58 yr. GENETICS: Approximately 40% of FTD cases have a positive family history, and several genes (Table 1) have been associated with the development of familial FTD. The most common are mutations in C9ORF72, MAPT, and GRN (Table 2).

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Frontotemporal Dementia TABLE 2  Gene Mutations Associated with Frontotemporal Dementia

Gene

Chromosome

Protein

Protein Function

C9ORF72 MAPT

9p21.2 17q21.31

GRN

17q21.31

Unknown Microtubule-associated tau protein Progranulin

Unknown Microtubule stabilization and assembly Activates signaling cascades for development, inflammation, and wound repair

Mode of Inheritance

Mutation Frequency in Familial FTD

Mutation Frequency in Sporadic FTD

Age of Onset (Mean, Range)

AD AD

21% 6.3%

6% 1.5%

50s (mid 20-80s) Mid-50s (20-80s)

AD

5%-15%

5%

60s (mid 30-80s)

AD, Autosomal dominant; FTD, frontotemporal dementia. From Deleon J, Miller BL: Frontotemporal dementia. In Daniel CK, Geschwind H, Paulson HL (eds), Handbook of clinical neurology, ed 148, Philadelphia, 2018, Elsevier, pp 409-430.

TABLE 3  International Consensus Criteria for Behavioral Variant FTD Must be present for any FTD clinical syndrome: • Shows progressive deterioration of behavior and/or cognition by observation or history Possible bvFTD • Three of the features (A-F) must be present; symptoms should occur repeatedly, not just as a single instance: A. Early (3 yr) behavioral disinhibition B. Early (3 yr) apathy or inertia C. Early (3 yr) loss of sympathy or empathy D. Early (3 yr) perseverative, stereotyped, or compulsive/ritualistic behavior E. Hyperorality and dietary changes F. Neuropsychological profile: executive function deficits with relative sparing of memory and visuospatial functions Probable bvFTD • All the following criteria must be present to meet diagnosis: A. Meets criteria for possible bvFTD B. Significant functional decline C. Imaging results consistent with bvFTD (frontal and/or anterior temporal atrophy on CT or MRI or frontal hypoperfusion or hypometabolism on SPECT or PET) Definite bvFTD • Criteria A and either B or C must be present to meet diagnosis: A. Meets criteria for possible or probable bvFTD B. Histopathological evidence of FTLD on biopsy at post mortem C. Presence of a known pathogenic mutation Exclusion criteria for bvFTD • Criteria A and B must both be answered negatively; criterion C can be positive for possible bvFTD but must be negative for probable bvFTD: A. Pattern of deficits is better accounted for by other non-degenerative nervous system or medical disorders B. Behavioral disturbance is better accounted for by a psychiatric diagnosis C. Biomarkers strongly indicative of Alzheimer disease or other neurodegenerative process Additional features • Presence of motor neuron findings suggestive of motor neuron disease • Motor symptoms and signs similar to corticobasal degeneration and progressive supranuclear palsy • Impaired word and object knowledge • Motor speech deficits • Substantial grammatical deficits bvFTD, Behavioral variant frontotemporal dementia; FTD, frontotemporal dementia; FTLD, frontotemporal lobar degeneration; SPECT, single-photon emission computed tomography. From Rascovsky K et al: Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia TT, Brain 2011;134:1-22.

• Psychiatric disorders (bipolar disorder, schizophrenia, obsessive-compulsive disorder, depression, personality disorders) • Metabolic disturbances or nutritional deficiencies (hypothyroidism, B12 deficiency) • Substance abuse/toxicities (ethanol, drugs of abuse, heavy metal poisoning) • Infections (meningitis, HIV-associated dementia, neurosyphilis) • Cerebrovascular disease (stroke, vascular dementia, lacunar infarctions) • CNS tumors

WORKUP • Careful history-taking with specific attention paid to initial symptoms, time course, progression of symptoms, family history, psychiatric history, and other medical history • Comprehensive neurologic physical exam to help rule out other CNS etiologies • Use of the International Behavioral Variant FTD Criteria for diagnosis (Table 3). • Genetic testing for causal mutations of FTD (C9ORF72, MAPT, and GRN).

• Medication review (especially drugs that may alter mental status, such as anticholinergics, opiates, benzodiazepines, barbiturates, and neuroleptics) • Neuropsychological tests of executive function, memory, and social cognition to rule out other neurodegenerative disorders • Psychiatric evaluation to rule out psychiatric disorders

LABORATORY TESTS • CBC, serum electrolytes, glucose, BUN/creatinine, liver function tests • Cerebrospinal fluid (CSF) analysis for infection and measurement of CSF tau and amyloid (which can help differentiate between FTD and AD) • Vitamin B12, thyroid function tests, HIV, and syphilis screening • Urine toxicity screen • In vivo histopathology: 1. Almost all cases of FTLD have one of the following protein inclusions found on pathologic examination: TAR DNAbinding protein with molecular weight 43 kDa (TDP-43), microtubule-associated protein tau (MAPT), or fusedin-sarcoma protein (FUS). If feasible and as medical technology advances, in vivo histopathologic testing can confirm the diagnosis. IMAGING STUDIES • In general, structural MRI and CT will show gray matter atrophy in the frontal and/or temporal lobes, anterior cingulate cortex, and insula with variation in distribution between the different FTD subtypes. 1. Patients with bvFTD specifically will usually show atrophy in the orbitofrontal, anterior cingulate, anterior insular, and anterior temporal cortices. 2. SD is associated with atrophy in the temporal poles, and PNFA with atrophy in the left perisylvian region. • A normal MRI scan does not exclude FTD, however, because changes may not be seen in early stages of the disorder. In these cases, PET or SPECT can be used to visualize areas of hypoperfusion/ hypometabolism.

Frontotemporal Dementia TREATMENT

NONPHARMACOLOGIC THERAPY • Due to the impulsivity and the risk for injury seen in bvFTD, discussions with family members about driving, the patient’s access to finances, and safety of the physical environment should be conducted early in management. • For patients with motor symptoms, regular exercise and physical therapy are helpful. • Speech therapy is helpful for patients with language deficits. • Diet counseling can aid in prevention of weight gain in patients with hyperphagia. ACUTE GENERAL Rx None

REFERRAL Patients who have severe or complex presentations should be referred to a neurologist with expertise in dementia or neurodegenerative disorders.

DISPOSITION • Patients with FTD benefit from having the social support and specialized care offered in dementia-focused care homes and skilled nursing facilities. • The range and severity of behaviors seen in FTD can put great burden on family and friends. Education, counseling, and connection with social support or referral to a dementia-focused care home can help reduce caregiver stress.

PATIENT & FAMILY EDUCATION The Association for Frontotemporal Degeneration (http://www.theaftd.org; 866-507-7222)

F

PEARLS & CONSIDERATIONS FTD is a complex neurologic disorder with a wide variety of presenting symptoms. The most common syndrome seen is bvFTD; therefore, patients with gradual-onset changes in personality, disinhibition, and increased impulsivity should be investigated for FTD. Therapy is aimed at management of the behavioral symptoms, most commonly through the use of SSRIs. Social support and dementia-specific care facilities are helpful for both patients and family members.

RELATED CONTENT Alzheimer Disease (Related Key Topic) Parkinson Disease (Related Key Topic) Dementia with Lewy Bodies (Related Key Topic) AUTHORS: Marco Pares, BS, MD Candidate, and Joseph S. Kass, MD, JD, FAAN

Diseases and Disorders

• No disease-modifying drugs currently exist for the treatment of FTD. With advances in the understanding of FTD pathophysiology and genetics, however, new therapies such as antisense oligonucleotides and tau-specific antibodies are being investigated for their efficacy in treating or altering the progression of the syndrome and may see eventual clinical application. • Current management of FTD is aimed at management of behavioral symptoms through both pharmacologic and nonpharmacologic means.

CHRONIC Rx • There are conflicting reports of the efficacy of several medications in the symptomatic treatment of FTD. These include selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors, and antipsychotics. • SSRIs have the most consensus on their benefit in the management of FTD. They have been shown to help decrease the severity of disinhibition, impulsivity, eating disorders, and repetitive behaviors. • The use of antipsychotics is controversial, but they are sometimes given to control symptoms of aggression, agitation, and psychosis. However, patients with FTD are also at an increased risk for extrapyramidal side effects due to poorly functioning dopaminergic pathways, and thus are usually used only when SSRIs are not successful.

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Frontotemporal Dementia SUGGESTED READINGS Bang J, Spina S, Miller BL: Frontotemporal dementia, Lancet 386(10004):16721682, 2015, https://doi.org/10.1016/S0140-6736(15)00461-4. Burrell JR, Kiernan MC, Vucic S, Hodges JR: Motor neuron dysfunction in frontotemporal dementia, Brain 134(9):2582-2594, 2011, https://doi.org/10.1093/ brain/awr195. Deleon J, Miller BL: Frontotemporal dementia. In Daniel CK, Geschwind H, Paulson HL, editors: Handbook of clinical neurology, ed 148, pp 409-430, Philadelphia, 2018, Elsevier, https://doi.org/10.1016/B978-0-444-64076-5.00027-2. Hogan DB et al: The prevalence and incidence of frontotemporal dementia: a systematic review, Can J Neurol Sci vol. 43:S96-S109, 2016, https://doi. org/10.1017/cjn.2016.25. Josephs KA: Frontotemporal lobar degeneration, Neurol Clin 25(3):683-696, 2007, https://doi.org/10.1016/j.ncl.2007.03.005. Knopman DS, Roberts RO: Estimating the number of persons with frontotemporal lobar degeneration in the US population, J Mol Neurosci 45(3):330-335, 2011, https://doi.org/10.1007/s12031-011-9538-y. Laforce R: Behavioral and language variants of frontotemporal dementia: a review of key symptoms, Clin Neurol Neurosurg vol. 115:2405-2410, 2013. https:// doi.org/10.10. Merrilees JJ, Miller BL: Long-term care of patients with frontotemporal dementia, J Am Med Dir Assoc 4(Suppl 6), 2003, https://doi.org/10.1016/S15258610(04)70408-9. Miller B, Llibre Guerra JJ: Frontotemporal dementia. In Victor DL, Reus I, editors: Handbook of clinical neurology, ed 165, pp 33-45, 2019, https://doi. org/10.1016/B978-0-444-64012-3.00003-4. Neary D, Snowden J, Mann D: Frontotemporal dementia, Lancet Neurol 4(11):771780, 2005, https://doi.org/10.1016/S1474-4422(05)70223-4. Onyike CU, Diehl-Schmid J: The epidemiology of frontotemporal dementia, Int Rev Psychiatr 25(2):130-137, 2013, https://doi.org/10.3109/09540261.2013.776523.

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Piguet O, Hornberger M, Mioshi E, Hodges JR: Behavioural-variant frontotemporal dementia: diagnosis, clinical staging, and management, Lancet Neurol vol. 10:162-172, 2011, https://doi.org/10.1016/S1474-4422(10)70299-4. Pressman PS, Miller BL: Diagnosis and management of behavioral variant frontotemporal dementia, Biol Psychiatr vol. 75:574-581, 2014, https://doi. org/10.1016/j.biopsych.2013.11.006. Rascovsky K et al: Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia TT Empfindlichkeit der revidierten Diagnosekriterien der Verhaltensvariante der frontotemporalen Demenz, Brain 134(9):1-22, 2011, https://doi. org/10.1093/brain/awr179. Ratnavalli E, Brayne C, Dawson K, Hodges JR: The prevalence of frontotemporal dementia, Neurology 58(11):1615-1621, 2002, https://doi.org/10.1212/ WNL.58.11.1615. Riedl L et al: Frontotemporal lobar degeneration: current perspectives, Neuropsychiatric Dis Treat vol. 10:297-310, 2014, https://doi.org/10.2147/ NDT.S38706. Rosen HJ et al: Patterns of brain atrophy in frontotemporal dementia and semantic dementia, Neurology 58(2):198-208, 2002, https://doi. org/10.1212/WNL.58.2.198. Seeley WW: Behavioral variant frontotemporal dementia, Continuum Lifelong Learning in Neurology vol. 25:76-100, 2019, https://doi.org/10.1212/ CON.0000000000000698. Waldö ML: The frontotemporal dementias, Psychiatr Clin North Am vol. 38:193209, 2015, https://doi.org/10.1016/j.psc.2015.02.001. Warren JD, Rohrer JD, Rossor MN: Clinical review. Frontotemporal dementia, Br Med J 347-f4827, 2013, https://doi.org/10.1136/bmj.f4827.

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Frostbite BASIC INFORMATION DEFINITION Frostbite represents tissue injury (or death) from freezing and vasoconstriction induced by severe environmental cold exposure. SYNONYM Cold-induced tissue injury ICD-10CM CODES T35.0 Superficial frostbite involving multiple body regions T34 Frostbite with tissue necrosis T345 Frostbite with tissue necrosis of wrist and hand T34.8 Frostbite with tissue necrosis of ankle and foot T34.9 Frostbite with tissue necrosis of other and unspecified sites T35.4 Superficial frostbite involving multiple body regions T33.9 Superficial frostbite of unspecified sites, initial encounter

EPIDEMIOLOGY & DEMOGRAPHICS • Environmental factors include windchill factor, temperature, duration of exposure, altitude, and degree of wetness. Hands and feet account for >90% of injuries; nose, cheeks, ears, and male genitalia are also more susceptible. • Host factors include psychiatric illness and neuroleptic and sedative drugs (especially alcohol, which, in addition to impairing judgment, inhibits shivering and causes cutaneous vasodilation). Other risk factors include immobility, previous frostbite, malnutrition, tobacco use, peripheral neuropathy, peripheral vascular disease, diabetes, exhaustion, and constricting clothing and footwear. • Patients at the extremes of age are at greatest risk, but frostbite is more common in adults between 30 and 49 yrs of age with a strong male predominance (10:1) PHYSICAL FINDINGS & CLINICAL PRESENTATION • Frostbite may be classified into four degrees of injury severity or, more practically, into superficial (corresponding to first and second degree) and deep (corresponding to third and fourth degree) groups. In both cases, the degree of frostbite can only be accurately determined after rewarming as initially most frostbite injuries appear similar. • Superficial frostbite involves the skin and subcutaneous tissue. The frozen part is waxy, white (or mottled), and firm but soft and resilient below the surface when gently depressed. After rewarming, there is an initial hyperemia that may be followed by swelling and formation of superficial blisters with clear or milky fluid within 6 to 24 hr. There is no ultimate tissue loss.

• Deep frostbite extends into the dermis and may involve muscles, nerves, tendons, or bones. The skin may be hard or wooden, without tissue resilience. Nonblanching cyanosis, hemorrhagic blisters, tissue necrosis (Fig. E1), and gangrene may develop. Affected tissue has a poor prognosis and debridement or amputation is generally required. • Patients initially feel numbness, prickling, and itching. More severe injury can produce paresthesias and stiffness, with burning or throbbing pain upon thawing.

PATHOPHYSIOLOGY Two phases of tissue injury: 1.  The actual freezing of the tissues, during which cellular damage is caused by the formation of extracellular ice crystals, which cause osmotic shifts, cellular dehydration, cell membrane lysis, and cell death. 2.  The reperfusion injury, during which the thawing of damaged endothelial cells releases a cascade of inflammatory mediators (e.g., prostaglandin F, thromboxane A2, bradykinins, histamine), resulting in capillary compression, vascular stasis, progressive is­ chemic injury, and thrombus formation. These conditions ultimately lead to the destruction of the microcirculation and to cell death.

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • Frostnip: A superficial nonfreezing cold injury associated with intense vasoconstriction and characterized by frost forming on the surface of the skin. Transient numbness, tingling, and pallor resolve quickly with warming • Pernio (chilblains): Self-limited, cold-induced vasculitis associated with purple plaques or nodules, often affecting dorsum of hands and feet; seen with prolonged cold exposure to above-freezing temperatures • Cold immersion (trench foot): Caused by ischemic injury resulting from sustained, severe vasoconstriction in appendages exposed to wet cold at temperatures above freezing WORKUP • Laboratory workup is not indicated unless the patient has systemic hypothermia. • Early presentation (24 hr from thawing): Noninvasive imaging with MRA or multiphase bone scintigraphy (ideally with SPECT/CT) can be used to predict the likely levels of tissue viability for future reconstruction after amputation.

TREATMENT (3 PHASES) 1.  FIELD MANAGEMENT • Prioritize treatment of hypothermia (core body temperature 1 cm) Chronic Salmonella typhi or paratyphi carrier status First-degree relative with gallbladder cancer IBD Intrahepatic biliary dysplasia Lynch syndrome Porcelain gallbladder PSC Segmental adenomyomatosis in patients ≥60 yr of age *Methylcholanthrene, O-aminoazotoluene, nitrosamines, and possibly others. IBD, Inflammatory bowel disease; PSC, primary sclerosing cholangitis. From Feldman M et al: Sleisenger and Fordtran’s gastrointestinal and liver disease, ed 10, Philadelphia, 2016, Elsevier.

• Female gender • Older age • Gallbladder polyps (size >1 cm) • Primary sclerosing cholangitis • Chronic infection from salmonella or helicobacter • Obesity

PHYSICAL FINDINGS & CLINICAL PRESENTATION • Early stage: Most patients are asymptomatic. • Late stage: Right-upper-quadrant pain, weight loss, malaise, nausea, vomiting, and obstructive jaundice. Patients can also present with symptoms of cholecystitis including fever and pain. • Physical exam may reveal Courvoisier law (palpable gallbladder and mild painless jaundice). • Can often be misdiagnosed as biliary colic or cholecystitis, resulting in delayed diagnosis ETIOLOGY/PATHOGENESIS Chronic inflammation of gallbladder from any cause can predispose to evolution from dysplasia to carcinoma in situ to invasive cancer subsequently. • Gallbladder cancer can spread early by hematogenous or lymphatic route or by direct invasion into the liver.

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • Cholangiocarcinoma • Acalculous cholecystitis • Carcinoma of the ampulla of Vater • Gallbladder mucocele • Gallstones • Gallbladder volvulus WORKUP • Initial work consists of laboratory evaluation and sonogram of abdomen. • Liver function tests might reveal bile duct obstruction with an elevated serum bilirubin or alkaline phosphatase. • Cancer antigen 19-9 (CA 19-9) or carcinoembryonic antigen (CEA) is frequently elevated, but they both have low sensitivity and specificity for diagnostic purposes. • Suspicious ultrasonographic findings, including calcification, thickened gallbladder wall, gallbladder polyps ≥10 mm, and protruding mass, are warranted for additional imaging studies with computed tomography (CT) of abdomen (Fig. E1), magnetic resonance imaging (MRI)/magnetic resonance cholangiopancreatography (MRCP), or endoscopic ultrasonography (EUS). • Chest CT should be done to complete staging work-up. PET/CT has limited sensitivity but high specificity in the detection of regional lymph node metastases. PET/CT may be considered when there is an equivocal finding on CT/MRI.

• Staging laparoscopy is very useful to determine resectability state. • Staging (Table E1).

TREATMENT • Surgery (Table E2) is the mainstay of treatment for curative intent. Incidental GBC is often operated by laparoscopic cholecystectomy and detected by pathology review postoperatively. In these cases, a radical re-resection is indicated depending on tumor stage. • Extended cholecystectomy is the preferred approach when GBC is suspected pre-operatively. • Adjuvant therapy: 1. T1a with negative margins: No adjuvant chemotherapy. 2. T1b or higher: Adjuvant chemotherapy with fluoropyrimidine-based or gemcitabine-based chemotherapy alone or fluoropyrimidine chemoradiotherapy. • Unresectable or metastatic disease: Gemcitabine/ cisplatin is considered first-line standard of care. Taxanes and fluoropyrimidine-containing regimens can be used upon disease progression. The role of immunotherapy and targeted agents is investigational. Pembrolizumab (PD-1 inhibitor) is appropriate for microsatellite instability high (MSI-H) tumors. • Neoadjuvant chemotherapy may downstage select patients with unresectable disease. Reevaluation by a surgeon should be considered. • Role of chemoradiotherapy can be considered in select cases in the adjuvant setting or as definitive management for unresectable disease.

SURVEILLANCE • Consider imaging every 6 mo for 2 yr if clinically indicated, and then annually up to 5 yr. • Consider CEA and CA 19-9 as clinically indicated. SUGGESTED READINGS Available at ExpertConsult.com AUTHORS: Sonali Harchandani, MD, and Patan Gultawatvichai, MD

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Gallbladder Cancer

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SUGGESTED READINGS Goetze TO: Gallbladder carcinoma: prognostic factors and therapeutic options, World J Gastroenterol 21:12211-12217, 2015. Siegel RL et al: Cancer statistics, CA cancer, J Clin 68:7-30, 2018. Valle JW et al: Cisplatin and gemcitabine for advanced biliary tract cancer: a meta-analysis of two randomised trials, Ann Oncol 25:391-398, 2014. Zaidi MY, Maithel SK: Updates on gallbladder cancer management, Curr Oncol Rep 20:21, 2018. Hickman L, Contreras C: Gallbladder cancer: diagnosis, surgical management and adjuvant therapies, Surg Clin North Am 99:337-355, 2019.

A

B

C FIG. E1  Imaging of gallbladder carcinoma. A, Axial computed tomography view of the abdomen. Cholelithiasis is seen inferior to the gallbladder mass (arrow). B, Coronal view of the same patient. C, Ultrasonography in the same patient showing a large mass (arrow) originating from the gallbladder wall and protruding into the lumen. (From Feldman M et al: Sleisenger and Fordtran’s gastrointestinal and liver disease, ed 10, Philadelphia, 2016, Elsevier.)

Gallbladder Cancer

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TABLE E1  TNM and American Joint Committee on Cancer (AJCC)/International Union Against Cancer (UICC) Staging Systems for Gallbladder Carcinoma TNM Stage

Criteria

Tx

Primary tumor cannot be assessed

T0 Tis T1a T1b T2 T3

No evidence of primary tumor Carcinoma in situ Tumor invades lamina propria Tumor invades muscularis propria Tumor invades perimuscular connective tissue without extension beyond serosa or into liver Tumor perforates the serosa AND/OR Tumor directly invades the liver AND/OR Tumor invades one other adjacent organ (i.e., stomach, duodenum, colon, pancreas, omentum, extrahepatic bile ducts) Tumor invades the portal vein or hepatic artery OR Tumor invades ≥2 extrahepatic organs or structures Regional lymph nodes cannot be assessed No regional lymph node metastases Lymph node metastases along the cystic duct, bile duct, hepatic artery, AND/OR portal vein Metastases to periaortic, pericaval, superior mesenteric artery, AND/OR celiac artery lymph nodes No distant metastases Distant metastases

T4 Nx N0 N1 N2 M0 M1 AJCC/UICC Stage 0 I II IIIA IIIB IVA IVB

Tumor Tis T1 T2 T3 T1-3 T4 Any T Any T

Node N0 N0 N0 N0 N1 N0-1 N2 Any N

Metastasis M0 M0 M0 M0 M0 M0 M0 M1

TNM, Tumor, node, metastasis. From Feldman M et al: Sleisenger and Fordtran’s gastrointestinal and liver disease, ed 10, Philadelphia, 2016, Elsevier.

TABLE E2  Recommended Management by Stage Stage

Surgical Management

Postoperative Management

T1a

Simple cholecystectomy

T1b

Radical cholecystectomy (i.e., segment IVb/V resection ­[preferred], hepatic wedge resection, right hepatic lobectomy, or ­ trisectionectomy with R0 resection) and portal lymphadenectomy

II III

See earlier for T1b tumors Consider diagnostic staging laparoscopy followed by operation for T1b tumors if no metastatic disease is identified Stage IVA (T4 N0-1 M0) disease may be amenable to resection (see stage III) N2 and M1 disease is a contraindication to attempts at curative resection. Patients may require palliative operation for relief of biliary obstruction but attempts at endoscopic/ percutaneous drainage should be considered first-line treatment

Review pathology report to confirm negative cystic duct margins No routine follow-up advised Staging workup with CT chest/abdomen/pelvis (or CT chest and MRI abdomen/pelvis) Adjuvant fluoropyrimidine chemoradiation versus gemcitabine-based or fluoropyrimidine-based chemotherapy Surveillance imaging See earlier for T1b tumors See earlier for T1b tumors

IVA IVB

CT, Computed tomography; MRI, magnetic resonance imaging. From Cameron JL, Cameron AM: Current surgical therapy, ed 12, Philadelphia, 2017, Elsevier.

Adjuvant fluoropyrimidine chemoradiation versus gemcitabine-based or ­fluoropyrimidine-based chemotherapy Unresectable disease: Combined gemcitabine/cisplatin therapy, fluoropyrimidinebased or gemcitabine-based chemotherapy regimens current

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Ganglia  BASIC INFORMATION DEFINITION A fluid-filled sac (cyst) overlying a tendon sheath or joint SYNONYM Ganglion ICD-10CM CODE M67.4 Ganglion

EPIDEMIOLOGY & DEMOGRAPHICS • Ganglia are more common in women than men (3:1). • Can occur at any age, but usually between the second and fourth decades of life. • Most common soft tissue tumor of the hand and wrist. PHYSICAL FINDINGS & CLINICAL PRESENTATION • Most ganglia occur on the dorsum of the wrist (50% to 70%) (Fig. E1). • The volar wrist (18% to 20%) is the next most common site. • Can also involve the proximal digital flexor tendons and the distal interphalangeal joints. • Left and right hands are equally affected. • Ganglia are usually solitary, firm, smooth, round, and fluctuant. • Pain from mass effect or compression against nearby structure may be present (e.g., median nerve and radial nerve).

ETIOLOGY Ganglia are believed to derive from synovial herniation or expansion from the joint capsule or tendon sheath. Repetitive movement as an etiology is uncertain, although it may cause enlargement of the lesion or worsen symptoms.

DIAGNOSIS Direct inspection and localization of the cyst often are enough to make the diagnosis of ganglia. Transillumination is an easy method of differentiating ganglia from solid tumors; ganglia transilluminate, but solid tumors do not.

DIFFERENTIAL DIAGNOSIS • Lipoma • Fibroma • Epidermoid inclusion cyst • Osteochondroma • Hemangioma • Infection (tuberculosis, fungi, and secondary syphilis) • Gout • Rheumatoid nodule • Radial artery aneurysm WORKUP The workup of ganglia usually consists of history, physical examination, and occasionally radiography. LABORATORY TESTS Blood tests are not specific in the diagnosis of ganglia. IMAGING STUDIES • Radiographs of the hand and wrist are taken to rule out other bone or joint abnormalities. • Ultrasound studies are helpful in the diagnosis of ganglia by demonstrating smooth cystic walls that may be septated. • CT scan can be done if the ultrasound is equivocal. • MRI helps differentiate malignant bone lesions from cystic structures. • Arthrography may demonstrate a communication between the joint and ganglia (not commonly done).

TREATMENT FIG. E1  Dorsal wrist ganglion. (From Hochberg MC et al: Rheumatology, ed 5, St Louis, 2011, Mosby.)

• Hand numbness may be present. • Patient may have hand muscle weakness. • Ganglia usually develop over a period of months but may arise suddenly.

Expectant treatment is appropriate if the mass is not painful or interfering with motor function.

NONPHARMACOLOGIC THERAPY • Attempts to rupture the cyst by sharp blows with a book or with finger compression are not recommended.

SUGGESTED READINGS Ho PC et al: Current treatment of ganglion of the wrist, Hand Surg 6(1):49, 2001. Nahra ME, Bucchieri JS: Ganglion cysts and other tumor related cysts of the hand and wrist, Hand Clin 20(3):249, 2004. Wang AA, Hutchinson DT: Longitudinal observation of pediatric hand and wrist ganglia, J Hand Surg 26(4):599, 2001.

• Aspiration, heat, and sclerotherapy have been tried but have met with high recurrence rates (60%).

ACUTE GENERAL Rx • Aspiration at the base with a large-bore needle (18-gauge) followed by injection of 20 to 40 mg of triamcinolone acetonide can be tried. • This may be repeated if the ganglia recurs (35% to 40%). CHRONIC Rx Total ganglionectomy and repair of the defect after tracing its connection to the tendon sheath is effective and the surgical procedure of choice. DISPOSITION • Ganglia spontaneously resolve in approximately 40% to 50% of cases. • Aspiration with steroid injection is successful in approximately 65% of cases. • Surgery provides cure in 85% to 95% of the cases. • Complications of ganglia include: 1. Carpal tunnel syndrome with pain and muscle atrophy 2. Radial nerve impingement 3. Radial artery compression • Complications of ganglion surgery include: 1. Infection 2. Recurrence (5% to 15%), usually from inadequate excision 3. Reflex sympathetic dystrophy 4. Scar formation REFERRAL It is best to refer patients with symptomatic ganglia to a hand surgeon.

PEARLS & CONSIDERATIONS • Dorsal ganglia usually originate from the scapholunate ligament. • Volar ganglia typically originate between the tendons of the flexor carpi radialis and brachioradialis.

COMMENTS A ganglion’s synovial membrane maintains its secretory function. Aspiration of ganglia often demonstrates a viscous, mucinous, clear fluid containing albumin, globulin, and hyaluronic acid. RELATED CONTENT Ganglia (Patient Information) AUTHOR: Fred F. Ferri, MD

ALG BASIC INFORMATION

SYNONYMS Gastric adenocarcinoma Stomach cancer Linitis plastica ICD-10CM CODES C16 Malignant neoplasm of stomach C16.0 Malignant neoplasm of cardia of stomach C16.1 Malignant neoplasm of stomach C16.2 Malignant neoplasm of body of stomach C16.3 Malignant neoplasm of pyloric antrum C16.5 Malignant neoplasm of lesser curvature of stomach, unspecified C16.6 Malignant neoplasm of greater curvature of stomach, unspecified C16.8 Malignant neoplasm of overlapping sites of stomach

EPIDEMIOLOGY & DEMOGRAPHICS • Gastric cancer is the fourth commonest cancer in the world, with an annual incidence of approximately 950,000 cases annually; of these, 70% occur in developing countries. Tis

Early gastric cancer T1 Advanced gastric cancer

T2

PHYSICAL FINDINGS & CLINICAL PRESENTATION • Medical history may reveal complaints of postprandial fullness with significant weight loss (70% to 80%), nausea/vomiting (20% to 40%), dysphagia (20%), and dyspepsia, usually unrelieved by antacids; epigastric discomfort, usually lessened by fasting and exacerbated by food intake, is also common. • Epigastric or abdominal mass (30% to 50%), epigastric pain. • Iron deficiency anemia is typically seen from tumor bleeding, and hemoccult-positive stools are detected. • Hard, nodular liver: May indicate metastatic disease to the liver. • Ascites, lymphadenopathy, or pleural effusions: May indicate metastases. T1

T1

T2

T3

ETIOLOGY RISK FACTORS: • Chronic Helicobacter pylori gastritis. Gastric cancer develops in persons infected with H. pylori but not in uninfected persons. Those with histologic findings of severe gastric atrophy, corpuspredominant gastritis, or intestinal metaplasia are at increased risk. Persons with H. pylori infection and duodenal ulcer are not at risk, whereas those with gastric ulcers, nonulcer dyspepsia, and gastric hyperplastic polyps are. Eradication of H. pylori reduces gastric cancer risk • Tobacco abuse, heavy alcohol consumption • Food additives (nitrosamines), smoked foods, occupational exposure to heavy metals, rubber, asbestos • Chronic atrophic gastritis with intestinal metaplasia, hypertrophic gastritis, and pernicious anemia • Box 1 summarizes risk factors for gastric adenocarcinoma

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • Gastric lymphoma (5% of gastric malig­nancies) • Hypertrophic gastritis • Peptic ulcer • Reflux esophagitis WORKUP Upper endoscopy (Fig. E2) with biopsy will confirm diagnosis. Endoscopic ultrasonography in combination with PET/CT scanning and operative lymph node dissection can be used in staging of the tumor. Table 1 and Fig. 1 describe staging systems for gastric carcinoma. LABORATORY TESTS • Complete blood count reveals microcytic anemia. • Hemoccult-positive stools are detected. • Chemistry tests can reveal hypoalbuminemia or abnormal liver enzymes in patients with metastasis to the liver.

T4

EUS appearance Mucosa (superficial)

Hyperechoic

Mucosa (deep)

Hypoechoic

Submucosa

Hyperechoic

Muscularis propria

Hypoechoic

Serosa

Hyperechoic

T3 T4

Adjacent organ

FIG. 1  Classification of gastric adenocarcinoma by depth of invasion (T classification). In the TNM classification, T denotes depth of invasion: Tis designates carcinoma in situ; T1 tumors are confined to the mucosa (T1a) and submucosa (T1b); T2 tumors invade the muscularis propria but not the serosa; T3 tumors penetrate the subserosal connective tissue without involving the visceral peritoneum or contiguous structures; and T4 tumors invade the serosa (visceral peritoneum) and may involve adjacent organs and tissues. In early gastric cancer, the disease is confined to the mucosa and submucosa (T1), regardless of nodal involvement. (From Feldman M et al [eds]: Sleisenger and Fordtran’s gastrointestinal and liver disease, ed 10, Philadelphia, 2016, Saunders.)

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Diseases and Disorders

DEFINITION Gastric cancer is an adenocarcinoma arising from the stomach. Cancers in the cardia arising within 5 cm of the gastroesophageal junction (GEJ) are typically classified as GEJ cancers. It is subdivided into intestinal and diffuse histology. The diffuse form of gastric cancer is more common in women and young patients, whereas the intestinal type is predominantly related to environmental factors (smoking, diet high in smoked, salted, and pickled food, nitrates and nitrites) and ethnicity (Asian and Pacific descent). The classification of gastric adenocarcinoma by depth of invasion is illustrated in Fig. 1.

The highest incidence is in Asia and the lowest in North America. Annual estimated deaths due to gastric cancer are 723,000 worldwide. • In the U.S., an estimated 27,510 new cases and 11,140 deaths were expected in 2019. • The incidence of gastric cancer is 6.7 in 100,000 persons in the U.S. Mortality rate is 3.4 per 100,000 persons. Although the incidence of distal stomach tumors has greatly declined over the past 30 yr, that of proximal tumors of the cardia and fundus is on the rise. • Gastric cancer is more common in male patients >65 yr (70% of patients are >50 yr). • Male/female ratio is 3:2. • Hereditary diffuse gastric cancer (HDGC) has an autosomal-dominant inheritance, and cancer develops at a young age (average age 37 yr). Germline truncating mutations in the tumor-suppressor E-cadherin gene (CDH1) are found in up to 50% of these families. It is associated with an 80% lifetime risk of gastric cancer. • Increased risk of gastric cancer is also seen with Lynch syndrome, FAP, Peutz-Jeghers, juvenile polyposis syndrome, and hyperplastic gastric polyps.

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BOX 1  Risk Factors for Gastric Adenocarcinoma Definite H. pylori infection Chronic atrophic gastritis Intestinal metaplasia Dysplasia* Adenomatous gastric polyps Cigarette smoking History of gastric surgery (especially Billroth II) Genetic factors: Family history of gastric cancer (firstdegree relative) Familial adenomatous polyposis (with fundic gland polyps) Hereditary nonpolyposis colorectal cancer Peutz-Jeghers syndrome Juvenile polyposis Probable High salt intake Obesity (adenocarcinoma of the cardia only) Snuff tobacco use History of gastric ulcer Pernicious anemia Regular aspirin or other NSAID use (­protective) Possible Statin use (protective) Heavy alcohol use Low socioeconomic status Ménétrier disease High intake of fresh fruits and vegetables (protective) High ascorbate intake (protective) Questionable Hyperplastic and fundic gland polyps Diet high in nitrates High green tea consumption (protective) *Surveillance for cancer is recommended in patients with this risk factor. From Feldman M et al (eds): Sleisenger and Fordtran’s gastrointestinal and liver disease, ed 10, Philadelphia, 2016, Saunders.

• Up to 25% of gastric cancers overexpress the HER2/neu growth factor receptor, and it is now standard practice to evaluate gastroesophageal tumors for HER2 overexpression. • Mutation-specific predictive genetic testing by polymerase chain reaction amplification followed by restriction: Enzyme digestion and DNA sequencing for truncating mutations in CDH1 is recommended in families of patients with familial diffuse cancer because gastric cancer develops in three of every four carriers of a mutant CDH1 gene. Genetic abnormalities in gastric adenocarcinoma are summarized in Table E2.

IMAGING STUDIES Chest and abdomen PET/CT scan (Fig. E3) to evaluate for metastases

TREATMENT ACUTE GENERAL Rx • Gastrectomy: Most curable tumors can be removed with adequate margins by subtotal

TABLE 1  TNM Staging Criteria and Stages for Gastric Carcinoma Based on AJCC 8th Edition T Category

T Criteria

TX T0 Tis

T4 T4a N Category NX N0 N1 N2 N3 N3a M Category M0 M1

Primary tumor cannot be assessed No evidence of primary tumor Carcinoma in situ: Intraepithelial tumor without invasion of the lamina propria, highgrade dysplasia Tumor invades the lamina propria, muscularis mucosae, or submucosa Tumor invades the lamina propria or muscularis mucosae Tumor invades the submucosa Tumor invades the muscularis propria Tumor penetrates the subserosal connective tissue without invasion of the visceral peritoneum or adjacent structures Tumor invades the serosa (visceral peritoneum) or adjacent structures Tumor invades the serosa (visceral peritoneum) N Criteria Regional lymph node(s) cannot be assessed No regional lymph node metastasis Metastasis in one or two regional lymph nodes Metastasis in three to six regional lymph nodes Metastasis in seven or more regional lymph nodes Metastasis in 7 to 15 regional lymph nodes M Criteria No distant metastasis Distant metastasis

Stage

pT

pN

M

Stage 0 Stage IA Stage IB

Tis T1 T1 T2 T1 T2 T3 T1 T2 T3 T4a T2 T3 T4a T4b T1 T2 T3 T4a T4b T3 T4a T4b Any T

N0 N0 N1 N0 N2 N1 N0 N3a N2 N1 N0 N3a N2 N1 or N2 N0 N3b N3b N3a N3a N1 or N2 N3b N3b N3a or N3b Any N

M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M1

T1 T1a T1b T2 T3

Stage IIA

Stage IIB

Stage IIIA

Stage IIIB

Stage IIIC

Stage IV

gastrectomy; total gastrectomy is used when mandated by proximal cancer location or disease extent. The preferred treatment for lesions arising in the body or antrum of the stomach is a radical distal subtotal resection (Fig. E4). This procedure removes approximately 80% of the stomach, along with the first portion of the duodenum, the gastrohepatic and gastrocolic omenta, and the nodal tissue adjacent to the three branches of the celiac axis. Extensive or proximal cancers

require a total gastrectomy to achieve an adequate proximal gastric margin (Fig. E5). If total gastrectomy is necessary, a splenectomy is sometimes performed, particularly in gastric cancers of the proximal third of the stomach and tumors of the body near the greater curvature. These cancers are more apt to metastasize to lymph nodes in the splenic hilum that cannot be completely excised without a splenectomy. Routine splenectomy is no longer practiced because of

Gastric Cancer

ALG results in improved overall survival. In the subset of patients with gastric cancer expressing HER2-2/neu oncogene (20% to 25% of patients), the addition of trastuzumab to platinum plus 5-FU or capecitabine prolongs overall survival. • Patients progressing after first-line chemotherapy can derive a survival benefit with the use of chemotherapy in combination with antivascular endothelial growth factor receptor-2 antibody ramucirumab. Immunotherapy with program death receptor-1 antibodies (nivolumab, pembrolizumab) has been shown to improve survival in previously treated patients with high-MSI tumors. • Treatment algorithms for newly diagnosed gastric or gastroesophageal junction cancer are illustrated in Figs. 6 and 7.

COMMENTS • Gastrectomy patients will need vitamin B12 replacement. They are also at risk for dumping syndrome and should be advised to ingest frequent, small meals. • Prophylactic gastrectomy should be considered in young, asymptomatic carriers of germ-line truncating CDH1 mutations who belong to families with highly penetrant heredity diffuse gastric cancer. • Gastric cancer screening for average-risk patients is not recommended in the U.S.

DISPOSITION • Median survival rate of metastatic or recurrent gastric carcinoma is 10 to 15 mo overall. • The 5-yr survival for early gastric cancers is >35%.

RELATED CONTENT Stomach Cancer (Patient Information)

 EARLS & P CONSIDERATIONS

SUGGESTED READINGS Available at ExpertConsult.com

AUTHOR: Ritesh Rathore, MD

Confirm histologic diagnosis (endoscopy with biopsy and ultrasound) Staging evaluation

T4, N0–1

T3N0—EG junction; T1–3N1—gastric/EG

Preop EBRT + chemo Evaluate different options of preoperative EBRT-chemotherapy • Alternate chemo-5-FU CDDP vs. Taxol-based • Cycles of chemo: number, sequence • Timing and intensity: 96 hour infusion weeks 1 and 5 vs. low-dose weekly

Resection ± IORT Postop maintenance chemotherapy

FIG. 6  Treatment algorithm: newly diagnosed gastric or gastroesophageal junction cancer. Adjuvant therapy precedes surgery. CDDP, Cisdiamminedichloroplatinum; chemo, chemotherapy; EBRT, external-beam radiation therapy; EG, esophagogastric; 5-FU, 5-fluorouracil; IORT, intraoperative radiation therapy; postop, postoperative; preop, preoperative. (From Niederhuber JE: Abeloff’s clinical oncology, ed 6, Philadelphia, 2020, Elsevier.) Confirm histologic diagnosis (endoscopy with biopsy) Staging evaluation Exploratory laparotomy; resection as indicated

Resected, negative margins

Resected but residual

Unresectable for cure

Low-relapse risk High-relapse risk (within wall, LN–) (>wall, LN+)

EBRT + chemo

Preop EBRT + chemo

Observation Phase III chemo EBRT 5-FU leucovorin vs. ECF

Resection/IORT Postop maintenance chemotherapy

FIG. 7  Treatment algorithm: newly diagnosed gastric or gastroesophageal junction cancer. Surgery precedes adjuvant therapy. chemo, Chemotherapy; EBRT, external-beam radiation therapy; ECF, epirubicin, cisplatin, 5-fluorouracil; 5-FU, 5-fluorouracil; IORT, intraoperative radiation therapy; LN, lymph node; postop, postoperative; preop, preoperative. (From Niederhuber JE: Abeloff’s clinical oncology, ed 6, Philadelphia, 2020, Elsevier.)

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the increased complications. A splenectomy should be performed when worrisome, palpable nodes are present in the splenic hilum. • In advanced cases, palliative gastrectomy (bleeding, obstruction) can be performed. Outlet obstruction can be addressed by performing a gastrojejunostomy. • In patients with operable gastric cancer, the perioperative regimen chemotherapy can decrease tumor size and stage while improving progression-free and overall survival. The current standard neoadjuvant regimen in use is the FLOT (5-fluorouracil [5-FU], leucovorin, oxaliplatin, docetaxel) regimen. • Postoperative adjuvant chemoradiotherapy using the older 5-FU and leucovorin regimen is an option for stage II to III patients. Alternatively, the modern approach is combination chemotherapy with FOLFOX (5-FU, leucovorin, oxaliplatin) or CAPOX (capecitabine, oxaliplatin) regimens with radiotherapy reserved for high-risk patients only. • In metastatic gastric cancer, the use of chemotherapy with triplet or doublet regimens

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Gastric Cancer SUGGESTED READINGS Al-Batran S et al: Perioperative chemotherapy with fluorouracil plus leucovorin, oxaliplatin, and docetaxel versus fluorouracil or capecitabine plus cisplatin and epirubicin for locally advanced, resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4): a randomised, phase 2/3 trial, Lancet 393(10):1948-1957, 2019. Badgwell B: Multi modality therapy of localized gastric adenocarcinoma, J Natl Compr Canc Netw 14(10):1321-1327, 2016. Choi IJ et al: Family history of gastric cancer and Helicobacter pylori treatment, N Engl J Med 382:427-437, 2020. Shitara K, Ohtsu A: Advances in systemic therapy for metastatic or advanced gastric cancer, J Natl Compr Canc Netw 14(10):1313-1320, 2016. Shum H, Rajdev L: Multimodality management of resectable gastric cancer: a review, World J Gastrointest Oncol 6(10):393-402, 2014. Siegel RL et al: Cancer statistics, CA Cancer J Clin 69(1):7-34, 2019.

FIG. E2  Polypoid gastric cancer. A trilobed polyp is apparent at the angularis. (From Feldman M et al [eds]: Sleisenger & Fordtran’s gastrointestinal and liver disease: pathophysiology/diagnosis/management, ed 8, Philadelphia, 2006, Saunders.)

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TABLE E2  Genetic Abnormalities in Gastric Adenocarcinoma Abnormalities Microsatellite instability DNA aneuploidy Deletion/Suppression p53 (tumor protein 53) FHIT (fragile histidine triad gene) APC (adenomatous polyposis coli gene) loss of heterozygosity DCC (deleted in colorectal cancer gene) loss of heterozygosity Decreased Expression Due to Hypermethylation p16 TFF1 (human trefoil factor 1 gene) p27 MLH1 (human mutL homolog 1 gene) E-cadherin Amplification/Overexpression COX-2 (cyclooxygenase-2) HGF (hepatocyte growth factor) VEGF (vascular endothelial growth factor) c-met AIB-1 (amplified in breast cancer-1) beta-Catenin EGFR (EGF receptor gene) Mutations PI3K (phosphatidylinositol 3-kinase gene) PTPRT (protein-tyrosine phosphatase receptor type gene)

Approximate Gene Frequency (%) 15-50 60-75 60-70 60 50 50 ≈50 ≈50 20 cm) tumors. • 60% of gastrinomas are malignant, with liver and regional lymph nodes the most common site of metastases. Histology is not a good predictor of the biology of gastrinomas. • 60% of patients with MEN-1 have gastrinomas. • 10% of patients with ZE syndrome have islet cell hyperplasia rather than gastrinomas; in 10% to 20% of patients, tumors cannot be located because of their small size.

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • Peptic ulcer disease (see Section I, “Peptic Ulcer Disease”) • Gastroesophageal reflux disease (see Section I, “Gastroesophageal Reflux Disease”) • Other endocrine tumors of the pancreas (see Table E1) WORKUP • Fig. E1 illustrates an algorithm for the diagnosis of ZES. Sensitivities of gastrinoma

TABLE E1  Characteristics of Endocrine Tumors of the Pancreas Tumor Type Insulinoma Glucagonoma

Gastrinoma Somatostatinoma

VIPoma

PPoma

Major Clinical Symptoms

Predominant Hormone

Islet Cell Type

Malignant (%)

Localization

Other Clinical Features

Hypoglycemia (fasting or nocturnal) 1. Diabetes mellitus 2. Migratory necrolytic erythema Recurrent peptic ulcer disease

Insulin

β

10

Catecholamine excess

Glucagon

α

90

Usually pancreatic; rarely extrapancreatic Usually pancreatic; rarely extrapancreatic

Gastrin

γ

90

Diarrhea/steatorrhea

1. Diabetes mellitus 2. Diarrhea, steatorrhea Watery diarrhea, hypokalemia, achlorhydria (WDHA syndrome) 1. Hepatomegaly 2. Abdominal pain

Somatostatin

δ

80

Usually pancreatic but frequently extrapancreatic Pancreatic and duodenal

Vasoactive intestinal polypeptide (VIP)

δ

50

Usually pancreatic but frequently extrapancreatic

Metabolic acidosis Hyperglycemia Hypercalcemia Flushing

Pancreatic polypeptide (PP)

PP cells

80

Usually pancreatic; rarely extrapancreatic

Occasional watery diarrhea

From Besser GM, Cudworth AG: Clinical endocrinology, Philadelphia, 1987, Lippincott/Gower Medical Publishing, p. 20.

Panhypoaminoaciduria Thromboembolism Weight loss

Hypochlorhydria Weight loss Gallbladder disease

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Serum gastrin concentration (pg/ml)

Symptoms such as those of PUD, severe GERD or chronic diarrhea. Signs such as prominent gastric folds on endoscopy (see left upper panel) or an imaging study.

ZES

Suspect ZES (Exclude retained antrum syndrome by history)

Measure fasting serum gastrin (FSG) Normal

Elevated (>98% ZES pts)

Not elevated (2

ZES possible

ZES unlikely 10-fold increased

FSG elevated (1–9.9-fold)

FSG normal

ZES present

ZES likely

ZES unlikely 1000

ZES present

120 Basal gastric acid output (mEq/hr)

(If strong clinical suspicion)

ZES possible

110

110

100

100

90

90

80

80

Previous gastric surgery

70

70

60

60

50

50

40

40 30

30

20

20

10

10

0

Fasting serum gastrin (fold normal)

No gastric surgery

n = 205

0

n = 30

FIG. E1  Algorithm for the diagnosis of Zollinger-Ellison syndrome (ZES). Right upper, Typical ZES patient with a positive secretin test result (i.e., ≥120-pg/ml increase in fasting gastrin level). Right lower, Marked elevations in mean basal acid output (BAO) with or without previous gastric acid–reducing surgery. The dotted horizontal lines show the proposed criterion of >15 mEq/hr or >5 mEq/hr proposed to distinguish patients with ZES from those without ZES. Left upper, Prominent gastric folds found on endoscopy in a ZES patient, compared with a normal subject. Left lower, Fasting serum gastrin levels in ZES expressed as a multiple of the upper limit of normal on the horizontal axis. Very few patients had normal values; 60% had less than tenfold serum gastrin increases. CU, Clinical units. (From Feldman M et  al [eds]: Sleisenger and Fordtran’s gastrointestinal and liver disease, ed 10, Philadelphia, 2016, Saunders.)

localization studies are summarized in Table E2 • Diagnosis of peptic ulcer: 1. Endoscopy • Gastric acid secretion: 1. Serum gastrin level (fasting) >150 pg/ml (criterion for diagnosis is serum gastrin >1000 pg/ml) (causes of false-positive results: Pernicious anemia, renal failure, retained gastric antrum syndrome, diabetes mellitus, rheumatoid arthritis)

• Provocative gastrin level tests: 1. Secretin stimulation 2. Calcium stimulation 3. Standard test meal stimulation • Gastrinoma localization: 1. Arteriography 2. Abdominal sonography 3. Abdominal CT scan 4. Abdominal MRI/PET scan 5. Selective portal vein branch gastrin level 6. Octreotide scan

TREATMENT • Surgical resection of the gastrinoma (note: 90% of gastrinomas can be located, resulting in a 40% overall cure rate). • Total gastrectomy or vagotomy (palliative in some patients). • Medical treatment:

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TABLE E2  Sensitivities of Gastrinoma Localization Studies % of Tumors Localized Overall

Study Preoperative Noninvasive Transabdominal ultrasonography Abdominal computed tomography Abdominal magnetic resonance imaging Octreoscan DOTA scan Invasive Endoscopic ultrasonography Intraoperative Palpation Intraoperative ultrasonography Duodenotomy

Pancreas

Duodenum

Liver Metastases

80

35

14 50 83

>90

50 >60-90

85

75-100

28-57

65 83 –

91 95 –

60 58 100

20-30 50 25 71-90 >90

>90

From Cameron JL, Cameron AM: Current surgical therapy, ed 12, Philadelphia, 2017, Elsevier.

Gastrinoma

Sporadic

Inherited (MEN 1)

Preoperative assessment (endoscopy, CT scan, MRI, PET, radiolabeled octreotide scanning, etc.)

Omeprazole

No metastasis

Resect local disease

Surgical debulking +/- omeprazole

Metastasis

Lesion not found

FIG. E2  Treatment algorithm for the management of a patient with gastrinoma. In some circumstances, patients with familial gastrinoma may also be candidates for surgical resection if disease is highly limited (dotted line). CT, Computed tomography; MEN 1, multiple endocrine neoplasia type 1; MRI, magnetic resonance imaging; PET, positron emission tomography. (From Melmed S et al: Williams textbook of endocrinology, ed 12, Philadelphia, 2011, Saunders.)

1.  Proton pump inhibitors (e.g., omeprazole, lansoprazole) is the mainstay of therapy. 2. Somatostatin or octreotide has an antiproliferative effect and controls diarrhea symptoms. 3. Targeted therapy: Everolimus, an oral inhibitor of mammalian target of rapamycin (mTOR), has shown a survival benefit in patients with advanced pancreatic neuroendocrine tumors, with low rates of severe adverse events. Another oral tyrosine kinase inhibitor, sunitinib, has also shown encouraging results on prolongation of survival in this setting.

4. T he use of a radioactive-labeled isotope lutetium Lu 177-dotatate has demonstrated a survival benefit in gastroenteric-pancreatic neuroendocrine tumors. It binds to somatostatin receptors to deliver radiation directly into tumor cells and is superior to octreotide depot in this setting. 5. Chemotherapy for metastatic gastrinoma with streptozotocin, 5-fluorouracil, and doxorubicin is of limited benefit. • Fig. E2 describes a treatment algorithm for gastrinoma.

PROGNOSIS Five-yr survival: • Two thirds of all patients

• 20% with liver metastases • 90% without liver metastases

REFERRAL To gastroenterologist, surgeon, and medical oncologist (upon development of metastatic disease)

RELATED CONTENT Gastrinoma (Zollinger-Ellison Syndrome) (Patient Information) AUTHOR: Bharti Rathore, MD

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SUGGESTED READINGS Cives M, Strosberg JR: Gastroenteropancreatic neuroendocrine tumors, CA Cancer J Clin 68(6):471-487, 2018. Epelboym I et al: Zollinger-Ellison syndrome: classical considerations and current controversies, Oncologist 19(1):44-50, 2014. Raymond E et al: Sunitinib malate for the treatment of pancreatic neuroendocrine tumors, N Engl J Med 364:501-513, 2011. Strosberg J et  al: Phase 3 trial of 177Lu-dotatate for midgut neuroendocrine tumors, N Engl J Med 376(2):125-135, 2017. Yao JC et al: Everolimus for advanced neuroendocrine tumors, N Engl J Med 364:514-523, 2011.

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Gastritis  BASIC INFORMATION DEFINITION Histologically, gastritis refers to inflammation in the stomach. Endoscopically, gastritis refers to a number of abnormal features such as erythema, erosions, and subepithelial hemorrhages. Gastritis can also be subdivided into erosive, nonerosive, and specific types of gastritis with distinctive features both endoscopically and histologically. SYNONYMS Erosive gastritis Hemorrhagic gastritis Helicobacter pylori gastritis ICD-10CM CODES K29.00 Acute gastritis without bleeding K29.01 Acute gastritis with bleeding K29.20 Alcoholic gastritis without bleeding K29.21 Alcoholic gastritis with bleeding K29.30 Chronic superficial gastritis without bleeding K29.31 Chronic superficial gastritis with bleeding K29.40 Chronic atrophic gastritis without bleeding K29.41 Chronic atrophic gastritis with bleeding K29.50 Unspecified chronic gastritis ­without bleeding K29.51 Unspecified chronic gastritis with bleeding K29.60 Other gastritis without bleeding K29.61 Other gastritis with bleeding K29.70 Gastritis, unspecified, without bleeding K29.71 Gastritis, unspecified, with bleeding K52.81 Eosinophilic gastritis or ­gastroenteritis

EPIDEMIOLOGY & DEMOGRAPHICS • Erosive and hemorrhagic gastritis is most commonly seen in patients taking nonsteroidal antiinflammatory drugs (NSAIDs), alcoholics, and critically ill patients (usually on ventilator support). • H. pylori infection with gastritis is believed to be present in 30% to 50% of the population; however, the majority are asymptomatic. • The prevalence of H. pylori infection increases with age from 50 yr. PHYSICAL FINDINGS & CLINICAL PRESENTATION • Patients with gastritis generally present with nonspecific clinical signs and symptoms (e.g., epigastric pain, abdominal tenderness, bloating, anorexia, nausea [with or without vomiting]). Symptoms may be aggravated by eating • Epigastric tenderness in acute alcoholic gastritis (may be absent in chronic gastritis)

• Foul-smelling breath • Hematemesis (“coffee grounds” emesis)

ETIOLOGY • Alcohol, NSAIDs, stress (critically ill patients usually on mechanical respiration), hepatic or renal failure, multiorgan failure • H. pylori infection • Bile reflux, pancreatic enzyme reflux • Gastric mucosal atrophy, portal hypertension gastropathy • Irradiation

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • Peptic ulcer disease • Gastroesophageal reflux disease • Nonulcer dyspepsia • Gastric lymphoma or carcinoma • Pancreatitis • Gastroparesis WORKUP Diagnostic workup includes a comprehensive history and endoscopy with biopsy. LABORATORY TESTS • H. pylori testing by urea breath test, stool antigen test (H. pylori stool antigen), endoscopic biopsy, or specific antibody test is recommended. 1. The urea breath test documents active infection (sensitivity and specificity >90%). It uses a flat breath card read by a small analyzer. 2. The stool antigen test is an enzymatic immunoassay (ELISA) that identifies H. pylori antigen in a stool specimen with a polyclonal anti–H. pylori antibody. It is as accurate as the urea breath test for diagnosis of active infection and follow-up evaluation of patients treated for H. pylori. A negative result on the stool antigen test 8 wk after completion of therapy identifies patients in whom eradication of H. pylori was successful. 3. Histologic evaluation of endoscopic biopsy samples is considered by many the gold standard for accurate diagnosis of H. pylori infection. However, detection of H. pylori depends on the site and number of biopsy samples, the method of staining, and experience of the pathologist. 4. Serologic testing for antibodies to H. pylori is easy and inexpensive; however, the presence of antibodies demonstrates previous but not necessarily current infection. Antibodies to H. pylori can remain elevated for months to yrs after infection has cleared; therefore antibody levels must be interpreted in light of patient’s symptoms and other test results (e.g., peptic ulcer disease [PUD] seen on upper gastrointestinal series).

• Vitamin B12 level in patients with atrophic gastritis. • Hematocrit (low if significant bleeding has occurred).

TREATMENT NONPHARMACOLOGIC THERAPY • Avoidance of mucosal irritants such as alcohol and NSAIDs • Lifestyle modifications with avoidance of tobacco and foods that trigger symptoms ACUTE GENERAL Rx • Eradication of H. pylori, when present, can be accomplished with various regimens: 1. Quadruple therapy: Proton pump inhibitor (PPI) (omeprazole 20 mg, lansoprazole 30 mg, pantoprazole 40 mg, rabeprazole 20 mg) bid plus clarithromycin 500 mg BID plus amoxicillin 1000 mg bid plus metronidazole 500 mg BID for 14 days. 2. Triple therapy: PPI bid plus clarithromycin 500 mg bid and metronidazole 500 mg bid for 14 days. This regimen is useful in those with penicillin allergy. 3. Triple therapy: Clarithromycin 500 mg BID plus amoxicillin 1 g BID plus PPI BID for 14 days. Useful only in areas with clarithromycin resistance 5 mm confined to folds but not continuous between the tops of mucosal folds Mucosal breaks continuous between tops of two or more mucosal folds but not the circumferential Circumferential mucosal break

Grade C Grade D

From Feldman M et al: Sleisenger and Fordtran’s gastrointestinal and liver disease, ed 10, Philadelphia, 2016, Elsevier.

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • Peptic ulcer disease • Unstable angina • Esophagitis (from infections such as herpes, Candida), medication induced (doxycycline, potassium chloride), eosinophilic esophagitis • Esophageal spasm (nutcracker esophagus) • Cancer of esophagus WORKUP • Aimed at eliminating the conditions noted in the differential diagnosis and documenting the type and extent of tissue damage. Generally, when symptoms of GERD are typical and the patient responds to therapy,

there is no need for further diagnostic tests to verify the diagnosis. • Upper GI endoscopy (Fig. E2) is useful to document the type and extent of tissue damage in persistent GERD and to exclude eosinophilic esophagitis and potentially malignant conditions such as Barrett esophagus. The American College of Physicians recommends endoscopy in the setting of GERD in people with heartburn and alarm symptoms (dysphagia, bleeding, anemia, weight loss, and recurrent vomiting). It is also indicated in people with GERD symptoms that persist despite a therapeutic trial of 4 to 8 wk of bid proton pump inhibitor (PPI) therapy in patients with severe erosive esophagus after a 2-mo course of PPI therapy to assess healing and rule out Barrett esophagus.

LABORATORY TESTS • 24-hr esophageal pH monitoring with transnasal catheter or a 48-hr wireless capsule are sensitive diagnostic tests to assess the degree of acid exposure in the esophagus in patients not responding to acid-reducing therapy; however, they are not practical and generally not done. They are useful in patients with atypical manifestations of GERD, such as chest pain or chronic cough. • High-resolution esophageal manometry (HRM) is indicated in patients with refractory reflux in whom surgical therapy is planned. • Helicobacter pylori testing is not indicated in GERD. IMAGING STUDIES An upper GI series is useful in patients unwilling to have endoscopy or with medical contraindications to the procedure. It can identify ulcerations and strictures; however, it may

TABLE 2  Modulators of Lower Esophageal Sphincter (LES) Pressure Increase LES Pressure

Decrease LES Pressure

Hormones/peptides

Gastrin Motilin Substance P

Neural agents

α-Adrenergic agonists β-Adrenergic antagonists Cholinergic agonists Protein

CCK Secretin Somatostatin Vasoactive intestinal peptide α-Adrenergic antagonists β-Adrenergic agonists Cholinergic antagonists Chocolate Fat Peppermint Barbiturates Calcium channel blockers Diazepam Dopamine Meperidine Morphine Prostaglandins E2 and I2 Serotonin Theophylline

Foods and nutrients

Other factors

Antacids Baclofen Cisapride Domperidone Histamine Metoclopramide Prostaglandin F2α

CCK, Cholecystokinin. From Feldman M et al: Sleisenger and Fordtran’s gastrointestinal and liver disease, ed 10, Philadelphia, 2016, Elsevier.

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DEFINITION Gastroesophageal reflux disease (GERD) is a motility disorder characterized primarily by heartburn and caused by the reflux of gastric contents into the esophagus. A current definition is a condition that develops when the reflux of stomach contents causes at least two heartburn episodes per week and/or complications. Table 1 describes a classification system for esophagitis.

ETIOLOGY • Incompetent lower esophageal sphincter (LES) (see Fig. E1) • Medications that lower LES pressure (calcium channel blockers, alpha-adrenergic antagonists, nitrates, theophylline, anticholinergics, sedatives, prostaglandins). • Foods that lower LES pressure (chocolate, yellow onions, peppermint). Table 2 summarizes modulators of lower esophageal sphincter (LES) pressure • Tobacco abuse, alcohol, coffee • Pregnancy • Gastric acid hypersecretion • Hiatal hernia (controversial) present in >70% of patients with GERD; however, most patients with hiatal hernia are asymptomatic • Obesity is associated with a statistically significant increase in the risk for GERD symptoms, erosive esophagitis, and esophageal carcinoma

Reflux Disease (GERD)

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594

Gastroesophageal Reflux Disease (GERD) miss mucosal abnormalities. Only one third of patients with GERD have radiographic signs of esophagitis on an upper GI series.

TREATMENT NONPHARMACOLOGIC THERAPY • Lifestyle modifications with avoidance of foods (e.g., citrus- and tomato-based products, onions, spicy foods, carbonated beverages, mint, chocolate, fried foods) and drugs that exacerbate reflux (e.g., caffeine, β-blockers, calcium channel blockers, α-adrenergic agonists, theophylline) • Avoidance of tobacco and alcohol use • Elevation of head of bed (4 to 8 in) with blocks • Avoidance of lying down directly after late or large evening meals, consumption of smaller and more frequent meals • Weight reduction to BMI 50% of women at this age versus ∼15% of premenopausal women. PREVALENCE: According to a cross-sectional population-based study, GSM and its features affect 57% of sexually active women in the United States aged 40 to 65 yr. RISK FACTORS: • Menopause • Nonmenopause hypoestrogenism • Bilateral oophorectomy • Cigarette smoking • Alcohol abuse • Decreased sexual frequency and abstinence • Ovarian failure • Lack of exercise • Absence of vaginal childbirth • Estrogen deficient because of cancer treatments PHYSICAL FINDINGS & CLINICAL PRESENTATION • Principal symptoms include vaginal dryness, dyspareunia, burning, itching, and dysuria. • Atrophy of the labia majora and vaginal introitus are observed, include labial thinning, narrowing of the introitus, decreased width and depth of the vagina, along with observed pale and dry vulvar and vaginal tissues with loss of rugae and elasticity. • Laboratory studies may suggest an increase in vaginal pH (>5.0) with loss of superficial cells on vaginal maturation index. • A thin, watery, yellowish vaginal discharge may be noticed. A urethral caruncle may develop.

ETIOLOGY • The etiology of GSM is secondary to hypoestrogenism, which is predominantly caused by decreased levels of endogenous estrogen during the transition between perimenopausal and postmenopausal yr in the female body. • Other etiologies of hypoestrogenism include postpartum and lactation, use of medications with antiestrogenic effects, bilateral oophorectomy, hypothalamic amenorrhea or amenorrhea combined with glucocorticoid therapy, primary ovarian insufficiency, breast cancer treatments including chemotherapy, pelvic surgery, radiation, and aromatase inhibitors (AIs).

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • Vaginal infections, including Candida vulvovaginitis, bacterial vaginosis, trichomoniasis, and desquamative inflammatory vaginitis • Irritant dermatitis in response to perfumes, deodorants, soaps, lubricants, spermicides, perineal pads, or panty liners • Vulvovaginal dermatoses, including lichen sclerosus, lichen planus, and lichen simplex chronicus • Cancer and precancerous lesions, including vulvar intraepithelial neoplasm, vulvar cancer, and extramammary Paget disease • Vulvodynia • Other etiologies of frequent urinary tract infection or associated symptoms WORKUP • Complete medical history focusing on use of medications with antiestrogenic effects and cancer treatments, which include chemotherapy, pelvic surgery, and radiation therapy • Pelvic examination: Changes in shape and color in external labia majora and minora; atrophy in clitoral hood and the clitoris; changes in vulvar and vaginal tissue; some patients may also experience inflammation with potential vaginal bleeding • Laboratory testing (see “Laboratory Tests”) LABORATORY TESTS • Vaginal pH may reach above 4.6 in the absence of other causes. • Vaginal maturation index (VMI): Microscopic findings on a smear of the vaginal epithelium may include increase of parabasal cells with a significant decrease of intermediate and superficial cells (50% of patients, as well as in their personal relationships.

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Genitourinary Syndrome of Menopause TABLE 1  Hormonal Therapy for Treatment of Genitourinary Syndrome of Menopause Dosage Treatment

Product

Initial

Maintenance

Comments

Vaginal Cream Estradiol-17b

Estrace (Allergan, Irvine, CA)

0.5-1.0 g, daily for 2 wk

0.5-1.0 g, 1-3 times weekly

Premarin (Pfizer, New York, NY)

0.5-1.0 g, daily for 2 wk

0.5-1.0 g, 1-3 times weekly

FDA-approved dose is higher (loading dose = 2.0-4.0 g, daily; maintenance dose = 1.0 g, 1-3 times weekly) FDA-approved dose is higher and administration is cyclic (for GSM, 0.5-2.0 g, daily for 21 days and then off for 7 days; for dyspareunia, [A] 0.5 g, daily for 21 days and then off for 7 days, or [B] 0.5 g, twice weekly)

Vagifem (Novo Nordisk, Bagsværd, Denmark), Yuvafem (Amneal, Bridgewater, NJ) TX-004HR

10-mcg insert, once daily for 2 wk

1 twice weekly

—

4, 10, or 25 mcg, daily for 2 wk 6.5 mg, once daily

1 twice weekly 6.5 mg, once daily

This product is not yet FDA approved —

Insert for 90 days (2-mg releases approximately 7.5 mcg daily) Insert for 90 days (12.4-mg or 24.8-mg releases 0.05 mg or 0.1 mg daily, respectively)

Change every 90 days

—

Change every 90 days

This product is delivered vaginally but it provides systemic hormone levels to treat VMS and GSM

60 mg, daily

60 mg, daily

FDA approved for dyspareunia

Conjugated estrogens

Vaginal Insert Estradiol hemihydrate Estradiol-17b softgel capsules DHEA (prasterone) Vaginal Ring Estradiol-17b Estradiol acetate

Intrarosa (AMAG Pharmaceuticals, Waltham, MA) Estring (Pfizer, New York, NY) Femring (Warner Chilcott UK Limited, Larne, Northern Ireland, UK)

Selective Estrogen Receptor Modulator Ospemifene Osphena (Duchesnay USA, Rosemont, PA)

FDA, U.S. Food and Drug Administration; VMS, vasomotor symptoms. From Faubion SS et al: Genitourinary syndrome of menopause: management strategies for the clinician, Mayo Clin Proc 92:1842-1849, 2017.

are detected combined with abdominal pain, blood in stool, and unexplained weight loss. • Recurrent urinary tract infection with other associated symptoms may require genitourinary workup and/or cystoscopy.

PEARLS & CONSIDERATIONS COMMENTS • The estradiol ring may dislodge with bowel movement, sexual intercourse, douching, or Valsalva maneuvers. Vaginal ring users are

encouraged to remove or replace the vaginal ring on their own. • The safety of systemic hormone therapy in women with breast cancer should be carefully considered. • With the use of local estrogen cream, dosing at least 12 hours before vaginal sexual activity is recommended to prevent estrogen absorption by a sexual partner.

PATIENT & FAMILY EDUCATION Clinicians should discuss the concept of maintaining sexual function for postmenopausal women. For women with a sexual partner,

regular vaginal intercourse or stimulation helps to maintain vaginal health, as well as provide comfort and satisfaction during sexual activities in the future. For women without a sexual partner, regular use of vaginal vibrator or other stimulators should be recommended to maintain healthy vaginal function.

RELATED TOPICS Genitourinary Syndrome of Menopause (Patient Information) Vaginitis, Estrogen-Deficient (Related Key Topic) AUTHORS: Jiaying Bi, MA, Matthew H. H. Young, MD, JD, and Rachel Wright Heinle, MD, FACOG

Genitourinary Syndrome of Menopause SUGGESTED READINGS Behnia-Willison F et  al: Safety and long-term efficacy of fractional CO2 laser treatment in women suffering from genitourinary syndrome of menopause, Eur J Obstet Gynecol Reprod Biol 213:39-44, 2017, https://doi.org/10.1016/j. ejogrb.2017.03.036. Gandhi J et  al: Genitourinary syndrome of menopause: an overview of clinical manifestations, pathophysiology, etiology, evaluation, and management, Am J Obstet Gynecol 215:704-711, 2016, https://doi.org/10.1016/j. ajog.2016.07.045. Gass MLS et al: Management of symptomatic vulvovaginal atrophy: 2013 position statement of the North American Menopause Society, Menopause 20(9):888902, 2013, https://doi.org/10.1097/gme.0b013e3182a122c2. Hodges AL et  al: Diagnosis and treatment of genitourinary syndrome of menopause, Nurs for Womens Health 22(5):423-430, 2018, https://doi. org/10.1016/j.nwh.2018.07.005. Kim HK et  al: The recent Review of the genitourinary syndrome of menopause, J Menopausal Med 21(2):65-71, 2015, https://doi.org/10.6118/ jmm.2015.21.2.65. Mac Bride MB et  al: Vulvovaginal atrophy, Mayo Clin Proc 85(1):87-94, 2010, https://doi.org/10.4065/mcp.2009.0413. Shifren JL: Genitourinary syndrome of menopause, Clin Obstet Gynecol 16:508516, 2018, https://doi.org/10.1097/grf.0000000000000380.

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Gestational Diabetes Mellitus (GDM) BASIC INFORMATION

SYNONYMS Gestational diabetes Diet-controlled gestational diabetes (A1) Medication-treated gestational diabetes (A2) ICD-10CM CODES O24.410 Gestational diabetes mellitus in pregnancy, diet controlled O24.414 Gestational diabetes mellitus in pregnancy, insulin controlled O24.419 Gestational diabetes mellitus in pregnancy, unspecified control O99.810 Abnormal glucose complicating pregnancy

EPIDEMIOLOGY & DEMOGRAPHICS INCIDENCE: Approximately 5% of pregnant women in the U.S. will be diagnosed with GDM using the two-step approach and 18% using the one-step approach. PREDOMINANT SEX AND AGE: Women of childbearing age; increased risk is observed in women over the age of 35 yr.

RISK FACTORS • Overweight or obesity • Family history of GDM or type 2 diabetes, particularly in first-degree relatives • Polycystic ovarian syndrome • Multiple gestation • Hypertensive disorder of pregnancy or chronic hypertension • Chronic systemic steroid use • History of macrosomia in prior pregnancy • Personal history of abnormal glucose tolerance or GDM in previous pregnancy • Hispanic, Native American, African American, Asian, or Pacific Islander ethnicity • Advanced maternal age (over age 25) • Unexplained perinatal loss or malformation in previous or current pregnancy may be suggestive of preexisting diabetes PHYSICAL FINDINGS & CLINICAL PRESENTATION Suspect GDM if: • Fetal size greater than dates on Leopold or increased fundal height measurement • Ultrasound findings of fetal macrosomia (especially enlarged abdominal circumference) or polyhydramnios • Marked maternal obesity or weight gain above expected range • Acanthosis nigricans (as underlying insulin resistance increases risk) • Symptoms of diabetes • Glucosuria • Hemoglobin A1C greater than or equal to 5.7 in the first trimester ETIOLOGY During normal pregnancy several mechanisms contribute to increased insulin resistance. Placental secretion of human placental lactogen (hPL) decreases maternal insulin sensitivity, decreases maternal glucose utilization, and increases lipolysis, all to ensure adequate glucose availability to the growing fetus. Maternal pancreatic beta cells are increased in order to

TABLE 1  White Classification for Pregnant Women with Diabetes (Gestational or Preexisting) Class

Description

A1 A2 B C D F H R T

DM diagnosed during pregnancy and controlled by diet DM diagnosed during pregnancy and requiring medication Insulin-requiring DM diagnosed before pregnancy, age >20 yr, lasting 10 yr or duration >20 yr, or associated with hypertension or background retinopathy DM with renal disease DM with coronary artery disease DM with proliferative retinopathy DM with renal transplant

DM, Diabetes mellitus.

secrete additional insulin to compensate for the increased circulating blood glucose. Insulin resistance is also exacerbated by an increase in maternal adipose deposition, decreased exercise, and increased caloric intake. GDM occurs when maternal insulin secretion cannot meet the increased glucose burden, resulting in carbohydrate intolerance and hyperglycemia.

G

DIAGNOSIS DIFFERENTIAL DIAGNOSIS Preexisting type 1 or 2 DM not previously diagnosed WORKUP • History with focus on personal medical history, prior pregnancy history, and family history • Routine prenatal examination • Laboratory evaluation (see the following) LABORATORY TESTS • Exclude preexisting diabetes • For women with risk factors (see above), order a 1-hr glucose tolerance test at the first prenatal visit, then repeat at 24 to 28 weeks if initial screen was normal. If abnormal at intake, consider the probability of undiagnosed preexisting DM or underlying insulin resistance and check hemoglobin A1c. A diagnosis of diabetes is made if a woman meets any of the following criteria: Fasting plasma glucose >126 mg/dl, A1c >6.5%, random plasma glucose >200 mg/dl. The authors consider a first-trimester A1c of ≥5.7 suggestive of preexisting insulin resistance, and would be inclined to monitor closely for hyperglycemia. • Two-step approach: 1. For screening without risk factors, a 1-hr, nonfasting 50-g oral glucose tolerance test (OGTT) is appropriate. If the result is abnormal (≥130 mg/dl, as defined by Carpenter and Coustan), a 3-hr, 100-g oral glucose tolerance test is performed. The diagnosis of GDM is made if two or more of the following glucose values are met or exceeded: a. Fasting: 95 mg/dl b. 1-hr plasma glucose: 180 mg/dl c. 2-hr plasma glucose: 155 mg/dl d. 3-hr plasma glucose: 140 mg/dl 2. If one of four values on 3-hr glucose tolerance test is abnormal, consider repeat testing in 1 month and recommend a lowcarbohydrate diet immediately and consultation with a nutritionist. At least one study has demonstrated increased perinatal risk in women with only one of four abnormal values on 3-hr OGTT • One-step approach: 1. Like the two-step, a one-step screening is performed at 24 to 28 weeks on all pregnant patients who have not already been diagnosed with diabetes. This is a 2-hr, 75-g oral glucose tolerance test performed after an overnight, 8-hr fast. A diagnosis of GDM is made if one or more of the following values are met or exceeded:

Diseases and Disorders

DEFINITION Gestational diabetes mellitus is hyperglycemia occurring during the second or third trimester in absence of a prepregnancy diagnosis of type 1 or type 2 diabetes. Screening for gestational diabetes mellitus in asymptomatic pregnant women after 24 weeks’ gestation is a grade B recommendation by the U.S. Preventive Services Task Force (USPSTF). In the U.S., a two-step approach to screening is commonly used and is currently endorsed by the American College of Obstetricians and Gynecologists (ACOG) and the National Institutes of Health (NIH). The International Association of Diabetes in Pregnancy Study Group has recommended a simplified one-step approach for screening and diagnosing GDM, which has been endorsed by the American Diabetes Association since 2011, with the acknowledgment that the one-step approach increases the prevalence of GDM without clear evidence of benefit. Pregnant women with diabetes mellitus (DM) (gestational or preexisting) are classified according to White classification (Table 1).

GENETICS: Higher rate in women with a family history of GDM or type 2 diabetes in a firstdegree relative; specific HLA alleles (DR3 or DR4) predispose to the development of DM type 2 after pregnancy.

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a. Fasting: ≥92 mg/dl b. 1-hr plasma glucose ≥180 mg/dl c. 2-hr plasma glucose ≥153 mg/dl • A fter pregnancy, women with GDM have an increased risk of developing diabetes during their lifetime. Women with GDM should be screened at or after 6 weeks postpartum with a 75-g 2-hour GTT to diagnose type 2 diabetes using the same criteria as nonpregnant patients. Alternatively, an HgbA1c can be performed at or after 12 weeks postpartum.

IMAGING STUDIES Ultrasound for fetal size is performed in women with GDM. It may be initiated at the time of diagnosis and repeated every 3 to 4 weeks if macrosomia is suspected. Clinicians should consider local standards of care.

TREATMENT NONPHARMACOLOGIC THERAPY • Glucose monitoring: 1. Four times daily: Fasting and 2-hr postprandial (defined as 2 hr after the start of each meal). 2. Goals: Fasting 50 yr. Inflammation primarily targets branches of the extracranial head and neck blood vessels (external carotids, temporal arteries, ciliary and ophthalmic arteries). The aorta and subclavian and brachial arteries can also be affected. Intracranial arteritis is rare. SYNONYMS Temporal arteritis Cranial arteritis GCA Horton disease ICD-10CM CODES M31.5 Giant cell arteritis with polymyalgia rheumatica M31.6 Other giant cell arteritis

EPIDEMIOLOGY & DEMOGRAPHICS INCIDENCE: Approximately 20 new cases per 100,000 persons >50 yr; peak incidence is in patients ages 60 to 80 yr. PREVALENCE: 200 cases per 100,000 persons; it is the most common primary vasculitis; female/male predominance of twofold to fourfold; more common in Caucasians. PHYSICAL FINDINGS & CLINICAL PRESENTATION GCA can present with the following clinical manifestations: TABLE 1  Atypical Manifestations of Giant Cell Arteritis Fever of unknown origin Respiratory symptoms (especially cough) Otolaryngeal manifestations Glossitis Lingual infarction Throat pain Hearing loss Large-artery disease Aortic aneurysm Aortic dissection Limb claudication Raynaud phenomenon Neurologic manifestations Peripheral neuropathy Transient ischemic attack (TIA) or stroke Dementia Delirium Myocardial infarction Tumorlike lesions Breast mass Ovarian and uterine mass Syndrome of inappropriate antidiuretic hormone secretion (SIADH) Microangiopathic hemolytic anemia From Harris ED et al: Kelly’s textbook of rheumatology, ed 7, Philadelphia, 2005, Saunders.

• Headache, often associated with marked scalp tenderness—noticed while brushing hair (hair comb allodynia) • Constitutional symptoms (fever, weight loss, anorexia, fatigue) • Polymyalgia rheumatica (aching and stiffness of the trunk and proximal muscle groups) • Visual disturbances (transient or permanent monocular or binocular visual loss) • Intermittent claudication of jaw and tongue on mastication that is especially prominent when solid food such as steak is chewed • Table 1 describes atypical manifestations of GCA Important physical findings in GCA: • Vascular examination: The temporal artery demonstrates tenderness, decreased pulsation, and nodularity (ropy) (Fig. E1); diminished or absent pulses in upper extremities may be seen.

ETIOLOGY Vasculitis of unknown etiology. An association with HLA-DRB*04 has been identified. Recent demonstration of varicella zoster virus virion, antigen, and DNA within the vessel walls of the temporal arteries on histopathologic specimens of giant cell arteritis suggest an association.

DIAGNOSIS Clinical history and vascular examination remain cornerstones of diagnosis. An algorithm for diagnosing GCA is described in Fig. 2. The American College of Rheumatology has proposed classification criteria to aid in the diagnosis of GCA. Presence of three or more of these criteria in a patient with suspected vasculitis is considered to be suggestive of GCA: • Age of onset of symptoms >50 yr • New-onset of or new type of localized headache

• Temporal artery abnormalities including tenderness or decreased pulsation • Westergren erythrocyte sedimentation rate (ESR) elevated (typically >50 mm/hr) • Temporal artery biopsy with vasculitis and mononuclear cell infiltrate or granulomatous changes

DIFFERENTIAL DIAGNOSIS • Other vasculitic syndromes • Nonarteritic anterior ischemic optic neuropathy (NAION) • Pituitary apoplexy • Primary amyloidosis • Transient ischemic attack, stroke • Infections • Occult neoplasm, multiple myeloma LABORATORY TESTS • E SR elevated although up to 22% of patients with GCA have normal ESR before treatment. • C-reactive protein (CRP) is typically included in laboratory investigation; it may have greater sensitivity than ESR. CRP typically rises before the ESR. • Mild to moderate normochromic normocytic anemia, elevated platelet count. IMAGING STUDIES Imaging studies do not play a major role in diagnosing GCA and are rarely indicated: • Color duplex ultrasonography (CDUS) of temporal artery produces three characteristic features—periluminal “halo” over the temporal artery involved, segmental arterial stenosis, and arterial luminal occlusion in severe cases. CDUS of the temporal artery has 40% to 75% sensitivity and 79% to 83% specificity for diagnosis of GCA. Clinical utility is not superior to clinical examination with biopsy.

Giant cell arteritis suspected

Temporal artery biopsy

Positive biopsy: GCA proven

Negative biopsy

GCA still strongly suspected

Perform second biopsy of temporal artery or occipital artery or perform imaging study if large artery involvement suspected

GCA suspicion low

No further biopsy

FIG. 2  Algorithm for diagnosing giant cell arteritis (GCA). (From Firestein GS et al: Kelly’s textbook of rheumatology, ed 9, Philadelphia, 2013, Saunders.)

ALG

TREATMENT ACUTE GENERAL Rx • If there is clinical suspicion of GCA, treatment should be initiated without waiting for results of laboratory or imaging studies. • IV methylprednisolone (250 to 1000 mg for 1 to 3 days) is considered standard of care in patients with severe clinical manifestations such as visual loss from ischemic optic neuropathy. • Oral prednisone (1 mg/kg/day): High-dose oral regimen should be continued at least until symptoms resolve and ESR returns to normal; usually 3 to 4 wk after treatment initiation. Steroid taper is very slow (10% to 20% per mo) with monitoring of clinical features as well as ESR and CRP. When dose 50% direct)

40 yr is estimated to be 1.86%, with 1.57 million white and 398,000 black patients affected. By 2020, we may expect more than 3 million cases in the U.S. • 150,000 patients have bilateral blindness. • Prevalence is higher in diabetics, those with high myopia, and older persons. • More common in African-American population (three times the age-adjusted prevalence than whites). There is a genetic tendency to OAG; multiple genes have been isolated that are associated with development of high IOP and optic nerve damage. PREDOMINANT AGE: • Persons >50 yr • Can occur in 30s and 40s, and juvenile forms are rare

ETIOLOGY • Uncertain hereditary tendency (multifactorial genetics) • Topical steroids can induce high IOP and cause glaucoma • Trauma • Inflammatory (e.g., history of uveitis) • High-dose oral corticosteroids taken for prolonged periods

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • Other optic neuropathies (previous retinal vascular disorders, optic nerve pits, or coloboma). • Physiologic cupping of the optic nerve: The optic nerve may appear similar to g­ laucoma damage but does not progress. This is ­followed for any signs of progression. • Ocular hypertension: IOP is chronically elevated, but not causing optic nerve damage, must monitor closely. • Secondary glaucoma from inflammation and steroid therapy. • Trauma

PHYSICAL FINDINGS & CLINICAL PRESENTATION • High intraocular pressures and/or large optic nerve cup (Fig. E2). Ocular Hypertension Treatment Study results help to delineate important risk factors, including high eye pressure, thin corneal central thickness, age, and visual field results. • Abnormal visual fields (with advanced glaucoma damage to the optic nerve). • Open anterior chamber angle—evaluated with gonioscopy at slit lamp • Figs. E3 and E4 illustrate stages of openangle glaucoma.

WORKUP • Comprehensive eye examination • Intraocular pressure • Slit lamp examination • Visual fields • Gonioscopy: To determine the type of glaucoma (narrow, open, or closed angles) • Nerve fiber analysis (e.g., OCT, and HRT) • Corneal thickness (thick central cornea will result in possible overestimation of the true physiologic IOP, and vice versa, so this is

Filtration angle

B

Narrow-angle

FIG. 1  A, Open-angle glaucoma: Drainage of the aqueous humor becomes obstructed, and impaired flow from the eye leads to gradually increased intraocular pressure. B, Narrow-angle glaucoma: When the iris moves forward, as may occur during pupil dilation, the angle is narrowed or even closed. Obstruction of aqueous humor flow leads to angle-closure glaucoma. (From Kaufman DM, Geyer HL, Milstein MJ: Kaufman’s clinical neurology for psychiatrists, ed 8, Philadelphia, 2017, Elsevier.)

Glaucoma, Open-Angle TABLE 1  Characteristics of Glaucoma Primary Open-Angle Glaucoma

Narrow-Angle Glaucoma

Occurrence Cause Age at onset Anterior chamber Chamber angle Symptoms

85% of all glaucoma cases Unclear* Variable Usually normal Normal Usually none Decreased vision, late

Cupping of disc Visual fields

Progressive if not treated Peripheral fields are involved early Central involvement is a very late sign Progressively higher if not medically controlled Late: High

15% of all glaucoma cases Closed angle prevents aqueous drainage 50 to 85 yr Shallow Narrow Headache Seeing halos around lights Sudden onset of severe eye pain Vomiting during attack After one or more untreated attacks Involvement is a late sign

Ocular pressure Other signs Treatment Prognosis

Medical Laser surgery Good if recognized early Very dependent on patient compliance

Early: Detected with provocative tests only Fixed, partially dilated pupil Conjunctival injection “Steamy” cornea† Surgical Good

*Thought to be a defect in the trabecular network ultrastructure. †Like looking through a steamy window. From Swartz MH: Textbook of physical diagnosis, history and examination, ed 7, Philadelphia, 2014, Elsevier.

important information in diagnosis and treatment of OAG)

LABORATORY TESTS Blood sugar IMAGING STUDIES • Optic nerve photography—stereo photographs • Visual field testing • Laser scan of nerve fiber layer, OCT, HRT. Rarely, MRI of orbits if the glaucoma findings are atypical or suspicious of other causes of optic nerve atrophy.

TREATMENT ACUTE GENERAL Rx • β-Blockers (e.g., timolol) qd to bid depending on individual response to drug.

• Carbonic anhydrase inhibitors (e.g., Diamox 250 mg qid or 500 mg bid). • Prostaglandin analogues (latanoprost, bimatoprost, travoprost, tafluprost) are commonly used as first-line treatment. They lower intraocular pressure by 25% to 30% by increasing uveoscleral outflow and reducing aqueous production. • Alpha-2 agonists and cholinergic agonists. • Hyperosmotic agents (mannitol) in acute treatment (IV). • Selective laser trabeculoplasty (SLT) may delay or forestall need for second eye drop. The effect may be temporary but the laser can be repeated.

CHRONIC Rx • At least biannual checks of intraocular pressure and adjustment of medication. • Surgical trabeculectomy and filter valve ­surgeries can be considered for glaucoma

DISPOSITION Must be followed by ophthalmologist REFERRAL Immediately to ophthalmologist

PEARLS & CONSIDERATIONS COMMENTS • Glaucoma is a serious blinding disease that must be monitored professionally by an ophthalmologist. It is mostly asymptomatic until late in the disease when visual problems arise. Even in developed countries half of glaucoma cases are undiagnosed. • Risk factors that should prompt referral to an ophthalmologist for evaluation of glaucoma are high intraocular pressure, family history of glaucoma, use of systemic or topical corticosteroids, older age, and black race. • Vision loss from glaucoma cannot be recovered. Early diagnosis and treatment may minimize visual loss. • Glaucoma is not solely caused by increased intraocular pressure because approximately 20% of patients with glaucoma have normal intraocular pressure. However, high pressure is definitely a risk factor to be considered. SUGGESTED READINGS Available at ExpertConsult.com RELATED CONTENT Glaucoma (Patient Information) AUTHOR: R. Scott Hoffman, MD

G

Diseases and Disorders

Feature

that progresses (optic nerve changes or visual field progression) despite maximal tolerated medical therapies. Recently, minimally invasive glaucoma surgeries (MIGS) have been advocated for IOP control. Some are performed at the time of cataract procedures and some are independent procedures. The effort is to reduce the risks associated with traditional trabeculectomy.

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SUGGESTED READINGS Gupta D, Chen PP: Glaucoma, Am Fam Physician 93(8):668-674, 2016. Quigley HA: Glaucoma, Lancet 377:1367-1377, 2011. Weinreb RN et  al: The pathophysiology and treatment of glaucoma, JAMA 311(18):1901-1911, 2014.

A

B FIG. E2  A and B, Optic cup asymmetry in glaucoma. The cup-disc ratio is approximately 30% in A (right eye) and 70% in B (left eye). (Swartz MH: Textbook of physical diagnosis, history and examination, ed 7, Philadelphia, 2014, Elsevier.)

Glaucoma, Open-Angle

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FIG. E3  Small paracentral scotoma in mild to moderate glaucoma. (From Bowling B: Kanski’s clinical ophthalmology: a systematic approach, ed 8, Philadelphia, 2016, Elsevier.)

A

B FIG. E4  Moderate to marked glaucoma. A and B, Stereo disc photographs showing inferior neuro-retinal rim shelving.

Glaucoma, Open-Angle

C FIG. E4, cont’d  C, Visual field from the same eye showing superior arcuate scotoma and nasal step (but note suboptimal reliability).

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Glaucoma, Open-Angle

D FIG. E4, cont’d  D, OCT from the same patient—note inferior abnormality on ganglion cell complex analysis of the left eye corresponding to the superior nasal step. (From Bowling B: Kanski’s clinical ophthalmology: a systematic approach, ed 8, Philadelphia, 2016, Elsevier.)

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Glaucoma, Primary Angle-Closure BASIC INFORMATION DEFINITION Primary angle-closure glaucoma occurs when elevated intraocular pressure is associated with closure of the filtration angle or obstruction in the circulating pathway of the aqueous humor. SYNONYMS Acute glaucoma, angle-closure glaucoma (ACG) Pupillary block glaucoma Narrow-angle glaucoma Angle-closure glaucoma ICD-10CM CODES H40.061 Primary angle closure without glaucoma damage, right eye H40.062 Primary angle closure without glaucoma damage, left eye H40.063 Primary angle closure without glaucoma damage, bilateral H40.069 Primary angle closure without glaucoma damage, unspecified eye

EPIDEMIOLOGY & DEMOGRAPHICS INCIDENCE (IN U.S.): • 2% to 8% of all patients with glaucoma. • Higher incidence among those with hyperopia, small eyes, dense cataracts, shallow anterior chambers. PEAK INCIDENCE: Greater >50 yr; high association with hyperopia, cataracts, and eye trauma PREDOMINANT SEX: Females are affected more often than males. PREDOMINANT AGE: 50 to 60 yr GENETICS: Family history is not particularly helpful; far-sighted (hyperopes) individuals with thickening lenses (i.e., cataracts) are often those with angle-closure attacks. PHYSICAL FINDINGS & CLINICAL PRESENTATION • A lthough angle-closure glaucoma can present with an acute painful crisis associated with blurred vision, more than 75% of patients present with an asymptomatic course with progressive loss of the visual field (similar to that in patients with primary open-angle glaucoma; referred to as intermittent, subacute, or chronic angle closure) • Hazy cornea • Narrow angle • Pain may be present (supraorbital headache is typical) • Injection of conjunctiva, red eye (often severe limbal conjunctival injection with very high intraocular pressure [IOP]) • Shallow anterior chamber (one can shine a light from the side to perceive the forward position of the iris with narrow AC angles) • Thick cataract • Pupil may be mid-dilated and nonreactive to light • Figs. E1 and E2 illustrate gonioscopy in primary angle-closure glaucoma

ETIOLOGY • Narrow angles with acute closure: Blockage of circulatory path of the aqueous humor (Fig. E3) causing increase in IOP. ACG (primary angle closure glaucoma) occurs more commonly in eyes with shorter axial length (farsightedness), shallower anterior chamber, and a relatively larger lens (enlarging cataract). • Secondary angle-closure glaucoma (more rare) resulting from neovascularization of iris, iris tumors, lens induced, iris scarring, trauma, chronic inflammation with scarring, malignant glaucoma with aqueous misdirection.

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • Open-angle glaucoma: Angle-closure glaucoma is distinguished from open-angle glaucoma by the closure of the angle between the iris and cornea, obstructing outflow of aqueous humor • High intraocular pressure (normal IOP is usually 8 to 21 mm Hg) • Optic nerve cupping • Shallow chamber • Open-angle glaucoma • Conjunctivitis • Corneal disease, keratitis • Uveitis • Scleritis • Allergies • Contact lens wearing with irritation WORKUP Comprehensive eye examination: If one suspects narrow angle or angle closure, avoid pupil dilation, as this may exacerbate the attack. • Intraocular pressure (with ACG, IOP can be extremely high, >60 mm Hg) • Gonioscopy for direct visualization of the chamber angle • Slit lamp examination • Visual field examination • Laser scan of nerve fiber layer and optic nerve, optical coherence tomography (OCT) • Optic nerve evaluation • Anterior chamber depth LABORATORY TESTS • Blood sugar and complete blood count (if diabetes or inflammatory disease is suspected) • Visual field • Nerve fiber analysis, OCT, Heidelberg retinal tomography IMAGING STUDIES • Fundus photography (optic nerve photos)— very helpful for comparing changes in optic nerve shape • Fluorescein angiography for neovascular disease such as diabetic retinopathy, retinal vein occlusions • Ultrasound biomicroscopy and anterior OCT can show relationships of anterior eye structures

TREATMENT The goal of treatment is to acutely lower pressure on the eye and keep it down.

NONPHARMACOLOGIC THERAPY Laser iridotomy early in disease process ACUTE GENERAL Rx • IV mannitol • Pilocarpine • β-Blockers • Diamox • Laser iridotomy • Anterior chamber paracentesis (as emergency treatment) CHRONIC Rx • Iridotomy: When there is an adequate peripheral hole in the iris, the chance for future angle closure is usually eliminated unless there are rare other angle anomalies (i.e., plateau iris or peripheral synechiae). • Lens removal (cataract extraction) can also eliminate the possibility of ACG. • Trabeculectomy and filter valve procedures for nonresponsive cases. • Other laser procedures, such as gonioplasty for atypical angle closures. DISPOSITION Refer to ophthalmologist immediately. REFERRAL If acute angle-closure episode is suspected, should refer emergently to ophthalmologist.

PEARLS & CONSIDERATIONS COMMENTS • Do not use antihistamines or vasodilators with narrow-angle glaucoma. • After iridotomy, the majority of patients will be totally cured and will need no further medication and have no visual loss. • Lower socioeconomic status and higher levels of social deprivation are risk factors for delayed detection and probable worse outcomes in glaucoma. • Risk factors that should prompt referral to an ophthalmologist for evaluation of glaucoma are high intraocular pressure, family history of glaucoma, use of systemic or topical corticosteroids, older age, and black race. • Glaucoma is undiagnosed in 9 out of 10 affected people worldwide and is undiagnosed in 50% of those in developed countries. • Angle closure has become rarer because most people have cataract extractions at an earlier stage than in the past. SUGGESTED READINGS Available at ExpertConsult.com RELATED CONTENT Glaucoma (Patient Information). Glaucoma, Open Angle (Related Key Topic) AUTHOR: R. Scott Hoffman, MD

Glaucoma, Primary Angle-Closure

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C FIG. E1  Primary angle closure suspect. A, On gonioscopy, only a double Schwalbe line and part of the nonpigmented trabecular meshwork are visible—the iris is apposed to the pigmented meshwork. B, Pigment smudging of the nonpigmented meshwork seen on indentation gonioscopy. C, Moderately but not critically narrow angle for comparison—sparsely pigmented Schwalbe line, nonpigmented meshwork, and pigmented meshwork. D, Very narrow angle on dark-room anterior segment optical coherence tomography (OCT). (From Bowling B: Kanski’s clinical ophthalmology, a systematic approach, ed 8, Philadelphia, 2016, Elsevier.)

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B FIG. E2  Primary angle closure. A, Closed inferior angle on gonioscopy. B, Peripheral anterior synechiae (PAS) on indentation gonioscopy—superior angle. (A, Courtesy L. MacKeen.) (From Bowling B: Kanski’s clinical ophthalmology, a systematic approach, ed 8, Philadelphia, 2016, Elsevier.)

FIG. E3  Angle closure due to pupillary block, with anterior iris bowing and iridocorneal contact. (From Bowling B: Kanski’s clinical ophthalmology, a systematic approach, ed 8, Philadelphia, 2016, Elsevier.)

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Glaucoma, Primary Angle-Closure SUGGESTED READINGS Gupta D, Chen PP: Glaucoma, Am Fam Physician 93(8):668-674, 2016. Quigley HA: Glaucoma, Lancet 377:1367-1377, 2011. Weinreb RN et  al: The pathophysiology and treatment of glaucoma, JAMA 311(18):1901-1911, 2014.

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Glenohumeral Dislocation BASIC INFORMATION DEFINITION Glenohumeral dislocation occurs when the humeral head exceeds its physiologic limitations, causing it to translate beyond the glenoid rim. It often requires some form of reduction in order to relocate the humeral head. Lesser events that are self-limited are termed subluxation or subjective instability. During these events, the humeral head translates too, but not past the glenoid rim. Often, the cause of dislocation is traumatic, with the most common direction of humeral head translation being anteriorly and inferiorly. Some anterior dislocations may cause a tear of the anteroinferior glenoid labrum (Bankart lesion). Less commonly the head may dislocate posteriorly, such as during seizures or electrocution. Multidirectional instability predisposes patients to dislocation and is present in a small number of patients. Frequent subluxations or dislocations may occur in multiple directions and result in excessive joint laxity. They may occur with minimal trauma and are often bilateral. ICD-10CM CODES M24.419 Recurrent dislocation, unspecified shoulder M24.819 Other specific joint derangements of unspecified shoulder, not elsewhere classified S43.016A Anterior dislocation of unspecified humerus, initial encounter S43.026A Posterior dislocation of unspecified humerus, initial encounter S43.036A Inferior dislocation of unspecified humerus, initial encounter

PHYSICAL FINDINGS & CLINICAL PRESENTATION Traumatic: • The arm is held in external rotation with anterior dislocation and internal rotation with posterior dislocation. • Slight movement is possible without pain. • The acromion may appear more prominent, and there may be an absence of the normal “fullness” beneath the acromion. • Status of the axillary nerve must always be checked before and after reduction (sensation to the lateral shoulder and ability to gently activate the deltoid).

• Fractures of the humeral head or glenoid rim may occur and predispose patients to future instability and dislocation events. Multidirectional: • Often present after minimal trauma or with recurrent episodes of “giving out,” weakness, and popping. • Sulcus sign may be positive (as the arm is pulled inferiorly with the patient upright, an indentation forms between the acromion and humeral head, indicating excessive inferior movement of the head). • Other signs of generalized joint laxity may be present, such as elbow hyperextension, extension of the small finger metacarpophalangeal joint >90 degrees, or flexion of the thumb down to the volar forearm (Beighton criteria).

• Posterior dislocations, inferior dislocations, or fracture-dislocations should be reduced by an experienced practitioner. • Gentle limited range-of-motion exercises as pain subsides followed by strengthening exercises at 2 wk.

ETIOLOGY • Anterior: Due to trauma, often with the arm abducted and externally rotated • Posterior: Often secondary to seizure or electrical shock • Multidirectional: Secondary to generalized joint laxity

REFERRAL Surgical reconstruction may be required in patients with recurrent dislocations.

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • Proximal humerus fracture • Grade 3 or greater acromioclavicular (AC) joint injury: Presents with pain and prominent AC joint IMAGING STUDIES • Acute shoulder injury: True anteroposterior (AP) (aimed 15 degrees across the body for a perpendicular view of the glenohumeral joint), scapular “Y” view, and an axillary lateral 1. Internal/external rotation variations in the true AP image may reveal bony injury to the proximal humerus. • CT: Useful to evaluate fractures of the glenoid and/or humerus. May include contrast arthrogram to evaluate labrum and rotator cuff • MRI: Useful to evaluate soft tissue only, including labral injury or rotator cuff tear

TREATMENT • Reduction of the acute dislocation by gentle distal traction in the relaxed patient should be followed by brief immobilization with a sling (less than 1 wk for simple dislocations).

DISPOSITION • Recurrence of anterior dislocation is common in the young population; patients under 30 should be referred to an orthopedist for further evaluation. • Primary dislocations in patients >40 yr old are not generally complicated by recurrence but may result in shoulder stiffness and associated rotator cuff tears. • There is an almost 100% recurrence after the third dislocation.

PEARLS & CONSIDERATIONS COMMENTS • X-rays in two orthogonal planes are always indicated to confirm dislocation or reduction. A single radiograph is never acceptable. • It is important to know if there was an injury involved in the first episode and if a radiograph was taken to determine direction of the dislocation. • Up to 50% of posterior dislocations are missed by the first examiner, usually the result of an inadequate lateral radiograph of the glenohumeral joint. • “Voluntary” dislocators should typically be treated nonsurgically. • Sports activities may be resumed when there is pain-free full motion with normal strength. • Multidirectional instabilities are usually treated nonsurgically with strengthening exercises, and rehabilitation. • Dislocations in either direction are occasionally overlooked. If the injury is over 2 to 4 wk old, enough tissue healing will have occurred to make closed reduction nearly impossible. Open surgical reduction may then be needed. AUTHORS: Stephen E. Marcaccio, MD, and Brett D. Owens, MD

Glenohumeral Dislocation SUGGESTED READINGS Gil JA et al: Current concepts in the diagnosis and management of traumatic, anterior glenohumeral subluxations, Orthop J Sport Med 5(3), 2017. https:// doi.org/10.1177/2F2325967117694338. Owens B et al: Pathoanatomy of first-time, traumatic, anterior glenohumeral subluxation events, J Bone J Surg Am 92(7):1605-1611, 2010. Reinold MM, Gill TJ: Current concepts in the evaluation and treatment of the shoulder in overhead-throwing athletes, part 1: physical characteristics and clinical examination, Sport Heal A Multidiscip Approach 2(1):39-50, 2010.

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Glossitis  BASIC INFORMATION DEFINITION Glossitis is an inflammation of the tongue that can lead to loss of filiform papillae. ICD-10CM CODES K14.0 Glossitis K14.2 Median rhomboid glossitis

EPIDEMIOLOGY & DEMOGRAPHICS Glossitis is seen more frequently in patients of lower socioeconomic status, malnourished patients, alcoholics, smokers, elderly patients, immunocompromised patients, and patients with dentures. PHYSICAL FINDINGS & CLINICAL PRESENTATION • The appearance of the tongue varies depending on the etiology of the glossitis (Fig. E1). Loss of filiform papillae results in a red, smooth-surfaced tongue. • The tongue may appear pale in patients with significant anemia. • Pain and swelling of the tongue may be present when glossitis is associated with infections, trauma, or lichen planus. • Ulcerations may be present in patients with herpetic glossitis, pemphigus, or streptococcal infection. • Excessive use of mouthwash may result in a “hairy” appearance of the tongue (Fig. E2).

ETIOLOGY • Nutritional deficiencies (vitamin E, riboflavin, niacin, vitamin B12, iron) • Infections (viral, candidiasis, tuberculosis, syphilis) • Trauma (generally caused by poorly fitting dentures) • Irritation of the tongue from toothpaste, medications, alcohol, tobacco, citrus • Lichen planus, pemphigus vulgaris, erythema multiforme • Neoplasms

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • Infections • Use of chemical irritants • Neoplasms • Skin disorders (e.g., Behçet syndrome, erythema multiforme) WORKUP • Laboratory evaluation to exclude infectious processes, vitamin deficiencies, and systemic disorders • Biopsy of lesion only when there is no response to treatment LABORATORY TESTS • Complete blood count: Decreased hemoglobin and hematocrit, low mean corpuscular volume (MCV) (iron-deficiency anemia), elevated MCV (vitamin B12 deficiency)

• Vitamin B12 level • 10% potassium hydroxide (KOH) scrapings in patients with white patches suspect for candidiasis

TREATMENT NONPHARMACOLOGIC THERAPY Avoidance of primary irritants such as hot foods, spices, tobacco, and alcohol ACUTE GENERAL Rx Treatment varies with the etiology of the glossitis. • Malnutrition with avitaminosis: Multivitamins • Candidiasis: Fuconazole 200 mg on day 1, then 100 mg/day for at least 2 wk or nystatin 400,000 U suspension qid for 10 days or 200,000 pastilles dissolved slowly in the mouth 4 to 5 times qd for 10 to 14 days • Painful oral lesions: Rinsing of the mouth with 2% lidocaine viscous, 1 to 2 tablespoons q4h prn; triamcinolone 0.1% applied to painful ulcers prn for symptomatic relief CHRONIC Rx • Lifestyle changes with elimination of tobacco, alcohol, and other primary irritants • Dental evaluation for correction of ill-fitting dentures • Correction of associated metabolic abnormalities such as hyperglycemia from diabetes mellitus DISPOSITION Most patients experience prompt improvement with identification and treatment of the cause of the glossitis. REFERRAL Surgical referral for biopsy of solitary lesions unresponsive to treatment to rule out neoplasm.

PEARLS & CONSIDERATIONS COMMENTS If the primary cause of glossitis is not identified or cannot be corrected, enteric nutritional replacement therapy should be considered in malnourished patients. RELATED CONTENT Glossitis (Patient Information) AUTHOR: Fred F. Ferri, MD

FIG. E1  Median rhomboid glossitis. (From White GM, Cox NH [eds]: Diseases of the skin, a color atlas and text, ed 2, St Louis, 2006, Mosby.)

FIG. E2  Black hairy tongue. (From White GM, Cox NH [eds]: Diseases of the skin, a color atlas and text, ed 2, St Louis, 2006, Mosby.)

Gonorrhea BASIC INFORMATION DEFINITION Gonorrhea is a sexually transmitted bacterial infection with a predilection for columnar and transitional epithelial cells. It commonly manifests as urethritis, cervicitis, or salpingitis. Infection may be asymptomatic. It differs between males and females in course, severity, and ease of recognition.

ICD-10CM CODES A54.9 Gonococcal infection, unspecified O98.211 Gonorrhea complicating pregnancy, first trimester O98.212 Gonorrhea complicating pregnancy, second trimester O98.213 Gonorrhea complicating pregnancy, third trimester O98.219 Gonorrhea complicating pregnancy, unspecified trimester O98.22 Gonorrhea complicating childbirth O98.23 Gonorrhea complicating the puerperium A54.03 Gonococcal cervicitis, unspecified A54.00 Gonococcal infection of lower genitourinary tract, unspecified

EPIDEMIOLOGY & DEMOGRAPHICS • The disease is common worldwide, affects both sexes and all ages, especially younger adults; highest incidence is in innercity areas. Per CDC reports, approximately 470,000 new cases were found in the U.S. in 2016 with over 60% found in metropolitan statistical centers. Gonorrhea is the second most commonly reported communicable disease. • Asymptomatic anterior urethral carriage may occur in 12% to 50% of cases in men. • Asymptomatic in 50% to 80% of cases in women. Most common dissemination is by mucosal passage to fallopian tubes, resulting in pelvic inflammatory disease (PID) in 10% to 15% of infected women. Hematogenous spread may result in septic arthritis and skin lesions. Conjunctivitis rarely occurs, but may result in blindness if not rapidly treated. Infection can occur in both men and women in oropharynx and anorectally. • The World Health Organization (WHO) reports that there were 78 million new cases of gonorrhea worldwide among adults in 2012. PHYSICAL FINDINGS & CLINICAL PRESENTATION • Males: Purulent discharge from anterior urethra (Fig. E1), with dysuria appearing 2 to 7 days after infecting exposure. May have

ETIOLOGY • Neisseria gonorrhoeae is also known as gonococcus. Plasmids coding for β-lactamase render some strains resistant to penicillin or tetracycline. There is an increasing frequency of chromosomally mediated resistance to penicillin, tetracycline, fluoroquinolones, and cefoxitin. In the Far East, high-level resistance to spectinomycin is endemic. • There is a rising number of cases of quinolone-resistant N. gonorrhoeae worldwide, with the expected number to rise in the U.S. from importation. • Men who have sex with men are vulnerable to the emerging threat of antimicrobial-resistant N. gonorrhoeae.

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • Nongonococcal urethritis (NGU) • Nongonococcal mucopurulent cervicitis • Chlamydia trachomatis WORKUP Diagnosis depends on bacteriologic investigation. Culture and nucleic acid amplification tests (NAAT) are available for the detection of genitourinary infection with N. gonorrhoeae. • NAATs are preferred testing modalities for the detection of genitourinary infection with N. gonorrhoeae. The performance of NAATs with respect to overall sensitivity, specificity, and ease of specimen transport is better than that of any of the other tests available for the diagnosis of gonococcal infections. NAATs should be used to detect gonorrhea except in cases of child sexual assault involving boys and rectal and oropharyngeal infections in prepubescent girls. When evaluating a potential gonorrhea treatment failure, case culture and susceptibility testing might be required. NAATs allow testing of the

widest variety of specimen types, including endocervical swabs, vaginal swabs, urethral swabs (men), and urine (from both men and women). • Culture: Gonorrhea culture on Thayer-Martin medium (organism is fastidious; requires aerobic conditions with increased carbon dioxide atmosphere; incubate ASAP). Culture has a sensitivity of 95% or more for urethral specimens from men with symptomatic urethritis and 80% to 90% for endocervical infection in women. Gram-negative intracellular diplococci are diagnostic in male urethral smears (Fig. E3). There is a falsenegative rate of 60% to 70% in female cervical or urethral smears. 1. Concomitant serologic testing for syphilis for all patients 2. Concomitant Chlamydia testing for all patients 3. Offer of HIV testing and counseling to all patients

LABORATORY TESTS • First-catch urine (or genital swab) sample NAAT is the preferred screening and diagnostic test for gonorrhea. These tests have largely replaced culture in many settings where persons are screened for asymptomatic genital infection. They are not more sensitive than culture for detecting N. gonorrhoeae in cervical or urethral specimen; however, they have specificities >99% and retain sensitivity when used to test voided urine or self-collected vaginal swabs. • Gonorrhea culture on Thayer-Martin medium (organism is fastidious; requires aerobic conditions with increased carbon dioxide atmosphere; incubate ASAP). Culture has a sensitivity of 95% or more for urethral specimens from men with symptomatic urethritis and 80% to 90% for endocervical infection in women. • Nonamplified DNA probe tests are less sensitive than culture or NAATs and are not useful in the diagnosis of rectal or pharyngeal infection or for testing urine; however, they are inexpensive, readily available and offered in many laboratories in combination assays for C. trachomatis. • Concomitant serologic testing for syphilis on all patients. • Concomitant Chlamydia testing on all patients. • Offer of HIV testing and counseling to all patients.

TREATMENT ACUTE GENERAL Rx Uncomplicated infections of the cervix, urethra, and rectum. Critical for the practitioner to know local resistance characteristics to best treat the patient: • Ceftriaxone 250 mg IM × 1 dose plus azithromycin 1 g PO single dose. Doxycycline 100 mg PO bid for 7 days can be substituted for

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Diseases and Disorders

SYNONYMS Gonococcal urethritis Gonococcal vulvovaginitis Gonococcal cervicitis Gonococcal bartholinitis GC

rectal infection causing pruritus, tenesmus, and discharge, or may be asymptomatic. • Females: Initial urethritis or cervicitis may occur a few days after exposure, frequently mild. Infections may be asymptomatic or may not produce recognizable symptoms until complications have occurred. In approximately 20% of cases uterine invasion occurs after menstrual period with signs and symptoms of endometritis, salpingitis, or pelvic peritonitis. The patient may have purulent discharge or inflamed Skene or Bartholin glands. • Classic presentation of acute gonococcal PID is fever, abdominal and adnexal tenderness, and, often, absence of purulent discharge. Physical examination may be normal if asymptomatic. Disseminated gonococcal infection (DGI) may manifest with petechial or pustular acral skin lesions (Fig. E2), asymmetric polyarthralgia, tenosynovitis, or oligoarticular septic arthritis. The infection is occasionally complicated by perihepatitis and, rarely, endocarditis or meningitis.

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Gonorrhea azithromycin in patients with azithromycin allergy. Alternative regimens if ceftriaxone is not available: • Ceftizoxime, cefoxitin with probenecid, and cefotaxime. None of these injectable cephalosporins offer any advantage over ceftriaxone. • Cefixime 400 mg PO × 1 dose plus azithromycin 1 g orally single dose. Doxycycline 100 mg PO bid for 7 days can be substituted for azithromycin in patients with azithromycin allergy. • If the patient has severe cephalosporin allergy, then azithromycin 2 g PO single dose plus single-dose gemifloxacin 320 mg PO or gentamicin 240 mg IM. • A test-of-cure is not needed for persons who receive a diagnosis of uncomplicated urogenital or rectal gonorrhea who are treated with any of the recommended or alternative regimens. Uncomplicated gonococcal infections of the pharynx: • Ceftriaxone 250 mg IM × 1 dose plus azithromycin 1 g PO single dose. Doxycycline 100 mg PO bid for 7 days can be substituted for azithromycin in patients with azithromycin allergy. • Treatment of the cephalosporin-allergic patient: Oral azithromycin 2 g plus single dose gemifloxacin 320 mg PO or 240 mg IM of gentamicin is effective. • Any person with pharyngeal gonorrhea who is treated with an alternative regimen should return 14 days after treatment for a test-ofcure using either culture or NAAT. Treatment of arthritis and arthritis-dermatitis syndrome: • Recommended regimen: Ceftriaxone 1 g IM or IV every 24 hours plus azithromycin 1 g orally as a single dose.

• Alternative regimens: Cefotaxime 1 g IV every 8 hours or ceftizoxime 1 g IV every 8 hours plus azithromycin 1 g orally in a single dose. Pregnancy • Pregnant women infected with N. gonorrhoeae should be treated with dual therapy consisting of ceftriaxone 250 mg in a single IM dose or azithromycin 1 g PO as a single dose. When cephalosporin allergy or other considerations preclude treatment and spectinomycin is not available, consultation with an ID specialist is recommended.

DISPOSITION • To reduce development of drug resistance, reculture should be done for patients who show continued symptoms despite treatment. These patients should be tested with a culture-based gonorrhea test that can detect antibiotic resistance. • All sexual partners should be identified, examined, tested, and receive presumptive treatment. • Patients should be counseled to avoid unprotected intercourse with partners for 1 wk after all partners have completed treatment. REFERRAL PID requiring hospitalization, disseminated gonococcal infection

PEARLS & CONSIDERATIONS COMMENTS • This is a reportable disease. • The proportion of gonorrhea cases in heterosexual men who are fluoroquinolone resistant (QRNG) has reached 6.7%, an elevenfold

increase from 0.6% in 2001. Fluoroquinolone antibiotics are no longer recommended to treat gonorrhea in the U.S. • The use of azithromycin as the second antimicrobial is preferred over doxycycline due to the high prevalence of tetracycline resistance. • The U.S. Preventive Services Task Force (USPSTF) recommends screening for gonorrhea in sexually active females younger than 25 yrs and in older women who are at increased risk for infection (multiple partners, new partner, partner who has concurrent partners). The USPSTF also concludes that the current evidence is insufficient to assess the balance of benefits and harms of screening for gonorrhea in men. • High-intensity counseling on sexual risk reduction has been shown to reduce sexually transmitted infections (STIs) in primary care and related settings.

SUGGESTED READINGS Available at www.expertconsult.com RELATED CONTENT Gonorrhea (Patient Information) Cervicitis (Related Key Topic) Chlamydia Genital Infections (Related Key Topic) Pelvic Inflammatory Disease (Related Key Topic) AUTHORS: Anthony Sciscione, DO, and Ella Stern, MD

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SUGGESTED READINGS Alirol E et al: Multidrug-resistant gonorrhea: a research and development roadmap to discover new medicines, PLoS Med 14(7):e1002366, 2017. Brill JR: Diagnosis and treatment of urethritis in men, Am Fam Physician 81(70):873-879, 2010. Centers for Disease Control and Prevention: Sexually transmitted diseases treatment guidelines, 2015, MMWR 64(3):1-110, 2015. (2010) [updated www.cdc .gov/std/tg2015/default.htm]. Kirkcaldy RD et  al: Neisseria gonorrhoeae antimicrobial resistance among men who have sex with men and men who have sex exclusively with women: the gonococcal isolate surveillance project, 2005-2010, Ann Intern Med 158:321328, 2013. O’Connor EA et al: Behavioural sexual risk-reduction counseling in primary care to prevent sexually transmitted infections: a systematic review for the U.S. Preventive Services Task Force, Ann Intern Med 161(12):874-883, 2014.

FIG. E1  Purulent urethral discharge from a man with gonococcal urethritis. (From Mandell GL et al: Principles and practice of infectious diseases, ed 6, Philadelphia, 2005, Churchill Livingstone.)

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C FIG. E2  Disseminated gonococcal infection: Skin lesions. A, Macules, papules, and pustules over an ankle. B, Hemorrhagic papules localized in trunk. C, Hemorrhagic vessel over a distal interphalangeal joint. (C Courtesy of Dr. Peter Schlessinger. From Hochberg MC et al: Rheumatology, ed 5, St Louis, 2011, Mosby.)

Gonorrhea

FIG. E3  Neisseria gonorrhoeae. Gram stain of urethral exudate in gonorrhea, showing intracellular gramnegative reniform diplococci. (Courtesy of Dr. S.E. Thompson. From Hochberg MC et al: Rheumatology, ed 5, St Louis, 2011, Mosby.)

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Goodpasture Disease agents or in other autoimmune diseases, including multiple sclerosis, rheumatoid arthritis, celiac disease, ulcerative colitis, and infective endocarditis

BASIC INFORMATION DEFINITION Anti-glomerular basement membrane disease (anti-GBM disease), also known as Goodpasture disease, is a rare, autoimmune, small-vessel vasculitis affecting blood vessels of the lungs and kidneys that results in a pulmonary-renal syndrome. A pulmonary-renal syndrome is defined as the coexistence of pulmonary alveolar hemorrhage (i.e., triad of hemoptysis, diffuse alveolar infiltrates, and anemia) and acute kidney injury (AKI) from rapidly progressive glomerulonephritis (RPGN). Notably, a pulmonary-renal syndrome may affect only the kidneys (AKI and RPGN) or kidneys and lungs simultaneously. Rarely, only the lungs are involved. SYNONYMS Anti-glomerular basement membrane disease Goodpasture syndrome ICD-10CM CODES N01.7 Rapidly progressive nephritic syndrome with diffuse crescentic glomerulonephritis N00.7 Acute nephritic syndrome with diffuse crescentic glomerulonephritis

EPIDEMIOLOGY & DEMOGRAPHICS • Anti-GBM disease has a bimodal age distribution, predominantly affecting young, white, male smokers, and, next most commonly, affecting older adults (>50 yr old, women more than men) • Goodpasture disease accounts for 5% to 15% of all cases of RPGN • HLA-DR2 locus is positive in 80% of patients. • Approximately 20% to 40% of patients with anti-GBM antibody have positive antineutrophil cytoplasmic auto-antibodies (ANCAs) • Anti-GBM disease can also occur with other glomerular diseases, such as ANCA- vasculitis, lupus, and membranous nephropathy • Anti-GBM disease may occur posttransplant due to newly formed antibodies in up to 5% of patients with Alport disease who undergo kidney transplantation • Secondary anti-GBM disease may occur in patients treated with immunomodulatory

PHYSICAL FINDINGS & CLINICAL PRESENTATION • Dyspnea, cough, hemoptysis • Skin pallor, fever, arthralgias (may be mild or absent at the time of initial presentation) • Hematuria may be noted • Frothy urine due to proteinuria, although nephrotic syndrome is uncommon ETIOLOGY Anti-GBM disease is caused by autoantibodies directed against the alpha-3 chain of type IV collagen, a primary component of the glomerular basement membrane (GBM). The presentation of the disease is due to the distribution of the antigen. Antibody deposition leads to immune celland complement-mediated tissue inflammatory damage resulting in pulmonary hemorrhage and glomerulonephritis. With appropriate treatment, there is eventual decline in antibody titers, and relapse with antibody production is rare.

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • Granulomatosis with polyangiitis • Systemic lupus erythematosus • Eosinophilic granulomatosis with polyangiitis (eGPA), formerly Churg-Strauss syndrome • Essential mixed cryoglobulinemia • Idiopathic rapidly progressive glomerulonephritis • Drug-induced renal pulmonary disease (e.g., penicillamine) WORKUP Laboratory and clinical evaluation, diagnostic imaging, and kidney biopsy LABORATORY & CLINICAL TESTS • Serum anti-GBM antibodies (commercial enzyme-linked immunosorbent assay (ELISA) has 95% sensitivity and 95% to 99% specificity) • Normal serum complement (C3 and C4) levels

• Absence of circulating immune complexes, antineutrophil cytoplasmic antibodies (except with overlap), and cryoglobulins • Urinalysis with microscopic hematuria, proteinuria, and red blood cell casts • Urine protein–to–creatinine ratio to quantify proteinuria • Elevated blood urea nitrogen and creatinine • Immunofluorescence studies of kidney biopsy specimens with anti-GBM antibody demonstrate linear staining pattern, often with C3 deposition • Complete blood count and serum iron studies demonstrate iron-deficiency anemia from urinary and pulmonary blood losses • Bronchoalveolar lavage may demonstrate presence of alveolar hemorrhage and exclude an infection

IMAGING STUDIES Chest radiograph with airspace disease composed of alveolar infiltrates or evidence of pulmonary hemorrhage (Fig. E1)

TREATMENT ACUTE GENERAL Rx • Plasmapheresis with albumin replacement for 1 to 2 wk (fresh frozen plasma used if bleeding risk present), with immunosuppression typically consisting of prednisone (1 mg/ kg per day) and oral cyclophosphamide (2 mg/kg per day). Intravenous cyclophosphamide has been used at some institutions. Rituximab has not been studied in trials but is used in patients who may not be good candidates for cyclophosphamide. • Hemodialysis if kidney failure occurs. • Factors influencing treatment decisions in Goodpasture disease are described in Table E1. DISPOSITION Life-threatening pulmonary hemorrhage and irreversible glomerular damage are major causes of death. REFERRAL • Referral for kidney biopsy to guide management • Consider kidney transplantation in patients with end-stage renal disease SUGGESTED READINGS Available at ExpertConsult.com RELATED CONTENT Goodpasture Syndrome (Patient Information) AUTHORS: Dhruti P. Chen, MD, and Koyal Jain, MD

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FIG. E1  Lung hemorrhage. A, Patient with early pulmonary hemorrhage. The chest radiograph still appears normal. B, Radiograph taken 4 days later shows the evolution of alveolar shadowing caused by lung hemorrhage. (From Floege J et al: Comprehensive clinical nephrology, ed 5, Philadelphia, 2015, Saunders, Figure 24–4).

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TABLE E1  Factors Influencing Decision to Treat Aggressively in Goodpasture Disease Factors Favoring Aggressive Treatment Pulmonary hemorrhage Present Oliguria Absent Creatinine 5.5-6.5 mg/dl (∼500-600 μmol/L) and ANCA negative Severe damage on kidney biopsy No desire for early kidney transplantation

Creatinine >5.5-6.5 mg/dl (∼500600 μmol/L) but Rapid and recent progression ANCA-positive Glomerular damage less severe than expected Crescents recent, nonfibrous Early renal transplantation is optimal Absent Unusually high risk from immunosuppression

ANCA, Antineutrophil cytoplasmic auto-antibodies. From Floege J et al: Comprehensive Clinical Nephrology, ed 5, Philadelphia, 2015, Saunders.

SUGGESTED READINGS Falk RJ et  al: Case 24–2018: a 71-year-old man with acute renal failure and hematuria, N Engl J Med 379(6):568-578, 2018. Greco A et  al: Goodpasture’s syndrome: a clinical update, Autoimmun Rev 14(3):246-253, 2015. McAdoo SP, Pusey CD: Anti-glomerular basement membrane disease, Clin J Am Soc Nephrol 12(7):1162-1172, 2017. Pedchencko V et  al: Molecular architecture of the goodpasture autoantigen in anti-GBM nephritis, N Engl J Med 363:343-354, 2010.

ALG BASIC INFORMATION

ICD-10CM CODES M10 Gout M10.0 Idiopathic gout M10.1 Lead-induced gout M10.2 Drug-induced gout M10.3 Gout due to impairment of renal function M10.4 Other secondary gout M10.9 Gout, unspecified

EPIDEMIOLOGY & DEMOGRAPHICS PREVALENCE: Self-reported prevalence in the U.S. is estimated at 3.9% of adults. PREDOMINANT SEX: Male:female ratio ∼4:1 PREDOMINANT AGE: 30 to 50 yr in men; older than 60 yr in women ETIOLOGY • Gout is induced by inflammation from monosodium urate (MSU) crystal deposition. The primary risk factor for MSU deposition is hyperuricemia, though local factors such as temperature, pH, and mechanical stress may play a role. Fig. E1 illustrates the pathophysiology of gout. • Hyperuricemia and gout develop from excessive uric acid production, a decrease in the renal excretion of uric acid, or both. • Primary hyperuricemia results from an inborn error of metabolism and may be attributed to several biochemical defects. • Secondary hyperuricemia may develop as a complication of acquired disorders (e.g., leukemia) or as a result of the use of certain drugs (e.g., diuretics). Consumption of alcohol, especially beer, increases the risk of gout, and fructose-rich beverage intake is associated with hyperuricemia. Gout promoters and inhibitors are summarized in Table 1. PHYSICAL FINDINGS & CLINICAL PRESENTATION ACUTE GOUT: • Rapid onset of pain and swelling and erythema of a distal joint and/or periarticular soft tissue. Box 1 summarizes clinical pearls in acute gout attacks. • May present as monoarthritis of any joint. Acute gout of the first metatarsophalangeal (MTP) joint is known as podagra. • 10% to 15% of attacks are polyarticular. • Spontaneous resolution occurs over days to wks.

DIAGNOSIS DIFFERENTIAL DIAGNOSIS OF ACUTE GOUT • Septic arthritis, cellulitis • Pseudogout, calcium pyrophosphate crystal deposition disease • Trauma DIFFERENTIAL DIAGNOSIS OF CHRONIC GOUT • Osteoarthritis (especially nodal OA in women) • Rheumatoid arthritis • Psoriatic arthritis Section II describes the differential diagnosis of acute monoarticular and oligoarticular arthritis. WORKUP Arthrocentesis and examination of synovial fluid LABORATORY TESTS • Uric acid: All patients with gout are hyperuricemic at some time, but during an acute attack the serum uric acid may be normal or low. • Synovial aspirate: Usually cloudy and markedly inflammatory in nature. Urate crystals in fluid are needle shaped and strongly negatively birefringent under polarized microscopy (Fig. E3). • CBC: Neutrophilic leukocytosis often present.

• Inflammatory markers: ESR and CRP often elevated.

IMAGING STUDIES • Plain radiography for diagnosis and evaluation. No typical findings in early gouty arthritis, but late disease is associated with characteristic punched-out marginal erosions (Fig. E4) and overhanging edges. • Musculoskeletal ultrasound has been shown to be an effective means of detecting monosodium urate crystal deposition. Ultrasound can differentiate urate crystals that are found on the surface of articular cartilage from CPPD crystals that are seen within the substance of the cartilage (Fig. E5). Double contour sign can be seen.

TREATMENT TREATMENT OPTIONS FOR ACUTE GOUT (TABLE 2) • Nonsteroidal antiinflammatory medication (see Table 3). 1. Indomethacin 75 mg bid 2. Ibuprofen 800 mg tid 3. Naproxen 500 mg bid 4. Celecoxib 20 mg bid • Low-dose colchicine (less toxic, as effective as traditional high-dose colchicine): 1.2 mg PO, followed by 0.6 mg PO 1 h later, then 0.6 mg daily or bid. Dose for renal function. • Intraarticular corticosteroid injection (treatment of choice for monoarticular large joint attack): Triamcinolone acetonide 40 mg or equivalent for knee. • Systemic corticosteroid therapy: prednisone 40 mg PO for 3 days, then taper over 10 days (effective and safe, but evidence is lacking).

TABLE 1  Gout Promoters and Inhibitors* Crystal formation

Triggering the acute flare (local factors)

Presence of susceptible phagocytes, mast cells (systemic events)

Seed nucleus (particulate) Immunoglobulin Phagocytes Low temperature Low pH Cation concentration Intraarticular dehydration Other (unknown) macromolecules Rapid change in urate level Microcrystal release IgG coat (apolipoproteins B, E inhibitory) Complement activation (classical, alternate, MAC) Inflammasome activation Cytokine and chemokine release Endothelial activation (e-selectin, ICAM-1, VCAM-1) Local trauma? Surgery, trauma Infections, other intercurrent systemic illness Alcohol, dietary intake Drugs that raise or lower circulating urate level

*A diverse array of proteins and other mediators have been identified on the surfaces of urate crystals. In addition to their proinflammatory effect through opsonizing existing crystals, immunoglobulin M (IgM) and immunoglobulin G (IgG) antibodies may promote crystal formation by providing a stable molecular platform for crystal nucleation and growth. Apolipoproteins are the best characterized of the antiinflammatory molecules that coat crystals. The characteristics of the phagocytes encountering the crystals may be crucial; macrophages that are more differentiated are less likely to elicit proinflammatory cytokines. ICAM-1, Intercellular adhesion molecule 1; Ig, immunoglobulin; MAC, membrane attack complex; VCAM-1, vascular cell adhesion molecule 1. From Hochberg MC: Rheumatology, ed 7, Philadelphia, 2019, Elsevier.

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Diseases and Disorders

DEFINITION Gout is a term used to refer to a group of disease states caused by tissue deposition of monosodium urate due to prolonged hyperuricemia. Clinical manifestations of gout include acute and chronic arthritis, soft tissue inflammation, tophus formation, gouty nephropathy, and nephrolithiasis. Untreated hyperuricemia in patients with gout may lead to chronic destructive deforming arthritis.

CHRONIC TOPHACEOUS GOUT (FIG. E2): • Insidious onset of painless arthritis and soft tissue swelling • Distal small joints characteristic • May be confused with nodal osteoarthritis • Box 2 summarizes clinical pearls in chronic gout

Gout

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BOX 1  Acute Gout: Clinical Pearls • Abrupt and rapid onset • Maximal symptom intensity at 8-12 hours • Attacks often come on at night or early morning • Most commonly monoarticular in men during first attack • Metatarsophalangeal joint is first affected in 50% of cases; other commonly affected joints: ankle, heel, knee, wrists, and hands • Joints are red, hot, swollen, and exquisitely tender • Attacks resolve within days to wks without treatment From Hochberg MC: Rheumatology, ed 7, Philadelphia, 2019, Elsevier.

BOX 2  Chronic Gout: Clinical Pearls • Pattern of symptoms changes: Time between attacks shortens; more joints may be involved • Tophaceous disease may result in a destructive arthropathy • Tophaceous deposits may be bothersome and cause marked reduction in quality of life • Increased risk for nephrolithiasis • Associated with comorbidities such as metabolic syndrome, diabetes mellitus, chronic kidney disease, cardiovascular disease, hyperlipidemia, and obesity From Hochberg MC: Rheumatology, ed 7, Philadelphia, 2019, Elsevier.

TREATMENT OF HYPERURICEMIA IN PATIENTS WITH GOUT The American College of Rheumatology and most international rheumatology guidelines recommend that every patient with gout who has tophi, more than two attacks of gout per yr, chronic kidney disease, or nephrolithiasis be treated with pharmacologic urate-lowering therapy. Serum uric acid should be monitored on a regular basis and urate-lowering therapy intensified until a target of less than 6 mg/dl is reached. In most cases, urate-lowering therapy should be continued for life. Fig. 6 summarizes pharmacologic serum urate–lowering treatment. The American College of Physicians Guidelines recommends a more conservative approach based on recurrence of symptoms. These guidelines have been criticized as ignoring the progressive nature of gout and perpetuating the well-documented underutilization and under-dosing of urate-lowering therapy. NONPHARMACOLOGIC THERAPY Lifestyle and dietary modification should always be a component of therapy for patients with gout, but this is rarely effective without con-

comitant pharmacologic urate-lowering therapy, as dietary modification can lower uric acid only about 1 mg/dl. Recommendations include reducing ingestion of red meat, kidney, liver, yeast extract, shellfish, and overall protein along with restricting alcohol intake. Discontinuation of diuretic therapy may help lower serum uric acid.

PHARMACOLOGIC TREATMENT OF SYMPTOMATIC HYPERURICEMIA ALLOPURINOL: Allopurinol is very effective and safe when used properly. Correct dosing and patient compliance are essential elements in the prevention of erosive and tophaceous gout. Patients with renal insufficiency are at increased risk for allopurinol hypersensitivity, which manifests as fever, rash, and hepatitis occurring most commonly in the first 3 mo of therapy. The rash may progress to life-threatening toxic epidermal necrolysis if not recognized early. Traditionally, therapy with allopurinol is initiated several wks after the acute attack has resolved. However, initiation of allopurinol at presentation may improve long-term compliance without reducing the efficacy of acute treatment. The initial dose should be low (≤100 mg/day depending on creatinine clearance) in patients with renal insufficiency and those with very high uric acid levels. High initial doses are associated with increased incidence of allopurinol hypersensitivity. The serum uric acid should be reevaluated after 4 to 6 wk of therapy, and the allopurinol dose adjusted to reduce the serum uric acid to less than 6 mg/dl. The most common therapeutic dosage of allopurinol is 300 mg/day, but dose may be increased by 50 to 100 mg every 2 to 3 wk until the target serum uric acid level is achieved. There is evidence that increasing allopurinol doses in patients with renal insufficiency does not result in significant toxicity, but concurrent use with statins and colchicine is associated with a higher incidence of adverse effects. Some authors have reported using doses as high as 800 mg daily without excess toxicity. It is recommended that patients of Han Chinese, Thai, and Korean ancestry be tested for HLA-B*5801 before initiating allopurinol as these individuals are at high risk of allopurinol hypersensitivity if this allele is present. FEBUXOSTAT: Febuxostat is a xanthine oxidase inhibitor that has been shown to be more potent than allopurinol 300 mg daily for reducing serum uric acid. The chemical structure of febuxostat is different from allopurinol, making cross-reactive allergy unlikely. The metabolism of febuxostat is primarily hepatic, which obviates the need for dose adjustments due to renal insufficiency. Some cases of hepatic toxicity have been reported, and it is recommended that liver function tests be monitored. Febuxostat may help preserve renal function in patients with chronic kidney disease (CKD) but has not been tested in patients with severe renal failure. The primary indication for febuxostat is demonstrated allergy to allopurinol. The cost of febuxostat may be as much as 40 times that of allopurinol, and there is some evidence suggesting that febuxostat may be associated with high-

er cardiovascular and all-cause mortality than allopurinol in patients with cardiovascular risk factors. In 2019, the FDA added a boxed warning for increased risk of death with febuxostat. PROBENECID: Uricosuric agents may be used in patients with good renal function and urinary uric acid less than 600 mg in a 24-h collection. Probenecid can be used in patients with intolerance to xanthene-oxidase inhibitors. Compliance is poor due to the necessity of taking the drug more often than once daily. LESINURAD: Lesinurad is a URAT1 and OAT4 inhibitor approved by the FDA in 2015 for gout-associated hyperuricemia unresponsive to xanthine oxidase inhibitor monotherapy, to be taken in combination with a xanthene oxidase inhibitor. This drug was withdrawn in 2019 because of business-related reasons without safety concerns noted. PEGLOTICASE: Intravenous PEGylated uricase is FDA approved for treatment of severe refractory tophaceous gout. It is a PEGylated recombinant mammalian uricase that rapidly degrades urate when given intravenously. Use is limited by very high cost and potential toxicities, including frequent gout flares and anaphylaxis. Rasburicase is a nonpegylated uricase used in tumor lysis syndrome and is not indicated for gout treatment.

PATIENT & FAMILY EDUCATION It is essential that patients, families, physicians, and other members of the health care team appreciate the importance of compliance with a daily allopurinol regimen if recurrent flares and progression to chronic arthritis and tophi are to be avoided. Allopurinol should be discontinued only for symptoms suggesting hypersensitivity; otherwise it should be continued during flares, medical illnesses, and surgical procedures. REFERRAL • Rheumatologist if diagnosis is not clear or therapy is complicated • Podiatrist for management of pedal complications

PEARLS & CONSIDERATIONS • T he interleukin-1 receptor antagonist anakinra (Kineret) is an effective off-label agent for treatment of gout in complex patients with contraindications to standard therapies. • Do not stop allopurinol during hospitalizations, surgery, or acute attacks unless there is evidence of drug allergy. The dosage of allopurinol should be adjusted in patients with acute kidney injury.

SUGGESTED READING Available at ExpertConsult.com RELATED CONTENT Gout (Patient Information) Hyperuricemia (Related Key Topic) AUTHOR: Kevin V. Plumley, MD, MPH

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Gout

TABLE 2  Therapeutic Options for Acute Gouty Inflammation Level of Evidence

Typical Regimens

COX-nonselective NSAIDs

Grade A evidence for each regimen listed

COX-2–selective NSAIDs

Grade A

Systemic corticosteroids

Grade A evidence for oral prednisolone, 35 mg/ day for five or six doses; lower evidence grades for other regimens

Intraarticular corticosteroids

Grade C evidence

ACTH

Grade C evidence

Oral colchicine

Grade A evidence for U.S. FDA-approved regimen

Off-label use in U.S.: IL-1 antagonism

Grade C for anakinra; grade A for canakinumab

Naproxen, 750-1000 mg PO daily in divided doses for 3 days; then 500750 mg total daily for 4-7 days Sulindac, 300-400 mg/day in divided doses for 7-10 days Indomethacin, 150-200 mg PO daily in divided doses for 3 days; then 100 mg PO daily in divided doses for 4-7 days For example: celecoxib, 800 mg; then 400 mg on day 1 followed by 400 mg bid for 7 days Prednisone, 30-60 mg/day for 3 days; then taper every 3 days by 10-15 mg less as a daily dose until discontinuation Oral prednisolone, 35 mg/day for 5-7 days Medrol dose pack (for less severe flares) or to initiate therapy In an NPO patient: • Triamcinolone, 60 mg IM once with additional corticosteroid treatment as needed • Methylprednisolone, 100-150 mg IV for 1-2 days Particularly useful for flares in a single large joint Triamcinolone acetonide preparations are especially useful Dose titrated to the size of the joint 25 USP units of synthetic ACTH SC for less severe flares; 40 USP units IM or IV once for more severe flares (including larger joint flares and polyarticular gout) One or two repeated doses of synthetic ACTH at intervals of 12 hr are often required with each of these regimens In the U.S.: To treat an early acute gout flare: 1.2 mg once followed by 0.6 mg in 1 hr and then 12 hr later; oral low-dose colchicine at prophylaxis doses until the acute gout flare resolves Outside the U.S.: 0.5 mg tid for several days is the EULAR-recommended dosing regimen Oral colchicine treatment of acute gout should be limited to once every 2 wk in those already taking a maintenance low dose of colchicine Use of anakinra (e.g., 100 mg SC daily for 3 days) or canakinumab (150 mg SC as single dose) for acute gout flare is not approved by the FDA, but canakinumab is approved by the EMA for this indication

ACTH, Adrenocorticotropic hormone; bid, twice a day; COX, cyclooxygenase; EMA, European Medicines Agency; EULAR, European League Against Rheumatism; FDA, U.S. Food and Drug Administration; IL-1, interleukin-1; IM, intramuscularly; IV, intravenously; NPO, nothing by mouth; NSAID, nonsteroidal antiinflammatory drug; PO, by mouth; SC, subcutaneously; tid, three times a day; USP, U.S. Pharmacopeia. From Hochberg MC: Rheumatology, ed 7, Philadelphia, 2019, Elsevier.

TABLE 3  Treatment of Gout Acute Gout

Interval Gout

Treatment of Hyperuricemia

NSAIDs (preferred): Indomethacin 50 mg qid or ibuprofen 800 mg tid (or other NSAID in full doses). Contraindicated in patients with renal insufficiency and gastrointestinal disorders. Or Colchicine, oral: 1.2 mg followed by a second dose of 0.6 mg 1 hr later. Contraindicated in patients with renal insufficiency and gastrointestinal disorders Or Intraarticular steroids (Treatment of choice for large joint monoarthritis): Triamcinolone 40 mg or equivalent for knee Or Systemic steroid therapy (for patients in whom NSAIDs and colchicine are contraindicated) Prednisone 30-50 mg PO daily or in divided doses. May use lower dose in diabetic or postsurgical patients.

Colchicine, oral: 0.6-1.2 mg/day as prophylaxis against recurrent attacks. NSAIDs may also be used for prophylaxis. Hypouricemic agent: Indicated for patients with recurrent attacks despite prophylaxis, severe hyperuricemia, presence of tophi, urolithiasis, or gouty arthritis Other: Weight loss, reduce alcohol (especially beer), diet low in seafood, red meat, organ meat, and fructose

Colchicine, oral: 0.6-1.2 mg/day for 4-6 wk before initiating hypouricemic therapy and for several mo afterward to prevent recurrent attacks during initiation of hypouricemic therapy. And Allopurinol: Initial dose 100 mg/day in patients with renal insufficiency or very high uric acid levels. Increase dose as needed to attain uric acid less than 6 mg/dl. Or Uricosuric agent (Use only in patients with good renal function and 500 ml/day Stage 2: Diarrhea >1000 ml/day Stage 3: Diarrhea >1500 ml/day Stage 4: Ileus, bleeding

Liver

Gastrointestinal tract

Upper: Nausea, vomiting, anorexia Lower: Diarrhea, abdominal cramps, distension, ileus, bleeding

From Hoffman R et al: Hematology: basic principles and practice, ed 7, Philadelphia, 2018, Elsevier.

• In mild cutaneous GVHD, topical steroids may be used along with optimization of prophylactic regimen. • Systemic methyl prednisone 2 mg/kg per day in divided doses should be used for grade 2 or higher GVHD, in addition to the optimization of prophylactic measures. Corticosteroid treatment can be tapered over several mo. • In GVHD with gastrointestinal involvement, systemic glucocorticoids plus oral nonabsorbable steroids should be used. In addition, octreotide may reduce diarrhea. • Patients who demonstrate progression of disease by day 5 of therapy or no response by day 7 are considered to have glucocorticoid resistance. There is no standard therapy for steroid refractory GVHD. Second-line agents in treatment of GVHD include mycophenolate mofetil, etanercept, pentostatin,

Graft-versus-Host Disease

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TABLE E3  Commonly Administered Drugs for Graft-versus-Host Disease Prophylaxis and Treatment Drug

Mechanism

Adverse Effects

Corticosteroids

Direct lymphocyte toxicity; suppress proinflammatory cytokines such as TNF-α Antimetabolite: inhibits T-cell proliferation IL-2 suppressor; blocks Ca2+dependent signal transduction distal to TCR engagement

Hyperglycemia, acute psychosis, severe myopathy, neuropathy, osteoporosis, cataract development Significant renal, hepatic, and gastrointestinal toxicities Renal and hepatic insufficiency, hypertension, hyperglycemia, headache, nausea and vomiting, hirsutism, gum hypertrophy, seizure with severe toxicity Similar to cyclosporine A

Methotrexate (MTX) Cyclosporine A (CSA) Tacrolimus (FK506) Mycophenolate mofetil (MMF) Sirolimus Antithymocyte globulin (ATG)

IL-2 receptor; blocks Ca2+dependent signal transduction distal to TCR engagement Inhibits de novo purine synthesis mTOR inhibitor Polyclonal immunoglobulin

Body aches, abdominal pain, nausea and vomiting, diarrhea, neutropenia Thrombocytopenia, hyperlipidemia, TTP Anaphylaxis, serum sickness

Ca2+, Calcium ion; IL-2, interleukin-2; mTOR, mammalian target of rapamycin; TCR, T-cell receptor; TNF-α, tumor necrosis factor-α; TTP, thrombotic thrombocytopenic purpura. From Hoffman R et al: Hematology: basic principles and practice, ed 7, Philadelphia, 2018, Elsevier.

TABLE E4  Glucksberg Criteria for Staging of Acute Graft-versus-Host Diseasea Overall Grade

Skin

Liver

I II III IV

1-2 1-3 2-3 2-4

0 1 2-4 2-4

Gut and/or and/or and/or

0 1 2-3 2-4

aSee

Table E2 for individual organ staging. Traditionally, individual organs are staged without regard to attribution. The overall grade of graft-versus-host disease, however, reflects the actual extent of graft-versus-host disease. To achieve each overall grade, skin disease, liver, and/or gut involvement are required. From Hoffman R et al: Hematology: basic principles and practice, ed 7, Philadelphia, 2018, Elsevier.

alpha-1 antitrypsin, sirolimus, ruxolitinib antithymocyte globulin, and extracorporeal photopheresis.

CHRONIC Rx Corticosteroids, tapered over several mo, can be used in chronic treatment of GVHD.

ACUTE GENERAL Rx Acute treatment involves topical or systemic corticosteroids. Second-line agents can be used in steroid-resistant cases.

DISPOSITION Patients should be directed to individuals who originally initiated organ or bone marrow transplantation surgery.

SUGGESTED READINGS Arai S et  al: Increasing incidence of chronic graft-versus-host disease in allogeneic transplantation: a report from the Center for International Blood and Marrow Transplant Research, Biol Blood Marrow Transplant 21:266274, 2015. Filipovich AH et  al: National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report, Biol Blood Marrow Transplant 11:945, 2005. Ringden O et  al: The graft-versus-leukemia effect using matched unrelated donors is not superior to HLA-identical siblings for HSCT, Blood 113:31103118, 2009.

REFERRAL Physicians with expertise in immunosuppression

PEARLS & CONSIDERATIONS COMMENTS GVHD is a potentially fatal disorder that occurs after an allogeneic transplant of bone marrow, peripheral blood stem cells, or solid organs. The donor bone marrow or peripheral blood stem cells attack the recipient’s organs. Immunosuppression is required to prevent and treat this disorder. GRADING OF GVHD: Severity is defined by the International Blood and Marrow Transplant Research (IBMTR) grading system: • Grade A: stage 1 skin involvement alone (maculopapular rash over 15 mg/dl; diarrhea >2000 ml/day or pain or ileus) Glucksberg criteria for staging of acute GVHD are summarized in Table E4. PREVENTION • Prophylactic regimen should be decided based on underlying disease, the degree of HLA disparity, the conditioning regimen, and patient characteristics. • Mycophenolate and calcineurin inhibitors should be used in patients undergoing reduced intensity allogeneic HSCT. • For patients who receive myeloablative or reduced intensity conditioning, antithymocyte globulin can be added to the prophylactic regimen. AUTHORS: Rohini Prashar, MD, and Vanji Karthikeyan, MD

Granuloma Annulare BASIC INFORMATION DEFINITION Granuloma annulare (GA) is a chronic, usually self-limited, inflammatory disorder of the dermis that classically presents as arciform to annular plaques located on the extremities. SYNONYMS Pseudorheumatoid nodule—subcutaneous granuloma annulare GA ICD-10CM CODE L92.0 Granuloma annulare

EPIDEMIOLOGY & DEMOGRAPHICS • Most common in children and young adults; most cases of localized GA are diagnosed in patients 10 lesions), subcutaneous (occurring primarily in children aged 2 to 5 yr), patch-type or macular GA, and perforating (rare form manifesting with 1- to 4-mm papules with a central crust usually appearing on the dorsal hands). • Localized GA starts as a small ring of colored skin or pale erythematous papules. More common in children and young to middleage adults. Usually, only one or a few lesions occur at any one time. • Lesions coalesce and evolve into annular plaques over several wk. • Plaques undergo central involution and increase in diameter over several mo (0.5 to 5 cm).

• Most frequently found on the lateral and dorsal surfaces of the hands and feet (Fig. E1 and Fig. E2). • Most lesions resolve spontaneously after several mo. • The generalized form of GA is characterized by hundreds of small (lesions rarely exceed 5 cm in diameter), flesh-colored papules in a symmetric distribution on the trunk and extremities. It most commonly affects women in the fifth or sixth decades but can also be seen in adolescents and children. Some patients are completely asymptomatic, whereas others complain of severe pruritus. • Macular GA is more common in women between ages 30 to 70 and manifests with flat or slightly palpable erythematous or redbrown lesions on upper medial thighs and in bathing-trunk distribution. • Deep dermal GA (subcutaneous GA) presents as large, painless, skin-colored nodules that are frequently mistaken for rheumatoid nodules. ETIOLOGY Unknown, but may be related to vasculitis, trauma, monocyte activation, or delayed hypersensitivity.

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • Tinea corporis • Lichen planus • Necrobiosis lipoidica diabeticorum • Sarcoidosis • Rheumatoid nodules • Late secondary or tertiary syphilis • Arcuate and annular plaques of mycosis fungoides • Papular GA can simulate insect bites, secondary syphilis, xanthoma • Annular elastolytic giant cell granuloma WORKUP • Diagnosis based on clinical appearance and presentation • Biopsy when diagnosis is unclear

LABORATORY TESTS • No laboratory tests will help confirm the diagnosis. • Biopsy shows focal degeneration of collagen and elastic fibers, mucin deposition, and perivascular and interstitial lymphohistiocytic infiltrate in the upper and middle dermis.

TREATMENT NONPHARMACOLOGIC THERAPY Reassurance, given the self-limited and benign nature of GA CHRONIC Rx High-potency topical corticosteroids with or without occlusion and intralesional steroid injection into elevated border with triamcinolone 2.5 to 10 mg/ml are useful first-line local therapies. • Cryosurgery, psoralen ultraviolet-A (UVA) range or UVA-1 therapy, and carbon dioxide laser treatment can also be used. • Systemic agents (e.g., niacinamide, hydroxychloroquine, chloroquine, cyclosporine, dapsone) are generally reserved for severe cases. Recent case reports indicate positive outcomes with tacrolimus and pimecrolimus and the tumor necrosis factor infliximab. DISPOSITION Most lesions resolve spontaneously within 2 yr. REFERRAL Dermatology referral recommended for symptomatic, disseminated disease

PEARLS & CONSIDERATIONS COMMENTS GA has been described as a paraneoplastic granulomatous reaction to Hodgkin disease, non-Hodgkin lymphoma, solid organ tumors, and mycosis fungoides. RELATED CONTENT Granuloma Annulare (Patient Information) AUTHOR: Fred F. Ferri, MD

FIG. E1  Granuloma annulare. Annular, flesh-colored, nonscaly plaques. (From Paller AS, Mancini AJ: Hurwitz clinical pediatric dermatology, a textbook of skin disorders of childhood and adolescence, ed 5, Edinburgh, 2016, Elsevier.)

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Granuloma Annulare

FIG. E2  Granuloma annulare. This patient's plaque reveals both cutaneous and subcutaneous (arrows) involvement. (From Paller AS, Mancini AJ: Hurwitz clinical pediatric dermatology, a textbook of skin disorders of childhood and adolescence, ed 5, Edinburgh, 2016, Elsevier.)

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Granuloma Inguinale BASIC INFORMATION DEFINITION Granuloma inguinale is a genital ulcerative disease caused by a gram-negative bacterium, Klebsiella granulomatis, which may be sexually transmitted. It can also be spread through close, long-term, nonsexual contact. SYNONYMS Donovanosis Calymmatobacterium granulomatis ICD-10CM CODE A58 Granuloma inguinale

EPIDEMIOLOGY & DEMOGRAPHICS INCIDENCE: Rare in the U.S. (400,000/μL). • Chemistry: Elevated serum creatinine, decreased creatinine clearance. • Urinalysis: May reveal hematuria, RBC casts, and proteinuria. • Inflammatory markers: Increased ESR, positive rheumatoid factor, and elevated C-reactive protein may be found. • Liver function, hepatitis serologies, cryoglobulins, HIV screens, ANA, C3, C4, anti-GBM, and cultures to exclude other processes with similar constitutional symptoms. IMAGING STUDIES • Chest x-ray: May reveal bilateral multiple nodules, cavitary mass lesions, pleural effusion (20%). Up to one third of patients without pulmonary signs or symptoms have an abnormal chest x-ray (Fig. E4). • Computed tomography of sinuses, (Fig. E5), computed tomography of chest, MRI of brain (Fig. E6) depending on symptoms

FIG. E3  A, Chest computed tomographic scan of a patient with granulomatosis with polyangiitis (GPA) shows typical nodular lung infiltrate with cavitation. B, Low-power view of granulomatous inflammation and geographic necrosis (arrow) in a lung biopsy from a patient with GPA. C, Granulomatous vasculitis involving a small pulmonary artery in the lung of a patient with GPA. The vessel wall is markedly thickened with an inflammatory infiltrate that includes multinucleated giant cells. D, Glomeruli showing segmental necrosis with early crescent formation (arrows). (From Adkinson NF et al: Middleton’s allergy principles and practice, ed 8, Philadelphia, 2014, WB Saunders.)

Granulomatosis with Polyangiitis

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• PFTs: Useful in detecting stenosis of the airways. • Fiber optic bronchoscopy with BAL and endoscopic ENT examination: Nasal crusting (“golden crusts”) are typical on evaluation (Fig. E7). • Biopsy of one or more affected organs should be attempted; the most reliable source for tissue diagnosis is the lung. Lesions in the nasopharynx can be easily biopsied, but biopsy yield is only 20%. Biopsy of radiographically abnormal pulmonary parenchyma provides the highest yield (>90%).

TREATMENT NONPHARMACOLOGIC THERAPY • Ensure proper airway drainage. • Give nutritional counseling.

FIG. E4  Chest radiograph shows multiple cavitary pulmonary nodules in patient with Wegener granulomatosis. (From Weinberg SE et  al: Principles of pulmonary medicine, ed 5, Philadelphia, 2008, WB Saunders.)

A

ACUTE GENERAL Rx • Immunosuppressive therapy should be considered in all patients with GPA.

B

FIG. E5  Computed tomography (CT) scans of the sinuses. A, Normal maxillary sinuses in a recently diagnosed Wegener granulomatosis (WG) patient. B, Sinus CT scan of a patient with long-standing WG: Nasal septal deviation to the left, destruction of the medial walls of the right maxillary sinus, opacification of both sinuses with soft tissue densities (arrows), and neo-ossification of all maxillary bony structures due to chronic inflammation. (From Hochberg MC et al: Rheumatology, ed 5, St Louis, 2011, Mosby.)

• Induction therapy in GPA consists of glucocorticoid with either cyclophosphamide or rituximab. Selected patients with severe disease may benefit from the addition of plasma exchange to this regimen. • Historically, the gold standard for treatment is pulse methylprednisolone followed by prednisone 60 to 80 mg/day and pulse cyclophosphamide (1 g/m2 every 4 wk) or daily oral cyclophosphamide (2 mg/kg/day). This was generally effective and used to control clinical manifestations. MESNA can be used with cyclophosphamide for the prevention of cyclophosphamide-induced hemorrhagic cystitis. • Based on the RAVE trial, rituximab (375 mg/ m2/wk ×4 wk) appears to be more effective than traditional therapy in treating GPA that presents with disease flares and is at least as effective as traditional therapy for the induction of remission. The RITUXVAS trial concluded that a combined cyclophosphamide-rituximab regimen was not inferior to pulse cyclophosphamide alone. Both of these studies used concurrent methylprednisolone followed by prednisone. • Methotrexate and glucocorticoids alone may be used with mild extrarenal disease or little to no renal involvement, or with limited sinus and upper airway involvement. • For severe active renal disease, the MEPEX trial demonstrated that plasma exchange in addition to cyclophosphamide and glucocorticoids may enhance renal function recovery. • Potentially useful agents for maintenance therapy include rituximab, methotrexate, azathioprine, and mycophenolate mofetil. The MAINRITSAN trial showed that rituximab may be preferable for maintenance therapy, and the CYCAZAREM (for azathioprine) and LEM (for leflunomide) trials showed that these agents can also be used. The WEGENT study showed oral methotrexate and azathioprine were noninferior for maintenance than intravenous cyclophosphamide.

Dural thickening

VP shunt

FIG. E6  Pachymeningitis in a patient with granulomatosis with polyangiitis. Magnetic resonance imaging findings. VP, Ventriculoperitoneal. (From Firestein GS et  al: Kelly’s textbook of rheumatology, ed 9, Philadelphia, 2013, WB Saunders.)

Granulomatosis with Polyangiitis

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preventing Pneumocystis jiroveci pneumonia (PJP), which occurs in 10% of patients receiving induction therapy. Dose of TMPSMX (160 mg/800 mg) for prophylaxis is 1 tablet three times/wk. If the patient is unable to tolerate TMP-SMX, PJP prophylaxis can also be achieved with dapsone, atovaquone, or inhaled pentamidine.

nasal septum

t

bd

nc c np

FIG. E7  Endoscopic view of nasal cavity of granulomatosis with polyangiitis patient showing crusting and bloody discharge. (From Holle et al: Rheum Dis Clin North Am 36[3]:507-526, 2010.)

• Maintenance therapy should generally be continued for at least 18 to 24 mo, and ultimate duration of immunosuppression is decided on a case-by-case basis. • Treatment with TMP-SMX (160 mg/800 mg bid) may reduce the incidence of relapses in patients with granulomatosis with polyangiitis in remission. It is also useful in

DISPOSITION • Five-yr survival with aggressive treatment is approximately 80%; without treatment 2-yr survival is 20%. • Age >50 yr, impaired renal function, pulmonary involvement at diagnosis, and lack of ENT changes at diagnosis are all associated with worse outcomes and increased mortality rate. • With standard therapy, remission is achieved by 90% to 94% of patients, but relapse is frequent (from 18% to 40% at 24 mo). REFERRAL • Rheumatology referral for treatment • ENT, surgical referral for biopsy

continued

PEARLS & CONSIDERATIONS COMMENTS • Granulomatosis with polyangiitis is characterized by granulomatous lesions and vasculitis involving the respiratory tract, lung, and kidneys.

SUGGESTED READINGS Berti A et al: The epidemiology of antineutrophil cytoplasmic autoantibody-associated vasculitis in Olmsted County, Minnesota (USA): a twenty-year populationbased study, Arthritis Rheumatol 69(12):2338-2350, 2017. Bossuyt X et al: Position paper: Revised 2017 international consensus on testing of ANCAs in granulomatosis with polyangiitis and microscopic polyangiitis, Nat Rev Rheumatol 13(11):683-692, 2017. Charles P et al: Comparison of individually tailored versus fixed-schedule rituximab regimen to maintain ANCA-associated vasculitis remission: Results of a multicenter, randomized controlled, phase III trial (MAINRITSAN2), Annals rheum dis 77(8):1143-1149, 2018. Hiemstra TF et  al: Mycophenate mofetil vs. azathioprine for remission maintenance in antineutrophil cytoplasmic antibody-associated vasculitis, JAMA 304(21):2381-2388, 2010. Holle JU et al: Clinical manifestations and treatment of Wegener’s granulomatosis, Rheum Dis Clin North Am 36(3):507-526, 2010. Holle JU et  al: Rituximab for refractory granulomatosis with polyangiitis (Wegener's granulomatosis): comparison of efficacy in granulomatous versus vasculitic manifestations, Ann Rheum Dis 71(3):327-333, 2012. Kallenberg CG: Key advances in the clinical approach to ANCA-associated vasculitis, Nat Rev Rheumatol 10(8):484-493, 2014. Singer O, McCune JW: Update on maintenance therapy for granulomatosis with polyangiitis and microscopic polyangiitis, Current opinion in rheum 29(3): 248-253, 2017. Stone JH et al: Rituximab versus cyclophosphamide for ANCA-associated vasculitis, N Engl J Med 363:221-232, 2010. Walsh M et al: Plasma exchange for renal vasculitis and idiopathic rapidly progressive glomerulonephritis: a meta-analysis, Am J Kidney Dis 57:566, 2011.

• C-ANCA levels should not dictate changes in therapy, because they correlate erratically with disease activity. • The incidence of venous thrombotic events in patients with granulomatosis with polyangiitis is significantly higher than in the general population. Clinicians should maintain a heightened awareness of the risks of venous thrombosis and a lower threshold for evaluating patients for possible DVT or pulmonary embolism. • Disease relapse remains a major problem in the course of the disease.

RELATED CONTENT Granulomatosis with Polyangiitis (Patient Information) AUTHORS: Nicole B. Yang, MD, and Anthony M. Reginato, PhD, MD

Granulomatous Arthritis BASIC INFORMATION DEFINITION The prototype of granulomatous arthritis is tuberculous arthritis. Atypical mycobacteria, sarcoidosis, and sporotrichosis can cause granulomatous involvement of the synovium, but these entities are much less common. SYNONYMS Tuberculous arthritis Pott disease ICD-10CM CODES M01.1 Tuberculous arthritis (A18.0+) M01.6 Arthritis in mycoses (B35-B49+) M01.8 Arthritis in other infections and parasitic diseases classified elsewhere M00.9 Pyogenic arthritis, unspecified

EPIDEMIOLOGY & DEMOGRAPHICS PEAK INCIDENCE: No seasonal predilection PREVALENCE (IN U.S.): Unknown PREDOMINANT SEX: Male = female PREDOMINANT AGE: Rare in childhood PHYSICAL FINDINGS & CLINICAL PRESENTATION • Often no constitutional symptoms (fever and weight loss) • Possibly no clinical or radiographic evidence of pulmonary tuberculosis (TB) • Spinal infection most often in the thoracic or upper lumbar area, with back pain as the most common symptom • Considerable local muscle spasm possible • Kyphosis and neurologic symptoms resulting from spinal cord compression in advanced disease • Chronic monoarticular arthritis in the peripheral joints • Single joint involved in 85% of patients • Pain, swelling, limitation of motion, and joint stiffness less dramatic than in acute bacterial arthritis; possibly present for mos to yrs • Seen more often in persons from developing countries, elderly patients, and hemodialysis patients ETIOLOGY • Hematogenous spread of organisms from a distant site of infection or by direct spread from bone • Most commonly affected area: 50% of cases in the spine; next most commonly affected area: Large joints (knee and hip) • Primary infection beginning in the lungs and spreading to the highly vascular synovium • Tuberculous osteomyelitis commonly involving an adjacent joint

• In peripheral joints, a granulomatous reaction in the synovium causing joint effusion and eventual destruction of underlying bone • In the spine, infection of the intervertebral disk spreading to adjacent vertebrae • Osteomyelitis of vertebrae causing collapse, kyphosis, or gibbous deformity, and possibly paraspinal “cold” abscess

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • Sarcoidosis • Fungal arthritis • Metastatic cancer • Primary or metastatic synovial tumors WORKUP • High index of suspicion needed • Gold standard: Synovial biopsy and culture for bacteria, including acid-fast bacilli, and fungi • Joint aspiration and culture of the synovial fluid performed while awaiting biopsy • Positive synovial fluid smear for acid-fast bacilli in 20% of cases; positive culture in 80% • Elevated synovial fluid protein, low glucose • Considerable variation in synovial fluid WBC count, but values of 10,000 to 20,000 cells/ mm3 typical; may be predominantly polymorphonuclear leukocytes • Usually positive tuberculin skin test result implies exposure to TB, not necessarily active disease. Interferon-gamma release assays also can detect exposure to TB but not active disease (QuantiFERON TB Gold Test, TB T-Spot test) • Anergy in elderly patients or in advanced disease • In spinal infections, percutaneous or open biopsy to obtain accurate C&S data LABORATORY TESTS Peripheral WBC count and ESR are elevated but nonspecific. IMAGING STUDIES • Plain radiographs of the affected joint. 1.  Typically demonstrate bony destruction with little new bone formation 2. Osteopenia and soft tissue swelling in early infections 3. Later, erosions at the joint margins 4. In the spine, disk space narrowing with vertebral collapse (wedging) causing characteristic kyphosis • CT scan: Useful in early diagnosis of infections of the spine and to detect paraspinal abscess. • Technetium and gallium scintigraphic scans: Findings may be positive but do not

SUGGESTED READING Hogan JI et al: Mycobacterial musculoskeletal infections, Infect Dis Clin North Am 31:369-382, 2017.

permit differentiation from inflammation or osteoarthritis.

TREATMENT NONPHARMACOLOGIC THERAPY Encourage range of motion exercises of the affected joint to prevent contractures. ACUTE GENERAL Rx • Combination chemotherapy 1. If sensitive TB suspected, give isoniazid 5 mg/kg/day (maximum 300 mg/day) plus rifampin 10 mg/kg/day (maximum 600 mg/day) for at least 6 mo and pyrazinamide 15 to 30 mg/kg/day (maximum 2 g/day) for at least the first 2 mo plus ethambutol 15 to 25 mg/kg/day until sensitivity results are available. 2.  Most patients are treated successfully with chemotherapy alone. 3. Urgent surgical intervention is necessary if spinal cord compression causes neurologic changes. • Surgical debridement in cases of extensive bone involvement CHRONIC Rx In long-standing extensive disease, arthrodesis of weight-bearing joints DISPOSITION Loss of cartilage and destruction of underlying bone if treatment is not initiated promptly REFERRAL • To a physician experienced in the management of TB • For consultation with an infectious diseases specialist if drug resistance is suspected or documented • For neurosurgical and/or orthopedic consultation if neurologic impairment suspected

PEARLS & CONSIDERATIONS COMMENTS As TB has become less prevalent in the U.S. in the past 10 yr, TB arthritis and osteomyelitis have also become less common. However, because of an increase in patients receiving antitumor necrosis factor-alpha therapy, there has been an increase of granulomatous diseases with nontuberculous mycobacteria such as Mycobacterium avium. RELATED CONTENT Tuberculosis, Miliary (Related Key Topic) Tuberculosis, Pulmonary (Related Key Topic) AUTHOR: Glenn G. Fort, MD, MPH

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Graves Disease BASIC INFORMATION

SYNONYM Thyrotoxicosis ICD-10CM CODES E05.00 Thyrotoxicosis with diffuse goiter without thyrotoxic crisis or storm E05.01 Thyrotoxicosis with diffuse goiter with thyrotoxic crisis or storm

EPIDEMIOLOGY & DEMOGRAPHICS INCIDENCE/PREVALENCE: Graves disease is the most common cause of hyperthyroidism. It affects 3% of women and 0.5% of men during their lifetime. There is a slight increased incidence among young African Americans. The annual incidence of Graves disease-associated ophthalmopathy is 16 cases per 100,000 women and 3 cases per 100,000 men. It is more common in whites than Asians. Cigarette smoking is a risk factor. PREDOMINANT AGE: Peak incidence is between 30 and 60 yr. GENETICS: Patients often report a family history of Hashimoto thyroiditis, Graves disease, or other autoimmune conditions. Increased prevalence of HLA-B8 and HLA-DR3 in whites with Graves disease. Concordance rate is 20% among monozygotic twins. PHYSICAL FINDINGS & CLINICAL PRESENTATION • Diffusely enlarged thyroid. Thyroid bruit may be present. Cervical lymphadenopathy may also be present • Elevated systolic blood pressure with a widened pulse pressure • Tachycardia, palpitations, tremor, hyperreflexia • Exophthalmos (50% of patients) (Fig. 1), lid retraction (lid lag), in which contraction of the levator palpebrae muscles of the eyelids shows immobility of the upper eyelid with downward rotation of the eye • Nervousness, weight loss (weight gain in 10% of patients), heat intolerance, pruritus, muscle weakness, atrial fibrillation

weight loss. Elderly patients can have an atypical presentation (apathetic hyperparathyroidism). For additional information, refer to the topic “Hyperthyroidism.” • Table 1 describes the clinical assessment of the patient with Graves ophthalmopathy.

ETIOLOGY Autoimmune etiology: Thyrotropin receptor antibodies (TRAb) mediated activation of TSH receptor (TSHR). The activity of the thyroid gland is stimulated by the action of T cells, which induce specific B cells to synthesize antibodies against thyroid-stimulating hormone (TSH) receptors in the follicular cell membrane.

IMAGING STUDIES • 24-hr radioactive iodine uptake (RAIU): Increased homogeneous uptake. • CT or MRI of the orbits (Fig. E2) is useful if there is uncertainty about the cause of ophthalmopathy.

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • Anxiety disorder • Premenopausal state • Thyroiditis • Other causes of hyperthyroidism (e.g., toxic multinodular goiter, toxic adenoma) • Other: Metastatic neoplasm, diabetes mellitus, pheochromocytoma WORKUP • The diagnosis is made clinically on most instances. • The diagnostic workup includes a detailed medical history followed by laboratory and imaging studies and ECG. Patients often present with anxiety, heat intolerance, menstrual dysfunction, increased appetite, and

A

B FIG. 1  Proptosis seen in the setting of Graves disease. A, Eye signs in Graves disease. B, Severe proptosis in Graves disease. (A and B, Courtesy Dr. Meir H. Kryger.) (From Kryger M et al: Principles and practice of sleep medicine, ed 6, Philadelphia, 2017, Elsevier.)

LABORATORY TESTS • Increased free thyroxine (T4) and free triiodothyronine (T3) • Decreased TSH • Measurement of thyroid-stimulating antibodies (TSI) and TRAb

TREATMENT NONPHARMACOLOGIC THERAPY • Patient education and discussion of therapeutic options. • Smoking cessation: Smoking is associated with an increased risk of progression of Graves ophthalmopathy. ACUTE GENERAL Rx • Antithyroid drugs (thionamides, ATDs) to inhibit thyroid hormone synthesis or peripheral conversion of T4 to T3: 1. Methimazole or propylthiouracil (PTU) are available. Methimazole is generally preferred because it has a longer half-life, allowing for once-daily dosing. PTU is preferred during pregnancy. 2. Side effects: Skin rash (3% to 5%), arthralgias, myalgias, granulocytopenia (0.5%); rare side effects: Aplastic anemia, hepatic necrosis (PTU), cholestatic jaundice. 3.  Thionamide antithyroid drug therapy results in a remission in 40% to 50% of patients treated for 12 to 18 mo. • Radioactive iodine (RAI): 1.  Treatment of choice for patients >21 yr and younger patients who have not achieved remission after 1 yr of ATD therapy 2.  Contraindicated during pregnancy and lactation 3. Following radioactive therapy there may be an acute elevation of thyroid antibody titers and exacerbation of ocular symptoms in 15% to 20% of patients. • Surgery: Near-total thyroidectomy. Indications: Obstructing goiters despite RAI and ATD therapy, patients who refuse RAI and cannot be adequately managed with ATDs, and pregnant women inadequately managed with ATDs. Complications of surgery include hypoparathyroidism (4%) and vocal cord paralysis (1%). • Adjunctive therapy: Beta-adrenergic receptor blockers (e.g., atenolol 50 to 100 mg/day) to alleviate the beta-adrenergic symptoms of

G

Diseases and Disorders

DEFINITION Graves disease is a hypermetabolic state caused by circulating immunoglobulin G (IgG) antibodies that bind to and activate the G-protein–coupled thyrotropin receptor. This activation stimulates follicular hypertrophy and hyperplasia, causing thyroid enlargement as well as increases in thyroid hormone production. It affects the thyroid, ocular muscles and shin. It is characterized by thyrotoxicosis, diffuse goiter, and infiltrative ophthalmopathy (edema and inflammation of the extraocular muscles and an increase in orbital connective tissue and fat); infiltrative dermopathy characterized by lymphocytic infiltration of the dermis; accumulation of glycosaminoglycans; and occasionally edema.

• Increased sweating, brittle nails, clubbing of fingers • Localized infiltrative dermopathy (1% to 2% of patients) is most frequent over the anterolateral aspects of the legs, commonly over the pretibial area (pretibial myxedema) but can be found at other sites (especially after trauma). It is non-pitting and indurated. It is typically patchy with a peau d’orange appearance to the skin • Men may have gynecomastia, reduced libido, and erectile dysfunction. Women often have irregular menses

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Graves Disease TABLE 1  Clinical Assessment of the Patient with Graves Ophthalmopathy Activity Measures* Spontaneous retrobulbar pain Pain on attempted up or down gaze Redness of the eyelids Redness of the conjunctiva Swelling of the eyelids Inflammation of the caruncle and/or plica Conjunctival edema Severity Measures Lid aperture: Distance between lid margins in millimeters with the patient looking in the primary position, sitting relaxed, and with distant fixation Swelling of the eyelids (absent/equivocal, moderate, severe) Redness of the eyelids (absent/present) Redness of the conjunctivae (absent/present) Conjunctival edema (absent, present) Inflammation of the caruncle or plica (absent, present) Exophthalmos: Measured in millimeters using the same Hertel exophthalmometer and the same intercanthal distance for an individual patient Subjective diplopia score† Eye muscle involvement (ductions in degrees) Corneal involvement (absent/punctate keratopathy/ulcer) Optic nerve involvement: Best-corrected visual acuity, color vision, optic disk, relative afferent pupillary defect (absent/present), plus visual fields if optic nerve compression is suspected *Based on the seven classic features of inflammation in Graves ophthalmopathy. The clinical activity score (CAS) is the total number of items present; a CAS ≥3 indicates active ophthalmopathy. †Subjective diplopia score: 0 = no diplopia; 1 = intermittent (i.e., diplopia in primary position of gaze, when tired, or when first awakening); 2 = inconstant (i.e., diplopia at extremes of gaze); 3 = constant (i.e., continuous diplopia in primary or reading position). From Melmed S et al: Williams textbook of endocrinology, ed 12, Philadelphia, 2011, WB Saunders.

hyperthyroidism (tachycardia, tremor); contraindicated in patients with bronchospasm. • Graves ophthalmopathy: Methylcellulose eye drops to protect against excessive dryness, sunglasses to decrease photophobia, intraocular and systemic high-dose corticosteroids for severe exophthalmos. Worsening of ophthalmopathy after RAI therapy is often transient and can be prevented by the administration of prednisone. Other treatment options include antiinflammatory and immunosuppressive agents, radiation, and corrective surgical procedures. The administration of the antioxidant selenium (100 μg PO bid) has been recently reported as effective in improving quality of life, reducing ocular involvement, and slowing progression

of the disease in patients with mild Graves orbitopathy. Its mechanism of action is believed to be an effect on the oxygen free radicals and cytokines that play a pathogenic role in Graves orbitopathy. Inhibition of the insulin-like growth factor I receptor (IGF-IR) is a new therapeutic strategy to combat the underlying autoimmune etiology of ophthalmopathy. Trials with teprotumumab, a human monoclonal antibody inhibitor of IGF-IR, in patients with active, moderate-to-severe ophthalmopathy have shown effectiveness in reducing proptosis.1 1Douglas

RS et al: Teprotumumab for the treatment of active thyroid eye disease, N Engl J Med 382(4):341352, 2020.

• Dermopathy and acropachy: Topical corticosteroids are often used but are generally ineffective. Trials using rituximab infusion for dermopathy have shown striking improvement.

CHRONIC Rx Patients undergoing treatment with ATDs should be seen every 1 to 3 mo until euthyroidism is achieved and every 3 to 4 mo while they are receiving ATDs. DISPOSITION • ATDs induce sustained remission in 50% within the first yr and 2% per yr thereafter. • Complications of surgery include hypothyroidism (28% to 43% after 10 yr), hypoparathyroidism (4%), and vocal cord paralysis (1%). • Successful treatment of hyperthyroidism requires lifelong monitoring for the onset of hypothyroidism or the recurrence of thyrotoxicosis. • RAI therapy is followed by the appearance or worsening of ophthalmopathy more often than is therapy with methimazole, particularly in patients who are cigarette smokers. It can be prevented with the administration of prednisone 0.5 mg/kg body weight per day starting 2 to 3 days after RAI, continued for 1 mo, then tapered off over 2 mo. • Mild to moderate ophthalmopathy often improves spontaneously. Severe cases can be treated with high-dose glucocorticoids, orbital irradiation, or both. Orbital decompression may be used in patients with optic neuropathy and exophthalmos (see “Hyperthyroidism”). SUGGESTED READINGS Available at ExpertConsult.com RELATED CONTENT Graves Disease (Patient Information) Hyperthyroidism (Related Key Topic) AUTHOR: Fred F. Ferri, MD

Graves Disease

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SUGGESTED READINGS Bahn RS: Graves’ ophthalmopathy, N Engl J Med 362:726-738, 2010. Burch HB, Cooper DS: Management of Graves disease: a review, J Am Med Assoc 314(23):2544-2554, 2015. Marsocci C et al: Selenium and the course of mild Graves' orbitopathy, N Engl J Med 364:1920-1931, 2011. Smith TJ, Hegedus L: Graves' disease, N Engl J Med 375:1552-1565, 2016.

A

B FIG. E2  Computed tomography scans of orbits in two patients with Graves orbitopathy. A, Notice the obviously grossly swollen medial rectus extraocular muscles in both orbits and the resulting proptosis. B, The patient shows considerable proptosis with only minimal muscle enlargement, suggesting the presence of a large amount of retroorbital fat. (Courtesy Dr. Peter Som, New York, NY.)

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Grief, Complicated or Prolonged BASIC INFORMATION DEFINITION Bereavement is a universal human experience, and grieving after the loss of a loved one is recognized as a normal and healthy response to loss. Normal grieving typically resolves on its own over time. In a small proportion of bereaved individuals, the process of grieving does not resolve on its own. In complicated or prolonged grief, intense grieving symptoms significantly impair functioning. Complicated grief was proposed as a diagnosis for DSM-5, and prolonged grief disorder has been recommended for inclusion in the ICD-11. Persistent complex bereavement disorder is included in the DSM-5 appendix in the section for conditions needing further study. SYNONYMS Prolonged grief disorder Persistent complex bereavement disorder ICD-10CM CODES Complicated grief and prolonged grief are not included as diagnoses in the DSM-5 or the ICD-10.

EPIDEMIOLOGY & DEMOGRAPHICS INCIDENCE: Studies indicate that of bereaved individuals, around 10% experience bereavement symptoms that grow or persist with the passage of time and significantly impair functioning. PREDOMINANT SEX AND AGE: Prolonged grief is more common among women than men, and more common in the elderly, who are exposed to more losses as they age. PHYSICAL FINDINGS & CLINICAL PRESENTATION The key feature of prolonged or complicated grief is impaired functioning in occupational, social, or other contexts beyond 6 to 12 mo after the loss, with symptoms that center around feelings of loss. Individuals struggling with prolonged or complicated grief may present with intense longing for the deceased, feelings of emptiness, prolonged reactivity to reminders of the loss, unwillingness to adopt new roles, difficulty engaging in social relationships, isolation and social disengagement, and fixation on the past and on reminders of the past. They may have difficulty envisioning life without the deceased person and may experience suicidal ideation or intent as a result.

ETIOLOGY The etiology is not known, but complications such as isolation or attentional biases impede normal resolution of grief and lead to prolonged or intensified grief symptoms. Risk factors include a history of trauma or loss, a history of mood or anxiety disorders, insecure attachment style, low perceived social support, increased stress, having been a caregiver for the deceased, pessimistic temperament, and violent cause of death of the deceased.

DIAGNOSIS Proposed criteria for prolonged difficulties with bereavement differ, but commonalities include having been bereaved (loss of a loved one) and experiencing a constellation of the symptoms listed below for at least 6 mo (different sets of criteria propose different minimum lengths of time ranging from 6 to 12 mo): • Experiencing intense yearning, sorrow, or pain, or preoccupation with the deceased • Feeling stunned or having difficulty accepting the death of the loved one • Feelings of emptiness or lack of self • Emotional numbness • Bitterness about the loss • Avoidance of reminders of the loss • Difficulty moving on with life and forging new friendships or pursuing hobbies or interests • Difficulty engaging in relationships • Difficulty imagining life without the deceased • Impairment in social, occupational, or other areas of functioning

DIFFERENTIAL DIAGNOSIS • Major depression: Whereas in major depression, wherein a globally pessimistic outlook prevails, with prolonged or complicated grief, negative feelings tend to be specifically centered on the loss of the loved one. • PTSD: Whereas PTSD is characterized predominantly by fear, horror, anger, guilt, shame, and hyperarousal, prolonged or complicated grief is characterized by yearning, loss, and emptiness. WORKUP A comprehensive clinical interview should assess when symptoms began, whether symptoms and negative feelings center on the loss of the loved one, impairment in functioning, and hopelessness or suicidal ideation or intent. The assessment should also explore attachment history and the history or presence of other psychiatric disorders.

SUGGESTED READINGS Jordan AH, Litz BT: Prolonged grief disorder: diagnostic, assessment, and treatment considerations, Prof Psychol Res Pract 45(3):180-187, 2014. Kendler et al: Does bereavement related major depression differ from major depression related to other stressful life events? Am J Psychiatry 165:1449-1455, 2008. Shear MK: Complicated grief, N Engl J Med 372:153-160, 2015. Zisook S et al: Treatment of complicated grief in survivors of suicide loss: a HEAL report, J Clin Psychiatry 79(e1-e7), 2018.

IMAGING STUDIES Imaging studies have shown activation of the nucleus accumbens on exposure to cues of the deceased in cases of complicated grief but not in cases of normal grief.

TREATMENT Studies have demonstrated the efficacy of various grief-specific therapies. Commonalities across treatments that have demonstrated efficacy include: • Psychoeducation about grief • A focus on processing the loss of the loved one, including feelings of loss and positive reminiscing about the loved one • A focus on restoring functioning and purposeful engagement in life • A focus on challenging thoughts that worsen negative feelings Some studies have found that antidepressant medications are not effective for prolonged grief symptoms, but more research is needed on psychopharmacology and prolonged grief. For example, some studies report that a subset of bereaved individuals (20%) meet criteria for MDD and have a course and treatment response similar to nonbereaved patients with MDD. A recent study found that among suicide-bereaved individuals, complicated grief therapy enhances compliance with antidepressant medication, improves functioning, and reduces suicidal ideation. Psychotherapies for depression, including interpersonal psychotherapy, have not been effective for prolonged or complicated grief.

DISPOSITION Compared with normal grief, prolonged or complicated grief is associated with debilitating distress and disability, suicidal ideation, and negative health outcomes.

 EARLS & P CONSIDERATIONS • It is important to assess patients 6 to 12 mo after a loss of a loved one and to determine whether they might be experiencing prolonged or complicated grief. • For patients with prolonged or complicated grief, grief-specific therapy has demonstrated efficacy and should be encouraged. • Treatments for depression that do not specifically address the loss have not been shown to be effective for complicated grief. • Suicidality must be assessed. AUTHOR: Abigail K. Mansfield, PhD

Guillain-Barré Syndrome BASIC INFORMATION

SYNONYMS AIDP (acute inflammatory demyelinating polyradiculoneuropathy) Acute polyneuropathy Ascending paralysis GBS Postinfectious polyneuritis ICD-10CM CODE G61.0 Guillain-Barré syndrome

EPIDEMIOLOGY & DEMOGRAPHICS INCIDENCE: 0.6 to 1.9 cases/100,000 persons annually without geographic variation. Incidence increases with age. A slight peak in incidence occurs between late adolescence and early adulthood. A slight male preponderance (1.25:1) also exists. PREDISPOSING FACTORS: Viral (HIV, CMV, EBV, influenza) and bacterial (Campylobacter jejuni, Mycoplasma pneumoniae) infections; systemic illness (Hodgkin lymphoma, immunizations). Major antecedents of GBS are described in Box E1. ETIOLOGY • Unknown, but believed to be caused by infection-induced aberrant immune response. • Preceding infectious illness 1 to 4 wk before disease onset has been noted. The most frequent antecedent infection is C. jejuni infection (associated with 30% of cases of GBS and 20% of cases of Miller Fisher syndrome). • Humoral and cell-mediated immune attack of peripheral nerve myelin, Schwann cells; sometimes with primary axonal involvement.

PHYSICAL FINDINGS & CLINCICAL PRESENTATION • Symmetric weakness, most commonly involving proximal muscles initially, subsequently involving both proximal and distal muscles; difficulty in ambulating, getting up from a chair, or climbing stairs (Box E2) • Depressed or absent reflexes bilaterally • Minimal to moderate glove and stocking paresthesias/dysesthesia/anesthesia or back pain • Pain (caused by involvement of posterior nerve roots) may be prominent • Autonomic abnormalities (bradyarrhythmias or tachyarrhythmias, hypotension or hypertension) • Respiratory insufficiency (caused by weakness of bulbar/intercostal muscles)

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • Toxic peripheral neuropathies: Heavy metal poisoning (lead [microcytic anemia], thallium [alopecia], arsenic [typically accompanied by acute GI illness]), medications (vincristine, disulfiram), organophosphate poisoning, hexacarbon (glue sniffer’s neuropathy) • Nontoxic peripheral neuropathies: Acute intermittent porphyria, fulminant vasculitic polyneuropathy, infectious (poliomyelitis, diphtheria, Lyme disease, West Nile virus), tick paralysis • Neuromuscular junction disorders: Myas­ thenia gravis, botulism, snake envenomation • Myopathies such as polymyositis and acute necrotizing myopathies caused by drugs • Metabolic derangements such as hypermagnesemia, hypokalemia, hypophosphatemia • Acute CNS disorders such as basilar artery thrombosis with brainstem infarction, brainstem encephalomyelitis, transverse myelitis, or spinal cord compression • Conversion disorder • Malingering • Table 1 differentiates clinical patterns of acute neuromuscular weakness WORKUP • Exclude other causes based on clinical history, examination, and laboratory tests. • Lumbar puncture (may be normal in the first 1 to 2 wk of the illness). Typical findings include elevated CSF protein with few mononuclear leukocytes (albuminocytologic dissociation) in 80% to 90% of patients. Elevated CSF cell counts is an expected feature in cases associated with HIV seroconversion. • EMG/nerve conduction study (NCS) may be normal in the first 10 to 14 days of the disease. The earliest electrodiagnostic abnormality is prolongation or absence of H-reflexes. NCS evidence of demyelination (prolonged distal latency, conduction velocity slowing, conduction block, temporal dispersion, and prolonged F-waves) in two or more motor nerves confirms diagnosis of AIDP in the appropriate clinical context.

LABORATORY TESTS • CBC may reveal early leukocytosis with left shift. Electrolytes are tested to exclude metabolic causes of weakness. • Heavy metal testing; urine porphyria screen; creatine kinase; HIV testing, including tests for HIV seroconversion, especially if CSF demonstrates lymphocytic pleocytosis. MRI brain and spinal cord with and without contrast may be indicated if diagnosis is uncertain. In GBS, a gadolinium-enhanced MRI of the lumbosacral spine may reveal nerve root enhancement. • Antibodies against ganglioside GQ1b may be present in up to 90% of patients with MFS. IgG antibodies against ganglioside GM1 may be associated with AMAN. There are no antiganglioside antibodies commonly associated with AIDP. • In equivocal cases, especially if peripheral nerve vasculitis is a concern, nerve biopsy may aid in confirming a diagnosis of GBS. Sensory nerve biopsy demonstrates segmental demyelination with infiltration of monocytes and T cells into the endoneurium. Axonal loss is commonly seen in sensory nerve biopsy specimens in GBS.

TREATMENT NONPHARMACOLOGIC THERAPY • Close monitoring of respiratory function (frequent measurements of vital capacity, negative inspiratory force, and tidal volume) and pulmonary toilet should be done because respiratory failure is the major complication in GBS • Frequent repositioning of patient to minimize formation of pressure sores • Prevention of venous thromboembolism with antithrombotic stockings as a supplement to pharmacologic venous thromboembolism prevention • Emotional support and social counseling for patient and family • Pain control • Cardiac monitoring to detect arrhythmias • Physical and occupational therapy once patient is medically stable and able to participate. • Avoidance of drugs that may worsen myasthenia gravis or interfere with neuromuscular transmission ACUTE GENERAL Rx • Option 1: Infusion of IV immunoglobulins (IVIG; 0.4 g/kg/day for 5 days). Always check serum IgA levels before infusion to prevent anaphylaxis in IgA-deficient patients. • Option 2: Early therapeutic plasma exchange (TPE or plasmapheresis: 200 to 250 ml/kg over five sessions every other day), started within 7 days of onset of symptoms, is beneficial in reducing the need for mechanical ventilation in patients with rapidly progressive disease and results in improved rate of recovery. It is contraindicated in patients with cardiovascular disease (recent

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Diseases and Disorders

DEFINITION Guillain-Barré syndrome (GBS) is an acute immune-mediated polyradiculoneuropathy (affects nerve roots and peripheral nerves), with predominant motor involvement. It is the most common cause of acute flaccid paralysis in the Western hemisphere and probably worldwide. By definition, maximal clinical weakness, the clinical nadir, occurs within 4 wk of disease onset.

• Facial paresis, ophthalmoparesis, dysphagia (secondary to cranial nerve involvement) • GBS consists of several clinical variants based on the pattern of clinical involvement and electrophysiologic findings. These include: 1. AIDP (most common form in Europe and North America) 2. Acute motor axonal neuropathy (AMAN; most prevalent form in China and Japan) 3. Acute motor and sensory axonal neuropathy (AMSAN; has more severe sensory involvement and is associated with more severe clinical course and poorer prognosis) 4.  Miller Fisher syndrome (MFS; triad of ophthalmoplegia, ataxia, and areflexia) 5. Acute pandysautonomia (rapid onset of parasympathetic and sympathetic failure without motor or sensory involvement) 6. Regional variants (e.g., pharyngeal-cervical-brachial GBS, pure ataxic GBS)

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Guillain-Barré Syndrome TABLE 1  Clinical Patterns of Acute Neuromuscular Weakness Cranial Nerve Involvement

Limb Weakness

Reflexes

Sensory

Autonomic Changes

Common, facial diplegia

Distal (ascending)

Absent

Common

Possible (20%)

Hallmark: Ophthalmoplegia

Variable hallmark: Ataxia

Absent

Rare

Rare

Common, ptosis, facial, oculomotor Symmetric diplopia, ptosis, dysarthria, dysphagia

Proximal (shoulders and thighs) Descending

Normal

Present

Present

Absent or decreased

No

Organophosphate poisoning

Bulbar dysfunction, dysarthria, dysphagia

Diffuse

Decreased

Late

Brainstem

Common, ocular movement

Increased

Common

Spinal cord

No

Crossed findings (face/ limbs) Quadriparesis or paraparesis

Yes (e.g., ileus, mydriasis, reduced salivation, urinary retention) Yes (e.g., bradycardia, sialorrhea, bronchorrhea, lacrimation, diarrhea, miosis causing blurry vision) Rare

Decreased then increased

Loss below level

Cause Guillain-Barré syndrome Miller Fisher syndrome Myasthenia gravis Botulism

If above thoracic level

From Parrillo JE, Dellinger RP: Critical care medicine: principles of diagnosis and management in the adult, ed 5, Philadelphia, 2019, Elsevier.

MI, unstable angina), active sepsis, and autonomic dysfunction. • Both therapies are equally effective and may shorten recovery time by 50%. There is no proven benefit from combining IVIG and plasma exchange. Glucocorticoids are contraindicated. • Mechanical ventilation may be needed if FVC is 3 cm but no >6 cm in greatest dimension and ENE(−) Metastasis in multiple ipsilateral lymph nodes, none >6 cm in greatest dimension and ENE(−) Metastasis in bilateral or contralateral lymph nodes, none >6 cm in greatest dimension and ENE(−) Metastasis in lymph node, >6 cm in greatest dimension and ENE(−); or metastasis in any node(s) and clinically overt ENE [ENE(+)] Metastasis in a lymph node >6 cm in greatest dimension and ENE(−) Metastasis in any node(s) and ENE(+)

Regional lymph nodes cannot be assessed No regional lymph node metastasis Metastasis in single ipsilateral lymph node, ≤3 cm in greatest dimension and ENE(−) Metastasis in single ipsilateral lymph node, ≤3 cm in greatest dimension and ENE(+), or >3 cm but not >6 cm in greatest dimension and ENE(−); or metastases in multiple ipsilateral lymph nodes, none >6 cm in greatest dimension and ENE(−); or in bilateral or contralateral lymph nodes, none >6 cm in greatest dimension and ENE(−) N2a Metastasis in single ipsilateral lymph node, ≤3 cm in greatest dimension and ENE(+), or a single ipsilateral node >3 cm but not >6 cm in greatest dimension and ENE(−) N2b Metastasis in multiple ipsilateral lymph nodes, none >6 cm in greatest dimension and ENE(−) N2c Metastasis in bilateral or contralateral lymph nodes, none >6 cm in greatest dimension and ENE(−) N3 Metastasis in lymph node, >6 cm in greatest dimension and ENE(−); or in a single ipsilateral node >3 cm in greatest dimension and ENE(+), or multiple ipsilateral, contralateral, or bilateral nodes, any with ENE(+) N3a Metastasis in a lymph node >6 cm in greatest dimension and ENE(−) N3b Metastasis in a single ipsilateral node >3 cm in greatest dimension and ENE(+), or multiple ipsilateral, contralateral, or bilateral nodes, any with ENE(+) Note : A designation of U or L may be used for any N category to indicate metastasis above the lower border of the cricoid (U) or below the lower border of the cricoid (L). Similarly, clinical and pathologic ENE should be recorded as ENE(−) or ENE(+). M: Metastasis M0 No distant metastasis M1 Present distant metastasis Staging for Cutaneous Squamous Cell Carcinoma Stage 0 Tis N0 M0 Stage I T1 N0 M0 Stage II T2 N0 M0 Stage III T3 N0 M0 Stage III T1 N1 M0 Stage III T2 N1 M0 Stage III T3 N1 M0 Stage IV T1 N2 M0 Stage IV T2 N2 M0 Stage IV T3 N2 M0 Stage IV Any T N3 M0 Stage IV T4 Any N M0 Stage IV Any T Any N M1 ENE, Extranodal extension. From American Joint Committee on Cancer staging manual, ed 8, 2017.

Head and Neck Squamous Cell Carcinoma

ACUTE GENERAL Rx • Early-stage disease (Stage I or II): 1.  Single-modality treatment with surgery or radiation alone may be appropriate for early-stage head and neck cancer. The choice between one or the other depends on the specific subsite of the head and neck that is involved and the side effects profile for each modality. 2.  Treatment of the potentially involved lymph nodes in the neck with either neck dissection or radiation is controversial and depends on the clinical scenario and the judgment of the treatment team. • Locoregionally advanced disease (Stage III or IV):

1. In general, these patients have large tumors >4 cm and/or cervical nodal metastases. Treatment typically involves multimodality therapy with either surgery followed by radiation therapy or upfront chemoradiation alone. Depending on the presence of certain adverse pathologic features of the surgical specimen, adjuvant chemoradiation may be necessary. If chemoradiation is the initial treatment modality, surgery may be needed in the adjuvant setting for residual or recurrent disease. 2.  Laryngeal cancers are the exception where select advanced disease with T3 or N1 tumors can be managed with singlemodality therapy with surgery or radiation alone. 3. Nasopharyngeal cancer is also an exception. This is not a surgical disease. Managed primarily by radiation to primary site and neck for early-stage disease. Chemoradiation is primary treatment for advanced disease. Surgery is reserved for recurrent or residual disease of primary site or neck following radiation therapy. • Metastatic disease (Stage IVC): 1. Palliation of symptoms is the primary goal of treatment. • All patients should be counseled on smoking cessation and avoidance of alcohol.

DISPOSITION • Prognosis depends on the specific subsite of the head and neck that is involved. Overall 5-yr survival rate for head and neck squamous cell carcinoma is about 55%. This varies with 5-yr survival rates for carcinoma of the lip as high as 89.7% and carcinomas of the hypopharynx as low as approximately 30%.

• Patients are followed on a regular basis multiple times a yr by a head and neck cancer specialist. After a 5-yr disease-free survival, patients are followed on a yearly basis.

H

REFERRAL Referral should be made to an otolaryngologist or oral surgeon who specializes in head and neck cancer.

PEARLS & CONSIDERATIONS PREVENTION • Encourage all patients to cease using tobacco and to limit alcohol consumption. • Examine the oral cavity and palpate the neck during the annual physical examination. Work up any suspicious masses or lesions. PATIENT & FAMILY EDUCATION www.entnet.org/content/head-and-neck-cancer www.cancer.gov/types/head-and-neck SUGGESTED READINGS Available at ExpertConsult.com RELATED CONTENT Laryngeal Carcinoma (Related Key Topic) Oral Cancer (Related Key Topic) AUTHOR: Louis Insalaco, MD

Diseases and Disorders

remove involved or potentially involved lymph nodes as clinically indicated. 2. Radiation: Allows for easier access to poorly exposed tumors such as those of the larynx, oropharynx, nasopharynx, or hypopharynx. Disadvantages include lengthy, time-intensive treatment course, xerostomia, pain, and higher surgical morbidity if salvage surgery is needed. 3. Chemotherapy: Useful only as an adjuvant to radiation therapy or for palliation. Single-agent cisplatin therapy is widely accepted in the U.S. as a standard for chemoradiation regimens for head and neck cancers of any site. Major toxicities include nausea, vomiting, renal toxicity, ototoxicity, and myelosuppression. 4. Reconstruction: Performed with the goal of optimizing functional and cosmetic outcomes. Options include primary closure, local flaps, regional flaps, skin grafts, and microvascular free flaps from other parts of the body (e.g., radial forearm, fibula, anterolateral thigh, latissimus, etc.).

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I

Head and Neck Squamous Cell Carcinoma SUGGESTED READINGS Boscolo-Rizzo P et al: New insights into human papillomavirus-associated head and neck squamous cell carcinoma, Acta Otorhinolaryngol Ital 33(2):77-87, 2013. Cooper JS et al: National cancer database report on cancer of the head and neck: 10-year update, Head Neck 31(6):748-758, 2009. Marur S, Forastiere AA: Head and neck squamous cell carcinoma: update on epidemiology, diagnosis, and diagnosis, and treatment, Mayo Clin Proc 91(3):386-396, 2016. Mehanna H et al: PET-CT surveillance versus neck dissection in advanced head and neck cancer, N Engl J Med 374:1444-1454, 2016. Siegel RL et al: Cancer statistics 2016, CA Cancer J Clin 66(1):7, 2016.

FIG. E1  Squamous cell carcinoma of the left tonsil (arrows). (From Richardson MA et al: Cummings otolaryngology–head and neck surgery, ed 5, Philadelphia, 2010, Mosby, pp. 1358-1374, Figure 100-8.)

FIG. E2  Oral squamous cell carcinoma. (From James WD et al: Andrews’ diseases of the skin: clinical dermatology, ed 12, Philadelphia, 2016, Elsevier.)

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Head and Neck Squamous Cell Carcinoma

FIG. E3  Computed tomography scan with contrast showing tumor of the base of the left oropharynx (arrowheads). (From Richardson MA et al: Cummings otolaryngology–head and neck surgery, ed 5, Philadelphia, 2010, Mosby, pp. 1393-1420, Figure 102-47.)

A

B

C FIG. E4  Head and neck tumors. A, Axial computed tomography (CT) image of the neck with intravenous contrast agent shows a mass in the left piriform sinus. B, Positron emission tomography (PET) and PET-CT images show right vocal cord cancer with intense tracer uptake. C, PET and PET-CT images from the lower level of the neck show nodal tracer uptake consistent with metastases. (Courtesy Dr. David Yousem, The Johns Hopkins University; in Niederhuber JE: Abeloff’s clinical oncology, ed 6, Philadelphia, 2020, Elsevier.)

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Head and Neck Squamous Cell Carcinoma

A

Radical neck dissection

B

Modified radical neck dissection: one or more of the nonlymphatic structures are preserved

D

Lateral neck dissection

E

Posterolateral neck dissection

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C

F

Supraomohyoid neck dissection

Anterior compartment neck dissection

FIG. E5  Types of neck dissection. A, Radical. B, Modified radical: one or more of the nonlymphatic structures are preserved. C, Supraomohyoid. D, Lateral. E, Posterolateral. F, Anterior compartment. (From Niederhuber JE: Abeloff’s clinical oncology, ed 6, Philadelphia, 2020, Elsevier.)

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Health Care–Associated Infections (HAIs) BASIC INFORMATION DEFINITION Health care–associated infections (HAIs) are infections associated with health care, generally occurring on or after the third calendar day of admission to a hospital. Surveillance classification criteria are established by the Centers for Disease Control and Prevention’s (CDC) National Healthcare Safety Network (NHSN). The definitions related to vascular catheter–related infections are summarized in Table E1. SYNONYMS Hospital-acquired condition (HAC)–CMS defines certain HAIs as HACs Nosocomial infections Hospital acquired infections ICD-10CM CODES A04.71 Enterocolitis due to Clostridium difficile, recurrent A04.72 Enterocolitis due to Clostridium difficile, not specified as recurrent B95.62 Methicillin-resistant Staphylococcus aureus infection as the cause of diseases classified elsewhere J15.212 Pneumonia due to methicillinresistant Staphylococcus aureus A41.02 Sepsis due to methicillin-resistant Staphylococcus aureus K68.11 Postprocedural retroperitoneal abscess T81.41XA Infection following a procedure, superficial incisional surgical site, initial encounter T81.42XA Infection following a procedure, deep incisional surgical site, initial encounter T81.43XD Infection following a procedure, organ and space surgical site, initial encounter T80.219A Unspecified infection due to central venous catheter, initial encounter J95.851 Ventilator-associated pneumonia T83.091A Other mechanical complication of indwelling urethral catheter, initial encounter T88.0XXA Infection following immunization, initial encounter T80.29XA Infection following other infusion, transfusion and therapeutic injection, initial encounter T80.211A Bloodstream infection due to central venous catheter, initial encounter T83.098A Other mechanical complication of other urinary catheter, initial encounter

EPIDEMIOLOGY & DEMOGRAPHICS INCIDENCE (IN U.S.): • Develop in at least 4% of hospitalized patients; over 1.7 million patients previously estimated.

• In 2011: 1.  HAIs accounted for more than 75,000 deaths. 2. HAIs in the U.S. cost between $28 and $33 billion annually. • At least one third of hospital-acquired infections are preventable. • Leads to increased morbidity and mortality. • Progress is tracked nationally to reduce HAIs. PREVALENCE (IN U.S.): Estimated 648,000 patients with at least one HAI/yr in 2011 PREDOMINANT SEX: • Overall, approximately equal • Elderly women: Predominantly nosocomial urinary tract infections PREDOMINANT AGE: Newborns and elderly patients (>60 yr) at highest risk PEAK INCIDENCE: Varies widely with infection site RISK FACTORS: Patients with the following conditions can develop HAIs at any age: • In ICU • Intubation • Chronic lung disease • Renal disease • Comatose • Chronic urethral or vascular catheterization • Malnutrition • Postoperative state • Diabetes

PHYSICAL FINDINGS & CLINICAL PRESENTATION Vary with specific HAIs

ETIOLOGY • Bacteria (gram-negative bacteria are responsible for >30% of HAIs) • Fungi • Viruses SOURCES AND MODES OF TRANSMISSION: • Patient’s own flora 1.  Comprises resistant organisms associated with hospitalization 2. Frequently maintained thereafter by persistent GI colonization • Unwashed hands of staff 1. Physicians 2. Nurses • Invasion of protective defenses (intact skin, respiratory cilia, urinary sphincters, and mucosa) 1. IV lines/central lines 2. Catheters 3. Respiratory equipment 4. Surgical wounds 5.  Scopes and other imaging devices. CP-CRE outbreaks occurred in recent yrs from difficult-to-clean duodenoscopes • Failure to provide adequate negative pressure, high-volume air flow chambers for airborne infection isolation of patients with TB or disseminated herpes zoster or chickenpox • Failure to rapidly identify and provide appropriate care (with isolation or precautions) for patients with communicable diseases • Food • Fomites • Personnel attire can become contaminated. Although studies have not yet verified the link

TABLE E1 Definitions

Catheter tip colonization

Exit-site infection

Definition

Comments

Positive culture of the catheter tip that grew to ≥15 cfu/ml (semiquantitative), 102 cfu/ml (quantitative sonication), or 103 cfu/ml quantitative vortexing Tenderness, erythema of site induration >2 cm

Qualitative culture should no longer be used

Catheterrelated bloodstream infection (CR-BSI)

One positive blood culture obtained from a peripheral vein and clinical manifestation of infection and (1) catheter tip colonization or (2) a differential time to positivity of more than 120 min and no obvious source of bacteremia except the catheter

Central line– associated bloodstream infection (CLA-BSI) Catheter-related clinical sepsis

One positive blood culture and clinical manifestation of infection in a patient with a catheter in place with no other source of bacteremia except the catheter Clinical manifestation of infection that disappears within 48 h of catheter removal and a positive catheter tip culture and no other obvious treated source of infection

BSI, Bloodstream infection; ICU, intensive care unit. From Vincent JL et al: Textbook of critical care, ed 7, Philadelphia, 2017, Elsevier.

Positive culture of exudate confirms the exit-site infection microbiologically Simultaneous quantitative culture from a peripheral vein and the catheter of 5:1 ratio is rarely used. NB: Exclusion of other sources of infection reveals important variability in the final classification in ICU patients. Purulence of the catheter exit site strongly implicates the catheter as the source of infection Easy-to-collect definitions for epidemiologic purposes. Exposed to an overestimation of the BSI due to catheter infection, especially in ICU and oncohematologic patients Represent 30%-50% of catheterrelated infections with general manifestations. Not easy to collect routinely but may need antimicrobial treatment (see text)

Health Care–Associated Infections (HAIs) between attire contamination and disease transmission, cross-contamination of previously washed hands can occur • Inattention to safe injection practices has led to outbreaks of hepatitis and fungal meningitis 1.  Do not administer medications from a syringe to multiple patients even if the needle is changed. 2. Use fluid infusion and administration sets (e.g., IV bags or bottles, tubing, connectors) for one patient only and dispose after each use. Do not use bags or bottles as a common source of supply for multiple patients. 3. Use single-dose vials for parenteral medications whenever possible and do not administer medications from single-dose vials to multiple patients or combine leftover contents for later use. 4. Single-dose, single-use vials do not have preservative and should be used for a single patient and a single case, procedure, and injection. 5.  When a single dose or single vial is accessed or opened, discard as per manufacturer or at the end of the case or procedure (whichever comes first). 6. Insulin pens should be used for one single designated person only even if the needle is changed. RISKS AMPLIFIED: • Use of broad-spectrum antibiotics 1. Select highly resistant bacteria. 2.  Establish multidrug-resistant bacteria as endemic flora in microenvironments within the hospital. 3. Consider antibiotic stewardship programs to reduce these risks. • May be required by accrediting agency or government • Highly vulnerable patients with specific risk factors 1. Immunosuppression (as a result of therapy, transplantation, AIDS) 2. Old age 3. Postsurgery 4. Prolonged surgery 5. Chronic lung disease 6. Ventilator dependence 7. Antacid therapy 8. Vascular lines 9. Hyperalimentation 10. ICU stay 11. Recent antibiotic therapy • Clustering of seriously ill patients 1.  Often with wounds or contaminated drainage 2. Intensifying probability of cross-infection PREVENTION STRATEGIES: Handwashing and hand hygiene between all patient contacts is the single most important method of decreasing HAI: • Regular soap and water for at least 15 sec. • Chlorhexidine (particularly good for grampositive organisms such as methicillin-resistant Staphylococcus aureus [MRSA]), alcohol hand rub, or other antiseptic for resistant organisms. • Purpose of soap and water handwashing: 1. Degrease hand surfaces. 2. Flush away oils and associated bacteria, removal of visible dirt or body fluids.

• Procedure: 1. Lukewarm water 2. Must include all surfaces 3. Special attention to areas between fingers and to the dirtier dominant hand (most people reflexively wash the cleaner, nondominant hand more vigorously) • Alcohol hand sanitizers: 1.  Improve handwashing frequency (less drying to hands, faster, and no need for wash basin and towels for drying) 2. Significantly reduce HAIs 3. Now recommended in essentially all routine health care settings 4. Rub hands until dry, approximately 15 sec • Environmental cleaning: 1. New supplemental no-touch technologies such as hydrogen peroxide vapor or mist or ultraviolet irradiation appear to reduce environmental contamination from Clostridium difficile spores, Norovirus, and resistant microorganisms. 2.  Clinical equipment should be properly disinfected or sterilized per manufacturer’s instructions. 3. High-touch items in patient environment should undergo frequent, thorough disinfection. 4. Follow manufacturer written instructions for required contact time with disinfectant. METHICILLIN-RESISTANT STAPHYLOCOCCUS AUREUS: • MRSA bacteremia decreased 13% between 2011 and 2014 in the U.S. • Health care–associated MRSA strains are typically resistant to many antibiotics, remaining susceptible to vancomycin and trimethoprim–sulfamethoxazole. • High-risk factors include dialysis, recent stay in acute or long-term care facilities. • Control measures include hand hygiene, disinfection of equipment, protective attire for isolation, and standard precautions. • Community-acquired MRSA (CA-MRSA) is associated with soft tissue, presenting as boils, rash, or so-called spider bite, and typically occurs in patients who have no recent health care or hospital interaction. • CA-MRSA often not found in nares. • CA-MRSA can be sensitive to fluoroquinolones, clindamycin, and/or erythromycin in addition to vancomycin and trimethoprim/ sulfamethoxazole. Refer to the topic “Methicillin-Resistant Staphylococcus aureus” for more information. VANCOMYCIN-RESISTANT ENTEROCOCCUS FAECIUM (VREF): • The percentage of HAIs caused by VREF increased more than twentyfold between 1989 and 1993, rising from 0% to 9%. By 2005, VREF, vancomycin-resistant E. faecalis, and other vancomycin-resistant species of enterococci had become common and endemic nosocomial pathogens accounting for 15% to 40% of all enterococci isolated in the hospital setting. • A high percentage of VREF isolated, 80%, are also ampicillin resistant. • Factors predisposing to VREF colonization or infection include a high percentage of

621.e5 hospital days receiving antibiotic therapy, use of IV, underlying disease, immunosuppression, and abdominal surgery. • Evidence suggests that the vehicle is the hands of health care workers (HCWs). • Control measures: 1.  Aggressive isolation of colonized or infected patients. 2. Restraint in using broad-spectrum antibiotics. 3.  Compliance with hand-hygiene best practices. Refer to the topic “Vancomycin-Resistant Enterococcus” for more information. CLOSTRIDIUM DIFFICILE: • Causes diarrhea as a result of pseudomembranous colitis. • Accounts for 15% to 25% of health care– associated diarrhea. Recent survey found C. difficile was the third most common HAI and accounted for 70% of gastrointestinal HAIs. • Warrants contact precautions and disinfection against spores, for example, properly diluted bleach, supplemental no-touch technology (silver, hydrogen peroxide vapor or mist, ultraviolet light, hypochlorous acid). • Alcohol hand sanitizer likely does not eliminate spores of this organism: Can use soap and water to wash hands at sink. • Spores can be dispersed in the air or room environment surrounding patients. • Treatment is tiered based on severity. Vancomycin or fidaxomicin is recommended to treat initial onset. • Rising incidence of C. difficile infection with emerging strains that have up to twentythreefold more toxin production. • Toxin assays vary widely in ability to detect toxin. • Only unformed stool specimens should be submitted for laboratory C. difficile testing. • Polymerase chain reaction (PCR) and nucleic acid amplification test/loop mediated isothermal DNA amplification (NAAT/LAMP) are more sensitive test methods than enzyme immunoassay (EIA). • Antibiotics can predispose persons by altering their normal gut flora. • Can present in healthy patients with no known risk factors. • Sometimes causes toxic megacolon or fulminant colitis. NOROVIRUS: • Patients present with sudden onset of nausea, vomiting, and/or diarrhea • Now considered yr round rather than seasonal • Disinfection with bleach or agent with efficacy against norovirus. • Often need to isolate exposed persons for average incubation period, such as 3 days, to prevent outbreak

SURVEILLANCE • Crucial for early identification of infections. Enables: 1. Immediate intervention 2. Education • Prospective, concurrent, hospital surveillance: 1. Electronic data mining provides accurate review

Health Care–Associated Infections (HAIs) 2. F easible with sophisticated computerized data collection and analysis • Targeted surveillance addresses high-risk procedures and patient populations. 1.  May be mandated by state or federal government • Routine rate calculations and statistical analyses: 1. Use device-specific days, procedure-specific cases, or patient-days as denominators. 2. Enhance early recognition of infections by body site and by organism. 3. Facilitate proper early control of potential outbreaks. • Active surveillance or screening cultures for multidrug-resistant organisms (MDROs); for example, high-risk populations for MRSA

DIAGNOSIS MOST COMMON HEALTH CARE–ASSOCIATED INFECTIONS: • Device-associated infections (26%) (central line–associated bloodstream infections, catheter-associated urinary tract infections, and ventilator-associated pneumonias) • Surgical site and other soft tissue infections (22%) • Pneumonia (22%) • GI infections (17%) HEALTH CARE–ASSOCIATED UTIS: • General associations: 1. Indwelling urinary (e.g., Foley) catheters 2.  Inappropriate catheter care (including opening catheter junctions) 3. Female sex 4. Absence of systemic antibiotics • Physical findings: 1. Fever 2. Dysuria 3. Leukocytosis 4. Pyuria 5. Flank or costovertebral angle tenderness • Usual organisms: 1.  E. coli 2.  Candida spp. 3.  Enterococcus spp. 4.  Pseudomonas spp. 5.  Klebsiella spp. 6.  Enterobacter spp. • Sepsis in 1% to 3% of hospital-associated UTIs • Prevention bundle to eliminate catheterassociated UTIs (CAUTIs): 1. Use meticulous aseptic technique during insertion and daily perineal care. 2.  Avoid unnecessary urinary catheters; remove promptly. 3. Never open the catheter-collection tubing junction (keep system closed). 4. Obtain all specimens using sterile syringe. 5. Secure the Foley. 6. Remove Foley catheters as soon as possible. 7. Substitute intermittent catheterization for Foley catheters. HEALTH CARE–ASSOCIATED BLOODSTREAM INFECTIONS: • General associations: 1. IV lines



2. Arterial lines 3. Central venous pressure (CVP) lines: Lead to catheter-associated bloodstream infection (CLABSI) 4. Phlebitis 5. Hyperalimentation 6. Lack of safe injection best practices • Fever possibly only presenting sign • Exit site of all vascular lines carefully evaluated for: 1. Erythema 2. Induration 3. Tenderness 4. Purulent drainage • Usual organisms for device-associated bacteremia: 1.  S. aureus (including MRSA) 2.  Staphylococcus epidermidis for longterm IV lines 3.  Enterobacter spp. 4.  Klebsiella spp. 5.  Candida spp. 6.  Pseudomonas aeruginosa may come from a water source or reflect cutaneous bacteria • Phlebitis in 1.3 million patients yearly • Approximately 10,000 annual deaths from IV sepsis • Prevention bundle to eliminate central lineassociated bloodstream infections (CLABSIs):

621.e6 1. Meticulous sterile technique during central catheter line insertion. 2. Emphasis should be placed on attention to detail, including handwashing, adherence to guidelines for catheter insertion and maintenance, appropriate use of antiseptic solutions such as chlorhexidine (CHG) to prepare the skin before central line insertion. 3. Modified catheter, for example, antiseptic-coated line, may reduce risk for endoluminal colonization and catheter-related sepsis in subclavian lines. 4. Decrease use of routine IVs and encourage PO intake. 5. Avoid using a femoral vein insertion site. Subclavian central line site is associated with lower infection rate than jugular. 6. Bundle to prevent CLABSIs includes hand hygiene, CHG skin prep for insertion of central lines, full barrier protection for insertion of central lines, removal of unnecessary lines, insertion checklist. 7. Consider daily CHG baths in ICUs. 8. In the U.S., 50% decrease in CLABSI between 2014 and 2018. 9.  Table E2 summarizes recommended strategies for prevention of catheterrelated bloodstream infections (CR-BSI) in ICU patients.

TABLE E2  Main Recommended Strategies for Prevention of CR-BSI in ICU Structure and Process of Care Adequate nurse-to-patient ratio Use only trained personnel who demonstrate competence for catheter insertion and maintenance Educate, assess knowledge, and audit adherence to guidelines of ICU HCWs Conduct a continuous quality-improvement program based on recommendations and adapted locally Organize a follow-up of the institution's process of care and CR-BSI rate Participate in a surveillance network Catheter Insertion Hand hygiene Full barrier precautions for CVC insertion Preparation of cutaneous site with chlorhexidine Subclavian rather than jugular or femoral access (should be weighed against the risk of mechanical complications) Avoid subclavian access for dialysis catheters Subcutaneous tunneling for internal jugular or femoral short-term CVCs Ultrasound guidance to reduce number of cannulation attempts and mechanical complications for jugular and femoral access Use a sterile sleeve for all pulmonary artery catheters Do not routinely replace CVCs (even using guidewire exchange procedure) Chlorhexidine-sulfadiazine impregnated for short-term CVCs only if the level of CR-BSI is high despite implementation of a comprehensive strategy to reduce the rate of CR-BSI Catheter Maintenance Immediate dressing change if loosened, soiled, or moistened Remove catheters as soon as possible after intended use Daily visual inspection of the catheter site Sterile transparent or gauze dressings for CVCs Gauze when blood is oozing from the insertion site Chlorhexidine-impregnated gels or chlorhexidine sponge dressings should be used to reduce CR-BSI from arterial catheters and CVCs Replace tubing used to administer blood products and lipid emulsions (including propofol) within 24 hours of initiating the infusion Replace administration sets no more frequently than at 4-day intervals, but at least every 7 days CR-BSI, Catheter-related bloodstream infection; CVC, central venous catheter; ICU, intensive care unit; HCW, health care worker. From Vincent JL et al: Textbook of critical care, ed 7, Philadelphia, 2017, Elsevier.

Health Care–Associated Infections (HAIs) HEALTH CARE–ASSOCIATED PNEUMONIAS: • More common in ICUs • General associations: 1. Aspiration 2. Intubation: Leads to ventilator-associated events (VAE) or ventilator-associated pneumonia (VAP) 3. Altered consciousness 4. Old age 5. Chronic lung disease 6. Postsurgery 7. Antacids 8. Head of bed not elevated • Signs of pneumonia common among patients on general wards: 1. Cough 2. Sputum 3. Fever 4. Leukocytosis 5. New infiltrate on chest x-ray examination • Signs more subtle in ICUs because many patients have purulent sputum because of chronic intubation: 1. Change in sputum character or volume 2. Small changes on chest x-ray examination • Usual organisms: 1.  S. aureus (including MRSA) 2.  Pseudomonas aeruginosa 3.  Enterobacter spp. 4.  Acinetobacter spp. 5.  Klebsiella spp. • Less common organisms: 1.  Stenotrophomonas spp. 2.  Legionella spp., Flavobacterium spp. 3. Respiratory syncytial virus (infants) 4. Adenovirus • 1% of hospitalized patients affected • Mortality rate high (40%) • Prevention bundle: 1. Use meticulous sterile technique during suctioning and handling airway. 2. Do not routinely change ventilator breathing circuits and components. For heat and moisture exchangers, no more frequently than every 48 hr. 3. Drain respirator tubing without allowing fluid to return to respirator. 4. Wash hands routinely to prevent colonization of patients and transfer of organisms among patients. 5. Use of a bundle to prevent VAEs and VAPs to include elevate the head of bed, provide deep vein thrombosis (DVT) prophylaxis, provide peptic ulcer disease (PUD) prophylaxis, hold sedation, test for ability to extubate, control glucose, gastric decontamination. 6. Consider oral mouth care with CHG for vented patients in ICUs. SURGICAL AND HEALTH CARE–ASSOCIATED SOFT TISSUE INFECTIONS: • Associations: 1. Decubitus ulcers 2. Surgical site risks: Contaminated or dirty or infected, the American Society of Anesthesiologists’ (ASA) physical status classification of ASA 3 or 4, duration of surgery over national average, usually 3 hr 3. Abdominal surgery 4. Presence of drain

5. Preoperative length of stay 6. Surgeon 7. Presence of other infection • Physical findings: 1. Decubitus ulcer with fluctuance at margin or under firm eschar 2. Erythema extending >2 cm beyond margin of surgical wound 3. Tenderness 4. Induration 5. Erythema 6. Fluctuance 7. Purulent drainage 8. Dehiscence of sutures • Usual organisms: 1.  S. aureus (including MRSA) 2.  Enterococcus spp. 3.  Enterobacter spp. 4.  Acinetobacter spp. 5.  E. coli spp. • Prevention: 1.  Use careful skin care and frequent, proper positioning of patient to prevent decubitus ulcer. 2.  Use meticulous sterile surgical technique. 3. Use properly washed and sterilized instruments, processed in accordance with manufacturer’s instructions. Minimize immediate-use steam sterilization (formerly known as flash sterilization). 4.  Wash hands to decrease colonization when handling postoperative wound. 5. Limit prophylactic antibiotics to 24 hr perioperatively. 6.  Double wrap contaminated dressings (hold in gloved hand and evert gloves over dressings) before disposal. 7.  Surgical Care Improvement Project (SCIP) bundle to include antibiotic prophylaxis selection, receipt of antibiotic within 1 hr before surgery, discontinuation of antibiotic within 24 hr of surgery end time, cardiac surgery patients with controlled 6 a.m. postoperative blood glucose, clip rather than shave prep, postoperative normothermia for colorectal surgery patients, removal of Foley catheter by end of postoperative day 2 (except for urologic, gynecologic, or perineal procedures, or on paralytics, vasopressors/inotropics during ICU stay). 8. Preadmission nares MRSA screening often beneficial for open heart and orthopedic implants when time is allowed for decolonization, chlorhexidine showers, and appropriate antibiotic prophylaxis selection. 9. Often, preadmission nares MRSA screening is also performed. 10.  Consider antiseptic shower the night before and the morning of surgery.

LABORATORY TESTS • Appropriate to specific HAI and specific patient’s condition • Cultures generally indicated for proper confirmation of responsible pathogens: 1. Urine

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2. Blood 3. Sputum 4. Soft tissue • Molecular analysis of health care–associated epidemics: 1. Plasmid fingerprinting 2. Restriction endonuclease digestion (plasmid and genomic DNA) 3. Peptide analysis 4. Immunoblotting 5. Ribosomal RNA (rRNA) typing 6. DNA probes 7. Multilocus enzyme electrophoresis 8. Restriction fragment length polymorphism (RFLP) 9. PCR 10. Provide confirmation of point-source or common strains and corroboration of hypotheses reached using classic epidemiology

IMAGING STUDIES Rarely needed for diagnosis of HAI; helpful for deep surgical site infection

TREATMENT ACUTE GENERAL Rx • Appropriate to etiologic organism: 1. Antibiotic 2. Antifungal 3. Antiviral • Specific therapy determined after careful consideration of resident flora within the microenvironment in which the patient was hospitalized. 1. Empiric therapy. 2. Frequently difficult to fashion accurately. 3.  Often undesirable unless the patient’s clinical condition requires urgent treatment. • Consultation for expert advice regarding antibiotic selection in view of known epidemiologic risks within the hospital (hospital epidemiologist or infectious disease specialist). • Avoid unnecessary treatment for organisms that are colonizing (no signs or symptoms of infection) but not infecting patients. • Prevention of spread of communicable diseases. 1. Isolation or precautions (airborne, droplet, contact isolation precautions, and combinations thereof). 2. Classic schema (strict, respiratory isolation and contact [skin and wound] precautions) have been replaced by more streamlined revised guidelines (airborne, droplet, contact isolation precautions, and combinations thereof). 3. Less careful response to some diseases (e.g., hemorrhagic fevers) inadvertently induced by removal of strict isolation category. 4. Universal or standard precautions to protect HCWs against splash or splatter of blood or body fluids. 5.  Tracking roommates of patients with communicable disease, such as norovirus

Health Care–Associated Infections (HAIs) or influenza, and using precautions during the incubation period. • Universal or standard precautions used for all patients during all anticipated contacts with blood, body fluids, or secretions. 1. Gloves. 2. Goggles or eye shield. 3.  Gowns that prevent blood or potentially infectious materials from passing through. • Consider aggressive isolation to restrict spread of multidrug-resistant organisms and their plasmids. 1. MRSA. 2. VREF. 3. MDR-GNRs (multidrug-resistant gramnegative rods) can include extendedspectrum β-lactamases (ESBL), carbapenem-resistant Enterobacteriaceae (CP-CRE), and some Acinetobacter baumannii. New microbiology interpretive criteria (breakpoints) can result in no longer reporting mechanism of resistance. 4.  New Delhi metallo-β-lactamase 1 (NDM-1): These are gram-negative Enterobacteriaceae with a new type of carbapenem-resistance gene. 5. Colistin-resistant E. coli. The mcr-1 gene that makes bacteria resistant to colistin was found twice in the U.S. Most recently, an mcr-9 gene was also found in a patient in the U.S. This resistance could move to other bacteria. Colistin is a last-resort antibiotic for treating patients with infection from multidrug-resistant organisms. 6. VIM- and IMP-type metallo-ß-lactamase producers. Refer to the topic “Multidrug-Resistant Gram Negative Rods” for more information.

DISPOSITION The infection prevention and control service or hospital epidemiologist should be notified when infectious complications occur in the hospital setting; most, but not all, HAIs are potentially avoidable, and every effort should be taken to minimize the risk of infections associated with health care. Nationwide success in achieving and sustaining zero CLABSIs, zero CAUTIs, and zero VAPs warrants widespread use of infection prevention bundles to target zero HAIs. REFERRAL • To infection preventionist • To hospital epidemiologist

PEARLS & CONSIDERATIONS COMMENTS • Sharp and splash injuries to staff are relatively rare, but nearly all are preventable. 1. Nurses incur most injuries. 2. Usual causes: a. Needle sticks b. Scalpel and surgical needle injuries c. Blood splashes 3. Prevention: a. Never recap needles. b.  Dispose of needles only in rigid, impermeable plastic containers. c. Clearly announce instrument passes in the operating room and during procedures. Use passing trays. d. Use needleless systems for vascular access and neutral displacement central line connectors. e.  Use gloves, mask, and goggles/eye shield if aerosol or splash is likely. f. Never leave needles or other sharp items in beds. g. Never dispose of sharp items in regular trash bags. 4.  Infection prevention and control or employee health staff should be consulted immediately after exposure to determine need for prophylaxis for hepatitis B or HIV. 5.  All clinical staff should be immune to hepatitis B (natural or vaccine). • Fungi previously considered to be contaminants are now risks for patients with cancer and organ transplantation. 1.  Candida spp. a.  C. auris b.  C. guilliermondii c.  C. krusei d.  C. parapsilosis e. C. tropicalis f.  Note that Candida auris has emerged with resistance, sometimes to all three major classes of antifungal drugs. The fungus has spread quickly, causing outbreaks and resulting in invasive infection with higher risk of death. These multidrug-resistant isolates are often misidentified by automated lab systems. Contact precautions in a private room are recommended, with attention to thorough daily and terminal environmental disinfection. Current recommendation is for a disinfectant effective against spores.

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2.  Aspergillus spp. 3.  Curvularia spp. 4.  Bipolaris spp. 5.  Exserohilum spp. 6.  Alternaria spp. 7.  Fusarium spp. 8.  Scopulariopsis spp. 9. Pseudallescheria boydii 10.  Trichosporon beigelii 11.  Malassezia furfur 12.  Hansenula spp. 13.  Microsporum canis • Focused, committed efforts by the entire health care staff continuously directed toward prevention: 1. Each HAI addressed as an opportunity to improve the delivery of safe patient care always using best practices 2. Essential for individual staff members to understand that small risks applied to large populations result in a large number of total events (i.e., HAIs) • Antibiotic stewardship: 1. Choose appropriate antibiotic. 2. Minimize vancomycin use. 3. Consider procalcitonin to guide antibiotic use for sepsis. 4. Follow CDC core elements and checklist. • The Centers for Medicare & Medicaid Services denies inpatient payments for certain HAIs. Total reimbursement is linked to performance by comparing HAI outcome with national benchmark, top percentile, and achieved standardized infection ratios (SIR). 1.  The number of surgical-site S. aureus infections acquired in the hospital, particularly cardiac or orthopedic, has been reduced by rapid screening and decolonizing of nasal carriers of S. aureus before surgery. 2. Universal decolonization of ICU patients for MRSA has been advocated without nares screening as a model to reduce bloodstream infection and MRSA clinical isolates.

RELATED CONTENT Clostridium difficile Infection (Related Key Topic) Methicillin-Resistant Staphylococcus aureus (Related Key Topic). Multidrug-Resistant Gram Negative Rods (Related Key Topic) Vancomycin-Resistant Enterococcus (Related Key Topic) AUTHOR: Marlene Fishman Wolpert, MPH, CIC, FAPIC

Health Care–Associated Infections (HAIs) SUGGESTED READINGS Bearman G et  al: Healthcare personnel attire in non-operating room settings, Infect Control Hosp Epidemiol 35(2):107-121, 2014. Best EL et  al: The potential for airborne dispersal of Clostridium difficile from symptomatic patients, Clin Infect Dis 50:1450-1457, 2010. Bode LG et  al: Preventing surgical-site infections in nasal carriers of Staphylococcus aureus, N Engl J Med 362:9-17, 2010. Calfee DP et al: Strategies to prevent methicillin-resistant Staphylococcus aureus transmission and infection in acute care hospitals: 2014 update, Infect Control Hosp Epidemiol 35:772-796, 2014. Castanheira M et  al: Detection of mcr-1 among Escherichia coli clinical isolates collected worldwide as part of the SENTRY antimicrobial surveillance program during 2014-15, Antimicrobial Agents and Chemotherapy, posted online. Available at: http://aac.asm.org/content/early/2016/06/22/AAC.0126716.abstract. Accessed 29 July 2019. Centers for Disease Control and Prevention: Tracking Candida auris. Available at: www.cdc.gov/fungal/candida-auris/tracking-c-auris.html. Accessed 29 July 2019; last reviewed July 12, 2019. Centers for Disease Control and Prevention: CRE Toolkit: Guidance for control of carbapenem-resistant Enterobacteriaceae (CRE). Available at: www.cdc.gov/h ai/organisms/cre/cre-toolkit/. [Accessed 29 July 2019]. Centers for Disease Control and Prevention: Core elements of hospital antibiotic stewardship programs. Available at: www.cdc.gov/antibioticuse/healthcare/implementation/core-elements.html. Accessed 29 July 2019. Centers for Disease Control and Prevention: Carbapenem-resistant Enterobacteriaceae containing New Delhi metallo-beta-lactamase in two patients—Rhode Island, March 2012, MMWR Morb Mortal Wkly Rep 61(24):446-448, 2012. Centers for Disease Control and Prevention (CDC): Guideline for hand hygiene in health-care settings. Available at: www.cdc.gov/handhygiene/providers/guidel ine.html. Accessed 29 July 2019, last reviewed 2016. Centers for Disease Control and Prevention: Management of multidrug-resistant organisms in healthcare settings. Available at: www.cdc.gov/infectioncontrol/ guidelines/MDRO/index.html. Accessed 29 July 2019. Chapin KC et al: Comparison of five assays for detection of Clostridium difficile toxin, J Mol Diagn 13(4):395-400, 2011. Clinical and Laboratory Standards Institute (CLSI): Performance standards for antimicrobial susceptibility testing, 21st informational supplement, CLSI document. M100–S24. Cohen SH et  al: Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the Society for Healthcare Epidemiology of America (SHEA) and the infectious diseases Society of America (IDSA), Infect Control Hosp Epidemiol 31(5):431-455, 2010.

Darouiche RO et  al: Chlorhexidine-alcohol versus povidone-iodine for surgical-site antisepsis, N Engl J Med 362:18-26, 2010. EPA. List K: Registered antimicrobial products effective against Clostridium difficile spores. Available at: www.epa.gov/sites/production/files/201801/documents/2018.10.01.listk_.pdf, updated 2018. Accessed 29 July 2019. EPA. List G: Registered antimicrobial products effective against norovirus, Availablewww.epa.gov/sites/production/files/2018-04/documents/list_g_ disinfectant_list_3_15_18.pdf . [Accessed 29 July 2019], 2018. updated. Huang SS et al: Targeted versus universal decolonization to prevent ICU infection, N Engl J Med 368(24):2255-2265, 2013. Kallen AJ et al: Healthcare–associated invasive MRSA infection, 2005-2008, J Am Med Assoc 304(6):641-647, 2010. Kufelnicka AM, Kirn TJ: Effective utilization of evolving methods for the laboratory diagnosis of Clostridium difficile infection, CID 52(12):1451-1457, 2011. Magill SS et al: Multistate point-prevalence survey of healthcare-associated infections, N Engl J Med 370:1198-1208, 2014. Available at: www.nejm.o rg/doi/pdf/10.1056/NEJMoa1306801. Accessed 29 July 2019. McDonald LC et  al: Clinical Practice Guidelines for Clostridium Difficile Infection in Adults and Children: 2017 Update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA), CID 66:e1-e48, 2018. Available at: https://academic.oup. com/cid/article/66/7/e1/4855916. Accessed 29 July 2019. National Action Plan to Prevent Healthcare-Associated Infections: Roadmap to Elimination. Available at: www.health.gov/hai/pdfs/hai-action-planexecutive-summary.pdf, 2013. Accessed 29 July 2019. O'Grady NP et al: Preventing ventilator-associated pneumonia: does the evidence support the practice? J Am Med Assoc 307(23):2534-2538, 2012. One and Only Campaign for Safe injections. Available at:. www.oneandonlyc ampaign.org. Accessed 29 July 2019. Otter JA et al: The role played by contaminated surfaces in the transmission of nosocomial pathogens, Infect Control Hosp Epidemiol 32(7):687-699, 2011. Peleg AY, Hooper DC: Hospital-acquired infections due to gram-negative bacteria, N Engl J Med 362:1804-1813, 2010. Saint S et al: A program to prevent catheter-associated urinary tract infection in acute care, N Engl J Med 374:2111-2119, 2016. Scott RD: The direct medical costs of healthcare-associated infection in U.S. hospitals and the benefits of prevention, Available at: www.cdc.gov/HA I/pdfs/hai/Scott_CostPaper.pdf, updated 2009. Accessed 29 July, 2019. Society for Healthcare Epidemiology of America (SHEA): Compendium of strategies to prevent healthcare-associated infections in acute care hospitals: 2014 update. Available at: www.shea-online.org/index.php/practiceresources/41-current-guidelines/417-2014-update. Accessed 29 July 2019.

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Heart Block, Complete BASIC INFORMATION DEFINITION Complete heart block (CHB) is the absence of electrical impulse transmission from the atria to the ventricles when atrioventricular (AV) junction is not physiologically refractory, due to a functional or anatomical impairment of the conduction system, resulting in a bradycardia characterized by AV dissociation. It may be acquired or congenital. CHB can be permanent or reversible. SYNONYMS Third-degree AV block CHB Complete AV block ICD-10CM CODE I44.2 Atrioventricular block, complete

EPIDEMIOLOGY & DEMOGRAPHICS • The prevalence of CHB is 0.04%. • The prevalence of CHB increases with age. PHYSICAL FINDINGS & CLINICAL PRESENTATION Physical examination may be normal. Cannon A waves may appear in the jugular vein periodically due to the right atrium contracting during ventricular systole. Patients may present with the following clinical manifestations: • Dizziness, palpitations • Syncope or presyncope (due to reduced cardiac output) • Fatigue, impaired exercise tolerance • Mental status changes • Congestive heart failure • Angina pectoris • Some patients may be asymptomatic (e.g., congenital CHB) ETIOLOGY • Fibrosis or sclerosis of the conduction system, Lenegre and Lev disease • Acute myocardial infarction—inferior (14%) or anterior (2%) wall of patients, usually within 24 hours • Drug effect (digitalis, calcium channel blockers, beta-blockers, amiodarone) • Cardiomyopathy and myocarditis • Infiltrative processes of the myocardium (amyloidosis, sarcoidosis, scleroderma, tumor) • Metabolic abnormalities (hyperkalemia, hypoxia, hypothyroidism) • Lyme carditis, rheumatoid nodules, polymyositis, Chagas disease • Neuromuscular disorders (Becker muscular dystrophy, myotonic muscular dystrophy) • Congenital (birth from mothers with systemic lupus) • Hyperkalemia • Familial: SCN5 sodium channel mutations have been associated with CHB

• Iatrogenic (cardiac surgery, catheter ablation of arrhythmias, percutaneous coronary intervention). Transcatheter aortic valve implantation (TAVI) is shown to be frequently associated with new conduction abnormalities; patients with preexisting right bundle branch block are at increased risk of CHB (resolves over time in most patients). • Paroxysmal due to phase 4 block of the HisPurkinje system

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • The differential diagnosis includes lesser degree of AV block, automatic accelerated junctional rhythms, and nonconducted premature atrial contractions. • The atrial rate must be faster than the ventricular rate (more As than Vs), and the junctional or ventricular rate is regular. Episodes of AV dissociation with an accelerated ventricular or junctional pacemaker overtaking the sinus node can often look like heart block on a single electrocardiogram. WORKUP • Workup such as routine labs, cardiac biomarkers, and cardiac imaging should be dictated by the clinical circumstances. • ECG: Diagnostic of the disease (Figs. 1 and 2): 1. P waves are present with a regular atrial rate that is faster than the ventricular rate. 2. P waves are not related to the QRS complexes. The PR intervals are variable. 3. RR intervals are regular. 4. QRS complexes may be narrow with a rate of 40 to 60 beats/min (block proximal to His bundle) or wide with a rate of 40 beats/min in the absence of cardiomegaly (Level of Evidence: C) 2. Asymptomatic second-degree AV block at intra- or infra-His levels found at electrophysiologic study (Level of Evidence: B ) 3. First-degree or second-degree AV block with symptoms similar to those of pacemaker syndrome (Level of Evidence: B ) 4. Asymptomatic type II second-degree AV block with a narrow QRS. When type II second-degree AV block occurs with a wide QRS, including isolated right bundle branch block, pacing becomes a Class I recommendation. (Level of Evidence: B ) Class IIb 1. AV block due to drug use or toxicity when the block is expected to recur even after withdrawal of the drug (Level of Evidence: B ) 2. Neuromuscular diseases, such as myotonic muscular dystrophy, Kearns–Sayre syndrome, Erb (limb-girdle) dystrophy, and peroneal muscular atrophy with any degree of AV block (including first-degree AV block), with or without symptoms of bradycardia (Level of Evidence: B ) Class III 1. Asymptomatic first-degree AV block (Level of Evidence: B ) 2. Asymptomatic type I second-degree AV block at a site above the His (i.e., the AV node) level or not known to be intra- or infra-Hisian by electrophysiologic study (Level of Evidence: B ) 3. AV block expected to resolve and unlikely to recur (e.g., drug toxicity, Lyme disease, nocturnally in sleep apnea, early postoperative status, transient increases in vagal tone) (Level of Evidence: B ) AV, Atrioventricular. From Bonow RO et al: Braunwald’s heart disease: a textbook of cardiovascular medicine, ed 9, Philadelphia, 2012, WB Saunders.

DISPOSITION • Mortality is highest in the neonatal period in congenital CHB. • Prognosis is favorable after insertion of a pacemaker and is related to the underlying etiology of complete AV block (e.g., myocardial infarction, cardiomyopathy). • Nonrandomized studies have shown that PPM insertion improves survival in patients with CHB. REFERRAL All patients with CHB should be referred to a cardiologist for consideration of temporary and/ or PPM implantation.

PEARLS & CONSIDERATIONS COMMENTS • Patients should be instructed to avoid activities that may damage the pacemaker (e.g., contact sports). • Pacemaker manufacturers do not recommend any special restrictions regarding proximity to typical household items. • All pacemaker manufacturers offer pacemakers that are MRI compatible. Older pacemaker models and leads may have a strong relative contraindication for MRI. • Leadless pacemakers that are implanted directly into the right ventricle using a special

delivery system are available for special indications and are primarily used for patients who are at high risk for traditional pacemakers and do not require dual-chamber pacing. • Some medical procedures, such as lithotripsy, hyperbaric chamber, and electrocautery used during surgery, may require pacemaker programming and testing perioperatively. • Table 3 describes the five-letter pacemaker code, and Table 4 summarizes common permanent pacemakers.

RELATED CONTENT Complete Heart Block (Patient Information) AUTHOR: John Wylie, MD, FACC

Heart Block, Complete TABLE 2  Complete Heart Block Management

H

Therapy

Asymptomatic–Acquired

• Rule out reversible causes, including: Hyperkalemia Acute inferior MI Digoxin toxicity Excess calcium channel blocker therapy Lyme disease • If HR 40 bpm, especially if the QRS complex is narrow. • CHB due to radio frequency ablation of the AV junction to control ventricular response rate in atrial fibrillation requires permanent pacing. May occur even if the patient is asymptomatic from a slow ventricular rate (40 bpm) that may be quite stable over time. Acquired CHB is associated with a poor short-term prognosis (>50% mortality in the first 6-12 mo after diagnosis). If irreversible, pacing is indicated. • A permanent pacemaker is indicated. • Temporary pacing is indicated if permanent pacing cannot be done expeditiously or if CHB has an identifiable and reversible cause (e.g., drug overdose). • Usually associated with a narrow QRS complex with an escape rhythm arising in the AVN. • Patients are usually asymptomatic. • In patients who are asymptomatic, the indications for a pacemaker are controversial. • Patients will need close follow-up, at least annually, for evaluation of symptoms suggesting chronotropic incompetence. • If symptomatic bradycardia, a permanent pacemaker is indicated. • If rate is consistently 80 per 1000 individuals among those >85 yr. Before age 75, the incidence of HF is higher in males, but both sexes are equally affected after this age cutoff. • In the U.S., 1.1 million hospital discharges and 3.2 million hospitalizations/ambulatory care visits were associated with HF in 2007. • Prevalence: 5.1 million persons in the U.S. and an estimated 23 million persons worldwide. The prevalence of HF is rising, especially in the elderly, particularly due to aging of the population and improved survival from other conditions. • The estimated (direct and indirect) cost of HF in the U.S. was >$40 billion in 2012, with over half of these costs spent on hospitalizations. The mean cost of HF-related hospitalizations is $23,077 per patient and is higher when HF was a secondary rather than the primary diagnosis. • HFrEF and HFpEF each make up about half of the overall HF burden. • Among patients with HF in one large population study, hospitalizations were common

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Heart Failure

TABLE 1  Compensatory Mechanisms in Heart Failure Compensatory Response Renin-angiotensin system activation Adrenergic ­activation

↑Natriuretic peptide secretion

Stimuli

Beneficial Effects

Adverse Effects

↓CO/BP ↓Renal blood flow ↑β-adrenergic activity ↓CO/BP

Maintain vital organ perfusion through vasoconstriction and sodium retention ↑CO through ↑ in heart rate and contractility ↑BP

ACE inhibitors ARBs

↑Antidiuretic hormone ↑Norepinephrine ↑Angiotensin II ↑Aldosterone ↓Renal blood flow Volume expansion (atrial stretch)

↑Preload → ↑stroke volume and CO

↑Afterload → worsened LV function Adverse LV remodeling (apoptosis, myocyte hypertrophy) ↑Ischemia ↑Afterload → worsened LV function ↑LVEDP → pulmonary congestion Adverse LV remodeling (apoptosis, myocyte hypertrophy) Pulmonary and systemic congestion Adverse LV remodeling None known

Natriuretic peptides

Diuresis Natriuresis Partial inhibition of renin-angiotensin system and norepinephrine

β-adrenergic blocking agents

Diuretics Aldosterone inhibitors ACE inhibitors, ARBs β-adrenergic blocking agents

ACE, Angiotensin-converting enzyme; ARB, angiotensin receptor blocker; BP, blood pressure; CO, cardiac output; LV, left ventricular; LVEDP, left ventricular end-diastolic pressure. From Sellke FW et al: Sabiston & Spencer surgery of the chest, ed 9, 2016, Elsevier.

TABLE 2  American College of Cardiology/American Heart Association (ACC/AHA) Stages of Heart Failure (HF) Compared to the New York Heart Association (NYHA) Functional Classification ACC/AHA Stages

NYHA Functional Classification

A

At high risk for HF but without structural heart disease or symptoms of HF. Structural heart disease but without signs or symptoms of HF.

None

Structural heart disease with prior or current symptoms of HF.

I

B C

I

II III D

Refractory HF requiring specialized interventions.

IV

No limitation of physical activity. Ordinary physical activity does not cause symptoms of HF. No limitation of physical activity. Ordinary physical activity does not cause symptoms of HF. Slight limitation of physical activity. Comfortable at rest, but ordinary physical activity results in symptoms of HF. Marked limitation of physical activity. Comfortable at rest, but less than ordinary activity causes symptoms of HF. Unable to carry on any physical activity without symptoms of HF, or symptoms of HF at rest.

From Zipes DP: Braunwald’s heart disease, a textbook of cardiovascular medicine, ed 11, Philadelphia, 2019, Elsevier.

after HF diagnosis, with 83% of patients hospitalized at least once and 43% hospitalized at least 4 times. More than half of the hospitalizations were related to noncardiovascular causes.

RISK FACTORS Several conditions are associated with an increased risk of developing heart failure. If these are identified and treated appropriately, it may be possible to delay, if not prevent, the onset of HF. • Hypertension: The incidence of HF is higher in patients with higher blood pressures, older age of the hypertensive patient, and in patients who have been hypertensive for longer.

• Diabetes mellitus: The incidence of HF is increased in patients with diabetes mellitus, independent of the presence of structural heart disease. • Metabolic syndrome: Appropriately treating hypertension, diabetes mellitus, and dyslipidemia can decrease the incidence of HF. • Atherosclerotic disease: Patients with atherosclerotic disease are likely to develop HF.

PHYSICAL FINDINGS & CLINICAL PRESENTATION The clinical and physical exam findings should be given the highest priority when determining the diagnosis of HF. These signs and symptoms are dependent on the severity of disease, precipitant factors, comorbid conditions, and

H

whether the HF symptoms are predominantly right-sided or left-sided. Clues in the patient’s history when evaluating HF are summarized in Table 4. • Common clinical manifestations are: 1. Dyspnea on exertion, that can progress to dyspnea at rest, caused by increasing pulmonary vascular congestion 2. Orthopnea, caused by increased venous return in the recumbent position and further elevated pulmonary venous pressure 3.  Paroxysmal nocturnal dyspnea (PND) resulting from multiple factors including increased venous return in the recumbent position, decreased PaO2, and decreased adrenergic stimulation of myocardial function during sleep 4. Nocturnal angina resulting from increased myocardial oxygen demand (secondary to increased venous return in the recumbent position causing increased preload) in patients with concomitant coronary artery disease (CAD) 5.  Cheyne-Stokes respiration (alternating phases of apnea and hyperventilation) caused by prolonged circulation time from lungs to brain as a result of impaired cardiac output 6.  Fatigue, lethargy, and decreased functional capacity resulting from low cardiac output and hypoperfusion of peripheral tissues 7.  Table 5 summarizes common presenting symptoms and signs of decompensated heart failure. • Physical examination (Table 6): 1. Fine pulmonary crackles, wheezes, tachypnea, hypoxia (due to elevated pulmonary pressures). Crackles may be absent in chronic and longstanding high pulmonary venous pressure because it allows for lymphatic drainage in the lungs to increase.

Diseases and Disorders

Renal salt and water retention

Potential Pharmacologic Interventions

631

I

632

Heart Failure

ALG

TABLE 3  Simplified Classification and Common Clinical Characteristics of Patients with Acute Heart Failure Clinical Classification

Signs and Symptoms

Symptom Onset

Triggers

Decompensated heart failure

Usually gradual

Noncompliance, ischemia, infections

Acute hypertensive heart failure

Usually sudden

Hypertension, atrial arrhythmias, ACS

Cardiogenic shock

Variable

Progression of advanced HF or major myocardial insult (e.g., large AMI, acute myocarditis)

Clinical Assessment

Course

Peripheral edema, orthopnea, dyspnea on exertion Dyspnea (often severe), tachypnea, tachycardia, rales common

SBP: Variable CXR: Often clear despite elevated filling pressures SBP: High (>180/100 mm Hg) CXR with pulmonary edema Hypoxemia common

Variable, high rehospitalization rate

End-organ hypoperfusion; Oliguria, confusion, cool extremities

SBP: Low or low normal LV function usually severely depressed RV dysfunction common Laboratory evidence of endorgan dysfunction (renal, hepatic)

High acuity, but patient often responds quickly to therapy with vasodilators, noninvasive ventilation Postdischarge mortality is low High inpatient mortality Poor prognosis unless readily reversible cause or mechanical support, transplantation

ACS, Acute coronary syndrome; AMI, acute myocardial infarction; CXR, chest x-ray film; LV, left ventricular; RV, right ventricular; SBP, systolic blood pressure. From Zipes DP: Braunwald’s heart disease, a textbook of cardiovascular medicine, ed 11, Philadelphia, 2019, Elsevier.

2. Tachycardia and narrowed pulse pressure (due to increased sympathetic tone) 3. S3 gallop, paradoxical splitting of S2, jugular venous distention, peripheral edema in dependent tissues, congestive hepatomegaly, ascites, and hepatojugular reflux (due to volume overload) 4.  Perioral and peripheral cyanosis, decreased capillary refill, pulsus alternans, and cool extremities (due to decreased cardiac output) • Six common clinical presentations identified by European Society of Cardiology of Acute Heart Failure Syndromes: 1.  ADHF presenting with hypertension (SBP >160): The hypertension leads to increased afterload causing pulmonary vascular congestion 2. Worsening or decompensation of chronic HF 3. Flash pulmonary edema 4. Cardiogenic shock 5.  Acute coronary syndrome (ACS) and ADHF 6. Isolated RV failure • Each of these scenarios may require different therapies to effectively stabilize and treat the patient. Acute precipitants of HF decompensation include noncompliance with salt restriction or medications (most common cause), any acute systemic illness, infection, arrhythmias (e.g., atrial fibrillation), ischemia or infarction, uncontrolled hypertension, new medications (e.g., negative inotropic agents such as calcium channel blockers/antiarrhythmic agents), nonsteroidal antiinflammatory drugs (NSAIDs), renal dysfunction, toxins (e.g., ethanol and anthracyclines), surgery, or valvular catastrophe.

ETIOLOGY LEFT VENTRICULAR FAILURE: The dichotomy of whether HF occurs in the setting of preserved or reduced LV systolic function plays an important role in treatment strategies. Patients with HFpEF may have significant abnormalities in

TABLE 4  Using the Medical History to Assess the Heart Failure Patient Symptoms Associated with HF Include: Fatigue Shortness of breath at rest or during exercise Dyspnea Tachypnea Cough Diminished exercise capacity Orthopnea Paroxysmal nocturnal dyspnea Nocturia Weight gain/weight loss Edema (of extremities, scrotum, or elsewhere) Increasing abdominal girth or bloating Abdominal pain (particularly if confined to right upper quadrant) Loss of appetite or early satiety Cheyne-Stokes respirations (often reported by family rather than patient) Somnolence or diminished mental acuity Historical Information Helpful in Determining if Symptoms Are Caused by HF A past history of HF Cardiac disease (e.g., coronary artery disease, valvular or congenital disease, previous myocardial infarction) Risk factors for heart failure (e.g., diabetes, hypertension, obesity) Systemic illnesses that can involve the heart (e.g., amyloidosis, sarcoidosis, inherited neuromuscular diseases) Recent viral illness or history of HIV infection or Chagas disease Family history of HF or sudden cardiac death Environmental and/or medical exposure to cardiotoxic substances Substance abuse Noncardiac illnesses that could affect the heart indirectly, including high-output states (e.g., anemia, hyperthyroidism, arteriovenous fistulas) HIV, Human immunodeficiency virus. From Zipes DP: Braunwald’s heart disease, a textbook of cardiovascular medicine, ed 11, Philadelphia, 2019, Elsevier.

active relaxation and passive stiffness of the LV as well as valvular disease. HFrEF denotes poor pump function. • Abnormal LV systolic function: 1. CAD (acute or chronic ischemia, myocardial infarction [MI], LV aneurysm), the most common cause of cardiomyopathy in the U.S., comprising 50% to 75% of HF patients. 2. Increased afterload or pressure overload (severe hypertension, aortic stenosis) 3.  Increased preload or volume overload (mitral regurgitation, aortic regurgitation) 4.  Cardiomyopathy: Idiopathic, infiltrative (nonischemic)

5. Infectious (Chagas, myocarditis) 6.  Infiltrative (amyloidosis, sarcoidosis, hemochromatosis) 7. Toxins (ethanol, cocaine, anthracyclines) 8.  Tachycardia induced (e.g., with atrial fibrillation) • Preserved LV systolic function (Table 7): 1. Impaired relaxation (myocardial ischemia, diabetes mellitus, metabolic syndrome) 2. Tachyarrhythmia (featuring reduced diastolic filling time) 3.  Restrictive cardiomyopathy (myocardial stiffness, such as hypereosinophilic syndrome, amyloidosis, hemochromatosis)

ALG TABLE 5  Common Presenting Symptoms and Signs of Decompensated Heart Failure Symptoms

Signs

From Zipes DP: Braunwald’s heart disease, a textbook of cardiovascular medicine, ed 11, Philadelphia, 2019, Elsevier.

4. High cardiac output (thiamine deficiency, anemia, thyrotoxicosis, arteriovenous malformations) 5. Increased afterload (uncontrolled hypertension, aortic stenosis, hypertrophic obstructive cardiomyopathy) 6. Hypervolemia (oliguric renal failure, iatrogenic) RIGHT VENTRICULAR FAILURE: • Left-sided HF • Chronic hypoxemic pulmonary disease • Valvular heart disease (mitral stenosis or regurgitation) • Pulmonary embolism • Primary pulmonary hypertension • Right-to-left shunts that cause systemic hypoxemia (e.g., large patent foramen ovale and tetralogy of Fallot) • Left-to-right shunts that cause volume overload (e.g., atrial and ventricular septal defects) • Bacterial endocarditis (right-sided) • Right ventricular infarction

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • COPD, asthma • Cirrhosis • Nephrotic syndrome • Venous insufficiency • Pulmonary embolism • ARDS (adult respiratory distress syndrome) • Pneumonia • Heroin overdose WORKUP • ACC/AHAA guidelines for initial and serial evaluation of heart failure are summarized in Table 8.

• Blood work (to diagnose potentially reversible causes, identify comorbidities, and assess disease severity): 1. CBC (to evaluate for anemia, infections), urinalysis, blood urea nitrogen (BUN), creatinine, electrolytes (worsening hyponatremia is a marker of disease severity and is associated with higher mortality rates), liver enzymes (hepatic congestion), thyroid function (especially in the elderly or patients with comorbid atrial fibrillation or known thyroid disease). 2.  Fig. 2 illustrates the use of biomarkers in HF. B-type natriuretic peptide (BNP) is a cardiac neurohormone secreted from the ventricles in response to elevated LV end-diastolic pressure. While the sensitivity is low in asymptomatic patients, low BNP level has a negative predictive value up to 90% in symptomatic patients. An elevated BNP correlates with severity of disease and parallels closely morbidity and mortality outcome measures. N-terminalpro-BNP (NT-pro-BNP) is the cleavage remnant of BNP. It has a longer half-life and is renally cleared, making it susceptible to alterations in renal function. A level of 65–70 (?) years?

Yes

Consider permanent mechanical support

No

End-of-life considerations or investigational therapy

Yes

Consider permanent mechanical support

No

End-of-life considerations or investigational therapy

Yes

Consider permanent mechanical support, unlikely candidate

No

End-of-life considerations or investigational therapy

Yes

Consider heart-lung transplantation

Yes

Nutritional modification

Yes

Consider heart-lung transplantation

No Active or recent malignancy? No Diabetes with severe end-organ damage? No FEV/FVC 35–40

Consider permanent mechanical support (VAD) to weight loss

No Irreversible pulmonary hypertension?

No

End-of-life considerations or investigational therapy

No Other comorbidity present? (cirrhosis, vascular disease, addictions, hepatitis C, HIV, social or psychiatric disorders)

Yes

Individual transplant team decisions

No Determine transplant status and immunologic status

Acceptable

List for transplant

FIG. E4  Algorithm for evaluation of the potential heart transplant recipient. BMI, Body mass index; FVC, forced vital capacity; FEV, forced expiratory volume; HIV, human immunodeficiency virus; VAD, ventricular assist device. (From Zipes DP: Braunwald’s heart disease, a textbook of cardiovascular medicine, ed 11, Philadelphia, 2019, Elsevier.)

Heart Failure SUGGESTED READINGS Aurigemma GP et al: Diastolic heart failure, N Engl J Med 351:1097-1105, 2004. Chen HH et al: Low-dose dopamine or low-dose nesiritide in acute heart failure with renal dysfunction, the Rose acute heart failure randomized trial, JAMA 310(23):2533-2543, 2013. DiNicolantonio JJ et al: Retraction. Low sodium versus normal sodium diets in systolic heart failure: systematic review and meta-analysis, Heart 99(11):820, 2013. Felker GM et al: Diuretic strategies in patients with acute decompensated heart failure, N Engl J Med 364:797-805, 2011. Heart Failure Society of America et al: HFSA 2010 Comprehensive Heart Failure practice guideline, J Card Fail 16:e1-e194, 2010. John R et al: Post-cardiac transplant survival after support with a continuous-flow left ventricular assist device: impact of duration of left ventricular assist device support and other variables, J Thorac Cardiovasc Surg 140(1):174-181, 2011. McMurray JJ: Systolic heart failure, N Engl J Med 362(3):228-238, 2010. McMurray JJ et al: Angiotensin-neprilysin inhibition versus enalapril in heart failure, N Engl J Med 371:993-1004, 2014. Nativi JN et al: Changing outcomes in patients bridged to heart transplantation with continuous- versus pulsatile-flow ventricular assist devices: an analysis of the registry of the International Society for Heart and Lung Transplantation, J Heart Lung Transplant 30(8):854-861, 2011. O’Connor CM et al: Effect of nesiritide in patients with acute decompensated heart failure, N Engl J Med 365:32, 2011. Qaseem A et al: Treatment of anemia in patients with heart disease: a clinical practice guideline from the American College of Physicians, Ann Int Med 159:770-779, 2013. Redfield MM: Heart failure with preserved ejection fraction, N Engl J Med 375:1868-1877, 2016. Roger VL et al: Heart disease and stroke statistics—2012 update, a report from the American Heart Association, Circulation 125(1):188-197, 2012. Ruschitzka F et al: Cardiac resynchronization therapy in heart failure with a narrow QRS complex, N Engl J Med 369:1395-1405, 2013. Sandhu AT et al: Cost-effectiveness of sacubitril-valsartan in patients with heart failure with reduced ejection fraction, Ann Intern Med 165(10):681-689, 2016. Swedberg K et al: Treatment of anemia with darbepoetin alfa in systolic heart failure, N Engl J Med 368:1210-1219, 2013. Velazquez EJ et al: Angiotensin-neprilysin inhibition in acute decompensated heart failure, N Engl J Med 380:539-548, 2019. Yancy CW et al: 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association task force on practice guidelines, J Am Coll Cardiol 62(16):e147e239, 2013. Zannad F et al: Eplerenone in patients with systolic heart failure and mild symptoms, N Engl J Med 364:11-21, 2011.

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Heat Exhaustion and Heat Stroke BASIC INFORMATION

SYNONYMS Heat illness Hyperthermia ICD-10CM CODES T67.5 Heat exhaustion, unspecified T67.0 Heatstroke and sunstroke T67.1 Heat syncope T67.2 Heat cramp T67.3 Heat exhaustion, anhydrotic T67.6 Heat fatigue, transient

EPIDEMIOLOGY & DEMOGRAPHICS INCIDENCE (IN U.S.): Incidence of heat stroke is approximately 20 cases/100,000 population. PREDOMINANT AGE: Heat exhaustion and stroke occur more frequently in elderly patients, especially those taking diuretics or medications that impair heat dissipation (e.g., phenothiazines, anticholinergics, antihistamines, betablockers). Table 1 describes factors predisposing to serious heat illness. PHYSICAL FINDINGS & CLINICAL PRESENTATION Heat exhaustion: • Generalized malaise, weakness, headache, muscle and abdominal cramps, nausea, vomiting, hypotension, tachycardia. • Rectal temperature is usually normal. • Sweating is usually present. Heat stroke: • Neurologic manifestations (seizures, tremor, hemiplegia, coma, psychosis, other bizarre behavior) • Evidence of dehydration (poor skin turgor, sunken eyeballs) • Tachycardia, hyperventilation • Skin is hot, red, and flushed • Sweating is often (not always) absent, particularly in elderly patients

ETIOLOGY • Exogenous heat gain (increased ambient temperature) • Increased heat production (exercise, infection, hyperthyroidism, drugs) • Impaired heat dissipation (high humidity, heavy clothing, neonatal or elderly patients, drugs [phenothiazines, anticholinergics, antihistamines, butyrophenones, amphetamines, cocaine, alcohol, β-blockers]) TABLE 1  Factors Predisposing to Serious Heat Illness Individual Factors Lack of acclimatization Low physical fitness Excessive body weight Dehydration Advanced age Young age Health Conditions Inflammation and fever Viral infection Cardiovascular disease Diabetes mellitus Gastroenteritis Rash, sunburn, and previous burns to large areas of skin Seizures Thyroid storm Neuroleptic malignant syndrome Malignant hyperthermia Sickle cell trait Cystic fibrosis Spinal cord injury Drugs Anticholinergic properties (atropine) Antiepileptic (topiramate) Antihistamines Glutethimide (Doriden) Phenothiazines Tricyclic antidepressants Amphetamines, cocaine, “ecstasy” Ergogenic stimulants (e.g., ephedrine, ephedra) Lithium Diuretics β-Blockers Ethanol Environmental Factors High temperature High humidity Little air motion Lack of shade Heat wave Physical exercise Heavy clothing Air pollution (nitrogen dioxide) From Goldman L, Schafer AI: Goldman’s Cecil medicine, ed 24, Philadelphia, 2012, WB Saunders.

• Diuretics, laxatives • Fig. E1 describes an algorithm of the pathophysiology of heat stroke

H

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • Infections (meningitis, encephalitis, sepsis) • Head trauma • Epilepsy • Thyroid storm • Acute cocaine intoxication • Malignant hyperthermia • Heat exhaustion can be differentiated from heat stroke by the following: 1. Essentially intact mental function and lack of significant fever in heat exhaustion 2. Mild or absent increases in creatine phosphokinase (CPK), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), and alanine aminotransferase (ALT) in heat exhaustion WORKUP • Heat stroke: Comprehensive history, physical examination, and laboratory evaluation. • Heat exhaustion: In most cases, laboratory tests are not necessary for diagnosis. LABORATORY TESTS Laboratory abnormalities may include the following: • Elevated blood urea nitrogen (BUN), creatinine, hematocrit • Hyponatremia or hypernatremia, hyperkalemia or hypokalemia • Elevated LDH, AST, ALT, CPK, bilirubin • Lactic acidosis, respiratory alkalosis (from hyperventilation) • Myoglobinuria, hypofibrinogenemia, fibrinolysis, hypocalcemia

TREATMENT • Treatment of heat exhaustion consists primarily of placing the patient in a cool, shaded area and providing rapid hydration and salt replacement. 1. Fluid intake should be at least 2 L q4h in patients without history of CHF. 2. Salt replacement can be accomplished by using one-quarter teaspoon of salt or two 10-grain salt tablets dissolved in 1 L of water. 3. If IV fluid replacement is necessary, young athletes can be given normal saline IV (3 to 4 L over 6 to 8 hr); in elderly patients, consider using D5½NS IV with the rate titrated to cardiovascular status. • Patients with heat stroke should undergo rapid cooling. 1. Remove the patient’s clothes and place the patient in a cool and well-ventilated room. 2. If patient is unconscious, position on his or her side and clear the airway. Protect airway and augment oxygenation (e.g., nasal O2 at 4 L/min to keep oxygen saturation >90%).

Diseases and Disorders

DEFINITION Heat exhaustion and heat stroke are part of a continuum of heat-related illness, and unless factors leading to heat exhaustion are corrected swiftly, affected patients can progress to heat stroke. • Heat exhaustion: An illness resulting from prolonged, heavy activity in a hot environment with subsequent dehydration, electrolyte depletion, and rectal temperature >37.8° C (100° F) but ≤40° C (104° F). • Heat stroke: A life-threatening heat illness characterized by extreme hyperthermia (core temperature >40° C [104.0° F]), dehydration, and neurologic manifestations. Heat stroke can be further subdivided into “exertional heat stroke” occurring in generally healthy individuals undergoing strenuous physical activity in warm conditions and “non-exertional heat stroke” often seen in elderly and/or debilitated patients with impaired thermal regulations due to illness or medications (see Etiology).

• Classic heat stroke generally develops slowly over days and occurs predominantly in older persons and in those with chronic illness. Exertional heat stroke is more common in young, healthy persons, has a more rapid onset, and is associated with higher core temperatures. Table 2 compares classic and exertional heat stroke. Box 1 summarizes organ dysfunction seen in patients with heat stroke

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Heat Exhaustion and Heat Stroke TABLE 2  Comparison of Classic and Exertional Heat Stroke Patient Characteristics

Classic

Exertional

Age Health Fever Prevailing weather Activity Drug use

Young children or elderly Chronic illness Unusual Frequent in heat waves Sedentary Diuretics, ­antidepressants, ­anticholinergics, ­phenothiazines Often absent Respiratory alkalosis Uncommon Uncommon Mildly elevated Mildly elevated Uncommon Uncommon Mild Uncommon

15-55 yr Usually healthy Common Variable Strenuous exercise Ergogenic stimulants or cocaine

Sweating Acid-base disturbances Acute renal failure Rhabdomyolysis CK ALT, AST Hyperkalemia Hypocalcemia DIC Hypoglycemia

Common Lactic acidosis Common (≈15%) Common (≈25%) Markedly elevated (500-1000 U/L) Markedly elevated Common Common Marked Common

ALT, Alanine aminotransferase; AST, aspartate aminotransferase; CK, creatine kinase; DIC, disseminated intravascular coagulation. From Goldman L, Schafer AI: Goldman’s Cecil medicine, ed 24, Philadelphia, 2012, WB Saunders.

BOX 1  Organ Dysfunction Seen in Patients with Heat Stroke Encephalopathy Rhabdomyolysis Acute renal failure Acute respiratory distress syndrome Myocardial injury Hepatocellular injury Intestinal ischemia and infarction Pancreatic injury Hemorrhagic complication (e.g., disseminated intravascular coagulation) From Adams JG et al: Emergency medicine, clinical essentials, ed 2, Philadelphia, 2013, Elsevier.



3. M  onitor body temperature every 5 min. Measurement of the patient’s core temperature with a rectal probe is recommended. The goal is to reduce the body

temperature to 39° C (102.2° F) in 30 to 60 min. Advantages, disadvantages, and efficacy of various cooling methods are described in Table E3. 4. Spray the patient with a cool mist and use fans to enhance airflow over the body (rapid evaporation method). 5.  Immersion of the patient in ice water, stomach lavage with iced saline solution, intravenous administration of cooled fluids, and inhalation of cold air are advisable only when the means for rapid evaporation are not available. Immersion in tepid water (15° C, 59° F) is preferred over ice water immersion to minimize risk of shivering. 6. Use of ice packs on axillae, neck, and groin is controversial because they increase peripheral vasoconstriction and may induce shivering. 7.  Antipyretics are ineffective because the hypothalamic set point during heat

stroke is normal despite the increased body temperature. 8.  Intubate a comatose patient, insert a Foley catheter, and start nasal O2. Continuous ECG monitoring is recommended. 9. Insert at least two large-bore IV lines and begin IV hydration with normal saline (NS) or Ringer lactate. 10. Draw initial laboratory studies: Electrolytes, complete blood count, blood urea nitrogen, creatinine, AST, ALT, CPK, LDH, glucose, PT (INR), PTT, platelet count, Ca2+, lactic acid, and arterial blood gases. 11. Treat complications as follows: a. Hypotension: Vigorous hydration with normal saline or Ringer lactate b. Convulsions: Diazepam 5 to 10 mg IV (slowly) c. Shivering: Chlorpromazine 10 to 50 mg IV d. Acidosis: Use bicarbonate judiciously (only in severe acidosis) • Observe for evidence of rhabdomyolysis and hepatic, renal, or cardiac failure and treat accordingly.

DISPOSITION Most patients recover completely within 48 hr. Central nervous system injury is permanent in 20% of cases. Mortality rate can exceed 30% in patients with prolonged and severe hyperthermia. Delayed access to cooling is the leading cause of morbidity and mortality in persons with heat stroke. SUGGESTED READINGS Available at ExpertConsult.com RELATED CONTENT Heat Exhaustion and Heat Stroke (Patient Information) Acute Kidney Injury (Related Key Topic) Rhabdomyolysis (Related Key Topic) AUTHOR: Fred F. Ferri, MD

Heat Exhaustion and Heat Stroke

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SUGGESTED READINGS Becker J, Stewart LK: Heat-related illness, Am Fam Physician 83(11):1325-1330, 2011. Centers for Disease Control and Prevention: Heat illness among high school athletes, U.S. 2005–2009, MMWR Morb Mort Wkly Rep 59(32), 2010.

Exertion or heat exposure

Heat stress

Thermoregulatory response

Cutaneous vasodilation

Splanchnic vasoconstriction

Sweating

Intestinal ischemia

Dehydration

↑ Intestinal wall permeability

Renal failure

Endotoxemia

Cytotoxic and inflammatory response

Heat shock protein production

↑ Vascular permeability

Coagulation cascade

Heat stroke and circulatory shock

FIG. E1  Algorithm of the pathophysiology of heat stroke. (From Adams JG et al: Emergency medicine, clinical essentials, ed 2, Philadelphia, 2013, Elsevier.)

TABLE E3  Advantages, Disadvantages, and Efficacy of Various Cooling Methods Cooling Method

Advantages

Antipyretics

Disadvantages

Effectiveness

Can worsen liver or renal injury

Not effective (the temperature set-point is not elevated in hyperthermia) Not effective in controlling pathologic inflammation Comparison studies show the cooling rate on average to be slower than immersion Published rate range: 0.05-0.31° C/min (32.0932.56° F/min) Comparison studies show the cooling rate on average to be faster than evaporation Published rate range: 0.04-0.35° C/min (32.0732.63° F/min) Slower cooling but appropriate for mildly ill patients, such as those with heat exhaustion

Evaporative ­cooling

Noninvasive, easy to ­monitor, readily available

Labor-intensive—requires constant moistening of skin

Immersion

Noninvasive, rapid

Cumbersome, poorly tolerated, safety questionable if comorbid conditions present, monitoring difficult, ­shivering and vasoconstriction

Immersion of the hands and ­forearms Ice packing

Noninvasive, easy to ­perform in the field

Shivering and vasoconstriction

Noninvasive, readily ­available

Shivering and vasoconstriction, poorly tolerated

Cold gastric or ­peritoneal lavage Dantrolene

Very rapid

Invasive, cumbersome (cold sterile saline needed for peritoneal lavage)

Benzodiazepines

In theory, decreases heat production by inhibiting muscle contraction Treatment of shivering to decrease heat production and heat-induced seizures

Sedation

From Adams JG et al: Emergency medicine, clinical essentials, ed 2, Philadelphia, 2013, Elsevier.

Less effective than immersion or evaporation Some authorities recommend using both evaporation and ice In canine studies, questionably faster than evaporation or immersion No clear efficacy; it may be more effective for exertional than for classic heat stroke Whether treatment increases cooling is unknown but may make cooling treatments tolerable Also effective for heat-related seizures

Heavy Menstrual Bleeding (Menorrhagia) BASIC INFORMATION

SYNONYMS Menometrorrhagia Dysfunctional uterine bleeding Irregular menstrual cycle ICD-10CM CODES N92.0 Excessive and frequent menstruation with regular cycle N92.1 Excessive and frequent menstruation with irregular cycle N92.2 Excessive menstruation at puberty N92.4 Excessive bleeding in the premenopausal period N92.6 Irregular menstruation, unspecified

EPIDEMIOLOGY & DEMOGRAPHICS INCIDENCE: 10% to 15% of reproductive-aged women; 30% of outpatient office visits; 70% of all gynecologic consults PEAK INCIDENCE: Reproductive-aged women, ages 13 to 50 PREVALENCE: 9% to 14% of all women PREDOMINANT SEX AND AGE: Female; peak in adolescence and perimenopausal periods GENETICS: Hereditary coagulopathy (most commonly von Willebrand disease, platelet dysfunction disorders) in 20% of women with heavy menstrual bleeding RISK FACTORS: Genetic predisposition, anticoagulation treatment, obesity, endocrinopathies, autoimmune disease, liver disease, renal d­ isease PHYSICAL FINDINGS & CLINICAL PRESENTATION • History: Age, age at menarche or menopause, menstrual bleeding patterns, severity of bleeding, pain, underlying medical conditions, surgical history, medications, family history, hirsutism, acne, symptoms of thyroid dysfunction or other endocrinopathy 1. If heavy bleeding since menarche, screen for signs and symptoms of hemostatic disorder, including postpartum hemorrhage, surgery-related bleeding, bleeding from dental work, easy bruising, epistaxis, and frequent gum bleeding

ETIOLOGY • Pregnancy/miscarriage • Endometrial polyps • Adenomyosis • Uterine leiomyoma • Endometrial hyperplasia or carcinoma • Coagulopathy, inherited or acquired • Ovulatory dysfunction, most likely PCOS • Endometrial • Arteriovenous malformation • Infection • Iatrogenic

DIAGNOSIS DIFFERENTIAL DIAGNOSIS Pregnancy, sexually transmitted infection, polycystic ovary syndrome (PCOS), thyroid dysfunction, anovulation due to immature hypothalamicpituitary-ovarian axis or perimenopausal transition, uterine pathology including endometrial hyperplasia or carcinoma, leiomyoma, adenomyosis, or endometrial polyp, coagulopathy, iatrogenic due to medications including oral contraceptives or anticoagulants (warfarin), nonuterine bleeding (urinary, gastrointestinal, vaginal, or cervical source) WORKUP • History • Physical exam • Laboratory, pathology, and imaging studies to determine etiology LABORATORY TESTS • Pregnancy test • Complete blood count (CBC) • Thyroid-stimulating hormone (TSH) • Chlamydia trachomatis testing if high risk • Pap smear if indicated • Targeted screening for bleeding disorders • Endometrial sampling by endometrial biopsy or hysteroscopic sampling for women >45 yr or 80 ml per cycle). Bleeding may also be prolonged, intermenstrual, frequent, and irregular. This language replaces prior terms such as metrorrhagia, polymenorrhea, or oligomenorrhea. PALM-COEIN classification of abnormal uterine bleeding was adopted in 2011 to standardize terminology and reflect etiology: Polyp, adenomyosis, leiomyoma, malignancy and hyperplasia, coagulopathy, ovulatory dysfunction, endometrial, iatrogenic, and not yet classified. AUB-P would refer to abnormal uterine bleeding due to polyps.

• Physical exam: Weight, hirsutism, acne, thyroid nodules, signs of insulin resistance (acanthosis nigricans), signs of bleeding disorder (petechiae, ecchymoses, pallor, swollen joints), pelvic examination including external, speculum, and bimanual exam of uterus

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Heavy Menstrual Bleeding (Menorrhagia) SUGGESTED READINGS Bradley LD, Gueye NA: The medical management of abnormal uterine bleeding in reproductive aged women, Am J Obstet Gynecol 214(1):31-44, 2016. Committee on Practice Bulletins-Gynecology: Practice bulletin no. 128: diagnosis of abnormal uterine bleeding in reproductive-aged women, Obstet Gynecol 120:197-206, 2012. Committee on Practice Bulletins-Gynecology: Practice bulletin no. 136: management of abnormal uterine bleeding associated with ovulatory dysfunction, Obstet Gynecol 122:176-185, 2013.

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Helicobacter pylori Infection BASIC INFORMATION DEFINITION Infection of the human gastric mucosa with the organism Helicobacter pylori, a spiral-shaped gram-negative organism with unique features that allow it to survive in the hostile gastric environment. SYNONYM Previously known as Campylobacter pylori ICD-10CM CODE B96.81 Helicobacter pylori [H. pylori] as the cause of diseases classified elsewhere

EPIDEMIOLOGY & DEMOGRAPHICS H. pylori is the most common chronic bacterial infection in human beings, probably affecting 50% of the Earth’s population in all age groups as well as 30% to 40% of the U.S. population. In developing nations, infection is acquired at an earlier age and occurs more frequently. CLINICAL PRESENTATION • H. pylori causes histologic gastritis in all affected individuals. The majority of cases are asymptomatic and unlikely to proceed to serious consequences. • H. pylori is a causative agent in peptic ulcer disease (PUD), gastric adenocarcinoma, and gastric mucosa-associated lymphoid tissue lymphoma, as well as a risk factor for iron-deficiency anemia and likely chronic idiopathic thrombocytopenic purpura. It may present with the signs and symptoms of these disorders, including abdominal pain, bloating, anorexia, and early satiety. Fig. 1

describes association of H. pylori infection and disease states. • “Alarm symptoms” that should prompt more immediate and aggressive workup include weight loss, dysphagia, protracted nausea or vomiting, anemia, melena, and palpable abdominal mass, particularly in older individuals.

ETIOLOGY • Route of acquisition is unknown but is presumed to be person to person by fecal-oral or possibly oral-oral transmission. • The majority of cases are acquired in childhood. Socioeconomic status and living conditions in childhood affect risk of acquisition of infection. These factors include housing density, number of siblings, overcrowding, sharing a bed, and lack of running water. • Iatrogenic transmission has been documented. • H. pylori does not invade gastroduodenal tissue, but disrupts the mucous layer, causing the underlying mucosa to be more vulnerable to acid peptic damage. • It is unclear what differentiates the subset of patients with H. pylori who go on to develop ulcers or cancer.

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • Infection with H. pylori should be considered in the face of PUD, gastric cancer, gastritis, and gastric mucosa-associated lymphoid tissue (MALT) lymphoma. • H. pylori should be considered in the differential diagnosis of upper gastrointestinal (GI) tract disease, along with nonulcer dyspepsia, Colonization with

Tissue response (inflammation)

Primary phenomenon:

Secondary phenomenon:

Clinical outcome:

Atrophic gastritis

Noncardia gastric adenocarcinoma

Hyperacidity

Duodenal ulceration

Antigenic stimulation

?

B-cell lymphoma

Reflux esophagitis and sequelae

6 to 20

0.2 to 0.7

Association with (odds ratio):

2 to 8

3 to 6

FIG. 1  Association of Helicobacter pylori colonization and disease states. After H. pylori acquisition, virtually all persons develop persistent colonization that lasts for life. Colonization induces tissue responses termed chronic gastritis. This process affects gastric physiology, including glandular structure, acid secretion, and antigen processing, which in turn affect disease risk. Colonization with H. pylori increases the risk for certain diseases (duodenal ulcer, gastric ulcer, noncardiac gastric adenocarcinoma, and B-cell lymphomas) but appears to decrease the risk for gastroesophageal reflux disease and its complications, including Barrett esophagus, and adenocarcinoma of the esophagus or gastric cardia. (From Mandell GL et al: Principles and practice of infectious diseases, ed 7, Philadelphia, 2010, Churchill Livingstone.)

reflux esophagitis, biliary tract disease, gastroparesis, pancreatitis, ischemic bowel, and unexplained iron deficiency anemia.

WORKUP • Workup is indicated in patients with active PUD, a past history of documented peptic ulcer, or gastric MALT lymphoma, as well as those with immune thrombocytopenic purpura (ITP), and otherwise unexplained iron deficiency. The role of routine screening in high-risk populations is not clear. However, numerous studies suggest that H. pylori eradication is protective against progression of premalignant gastric lesions. Consider testing those starting long-term NSAID, low-dose aspirin, or proton pump inhibitor (PPI) therapy. Routine identification and treatment of H. pylori in cases of n­ onulcer dyspepsia, gastroesophageal reflux disease (GERD), and in asymptomatic individuals in populations at high risk for gastric cancer is considered controversial. There is insufficient evidence to advocate screening in asymptomatic first-degree relatives of gastric cancer patients. A test-and-treat strategy may be used in patients younger than 55 with uncomplicated dyspepsia who have no alarm symptoms. • Results of testing must be interpreted in relation to the individual patient’s likelihood of H. pylori infection based on demographic risk factors. In the U.S. population, increased probability of infection exists in African Americans, Hispanics/Latinos, immigrants from developing nations, patients with poor socioeconomic status, Native Americans from Alaska, and persons >50 yr. • Routine screening for H. pylori is not indicated in asymptomatic patients who are at low risk of infection. • Infected patients with functional dyspepsia often benefit from treatment and should be evaluated for H. pylori. LABORATORY TESTS • Testing may be invasive or noninvasive depending on the need for endoscopy for other indications. There is no indication for endoscopy solely to diagnose H. pylori. • Tests for H. pylori are differentiated as active or passive. Active tests provide direct evidence that H. pylori infection is currently present and include urea breath testing and stool antigen testing. Passive testing, which includes all serologic testing for H. pylori, detects the presence of antibodies to the organism. It is limited by its inability to distinguish between active current infection and prior infection that has resolved. • Tests that use urease as a marker (urea breath and stool antigen tests and biopsy for urease activity) may result in false-negative results in patients taking antibiotics, bismuth, or antisecretory therapy, as well as those with active ulcer bleeding. Patients should be off antibiotics for 4 wk and off protein pump inhibitors for 2 wk before urea breath or stool antigen testing.

Helicobacter pylori Infection

TREATMENT ACUTE GENERAL Rx • Test only patients whom you intend to treat if positive (see “Workup”). At this time, the value of eradicating H. pylori infection has been clearly demonstrated in patients with PUD or gastric MALT lymphoma. • The optimal antibiotic regimen remains undefined. In addition to efficacy, side effects, cost, and ease of administration must be considered. • Due to increasing resistance to clarithromycin, decisions regarding appropriate regimens should take into account local rates of clarithromycin resistance, as well as any prior macrolide exposure for the patient. Clarithromycin resistance can be assumed to be >15% in the U.S., unless local resistance information is available. • The following regimens may be considered for first-line therapy: 1. Quadruple therapy: PPI (esomeprazole 20 mg, lansoprazole 30 mg, pantoprazole 40 mg, omeprazole 40 mg, or rabeprazole 20 mg, all given bid), with twice-daily clarithromycin (500 mg) amoxicillin (1 g bid), and metronidazole 500 mg bid for 10 to 14 days. 2. Bismuth quadruple therapy: PPI twice daily (see earlier) combined with bismuth

subsalicylate (Pepto-Bismol and others) 262 or 525 mg four times daily, as well as tetracycline (500 mg qid) and metronidazole (250 mg qid or 500 mg tid-qid) for 10 to 14 days. This is now recommended as first-line therapy in areas of high clarithromycin resistance and in patients with penicillin allergy. • Current guidelines recommend extended treatment of 10 to 14 days. Use of combination capsules may improve compliance but is likely to be more expensive. • Recent guidelines suggest multiple other regimens that can be considered based on local resistance patterns and patient’s allergy profile. • Prior exposure to a macrolide or metronidazole, for any reason, is associated with increased resistance. A preferable regimen would include medications to which the patient has not been previously exposed. • Diarrhea and abdominal cramping are commonly observed with many of the regimens. (Probiotics may diminish this effect.) Other side effects may include a metallic taste with metronidazole or clarithromycin, neuropathy, seizures, and disulfiram-like reaction with metronidazole, diarrhea with amoxicillin, photosensitivity with tetracycline, and Clostridium difficile infection with any antibiotic exposure. Bismuth may cause black stool and constipation. Tetracycline is contraindicated in pregnant patients. • 20% of patients may not respond to initial therapy. It is important to reinforce compliance. Second-line therapy should avoid antibiotics used in initial treatment and should include either bismuth-containing quadruple therapy or levofloxacin-containing triple therapy (regardless of local clarithromycin resistance patterns). When possible, management of those who do not respond to two courses of therapy should be guided by antimicrobial sensitivity testing (endoscopy with biopsy for cultures and sensitivity).

CHRONIC Rx • It is essential to document clearance of infection after the completion of treatment. Repeat testing is generally performed 1 mo after completion of antibiotics and at least 2 wk after cessation of PPI therapy. • Active tests such as urea breath test and stool antigen testing should be used. They are equally accurate in confirming eradication, and either may be used depending on availability and patient preference.

• Serology does not reliably revert to undetectable levels after treatment and should not be used to determine eradication.

H

DISPOSITION Consider further evaluation in patients with recurrent symptoms after appropriate treatment. REFERRAL • Patients with gastric MALT lymphoma should be followed by a gastroenterologist and oncologist with expertise in the care of lymphoid neoplasms. • Patients with dyspepsia who have tested positive for H. pylori and failed two courses of treatment should be referred for endoscopy and biopsy for culture and sensitivity.

PEARLS & CONSIDERATIONS • It remains unclear whether H. pylori eradication reduces the risk of progression to gastric cancer. • Outcomes in PUD and gastric MALT lymphoma are improved with treatment of associated H. pylori infection. • Tests that provide direct evidence of active H. pylori infection (urea breath and stool antigen testing) are preferred. These may result in false-negative results in patients taking antibiotics, bismuth, or antisecretory agents, which should be stopped at an appropriate time interval before testing. • Serologic testing does not differentiate active from prior infection. If performed, positive results should be confirmed with active testing. • Be aware of high-risk populations in lowprevalence settings, including immigrants from Mexico, South America, Southeast Asia, and Eastern Europe.

SUGGESTED READINGS Available at ExpertConsult.com RELATED CONTENT Helicobacter pylori Infection (Patient Information) Gastritis (Related Key Topic) Peptic Ulcer Disease (Related Key Topic) AUTHOR: Margaret Tryforos, MD

Diseases and Disorders

• When diagnostic endoscopy is indicated (for suspicion or follow-up of PUD or gastric MALT), antral biopsy should be tested for urease activity. If urease testing is likely to show a false-negative result because of recent proton pump inhibitor (PPI), bismuth, or antibiotic use or active ulcer bleeding, the sample should undergo histologic examination. • In cases in which biopsy is not indicated, urea breath testing or stool antigen testing is indicated to evaluate for active infection. Urea breath testing is slightly more expensive than stool antigen testing, but both costs are in the modest range. Choice can be made based on patient preference and availability. The sensitivities and specificities of these two tests are similar (>90%), but sensitivity may be reduced in the face of active upper GI bleed or recent PPI use. • Serologic testing should be avoided, although it may be useful in low-risk patients in areas with low prevalence to confirm lack of infection. In this situation, positive results should be confirmed with an active testing method.

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Helicobacter pylori Infection SUGGESTED READINGS Chey WD et al: ACG Clinical Guideline: treatment of Helicobacter pylori infection, Am J Gastroenterol 112(2):212-239, 2017. Crowe SE: Helicobacter pylori infection, N Engl J Med 380(12):1158-1165, 2019. Malfertheiner P et al: For the European Helicobacter Study Group. Management of Helicobacter pylori infection—the Maastricht IV/Florence consensus report, Gut 61(5):646-664, 2012. McColl KEL: Helicobacter pylori infection, N Engl J Med 362:1597-1604, 2010.

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HELLP Syndrome 

ALG

BASIC INFORMATION DEFINITION The HELLP syndrome is a serious variant of preeclampsia. HELLP is an acronym for hemolysis, elevated liver enzymes, and low platelet count. It is the most frequently encountered microangiopathy of pregnancy. Two classification systems exist (Mississippi Classification and Tennessee Classification); degree of maternal thrombocytopenia is a primary indicator of disease severity: Tennessee

Class 1:

Class 2:

Class 3:

Mississippi

Platelets Platelets 70 IU/L IU/L Platelets >50,000/ mm3 to 70 IU/L Platelets >100,000/ mm3 to 1290, and platelets 35 yr, white, multiparity, heritable genetics RECURRENCE RATE: 3% to 25%

PHYSICAL FINDINGS & CLINICAL PRESENTATION • Definitive laboratory criteria remain to be validated prospectively. • Most commonly used criteria include hemolysis defined by the presence of an abnormal peripheral smear with schistocytes, lactate dehydrogenase (LDH) >600 U/L, and total bilirubin >1.2 mg/dl; elevated liver enzymes (serum aspartate aminotransferase (AST) >70 U/L); low platelet count as less than 100,000/ml. • Although many women with HELLP syndrome are asymptomatic, 80% report right upper quadrant pain, and 50% to 60% present with excessive weight gain and worsening edema. ETIOLOGY As with other microangiopathies, endothelial dysfunction, with resultant activation of the intravascular coagulation cascade, has been proposed as the central pathogenesis of HELLP syndrome.

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • Acute fatty liver of pregnancy • Thrombotic thrombocytopenic purpura/ hemolytic-uremic syndrome • Appendicitis • Gallbladder disease • Peptic ulcer disease • Enteritis • Hepatitis • Pyelonephritis • Systemic lupus erythematosus • Box E1 summarizes medical and surgical disorders often confused with HELLP syndrome WORKUP Because HELLP syndrome is a disease entity based on laboratory values, initial assessment is detailed below. LABORATORY TESTS • Initial assessment of suspected HELLP syndrome should include a complete blood count to evaluate platelets, urinalysis, serum creatinine, LDH, uric acid, indirect and total bilirubin levels, and AST/alanine aminotransferase (ALT). • Tests of prothrombin time, partial thromboplastin time, fibrinogen, and fibrin split products are reserved for women with a platelet count well below 100,000/mm3.

IMAGING STUDIES Imaging should be considered in the setting of severe abdominal pain and transaminitis to evaluate for hepatic hematoma and rupture.

TREATMENT Treatment depends on gestational age of the fetus, severity of condition, and maternal status. Stabilization of the mother is the first priority. Fig. E1 describes an algorithm for the management of HELLP syndrome.

ACUTE GENERAL Rx • Assess gestational age thoroughly. Fetal status should be monitored with nonstress tests, contraction stress tests, and/or biophysical profile. • Maternal status should be evaluated by history, physical examination, and laboratory testing. • Magnesium sulfate is administered for seizure prophylaxis regardless of blood pressure. • Blood pressure control is achieved with agents such as hydralazine or labetalol. • Indwelling Foley catheter to monitor maternal volume status and urine output. • Eculizumab has also been proposed as a possible therapy in case reports. CHRONIC Rx • In pregnancies of 34 wk or with class 1 HELLP syndrome, delivery, either vaginal or abdominal, within 48 hr is the goal. • In the preterm fetus, corticosteroid therapy to enhance fetal lung maturation is indicated. • Some reports have shown temporary amelioration of HELLP severity with the administration of high-dose steroids measured by increased urine output, improvement in platelet count, and liver function test. A 2015 meta-analysis of multiple studies BOX E1  Medical and Surgical Disorders Often Confused with HELLP Syndrome • • • • • • • • • • •

 cute fatty liver of pregnancy A Appendicitis Gallbladder disease Glomerulonephritis Hemolytic uremic syndrome Hepatic encephalopathy Hyperemesis gravidarum Idiopathic thrombocytopenia Pyelonephritis Systemic lupus erythematosus Antiphospholipid antibody syndrome • Thrombotic thrombocytopenic purpura • Viral hepatitis • HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome From Gabbe SG: Obstetrics, ed 6, Philadelphia, 2012, WB Saunders.

HELLP Syndrome ALG

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• Refer to tertiary care facility (less than 35 wk) • Admit to labor and delivery area • IV magnesium sulfate • Antihypertensives if systolic blood pressure is at least 160 mm Hg and diastolic blood pressure is at least 105 mm Hg

• Less than 24 wk or limits of viability • Greater than or equal to 34 wk • Fetal distress • Maternal distress: Eclampsia Disseminated intravascular coagulopathy Renal failure Abruptio placentae Respiratory distress Suspect liver hematoma

Ye s

Delivery

No 24 to 34 wk

• Complete steroid course • 24 to 48 hours latency

FIG. E1  An algorithm for the management of HELLP syndrome. IV, intravenous. (From Gabbe SG: Obstetrics, ed 6, Philadelphia, 2012, WB Saunders.)

suggested improvement in lab parameters and decreased length of ICU stay with steroid administration. However, there was not better maternal mortality and morbidity. • Judicious use of blood products, especially in those requiring surgery. • The patient requires intensive observation. Laboratory levels may worsen immediately postpartum but should begin to improve within 48 hr.

DISPOSITION The natural history of this disorder is a rapidly deteriorating condition requiring close monitoring of maternal and fetal well-being.

REFERRAL Preterm patients with HELLP syndrome should be stabilized hemodynamically and transferred to a tertiary care center. Term patients can be treated at a local hospital depending on the availability of obstetric, neonatal, and blood banking services.

 EARLS & P CONSIDERATIONS • Not all women with HELLP have hypertension or proteinuria.

SUGGESTED READINGS Aloizos S et al: HELLP syndrome: understanding and management of a pregnancy-specific disease, J Obstet Gynaecol 33(4):331-337, 2013. del-Rio-Vellosillo M, Garcia-Medina JJ: Anesthetic considerations in HELLP syndrome, Acta Anaesthesiol Scand 60:144-157, 2016. PMID 2644688. Woudstra DM et al: Corticosteroids for HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome in pregnancy, Cochrane Database Syst Rev 9:CD008148, 2010.

• Life-threatening hemorrhage is a rare event in HELLP syndrome. Identifiable risk factors predictive of a major hemorrhage are thrombocytopenia (70 IU/L, and previous gestations. • The most effective therapy for HELLP is emergent delivery of the fetus.

RELATED CONTENT Eclampsia (Related Key Topic) Preeclampsia (Related Key Topic) AUTHORS: Robert Matera, MD, and John L. Reagan, MD

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Hemochromatosis 

ALG

BASIC INFORMATION DEFINITION Hemochromatosis is an autosomal-recessive disorder that disrupts the body’s regulation of iron and is characterized by increased accumulation of iron in various organs (adrenals, liver, pancreas, heart, testes, kidneys, pituitary) and eventual dysfunction of these organs if not treated appropriately. SYNONYMS Bronze diabetes Hereditary hemochromatosis HH ICD-10CM CODES E83.110 Hereditary hemochromatosis E83.111 Hemochromatosis due to repeated red blood cell transfusions E83.118 Other hemochromatosis E83.119 Hemochromatosis, unspecified

EPIDEMIOLOGY & DEMOGRAPHICS INCIDENCE: In whites, approximately 1 in 385 persons PREDOMINANT SEX AND AGE: Generally diagnosed in males in their fifth decade. Diagnosis in females is generally not made until 10 to 20 yr after menopause. GENETICS: Most common genetic disorder in North European ancestry. Homozygosity for the C282Y mutation is now found in approximately 5 of every 1000 persons of European descent. PHYSICAL FINDINGS & CLINICAL PRESENTATION • In earlier stages patients completely asymptomatic and diagnosed due to abnormal laboratory tests • Hepatic dysfunction leading to hepatomegaly, fibrosis, and eventually cirrhosis • Noninflammatory arthropathy (Fig. E1) • Gonadal insufficiency leading to loss of libido and testicular atrophy • Diabetes mellitus: Risk greater in patients with family history • Iron-induced cardiac disease resulting in cardiomyopathy, heart failure, and arrhythmias • Skin pigmentation ETIOLOGY • The majority of the patients diagnosed with hemochromatosis have mutation in the HFE gene and are either homozygous for the C282Y mutation (C282Y/C282Y) or compound heterozygote for the C282Y mutation and either the mutation H63D (C282Y/H63D) or less commonly the S65C (C282Y/S65C). • The remainder of the patients are classified as non–HFE-associated hemochromatosis.

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • Hereditary anemias with defect erythropoiesis

of

• Cirrhosis, chronic liver disease, porphyria cutanea tarda • Repeated blood transfusions • Table 1 summarizes hereditary causes of iron overload

WORKUP Medical history, physical examination, and laboratory evaluation should be focused on affected organ systems (see “Physical Findings & Clinical Presentation”). Fig. E2 outlines evaluation for possible hereditary hemochromatosis in an individual with negative family history. Liver biopsy is the gold standard for diagnosis; it reveals iron deposition in hepatocytes, bile ducts, and supporting tissues. LABORATORY TESTS • Transferrin saturation is the best screening test. Values >45% are an indication for further testing. • Elevated serum ferritin is good evidence of iron overload, but other causes like chronic inflammatory conditions, malignancy, and so forth need to be ruled out as ferritin is also an acute phase reactant. • Genotypical screening for C282Y and H63D mutation in HFE gene should be done in patients with high transferrin saturation, elevated ferritin, or both. • Liver biopsy (Fig. E3) is the gold standard but is not needed in somebody who has a persistently elevated transferrin saturation, elevated ferritin, or both. • Hepatic iron index can help differentiate between various causes of iron overload. • Elevated aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase are seen. • Hyperglycemia is found. • Endocrine abnormalities (decreased testosterone, luteinizing hormone, follicle-stimulating hormone) are noted. • Table 2 describes laboratory findings in patients with hereditary hemochromatosis. IMAGING STUDIES Routine radiologic imaging is not needed. MRI (Fig. E4) may show low signal intensity in the liver and can be used to estimate hepatic iron concentration.

TREATMENT The goal of therapy is the removal of excess iron and maintaining it at a normal or near-normal level. Phlebotomy is first line treatment. The goal is to reduce serum ferritin to 50 to 100 mg/ ml. Box E1 summarizes the treatment of HFErelated hereditary hemochromatosis.

NONPHARMACOLOGIC THERAPY Phlebotomy is the treatment of choice. ACUTE GENERAL Rx • The timing and frequency of phlebotomy needs to be individualized for each patient. • For patients with heavy iron overload, twiceweekly phlebotomies should be started. In most patients, weekly phlebotomy is adequate.

• The effectiveness of treatment is monitored by periodic ferritin measurement. The goal is to bring ferritin level below 50 ng/ml. • Patients with iron overload due to transfusion-dependent anemias may not tolerate phlebotomy. For these patients, iron chelation may be needed. • The chelating agent deferoxamine has to be given daily as a 9- to 12-hr IV or SC infusion, and compliance is difficult. • The oral chelating agent deferasirox (Exjade) is effective, but should not be used in patients with high-risk myelodysplastic syndrome because it can cause renal impairment, hepatic impairment, or gastrointestinal hemorrhage, which can be fatal.

CHRONIC Rx After the ferritin has been brought to less than 50 ng/ml, phlebotomy is needed on an asneeded basis to keep the ferritin at that level. DISPOSITION • Serum ferritin measurement is the most useful prognostic indicator of disease severity. • Prognosis is good if phlebotomy is started early (before onset of cirrhosis or diabetes mellitus); women can have the full phenotypic expression of the disease, including cirrhosis, and should also be aggressively treated. REFERRAL For liver biopsy if diagnosis is uncertain

PEARLS & CONSIDERATIONS COMMENTS • Persons who are homozygous for the HFE gene mutation C282Y comprise 85% to 90% of phenotypically affected individuals. Patients who are heterozygous for both C282Y and H63D generally do not have clinically evident disease unless coexisting factors (e.g., excessive alcohol intake) are present. • Patients with hemochromatosis and serum ferritin levels 45%

Later increase after third decade of life Later increase after third decade of life Increased by second decade of life Increased by second decade of life Normal to moderately elevated Increased

Hereditary hemochromatosis, TFR2-associated (type 3; OMIM604250)

TFR2, 7q22

Autosomal recessive

Early increase; >45%

Juvenile hemochromatosis, hemojuvelin-associated (type 2A; OMIM 602390) Juvenile hemochromatosis, hepcidinassociated (type 2B; OMIM613313) Hemochromatosis, DMT1associated (OMIM 206100) Atransferrinemia (OMIM 209300)

HJV, 1q21

Autosomal recessive

Early increase; >45%

HAMP, 19q13

Autosomal recessive

Early increase; >45%

SCL11A2, 12q13

Autosomal recessive Autosomal recessive

Early increase; >45% No plasma transferrin

Aceruloplasminemia (OMIM 604290)

CP, 3q24-q25

Decreased

Increased

Hemochromatosis, ferroportin-associated, with impaired iron export (type 4A; OMIM606069) Hemochromatosis, ferroportin-associated, with hepcidin resistance (type 4B; OMIM606069)

SLC40A1, 2q32

Autosomal recessive Autosomal dominant

Remains normal or low

Early increase

SLC40A1, 2q32

Autosomal dominant

Early increase; >45%

Early increase

Iron Deposition Sites Parenchymal iron overload affecting hepatocytes, heart, pancreas, other organs Parenchymal iron overload affecting hepatocytes, heart, pancreas, other organs Parenchymal iron overload affecting hepatocytes, heart, pancreas, other organs Parenchymal iron overload affecting hepatocytes, heart, pancreas, other organs Hepatic iron overload, predominantly in hepatocytes

Clinical Manifestations Liver and heart disease, diabetes, gonadal failure, arthritis, skin pigmentation Liver and heart disease, diabetes, gonadal failure, arthritis, skin pigmentation As for hereditary hemochromatosis, but liver involvement less prominent As for hereditary hemochromatosis, but liver involvement less prominent Severe microcytic anemia, liver dysfunction

Parenchymal iron overload affecting hepatocytes, heart, pancreas; no iron stores in bone marrow or spleen Marked iron accumulation in basal ganglia, liver, pancreas Predominantly macrophage iron deposition

Transfusion-dependent iron-deficiency anemia, growth retardation, poor survival Diabetes, progressive neurologic disease, retinal degeneration None

Parenchymal iron overload affecting hepatocytes, heart, pancreas, other organs

Similar to HFEassociated hemochromatosis

From Hoffman R et al: Hematology: basic principles and practice, ed 7, Philadelphia, 2018, Elsevier.

TABLE 2  Laboratory Findings in Patients with Hereditary Hemochromatosis Measurements Blood (Fasting) Serum iron level (μg/dl) Serum transferrin level (mg/dl) Transferrin saturation (%) Serum ferritin level (ng/ml) Men Women Genetic (HFE Mutation Analysis) C282Y/C282Y C282Y/H63D* Liver Hepatic iron concentration μg/g dry weight μmol/g dry weight Hepatic iron index† Liver histology Perls Prussian blue stain

Patients with Hereditary Hemochromatosis

Normal Subjects

Asymptomatic

Symptomatic

60-180 220-410 20-45

150-280 200-280 45-100

180-300 200-300 80-100

20-200 15-150

150-1000 120-1000

500-6000 500-6000

wt/wt‡ wt/wt

C282Y/C282Y C282Y/H63D

C282Y/C282Y C282Y/H63D

300-1500 5-27 1.9

8000-30,000 140-550 >1.9

0, 1+

2+ to 4+

3+, 4+

*Compound heterozygote. †Calculated by dividing the hepatic iron concentration (in μmol/g dry weight) by the age of the patient (in yr). With the increased use of genetic testing in patients with iron overload, the specificity of the hepatic iron index has diminished. ‡wt/wt: wild type (normal). From Goldman L, Schafer AI: Goldman’s Cecil medicine, ed 24, Philadelphia, 2012, Saunders.

• In patients who are heterozygous for C282Y or H63D mutation, clinically meaningful iron overload does not develop. • Screening for hepatocellular carcinoma is reserved for those with hereditary hemochromatosis and cirrhosis.

SUGGESTED READINGS Available at ExpertConsult.com RELATED CONTENT Hemochromatosis (Patient Information) AUTHOR: Fred F. Ferri, MD

Diseases and Disorders

Hereditary hemochromatosis, HFE-associated (type 1; OMIM235200)

TF, 3q22

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Hemochromatosis

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SUGGESTED READINGS Bacon BR et  al: Diagnosis and management of hemochromatosis: 2011 practice guideline by the American Association for the Study of Liver Diseases, Hepatology 54(1):328-343, 2011. Crownover BK, Covey CJ: Hereditary hemochromatosis, Am Fam Physician 87(3):183-190, 2013.

A

B

FIG. E1  The iron fist sign in hereditary hemochromatosis (HH) arthropathy. (A) A normal hand. (B) Hand in a patient with HH arthropathy. The poor flexion in the index and middle fingers in HH arthropathy is caused by a lack of flexion in the “damaged” metacarpophalangeal 2,3 joints. (From Hochberg MC: Rheumatology, ed 7, Philadelphia, 2019, Elsevier.)

Transferrin saturation Normal (2.0 almost always shows functional assay positivity (89% to 100%). A higher OD is also associated with a higher pretest probability score and increased risk of thrombosis. Of note, the HIT antibody IgG subtype is the pathologic antibody for HIT, and thus the use of IgG-specific ELISA kits increases the test specificity over the polyspecific (IgA/M/G) antibody. In general, patients with low pretest probability via the 4T clinical prediction score should not have HIT antibody testing performed because it has a more than 99% negative predictive value, while all patients with intermediate and high pretest probability of HIT benefit from HIT antibody testing. The gold standard test for HIT is to measure heparin-dependent platelet activation via the functional serotonin release assay (14C-SRA). This is both a highly sensitive and specific test. Donor platelets are radiolabeled with serotonin and then incubated with patient serum and heparin. If antibodies to the platelet factor 4-heparin complex are present in the patient’s serum, the platelets react and release the radiolabeled serotonin, which is then measured. Availability and turnaround time of this test is dependent on the institution, which can influence the test’s clinical utility. Cases where there is intermediate pretest probability with only a weakly positive HIT antibody OD most benefit from confirmatory SRA testing. Overall, the diagnosis of HIT can be considered confirmed by (1) a positive ELISA with OD >2.00 or (2) a positive functional assay.

DIAGNOSIS DIFFERENTIAL DIAGNOSIS Thrombocytopenia due to other causes including: • Sepsis or infection • Disseminated intravascular coagulation • Immune thrombocytopenia • Thrombocytopenic thrombotic purpura • Hemolytic uremic syndrome • Drug-induced thrombocytopenia (other than heparin) • Antiphospholipid antibody syndrome • Liver failure • Splenic sequestration • Intravascular devices WORKUP HIT is, first and foremost, a clinical diagnosis that is confirmed with laboratory testing. See Table 2 for workup based on pretest probability. If the patient has a low pretest probability score, heparin can be safely continued, and there is no need to send further testing for HIT. A patient with moderate-to-high pretest probability requires HIT testing (Table 3), imaging studies for lowerextremity deep venous thrombosis (also consider imaging of upper extremities if swelling is present or venous catheters are in place), cessation of heparin products, and initiation of alternative

TABLE 1  Risk Factors for Heparin-Induced Thrombocytopenia Heparin Type Patient type Dosea Duration Sex

Unfractionated > Low-Molecular-Weight Heparin > Fondaparinux Postoperative (major > minor surgery) > medical > obstetric/pediatric Prophylactic dose > therapeutic dose > flushes 11-14 daysb > 5-10 days > 4 days or fewer Female > male

IMAGING STUDIES Doppler ultrasonography of the extremities in the correct clinical setting.

aImportance of heparin dose is uncertain because of compounding effect of patient type (e.g., postoperative patients tend to receive

prophylactic-dose heparin whereas medical patients [e.g., with venous thromboembolism] are more likely to receive therapeutic-dose heparin); nevertheless, reported frequencies of heparin-induced thrombocytopenia (HIT) are relatively high in patients given postoperative prophylactic-dose heparin. bHeparin exposure beyond 14 days does not usually increase the risk of HIT beyond that of an 11- to 14-day exposure. From Hoffman R et al: Hematology, basic principles and practice, ed 7, Philadelphia, 2018, Elsevier.

TREATMENT • For patients with a moderate or high pretest probability, discontinue all heparin

Heparin-Induced Thrombocytopenia TABLE 2  The 4Ts Score for Estimating the Pretest Probability of Heparin-Induced Thrombocytopenia POINTS (0, 1, or 2 for each of the four parameters; maximum points = 8) Thrombocytopenia (acute) Timing of fall in platelet count or other sequelae Thrombosis or other sequelae

1

0

>50% platelet count fall to nadir ≥20 × 109/L Onset day 5-10 or Day 10, timing unclear, or 15 to 20 μg/dl, or who has any clinical evidence of hepatic failure. Table 2 summarizes indications for prompt or urgent treatment of hepatitis B. • IV therapy needed (rarely) for hydration during severe vomiting. • Avoid hepatically metabolized drugs. • No therapeutic measures are beneficial. • Steroids not shown helpful.

CHRONIC Rx • Treatment of chronic HBV infection is dependent on which phase the patient is found to be in: 1. Therapy is warranted for patients in immune-active CHB stage (HBeAg negative or HBeAg positive) to decrease the risk of liver-related complications. Treatment options include: a. Pegylated interferon 2a: 180 mcg subcutaneously weekly for 48 wk. This will lead to seroconversion rates of 20% to 30% (HBeAg to anti-HBe), and 65% of patients will have HBV DNA 40 with normal ALT and elevated HBV DNA (≥1 million IU/ml) with liver biopsy showing significant necroinflammation or fibrosis. 3.  HBeAg-positive adults without cirrhosis who seroconvert to anti-HBe on therapy with entecavir or tenofovir disoproxil can discontinue treatment after a period of treatment consolidation. 4. It is recommended that patients receive indefinite therapy with entecavir or tenofovir disoproxil if HBeAg-negative immune-active CHB is present, unless there is a competing rationale for treatment discontinuation. 5. Adults with compensated cirrhosis and low levels of viremia (200,000 IU/ ml. Can use tenofovir disoproxil, lamivudine, or telbivudine. Tenofovir may be preferred because it has a better resistance profile and there are more safety data in pregnany women with hepatitis B. Fig. 3 describes an algorithm for the treatment of hepatitis B surface antigen (HBsAg)-positive mothers during pregnancy. • Preventing before exposure: 1. Lifestyle changes. 2. Meticulous testing of blood supply (although some chronically infected, infectious donors are HBsAg negative). 3. Sterilization via steam or hypochlorite. 4. Hepatitis B vaccine for high-risk groups given IM in deltoid to induce HBsAb (response should be confirmed) is protective (>90% effective). The FDA has recently approved a two-dose hepatitis B virus vaccine (HEPLISAV-B) for use in adults ≥18 yr old, administered at 0 and 1 mo. 5. Recommendation for universal childhood immunization with doses at birth, 1 mo, and 6 mo.

H

Diseases and Disorders

Well compensated Acute Liver Failure HBV reactivation

Indications

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668

Hepatitis B

ALG • Prevention after exposure: 1. HBV hyperimmune globulin (HBIG) (0.06 ml/kg IM) given immediately after needlestick, within 14 days of sexual exposure, or at birth, followed by HBV vaccination. A second dose of HBIG is given in 28 days for those refusing vaccine or vaccine nonresponders. 2.  Standard immune globulin: Nearly as effective as HBIG. • Preventive therapy with entecavir or tenofovir disoproxil for patients who test positive for HBsAg and are undergoing chemotherapy may reduce the risk for HBV reactivation and HBV-associated morbidity and mortality. • Hepatitis B prophylaxis is described in Section V. • Table 3 summarizes interpretation of serologic markers and serum DNA in hepatitis B.

HBsAg-positive pregnant mother HBV DNA ≥107 copies/ml

HBV DNA 105 copies/ml. anti-HBc IgG, Hepatitis B core antibody (IgG type); anti-HBc IgM, hepatitis B core antibody (IgM type); anti-HBe, hepatitis B early antibody; anti-HBs, hepatitis B surface antibody; HBeAg, hepatitis Be antigen; HBsAg, hepatitis B surface antigen; HBV DNA, hepatitis B viral DNA. From Andreoli TE et al: Andreoli and Carpenter’s Cecil essentials of medicine, ed 8, Philadelphia, 2010, WB Saunders.

Hepatitis B

668.e1

SUGGESTED READINGS Brahmania M et al: New therapeutic agents for chronic hepatitis B, Lancet Infect Dis 16(2):e10-e21, 2016. Chen GF et  al: Treatment of chronic hepatitis B infection-2017, Liver Int 1(37 Suppl):59-66, 2017. Han SH, Tran TT: Management of chronic hepatitis B: an overview of practice guidelines for primary care providers, J Am Board Fam Med 28:822-837, 2015. Pan CQ et al: Tenofovir to prevent hepatitis B transmission in mothers with high viral load, N Engl J Med 374:2324-2334, 2016. Tang LSY et al: Chronic hepatitis B infection: a review, JAMA 319:1801-1813, 2018. Terrault NA et  al: AASLD guidelines for treatment of chronic hepatitis B, Hepatology 63(1):261-283, 2016. Wang Q et al: Chronic hepatitis B and C virus infection and risk for non-Hodgkin lymphoma in HIV-infected patients: a cohort study, Ann Intern Med 166(1):917, 2017. Wilkins T et al: Hepatitis B: screening, prevention, diagnosis, and treatment, Am Fam Physician 99(5):314-323, 2019.

ACUTE VIRAL HEPATITIS Nausea/Anorexia

Fatigue/Malaise

••• Antiviral Antibody

Bilirubin Elevations

IgM Antibody Aminotransferase Elevations

Viral Replication ••• Incubation Period

Preicteric

Icteric Phase

Convalescent Phase

Time after Exposure

FIG. E1  The typical course of acute viral hepatitis. IgM, Immunoglobulin M. (From Goldman L, Ausiello D [eds]: Cecil textbook of medicine, ed 22, Philadelphia, 2004, WB Saunders.)

Hepatitis C BASIC INFORMATION DEFINITION Hepatitis C is an acute liver parenchymal infection caused by hepatitis C virus (HCV). SYNONYM Transfusion-related non-A, non-B hepatitis (incubation period averages 6 wk, intermediate between hepatitis A and B)

EPIDEMIOLOGY & DEMOGRAPHICS Hepatitis C infection is the most common chronic blood-borne infection in the United States. About 3% of baby boomers test positive for the virus. The CDC now recommends testing for hepatitis C for anyone born from 1945 to 1965. INCIDENCE: HCV infects more than 185 million individuals worldwide. Approximately 20% of patients chronically infected with HCV progress to cirrhosis. • 150,000 new cases/yr (37,500 symptomatic; 93,000 later chronic liver disease; 30,700 cirrhosis). The incidence of acute HCV has declined substantially over the past 30 yr (from 7.4/100,000 to 0.7/100,000). • ∼9000 of these ultimately die of HCV infection; most common (40%) cause of nonalcoholic liver disease in the United States PREVALENCE (IN U.S.): • Overall prevalence of anti-HCV antibody is 1% to 1.2% (an estimated 2.7 million persons nationwide). • Highest prevalence in hemophiliacs transfused before 1987 and users of injection drugs, 72% to 90%. Over past 30 yr, blood

PHYSICAL FINDINGS & CLINICAL PRESENTATION • Symptoms usually develop 7 to 8 wk after infection (range of 2 to 26 wk), but 70% to 80% of cases are subclinical. • 10% to 20% report acute illness with jaundice and nonspecific symptoms (abdominal pain, anorexia, malaise). • Fulminant hepatitis may rarely occur during this period. • After acute infection, 15% to 25% have complete resolution (absence of HCV RNA in serum, normal ALT). • Progression to chronic infection is common, 50% to 84%. 74% to 86% have persistent viremia; spontaneous clearance of viremia in chronic infection is rare. 60% to 70% of patients will have persistent or fluctuating ALT levels; 30% to 40% with chronic infection have normal ALT levels. • 15% to 20% of those with chronic HCV will develop cirrhosis over a period of 20 to 30 yr; in most others, chronic infection leads to hepatitis and varying degrees of fibrosis. Table 1 summarizes factors associated with progression of hepatic fibrosis in patients with chronic HCV infection. Table 2 describes factors associated with cirrhosis in persons with hepatitis C infection. • 0.4% to 2.5% of patients with chronic infection develop hepatocellular carcinoma (HCC).

TABLE 1  Factors Associated With Progression of Hepatic Fibrosis in Patients With Chronic Hepatitis C Virus Infection Established

Possible

Not Associated

Age >40 yr Alcohol consumption Hepatitis B virus coinfection HIV coinfection Immunosuppressed state Insulin resistance Marijuana use Obesity Schistosomiasis Severe hepatic necroinflammation Smoking White race

Increased hepatic iron concentration Male gender Serum ALT level

Viral genotype Viral load

ALT, Alanine aminotransferease; HIV, human immunodeficiency virus. From Feldman M et al [eds]: Sleisenger and Fordtran’s gastrointestinal and liver disease, ed 10, Philadelphia, 2016, Saunders.

• 25% of patients with chronic infection continue to have an asymptomatic course with normal LFTs and benign histology. • In chronic HCV infection, extrahepatic sequelae include a variety of immunologic and lymphoproliferative disorders (e.g., cryoglobulinemia, membranoproliferative glomerulonephritis, and possibly Sjögren syndrome, autoimmune thyroiditis, polyarteritis nodosa, aplastic anemia, lichen planus, porphyria cutanea tarda, B-cell lymphoma, others). • Fig. 1 illustrates the natural history of HCV infection.

ETIOLOGY • Caused by HCV (single-stranded RNA flavivirus). HCV genotype 1 accounts for about 75% of HCV in the US. Genotypes 2 and 3 account for about 20-25% of infections, genotype 4 for 6%, and genotypes 5 and 6 for about 1%. • Most HCV transmission is parenteral. • In the United States, advances in screening of blood and blood products have made transfusion-related HCV infection rare (the risk is estimated to be 0.001% per unit transfused). • Injecting-drug use accounts for most HCV transmission in the United States (60% of newly acquired cases, 20% to 50% of chronically infected persons). • Occupational needlestick exposure from an HCV-positive source has a seroconversion rate of 1.8% (range 0% to 7%). • Nosocomial transmission rates (from surgery and procedures such as colonoscopy and hemodialysis) are extremely low. • Sexual transmission and maternal-fetal transmission are infrequent (estimated at 5%). • No identifiable risk in 40% to 50% of community-acquired hepatitis C, but snorting of cocaine by shared use of straw or rolled-up paper has been identified as a risk factor because it causes microscopic bleeding of nasal mucosa. • HCV infection may stimulate production of cytotoxic T lymphocytes and cytokines (INFγ), which probably mediate hepatic necrosis.

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • Other hepatitis viruses (A, B, D, E). • Other viral illnesses producing systemic disease (e.g., yellow fever, EBV, CMV, HIV, rubella, rubeola, coxsackie B, adenovirus, HSV, HZV). • Nonviral hepatitis (e.g., leptospirosis, toxoplasmosis, alcoholic hepatitis, drug-induced hepatitis [acetaminophen, INH], toxic hepatitis). WORKUP • Acute hepatitis C antibody, viral genotyping, viral titers. • LFTs; CBC. note: ALT is an easy and inexpensive test to monitor infection and efficacy of therapy. However, ALT levels may fluctuate or even be

H

Diseases and Disorders

ICD-10CM CODES B17.1 Acute hepatitis C B18.2 Chronic viral hepatitis C B17.10 Acute hepatitis C without hepatic coma B17.11 Acute hepatitis C with hepatic coma B19.20 Unspecified viral hepatitis C without hepatic coma B19.21 Unspecified viral hepatitis C with hepatic coma

transfusion as a risk factor declined from 15% of cases to 1.9%. • Among low-risk groups, prevalence 0.6%. PREDOMINANT SEX: Slight male predominance. PREDOMINANT AGE: Highest prevalence in 30to 49-yr age group (65%). PEAK INCIDENCE: • 20 to 39 yr of age. • African Americans and whites have similar incidence of acute disease; Hispanics have higher rates. • Prevalence is substantially higher among non-Hispanic blacks than among non-Hispanic whites. GENETICS: Neonatal infection is rare; increased risk with maternal HIV-1 coinfection.

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Hepatitis C TABLE 2  Factors Associated With Cirrhosis in Persons With Hepatitis C Infection Factor Environmental Alcohol use Host HIV infection HBV infection Age Body mass index Duration of HCV infection HLA type Viral Quasispecies complexity HCV genotype 1 Quantitative measures of viremia (serum or plasma HCV RNA level)

Impact

Comment

+4

The importance of minimal alcohol ingestion (40 yr, Asian females >50 yr, all cirrhotic hepatitis B carriers, family history

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674

Hepatocellular Carcinoma of HCC and North American blacks/Africans older than age 20 yr • Cirrhosis (nonhepatitis B): Hepatitis C, alcoholic cirrhosis, hemochromatosis, primary biliary cirrhosis, and possibly α1-antitrypsin deficiency, autoimmune hepatitis, and nonalcoholic steatohepatitis STAGING: The commonly used Barcelona Clinic Liver Cancer (BCLC) staging system includes patient performance status, cancer symptoms, number and size of nodules, and liver function. The TNM staging classification is described in Table 2. Treatment is determined according to stage (Fig. 3): • Early stage (A): Asymptomatic single tumor 5 cm or 3 nodules, each ≤3 cm • Intermediate stage (B): Patients with tumors that exceed early criteria but do not yet show cancer-related symptoms, vascular invasion, or metastases • Advanced stage (C): Patients with mild cancer-related symptoms and/or vascular invasion or extrahepatic spread • End-stage (D): Patients with advanced, symptomatic disease

ALG TREATMENT

• Treatment options for hepatocellular carcinoma are summarized in Table 3. Fig. 4 describes a treatment algorithm for HCC. • Early stage: Curative treatment (surgical resection or liver transplantation). Patients who have a single lesion can be offered surgical resection if they are noncirrhotic or have cirrhosis with well-preserved liver function, normal bilirubin, and no significant portal hypertension. Liver transplantation is an effective option for patients with HCC corresponding to the Milan criteria (Table 4). Living donor transplantation can be offered for HCC if the waiting time is expected to be long. Local ablation is safe and effective therapy for patients who cannot undergo resection or as a bridge to transplantation. With these options, survival at 5 yr ranges from 50% to 70%. Radiofrequency ablation (RFA) is used in patients with early HCC who are not surgical candidates, and very high local control rates at 2 yr are obtained (>90%), but eventual recurrence rates can approach 70% at 5 yr. • Intermediate stage: Transarterial chemoembolization (TACE) is recommended as

TABLE 2  Hepatocellular Carcinoma TNM Staging Classification and Milan Criteria for Liver Transplantation T stage Tx

The primary tumor is not assessable

T0 T1

No tumor is present A single tumor (of any size) without blood vessel invasion T1a: Solitary tumor 2 cm (greatest dimension) without vascular invasion A single tumor >2 cm with vascular invasion or multiple tumors (none >5 cm) Multiple tumors, any more >5 cm Tumor(s) invading a major branch of the portal or hepatic vein with direct invasion of adjacent organs including the diaphragm (other than gallbladder) or with perforation of the visceral liver peritoneum

T2 T3 T4

N stage Nx

The lymph nodes are not assessable

N0 N1

There is no regional nodal involvement There is regional nodal involvement

M stage M0

There is no distant tumor spread

M1

There is distant tumor spread

Milan criteria for liver transplantation 1 tumor ≤5 cm in diameter, or Up to 3 tumors ≤3 cm in diameter + No vascular invasion + No extrahepatic disease

Note The TNM staging classification does not consider the background liver function, which is often impaired in cirrhosis and will affect treatment options and prognosis. Other staging systems consider both disease extent and liver function, but have not been compared accurately against one another: • Barcelona Clinic Liver Cancer (BCLC) system • Cancer of the Liver Italian Program (CLIP) system • Okuda system

first-line, noncurative therapy for nonsurgical patients with large/multifocal HCC who do not have vascular invasion or extrahepatic spread. More recently, transarterial use of selective internal radiation therapy (SIRT) with yttrium-90 radiolabeled glass microspheres is an alternative to traditional TACE approaches in this setting. Median survivals exceed 2 yr. • Advanced stage: Palliative targeted therapy, immunotherapy, or clinical trials are used in this stage. Sorafenib and lenvatinib are oral multikinase inhibitors, which are both approved as standard first-line therapy options. • In patients who have previously received first-line targeted therapy, the oral multikinase inhibitors regorafenib and cabozantinib have shown improved survival. In addition, the immune checkpoint inhibitors nivolumab and pembrolizumab have demonstrated improved survival when used in the secondline setting. • The antiangiogenic agent ramucirumab was recently approved in the second-line treatment of HCC patients previously treated with sorafenib.

DISPOSITION • For resectable HCC, the 5-yr survival after liver transplantation is 50% to 70% and 30% to 50% with surgical resection. For unresectable HCC, the overall prognosis is poor. • Tumor size is an independent prognostic factor for resected small HCC (≤50 mm in diameter). Patients with tumors of 0 to 35 mm diameter have a better 60-mo HCC specific survival rate than do those with larger tumors (36 to 50 mm).1 • In the U.S. the 5-yr overall survival rate for HCC is approximately 10%. REFERRAL Multidisciplinary gastrointestinal cancer team for treatment planning

PEARLS & CONSIDERATIONS • Universal hepatitis B vaccination in children in endemic areas has been shown to decrease the incidence of HCC. • Treatment of patients with chronic hepatitis B–associated cirrhosis with lamivudine reduces the incidence of HCC. Treatment with entecavir in chronic hepatitis B-HCC can improve hepatic function and MELD score. • Treatment with interferon-based therapy in patients with noncirrhotic hepatitis C reduces risk of HCC in patients demonstrating a sustained viral response. • HCC screening is recommended in highrisk patients because curative therapies are available only for small and early HCC. 1 Zhang W et al: Effect of tumor size on cancer-specific

survival in small hepatocellular carcinoma, Mayo Clin Proc 90(9):1187-1195, 2015.

From Grant, LA: Grainger & Allison’s diagnostic radiology essentials, ed 2, Philadelphia, 2019, Elsevier.

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ALG

Hepatocellular Carcinoma

HCC

H

Stage 0

Stage A-C

Stage D

PST 0, Child-Pugh A

PST 0-2, Child-Pugh A-B

PST >2, Child-Pugh C*

Early stage (A)

Intermediate stage (B)

Advanced stage (C)

Single 60 mo; 5-yr survival: 40-70%

TACE

Sorafenib

Best supportive care

Target: 20% OS: 20 mo (45-14)

Target: 40% OS: 11 mo (6-14)

Target: 10% OS: 1000 are at increased risk for recurrence after transplantation regardless of tumor size. • There are numerous ongoing trials with tyrosine kinase inhibitors and monoclonal antibodies for advanced HCC in patients

who are intolerant or resistant to sorafenib. The future of therapy for advanced HCC will likely lead to the personalized combination of multiple agents targeting different oncogenic pathways to optimize treatment success.

SUGGESTED READINGS Available at ExpertConsult.com RELATED CONTENT Liver Cancer (Patient Information) AUTHOR: Bharti Rathore, MD

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Hepatocellular Carcinoma

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Cirrhotic liver Nodular hepatoma

Test area for normal left lobe Inferior vena cava Aorta Hepatoma Spleen

FIG. E2  Hepatocellular carcinoma. Laparoscopic view shows a cirrhotic liver with a nodular hepatoma. (From Skarin AT: Atlas of diagnostic oncology, ed 4, St Louis, 2010, Mosby.)

FIG.E1  Hepatoma. Computed tomography scan shows a diffuse lesion in the right lobe of an otherwise normal liver. (From Skarin AT: Atlas of diagnostic oncology, ed 3, St Louis, 2003, Mosby.)

SUGGESTED READINGS Abou-Alfa GK et  al: Cabozantinib in patients with advanced and progressing hepatocellular carcinoma, N Engl J Med 379(1):54-63, 2018. American Cancer Society: Global cancer: facts & figures, 3rd ed, www.cancer.org/acs/groups/content/@research/documents/document/acspc -044738.pdf, 2015. Bouattour M et  al: Systemic treatment for advanced hepatocellular carcinoma, Liver Cancer 8(5):341-358, 2019. Bruix J, Sherman M: AASLD practice guideline. Management of hepatocellular carcinoma: an update, Hepatology 53(3):1020-1022, 2011. El-Serag HB: Hepatocellular carcinoma, N Engl J Med 365:1118-1127, 2011. Jin YJ et al: Suppressive effects of entecavir on hepatitis B virus and hepatocellular carcinoma, J Gastroenterol Hepatol 26(9):1380-1388, 2011. Kudo M et al: Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial, Lancet 391(10126):1163-1173, 2018. Petrick J et al: Future of hepatocellular carcinoma incidence in the United States forecast through 2030, J Clin Oncol 34(15):1787-1794, 2016. Saunders D: Systematic review: the association between obesity and hepatocellular carcinoma—epidemiological evidence, Aliment Pharmacol Ther 31(10):1051, 2010. Siegel RL et al: Cancer statistics, CA Cancer J Clin 69(1):7-34, 2019. Villanueva A, Llovet JM: Targeted therapies for hepatocellular carcinoma, Gastroenterology 140(5):1410-1426, 2011. Villanueva A: Hepatocellular carcinoma, N Engl J Med 380:1450-1462, 2019.

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Hepatopulmonary Syndrome BASIC INFORMATION DEFINITION Hepatopulmonary syndrome (HPS) is defined by the presence of (1) liver disease (usually chronic), (2) reduced arterial oxygenation, and (3) evidence of intrapulmonary vascular dilations (IPVDs). SYNONYM HPS ICD-10CM CODE K76.81 Hepatopulmonary syndrome

EPIDEMIOLOGY & DEMOGRAPHICS PREVALENCE: Between 4% and 47% of patients with cirrhosis; the wide range is due to lack of diagnostic criteria PREDOMINANT SEX AND AGE: No data on age or gender prevalence GENETICS: New data suggest that polymorphisms in genes involved in the regulation of angiogenesis are associated with increased HPS risk. RISK FACTORS: HPS occurs with any degree or etiology of liver disease but is more prevalent in patients with established cirrhosis and portal hypertension. There is no clear relationship between severity of hepatic dysfunction and level of systemic hypoxemia. PHYSICAL FINDINGS & CLINICAL PRESENTATION • Dyspnea • Platypnea: Worsened dyspnea when sitting upright compared with supine position due to further ventilation-perfusion mismatch • Orthodeoxia: Decreased PaO2 when the patient is sitting upright compared with supine position due to ventilation-perfusion mismatch • Increased spider angiomata • Signs of severe hypoxemia (e.g., cyanosis and clubbing of the digits) ETIOLOGY Dilation of intrapulmonary arterioles and dilated vascular channels between pulmonary arteries and veins leads to a ventilation-perfusion mismatch and right-to-left shunting. Research shows that nitric oxide (NO) plays a role in vasodilation. The relationship of vasodilation to liver disease is unclear. Fig. E1 illustrates a proposed pathophysiology of hepatopulmonary syndrome. New areas of research include endothelin-1, which is produced by proliferating cholangiocytes, pulmonary angiogenesis, and opiate receptors’ influence on NO production.

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • Portopulmonary hypertension • Cavopulmonary anastomosis

ALG

• Hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber syndrome) • Chronic lung disease (e.g., COPD or pulmonary fibrosis) with coexisting liver disease

• Pulmonary angiography is rarely used unless there is a potential to embolize arteriovenous malformations (AVM).

TREATMENT

WORKUP • Diagnosis should be suspected in patients with cirrhosis who develop hypoxemia in the absence of other causes (e.g., COPD, thromboembolism). • Workup includes lab testing and imaging studies (see following), but diagnosis is based on clinical findings.

Ideal treatment would be targeted against pulmonary vasodilation. Most medications have targeted NO production, the activity of NO synthase or endothelin-1, pulmonary angiogenesis, or even bacterial translocation, but no controlled trials exist. Liver transplantation is the only successful treatment, which leads to improvement in gas exchange or complete resolution in gas exchange in the majority of patients. However, severe hypoxemia with Pao2 50 red blood cells per high-power field) - Normal findings on renal ultrasonography *This criterion would not be included in cases of known preexisting structural chronic kidney disease (e.g., diabetic or hypertensive nephropathy). From Angeli P et  al: Diagnosis and management of acute kidney injury in patients with cirrhosis: revised consensus recommendations of the International Club of Ascites, J Hepatol 62:968-974, 2015.

BOX E1  Management of Hepatorenal Syndrome (HRS) • • •



•

•

 easures to prevent variceal bleeding (e.g., beta blockers, band ligation) M Treatment of severe alcoholic hepatitis Prevention of HRS • Avoid intravascular volume depletion (diuretics, excessive lactulose, GI bleeding, large-volume paracentesis without adequate volume repletion) • Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers should be avoided or used with caution in patients with cirrhosis and ascites. Judicious management of nephrotoxins (NSAIDs, antibiotics). Prompt diagnosis and treatment of infections (SBP, sepsis) • SBP prophylaxis: Long-term use of norfloxacin (or trimethoprim/sulfamethoxazole) can be justified if the ascitic fluid protein 1.2 mg/dl, BUN >25 mg/dl or serum Na 9 and bilirubin >3 mg/dl) (Class I, Level A) • Avoid use of proton pump inhibitors without indications as can precipitate SBP. Treatment of HRS • Stop all nephrotoxic or volume-depleting agents (ACEIs, ARBs, NSAIDs, diuretics) • Antibiotics for infections • IV albumin—bolus of 1 g/kg/day on presentation (maximum dose, 100 g daily). Continue at dose of 20–60 g daily as needed to maintain central venous pressure 10–15 cm H2O • Vasopressor therapy (in addition to albumin): ■ Terlipressin*—start at 1 mg IV every 4 h and increase up to 2 mg IV every 4 h if baseline serum creatinine level does not improve by 25% at day 3 of therapy OR ■ Midodrine and octreotide—begin midodrine at 2.5–5 mg orally 3 times daily and increase to a maximum dose of 15 mg 3 times daily. Titrate to a MAP increase of at least 15 mm Hg; begin octreotide at 100 μg subcutaneously 3 times daily and increase to a maximum dose of 200 μg subcutaneously 3 times daily, or begin octreotide as a 25-μg IV bolus and continue at a rate of 25 μg/h OR ■ Norepinephrine—0.1 to 0.7 μg/kg per minute as an IV infusion. Increase by 0.05 μg/kg per minute every 4 h and titrate to a MAP increase of at least 10 mm Hg ■ Duration of vasopressor treatment is generally a maximum of 2 wk until reversal of hepatorenal syndrome or liver transplantation Evaluate patient for liver transplantation

*Not available in the U.S. ACEI, Angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; BUN, blood urea nitrogen; CKD, chronic kidney disease; GI, gastrointestinal; IV, intravenous; MAP, mean arterial pressure; NSAID, nonsteroidal anti-inflammatory drug; SPB, spontaneous bacterial peritonitis. From Feldman M et al: Sleisenger and Fortran’s gastrointestinal and liver disease, ed 10, Philadelphia, 2016, Elsevier.

Hepatorenal Syndrome TABLE E4  Prevention of Acute Kidney Injury in Patients with Cirrhosis Risk Factors

Preventive Approaches

Hepatorenal syndrome development

Judicious use of diuretics and lactulose to avoid hypovolemia Antibiotic prophylaxis following GI bleeding Albumin administration during large volume paracentesis (6 to 8 g/L of ascitic fluid removed) Spontaneous bacterial peritonitis (SBP) prophylaxis in patients with low-protein ascites Early recognition and treatment of SBP with antibiotics and albumin at the dose of 1.5 g per kg of body weight at the time of diagnosis of SBP and 1 g per kg of body weight at the third day of treatment Avoid nephrotoxic medications if possible Appropriate drug dosing based on pharmacokinetics and close monitoring of drug toxicity, early recognition of drug-induced AKI, and discontinuation of offending agent if possible Use of lipid formulations of amphotericin B rather than conventional formulations of amphotericin B Use of azole antifungal agents and/or the echinocandins rather than conventional amphotericin B, if equal therapeutic efficacy can be assumed Consider alternative imaging methods or avoidance of IV contrast if possible Use of low or iso-osmolar agents with lowest volume possible IV volume replacement prior to contrast exposure Paracentesis, with coadministration of albumin, in patients with tense ascites

Nephrotoxic medication exposure

Radiocontrast exposure Intraabdominal hypertension

AKI, Acute kidney injury; IV, intravenous. From Ronco C et al: Critical care nephrology, ed 3, Philadelphia, 2019, Elsevier.

SUGGESTED READINGS Allegretti AS et al: Prognosis of patients with cirrhosis and AKI who initiate RRT, Clin J Am Soc Nephrol 13:16-25, 2018. Angeli P et al: Diagnosis and management of acute kidney injury in patients with cirrhosis: revised consensus recommendations of the International club of Ascites, J Hepatol 62:968-974, 2015. Angeli P et al: News in pathophysiology, definition and classification of hepatorenal syndrome: a step beyond the International Club of Ascites (ICA) consensus document, J Hepatol 2019. https://doi: 10.1016/j.jhep.2019.07.002. [Epub ahead of print]. Arroyo V, Fernández J: Management of hepatorenal syndrome in patients with cirrhosis, Nat Rev Nephrol 7:517-526, 2011. Bansho EETO et al: Prognostic significance of the new criteria for acute kidney injury in cirrhosis, Ann Hepatol 17:461-469, 2018. Best LM et  al: Treatment for hepatorenal syndrome in people with decompensated liver cirrhosis: a network meta-analysis, Cochrane Database Syst Rev 9:CD013103, 2019. Facciorusso A et al: Comparative efficacy of pharmacological strategies for management of type 1 hepatorenal syndrome: a systematic review and network meta-analysis, Lancet Gastroenterol Hepatol 2:94-102, 2017. Nassar Junior AP et  al: Terlipressin versus norepinephrine in the treatment of hepatorenal syndrome: a systematic review and meta-analysis, PloS One 9:e107466, 2014. Tandon P et al: Relevance of new definitions to incidence and prognosis of acute kidney injury in hospitalized patients with cirrhosis: a retrospective populationbased cohort study, PLoS One 11:e0160394, 2016.

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Hereditary Breast and Ovarian Cancer BASIC INFORMATION

SYNONYMS Hereditary breast and ovarian cancer syndrome (HBOC)

nonpolyposis

ICD-10CM CODES Z84.81 Family history of carrier of genetic disease Z80.3 Family history of malignant neoplasm of breast Z80.41 Family history of malignant neoplasm of ovary Z80.49 Family history of malignant neoplasm of other genital organs (uterus, vagina, for example) Z15.01 Genetic susceptibility to malignant neoplasm of breast Z15.02 Genetic susceptibility to malignant neoplasm of ovary

EPIDEMIOLOGY & DEMOGRAPHICS INCIDENCE: Overall, an estimated 6% to 10% of gynecologic cancers are heritable. Approximately 7% to 10% of the estimated 235,000 new breast cancer cases are likely to be associated with heredity. Inherited pathogenic BRCA 1, 2 mutations account for an estimated 11% to 15% of ovarian cancer cases. Less than 1% of the general population has a pathogenic mutation in the BRCA 1 or 2 gene. As noted above, Lynch syndrome–associated mutations increase ovarian and uterine cancer as well as colorectal (up to 5% of colorectal cancers are considered heritable), pancreatic, and gastric cancers. This article will, however, focus on gynecologic disease. Tables 1 and 2 summarize genes associated with hereditary breast and ovarian cancer predisposition. PREDOMINANT SEX AND AGE: Although females are predominantly affected, males who carry

deleterious mutations in BRCA 1, 2 are at a significantly higher risk for cancer. Both sexes can transmit the altered gene to their offspring. GENETICS: The transmission pattern is autosomal dominant. A child whose father or mother has a BRCA mutation has a 50% chance of inheriting that genetic mutation. RISK FACTORS: BRCA1 and BRCA2 mutations can generate a greater risk of breast cancer than other such well-established factors as increased breast density, history of atypical ductal or lobular hyperplasia, nulliparity, obesity, and family history. Up to 37% of breast cancer patients and 100% of ovarian/tubal/peritoneal cancer patients are at risk for hereditary breast and ovarian cancer syndrome. Hereditary Breast and Ovarian Cancer Syndrome (HBOC): • Individuals with BRCA1, BRCA2 mutations (Fig. 1) • Red flags (not an exhaustive list) for possible HBOC include personal or family history of: 1.  Personal breast cancer diagnosed at ≤45 yr old 2. Triple-negative breast cancer (ER-, PR-, Her2-) 3.  Ovarian cancer: Very important factor (mostly papillary serous) 4. Male breast cancer 5. Two primary breast cancers 6. Ashkenazi Jewish ancestry 7. Breast cancer with ≥2 relatives with an HBOC-associated cancer (breast, ovary, prostate, pancreatic cancers) 8. A previously identified HBOC mutation 9. Two or more close relatives with breast cancer, one of whom was diagnosed at age 50 yr or younger

TABLE 1  Genes Associated with Hereditary Breast Cancer Predisposition Gene

Syndrome

Relative Risk of BC

BC Risk by Age 80 Yr

Associated Cancers

High Penetrance BRCA1 HBOC BRCA2 HBOC p53 Li-Fraumeni syndrome

∼15-30 ∼10-20 100

70% 70% 50% by 60 yr

PTEN

Cowden syndrome

No reliable estimate

70%-80%

Ovarian, other Ovarian, pancreatic, prostate, other Soft tissue sarcoma, osteosarcoma, brain tumors, adrenocortical carcinoma, leukemia, other Thyroid (follicular and rarely papillary) endometrial, genitourinary, other

STK11

Bannayan-Riley-Ruvalcaba syndrome Proteus Proteus-like syndrome Peutz-Jeghers syndrome

No reliable estimate

30% by age 60

CDH1 Hereditary diffuse gastric carcinoma Lower or Moderate Penetrance ATM (heteroAtaxia-telangiectasia in homozygotes zygote) CHK2 (CHEK2) Li-Fraumeni variant

∼3.25

39%

Small intestine, colorectal, uterine, testicular and ovarian sex chord tumors, other Lobular breast, diffuse gastric, other

∼3

30

Undefined in heterozygotes

1.5-3

20%-30%

Undefined

PALB2

5

∼40

Undefined in heterozygotes

None known

BC, Breast cancer; HBOC, hereditary breast and ovarian cancer syndrome. From Niederhuber JE: Abeloff’s clinical oncology, ed 6, Philadelphia, 2020, Elsevier.

H

Diseases and Disorders

DEFINITION Hereditary breast and ovarian cancer syndrome (HBOC) patients carry a significant cancer-associated alteration in the BRCA1 and/or BRCA2 gene. These genetic mutations can confer a heightened risk of malignancy in the breast, ovary, fallopian tube, and peritoneum in women and an elevated risk of prostate and breast cancer in men. Additionally, the risk of pancreatic cancer and skin cancer are elevated for both men and women. Another condition, Lynch syndrome, or hereditary nonpolyposis colorectal cancer (HNPCC), is associated with an increased risk of endometrial cancer and ovarian cancer in women and cancer of the colon, stomach, pancreas, and small bowel in both women and men. Patients with Lynch syndrome carry significant pathogenic alterations in five genes, as noted below. The risk for a particular verified genetically associated cancer is significantly greater than the cancer risk associated with the general population or with one’s personal and/or family cancer history alone, without a positive genetic test. Frequently, a cancer that is associated with a heritable genetic mutation presents at a younger age than that seen in the general population is a relatively rare type of cancer and/or affects multiple same-side family members. Identifying carriers can significantly reduce the morbidity and mortality of the patient and her/his close family members.

Lynch syndrome/hereditary colorectal cancer (HNPCC) Hereditary cancer syndrome

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Hereditary Breast and Ovarian Cancer 10.  Three or more HBOC-associated cancers at any age note: • One half of BRCA carriers inherit the mutation from their father. • Early onset of cancer may be a more important red flag than the number of affected family members, especially if the number of family members is small to begin with. • Testing criteria (Tables 3 and 4), as per National Comprehensive Cancer Network (NCCN) guidelines, may differ from the red flags noted previously. • Family history extends to first-, second-, and third-degree relatives.

• Consider Lynch syndrome–associated cancers (e.g., colorectal, gastric, brain, pancreas, small bowel, skin, ureter, renal pelvis, GI polyps), as Lynch syndrome is associated also with ovarian and uterine (endometrial) cancer. • BRCA stands for BReast CAncer. 1. The majority (84%) of the approximately 7% of breast cancers and 14% of ovarian cancers that result from a heritable mutation are due to a BRCA1 (52%) and BRCA2 (32%) gene mutation. 2. By age 70, in comparison to the 7.3% risk of breast cancer in the general population, or approximately double that risk if one has an affected first-degree

TABLE 2  Genes Associated with Hereditary Ovarian Cancer Predisposition Relative Risk of OC

OC Risk by Age 80 Yr

Associated Cancers

∼50

∼40%

Breast, other

∼8

11%-26%

∼4

∼20%

Breast, pancreas, prostate, other Colon Uterine Stomach Small intestine Urinary tract Pancreatic Possible other sites

Lower or Moderate Penetrance RAD51C None

∼5

∼6%

RAD51D

∼12

∼14%

Gene

Syndrome

High Penetrance BRCA1 Hereditary breast ovarian cancer syndrome BRCA2 Hereditary breast ovarian cancer syndrome MLH1 Lynch syndrome MSH2 MSH6 PMS2 EPCAM

None

Undefined Autosomal recessive Fanconi anemia Undefined Autosomal recessive Fanconi anemia

OC, Ovarian cancer. From Niederhuber JE: Abeloff’s clinical oncology, ed 6, Philadelphia, 2020, Elsevier.

Site-specific breast cancer (BRCA1 & BRCA2) SBLA (Li-Fraumeni syndrome) (p53) Cowden’s disease

Breast/ovarian cancer (BRCA1/BRCA2) Hereditary diffuse gastric cancer (Lobular carcinoma of breast) CDH1 CHEK2 (HBCC) Extraordinarily early onset breast cancer (BRCA-1) Breast and miscellaneous tumors Ataxia telangiectasia (homozygotes and heterozygotes) Polygenic

Fanconi anemia Bloom syndrome Others?

Sporadic

FIG. 1  Schematic depicting heterogeneity in breast cancer. HBCC, Hereditary breast and colorectal cancer; SBLA, sarcoma, breast and brain tumors, leukemia, laryngeal and lung cancer, and adrenal cortical carcinoma. (From Goldman L, Schafer AI: Goldman’s Cecil medicine, ed 24, Philadelphia, 2012, WB Saunders.)

relative, BRCA1 and BRCA2 mutation carriers have up to an 87% reported risk of developing breast cancer. As opposed to a general-population risk of 2% for developing a second breast primary within 5 yr of a first diagnosis, women with HBOC mutations have a 12% to 27% risk. This risk climbs to a reported 50% (BRCA2) and up to 64% (BRCA1) by age 70. 3. By age 70, in contrast to the 0.7% risk of ovarian cancer in the general population, there is a reported risk of up to 27% to 63% for BRCA2 and BRCA1 mutation carriers, respectively. The risk for ovarian cancer within 10 yr of a breast cancer diagnosis is 6.8% (BRCA2) to 12.7% (BRCA1) as opposed to a general-population risk of less than 1.0%. 4. Men with HBOC have an up to tenfold increased risk for breast cancer and a more than twofold increase in prostate cancer in comparison to the generalpopulation risk. In men, the BRCA2 mutation increases the cancer risk more than the BRCA1 mutation. In fact, the breast cancer risk for a male with a BRCA2 mutation is up to 80 times the risk seen in the general population. 5. Both men and women have an elevated risk (up to sevenfold) for pancreatic cancer (BRCA2 >1) and for melanoma (2.5fold increase with BRCA2). 6.  Ashkenazi Jewish ancestry is associated with founder mutations 187delAG (BRCA1), 5382insC (BRCA1), and 6174delT (BRCA2), which confer a significantly elevated risk for breast and ovarian cancer. As opposed to the 1 in 400 risk in the general population, 1 in 40 individuals of Ashkenazi Jewish descent have a BRCA 1 or 2 mutation. Lynch Syndrome (Hereditary Nonpolyposis Colorectal Cancer): • Individuals with MLH1, MSH2, MSH6, PMS2, EPCAM mutations. • By age 70, Lynch syndrome carriers have— in addition to an increased risk for colorectal, gastric, hepatobiliary, urinary tract, small bowel, brain, skin, and pancreatic cancers— up to an approximately twentyfold increase in ovarian cancer (4% to 12% risk vs. the general-population risk of 0.7%) and up to an approximately fortyfold increase in uterine cancer (25% to 60+% risk vs. the generalpopulation risk of 1.6%). • The previously listed genes and others (e.g., PTEN, TP53, CDH1, STK11) that are found less frequently are considered high-penetrance genes, as they can increase the relative risk of their respective syndromes by greater than four- to fivefold. • Other, more moderate-penetrant genes (e.g., CHEK2, ATM, PALB2, BRIP1, RAD51C, RAD51D), that is, those that are associated with a two- to fourfold increase in the relative risk of cancer, should be considered when assessing risk and ordering genetic tests.

Hereditary Breast and Ovarian Cancer TABLE 3  Testing Criteria for Breast Ovarian Cancer Syndrome*

*For more detailed information, see the National Comprehensive Cancer Network (NCCN) guidelines. From Disaia PJ et al: Clinical gynecologic oncology, ed 9, Philadelphia, 2017, Elsevier.

TABLE 4  National Comprehensive Cancer Network (NCCN) Guidelines for Recommending Genetic Testing for BRCA1 or BRCA2 Mutations* Personal history of breast cancer and one or more of the following: • Diagnosed at age ≤45 yr • Diagnosed with at least two breast cancer primaries (bilateral, separate ipsilateral), the first at age 50 yr • Diagnosed at age ≤50 yr with one or more close relatives† with breast cancer (prostate or pancreatic) at any age • Diagnosed with triple-negative breast cancer at age ≤60 yr • Diagnosed at any age with one or more close relatives with breast cancer at age ≤50 yr • Diagnosed at any age with two or more close relatives at any age • Diagnosed at any age with one or more close relatives with invasive ovarian cancer (including fallopian tube and primary peritoneal) at any age • Diagnosed at any age with two or more close relatives with pancreatic and/or prostate cancer • Having a close male relative with breast cancer at any age *Individuals with a limited or unknown family history may have an underestimated probability of a familial gene mutation detection. †Close relative pertains to first-, second-, or third-degree blood relatives on the same side (either maternal or paternal) of the family. From Disaia PJ et al: Clinical gynecologic oncology, ed 9, Philadelphia, 2017, Elsevier.

• More than 12 known gene mutations are associated with an elevated risk for breast cancer, and a similar number are associated with an elevated risk for ovarian cancer. As such, screening for BRCA1, BRCA2 alone will miss these mutations. • In addition to established deleterious mismatch repair gene mutations, gene alterations that are categorized in the literature as emerging risk mutations are also associated with hereditary gynecologic and other cancers.

PHYSICAL FINDINGS & CLINICAL PRESENTATION • Present at a younger age

• Bilaterality more likely • Multiple primaries in one individual

ETIOLOGY Hereditary cancers are typically due to a genetic mutation in a tumor suppression gene that interferes with DNA repair and allows an otherwise potentially avoidable cancer to develop. This is distinct from familial cancers in which there is no isolated gene mutation but, nonetheless, cancers appear in the family to a degree more than that which would be statistically seen in the general population. Nongenetic factors such as lifestyle habits and environmental influences contribute to cancer risk as well.

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • General (sporadic) population or familial basis for the cancer in question. • Hereditary cancer is more likely to present at a younger age, to span a number of generations, to affect more family members than would be expected (if a large enough family), especially in a suspicious pattern, and to include some rare (ovary, male breast cancer, for example) presentations. • In addition to the more common syndromes listed previously, consider Cowden (PTEN), Peutz-Jeghers (STK11), Li-Fraumeni (TP53), and others. WORKUP Family history questionnaire, patient and family interviews, genetic counseling/risk assessment (including tools such as TyrerCuzick/Gail/Claus models), and tailored genetic testing. LABORATORY TESTS • A simple blood or saliva sample drawn in the office or a lab, after informed consent, is needed. This specimen should be sent to a reliable laboratory recognized nationally for its genetic cancer testing accuracy (technologic and interpretative), reporting format, and the support staff ability and availability for consultation, office counseling, and testing integration. Look for a laboratory that has published peer-reviewed data and has an accurate classification methodology that relies on an extensive database. Realize that these labs are not FDA approved and that CLIA certification, while needed, relies on just in-house data. Remember also that most patients get tested only once in their lifetime, and so accuracy is imperative. • Options include: 1. Syndrome specific: For example, HBOCBRCA testing (including large rearrangement detection); Lynch syndrome; founder mutation testing (187delAG, 5382insC, 6174delT)—Ashkenazi Jewish population (often recommended as the first test for this population); single-site testing (if a previously identified gene mutation is known in the family); cancer specific, for example, breast cancer panel—BRCA 1, 2 with/without reflex to broader panel (i.e., sequential testing). 2. Comprehensive panel testing (can include HBOC syndrome BRCA1, BRCA2), Lynch syndrome (MLH1, MSH2, MSH6, PMS2, EPCAM), Li-Fraumeni (TP53), Cowden (PTEN), Peutz-Jeghers (STK11), PALB2, CHEK2, ATM, BRIP1, RAD51C, and others [upward of 28+ genes]). • Choice of the test is generally based on personal/family history, although thoroughness of the risk assessment may be limited by

H

Diseases and Disorders

Individual from a family with a known deleterious BRCA1 or BRCA2 gene mutation Personal history of breast cancer plus one or more of the following: • Diagnosed at ≤45 yr of age • Diagnosed at ≤50 yr of age with • An additional breast cancer primary • At least one close blood relative with breast cancer at any age • At least one close relative with pancreatic cancer • At least one close relative with prostate cancer • An unknown or limited family history • Diagnosed at age 60 with • Triple-negative breast cancer • Diagnosed at any age with • At least one close blood relative with breast cancer before 50 yr of age • At least two close blood relatives with breast cancer at any age • At least one close blood relative with ovarian cancer • At least one close blood relative with pancreatic cancer • At least two close blood relatives with prostate cancer • A close female blood relative with ovarian cancer • An individual of ethnicity associated with a higher mutation frequency • Personal history of ovarian cancer • Personal history of male breast cancer • Personal history of prostate cancer at any age with a close relative with breast, ovarian, or pancreatic cancer at any age • Personal history of pancreatic cancer and Ashkenazi Jewish ancestry • Family history meeting any of the above criteria See NCCN guidelines for the most up-to-date and detailed description for counseling and testing.

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Hereditary Breast and Ovarian Cancer attempting to choose a gene test based on history/phenotype alone. • Comprehensive panel testing has been shown to increase mutation detection and to aid in test selection when patients qualify for more than one syndrome/cancer-specific test, or it can be used to capture a potentially broader view of risk. There is a concern, however, for detecting mutations that are not clinically actionable, at this time. • Categories of results include (1) positive or negative for a deleterious mutation or (2) a genetic variant of uncertain significance, in which a cancer risk is not yet established or ruled out. It is critical that the classification of these variants is accurate.

IMAGING STUDIES Screening transvaginal ultrasonography, annual mammography, annual MRI (when breast cancer risk is 20% or more based on Tyrer-Cuzick or other breast cancer risk screening models)

TREATMENT/RISK REDUCTION • Heightened surveillance, judicious chemoprevention, and prophylactic surgery have been associated with improved outcomes. • Surveillance includes patient breast awareness, clinical breast exam, mammography, MRI, transvaginal ultrasonography, and CA-125 blood testing, for example. • Chemopreventive approaches have been shown to reduce the risk of ovarian cancer by up to 60% (with an oral contraceptive) and risk of contralateral breast cancer by as much as 53% (with tamoxifen). • In HBOC patients, prophylactic total mastectomy can reduce the risk for breast cancer by 90%, and a bilateral salpingo-oophorectomy, after childbearing or by age 40, can reduce the risk of ovarian cancer by up to 96% and the risk of breast cancer by up to 68%. • Consider preimplantation genetic diagnosis in conjunction with in vitro fertilization.

REFERRAL If services are needed beyond one’s practice or comfort level, consider consulting with knowledgeable genetic counselors, gynecologists, gynecologic oncologists, breast surgeons, and gastroenterology specialists, among others.

PEARLS & CONSIDERATIONS • Be vigilant. Be motivated by the risks: Women with these mutations are approximately 10 times more likely to develop breast cancer and 20 to 30 times more likely to develop ovarian cancer. Look for red flags during every encounter, regardless of the patient’s

chief complaint or scheduled visit type, and inquire and regularly update information about the patient’s personal and family history of cancer. Consider that approximately 10% of general practice patients have a significant family history. Supply a printed family history questionnaire. Always consider your patient’s cancer risk, especially when charting a new treatment course or planning a surgical procedure. Oftentimes, a more comprehensive approach may be taken if a patient proves to be a mutation carrier. • Adjust the age at which screening/treatment is initiated and the frequency of the visits depending on the age of the youngest affected family member, the at-risk cancer site, and the carrier status of the patient. • Encourage input from the patient during the screening, workup, follow-up, and treatment. • Recommend that the patient verify any questionable family history, collect appropriate family documentation/testing, and involve her family in the process; this involvement can include advising, counseling, and testing for close relatives. • Try to counsel and test (if appropriate) those family member(s) who, if tested, would render testing of progeny/other family members less necessary. Testing an affected family member is oftentimes the most appropriate, efficient, cost-effective, and informative approach. • Genetic testing can more accurately predict risk and enable a more tailored management approach than relying on one’s family history alone. Be mindful that there may be other, although as yet unidentified, mutations at the root of one’s patient’s personal or family cancer history. • Refer to your professional societies and the NCCN for screening and surveillance/imaging/treatment guidelines. Don’t hesitate to engage the assistance of a genetic counselor, gynecologist, oncologist, breast surgeon, and/or a gastroenterologist during this initial phase. • Involve other appropriate specialists in the patient’s short- and long-term care, depending on the at-risk anatomic systems. • Remember that BRCA1- and BRCA2-positive men are at a significantly higher risk for breast and prostate cancer. • Consider prophylactic bilateral mastectomy or bilateral salpingo-oophorectomy. • Encourage high-risk patients to complete childbearing at a younger age and consider, as appropriate, subsequent prophylactic bilateral salpingo-oophorectomy and menopause hormone therapy options. • Recommend prophylactic bilateral salpingectomy for at-risk patients during any other surgical procedure—once childbearing is complete. Consider such assistive reproductive options as preimplantation genetic diagnosis.

• Genetic information cannot be used as the basis for a “preexisting condition” with regard to health insurance or employment, according to federal and state laws. It may play a role in life insurance, disability insurance, and long-term care insurance. • While insurance coverage generally is available, panel testing reimbursement may occasionally be challenged. Vocalize and document your support of the appropriate testing and management, with both your patient and her/his insurance company. Enlist the assistance of your local professional society, as needed. • There may be a medical-legal risk if a failure to identify and/or genetically counsel or test a high-risk patient and/or her family results in a delay in the diagnosis of breast or ovarian cancer. The provider, laboratory, insurance company, and the employer may have legal exposure for failing to order testing, for providing inaccurate results, or for denial of coverage, respectively. • Being aware of a patient’s cancer risk facilitates initiation of those preventive screenings and management strategies that have been shown to reduce the likelihood of cancer and improve early cancer detection rates. This can be of tremendous benefit for the patient’s family members as well as the patient.

PREVENTION Consider appropriate screening and surveillance (awareness/physical exam by patient and health care provider, imaging studies, diagnostic procedures, counseling, and genetic testing) as well as prophylactic surgery and chemopreventive measures. PATIENT & FAMILY EDUCATION Always encourage patients to revisit their personal and family history and to update this information with all of their health care providers and their family members. Recommend that patients initiate discussions with their family members and other health care providers in an ongoing effort to reduce their and their loved ones’ risk of heritable cancer. Refer to NCCN guidelines (www.nccn.org) and national specialty society recommendations. SUGGESTED READINGS Available at ExpertConsult.com RELATED CONTENT Breast Cancer (Related Key Topic) Lynch Syndrome (Related Key Topic) Ovarian Cancer (Related Key Topic) AUTHOR: David I. Kurss, MD, FACOG, NCMP

Hereditary Breast and Ovarian Cancer SUGGESTED READINGS Hartmann LC, Lindor NM: The role of risk-reducing surgery in hereditary breast and ovarian cancer, N Engl J Med 374:454-468, 2016. Heemskerk-Gorritsen BA et al: Breast cancer risk after salpingo-oophorectomy in health BRCA1/2 mutation carriers: revisiting the evidence for risk reduction, J Natl Cancer Inst 107:107, 2015.

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Hereditary Hemorrhagic Telengiectasia BASIC INFORMATION DEFINITION Hereditary hemorrhagic telangiectasia (HHT), also known as Osler-Rendu-Weber syndrome, is a hereditary vascular disorder characterized by the development of arteriovenous malformations throughout the body. SYNONYMS Osler-Rendu-Weber syndrome HHT Osler disease ICD-10CM CODE I78.0 Hereditary hemorrhagic telangiectasia

EPIDEMIOLOGY & DEMOGRAPHICS INCIDENCE: 1 in 8,000 to 16,500 PREVALENCE: Approximately 1.2 million people worldwide PREDOMINANT SEX AND AGE: • Men = women • Individual variability GENETICS: Inherited dominant mutation. Mutations in the endoglin gene, a cell surface component of the transforming growth factor–β (TGF-β) receptor complex, causes this syndrome. PHYSICAL FINDINGS & CLINICAL PRESENTATION • Recurrent epistaxis and gastrointestinal (GI) bleeds due to lesions in the oropharyngeal epithelium and gut. The most common manifestation is recurrent and spontaneous epistaxis occurring in 90% to 95% of patients due to fragile telangiectasia on the nasal mucosa. • 40% to 50% of patients develop GI bleeding sometime during the course of their disease. • Telangiectasia lesions may be present on the lips, tongue (Fig. E1), nasal mucosa, retina, hands, chest, and lower extremities. There may be many erythematous macules and papules. • Telangiectasias either are round and mildly raised or are stellate without a well-defined border. • Mucocutaneous lesions are 1 to 4 mm, sharply demarcated red to purple macules, or spiderlike projections. They usually develop at puberty.

• Arteriovenous (AV) malformations of the lungs, central nervous system, or liver. • Multiple AV malformations causing liver involvement or atypical cirrhosis are rare but can occur. Liver left-to-right shunting can predispose patients to high-output heart failure.

ETIOLOGY • Autosomal dominant disorder with incomplete penetrance. • Mutations in ENG and ACVRLK1 that code for endoglin and ALK, which are TGF-β receptors that function in integrity of vessel structures. • Type 1 (HHT1) is due to loss of function gene mutation of ENG (9q3). • Type 2 (HHT2) is due to loss of function gene mutation of ALK1 (12q13). • There is a third type of HHT associated with juvenile polyposis.

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • Generalized essential telangiectasia • Unilateral nevoid telangiectasia • Scleroderma with CREST syndrome • Rosacea • Actinic keratosis • Ataxia telangiectasia • Venous hypertension • Cushing syndrome WORKUP Diagnosis can generally be made from a detailed history and physical exam if at least three of these four criteria are present: 1. Spontaneous recurrent epistaxis 2. Multiple telangiectasias (in multiple sites such as face, mouth, and lips) 3. Visceral lesions such as arteriovenous malformations (AVMs) may result in GI bleeding or hepatic, pulmonary, cerebral, or spinal hemorrhage 4. First-degree relative with diagnosed HHT If two criteria are present, there is a possible diagnosis. LABORATORY TESTS • Complete blood cell count (CBC), including platelet count, to evaluate anemia and rule out thrombocytopenia; coagulation profile. Patients with this disorder have normal levels of clotting factors and an intact clotting mechanism • Ferritin level, stool for occult blood • Endoscopy (upper and lower), angiography IMAGING STUDIES • Electron microscopy shows lack of pericytes. • Chest radiograph.

TREATMENT

FIG. E1  Hereditary hemorrhagic telangiectasia. (From James WD et al: Andrews’ diseases of the skin, ed 12, Philadelphia, 2016, Elsevier.)

NONPHARMACOLOGIC THERAPY • Laser ablation of symptomatic lesions • GI bleeding prophylaxis • Angiographic embolization • Segmental bowel resection • Surgical correction of AV malformations • Dermoplasty of the bleeding nasal septum

ACUTE GENERAL Rx • Optimal therapy remains elusive. Trials comparing topical intranasal treatment with bevacizumab vs. estriol vs tranexamic acid vs. nasal saline spray showed that there was no advantage to topical therapy with these medications compared with frequent saline sprays for reducing the frequency of epistaxis in patients with HHT. • In those without a history of pulmonary AV malformations, tamoxifen 20 mg/day (antiestrogen) or aminocaproic acid (antifibrinolytic) therapies may be considered. • In severe cases may consider use of agents such as thalidomide or lenalidomide to block VEGF (high VEGF levels lead to disorganized and tortuous vessels). • Trials suggest some potential use of phosphoinositide 3-kinase inhibitor BKM120. CHRONIC Rx Iron replacement for anemia due to blood loss DISPOSITION Prognosis depends on areas affected by AV malformations. REFERRAL To ENT and vascular surgeon for correction of vascular malformations, gastroenterologist for esophagogastroduodenoscopy

PEARLS & CONSIDERATIONS • Primary manifestations usually occur before puberty and are characterized as epistaxis. Later, hemorrhages of GI and genitourinary (GU) tracts occur. • Vascular abnormalities may result in portal hypertension, pulmonary AV malformations with hemoptysis, cerebrovascular accidents, and hematuria in addition to GI bleeding and anemia. • Genetic screening of first-degree relatives should be performed. • 5% to 10% of patients have pulmonary AV malformations. • In two thirds of individuals who have neurologic symptoms, the source is pulmonary AV malformations. • Those with history of pulmonary AV malformations require antibacterial prophylaxis for surgical or dental operations. • Approximately 15% to 20% of patients with AV malformations in the lungs present with stroke due to embolic abscesses.

COMMENTS Affected children may experience recurrent epistaxis before detection of the characteristic skin and mucous membrane lesions. PREVENTION Seek genetic counseling if one has a family history of Osler-Rendu-Weber syndrome. PATIENT & FAMILY EDUCATION HHT Foundation International: http://hht.org AUTHORS: Fred F. Ferri, MD, and Heather Ferri, DO

Hereditary Hemorrhagic Telengiectasia SUGGESTED READINGS Dupuis-Girod S et al: Effect of bevacizumab nasal spray on epistaxis duration in hereditary hemorrhagic telangiectasia, JAMA 316(9):934-942, 2016. Guldmann R et al: Bevacizumab nasal spray: noninvasive treatment of epistaxis in patients with Rendu-Osler disease, Laryngoscope 122:952-955, 2012. Wang XY et al: Successful treatment of thalidomide for recurrent bleeding due to gastric angiodysplasia in hereditary hemorrhagic telangiectasia, Eur Rev Med Pharmacol Sci 17(8):1114-1116, 2013. Whitehead KJ et al: Effect of topical intranasal therapy on epistaxis frequency in patients with hereditary hemorrhagic telangiectasia, J Am Med Assoc 316(9):943-951, 2016. Yaniv E et al: Anti-estrogen therapy for hereditary hemorrhagic telangiectasia: a long-term clinical trial, Rhinology 49(2):214-216, 2011.

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Herpangina BASIC INFORMATION DEFINITION Herpangina is a self-limited upper respiratory tract infection associated with a characteristic vesicular rash on the soft palate. SYNONYMS Vesicular stomatitis Acute lymphonodular pharyngitis ICD-10CM CODE B08.5 Enteroviral vesicular pharyngitis

EPIDEMIOLOGY & DEMOGRAPHICS PREDOMINANT SEX: Male = female PREDOMINANT AGE: 3 to 10 yr PHYSICAL FINDINGS & CLINCIAL PRESENTATION • Characterized by ulcerating lesions typically located on the soft palate (Fig. E1) • Usually fewer than six lesions that evolve rapidly from a diffuse pharyngitis to erythematous macules and subsequently to vesicles that are moderately painful

• Fever, vomiting, and headache in the first few days of illness but subsiding spontaneously • Pharyngeal lesions typical for several more days

ETIOLOGY • Most cases caused by coxsackie A viruses (most frequently A8, A10, and A16). • Occasional cases caused by other enteroviruses (echovirus and enterovirus 71).

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • Herpes simplex • Bacterial pharyngitis • Tonsillitis • Aphthous stomatitis • Hand-foot-mouth disease WORKUP Diagnosis is typically based on characteristic lesions on the soft palate. LABORATORY TESTS • Viral and bacterial cultures of the pharynx to exclude herpes simplex infection and

streptococcal pharyngitis if the diagnosis is in doubt. • The type-specific antibodies appear in the blood about 1 wk after infection has occurred and attain their maximum titer in 3 wk.

TREATMENT • Give symptomatic treatment for sore throat: Saline gargles and analgesics, and encourage oral fluids. • No antiviral therapy indicated; avoid antibacterial agents because they are ineffective, increase cost, might result in side effects, and promote antibiotic resistance.

NONPHARMACOLOGIC THERAPY Analgesic throat lozenges are helpful in some cases. ACUTE GENERAL Rx Antipyretics when indicated CHRONIC Rx Self-limited infection DISPOSITION • Generally, resolution of symptoms within 1 wk • Persistence of fever or mouth lesions beyond 1 wk suggestive of an alternative diagnosis (see “Differential Diagnosis”) REFERRAL For consultation with otolaryngologist or infectious disease specialist if the diagnosis is in doubt.

PEARLS & CONSIDERATIONS COMMENTS Household outbreaks may occur, especially during the summer months. RELATED CONTENT Herpangina (Patient Information) AUTHOR: Fred F. Ferri, MD

FIG. E1  Herpangina with shallow ulcers in the roof of the mouth. (From Bennett JE et al [eds]: Mandell, Douglas, and Bennett’s principles and practice of infectious diseases, ed 8, Philadelphia, 2015, Elsevier.)

Herpes Simplex BASIC INFORMATION

SYNONYMS Genital herpes Herpes labialis Herpes gladiatorum Herpes digitalis Oral herpes ICD-10CM CODES A60 Anogenital herpesviral (herpes simplex) infections A60.04 Herpesviral vulvovaginitis B00

Herpesviral (herpes simplex) infections

B00.1

Herpesviral vesicular dermatitis

B00.82 Herpes simplex myelitis B00.9

Herpesviral infection, unspecified

P35.2

Congenital herpesviral (herpes simplex) infection

EPIDEMIOLOGY & DEMOGRAPHICS • More than 85% of adults have serologic evidence of HSV-1 infection. The seroprevalence of adults with HSV-2 in the U.S. is 25%; however, only approximately 20% of these persons recall having symptoms of HSV infection. • Most cases of eye or digital herpetic infections are caused by HSV-1. • Worldwide, more than 400 million persons have genital herpes caused by HSV-2. In the U.S., 1 in 5 adults is infected with HSV-2, and 1 million new infections occur yearly. • Frequency of recurrence of HSV-2 genital herpes is higher than HSV-1 oral labial infection. • The frequency of recurrence is lowest for oral labial HSV-2 infections. • The incidence of complications from herpes simplex (e.g., herpes encephalitis) is highest in immunocompromised hosts. • Male circumcision significantly reduces the incidence of HSV-2. PHYSICAL FINDINGS & CLINCIAL PRESENTATION PRIMARY INFECTION: • Symptoms occur from 3 to 7 days after contact (respiratory droplets, direct contact). • Constitutional symptoms include low-grade fever, headache and myalgias, regional lymphadenopathy, and localized pain.

ETIOLOGY HSV-1 and HSV-2 are both DNA viruses.

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • Impetigo • Behçet syndrome • Coxsackie virus infection • Syphilis • Stevens-Johnson syndrome • Herpangina • Aphthous stomatitis • Varicella • Herpes zoster WORKUP Diagnosis is based on clinical presentation. Laboratory evaluation confirms diagnosis.

LABORATORY TESTS • Direct immunofluorescent antibody slide tests provide a rapid diagnosis. • Viral culture is the most definitive method for diagnosis; results are generally available in 1 or 2 days. The lesions should be sampled during the vesicular or early ulcerative stage; cervical samples should be taken from the endocervix with a swab. • Pap smear will detect HSV-infected cells in cervical tissue from women without symptoms. • Serologic tests for HSV: Immunoglobulin (Ig) G and IgM serum antibodies. Antibodies to HSV occur in 50% to 90% of adults. The presence of IgM or a fourfold or greater rise in IgG titers indicates a recent infection (convalescent sample should be drawn 2 to 3 wk after the acute specimen is drawn). • Tzanck smear is a readily available test that will demonstrate multinucleated giant cells. However, it is not a highly sensitive test.

TREATMENT • Table 1 summarizes antiviral chemotherapy for HSV infection. • Topical acyclovir, penciclovir, and docosanol are optional treatments for recurrent herpes labialis, but they are less effective than oral treatments.

DISPOSITION Most patients recover from the initial episode or recurrences without complications; immunocompromised hosts are at risk for complications (e.g., disseminated herpes simplex infection, herpes encephalitis). REFERRAL • Hospital admission in patients with herpes encephalitis or herpes meningitis and in immunocompromised hosts with diffuse herpes simplex infection • Ophthalmology referral in patients with suspected ocular herpes

PEARLS & CONSIDERATIONS COMMENTS • Provide patient education regarding transmission of HSV. • Condom use offers significant protection against HSV-1 infection in susceptible women. • Patients should be instructed on the use of condoms for sexual intercourse and on avoiding kissing or sexual intercourse until lesions are crusted. Pericoital application of tenofovir gel, an antiretroviral vaginal gel, has also been shown to reduce the risk of HSV-2 in women. This may be useful in regions of the world where use of condoms is shunned. • Patients should also avoid contact with immunocompromised hosts or neonates while lesions are present.

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Diseases and Disorders

DEFINITION Herpes simplex is a viral infection caused by the herpes simplex virus (HSV). HSV-1 is associated primarily with oral infections, and HSV-2 causes mainly genital infections. However, either type can infect any site. After the primary infection, the virus enters the nerve endings in the skin directly below the lesions and ascends to the dorsal root ganglia, where it remains in a latent stage until it is reactivated.

• Pain, burning, itching, and tingling last several hours. • Grouped vesicles, usually with surrounding erythema, appear and generally ulcerate or crust within 48 h (Fig. E1). • The vesicles are uniform in size (differentiating it from herpes zoster vesicles, which vary in size). Scattered erosions covered with exudate may be noted on genitals (Fig. E2). • During the acute eruption the patient is uncomfortable; involvement of lips and inside of mouth (Fig. E3) may make it unpleasant for the patient to eat; urinary retention may complicate involvement of the genital area. • Lesions generally last from 2 to 6 wk and heal without scarring. RECURRENT INFECTION: • Generally caused by alteration in the immune system; fatigue, stress, menses, local skin trauma, and exposure to sunlight are contributing factors. • The prodromal symptoms (fatigue, burning and tingling of the affected area) last 12 to 24 hr. • A cluster of lesions generally evolves within 24 hr from a macule to a papule and then vesicles surrounded by erythema; the vesicles coalesce and subsequently rupture within 4 days, revealing erosions covered by crusts. • The crusts are generally shed within 7 to 10 days, revealing a pink surface. • The most frequent location of the lesions is on the vermilion border of the lips (HSV-1), the penile shaft or glans penis and the labia (HSV-2), buttocks (seen more frequently in women), fingertips (herpetic whitlow), and trunk (may be confused with herpes zoster). • Rapid onset of diffuse cutaneous herpes simplex (eczema herpeticum) may occur in certain atopic infants and adults. It is a medical emergency, especially in young infants, and should be promptly treated with acyclovir. • Herpes encephalitis, meningitis, and ocular herpes can occur in patients with immunocompromised status and occasionally in normal hosts.

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Herpes Simplex TABLE 1  Topical and Oral Antiviral Medications Used for Herpes Simplex Virus Infections* Drug Topical Acyclovir

Penciclovir Docosanol Oral (all Rx) Acyclovir

Famciclovir

Valacyclovir

Formulation

Regimen

Indication/Comment

5% cream (2 g, 5 g) 5% ointment (15 g, 30 g) 1% cream (1.5 g, 5 g)

Apply 5 times/day Apply 6 times/day

Recurrent HL; A: ≥12 yr; 4 days; Rx Initial GH, localized HSV; A: adults; 7 days; Rx Recurrent HL; A: ≥12 yr; 4 days; Rx

10% cream (2 g)

Apply q2h (awake) Apply 5 times/day

HL; A: ≥12 yr; treat until healed; OTC A: ≥2 yr

200 mg capsule 400 mg, 800 mg tablet 200 mg/5 ml susp 200 mg 5 times/ day 200 mg 5 times/ day 400 mg 2 times/ day

Initial GH; 10 days

1500 mg single dose 1000 mg 2 times/day 250 mg 2 times/ day

Recurrent HL

125, 250, 500 mg tablet

500 mg, 1 g caplet 1 g 2 times/day 500 mg 2 times/ day 500 mg-1 g once daily 2 g 2 times/day

Recurrent GH; 5 days Suppression, recurrent GH; up to 12 mo, then reevaluate A: ≥18 yr

Recurrent GH; 1 day Suppression, recurrent GH; up to 12 mo A: adults and ≥12 yr for HL Initial GH; 10 days Recurrent GH; 3 days Suppressive GH HL; 1 day; both adults and children ≥12 yr

*Approved indications and regimens listed; often used off-label. A, Approved; GH, genital herpes; HL, herpes labialis; HSV, herpes simplex virus; OTC, over-the-counter; Rx, by prescription. From Paller AS, Mancini AJ: Hurwitz clinical pediatric dermatology: a textbook of skin disorders of childhood and adolescence, ed 5, Philadelphia, 2016, Elsevier.

• Proper handwashing techniques should be explained. • Patients with herpes gladiatorum (cutaneous herpes in athletes involved in contact sports) should be excluded from participation in active sports until lesions have resolved. • Many new HSV-2 infections are asymptomatic. Since HSV-2 antibody tests have become commercially available, an increasing number of persons have learned that they have genital herpes through serologic testing. Persons with asymptomatic HSV-2 infection shed virus in the genital tract less frequently than persons with symptomatic infection, but much of the difference is attributable to less frequent genital lesions because genital lesions are accompanied by frequent viral shedding. The U.S. Preventive Services Task Force (USPSTF) recommends against routine serologic screening for genital HSV infection in asymptomatic adolescents and adults, including those that are pregnant. • Suppressive treatment of HSV-2 infection lowers the incidence of genital lesions by 70% to 80%, but cuts the rate of HSV-2 transmission to uninfected partners by only 50%. • Pregnancy: Antiviral prophylaxis with acyclovir is recommended from 36 wk of gestation until delivery in women with a history of genital herpes. Elective cesarean delivery should be performed in laboring patients with active lesions to decrease the risk of neonatal herpes. • Trials involving investigational herpes simplex vaccine have found it to be effective in preventing HSV-1 genital disease and infection, but not in preventing HSV-2 disease or infection.

RELATED CONTENT Genital Herpes (Patient Information) Oral Herpes (Patient Information) AUTHOR: Fred F. Ferri, MD

High-Altitude Sickness

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FIG. E1  Herpetic gingivostomatitis. Multiple erosions with crusting. Note the associated lesions involving the chin. (From Paller AS, Mancini AJ: Hurwitz clinical pediatric dermatology: a textbook of skin disorders of childhood and adolescence, ed 5, 2016, Elsevier.)

A

B

FIG. E2  Primary herpes simplex. A, Scattered erosions covered with exudate. B, Numerous erosions appeared 4 days after contact with an asymptomatic carrier. (From Habif TP: Clinical dermatology, ed 4, Philadelphia, 2004, Mosby.)

Herpes Simplex

FIG. E3  Herpes labialis. Erythematous erosions clustered on the right lower lip in a patient with labial herpes. This young girl also had herpes-associated erythema multiforme. (From Paller AS, Mancini AJ: Hurwitz clinical pediatric dermatology: a textbook of skin disorders of childhood and adolescence, ed 5, 2016, Elsevier.)

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Herpes Simplex Keratitis BASIC INFORMATION DEFINITION Corneal infection with herpes simplex virus (HSV-1 or HSV-2). SYNONYMS Herpes simplex keratoconjunctivitis Herpes simplex dendritic keratitis Herpes simplex stromal keratitis Herpetic keratitis ICD-10CM CODE B00.52  Herpes viral keratitis

EPIDEMIOLOGY & DEMOGRAPHICS INCIDENCE: 5/100,000 to 15/100,000 per yr PEAK INCIDENCE: After an episode of ocular HSV, there is a 30% chance of a recurrence within a 1-yr period. PREVALENCE: 149/100,000 people PREDOMINANT SEX & AGE: Equal, although some studies report a slight male predominance. There are no known patterns of age of presentation. GENETICS: There are no known patterns of genetic inheritance. RISK FACTORS: Risk factors include close physical contact with an HSV disease carrier and primary or latent infection with HSV-1 or HSV-2. Neonatal ocular HSV can result from direct maternal transmission. The landmark Herpetic Eye Disease Study (HEDS) found that prior stromal keratitis increases the chances of recurrent stromal keratitis, but prior epithelial keratitis does not increase the chance of recurrent epithelial keratitis. That study also found that proposed triggers of recurrent disease, including psychological stress, systemic infection, sunlight exposure, menstruation, contact lens wear, and eye injury, are not associated with an increased recurrence rate. PHYSICAL FINDINGS & CLINCIAL PRESENTATION • Ocular manifestations of HSV infection include periocular vesicular skin lesions, conjunctival injection, follicular conjunctivitis, iridocyclitis, elevated intraocular pressure, and keratitis. • Patients commonly present with a red eye, ocular pain, tearing, and/or photophobia. • HSV can affect any part of the cornea and present as epithelial keratitis, stromal keratitis, or endotheliitis. Corneal findings are best visualized using slit-lamp microscopy. Classic dendritic lesions in epithelial keratitis can be seen with a cobalt blue light or a Wood’s light following administration of topical fluorescein. • Presentation is usually unilateral and may occur in the setting of a concurrent upper respiratory infection or other systemic conditions. Recurrent HSV infections may occur

in a patient with a history of prior “eye infections.”

ETIOLOGY HSV keratitis results from HSV-1 or (less commonly) HSV-2 infection of the cornea and the subsequent host immune and inflammatory response. HSV keratitis most often represents reactivation of a latent infection in the trigeminal ganglion. Primary infection is rarely clinically evident.

DIAGNOSIS DIFFERENTIAL DIAGNOSIS Herpes zoster ophthalmicus, corneal abrasion, recurrent corneal erosion, viral conjunctivitis, allergic conjunctivitis, acanthamoeba keratitis WORKUP Ocular HSV disease is most often a clinical diagnosis, although diagnosis may be aided by cytologic, molecular, and immunologic assays described in the following. LABORATORY TESTS Culture of corneal or vesicular skin lesion scrapings or cytologic examination with Giemsa stain. PCR and a variety of immunologic assays can also aid with diagnosis but are of limited availability. Serologic antibody testing can help exclude HSV as a diagnosis with a negative result, but positive results are of limited value given the high seroprevalence of HSV.

TREATMENT The treatment of ocular herpetic disease is determined by the location and extent of disease involvement, with several recommendations resulting from the HEDS study. Oral antivirals and topical antivirals are the mainstay of treatment. Topical antivirals are typically reserved for epithelial keratitis. Oral antivirals are preferred for stromal and endothelial disease. Topical antibiotics and topical corticosteroids are also used in select cases.

NONPHARMACOLOGIC THERAPY • Corneal epithelial involvement may benefit from the addition of epithelial debridement, and nonhealing epithelial defects may be addressed with bandage contact lenses or tarsorrhaphy. • After resolution of keratitis, corneal stromal scars may be managed surgically with partial-thickness (i.e., deep anterior lamellar keratoplasty) or full-thickness penetrating keratoplasty (corneal transplantation). ACUTE GENERAL Rx • Systemic antiviral treatment options: Acyclovir 400 mg PO five times daily, valacyclovir 500

mg PO bid, famciclovir 125 to 250 mg PO bid for 7 to 14 days • Eyelid involvement only: Systemic antiviral, antibiotic ointment bid, and warm or cool compresses PRN for comfort • Eyelid margin, corneal epithelial, and/or conjunctival involvement: Systemic antiviral or topical antiviral (ganciclovir 0.15% gel, trifluridine 1% drops) five times daily, topical antibiotic qid (i.e., fourth-generation fluoroquinolone) • Corneal stromal involvement: Systemic antiviral, topical steroid (i.e., prednisolone acetate 1% qid), cycloplegic (i.e., cyclopentolate 1% bid) • Iridocyclitis/trabeculitis: Systemic antiviral, topical steroids with or without systemic steroids

CHRONIC Rx • When used, topical antivirals are typically continued for 1 to 2 wk until the epithelial defect is healed. • Topical steroids for corneal stromal involvement are tapered slowly over wks to mos. • Prophylactic oral antivirals (acyclovir 400 mg or famciclovir 125 mg PO bid) may be used indefinitely for severe cases and have been shown to reduce the rate of recurrences. DISPOSITION Patients with ocular HSV require referral and close follow-up with ophthalmology, initially every 1 to 2 days, with extended follow-up based on clinical course. REFERRAL A patient with suspected ocular herpetic disease should be started on systemic antivirals and then referred promptly for evaluation by an ophthalmologist.

PEARLS & CONSIDERATIONS COMMENTS Herpes simplex is one of the most common causes of corneal blindness. Physicians from all specialties should be aware of the high seroprevalence of the herpes simplex virus and maintain a high index of suspicion for ocular herpetic disease when patients with or without a known history of herpes simplex present with ocular complaints such as red eye, ocular pain, and photophobia. Treatment with systemic antiviral medication and prompt referral to an ophthalmologist are crucial early steps in the management of suspected disease. PREVENTION Despite significant interest, there is currently no HSV vaccine available. Given the high prevalence of HSV in the community, it is difficult to prevent systemic and ocular HSV infection. In

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Herpes Simplex Keratitis patients who have a history of ocular HSV, there is evidence to support the efficacy of maintenance systemic antiviral medication to prevent disease recurrences.

PATIENT & FAMILY EDUCATION American Academy of Ophthalmology: http://www.aao.org/eye-health/diseases/herpeskeratitis

SUGGESTED READING White ML, Chodosh J: Herpes simplex virus keratitis: a treatment guideline 2014, Ophthalmology 2014. Available at https://www.aao.org/clinical-statement/herpes-simplex-virus-keratitis-treatment-guideline.

682.e4 RELATED CONTENT Herpes Simplex (Related Key Topic) Herpes Zoster (Related Key Topic) AUTHOR: Thomas H. Dohlman, MD

ALG   Herpes BASIC INFORMATION

SYNONYMS Shingles HZ ICD-10CM CODES B02 Herpes zoster B02.0 Zoster encephalitis B02.1 Zoster meningitis B02.30 Zoster ocular disease, unspecified B02.31 Zoster conjunctivitis B02.32 Zoster iridocyclitis B02.33 Zoster keratitis B02.34 Zoster scleritis B02.39 Other herpes zoster eye disease B02.7 Disseminated zoster B02.8 Zoster with other complications B02.9 Zoster without complications

EPIDEMIOLOGY & DEMOGRAPHICS • Herpes zoster occurs during the lifetime of 10% to 20% of the population. There are approximately 1 million cases annually in the U.S. The incidence of herpes zoster has increased fourfold over the past six decades. • There is an increased incidence in immunocompromised patients (chemotherapy, radiotherapy, immunosuppression due to corticosteroids, AIDS, DM, malignancy), the elderly (most common after age 60) (Fig. E1), and children who acquired chickenpox when younger than 2 mo. PHYSICAL FINDINGS & CLINCIAL PRESENTATION • Pain generally precedes skin manifestation by 3 to 5 days and is generally localized to the dermatome that will be affected by the skin lesions. • Constitutional symptoms are often present (malaise, fever, headache). • The initial rash consists of erythematous maculopapules generally affecting one dermatome (thoracic region in majority of cases [Fig. E2]). Typically the rash does not cross the midline. Some patients (70% of patients.

• Rates of HZ recurrence are more frequent than previously reported and are comparable to rates of first HZ occurrence in immunocompetent individuals.

REFERRAL • Hospitalization for IV acyclovir in patients with disseminated herpes zoster. • Patients with herpes zoster ophthalmicus should be referred to an ophthalmologist. • Consultation with an otolaryngologist is advisable in patients with Ramsey Hunt syndrome. • Vaccination: In the absence of the herpes zoster vaccine, persons who live to 85 yr of age have a 50% risk of herpes zoster. Immunocompetent adults ≥50 yr (including those who have already received Zostavax) are appropriate candidates for recombinant varicella zoster virus vaccine (Shingrix). It consists of 2 doses 2 to 6 mo apart and is

preferred over Zostavax for herpes zoster prevention. Adults who are VZV seronegative (never had varicella) should be immunized against varicella with two doses of varicella vaccine (Varivax). Despite its efficacy and safety, use of this vaccine remains low (2 cm of gastric rugal fold seen above the margins of the diaphragmatic crura is diagnostic. • Abdominal ultrasonography: Simple, well tolerated. A transdiaphragmatic esophageal diameter of ≥18 mm is highly suggestive of the presence of a sliding hiatal hernia. • Computed tomography: Hiatal hernia is often seen as an incidental finding on CT scans done for other reasons.

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TREATMENT NONPHARMACOLOGIC THERAPY • Lifestyle modifications: Avoid foods and drugs that decrease lower-esophageal pressure (e.g., caffeine, chocolate, mint, calcium channel blockers, and anticholinergics). • Weight loss, decrease in abdominal circumference. • Avoid large meals. • Sleep with the head of the bed elevated 6 inches. ACUTE GENERAL Rx • Antacids may be useful to relieve mild symptoms.

FIG. E2  Type II hiatal hernia. (From Sellke FW et  al: Sabiston & Spencer surgery of the chest, ed 9, Philadelphia, 2016, Elsevier.)

A

• H2 antagonists (e.g., ranitidine 150 mg bid or 300 mg qd, or famotidine 20 mg bid). • If significant GERD is present with documented esophagitis, proton pump inhibitors (PPIs, e.g., omeprazole 20 mg qd or lansoprazole 30 mg qd) are used. Refractory symptoms may require higher doses (e.g., bid dosing). • Prokinetic agents (e.g., metoclopramide 10 mg taken 30 min before each meal) can be added to an H2 antagonist or PPI.

CHRONIC Rx • When indicated, surgery (laparoscopic or open) can be done in patients with refractory symptoms impairing quality of life or causing intestinal (e.g., recurrent GI bleeds) or extraintestinal complications (e.g., aspiration pneumonia, asthma, or ear, nose, and throat complications). • Prophylactic surgery is a consideration in all paraesophageal hernias because they have a higher incidence of strangulation. DISPOSITION • More than 90% of patients with GERD symptoms respond well to medical therapy. • Complications of hiatal hernias are similar to complications occurring in patients with GERD: 1. Erosive esophagitis 2. Ulcerative esophagitis 3. Barrett esophagus 4. Peptic stricture 5. GI hemorrhage 6. Extraintestinal complications 7.  Lung collapse or heart failure (severe cases)

B

FIG. E3  Type III hiatal hernia. Barium esophagram demonstrates a type III hiatal hernia with organoaxial rotation. A, Posteroanterior view. B, Lateral view. (From Sellke FW et al: Sabiston & Spencer surgery of the chest, ed 9, Philadelphia, 2016, Elsevier.)

Hiatal Hernia

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REFERRAL • Gastroenterologist for symptoms refractory to conventional therapy (H2 antagonists, antacids, and PPIs) or having complications previously mentioned. • General surgery evaluation for large hiatal hernia or severe complications. • Indications for emergent surgical evaluation include acute volvulus, uncontrolled bleeding, obstruction, strangulation, perforation, or respiratory compromise.

PEARLS & CONSIDERATIONS COMMENTS • Gastric ulceration and erosions (Cameron lesion) can occur in the paraesophageal hernia pouch and are an uncommon cause of UGI bleeding. • May cause iron deficiency anemia.

A

• Gastric volvulus or torsion can also occur and presents as dysphagia and postprandial pain. • High incidence of esophagitis even after the eradication of Helicobacter pylori. • The appearance of hiatal hernia may resemble a left atrial mass by echocardiography.

RELATED CONTENT Hiatal Hernia (Patient Information) AUTHORS: Ana Castaneda-Guarderas, MD, and Caleb Cantrell, BS

B

C FIG. E4  Type IV hiatal hernia. A, Barium esophagram demonstrates a type III hiatal hernia with organoaxial rotation. Three days later, barium is seen in colonic diverticulum on preoperative chest radiograph. B, Posteroanterior view. C, Lateral view. Therefore, this is a type IV hiatal hernia. (From Sellke FW et al: Sabiston & Spencer surgery of the chest, ed 9, Philadelphia, 2016, Elsevier.)

Hiatal Hernia SUGGESTED READINGS Menon S, Trudgill N: Risk factors in the aetiology of hiatus hernia: a meta-analysis, Eur J Gastroenterol Hepatol 23(2):133-138, 2011. Siegal SR et al: Modern diagnosis and treatment of hiatal hernias, Langenbecks Arch Surg, 2017.

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Hidradenitis Suppurativa BASIC INFORMATION DEFINITION Hidradenitis suppurativa (HS) is a chronic, relapsing suppurative cutaneous disease affecting skin that bears apocrine glands and is manifested by abscesses, fistulating sinus tracts, and chronic infection leading to scarring. SYNONYMS Acne inversa Apocrinitis Verneuil disease HS ICD-10CM CODE L73.2 Hidradenitis suppurativa

EPIDEMIOLOGY & DEMOGRAPHICS Onset is postpubertal, with an average age of onset of 23 yr; rates decline after age 55 yr. PREVALENCE: Overall prevalence in the United States is ∼1% to 2%. PREDOMINANT SEX: Female: male ratio is 3:1. PREDOMINANT AGE: HS most often manifests after puberty, usually in the second or third decade of life. It is rare in the elderly. RISK FACTORS: • Obesity and metabolic syndrome • Family history (approximately 30%) • Hyperandrogenism in women • Cigarette smoking PHYSICAL FINDINGS & CLINICAL PRESENTATION The diagnosis is primarily clinical, based on the development of typical lesions in a characteristic distribution, with a relapsing nature. The course of HS is prolonged and marked by intermittent periods of activity and remission. • Early symptoms include pain, itching, burning, erythema, and hyperhidrosis. • Typical lesions include: 1. Painful erythematous papules and nodules leading to painful abscesses with foul-smelling discharge. 2. Dermal contractures and ropelike elevation of the skin. 3. Comedones in the apocrine, gland-bearing skin. • Classified into Hurley Stages (Table E1): 1. Stage I: Abscesses without sinus tracts or scarring. 2. Stage II: Multiple abscesses plus sinus tracts and scarring. 3.  Stage III: Diffuse involvement of entire area with abscesses, sinus tracts, and scarring. • The axilla is the most common site (Fig. E1). • Less common sites include the inguinal region, the breasts (more often in women), and the perineal or perianal skin (more often in men). • There is a strong tendency toward relapse and recurrence.

TABLE E1  Hidradenitis Suppurativa—Grading Systems and Therapeutic Ladder Hurley Staging System • Stage I—one or more abscesses with no sinus tract or scar formation • Stage II—one or more widely separated recurrent abscesses, with sinus tract and scar formation • Stage III—multiple interconnected sinus tracts and abscesses throughout an affected region; more extensive scarring

Sartorius Grading System • Anatomical regions involved: Axilla (left and/or right), groin (left and/or right), gluteal (left and/or right), or other region (e.g., inframammary): 3 points per region involved • Number and scores of lesions for each region: Nodules = 1; fistulae = 6 • The longest distance between two relevant lesions* (i.e., nodules and fistulae) in each region: 10 cm = 9 • Are all lesions clearly separated by normal skin? In each region—yes 0/no (Hurley III) 9

Therapeutic Ladder Indication

Therapeutic Interventions

General measures

• If obese or overweight, weight reduction • Reduce friction and moisture via loose undergarments, absorbent powders, and topical aluminum chloride • Antiseptic soaps • Smoking cessation • Intralesional triamcinolone (5 mg/ml) injections into early inflammatory lesions • Topical clindamycin • Eradication of S. aureus carriage with topical mupirocin in nose, axillae, umbilicus, and perianal regions • Oral antibiotics tailored to results of bacterial cultures from pustular discharge or abscess contents • Oral antibiotic therapy (alone or in combination) for its anti-inflammatory effect (rifampin + clindamycin, tetracycline, doxycycline, minocycline, dapsone, trimethoprim–sulfamethoxazole) • Oral anti-androgen therapy (e.g., finasteride) • Oral antibiotic therapy (see Stage I) • Acitretin • Systemic immunosuppressive agents including adalimumab,† infliximab, and cyclosporine • Surgical treatments‡ • Limited local excisions with second intention healing • CO2 laser ablation with second intention healing • Nd:YAG laser treatments, at least 3-4 monthly sessions

Hurley Stage I

Hurley Stage II

Hurley Stage III

Medical treatments outlined for Stages I and II Surgical treatments‡ • Early wide surgical excision of involved areas • CO2 laser ablation with second intention healing

†FDA-approved

dosing regimen: 160 mg (four 40 mg injections) on day 1, or 80 mg daily on days 1 and 2 followed by 80 mg on day 15 and then 40 mg on day 29 and weekly thereafter. ‡Incision and drainage are discouraged given high rate of recurrence. From Bolognia J: Dermatology, ed 4, Philadelphia, 2018, Elsevier.

• There is often a poor response to conventional antibiotics and no pathogens isolated from cultures of lesions. • The disease is often mistaken for a simple infection and a long delay in diagnosis is common. • Three clinical subtypes of HS have been recently proposed1: 1. A classic axillary-mammary HS subtype, representing 48% of cases and characterized by breast and axillary involvement and hypertrophic scarring. 2. A follicular HS subtype, representing 26% of cases manifesting primarily in male 1Woodruff

CM, Charlie AM, Leslie KS: Hidradenitis suppurative: a guide for the practicing physician, Mayo Clin Proc 90(12):1679-1693, 2015.

smokers with a family history of HS and characterized by follicular lesions, including epidermal cysts, pilonidal sinus, comedones, and severe acne. 3. A gluteal HS subtype, representing 26% of cases, most often seen in smokers with lower body mass index (BMI) and with a morphology characterized by follicular papules, folliculitis, and gluteal involvement.

ETIOLOGY • Keratinous materials plug apocrine glands in hair follicles leading to stasis, dilation, rupture, and re-epithelialization. Fig. E2 illustrates the pathogenesis of hidradenitis suppurativa.

Hidradenitis Suppurativa

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B

A

C

D FIG. E1  Hidradenitis suppurativa. A and B, Papulopustules, nodules, sinus tracts, and scarring in the axilla (Hurley stage II [A] and III [B]). C, Superficial sinus tracts that serve as a clue to the diagnosis, even in the absence of active disease. D, Severe disease with inflammatory nodules, hypertrophic scarring, draining fistulae, and sinus tract formation of the perianal region, buttocks, and upper thighs. This is the type of patient who is at risk for the development of squamous cell carcinoma and secondary amyloidosis. (A, Courtesy, Kalman Watsky, MD; B, Courtesy, Marco Romanelli, MD. In Bolognia J: Dermatology, ed 4, 2018, Elsevier.)

• Bacteria are trapped and multiply, leading to gland rupture with surrounding inflammation and local bacterial infection. • Over time, repeated nodules and infections cause scarring, which can lead to deep tissue damage and sinus tracts. • Infectious agents such as Streptococcus, Staphylococcus, and Escherichia coli, and enteric flora have been identified in cultures but are likely a secondary component of the disease. • There is likely a significant genetic component to the disease. 35% to 40% of patients report a family history of HS. An HS spectrum of different phenotypes has been characterized involving genetic factors that are not

yet well described but may be important for future therapy. • HS has been associated with other endocrine and autoimmune disorders such as diabetes, Cushing syndrome, acromegaly, Crohn disease, and inflammatory arthritis. • Metabolic syndrome affects as many as 50% of patients with HS and may exacerbate the associated inflammation.

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • Follicular pyodermias such as folliculitis, furuncles, carbuncles, and pilonidal cysts

• Noduloulcerative syphilis • Cat scratch disease • Granuloma inguinale • Perianal and vulvar manifestations of Crohn disease • Actinomycosis • Lymphogranuloma venereum • Dermoid, epidermoid, or Bartholin cysts • Tuberculous inflammation of the skin • Lymphadenitis • Erysipelas

WORKUP Primarily a clinical diagnosis based on typical lesions (see “Physical Findings & Clinical Presentation”).

Hidradenitis Suppurativa

684.e8 • Adalimumab, an antitumor necrosis factor-α antibody given once per week (dose 40 mg/ wk) has shown significantly higher clinical response as compared to placebo in phase 3 trials. Infliximab has also been used in trials with variable success rates, with most patients exhibiting clinical improvement within 8 wk.

A

B

C

FIG. E2  Pathogenesis of hidradenitis suppurativa, an inflammatory disease of the apocrine sweat glands and adjacent connective tissue. A, The initiating event is occlusion of the apocrine duct by a keratinous plug. B, Bacteria are trapped beneath the keratinous plug and multiply to form an abscess, which can rupture into adjacent tissue. C, The end result is recurrent abscesses, chronic draining sinuses, and indurated scarred skin and subcutaneous tissues. Often, multiple tracts are interconnected and lead to the skin. (From James WD et al: Andrews’ diseases of the skin, ed 12, Philadelphia, 2016, Elsevier.)

LABORATORY TESTS • Patients with acute lesions may have an elevated erythrocyte sedimentation rate or WBC. • Febrile and toxic-appearing patients should have complete blood count, chemistries, and blood cultures. • Any pus should be sampled for bacterial culture and sensitivity.

TREATMENT There is no definitive cure for hidradenitis.

NONPHARMACOLOGIC THERAPY • Weight loss and control of metabolic syndrome • Smoking cessation • Avoidance of shaving, depilatory creams, deodorants • Avoidance of tight-fitting clothing • Warm compresses • Incision and drainage of nonpurulent lesions is not recommended due to recurrence and scarring • Laser therapy, radiotherapy, and cryotherapy currently under study • Wide local excision for stage III disease with or without vacuum-assisted closure device ACUTE AND CHRONIC Rx • NSAIDs for inflammation and pain, consider gabapentin, pregabalin, SSRIs for chronic pain management.

• Antibiotics never proven to be effective; however, they are a mainstay of treatment. Can base treatment on the basis of aspirate culture and sensitivities or empirically. 1. Clindamycin is the only topical antibiotic proven to be effective in randomized controlled trial and is appropriate for stage I disease. 2. For oral therapy in stage II: Consider clindamycin and rifampin in combination. Cephalosporins, dicloxacillin, erythromycin, minocycline, and tetracycline have also been used. 3. Severe, recurrent disease can require up to 3 to 6 mo of antibiotics. • Oral contraceptives with low androgenic progesterone (norgestimate, desogestrel, or gestodene) for women show mixed effectiveness. They are especially advantageous for female patients of childbearing age who also require some form of birth control. • Isotretinoin has been used with mixed effectiveness. It should be avoided in women of childbearing age. • Metformin has mixed effectiveness, possibly due to related metabolic syndrome and hyperandrogenism. • Trials using zinc gluconate 75 to 118 mg/day in patients with mild (grade 1) disease have shown mixed effectiveness. • Corticosteroids and other immune suppressants such as cyclosporin, infliximab, and etanercept have been used for stage II disease, with mixed results.

COMPLICATIONS • Squamous cell carcinoma • Scarring leading to restricted limb mobility or lymphedema • Rectal or urethral fistulas • Psychological effects related to disfiguring nature of disease REFERRAL • Referral to dermatology during stage I to II disease. • Referral to a surgeon is indicated for stage III disease. • Surgical approaches include laser surgery and excisional surgery.

PEARLS & CONSIDERATIONS COMMENTS • Patients with hidradenitis are at risk for severe depression, social isolation, and negatively impacted sexuality as a result of their disease. • There is an average delay in diagnosis of 12 yr and most patients are diagnosed in stage II of the disease. • It is important to maximize nonmedical treatment, start medical treatment, and refer to a surgeon early in the disease course to ensure the best quality of life for patients. • The only definitive treatment for hidradenitis is wide excision of the involved skin. SUGGESTED READINGS Available at ExpertConsult.com AUTHOR: Fred F. Ferri, MD

Hidradenitis Suppurativa SUGGESTED READINGS Collier F: Diagnosis of hidradenitis suppurativa, Br Med J 346:2121-2127, 2013. Jemec GBE: Hidradenitis suppurativa, N Engl J Med 366:158-164, 2012. Kimball AB et al: Adalimumab for the treatment of moderate to severe hidradenitis suppurativa, Ann Intern Med 157:846-855, 2012. Kimball AB et al: Two phase 3 trials of adalimumab for hidradenitis suppurativa, N Engl J Med 375:422–434, 2016. Rambhatla P et al: A systematic review of treatments for hidradenitis suppurativa, Arch Dermatol 148:439-446, 2012. Woodruff CM: Hidradenitis suppurative: a guide for the practicing physician, Mayo Clin Proc 90(12):1679-1693, 2015.

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High-Altitude Sickness BASIC INFORMATION

SYNONYMS Altitude sickness High-altitude headache Acute mountain sickness AMS High-altitude pulmonary edema High-altitude cerebral edema ICD-10CM CODES T70.29 Other and unspecified effects of high altitude W94 Exposure to high and low air pressure and changes in air pressure

EPIDEMIOLOGY & DEMOGRAPHICS • Millions of people worldwide are at risk of developing altitude sickness annually. • 80% of people who ascend to high altitudes have high-altitude headache (HAH2). • AMS is the most common of the altitude diseases. It affects approximately 40% to 50% of people ascending to 14,000 ft (4200 m) from lowland and 25% of visitors to an altitude of 2000 m (6560 ft). • The incidence of HACE is reported to be 0.1% to 2% at elevations in excess of 12,000 ft (3000 m). HACE is often complicated by concomitant HAPE. • Men are five times more likely to develop HAPE than are women. • AMS and HACE affect men and women equally. • Some studies have suggested that climbers with a prior history of HAPE have a roughly 60% chance of recurrence if they ascend to the same elevation at the same rate. PHYSICAL FINDINGS & CLINCIAL PRESENTATION (TABLE E1) HAH1 • Headache that develops within 24 hr of ascent. • Bilateral, frontal or frontotemporal, dull or pressing quality. • Mild to moderate intensity and aggravated by exertion, movement, straining, coughing, or bending. • Headache resolves within 8 hr of descent. • HAH should resolve with analgesics and/or 10 to 15 min of supplementary oxygen. • Difficult to distinguish from headaches secondary to dehydration. AMS • AMS is thought to be a progression of HAH2.

ETIOLOGY • During ascent to altitudes above sea level, the atmospheric pressure decreases. Although the percentage of oxygen in the air remains the same, the partial pressure of oxygen decreases with increased altitude, and can cause hypoxemia. Fig. E2 illustrates the effect of altitude on alveolar Pao2 and oxygen saturation. • Increased cerebral blood flow and the loss of autoregulation of intracranial pressure may contribute to increased cerebral vascular permeability and subsequent brain edema (HACE). • Hypobaric hypoxia can trigger elevated pulmonary pressures, resulting in protein-rich, hemorrhagic exudates into the lung alveoli due to a breakdown in the pulmonary bloodgas barrier (HAPE). • The body responds to low oxygen partial pressures through a process of acclimatization (see “Comments”).

DIAGNOSIS Made by clinical presentation and physical findings

DIFFERENTIAL DIAGNOSIS • Dehydration • Carbon monoxide poisoning • Hypothermia

• Infection • Substance abuse • Congestive heart failure • Pulmonary embolism • Cerebrovascular accident • Box E1 summarizes the differential diagnosis of high-altitude illnesses

WORKUP Typically the diagnosis is self-evident after history and physical examination. Laboratory tests and imaging studies help monitor cardiopulmonary and central nervous system status in patients admitted to the intensive care unit for pulmonary and/or cerebral edema. In patients with HAPE occurring at lower altitudes ( male • Caucasian > African American • 90% >65 yr old • Mean age, 80 yr old MORTALITY: 20% to 25% mortality within the first yr following the fracture RISK FACTORS • Osteoporosis • Age >75 yr old • Gait instability, foot deformities, and muscular weakness • Sensory impairment such as neuropathy • Polypharmacy • Impaired cognition, depression • Use of alcohol or benzodiazepines

• Orthostatic hypotension • Environmental hazards at home (e.g., loose rugs, exposed cords) • Subclinical hyperthyroidism

PHYSICAL FINDINGS & CLINCIAL PRESENTATION • Hip or groin pain • Displaced fractures: Affected extremity may be shortened and externally rotated (less often internally rotated) • Impacted/stressed/nondisplaced fracture: Pain with motion or ambulation; often without obvious deformity • Ecchymosis or bruising about the hip • Inability to bear weight and tenderness to palpation ETIOLOGY • Trauma • Age-related bone fragility secondary to osteoporosis or decreased bone mineral density • Increased risk of fractures in elderly (decline in muscle function, reduced bone quality, polypharmacy, or use of psychotropic medication, etc.) • Stress fractures

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • Osteoarthritis/rheumatoid arthritis of the hip • Hip dislocation • Pathologic fracture • Muscle strain or tendonitis • Lumbar disk syndrome with radicular pain • Insufficiency fracture of pelvis or pubic ramus fracture • Trochanteric bursitis • Septic hip joint • Pelvic fracture • Lateral femoral cutaneous nerve entrapment (meralgia paresthetica) • Labral tear or pathology • Paget disease • Neoplasm

WORKUP In most cases, the diagnosis is based on clinical presentation and plain radiographs (Figs. E2 and E3). Fig. E4 illustrates the Garden classification of femoral neck fractures, which classifies the fracture based on the amount of displacement or gapping between the fracture fragments and relative stability of the fracture pattern. Additional imaging may be required to aid in the diagnosis of subtle hip fractures not evident on plain radiographs (e.g., MRI for stress or occult fractures). IMAGING STUDIES • Standard radiographs should include an anteroposterior view of the pelvis and hip, and a cross-table lateral view of the hip to confirm the diagnosis. Full-length femur and knee films should also be obtained. • If initial radiographs are negative, then computed tomography (CT) or MRI may be indicated. Stress fractures can be diagnosed

Femoral head fracture

Femoral neck fracture

Intertrochanteric fracture

Subtrochanteric fracture

Greater trochanter fracture

Lesser trochanter fracture

FIG. E1  Types of hip fractures. (From Adams JG et al: Emergency medicine, clinical essentials, ed 2, Philadelphia, 2013, Elsevier.)

TABLE E1  Garden Classification of Femoral Neck Fractures Type I

Type II

Type III

Type IV

Nondisplaced, slightly impacted, incomplete fracture line The medial trabeculae of the femoral head and neck form an angle of 180 degrees The femoral head is tilted into valgus The distal fragment lies in external rotation Nondisplaced, complete fracture line The medial trabeculae of the femoral head and neck form an angle of 160 degrees Nondisplaced femoral head Normal distal alignment Complete fracture line, with displacement 50% and dissociation The femoral head trabeculae lie in alignment with those of the pelvis The femoral head is detached and frequently realigns with the acetabulum The distal fragment is proximally displaced and lies in external rotation

From Pope TL et al: Musculoskeletal imaging, ed 2, Philadelphia, 2014, Saunders.

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Hip Fracture

686.e4

shelf of femoral head due to displacement of fracture

major fracture line runs obliquely between greater and lesser trochanter zone of fracture with overlapping trabeculae

A fragment of lesser trochanter

normal lesser trochanter

FIG. E2  Intertrochanteric femur fracture: Three parts (proximal, distal, and one trochanter). Intertrochanteric femur fractures are common, with the mechanism often being a fall from standing in an elderly patient. The major fracture line usually runs obliquely between the greater and the lesser trochanters. These fractures may have two, three, or four parts classically, although severely comminuted combinations are also possible. Two-part fractures consist of the proximal and distal fragments. Threepart fractures also include a fragment of one trochanter. Four-part fractures include fragments of both trochanters. This 86-yr-old woman had an unwitnessed fall. She has a typical three-part fracture, with a fragment of the lesser trochanter visible. Note her generalized severe osteopenia. (From Broder JS: Diagnostic imaging for the emergency physician, Philadelphia, 2011, Saunders.)

with CT scan; however, MRI is the preferred study for the diagnosis of occult fractures. Bone scanning may also be used to identify fractures.

TREATMENT • Orthopedic consultation: The majority of hip fractures are treated surgically, with nonoperative management reserved for patients with significant medical comorbidities, severe dementia, or patients who are nonambulatory preinjury. • Preoperative workup: CBC, BMP, type and screen, coagulation panel, chest radiograph, ECG, and urinalysis. • Surgery is indicated in most cases, with the goal of surgical fixation within 24 to 48 h. Repair within 24 h is associated with lower complication rates and lower 30-day mortality. Treatment depends on fracture pattern and stability: 1. Femoral neck, nondisplaced/valgus impacted: Internal fixation with 3 cannulated screws 2. Displaced femoral neck: 65 yr old: Total hip arthroplasty for healthy, active patients and hemiarthroplasty for frail or sick patients

B

FIG. E3  Femoral neck fracture. This 84-yr-old woman had an unwitnessed fall. A, Normal right hip, osteoporotic. B, Left hip, another relatively subtle femoral neck fracture. Note the smudging of the trabeculae of the femoral neck. In addition, the distal fragment has shifted medially, creating an overhanging ledge of the femoral head not seen on the opposite normal side. Some femoral neck fractures are more obvious. (From Broder JS: Diagnostic imaging for the emergency physician, Philadelphia, 2011, Saunders.)

4. Intertrochanteric fractures: Intramedullary nail (IMN) or dynamic hip screw (DHS) 5. Unstable intertrochanteric/reverse obliquity: IMN, blade plate, dynamic condylar screw (not DHS) • Deep vein thrombosis (DVT) prophylaxis (enoxaparin, fondaparinux, heparin). Mechanical DVT prophylaxis in the nonaffected limb. Pharmacologic DVT prophylaxis is usually continued for 14 to 30 days postoperatively. • Pain management: Effective pain management is a primary goal in hip fracture. Opioid analgesics have a high incidence of delirium and constipation. Nerve blockade is effective in reducing acute pain following a hip fracture. A bowel regimen and adequate hydration are recommended in patients taking narcotics. • Prophylactic antibiotics should be administered before surgery and continued for 24 hours after surgical repair. • Rehabilitation is a major component of hip fracture treatment and should be initiated on the first day postoperatively. • Conservative therapy and pain control should be considered in patients who are not surgical candidates (e.g., significant medical risk, bed-/wheelchair-bound, or severe dementia).

DISPOSITION • Mortality associated with surgery typically ranges from 2% to 4% but varies based on the patient’s risk profile. Elderly patients have a fivefold to eightfold increased risk for all-cause mortality during the first 3 mo after a hip fracture. • Mortality rate within 1 yr in elderly patients is 20% to 30%. • Increased annual mortality persists over time for both women and men, but at any given age, the annual mortality following a hip fracture is higher in men than in women. • Dementia is a particularly poor prognostic sign. REFERRAL To orthopedic surgeon for surgical consideration when the diagnosis is made

PEARLS & CONSIDERATIONS COMMENTS • Complications: Nonunion, malunion, infection, avascular necrosis, DVT, delirium, decubitus ulcers, persistent pain, loosening of prosthesis, and periprosthetic fractures. • Nonoperative management: 1.  Should be considered for nonambulatory patients, patients with severe dementia, or patients who are at high risk of complications associated with surgery (e.g., severe cardiac or pulmonary disease). 2. Early bed-to-chair mobilization and vigilant nursing care to avoid skin breakdown and decubitus ulcers. 3. Patients may experience pain relief prior to physiologic union of the fracture. • Severe groin pain or inability to ambulate may be the only finding associated with an occult fracture of the femoral neck. If suspected, MRI can be obtained. • In the U.S., hip fracture rates and subsequent mortality among persons aged ≥65 yr old are declining, and comorbidities among patients with hip fractures are very expensive ($40,000 in the first yr following hip fracture for direct medical costs and $5000 in subsequent yrs). The estimated cost related to hip fractures was >$20 billion in 2007. • Fragility (or low-energy) hip fractures are common in elderly patients with reduced bone quality. These types of fractures are associated with a 1-yr mortality of 26% and 58% of patients requiring long-term care in a nursing facility. Diagnosis of a fragility fracture of the hip is associated with a second fragility fracture within the next 5 yr. • Concurrent prolonged use of proton-pump inhibitors (≥1 yr) is associated with reduced effectiveness of alendronate for preventing hip fractures in older adults.

Hip Fracture PREVENTION • The rate of hip fracture could be reduced by: 1.  Elimination of environmental hazards (e.g., poor lighting, loose rugs, low sitting furniture) 2. Regular exercise for balance and strength 3. Patient education about fall prevention

686.e5 4.  Medication review to minimize side effects and polypharmacy 5. Prevention and treatment of osteoporosis (e.g., calcium/vitamin D, resistance exercise, reversal of underlying pathology)

Stage I

Stage III

RELATED CONTENT Hip Fracture (Patient Information) AUTHOR: James H. Dove, MD

Stage II

Stage IV

FIG. E4  Garden classification of femoral neck fractures. (From Kyle RF: Fractures of the hip. In Gustilo RB et al [eds]: Fractures and dislocations, St Louis, 1993, Mosby.)

SUGGESTED READINGS Abou-Setta AM et al: Comparative effectiveness of pain management interventions for hip fracture: a systematic review, Ann Intern Med 155:234-245, 2011. Abrahamsen B et al: Proton pump inhibitor use and the antifracture efficacy of alendronate, Arch Intern Med 171:998-1004, 2011. Boddaert J et al: Perioperative management of elderly patients with hip fracture, Anesthesiology 121(6):1336-1341, 2014. Bokshan SL et al: Factors influencing survival following hip fracture among octogenarians and nonagenarians in the United States, Injury 49:685-690, 2018. Bretherton CP, Parker MJ: Early surgery for patients with a fracture of the hip decreases 30-day mortality, Bone Joint J 97(1):104-108, 2015. Brunskill SJ et al: Red blood cell transfusion for people undergoing hip fracture surgery, Cochrane Database Syst Rev 4:CD009699, 2015. Chatterton BD et al: Cause of death and factors associated with early in-hospital mortality after hip fracture, Bone Joint J 97(2):246-251, 2015. Christmas C et al: In the clinic: hip fracture, Ann Intern Med 155(11), 2011. ITC6–1. Elkbuli A et al: “Isolated hip fracture in the elderly and time to surgery: is there an outcome difference?” Trauma surgery & acute care open 3, 2018. Forni S et al: Mortality after hip fracture in the elderly: the role of a multidisciplinary approach and time to surgery in a retrospective observational study on 23,973 patients, Arch Gerontol Geriatr 66:13-17, 2016. HEALTH Investigators et al: Total hip arthroplasty or hemiarthroplasty for hip fracture, N Engl J Med 381(23):2199-2208, 2019.

Gregersen M et al: Postoperative blood transfusion strategy in frail, anemic elderly patients with hip fracture: the TRIFE randomized controlled trial, Acta Orthopaedica 86(3):363-372, 2015. Haentjens P et al: Meta-analysis: excess mortality after hip fracture among older women and men, Ann Intern Med 152:380-390, 2010. Hung WW et al: Hip fracture management: tailoring care for the older patient, J Am Med Assoc 307:2185-2194, 2012. Kanis JA et al: A systematic review of hip fracture incidence and probability of fracture worldwide, Osteoporos Int 23:2239-2256, 2012. Pincus D et al: Association between wait time and 30-day mortality in adults undergoing hip fracture surgery, J Am Med Assoc 318:1994, 2017. Radcliff TA et al: Patient risk factors, operative care, and outcomes among older community-dwelling male veterans with hip fracture, J Bone Joint Surg Am 90(34), 2008. Saunders S, Geraci SA: Outpatient management of the elderly patient following fragility hip fracture, Am J Med 124:408-410, 2011. Tsang C et al: Predicting 30-day mortality after hip fracture surgery: evaluation of the National Hip Fracture Database case-mix adjustment model, Bone Joint Res 6(9):550-556, 2017. von Friesendorff M et al: Hip fracture, mortality risk, and cause of death over two decades, Osteoporos Int 27:2945-2953, 2016.

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Hirsutism BASIC INFORMATION DEFINITION Hirsutism is the development of stiff, pigmented (terminal) facial and body hair (male distribution) in women as a result of excess androgen production. SYNONYM Excessive hair growth ICD-10CM CODE L68.0 Hirsutism

EPIDEMIOLOGY & DEMOGRAPHICS • Overall prevalence unknown, estimated 5% to 10% in reproductive age women. • Race and genetics should be considered. Some distinct ethnic populations have minimal body hair and others (Mediterranean, Middle Eastern, South Asian) have moderate to large amounts of body hair while serum androgen levels are similar. • Social norms and culture also determine how much body hair is cosmetically acceptable. • Half of all cases of mild hirsutism do not have hyperandrogenemia. “Patient-important hirsutism” refers to hirsutism causing woman sufficient distress to seek care. • Incidence and presentation of hirsutism is dependent on underlying cause of androgen excess (see “Differential Diagnosis”). • Most women with hirsutism have polycystic ovary syndrome (PCOS). PCOS accounts for 95% of cases of hirsutism. PHYSICAL FINDINGS & CLINICAL PRESENTATION • Timing of symptoms: Abrupt onset, short duration, rapid progression, progressive worsening, more severe signs of virilization (Fig. E1), or later age of onset suggest

a­ndrogen-producing tumor, late-onset congenital adrenal hyperplasia, or Cushing syndrome. Weight increases may produce increased androgen production. • Menstrual history: Menarche, cycle regularity and symptoms of ovulation, fertility, and contraception use. Anovulatory cycles are the most common underlying cause of androgen excess. • Medication use history: Some drugs cause hirsutism or produce androgenic effects (danazol, phenytoin, valproic acid, androgenic progestins [e.g., norgestrel], cyclosporin, minoxidil, metoclopramide, phenothiazines, methyldopa, diazoxide, and penicillamine). • Family history: Known or suspected family history of hirsutism, congenital adrenal hyperplasia, insulin resistance, polycystic ovary syndrome (PCOS), infertility, obesity, menstrual irregularity may be found. • Physical exam reveals deepening voice, body habitus, increased muscle mass, galactorrhea; abdominal and pelvic exam. • Associated cutaneous manifestations (Fig. E2) are acne, acanthosis nigricans, striae, hair distribution, location and quantity, frontotemporal balding, muscle mass, clitoromegaly. • Ferriman-Gallwey scale, a simple, pictorial system of scoring nine body areas, is the most common tool used to quantify hirsutism. It may be unreliable in non-Caucasian women of other ethnicities.

ETIOLOGY • Presence of hirsutism indicates androgen excess. Total testosterone may be normal, but free testosterone is elevated. • Androgens induce vellus hair follicles (soft, unpigmented hair) in sex-specific areas (upper lip, chin, midsternum, upper abdomen, back, buttocks) to develop into thicker, more heavily pigmented terminal hairs. • Anovulatory ovaries are usual source of excess androgens through thecal cell steroidogenesis and conversion of androstenedione to

testosterone. The most common cause of hirsutism is polycystic ovary syndrome, which accounts for three out of every four cases. • Conditions that decrease hepatic production of sex hormone binding globulin (SHBG) decrease protein-bound testosterone and increase free testosterone fraction (e.g., low estrogen, high androgen, and hyperinsulinemic states). • Late-onset, congenital adrenal hyperplasia enzyme deficiency (most commonly 21-hydroxylase deficiency) produces excess 17 hydroxyprogesterone (17-OHP) and overproduction of androstenedione. • Rare ovarian tumors primarily derived from Sertoli-Leydig cells, granulosa theca cells, or hilus cells produce excess androgens. • Rare adrenal tumors produce excess androgens. • Rare pituitary or hypothalamic tumors produce excess prolactin and can lead to anovulation. • Box E1 summarizes causes of androgen excess in women of reproductive age.

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • Androgen-independent vellus hair: Soft, unpigmented hair that covers entire body • Hypertrichosis: Diffusely increased total body hair (vellus or lanugo-type) not restricted to androgen-dependent areas often an adverse response to a medication or systemic illness (e.g., anorexia nervosa, porphyria, malnutrition, hypothyroidism) • PCOS 75% • Idiopathic 5% to 15% • Congenital adrenal hyperplasia 1% to 8% • Insulin resistance syndrome 3% to 4% • Cushing syndrome flat bones (ribs, pelvis, vertebrae) Cervical most common

Diffuse micronodular pattern on radiography

Pancytopenia portends a poor prognosis Swelling, erythema, erosions, petechiae Diabetes insipidus most common

From Paller AS, Mancini AJ: Hurwitz clinical pediatric dermatology, a textbook of skin disorders of childhood and adolescence, ed 5, Philadelphia, 2016, Elsevier.



6. Loose teeth 7. Gingival hypertrophy • Skin is involved in 40% of the patients (Fig. E2, Fig. E3), and common manifestations are brown to purplish papules or eczematous rash. Common sites: Scalp, neck, trunk, groin, and extremities. Cutaneous clues to Langerhans cell histiocytosis are summarized in Box E2. • Lymphadenopathy is present in nearly 20% of patients. Cervical nodes are commonly involved. Involved lymph nodes are usually soft and matted on physical examination. Pulmonary disease is seen in approximately 10% of cases. More common in adults than in children. Patients with lung involvement may present with spontaneous pneumothorax or nonproductive cough, dyspnea, chest pain, or constitutional symptoms such as fever or weight loss. Diffuse emphysema associated with pulmonary fibrosis is the end stage of a mixed restrictive and obstructive pattern of disease. • Liver involvement is seen in 15% to 20% of cases and presents as tumor-like or cystic lesions or as hepatomegaly. It can be accompanied by liver function abnormalities such as hyperbilirubinemia, elevated liver enzymes, or clotting factor deficiencies. Involvement of the biliary tree may present as progressive sclerosing cholangitis. • Involvement of the spleen may present as massive splenomegaly (5% to 10%) with or without hypersplenism. • Histocytosis X involves CNS in approximately 6% of the patients at the time of diagnosis. However, lesions of facial bone and those in the cranial fossa can have CNS involvement in approximately 25% of patients. The most common site affected is the hypothalamicneurohypophyseal region, where infiltration and destruction usually manifest as diabetes insipidus, which manifests as insatiable thirst and urination. The other common CNS manifestations are symptoms of neurodegeneration (ataxia, cognitive dysfunction). Involvement of the thymus, parotid glands, and GI tract has been reported in rare cases.

ETIOLOGY Historically, LCH has been presumed to arise from transformed or pathologically activated epidermal dendritic cells called Langerhans cells. New evidence suggests that LCH occurs as a consequence of misguided differentiation of myeloid dendritic cell precursors. Genetic, molecular, and functional data implicate activation of the ERK signaling pathway at critical stages in myeloid differentiation as an essential and universal driver of LCH pathology. A recent meta-review comprising 653 patient samples assessed an overall frequency of 48.5% for the BRAF V600E point mutation in LCH.

DIAGNOSIS The diagnosis of LCH is made based on the biopsy of the involved organ. The key biopsy feature is identification of the LCH cells, which

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Histocytosis X (Langerhans Cell Histocytosis)

A

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B

FIG. E1  Langerhans cell histiocytosis. Plain radiography reveals multiple lytic lesions in the tibia (A) and the skull (B) of a 4-yr-old child with disseminated disease. (From Paller AS, Mancini AJ: Hurwitz clinical pediatric dermatology, a textbook of skin disorders of childhood and adolescence, ed 5, Philadelphia, 2016, Elsevier.)

FIG. E2  Langerhans cell histiocytosis (LCH). Erythematous, crusted papules on the palm in this newborn with congenital multisystem LCH. (From Paller AS, Mancini AJ: Hurwitz clinical pediatric dermatology, a textbook of skin disorders of childhood and adolescence, ed 5, Philadelphia, 2016, Elsevier.)

FIG. E3  Neonatal Langerhans cell histiocytosis (LCH). These crusted, vesicular lesions were initially felt to be suggestive of neonatal varicella in this 10-day-old female. Biopsy confirmed LCH. (From Paller AS, Mancini AJ: Hurwitz clinical pediatric dermatology, a textbook of skin disorders of childhood and adolescence, ed 5, Philadelphia, 2016, Elsevier.)

BOX E2  Cutaneous Clues to Langerhans Cell Histiocytosis Recalcitrant seborrheic dermatitis-like eruption Localization of rash to scalp, posterior auricular regions, perineum, axillae Eroded papules in flexural areas Petechial or purpuric papules Crusted papules on palms and/or soles (scabies preparation negative) Any of the above lesions in combination with lymphadenopathy From Paller AS, Mancini AJ: Hurwitz clinical pediatric dermatology, a textbook of skin disorders of childhood and adolescence, ed 5, Philadelphia, 2016, Elsevier.

Histocytosis X (Langerhans Cell Histocytosis) TABLE E2  Distinguishing Characteristics of the Reactive Lymphohistiocytoses Genetic History

Virus Infection

Cellular Immune Function

HLH, genetic

Autosomal recessive

Possibly associated

Secondary infection– associated

Sporadic

Yes

XLP

X-linked sporadic

EBV

SHML LG

Sporadic Sporadic

?EBV EBV

↓ CMI ↓ NK cell activity ↓ Monocyte killing ↓ CMI ↓ CMI NL or ↑ NK cell in instances associated with EBV ↓ Anomalous EBVrelated killing NL or ↑ NK cell NL or ↑ anomalous EBV-related killing Not reported ↓ CMI

Miscellaneous Perforin deficiency Hypertriglyceridemia, perforin (PRF1), Munc 13-4 mutations Coagulopathy early in the course of the disease

SH2DIA mutation Severe, often fatal hepatitis Autoimmune phenomena Lymphoma development

CMI, Cell-mediated immunity; EBV, Epstein-Barr virus; HLH, hemophagocytic lymphohistiocytosis; LG, lymphomatoid granulomatosis: NK, natural killer; NL, normal; SHML, sinus histiocytosis with massive lymphadenopathy; XLP, X-linked lymphoproliferative syndrome. From Nathan DG et al [eds]: Nathan and Oski’s hematology of infancy and childhood, ed 6, Philadelphia, 2003, WB Saunders.

are oval with grooved, folded, indented, or lobulated nuclei with fine chromatin, inconspicuous nucleoli, and thin nuclear membranes. The characteristic milieu includes a variable number of eosinophils, histiocytes, neutrophils, and small lymphocytes. Occasionally, eosinophilic abscesses with central necrosis, rich in CharcotLeyden crystals, may be found. The ultrastructure hallmark is the cytoplasmic Birbeck granules. Langerhans cells consistently express CD1a, CD207, langerin, and S100 protein.

DIFFERENTIAL DIAGNOSIS The differential diagnosis of LCH is extensive because it is an uncommon disease that can affect multiple organ systems. LCH in bone, lymph nodes, thymus, and spleen can be confused with lymphoma, solid tumors, or CNS tumors, including germinoma and meningioma. Cutaneous involvement can mimic vasculitis and cutaneous lymphoma, and pulmonary involvement can mimic multiple diseases that cause interstitial lung disease. Histologically and immunophenotypically, LCH must be distinguished from other histiocytic and dendritic cell disorders, metastatic solid or hematopoietic neoplasms, and hemophagocytic lymphohistiocytic and macrophage activation syndromes. The common differential diagnoses are: 1. Erdheim Chester disease (ECD): Rare multisystem histiocytic disorder seen in adults. 2. Juvenile xanthogranuloma: Benign proliferative disorder of the histiocytic cells of the dermal dendrocytic phenotype. 3. Multiple myeloma. 4. Hemophagocytic lymphohistiocytiosis (HLH): HLH and related macrophage activation syndrome are systemic disorders with tissue infiltration by nonneoplastic histocytes. 5. Rosai Dorfman disease: A disease characterized by sinus histiocytosis with massive lymphadenopathy.

Histiocytosis syndromes of childhood are three classes based on histopathologic findings. Class I histiocytosis (also known as LCH) includes the clinical entities of eosinophilic granuloma, Hand-Schüller-Christian disease, and Letterer-Siwe disease. Class II histiocytoses are nonmalignant proliferative disorders that are characterized by accumulation of macrophages. The two major diseases among the class II histiocytoses are hemophagocytic lymphohistiocytosis (FHLH) and infection-associated hemophagocytic syndrome (IAHS). These diseases are grouped together under the term hemophagocytic lymphohistiocytosis (HLH) (see Table E2). Class III histiocytoses are malignancies of cells of monotype-macrophage lineage (acute monocytic leukemia) and true malignant histiocytoses.

WORKUP Baseline evaluation should include: • Routine laboratory tests: CBC with differentials, chemistries with liver and renal functions, ESR, LDH, ferritin, uric acid, and urinalysis. • Unilateral bone marrow aspiration and biopsy is indicated in patients with liver and spleen involvement, for patients with unexplained cytopenias, and for children younger than 2 yr of age. • BRAF V600E mutation testing. This mutation is positive in about 65% of the pathologic dendritic cells. • Radiographic evaluation should include a skeletal survey, skull series, bone scan, and chest radiograph. PET scan is also helpful in measuring the initial extent of disease. • Other laboratory testing or radiologic imaging should be done depending on the symptoms and laboratory abnormalities. LABORATORY TESTS • CBC may reveal cytopenias in patients with bone marrow involvement or those with hypersplenism.

686.e11 • Electrolytes, BUN, creatinine, urinalysis, and urine and serum osmolality are helpful in the diagnosis of diabetes insipidus. • Results of liver function tests (LFTs) may be abnormal in patients with liver involvement. • Bronchoalveolar lavage may show increased numbers of CD1a-positive histiocytes or Langerhans cells in patients with pulmonary LCH.

IMAGING STUDIES • Radiograph studies of affected areas show lytic lesions with or without sclerotic margins. • Panoramic dental view of the mandible and maxilla for children with oral involvement. • Chest radiograph can show interstitial reticulonodular infiltrates. This pattern typically progresses toward frank honeycombing fibrosis later in the course of the disease (Fig. E4). • High-resolution CT scan of the chest confirms interstitial lung scarring, nodules, and cysts and represents an excellent noninvasive means for diagnosis and follow-up of pulmonary LCH. Pulmonary cysts are bilateral and symmetric, showing slight upper-lobe predominance with relative sparing of the costophrenic angles. • CT scan of the temporal bone is indicated for evaluation of mastoid and inner and middle ear involvement. • Ultrasound of the abdomen is helpful for evaluation of hepatosplenomegaly. • Conventional cholangiography or MRI cholangiopancreatography can confirm the presence of biliary involvement. • MRI of the brain is indicated to visualize the hypothalamic-hypophyseal region in patients suspected of having diabetes insipidus.

TREATMENT Treatment is based on organ involvement and the extent of disease. LCH is usually stratified into single or multisystem LCH based on the organ system involvement. Single-system LCH patients typically do not have systemic symptoms. Multisystem LCH have two or more organ or system involvement. • Single-system disease:   Patients with truly limited single-site disease such as skin or bone may not need upfront intervention. The commonly available topical therapies for single organ or system involvement are as follows: 1. Isolated bone lesions: a. Curettage of affected site and implantation of allograft bone chips or polymethylmethacrylate b. Intralesional prednisone c. Bisphosphonates d. NSAIDs e. Radiation therapy is useful for vertebrae or femoral neck lesions at risk of collapse 2. Single skin lesions are treated with: a.  Topical steroid (e.g., triamcinolone acetonide) applied bid b. Nitrogen mustard in 20% solution c. Surgery d. Intralesional interferon e. Isotretinoin

Histocytosis X (Langerhans Cell Histocytosis)

686.e12 involvement who do not respond promptly to therapy. • Involvement of bone marrow, liver, and lung are regarded as high-risk factors. • Progression from initial focal disease to multisystem involvement can occur, most commonly in infants. • Systemic and (rarely) multifocal disease can be complicated by hemophagocytic syndrome.

REFERRAL Multidisciplinary approach: Pediatric oncologist, radiation oncologists, oral maxillary surgeons, ear-nose-throat specialists, audiology, dermatology, endocrinology, and family counseling FIG. E4  Langerhans cell histiocytosis (LCH; histiocytosis X). There is a reticular nodular pattern in the upper lobes. The lung volumes are preserved.

3. Treatment of solitary lymph node involvement: a. Excision at the time of diagnosis b. Systemic oral prednisone • Multisystem disease:   Treatment of multisystem disease includes systemic chemotherapy (vinblastine and prednisone with mercaptopurine added for high-risk patients). Typically induction therapy is given for 6 wk, and if there is a response to therapy, the therapy is continued for a total of 1 yr. Patients with multisystem disease and risk of organ involvement (i.e., liver, spleen, and bone marrow) seem to benefit from combination chemotherapy regimens. Approximately 50% of patients fail to respond to standard systemic chemotherapy, justifying continued need for clinical trials. 1. For severe, high-risk, disseminated cases not responding within 6 wk of initial treatment, salvage therapy, including high dose of the purine analogue cladribine along with high-dose cytosine arabinoside followed by allogeneic blood stem cell transplantation, should be consid-

PEARLS & CONSIDERATIONS

ered. Additionally, liver or lung transplantation might be the treatment of choice for terminal liver and lung failure patients. 2.  Targeted therapy using vemurafenib has resulted in clinical responses in the majority of cases with the BRAF mutation. 3. Diabetes insipidus is treated with DDAVP. 4. Adults with isolated pulmonary LCH do not require aggressive treatment and benefit from smoking cessation. 5. Empirical steroids, in either short pulses or longer exposures, has been used in the treatment of pulmonary disease; however, data regarding effectiveness are limited. 6.  Lung transplantation has been tried in both children and adults with advanced pulmonary disease and limited lung function, but failure rates are high because of local recurrence after transplantation.

COMMENTS • The course of LCH is often unpredictable and varies from spontaneous resolution to rapid progression and death or multiple recurrences and regressions with risk for permanent sequelae. • The association of LCH with other malignancies (e.g., acute lymphocytic leukemia, acute myeloid leukemia, and solid tumors) has been cited.

PROGNOSIS & PREDICTIVE FACTORS • Clinical course is related to staging of the disease at presentation, with 99% or greater survival for unifocal disease and 66% mortality for younger children with multisystem

AUTHOR: Bharti Rathore, MD

SUGGESTED READINGS Allen CE et al: Langerhans-cell histiocytosis, N Engl J Med 379:856-868, 2018. Donadieu J et al: Vemurafenib for refractory multisystem langerhans cell histiocytosis in children: an international observational study, J Clin Oncol 37(31):2857-2865, 2019. Gadner H et al: Therapy prolongation improves outcome in multisystem Langerhans cell histiocytosis, Blood 121(25):5006-5014, 2013. Monsereenusorn C et al: Clinical characteristics and treatment of Langerhans cell histiocytosis, Hematol Oncol Clin North Am 29(5):853-873, 2015. Zinn DJ et al: Langerhans cell histiocytosis: emerging insights and clinical implications, Oncology (Williston Park) 30(2):122-132, 139, 2016.

PATIENT & FAMILY EDUCATION • Instruct patients to promptly report the development of hemoptysis. This symptom may indicate malignancy or superimposed bacterial–fungal infection, such as Aspergillus species infection. • Educate about the likely etiologic role of cigarette smoking.

Histoplasmosis BASIC INFORMATION DEFINITION Histoplasmosis is caused by the fungus Histo­ plasma capsulatum and characterized by a primary pulmonary focus with occasional progression to chronic pulmonary histoplas­ mosis (CPH) or various forms of dissemination. Progressive disseminated histoplasmosis (PDH) may present with a diverse clinical spectrum, including adrenal necrosis, pulmonary and mediastinal fibrosis, and ulcerations of the oropharynx and GI tract. In those patients coinfected with HIV, it is a defining disease for AIDS. SYNONYMS • North American histoplasmosis • Ohio Valley fever • Vanderbilt disease EPIDEMIOLOGY & DEMOGRAPHICS INCIDENCE (IN U.S.): • Unknown for acute pulmonary disease • For CPH, estimated at 1/100,000 cases in endemic areas • For PDH in immunocompetent adults, estimated at 1/2000 cases of histoplasmosis PREVALENCE: Unknown PREDOMINANT SEX: Clinically evident disease is most common in males; male:female ratio of 4:1 PREDOMINANT AGE: • CPH is most often seen in males >50 yr old with an associated history of COPD. • Presumed ocular histoplasmosis syndrome (POHS) is seen between ages of 20 and 40 yr. PEAK INCIDENCE: Unknown PHYSICAL FINDINGS & CLINICAL PRESENTATION • Conidia are deposited in alveoli then converted to yeast forms where they spread to regional lymph nodes and other organs, especially liver and spleen. • 1 to 2 wk later, a granulomatous inflammatory response begins to contain the yeast in the form of discrete granulomas. • Delayed-type hypersensitivity to Histoplasma antigens occurs 3 to 6 wk after exposure. • Clinical disease manifests in various forms (Box E1), depending on host cellular immunity and inoculum size: 1. Acute primary pulmonary histoplasmosis: a. An overwhelming number of patients are asymptomatic. b.  Most clinically apparent infections manifest by complaints of fever, headache, malaise, pleuritic chest pain, nonproductive cough, and weight loss. c. Less than 10%, mainly women, complain of arthralgias, myalgias, and skin manifestations such as erythema multiforme or erythema nodosum (Fig. E1).



d. Acute pericarditis presents in a smaller percentage of patients. e.  Hepatosplenomegaly is most commonly observed in children. f. With particularly heavy exposure, there is severe dyspnea, marked hypoxemia, impending respiratory failure. g. Most patients are asymptomatic within 6 wk.



2. CPH: a.  Presents insidiously with low-grade fever, malaise, weight loss, cough, sometimes with blood-streaked sputum or frank hemoptysis. b.  Most patients with cavitary lesions present with associated COPD or chronic bronchitis, masking underlying fungal disease.

BOX E1  Clinical Manifestations of Histoplasmosis • A  symptomatic infection • Pneumonia • Progressive disseminated infection (HIV, immunocompromise, infancy) • Mediastinal lymphadenopathy • Cavitary pneumoniaa • Asthma-like illness • Pleural effusion or granulomatous pleuritisa • Obstruction or dysfunction of contiguous mediastinal structures (bronchi, esophagus) by granulomatous inflammation of lymph nodes (mediastinal granuloma) • Isolated cervical or supraclavicular lymphadenopathya • Superior vena cava syndromea • Mediastinal fibrosisa • Vocal cord granuloma • Vocal cord paralysis • Hemoptysis

• • • • • • • • • • • • • • • • • • •

 roncholithiasis with lithoptysisa B Chylothoraxa Diaphragmatic weakness or ­paralysis Esophageal diverticulum or fistula Pericarditis Erythema nodosum Meningitis or focal cerebritisa Arthritis or arthralgias Parotitis Nephrocalcinosis Interstitial nephritisa Hypercalcemia Gastrointestinal tract ulceration or hemorrhage Gastrointestinal tract ­pseudomalignancy Crohn disease–like illness Biliary obstructiona Ocular histoplasmosis, choroiditisa Endocarditisa Adrenal massa

aRare

in children. From Cherry JD et al: Feigin and Cherry’s pediatric infectious diseases, ed 8, Philadelphia, 2019, Elsevier.

FIG. E1  Erythema nodosum in an adolescent boy with pulmonary histoplasmosis. (From Cherry JD et al: Feigin and Cherry’s pediatric infectious diseases, ed 8, Philadelphia, 2019, Elsevier.)

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Histoplasmosis

c. Tends to worsen preexisting pulmonary disease and further contribute to eventual respiratory insufficiency. 3.  PDH: a. In both acute and subacute forms, constitutional symptoms of fever, fatigue, malaise, and weight loss are common. b. Acute form (seen in infants and children) presents with respiratory symptoms, fever ≥101° F(38.3° C), generalized lymphadenopathy, marked hepatosplenomegaly, and fulminant course resembling septic shock associated with a high fatality rate. c.  Subacute form is more common in adults and associated with lower temperatures, ­hepatosplenomegaly, oropharyngeal ulceration, focal organ involvement (including a­drenal destruction, endocarditis, chronic meningitis, and intracerebral mass lesions). d. Course of subacute form is relentless, with untreated patients dying within 2 yr. e.  Chronic PDH is found in adults and marked by gradual symptoms of weight loss, weakness, easy fatigability; lowgrade fever when present; oropharyngeal ulcerations and hepatomegaly and/ or splenomegaly in one third of patients. f. Less clinical evidence of focal organ involvement in chronic form than in subacute form. g. Natural history of chronic form is protracted and intermittent, spanning mos to yrs. • Histoplasmoma: 1. A healed area of caseation necrosis surrounded by a fibrous capsule 2. Usually asymptomatic • Mediastinal fibrosis: 1. A rare consequence of a fibroblastic process that encases caseating mediastinal lymph nodes producing severe retraction, compression, and distortion of mediastinal structures 2. Constriction of the bronchi resulting in bronchiectasis, also esophageal stenosis associated with dysphagia, and superior vena cava syndrome • POHS: 1. Diagnosis characterized by distinct clinical features, including atrophic choroidal scars and maculopathy in patients with histories suggestive of exposure to the fungus (e.g., residence in an endemic area) 2. Patient complains of distortion or loss of central vision without pain, redness, or photophobia 3. Usually no evidence of infection except for a positive skin reaction to histoplasmin • In patients with AIDS: 1. Possible presentation as overwhelming infection similar to acute PDH seen in children 2. Constitutional symptoms: Fever, weight loss, malaise, cough, dyspnea 3. About 10% with cutaneous maculopapular, erythematous eruptions or purpuric lesions on face, trunk, and extremities

686.e14 4. U  p to 20% with CNS involvement, manifesting as intracerebral mass lesions, chronic meningitis, or encephalopathy

ETIOLOGY • H. capsulatum is a dimorphic fungus present in temperate zones and river valleys worldwide. • In the U.S., it is highly endemic in southeastern, mid-Atlantic, and central states (Ohio and Mississippi River valleys). Outside the U.S. it is distributed in Central and South America, the Caribbean, and in regions of Australia, India, and Africa. • Exists as mold at ambient temperature and favors soils enriched with bird or bat droppings.

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • Acute pulmonary histoplasmosis: 1. Mycobacterium tuberculosis 2. Community-acquired pneumonias caused by Mycoplasma and Chlamydia 3. Other fungal diseases, such as those caused by Blastomyces dermatitidis and Coccidioides immitis • Chronic cavitary pulmonary histoplasmosis: M. tuberculosis • Histoplasmomas: True neoplasms • Sarcoidosis WORKUP • Suspect diagnosis in patients who present with a history of residence or travel in an endemic area, especially if engaged in occupations (e.g., outside construction or street cleaning) or hobbies (e.g., cave exploring) that increase the likelihood of exposure to fungal spores. • Suspect diagnosis in immunosuppressed patients with remote history of exposure, especially if associated with characteristic calcifications on chest x-ray. LABORATORY TESTS • Detection of Histoplasma antigen in serum and urine. Urine antigen is 75% accurate in normal hosts and 95% in immunocompromised patients with disseminated disease. The sensitivity and specificity of the urinary antigen is also dependent on the stage of

A

infection exceeding 80% in acute and disseminated infection but decreasing to less than 50% in chronic infection. The serum test is close to 100% accurate, but with Blastomyces and Coccidioides, tests may cross-react with infections. Tests can also be performed on bronchoalveolar lavage. • Demonstration of organism on culture from body fluid or tissues biopsy (Fig. E2) will confirm the diagnosis in clinically suspected cases and negative urinary antigen. 1. Especially high yield in patients with AIDS 2. Characteristic oval yeast cells in neutrophils with Giemsa stain from peripheral smear 3.  Preparations of infected tissue with Gomori silver methenamine for revealing yeast forms, especially in areas of caseation necrosis • Serologic tests, including complement-fixing (CF) antibodies and immunodiffusion assays. • In PDH: 1. Pancytopenia 2. Marked elevations in alkaline phosphatase and alanine aminotransferase (ALT) common • In chronic meningitis (majority of cases): 1. CSF pleocytosis with either lymphocytes or neutrophils predominating 2. Elevated CSF protein levels 3. Hypoglycorrhachia

IMAGING STUDIES • Chest x-ray in acute pulmonary histoplasmosis: 1. Singular or multiple patchy infiltrates, especially in the lower lung fields 2. Hilar or mediastinal lymphadenopathy with or without pneumonitis 3.  Diffuse nodular or confluent bilateral miliary infiltrates characteristic of heavier exposure 4. Infrequent pleural effusions, except when associated with pericarditis • Chest x-ray in histoplasmoma: Coin lesion displaying central calcification, ranging from 1 to 4 cm in diameter, predominantly located in the subpleural regions • Chest x-ray in CPH (Fig. E3): 1. Upper lobe disease frequently associated with cavities

B

FIG. E2  A, Photomicrograph shows a tissue biopsy specimen from a patient with slowly progressing disseminated histoplasmosis. Granulomas are well formed, and no organisms are seen. Hematoxylin and eosin stain, ×450. B, Special stains better demonstrate yeast in tissue sections. Silver methenamine stain, ×450. (From Mason RJ: Murray & Nadel’s textbook of respiratory medicine, ed 5, Philadelphia, 2010, WB Saunders.)

Histoplasmosis

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A

B

C

D

FIG. E3  The evolution of chronic pulmonary histoplasmosis in a smoker. A, At the onset of the illness, the chest radiograph shows multiple cavity-like air spaces. B, 2.5 yr later, fibrosis has occurred with volume loss of the lobe and retraction of the hilum. C, A further 17 mo later, the entire right upper lobe appears to be destroyed. D, There are signs of continued activity and a residual cavity at the time of diagnosis. The sputum culture was positive for Histoplasma capsulatum. (From Mason RJ: Murray & Nadel’s textbook of respiratory medicine, ed 5, Philadelphia, 2010, WB Saunders.)

2. P reexisting calcifications in the hilum associated with peribronchial streaking extending to the parenchyma • Chest x-ray in acute PDH: Hilar adenopathy and/or diffuse nodular infiltrates • CT scan of adrenals to reveal bilateral enlargement and low-attenuation centers

TREATMENT NONPHARMACOLOGIC THERAPY For life-threatening disease seen in acute disseminated disease or infection in patients with AIDS: Supportive therapy with IV fluids ACUTE GENERAL Rx • No drug therapy is required for asymptomatic pulmonary disease. • A course of therapy with itraconazole 200 mg PO tid for 3 days, then 200 mg/day PO for 6 to 12 wk may be beneficial in some patients with acute pulmonary distress. Avoid fluconazole because it is not as active. • Same therapy appropriate for immunocompetent, mild to moderately symptomatic patients with CPH and subacute and chronic forms of PDH, but duration for 6 to 12 mo.

• Use amphotericin B 0.7 to 1 mg/kg IV q day for initial therapy in moderate to severe disease and then transition to oral itraconazole within 1 to 2 wk. Lipid formulations of amphotericin can be used to avoid nephrotoxicity of amphotericin B, and they produce better outcomes in terms of mortality, rates of culture conversion, and side effects. • Liposomal amphotericin: 3 mg/kg/day IV or amphotericin B lipid complex: 5 mg/kg/day. • Posaconazole is highly effective as well, but voriconazole is less active in vitro than itraconazole and posaconazole. Isavuconazole is also active in vitro, but echinocandins such as micafungin are not effective. • Chronic cavitary pulmonary histoplasmosis: Itraconazole 200 mg PO tid for 3 days, then once or twice daily for at least 12 mo. • CNS histoplasmosis: Liposomal amphotericin B, 5 mg/kg/day for a total of 175 mg/kg over 4 to 6 wk, then itraconazole 200 mg 2 to 3×/ day for at least 12 mo. • Endocarditis: Surgical treatment with excision of infected valve or graft combined with amphotericin for a total dose of 35 mg/kg or 2.5 g. • For pericardial disease: 1. Antifungal therapy: No apparent benefit 2. Best managed with NSAIDs

• For POHS: 1. Antifungal therapy: No apparent benefit 2. May respond to laser therapy

CHRONIC Rx • In patients with AIDS: Lifelong suppressive therapy with either itraconazole, given 200 mg PO q day, or IV amphotericin B at a dose of 50 mg once weekly; a triazole compound posaconazole (400 mg PO bid) may be useful in refractory cases, but clinical experience is limited at this point • Prophylaxis in HIV-infected patients with 2 standard deviations elevation in CBV. (Tucker KA et al: Neuroimaging in human immunodeficiency virus infection, J Neuroimmunol 157[1-2]:153-162, 2004.)

HIV-Associated Cognitive Dysfunction

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 EARLS & P CONSIDERATIONS

A

B

FIG. E2  Advanced HIV encephalopathy. Axial T2WI. There is diffuse confluent and symmetrical abnormal high signal returned from the white matter of the cerebral hemispheres (A), which is also extending into the brainstem to involve the cerebral peduncles (B). In this patient there is also generalized atrophy. Features that help to differentiate HIV from PML are the symmetry of the changes and the lack of signal abnormalities on T1WI. (From Adam A, Dixon AK, Grainger RG, Allison DJ. Grainger & Allison's diagnostic radiology, 5th ed. Churchill Livingstone, 2007, in Grant, LA: Grainger & Allison’s Diagnostic Radiology Essentials, ed 2, 2019, Elsevier.)

electroencephalography, evoked potentials, nerve conduction studies), but they do not seem to have a predictive value for the later onset of HIV-associated dementia, which correlates most with a history of the CD4+ T-lymphocyte nadir of less than 200 cells/ microliter. • Potential causes for cognitive impairment that must be ruled out include: 1. Opportunistic central nervous system (CNS) processes (e.g., toxoplasmosis, primary CNS lymphoma, progressive multifocal leukoencephalopathy, cytomegalovirus encephalitis, cryptococcal meningitis) 2. HIV-mediated CD8 encephalitis 3. General paresis of the insane due to syphilis

4. V itamin B12 deficiency resulting in subacute combined degeneration 5. Substance use 6. Alcoholism 7. Psychiatric disorders such as depression, anxiety, bipolar disorder, or schizophrenia 8. Side effects of prescribed medications

TREATMENT Early treatment with antiretroviral therapy (ART) may lead to clinical improvement in some patients, but in many cases, cognitive dysfunction persists despite ART. Maintaining high CD4 count and not allowing CD4 count to nadir below 200 cells/microliter may protect against the development of HAND.

SUGGESTED READINGS Heaton RK et  al: HIV-associated neurocognitive disorders persist in the era of potent antiretroviral therapy: CHARTER Study, Neurology 75(23):2087-2096, 2010. Heaton RK et al: HIV-associated neurocognitive disorders before and during the era of combination antiretroviral therapy: differences in rates, nature, and predictors, J Neurovirol 17(1):3-16, 2011. Lescure FX et al: CD8 encephalitis in HIV-infected patients receiving cART: a treatable entity, Clinical Infectious Diseases 57(1):101-108, 2013. McArthur JC et  al: Human immunodeficiency virus-associated neurocognitive disorders: mind the gap, Ann Neurol 67(6):699-714, 2010. Zarkali A, Gorgoraptis N, Miller R et al: CD8+ encephalitis: a severe but treatable HIV-related acute encephalopathy, Practical Neurology 17:42-46, 2017.

• Initiation of ART can lead to rapid improvement in cognitive function in early stages • Untreated, life span of patient with HIVassociated dementia is typically 4 to 6 mo. • Most common presenting complaint in children infected with HIV. • Patients may have other medical or psychiatric conditions or a social history that seriously confounds the diagnosis of HIV-associated neurocognitive disorder. • Five HIV-related opportunistic infections that commonly cause cognitive impairment are toxoplasmosis, cryptococcal meningitis, progressive multifocal leukoencephalopathy, primary CNS lymphoma, and cytomegalovirus encephalitis. • HIV-associated CD8 encephalitis is subacute, progressive encephalopathy characterized by diffuse perivascular and intraparenchymal CD8+ lymphocytic infiltration. MRI shows hyperintensity of the white matter on T2 sequences and linear or punctate enhancement in a perivascular distribution on T1 post-gadolinium sequences. CSF analysis reveals elevated protein and a CD8+ T-cellpredominant pleocytosis. Treatment is with high-dose corticosteroids and can result in a good outcome despite an initially poor neurological status.

REFERRALS • Upon diagnosis/clinical suspicion for HIVassociated cognitive dysfunction, referral to neurology is recommended. • Referral to neuropsychology may be considered. • Referral to infectious disease specialist to manage HIV infection. AUTHOR: Joseph S. Kass, MD, JD, FAAN

Hoarding Disorder BASIC INFORMATION DEFINITION Compulsive hoarding is defined as the acquisition of and failure to discard a large number of possessions that appear to be useless or of limited value, with living spaces sufficiently cluttered so as to preclude activities for which those spaces were designed and significant distress or impairment in functioning caused by the hoarding. Hoarding has historically been a criterion of obsessive-compulsive personality disorder. With the publication of the DSM-5 (2013), compulsive hoarding is now recognized as a distinct form of psychopathology. • Persistent difficulty discarding or parting with possessions, regardless of the value others may attribute to these possessions. (The Work Group is considering alternative wording: “Persistent difficulty discarding or parting with possessions, regardless of their actual value.”) • This difficulty is due to strong urges to save items and/or distress associated with discarding. • The symptoms result in the accumulation of a large number of possessions that fill up and clutter active living areas of the home or workplace to the extent that their intended use is no longer possible. If all living areas become decluttered, it is only because of the interventions of third parties (e.g., family members, cleaners, authorities). • The symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning (including maintaining a safe environment for self and others). • The hoarding symptoms are not due to a general medical condition (e.g., brain injury, cerebrovascular disease). • The hoarding symptoms are not restricted to the symptoms of another mental disorder (e.g., hoarding due to obsessions in obsessive-compulsive disorder, decreased energy in major depressive disorder, delusions in schizophrenia or another psychotic disorder, cognitive deficits in dementia, restricted interests in autism spectrum disorder, food storing in Prader-Willi syndrome). Specify if: • With excessive acquisition: If discarding possessions is accompanied by excessive acquisition of items that are not needed or for which there is no available space Specify if: • With good or fair insight • With poor insight • With absent insight/delusional beliefs SYNONYMS Hoarding Obsessive-compulsive disorder Obsessive-compulsive personality disorder Anankastic personality disorder Saving Collecting Clutter

ICD-10CM CODE F42.9 Obsessive compulsive disorder, unspecified DSM-5 CODE 300.3 Obsessive compulsive disorder

EPIDEMIOLOGY, PREVALENCE & DEMOGRAPHIC • Community surveys suggest that the prevalence of clinically significant compulsive hoarding is estimated to be somewhere between 2% and 6%. National studies on prevalence are not yet available. • Clinical samples suggest a higher prevalence among females, but some epidemiologic studies suggest a higher prevalence among males. • Hoarding onset typically starts in early adolescence. • Late-onset hoarding is rare. • Available data outside of the U.S. suggest that hoarding is a universal phenomenon. • Hoarding tendencies tend to begin in childhood or adolescence and become clinically significant by middle age. • Hoarding may have a sudden onset in adulthood after experiencing a traumatic event. • A large percentage of individuals who hoard report having at least one first-degree relative who experiences hoarding problems. The link appears to be stronger among first-degree female relatives (e.g., mothers, sisters). • It is estimated that one in four people with OCD are hoarders. • Hoarding tends to be a chronic condition with spontaneous remission a rarity. Associated with Axis I (Major Depressive Disorder, Social Phobia, Obsessive-Compulsive Disorder, Generalized Anxiety Disorder, and Attention-Deficit Hyperactivity Disorder) and Axis II (Borderline Personality Disorder and Avoidant Personality Disorder). RISK FACTORS • Genetic vulnerabilities and early attachment experiences are thought to contribute to hoarding behavior. • Social isolation can lead to hoarding behavior as a way to provide comfort. • A sudden traumatic event can lead to hoarding behavior as a coping mechanism. • Family history. • Age. ETIOLOGY Although the etiology is unknown, hoarders share a number of characteristics, including problems with emotional attachments to possessions (i.e., viewing their possessions as extensions of themselves), behavioral avoidance (i.e., a fear of making a decision about what to do with a possession), beliefs about the nature of possessions (i.e., an exaggerated desire for control over possessions and a sense of responsibility to take care of the possessions and to be prepared for the future), perfectionism (i.e., possessions must be used perfectly such as a belief

that a newspaper must be thoroughly read), information-processing deficits (i.e., deficits in decision making, difficulty in memory functions, and deficits in categorization and organization), and an avoidance of waste. Physical abuse and sexual trauma have been associated with greater acquiring tendencies but not with saving. Intense negative emotional reactions (sadness) may also play a role in the etiology. Hoarding in children has been associated with behavioral and emotional dysregulation.

DIAGNOSIS WORKUP Hoarding disorder is not diagnosed if the hoarding behavior is determined to be the direct consequence of another medical condition, including traumatic brain injuries, surgery for seizure control, cerebrovascular disease, infections of the central nervous system, neurogenetic conditions, autism, schizophrenia, major depressive episode, obsessive-compulsive disorder, or neurocognitive disorders.

TREATMENT NONPHARMACOLOGIC THERAPY • Frost and Hartl developed a cognitivebehavioral model of hoarding, which ­conceptualizes hoarding as a consequence of (1) information-processing deficits, (2) problems in forming emotional attachments, (3) behavioral avoidance, and (4) erroneous beliefs about the nature of possessions. • Steketee and Frost published a specialized cognitive-behavioral therapy (CBT) compulsive hoarding treatment manual that uses cognitive-behavioral strategies to address these areas. The authors recommend 26 therapy sessions over a period of 1 yr. Treatment can be individual or group therapy with a combination of office and in-home sessions. Family consultation is recommended, with an emphasis on education and the treatment of hoarding behavior. • Specific variables, including female gender, younger age, a greater number of CBT sessions, and a greater number of home visits, have been associated with a better clinical outcome. ACUTE GENERAL Rx Antidepressants may be helpful for underlying mood or anxiety disorders. CHRONIC Rx • CBT is the preferred treatment for hoarding disorder, but selective serotonin reuptake inhibitors (SSRIs) are the preferred pharmacologic intervention for severe cases. • A recent review of CBT, pharmacologic, and family-based interventions yielded modest statistically significant improvements. • A systematic review of treatment with cognitive-behavioral therapy for hoarding that compared therapy traditionally used to treat

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Hoarding Disorder obsessive-compulsive disorder with therapy specifically designed for hoarding disorder suggested improvement in hoarding symptoms with both interventions. However, when compared to each other, the efficacy of these treatments is inconclusive. • New research suggests the potential benefit of Internet-based CBT for hoarding disorder.

DISPOSITION Long-term follow-up is essential for recurring hoarding behavior and to address underlying mood disorders. REFERRAL • CBT is the preferred treatment. • If underlying mood symptoms such as depression and anxiety interfere with treatment, a referral for medication is encouraged.

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 EARLS & P CONSIDERATIONS Patients with hoarding disorder can be challenging to treat because many with the disorder do not recognize that they have a problem nor do they understand the negative impact hoarding has on their lives and the lives of their loved ones. They often do not believe that they need treatment, and they take great comfort in their possessions. Patient and family education is an important first step in the treatment of hoarding disorder. Family members are often frustrated and angry at the individual who hoards because of a perception that the hoarder is simply “messy,” “lazy,” etc. Psychoeducation helps family members understand the complicated nature of the illness. They can be instructed on

SUGGESTED READINGS Fitzpatrick M et al: “Blended” therapy: the development and pilot evaluation of an Internet-facilitated cognitive behavioral intervention to supplement face-toface therapy for hoarding disorder, Internet Interv (12)16-25, 2018. Ivanov VZ et al: Enhancing group cognitive-behavioral therapy for hoarding disorder with between-session Internet-based clinician support: a feasibility study, J Clin Psychol 74(7):1092-1105, 2018, https://doi.org/10.1002/jclp.22589. Epub. Muroff J et al: Pilot trial of cognitive and behavioral treatment for hoarding disorder delivered via webcam: feasibility and preliminary outcomes, J Obsessive Compuls Relat Disord (18)18-24, 2018. Thompson C et al: A systematic review and quality assessment of psychological, pharmacological, and family based interventions for hoarding disorder, Asian J Psychiatr 27:53-66, 2017. Wincze JP et al: Categorization in compulsive hoarding, Behav Res Ther 45:63, 2007.

how to become “surrogate therapists” rather than distress the family member who hoards by taking it upon themselves to throw items away. It is essential that they work with a therapist who has expertise with hoarding behavior.

PATIENT & FAMILY EDUCATION International OCD Foundation: http://208.88. 128.33/hoarding/ AUTHOR: Jeffrey P. Wincze, PhD

Hodgkin Lymphoma BASIC INFORMATION DEFINITION Hodgkin lymphoma is a malignant disorder arising from germinal center B cells and characterized histologically by the presence of multinucleated giant cells (Reed-Sternberg cells) in a mixed inflammatory background.

EPIDEMIOLOGY & DEMOGRAPHICS • There is a bimodal age distribution (15 to 34 yr and >50 yr). • Incidence is 4 in 100,000 cases; >8000 new cases of Hodgkin lymphoma diagnosed annually in the U.S. • Concordance for Hodgkin lymphoma in identical twins suggests that a genetic susceptibility underlies Hodgkin lymphoma in young adulthood. • There is association between certain HLA haplotypes, especially HLA-A1. • The disease is more common in males (in childhood Hodgkin lymphoma, >80% occur in males), whites, and higher socioeconomic groups.

PHYSICAL FINDINGS & CLINICAL PRESENTATION • Painless palpable lymphadenopathy is the most common presenting symptom • The most common site of involvement is the neck region • Fever and night sweats: Fever in a cyclical pattern (days or wks of fever alternating with afebrile periods) is known as Pel-Ebstein fever • Unexplained weight loss, generalized malaise • Persistent, nonproductive cough • Lymph node pain associated with alcohol ingestion often because of heavy eosinophil infiltration of the tumor sites is relatively uncommon • Generalized pruritus • Hepatosplenomegaly • Other: Superior vena cava syndrome, spinal cord compression (rare), erythema nodosum (very rare), ichthyosis (very rare) ETIOLOGY • Evidence implicating Epstein-Barr virus remains controversial. • Cigarette smoking has also been implicated.

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • Non-Hodgkin lymphoma • Sarcoidosis • Infections (e.g., cytomegalovirus, EpsteinBarr virus, toxoplasmosis, HIV, tuberculosis) • Drug reaction WORKUP Diagnosis is confirmed by lymph node biopsy. The World Health Organization classifies Hodgkin lymphoma into two groups: Classical Hodgkin lymphoma (92% to 97%) and nodular lymphocyte-predominant Hodgkin lymphoma (3% to 8%). Classical Hodgkin lymphoma has four main histologic subtypes based on the number of lymphocytes, Reed-Sternberg cells, and the presence of fibrous tissue (Table 1): • Nodular sclerosis (Fig. E1) • Mixed cellularity (Fig. E2) • Lymphocyte rich • Lymphocyte depleted Nodular sclerosis occurs mainly in young adulthood, whereas the mixed cellularity type is more prevalent after age 50 yr. Table 2 summarizes key features of Hodgkin lymphomas.

Staging: Table 3 describes the Cotswolds Staging Classification. Proper staging requires the following: • Detailed history (with documentation of “B symptoms” and physical examination) • Excisional biopsy with histologic, immunophenotypic and immunohistochemical analysis • Laboratory evaluation (complete blood count, erythrocyte sedimentation rate [ESR], blood urea nitrogen, creatinine, liver function tests, albumin, lactate dehydrogenase, HIV test), immunophenotypic markers (see Table 4) • Positron emission tomography (PET)/computed tomography (CT) scan of the chest, abdomen, and pelvis • Unilateral bone marrow biopsy in selected patients Box 1 summarizes recommended staging procedures for Hodgkin lymphoma.

H

Diseases and Disorders

ICD-10CM CODES C81.90 Hodgkin lymphoma, unspecified, unspecified site C81.00 Nodular lymphocyte predominant Hodgkin lymphoma, unspecified site C81.10 Nodular sclerosis classical Hodgkin lymphoma, unspecified site C81.20 Mixed cellularity classical Hodgkin lymphoma, unspecified site C81.30 Lymphocyte depleted classical Hodgkin lymphoma, unspecified site C81.79 Other classical Hodgkin lymphoma, extranodal and solid organ sites C81.90 Hodgkin lymphoma, unspecified, unspecified site C81.91 Hodgkin lymphoma, unspecified, lymph nodes of head, face, and neck C81.92 Hodgkin lymphoma, unspecified, intrathoracic lymph nodes C81.93 Hodgkin lymphoma, unspecified, intra-abdominal lymph nodes C81.94 Hodgkin lymphoma, unspecified, lymph nodes of axilla and upper limb C81.95 Hodgkin lymphoma, unspecified, lymph nodes of inguinal region and lower limb C81.96 Hodgkin lymphoma, unspecified, intrapelvic lymph nodes C81.97 Hodgkin lymphoma, unspecified, spleen C81.98 Hodgkin lymphoma, unspecified, lymph nodes of multiple sites C81.99 Hodgkin lymphoma, unspecified, extranodal and solid organ sites

• There is an increased risk in smokers and HIV-infected individuals.

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I

TREATMENT ACUTE GENERAL Rx The main therapeutic modality includes chemotherapy with or without radiotherapy depending on stage and other risk factors (Table 5). In general, chemotherapy plus involved-site radiotherapy is standard treatment for Hodgkin lymphoma in the early stages; however, recent data suggest that chemotherapy alone is appropriate for a significant proportion of patients. Chemotherapy (Table 6) is used for advanced stage disease with radiotherapy in selected patients, such as those with bulky disease. Most oncologists prefer the combination of adriamycin (doxorubicin), bleomycin, vinblastine, and dacarbazine (ABVD). ABVD does not cause infertility or stem cell damage and has also shown to be effective in patients with HIV infection and Hodgkin lymphoma. Table 7 describes characteristics of the ABVD regimen. Recent trials have shown that in patients with early-stage Hodgkin lymphoma and favorable prognosis, defined by fewer than three nodal sites without bulky or extranodal disease in the absence of ESR >50 without symptoms or 30 with symptoms, treatment with two cycles of ABVD followed by 20 Gy of involved-field radiation therapy may be as effective as, and less toxic than, four cycles of ABVD followed by 30 Gy of involved-field radiation therapy. For patients with early stage disease who do not meet these criteria, options include three or four cycles of ABVD plus involved site radiotherapy

TABLE 1  Frequency of Histologic Subtypes of Hodgkin Lymphoma According to the 2008 WHO Classification Classic Hodgkin Lymphoma (cHL) • Nodular sclerosis classic Hodgkin lymphoma (NSCHL) • Mixed cellularity classic Hodgkin lymphoma (MCCHL) • Lymphocyte-rich classic Hodgkin lymphoma (LRCHL) • Lymphocyte-depleted classic Hodgkin lymphoma (LDCHL) Nodular Lymphocyte Predominant Hodgkin Lymphoma (NLPHL)

95% 70% 20%-25% 5% F, 30-50 yr, with peripheral lymphadenopathy M = F, F; median age, 38 yr; peripheral lymphadenopathy common, spleen, BM; B symptoms common; patients often stage III or IV M > F; median age, 30-37 yr; B symptoms, advanced stage common; associated with HIV M > F, older age; peripheral lymphadenopathy; B symptoms rare; most patients with stage I or II disease

Mixed cellularity Lymphocyte depletion Lymphocyte-rich classical

Morphology

Cell Surface Markers

Prognosis

Mononuclear cells with convoluted nuclei (popcorn or L&H cells) loosely aggregated in nodules of small B cells Broad bands of collagen, nodules of lymphoid tissue with aggregates of HRS cells and lacunar cells, multinucleated variants Classic HRS cells in mixture of lymphocytes, plasma cells, eosinophils, histiocytes

CD45, CD20, bcl-6, J-chain, Oct-2, BOB.1, EBV absent in LP cells CD15, CD30, CD45-EBV in 1%-40%

Excellent for stages I, II

CD15, CD30, CD45-EBV in 75%

Good with systemic therapy

Classic HRS cells common with paucity of background lymphocytes; pleomorphic HRS cells mimic sarcoma Scattered classic HRS cells among numerous small lymphocytes; nodular growth pattern

CD15, CD30, CD45-EBV positive in HIV-affected patients CD15, CD30; Oct2 and BOB.1 vary; J-chain absent; EBV in 40%-75%

Associated with advanced stage

Good with systemic therapy

Good, similar to NLPHL

BM, Bone marrow; EBV, Epstein-Barr virus; F, female; HIV, human immunodeficiency virus; HRS, Hodgkin Reed-Sternberg; L&H, lymphocytic and histiocytic; LP, lymphoplasmacytic; M, male. From McPherson RA, Pincus MR: Henry’s clinical diagnosis and management by laboratory methods, ed 23, St Louis, 2017, Elsevier.

TABLE 3  Cotswolds-Modified Ann Arbor Staging System for Hodgkin Lymphoma Stage

Criteria

I

Disease affecting a single lymph node region or lymphoid structure (e.g., spleen, thymus, Waldeyer ring) Disease affecting two or more discrete lymph node regions confined to the same side of the diaphragm Disease affecting two or more discrete lymph node regions or lymphoid structures on both sides of the diaphragm Disease that has spread to one or more extranodal sites (that do not meet the criteria for E) or extralymphatic structure including involvement of the bone marrow, liver, or lungs

II III IV

Designation

Criteria

A B S E

Absence of B symptomsa Presence of B symptomsa Involvement of the spleen Single extranodal site or involvement of an extranodal site that is contiguous to an involved nodal region Bulky disease as defined as >1/3 mediastinum at its widest part or a nodal mass >10 cm at its greatest diameter

X aB

symptoms: Constitutional symptoms including night sweats, fevers, or weight loss (>10% over 6 mo). From Hoffman R et al: Hematology, basic principles and practice, ed 7, Philadelphia, 2018, Elsevier.

TABLE 4  Selected Immunophenotypic Markers and Histologic Characteristics of Use in the Differential Diagnosis of Hodgkin Lymphoma and Other Lymphoid Neoplasms Marker

Classical HL

Nodular Lymphocyte Predominant HL

TCRBCL

ALCL

CD30 CD15 CD20 CD45 CD79a ALK EMA Nodular growth protein

+ + −/+* − − − − +/−†

− − + + + − + +

− − + + + − + −

+ − − +/− − +/− + −

*CD20 positivity in classical Hodgkin lymphoma is quite heterogeneous, with a wide range in brightness of staining. †In classical Hodgkin lymphoma, a nodular growth pattern is confined to the nodular sclerosing subtype. +, >90% of cases positive; +/−, majority of cases positive; −/+, minority of cases positive; −, 1 lesion) (C) Elevated ESR (>50 mm/h without B symptoms; >30 mm/h with B symptoms)b (D) ≥3 nodal areas (out of 11 GHSG areas)

CS III-IV

Early-unfavorable (Intermediate) Advanced Prognostic factors

( A) Bulky mediastinal massa (B) Age ≥50 yr (C) Elevated ESR (>50 mm/h without B symptoms; >30 mm/h with B symptoms)b (D) ≥4 nodal areas (out of 5 supra-diaphragmatic EORTC areas)

( A) Bulky mediastinal massa (B) Bulk >10 cm (C) Elevated ESR (>50 mm/h without B symptoms) (D) B symptoms (E) ≥4 nodal areas (out of 17 Ann Arbor regions)

mediastinal mass: Ratio ≥0.035 of the maximum horizontal chest diameter (EORTC); ratio ≥1/3 of the maximum horizontal chest diameter (GHSG); ratio >1/3 of the maximum horizontal chest diameter (NCCN). bB symptoms: Night-sweats, fever, weight loss (unexplained, >10% over 6 mo). CS, Clinical stage; EORTC, European Organization for Research and Treatment of Cancer; ESR, estimated sedimentation rate; GHSG, German Hodgkin Study Group; NCCN, National Comprehensive Cancer Network. From Hoffman R et al: Hematology, basic principles and practice, ed 7, Philadelphia, 2018, Elsevier. aBulky

TABLE 11  International Prognostic Score (IPS) for Advanced Hodgkin Lymphoma No. of Prognostic Factors

% of patients

5-yr FFP (%)

5-yr OS (%)

0-1 (low-risk) 2-3 (intermediate-risk) 4-7 (high-risk)

29 52 19

79 64 47

90 80 59

FFP, Freedom from progression; OS, overall survival. From Hoffman R et al: Hematology, basic principles and practice, ed 7, Philadelphia, 2018, Elsevier.

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Hodgkin Lymphoma TABLE 12  Second Neoplasms Seen With Increased Frequency After Successful Hodgkin Lymphoma Treatment

SUGGESTED READINGS Available at ExpertConsult.com

H

RELATED CONTENT Hodgkin Lymphoma (Patient Information) AUTHORS: Jorge J. Castillo, MD, and Ann S. LaCasce, MD, MMSc

BEACOPP, Bleomycin, etoposide, Adriamycin (doxorubicin), cyclophosphamide, Oncovin (vincristine), procarbazine, and prednisone. From Abeloff MD: Clinical oncology, ed 3, Philadelphia, 2004, Saunders.

Diseases and Disorders

Acute myelogenous leukemia/myelodysplasia (BEACOPP) Non-Hodgkin lymphoma Melanoma Soft tissue sarcoma Adenocarcinoma: Breast Thyroid Lung Stomach and esophagus: Squamous cell carcinoma Skin Uterine cervix Head and neck

though the risk of infertility with ABVD is low. Symptomatic males, particularly with advanced stage Hodgkin lymphoma, may have disease-related oligospermia at diagnosis. • Chemotherapy with or without involvedfield radiotherapy should be the standard treatment for Hodgkin lymphoma with early stage disease. Chemotherapy with radiation in selected cases should be the standard of care for advanced stage. • After failure of ABVD therapy, more than 60% of patients who have had a relapse and about 30% of patients with initially refractory lymphoma can be reliably cured with high-dose chemotherapy and autologous hematopoietic stem-cell transplantation.

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TABLE 13  Potential Late Complications of Hodgkin Lymphoma Treatment and Appropriate Clinical Responses and Preventive Strategies Risk/Problem

Incidence/Response

Dental caries

Neck or oropharyngeal irradiation can cause decreased salivation. Patients should have careful dental care follow-up and should make their dentist aware of the previous irradiation. After external beam irradiation that encompasses the thyroid with doses sufficient to cure Hodgkin lymphoma, at least 50% of patients will eventually become hypothyroid. All patients whose TSH level becomes elevated should be treated with lifelong thyroxine replacement in doses sufficient to suppress TSH levels to low normal. This is also necessary to ensure that the radiation-damaged thyroid is not subjected to long-term stimulation by thyroid-stimulating hormone, which can increase the risk of thyroid neoplasm. ABVD is not known to cause any permanent gonadal toxicity, although oligospermia for 1-2 yr after treatment is common. Direct or scatter radiation to gonadal tissue can cause infertility, amenorrhea, or premature menopause, but this seldom occurs with the current fields used for the treatment of Hodgkin lymphoma. Thus, with the current chemotherapy regimens and radiation fields used, most patients will not develop these problems. In general, after treatment, women who continue menstruating are fertile, but men require semen analysis to provide a specific answer. High-dose chemoradiotherapy and hematopoietic stem cell transplantation almost always cause permanent infertility in both genders, although some young women occasionally recover fertility. Hodgkin lymphoma and its treatment can lead to lifelong impairment of full immunity to infection. All patients should be given annual influenza immunization and pneumococcal immunization every 5 yr. Patients whose spleen has been irradiated or removed should also be immunized against meningococcal types A and C and Haemophilus influenza type B. As for all adults, diphtheria and tetanus immunizations should be kept up-to-date. Although uncommon, certain secondary neoplasms occur with increased frequency in patients who have been treated for Hodgkin lymphoma. These include acute myelogenous leukemia, thyroid, breast, lung, and upper gastrointestinal carcinoma and melanoma, and cervical carcinoma in situ. It is appropriate to screen for these neoplasms for the rest of the patient’s life because they might have lengthy induction periods.

Hypothyroidism

Infertility

Impaired immunity to infections

Secondary neoplasms

ABVD, Adriamycin, bleomycin, vinblastine, dacarbazine; TSH, thyroid-stimulating hormone. From Abeloff MD: Clinical oncology, ed 3, Philadelphia, 2004, WB Saunders.

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SUGGESTED READINGS Armitage JO: Early-stage Hodgkin’s lymphoma, N Engl J Med 363:653-662, 2010. Canellos GP et al: Treatment of Hodgkin lymphoma: a 50-year perspective, J Clin Oncol 32:163-168, 2014. Chen R et  al: Phase II study of the efficacy and safety of pembrolizumab for relapsed/refractory classic Hodgkin lymphoma, J Clin Oncol 35:2125-2132, 2017. Connors JM: Hodgkin’s lymphoma, the great teacher, N Engl J Med 365(3), 2011. Connors JM et  al: Brentuximab vedotin with chemotherapy for stage III or IV Hodgkin's lymphoma, N Engl J Med 378(4):331-344, 2018. Engert A et al: Reduced treatment intensity in patients with early-stage Hodgkin’s lymphoma, N Engl J Med 363:640-652, 2010. Meyer RM et  al: ABVD alone versus radiation-based therapy in limited-stage Hodgkin’s lymphoma, N Engl J Med 366:399-408, 2012. Moskowitz CH et al: Brentuximab vedotin as consolidation therapy after autologous stem-cell transplantation in patients with Hodgkin’s lymphoma at risk of relapse or progression (AETHERA): a randomised, double-blind, placebocontrolled, phase 3 trial, Lancet 385:1853-1862, 2015. Radford J et al: Results of a trial of PET-directed therapy for early-stage Hodgkin’s lymphoma, N Engl J Med 372:1598-1607, 2015. Steidl C et al: Tumor-associated macrophages and survival in classic Hodgkin’s lymphoma, N Engl J Med 382:875-885, 2010. Viviani S et al: ABVD versus BEACOPP for Hodgkin’s lymphoma when high-dose salvage is planned, N Engl J Med 365:203-212, 2011. Younes A et al: Nivolumab for classical Hodgkin’s lymphoma after failure of both autologous stem-cell transplantation and brentuximab vedotin: a multicentre, multicohort, single-arm phase 2 trial, Lancet Oncol 17:1283-1294, 2016. Younes A et  al: Results of a pivotal phase II study of brentuximab vedotin for patients with relapsed or refractory Hodgkin’s lymphoma, J Clin Oncol 30:2183-2189, 2012.

A

B

C

D

FIG. E1  Hodgkin lymphoma. Morphology of classical Hodgkin lymphoma (CHL). A, Nodular sclerosis CHL. Cellular nodules are separated by concentric bands of mature collagen. B, Close-up of cellular nodule shows numerous lacunar cells with clear cytoplasm intermingled with lymphocytes, neutrophils, and eosinophils. Note collagen bands rimming the nodule. C, Nodular sclerosis CHL grade II. Confluent sheets of neoplastic cells with partly anaplastic features intermingled with a minority of inflammatory cells. This morphology is consistent with the so-called syncytial variant of CHL. D, Lymphocyte-depleted CHL, diffuse fibrosis subtype. Neoplastic ReedSternberg and Hodgkin cells in a hypocellular background with histiocytes and fibroblasts. This case lacks nodularity and ordered collagen bands. (From Jaffe ES et al: Hematopathology, Philadelphia, 2011, WB Saunders.)

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Hodgkin Lymphoma

A

B

C

E

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D

F

FIG. E2  Hodgkin lymphoma. Cytologic features of Reed-Sternberg (RS) cells and Hodgkin cells. A, Classic RS cells and variants in mixed cellularity—classical Hodgkin lymphoma (CHL), with amphophilic cytoplasm, large nuclei with clear karyoplasm, and huge viral inclusion-like nucleoli. B, Typical lacunar cells in a case of nodular sclerosis CHL. Note the delicate folded nuclear membranes, less conspicuous nucleoli, and ample clear cytoplasm with threadlike protrusions. C, Typical RS cells, including a binuclear variant, in mixed cellularity CHL. D, Abundant, sometimes bizarre multinucleated tumor cells in a case of nodular sclerosis grade II. E, So-called mummified RS cell with condensed, deeply basophilic cytoplasm. F, Two classic mononuclear Hodgkin cells in a case of mixed cellularity CHL. (From Jaffe ES et al: Hematopathology, Philadelphia, 2011, WB Saunders.)

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Hodgkin Lymphoma

A

C

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B

D

FIG. E3  Imaging of Hodgkin lymphoma. Bulky Hodgkin disease as seen on chest radiograph (A), computed tomography (CT) of the chest (B), gallium scan (C), and positron emission tomography (PET) (D). The arrows indicate sites of disease. Note that the PET and CT scans provide more detailed information than the chest radiograph and gallium scan. (From Goldman L, Schafer AI: Goldman’s Cecil medicine, ed 24, Philadelphia, 2012, WB Saunders.)

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Hookworm BASIC INFORMATION DEFINITION Hookworm is a parasitic infection of the intestine caused by the soil helminths Necator americanus (North and South America, Central Africa and parts of Asia) and Ancylostoma duodenale (Mediterranean nations, India, Iran, Far East). The hookworm of dogs and cats, Ancylostoma ceylanicum, (India, Southeast Asia) also can affect humans. SYNONYMS Ground itch Ancylostoma duodenale infection Necator americanus infection EPIDEMIOLOGY & DEMOGRAPHICS INCIDENCE (IN U.S.): • Varies greatly in different areas of the U.S. • Most common in rural areas of southeastern U.S. • Poor sanitation and increased rainfall increase incidence. PREVALENCE (IN U.S.): Varies from 10% to 90% in regions where it is found. PREDOMINANT AGE: Schoolchildren PHYSICAL FINDINGS & CLINICAL PRESENTATION • Nonspecific abdominal complaints • Symptoms related to iron deficiency anemia depending on the amount of iron in the diet and worm burden (these organisms consume host’s RBCs) • Fatigue, tachycardia, dyspnea, and highoutput failure

• Hypoproteinemia and edema from loss of proteins into the intestinal tract • Unusual for pulmonary manifestations to occur when the larvae migrate through the lungs • Skin rash at sites of larval penetration in some individuals without prior exposure: Ground itch

ETIOLOGY Two main species can cause this disease: N. americanus and A. duodenale. N. americanus is the predominant cause of hookworm in the U.S. They are soil nematodes (geohelminthic infections) that are acquired by skin contact (i.e., bare feet) with contaminated soils in moist, warm climate. Worldwide, over 700 million people are infected. • Infection occurs via penetration of the skin by the larval form, with subsequent migration via the bloodstream to the alveoli, up the respiratory tract, then into the GI tract (Fig. 1). • Ancylostoma spp. infection can also occur via the oral route through ingestion of contaminated water supplies. • Sharp mouth parts allow for attachment to intestinal mucosa. • Ancylostoma spp. are more likely to cause iron deficiency anemia because they are larger and remove more blood daily from the bowel wall than the other hookworm species, N. americanus.

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • Strongyloidiasis • Ascariasis • Other causes of iron deficiency anemia and malabsorption

WORKUP Examine stool for hookworm eggs. Shedding of eggs starts around 8 wk after skin penetration in N. americanus infections and longer with A. duodenale, but eggs are indistinguishable between the two species. PCR stool assays are available in reference labs. LABORATORY TESTS CBC to show hypochromic, microcytic anemia; possible mild eosinophilia and hypoalbuminemia IMAGING STUDIES Chest x-ray: Generally not helpful, occasionally shows opacities

TREATMENT NONPHARMACOLOGIC THERAPY • Prevention of disease by not walking barefoot and by improving sanitary conditions. • Vaccines are in development. ACUTE GENERAL Rx • Albendazole 400 mg PO as a single dose or daily for 3 days is the preferred treatment. • Mebendazole 100 mg PO bid for 3 days is more effective than as a 500-mg single dose. • Pyrantel pamoate 11 mg/kg (to max dose of 1 g) PO qd × 3 days. • Iron supplementation may be helpful in patients with iron deficiency. DISPOSITION Easily treated REFERRAL To gastroenterologist and infectious disease specialist if diagnosis uncertain

PEARLS & CONSIDERATIONS A.l.

A.d.

S.s.

COMMENTS • Appropriate disposal of human waste is important in controlling the disease in areas with a high prevalence of hookworm infestation. • Wearing shoes will avoid contact with contaminated soil, and the provision of safe water and sanitation for disposing human excreta is important in control of hookworm. SUGGESTED READINGS Available at ExpertConsult.com

FIG. 1  Life cycle of intestinal nematodes with a migratory phase through the lungs. Eggs are passed with stools in Ascaris lumbricoides (A.l.), Necator americanus, or Ancylostoma duodenale (A.d.), or they hatch on their way out in Strongyloides stercoralis (S.s.). Ascaris eggs mature in soil, and humans are infected upon ingestion of these eggs. With hookworm and strongyloidiasis, humans are infected via skin penetration by filariform larvae. In all three infections, larvae pass through a migratory phase via the lungs before reaching maturity at their final habitat in the small intestine. (From Mandell GL et al: Principles and practice of infectious diseases, ed 7, Philadelphia, 2010, Churchill Livingstone.)

RELATED CONTENT Hookworm Infection (Patient Information) AUTHOR: Glenn G. Fort, MD, MPH

Hookworm SUGGESTED READINGS Loukas A et al: Hookworm infection, Nat Rev Dis Primers 8(2):16088, 2016. Starr MC, Montgomery SP: Soil-transmitted Helminthiasis in the United States: a systematic review: 1940-2010, Am J Trop Med Hyg 85(4):680-684, 2011.

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Horner Syndrome BASIC INFORMATION DEFINITION Horner syndrome is the clinical triad of ipsilateral ptosis, miosis, and sometimes facial anhidrosis. Disruption of any of the three neurons in the oculosympathetic pathway (first-order, second-order, or third-order) can cause Horner syndrome. SYNONYMS Oculosympathetic paresis Raeder paratrigeminal syndrome: Horner syndrome of the third-order neuron associated with pain in the trigeminal nerve distribution ICD-10CM CODE G90.2

Horner syndrome

EPIDEMIOLOGY & DEMOGRAPHICS Congenital or acquired PHYSICAL FINDINGS & CLINICAL PRESENTATION • Ptosis is usually mild. It results from loss of sympathetic tone to Müller muscle, which contributes approximately 2 mm of upper eyelid elevation. Weakness of the corresponding muscle in the lower eyelid causes it to elevate slightly. This combination causes

narrowing of the palpebral fissure. Levator function of the eyelid is preserved. • Miosis results from loss of sympathetic innervation to the iris dilator muscle. The affected pupil reacts normally to bright light and accommodation. Anisocoria is greater in dim light. 1.  Dilation lag: Horner pupil dilates more slowly than the normal pupil when lights are dimmed (20 vs. 5 sec) because it dilates passively as a result of relaxation of the iris sphincter. • Presence of facial anhidrosis is variable and depends on the site of injury. It occurs with lesions affecting first-order or second-order neurons. • Congenital Horner syndrome may result in heterochromia. The affected eye has a lighter-colored iris. • Acute cases may also present with facial flushing, conjunctival injection, and nasal stuffiness from the loss of sympathetic vasoconstriction.

ETIOLOGY Disruption of the ipsilateral sympathetic innervation to the eye and face. Lesions can damage any of the three neurons in the oculosympathetic pathway (Fig. E1). First-order neuron lesions are least common but are usually caused by pathology in the hypothalamus, brain stem, or cervicothoracic spinal cord. Second-order neuron lesions are often caused by disease involv-

ing the cervicothoracic spinal cord, lung apex, or anterior neck. Third-order neuron lesions are usually seen with disease in the internal carotid artery, skull base, cavernous sinus, or orbital apex. Location is often suggested by the presence of associated findings. Vascular disease and neoplasm must be considered. One large study found that 65% of patients with Horner syndrome had an identifiable cause, 13% had a first-order neuron lesion, 44% had a second-order neuron lesion, and 43% had a third-order neuron lesion. Mechanical: • Syringomyelia • Trauma • Tumors: Benign, malignant head and neck cancers (thyroid, apical lung, mediastinal) • Cervical rib Vascular (ischemia, hemorrhage or arteriovenous malformation): • Brain stem lesion: Commonly occlusion of the posterior inferior cerebellar artery but other arteries may be responsible (vertebral; superior, middle or inferior lateral medullary arteries; superior or anterior inferior cerebellar arteries) • Carotid artery aneurysm, dissection, arteritis: Can also be from injury to other major vessels (internal carotid artery, subclavian artery, ascending aorta) • Jugular venous ectasia • Cavernous sinus thrombosis • Cluster headache, migraine

First-order neuron

Third-order neuron to pupil dilator and lid

Third-order neuron to facial sweat glands

Second-order neuron

Common carotid artery Subclavian artery Apex of lung

FIG. E1  Anatomy of sympathetic pathways to the eye. The sympathetic innervation of the eye consists of three neurons connected in a series: first-order neurons, second-order neurons, and third-order neurons. The first-order neurons (central neurons) extend from the posterior hypothalamus to the C8 to T2 level of the spinal cord. The second-order neurons (preganglionic neurons) leave the spinal cord and travel over the lung apex, around the subclavian artery, and along the carotid artery to the superior cervical ganglion. The third-order neurons (postganglionic neurons) diverge and take two paths: those to the pupil and lid muscles travel along the internal carotid artery through the cavernous sinus to reach the orbit; those to the facial sweat glands travel with the external carotid artery to the face. Lesions in any of these neurons cause Horner syndrome and distinct associated physical signs. (From McGee [ed]: Evidence-based physical diagnosis, ed 3, Philadelphia, 2012, WB Saunders.)

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Miscellaneous: • Idiopathic • Congenital • Demyelination (multiple sclerosis) • Infection (apical tuberculosis, herpes zoster, Lyme disease) • Myelitis • Pneumothorax • Iatrogenic (angiography, internal jugular/subclavian catheter, chest tube, neck or upper thoracic surgery, epidural spinal anesthesia)

DIAGNOSIS DIFFERENTIAL DIAGNOSIS Causes of anisocoria (unequal pupils): • Normal variant • Mydriatic use, medications • Prosthetic eye • Prior eye surgery, trauma • Iritis • Acute angle-closure glaucoma • Adie tonic pupil • Third nerve palsy Causes of ptosis are described in Section II. WORKUP History, physical examination, pharmacologic testing, imaging

PHARMACOLOGIC TESTING These medications may not be readily available. Pharmacologic testing should not delay evaluation in acute, painful, or traumatic cases or in patients with a history of malignancy. • Topical cocaine test (Fig. E2): Confirms diagnosis (drops increase anisocoria by dilating normal pupil but not Horner pupil). • Topical apraclonidine test: Confirms diagnosis (drops reverse anisocoria by causing dilation of Horner pupil and slight constriction of normal pupil). Less reliable than topical cocaine in acute Horner syndrome (Box E1). • Topical hydroxyamphetamine test: Distinguishes first- and second-order neuron lesions from third-order sympathetic lesions (drops dilate normal pupil and first- or second-order Horner pupil, but not thirdorder Horner pupil). Testing must be delayed >48 hr after topical cocaine or apraclonidine testing. IMAGING STUDIES • One approach is to image the entire oculosympathetic pathway with an MRI of the brain to the upper chest and an MRA of the neck (or CT/CTA if acute presentation or MR not possible)

• Other approaches suggest using results of pharmacologic testing, as well as accompanying signs and symptoms to guide imaging • MRI brain: Brain stem (diplopia, eye movement abnormalities, vertigo, ataxia, lateral medullary syndrome); cavernous sinus (sixth nerve palsy) • MRI cervical and upper thoracic spinal cord: Sensory changes/weakness of extremities, bowel/bladder dysfunction • MRI/MRA or CTA neck: Carotid artery dissection (acute Horner syndrome with face or neck pain) • CT chest and neck: Evaluate lung apex, perivertebral areas, mediastinum if symptoms do not localize to the central nervous system; brachial plexus lesion (arm/hand pain or weakness)

TREATMENT • Treatment depends on underlying cause. • Ptosis can be surgically corrected or treated with medication (phenylephrine drops).

REFERRAL Ophthalmologist for pharmacologic testing to confirm diagnosis and localize lesion

After cocaine eyedrops

Normal pupil dilates markedly Before eyedrops

Miosis and ptosis After apraclonidine eyedrops

Horner pupil dilates (reversal of anisocoria) Eyedrop

Horner pupil

Normal pupil

Cocaine

No change

Dilates

Apraclonidine

Dilates

No change

FIG. E2  Confirmation of Horner syndrome: the cocaine and apraclonidine eyedrop tests. This patient has a right Horner syndrome with right miosis and ptosis (middle row). 45 min after installation of cocaine drops into each eye (top row), the Horner pupil fails to dilate, but the normal pupil dilates, markedly aggravating the anisocoria and confirming the diagnosis of Horner syndrome. 45 min after installation of apraclonidine drops into each eye (performed on a different day than the cocaine test; bottom row), the right Horner pupil dilates, but there is no response in the normal pupil, thus reversing the anisocoria and also confirming the diagnosis of Horner syndrome. Cocaine eyedrops block the reuptake of norepinephrine at the myoneural junction of the iris dilator, causing the pupil to dilate unless norepinephrine is absent because of sympathetic denervation. Apraclonidine eyedrops have no effect on normal pupils, but after sympathetic denervation from Horner syndrome, the affected pupil is supersensitive to their effect. Apraclonidine may also cause elevation of the lid in Horner syndrome (bottom row), although only the response of the pupil is used when interpreting the test. (From McGee S: Evidence-based physical diagnosis, ed 4, Philadelphia, 2018, Elsevier.)

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BOX E1  Horner Syndrome, Eyedrop Tests LIKELIHOOD RATIO IF FINDING IS Finding (Reference)

Sensitivity (%)

Specificity (%)

Present

Absent

95 95

99 90-95

96.8 14.0

0.1 0.1

83-92

79-96

9.2

0.2

88 53

79 78

4.2 NS

NS 0.6

Detecting Horner Syndrome

Anisocoria ≥1 mm after topical cocaine Reversal of anisocoria after topical apraclonidine

Diagnosing First- or Second-Order Nerve Lesion in Horner Syndrome

Small pupil dilates with topical hydroxyamphetamine (Paredrine) Small pupil fails to dilate with dilute phenylephrine Asymmetric facial sweating

NS, Not significant. From McGee S: Evidence-based physical diagnosis, ed 4, Philadelphia, 2018, Elsevier.

 EARLS & P CONSIDERATIONS • May be the presentation of a life-threatening condition. Horner syndrome presenting acutely or associated with head/neck pain, trauma, or history of malignancy should be evaluated urgently. • Normal variant anisocoria: 1. Occurs in 20% of people

2. Usually 1 mg/dl above upper limit normal) c. Creatinine clearance 400 mg/dl (>10 mmol/dl) e. Presence of nephrolithiasis or nephrocalcinosis by x-ray, ultrasound, or CT

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ALG

Hyperparathyroidism

Abnormally elevated serum calcium 6 mo after a parathyroidectomy for HPT

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H

Confirm diagnosis of HPT (assess vitamin D levels). Physical examination of the patient (placement of the incision, body habitus, voice changes, etc.). Vocal cord assessment. Family history review. Review prior imaging studies, records from initial operation, and pathology reports from initial operation.

Diseases and Disorders

Persistent HPT Serum calcium levels remain abnormally high during the first 6 mo postoperatively and never normalize Causes Missed gland Multigland disease Incomplete resection Parathyroid cancer

Recurrent HPT Serum calcium levels normalize during the first 6 mo after initial operation and then increase to abnormal levels Causes Multigland disease Multiple endocrine neoplasia type 1 Parathyroid cancer Regrowth of remnant Parathyromatosis

I

Perform a combination of cervical US, sestamibi, and 4D CT. Consider FNA to obtain PTH levels and cytology. Utilize venous sampling selectively.

If the location of a single missed gland is confirmed, proceed to reoperation. Utilize as needed: IOPTH assay, intraoperative US, IONM.

If multifocal disease is suspected, review location of glands removed, plan completion, subtotal parathyroidectomy

If culprit gland(s) are not identified, continue monitoring, reevaluate the patient’s status with new imaging studies in 1-2 yr

FIG. 7  Algorithm for managing persistent or recurrent hyperparathyroidism (HPT). 4D CT, Fourdimensional computed tomography; FNA, fine-needle aspiration; IONM, intraoperative neurophysiologic monitoring; IOPTH, intraoperative parathyroid hormone; PTH, parathyroid hormone; sestamibi, technetium (99mTc) sestamibi imaging; US, ultrasonography. (From Cameron JL, Cameron AM: Current surgical therapy, ed 12, Philadelphia, 2017, Elsevier.)

BOX 1  Indications for Parathyroidectomy in Patients With Secondary and Tertiary Hyperparathyroidism Indications for Parathyroidectomy in Patients with Secondary Hyperparathyroidism (SHPT) SHPT refractory to medical therapy: • Parathyroid hormone >1000 pg/ml • Calcium × Phosphorus product >55 Renal osteodystrophy Calciphylaxis Other retractable symptoms, including uremic pruritus, persistent anemia, bone pain, muscle pain, abdominal pain, fatigue, and weakness Indications for Parathyroidectomy in Patients With Tertiary Hyperparathyroidism Severe hypercalcemia (calcium >12.5 mg/dl) Persistent hypercalcemia ≥2 yr after renal transplantation, associated with: • Decline in renal function, without graft rejection • Nephrolithiasis • Progressive bone disease • Pancreatitis From Cameron JL, Cameron AM: Current surgical therapy, ed 12, Philadelphia, 2017, Elsevier.

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Hyperparathyroidism thyroid gland. It decreases PTH production and subsequently normalizes or decreases serum calcium levels, without significant BMD changes. It is indicated for the treatment of severe hypercalcemia in patients with primary hyperparathyroidism who are unable to undergo surgery. It is also indicated for the treatment of secondary hyperparathyroidism associated with chronic kidney disease and for hypercalcemia associated with parathyroid carcinoma. b. Agents such as bisphosphonates (e.g., alendronate, zoledronate) that inhibit bone resorption and increase BMD should be considered when improvement in BMD is the primary goal in patients with hyperparathyroidism. • Medical monitoring is recommended for asymptomatic primary hyperparathyroidism. The majority of patients do not manifest disease progression during observation. However, approximately 25% of asymptomatic patients require surgery over a 10-yr follow-up period. 1. Indications for medical monitoring: a. Clinically asymptomatic and >50 yr old b. Serum calcium level only mildly elevated (60 ml/min and no nephrolithiasis or nephrocalcinosis d. No evidence of osteoporosis e. Medically unfit for surgery or refusing surgery • Symptoms should be assessed regularly. Serum calcium, PTH, creatinine, and eGFR should be checked semiannually. DXA performed at three sites every 1 to 2 yr or vertebral fracture assessment of the spine is clinically indicated (e.g., height loss, back pain).

ACUTE GENERAL Rx Severe and/or symptomatic hypercalcemia may require hospitalization, especially if serum calcium >12 mg/dl. Acute management of hypercalcemia includes: • Vigorous hydration with IV normal saline (2 to 4 L/day). Fluid status must be monitored in patients with cardiac dysfunction or renal insufficiency in order to avoid fluid overload. • Bisphosphonates can effectively decrease calcium levels. Zoledronate (4 mg IV over 15 min) or pamidronate (60 to 90 mg IV over 4 hours) are both effective. Onset of action is 24 to 48 hours. • Calcitonin (4 units/kg IM/SC every 12 hours) may be used with bisphosphonates to achieve a more rapid reduction of calcium levels. Onset of action is within hours.

 EARLS & P CONSIDERATIONS COMMENTS • Parathyroidectomy should be considered for all patients with symptomatic hyperparathyroidism. If surgery is contraindicated or not desired, cinacalcet and bisphosphonates can be used. • Asymptomatic patients can be monitored with serial calcium, creatinine, eGFR, and bone mineral density measurements. Disease progression may result in surgery. • Most patients can be managed medically by limiting factors that result in hypercalcemia (e.g., dehydration, immobilization, thiazide diuretics) and maintaining normal calcium and vitamin D intake. • Patients with osteopenia and high fracture risk may require antiresorptive therapy such as bisphosphonates. SUGGESTED READINGS Available at ExpertConsult.com RELATED CONTENT Hyperparathyroidism (Patient Information) AUTHOR: Vicky Cheng, MD

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SUGGESTED READINGS Bilezikian JP et  al: Guidelines for the management of asymptomatic primary hyperparathyroidism: summary statement from the Fourth International Workshop, J Clin Endocrinol Metab 99(10):3561-3569, 2014. Insogna KL: Primary hyperparathyroidism, N Engl J Med 379(11):1050-1059, 2018. Kunstman JW et al: Superiority of minimally invasive parathyroidectomy, Adv Surg 45:171-189, 2012. Press DM et al: The prevalence of undiagnosed and unrecognized primary hyperparathyroidism: a population-based analysis from the electronic medical record, Surgery 154:1232-1237, 2013. Rolinghed L et al: Vitamin D treatment in primary hyperparathyroidism: a randomized placebo controlled trial, J Clin Endocrinol Metab 99(3):1072-1080, 2014. Silva BC et al: Primary hyperparathyroidism, Best Pract Res Clin Endocrinol Metab 32:593-607, 2018. Udelsman R et al: The surgical management of asymptomatic primary hyperparathyroidism: proceedings of the Fourth International Workshop, J Clin Endocrinol Metab 99(10):3595-3606, 2014. Wentworth K, Shoback D: Applying the guidelines for primary hyperparathyroidism: the path not taken, JAMA Intern Med 2019 [Epub ahead of print].

FIG. E2  Role of scintigraphy in detecting parathyroid adenomas. A 66-yr-old woman with hypercalcemia. CT (not shown) did not reveal a parathyroid adenoma. 99m Tc-sestamibi radionuclide imaging demonstrates uptake in both thyroid and parathyroid parenchyma in the 10-min delayed image (left); however, at 2-hour delay, imaging (right) demonstrates persistent uptake in the right lobe of the thyroid gland, representing the parathyroid adenoma (From Adam A, Dixon AK, Gillard JH, Schaefer-Prokop CM: Grainger and Allison’s diagnostic radiology, ed 6, Elsevier, 2015, in Grant LA: Grainger & Allison’s diagnostic radiology essentials, ed 2, 2019, Elsevier.) FIG. E1  Radiograph of hand from a patient with severe primary hyperparathyroidism. Note the dramatic remodeling associated with the intense region of high bone turnover in the third metacarpal, in addition to widespread evidence of subperiosteal and trabecular resorption. (Courtesy Fuller Albright Collection, Massachusetts General Hospital. From Larsen PR et al [eds]: Williams textbook of endocrinology, ed 10, Philadelphia, 2003, WB Saunders.)

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A

C

E

B

D

F

FIG. E5  Hyperparathyroidism. Chondrocalcinosis in the knee menisci (A) and (B) the symphysis pubis. (C) Subperiosteal erosions along the radial side of the middle phalanx of the 2nd finger. Acro-osteolysis is also present. Metastatic calcification of the digital artery confirms this is secondary hyperparathyroidism. (D) cortical “tunneling” in the proximal phalanges. (E) Brown tumor within the distal tibia. (F) Precipitation of amorphous calcium phosphate in the soft tissues of the shoulder (hyperparathyroidism secondary to chronic renal disease. (From Adam A et al: Grainger & Allison's diagnostic radiology, ed 5, 2007, Churchill Livingstone; in Grant LA: Grainger & Allison’s diagnostic radiology essentials, ed 2, 2019, Elsevier.)

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Hypersensitivity Pneumonitis BASIC INFORMATION

SYNONYMS HP - Extrinsic allergic alveolitis (EAA) Bird fancier’s lung Farmer’s lung Malt worker’s lung “Ventilation” pneumonitis Maple bark-stripper’s lung Sauna taker’s lung Hot tub lung ICD-10CM CODES J67.x Hypersensitivity pneumonitis due to specific organic dusts J67.9 Hypersensitivity pneumonitis due to unspecified organic dust

EPIDEMIOLOGY & DEMOGRAPHICS • Estimates of the prevalence and incidence of HP vary considerably and depend on the definition and methods used to establish the diagnosis. • Clinical presentation depends on the intensity of exposure, environmental conditions, and genetic risk factors that remain poorly understood. • More than 300 causative agents have been identified, and the number continues to grow. • Causative agents in residential and occupational exposures include birds, mold, humidifiers, fountains, steam irons, dry sausage molds, moldy cheese, contaminated wood, biofilm contained within wind instruments (e.g., trombone, saxophone), and organic and inorganic chemicals, including metalworking fluids. • It is likely that genetic factors are also involved that result in an exaggerated lung response to an offending agent. The major histocompatibility complex is the most studied thus far. PHYSICAL FINDINGS & CLINICAL PRESENTATION Vary depending on frequency and intensity of antigen exposure. • Acute: Fever, cough, malaise, and dyspnea 4 to 6 hours after an intense exposure. Symptoms resolve with removal of the inciting agent, typically within 12 to 24 hours • Often misdiagnosed initially as a viral illness or asthma

ETIOLOGY • Numerous environmental agents, often encountered in occupational settings. • Common sources of antigens: “Moldy” hay, silage, grain, or vegetables; bird droppings or feathers (including those found commonly in down pillows, blankets, and upholstered furniture); low-molecular-weight chemicals (e.g., isocyanates); pharmaceutical products. • Fig. E1 illustrates the pathogenesis of hypersensitivity pneumonitis.

DIAGNOSIS • Accurate diagnosis is important for differentiating HP from other interstitial lung diseases because the prognosis and treatment may differ. • The clinical syndrome of acute HP is indistinguishable from an acute respiratory infection with a history of illness occurring within hours of exposure to an antigen. • Need high index of suspicion. • Detailed occupational and home exposure history is required. • Lung biopsy is often necessary for diagnosis.

DIFFERENTIAL DIAGNOSIS Acute Stages

Chronic Stages

Allergic bronchopulmonary aspergillosis Pulmonary embolism Asthma Aspiration pneumonia Bacterial pneumonia Fungal or mycobacterial pneumonia Bronchiolitis obliterans–organizing pneumonia Eosinophilic pneumonia Churg-Strauss syndrome Wegener granulomatosis

Idiopathic pulmonary fibrosis (IPF) Bronchiectasis Chronic bronchitis Nonspecific interstitial pneumonia (NSIP) Connective ­tissue– related lung disease Sarcoidosis

H

Diseases and Disorders

DEFINITION Hypersensitivity pneumonitis (HP) is a group of immunologically mediated pulmonary diseases, with or without systemic manifestations (e.g., fever, weight loss), caused by the inhalation of an antigen to which the patient is sensitized and hyperresponsive. Sensitization and exposure alone in the absence of symptoms do not define the disease.

• Subacute: Insidious onset of productive cough, dyspnea on exertion, anorexia, and weight loss, usually from a heavy, sustained exposure • Chronic: Gradually progressive cough, dyspnea, malaise, and weight loss, usually from low-grade or recurrent exposure • Physical examination: Hypoxemia, cyanosis, rales, possible fever

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WORKUP No single radiologic, physiologic, or immunologic test is specific for the diagnosis of HP. HP must be suspected in any patient presenting with cough, dyspnea, fever, and malaise. A thorough history focusing on potential exposures is essential. Table 1 describes examples of occupational causes of HP. Environmental and occupational history questions should ask about grain dusts, animal handling, food processing, cooling towers, fountains, metal-working fluids, symptom improvement away from exposure, pets (particularly

TABLE 1  Examples of Occupational Causes of Hypersensitivity Pneumonitis Occupation

Cause

Farmer Metal worker

Thermophilic actinomycetes in moldy hay Contamination of metal-working fluids with microorganisms such as Mycobacteria immunogens or fungi Contamination with microorganisms such as protozoa or fungi Moldy sugarcane (bagassosis) Fungi Avian proteins Penicillin Soybeans Microorganisms contaminating air conditioners or humidifiers Fungal contamination in sprays around pool area Rat proteins Fungi Weevil-infested flour Fungi Methylene diphenyl diisocyanate, hexamethylene diisocyanate, toluene diisocyanates

Worker exposed to humidifiers Sugarcane worker Maple bark stripper Chicken or turkey worker Pharmaceutical worker Food handler Office worker Swimming pool attendant Animal worker Mushroom worker Wheat farmer or handler Greenhouse worker Workers spraying urethane paint or adhesives/ sealants (or less often, other workers using diisocyanate) Chemical worker using plastics, resins, paints

Trimellitic anhydride

From Goldman L, Schafer AI: Goldman’s Cecil medicine, ed 24, Philadelphia, 2012, WB Saunders.

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Hypersensitivity Pneumonitis birds), hobbies involving chemicals, feathers, or fur, organic dusts, presence of humidifiers, dehumidifiers, or hot tubs/saunas, leaking or flooding indoors, visible fungal growth in living or working environment, feather pillows, bedding, or upholstered furniture. Major diagnostic criteria: • History of compatible clinical symptoms, physical exam, changes on chest radiograph or high-resolution CT (HRCT) of the chest, and pulmonary function tests. Particularly suspicious if symptoms appear to worsen within hours after antigen exposure • Confirmation of exposure to the offending agent by history, investigation of the environment, serum precipitin tests to potential agents (often referred to as a “hypersensitivity panel” by many labs) • BAL fluid lymphocytosis (if performed) • Compatible histologic changes by lung biopsy (if performed): Poorly formed granulomas or mononuclear cell infiltrate • Positive natural challenge (reproduction of symptoms and laboratory abnormalities after exposure to the suspected environment) or controlled inhalation challenge

LABORATORY TESTS • Routine laboratory tests do not make the diagnosis, but typically the erythrocyte sedimentation rate, C-reactive protein, lactate dehydrogenase, and leukocyte count are increased; elevated immunoglobulins IgG and IgM are nonspecific; rheumatoid factor (RF) and immune complexes are often positive; peripheral eosinophil count and serum IgE are generally normal. • Lactate dehydrogenase (LDH) is increased and tends to decrease with improvement. • Pulmonary function tests: Restrictive ventilatory pattern is typically seen. Decreased FEV1, decreased forced vital capacity, decreased total lung capacity, decreased diffusion capacity, and decreased static compliance. • Arterial blood gases show mild hypoxemia (worsens with exercise). • A-a gradient shows slight increase. • Serum precipitin test for IgG antibodies against offending antigen may be positive in serum. Precipitins are sensitive but not specific for HP (asymptomatic patients may have IgG antibodies in serum). HP may also be present without a positive precipitin test. • Skin testing is generally not helpful in establishing a diagnosis. IMAGING STUDIES Chest x-ray: Nonspecific; may be normal in early stage. • Acute/subacute: Bilateral interstitial and alveolar nodular infiltrates in a patchy or homogeneous distribution. • Chronic: Diffuse reticulonodular infiltrates and fibrosis. High-resolution chest CT scan (Fig. 2): No pathognomonic features but demonstrates airspace and interstitial patterns in the acute and subacute stage. The chronic stage reveals honeycombing, air trapping, and bronchiectasis.

FIG. 2  In this patient with hypersensitivity pneumonitis, patchy ground-glass opacity is visible bilaterally. (From Mason RJ: Murray & Nadel’s textbook of respiratory medicine, ed 5, Philadelphia, 2010, WB Saunders.)

TREATMENT NONPHARMACOLOGIC THERAPY Early recognition and avoidance of the causative antigen ACUTE GENERAL Rx • Glucocorticoids accelerate initial lung recovery but may have no effect long term (from a controlled study in farmer’s lung). No prospective, randomized, placebo-controlled trials for other types of HP or subacute and chronic stages. • Prednisone 0.5 to 1 mg/kg usually over 1 to 2 wk then tapered over 4 wk. Some patients, particularly those with subacute or chronic presentation, may require a longer course of therapy. DISPOSITION/PROGNOSIS Prognosis is generally better in patients with acute or subacute HP. Prognosis is worse in those with older age, desaturation during exercise, and findings of severe fibrosis by lung biopsy. Acute: 4 to 48 hours • Clinical: Fever, chills, cough, hypoxia, malaise • HRCT: Ground-glass infiltrates • Immunopathology: Poorly formed, noncaseating granulomas or mononuclear cell infiltration in a peribronchial distribution, frequently with giant cells • Prognosis: Good Subacute: Wks to 4 mo • Clinical: Dyspnea, cough, episodic flares • HRCT: Micronodules, air trapping • Immunopathology: More well-formed, noncaseating granulomas, bronchiolitis, organizing pneumonia, and interstitial fibrosis • Prognosis: Good Chronic: 4 mo to yr • Clinical: Dyspnea, cough, fatigue, weight loss • HRCT: Fibrosis (possible), honeycombing, emphysema • Immunopathology: Granulomatous inflammation may be seen in addition to bronchiolitis obliterans (with or without organizing pneumonia) and honeycombing and fibrosis, lymphocytic infiltration, centrilobular and bridging fibrosis, neutrophil-mediated air space destruction, giant cells • Prognosis: Generally poor

REFERRAL • Bronchoscopy: BAL provides useful supportive data in the diagnosis of HP. Usually reveals intense lymphocytosis (typically T cells >50%) of predominantly CD8+ suppressor cells. In the acute stage, neutrophils predominate, but as the disease progresses to chronic form, the ratio of CD4+ to CD8+ cells increases. When fibrosis is present the number of neutrophils increases. • Lung biopsy: The histopathologic features of HP are distinctive but not pathognomonic. Bronchiolitis and interstitial pneumonitis with granuloma formation typically is seen. Variable degrees of interstitial fibrosis are seen in the chronic form. Chronic HP may be difficult to distinguish from IPF or NSIP pathologically. • Laboratory inhalation challenge: Testing to prove a direct relation between a suspected antigen and disease; extract of antigen is inhaled by nebulizer.

PEARLS & CONSIDERATIONS A clinical prediction rule using six features has high specificity and sensitivity for the diagnosis of acute and subacute HP: • Exposure to a known offending agent • Positive specific precipitating antibody • Recurrent episodes of symptoms • Inspiratory crackles • Symptoms occurring 4 to 8 hr after exposure • Weight loss HP occurs more frequently in smokers than nonsmokers (likely from an immunosuppressive effect).

SUGGESTED READINGS Available at ExpertConsult.com RELATED CONTENT Hypersensitivity Pneumonitis (Patient Information) AUTHOR: Melissa H. Tukey, MD, MS

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SUGGESTED READINGS Churg A: Chronic hypersensitivity pneumonitis, Am J Surg Pathol 30(2):201, 2006. Costabel U et al: Chronic hypersensitivity pneumonitis, Clin Chest Med 33:151163, 2012. Fishwick D et  al: New occupational and environmental causes of asthma and extrinsic allergic alveolitis, Clin Chest Med 33:605-616, 2012. Lacasse Y et al: Recent advances in hypersensitivity pneumonitis, Chest 142:208217, 2012. Metzger F et al: Hypersensitivity pneumonitis due to molds in a saxophone player, Chest 138(3), 2010.

Exposure to antigen Molds Birds Chemicals Mycobacteria Viral infection Endotoxins

Genetic susceptibility

Reduced lymphocyte apoptosis

Th1 and Th2 response

Antigen-IgG immunocomplex

Large influx lymphocytes

Complement activation

Abnormal Treg function (IL-17 mediated)

Neutrophils

Th1 predominance

Macrophage

CXCL8 CCL5 CCL3

Acute HP

Th2 response skewing

↓ IFN-γ

Tissue damage fibrosis

↑ IL-4, IL-13

Subacute/chronic HP

FIG. E1  Pathogenesis of hypersensitivity pneumonitis (HP). Chronic and repeated exposure to antigens in genetically susceptible individuals triggers an inflammatory process. A T-helper (Th) 1 response predominates in the early stages, whereas Th2 skewing occurs in later stages, both leading to tissue damage from inflammatory propagation and cytokine release. Lung tissue lymphocytes are increased because of decreased lymphocyte apoptosis and impaired regulatory T cell (Treg) function (mediated by interleukin [IL]-17). Early inflammatory changes include IgG binding to antigen and complement pathways with macrophage activation and secretion of chemoattractants (CXCL8, CCL5, CCL3) that induce neutrophilic airway infiltration and tissue destruction. IFN, Interferon; Ig, immunoglobulin. (From Adkinson NF et al: Middleton’s allergy principles and practice, ed 8, Philadelphia, 2014, WB Saunders.)

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  Hypersplenism BASIC INFORMATION DEFINITION Hypersplenism is a syndrome characterized by splenomegaly, cytopenias (one or more of the following: Anemia, thrombocytopenia, or leukopenia), and compensatory hyperplastic bone marrow. These cytopenias are correctable with splenectomy.

EPIDEMIOLOGY & DEMOGRAPHICS Most often seen in patients with liver disease, hematologic malignancy, and infection. PHYSICAL FINDINGS & CLINICAL PRESENTATION • Symptoms depend on the size of the spleen, rate of growth, and underlying disease • History: Early satiety, abdominal discomfort or fullness, acute left upper quadrant (LUQ) pain (infarction, sequestration crisis), referred pain to left shoulder • Physical examination: Splenomegaly (normal spleen usually not palpable), LUQ tenderness, presence of a rub in LUQ (suggestive of splenic infarct), stigmata of cytopenias ETIOLOGY • The spleen is an important component of the hematologic and immune systems (antigen processing and antibody synthesis). The spleen is responsible for the modification (removal of particles and parasites) and clearance of senescent or poorly deformable red blood cells (RBCs). It also filters blood, removing foreign particles (microorganisms) and other particulates (e.g., complement- or antibodycoated cells) from the circulation. The spleen is a platelet reservoir, storing 30% of platelet mass. It can become the site of hematopoiesis in certain disease states. The spleen’s normal activities are augmented when enlarged. • Splenomegaly increases the proportion of blood channeled through the red pulp, causing inappropriate splenic pooling of both normal and abnormal blood cells. The size of the spleen determines the amount of cell sequestration. Up to 90% of platelets may be pooled in an enlarged spleen. Prolonged sequestration leads to increased destruction of RBCs. Platelets and white blood cells (WBCs) have about normal survival time even when sequestered and may be available if needed. • Splenomegaly exacerbates cytopenias by dilution, possibly due to plasma volume expansion.

DIAGNOSIS DIFFERENTIAL DIAGNOSIS Hypersplenism can be caused by splenomegaly of almost any cause. • Splenic congestion: Cirrhosis (portal hypertension); congestive heart failure; portal, splenic, or hepatic vein thrombosis

WORKUP History (including travel), physical examination, laboratory tests, imaging studies LABORATORY TESTS • CBC with differential: Cytopenias, neutrophilia (infection) • Peripheral smear: RBC and WBC morphology (abnormal cells may suggest infection, malignancy, bone marrow disease, rheumatologic disease), organisms (bacteria, malaria, babesiosis) • Bone marrow aspiration/biopsy: Hyperplasia of cytopenic cell lines; hematologic, infiltrative, or infectious disorders • Tests to diagnose suspected cause of splenomegaly: Liver function, hepatitis serology, HIV, rheumatoid factor, antinuclear antibody, tissue biopsy • Note: Red cell mass (51Cr assay) may be used to assess severity of anemia. RBC mass measurement will differentiate true anemia (decrease in RBCs) from dilutional anemia (plasma volume expansion) IMAGING STUDIES Choice of imaging study depends on suspected underlying pathology. • Ultrasound: Splenic size, presence of cyst or abscess • CT with contrast: Estimate volume, obtain structural information: Cyst, abscess, malignancy • MRI: Most useful for assessing vascular lesions and infections • Nuclear medicine: Liver-spleen scan: Assess anatomy and function; may suggest presence of portal hypertension • Consider additional tests as suggested by history and exam: Chest radiograph, echocardiogram, PET scan

TREATMENT ACUTE GENERAL Rx • Treat underlying disease • Splenectomy is considered if: 1.  Indicated for the management of the underlying cause 2. Persistent symptomatic disease (severe cytopenia) not responding to therapy

3. Necessary for diagnosis RISKS: • Infections (especially encapsulated organisms): Risk greatest in the first 2 yr after splenectomy. Asplenic patients have a twofold to threefold increase of sepsis and infection-related mortality. Attempts to decrease risk include: 1. Immunization with pneumococcal (PCV13 and PPSV23), meningococcal (MenACWY and MenB), and Haemophilus influenza type b (Hib) vaccines (if not previously vaccinated) at least 2 wk before splenectomy. Preferred: PCV13 vaccination followed by PPSV23 vaccination at least 8 wk later. If already immunized with PPSV23, PCV13 vaccine should be given at least 1 yr later. Revaccination with PPSV23 in 5 yr and again after age 65 yr (and 5 yr after most recent dose). Revaccination for meningococcal (MenACWY) every 5 yr. Annual inactivated or recombinant influenza vaccination. note: If unable to vaccinate 2 wk before splenectomy, vaccinate 2 wk after surgery. Ensure all age-appropriate vaccinations are up to date. 2. Prophylactic antibiotics after splenectomy in highest-risk patients. 3. Patient education regarding the importance of rapid initiation of antibiotics and seeking emergent care at the first sign of infection. • Thromboembolic complications, especially high risk of portal vein thrombosis. • Possible increased risk of atherosclerotic heart disease and cancer. • Splenectomy should not be performed if the spleen is the main site of hematopoiesis as a result of bone marrow failure (e.g., myelofibrosis). • Other options include partial splenectomy, partial splenic artery embolization, radiofrequency ablation, portosystemic shunting (for congestive splenomegaly).

H

Diseases and Disorders

ICD-10CM CODE D73.1 Hypersplenism

• Hematologic causes: Hemolytic anemia, spherocytosis, elliptocytosis, sickle cell anemia, thalassemia, extramedullary hematopoiesis, chronic transfusions, following use of granulocyte colony-stimulating factor • Infections: Viral (hepatitis, infectious mononucleosis, cytomegalovirus, HIV/AIDS), bacterial (endocarditis, sepsis, tuberculosis, salmonella, brucella), parasitic (babesiosis, malaria, leishmaniasis, schistosomiasis, toxoplasmosis), fungal • Malignancy: Acute or chronic leukemia, lymphoma, myeloproliferative diseases (polycythemia vera, essential thrombocythemia, myelofibrosis), splenic or metastatic tumors • Inflammatory diseases: Rheumatic fever, rheumatoid arthritis (Felty syndrome), systemic lupus erythematosus, sarcoid, serum sickness • Infiltrative diseases: Amyloidosis, Gaucher disease, Niemann-Pick disease, glycogen storage disease

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DISPOSITION • Cytopenias are usually correctable with splenectomy; normal cell counts return within a few weeks. • Splenectomy may alleviate portal hypertension. • Prognosis depends on the underlying disease. REFERRAL Hematology

PEARLS & CONSIDERATIONS Thrombocytopenia in hypersplenism is usually moderately severe (>50 × 109/L) and asymptomatic; severe thrombocytopenia (2 different occasions. • Nonoffice (home, workplace, 24-hr ambulatory) BP determination to establish the pattern of HTN (sustained, “white coat,” or “masked” HTN) in selected patients. • Measure heart rate, height, weight, body mass index, and waist circumference. • Some general clinical clues for when to screen for secondary HTN include: 1. Severe or resistant HTN 2. An acute rise in BP developing in a patient with previous stable BP 3.  Age less than 30 yr, non-obese, nonblack with no family history of HTN 4. Sudden onset or accelerated hypertension 5. Age of onset before puberty. If above is suspected, additional tests for secondary HTN should be done including renin, aldosterone, cortisol levels, 24-hr urine metanephrines, and serum catecholamines • Physical examination should include searching for secondary causes, and sequelae of hypertension. • Examine skin for the presence of café-au-lait spots (neurofibromatosis), uremic appearance (renal failure), and violaceous striae (Cushing syndrome). • Perform careful funduscopic examination; check for papilledema, retinal exudates, hemorrhages, arterial narrowing, arteriovenous compression. • Examine neck for carotid bruits, distended neck veins, and enlarged thyroid gland.

• Perform extensive cardiopulmonary examination: Check for a laterally displaced point of maximal intensity, an S3 or S4, and valvular murmurs. • Palpate abdomen for renal masses (pheochromocytoma, polycystic kidneys), and auscultate for bruit over the aorta and renal arteries. • Examine arterial pulses (dilated or absent femoral pulses and BP greater in upper extremities than lower extremities suggest aortic coarctation). • Look for truncal obesity (Cushing syndrome) and pedal edema (congestive heart failure [CHF]). • Table 2 provides a guide to evaluation of identifiable causes of HTN. • Table 3 summarizes clinical clues to guide the investigation in young patients with hypertension that has a potentially hereditary cause.

ETIOLOGY • Essential (primary) HTN (85%) • Drug induced or drug related (5%) 1. NSAIDs 2. Oral contraceptives 3. Corticosteroids • Renal HTN (5%) 1. Renal parenchymal disease (3%) 2. Renovascular HTN (RVH) (250 mg/day. • PTH replacement: 1.  Injectable synthetic human PTH (1-84) decreases urinary calcium excretion and maintains serum calcium in the normal range with reduced requirements for calcium and vitamin D supplementation. 2. PTH (1-84, Natpara, an 84-amino acid single-chain polypeptide identical to native parathyroid hormone) is the first FDAapproved product for use in the treatment of hypoparathyroidism as an adjunct to calcium and vitamin D. PTH (1-84) is recommended for patients who cannot be well controlled on conventional therapy alone. The cost for a 4-wk supply of Natpara exceeds $7000.

ACUTE GENERAL Rx Severe and/or symptomatic hypocalcemia requires hospitalization. Acute management of hypocalcemia includes: • Telemetry monitoring for arrhythmias associated with severe hypocalcemia

• IV infusion of calcium gluconate 10 ml of 10% solution to receive a bolus of 90 mg of elemental calcium followed by an infusion of 0.5 to 2 mg/kg/hr until calcium levels are in the low-normal range

H

PEARLS & CONSIDERATIONS COMMENTS • The mainstay of treatment for primary hypoparathyroidism is calcitriol and calcium supplementation to maintain a goal serum calcium level in the low-normal range. IV calcium should be considered if calcium 18 μg/dl, or ≥5 μg/dl Peak 11-DOC ≥7 μg/dl Peak cortisol ≤7 μg/dl Peak ACTH >75 pg/ml Peak ACTH ≥2-4-fold Peak cortisol ≥20 μg/dl or ↑ ≥7 μg/dl Peak cortisol ≥20 μg/dl

200-500 μg IV

Peak TSH ≥2.5-fold, or ↑ ≥5-6 mU/L (females) or ≥2-3 mU/L (males)

Flushing, nausea, urge to micturate

200-500 μg IV

PRL ↑ ≥2.5-fold

Flushing, nausea, urge to micturate

100 μg IV

Elevated in menopause and in men with primary testicular failure (otherwise normal) 300-900 ng/ml LH ≥2-3-fold, or ↑ by 10 IU/L FSH ≥1.5-2-fold, or ↑ ≥2 IU/L

Rare

0.1-0.15 U/kg Arginine 0.5 g/kg (maximum, 30 g) IV over 30-120 min

GH peak >5 μg/L GH peak >0.4 μg/L

Sweating, palpitation, tremor Nausea

GHRH 1-5 μg/kg

GH peak >4 μg/L

Flushing

ACTH

GH Insulin tolerance l-Arginine Plus GHRH

Flushing Rare

ACTH, Adrenocorticotropic hormone; CRH, corticotropin-releasing hormone; 11-DOC, 11-deoxycorticosterone; FSH, follicle-stimulating hormone; GH, growth hormone; GHRH, growth hormone–releasing hormone; GnRH, gonadotropin-releasing hormone; IM, intramuscular; IV, intravenous; LH, luteinizing hormone; PO, by mouth; PRL, prolactin; T3, triiodothyronine; T4, thyroxine; TRH, thyrotropin-releasing hormone; TSH, thyroid-stimulating hormone; TRH, thyrotropin-releasing hormone. From Melmed S et al: Williams textbook of endocrinology, ed 12, Philadelphia, 2011, WB Saunders, Elsevier Inc.

TABLE 3  Replacement Therapy for Adult Hypopituitarism* Deficient Hormone Treatment ACTH Hydrocortisone: 10-20 mg/day in divided doses Cortisone acetate: 15-25 mg/day in divided doses TSH l-Thyroxine: 0.05-0.2 mg/day according to T4 levels FSH/LH (in males) Testosterone enanthate: 200 mg IM q2-3 wk Testosterone skin patch: 2.5-5.0 mg/day (or up to 7.5 mg/day) Testosterone gel: 3-6 g/day For fertility: hCG three times weekly, or hCG + either FSH or menopausal gonadotropin or GnRH FSH/LH (in females) Conjugated estrogen: 0.3-0.625 mg/day Micronized estradiol: 1 mg/day Estradiol valerate: 2 mg Piperazine estrone sulfate: 1.25 mg Estradiol skin patch: 4-8 mg twice weekly All of the estrogens are administered with progesterone or progestin sequentially or in combination if uterus is present For fertility: Menopausal gonadotropin, and hCG, or GnRH Growth hormone Somatotropin (in adults): 0.2-1.0 mg/day SC Somatotropin (in children): 0.02-0.05 mg/kg per day Vasopressin Intranasal desmopressin: 10-20 μg bid Oral DDAVP: 300-600 μg/day, usually in divided doses ACTH, Adrenocorticotropic hormone; bid, twice per day; DDAVP, desmopressin acetate; FSH, follicle-stimulating hormone; GnRH, gonadotropin-releasing hormone; hCG, human chorionic gonadotropin; IM, intramuscular; LH, luteinizing hormone; SC, subcutaneous; T4, thyroxine; TSH, thyroid-stimulating hormone. From Melmed S, Polonsky KS, Larsen PR, Kronenberg HM: Williams textbook of endocrinology, ed 12, Philadelphia, 2011, WB Saunders, Elsevier Inc.

• Stress doses of corticosteroids are indicated before surgery or for any medical emergency (e.g., sepsis, acute myocardial infarction). • Antidiuretic hormone deficiency may be masked if there is ACTH deficiency with symptoms only appearing when cortisol has been replaced.

COMMENTS • Mineralocorticoid replacement is not necessary in secondary adrenal insufficiency because the renin-angiotensin-aldosterone system is unaffected by pituitary failure. • Patients with adult-acquired GH deficiency must meet at least two criteria before replacement therapy: A poor GH response to at least two standard stimuli and hypopituitarism from pituitary or hypothalamic damage. The criteria are different in children in whom GH is required for normal growth. • Prevention of acute decompensation can be accomplished by reminding patients to increase the dose of hydrocortisone in response to stress. • Medical therapy should precede surgical therapy. RELATED CONTENT Hypopituitarism (Patient Information) AUTHOR: Fred F. Ferri, MD

Hypopituitarism

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B FIG. E1  T1-weighted gadolinium-enhanced MR of a pituitary adenoma. (A) Sagittal and (B) coronal images. (Courtesy of D. Thomas. From Bowling B: Kanski’s clinical ophthalmology, ed 8, Philadelphia, 2016, Elsevier.)

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Hypospadias BASIC INFORMATION DEFINITION Hypospadias is a developmental abnormality of the penis characterized by: • Abnormal ventral opening of the urethral meatus anywhere from the ventral aspect of the glans penis to the perineum • Ventral curvature of the penis (chordee) • Dorsal foreskin hood ICD-10CM CODES Q54.1 Hypospadias, penile Q54.2 Hypospadias, penoscrotal Q54.3 Hypospadias, perineal Q54.4 Congenital chordee Q54.8 Other hypospadias Q54.9 Hypospadias, unspecified

EPIDEMIOLOGY & DEMOGRAPHICS PREVALENCE: • One of the most common congenital anomalies in males • Prevalence is highest in North America at 34.2 per 10,000 births, and lowest in Asia at 0.6 per 10,000 births PHYSICAL FINDINGS & CLINICAL PRESENTATION • Genetics: Normal karyotypes are seen with glanular hypospadias; abnormal karyotypes are noted in more severe forms of hypospadias • Cryptorchidism: 8% to 9% occurrence • Inguinal hernia: 9% to 10% occurrence • Hydrocele: 9% to 16% occurrence PENILE CURVATURE (CHORDEE): Three theories: • Abnormal development of the urethral plate • Abnormal fibrotic mesenchymal tissue at the urethral meatus • Corporal disproportion ETIOLOGY Multifactorial: • Genetic predisposition: 1. There is a 9% to 17% recurrence rate in male siblings and an 8% recurrence rate in male offspring of men who have hypospadias. 2. Only 30% of hypospadias cases have a clear genetic cause. 3. The condition has an estimated 57% to 77% heritability and is equally transmitted through maternal and paternal sides of the family. • Maternal and other influences:

1. There is increased incidence in small for gestational age infants and monochorionic twins. 2. Severe hypospadias is seen in patients with maternal hypertension, oligohydramnios, and preterm delivery, suggesting placental insufficiency may play a role. 3. Males conceived by in vitro fertilization (IVF)/ intracytoplasmic sperm injection (ICSI) may have a fivefold increased risk of hypospadias, according to some studies. • Hormonal factors: 1. Disruption in prenatal androgen exposure 2. Fetal exposure to maternal estrogenic compounds (progestin or diethylstilbestrol) 3. Possible link to disturbed testicular development as seen in testicular dysgenesis syndrome

DIAGNOSIS WORKUP Made by observation and examination (Fig. E1) LABORATORY TESTS The clinician always should consider a disorder of sex development (DSD) if there is associated cryptorchidism. The evaluation should include ultrasound; genitographic studies; and chromosomal, gonadal, biochemical, and molecular studies.

TREATMENT ACUTE GENERAL Rx CLASSIFICATION BASED ON MEATAL POSITION: • Distal (glandular, coronal, subcoronal): 60% • Middle (distal shaft, midshaft, posterior penile): 25% • Proximal (penoscrotal, scrotal, perineal): 15% SPECIAL CONSIDERATIONS: • The major reason for operating on any patient with hypospadias is to correct deformities that interfere with the function of urination and procreation. • Another reason for intervention is cosmetic concern. • The American Academy of Pediatrics recommends the best time for surgical intervention to be 6 to 12 mo. HORMONAL MANIPULATION: • Controversial. • Human chorionic gonadotropin (hCG) administration is given before repair of proximal hypospadias. • The effect of hCG administration is decreased hypospadias and chordee severity in all

patients and increased vascularity and thickness of the proximal corpus spongiosum. • Application of topical testosterone increases mean penile circumference and length without any lasting side effects. • Prepubertal exogenous testosterone does not adversely affect ultimate penile growth.

CHRONIC Rx Surgical procedures: • Orthoplasty (correcting penile curvature) • Urethroplasty • Meatoplasty • Glanuloplasty • Skin coverage There is no single universally acceptable applicable technique for hypospadias repair. Complications may occur up to 5 yr after the procedure, and therefore the patients should be monitored beyond the first yr, particularly in cases of middle or proximal hypospadias. TYPES OF REPAIR • Urethral plate tubularization: Makes a new urethra by rolling a ventral strip of skin from the penile shaft in glandular and penile shaft repairs • Urethral plate augmentation: Used for more severe hypospadias where a urethra is created using a vascular strip of inner foreskin that is transferred to the ventral skin • Urethral plate substitution (two stage repair): Used in the most extreme/severe cases 1. Stage one: Corrects the penile curvature and transfers dorsal foreskin to the ventral side of the penis 2. Stage two: Urethroplasty that occurs 6 mo after the first operation COMPLICATIONS OF REPAIR: Hematoma, meatal stenosis, fistula, urethral stricture, urethral diverticulum, wound infection, impaired healing, balanitis xerotica obliterans, penile curvature

PEARLS & CONSIDERATIONS • Apparent simple isolated hypospadias may be the only visible indication of an underlying abnormality. • The dorsal hood of redundant foreskin is used in the repair of hypospadias, so the patient with hypospadias and a dorsal hood should not be circumcised.

RELATED CONTENT Hypospadias (Patient Information) AUTHORS: Helen Toma, MD, MSPH, and Anthony Sciscione, DO

Hypospadias

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FIG. E1  Varying forms of hypospadias. A through F illustrate various degrees of hypospadias. (From Kliegman RM et al: Nelson textbook of pediatrics, ed 19, Philadelphia, 2011, WB Saunders.)

SUGGESTED READING Van der Horst HJR, de Wall LL: Hypospadias, all there is to know, Eur J Pediatrics 176:435-441, 2017.

Hypothermia BASIC INFORMATION DEFINITION Hypothermia is a rectal temperature 700 persons in the U.S. die from hypothermia annually. PHYSICAL FINDINGS & CLINICAL PRESENTATION The clinical presentation varies with the severity of hypothermia. Shivering may be absent if body temperature is 10 mU/L and with presence of goiter or thyroid autoantibodies or patient has risk factors. Congenital hypothyroidism is a pediatric disorder with an observed prevalence of one in 2000 to 4000 live births in the U.S. Screening is conducted in all newborns in all states and accomplished by measuring TSH from dried whole blood spots collected on a newborn by 1Stott

DJ et  al: Thyroid hormone therapy for older adults with subclinical hypothyroidism, N Engl J Med 376:2534-2544, 2017.

heel stick within the first 24 to 48 hours of life. Currently 14 states perform a routine second screen at approximately 2 wk of age. A twoscreen approach is preferred because retrospective analysis found that 20% of congenital hypothyroidism cases were in infants who had normal TSH on the first screen but elevated TSH concentrations on the second screen.

SUGGESTED READINGS Available at ExpertConsult.com RELATED CONTENT Hypothyroidism (Patient Information) Myxedema Coma (Related Key Topic) AUTHOR: Fred F. Ferri, MD

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FIG. E1  A and B, Typical appearance of patients with moderately severe primary hypothyroidism or myxedema. Notice the dry skin and sallow complexion; absence of scleral pigmentation differentiates the carotenemia from jaundice. Both individuals demonstrate periorbital myxedema. The patient in B illustrates the loss of the lateral aspect of the eyebrow, sometimes termed Queen Anne sign. That finding is not unusual in the age group that is commonly affected by severe hypothyroidism and should not be considered a specific sign of the condition. (From Melmed S et al: Williams textbook of endocrinology, ed 12, Philadelphia, 2011, WB Saunders.)

SUGGESTED READINGS Azim S, Nasr C: Subclinical hypothyroidism: when to treat, Cleve Clin J Med 86(2):101-110, 2019. Bekkering GE et al: Thyroid hormones treatment for subclinical hypothyroidism: a clinical practice guideline, BMJ 365:12006, 2019. Burch HB et al: Drug effects on the thyroid, N Engl J Med 381(8):749-761, 2019. Casey BM et al: Treatment of subclinical hypothyroidism or hypothyroxinemia in pregnancy, N Engl J Med 376:815-825, 2017. Gaitonde DY et al: Hypothyroidism: an update, Am Fam Phys 86(3):244-251, 2012. Jones DE et al: Identification of primary congenital hypothyroidism based on two newborn screens - Utah, 2010-16, MMWR Morb Mortal Wkly Report 67(28):782-785, 2018. Peeters RP et al: Subclinical hypothyroidism, N Engl J Med 376:2556-2565, 2017. Rodondi N et al: Subclinical hypothyroidism and the risk of coronary heart disease and mortality, JAMA 304(12):1365-1374, 2010. Rugge JB et al: Screening and treatment of thyroid dysfunction: an evidence review for the U.S. Preventive Services Task Force, Ann Intern Med 162:3545, 2015.

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ID Reaction BASIC INFORMATION DEFINITION ID reaction refers to an acute dermatitis developing at cutaneous sites distant from a primary inflammatory focus (Fig. E1) and is not explained by the inciting primary inflammation. SYNONYM Autoeczematization ICD-10CM CODES L30.2 Cutaneous autosensitization L30.8 Other specified dermatitis L30.9 Dermatitis, unspecified

EPIDEMIOLOGY & DEMOGRAPHICS • Exact prevalence in the U.S. is unknown. • Seen in all ages. • Males and females are equally affected. • No particular race or ethnicity is more vulnerable. ETIOLOGY Infection with dermatophytes, mycobacterium, histoplasma, viruses, bacteria, or parasites (e.g., lice): • Dermatitis such as contact, stasis, or eczematous. • Other causes include retained sutures, ionizing radiation, and blunt trauma. PATHOGENESIS Unknown but possible explanations include: • Abnormal immune recognition of autologous skin antigens • Stimulation of normal T cells by altered skin constituents • Lowering of the threshold for skin irritation • Dissemination of infectious antigen resulting in a secondary response • Hematogenous dissemination of cytokines from the primary site of inflammation CLINICAL FEATURES • Usually associated with exacerbation of primary dermatitis. • Characteristics of the rash in ID reaction include: 1. Sudden onset of rash appearing within 1 or 2 wk of primary inflammation 2. The rash could not be identified as a common dermatosis

FIG. E1  ID reaction. Papular eruption of the face associated with severe tinea infection of the hand. (From Kliegman RM: Nelson Textbook of Pediatrics, ed 21, Philadelphia, 2020, Elsevier.)

3. Lesions are most commonly seen in the side of the fingers. However, ID reaction could be generalized. Particularly in patients with stasis dermatitis, it appears in forearms, thighs, legs, trunk, face (Fig. E2), hands, neck, and feet in descending order of frequency 4. Extremely pruritic 5. Often symmetric in distribution 6. Most of the time it is vesicular • It resolves upon treatment of primary inflammation.

DIAGNOSIS • It is a clinical diagnosis. The diagnosis should not be made conclusively unless there is an acute inflammatory process at a distant site and the ID reaction disappears shortly after the acute inflammation is controlled. • Fungus, when suspected, could be isolated only from the primary site by using potassium hydroxide or by using fungal culture. • At times, skin biopsy is done. The biopsy findings are not pathognomonic for ID reaction. These include spongiotic epidermal vesicles associated with superficial perivascular lymphocytic infiltration of dermis, which may also contain scattered eosinophils. Whereas most of the lymphocytes in the epidermis are CD3 and CD8 T cells, those in the dermis are primarily CD4 cells. • Patch testing may be considered to exclude primary or secondary allergic contact dermatitis.

DIFFERENTIAL DIAGNOSIS • Atopic dermatitis • Contact dermatitis • Drug eruptions • Dyshidrotic eczema • Folliculitis • Scabies • Dermatophytic infection • Viral exanthema

TREATMENT • The treatment is best directed toward the inciting cause. • Medications used for symptomatic treatment of ID reaction include: 1. Local or systemic steroids 2. Local or systemic antihistamines 3. Topical or systemic antibiotics for secondary bacterial infection 4. Aluminum sulfate or calcium acetate for weeping skin lesions 5. Rarely, local or systemic macrolactams (e.g., cyclosporine)

COMPLICATION Secondary bacterial infection PROGNOSIS It almost always resolves within days when the primary dermatitis is adequately treated. PATIENT & FAMILY EDUCATION Treat primary dermatitis promptly. AUTHOR: Fred F. Ferri, MD

ID Reaction

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B FIG. E2  ID reactions in children due to allergic contact dermatitis (ACD) to nickel. A, Multiple flattopped papules, several of which have been excoriated, in addition to patches of eczema. B, Square-shaped area of ACD due to nickel in a buckle with an associated ID reaction. The latter consists of edematous crusted papules that are separate from the area of direct nickel contact. (From Bolognia JL et al: Dermatology, ed 4, Philadelphia, 2018, Elsevier.)

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Idiopathic Intracranial Hypertension BASIC INFORMATIONS DEFINITION Idiopathic intracranial hypertension (IIH) is a syndrome of increased intracranial pressure (ICP) without either underlying hydrocephalus or mass lesion and with normal cerebrospinal fluid analysis. SYNONYMS Pseudotumor cerebri IIH Benign intracranial hypertension ICD-10CM CODE G93.2 Benign intracranial hypertension

EPIDEMIOLOGY & DEMOGRAPHICS • 90% of affected persons are women of childbearing age with elevated body mass index (BMI). INCIDENCE: • General population: 1 to 2 per 100,000 (including children) • Women (obese females in reproductive age group): 20 per 100,000 • Men: 0.3 to 1.5 cases per 100,000 • Female:male ratio 9:1 • More than 90% of IIH patients are obese • Mean age at diagnosis is 30 yr RISK FACTORS: • Obesity • Medications: Vitamin A and retinoids (used in treatment of acne and leukemia), chronic oral medications used for acne (tetracycline, minocycline), glucocorticoid use or withdrawal • Systemic conditions: Chronic kidney disease, polycystic ovarian syndrome, obstructive sleep apnea PHYSICAL FINDINGS & CLINICAL PRESENTATION SYMPTOMS: • Headaches: Generalized, throbbing, slowly progressive, worse with straining maneuvers, worse in the morning • Transient visual obscuration: A brief blurring of vision or scotomata lasting 250 mm H2O with normal fluid composition. • Ophthalmologic examination: All patients with IIH need an ophthalmologic examination including visual fields at baseline and followup visits. Enlargement of the blind spot and reduction in peripheral fields are commonly seen.

LABORATORY TESTS CSF analysis shows normal protein, glucose, and cell count. IMAGING STUDIES • MRI of the brain to rule out underlying structural lesions 1. Absence of specific causes of raised ICP listed previously 2. Empty sella sign often associated with chronic raised ICP but not pathognomonic • MR or CT venography to exclude cortical venous thrombosis 1. May show transverse sinus stenosis in IIH without thrombosis. Absence of specific causes of raised ICP listed previously • CT head 1. May show slit-like ventricles

TREATMENT NONPHARMACOLOGIC THERAPY • Treatment is aimed primarily at preservation of vision • Weight loss in obese patients • Continuous positive airway pressure if obstructive sleep apnea is suspected ACUTE GENERAL Rx • Acetazolamide 250 mg to 4 g per day: Reduces CSF production by inhibition of carbonic anhydrase, occasionally causing anorexia and resultant weight loss. Dose can be increased to a maximum of 4 g a day in resistant cases with visual loss. • Furosemide 40 to 120 mg/day in divided doses: Apparent mechanism of action is by reduced sodium transport, leading to decreased total CSF volume. • Topiramate 100 to 400 mg/day: Reported to be effective in treatment of IIH. It is a weak carbonic anhydrase inhibitor with weight loss as one of its primary side effects. • Serial lumbar punctures (LP): SHOULD NOT BE CONSIDERED AS STANDARD TREATMENT OF IIH. LP should be attempted in patients with severe headaches resistant to medical therapy. Goal is to reduce spinal fluid pressure to allow immediate reduction in headache severity. This treatment should be reserved for the most resistant cases and should be used as a conduit to future surgical intervention. Serial LP should not be used as treatment for IIH with progressive visual loss. CHRONIC Rx Surgical intervention is indicated in cases of treatment failure and progressive visual loss. • Optic nerve fenestration: Preferred for patients with visual loss and easily controlled headaches. Proposed mechanism is decompression of the optic nerve. Highly effective; however, has been associated with significant number of failure rates • CSF shunting: Neurosurgical procedure; performed in patients with significant visual deterioration and difficult-to-control headaches. Provides rapid improvement in

Idiopathic Intracranial Hypertension symptoms; however, reported to have significant rates of shunt revisions because of shunt malfunction

DISPOSITION • IIH is a potentially blinding condition, with severe vision loss in 5% to 10% of patients; patients should be co-managed by neurologists and ophthalmologists (preferably by a neuro-ophthalmologist). Monthly follow-up is essential until visual fields stabilize. More frequent follow-up is needed in patients with severe papilledema or visual loss at presentation. • All patients with IIH should undergo MR or CT venography to rule out the possibility of venous sinus thrombosis. REFERRAL • Neuroophthalmology for serial evaluation of visual fields and fundus photographs

• Nutritionist for weight loss • General neurologist for the initial workup and eventual treatment of raised ICP

PEARLS & CONSIDERATIONS COMMENTS • IIH is a potentially blinding condition. • IIH is a diagnosis of exclusion. • IIH is a disease of young obese women of childbearing age (90% of affected patients). PREVENTION Maintenance of ideal body weight is one of the best preventive mechanisms for avoidance of IIH. However, it does occur in patients with normal body weight. In these cases there are no known preventable risk factors.

SUGGESTED READINGS Biousse V et  al: Update on the pathophysiology and management of idiopathic intracranial hypertension, J Neurol Neurosurg Psychiatry 83:488, 2012. NORDIC Idiopathic Intracranial Hypertension Study Group Writing Committee et al: Effect of acetazolamide on visual function in patients with idiopathic intracranial hypertension and mild visual loss: the idiopathic intracranial hypertension treatment trial, J Am Med Assoc 311(16):1641-1651, 2014.

774.e5 PATIENT & FAMILY EDUCATION The combination of weight loss and medical therapy is highly effective in treatment of IIH. Given that most patients with IIH are young and otherwise healthy, high success rates can be accomplished. RELATED CONTENT Diplopia (Section II, Differential Diagnosis) Optic Atrophy (Related Key Topic) AUTHOR: Sachin Kedar, MBBS, MD

  Idiopathic Pulmonary Fibrosis BASIC INFORMATION

SYNONYMS Cryptogenic fibrosing alveolitis IPF Pulmonary fibrosis Usual interstitial pneumonia ICD-10CM CODE J84.112 Idiopathic pulmonary fibrosis

EPIDEMIOLOGY & DEMOGRAPHICS • Incidence: 7 to 16 cases/100,000 persons worldwide. Clinically IPF affects >50,000 people in the U.S. and accounts for 20% to 30% of interstitial lung diseases. It is the most common idiopathic interstitial pneumonia • Most commonly presents in sixth and seventh decades • More common in men than women • More common in current and past smokers • Familial forms account for 3% to 25% of cases. Genetic variants: Include mutations in surfactant protein C and telomerase as well as polymorphisms of the MUC5B gene • No distinct geographic distribution; no clear racial predilection

ETIOLOGY • Unknown. Fig. 2 illustrates a proposed pathogenetic sequence in IPF. • Cigarette smoking, environmental exposures, gastroesophageal reflux, and microaspiration have been associated with IPF. • Aberrant tissue repair and fibrosis are believed to play a greater role in the pathogenesis than generalized inflammation. Immune system activation and increased vascular permeability contribute to the underlying pathology.

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • Sarcoidosis • Drug-induced interstitial lung disease

• Pulmonary manifestations of collagen vascular diseases (e.g., rheumatoid arthritis [RA], systemic sclerosis); ILD may be an initial sign of disease • Hypersensitivity pneumonitis (HP) • Occupational exposures (e.g., asbestos, silica) may cause pneumoconiosis that mimics IPF • Other idiopathic interstitial pneumonias: 1. Desquamative interstitial pneumonia (DIP) 2.  Respiratory bronchitis–interstitial lung disease (RB-ILD) 3. Acute interstitial pneumonia (AIP) 4. Nonspecific interstitial pneumonia (NSIP) 5. Cryptogenic organizing pneumonia (COP) • IPF is considered a diagnosis of exclusion

WORKUP • Almost all patients have abnormal chest radiograph at presentation, with bilateral reticular opacities most prominent in the periphery and lower lobes. Peripheral honeycombing may be seen. • High-resolution CT scan (Fig. 3) is the best diagnostic test. It shows patchy peripheral reticular abnormalities with intralobular linear opacities, irregular septal thickening, subpleural honeycombing, and minimal, if any, ground-glass opacities. • Pulmonary function testing shows restrictive pattern and reduced carbon monoxide diffusion into the lung. • Six-minute walk test may show reduced exercise tolerance and/or exertional hypoxia. • Laboratory abnormalities (nondiagnostic): Mild anemia; increases in erythrocyte sedimentation rate, lactate dehydrogenase, C-reactive protein; low titer antinuclear antibody seen in up to 30% of patients. • The need for autoimmune serologies is not well defined. Any signs or symptoms that might suggest underlying autoimmunity should be evaluated fully.

Influx of inflammatory cells Initiating stimulus/ source of alveolar epithelial injury

Injury to epithelial cells

Disruption of basement membrane and remodeling of extracellular matrix

Cytokine mediators (e.g., TGF-β1, PDGF)

Fibroblast proliferation (fibroblastic foci)

Abnormal “wound healing” with fibrosis

FIG. 2  Proposed pathogenetic sequence in idiopathic pulmonary fibrosis. Dotted lines indicate that although there is an influx of inflammatory cells, this is not thought to be a primary component of pathogenesis. PDGF, Platelet-derived growth factor; TGF-β1, transforming growth factor-β1. (From Weinberger SE: Principles of pulmonary medicine, ed 7, Philadelphia, 2019, Elsevier.)

FIG. 3  Pulmonary fibrosis, honeycombing, and a usual interstitial pneumonia (UIP) pattern in idiopathic pulmonary fibrosis (IPF). Coronal high-resolution computed tomography reconstruction shows honeycombing (arrows) with a basal and subpleural predominance. This is typical of a UIP pattern. (Webb WR, Brant WE, Major NM: Fundamentals of body CT, ed 4, Philadelphia, 2015, Saunders.)

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DEFINITION Idiopathic pulmonary fibrosis (IPF) is a specific form of chronic fibrosing interstitial pneumonia with histopathologic characteristics of usual interstitial pneumonia (UIP) occurring in the absence of an identifiable cause of lung injury. Clinically, it is characterized by progressive parenchymal scarring and loss of pulmonary function.

PHYSICAL FINDINGS & CLINICAL PRESENTATION • Most present with gradual onset (>6 mo) of exertional dyspnea and nonproductive cough. Progressive dyspnea is usually the most prominent symptom. Cough affects up to 80% of patients with IPF, is frequently disabling, and lacks effective therapy. • Fine bibasilar inspiratory crackles, “velcro inspiratory crackles” in >80% of patients, with progression upward as the disease advances. • Clubbing is found in 25% to 50% of patients. • Cyanosis and right heart failure (cor pulmonale) may occur late in the disease course. • There are no extrapulmonary manifestations beyond clubbing and complications of right heart failure. Fever and wheezing are rare and suggest alternative diagnosis. • Fig. E1 is a chest radiograph showing diffuse bilateral lower lung predominant reticular opacities in a patient with IPF.

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Idiopathic Pulmonary Fibrosis TABLE 1  Summary of Histologic Findings for Immunologic Lung Diseases Disease

Histology

Granulomatous Foreign body, inorganic dust Hypersensitivity pneumonitis Infections Tuberculosis Sarcoidosis Granulomatous Vasculitides Wegener granulomatosis Churg-Strauss syndrome Eosinophilic pneumonias Histiocytosis X Alveolitic Drug-associated injury Goodpasture syndrome

Simple granuloma Granulomas with CD4+/CD8+ T cells; interstitial edema; fibrosis in later stages Caseating granulomas Noncaseating granulomas Necrotizing granulomas involving vasculature Necrotizing granulomas involving vasculature Granulomas with eosinophilic predominance; interstitial edema Granulomas with Langerhans cells Interstitial edema with inflammatory cells Linear staining of basement membrane with anti-IgG antibodies typically seen on renal biopsy; interstitial edema with inflammatory cells

Idiopathic Interstitial Pneumonias Idiopathic pulmonary fibrosis Interstitial edema and/or fibrosis with inflammatory cells; patchy fibrotic change Desquamative interstitial pneuInterstitial edema with sparse inflammatory cells; mild diffuse fibrotic monia change Idiopathic nonspecific interstitial Thickened interstitium with inflammatory cells; some patchy fibrosis pneumonia Acute interstitial pneumonia Diffuse alveolar damage with thickened fibrotic interstitium; proliferating fibroblasts Respiratory bronchiolitis–associMacrophages infiltrating distal bronchioles ated interstitial lung disease Cryptogenic organizing pneumonia Chronically inflamed alveoli with granulation tissue in bronchioles and macrophages in alveoli Lymphocytic interstitial pneumonia Diffuse lymphocytic and plasma cell infiltration; minimal alveolar injury Idiopathic pleuroparenchymal Diffuse alveolar damage with fibrosis fibroelastosis From Sellke FW et  al: Sabiston & Spencer surgery of the chest, ed 9, 2016, Elsevier.

• There is a limited role for bronchoalveolar lavage either in diagnosis or monitoring IPF. • Gold standard for diagnosis is lung biopsy (open thoracotomy or video-assisted thoracoscopy). Hallmark features: Heterogeneous distribution of parenchymal fibrosis against background of mild inflammation (UIP). In patients with characteristic chest CTs, lung biopsies can be avoided. • When there is uncertainty, lung biopsy is critical to distinguish IPF from diseases with better prognosis and different treatment options. • Table 1 summarizes histologic findings for immunologic diseases. • A multidisciplinary approach involving the collaboration of pulmonology, radiology, and pathology to secure a diagnosis is considered standard of care.

TREATMENT • Two FDA-approved oral therapies have similar proven efficacy in slowing disease progression, but neither elevates patients’ perceived quality of life, and both are associated with substantial side effects. Combination therapy with both medications has not been investigated. Pirfenidone is an antifibrotic medication without a known mechanism of action. It is taken three times a day with food.

Its major side effects are nausea, abdominal discomfort, and photosensitivity. LFTs require periodic surveillance. • Nintedanib is a tyrosine kinase inhibitor taken twice daily. Its major side effect is diarrhea, which often resolves. LFTs also need to be followed. • Additional new therapies are being investigated and are in phase I, II and III testing. Recent trials have shown that adding sildenafil to nintedanib did not improve quality of life or lessen 24-week mortality.1 • In patients with advanced disease, treatment options include supportive care (pulmonary rehabilitation, supplemental oxygen, influenza and pneumococcal vaccination) and potential lung transplantation. • Treatment of asymptomatic gastroesophageal reflux may be reasonable given association between pulmonary fibrosis and reflux or microaspiration. • Lung transplantation is the only therapy shown to prolong survival in IPF. Guidelines for transplantation by pulmonary disease are summarized in Box 1. Box 2 summarizes absolute contraindications to lung 1Peljto

AL et  al: Association between the MUC5B promoter polymorphism and survival in patients with idiopathic pulmonary fibrosis, JAMA 309(21):22322239, 2013.

transplantation. Posttransplant 5-yr survival for IPF patients is approximately 50% to 60%. Median survival time is longer after bilateral lung transplantation than single lung transplantation but is associated with more complications during the first yr. • Acute exacerbation of IPF, defined as worsening dyspnea (50 mm Hg) • Pulmonary hypertension or cor pulmonale, or both, despite oxygen therapy • FEV1 20,000 to 30,000/mm3. The threshold for treatment depends on comorbid risk factors for bleeding and risk of trauma. Higher platelet counts may be appropriate for surgery or after trauma. Medications can be used individually, but combinations of azathioprine and danazol (or corticosteroids) may provide added benefit and allow lower doses to be used. IVIG and anti-D are generally reserved for severe thrombocytopenia unresponsive to oral agents. The decision to proceed to splenectomy depends on intensity of therapy required, tolerance to side effects, risk of surgery, and patient preference. IVIG and/or methylprednisolone may help to increase the platelet count immediately before splenectomy. Laparoscopic and open splenectomy have comparable outcomes. The decision to treat patients who have platelet counts lower than 20,000 to 30,000/mm3 after splenectomy involves an assessment of the risk of hemorrhage versus the side effects of each form of therapy. ITP, Immune thrombocytopenic purpura; IV, intravenous; pm, precision medicine; PO, by mouth; Rx, prescription. (Modified from Hoffman R et al: Hematology, basic principles and practice, ed 7, Philadelphia, 2018, Churchill Livingstone.)

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Immune Thrombocytopenic Purpura • Fostamatinib is an inhibitor of the enzyme spleen tyrosine kinase (Syk). Syk plays an important role in phagocytosis of FcγRmediated signal transduction and inflammatory propagation. It received FDA approval of chronic ITP in adults who had an insufficient response to previous treatment including corticosteroids, intravenous immunoglobulin (IVIG), splenectomy and/or a TPO-RA. The recommended initial dose is 100 mg oral twice daily. It can be increased to 150 mg twice daily if the platelet count has not responded to at least 50 × 109/mm3 at 1 mo.

PREGNANCY Rx • No treatment is required when platelet count is >30,000/mm3 or higher until 36 weeks’

ALG

gestation, or earlier in case of premature labor. • Oral corticosteroids and IVIG. • Refractory ITP may require splenectomy in the second trimester.

DISPOSITION • More than 80% of children have a complete remission within 8 wk. • In adults, the course of the disease is chronic; only 5% of adults have spontaneous remission. • The principal cause of death from ITP is intracranial hemorrhage (1% of children, 5% of adults).

SUGGESTED READINGS Available at ExpertConsult.com RELATED CONTENT Immune Thrombocytopenic Purpura (Patient Information). AUTHORS: Kittika Poonsombudlert, MD, and Patan Gultawatvichai, MD

Immune Thrombocytopenic Purpura

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SUGGESTED READINGS Cooper N, Ghanima W: Immune thrombocytopenia, N Engl J Med 381(10):945955, 2019. George JN: Management of immune thrombocytopenia—something old, something new, N Engl J Med 363:1959, 2011. Imbach P, Crowther M: Thrombopoietin-receptor agonists for primary immune thrombocytopenia, N Engl J Med 365:734-741, 2011. Kuter DJ et al: Romiplostim or standard of care in patients with immune thrombocytopenia, N Engl J Med 363:1889, 2010. Mithoowani S et al: High-dose dexamethasone compared with prednisone for previously untreated primary immune thrombocytopenia: a systematic review and meta-analysis, Lancet Haematol 3(10):e489-e496, 2016. Neunert C et al: American Society of Hematology 2019 guidelines for immune thrombocytopenia, Blood Adv 3(23):3829-3866, 2019. Rajasekhar A et al: 2013 clinical practice guide on thrombocytopenia in pregnancy, Am Soci Hematol, 2013. Thota S et al: Immune thrombocytopenia in adults: an update, Cleve Clin J Med 79:641, 2012.

A

B

FIG. E1  Immune thrombocytopenic purpura. A, Peripheral blood smear of immune thrombocytopenic purpura. A single large platelet is seen at the center. Large platelets reflect early release from the bone marrow. B, The bone marrow trephine biopsy section contains increased numbers of megakaryocytes. (From Jaffe ES et al: Hematopathology, Philadelphia, 2011, WB Saunders.)

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Impetigo BASIC INFORMATION DEFINITION Impetigo is a highly contagious superficial skin infection generally caused by Staphylococcus aureus and/or Streptococcus spp. Common presentations are bullous impetigo (generally caused by staphylococcal disease) and nonbullous impetigo (from streptococcal infection and possible staphylococcal infection); the bullous form is caused by an epidermolytic toxin produced at the site of infection. SYNONYMS Impetigo vulgaris Pyoderma Impetigo contagiosa Bullous impetigo ICD-10CM CODES L01.00 Impetigo, unspecified L01.01 Nonbullous impetigo L01.02 Bockhart impetigo L01.03 Bullous impetigo L01.09 Other impetigo

EPIDEMIOLOGY & DEMOGRAPHICS • Impetigo is the most common bacterial skin infection in children 2 to 5 yr of age. Bullous impetigo accounts for 30% of cases and nonbullous for 70% of cases. Impetigo is most common in temperate zones, mostly during the summer in hot, humid weather. Common sources for children are dirty fingers, pets, and other children in school or day care centers. Impetigo often complicates insect bites, pediculosis, scabies, eczema, and poison ivy. • Bullous impetigo is most common in infants and children. The nonbullous form is most common in children ages 2 to 5 yr with poor hygiene in warm climates. • The overall incidence of acute nephritis with impetigo varies between 2% and 5%. PHYSICAL FINDINGS & CLINICAL PRESENTATION • Nonbullous impetigo begins as a single red macule or papule that quickly becomes a vesicle. Rupture of the vesicle produces an erosion of which the contents dry to form honey-colored crusts. Multiple lesions with golden yellow crusts (Fig. E1) and weeping areas are often found on the skin around the nose, mouth, and limbs. • Bullous impetigo is manifested by the presence of vesicles that enlarge rapidly to form bullae with contents that vary from clear to cloudy. There is subsequent collapse of the center of the bullae (Fig. E2); the peripheral areas may retain fluid, and a honey-colored crust may appear in the center (Fig. E3). As the lesions enlarge and become contiguous with the others, a scaling border replaces the fluid-filled rim; there is minimal erythema surrounding the lesions.

• Regional lymphadenopathy is most common with nonbullous impetigo. • Constitutional symptoms are generally absent.

ETIOLOGY • S. aureus coagulase positive is the dominant microorganism (50% to 70% of cases). • S. pyogenes (group A β-hemolytic streptococci): M-T serotypes of this organism associated with acute nephritis are 2, 49, 55, 57, and 60. Group B streptococci are associated with newborn impetigo.

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • Atopic dermatitis • Herpes simplex infection • Ecthyma

• Folliculitis • Dermatitis herpetiformis • Insect bites • Scabies, pediculosis • Tinea corporis, cutaneous candidiasis • Pemphigus vulgaris and bullous pemphigoid • Chickenpox • Thermal burns • Contact dermatitis • Stevens-Johnson syndrome, Sweet syndrome

WORKUP Diagnosis is clinical. LABORATORY TESTS • Generally not necessary • Gram stain and culture and sensitivity to confirm the diagnosis when the clinical presentation is unclear • Sedimentation rate parallel to activity of the disease

FIG. E1  Nonbullous (crusted) impetigo. Erythematous papules with honey yellow–colored crusting. (From Paller AS, Mancini AJ: Hurwitz clinical pediatric dermatology, a textbook of skin disorders of childhood and adolescence, ed 5, 2016, Elsevier.)

FIG. E2  Bullous impetigo. Thin-walled vesicles and shallow erosions with peripheral collarettes and mild crusting on the buttock and posterior thigh. (From Paller AS, Mancini AJ: Hurwitz clinical pediatric dermatology, a textbook of skin disorders of childhood and adolescence, ed 5, 2016, Elsevier.)

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782.e3 methicillin-sensitive Staphylococcus aureus [MSSA]) or trimethoprim-sulfamethoxazole [TMP-SMX] (for methicillin-resistant Staphylococcus aureus [MRSA]). • Fingernails should be kept short, and patients should be advised not to scratch any lesions to avoid spread of infection.

DISPOSITION Most cases of impetigo resolve promptly with appropriate treatment. Both bullous and nonbullous forms of impetigo heal without scarring. REFERRAL Nephrology referral in patients with acute nephritis FIG. E3  Bullous impetigo. Multiple tender, erythematous patches with a peripheral collarette, representing remnants of the blister roof. (From Paller AS, Mancini AJ: Hurwitz clinical pediatric dermatology, a textbook of skin disorders of childhood and adolescence, ed 5, 2016, Elsevier.)

• Increased anti-DNAse B and antihyaluronidase • Urinalysis revealing hematuria with erythrocyte casts and proteinuria in patients with acute nephritis (most frequently occurring in children between ages 2 and 4 yr in the southern part of the U.S.) • If recurrent staphylococcal impetigo develops, a culture of the anterior nares should be done to rule out a carrier state

TREATMENT NONPHARMACOLOGIC THERAPY Remove crusts by soaking with wet cloth compresses (crusts block the penetration of antibacterial creams). GENERAL Rx • Treatment consists of topical or oral antibotics that are active against both S. aureus and β-hemolytic streptococci.

• Application of 2% mupirocin ointment tid for 10 days or retapamulin 1% applied bid for 5 days to the affected area or until all lesions have cleared. • Ozenoxacin is a topical nonfluorinated quinolone antibiotic recently FDA-approved for treatment of impetigo in patients 2 mo old. Cost is a limiting factor. • Oral antibiotics are used in severe cases: Commonly used agents are dicloxacillin 250 mg qid for 7 to 10 days, cephalexin 250 mg qid for 7 to 10 days, azithromycin 500 mg on day 1, 250 mg on days 2 through 5, amoxicillin/clavulanate 500 mg q8h. • Impetigo can be prevented by prompt application of mupirocin or triple-antibiotic ointment (bacitracin, Polysporin, and neomycin) to sites of skin trauma. • Patients who are carriers of S. aureus in their nares should be treated with mupirocin ointment applied to their nares bid for 5 days or a 10-day course of rifampin, 600 mg/day, combined with dicloxacillin (for

SUGGESTED READINGS Bangert S et al: Bacterial resistance and impetigo trend: a review, Pediatr Dermatol 29(3):431-434, 2012. Hartman-Adams H et al: Impetigo: diagnosis and treatment, Am Fam Physician 90(4):229-235, 2014.

PEARLS & CONSIDERATIONS COMMENTS • Patients should be instructed on use of antibacterial soaps and avoidance of sharing of towels and washcloths because impetigo is extremely contagious. • Children attending day care should be removed until 48 to 72 hr after initiation of antibiotic treatment. • Bullous impetigo may be an early manifestation of HIV infection. RELATED CONTENT Impetigo (Patient Information) AUTHOR: Fred F. Ferri, MD

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Inclusion Body Myositis BASIC INFORMATION DEFINITION Inclusion body myositis (IBM) is the most common acquired idiopathic myopathy with onset after the age of 50. The idiopathic inflammatory myopathies include polymyositis (PM), dermatomyositis (DM), autoimmune necrotizing myopathy, and inclusion body myositis. They are associated with inflammatory involvement of muscle fibers and recurrent weakness. Although IBM is classified among the inflammatory myopathies, its underlying pathophysiology has not yet been delineated, and antiinflammatory medications do not improve weakness. SYNONYM IBM ICD-10CM CODE G72.41 Inclusion body myositis [IBM]

EPIDEMIOLOGY & DEMOGRAPHICS INCIDENCE: 0.22 to 0.79 cases/100,000 persons; uncommon in Asians and African Americans PREVALENCE: 0.5 to 7.1 cases/100,000 persons PREDOMINANT SEX: Male:female ratio: 1.3:1 PREDOMINANT AGE: 87% older than 50 yr; mean age of 60 yr PEAK INCIDENCE: Seventh decade RISK FACTORS: None known GENETICS: Less than 10% of cases familial PHYSICAL FINDINGS & CLINICAL PRESENTATION • Insidious onset of slowly progressive proximal leg and distal arm weakness. • Time to diagnosis from symptom onset often lags by yrs to a decade. Most patients report a history of preexisting weakness averaging 5 to 7 yr. • Functional loss of strength in the legs most often precedes arm weakness. • The cardinal clinical features include early weakness and atrophy of quadriceps muscles (difficulty climbing stairs, rising from chairs, and getting out of cars) along with wrist and finger flexor muscles (difficulty grasping, opening jars, and turning doorknobs). Ankle dorsiflexion weakness may also be prominent leading to foot drop and tripping. • When examining strength, side-to-side asymmetries are seen in one or more muscle groups in the majority of patients. This stands in contrast to the symmetrical, proximal involvement of polymyositis and most muscular dystrophies. • Dysphagia and/or mild facial weakness are present in about one third to one half of cases. Dysphagia may be the presenting symptom. • Although sensory symptoms are usually lacking, one third have evidence of peripheral neuropathy on physical examination and/or electrodiagnostic testing.

• 10% to 15% of patients have concomitant autoimmune disorders such as systemic lupus erythematosus, Sjögren syndrome, scleroderma, sarcoidosis, or thrombocytopenia. However, unlike polymyositis and dermatomyositis, IBM does not portend an increased risk of heart disease, lung disease, or cancer.

ETIOLOGY The pathogenesis of IBM is not known. Inflammatory, degenerative, viral, and prion etiologies have been postulated, but none substantiated.

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • Polymyositis (Table E1) • Dermatomyositis • Amyotrophic lateral sclerosis • Late-onset muscular dystrophies • Acid maltase deficiency WORKUP • Thorough neurologic examination with emphasis on the motor exam. • Nerve conduction studies should be performed to exclude other causes and EMG to document a myopathy. • The diagnosis of definite IBM requires the following features on muscle biopsy (Fig. E1): (1) Inflammation, (2) inflammatory cells invading healthy muscle fibers, (3) vacuoles, and (4) amyloid deposits by Congo red staining, TDP-43 sarcoplasmic staining, or tubulofilaments on electron microscopy. LABORATORY TESTS • Creatine kinase level (mildly elevated early in disease but less than 10× normal levels; creatine kinase levels may normalize as the disease progresses). • Complete blood count and coagulation studies should be drawn in anticipation of the muscle biopsy. IMAGING STUDIES MRI may reveal atrophy and signal abnormalities in volar forearm muscle groups and quadriceps atrophy with relative preservation of the rectus femoris muscle.

TREATMENT NONPHARMACOLOGIC THERAPY • Physical therapy and occupational therapy with the use of assistive mobility devices such as canes, walkers, and wheelchairs are the mainstay of therapy. • Occasionally knee orthoses or anklefoot orthoses may improve and prolong ambulation. ACUTE GENERAL Rx None

CHRONIC Rx • Experts have not found clinically significant improvement in functional strength with any pharmacologic therapy. Clinical trials of corticosteroids, methotrexate, intravenous immunoglobulin, anti-T lymphocyte globulin, etanercept, interferon β-1a, and oxandrolone have all failed to demonstrate functional improvements in limb strength. • A short, small trial of a home exercise program demonstrated mild improvements in strength. • IBM is generally refractory to therapy. COMPLEMENTARY & ALTERNATIVE MEDICINE Some patients choose to self-treat with creatine supplementation, coenzyme Q10, or lithium. There is no evidence supporting these treatments. REFERRAL • Patients with suspected IBM should be referred to a neurologist with subspecialty expertise in neuromuscular medicine. • Physical therapy and occupational therapy consultations help the patient optimize ambulation and fine motor tasks, respectively. • Speech therapy consultations can assist with symptomatic dysphagia. PROGNOSIS Life expectancy is not significantly altered in this late-onset, slowly progressive disorder. Some patients require wheelchair use 10 to 20 yr after disease onset.

PEARLS & CONSIDERATIONS COMMENTS • In contrast to PM and DM, muscle weakness in IBM generally affects both distal and proximal muscles. Although typically symmetric, muscle distribution may be asymmetric. • A key to diagnosis rests in finding weakness of wrist and/or finger flexors (especially the deep finger flexors at the DIP joints) on examination. PREVENTION None known PATIENT & FAMILY EDUCATION Patient information and support groups can be found at: www.ninds.nih.gov/Disorders/AllDisorders/Inclusion-Body-Myositis-InformationPage and www.myositis.org. RELATED CONTENT Inflammatory Myopathies (Related Key Topic) AUTHORS: Emma H. Weiss, MD, Matthew P. Wicklund, MD, and Joseph S. Kass, MD, JD, FAAN

These proofs may contain color figures. Those figures may print black and white in the final printed book if a color print product has not been planned. The color figures will appear in color in all electronic versions of this book.

 Inclusion Body Myositis

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SUGGESTED READING Greenberg SA: Inclusion body myositis, Curr Opin Rheumatol 23:574, 2011.

TABLE E1  Clinical and Laboratory Features of Idiopathic Inflammatory Myopathy Subgroups Clinical Features Age Disease onset Muscle weakness Symmetry Systemic features Skin changes Calcinosis Associated connective tissue disease Associated malignancy Laboratory features Serum enzymesi Abnormal EMGj Abnormal muscle biopsy

Dermatomyositis

Polymyositis

Inclusion Body Myositis

Children and adults Subacute Proximal Symmetric Yesc Yese Yesf Yesg Yes

Adultsa

Adults >50 yr Chronic Selective patternb Asymmetric Yesd No No Yesh Yes

Normal to high Yes Perifascicular atrophy, capillary depletion, patchy MHC class I expression and microinfarcts

Normal to high Yes CD8+ T cell invasion of nonnecrotic fibers and MHC class I expression on fibers

Subacute Proximal Symmetric Yesc No Rarely Yesg Yes

Normal to high Yes CD8+ T cell invasion, MHC expression, vacuolated fibers, and tubulofilamentous inclusions in fibers

CD8+ T cell, cytotoxic T lymphocyte cell; EMG, electromyogram; MHC, major histocompatibility complex. aRarely in children. bEarly involvement of finger flexor, wrist flexor or wrist extensor weakness, and involvement of quadriceps femoris. cSome patients have dysphagia, synovitis, and interstitial lung disease. dSome patients have dysphagia. eGottron sign and heliotrope rash. fEspecially in children. gOverlap with scleroderma, systemic lupus erythematosus, rheumatoid arthritis, Sjögren syndrome, and mixed connective tissue disease. hAssociated with Sjögren syndrome but less frequently associated with other connective tissue diseases. iSerum creatine kinase, aspartate transaminase, lactate dehydrogenase, and aldolase vary from normal to very high levels. jMyopathic motor unit potentials with spontaneous discharges in dermatomyositis, with and without spontaneous discharges in polymyositis, and mixed pattern of short- and long-duration motor unit potentials in inclusion body myositis. From Firestein GS et al: Kelley’s textbook of rheumatology, ed 9, Philadelphia, 2013, WB Saunders.

A

B

FIG. E1  Trichrome, hematoxylin, and eosin staining of inclusion body myositis biopsy. Note the red-rimmed inclusions (A) and marked variation in muscle fiber size (A and B). (Courtesy Dr. Paul Plotz.)

These proofs may contain color figures. Those figures may print black and white in the final printed book if a color print product has not been planned. The color figures will appear in color in all electronic versions of this book.

ALG BASIC INFORMATION DEFINITION Fecal incontinence is defined as the involuntary loss of gas or liquid stool (minor incontinence) or the involuntary loss of solid stool (major incontinence).

ICD-10CM CODES R15.9 Full incontinence of feces F98.1 Encopresis not due to a substance or known physiological condition

EPIDEMIOLOGY & DEMOGRAPHICS INCIDENCE: Affects 0.5% to 1.5% of the population younger than age 65, but >10% older than 65. More common in institutionalized patients. PREVALENCE: Varies widely depending on definition used and population studied; often underreported. In community-based studies, ranges from 1% to 24%. Increases with age and BMI in women. PREDOMINANT SEX AND AGE: Slightly more common in females than males and those of advanced age (older than 65 yr).

RISK FACTORS: • Cognitive or behavioral dysfunction • Structural anorectal abnormalities (e.g., rectal prolapse) • Neurologic disorders, comorbidities (e.g., diabetes mellitus), inflammatory bowel disease (IBD) • Poor mobility in female gender, advanced age • Anal sphincter trauma (surgery, obstetrical injury) • Fecal impaction from constipation or diarrhea

PHYSICAL FINDINGS & CLINICAL PRESENTATION • Inspect perianal area to evaluate for the presence of fecal material, prolapsing hemorrhoids, chemical dermatitis, scars, fistula or rectal prolapse. • Assess for anocutaneous reflex. This may be elicited by stroking skin in each perianal quadrant (normal response is a brisk anal wink). Absent reflex is suggestive of nerve damage. • Digital rectal examination to assess for impaction, mass, and resting to squeezing anal tone by asking the patient to bear down. Ask patient to bear down to assess for rectal prolapse or excessive perianal descent. ETIOLOGY • Usually multifactorial. Table 1 summarizes the mechanisms, causes, and pathophysiology of fecal incontinence. Common types of anorectal dysfunction causing rectal outlet delay in the elderly are summarized in Table 2

• Overflow due to fecal impaction • Anal sphincter weakness: 1. Trauma (e.g., anorectal surgery, childbirth). 2. Nontraumatic (e.g., neurologic, spinal cord lesions, diabetes, scleroderma). • Anorectal inflammation: 1. Radiation, IBD • CNS disorders (e.g., dementia, multiple sclerosis, stroke) • Anatomic disturbance of pelvic floor: 1. Fistula, prolapse • Idiopathic

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • Fecal encopresis • Irritable bowel syndrome or IBD WORKUP • Requires detailed history taking that includes the onset and precipitating events, duration and severity, stool consistency and urgency. Important to evaluate for history of urinary incontinence, anorectal surgery or radiation, neurologic disorders, or prior vaginal deliveries and complete a thorough physical exam. An algorithm for the evaluation and management of patients with fecal incontinence is illustrated in Fig. 1. • Diagnostic workup may include endoscopy, anorectal manometry, endorectal ultrasound (simple and economical), MRI, defecography,

TABLE 1  Mechanisms, Causes, and Pathophysiology of Fecal Incontinence Mechanism

Causes

Abnormal Anorectal or Pelvic Floor Structures Anal sphincter muscles Hemorrhoidectomy, neuropathy, obstetric injury Puborectalis muscle Aging, excessive perineal descent, trauma Pudendal nerve Excessive straining, obstetric or surgical injury, perineal descent Nervous system, spinal cord, autonomic Avulsion injury, spine surgery, diabetes mellitus, nervous system head injury, multiple sclerosis, spinal cord injury, stroke Rectum Aging, IBD, IBS, prolapse, radiation Abnormal Anorectal or Pelvic Floor Function Impaired anorectal sensation Autonomic nervous system disorders, central nervous system disorders, obstetric injury Fecal impaction Dyssynergic defecation Altered Stool Characteristics Increased volume and loose consistency Drugs, bile salt malabsorption, infection, IBD, IBS, laxatives, metabolic disorders Hard stools, retention Drugs, dyssynergia Miscellaneous Physical mobility, cognitive function Aging, dementia, disability Psychosis Willful soiling Drugs* Anticholinergics Antidepressants Caffeine Laxatives Muscle relaxants Food intolerance Fructose, lactose, or sorbitol malabsorption

Pathophysiology Sphincter weakness, loss of sampling reflex Obtuse anorectal angle, sphincter weakness Sphincter weakness, sensory loss, impaired reflexes Loss of sensation, impaired reflexes, secondary myopathy, loss of accommodation Loss of accommodation, loss of sensation, hypersensitivity Loss of stool awareness, rectoanal agnosia Fecal retention with overflow, impaired sensation Diarrhea and urgency, rapid stool transport, impaired accommodation Fecal retention with overflow Multifactorial changes Multifactorial changes Constipation Altered sensation, constipation Relaxation of sphincter tone Diarrhea Relaxation of sphincter tone Diarrhea, flatus

*Pathophysiology is noted for each class of drugs. From Feldman M, Friedman LS, Brandt LJ: Sleisenger and Fordtran’s gastrointestinal and liver disease, ed 10, Philadelphia, 2016, Elsevier.

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SYNONYMS Anal or bowel incontinence Accidental bowel leakage Fecal incontinence

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TABLE 2  Types of Anorectal Dysfunction Causing Rectal Outlet Delay in Older People Pathophysiology

Clinical Picture

Rectal dysmotility

Reduced rectal motility and contractions Increased rectal compliance Variable degree of rectal dilation Impaired rectal sensation with blunting of urge to pass stool Over time, increasing rectal distention required to reflexively trigger the defecation mechanism

Pelvic floor dyssynergia

Paradoxical contraction or failure to relax the pelvic floor and external anal sphincter muscles during defecation Manometric studies show paradoxical increases in anal canal pressure on straining Increased rectal tone and reduced compliance Lower pain threshold on distending the rectum during anorectal function tests

Irritable bowel syndrome

Rectal hard or soft stool retention on digital examination of which patient may be unaware Chronic rectal distention leads to relaxation of the internal sphincter and fecal soiling One postulated cause is diminished parasympathetic outflow as a result of impaired sacral cord function (e.g., from ischemia or spinal stenosis); may also develop through persistent disregard or suppression of the urge to defecate as a result of dementia, depression, immobility, or painful anorectal conditions Severe and long-standing symptoms of rectal outlet delay Parkinson disease More common in younger women Usually constipation-predominant in older people Rome criteria symptoms: Abdominal distention or pain relieved by defecation, passage of mucus, and feeling of incomplete emptying

From Fillit HM: Brocklehurst’s textbook of geriatric medicine and gerontology, ed 8, 2017, Elsevier.

History, physical examination (including digital rectal examination)

Diarrhea + incontinence

Obstetric, surgical, neurologic injury

Local anorectal problem

Appropriate treatment (see Section I: "Hemorrhoids, Perirectal Abscess")

Flexible sigmoidoscopy, colonoscopy, and/or barium enema + routine blood tests

Suspected rectal prolapse Clinically confirmed

Not confirmed

All test results negative Trial of loperamide, diphenoxylate and atropine, or other antidiarrheal agent

Improved

Not improved

Weak sphincter or sphincter defect + No or mild neuropathy Neuromuscular training

Anorectal manometry + Anal endosonography ± Balloon expulsion test ± Neurophysiology tests

Surgery

Neuromuscular training or colostomy

Defecography ± MRI

Normal ? Factitious incontinence

(EMG/PNTML/MEP testing)

Weak sphincter or sphincter defect + neuropathy

Positive

Impaired sensation

Dyssynergic defecation ± impaired evacuation

Neuromuscular training

Neuromuscular training

If ineffective Sphincteroplasty or sphincter repair Sacral nerve stimulation Artificial bowel sphincter Colostomy

Decreased rectal reservoir Rectal augmentation surgery

FIG. 1  Algorithm for the evaluation and management of patients with fecal incontinence. EMG, Electromyography; MEP, motor-evoked potential; PNTML, pudendal nerve terminal motor latency. (From Feldman M, Friedman LS, Brandt LJ: Sleisenger and Fordtran’s gastrointestinal and liver disease, ed 10, Philadelphia, 2016, Elsevier.)

ALG pudendal nerve terminal latency, balloon expulsion test, and anal electromyography (EMG), depending on signs and symptoms. Diagnostic tests for fecal incontinence are summarized in Table 3.

TREATMENT

• Medications focus on decreasing stool frequency and improving consistency. 1. Fiber supplements (e.g., methylcellulose) 2. Antidiarrheals: Loperamide, diphenoxylate/atropine sulfate, cholestyramine 3. Topical phenylephrine, oral valproate sodium to increase smooth muscle tone 4. Injectable anal bulking agent: Dextranomer -hyaluronic acid gel is FDA approved for the treatment of fecal incontinence in adults who fail conservative therapy. Given as four 1-ml injections into the deep submucosal layer of the anal canal.

If inadequate response after at least 4 wk, a second course can be attempted.

NONPHARMACOLOGIC THERAPY • Supportive therapy: 1. Education, behavioral training, pelvic floor exercises 2.  Dietary modifications (e.g., increased fiber/fluid intake, less caffeine), food diary 3. Incontinence pads, barrier cream (e.g., zinc oxide) • Biofeedback therapy • Electrical stimulation:

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• Therapy is focused on patient education (Table E4), supportive care, medications, biofeedback, and surgery. Table 5 summarizes bowel preparation in the elderly prior to colonoscopy.

Incontinence, Bowel, Elderly Patient

TABLE 3  Diagnostic Tests for Fecal Incontinence Clinical Use Advantages

Disadvantages

Quality of Evidence Comments

Anorectal manometry

Quantifies EAS and IAS pressures; identifies rectal hyposensitivity, rectal hypersensitivity, impaired rectal compliance, dyssynergic defecation

Lack of standardization

Good

Useful for detecting anal sphincter weakness, altered rectal sensation and accommodation, and dyssynergia

Needle EMG

Quantifies spike potentials and re-inner- Invasive, painful; not widely vation pattern indicating neuropathy or available myopathy

Fair

Useful but used largely in research laboratories

Surface EMG

Displays EMG activity; can provide infor- Inaccurate, frequent artifacts mation on normal or weak muscle tone

Fair

Used largely for neuromuscular training

Pudendal nerve terminal motor latency (PNTML)

Measures latency of the terminal portion of the pudendal nerve, simple to perform

Minimally invasive, low sensitivity, interobserver differences

Fair

Conflicting data; correlation with other tests and surgical outcome unclear

Translumbar and transsacral motor-evoked potentials

Quantifies the nerve conduction time of the entire spinoanal and spinorectal pathways; minimally invasive

Lack of standardization, training, controlled studies, and availability

Fair

Promising noninvasive test; more objective and higher yield than PNTML

Colonic transit study with radiopaque markers

Evaluates the presence of fecal retention; inexpensive and widely available

Inconsistent methodology, validity has been questioned

Good

Useful for identifying patients with fecal seepage and older persons with impaction

Balloon expulsion test (BET)

Simple, inexpensive, bedside assessment of ability to expel a simulated stool; identifies dyssynergic defecation

Lack of standardization

Good

Normal BET does not exclude dyssynergia; should be interpreted in the context of other anorectal test results

Test Physiologic

Imaging Anorectal US

Visualizes IAS and EAS defects, thickness, Interobserver bias; scars difficult to and atrophy and puborectalis muscles identify

Good

Most widely available

Defecography

Detects prolapse, intussusception, obtuse anorectal angle, and pelvic floor weakness, as well as rectoceles and megarectum

Radiation exposure, embarrassment, availability, interobserver bias, inconsistent methodology

Fair

Useful and complementary with other tests

MRI

Simultaneously evaluates global pelvic floor anatomy and dynamic motion; reveals sphincter morphology and pathology outside the anorectum

Expensive, lack of standardization and availability

Fair

Used as an adjunct to other tests

Plain abdominal film

Identifies excessive amount of stool in the colon; simple, inexpensive, widely available

Lack of standardization of interpretation, lack of controlled studies

Poor

Not recommended for routine evaluation but useful in older adults and children with incontinence and fecal impaction

Barium enema

Identifies megacolon, megarectum, steno- Lack of standardization, embarrasssis, diverticulosis, extrinsic compresment, radiation exposure, lack of sion, and intraluminal masses controlled studies

Poor

Not recommended as part of routine evaluation

Directly visualizes the colon to exclude mucosal lesions (e.g., solitary rectal ulcer syndrome, inflammation, malignancy)

Poor

Indicated in patients with unexplained diarrhea and seepage and patients >age 50

Endoscopy Flexible sigmoidoscopy and colonoscopy

Invasive, risks related to procedure (perforation, bleeding) and sedation

EAS, External anal sphincter; EMG, electromyography; IAS, internal anal sphincter. Feldman M, Friedman LS, Brandt LJ: Sleisenger and Fordtran’s gastrointestinal and liver disease, ed 10, Philadelphia, 2016, Elsevier.

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TABLE 5  Bowel Preparation in Older People • Older age, constipation, reported laxative use, tricyclic antidepressants, stroke, diabetes, and dementia are associated with inadequate preparation and taking longer to perform full colonoscopy. • Even when patients take 75% to 100% of their prescribed treatments, bowel preparation is satisfactory only 50% of the time. Guidance • Give regular laxatives (e.g., Movicol 2 sachets daily) and enemas or suppositories for at least 1 wk before the procedure, with a longer run-up period in patients known to have constipation and those with comorbidities such as diabetes. • Individualize the cathartic regimen (e.g., 1 to 2 L of GoLYTELY daily over 2 to 3 days in those unable to drink 4 L, or use of alternative preparations such as sodium picosulfate). • Identify potential nonadherence. (“Can the patient drink 4 L of GoLYTELY in 24 hours?”) • Preempt unpleasant side effects. (“Will the patient be able to reach the toilet in time to avoid fecal leakage?”) • Use oral phospho soda with caution as administration in older people increases serum phosphate, even in patients with normal creatinine clearance. • Consider preprocedure plain abdominal x-ray for evaluation of persistent fecal loading. • Where possible, give a clear fluid diet before administration of bowel preparation. From Fillit HM: Brocklehurst’s textbook of geriatric medicine and gerontology, ed 8, 2017, Elsevier.



1. Anal electrodes 2. Sacral nerve stimulation 3. Posterior tibial nerve stimulation • Surgery: 1. Anal sphincteroplasty 2.  Implanted devices (e.g., artificial anal sphincter). 3. Colostomy (if intractable symptoms and/ or failed all other therapies) 4. Miscellaneous: Radiofrequency ablation, anal sling

REFERRAL Colorectal surgery

PEARLS & CONSIDERATIONS

• Routine episiotomy is the most easily preventable risk factor for fecal incontinence in females.

COMMENTS The shame, embarrassment, and stigma associated with fecal and urinary incontinence pose significant barriers to seeking professional treatment, resulting in many people suffering from these conditions without help. Therefore, during routine office visits, asking all patients older than 70 about incontinence may be helpful.

PATIENT & FAMILY EDUCATION https://www.niddk.nih.gov/health-information/digestive-diseases/bowel-control-problemsfecal-incontinence

PREVENTION • Reduce constipation and avoid straining during bowel movements.

AUTHOR: Fred F. Ferri, MD

SUGGESTED READINGS Available at ExpertConsult.com

Incontinence, Bowel, Elderly Patient TABLE E4  Patient Education Toilet Habits and Positioning • Do not delay having a bowel movement when you feel the urge. • Put aside a particular time each day (we would advise after breakfast) when you can sit on the toilet without being in a hurry. • A relaxed attitude to bowel evacuation will help, especially if you have problems with straining or a feeling of anal blockage. • If straining is a problem, place a footstool under your feet while sitting on the toilet because this increases the ability of your abdominal muscles to help evacuate stool.

Abdominal Massage • Lie on the bed with pillows under your head and shoulders. • Bend your knees, and place a pillow underneath them for support. • Cover your abdomen with a light sheet. • Massage your abdomen with firm but gentle circular movements, starting at the right side and working across to the left side. • Continue the massage for about 10 min. • This massage should be a pleasant experience; if you feel any discomfort, stop.

Diet • To help prevent constipation, you should eat more of the food from list A and less of the food from list B. Foods from list A tend to make the stool softer and easier to pass because they are high in fiber. Foods from list B tend to make the stool harder because they bind together the contents of the bowel. 1. List A: Fresh fruit, prunes and other dried fruit, whole meal bread, bran cereals, porridge, salad, cooked vegetables (with skin where possible), beans, lentils 2. List B: Milk, hard cheese, yogurt, white bread or crackers, refined cereals, cakes, pancakes, noodles, white rice, chocolate, creamed soups • You should increase your fiber intake gradually because sudden change in fiber content may cause temporary bloating and irregularity. It is important to eat food that contains fiber throughout the day and not just at one meal such as breakfast. • Increase the amount of fluid you drink gradually, up to 10 glasses a day. Try to drink more water, fruit juices, and carbonated drinks.

Sphincter Strengthening Learning to Do Your Exercises • Sit in a comfortable position with your knees slightly apart. Now imagine that you are trying to stop yourself from passing wind from the rectum. To do this, you must squeeze the muscle around the back passage. Try squeezing and lifting that muscle as tightly as you can. You should be able to feel the muscle move. Your buttocks, abdomen, and legs should not move at all. You should be aware of the skin around the back passage tightening and being pulled up and away from your chair. Really try to feel this. You now are exercising your anal sphincter muscles. (You do not need to hold your breath when you tighten the muscles.)

Practicing Your Exercises • Tighten and pull up the anal sphincter muscles as much as you can. Hold tightened for at least 5 seconds, then relax for at least 10 seconds. • Repeat the exercise at least 5 times. This will improve the strength of your muscles. • Next, pull the muscles to about half of their maximum squeeze and see how long you can hold this. Then relax for at least 10 seconds. • Repeat at least 5 times. This will improve the endurance, or staying power, of your muscles. • Pull up the muscles as quickly and tightly as you can, relax, then pull up again. See how many times you can do this before you get tired. Try for at least 5 quick pullups. Try this quick exercise at least 10 times each day. • Do all these exercises as hard as you can several times a day. As the muscles get stronger, you will find that you can do more pull-ups each time without getting tired. • It takes time for exercises to make muscle stronger. You may need to exercise regularly for several mo before the muscles reach their full strength.

Instructions for Using Suppositories • These may be inserted into your rectum by your nurse or caregiver, or yourself if you are physically able. • If necessary, first go to the toilet and empty your bowels if you can. • Wash your hands. • Remove any foil or wrapping from the suppository. • Either squat or lie on your side with your lower leg straight and your upper leg bent toward your waist. • Gently but firmly insert the suppository, narrow end first, into the rectum using a finger. Push far enough (about 1 inch) so that it does not come out again. • You may find your body wanting to push out the suppository. Close your legs and keep still for a few minutes. • Try not to empty your bowels for at least 10 to 20 min. From Fillit HM: Brocklehurst’s textbook of geriatric medicine and gerontology, ed 8, 2017, Elsevier.

SUGGESTED READINGS Bharucha AE et  al: Epidemiology, pathophysiology, and classification of fecal incontinence: state of the science summary for the National Institute of Diabetes and Digestive Kidney Diseases (NIDDK) workshop, Am J Gastroenterol 110:127-136, 2015. Van Koughnett JA, Wexner SD: Current management of fecal incontinence: choosing amongst treatment options to optimize outcomes, World J Gastroenterol 19(48):9216-9230, 2013. Wald A: Update on the management of fecal incontinence for the gastroenterologist, Gastroenterol Hepatol 12(3):155-164, 2016. Whitehead WE et al: Treatment of fecal incontinence: state of the science summary for the National Institute of Diabetes and Digestive and Kidney Diseases workshop, Am J Gastroenterol 110:138-146, 2015.

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Incontinence, Urinary BASIC INFORMATION DEFINITION Urinary incontinence is the involuntary loss of urine. SYNONYMS Urinary incontinence UI

EPIDEMIOLOGY & DEMOGRAPHICS INCIDENCE/PREVALENCE: In the general population between the ages of 15 and 64 yr, 1.5% to 5% of men and 25% to 57% of women have urinary incontinence. In the nursing home population, 75% of the population has some degree of incontinence. Nearly 20% of children through the mid-teenage yrs have episodes of urinary incontinence. CLINICAL, PSYCHOLOGICAL, & SOCIAL IMPACT Fewer than 50% of women living with incontinence in the U.S. consult health care professionals for care, resulting in significant physical and psychological limitations. Many women choose to turn to home remedies, commercially available absorbent materials, and supportive aids. As the incontinence worsens, many women become depressed, limit social interaction, refrain from sexual intimacy, and become homebound. It is estimated that $19.5 billion in direct costs is spent annually on incontinence in the U.S. Urinary incontinence contributes to approximately 6% of nursing home admissions in the older population, leading to a cost of $3 billion per yr. With aging populations around the world, this cost is dramatically increasing every yr. The continence mechanisms are complex and include multiple levels of control—central and peripheral nervous systems, detrusor muscle, urethra, and pelvic floor muscle. Normal function depends on multiple levels of control and dysfunction at any of these levels can lead to incontinence. MAJOR TYPES OF INCONTINENCE (FIG. 1) • Stress urinary incontinence (SUI) (Table E1) is the complaint of involuntary loss of urine with effort or physical exertion (sporting activities), or on sneezing or coughing (any activity that increases intraabdominal pressure). SUI may be demonstrated in the office with a simple cough stress test during examination. The cotton swab test can determine the degree of urethral mobility, which may be helpful in determining which type of

SUI

Mixed UI

by improving the patient’s functional status, treating comorbidities, changing medications, and reducing environmental barriers. • Extraurethral urinary incontinence is leakage that bypasses the urethral meatus (i.e., vesicovaginal fistula or ectopic ureter).

I

DIAGNOSIS HISTORY • Since many women are hesitant to bring up symptoms of incontinence, these symptoms should be elicited through simple screening. • History of present illness, psychosocial factors, congenital disorders, access issues for the physically challenged, neurologic disorders, and medication use are coexistent disorders that may affect the urinary tract. • Urinary incontinence may be characterized by frequency of incontinence episodes, severity, and extent of bother. • Voiding diary to assess total voided volume, frequency of micturition, mean volume voided, largest single volume, diurnal distribution, nature and severity of incontinence. • Assessments of the severity of symptoms and goals for treatment are important parts of the history. WORKUP • General physical examination: 1. Confounding conditions including mobility issues. Comorbid conditions that can cause or contribute to urinary incontinence in elderly patients are summarized in Table 2. Table 3 describes medications that can cause or contribute to urinary incontinence 2.  Neuromuscular deficits (gait of the patient) • Pelvic exam: 1. Concurrent pelvic organ prolapse 2. Vaginal discharge 3. Estrogen status 4. Pelvic floor strength assessment

“OAB wet”

“OAB dry”

FIG. 1  Incontinence may be stress urinary incontinence (SUI), mixed urinary incontinence (UI), or urgency urinary incontinence (“overactive bladder [OAB] wet”), especially in women. SUI can coexist with “OAB dry,” giving rise to mixed symptoms of stress incontinence and urgency. (From Wein AJ et al: Campbell-Walsh urology, ed 11, Philadelphia, 2016, Elsevier.)

Diseases and Disorders

ICD-10CM CODES R32 Unspecified urinary incontinence N39.3 Stress incontinence (female) (male) N39.41 Urgency urinary incontinence N39.46 Mixed incontinence N39.49 Disorder of urinary system, unspecified R39.81 Functional urinary incontinence

surgical procedure to perform, but this test is not useful for diagnosing SUI. • Intrinsic sphincter deficiency (ISD) is the most severe form of SUI and indicates a urethra that cannot remain closed even at rest. Urodynamically, this is diagnosed with a maximal urethral closure pressure 20 yr • More common in females • Least common inflammatory myopathy • Exact incidence unknown PHYSICAL FINDINGS & CLINICAL PRESENTATION DM and PM: • Most patients have a subacute onset over wks to mos. • Pattern is typically symmetric proximal muscle weakness involving the proximal limbs (shoulder and pelvic girdles). • Weakness of neck flexion and extension is common.

• Difficulty getting up from a chair, climbing stairs, reaching for objects above head, or combing hair. • Distal muscle involvement and ocular involvement are uncommon. • Sensation is preserved. • Reflexes may be preserved or diminished. • Dysphagia and dysphonia result from involvement of striated muscle of the pharynx and proximal esophagus. • Esophageal dysmotility is common in DM. • Respiratory failure from associated pulmonary fibrosis. • Cardiac conduction abnormalities can be seen with DM. • Systemic autoimmune disease occurs frequently in PM, and rarely in DM. • Skin findings in DM: 1. Heliotrope rash on the upper eyelids (Fig. E1) 2. Erythematous rash on the face 3. May also involve the back and shoulders (shawl sign), neck and chest (V-shape), knees (Fig. E2), and elbows 4. Photosensitivity 5.  Gottron papules (violaceous papules overlying dorsal interphalangeal or metacarpophalangeal areas, elbow or knee joints [Fig. E3]) 6. Nail cracking, thickening, and irregularity (Fig. E4) with periungual telangiectasia 7. Mechanic’s hand: Fissured, hyperpigmented, scaly, and hyperkeratotic; also associated with increased risk of interstitial lung disease

ETIOLOGY DM: Complex, immune-mediated microangiopathy. Adaptive immune response via humorally mediated complement attack PM: Unknown: • Cell-mediated immune major histocompatibility-I (MHC-1) process directed against muscle fibers is likely, given biopsy features. • A viral etiology has been proposed secondary to the presence of autoantibodies to histidyl transferase, anti-Jo-1, and signal recognition particle.

DIAGNOSIS • The diagnosis of each subtype of inflammatory myopathy is based on clinical history, pattern of muscle involvement, electromyographic findings, muscle biopsy, and presence of certain antibodies. • Myopathic pattern of muscle weakness. • Characteristic rash in DM. • Electromyography (EMG) shows myopathic (small-amplitude, short-duration, polyphasic) motor potentials with early recruitment. • Majority of patients have “irritable” features (fibrillations and positive sharp waves) on EMG. • See “Laboratory Tests.” • Biopsy is required for diagnosis and should confirm inflammation before treatment is started. Table 1 describes histologic features of idiopathic inflammatory myopathies. In idiopathic inflammatory myopathies, myopathic features (variation in fiber size, fiber splitting, fatty replacement of muscle tissue,

and increased endomysial connective tissue) should be seen in addition to the following: 1. DM: Perifascicular atrophy, membrane attack complex (MAC) deposition along capillaries 2. PM: Endomysial infiltrates composed of CD8+ T cells and macrophages invading nonnecrotic muscle fibers that express MHC-I antigen

DIFFERENTIAL DIAGNOSIS • IBM • Muscular dystrophies • Amyloid myoneuropathy • Amyotrophic lateral sclerosis • Myasthenia gravis • Eaton-Lambert syndrome • Drug-induced myopathies (e.g., quinidine, NSAIDs, penicillamine, HMG-CoA-reductase inhibitors) • Diabetic amyotrophy • Guillain-Barré syndrome • Hyperthyroidism or hypothyroidism • Lichen planus • Amyopathic DM (rash without weakness) • DM sine rash (weakness with characteristic biopsy, but no rash) • Systemic lupus erythematosus (SLE) • Contact atopic or seborrheic dermatitis • Psoriasis LABORATORY TESTS • Creatine kinase (CK) is the most sensitive muscle enzyme test for muscle breakdown. It should be checked at onset, and serially monitored several times during treatment. • CK is typically elevated (5 to 50× normal) in active PM. • CK may be normal or only slightly elevated in DM. • Aldolase, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and lactate dehydrogenase (LDH) may be elevated. • Anti-Jo-1 antibodies are seen in myositis with associated interstitial lung disease but are not specific for either DM or PM. • Myositis-specific and myositis-associated autoantibodies in adult polymyositis and dermatomyositis and juvenile dermatomyositis are summarized in Table E2. • DM: Anti-MDA-5, anti-Mi-2, anti-TIF-1, and anti-NXP2 (implicated in cancer-associated dermatomyositis). • PM: Antisynthetase antibodies (often seen in overlap myositis) associated with interstitial lung disease, arthritis, fever, and “mechanic’s hands.” • Electrolytes, thyroid-stimulating hormone (TSH), Ca, and Mg should be evaluated to exclude other causes of weakness. • Check ECG for cardiac involvement. IMAGING STUDIES • Chest x-ray is used to rule out pulmonary involvement. If suspicious for pulmonary interstitial disease, a high-resolution CT scan of the chest may be helpful. • Radiography is an efficient means of identifying and characterizing soft-tissue calcinosis (Fig. E5). • Although MRI arguably has greater diagnostic value than electromyography or serum enzyme

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Diseases and Disorders

DEFINITION Inflammatory myopathies are idiopathic diseases of muscle characterized clinically by muscle weakness and pathologically by inflammation and muscle fiber breakdown. The four most common are dermatomyositis (DM), necrotizing autoimmune myositis, polymyositis (PM), and inclusion body myositis (IBM). See separate topics on “Inclusion Body Myositis” and “Necrotizing Autoimmune Myopathy” for details regarding these topics.

Inflammatory Myopathies

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Inflammatory Myopathies

ALG

TABLE 1  Histologic Features of Idiopathic Inflammatory Myopathies Feature

Dermatomyositis

Polymyositis

Inclusion Body Myositis

Necrosis of muscle fibers Variation in fiber diameter Regeneration of muscle fibers Proliferation of connective tissue Infiltration of mononuclear cells* Perivascular and perimysial inflammation Endomysial inflammation Perifascicular atrophy Abnormally dilated capillaries Reduced capillary density Deposition of complement on vessel walls Microinfarcts Invasion of non-necrotic fibers by cytotoxic T lymphocytes and macrophages Expression of major histocompatibility complex class I on muscle fibers Rimmed vacuoles with amyloid deposits and tubulofilaments† Angulated or atrophic and hypertrophic fibers Ragged red or cytochrome oxidase–negative fibers

+ + +

+ + +

+ + +

+

+

+

+

+

+

+

−/+

−/+

−/+ + + + +

+ − −/+ −/+ −/+

+ − − − −

+ −

− +

− +

−/+

+

+

−

−

+

−

−

+

−

−

+

*Inflammation is absent in a small proportion of polymyositis and dermatomyositis biopsies. †Also seen in chronic neurogenic conditions and distal myopathies. From Firestein GS et al: Kelley’s textbook of rheumatology, ed 9, Philadelphia, 2013, Saunders, Elsevier.

measurements in cases of suspected idiopathic inflammatory myopathy, MRI findings have not been formalized as a diagnostic criterion for idiopathic inflammatory myopathy. The acceptance of MRI as a diagnostic tool in myositis may be inhibited by the high cost and the need for more reliable and validated methods of summarizing the findings of MRI. MRI evaluation before biopsy, however, has become routine at many tertiary care centers. Fascial disease is manifested on MRI by fascial or perifascial hyperintensity on fluidsensitive sequences. The edema-like signal in the deep subcutis may accompany fasciitis and can indicate associated panniculitis. • Video fluoroscopy or barium swallow study to look for upper esophageal dysfunction in patients with dysphagia and DM. • Table E3 summarizes affected organs and their evaluation in inflammatory muscle disease.

TREATMENT Goal: Maintain function, minimize disease/iatrogenic sequelae

NONPHARMACOLOGIC THERAPY • Sun-blocking agents with SPF 15 or greater for skin protection in patients with DM

• Physical therapy beneficial for gait training and increasing muscle tone and strength • Occupational therapy assists with activities of daily living • Speech therapy to monitor patients with swallowing dysfunction

ACUTE GENERAL Rx • Corticosteroids are the mainstay of therapy. Start prednisone 1 to 2 mg/kg per day, up to a maximum dose of 100 mg/day. Continue until muscle strength improves or muscle enzymes have normalized for at least 4 wk. Begin tapering by 10 mg/mo until 60 mg/day, then slowly taper by 5 mg/ mo. Consider every-other-day prednisone treatment at same dose (may decrease side effects). • Consider IV immunoglobulin (IVIG) if patient fails to improve on prednisone, or muscle enzymes begin rising when tapering off prednisone. See “Chronic Rx” for specific dosage. • Hydroxychloroquine can be used to treat the cutaneous lesions of DM. • A treatment algorithm for adult patients with inflammatory myopathies is illustrated in Fig. 6.

CHRONIC Rx • Chronic prednisone therapy may be needed for yrs, but other immunosuppressive (“steroid-sparing”) agents may be added early to decrease long-term steroid side effects. • Azathioprine 2 to 3 mg/kg per day tapered to 1 mg/kg per day once steroid is tapered to 15 mg/day. Reduce dosage monthly by 25-mg intervals. Maintenance dosage is 50 mg/day. • Methotrexate 7.5 to 10 mg PO/wk, increased by 2.5 mg/wk to total of 25 mg/wk; consider IM dosing if PO is ineffective. • IV immunoglobulin 2 g/kg total dose over 2 to 5 days. • IV cyclophosphamide 1 g/M2 monthly for 6 mo is preferred to oral dosing for refractory cases. However, oral dosing of cyclophosphamide is 1 to 3 mg/kg per day PO or 2 to 4 mg/ kg per day in conjunction with prednisone. • Cyclosporine A: Initial dose 2.0 to 2.5 mg/kg bid; long-term maintenance is lowest effective dose. • Mycophenolate mofetil 500 mg PO bid, titrate to 1500 mg PO bid over 1 to 2 mo. • Hydroxychloroquine 200 mg PO daily; monitor for visual changes. DISPOSITION • 30% to 40% of patients achieve clinical remission with treatment. • In patients with residual weakness, deficits typically remain stable over long-term follow-up. • 10% experience recurrent disease. • Serum CK often returns to normal before symptoms improve. • During exacerbations, enzymes may rise before clinical symptoms appear. • Poor prognostic indicators include delay in diagnosis, older age, recalcitrant disease, malignancy, interstitial pulmonary fibrosis, dysphagia, leukocytosis, fever, and anorexia. • Infection, malignancy, and cardiac and pulmonary dysfunction are the most common causes of death. • With early treatment, 5- and 8-yr survival rates of 80% and 73%, respectively, have been reported. REFERRAL Neurology or rheumatology referral should be made to help establish the diagnosis and implement treatment.

PEARLS & CONSIDERATIONS • Do not implement treatment before muscle biopsy. • When assessing response to treatment, clinical muscle strength is more important than muscle enzyme tests. • The concern for malignancies (ovary, lung, breast, GI) associated with DM is legitimate and merits screening in patients older than age 40 at time of diagnosis and every 2 to 3 yr thereafter. • No association exists between juvenile DM and malignancy.

ALG

5. Psychiatric side effects including depression or psychosis 6. Poor sleep 7. Peptic ulcer disease (prescribe H2 antagonist or proton pump inhibitor) • Clinical and immune response features can be used for categorizing heterogeneous myositis syndromes and mutually exclusive and stable phenotypes and are useful for predicting clinical signs and symptoms, associated environmental and genetic risk factors, and responses to therapy and prognosis.

SUGGESTED READINGS Available at ExpertConsult.com

AUTHORS: Joseph S. Kass, MD, JD, FAAN, and Gavin Brown, MD

I

Confirm diagnosis and type of inflammatory myopathy and the degree of active inflammation and damage

Polymyositis

Sunscreens Hydroxychloroquine and below

Good prognosis

Poor prognosis

Corticosteroids Rehabilitation

Corticosteroids Rehabilitation plus below

Good response Slowly taper therapies Advance rehabilitation

Good response

Good response

Inclusion body myositis

Rehabilitation if evidence of active inflammation then 6-month trial of low-dose prednisone and methotrexate or IVIG

Some response

Inadequate response

Inadequate response

Methotrexate or azathioprine Consider IVIG

Advance rehabilitation Taper pharmacologic therapy

Inadequate response

Consider IV corticosteroids, mycophenolate, rituximab, tacrolimus, cyclosporine, abatacept, and/or anti-TNF

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RELATED CONTENT Dermatomyositis and Polymyositis (Patient Information) Inclusion Body Myositis (Related Key Topic) Necrotizing Autoimmune Myopathy (Related Key Topic)

TENTATIVE ALGORITHM FOR THE MANAGEMENT OF INFLAMMATORY MYOPATHIES

Dermatomyositis

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Inadequate response

Diseases and Disorders

• Overlap syndrome refers to patients with DM who also meet criteria for a connective tissue disorder (e.g., rheumatoid arthritis, scleroderma, SLE). • In any patient taking steroids, closely monitor for: 1. Diabetes or glucose intolerance (2-hr oral glucose tolerance test) 2. Osteopenia/osteoporosis (DEXA scan q6mo) 3. Cataracts (yearly ophthalmologic appointment) 4. Hypertension

Inflammatory Myopathies

Consider experimental therapy (clinicaltrials.gov)

FIG. 6  Tentative algorithm for the management of inflammatory myopathies. anti-TNF, Anti–tumor necrosis factor; IVIG, intravenous immunoglobulin. (From Hochberg MC: Rheumatology, ed 7, Philadelphia, 2019, Elsevier.)

Inflammatory Myopathies

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SUGGESTED READINGS Dalakas MC: Inflammatory muscle diseases, N Engl J Med 372:1734–1747, 2015. Milone M: Diagnosis and management of immune-mediated myopathies, Mayo Clin Proc 92(5):826–827, 2017.

A

B FIG. E1  Dermatomyositis—eyelid edema and heliotrope sign. A, Inflammation of the upper eyelid can be more subtle in darkly pigmented skin; note involvement of the lateral nasal root and cheeks. Eyebrow alopecia is due to chemotherapy. B, The characteristic pink-violet color is seen with involvement of the hairline, lower forehead, upper eyelids, and cheeks; the edema is striking and involves the nasal root as well as the eyelids. (From Bolognia J: Dermatology, ed 4, 2018, Elsevier.)

FIG. E2  Violaceous plaques on the knees in a patient with dermatomyositis (Gottron sign). (From Hochberg MC et  al: Rheumatology, ed 5, St Louis, 2011, Mosby.)

Inflammatory Myopathies

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A

B

C FIG. E3  Dermatomyositis—Gottron papules. A, Only a few Gottron papules are present, but there is definite accentuation of the pink-violet inflammation over the metacarpophalangeal (MCP) joints and proximal and distal interphalangeal (PIP, DIP) joints as well as the proximal nail folds. Note the ragged cuticles. B, The flat-topped (lichenoid) papules overlying the DIP, PIP, and MCP joints (knuckles) are subtle and were misdiagnosed as verrucae vulgares in this child. C, More obvious disease in which the multiple pink-violet lichenoid papules are coalescing and there is some involvement of the interphalangeal skin. (A, Courtesy Kalman Watsky, MD; B, Courtesy Julie V Schaffer, MD. In Bolognia J: Dermatology, ed 4, 2018, Elsevier.)

FIG. E4  Enlarged nail fold capillaries in a patient with dermatomyositis. (From Hochberg MC et al: Rheumatology, ed 5, St.Louis, 2011, Mosby.)

Inflammatory Myopathies

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TABLE E2  Myositis-Specific and Myositis-Associated Autoantibodies in Adult Polymyositis and Dermatomyositis and Juvenile Dermatomyositis Autoantibody

Autoantigen

Clinical Features

Jo-1, non–Jo-1 (PL7, PL12, EJ, OJ, KS, Tyr, Zo) SRP

Amino-acyl-tRNA synthetase

Fever, Raynaud phenomenon, mechanic's hands, myositis, polyarthritis, ILD

Mi-2 PM-Scl U1RNP SUMO-1 (small ubiquitin-like modifier 1) TIF1-γ (p155/140)

NXP2/MJ (p140)

MDA-5 (cADM-140) PMS1 Ku1

HMGCR (200/100 kDa)2,3

Signal recognition particle (cytoplas- Severe necrotizing myopathy; predominantly mic protein translocation) PM Helicase DM (adult > children); “shawl” sign and other DM rashes Nucleolar macromolecular complex Overlap features of myositis and SSc (or either disease alone); mechanic's hands Small nuclear ribonucleoprotein Overlap syndromes (MCTD) Small ubiquitin-like modifier Adult DM, ILD enzyme (posttranslational modification) Transcriptional intermediary factor Cancer-associated myositis in adults; >20% 1-γ (TIF1-γ) frequency in JDM cohorts; severe cutaneous disease in adult DM and JDM NXP-2 (SUMO target; possible role 20%-25% frequency in JDM cohorts; calcinoin SUMO-mediated transcripsis; severe disease (atrophy or contractures) tional repression) RNA helicase ADM, ILD; palmar papules and cutaneous ulcerations PMS1 (DNA mismatch repair Myositis (specifics not known) enzyme) 70- and 80-kDa nuclear/nucleolar UCTD and overlap syndromes (Raynaud pheprotein complex (DNA break repair nomenon, ILD, myositis, arthritis) and recombination) HMG CoA reductase Necrotizing myopathy

ADM, Amyopathic dermatomyositis; DM, dermatomyositis; HMG CoA, hydroxymethylglutaryl–coenzyme A; ILD, interstitial lung disease; JDM, juvenile DM; MCTD, mixed connective tissue disease; PM, polymyositis; SSc, systemic sclerosis; UCTD, undifferentiated connective tissue disease. (1)Rozelle A, Trieu S, Chung L: Malignancy in the setting of the anti-synthetase syndrome, J Clin Rheumatol 14:285-288, 2008. (2)Zhang L et al: Cardiac involvement in adult polymyositis or dermatomyositis: a systematic review, Clin Cardiol 35(11):686-691, 2012. (3)Oddis CV et  al: International consensus guidelines for trials of therapies in the idiopathic inflammatory myopathies, Arthritis Rheum 52(9):2607-2615, 2005. From Hochberg MC: Rheumatology, ed 7, Philadelphia, 2019, Elsevier.

FIG. E5  Advanced calcinosis. Radiograph of the arm in a girl with juvenile dermatomyositis, showing extensive amorphous and wispy calcification corresponding to subcutaneous calcinosis. Sheetlike calcification outlining muscles corresponds to deep fascial calcification. (From Pope TL et  al: Musculoskeletal imaging, ed 2, Philadelphia, 2015, Saunders.)

Inflammatory Myopathies

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TABLE E3  Affected Organs and Their Evaluation in Inflammatory Muscle Disease Organ or System

Modalities of Evaluation

Pathologic Processes

Findings

Muscle

Biopsy

Myofiber degeneration and regeneration Inflammation Fibrosis Myofiber destruction

Myofiber size variation; vacuolated, necrotic fibers Large central nuclei, basophilic sarcoplasm Mononuclear cell infiltration Increased interstitium and fatty replacement of muscle Low-amplitude, short, polyphasic potential; spontaneous fibrillations; irritability

Fibrosis Inflammation Myocarditis, fibrosis Myocarditis, fibrosis Inflammation, fibrosis Inflammation, fibrosis, restrictive lung disease Inflammation, fibrosis Inflammation, fibrosis Inflammation, fibrosis Inflammation Inflammation, fibrosis

Atrophy of muscle, scarring Bright signal in inflamed muscle Arrhythmias, left ventricular hypertrophy Myofiber size variation, mononuclear cell infiltrates, fibrosis Interstitial markings Decreased TLV, FVC, and Dlco

EMG

Heart Lungs

Skin GI system

MRI T1 image STIR image ECG, echo Biopsy CXR, HRCT PFTs Radionuclide scan BAL Biopsy Biopsy Radiographic studies

Ventilation–perfusion mismatches Abnormal leukocyte numbers and differentials Mononuclear cell infiltration, destruction of alveolar space and fibrosis Vacuolization of the basal layer; mononuclear cell infiltration Reflux and uncoordinated peristalsis

BAL, Bronchoalveolar lavage; CXR, chest radiography; echo, echocardiography; Dlco, diffusion capacity for carbon monoxide; ECG, electrocardiography; EMG, electromyography; FVC, forced vital capacity; GI, gastrointestinal; HRCT, high-resolution computed tomography; MRI, magnetic resonance imaging; PFT, pulmonary function tests; STIR, short tau inversion recovery; TLV, total lung volume. From Hochberg MC: Rheumatology, ed 7, Philadelphia, 2019, Elsevier.

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Influenza  BASIC INFORMATION DEFINITION Influenza is an acute febrile illness caused by infection with influenza type A or B virus. Seasonal influenza can include the H1N1 virus. A similar respiratory illness is severe acute respiratory syndrome (SARS) caused by a coronavirus called SARS-associated coronavirus (SARS-CoV). A new novel coronavirus was recognized in two patients in September 2012. This is a very different virus from the SARS agent; the two patients exhibited acute respiratory distress syndrome, renal failure, consumptive coagulopathy, and/or pericarditis. Now called the Middle East respiratory syndrome (MERS-CoV) virus, it has affected more than 2,200 persons in 27 countries since 2012. Patients have fever and pneumonia requiring hospitalization. Transmission spread in 2015 from the Middle East to Korea and China, resulting in more than 185 cases. There were 558 cases in Saudi Arabia from January 2015 through early June 2016, and 75 in 2018. Persons who are immunocompromised or have diabetes, renal failure, or chronic lung disease are thought to be at greater risk of severe illness. Dromedary camels and their milk are documented to harbor MERS-CoV. Refer to the “Influenza, Avian” topic for more information. SYNONYMS Flu Influenza-like illness (ILI) ICD-10CM CODES J10.00 Influenza due to other identified influenza virus with unspecified type of pneumonia J10.1 Influenza due to other identified influenza virus with other respiratory manifestations J11.1 Influenza due to unidentified influenza virus with other respiratory manifestations J12.9 Viral pneumonia, unspecified

EPIDEMIOLOGY & DEMOGRAPHICS PEAK INCIDENCE: Winter outbreaks lasting 5 to 6 wk PREDOMINANT SEX: Male = female PREDOMINANT AGE: Attack rates are usually higher among children than adults, although children are less prone to pulmonary complications. The severity of the 2017 to 2018 flu season was described by the Centers for Disease Control and Prevention (CDC) as high for all age groups: children, adults and older adults. Of the 171 reported pediatric deaths in the 2017 to 2018 season, 22% of the vaccine-eligible children had received vaccine. INCIDENCE (IN U.S.): Annual incidence of influenza-related deaths is between 12,000 and 51,000 deaths/yr.

PHYSICAL FINDINGS & CLINICAL PRESENTATION • “Classic flu” is characterized by abrupt onset of fever, headache, myalgias, anorexia, and malaise after a 1- to 2-day incubation period. • Clinical syndromes are similar to those produced by other respiratory viruses, including pharyngitis, common colds, tracheobronchitis, bronchiolitis, and croup. • Respiratory symptoms such as cough, sore throat, and nasal discharge are usually present at the onset of illness, but systemic symptoms predominate. • Elderly patients may experience fever, weakness, and confusion without any respiratory complaints. • Acute deterioration to status asthmaticus may occur in patients with asthma. • Influenza pneumonia: Rapidly progressive cough, dyspnea, and cyanosis may occur after typical flu onset. This may be caused by primary influenza pneumonia or secondary bacterial pneumonia (often pneumococcal or staphylococcal co-infection). • For influenza A (H3N2v), children younger than 10 yr lack immunity. People ≥65 yr and those with morbid obesity are at high risk. ETIOLOGY • Variation in the surface antigens of the influenza virus, hemagglutinin (HA) and neuraminidase (NA), leading to infection with variants to which immunity is inadequate in the population at risk • Droplet transmission by small-particle aerosols and deposited on the respiratory tract epithelium

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • Respiratory syncytial virus, adenovirus, parainfluenza virus infection • Secondary bacterial pneumonia or mixed bacterial-viral pneumonia WORKUP • The accuracy of clinical diagnosis of influenza on the basis of symptoms alone is limited because symptoms from illness caused by other pathogens can overlap considerably with influenza. Diagnostic tests available for influenza include viral cultures, serology, rapid influenza diagnostic tests (RIDTs), reverse transcription-polymerase chain reaction (RT-PCR), and immunofluorescence assays. • Virus isolation from nasal or throat swab or sputum specimens is the most rapid diagnostic method in the setting of acute illness. • Specimens are placed into virus transport medium and processed by a reference laboratory. • For serologic diagnosis: 1. Paired serum specimens, acute and convalescent, the latter obtained 10 to 20 days later. 2. Fourfold rises or falls in the titer of antibodies (various techniques) considered diagnostic of recent infection.

3. C  ommercial rapid influenza diagnostic tests (RIDTs) are available. They can detect influenza virus antigens within 15 min of testing. Rapid flu test should be collected as early as possible, ideally within 4 days of onset. False-negative results are common during the flu season. A negative test result does NOT exclude diagnosis of influenza. 4.  Commercial RIDTs cannot determine if an H3N2 is a variant virus; when suspect H3N2v virus infection, send nasopharyngeal swab or aspirate in viral transport medium to state public health laboratory for rRT-PCR testing using Centers for Disease Control and Prevention (CDC) FLU rRT-PCR diagnostic panel assay. Novel digital immunoassay (DIAs) and rapid nucleic amplification tests (NAATs) have a markedly higher sensitivity for influenza A and B than traditional RIDTs.

LABORATORY TESTS Septic syndrome presentation: CBC, ABG analysis, blood cultures IMAGING STUDIES • Chest x-ray examination when suspecting viral pneumonia: Peribronchial and patchy interstitial infiltrates in multiple lobes with atelectasis. Table 1 describes x-ray pulmonary findings based on virus type. • Possible progression to diffuse interstitial pneumonitis.

TREATMENT NONPHARMACOLOGIC THERAPY • Bed rest • Hydration ACUTE GENERAL Rx • Supportive care: Antipyretics; avoid use of aspirin in children because of the association with Reye syndrome. • Antibiotics if bacterial pneumonia is proved or suspected. • Amantadine is NOT recommended due to resistant isolates. • Neuraminidase inhibitors block release of virions from infected cells, resulting in shortened duration of symptoms and decrease in complications; effective against both influenza A and B, including A (H3N2v) for all hospitalized patients, those with severe and progressive illness, and high-risk patients with suspected or confirmed H3N2v. 1. Oseltamivir, administered orally: a. For treatment, 75 mg PO twice daily for 5 days b. For prevention, 75 mg PO once daily for a minimum of 2 wk in an outbreak setting or 7 days after exposure for an adult 2. Zanamivir, administered via inhaler: a. For treatment, 10 mg (2 inhalations of 5 mg each) twice daily for 5 days.

Influenza TABLE 1  Pulmonary Radiographic Findings Based on Virus Type Centrilobular Nodules

Lobar Ground-Glass

Diffuse Ground-Glass

Influenza Epstein-Barr Cytomegalovirus Varicella-zoster Herpes simplex Measles Hantavirus Adenovirus

+++ + ++ +++ + ++

+++ + ++ + +++ +

+ + ++ + + + +++

++

+

I

Thickened Interlobular Septa

Consolidation

+

+ + +

+

+++ + ++ +++

From Weissleder R et al: Primer of diagnostic imaging, ed 5, St Louis, 2011, Mosby.



b. For prevention in households, 10 mg (2 inhalations of 5 mg each) once daily for 7 days. Not recommended in persons with underlying airways disease such as asthma or chronic obstructive pulmonary disease. c.  Adjust dosing in patients with renal impairment or end-stage renal disease. 3. Baloxavir (Xofluza) was approved by the FDA in 2018 for acute uncomplicated influenza infection in patients ≥ 12 yr of age. Its mechanism of action is through inhibition of an endonuclease involved in viral RNA replication. It is a single dose drug. • Placebo-controlled studies have suggested that antiviral therapy with any of the previously mentioned agents must ideally be initiated within 1 to 2 days of the onset of symptoms and reduces the duration of illness by ∼1 day. • Oseltamivir resistance developed on therapy in individuals with avian flu (H5N1) in Asia, and this is associated with poor outcome. • Amantadine and rimantadine resistance are documented for novel (H1N1) influenza and H3N2 influenza virus. • Systemic corticosteroids should not be routinely administered to patients with suspected or confirmed influenza, including H3N2v virus infection, except for patients on chronic corticosteroid therapy for COPD, asthma. • Recent trials1 have shown that in patients hospitalized with severe influenza infection, triple therapy with clarithromycin 500 mg, naproxen 200 mg, and oseltamivir 75 mg bid for 30 days reduced mortality and did not increase complications compared with oseltamivir (75 mg bid for 5 days) alone.

DISPOSITION Patients are hospitalized if signs of pneumonia are present. REFERRAL Infectious disease and/or pulmonary consultation when influenza pneumonia is suspected 1Hung

IFN et al: Efficacy of clarithromycin-naproxenoseltamivir combination in the treatment of patients hospitalized for influenza (H3N2) infection: an openlab, randomized, controlled, phase IIb/III trial, Chest 151:1069-1080, 2017.

PEARLS & CONSIDERATIONS COMMENTS • Prevention of influenza in patients at high risk is an important goal of primary care. • Vaccines reduce the risk of infection and the severity of illness. 1. Antigenic composition of the vaccine is updated annually. The northern hemisphere’s 2019 to 2020 season trivalent vaccine includes an A/Brisbane/02/2018 (H1N1) pdm09-like virus (updated), an A/Kansas/14/2017 (H3N2)-like virus (updated), and a B/Colorado/06/2017like (Victoria lineage) virus. 2.  Quadrivalent vaccines contain these three vaccine viruses, plus a second influenza B vaccine virus strain called B/ Phuket/3073/2013-like (Yamagata lineage) virus. 3. Revaccination is recommended annually before onset of influenza activity in the community, even for those who received the vaccine in the previous season. 4.  Delaying vaccination to ensure persistence of vaccine-induced protection during flu season could result in missed opportunities to vaccinate. 5.  Seasonal influenza vaccine does not provide protection against the influenza A (H3N2v) virus that is associated with agricultural fairs. 6. Vaccination should be given at the start of the flu season (September-October) for all persons aged ≥6 mo who do not have contraindications. Vaccination is particularly important for persons who are at high risk and their contacts/caregivers. When vaccine supply is limited, vaccination efforts should focus on the following groups: a. All children aged 6 mo to 4 yr (59 mo) b. People 50 yr and older c. Adults and children with chronic cardiac (except hypertension) or pulmonary (including asthma), renal, hepatic, neurologic, hematologic or metabolic disease (including diabetes mellitus)



d. Immunocompromised patients (including HIV-infected persons or patients immunosuppressed due to medications) e. Women who are or will be pregnant during the influenza season f. Children aged 6 mo to 18 yr who are receiving long-term aspirin therapy g. Residents of nursing homes and other long-term care facilities h. American Indians/Alaska Natives i. Persons who are morbidly obese (BMI ≥40) j. Health care workers (HCWs) k. Household contacts and caregivers of persons in the previous groups 7. Vaccination precautions include: a. Guillain-Barré syndrome within 6 wk following a previous dose of influenza vaccine b. Moderate or severe acute illness with or without fever c. Asthma in persons >5 yr (LAIV4) d. Other underlying medical conditions that might predispose to complications after wild-type influenza infection (e.g., chronic pulmonary, cardiovascular [excluding isolated hypertension], renal, hepatic, neurologic, hematologic, or metabolic disorders [underlying diabetes mellitus]) (LAIV4) 8. Contraindication to receiving vaccine: a.  Previous severe allergic reaction to influenza vaccine b.  For LAIV4: Concomitant aspirin- or salicylate-containing therapy in children and adolescents c.  For LAIV4: Children 2 to 4 yr with asthma Dx in past 12 mo d. For LAIV4: Immunocompromised due to any cause including medications or HIV infection e. For LAIV4: Close contacts and caregivers of severely immunosuppressed persons who require a protected environment f. For LAIV4: Pregnancy g. For LAIV4: Received influenza antiviral medication within past 48 hr 9. Special efforts should be made to vaccinate high-risk patients 65 yr) • Volume depletion • Underlying kidney disease • Congestive heart failure • Diabetes • HIV infection

PHYSICAL FINDINGS & CLINICAL PRESENTATION SIGNS AND SYMPTOMS: • For AIN, the most common presentation is a rise in serum creatinine and blood urea nitrogen (BUN) levels that is asymptomatic. When AIN is advanced, it is associated with nonspecific symptoms of AKI from any cause, including the following: 1. Malaise 2. Anorexia 3. Nausea and vomiting 4. Oliguria or polyuria 5. Hematuria 6. Flank pain • Classic triad (fever, maculopapular rash, and eosinophilia) is present in only 5% of cases: 1. When present, the rash is usually a truncal maculopapular morbilliform eruption. 2.  Triad was characteristic of methicillinrelated AIN, which has not been used in the U.S. for decades. • A small minority present with tubulo-interstitial nephritis and uveitis (TINU) syndrome. The uveitis may be symptomatic or subclinical and may develop before, during, or after the renal injury. Adolescent females are most often affected by TINU. • For chronic interstitial nephritis, there may be a subacute to protracted subtle rise in creatinine without any obvious symptoms as seen with AIN. ETIOLOGY ACUTE INTERSTITIAL NEPHRITIS: • Drug-induced (70%). More than 150 agents have been implicated. AKI usually develops 10 to 14 days after exposure to the drug, but may develop sooner if there was a previous exposure. 1.  Antibiotics (beta-lactams, sulfonamides, rifampin, fluoroquinolones) 2. NSAIDs (including selective COX-2 inhibitors) 3. Proton pump inhibitors and H2 blockers (primarily cimetidine) 4. Loop diuretics (furosemide, bumetanide) 5. Antineoplastic agents 6. Anticonvulsants 7. Allopurinol (particularly common cause of drug rash or reaction with eosinophilia and systemic symptoms [DRESS] with AIN) 8.  Immunotherapy: Checkpoint pathway inhibitors • Infection (10% to 15%). May be systemic or localized to genitourinary system. 1. Bacteria: Streptococci, Corynebacterium diphtheria, Legionellae, Yersinia, Mycobacteria, Mycoplasmas, Rickettsiae 2. Viruses: Cytomegalovirus, Epstein-Barr virus, hantaviruses, hepatitis C virus, her-

pes simplex virus, HIV, mumps, polyomavirus, influenza A virus 3. Other: Treponema pallidum, Toxoplasma gondii, Babesia species • Other Causes (15% to 20%) 1. Idiopathic (10%) 2. Immune disorders: Systemic lupus erythematosus, Sjögren syndrome, smallvessel vasculitides, autoimmune pancreatitis 3. Neoplastic disorders (multiple myeloma) 4. DRESS syndrome 5. IgG4-related disease 6. Hypocomplementemic tubulointerstitial nephritis (likely related to IgG4 disease) CHRONIC INTERSTITIAL NEPHRITIS: • Metabolic diseases (urate nephropathy, hypercalcemic nephropathy, hypokalemic nephropathy, oxalate nephropathy) • Sarcoidosis • Heavy metals • Chronic urinary tract obstruction • Aristolochic acid • Diabetic kidney disease • Hypertensive kidney disease OVERLAP OF ACUTE AND CHRONIC INTERSTITIAL NEPHRITIS: Some metabolic processes and autoimmune disorders can present either as acute or chronic interstitial nephritis. For example, oxalate nephropathy can present with acute interstitial nephropathy in the setting of ethylene glycol ingestion, or with chronic interstitial nephritis in patients with prior bariatric surgery and a high oxalatecontaining diet.

DIAGNOSIS DIFFERENTIAL DIAGNOSIS Other causes of AKI or chronic kidney disease (CKD), including acute tubular necrosis (ATN), atheroembolic disease, glomerulonephritis, hypertensive nephrosclerosis, prerenal azotemia, obstructive nephropathy, and renal vascular disease WORKUP • Diagnosis is most often made by defining the temporal relationship between onset and resolution of an AKI episode with use and discontinuation of a known culprit drug. • Gold standard for diagnosis is kidney biopsy. This is reserved for clinical situations with an unclear diagnosis, when removal of the offending agent does not result in improvement or may impact medical care, or when steroid initiation is being considered. LABORATORY TESTS • No single laboratory test has sufficient positive or negative predictive value to be useful in diagnosing interstitial nephritis. • Diagnosis may be made based on clinical history, constellation of urine and serum abnormalities, and clinical course.

Interstitial Nephritis

BLOOD TESTS: • Serum chemistry profile: Elevated BUN, elevated creatinine, low serum phosphorus, low serum urate may be seen. • Complete blood count with differential may reveal the following: 1.  Eosinophilia (not sensitive; if present, this finding greatly increases clinical suspicion for a systemic drug reaction. Eosinophilia may also occur in other causes of AKI including cholesterol emboli, vasculitis, and hematologic or solid organ malignancy). 2. A hemoglobin level that is disproportionately low compared with the degree of AKI. This is attributed to loss of interstitial erythropoietin-producing cells, which may be impacted by the inflammatory cellular congestion). • If drug-related AIN is not suspected, laboratory workup for infection, vasculitis, and autoimmune disorders may be warranted depending on the clinical context.

IMAGING STUDIES Gallium scintigraphy, positron emission tomography, and computed tomography have been used to evaluate AIN in patients. These tests may distinguish between AIN and other forms of AKI in patients too unstable for a renal biopsy. KIDNEY BIOPSY Critical in diagnosis of interstitial nephritis in patients in whom the differential of AKI is broad. Biopsy findings include (Fig. E2): • Predominant lymphocytic and monocytic infiltrate (Fig. E2, B).

• Presence of eosinophils is suggestive of drug-induced AIN (Fig. E2, C). • Tubulitis (renal tubular invasion by inflammatory cells) is suggestive of AIN. • Early on, inflammation is associated with edema, but may transition to fibrosis with underlying tubular atrophy as the process becomes more chronic (Fig. E2, D). • Granuloma formation may be more suggestive of infectious AIN, especially in regions where the infectious etiologies described earlier are endemic.

TREATMENT NONPHARMACOLOGIC THERAPY Largely supportive; removal of offending agent, if known, will resolve 60% of cases. ACUTE GENERAL Rx • Maintain adequate hydration and urine output and avoid volume overloading. • Identify and treat infection if present. • Avoid nephrotoxins and medications that impair renal blood flow. • Uveitis in TINU syndrome may be asymptomatic. Ophthalmologic exam is recommended in idiopathic AIN. • Retrospective studies and anecdotal literature have shown that steroid treatment, initiated within 7 days of diagnosis, may reduce the requirement for chronic dialysis in patients with drug-induced AIN who have not responded to drug withdrawal alone. Steroids are the basis of treatment in idiopathic AIN, AIN associated with systemic disease, and TINU. Regimens vary. Some include an initial steroid pulse of methylprednisolone, 250 to 500 mg for 3 consecutive days, followed by 1 mg/kg prednisone. Others start with 1 mg/kg of prednisone with no intravenous, with tapering over 4 to 6 wk. Steroids are not administered to patients with significant kidney fibrosis on histologic examination. • Cyclophosphamide, cyclosporine, and mycophenolate mofetil have all been used anecdotally as therapy in steroid-resistant disease. Among these, mycophenolate mofetil has the largest body of evidence for use as a steroid-sparing agent, if AKI recurs when steroids are tapered or discontinued, or when patients develop adverse effects from steroid therapy. CHRONIC Rx • Limit exposure to known nephrotoxic agents. • Adjust dosages of all medications as indicated by glomerular filtration rate.

• Rigorous control of blood pressure, diabetes, and cholesterol. • Relieve any sources of chronic obstruction.

DISPOSITION With AIN: • Complete recovery with return to baseline creatinine occurs in 60% to 65% of cases. • Partial recovery is seen in 10% to 20%. • Irreversible damage in 5% to 10%. • Relapse is common with repeated exposure to offending agents. REFERRAL Renal consultation is often necessary, especially if the diagnosis is unclear, biopsy is required, or there is treatment-resistant disease.

PEARLS & CONSIDERATIONS COMMENTS Acute interstitial nephritis is most often due to drugs started in the preceding 30 days. The most common drug classes are beta-lactam antibiotics, NSAIDs, and proton pump inhibitors (PPIs). In contrast to ATN, which is often associated with oliguria, early AIN may be associated with polyuria; therefore, a high index of suspicion in this clinical setting is essential for early diagnosis. PREVENTION Use known offending agents with care, especially in the elderly and those with known underlying kidney disease. PATIENT & FAMILY EDUCATION www.nlm.nih.gov/medlineplus/ency/article/000 464.htm SUGGESTED READINGS Available at ExpertConsult.com RELATED CONTENT Interstitial Nephritis (Patient Information) AUTHORS: Evan Zeitler, MD, and Koyal Jain, MD

I

Diseases and Disorders

URINE TESTS: • Urine eosinophilia historically was considered a marker of AIN, but this urinary finding is neither sensitive nor specific for AIN and has a low positive and negative predictive value, i.e., urine eosinophils do not establish or rule out AIN. Eosinophiluria may be found in a variety of kidney diseases. • Urinalysis findings may include sterile pyuria, microhematuria, glucosuria, and proteinuria. Nephrotic syndrome is present in less than 1% of patients. • Urine sediment analysis may include leukocytes, leukocyte casts, red cells, and tubular epithelial cells (Fig. E1). However, a bland urine sediment can also be seen in interstitial nephritis, especially if chronic. A lack of pyuria does not exclude AIN. Additionally, granular casts may be noted when tubulitis is present.

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I

Interstitial Nephritis SUGGESTED READINGS González E et al: Early steroid treatment improves the recovery of renal function in patients with drug-induced acute interstitial nephritis, Kidney Int 73:940946, 2008. Moledina DG, Perazella MA: Drug-induced acute interstitial nephritis, Clin J Am Soc Nephrol 12:12, 2017. Muriithi AK, Nasr SH, Leung N: Utility of urine eosinophils in the diagnosis of acute interstitial nephritis, Clin J Am Soc Nephrol 8(11):1857-1862, 2013. Perazella MA: Diagnosing drug-induced AIN in the hospitalized patient: a challenge for the clinician, Clin J Am Soc Nephrol 81(6):381-388, 2014. Praga M et al: Changes in the aetiology, clinical presentation and management of acute interstitial nephritis, an increasingly common cause of acute kidney injury, Nephrol Dial Transplant 30(9):1472-1479, 2015. Praga M, Gonzalez E: Acute interstitial nephritis, Kidney Int 77:956-961, 2010. Raghavan R, Eknoyan G: Acute interstitial nephritis—a reappraisal and update, Clin Nephrol 82(3):149-162, 2014.

FIG. E1  Urinary sediment showing white blood cells and white blood cell cast. (Courtesy Randy L. Luciano, MD.)

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Interstitial Nephritis

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A

B

C

D

FIG. E2  A, Normal biopsy showing tubular lumen with no cells in interstitium. B, Acute interstitial nephritis with significant interstitial infiltrate and compressed tubules. C, High-power view of cellular infiltrate showing lymphocytes, monocytes, and eosinophils (cells with red cytoplasm). D, Chronic interstitial nephritis with areas of fibrosis (pink, cell-sparse areas). (Courtesy Randy L. Luciano, MD.)

Intraventricular Conduction Delay (IVCD) BASIC INFORMATION DEFINITION Provided that criteria for right bundle branch block (RBBB), left bundle branch block (LBBB), or hemifascicular block (Fig. E1) are not met, intraventricular conduction delay (IVCD) is defined by a QRS >110 ms in adults, >90 ms in children 8 to 16 yr, and >80 ms in children younger than 8 yr. It is a common clinical abnormality related to a conduction disturbance that occurs at various levels in the His-Purkinje system. Abnormal activation of the local myocardium can coexist. It can be caused by anatomic abnormalities and the physiologic properties of cardiac tissue. It may occur between ventricles (interventricular), within Purkinje fibers or ventricular myocardium (intraventricular), or between layers of the myocardium (intramural). Parietal block occurs in the terminal Purkinje system and presents with prolonged QRS in leads V1 to V3 compared with V4 to V6. This particular type of IVCD is associated with right ventricular arrhythmogenic dysplasia. It is considered to take place beyond the Purkinje myocardial gates and is due to an abated cell-to-cell conduction. SYNONYMS IVCD Nonspecific/unspecified intraventricular conduction disturbance Intraventricular conduction delay/defect/block Fragmented QRS complex Prolonged/wide QRS ICD-10CM CODES I45.4 Non-specific intraventricular block I45.8 Other specified conduction disorders I45.9 Conduction disorder, unspecified

EPIDEMIOLOGY • The prevalence of IVCD in the general population increases with age. • A Finnish Social Security study, on 10,899 subjects with baseline ECGs, showed a prevalence of IVCD in 0.6% of the total population. 45.6% of subjects with QRS ≥110 ms without evidence of cardiac disease or bundle branch block, had an increased

risk of all-cause mortality with relative risk 1.75. • IVCD has a consensus prevalence of 30% in patients with heart failure (HF) ranging between 14% and 47% in various studies. • The reported prevalence in military aviators was similar to RBBB at 0.2%.

PHYSICAL FINDINGS & CLINICAL PRESENTATION IVCD per se is asymptomatic and is recognizable only with a 12-lead ECG.

ETIOLOGY IVCD is usually the result of abnormal ventricular activation caused by delay in one or more levels of the conduction system. Activation abnormalities of the local myocardium can coexist and further alter the pattern of ventricular excitation. Patients with IVCD are not a homogeneous group but rather reflect the underlying causative conditions such as dilated cardiomyopathy, hypertensive cardiomyopathy, ischemic cardiomyopathy, or other conditions. Therefore grouping patients on the basis of IVCD is not clinically meaningful. The most common clinical conditions associated with IVCD are the following: • Coronary artery disease • Infiltrative cardiomyopathy: Amyloidosis, sarcoidosis, hemosiderosis, etc. • Cardiomyopathies of other etiologies • Left ventricular hypertrophy • Endocarditis of the aortic valve • Myocarditis • Chagas disease (parasitic) • Primary conduction diseases: Lenegre disease, Lev disease • Congenital anomalies • Progressive systemic scleroderma • Pulmonary embolism • Cyclic antidepressants • Hyperkalemia • Hypothermia • Intracardiac catheter manipulation Antiarrhythmic drugs, class IA (e.g., procainamide, disopyramide, quinidine), and class IC (e.g., flecainide, encainide, and propafenone), amantadine, carbamazepine, cocaine, diphenhydramine, mesoridazine, and thioridazine may cause IVCD. In addition, propoxyphene and propranolol can also cause IVCD by sodium channel blockade in older adults due to myocardial fibrosis caused by apoptosis. Etiology can be unknown in many cases.

Intraventricular conduction delay is usually an incidental ECG finding. By definition, this defect does not meet criteria for RBBB, LBBB, or hemifascicular block.

Sinus rhythm 1

aVR

V1

V4

2

aVL

V2

V5

3

aVF

V3

V6

FIG. E1  Normal sinus rhythm baseline with intraventricular conduction delay resembling left bundle branch block (LBBB). aVF, Augmented vector foot; aVL, augmented vector left; aVR, augmented vector right. (From Issa ZF: Clinical arrhythmology and electrophysiology: a companion to Braunwald’s heart disease, ed 2, Philadelphia, 2012, Saunders.)

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DIAGNOSIS

DIFFERENTIAL DIAGNOSIS • Unifascicular block • Bifascicular block • Wolff-Parkinson-White (WPW) pattern and variants • LBBB • RBBB EVALUATION The evaluation of the patient with IVCD should be oriented toward the cause of the ECG abnormality to implement appropriate therapy and counseling. Thorough history and physical exam must be performed to implement adequate laboratory and imaging testing based on the level of suspicion for the causes of IVCD listed earlier. Such tests could include but are not limited to: • Standard laboratory testing appropriate for age, gender, and metabolic abnormalities • Resting ECG • Exercise ECG, with or without imaging • Ambulatory ECG • Echocardiogram • Specialized studies based on known comorbidities and risk assessment or suspicion of them such as heart failure, myocardial infarction, or cardiomyopathies

TREATMENT Optimize the treatment of the underlying contributing conditions. In selected patients at risk for sudden cardiac death due to significant coronary artery disease or arrhythmogenic right ventricular dysplasia, appropriate referral should be made. Although cardiac resynchronization therapy has been effective in reducing clinical events in patients with LBBB, patients with IVCD have not demonstrated similar benefit. In the absence of LBBB, cardiac resynchronization therapy offers no benefit for the management of patients with IVCD. In fact there may be an increased risk of ventricular tachycardia for this group when receiving defibrillator devices with or without cardiac resynchronization. However, intraventricular dyssynchrony has been found to be directly related to IVCD and to have major implications in the identification of adequate electronic pacing sites in patients who require device implantation therapy.

PROGNOSIS Different studies have shown that IVCD is associated with increased all-cause mortality

These proofs may contain color figures. Those figures may print black and white in the final printed book if a color print product has not been planned. The color figures will appear in color in all electronic versions of this book.

Intraventricular Conduction Delay (IVCD) with relative risk (RR) 1.75 to 2.01, increased cardiac mortality with RR 1.87 to 4.25, and a markedly elevated risk of sudden arrhythmic death with RR 2.9 to 3.11. A Finnish study in a community cohort, published in 2015, showed that IVCD had a notably high hazard ratio for cardiovascular mortality at 4.25 (95% CI 1.95 to 9.26). Prognosis depends on the underlying associated clinical conditions. The presence of IVCD constitutes a prognostic marker for cardiac events in CAD, hypertrophic cardiomyopathy, structural heart disease with implanted cardiac defibrillators, Chagas disease, arrhythmogenic right ventricular dysplasia, Brugada syndrome, and acquired long QT syndrome. It is associated

with heart failure hospitalization in patients with hypertrophic cardiomyopathy. An area of increasing interest is the presence of intra- and interatrial conduction delay as it relates to the generation of atrial fibrillation. It is more reliable than left atrial volume and dimension in the prediction of atrial fibrillation and ischemic stroke. It has a direct correlation with aortic strain in patients with hypertension, and it correlates with increased symptoms and mortality in patients with systolic heart failure.

REFERRAL Refer to a cardiologist if there is history of palpitations, dizziness, heart failure, myocardial infarction, or an abnormal cardiac exam.

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 EARLS & P CONSIDERATIONS • IVCD can be due to drugs such as Class I antiarrhythmic drugs. • IVCD can be a normal variant and is not always associated with cardiac pathology. • Clinical correlation is needed to identify associated cardiac abnormalities. • In patients with heart failure, cardiac resynchronization for IVCD in the absence of LBBB is not associated with clinical benefit. AUTHORS: John Wylie, MD, FACC, and Ioannis Koulouridis, MD, MS

SUGGESTED READINGS Aro AL et al: Intraventricular conduction delay in a standard 12-lead electrocardiogram as a predictor of mortality in the general population, Circ Arrhythm Electrophysiol 5:704-710, 2011. Cinca J et al: Differential clinical characteristics and prognosis of intraventricular conduction defects in patients with chronic heart failure, Eur J Heart Fail, 2013. http://dx.doi.org/10.1093/eurjhf/hft042. First published online: March 19, 2013. Eschalier R et al: Nonspecific intraventricular conduction delay: definitions, prognosis, and implications for cardiac resynchronization therapy, Heart Rhythm 12:1071-1079, 2015. Sipahi I et al: Effect of QRS morphology on clinical event reduction with cardiac resynchronization therapy: meta-analysis of randomized controlled trials, Am Heart J 163:260-267, 2012.

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Irritable Bowel Syndrome BASIC INFORMATION DEFINITION Irritable bowel syndrome (IBS) is a chronic functional disorder manifested by alteration in bowel habits and recurrent abdominal pain and bloating. IBS is a symptom complex influenced by a variety of physiologic determinants from gut to brain and back. The ROME IV criteria for diagnosis of IBS are: • Patient has recurrent abdominal pain ≥1 day per wk, on average, in the previous 3 mo, with an onset ≥6 mo before diagnosis • Abdominal pain is associated with at least two of the following three symptoms: 1. Pain related to defecation 2. Change in frequency of stool 3. Change in form (appearance) of stool • Patient has none of the following warning signs: 1. Age ≥50 yr, no previous colon cancer screening, and presence of symptoms 2. Recent change in bowel habit 3. Evidence of overt GI bleeding (e.g., melena or hematochezia) 4. Nocturnal pain or passage of stool 5. Unintentional weight loss 6.  Family history of colorectal cancer or inflammatory bowel disease 7. Palpable abdominal mass or lymphadenopathy 8.  Evidence of iron-deficiency anemia on blood testing 9. Positive test for fecal occult blood • The criteria must be fulfilled for at least the past 3 mo with symptom onset at least 6 mo before the diagnosis. • Table 1 subtypes IBS by predominant stool pattern. SYNONYMS Irritable colon Spastic colon IBS ICD-10CM CODES K58 Irritable bowel syndrome K58.9 Irritable bowel syndrome without diarrhea K58.0 Irritable bowel syndrome with ­diarrhea

EPIDEMIOLOGY & DEMOGRAPHICS • IBS is the most common functional bowel disorder. An estimated 15 million people in the U.S. have IBS. • IBS occurs in 7% to 21% of the general population of industrialized countries and is responsible for >50% of gastrointestinal (GI) referrals. Worldwide adult prevalence is 12%. Incidence increases during adolescence and peaks in third and fourth decades of life. • Female:male ratio is 2:1. Peak prevalence is from 20 to 39 yr of age. • Nearly 50% of patients have psychiatric abnormalities, with anxiety disorders being most common.

ALG

PHYSICAL FINDINGS & CLINICAL PRESENTATION • The clinical presentation of IBS consists of abdominal pain and abnormalities of defecation, which may include loose stools, usually after meals and in the morning, alternating with episodes of constipation. • Physical examination is generally normal. • Nonspecific abdominal tenderness and distention may be present. ETIOLOGY • Unknown, believed to be multifactorial. Fig. 1 illustrates a biopsychological model of IBS pathophysiology • Associated pathophysiology includes altered GI motility, alteration in gut flora, and increased gut sensitivity • Risk factors: Anxiety, depression, personality disorders, history of childhood sexual abuse, and domestic abuse in women

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • Inflammatory bowel disease (IBD) • Diverticulitis • Colon malignancy • Endometriosis • Peptic ulcer disease • Biliary liver disease • Chronic pancreatitis • Constipation caused by medications (opiates, calcium channel blockers, anticholinergics) • Diarrhea caused by medications (metformin, colchicine, proton pump inhibitors, antacids, antibiotics) • Small-bowel overgrowth • Celiac disease • Parasites • Lymphoma of GI tract • Pelvic floor dyssynergia

TABLE 1  Subtyping Irritable Bowel Syndrome by Predominant Stool Pattern • IBS with constipation (IBS-C)—hard or lumpy stools* ≥25% and loose (mushy) or watery stools† ≥25% of bowel movements‡ • IBS with diarrhea (IBS-D)—loose (mushy) or watery stools† ≥25% and hard or lumpy stool* ≥25% of bowel movements‡ • Mixed IBS—hard or lumpy stools* ≥25% and loose (mushy) or watery stools† ≥25% of bowel movements‡ • Unsubtyped IBS (IBS unclassified)—insufficient abnormality of stool consistency to meet criteria for IBS with constipation, diarrhea, or mixed‡ IBS, Irritable bowel syndrome. *Bristol Stool Form Scale 1-2 (separate hard lumps like nuts [difficult to pass] or sausage-shaped but lumpy). †Bristol Stool Form Scale 6-7 (fluffy pieces with ragged edges, a mushy stool or watery, no solid pieces, entirely liquid). ‡In the absence of use of antidiarrheals or laxatives. Adapted from Sayuk GS, Gyawali CP: Irritable bowel syndrome: modern concepts and management options, Am J Med 128(8):817-827, 2015.

WORKUP Diagnostic workup (Table 2) is aimed primarily at excluding the conditions listed in the differential diagnoses. A step-wise approach is critical. It is important to identify red flags of other diseases, such as weight loss, rectal bleeding, onset in patients >50 yr, fever, nocturnal pain, and family history of malignancy or IBD. Additional red flags include abnormal examination (e.g., mass, enlarged lymph nodes, stool positive for occult blood, muscle wasting) and abnormal laboratory values (anemia, leukocytosis, abnormal chemistry). LABORATORY TESTS • Blood work is generally normal. CBC is reasonable to evaluate for anemia. The presence of anemia should alert to the possibility of a colonic malignancy or IBD. • Other reasonable tests include C-reactive protein, tissue transglutaminase antibody (rule out celiac disease) and TSH (rule out thyroid abnormalities). • Fecal calprotectin level is useful to differentiate IBS from inflammatory bowel disease in patients who have IBS with diarrhea or with both diarrhea and constipation. Fecal calprotectin levels less than 40 mcg/g exclude IBD in patients with IBS. • Testing of stool for ova and parasites should be considered only in patients with chronic diarrhea. Evaluation of stool for Clostridium difficile may be helpful in patients with predominant diarrhea symptoms who have recently taken antibiotics. IMAGING STUDIES • Imaging studies (e.g., flat and upright abdominal radiograph, small-bowel series, sonogram or CT of abdomen and pelvis) are normal and not necessary for diagnosis. • Lower endoscopy is generally normal except for the presence of some spasms. Colonoscopic imaging should be performed only in persons who have alarm features to rule out organic disease and in persons older than 50 yr to screen for colorectal cancer.

TREATMENT NONPHARMACOLOGIC THERAPY • The patient should be encouraged to maintain an adequate fiber intake and to eliminate foods that aggravate symptoms. Avoidance of caffeine, dairy products, fatty foods, and dietary excesses is also helpful. Several clinical trials have shown that a diet low in fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAPs) improves symptoms in nearly 70% of patients with IBS. • Cognitive-behavioral therapy is also recommended, particularly in younger patients because psychosocial stressors are important triggers of IBS. Reassurance that the disorder is benign and education about trigger avoidance and stress management are important. • Importance of regular exercise and adequate fluid intake should be stressed.

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Environmental factors • Genetics • Early life (breastfeeding) • Diet (FODMAPs, gluten, disaccharide intolerance) • Fiber/H2O intake • GI infection/enteritis

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Gut physiology • GI motility (5-HT3, 5-HT4) • Sensation (cGMP) • Inflammation • Intestinal permeability • Brain response to afferent pain signals • Altered intestinal flora • Bile acid malabsorption • Pancreatic insufficiency

Diseases and Disorders

Psychosocial factors • Life stress • Abuse history • Mood disorders (depression, anxiety) • Somatization • Personality (neuroticism) • Maladaptive coping • Social support • Education

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IBS • Symptoms • Behavior • HRQOL

FIG. 1  A biopsychosocial model of irritable bowel syndrome pathophysiology. Irritable bowel syndrome is thought to be a multifactorial disorder, deriving from a potential multitude of etiopathogenic factors, including environmental, psychological, and physiologic factors. This model highlights the complex, often bidirectional interplay of these factors in the experience of irritable bowel syndrome symptoms. cGMP, Cyclic guanosine monophosphate; 5-HT3, serotonin type 3; 5-HT4, serotonin type 4; FODMAPS, fermentable oligosaccharides, disaccharides, monosaccharides, and polyols; HRQOL, health-related quality of life; IBS, irritable bowel syndrome. (Modified from Sayuk GS, Gyawali CP: Irritable bowel syndrome: modern concepts and management options, Am J Med 128(8):817-827, 2015.)

• Fig. E2 illustrates the management of irritable bowel syndrome.

GENERAL Rx • The mainstay of treatment of IBS is a highfiber diet. Fiber is helpful for relief of constipation but not for relief of pain. Because symptoms are chronic, the use of laxatives should generally be avoided. • Soluble fiber (psyllium) is more effective in symptom relief than insoluble fiber (bran). Fiber supplementation with psyllium 1 tbsp bid or calcium polycarbophil (FiberCon) 2 tablets one to four times daily followed by 8 oz of water may be necessary in some patients. • Patients should be instructed that there might be some increased bloating on initiation of fiber supplementation, which should resolve within 2 to 3 wk. It is important that patients take these fiber products on a regular basis and not only as needed. Fiber is not effective in patients with diarrhea-predominant IBS and may worsen symptoms in these patients. • Patients who appear anxious can benefit from use of sedatives or selective serotonin reuptake inhibitors (SSRIs). Tricyclic antidepressants in low doses are also effective in some patients with diarrhea-predominant IBS.

• C-2 chloride channel activators: Lubiprostone (Amitiza) is a chloride channel activator that stimulates chloride-rich intestinal fluid secretion and accelerates small intestine and colonic transmit time. It may be effective in chronic constipation-predominant IBS unresponsive to conventional treatment. Usual dose is 8 to 24 mcg bid with food. Side effects include headache and nausea. • Linaclotide (Linzess) is a guanylate cyclaseC (GC-C) agonist FDA approved for IBS with constipation. It stimulates secretion of chloride and bicarbonate into the intestinal lumen, mainly through activation of the CFTR ion channel, resulting in increased intestinal fluid and accelerated transit. Usual dose for IBS is 290 mcg 30 min before eating. The most common adverse effects are diarrhea, abdominal pain, flatulence, and abdominal distension. • Eluxadoline (Viberzi) is a μ-opioid receptor agonist and Δ-opioid receptor antagonist FDA approved for IBS with diarrhea. It decreases muscle contractility, inhibits water and electrolyte secretion, and increases rectal sphincter tone. Usual dose is 100 mg PO bid taken with food. • Loperamide is effective for diarrhea. Alosetron, a serotonin type-3 receptor

antagonist previously withdrawn because of severe constipation and ischemic colitis, has been reintroduced with limited availability. It is indicated only for women with severe chronic diarrhea-predominant IBS unresponsive to conventional therapy and not caused by anatomic or metabolic abnormality. Starting dose is 1 mg qd. • Alterations in gut flora have been identified as potentially contributing to IBS (84% of IBS patients have an abnormal lactulose breath test, suggesting small-intestinal bacterial overgrowth). Rifaximin, a gut-selective antibiotic, has been used in recent trials to eradicate bacterial overgrowth (70% eradication rate). A dose of 400 mg tid for 10 days was reported effective in improving IBS symptoms up to 10 wk after discontinuation of therapy. Until additional evidence is available, use of rifaximin or other antibiotics in IBS should be reserved for patients with proven bacterial overgrowth. • A ntispasmodics-anticholinergics (e.g., dicyclomine, hyoscyamine) are often used, but efficacy data from clinical trials are inconclusive. • Probiotics: Bifidobacteria and some combinations of probiotics have shown some limited efficacy. Lactobacilli do not appear to be

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TABLE 2  Irritable Bowel Syndrome Treatment Strategy: A Way Forward 1. Evaluation a. Consider conditions that mimic IBS (e.g., celiac disease, microscopic colitis, bile acid diarrhea, pancreatic insufficiency, carbohydrate intolerances, medication side effects, postsurgical neoanatomy) b. Assess for the presence of alarm symptoms c. Evaluate for symptom triggers (e.g., stressors, diet) d. Explore presence of other functional GI (e.g., functional dyspepsia) and non-GI disorders (e.g., fibromyalgia), psychiatric comorbidity, and drug intolerances e. Understand previous IBS treatment experiences 2. Selection of treatment approach a. Predicated on symptom severity and dominant symptoms b. Symptom severity (intensity, bother, effects on quality of life) i. Mild symptoms, intermittent symptoms, low symptom burden: Symptomatic or peripheral therapy ii. Moderate symptoms: Centrally acting neuromodulators, especially if symptomatic therapy does not provide adequate benefit iii. Severe symptoms and those with comorbidities (non-GI functional disorders, psychiatric): Both centrally acting neuromodulators and peripheral therapy a. Concurrent affective disorders need to be managed. b. Other central therapies (cognitive and behavioral therapy, hypnosis, stress reduction) may need to be considered. c. Dominant symptoms (diarrhea, constipation, pain, other GI symptoms) i. Constipation predominant a. Laxatives, fiber b. Novel agents (linaclotide, lubiprostone) ii. Diarrhea predominant a. Antidiarrheals b. Alosetron c. Address dysbiosis (rifaximin, probiotics) d. Diet (low FODMAP) e. Bile binders (cholestyramine, colesevelam) f. Disaccharidases (lactase) iii. Pain predominant a. Antidepressants (TCAs and SNRIs preferred) b. Linaclotide when constipation present c. Avoid narcotics 3. Education and therapeutic alliance a. Inform patient about etiopathogenesis. b. Reaffirm legitimacy of diagnosis; allay concerns about organic disease. c. Provide information about support organizations (International Foundation for Functional Gastrointestinal Disorders). FODMAP, Fermentable oligosaccharides, disaccharides, monosaccharides, and polyols; GI, gastrointestinal; IBS, irritable bowel syndrome; SNRI, serotonin-norepinephrine reuptake inhibitor; TCA, tricyclic antidepressant.

effective for the treatment of IBS. Additional data showing efficacy is needed before probiotics can be endorsed for treatment of IBS. • Antidepressants: SSRIs are more effective than placebo for relief of global IBS symptoms.

DISPOSITION More than 60% of patients respond successfully to treatment over the initial 12 mo; however, IBS is a chronic, relapsing condition and requires prolonged therapy.

REFERRAL GI referral is recommended in patients with rectal bleeding, fever, nocturnal diarrhea, anemia, weight loss, or onset of symptoms >40 yr. Consultation is also necessary if specialized diagnostic procedures such as endoscopy are necessary.

PEARLS & CONSIDERATIONS COMMENTS • Patients should be educated regarding maintenance of a high-fiber diet and elimination of stressors, which can precipitate attacks of IBS. They should be reassured that their condition does not lead to cancer. • Recent drug efforts (alosetron, tegaserod) are aimed at serotonergic receptors in the gut because most of the serotonin in the body is found in the GI tract and is believed to be involved in the mediation of visceral sensation and motility. • Cognitive-behavioral therapy is effective in the treatment of patients with IBS and should be considered as part of the armamentarium against this disorder. • Some patients with IBS but without celiac disease show symptom improvement on a wheat-free diet. A 2- to 3-wk trial of wheat avoidance may be reasonable in patients with treatment-resistant IBS. SUGGESTED READINGS Available at ExpertConsult.com RELATED CONTENT Irritable Bowel Syndrome (Patient Information) AUTHOR: Fred F. Ferri, MD

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SUGGESTED READINGS Camiueri M: Peripheral mechanisms in irritable bowel syndrome, N Engl J Med 367:1626-1635, 2012. Carroccio A et al: Non-celiac wheat sensitivity diagnosed by double-blind placebo-controlled challenge: exploring a new clinical entity, Am J Gastroenterol 107:1898-1906, 2012. Chey WD et al: Irritable bowel syndrome: a clinical review, J Am Med Assoc 313(9):949-958, 2015. Dugum M et al: Managing irritable bowel syndrome: the low-FODMAP diet, Cleve Clin J Med 83:655-662, 2016. Ford AC et al: Irritable bowel syndrome, N Engl J Med 376:2666–2678, 2017. Lembo AJ et al: Eluxadoline for irritable bowel syndrome with diarrhea, N Engl J Med 374:242-253, 2016. Marteaus P: Probiotics in functional intestinal disorders and IBS: proof of action and dissecting the multiple mechanisms, Gut 59:285-286, 2010. Mearin F et al: Bowel disorders, Gastroenterology 150:1393-1407, 2016. Pimentel M et al: Rifaximin therapy for patients with irritable bowel syndrome without constipation, N Engl J Med 364:22-32, 2011. Rao VL et al: Pharmacologic management of irritable bowel syndrome, J Am Med Assoc 314:2684-2685, 2015. Sayuk GS, Gyawali CP: Irritable bowel syndrome: modern concepts and management options, Am J Med 128:817-827, 2015. Simrén M et al: Management of the multiple symptoms of irritable bowel syndrome, Lancet Gastroenterol Hepatol 2(2):112-122, 2017. Wilkins T et al: Diagnosis and management of IBS in adults, Am Fam Physician 86(5):419-426, 2012.

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Chronic or recurrent abdominal pain and erratic bowel disturbance Positive history for IBS: make a positive diagnosis Tests to make a non-IBS diagnosis CBC Routine biochemistry Celiac serology (tissue transglutaminase antibody, endomysial antibody) Stool for ova, parasites, and blood Colonoscopy Thyroid function Special tests (depend on symptom pattern)

Exclude: Colorectal cancer Inflammatory bowel disease Metabolic disease

Normal tests and symptoms persist

Mildly troubled

Reassurance Education Diet/fiber supplements Support

No further treatment Follow-up

Persistent specific complaints

Psychiatric component Difficult

Treat comorbid psychiatric disease, e.g., depression Antidepressants

Target drugs to specific complaints

Pain

Constipation

Anticholinergics Antidepressants (low dose initially) Pain clinic

Fiber/liquids/exercise Lubiprostone Linaclotide Probiotics Tegaserod Osmotic laxatives

Diarrhea

Rifamixin Eluxadoline Alosetron Loperamide Cholestyramine Tricyclic antidepressants

FIG. E2  Management of irritable bowel syndrome. cGMP, Cyclic guanosine monophosphate; FODMAP, fermentable oligosaccharides, disaccharides, monosaccharides, and polyols; GI, gastrointestinal; H2O, water; HRQOL, health-related quality of life. (Modified from Palmer KR, Penman ID: 22 Alimentary tract and pancreatic disease. In Colledge NR, Walker BR, Ralston SH: Davidson’s principles and practice of medicine, Philadelphia, 2010, Elsevier.)

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ALG   BASIC INFORMATION DEFINITION Ischemic colitis (IC) is tissue damage and inflammation of the large intestine due to a reduction in blood flow.

ICD-10CM CODES K51.50 Left-sided colitis without complications K51.51 Left-sided colitis with complications K51.511 Left-sided colitis with rectal bleeding K51.512 Left-sided colitis with intestinal obstruction K51.513 Left-sided colitis with fistula K51.514 Left-sided colitis with abscess K51.518 Left-sided colitis with other complication K51.519 Left-sided colitis with unspecified complications K52.3 Indeterminate colitis K55.0 K55.031 K55.032 K55.039 K55.9

Acute vascular disorders of intestine Focal (segmental) acute (reversible) ischemia of large intestine Diffuse acute (reversible) ischemia of large intestine Acute (reversible) ischemia of large intestine, extent unspecified Vascular disorder of intestine, unspecified

EPIDEMIOLOGY & DEMOGRAPHICS INCIDENCE: It is the most common type of intestinal ischemia with an annual incidence of 15.6 to 17.7 per 100,000. PEAK INCIDENCE: Unknown PREVALENCE: Unknown PREDOMINANT SEX AND AGE: • More common among older patients (60s to 70s) • Female predominance RISK FACTORS: • Older age (60s to 70s) • Atherosclerotic disease • Hemodialysis • Hypertension • Atrial fibrillation • Diabetes • Small vessel disease • Sickle cell disease • Infection (CMV, E. coli) • Aortic surgery, endovascular intervention, cardiopulmonary bypass surgery • Long-distance running, extreme exercise • Hypercoagulable state • Myocardial ischemia • Mechanical obstruction

PHYSICAL FINDINGS & CLINICAL PRESENTATION • Key historical points: 1.  Rapid-onset cramping and abdominal pain (classically thought to involve the left side more often, but newer literature suggests that no one region is affected predominantly). Pain secondary to large intestine ischemia is often not as severe as pain associated with small intestine ischemia 2. Urge to defecate may accompany developing abdominal pain 3. Hematochezia (usually within 24 hrs). More commonly associated with ischemic colitis of the large bowel compared with small bowel involvement • Physical exam findings suggestive of ischemic colitis: 1.  Abdominal exam may be nonspecific early on 2. May have peritoneal signs in severe illness or bowel perforation 3. Hypotension and tachycardia in severe cases 4. Guaiac positive stool ETIOLOGY GENERAL: • Caused by a reduction in blood flow, usually sudden, to a segment of the large intestine. The resulting blood flow is not enough to provide the oxygen and nutrients necessary for normal cellular metabolism. • Particularly affected are the watershed regions of the colon (Fig. E1), which have limited collateral circulation (splenic flexure and sigmoid colon). • Medical and surgical conditions associated with ischemic colitis are summarized in Box 1. SPECIFIC: • Nonocclusive disease: 1. Hypoperfusion: Cardiac failure, septic shock, hemorrhagic shock, hemodialysis 2. Iatrogenic: Drugs (especially constipation-inducing). Medications associated with ischemic colitis are summarized in Box 2 3. Colonic obstruction: Colon cancer, constipation, volvulus 4. Long-distance running • Occlusive disease: 1. Arterial: Thrombus/emboli, cholesterol emboli, small vessel disease (atherosclerosis, diabetes, vasculitis, rheumatoid arthritis, radiation, amyloidosis), trauma 2. Surgical: Aortic aneurysm repair, cardiac catheterization, cardiopulmonary bypass, colectomy, endoscopy, renal transplant 3. Venous: Mesenteric venous thrombosis, hypercoagulable state, sickle cell disease, pancreatitis, portal hypertension, lymphocytic phlebitis

DIAGNOSIS

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DIFFERENTIAL DIAGNOSIS • Infectious colitis (e.g., Clostridium difficile, Salmonella, Shigella) BOX 1  Medical and Surgical Conditions Associated with Ischemic Colitis Cardiovascular/Pulmonary Atherosclerosis* Atrial fibrillation Chronic obstructive pulmonary disease Hypertension Gastrointestinal Constipation Diarrhea Irritable bowel syndrome Low Flow State Septic shock Congestive heart failure Hemorrhagic shock Hypotension Surgery Abdominal surgery Aortic surgery Cardiovascular surgery Invasive Interventions Postendovascular abdominal manipulations (e.g., chemoembolization) Postcolonoscopy Metabolic/Rheumatoid Diabetes mellitus Dyslipidemia Rheumatoid arthritis Systemic lupus erythematosus Miscellaneous Hypercoagulable states† Sickle cell disease Long-distance running

Diseases and Disorders

SYNONYMS Intestinal ischemia Colonic ischemia IC

• Hypoalbuminemia • Pharmacologic • Shock

Ischemic Colitis

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*For example, ischemic heart disease, cerebrovascular disease, peripheral vascular disease. † Antiphospholipid syndrome, factor V Leiden deficiency, protein C and S deficiency. From Cameron JL, Cameron AM: Current surgical therapy, ed 12, Philadelphia, 2017, Elsevier.

BOX 2  Drugs Associated with Ischemic Colitis Constipation-inducing drugs (opioids and nonopioids) Immunomodulator drugs (antiTNFα, type 1 interferon-α, type 1 interferon-β) Chemotherapeutic drugs (e.g., Taxanes) Cocaine and methamphetamines Female hormones Oral contraceptive medications Antibiotics Pseudoephedrine Serotoninergic (e.g., Alosetron, Sumatriptan) Diuretics TNF, Tumor necrosis factor. From Cameron JL, Cameron AM: Current surgical therapy, ed 12, Philadelphia, 2017, Elsevier.

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• Inflammatory bowel disease, inflammatory bowel syndrome, celiac disease • Small bowel ischemia • Constipation • Diverticulitis • Bowel obstruction • Pancreatitis • Malignancy • Radiation enteritis

WORKUP The clinical presentation is often vague and can be variable from patient to patient. A high index of suspicion must be maintained in any patient presenting with abdominal pain and bloody stool. In addition to the physical exam, the following are key to confirming the diagnosis: • Lab studies • Computed tomography • Lower endoscopy LABORATORY TESTS • General: 1. CBC (may see leukocytosis) 2. Metabolic panel 3. Liver function panel • Specific markers: There are no specific laboratory tests for ischemic colitis. However, elevated levels of certain markers suggest inadequate global perfusion: 1. Lactate 2. Lactate dehydrogenase 3. CK 4. Amylase • Coagulation studies • Stool studies: Stool culture, ova and parasite, C. difficile toxin assay, tests for Salmonella, Shigella, Campylobacter, and E. coli IMAGING STUDIES • Abdominal CT with contrast: Although findings can be nonspecific, the value of CT is in distinguishing ischemic colitis from nonischemic causes of abdominal pain. It also can assess the degree of ischemia and gauge the need for surgical intervention. It may identify arterial emboli or venous obstruction. Specific findings suggestive of ischemic colitis include, but are not limited to, intestinal wall thickening, thumbprinting, pericolonic stranding, and peritoneal free fluid or free air. Pneumatosis (the presence of gas in the colonic wall), portal venous gas, and the presence of megacolon usually indicate severe disease favoring immediate surgical intervention. • Abdominal radiograph: X-rays are rarely helpful in diagnosing ischemic colitis. Findings may be subtle or absent unless transmural necrosis and perforation have occurred, causing pneumoperitoneum. • Lower endoscopy: This is the gold standard for confirming diagnosis of ischemic colitis. In the absence of peritoneal signs, colonoscopy is the test of choice to evaluate the degree of ischemia. If ischemia is suspected, lower endoscopy should be performed within the first 24 to 48 hrs. In most cases, visual inspection of the colonic wall using this

technique will confirm the diagnosis and dictate the need for conservative versus surgical management. However, endoscopy should not be performed in patients with acute peritonitis or evidence of irreversible ischemic damage on CT.

TREATMENT • Treatment depends on the severity of disease and the specific etiology of colonic ischemia. However, the mainstay of therapy consists of optimizing blood flow to ischemic regions of bowel and removing any potential exacerbating factors. Initial supportive care consists of aggressive IV crystalloid resuscitation, bowel rest, and broad-spectrum antibiotics with aerobic and anaerobic coverage. A treatment algorithm is illustrated in Fig. 2. • In mild cases where patients are hemodynamically stable and do not have signs of peritonitis, colonoscopy should be performed. Patients with nonviable bowel seen on endoscopy require immediate operative intervention. However, the remainder of patients should be managed medically with continued IV fluids, bowel rest, and broadspectrum antibiotics. Consider the use of a nasogastric tube in patients with abdominal distention or signs of ileus or bowel obstruction. Avoid vasoconstrictive medications as these can exacerbate colonic hypoperfusion. Monitor signs of adequate end organ perfusion (e.g., mental status, abdominal pain, urine output). Management of underlying causes (e.g., heart failure, vascular disease, sepsis) should be considered. • In severe cases not responding to supportive therapy, where patients are exhibiting acute peritonitis, sepsis, hypotension, or pain out of proportion to clinical exam, surgical abdominal exploration is warranted. Resection of gangrenous segments of bowel may be necessary. Colonoscopy should be avoided in these patients.

NONPHARMACOLOGIC THERAPY • Open or laparoscopic abdominal exploration to identify necrotic bowel. Box 3 summarizes indications for surgical intervention in patients with ischemic colitis • NG tube for bowel decompression if ileus is present ACUTE GENERAL Rx • Supportive care: 1. IV fluids 2. Bowel rest 3. Broad-spectrum antibiotics (aerobic and anaerobic coverage) • Anticoagulation (not indicated in nonocclusive ischemia but may be considered in proven arterial occlusion or mesenteric vein thrombosis) • Abdominal exploration: 1. Bowel prep should be given 2.  Bowel resection may be indicated in severe colitis

3. Repeat surgical exploration normally is performed within 12 to 24 hrs, especially after colonic resection, to assess the viability of colonic tissue and state of the anastomosis. Intraoperative infrared angiography based on IV injection of indo cyanine green (Fig. E3) can be used as an adjunct for decisions of whether to resect in determining margins and the integrity of intestinal anastomoses 4. Note that primary anastomosis after colonic resection is contraindicated in certain cases (e.g., presence of aortic or iliac grafts; or when tissue is too friable for stable anastomosis)

CHRONIC Rx • Avoid overly aggressive treatment. • Avoid dehydration. • Avoid extreme exercise.

hypertension

DISPOSITION • Most cases of acute ischemic colitis are nongangrenous and resolve completely with medical care in 1 to 2 days. However, the need for surgery in more severe cases portends a worse prognosis and is associated with increased morbidity and mortality. Any risk factors for ischemic colitis should be identified and mitigated as much as possible. REFERRAL Prompt general surgery consultation is indicated in patients with the following: • Hemodynamic instability and peritoneal signs on examination • CT showing signs of bowel infarction or perforation • Endoscopy showing nonviable bowel or peritoneal signs

PEARLS & CONSIDERATIONS COMMENTS Ischemic colitis typically occurs in older patients who have multiple comorbidities. A high index of suspicion should be maintained for patients with recent endovascular procedures. These patients require close outpatient follow-up and management by a primary care provider. PREVENTION Avoid overly aggressive hypertension treatment, dehydration, and extreme exercise. SUGGESTED READINGS Available at ExpertConsult.com RELATED CONTENT Mesenteric Venous Thrombosis (Related Key Topic) Acute Mesenteric Ischemia (Related Key Topic) AUTHORS: Paul White, MD, and Mark F. Brady, MD, MPH, MMSc

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Symptoms: Abdominal pain, tenesmus, bright red blood per rectum, diarrhea

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History: Comorbid conditions, surgical and recent procedural history, medications Physical exam & initial laboratory evaluation: Complete blood count, blood chemistry, arterial blood gases, serum lactate, coagulation studies

Initial treatment: Broad-spectrum antibiotics, hydration, analgesics

Localized tenderness

CT Oral and IV contrast

Diseases and Disorders

Peritonitis

I Surgery Consider resection, determine margins using visual inspection, indocyanine green, or fluorescein; anastomosis vs. Hartmann and diversion

Pneumoperitoneum pneumatosis, portal air

Segmental colon thickening, pericolonic inflammation

Apparent transmural necrosis

Endoscopy

Segmental edema, erythema and petechial hemorrhages, ulceration

Repeat endoscopy/CT

Continued symptoms

Observation, IV fluids, bowel rest, antibiotics

Late complications (e.g., stricture)

Resolution

FIG. 2  Treatment algorithm for ischemic colitis. CT, Computed tomography; IV, intravenous. (From Cameron JL, Cameron AM: Current surgical therapy, ed 12, Philadelphia, 2017, Elsevier.)

BOX 3  Indications for Surgical Intervention in Patients with Ischemic Colitis Acute Peritonitis Bowel perforation Bowel necrosis Fulminant colitis Massive hemorrhage Sepsis Chronic Intractable symptoms (abdominal pain, bloody diarrhea, etc.) lasting >2 weeks Recurrent sepsis Chronic colitis Ischemic stricture Malnutrition from protein-losing enteropathy From Cameron JL, Cameron AM: Current surgical therapy, ed 12, Philadelphia, 2017, Elsevier.

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SUGGESTED READINGS FitzGerald JF et al: Ischemic colitis, Clin Colon Rectal Surg 28:93-98, 2015. Washington C et  al: Management of ischemic colitis, Clin Colon Rectal Surg 25:228-235, 2012.

Superior mesenteric artery

Arch of Riolan

Middle colic artery

Marginal artery of Drummond Right colic artery

Ileocolic artery

Left colic

Inferior mesenteric artery

Sigmoidal arteries

Superior hemorrhoidal artery

FIG. E1  Arterial supply to the colon. Shaded areas depicting potential watershed regions. (From Cameron JL, Cameron AM: Current surgical therapy, ed 12, Philadelphia, 2017, Elsevier.)

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B FIG. E3  Indocyanine green-based infrared angiography. A, Colon before injection. B, Colon after injection: (short blue arrow) Ischemia of resection margin; (yellow arrow) normal perfusion of colon. (From Cameron JL, Cameron AM: Current surgical therapy, ed 12, Philadelphia, 2017, Elsevier.)

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Ischemic Hepatitis BASIC INFORMATION DEFINITION • A common form of vascular liver disease • Occurs when a severe systemic disturbance leads to decreased perfusion to the liver resulting in tissue hypoxia SYNONYMS Hypoxic hepatitis Shock liver Ischemic hepatopathy Hepatic necrosis ICD-10CM CODES K76.2 Central hemorrhagic necrosis of liver K75.89 Other specified inflammatory liver disease

EPIDEMIOLOGY & DEMOGRAPHICS • Occurs worldwide INCIDENCE: • Less than 1% on the inpatient medical wards • Incidence is higher (2.5%) in intensive care unit PEAK INCIDENCE: Highest in the cardiac care units PREVALENCE: • Recognized as most frequent cause of acute liver injury • 57% of patients with liver enzymes >1000 IU/L have ischemic hepatitis • Prevalence up to 10% in the intensive care setting PREDOMINANT AGE AND SEX: • Can occur in all ages • Most common in elderly GENETICS: No genetic predisposition RISK FACTORS: • Most common is cardiovascular disease • Chronic heart failure • Cirrhosis PHYSICAL FINDINGS & CLINICAL PRESENTATION • Altered mental status may be present due to decreased cerebral perfusion. • Other symptoms are often masked by the overall disease state. • Hepatic synthetic function is usually preserved in ischemic hepatitis. ETIOLOGY • Cardiac disease in the most common (Fig. E1) • This includes myocardial infarction, arrhythmias, cardiac tamponade, and cardiogenic shock • Majority of patients have markedly increased cardiac filling pressures • Respiratory failure and sepsis are the second and third most common • Hypovolemic shock from hemorrhage, dehydration, and heat stroke • Hypotension (only 1 in 2 patients have documented low blood pressures) • See Table 1 for a brief summary of the different causes of ischemic hepatitis

DIAGNOSIS DIFFERENTIAL DIAGNOSIS (TABLE 2) • Acute viral hepatitis • Autoimmune hepatitis • Drug-induced liver injury • Other toxins and medications (i.e., acetaminophen toxicity) WORKUP • Diagnosed by laboratory parameters and the clinical context of a hospitalized patient. • Workup is directed at identifying the predisposing cause. • Liver biopsy is not required. • Histology shows centrilobular (zone 3) necrosis with preservation of the hepatic architecture. • Necrosis can extend to the midzonal hepatocytes in the setting of prolonged ischemia. LABORATORY TESTS • Extremely elevated aminotransferase levels, often exceeding 200 times the upper limit of normal. • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) rapidly rise after the ischemic insult. • They peak within 1 to 3 days. • They usually return to normal within 7 to 10 days if the initial ischemic insult is resolved. • Lactate dehydrogenase (LDH) level is extremely elevated. • ALT/LDH ratio of less than 1.5 is suggestive. • Prothrombin time can be slightly prolonged. • The serum bilirubin can be mildly increased. • Serum bilirubin peaks after the aminotransferases peak. • Increased blood urea nitrogen and creatinine levels from acute tubular necrosis and renal dysfunction. IMAGING STUDIES Imaging is not required for the diagnosis.

TREATMENT NONPHARMACOLOGIC THERAPY Management is directed at treating the underlying illness causing the systemic disturbance. ACUTE GENERAL Rx • Hemodynamic resuscitation • Inotropic agents for cardiogenic shock • Intravenous fluid resuscitation with or without vasoconstrictors for septic or hypovolemic shock • Blood transfusions if hypovolemic shock from blood loss • These measures optimize hepatic perfusion and resolve tissue hypoxia • There is no role for N-acetylcysteine administration

TABLE 1  Causes of Ischemic Hepatitis Cardiovascular disease (most common): Cardiogenic shock Respiratory failure Sepsis/septic shock Hypovolemic shock: Hemorrhage, volume depletion Hypotension

TABLE 2  Common Differentials of Ischemic Hepatitis Acute viral hepatitis (e.g., hepatitis A, hepatitis B) Autoimmune hepatitis Toxins (e.g., herbal supplements) Medications (e.g., acetaminophen)

CHRONIC Rx • Ensure stability of underlying illness • No specific liver-directed therapy DISPOSITION • Most commonly a self-limited and benign condition if promptly managed. • Occasionally associated with significant mortality. • Prognosis is determined by the severity of the underlying illness. In-hospital mortality associated with ischemic hepatitis is roughly 50%. • Patients with underlying chronic heart failure or cirrhosis have worse outcomes. • Other poor prognostic factors include persistently elevated aminotransferase and multiorgan failure. REFERRAL • Referral to a hepatologist is not required once illness is resolved. • Referral is appropriate if patient has underlying cirrhosis.

PEARLS & CONSIDERATIONS COMMENTS • Have a high index of suspicion for this diagnosis in a hospitalized patient with severe systemic illness and significantly elevated AST and ALT. • Use ALT/LDH ratio to aid in the diagnosis. • Do not be alarmed if bilirubin continues to rise after AST and ALT peak. • Hypotension is often not documented or not present at all. • Patients with significantly elevated liver enzymes should be evaluated for occult heart failure. PREVENTION Ensure stability of comorbidities (e.g., cardiac disease) AUTHOR: Hiresh D. Trivedi, MD

These proofs may contain color figures. Those figures may print black and white in the final printed book if a color print product has not been planned. The color figures will appear in color in all electronic versions of this book.

Ischemic Hepatitis

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Cardiac failure

Forward failure

Backward failure

Reduce cardiac output

Venous engorgement

Reduced hepatic blood flow

Hepatic congestion

Reduced liver oxygen supply

Cellular hypoxia

Centrolobular necrosis

FIG. E1  The most common cause of hypoxic hepatitis is a combination of liver congestion due to chronic cardiac failure and an acute drop in cardiac output causing liver ischemia. (From Parrillo JE, Dellinger RP: Critical care medicine: Principles of diagnosis and management in the adult, ed 4, Philadelphia, 2014, Saunders.)

These proofs may contain color figures. Those figures may print black and white in the final printed book if a color print product has not been planned. The color figures will appear in color in all electronic versions of this book.

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Ischemic Optic Neuropathy BASIC INFORMATION DEFINITION Ischemic optic neuropathy (ION) is a general term for dysfunction of the optic nerve due to decreased blood supply and subsequent neuronal death. Subclassifications: • Arteritic anterior ischemic optic neuropathy (AAION) • Nonarteritic anterior ischemic optic neuropathy (NAION) • Posterior ischemic optic neuropathy (PION) SYNONYMS ION AAION NAION PION ICD-10CM CODE H47.01 Ischemic optic neuropathy

EPIDEMIOLOGY & DEMOGRAPHICS INCIDENCE: • 2.3 to 10 cases of anterior ischemic optic neuropathy per 100,000 per yr (15% AAION, 85% NAION).

A

• PION is much less common than anterior ischemic optic neuropathy (AION). PREDOMINANT AGE, RACE, AND SEX: • Age >50, though may occur at any age. • White women are at particular risk of AAION due to giant cell arteritis (GCA). • 95% of NAION patients are white. RISK FACTORS: • NAION: Diabetes mellitus, hypertension, episodic hypotension, obstructive sleep apnea, hypercholesterolemia. Emboli can be refractile yellow-white cholesterol (Hollenhorst) plaques (Fig. E1, A ), grayish elongated fibrinplatelet aggregates (Fig. E1, B ), or nonscintillating white calcific particles (Fig. E1, C ) • PION: Surgery (hemodilution, prolonged hypotension, orbital edema, and orbital compression), or factors associated with AAION and NAION

CLINICAL PRESENTATION • AAION: Sudden, unilateral, often painless vision loss. Will commonly have systemic symptoms of GCA including headache, jaw claudication, scalp tenderness, fever, and weight loss, but vision loss may be the only presenting sign/symptom • NAION: Sudden, unilateral, painless vision loss, often upon awakening • PION: Sudden, painless loss of vision that is either unilateral or bilateral. Typically bilateral

if following surgery or unilateral in its arteritic or nonarteritic form with symptoms similar to AAION and NAION, respectively

PHYSICAL FINDINGS • All types of ION may result in a relative afferent pupillary defect and/or dyschromatopsia in the affected eye. • AAION: Severe vision loss with visual acuity worse than 20/200 in a majority of patients. Fundoscopic view of the optic nerve head in the affected eye will show pallid edema (“chalky white” disc). • NAION: Blurring/cloudiness of vision with relatively preserved central visual acuity (>20/64 in 31% to 52% of patients). Fundoscopic view of the optic nerve head during the acute phase will show edema and surface capillary dilation with peripapillary splinter hemorrhages. The unaffected eye will likely reveal a small cup-to-disc ratio. • PION: Vision loss is worst in surgical PION, otherwise similar to AAION and NAION. Fundoscopic exam typically normal in acute setting, but may show pallor weeks later. ETIOLOGY • AAION: Sudden occlusion of the short posterior ciliary arteries that supply the optic nerve head as a result of vasculitis. The most common vasculitis is GCA, but others include

B

C FIG. E1  Retinal emboli. A, Hollenhorst plaque; B, fibrin-platelet emboli; C, calcific embolus at the disc. (From Bowling B: Kanski’s clinical ophthalmology: a systematic approach, ed 8, Edinburgh, 2016, Elsevier.)

Ischemic Optic Neuropathy 814.e3 eosinophilic granulomatosis with angiitis (previously Churg-Strauss syndrome), polyarteritis nodosa, or rheumatoid arthritis. • NAION: It is hypothesized that hypoxia of the optic nerve head results in slight edema of the axons of the optic nerve. As the edema increases, a compartment syndrome develops resulting in the occlusion of the short posterior ciliary arteries in the optic nerve head. • PION: Ischemia in the retrobulbar optic nerve due to hypoperfusion of the pial plexus. This may be secondary to either surgery or arteritic/nonarteritic causes as discussed previously.

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • Optic neuritis: Typically associated with painful vision loss and may be the presenting sign of multiple sclerosis or neuromyelitis optica • Toxic/nutritional optic neuropathy: Typically bilateral, symmetric, painless, and slowly progressive, although may be acute (such as with methanol or ethylene glycol poisoning) • Radiation-induced optic neuropathy: Typically develops within 3 yr of radiation to structures near the optic nerve. Progresses within weeks with no recovery of vision • Infectious optic neuropathy: Optic neuropathy can develop as a result of a number of infections including bacterial (B. henselae, M. tuberculosis), spirochetes (B. burgdorferi, T. pallidum), fungi (Cryptococcus sp., Aspergillus sp.), or viruses (cytomegalovirus, Epstein-Barr virus, or varicella-zoster virus in immunocompromised patients) • Compressive optic neuropathy (e.g., from tumor): Typically progressive vision loss but may present acutely WORKUP • Complete history focused on pertinent symptoms and risk factors. • Workup should focus on excluding GCA (headache, jaw claudication, scalp tenderness, fever), as treatment delay may result in permanent vision loss in both eyes.

• Careful examination of optic disc, look for “chalky white” pallor suggestive of AAION or edema and peripapillary hemorrhages suggestive of NAION. • The unaffected eye should also be examined and compared.

LABORATORY TESTS • Complete blood count with C-reactive protein (level above 2.45 mg/dl highly suggestive of GCA) and erythrocyte sedimentation rate • Tests to rule out infectious optic neuropathy as appropriate IMAGING STUDIES • Visual field testing: May detect any visual field defects associated with optic nerve injury (including altitudinal, arcuate, and central visual field defects). PION in particular is associated with central visual field defects. • Optical coherence tomography: May show swelling of the optic disc. • Fluorescein angiography: May show generalized choroidal filling delay (AAION) or delayed filling in the optic disc prelaminar layers (NAION). PION will show no abnormalities. WORKUP Temporal artery biopsy if high suspicion for GCA.

TREATMENT • AAION: Treatment should begin as soon as GCA is suspected. Corticosteroids are the mainstay of treatment. Recommendations include either oral prednisone (80-120 mg daily) or intravenous methylprednisolone (1 g daily) for 3 to 5 days followed by 1 to 2 mg/ kg/day oral prednisone for 4 to 6 weeks and tapered gradually to 10 to 15 mg/day and maintained for 12 or more months. • NAION: There is currently no effective treatment for NAION. Proposed treatments that have not been shown to be efficacious include corticosteroids, intravitreal anti-VEGF injections, aspirin, hyperbaric oxygen, and surgical decompression. • PION: Arteritic and nonarteritic forms of PION should be treated as for AAION, and there is

SUGGESTED READINGS Biousse V, Newman NJ: Ischemic optic neuropathies, N Engl J Med 372:24282436, 2015. Fontal MR et al: Ischemic optic neuropathy, Semin Neurol 27(3):221-232, 2007. Peeler C, Cestari DM: Non-arteritic anterior ischemic optic neuropathy (NAION): a review and update on animal models, Semin Ophthalmol 31(-2):99-106, 2016.

currently not an effective treatment for surgical PION.

DISPOSITION • AAION: If not treated, the second eye is similarly affected in 50% to 95% of patients. With treatment, contralateral eye involvement is generally prevented and some patients have slight improvement in affected eye. • NAION: Approximately 20% to 25% will spontaneously recover some vision, and the same amount may have some worsening. Although recurrent NAION in the same eye is not likely (3% to 8%), up to 30% to 40% of patients experience contralateral eye involvement in their lifetime. • PION: Arteritic/nonarteritic forms as mentioned previously, patients with surgical PION generally have little change following vision loss. REFERRAL Recommend referral to an ophthalmologist or neuroophthalmologist for evaluation and workup. Again, if GCA is suspected, begin treatment immediately.

PEARLS & CONSIDERATIONS • Ischemic optic neuropathy can be classified as either anterior or posterior, and may be due to arteritic, nonarteritic, or surgical causes. • Correct identification of the underlying etiology is key to preventing further vision loss, especially in patients with GCA. • Patients suspected of having GCA should be treated with corticosteroids immediately and undergo temporal artery biopsy within a week of starting corticosteroid treatment. AUTHORS: Paul D. Chamberlain, MD, and Joseph S. Kass, MD, JD, FAAN

ALG BASIC INFORMATION DEFINITION Jaundice is a yellowish discoloration of the sclera, skin, and mucous membranes caused by an excessive amount of bilirubin in the bloodstream. Clinically detectable jaundice in adults is a serum bilirubin of 2.5 to 3 mg/dl.

ICD-10CM CODE R17 Unspecified jaundice

EPIDEMIOLOGY & DEMOGRAPHICS The prevalent causes of jaundice by age and sex: • Young adulthood (for either sex): Viral hepatitis, Gilbert disease • Middle adulthood (for either sex): Druginduced hepatitis and cirrhosis • Middle-aged and older men: Alcoholic liver disease, pancreatic cancer, hepatoma, primary hemochromatosis • Women: Primary biliary cirrhosis, chronic active hepatitis, choledocholithiasis, carcinoma of the gallbladder PHYSICAL FINDINGS & CLINICAL PRESENTATION Presentation can vary from an incidental finding to acute and life threatening. History and physical examination give important clues to the underlying condition. Key history of present illness findings: • Duration of jaundice • Associated symptoms: Abdominal pain, fever, nausea, malaise, pruritus, chills, changes in urine and stool color, anorexia and/or weight loss Key social history/exposure findings: • Alcohol use, injection of illicit drugs, use of hepatotoxic medication or herbal products, blood transfusions, unprotected sex, ingestion of shellfish, travel, occupational exposure to toxins Key medical history findings: • Prior abdominal/biliary surgery, prior episodes of jaundice, prior diagnosis of hepatitis B or C, inflammatory bowel disease Key physical findings: • Vital sign abnormalities: Fever, hypotension, tachycardia • Signs of acute disease: Abdominal tenderness, splenomegaly, abdominal mass, encephalopathy, Murphy sign • Signs of chronic liver disease: Palmar erythema, spider angiomas, bruising, gynecomastia, testicular atrophy, ascites, weight loss, Kayser-Fleischer rings (Wilson), caput medusa, internal hemorrhoids, scleral icterus ETIOLOGY Disruption in any of the three phases of bilirubin metabolism can lead to jaundice:

• Prehepatic phase: An increase in heme degradation products from red blood cell catabolism, ineffective erythropoiesis, or breakdown of muscle myoglobin and cytochromes; leads to indirect (unconjugated) hyperbilirubinemia • Intrahepatic phase: Destruction of the hepatocytes or disruption of either of the two separate biochemical processes that conjugate bilirubin in the hepatocyte; may lead to indirect (unconjugated) or direct (conjugated) hyperbilirubinemia • Posthepatic phase: Blockage of the release of water-soluble bilirubin from the hepatobiliary system, preventing excretion into the stool or urine or recycling within the gut flora; leads to direct (conjugated) hyperbilirubinemia

DIAGNOSIS DIFFERENTIAL DIAGNOSIS Prehepatic causes: • Hemolytic processes (e.g., sickle cell disease, spherocytosis, thalassemia, G6PD, immune hemolysis, HUS), ineffective erythropoiesis (e.g., thalassemia, folate, severe iron deficiency), or large hematoma reabsorption Intrahepatic causes: • If unconjugated hyperbilirubinemia: Enzyme metabolism disorders (Gilbert disease, Crigler-Najjar syndrome), drugs that alter the enzymatic pathways such as rifampin, isoniazid, and probenecid • If conjugated hyperbilirubinemia: Intrahepatic cholestasis caused by: 1. Viruses: Hepatitis A, B, and C; EpsteinBarr, hemorrhagic viruses (yellow fever, Ebola) 2. Other infections: Bacteria (leptospirosis, MAI), parasites (schistosomiasis, malaria, amebiasis), fungal (Blastomyces, Histoplasma) 3. Alcohol: Alcoholic hepatitis, alcoholic cirrhosis 4. Autoimmune: Primary biliary cirrhosis, primary sclerosing cholangitis, autoimmune hepatitis 5. Hepatotoxic drug-induced: Acetaminophen (most common), penicillins (most commonly Augmentin), chlorpromazine, steroids (estrogenic or anabolic), NSAIDs, valproic acid, some herbals such as kava, ma huang, and off-market weight-loss supplements 6. Hereditary/metabolic: Sickle cell disease and other RBC dyscrasias, hemochromatosis, Wilson disease, Dubin-Johnson and Rotor syndromes, α-antitrypsin deficiency, glycogen storage disease, NASH (nonalcoholic steatohepatitis), porphyria, benign recurrent intrahepatic cholestasis 7. Systemic disease: Invading liver: Sarcoidosis, amyloidosis, hemochromatosis, tuberculosis, Mycobacterium avium intracellulare 8.  Other: Cirrhosis, sepsis, total parenteral nutrition, intrahepatic cholestasis of pregnancy, graft-versus-host disease, environmental toxins, benign postoperative state

Posthepatic causes: • Intrinsic or extrinsic obstruction of the biliary system: 1.  Blockage within hepatobiliary tree: Strictures, cholangiocarcinoma, gallbladder cancer, carcinoma of ampulla of Vater, infection (e.g., cytomegalovirus, Cryptosporidium in patients with AIDS, parasites), choledocholithiasis 2.  Blockage outside of hepatobiliary tree: Pancreatitis, pancreatic carcinoma, pancreatic pseudocyst, lymphoma • Pseudojaundice: Not related to bilirubin but rather resulting from excessive ingestion of foods containing beta carotene (e.g., carrots, melons, squash)

WORKUP • History, physical examination, and first-line lab tests can often clarify diagnosis. Fig. 1 describes a clinical approach to jaundice. • Table 1 summarizes the differential diagnosis of critical and emergent diagnoses in patients with jaundice. LABORATORY TESTS • First-line tests: 1. Serum total and direct bilirubin 2. Urinalysis 3. Liver function tests (AST, ALT, GGTP, alkaline phosphatase), CBC, liver synthetic function (albumin, PT, PTT), pancreatic function (amylase, lipase) • If serum total bilirubin and direct bilirubin are elevated and urine is positive for bilirubin, consider intrahepatic or posthepatic process. If serum total bilirubin is elevated but direct bilirubin is normal (unconjugated hyperbilirubinemia) and urine is negative for bilirubin, consider prehepatic or intrahepatic processes Additional tests if diagnosis unclear: • Screen for hepatitis A, B, and C; if still unclear, then consider following options based on H&P • Other viruses: EBV, CMV • Autoimmune disorders: Antimitochondrial antibody (elevated in primary biliary cirrhosis); anti-smooth muscle antibody, ANA (elevated in autoimmune hepatitis); antinuclear cytoplasmic antibody (elevated in primary sclerosing cholangitis) • Ceruloplasmin (elevated in Wilson disease) • Alpha-1 antitrypsin deficiency (elevated in cirrhosis and emphysema) • Ferritin, Fe saturation (elevated in hemochromatosis) • Blood smear (RBC dyscrasias) • Diagnosis of exclusion: Gilbert syndrome • Liver biopsy: Essential in diagnosis of chronic hepatitis. Can be used for diagnosis of liver masses but carries a substantial risk IMAGING STUDIES • A bdominal ultrasound: First-line study (Figs. E2 and E3) may be completed bedside, most sensitive for proximal biliary tract disease; presence of dilated ducts hints at an extrahepatic process.

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Jaundice in the Adult Patient

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Jaundice in the Adult Patient

ALG Patient with jaundice Stabilize serious signs and symptoms

History • Abdominal pain, fever, chills • Prior abdominal surgery • Older age Physical • High fever • RUQ abdominal tenderness • Palpable mass • Evidence of prior abd surgery

History • Viral prodrome • Alcohol/IVDU • H/O transfusion • Hepatotoxin exposure • Known hepatitis exposure • Pregnancy • Malignancy

History • Trauma • Recent transfusion • Hematopoietic disorder Physical • Hematoma • Evidence of trauma • Paucity of exam findings

Physical • Hepatomegaly • Ascites • Asterixis • Encephalopathy • Spider angiomata • Caput medusae • Gynecomastia • Testicular atrophy • Excoriations Laboratory evaluation

Direct bili >indirect bili •  AST/ALT • Alk phos •  Amylase

Indirect bili >direct bili Direct bili >indirect bili

• Normal LFT results • Abnormal hemogram

• AST/ALT • Mild Alk phos • Normal amylase: normal/ PT/PTTAlk phos

Suggests obstructive process

Suggests hematologic process

Suggests hepatocellular/cholestatic process (including fulminant hepatic failure) Reassess and treat signs and symptoms

Radiographic evaluation • Ultrasound or CT • Direct bile duct visualization • ERCP/surgical • GI and surgical consultations

• Observation • GI consultation • Remove toxins • Viral markers

• Type and crossmatch blood • Hematologic consultation

FIG. 1  Management of the patient with jaundice. Alk phos, Alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; bili, bilirubin; CT, computed tomography; ERCP, endoscopic retrograde cholangiopancreatography; GI, gastrointestinal; H/O, history of; IVDU, intravenous drug use; LFT, liver function test; PT, prothrombin time; PTT, partial thromboplastin time; RUQ, right upper quadrant. (From Marx AJ et al: Rosen’s emergency medicine: concepts and clinical practice, ed 7, Philadelphia, 2010, Elsevier.)

• Abdominal CT: Often necessary to elucidate more information on liver, pancreas, and distal biliary system. • Endoscopic retrograde cholangiopancreatography: Rarely necessary for diagnostics. Refer to GI consultant. • Percutaneous transhepatic cholangiography: Rarely necessary for diagnostics. Refer to GI or surgical consultant.

• M agnetic resonance cholangiopancreatography: Noninvasive visualization of bile and pancreatic ducts. Refer to GI consultant. • Endoscopic ultrasound: Used for characterization and, if needed, biopsy of any focal lesions found within biliary tree and/or pancreas. Refer to GI consultant.

TREATMENT NONPHARMACOLOGIC THERAPY Depends on underlying cause of the jaundice and clinical stability of the patient. Generally, obstructive causes require surgical treatment, while nonobstructive causes require medical treatment.

ALG

Jaundice in the Adult Patient

TABLE 1  Jaundice: Differential Diagnosis of Critical and Emergent Diagnoses Critical

Emergent

Nonemergent

Hepatic

Fulminant hepatic failure

Hepatitis of any cause with confusion, bleeding, or coagulopathy Wilson disease Primary biliary cirrhosis Autoimmune hepatitis Liver transplant rejection Infiltrative liver disease Drug induced (isoniazid, phenytoin, acetaminophen, ritonavir, halothane, sulfonamides) Toxin ingestion or exposure Bile duct obstruction (stone, inflammation, stricture, neoplasm) Sarcoidosis Amyloidosis Graft-versus-host disease Right-sided congestive heart failure Veno-occlusive disease

Hepatitis with normal mental status, normal vital signs, and no active bleeding

Hemolytic anemia Massive malignant infiltration Inborn error of metabolism Pancreatic head tumor Metastatic disease Hyperemesis gravidarum

Gilbert syndrome Physiologic neonatal jaundice

Toxin Virus Alcohol Ischemic insult Reye syndrome

Biliary

Cholangitis

Systemic

Sepsis Heatstroke

Cardiovascular

Obstructing AAA Budd-Chiari syndrome Severe congestive heart failure Transfusion reaction

Hematologic-oncologic

Reproductive

Preeclampsia or HELLP syndrome Acute fatty liver of pregnancy

Posttraumatic hematoma resorption Total parenteral nutrition

Cholestasis of pregnancy

AAA, Abdominal aortic aneurysm; HELLP, hemolysis, elevated liver enzymes, low platelets. From Marx JA et al: Rosen’s emergency medicine, ed 8, Philadelphia, 2014, Saunders.

ACUTE GENERAL Rx Acute, life-threatening illness (e.g., cholecystitis or ascending cholangitis) requires prompt diagnosis with basic labs and bedside diagnostics, with early surgical and GI consultation in conjunction. Suspicious medications should be stopped. Initiate medical management of symptoms with analgesia, IV fluids, correction of coagulopathies, and consideration of antibiotics. N-Acetylcysteine can be given for acetaminophen overdose. CHRONIC Rx Reversible causes must be ruled out first—suspicious medications and EtOH must be discontinued. Consider GI consult for management of many intrahepatic diseases, such as treatment of hepatitis B or C, Wilson disease with penicil-

lamine, hemochromatosis with phlebotomy, or for stent insertion with ERCP for posthepatic obstruction. Consider surgical consult for resection of pancreatic masses, cholecystectomy, etc. Symptomatic pruritus may be treated with cholestyramine for bilirubin binding or with antihistamines to decrease the itch reflex. Ursodiol may be used to treat primary biliary cirrhosis and for gallstone prevention/dissolution.

 EARLS & P CONSIDERATIONS COMMENTS • Heed the warning signs of unstable vital signs to diagnose life-threatening illness; early collaboration with surgical and gastroenterology

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colleagues is helpful in complex patient care scenarios. • Careful history and physical examination, basic labs, and prompt bedside imaging frequently lead to accurate diagnosis. • Very high serum bilirubin (>15 mg/dl) is most likely to be seen in cirrhosis. Watch for hepatorenal syndrome in these patients.

SUGGESTED READINGS Available at ExpertConsult.com RELATED CONTENT Jaundice (Patient Information) AUTHORS: Alla Goldburt, MD, and Paolo G. Pace, MASc, MD

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Jaundice in the Adult Patient SUGGESTED READINGS Nguyen KD et  al: Atypical causes of cholestasis, World J Gastroenterol 20(28):9418, 2014. Privette TW et al: Emergencies of liver, gallbladder, and pancreas, Emerg Med Clin North Am 29(2):293-317, 2011.

FIG. E2  Ultrasound showing a large calculus in the extrahepatic biliary tree. Dilated bile ducts can be seen to the left. (Courtesy Dr. M.C. Collins. Forbes A et al [eds]: Atlas of clinical gastroenterology, ed 3, St Louis, 2005, Mosby.)

dilated intrahepatic bile ducts

FIG. E3  Schematic representation of ultrasound abnormality seen in Fig. E2. (From Forbes A et al [eds]: Atlas of clinical gastroenterology, ed 3, St Louis, 2005, Mosby.)

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Junctional Rhythm BASIC INFORMATION DEFINITION Junctional rhythm is an abnormal cardiac rhythm originating in the His bundle or atrioventricular (AV) node. This diagnosis includes three distinct entities based on rate: 1. A junctional escape rhythm has a rate of 4060 bpm. 2. Accelerated junctional rhythm has a rate of 60-100 bpm. 3. Junctional ectopic tachycardia (JET) has a rate of >100 bpm. SYNONYMS Junctional escape rhythm Accelerated junctional rhythm Junctional ectopic tachycardia (JET) Nodal rhythm disorder Ectopic rhythm disorder Junctional premature depolarization ICD-10CM CODE I49.2  Junctional premature depolarization

EPIDEMIOLOGY & DEMOGRAPHICS INCIDENCE: Junctional rhythm occurs more commonly in children due to higher vagal tone (13% of 10- to 13-yr-old boys, 45% of 7- to 10-yr-old children, and 19% of infants have junctional rhythm during sleep).1 Endurance athletes have a 20% incidence of junctional rhythm, for a similar reason. PREVALENCE: Junctional tachycardia is a rare cause of supraventricular tachycardia. It is rare in the pediatric population and even less common in adults. On the contrary, junctional rhythm is common although the prevalence is not well defined. GENETICS: There is no known hereditary component. RISK FACTORS: Conduction system disease, heart block, digitalis intoxication, heart surgery, endocarditis PHYSICAL FINDINGS & CLINICAL PRESENTATION ESSENTIAL HISTORY: • Previous history of syncope, presyncope, lightheadedness. • Drugs, especially digoxin. Amount taken, time of ingestion. The digestion time is especially important because the serum digoxin level ideally should be measured at least 6 hours after ingestion to ensure accuracy. Obtain a thorough medication history to determine if any recent additions or dosing changes were made. SYMPTOMS: • Lightheadedness • Syncope • Palpitations • Symptoms associated with digitalis intoxication: Gastrointestinal symptoms such as 1Drago

F et  al: Neonatal and pediatric arrhythmias: clinical and electrocardiographic aspects, Card Electrophysiol Clin 10(2):397-412, 2018.

anorexia, nausea, vomiting, and abdominal pain. Neurologic manifestation such as lethargy, fatigue, delirium, confusion, weakness. Visual changes: Alteration in color vision, diplopia, photophobia, decreased visual acuity PHYSICAL EXAMINATION: • Vital signs • Look for evidence of hypoperfusion and end organ dysfunction • Cannon A-waves on examination of the jugular pulse

ETIOLOGY Junctional tachycardia can occur as a primary arrhythmia (usually in children-JET), secondary to digitalis intoxication or catecholamine intoxication, or in the setting of injury to the His bundle (e.g., after valve surgery, abscess, sarcoidosis, myocarditis, ischemia, etc.).

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • AVNRT (atrioventricular nodal reentrant tachycardia) • AVRT (atrioventricular reentrant tachycardia) • Accelerated idioventricular rhythm–in the case of junctional rhythm with aberrant conduction • Fig. 1 illustrates arrhythmias originating in the atrioventricular node WORKUP • Vital signs • 12-lead ECG (Figs. 2 and 3). The rhythm is almost perfectly regular and the QRS complex is generally narrow and similar to the complex seen during sinus rhythm. Retrograde P waves with a very short interval from QRS to P wave can be seen • History of cardiac surgery, fevers, drug ingestion

LABORATORY TESTS • Serum digoxin concentration • Serum potassium concentration • Creatinine and blood urea nitrogen (BUN) to assess renal function • Troponin IMAGING STUDIES Echocardiogram

TREATMENT Junctional tachycardia may be a marker for a serious underlying condition such as digitalis toxicity, postcardiac surgery, endocarditis, hypokalemia, or myocardial ischemia. Underlying conditions should be sought and corrected accordingly.

NONPHARMACOLOGIC THERAPY • Junctional escape rhythm in the setting of sinus arrest or complete heart block without reversible cause necessitates permanent pacemaker implantation. • Junctional ectopic tachycardia can be treated with antiarrhythmics or radiofrequency ablation. ELECTROPHYSIOLOGY STUDY: The origin of this tachycardia is within the His bundle or AV node, and it can be diagnosed definitively by intracardiac recordings. Junctional rhythm most frequently takes the form of escape rhythms in the presence of sinus node dysfunction or AV nodal block, which can be diagnosed on electrophysiology (EP) study. These escape rhythms usually have a QRS morphology identical to that seen during sinus rhythm. In such cases, there is no P wave before the QRS complexes. The P waves can occur simultaneously with the QRS complexes; more commonly, they are retrograde. When the junctional rhythm is faster than 100 beats/min, it is called junctional tachycardia. RR

2XRR

Nodal Premature Beat

P′

Sinus Pause and Nodal Escape Beat

Nodal or Junctional Rhythm P′

P′

P′

P′

Nodal Tachycardia

FIG. 1  Arrhythmias originating in the atrioventricular node. (From Park MK: Park’s pediatric cardiology for practitioners, ed 6, Philadelphia, 2014, Elsevier.)

Junctional Rhythm

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FIG. 2  Electrocardiogram of a patient with junctional rhythm and complete heart block. Note the narrow QRS complex and dissociated P waves. aVF, Augmented vector foot; aVL, augmented vector left; aVR, augmented vector right.

I

aVR

V1

V4

II

aVL

V2

V5

III

aVF

V3

V6

FIG. 3  Junctional rhythm with retrograde P waves that are negative in the inferior leads. aVF, Augmented vector foot; aVL, augmented vector left; aVR, augmented vector right. (From Parrillo JE, Dellinger RP: Critical care medicine: principles of diagnosis and management in the adult, ed 4, Philadelphia, 2014, Elsevier.)

ACUTE GENERAL Rx The mainstay of managing nonparoxysmal junctional tachycardia is to correct the underlying abnormality. Withholding digitalis when junctional tachycardia is the only clinical manifestation of toxicity is usually adequate. If, however, ventricular arrhythmias or high-grade heart block are observed, then treatment with digitalis-binding agents may be indicated. COMPLEMENTARY & ALTERNATIVE MEDICINE N/A DISPOSITION Admit to cardiac telemetry if symptomatic. Consider specialty referral to cardiac electrophysiology.

REFERRAL Refer to cardiologist.

PEARLS & CONSIDERATIONS COMMENTS • Junctional rhythm often is observed in patients with AV dissociation, which can lead to atrial contraction against closed atrioventricular valves, resulting in cannon A waves. This wave will cause pulsation in the neck and abdomen, headache, cough, jaw pain and possible hypotension. • The presence of a perfectly regular rhythm in a patient with atrial fibrillation often indicates junctional rhythm with complete heart block.

PREVENTION N/A SUGGESTED READING Available at ExpertConsult.com RELATED CONTENT Digoxin Overdose (Related Key Topic) Sick Sinus Syndrome (Related Key Topic) Heart Block, Complete (Related Key Topic) Heart Block, Second-Degree (Related Key Topic) AUTHOR: John Wylie, MD, FACC

Junctional Rhythm SUGGESTED READING 2015 ACC/AHA/HRS guideline for the management of adult patients with supraventricular tachycardia, 2016 2015 ACC/AHA/HRS guideline for the management of adult patients with supraventricular tachycardia: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society, J Amer Col Card 13:e27-e115, 2016.

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Juvenile Idiopathic Arthritis BASIC INFORMATION DEFINITION Juvenile idiopathic arthritis (JIA), previously referred to as juvenile rheumatoid arthritis (JRA), is a diverse spectrum of chronic arthritides, involving ≥1 joints for ≥6 wk in a patient ≤16 yr of age. Other causes of arthritis must be excluded. SYNONYMS JIA JRA Juvenile rheumatoid arthritis (JRA) Still disease (specifically systemic JIA) ICD-10CM CODES M08.00 Unspecified juvenile rheumatoid arthritis of unspecified site M08.09 Unspecified juvenile rheumatoid arthritis, multiple sites M08.20 Juvenile rheumatoid arthritis with systemic onset, unspecified site M08.29 Juvenile rheumatoid arthritis with systemic onset, multiple sites M08.40 Pauciarticular juvenile rheumatoid arthritis, unspecified site

EPIDEMIOLOGY & DEMOGRAPHICS PREVALENCE: 1 per 1000 children in the U.S.; more common in children of European ancestry

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PHYSICAL FINDINGS & CLINICAL PRESENTATION • JIA is subdivided into seven categories based on the International League of Associations for Rheumatology (ILAR) classification criteria (summarized in Table 1). Characteristics of the various categories of JIA are summarized in Table 2. 1. Systemic onset JIA (sJIA) (4% to 17%) a. Arthritis in ≥1 joints with or preceded by fever (Fig. E1) of at least 2-wk duration that is quotidian (once daily) for at least 3 days and associated with at least one of the following: (1) evanescent erythematous rash (Fig. E2); (2) generalized lymphadenopathy; (3) hepatomegaly, splenomegaly, or both; and (4) serositis. • Oligoarticular JIA (Fig. E3) (27% to 56%) 1. Arthritis in 4 joints after 6 mo. • Polyarthritis, rheumatoid factor (RF) negative (11% to 28%) 1. Arthritis in >5 joints during first 6 mo of the disease with negative RF. • Polyarthritis, RF positive (2% to 7%) 1. Arthritis involves ≥5 joints during first 6 mo of the disease with positive RF on >2 tests run 3 mo apart. 2.  Anticyclic citrullinated (CCP) antibodies may also be present. 3. Most similar to adult rheumatoid arthritis; most likely to progress.

• Psoriatic arthritis (2% to 11%) 1. Psoriasis and arthritis or psoriasis and ≥2 of the following: a. Dactylitis, nail pitting, onycholysis, and psoriasis in a first-degree relative. • Enthesitis-related arthritis (3% to 11%) 1. Arthritis or enthesitis and ≥2 of the following: a. Sacroiliac tenderness, positive HLAB27, male age >6 yr, acute anterior uveitis, or first-degree relative with HLA-B27-associated disease. • Undifferentiated arthritis (11% to 21%) 1. Fulfills criteria in ≥2 categories above, or none of them

ETIOLOGY Genetically susceptible individuals may develop an inappropriate immune response toward a self-antigen after exposure to an environmental trigger. Variants in HLA, PTPN22, and STAT4 loci may be associated with disease.

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • Infection: Viral (parvovirus, toxic synovitis) or bacterial (Lyme, osteomyelitis, septic joints) • Inflammation: Lupus, serum sickness, inflammatory bowel disease • Reactive: Poststreptococcal, rheumatic fever • Malignancy: Leukemia, bone tumors • Table 3 summarizes conditions with arthralgia or arthritis that might be confused with JIA

TABLE 1  Overview of the Main Features of the Subtypes of Juvenile Idiopathic Arthritis ILAR Subtype

Peak Age of Female:Male; Onset (yr) % of All JIA

Arthritis Pattern

Extraarticular Features

Systemic arthritis

2-4

1:1; ∼10% of JIA cases

Polyarticular, often knees, wrists, and ankles; also fingers, neck, and hips

Daily fever; evanescent rash; pericarditis; pleuritis

Oligoarthritis

>6

4:1; 50%-60% of JIA Knees ++; ankles, fingers + Uveitis in ∼30% (but ethnic variation)

Polyarthritis, RF negative

6-7

3:1; 30% of JIA cases

Symmetric or asymmetric; small and large joints; cervical spine; TMJ

Polyarthritis, RF positive

9-12

9:1; >10% of JIA cases

Aggressive symmetric poly- Rheumatoid nodules in arthritis 10%; low-grade fever

Psoriatic arthritis

7-10

2:1; >10% of JIA cases

Asymmetric arthritis of small Uveitis in 10%; or medium sized joints psoriasis in 50%

Enthesitis-related arthritis

9-12

1:7; 10% of JIA cases

Predominantly lower limb joints affected; sometimes axial skeleton (but less than adult AS)

Uveitis in ∼10%

Acute anterior uveitis; association with reactive arthritis and IBD

Investigations

Notes on Therapy

Anemia; WBC↑↑; ESR↑↑; CRP↑↑; ferritin;↑ platelets↑↑ (normal or ↑ in MAS)

Less responsive to standard treatment with MTX and anti-TNF agents; consider IL-1Ra in resistant cases NSAIDs and intraarticular steroids; occasionally require MTX

ANA positive in 60%; other tests usually normal; may have mildly ↑ ESR/CRP ANA positive in 40%; RF negative; ESR ↑ or; ↑↑ CRP↑/normal; mild anemia RF positive; ESR ↑↑; CRP ↑/normal; mild anemia

Standard therapy with MTX and NSAIDs, then if nonresponsive, anti-TNF agents or other biologics Long-term remission unlikely; early aggressive therapy is warranted ANA positive in NSAIDs and intraarticular 50%; ESR ↑; CRP ↑/ steroids; second-line normal; mild anemia agents less commonly 80% HLA-B27 NSAIDs and intraarticular steroids; consider sulfasalazine as alternative to MTX

ANA, Antinuclear antibody; AS, ankylosing spondylitis; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; IBD, inflammatory bowel disease; ILAR, International League of Associations for Rheumatology; IL-1Ra, interleukin-1 receptor antagonist; JIA, juvenile idiopathic arthritis; MAS, macrophage activation syndrome; MTX, methotrexate; NSAID, nonsteroidal antiinflammatory drug; RF, rheumatoid factor; TMJ, temporomandibular joint; TNF, tumor necrosis factor; WBC, white blood cell count. From Firestein G et al: Kelley’s textbook of rheumatology, ed 9, Philadelphia, 2013, WB Saunders.

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Juvenile Idiopathic Arthritis

TABLE 2  Characteristics of the Various Categories of Juvenile Idiopathic Arthritis Age at Onset

Affected Joints

Systemic Features

Major Complications

Oligoarticular persistent Oligoarticular extended Polyarticular RF negative Polyarticular RF positive Systemic

Early childhood

Large joints, asymmetric (knee, ankle, wrist, elbow, temporomandibular, cervical spine) Same as above, but more than four joints involved after the first 6 mo of disease Any, often symmetric, often small joints

No

Any, usually symmetric and involving small joints Any (not necessarily at disease onset)

Malaise (subfebrile)

Psoriatic

Late childhood

Enthesitis related

Late childhood

Chronic uveitis Local growth disturbances Chronic uveitis Local growth disturbances Chronic uveitis Local growth disturbances Local growth disturbances and articular damage Acute: Macrophage activation syndrome Chronic: General growth disturbance, amyloidosis Psoriasis Local growth disturbances Acute symptomatic uveitis

Early childhood Throughout childhood Teenage years Throughout childhood

Spine, lower extremities, distal interphalangeal joints, dactylitis Spine, sacroiliac, lower extremities, thoracic cage joints

No Malaise (subfebrile)

High fever, rash, polyserositis, marked acute-phase response

Inflammatory bowel disease

RF, Rheumatoid factor. From Hochberg MC: Rheumatology, ed 7, Philadelphia, 2019, Elsevier.

TABLE 3  Conditions with Arthralgia or Arthritis that Might Be Confused with Juvenile Idiopathic Arthritis Type of Condition

Examples

Infections

Bacterial arthritis and osteomyelitis Borreliosis (Lyme disease) Viral and mycoplasmal arthritis Tuberculosis Rheumatic fever Poststreptococcal arthritis Postenteritis and other reactive arthritis (Salmonella, Campylobacter, Chlamydia) Hypermobility and Ehlers-Danlos syndrome Growing pains, trauma, patellofemoral and other overuse syndromes Osgood-Schlatter disease and other juvenile osteochondroses Legg-Calvé-Perthes disease Slipped capital femoral epiphysis Foreign body synovitis Other congenital and genetic disorders of supportive tissue Sickle cell anemia Hemophilia von Willebrand disease Juvenile systemic lupus erythematosus Juvenile dermatomyositis Mixed connective tissue disease Scleroderma Vasculitis (e.g., Henoch-Schönlein purpura, Kawasaki disease, Behçet disease) Cryopyrin-associated periodic syndrome Familial Mediterranean fever Other monogenic diseases (e.g., mevalonate kinase deficiency [hyperimmunoglobulinemia D], Blau syndrome, tumor necrosis factor receptor–associated periodic syndrome) Chronic recurrent multifocal osteomyelitis Periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA syndrome) Leukemia Neuroblastoma Localized bone tumors Complex regional pain syndrome Pain amplification syndromes and fibromyalgia Nonspecific musculoskeletal pain Primary immunodeficiencies Sarcoidosis

Postinfectious conditions

Noninflammatory conditions

Hematologic disorders

Systemic inflammatory disorders

Autoinflammatory disorders

Malignancies

Pain

Miscellaneous conditions

From Hochberg MC: Rheumatology, ed 7, Philadelphia, 2019, Elsevier.

J

Diseases and Disorders

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Juvenile Idiopathic Arthritis

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FIG. 4  Juvenile idiopathic arthritis (JIA). Oligoarticular-onset JIA in an 8-year-old. Epiphyseal destruction and undergrowth of the third metacarpophalangeal joint of the left hand are seen, as well as overgrowth of the carpal bones of the right wrist compared with the left wrist. Also note the widened appearance of the third phalanges caused by periosteal new bone formation. (From Hochberg MC et al: Rheumatology, ed 5, St Louis, 2011, Mosby.)

LABORATORY TESTS • No single diagnostic test. Must rule out other causes of arthritis • Elevated sedimentation rate and C-reactive protein; high ferritin • Mild anemia, leukocytosis (WBC can be very high) • Rheumatoid factor • Antinuclear antibodies: Elevation associated with ocular complications • Pancytopenia, a consumptive coagulopathy, elevated ferritin, and elevated liver enzymes are concerning for macrophage activation syndrome (MAS) in sJIA IMAGING STUDIES • Radiographs show soft tissue swelling and periarticular osteopenia early in the disease (Fig. 4). • Joint destruction (Fig. 5) is less frequent, but bony erosion and cyst formation may be present.

TREATMENT NONPHARMACOLOGIC THERAPY Collaboration among the patient’s pediatrician, rheumatologist, orthopedist, and physical thera-

FIG. 5  Severe hip disease in a 13-year-old boy with active, systemic-onset juvenile idiopathic arthritis. Radiograph shows destruction of the femoral head and acetabula, joint space narrowing, and subluxation of left hip. The patient had received corticosteroids systemically for 9 years. (From Kliegman RM et al: Nelson textbook of pediatrics, ed 19, Philadelphia, 2011, WB Saunders.)

pist, along with education regarding weight management, is essential.

CHRONIC GENERAL RX • NSAIDs: Used as monotherapy or in conjunction with intraarticular steroids • D MARDs: Methotrexate, leflunomide, sulfasalazine 1. Required by two thirds of children 2. Axial involvement is less responsive to methotrexate • Biologics: Improve morbidity associated with JIA. Individual subtypes show different responses to therapy. 1. Tumor necrosis factor antagonists such as etanercept and adalimumab 2. T-cell modulator, abatacept 3.  IL-1 (anakinra) and IL-6 antagonists (tocilizumab) useful in sJIA Meta-analysis of randomized controlled trials did not show statistically significant differences in the efficacy or safety profile of these agents. • Systemic corticosteroids should be limited when possible. • Major medications and indications for treatment of JIA are summarized in Table 4. Fig. 6 illustrates an algorithm for medical treatment of oligoarticular-onset JIA. Treatment of

DISPOSITION • More than 50% continue to have active disease into adulthood. • Patients with persistent oligoarticular disease are most likely to achieve remission, while those who are RF positive are least likely to achieve remission. • Macrophage activation syndrome is a lifethreatening complication of sJIA. • Asymmetric joint involvement can lead to growth failure and limb length discrepancies. REFERRAL • Early rheumatology consultation • Ophthalmology consultation at diagnosis and at least annually • Children 1 cm in diameter. Intralesional injection of interferon alfa2b has also been reported as effective and well tolerated. • Other local therapies used include laser therapy, cryotherapy, photodynamic therapy, and topical alitretinoin gel. • Indications for systemic chemotherapy include widespread skin involvement, extensive oral KS, rapidly progressive disease, symptomatic visceral disease, and disease flare. • Liposomal anthracyclines and paclitaxel are FDA-approved as first-line and second-line monotherapy for advanced KS. Interferon-α has been used with responses dependent upon the underlying immune status of the patient; the best responses are seen in patients with CD4 counts >400/μL.

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Kaposi Sarcoma

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• Current trials have shown encouraging initial responses in patients with relapsed KS with the use of thalidomide and immune checkpoint inhibitor therapy. • Sirolimus is effective in inhibiting the progression of dermal KS in kidney transplant recipients.

PEARLS & CONSIDERATIONS

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RELATED CONTENT Kaposi Sarcoma (Patient Information) Acquired Immunodeficiency Syndrome (Related Key Topic) AUTHOR: Ritesh Rathore, MD

COMMENTS • Immunosuppression-associated KS usually regresses with the cessation, reduction, or

A

B

C

E

D

FIG. E1  Kaposi sarcoma: epidemic human immunodeficiency virus associated. A and B, Plaque lesions. C, Violaceous lesion affecting the lateral lower eyelid. D, Confluent plaque on the hard palate. E, Nodular lesion on the gingiva and nose. (Swartz MH: Textbook of physical diagnosis, history and examination, ed 7, Philadelphia, 2014, WB Saunders.)

Kaposi Sarcoma

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B

A

C

E

D

FIG. E2  Classic Kaposi sarcoma with involvement of the lower extremities. Violaceous patches become plaques (A, B) and may develop a nodular component (C, E) or verrucous appearance (D, E). (B, Courtesy Frank Samarin, MD. C, Courtesy Kalman Watsky, MD.) (From Callen JP et al: Dermatological signs of systemic disease, ed 5, Philadelphia, 2017, Elsevier.)

Kaposi Sarcoma

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Histologic confirmation of KS

H and P (including oral cavity and entire skin) Stool for occult blood CXR CD4 count HIV viral load

Good risk (T0)

Poor risk (T1) Rapid progressive mucocutaneous disease

Start cART

cART plus: Pegylated liposomal doxorubicin, or Liposomal daunorubicin

No progression

Local progression

Continue cART

Intralesional chemotherapy (vinblastine, vincristine, bleomycin) Radiotherapy Topical retinoids Cryotherapy Photocoagulation

Rapid/systemic progression

Paclitaxel

Oral etoposide Clinical trials

FIG. E3  Algorithms for management of AIDS-associated Kaposi sarcoma (KS). cART, Combination antiretroviral therapy; CXR, chest radiograph. (Niederhuber JE: Abeloff’s clinical oncology, ed 6, Philadelphia, 2020, Elsevier.)

SUGGESTED READINGS Antman K, Chang Y: Kaposi's sarcoma, N Engl J Med 342(14):1027-1038, 2000. Dalla Pria A et al: Recent advances in HIV-associated Kaposi sarcoma, F1000Res 8(F1000 Faculty Rev):970, 2019. Dittmer DP et al: Kaposi sarcoma-associated herpesvirus: immunobiology, oncogenesis, and therapy, J Clin Invest 126(9):3165-3175, 2016. Hoffmann C, Sabranski M, Esser S: HIV-associated Kaposi's sarcoma, Oncol Res Treat 40(3):94–98, 2017. Radu O et al: Kaposi sarcoma, Arch Pathol Lab Med 137(2):289-294, 2013.

Kawasaki Disease BASIC INFORMATION DEFINITION Kawasaki disease (KD) is an acute, febrile illness of unknown etiology that predominantly affects children younger than 5 yr old. It is the most common cause of acquired heart disease in children in developed countries. The pathology demonstrates a vasculitis of small- and medium-size blood vessels, with a predilection for the coronary arteries, which can result in coronary artery aneurysms. It is usually a selflimiting condition lasting an average of 12 days if not treated. Box E1 summarizes diagnostic criteria for classic or typical Kawasaki disease. SYNONYMS Kawasaki syndrome Mucocutaneous lymph node syndrome Infantile polyarteritis KD ICD-10CM CODE M30.3 Mucocutaneous lymph node syndrome [Kawasaki]

EPIDEMIOLOGY & DEMOGRAPHICS • KD is the leading cause of acquired heart disease in children in developed countries, including the U.S. and Japan. Rheumatic disease is still more common in underdeveloped countries. • Commonly occurs in children 104.0 °F (40 °C). If untreated, it lasts for an average of 12 days. • The rash of KD can be maculopapular, diffuse erythroderma, or erythema multiforme-like; however, vesicles, bullae, purpura, and petechiae are never observed. • The pericardium, myocardium, endocardium, valves, and coronary arteries may be inflamed during acute illness. Cardiac abnormalities in Kawasaki disease are summarized in Box E2. • Valvular dysfunction occurs in about 25% of patients regardless of coronary artery involvement and most often involves the mitral valve. • Approximately 5% of children with KD in the U.S. have cardiovascular collapse and shock at clinical presentation. Often, a diagnosis of bacterial sepsis is suspected at the outset, frequently with negative cultures and persistent fevers, in which case the diagnosis of KD should be suspected. • Coronary artery aneurysms can develop in as many as 25% of untreated children between 1 to 4 weeks of illness. This subset of patients can develop myocardial infarction (MI) and congestive heart failure over time, which may lead to death. • New aneurysms seldom form after 6 weeks. Half of the aneurysms show angiographic regression in 1 to 2 yr. • Coronary z-scores are the preferred method for describing internal diameter of the coronary artery normalized by body surface area and should be used to describe the left anterior descending artery and right coronary arteries over time. • Morbidity and mortality rates are highest if the aneurysm has both a z-score ≥10 and an absolute dimension ≥8 mm (“giant aneurysms”). • Children with KD who are 6 yr are more likely to develop the cardiac sequelae and are least likely to respond to treatment.

FIG. E1  Cheilitis and oral mucosal involvement observed in a child with Kawasaki disease. (Courtesy Joseph F. Merola. From Callen JP et al: Dermatological signs of systemic disease, ed 5, Philadelphia, 2017, Elsevier.)

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Kawasaki Disease

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BOX E3  Associated Noncardiac Features of Kawasaki Disease

FIG. E2  Polymorphous, exanthematous eruption seen in a patient with Kawasaki disease. (Courtesy Joseph F. Merola. From Callen JP et  al: Dermatological signs of systemic disease, ed 5, Philadelphia, 2017, Elsevier.)

BOX E2  Cardiac Abnormalities in Kawasaki Disease Acute Stage • Pericardial effusion • Decreased myocardial function • Mitral regurgitation • Enlargement (ectasia) of coronary arteries • Arrhythmia (rare) Subacute Stage • Coronary aneurysms, irregularity, ectasia • Significant mitral or aortic regurgitation, or both (rare) • Coronary aneurysm rupture (very rare) • Myocardial infarction (rare) Convalescent Stage • Persistent coronary aneurysms • Regressed coronary aneurysms (residual fibrosis) • Coronary artery stenosis • Coronary aneurysm rupture (very rare) • Myocardial infarction (rare) From Cherry JD et al: Feigin and Cherry’s pediatric infectious diseases, ed 8, Philadelphia, 2019, Elsevier.

• Cervical lymphadenopathy is the most commonly absent physical manifestation in atypical KD, followed by exanthem and then extremity changes. • Oral mucosal changes are the most common manifestations of KD, affecting approximately 90% of cases (either typical or atypical). • Sensitivity to light, uveitis, as well as nonexudative conjunctivitis may develop.

Musculoskeletal System • Arthritis or arthralgia Central Nervous System • Aseptic meningitis • Facial nerve palsy • Marked irritability • Sensorineural hearing loss Gastrointestinal System • Hydrops of gallbladder • Abdominal pain, diarrhea • Hepatic dysfunction, obstructive jaundice • Pancreatitis Genitourinary System • Urethritis, meatitis Respiratory System • Perihilar infiltrates or pulmonary nodules • Preceding respiratory illness Other • Erythema and induration of bacille Calmette-Guérin vaccine site • Anterior uveitis (mild) • Desquamating groin rash • Flare of atopic dermatitis or psoriasis • Peripheral gangrene (young infants) From Cherry JD et al: Feigin and Cherry’s pediatric infectious diseases, ed 8, Philadelphia, 2019, Elsevier.

• Redness and induration can be seen at the site of prior bacille Calmette-Guérin (BCG) inoculation. • Beau lines (transverse lines across the nails), diarrhea, acute myocarditis, cough, rhinorrhea, dyspnea, arthralgia, and myalgia may also be seen. • Aseptic meningitis can develop in 40% of cases. • Interstitial nephritis, acute renal failure in rare cases, KD shock syndrome, and macrophage activation syndrome can also occur. • Self-limiting arthritis involving large joints including knees, ankles, and hips was reported in 7.5% to 25% of patients, commonly in the second to third week of illness. • Associated noncardiac features of Kawasaki disease are summarized in Box E3.

ETIOLOGY • The cause of KD is still unknown despite decades of research. • Evidence suggests an infectious etiology precipitating an immune-mediated reaction in genetically susceptible individuals. • One hypothesis is that tropospheric winds from northeastern China carry the etiologic agent of Kawasaki disease from its source to Japan.

DIAGNOSIS Diagnosis of KD is made on the basis of clinical features (see “Physical Findings & Clinical Presentation”). The hallmark of KD is fever lasting >5 days. Typically, the clinical

BOX E4  Laboratory Features of Kawasaki Disease • L  eukocytosis with neutrophilia • Elevated erythrocyte sedimentation rate • Elevated C-reactive protein (and other acute-phase reactants) • Anemia • Thrombocytosis after week 1 • Sterile pyuria • Hypoalbuminemia • Hyponatremia • Elevated serum levels of aminotransferases and γglutamyltransferase • Plasma lipid abnormalities • Cerebrospinal fluid pleocytosis • Synovial fluid pleocytosis From Cherry JD et al: Feigin and Cherry’s pediatric infectious diseases, ed 8, Philadelphia, 2019, Elsevier.

signs appear over the course of several days. Laboratory evaluation may be helpful in making the diagnosis in atypical KD. The timely diagnosis and treatment of KD are important in preventing complications, especially cardiac complications.

DIFFERENTIAL DIAGNOSIS • Scarlet fever • Stevens-Johnson syndrome • Drug eruption • Henoch-Schönlein purpura • Toxic shock syndrome • Measles • Rocky Mountain spotted fever • Epstein-Barr virus, adenovirus, echovirus, and enterovirus • Juvenile rheumatoid arthritis • Mercury hypersensitivity (acrodynia) • Leptospirosis WORKUP Clinical findings in addition to laboratory and imaging studies are useful in searching for multiorgan system involvement and complications (e.g., cardiac, lung, liver). LABORATORY TESTS The diagnostic criteria do not include any laboratory tests for KD. However, systemic inflammation is characteristic of KD and evidence of systemic inflammation is helpful for the diagnosis of cases suspicious for atypical KD. Laboratory features of Kawasaki disease are summarized in Box E4. • Complete blood count commonly shows leukocytosis with neutrophil predominance, normochromic normocytic anemia, and thrombocytosis, which usually rises by the second week. • Abnormal liver function tests are found: Elevated transaminases (hepatic congestion), elevated bilirubin (gallbladder hydrops), and low albumin. • Inflammatory markers will be increased in KD. If erythrocyte sedimentation (ESR), C-reactive protein (CRP), and platelet count are normal after 7 days of illness, KD is an

Kawasaki Disease unlikely diagnosis. Ongoing inflammation is manifested by: 1. Elevated ESR often ≥40 mm/hr and not uncommonly elevated to levels of >100 mm/hr. 2. Elevated CRP ≥3 mg/dl. • Thrombocytosis is a characteristic feature of KD but generally does not occur until the second week and peaks in the third week. • Thrombocytopenia can be seen in the first or second weeks of illness; however, it can be a sign of consumptive coagulopathy (disseminated intravascular coagulation) and a risk factor for development of coronary artery abnormalities. • Hyponatremia is associated with increased risk of coronary aneurysms. • Urinalysis may show sterile pyuria. • Impaired serum lipid profiles with decreased high-density lipoproteins (HDL) and elevated triglycerides and low-density lipoproteins (LDL) can occur. • Cerebrospinal fluid (CSF) with increased white cell count and a mononuclear cell predominance without elevated CSF protein or glucose is found. • Arthrocentesis of joints usually demonstrates purulent-appearing fluid with 125,000 to 300,000 white cells/mm3, normal glucose level, and negative gram stain and cultures. • The discovery of a 13-transcript gene expression signature distinguished patients with KD from others with bacterial, viral, and inflammatory illnesses and provides hope for development of a diagnostic test that will allow earlier detection of KD.

IMAGING STUDIES • ECG changes including arrhythmias, abnormal Q waves, prolonged PR and/or QT intervals, occasionally low voltage, and ST-T wave changes can be seen. • Chest radiograph may reveal pulmonary infiltrates. Cardiomegaly may also be present. • Echocardiogram is the mainstay of diagnosis of KD. It is recommended at the time of illness and repeated in 1 to 2 weeks and then again 4 to 6 weeks after treatment (Class IB indication) for uncomplicated KD. Echocardiogram should include careful assessment of the coronary arteries for size and aneurysms, mural or intraluminal thrombi, effusions, valve function, and myocardial function. • Patients with complicated KD or evolving coronary artery abnormalities (Z score >2.5) detected during acute illness should have echocardiographic evaluation repeated at least twice per week until luminal dimensions have stopped progressing, to determine risk for and presence of thrombosis (Class IB). • A monthly echocardiogram until the third month after illness onset is recommended because failure to escalate thromboprophylaxis in time with the rapid expansion of aneurysms is the primary cause of morbidity and mortality (Class IIa). • With respect to cardiovascular testing during long-term follow-up, echocardiographic measurements of the coronary artery become less reliable as patients grow. For

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BOX E5  Treatment of Kawasaki Disease Acute and Subacute Stages • IVIG 2 g/kg infusion over 10 to 12 hours plus aspirin 80 to 100 mg/kg per day in four divided doses (until patient is afebrile at least 3 to 4 days; some recommend until 14th day of illness); then 3 to 5 mg/kg once daily for 6 to 8 weeks. • IVIG may be repeated if fever persists or recurs together with at least one classic sign of disease and/or elevated C-reactive protein level. • For patients thought to be at particularly high risk of coronary complications, an adjunctive course of corticosteroid may be considered, although optimal dosing and duration are unclear. Convalescent Stage • No coronary abnormalities: No therapy • Transient coronary abnormalities: Aspirin 3 to 5 mg/kg once daily at least until resolution of coronary abnormalities • Persistent, small to medium coronary aneurysms: Aspirin 3 to 5 mg/ kg once daily • Giant or multiple small coronary aneurysms: Aspirin 3 to 5 mg/kg once daily, with or without clopidogrel 1 mg/kg/day, with warfarin or low-molecular-weight heparin for most patients • Coronary obstruction: Thrombolytic therapy, surgical or interventional procedures IVIG, intravenous immunoglobulin From Cherry JD et al: Feigin and Cherry’s pediatric infectious diseases, ed 8, Philadelphia, 2019, Elsevier.

that reason, advanced imaging techniques, such as computerized tomographic angiography (CTA) and magnetic resonance angiography (MRA), are becoming more popular. • Intravascular ultrasound can assess for luminal irregularities of the coronary arteries. • Exercise testing with myocardial perfusion studies can be done to assess for coronary blood flow and the presence of myocardial ischemia.

TREATMENT The goal of treatment of KD in the acute phase is directed at reducing clinical symptoms and reducing inflammation in the systemic and coronary arteries and preventing arterial thrombosis. Standard treatment, including IVIG and aspirin, is usually effective. The disease may recur. Coronary artery abnormalities are serious sequelae of Kawasaki disease. Long-term therapy in individuals who develop coronary aneurysms is aimed at preventing myocardial ischemia or infarction. Box E5 summarizes treatment of Kawasaki disease.

BOX E6  Rescue Therapy for Patients Not Responding to Standard Therapy









• P  ersistent or recurrent fever and/ or elevated serum CRP levels 36 to 48 hours after primary therapy 1. Repeat 2 g/kg IVIG 2. Failure of two doses of IVIG: Therapeutic options a. Third dose of IVIG (2 g/ kg) with or without tapering course of prednisone starting at 2 mg/kg b. IV methylprednisolone (usually 30 mg/kg daily in three doses) with or without subsequent oral steroid, tapered over 1 to 3 weeks c. Infliximab (5 mg/kg) single dose d. Cyclosporine (4 to 8 mg/ kg daily for 14 to 21 days), usually IV, with monitoring of serum levels and dosing adjustments e. Methotrexate orally (10 mg/ m2) × 1 or 2 doses

CRP, C-reactive protein; IV, intravenous; IVIG, intravenous immunoglobulin From Cherry JD et al: Feigin and Cherry's pediatric infectious diseases, ed 8, Philadelphia, 2019, Elsevier.

Box E6 describes rescue therapy for patients not responding to standard therapy.

ACUTE GENERAL Rx • IV immunoglobulin (IVIG) with high-dose aspirin is the treatment of choice in children diagnosed with complete KD or suspected KD, and ideally should be given within the first 10 days of the illness. • IVIG is given as 2 g/kg over 10 to 12 hr as a single infusion with high-dose ASA of 80 to 100 mg/kg/day (antiinflammatory dosing) divided into four doses. • High-dose ASA is given until the patient is afebrile for 48 to 72 hours. Low-dose ASA of 3 to 5 mg/kg/day (antithrombotic dosing) in a single daily dose is given until the followup echocardiogram at 6 to 8 weeks is normal, or it is continued indefinitely if coronary artery abnormalities exist. • IVIG should not be administered beyond the tenth day of illness in absence of fever, significant elevation of inflammatory markers, or coronary artery abnormalities. • IVIG infusion results in ESR elevation. CRP is not affected by IVIG and can be used to follow disease activity. • NSAIDs (e.g., ibuprofen) are not effective in the treatment of KD and may be harmful due to their involvement in the cyclooxygenase pathway. • Single-dose methylprednisolone should not be administered with IVIG as routine primary therapy for patients with KD (Class IIIB). • Approximately 10% to 20% of patients develop recrudescent or persistent fever. If fever persists beyond 36 hours after completion of IVIG, patients are considered IVIG resistant. • A second dose of IVIG 2 g/kg IV over 8 to 12 hr should be considered at least 36 hr after

Kawasaki Disease the end of the first IVIG infusion (Class IIB) in IVIG-resistant patients. Most experts recommend withholding glucocorticoids unless fever persists after at least two courses of IVIG. Administration of pulse dose methylprednisolone 20 to 30 mg/kg intravenously for 3 days with or without subsequent course and taper of oral prednisone may be considered as an alternative to a second IVIG infusion for retreatment in patients with recurrent or recrudescent fever. • Administration of a longer course of tapered corticosteroids (2 to 3 weeks), together with IVIG and ASA, may be considered for treatment in IVIG-resistant patients (Class IIB). • Other therapies including urinary trypsin inhibitor (ulinastatin), pentoxifylline, infliximab (monoclonal antibody against tumor necrosis factor-α), etanercept, plasma exchange, abciximab (platelet glycoprotein IIb/IIIa receptor inhibitor), and immunosuppressive agents such as cyclosporine A have been used, but data are limited. • Infliximab may be considered as an alternative to a second IVIG infusion or corticosteroid infusion in IVIG-resistant patients. • Cyclosporine may be considered for patients in whom a second IVIG infusion, infliximab, or steroids have failed. • Immunomodulatory monoclonal antibody therapy (except TNF-α blockers), cytotoxic agents and plasma exchange may be considered in those who are highly refractory. • Patients with giant coronary artery aneurysms (>8 mm diameter) have a higher risk of coronary artery thrombosis. Aggressive systemic anticoagulation with either lowmolecular-weight heparin or warfarin for an international normalized ratio (INR) target of 2.0 to 3.0 and antiplatelet therapy with ASA is needed to improve outcomes and prevent thrombosis within the aneurysm and MI. • Most patients with moderate to large aneurysms should be maintained on a second antiplatelet agent. • Acute coronary thrombosis should be managed with thrombolytic agents under cardiology supervision.

CHRONIC Rx • All patients with a history of coronary artery aneurysm require lifelong surveillance to prevent coronary thrombosis and to treat myocardial ischemia and associated complications.

824.e10 • Based upon the size of the aneurysm and the age of the patient, other anticoagulation and antiplatelet therapy may be added. • C oronary revascularization (surgical or percutaneous) is performed for symptoms of angina or evidence of a significant territory of inducible ischemia on stress testing.

NONPHARMACOLOGIC THERAPY • Emollient creams for peeling skin and balms for fissured lips • Salt restriction in patients with congestive heart failure • Oxygen in selected patients DISPOSITION • Mortality rate of children with KD is 0.5% to 2.8%, usually from coronary aneurysm thrombosis and MI. • Death usually occurs in the third to fourth week of the illness. • Before the use of IVIG, 25% of all patients with KD developed coronary artery aneurysms; this has fallen to 3% to 5% with the use of IVIG. • Despite treatment with IVIG, 20% of children develop transient coronary artery dilation in the proximal LAD or proximal RCA, 5% develop coronary artery aneurysms, and 1% develop giant aneurysms. • 50% of coronary artery aneurysms return to normal lumen diameter by 1 to 2 yr after onset of illness. • Aspirin in high dose decreases the coronary artery involvement to 10 days. 2. Age 6 yr. 3. Male. 4. Recurrence of fever. • A subset of genetically susceptible children (23 hr/day for 6-12 mo) before significant effect can be achieved. Unfortunately, many parts of the body are not amenable to this pressure. Patient discomfort frequently reduces compliance. 6. Radiation after surgery can also reduce the recurrence rate. X-rays of 700 to 1500 cGy in fractions over five to six treatments are the most frequently used treatment. Radiation is usually initiated within 10 days, preferably within 24 hr of surgery. It is avoided in pediatric and pregnant patients. At times, brachytherapy with interstitial iridium 192 is used. Most physicians use radiation only for keloids over the extremities. The reported risk of radiation-induced malignancy is theoretical. 7. 5-Fluorouracil can be used as an individual agent, after surgery, or in combination with intralesional steroids. Weekly injection of 0.5 to 2 ml at a 50 mg/ml concentration of 5-fluorouracil for 12 wk is the recommended dose.

8. S uperiority of laser use to simple excision currently has not been demonstrated. 9. Topical 5% imiquimod cream has some role when used following surgery locally every night for a minimum of 2 mo. 10. Other treatments include Cordran tape, bleomycin, interferon, vitamin A, nitrogen mustard, antihistamines, zinc, tacrolimus, sirolimus, allantoin, botulinum toxin, colchicine, salicylic acid, calcipotriol, NSAIDs, d-penicillamine, relaxin, quercetin, dinoprostone, doxorubicin, ACE inhibitors, hyaluronidase, pentoxifylline, tranilast, mitomycin-C, tamoxifen, silver sulfadiazine, onion extract, vitamin E, intralesional verapamil.

FOLLOW-UP Because of the high risk of recurrence, a followup of at least 12 mo is necessary to fully evaluate the effectiveness of therapy. PREVENTION • Avoid nonessential surgery such as body piercing, which carries a high risk for keloid formation. • LASIK eye surgery and CO2 laser resurfacing should be avoided in patients with a tendency for keloids. • Use a laparoscopic approach when surgery is needed. • Avoid making incisions over joint spaces or over midchest and ensure that they follow skin creases. • Handle tissue gently during surgery. • Ensure good hemostasis intraoperatively. • Use tension-free primary wound closure. • Use monofilament, synthetic permanent sutures. • Use adhesives instead of sutures when possible for closure of wounds. • Compressive pressure dressing is preferred in high-risk patients following surgery. • Avoid wound infection. • Avoid tattoos. • Aggressively treat inflammatory acne. COMPLICATIONS • Psychological effects secondary to disfigurement. • Contracture from keloids may result in loss of function if overlying a joint. PROGNOSIS • Unlike hypertrophic scars, keloids do not regress with time. However, they may continue to expand in size for decades. • Regardless of the type of treatment, there is a high recurrence rate. • Keloids never become malignant. RELATED CONTENT Keloids (Patient Information) AUTHOR: Fred F. Ferri, MD

  Klinefelter Syndrome BASIC INFORMATION DEFINITION Klinefelter syndrome is a congenital disorder in which a 47,XXY chromosome complement is associated with hypogonadism and infertility. SYNONYM 47,XXY Hypogonadism ICD-10CM CODE Q98.4 Klinefelter syndrome, unspecified

EPIDEMIOLOGY & DEMOGRAPHICS INCIDENCE: 1 in 500 men (most common sex chromosome disorder) GENETICS: The most common mosaic complement is 46,XY/47,XXY. 47,XXY karyotypes 48,XXYY, 48,XXXY, and 49,XXXXY have been reported. The manifestations vary in severity by patient (Table E1). This sex chromosome mosaicism is believed to account for the variable presentation. Fertility, although very rare, has been reported in men with Klinefelter syndrome. TABLE E1  Clinical Features of Klinefelter Syndrome Karyotype

47,XXY

Inheritance

Sporadic; associated with advanced maternal age; nondisjunction during first or second meiotic division in either parent (67% maternal, 33% paternal); mitotic nondisjunction Male Normal

Genitalia Wolffian duct derivatives Müllerian duct derivatives Gonads

Habitus

Hormone profile

Absent Small, firm testes; seminiferous tubule dysgenesis; azoospermia; Leydig cell hyperplasia Poor to normal virilization at puberty: Gynecomastia; disproportionately long legs Testosterone levels variable but usually decreased; increased levels of plasma LH and FSH postpubertally

FSH, Follicle-stimulating hormone; LH, luteinizing hormone. From Larsen PR et al: Williams textbook of endocrinology, ed 10, Philadelphia, 2003, Saunders.

PHYSICAL FINDINGS & CLINICAL PRESENTATION • Classic triad: Small firm testes, azoospermia, and gynecomastia. • Prepubertal: Small testes; gonadal volume 45 yr. 2. Of note, the extra X chromosome has a paternal origin as often as a maternal origin.

DIAGNOSIS • Markedly elevated follicle-stimulating hormone levels. • Total plasma testosterone levels are decreased in 50% to 60% of patients. • Free testosterone levels are decreased. • Plasma estradiol is increased, stimulating the increase in levels of testosterone-binding globulin with resultant decrease in the testosterone/estradiol ratio, which is thought to be the cause of gynecomastia.

LABORATORY TESTS • Normal to low serum testosterone • Increased sex hormone–binding globulin (acts to further suppress any available free testosterone) • Normal to increased estradiol (a result of augmented peripheral conversion of testosterone to estradiol) • Testis biopsy shows azoospermia, Leydig cell hyperplasia, hyalinization, and fibrosis of the seminiferous tubules. Mosaics may have focal areas of spermatogenesis and, on rare occasions, sperm may appear in the ejaculate. The extra X chromosome is the pivotal factor controlling spermatogenesis and also affects neuronal function directly, leading

to the behavioral abnormalities related to decreased IQ • Buccal smear: One sex chromatin body • Prepubertal males: Gonadotropin levels are normal • Postpubertal males: Gonadotropin levels are elevated even when the testosterone level is normal • Disease associations: 1. Malignancies: Breast cancer (20 times >XY men and 20% the rate of occurrence in women), nonlymphocytic leukemia, lymphomas, marrow dysplastic syndromes, extragonadal germ cell neoplasms 2. Autoimmune disorders: Chronic lymphocytic thyroiditis, Takayasu arteritis, taurodontism (enlarged molar teeth), mitral valve prolapse, varicose veins, asthma, bronchitis, osteoporosis, abnormal glucose tolerance testing, diabetes, varicose veins

TREATMENT • Revolves around three facets of Klinefelter syndrome: 1. Hypogonadism: Androgen replacement in the form of testosterone 2. Gynecomastia: Cosmetic surgery 3. Psychosocial problems: Androgen therapy and educational support • After extensive genetic counseling, intracytoplasmic sperm insertion has been used to treat infertility with limited success in mosaic men

 EARLS & P CONSIDERATIONS COMMENTS • Androgen therapy should not be used in the case of severe mental retardation • Rule out breast and prostate cancer before initiating or continuing androgen therapy • Androgen therapy will not improve fertility; it may suppress any spermatogenesis that is taking place within the testes • Other causes of primary hypogonadism: 1. Myotonic muscular dystrophy 2. Sertoli cell–only syndrome 3. Kartagener syndrome 4. Anorchia 5. Acquired hypogonadism RELATED CONTENT Klinefelter Syndrome (Patient Information) AUTHOR: Fred F. Ferri, MD

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Korsakoff Psychosis BASIC INFORMATION DEFINITION Korsakoff psychosis (KP) is a disorder of declarative learning and memory that results from thiamine deficiency, largely (90%) secondary to chronic alcohol abuse in industrialized nations. It is classically, but not always, seen following the presentation of Wernicke encephalopathy (see “Wernicke Syndrome”). SYNONYMS Korsakoff syndrome Wernicke-Korsakoff syndrome Alcoholic polyneuritic psychosis KPF ICD-10CM CODE F10.96 Alcohol use, unspecified with alcohol-induced persisting amnestic disorder

EPIDEMIOLOGY & DEMOGRAPHICS • The incidence of KP is declining as a result of improved patient nutrition and awareness by health professionals • More common in males • Age of onset evenly distributed between ages 30 and 70 yr PHYSICAL FINDINGS & CLINICAL PRESENTATION • Impaired anterograde memory as a core feature, and commonly retrograde memory is impaired to a varying extent as well. • Remote memory is relatively less impaired on neuropsychiatric testing. • Confabulation (the fabrication of false memories to fill memory gaps) is common. • Severe declarative amnesia and concomitant deficits in executive function result in compromised autonomy. ETIOLOGY KP is the result of thiamine deficiency. Thiamine deficiency is commonly seen in chronic alcoholism and other malnourished populations (anorexia, bariatric surgery, malignancy). It may also occur from prolonged infusion of dextrosecontaining fluids without thiamine repletion.

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • Stroke, trauma, or tumor affecting the temporal lobes or hippocampi • Cerebral anoxia • Transient global amnesia • Dementia of multiple causes WORKUP A high index of suspicion should be maintained in chronic alcoholism and malnourished states. LABORATORY TESTS • CBC • Serum chemistries • Erythrocyte thiamine transketolase concentration before and after replacement with thiamine pyrophosphate IMAGING STUDIES MRI brain may show nonspecific T2 hyperintensities in the diencephalon and mesencephalon but is not pathognomonic. However, MRI/CT may be helpful in ruling out other diagnoses.

TREATMENT NONPHARMACOLOGIC THERAPY A supervised environment may be required. • Acute: Treatment should be initiated in all patients with clinical suspicion of Wernicke encephalopathy (WE). Thiamine supplementation should precede glucose administration in all patients at risk for WE lest they develop Korsakoff syndrome. • Alcoholics with WE: Treat with 500 mg of thiamine hydrochloride (dissolved in 100 ml of normal saline) infused intravenously over 30 minutes three times daily for 2 to 3 days. • If a response is observed, continue with 250 mg of thiamine hydrochloride intravenously or intramuscularly daily until clinical improvement ceases. • Nonalcoholics with WE: Treat with 200 mg of thiamine hydrochloride (dissolved in 100 ml of normal saline) infused intravenously over 30 minutes three times daily for 2 to 3 days. • Parenteral magnesium must be infused concurrently with thiamine.

SUGGESTED READING Oudman E et al: Procedural learning and memory rehabilitation in Korsakoff’s syndrome: a review of the literature, Neuropsychol Rev 25:134-148, 2015.

• Side effects of parenteral thiamine hydrochloride may include generalized pruritus, transient local irritation or, rarely, anaphylactic or anaphylactoid reactions.

CHRONIC Rx Recommended oral dose after completed parenteral treatment for WE: Thiamine 30 to 100 mg twice daily for long-term thiamine replacement. • Individuals with KP rarely recover; therefore, one must consider the need for additional support and supervision within the home versus placement in a long-term care facility. REFERRAL • Neurology to confirm the diagnosis and rule out other causes • Neuropsychiatric testing to assess baseline functioning and further deterioration

PEARLS & CONSIDERATIONS COMMENTS • KP is frequently misdiagnosed or underdiagnosed! • Memory problems may persist even in “recovered” patients. • Replace thiamine in patients at risk even if clinical symptoms are not evident. • Prolonged use of dextrose-containing IV fluids without supplemental thiamine may precipitate KP. • Strengthening of procedural memory and encouragement of procedural learning can help restore some of the patient’s autonomy. RELATED CONTENT Alcohol Use Disorder (Related Key Topic) Delirium (Related Key Topic) Vitamin Deficiency (Hypovitaminosis) (Related Key Topic) Wernicke Syndrome (Related Key Topic) AUTHORS: Angad Jolly, PhD, Joseph S. Kass, MD, JD, FAAN, and Alexandra Boske, MD

Labyrinthitis BASIC INFORMATION DEFINITION Labyrinthitis is a peripheral vestibulopathy characterized by acute onset of vertigo usually associated with nausea and vomiting. It can be associated with hearing loss and gait abnormalities and may be either serous or purulent.

ICD-10CM CODES H81.23 Vestibular neuronitis, bilateral H83.09 Labyrinthitis, unspecified ear H83.01 Labyrinthitis, right ear H83.02 Labyrinthitis, left ear H83.03 Labyrinthitis, bilateral

EPIDEMIOLOGY & DEMOGRAPHICS INCIDENCE (IN U.S.): Most common cause of prolonged spontaneous vertigo associated with nausea at any age PREDOMINANT AGE: Any PHYSICAL FINDINGS & CLINICAL PRESENTATION CLINICAL PRESENTATION: • Vertigo, nausea, and vomiting with onset over several hours. • Symptoms usually peak within 24 hours, then resolve gradually over several weeks. • During the first day, the patient usually has difficulty focusing the eyes because of spontaneous nystagmus. • Usually has benign course with complete recovery within 1 to 3 mo, although older patients may have intractable dizziness that persists for many months. PHYSICAL FINDINGS • Nystagmus • Nausea • Vomiting • Vertigo worsening with head movement • Abnormal caloric ENG tests • May have hearing loss in the affected ear or ears • Normal otoscopic exam typically • Normal neurologic exam; may have signs of vestibular loss, such as a positive head thrust test ETIOLOGY Symptoms often preceded for 1 to 2 wk by a viral-like illness. Labyrinthitis may be either bacterial or viral and may be either tympanogenic (i.e., resulting from spread of infection

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • Acute labyrinthine ischemia (ischemic stroke of the labyrinthine artery) • Labyrinthine fistula • Benign paroxysmal positional vertigo • Ménière disease • Cholesteatoma • Drug-induced vestibulocochlear nerve damage • Vestibulocochlear nerve (cranial nerve VIII) tumor • Head trauma • Vertebrobasilar stroke • Dehiscence of the superior semicircular canal WORKUP • Otoscopic examination • Neurologic examination, with close attention to cranial nerves • Bedside test of vestibular function, specifically head thrust or head heave test • Audiogram if symptoms accompanied by hearing loss • Caloric test if presentation is atypical LABORATORY TESTS • Routine laboratory tests are generally not helpful. • If there is a history of significant emesis, check electrolytes, BUN, and creatinine. IMAGING STUDIES • Imaging studies are usually not necessary. • Gadolinium-enhanced MRI may show enhancement of bony labyrinth. MRI of the brain with and without contrast with fine cuts through the internal auditory canal is indicated if there is an abnormal cranial nerve exam, headache, concern for stroke, or suspicion of cranial nerve VIII nerve tumor. • Head CT with fine cuts through temporal bones is indicated if there is a history of trauma or suspicion of cholesteatoma.

TREATMENT NONPHARMACOLOGIC THERAPY • Reassurance • Initial bed rest, then encourage increase in activity as tolerated

ACUTE GENERAL Rx • Treatment is with antiemetics such as promethazine or ondansetron; vestibular suppressants such as the antihistamines meclizine or diphenhydramine; the anticholinergic scopolamine; and the benzodiazepines diazepam or lorazepam. These medications should only be continued for a few days during the acute phase. Some of these medications, especially scopolamine, should be used with caution in the elderly. Methylprednisolone 100 mg per day for 3 days, with slow taper over 3 wk. • Valacyclovir has not been shown to be helpful. CHRONIC Rx • No specific pharmacologic chronic therapy. • Vestibular rehabilitation is useful for patients with persistent symptoms. DISPOSITION Usually does not require hospital admission unless the patient is unable to tolerate oral intake of liquids REFERRAL • Refer if symptoms persist or neurologic abnormalities are present. • Consider vestibular rehabilitation, particularly in the elderly.

PEARLS & CONSIDERATIONS COMMENTS Labyrinthitis is a term that usually implies peripheral vestibulopathy associated with hearing loss. The term vestibular neuronitis is typically used when hearing is not affected. Despite this technical distinction, many physicians use these terms interchangeably. RELATED CONTENT Labyrinthitis (Patient Information) Benign Paroxysmal Positional Vertigo (Related Key Topic) Vestibular Neuronitis (Related Key Topic) AUTHORS: Michael Pohlen, MD, Joseph S. Kass, MD, JD, FAAN, and Sharon S. Hartman Polensek, MD, PhD

L

Diseases and Disorders

SYNONYMS Acute labyrinthitis Acute vestibular neuronopathy Vestibular neuronitis Viral neurolabyrinthitis

into the inner ear from the middle ear, antrum, or petrous apex), meningogenic, or hematogenic from encephalitis or brain abscess. The round window membrane is considered the most likely pathway of inflammatory mediators from the middle to the inner ear that subsequently give rise to labyrinthitis.

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Lactic Acidosis BASIC INFORMATION DEFINITION Lactic acidosis (LA) is a life-threatening condition characterized by accumulation of lactate, especially L-lactate, in the body. It represents an imbalance of lactate overproduction or underutilization usually resulting from tissue hypoperfusion and hypoxia (type A LA), or caused by toxins or medication-induced cellular toxicity (type B LA). SYNONYMS Lactic acidosis Hyperlactatemia LA ICD-10CM CODE E87.2 Acidosis

EPIDEMIOLOGY & DEMOGRAPHICS RISK FACTORS: • Sepsis • Liver disease • Severe anemia • Severe trauma • Advanced heart failure • Cardiogenic shock • Hypovolemic shock • Diabetes mellitus • Seizures • Vigorous exercise • Cocaine • Medications (metformin, salicylates, beta 2 agonists, propofol, nucleoside reverse-transcriptase inhibitors) • Thiamine deficiency • Pheochromocytoma PHYSICAL FINDINGS & CLINICAL PRESENTATION • Shock, dehydration (tachycardia, decreased skin turgor, decreased urine output, hypotension, dry mucous membranes) • Possible clues or precipitating factors (sepsis, bleeding, intoxication) • Altered mental status • Nausea, vomiting, abdominal pain • Weakness, lethargy • Tachypnea, rapid shallow breathing caused by acidosis (Kussmaul breathing) ETIOLOGY • Table E1 summarizes medication-induced lactic acidosis. Table E2 describes other pathologies associated with lactic acidosis. • Type A: Related to tissue hypoperfusion or hypoxia, is probably the most common cause of LA. 1. Sepsis leading to systemic hypotension and microcirculation dysfunction leading to decreased extraction of oxygen and lactate clearance by the peripheral tissues 2. Shock: Cardiogenic, hemorrhagic and obstructive shock; LA in those conditions is thought to be related to decreased clearance 3. Regional ischemia, such as acute mesenteric ischemia 4. Burns

• Type B: Related to toxins, medications and liver dysfunction, alcoholism, malignancy. 1. Metformin: Patients who are at increased risk of LA are those who are taking metformin and have renal or hepatic dysfunction, cardiac dysfunction, or those who overdose on the medication 2. Cyanide poisoning, beta 2 agonist excessive use, thiamine deficiency 3. Seizure D-lactic acidosis is a rare type of LA that is associated with short bowel syndrome and bacterial overgrowth.

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • Alcoholic ketoacidosis • Uremic acidosis • Diabetic ketoacidosis • Fulminant hepatic failure WORKUP • Laboratory measurement of lactic acid to confirm diagnosis and assess for precipitating factors • Identification of triggering conditions such as infections (blood cultures, urine cultures, chest radiographs), blood drug and toxins level (alcohol, metformin, cyanide); liver and kidney function tests (hepatitis, acute kidney insufficiency) LABORATORY TESTS • Normal lactate level is 2.0 to 2.5 mEq/L. • LA is defined by serum lactate concentration >4 mEq/L. An elevated blood lactate level is essential for confirmation of the diagnosis. • Arterial blood gas analysis demonstrates metabolic acidosis usually with PH 600 mg/L with ethanol treatment; >500 mg/L in the absence of antidote); in the setting of altered osmolar gap when methanol level is absent. 3. In the context of impaired renal function.

Occurs in about 4.3 patients per 100,000 patient-yr. Metformin plasma concentration correlates with plasma lactate levels, pH, and creatinine.

Comments

Lactic Acidosis 825.e2

Multiple mechanisms: Carboxyhemoglobinemia alters oxygen transport to the tissues and induces a leftward shift of the oxyhemoglobin curve, thus causing tissue dysoxia. More importantly, however, carbon monoxide binds to cytochromes in the electron transport chain, impairing OXPHOS and contributing to ROS production.

Thought to be caused by mitochondrial toxicity secondary to inhibition of DNA polymerase-γ, which uncouples OXPHOS.

Lactic acidosis occurs secondary to uncoupling of OXPHOS and impaired oxidation of fatty acids.

Carbon monoxide

Antiretroviral agents

Propofol

Mild-moderate hyperlactatemia (i.e., 2.5-5 mmol/L) occurs in 25% of patients with human immunodeficiency virus under treatment with nucleoside reverse transcriptase inhibitors (particularly stavudine). Hyperlactatemia occurs in the setting of the “propofol infusion syndrome,” or PIS, which consists of lactic acidosis, heart failure, rhabdomyolysis, and acute kidney injury.

Cyanide poisoning usually occurs as a result of smoke inhalation or in the context of a suicide attempt. Cyanide levels offer little help because of prolonged sample processing time. Cyanide poisoning should be suspected in patients exhibiting hyperlactatemia with neurologic and/or cardiovascular manifestations (i.e., confusion, seizures, coma, hypotension). Cyanide toxicity derived from nitroprusside treatment occurs particularly with prolonged infusions (i.e., >72 hours) and with high doses (>2 mg/kg/min). This also can occur with short infusions of very high doses that deplete thiosulfate stores. The best evaluation for possible toxicity in this setting is clinical (i.e., tachycardia, agitation, seizures) and measurement of blood lactate concentrations. Lactic acidosis can be eliminated by routine addition of sodium thiosulfate in the infusion bag. Leading cause of unintentional poisoning worldwide. It occurs most commonly in males, during winter, and often involves heating or cooking appliances. Burn victims are at risk of CO poisoning. CO levels usually do not correlate with symptoms.

Usually occurs in patients receiving infusions of propofol exceeding 5 mg/ kg/hr for more than 48 hours.

Signs of CO poisoning: Neuro: Headache, dizziness, confusion, blurry vision, syncope, seizures, incontinence, coma (neuronal excitability Kv2.1 and Trek-1 channels, activation of soluble guanylyl cyclase and vasodilatation) Cardiovascular: Hypotension, palpitations, chest pain, myocardial ischemia Lung: Noncardiogenic pulmonary edema (epithelial sodium channel compromise [ENaC] and ROS generation) Abdominal: Nausea, vomiting, abdominal pain (ENaC, ROS generation, increased NO production), LFT elevation Muscle: Rhabdomyolysis (myoglobin binding), rigors (peripheral neuronal hyperexcitability from Nav1.5 and Kv2.1 channels)

AG, Anion gap; ATPase, adenosine triphosphatase; CO, carbon monoxide; ETC, electron transport chain; HD, hemodialysis; ICU, intensive care unit; LFT, liver function test; NO, nitric oxide; OXPHOS, oxidative phosphorylation; ROS, reactive oxygen species. From Ronco C et al: Critical care nephrology, ed 3, Philadelphia, 2019, Elsevier.

Cyanide combines with cytochrome c and inhibits OXPHOS, thus inducing hyperlactatemia. Nitroprusside infusion can cause cyanide toxicity.

Cyanide and ­nitroprusside

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Increased lactate production from respiratory muscles. However, the peak of hyperlactatemia occurs while the patient is recovering and thus it is more likely that the mechanism relates to stimulatory effect of β2 agonists on glycolytic flux. Increase in lactate production from Kupffer cells and the lung. Impaired lactate clearance by hepatocytes. Increased hepatic lactate production from accelerated glycolytic rate.

Asthma

Impairment of PDH because thiamine pyrophosphate is an essential co-factor of PDH. Impairs OXPHOS of pyruvate in the Krebs cycle, which stimulates the glycolytic flux. Hyperglycemia and the administration of epinephrine, norepinephrine, and dobutamine are associated with hyperlactatemia in this setting. The contribution of tissue hypoperfusion to hyperlactatemia has been challenged: Microdialysis measurements during CPB have shown no association between tissue and plasma lactate. Hyperlactatemia has been shown to occur in patients with no evidence of tissue hypoperfusion. Local lung production after CPB has been found to be a significant contributor to hyperlactatemia. Cytokine-mediated and systemic inflammation resulting from exposure of blood to the extracorporeal circuit. Depletion of intracellular ATP and decreased 2,3-diphosphoglyceric acid. Nonanion gap acidosis secondary to impaired tubular reabsorption of bicarbonate. Mutations or deletions in respiratory chain genes or in the pyruvate dehydrogenase complex.

Thiamine deficiency

Hypoglycemia is a potent stimulant of the sympathetic nervous system, releasing epinephrine, which increases glycolytic flux in muscle and thus the release of lactate. In addition, in hepatic dysfunction, a minimal amount of glucose is required as an energy source for effective conversion of lactate into glucose through gluconeogenesis.

Hypoglycemia

Manifests as episodes of lactic acidosis with neurologic and developmental abnormalities. Suspect a mitochondrial cause if in the absence of hypoxia or sepsis, the patient has muscle weakness, or it is difficult to wean from mechanical ventilation. Other neurologic manifestations include stroke, seizures, dementia, migraines, and ophthalmoplegia. Occurs in patients with short bowel syndrome secondary to resection or bypass surgery or with chronic pancreatic insufficiency. Associated with neurologic manifestations—slurred speech, confusion, ataxia, triggered by ingestion of large amounts of carbohydrates lasting hours to days. Patients with chronic renal or hepatic disease.

Severe hypophosphatemia (i.e., phosphate 3 mmol/L.

Usually appears during infancy or early childhood, but some may manifest until adulthood.

Hyperlactatemia during cardiac surgery is associated strongly with mortality.

Lactic acidosis develops only in some patients after β2 agonist treatment. The reason for this selectivity is unknown but may be related to polymorphisms in the β2 receptor gene. Hyperlactatemia is unusual if there is no increased lactate production during chronic liver dysfunction. Hyperlactatemia has prognostic importance in this patient population. More frequent in leukemia or lymphomas but also in solid tumors with liver or bone marrow metastases. Lactic acidosis persists even after correction of hypoglycemia. Can develop rapidly (days) in critically ill patients because of decreased intake or increased urinary or GI losses.

Comments

ATP, Adenosine triphosphate; CPB, cardiopulmonary bypass; GI, gastrointestinal; IL-10, interleukin-10; OXPHOS, oxidative phosphorylation; PDH, pyruvate dehydrogenase; TNF-β, tumor necrosis factor-beta. From Ronco C et al: Critical care nephrology, ed 3, Philadelphia, 2019, Elsevier.

In patients with short bowel syndrome, ingested carbohydrates are malabsorbed and reach the colon undigested, where they are fermented by bacteria into organic acids. This acidifies the colonic milieu promoting overgrowth of gut flora with acid-tolerant mechanisms that produce D-lactate.

D-lactic acidosis

Congenital

Severe hypophosphatemia

Cardiopulmonary bypass

Cytokine-mediated stimulation of glycolytic flux in neoplastic cells.

Malignancy

Acute liver failure

Source and/or Mechanism

Condition

TABLE E2  Other Pathologies Associated with Lactic Acidosis

Lactic Acidosis 825.e4

Lactic Acidosis SUGGESTED READINGS Andersen LW et al: Etiology and therapeutic approach to elevated lactate, Mayo Clin Proc 88(10):1127-1140, 2013. Kraut JA, Madias NE: Lactic acidosis, N Engl J Med 371:2309–2319, 2014. Reddy AJ et al: Lactic acidosis: clinical implications and management strategies, Clev Clin J Med 82:615-622, 2015.

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Lactose Intolerance BASIC INFORMATION DEFINITION Lactose intolerance is the insufficient concentration of lactase enzyme, leading to fermentation of malabsorbed lactose by intestinal bacteria with subsequent production of intestinal gas and various organic acids, manifesting clinically with diarrhea, abdominal pain, flatulence, or bloating after lactose intake. Lactose malabsorption occurs when a substantial amount of lactose is not absorbed in the intestine. Lactase deficiency is defined as brush-border lactase activity that is markedly reduced relative to the activity observed in infants. SYNONYM Lactose malabsorption Lactase deficiency Milk intolerance Carbohydrate malabsorption ICD-10CM CODES E73.9 Lactose intolerance, unspecified E73.8 Other lactose intolerance

EPIDEMIOLOGY & DEMOGRAPHICS • Nearly 50 million people in the U.S. have partial or complete lactose intolerance. There are racial differences, with 85% of Asian Americans and >60% of African Americans having some form of lactose intolerance. • There are geographic variations: highest in Asians (up to 90%), lowest in northern Europeans (approximately 10%), intermediate in southern Europeans and Middle Eastern populations (up to 40%). PHYSICAL FINDINGS & CLINICAL PRESENTATION • Abdominal tenderness and cramping, bloating, flatulence. • Diarrhea. • Symptoms are directly related to the ­osmotic pressure of substrate in the colon and occur approximately 2 hr after ingestion of lactose. • Physical examination: May be entirely within normal limits. ETIOLOGY • Before it can be absorbed, lactose is cleared to glucose and galactose by the enzyme lactase in the brush border of the small intestine. If the amount of lactase is marginal or its expression is left, lactose intolerance will result. • Congenital lactase deficiency: Common in premature infants; rare in term infants and

generally inherited as a chromosomal recessive trait. • Secondary lactose intolerance: Usually a result of injury of the intestinal mucosa (Crohn disease, viral gastroenteritis, AIDS enteropathy, cryptosporidiosis, Whipple disease, sprue). • Acquired primary lactase deficiency (adulttype hypolactasia OMIM # 223100) is the most common form of lactase deficiency worldwide. The decline in lactase activity is a multifactorial process that is regulated at the gene transcription level and leads to decreased biosynthesis, retardation of intracellular transport, or maturation of the enzyme lactase-phlorizin hydrolase.

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • Inflammatory bowel disease • Irritable bowel syndrome • Pancreatic insufficiency • Nontropical and tropical sprue • Cystic fibrosis • Diverticular disease • Bowel neoplasm • Laxative abuse • Celiac disease • Parasitic disease (e.g., giardiasis) • Viral or bacterial infections WORKUP • A detailed dietary history is essential in the evaluation of patients with suspected carbohydrate malabsorption. • The diagnosis can usually be made on the basis of the history and improvement with dietary manipulation. • Diagnostic workup may include confirming the diagnosis with hydrogen breath test and excluding other conditions listed in the differential diagnosis that may also coexist with lactase deficiency. LABORATORY TESTS • Laboratory evaluation may not be necessary in patients with significant history. • Lactose breath hydrogen test: A rise in breath hydrogen >20 ppm within 90 min of ingestion of 50 g of lactose is positive for lactase deficiency. This test is positive in 90% of patients with lactose malabsorption. Common causes of false-negative results are recent use of oral antibiotics or recent high colonic enema. Fig. E1 illustrates the role of symptoms in determining the clinical importance of lactose malabsorption. • The lactose tolerance test is an older and less accurate testing modality (20% rate of false-positive and false-negative results). The patient is administered an oral dose of 1 to 1.5 g of lactose/kg body weight. Serial measurement of blood glucose level on an hourly

basis for 3 hr is then performed. The test is considered positive if the patient develops intestinal symptoms and the blood glucose level rises 100% increment on fast RNS (20 to 50 Hz) or immediately after 10 sec of maximum exercise (post-exercise facilitation). LABORATORY TESTS Check P/Q calcium channel antibody titers (commercially available). IMAGING STUDIES Screen for an underlying malignancy. Presen­ tation with LEMS may precede diagnosis of SCLC by up to 5 yr; hence, CT of the chest or positron emission tomography (PET) scan may be required every 6 to 12 mo to evaluate for SCLC.

TREATMENT Treatment consists of treating any underlying malignancy or immunosuppression, intravenous immunoglobulin (IVIG), or plasmapheresis when dealing with a purely autoimmune disease. Amifampridine is the only FDA-approved treatment for symptomatic treatment of LEMS. Amifampridine works by blocking presynaptic potassium channels, thereby increasing presynaptic calcium concentrations and enhancing acetylcholine release.

NONPHARMACOLOGIC THERAPY Symptomatic treatment for autonomic dysfunction

ACUTE GENERAL Rx • Amifampridine: Start 15 to 30 mg/day PO divided tid to qid and then increase by 5 mg/ day every 3 to 4 days for a maximum of 20 mg per dose and 80 mg/day. • Plasma exchange (200 to 250 ml/kg over 10 to 14 days) or IVIGs (2 g/kg divided over 2 to 5 days) often produces significant, temporary improvement. • Prednisone 1.0 to 1.5 mg/kg/day can be gradually tapered over months to minimal effective dose. • Azathioprine can be given alone or in combination with prednisone. Give up to 2.5 mg/ kg/day. If patient is intolerant, can administer cyclosporine up to 3 mg/kg/day instead. CHRONIC Rx Treat underlying malignancy if present Amifampridine for symptoms of weakness DISPOSITION • Gradually progressive weakness leading to impaired mobility if untreated • Clinical remission may occur with chronic immunosuppressive therapy in 43% of cases • Possible substantial improvement with successful treatment of underlying malignancy REFERRAL • Referral to a neurologist is highly recommended because this is a rare disease requiring highly specialized treatment in the context of weighing risk vs. benefit of the different therapeutic options. • Surgical referral for tumor debulking in paraneoplastic forms necessary.

PEARLS & CONSIDERATIONS COMMENTS • Prominent autonomic symptoms (dry eyes, dry mouth, impotence, orthostasis) are often clues to the diagnosis in the appropriate clinical context. • Many drugs may worsen weakness and should be used only if absolutely necessary. Included are succinylcholine, d-tubocurarine, quinine, quinidine, procainamide, aminoglycoside antibiotics, β-blockers, and calcium channel blockers.

PATIENT INFORMATION Document link available through http://www. lems.com/resources. AUTHORS: Divya Singhal, MD, and Joseph S. Kass, MD, JD, FAAN

SUGGESTED READINGS Titulaer MJ et al: Lambert-Eaton myasthenic syndrome: from clinical characteristics to therapeutic strategies, Lancet Neurol 10(12):1098-1107, 2011. U.S. National Library of Medicine. PubChem compound summary: 3,4-Diaminopyridine. https://pubchem.ncbi.nlm.nih.gov/compound/3_4-diaminopyridine

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Large Bowel Obstruction BASIC INFORMATION DEFINITION A mechanical or functional interruption of normal intraluminal flow through the colon SYNONYM Colorectal obstruction ICD-10CM CODES K56.609 Unspecified intestinal obstruction K56.699 Other intestinal obstruction

EPIDEMIOLOGY & DEMOGRAPHICS PEAK INCIDENCE: 73 yr of age, higher in the elderly due to increased rates of colorectal cancer PREVALENCE: 25% of intestinal obstructions PREDOMINANT SEX AND AGE: Affects males and females equally, more common in the elderly RISK FACTORS: Colorectal cancer, prior abdominal surgery, prior colorectal resection, chronic constipation, radiation, diverticulitis PHYSICAL FINDINGS & CLINICAL PRESENTATION • History: 1. Patients commonly present with abdominal pain, abdominal distension, and obstipation. 2. Patients may have nausea and vomiting, but these are very late-presenting symptoms. 3. Patients may report a history of bloating or constipation prior to the onset of more severe symptoms. 4. Inquiries should be made concerning recent weight loss or gain, bowel habits, narcotic use, prior surgery, and malignancy. • Physical exam: 1. Patient may be tachycardic or febrile from perforation, strangulation, or ischemia. 2. Exam should include palpation of the abdomen, investigation for umbilical, inguinal and femoral hernias, as well as a rectal exam. 3. Physical exam findings may include: a. Distended, tympanitic abdomen b.  Nonspecific tenderness to palpation of the lower abdomen c. A palpable hernia d. Rectal mass or frank blood on rectal exam 4. If possible, proctoscopy should be performed in the office to evaluate for volvulus or sigmoid mass. ETIOLOGY • Colorectal cancer, volvulus, diverticulitis, abscess, adhesions, anastomotic strictures, hernia, fecal impaction, inflammatory bowel disease, ischemic colitis, intussusception, colonic pseudoobstruction, narcotic

associated adynamic ileus, sepsis or C. difficile infection. • Box 1 summarizes causes of adult large bowel obstruction.

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • Colorectal cancer • Volvulus • Diverticulitis • Abdominal abscess • Abdominal adhesions • Anastomotic stricture • Hernia • Fecal impaction • Crohn disease • Ischemic colitis • Intussusception • Pseudoobstruction (Ogilvie syndrome) • Constipation • Toxic megacolon WORKUP • Establish IV access with two large-bore IVs. • Make the patient NPO. • Flexible sigmoidoscopy or colonoscopy in stable patients. LABORATORY TESTS • Complete blood count with differential • Basic metabolic panel IMAGING STUDIES • Acute abdominal series should demonstrate dilation of the colon (Fig. E1): 1. Sensitivity 84% 2. Specificity 72%

BOX 1  Causes of Adult Large Bowel Obstruction Mechanical • Neoplasm • Volvulus (sigmoid, cecal, transverse colon) • Diverticulitis • Cecal bascule • Intussusception • Inflammatory bowel disease • Incarcerated hernia • Infection (abscess, inflammation) • Fecal impaction • Adhesion-related obstruction • Foreign body Functional • Acute toxic or chronic megacolon • Colonic pseudoobstruction (Ogilvie syndrome)

• CT abdomen and pelvis imaging is useful to pinpoint the obstruction and possibly identify the etiology (Fig. E2): 1. Sensitivity 83% 2. Specificity 93% • Water contrast enema is useful for evaluating volvulus or distal obstruction cancer: 1. Sensitivity 96% 2. Specificity 98% 3. Occasionally therapeutic

TREATMENT • IV fluid resuscitation: 1. Consider placing Foley catheter to monitor UOP • Correction of electrolyte abnormalities • Nasogastric tube to decompress the GI tract • Cessation of narcotics and antihistamines

NONPHARMACOLOGIC THERAPY • Emergent laparotomy for perforation, closed loop obstruction, peritonitis, or ischemia 1. Placement of loop colostomy • Rectal cancer: Loop colostomy for cancer, then neoadjuvant chemoradiation • Colon cancer: Depends on location; Hartmann for sigmoid colon cancer, partial or total colectomy for other colon cancers • Flexible sigmoidoscopy for colonic decompression of volvulus • Endoscopic stenting for palliation or as a bridge to surgery ACUTE GENERAL Rx Neostigmine for pseudoobstruction CHRONIC Rx Not indicated DISPOSITION Immediate referral to general surgery and hospital admission REFERRAL General surgery SUGGESTED READINGS Available at ExpertConsult.com RELATED CONTENT Acute Colonic Pseudo-Obstruction (Ogilvie Syndrome) (Related Key Topic) Constipation (Related Key Topic) Colorectal Cancer (Related Key Topic) AUTHORS: Justin Pinkston, MD, and Mark F. Brady, MD, MPH, MMSc

From Cameron JL, Cameron AM: Current surgical therapy, ed 12, Philadelphia, 2017, Elsevier.

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SUGGESTED READINGS Fabrizio AC, Wick EC: The management of large bowel obstructions. In Cameron JL, Cameron AM, editors: Current surgical therapy, ed 12, Philadelphia, 2017, Elsevier. Mahmoud NN et al: Large bowel obstruction and pseudo-obstruction. In Townsend CM et al., editor: Sabiston textbook of surgery, Philadelphia, 2017, Elsevier.

FIG. E1  Sigmoid volvulus. (Courtesy Harisinghani Mukesh, MD, MGH Radiology. In Cameron JL, Cameron AM: Current surgical therapy, ed 12, Philadelphia, 2017, Elsevier.)

A

B FIG. E2  A and B, Obstructing sigmoid colon cancer. (Courtesy Harisinghani Mukesh, MD, MGH Radiology. In Cameron JL, Cameron AM: Current surgical therapy, ed 12, Philadelphia, 2017, Elsevier.)

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Laryngeal Carcinoma BASIC INFORMATION DEFINITION Laryngeal carcinoma is cancer of the larynx, including the vocal cords (glottis), supraglottis, and subglottis. SYNONYMS Laryngeal cancer Head and neck cancer (subsite) ICD-10CM CODES D02.0 Carcinoma in situ of larynx C32.8 Malignant neoplasm of overlapping sites of larynx C32.9 Malignant neoplasm of larynx, unspecified D14.1 Benign neoplasm of larynx D38.0 Neoplasm of uncertain behavior of larynx

EPIDEMIOLOGY & DEMOGRAPHICS It is estimated that there were 12,410 new cases and 3,760 deaths in 2019 in the U.S. The peak incidence is in the sixth decade, with 80% of cases detected in males. Approximately 60% of cases present as advanced disease (stages III to IV). Compared with Caucasians, African Americans develop laryngeal cancer at a younger age and have a higher incidence and mortality. PHYSICAL FINDINGS & CLINICAL PRESENTATION • Glottis: Early diagnosis possible because of voice change (hoarseness). Any voice change of more than 2 wks’ duration should prompt a laryngeal examination. • Supraglottis: 1. No early symptoms 2. Cervical lymphadenopathy 3. Neck or ear pain 4. Discomfort and/or pain during swallowing 5. Later: Hoarseness, dysphagia, airway obstruction • Subglottis: Even more subtle than supraglottic lesion; the same signs occur, only later in the course. ETIOLOGY The following factors are implicated in the development of laryngeal cancer: • Smoking • Alcohol intake/abuse • Diet (red meat) • Gastroesophageal and laryngopharyngeal reflux • Chronic laryngitis • Exposure to textile dust, asbestos, polycyclic aromatic hydrocarbons • Exposure to radiation • Human papillomavirus is detected in 20% to 30% cases, but the causative aspects are yet to be determined

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • Laryngitis • Allergic and nonallergic rhinosinusitis • Gastroesophageal reflux • Voice abuse leading to hoarseness • Laryngeal papilloma TNM STAGING (AJCC EIGHTH EDITION): Primary Tumor: • Tx: Primary tumor cannot be assessed • Tis: Carcinoma in situ Supraglottic cancers: • T1: Tumor limited to one subsite with normal cord mobility • T2: Tumor invades mucosa of more than one adjacent subsite (e.g., base of tongue, vallecula, pyriform sinus) without fixation of larynx • T3: Tumor is limited to larynx with vocal cord fixation and/or invasion of postcricoid area, pre-epiglottic space, paraglottic space, and/ or inner cortex of thyroid cartilage • T4a: Moderately advanced local disease; tumor invades thyroid cartilage or extends into tissues beyond larynx (trachea, soft tissue of the neck, strap muscles, thyroid, or esophagus) • T4b: Very advanced local disease; tumor invades prevertebral space, encases carotid artery, or invades mediastinal structures Glottic cancers: • T1: Tumor limited to vocal cord with normal mobility • T1a: Tumor limited to one vocal cord • T1b: Tumor involves both vocal cords • T2: Tumor extends to supraglottis and/or subglottis and/or impairs cord mobility • T3: Tumor limited to larynx with cord fixation and/or invasion of paraglottic space and/or inner cortex of thyroid cartilage • T4: T4a and T4b—same as supraglottic staging Subglottic cancers: • T1: Tumor limited to subglottis • T2: Tumor extends to vocal cord(s), with normal or impaired mobility • T3: Tumor limited to larynx with vocal cord fixation and/or inner cortex of thyroid cartilage • T4: T4a and T4b—same as supraglottic staging Nodal status: • Nx: Nodes cannot be assessed • N0: No regional node metastases • N1: Metastasis in a single ipsilateral node 3 cm but 6 cm in size • N2c: Metastasis in bilateral nodes none >6 cm in size • N3a: Metastasis in one or more nodes >6 cm in size • N3b: Metastasis in any lymph node with clinically overt extranodal extension Distant metastases: • M0: No distant metastases

• M1: Distant metastases present Stage grouping: • Stage I: T1, N0, M0 • Stage II: T2, N0, M0 • Stage III: T3, N0, M0; or T1-3, N1, M0 • Stage IVA: T1-3, N2, M0 • Stage IVB: Any T, N3, M0; T4b, any N, M0 • Stage IVC: Any T, any N, M1

WORKUP • Primary workup includes either biopsy or fine-needle aspiration (FNA) of the presenting lesion or suspected neck lymph node for histopathologic analysis. HPV assessment with p16 immunohistochemical staining and confirmatory in situ hybridization (ISH) testing is not usually indicated unless extension of a primary pharyngeal tumor is suspected. • Detailed examination of the oral cavity, pharynx, larynx, neck, ears, nose, and cranial nerves should be performed. • Laryngoscopy and examination under anesthesia are commonly performed. • Pretreatment evaluation of tumor size, the extent of invasion, and the presence or absence of regional lymph node metastases is critical for planning treatment. • Laboratory workup can include complete blood count, complete chemistry panel, and thyroid function. • Staging workup includes CT or MRI imaging (Fig. E1) of the head and neck and a chest x-ray. If locoregional or advanced disease is a consideration, a PET scan is typically completed. HISTOLOGIC CLASSIFICATION Epithelial cancers: • Squamous cell carcinoma • Superficially invasive cancer • Verrucous carcinoma • Pseudosarcoma • Anaplastic cancer • Transitional cell carcinoma • Lymphoepithelial cancer • Adenocarcinoma • Neuroendocrine tumors, including small cell and carcinoid Sarcomas: • Metastatic or primary

TREATMENT GENERAL Rx The guiding treatment principles are focused on definitive cancer-directed therapy, larynx preservation, and voice rehabilitation in all patients. • Early-stage (T1 to T2) patients can be treated with conservative surgery with or without neck dissection. Surgical options include transoral laser microscopic surgery or open conservation laryngeal surgery. Alternatively, definitive radiotherapy is also a curative option.

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Laryngeal Carcinoma

828.e3 antibody cetuximab. A recent study has demonstrated the superiority of frontline therapy with platinum plus 5-flurouracil chemotherapy in combination with the checkpoint inhibitor, pembrolizumab. • In patients who have not received checkpoint inhibitor therapy previously, the use of nivolumab and pembrolizumab has been shown to improve survival outcomes after failure of first-line chemotherapy.

A

B

C

D

FIG. E1  Carcinoma of the larynx. (A,B) Coronal STIR and (C,D) axial T1WI + Gad FS. The coronal images demonstrate the superior and inferior extents while the axial images define the extent more accurately. (From Grant, LA: Grainger & Allison’s diagnostic radiology essentials, ed 2, Philadelphia, 2019, Elsevier.)

• Intermediate-stage patients can be treated with definitive radiotherapy, supraglottic laryngectomy with neck dissection with or without radiotherapy, or concurrent chemotherapy and radiotherapy. • Advanced-stage patients are treated with concurrent chemotherapy and radiotherapy as initial therapy; salvage laryngectomy is reserved for cases of treatment failure. In glottic cancers, early-stage and intermediate-stage cases are treated similarly as above. For advanced cases (T4), total laryngectomy and neck dissection followed by postoperative radiation with or without chemotherapy in high-risk situations is a standard approach. Concurrent chemotherapy and radiotherapy can be considered for medically inoperable candidates.

Subglottic cancers require a total laryngectomy and neck surgery followed by radiotherapy with or without chemotherapy. In case of unresectable cancers, the treatment consists of definitive chemotherapy and radiotherapy followed by neck dissection. If hypopharyngeal involvement exists, then laryngopharyngectomy with neck dissection and postoperative radiotherapy with or without chemotherapy is required. Metastatic cancers: • Patients who have metastatic cancers or unresectable locoregional recurrences are usually treated with systemic chemotherapy. • Standard doublet chemotherapy regimens (platinum plus either 5-fluorouracil or a taxane) can be combined with the epidermal growth factor receptor (EGFR)–targeting

DISPOSITION • Survival depends upon location of the tumor, with supraglottic cancers typically having better stage-for-stage 5-yr survival rates compared with glottic cancers. • Voice rehabilitation, including the use of tracheoesophageal prosthesis, is associated with improved quality of life in patients receiving treatment for laryngeal cancers. • Patients with metastatic cancers have improved outcomes with introduction of targeted therapies and immunotherapy drugs. • Multiple molecular targets, including tyrosine kinase receptors (such as epidermal growth factor receptor [EGFR], fibroblast growth factor receptor 1 [FGFR1], and Erb-B2 receptor tyrosine kinase 2 [ERBB2]), oncogenes (cyclin-D1 [CCND1], Harvey rat sarcoma viral oncogene homolog [HRAS]), tumor suppressor genes (tumor protein 53 [TP53], neurofibromin 1 [NF1]), and the phosphoinositide 3-kinase (PI3-K) pathway have been identified, which can potentially be utilized as therapeutic targets. REFERRAL To multidisciplinary team consisting of an ENT or head and neck physician, radiation oncologist, and medical oncologist RELATED CONTENT Laryngeal Cancer (Patient Information) Head and Neck Squamous Cell Carcinoma (Related Key Topic) AUTHOR: Ritesh Rathore, MD

SUGGESTED READINGS Bar-Ad V, et al.: Current management of locally advanced head and neck cancer: the combination of chemotherapy with locoregional treatments, Semin Oncol 41(6):798–806, 2014. Burtness B, et al.: Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048): a randomised, open-label, phase 3 study. Lancet. 2019, pii: S0140-6736(19)32591-32597. doi: 10.1016/S01406736(19)32591-7. [Epub ahead of print] Forastiere AA, et al.: Concurrent chemotherapy and radiotherapy for organ preservation in advanced laryngeal cancer, N Engl J Med 349(22):2091–2098, 2013. Siegel RL, et al.: Cancer statistics, CA Cancer J Clin 69(1):7–34, 2019. Steuer CE, et al.: An update on larynx cancer, CA Cancer J Clin 67(1):31–50, 2017.

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Laryngitis

DEFINITION Laryngitis is an acute or chronic inflammation of the laryngeal mucous membranes. SYNONYM Lower respiratory tract infection ICD-10CM CODES J04.0 Acute laryngitis J37.0 Chronic laryngitis

EPIDEMIOLOGY & DEMOGRAPHICS It is a common illness worldwide in both genders and all age groups, but the diagnosis is imprecise and, therefore, statistics are not readily available with respect to incidence and prevalence. PHYSICAL FINDINGS & CLINICAL PRESENTATION ACUTE LARYNGITIS: • Clinical syndrome characterized by the onset of hoarseness, voice breaks, or episodes of aphonia; may also have accompanying sore throat, cough, nasal congestion, and rhinorrhea • Usually associated with viral upper respiratory infection • Larynx with diffuse erythema, edema, and vascular engorgement of the vocal folds, and occasionally mucosal ulceration • In young children subglottis is often affected, resulting in airway narrowing with marked hoarseness, inspiratory stridor, dyspnea, and restlessness • Respiratory compromise rare in adults CHRONIC LARYNGITIS: Characterized by hoarseness or dysphonia persisting for longer than 2 wk. ETIOLOGY ACUTE LARYNGITIS: • Most often caused by viruses so treatment consists of supportive measures as outlined in “Nonpharmacologic Therapy” section. • Studies evaluating the use of antibiotics (erythromycin, penicillin) in acute laryngitis failed to show objective clinical benefit over placebo so they are not routinely recommended. Antibiotics and other antimicrobials may be indicated in cases in which specific treatable pathogens are identified. • Avoid decongestants because of their drying effect. • Guaifenesin may be a useful adjunct as a mucolytic agent. • In gastroesophageal reflux disease (GERD)associated laryngitis use acid-suppressive

therapy (H2 blockers, proton pump inhibitors) and nocturnal antireflux precautions. CHRONIC LARYNGITIS: • Results from any of the following: Tuberculosis, usually through bronchogenic spread; leprosy, from nasopharyngeal or oropharyngeal spread; syphilis, in secondary and tertiary stages; rhinoscleroma, extending from the nose and nasopharynx; actinomycosis; cryptococcosis; histoplasmosis; blastomycosis; paracoccidioidomycosis; coccidiosis; candidiasis; aspergillosis; sporotrichosis; rhinosporidiosis; parasitic infections including leishmaniasis and Clinostomum infection following raw fresh-water fish ingestion. • Noninfectious causes of both acute and chronic laryngitis include malignancy, voice abuse (singers), GERD, and chemical or environmental irritants such as cigarettes and allergens. Other causes of inflammatory or granulomatous lesions of the larynx include relapsing polychondritis, Wegener granulomatosis, and sarcoidosis.

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • Young children with signs of airway obstruction: 1. Supraglottitis (epiglottitis) 2. Laryngotracheobronchitis 3. Tracheitis 4. Foreign body aspiration • In adults with persistent hoarseness, consider noninfectious causes of laryngitis as listed previously • Table E1 summarizes the classification and definition of infectious illnesses involving the larynx and supraglottic and infraglottic regions WORKUP • History and physical examination: Diagnosis is usually apparent. • Laryngoscopy for severe or persistent cases. • Laryngeal cultures should be performed if a cause other than acute viral infection is suspected. • Imaging not indicated unless there is evidence of airway compromise. Obtain plain radiographs of neck, anteroposterior and lateral views, to differentiate laryngitis from acute laryngotracheobronchitis or supraglottitis.

TREATMENT

• Use an air humidifier. • Ensure adequate hydration. Avoid alcohol and caffeine because of diuretic effect.

L

ACUTE GENERAL Rx • Antibiotics and other antimicrobials should generally not be used. They are indicated only when a specific pathogen is isolated; commonly employed antibacterial agents are macrolides; clarithromycin 500 mg by mouth bid for 5 to 7 days or azithromycin 500 mg followed by 250 mg once daily for 4 to 5 days if the cause of laryngitis is found to be Mycoplasma pneumoniae or Chlamydophila pneumoniae (the new name for what was formerly known as Chlamydia pneumoniae). • Avoid decongestants because of their drying effect. • Guaifenesin may be a useful adjunct as a mucolytic agent. • In GERD-associated laryngitis use acidsuppressive therapy (H2 blockers, proton pump inhibitors) and nocturnal antireflux precautions.

Diseases and Disorders

BASIC INFORMATION

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I

DISPOSITION Uncomplicated laryngitis is usually benign, with gradual resolution of symptoms. REFERRAL • If symptoms persist for >2 wk, refer to otolaryngologist for laryngoscopy. • Consider referral to gastroenterologist if GERD is suspected.

PEARLS & CONSIDERATIONS • Most cases of uncomplicated acute laryngitis are viral in origin, and antibacterial agents should not be routinely administered. • A recent Cochrane analysis in 2013 found no evidence for the use of empiric antibiotics in adults with laryngitis. • The most difficult clinical challenge is often convincing patients with acute laryngitis that they do not need and will not benefit from antibacterial agents.

SUGGESTED READING Available at Expertconsult.com RELATED CONTENT Laryngitis (Patient Information) AUTHOR: Glenn G. Fort, MD, MPH

NONPHARMACOLOGIC THERAPY • Rest the voice.

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SUGGESTED READING Reveiz L, Cardona AF: Antibiotics for acute laryngitis in adults, Cochrane Database Syst Rev Mar 28(3):CD004783, 2013.

TABLE E1  Classification and Definition of Infectious Illnesses Involving the Larynx and Supraglottic and Infraglottic Regions Category

Other Terms

Definitions

Supraglottitis

Epiglottitis

Infection of the epiglottis and/or arytena-epiglottic folds and ventricular bands of the base of the epiglottis, resulting in swelling and upper airway obstruction Inflammation of larynx resulting in hoarseness; usually occurs in older children and adults in association with common upper respiratory viral infections Infection involving larynx and other areas of upper and lower airway due to Corynebacterium diphtheriae, resulting in gradually progressive obstruction of airway and associated inspiratory stridor Inflammation of larynx and trachea most often caused by infection with parainfluenza and influenza viruses Inflammation of larynx, trachea, and of bronchi or lung or all three; usually similar in onset to laryngotracheitis, but a more severe illness; bacterial infection frequently has causative role Severe form of laryngotracheitis, laryngotracheobronchitis, or laryngotracheobronchopneumonitis due to bacterial infection

Laryngitis Laryngeal diphtheria

Membranous croup, true croup, diphtheritic croup

Laryngotracheitis

False croup, virus croup, acute obstructive subglottic laryngitis Membranous laryngotracheobronchitis, pseudomembranous croup

Laryngotracheobronchitis and laryngo-tracheobronchopneumonitis Bacterial croup Spasmodic croup

Bacterial tracheitis, membranous croup, membranous tracheitis, membranous laryngotracheobronchitis, pseudomembranous croup Spasmodic laryngitis, catarrhal spasm of the larynx, subglottic allergic edema

Illness characterized by sudden nighttime onset of inspiratory stridor; associated with mild upper respiratory infection without inflammation or fever but with edema in subglottic region

From Cherry JD et al: Feigin and Cherry’s pediatric infectious diseases, ed 8, Philadelphia, 2019, Elsevier.

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Lead Poisoning  BASIC INFORMATION DEFINITION Lead is a potent, pervasive neurotoxicant. Lead poisoning refers to multisystem abnormalities resulting from excessive lead exposure. SYNONYM Plumbism ICD-10CM CODES T56.0X1A Toxic effect of lead and its ­compounds, accidental ­(unintentional), initial encounter T56.0X1D Toxic effect of lead and its ­compounds, accidental ­(unintentional), subsequent encounter T56.0X1S Toxic effect of lead and its ­compounds, accidental ­(unintentional), sequela T56.0X2A Toxic effect of lead and its compounds, intentional self-harm, initial encounter T56.0X2D Toxic effect of lead and its compounds, intentional self-harm, subsequent encounter T56.0X2S Toxic effect of lead and its compounds, intentional self-harm, sequela T56.0X3A Toxic effect of lead and its ­compounds, assault, initial encounter T56.0X3D Toxic effect of lead and its compounds, assault, subsequent encounter T56.0X3S Toxic effect of lead and its ­compounds, assault, sequela T56.0X4A Toxic effect of lead and its compounds, undetermined, initial encounter T56.0X4D Toxic effect of lead and its ­compounds, undetermined, ­subsequent encounter T56.0X4S Toxic effect of lead and its compounds, undetermined, sequela

EPIDEMIOLOGY & DEMOGRAPHICS • Lead poisoning is most common in children ages 1 to 5 yr (17,000 cases/100,000 persons). The highest rates are among blacks, those with low income, and urban children. • In 1991 the Centers for Disease Control and Prevention (CDC) lowered the definition of a safe blood lead level to 15% of preschoolers in the U.S. have a blood lead level >15 mcg/dl. PHYSICAL FINDINGS & CLINICAL PRESENTATION • Findings vary with the degree of toxicity (Table 1). Examination may be normal in patients with mild toxicity.

• Myalgias, irritability, headache, and general fatigue may be present initially. • Abdominal cramping, constipation, weight loss, tremor, paresthesias and peripheral neuritis, seizures, and coma may occur with severe toxicity. • Motor neuropathy is common in children with lead poisoning; learning disorders are also frequent.

ETIOLOGY Chronic, repeated exposure to paint containing lead, plumbing, storage of batteries, pottery, or lead soldering. Concentration of lead is generally highest in lead-based paint on exterior surfaces. Among interior surfaces, windows are most likely to have the highest lead content. Table 2 summarizes common sources of lead.

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • Polyneuropathies from other sources • Anxiety disorder, attention deficit disorder • Malabsorption, acute abdomen • Iron-deficiency anemia WORKUP Laboratory screening: All U.S. children should be considered to be at risk for lead poisoning and should be screened routinely starting at age 1 yr for low-risk children and age 6 mo for high-risk children. LABORATORY TESTS • Venous blood lead level: Normal level, 70 mcg/dl, associated with severe poisoning • Mild anemia with basophilic stippling on peripheral smear • Elevated zinc protoporphyrin levels or free erythrocyte protoporphyrin level

• An increased body burden of lead with previous high-level exposure in patients with occupational lead poisoning can be demonstrated by measuring the excretion of lead in urine after premedication with calcium ethylenediamine tetraacetic acid (EDTA) or another chelating agent

IMAGING STUDIES • Imaging studies are generally not necessary. • A plain abdominal film can visualize lead particles in the gut. • “Lead lines” may be noted on x-ray films of long bones.

TREATMENT NONPHARMACOLOGIC THERAPY • Provide adequate amounts of calcium, iron, zinc, and protein in patient’s diet. • Family education on sources of lead exposure and potential adverse health effects. ACUTE GENERAL Rx • The use of chelation in cases of acute lead poisoning is guided by the patient’s clinical status and the blood lead level (BLL). For children with blood levels of 10 to 19 mcg/ dl, the CDC recommends nonpharmacologic interventions (see “Nonpharmacologic Therapy”). • For children with blood levels between 20 and 44 mcg/dl, the CDC recommendations include case management by a qualified social worker, clinical management, environmental assessment, and lead hazard control. Chelation therapy should be considered in children with refractory blood lead levels. Chelation therapy (Table 3) is indicated in children with blood lead levels >45 mcg/dl. • Succimer (DMSA) 10 mg/kg PO q8h for 5 days then q12h for 2 wk can be used in patients with levels between 45 and 70 mcg/dl.

TABLE 1  Serum Lead Levels and Symptoms Symptoms Level (μg/dl)

Adults

Children

10

None

20

50 70

Increased protoporphyrin No symptoms Increased blood pressure Decreased hearing Peripheral neuropathies Nephropathy Infertility (men) Decreased hemoglobin synthesis Anemia

Decreased IQ Decreased hearing Decreased growth Decreased nerve conduction velocity Increased protoporphyrin Decreased vitamin D metabolism

100

Encephalopathy

30 40

Decreased hemoglobin synthesis

Lead colic Anemia Encephalopathy Nephropathy Death

IQ, Intelligence quotient. From Marx JA et al: Rosen’s emergency medicine, ed 8, Philadelphia, 2014, Saunders.

These proofs may contain color figures. Those figures may print black and white in the final printed book if a color print product has not been planned. The color figures will appear in color in all electronic versions of this book.

Lead Poisoning • Edetate calcium disodium (EDTA) and dimercaprol (BAL) are effective in patients with severe toxicity. • Use of both EDTA and DMSA is indicated in children with blood levels >70 mcg/dl. • d-Penicillamine (Cuprimine) can also be used for lead poisoning, but it is not FDA approved for this condition. TABLE 2  Sources of Lead

From Kliegman RM: Nelson’s textbook of pediatrics, ed 21, Philadelphia, 2020, Elsevier.

DISPOSITION Patients with mild to moderate toxicity generally improve without any residual deficits. The presence of encephalopathy at diagnosis is a poor prognostic sign. Residual neurologic deficits may persist in these patients. Chelation therapy seems to slow the progression of renal insufficiency in patients with mildly elevated body lead burden. REFERRAL If exposure to lead is work related, it should be reported to the Office of the United States Occu­ pational Safety and Health Administration (OSHA). Follow-up testing is mandatory in all patients after an abnormal screening blood lead level.

lower cognitive function and socioeconomic status at age 38 yr, with declines in IQ, and downward social mobility.1 • Screening of household members of affected individuals is recommended. • In children with blood lead levels of >45 mg/ dl, treatment with succimer does not improve scores on tests of cognition, behavior, or neuropsychological function. • Lead toxicity may delay growth and pubertal development in girls. • Low-level environmental lead exposure may accelerate progressive renal insufficiency in patients without diabetes who have chronic renal disease. Repeated chelation therapy may improve renal function and slow the progression of renal failure.

RELATED CONTENT Lead Poisoning (Patient Information)

L

Diseases and Disorders

Paint chips Dust Soil Parent's or older child's occupational exposure (auto repair, smelting, construction, remodeling, plumbing, gun/bullet exposure, painting, e-scrap) Glazed ceramics Herbal remedies (e.g., Ayurvedic medications) Home remedies including antiperspirants, deodorants (litargirio) Jewelry (toys or parents’) Stored battery casings (or living near a battery smelter) Lead-based gasoline Moonshine alcohol Mexican candies; Ecuadorian chocolates Indoor firing ranges Retained bullet fragments Imported spices (svanuri marili, zafron, kuzhambu) Lead-based cosmetics (kohl, surma) Lead plumbing (water) Imported foods in lead-containing cans Imported toys Home renovations Antique toys or furniture

CHRONIC Rx • Reduce exposure, remove any potential lead sources. • Correct iron deficiency and any other nutritional deficiencies. • Recheck blood lead level 7 to 21 days after chelation therapy.

831

I

AUTHOR: Fred F. Ferri, MD

PEARLS & CONSIDERATIONS COMMENTS • Even blood lead concentrations as low as 5 to 10 mcg/dl are inversely associated with children’s IQ scores at age 3 and 5 yr. A recent study evaluating long-term ramifications of childhood lead exposure revealed that childhood lead exposure was associated with

1Reuben

A et al: Association of childhood blood lead levels with cognitive function and socioeconomic status at age 38 and with IQ change and socioeconomic mobility between childhood and adulthood, JAMA 317(12):1244–1251, 2017.

TABLE 3 Chelators* Chelator

Dose

Indications

Contraindications

Deferoxamine

Iron level >500 g/dl or systemic symptoms Lead level >70 g/dl or encephalopathy Arsenic: Symptomatic patient with known exposure Mercury: Inorganic

Peanut allergy Organic mercury ­poisoning

Succimer (DMSA)

15 mg/kg/hr up to 24 hr (titrate up slowly because of hypotension) Lead encephalopathy: 75 mg/m2 deep IM injection every 4 hr for 5 days in children or 4 mg/kg every 4 hr for adults Arsenic (severe): No established regimen; consider 3 mg/kg IM every 4 hr for 48 hr; then twice daily for 7-10 days Mercury: 5 mg/kg IM first; then 2.5 mg/kg every 12-24 hr 1500 mg/m2/day continuous IV infusion 50 mg/kg/day or 1000 mg/m2/day in 2-4 divided doses for up to 5 days if less severe symptoms 10 mg/kg q8h × 5 days; then q12h for 14 days

d-Penicillamine

25 mg/kg q6h × 5 days

Penicillin allergy

DMPS (investigational)

5 mg/kg/dose IM q6-8h day 1, q8-12h day 2, q12-24h day 3 and until 24-hr urine is 65% of cases within the first year. • Spontaneous remission of oral LP usually occurs by 5 yr. • Approximately 10% to 20% of patients will have recurrence.

FIG. E4  Shiny, flat-topped, polygonal, violaceous papules of lichen planus. Note the Wickham striae (linear, whitish-gray streaks) on the surface. (From Paller AS, Mancini AJ: Hurwitz clinical pediatric dermatology, a textbook of skin disorders of childhood and adolescence, ed 5, 2016, Elsevier.)

DIAGNOSIS • Clinical history and physical findings usually establish the diagnosis of LP. • Skin biopsy (deep shave or punch biopsy of the most developed lesion) can be performed to confirm the diagnosis.

DIFFERENTIAL DIAGNOSIS • Drug eruption, psoriasis, Bowen disease, leukoplakia, candidiasis, lupus rash, secondary syphilis, seborrheic dermatitis, chronic graft-versus-host disease • Table E1 summarizes variants of lichen planus WORKUP If the diagnosis is questionable, a skin biopsy is performed.

LABORATORY TESTS Laboratory tests are not specific for the diagnosis of LP. Lipid panels screening is useful since increases in serum triglycerides and decreases in HDL cholesterol are common in patients with LP. IMAGING STUDIES Imaging studies are not helpful in diagnosing LP.

TREATMENT NONPHARMACOLOGIC THERAPY • Avoid scratching. • Use mild soaps and emollients after bathing to prevent dryness.

REFERRAL To dermatologist if diagnosis is unclear

PEARLS & CONSIDERATIONS COMMENTS • LP can be remembered as purple, planar, pruritic, polygonal, papules, and plaques (six Ps). • Lesions can develop at the site of prior skin injury (Koebner phenomenon). • Although there is an increased risk of squamous cell carcinoma in chronic lesions of mucosal LP, transformation to skin cancer is uncommon. RELATED CONTENT Lichen Planus (Patient Information) AUTHOR: Fred F. Ferri, MD

Lichen Planus

833.e4

A

B FIG. E5  A and B, Lichen planus. Note the fine, reticulated white scales. (Swartz MH: Textbook of physical diagnosis, history and examination, ed 7, Philadelphia, 2014, Saunders.)

FIG. E6  Oral lichen planus. Wickham striae on the buccal mucosa. (From Paller AS, Mancini AJ: Hurwitz clinical pediatric dermatology, a textbook of skin disorders of childhood and adolescence, ed 5, 2016, Elsevier.)

Lichen Planus

FIG. E7  Lichen planus. The plaques of lichen planus may be hypertrophic but show the characteristic violaceous coloration and intense hyperpigmentation. (From Paller AS, Mancini AJ: Hurwitz clinical pediatric dermatology, a textbook of skin disorders of childhood and adolescence, ed 5, 2016, Elsevier.)

TABLE E1  Variants of Lichen Planus Variant Type

Characteristics

Bullous LP pemphigoides

Bullae develop on existent LP lesions LP + bullous pemphigoid with autoimmune reactivity, usually against type XVII collagen (bullous pemphigoid 180 antigen) Onset during spring, summer; primarily sun-exposed surfaces (face, neck, dorsum of arms and hands); often annular configuration; most common in children and young adults Occur in 10% of patients, often scattered amid typical lesions of LP Thick, pruritic, hyperkeratotic plaques, especially on the legs and dorsal regions of the feet; persistent May represent a resolving phase in which larger plaques become centrally depressed with residual hyperpigmentation Shows nonblanching component on diascopy

Actinic

Annular Hypertrophic Atrophic Hemorrhagic/purpuric Linear Erosive/ulcerative LP/lupus erythema­ tosus Lichen planopilaris

LP occurring spontaneously along the lines of Blaschko; presumably reflects somatic mosaicism Intensely painful ulcerations on the palms and soles; chronic lesions may evolve into squamous cell carcinoma; erosive lesions may occur on mucosal surfaces Overlapping features of lupus and LP; lesions are usually acral and patients may show high titers of ANA Follicular LP; keratotic plugs surrounded by violaceous erythema, especially on scalp but can affect any hair-bearing area; usually results in cicatricial alopecia

ANA, Anti-nuclear antibodies; LP, lichen planus. From Paller AS, Mancini AJ: Hurwitz clinical pediatric dermatology, a textbook of skin disorders of childhood and adolescence, ed 5, 2016, Elsevier.

SUGGESTED READINGS Arias-Santiago S et al: Cardiovascular risk factors in patients with lichen planus, Am J Med 124:543–548, 2011. Le Cleach L, Chosidow O: Lichen planus, N Engl J Med 366:723-732, 2012.

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Lichen Sclerosus BASIC INFORMATION DEFINITION Lichen sclerosus (LS) is a chronic inflammatory condition of the skin usually affecting the vulva, penis, perianal area, and groin. SYNONYMS Lichen sclerosus et atrophicus Kraurosis vulvae Balanitis xerotica obliterans LS ICD-10CM CODE L90.0 Lichen sclerosus et atrophicus

EPIDEMIOLOGY & DEMOGRAPHICS • Most common in postmenopausal women and men between ages 40 and 60 yr. • More common in females (female:male ratio of 5:1). It affects 1.7% of the general adult female population. • Can occur in children (usually prepubertal girls with involvement of the vulva and perineum). PHYSICAL FINDINGS & CLINICAL PRESENTATION • Erythema may be the only initial sign. A characteristic finding is the presence of ivory-white atrophic lesions on the involved area. • Close inspection of the affected area will reveal the presence of white-to-brown follicular plugs on the surface (dells). • When the genitals are involved, the white, parchment-like skin assumes an hourglass configuration around the introital and perianal area (“keyhole” distribution; Fig. E1, Fig. E2). Inflammation, subepithelial hemorrhages, and chronic ulceration may develop. • In males, lesions are atrophic and may be hypopigmented or depigmented, resembling vitiligo. Phimosis and paraphimosis are common complications in uncircumcised males with LS. • Lesions may be surrounded by an erythematous to violaceous halo. • Dyspareunia, genital bleeding, and anal bleeding are common. • Pruritus may be a prominent symptom.

• Table E1 summarizes the differential diagnosis of common vulvar mucocutaneous disorders

WORKUP Diagnosis is based on close examination of the lesions for the presence of ivory-white atrophic lesions and typical location. LABORATORY TESTS • Punch or deep shave biopsy can be used to confirm the diagnosis. • Autoantibodies to extracellular matrix protein 1 (ECM-1) are present in 80% of LS patients and the ECM-1 titer correlates with disease activity.

TREATMENT NONPHARMACOLOGIC THERAPY • Attention to hygiene and elimination of irritants or excessive bathing with harsh soaps. • Cryotherapy and photodynamic therapy can be used in refractory cases. GENERAL Rx • Application of clobetasol propionate 0.05% topically bid for up to 4 wk is usually effective. Repeat courses of corticosteroids may be necessary because of the chronic nature of this disorder. Continual application of topical steroids may lead to atrophy of the vulva.

• There is no substantial evidence that use of topical sex hormones (e.g., topical testosterone [2%]) is effective in genital lichen sclerosus. • Lubricants (e.g., Nutraplus cream) are useful to soothe dry tissues. • Hydroxyzine 25 mg at bedtime is effective in decreasing nocturnal itching. • Use of intralesional steroids, etretinate, and surgical management is usually reserved for refractory cases.

DISPOSITION • The disease persists in approximately one third of patients. • Most prepubertal girls improve spontaneously at menarche. • Squamous cell carcinoma can develop within the lesions in 3% to 10% of older patients; therefore periodic examination and biopsy of suspicious areas are indicated.

PEARLS & CONSIDERATIONS COMMENTS • Prepubertal lichen sclerosus may be confused with sexual abuse in prepubertal girls and may lead to false accusations and investigations. • Pregnancy leads to improvement and often complete resolution of lesions, suggesting a hormonal component to etiology of lesions.

ETIOLOGY Unknown. There may be an autoimmune association and a genetic familial component.

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • Localized scleroderma (morphea) • Cutaneous discoid lupus erythematosus • Atrophic lichen planus • Psoriasis • Lichen simplex chronicus • Vulvar intraepithelial neoplasm • Extramammary Paget disease

FIG. E1  Lichen sclerosus with stenosis of the introitus, fissuring in the posterior fourchette, and perianal involvement producing the “keyhole appearance.” (Fishe BK and Margesson LJ: Genital skin disorders: Diagnosis and treatment. In Disaia PJ et al: Clinical gynecologic oncology, ed 9, Philadelphia, 2017, Elsevier.)

Lichen Sclerosus

833.e7 • Lichen sclerosus of the vulva (kraurosis vulvae) usually occurs after menopause and is generally chronic. It can be painful and interfere with sexual activity. • Lichen sclerosus of the penis (balanitis xerotica obliterans) is seen more commonly in uncircumcised males. It affects the glans and prepuce and may lead to stricture if it encroaches into the urinary meatus.

RELATED CONTENT Lichen Sclerosus (Patient Information) AUTHOR: Fred F. Ferri, MD

A

B FIG. E2  A, Clinical appearance of lichen sclerosus. Note the atrophy of the labium minus. B, Lichen sclerosus with a prominent hourglass appearance. (From Crum CP et al: Diagnostic gynecologic and obstetric pathology, ed 3, Philadelphia, 2018, Elsevier.) TABLE E1  Differential Diagnosis of Common Vulvar Mucocutaneous Disorders Diagnosis

Acan

Lichen simplex chronicus (LSC) Lichen sclerosus (LS) Eczema Lichen planus LSC + LS Eczema + LSC Zoon Psoriasis

+

PK

Spong

HK

±

+

± ± ± + + +

+

+ ±

LI

ID

±

±

±

± ± + +

+ +

+

+

+

IEN

Sclerosis

+

Atroph

TTR

Exclude

±

Candida

±

dVIN

+ ± ±

Seborrheic dermatitis Early LS dVIN Candida Syphilis LSC, Candida

Acan, Acanthosis; Atroph, atrophy; dVIN, differentiated vulvar intraepithelial neoplasia; HK, hyperkeratosis; ID, interface dermatitis; IEN, intraepithelial neutrophils; LI, lichenoid infiltrate; PK, parakeratosis; Spong, spongiosis; TTR, test tube rete; ±, may be present. From Crum CP et al: Diagnostic gynecologic and obstetric pathology, ed 3, Philadelphia, 2018, Elsevier.

SUGGESTED READING Chi CC et al: Topical interventions for genital lichen sclerosus, Cochrane Database Syst Rev 12:CD008240, 2011.

833.e8

Lichen Simplex Chronicus BASIC INFORMATION DEFINITION Lichen simplex chronicus (LSC) is neurodermatitis manifesting with localized areas of thickened, hyperplastic scaly skin due to prolonged and severe scratching in patients with no underlying dermatologic condition. SYNONYMS LCS Neurodermatitis from rubbing Circumscribed neurodermatitis ICD-10CM CODE L28.0 Lichen simplex chronicus

EPIDEMIOLOGY & DEMOGRAPHICS PEAK INCIDENCE: Between 35 and 50 yr old PREVALENCE: Increased in patients with underlying anxiety disorders PREDOMINANT SEX AND AGE: • Sex: Females > males (2:1) • Age: Adults over 60 RISK FACTORS: Anxiety disorders, dry skin, insect bites PHYSICAL FINDINGS & CLINICAL PRESENTATION • Patients present with profound pruritus and localized scaly plaques with accentuated skin markings said to resemble tree bark. • Lichenified circumscribed plaques. Trauma from rubbing and scratching accounts for persistence of the plaque. • Commonly involved areas include hands and wrists, back and sides of neck (Fig. E1), anterior tibias, anogenital areas (Fig. E2), the scalp, the upper eyelid, the orifices of both ears, and ankles. ETIOLOGY • Neurodermatitis due to long-term chronic rubbing and scratching more vigorously than a normal pain threshold would allow, resulting in thickened and leathery skin. • Common triggers are excess dryness of skin, heat, sweat, and psychological stress. It can also accompany other conditions such as obsessive-compulsive disorder, the fungal infections candidiasis or tinea cruris, or psoriasis, lichen sclerosus, and neoplasia, leading to squamous cell hyperplasia.

A

• Other causes include atrophic dermatitis and insect bites. Rare cases have shown links to lithium use, hair dye containing PPD, and long-term exposure to vehicle pollution.

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • Lichen planus • Psoriasis • Atopic dermatitis • Insect bite • Nummular eczema • Contact dermatitis • Stasis dermatitis WORKUP Patient history and skin examination. Skin biopsy when diagnosis is unclear or persistent symptoms. LABORATORY TESTS • Not generally necessary. • Biopsy reveals hyperkeratosis, acanthosis, and mild to moderate lymphohistiocytic inflammatory infiltrate with prominent lichenification.

TREATMENT NONPHARMACOLOGIC THERAPY • Patient education is essential to break the itch-scratch cycle and facilitate treatment of any underlying dermatitis. • Psychotherapy. ACUTE GENERAL Rx • Cessation of pruritus is the goal. Antihistamine hydroxyzine 25 mg at bedtime is effective in decreasing nocturnal itching. Moisturizers are also helpful • High-potency topical corticosteroids can be used initially but not indefinitely because of potential for steroid-induced atrophy • Steroid-containing tape may be effective in providing both occlusion and antiinflammatory effect • Intralesional corticosteroids • Anxiolytics, SSRIs • Oral doxepin (an antidepressant and anxiolytic) • Mirtazapine • Tropical calcineurin inhibitor for vulvar lichenification

B

FIG. E1 (A and B) Lichen simplex chronicus. Localized plaques of dermatitis that result from repeated scratching and rubbing of the involved area. (From Paller AS, Mancini AJ: Hurwitz clinical pediatric dermatology, a textbook of skin disorders of childhood and adolescence, ed 5, 2016, Elsevier.)

• Cyclosporin A • Topical tacrolimus, 0.1% ointment, can be used for sensitive skin, face • Botulinum intradermal injections • Alitretinoin, 30 mg daily for 3 mo, has shown some clinical improvement in case studies but needs further investigation as a potential Rx

CHRONIC Rx Constant irritation of the skin must be avoided. Keeping skin moisturized, covering to prevent scratching, or filing nails may be necessary. DISPOSITION Psychological intervention improves recovery. Regular follow-up visits facilitate long-term management. REFERRAL Refer to a psychologist for psychological evaluation and consultation, and a dermatologist in resistant cases.

PEARLS & CONSIDERATIONS • Significant scratching may occur during nocturnal hours. • The involved area is always at a site that is easily reached for scratching. • Chronic scratching can also cause keratinocyte necrosis and the development of amyloid in the papillary dermis, called lichen amyloidosis.

COMMENTS Patients may be at increased risk for scarring of the skin, changes in skin pigmentation, and bacterial and fungal infections of the involved skin. PREVENTION Prevent future incidences by continued therapy, stress management, and avoidance of common triggers and accompanying conditions. AUTHORS: Fred F. Ferri, MD, and Heather Ferri, DO

Lichen Simplex Chronicus 

A

B FIG. E2  A, Lichen simplex chronicus is characterized clinically by thickening of the mucosa, lending a leathery appearance that often is discolored (as in this case). B, Lichen simplex chronicus with pronounced changes associated with itch-scratch cycle. (From Crum CP et al: Diagnostic gynecologic and obstetric pathology, ed 3, Philadelphia, 2018, Elsevier.)

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Listeriosis  BASIC INFORMATION DEFINITION Listeriosis is a systemic infection caused by the gram-positive aerobic bacterium Listeria monocytogenes. The range of clinical syndromes varies from gastroenteritis to life-threatening meningitis and tends to be more severe in immunocompromised patients and in patients who are pregnant. SYNONYMS Listerial infection Granulomatosis infantisepticum ICD-10CM CODES A32 Listeriosis A32.0 Cutaneous listeriosis A32.11 Listeria meningitis A32.81 Oculoglandular listeriosis A32.89 Other forms of listeriosis P37.2 Neonatal (disseminated) listeriosis

EPIDEMIOLOGY & DEMOGRAPHICS INCIDENCE (IN U.S.): • Listeria meningitis: About 0.7 cases/100,000 persons (fourth most common cause of community-acquired bacterial meningitis in adults) • In pregnant women: 3.0 cases per 100,000 population • In general population: 0.29 confirmed cases per 100,000 persons in 2009 to 2011 in the United States, but 1.3 per 100,000 cases in persons over the age of 65 • Approximately 800 lab-confirmed cases are reported in the U.S. annually PREDOMINANT SEX: Pregnant women are more susceptible to Listeria bacteremia, accounting for up to one third of reported cases. PREDOMINANT AGE: • Pregnant women • Immunocompromised patients of any age • Elderly patients are susceptible even in the absence of recognized immunocompromised states GENETICS: Congenital infection: • With transplacental transmission, syndrome termed granulomatosis infantisepticum in neonate • Characterized by disseminated abscesses in multiple organs, skin lesions, and conjunctivitis • Mortality: 33% to 100% Neonatal infection: • Infant becoming ill after 3 days of age; mother invariably asymptomatic • Clinical picture is of sepsis of unknown origin PHYSICAL FINDINGS & CLINICAL PRESENTATION • Infections in pregnancy 1. More common in third trimester 2.  Usually present with fever and chills without localizing symptoms or signs of infection

• Meningoencephalitis 1. More common in neonates and immunocompromised patients, but up to 30% of adults have no underlying condition 2. In neonates: Poor appetite with or without fever possibly the only presenting signs 3. In adults: Presentation often subacute, with low-grade fever and personality change as only signs 4.  Focal neurologic signs seen without demonstrable brain abscess on CT scan • Cerebritis/rhombencephalitis 1. Headache and fever may be only presenting complaints 2. Progressive cranial nerve palsies, hemiparesis, seizures, depressed level of consciousness, cerebellar signs, respiratory insufficiency may also be seen • Focal infections 1. Ocular infections (purulent conjunctivitis) and skin lesions (granulomatosis infantisepticum) as a result of inadvertent inoculation by laboratory and veterinary personnel 2.  Others: Arthritis, prosthetic joint infections, peritonitis, osteomyelitis, organ abscesses, cholecystitis

• Cerebral toxoplasmosis • Lyme disease • Sarcoidosis

ETIOLOGY • Listeria is a gram-positive rod that acts as a facultative intracellular parasite that helps protect the cell from host innate and adaptive immune responses. The primary habitat for the bacterium is soil and decaying vegetable matter. • Listeria is a hardy organism that can withstand a wide range of conditions including refrigeration (can grow at standard refrigerated temperature of 40 degrees Fahrenheit), freezing, heat, and relatively high levels of acid, salinity and alcohol. • Incubation period is between 11 and 70 days, with a mean of 31 days. • Direct invasion of skin and eye has been documented, but most cases involve GI tract at the level of the intestine, with Listeria crossing the mucosal barrier by active endocytosis of the bacteria by endothelial cells. Once in the bloodstream, the organism can disseminate to any site, with a predilection for CNS and placenta. • Organism’s intracellular life cycle explanatory of: 1. Importance of cell-mediated immunity in host defense 2. Increased infection in neonates, pregnant women, and immunocompromised hosts

ACUTE GENERAL Rx • Drugs of choice: Meningitis, meningoencephalitis and bacteremia 1. IV ampicillin 2 g IV q 4 hr for adults. Children: 300 mg/kg per day IV in 4 to 6 divided doses. Infants 8 days to 1 mo: 150 to 200 mg/kg per day divided in four doses. For infants ≤7 days: 100 mg/kg per day divided in two doses for infants weighing 460 ms in women and >440 ms in men). Notably, 20% to 25% genotype positive LQTS may have normal QTc on resting ECG. • In case of congenital LQTS, the presentation of syncope or SCD is typically triggered by exercise and swimming in LQT1 patients, in LQT2 patients by emotion, pregnancy, or noise, and patients with LQT3 are at highest risk of events when at rest or asleep. ETIOLOGY • Cardiac repolarization abnormality • Congenital cause (hundreds of mutations on more than 10 genes have been identified) • Most of the gene mutations affect function of ion channels leading to prolonged repolarization (i.e., sodium and potassium channels resulting in either increased Na+ influx or decreased K+ efflux). These mutations

prolong depolarization and predispose the patient to torsades de pointes • Acquired causes: 1.  Drugs: Dofetilide, ibutilide, bepridil, quinidine, procainamide, sotalol, amiodarone, ranolazine, disopyramide, phenothiazines and antiemetic agents (droperidol, domperidone), tricyclic antidepressants, antipsychotics (quetiapine, ziprasidone, iloperidone), citalopram, antihistamines, quinolones, azithromycin, astemizole or cisapride given with ketoconazole or erythromycin, clarithromycin, and antimalarials, particularly among patients with asthma or those using potassium-lowering medications; also common in patients receiving methadone 2. Hypokalemia, hypomagnesemia, hypocalcemia (especially in patients with malabsorption syndrome) 3. Liquid protein diet 4. Central nervous system lesions 5. Ischemia 6. Hypothyroidism

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • See “Syncope.” • Brugada syndrome, arrhythmogenic right ventricular dysplasia, and LQTS are major causes of genetic sudden death syndromes (Fig. 1).

TABLE 1  Common Types of Long QT (LQT) Syndrome

Pathophysiology Gene Protein Ionic current Clinical Presentation Incidence of cardiac events Incidence of SCD Arrhythmia triggers

LQT1

LQT2

LQT3

KCNQ1 (KvLQT1) Kv7.1 Decreased IKs

KCNH2 (HERG) Kv11.1 Decreased IKr

SCN5A Nav1.5 Increased late INa

63%

46%

18%

4% Emotional/physical stress (swimming, diving)

4% Emotional stress, arousal (alarm clock, telephone), rest, postpartum period Low-amplitude, bifid T wave

4% Sleep/rest

ECG

Broad-based T wave

QT response to exercise

Attenuated QTc shortening and an exaggerated QTc prolongation during early and peak exercise

Normal QT during exercise but with exaggerated QT hysteresis

+++ +++

++ +++

? ?

+ ++

++ ++

+ ++

+

+

++

Management Exercise restriction Response to beta blockers Potassium supplement Left cervicothoracic sympathectomy Response to mexiletine

From Issa Z et al: Clinical arrhythmology and electrophysiology, ed 2, Philadelphia, 2012, Saunders.

Long isoelectric ST segment Supernormal QT shortening

Long QT Syndrome

QT 0.52

A

V2

V3

B

V1

ECG Criteria QTc >480 ms QTc 460-480 ms QTc 450-460 ms (males) QTc 4th minute of recovery from exercise stress test >480 ms Torsade de pointes T-wave alternans Notched T wave in three leads Bradycardia History Syncope with stress Syncope without stress Congenital deafness Definite family history of long QT Unexplained cardiac death in first-degree relative 90% of all genotyped LQTS patients, whereas the remaining genes are responsible for a minority of cases. • Risk stratification for each genetic variant on the basis of gender and QTc: Groups are defined on the basis of the probability of the first cardiac event (syncope, cardiac arrest, or sudden death) before the age of 40 yr or before therapy. Specific mutations, depending on type, location, and degree, may confer a high risk even if the ECG abnormalities are mild. Clinically, QT interval duration was the strongest predictor of risk for cardiac events; a QTc exceeding 500 ms identifies patients with the highest risk. 1. High risk (>50% of cardiac event): QTc ≥500 ms and LQT1 or LQT2, or male with LQT3. 2. Moderate risk (30% to 50%): QTc leg

Acute + − + − −

Insidious + − − + −

Leg > back Acute − + + − +

Insidious + − − + −

Leg > back Insidious + − − + −

−

+

−

+

+

*+ denotes presence of finding or pain with movement; − denotes absence of finding or pain with movement. From Hochberg MC: Rheumatology, ed 7, Philadelphia, 2019, Elsevier.

Lumbar Disk Syndrome therapists generally use the McKenzie method. • Lumbosacral corset brace during rehabilitation process in conjunction with exercise

838.e3 program is beneficial in only a minority of cases.

CUTANEOUS INNERVATION OF THE LOWER EXTREMITIES: ANTERIOR VIEW Peripheral Nerves

Dermatomes

Iliohypogastric, hypogastric branch (L1)

L1

Lumboinguinal, genitofemoral branch (L1, L2) L2

Ilioinguinal (L1) Lateral femoral cutaneous (L2, L3) Obturator (L2–L4)

L3 Anterior femoral cutaneous (L2, L3) Common peroneal (L5, S1, S2)

L5

Superficial peroneal (L4, L5, S1) L4

Saphenous (L2, L4)

S1 Deep peroneal (L3, L4)

FIG. E1  Cutaneous sensory innervation. Anterior view of the lower extremities illustrating skin areas supplied by nerve roots (right) and peripheral nerves (left). (From Hochberg MC: Rheumatology, ed 7, Philadelphia, 2019, Elsevier.)

• Percutaneous electrical nerve stimulation may be beneficial in selected patients with chronic back pain. • Acupuncture is modestly effective. • A recent trial of spinal manipulation therapy (SMT) and home exercise with advice (HEA) for subacute and chronic back-related leg pain revealed that SMT plus HEA was more effective than HEA alone after 12 wk, but at 52 wk the benefit was sustained only for global improvement, satisfaction, and medication use and not for self-reported low-back pain, disability, and general health status.

ACUTE GENERAL Rx • NSAIDs. • Muscle relaxants for sedative effect are commonly used; however, trials have shown that among patients with acute, nontraumatic, nonradicular LBP presenting to the emergency department, adding cyclobenzaprine or oxycodone/acetaminophen to naproxen alone did not improve functional outcomes or pain at 1-wk follow-up. These findings do not support use of these additional medications in this setting. • Analgesics provide only modest benefit. • Injection therapy for low back pain and sciatica has limited clinical benefit and is generally not recommended. Epidural steroid injection for leg symptoms only in selected patients. • Surgical management can be considered if the symptoms do not improve after conservative treatment. Patients with predominantly radiating leg pain or leg symptoms tend to benefit more from surgery than those with isolated low back pain. DISPOSITION • Almost all lumbar disk syndromes improve with time. • Recurrent episodes usually respond to medical management. • Recovery from the rare paralytic event is often incomplete. REFERRAL • For orthopedic or neurosurgical consultation for intractable pain or significant neurologic deficit • Emergency referral for cauda equina syndrome • Table E4 summarizes indications for surgical referral

TABLE E2  Symptoms and Signs of Common Root Compression Syndromes Produced by Lumbar Disk Prolapse Root Lesion

Pain

Sensory Loss

Motor Weakness

Reflex Lost

Other Signs

S1

From buttock down back of thigh and leg to ankle and foot From buttock to lateral aspect of leg and dorsum of foot Lateral aspect of thigh to medial side of calf

Sole of foot and posterior calf

Plantar flexion of ankle and toes

Ankle jerk

Diminished straight leg raising

Dorsum of foot and anterolateral aspect of lower leg Medial aspect of calf and shin

Dorsiflexion of foot and toes

None

As above

Dorsiflexion and inversion of ankle; extension of knee

Knee jerk

Positive femoral stretch test

L5

L4

From Ballinger A: Kumar & Clark’s essentials of clinical medicine, ed 6, Edinburgh, 2012, Saunders.

Lumbar Disk Syndrome

838.e4

TABLE E3  Red Flags for Potentially Serious Underlying Causes of Low Back Pain

TABLE E4  Indications for Surgical Referral Disk Herniation

Spinal Fracture

• Cauda equina syndrome (emergency) • Serious neurologic deficit • Progressive neurologic deficit • Greater than 6 wk of disabling radiculopathy (elective)

• Significant trauma • Prolonged glucocorticoid use • Age >50 yr

Infection or Cancer • History of cancer • Unexplained weight loss • Immunosuppression • Injection drug use • Nocturnal pain • Age >50 yr

Spinal Stenosis

Cauda Equina Syndrome

• Serious or progressive neurologic deficit

• Serious neurologic deficit • Progressive neurologic deficit • Persistent and disabling pseudoclaudication (elective)

Spondylolisthesis

• Urinary retention • Overflow incontinence • Fecal incontinence • Bilateral or progressive motor deficit • Saddle anesthesia

From Firestein GS et al: Kelley’s textbook of rheumatology, ed 9, Philadelphia, 2013, Saunders.

Spondyloarthritis • Severe morning stiffness • Pain improves with exercise, not rest • Pain during second half of night • Alternating buttock pain • Age 75%; affects presynaptic neuronal calcium channel activity Antineuronal nuclear antibodies, also known as antiHu; others unknown Unknown

Hypercalcemia Cushing syndrome Lambert-Eaton myasthenic syndrome Other neuromyopathic disorders Thrombophlebitis

SCLC most common; may be any type All types

ACTH, Adrenocorticotropic hormone; SCLC, small cell lung cancer; SIADH, syndrome of inappropriate secretion of antidiuretic hormone. Adapted from Andreoli TE et al: Andreoli and Carpenter’s Cecil essentials of medicine, ed 8, Philadelphia, 2010, Saunders.

841

L

Diseases and Disorders

DEFINITION A primary lung neoplasm is a malignancy arising from lung tissue. The different types are non–small cell lung cancer (NSCLC, 85% of all lung cancers; squamous cell carcinoma, adenocarcinoma, and large cell carcinoma) and small cell lung cancer (SCLC, 15% of all lung cancers). ADENOCARCINOMA: Represents 35% to 40% of lung carcinomas; frequently located in midlung and periphery; initial metastases are to lymphatics; frequently associated with peripheral scars; adenocarcinoma is described as preinvasive, minimally invasive, or invasive. SQUAMOUS CELL: Represents 20% to 30% of lung cancers; central location; metastasis by local invasion; frequent cavitation and obstructive phenomena. SMALL CELL: Represents 15% of lung carcinomas; central location; metastasis through lymphatics; associated with lesion of the short arm of chromosome 3; high cavitation rate. LARGE CELL: Represents 10% to 15% of lung carcinomas; frequently located in the periphery; metastasis to central nervous system and mediastinum; rapid growth rate with early metastasis. LEPIDIC-PREDOMINANT PATTERN (BRONCHO­ ALVEOLAR): Represents 5% of lung carcinomas; frequently located in the periphery; may be bilateral; initial metastasis through lymphatic, hematogenous, and local invasion; no correlation with cigarette smoking; cavitation rare.

Lung Neoplasms, Primary

I

842

Lung Neoplasms, Primary

ALG

T

A

V

B FIG. 1  Pancoast tumor with chest wall invasion. A, On computed tomography, a right apical mass is associated with invasion of the chest wall and rib destruction (arrows) . Although the tumor appears to contact the vertebral body, it appears intact. B, Coronal magnetic resonance imaging shows the relationship of the tumor (T ) to the vertebral body (V ) and the brachial plexus (arrow), which appears to be involved. (From Webb WR et al: Fundamentals of body CT, ed 4, Philadelphia, 2015, Elsevier.)

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • Pneumonia • Tuberculosis (TB) • Metastatic carcinoma to the lung • Lung abscess • Granulomatous disease • Carcinoid tumor • Sarcoidosis • Benign lesions that simulate thoracic malignancy: 1. Lobar atelectasis: Pneumonia, chronic inflammatory disease, allergic bronchopulmonary aspergillosis 2.  Multiple pulmonary nodules: Septic emboli, Wegener granulomatosis, sarcoidosis, rheumatoid nodules, fungal disease, multiple pulmonary atrioventricular fistulas 3.  Mediastinal adenopathy: Sarcoidosis, lymphoma, primary TB, fungal disease, silicosis, pneumoconiosis, drug-induced (e.g., phenytoin, trimethadione) 4. Pleural effusion: Congestive heart failure, pneumonia with parapneumonic effusion, TB, viral pneumonitis, ascites, pancreatitis, collagen-vascular disease

of lung tumors are summarized in Table 2. Table 3 describes common molecular alterations in lung tumors. • Additional lab tests include CBC, serum chemistry studies. • Diagnosis and staging of lung cancer should be performed simultaneously to minimize invasive testing.

WORKUP • The workup generally includes chest CT, positron-emission tomographic (PET) scan, and tissue biopsy. Molecular testing for treatable oncogenic alterations should be performed to further classify NSCLC. This includes testing for mutations in the gene encoding epidermal growth factor receptor (eGFR) and in BRAF v600e, searching for translocations in the genes encoding anaplastic lymphoma kinase (ALK) and rat osteosarcoma (ROS1), and assessing expression of programmed death-ligand-1 (PD-L1).1 Common immunohistochemical markers used in the diagnosis

LABORATORY TESTS Various modalities are available to obtain a tissue diagnosis: • Biopsy of any suspicious lymph nodes (e.g., supraclavicular or mediastinal node) • Flexible fiberoptic bronchoscopy: Brush and biopsy specimens are obtained from any visualized endobronchial lesions. The use of a gene-expression classifier has a high sensitivity across different lesion sizes, locations, stages, and cell type of lung cancer. The combination of the classifier plus bronchoscopy has a sensitivity of >85%. In intermediate-risk patients with a nondiagnostic bronchoscopic examination, a negative classifier score provides support for a more conservative diagnostic approach2 • Transbronchial needle aspiration: Done with a special needle passed through the bronchoscope; this technique is useful to sample mediastinal masses or paratracheal lymph nodes • Transthoracic fine-needle aspiration biopsy with fluoroscopic or CT scan guidance to evaluate peripheral pulmonary nodules • Endobronchial ultrasound (EBUS) guided biopsy and staging is now routinely used to evaluate suspected mediastinal and hilar nodes • Mediastinoscopy and anteromedial sternotomy in suspected tumor involvement of the mediastinum • Pleural biopsy in patients with pleural effusion • Thoracentesis of pleural effusion and cytologic evaluation of the obtained fluid may confirm diagnosis

1Silvestri

2Silvestri

GA et al: A bronchial genomic classifier for the diagnostic evaluation of lung cancer, N Engl J Med 373:243–251, 2015.

GA et al: A bronchial genomic classifier for the diagnostic evaluation of lung cancer, N Engl J Med 373:243–251, 2015.

IMAGING STUDIES • Chest x-ray (Fig. 4): The radiographic presentation often varies with the cell type. Presence of pleural effusion, lobar atelectasis, and mediastinal adenopathy can occur in any cell type. • CT scan of the chest (Fig. 5) can evaluate mediastinal and pleural extension. The chest CT should include liver and adrenal glands (common sites of metastases). CT or MRI of brain should be considered in a patient presenting with neurologic symptoms (e.g., headaches, vision disturbances). • PET with 18F-fluorodeoxyglucose (18FDG-PET) (Fig. E6) is superior to CT in detecting mediastinal and distant metastases in NSCLC. It is useful for preoperative staging of NSCLC. • The use of PET-CT (Fig. E7) for preoperative staging of NSCLC reduces both the total number of thoracotomies and the number of futile thoracotomies. STAGING After confirmation of diagnosis, patients should undergo staging: • In NSCLC, the TNM staging system is used. Table 4 summarizes TNM stage groups. Both stage I (no lymph node involvement) and stage II (ipsilateral bronchopulmonary/ hilar lymph nodes or T3 tumor) include localized tumors for which surgical resection is the preferred treatment. Stage III is subdivided into IIIA (potentially resectable) and IIB/IIIC (unresectable). Stage IV indicates metastatic disease with stage IVA referring to intrathoracic metastases or pleural involvement or single extra-thoracic metastasis. stage IVB includes tumors with multiple extra-thoracic metastases • In SCLC, the staging system developed by the Veterans Administration Lung Cancer Study Group is used. It contains two stages: 1.  Limited-stage disease: Confined to the regional lymph nodes and to one hemithorax (excluding pleural surfaces), which can be included in a single radiation portal

ALG

Lung Neoplasms, Primary

TABLE 2  Common Immunohistochemical Markers Used in the Diagnosis of Lung Tumors

TABLE 3  Examples of Common Molecular Alterations in Lung Tumors

Diagnosis

Positive Immunohistochemical Markers

Squamous cell carcinoma

Cytokeratin (CK) cocktail (e.g., AE1/AE3) p63 p40 CK5/6 CK7 in up to 30% CK cocktail CK7 TTF-1 Napsin A CK cocktail CK7 CK20 cdx-2 TTF-1 rare CK cocktail TTF-1 CD56 Chromogranin A Synaptophysin CK cocktail TTF-1 (weaker than in high-grade neuroendocrine tumors) CD56 Chromogranin A Synaptophysin CK cocktail (tends to be patchy) TTF-1 (weaker than in high-grade neuroendocrine tumors) CD56 Chromogranin A Synaptophysin

Diagnosis

CK20+/CK7− CK7+/CK20−

COX-2, Cyclooxygenase 2; EGFR, epidermal growth factor receptor; LOH, loss of heterozygosity. From Niederhuber JE: Abeloff’s clinical oncology, ed 6, Philadelphia, 2020, Elsevier.

In situ and invasive mucinous adenocarcinoma

Large cell neuroendocrine carcinoma

Carcinoid tumor

Atypical carcinoid tumor

Common differential diagnoses: • Colonic adenocarcinoma • Lung, breast, pancreatobiliary, upper gastrointestinal adenocarcinoma • Urothelial carcinoma • Prostatic adenocarcinoma • Mesothelioma • Malignant melanoma

CK7+/CK20+ CK7−/CK20− Calretinin, WT1, CK5/6 S-100, HMB-45, Melan-A

From Niederhuber JE: Abeloff’s clinical oncology, ed 6, Philadelphia, 2020, Elsevier.

2. Extensive-stage disease: Spread beyond the confines of limited-stage disease • Pretreatment staging procedures for lung cancer patients, in addition to complete history and physical examination, generally include the following tests: 1.  Chest radiograph (posteroanterior and lateral), ECG 2.  Laboratory evaluation: Complete blood count, complete metabolic panel; arterial blood gases and pulse oximetry in selected cases 3. Pulmonary function studies 4. CT scan of chest and PET scan: Trials have shown a reduction in futile thoracotomies for patients with suspected NSCLC who undergo preoperative assessment with PET in addition to conventional workup

5.  Mediastinoscopy or anterior mediastinotomy in patients being considered for possible curative lung resection 6. Biopsy of any accessible suspect lesions 7. CT scan to include liver and brain 8. Bone marrow aspiration and biopsy only in selected patients with small cell carcinoma of the lung. In the absence of an increased lactate dehydrogenase or cytopenias, routine bone marrow examination is not recommended 9. Newer technologies in preoperative staging include endoscopic bronchial ultrasonography and esophageal ultrasonography to guide biopsies; however, cervical mediastinoscopy is standard criterion in preoperative nodal staging (sensitivity >93%, specificity >95%)

Squamous cell carcinoma

Large cell carcinoma Large cell neuroendocrine carcinoma

Small cell carcinoma

L

Common Molecular Alterations LOH—3p, 9p21, 8p21–23, aneuploidy, methylation LOH—3p, 9p, aneuploidy K-ras codon 12 mutation p53 mutation p16 mutation/inactivation K-Ras (42%); smokers more common EGFR overexpression (40%) EGFR mutation Her2/neu, COX-2 overexpression p53 mutation p16 inactivation Allelic loss 3p EGFR overexpression (80%) K-Ras, p53, loss p16 p53 bcl-2 overexpression Rb mutation 3p21, FHIT, 3p22–24, 5q21,9p21 Rb mutation (80+%) p53 mutation 50%–80% BCL-2 expression 3p21, FHIT, 3p22–24, 5q21,9p21

TREATMENT NONPHARMACOLOGIC THERAPY • Nutritional support • Avoidance of tobacco and other substances toxic to the lungs • Supplemental oxygen ACUTE GENERAL Rx NON–SMALL CELL CARCINOMA: • Surgical resection is standard in patients with operable NSCLC (stage I or II) who are surgical candidates. Lobectomy is the best standard surgical approach. Lesser resections may be necessary in patients with marginal pulmonary reserve. Video-assisted thoracic surgery (VATS) decreases morbidity and shortens the hospital stay. 1. Surgical resection is indicated in patients with limited disease (not involving mediastinal nodes, ribs, pleura, or distant sites). This represents approximately 15% to 30% of diagnosed cases. Stereotactic ablative radiotherapy is a

Diseases and Disorders

Adenocarcinoma including adenocarcinoma in situ or minimally invasive adenocarcinoma, nonmucinous

Squamous preneoplasia Atypical adenomatous hyperplasia Adenocarcinoma

843

I

844

Lung Neoplasms, Primary

ALG

Right lower lobe density

A

B

Right lower lobe density

FIG. 4  Lung neoplasm, primary. Lung mass presenting with hemoptysis. A, Posterior-anterior (PA) chest x-ray. B, Lateral chest x-ray. This 83-yr-old female presented with hemoptysis of a quarter-sized clot. Her posterior-anterior chest x-ray shows a rounded right lower lobe density. On the lateral view, this is visible in the retrocardiac space. This density measures 7.6 cm in diameter. Pneumonia, neoplasm, or abscess could have this appearance on chest x-ray. Computed tomography was performed to further delineate the pathology (see Fig. 5). (From Broder JS: Diagnostic imaging for the emergency physician, Philadelphia, 2011, Saunders.)

Major fissure

Solid mass consistent with neoplasm

A

B

FIG. 5  Lung neoplasm, primary. Lung mass presenting with hemoptysis. Same patient as in Fig. 4. Noncontrast computed tomography was performed (contrast was withheld as a consequence of the patient’s renal dysfunction) and shows a 6 by 6 cm round lesion abutting the oblique fissure (also called the major fissure) and lateral chest wall. A, Soft tissue windows. B, Lung windows. On soft tissue windows, the center appears slightly darker, indicating lower density that may represent central necrosis. If IV contrast had been given, an area of necrosis would have failed to enhance. Infection or infarction is technically possible, but a pulmonary neoplasm is the most likely explanation for this lesion. Biopsy showed this to be a moderately differentiated squamous cell carcinoma. (From Broder JS: Diagnostic imaging for the emergency physician, Philadelphia, 2011, Saunders.)

reasonable option for patients with localized NSCLC who are not surgical candidates. Multimodality treatment guidelines are summarized in Table 5. 2. Preoperative evaluation includes cardiac status and pulmonary function assessment. Pneumonectomy is possible if the patient has a preoperative FEV1 = 2 L or if the maximal voluntary ventilation is >50% of predicted capacity. Individuals with FEV1 >1.5 L are suitable for lobectomy without further evaluation unless there is evidence of interstitial lung disease or undue dyspnea on exertion. In

that case, carbon dioxide diffusion in the lung (DLCO) should be measured. If the DLCO is 50% PD-L1 expression. When pembrolizumab is combined with chemotherapy in patients with 1-50% PD-L1 expression, there is an improvement in overall survival. In addition, atezolizumab and nivolumab (other checkpoint inhibitors) have been shown to have superior survival benefit versus docetaxel in advanced NSCLC that had previously received chemotherapy.

ALG

TABLE 4  TNM Stage Groups for Non–Small Cell Lung Cancer Stage

T

N

M

Stage 0 Stage IA1 Stage IA2 Stage IA3 Stage IB Stage IIA Stage IIB

Tis Tmi or T1a T1b T1c T2a T2b T1a-c T2a-b T3 T1a-c T2a-b T3 T4 T1a-c T2a-b T3-4 T3-4 Any T Any T

N0 N0 N0 N0 N0 N0 N1 N1 N0 N2 N2 N1 N0-1 N3 N3 N2 N3 Any N Any N

M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M1a-1b M1c

Stage IIIA

Stage IIIB

Stage IIIC Stage IVA Stage IVB

TNM, Tumor, node, metastases.

inhibitors crizotinib, ceritinib, alectinib, brigatinib, or lorlatinib. Approximately 2% of adenocarcinomas have genetic rearrangements involving the ROS1 proto-oncogenic receptor tyrosine kinase (ROS1), and these patients can be treated with the oral inhibitors crizotinib and ceritinib. Also, approximately 2% of adenocarcinomas harbor the BRAF V600E mutation, and these patients can be treated with the combination of BRAF inhibitor and MEK inhibitor therapy. 7. The addition of chemotherapy to radiotherapy (CRT) improves survival in patients with locally advanced, unresectable stages III NSCLC. The addition of the checkpoint inhibitor durvalumab has recently shown improvement in overall survival in this population when administered sequentially after CRT. 8. Early initiation of palliative care focusing on management of symptoms, psychosocial support, and assistance with decision making in patients with metastatic NSCLC leads to improved quality of life, longer survival, and less use of aggressive end-of-life care. SMALL CELL LUNG CANCER: • Limited-stage disease: Standard treatments include thoracic radiotherapy and chemotherapy (cisplatin and etoposide). • Extensive-stage disease: Standard treatments include combination chemotherapy (platinum plus etoposide or platinum plus irinotecan). The addition of the PD-1 antibody atezolizumab to standard first-line therapy has now been proven to improve overall survival and is considered the standard of care approach. • Prophylactic cranial irradiation for patients in complete remission to decrease the risk of central nervous system metastasis. • Despite high initial response rates, most patients eventually relapse. Topotecan or irinotecan may be an option for these patients. The anti-PD-1 antibody, nivolumab, has demonstrated survival benefit in SCLC patients who have failed standard therapies.

DISPOSITION • The 5-yr survival of patients with NSCLC when the disease is resectable is approximately 30%. The 5-yr survival for stage 4 patients is now increasing, with long-term survivors seen after immunotherapy use and survival rates >20% reported in current trials. • Median survival time in patients with limitedstage disease SCLC is 15 mo; in patients with extensive-stage SCLC, it is 9 mo. • Among patients with metastatic NSCLC, early palliative care results in longer survival and significant improvements in both quality of life and mood.

PEARLS & CONSIDERATIONS CT screening with use of low-dose computed tomography (LDCT) for detection of lung cancer among persons with a heavy history of smoking increases the percentage of lung cancer cases that are diagnosed in stage 1 and reduces mortality from lung cancer. The National Lung Screening Trial (NLST) showed that lung cancer screening with LDCT resulted in a 20% reduction in lung cancer mortality. New guidelines recommend annual LDCT for those who are current or former smokers aged 55 to 74. Screening should be discontinued once a person has not smoked for 15 yr or develops a health problem that substantially limits life expectancy or the ability or willingness to have curative lung surgery.

SUGGESTED READINGS Available at ExpertConsult.com RELATED CONTENT Lung Cancer (Patient Information) Lung Cancer Screening (Patient Information) Horner Syndrome (Related Key Topic) Lambert-Eaton Myasthenic Syndrome (Related Key Topic) Paraneoplastic Syndromes (Related Key Topic) Superior Vena Cava Syndrome (Related Key Topic) AUTHOR: Ritesh Rathore, MD

TABLE 5  Summary of Multimodality Guidelines Stage

Surgery

Adjuvant Therapy

Radiation

Chemotherapy

Level of Evidence

I

Yes

No

No

No

II

Yes

Yes

No

Yes

1B—Surgical resection 1B—Against postoperative chemotherapy 1A—Against postoperative radiation therapy 1B—Surgical resection 1A—Postoperative chemotherapy 2A—Against postoperative radiation therapy

IIIA (N2-occult)

Yes

Yes

(N2-discrete)

Yes

No

IIIB (N2, N3)

No

No

May be considYes ered Yes Yes (Definitive or induction recommended) Yes Yes (Definitive concurrent)

From Sellke FW, et al.: Sabiston & Spencer surgery of the chest, ed 9, 2016, Elsevier.

1A—Adjuvant chemo 2C—Adjuvant radiation 1A—Definite or induction followed by surgery 1C—Against primary resection followed by adjuvant therapy 1A—Definitive concurrent 1A—Against induction followed by surgery

845

L

Diseases and Disorders

5. Tyrosine kinase inhibitors targeting activating mutations are of use in patients whose adenocarcinomas harbor the EGFR mutations, which are more commonly detected in patients who never smoked or are light smokers and in Asian patients. Gefitinib, erlotinib, afatinib, osimertinib, and dacomitinib are oral EGFR inhibitors that have showed impressive responses and improvements in median overall survival to the range of 30 mo. Currently, first-line therapy with the oral inhibitor osimertinib is the preferred option based on updated data demonstrating median overall survival of 36 mo. 6.  Oncogenic fusion genes consisting of EML4 and anaplastic lymphoma kinase (ALK) are present in 4% to 5% of adenocarcinomas and can be treated with

Lung Neoplasms, Primary

I

Stage I NSCLC • ECOG PS ≥2 • CCI ≥3 • Prolonged postop recovery >8 wks

No

Yes No adjuvant Rx

• Tumor size >3 cm • VPI

• LVI (lesser) • Cavitation (lesser)

No

Yes

• Adequate LND/LNS

Adjuvant Rx

Yes

No

No adjuvant Rx

Consider adjuvant Rx

FIG. 8  Algorithm for selecting patients with stage I non–small cell lung cancer (NSCLC) for postoperative adjuvant chemotherapy. CCI, Charlson Comorbidity Index; ECOG PS, Eastern Cooperative Oncology Group Performance Status; LND, mediastinal lymph node dissection; LNS, systematic mediastinal lymph node sampling; LVI, lymphovascular invasion; Rx, treatment; VPI, visceral pleural invasion. (From Niederhuber JE: Abeloff’s clinical oncology, ed 6, Philadelphia, 2020, Elsevier.)

TABLE 6  Selected Non–Small Cell Lung Cancer Oncogenes and Targeted Therapy Oncogene Alteration

Incidence (%)

Clinical Relevance

Treatment

BRAF Mutation

1-3

V600E mutation: Most common, equal association with smokers and nonsmokers May be mechanism of acquired EGFR TKI resistance

dabrafenib plus trametinib

EGFR (ErbB1, HER1) Mutation

13-50

Exon 19 deletion and Exon 21 point mutation are the most common Predominantly adenocarcinoma and nonsmokers; up to 50% ­frequency in Asians

TKI: Gefitinib, erlotinib, afatinib, osimertinib

EML4-ALK Fusion

3-7

Most frequent in adenocarcinomas, nonsmokers, men, and younger patients

Nonspecific TKI: Crizotinib, ceritinib, alectinib, brigatinib No approved therapy

2-6 23

Mostly adenocarcinomas and nonsmokers Mechanism of resistance to EGFR TKI

5-30

Mostly adenocarcinomas and smokers May contribute to resistance to ALF, BRAF, and PI3K inhibitors

Her2/neu (ErbB2) Mutation Amplification KRAS Mutation MET Mutation Amplification PIK3CA Mutation

No approved therapy No approved therapy

60 parasites/μL, lower with less parasitemia 40% in travelers when 93% when >100 parasites/μL 97% for P. falciparum 44% for P. vivax

Sensitivity increased to 96% for pure P. falciparum infection Overall specificity of 99% FDA-approved for use in the U.S. Antigen persists for 6-7 days 6 in 11.9%20% of subjects whose blood smears had cleared Not FDA approved for use in the U.S. Specificity of 90% for P. falciparum Specificity of 100% for P. vivax Not FDA-approved for use in the U.S. Specificity of 100% P. falciparum, 75%-85% for P. vivax Not FDA approved for use in the U.S. Specificity of 100% for P. falciparum, 99% for P. vivax, 90% for P. malariae, and 60% for P. ovale Not FDA-approved for use in the U.S.

85-95%; decreased with lower parasite density 93% specificity of 100%, with sensitivities of 99%, 90.0%, 86%, and 60%, respectively, for P. falciparum, P. vivax, P. malariae, and P. ovale

FDA, Food and Drug Administration; HRP-2, histidine-rich protein-2; ICT, immunochromatographic diagnostic test; LDT, laboratory developed test; RDT, rapid diagnostic test. aDirect microscopy should be performed where available with a negative RDT, given higher false-negative rates with low parasitemia, and when severe malaria is suspected. From Cherry JD et al: Feigin and Cherry’s textbook of pediatric infectious diseases, ed 8, Philadelphia, 2019, Elsevier.

TREATMENT NONPHARMACOLOGIC THERAPY ANTIMOSQUITO MEASURES: • Eradication of mosquito breeding places by chemical spray • Use of mosquito nets properly in the endemic areas • Use of protective clothing • Use of insect spray (permethrin), mosquito coils, or repellents such as diethyltoluamide (DEET). For adults, DEET (30% to 50%) is generally protective for at least 4 hr. For smaller children, use DEET at ≤20% concentration ACUTE GENERAL Rx A definitive diagnosis of malaria is essential for specific antimalarial chemotherapy. UNCOMPLICATED CHLOROQUINE-SENSITIVE PLASMODIUM VIVAX, PLASMODIUM OVALE, OR PLASMODIUM MALARIAE (NONFALCIPARUM MALARIA): • Chloroquine: 1. Adults: 600 mg base (= 1000 mg salt) orally immediately, followed by 300 mg base (= 500 mg salt) orally at 6, 24, and 48 hrs. 2. Children: 10 mg base/kg orally immediately, followed by 5 mg base/kg orally at 6, 24, and 48 hrs. 3. Maximum total dose: 1500 mg base (= 2500 mg salt). 4. An alternative agent is hydroxychloroquine (Plaquenil): 620 mg base (= 800 mg salt) orally immediately, followed by 310 mg base (= 400 mg salt) orally at 6, 24, and 48 hrs.

• In the case of P. vivax and P. ovale, treatment with primaquine 15 mg daily for 14 days is needed to eradicate the exoerythrocytic forms, especially the hypnozoites responsible for relapses. • G6PD should be measured before primaquine is given. Primaquine is not recommended for those who are glucose-6-phosphate dehydrogenase deficient, because primaquine can cause hemolysis and even death in G6PDdeficient persons. Normal G6PD levels must be documented before using primaquine for either chemoprophylaxis or treatment. • Chloroquine-resistant P. vivax has been documented; in that case use quinine sulfate (10 mg/kg) plus either tetracycline or doxycycline or clindamycin for 7 days. UNCOMPLICATED FALCIPARUM MALARIA OR SPECIES NOT IDENTIFIED: • Chloroquine can be used cautiously for falciparum malaria acquired in chloroquinesensitive areas (chloroquine is more rapidly effective than quinine). • For uncomplicated P. falciparum, an oral artemisinin combination therapy (ACT), is recommended by the CDC as the firstline agent. While there are numerous ACT combinations, the only ACT approved in the U.S. is artemether-lumefantrine (Coartem), which is not widely available. Do not delay therapy in trying to obtain it; use another first-line agent. Dosage for adults: 4 tablets artemether-lumefantrine (20/120 mg) as a single dose, then 4 tablets again after 8 hr, then 4 tablets q12h for 2 days (take with food). Can cause prolongation of QT interval. Not recommended in infants 35 kg: Treat as adult • Atovaquone-proguanil (Malarone): 250 mg atovaquone/100 mg proguanil): 4 adult tabs PO once a day for 3 days with food. Pediatric dosage: Pediatric tablets (62.5 mg atovaquone/25 mg proguanil) are used based on weight: 1. 5 to 8 kg: 2 pediatric tabs PO once daily for 3 days 2. 9 to 10 kg: 3 pediatric tabs PO once daily for 3 days 3. 11 to 20 kg: 1 adult tab PO once daily for 3 days 4. 21 to 30 kg: 2 adult tabs PO once daily for 3 days 5. 31 to 40 kg: 3 adult tabs PO once daily for 3 days 6. >40 kg: 4 adult tabs PO once daily for 3 days • Another first-line option for treatment in adults is oral quinine sulfate 10 mg (salt)/ kg (usually 650 mg) q8h for 3 to 7 days plus doxycycline 100 mg PO bid, both for 7 days. Pediatric dosage: Quinine sulfate 10 mg/kg PO tid plus clindamycin 20 mg/kg per day divided tid, both for 7 days. • Table 4 summarizes some treatment guidelines for severe Plasmodium falciparum malaria. ALTERNATIVES: • Quinine sulfate plus clindamycin 900 mg tid for 7 days in adults • Mefloquine 750 mg PO, then 500 mg PO 6 to 12 hr later in adults

Diseases and Disorders

Malaria Antigen Target

859

I

860

Malaria TABLE 4  Treatment Guidelines for Severe Plasmodium falciparum Malaria Drug

Dose

Comments

2.4 mg/kg IV bolus at 0, 12, 24 hours, then daily until patient is able to transition to the following oral regimen: 1. Artemether + lumefantrine: Tablets containing 20 + 120 mg, 40 + 240 mg of artemether and lumefantrine, respectively • Adults ≥35 kg: 80 + 480 mg twice daily for 3 days • Children: • 5 to 48 hr Lack of perioperative glucose control Placement of tracheostomy Postoperative myocardial infarction Receipt of multiple blood products Postoperative low cardiac output state

CABG, Coronary artery bypass grafting; COPD, chronic obstructive pulmonary disease; ICU, intensive care unit. From Bennett JE et al: Mandell, Douglas, and Bennett’s principles and practice of infectious diseases, ed 8, Philadelphia, 2015, WB Saunders.

• Chest CT (Fig. E2): Can show the same as x-ray but is more sensitive in determining degree of mediastinal involvement and may guide drainage procedures for treatment or diagnosis. • MRI may be superior to CT for sclerosing mediastinitis.

TREATMENT NONPHARMACOLOGIC THERAPY Surgery remains the gold standard treatment of mediastinitis for optimal drainage and debridement. • Open techniques: Debridement of infected tissue and open packing of the wound with delayed closure or use of vacuum-assisted closure for acute mediastinitis • Closed techniques: Debridement of infected tissues, closure of the sternum, and postoperative irrigation through drainage tubes for acute mediastinitis ACUTE GENERAL Rx • Intravenous antibiotics: Also a cornerstone of therapy but without surgery may fail. Broad-spectrum antibiotics should be used until cultures are finalized. Combination

M

Diseases and Disorders

Preoperative Risk Factors

871

of piperacillin-tazobactam or meropenem plus vancomycin offers good initial coverage for acute mediastinitis. Other options include ciprofloxacin or cefepime for gramnegative rods, linezolid for gram-positive bacteria, metronidazole for anaerobic bacteria. • Therapy is 2 to 3 wk, but some cases may require 4 to 6 wk.

CHRONIC Rx There is no definitive cure for chronic fibrosing or sclerosing mediastinitis. Antifungal agents and steroids generally do not work. The goal of therapy is to palliate symptoms by relieving airway, vascular, or esophageal obstruction. Surgery in patients with extensive fibrosis has high morbidity and mortality. DISPOSITION Patients may need extensive wound care and possible vacuum-assisted closure and prolonged intravenous antibiotics. REFERRAL • Thoracic surgeon and/or head and neck surgeon for surgery and debridement • Infectious diseases consultant for antibiotic selection and long-term management

I PEARLS & CONSIDERATIONS

COMMENTS Histoplasma capsulatum is a dimorphic fungus found commonly in bird and bat fecal material and is most prevalent in the Ohio and Mississippi river valleys of the United States. PREVENTION Antibiotic prophylaxis should be given within 60 min before incision for surgeries requiring sternotomy. Options include cefazolin 1 g IV if 80 kg, or cefuroxime 1.5 g IV. If the patient is penicillin allergic or has a history of methicillin-resistant S. aureus (MRSA) infection or surgery is to be done in a hospital where MRSA infection is common, use vancomycin 1 g IV. SUGGESTED READINGS Available online at ExpertConsult.com AUTHOR: Glenn G. Fort, MD, MPH

Mediastinitis SUGGESTED READINGS Abu-Omar Y et al: European association for Cardio-Thoracic surgery expert consensus statement on the prevention and management of mediastinitis, Eur J Cardiothorac Surg 51(1):10-29, 2017. Athanassiadi K: Infections of the mediastinum, Thorac Surg Clin 19:34-37, 2009. Pastene B et al: Mediastinitis in the intensive care unit patient: a narrative review, Clin Microbiol Infect S1198-743X(19):30394-30395, 2019. Peikert T et  al: Fibrosing mediastinitis: clinical presentation, therapeutic outcomes, and adaptive immune response, Medicine 90(412), 2018.

FIG. E1  Mediastinitis. Chest radiograph shows large pneumomediastinum and pneumopericardium (arrows) in a patient with mediastinitis. (From Bennett JE et al: Mandell, Douglas, and Bennett’s principles and practice of infectious diseases, ed 8, Philadelphia, 2015, WB Saunders.)

FIG. E2  Contrast-enhanced computed tomography scan shows a 3 cm × 3 cm heterogeneous enhancing abscess (arrow) in the anterior mediastinum of a child acutely ill with Streptococcus pneumoniae bacteremia and pneumonia with empyema. Cultures from the mediastinal abscess at the time of surgical drainage were sterile. (From Cherry JD et al: Feigin and Cherry's textbook of pediatric infectious diseases, ed 8, Philadelphia, 2019, Elsevier.)

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Medical Marijuana BASIC INFORMATION DEFINITION Medical cannabis refers to the use of the unprocessed marijuana plant or part of the plant or extracts from the marijuana plant as medical therapy to treat disease or alleviate symptoms. SYNONYMS Medical cannabis Cannabinoids—are biologically active compounds that have affinity or activity to the cannabinoid receptors. They may be derived from the plant or be synthetic. CBD—cannabinol THC—Δ9 -tetrahydrocannabinol ICD-10CM CODES F12.9 Cannabis use, unspecified Z02.79 Encounter for issue of other medical certificate Z79.899 Other long term (current) drug therapy

BACKGROUND • First medical marijuana law (MML) was enacted in California in 1996, allowing for use of medical cannabis despite lack of Food and Drug Administration (FDA) testing for safety and efficacy. • In 2014, 0.8% of the U.S. population used medical marijuana exclusively, and 0.5% used medical and recreational marijuana. • Of 2014 marijuana smokers, 6.2% used medical marijuana only and 3.6% used medical and recreational marijuana. • In 2015, 1.57% U.S. population used medical marijuana; highest increase in prevalence noted to be in 2015. • Residents of medical marijuana states were 1.3 times more likely to use medical marijuana in 2015 compared to 2013. • As of July 2019, state-level referendum and legislation resulted in 33 U.S. states, DC, Guam, and Puerto Rico with policies that legalized marijuana use for medical purposes. MECHANISM OF ACTION • Cannabinoids elicit their effects by interacting with cannabinoid receptors in various central nervous system (CNS) locations, eliciting diverse CNS and peripheral nervous system (PNS) effects. • Primarily bind to CB1 G-protein-coupled receptors in the basal ganglia, hippocampus, cortex, and cerebellum, eliciting antinociception, locomotor, and psychoactive effects. • Marijuana contains roughly 60 plant-derived cannabinoid compounds, with the major phytocannabinoids being cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC). FORMULATIONS Research has demonstrated a wide range of THC and CBD concentrations in various formulations, with frequent inaccurate labelling.

• Cigarettes • Tinctures • Capsules • Vaporization cartridges • Purified cannabinoids butane hash oil • Supercritical fluid extracts (SFEs or “dabs”) • Buccal sprays • Edibles • Lozenges • Transdermal patches

INDICATIONS • Variable evidence for treatment of: 1. Chronic pain 2. Chemotherapy-induced nausea/vomiting 3. HIV-related anorexia 4. Glaucoma 5. Anxiety 6. Multiple sclerosis (MS) 7. Seizures • Marijuana has not been FDA approved as safe and effective for any indication and remains a Schedule I drug. • However, there are phytocannabinoids and synthetic phytocannabinoid analogs that are FDA approved. 1. Dronabinol and Nabilone (synthetic THC analogs) are schedule II FDA approved medications for AIDS associated anorexia and chemotherapy induced nausea, respectively. 2. Purified cannabidiol oral solution (Epidiolex) is FDA approved for seizures associated with Dravet or Lennox-Gastaut syndrome. • Qualifying diagnoses for certification for prescription medical marijuana vary by state, but typically include: 1. Cancer 2. Glaucoma 3. HIV/AIDS 4. Hepatitis C 5. Cachexia 6. Severe, debilitating, chronic pain 7. Severe nausea 8. Seizures 9. Severe muscle spasms 10. Crohn disease 11. Alzheimer disease 12. PTSD 13. Sickle cell disease EFFICACY • There is evidence in the medical literature demonstrating that marijuana improves non− cancer-related pain, chemotherapy-induced nausea and vomiting, and spasticity in multiple sclerosis. 1. A 2011 systematic review of randomized controlled trials (RCTs) demonstrated statistically significant improvement in pain scores for non–cancer-related chronic pain in 15 of 18 trials with no serious adverse effects. 2. A 2015 systematic review and metaanalysis showed improved response in nausea and vomiting compared to placebo (OR 3.82). 3. A 2018 systematic review demonstrated a decrease in nausea and vomiting

following chemotherapy (RR 3.60 compared to placebo), improved spasticity with MS (RR 1.45 compared to placebo), and a modest benefit with primarily neuropathic pain (RR 1.37 compared to placebo) with frequent adverse effects including psychosis, “feeling high,” and somnolence (number needed to harm = 5 to 8). a.  No statistically significant improvement was noted in acute pain. 4. A Cochrane review in 2013 found no statistically significant weight gain with dronabinol in HIV/AIDS patients, and multiple RCTs have identified megestrol acetate as superior to dronabinol for weight gain in cancer patients.

RISKS OF USE • Marijuana use has been demonstrated to impair short-term memory consolidation, reaction time, and concept formation, and to increase incidence of road traffic accidents, ataxia, euphoria, disorientation, dry mouth, somnolence, and, at high doses, psychosis, panic, and paranoia. • Meta-analyses demonstrate increased respiratory symptoms of cough, sputum production, and wheeze with smoking marijuana; however, there was no statistical difference in pulmonary function. • Concomitant use of other medications such as opiates and benzodiazepines should be avoided as it could lead to somnolence and respiratory suppression. • Acute marijuana intoxication is associated with reversible changes in P and T waves and ST segments (pseudo-Wellens syndrome).1 • Medical marijuana should be stored away from children given the risk of toxic ingestion. PRESCRIBING • Marijuana remains classified as a schedule I drug under the Controlled Substance Act of 1970. • However, the Justice Department declared it would not prosecute any physician who recommends medical marijuana for a legitimate medical indication in a state where it has been legalized. • Medical marijuana card (MMC) 1. MMC allows a patient to possess a certain amount of marijuana for medical use and not be prosecuted for possession of marijuana. 2. In order to obtain an MMC, a patient must obtain physician certification confirming a clinical indication for medical marijuana. 3. With an MMC, the patient can go to a licensed medical marijuana compassion center (dispensary), which will dispense a dose and formulation of medical marijuana appropriate for the patient’s medical condition. 4. Physicians do not prescribe the dose or formulation of medical marijuana. • To certify a patient for a medical marijuana card, physicians must 1Co

MLF et al: Pseudo-Wellens syndrome after heavy marijuana use, Cleve Clin J Med 84(8):590-591, 2017.

 EARLS & P CONSIDERATIONS • Medical marijuana has been shown to improve non−cancer-related pain, chemotherapy-induced nausea and vomiting, and spasticity in multiple sclerosis. 1. However, qualifying diagnoses for a medical marijuana card include cancer, glaucoma, HIV/AIDS, hepatitis C, cachexia, debilitating chronic pain, severe nausea, seizures, severe muscle spasms, Crohn disease, Alzheimer disease, PTSD, and

sickle cell disease. Qualifying diagnoses may vary from state to state. 2. Adverse effects include increased incidence of road traffic accidents and pulmonary and cognitive side effects. At high doses, psychosis, panic, and paranoia can occur. 3. Hospitals may also have specific restrictions and policies regarding medical marijuana for inpatient stays. • Medical marijuana laws and regulations permit patients to use medical marijuana if certified by a physician but vary by state. 1. Physician certification involves documentation that a patient has a qualifying clinical condition. 2.  A medical marijuana card entitles a patient or designated caregiver to possess a given amount of marijuana and therefore will not be prosecuted for possession of marijuana. 3.  Medical marijuana can be obtained at state regulated medical marijuana compassion centers (dispensaries). Compassion centers obtain marijuana from licensed cultivators and offer a variety of formulations that are regulated by the state. 4. There is no FDA oversight of the compassion centers. • Physicians do not prescribe the dose or formulation of medical marijuana. • Physicians are under no obligation to issue medical marijuana certifications. • Emergency department (ED) visits attributable to inhaled cannabis are more frequent

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than those attributable to edible cannabis, although the latter is associated with more acute psychiatric visits and more ED visits than expected.2

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PATIENT & FAMILY EDUCATION • Patients must possess a valid state-issued ID and apply for a state medical marijuana card. • Patients can obtain medical marijuana from compassion centers without a medical marijuana card but could then be prosecuted for possession of marijuana. • Patients should be aware that concomitant use of other medications such as opiates and benzodiazepines should be avoided as it could lead to somnolence and respiratory suppression. • Patients should store medical marijuana away from children given the risk of toxic ingestions. SUGGESTED READINGS Available at ExpertConsult.com RELATED CONTENT Pain Management in Chronic Pain (Related Key Topic) Chemotherapy-Induced Nausea and Vomiting (Related Key Topic) AUTHORS: Anjulika Chawla, MD, and Seth Clark, MD, MPH 2Monte

AA et al: Acute illness associated with cannabis use, by route of exposure: an observational study, Ann Intern Med 170(8):531-537, 2019.

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1. Complete a Department of Health certification form. a. Forms vary by state, but typically consist of a single-page form indi­cating a qualifying diagnosis that is to be signed by the physician. 2. Complete and document a full medical history and physical exam. 3.  Explain the risks, benefits, and side effects of medical marijuana. 4. Continue an ongoing role on the patient’s health care team. 5. Maintain accurate medical records and documentation of the patient’s clinical indication for medical marijuana. • Some states require additional physician training and registration with the state medical marijuana program prior to being able to certify patients. • Physicians are under no obligation to issue medical marijuana certifications.

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Medical Marijuana SUGGESTED READINGS Allan G et  al: Systematic review of systematic reviews for medical cannabinoids: pain, nausea and vomiting, spasticity, and harms, Can Fam Physician 64(2):e78-94, 2018. Ghasemiesfe M et al: Marijuana use, respiratory symptoms, and pulmonary function: a systematic review and meta-analysis, Ann Intern Med 169:106-115, 2018, https://doi.org/10.7326/M18-0522. Han B et  al: Trends in and correlates of medical marijuana use among adults in the United States, Drug Alcohol Depend 120-129, 2018, https://doi. org/10.1016/j.drugalcdep.2018.01.022. Hauser W et al: European Pain Federation (EFIC) position paper on appropriate use of cannabis-based medicines and medical cannabis for chronic pain management, European Journal of Pain 22:1547-1564, 2018. Keyhani S et al: Risks and benefits of marijuana use, Ann Intern Med 169:282290, 2018. Lutge E et al: The medical use of cannabis for reducing morbidity and mortality in patients with HIV/AIDS, Cochrane Database Syst Rev 4:CD005175, 2013. National Conference of State Legislatures: State Medical Marijuana Laws. Available at www.ncsl.org/research/health/state-medical-marijuana-laws.aspx. Nugent SM et al: The effects of cannabis among adults with chronic pain and an overview of general harms, Ann Int Med 167:319-331, 2017. Thomas BF, Pollard GT: Preparation and distribution of cannabis and cannabisderived dosage formulations for investigational and therapeutic use in the United States, Front Pharmacol 7:285, 2016. Whiting PF et al: Cannabinoids for medical use: a systematic review and metaanalysis, JAMA 313(24):2456-2473, 2015.

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Medication-Related Osteonecrosis of the Jaw BASIC INFORMATION DEFINITION The American Association of Oral and Maxillofacial Surgeons (AAOMS) defines bisphosphonaterelated osteonecrosis of the jaw (BRONJ) as an exposure of bone in the maxillofacial region that does not heal within 8 wk, in patients receiving therapeutic doses of bisphosphonates (BPs) who have not undergone radiation therapy to the craniofacial region and who do not have evidence of metastatic disease in the jaw. Osteoclast apoptosis may occur due to the antiresorptive effects of BPs, preventing the release of bone-regenerative proteins and thus preventing bone renewal and remodeling. This results in tissue loss and exposed bone. BRONJ primarily involves the jawbone due to its higher risk for complications from minor injury and infection when the healing potential or vascular supply is compromised. Cases of ONJ have also been reported in patients receiving denosumab as well as chemotherapeutic and immunosuppressive agents, such as bevacizumab, sirolimus, sorafenib, and sunitinib. The AAOMS therefore uses the term medication-related osteonecrosis of the jaw (MRONJ). SYNONYMS Bisphosphonate-induced osteonecrosis of the jaw (BIONJ) Medication-related osteonecrosis of the jaw (MRONJ) Antiresorptive agent-related osteonecrosis of the jaw (ARONJ) Denosumab-related osteonecrosis of the jaw (DRONJ) ICD-10CM CODE M87.180 Osteonecrosis due to drugs, jaw

EPIDEMIOLOGY & DEMOGRAPHICS INCIDENCE: • A 2015 systematic review and consensus of 14 national and international societies describe the incidence of BRONJ in patients receiving oral BPs for the treatment of osteoporosis as 1.04 to 69 per 100,000 patientyrs. The incidence of BRONJ in patients receiving intravenous (IV) BPs ranged from 0 to 90 per 100,000 patient-yrs. • BRONJ has been estimated at 3.9% with oral BPs and at 14.8% with IV BPs at 42 mo after tooth extraction. • DRONJ has been estimated at 0.68% in patients with postmenopausal osteoporosis who underwent invasive oral procedures vs. 0.05% for those who did not. The overall exposure-adjusted rate of DRONJ was 5.2 per 10,000 patient-yrs. PEAK INCIDENCE: • BRONJ has been identified as early as 7 mo after the use of IV BPs in patients with malignancy and as early as 13 mo in patients with osteoporosis. Incidence may depend on when dentoalveolar surgery occurs during BP treatment.

• A 2017 retrospective secondary analysis of 349 patients made the following estimates of median time to onset for 50% of patients to develop BRONJ: (1) 6 yr for those treated with oral alendronate, (2) 2.2 yr for those treated with IV zoledronate, (3) 5.3 yr for patients with osteoporosis, and (4) 2.2 yr for those with malignancy. • A 2016 case series of 13 patients with malignancy receiving denosumab and with no history of BP treatment reported that DRONJ occurred after 5 to 36 doses of denosumab 120 mg subcutaneous every 4 to 6 wk. PREVALENCE: • Prevalence in 2008: estimated 13.3% of patients with malignancy receiving an IV BP. • Most prevalent in patients with multiple myeloma or breast cancer versus other cancers or osteoporosis. PREDOMINANT SEX AND AGE: • Sex not statistically associated with MRONJ. • Age as a risk factor for adults is variably reported in the literature. GENETICS: • Single nucleotide polymorphisms have been identified in the CYP2C8 gene among patients with multiple myeloma and exposure to IV BPs. • Polymorphisms in the RBMS3 gene in white patients of European descent have been associated with a nearly six fold increase in the risk of developing BRONJ. • A 2014 study of patients in Taiwan who received alendronate estimated an incidence rate of 283 per 100,000 person-yrs, suggesting a higher incidence in this ethnic group. RISK FACTORS: • Patients with malignancy who are exposed to IV BPs and undergo dentoalveolar surgery have an estimated five- to twenty-one fold increased risk for BRONJ compared with similar patients who do not undergo this surgery • The 2014 AAOMS position paper estimates that the risk of MRONJ is about 100 times greater for patients with malignancy who receive antiresorptive agents versus patients with osteoporosis • With IV formulations such as zoledronic acid, the risk ratio for developing BRONJ is 14.6 with IV versus oral products • Longer duration of antiresorptive therapy • Concomitant antiangiogenic agents and corticosteroids • History of periodontal and dental abscesses • Trauma due to invasive oral procedures such as tooth extractions • Bacterial infection • Chronic inflammation • Poor oral hygiene • Smoking • Concomitant diabetes • Ill-fitting dentures, resulting in mechanical injury • Renal impairment and advanced age may be associated with increased MRONJ severity • Rheumatoid arthritis (RA): 1. Compain et  al (2018) found that BRONJ seems to occur earlier in patients with RA than with osteoporosis (46.8 vs. 63.6 mo); likely due to age at initiation of BP, cumu-

lative dose, immunosuppression, chronic vasculitis, dental health status, and concomitant disease-modifying treatments.

PHYSICAL FINDINGS & CLINICAL PRESENTATION • Exposed areas of necrotic bone in the mandible or maxilla, with 65% of cases involving the mandible. Multifocal or bilateral involvement is possible but uncommon. Pathologic fracture of the jaw may occur. • Pain in the maxillofacial region, although one third of lesions may be painless. • Paresthesia of the chin is an early sign. • Tooth mobility or spontaneous tooth loss. • Mucosal swelling, erythema, ulceration, altered sensation. • Infection. • BRONJ due to IV BPs may produce larger and more frequent buccolingual cortical bone perforations than oral BPs. • DRONJ may produce large sequestrum and periosteal reaction. ETIOLOGY Exposure to BPs as well as other antiresorptive and antiangiogenic agents

DIAGNOSIS The AAOMS considers a diagnosis of MRONJ if the following three characteristics are present: 1. Current or previous treatment with a BP, denosumab, or antiangiogenic agent 2. Exposed bone or bone that can be probed through intraoral or extraoral fistulae in the maxillofacial region persisting for more than 8 wk 3. No history of radiation therapy to the maxillofacial region or evident metastatic disease to the jaw

DIFFERENTIAL DIAGNOSIS • Suppurative osteomyelitis of the jaw (SOJ) • Osteoradionecrosis of the jaw (ORNJ) • Alveolar osteitis, gingivitis, sinusitis, fibroosseous lesion, sarcoma, sclerosing osteomyelitis, periodontitis, dental caries, and temporomandibular joint disorders WORKUP • Treatment history, including medications and radiation therapy • Past medical history, including osteoporosis and malignancy LABORATORY TESTS A validated diagnostic test is not available to identify patients at an increased risk of BRONJ. Tissue biopsy should only be performed if metastatic disease is strongly suspected and its detection would change the management of BRONJ. Histopathology of BRONJ shows empty osteocytic lacunae, empty Haversian and Volkmann canals, an absence of inflammatory cells or blood vessels in the marrow space, and absence of extracellular collagenase. IMAGING STUDIES Panoramic and periapical radiographs

Medication-Related Osteonecrosis of the Jaw TREATMENT Goals of treatment for MRONJ include: • Control or reduce pain. • Control secondary infection. • Minimize progression or occurrence of bone necrosis, as well as extension of lesion(s).

NONPHARMACOLOGIC THERAPY The AAOMS recommends the following surgical strategies based on MRONJ staging: • Stage 0 (no clinical evidence of necrotic bone, nonexposed bone variant): No surgery • Stage 1 (exposed and necrotic bone, or fistulae that probe to bone, asymptomatic, no infection): No surgery • Stage 2 (exposed and necrotic bone, or fistulae that probe to bone, with pain or infection): Superficial debridement • Stage 3 (exposed and necrotic bone with pain, infection, and one of the following features: necrosis extending beyond alveolar bone, pathologic fracture, extraoral fistula, oral antral or nasal communication, osteolysis extending to mandible of sinus floor): Surgical debridement or resection for palliation of infection and pain Literature suggests that success rates with surgical management are higher and less variable than with conservative management. The AAOMS recommends surgery for patients with stage 3 MRONJ. However, a surgical margin with viable bone can be difficult to obtain. The entire jawbone likely has been exposed to accumulation of the drug (especially BPs), and therefore successful eradication of necrotic bone is often not possible. Those areas of necrosis that consistently irritate soft tissues should undergo debridement as necessary because dead tissue will interfere with wound healing and will be prone to infection. Another consideration is that some patients may not be surgical candidates if their overall health is poor and/or if chemotherapy is incomplete. Limited evidence supports the use of hyperbaric oxygen as adjunct to surgery and antibiotics to slow progression and improve pain. Small case reports have documented the use of platelet-rich plasma, low-level laser irradiation, parathyroid hormone, and bone morphogenic protein; however, the efficacy of these methods has not been established through controlled studies. With regards to surgery for stages 2 and 3, Kagami et al (2015) found that curettage under local anesthesia had a higher risk of relapse than sequestrectomy, saucerization, or mandibulectomy. Shibahara et  al (2018) observed that the majority of patients with stage 2 BRONJ who underwent surgery (N = 936) achieved remission (46.3%) or improvement in BRONJ (30.6%). Stage 2 surgery may also be reasonable for older patients or those with limited life expectancy, rather than lengthy debridement that may significantly decrease quality of life. ACUTE GENERAL Rx Both chlorhexidine mouth rinse and antibiotics for 1 to 3 wk have been found useful for stage reduction. Most microbes are sensitive to penicillin antibiotics.

• Chlorhexidine 0.12% antibacterial mouth rinse daily for stages 1 to 3 • Oral antibiotics for symptomatic stage 2 and oral or IV antibiotics for stage 3 • Analgesics for stages 2 or 3

CHRONIC Rx • Determine whether discontinuation of antiresorptive agent is appropriate. A multicenter retrospective chart review by Hayashida et  al (2019) evaluated 427 cases in patients with osteoporosis or malignancy. Discontinuation of antiresorptive therapy significantly increased cure rate in those with osteoporosis who underwent nonsurgical treatment and did not impact any patients who underwent surgical treatment. 1.  Evaluate potential benefit of continuing antiresorptive agent, such as relief of bone pain in malignancy or prevention of fractures with high morbidity and mortality. 2. BPs have a prolonged half-life, so return to normal osteoclast function and bone turnover may be too gradual. 3. Consider other risks of antiresorptive agents, such as atypical femoral fractures. • If discontinuing antiresorptive agents, consider alternative treatments for osteoporosis or bone pain. • Anecdotal case reports exist for using teriparatide (unless the patient has bone metastases or is at risk for osteosarcoma) or pentoxifylline plus tocopherol to heal BRONJ. • Patients with malignancy and any stage of MRONJ: Dental specialist should re-evaluate lesions every 8 wk and communicate condition to oncologist. DISPOSITION A retrospective cohort study in Japan by Shibahara et al (2018) showed that lack of risk factors for BRONJ, performing surgical removal/ reduction/resection in stage 2 BRONJ, a completely closed wound, and discontinuing BPs were all associated with a positive prognosis. • Patients with involvement of the maxilla appear to have a greater likelihood of repeat surgery. • Patients taking oral rather than IV BPs may have less severe complications and may have a better response. • Treatment with antibiotics and chlorhexidine mouth rinse, withdrawal of BPs, and surgical removal of loose sequestra may possibly reduce pain and lesions of osteonecrosis. Concomitant diabetes, lower serum albumin, malignancy as indication for antiresorptive agent, and nonsurgical treatment of MRONJ were associated with worse outcomes, including poor healing rate, in the chart review by Hayashida et al (2019). REFERRAL Oral and maxillofacial surgeon

PEARLS & CONSIDERATIONS COMMENTS • Patients may be asymptomatic for wk to yrs before BRONJ is apparent.

873.e3 • Radiographic changes may not be observed until significant disease has developed. • Tooth extraction may be difficult to avoid in patients at high risk of BRONJ if an underlying bacterial infection is present. • Patients with malignancy are at highest risk because the dosages of BPs are much higher than for osteoporosis. • Use of BPs in pediatric patients has increased without identified cases of BRONJ to date. Further evaluation of long-term use of BPs in these patients is warranted.

PREVENTION • Regular dental hygiene and routine (every 3 mo for patients with malignancy) dental examinations. 1. Results from Coello-Suanzes et al (2018) for 255 patients with malignancy showed that patients who received dental procedures prior to initiation of zoledronic acid had a statistically significant lower incidence of BRONJ (7.3% vs. 36.5%). • Appropriate fitting of dentures with periodic mucosal examination. • Assessment of patients for other risk factors of MRONJ. • Completion of any anticipated dental procedures before beginning antiresorptive therapy. • Asymptomatic patients receiving IV BPs: Limit dental surgery to removal of nonrestorable teeth and avoid dental implants in patients who also have cancer. • The 2014 AAOMS position paper supports a 2-mo drug holiday before oral surgery for patients who have received BPs for greater than 4 yr or for patients exposed to less than 4 yr of BPs and taking concomitant corticosteroids or antiangiogenics. Allow osseous healing to complete before restarting BPs. A 2017 retrospective study did not find a difference in ONJ incidence due to preextraction drug holidays of 2 or 3 mo. In terms of longterm BP drug holidays: 1. Results from the FLEX trial suggest that women with postmenopausal osteoporosis who have taken alendronate for 5 yr and are at low risk of vertebral fractures may discontinue the drug for up to 5 yr. 2. Results from the HORIZON-PFT extension trial suggest that women with postmenopausal osteoporosis who have taken IV zoledronic acid for 3 yr and are at low risk of vertebral fractures may discontinue for up to 3 yr. • Careful monitoring of patients after dentoalveolar surgery and delayed initiation of BPs by at least 2 to 3 wk to allow for osseous healing. • Evidence suggests a threefold reduction in the incidence of ONJ when preventive measures are practiced. PATIENT & FAMILY EDUCATION • All health care providers should be aware of past and current use of antiresorptive agents. • Contact a health care provider if any of the following are observed: 1. Presence of exposed bone in the maxillofacial area 2. Persisting pain in the maxillofacial area

Medication-Related Osteonecrosis of the Jaw 3. S igns of infection such as fever, pus, and swelling • Practice good dental hygiene and keep regular dental appointments. • Patients needing assistance with access to dental care may contact the AAOMS, the

Centers for Medicare & Medicaid Services, the United Way, nearby dental schools, or their local health department. AUTHORS: Christine Eisenhower, PharmD, and Connie Wang, PharmD

SUGGESTED READINGS American Association of Oral and Maxillofacial Surgeons: Medication-Related Osteonecrosis of the Jaw. Retrieved from www.aaoms.org/docs/govt_affairs/a dvocacy_white_papers/mronj_position_paper.pdf. Aparecida Cariolatto F et al: Recommendations for the prevention of bisphosphonate-related osteonecrosis of the jaw: a systematic review, J Evid Based Dent Pract 18:142-152, 2018. Hayashida S et al: Drug holiday clinical relevance verification for antiresorptive agents in medication-related osteonecrosis of the jaw, J Bone Miner Metab, 2019, https://doi.org/10.1007/s00774-019-01035-7. [epub ahead of print]. Shibahara T et al: National survey on bisphosphonate-related osteonecrosis of the jaws in Japan, J Oral Maxillofac Surg 76:2105-2112, 2018.

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Meigs Syndrome BASIC INFORMATION DEFINITIONS • Classic Meigs syndrome: A triad characterized by the presence of ascites and pleural effusion (usually right-sided) in association with a benign fibroma or fibroma-like ovarian tumor (thecoma, granulosa cell tumor, or Brenner tumor). • Nonclassic Meigs syndrome: Characterized by ascites and pleural effusion in conjunction with a benign ovarian, fallopian tube, or broad ligament tumor that is not included in the definition of classic Meigs syndrome. • Pseudo-Meigs syndrome: Characterized by both ascites and pleural effusion but caused by a pelvic or abdominal tumor, either benign or malignant, not included in either classic Meigs or nonclassic Meigs syndrome, such as leiomyomas, struma ovarii, mucinous cystadenoma, teratoma, and malignancies that are metastatic to the ovary (particularly colorectal cancer). • Pseudo-pseudo Meigs (Tjalma) syndrome: Characterized by the triad of ascites, pleural effusion, and an elevated CA-125 (Cancer antigen 125) in a patient with systemic lupus erythematosus. ICD-10CM CODES C56.9 Malignant neoplasm of unspecified ovary D27.9 Benign neoplasm of unspecified ovary D28.2 Benign neoplasm of uterine tubes and ligaments D28.7 Benign neoplasm of other specified female genital organs J91.8 Pleural effusion in other conditions classified elsewhere R18.0 Malignant ascites R18.8 Other ascites

EPIDEMIOLOGY & DEMOGRAPHICS • Occurs in 1% to 2% of ovarian fibromas (associated with approximately 0.004% of ovarian tumors) • 50). A personal history of any skin cancer or a family history of melanoma also increases the risk. • Melanoma is the leading cause of death from skin cancer. Although it represents 6 mm) E: Evolving (mole changing in size, shape, or color, or mole that differs visibly from surrounding moles [“ugly duckling” sign])

ETIOLOGY • Ultraviolet light is the most important cause of malignant melanoma. • There is a modest increase in melanoma risk in patients with small nondysplastic nevi and a much greater risk in those with dysplastic lesions. • The CDKN2A gene, residing at the 9p21 locus, is often deleted in patients with familial melanoma. • A mutated signal transduction molecule, v-raf murine sarcoma viral oncogene homolog B (BRAF), has been identified in 40% to 60% of patients with melanoma.

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • Dysplastic nevi • Solar lentigo • Vascular lesions • Blue nevus • Basal cell carcinoma • Seborrheic keratosis WORKUP • Dermoscopy (use of an instrument that shines polarized light on skin surfaces and magnifies skin lesions) can increase the accuracy in diagnosing melanoma by 10% to 27%.

TABLE 1  Four Histologic Subtypes of Cutaneous Melanoma SUPERFICIAL SPREADING MELANOMA • Incidence: Accounts for 70% of all melanomas, tends to occur in younger patients (median age, 50) • Anatomic site: Any; predominantly trunk and extremities, anatomic sites associated with intermittent sun exposure • Clinical appearance: Change in the appearance of a large mole, asymmetry, irregular border, variegated color (brown, black, pink, white, gray, and blue), often arising in a precursor mole • Can be associated with mutation in BRAF LENTIGO MALIGNA MELANOMA • Incidence: Accounts for 4% to 10% of all melanoma; tends to occur more commonly in older patients • Anatomic site: Areas with chronic exposure to the sun, head and neck regions, and distal extremities • Clinical appearance: Macular (flat) lesion; arising in a lentigo maligna, which often appears as a flat, light brown skin lesion • Can be associated with mutation in KIT NODULAR MELANOMA • Incidence: Accounts for 15% of melanomas • Anatomic site: Any • Clinical appearance: Rapidly enlarging, elevated, or polypoid lesion; often arising in normal skin; often blue, black, or pink and can be amelanotic ACRAL LENTIGINOUS MELANOMA • Incidence: 5%-10% • Anatomic site: Most commonly on the palms or soles or subungual (under the nail bed) • Clinical appearance: Darkly pigmented, flat to nodular lesion, highly irregular borders • Can be associated with mutation in KIT From Niederhuber JE: Abeloff’s clinical oncology, ed 6, Philadelphia, 2020, Elsevier.

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Diseases and Disorders

DEFINITION Melanoma is a skin neoplasm arising from the malignant degeneration of melanocytes. It is classically subdivided in four types (Table 1): 1. Superficial spreading melanoma (70%) 2. Nodular melanoma (15% ) 3. Lentigo maligna melanoma (4% to 10%) (Fig. E1) 4. Acral lentiginous melanoma (5% to 10%)

PHYSICAL FINDINGS & CLINICAL PRESENTATION Variable depending on the subtype of melanoma: • Superficial spreading melanoma is most often found on the lower legs, arms, and upper back. It may have a combination of many colors or may be uniformly brown or black. • Nodular melanoma can be found anywhere on the body, but it most frequently occurs on the trunk on sun-exposed areas. It has a dark-brown or red-brown appearance and can be dome shaped (Fig. E2) or pedunculated. Lesions are frequently misdiagnosed because they may resemble a blood blister or hemangioma and may also be amelanotic. • Lentigo maligna melanoma is generally found in older adults in areas continually exposed to the sun and frequently arising from lentigo maligna (Hutchinson freckle) or melanoma in situ. It might have a complex pattern and variable shape; color is more uniform than in superficial spreading melanoma. • Acral lentiginous melanoma frequently occurs on soles, subungual mucous membranes, and palms (sole of the foot is the most prevalent site). Unlike other types of melanoma, it has a similar incidence in all ethnic groups. • The warning signs that the lesion may be a melanoma can be summarized with the ABCDE mnemonic (Table 2): A: Asymmetry (e.g., lesion is bisected and halves are not identical) B: Border irregularity (uneven, ragged border) (Fig. E3)

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Melanoma TABLE 2  Clinical Features (ABCDE Signs) of Malignant Melanoma Clinical Feature

Comment

A B C D

Asymmetry Border irregularity Color changes Diameter >6 mm

E

Enlargement

The two halves of the lesion are not alike Borders notched, scalloped, irregular Especially blue, red, black, white Size of a pencil eraser; not applicable to congenital nevi, which are often >6 mm early in their evolution Evolutionary change in the lesion

From Paller AS, Mancini AJ: Hurwitz clinical pediatric dermatology, a textbook of skin disorders of childhood and adolescence, ed 5, Philadelphia, 2016, Elsevier.

• Any suspicious lesion (Fig. E4) should be biopsied. Perform excisional biopsy with elliptical excision that includes 1 to 2 mm of normal skin surrounding the lesion and extends to the subcutaneous tissue; incisional punch biopsy is sometimes necessary in surgically sensitive areas (e.g., digits, nose). It is essential that the size of the specimen be adequate to determine the histologic depth of penetration, which is known as the Breslow depth. • Sentinel lymph node excision (SLNE) is the most important staging and potentially therapeutic procedure for patients with melanoma. It should be considered in patients with intermediate (1 to 4 mm) melanomas or high-risk skin tumors to obtain information regarding a patient’s subclinical lymph node status with minimal morbidity. The National Comprehensive Cancer Network (NCCN) recommends that SLNE be discussed with and offered to patients classified as stage IB or II, and should be considered for patients with stage IA melanoma and “adverse” features that might portend a higher risk of sentinel node involvement (e.g., Clark level IV or V, tumor thickness of 0.75 mm or more, lymphovascular invasion, positive deep margins). SLNE involves the use of radiologic lymphoscintigraphy to map lymphatic drainage from the site of the primary melanoma to the first sentinel lymph node in the region. When properly performed, if the sentinel node is negative the remaining lymph nodes in the region will not have metastases in more than 98% of cases. If the sentinel nodes are negative, no additional regional surgery is recommended. The staging of intermediate thickness (1.2 to 3.5 mm) primary melanomas, according to the results of sentinel node biopsy, provides important prognostic information and identifies patients with nodal metastases whose survival can be prolonged by immediate lymphadenectomy. • The staging system for melanoma adapted by the American Joint Committee on Cancer (AJCC) can be found in Table 3.

LABORATORY TESTS The pathology report should indicate the following: • Tumor thickness (Breslow microstage). • Tumor depth: The depth of invasion is the most important histologic prognostic parameter in evaluating the primary tumor.

• Mitotic rate: Tabulated as mitoses per square millimeter in the dermal part of the tumor in which most mitoses are identified. • Radial growth rates versus vertical growth rate: Radial growth phase describes the growth of melanoma within the epidermis and along the dermal-epidermal junction. • Tumor infiltrating lymphocytes have a strong predictive value in vertical growth phase melanomas and are defined as brisk, nonbrisk, or absent. • Histologic regression: Characterized by the absence of melanoma in the epidermis and dermis flanked on one or both sides by melanoma. • Reverse-transcription polymerase chain reaction assay for tyrosine messenger RNA is a useful marker for the presence of melanoma cells. It is performed on sentinel lymph node biopsy and is useful for detection of submicroscopic metastases.

TREATMENT • Initial excision of the melanoma • Re-excision of the involved area after histologic diagnosis: 1. The margins of re-excision depend on the Breslow depth. For melanoma in situ with Breslow depth ≤2.0 mm, recommended surgical margin is 1 cm. If Breslow depth is ≤2.0 mm, margin should be 2 cm. For melanoma in situ, margin should be 5 mm. 2. Low-risk or intermediate-risk tumors require excision of 1 to 3 cm. 3. Melanomas of moderate thickness (0.9 to 2.0 mm) can be excised safely with 2-cm margins. 4. A 1-cm margin of excision for melanoma with a poor prognosis (as defined by a tumor thickness ≥2 mm) is associated with a significantly greater risk of regional recurrence than is a 3-cm margin, but with a similar overall survival rate. Randomized clinical trials have also shown that radical surgery with 2-cm excision margins did not differ from that with 4-cm margins for survival in patients with cutaneous melanoma >2 mm thick. • Lymph node dissection: Recommended in all patients with enlarged lymph nodes. Lymph node evaluation is important in patients with melanoma 1 mm in depth because it

determines the overall prognosis and need for therapeutic lymph node dissection or adjuvant treatment. 1. Elective lymph node dissection remains controversial. 2. It is indicated with positive sentinel node. It may be considered in those with a primary melanoma between 1 and 4 mm thick (especially in patients >60 yr). • Adjuvant therapy: 1. Interferon alfa-2b and Peginterferon alfa2b have been previously used for the adjuvant treatment resected stage III melanoma despite modest benefits. 2. Ipilimumab, an antibody that blocks cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4), improves survival in stage III high-risk resected melanoma but is associated with significant immune adverse events. 3. Immune checkpoint PD-1 (programmed death receptor-1) antibodies nivolumab and pembrolizumab have demonstrated superiority to ipilimumab in patients with resected high-risk stage III melanoma; currently only nivolumab is approved in this setting. 4. The combination regimen of BRAF inhibitor and MEK inhibitor (dabrafenib plus trametinib) has shown improved relapsefree survival in cases of resected BRAF V600-mutant stage III melanoma and is another option for these patients. • Advanced disease: 1. The use of immune checkpoint inhibitors has improved overall survival in patients with previously treated or untreated metastatic melanoma irrespective of BRAF mutation status. Monotherapy with the PD-1 inhibitors nivolumab or pembrolizumab has been approved for the treatment of metastatic melanoma in treatment-naïve patients and also in cases of progression after initial therapy with ipilimumab. 2. Combination immunotherapy with the use of nivolumab and ipilimumab in previously untreated patients with unresectable or metastatic melanoma has been shown to be more effective than ipilimumab alone as first-line treatment in high-risk patients though severe immune toxicity is seen in the majority of patients. 3. In patients who carry the V600E BRAF mutation, the combination of oral BRAF inhibitors and oral MEK inhibitors improves overall survival in patients with previously untreated melanoma. Three such combination regimens (vemurafenib plus cobimetinib; dabrafenib plus trametinib; and encorafenib plus binimetinib) are approved by the FDA for use in this setting. Targeted therapy is useful in patients with rapidly growing melanoma with BRAF mutations, but resistance appears in almost all patients, and median progression-free survival is 15 to 18 mo. Interestingly, the

Melanoma TABLE 3  The TNM Classification for Melanoma Adapted by the American Joint Committee on Cancer (AJCC, 8th edition) Thickness

Ulceration status/mitoses

Tis (in situ) T1 T1a T1b T2 T2a T2b T3 T3a T3b T4 T4a T4b

n/a 1.0-2.0 mm >1.0-2.0 mm >2.0-4.0 mm >2.0-4.0 mm >2.0-4.0 mm >4.0 mm >4.0 mm >4.0 mm

n/a Unknown or unspecified Without ulceration With/without ulceration Unknown or unspecified Without ulceration With ulceration Unknown or unspecified Without ulceration With ulceration Unknown or unspecified Without ulceration With ulceration

Number of nodes

Presence of in-transit, satellite and/or microsatellite metastases

Regional nodes (N) N0 N1

0 One tumor-involved node or any number of in-transit, satellite, and/or microsatellite metastases with no tumor-involved nodes One clinically occult (sentinel biopsy detected) One clinically detected No regional node Two or three tumor-involved nodes or any number of in-transit, satellite, and/ or micro-satellite metastases with one tumor-involved node Two or three clinically occult (sentinel biopsy detected) Two or three, at least one clinically detected One clinically occult or clinically detected Four or more tumor-involved nodes or any number of in-transit, satellite, and/ or microsatellite metastases with two or more tumor-involved nodes, or any number of matted nodes without or with in-transit, satellite, and/or microsatellite metastases Four or more clinically occult (sentinel biopsy detected) Four or more, at least one of which was clinically detected, or the presence of any number of matted nodes Two or more clinically occult or clinically detected and/or presence of any number of matted nodes

None

M category

Anatomic site

LDH level

M0 M1 M1a

No distant metastases Evidence of distant metastases Distant metastasis to skin, soft tissue including muscle, and/or nonregional lymph node Distant metastasis to lung with or without M1a sites of disease Distant metastasis to non-CNS visceral sites with or without M1a or M1b sites of disease Distant metastasis to CNS with or without M1a, M1b, or M1c sites of disease

n/a

N1a N1b N1c N2

N2a N2b N2c N3

N3a N3b N3c

M1b M1c M1d

No No Yes

No No yes

DISPOSITION • Prognosis varies with the stage of the melanoma. The 5-yr survival related to thickness is as follows: 4 mm, 44%. • The 5-yr survival in patients with distant metastasis was historically 20%. • Treatment of advanced disease consists (in addition to surgical excision and lymph node dissection) of chemotherapy, immunotherapy, and radiation therapy. Nivolumab combined with ipilimumab has shown clinically meaningful activity in melanoma metastatic to the brain (see Tawbi HA et  al in Suggested Readings). SUGGESTED READINGS Available at ExpertConsult.com

No No Yes

M1a(0): Normal M1a(1): Elevated M1b(0): Normal M1b(1): Elevated M1c(0): Normal M1c(1): Elevated M1d(0): Normal M1d(1): Elevated

CNS, Central nervous system; LDH, lactic dehydrogenase; TNM, tumor, nodes, metastases.

RELATED CONTENT Melanoma (Patient Information) AUTHOR: Bharti Rathore, MD

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Diseases and Disorders

T classification

majority of patients with melanoma CNS metastases in this setting have similar response rates in the CNS as systemically. 4. The combination of atezolizumab (PD-L1 checkpoint inhibitor), cobimetinib (MEK inhibitor), and vemurafenib (BRAF inhibitor) has been shown to improve progression-free survival compared with placebo in patients with BRAF mutated advanced melanoma and is likely to be another option in this setting. • Patients with a history of melanoma should be followed up with skin examinations every 6 mo or sooner if patient detects any new lesions; the assessments usually consist of medical history, physical examination, laboratory values, and chest radiograph.

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Melanoma SUGGESTED READINGS Cohen JV, Buchbinder EI: The evolution of adjuvant therapy for melanoma, Curr Oncol Rep 21(12):106, 2019. Gershenwald JE, Ross MI: Sentinel-lymph-node biopsy for cutaneous melanoma, N Engl J Med 364:1738-1745, 2011. Gillgren P et al: 2 cm versus 4 cm surgical excision margins for primary cutaneous melanoma thicker than 2 mm: a randomized, multicenter trial, Lancet 378:1635-1642, 2011. Larkin J et  al: Five-year survival with combined nivolumab and ipilimumab in advanced melanoma, N Engl J Med 381(16):1535-1546, 2019. Luther C et al: Advanced stage melanoma therapies: detailing the present and exploring the future, Crit Rev Oncol Hematol 133:99-111, 2019. Morton DL: Final trial report of sentinel-node biopsy versus nodal observation in melanoma, N Engl J Med 370:599-609, 2014. Postow MA et al: Nivolumab and ipilimumab versus ipilimumab in untreated melanoma, N Engl J Med 372:2002-2017, 2015. Robert C et al: Five-year outcomes with dabrafenib plus Trametinib in Metastatic Melanoma, N Engl J Med 381(7):626-636, 2019. Shenenberger D: Cutaneous malignant melanoma: a primary care perspective, Am Fam Physician 85(2):161-168, 2012. Siegel RL et al: Cancer statistics, CA Cancer J Clin 69(1):7-34, 2019. Sondak VK et  al: Risk-stratified screening for detection of melanoma, JAMA 313:616-617, 2015. Stoffels I et al: Association between sentinel lymph node excision with or without pre-operative SPECT/CT and metastatic node detection and disease-free survival in melanoma, JAMA 308(10):1007-1014, 2012.

FIG. E1  Lentigo maligna melanoma. (From James WD et al: Andrews’ diseases of the skin: clinical dermatology, ed 12, Philadelphia, 2016, Elsevier.)

FIG. E2  Malignant melanoma (MM). (This small, black papule was noted on this 10-year-old male with fair skin and red hair; excision confirmed a nodular MM. (From Paller AS, Mancini AJ: Hurwitz clinical pediatric dermatology, a textbook of skin disorders of childhood and adolescence, ed 5, Philadelphia, 2016, Elsevier.)

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FIG. E3  Subungual melanoma with Hutchinson sign (pigment spreading from under the nail to involve the adjacent skin, usually of the proximal or lateral nail fold). (These lesions are thought to emanate from the nail matrix. (From White GM, Cox NH [eds]: Diseases of the skin, a color atlas and text, ed 2, St Louis, 2006, Mosby.)

FIG. E4  Melanoma of the vulva. (enign nevi, vulva melanosis, and melanoma may occur in the vulvar region. Any suspicious pigmented lesion should be biopsied. The patient here is 75 yrs old. (Courtesy Paul Koonings, MD; From White GM, Cox NH [eds]: Diseases of the skin, a color atlas and text, ed 2, St Louis, 2006, Mosby.)

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Ménière Disease BASIC INFORMATION DEFINITION Ménière disease is a syndrome characterized by recurrent vertigo with fluctuating hearing loss, tinnitus, and fullness in the ear. SYNONYMS Endolymphatic hydrops Lermoyez syndrome Idiopathic endolymphatic hydrops ICD-10CM CODES H81.01 Ménière disease, right ear H81.02 Ménière disease, left ear H81.03 Ménière disease, bilateral H81.09 Ménière disease, unspecified ear

EPIDEMIOLOGY & DEMOGRAPHICS INCIDENCE (IN U.S.): Approximately 190/ 100,000 persons PREDOMINANT SEX: Female:male ratio of 1.3:1 PEAK INCIDENCE: Fourth to sixth decade of life PHYSICAL FINDINGS & CLINICAL PRESENTATION • Hearing may be unilaterally decreased. • Pallor, sweating, and nausea may occur during a severe attack. • Usually the patient develops a sensation of fullness and pressure along with decreased hearing and tinnitus in a single ear. • The patient typically experiences severe vertigo, which peaks within minutes, then slowly subsides over hours. • May see spontaneous nystagmus on examination. • Persistent sense of disequilibrium for days is typical after an acute episode. • May have vestibulopathy demonstrable with a positive head thrust test. ETIOLOGY • Unknown; viral, autoimmune, and genetic causes have been suggested.

• Endolymphatic hydrops is the postmortem histologic hallmark. Endolymphatic hydrops may create cytochemical changes that disturb endolymphatic fluid homeostasis, leading to spiral ganglion cell death.

DIAGNOSIS Proposed guidelines by the American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS) for diagnosis of Ménière disease:

DIFFERENTIAL DIAGNOSIS • Acoustic neuroma • Migrainous vertigo • Multiple sclerosis • Autoimmune inner ear syndrome • Otitis media • Vertebrobasilar disease • Labyrinthitis WORKUP • Diagnosis is primarily made by history, although further diagnostic tests may help support the diagnosis. Guidelines to define Ménière disease are described in Table 1. • Audiogram may show sensorineural hearing loss with lower frequencies primarily affected. Hearing loss may recover either partially or completely after an attack. Recurrent attacks may lead to a persistent and progressive sensorineural hearing loss. • Electronystagmography may show peripheral vestibular deficit. • Both vestibular-evoked myogenic potential (VEMP) studies and electrocochleography (ECoG) have low sensitivity and specificity for Ménière disease and are not clinically useful. LABORATORY TESTS No laboratory serologic test is specific for Ménière disease. A thyroid panel, glucose, hemoglobin A1C, antinuclear antibodies, urinalysis, chemistry panel, rapid plasma reagin, Lyme disease antibodies, and allergy testing can be ordered to screen for other disorders such as thyroid or autoimmune diseases, diabetes, otorenal syndrome, syphilis, Lyme disease, and allergy-mediated Ménière disease.

TABLE 1  Guidelines to Define Ménière Disease Definition

Symptoms

Certain Ménière disease Definite Ménière disease

Histopathologic confirmation ≥2 definitive spontaneous episodes of vertigo 20 min to 12 hr Audiometrically documented low- to medium-frequency sensorineural hearing loss in one ear, defining the affected ear on at least one occasion before, during, or after one of the episodes of vertigo Fluctuating aural symptoms (hearing, tinnitus, or fullness) in the affected ear Not better accounted for by another vestibular diagnosis One definite episode of vertigo Audiometrically documented hearing loss on at least one occasion Tinnitus or aural fullness in the treated ear Other causes excluded Episodic vertigo without documented hearing loss, or sensorineural hearing loss (SNHL) fluctuating or fixed, with disequilibrium but nonepisodic Other causes excluded

Probable Ménière disease

Possible Ménière disease

IMAGING STUDIES • MRI to rule out acoustic neuroma or other retrocochlear lesion, especially if cerebellar or CNS dysfunction is present. • Recent efforts have shown a role for MRI with intratympanic gadolinium.

TREATMENT NONPHARMACOLOGIC THERAPY Limit activity during attacks. ACUTE GENERAL Rx • Prochlorperazine 5 to 10 mg PO q6h or 25 mg PO bid • Promethazine 12.5 to 25 mg PO q4 to 6h • Diazepam 5 to 10 mg IV/PO for acute attack • Meclizine 25 mg q6h • Scopolamine patch CHRONIC Rx • Diuretics such as furosemide, hydrochlorothiazide, or acetazolamide. • Lifestyle modification recommendations include salt restriction and avoidance of caffeine. • For refractory cases, intratympanic gentamicin injections to the affected ear; endolymphatic sac surgery. DISPOSITION • Patients are usually followed by an otoneurologist or ENT specialist. • Usual course of disease consists of alternating attacks and remissions. • Majority of patients can be managed medically. Of all patients, 10% to 30% will undergo surgical intervention for persistent incapacitating vertigo. REFERRAL To an otolaryngologist for surgical intervention if attacks persist despite medical therapy SUGGESTED READINGS Available at ExpertConsult.com RELATED CONTENT Ménière Disease (Patient Information) AUTHORS: Katherine Kostroun, MD, Joseph S. Kass, MD, JD, FAAN, and Sharon S. Hartman Polensek, MD, PhD

Ménière Disease SUGGESTED READINGS Harris JP, Alexander TH: Current-day prevalence of Ménière’s syndrome, Audiol Neurootol 15(318), 2010. Le CH et al: Novel techniques for the diagnosis of Ménière’s disease, Curr Opin Otolaryngol Head Neck Surg 21:492-496, 2013. Lopez-Escamez JA et al: Diagnostic criteria for Menière’s disease, J Vestib Res 25(1), 2015. Semaan MT, Megerian CA et al: Contemporary perspectives on the pathophy­ siology of Ménière’s disease: implications for treatment, Curr Opin Otolaryngol Head Neck Surg 18:392-398, 2010.

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   Meningioma BASIC INFORMATION DEFINITION Meningiomas are generally slow-growing tumors arising from arachnoid cells of the arachnoid villi; 90% are benign. ICD-10CM CODE D32.0 Benign neoplasm of cerebral meninges

PHYSICAL FINDINGS & CLINICAL PRESENTATION • Neurologic symptoms vary with location and size (see Table 1); meningiomas can arise from the dura at any site, although they most commonly occur within the skull and at sites of dural reflection (i.e., the cerebral convexities and the falx). Other less common locations include the sphenoid wing, olfactory groove, and optic nerve sheath. • The presence of focal symptoms such as vision loss, hearing loss, or mental status change depend on the site of origin and the time course of growth. • Most common presentation is with a focal or generalized seizure or gradually worsening neurologic deficit. Seizures are present preoperatively in 30% to 40%. • Typically are slow growing and asymptomatic; many meningiomas are asymptomatic and/or discovered incidentally on a neuroimaging study or at autopsy. ETIOLOGY • Meningiomas are thought to arise from a multistep progression of genetic changes. • Mutations of the NF2 gene on chromosome 22 are found in patients with neurofibromatosis type 2 and >50% of sporadic meningiomas. This gene is thought to act as a tumor suppressor gene; the protein product, merlin, is also involved in cytoskeletal organization. • DAL-1, located on chromosome 18p, is another tumor suppressor gene that has been identified in a subset of the approximately 40% of sporadic meningiomas with neither the NF2 gene mutations nor allelic loss of chromosome 22q. • Cranial radiation may be responsible for some cases following an appropriate latency period from 10 to 20 yr. Meningiomas that result from radiation are generally more aggressive. • The link with steroid hormones and their receptors is suggested by the increase in growth rate and/or development of meningiomas during pregnancy, increased incidence in

women who use postmenopausal hormones, and in association with breast carcinomas.

DIAGNOSIS DIFFERENTIAL DIAGNOSIS Other well-circumscribed intracranial tumors that involve the dura or subdural space: • Acoustic schwannoma (typically at the pontocerebellar junction) • Ependymoma, lipoma, and metastases within spinal cord • Metastatic disease from lymphoma/ adenocarcinoma • Inflammatory disease such as sarcoidosis and Wegener granulomatosis • Infections such as tuberculosis WORKUP Imaging studies with CT or MRI, followed by surgical removal with histologic confirmation LABORATORY TESTS According to the World Health Organization (WHO) classification, there are nine benign histologic variants (account for 90% of all meningiomas) and four variants associated with increased recurrence and rates of metastasis. 80% of meningiomas are classified as benign meningiomas or WHO grade I. IMAGING STUDIES • Cranial CT scanning or MRI can detect and determine the extent of meningiomas (Fig. 1). CT can show hyperostosis and/or intratumoral calcifications. MRI with contrast (Fig. 2) is the imaging modality of choice to demonstrate the dural origin of the tumor in most cases, with the characteristic “tail” sign that tracks along the dura outside brain parenchyma. • On nonenhanced scans, meningiomas are typically isodense or slightly hyperdense to

TABLE 1  Locations and Presentations of Meningiomas Location

Presenting Manifestation

Parasagittal Lateral convexity

Urinary incontinence, dementia, gradual paraparesis, seizures Variable depending on structures compressed, including slow hemiparesis, speech abnormalities Anosmia, visual disturbance, dementia, Foster-Kennedy syndrome Hormonal failure, bitemporal hemianopsia, optic atrophy Extraocular nerve paresis, exostoses, proptosis, seizures

Olfactory groove Suprasellar Sphenoid ridge

From Goetz CG, Pappert EJ: Textbook of clinical neurology, Philadelphia, 1999, WB Saunders.

M

FIG. 1  Contrast-enhanced computed tomography scan demonstrates a large contrastenhancing right sphenoid wing meningioma. (From Specht N [ed]: Practical guide to diagnostic imaging, St Louis, 1998, Mosby.)

Diseases and Disorders

EPIDEMIOLOGY & DEMOGRAPHICS INCIDENCE: 7.92/100,000 persons/yr, but increases with age. Most common primary type of central nervous system tumor, and most common nonmalignant primary central nervous system tumor. PREDOMINANT SEX AND AGE: Female:male ratio of almost 3:1 (in ages 35 to 54) in the brain and up to 6:1 in the spinal cord; 1:1 in childhood PEAK INCIDENCE: Males: Sixth decade, females: Seventh decade, incidence increases with age, dramatic increase in incidence after age 65; rare in childhood RISK FACTORS: Ionizing radiation results in increased incidence and a shorter latency period. Neurofibromatosis type 2 (NF2) is an autosomal dominant genetic disorder that predisposes to multiple intracranial tumors. Approximately half of all individuals with NF2 have meningiomas, most of which are intracranial. Studies have suggested a link between hormonal factors and development of meningioma, specifically estrogen exposure. Multiple prospective cohorts studies have also found an association between higher body mass index and meningioma, possibly relating to increased levels of circulating estrogen through increased adipose tissue. At present, there is no conclusive evidence to support a causal relationship with cell phone usage and subsequent development of meningioma. GENETICS: Meningiomas may be isolated or found in association with other genetic diseases, such as NF2 and familial meningioma. Other genetic conditions associated with increased incidence of meningioma include BAP1 tumor predisposition syndrome, Rubinstein-Taybi syndrome, multiple endocrine neoplasia, type 1, Gorlin syndrome, Cowden syndrome 1, Werner syndrome, and familial meningiomatosis. Approximately half of meningiomas have allelic losses involving the NF2 and DAL-1 genes. Allelic losses of chromosomes 1p, 2p, 6q,

9q, 10q, 14q, 17p, and 18q may be associated with histologic progression. Genome-wide association studies (GWAS) have discovered two genomic variants associated with increased meningioma risk in genes for MLLT10 and possibly RIC8A. Further, GWAS analysis also demonstrates an association between longer telomere length and increased risk of meningiomas.

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Meningioma hydroxyurea, there is no established effective systemic therapy. • Inhibition of hormone receptors, such as progesterone, estrogen, and androgen, has failed to demonstrate clinical benefit. • Treatment with molecularly targeted approaches, such as angiogenesis inhibition, is currently under way.

FIG. 2  Magnetic resonance imaging picture of a posterior fossa meningioma, demonstrated an extra-axial homogeneously contrastenhanced mass arising from the tentorium and compressing the cerebellar hemisphere. (From Goetz CG, Pappert EJ: Textbook of clinical neurology, Philadelphia, 1999, WB Saunders.)

brain and are homogeneous in appearance. They show homogeneous contrast enhancement; gadolinium can facilitate imaging of smaller additional lesions that are missed on unenhanced images. • Indistinct margins, marked edema, mushroom-like projections from tumor, brain parenchymal infiltration, and heterogeneous enhancement are suggestive of more aggressive behavior. • Positron emission tomography (PET) scan may help in predicting the aggressiveness of the tumor and the potential for recurrence, but it is not used routinely.

TREATMENT Primary management depends on signs or symptoms, age of patient, and location and size of tumor. Observation may be appropriate if tumors are discovered incidentally and/ or if growth is indolent and unlikely to cause symptoms.

PHARMACOLOGIC THERAPY • Although a variety of chemotherapeutic agents have been studied, such as

NONPHARMACOLOGIC THERAPY • The mainstay of treatment for meningiomas remains surgical removal. Complete resection is usually attempted, when feasible. After total excision, recurrence rates of 0% to 20% have been observed, while 20% to 50% of patients recur within 5 yr of a subtotal resection. • Active surveillance to monitor for tumor recurrence is important. • Radiation therapy is the only validated form of adjuvant therapy and may be beneficial in patients with incomplete resections or inoperable tumors. Stereotactic radiosurgery can provide local control with more limited toxicity. ACUTE GENERAL Rx • For lesions that cause significant mass effect, steroids are sometimes used to decrease brain edema. • Anticonvulsants are used if the patient presents with seizures. CHRONIC Rx • Prophylactic use of anticonvulsants is not recommended in patients without a history of seizures. • There is limited data on the efficacy of traditional chemotherapy, and the evidence is largely anecdotal. The most extensively evaluated agents are hydroxyurea, mifepristone (RU486), and interferon alfa-2b. Recently, somatostatin analogs have been evaluated in multicenter clinical trials, primarily in malignant meningiomas. DISPOSITION • Estimated surgical mortality is 7%. Significant morbidity and mortality can be observed in meningiomas with otherwise favorable pathology secondary to unfavorable location (e.g., skull base). 10-yr relative survival is 80.4% in the cerebral meninges vs. 93.2% in spinal meninges. • Long-term outcome varies based on pathology, tumor grade, location, and completeness of resection. 10-yr relative survival for

nonmalignant meningioma is 81.5%, with highest survivability in the youngest age group. 10-yr relative survival for malignant meningioma is 53.5%, with similar agebased effects. • Most incidentally discovered meningiomas remain asymptomatic and have a slow rate of growth. Calcified tumors may be less likely to progress than noncalcified ones. • Meningiomas may recur after surgical resection or progress to a higher grade. Risk factors for recurrence include multiple allelic chromosomal losses, local brain invasion, high rate of mitosis, and highly anaplastic features.

REFERRAL • Neurosurgical consultation for all cases • Neurology, radiation oncology, and oncology consults depending on presence of other sequelae or in the setting of recurrence

PEARLS & CONSIDERATIONS COMMENTS • Many meningiomas are discovered incidentally; most are benign and remain asymptomatic. A first follow-up MRI should be performed 3 to 6 mo after the tumor is identified to rule out an atypical meningioma with rapid growth. • “Dural tail,” which is the thickening of the dura adjacent to the mass, is a classic finding on neuroimaging studies. • Individuals with neurofibromatosis type 2 are at high risk to develop meningiomas. PATIENT & FAMILY EDUCATION • Meningioma Mommas: meningiomamommas.org • Meningioma Support and Patient Information Group • National Brain Tumor Society • Meningioma Online Support Group: brainstrust.org/meningioma.htm SUGGESTED READINGS Available at ExpertConsult.com RELATED CONTENT Meningioma (Patient Information) AUTHOR: Lily Pham, MD

Meningioma SUGGESTED READINGS Braganza MZ et al: Lonizing radiation and the risk of brain and central nervous system tumors: a systematic review, Neuro Oncol 14:1316, 2012. Ostrom QT et al: “CBTRUS Statistical report: primary brain and other central nervous system tumors diagnosed in the United States in 2011–2015, NeuroOncology 20(Suppl 4):1-86, iv, 2018, https://doi.org/10.1093/neuonc/noy131. Ostrom QT et al: “Risk factors for childhood and adult primary brain tumors,” Neuro-Oncology 21(11):1357-1375, 2019, https://doi.org/10.1093/neuonc/ noz123. Wiemels J et al: Epidemiology and etiology of meningioma, J Neurooncol 99:307, 2010.

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ALG BASIC INFORMATION DEFINITION Bacterial meningitis is an inflammation of meninges with increased intracranial pressure, and pleocytosis or increased WBCs in cerebrospinal fluid (CSF) secondary to bacteria in the pia-subarachnoid space and ventricles, leading to neurologic sequelae and abnormalities.

ICD-10CM CODES G00.9 Bacterial meningitis, unspecified G00.8 Other bacterial meningitis G01 Meningitis in bacterial diseases classified elsewhere

EPIDEMIOLOGY & DEMOGRAPHICS INCIDENCE (IN U.S.): 1.3 to 2.0 cases/100,000 persons; 1.2 million cases per yr in the world; 135,000 deaths annually worldwide. The rate of bacterial meningitis declined dramatically in the U.S. starting in the early 1990s with the introduction of the Haemophilus influenzae type b (Hib) vaccine and in 2000 with the introduction of the conjugate pneumococcal vaccine. PREDOMINANT SEX: Male = female PREDOMINANT AGE: All ages, neonate to geriatric PHYSICAL FINDINGS & CLINICAL PRESENTATION • Fever • Headache • Neck stiffness, nuchal rigidity, meningismus • Altered mental state, lethargy • Vomiting, nausea • Photophobia • Seizures • Coma; lethargy, stupor • Rash: Petechial and purpuric lesions (Fig. E1) associated with meningococcal infection, purpura fulminans • Myalgia • Cranial nerve abnormality (unilateral) • Papilledema • Dilated, nonreactive pupil(s) • Posturing: Decorticate/decerebrate • Physical examination findings of Kernig sign and Brudzinski sign (Fig. E2) in adults with meningitis are often seen later in the course of disease and may not be helpful in determining early meningeal inflammation ETIOLOGY The bacterial etiology of meningitis depends on the age of the patient. Neisseria meningitidis is now more common than Haemophilus influenzae as a cause of bacterial meningitis in children as well as adults, and streptococci (Streptococcus pneumoniae) are still common causes of community-acquired bacterial meningitis. H. influenzae is the cause of >30% of

DIAGNOSIS Diagnostic approach is based on patient presentation and physical examination (Fig. 3). Lumbar puncture should be performed as soon as possible. Key elements to diagnosis are CSF evaluation and CT scan or MRI if the patient is in a coma or has focal neurologic deficits, pupillary abnormalities, or papilledema. Table 1 describes tests of CSF in patients with suspected CNS infection.

DIFFERENTIAL DIAGNOSIS (BOX E1) • Endocarditis, bacteremia • Intracranial tumor • Lyme disease • Brain abscess • Partially treated bacterial meningitis • Medications • SLE • Seizures • Acute mononucleosis • Other infectious meningitides • Neuroleptic malignant syndrome • Subdural empyema • Subarachnoid hemorrhage (Table 2) • Rocky Mountain spotted fever WORKUP CSF examination (Table 3): • Opening pressure >100 to 200 mm Hg • WBC usually >1000/mm3 • Neutrophilic predominance: >80% • Gram stain of CSF: Positive in 60% to 90% of patients

• CSF protein: >50 mg/dl • CSF glucose: 15 to 30 ml and >1 to 1.5 ml/kg for ethylene glycol. • Sequential metabolism by alcohol and aldehyde dehydrogenases converts methanol to formaldehyde and then formic acid, while ethylene glycol is converted to glycoaldehyde, glycolic acid, and then oxalate. • Fig. E1 depicts the pathways involved in methanol metabolism. • While methanol metabolites primarily cause retinal injury, ethylene glycol metabolites produce renal tubular injury and calcium oxalate stones. 1.  Formaldehyde binds to tissue proteins and is likely the major toxin in methanol poisoning involving necrosis of retinal and optic neurons and the basal ganglia (putamen). Formic acid, the acid produced in the largest quantity, inhibits cytochrome oxidase, preventing oxygen utilization by mitochondria and causing further organ dysfunction. Leukotriene has been implicated in the inflammation and neurotoxicity characteristic of acute methanol poisoning. 2. Glycoaldehyde may be the major nephrotoxin, while glycolic acid is the acid produced in the largest quantity in ethylene glycol poisoning, with a small quantity converted to oxalic acid by lactate dehydrogenase. Oxalate then forms calcium oxalate crystals, which are deposited in the renal parenchyma, cerebral blood vessels, and meninges, causing hypocalcemic tetany.

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • Other causes of a high anion gap metabolic acidosis include lactic acidosis, diabetic and alcoholic ketoacidosis, kidney failure (acute and chronic), early toluene toxicity, and salicylate intoxication. Of note, L-lactate may be elevated in methanol toxicity due to cytochrome oxidase inhibition by formic acid and an increase of the NADH:NAD+ ratio that is driven by methanol metabolism. • Elevated plasma osmolal gap may be encountered in ethyl alcohol or isopropyl alcohol ingestion. EVALUATION AND WORKUP • Diagnosis depends on history, clinical presentation, and laboratory abnormalities. • High anion gap metabolic acidosis (AG >12 mEq/L) with elevated plasma osmolal gap (>10 mOsm/kg; usually >25 mOsm/Kg) in an appropriate clinical setting should raise the suspicion of methanol or ethylene glycol ingestion. • In either intoxication, an osmolal gap will initially be positive, but as the parent compound

is converted to its metabolites, the osmolal gap will normalize and the serum anion gap will increase. • Serum methanol and ethylene glycol levels are elevated in their respective ingestions. • Acute kidney injury, hypocalcemia with prolonged QT interval, and calcium oxalate crystalluria are seen with ethylene glycol toxicity. • Metabolic acidosis in the absence of acute kidney injury suggests methanol toxicity; that is, ethylene glycol is more often associated with acute kidney injury. • Wood’s light uses ultraviolet light to detect urinary presence of fluorescein, which is contained in some ethylene glycol preparations. Fluorescence lacks sensitivity and specificity. Therefore, fluorescence is not considered a reliable clinical tool.

LABORATORY TESTS • Calculation of the anion gap and serum osmolal gap 1. Anion gap determination: Electrolytes and albumin 2. Osmolal gap determination: Measured and calculated serum osmolalities (sodium, BUN, glucose, ± ethanol) • Arterial blood gas analysis, lactate, calcium, and creatine kinase • Creatinine and urinalysis to evaluate presence of tubular injury and calcium oxalate crystals • ECG to evaluate QT interval • Toxicology screen with quantification: Acetaminophen, salicylate, ethanol, methanol, ethylene glycol, and isopropyl alcohol

TREATMENT High index of suspicion and immediate recognition with early treatment remain crucial to reduce mortality. Box 1 describes common commercial products that may contain ethylene glycol.

NONPHARMACOLOGIC THERAPY • Cardiorespiratory support as required. • Rapid (within 60 min) gastric decontamination (charcoal and/or gastric lavage). Later intervention is not beneficial due to rapid and complete invasion (methanol). • Induction of vomiting is contraindicated even in conscious patients given the risks BOX 1  Common Commercial Products That May Contain Ethylene Glycol Paints and lacquers Polishes and detergents Inks Cosmetics Hydraulic brake fluids Solar collector fluids Car wash fluids Data are from Kruse JA: Methanol, ethylene glycol, and related intoxications. In Carlson RW, Geheb MA (eds): Principles and practice of medical intensive care, Philadelphia, 1993, WB Saunders.

of development of central nervous system depression in these patients.

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DISPOSITION Transfer to a hospital with an intensive care unit and hemodialysis capabilities should be carried out early in the course of intoxication.

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• In contrast, the observed half-life of ethylene glycol with use of fomepizole is only around 17 hours. Ethylene glycol poisoning (even with levels greater than 50 mg/dl) in patients without kidney injury or acidosis can be managed with fomepizole alone, and without hemodialysis. • Hemodialysis is indicated for likely or confirmed methanol poisoning in the setting of any of the following: New vision or neurologic deficit (particularly seizure or coma); metabolic acidosis or acidemia with pH ≤7.15; elevated anion gap >24 mmol/L; methanol concentration >70 mg/dl (or 21.8 mmol/L) in the context of fomepizole, or >50 mg/dl (or 15.6 mmol/L) in the absence of an ADH blocker. • Hemodialysis is indicated for likely or confirmed ethylene glycol poisoning in the setting of any of the following: Acute kidney injury; anion gap metabolic acidosis; EG level >50mg/dl (see earlier regarding use of fomepizole when elevated levels without acidosis or acute kidney injury are present). • Hemodialysis also should be considered in patients with poisoning and electrolyte imbalances refractory to pharmacologic treatments, or hemodynamic instability. • Average duration of dialysis in studies was 8.4 ± 3.2 hr. 1. Treatment with medications and/or hemodialysis is continued until the methanol or ethylene glycol concentration is 10 mOsm/kg OR 3. Suspected ingestion with at least two of the following criteria: a. Arterial pH 4 hr before antiemetic effect is required. • Oral promethazine is effective but highly sedating. • Over-the-counter oral preparations (e.g., Dramamine) are less effective. • Meclizine 12.5 to 25 mg q6h may be effective but is very sedating. CHRONIC Rx • Rarely chronic • Symptoms generally resolve completely with cessation of motion exposure DISPOSITION Follow-up is not needed.

Cortex

Sensory input

• Drowsiness • Lethargy • Dizziness

Visual Vestibular Proprioception

Vestibular nuclei

Autonomic system Parasympathetic

Sympathetic

• Sweating • Flushing

• Pallor • Dry mouth • Vasoconstriction

Reticular formation

Vomit center • Nausea • Vomiting

FIG. E1  Proposed neural pathway resulting in motion sickness. (From Kuhn SM: Motion sickness. In Keystone JS et al: Travel medicine, ed 2, Philadelphia, 2008, Elsevier, pp. 435-440.)

REFERRAL If another diagnosis is suspected (e.g., purulent ear, fever, cranial nerve abnormalities)

PEARLS & CONSIDERATIONS COMMENTS • Many patients with migraine report having had severe motion sickness as a child. • Improved ventilation, avoidance of large meals before travel, semirecumbent sitting, and avoidance of reading while in motion will minimize the risk of motion sickness. RELATED CONTENT Motion Sickness (Patient Information) AUTHOR: Fred F. Ferri, MD

Mucormycosis BASIC INFORMATION DEFINITION Mucormycosis is a fungal infection by Zygomycetes fungi and includes species in the order Mucorales (Rhizopus sp., Rhizomucor, Cunninghamella, Apophysomyces, Saksenaea, Absidia, Syncephalastrum, Cokeromyces, Mortierella) and in the order Entomophthorales (Conidiobolus and Basidiobolus). SYNONYM Zygomycosis ICD-10CM CODES B46.0 Pulmonary mucormycosis B46.1 Rhinocerebral mucormycosis B46.3 Cutaneous mucormycosis B46.4  Disseminated mucormycosis B46.5 Mucormycosis, unspecified

EPIDEMIOLOGY & DEMOGRAPHICS • Mucormycosis is the third most frequent cause of invasive fungal infections in immunocompromised hosts. These fungi are ubiquitous in nature and can be found in soil and decaying vegetation. Infection is seen in association with underlying conditions, including diabetes mellitus especially with ketoacidosis, hematologic malignancies, stem cell or solid organ transplants, severe burns or trauma, treatment with deferoxamine or iron overload states, steroid treatment, immunodeficiency states (e.g., AIDS), injection drug use, and malnutrition. Immunocompetent hosts may become infected in tropical climates. • The fungus gains entry to the body most commonly through the respiratory tract. The spores are deposited in the nasal turbinates and may be inhaled into the pulmonary alveoli. In cases of cutaneous mucormycosis, the spores are introduced directly into the skin lesion. • After a tornado with winds >200 mph struck Joplin, Missouri, in May 2011, there were 13 confirmed cases of mucormycosis (Apophysomyces trapeziformis), including five deaths. While two patients had diabetes, none were immunocompromised. It was felt that the fungus entered through wounds sustained during the tornado. Wooden splinters were found in four patients. PHYSICAL FINDINGS & CLINICAL PRESENTATION • Rhinocerebral-rhinoorbital-paranasal syndrome (Fig. E1) is the most common presentation, which presents with fever, facial and orbital pain, headache, diplopia, loss of vision, facial or orbital cellulitis, facial anesthesia, cranial nerve dysfunction, black nasal discharge, epistaxis, and seizure. Physical findings in this situation include proptosis; chemosis; nasal, palatal, or pharyngeal necrotic ulcerations; and retinal infarction.

Thrombosis of the cavernous sinus or internal carotid artery may occur. This form of mucormycosis is found most commonly in diabetics, primarily in the presence of acidosis, and in patients with leukemia and neutropenia. Isolated CNS mucormycosis may result from hematogenous spread (can occur with injection drug users). • Pulmonary mucormycosis can present with pneumonia, lung abscess, pulmonary infarction, pleurisy, pleural effusion, hemoptysis, chills, and fever. This form of mucormycosis is found most commonly in immunocompromised neutropenic hosts after chemotherapy for hematologic malignancies. • Gastrointestinal zygomycosis presents with abdominal pain, diarrhea, gastrointestinal hemorrhage, ulcers, peritonitis, and bowel infarction. This form of mucormycosis is found most commonly in patients with extreme malnutrition and is believed to arise from ingestion of spores of the fungi. • Cutaneous zygomycosis presents as nodular lesions (hematogenous seeding) or a wound infection. It primarily involves the epidermis and dermis after use of occlusive dressings that have not been properly sterilized. • Cardiac mucormycosis is a form of endocarditis. • Septic arthritis and osteomyelitis. • Brain abscess occurs most often from extension of the fungus from the nose or paranasal sinuses through adjacent bones in severely debilitated patients. • Disseminated zygomycosis (rare but uniformly fatal). • Physical findings depend on the location of the infection.

ETIOLOGY & PATHOGENESIS The cause of mucormycosis is infection by a fungus of the Zygomycetes class (see “Definition”). Rhizopus and mucor species are the most common causes. Normal host defenses include leukocytes and pulmonary macrophages. Quantitative (e.g., neutropenia) or qualitative (e.g., diabetes mellitus or steroid treatment) disruption in the host defenses predisposes the patient to infection. Patients treated with deferoxamine for iron-overload states are also at risk.

DIAGNOSIS A high index of suspicion is critical since mucormycosis infection is acute and rapidly faster if untreated. The hallmark of mucormycosis is infarction and necrosis of host tissues that result from invasion of the vasculature by the fungal elements. Black eschars and discharges should be closely evaluated. Diagnosis depends on the demonstration of the organism in the tissue of a biopsy specimen.

DIFFERENTIAL DIAGNOSIS • Infection of the sites described previously by other organisms (bacterial [including

tuberculosis and leprosy], viral, fungal, or protozoan) • Noninfectious tissue necrosis (e.g., neoplasia, vasculitis, degenerative) of the sites described previously

WORKUP • Biopsy of infected tissue with direct-light microscopy examination establishes the diagnosis within minutes of the biopsy in the case of nasopharyngeal infection. Fungal hyphae are broad (5- to 15-micron diameter) and irregularly branched and have rare septations, in contrast to molds such as Aspergillus, which are narrower, have regular branching, and have many septations. • Bronchoalveolar lavage or bronchoscopy with biopsy for smear, culture, and histologic examination. • Radiographs and other imaging studies such as CT of symptomatic sites may be required before infection is suspected and tissue specimens are obtained. • It should be noted that serum tests that measure fungal cell wall components, such as the 1, 3-beta D glucan assay and the Aspergillus galactomannan assay used to diagnosis other invasive fungal diseases, will be negative in mucormycosis, as mucormycosis agents lack these cell wall components.

TREATMENT • Aggressive correction of underlying disease (e.g., hyperglycemia, high steroid doses, use of immunosuppressive drugs) should be undertaken. • Standard therapy consists of aggressive surgical debridement of involved tissues and antifungal therapy. For invasive mucormycosis recommended treatment is with a lipid formulation of amphotericin B that allows higher doses with less nephrotoxicity. The start dose is 5 mg/kg of liposomal amphotericin B or amphotericin B lipid complex. Doses as high as 10 mg/kg have also been used. Weeks of therapy are usually required. • Traditional amphotericin B given IV at a daily dose of 1.0 to 1.5 mg/kg infused over 2 to 4 hr daily for a total of 1 to 4 g can also still be used, but is associated with significant nephrotoxicity and adverse reactions such as fever, chills, myalgias, vomiting, and electrolyte disturbances. 1. Other antifungals do not appear to be effective except posaconazole, which may serve as an oral step-down therapy after amphotericin B at a dose of 400 mg bid with a fatty meal. Isavuconazole is another agent with efficacy in mucormycosis that, like posaconazole, comes in IV and oral formulation and can serve to transition patient from IV to PO. 2. Some studies suggest that caspofungin with amphotericin B may be synergistic for Rhizopus oryzae infections only. 3.  The role of colony-stimulating factors remains unclear, beyond that of increas-

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Mucormycosis ing the neutrophil count in patients with neutropenia. 4.  Hyperbaric oxygen has been used in some patients but its utility in therapy is still not clear.

923.e8 PROGNOSIS • Sinus infection with no underlying disease: 75% survival • Sinus infection with diabetes: 60% survival • Sinus infection with renal disease: 25% survival

SUGGESTED READINGS Duffy J et al: Mucormycosis outbreak associated with hospital linens, Pediatr Infect Dis 33:472-476, 2014. Farmakiotis D, Kontoyiannis DP: Mucormycosis, Inf Dis Clinics North Am 30:143163, 2016. Riley TT et al: Breaking the mold: a review of mucormycosis and current pharmacological treatment options, Ann Pharmacother 50:747-757, 2016. Sun HY, Singh N: Mucormycosis: its contemporary face and management strategies, Lancet Infect Dis 11(4):301-311, 2011. Zahoor B et al: Cutaneous mucormycosis secondary to penetrative trauma, Injury 47:1383-1387, 2016.

FIG. E1  Extensive central necrosis and associated swelling and erythema in a patient with mucormycosis. (From Callen JP et al: Dermatological signs of systemic disease, ed 5, Philadelphia, 2017, Elsevier.)

AUTHOR: Glenn G. Fort, MD, MPH

Multidrug-Resistant Gram-Negative Rods (MDR-GNRs) BASIC INFORMATION DEFINITION These are gram-negative bacteria that are resistant to at least one antimicrobial in three or more antimicrobial classes (antipseudomonal penicillins, third-generation cephalosporins, fluoroquinolones, carbapenems, and aminoglycosides). SYNONYMS Carbapenem-resistant Enterobacteriaceae (CRE) Extended-spectrum beta-lactamases (ESBL) Multidrug-resistant gram-negative bacilli (MDRGNB) Multidrug-resistant organisms (MDRO) New Delhi metallo-beta-lactamase-1 (NDM-1) ICD-10CM CODES Z16.10 Resistance to unspecified beta lactam antibiotics Z16.30 Resistance to unspecified antimicrobial drugs

EPIDEMIOLOGY & DEMOGRAPHICS INCIDENCE: There is an increasing incidence of these bacteria in hospitals and long-term care facilities in the U.S. and around the world. ESBL bacteria were first discovered in Europe in 1984 and in the U.S. in 1988. CRE bacteria were first described in the late 1990s in the U.S. The NDM-1 bacteria were first noted in 2009 in Sweden in a patient from India. PREDOMINANT SEX & AGE: These bacteria can be seen in any age group. They may be more frequent in women due to increased risk of urinary tract sepsis. RISK FACTORS: In general, these bacteria are more common in hospitals and longterm care facilities, but they are spread nosocomially through patient care and thus are now ­entering the community, where the incidence is also increasing. Specific risk ­factors include: • Length of stay in the hospital • Length of ICU stay • Use of central line catheters • Abdominal surgery • Presence of gastrostomy or jejunostomy tube • Prior administration of any antibiotic • Prior residence in a long-term care facility • Presence of indwelling urinary catheter PHYSICAL FINDINGS & CLINICAL PRESENTATION All these resistant bacteria have the capability of causing diverse infections, including: • Pneumonia • Bacteremia • Urinary tract sepsis • Central line–associated infections • Ventilator-associated pneumonia (VAP) • Surgical site infections • VAP from A. baumannii now accounts for 8.4% of GNR pneumonias in the ICU

ETIOLOGY • Several different classes of MDR-GNRs exist based on their resistance mechanism. 1. ESBL: These bacteria contain enzymes that break open the beta-lactam ring of penicillins, cephalosporins, and aztreonam and thus inactivate antibiotics from those classes. Enzymes conferring resistance include: a. TEM beta-lactamases b. SHV beta-lactamases c. CTX-M beta lactamases d. OXA beta-lactamases e. These enzymes are plasmid-mediated and thus can spread from one gramnegative bacteria to another, causing outbreaks in a single institution 2. CRE: Enzymes conferring resistance include: a. Class A beta-lactamases: Encoded on chromosomes or plasmids (e.g., Klebsiella pneumoniae carbapenemase [KPC], which has caused outbreaks in hospitals around the world) b.  Class B: Metallo-beta-lactamases (e.g., NDM-1). Encoded on a mobile plasmid that can spread to other gram-negative bacteria c. Class C and class D beta-lactamases 3.  MCR-1 gene: In May 2016, the MCR-1 gene was reported for the first time in E. coli from a patient (urine culture) in the U.S. This gene makes bacteria resistant to the antibiotic colistin, which is used to treat other MDR-GNR organisms. This raises the concern that this plasma-encoded gene could be spread to CRE bacteria. • Stenotrophomonas maltophilia: MDR-GNR that acts as an opportunistic pathogen among mostly hospitalized patients with high morbidity and mortality. It has intrinsic or acquired resistance mechanisms to multiple antibiotic classes and has the ability to adhere to foreign materials and form a biofilm, which escapes host defenses. • Acinetobacter sp. (e.g., Acinetobacter baumannii): Strains have emerged that are resistant to all commercially available antibiotics. These bacteria have the capability to acquire diverse mechanisms of resistance including: 1. AmpC beta-lactamases 2.  Beta-lactamases: Serine and metallobeta-lactamases

DIAGNOSIS DIFFERENTIAL DIAGNOSIS Other gram-negative rods such as: • Pseudomonas aeruginosa • Klebsiella pneumoniae that are not ESBL or CRE by resistance pattern • Morganella morganii • Providencia, Proteus sp., Serratia WORKUP • Detection of ESBL and CRE bacteria can pose problems for the clinical microbiology laboratory: 1. To detect ESBL bacteria: Automated systems such as Vitek use disk diffusion or

broth dilution techniques, or double disk test or E-test strip with clavulanate. 2. To detect CRE: Modified Hodge test to detect carbapenemase-producing bacteria. Polymerase chain reaction testing, pulsed-field gel electrophoresis, and whole genome sequencing are useful for detecting CRE. 3. In 2010, testing guidelines with respect to susceptibility involving several beta-lactam antibiotics were changed to better identify these bacteria via automated systems.

LABORATORY TESTS Clinical testing is the same in infections from these resistant organisms as with nonresistant organisms: • Cultures of any wounds, blood, sputum, urine, catheter tips • CBC, liver function tests, urinalysis

TREATMENT • Because of multidrug resistance, only a few reliable antibiotics are available to treat these infections. 1. ESBL bacteria: Carbapenem antibiotics such as imipenem, meropenem, ertapenem, or the cephalosporin cefoxitin or tigecycline. 2. CRE bacteria: Selection of antibiotic will depend on testing but tigecycline may be used clinically. Other alternatives include: a. IV colistin. b.  Stenotrophomonas maltophilia: Only available agents are Bactrim (drug of choice), Levaquin, and minocycline. c.  A. baumannii: Will depend on susceptibility testing, but ampicillin-sulbactam, imipenem or meropenem, or tigecycline can be used for MDR strains. For pan-resistant strains, IV colistin ± rifampin can be used. Inhaled colistin can be used for pneumonia patients. d.  Newer antibiotics such as ceftolozane/tazobactam and ceftazidime/ avibactam offer coverage for some of the resistant enzymes, but not all, and thus they require susceptibility testing to confirm. e. A next generation aminoglycoside plazomicin (Zemdri) was approved in 2018 for complicated urinary tract infections and has efficacy against CRE.

DISPOSITION • Morbidity and mortality can be quite high with infections from these MDR bacteria. 1. Nosocomial Acinetobacter pneumonia carries a mortality rate of 35% to 70%. 2.  Stenotrophomonas infections carry a mortality rate of 21% to 69%. 3. ESBL infections carry a mortality rate of 3.7% despite therapy with carbapenem antibiotics. AUTHOR: Glenn G. Fort, MD, MPH

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Multidrug-Resistant Gram-Negative Rods (MDR-GNRs) SUGGESTED READINGS Avery LM, Nicolau DP: Investigational drugs for the treatment of infections caused by multidrug-resistant gram-negative bacteria, Expert Opin Investig Drugs 27:325-338, 2018. Elbadawi LI: Carbapenem-resistant enterobacteriaceae transmission in health care facilities–Wisconsin, February-May 2015, MMWR 65(34):906-909, 2016. Hebert C, Weber SG: Common approaches to the control of multidrug-resistant organisms other than methicillin-resistant Staphylococcus aureus (MRSA), Infect Dis Clin North Am 25:181-200, 2011. Iovleva A, Doi Y: Carbapenem-resistant enterobacteriaceae, Clin Lab Med 37:303315, 2017. Lim LM et al: Resurgence of colistin: a review of resistance, toxicity, pharmacodynamics, and dosing, Pharmacotherapy 30:1279-1291, 2010. Perez F, Van Duin D: Carbapenem-resistant enterobacteriaceae: a menace to our most vulnerable patients, Cleve Clin J Med 80(4):225-233, 2013. Teerawattanapong N et  al: Prevention and control of multidrug-resistant gramnegative bacteria in adult intensive care units: a systematic review and ­network meta-analysis, Clin Infect Dis 64(Suppl 2):S51-S60, 2017.

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Multifocal Atrial Tachycardia BASIC INFORMATION DEFINITION Multifocal atrial tachycardia (MAT) is a supraventricular tachyarrhythmia (rate greater than 100 beats/min) with P waves having at least three or more different morphologies and irregular P-P, P-R, and R-R intervals. MAT is differentiated from atrial fibrillation by discrete P wave depolarizations and an isoelectric baseline between P waves. SYNONYMS MAT Chaotic atrial rhythm Chronic atrial tachycardia Repetitive multifocal paroxysmal atrial tachycardia Multifocal ectopic atrial tachycardia The term wandering pacemaker is used for a similar arrhythmia associated with a normal or slow heart rate (4.0 and Mg2+ >2.0, if possible. • Rapid rate and ineffective atrial kick (PR interval 7 g/dl Immunofixation for IgD or IgE in select cases CT, Computed tomography; Ig, immunoglobulin; ISS, International Staging System; LDH, lactate dehydrogenase; MRI, magnetic resonance imaging; PET, positron emission tomography. From Hoffman R et al: Hematology, basic principles and practice, ed 7, Philadelphia, 2018, Elsevier.

FIG. 2  Increased rouleaux formation is seen in this blood smear from a patient with a large M protein. Marked rouleaux formation is often a clue to the diagnosis of a plasma cell neoplasm but may also be observed in other conditions (Wright-Giemsa stain). (From Jaffe ES et al: Hematopathology, Philadelphia, 2011, WB Saunders.)

• Hypercalcemia is present in 15% of patients at diagnosis. • Elevated blood urea nitrogen, creatinine, uric acid, and total protein. • Urine protein immunoelectrophoresis: Proteinuria from overproduction and secretion

X-ray

Bone marrow

Electrophoresis

FIG. 3  Common diagnostic features in multiple myeloma. Light chain–restricted plasma cells in a bone marrow aspirate; multiple lytic lesions in a skull radiograph; large monoclonal spike in the g-globulin area in serum electrophoresis. (From Hoffman R et al: Hematology, basic principles and practice, ed 5, Philadelphia, 2009, Churchill Livingstone.)

of free monoclonal kappa or lambda chains (Bence Jones protein). • Serum protein immunoelectrophoresis: Monoclonal spike (M spike) on protein immunoelectrophoresis in approximately 75% of patients (Fig. 3); decreased levels of normal immunoglobulins (Ig). 1. The increased immunoglobulins are generally IgG (70%) and IgA (20%). 2. Approximately 5% to 10% of patients have only increased light chains in the urine by electrophoresis (light chain MM). 3. A small percentage (10% of the bone marrow. • Serum beta 2-microglobulin is useful for prognosis, and elevated levels indicate high tumor mass and advanced stage disease. • Elevated serum lactate dehydrogenase at diagnosis defines a subgroup of myeloma patients with very poor prognosis. • Nearly all patients with MM present with abnormal chromosomes (Table 3) identified by fluorescence in situ hybridization (FISH). High-risk patients (5.5 mg/L AND either elevated LDH OR high-risk chromosomal abnormalities by FISH [(del 17(p) and/or translocation t(14;16) and/or translocation t(4;14)]

II III

FISH, Fluorescence in situ hybridization; LDH, lactate dehydrogenase.

TABLE 6  Risk Stratification in Multiple Myeloma Investigations Recommended for Risk Stratification Serum albumin and β2-microglobulin to determine ISS stage Bone marrow examination for t(4;14), t(14;16), and del(17p) on identified PCs by FISH LDH Immunoglobulin type: IgA Histology: Plasmablastic disease or plasma cell leukemia Additional Investigations for Risk Stratification Cytogenetics Gene expression profiling Labeling index MRI/PET scan DNA copy number alteration by CGH/SNP array CGH/SNP, Comparative genomic hybridization/single-nucleotide polymorphism; DNA, deoxyribonucleic acid; FISH, fluorescence in situ hybridization; IgA, immunoglobulin A; ISS, International Staging System; LDH, lactate dehydrogenase; MRI, magnetic resonance imaging; PC, plasma cell; PET, positron emission tomography. From Hoffman R et al: Hematology, basic principles and practice, ed 7, Philadelphia, 2018, Elsevier.

TABLE 7  Standard Risk Factors for Multiple Myeloma and the Revised International Staging System Prognostic Factor

Criteria

ISS stage I Serum β2-microglobulin 1 relapse). Although the

rate of disease progression is highly variable, there is higher risk of greater long-term disability with higher relapse rate during the first 2 to 5 yr, poor recovery from initial relapses, older age of onset, involvement of multiple systems, male sex, African American, and primary progressive disease. Disease-modifying treatment has improved, and the current treatment goal is no relapses and no disease progression on imaging.

REFERRAL • Referral to neurologist is highly recommended. Referral to MS specialist should be considered in cases of poor response to therapy and/or if there is concern about complications of therapies. • Consider referrals for physical, speech, and occupational therapy. • Consider referral to urology if bladdersphincter dyssynergia is possible or if not responsive to treatment.

PEARLS & CONSIDERATIONS • Clinically isolated syndrome (CIS): Isolated demyelinating event and assessing risk of CDMS 1) in optic neuritis, if brain MRI is completely normal, there is 20% to 25% chance of CDMS over 15 yr. 2) In CIS, if there are >1 T2 hyperintensity on brain MRI, there is 84% risk, and if there are >2 Gd + lesions there is a 96% risk of CDMS over 18 mo. • Pseudorelapses may occur with heat, fever, or infections (urinary tract infections common in patients with MS). • Headache, fever, altered mental status, elevated CSF WBCs, or recurrent relapses over days to weeks raises concern for CNS infection or ADEM.

SUGGESTED READINGS Available at ExpertConsult.com RELATED CONTENT Multiple Sclerosis (Patient Information) AUTHORS: Corey Goldsmith, MD, and Alexandra Degenhardt, MD, MMSc

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Diseases and Disorders

1.  Fingolimod (Gilenya), a sphingosine1-phosphate receptor modulator and lymphocyte sequester. Possible side effects: Liver toxicity, bradycardia with first dose (requiring cardiac monitoring and ECG for at least 8 hr after administration of first dose), arrhythmia, pancytopenia, macular edema (ophthalmologic exam at baseline, at 3 mo, and thereafter for those with hx DM or uveitis), and reduced pulmonary function. Obtain varicella-zoster virus (VZV) serology. 2.  Teriflunomide (Aubagio), reversible inhibitor of pyrimidine synthesis (enzyme dihydroorotate dehydrogenase). Possible side effects: Diarrhea, abnormal liver function tests, nausea, and hair loss; pregnancy category X. Men should not impregnate their partners while on teriflunomide. Serum levels can be measured, and drug can be eliminated by charcoal or cholestyramine. Obtain TB test. 3.  Dimethyl fumarate (Tecfidera), mechanism includes inhibition of transcription of Nuclear factor-κB NF-κB. Frequent side effects include nausea, abdominal discomfort, and flushing—especially during the first month—and rarely leukopenia. 4. Siponimod (Mayzent): A selective sphingosine-1-phosphate receptor modulator and lymphocyte sequester. This is the only drug approved not only for relapsing forms of MS but also for secondary progressive MS. Possible side effects: Liver toxicity but does not cause first-dose bradycardia and requires observation. Obtain VZV serology. 5. Cladribine (mavenclad) is a purine antimetabolite recently FDA approved for oral treatment of adults with relapsing form of MS who cannot tolerate or have had an inadequate response to other MS treatments. • Disease-modifying IV therapy: These medications are newer and more efficacious in preventing multiple sclerosis relapses; however, they have a higher risk of serious side effects and infections. 1.  Natalizumab (Tysabri) is a monoclonal humanized Ab that binds integrin-α4 interfering with binding to VCAM-1. It has been associated with a higher risk of progressive multifocal leukoencephalopathy (JC virus) than other immunomodulatory therapies. Test for JC virus Ab at least annually because conversion to a positive antibody occurs at increased frequency while on this drug. If positive, progressive multifocal leukoencephalopathy

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Multiple Sclerosis SUGGESTED READINGS Handunnetthi L et al: Multiple sclerosis, vitamin D, and HLADRB1*15, Neurology 74(23):1905-1910, 2010. Harrison DM: In the clinic: multiple sclerosis, Ann Intern Med 160(7):ITC42–ITC4-18, 2014, quiz ITC4-16. Hauser SL et al: Ocrelizumab versus interferon beta-1a in relapsing multiple sclerosis, N Engl J Med 376:221-234, 2017. Kappos L et al: Daclizumab HYP versus Interferon beta-1a in relapsing multiple sclerosis, N Engl J Med 373:1418-1428, 2015. O'Connor P et al: Randomized trial of oral teriflunomide for relapsing MS, N Engl J Med 365(14):1293-1303, 2011. Pelletier D, Hafler DA: Fingolimod for multiple sclerosis, N Engl J Med 366:339347, 2012. Ramagopalan SV et al: Epidemiology of MS, Neurol Clin 29(2):207-217, 2010. Saguil A et al: Multiple sclerosis: a primary care perspective, Am Fam Physician 90(9):644-652, 2014. Scalfari A et al: The natural history of MS, study 10: relapses and long-term disability, Brain 133:1914-1929, 2010. Thompson AJ et al: Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria, Lancet Neurol 17:162-173, 2018. Thompson AL et al.: Multiple sclerosis, Lancet 391:1622-1636, 2018.

FIG. E3  This magnetic resonance image of a patient with multiple sclerosis reveals a plaque—the hyperintense lesion—in the high cervical spinal cord. (From Kaufman DM, Geyer HL, Milstein MJ: Kaufman’s clinical neurology for psychiatrists, ed 8, Philadelphia, 2017, Elsevier.)

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Multiple System Atrophy BASIC INFORMATION DEFINITION Multiple system atrophy (MSA) is an adult-onset (>30 yr) fatal neurodegenerative disorder characterized by autonomic failure associated with parkinsonism and/or cerebellar symptoms. MSA is further subdivided into two main types: • MSA-P (parkinsonism subtype), previously striatonigral degeneration • MSA-C (cerebellar subtype), previously olivopontocerebellar atrophy SYNONYMS MSA Atypical parkinsonism Synucleinopathy Shy-Drager syndrome Olivopontocerebellar atrophy Striatonigral degeneration ICD-10CM CODES G23.2 Striatonigral degeneration G23.8 Olivopontocerebellar degeneration

EPIDEMIOLOGY & INCIDENCE INCIDENCE: Estimated mean incidence is 0.6 to 0.7 cases per 100,000 persons per yr, with a range of 0.1 to 2.4 cases. PREVALANCE: • Estimated point prevalence is 4.4 cases per 100,000 patients • Rises to about 7.8 cases per 100,000 for age >40 yr • Subtype distribution: 1. MSA-P: 68% of cases 2. MSA-C: 32% of cases PREDOMINANT SEX & AGE: • Male:female ratio is 1.3:1 • Mean age of onset is 57.8 yr • In Japan, the predominant subtype is MSA-C and mean survival is short RISK FACTORS: People with MSA perform some activities more often than the general population, such as drinking alcohol and tea, eating seafood, taking aspirin, and working in plant and machine operations. However, it is not clear if these behaviors are risk factors or coincidence. GENETICS: A large, genome-wide association study found no significant loci, including no

association with the SNCA and COQ2 gene variants that previously had been suggested.

PHYSICAL FINDINGS & CLINICAL PRESENTATION • Parkinsonism (see “Parkinson Disease”): 1. Tremor: Resting tremor in MSA is more likely to be a jerky tremor or myoclonic tremor. It is usually faster and symmetrical. 2. Rigidity: Usually symmetric. 3. Postural instability: Seen early in the disease, usually within 1 to 3 yr of onset, and is rapidly progressive, with patients being wheelchair dependent within 5 yr. Falls are common early in MSA (within 3 yr) and are more common in MSA-C. • Dysautonomia: 1. Hallmark of MSA, present in both subtypes (99% of patients). 2. Orthostatic hypotension is symptomatic in 75% of the patients with lightheadedness or dizziness, especially in early morning and when quickly getting up after prolonged sitting. Drop in blood pressure of 30/15 mm Hg within in 3 min of standing is required for diagnosis. 3. Erectile dysfunction is seen in 84% of males with MSA. 4. Cold hands or feet with red hand sign due to Raynaud phenomenon. 5. Respiratory dysfunction with inspiratory stridor or sighs. • Sleep-related breathing disorders: More commonly obstructive sleep apnea and stridor. This results from airway obstruction and vocal cord restriction (in >50%). Nocturnal stridor and snoring and later daytime stridor are common. • Urine incontinence (73% of patients). ETIOLOGY • Etiology of MSA is unclear. It is generally considered a sporadic disease. Many different factors have been proposed, including environmental toxins such as formaldehyde, malathion, diazinon, benzene, hexane, ketone, and pesticides. • MSA is a synucleinopathy similar to Parkinson disease (PD) and Lewy body disease. Deposition of alpha-synuclein is seen in cerebellar subcortical white matter and early on in cerebellar brain stem projections with gradual spread.

DIAGNOSIS • Definitive diagnosis of MSA requires pathologic confirmation on autopsy. • Possible and probable diagnoses of MSA are based on clinical findings (Table E1).

DIFFERENTIAL DIAGNOSIS • Progressive supranuclear palsy: Atypical parkinsonism that presents with early falls and postural instability and can be differentiated by lack of tremors, supranuclear ocular palsy, lack of myoclonus, and, most important, less frequent dysautonomia. • PD: PD can develop mild dysautonomia and postural instability. Key in differentiation is timing of onset of these symptoms (much later for PD), levodopa responsiveness, asymmetry of PD, and much slower progression of PD. • Corticobasal syndrome: Atypical parkinsonism that can present with early falls and postural instability and can have myoclonus. Differentiated due to marked asymmetry of the disease, early cognitive involvement, and presence of apraxia. • Secondary parkinsonism: Usually lacks the presence of dysautonomia and may be more slowly progressive. • Main differential diagnosis of MSA-C includes sporadic late-onset ataxias and autosomal dominant spinocerebellar ataxias (SCA). • Fragile X associated tremor ataxia syndrome (FXTAS) must be distinguished from MSA and can be present in up to 5% of adult-onset progressive cerebral ataxia. WORKUP Autonomic failure early in disease can differentiate MSA and can be determined with: • Thermoregulatory testing • Thermal skin sweat test • Tilt table test • Ambulatory 24-hour blood pressure monitoring LABORATORY TESTS • No routine laboratory tests are indicated. • It is important to work up for secondary causes of parkinsonism and dysautonomia as appropriate.

TABLE E1  Diagnostic Criteria for Multiple System Atrophy (MSA) Possible MSA

Probable MSA Definitive MSA

A sporadic, progressive, adult (>30 yr) onset disease characterized by • Parkinsonism or cerebellar syndrome • At least one feature of autonomic or urogenital dysfunction • At least one of the additional features A sporadic, progressive, adult (>30 yr) onset disease characterized by • Autonomic failure involving urinary dysfunction • Poorly levodopa-responsive parkinsonism or cerebellar dysfunction A sporadic, progressive, adult (>30 yr) onset disease pathologically confirmed by presence of high-density glial cell inclusions in association with degenerative changes in striatonigral and olivopontocerebellar pathways

MRI, Magnetic resonance image.

Additional Features: • Stridor • Babinski sign • Rapidly progressive parkinsonism • Poor response to levodopa • Postural instability within 3 yr • Cerebellar ataxia • Dysphagia within 5 yr • MRI changes suggestive of MSA

Multiple System Atrophy IMAGING STUDIES Some changes have been described on MRI of the brain in MSA, although they are not common or exclusive. • Hot cross bun sign or T2 hyperintensity in a crosslike fashion in the basis pontis. • T2 linear hyperintensities on the outer margin of the putamen. • Middle cerebellar peduncle atrophy and infratentorial atrophy. • Changes in diffusion tensor imaging in putamen and middle cerebellar peduncle. • Ancillary neuroimaging tests include FDG-PET, transcranial ultrasonography, F-DOPA PET, 18F-fluorodopamine PET, and 123I-IBZM SPECT.

TREATMENT • Parkinsonism in MSA may respond to levodopa in 60% patients; however, 90% patients, usually 2 to 3 yr on average. • Parkinsonism in MSA does NOT respond to deep brain stimulation (DBS) surgery and is a diagnosis of exclusion for DBS surgery. Currently, there is no surgical treatment for parkinsonism in MSA. • Antiaggregation and truncation of alphasynuclein is under investigation as a treatment strategy.

NONPHARMACOLOGIC THERAPY Most often, the initial treatment for orthostatic hypotension includes physical and supportive countermeasures to raise blood pressure, such as:

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• Crossed leg stance with leaning against the wall • Elastic stockings • Correcting volume depletion and anemia • Avoiding dehydration • Liberal salt use

ACUTE GENERAL Rx ORTHOSTATIC HYPOTENSION: • Second FDA-approved medication for neurogenic orthostatic hypotension is Droxidopa (with midodrine being the only other medication). • Recently approved droxidopa is a synthetic amino acid prodrug of norepinephrine that is orally bioavailable and has limited crossover through the blood-brain barrier and increases norepinephrine levels in brain. • Other medications are used frequently to treat orthostatic hypotension (generally before droxidopa), including pyridostigmine, fludrocortisone, midodrine, and octreotide (Table E2). CHRONIC Rx • Bladder dysfunction: Medication used includes oxybutynin, tolterodine, solifenacin, darifenacin, tamsulosin, prazosin, and moxisylyte (specific antagonist of bladder α-adrenergic receptors), and use of botulinum toxin for bladder spasticity and urgency. • Erectile dysfunction: Medication used includes sildenafil and tadalafil. • Constipation: Medications include polyethylene glycol, bisacodyl, magnesium sulphate, macrogol, lubiprostone, and botulinum toxin. Long-term use of polyethylene glycol is safe

in parkinsonian patients and is the recommended treatment of choice in PD. • Sleep apnea: Usually treated with continuous positive airway pressure or bilevel positive airway pressure. • Stridor: Continuous positive airway pressure is first-line therapy, but tracheostomy may be required for persistent and severe stridor.

COMPLEMENTARY & ALTERNATIVE MEDICINE No evidence-based therapy. Patients with parkinsonism use Mucuna pruriens powder and fava beans. Both of them have levodopa in varying concentration and are not known to be any superior to carbidopa/levodopa. DISPOSITION MSA is a relentlessly and rapidly progressive disabling disease. Mean survival in both subtypes is 7 to 9 yr; sudden death and pneumonia are the two most common causes of death. Older age of onset and early autonomic dysfunction are predictive factors for rapid progression with shorter disease survival. REFERRAL • Neurology consultation is important to make the distinction between MSA and other causes of parkinsonism. Yearly evaluation for diagnosis may be needed. Reliability of diagnosis by a movement disorders expert is superior to that from a general neurologist (95% vs. 70%). • Due to high incidence of nonmotor complications, a close coordination by different care providers is needed.

TABLE E2  Medications for Orthostatic Hypotension in Parkinsonism Medication

Mechanism of Action

Suggested Dosage

Common/Serious Side Effects

Fludrocortisone*,†

A synthetic corticosteroid with mineralocorticoid effect on the kidney (inducing permease), enhancing Na+ reabsorption and increasing K+ excretion Midodrine is converted to active metabolite desglymidodrine by that selectively binds to and activates alpha-1-adrenergic receptors of vasculature

0.1-0.5 mg per day

An orally active synthetic precursor of epinephrine that crosses blood-brain barrier and increases brain epinephrine levels Binds reversibly to acetyl-cholinesterase in PNS and increases ACH, leading to muscarinic effects of contraction of bronchial and intestinal smooth muscles, exocrine gland secretions, and nicotinic effect of skeletal muscle contraction A synthetic somatostatin analogue; even more potent inhibitor of growth hormone, glucagon, and insulin

200-2000 mg per day

Acute withdrawal adrenal insufficiency, edema, hypokalemia, interaction with lithium and through CYP450. Contraindicated in patients with severe organic heart disease, acute renal disease, urinary retention, pheochromocytoma, or thyrotoxicosis. Headache, dizziness, and nausea. No significant known toxicity.

(9 alpha-fluoro-17-hydroxy-corticosterone) Midodrine*,† (2-amino-N[dimethoxyphenylhydroxyethyl]-acetamide) Droxidopa*,† (D,L Threo 3,4-Dihydroxyphenylserine) Mestinon† (hydroxymethyl-pyridinium bromide dimethylcarbamate) Octreotide‡ (pentaoxo-dithiapentazacycloicosane4-carboxamide)

ACH, Acetylcholine; CYP450, cytochrome P450; PNS, peripheral nervous system; QID, four times daily. *Drug warning: Potentially serious side effect of marked elevation of supine blood pressure. †FDA Pregnancy Risk Category C. ‡FDA Pregnancy Risk Category B.

5-10 mg per day

120 to 660 mg per day in divided doses (usually QID)

Toxicity with confusion, ataxia, seizures; generalized weakness, fatigue and twitching, nausea, vomiting and cramps. Coma and death can occur. Antidote is atropine.

100-1500 μg per day subcutaneously

Abdominal pain, decreased appetite, diarrhea

Multiple System Atrophy  EARLS & P CONSIDERATIONS Red flags for MSA in patient presenting with parkinsonism: • Early postural instability, especially if wheelchair bound within 5 yr • Rapid progression • Abnormal postures, such as Pisa syndrome • Severe bulbar dysfunction • Respiratory dysfunction: Inspiratory stridor or inspiratory signs • Emotional lability

PATIENT & FAMILY EDUCATION The Multiple System Atrophy Coalition supporting patients and caregivers: https://www.multip lesystematrophy.org RELATED CONTENT Parkinson Disease (Related Key Topic) AUTHOR: Danish Bhatti, MD

SUGGESTED READINGS Bassil F et  al: Reducing C-terminal truncation mitigates synucleinopathy and neurodegeneration in a transgenic model of multiple system atrophy, Proc Natl Acad Sci U S A 113(34):9593-9598, 2016. Fanciulli A, Wenning GK: Multiple-system atrophy, N Engl J Med 372:249-263, 2015. Levin J et al: The PROMESA-protocol: progression rate of multiple system atrophy under EGCG supplementation as anti-aggregation-approach, J Neural Transm 123(4):439-445, 2016. Rulseh AM, et  al: Diffusion tensor imaging in the characterization of multiple system atrophy, Neuropsychiatr Dis Treat 12:2181-2187, 2016. Sailer A et  al: A genome-wide association study in multiple system atrophy, Neurology 87(5):1591-1598, 2016.

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Mumps BASIC INFORMATION DEFINITION Mumps is an acute generalized viral infection that is usually characterized by nonsuppurative swelling and tenderness of one or both parotid glands. It is caused by mumps virus, a singlestranded RNA paramyxovirus, of which humans are the only natural host. SYNONYMS Viral parotitis Parotitis ICD-10CM CODES B26.0 Mumps orchitis B26.1 Mumps meningitis B26.2 Mumps encephalitis B26.3 Mumps pancreatitis B26.81 Mumps hepatitis B26.82 Mumps myocarditis B26.83 Mumps nephritis B26.84 Mumps polyneuropathy B26.85 Mumps arthritis B26.89 Other mumps complications B26.9 Mumps without complication

EPIDEMIOLOGY & DEMOGRAPHICS INCIDENCE (IN U.S.): • In 2016 there were 6369 cases in the U.S., and in 2017 there were 5629 cases in the U.S., which was the highest in a decade. Sporadic outbreaks still occur in schools, colleges, military posts, or summer camps started by an unvaccinated person. • Recent mumps outbreaks in the U.S.: At an Ohio university in 2014 (386 cases), at a California university in 2011 (29 cases). • More than 150,000 cases/yr before licensure of mumps vaccine in 1967. PREDOMINANT SEX: Males = females PREDOMINANT AGE: 75% of disease in teenage years PEAK INCIDENCE: Late winter and early spring months GENETICS: • Congenital infection: 1.  First-trimester infection is associated with excessive fetal deaths. 2. Second- and third-trimester infection is not associated with increased fetal mortality. • Neonatal infection: 1. Uncommon 2. Uncommon in infants 3.5 g/24 hr), hypoalbuminemia, hyperlipidemia, lipiduria, and edema. Nephrotic-range proteinuria involves urine protein excretion of >3.5 g/24 hours without other features of the nephrotic syndrome. Proteinuria, primarily in the form of albuminuria, can have many causes that share a common mechanism of glomerular injury , the most common being diabetes, focal segmental glomerulosclerosis, membranous nephropathy, minimal change disease, and amyloidosis. Though less common, disorders that are classically categorized under the nephritic syndrome also may lead to nephrotic-range proteinuria.

EPIDEMIOLOGY & DEMOGRAPHICS • Among children (especially 4 mg mg/m2/hr or >100 mg mg/m2/hr Urine dipstick 3+ or proteinuria >40 mg/ m2/hr occurring on 3 days within 1 wk

Reduction in proteinuria between 0.3 g/24 hours and 3.5 g daily with ≥50% decrease in proteinuria from baseline Increase in proteinuria to >3.5 g daily after one mo of complete or partial remission Two consecutive relapses occurring during therapy or within 14 days of completing therapy Persistence of proteinuria without significant reduction despite prednisone therapy at 1 mg/kg for 16 wk

Two relapses of proteinuria within 14 days after stopping or during alternate-day steroid therapy Persistence of proteinuria despite prednisone therapy at 60 mg/m2 for 4 wk

*These definitions only truly apply to diseases such as minimal change disease and FSGS. (Adapted from Cattran DC et al: Cyclosporine in idiopathic glomerular disease associated with the nephrotic syndrome: workshop recommendations, Kidney Int 72(12):1429-1447, 2007, and KDIGO clinical practice guidelines for glomerulonephritis.)

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • Other states that present with edema (CHF, cirrhosis, protein-losing enteropathy, severe malnutrition) • Glomerulonephritis from disorders commonly associated with inflammatory urinary sediment and glomerular inflammation • Mimickers of glomerulonephritis (thrombotic microangiopathy due to malignant HTN, preeclampsia, or antiphospholipid syndrome) WORKUP • Evaluation includes determining the rate of change of serum creatinine, quantification of proteinuria by 24-hr collection, and urinary sediment examination. • Abnormalities in any of the above tests should prompt nephrology consultation. • Serologic testing may include urine and serum electrophoresis, HIV, hepatitis B surface antigen, hepatitis C virus (HCV) antibody, and antinuclear antibody (ANA). As urinary sediment examination is not 100% sensitive in ruling out an inflammatory process, C3 and C4 can be checked, as complement levels are often low in many inflammatory glomerulonephritides and often low in MPGN. Low complement levels may change the nature of the differential diagnosis before kidney biopsy. Depending on practice patterns, these tests are used selectively before or (in some cases) after biopsy to better define an etiology. • A newer serological test available to clinicians commercially is an antiphospholipase A2 receptor antibody (anti-PLA2r) titer. Positive titers are seen in primary membranous nephropathy but less commonly in secondary membranous nephropathy. With treatment, patients may go into an immunologic remission (decreasing titers) prior to a

clinical remission based on urine proteinuria. Thus, monitoring titers during the course of treatment may help guide treatment duration and limit toxic side effects of therapy. • Patients should have a kidney ultrasound to document organ size and the presence of two kidneys prior to biopsy.

TREATMENT NON-IMMUNOSUPPRESSIVE THERAPY • Control of proteinuria is key to mitigating risk of progression. Almost all trials of non-diabetic chronic kidney disease demonstrate that reducing proteinuria improves renal survival. Angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers should be used at maximally tolerated doses, except in MCD, where proteinuria reduction is often seen rapidly with treatment. Dual angiotensin-converting enzyme inhibitor and angiotensin II receptor blocker therapy is generally not recommended due to increased risks of hyperkalemia and elevating the serum creatinine. Non-dihydropyridine calcium channel blockers (verapamil and diltiazem) can be used to in lieu of angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers when the latter are contraindicated. • For proteinuria >1 gram per day, target blood pressure is 15 mm in postpubertal patients 2. Two or more neurofibromas of any type or one plexiform neurofibroma 3. Axillary or inguinal freckling 4. Optic glioma 5. Two or more Lisch nodules (iris hamartomas) 6. Sphenoid wing dysplasia or cortical thinning of long bones, with or without pseudoarthrosis 7. A first-degree relative (parent, sibling, or child) with NF1 based on the previous criteria • NF2 is diagnosed if the person has either of the following two criteria: 1. Bilateral eighth nerve masses seen by appropriate imaging studies (e.g., CT, MRI) 2. A first-degree relative with NF2 and either a unilateral eighth nerve mass or two of the following: Neurofibroma, meningioma, glioma, schwannoma, or juvenile posterior subcapsular lenticular opacity

A

B

C

D

FIG. 1  Systemic features of Neurofibromatosis type 1. A, Discrete neurofibromas. B, Nodular plexiform neurofibroma of the eyelid. C, Elephantiasis nervosa. D, Cafe-au-lait spots. (Courtesy S. Kumar Puri; From Kanski JJ, Bowling B: Clinical ophthalmology, a systematic approach, ed 7, Philadelphia, 2010, WB Saunders.)

Diseases and Disorders

SYNONYMS NF1: von Recklinghausen disease, peripheral NF NF2: Bilateral acoustic neurofibromatosis, central NF

4. Lisch nodule (small hamartoma of the iris) found in >90% of adult cases 5. Visual defects possibly related to optic gliomas (2% to 5%) 6.  Neurodevelopment problems such as learning disability and mental retardation (30% to 40%) 7. Skeletal disorders, including long bone dysplasia, pseudoarthrosis, scoliosis, short stature, and decreased bone mineral density • Common features of NF2 include: 1. Hearing loss and tinnitus related to bilateral acoustic neuromas (>90% of adults) 2. Cataracts (81%) 3. Headache (may be due to intracranial meningiomas, which are present in 80% of patients) 4. Unsteady gait 5. Cutaneous and subcutaneous neurofibromas but fewer than in NF1 6. Café-au-lait macules (1%) (Fig. 3) • Common features of SWN include painful multiple schwannomas of the spinal (74%), peripheral (89%), or cranial nerves except the vestibular nerve (9%)

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Neurofibromatosis 2.  One nonvestibular schwannoma and a first-degree relative fitting the above criteria

DIFFERENTIAL DIAGNOSIS • Abdominal NF • Myxoid lipoma • Nodular fasciitis • Fibrous histiocytoma • Segmental NF WORKUP The diagnosis of NF is usually self-evident. Workup is dictated by clinical symptoms in NF1 and usually includes MRI evaluation of the head and spine in NF2 and SWN. In fact, if NF2 is suspected but no vestibular nerve schwannomas are found, the diagnosis points to SWN.

FIG. 2  Multiple neurofibromas are present in this individual. (From Callen JP et  al: Dermatological signs of systemic disease, ed 5, Philadelphia, 2017, Elsevier.)

LABORATORY TESTS • Genetic testing is possible in individuals who desire prenatal diagnosis for NF1. There is no single standard test and multiple tests are required. Results can only tell if an individual is affected but cannot predict the severity of the disease due to variable expression. • In NF2, linkage analysis testing provides a >99% certainty the individual has NF2. IMAGING STUDIES • MRI with gadolinium is the imaging study of choice in both NF1 and NF2 patients. MRI increases detection of optic gliomas, tumors of the spine, acoustic neuromas, and “bright spots” believed to represent hamartomas. • MRI of the spine is recommended in all patients diagnosed with NF2 to exclude intramedullary tumors. OTHER TESTS • Wood’s lamp examination may be useful in patients with very pale skin for visualizing café-au-lait spots. • Slit-lamp examination is recommended for children >6 yr to confirm the presence of Lisch nodules and subcapsular opacity.

TREATMENT Treatment is directed primarily at symptoms and complications of NF1 and NF2. As for SWN, resection should be reserved for tumors that are symptomatic or threaten to cause spinal cord compression. FIG. 3  A café-au-lait spot and multiple freckles (Crowe sign) in the axillary vault is seen in this patient with neurofibromatosis. (From Callen JP et  al: Dermatological signs of systemic disease, ed 5, Philadelphia, 2017, Elsevier.)

NONPHARMACOLOGIC THERAPY • Counseling addressing prognosis and genetic, psychological, and social issues. • Hearing testing and speech pathology evaluation.

• SWN is diagnosed in an individual >30 yr having either of the following two criteria: 1.  Two nonintradermal schwannomas, no vestibular tumor found on MRI scan, no NF2 mutation

ACUTE GENERAL Rx • Surgery is usually not done on skin tumors unless cosmetically requested or if suspicion of malignant transformation exists.

• Surgery may be indicated for spinal or cranial neurofibromas, gliomas, or meningiomas. • Acoustic neuromas can be treated by surgical excision.

CHRONIC Rx • Radiation may be indicated in optic nerve gliomas and patients whose central nervous system tumors show radiographic progression. • Stereotactic radiosurgery with a gamma knife may be an alternative approach to surgery for acoustic neuromas. • Bevacizumab continues to be studied as a treatment option for NF2 meningiomas (which express vascular endothelial growth factor [VEGF]). DISPOSITION • Prognosis varies according to the severity of involvement. • There is no cure for NF. REFERRAL A multidisciplinary team of consultants is needed in patients with NF, including neurosurgeon, otolaryngologist, dermatologist, neurologist, audiologist, speech pathologist, geneticist, and neuropsychologist.

PEARLS & CONSIDERATIONS • Friedrich Daniel von Recklinghausen first reported his cases in 1882, although there had been similar accounts dating back to the 1600s. • A high SPRED1 mutation detection rate has been identified in NF1 mutation-negative families with an autosomal dominant phenotype of café-au-lait macules with or without freckling and no other NF1 features.

COMMENTS For additional information and patient resources, refer to the Neurofibromatosis Network or Neurofibromatosis Inc. (www.nfnetwork.org). SUGGESTED READINGS Available at ExpertConsult.com RELATED CONTENT Neurofibromatosis Type 1 (Patient Information) Neurofibromatosis Type 2 (Patient Information) AUTHOR: Craig Blakeney, MD

Neurofibromatosis SUGGESTED READINGS Blakeley JO, Plotkin SR: Therapeutic advances for the tumors associated with neurofibromatosis type 1, type 2, and schwannomatosis, Neuro Oncol 18(5):624-638, 2016. Shah KN: The diagnostic and clinical significance of café-au-lait macules, Pediatr Clin North Am 57(5):1131-1153, 2010.

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Neuroleptic Malignant Syndrome BASIC INFORMATION DEFINITION Neuroleptic malignant syndrome (NMS) is a disorder characterized by hyperthermia, muscular rigidity, autonomic dysfunction, and depressed/ fluctuating levels of arousal that evolve over 24 to 72 hr. This occurs as an idiosyncratic adverse reaction to medications that affect the central dopaminergic system, usually D2 receptors blockade. SYNONYM NMS ICD-10CM CODE G21.0 Malignant neuroleptic syndrome

EPIDEMIOLOGY & DEMOGRAPHICS INCIDENCE (IN U.S.): 0.02% to 0.2% annual incidence in psychiatric population PREDOMINANT SEX: More than two thirds of patients are male. PREDOMINANT AGE: Young and middle-aged adults PREDISPOSING FACTORS: History of intake of dopamine antagonists, e.g., antipsychotics

PHYSICAL FINDINGS & CLINICAL PRESENTATION • Syndrome typically begins abruptly while the patient is taking therapeutic (not toxic) dosages of neuroleptics and reaches maximum severity within 72 hr • Severe muscle rigidity (hypertonia, cogwheeling, or “lead pipe” rigidity) • Hyperthermia (38.6° to 42.3° C [101.48° to 108.14° F], usually 70% of patients.

SUGGESTED READING Gurrera RJ et  al: An international consensus study of neuroleptic malignant syndrome diagnostic criteria using the Delphi method, J Clin Psychiatry 72:1222-1228, 2011.

972.e3 • Rhabdomyolysis is the most common complication. Other complications include acute kidney injury, respiratory failure, pneumonia, and sepsis. • Causes of death include cardiac arrhythmias, myocardial infarction, renal failure secondary to rhabdomyolysis, seizures, pulmonary edema, and bronchopneumonia. • Factors adversely affecting mortality are increased age, acute respiratory failure, renal failure, and core temperature >104° F (40° C). • Patients should be monitored closely for future complications of pharmacologic therapy.

REFERRAL If the patient’s condition is critical, it is preferable to treat the patient in a medical/neurologic ICU.

PEARLS & CONSIDERATIONS COMMENTS • Early detection and diagnosis lead to a more favorable outcome. Refer to recent consensus diagnostic criteria as a guide. Treatment is a medical emergency. • Sudden withdrawal from dopaminergic agents (such as those used in Parkinson disease) may lead to “levodopa withdrawal syndrome” that presents with similar clinical manifestations. • Patients with dementia with Lewy bodies have increased susceptibility to neuroleptic malignant syndrome. SUGGESTED READING Available at ExpertConsult.com AUTHORS: Chloe Mander Nunneley, MD, Joseph S. Kass, MD, JD, FAAN, and Fariha Jamal, MD

ALG BASIC INFORMATION

SYNONYM Neuralgia ICD-10CM CODES B02.29 Postherpetic neuralgia G50.0 Trigeminal neuralgia G58.0 Intercostal neuropathy G58.7 Mononeuritis multiplex G58.8 Other specified mononeuropathies G58.9 Mononeuropathy, unspecified G61.9 Inflammatory polyneuropathy, unspecified G62.0 Drug-induced polyneuropathy G62.1 Alcoholic polyneuropathy G62.9 Polyneuropathy, unspecified G63.2 Diabetic polyneuropathy G63.5 Polyneuropathy in systemic connective tissue disease G63.8 Polyneuropathy in other diseases classified elsewhere M79.2 Neuralgia and neuritis, unspecified

EPIDEMIOLOGY & DEMOGRAPHICS • Estimates of the prevalence of neuropathic pain in the general population range from 1.6% to 8.2% • Demographics vary widely depending on etiology, for example: 1. Postherpetic neuralgia: Affects elderly, pain seen in almost 100% of cases 2. AIDS: 30% of patients affected 3. Diabetes mellitus: 20% to 24% affected (prevalence rates vary, increasing with longer disease duration) 4. Fabry disease: Affects mostly children, pain in 81% to 90% of patients PHYSICAL FINDINGS & CLINICAL PRESENTATION • History: Localize the disease with questions 1.  Quality (description) of neuropathic pain: Burn­ing, hot or cold, “icy hot,” “pins and need­ les,” stinging, lancinating, sharp, shooting 2. Distribution of symptoms may aid in localization (i.e., “stocking-glove” ­symptoms in ­generalized neuropathy, numbness in a peripheral nerve territory in focal ­neuropathy)

ETIOLOGY & LABORATORY EVALUATION (Table 3) • Metabolic: Diabetes mellitus; malnutrition and alcoholism; vitamin B12 deficiency; thiamine deficiency; porphyria; Fabry disease • Inflammatory: Autoimmune diseases (systemic vasculitides, systemic lupus erythematosus, Sjögren syndrome, etc.), acute inflammatory demyelinating polyneuropathy (classically presents with ascending weakness and numbness, although pain is also

a common feature), chronic inflammatory demyelinating polyneuropathy, sarcoidosis, multiple sclerosis • Infiltrative: Amyloidosis, paraproteinemias (e.g., monoclonal gammopathy of uncertain significance [MGUS] associated neuropathy) • Infectious: Postviral (brachial neuritis), HIV/ AIDS, HSV, varicella-zoster virus (VZV; postherpetic neuralgia), Lyme disease, leprosy (thickened nerves and skin lesions), syphilis • Neoplastic and paraneoplastic-­carcinomatous infiltration of nerve/nerve root, anti-Hu • Drugs/toxins: History of exposure to alcohol, chemotherapeutic agents (paclitaxel, vincristine), isoniazid, metronidazole, or heavy metals (thallium, arsenic)

DIAGNOSIS LABORATORY TESTS • Fasting blood glucose (FBG) • 2-hour oral glucose tolerance test (OGTT) • Vitamin B12 level • If B12 level normal: Serum methylmalonic acid and homocysteine levels • Serum erythrocyte sedimentation rate (ESR), ANA, SS-A and SS-B, c-ANCA, p-ANCA • RPR or FTA-ABS • Serum ACE level (sarcoid) • HIV antibody • SPEP, UPEP, immunofixation • Urine and stool protoporphyrins, if porphyria is suspected clinically

TABLE 1 Examination Exam Finding

Localization

Pinprick/temperature loss alone Pinprick/temperature loss + vibratory/proprioceptive loss Sensory loss and motor dysfunction worse distally than proximal Sensory loss and motor dysfunction along single nerve distribution Sensory loss and motor dysfunction along multiple single nerves

Small fibers only Small and large fibers Large fiber neuropathy Single nerve Multiple mononeuropathies (i.e., mononeuropathy multiplex) Plexopathy

Motor and sensory loss involving multiple nerves belonging to ­specific region of brachial or lumbar plexus Sensory loss along dermatome with multiple myotomal muscles affected Asymmetric sensory loss without weakness and pseudoathetosis Vibratory/proprioceptive loss without pinprick/temperature loss Sensory level with weakness below the level of lesion and long tract signs (spasticity/Babinski sign) Hemisensory hyperalgesia

Nerve root lesion Dorsal root ganglion Dorsal column dysfunction (from compressive lesion, B12 deficiency, or tabes dorsalis from neurosyphilis) Spinal cord lesion Contralateral thalamus

TABLE 2  Joint Involvement in Neuropathic Arthropathy Disease

Site of Involvement

Diabetes mellitus Syringomyelia Amyloidosis Congenital sensory neuropathy Tabes dorsalis Leprosy

Midtarsal, metatarsophalangeal, tarsometatarsal Shoulder, elbow, wrist Knee, ankle Knee, ankle, intertarsal, metatarsophalangeal Knee, hip, ankle Tarsal, tarsometatarsal

From Hochberg MC et al: Rheumatology, ed 5, St Louis, 2011, Mosby.

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N

Diseases and Disorders

DEFINITION Neuropathic pain is not itself a disease but rather a symptom that is associated with multiple different diseases. Thus, it is not enough to define its presence without searching for a cause. It is defined as the sensation derived from the abnormal discharges of impaired or injured neural structures in either the peripheral or central nervous system. Descriptors include: • Hyperesthesia: Heightened sensitivity to nonpainful stimuli (e.g., light touch) • Hyperalgesia: Heightened sensitivity to painful stimuli (e.g., pinprick), or reduced threshold to feel pain • Allodynia: Pain provoked by a stimulus that is not normally painful

3. G  eneralized small fiber neuropathy: Dysesthesias without numbness common, but many etiologies (e.g., diabetes) cause both small and large fiber dysfunction 4. Large fiber neuropathy (LFPN): Coexisting numbness, hyporeflexia, or weakness may be seen, usually worse distally 5. Nerve root: Coexisting neck or low back pain that radiates along a specific dermatome; most common cause is structural compression 6. Spinal cord symptoms: Coexisting spasticity, bowel or bladder involvement, sensory level 7. Prior history of thalamic stroke in central thalamic pain syndrome (Dejerine-Roussy syndrome) 8. Family history may suggest a genetic cause • Examination: See Table 1. Table 2 describes joint involvement in neuropathic arthropathy. Fig. 1 illustrates a diagnostic approach to neuropathic pain. Fig. 2 shows a neuropathic ankle

Neuropathic Pain

I

974

Neuropathic Pain

ALG History+Physical Exam ENMG

Demyelinating

Symmetrical

Acute AIDP Diphtheria

Chronic CMT1

Axonal

Symmetrical

Asymmetrical

Acute AIDP

Chronic CIDP α-MAG

Acute AMAN AMSAN

Chronic Diabetic CIP HIV Meds/Toxins

Asymmetrical

Acute Vasculitic Diabetic

Chronic MMN

FIG. 1  A systematic approach to evaluate neuropathy. The diseases listed are examples of neuropathies associated with specific neurophysiologic and clinical findings. Diabetic distal, predominantly sensory neuropathies are manifested as chronic axonal neuropathies; acute asymmetric neuropathies can also occur with diabetes. Most neuropathies caused by toxins or by side effects of medication are chronic, symmetric axonal neuropathies. AIDP, AMAN, and AMSAN are subtypes of Guillain-Barré syndrome. These and other examples are discussed in more detail in the text. AIDP, Acute inflammatory demyelinating polyradiculoneuropathy; AMAN, acute motor axonal neuropathy; AMSAN, acute motor and sensory axonal neuropathy; CIDP, chronic inflammatory polyradiculoneuropathy; CIP, chronic illness polyneuropathy; CMT1, Charcot-Marie-Tooth disease type 1, a genetic disorder; ENMG, electroneuromyography; HIV, human immunodeficiency virus–related neuropathy; α-MAG, alpha-myelin-associated glycoprotein; MMN, multifocal motor neuropathy. (From Goldman L, Schafer AI: Goldman’s Cecil medicine, ed 24, Philadelphia, 2012, WB Saunders.)

PATHOLOGY STUDIES • Nerve biopsy is occasionally useful in selected cases, particularly when vasculitis, sarcoidosis, or amyloid neuropathy are in the differential. • Skin biopsy for intraepidermal nerve fiber (IENF) density may be useful for small fiber neuropathy when other studies are normal. • Rectal or abdominal fat pad biopsy may show amyloid deposition in systemic amyloidosis.

FIG. 2  Neuropathic ankle. Marked instability of the subtalar and midtarsal joints is seen with collapse on weight bearing. (From Hochberg MC et al: Rheumatology, ed 5, St Louis, 2011, Mosby.)

• Hu antibody: Can be seen in both small cell and non–small cell lung cancers, may be positive without evidence of lung cancer • Lumbar puncture: Protein elevation, oligoclonal bands, CSF/serum IgG index

ELECTROPHYSIOLOGY STUDIES • Electrophysiologic testing (electromyography with nerve conduction studies): May be normal in small fiber neuropathies or CNS lesion, but is often abnormal in large fiber neuropathies • Quantitative sensory testing: Abnormal in small and large fiber neuropathy • Evoked potentials (only if suspicion for spinal cord lesion)

IMAGING STUDIES Based on localization: • MRI (with and without contrast): 1. Of the brain to exclude thalamic pathology if symptoms and signs are consistent with thalamic lesion (hemibody pain) 2.  Of the spinal cord and nerve roots to exclude structural, inflammatory, neoplastic, or infectious causes 3. Of the lumbar spine to evaluate for arachnoiditis • If MRI cannot be performed, consider: 1. CT of the brain for thalamic pathology 2. CT myelography of the spinal cord to evaluate for structural/neoplastic disease, but only if clinical signs of spinal or nerve root compromise are present

TREATMENT NONPHARMACOLOGIC THERAPY • Counseling should be initiated at the beginning of therapy to address psychological issues exacerbating physiologic pain.

• Physical therapy: Especially in cases of chronic neck and low back pain. • Cognitive behavioral therapy

ACUTE GENERAL Rx • Treatment of the underlying cause if possible will help slow or prevent worsening. • Medications may reduce or alleviate pain but do not affect numbness. • Antidepressants: 1. Tricyclic antidepressants (TCAs): Nortri­ ptyline preferred over amitriptyline (fewer anticholinergic side effects with nortriptyline). Begin 25 mg PO qd in adults, or 10 mg qd in elderly. Increase dose by 25 mg every wk as tolerated until usual maximal effective dose of 150 mg/day. 2. Duloxetine: Begin 30 mg daily, increase to 60 to 120 mg daily. Duloxetine is effective in diabetic neuropathy, post-herpetic neuropathy, and chemotherapy-induced painful peripheral neuropathy. 3. Venlafaxine. • Antiepileptics: 1. Gabapentin: Begin 300 mg PO qd, advance to 300 mg PO tid by the end of the first wk. Effective dose: Higher than 1600 mg/day. Max dose: 1200 mg PO tid. 2. Carbamazepine: For trigeminal neuralgia. Begin 400 mg PO bid, increase to tid if necessary. Side effects and drug levels help to determine optimal dosing. Risk of aplastic anemia and hyponatremia (monitor CBC and chemistries). Risk of StevensJohnson syndrome, especially in Asian population (check HLA before starting).

ALG

Neuropathic Pain

TABLE 3  Clinical Presentation and Laboratory Findings

N

Predisposition

Examination Findings

EMG/NCS

Laboratory Analysis

Idiopathic small fiber PN

Age >50

Normal

Diabetic PN Inherited PN

Long-standing disease Family history Family history

Serum studies: Normal skin biopsy: Abnormal sudomotor studies: Abnormal Abnormal glucose tolerance: High fasting glucose Genetic studies may be abnormal, other studies normal

Familial amyloid PN

Family history

Strength: Normal Reflexes: Normal Pos/vib: Normal Pain/ temp: Decreased distally Strength normal to reduced, sensation reduced distally Pes cavus, hammer toes, reduced reflexes, sensation reduced distally Pain/temp loss, reduced reflexes, orthostasis

Acquired amyloid PN

Monoclonal gammopathy

Pain/temp loss, reduced reflexes, orthostasis

Fabry disease

Age, renal failure, strokes

PN + mixed connective ­tissue disease

History of lupus, rheumatoid arthritis, Sjögren syndrome Asymmetric disease

Normal; possible reduced pain/ temp sensation Reduced reflexes and distal sensation

Peripheral nerve vasculitis Paraneoplastic neuropathy

Lung cancer risk factors, chemical exposures

Sarcoidosis

Pulmonary sarcoid

Arsenic

Pesticides, copper smelting

HIV

Promiscuity, unprotected sex, IV drug abuse, blood transfusion

Abnormal Abnormal if large fibers affected; also carpal tunnel syndrome Abnormal if large fibers affected; also carpal tunnel syndrome Normal Abnormal

Multiple peripheral nerves involved Asymmetric sensory loss, pseudoathetosis, relatively preserved strength Multiple mononeuropathies

Abnormal

Reduced reflexes and distal sensation Variable, but most often reduced reflexes and distal sensation

Abnormal

Transthyretin genetic study SPEP, UPEP, immunofixation abnormal α-Galactosidase levels in cultured fibroblasts ANA, RF, SS-A/SS-B may be abnormal ANA, RF, SS-A/SS-B, ANCA, cryoglobulins may be abnormal Anti-Hu

Abnormal Abnormal

Abnormal if large fibers involved

Abnormal biopsy, elevated serum ACE, CXR abnormal Elevated arsenic in plasma, urine, and hair HIV antibody

ACE, Angiotensin-converting enzyme; ANA, antibody to nuclear antigens; ANCA, antineutrophil cytoplasmic antibodies; CXR, chest x-ray; EMG, electromyography; HIV, human immunodeficiency virus; IV, intravenous; NCS, nerve conduction studies; PN, polyneuropathy; Pos, position sensation; RF, rheumatoid factor; SPEP, serum protein electrophoresis; SS-A, Sjögren syndrome A; SS-B, Sjögren syndrome B; Temp, temperature sensation; UPEP, urine protein electrophoresis; Vib, vibration sensation. Adapted from Mendell JR, Sahenk Z: Painful sensory neuropathy, N Engl J Med 348(13):1243, 2003.

3. O  xcarbazepine: Better tolerated than carbamazepine. Start 150 mg PO bid and gradually increase to a dose of 600 mg bid. Maximum dose is 1200 mg bid. 4. Pregabalin: Begin 50 mg PO tid, increase slowly to 100 to 200 mg PO tid. • Analgesics: When first-line agents are ineffective. While effective, the use of opioids is associated with substantial adverse effects as well as novel pain syndromes. Chronic use of opioids leads to tolerance and escalation of dose: 1. Tramadol: 150 mg/day (50 mg tid), increase by 50 mg/wk, max 200 to 400 mg/day. 2. Morphine (oral): 15 to 30 mg q8h, max 90 to 360 mg/day. 3. Oxycodone: 20 mg q12h, increase by 10 mg/wk, max 40 to 160 mg/day. 4. Fentanyl patch: 25 to 100 mcg transdermally q3 days. • Topical anesthetics: 1. 5% lidocaine patch, apply to area of pain, max three patches every 12 hr. 2. Capsaicin cream and patches are inconsistent in their ability to relieve pain and may exacerbate it. A capsaicin 8% patch is approved specifically for post-herpetic neuralgia and is applied for 60 min under medical supervision.

• Procedural/surgical: This option is considered mostly when the patient suffers from pain secondary to spinal cord or cauda equina injury. Studies are limited and benefit is not completely established. Procedures should be considered only when all other therapeutic modalities have failed. In addition, the patient should be cautioned that surgical procedures may not result in pain relief and may be associated with significant morbidity and even mortality. 1. Dorsal root rhizotomy. 2. Nerve blocks. 3. Spinal cord stimulator.

DISPOSITION Prognosis depends on multiple factors, including: • Etiology of pain • Treatment of any underlying condition • Initiation of appropriate (often multiple) therapeutic modalities • Patient compliance with prescribed regimen Most care is accomplished in the outpatient setting, except when surgery is required. REFERRAL • Pain clinic • Neurology • Psychiatry

• Psychology • Physiatry • Anesthesiology (nerve blocks) • Neurosurgery if considering management

surgical

 EARLS & P CONSIDERATIONS • Factitious disorder and malingering frequently manifest with pain complaints. These are diagnoses of exclusion and require negative evaluation for organic etiologies before diagnosis is made. • Peripheral neuropathy in diabetics increases the risk of foot ulceration by sevenfold. Abnormal results in monofilament testing and vibratory perception (alone or in combination with the appearance of the feet, ulceration, and ankle reflexes) are the most helpful sign for the detection of LFPN.

SUGGESTED READINGS Available at ExpertConsult.com AUTHORS: Joseph S. Kass, MD, JD, FAAN, Gavin Brown, MD, and Corey Goldsmith, MD

Diseases and Disorders

Neuropathy Type

Abnormal

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Neuropathic Pain SUGGESTED READINGS Callaghan BC et al: Distal symmetric polyneuropathy: a review, JAMA 314(20):2172-2181, 2015. Kanji JN et al: Does this patient with diabetes have large-fiber peripheral neuropathy? JAMA 303(15):1526-1532, 2010. Smith EM et al: Effect of duloxetine on pain, function, and quality of life among patients with chemotherapy-induced painful peripheral neuropathy: a randomized clinical trial, JAMA 309(13):1359-1367, 2013.

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Neuropathy, Hereditary BASIC INFORMATION DEFINITION Any disorder affecting the peripheral nervous system, including nerve roots, plexuses, and individual peripheral nerves, that has a genetic basis of inheritance and has been or is capable of being transmitted along generations. There are many different types of hereditary peripheral neuropathies, including DejerineSottas disease, inherited metabolic neuropathies, hereditary sensory and autonomic neuropathies (HSANs), and hereditary motor neuropathies. Most disorders are diagnosed in infancy or childhood; as such, adult clinicians rarely see these patients. For this reason, this chapter discusses only the hereditary motor and sensory neuropathies that an adult clinician might encounter. SYNONYMS Charcot-Marie-Tooth (CMT) disease Hereditary motor-sensory neuropathy (HMSN) Hereditary neuropathy with liability to pressuresensitive palsies (HNPP) ICD-10CM CODES G60.0 Hereditary motor and sensory neuropathy G60.8 Other hereditary and idiopathic neuropathies G60.9 Hereditary and idiopathic neuropathy, unspecified

EPIDEMIOLOGY & DEMOGRAPHICS All CMT: Approximately 30 per 100,000 • CMT type 1 (demyelinating pathophysiology): 1 in 2500 • CMT type 2 (axonal pathophysiology): 7 in 1000 • CMT type 4 and CMT-X: Rare (either axonal or demyelinating pathophysiology) HNPP: 2 to 5 per 100,000 PHYSICAL FINDINGS & CLINICAL PRESENTATION CMT: Highly variable • Age at onset earlier for CMT-1 than CMT-2, but both may present from childhood to old age. • Severely affected patients have severe distal weakness and muscle atrophy with hand (prominently affecting interossei) and foot deformities (pes cavus, high arched feet, hammer toes). • Mildly affected patients may have only foot deformity (pes cavus) with little or no weakness/sensory loss. • Legs can be affected greater than arms, and patients will complain of gait abnormalities (steppage), which cause them to trip and fall. • Sensory complaints (paresthesias, numbness, dysesthesia) are uncommon despite physical findings of impaired sensation. • Decreased or absent reflexes.

• Some patients may have postural tremor of the upper limbs. HNPP (a.k.a. tomaculous neuropathy): • Age at onset is commonly adolescence. • Disorder is characterized by recurrent entrapment of peripheral nerves with accompanying signs and symptoms (paresthesias and/ or weakness in anatomic distributions). Most common are: 1. Median nerve at the wrist (carpal tunnel syndrome) 2. Ulnar nerve at the elbow (cubital tunnel syndrome) 3. Painless brachial plexopathies 4. Lateral femoral cutaneous nerve (meralgia paresthetica) 5. Peroneal nerve at the fibular head • May be associated with a generalized polyneuropathy.

ETIOLOGY CMT: More than 30 subgroups have been identified and have various chromosomal abnormalities. • Most common mutation is PMP-22 duplication, giving rise to CMT 1A demyelinating phenotype. • Other mutations include P0 (demyelinating) and neurofilament light chain mutations (demyelinating or axonal phenotype)

DIAGNOSIS DIFFERENTIAL DIAGNOSIS CMT: Other genetic, metabolic, and multisystem disorders including: • Spinocerebellar ataxias • Friedreich ataxia • Leukodystrophies • Refsum disease (elevated serum phytanic acid) • Distal spinal muscular atrophies and distal myopathies, which can present with pes cavus and other foot deformities • Chronic inflammatory demyelinating polyneuropathy (CIDP) HNPP: • Hereditary neuralgic amyotrophy (HNA), which typically is painful rather than painless. In addition, in HNA, there is no evidence of generalized polyneuropathy • Multifocal motor neuropathy with conduction block (MMNCB)—autoimmune-mediated pure motor neuropathy • Neuropathy associated with renal failure • Lead neuropathy • Neuropathy relating to paraproteinemia (demyelinating pathophysiology) EVALUATION CMT: • History of gradual onset symptoms is important to distinguish CMT from other forms of neuropathy. • Detailed family history with pedigree is essential. Consider examination of multiple family members. • History should evaluate for potential heavy metal exposure.

• History of dysesthesias is uncommon and should prompt search for acquired neuropathy or other inherited neuropathies (e.g., Fabry disease). HNPP: Genetic testing after identification of multiple entrapment neuropathies on electromyography (EMG) and nerve conduction studies

LABORATORY TESTS • Neurophysiology: EMG and nerve conduction studies (NCSs) must be done first to determine type of pathophysiology: demyelinating or axonal. This will guide genetic testing. • NCSs in CMT-1 will reveal demyelinating physiology characterized by very slow conduction velocities (around 15 to 30 m/s) with prolonged distal latencies. Inherited demyelinating disorders can be distinguished from acquired demyelinating disorders (e.g., chronic inflammatory demyelinating polyneuropathy or CIDP) by the presence of conduction block in the latter. • In HNPP, diffusely prolonged distal latencies with superimposed entrapment neuropathies at common sites will be seen on NCSs. • EMG will reveal reinnervation characterized by long-duration, large-amplitude, polyphasic motor unit potentials (MUPs) with decreased MUP recruitment. • Genetic tests are available for some CMT subtypes: 1. CMT-1A: Chromosome 17p11-PMP-22 duplication 2. CMT-1B: Chromosome 1q22-P0 mutation 3.  CMT-2E: Chromosome 8p21-neurofilament light chain (NF-L) point mutation 4. CMT-X: Connexin 32 mutations 5. HNPP: Chromosome 17p11 deletion, which includes the PMP-22 gene • Serum and 24-hour urine levels of heavy metals (arsenic, lead, etc.). • Serum protein electrophoresis (SPEP), urine protein electrophoresis (UPEP), immunofixation (for paraprotein). • Anti-GM1 antibody (positive in ∼50% of patients with MMNCB). • Lumbar puncture may reveal elevated CSF protein in CIDP. • Peripheral nerve biopsy: 1. Demyelination with “onion bulb formation.” Tomaculae, or focal thickening of myelin sheaths, is seen in HNPP. 2. Generally not indicated unless diagnosis is uncertain. IMAGING STUDIES • Spine plain films: For evaluation of scoliosis. • MRI: Indicated if dissociative sensory loss (dorsal column dysfunction with intact spinothalamic tract function) or if upper motor neuron findings (spasticity, Babinski sign, clonus, increased tendon reflexes) are present. • Exclusion of involvement of brain or spinal cord compressive lesions causing arm or leg weakness. • Some inherited peripheral demyelinating disorders (i.e., CMT-X) are associated with intracerebral white matter abnormalities on MRI. • Exclusion of structural, infectious, or inflammatory nerve root pathology.

Neuropathy, Hereditary TREATMENT There is no known cure for any of these disorders. Management is supportive.

NONPHARMACOLOGIC THERAPY • Physical therapy (PT) and occupational therapy (OT) to provide assistance with gait and coordination • PT and OT might provide walking aid such as ankle foot orthosis (AFO), cane, walker, or wheelchair depending on the severity of the neuropathy • Wrist splints for superimposed carpal tunnel syndrome • Elbow pads (Heelbo Pads) to cushion the ulnar nerve at the elbow • Heel-cord strengthening • Stretching exercises • Analgesics for pain associated with foot deformity • Surgical correction of foot deformities by orthopedic surgeons if indicated Vincristine may worsen existing neuropathy (important for oncologist to know if patient develops cancer requiring chemotherapy).

SURGICAL TREATMENT • Patients with HNPP should probably not undergo surgical decompression of the

975.e3 median nerve at the wrist or the ulnar nerve at the elbow; these nerves are sensitive to manipulation. Poor results have been reported with ulnar nerve transposition. • A nesthesiologists should be aware of HNPP diagnosis in patients undergoing surgery to prevent compression neuropathies from occurring during surgical procedures.

GENETIC COUNSELING Must be routinely done for patient and family when diagnosis is established. Many aspects of the patient and family’s life are affected, including: • Future progeny of patient and/or patient’s parents or children • Psychosocial aspects including social functioning, marriage, employment • Financial needs • Medical and life insurability PROGNOSIS • CMT: Slowly progressive, and patients often remain ambulatory until late in life. Life expectancy is normal. Patients with respiratory involvement (i.e., phrenic nerve involvement with diaphragm paresis) may have shorter life expectancy. • HNPP: Benign prognosis.

DISPOSITION Outpatient care. Routine follow-up appointments should be done initially every 6 mo, and then every 1 to 2 yr. REFERRAL • Neurology and/or neuromuscular disease specialist • Podiatry for recurrent foot problems, including appropriate arches

PEARLS & CONSIDERATIONS PATIENT & FAMILY EDUCATION Patients can benefit from use of Muscular Dystrophy Association (MDA) resources. RELATED CONTENT Charcot-Marie-Tooth Disease (Related Key Topic) Neuropathic Pain (Related Key Topic) AUTHORS: Joseph S. Kass, MD, JD, FAAN, and Gavin Brown, MD

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New Onset Seizures BASIC INFORMATION DEFINITION An unprovoked seizure is a seizure that occurs without triggers or precipitating factors. In contrast, an acute symptomatic seizure occurs in the setting of an insult to the brain (infectious, toxic, etc.). The presentation of a new seizure can vary greatly depending on the type (focal or generalized), progression, and severity. SYNONYM Convulsions ICD-10CM CODES G40.001 Localization-related (focal) (partial) idiopathic epilepsy and epileptic syndromes with seizures of localized onset, not intractable, with status epilepticus G40.009 Localization-related (focal) (partial) idiopathic epilepsy and epileptic syndromes with seizures of localized onset, not intractable, without status epilepticus G40.10 Localization-related (focal) (partial) symptomatic epilepsy and epileptic syndromes with simple partial seizures, not intractable G40.101 Localization-related (focal) (partial) symptomatic epilepsy and epileptic syndromes with simple partial seizures, not intractable, with status epilepticus G40.109 Localization-related (focal) (partial) symptomatic epilepsy and epileptic syndromes with simple partial seizures, not intractable, without status epilepticus G40.201 Localization-related (focal) (partial) symptomatic epilepsy and epileptic syndromes with complex partial seizures, not intractable, with status epilepticus G40.209 Localization-related (focal) (partial) symptomatic epilepsy and epileptic syndromes with complex partial seizures, not intractable, without status epilepticus G40.301 Generalized idiopathic epilepsy and epileptic syndromes, not intractable, with status epilepticus G40.309 Generalized idiopathic epilepsy and epileptic syndromes, not intractable, without status epilepticus G40.A01 Absence epileptic syndrome, not intractable, with status epilepticus G40.A09 Absence epileptic syndrome, not intractable, without status epilepticus G40.4 Other generalized epilepsy and epileptic syndromes G40.401 Other generalized epilepsy and epileptic syndromes, not intractable, with status epilepticus G40.409 Other generalized epilepsy and epileptic syndromes, not intractable, without status epilepticus

ALG G40.501 Epileptic seizures related to external causes, not intractable, with status epilepticus G40.509 Epileptic seizures related to external causes, not intractable, without status epilepticus G40.909 Epilepsy, unspecified, not intractable, without status epilepticus

EPIDEMIOLOGY & DEMOGRAPHICS INCIDENCE: 29 to 39 per 100,000 per yr for acute symptomatic seizures. 23 to 61 per 100,000 person-yr for unprovoked seizures. Approximately 8% to 10% of the population will experience a seizure during their lifetime; however, less than 3% go on to develop epilepsy. PREVALENCE: 5 to 8.4 cases per 1000 persons PREDOMINANT SEX AND AGE: Males younger than 12 mo and older than 65 yr RISK FACTORS: • Age of onset • Family history of epilepsy • Excessive sleep deprivation, use of alcohol, or illicit drugs • History of head trauma, diseases of the brain, brain surgeries, and strokes • History of congenital cerebral anomalies or developmental delay GENETICS Although some new onset seizures are related to specific genes, most are not. PHYSICAL FINDINGS & CLINICAL PRESENTATION • Patients with generalized seizures will typically have normal physical exams. Patients with focal seizures due to persistent structural CNS damage may have exam findings consistent with the location of the lesion. • A generalized seizure may start without warning and can typically last from 30 to 120 seconds, during which the patient will be unconscious and may have increased rigidity and/or jerking of the whole body, or staring spells. Cyanosis (especially of the lips and face) can result from temporary airway compromise due to muscle spasms. Tonic-clonic seizures can cause injuries, tongue biting, and bladder incontinence. Patients are usually unaware of the seizure afterwards. A postictal state characterized by confusion, lethargy, headaches, or drowsiness may result and can last from min to hours depending on the severity of the seizure. • During a focal seizure, a patient may be aware (focal aware seizure) or have impaired consciousness (focal impaired awareness seizures). A focal impaired awareness seizure may be associated with an aura (itself a focal aware seizure) and lasts between 30 and 120 seconds. Motor or nonmotor symptoms may predominate in focal seizures, including jerking of one limb, automatisms, head turning, auditory hallucinations, or feelings of derealization. A focal seizure may progress to a generalized seizure, which usually involves the head and eye turning to one side.

Postictal weakness may result after focal seizures and can last for hours but usually resolves within 1 day. Persistent neurological deficits beyond this time may indicate other causes and should be investigated.

ETIOLOGY • New, unprovoked seizures are often idiopathic. • Acute symptomatic seizures can be due to cerebral abnormalities (e.g., infections/abscesses, subarachnoid hemorrhages, ischemic strokes, tumors, arteriovenous malformations, venous malformations) or systemic causes (e.g., electrolyte abnormalities, hypoglycemia, hyperthyroidism, drug intoxication or withdrawal).

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • Syncope • Transient ischemic attacks • Migraines • Sleep disorders • Paroxysmal movement disorders • Panic attacks, hallucinations, and other psychiatric disorders WORKUP • Ambulatory 30-min EEG if patient fully recovers after seizure within 30 to 60 min. May be delayed if treatment does not depend on EEG result. • Consider inpatient continuous EEG if patient does not fully recover within 60 min or for recurrent seizures. • ECG. • Fig. 1 illustrates an algorithm for the approach to the child with a suspected convulsive disorder. LABORATORY TESTS Comprehensive metabolic panel and urine drug screen IMAGING STUDIES • Acutely, CT of the head with and without contrast to evaluate for hemorrhage and space-occupying lesions • Brain MRI with and without contrast with epilepsy protocol in patients with recurrent seizures, in consultation with a neurologist

TREATMENT • Provoked seizures do not need long-term treatment. • The choice of treatment depends largely on seizure type and etiology. Antiepileptics may be thought of as narrow- or wide-spectrum drugs. Treatment with wide-spectrum antiepileptics is advisable in generalized seizures or those of unknown type, whereas partial seizures are better controlled with narrowspectrum antiepileptics. • Narrow-spectrum drugs include carbamazepine, oxcarbazepine, gabapentin, pregabalin, lacosamide, and phenytoin. Wide-spectrum drugs include valproate, topiramate, zonisamide, lamotrigine, and levetiracetam.

ALG

New Onset Seizures

Did the child have a seizure?

NO

Abnormal Symptomatic Seizures Treat underlying cause (hypoglycemia, urea cycle abnormality, meningitis, temporal lobe tumor, etc.) Antiepileptic drugs if necessary

N YES

Initial Seizure Fasting blood sugar, calcium, metabolic studies dictated by history and physical; EEG? CT scan? MRI? CSF examination?

Recurrent Seizures Drug compliance? Improper dose? Incorrect drug? Metabolic disorder? Underlying structural lesion? Drug interaction? CNS degenerative disease? Intractable seizures?

I

Studies and Examination

Normal Isolated first seizure with normal EEG Negative family history No continuous drug treatment Close observation Prescribe rescue medications (rectal diazepam) for seizures longer than 5 min

Normal (except EEG) Consider drug therapy

Follow-up

Good Control Regular follow-up Antiepileptic drug levels Monitor toxicity (CBC, liver function, behavioral, learning) EEG as indicated

Poor Control Consider hospitalization Prolonged EEG recording and video monitoring for possible epilepsy surgery candidacy Readjust medication Reconsider underlying pathology with reinvestigation with CT or MRI Frequent follow-up

FIG. 1  Algorithm for the approach to the child with a suspected convulsive disorder. CBC, Complete blood count; CT, computed tomography; CNS, central nervous system; CSF, cerebrospinal fluid; EEG, electroencephalogram; MRI, magnetic resonance imaging. (From Kliegman RM: Nelson textbook of pediatrics, ed 21, Philadelphia, 2020, Elsevier.)

• In patients with significant comorbidities, the use of antiepileptics with limited drug interactions is advised (lamotrigine, levetiracetam, lacosamide). • Older patients may benefit from lamotrigine, levetiracetam, or gabapentin due to a lower risk of adverse events.

NONPHARMACOLOGIC THERAPY None ACUTE GENERAL Rx • Patients with a first unprovoked seizure who have a normal EEG, imaging, lab values, and physical exam do not require treatment with antiepileptic drugs but may be offered therapy because the use of an antiepileptic drug after a first unprovoked seizure in an adult reduces the absolute risk of seizure

Diseases and Disorders

Benign paroxysmal vertigo Breath holding Cough syncope Familial choreoathetosis Hereditary chin trembling Shuddering attacks Narcolepsy Night terror Pseudoseizures Rage attack Benign myoclonus of infancy Tics

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recurrence at 2 yr by 35%. However, there is no difference at 3 yr. • For generalized seizures: Levetiracetam initial dose of 500 mg bid. If recurrent seizures, increase by 500 mg every 1 to 2 wk until maximum dose of 1500 mg bid is reached. • For partial seizures: Oxcarbazepine initial dose 300 mg bid, increase by 300mg/day every 3 days to 600 mg bid. If recurrent seizures, continue to titrate by 300 mg/day every 3 days to 1200 mg bid.

CHRONIC Rx Patients with two or more unprovoked seizures, or those with one seizure and an abnormal workup consistent with epilepsy findings, should be continued on antiepileptic drugs. Patients electing antiepileptic therapy after first

unprovoked seizure with negative workup may be weaned off antiepileptic drug if seizure-free after 2 yr.

COMPLEMENTARY & ALTERNATIVE MEDICINE Not applicable DISPOSITION • Patients should avoid swimming unobserved, bathing alone, working at heights, using heavy machinery, or other activities that may be high-risk in the event of a seizure. • Discontinue driving until seizures are well controlled and in accordance with state laws. REFERRAL Patients may be referred to a neurologist.

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New Onset Seizures

ALG

 EARLS & P CONSIDERATIONS COMMENTS • Driving: Physicians should be aware of the law in their jurisdiction about driving after a seizure. Although a few U.S. states require physicians to notify the state government authority that issues driver’s licenses, most do not impose such an obligation on physicians. However, states do require patients to self-report and abstain from driving until seizure-free for a specified period of time, depending on the state. • Recurrence risk: Greatest recurrence risk in an adult with a first unprovoked seizure is within the first 2 yr and is between 21% and 45%. The recurrence risk is lower in patients treated with an antiepileptic drug and higher in patients with a brain MRI abnormality causing the seizure or an EEG showing epileptiform activity.

PREVENTION Patients with recurrent seizures should be extensively counseled on avoiding seizure triggers such as sleep deprivation, alcohol or drug use, stress, and exposure to excessive flashing lights. Such patients may need dose titration of antiepileptic drug and referral to a neurologist. PATIENT & FAMILY EDUCATION • Physicians should inform patients with firsttime seizures that they are subject to state law restrictions on driving after a seizure. Physicians should also counsel patients with epilepsy about not swimming unattended, not climbing heights, and taking showers rather than baths (because of the risk of drowning in a bathtub during a generalized seizure). Physicians should counsel women of childbearing potential about effects of antiepileptic drugs on both oral contraceptive efficacy and on a developing fetus. They should recommend supplemental folic acid for such women if they are taking antiepileptic drugs. They should also recommend that

women plan pregnancy if they are on antiepileptic drugs to minimize adverse effects on the pregnancy. All such counseling should be documented in the medical record. • A diagnosis of epilepsy has significant medical, social, and emotional consequences. Patient information on seizures and locating support groups can be found at the Epilepsy Foundation website: http://www.epilepsy.com.

SUGGESTED READING Available at ExpertConsult.com RELATED CONTENT Absence Seizures (Related Key Topic) Febrile Seizures (Related Key Topic) Seizures, Generalized Tonic-Clinic (Related Key Topic) Focal Seizures (Related Key Topic) Status Epilepticus (Related Key Topic) AUTHORS: Sudad Kazzaz, MD, and Corey Goldsmith, MD

New Onset Seizures SUGGESTED READINGS Gavvala J et al: New-onset seizure in adults and adolescents: a review, J Am Med Assoc 316(24):2657-2668, 2016. Hauser WA et al: First seizure definitions and worldwide incidence and mortality, Epilepsia 49(8-12), 2008. Krumholz A et al: Evidence-based guideline: management of an unprovoked first seizure in adults: report of the guideline development subcommittee of the American Academy Of Neurology and American Epilepsy Society, Neurology 84(16):1705-1713, 2015.

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Nocardiosis BASIC INFORMATION DEFINITION Nocardiosis is an infection caused by aerobic actinomycetes found in soil and characterized by lung, soft tissue, or central nervous system (CNS) involvement. SYNONYMS Mycetoma Nocardia ICD-10CM CODES A42.9 Actinomycosis, unspecified A43.0 Pulmonary nocardiosis A43.1 Cutaneous nocardiosis A43.8 Other forms of nocardiosis A43.9 Nocardiosis, unspecified

EPIDEMIOLOGY & DEMOGRAPHICS • Nocardia species are found worldwide in the soil. • Nocardiosis is found most commonly in patients who are immunocompromised (e.g., chronic corticosteroid or immunosuppressive therapy, lymphoma, leukemia, AIDS, lung cancer, transplant recipients, chronic pulmonary infections). • Other underlying conditions associated with nocardiosis are pemphigus vulgaris, Whipple disease, Goodpasture syndrome, Cushing disease, liver cirrhosis, ulcerative colitis, rheumatoid arthritis, and pulmonary alveolar proteinosis.

• Use of steroids is an independent risk factor for developing nocardiosis. • Between 500 and 1000 new cases are diagnosed each yr in the U.S. Approximately 2% of patients with AIDS develop nocardiosis. • Occurs more commonly in men than in women (2:1). • Adults are affected more often than children.

PHYSICAL FINDINGS & CLINICAL PRESENTATION • Inhalation of Nocardia organisms is the most common mode of entry, and pneumonia is the most common presentation, with 75% manifesting with fever, chills, dyspnea, and a productive cough (Fig. E1). 1. Presentation can be acute, subacute, or chronic. 2. Nocardiosis should be suspected if soft tissue abscesses or CNS tumors or abscesses form in conjunction with the pulmonary infection. 3. Pulmonary infection may spread into the pericardium, mediastinum, and superior vena cava. • Cutaneous disease usually occurs by direct inoculation of the organism as a result of skin puncture by a thorn or splinter, surgery, IV catheter use, or animal scratches or bites manifesting in: 1. Cellulitis. 2.  Lymphocutaneous nodules appearing along lymphatic sites draining the infected puncture wound. 3.  Mycetoma (Madura foot), a chronic deep nodular infection usually involving the hands or feet that can cause skin breakdown or fistula formation and that

spreads along the fascial planes to infect surrounding skin, subcutaneous tissue, and bone. • The CNS is infected in approximately one third of all cases. Brain abscess is the most common pathologic finding. • Dissemination of nocardiosis may infect other tissues and organs, including the kidney, heart, skin, and bone.

ETIOLOGY • The most common Nocardia species leading to infection in human beings are: 1.  N. asteroides (causing more than 80% of the cases of pulmonary nocardiosis) 2.  N. brasiliensis (most common cause of mycetoma) 3.  N. otitidiscaviarum • N. asteroides has two subgroups: 1.  N. farcinica 2.  N. nova

DIAGNOSIS The diagnosis of nocardiosis requires a high index of clinical suspicion in the proper clinical setting and is confirmed by bacteriologic staining and growth of the organism in culture.

DIFFERENTIAL DIAGNOSIS There are no pathognomonic findings separating nocardiosis pneumonia from other infectious etiologies of the lung. Diagnoses presenting in a similar manner and often confused for nocardiosis include: • Tuberculosis • Lung abscess • Lung tumor • Other causes of pneumonia • Actinomycosis • Mycosis • Cellulitis • Coccidioidomycosis • Histoplasmosis • Aspergillosis • Kaposi sarcoma WORKUP All patients with suspected nocardiosis need laboratory identification of the microorganism by obtaining sputum in the case of pneumonia, cultures of the infected skin lesions in mycetoma or lymphocutaneous disease, or the sampling of any purulent material (e.g., brain abscess, lung abscess, or pleural effusion).

FIG. E1  Right lower lobe Nocardia pneumonia in a kidney transplant recipient. (From Gorbach SL: Infectious diseases, ed 2, Philadelphia, 1998, WB Saunders.)

LABORATORY TESTS • Blood tests are not very sensitive in the diagnosis of nocardiosis. • Gram stain shows gram-positive beaded filaments with multiple branches (Fig. E2). Gomori methenamine silver staining may detect the organism. • Nocardia species are acid-fast on a modified Ziehl-Neelsen stain. • Nocardia are slow-growing organisms; colony growth in cultures may take up to 2 to 3 wk.

Nocardiosis IMAGING STUDIES • Chest radiograph or CT of chest (Fig. E3) may demonstrate infiltrates, densities, nodules, cavitary masses, or multiple abscesses. • CT scan of the brain is indicated in the appropriate clinical setting to exclude CNS brain abscesses.

TREATMENT NONPHARMACOLOGIC THERAPY • Supportive therapy with oxygen in patients with pneumonia • Chest physiotherapy • For any abscess formation, surgical drainage is indicated (e.g., skin, lung, or brain) ACUTE GENERAL Rx • There are no prospective, randomized trials to date highlighting the most effective treatment of nocardiosis. Culture and

978.e3 sensitivity should always be done on the specimen • For cutaneous infection, trimethoprim-sulfamethoxazole (TMX-SMX) 5 mg/kg of the trimethoprim component divided in 2 doses • Nocardia infection that does not involve CNS: TMX-SMX (15 mg/kg/day of TMP component IV in 2 to 4 divided doses) plus (amikacin 7.5 mg/kg q12h). An alternate regimen consists of imipenem 500 mg IV q6h plus amikacin 7.5 mg/kg IV q12h • In patients with CNS disease, TMX-SMX 15 mg/kg/day of TMP component IV divided in 2 to 4 doses plus imipenem 500 mg q6h IV. If multiorgan involvement, add amikacin 7.5 mg/kg q12h. Measure peak sulfonamide levels; target is 100 to 150 mcg/ml 2 hr post dose. An alternative regimen consists of linezolid 600 mg IV or PO q12h plus meropenem 2 g q8h. For infections without involvement of the CNS the patient can be switched to oral therapy after the initial IV therapy for 3 to 6 wk or until clinical improvement. For

FIG. E2  Nocardia pneumonia. Thin, branching, irregularly staining gram-positive bacilli course through necrotic pulmonary tissue (Brown-Hopps Gram, ×1000). (From Silverberg SG et al [eds]: Silverberg’s principles and practice of surgical pathology and cytopathology, ed 4, Philadelphia, 2006, Churchill Livingstone.)

A

B

infections involving CNS the initial IV therapy should be continued for minimum of 6 wk and clear evidence of clinical improvement before switching to combination oral therapy. The combination oral antibiotics that can be used following initial IV therapy include: 1. TMP/SMX (10 mg/kg per day of the trimethoprim component in two to three divided doses) and/or 2. Minocycline (100 mg twice daily) and/or 3. Amoxicillin/clavulanic acid (875 mg) twice daily • Alternative drug treatment includes: 1. Third-generation cephalosporin 2. Minocycline 100 to 200 mg bid 3. Extended-spectrum fluoroquinolones (moxifloxacin) 4. Linezolid (use of linezolid >4 wk is associated with hematologic toxicity) 5. Tigecycline 6. Dapsone

CHRONIC Rx • Although the optimal duration of therapy has not been determined, long-term therapy is generally recommended for all infections caused by Nocardia. • Patients with cellulitis and lymphocutaneous syndrome are treated for 2 to 4 mo depending on whether there is bone involvement. • Mycetomas are best treated with antibiotics for 6 to 12 mo but may require surgical drainage. • Pulmonary and systemic nocardiosis excluding the CNS is treated for at least 6 mo in immunocompromised hosts. • CNS involvement is treated with drainage and antibiotics for 12 mo. • All immunosuppressed patients should receive 12 mo of antibiotic therapy. DISPOSITION • Patients with pulmonary nocardiosis have a mortality rate of 15% to 30%.

C

FIG. E3  Nocardiosis with multiple nodules. A to C, Multiple ill-defined nodules reflect nocardia pneumonia in an immunosuppressed patient. (From Webb WR et al: Fundamentals of body CT, ed 4, Philadelphia, 2015, WB Saunders.)

Nocardiosis • CNS involvement carries a >40% mortality rate. • Isolated skin lesions have a low mortality rate.

REFERRAL Whenever the diagnosis of nocardiosis is suspected, consultation with infectious disease is indicated. Pulmonary evaluation and assistance may be needed in pulmonary nocardiosis. Neurosurgery consultation is indicated in patients with single or multiple brain abscesses.

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 EARLS & P CONSIDERATIONS • Nocardiosis does not spread from animal to animal. • Nocardiosis is not transmitted from person to person. • Nocardiosis is distinguished by its ability to disseminate to any organ and its tendency to relapse despite appropriate antibiotic therapy.

COMMENTS Tuberculosis and nocardiosis may coexist in the same patient. RELATED CONTENT Nocardiosis (Patient Information) AUTHOR: Maher Tabba, MD, FACP, FCCP

ALG BASIC INFORMATION

SYNONYMS Nonalcoholic steatohepatitis (NASH) NAFLD Fatty liver hepatitis Diabetes hepatitis Alcohol-like liver disease Laënnec disease ICD-10CM CODE K76.0 Fatty (change of) liver, not elsewhere classified

EPIDEMIOLOGY & DEMOGRAPHICS • NAFLD affects 30% to 40% of the adult general population in the U.S. • Increased prevalence in obese persons (57% to 74%), type 2 diabetes mellitus, and hyperlipidemia (primarily hypertriglyceridemia). • Most common cause of abnormal liver test results in adults in the United States (accounts for up to 90% of cases of asymptomatic ALT elevations). • NAFLD is more prevalent in men than women. • NAFLD is more prevalent in the Hispanic population. • Approximately 20% of patients with NAFLD have NASH, and 10% to 30% of patients with NASH have NASH cirrhosis. PHYSICAL FINDINGS & CLINICAL PRESENTATION • Most patients are asymptomatic. • Patients may report a sensation of fullness or discomfort on the right side of the upper abdomen.

• Nonspecific complaints of fatigue or malaise may be reported. • Hepatomegaly (Table 1) is generally the only positive finding on physical examination. • Acanthosis nigricans may be found in children.

ETIOLOGY • Metabolic syndrome and insulin resistance are the most reproducible factors in the

development of NAFLD and accumulation of triglycerides within the liver. High baseline and continuously increasing fasting insulin levels are independent determinants for future development of NAFLD. The transition from NAFLD to NASH is poorly understood; there may be a genetic component. The presence of the I48M variant of PNPLA3 increases risk for and severity of NAFLD.

TABLE 1  Symptoms, Signs, and Laboratory Features of Nonalcoholic Fatty Liver Disease Symptoms

Signs

Laboratory Features

Common None (48%-100% of patients)

Hepatomegaly

2- to 4-fold elevation of serum ALT and AST levels AST/ALT ratio 28, triglycerides >150 mg/dl. • Statins are not contraindicated in patients with NASH and should be considered in hypercholesterolemic patients. • A recent trial has shown that daily aspirin use is associated with reduced risk for fibrosis progression in patients with NAFLD.2 SUGGESTED READINGS Available at ExpertConsult.com RELATED CONTENT Fatty Liver (Patient Information) AUTHOR: Fred F. Ferri, MD

1Cusi

K et al: Long-term pioglitazone treatment for patients with nonalcoholic steatohepatitis and prediabetes or type 2 diabetes mellitus: a randomized trial, Ann Intern Med 165:305-315, 2016. 2Simon TG et al: Daily aspirin use associated with reduced risk for fibrosis progression in patients With nonalcoholic fatty liver disease, Clin Gastroenterol Hepatol 17(13):2776-2784.e4, 2019.

Nonalcoholic Fatty Liver Disease

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SUGGESTED READINGS Bril F et al: Role of vitamin E for nonalcoholic steatohepatitis in patients with type 2 diabetes: a randomized controlled trial, Diabetes Care 42(8):1481-1488, 2019. Libman H et al: How would you manage this patient with nonalcoholic fatty liver disease?: Grand rounds discussion from Beth Israel Deaconess Medical Center, Ann Intern Med 171(3):199-207, 2019. Petersen KF et al: Apolipoprotein C3 gene variants in non-alcoholic fatty liver disease, N Engl J Med 362:1082-1089, 2010. Rhee EJ et al: Hyperinsulinemia and the development of nonalcoholic fatty liver disease in nondiabetic adults, Am J Med 124:69-76, 2011. Romeo S: Notch and nonalcoholic fatty liver and fibrosis, N Engl J Med 380(7):681-683, 2019. Sanyal AJ et al: Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis, N Engl J Med 362:1675, 2010. Targher G et al: Risk of cardiovascular disease in patients with nonalcoholic fatty liver disease, N Engl J Med 363:1341-1350, 2010. Wang XJ, Mahli H: In the clinic: nonalcoholic fatty liver disease, Ann Intern Med 169(9):ITC65-ITC80, 2018. Zhang HJ et al: Effects of moderate and vigorous exercise on nonalcoholic fatty liver disease: a randomized trial, JAMA Intern Med 176(8):1074-1082, 2016.

Elevated serum aminotransferase levels and/or hepatomegaly

Exclude excessive alcohol use and other forms of liver disease by history and laboratory tests

Image the liver with US, CT, or MRI

Normal

Liver biopsy

Fatty liver present

Consider transient elastography (FibroScan) if available, MR elastography, or liver biopsy to stage the disease and define the risk of progression

FIG. E1  Algorithm for a diagnostic approach to the patient with suspected nonalcoholic fatty liver disease (NAFLD). The diagnosis of NAFLD is based on clinical and histologic criteria. Most patients are evaluated because of elevated serum aminotransferase levels and/or hepatomegaly. The diagnosis of NAFLD should be considered when excessive alcohol use is absent and laboratory test results exclude other causes of liver disease. Imaging studies may demonstrate fatty liver. Liver biopsy is the standard means of diagnosis and the only test that can reliably differentiate simple steatosis from NASH, although noninvasive methods for assessing fibrosis, such as transient elastography, are being used increasingly to identify hepatic fibrosis. CT, Computed tomography; MR, magnetic resonance; MRI, magnetic resonance imaging; NASH, nonalcoholic steatohepatitis; US, ultrasound. (Modified from Feldman M et al: Sleisenger and Fordtran’s gastrointestinal and liver disease, ed 10, Philadelphia, 2016, Elsevier.)

FIG. E2  Focal sparing. Two islands of normal parenchyma (arrowheads) in segment IVb and the caudate lobe (segment 1) simulate mass lesions in a liver with extensive fatty infiltration. Most of the liver parenchyma shows fatty infiltration, making these islands of normal parenchyma appear of high attenuation by comparison. (Webb WR et al: Fundamentals of body CT, ed 4, Philadelphia, 2015, WB Saunders.)

Nonallergic Rhinitis BASIC INFORMATION

SYNONYMS Chronic nonallergic rhinitis Idiopathic rhinitis Intrinsic rhinitis NAR Nonallergic-noninfectious chronic rhinitis Vasomotor rhinitis ICD-10CM CODES J30.0 Vasomotor rhinitis J31.0 Chronic rhinitis NOS (atrophic, granulomatous, hypertrophic, obstructive rhinitis)

EPIDEMIOLOGY & DEMOGRAPHICS • Nonallergic rhinitis affects approximately 17 to 22 million individuals in the U.S. • Approximately 50% of patients presenting with rhinitis may have NAR alone or a “mixed form” that includes both allergic and nonallergic components. • Nonallergic rhinitis usually presents in adulthood with 70% of patients presenting after 20 yr of age. Onset of allergic rhinitis typically occurs in childhood. • Risk factors for nonallergic rhinitis include female sex and age of >40 yr. • May have genetic component in those individuals whose parents have allergic rhinitis. • Medications that can cause chronic nasal symptoms are summarized in Table 1. • Table 2 describes occupations with increased prevalence of work-related rhinitis. PHYSICAL FINDINGS & CLINICAL PRESENTATION • Patients tend to present with a specific set of symptoms, predominantly rhinorrhea, postnasal drip, and throat clearing. Conversely, allergic symptoms such as nasal pruritus, sneezing, and conjunctival irritation are traditionally absent but can be variably present in mixed disease.

ETIOLOGY • NAR is composed of a heterogeneous group of diseases without a clear unifying theory of pathogenesis. In general, inflammatory NAR involves elevated numbers of immune cells (eosinophils, mast cells, neutrophils) leading to mediator release and inflammatory changes. For noninflammatory NAR, it is postulated that an abnormality in the autonomic nervous system is present with increased concentrations of intranasal neuropeptides. These are often triggered by perfumes, strong odors, changes in climate, and smoke. Specific subtypes likely have unique pathophysiologies: 1.  Infectious rhinosinusitis: Viral, bacterial, or fungal infections. Typically occurs following an acute viral infection. 2. Nonallergic rhinitis with eosinophilia syndrome (NARES): Unknown etiology. 3. Gustatory rhinitis: Abnormal vagally mediated rhinitis after ingestion of any food. 4. Atrophic rhinitis: Unknown etiology but bacterial infection is thought to be involved. 5. Rhinitis medicamentosa: Rebound nasal congestion from prolonged use of decongestant/vasoconstrictor agents (phenylephrine, oxymetazoline). Can also occur from cocaine, α-receptor antagonist, or phosphodiesterase-5-selective inhibitors. 6. Hormone-induced rhinitis: Pregnancyassociated, menstrual cycle–associated, and oral contraceptive–related hormonal changes. 7. Rhinitis associated with systemic disease: Severe hypothyroidism, diabetes mellitus.

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • Allergic rhinitis (sensitivity to pollens, indoor allergens, occupational allergens) • Systemic diseases with nasal manifestations (e.g., systemic lupus erythematosus, granulomatous disease, GERD) • Mechanical obstruction (e.g., deviated septum, nasal polyps, nasal neoplasms, foreign bodies) • Cerebral spinal fluid (CSF) leak from head trauma as it may represent a skull base fracture, postoperative complication from sinus surgery, or spontaneous leak • Local allergic rhinitis • Chronic rhinosinusitis • Box 1 summarizes the differential diagnosis in chronic rhinitis WORKUP • A detailed history and physical examination can be helpful to determine if diagnostic testing is necessary. • Distinguishing NAR from allergic rhinitis or other forms of rhinitis can be difficult, but a detailed history (lack of allergic symptoms such as sneezing, nasal pruritus) can be helpful. Questionnaires, including the Cincinnati Irritant Index Scale, have proven useful in differentiating NAR from allergic rhinitis. 1. Because allergic rhinitis cannot be definitively ruled out with history alone, skin testing or assessment for serum-specific IgE should be considered. Adding to the diagnostic complexity, many individuals have a “mixed form” of rhinitis including both allergic and nonallergic types. 2. Given the common overlap between NAR and AR, it may be reasonable to revisit diagnostic testing if patients do not respond to therapy as expected. • Although not typically performed routinely in a clinical setting, examination of nasal smears for the presence of neutrophils and eosinophils may be helpful.

TABLE 1  Medications Associated with Chronic Nasal Symptoms Category

Example(s)

Antihypertensives

Angiotensin-converting enzyme inhibitors β-Adrenergic blockers Amiloride Prazocin Hydralazine Risperidone Chlorpromazine Amitriptyline Sildenafil Tadalafil Vardenafil Ibuprofen Gabapentin

Psychotropics

Phosphodiesterase-5 inhibitors

Nonsteroidal antiinflammatory drugs Others

From Adkinson NF et al: Middleton’s allergy principles and practice, ed 8, Philadelphia, 2014, Elsevier.

N

Diseases and Disorders

DEFINITION Nonallergic rhinitis (NAR) is characterized by chronic episodic or perennial symptoms of rhinitis (congestion, rhinorrhea, and postnasal drainage) that are not the result of IgEmediated events. It is a heterogeneous group of diseases classified as inflammatory (infectious rhinosinusitis, nonallergic rhinitis with eosinophilia syndrome) or noninflammatory (including but not limited to gustatory rhinitis, atrophic rhinitis, rhinitis medicamentosa, hormone-induced rhinitis, rhinitis in the elderly, rhinitis associated with systemic disease). Vasomotor rhinitis has previously been used interchangeably with NAR but is being phased out, as the term is too narrow with regard to the multiple mechanisms of action associated with NAR.

• Physical exam can be completely unremarkable, but it can present with the following features: 1. Clear nasal secretions 2. Nasal crusting 3.  Anosmia can be consistent with some forms (e.g., atrophic rhinitis) 4. Inspection of turbinates may be erythematous or pale

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Nonallergic Rhinitis TABLE 2  Occupations with Increased Prevalence of Work-Related Rhinitis Category

Occupation

Likely Trigger

Irritant

Drywall installer Makeup artist Janitor Chemistry technician

Gypsum dust Cosmetic powder, perfume Ammonia Hydrochloric acid

Baker Furrier Livestock breeder Veterinarian Food-processing worker Pharmacist Boat builder

Grain flour Animal dander Animal dander Animal dander Foodstuffs Medication powders Anhydrides

Corrosive Immunologic Immunoglobulin E

Low-molecular-weight substances

From Adkinson NF et al: Middleton’s allergy principles and practice, ed 8, Philadelphia, 2014, Elsevier.

• Anterior rhinoscopy or nasal endoscopy may be necessary to rule out nasal polyps or anatomic deformity, which may contribute to chronic rhinorrhea.

TREATMENT NONPHARMACOLOGIC THERAPY • Identification and avoidance of specific triggers (e.g., smoke/smog, specific foods, perfumes, strong odors, occupational irritants) may provide relief. • Discontinuing any medication/drugs that could be contributing, including topical decongestants/vasoconstrictors, oral contraceptives (OCPs), cocaine, and alcohol (Table 1). • Daily nasal lavage (distilled water mixed with saline packets) and over-the-counter nasal saline sprays have been shown to improve symptoms. • Surgical intervention (turbinectomy, vidian nerve resection, turbinoplasty) may be considered if medical measures fail, but such surgeries are not commonly performed in the U.S. There is limited data showing the efficacy of turbinoplasty with regard to symptom reduction, although there is a risk of empty nose syndrome (ENS). ACUTE AND CHRONIC Rx • Second-generation antihistamines have not been shown to be beneficial in nonallergic rhinitis. Although first-generation antihistamines may improve rhinorrhea due to their anticholinergic properties, topical therapies including intranasal steroids (fluticasone propionate, triamcinolone, mometasone), intranasal antihistamines (azelastine, olopatadine), and intranasal anticholinergics (ipratropium bromide) have been shown to be most efficacious. • Treatments should be individualized to the underlying pathophysiology. 1.  Vasomotor rhinitis: Initial therapy typically involves intranasal steroids with the addition of an intranasal antihistamine or intranasal ipratropium bromide if symptoms are not well controlled. A combination intranasal steroid and intranasal

antihistamine is now available that may be more convenient. 2.  Infectious rhinosinusitis: Supportive care and intranasal saline spray. May take up to 6 to 8 wk to improve after resolution of acute infection. 3.  Nonallergic rhinitis with eosinophilia syndrome (NARES): Topical nasal corticosteroids. 4. Gustatory rhinitis: Preprandial intranasal ipratropium bromide and/or dietary modification also may be useful in patients with specific triggers. 5. Atrophic rhinitis: Frequent irrigation with nasal saline, antibiotics to treat potential underlying bacterial infection; debridement and possible surgical intervention to reduce nasal cavity size can be considered. 6.  Rhinitis medicamentosa: Discontinuation of offending agent (topical decongestant/ vasoconstrictor agent, cocaine, α-receptor antagonist or phosphodiesterase-5-selective inhibitors). Patient may require short course of nasal or oral corticosteroids during withdrawal process. 7. Hormone-induced rhinitis: Typically resolves with delivery if during pregnancy. Consider discontinuing OCP if offending agent. Nasal saline spray alone can be efficacious. 8.  Rhinitis associated with systemic disease: Optimally managing the underlying condition. 9.  Rhinitis in the elderly: Intranasal ipratropium bromide. • Several studies have shown that repeated administration of topical capsaicin has a long-term beneficial effect on symptoms in patients with idiopathic rhinitis. Comparative studies on NAR with capsaicin vs. steroids demonstrate the superiority of capsaicin; however, the exact dose and frequency have not been determined. • A lternative treatments: Silver nitrate, acupuncture.

DISPOSITION Most patients experience mild to moderate symptomatic relief with avoidance of triggers

BOX 1  Differential Diagnosis in Chronic Rhinitis • • • • • • • • • • •

 oncha bullosa C Nasal septal deviation Adenoidal enlargement Nasal polyps Nasal cancer Nasal foreign body Basilar skull fracture Allergic rhinitis Cholinergic toxidromes Relapsing polychondritis Hypertrophic turbinates without rhinitis • Choanal atresia • Sarcoidosis • Primary ciliary dyskinesia Adapted from Adkinson NF et al: Middleton’s allergy principles and practice, ed 8, Philadelphia, 2014, Elsevier.

and appropriate use of medications. Up to 52% of patients with NAR report worsening symptoms at 3- to 7-yr follow-ups. Periodic reevaluations should be performed, as there is evidence supporting increase in comorbidities (asthma, allergic rhinitis, conjunctivitis) with length of NAR diagnosis. Furthermore, diagnostic testing is not precise for NAR versus AR. In a systematic review published in 2017, Nasal Allergen Provocation Testing (NAPT) was shown to better separate patients with NAR versus AR. Approximately 26% of patients presumed to have NAR had positive testing with NAPT despite negative skin-prick and/or serum IgE testing. It would be reasonable to revisit the diagnosis periodically and adjust management.

REFERRAL Referral to allergist and/or ENT may be appropriate when severe symptoms are unresponsive to standard therapy and/or diagnosis is uncertain.

PEARLS & CONSIDERATIONS COMMENTS • Nonallergic rhinitis symptoms are nonspecific, and a specific trigger is often never identified. Compared to allergic rhinitis, patients typically lack symptoms of sneezing, nasal pruritus, and conjunctival symptoms. • Second-generation oral antihistamines are typically not efficacious, and the treatment of nonallergic rhinitis should be individualized based on its underlying pathophysiology. SUGGESTED READINGS Available at ExpertConsult.com RELATED CONTENT Allergic Rhinitis (Patient Information) Allergic Rhinitis (Related Key Topic) AUTHORS: Shyam Joshi, MD, and Charles Fox Sherrod IV, MD

Nonallergic Rhinitis SUGGESTED READINGS Gevorgyan A et al: Capsaicin for non-allergic rhinitis, Cochrane Database Syst Rev 7:CD010591, 2015. Hamizan AW et al: Positive allergen reaction in allergic and non-allergic rhinitis: a systematic review, Int Forum Allergy Rhinol 9:868-877, 2017. Hellings PW et al: Non-allergic rhinitis: position paper of the European academy of allergy and clinical immunology, Allergy 72:1657-1665, 2017. Lieberman P, Smith P: Nonallergic rhinitis—treatment, Immunol Allergy Clin North Am 36:305-319, 2016. Seidman MD et al: Clinical practice guideline: allergic rhinitis, Otolaryngol Head Neck Surg 152:S1-S43, 2015. Settipane RA, Kaliner MA: Nonallergic rhinitis, Am J Rhinol Allergy 27(3):48-51, 2013.

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Non-Celiac Gluten Sensitivity BASIC INFORMATION

SYNONYMS Non-celiac wheat sensitivity (NCWS) NCGS ICD-10CM CODE K90.41 Non-celiac gluten sensitivity

EPIDEMIOLOGY & DEMOGRAPHICS • Prevalence of NCGS ranges from 0.6% to 13% in the general population. Its actual prevalence is not well established due to the absence of diagnostic markers and is based primarily on self-reported questionnaires for gluten sensitivity. • Reported prevalence has increased significantly over the past decade, directly correlating to the increase in sales of gluten-free foods, which have doubled since 2011. • NCGS is reported more often in women than in men. • It is more commonly reported in urban areas. • The median age of diagnosis is in the fourth decade of life. PHYSICAL FINDINGS AND CLINICAL PRESENTATION • Intestinal symptoms include abdominal pain, bloating, diarrhea (with or without alternating constipation), and flatulence. • Extraintestinal findings may include constitutional symptoms such as fatigue and weight loss as well as neurological changes (headache, brain fog, numbness) and psychological changes (anxiety). Less commonly, anemia and dermatological findings such as eczema may be seen. • Symptoms of NCGS greatly overlap with IBS and therefore may be difficult to distinguish. ETIOLOGY • There is no known biomarker or diagnostic test for NCGS, making the pathogenesis unclear. • It has been suggested that in patients with NCGS, ingestion of gluten may lead to

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • Celiac disease • Wheat allergy • Irritable bowel syndrome (IBS) WORKUP • There are no strict diagnostic criteria; therefore, there is a great deal of dependence on the patient’s perception of symptoms and nocebo effect. • Salerno Experts’ Criteria is the most widely used method for diagnosing NCGS. 1. Patient must be on a normal gluten-containing diet for at least 6 weeks. During this time, the patient is assessed by a diagnostic questionnaire (Table E1) at week −2, −1, and 0 to establish baseline symptoms. 2. At time 0, patient begins a strict GFD as instructed by a dietician. Patient will remain on GFD for 6 weeks with weekly data recording via the questionnaire. 3. Response is assessed, with a positive result defined as a decrease of ≥30% in the baseline score in 1 to 3 categories for ≥50% of the observation time. 4.  The diagnosis of NCGS is excluded in subjects failing to show symptomatic improvement after six weeks. These patients should be worked up for other causes of IBS-like symptoms, including intolerance to fermentable oligo-, di- and monosaccharides and polyols (FODMAPS) or small bowel bacterial overgrowth. 5. This 6-wk test study is followed by a double-blind placebo-controlled challenge of ≥8 g/day of gluten (or placebo) for a week of each. Gluten is given in a “vehicle” such as a bar, bread, or muffin. Gluten and placebo must be indistinguishable in look, texture, and taste. 6. Again, a positive result is defined as a variation of ≥30% between gluten and placebo. 7. While the Salerno Expert Criteria is the proposed method for diagnosis of NCGS, it is often impractical to perform in the primary

care setting. Therefore, simply asking the patient to adopt a GFD will achieve the same desired clinical outcome.

N

LABORATORY TESTS • Mainly a clinical diagnosis as there are no diagnostic tests or biomarkers for NCGS • Celiac disease and wheat allergy must be excluded through their respective laboratory tests prior to the diagnosis of NCGS

TREATMENT NONPHARMACOLOGIC THERAPY Treatment of NCGS is strict elimination of gluten from the diet. A low-FODMAPS diet may be indicated if symptoms are not responding to a GFD. ACUTE GENERAL Rx • Correct nutritional deficiencies • Lifelong elimination of gluten or wheat DISPOSITION Unlike celiac disease, which requires a strict, lifelong gluten-free diet, it is unclear whether NCGS is a permanent condition. Some authors have suggested reintroduction of gluten after 1 to 2 yr. REFERRAL A multidisciplinary team approach is recommended for patients with NCGS, with involvement of the primary doctor, gastroenterologist, and nutritionist.

PEARLS AND CONSIDERATIONS COMMENTS • The gluten-free market is rising, likely due to the perceived health benefits of a GFD. This, however, is debatable, as grains should be the main energy source in the human diet. A GFD is poor in trace elements and vitamins such as zinc, iron, magnesium, calcium, vitamin D, vitamin B12, folate, and fiber. It is also high in calories, fat, sugar, and salt. • Studies show that intake of gluten through whole grains is associated with a lower risk of elevated triglycerides and lower risk of cardiovascular disease. RELATED CONTENT Celiac Disease (Related Key Topic) Irritable Bowel Syndrome (Related Key Topic) AUTHOR: Christina M. Bortz, MD

Diseases and Disorders

DEFINITION Non-celiac gluten sensitivity (NCGS) is an intestinal and/or extraintestinal reaction to ingested gluten or wheat that improves once glutencontaining foods have been eliminated from the diet. Gluten is a group of proteins found in grains (wheat, rye, barley, and oats). The two main protein components of gluten are gliadin and glutenin. Celiac disease and wheat allergy must be excluded before the diagnosis of NCGS can be made.

increased intestinal permeability by increasing serum concentration of zonulin, a protein that increases permeability through changes in epithelial tight junctions. The rise in zonulin leads to breaks and leakage through the intestinal epithelial wall. • Several studies have found changes in the intestinal microbiome of patients with NCGS compared with those in healthy controls. These changes revert to normal following initiation of a gluten-free diet (GFD).

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Non-Celiac Gluten Sensitivity SUGGESTED READINGS Khan A et al: Nonceliac gluten and wheat sensitivity, Clinical Gastroenterology and Hepatology 17:5, 2019. Roszkowska A et  al: Non-celiac gluten sensitivity: a review, Medicina (Kaunas, Lithuania) 55:222, 2019.

TABLE E1  Diagnostic Questionnaire During each week of gluten-free diet, rate symptoms on a scale from 1-10. (Score of 1 = minimal symptoms / 10 = severe symptoms) Wk 0 Wk 1 Wk 2 Wk 3 Wk 4 Wk 5 Wk 6 Abdominal pain Acid reflux Nausea/vomiting Borborygmus Abdominal distention Belching Flatulence Decreased stool frequency Increased stool frequency Diarrhea Constipation Fecal urgency Feeling of incomplete evacuation Dermatitis Headache Foggy mind Fatigue Limb numbness Joint/muscle pain Fainting Oral/tongue lesions

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Non-Hodgkin Lymphoma BASIC INFORMATION DEFINITION Non-Hodgkin lymphoma (NHL) is a h­ eterogeneous group of malignancies of the lymphoreticular system. There are approximately 60 different NHL subtypes. The WHO classification of lymphomas is summarized in Table 1 and Fig. 1. SYNONYM NHL ICD-10CM CODES C85.90 Non-Hodgkin lymphoma, unspecified, unspecified site C85.91 Non-Hodgkin lymphoma, unspecified, lymph nodes of head, face, and neck C85.92 Non-Hodgkin lymphoma, unspecified, intrathoracic lymph nodes

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C85.93 Non-Hodgkin lymphoma, unspecified, intra-abdominal lymph nodes C85.94 Non-Hodgkin lymphoma, unspecified, lymph nodes of axilla and upper limb C85.95 Non-Hodgkin lymphoma, unspecified, lymph nodes of inguinal region and lower limb C85.96 Non-Hodgkin lymphoma, unspecified, intrapelvic lymph nodes C85.97 Non-Hodgkin lymphoma, unspecified, spleen C85.98 Non-Hodgkin lymphoma, unspecified, lymph nodes of multiple sites C85.99 Non-Hodgkin lymphoma, unspecified, extranodal and solid organ sites

EPIDEMIOLOGY • Sixth most common neoplasm in the U.S. (>70,000 new cases annually). Incidence

increases with age; majority of patients are above 60 yr of age. • In the U.S. and Europe, diffuse large B-cell lymphoma (DLBCL) is the most common subtype (30% of the cases), and follicular lymphoma (FL) is the second most common subtype (25% of the cases). • In patients with HIV, NHL is the most common tumor (followed by Kaposi sarcoma). DLBCL accounts for 80% to 90% of the cases of HIVassociated NHL. • Factors associated with an increased risk of non-Hodgkin lymphoma are summarized in Box 1.

PHYSICAL FINDINGS & CLINICAL PRESENTATION • Patients often present with lymphadenopathy. • Approximately one third of the NHL involve extranodal sites, which can result in

TABLE 1  World Health Organization Classification of Lymphomasa Mature B-Cell Neoplasms Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma • B-cell prolymphocytic leukemia • Splenic B-cell marginal zone lymphoma • Hairy cell leukemia • Splenic B-cell lymphoma/leukemia, unclassifiable • Splenic diffuse red pulp small B-cell lymphoma • Hairy cell leukemia-variant • Lymphoplasmacytic lymphoma • Waldenström macroglobulinemia • Heavy chain diseases • Alpha heavy chain disease • Gamma heavy chain disease • Mu heavy chain disease Plasma Cell Myeloma • Solitary plasmacytoma of bone • Extraosseous plasmacytoma Extranodal Marginal Zone Lymphoma of Mucosa-Associated Lymphoid Tissue (MALT Lymphoma) • Nodal marginal zone lymphoma • Pediatric nodal marginal zone lymphoma Follicular Lymphoma • Pediatric-type follicular lymphoma • Primary cutaneous follicle center lymphoma Mantle Cell Lymphoma Diffuse Large B-Cell Lymphoma (DLBCL), NOS • T-cell/histiocyte–rich large B-cell lymphoma • Primary DLBCL of the CNS • Primary cutaneous DLBCL, leg type • EBV-positive DLBCL • DLBCL associated with chronic inflammation • Lymphomatoid granulomatosis • Primary mediastinal (thymic) large B-cell lymphoma • Intravascular large B-cell lymphoma • ALK-positive large B-cell lymphoma • Plasmablastic lymphoma • HHV8-positive diffuse large B-cell lymphoma and primary effusion lymphoma • Burkitt lymphoma • High grade B-cell lymphomas, with MYC and BCL2 and/or BCL6 rearrangements • B-cell lymphoma unclassifiable, with features intermediate between diffuse large B-cell lymphoma and classic Hodgkin lymphoma aMost

Mature T-Cell and NK-Cell Neoplasms • T-cell prolymphocytic leukemia • T-cell large granular lymphocytic leukemia • Chronic lymphoproliferative disorder of NK-cells • Aggressive NK leukemia • Systemic EBV-positive T-cell lymphoma of childhood • Hydroa vacciniforme-like lymphoma • Adult T-cell leukemia/lymphoma • Extranodal NK/T-cell lymphoma, nasal type • Enteropathy-associated T-cell lymphoma • Monomorphic epitheliotropic intestinal T-cell lymphoma • Hepatosplenic T-cell lymphoma • Subcutaneous panniculitis-like T-cell lymphoma Mycosis Fungoides • Sézary syndrome • Primary cutaneous CD30-positive T-cell lymphoproliferative disorders • Lymphoid papulosis • Primary cutaneous anaplastic large cell lymphoma • Primary cutaneous gamma-delta T-cell lymphoma • Primary cutaneous CD8-positive aggressive epidermotropic cytotoxic T-cell lymphoma • Primary cutaneous CD4-positive small/medium T-cell lymphoproliferative disease Peripheral T-Cell Lymphoma, NOS Angioimmunoblastic T-Cell Lymphoma Anaplastic Large Cell Lymphoma, ALK-Positive • Anaplastic large cell lymphoma, ALK-negative Hodgkin Lymphoma Nodular Lymphocyte Predominant Hodgkin Lymphoma Classic Hodgkin Lymphoma Nodular Sclerosis Hodgkin Lymphoma • Lymphocyte-rich classic Hodgkin lymphoma • Mixed cellularity classic Hodgkin lymphoma • Lymphocyte-depleted classic Hodgkin lymphoma

common entities are underlined. Provisional entities are in italics. Some rare entities or variants are omitted. ALK, Anaplastic lymphoma kinase; CNS, central nervous system; EBV, Epstein-Barr virus; HHV-8, human herpesvirus-8; NK, natural killer; NOS, not otherwise specified. From Hoffman R et al: Hematology, basic principles and practice, ed 7, Philadelphia, 2018, Elsevier.

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Non-Hodgkin Lymphoma

Non-Hodgkin lymphoma (NHL)

N

T/NK-cell neoplasms

Mature T/NK-cell neoplasms

Precursor lymphoid neoplasms

2008 WHO classification of major subtypes

T-lymphoblastic leukemia/lymphoma

Cutaneous

Extranodal

Nodal

Leukemic

Mycosis fungoides (MF)

NKTCL nasal type

Peripheral TCL-NOS

Adult T-cell leukemia/ lymphoma

Transformed MF

Enteropathyassociated TCL

Anaplastic large cell lymphoma (ALK+/–)

Aggressive NK-cell leukemia

Sézary syndrome

Hepatosplenic TCL

Angioimmunoblastic TCL

T-cell prolymphocytic leukemia

Primary cutaneous CD30+ T-cell disorders

Subcutaneous panniculitis-like TCL

Primary cutaneous γ/δ TCL

T-cell large granular lymphocytic leukemia Aggressive Indolent

FIG. 1  World Health Organization (WHO) classification of the mature T-cell neoplasms. NK, Natural killer; NKTCL, nasal NK/T-cell lymphoma; NOS, not otherwise specified; TCL, T-cell lymphoma; WHO, World Health Organization. (From Hoffman R et al: Hematology, basic principles and practice, ed 7, Philadelphia, 2018, Elsevier.)

BOX 1  Factors Associated with an Increased Risk of Non-Hodgkin Lymphoma Immunosuppression, acquired After solid-organ or hematopoietic stem cell transplantation HIV/AIDS Congenital immunodeficiency syndromes Increasing age (waning immunity) Previous history of HL or NHL Family history of NHL Drugs Methotrexate TNF-α inhibitors Occupational exposures Herbicides, pesticides, wood dust, epoxy glue, organic solvents Farming, forestry, painting, carpentry, tanning AIDS, Acquired immunodeficiency syndrome; HIV, human immunodeficiency virus; HL, Hodgkin lymphoma; NHL, non-Hodgkin lymphoma; TNF, Tumor necrosis factor. From Niederhuber JE: Abeloff’s clinical oncology, ed 6, Philadelphia, 2020, Elsevier.

unusual presentations (e.g., gastrointestinal tract involvement can simulate peptic ulcer disease). • Presence of B symptoms like unexplained weight loss, fever, fatigue, and night sweats are seen typically in aggressive or highly aggressive lymphomas. • Aggressive lymphomas have acute or subacute presentation with increasing size of the mass and B symptoms. • Indolent lymphomas have a more chronic course, with asymptomatic lymphadenopathy and/or slowly progressive cytopenias. • Hepatomegaly and splenomegaly may be present. • Cough, dyspnea with bulky mediastinal involvement.

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • Hodgkin lymphoma • Viral infections • Metastatic carcinoma • Autoimmune conditions • Sarcoidosis

WORKUP Initial laboratory evaluation may be entirely normal. Elevated LDH may be seen in aggressive lymphoma or in indolent lymphoma with high disease bulk. In cases of highly aggressive NHL (e.g., Burkitt lymphoma), spontaneous tumor lysis syndrome (TLS) may be seen, but rarely; it is characterized by hyperkalemia, hyperuricemia, hypocalcemia, hyperphosphatemia, and acidosis. TLS can be life threatening and is considered a medical emergency. Acute management includes aggressive IV fluid repletion and rasburicase. Proper staging of NHL includes the following: • A thorough history and physical examination. • Excisional or incisional surgical biopsy is preferred. Image-guided core needle biopsies may be acceptable in patients without peripheral adenopathy. Fine needle aspirates are not adequate for precise lymphoma subclassification. Laparoscopic lymph node biopsy or mediastinoscopy can be used on an outpatient basis for most patients with intraabdominal or mediastinal lymphoma, respectively. • Tissue biopsy with histologic, immunophenotypic, and genetic studies interpretation.

Diseases and Disorders

NHL neoplasm grouping

B-cell neoplasms

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TABLE 2  Major Molecular Alterations in Non-Hodgkin Lymphomas Cases Affected (%)

Proto-Oncogene Involved

Mechanism of ProtoOncogene Activation

Proto-Oncogene Function

MYD88 L265P mutation t(14;18)(q32;q21) t(11;14)(q13;q32) t(11;18)(q21;q21) t(1;14)(p22;q32) der(3)(q27)

95

MYD88

Activation

B-cell signaling

90 70 50 35

BCL-2 BCL-1/cyclin D1 API2/MLT BCL-10 BCL-6

Transcription deregulation Transcription deregulation Fusion protein Transcription deregulation Transcription deregulation

t(14;18)(q32;q21) t(8;14)(q24;q32)

15 10

BCL-2 MYC

Transcription deregulation Transcription deregulation

t(8;14)(q24;q32) t(2;8)(p11;q24) t(8;22)(q24;q11) t(2;5)(p23;q35)

80 15 5 60

MYC MYC MYC NPM/ALK

Transcription deregulation

Negative regulator of apoptosis Cell cycle regulator API2 has antiapoptotic activity Antiapoptosis Transcriptional repressor required for GC formation Negative regulator of apoptosis Transcription factor regulating cell proliferation and growth Transcription factor regulating cell proliferation and growth

NHL Histologic Type

Alteration

Lymphoplasmacytic lymphoma Follicular lymphoma Mantle cell lymphoma MALT lymphoma Diffuse large B-cell lymphoma

Burkitt lymphoma

Anaplastic large T-cell lymphoma

Fusion protein

ALK is a tyrosine kinase

GC, Gastric cancer; MALT, mucosa-associated lymphoid tissue; NHL, non-Hodgkin lymphoma. From Niederhuber JE: Abeloff’s clinical oncology, ed 6, Philadelphia, 2020, Elsevier.

Major molecular alterations in non-Hodgkin lymphomas are summarized in Table 2. • Routine laboratory evaluation (complete blood count, flow cytometry in selected circumstances, ESR, urinalysis, LDH, blood urea nitrogen, creatinine, serum calcium, uric acid, liver function tests, serum protein electrophoresis). • HIV and hepatitis B testing. • Bone marrow evaluation (aspirate and biopsy) (Fig. E2). • CT scan of chest, abdomen, and pelvis with IV contrast, if possible. • Fluorine-18 fluorodeoxyglucose (FDG) positron emission tomography (PET) integrated with CT (Fig. E3) has emerged as a powerful tool for staging, response evaluation, and posttreatment surveillance in patients with aggressive subtypes of NHL. • Depending on the histopathology, the results of the previous studies, and the planned therapy, some other tests may be performed. • Lumbar puncture is needed in some patients with aggressive NHL, and most patients with HIV-associated NHL, to evaluate for CNS involvement by lymphoma. • The evaluation of a new patient with nonHodgkin lymphoma is summarized in Table 3. CLASSIFICATION: For clinical approach, NHL is subdivided lymphomas into indolent, aggressive, and highly aggressive disease. STAGING: The Ann Arbor staging system that was initially developed for Hodgkin lymphoma (HL) was revised as the Lugano criteria and remains the current standard; but unlike HL, NHL does not spread predictably via lymphatic channels to contiguous nodal regions, so stage is only one of multiple contributors to prognosis (Table 4). Histopathology has greater therapeutic implications in NHL than in Hodgkin lymphoma.

TABLE 3  Evaluation of a New Patient with Non-Hodgkin Lymphoma Evaluation

Mandatory

As Indicated

Confirm diagnosis

Adequate biopsy reviewed by ­experienced hematopathologists

General overview and risks of therapy

History and physical examination Complete blood cell count Chemistry screen (including liver and renal function studies) HIV serology Hepatitis B serologies

Prognostic ­categorization Anatomic ­disease

Serum lactate dehydrogenase Serum albumin Chest, abdominal, and pelvic CT with contrast enhancement

Immunophenotyping with ­immunohistochemistry +/− flow cytometry Cytogenetics/molecular studies Blood coagulation studies EBV serology and PCR assay Hepatitis C serology Serum electrolytes, uric acid Assessment of cardiac ejection fraction Pregnancy testing in women Discussion of fertility issues Erythrocyte sedimentation rate Serum β2-microglobulin Ultrasonography FDG-PET/CT MRI Unilateral bone marrow biopsy with aspirate Lumbar puncture with flow cytometry of CSF Biopsy of suspicious sites Blood flow cytometry

Occult sites of involvement

CSF, Cerebrospinal fluid; CT, computed tomography; EBV, Epstein-Barr virus; FDG-PET, fluorodeoxyglucose-18–labeled positron emission tomography; HIV, human immunodeficiency virus; MRI, magnetic resonance imaging; PCR, polymerase chain reaction. From Niederhuber JE: Abeloff’s clinical oncology, ed 6, Philadelphia, 2020, Elsevier.

TABLE 4  Non-Hodgkin Lymphoma: Lugano Staging Classification Stage

Features

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Involvement of a single lymph node region or lymphoid structure (e.g., spleen, thymus, Waldeyer ring), or a single extranodal location without nodal involvement (IE) Involvement of two or more lymph node regions on the same side of the diaphragm or limited nodal disease with limited contiguous extranodal involvement (IIE) Involvement of lymph node regions or structures on both sides of the diaphragm Involvement of diffuse or noncontiguous extranodal site(s)

II III IV

From Niederhuber JE: Abeloff’s clinical oncology, ed 6, Philadelphia, 2020, Elsevier.

ALG Fig. 4 illustrates a diagnostic algorithm outlining the steps in classification of B-cell lymphomas composed of cells of small to intermediate size.

TREATMENT

• The addition of rituximab to chemotherapy is generally well tolerated and has increased response and survival rates in NHL patients. Patients who received rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) had higher response rates (96% vs. 90%) with a better 2-yr overall survival rate (95% vs. 90%) than patients who received CHOP without rituximab. Similarly, patients who received rituximab, cyclophosphamide, vincristine, and prednisone (R-CVP) had higher response rates (81% vs. 57%) and better overall survival at 4 yr (83% vs. 77%) than patients who were treated with CVP without rituximab. • In a recent phase III noninferiority study, the combination of bendamustine and rituximab was associated with better progression-free survival rates than R-CHOP (70 vs. 31 mo)

with fewer toxic effects. Subset analyses showed better progression-free survival in patients with follicular lymphoma, mantle cell lymphoma, and lymphoplasmacytic lymphoma. • Maintenance rituximab after rituximab-containing regimens has been associated with a better progression-free survival at 3 yr (75% vs. 58%) than observation alone without a difference in overall survival. • The combination of obinutuzumab and chemotherapy followed by obinutuzumab maintenance was approved by the FDA in previously untreated patients with follicular lymphoma based on a randomized study, in which obinutuzumab and chemotherapy were associated with longer median progression-free survival than rituximab and chemotherapy.

DIAGNOSTIC ALGORITHM: B CELL NEOPLASMS OF SMALL TO INTERMEDIATE CELL SIZE Step 1: Confirm B cell lineage (CD19, CD20, and/or CD79a) AND Assess for clonality (kappa, lambda, smig negative). Step 2: Evaluate expression of CD5 and CD10. CD5+ If

CD10+

Dim CD20 and smIg

CD5/CD10 negative If the neoplastic cells have increased SSC, bright CD19/CD20, the patient has monocytopenia, or there is clinical concern for HCL, perform additional markers: CD11c, CD25, CD103; CD123

Bright CD20 and smIg

CLL>MCL MCL>CLL Perform additional markers CD23+ FMC7+ CD200+ CD23– FMC7– CD200–

Suspected diagnosis by flow cytometry CLL

MCL

FL

MZL vs LPL

CD11c+ CD25+ CD103+ HCL CD123+

Step 3: Confirm the suspected diagnosis with additional data CLL Clinical and laboratory correlation need >5000 abnormal cells/µl or disease related sequelae to distinguish MBL and CLL

MCL Cyclin D1 over-expression by IHC or a t(11;14) is required to confirm the diagnosis of MCL

FL Morphology Note: Typically, CD38 is low to absent while BCL2 is over-expressed in FL. These features help distinguish FL from BL

MZL vs LPL

HCL

Morphology between MZL and LPL may overlap

Flow cytometry allows for definitive diagnosis

To distinguish: 1. Lab dataA large lgM monoclonal spike would favor LPL 2. Clinical dataWaldenstrom would favor LPL

BRAF V600E mutation positive but not needed for diagnosis.

FIG. 4  This diagnostic algorithm outlines the steps in classification of B-cell lymphomas composed of cells of small to intermediate size. BL, Burkitt lymphoma; CLL, chronic lymphocytic leukemia; FL, follicular lymphoma; HCL, hairy cell leukemia; IgM, immunoglobulin M; IHC, immunohistochemistry; LPL, lymphoplasmacytic lymphoma; MBL, monoclonal B-cell lymphocytosis; MCL, mantle cell lymphoma; MZL, marginal zone lymphoma; SmIg, surface immunoglobulin; SSC, scleroderma and systemic sclerosis. (From McPherson RA, Pincus MR: Henry’s clinical diagnosis and management by laboratory methods, ed 23, Philadelphia, 2017, Elsevier.)

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Diseases and Disorders

ACUTE GENERAL Rx The therapeutic regimen varies with specific lymphoma subtype and pathologic stage. Following are the commonly used therapeutic modalities: INDOLENT NHL: • Deferment of therapy and careful observation in asymptomatic patients with low volume disease. • Local radiotherapy for stage I disease. • Rituximab, an anti-CD20 monoclonal antibody, with or without chemotherapy is used in patients with symptomatic or progressive disease.

Non-Hodgkin Lymphoma

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Non-Hodgkin Lymphoma • The combination of obinutuzumab and bendamustine followed by obinutuzumab maintenance was approved by the FDA for the treatment of patients with rituximabrefractory follicular lymphoma. • The oral BTK inhibitor ibrutinib is FDAapproved for the treatment of patients with relapsed mantle cell lymphoma, lymphoplasmacytic lymphoma, and marginal zone lymphoma. Acalabrutinib, a second-generation BTK inhibitor, has also been approved for relapsed mantle cell lymphoma. • The oral PI3K inhibitors idelalisib and copanlisib, as well as the novel anti-CD20 monoclonal antibody obinutuzumab, have been FDA-approved for the treatment of relapsed follicular lymphoma. • The proteasome inhibitor bortezomib and the immunomodulating agent lenalidomide are FDA-approved for the treatment of relapsed mantle cell lymphoma. • H. pylori-associated gastric marginal zone lymphoma can be treated with a course of antibiotics. For persistent cases after eradication or H. pylori-negative cases, radiotherapy is highly effective. • Splenic marginal zone lymphoma is typically treated with rituximab or splenectomy. Chemoimmunotherapy or ibrutinib may be appropriate in relapsed disease.

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• Stem cell transplantation (autologous or allogeneic) may confer long-term disease control in multiple relapsed or refractory disease. • Table 5 summarizes chemotherapy regimens in indolent lymphomas. AGGRESSIVE NHL: The most common aggressive NHL is DLBCL. The addition of rituximab against CD20 B-cell lymphoma to the CHOP regimen (R-CHOP) increased the complete response rate and prolonged overall survival in patients with DLBCL, based on randomized controlled trials, without clinically significant increase in toxicity. R-CHOP has shown to be safe and effective in patients with HIV-associated NHL with CD4+ counts >50 cells/mm3. Most common regimens used in DLBCL include: • Three cycles of R-CHOP followed by involvedfield radiotherapy or 6 cycles of R-CHOP alone are appropriate approaches in patients with localized DLBCL. • 6 cycles of R-CHOP with or without radiotherapy are appropriate in patients with advanced-stage DLBCL. • For patients with double-hit lymphomas (defined as harboring rearrangement of MYC, BCL-2, and/or BCL-6), who have poorer outcomes to R-CHOP than regular DLBCL, the use of R-EPOCH (infusional etoposide, doxorubicin, and vincristine, along with cyclophosphamide, prednisone, and rituximab) might also be effective.

• Granulocyte-colony stimulating factor (e.g., filgrastim, MYC) may be effective in reducing the risk of febrile neutropenia in patients over 65 yr with aggressive lymphoma undergoing chemotherapy. • Treatment with high-dose chemotherapy and autologous bone marrow transplant: Compared with conventional chemotherapy, increases overall survival in patients with chemotherapy-sensitive relapsed DLBCL. • Chimeric antigen receptor T-cell therapy was recently approved for patients with relapsed or refractory diffuse large B-cell lymphoma after two prior lines of chemotherapy. • Combination chemotherapy regimens for NHL are described in Table 6. HIGHLY AGGRESSIVE NHL: The most common high-grade NHL subtype is Burkitt lymphoma (BL). BL affects younger patients than DLBCL and is common in HIV-infected individuals. Regimens more intensive than R-CHOP are needed to cure patients with high-grade NHL. The most commonly used multi-agent regimens include hyper-CVAD, CODOX-M/IVAC, and doseadjusted EPOCH, usually in combination with rituximab. The 5-yr survival approximates 75%.

DISPOSITION • Patients with indolent NHL in the rituximab era experience long survival despite the

TABLE 5  Chemotherapy Regimens in Indolent Lymphomas BR (Every 28 Days) • Bendamustine 120 mg/m2 days 1 and 2 • Rituximab 375 mg/m2 IV day 1 CVP-R (Every 21 Days) • Cyclophosphamide 750 mg/m2 IV on day 1 • Vincristine 1.4 mg/m2, up to a maximal dose of 2 mg IV, on day 1 • Prednisone 40 mg/m2 daily PO days 1-5 • Rituximab 375 mg/m2 IV day 132 R-CHOP (Every 21 Days) • Cyclophosphamide 750 mg/m2 IV on day 1 • Doxorubicin 50 mg/m2 IV on day 1 • Vincristine 1.4 mg/m2, up to a maximal dose of 2 mg IV, on day 1 • Prednisone 100 mg daily orally on days 1-5 • Rituximab 375 mg/m2 IV on day 1 of each therapy cycle33 or by alternate schedule34 CNOP (Every 21 Days) • Cyclophosphamide 750 mg/m2 IV on day 1 • Mitoxantrone 10 mg/m2 IV on day 1 • Vincristine 1.4 mg/m2, up to a maximal dose of 2 mg IV, on day 1 • Prednisone 50 mg/m2 daily orally on days 1-5 R-CHVP-IFN (Every 28 Days for 6 Mo, Then Every 2 Mo for 6 Mo). 35 • Cyclophosphamide 600 mg/m2 • Doxorubicin 25 mg/m2 • Etoposide 100 mg/m2 on day 1 (replaces original teniposide 60 mg/m2 on day 1) • Prednisolone 40 mg/m2 on days 1-5 • Interferon-α 5-3 times a wk • Patients being treated with R-CHVP also received 375 mg/m2 of rituximab IV on day 1 of each therapy cycle for 6 cycles FMD (Every 28 Days) • Fludarabine 25 mg/m2 IV on day 1-3 • Mitoxantrone 10 mg/m2 IV on day 1 • Dexamethasone 20 mg/day PO days 1-5 • Patients being treated with R-FMD also received 375 mg/m2 of rituximab IV on day 1 of each therapy cycle note:

Reference endnotes retained from the source. IV, Intravenous; PO, by mouth. From Hoffman R et al: Hematology, basic principles and practice, ed 7, Philadelphia, 2018, Elsevier.

ProMACE-MOPP • Cycles repeated every 28 days Day 1 • Cyclophosphamide 650 mg/m2 IV • Doxorubicin 25 mg/m2 IV • Etoposide 120 mg/m2 IV • Prednisone 60 mg/m2 orally daily days 1-14 Day 8 • Mechlorethamine 6 mg/m2 IV • Vincristine 1.4 mg/m2 (maximum 2 mg) IV on day 8 • Procarbazine 100 mg/m2 orally daily days 8-14 Day 15 • Methotrexate 500 mg/m2 IV on day 15 with leucovorin 50 mg/m2 orally every 6 hours for four doses beginning 24 hours after methotrexate R-Hyper-CVAD (Every 21 Days)36 Cycles 1, 3, 5, and 7 • Rituximab 375 mg/m2 IV on day 1 • Cyclophosphamide (with mesna) 300 mg/m2 IV over 3 hours every 12 hours on days 2-4 (total 6 doses) • Vincristine 1.4 mg/m2 (maximum 2 mg) IV on days 5 and 12 • Doxorubicin 16.6 mg/m2 IV by continuous infusion on days 5-7 • Dexamethasone 40 mg/day PO/IV on days 2–5 and days 12-15 Cycles 2, 4, 6, and 8 • Rituximab 375 mg/m2 IV on day 1 • Methotrexate 200 mg/m2 IV over 2 hours, followed by 800 mg/m2 IV continuous infusion over 22 hours on day 2 • Leucovorin 50 mg PO starting 12 hours after completion of methotrexate infusion, followed by 15 mg PO every 6 hours for 8 dosed until the methotrexate level is less than 0.1 μM/L • Cytarabine 3000 mg/m2 IV over 2 hours every 12 hours on days 3 and 4 (4 doses total) Rituximab Monotherapy Rituximab 375 mg/m2 weekly for 4 wk

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TABLE 6  Combination Chemotherapy Regimens for Non-Hodgkin Lymphoma Regimen

Days of Administration

90 mg/m2 IV 375 mg/m2 IV

1-2 1

750 mg/m2 IV 50 mg/m2 IV 1.4 mg/m2 IV 100 mg PO 375 mg/m2 IV

1 1 1 1-5 1

1000 mg/m2 IV 1.4 mg/m2 IV 100 mg PO 375 mg/m2 IV

1 1 1-5 1

Frequency Every 28 days

Every 21 days

Every 21 days

IV, Intravenous; PO, by mouth. Adapted from Goldman L, Schafer AI: Goldman’s Cecil medicine, ed 24, Philadelphia, 2012, WB Saunders.

TABLE 7  Clinical Prognostic Indexes International Prognostic Index (IPI) for Aggressive Lymphomas1 Risk Group

IPI

Low Low intermediate High intermediate High

0, 1 2 3 4,5

Scorea

CR Rate (%)

5-Yr OS Rate (%)

87 67 55 44

73 51 43 26

Follicular International Prognostic Index (FLIPI)2 Risk Group

FLIPI Scoreb

Distribution (%)

5-Yr OS Rate (%)

Low Intermediate Poor

0-1 1-2 ≥3

36 37 27

90.6 77.6 52.5

Risk Group

MIPI Scorec

Distribution (%)

Median Survival Rate

Low Intermediate High

0-3 4-5 6-11

44 35 21

Not reached 51 mo 29 mo

Mantle Cell International Prognostic Index (MIPI)3

CR, Complete response; OS, overall survival. aOne point is given for the presence of each of the following characteristics: age older than 60 yr, elevated serum lactate dehydrogenase (LDH) level, Eastern Cooperative Oncology Group performance status ≥2, Ann Arbor stage III or IV, and more than two extranodal sites. bOne point is given for the presence of each of the following characteristics: age older than 60 yr, elevated serum LDH level, hemoglobin level 102 cm (40 inches) in men and >88 cm (35 inches) in women. ICD-10CM CODES E66.01 Morbid (severe) obesity due to excess calories E66.09 Other obesity due to excess calories E66.1 Drug-induced obesity E66.2 Morbid (severe) obesity with alveolar hypoventilation E66.8 Other obesity E66.9 Obesity, unspecified O99.210 Obesity complicating pregnancy, unspecified trimester O99.211 Obesity complicating pregnancy, first trimester O99.212 Obesity complicating pregnancy, second trimester O99.213 Obesity complicating pregnancy, third trimester O99.214 Obesity complicating childbirth O99.215 Obesity complicating the puerperium

EPIDEMIOLOGY & DEMOGRAPHICS • The World Health Organization first recognized obesity as a worldwide epidemic in 1997. As of 2005, 1.6 billion adults worldwide were classified as overweight, 400 million of whom were obese. It is predicted that the combination of overweight and obesity will soon eclipse public health issues such as malnutrition and infectious diseases as the most significant cause of poor health. • Worldwide, data from the Global Burden of Disease Study from 1980 to 2013 indicate the prevalence of adult obesity has increased from 28.8% to 36.9% in men and 29.8% to 38% in women. The prevalence of childhood and adolescent obesity has also substantially increased. • Based on U.S. NHANES data from 2011 to 2012, the prevalence of abdominal obesity was 54%. It is estimated that by 2020, 2 in every 5 adults and 1 in every 4 children in the U.S. will be categorized as obese. • The present cost of obesity in the U.S. population is estimated at $100 billion annually. Approximately two thirds of people living in the United States are overweight, which is the highest percentage in the world (Marie Ng, 2014). • For persons with a BMI ≥30 kg/m2, all-cause mortality is increased by 50% to 100% above that of persons with BMI in the range of 20 to 25 kg/m2.

• Obesity is an independent risk factor for cardiovascular disease (CVD), type 2 diabetes, hypertension, cancer (particularly colon, prostate, breast, and gynecologic malignancies), sleep apnea, degenerative joint disease, thromboembolic disorders, digestive tract diseases (gallstones), and dermatologic disorders. • Significant morbidity and risk of death are projected to begin in young adulthood, resulting in >100,000 excess cases of CHD by 2035, even with the most modest projection of future obesity. • When children enter kindergarten, 12.4% are obese, and another 14.9% are overweight. Data show that incident obesity between the ages of 5 and 14 yr is more likely to have occurred at younger ages.1 • Obesity in adolescence is significantly associated with increased risk of incident severe obesity in adulthood, with variations by sex and race/ethnicity. Overweight or obese adults who were obese as children have increased risk of type 2 DM, dyslipidemia, hypertension, and carotid artery atherosclerosis. • Obesity is a major preventable cause of death and disability in the U.S. (the other is tobacco). • Extensive data indicate that weight loss can reverse or arrest the harmful effects of obesity. • In 2013 nearly 180,000 bariatric surgery procedures were performed in the U.S. Of these procedures 42% were laparoscopic sleeve gastrectomy, 34% were Roux-en-Y gastric bypass, and 15% were laparoscopic adjustable gastric banding.

PHYSICAL FINDINGS & CLINICAL PRESENTATION • Physical examination should assess the degree and distribution of body fat, signs of secondary causes of obesity, and obesityrelated comorbidities. • Increased waist circumference is apparent. Excess abdominal fat is clinically defined as a waist circumference >40 inches (>102 cm) in men and >35 inches (>88 cm) in women (in Asian men and women, >36 inches and >33 inches, respectively). Central obesity is a risk factor for mortality even among individuals with normal BMIs. • Symptoms associated with hypertension, coronary artery disease (CAD), and diabetes (e.g., polyuria, polydipsia, acanthosis nigricans, retinopathy, and neuropathy) may be present. • Obesity is associated with cardiac hypertrophy, diastolic dysfunction, and decreased aortic compliance, which are independent predictors of cardiovascular risk. • Joint pain and swelling are associated with degenerative joint disease secondary to obesity. 1Cunningham

SA et al: Incidence of childhood obesity in the United States, N Engl J Med, 370:403-411, 2014.

• The physical exam and ECG often underestimate the presence and extent of cardiac dysfunction in obese patients. Jugular venous distention and hepatojugular reflux may not be seen and heart sounds are frequently distant. • A large quantity of fluid is present in the interstitial space of adipose tissue, as the interstitial space is ∼10% of the tissue wet weight. This excess fluid in this compartment, if redistributed into the circulation, can have negative repercussions in obese individuals with heart failure. Obese individuals have higher cardiac output and a lower total peripheral resistance than do lean individuals, and obesity is associated with persistence of elevated cardiac filling pressure during exercise. • Obesity predisposes to heart failure through several different mechanisms: increased total blood volume, increased cardiac output, LVH, left ventricular diastolic dysfunction, and adipositas cordis (excessive epicardial fat and fatty infiltration of the myocardium).

ETIOLOGY • The pathophysiology of obesity is complex and poorly understood, but includes social, nutritional, physiologic, psychological, and genetic factors. • Environmental factors such as a sedentary lifestyle and chronic ingestion of excess calories can cause obesity. • Obesity may be related to genetic factors, which are thought to be polygenic. Genetic studies with adopted children have demonstrated that they have similar BMIs to their biologic parents but not their adoptive parents. Twin studies also demonstrate a genetic influence on BMI. • Secondary causes of obesity can result from medications (antipsychotics, steroids, and protease inhibitors being common ones) and neuroendocrine disorders (like Cushing syndrome and hypothyroidism).

DIAGNOSIS • BMI will establish the diagnosis of obesity. BMI is defined as the adult’s weight in kilograms divided by the square of his or her height—and is closely correlated with total body fat content. • BMI values can categorize patients into three classes of obesity: 1. Class I (mild): BMI of 30.0 to 34.9 kg/m2 2. Class II (moderate): BMI of 35.0 to 39.9 kg/m2 3. Class III (severe): BMI of ≥40 kg/m2 • Although BMI is commonly used to define obesity, it is not a highly accurate indicator of body fat composition in children, who are undergoing rapid changes in height, or in bodybuilders or athletes who have large amounts of muscle tissue. • Waist circumference or waist-hip ratio is indicative of visceral adipose tissue/intraabdominal fat, which may be more deleterious than overall overweight or obesity.

ALG DIFFERENTIAL DIAGNOSIS It is important to evaluate obese patients for secondary medical causes of obesity. Hypothalamic disorders, hypothyroidism, Cushing syndrome, insulinoma, depression, and drugs (corticosteroids, antidepressants, second-generation antipsychotics, sulfonylureas, and HIV protease inhibitors) can cause obesity. In children, certain genetic conditions, such as Prader-Willi syndrome, are associated with obesity.

LABORATORY TESTS • Obese patients should be assessed for medical consequences of their obesity by screening for metabolic syndrome. This includes measurement of fasting lipid profile, blood pressure, and waist circumference and screening for diabetes or prediabetes (oral glucose tolerance test, fasting glucose, or hemoglobin A1C). • Polycythemia might warrant screening for sleep apnea. Liver function tests should be obtained to screen for hepatic steatosis. • In the proper clinical setting, thyroid function studies and dexamethasone suppression testing will exclude hypothyroidism and Cushing syndrome as underlying causes of obesity. If insulinoma is suspected, the patient will need to undergo a 72-hr fast to confirm hypoglycemia with inappropriate insulin secretion. • Obesity is associated with changes in the ECG, including a reduction in voltage and nonspecific ST-T changes that may interfere with diagnosis of left ventricular hypertrophy (LVH) or CAD. IMAGING STUDIES • Several methods are available for determining or calculating total body fat but offer no significant advantage over the BMI. These include measurement of total body water, total body potassium, bioelectrical impedance, and dual-energy x-ray absorptiometry. • Buoyancy testing is an accurate method for determining total body fat composition. OTHER STUDIES Obesity increases the risk of obstructive sleep apnea, which, in turn, increases the risks of hypertension, cardiac arrhythmias, CVD, stroke, and heart failure. Therefore, one should have a low threshold to screen obese patients for obstructive sleep apnea via sleep study/polysomnography.

TABLE 1  Weight-Loss Treatment Guidelines from the National Heart, Lung, and Blood Institute*

991

O

BMI Treatment

25.0-26.9

27.0-29.9

30.0-34.9

35.0-39.9

>40.0

Diet, physical activity, behavioral therapy, or all three Pharmacotherapy†

Yes

Yes

Yes

Yes

Yes

In patients with Yes obesity-related diseases

Yes

Yes

Surgery‡

In patients with Yes obesity-related diseases

*Data are from www.nhlbi.nih.gov/science/obesity-nutrition-and-physical-activity. These guidelines are generally consistent with those from the American Heart Association, the American Medical Association, the American Diabetic Association, the Obesity Society (Practical Guide), the American Diabetes Association, the American Academy of Family Physicians, the American College of Sports Medicine, and the American Cancer Society. BMI denotes body mass index, calculated as the weight in kilograms divided by the square of the height in meters. †Pharmacotherapy should be considered only in patients who are not able to achieve adequate weight loss with available conventional lifestyle modifications and who have no absolute contraindications for drug therapy. ‡Bariatric surgery should be considered only in patients who are unable to lose weight with available conventional therapy and who have no absolute contraindications for surgery.

TREATMENT The National Heart, Lung, and Blood Institute (NHLBI) developed guidelines for selecting treatment strategies for overweight and obese patients based on BMI and comorbidities. They recommend a combination of dietary management, physical activity management, and behavior therapy for anyone with a BMI ≥25 or with a high-risk waist circumference and two or more obesity-associated comorbidities. Pharmacotherapy should be considered for patients with a BMI ≥30 or ≥27 with comorbidities. Bariatric surgery is indicated for patients with a BMI ≥35 with comorbidities and for any patient with a BMI ≥40 (Table 1).

NONPHARMACOLOGIC THERAPY • The cornerstones for weight management and reduction are calorie restriction, exercise, and behavioral modification. Assessment of patient’s willingness to make changes must be evaluated, as treatment is more likely to succeed in motivated patients. • The NHLBI guidelines recommend an initial diet to produce a calorie deficit of 500 to 1000 kcal/day. This has been shown to reduce total body weight by an average of 8% over 3 to 12 mo. • These guidelines recommend the use of a food diary to focus on dietary substitutes. • Thirty min of moderate-intensity activity on 5 or more days of the wk results in health benefits for obese individuals. Moreover, several studies indicate that 60 to 80 min of moderate to vigorous physical activity may provide additional benefit. • Increased physical activity without caloric restriction (minimal or no weight loss) can reduce abdominal (visceral) adipose tissue and improve insulin resistance.

• The key features of the standard behavioral modification program include goal setting, self-monitoring, stimulus control (modification of one’s environment to enhance behaviors that will support weight management), cognitive restructuring (increased awareness of perceptions of oneself and one’s weight), and prevention of relapse (weight regain). • Mammalian sleep is closely integrated with the regulation of energy balance. Trials have shown that the amount of human sleep contributes to the maintenance of fat-free body mass at times of decreased energy intake. Lack of sufficient sleep may compromise the efficacy of typical dietary interventions for weight loss and related metabolic risk reduction.

ACUTE GENERAL Rx • According to the NHLBI Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults and the U.S. Food and Drug Administration (FDA), pharmacotherapy is indicated for: 1. Obese patients with a BMI ≥30 2. Overweight patients with a BMI of ≥27 and concomitant obesity-related risk factors or diseases, such as hypertension, diabetes, or dyslipidemia • Pharmacologic treatment options include: 1. Gastrointestinal lipase inhibitors: Orlistat is the only drug available for long-term treatment of obesity. It blocks the digestion and absorption of ingested dietary fat. It is a reversible inhibitor of pancreatic, gastric, and carboxyl ester lipases and phospholipase A2, which are required for the hydrolysis of dietary fat in the gastrointestinal tract. Side effects include flatulence, fecal incontinence, cramps, and oily spotting. There can also be impairment of absorption of fat-soluble vitamins (A, D, E, K) and beta-carotene.

Diseases and Disorders

WORKUP History should be obtained regarding weight change, family history of obesity, and eating and exercise behavior. Assessment for eating disorders and depression should be made. Attention should be directed to the use of nutritional supplements, over-the-counter medications, hormones, diuretics, and laxatives. The workup of an obese patient typically requires laboratory work to assess for risks and complications as well as to rule out underlying causative medical conditions. Fig. E1 describes the evaluation of patients with suspected endocrine cause of obesity.

Obesity

I

992

Obesity











ALG

Oxalate-associated acute kidney injury and rare severe liver injury have also been reported. 2.  C serotonin agonists: Lorcaserin is a selective serotonin agonist that acts centrally to reduce appetite, aiding weight loss. Adverse effects include headache, upper respiratory infections, dizziness, and nausea. While there is little evidence of serotonin-associated cardiac valvular disease or pulmonary hypertension (as seen with nonselective serotonergic agonists fenfluramine and dexfenfluramine), long-term data is currently limited. 3. Sympathomimetic medications: Phentermine and diethylpropion are currently approved for short-term treatment of obesity. They reduce food intake by causing early satiety. Side effects include increased blood pressure and increased pulse. They are Schedule IV drugs with a potential for abuse. Other sympathomimetic drugs that have been removed from the market due to concerns about cardiovascular safety are sibutramine, phenylpropanolamine, and ephedrine. 4. Antidepressants: While not FDAapproved for treatment of obesity alone, bupropion and fluoxetine are antidepressants that have been associated with modest weight loss. The FDA has recently approved a fixed-dose combination of bupropion with the opioid receptor antagonist naltrexone. It is called Contrave and approved for use as an adjunct to diet and exercise in patients with BMI ≥30 kg/m2 or a BMI ≥27 kg/m2 and one or more weight-related comorbidities (e.g., diabetes, hypertension, dyslipidemia). 5. Antiepileptic drugs: Zonisamide and topiramate (also used in migraine therapy) have been associated with weight loss in clinical trials but are not currently FDAapproved for treatment of obesity alone. 6. Diabetes drugs: While not FDA-approved for treatment of obesity alone, metformin, pramlintide (synthetic human amylin), and glucagon-like polypeptide-1 agonists (GLP-1) (exenatide) have been associated with weight loss in the treatment of individuals with diabetes. The GLP-1 receptor agonist liraglutide (Victoza) is now FDA approved at a higher dose as Saxenda for chronic weight management in adults with BMI ≥30 or a BMI ≥27 with a weight-related comorbidity such as hypertension, dyslipidemia, or diabetes.

CHRONIC Rx • According to the NHLBI guidelines, surgical intervention is an option for selected patients with clinically severe obesity (a BMI ≥40 or a BMI ≥35 with comorbid conditions), when patients are at high risk for obesityassociated morbidity or death, and when less invasive methods of weight loss have failed. Box 1 summarizes patient requirements for bariatric surgery.

BOX 1  Patient Requirements for Bariatric Surgery 1. Patients with a BMI of 40 kg/m2 or greater are potential candidates for bariatric surgery. 2. Patients with a BMI of 35 to 40 kg/m2 with significant obesity-related comorbidity are also potential candidates for bariatric surgery. 3. Patients with a history of dieting. 4. Patients with no recent substance abuse. 5. Patients should be evaluated by a multidisciplinary team that includes a dietician and psychologic evaluation before surgery. BMI, Body mass index. From Cameron JL, Cameron AM: Current surgical therapy, ed 12, Philadelphia, 2017, Elsevier.

• Eligible patients should also be at an acceptable risk for surgery, well informed, and motivated. • Restrictive surgeries limit the amount of food the stomach can hold and slow the rate of gastric emptying. These include vertical banded gastroplasty and laparoscopic adjustable silicone gastric banding (LAGB). Band slippage is the most common LAGB complication. Other potential complications include port or tubing malfunction, stomal obstruction, band erosion, pouch dilatation, and port infection. Gastric necrosis of the stomach wall is a rarer late complication that results from ischemia caused by a combination of gastric prolapse—the part of the stomach below the band herniates up through the device —and pressure from the band. Complications of bariatric surgery are summarized in Box 2. • Gastric bypass has better outcomes than gastric band procedures for long-term weight loss, type 2 diabetes control and remission, hypertension, and hyperlipidemia. These procedures have benefits that include lower perioperative mortality rate, a quicker recovery period, and no malabsorption issues. However, they are not as effective as gastric bypass for weight reduction and comorbidity improvement. 1. Malabsorptive surgeries reduce nutrient absorption by shortening the length of small intestine. These include jejunoileal bypass and the duodenal switch operation (DS). 2. Restrictive malabsorptive bypass procedures combine the elements of gastric restriction and selective malabsorption. These include Roux-en-Y gastric bypass (considered the gold standard because of its high level of effectiveness and durability) and biliopancreatic diversion. These procedures have higher rates of comorbidity improvement than restrictive surgeries, but can be complicated by malabsorption and nutritional deficiencies. • Compared with usual care, bariatric surgery is associated with reduced number of cardiovascular deaths and lower incidence of cardiovascular events in obese adults. A study on bariatric surgery patients demonstrated a significant reduction in long-term cardiovascular events. Ten-yr follow-up estimated relative risk reductions

BOX 2  Complications of Bariatric Surgery Complications Common to All Bariatric Procedures Early (Up to 30 Days After Surgery) Venous thromboembolic disease Bleeding Anastomotic leaks Wound infections Persistent nausea/vomiting, dehydration Regional abdominal organ trauma Incisional and internal hernias Bowel obstruction Atelectasis Pneumonia Cardiac dysrhythmias Urinary tract infection Death Late (Beyond 30 Days After Surgery) Incisional and internal hernias Bowel obstruction from adhesions Nutritional deficiencies Anastomotic strictures and marginal ulcers or erosions Cholelithiasis Anemia Persistence or recurrence of obstructive sleep apnea Need for body contouring Regaining weight Procedure-Unique Complications/ Adverse Effects Roux-en-Y Gastric Bypass Dumping syndrome Laparoscopic Adjustable Gastric Banding Band slippage or erosion Port or device malfunction Vertical Sleeve Gastrectomy Refractory reflux Biliopancreatic Diversion Loose, foul-smelling stools Protein-calorie malnutrition From Kryger M et al: Principles and practice of sleep medicine, ed 6, Philadelphia, 2017, Elsevier

ranging from 18% to 79% according to the Framingham risk score, and 8% to 62% with the PROCAM risk score. • A long-term observational study of obese patients with type 2 diabetes showed that bariatric surgery was associated with higher diabetes remission rates and fewer complications than usual care (Sjöström et al., 2014). Remission of type 2 DM occurs in 60% to 80% of patients 2 yr after surgery

Obesity

993

• Data are lacking for the role of pharmacotherapy and bariatric surgery in the elderly population.

O

ALG

DISPOSITION • The incidence of venous thromboembolism in the upper tertile of BMI was 2.42 times that of the lowest BMI tertile. Obese patients have a higher incidence of postoperative thromboembolic events when undergoing noncardiac surgery. • Obesity may be associated with higher rates of postoperative pulmonary complications and poor wound healing. • Weight-stable obese subjects have an increased risk of arrhythmias and sudden death even in the absence of cardiac dysfunction. • Obesity and the cardiac autonomic nervous system are intrinsically related. A 10% increase in body weight is associated with a decline in parasympathetic tone accompanied by a rise in mean heart rate. Conversely, a 10% weight loss in severely obese patients is associated with significant improvement in autonomic nervous system cardiac modulation, including decreased heart rate and increased heart rate variability. • Postmortem Determinants of Atherosclerosis in Youth (PDAY) study data provided convincing evidence that obesity in adolescents and young adults accelerates the progression of atherosclerosis decades before the appearance of clinical manifestations.

• Obesity accelerates the progression of native coronary atherosclerosis and after coronary artery bypass grafting. • In older adults, obesity is associated with protection against hip fracture, but this protective effect on bone status does not offset the extensive array of potential adverse effects on conditions common in the older population.

REFERRAL Obesity is commonly seen in the primary care setting. If pharmacologic therapy is considered, consultation with physicians specializing in obesity and experienced with the use of the drug is recommended. In addition, consultation with nutritionists and behavioral therapists is helpful. A consultation with general surgery is indicated in patients being considered for surgical intervention.

PEARLS & CONSIDERATIONS COMMENTS • Enhanced weight-loss counseling helps about one third of obese patients achieve long-term, clinically meaningful weight loss. Adults can lose 1 to 2 lb (0.45 to 0.9 kg per wk) by consuming 500 to 1000 fewer calories per day. • The NHLBI launched the Obesity Education Initiative in January 1991. The overall purpose of the initiative is to help reduce the prevalence of overweight along with the prevalence of physical inactivity to reduce the risk of CHD and overall morbidity and mortality rates from CHD. • A recent study on BMI and all-cause mortality in a large prospective study suggests that optimal BMI range is between 20 and 24.9 (Patel AV, 2014). • Recent research indicates that brown adipose tissue represents a natural target for the modulation of energy expenditure. The presence of brown adipose tissue in humans may be quantified with the use of 18F-FDG PET-CT. The amount of brown adipose tissue is inversely correlated with BMI, suggesting a potential role of brown adipose tissue in adult human metabolism. • Obesity, glucose intolerance, and hypertension in childhood are strongly associated with increased rates of premature death from endogenous causes in this population. • Recent trials have shown that among persons living in a controlled setting, calories alone account for the increase in fat. Protein affected energy expenditure and storage of lean body mass, but not body fat storage. • There have been no evidence-based studies supporting combination medical therapy for weight loss.

PREVENTION • Prevention of overweight and obesity involves both increasing physical activity and dietary modification to reduce caloric intake. • There is compelling evidence that prevention of weight regain in formerly obese individuals requires 60 to 90 min of moderate-intensity activity or lesser amounts of vigorous intensity activity. • Moderate-intensity activity of approximately 45 to 60 min per day, or 1.7 physical activity level (PAL), is required to prevent the transition to overweight or obesity. For children, even more activity time is recommended. • Clinicians can help guide patients to develop personalized eating plans and help them recognize the contributions of fat, concentrated carbohydrates, and large portion sizes. • Clinicians must work with patients to modify other risk factors such as tobacco use, high glycemic intake, and elevated blood pressure to prevent the long-term chronic disease sequelae of obesity. Generally lower carbohydrate, moderate fat intake, with stable protein and energy intake results in higher energy expenditure during weight-loss maintenance.3 • Regular screening of body weight and BMI measurements at routine office visits can help identify early weight gain. • Among obese adolescents, the most rapid weight gain occurs between 2 and 6 yr of age. Most children who are obese at that age are obese in adolescence.2 PATIENT & FAMILY EDUCATION Information can be obtained on the American Obesity Association website (www.obesity.org) and the American Medical Association website (www.ama-assn.org). SUGGESTED READINGS Available at ExpertConsult.com RELATED CONTENT Obesity, Female (Patient Information) Obesity, Male (Patient Information) Obesity, Child (Patient Information) AUTHOR: Fred F. Ferri, MD

2Geserick

M et al: Acceleration of BMI in early childhood and risk of sustained obesity, N Engl J Med 379:303-312, 2018. 3Ebbeling CB et al: Effects of a low carbohydrate diet on energy expenditure during weight loss maintenance: randomized trial, BMJ 363:k4583, 2018.

Diseases and Disorders

and persists in about 30% of patients 15 yr after Roux-en-Y gastric bypass. • Liposuction is removal of fat by aspiration after injection of physiologic saline. This technique reduces the subcutaneous fat but has failed to improve insulin sensitivity or risk factors for CHD. • The Maestro Rechargeable System is a subcutaneously implanted device recently FDA approved for weight loss in adults with a BMI of 40 to 45 or with a BMI of ≥35 and at least one obesity-related comorbidity. It utilizes high-frequency electrical pulses to block vagus nerve signals between the brain and stomach. It is less effective than bariatric surgery for weight loss. The list price for the Maestro system exceeds $15,000. • The AspireAssist device is FDA approved for weight loss in adults ≥22 yr old with a BMI of 35 to 55. It requires the insertion of a PEG tube endoscopically and pulled through a percutaneous incision. Thirty min after a meal, the patient attaches a connector to it and drains a portion of their stomach content into a toilet. The tube is then flushed with potable water. The connector stops working after 115 cycles (6 wk) and is replaced at a follow-up appointment. Estimated cost for procedure and follow-ups are $13,000 for the first yr.

I

Obesity SUGGESTED READINGS Arterburn D et al: Comparative effectiveness and safety of bariatric procedures for weight loss, Ann Int Med 169:741-760, 2018. Bray GA et al: Effect of dietary protein content on weight gain, energy expenditure, and body composition during overeating, JAMA 307(1):47-55, 2012. Casazza K et al: Myths, presumptions, and facts about obesity, N Engl J Med 368:446-454, 2013. DeMaria EJ: Bariatric surgery for morbidly obese, N Engl J Med 356:2176, 2008. deShazo RD et al: Obesity bias, medical technology, and the hormonal hypothesis: should we stop demonizing fat people? Am J Med 128:456-460, 2015. Erlandson M et  al: Update on office-based strategies for the management of obesity, Am Fam Physician 94(5):361-368, 2016. Franks PW et al: Childhood obesity, other cardiovascular risk factors, and premature death, N Engl J Med 362:485-493, 2010. Heymsfield SB et al: Mechanisms, pathophysiology, and management of obesity, N Engl J Med 376:254-266, 2017. James WPT et al: Effect of sibutramine on cardiovascular outcomes in overweight and obese subjects, N Engl J Med 363:905-917, 2010. Juonala M et al: Childhood adiposity, adult adiposity, and cardiovascular risk factors, N Engl J Med 365:1876-1885, 2011. King WC et al: Change in pain and physical function following bariatric surgery for severe obesity, JAMA 315(13):1362-1371, 2016. Kodner C, Hartman DR: Complications of adjustable gastric banding surgery for obesity, Am Fam Physician 89(10):813-818, 2014. Kumar S, Kelly AS: Review of childhood obesity: from epidemiology, etiology, and comorbidities to clinical assessment and treatment, Mayo Clin Proc 92(2):251265, 2017. Maggard-Gibbons M et al: Bariatric surgery for weight loss and glycemic control in nonmorbidly obese adults with diabetes, JAMA 309(21):2250-2261, 2013. Moyer VA et  al: Screening for and management of obesity in adults: U.S. Preventive Services Task Force recommendation statement, Ann Intern Med 157:373-378, 2012. Nedeltcheva AV et al: Insufficient sleep undermines dietary efforts to reduce adiposity, Ann Intern Med 153:435-441, 2010. O’Brien PE et al: Laparoscopic adjustable gastric binding in severely obese adolescents, JAMA 303(6):519-526, 2010. Puzziferri N et al: Long-term follow-up after bariatric surgery: a systematic review, JAMA 312(9):934-942, 2014. Rao G: Office-based strategies for the management of obesity, Am Fam Physician 81:11449-11455, 2010. Schauer PR et al: Bariatric surgery versus intensive medical therapy in obese patients with diabetes, N Engl J Med 366:1567-1576, 2012. Schroeder R et  al: Treatment of adult obesity with bariatric surgery, Am Fam Physician 93(1):31-37, 2016. Shikora SA et al: Sustained weight loss with vagal nerve blockade but not with sham: 18-month results of the ReCharge Trial, J Obes 365604, 2015. Sjöström L et al: Bariatric surgery and long-term cardiovascular events, JAMA 307(1):56-65, 2012. The NS et al: Association of adolescent obesity with risk of severe obesity in adulthood, JAMA 304(18):2042-2047, 2010. Wadden TA et al: A two-year randomized trial of obesity treatment in primary care practice, N Engl J Med 365:1969-1979, 2011.

993.e1

Obesity

993.e2

Obesity

Specific endocrine diseases

Menstrual or reproductive disorders

Miscellaneous

Weight gain or inability to lose weight

History—clinical examination—initial screening tests OGTT, FBS, HbA1C Lipid profile Serum urate

LH, FSH, testosterone SHBG, prolactin

Suspected Cushing syndrome

Suspected pituitary/ thyroid dysfunction

24-hour UFC Diurnal plasma Cortisol Dexamethasone suppression

TSH Day plasma cortisols GnRH test Pituitary imaging

Cushing syndrome

Plasma ACTH CRF test Adrenal/pituitary imaging Petrosal sampling

Hypopituitarism

Ovarian failure

Karyotype laparoscopy

Polycystic ovary syndrome

Pelvic ultrasound

Normal

Diabetes mellitus Hyperlipidemia Gout

Calorimetry double-labeled water

FIG. E1  Endocrine evaluation of obesity. ACTH, Adrenocorticotropic hormone; CRF, corticotropin-releasing factor; FBS, fasting blood sugar; FSH, follicle-stimulating hormone; GnRH, gonadotropin-releasing hormone; HbA1C, glycohemoglobin; LH, luteinizing hormone; OGTT, oral glucose tolerance test; SHBG, sex hormone-binding globulin; TSH, thyroid-stimulating hormone; UFC, urinary free cortisol. (Modified and updated from Besser CM, Thorner MO: Comprehensive clinical endocrinology, ed 3, St Louis, 2002, Mosby.)

994

Obesity-Hypoventilation Syndrome BASIC INFORMATION DEFINITION The obesity-hypoventilation syndrome (OHS), also known as Pickwickian syndrome, is conventionally defined as a combination of obesity (body mass index [BMI] ≥30 kg/m2) and daytime hypercapnia (PaCO2 ≥45 mm Hg in arterial blood gas analysis) in the absence of other causes for hypoventilation. This syndrome is often accompanied by obstructive sleep apnea (apnea-hypopnea index [AHI] ≥5 events/hour) or nonobstructive sleep hypoventilation (AHI 55 mm of Hg for more than 10 min or an increase in the PaCO2 >10 mm of Hg compared with daytime PaCO2, to a value >50 mm of Hg for >10 min during sleep). The hypercapnia stems from low tidal volumes and from inappropriate central respiratory response to hypoxemia and elevated PCO2 levels. SYNONYMS Pickwickian syndrome OHS Extreme obesity with alveolar hypoventilation Obesity alveolar hypoventilation syndrome ICD-10CM CODE E66.2 Obesity hypoventilation syndrome (OHS)

EPIDEMIOLOGY & DEMOGRAPHICS PREVALENCE: The worldwide prevalence of obesity more than doubled in the last 30 yr and has become a global epidemic. In 2014, the World Health Organization estimated that more than 600 million adults were obese. A Centers for Disease Control report in 2015 estimated the prevalence of obesity among U.S. adults during 2011 to 2014 at 36.5%. The obesity epidemic is likely to increase the prevalence of myriad complications such as OHS. The prevalence of OHS in the general population is estimated to be 0.6%, and 8% to 20% in patients evaluated for sleep breathing disorders at sleep clinic centers. PREDOMINANT SEX & AGE: Male gender and 50 to 60 yr of age RISK FACTORS: • Male gender • 50 to 60 yr of age • Morbidly obese (BMI ≥40 kg/m2) • Severe OSA (≥30 obstructive respiratory events/hour of sleep) • Increased waist-hip ratio • Neck circumference >45 cm PHYSICAL FINDINGS & CLINICAL PRESENTATION Most of the OHS symptoms are similar to OSA: • Excessive daytime somnolence • Fatigue • Disorientation • Loss of concentration • Change in mood • Amnesia

ALG

• Morning headache Symptoms and signs most common in OHS compared with OSA: • Injected sclera (probably related to high PCO2 leading to cerebral vasodilation) • Anasarca, dyspnea on exertion, signs of circulatory congestion, and cor pulmonale on cardiac and hepatic exam

ETIOLOGY • Etiology of hypoventilation in obese patients depends on many factors. • Three hypotheses for chronic hypoventilation are widely accepted (Fig. E1): the increase in mechanical load on respiratory muscles from obesity; leptin resistance inhibiting central respiratory drive causing worsening hypoventilation; and decreased response to elevated PCO2 levels in OSA. • Often subclinical OHS becomes clinical with external triggers such as sedative medications, overdiuresis, and other systemic disease.

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • Anemia • Heart failure with excessive diuresis • Liver failure • Stroke • Central sleep apnea • OSA • Circadian rhythm disorder • Drug or alcohol abuse • Depression • Hypothyroidism • Sedative medication • Metabolic abnormalities (e.g., hypo- or hypernatremia, hypercalcemia) • Neuromuscular disease

• Pulmonary and lung disease • Restless legs syndrome

WORKUP • Detailed history and physical examination are helpful to identify patients who are at high risk for OHS. Fig. 2 illustrates a decision tree to screen for obesity-hypoventilation syndrome. Diagnostic features of obesityhypoventilation syndrome are summarized in Box E1. Physiologic differences between eucapnic morbidly obese patients and those with obesity-hypoventilation syndrome are summarized in Box 2. • Screen for OHS in men or women with BMI ≥30 or with sleep breathing disorder. • The Epworth Sleepiness Scale (ESS) and the Stanford Sleepiness Scale (SSS) are the most commonly used scales for daytime sleepiness. • If OSA is suspected, screen with STOP-BANG questionnaire (snoring, tiredness, observed apnea, blood pressure, BMI, age >50, neck circumference >16 inches, and gender). • Overnight polysomnography to confirm whether AHI >5. • Assess daytime oxygen saturation (SpO2) levels to assess blood oxygenation level and serum bicarbonate level to assess carbon dioxide retention. • If SpO2 27 mEq/L, and BMI >30 with underlying sleep breathing disorder, consider obtaining an arterial blood gas to diagnose OHS. • Consider forced vital capacity (FVC) and negative inspiratory force (NIF) if any suspicion of neuromuscular disease. • ECG and echocardiogram are helpful to assess structural changes of the heart and pulmonary hypertension.

OSA and BMI 30 kg/m2 (n = 522)

Serum HCO3– 27 mEq/L (n = 257) 50% with OHS

Lowest SpO2 during sleep >60% or AHI 60% or AHI >100 (n = 79) 76% with OHS

FIG. 2  Decision tree to screen for obesity-hypoventilation syndrome (OHS) based on observation in 522 obese patients with OSA (BMI ≥30 kg/m2 and AHI ≥5). Among those with a venous serum bicarbonate level above 27 mEq/L, OHS was present in 50% of patients. Very severe OSA (AHI >100 events/ hour or SpO2 nadir during sleep 27 mEq/L) can be used as a great screening tool for OHS in an appropriate clinical setting. In a patient with normal kidney function, respiratory acidosis from OHS is usually compensated by retaining serum bicarbonate. • Several studies showed serum bicarbonate level 27 mEq/L from capillary blood gas Sleep Breathing Disorder Obstructive sleep apnea (apnea-hypopnea index [AHI] ≥5 events/hour) Nonobstructive sleep hypoventilation (AHI 50 mm Hg for >10 min during sleep, or sustained hypoxemia with oxygen saturation ≤88% without obstructive respiratory events) Exclusion of Other Causes of Hypoventilation Severe obstructive airways disease (e.g., chronic obstructive pulmonary disease) Severe interstitial lung disease Severe chest wall disorders (e.g., kyphoscoliosis) Severe hypothyroidism Neuromuscular disease Congenital hypoventilation syndromes PaCO2, Partial pressure of carbon dioxide in arterial blood; PCO2, partial pressure of carbon dioxide. From Kryger M et al: Principles and practice of sleep medicine, ed 6, Philadelphia, 2017, Elsevier.

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Obsessive-Compulsive Disorder (OCD) BASIC INFORMATION DEFINITION Obsessive-compulsive disorder (OCD) is characterized by obsessions (recurrent and persistent thoughts, urges, or images experienced as intrusive and unwanted) and/or compulsions (repetitive behaviors or mental acts performed in response to obsessions, or according to rules that must be applied rigidly) that are time-consuming (e.g., >1 hr/day) or cause marked impairment or distress. The symptoms are usually, but not always, perceived as excessive and unreasonable. SYNONYM OCD ICD-10CM CODES F42 Obsessive-compulsive disorder F60.5 Obsessive-compulsive personality disorder DSM-5 CODES 300.3 Obsessive-compulsive disorder 301.4 Obsessive-compulsive personality disorder

EPIDEMIOLOGY & DEMOGRAPHICS PEAK INCIDENCE: Mean age at onset is 19.5 yr. 12-MO PREVALENCE: 1.2% of adults in the U.S., international prevalence estimates are similar (1.1% to 1.8%). PREDOMINANT SEX: Slightly more common among females than males in adulthood, although males are more commonly affected in childhood. PREDOMINANT AGE: • Modal age of onset for females is between 20 and 29 yr. • Modal age of onset for males is between 6 and 15 yr. DISEASE COURSE: • Condition is chronic with waxing and waning pattern. • Symptoms typically worsen with stress. • 15% show progressive deterioration, whereas 5% show an episodic course with little impairment between episodes. GENETICS: • OCD is a multifactorial familial condition that involves both polygenic and environmental risk factors. • Rate of concordance is higher in monozygotic (57%) compared with dizygotic (27%) twins. • Rate of disorder is also much higher in firstdegree relatives of individuals with OCD and Tourette disorder (8.2%) than in the general population (2%). PHYSICAL FINDINGS & CLINICAL PRESENTATION • Persistent and recurrent intrusive and egodystonic obsessive ideas, thoughts, urges, or images that are perceived as alien and beyond one’s control. • Frequent experiencing of obsessions related to contamination (e.g., when using the telephone),

excessive doubt (e.g., was the door locked?), organization (the need for a particular order), violent impulses (e.g., to yell obscenities in church), or intrusive sexual imagery. • Compulsive behaviors (e.g., repeated hand washing, checking, rearranging) or mental rituals (e.g., counting, repeating phrases) meant to temporarily ameliorate anxiety caused by obsessions. • Obsessions and compulsions are almost always accompanied by high anxiety and subjective distress. Both are usually, but not always, seen as excessive and unreasonable.

ETIOLOGY • Strong evidence of cortico-striato-thalamocortical circuit dysfunction. • OCD onset may be temporally associated with infectious illness of CNS (e.g., Von Economo encephalitis, Sydenham chorea). • A condition called Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS) usually involves children under age 12. It is diagnosed when OCD and/or tic disorders suddenly appear following a streptococcal infection (e.g., strep throat or scarlet fever) or symptoms of OCD or tic symptoms worsen after a strep infection. • OCD may follow head trauma or other premorbid neurologic condition, including birth hypoxia and Tourette syndrome. • Intrusive, obsessive thinking may be part of the picture in patients with complex partial seizures. • Serotonergic, dopaminergic, and glutamatergic systems believed important in some ritualistic instinctual behaviors, with dysfunction of these pathways possibly giving rise to OCD.

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • Obsessive-compulsive personality disorder (OCPD) is a maladaptive personality style defined by excessive rigidity, need for order and control, preoccupation with details, and excessive perfectionism. Unlike OCD, OCPD is ego-syntonic. • Other psychiatric disorders in which obsessive or intrusive thoughts occur (e.g., body dysmorphic disorder, eating disorders, hypochondriasis, phobias, posttraumatic stress disorder). • Impulse control disorders (e.g., trichotillomania [hair-pulling disorder], excoriation [skin-picking] disorder, pathologic gambling disorder, compulsive shopping, kleptomania, paraphilias/sexual compulsions). • Neurologic disorders with repetitive behaviors (e.g., Tourette syndrome, Sydenham chorea, torticollis, autism). • Delusions or psychosis, which may be mistaken for obsessive thoughts; unlike OCD, these individuals do not believe their obsessions are unreal and may likely meet criteria for another psychotic spectrum disorder that fully accounts for the obsessions (e.g., schizophrenia).

WORKUP • Careful history leading to diagnosis • In adolescents and children: Psychological testing to reveal learning disabilities • Screen for presence of past or current tic disorder, and ascertain degree of insight (good or fair, poor, absent/delusional) into OCD beliefs

TREATMENT NONPHARMACOLOGIC THERAPY • Cognitive-behavioral therapy (CBT), comprising exposure/response prevention with or without cognitive reappraisal, is successful in up to 70% of patients. Best results are found for contamination obsessions and washing compulsions. • Barriers to CBT include lack of availability/access, intense time requirements, and patient motivation to engage in treatment (e.g., anxiety resulting from exposure exercises). ACUTE GENERAL Rx • Antidepressants with serotonin reuptake blockade, including clomipramine, fluvoxamine, fluoxetine, paroxetine, sertraline, citalopram, and escitalopram; optimal dosages are typically at the high end of the prescription range. Risk/benefit/alternatives discussion is crucial (e.g., dose-related risk of QT interval prolongation with serotonin reuptake inhibitors in general and clomipramine, citalopram, and escitalopram in particular). • Benzodiazepines (e.g., clonazepam) have limited efficacy in OCD. • Most experience some symptom relief with treatment, but even after adequate treatment trials, 40% to 60% of patients endorse significant residual symptoms. • Likely indefinite treatment. Relapse is common if medications are discontinued. • Recent studies suggest that combination CBT and pharmacotherapy yields superior outcomes. More severe symptoms warrant combination therapy. • Patients who do not respond to first-line treatments and those with comorbid psychosis and/or tic disorders may benefit from augmentation with a first- or second-generation antipsychotic medication (e.g., haloperidol, olanzapine, risperidone). • Neurosurgical intervention (e.g., cingulotomy, deep brain stimulation) is reserved for the most severely symptomatic and treatmentresistant cases. DISPOSITION • Most mild to moderate cases can be managed on a regular outpatient basis. Treatment should typically start with SSRI monotherapy with regular follow-up to assess treatment response and side-effect management. Dose should be increased to maximum tolerated. • Patient and family education may help improve medical adherence and support.

Obsessive-Compulsive Disorder (OCD)  EARLS & P CONSIDERATIONS Patients with OCD typically have insight regarding the irrationality of their obsessions and compulsions but lack the ability to control them. This may cause intense shame and avoidance of medical care unless patient education and

support are provided. Screen for OCD, especially among patients who present with “depression” or “anxiety.”

995.e3 RELATED CONTENT Obsessive-Compulsive Disorder (OCD) (Patient Information) AUTHOR: Agustin G. Yip, MD, PhD

SUGGESTED READINGS Available at ExpertConsult.com

SUGGESTED READINGS Gillan CM et al: A trans-diagnostic perspective on obsessive-compulsive disorder, Psychol Med 47:1528, 2017. Hirschtritt ME et  al: Obsessive-compulsive disorder: advances in diagnosis and treatment, JAMA 317:1538, 2017. Skapinakis P et  al: Pharmacological and psychotherapeutic interventions for management of obsessive-compulsive disorder in adults: a systematic review and network meta-analysis, Lancet Psychiatry 3:730, 2016.

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Ocular Foreign Body BASIC INFORMATION DEFINITION The term ocular foreign body refers to a foreign body on the surface of the corneal or conjunctival epithelium. ICD-10CM CODES T15 Foreign body on external eye T15.0 Foreign body in cornea T15.1 Foreign body in conjunctival sac T15.8 Foreign body in other and multiple parts of external eye T15.9 Foreign body on external eye, part unspecified

EPIDEMIOLOGY & DEMOGRAPHICS INCIDENCE (IN U.S.): Universal, with a predominance in active people. Common with industrial jobs and activities such as metal work, landscaping, and woodworking. PREDOMINANT SEX: Perhaps slightly more common in men PREDOMINANT AGE: Childhood through active adult yrs PEAK INCIDENCE: Childhood through active adult yrs PHYSICAL FINDINGS & CLINICAL PRESENTATION • Pain with foreign body sensation is the most common symptom. • Sudden onset: Patient may pinpoint the exact moment it occurred. • Causes of most common foreign bodies: 1. Grinding 2. Drilling 3. Auto repair 4. Airborne particles, such as blown by fans

• Fig. E1 illustrates various ocular foreign bodies.

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • History of corneal foreign body seen (small, white, superficial ring scars on cornea) • Hemorrhage, loss of vision (with perforation of the globe) • Distorted anterior chamber, soft eye • Corneal abrasion • Corneal ulceration (infection, bacterial or viral keratitis) or laceration • Other keratitis • Intraocular foreign body WORKUP • Fluorescein stain, slit-lamp examination if no foreign body is found • Ultrasound examination • Plain radiographs LABORATORY TESTS Intraocular pressure to make certain that eye has not been penetrated IMAGING STUDIES Occasionally, MRI of the orbits to identify foreign bodies not found by other means. Do not perform MRI if suspect metallic foreign body. Plain radiographs and ultrasound are sufficient.

TREATMENT NONPHARMACOLOGIC THERAPY • Remove foreign body • Treat infection • Repair eye if ruptured • Treat corneal abrasion or injury

ACUTE GENERAL Rx • Saline irrigation • Removal of foreign body with moist cottontipped applicator after instillation of topical anesthetic drops • Use burr or more aggressive treatment if needed (often needed for deeper “rust ring” after metallic foreign body) • Cycloplegics, antibiotics, and pressure dressing after removal of foreign body • Repair corneal laceration or perforated eye (refer urgently to ophthalmologist) DISPOSITION If symptoms persist 24 hr after examination, refer to an ophthalmologist. REFERRAL To ophthalmology within 24 hr if patient not completely comfortable

PEARLS & CONSIDERATIONS COMMENTS • Make sure foreign body is not intraocular (inside eye). • Alkaline or acidic chemical foreign bodies can be dangerous; pH test must be performed if either of these is suspected (for all chemical foreign bodies). RELATED CONTENT Corneal Foreign Body (Patient Information) AUTHOR: R. Scott Hoffman, MD

Ocular Foreign Body

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A

B

C

D

FIG. E1  Superficial foreign bodies. A, Retained subtarsal foreign body. B, Barbed insect leg embedded in the subtarsal conjunctiva. C, Recently embedded foreign body with mild surrounding cellular infiltration. D, Rust ring after removal of metallic foreign body. (From Bowling B: Kanski’s clinical ophthalmology, a systemic approach, ed 8, Philadelphia, 2016, Elsevier.)

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Opioid Overdose BASIC INFORMATION DEFINITION Excessive use of an opioid, either derived from the opium poppy or semi- or fully synthetic, resulting in respiratory depression, central nervous system depression, and/or death SYNONYMS Opiate overdose Heroin overdose Narcotic overdose Opioid poisoning ICD-10CM CODES T40.0X1 Poisoning by opium, accidental (unintentional) T40.0X2 Poisoning by opium, intentional self-harm T40.0X3 Poisoning by opium, assault T40.0X4 Poisoning by opium, undetermined T40.0X5 Adverse effect of opium T40.1X Poisoning by heroin T40.4 Poisoning by other synthetic narcotics

EPIDEMIOLOGY & DEMOGRAPHICS INCIDENCE: Drug overdose deaths and opioidinvolved deaths continue to increase in the U.S. The majority of drug overdose deaths (more than six out of ten) involve an opioid. 91 Americans die every day from an opioid overdose. PREVALENCE: From 1999 to 2017 more than 700,000 U.S. residents died from drug overdoses. From 2013 to 2017, the number of opioid-involved overdose deaths (opioid deaths) in the U.S. increased 90% from 25,052 to 47,600. This increase was primarily driven by substantial increases in deaths involving illicitly manufactured fentanyl (IMF) or fentanyl analogs mixed with heroin, sold as heroin, or pressed into counterfeit prescription pills. PREDOMINANT SEX AND AGE: The “typical” heroin death involves experienced users in their 20s to 30s using coingestants, with a male predilection. RISK FACTORS: The majority of drug-overdose deaths are unintentional or accidental (74%). The following increase risk for opioid overdose: • Opioid dependence, in particular ­following reduced tolerance (following ­ detoxification, release from incarceration, cessation of treatment) • Injecting opioids • Using prescription opioids, in particular taking higher doses • Using opioids in combination with other sedating substances • Using opioids and having comorbidities such as HIV, liver or lung disease, or suffering from depression • Household members of people in possession of opioids (including prescription opioids) The highest drug-induced mortality is associated with the following factors: 40 to 49 yr of age, male gender, non-Hispanic whites, and living in

the South, all of which account for approximately 38.2% of drug-induced deaths in the U.S.

PHYSICAL FINDINGS & CLINICAL PRESENTATION Patients with opioid overdose classically present with the triad of altered mental status, pinpoint pupils, and respiratory depression. Patients may be apneic or with low respiratory rate and tidal volumes. Respiratory depression becomes profound enough to cause anoxia, leading to death. Little to no response will be elicited from painful stimuli. Look for clinical clues, such as “track marks” or darkening along the length of veins from injection drug use that may suggest opioid overdose. The use of coingestants, which is exceedingly common in opioid overdose, can alter the classic exam findings one may expect. For example, use of sympathomimetics like cocaine can cause pupillary dilation. Respiratory rate 1 yr 2. Two failed previous treatment attempts 3. Patients not appropriate for office-based treatment 4. Eligible without active “use” if prior methadone maintenance patient within previous 2 mo 5. Pregnancy

TABLE 5  Organizations Providing Referral Information for Patients

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Opioid Use Disorder SUGGESTED READINGS Babu KM et al: Prevention of opioid overdose, N Engl J Med 380(23):2246-2255, 2019. Ballantyne JC et al: Opioid dependence vs addiction: a distinction without a difference? Arch Intern Med 172:1342-1343, 2012. Bowman S: Reducing the health consequences of opioid addiction in primary care, Am J Med 126:565-571, 2013. Bruneau J et al: Management of opioid use disorders: a national clinical practice guideline, CMAJ 190:E247-E257, 2018. Chou R et al: Rethinking opioid dose tapering, prescription opioid dependence, and indications for buprenorphine, Ann Intern Med 171(6):427-429, 2019. Coffin PO: Nonrandomized intervention study of naloxone coprescription for primary care patients receiving long-term opioid therapy for pain, Ann Intern Med 165:245-252, 2016. Compton WM: Relationship between nonmedical prescription-opioid use and heroin use, N Engl J Med 374:154-163, 2016. Dunlap B, Cifu AS: Clinical management of opioid use disorder, JAMA 316(3):338339, 2016. Frank JW et  al: Patient outcomes in dose reduction or discontinuation of longterm opioid therapy, Ann Intern Med 167:181-191, 2017. Gladden RM: Fentanyl law enforcement submissions and increases in synthetic opioid-involved overdose deaths—27 states, 2013-2014, MMWR Morb Mortal Wkly Rep 65:837-843, 2016.

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Han B et al: Prescription opioid use, misuse, and use disorders in U.S. adults: 2015 National Survey on drug use and health, Ann Intern Med 167:293301, 2017. Krupitsky E: Injectable extended-release naltrexone for opioid dependence: a double-blind, placebo-controlled, multicenter randomized trial, Lancet 377:1506-1513, 2011. Larochelle MR: Medications for opioid use disorder after nonfatal opioid overdose and association with mortality, Ann Int Med 169:137-145, 2018. Martin SA: The next stage of buprenorphine care for opioid use disorder, Ann Intern Med 169:628–635, 2018. Murphy SM: Cost-effectiveness of buprenorphine-naloxone versus extendedrelease naltrexone to prevent opioid relapse, Ann Int Med 170:90-98, 2019. Pace CA: Samet JH: In the clinic: substance use disorders, Ann Intern Med 164(7):ITC49-ITC64, 2016. Shapiro B: A primary care approach to substance misuse, Am Fam Physician 88(2):113-121, 2013. Volkow ND: Neurobiologic advances from the brain disease model of addiction, N Engl J Med 374:363-371, 2016. Volkow ND, McLellan AT: Opioid abuse in chronic pain misconceptions and mitigation strategies, N Engl J Med 374:1253-1263, 2016. Von Korff M, et  al: Long-term opioid therapy reconsidered, Ann Intern Med 155:325-328, 2011.

TABLE E6  Recommendations for Integrating Risk Reduction Strategies for Addressing Opioid Misuse in the Primary Care Setting Risk Reduction Tools

Type of Client

Delivery Recommendations

Brief substance abuse screening

All clients, particularly those individuals prescribed opioid medications or with a history of substance abuse problems Clients who have identified opioid use or abuse

Administer CAGE-AID* or similar screening tool as part of routine treatment.

Motivational interviewing Comprehensive tools for safer injections, including safer injection education Naloxone prescription and distribution Buprenorphine prescription

Clients who have reported or are suspected of injection drug use; tools should be available to all patients, not just those identified as drug users. Targeting individuals using illicit or prescribed opioids, including individuals prescribed opioids Targeting individuals using illicit or prescribed opioids, seeking medication assisted treatment

Standard procedure may be delivered by primary care provider or other clinic staff. Resources including educational materials, syringes, alcohol wipes, etc. distributed and discussed by the primary care provider or other clinic staff. Discussion, prescription of naloxone by the primary care provider; additional education may be delivered by other clinic staff. Discussion and prescription by the primary care provider

*For a full definition of CAGE-AID, see Table 1. From Bowman S et al: Reducing the health consequences of opioid addiction in primary care, Am J Med 126, 565-571, 2013.

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Oppositional Defiant Disorder (ODD) BASIC INFORMATION DEFINITION Oppositional defiant disorder (ODD) is an ongoing pattern of angry/irritable mood, argumentative/defiant behavior, or vindictiveness, that is not developmentally appropriate, lasts more than 6 mo, and leads to impairment in social, academic, or occupational functioning for a child or adolescent. SYNONYM ODD ICD-10CM CODE F91.3 Oppositional defiant disorder DSM-5 CODE 313.81 Oppositional defiant disorder

EPIDEMIOLOGY & DEMOGRAPHICS PEAK INCIDENCE: Usually diagnosed in schoolaged children (roughly ages 6-12) PREVALENCE: Ranges from 1% to 16% based on source (community prevalence) PREDOMINANT SEX AND AGE: • Males more than females • Highest diagnosis in prepubertal children • Usually present by age 8 GENETICS: Some evidence for genetic factors, but studies are not usually specific to ODD (e.g., studies also include conduct disorder or more generally refer to aggressive or delinquent behaviors) and include potential confounding factors (e.g., difficult to distinguish between genetic and environmental contribution) RISK FACTORS: • Male gender, low socioeconomic status • The following risk factors have been identified more generally for development of disruptive behavior disorders or aggression: 1.  Family history (especially parental) of aggressive or criminal behaviors 2.  Parental substance abuse (e.g., fetal alcohol syndrome) 3. Prenatal or early childhood exposure to toxins (e.g., lead) 4. Perinatal complications 5. Head injuries 6. Cognitive impairment 7. Learning disabilities 8. History of abuse or witnessed domestic violence 9. Overall family instability PHYSICAL FINDINGS & CLINICAL PRESENTATION DSM-5 criteria are met when there is a pattern of angry/irritable mood, argumentative/defiant behavior, or vindictiveness for at least 6 mo, and four or more symptoms from any category are present • Angry/irritable mood: 1. Often loses temper 2. Is touchy or easily annoyed 3. Is often angry and resentful

• Argumentative/defiant behavior: 1. Often argues with adults 2. Often actively defies or refuses to comply with requests from authority figures or with rules 3. Often deliberately annoys others 4. Often blames others for his or her mistakes/misbehavior • Vindictiveness: 1. Has been spiteful/vindictive at least twice within the past 6 mo Symptoms are associated with distress in the individual or others, or they negatively impact social, educational, occupational, or other important areas of functioning. Symptoms may not occur only during the course of a psychotic, mood, or substance use disorder. Also, criterion must not be met for disruptive mood dysregulation disorder and, if 18 yr or older, for antisocial personality disorder. Symptoms are classified in terms of severity based on whether they are confined to only one setting, e.g., at home or at school (mild), to at least two settings (moderate), and three or more settings (severe). Finally, the DSM-5 specifies that symptoms may not occur only in the context of a sibling relationship.

ETIOLOGY Multiple hypothetical models have been developed for disruptive behavior disorders and antisocial behaviors in general, including a few focused specifically on ODD that address the complex interaction between various predisposing and protective factors. These models identify some biologic factors (including genetic, structural, toxin exposure, etc.), some child functional factors (including cognitive, social, and neuropsychological deficits), and broad psychosocial factors that focus on parenting styles (including history of physical abuse), peer involvement, and other environmental factors.

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • Child abuse or neglect • Learning disorder or other deficits in executive functioning • Intellectual disability (intellectual developmental disorder) • Communication disorders (including language disorder, speech sound disorder, childhood-onset fluency disorder, and social communication disorder) • Attention deficit hyperactivity disorder • Intermittent explosive disorder • Conduct disorder • Antisocial personality disorder • Mood disorder (bipolar disorder or depression) • Psychotic disorders • Substance use disorders • Parent-child relational problem WORKUP Diagnosis is made based on history, including individual and family interviews as well as

c­ ollateral data from additional sources (parents, teachers, other medical providers, therapist, etc).

LABORATORY TESTS None indicated IMAGING STUDIES None indicated

TREATMENT Initial treatment of ODD should include psychosocial interventions aimed at changing the maladaptive patterns of interaction between the child or adolescent and his or her family and environment. If the interventions listed here are not effective, or if serious concerns exist regarding safety or impairment in functioning, pharmacologic interventions targeting specific symptoms (such as aggression) or comorbid disorders (such as ADHD, anxiety disorders, or mood disorders) may help. There are currently no medications approved by the FDA for the treatment of ODD.

NONPHARMACOLOGIC THERAPY • Parent management training • Cognitive problem-solving skills training • Social skills training • Individual psychotherapy • Family psychotherapy ACUTE GENERAL Rx • Medication may be considered as an adjunct to behavioral treatment or in cases where comorbidity is a factor. There is some evidence for symptom improvement with trials of stimulants, mood stabilizers, or atypical antipsychotics, but medication should never be used alone or as first-line treatment for ODD. • Higher levels of care such as a hospital or acute residential setting may be required for stabilization if acute safety concerns develop in the context of ODD, such as severe aggression. COMPLEMENTARY & ALTERNATIVE MEDICINE No evidence-based treatments are available. DISPOSITION • Most patients with ODD can be managed in an outpatient setting with either standard or intensive, home-based support; treatment should always be provided in the least restrictive setting possible. • Hospitalization is sometimes necessary for crisis management only; consideration of different levels of care, including day treatment, therapeutic school settings, or residential facilities, may be appropriate for more severe cases or in situations where the family is not willing or able to participate adequately in the outpatient regimen. REFERRAL Consider referral to a mental health provider specializing in the treatment of children, adolescents, and families (including potentially a

Oppositional Defiant Disorder (ODD) child and adolescent psychiatrist) if the patient and family are not responding to basic parenting interventions or are demonstrating significant safety concerns or other evidence of impairment in functioning at home, in school, or in the community.

PEARLS & CONSIDERATIONS COMMENTS • Involvement of the family and school is crucial in the management of patients with this disorder. • Polypharmacy (the prescribing of multiple medications simultaneously) to target the more complicated symptoms of this disorder should be implemented with great caution and only after discrete trials of therapeutic interventions and single medication agents have failed. • Standardized assessment tools used to identify ADHD, disruptive behavior disorders, and

general child and adolescent psychopathology may be helpful in confirming the diagnosis of ODD and/or monitoring progress throughout treatment. • ODD symptoms are independently associated with increased externalizing symptoms, internalizing symptoms, delinquent behaviors, and social and academic functioning. • One-time, intensive interventions are not considered effective treatment options (including boot camps, shock incarceration) and may carry additional risks. • When ODD coexists with attention deficit hyperactivity disorder, stimulant therapy can reduce the symptoms of both disorders.

PREVENTION Most effective prevention strategies include both individualized treatment and universal interventions that incorporate a parent-directed component as one of the primary elements. They also may incorporate social-cognitive skills training, academic skills training, ­proactive classroom

SUGGESTED READINGS Carliner H et  al: Trauma exposure and externalizing disorders in adolescents: results from the National Comorbidity Survey Adolescent Supplement, J Am Acad Child Adolesc Psychiatry 56(9):755-764, 2017. Noordermeer SD et  al: A systematic review and meta-analysis of neuroimaging in oppositional defiant disorder (ODD) and conduct disorder (CD) taking attention-deficit hyperactivity disorder (ADHD) into account, Neuropsychol Rev 26:44, 2016. Ghosh A et al: Oppositional defiant disorder: current insight, Psychol Res Behav Manag 10:353-367, 2017. Leadbeater BJ et  al: The longitudinal effects of oppositional defiant disorder symptoms on academic and occupational functioning in the transition to young adulthood, J Abnorm Child Psychol 45(4):749-763, 2017.

999.e3 management and teacher training, and group therapy. These may take place in schools, clinics, and other community-based settings in addition to targeted clinical work.

PATIENT & FAMILY EDUCATION ODD: A Guide for Families by the American Academy of Child and Adolescent Psychiatry (www.aacap.org/AACAP/Families_and_Youth/ Resource_Centers/Oppositional_Defiant_Dis order_Resource_Center/home.aspx) American Academy of Pediatrics: HealthyChildren. org (www.healthychildren.org/English/healthissues/conditions/emotional-problems/ Pages/Disruptive-Behavior-Disorders.aspx) RELATED CONTENT Attention Deficit Hyperactivity Disorder (Related Key Topic) Conduct Disorder (Related Key Topic) AUTHORS: Hassan M. Minhas, MD, and Elizabeth A. Lowenhaupt, MD

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Optic Atrophy BASIC INFORMATION DEFINITION • Optic atrophy refers to the degeneration of axons of the optic nerve. • It is a sign indicative of optic nerve insult rather than a distinct disease entity. SYNONYM Unilateral/bilateral optic atrophy ICD-10CM CODE H47.2 Optic atrophy

EPIDEMIOLOGY & DEMOGRAPHICS PREDOMINANT SEX: Depends on etiology PREDOMINANT AGE: Variable PEAK INCIDENCE: Varies depending on cause PHYSICAL FINDINGS & CLINICAL PRESENTATION • Optic atrophy is identified weeks to months after an initial insult such as optic neuritis, trauma, or ischemia. Frequently, it is noted by the physician during a routine eye exam. • Asymmetry of disc color is often first subtle finding. • Temporal part of optic disc is pale initially; later, the entire disc becomes pale/white. • Optic disc pallor (Fig. E1) occurs 4 to 6 wk after optic nerve insult. • Unilateral lesion produces a relative afferent pupillary defect (RAPD): Swing flashlight eye to eye; abnormal pupil dilates to direct light. • Decreased visual acuity, blurred vision, visual field deficits (e.g., central scotoma), abnormal color vision (e.g., red desaturation). ETIOLOGY • Inflammatory optic neuritis: MS, sarcoidosis, neuromyelitis spectrum disorder, infections (syphilis, CMV, HIV, Lyme disease, cat-scratch disease) • Vascular: Ischemic optic neuropathy, central retinal artery occlusion, temporal arteritis • Compression: Pituitary tumor, meningioma, thyroid eye disease

• Hereditary: Leber hereditary optic neuropathy, dominant optic atrophy • Nutritional, toxic, and metabolic: Amiodarone, isoniazid, B12 deficiency, tobacco, alcohol • Trauma • Glaucoma (end-stage disease)

DIAGNOSIS DIFFERENTIAL DIAGNOSIS Optic disc anomalies such as myelinated nerve fibers, “blonde” fundus WORKUP • A detailed history to identify onset and course, exposure to risk factors such as toxic/ nutritional factors, detailed family history, and associated findings such as headache, eye pain, proptosis, or neurologic deficits. • Ophthalmic examination to document deficits of visual acuity, color vision, contrast sensitivity, and visual fields must be performed. Relative afferent pupillary defect (RAPD) on swinging flashlight examination is sine qua non for unilateral optic nerve disease and must be documented. Absence indicates retinal disease or bilateral lesions. • General examination and neurologic examination can provide clues to an underlying cause. • Pertinent laboratory testing as noted below; genetic studies with a genetic consultation can be obtained in cases with a suggestive history. • In the absence of an obvious cause, contrasted MRI of brain and orbits should be obtained to evaluate for demyelinating lesions and compressive lesions of the anterior visual pathways. Lumbar puncture should be obtained in patients with unexplained optic atrophy, especially with neurologic deficits. LABORATORY TESTS • Depends on suspected cause: None for trauma, tumor, or MS • Serum B12, RPR, HIV • Autoimmune diseases: ESR, ANA, ACE, aquaporin-4 antibodies (NMO IgG)

IMAGING STUDIES • MRI of the brain and orbits with contrast , fat suppression, and special (thin) cuts through orbits is necessary to identify compressive lesions in all patients with unexplained optic atrophy; especially important in patients with positive predictive factors for abnormal imaging (e.g., young age, progression, bilateral findings). • If sarcoid is suspected, order chest x-ray and/ or chest CT.

TREATMENT ACUTE GENERAL Rx Treat the underlying cause—discontinue identifiable toxins, use B12 replacement, neurosurgical intervention is necessary if tumor is found; consider IV steroids if there is evidence for active demyelinating disease. CHRONIC Rx The optic nerve does not regenerate, although symptoms often improve. DISPOSITION • Visual loss usually occurs over weeks to months • Appointment with neurologist or ophthalmo­ logist REFERRAL Depends on the underlying disease process

PEARLS & CONSIDERATIONS COMMENTS • An experienced clinician should be able to identify pale optic discs and a RAPD. • Pupillary dilation with mydriatic agents (e.g., tropicamide) may be necessary to optimize funduscopic examination. • Patient education material can be obtained from the National Eye Institute, Department of Health and Human Services, 9000 Rockville Pike, Bethesda, MD 20814. AUTHOR: Sachin Kedar, MBBS, MD

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D FIG. E1  Optic atrophy. A, Primary due to compression. B, Primary due to nutritional neuropathy—note predominantly temporal pallor. C, Secondary due to chronic papilloedema—note prominent Paton lines (see text). D, Consecutive due to vasculitis. (Courtesy P. Gili, Fig. C. From Bowling B: Kanski’s clinical ophthalmology: a systemic approach, ed 8, Philadelphia, 2016, Elsevier.)

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Optic Neuritis BASIC INFORMATION DEFINITION Optic neuritis is an inflammation of the optic nerve resulting in impaired visual function. SYNONYMS Optic papillitis Retrobulbar neuritis ICD-10CM CODES H46.8 Other optic neuritis H46.9 Unspecified optic neuritis

EPIDEMIOLOGY & DEMOGRAPHICS INCIDENCE (IN U.S.): 1 to 5/100,000 person(s) per yr; rates vary according to incidence of multiple sclerosis (MS). Optic neuritis affects 1% to 5% of patients with neurosarcoid. PREVALENCE (IN U.S.): Common in patients with MS PREDOMINANT SEX: Female:male ratio: 1.8:1 PEAK INCIDENCE: 20 to 49 yr, mean 30 GENETICS: Unknown. If due to MS, it is more common in patients with certain human lymphocyte antigen (HLA) blood types and in monozygotic twins of affected siblings. PHYSICAL FINDINGS & CLINICAL PRESENTATION • Presentation with acute or subacute (days) visual loss, often accompanied by periocular tenderness that worsens with eye movements. • Marcus Gunn pupil (relative afferent pupillary defect [RAPD]): Direct and consensual response is normal; however, when flashlight is swung from eye to eye, the affected eye’s pupil dilates to direct light. • Decreased visual acuity. • Unilateral visual field abnormalities—often a central scotoma (Fig. E1). • Color desaturation; red is most often affected. • Normal fundus examination in 66% cases; disc edema is noted in 33%. Other abnormalities include uveitis or periphlebitis. In neurosarcoid, the optic nerve head may exhibit a lumpy appearance suggestive of granulomatous infiltration, and there may be associated vitritis (Fig. E2). • May have movement or light-induced phosphenes (flashes of light lasting 1 to 2 sec). • Uhthoff phenomenon (benign exercise- or heatinduced deterioration of vision) is seen in some. Vision may also worsen in bright sunlight. • Over time the optic disc may atrophy and become pale. ETIOLOGY An inflammatory response associated with an infection or autoimmune disease (such as col-

lagen vascular disease, granulomatous disease, MS, or neuromyelitis optica).

DIAGNOSIS Diagnosis is clinically established in a young patient with acute onset of monocular vision loss associated with retroorbital pain associated with eye movements and presence of RAPD lasting more than 24 hr. Absence of other orbital or ocular pathology is based on clinical examination.

DIFFERENTIAL DIAGNOSIS For optic neuritis: • Inflammatory: MS, neuromyelitis optica spectrum disorder (NMOSD), sarcoidosis, lupus, Sjögren, Behçet, postinfectious, postvaccination, neuroretinitis, acute disseminated encephalomyelitis, paraneoplastic, autoimmune optic neuropathy • Infectious: Syphilis, TB, Lyme disease, Bartonella, HIV, cytomegalovirus (CMV), herpes, helminths, chickenpox, Q fever, periorbital infections, Toxocara sp. • Ischemic: Anterior and posterior ischemic optic neuropathies, diabetic papillopathy, branch or central retinal artery or vein occlusion • Drugs and toxins: Arsenic, methanol, ethambutol, cyclosporine, etc. • Mitochondrial: Leber hereditary optic neuropathy, other mitochondrial WORKUP A thorough neurologic examination; dilated ophthalmoscopy LABORATORY TESTS Acute optic neuritis is a clinical diagnosis based on presentation with classical features: acute, painful unilateral loss of vision associated with RAPD in a young person with no other apparent causes such as trauma. In atypical cases additional studies may be considered. • CBC, antinuclear antibody (ANA), ACE, erythrocyte sedimentation rate (ESR) • Consider HIV Ab, Lyme titer, rapid plasma reagin (RPR), other autoimmune or infectious causes • Bilateral or recurrent optic neuritis (ON): neuromyelitis optica (NMO) immunoglobulin (IgG), myelin oligodendrocyte glycoprotein (MOG IgG), paraneoplastic CRMP-5-IgG IMAGING STUDIES • Contrast-enhanced MRI of the brain is performed to assess the risk of developing MS. Often enhancement of the optic nerve is seen. MRI orbits with thin sections of fat suppressed sequences may be needed if the patient demonstrates atypical features (Fig. E3). • Consider using optical coherence tomography to follow optic nerve atrophy objectively longitudinally.

TREATMENT NONPHARMACOLOGIC THERAPY Assure patient that in most cases of typical optic neuritis, there is near complete recovery of vision. ACUTE Rx Treat if the visual loss is significant, atypical features, or if there is an abnormal MRI (higher risk of MS). Treatment is with methylprednisolone (MP) 250 mg IV every 6 hr (or 1 g IV daily) for 3 days followed by an oral prednisone taper of 11 days. Optic neuritis from NMOSD is often more severe and has a worse prognosis; therefore plasma exchange can be considered. CHRONIC Rx Depends on underlying cause. Diseasemodifying treatment when increased risk of developing MS or neuromyelitis optica spectrum disorder. See topic “Multiple Sclerosis.” DISPOSITION Most often vision is worst at the end of wk 1, followed by recovery over months. In the Optic Neuritis Treatment Trial (ONTT), 90% had 20/40 or better vision at 1 yr and 3% had 20/200 or worse. Of initial 20/200 or worse cases, only 5% remained in that group at 6 mo. REFERRAL • To neurologist for other neurologic signs and to assess risk of developing MS. In ONTT (Optic Neuritis Treatment Trial), risk of MS >15 yr was 72% with ≥1 lesion(s) on MRI, and 25% with a normal MRI. • To ophthalmologist when atypical features or slowly progressive; urgently when other ocular pathology is present or if vision worsens or does not improve after several wk, or pain is severe.

PEARLS & CONSIDERATIONS • Bilateral optic neuritis suggests a systemic inflammatory disorder, infection, NMOSD, or paraneoplastic, but can also occur in MS. • Acute bilateral loss of vision with a severe headache or diplopia should raise concern for pituitary apoplexy and/or giant cell arteritis.

RELATED CONTENT Idiopathic Intracranial Hypertension (Related Key Topic) Multiple Sclerosis (Related Key Topic) AUTHORS: Sachin Kedar, MBBS, MD, and Corey Goldsmith, MD

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FIG. E1  Visual field defects in optic neuritis. A, Central scotoma. B, Centrocecal scotoma. C, Nerve fiber bundle. D, Altitudinal. (From Kanski JJ, Bowling B: Clinical ophthalmology: a systematic approach, ed 7, Philadelphia, 2010, WB Saunders.) FIG. E2  Sarcoid granuloma of the optic nerve head with overlying vitreous haze. (From Bowling B: Kanski’s clinical ophthalmology, a systemic approach, ed 8, Philadelphia, 2016, Elsevier.)

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FIG. E3  Right optic neuritis. Coronal fat-suppressed T2-weighted fast spin-echo (A) and fat-suppressed contrast-enhanced T1-weighted MR images. There is hyperintensity of the right optic nerve, with diffuse enhancement (arrows) (B). (From Grant LA: Grainger & Allison’s diagnostic radiology essentials, ed 2, Philadelphia, 2019, Elsevier.)

ALG BASIC INFORMATION

SYNONYMS Head and neck cancer Oral malignant neoplasm OSCC ICD-10CM CODES C01 Malignant neoplasm of base of tongue C03 Malignant neoplasm of gum C04 Malignant neoplasm of floor of mouth C05 Malignant neoplasm of palate C06 Malignant neoplasm of other and unspecified parts of mouth C09 Malignant neoplasm of tonsil C10 Malignant neoplasm of oropharynx C11 Malignant neoplasm of nasopharynx C12 Malignant neoplasm of piriform sinus C13 Malignant neoplasm of hypopharynx C14 Malignant neoplasm of other and illdefined sites of lip, oral cavity and larynx C14.0 Malignant neoplasm of pharynx, unspecified C14.2 Malignant neoplasm of Waldeyer ring C14.8 Malignant neoplasm of overlapping sites of lip, oral cavity and pharynx

EPIDEMIOLOGY & DEMOGRAPHICS INCIDENCE & PREVALENCE: OSCC comprise the sixth most common cancer in the world. An estimated 530,000 cases are diagnosed annually around the globe, and the rates have been rising, particularly in young people and among minorities. It was estimated that in 2019, approximately 53,000 new cases and 10,860 deaths would occur in the U.S. The incidence of oral cancers linked to alcohol and tobacco use has been declining in the U.S., whereas those linked to human papillomavirus (HPV), primarily HPV type 16, are on the rise, especially for cancers located in the tonsils and base of tongue. In developed countries across the world, HPV is increasingly implicated in the growing incidence of oral cancer. In Asian countries where chewing betel nut is customary, oral cancer accounts for up to 40% of cancers in some regions. Squamous cell carcinoma is the most common malignancy that occurs in the oral cavity. PREDOMINANT SEX & AGE: The ratio of oral cancer in males: females is 2.5:1 in the U.S. Black males have a higher early incidence in the 50- to 60-yr age group, but with increasing age, white men predominate.

PHYSICAL FINDINGS & CLINICAL PRESENTATION • Specific patient complaints may include the following: oral ulcers or mass, choking, difficulty breathing, dysphagia, odynophagia, voice hoarseness, globus sensation, otalgia, ear or nose stuffiness, hemoptysis, trismus, neck mass, and pain in the head/neck region. • Generalized symptoms and signs may include weight loss, fatigue, anorexia, altered mood, and sleep. Age Gender Race/ethnicity Immunodeficiency Oral cancer history Genotype Comorbidities

Tobacco Alcohol Sunlight Nutrition

Systemic

Environmental Oral cancer

Economic

Socioeconomic status Access to care

FIG. 1  Risk model for oral cancer. Oral cancer is a multifactorial disease process that includes systemic, environmental, and economic effects. The interplay of these variables ultimately leads to the incidence of this disease. The multifactorial nature of oral cancer should be addressed in the assessment of a patient’s risk. (From Jones DL, Rankin KV: Oral cancer and associated risk factors. In Cappelli D, Mobley C [eds]: Prevention in clinical oral health care, St Louis, 2008, Elsevier, pp 68-77.)

• Clinically, oral cancers can present as: 1. Erythroplakia (flat red patch); can mimic inflammatory or traumatic lesions 2. Leukoplakia (white patch; Fig. E2) 3. Raised lesion 4. Ulcerated lesion 5. Warty lesion or growth

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DIAGNOSIS DIFFERENTIAL DIAGNOSIS • Oral leukoplakia • Invasive fungal infections • Chancre of early syphilis and gumma of tertiary syphilis • Chronic ulcer • Metastatic or locally invading cancers from sinuses or other sites of the body PATIENT WORKUP • Primary workup includes either biopsy or fineneedle aspiration (FNA) of the presenting lesion or suspected neck lymph node for histopathologic analysis. HPV assessment with p16 immunohistochemical staining and confirmatory in situ hybridization (ISH) testing is performed when indicated for oropharynx primary tumors. • Detailed examination of the oral cavity, pharynx, larynx, neck, ears, nose, and cranial nerves should be performed. • Laryngoscopy and examination under anesthesia are commonly performed. • Pretreatment evaluation of tumor size, the extent of invasion, and the presence or absence of regional lymph node metastases is critical for planning treatment. • Laboratory workup can include complete blood count, complete chemistry panel, and thyroid function. • Staging workup includes CT or MRI imaging of the head and neck and a chest x-ray. If locoregional or advanced disease is a consideration, a PET scan is typically completed. • The TNM system is used for staging of OSCC and is subdivided according to primary tumor sites: (1) lip and oral cavity, (2) pharynx.

TREATMENT • Surgery, radiation therapy, and chemotherapy are treatment modalities involved in the treatment plan for OSCC. • The use of supportive and special therapeutic modalities such as nutritional therapy including feeding gastrostomy, speech and swallowing therapy, reconstructive surgery, and speech prosthesis is required often. • For treatment purposes OSCC are classified as early (T1 or T2 lesions), locoregional (T3-4 or any N), or metastatic (M1) stages. Sitespecific TNM staging is done as per the primary tumor site (e.g., oral cavity, oropharynx, hypopharynx, etc.). • After staging completion, the initial treatment considerations include: 1. Determination of primary tumor resectability (resectable vs. unresectable) 2. Management of neck nodes

Diseases and Disorders

DEFINITION Oral cancers refer to malignant transformation of the oral tissues usually preceded by a process of sequential dysplastic changes leading to the development of squamous carcinoma. Oral squamous cell cancers (OSCC) include oral cavity cancers (lip, floor of mouth, buccal mucosa, anterior tongue, gingivae, hard palate, retromolar trigone), oropharynx cancers (base of tongue, tonsils, soft palate, pharyngeal walls), and hypopharynx cancers (pyriform sinus, postcricoid area, posterior pharyngeal wall).

GENETICS: The genes that are critically altered in OSCC include TP53, the retinoblastoma family, p16 and cyclin D1. The TP53, CCND1, and CDKN2A genes are established cancer genes in HPV-negative cancers. TP53 and the genes encoding the Rb family are established cancer genes in HPV-positive cancers. Signaling pathways that are involved in the pathogenesis of oral cancers include that of the human epidermal receptor (HER) family, vascular endothelial growth factor (VEGF) receptor, and signal transducer and activator of transcription 3 (STAT 3). The tumor suppressor gene TP53 is frequently mutated in HPV-negative tumors. RISK FACTORS (Fig. 1): The following factors are implicated in the development of oral cancer: • Tobacco use • HPV infection (primarily types 16 and 18) • Alcohol • Immune deficiency • Radiation • Betel nut consumption • Solar radiation

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3. Intent of radiation therapy (curative vs. palliative) 4. Need for organ preservation 5. Need for reconstructive surgery 6. Need for chemotherapy 7. HPV status of tumor • Localized tumors (stage I or II) can be approached by initial surgical resection or definitive radiotherapy. Loco-regionally advanced tumors (stage III and localized IV) that are resectable are typically approached by upfront surgery followed by adjuvant radiation and/or chemotherapy. Unresectable patients are typically treated with definitive chemotherapy and radiotherapy. Patients with distant metastatic disease are treated with systemic chemotherapy, while locally recurrent tumors can be approached with either surgery or chemotherapy or both. • Surgery is typically associated with less long-term morbidity than radiation therapy. Surgical therapy traditionally involved wide-exposure approaches (mandibulotomy, transpharyngeal access). Newer surgical techniques allow tumor resection through the mouth. Recently, transoral robotic surgery (TORS) has been developed to improve access to oropharyngeal squamous cell carcinomas with excellent oncologic outcomes. 1. Acute surgical complications can include infection, bleeding, aspiration, wound breakdown, fistula, and flap loss. 2. Surgical procedures can cause functional deficits in speech and swallowing, but these adverse effects can be minimized by appropriate reconstruction and prostheses. • Definitive radiation therapy is reserved for patients who cannot tolerate surgery or for whom surgical resection would result in particularly severe functional impairment. 1.  Radiation therapy can include external beam radiation and brachytherapy.

2.  Radiation therapy side effects include mucositis, radiation dermatitis, loss of taste, dysphagia, dental caries and decay, and xerostomia. 3. Late complications can include skin/soft tissue atrophy and fibrosis, osteoradionecrosis, and trismus. • Systemic chemotherapy can be administered alone or in combination with radiotherapy, depending on the disease stage. Agents typically used include cisplatin, carboplatin, 5-fluorouracil, taxanes, and the epidermal growth factor receptor (EGFR) antibody cetuximab. • For locally advanced OSCC, the combination of cisplatin and radiotherapy is the regimen of choice. In selected patients with large primary tumors or bulky nodal disease, neoadjuvant chemotherapy may be utilized prior to chemoradiotherapy administration. • Patients who have metastatic cancers or unresectable locoregional recurrences usually are treated with systemic chemotherapy. • Standard doublet chemotherapy regimens (platinum plus either 5-fluorouracil or a taxane) can be combined with the epidermal growth factor receptor (EGFR)–targeting antibody cetuximab. A recent study has demonstrated the superiority of frontline therapy with platinum plus 5-fluorouracil chemotherapy in combination with the checkpoint inhibitor pembrolizumab. • In patients who have not received checkpoint inhibitor therapy previously, nivolumab and pembrolizumab have been shown to improve survival outcomes after failure of first-line chemotherapy. • The negative predictive value of post-treatment PET imaging in patients with locally advanced cancer who have been treated with chemoradiotherapy is 98% to 99%.

DISPOSITION • Prognosis depends on the staging and resectability of the primary tumor as well as on patient performance status. • Tumor HPV status is a strong and independent prognostic factor for survival among patients with base of tongue and oropharyngeal cancer. REFERRAL Referral to multidisciplinary head and neck cancer team consisting of ENT or head/neck surgeon, radiation oncologist, and medical oncologist

PEARLS & CONSIDERATIONS COMMENTS • Oral and pharyngeal cancer is the sixth most common cancer globally. • Biopsy with HPV-status assessment is the key for accurate diagnosis. • Posttreatment rehabilitation and surveillance is important. PREVENTION • Encourage patients to stop using any type of tobacco and drinking alcohol. • Examine oral cavities at annual checkups and work up suspicious lesions. SUGGESTED READINGS Available at ExpertConsult.com RELATED CONTENT Mouth Cancer (Patient Information) AUTHOR: Ritesh Rathore, MD

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C FIG. E2  Squamous cell carcinoma of the oral mucosa. A, Leukoplakia. B, Invasive carcinoma of the floor of the mouth. C, Invasive carcinoma of the tongue. (Courtesy G. Putnam. In White GM, Cox NH [eds]: Diseases of the skin: a color atlas and text, ed 2, St Louis, 2006, Mosby.)

SUGGESTED READINGS Ang KK et al: Human papillomavirus and survival of patients with oropharyngeal cancer, N Engl J Med 363:24-35, 2010. Ayaz B et al: A clinico-pathological study of oral cancer, Biomedica 27:29-32, 2011. Bar-Ad V et al: Current management of locally advanced head and neck cancer: the combination of chemotherapy with locoregional treatments, Semin Oncol 41(6):798-806, 2015. Burtness B et al: Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048): a randomised, open-label, phase 3 study, Lancet 394(10212):P1915-P1928, 2019. Gillison ML et al: Prevalence of oral HPV infection in the United States, 2009-2010, JAMA 307(7):693-703, 2012. Leemans CR C et al: The molecular biology of head and neck cancer, Nat Rev Cancer 11(9-22), 2010. Marur S, Forastiere AA: Head and neck squamous cell carcinoma: update on epidemiology, diagnosis, and treatment, Mayo Clin Proc 91(3):386-396, 2016. Moore EJ et al: Long-term functional and oncologic results of transoral robotic surgery for oropharyngeal squamous cell carcinoma, Mayo Clin Proc 87(3):219-225, 2012. Siegel RL et al: Cancer statistics, CA Cancer J Clin 69(1):7-34, 2019.

Oral Hairy Leukoplakia BASIC INFORMATION DEFINITION Oral hairy leukoplakia (OHL) is a painless, white, nonremovable, plaquelike lesion typically located on the lateral aspect of the tongue. SYNONYMS Oral hairy leukoplakia OHL

EPIDEMIOLOGY & DEMOGRAPHICS INCIDENCE AND PREVALENCE: Epstein-Barr virus (EBV) is implicated in the etiology of OHL, and the incidence of EBV seroprevalence is high in individuals who are HIV seropositive. However, OHL occurs in only 25% of these cases but may also occur in other immunosuppressed individuals, for example, organ transplant recipients. RISK FACTORS: OHL is usually found in HIVseropositive individuals (median CD4 count is 468/ml) but may also be identified in smokers and other immunocompromised patients such as transplant recipients (particularly renal) and patients taking steroids. Diagnosing OHL is an indication to institute a workup to evaluate and manage HIV disease. PHYSICAL FINDINGS & CLINICAL PRESENTATION • Varying morphology and appearance, which may change daily. • May be unilateral or bilateral. • White plaques can be small with fine, vertical corrugations on the lateral margin of the tongue (Fig. 1). The plaques from OHL are adherent to the tongue surface (in contrast to candidal plaques, which may be easily scraped off). • Irregular surface; may have prominent folds or projection, occasionally markedly resembling hairs.

ETIOLOGY EBV is implicated in its etiology, and OHL is a result of unchecked lytic replication of EBV in the epithelium of keratinized cells. OHL differs from most EBV-related diseases in that infection is predominantly lytic rather than latent, with abundant virus production resulting in cell lysis.

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • Oral homogenous/non-homogenous leukoplakia • Candida albicans • Lichen planus • Idiopathic leukoplakia • White sponge nevus • Dysplasia • Squamous cell carcinoma WORKUP Requires physical examination and evaluation of HIV disease LABORATORY TESTS The provisional diagnosis is clinical and based on: • Visual inspection • Inability to scrape the lesion off the tongue with a blade • Failure to respond to antifungal therapy The presumptive diagnosis requires biopsy and histologic demonstration of:

• Epithelial hyperplasia with hairs • Absence of inflammatory cell infiltrate The definitive diagnosis requires: • In situ hybridization of histologic or cytologic specimens revealing EBV DNA or • Electron microscopy of specimens revealing herpes-like particles • Measurement of the DNA content in cells of oral leukoplakia may be used to predict the risk of oral carcinoma   note: Specimens obtained from lesions may demonstrate hyphae of Candida albicans, which may coexist and potentiate EBVinduced OHL.

TREATMENT NONPHARMACOLOGIC THERAPY OHL is usually asymptomatic and requires no specific therapy. It may resolve spontaneously and is generally benign in HIV-seropositive patients. ACUTE GENERAL Rx • Antiretroviral therapy (ART) has considerably changed the frequency of oral lesions caused by opportunistic infections in HIVseropositive individuals. • Topical retinoids (0.1% vitamin A) may improve the appearance of OHL-affected oral surfaces through their dekeratinizing and immunomodulation effects; however, they are expensive, and prolonged use may result in a burning sensation over the treated area. • Topical podophyllin resin 25% solution has been reported to induce resolution. • Surgical excision and cryotherapy may help, but the lesions may recur. • High-dose acyclovir 800 mg five times per day, valacyclovir 1000 mg tid, famciclovir 500 mg tid, ganciclovir 1000 mg tid, or foscarnet 40 mg/kg IV tid will cause lesions to resolve but only temporarily. REFERRAL Referral to ENT or oral surgeon for biopsy of tongue to confirm diagnosis

PEARLS & CONSIDERATIONS • OHL may be the presenting sign of patients infected with HIV who are unaware of their status. • The incidence has decreased significantly in the era of antiretroviral therapy.

RELATED CONTENT Acquired Immunodeficiency Syndrome (Related Key Topic) Oral Hairy Leukoplakia (Patient Information) Epstein-Barr Virus Infection (Related Key Topic) Human Immunodeficiency Virus (Related Key Topic) AUTHOR: Sajeev Handa, MD, SFHM

FIG. 1  Oral hairy leukoplakia. (From Callen JP et al: Dermatological signs of systemic disease, ed 5, Philadelphia, 2017, Elsevier.)

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Diseases and Disorders

ICD-10CM CODE K13.3 Hairy leukoplakia

• May spread to cover the entire dorsal surface or spread onto the ventral surface of the tongue where the lesions usually appear flat. • Rarely, lesions can manifest on the soft palate, buccal mucosa, or posterior oropharynx. • Usually asymptomatic, but some patients have mouth pain, soreness, or a burning sensation; impaired taste, or difficulty eating; others complain of its unsightly appearance. • OHL may rarely progress to oral squamous cell carcinoma, particularly in smokers, which has a poor prognosis.

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Orchitis BASIC INFORMATION DEFINITION Orchitis is an inflammatory process (usually infectious) involving the testicles. Infection may be viral or bacterial and can be associated with infection of other male sex organs (prostate, epididymis, or bladder) or lower urogenital tract or sexually transmitted diseases often via hematogenous spread. Common causes are: • Viral: Mumps—20% postpubertal; Coxsackie B virus • Bacterial: Pyogenic via spread from involving epididymis; bacteria include Escherichia coli, Klebsiella pneumoniae, P. aeruginosa, Staphylococcus, Streptococcus or Rickettsia, Brucella spp. • Other: 1. Viral—HIV-associated, CMV 2. Fungi a. Cryptococcosis b. Histoplasmosis c.  Candida d. Blastomycosis e. Syphilis 3.  Mycobacterium tuberculosis and M. leprae 4. Parasitic causes: Toxoplasmosis, filariasis, schistosomiasis • Table 1 describes a classification of epididymitis and orchitis based on etiology. SYNONYMS Epididymo-orchitis Testicular infection Testicular inflammation ICD-10CM CODES N45.9 Orchitis, epididymitis, and epididymo-orchitis without abscess A54.1 Gonococcal orchitis A56.1 Chlamydial orchitis N51.1 Mumps orchitis

EPIDEMIOLOGY & DEMOGRAPHICS PREDOMINANT SEX: Male PREDOMINANT ORGANISM: The leading cause of viral orchitis is mumps. The mumps virus rarely causes orchitis in prepubertal males but involves one or both testicles in nearly 30% of postpubertal males.

PHYSICAL FINDINGS & CLINICAL PRESENTATION • Testicular pain, unilateral or bilateral swelling • May have associated epididymitis, prostatitis, fever, scrotal edema, erythema, cellulitis • Inguinal lymphadenopathy • Acute hydrocele (bacterial) • Rare development: Abscess formation, pyocele of scrotum, testicular infarction • Spermatic cord tenderness may be present • Granulomatous

DIAGNOSIS Clinical presentation as described previously with possible history of acute viral illness or concomitant epididymitis

DIFFERENTIAL DIAGNOSIS • Epididymo-orchitis-gonococcal • Autoimmune disease • Vasculitis • Epididymitis • Mumps, with or without parotitis • Neoplasm • Hematoma • Spermatic cord torsion LABORATORY TESTS • CBC with differential • Urinalysis • Viral titer—mumps. Mumps IgM will be detectable after 5 days of onset of clinical mumps and remain positive for up to 4 wk. A reverse-transcriptase PCR (RT-PCR) on serum or buccal or oral swab is another option. • Urine culture for mumps virus • Ultrasound of testicle to rule out abscess IMAGING STUDIES Ultrasound if abscess suspected

TREATMENT • Dependent on cause • Viral (mumps): Observation; bed rest, ice packs, analgesics, and a scrotal sling for support may provide some relief of discomfort that accompanies mumps orchitis • Bacterial: Empiric antibiotic treatment with parenteral antibiotic treatment until pathogen

TABLE 1  Classification of Epididymitis and Orchitis Acute Epididymitis or Epididymo-orchitis

Granulomatous Epididymitis or Orchitis

Viral Orchitis

Neisseria gonorrhoeae Chlamydia trachomatis Escherichia coli Streptococcus pneumoniae Klebsiella spp. Salmonella spp. Other urinary tract pathogens Idiopathic

Mycobacterium tuberculosis Treponema pallidum

Mumps Enteroviruses

Brucella spp. Sarcoid Fungal Parasitic Idiopathic

From Cohen J, Powderly WG: Infectious diseases, ed 2, St Louis, 2004, Mosby.

identified: Ceftriaxone (250 mg IM once) plus doxycycline (100 mg PO bid for 10 days), in men 35 yr old: Levofloxacin 500 to 750 mg IV/PO qd for 10 to 14 days or ampicillin-sulbactam or third-generation cephalosporin or piperacillin/tazobactam • Surgery for abscess, pyogenic process

DISPOSITION Follow-up for evidence of recurrence, hypogonadism, and infertility may be needed with bilateral orchitis. REFERRAL • To a urologist if surgical drainage is needed • To an endocrinologist if hypogonadism develops • To a fertility specialist if infertility develops

PEARLS & CONSIDERATIONS Consider tuberculous orchitis if symptoms fail to respond to standard antibacterial therapy, even in the absence of chest radiographic evidence of pulmonary tuberculosis.

SUGGESTED READINGS Available at ExpertConsult.com RELATED CONTENT Orchitis (Patient Information) Epididymitis (Related Key Topic) Mumps (Related Key Topic) AUTHOR: Glenn G. Fort, MD, MPH

Orchitis SUGGESTED READINGS Davis NF et  al: The increasing incidence of mumps orchitis: a comprehensive review, BJU Int 105:1060-1065, 2010. Raynor MC et al: Urinary infections in men, Med Clin North Am 95(1):43-54, 2011. Ternavasio-de la Vega HG et al: Mumps orchitis in the post-vaccine era (19672009): a single-center series of 67 patients and review of clinical outcome and trends, Medicine (Baltimore) 89(2):96-116, 2010.

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Orthostatic Hypotension BASIC INFORMATION

SYNONYMS Postural hypotension OH ICD-10CM CODE I95.1 Orthostatic hypotension

EPIDEMIOLOGY & DEMOGRAPHICS • The incidence of OH is increased in older people. Surveys have shown OH to be present in approximately 20% of adults over 65 yr of age. • Also, higher incidence noted in those with diseases associated with autonomic dysfunction (e.g., Parkinson disease, diabetes mellitus). • OH may cause up to 30% of all syncopal events in the elderly, and OH is associated with an increased risk of heart failure among those aged 45 to 55 yr and an increased risk of cardiovascular disease and all-cause mortality among those aged 55 yr and older. • There is an association between orthostatic hypotension and cognitive dysfunction among older adults. PHYSICAL FINDINGS & CLINICAL PRESENTATION • Symptoms may include dizziness, lightheadedness, syncope, visual and auditory disturbances, weakness, diaphoresis, pallor, and nausea. • OH may be asymptomatic, especially in older hypertensive patients with autonomic dysfunction. These patients tend to have systolic hypertension when seated or supine. • Associated with increased autonomic activity during meals (from increased splanchnic blood flow), exercise, prolonged standing, and hot weather. • Supine and nocturnal hypertension in patients with OH may indicate an underlying autonomic dysfunction. 1Juraschek

SP et al: Associated of history of dizziness and long-term adverse outcomes with early vs. later orthostatic hypotension assessment times in middleaged adults, JAMA Intern Med 2017.

DIAGNOSIS DIFFERENTIAL DIAGNOSIS Common: • Medications: Antihypertensives, antidepressants (tricyclics), antipsychotics (phenothiazines), alcohol, narcotics, barbiturates, insulin, nitrates, PDE-5 inhibitors, alpha-adrenergic antagonists • Reduced intravascular volume (hemorrhage, dehydration, hyperglycemia, hypoalbuminemia) • Postprandial effect (especially in the elderly) • Vasovagal syncope • Deconditioning • Central autonomic dysfunction (Parkinson disease) • Peripheral autonomic dysfunction (diabetes mellitus, Guillain-Barré syndrome) Uncommon: • Central autonomic dysfunction (Shy-Drager syndrome) • Postganglionic autonomic dysfunction: Impaired norepinephrine release • Autoimmune autonomic dysfunction: Nicotinic acetylcholine receptor autoantibodies • Paraneoplastic autonomic dysfunction: AntiHu antibodies (in small-cell lung cancer) • Postural tachycardia syndrome (POTS): Usually occurs in young women; an abnormally large increase in heart rate is observed in the upright position, caused by increased venous pooling from autonomic dysfunction of the lower extremities, but blood pressure is not affected because of an excess of plasma norepinephrine

• Impaired cardiac output (myocardial infarction, aortic stenosis, arrhythmias) • Cerebrovascular accident • Adrenal insufficiency • Deconditioning • Carotid sinus hypersensitivity • Anxiety, panic attacks • Seizures • Sepsis • Idiopathic

WORKUP • Obtain a detailed history including medication list, recent history of potential volume loss, medical history of congestive heart failure, malignancy, diabetes and alcoholism, evidence on history and physical examination of parkinsonism, ataxia, peripheral neuropathy, or dysautonomia. • Measure supine blood pressure after the patient has been resting comfortably. The duration of time that the patient should spend supine and standing when measuring orthostatic hypotension is controversial. Limited evidence supports having the patient remain supine for 5 to 10 min before obtaining the supine blood pressure, followed by blood pressure measurement within 1 min of standing and again after 3 min of standing. The blood pressure cuff must be held at the level of the right atrium; holding the cuff below this level will result in a 5 to 10 mm Hg underestimation of blood pressure. • Thorough neurologic examination should be performed. LABORATORY TESTS • Hemoglobin and hematocrit • Consider BUN/Creatinine if suspecting dehydration as the cause • EKG if suspecting underlying cardiac cause • Consider when treatable causes of OH have been ruled out: 1. Blood pressure and heart rate monitoring with a tilt table test 2. Plasma norepinephrine measurements (to distinguish postganglionic from preganglionic autonomic dysfunction) 3. Other methods, which use the Valsalva maneuver or measure sweating as indirect means of evaluating the autonomic nervous system IMAGING STUDIES None

TREATMENT NONPHARMACOLOGIC THERAPY • Patient education (leg crossing, prolonged sitting before first standing in the morning, avoid excessive straining and hot baths) • High-salt diet (e.g., bouillon cubes); caution if history of heart failure • Liberal fluid intake • Take needed antihypertensive medications at different times of the day • Raise the head of the bed at night

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DEFINITION Orthostatic hypotension (OH) is defined as the presence of at least one of the following: • Decrease in systolic blood pressure by ≥20 mm Hg or • Decrease in diastolic blood pressure by ≥10 mm Hg, within 3 min of standing. It is a physical sign that requires further investigation to discern its underlying etiology. Recent studies have shown that blood pressure measurements within 1 min might be more useful in predicting fractures, falls, and other adverse events and for most patients, assessment within 1 min of standing rather than waiting for 3 min may be sufficient.1

ETIOLOGY • There are two main mechanisms for OH: autonomic dysfunction and volume depletion. • Normal response: Assumption of an upright posture results in the pooling of approximately 500 ml of blood in the lower extremities due to gravity and decreased venous return, decreased cardiac output, and decreased arterial pressure. The consequent increase in sympathetic tone due to increased carotid baroreceptor activity causes arterial and venous constriction as well as positive inotropic and chronotropic effects, thereby limiting the fall in upright blood pressure. Peripheral vasoconstriction is also mediated by increased activity of the renin-angiotensin system and decreased activity of atrial natriuretic factor. • Autonomic Dysfunction: Impairment of the baroreceptor reflex, as in central (such as Parkinson disease) or peripheral autonomic dysfunction (such as diabetes) and aging, may cause OH because decreased blood pressure cannot be counteracted by the aforementioned regulatory mechanisms. • Volume depletion: May be caused by diuretics, vomiting, hemorrhage, and hyperglycemia. Mechanism of OH in these patients is similar to what is described earlier, with failure of the regulatory mechanisms kicking in.

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Orthostatic Hypotension TABLE 1  Management of Orthostatic Hypotension in Older Adults Identify and treat correctable causes. Reduce or eliminate drugs causing orthostatic hypotension. Avoid situations that may exacerbate orthostatic hypotension. • Standing motionless • Prolonged recumbency • Large meals • Hot weather • Hot showers • Straining at stool or with voiding • Isometric exercise • Ingesting alcohol • Hyperventilation • Dehydration Raise the head of the bed to a 5- to 20-degree angle. Wear waist-high, custom-fitted, elastic stockings and an abdominal binder. Participate in physical conditioning exercises. Participate in controlled postural exercises using the tilt table. Avoid diuretics and eat salt-containing fluids (unless congestive heart failure is present). Drug therapy: • Caffeine • Fludrocortisone • Midodrine • Desmopressin • Erythropoietin From Fillit HM: Brocklehurst’s textbook of geriatric medicine and gerontology, ed 8, Philadelphia, 2017, Elsevier.

• Compression stockings (to include splanchnic circulation) • Multiple low-carbohydrate meals to avoid postprandial OH • Avoid large carbohydrate loads and excess alcohol consumption

ACUTE GENERAL Rx • Correction of volume status and impairment of cerebral perfusion. • Review medication list and attempt to eliminate those potentially contributing to OH. CHRONIC Rx • Fludrocortisone: 0.1 mg/day (may combine with an alpha-1 agonist to lower the dose of each); monitor for electrolyte disturbances and supine hypertension • Midodrine (alpha-1 agonist): 10 mg three times a day; monitor for supine hypertension • Erythropoietin (consider if anemic) • Caffeine (for postprandial hypotension) Table 1 summarizes management of orthostatic hypotension in older adults. OTHER TREATMENTS • Pyridostigmine (enhances renal sodium reabsorption): 0.2 to 0.6 mg/day (not FDAapproved for this indication) • Octreotide: 300 to 600 mg/day (not FDAapproved for this indication) • Indomethacin (prostaglandin inhibitor) • DDAVP (experimental) • Droxidopa (used for patients with autonomic dysfunction to increase the availability of norepinephrine) has been FDA approved for treatment of adults with symptomatic neurogenic orthostatic hypotension caused by primary autonomic failure or nondiabetic autonomic neuropathy

PEARLS & CONSIDERATIONS COMMENTS • The presence of OH should always trigger a search for an underlying etiology.

• OH is diagnosed by observing changes in blood pressure, not heart rate. • Volume depletion should cause an increased heart rate on standing; a lack of heart rate response in this setting suggests autonomic dysfunction. • Pharmacotherapy with mineralocorticoids may require concomitant potassium replenishment and monitoring for hypertension. • Evidence to support the efficacy of pharmacologic interventions to treat OH, including midodrine, is limited. • The etiology of OH is often multifactorial in older patients, but increased susceptibility to volume depletion due to decreased baroreceptor reflexes frequently contributes. Chronic vitamin D deficiency is associated with the development of OH. • Intensive blood pressure control did not increase injurious falls compared with controls among community-dwelling older adults participating in the Systolic Blood Pressure Intervention Trial (SPRINT). • The physical examination of patients with dizziness, gait disturbance, and/or falls should include an assessment for OH. OH is an independent predictor of unexplained falls in older adults. • Because OH may be asymptomatic, physical examination of those at risk must include assessment of blood pressure in both the supine and upright positions.

SUGGESTED READINGS Available at ExpertConsult.com AUTHORS: Timothy W. Farrell, MD, AGSF, and Hussain R. Khawaja, MD

Orthostatic Hypotension SUGGESTED READINGS Biaggioni I et  al: Randomized withdrawal study of patients with symptomatic neurogenic orthostatic hypotension responsive to droxidopa, Hypertension 65:101-107, 2015. Cremer A et  al: Orthostatic hypotension and risk of incident dementia: results from a 12-year follow-up of the three-city study cohort, Hypertension 70:4449, 2017. Duval GT et al: Vitamin D deficiency and incident onset of orthostatic hypotension in older adults: preliminary results from the ‘MERE’ study, J Am Geriatr Soc 63:1245-1247, 2015. Juraschek SP et  al: Orthostatic hypotension and risk of clinical and subclinical cardiovascular disease in middle-aged adults, J Am Heart Assoc 7:10, 2018, https://doi.org/10.1161/JAHA.118.008884. Logan IC, Witham MD: Efficacy of treatments for orthostatic hypotension: a systematic review, Age Ageing 41:587-594, 2012. Menant JC et al: Depressive symptoms and orthostatic hypotension are risk factors for unexplained falls in community-living older people, J Am Geriatr Soc 64:1073-1078, 2016. Parsaik AK: Midodrine for orthostatic hypotension: a systemic review and metaanalysis of clinical trials, J Gen Intern Med 28:1496-1503, 2013. Supiano MA, Williamson JD: Applying the systolic blood pressure intervention trial results to older adults, J Am Geriatr Soc 65:16-21, 2017.

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Osgood-Schlatter Disease BASIC INFORMATION DEFINITION Osgood-Schlatter disease is painful swelling of the growing tibial tuberosity in adolescents. SYNONYMS Juvenile osteochondrosis Tibial tubercle apophysitis ICD-10CM CODE M92.40 Juvenile osteochondrosis of patella, unspecified knee

EPIDEMIOLOGY & DEMOGRAPHICS PREVALENCE: 4 cases/100 adolescents. PREDOMINANT SEX: Male:female ratio of 3:1. PREDOMINANT AGE: Males: Ages 13 to 15 yr, females: Ages 11 to 13 yr PHYSICAL FINDINGS & CLINICAL PRESENTATION • Gradual onset of pain and swelling of the tibial tubercle • Worsening of pain with athletic activity • Dull ache exacerbated by jumping or climbing stairs • Tenderness to touch over tibial tubercle, particularly with resisted knee extension

ACUTE GENERAL Rx • Ice, especially after exercise • Nonsteroidal antiinflammatory drugs • Quadriceps stretching exercises and crosstraining with low-impact sports • Injections of local anesthetic mixed with dextrose have shown efficacy in randomized controlled trials • Surgical (open or arthroscopic) debridement indicated in refractory cases, although this is controversial • Newer arthroscopic techniques have been developed in order to minimize patient morbidity DISPOSITION • Condition usually heals when the epiphysis closes. • 90% of patients respond to conservative treatment. • Recent studies have shown promising results with the use of hyperosmolar dextrose injections in recalcitrant disease. • Surgery is rarely needed in the treatment of Osgood-Schlatter disease but can be used

for relief of persistent symptoms in patients that have separated ossicles or an abnormally ossified tibial tuberosity.

REFERRAL Orthopedic consultation is recommended when symptoms persist >6 to 8 wk. with conservative treatment.

PEARLS & CONSIDERATIONS COMMENTS Larsen-Johansson disease is a similar disorder. While the diagnosis of Osgood-Schlatter disease is clinical, imaging may be needed to rule out infection, fracture, and malignancy. RELATED CONTENT Osgood-Schlatter Disease (Patient Information) AUTHOR: Steven L. Bokshan, MD

ETIOLOGY • Repetitive microtrauma and avulsion of the developing ossification center of the tibial tuberosity • Anatomic variants such as patella alta • Baseline muscle tightness (quadriceps, gastrocnemius, soleus) • Lower strain in the patellar tendon leads to faster force transmission

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • Stress fracture of the proximal tibia • Hoffa disease • Sinding-Larsen-Johansson syndrome • Patellar tendinitis WORKUP • The diagnosis of Osgood-Schlatter disease is made with history and physical examination. • Imaging may be indicated to exclude fracture or bony tumors. IMAGING STUDIES • Lateral x-rays may show separation and fragmentation of the upper tibial epiphysis (Fig. E1). • Musculoskeletal ultrasound (Fig. E2) can also be used and may show shorter patellar tendon excursion per force applied compared with normal tendons.

TREATMENT NONPHARMACOLOGIC THERAPY • Activity modification with increased periods of rest • Physical therapy

FIG. E1  Osgood-Schlatter disease. Fragmentation may be seen and a portion of the tibial tubercle ossification center is elevated. (From Grant LA: Grainger & Allison’s diagnostic radiology essentials, ed 2, Philadelphia, 2019, Elsevier.)

PT P

TA H

LONG

FIG. E2  Extended field of view (EFOV) of a patient with Osgood-Schlatter disease in the long axis with a knee in extension showing irregularity and fragmentation of the distal tibial apophysis. H, Hoffa fat; P, Patella; PT, patella tendon; TA, tibial apophysis. (From McNally E: Practical musculoskeletal ultrasound, ed 1, New York, 2005, Churchill Livingstone, p. 146.)

Osgood-Schlatter Disease SUGGESTED READINGS Circi E, Beyzadeoglu T: Results of arthroscopic treatment in unresolved OsgoodSchlatter disease in athletes, Int Orthop 41(2):351–356, 2017. Enomoto S et al: The passive mechanical properties of muscles and tendons in children affected by Osgood-Schlatter disease, J Pediatr Orthop, 2019 Jul 23, https://doi.org/10.1097/BPO.0000000000001426. [Epub ahead of print]. Indiran V, Jagannathan D: Osgood-Schlatter disease, NEJM 378(11):e15, 2018. Pagenstert G, et  al.: Reduction osteotomy of the prominent tibial tubercle after Osgood-Schlatter disease, Arthroscopy 33(8):1551–1557, 2017. Topol GA, et al.: Hyperosmolar dextrose injection for recalcitrant Osgood-Schlatter disease, Pediatrics 128(5):e1121–e1128, 2011.

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ALG   Osteoarthritis BASIC INFORMATION

SYNONYMS Degenerative joint disease (DJD) DJD Arthrosis OA ICD-10CM CODES M15.1 Heberden nodes (with arthropathy) M15.2 Bouchard nodes (with arthropathy) M15.3 Secondary multiple arthritis M15.4 Erosive OA M15.8 Other polyosteoarthritis M15.9 Polyarthrosis, unspecified M17 Gonarthrosis (arthrosis of knee) M18 Arthrosis of first metacarpal joint M19 Other arthrosis M19.8 Other specified arthrosis M19.9 Arthrosis, unspecified

EPIDEMIOLOGY & DEMOGRAPHICS PREVALENCE: Affects more than 30 million individuals in the U.S. Approximately 10% of men and 18% of women over the age of 60 yr are affected. PREDOMINANT SEX: Prior to age 50, there is almost no gender discrepancy. After age 50, there is increased incidence of OA in females compared to males. PREDOMINANT AGE: Occurs more frequently after 50 yr of age, but it is increasingly being recognized that OA may occur as early as 30 yr of age. GENETICS: 39% to 65% heritability rate in twin studies of women who have generalized OA, concordance rate of 0.64 in monozygotic twins. In genome-wide association studies, 11 candidate loci have been identified, but all with a very small effect size. RISK FACTORS: Osteoarthritis is considered predominantly a mechanical noninflammatory form of arthritis (Fig. 1). OA is thought to be the result of hostile biomechanics on an already susceptible joint (Fig. E2). Risk factors may be

genetics (candidate genes being evaluated include IGF-1 gene, cartilage oligomeric protein gene, vitamin D receptor gene). That said, there is no concrete evidence showing that preventing the disease or reducing disease progression can be achieved by supplemental vitamin D, antioxidants, or estrogen. Obesity also increases the susceptibility of developing osteoarthritis via systemic adipokines.

PHYSICAL FINDINGS & CLINICAL PRESENTATION • Similar symptoms in most forms: Pain generally with activity, stiffness, or gelling (generally short-lived and morning stiffness lasting less than 30 min), crepitus

TABLE 1  American College of Rheumatology Classification Criteria for Osteoarthritis Hip

Knee (Clinical Criteria)

Hand

Pain in the hip and two of the following: ESR 50 female PREDOMINANT AGE: All ages PHYSICAL FINDINGS & CLINICAL PRESENTATION HEMATOGENOUS OSTEOMYELITIS: • Usually occurs in tibia/fibula (children) • Localized inflammation: Often secondary to trauma with accompanying hematoma or cellulitis • Abrupt fever • Lethargy • Irritability • Pain in involved bone VERTEBRAL OSTEOMYELITIS: • Usually hematogenous • Fever: 50% • Localized pain/tenderness. Back pain is the most common initial symptom (86% of cases) • Neurologic defects: Motor/sensory (sensory loss, weakness, radiculopathy) CONTIGUOUS OSTEOMYELITIS: • Direct inoculation • Associated with trauma, fractures, surgical fixation • Chronic infection of skin/soft tissue • Fever, drainage from surgical site CHRONIC OSTEOMYELITIS: • Bone pain • Sinus tract drainage, nonhealing ulcer • Chronic low-grade fever • Chronic localized pain ETIOLOGY • Staphylococcus aureus • MRSA: Methicillin-resistant S. aureus • Pseudomonas aeruginosa • Enterobacteriaceae • Streptococcus pyogenes • Enterococcus • Mycobacteria • Fungi • Coagulase-negative staphylococci • Salmonella (in sickle cell disease)

IMAGING STUDIES • Bone radiograph examination (Fig. E1): Initial study but not sensitive in early osteomyelitis as may not show changes for as much as 2 wks • MRI with and without contrast (Fig. E2): Most accurate imaging study. CT only if patient has contraindication to MRI • Triple-phase technetium-99m bone scan (Fig. E3) when MRI is unavailable or contraindicated. Typically positive within a few days after onset of symptoms but accuracy is lower than that of MRI • Gallium scan (Ga-67) scintigraphy with single-photon emission CT (SPECT) has higher accuracy than bone scan but is less sensitive for detection of epidural abscess in vertebral osteomyelitis • Indium-111–labeled leukocyte scintigraphy scan; low sensitivity (2 yr is not recommended. It stimulates bone formation and reduces the risk of fracture but may increase the risk of stroke in older women with osteoporosis. Common side effects include headaches,

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ALG Postmenopausal women 65 yr

All patients with fragility fractures

Postmenopausal women 65 yr with risk factors

Bone densitometry

Men with risk factors (e.g., chronic corticosteroid use) T-score Above 1.0*

T-score 1.0 to 2.5

Low

T-score Below 2.5 Hig

h ri

risk

Observe and recommend • Calcium • Vitamin D • Exercise • Repeat BMD in 2-5 yr

sk

Evaluate for secondary causes

Recommend • Calcium, vitamin D, exercise plus • Antiresorptive therapy

Treat secondary causes

*Patients with fragility fractures and a T-score above 1.0 should be evaluated for other causes of pathologic fracture.

FIG. 3  Diagnosis and management of osteoporosis.

BOX 5  Recommended Laboratory Investigations for Individuals with Osteoporosis Recommended screening in all ­patients Serum calcium, albumin, ­phosphorus*,†,‡,§ Serum creatinine*,†,‡,§ Liver function tests* Bicarbonate* Complete blood count* 24-hour urinary calcium level*,†,‡,§ 25-hydroxyvitamin D level*,†,‡,§ Thyroid-stimulating hormone level*,†,‡,§ Other testing, if appropriate Biochemical markers of bone turnover*,†,‡,§ Cortisol levels*,‡ Protein electrophoresis*,†,§ Parathyroid hormone level*,§ * American Association of Clinical Endocrinologists guidelines. † National Osteoporosis Foundation Physician's Guide. ‡U.S. Surgeon General's report. § American College of Obstetricians and Gynecologists. From Hochberg MC: Rheumatology, ed 7, Philadelphia, 2019, Elsevier.

TABLE 3  Diagnostic Categories for Osteoporosis Based on World Health Organization Criteria Category

Definition

Normal Low bone mass (osteopenia) Osteoporosis

BMD not more than 1 SD below the young adult mean value BMD lying between 1 and 2.5 SD below the young adult mean value BMD more than 2.5 SD below the young adult mean value

BMD, Bone mineral density; SD, standard deviation. From World Health Organization data, 1994. In Hochberg MC: Rheumatology, ed 7, Philadelphia, 2019, Elsevier.

TABLE 4  Recommended Supplementation of Calcium and Vitamin D Individual Age Categories

Elemental Calcium

Vitamin D*

Birth-6 mo 6-12 mo 1-10 yr 11-24 yr Women and men 25-65 yr: Premenopausal or postmenopausal women taking estrogen Postmenopausal women, no estrogen

400 mg 600 mg 800 mg 1200-1500 mg/day 1000 mg/day

200 IU 200 IU 200 IU 400 IU 400-600 IU

1500 mg/day

Pregnant and lactating women National Osteoporosis Foundation guidelines

1200-1500 mg/day 1200 mg

400-600 IU for men and women >65 yr 400 IU 800-1000 IU

*These recommendations are guidelines and may be sufficient for healthy individuals with normal 25-hydroxyvitamin D levels. In many circumstances, however, they are insufficient. From Hochberg MC: Rheumatology, ed 7, Philadelphia, 2019, Elsevier.

ALG tive measures for all women lifelong; institution of treatment modalities that will result in a decrease in fracture risk; and reduction of morbidity, mortality, and unnecessary institutionalization, thereby improving quality of independent life and productivity. Table E5 summarizes the effect of major treatment options on the risk of vertebral, nonvertebral, and hip fractures.

CHRONIC Rx • Lifelong attention to behavior modification issues (nutrition, physical activity, fracture prevention strategies) and compliance with pharmacologic intervention. Recommendations include weight-bearing and muscle-strengthening exercises, smoking cessation, reduced alcohol intake, and adoption of fall prevention strategies. • There is little evidence to guide physicians about long-term bisphosphonate therapy. The decision to continue drug therapy beyond 5 yr should reflect reassessment of risk and benefit. The risk of atypical fracture of the femur increases after 5 yr of bisphosphonate use. It is reasonable to consider a drug holiday in postmenopausal women who are not at high fracture risk after 3 yr (IV) to 5 yr (oral) of bisphosphonate therapy. Continued treatment may be advisable in those at highest risk. • Continuing need to eliminate high-risk factors when possible and to optimally manage secondary causes of osteoporosis.

REFERRAL • To reproductive endocrinologist, medical endocrinologist, gynecologist, or rheumatologist if unfamiliar with diagnosis and management of osteoporosis • If multidisciplinary management is required, to other specialties depending on presence of acute fracture and/or secondary associated disorders

DISPOSITION Goals for diagnosis and treatment include identification of women at risk; initiation of preven-

PEARLS & CONSIDERATIONS COMMENTS • Osteonecrosis of the jaw is a known complication of high-dose IV bisphosphonate therapy for cancer; however, there is considerable debate on whether low-dose bisphosphonates used for osteoporosis can also cause this disorder. Evidence for this is inconclusive. • Long-term use (>10 yr) of bisphosphonates has been reported to increase risk of atypical subtrochanteric or femoral shaft fractures in several uncontrolled case series. Prodromal symptoms of thigh pain, lack of trauma prior to the procedure, and specific

radiologic characteristics (cortical thickening) have been reported. The evidence remains inconclusive. Patients can be reassured that short or intermediate use of bisphosphonates does not increase the risk of atypical femoral fractures. Current strategies should include considering a 12-mo interruption in therapy after 5 yr in patients who are clinically stable and considering teriparatide treatment in individuals who experience an atypical fracture while receiving bisphosphonate therapy. • Increased risk of esophageal cancer and atrial fibrillation have been reported as possible adverse effects of bisphosphonate therapy.

SUGGESTED READINGS Available at ExpertConsult.com RELATED CONTENT Osteoporosis (Patient Information) Medication-Related Osteonecrosis of the Jaw (Related Key Topic) Vertebral Compression Fractures (Related Key Topic) AUTHORS: Emily E. Nuss, MD, and Rachel Wright Heinle, MD, FACOG

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myalgia, hypercalcemia, and hypercalciuria. Trials involving abaloparatide, a selective activator of the parathyroid hormone type 1 receptor have also shown reduced risk of new vertebral and nonvertebral fractures in postmenopausal women with osteoporosis. • Estrogen prescription drugs or raloxifene should not be prescribed to treat women with osteoporosis.

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SUGGESTED READINGS Black DM: Bisphosphonates and fractures of the subtrochanteric or diaphyseal femur, N Engl J Med 362:1761-1771, 2010. Black DM, Rosen CJ: Clinical practice: postmenopausal osteoporosis, N Engl J Med 374:254-262, 2016. Boonen J et al: Fracture risk and zoledronic acid therapy in men with osteoporosis, N Engl J Med 367:1714-1723, 2012. Buckley L, Humphrey MB: Glucocorticoid-induced osteoporosis, N Engl J Med 379:2547-2556, 2018. Committee on Practice Bulletins-Gynecology: The American College of Obstetricians and gynecologists: ACOG practice Bulletin N. 129. Osteoporosis, Obstet Gynecol 120(3):718-734, 2012. Cosman F et al: Romosozumab treatment in postmenopausal women with osteoporosis, N Engl J Med 375:1532-1543, 2016. Cummings SR et al: Lasofoxifene in postmenopausal women with osteoporosis, N Engl J Med 362:686-696, 2010. Favus MJ: Bisphosphonates for osteoporosis, N Engl J Med 363:2027-2035, 2010. Fink HA et al: Long-term drug therapy and drug discontinuations and holidays for osteoporosis fracture prevention: a systematic review, Ann Intern Med 171(1):37-50, 2019.

McClung M et al: Bisphosphonate therapy for osteoporosis: benefits, risks, and drug holiday, Am J Med 126:13-20, 2013. Miller PD et al: Effect of abaloparatide vs placebo on new vertebral fractures in postmenopausal women with osteoporosis: a randomized, clinical trial, J Am Med Assoc 316(7):722-733, 2016. O'Connor KM: Evaluation and treatment of osteoporosis, Med Clin North Am 100(4):807-826, 2016. Ott SM: What is the optimal duration of bisphosphonate therapy? Clev Clin J Med 78:619, 2011. Qaseem A et al: Treatment of low bone density or osteoporosis to prevent fractures in men and women: a clinical practice guideline update from the American College of Physicians, Ann Int Med 166:818-839, 2017. Schilcher J et al: Bisphosphonate use and atypical fractures of the femoral shaft, N Engl J Med 364:1728-1737, 2011. Sellmeyer DE: Atypical fractures as a potential complication of long-term bisphosphonate therapy, J Am Med Assoc 304(13):1480-1484, 2010. South-Paul JE: Osteoporosis: part I. Evaluation and assessment, Am Fam Physician 63(5):897-904, 2001. Yu EW, Finkelstein JS: Bone density screening intervals for osteoporosis: one size does not fit all, J Am Med Assoc 307:2591-2592, 2012.

BOX E4  Investigations for Secondary Osteoporosis in Older People with Low Trauma Fractures or Low Bone Mineral Density Full blood count ESR or CRP Biochemical profile: Including renal function, adjusted serum calcium, and alkaline phosphatase Thyroid function tests Consider serum testosterone, sex hormone–binding globulin, LH, FSH (men) Serum and urine electrophoresis (vertebral fractures) Serum 25OHD and PTH CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; FSH, follicle-stimulating hormone; LH, luteinizing hormone; PTH, parathyroid hormone; 25OHD, 25 hydroxyvitamin. From Fillit HM: Brocklehurst’s textbook of geriatric medicine and gerontology, ed 8, Philadelphia, 2017, Elsevier.

FIG. E4  Regional osteoporosis. Hand radiograph in early rheumatoid arthritis (RA) shows periarticular osteopenia at the metacarpophalangeal and interphalangeal joints, with joint space narrowing and juxtaarticular erosions. The periarticular osteopenia is the earliest radiographic feature of RA and is related to hyperemia, synovial inflammation, and local cytokines that stimulate osteoclastic bone resorption. (From Pope TL et al: Musculoskeletal imaging, ed 2, Philadelphia, 2015, WB Saunders.)

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A

B

FIG. E5  General osteoporosis. Radiographic features include reduced radiographic density (osteopenia) with reduction in the number of trabeculae, which may be destroyed completely, and the bone cortex becomes thinned as evident in the lateral radiograph of the calcaneus (A) and radiograph of the phalanx (B). When these features are present, bone densitometry using dual-energy x-ray absorptiometry (DEXA) should be suggested. (From Pope TL et al: Musculoskeletal imaging, ed 2, Philadelphia, 2015, WB Saunders.)

TABLE E5  Effect of Major Treatment Options on the Risk of Vertebral, Nonvertebral, and Hip Fractures

Alendronate Etidronate Risedronate Raloxifene Strontium ranelate Teriparatide Denosumab Zoledronate* Ibandronate* Calcium and vitamin D*

Vertebral Fractures

Nonvertebral Fractures

Hip Fractures

A A A A A A A A A ND

A ND A ND A A A A (A) A

A ND A ND (A) ND A A ND A

A indicates evidence from randomized, controlled trials and/or meta-analysis; (A) reflects that a beneficial effect on fracture risk was found only in post hoc subgroup analysis; ND indicates that fracture reduction has not been demonstrated. *Not included in current National Institute for Health and Clinical Excellence (NICE) guidance. From Fillit HM: Brocklehurst’s textbook of geriatric medicine and gerontology, ed 8, 2017, Elsevier.

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Otitis Externa  BASIC INFORMATION DEFINITION Otitis externa refers to a variety of conditions causing inflammation and/or infection of the external auditory canal (and/or auricle and tympanic membrane). There are six subgroups of otitis externa: 1. Acute localized otitis externa (furunculosis) 2.  Acute diffuse bacterial otitis externa (i.e., “swimmer ear”) 3. Chronic otitis externa 4. Eczematous otitis externa 5. Fungal otitis externa (otomycosis) 6. Invasive or necrotizing (malignant) otitis |externa SYNONYMS See “Definition.” ICD-10CM CODES H60.90 Unspecified otitis externa, unspecified ear H60.2 Malignant otitis externa H60.3 Other infective otitis externa H60.5 Acute otitis externa, non-infective H60.8 Other otitis externa

EPIDEMIOLOGY & DEMOGRAPHICS INCIDENCE (IN U.S.): • Among the most common disorders • An estimated 10% of people develop external otitis during their lifetime • Affects 3% to 10% of patients seeking otologic care PREVALENCE (IN U.S.): • Diffuse otitis externa is most often seen in swimmers and in hot, humid climates, conditions that lead to water retention in the ear canal. In the U.S., 44% of AOErelated healthcare visits occur June to August. • Necrotizing otitis externa is more common in elderly, diabetics, and immunocompromised patients. PREDOMINANT SEX: None PREDOMINANT AGE: • Occurs at all ages, however incidence is highest during childhood and decreases with age • Necrotizing otitis externa: Typically occurs in elderly: Mean age >65 yr PHYSICAL FINDINGS & CLINICAL PRESENTATION The two most common symptoms are otalgia, ranging from pruritus to severe pain exacerbated by motion (e.g., chewing), and otorrhea. Patients may also experience aural fullness and hearing loss as a result of swelling with occlusion of the canal. More intense symptoms may occur with bacterial otitis externa, with or without fever, and lymphadenopathy (anterior to tragus). Findings unique to specific forms of the infection include: • Acute localized otitis externa (furunculosis):

1. Occurs from infected hair follicles, usually in the outer third of the ear canal, forming pustules and furuncles 2. Furuncles are superficial and pointing or deep and diffuse • Impetigo: 1. In contrast to furunculosis, this is a superficial spreading infection of the ear canal that may also involve the concha and the auricle 2. Begins as a small blister that ruptures, releasing straw-colored fluid that dries as a golden crust • Erysipelas: 1.  Caused by group A streptococcus (Streptococcus pyogenes, GAS) 2. May involve the concha and canal 3. May involve the dermis and deeper tissues 4. Area of cellulitis, often with severe pain 5. Fever, chills, malaise 6. Regional adenopathy • Eczematous or seborrheic otitis externa: 1.  Stems from a variety of dermatologic problems that can involve the external auditory canal 2. Severe itching, erythema, scaling, crusting (Fig.E1), and fissuring possible • Acute diffuse otitis externa (swimmer ear): 1. Begins with itching and a feeling of pressure and fullness in the ear that becomes increasingly tender and painful 2. Mild erythema and edema of the external auditory canal, which may cause narrowing and occlusion of the canal (Fig.E2), leading to hearing loss 3.  Minimal serous secretions, which may become profuse and purulent 4.  Tympanic membrane may appear dull and infected 5. Usually absence of systemic symptoms such as fever, chills • Otomycosis: 1. Chronic superficial infection of the ear canal and tympanic membrane 2. In primary fungal infection, major symptom is intense itching 3. In secondary infection (fungal infection superimposed on bacterial infection), major symptom is pain 4. Fungal growth of variety of colors • Chronic otitis externa: 1. Dry and atrophic canal 2. Typically lack of cerumen 3. Itching, often severe, and mild discomfort rather than pain 4. Occasionally mucopurulent discharge 5. With time, thickening of the walls of the canal, causing narrowing of the lumen • Necrotizing otitis externa (also known as malignant otitis externa). Typically seen in older patients with diabetes or in patients who are immunocompromised 1. Redness, swelling, and tenderness of the ear canal 2. Classic finding of granulation tissue on the floor of the canal and the bone–cartilage junction

3. Small ulceration of necrotic soft tissue at bone–cartilage junction 4.  Most common symptoms: Pain (often severe) and otorrhea 5. Lessening of purulent drainage as infection advances 6. As the infection advances, osteomyelitis of the base of the skull and temporomandibular joint osteomyelitis can develop 7. Facial nerve palsy often the first and only cranial nerve defect 8.  Possible involvement of other cranial nerves

ETIOLOGY • Box 1 summarizes common pathogens in otitis externa • Acute localized otitis externa: Staphylococcus aureus • Impetigo: 1.  S. aureus including MRSA 2.  Streptococcus pyogenes (GAS) • Erysipelas: GAS • Eczematous otitis externa: 1. Seborrheic dermatitis 2. Atopic dermatitis 3. Psoriasis 4. Neurodermatitis 5. Lupus erythematosus • Acute diffuse otitis externa: 1. Swimming 2. Hot, humid climates 3. Tightly fitting hearing aids 4. Use of ear plugs 5.  Pseudomonas aeruginosa 6.  S. aureus including MRSA • Otomycosis: 1. Prolonged use of topical antibiotics and steroid preparations 2. Uncontrolled diabetes mellitus can contribute to risk 3.  Aspergillus (80% to 90%) 4.  Candida • Chronic otitis externa: Persistent low-grade infection and inflammation • Necrotizing otitis externa (NOE):

BOX 1  Common Pathogens in Otitis Externa Gram-negative Organisms Pseudomonas aeruginosa Pseudomonas spp. Nov. “otitidis” Proteus mirabilis Serratia marcescens Gram-positive Organisms Staphylococcus aureus Staphylococcus epidermidis Corynebacterium auris Enterococcus faecalis Fungi and Yeasts Aspergillus fumigatus Candida albicans Candida parapsilosis From Cherry JD et al: Feigin and Cherry’s pediatric infectious diseases, ed 8, Philadelphia, 2019, Elsevier.

Otitis Externa 1. Complication of persistent otitis externa 2. Extends through Santorini fissures, small apertures at the bone-cartilage junction of the canal, into the mastoid and along the base of the skull 3.  P. aeruginosa

DIAGNOSIS

WORKUP Thorough history and physical examination LABORATORY TESTS • Cultures from the canal are usually not necessary unless the condition does not respond to treatment. • Leukocyte count normal or mildly elevated. • Erythrocyte sedimentation rate is often quite elevated in malignant otitis externa. IMAGING STUDIES • CT scan is the best technique for defining bone involvement and extent of disease in malignant otitis externa. • MRI is slightly more sensitive in evaluation of soft tissue changes and intracranial extension of infection. • Gallium scans are more specific than bone scans in diagnosing NOE. • Follow-up scans are helpful in determining efficacy of treatment. note: Expert opinion supports history and physical examination as the best means of diagnosis. Persistent pain that is constant and severe should raise the question of NOE (particularly in the elderly, diabetics, and immunocompromised patients).

TREATMENT NONPHARMACOLOGIC THERAPY • Cleansing and debridement of the ear canal with cotton swabs and hydrogen peroxide or other antiseptic solution allows a more thorough examination of the ear. • If the canal lumen is edematous and too narrow to allow adequate cleansing, a cotton wick or gauze strip inserted into the canal serves as a conduit for topical medications to be drawn into the canal. Usually remove wick after 2 days.

ACUTE GENERAL Rx Topical medications: • An acidifying agent such as 2% acetic acid (Vosol) inhibits growth of bacteria and fungi • Topical antibiotics (in the form of otic or ophthalmic solutions) or antifungals, often in combination with an acidifying agent and a steroid preparation. Direct application of topical agents to the infected site is a key element in the treatment of external otitis regardless of severity. Proper installation of eardrops entails tilting the head toward the opposite shoulder, pulling the superior aspect of the auricle upward, and filling the ear canal with drops. In young children, the earlobe should be pulled downward to fill the canal • The ideal antibiotic regimen should have coverage against the most common pathogens, S. aureus and P. aeruginosa • Side effect profile can also influence choice of treatment. Ototoxicity is the most important concern with aminoglycoside drugs, including neomycin, tobramycin, and gentamicin. Aminoglycosides are a significant potential source for iatrogenic hearing loss and balance dysfunction, particularly in the presence of tympanic membrane perforation. Allergic contact dermatitis is commonly associated with neomycin when used for

prolonged courses. Topical fluoroquinolones can cause local irritation • The following are some of the available preparations: 1. Neomycin otic solutions and suspensions: a. With polymyxin-B-hydrocortisone (Cortisporin) b. With hydrocortisone-thonzonium (Coly-Mycin S) 2. Polymyxin-B-hydrocortisone (Otobiotic) 3. Quinolone otic solutions: a. Ofloxacin 0.3% solution (Floxin Otic) b. Ciprofloxacin 0.3% with hydrocortisone (Cipro HC) 4. Quinolone ophthalmic solutions: a. Ofloxacin 0.3% (Ocuflox) b. Ciprofloxacin 0.3% (Ciloxan) 5. Aminoglycoside ophthalmic solutions: a. Gentamicin sulfate 0.3% (Garamycin) b. Tobramycin sulfate 0.3% (Tobrex) c. Tobramycin 0.3% and dexamethasone 0.1% (TobraDex) 6. Chloramphenicol 0.5% otic solution or 0.25% ophthalmic solution (Chloromycetin) 7. Gentian violet (methylrosaniline chloride 1%, 2%) 8. Antifungals: a. Amphotericin B 3% (Fungizone lotion) b. Clotrimazole 1% solution (Lotrimin) c. Tolnaftate 1% (Tinactin) • Topical preparations should be applied qid (bid for quinolones, antifungals), generally for 3 days after cessation of symptoms (average 10-14 days total)

TABLE 1  Differential Diagnosis of Painful External Ear and Auditory Canal Disorders Disorder

Clinical Features

Acute otitis externa Malignant otitis externa Dermatitis  Eczema

Diffuse redness, swelling, and pain of the canal with greenish to whitish exudate; often very tender pinna Rapidly progressive, severe swelling and redness of pinna, which may be laterally displaced

 Contact  Seborrhea  Psoriasis Cellulitis Furuncles Infected periauricular cyst Insect bites Herpes zoster Perichondritis Tumors Foreign body Trauma

History of atopy, presence of lesions elsewhere; lesions are scaly, red, pruritic, and weeping History of cosmetic use or irritant exposure; lesions are scaly, red, pruritic, and weeping Scaly, red, papular dermatitis; scalp may have thick, yellow scales History or presence of psoriasis elsewhere; erythematous papules that coalesce into thick, white plaques Diffuse redness, tenderness, and swelling of the pinna Red, tender papules in areas with hair follicles (distal third of the ear canal) Discrete, palpable lesions; history of previous swelling at same site; cellulitis may develop, obscuring cystic structure History of exposure; lesions are red, tender papules Painful, vesicular lesions in the ear canal and tympanic membrane in the distribution of cranial nerves V and VII Inflammation of the cartilage, usually secondary to cellulitis Palpable mass, destruction of surrounding structures Foreign body may cause secondary trauma to the ear canal or become a nidus for an infection of the ear canal Bruising and swelling of external ear; there may be signs of basilar skull fracture (cerebrospinal fluid otorrhea, hemotympanum)

From Kliegman RM, Lye PS, Bordini BJ, et al, editors: Nelson pediatric symptom-based diagnosis, Philadelphia, 2018, Elsevier, table 4.1, p. 62, in Kliegman, RM: Nelson textbook of pediatrics, ed 21, Philadelphia, 2020, Elsevier.

O

Diseases and Disorders

DIFFERENTIAL DIAGNOSIS • Acute otitis media • Bullous myringitis • Mastoiditis • Foreign bodies • Neoplasms • Contact dermatitis • Eczema • Ramsey-Hunt syndrome • Seborrhea • Otomycosis • Referred pain • Table 1 describes the differential diagnosis of painful external ear and auditory canal disorders.

• Local heat is useful in treating deep furunculosis. • Incision and drainage is indicated in treatment of superficial pointing furunculosis.

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Otitis Externa Systemic antibiotics: • Reserved for when the infection has spread beyond the ear canal. • Treatment usually for 10 days with ciprofloxacin 750 mg q12h or ofloxacin 400 mg q12h, or with antistaphylococcal agent (e.g., dicloxacillin or cephalexin 500 mg q6h). Use Bactrim or clindamycin when MRSA suspected or cultured at one DS twice a day instead of cephalexin or dicloxacillin. For malignant otitis externa (due to Pseudomonas aeruginosa in >90% of cases), effective agents are meropenem 1 g IV q8h or ciprofloxacin 400 mg IV q12h or 750 mg PO q12h or cefepime 2 g q12h. Treatment for NOE: • Requires prolonged therapy up to 3 mo; whether to use oral parenteral therapy is based on clinical judgment • Oral quinolones, ciprofloxacin 750 mg q12h or ofloxacin 400 mg q12h may be appropriate initial therapy or used to shorten the course of IV therapy • Intravenous antipseudomonals with or without aminoglycosides are also appropriate • Local debridement

Pain control: • May require NSAIDs or opioids • Topical corticosteroids to reduce swelling and inflammation

CHRONIC Rx • Patients prone to recurrent infections should try to identify and avoid precipitants to infection. • Swimmers should try tight-fitting ear plugs or tight-fitting bathing caps and remove all excess water from the ears after swimming. • Treat underlying systemic diseases and dermatologic conditions that predispose to infection. • Hearing aids should be removed nightly and regularly cleaned. DISPOSITION Inadequate treatment of otitis externa may lead to NOE and mastoiditis. REFERRAL To an otolaryngologist: • NOE • Treatment failure • Severe pain

 EARLS & P CONSIDERATIONS Otitis externa varies in severity from a mild irritation of the external acoustic canal (swimmer ear) that resolves spontaneously by simply removing the offending agent (stay out of freshwater or wear ear plugs when swimming) to a life-threatening infection with the risk of intracranial extension, gram-negative bacterial meningitis, and severe neurologic impairment with multiple cranial neuropathy. Do not miss severe malignant otitis externa in patients who are diabetic or immunocompromised.

SUGGESTED READINGS Available at ExpertConsult.com RELATED CONTENT Otitis Externa (Patient Information) AUTHOR: Russell J. McCulloh, MD

Otitis Externa SUGGESTED READINGS Kausnik V et al: Interventions for acute otitis externa, Cochrane Database Syst Rev 1:CD004740, 2010. Long M: Otitis externa, Pediatr Rev 34(3):143-144, 2013. Rosenfeld RM et al: Clinical practice guideline: acute otitis externa, Otolaryngol Head Neck Surg 150(1):S1-S24, 2014.

FIG. E1  Patient with acute otitis externa, with purulent drainage from the ear canal and mild edema and erythema of the pinna. (From Cherry JD et al: Feigin and Cherry’s pediatric infectious diseases, ed 8, Philadelphia, 2019, Elsevier.)

FIG. E2  Acute otitis externa. (From Swartz MH: Textbook of physical diagnosis, history and examination, ed 7, Philadelphia, 2014, Elsevier.)

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Otitis Media BASIC INFORMATION

SYNONYMS Acute suppurative otitis media Purulent otitis media Acute otitis media AOM ICD-10CM CODES H65.3 Chronic mucoid otitis media H66.0 Acute suppurative otitis media H66.4 Suppurative otitis media, unspecified H66.9 Otitis media, unspecified H66.1 Chronic tubotympanic suppurative otitis media H66.2 Chronic atticoantral suppurative otitis media

EPIDEMIOLOGY & DEMOGRAPHICS INCIDENCE (IN U.S.): • Affects patients of all ages but is largely a disease of infants and young children. • Affects approximately 80% of all children by age 5 yr. • Occurs three or more times in one third of all children by age 3 yr. • Costs associated with otitis media exceed $5 billion, with 40% of the costs occurring from patients ages 1 to 3. • One of the most common indications for antibiotic prescription among children. PEAK INCIDENCE: • AOM occurs at all ages but is most prevalent between 6 and 24 mo of age. • A second peak in incidence occurs between 4 and 6 yr of age. • AOM is most frequent in the fall, winter, and early spring (coincident with peak respiratory virus prevalence in the community). • Incidence of infection declines with age; AOM is seen infrequently in adults. RISK FACTORS: • Daycare attendance • Limited or no breastfeeding • Tobacco smoke exposure • Pacifier use • Craniofacial anomalies • Immune globulin G (IgG) or subclass deficiencies PHYSICAL FINDINGS & CLINICAL PRESENTATION • Moderate to severe bulging of the TM. • Fluid in the middle ear along with signs and symptoms of local inflammation.

ETIOLOGY • Most common etiology is a viral upper respiratory tract infection, which causes inflammation and dysfunction of the eustachian tube and transient aspiration of nasopharyngeal secretions into the middle ear (Fig. 2). Bacterial colonization from the nasopharynx in conjunction with eustachian tube dysfunction leads to infection. • May occasionally develop as a result of hematogenous spread or by direct invasion from the nasopharynx. • Conjugated pneumococcal vaccination of children has resulted in decreases in Streptococcus pneumoniae causing AOM. • Most common bacterial pathogens: 1.  S. pneumoniae causes up to half of cases and is the least likely of the major pathogens to resolve without treatment. 2.  Haemophilus influenzae. 3.  Moraxella catarrhalis. 4.  Of increasing importance, infection caused by penicillin-nonsusceptible S. pneumoniae (MIC >0.1 mg/ml), ranging from 8% to 34%. About 50% of PNSSP

isolates are penicillin-intermediate (MIC 0.1 to 2.0 mg/ml). 5. Group A streptococci is associated with higher rates of TM perforation than AOM caused by other pathogens. • Viral pathogens: 1. Respiratory syncytial virus (RSV) 2. Rhinovirus 3. Adenovirus 4. Influenza • Others: 1.  Mycoplasma pneumoniae 2.  Chlamydia trachomatis 3.  Streptococcus pyogenes (Latin America)

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • Otitis externa • Otitis media with effusion (OME): An algorithm for distinguishing between acute otitis media and otitis media with effusion is illustrated in Fig. 3 • Referred pain from mouth, nasopharynx, or throat • Section II describes the differential diagnosis of earache WORKUP Thorough otoscopic examination. AOM is a visual diagnosis based on viewing the tympanic membrane. Adequate visualization of the tympanic membrane may require removal of cerumen and debris. • Tympanometry 1.  Measures compliance of the tympanic membrane and middle ear pressure 2. Detects the presence of fluid, but cannot determine whether the fluid is infected • Acoustic reflectometry 1.  Measures sound waves reflected from the middle ear 2. Is useful in infants >3 mo 3. Increased reflected sound correlated with the presence of effusion, but cannot determine whether the fluid is infected LABORATORY TESTS • Tympanocentesis. 1. Not necessary in most cases because the microbiology of middle ear effusions has been shown to be extremely consistent 2. May be indicated in: a. Patients who do not respond to treatment in 72 hours or those who experience multiple treatment failures b. Immunocompromised patients • Cultures of the nasopharynx are not helpful. • Blood counts (generally unnecessary)usually reveal leukocytosis with polymorphonuclear elevation. • Plain mastoid radiographs (generally unnecessary) reveal haziness in the periantral cells that may extend to entire mastoid. • CT or MRI may be indicated if serious complications are suspected (meningitis, brain abscess, severe mastoiditis).

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Diseases and Disorders

DEFINITION Acute otitis media (AOM) is defined by infected middle ear fluid resulting in moderate to severe bulging of the tympanic membrane (TM) or new onset of otorrhea not due to acute otitis externa. Care should be taken to differentiate AOM from serous otitis media, which involves noninfected middle ear fluid that does not result in bulging of the TM. Serous otitis media does not require antibiotic treatment.

1.  Erythema with diminished light reflex (Fig. E1) • As infection progresses, middle ear exudation occurs (exudative phase); the exudate rapidly changes from serous to purulent (suppurative phase). • Retraction and poor mobility of the TM ensue, and the TM begins to bulge. • At any time during the suppurative phase, the TM may rupture, releasing the middle ear contents (otorrhea). • Erythema of the TM without other abnormalities is not a diagnostic criterion for acute otitis media (AOM) because it may occur with any inflammation of the upper respiratory tract, crying, or nose blowing. • Symptoms: 1. Rapid- or recent-onset otalgia, ranging from slight discomfort to severe, is the most common presenting symptom. 2.  Hearing loss while middle ear fluid is present. 3. Otorrhea (if TM has ruptured). 4. Systemic symptoms such as fever, listlessness, irritability, decreased appetite, vomiting, and diarrhea are common. Vertigo, facial swelling, nystagmus, tinnitus, lethargy, and facial nerve palsies can occur as complications of AOM. 5.  Table 1 summarizes symptom scoring systems designed to aid in diagnosis. • After an episode of AOM: 1. Persistence of effusion for wks or mos (called secretory, serous, or nonsuppurative otitis media). 2. Fever and otalgia usually absent. 3. Hearing loss possible (10 to 50 dB, with predominant involvement of the low frequencies). 4. Manifestations of the sequelae and complications of otitis media are summarized in Table E2.

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Otitis Media TABLE 1  Acute Otitis Media Symptom Scoring Systems Designed to Aid in Diagnosis 3-Item Otitis Media Score (OM-3) Physical suffering Emotional distress Limitation of activities

Ear Treatment Group Symptom Questionnaire (ETG-5) Ear pain Fever Irritability

Acute Otitis Media Faces Scale (AOM-FS) Seven facial expressions ranging from no problem to extreme problem

Appetite

Otoscopic Severity Scale (OS-8) Eight categories of TM inflammationb

Sleep quality

Acute Otitis Media Severity of Symptom Scale (AOM-SOS)

Otitis Media Clinical Severity Index (OM-CSI) 30-Point Scalea

Otitis Media Clinical Severity Index (OM-CSI) 10-Point Scalea

Ear pain Ear tugging Irritability

Ear pain Fever Irritability

Ear pain Fever Irritability

Decreased play

Fever at examination TM erythema

Fever at examination

TM mobility TM position Effusion color Otorrhea

TM mobility TM position Effusion color Otorrhea

Decreased appetite Difficulty sleeping Fever

TM erythema

TM, Tympanic membrane. aThe 30-point scale used a 2- to 5-point Likert scale and the 10-point scale used a 2- to 3-point Likert scale. b0 = normal; 1 = erythema only; 2 = erythema, air-fluid level, clear fluid; 3 = erythema, complete effusion, no opacification; 4 = erythema, opacification with air-fluid level or air bubbles, no bulging; 5 = erythema, complete effusion, opacification, no bulging; 6 = erythema, bulging rounded doughnut appearance of the tympanic membrane; 7 = erythema, bulging, complete effusion and opacification with bulla formation. From Cherry JD et al: Feigin and Cherry’s pediatric infectious diseases, ed 8, Philadelphia, 2019, Elsevier.

Upper respiratory tract viral infection Inflammation in the nasopharynx and eustachian tube Increased inflammatory mediators Increased bacterial colonization and adherence Decreased mucociliary clearance of the nasopharynx, eustachian tube, and middle ear mucosal cells Eustachian tube dysfunction/obstruction and development of negative middle ear pressure Mucus production and development of middle ear effusion Reflux of colonized otopathogens and URI viruses into the middle ear space Immune and inflammatory responses in the middle ear space with development of purulent material Acute otitis media signs and symptoms

FIG. 2  Pathogenesis of virus-induced acute otitis media. URI, Upper respiratory infection. (From Cherry JD et al: Feigin and Cherry’s pediatric infectious diseases, ed 8, Philadelphia, 2019, Elsevier.)

TREATMENT ACUTE GENERAL Rx Hydration, avoidance of irritants (e.g., tobacco smoke), nasal decongestants, cool mist humidifier, and oral ibuprofen or acetaminophen. Topical procaine or lidocaine prepara-

tions (if available) are an alternative to oral analgesics for children ≥2 yr but should not be used in children with tympanic membrane perforation. Antimicrobials: note: Most uncomplicated cases of AOM resolve spontaneously, without complications. Studies have demonstrated limited therapeutic

benefit from antibiotic therapy. Watchful waiting is appropriate for children who look well, can be comforted with supportive care, and are old enough to easily evaluate. Children 4 regional lymph nodes

DISTANT METASTASES (M): MX M0 M1

Presence of distant metastasis cannot be assessed No distant metastasis Distant metastasis

STAGING GROUPS: IA IB IIA IIB III IV

T1, N0, M0 T2, N0, M0 T3, N0, M0 T1-3, N1, M0 T1-3, N2, M0 T4, any N, M0 Any T, any N, M1

TREATMENT Treatment sequencing strategies are summarized in Fig. 5 and Table 3.

SURGERY FOR RESECTABLE DISEASE • Classification of resectability of pancreatic cancer per the National Comprehensive Cancer Network and Surgical Oncology Expert Consensus Statement is summarized in Table 4. • Curative cephalic pancreaticoduodenectomy (Whipple procedure) for tumors in the head and neck of the pancreas is appropriate for only 10% to 20% of patients whose lesion is 180 degrees with contour irregularity of the vein or thrombosis of the vein but with suitable vessel proximal and distal to the site of involvement, allowing for safe and complete resection and vein reconstruction • Solid tumor contact with the IVC • Solid tumor contact with the common hepatic artery without extension to the celiac axis or hepatic artery bifurcation, allowing for safe and complete resection and reconstruction • Solid tumor contact with the SMA ≤180 degrees • Solid tumor contact with variable anatomy (e.g., accessory right hepatic artery, replaced right hepatic artery, replaced common hepatic artery, and the origin of replaced or accessory artery), and the presence and degree of tumor contact should be noted if present, as it may affect surgical planning • For tumors of the body or tail: • Solid tumor contact with the celiac axis of ≤180 degrees • Solid tumor contact with the celiac axis >180 degrees without involvement of the aorta and with an intact and uninvolved gastroduodenal artery, thereby permitting a modified Appleby procedure (although some members of the consensus committee preferred this criterion to be in the unresectable category) • Head of pancreas or uncinate lesions: • Solid tumor contact with the SMA >180 degrees • Solid tumor contact with the celiac axis >180 degrees • Solid tumor contact with the first jejunal SMA branch • Unreconstructable SMV or portal vein because of tumor involvement or occlusion (can be because of tumor or bland thrombus) • Contact with the most proximal draining jejunal branch into the SMV • Body and tail lesions: • Solid tumor contact of >180 degrees with the SMA or celiac axis • Solid tumor contact with the celiac axis and aortic involvement • Unreconstructable SMV or portal vein because of tumor involvement or occlusion (can be because of tumor or bland thrombus) • For all sites: • Distant metastases • Metastases to lymph nodes beyond the field of resection • Any presence of distant metastases

Borderline resectable

Unresectable/locally advanced

Metastatic

From Niederhuber JE: Abeloff’s Clinical Oncology, ed 6, Philadelphia, 2020, Elsevier.

asymptomatic adults by abdominal palpation, ultrasonography, or serologic markers. The USPSTF found no evidence that screening for pancreatic cancer is effective in reducing mortality rates. There is potential for significant harm because of the low prevalence of pancreatic cancer, limited accuracy of available screening tests, invasive nature of diagnostic tests, and poor outcome of treatment. Alcohol consumption, specifically liquor consumption of three or more drinks per day, increases pancreatic cancer mortality independent of smoking. • Patients should be referred for pancreatic cancer surgery to high-volume medical

centers that perform at least 15 to 20 cases a yr. • Adjuvant chemotherapy with either a singleagent or doublet regimen for 6 mo has been shown to improve survival and should be recommended in all patients with a maintained performance status after surgical resection. The role of radiotherapy in the adjuvant setting is best restricted to patients who have a high risk for locoregional recurrence.

SUGGESTED READINGS Available at ExpertConsult.com

RELATED CONTENT Pancreatic Cancer (Patient Information) AUTHOR: Ritesh Rathore, MD

ALG

Pancreatic Cancer (Exocrine)

TABLE 5  Acceptable Chemotherapy Regimens for Locally Advanced and Metastatic Diseasea Metastatic Disease

Options for patients with good performance status: • FOLFIRINOX • Gemcitabine + albumin bound-paclitaxel • Gemcitabine + erlotinib • Gemcitabine + capecitabine • Gemcitabine + cisplatin (especially for in patients with BRCA1/2 mutation and/or family history) • Capecitabine single agent • CI 5-FU • Fixed-dose gemcitabine/docetaxel/capecitabine (GTX regimen) • Fluoropyrimidine + oxaliplatin • Chemotherapy (any of above) followed by chemoradiation or SBRT • Chemoradiation or SBRT Options for patients with poor performance status: • Gemcitabine • Capecitabine • CI 5-FU

Options for patients with good performance status: • FOLFIRINOX (category 1) • Gemcitabine + albumin bound-paclitaxel (category 1) • Gemcitabine + erlotinib (category 1) • Gemcitabine (category 1) • Gemcitabine + capecitabine • Gemcitabine + cisplatin (especially for in patients with BRCA1/2 mutation and/or family history) • Fixed-dose gemcitabine/docetaxel/capecitabine (GTX regimen) (category 2B) • Fluoropyrimidine + oxaliplatin (category 2B)

Options for patients with poor performance status: • Gemcitabine (category 1) • Capecitabine (category 2B) • CI 5-FU (category 2B)

aLevel

of Recommendation is based on National Comprehensive Cancer Network (NCCN) Guidelines. Category 1 is based on high-level evidence with uniform NCCN consensus that the intervention is appropriate. Category 2B is based on lower level evidence with NCCN consensus that the intervention is appropriate. CI, Continuous infusion; 5-FU, 5-fluoroacil; FOLFIRINOX, 5-FU, irinotecan, oxaliplatin; GTX, gemcitabine, docetaxel, capecitabine; SBRT, stereotactic body radiation therapy. From Niederhuber JE: Abeloff’s clinical oncology, ed 6, Philadelphia, 2020, Elsevier.

TABLE 6  Risk Factors for Pancreatic Cancer Risk Factor High Risk (>10-fold) FAMMM Hereditary pancreatitis Peutz-Jeghers syndrome Three or more first-degree relatives with PC Moderate Risk (5- To 10-fold) Two first-degree relatives with PC Cystic fibrosis Chronic pancreatitis BRCA2 mutation carrier PALB2 mutation carrier Low Risk (48 hours) • T he BALI Score2 evaluates only four variables: 1. BUN ≥25 mg/dl 2. Age ≥65 yr 3. LDH ≥300 U/L 4. Interleukin-6 level ≥300 pg/ml • T hese measurements are taken at admission and at 48 hours. Mortality is >25% for a score of 3 and exceeds 50% with a score of 4. • Severe acute pancreatitis (SAP) is diagnosed by the presence of any of the following four criteria: 1. Organ failure with one or more of the following: Shock (systolic blood pressure 2 mg/dl after rehydration), and gastrointestinal bleeding (>500 ml/24 hr) 2. Local complications such as necrosis, pseudocyst, or abscess 3. At least three of Ranson criteria (see tables) or 4. At least eight of the Acute Physiology and Chronic Health Evaluation II (APACHE II) criteria ICD-10CM CODES K85.0 Idiopathic acute pancreatitis K85.1 Biliary acute pancreatitis K85.2 Alcohol induced acute pancreatitis K 85.3 Drug induced pancreatitis K85.6 Other acute pancreatitis K85.9 Acute pancreatitis, unspecified

1 Banks

PA, et  al: Acute Pancreatitis Classification Working Group: classification of acute pancreatitis-2012: revision of the Atlanta classification and definitions by international consensus, Gut 62(1):102-111, 2013. 2 Spitzer AL, et  al: Applying Ockham’s razor to pancreatitis prognostication: a four-variable predictive model, Ann Surg 243(3):380-388, 2006.

EPIDEMIOLOGY & DEMOGRAPHICS • The incidence of pancreatitis is increasing in the U.S. Admissions for acute pancreatitis have increased dramatically, and acute pancreatitis was the number-one GI-related cause for admission across U.S. hospitals in 2012. There are >270,000 cases of acute pancreatitis reported annually in the U.S., with 40%+ due to gallstone disease (most common cause) and 30% due to alcohol. • Incidence in urban areas is twice that of rural areas (20/100,000 persons in urban areas). • 20% of patients have necrotizing pancreatitis; the remainder have interstitial, or edematous, pancreatitis. • Drugs are responsible for less than 5% of all cases of acute pancreatitis. PHYSICAL FINDINGS & CLINICAL PRESENTATION • Epigastric tenderness and guarding, often radiating to the back; pain usually developing suddenly, reaching peak intensity within 10 to 30 min, severe and lasting several hours without relief. Rarely, some patients can have painless severe pancreatitis

• Nausea and vomiting (up to 90% of cases) • Hypoactive bowel sounds (from ileus) • Tachycardia, shock (from decreased intravascular volume) • Confusion (from metabolic disturbances) • Fever (SIRS response or infection when pancreatic necrosis is present) • Decreased breath sounds (pleural effusions) or rales (atelectasis, acute respiratory distress syndrome [ARDS]) • Jaundice (from obstruction or compression of biliary tract) • Ascites (from tear in pancreatic duct, leaking pseudocyst) • Palpable abdominal mass (pseudocyst, phlegmon, abscess, carcinoma) • Evidence of hypocalcemia (Chvostek sign, Trousseau sign) • Evidence of retroperitoneal bleeding (hemorrhagic pancreatitis): 1. Ecchymosis around the umbilicus (Cullen sign) 2. Ecchymosis involving the flanks (Grey Turner sign) • Tender subcutaneous nodules (caused by subcutaneous fat necrosis)

TABLE 1  Commonly Used Scoring Systems: Advantages and Disadvantages System

Scoring

Advantages

Disadvantages

Ranson criteria on admission:

One point for each factor listed; score >3 indicates SAP

Well known, relatively easy to calculate

Requires 48 hr to complete evaluation

Score >8 predicts SAP

Can be calculated within 24 hr of admission Ease of use, available within 24 hr of admission

Requires large dataset for processing

Excellent predictor of local complications; can show infected pancreatic necrosis

Requires 72 to 96 hr, making it a poor test for guiding decisions at admission

1 . Age >55 yr 2. WBC >16 × 109/L 3. LDH >350 U/L 4. AST >250 U/L 5. Glucose >200 mg/dl During initial 48 hr: 1. Hgb falls below 10 mg/dl 2. BUN rises by >5 mg/dl 3. Ca 6 L APACHE II*

BISAP 1. BUN >25 mg/dl 2. Altered mental status 3. Presence of SIRS 4. Age >60 yr 5. Pleural effusions CTSI

One point for each factor listed; score >3 indicates SAP Based on radiographic data

Significantly lower sensitivity than either Ranson or APACHE II; results in greater likelihood of missing severe AP

AP, Acute pancreatitis; APACHE, Acute Physiology and Chronic Health Evaluation; AST, aspartate aminotransferase; BISAP, Bedside Index for Severity in Acute Pancreatitis; BUN, blood urea nitrogen; Ca, serum calcium; CTSI, Computed Tomography Severity Index; Hgb, hemoglobin; LDH, lactate dehydrogenase; SAP, severe acute pancreatitis; SIRS, systemic inflammatory response syndrome; WBC, white blood cell count. *Based on diverse variables, including age, physiology, and long-term health; equation available at www.sfar.org/scores2/apache 22.html#calcul. Adding body mass index (BMI) to APACHE II (the APACHE 0 score) increases discrimination (1 point added for BMI 26-30; 2 points for BMI >30). From Cameron JL, Cameron AM: Current surgical therapy, ed 10, Philadelphia, 2011, Saunders.

ALG

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • PUD • Acute cholangitis, biliary colic • High intestinal obstruction • Early acute appendicitis • DKA • Pneumonia (basilar) • Myocardial infarction (inferior wall) • Renal colic • Ruptured or dissecting aortic aneurysm • Mesenteric ischemia LABORATORY TESTS Pancreatic enzymes: Amylase is increased, usually elevated in the initial 3 to 5 days of acute pancreatitis. Isoamylase determinations (separation of pancreatic cell isoenzyme components of amylase) are useful in excluding occasional cases of salivary hyperamylasemia. The use of isoamylase rather than total serum amylase reduces the risk of erroneously diagnosing pancreatitis and is preferred by some as initial biochemical test in patients suspected of having acute pancreatitis.

Inflammatory Dilated fat stranding gallbladder

Pancreas with inflammatory stranding

Normal pancreas

Normal peripancreatic fat

Gallstone

A

Inferior vena cava

Aorta

B

Normal subcutaneous fat

FIG. 1  Gallstone pancreatitis and normal pancreas for comparison, axial computed tomography without contrast. A, Gallstone pancreatitis CT. A dilated gallbladder is visible with a hyperdense dependent lesion consistent with a gallstone. The region of the pancreas shows significant inflammatory stranding. In this patient, the pancreas lies just anterior to the left renal vein, which can be seen crossing anterior to the aorta and entering the inferior vena cava. B, A normal pancreas is visible. This pancreas is surrounded by uninflamed fat, which is dark (nearly black). Compare this normal fat with normal subcutaneous fat. (From Broder JS: Diagnostic imaging for the emergency physician, Philadelphia, 2011, Saunders.)

Urinary amylase determinations are useful to diagnose acute pancreatitis in patients with lipemic serum, to rule out elevated serum amylase caused by macroamylasemia, and to diagnose acute pancreatitis in patients whose serum amylase is normal. Serum lipase levels are elevated in acute pancreatitis; the elevation is less transient than serum amylase and more sensitive in patients with alcoholic pancreatitis. Concomitant evaluation of serum amylase and lipase increases diagnostic accuracy of acute pancreatitis. Elevated serum trypsin levels are diagnostic of pancreatitis (in absence of renal failure). Serum C-reactive protein is an excellent laboratory marker of severity; a level >150 mg/dl at 48 hours is associated with severe pancreatitis. Rapid measurement of urinary trypsinogen-2 (if available) is useful in the emergency department as a screening test for acute pancreatitis in patients with abdominal pain; a negative dipstick test for urinary trypsinogen-2 rules out acute pancreatitis with a high degree of probability, whereas a positive test indicates need for further evaluation. Interleukin-6 level: Worse prognosis with level ≥300 pg/ml.

ADDITIONAL TESTS • Complete blood count: Reveals leukocytosis; hematocrit (Hct) may be initially increased as a result of hemoconcentration; decreased Hct may indicate hemorrhage or hemolysis. • Blood urea nitrogen (BUN) is increased because of dehydration. Serial BUN measurements are the most valuable lab test for predicting mortality during the initial 48 hr. • Elevation of serum glucose in a previously normal patient correlates with the degree of pancreatic malfunction and may be related to increased release of glycogen, catecholamines, and glucocorticoid release and decreased insulin release. • Liver profile: Aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) are

increased as a result of tissue necrosis; bilirubin and alkaline phosphatase may be increased from common bile duct obstruction. A threefold or greater rise in serum alanine aminotransferase concentrations is an excellent indicator (95% probability) of biliary pancreatitis. • Serum calcium is decreased as a result of saponification, precipitation, and decreased parathyroid hormone response. • Arterial blood gases: Pao2 may be decreased as a result of ARDS, pleural effusion(s); pH may be decreased as a result of lactic acidosis, respiratory acidosis, and renal insufficiency. • Serum electrolytes: Potassium may be increased from acidosis or renal insufficiency; sodium may be increased from dehydration.

IMAGING STUDIES • Abdominal plain films are useful initially to distinguish other conditions that may mimic pancreatitis (perforated viscus). They may reveal localized ileus (sentinel loop), pancreatic calcifications (chronic pancreatitis), blurring of left psoas shadow, dilation of transverse colon, calcified gallstones. • Chest x-ray may reveal elevation of one or both diaphragms, pleural effusions, basilar infiltrates, or platelike atelectasis. • Abdominal ultrasonography is useful in detecting gallstones (sensitivity of 60% to 70% for detecting stones associated with pancreatitis). Its availability and noninvasive nature make it the initial imaging study of choice; its major limitation is the presence of distended bowel loops overlying the pancreas. • CT scan (Fig. 1) is less sensitive than ultrasound in identifying gallstones and exposes the patient to risk of contrast-induced nephropathy. It is, however, superior to ultrasonography in identifying pancreatitis and defining its extent, and it also plays a role in diagnosing pseudocysts (they appear as

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ETIOLOGY • In >90% of cases: Biliary tract disease (calculi or sludge) or alcohol, most common after 5 to 10 yr of heavy drinking • Hypertriglyceridemia (usually >1000 mg/dl) from any cause • Drugs (e.g., thiazides, furosemide, corticosteroids, tetracycline, estrogens, valproic acid, metronidazole, azathioprine, methyldopa, pentamidine, ethacrynic acid, procainamide, amiodarone, sulindac, nitrofurantoin, angiotensin-converting enzyme inhibitors, danazol, cimetidine, piroxicam, gold, ranitidine, sulfasalazine, isoniazid, acetaminophen, cisplatin, didanosine, opiates, erythromycin, metformin, GLP-1 receptor agonists, incretin mimetics) • Abdominal trauma • Surgery • Endoscopic retrograde cholangiopancreatography (ERCP), especially with manipulation of the pancreatic duct • Infections (predominantly viral) • Peptic ulcer (penetrating duodenal ulcer) • Pancreas divisum (congenital failure to fuse of dorsal or ventral pancreas) • Idiopathic • Pregnancy • Vascular (vasculitis, ischemic) • Hypercalcemia • Pancreatic carcinoma (primary or metastatic) • Renal failure • Hereditary pancreatitis, such as in patients with cystic fibrosis • IgG4 disease • Occupational exposure to chemicals: Methanol, cobalt, zinc, mercuric chloride, creosol, lead, organophosphates, chlorinated naphthalenes • Others: Scorpion venom, obstruction at ampulla region (neoplasm, duodenal diverticula, Crohn disease, rarely celiac disease), hypotensive shock, autoimmune pancreatitis

Pancreatitis, Acute

I

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Pancreatitis, Acute

ALG

TABLE 2  Computed Tomography (CT) Severity Index Score for Pancreatitis* Grade†

CT Findings

Score

A B

Normal pancreas Focal or diffuse enlargement of the pancreas, contour irregularities, heterogeneous attenuation, no peripancreatic inflammation C Grade B plus peripancreatic inflammation D Grade C plus a single fluid collection E Grade C plus multiple fluid collections or gas Percent Necrosis Present on CT 0 50

0 1 2 3 4

*Severity Index Score = Grade score + Percent necrosis score. Maximum score = 10; severe disease = 6 or higher. †Severity of the acute inflammatory process. From Adams JG et al: Emergency medicine, clinical essentials, ed 2, Philadelphia, 2013, Elsevier.

a well-defined area surrounded by a highdensity capsule); gastrointestinal fistulization or infection of a pseudocyst can also be identified by the presence of gas within the pseudocyst. Sequential contrast-enhanced CT is useful for detection of pancreatic necrosis. The severity of pancreatitis can also be graded by CT scan (Table 2). (A = normal pancreas, B = enlarged pancreas [1 point], C = pancreatic and/or peripancreatic inflammation [2 points], D = single peripancreatic collection [3 points], E = at least two peripancreatic collections and/or retroperitoneal air [4 points]. Percentage of pancreatic necrosis 50% [6 points]. The CT severity index is calculated by adding grade points to points assigned for percentage of necrosis.) • Magnetic resonance cholangiopancreatography (MRCP) has >90% sensitivity for choledocholithiasis and can identify other anatomic abnormalities. • Endoscopic ultrasonography (EUS) is a minimally invasive test that provides high-resolution imaging of the pancreas. It is useful to identify anatomic abnormalities of the pancreas and has good sensitivity and specificity for small gallstones (≤5 mm). • ERCP indications: Useful to perform biliary sphincterotomy and stone removal in the presence of a retained bile duct stone seen on imaging. The role and timing of ERCP in patients with acute biliary pancreatitis has been controversial. Guidelines from the American College of Gastroenterology suggest that urgent ERCP (within 24 hr of admission) is indicated in patients with biliary pancreatitis who have concurrent acute cholangitis, but it is not needed in most patients who do not have evidence of ongoing biliary obstruction.3,4,5 3 Fogel EL, Sherman S: ERCP for gallstone pancreatitis,

N Engl J Med 370:150-157, 2014.. 4 Tenner S, et al: American College of Gastroenterology guidelines: management of acute pancreatitis, Am J Gastroenterol 108:1400-1415, 2013. 5 Bakker OJ, et al: Early versus on-demand nasogastric tube feeding in acute pancreatitis, N Engl J Med 371:1983-1993, 2014.

TREATMENT NONPHARMACOLOGIC THERAPY • Bowel rest with avoidance of liquids or solids during the acute illness. Limited data suggest that early feeding in patients with acute pancreatitis does not seem to increase adverse events and, for patients with mild to moderate pancreatitis, may reduce length of hospital stay.6 • Avoidance of alcohol and any drugs associated with pancreatitis. ACUTE GENERAL Rx GENERAL MEASURES: • Assess severity of pancreatitis (see Table 1). • An algorithm for the management of acute pancreatitis is described in Fig. 2. • Maintain adequate intravascular volume with vigorous IV hydration. Aggressive fluid resuscitation (250 to 500 ml/hr) with isotonic crystalloids is critical in managing acute pancreatitis, unless cardiac or renal disease precludes it. • Patient should remain NPO until clinically improved, stable, and hungry. Enteral feedings are preferred over total parenteral nutrition if supplemental nutrition is necessary. Enteral nutrition reduces mortality, multiple organ failure, systemic infections, and operative interventions more than total parenteral nutrition does in patients with acute pancreatitis. Parenteral nutrition may be necessary in patients who do not tolerate enteral feeding or in whom an adequate infusion rate cannot be reached within 2 to 4 days. Early (within 24 to 48 hr of admission) enteral feeding through a nasogastric (NG) feeding tube has limited evidence to support this strategy. A recent trial did not show superiority of early NG tube feeding, as compared with oral diet after 72 hours, in reducing the rate of infection or death in patients with acute pancreatitis at high risk for complications. 6 Vaughn

VM, et  al: Early versus delayed feeding in patients with acute pancreatitis, a systematic review, Ann Intern Med 66:883-892, 2017.

• Nasogastric suction is useful only in severe pancreatitis to decompress the abdomen in patients with ileus. • Control pain: IV hydromorphone or fentanyl. Meperidine and morphine are also commonly used narcotics for pain control, although morphine has been shown to increase sphincter of Oddi pressure and has delayed metabolite clearance in patients with concomitant renal failure. • Correct metabolic abnormalities (e.g., replace calcium and magnesium as necessary). • Prophylactic antibiotics are not recommended, regardless of the severity or presence of pancreatic necrosis. • An algorithm for the management of acute pancreatitis at various stages is described in Fig. 2. SPECIFIC MEASURES: • Pancreatic or peripancreatic infection develops in 30% of patients with pancreatic necrosis. The use of antibiotics is justified if the patient has evidence of septicemia, pancreatic abscess, or pancreatitis caused by biliary calculi with concomitant cholangitis. Their use should generally be limited to 5 to 7 days to prevent development of fungal superinfection. Appropriate empiric antibiotic therapy should penetrate pancreatic necrosis. Options include a carbapenem alone (due to anaerobic coverage) or a quinolone, ceftazidime, or cefepime, combined with an enteric anaerobic agent such as metronidazole. CT-guided fine-needle aspiration (FNA) can be performed to culture the infected necrosis and tailor antibiotic therapy. If sampling of infected necrosis occurs and is sterile, antibiotics should be discontinued • Surgical therapy has a limited role in acute pancreatitis; it is indicated in the following: 1. G allstone-induced pancreatitis: Cholecystectomy when acute pancreatitis subsides. However, randomized trials have shown that patients with mild gallstone pancreatitis can undergo cholecystectomy safely during the first 48 hr of hospitalization 2. Perforated peptic ulcer 3. Necrotizing pancreatitis with infected necrotic tissue is associated with an elevated rate of complications and increased risk of death. Traditional treatment has been open necrosectomy; surgical necrosectomy induces a proinflammatory response and is associated with a high complication rate. Recent trials have shown that a stepup approach consisting of percutaneous drainage followed, if necessary, by minimally invasive retroperitoneal necrosectomy may have a lower rate of complications and death. Endoscopic transgastric necrosectomy, a form of natural orifice transluminal endoscopic surgery, has been shown in recent trials to be effective in reducing the proinflammatory response as well as reducing complications • Identification and treatment of complications: 1. Pseudocyst: Round or spheroid collection of fluid, tissue, pancreatic enzymes, and blood

ALG Early course: 0-72 hours Is there organ failure? No

Yes

Admission to medical/surgical floor NPO, IV hydration (250-400 cc/hr) Nasal oxygen Frequent evaluation of oxygen saturation Hematocrit daily/BUN twice daily for 48 hours Serum electrolytes daily Pain control

Later course: >72 hours Evidence of severe disease or organ failure?

Early refeeding Evaluate for etiology If gallstones, early cholecystectomy If alcohol, address psychosocial issues If high serum TG, medical therapy

Interstitial pancreatitis on CT without peripancreatic necrosis: Continue supportive care Observation

3.

4. Yes

To ICU if patient not already there Observe for biliary sepsis; if present, consider emergency ERCP Enteral feedings (NJ or NG) CT to evaluate for necrosis

Pancreatic/peripancreatic necrosis on CT: Continue supportive care Enteral feedings If infection suspected, consider antibiotics

5.

6.

7. Late course: 7-28 days Patient improving? Yes

No

Consider oral refeeding

If on antibiotics, consider FNA of pancreas for culture and change of antibiotics If not on antibiotics and FNA negative, keep off antibiotics Beyond 28 days Patient improving?

Yes

No

Consider refeeding If patient cannot tolerate feedings, consider necrosectomy

Consider necrosectomy by endoscopic, radiologic, or surgical means

FIG. 2  Algorithm for the management of acute pancreatitis at various stages in its course. NJ, Nasojejunal. (From Feldman M, Friedman LS, Brandt LJ: Sleisenger and Fordtran’s gastrointestinal and liver disease, ed 10, Philadelphia, 2016, Elsevier.)



a. D  iagnosed by CT scan or sonography. b. Treatment: Pancreatic pseudocysts can be drained surgically or endoscopically. The endoscopic approach is preferable when the patient’s anatomy is suitable and an experienced endoscopist is available. CT scan or ultrasound-guided percutaneous drainage (with a pigtail catheter left



in place for continuous drainage) can be used, but the recurrence rate is high; the conservative approach is to reevaluate the pseudocyst (with CT scan or sonography) after 6 to 7 wk and surgically drain it if the pseudocyst has not decreased in size. c. Generally, pseudocysts 5 cm require surgical intervention after the wall has matured. Phlegmon: Represents pancreatic edema. It can be diagnosed by CT scan or sonography. Treatment is supportive as it usually resolves spontaneously Pancreatic abscess: Diagnosed by CT scan (presence of air in the retroperitoneum); Gram staining and cultures of fluid obtained from guided percutaneous aspiration usually identify bacterial organism. Therapy is surgical (or catheter) drainage and IV antibiotics (carbapenem is the drug of choice) Pancreatic ascites: Usually caused by leaking of pseudocyst or tear in pancreatic duct. Paracentesis reveals very high amylase and lipase levels in the pancreatic fluid; ERCP may demonstrate the lesion. Treatment is surgical correction if exudative ascites from severe pancreatitis does not resolve spontaneously Abdominal compartment syndrome: Caused by intraabdominal leakage of fluids from volume resuscitation or ascites. Diagnosed with sustained intraabdominal pressure >20 mm Hg with new-onset organ failure Gastrointestinal bleeding: Caused by alcoholic gastritis, bleeding varices, stress ulceration, or disseminated intravascular coagulation (DIC) Renal failure: Caused by hypovolemia, resulting in oliguria or anuria, cortical or tubular necrosis (shock, DIC), or thrombosis of renal artery or vein Hypoxia: Caused by ARDS, pleural effusion, or atelectasis Vascular: Splenic, portal, or superior mesenteric vein thrombosis; pseudoaneurysm

THERAPY OF UNCOMMON FORMS OF PANCREATITIS • A utoimmune pancreatitis (AIP): Fibroinflammatory disease characterized by an IgG4 lymphoplasmacytic infiltrate. It is a variant of chronic pancreatitis and has been associated with other autoimmune disorders (e.g., primary sclerosing cholangitis, Sjögren syndrome). The inflammatory process is generally responsive to corticosteroid therapy. Older men aged 60 to 70 yr are primarily affected. Patients present with abdominal pain, weight loss, anorexia, and obstructive jaundice. Immunoglobulin G4 levels are elevated. Radiographically on CT, the pancreas is diffusely enlarged, with a characteristic smooth, capsulelike rim (“sausage pancreas”). Features of type 1 and type 2 autoimmune pancreatitis are summarized in Table 3. Type II autoimmune hepatitis (idiopathic duct-centric chronic pancreatitis) is associated with inflammatory bowel disease and not related to IgG4 cell deposition. • Hypertriglyceridemic pancreatitis (HTGP): IV insulin therapy is the cornerstone of immediate treatment, with supplemental IV

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No

Admission to an ICU Same orders as for floor admission Central line placement Evaluate need for assisted ventilation Assess for bile duct obstruction If bilirubin rising, consider urgent ERCP

2.

Pancreatitis, Acute

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TABLE 3  Features of Type 1 and Type 2 Autoimmune Pancreatitis Feature

Type 1

Type 2

Histology

Lymphoplasmacytic infiltration Dense periductal infiltrate without damage to ductal epithelium Storiform fibrosis Obliterative phlebitis Abundant (>10 cells/HPF) IgG4-positive cells Fibroinflammatory process may extend to peripancreatic region 60-70 yr

Periductal lymphoplasmacytic and neutrophilic infiltration Destruction of the duct epithelium by neutrophils (granulocytic epithelial lesion, or GEL) Obliterative phlebitis is rare No IgG4-positive cells

Average age at presentation Gender predominance Usual clinical presentations Pancreatic imaging IgG4 Other organ involvement

Associated diseases Long-term outcome

Male Obstructive jaundice (75%) Acute pancreatitis (15%) Diffuse pancreatic enlargement (40%) Focal pancreatic enlargement (60%) Level elevated in serum (~2/3 of patients) Positive in staining of involved tissues Biliary strictures Pseudotumors Kidney Lung Others Retroperitoneal fibrosis Sialoadenitis See above (other organ involvement) Frequent relapses

40-50, but may present in young adults and even children Equal Obstructive jaundice (50%) Acute pancreatitis (33%) Diffuse pancreatic enlargement (15%) Focal pancreatic enlargement (85%) Not associated Not associated

PEARLS & CONSIDERATIONS IBD Rare or no relapse

HPF, High power field; IBD, inflammatory bowel disease; IgG4, Immunoglobulin G, subclass 4. From Feldman M, Friedman LS, Brandt LJ: Sleisenger and Fordtran’s gastrointestinal and liver disease, ed 10, Philadelphia, 2016, Elsevier.

TABLE 4  Prognostic Criteria for Acute Pancreatitis Ranson Criteria* On admission: Age >55 yr WBC >16,000/μL AST >250 U/L LDH >350 U/L Glucose >200 mg/dl 48 hr after admission: Hematocrit decrease by >10 BUN increase by >5 mg/dl Ca2+ 6 L

Simplified Glasgow Criteria†

Computed Tomography Criteria‡

Within 48 hr of admission: Age >55 yr WBC >15,000/μL LDH >600 U/L Glucose >180 mg/dl Albumin 70 yr, 700/100,000 are affected. • Lifetime risk of Parkinson disease is 2% in men and 1.3% in women. PHYSICAL FINDINGS & CLINICAL PRESENTATION • Tremor (Fig. E1)—typically a resting tremor with a frequency of 4 to 6 Hz that is often first noted in the hand as a pill-rolling tremor (thumb and forefinger). Can also involve the leg and lip. Tremor improves with purposeful movement. Usually starts asymmetrically. • Rigidity—increased muscle tone that persists throughout the range of passive movement of a joint. Rigidity, like resting tremor, is usually asymmetric at onset. • Akinesia/bradykinesia—slowness in initiating movement and decrement with repeated movements. • Postural instability—tested by “pull test.” Ask patient to stand in place with back to examiner. Examiner pulls patient back by the shoulders, and proper response would be to take no steps back or very few steps back without falling. Retropulsion is a positive test, as is falling straight back. Postural instability is not usually severe early on. If falls and postural reflexes are greatly impaired early on, then consider other disorders, such as progressive supranuclear palsy. • Masked facies (hypomimia)—face seems expressionless, giving the appearance of depression. Decreased blink; often there is excess drooling.

• Gait disturbance. • Stooped posture, decreased arm swing. • Difficulty initiating the first step; small shuffling steps that increase in speed (festinating gait). Steps become progressively faster and shorter while the trunk inclines further forward. • Other complaints and findings early on include handwriting becoming smaller (micrographia), and voice becoming softer and often “gruffer” (hypophonia). • Nonmotor symptoms in Parkinson disease include neuropsychiatric (depression, apathy, impulse control disorders, hallucinations), cognitive, dysautonomia (especially orthostatic hypotension, sexual dysfunction, and anosmia), and sensory abnormalities. These symptoms also may be subject to fluctuations during “on” versus “off” states. • Common premotor symptoms of Parkinson disease include constipation, anosmia, depression, and REM sleep behavior disorder.

ETIOLOGY • Most cases are sporadic. Age is the most common risk factor, although a combination of both environmental and genetic factors likely contributes to disease expression. • Approximately 5% to 10% have a genetic etiology. Several different genes have been identified; these include the parkin gene, a significant cause of early-onset autosomal recessive PD, and LRRK2, the most common cause of familial and sporadic parkinsonism.

DIAGNOSIS • A clinical diagnosis can be made based on a comprehensive history and physical examination. The four cardinal signs used to diagnose PD are (mnemonic = TRAP): 1.  Tremor (resting, typically 4-6 Hz) 2.  Rigidity, of the cogwheel type 3.  Akinesia/bradykinesia—slowing and decrement of movement 4.  Postural instability—failure of postural “righting” reflexes leading to poor balance and falls • Bradykinesia plus at least one other sign are necessary, but all four cardinal signs do not need to be present to make a presumptive diagnosis of PD and begin treatment.

DIFFERENTIAL DIAGNOSIS • Multiple system atrophy—distinguishing features include early autonomic dysfunction (including urinary incontinence, orthostatic hypotension, and erectile dysfunction), parkinsonism, cerebellar signs, and normal cognition • Dementia with Lewy bodies—parkinsonism with concomitant dementia: Patients often have early hallucinations and fluctuations in level of alertness and mental status • Corticobasal syndrome—often begins asymmetrically with apraxia, cortical sensory loss in one limb, and sometimes, alien limb phenomenon

• Progressive supranuclear palsy—tends to have axial rigidity greater than appendicular (limb) rigidity. These patients have early and severe postural instability. Hallmark is supranuclear gaze palsy that usually involves vertical gaze (especially downward) before horizontal • Essential tremor—bilateral postural and action tremor • Secondary (acquired) parkinsonism (Box 1): 1. Iatrogenic—any of the neuroleptics and antipsychotics. The high-potency D2blocker neuroleptics are most likely to cause parkinsonism. Quetiapine is an atypical antipsychotic with lower risk of parkinsonism. Metoclopramide can also cause parkinsonism. Abuse of methamphetamine has been recently linked to risk of PD 2. Postinfectious parkinsonism—von Economo encephalitis 3. Dementia pugilistica—parkinsonism and dementia after repeated head trauma 4. Toxins (e.g., MPTP, manganese, carbon monoxide) 5. Cerebrovascular disease “vascular parkinsonism” (basal ganglia infarcts); often lower limbs (especially gait) affected more than upper extremities

WORKUP • Identification of clinical signs and symptoms associated with PD (see “Physical Findings”), and elimination of conditions that may mimic it with a comprehensive history and physical examination. • Routine genetic testing is not recommended. IMAGING STUDIES Computed tomographic (CT) scan has almost no role in investigations. Magnetic resonance imaging (MRI) of the head may sometimes distinguish between idiopathic PD and other conditions that present with signs of parkinsonism (see “Differential Diagnosis”). Dopamine transporter imaging (DaTscan with [123I]β-CIT SPECT) evaluates the level of dopamine in the striatum and can be used to confirm parkinsonism in atypical cases. DaTscan is approved to distinguish essential tremor from parkinsonism but cannot distinguish between different causes of parkinsonism. Interpretation can be tricky, and routine use is not recommended at this time.

TREATMENT NONPHARMACOLOGIC THERAPY • Physical therapy, patient education and reassurance, treatment of associated conditions (e.g., depression) are important. A safe, practical, and reasonable exercise regimen must be encouraged. • Avoidance of drugs that can induce or worsen parkinsonism: neuroleptics (especially high potency), certain antiemetics (prochlorperazine, trimethobenzamide), metoclopramide, nonselective MAO inhibitors (may induce hypertensive crisis), reserpine, methyldopa.

Parkinson Disease

Primary Parkinsonism • Parkinson disease (idiopathic/sporadic parkinsonism) Secondary Parkinsonism • Drug-induced parkinsonism • Neuroleptic drugs • Calcium blocker cinnarizine • Vascular parkinsonism (pseudoparkinsonism) • Multi-infarct states • Single basal ganglia/thalamic infarct • Binswanger disease • Multisystem degenerative diseases • Progressive supranuclear palsy • Multiple system atrophy (striatonigral type) • Corticobasal degeneration • Alzheimer disease • Wilson disease (young-onset parkinsonism) • Dementia with Lewy bodies • Neurofibrillary tangle parkinsonism • Toxins • MPTP • Manganese • Familial parkinsonism • Postinfectious parkinsonism • Creutzfeldt-Jakob disease • AIDS • Postencephalitis (encephalitis lethargica) • Miscellaneous causes • Hydrocephalus • Posttraumatic • Tumors • Metabolic causes (postanoxic) AIDS, Acquired immunodeficiency syndrome; MPTP, 1-methyl-4-phenyl-1,2,2,6-tetrahydropyridine. From Fillit HM: Brocklehurst’s textbook of geriatric medicine and gerontology, ed 8, Philadelphia, 2017, Elsevier.

CHRONIC Rx • Levodopa therapy: 1. The most efficacious treatment and cornerstone of symptomatic therapy— should be used with a peripheral dopa decarboxylase inhibitor (carbidopa) to minimize side effects (nausea, lightheadedness, postural hypotension). The combination of the two drugs is marketed under the trade name Sinemet. Levodopa therapy has been found to reduce morbidity and mortality in PD patients. 2. Usual starting dose is 25/100 mg (carbidopa/levodopa) tid 1 hr before (or after) meals.

Parkinson disease

Nonpharmacologic treatment (Physical therapy)

Pharmacologic treatment

Neuroprotective agent(s)

Functional impairment?

DA agonists

65 yr old and cognitively normal

L-dopa

Additional drugs: Anticholinergics Amantadine

(CR)

Yes

No

65 yr old or cognitively impaired

COMT inhibitors

Neurostimulation

Combination therapy

Drug modification to improve efficacy and reduce side effects

Surgery

FIG. 2  Diagrammatic representation of a therapeutic approach to patients with parkinsonism. COMT, Catechol-O-methyl transferase; CR, controlled release; DA, dopamine. (Modified from Goldman L, Ausiello D [eds]: Cecil textbook of medicine, ed 24, Philadelphia, 2012, WB Saunders.)

P

Diseases and Disorders

ACUTE GENERAL Rx • There continues to be controversy whether levodopa or dopamine agonists should be the initial treatment. In younger patients, agonists may be favored; in patients >65 yr, levodopa is typically the preferred initial therapy. • It is appropriate to initiate pharmacotherapy when required by symptoms; prior practice of waiting for limitation of ADLs is now outdated. Fig. 2 describes an approach to patients with parkinsonism. • Motor complications do develop during the course of the disease and likely reflect the combination of disease progression together with the side effects of dopaminergic medications.

BOX 1  Causes of Parkinsonism

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Parkinson Disease 3. C  ontrolled-release (Sinemet CR) and extended-release (Rytary) preparations are also available, but their use should be supervised by a neurologist. 4. Stalevo (combination Sinemet and entacapone, a COMT inhibitor). Useful for patients with motor fluctuations (wearing off); has no role in treating early patients with PD. 5. Duopa (carbidopa/levodopa), administered via a 16-hour infusion to the jejunum through either a nasojejunal tube (short-term) or PEG-J tube (long-term), is used for treating motor fluctuations in patients with advanced PD. • Dopamine receptor agonists (ropinirole, pramipexole, rotigotine) are not as potent as levodopa, but they are often used as initial treatment in younger patients to attempt to delay the onset of complications (dyskinesias, motor fluctuations) associated with levodopa therapy. These medications are more expensive than levodopa. In general, they cause more side effects than levodopa, including nausea, vomiting, light-headedness, peripheral edema, confusion, and somnolence. They can also cause impulse control behaviors such as hypersexuality, binge eating, and compulsive shopping and gambling. Presence of these must be assessed at each visit as the appearance of these side effects is often under-reported and their consequences can be severe. Dopamine agonists also can be associated with a prolonged withdrawal syndrome. 1. Ropinirole: Initial dose is 0.25 mg tid but must be titrated over the course of 4 weeks to 1 mg tid and then may be increased by 1.5 mg/week to a maximum of 24 mg/day. An extended-release formulation is also available. 2. Pramipexole: Initial dose is 0.125 mg tid but must be titrated over the course of weeks to 1.5 to 4.5 mg/day in three doses. An extended-release formulation is also available. 3. Rotigotine: 2 mg to 6 mg/24 hour transdermal patch. 4. Apomorphine: A dopamine agonist used for acute, intermittent treatment of unpredictable “off” episodes with advanced Parkinson disease. • COMT inhibitors (entacapone and tolcapone) are used as adjunct to levodopa therapy to treat end-of-dose wearing off. • MAO-B inhibitors can be used as monotherapy early in the disease or as adjunctive therapy in later stages; they have been shown to have milder symptomatic benefit than dopamine agonists or levodopa. They are well tolerated and easy to titrate. Concurrent use of stimulants and sympathomimetics should be avoided. Certain food restrictions may apply. 1. Rasagiline: Initial dose is 0.5 mg qd, then 1 mg daily. The ADAGIO study suggests that 1 mg rasagiline may have diseasemodifying benefits, but results must be interpreted with caution.

2. S elegiline: Usual dose, 5 mg bid with breakfast and lunch. Has amphetamine byproduct so has mild stimulant-like effects, which can be beneficial in some patients. 3. Safinamide: FDA approved as add-on therapy for carbidopa-levodopa that reduces “off time” and increases “on time” with fewer dyskinesias. Starting dose is 50 mg daily for 2 weeks, which can be increased if needed to 100 mg daily. 4. Istradefylline is the first FDA-approved adenosine A 2A receptor agonist for use as an adjunct to carbidopa/levodopa in adults with Parkinson disease experiencing “off” episodes. • Amantadine (unclear mechanism of action, but reported to modulate the dopamine and glutamate systems in the CNS) can be used alone early in the disease. Later in the disease, it is especially useful in the treatment of dyskinesias. Dosage is 100 mg tid (titrate q week from 100 mg qd). Must adjust for elderly and renal impairment. The most notable side effect, especially in the elderly, is confusion. An extended-release version is now FDA approved for the treatment of dyskinesia. • Anticholinergic agents are only helpful in treating tremor but may be more effective than levodopa for tremor in some circumstances. They can also be used to treat drooling in patients with PD. Potential side effects include constipation, urinary retention, memory impairment, and hallucinations. They should be avoided in the elderly. 1. Trihexyphenidyl: Initial dose, 1 mg PO tid. 2. Benztropine: Usual dose, 0.5 to 1 mg qd or bid. • Treatment of nonmotor symptoms: Nonmotor symptoms such as depression, anxiety, irritability, dementia, psychosis, urinary and sexual dysfunction, sleep disturbances such as REM behavior disorder, decreased sense of smell, and impulsive behavior among others often cause a great deal of distress for patients and caretakers alike. Treatable symptoms should be addressed pharmacologically using medications appropriate for elderly patients sensitive to antidopaminergic medications. In addition, two medications are specifically indicated for nonmotor symptoms associated with PD. • Psychosis: Pimavanserin (Nuplazid) is FDA approved for the treatment of Parkinson disease psychosis and has been shown effective for the treatment of hallucinations and delusions associated with Parkinson disease psychosis. The medication is an inverse agonist of 5-HT2A and 5-HT2C receptors without any evidence of dopamine blockade. • Parkinson disease dementia: Rivastigmine (Exelon), a cholinesterase inhibitor available both orally and transdermally as a patch (with few GI side effects), is approved to treat not only Alzheimer disease but also Parkinson disease dementia.

SURGICAL OPTIONS • Pallidal (globus pallidus interna) and subthalamic deep-brain stimulation (subthalamic nucleus) are currently the surgical options of choice for patients with advanced PD; similar improvement in motor function and adverse effects have been reported after either procedure. Compared with ablative procedures, DBS has the advantage of being reversible and adjustable. Thalamic DBS may be useful for refractory tremor. It improves the cardinal motor symptoms, extends medication “on” time, and reduces motor fluctuations during the day. In general, patients are likely to benefit from this therapy if they show a clear response to levodopa. Therefore, when considering DBS, patients should be evaluated for motor response to levodopa by stopping levodopa overnight and evaluating motor response before and after a dose of levodopa. • Surgery is often limited to patients with disabling, medically refractory problems, and patients must still have a good response to l-dopa to undergo surgery. Yet for many patients, earlier stimulation might provide an improved motor benefit before disability from other symptoms has occurred and should be considered at an earlier stage of PD. DBS results in decreased dyskinesias, fluctuations, rigidity, and tremor. DISPOSITION PD usually follows a slowly progressive course leading to disability over the course of several yr. However, every patient will progress individually, and patients should be reassured that this diagnosis does not, by definition, result in being either wheelchair- or bed-bound. REFERRAL • Neurology consultation is recommended at initial diagnosis of PD. • Exercise is important for all patients with PD. • Participation in outpatient physical therapy program is recommended for patients with moderate to advanced disease.

PEARLS & CONSIDERATIONS • Asymmetry of symptoms at onset is typical of PD and therefore very useful in distinguishing PD from other causes of parkinsonism. • Although resting tremor is a common presenting symptom, up to 25% of patients with idiopathic PD do not have classic resting tremor.

SUGGESTED READINGS Available at ExpertConsult.com RELATED CONTENT Parkinson Disease (Patient Information) AUTHORS: Corey Goldsmith, MD, and U. Shivraj Sohur, MD, PhD

Parkinson Disease

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B

D

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FIG. E1  The parkinsonian syndrome. A, The “pill-rolling” tremor. B, Tremor that can worsen with emotional stress. C, Handwriting abnormalities, including micrographia. D, Typical posture and gait, which becomes faster (festination). E, Lack of facial expression as well as “stare” from decreased blinking.

SUGGESTED READINGS Connolly BS, Lang EL: Pharmacologic treatment of Parkinson disease, a review, JAMA 311(16):1670-1683, 2014. Follett KA et al: Pallidal versus subthalamic deep-brain stimulation for Parkinson’s disease, N Engl J Med 362:2077-2091, 2010. Hauser RA et  al: Preladenant in patients with Parkinson’s disease and motor fluctuations: a phase 2, double-blind, randomised trial, Lancet Neurol 10:221229, 2011. Homayoun H: In the clinic: Parkinson disease, Ann Int Med 2018. Kuehl BM: Meth use linked to risk of Parkinson disease, JAMA 306:814, 2011. Li F et  al: T’ai chi and postural stability in patients with Parkinson’s disease, N Engl J Med 366:511-519, 2012. Machado A et al: Deep brain stimulation: what can patients expect from it? Clev Clin J Med 79:113, 2012. Okun MS: Deep brain stimulation for Parkinson’s disease, N Engl J Med 367:1529-1538, 2012. Schuepbach WM et al: Neurostimulation for Parkinson’s disease with early motor complications, N Engl J Med 368:610-622, 2013. Van Nuenen BFL et  al: Cerebral pathological and compensatory mechanisms in the premotor phase of leucine-rich repeat kinase 2 parkinsonism, Brain 135:3687-3698, 2012.

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Paronychia BASIC INFORMATION DEFINITION Paronychia is a localized superficial infection or abscess of the lateral and proximal nail fold. Paronychia may be acute or chronic. SYNONYMS Nail bed infection Nail bed abscess ICD-10CM CODES B37.2 Candidiasis of skin and nail L03.019 Cellulitis of unspecified finger

EPIDEMIOLOGY & DEMOGRAPHICS • Acute paronychia affects males and females equally. • Chronic paronychia is more common in females than males (9:1). • Acute paronychia most often occurs in children. • Chronic paronychia usually presents in the fifth or sixth decade of life. • Paronychia is the most common infection of the hand. PHYSICAL FINDINGS & CLINICAL PRESENTATION • Acute paronychia usually presents with the sudden onset of redness, swelling, and pain with abscess or cellulitis formation in the nail fold. Fluid with purulence is often present (Fig. E1). • Chronic paronychia is insidious, presenting with mild swelling and erythema of the nail folds. • Acute paronychia usually involves only one finger.

• Chronic paronychia may involve more than one finger. • Acute paronychia usually involves the thumb. • Chronic paronychia commonly involves the middle finger.

ETIOLOGY • Any disruption of the seal between the proximal nail fold and the nail plate can cause paronychial infections. • Acute paronychia is almost always bacterial in origin (e.g., methicillin-sensitive Staphylococcus aureus [most common, but also consider MRSA], Streptococcus pyogenes, Enterococcus faecalis, Proteus and Pseudomonas species, and anaerobes). • Paronychia can also be associated with use of lamivudine and indinavir, which are used in HIV therapy. • Chronic paronychia is commonly caused by Candida albicans (70%), with bacterial organisms accounting for the remaining 30%. • Trauma, nail biting, hangnails, diabetes, and long-term exposure to water are common predisposing features of paronychia.

DIAGNOSIS The diagnosis of paronychia is self-evident on physical examination.

DIFFERENTIAL DIAGNOSIS • Herpetic whitlow caused by herpes simplex • Pyogenic granuloma • Viral warts • Ganglions • Squamous cell carcinoma WORKUP A workup is usually not pursued unless there is treatment failure.

FIG. E1  Paronychia with pus visible at the paronychial fold and a collection extending below the eponychial fold. (From Cameron JL, Cameron AM: Current surgical therapy, ed 12, Philadelphia, 2017, Elsevier.)

LABORATORY TESTS • Gram stain and culture any purulent drainage. • Potassium hydroxide (KOH) mount may show pseudohyphae. IMAGING STUDIES Radiographs of the digit if concerned about osteomyelitis

TREATMENT NONPHARMACOLOGIC THERAPY • For acute paronychia without purulent drainage, warm soaks tid or qid are helpful. If pus is present, surgical drainage is required (Fig. E2). • For chronic paronychia, avoid frequent immersion in water or exposure to moisture. ACUTE GENERAL Rx • Trimethoprim-sulfamethoxazole DS 1 PO bid for 7 days is usually the antibiotic of choice for acute paronychia as it covers methicillinsusceptible Staphylococcus aureus strains (MSSA) and methicillin-resistant S. aureus (MRSA) strains. • Alternative antibiotic choices include dicloxacillin 500 mg qid, cephalexin 500 mg qid, clindamycin, and amoxicillin-clavulanate. • Surgical drainage is indicated if purulent discharge is noted. • Use local anesthesia such as digital block or ethyl chloride spray. • A No. 11 blade scalpel is used to lift the lateral perionychium and proximal eponychium off the nail, facilitating drainage. • If the pus is located beneath the nail, the lateral edge of the nail can be lifted off the nail bed and excised.

FIG. E2  Surgical drainage of acute paronychia. The lateral nail on the affected side is elevated gently from the nail bed, and a longitudinal strip of nail is removed. If this does not decompress the infection adequately, the margins of the nail fold are opened gently to drain the adjacent soft tissues. (From Cameron JL, Cameron AM: Current surgical therapy, ed 12, Philadelphia, 2017, Elsevier.)

Paronychia CHRONIC Rx • If no fungal organism is found, tincture of iodine (2 drops bid) helps keep the nail and skin dry. • Chronic paronychia caused by Candida albicans is treated with topical antifungal agents (e.g., miconazole or ketoconazole applied tid). • Unresponsive cases may be treated with oral itraconazole, fluconazole, or terbinafine, but this should be done in consultation with dermatology and/or infectious disease as it requires prolonged therapy and has significant drug-to-drug interactions. • One study suggested that topical steroids such as methylprednisolone aceponate were more effective than antifungals, implying that

1060.e3 the origin is chronic dermatitis, not fungus. Topical tacrolimus ointment 0.1% has also been found effective. • Surgery may be needed in refractory cases.

DISPOSITION • Most acute paronychias with appropriate treatment resolve within 7 to 10 days. • Osteomyelitis is a potential complication of paronychia. • Untreated chronic paronychia leads to thickening and discoloration with eventual nail loss. REFERRAL Chronic paronychia refractory to topical medical therapy is best referred to dermatology and/

SUGGESTED READINGS Leggit JC: Acute and chronic paronychia, Am Fam Physician 96:44-51, 2017. Lomax A et al: Toenail paronychia, Foot Ankle Surg 22:219-223, 2016. Shafritz AB, Coppage JM: Acute and chronic paronychia of the hand, J Am Acad Orthop Surg 22(3):165-174, 2014.

or infectious disease. A hand surgeon is consulted if abscess drainage or surgery is being considered.

PEARLS & CONSIDERATIONS COMMENTS The gastrointestinal tract, including the mouth and bowel, and the genitourinary tract in women are the usual sources of C. albicans in chronic paronychia. RELATED CONTENT Paronychia (Patient Information) AUTHOR: Glenn G. Fort, MD, MPH

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Paroxysmal Cold Hemoglobinuria BASIC INFORMATION DEFINITION Paroxysmal cold hemoglobinuria (PCH) was the first, albeit rarest, autoimmune hemolytic anemia to be identified. It is characterized by transient or episodic massive intravascular hemolysis after exposure to cold temperatures and was first described in patients with secondary or tertiary syphilis. In modern times, chronic PCH is very rare, usually occurs in the elderly, and is associated with malignancy. Most cases are of the acute transient type, which is usually idiopathic in adults and secondary to a viral syndrome or immunization in children. SYNONYMS PCH Donath-Landsteiner hemoglobinuria ICD-10CM CODE D59.6 Hemoglobinuria due to hemolysis from other external causes

EPIDEMIOLOGY & DEMOGRAPHICS INCIDENCE: Estimated at 0.4 cases per 100,000 people PREVALENCE: Accounts for up to 5% of all adult hemolytic anemias and 30% to 40% of childhood cases PREDOMINANT SEX AND AGE: Mild male sex predilection with reported male-to-female ratio of 2:1 to 5:1. PCH affects both young children (acute form) and the elderly (chronic form). GENETICS: None RISK FACTORS: Age (most common in young population), infections, and neoplasms have been associated with the development of Donath-Landsteiner antibody. PHYSICAL FINDINGS & CLINICAL PRESENTATION • Within min to a few hours after cold exposure, there is a sudden onset of fever, rigors, and chills followed by red to brown urination. • Associated symptoms include back, leg, and abdominal pain. • Headaches, nausea, vomiting, diarrhea, and esophageal spasm are common. • Oliguria and anuria can develop following renal dysfunction. • May be associated with Raynaud phenomenon. • Associated with cold urticaria. • Transient splenomegaly and hepatomegaly with jaundice may occur. • Symptoms and gross hemoglobinuria usually resolve within hours. • Symptoms believed to be mediated by smooth muscle dysfunction as a result of nitric oxide deficiency associated with hemoglobinemia. ETIOLOGY • The Donath-Landsteiner antibody is a biphasic, usually polyclonal, immunoglobulin G (IgG). It is known to bind to various antigens

such as I-, i-, p-, Pr-, which are normally present on the red blood cell (RBC) surface, yet the glycosphingolipid P antigen is considered its primary target. The antibody in PCH also has thermal properties. It sensitizes RBCs in peripheral circulation (where typical thermal range for RBC binding is 5 yr after diagnosis). DISPOSITION Outpatient management REFERRAL Consider referral to orthopedics for surgical evaluation as a last resort if conservative thera­ pies fail. Surgical options include release of the lateral retinaculum, articular cartilage proce­ dures, and proximal realignment, usually with anteromedialization of the tibial tubercle.

PEARLS & CONSIDERATIONS PATIENT & FAMILY EDUCATION The American Academy of Family Practice web­ site www.familydoctor.org contains frequent­ ly asked questions, patient information, and example stretching and strengthening exer­ cises. Information is available in English and Spanish. RELATED CONTENT Knee Pain (Patient Information) Patellofemoral Pain Syndrome (Patient Information) AUTHOR: Kate Cahill, MD

Earl JE et  al: A proximal strengthening program improves pain, function, and biomechanics in women with patellofemoral pain syndrome, Am J Sports Med 39:154-163, 2011. Peterson W et  al: Patellofemoral pain syndrome, Knee Surg Sports Traumatol Arthrosc 22:2264-2274, 2014.

Patent Ductus Arteriosus BASIC INFORMATION DEFINITION The ductus arteriosus (DA) is a fetal vascular communication between the proximal descending aorta and main pulmonary artery. It derives from the left sixth aortic arch. During development, this connection allows right ventricular blood to bypass the increased pulmonary vascular resistance of the nonfunctional fetal lungs into the low resistance system of aortic and placental circulation. Closure typically occurs first functionally within hours of delivery, then anatomically within the first few days, though this may take longer in premature infants. If a ductus fails to close within 72 hours of birth in a full-term infant, diagnosis of a patent ductus arteriosus (PDA) can be made. Postnatal DA closure and obliteration are driven by multiple mechanisms, including increased oxygen saturation, decreased levels of endogenous prostaglandins and nitric oxide, and intimal proliferation and fibrosis. Failure of complete closure results in PDA, which may have hemodynamic consequences, the severity of which depends on the size and length of the defect. SYNONYM PDA ICD-10CM CODE Q25.0 Patent ductus arteriosus

EPIDEMIOLOGY & DEMOGRAPHICS • PDA is the third most common congenital abnormality. • Prevalence is 2.9 per 10,000 live births. Incidence has increased due to improved survival of premature infants (especially those born 1.5) b. Pulmonary vascular reactivity to testing (preferred with nitric oxide) 4. Consider closure in patients with small PDAs with continuous murmur. • Avoid PDA closure in patients with Eisenmenger syndrome or exercise-induced lower limb desaturation. • Closure of PDA should not be performed in patients with a very small PDA without murmur. • More than 95% of PDAs can successfully be closed percutaneously with a low rate of complications. Various occlusion devices may be used, depending on the underlying morphology. • In patients with pulmonary hypertension, treatment with pulmonary vasodilators should be considered prior to closure. • Surgical closure may be performed when a patient is undergoing cardiac surgery for other reasons or when the PDA is not suitable for device closure, such as in the case of very large defects, distorted ductal anatomy (e.g., aneurysm, endarteritis), or when the child is too small (30 days duration).

ICD-10CM CODES A18.17 Tuberculous female pelvic inflammatory disease A52.76 Syphilitic pelvic inflammatory disease A54.2* Gonococcal pelviperitonitis and other gonococcal genitourinary infections A54.24 Gonococcal female pelvic ­inflammatory disease A56.1* Chlamydial infection of pelviperitoneum and other genitourinary organs A56.11 Chlamydial female pelvic ­inflammatory disease A56.19 Other chlamydial genitourinary infection N70* Salpingitis and oophoritis N70.0* Acute salpingitis and oophoritis N70.01 Acute salpingitis N70.02 Acute oophoritis N70.03 Acute salpingitis and oophoritis N70.1* Chronic salpingitis and oophoritis N70.11 Chronic salpingitis N70.12 Chronic oophoritis N70.13 Chronic salpingitis and oophoritis N70.9* Salpingitis and oophoritis, unspecified N70.91 Salpingitis, unspecified N70.92 Oophoritis, unspecified N70.93 Salpingitis and oophoritis, unspecified N71* Inflammatory disease of uterus, except cervix N71.0 Acute inflammatory disease of uterus N71.1 Chronic inflammatory disease of uterus N71.9 Inflammatory disease of uterus, unspecified N72 Inflammatory disease of cervix uteri N73* Other female pelvic inflammatory diseases N73.0 Acute parametritis and pelvic cellulitis N73.1 Chronic parametritis and pelvic cellulitis N73.2 Unspecified parametritis and pelvic cellulitis N73.3 Female acute pelvic peritonitis N73.4 Female chronic pelvic peritonitis N73.5 Female pelvic peritonitis, unspecified N73.6 Female pelvic peritoneal adhesions (postinfective) N73.8 Other specified female pelvic inflammatory diseases

*Indicates nonbillable codes

EPIDEMIOLOGY & DEMOGRAPHICS INCIDENCE/PREVALENCE: Pelvic inflammatory disease is most often diagnosed in young, sexually active women. The incidence of PID is difficult to ascertain given its broad diagnostic criteria, its propensity to be missed as a diagnosis, and the challenges with follow-up due to patients seeking urgent or emergent care for this condition. The Centers for Disease Control and Prevention estimates 1 million new cases of PID are diagnosed yearly. The incidence may be rising given recent sharp increases in STDs associated with PID in the United States. PID has long-term health risks for women, including recurrent infection, chronic pelvic pain, pelvic adhesive disease, and tubal disease resulting in ectopic pregnancy and infertility. RISK FACTORS: • Sexually active adolescent and young women • Previous episode of PID • Prior chlamydial infection • Multiple or new sexual partners within past 12 mo • Sexual partner diagnosed with sexually transmitted infection (STI) • Nonuse of barrier contraception PHYSICAL FINDINGS & CLINICAL PRESENTATION • Lower abdominal pain • Abnormal vaginal discharge • Abnormal uterine bleeding • Postcoital bleeding • Dysuria • Dyspareunia • Fever • Nausea and vomiting (suggestive of peritonitis) PHYSICAL FINDINGS • Fever • Abdominal tenderness • Abnormal vaginal discharge • Cervical friability • Cervical motion tenderness • Adnexal tenderness • Adnexal mass • Right upper quadrant tenderness (perihepatitis): 5% of PID cases note: Women with PID may be asymptomatic and/or have a benign physical examination. ETIOLOGY Pelvic inflammatory disease occurs as a result of ascending infection from the lower genital tract. Infections are often polymicrobial, and although gonorrheal and chlamydial infections are commonly implicated in the development of PID, fewer than 50% of women test positive for these organisms. This is likely due in part to increased STI screening efforts. PID may also arise in the setting of organisms associated with normal vaginal flora such as: • Bacteroides fragilis

• Escherichia coli and other enteric gram-­ negative rods • Gardnerella vaginalis • Haemophilus influenzae Rarer infectious causes include the following: Mycoplasma hominis, Ureaplasma urealyticum, Mycoplasma genitalium (a concern due to antibiotic resistance), Mycobacterium tuberculosis (an important cause in developing countries), and cytomegalovirus (CMV).

DIAGNOSIS Diagnosis of PID is made when a patient has clinical or pathologic evidence of upper genital tract infection and inflammation. Although no single test or measure reliably diagnoses the spectrum of disorders that comprise PID: • Providers should maintain a low threshold for diagnosis and treatment of PID given significant long-term health risks associated with the disease, especially if untreated • Definitive criteria for diagnosis of PID include: 1. Laparoscopic abnormalities consistent with PID 2. Histopathologic evidence of endometritis in women with clinical suspicion for PID 3. Transvaginal sonography or other imaging techniques showing thickened, fluidfilled tubes, with or without free pelvic fluid or tubo-ovarian complex • The CDC suggests that women with risk factors, abdominal or pelvic pain, and any pelvic tenderness (cervical, uterine, and/or adnexal) be treated for PID

DIFFERENTIAL DIAGNOSIS • Appendicitis • Ectopic pregnancy • Intrauterine/other pregnancy • Ovarian cyst • Adnexal torsion • Endometriosis • Urinary tract infection (cystitis or pyelonephritis) WORKUP • History—as in risk factors and clinical presentation, previously • Physical examination—as in physical findings, previously LABORATORY TESTS • Wet mount: Clue cells, increased white cells • Gram stain of endocervical exudate: >30 polymorphonuclear cells per high-power field correlates with chlamydial or gonococcal infection • Endocervical cultures for N. gonorrhoeae and C. trachomatis • Fallopian tube aspirate or peritoneal exudate culture if laparoscopy performed • WBC: Leukocytosis • Elevated acute phase reactants: ESR >15 mm/hr, C-reactive protein • HCG to rule out intrauterine or ectopic pregnancy • HIV, with consideration for other STI screening such as RPR, HBsAg, Hep C Ab (HIV increases incidence of TOA)

P

Diseases and Disorders

SYNONYMS PID Salpingitis Oophoritis Adnexitis Pyosalpinx Tubo-ovarian abscess TOA

N73.9 Female pelvic inflammatory disease, unspecified N74 Female pelvic inflammatory disorders in diseases classified elsewhere

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Pelvic Inflammatory Disease IMAGING STUDIES Ultrasonography is commonly used to assess for PID and can be used to determine inpatient vs. outpatient treatment by presence or absence of TOA. Findings include: • Thick-walled adnexal mass with heterogenous or cystic contents suggestive of abscess • Dilated fallopian tubes (note that normal fallopian tubes are rarely identified on ultrasonography) • “Cogwheel sign” indicating thickened fallopian tube walls • Heterogenous fluid within the endometrium CT scan or MRI may be useful to better characterize adnexal masses and/or rule out other pathology such as appendicitis or renal calculus. Choice of imaging modality will depend on clinical suspicion, logistical access, and associated cost. PROCEDURES Endometrial biopsy that reveals endometritis may support a diagnosis of PID. Laparoscopy has been utilized as a gold standard for diagnosing PID, but due to the invasive nature of this procedure and the risks, and costs associated, it is rarely indicated as a diagnostic tool.

TREATMENT Primary management of PID is medical, with broad-spectrum antibiotics administered in an outpatient setting. Inpatient treatment should be initiated when: • Surgical emergency is not excluded • Tubo-ovarian abscess is present • Patient is unable or unwilling to complete outpatient treatment (including medication regimen and clinical follow-up) • Outpatient treatment fails to improve symptoms in 48 to 72 hours • Pregnancy, immunodeficiency, or other complicating medical condition exists Evidence-based guidelines recommended by the CDC for acute PID are as follows:

INPATIENT REGIMENS Recommended parenteral regimens • Cefotetan 2 g IV q12h PLUS doxycycline 100 mg PO or IV q12h OR • Cefoxitin 2 g IV q6h PLUS doxycycline 100 mg PO or IV q12hOR • Clindamycin 900 mg IV q8h PLUS gentamicin loading dose IV or IM (2 mg/kg of body weight), followed by a maintenance dose (1.5 mg/kg) q8h. Single daily dosing (3-5 mg/kg) can be substituted. Alternative parenteral regimen • Ampicillin/sulbactam 3 g IV q6h PLUS doxycycline 100 mg PO or IV q12h When clinical improvement is apparent based on symptoms, physical exam, and laboratory criteria, antibiotics may be transitioned from IV to PO with doxycycline PO or clindamycin PO (depending on the regimen selected) administered to complete 14 days of total antibiotic therapy. If a patient does not improve despite

use of a recommended antibiotic regimen, further workup and potential procedural intervention are warranted. OUTPATIENT REGIMENS Recommended intramuscular/oral regimens • Ceftriaxone 250 mg IM in a single dose PLUS doxycycline 100 mg PO bid for 14 days   WITH or WITHOUT metronidazole 500 mg PO bid for 14 days   OR • Cefoxitin 2 g IM in a single dose and probenecid, 1 g PO administered concurrently in a single dose PLUS doxycycline 100 mg PO bid for 14 days   WITH or WITHOUT metronidazole 500 mg PO bid for 14 days   OR • Other third-generation cephalosporin (ceftizoxime or cefotaxime) PLUS doxycycline 100 mg orally bid for 14 days   WITH or WITHOUT metronidazole 500 mg orally twice a day for 14 days Alternative intramuscular/oral regimen • Azithromycin 1 g PO once weekly for 2 wk PLUS ceftriaxone 250 mg IM in a single dose

TREATMENT CONSIDERATIONS • Antimicrobials should include coverage against N. gonorrhoeae and C. trachomatis even if these organisms are not identified on culture. • Due to increasing antibiotic resistance of N. gonorrhoeae, fluoroquinolones should be avoided in the treatment of PID. If gonorrhea is isolated in a woman with PID, addition of azithromycin 1 g orally one time should be considered in treatment. • Women should avoid sexual activity until they and their sexual partners have been adequately treated and symptoms have resolved. • TOA may require drainage, which may be accomplished by interventional radiology via aspiration or placement of a drain, or by a gynecologist via vaginal or laparoscopic means. Recurrent/persistent TOAs may be managed by total abdominal hysterectomy with bilateral salpingo-oophorectomy after acute treatment of infection. • Treatment of PID in women with intrauterine devices (IUDs) does not include/require removal of the device unless there is no clinical improvement after 48 to 72 hours of treatment with an approved regimen. IUDs rarely serve as a source for PID, especially greater than 3 wk after insertion. • Sexual partners of patients diagnosed with PID or other STIs should be evaluated and treated appropriately. In the setting of PID, treat all sexual partners within 60 days of onset of symptoms. Some states allow for expedited partner therapy (EPT), such that a woman’s provider is able to supply her with enough medication to treat herself and her partner(s). • Treatment of chronic PID may be aimed at a different spectrum of microbes and should be tailored appropriately.

DISPOSITION • Given the risk of reinfection, all women should be retested for gonorrhea and chlamydia 3 to 6 mo after treatment. • Follow-up includes confirmation of partner treatment, education on use of barrier contraception, and risks of PID and long-term sequelae, including: 1. Recurrent PID. 2. Chronic pelvic pain. 3.  Fallopian tubal damage that leads to infertility and/or ectopic pregnancy. 4. Fitz-Hugh-Curtis syndrome. 5. Potential risk for cancer: Limited studies have suggested a small association between PID and ovarian, endometrial, and colon cancer.

PEARLS & CONSIDERATIONS COMMENTS • Maintain a low threshold for the diagnosis and treatment of PID given the risks for progression to severe infection and to significant and chronic medical and reproductive complications. • Most patients are candidates for outpatient therapy, but inpatient hospitalization is recommended in select cases. • Use only CDC-recommended treatment regimens unless contraindicated due to severe patient allergy; in such cases, check local susceptibilities of suspected pathogen. • Offer HIV and other STI screening to all women with suspected or diagnosed PID. • IUDs may be retained unless women have failed to improve with 48 to 72 hours of treatment. • Treat sexual partners of women with PID, with EPT if possible. • Counsel patients on abstinence until they and their partners have completed treatment. • Test for reinfection with gonorrhea and chlamydia 3 to 6 mo after treatment. PREVENTION Women aged 50%. The importance of minimizing partner exposures and using barrier contraception (either alone or in conjunction with another method) should also be emphasized. SUGGESTED READINGS Available at ExpertConsult.com RELATED CONTENT Pelvic Inflammatory Disease (Patient Information) Chlamydia Genital Infections (Related Key Topic) Gonorrhea (Related Key Topic) Pelvic Abscess (Related Key Topic) AUTHOR: Gretchen Makai, MD

Pelvic Inflammatory Disease SUGGESTED READINGS Brunham RC: Pelvic inflammatory disease, N Engl J Med 372:2039-2048, 2015. Centers for Disease Control and Prevention: Sexually transmitted diseases treatment guidelines. www.cdc.gov/std/tg2015/pid.htm. Centers for Disease Control and Prevention: New CDC analysis shows steep and sustained increases in STDs in recent years. www.cdc.gov/nchhstp/newsroo m/2018/press-release-2018-std-prevention-conference.html. Gradison M: Pelvic inflammatory disease, Am Fam Physician 85(8):791-796, 2012. Romosan G, Valentin L: The sensitivity and specificity of transvaginal ultrasound with regard to acute pelvic inflammatory disease: a review of the literature, Arch Gynecol Obstet 289(4):705-714, 2014.

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Pelvic Organ Prolapse BASIC INFORMATION

SYNONYMS Vaginal prolapse Uterine prolapse Genital prolapse Uterine descensus POP Pelvic floor disorder PFD ICD-10CM CODES N81.l8 Other female genital prolapse N81.2 Incomplete uterovaginal prolapse N81.4 Uterovaginal prolapse, unspecified N81.5 Vaginal enterocele N81.6 Rectocele N81.82 Incompetence or weakening of pubocervical tissue

EPIDEMIOLOGY & DEMOGRAPHICS INCIDENCE AND PREVALENCE: Exact prevalence estimates are difficult to determine due to varying definitions of POP and various diagnostic criteria. Based on self-reported symptoms in the National Health and Nutrition Examination Survey, the prevalence of POP is 3% to 4%. However, based on physical examination, the prevalence of POP is much higher. The incidence of POP surgery is 1.5 to 1.8 surgeries per 1000 women yrs. Annual direct health care costs are high, and repeat operations are common. GENETICS: Data suggest a heritable component to POP; however, no specific genes or genetic factors outside of specific connective tissue diseases have been identified. Connective tissue disorders associated with an increased risk include Marfan syndrome and Ehlers-Danlos syndrome. In general, a genetic susceptibility exists in certain families, which is then affected by external factors to increase an individual woman’s risk of POP. RISK FACTORS: POP has a long latency and is multifactorial. Multiple risk factors have been

ETIOLOGY • The cause of pelvic organ prolapse is usually multifactorial, but pregnancy is the most commonly associated risk factor. • Muscle injury (levator ani) and connective tissue damage (pubocervical fascia) cause failure of pelvic floor support. • Increased intraabdominal pressure results in strain on pelvic floor support structures. • Injury to pelvic floor muscles or connective tissue supports results in uncompensated forces on pelvic floor, resulting in further injury to pelvic floor support structures. 1.  Acute (traumatic) injury to pelvic floor support can result from vaginal delivery, labor, or surgery. 2. Chronic injury or strain on pelvic floor connective tissue and muscle can result from conditions such as COPD with chronic coughing or chronic constipation. 3. Neurologic injury from acute or chronic strain on pelvic floor can result in denervation and subsequent muscular atrophy. 4.  Diseases or medications that weaken connective tissue (Marfan syndrome, corticosteroids) can predispose to injury. 5.  Hypoestrogenism may weaken pelvic floor tissue and impair ability to heal from injury. • With injury to pelvic floor support structures, vaginal tissue becomes subjected to the forces from intraabdominal pressure and will stretch, allowing the bladder, uterus, or

intestines to be displaced downward into the vaginal canal, resulting in clinical symptoms.

PHYSICAL FINDINGS & CLINICAL PRESENTATION • Bulge symptoms 1. Vaginal pressure 2. Protrusion from vagina (Fig. E4) • Urinary symptoms 1. Urinary hesitancy 2. Urinary frequency or urgency 3. Manual reduction of prolapse to complete urination 4. Incomplete emptying 5. Weak urinary stream • Bowel symptoms 1. Incomplete defecation 2. Altered rectal sensation (urgency, lack of sensation) 3. Splinting of vagina/perineum to defecate • Sexual symptoms 1. Dyspareunia 2. Difficulty with vaginal penetration • Other 1. Vaginal bleeding from excoriated vaginal epithelium from chronic exteriorization 2. Incarcerated prolapse with inability to be manually reduced

DIAGNOSIS WORKUP • Elicit specific symptoms. Determine the degree of bother with symptoms. • Perform detailed pelvic exam. Examine anterior, posterior, and apical segments of vagina independently. Assess pelvic floor muscle tone. 1. Exam is done in standard lithotomy position, and POP is assessed with Valsalva during exam. 2. If symptoms are out of proportion to findings, repeat exam in standing position. • Describe exam findings objectively (Boxes 1, 2, and 3). 1. Quantitatively with POP-Q 2. Descriptively with Baden-Walker halfway systems • Urinary symptoms should be evaluated separately. 1. POP is associated with urinary incontinence but does not cause urinary incontinence.

TABLE 1  Types of Genital Prolapse Original Position of Organs Anterior Central Posterior

Prolapse Urethrocele Cystocele Cervix/uterus: 1st, 2nd, and 3rd degree Procidentia Rectocele Enterocele

Symptoms (in addition to the general symptoms of discomfort, dragging, the feeling of a “lump,” and, rarely, coital problems) Urinary symptoms (stress incontinence, urinary ­frequency) Bleeding and/or discharge from ulceration in association with procidentia Bowel symptoms, particularly the feeling of incomplete evacuation and sometimes having to press the ­posterior wall backward to pass stool

P

Diseases and Disorders

DEFINITION Pelvic organ prolapse (POP) refers to descent of vaginal tissue and/or the uterus into the vaginal canal. It results from injury to or weakness in the connective tissue and muscles of the pelvic floor. Modern definitions of POP describe anterior and posterior vaginal wall defects, as well as apical defects in pelvic floor connective tissue. Synonyms for POP include cystocele (Fig. E1), rectocele, uterine prolapse (Fig. E2), enterocele (Fig. E3), and vaginal vault prolapse. Descriptions of this condition as a “dropped bladder,” “dropped uterus,” or defect in other pelvic organs should be avoided. These types of descriptions do not accurately reflect the pathophysiology of POP and often create confusion and unnecessary stress for patients. Table 1 describes the various types of POP affecting each vaginal compartment with corresponding ICD-10 codes.

identified. Some are modifiable, suggesting POP may be preventable; however, many risk factors are not. Some of the most common risk factors include: • Pregnancy, labor, and vaginal childbirth • Parity • Age • Chronic obstructive pulmonary disease (COPD) and chronic coughing • Smoking • Chronic constipation • Chronic heavy lifting • Chronic steroid use • Connective tissue diseases (Marfan syndrome, Ehlers-Danlos syndrome) • Pelvic surgery • Menopause • Family history • Caucasian and Hispanic race

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Pelvic Organ Prolapse BOX 1  Points of Reference for POP-Q Point

Description

Range of Values

Aa

3 cm above the hymen on anterior vaginal wall roughly ­corresponds with the urethrovesical junction. The lowest extent of the segment of vagina between point Aa and the apex of the vagina. Unlike point Aa, it is not fixed but will be the same as Aa if point Aa is the most protruding point. In maximal prolapse, it will be the same as point C. Most distal edge of cervix (vaginal cuff if uterus/cervix absent). Posterior fornix (n/a if hysterectomy). 3 cm above the hymen on posterior vaginal wall. The lowest extent of the segment of vagina between point Ap and the apex of the vagina. Unlike point Ap, it is not fixed but will be the same as Ap if point Ap is the most protruding point. In maximal prolapse it will be the same as point D. From urethral meatus to inferior hymenal ring.

−3 cm to +3 cm

Ba

C D Ap Bp

GH (Genital Hiatus) PB (Perineal Body) TVL (Total Vaginal Length)

−3 cm to + TVL

−3 cm to +3 cm −3 cm to + TVL

From inferior hymenal ring to middle of anal orifice. Without stretch or Valsalva.

Key Points: Measure position of six points with respect to the position of the hymen. Points above the hymen (inside) are negative, points below the hymen are positive, and points at the hymen are 0. Modified from Pemberton J (ed): The pelvic floor, Philadelphia, 2002, WB Saunders; and Bump RC et al: Am J Obstet Gynecol 175(1):13, 1996.

BOX 2  POP-Q Examination and Staging Stage 0 Stage I Stage II Stage III Stage IV

No prolapse Leading edge ≥1 cm above hymenal ring Leading edge ≤1 cm above hymenal ring but ≤1 cm below hymenal ring Most distal point is >1 cm but < (TVL-2) cm below the hymenal ring Leading edge ≥ (TVL-2) cm below hymenal ring

BOX 3  Baden Walker Halfway System Grade 0 Normal position for each ­respective site Grade 1 Descent halfway to the hymen Grade 2 Descent to the hymen Grade 3 Descent halfway past the hymen Grade 4 Maximum possible descent for each site

• Evaluate postvoid residual urine volume in advanced POP (stage 3 and stage 4). 1. Bladder ultrasound or catheterization at time of exam

LABORATORY TESTS • Not indicated for routine evaluation of POP. Urine testing may be indicated based on presence or absence of urinary tract symptoms. Urodynamic testing may be performed for additional information and surgical planning. IMAGING STUDIES • Not indicated for routine evaluation of POP. Imaging studies for other gynecologic or urologic conditions may be indicated. • Pelvic ultrasound may be considered in the absence of POP in patients with specific symptoms (i.e., pelvic pressure) (Fig. E5).

TREATMENT PRIMARY PREVENTION: • Diagnosis and treatment of chronic cough • Correction of constipation • Weight control, nutrition, and smoking cessation counseling • Pelvic muscle exercises • Proper management of vaginal apex at time of hysterectomy in patients without POP

• McCall culdoplasty to prevent vaginal vault prolapse • Cesarean delivery NOT indicated for prevention of POP • Untreated urinary retention, even if asymptomatic, can cause bladder infection, reflux, and renal damage POP TREATMENT OPTIONS: • Expectant management: Can be appropriate, except in cases of incomplete bladder emptying. • Pessaries (Fig. E6): 1. Support device 2. Silicone, not latex 3. Exists in various shapes and sizes a. Use the simplest and smallest pessary that works 4. 85% of women can be fitted successfully with a pessary (Fig. E7) a. Includes sexually active womena. 5. Self-care can be learned by the majority of women a. Usually remove and clean once per mo; otherwise, office visit every 3 mo for cleaning and exam. 6. Side effects/complications: a. Risk of UTI. b. Small vaginal erosions and very mild bleeding or spotting are common 1) First episode of vaginal bleeding needs evaluation in postmenopausal patients c. Neglected pessaries can cause vaginitis, odor, severe vaginal erosion/ bleeding, and fistula d. Vaginal estrogen may prevent or treat erosions and minimize risk of vaginitis and UTI • Surgery: 1. Indicated for bothersome POP and when patients fail or decline nonsurgical treatments. 2. Goals of surgery are to eliminate vaginal bulge and improve associated ­symptoms. a. Most reliable symptom resolution is elimination of bulge/protrusion. b.  Resolution of bladder and bowel symptoms is not routinely associated with surgical correction of POP. c. Choice of operation should be tailored to patient’s presenting problems, lifestyle, and goals for the surgery. 3. Evaluate and treat all defects present on exam. a.  Combination defects are the most common presentation. Seen in 60% of patients. b.  Anterior and apical combination is most common. 4.  There are multiple ways to classify operations for POP (Table 2). a. Obliterative: 1)  Narrow, shorten, or completely close off the vagina. 2) High success rates with low ­morbidity. 3) First-line treatment for women with significant medical ­ comorbidities

Pelvic Organ Prolapse TABLE 2  Surgical Approach to Pelvic Organ Prolapse Vaginal

Abdominal

Aa Urethra Ba Bladder

Anterior repair Bladder neck suspension sling Anterior repair Paravaginal repair Colpocleisis Uterosacral ligament suspension Iliococcygeus suspension Sacrospinous fixation Manchester operation Hysteropexy Vaginal hysterectomy Colpocleisis McCall culdoplasty

Retropubic urethropexy

C Cervix/cuff

D Cul-de-sac Ap

Wedge colpectomy Paravaginal repair Abdominal sacrocolpopexy Abdominal hysterectomy Uterosacral ligament suspension Abdominal sacral colpopexy Uterine suspension

Rectovaginal plication (posterior repair) Site-specific repairs

Halban culdoplasty Moschcowitz culdoplasty Colpoperineopexy

POP-Q, Pelvic Organ Prolapse Quantification System. From Wein AJ et al: Campbell-Walsh urology, ed 11, Philadelphia, 2016, Elsevier.

TABLE 3  Procedures for POP Classification Obliterative Reconstructive

Restorative

Compensatory Mesh Nonmesh









Procedure

Compartment(s)

Le Fort colpocleisis Total colpocleisis Uterosacral ligament suspension Hysteropexy Paravaginal defect repair Anterior colporrhaphy Posterior colporrhaphy Defect-directed posterior repair Perineorrhaphy

All All Apex Apex Anterior Anterior Posterior Posterior Posterior

Sacral colpopexy Sacral hysteropexy Transvaginal mesh Sacrospinous ligament suspension Ileococcygeus suspension Enterocele repair

All Apex All Apex Apex Posterior

who do not desire future vaginal intercourse. 4)  Associated with high rates of postoperative incontinence; most surgeons offer antiincontinence procedure at the same setting. b. Reconstructive: 1)  Restorative procedures use normal anatomic relationships and structures. 2)  Compensatory procedures utilize nonanatomic relationships and may or may not use synthetic meshes and graphs. 5.  Table 3 categorizes various common procedures for POP. 6. Hysterectomy alone does not treat POP.



a. Often performed concomitantly with POP repair as necessary step to expose critical anatomy. 7.  For symptomatic women who desire childbearing: Management with pessaries or pelvic muscle exercises is recommended; if surgical correction is required, uterosacral ligament hysteropexy is the preferred method. a.  Patients should be counseled that repair will likely break down with subsequent pregnancy. 8. Women without stress incontinence undergoing vaginal surgery for POP are at risk for postoperative urinary incontinence. a. Use of a prophylactic midurethral sling inserted during vaginal prolapse surgery has been shown to result in a

DISPOSITION • Surgical success rates range between 70% and 95%. • Up to 30% of patients may require a second operation for POP. • Untreated POP does not necessarily worsen. REFERRAL • To a urogynecologist/gynecologist if surgical intervention is needed or for complex cases involving bladder dysfunction. • Treating physicians should have special training with synthetic mesh products, if they are used.

PEARLS & CONSIDERATIONS • POP rarely, if ever, causes pain. • Stage of POP does not dictate treatment or prognosis. • Treatment for POP is based on symptoms and patient bother. • Options for most patients are no treatment, pessary, or surgery.

SUGGESTED READINGS Available at ExpertConsult.com RELATED CONTENT Pelvic Organ Prolapse (Patient Information) Uterine Prolapse (Patient Information) Incontinence, Urinary (Related Key Topic) AUTHORS: Shivani Shah, MD, and Matthew J. Fagan, MD, FACOC

P

Diseases and Disorders

POP-Q Site

lower rate of urinary incontinence at 3 and 12 mo, but also in a higher rate of adverse events (UTIs, major bleeding complications, incomplete bladder emptying). 9.  Abdominal mesh-based repairs and anterior vaginal mesh repairs have superior durability but higher risk and potential for unique complications. a. Use of mesh with posterior repairs does not improve outcomes and is associated with increased complications. 10. Mesh erosion rates have been reported up to 10%, with similar incidence between biologic and synthetic graft. However, synthetic graft erosion often requires surgical revision.

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SUGGESTED READINGS Altman D et al: Anterior colporrhaphy versus transvaginal mesh for pelvic-organ prolapse, N Engl J Med 364:1826-1836, 2011. Anderson KM et al: Urinary incontinence and pelvic organ prolapse, Med Clin North Am 99(2):405-416, 2015. Barber MD et al: Comparison of 2 transvaginal surgical approaches and perioperative behavioral therapy for apical vaginal prolapse, the Optimal Randomized Trial, JAMA 311(10):1023-1034, 2014. Iglesia C, Smithling KR: Pelvic organ prolapse, Am Fam Phys 96(3):179-186, 2017. Kuncharapu I et al: Pelvic organ prolapse, Am Fam Physician 81(9):1117-1120, 2010. Maher C et al: Surgical management of pelvic organ prolapse in women, Cochrane Database Syst Rev 4:CD004014, 2013. Rapp DE et al: Comprehensive evaluation of anterior elevate system for the treatment of anterior and apical pelvic floor descent: 2-year follow-up, J Urol 191:389-394, 2014. Wei JT et al: A midurethral sling to reduce incontinence after vaginal prolapse repair, N Engl J Med 366:2358-2367, 2012.

Uterus Bladder Rectum Vagina Anus

A

B FIG. E1  (A,B) Cystocele. (From Magowan BA: Clinical Obstetrics & Gynecology, ed 4, 2019, Elsevier.)

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Loop of small bowel Everted uterus

Uterus Bladder

Bladder

Rectum

Rectum

Vagina

Cervix

Anus Anus

A

FIG. E3  Enterocele. (From Magowan BA: Clinical Obstetrics & Gynecology, ed 4, 2019, Elsevier.)

Everted uterus Bladder Rectum Cervix Anus

B

Rectum Bladder Anus

C

Cervix

FIG. E2  Uterine prolapse. (A) Stage I; (B) stage II, and (C) stage III. (From Magowan BA: Clinical Obstetrics & Gynecology, ed 4, 2019, Elsevier.)

FIG. E4  Vaginal prolapse, resulting in edema of the vagina. (From Crum, CP et al: Diagnostic gynecologic and obstetric pathology, ed 3, Philadelphia, 2018, Elsevier.)

B R

A

B

C

V

FIG. E5  A, Moderate global pelvic prolapse in a woman with stress urinary incontinence, pelvic heaviness, and constipation after three vaginal deliveries. At rest, all viscera are normally situated in the pelvis. B, With Kegel contraction, note that all viscera remain normally situated in the pelvis. C, With maximal strain, bladder (B), vagina (V), and rectum (R) are well below the pelvic floor. (From Fielding JR et al: Gynecologic imaging, Philadelphia, 2011, WB Saunders.)

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FIG. E6  A selection of the commonly used vaginal pessaries. (From Magowan BA: Clinical Obstetrics & Gynecology, ed 4, 2019, Elsevier.)

Uterus Bladder Rectum Vagina Anus

FIG. E7  Ring pessary in situ. Note that the anterior vaginal wall is elevated to reduce the cystocele and the uterine prolapse has been corrected. (From Magowan BA: Clinical Obstetrics & Gynecology, ed 4, 2019, Elsevier.)

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Pemphigus Vulgaris BASIC INFORMATION DEFINITION The word “pemphigus” is derived from the Greek word pemphix, meaning blister. The pemphigus dermatoses encompass a group of rare, potentially fatal, chronic, autoimmune bullous diseases that are characterized by intraepidermal blisters of the skin and mucous membranes. Pemphigus has four main subtypes: • Pemphigus vulgaris (PV) (Fig. E1): The most common of the pemphigus diseases 1. Pemphigus vegetans of Neumann, a rare clinical variant of PV in which healing is accompanied by vegetative proliferation of the epidermis 2.  Pemphigus vegetans of Hallopeau, a milder clinical variant of PV in which bullae do not precede vegetativing plaques. Most common on intertriginous areas • Pemphigus foliaceus (PF): A superficial form of pemphigus without oral mucosa involvement and a more favorable prognosis than that of PV. 1. Pemphigus seborrhoicus, a rare clinical variety of PF in which lesions occur in a seborrheic distribution 2.  Pemphigus erythematosus, a localized variant of PF that mainly affects the elderly and can resemble cutaneous lupus erythematosus; the majority of cases will have positive antinuclear antibody (ANA) and negative anti–double-stranded DNA antibody (anti-dsDNA) 3. Endemic pemphigus foliaceus (fogo selvagem), an endemic variant of PF that is seen mainly in endemic regions of Brazil and North Africa. The black fly (Simulium nigrimanum) may serve as a vector 4. Pemphigus herpetiformis, pemphigus vulgaris or pemphigus foliaceus with urticarial plaques and vesicles in a herpetiform pattern • Paraneoplastic pemphigus: Presents with hemorrhagic stomatitis and mucous membrane erosions; associated with malignancy (most commonly non-Hodgkin lymphoma and chronic lymphocytic leukemia [CLL]); complete neoplastic workup is required when diagnosis is suspected • Immunoglobulin (Ig) A pemphigus: Fluid-filled blisters that progress to pustules and have a tendency to coalesce; mucosal involvement is rare 1. Subcorneal pustular dermatosis-type IgA pemphigus 2. Intraepidermal neutrophilic IgA dermatosis

EPIDEMIOLOGY & DEMOGRAPHICS • Pemphigus vulgaris makes up 80% of all pemphigus cases • Incidence is estimated at 1 to 5 cases per 1 million person-yr, but it is substantially higher in geographic regions with large populations of Ashkenazi Jewish or Mediterranean descent • Typically occurs in the fourth to sixth decades of life, although range of ages affected is broad and may occur in the very young or the elderly • Slight female predilection (1.5:1) PHYSICAL FINDINGS & CLINICAL PRESENTATION • History: 1. Multiple oropharyngeal ulcerations (Fig. E2) and erosions typically occur first (50% to 70% of cases), which can then be followed by a more generalized bullous eruption involving the skin within several weeks or months: a. Blisters are flaccid and rupture easily, leaving painful nonhealing erosions and ulcerations that may be the predominant clinical finding. b.  Pain associated with oral mucosal blistering often results in dysphagia and hoarseness; nasal cavity involve-

ment can lead to nasal congestion and mucus discharge. c. Skin bullae may occasionally be the initial manifestation of PV; most commonly involves the scalp (Fig. E3), upper chest, and back. d. Not commonly pruritic. Physical findings: 1. Anatomic distribution: a. Oral mucosa: Most common sites are buccal, labial, and palatal mucosa, along with the tongue b. Can also involve the pharynx, larynx, vagina, penis, anus, and conjunctival mucosa; a recent study reported that 39% of patients with PV had pharyngoesophageal involvement as determined by upper gastrointestinal endoscopy c.  Generalized cutaneous involvement (Fig. E4) 2. Other clinical findings: a. Nail dystrophy, paronychia, and subungual hematomas b.  Ocular symptoms, though rare, may include conjunctival injection, pain, tearing, photophobia, and irritation; visual acuity is not affected; associated conjunctival papillomas and inflammatory masses have recently been reported

FIG. E1  Pemphigus vulgaris. (Courtesy Dr. Lawrence Lieblich. From James WD et al: Andrews’ diseases of the skin, ed 12, Philadelphia, 2016, Elsevier.)

SYNONYMS Pemphigus PV Fogo selvagem: Endemic pemphigus foliaceus Senear-Usher syndrome: Pemphigus erythematosus ICD-10CM CODE L10.0 Pemphigus vulgaris

FIG. E2  Oral pemphigus vulgaris. (From James WD et al: Andrews’ diseases of the skin, ed 12, Philadelphia, 2016, Elsevier.)

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DIAGNOSIS The diagnosis of pemphigus vulgaris should be suspected in patients with painful oral erosions and flaccid bullae or erosions on the skin. The diagnosis is confirmed by histology, direct immunofluorescence (DIF) pattern of perilesional skin, indirect immunofluorescence (IIF) testing of serum, or ELISA testing for anti-desmoglein 1 and anti-desmoglein 3 autoantibodies.

FIG. E3  Chronic pemphigus vulgaris of the scalp. (From James WD et al: Andrews’ diseases of the skin, ed 12, Philadelphia, 2016, Elsevier.)

FIG. E4  Pemphigus vulgaris. (From James WD et al: Andrews’ diseases of the skin, ed 12, Philadelphia, 2016, Elsevier.)













3. Lesion configuration: a. Mucosal membranes b. No preferential distribution 4. Lesion morphology: a. Flaccid bullae and vesicles progressing to ulcerations and erosions with a collarette of loose epidermis. b. Positive Nikolsky sign: When the clinician applies lateral pressure to normal-appearing skin at the periphery of active lesions, separation of the superficial epidermis occurs. c. Positive Asboe-Hansen sign: When gentle pressure is applied on intact bulla, the fluid spreads under the adjacent skin, thereby enlarging the blister. d. In the absence of treatment, healing with crusting followed by reepithelialization may occur; scarring is rare, but some patients experience hyperpigmentation. e. Possibility for large areas of denuded skin with resulting bacterial superinfection.

ETIOLOGY Autoimmune disease caused by autoantibodies against the cell surface of keratinocytes

leading to separation of adjacent keratinocytes (called acantholysis). The predominant antibody in PV is directed against desmoglein 3 (Dsg-3) or both Dsg-3 and desmoglein 1 (Dsg-1; in PF it is directed against desmoglein 1. Desmoglein 1 is concentrated mainly in superficial epidermal layers, whereas desmoglein 3 is present mainly in the deeper epidermis layers, thus accounting for the differences in the sites of blister formation in PV versus PF. Additional antibodies directed toward keratinocyte acetylcholine receptors have also been identified. Circulating antibodies are detected in approximately 80% of patients with active disease, and levels generally correlate with disease severity. Immunoglobulin (Ig) G, and rarely IgM, IgA, or complement protein C3, deposition occurs in lesional and healthy perilesional skin in 90% of patients. Several drugs, including captopril, penicillamine, aspirin, calcium channel blockers, and rifampin, have been identified as potential triggers in the development of PV. Cessation of use generally leads to rapid resolution. Ultraviolet radiation, including phototherapy, may also exacerbate pemphigus vulgaris and foliaceus.

DIFFERENTIAL DIAGNOSIS • Herpetic stomatitis • Aphthous stomatitis • Erythema multiforme • Stevens-Johnson syndrome • Drug eruptions • Lichen planus • Systemic or bullous lupus erythematosus • Mucous membrane or cicatricial pemphigoid • Paraneoplastic pemphigus • Pemphigus foliaceus • Linear IgA bullous dermatosis • Hailey-Hailey disease • Grover disease • Bullous pemphigoid (Table E1) • Behçet syndrome • Dermatitis herpetiformis • Epidermolysis bullosa acquisita • IgA pemphigus WORKUP Skin biopsy is diagnostic; specimens should be sent for routine histochemical staining and direct immunofluorescence. An upper endoscopy should be considered in patients with dysphagia to determine degree of esophageal involvement and check for esophageal Nikolsky sign. Airway evaluation is indicated for patients with any evidence of airway obstruction. DIF is positive in all patients with PV or PF. Alternative diagnosis should be considered if DIF is negative. DIF is negative in some patients with drug-induced pemphigus. LABORATORY TESTS • Light microscopy: Intraepithelial blisters with acantholysis; basal layer with single layer of intact cells (known as “tombstoning”) • DIF: Intercellular IgG and C3 deposition in “chicken-wire” lattice pattern • IIF: Tests for presence and titer of antibodies; should be used in conjunction with clinical, histopathological, and DIF evaluation; estimated 90% positive predictive value and low negative predictive value; titers may correlate with disease state and can potentially be used for tracking progression and treatment response • ELISA: Similar sensitivity but inferior specificity compared to IIF; antidesmoglein antibodies titers correlate with disease activity (however, there is a subset of patients with high antiDsg-3 antibodies but low disease activity)

TREATMENT A rating scale, such as the Pemphigus Disease Area Index (PDAI), can be used to assess disease severity. This scale correlates well with

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TABLE E1  Differentiation of Pemphigus Vulgaris and Bullous Pemphigoid Characteristics

Pemphigus Vulgaris

Bullous Pemphigoid

Age Site

Usually occurs in middle-aged persons Oral mucosa, face, chest, groin

Findings

Flaccid bullae and erosions, intraepidermal blisters, IgG autoantibodies against keratinocyte surfaces Prednisone 0.5-1.5 mg/kg/day with adjuvant immunosuppressant agents; refractory disease may require rituximab, intravenous immunoglobulin, immunoadsorption, plasmapheresis, or extracorporeal photochemotherapy >90% respond; steroid side effects significant; mortality rate under 5%

Usually occurs in elderly persons Flexural areas, groin, axilla; less often involving mucosal surfaces Intact tense bullae, subepidermal blisters, IgG autoantibodies against hemidesmosomal antigens Prednisone 0.5-1 mg/kg/day with adjuvant ­immunosuppressant therapy as needed for refractory cases; ­localized disease may be controlled with topical steroids

Treatment

Prognosis

>90% respond; remissions and recurrences common; ­mortality rate up to 23%

IgG, Immunoglobulin G.

physician’s assessment of disease severity and can be used for patients with even mild disease. Briefly, it requires quantitative measurement of the number and size of total skin and mucosal lesions and incorporates disease activity and damage. Similar to severe burns, PV can be fatal without adequate treatment due to secondary infections and metabolic disturbances. The mainstay of therapy is systemic corticosteroids with the goal of complete absence of, or only occasional, blistering.

NONPHARMACOLOGIC THERAPY • Mild soaps and emollients to skin. • Burow solution may be useful for weeping erosions. • Avoid trauma to the skin. • When there are extensive raw surfaces, daily baths are helpful in removing the thickened crusts and reducing foul odor; can be followed with nonstick bandaging (e.g., petrolatum gauzes). • Soft diet and viscous lidocaine can be used in patients with oral lesions; flossing should be avoided in the presence of symptomatic lesions. • A mixture of equal parts of simethicone (Maalox), elixir of diphenhydramine, and viscous lidocaine is also effective. ACUTE GENERAL Rx • For localized disease, topical steroids may be effective. • For generalized disease, oral glucocorticoids are the mainstay of therapy and often work rapidly to halt blistering. 1. Optimum dosing guidelines have not yet been established. 2. Initial dose of prednisone is usually 0.5 to 1.5 mg/kg/day; if new lesions continue to form, the dose can be increased up to 2 mg/kg/day. Pulsed dosing may also be used. 3. Adjuvant therapy with rituximab administered with prednisone as initial therapy may lead to improve mortality rates compared to prednisone alone. 4. Alternative adjuvant therapies can also be initiated simultaneously with p­rednisone









include azathioprine, mycophenolate mofetil (MMF), cyclophosphamide, cyclosporine, dapsone, infliximab, intravenous immunoglobulin, and plasma exchange. These agents help reduce the risk of relapse. 5. Tumor necrosis factor (TNF)-α blockers should be avoided, given conflicting data regarding their efficacy in the treatment of PV. 6. For patients with severe disease requiring initial prednisone dosing greater than 100 mg daily, treatment with pulse oral or intravenous (IV) steroids can be very effective; a common regimen is IV dexamethasone 100 mg for 3 days and repeated every 2 to 3 wk. 7. Steroid tapering should begin once no new lesions have developed for at least 2 wk and approximately 80% of the existing lesions have healed. The steroid dose should be decreased by 25% at biweekly intervals, with slower reductions once a dose of 20 mg per day is reached. If fewer than three new lesions form during taper, increase steroid dose to last effective dose. If three or more new lesions form during taper, increase steroid dose back to prior doses. 8. Ocular involvement in PV generally responds to prednisone and/or immunosuppressant therapy; lubricating artificial tears or topical ophthalmic corticosteroids can provide further symptomatic relief.

CHRONIC Rx • Adjuvant therapy such as immunosuppressants, antiinflammatories, chemotherapeutic agents, and biologics are useful for disease control and to shorten the length of treatment with oral steroids. Azathioprine, MMF, dapsone, methotrexate, cyclophosphamide, and cyclosporine can also be used as monotherapy for patients with contraindications to corticosteroids. Treatment duration and dosing are determined by clinical response: 1. Azathioprine: First-line adjuvant immunosuppressant. 1 to 3 mg/kg/day based on thiopurine methyltransferase (TPMT)

activity; an initial dose of 50 mg daily can be started and increased after a week in the absence of adverse effects. 2. Mycophenolate mofetil (MMF): Steroidsparing agent. 2 g daily for average patient of 75 kg, or 1 g daily for elderly patients. 3. Cyclophosphamide: Second-line immunosuppressant adjuvant agent. 500 mg IV infusion or 2 mg/kg/day PO. Use limited by potential long-term side effects, including infertility, infections, increased risk of cancers, and genitourinary complications. 4. Methotrexate: Steroid-sparing agent. 10 to 20 mg/wk. 5. Dapsone 100 mg daily or up to ≤1.5 mg/ kg/day; serum G6PD activity should be checked prior to beginning therapy. 6. Rituximab (anti-CD20 monoclonal antibody): Typical regimen is 1000 mg IV at baseline and 2 wk, then 500 mg every 6 mo. Refractory disease: • A relapse or flare is defined as the appearance of three or more lesions in a month without spontaneous resolution, or the extension of established lesions in a patient who has previously attained control of disease activity. A variety of treatment modalities are available: 1. Intravenous immunoglobulin (IVIG): Refractory disease or for patients with contraindications to immunosuppressants. Dosing is 2 g/kg per cycle administered over 2 to 5 consecutive days each month. Contraindicated in IgA deficiency; can lead to aseptic meningitis in patients with history of chronic migraines. 2. Immunoadsorption: Rapid removal of circulating antibodies. Indicated in PV patients who have failed corticosteroid therapy combined with azathioprine or MMF. Recommended schedule is four treatments on 4 consecutive days (2.5-fold plasma volume/day) repeated monthly. Can be combined with rituximab or cyclophosphamide therapy. 3. Plasmapheresis: No standardized protocol. Four to five plasma exchanges of 1 to 1.5 plasma volumes over a period of 7 to 10 days is sufficient to remove 90% of total body initial immunoglobulin burden.

Pemphigus Vulgaris

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Should be used with caution in patients with cardiac dysfunction. 4. E xtracorporeal photochemotherapy: Collection and reinfusion of mononuclear cells after extracorporeal irradiation with ultraviolet-A light in the presence of 8-metoxypsoralen. Case series have reported excellent clinical response with no adverse effects.

than 5%. However, patients with PV continue to have significantly increased mortality risks compared with the general population. • The risk of all-cause mortality in PV patients is two to three times greater than expected for the general population. Death generally occurs from systemic and respiratory tract infections or complications related to medical therapy.

DISPOSITION • Medication is continued until clinical disease is suppressed. • Age of onset ≥65 yr, presence of coronary heart disease and/or cardiac arrhythmias at time of diagnosis, and level of anti-Dsg-1 autoantibodies ≥100 U/ml at diagnosis to be associated with greater mortality in PV patients. • Before the use of oral corticosteroids, PV was usually a fatal disease with a mortality rate of greater than 73% and survival measured in months after diagnosis. • Combined corticosteroids and adjuvant therapy have decreased mortality rates to less

REFERRAL • Dentistry • Dermatology • Ophthalmology • Otolaryngology

• Monitoring anti-Dsg-1 antibodies during treatment course may be helpful, as persistently high levels are a positive predictive marker for cutaneous relapse. In contrast, high levels of anti-Dsg-3 do not always correlate with a mucosal relapse. • Because PV is mediated by IgG autoantibodies that can cross the placenta, neonates born to mothers with active PV can present with transient disease that self-resolves as the antibody is degraded.

RELATED CONTENT Pemphigus Vulgaris (Patient Information)

PEARLS & CONSIDERATIONS

AUTHORS: Sara Moradi Tuchayi, MD, and Kachiu C. Lee, MD, MPH

COMMENTS • PV, unlike bullous pemphigoid, is generally a disease of middle-aged persons. • Prednisone is the mainstay of treatment.

SUGGESTED READINGS Avgerinou G et al: Correlation of antibodies against desmogleins 1 and 3 with indirect immunofluorescence and disease status in a Greek population with pemphigus vulgaris, J Eur Acad Dermatol Venereol 27(4):430-435, 2013. Avisar I et al: Multiple conjunctival papillomas of eyelid margins in pemphigus vulgaris, Case Rep Ophthalmol Med 2011:174912, 2011. Baum S et al: Diagnosis and classification of autoimmune blistering diseases, Autoimmun Rev 13(4-5):482-489, 2014. Brenner S, Goldberg I: Drug-induced pemphigus, Clin Dermatol 29(4):455-457, 2011. Broussard KC et al: Autoimmune bullous diseases with skin and eye involvement: cicatricial pemphigoid, pemphigus vulgaris, and pemphigus paraneoplastica, Clin Dermatol 34(2):205-213, 2016. Gregoriou S et al: Management of pemphigus vulgaris: challenges and solutions, Clin Cosmet Investig Dermatol 8:521-527, 2015. Huang YH et al: Incidence, mortality, and causes of death of patients with pemphigus in Taiwan: a nationwide population-based study, J Invest Dermatol 132(1):92-97, 2012. Joly P et al: First-line rituximab combined with short-term prednisone versus prednisone alone for the treatment of pemphigus (Ritux 3): a prospective, multicentre, parallel-group, open-label randomised trial, Lancet 389(10083):2031-2040, 2017.

Kneisel A, Hertl M: Autoimmune bullous skin diseases. Part 1: clinical manifestations, J Dtsch Dermatol Ges 9(10):844-856, 2011. quiz 857. Knudson RM et al: The management of mucous membrane pemphigoid and pemphigus, Dermatol Ther 23(3):268-280, 2010. Kridin K et al: Mortality and cause of death in patients with pemphigus, Acta Derm Venereol 97(5):607-611, 2017. Okamura A et al: Evaluation of pharyngo-oesophageal involvement in pemphigus vulgaris and its correlation with disease activity, Br J Dermatol 176(1):224226, 2017. Santoro FA et al: Pemphigus, Dent Clin North Am 57(4):597-610, 2013. Sticherling M, Erfurt-Berge C: Autoimmune blistering diseases of the skin, Autoimmun Rev 11(3):226-230, 2012. Tsuruta D et al: IgA pemphigus, Clin Dermatol 29(4):437-442, 2011. Uludag HA et al: An uncommon ocular manifestation of pemphigus vulgaris: conjunctival mass, Ocul Immunol Inflamm 21(5):400-402, 2013.

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Peptic Ulcer Disease BASIC INFORMATION DEFINITION Peptic ulcer disease (PUD) is an ulceration in the stomach or duodenum resulting from an imbalance between mucosal protective factors and various mucosal damaging mechanisms (see “Etiology”). SYNONYMS PUD Duodenal ulcer (DU) Gastric ulcer (GU) ICD-10CM CODES K25.3 Acute gastric ulcer without ­hemorrhage or perforation K25.7 Chronic gastric ulcer without ­hemorrhage or perforation K26.3 Acute duodenal ulcer without ­hemorrhage or perforation K26.7 Chronic duodenal ulcer without hemorrhage or perforation K27.0 Acute peptic ulcer, site unspecified, with hemorrhage K27.1 Acute peptic ulcer, site unspecified, with perforation K27.2 Acute peptic ulcer, site ­unspecified, with both hemorrhage and ­perforation K27.3 Acute peptic ulcer, site unspecified, without hemorrhage or perforation K27.4 Chronic or unspecified peptic ulcer, site unspecified, with hemorrhage K27.5 Chronic or unspecified peptic ulcer, site unspecified, with perforation K27.6 Chronic or unspecified peptic ulcer, site unspecified, with both ­hemorrhage and perforation

K27.7

Chronic peptic ulcer, site ­unspecified, without hemorrhage or perforation K27.9 Peptic ulcer, site unspecified, unspecified as acute or chronic, without hemorrhage or perforation P78.82 Peptic ulcer of newborn Z87.11 Personal history of peptic ulcer disease

EPIDEMIOLOGY & DEMOGRAPHICS • Incidence: 250,000 to 500,000 (200,000 to 400,000 duodenal; 50,000 to 100,000 gastric) annually; duodenal ulcer/gastric ulcer ratio is 4:1. • Anatomic location: 90%) in other parts of the world. Eradication of H. pylori markedly reduces peptic ulcer recurrence • Medications (NSAIDs, glucocorticoids). Risk factors for development of NSAID-related ulcers are described in Table 1 • Incompetent pylorus or lower esophageal sphincter • Bile acids • Impaired proximal duodenal bicarbonate secretion • Decreased blood flow to gastric mucosa • Acid secreted by parietal cells and pepsin secreted as pepsinogen by chief cells • Cigarette smoking • Alcohol

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • Gastroesophageal reflux disease • Cholelithiasis syndrome • Pancreatitis • Gastritis • Nonulcer dyspepsia • Neoplasm (gastric carcinoma, lymphoma, pancreatic carcinoma) • Angina pectoris, myocardial infarction, pericarditis • Dissecting aneurysm • Other: High small-bowel obstruction, pneumonia, subphrenic abscess, early appendicitis WORKUP Comprehensive history and physical exam to exclude other diagnoses. Diagnostic modalities include endoscopy or upper GI series. Endoscopy is preferred and remains the gold standard for diagnosis of PUD. The presence of a mucosal break ≥5 mm in the stomach or duodenum confirms the diagnosis.

TABLE 1  Risk Factors for Development of NSAID-Related Ulcers Definite Advanced age History of ulcer Concomitant corticosteroid therapy Concomitant anticoagulation therapy High doses of NSAIDs Serious systemic disorders Possible Concomitant infection with Helicobacter pylori Cigarette smoking Consumption of alcohol NSAID, Nonsteroidal antiinflammatory drug. From Andreoli TE et al: Andreoli and Carpenter’s Cecil essentials of medicine, ed 8, Philadelphia, 2010, Saunders.

Peptic Ulcer Disease

IMAGING STUDIES • Conventional upper GI barium studies identify approximately 70% to 80% of PUD; accuracy can be increased to approximately 90% by using double contrast. • Abdominal CT is helpful when suspecting perforating peptic ulcer disease (sensitivity >95%).

TREATMENT NONPHARMACOLOGIC THERAPY • Stop smoking; smoking increases the risk of PUD, decreases the healing rate, and increases the frequency of recurrence. • Avoid NSAIDs and alcohol. • Special diets have been proved unrelated to ulcer development and healing; however, avoid foods that cause symptoms. ACUTE GENERAL Rx Eradication of H. pylori, when present, can be accomplished with various regimens (see “Helicobacter pylori Infection”) PUD patients testing negative for H. pylori should be treated with antisecretory agents: • H2 receptor antagonists (H2RAs): Ranitidine, famotidine, and nizatidine are all effective; they are usually given in split dose or at nighttime. • PPIs: Can also induce rapid healing; they are usually given 30 min before meals. Antacids and sucralfate are also effective agents for the treatment and prevention of PUD. CHRONIC Rx Maintenance therapy in peptic ulcer patients is indicated in the following situations: • Persistent smokers • Recurrent ulcerations • Long-term treatment with NSAIDs, glucocorticoids • Elderly or debilitated patients • Aggressive or complicated ulcer disease (e.g., perforation, hemorrhage) • Asymptomatic bleeders DISPOSITION • The recurrence rate for untreated PUD is ∼60% (>70% in smokers). Treatment decreases the recurrence rate by nearly 30%. • Patients with recurrent ulcers should be re-treated for an additional 8 wk and then placed on maintenance therapy with H2RAs, PPIs, sucralfate, or antacids. • An ulcer is considered refractory to treatment if healing is not evident after 8 wk for duodenal ulcers and 12 wk for gastric ulcers. In these patients, maximum acid inhibition (e.g., esomeprazole 40 mg bid) is preferred over continued therapy with standard antiulcer therapy. • Eradication of H. pylori (when present) is indicated in all patients. A negative stool antigen test for H. pylori 6 wk after treatment accurately confirms cure of H. pylori infection with

reasonable sensitivity in initially seropositive healthy subjects. • Screening for ZE syndrome should also be considered in patients with multiple recurrent ulcers; in patients with ZE, the serum gastrin level is >1000 pg/ml and the basal acid output is usually >15 mEq/hr. • Surgery for refractory ulcers is now only rarely performed; it consists of highly selective vagotomy for duodenal ulcers or ulcer removal with antrectomy or hemigastrectomy without vagotomy for gastric ulcers.

REFERRAL • GI referral for patients requiring endoscopy • Surgical referral for patients with nonhealing ulcers despite appropriate medical therapy

PEARLS & CONSIDERATIONS COMMENTS • Patients with gastric ulcers should generally have repeat endoscopy after 8 to 12 wk of antisecretory therapy to document healing and test exfoliative cytology for gastric carcinoma. Patients with duodenal ulcers and those with low risk gastric ulcers, such as young patients on NSAIDs, generally do not require endoscopic surveillance. • After endoscopic treatment of bleeding peptic ulcers, bleeding recurs in up to 20% of patients. PPI administration intravenously by continuous infusion substantially reduces the risk of recurrent bleeding. High-dose IV esomeprazole (80 mg IV bolus followed by 8 mg/hr infusion over 72 hr) given after successful endoscopic therapy to patients with high-risk peptic ulcer bleeding has been reported to reduce recurrent bleeding at 72 hr and to maintain sustained clinical benefits for up to 30 days. • Among low-dose aspirin recipients who had peptic ulcer bleeding, continuous aspirin therapy may increase the risk for recurrent bleeding. RELATED CONTENT Peptic Ulcer (Patient Information) Helicobacter pylori Infection (Related Key Topic) AUTHOR: Fred F. Ferri, MD

P

Diseases and Disorders

LABORATORY TESTS • Routine laboratory evaluation is usually unremarkable. • Anemia may be present in patients with significant GI bleeding. • H. pylori testing by endoscopic biopsy, urea breath test or stool antigen test (H. pylori stool antigen) is recommended: 1. The urea breath test documents active infection (sensitivity and specificity >90%). The patient ingests a small amount of urea labeled with carbon 13 or carbon 14. If urease is present (produced by the organism), the urea is hydrolyzed and the patient exhales labeled carbon dioxide that is then collected and measured. Use of proton pump inhibitors (PPI) within 2 wk of the urea breath test may interfere with test results. 2. Stool antigen test is an ELISA that identifies H. pylori antigen in a stool specimen through a polyclonal anti–H. pylori antibody. It is as accurate as the urea breath test for diagnosis of active infection and follow-up evaluation of patients treated for H. pylori. A negative result on the stool antigen test 6 wk after completion of therapy identifies patients in whom eradication of H. pylori was successful. 3.  Serologic testing for antibodies to H. pylori is easy and inexpensive; however, the presence of antibodies demonstrates previous but not necessarily current infection. Antibodies to H. pylori can remain elevated for mos to yrs after infection has cleared; therefore antibody levels must be interpreted in light of the patient’s symptoms and other test results (e.g., PUD seen on upper GI series). 4. Histologic evaluation of endoscopic biopsy samples is considered by many the gold standard for accurate diagnosis of H. pylori infection. However, detection of H. pylori depends on the site and number of biopsy samples, the method of staining, and experience of the pathologist. • Additional laboratory evaluation is indicated only in specific cases (e.g., amylase level in suspected pancreatitis, serum gastrin level in suspected Zollinger-Ellison [ZE] syndrome).

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Pericarditis

ALG

BASIC INFORMATION DEFINITION Acute pericarditis is the inflammation (or infiltration) of the pericardium. It is characterized by at least two of the following four criteria: (1) chest pain, (2) specific electrocardiographic changes, (3) pericardial friction rub, or (4) pathognomonic pericardial friction rub. ICD-10CM CODES I30.0 Acute nonspecific idiopathic ­pericarditis I30.1 Infectious pericarditis I30.8 Other forms of acute pericarditis I30.9 Acute pericarditis, unspecified I301.0 Chronic adhesive pericarditis I31.1 Chronic constrictive pericarditis I31.3 Pericardial effusion (non-­ inflammatory) I31.9 Diseases of pericardium, ­unspecified (tamponade) I31.2 Hemopericardium

EPIDEMIOLOGY & DEMOGRAPHICS • Most common form of pericardial disease worldwide • It is diagnosed in 0.1% to 0.2% of hospitalized patients and is responsible for 5% of patients admitted for nonischemic chest pain. PHYSICAL FINDINGS & CLINICAL PRESENTATION • Chest pain: Characteristically sharp, pleuritic, positional (improved by sitting up and leaning forward). • Pericardial rub: A triphasic (ventricular systole, early diastole, atrial contraction), scratchy sound best heard at the lower left sternal border is pathognomonic. Unlike pleural friction rub, the rub of pericarditis is not affected by respiration. • Pericardial effusion: Beck triad (hypotension, elevated jugular venous pressure, and muffled heart sounds) suggests pericardial tamponade. ETIOLOGY • Etiology is dichotomized into infectious and noninfectious causes. • In developed countries, viral and idiopathic etiologies are the most common causes of pericarditis. Tuberculosis accounts for 80% to 90% of pericarditis in developing countries. • Other infectious agents include HIV, fungus, parasites, and bacteria. • Noninfectious causes include neoplasm (7% to 13%), autoimmune syndromes (3% to 4%), and perimyocardial infarction (Dressler syndrome, typically 2 wk after MI). • Drug-induced: Procainamide, hydralazine, phenytoin, isoniazid, rifampin, doxorubicin, mesalamine, adalimumab. • Metabolic: Uremia, myxedema, anorexia nervosa.

• Posttraumatic: Postpericardiotomy, postpacemaker lead placement, postcatheter ablation, post-CPR.

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • Angina pectoris and acute coronary syndrome • Myopericarditis/perimyocarditis • Dissecting aortic aneurysm • Pulmonary causes: Embolism, infarction, pneumothorax, pneumonia with pleurisy • Gastrointestinal causes: Hepatitis, cholecystitis, GERD, esophageal spasm or rupture • Costochondritis • Box 1 summarizes the differential diagnosis of pericardial effusion by etiology WORKUP (TABLE 1) Table 2 summarizes an initial approach to acute pericarditis. Diagnosis of pericarditis requires at least two of the four following clinical criteria: • Typical pleuritic chest pain • Pericardial friction rub • Suggestive ECG changes (diffuse concave ST segment elevation, PR depression in all leads except for AVR where there is elevation) • New or worsening pericardial effusion LABORATORY TESTS Laboratory tests may help elucidate the underlying cause and are adjunctive to the clinical criteria. • Inflammatory markers: Erythrocyte sedimentation rate, (high-sensitivity) C-reactive protein (CRP), and complete blood count with differential are elevated in pericarditis. • Basic metabolic profile. • Cardiac biomarkers (troponin I and T) when elevated indicate involvement of the myocardium (i.e., myopericarditis). The following tests may be useful when specific etiologies of pericarditis are suspected: • HIV • PPD

• Antinuclear antibody, rheumatoid factor • Routine viral studies are not indicated since they are low yield

PERICARDIAL SAMPLING Indications for echocardiogram or pericardiocentesis are: • Tamponade physiology • Moderate to large pericardial effusion with symptoms, or refractory to medical therapy • Suspicion of a neoplastic, bacterial, or tuberculous process • Evidence of constrictive or effusive-constrictive pericarditis • Pericardiocentesis is for diagnostic and therapeutic purposes. The pericardial fluid should be analyzed for RBC, WBC, Gram stain, culture, cytology, glucose, pH, LDH, and protein. In select cases, consider checking triglyceride for chylopericardium, ADA or PCR for tuberculosis • Pericardial biopsy may be helpful in recurrent pericardial effusion with an elusive diagnosis and when malignancy or tuberculosis is suspected IMAGING STUDIES • ECG (Fig. 1): Changes in the ECG reflect inflammation of the epicardium, since the parietal pericardium is electrically inert. The ECG changes are staged as follows: 1. Stage I (Acute phase): Hours to few days. PR-segment depression in all leads except aVR (where PR elevation is seen) and diffuse concave ST-segment elevations 2. Stage II (Intermediate phase): Seen in first wk with return of PR and ST segments to baseline 3. Stage III (Intermediate): T-wave inversion in leads previously showing ST-segment elevation 4. Stage IV (Late phase): Normalization of the ECG or indefinite persistence of T-wave inversions

BOX 1  Major Differential Diagnosis of Pericardial Effusion by Etiology Noninfectious • Malignancy (usually metastatic) • Myocardial infarction associated (Dressler syndrome) • Uremia • Myxedema (rare cause of tamponade physiology) • Trauma (penetrating or nonpenetrating) • Chylopericardium • Acute idiopathic • Rheumatic fever • Collagen vascular disease (systemic lupus erythematosus, rheumatoid arthritis, scleroderma, Wegener granulomatosis) • Postsurgical (cardiac and intrathoracic) • Drug induced (procainamide, hydralazine, phenytoin, doxorubicin, isoniazid) Infectious • Viral (coxsackievirus, echovirus, mumps, adenovirus, hepatitis, human immunodeficiency virus) • Bacterial (pneumococcus, streptococcus, staphylococcus) • Tuberculous • Fungal (histoplasmosis, coccidiomycosis, Candida, particularly in immunosuppressed patients) From Niederhuber JE: Abeloff’s clinical oncology, ed 6, Philadelphia, 2020, Elsevier.

ALG

Pericarditis

TABLE 1  Diagnostic Pathway and Sequence of Performance in Acute Pericarditis Diagnostic Measure

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Characteristic Findings

Obligatory Auscultation ECG*

CK-MB, Creatine kinase-MB; CT, computed tomography; ECG, electrocardiogram; MRI, magnetic resonance imaging. *Typical lead involvement: I, II, aVL, aVF, and V3-V6. The ST segment is always depressed in aVR, frequently in V1, and occasionally in V2. Stage IV may not occur, and there are permanent T-wave inversions and flattenings. If an ECG is first recorded in stage III, pericarditis cannot be differentiated by ECG from diffuse myocardial injury, “biventricular strain,” or myocarditis. ECG in early repolarization is very similar to stage I. Unlike stage I, this ECG does not acutely evolve, and J-point elevations are usually accompanied by a slur, oscillation, or notch at the end of the QRS just before and including the J point (best seen with tall R and T waves—large in an early repolarization pattern). Pericarditis is likely if, in lead V6, the J point is greater than 25% of the height of the T-wave apex (using the PR segment as a baseline). †A rise in cardiac muscle troponin I (cTnI) is detected in 32.2% of patients, more frequently in younger, male patients, with ST segment elevation and pericardial effusion at presentation. An increase beyond 1.5 ng/ml is uncommon (7.6%) and associated with CK-MB elevation. cTnI increase and is not a negative prognostic marker for the incidence of recurrences, constrictive pericarditis, cardiac tamponade, or residual left ventricular dysfunction. From Vincent JL et al: Textbook of critical care, ed 7, Philadelphia, 2017, Elsevier.

TABLE 2  Initial Approach to the Patient with Definite or Suspected Acute Pericarditis 1. If the diagnosis is suspected but not certain, listen often for pericardial rub and obtain ECGs frequently to check for diagnostic findings. 2. If the diagnosis is suspected or certain, obtain the following tests to help confirm the diagnosis (if necessary) and determine whether a specific causative diagnosis and/or significant associated conditions and/or complications are present: Hemogram hsCRP Troponin I Chest radiograph Echocardiogram Consider additional testing on the basis of clinical suspicion of a specific etiology 3. If the diagnosis is likely or certain, initiate therapy with an NSAID plus colchicine. From Zipes DP: Braunwald’s heart disease, a textbook of cardiovascular medicine, ed 11, Philadelphia, 2019, Elsevier.

• Echocardiogram is used to evaluate for pericardial effusion (present in 50% to 60% of patients) (Fig. 2). Echocardiogram can help exclude STEMI (through absent wall motion abnormality) and make the diagnosis of constrictive pericarditis or tamponade. • Chest x-ray: Done primarily to rule out abnormalities of the mediastinum or lung fields that may cause chest pain. Cardiac silhouette may appear enlarged in patients with

pericardial effusion if ≥200 ml of fluid has accumulated (Fig. 3). Calcifications around the heart may be seen with chronic constrictive pericarditis. • Computed tomography: Evaluation of associated pleuropulmonary and extra thoracic diseases and pericardial calcifications. • MRI (Fig. 4) may be useful in patients with chronic constrictive pericarditis and when malignancy is suspected.

TREATMENT NONPHARMACOLOGIC THERAPY • Physical activity restriction until pain abates and normalization of (high sensitivity) CRP, ECG, and echo • Athletes should avoid competitive activity for 3 mo, whereas nonathletes can resume activities after remission (expert consensus) • Patient education regarding potential complications: e.g., cardiac tamponade, recurrent pericarditis (which can occur in up to one third of patients), and chronic constrictive pericarditis ACUTE GENERAL Rx • High-dose aspirin (750 to 1000 mg tid) or NSAIDs (e.g., ibuprofen 600 to 800 mg tid, indomethacin 50 mg tid) for 1 to 2 wk. Proton pump inhibitor should be provided for gastric protection. NSAIDs should be avoided in patients with recent MI, CHF, acute renal failure, and upper GI bleed. • Colchicine 0.5 to 0.6 mg once daily (70 kg) for 3 mo. Current evidence (COPE, CORE, CORP, ICAP, CORP-2 trials) supports the effectiveness of colchicine in symptomatic relief and prevention of recurrent pericarditis. • Corticosteroids should be used only as second-line treatment. They are associated with

Diseases and Disorders

Pericardial rub (monophasic, biphasic, or triphasic) Stage I: Anterior and inferior concave ST segment elevation. PR segment deviations opposite to P wave polarity Early stage II: All ST junctions return to the baseline. PR segments deviated Late stage II: T waves progressively flatten and invert Stage III: Generalized T-wave inversions in most or all leads Stage IV: ECG returns to prepericarditis state Echocardiography Effusion types B to D (Horowitz) Signs of tamponade Blood analyses Erythrocyte sedimentation rate, C-reactive protein, lactate dehydrogenase, leukocytes (inflammation markers) Troponin I,† CK-MB (markers of myocardial involvement) Chest radiograph Ranging from normal to “water bottle” shape of the heart shadow Performed primarily to reveal pulmonary or mediastinal pathology Mandatory in Tamponade, Optional in Large/Recurrent Effusions or if Previous Tests Inconclusive in Small Effusions Pericardiocentesis/drainage Polymerase chain reaction and histochemistry for etiopathogenetic classification of infection or neoplasia Optional or if Previous Tests Inconclusive CT Effusions, pericardium, and epicardium MRI Effusions, pericardium, and epicardium Pericardioscopy, pericardial/epicardial biopsy Establishing the specific etiology

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Pericarditis

ALG

severe adverse effects, more hospitalizations, and higher rates of recurrences. • Low- to moderate-dose (0.25 to 0.5 mg/ kg/day) systemic steroid therapy for 1 mo, followed by taper (6 to 12 wk), is restricted to patients with rheumatologic disease, renal failure, or contraindication to NSAID/ colchicine. • Azathioprine, intravenous immunoglobulins, anakinra can be considered for patients with refractory recurrent pericarditis. • Pericardiectomy and pericardiotomy at specialized centers are reserved for recurrent cardiac tamponade or refractory pericarditis. • Avoidance of anticoagulants (increased risk of hemopericardium). TREATMENT OF UNDERLYING CAUSE: • Bacterial pericarditis: Systemic antibiotics and drainage of pericardium • Collagen vascular disease: Steroid (prednisone) • Tuberculous pericarditis: Rifampicin, isoniazid, pyrazinamide, and ethambutol for 2 mo, then isoniazid and rifampicin for 6 mo • Thyroid-related pericardial effusion: Thyroid replacement therapy • Uremic: Dialysis • Malignant pericardial effusion: Fig. 5 POTENTIAL COMPLICATIONS FROM PERICARDITIS: • Chronic constrictive pericarditis: Occurs in 4 mm), >25% mitral and >50% tricuspid valve inflow variation with respiration, interventricular septal bounce; and mitral annulus reversus (medial e’ velocity > lateral e’ velocity) suggests constrictive pericarditis.1 5. Hemodynamics (Fig. 6): Elevation of rightsided filling pressures, equalization of diastolic pressures, as well as prominent “x” and rapid “y” descent in the atrial tracing are seen in constrictive pericarditis. Right ventricular pressure tracing typically shows a “dip and plateau” (square root sign) that is due to the 1 Welch

TD, Ling LH, Espinosa RE et  al: Echocardiographic diagnosis of constrictive pericarditis, Circ Cardiovasc Imaging 7(3):526–534, 2014.

V1

I

V2 II V3 III V4 aVR

aVL

V5

aVF

V6

FIG. 1  Typical electrocardiographic changes in acute pericarditis: PR depression (small arrow) and concave ST-segment elevation (large arrow). aVF, Augmented vector foot; aVL, augmented vector left; aVR, augmented vector right. (From Vincent JL et al: Textbook of critical care, ed 7, Philadelphia, 2017, Elsevier.)

PEff RV

X

LV

A

PEff

FIG. 2  Bedside echocardiogram showing pericardial effusion compressing the right ventricle during diastole, consistent with cardiac tamponade. LV, Left ventricle; PEff, pericardial effusion; RV, right ventricle.

unimpeded early filling of the RV with an abrupt halt to the late diastolic filling by the stiff pericardium. Discordance of right ventricular and left ventricular systolic pressures during respiration is also suggestive of constrictive pericarditis. 6.  Therapy: Complex surgical stripping or removal of both layers of the constricting pericardium improves the functional class in majority of late survivors, but has high operative mortality.2 2 Vustarini

N, Chen C, Mazine A et al: Pericardiectomy for constrictive pericarditis: 20 years of experience at the Montreal Heart Institute, Ann Thorac Surg 100(1):107–113, 2015.

B FIG. 3  Chest x-ray. A, Patient’s chest radiograph 1 yr before presentation with cardiac tamponade. B, Same patient’s chest radiograph on presentation to the emergency department with cardiac tamponade. (From Adams JG et al: Emergency medicine, clinical essentials, ed 2, Philadelphia, 2013, Elsevier.)

• Cardiac tamponade: Occurs in 5% to 15% of patients with idiopathic pericarditis, but in up to 60% of those with neoplastic, tuberculous, or purulent pericarditis. 1. Signs and symptoms: Dyspnea, orthopnea, chest pain, fatigue 2. Physical examination: Beck triad (distended neck veins, distant heart sounds, hypotension), reduced apical impulse, diaphoresis, tachypnea, tachycardia, narrowed pulse pressure, or pulsus para-

ALG

RV LV RV

LV

P1 Eff

Asymptomatic

Systemic therapy as appropriate Monitor for progression

Symptomatic Tamponade? No, mild symptoms

Yes

Hemodynamically stable

Hemodynamically unstable

Semi-elective subxiphoid pericardiostomy

Aggressive volume resuscitation Emergent pericardiocentesis + drainage catheter

FIG. 5  Treatment approach algorithm to malignant pericardial effusions. (From Niederhuber JE: Abeloff’s clinical oncology, ed 6, Philadelphia, 2020, Elsevier.)

CONSTRICTIVE PERICARDITIS

RV

LV

Inspiration

RV

LV

Expiration

FIG. 6  Ventricular interdependence in constrictive pericarditis. LV, left ventricle; RV, right ventricle. (Courtesy Miguel Quinones, MD, Houston Methodist DeBakey Heart and Vascular Center. In Parrillo JE, Dellinger RP: Critical care medicine, principles of diagnosis and management in the adult, ed 5, Philadelphia, 2019, Elsevier.)

doxus (decrease in systolic blood pressure ≥10 mm Hg during inspiration; most specific sign) 3. ECG: Decreased amplitude of the QRS complex, electrical alternans (occurs more frequently with large neoplastic effusions)

4.  Chest x-ray: Cardiomegaly (“water-bottle” configuration of the cardiac silhouette may be seen) with clear lungs 5. Echocardiography (Table 3): Pericardial effusion, >25% mitral and >50% tricuspid valve inflow variation with respiration, paradoxical motion of interventricular

septum, diastolic right or left atrium collapse, diastolic right ventricular collapse (pathognomonic) 6. Hemodynamics: Equalization of diastolic pressures within chambers of the heart, elevation of right atrial pressure with a prominent “x” but blunted “y” descent. Table 4 summarizes hemodynamics in cardiac tamponade and constrictive pericarditis 7. Therapy: Cardiac tamponade is a lifethreatening condition usually requiring emergent pericardiocentesis. Avoid drugs (diuretics, nitrates) or therapies (high PEEP) that reduce the preload, as volume repletion may be required. In patients with recurrent effusions (e.g., neoplasms), placement of a percutaneous drainage catheter or pericardial window may be necessary • E ffusive-constrictive pericarditis: Uncommon syndrome characterized by concomitant tamponade caused by tense pericardial effusion and constriction caused by the visceral pericardium. 1. Signs and symptoms of both tamponade and or constriction. Pulsus paradoxus is present but Kussmaul sign and pericardial knock are typically absent. 2. Echocardiography: Low sensitivity to distinguish effusive-constrictive pericarditis from other types. 3. Cardiac catheterization: Before drainage, “y” descent is usually less prominent than expected, and right atrial “v” wave persists. After drainage, may continue to have elevated right atrial and pulmonary wedge pressures. 4. Therapy: Extensive epicardiectomy (with disruption of the visceral layer of pericardium) is the procedure of choice in symptomatic patients. • Myopericarditis: Myocarditis and pericarditis may coexist in 20% to 30% of patients presenting with pericarditis. The laboratory hallmark is the elevation of cardiac enzymes. Overall, myopericarditis has a good prognosis with very low rates of morbidity, mortality, and heart failure.

DISPOSITION • Complete resolution of pain and other signs and symptoms during the initial 3 wk of therapy occurs in 70% to 90% of cases. • Admission is highly recommended if any of the following poor prognostic features (high risk factors) is present: Fever >38° C (100.4° F), subacute onset, large pericardial effusion/ tamponade, failure to respond to 1 wk of outpatient treatment. • The following are considered moderate risk factors but should also prompt admission: myopericarditis, trauma, immunosuppression, oral anticoagulant therapy. • Recurrent pericarditis occurs after 4 to 6 wk of a symptom-free interval after a first episode of pericarditis. Incidence is reported as 10% to 15% and increases to 50% in patients who are not on colchicine.

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FIG. 4  Cardiovascular magnetic resonance in a patient with constrictive pericarditis. On the right is a basal short-axis view of the ventricles showing a thickened pericardium encasing the heart (arrows). On the left is a transaxial view, again showing the thickened pericardium, particularly over the right heart, but also a pleural effusion (Pl Eff). LV, Left ventricle; RV, right ventricle. (From Zipes DP et al [eds]: Braunwald’s heart disease, ed 7, Philadelphia, 2005, Saunders.)

Pericarditis

I

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Pericarditis

ALG

TABLE 3  Hemodynamic and Echocardiographic Features of Constrictive Pericarditis Compared with Restrictive Cardiomyopathy

Prominent y descent in venous pressure Paradoxic pulse Pericardial knock Equal right- and left-sided filling pressures Filling pressures >25 mm Hg Pulmonary artery systolic pressure >60 mm Hg Square root sign Respiratory variation in left-sided andright-sided pressures/flows Ventricular wall thickness Pericardial thickness Atrial size Septal bounce Tissue Doppler E′ velocity Speckle tracking

Constriction

Restriction

Present ~1/3 cases Present Present Rare No

Variable Absent Absent Left at least 3-5 mm Hg higher than right Common Common

Present Exaggerated

Variable Normal

Normal Increased Possible LA enlargement Present Increased Normal longitudinal, decreased circumferential restoration

Usually increased Normal Biatrial enlargement Absent Reduced Decreased longitudinal, normal circumferential restoration

From Zipes DP: Braunwald’s heart disease, a textbook of cardiovascular medicine, ed 11, Philadelphia, 2019, Elsevier.

TABLE 4  Hemodynamics in Cardiac Tamponade and Constrictive Pericarditis

Paradoxical pulse Equal left/right-sided filling pressure Systemic venous wave morphology Inspiratory change in systemic venous pressure “Square root” sign in ventricular pressure

Tamponade

Constriction

Usually present Present Absent y descent Decrease (normal)

Present in ~1/3 Present Prominent y descent (M or W shape) Increase or no change (Kussmaul sign)

Absent

Present

From Mann DL, Zipes DP, Libby P, Bonow RO: Braunwald’s heart disease, ed 10, Philadelphia, 2015, Elsevier.

• Incessant pericarditis is defined as pericarditis lasting for >4 to 6 wk but 3 mo. • In patients with pericardial effusion after cardiac surgery, use of NSAIDs is not recommended because they have not been shown to reduce the size of the effusions or prevent late cardiac tamponade. The COPPS trial suggested that prophylactic colchicine may reduce the risk of developing a postpericardiotomy pericarditis.

SUGGESTED READINGS Available at ExpertConsult.com RELATED CONTENT Pericarditis (Patient Information) Cardiac Tamponade (Related Key Topic) AUTHOR: Maxwell Eyram Afari, MD

Pericarditis SUGGESTED READINGS Adler Y et al: 2015 ESC Guidelines for the diagnosis and management of pericardial diseases, Eur Heart J 36(42):2921-2964, 2015. Brucato A et al: Management of idiopathic recurrent pericarditis in adults and in children: a role for IL-1 receptor antagonism, Intern Emerg Med 13(4):475489, 2018. Imazio M et al: Colchicine for recurrent pericarditis, Ann Intern Med 155:409-414, 2011. Imazio M et al: A randomized trial of colchicine for acute pericarditis, N Engl J Med 369:1522-1528, 2013. Imazio M et al: Evaluation and treatment of pericarditis, a systemic review, J Am Med Assoc 314(14):1498-1506, 2015. Khandaker MH et al: Pericardiectomy vs medical management in patients with relapsing pericarditis, Mayo Clin Proc 87(11):1062-1070, 2012. LeWinter MM: Clinical practice acute pericarditis, N Engl J Med 371:2410-2416, 2014. Mevrin P et al: NSAID treatment for postoperative pericardial effusion, Ann Intern Med 152:137-143, 2010. Mody P et al: Trends in acute pericarditis hospitalizations and outcomes among the elderly in the USA, 1999-2012, Eur Heart J Qual Care Clin Outcomes 4(2):98-105, 2018. Søgaard KK et al: Pericarditis as a marker of occult cancer and a prognostic factor for cancer mortality, Circulation 136(11):996-1006, 2017.

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Periodic Limb Movement Disorder BASIC INFORMATION DEFINITION A disorder characterized by periodic episodes of involuntary repetitive limb movements during sleep, causing sleep disturbances that are not due to a primary sleep disorder. They consist of triple flexion movements of the legs that repeat in 5- to 90-second cycles during sleep.

ICD-10CM CODE G47.61 Periodic limb movement disorder

EPIDEMIOLOGY & DEMOGRAPHICS INCIDENCE: Unknown PEAK INCIDENCE: None PREVALENCE: 5% to 8% PREDOMINANT SEX AND AGE: Prevalence is higher in females and increases with age. GENETICS: Unknown, but may share autosomal dominant inheritance pattern if concurrent with restless leg syndrome. RISK FACTORS: • Musculoskeletal disease, heart disease, obstructive sleep apnea, narcolepsy, psychiatric disorders, diabetes mellitus • Shift work • Snoring • Stress • Restless leg syndrome • Parkinson disease, idiopathic REM sleep behavior disorder PHYSICAL FINDINGS & CLINICAL PRESENTATION • Patients may complain of excessive daytime sleepiness, fatigue, and unrestful sleep. • During an episode of periodic limb movements, the patient may experience repetitive dorsiflexion of the ankle and extension of the big toe, but other movements may occur, such as kicking. These movements last up to 5 seconds and may recur every 5 to 90 seconds, with the total episode lasting minutes to an hour. The movements are typically involuntary, and the patient is unaware of their occurrence, in contrast to those of restless leg syndrome (RLS). • Neurologic examination is usually normal but may reveal an associated neuropathy or myelopathy. • Periodic leg movements of sleep are present in most patients with RLS but are not specific nor sensitive for RLS.

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • Restless leg syndrome • Neuroleptic-induced akathisia • Positional discomfort • Nocturnal leg cramps WORKUP In addition to a history of excessive daytime sleepiness or sleep disturbance, the diagnosis of PLMD requires a polysomnographic study to exclude other sleep disorders and to document the periodic limb movements resulting in sleep disturbances. During the study, the movements must occur in a series of at least four, recurring every 5 to 90 seconds, each with a duration of 0.5 to 5 seconds. LABORATORY TESTS • No laboratory tests are required to diagnose PLMD. • A CBC, iron panel, and BMP may be ordered if RLS is suspected. IMAGING STUDIES Imaging studies are not required for diagnosis of PLMD.

TREATMENT • Patients with periodic limb movements only, without sleep disturbances of insomnia or excessive daytime sleepiness, do not require treatment. • The treatment of PLMD is the same as that for RLS. • Calcium channel ligands such as gabapentin or pregabalin are effective and do not worsen symptoms with long-term use. • Dopaminergic agonists such as pramipexole or ropinirole have been shown to decrease PLMS, but long-term use may be associated with worsening of symptoms (augmentation). • Iron replacement should be started in case of iron deficiency, and the cause of irondeficiency investigated.

NONPHARMACOLOGIC THERAPY • Follow good sleep hygiene. • Minimize shift work. • Avoid caffeine, alcohol, nicotine.

ACUTE GENERAL Rx • Treatment is indicated when PLMD is suspected and causing significant sleep fragmentation • For calcium channel ligands: Gabapentin initial dose of 100 to 300 mg/day before bedtime, with therapeutic range of 300 to 2400 mg/day. Pregabalin initial dose of 50 to 75 mg/day, with therapeutic range of 75 to 450 mg/day • For dopamine agonists: Pramipexole initial dose of 0.125 mg before bedtime, with a therapeutic range of 0.125 to 0.75 mg/day. Ropinirole initial dose of 0.25 mg/day, with a therapeutic range of 0.25 to 4 mg/day CHRONIC Rx For patients treated with dopamine agonists, close monitoring is recommended to screen for augmentation of symptoms. COMPLEMENTARY & ALTERNATIVE MEDICINE None REFERRAL Refer to neurologist if diagnosis is uncertain or an underlying disorder is suspected.

PEARLS & CONSIDERATIONS COMMENTS • Periodic limb movements disorder is a diagnosis of exclusion. PLMS occur during many sleep disorders and do not support a diagnosis of PLMD until all possible underlying causes are excluded. • Certain medications such as antihistamines, dopamine receptor blockers, selective serotonin reuptake inhibitors, and stimulants may worsen PLMS and should be avoided if possible. PREVENTION: As mentioned in “Nonpharma­ cologic Therapy.” PATIENT & FAMILY EDUCATION Patient information on PLMD and other sleep disorders can be found at the National Sleep Foundation website: www.sleepfoundation.org SUGGESTED READINGS Available at ExpertConsult.com RELATED CONTENT Restless Legs Syndrome (Related Key Topic) AUTHORS: Sudad Kazzaz, MD, and Corey Goldsmith, MD

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SYNONYMS PLMD Periodic leg movements of sleep (PLMS) Nocturnal myoclonus

ETIOLOGY The exact etiology is unknown. It is hypothesized that PLMD may share a common pathophysiology with restless leg syndrome, which involves iron metabolism and dopaminergic pathways in the brain.

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Periodic Limb Movement Disorder SUGGESTED READINGS Figorilli M et al: The clinical importance of periodic leg movements in sleep, Curr Treat Options Neurol 19:10, 2017. Wijeemanne S et  al: Restless legs syndrome: clinical features, diagnosis and a practical approach to management, Pract Neurol 17:444-452, 2017. Winkelman JW et  al: Practice guideline summary: treatment of restless legs syndrome in adults. Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology, Neurology 87(1-9), 2016.

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Peripheral Artery Disease BASIC INFORMATION DEFINITION Peripheral artery disease (PAD) refers to atherosclerotic, inflammatory, occlusive, and aneurysmal diseases involving the abdominal aorta and its branch arteries. (This topic focuses on lower-extremity PAD.) SYNONYMS PAD Peripheral vascular disease (PVD) Arteriosclerosis obliterans Atherosclerotic occlusive disease Atherosclerosis of the extremities Peripheral arterial stenosis Vasoocclusive disease of the legs Chronic critical limb ischemia ICD-10CM CODES I70 Atherosclerosis I70.2 Atherosclerosis of native arteries of the extremities I70.21 Atherosclerosis of native arteries of extremities with intermittent claudication I70.22 Atherosclerosis of native arteries of extremities with rest pain I70.3 Atherosclerosis of unspecified type of bypass graft(s) of the extremities I73 Other specified peripheral vascular diseases I73.8 Other specified peripheral vascular diseases I73.9 Peripheral vascular disease, unspecified I79 Disorders of arteries, arterioles, and capillaries in diseases classified elsewhere

EPIDEMIOLOGY & DEMOGRAPHICS • There are >202 million patients afflicted with PAD globally; it affects approximately 8.5 million Americans above the age of 40. • The prevalence is nearly equal in men and women. It increases with age, from 5.28% in those aged 40 to 49 yr to 18.83% in those aged 70 to 79 yr. However, symptoms of claudication are more likely to be present in males with PAD (50%) vs. women with PAD (25%). • As per the PARTNERS study, the prevalence of PAD in patients >70 yr or 50 to 69 yr with history of smoking or diabetes was 29%. • Risk factors that increase risk of PAD according to a 2013 meta-analysis of 112,027 studied patients include: 1. Smoking (odds ratio 2.72). 2. Diabetes (odds ratio 1.88). 3. Hypertension (odds ratio 1.55). 4. Hypercholesterolemia (odds ratio 1.19). • Smoking is three times more likely to lead to PAD than CAD. Conversely, the association of HTN and hyperlipidemia with PAD is lower than that with CAD and cerebrovascular disease.

• Patients at increased risk of PAD include those aged greater than 65 yr, those aged 50 to 64 yr with risk factors of atherosclerosis, those aged less than 50 yr with diabetes and an additional risk factor, as well as those individuals with known atherosclerotic disease in another vascular bed. • Black race/ethnicity has greater prevalence according to NHANES data (odds ratio 2.83). • Patients with newly diagnosed PAD are six times more likely to die within the next 10 yr when compared with patients without PAD. • The total annual costs associated with the hospitalization of patients with PAD in the U.S. exceed $21 billion, and account for ∼13% of all Medicare Part A and B expenditures.

PHYSICAL FINDINGS & CLINICAL PRESENTATION • Peripheral artery disease may present in a variety of ways: 1. 20% to 50%: Asymptomatic 2.  10% to 35%: Intermittent claudication (IC), defined as aching pain, cramping, weakness, numbness, or heaviness of the leg induced by exercise, relieved by rest 3. 1% to 2%: Critical limb ischemia (CLI), defined as chronic (>2 wk) rest pain, or tissue loss with nonhealing ulceration, necrosis, or gangrene (Fig. E1) 4. 40% to 50%: Atypical symptoms involving the calf, thigh, or buttock 5. Acute limb ischemia (ALI) will be present in 14 per 100,000 individuals in the general population. It is defined as acute (65 yr, or age >50 yr with smoking or diabetes history) • ABI of each leg is calculated by dividing the highest dorsalis pedis or posterior tibial systolic blood pressure by the highest systolic brachial pressure obtained from either the right or left arm 1. Noncompressible/calcified: >1.40 2. Normal: 1.00 to 1.40 at rest

ALG

Peripheral Artery Disease

P

Normal ABI Laminar flow

Endothelial cell– mediated vasodilation

Distal pressure and flow maintained

1079

Matched 0 supply-demand Efficient oxidation Low oxidative stress

NORMAL Collateral vessel

Reduced ABI Disturbed flow Impaired pressure drop endothelial across stenosis function

Inefficient oxidation High oxidative stress

Diseases and Disorders

80% stenosis High resistance

Inability to increase flow with exercise

PERIPHERAL ARTERY DISEASE

FIG. 2  Pathophysiology of intermittent claudication. In healthy arteries (top), flow is laminar and endothelial function is normal; therefore blood flow and oxygen delivery match muscle metabolic demand at rest and during exercise. Muscle metabolism is efficient and results in low oxidative stress. In contrast, in peripheral artery disease (PAD) (bottom), arterial stenosis results in disturbed flow, and the loss of kinetic energy results in a drop in pressure across the stenosis. Collateral vessels have high resistance and only partially compensate for the arterial stenosis. In addition, endothelial function is impaired, thereby resulting in further loss of vascular function. These changes limit the blood flow response to exercise and result in a mismatch of oxygen delivery to muscle metabolic demand. Changes in skeletal muscle metabolism further compromise the efficient generation of high-energy phosphates. Oxidant stress, the result of inefficient oxidation, further impairs endothelial function and muscle metabolism. ABI, Ankle-brachial index. (From the text Anatomie, physiologie, pathologie des vaisseaux lymphatiques by PC Sappey [1874], courtesy Harvard Medical Library, Francis A. Countway Library of Medicine, in Hiatt WR, Brass EP: Pathophysiology of intermittent claudication. In Creager MA et al [eds]: Vascular medicine. A companion to Braunwald’s heart disease, ed 2, Philadelphia, 2013, Elsevier.)

TABLE 1  Fontaine Classification of Peripheral Artery Disease Stage

Symptoms

I II IIa IIb III IV

Asymptomatic Intermittent claudication Pain free, claudication walking >200 m Pain free, claudication walking 0.9) and symptoms of claudication are suggestive • Toe-brachial index should be used in patients suspected of PAD with ABI of >1.4. A TBI of 80% stenosis

Acceptable procedural risk and patient wishes to pursue endovascular treatment No

Yes

MRA, CTA, or invasive angiography shows lesion treatable by endovascular approach at acceptable risk Yes

Endovascular revascularization

Yes

No

Acceptable operative risk for surgical revascularization and patient agrees No

Yes

Surgical revascularization

No

Maintain activity and medical therapy to reduce CV risk e.g., Lower LDL cholesterol Control blood pressure Stop smoking

FIG. 5  Approach to a patient with peripheral artery disease. This strategy is based on assessment of the risk for adverse events with and without treatment by taking into consideration procedural or operative risks and the patient's informed decision to proceed with revascularization. CLI, Critical limb ischemia; CTA, computed tomographic angiography; CV, cardiovascular; LDL, low-density lipoprotein; MRA, magnetic resonance angiography; TIA, transient ischemic attack. (From Zipes DP: Braunwald’s heart disease, a textbook of cardiovascular medicine, ed 11, Philadelphia, 2019, Elsevier.)

ALG

Peripheral Artery Disease

TABLE 2  ACCF/AHA Guidelines for Medical Therapy for Patients with Peripheral Artery Disease COR

Indication

LOE

I

1. Antiplatelet therapy with aspirin alone (range, 75 to 325 mg/day) or clopidogrel alone (75 mg/day) is recommended to reduce MI, stroke, and vascular death in patients with symptomatic PAD. 2. Treatment with a statin medication is indicated for all patients with PAD. 3. Antihypertensive therapy should be administered to patients with hypertension and PAD to reduce the risk of MI, stroke, heart failure, and cardiovascular death. 4. Patients with PAD who smoke cigarettes or use other forms of tobacco should be advised at every visit to quit. 5. Patients with PAD who smoke cigarettes should be assisted in developing a plan for quitting that includes pharmacotherapy (varenicline, bupropion, and/or nicotine replacement therapy) and/or referral to a smoking cessation program. 6. Patients with PAD should avoid exposure to environmental tobacco smoke at work, at home, and in public places. 7. Management of diabetes mellitus in the patient with PAD should be coordinated between members of the health care team. 8. Cilostazol is an effective therapy to improve symptoms and increase walking distance in patients with claudication. 9. Patients with PAD should have an annual influenza vaccination. 1. In asymptomatic patients with PAD (ABI ≤0.90), antiplatelet therapy is reasonable to reduce the risk of MI, stroke, or vascular death. 2. The use of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers can be effective to reduce the risk of cardiovascular ischemic events in patients with PAD. 3. Glycemic control can be beneficial for patients with CLI to reduce limb-related outcomes. 1. In asymptomatic patients with borderline ABI (0.91-0.99), the usefulness of antiplatelet therapy to reduce the risk of MI, stroke, or vascular death is uncertain. 2. The effectiveness of dual-antiplatelet therapy (aspirin and clopidogrel) to reduce the risk of cardiovascular ischemic events in patients with symptomatic PAD is not well established. 3. Dual-antiplatelet therapy (aspirin and clopidogrel) may be reasonable to reduce the risk of limb-related events in patients with symptomatic PAD after lower extremity revascularization. 4. The overall clinical benefit of vorapaxar added to existing antiplatelet therapy in patients with symptomatic PAD is uncertain. 5. The usefulness of anticoagulation to improve patency after lower extremity autogenous vein or prosthetic bypass is uncertain. 1. Anticoagulation should not be used to reduce the risk of cardiovascular ischemic events in patients with PAD. 2. Pentoxifylline is not effective for treatment of claudication. 3. Chelation therapy (e.g., ethylenediaminetetraacetic acid) is not beneficial for treatment of claudication. 4. B-complex vitamin supplementation to lower homocysteine levels for prevention of cardiovascular events in patients with PAD is not recommended.

A

IIb

III

A A A A B-NR C-EO A C-EO C-EO A B-NR B-R B-R C-LD B-R B-R A B-R B-R B-R

ABI, Ankle-brachial index; ACCF, American College of Cardiology Foundation; AHA, American Heart Association; CLI, critical limb ischemia; COR, class of recommendation; LOE, level of evidence; MI, myocardial infarction. From Zipes DP: Braunwald’s heart disease, a textbook of cardiovascular medicine, ed 11, Philadelphia, 2019, Elsevier.

vascular death in individuals with symptomatic PAD with either aspirin (75 to 325 mg) or clopidogrel (75 mg) (Class I) and in asymptomatic patients (Class IIa). Uncertain benefit has been observed with combination aspirin and clopidogrel therapy (Class IIb). Limited data on use of newer P2Y12 receptor antagonists in PAD. In the EUCLID trial, ticagrelor was not shown to be superior to clopidogrel for the reduction of cardiovascular events, with major bleeding being similar in the two groups. Uncertain benefit with vorapaxar (Class IIb). • Anticoagulation with low-dose (2.5 mg twice daily) rivaroxaban (Xarelto) plus aspirin daily showed significant reductions in both major cardiovascular and limb events, including amputations, in patients with peripheral arterial disease in the COMPASS trial. • Warfarin is not indicated except in select postsurgical bypass conditions. • Lipid-lowering therapy in patients with lower limb PAD has been shown to help slow disease progression, alleviate symptoms, and improve walking distance. The 2018 ACC/ AHA Guideline on the Treatment of Blood Cholesterol recommends that patients with atherosclerotic PAD receive high-intensity statin therapy in order to lower risk of cardiovascular events regardless of baseline cholesterol values (Class I). In patients who

are judged to be very high risk and considered for PCSK9 inhibitor therapy, maximally tolerated LDL-C lowering therapy should include maximally tolerated statin therapy and ezetimibe (Class I). Prior guidelines have recommended goal LDL cholesterol of 24 hr after delivery but within 12 wk following delivery. SYNONYMS Obstetric hemorrhage Maternal hemorrhage PPH ICD-10CM CODES O72.0 Third stage hemorrhage O72.1 Other immediate postpartum hemorrhage O72.2 Delayed and secondary postpartum hemorrhage O72.3 Postpartum coagulation defects

EPIDEMIOLOGY & DEMOGRAPHICS INCIDENCE: Depending on definitions used and scope considered, anywhere from 1% to 6% of obstetric patients will experience postpartum hemorrhage. Postpartum hemorrhage is the leading cause of maternal mortality worldwide and is implicated in >10% of maternal deaths in the U.S. PREDOMINANT SEX AND AGE: Female of reproductive age RISK FACTORS: Antepartum factors: History of PPH, primiparity or high parity, macrosomic infant, multiple gestation, polyhydramnios, uterine fibroids, prior uterine surgery, abnormal placentation, bleeding disorder Intrapartum factors: prolonged labor, augmented labor, rapid labor, preeclampsia, chorioamnionitis, operative delivery, episiotomy, lacerations, retained products, placental abruption, fetal demise PHYSICAL FINDINGS & CLINICAL PRESENTATION (TABLE 1) • Bleeding is generally brisk at time of delivery. • Examination findings include boggy uterus with continued passage of clot or blood with fundal pressure. • Objective findings can also include hypotension, tachycardia, and oliguria with substantial blood loss. ETIOLOGY • Primary: Uterine atony (70% to 80%), retained placenta, lacerations and coagulopathies • Secondary: Subinvolution of placental site, retained products (includes abnormal placentation), infection and coagulopathies

DIAGNOSIS WORKUP • Bladder should be emptied

ALG

• Bimanual examination to evaluate for atony; remove clots; massage if it is present • Examination to verify that no lacerations are present, including cervical examination with necessary lighting and retractors • Ensure adequate IV access • Ultrasonography at bedside to evaluate for retained tissue or clot • Examination to verify that placenta is intact

LABORATORY TESTS Significant hemorrhage can lead to disseminated intravascular coagulation (DIC). If DIC is suspected, complete blood count and coagulation panels should be ordered. Similarly, if coagulopathy is suspected, evaluation of clotting factors should be ordered. IMAGING STUDIES Ultrasonography can be used to scan for retained products, including clot or placenta. It can be performed to assess the need for more invasive measures, such as instrumentation or a manual sweep.

TREATMENT The most effective strategy for the prevention of postpartum hemorrhage is active management of the third stage of labor (AMTSL). Medical management with uterotonics is generally the first line of treatment: • Oxytocin (IV, 10 to 40 units diluted into IV solution, or 10 units IM); often given prophylactically immediately after delivery to minimize EBL with delivery of placenta • Methergine (IM, 0.2 mg)—contraindicated in hypertensive patient • Hemabate (IM, 0.25 mcg)—contraindicated in patient with history of asthma • Misoprostol (400 to 800 mcg sublingually, buccally, or rectally) Other medical management: • Tranexamic acid (IV, 1 g)

NONPHARMACOLOGIC THERAPY • Active management of third stage of labor: controlled cord traction (Brandt-Andrews maneuver) and uterine massage after delivery of placenta • Uterine tamponade (Fig. E1): Packing with gauze, Foley catheter, or tamponade balloon (Bakri) • Uterine curettage for suspected retained products • Uterine artery embolization • Surgical management with laparotomy: 1. Hypogastric artery ligation 2. Bilateral uterine artery ligation (O’Leary sutures) 3. B-lynch sutures 4. Hysterectomy ACUTE GENERAL Rx • Uterotonics, surgical management, embolization, blood transfusion. Fig. 2 outlines the management of postpartum hemorrhage. • Table 2 describes therapeutic response to initial fluid resuscitation. Dosing regimen for oxytocic drugs is summarized in Table 3. Blood product replacement is described in Box 1. CHRONIC Rx For anemia (Hb 2 L) and hemodynamic instability, intensive care unit admission may be warranted.

TABLE 1  Presentation of Symptoms in Postpartum Hemorrhage % Blood loss (ml)

Systolic blood pressure (mm Hg)

Signs and symptoms

10-15 (500-1000) 15-25 (1000-1500) 25-35 (1500-2000) 35-45 (2000-3000)

Normal Low-normal 70-80 50-70

Tachycardia, palpitations, dizziness Tachycardia, weakness, diaphoresis Restlessness, pallor, oliguria Collapse, air hunger, anuria

From Vincent JL et al: Textbook of critical care, ed 6, Philadelphia, 2011, WB Saunders.

TABLE 2  Therapeutic Response to Initial Fluid Resuscitation Response

Description

Rapid response Transient response Minimal or no response

40% blood vol- Continue aggressive fluid and blood ume lost product replacements.

Follow-up treatment

From Vincent JL et al: Textbook of critical care, ed 6, Philadelphia, 2011, WB Saunders.

These proofs may contain color figures. Those figures may print black and white in the final printed book if a color print product has not been planned. The color figures will appear in color in all electronic versions of this book.

ALG TABLE 3  Dosing Regimens for Oxytocic Drugs Regimens

Oxytocin (Pitocin)

5-unit IV bolus Add 20-40 units oxytocin to 1 L of fluids for continuous infusion 10 units intramyometrially 0.2 mg IM every 2-4 h 100-125 μg IM or intramyometrially every 2-4 h 200-250 μg IM Total dose 1.25 mg 250 μg IM or intramyometrially every 15-90 min Total dose 2 mg (8 doses maximum) 800-1000 μg PR, oral, or sublingual

Methylergonovine (Methergine) Ergonovine maleate (Ergotrate)

Carboprost (Hemabate) Misoprostol

IM, intramuscular; IV, intravenous; PR, per rectum. From Vincent JL et al: Textbook of critical care, ed 7, Philadelphia, 2017, Elsevier.

BOX 1  Blood Product Replacement Crossmatched blood. Type-specific or “saline crossmatched” blood. Compatible ABO and Rh blood types. Rh-negative blood is preferable. Warm the blood, if possible, especially if the rate of infusion is >100 ml/min or if the total volume transfused is high; cold blood is associated with an increased incidence of arrhythmias and paradoxic hypotension. Administer calcium if blood is transfused rapidly at >100 ml/min because of binding of calcium by anticoagulants in banked blood. Give 6-10 units fresh frozen plasma (FFP) for every 10 units of packed red blood cell (PRBC) transfusions. Give 10-12 units of platelets if the platelet count decreases to 1 mo after the trauma and result in significant distress and functional impairment. Key PTSD symptoms: • Distressing memories or dreams of the event. note: Children older than 6 yr may express this symptom in repetitive play • Flashbacks • Intense distress after reminders of the event • Avoidance due to trauma-related thoughts or feelings • Persistent negative trauma-related emotions • Feeling detached • Aggressive or reckless behavior • Hypervigilance • Problems with concentration or sleep • Depersonalization ETIOLOGY • Common types of trauma: Violent personal assault, natural disaster, military combat, rape, motor vehicle accident, childhood abuse and neglect, critical illness or hospitalization in ICU, severe physical injury, diagnosis of life-threatening illness. • Risk factors: Previous trauma, initial severity of reaction to event, psychiatric history, traumatic brain injury, childhood abuse or neglect, poor social support, gender, age. • Interpersonal violence is more likely to cause PTSD than events such as motor vehicle accidents or natural disasters. • Severity of physical injury is a weaker predictor of PTSD than the psychological distress; stress duration and social support are factors, among others. • Proposed mechanisms include activation of the amygdala, disruption of prefrontal cortex modulation of the amygdala, and excessive stressinduced HPA and alpha-1 receptor activation.

DIAGNOSIS Diagnosis is made when the stressor is consistent with DSM-5 definition, with symptoms of reexperiencing, avoidance, negative mood and cognition, and arousal and reactivity. The symptoms must be present for >1 mo, must cause impairment in functioning, and must not be attributable to substance use or other medical conditions. Subtypes include dissociative (PTSD criteria and depersonalization or derealization) and delayed onset (PTSD criteria starting at least 6 mo after the event).

Definition of stressor: • Exposure to death, threatened death, actual or threatened serious injury, or actual or threatened sexual violence with directly experiencing the event, witnessing the event occur to others, or learning that a close relative or close friend was exposed to trauma. If the event involved actual or threatened death, it must have been violent or accidental. • Repeated or extreme indirect exposure to aversive details of the event(s), usually in the course of professional duties (e.g., first responders collecting body parts; professionals repeatedly exposed to details of child abuse).

DIFFERENTIAL DIAGNOSIS • Adjustment disorders: Precipitating stress is less catastrophic and psychological reaction is less specific • Mood disorder: Depression or bipolar • Anxiety disorders • Somatic symptom or conversion disorder (functional neurological symptom disorder) • Psychotic disorder • Traumatic brain injury

P

Diseases and Disorders

DEFINITION Posttraumatic stress disorder (PTSD) develops in some people after witnessing or experiencing a traumatic event that involves actual or threatened injury to self or others. Symptoms continue longer than a mo after the event or may have delayed onset and include intrusive thoughts, nightmares, flashbacks, avoidance of things associated with the trauma, hypervigilance, sleep disturbance, and negative changes in mood and cognition. These symptoms cause distress and a decline in interpersonal, social, and occupational functioning. People with PTSD may feel numb or irritable, may be easily startled or frightened, and sometimes isolate themselves from others. They are at risk for comorbid psychiatric illness, substance abuse, and suicide.

GENETICS: Several studies, including twin studies, have demonstrated genetic factors associated with increased risk of developing PTSD after trauma exposure.

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WORKUP • Validated self-report questionnaires and structured diagnostic instruments include the Posttraumatic Diagnostic Scale and Clinician Administered PTSD Scale (CAPS). • Although numerous potential biomarkers have been identified and are under investigation, at this time evidence is not conclusive. To date, laboratory and imaging are not clinically useful. • Primary care PTSD (PC-PTSD) screen recommended by the Veterans’ Administration. • “Yes” answer to three of four of the following questions is a positive screen. In your life, have you ever had any experience that was so frightening, horrible, or upsetting that, in the past mo, you: 1. Have had nightmares about it or thought about it when you did not want to? 2. Tried hard not to think about it or went out of your way to avoid situations that reminded you of it? 3. Were constantly on guard, watchful, or easily startled? 4. Felt numb or detached from others, activities, or your surroundings?

TREATMENT • According to the most recent International Society for the Study of Traumatic Stress (ISTSS) treatment guidelines, cognitivebehavioral therapy approaches, including prolonged exposure (PE) and cognitive processing therapy (CPT), have the greatest empirical support to date among psychotherapy approaches. • Prolonged exposure (PE) includes psychoeducation on the stress response, imaginal exposure focused on recounting trauma memories, and in vivo exposure focusing on reducing avoidance of anxiety-provoking situations associated with the trauma.

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Posttraumatic Stress Disorder • CPT includes written exposure to the trauma memory combined with cognitive therapy. • A recent clinical trial found that brief written exposure therapy intervention was noninferior to standard CPT and had fewer dropouts. • Group therapy. Current standards recommend individual therapy as first-line. A growing number of studies have demonstrated efficacy of cognitive behavioral therapy (CBT) in a group format, although results are mixed, with some studies finding individual therapy to be superior. • Eye movement desensitization reprocessing (EMDR) is considered an evidence-based treatment for PTSD in treatment guidelines, demonstrating comparable efficacy to traditional CBT approaches in clinical trials. However, to date it is unclear whether it offers advantages over, or operates through distinct mechanisms from, traditional CBT approaches. Evidence supporting the efficacy of the eye movements and parallel stimulation component is limited. • A growing number of studies have demonstrated efficacy of CBT approaches for PTSD delivered through novel formats, including exposure therapy integrating virtual reality technology and Internet- and telephonedelivered CBT, although more research is needed to ascertain whether these approaches are comparable to traditional formats. • Couples therapy when appropriate.

MEDICATIONS There is no definitive cure for PTSD, and individuals have varying responses to different medications. Sertraline and paroxetine, both SSRIs, are the only FDA-approved medications for PTSD. Other medication use is off-label with differing levels of evidence to support use. Medications are used to target symptoms and the physiologic changes associated with PTSD and with psychiatric disorders that are frequently comorbid with PTSD. According to ISTSS treatment guidelines, SSRIs and SNRIs are currently considered the first-line pharmacologic treatments for PTSD, and it is recommended that they be prescribed for duration of at least 8 to 12 wk, with some studies demonstrating maximum benefit reached as late as 36 wk. • SSRIs: Sertraline, paroxetine, fluoxetine. • SNRIs: Venlafaxine, duloxetine. • Other antidepressants: Mirtazapine has shown efficacy in small randomized trials.

• Alpha-adrenergic receptor blockers: Prazosin has demonstrated some efficacy in reducing nightmares. A meta-analysis of six RCTs comparing prazosin to placebo found a significant reduction in distress and/or frequency of nightmares, but a recent RCT in military veterans with PTSD did not show efficacy. • Atypical antipsychotics (e.g., risperidone, quetiapine, olanzapine) have demonstrated efficacy as augmenting agents for individuals with partial response to SSRIs and may be particularly beneficial for individuals with paranoia, extreme anxiety, or angry outbursts. • Transcranial magnetic stimulation (TMS) is being evaluated as a possible effective treatment modality. • Ketamine: Recent clinical trials of intravenous ketamine infusion showed PTSD and depression symptom reduction, although more research is needed. • N-methyl-D-aspartate (NMDA) agonists and partial agonists have shown some efficacy in early clinical trials, although more research is needed. • Recent efforts are underway to examine the efficacy of pharmacologic interventions in preventing development of PTSD early after exposure to trauma, though more research is needed.

ACUTE GENERAL Rx • Immediate post-incident debriefing may worsen outcome. • Benzodiazepines are not currently recommended as monotherapy for the treatment of PTSD, as there is no evidence that they reduce reexperiencing and avoidance/numbing symptoms. • Betaadrenergic blockers may be helpful if given within hours after the trauma to disrupt the physiologic stress response, although more research is needed. • Sedating antidepressants or sleep aids may be helpful for initial insomnia. DISPOSITION • Recovery rates are highest in the first 12 mo after onset. • Average duration of symptoms is 36 mo for those who undergo treatment and 64 mo for those never treated. • 50% chance of remission at 2 yr; 50% have chronic symptoms.

• Predictors of chronic course include previous trauma, premorbid psychiatric function, panic reaction at time of event, prolonged terror, or dissociation at time of event.

REFERRAL Because early intervention improves outcome, refer to a specialist as soon as diagnosis made.

PEARLS & CONSIDERATIONS • PTSD is associated with increased occurrence of suicidal ideation and attempts. • PTSD can be associated with aggressive and violent behavior. • Traumatic medical experiences such as being in the ICU, myocardial infarction, or an emergent cesarean section can cause PTSD. • Individuals with PTSD frequently present with comorbid psychiatric disorders, including substance abuse, major depression, anxiety disorders, and personality disorders. • Among combat veterans of recent wars, there is a 41% cooccurrence with mild TBI. • PTSD may vary culturally and present as culturally specific syndromes and idioms of distress. • Treatment can be effective even if it begins yrs after the traumatic event occurred. • Cannabis is available from medical dispensaries in many states for treating PTSD, yet its efficacy in treating PTSD symptoms remains uncertain. Current evidence is insufficient to draw conclusions about the benefits and harms of plant-based cannabis preparations in patients with PTSD, but several ongoing studies may soon provide answers.1

SUGGESTED READINGS Available at ExpertConsult.com RELATED CONTENT Posttraumatic Stress Disorder (PTSD) (Patient Information) AUTHOR: Catherine D’Avanzato, PhD

1 O’Neil

MF et al: Benefits and harms of plant-based cannabis for posttraumatic stress disorder, Ann Int Med 167:332-340, 2017.

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SUGGESTED READINGS Amos T et al: Pharmacological interventions for preventing post-traumatic stress disorder (PTSD), Cochrane Database Syst Rev 7:CD006239, 2014. Cusack K et  al: Psychological treatments for adults with posttraumatic stress disorder: a systematic review and meta-analysis, Clin Psychol Rev 43:128141, 2016. Edmundson D et  al: Posttraumatic stress prevalence and risk of recurrence in acute coronary syndrome patients: a meta-analytic review, PloS One 7(6):e38915, 2012. Feder A et  al: Efficacy of intravenous ketamine for treatment of chronic posttraumatic stress disorder: a randomized clinical trial, JAMA Psychiatry 71:681, 2014. Shalev A et al: Post-traumatic stress disorder, N Engl J Med 376(25):2459-2469, 2017. Sloan DM et al: A brief exposure-based treatment vs cognitive processing therapy for posttraumatic stress disorder: a randomized noninferiority clinical trial, JAMA Psychiatry 75:233-239, 2018. Watts BV et  al: Meta-analysis of the efficacy of treatments for posttraumatic stress disorder, J Clin Psychiatry 74(6):e541-e550, 2013.

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Postural Orthostatic Tachycardia Syndrome (POTS) BASIC INFORMATION DEFINITION Postural orthostatic tachycardia syndrome (POTS) is an under-recognized autonomic disorder defined as a form of orthostatic intolerance in which an exaggerated increase in heart rate (HR >30 beats per min from baseline, or an increase to 120 beats per min within the first 10 min of standing or tilt table testing) occurs during postural change, without orthostatic hypotension. Symptoms occur while standing and are relieved by recumbency. The orthostatic intolerance should be chronic, lasting for at least 3 to 6 months. Symptoms may be profoundly exacerbated by simple activities, dehydration, or even eating; thus, POTS can be very disabling. SYNONYMS Orthostatic tachycardia Orthostatic intolerance POTS Postural tachycardia syndrome Chronic orthostatic intolerance Neurocirculatory asthenia ICD-10CM CODE I49.8 Disorder of the autonomic nervous system, unspecified

EPIDEMIOLOGY & DEMOGRAPHICS INCIDENCE: Unknown PREVALENCE: Most prevalent form of orthostatic intolerance—estimated to be 5 to 10 times more common than orthostatic hypotension; ∼3,000,000 patients in the United States (25% are disabled and unable to work) PREDOMINANT SEX AND AGE: Female:male ratio of 5:1. Mean age is 30 yr old (most commonly between 15 to 50 yr old). GENETICS: POTS is a heterogeneous entity, and thus, no single mutation is responsible for the syndrome. Mutations in a norepinephrine transporter have been identified in one case of familial POTS. They result in decreased norepinephrine clearance at the synaptic cleft, causing excessive sympathetic activation. Additionally, polymorphisms in genes encoding the beta-2 adrenoreceptor and nitric oxide synthase may also play a role in some patients. RISK FACTORS: • Female sex • Family history • Preceding viral infection or systemic illness (up to 50% of cases) • Deconditioning and prolonged bed rest • Medications (e.g., vasodilators, diuretics, antidepressants, anxiolytic agents) • Predisposition to hypovolemia • Autoimmune disorders (e.g., multiple sclerosis, mast cell activation syndrome) • Excessive sympathetic states (e.g., sepsis, trauma, surgery) • Underlying autonomic neuropathy such as in advanced diabetic states

• Chronic fatigue syndrome (40% have POTS) • Mitral valve prolapse • Joint hypermobility disorders (e.g., EhlersDanlos syndrome)

PHYSICAL FINDINGS & CLINICAL PRESENTATION Symptoms vary and may be related to orthostasis (with cerebral hypoperfusion) or autonomic dysfunction. In some patients, symptoms manifest as non-orthostatic, generalized complaints. Common symptoms on presentation include: • Palpitations, particularly with standing • Anxiety, depression, or memory problems • Tremulousness • Dizziness, lightheadedness, blurred vision, presyncope, and syncope • Intolerance to exercise or heat and constantly feeling cold • Nausea, abdominal pain, and irritable bowel syndrome • “Coat-hanger” headaches involving the upper trapezius muscle • Cyclic nature (e.g., worsening with intravascular volume changes during menstrual cycle) • Chronic fatigue and daytime sleepiness Physical findings are key in raising clinical suspicion for POTS. Important physical findings include the orthostatic hemodynamic changes and a reduced pulse pressure with marked beat-to-beat variability of both pulse pressure and HR. Flack sign is the difficulty in palpating a radial pulse with continued standing or Valsalva maneuver. There may be venous prominence with continued standing resulting in acrocyanosis and swelling of the feet. • 10% of dysautonomic POTS may progress to paroxysmal atrial fibrillation. • Recent studies suggest a link between dysautonomia, POTS, and joint hypermobility syndrome.

ETIOLOGY Heterogenous etiologies, which overlap in different types of POTS: • Hypovolemic POTS: Decreased effective intravascular volume with peripheral and splanchnic venous pooling that worsens with standing. Studies have demonstrated a reduced plasma volume and red blood cell count in patients with POTS. These patients were also noted to have low renin and aldosterone levels despite their hypovolemic states, which suggests a renal involvement in the pathophysiology of POTS. • Neuropathic or dysautonomic POTS: Patchy sympathetic denervation of lower extremities and kidneys resulting in orthostatic venous pooling and relative hypovolemia with failure of the peripheral vasculature to vasoconstrict properly upon standing. • Hyperadrenergic or beta hypersensitivity POTS: High orthostatic plasma norepinephrine levels (≥600 pg/ml); prominent symptoms are of sympathetic over-activation. Patients may have significant orthostatic hypertension. An underlying genetic disorder may be a possible cause. • Deconditioned POTS: Venous pooling in lower extremities due to weak leg “muscle pump”; fibromyalgia-type symptoms with anxiety, exercise intolerance, and fatigue. • Immune-related POTS: Classically associated with mast cell activation syndrome (MCAS), though can occur in the setting of other autoimmune disorders. Patients will complain of episodic flushing with tachycardia. Hypertension with orthostatic tachycardia is common.

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • Orthostatic hypotension • Inappropriate sinus tachycardia

FIG. E1  Schematic drawing of changes in heart rate (HR) and blood pressure (BP) observed during the head-up tilt test. Thin arrows mark the start of orthostatic stress. Large unfilled arrows indicate the appearance of symptoms with changes seen in HR and BP. In normal individuals, the HR increases slightly with no change or a slight reduction in BP. In patients with vasovagal syncope, both the HR and BP drop precipitously with the appearance of symptoms. Postural hypotension is characterized by a drop in BP by 10 to 15 mm Hg as symptoms appear within 10 minutes of standing. Postural hypotension may not occur in the presence of good hydration. In POTS, the HR increases significantly by more than 30 beats/min (or the HR is 120 beats/min or higher) with development of symptoms within 10 minutes of standing. POTS, Postural orthostatic tachycardia syndrome. (Park MK: Park’s pediatric cardiology for practitioners, ed 6, Philadelphia, 2014, WB Saunders.)

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Postural Orthostatic Tachycardia Syndrome (POTS) BOX E1  Pharmacologic Management of POTS I β-adrenergic antagonists • Atenolol 1-2 mg/kg per day • Metoprolol 1-2 mg/kg per day • Propranolol 0.5-4 mg/kg per day • Nadolol II α-adrenergic agonists • Midodrine 2.5-10 mg tid • Pseudoephedrine 60 mg bid • Methylphenidate 5-10 mg tid III Mineralocorticoids • Fludrocortisone 0.1-0.3 mg/day IV Pyridostigmine 30 mg bid V Selective serotonin receptor reuptake inhibitors • Fluoxetine 10-20 mg/day • Sertraline 25-50 mg/day POTS, Postural orthostatic tachycardia syndrome. From Swaiman KF et al: Swaiman’s pediatric neurology, principles and practice, ed 6, Philadelphia, 2017, Elsevier.

• Dehydration or anemia • Medication side effects • Other forms of autonomic neuropathies • Other forms of central dysautonomia • Deconditioning • Anxiety and panic attacks • Vasovagal syncope • Structural cardiac abnormalities (heart failure, valvulopathy, congenital heart disease)

WORKUP • Full autonomic system review to evaluate for autonomic neuropathies • Orthostatic vital signs • 12-lead electrocardiogram • Holter monitor in patients with syncope to rule out malignant tachyarrhythmias • Head-up tilt table testing is diagnostic (Fig. E1). It should be considered in patients where clinical suspicion is high, but HR criteria have not been met after 10 min of standing. To improve diagnostic sensitivity, testing should take place in the morning. Findings during head-up tilt include: 1.  Increase in HR of ≥30 beats/min from baseline, or ≥120 beats/min within 10 min 2. Absence of hypotension 3.  Orthostatic intolerance symptoms (see earlier) 4. In select patients, plasma catecholamines can be measured during tilt-table, first while supine and again after standing for 15 min. In 50% of patients who are standing, norepinephrine level ≥600 pg/ml is found, signifying a hyperadrenergic response LABORATORY TESTS • Iron studies and complete blood count to evaluate for anemia • Thyroid stimulating hormone to evaluate for thyroid disease

• 24-hr urine sodium; a level 70% of patients with POTS. • Atrioventricular node ablation and pacemaker implantation can be considered for recurrent syncope refractory to all other therapies. ACUTE GENERAL Rx • Volume expansion with 1 L of normal saline over 1 to 3 hours

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• Discontinuation of exacerbating factors

CHRONIC Rx Appropriate pharmacologic treatment of POTS is dependent on the subtype. Treatments that are beneficial for one subtype may worsen other subtypes. • Volume expanders such as fludrocortisone or desmopressin (DDAVP) can be useful for hypovolemic and neuropathic POTS. • β-blockers (propranolol and atenolol) for neuropathic (allow for unopposed α-receptormediated vasoconstriction) and hyperadrenergic (block β1 receptors in heart) POTS. They may worsen symptoms in hypovolemic POTS by decreasing cardiac output. • Ivabradine, which decreases HR but does not affect BP, improved symptoms in 60% of patients in one study. Especially helpful in hyperadrenergic POTS. • SSRIs for neuropathic and hyperadrenergic POTS (decrease the central production of serotonin). • Vasoconstrictors such as midodrine may be helpful for neuropathic POTS. Droxidopa should only be considered in refractory cases. • Central sympatholytic agents (clonidine and methyldopa) for hyperadrenergic POTS. • Erythropoietin for refractory neuropathic or hypovolemic POTS (increases sensitivity to angiotensin II). • Pyridostigmine reduces tachycardia and may be an effective agent. • Immunomodulatory agents such as IVIG and rituximab are being studied in the treatment of POTS to target immune dysautonomia but as of now are purely investigational. DISPOSITION Can usually be managed in an outpatient setting REFERRAL Cardiology and occasionally expertise in electrophysiology as needed

PEARLS & CONSIDERATIONS COMMENTS This syndrome remains poorly understood, and current therapies may not be effective. Because of its debilitating nature, young age of presentation, and recurrent symptoms, patients often feel discouraged and may need psychological support. PREVENTION None except therapies previously mentioned SUGGESTED READINGS Available at ExpertConsult.com RELATED CONTENT Orthostatic Hypotension (Related Key Topic) AUTHORS: Esseim Sharma, MD, and Aravind Rao Kokkirala, MD, FACC

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SUGGESTED READINGS Arnold AC et al: Low-dose propranolol and exercise capacity in postural tachycardia syndrome: a randomized study, Neurology 80:1927, 2013. Benarroch EE: Postural tachycardia syndrome: a heterogeneous and multifactorial disorder, Mayo Clin Proc 87(12):1214-1225, 2012. Kimpinski K et al: A prospective, 1 year follow-up study of postural tachycardia syndrome, Mayo Clin Proc 87(8):746-752, 2012. Lei LY et al: Evaluating and managing postural tachycardia syndrome, Clev Clin J Med 86;333-344, 2019. Noyes AM et al: A tale of two syndromes: Lyme disease preceding postural orthostatic tachycardia syndrome, Ann Noninvasive Electrocardiol 20(1):8286, 2015. Ojha A et al: Comorbidities in pediatric patients with postural tachycardia syndrome, J Pediatr 158:20, 2011. Sheldon RS et al: 2015 Heart Rhythm Society expert consensus statement on the diagnosis and treatment of postural tachycardia syndrome, inappropriate sinus tachycardia, and vasovagal syncope, Heart Rhythm 12(6):e41-e63, 2015. Thanavaro JL et al: Postural orthostatic tachycardia syndrome: diagnosis and treatment, Heart Lung 40(6):554-560, 2011. Zadourian A et al: Postural orthostatic tachycardia syndrome: prevalence, pathophysiology, and management, Drugs 78(10):983-994, 2018.

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ALG   Precocious BASIC INFORMATION DEFINITION Precocious puberty is defined as the development of secondary sexual characteristics before age 8 in females and age 9 in males. SYNONYM Pubertas praecox ICD-10CM CODE E30.1 Precocious puberty

EPIDEMIOLOGY & DEMOGRAPHICS INCIDENCE: Estimated to be between 1 in 5000 to 1 in 10,000 PREDOMINANT SEX: Females are affected five times more often than males for the idiopathic variant; for other causes, it is dependent on the underlying etiology. GENETICS: The genetics for some of the etiologies of precocious puberty is known. The most common genetic cause of central precocious puberty (CPP) in humans is a deficiency of MKRN3 (makorin ring finger protein 3). Other reported genetic causes of CPP include a MRF3 (MA3 domaincontaining translation regulatory factor) loss of function mutation and a KISS1 (KiSS-1 metastasis suppressor) gain of function mutation. PHYSICAL FINDINGS & CLINICAL PRESENTATION • In females: Breast development, pubic hair development, accelerated growth, menarche • In males: Increase in testicular volume (>4 ml) and penile length, pubic hair development, accelerated growth, muscular development, acne, change in voice, penile erections ETIOLOGY • Central (Gonadotropin hormone-releasing hormone [GnRH]-dependent, “true precocious puberty”): 1. Idiopathic (74%)—diagnosis of exclusion 2. CNS problem (7%) a.  Tumor, encephalitis, head trauma, hydrocephalus • Peripheral (GnRH-independent, incomplete, pseudopuberty): 1. Ovarian cyst or tumor (11%) 2. McCune-Albright syndrome (5%) 3. Adrenal feminizing or masculinizing (2%) 4. Ectopic gonadotropin production (0.5%) 5. Severe hypothyroidism (very rare)

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • Most common diagnoses to consider: Premature thelarche (breast tissue development in absence of other secondary sex characteristics or menarche) and premature adrenarche (axillary or pubic hair growth, acne, and/or body odor in absence of other secondary sex characteristics or menarche)

• Constitutional precocity—onset near 8 yr of age, familial • GnRH-dependent precocious puberty: Idiopathic, CNS tumors, hypothalamic hamartomas, neurofibromatosis type I, tuberous sclerosis, hydrocephalus, status after acute head injury, ventricular cysts, status after CNS infection • GnRH-independent precocious puberty: Congenital adrenal hyperplasia, adrenocortical tumors (males), McCune-Albright syndrome (females), gonadal tumors, ectopic human chorionic gonadotropin (hCG)-secreting tumors (chorioblastoma, hepatoblastoma), exposure to exogenous sex steroids, severe hypothyroidism • Table E1 summarizes the differential diagnosis of sexual precocity

WORKUP Priorities: • Rule out life-threatening disease (neoplasm of central nervous system [CNS], gonad, adrenal). A classification of sexual precocity is summarized in Table E2. • Establish velocity of process. • A thorough history and physical examination are essential to determine if the patient has true precocious puberty. Particular attention should be paid to growth, development, order of appearance of the secondary sexual characteristics, pubertal development in family members, medications, neurologic symptoms, Tanner staging, abdominal and neurologic examination. Flowcharts for diagnosing sexual precocity in females and males are shown in Figs. 1 and 2. LABORATORY TESTS • GnRH stimulation testing will help determine if dependent or independent cause. • Sex hormone studies: Luteinizing hormone, follicle-stimulating hormone, hCG, testosterone (males), estrogen (females). Levels of sex steroids should be determined in the morning, with use of assays that have detection limits adapted to pediatric values. In girls, serum estradiol levels are highly variable and have a rather low sensitivity for the diagnosis of precocious puberty. • Free T4, thyroid-stimulating hormone (TSH). IMAGING STUDIES • Bone age: Left hand/wrist x-ray establishes severity of process • CT scan or MRI of the brain to evaluate for CNS pathology • Consideration of pelvic ultrasound in female patients to evaluate for ovarian cysts or tumors • Abdominal imaging with CT scan if intraabdominal pathology suspected

TREATMENT

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• Psychological support for the child may be needed to address issues with self-image and peer acceptance. • Given that sexual development occurs in advance of aging and maturity, social and emotional difficulties may occur. These children are also particularly vulnerable to sexual abuse.

ACUTE GENERAL Rx There is no acute therapy for precocious puberty. CHRONIC Rx Therapy depends on the etiology of precocious puberty. For the treatment of central or gonadotropin-dependent precocious puberty depot GnRH agonists (leuprorelin, leuprolide, triptorelin, goserelin, histrelin, buserelin) are effective. • Leuprolide is given 0.25 to 0.3 mg/kg with a 7.5 mg minimum IM every 4 wk. Local side effects include pain, erythema, and inflammatory reactions. Other side effects include headaches and menopausal-like symptoms (asthenia, hot flashes). • For other CNS lesions and extragonadal tumors, therapy is dependent on the type of lesion, location of the lesion, and the overall prognosis of the underlying problem. • For severe hypothyroidism, treatment with thyroid hormone will result in regression of the sexual development. The child will subsequently undergo appropriate pubertal development later in life. • For familial male gonadotropin-independent precocious puberty, the androgen-synthesis inhibitor ketoconazole can be used at doses of 600 mg/day divided tid, or a combination of the aromatase inhibitors testolactone or anastrozole and spironolactone can be used. DISPOSITION • For true precocious puberty and some CNS lesions, long-term outcome is usually favorable. When pharmacological therapy is initiated, it is typically continued until the child is deemed to be of an appropriate age to progress through puberty. • For other cases, long-term outcomes depend on the prognosis of the underlying cause. REFERRAL • Initial workup can be instituted by the primary care provider. • Referral to an endocrinologist is indicated for most children for long-term management, monitoring, and treatment. • Attention to the emotional well-being of the child is important. RELATED CONTENT Precocious Puberty (Patient Information) AUTHORS: Rachel Wright Heinle, MD FACOG, and Ashlie Sewdass Carter, MD

NONPHARMACOLOGIC THERAPY • Good communication with parents is essential to care.

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TABLE E1  Differential Diagnosis of Sexual Precocity Disorder

Plasma Gonadotropins

Lh Response to GnRH

Gonadotropin Dependent True (central) Prominent LH pulses Pubertal LH precocious puberty (premature reacresponse tivation of GnRH initially during pulse generator) sleep Gonadotropin Independent Males Chorionic gonadotropin- High hCG, low LH Prepubertal LH secreting response tumor in males

Serum Sex Steroid Concentration

Gonadal Size

Miscellaneous

Pubertal values of testosterone or estradiol

Normal pubertal testicular enlargement or ovarian and uterine enlargement

MRI of brain to rule out CNS tumor or other abnormality

Pubertal value of testosterone

Slight to moderate uniform enlargement of testes

Hepatomegaly suggests hepatoblastoma; MRI of brain if chorionic gonadotropin-secreting CNS tumor suspected

Irregular, asymmetric enlargement of testes Testes symmetric and Activating mutation of >2.5 cm but smaller the LHCG receptor; than expected for autosomal dominant pubertal development; transmission spermatogenesis occurs Testes prepubertal Autosomal recessive, variable severity/age of onset; may have salt loss in CYP21 deficiency or hypertension in CYP11B1 deficiency Testes prepubertal CT, MRI, or US of abdomen

Leydig cell tumor in males Familial, male-limited precocious puberty (FMPP, “testotoxicosis”)

Suppressed

No LH response

High testosterone

Suppressed

No LH response

Pubertal values of testosterone

Virilizing congenital adrenal hyperplasia

Prepubertal

Prepubertal LH response

Virilizing adrenal tumor Females Granulosa cell tumor (follicular cysts may present similarly) Follicular cyst

Prepubertal

Prepubertal LH response

Elevated 17-OHP in CYP21 deficiency or elevated 11deoxycortisol in CYP11B1 deficiency High DHEAS, DHEA, and/or androstenedione values

Suppressed

Prepubertal LH response

Very high estradiol

Suppressed

Prepubertal LH response

Prepubertal to very high estradiol

Feminizing adrenal tumor Nonclassical congenital adrenal hyperplasia In Both Sexes McCune-Albright syndrome

Suppressed

Prepubertal LH response Prepubertal LH response

High estradiol, variable DHEAS increase Elevated 17-OHP in basal or corticotropinstimulated state

Ovaries prepubertal

Suppressed

Sex steroid pubertal; estradiol may be quite high in girls

Ovarian enlargement Skeletal survey/bone (asymmetrical) on scan for polyostotic US; slight (usually fibrous dysplasia and symmetrical) testicular skin examination for enlargement café au lait spots Testicular enlargement; TSH and prolactin ovaries cystic elevated; T4 low

Prepubertal

Suppressed

Primary hypothyroidism

LH prepubertal; Prepubertal; FSH FSH may be response flat slightly elevated Incomplete Precocity/Variations Of Puberty Premature Prepubertal Prepubertal LH thelarche Premature Prepubertal Prepubertal LH adrenarche response (males) Premature adrenarche (females)

Prepubertal

Prepubertal LH response

Estradiol may be pubertal

Ovarian enlargement on physical examination, CT, MRI, or US Ovarian enlargement on physical examination, CT, MRI, or US

Ovaries prepubertal

Prepubertal or early pubertal Ovaries prepubertal estradiol response Prepubertal testosterone; Testes prepubertal DHEAS, or urinary 17-ketosteroid values appropriate for pubic hair stage 2 Prepubertal estradiol; DHEAS Ovaries prepubertal or urinary 17-ketosteroid values appropriate for pubic hair stage 2

Tumor often palpable on physical examination Single or recurrent episodes of menses and/ or breast development; exclude McCuneAlbright syndrome Unilateral adrenal mass Autosomal recessive

Onset usually before 3 yr of age Onset usually after 6 yr of age; more frequent in CNS-injured children Onset usually after 6 yr of age; more frequent in brain-injured children

CNS, Central nervous system; CT, computed tomography; CYP, P450 cytochrome isoenzyme; DHEAS, dehydroepiandrosterone sulfate; FSH, follicle-stimulating hormone; GnRH, gonadotropin-releasing hormone; hCG, human chorionic gonadotropin; LH, luteinizing hormone; MRI, magnetic resonance imaging; 17-OHP, 17-hydroxyprogesterone; T4, thyroxine; TSH, thyrotropin; US, ultrasonography. Modified from Styne DM, Grumbach MM: Physiology and disorders of puberty. In Melmed S et al (eds): Williams textbook of endocrinology, ed) 13, Philadelphia, 2016, Elsevier, Table 25.41, pp 11961197. In Kliegman RM: Nelson textbook of pediatrics, ed 21, Philadelphia, 2020, Elsevier.

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Precocious Puberty

ALG

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TABLE E2  Classification of Sexual Precocity True Precocious Puberty Or Complete Isosexual Precocity (GnRH-Dependent Sexual Precocity Or Premature Activation Of The Hypothalamic GnRH Pulse Generator) Idiopathic true precocious puberty CNS tumors Optic glioma associated with neurofibromatosis type 1 Hypothalamic astrocytoma Other CNS disorders: Developmental abnormalities including hypothalamic hamartoma of the tuber cinereum Encephalitis Static encephalopathy Brain abscess Sarcoid or tubercular granuloma Head trauma Hydrocephalus Arachnoid cyst Myelomeningocele Vascular lesion Cranial irradiation True precocious puberty after late treatment of congenital virilizing adrenal hyperplasia or other previous chronic exposure to sex steroids True precocious puberty due to mutations: in KISS1R/GRP54 gene in KISS1 gene MKRN3 gene

Incomplete Isosexual Precocity (Hypothalamic GnRH-Independent) Males Gonadotropin-secreting tumors: hCG-secreting CNS tumors (e.g., chorioepitheliomas, germinoma, teratoma) hCG-secreting tumors located outside the CNS (hepatoma, teratoma, choriocarcinoma) Increased androgen secretion by adrenal or testis: Congenital adrenal hyperplasia (CYP21 and CYP11B1 deficiencies) Virilizing adrenal neoplasm Leydig cell adenoma Familial testotoxicosis (sex-limited autosomal dominant pituitary gonadotropin-independent precocious Leydig cell and germ cell maturation) Cortisol resistance syndrome

Females Ovarian cyst Estrogen-secreting ovarian or adrenal neoplasm Peutz-Jeghers syndrome with SCTAT

Both Sexes McCune-Albright syndrome Hypothyroidism Iatrogenic or exogenous sexual precocity (including inadvertent exposure to estrogens in food, drugs, or cosmetics)

Variations Of Pubertal Development Premature thelarche Premature isolated menarche Premature adrenarche Adolescent gynecomastia in boys Macroorchidism

Contrasexual Precocity Feminization in Males Adrenal neoplasm Chorioepithelioma CYP11B1 deficiency Testicular neoplasm (Peutz-Jeghers syndrome) Increased extraglandular conversion of circulating adrenal androgens to estrogen Iatrogenic (exposure to estrogens)

Virilization in Females Congenital adrenal hyperplasia: CYP21 deficiency CYP11B1 deficiency 3β-HSD deficiency Virilizing adrenal neoplasm (Cushing syndrome) Virilizing ovarian neoplasm (e.g., arrhenoblastoma) Iatrogenic (exposure to androgens) Cortisol resistance syndrome Aromatase deficiency CNS, Central nervous system; CYP11B1, 11-hydroxylase; CYP21, 21-hydroxylase; GnRH, gonadotropin-releasing hormone; hCG, human chorionic gonadotropin; 3β-HSD, 3β-hydroxysteroid dehydrogenase 4,5-isomerase; KISS1R/GPR54, kisspeptin/G protein–coupled receptor 54; SCTAT, sex cord tumor with annular tubules. Modified from Styne DM, Grumbach MM: Physiology and disorders of puberty. In Melmed S et al (eds): Williams textbook of endocrinology, ed 13, Philadelphia, 2016, Elsevier, Table 25.25, p 1163. In Kliegman RM: nelson textbook of pediatrics, ed 21, Philadelphia, 2020, Elsevier.

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1144.e8

Precocious Puberty

ALG Breast development before 7 yr Yes Pubic hair

Yes

No

Basal and LHRHstimulated LH

Possibility of exogenous estrogen?

No

Yes

Basal LH or LH response to GnRH Pubertal

Prepubertal

Prepubertal or suppressed Serum estradiol Elevated

True precocious puberty

Ultrasound of ovary and uterus Premature thelarche

Ovarian cyst, ovarian tumor

MRI

Normal

Free T4

Abnormality

Exogenous estrogen exposure

Skeletal scintigraphy

High TSH

Normal

Primary hypothyroidism

Ovarian cyst or tumor

Polyostotic fibrous dysplasia McCune-Albright syndrome

Idiopathic

Hamartoma of the tuber cinereum

CNS tumor or other lesion

Café au lait macules likely

FIG. E1  Flowchart for diagnosing sexual precocity in girls. CNS, Central nervous system; GnRH, gonadotropin-releasing hormone; LH, luteinizing hormone; LHRH, luteinizing hormone-releasing hormone; MRI, magnetic resonance imaging; T4, thyroxine; TSH, thyroid-stimulating hormone. (From Melmed S et al: Williams textbook of endocrinology, ed 3, Philadelphia, 2011, WB Saunders.)

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Precocious Puberty

ALG

1144.e9

Phallic enlargement before age 9 yr

Yes

No

Possibility of exogenous androgens or hCG?

Pubic hair present

Serum DHEAS No

Yes

Testicular size

4 lb/wk), even in the absence of edema, is common but is nonspecific and is seen in many normal pregnancies. • Auscultation of pulmonary rales. • Cerebral symptoms: headache, vision changes • Right upper quadrant pain (HELLP syndrome [hemolysis, elevated liver enzymes, and low platelet count] or subcapsular liver hematoma). • Hyperreflexia or clonus. • Vaginal bleeding (placental abruption). • Chronic fetal compromise manifested by intrauterine growth restriction or acute fetal compromise manifested by nonreassuring fetal testing.

TABLE 1  Criteria for the Diagnosis of Preeclampsia with Severe Features In patients with preeclampsia, preeclampsia with severe features can be diagnosed if any one of the following criteria is present: Blood pressure ≥160 mm Hg systolic or ≥110 mm Hg diastolic on two separate occasions at least 4 hr apart Serum creatinine >1.1 mg/dl or a doubling of the serum creatinine New onset of cerebral or visual disturbances Pulmonary edema Hepatocellular injury (serum transaminases at least twice normal) or severe persistent right upper quadrant or epigastric pain Thrombocytopenia 7 yr • Family history of preeclampsia • Woman born small for gestational age • Obesity/gestational diabetes • Multifetal gestation • Preeclampsia in a previous pregnancy • Poor outcome in a previous pregnancy • Fetal growth restriction, placental abruption, fetal death • Preexisting medical-genetic conditions • Chronic hypertension • Renal disease • Type 1 (insulin-dependent) diabetes mellitus • Antiphospholipid antibody syndrome From Gabbe SG et  al: Obstetrics, ed 7, 2016, Philadelphia, Elsevier.

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1146

Preeclampsia • Viral hepatitis • Medications or medication withdrawal

WORKUP Hypertension: • Two blood pressure measurements at least 4 hr apart, with the patient sitting or semireclining with the back supported, with an absolute pressure ≥140 mm Hg systolic or ≥90 mm Hg diastolic

• Blood pressure ≥160 mm Hg systolic or ≥110 mm Hg diastolic • Hypertension can be confirmed in a brief period to allow for immediate treatment of severe range blood pressure. Proteinuria: • ≥300 mg per 24-hr urine collection • Protein/creatinine ratio ≥0.3 • +1 on dipstick ONLY IF OTHER METHODS NOT AVAILABLE

TABLE 3  Potential Secondary Effects of the Metabolic, Inflammatory Endothelial Alternatives in Preeclampsia CVS Lungs Renal Clotting Liver CNS Fetus

Increased peripheral resistance leading to hypertension; increased vascular permeability and reduced maternal plasma volume. Laryngeal and pulmonary edema. Glomerular damage leading to proteinuria, hypoproteinemia, and reduced oncotic pressure, which further exacerbates the hypovolemia. May develop acute renal failure ± cortical necrosis. Hypercoagulability, with increased fibrin formation and increased fibrinolysis (i.e., disseminated intravascular coagulation). HELLP syndrome hepatic rupture. Thrombosis and fibrinoid necrosis of the cerebral arterioles. Eclampsia (convulsions), cerebral hemorrhage, and cerebral edema. Impaired uteroplacental circulation, potentially leading to FGR, hypoxemia, and intrauterine death.

CVS, Cardiovascular system; CNS, central nervous system; FGR, fetal growth restriction; HELLP, hemolysis, elevated liver enzymes, low platelets. From Drife J, Magowan B: Clinical obstetrics and gynecology, Philadelphia, 2004, WB Saunders.

• • • • •

• In the absence of proteinuria, preeclampsia may be diagnosed with new onset of hypertension and one of the following: 1. Platelet count less than 100,000/ml 2. New-onset, progressive renal insufficiency, serum creatinine concentrations greater than 1.1 mg/dl, or doubling of serum Cr levels in the absence of other renal disease 3. Elevated serum liver transaminases to twice the normal concentration 4. Pulmonary edema 5. New-onset cerebral or visual symptoms • Because of the insidious nature of the disease with potential for multiple organ involvement, as well as its prevalence, complete evaluation for preeclampsia in any pregnant patient presenting with central nervous system derangement or gastrointestinal symptoms after 20 wk of gestation • Evaluation for associated conditions such as disseminated intravascular coagulation, hepatic dysfunction, or subcapsular hematoma • Fig. 1 outlines a management plan for patients with severe preeclampsia

Admit to labor and delivery, observe for 24–48 hours Corticosteroids, magnesium sulfate prophylaxis Antihypertensives for severe blood pressure Ultrasound, fetal heart rate monitoring Monitor symptoms and laboratory tests

Contraindications to continued expectant management?

Delivery

Yes

• • • • • •

Eclampsia 160 mm Hg systolic or >110 mm Hg diastolic either with hydralazine 5 to 10 mg IV, then 10 mg, every 20 min to a max dose of 20 mg; or with labetalol hydrochloride 20, 40, 80, 80 mg IV, escalating dosage every 10 min to a max dose of 300 mg IV; or with nifedipine 10 to 20 mg orally every 20 min for acute blood pressure control, to a max dose of 180 mg/day. If maximum dose of one medication is reached, add an additional medication to reach goal of BP 140 to 150/90 to 100 mm Hg. • Continuous fetal monitoring. • Epidural is anesthesia of choice for pain management in labor or cesarean section. • All patients undergoing induction of labor or cesarean section should receive antiseizure medications (magnesium sulfate) if disease with severe features, for delivery and 24 hr postpartum.

CHRONIC Rx • Preeclampsia without severe features 30, and in exceptional circumstances, the use of artificial nutrition for those with good performance status.

P

Diseases and Disorders

• Do not debride hard, dry, stable eschar on heels or ischemic limbs. • No single dressing or product is superior; keep wound bed moist and protect it from urine/stool. Silver dressings, topical pheny­ toin, and growth factors should be limited to difficult-to-heal wounds, chronic ulcers, and extensive burns given their extra cost and limited scientific validation. Reduce pressure by using foam mattress, dynamic support surface (e.g., low–air loss bed), and frequent repositioning (e.g., every 2 hours or, in case of poor perfusion, more frequently). • Hyperbaric oxygen therapy when used for some wounds provided temporary benefit. There have been no studies specifically looking at treatment of pressure injuries. Moreover, serious adverse events such as pneumothorax and seizures can occur. • The data on the efficacy of ultrasound as wound therapy is limited. Similarly RCTs on electromagnetic therapy found no evidence of benefit on wound healing. • Use of topical agents such as phenytoin, becaplermin gel, sucralfate, and medicinal manuka honey showed limited evidence for the healing of stage 2 ulcers. • Negative-pressure wound therapy (NPWT) may be useful for wounds that have significant drainage. They help improve healing by promoting angiogenesis, improving tissue perfusion, and decreasing bacterial count. Calcium alginate and foam dressings may also be beneficial for such wounds. Randomized studies have not identified any significant differences to quantitative wound healing; however, it provided some level of patient and provider comfort. • Although controlling poor nutrition has been shown to be beneficial, a recent large investigation demonstrated that feeding tubes did not prevent or heal pressure injuries, but increased the risk for their development. • Minimize or promptly remove urinary and/or fecal contamination. • No RCTs have compared debridement versus no debridement in the treatment of pressure injuries. 1. Thirty-two RCTs have compared different debridement agents, but there is insufficient evidence to promote the use of one particular agent. 2. One RCT demonstrated pressure injuries treated with collagenase healed significantly more quickly than those treated with hydrocolloid. 3. One RCT comparing honey-treated dressings with saline-soaked dressings showed faster healing times with the honey-treated group. 4. A meta-analysis and one RCT found significant benefit in rates of healing with use of hydrocolloid dressings versus traditional saline gauze dressings but not over other forms such as hydrogels, foam dressings, or collagenase. • Malnutrition is an independent risk factor for pressure injury. However no benefit was found with nutritional and vitamin

1153

I

PEARLS & CONSIDERATIONS COMMENTS • Up to 10% of older persons will have a pressure injury.

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1154

Pressure Injury • Because 70% of pressure injuries occur in older persons, the approach should be similar to other multifactorial geriatric syndromes with an interprofessional team approach. • Identify and reduce all modifiable risk factors for pressure injuries. • Treat the pain associated with pressure injuries. • Proper skin care, use of support surfaces, mobilization, and nutritional support are integral for prevention and treatment. Of these, pressure redistribution is the most important factor for prevention.

• Effective prevention practices consist of timely wound reassessments, regular communication with team members, patient and caregiver empowerment, and utilization of clinical decision support tools for health care providers. • Clinical studies have not revealed that any one dressing product is superior to another. • Nonhealing pressure injuries require assessment for debridement, infection, abscess, and/or referral to a wound center.

SUGGESTED READINGS Available at ExpertConsult.com RELATED CONTENT Bed Sores (Patient Information) AUTHORS: Mary-Beth Welesko, MS, APRN-BC, WCC, and Noelle Marie Javier, MD

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Pressure Injury

1154.e1

SUGGESTED READINGS Anvar B et al: Serial surgical debridement of common pressure injuries in the nursing home setting: outcomes and findings, Wounds 29:215-221, 2017. Chaboyer Ws et al: Adherence to evidence-based pressure injury prevention guidelines in routine clinical practice: a longitudinal study, Int Wound J 14:1290-1298, 2017, https://doi.org/10.1111/iwj.12798. Chew J et al: Turning frequency in adult bedridden patients to prevent hospitalacquired pressure ulcer: a scoping review, Int Wound J 15(2):225-236, 2018. Delmore B et  al: Refining heel pressure injury risk factors in the hospitalized patient, Adv Skin Wound Care 32(10):1-8, 2019. Gaspar S et al: Effectiveness on hospital-acquired pressure ulcers prevention: a systematic review, Int Wound J 16(5):1087-1102, 2019, https://doi. org/10.1111/iwj.13147. Gould LJ et al: Pressure Ulcer Summit 2018: an interdisciplinary approach to improve our understanding of the risk of pressure induced tissue damage, Wound Repair Regen 27(5):497-508, 2019, https://doi.org/10.1111/wrr.12730. Hajhosseini B et al: Pressure injury, Ann Surg 20(20):1-15, 2019. Jackson D et al: Health service provision and the use of pressure redistributing devices: mixed methods study of community dwelling individuals with pressure injuries, Contemp Nurse 8:1-28, 2017. Kayser SA et al: Prevalence and analysis of medical device-related pressure injuries: results from the international pressure ulcer prevalence survey, Adv Skin Wound Care 31(6):276-284, 2018. Martin D et al: Healthy skin wins: a glowing pressure ulcer prevention program that can guide evidence-based practice, Worldviews Evid Based Nurs 14(6):473-483, 2017, https://doi.org/10.1111/wvn.12242. McInnes E et al: Support surfaces for treating pressure ulcers, Cochrane Database Syst Rev 10:CD009490, 2018, https://doi.org/10.1002/14651858.CD009490. pub2. National Pressure Ulcer Advisory Panel: NPUAP pressure injury stages. Available at: https://npiap.com/page/PressureInjuryStages. Pittman J et al: Hospital-acquired pressure injuries in critical and progressive care: avoidable versus unavoidable, Am J Crit Care 28(5):338-350, 2019. Rae KE et al: Support surfaces for the treatment of pressure ulcers: a systematic literature review, J Wound Care 27(8):467-474, 2018. Ricci JA et al: Evidenced-based medicine: the evaluation and treatment of pressure injuries, Plast Reconstr Surg 139:275-286, 2017.

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Preterm Labor BASIC INFORMATION DEFINITION Preterm labor is defined as regular contractions that result in cervical dilation or effacement prior to 37 wk gestation. Preterm birth is one that occurs after 20 wk gestation and before the completion of 37 wk gestational age.

ICD-10CM CODES O60.0 Preterm labor without delivery O60.1 Preterm spontaneous labor with preterm delivery O60.2 Preterm spontaneous labor with term delivery

EPIDEMIOLOGY & DEMOGRAPHICS INCIDENCE: The incidence of preterm births in the U.S. increased from 9.5% in 1981 to 12.7% in 2006 before falling gradually to 11.4% by 2013. The increase since 1981 is attributed to improvements in pregnancy dating by ultrasound, increased use of assisted reproductive technology, and increased preterm induction or preterm operative delivery for maternal or fetal indications. Between 40% and 45% of these births follow spontaneous preterm labor; either the remaining preterm births result from preterm premature rupture of membranes (PPROM), or they occur secondary to intentional delivery for maternal or fetal indications. PREDOMINANT AGE AND RACIAL DIFFERENCES: Pregnant women at the extremes of reproductive age (35 yr) are at greatest risk. Black race is one of the most significant risk factors with the rate of preterm birth averaging 18.4% between 2005 and 2007 compared to 10.8% among Asian Americans and 11.6% in white women. The disparity between African-American and other ethnic American races persists after adjusting for income, education, and other medical risk factors. GENETICS: A genetic component has been suggested. Women with sisters who have had preterm births and women with grandparents who were born preterm may be at increased risk for having preterm deliveries themselves. Single-nucleotide polymorphisms have also been associated with preterm labor. RISK FACTORS: Risk factors for premature labor include a prior preterm delivery, intrauterine infection, systemic or genital tract infections, periodontal disease, short interpregnancy interval (200 rare disorders involving the absence or malfunction of integral parts of the immune system. The etiologies of PIDDs are not communicable in the infectious sense, but vertically transmissible via transfer of inherited genetic defects. Although some defects affect a single part of the immune system, others cause multicomponent breakdown of combined innate and cellular immune responses and suggest the interplay of epigenetic influences. To be considered a PIDD, the cause must not be secondary to another disease, drug/chemical, or environmental exposure. Primary immunodeficiency disease onset may occur at birth, as most do, or at any subsequent developmental stage and may affect anyone, with only specific regard to gender or ethnicity. SYNONYMS PID PIDD PI ICD-10CM CODES D80.5 Immunodeficiency with increased immunoglobulin M [IgM] D80.9 Immunodeficiency with predominantly antibody defects, unspecified D81.0 Severe combined immunodeficiency [SCID] with reticular dysgenesis D81.1 Severe combined immunodeficiency [SCID] with low T- and B-cell numbers D81.2 Severe combined immunodeficiency [SCID] with low or normal B-cell numbers D81.9 Combined immunodeficiency, unspecified D82.2 Immunodeficiency with short-limbed stature D82.3 Immunodeficiency following hereditary defective response to EpsteinBarr virus D82.8 Immunodeficiency associated with other specified major defects D82.9 Immunodeficiency associated with major defect, unspecified D83.0 Common variable immunodeficiency with predominant abnormalities of B-cell numbers and function D83.1 Common variable immunodeficiency with predominant immunoregulatory T-cell disorders D83.2 Common variable immunodeficiency with autoantibodies to B- or T-cells D83.9 Common variable immunodeficiency, unspecified D84.9 Immunodeficiency, unspecified

EPIDEMIOLOGY & DEMOGRAPHICS Overall about 1:500 are born with and 1:1200 currently live with a PIDD, these numbers generally exclude the milder forms of immunodeficiency (e.g., IgA deficiency). The predilection for age and gender varies according to the specific disorder.

ALG

PHYSICAL FINDINGS & CLINICAL PRESENTATION The history, signs, and symptoms depend on the precise genetic disorder. Recurrent, persistent, or unusual infections, as well as developmental delay or congenital anomalies, are among the most common attributes present when considering a primary immunodeficiency as a potential diagnosis. ETIOLOGY Inherited

DIAGNOSIS Criteria for the diagnosis of common variable immunodeficiency disease are summarized in Box E1. The International Union of Immunological Societies (IUSIS) PID expert committee has set forth a PID classification system that is updated every other year. The PIDs are grouped into eight categories, based on the primary mechanism of each disease. Due to the complexity of the classification system in clarifying a PID case and the reasoning that most PIDs will present in nonimmunological fields of medicine, a phenotype-based algorithmic approach highlighting the clinical and biological characteristics of a particular PID has been synthesized to aid in diagnosis (Fig. E1). • Combined T-cell and B-cell immunodeficiencies (Boxes E2 and E3) • Well-defined syndromes with immunodeficiency (Table E1) • Predominantly antibody deficiencies (Table E2) • Disease of immune dysregulation • Congenital defects of phagocyte number, function, or both • Defects of innate immunity (Box E4) • Autoinflammatory disorders • Complement deficiencies (Table E3)

DIFFERENTIAL DIAGNOSIS Secondary immunodeficiency, primary infections

WORKUP A thorough history detailing the type, location, and frequency of the infections, as well as any physical exam findings that may indicate recurrent or persistent infections (e.g., scarred tympanic membranes) is essential in the initial characterization of the suspect immunodeficiency (Table E4). Box E5 summarizes when to suspect an immunodeficiency disorder. Screening tests for suspected primary immunodeficiency disease are summarized in Table E5. LABORATORY TESTS • Screening tests: 1. Complete blood count with a manual differential: The most important test upon initial evaluation is whether lymphocyte, neutrophil, and platelet counts are normal. 2. Quantitative immunoglobulin levels (IgG, IgA, IgM, IgE): The specimen should be processed at a CLIA (Clinical Laboratories Improvement Act)-approved laboratory and be evaluated within the context of the patient’s age and clinical presentation. 3. Vaccine responsive antibody quantification: Important to the evaluation of an antibody deficiency disorder is evaluating whether there are truly low serum immunoglobulin responses to both polysaccharide- and protein-based vaccines. Table E6 describes antibody specificities commonly used in flow cytometry for immunodeficiency assessment. 4. Any further investigation should defer to an immunologist for guidance based on history, symptoms, and clinical presentation and may involve a more precise analysis of immunoglobulin subtypes, T and B lymphocytic subsets, cell surface markers, complement levels, and gene sequencing.

TREATMENT Treatment depends highly on the specific immunodeficiency and should always include

BOX E1  Criteria for the Diagnosis of Common Variable Immunodeficiency Disease • • • • • •

 t least one of the following: A 1. Increased susceptibility to infection 2. Autoimmune manifestations 3. Granulomatous disease 4. Unexplained polyclonal lymphoproliferation 5. Affected family member with antibody deficiency And marked decrease of IgG and marked decrease of IgA with or without low IgM levels (measured at least twice; M) Median, 65-75 yr, M > F

Neutrophilia >2K/μL Major criteria: Hb >18.5 g/dl in M or >16.5 g/dl; JAK2 V617F (or Exon 12) Minor criteria: hypercellular marrow with panmyelosis; ↓EPO; endogenous erythroid colony formation in vitro; 2 major plus 1 minor, or first major plus 2 minor criteria Major criteria: Megakaryocyte proliferation/ atypia with marrow fibrosis; CML, PV, MDS ruled out; JAK2 V617F Minor criteria: Leukoerythroblastosis, ↑LD, anemia, splenomegaly; all three major plus two minor criteria Platelet count >450 K; BM with proliferation of mature megakaryocytes; PV, PMF, CML, MDS ruled out; JAK2 V617F Note: All four criteria must be met. Monocytosis >1000, cytopenias, myeloid dysplasias, F

Myeloid/ lymphoid neoplasms w/↑eos and PDGFR/ FGFR1 Mastocytosis

M 25-55 yr

CEL NOS, idiopathic HES

Usually adult M; any age or sex

All ages

Monocytosis >1000, blasts 10K, clonal abnormalities, GM-CSF hypersensitivity PB w/inc eos, BM eos with mast cells

Mononuclear w/central nuclei, variable basophilic granules (often not seen in fixed tissue); dense aggregates of spindle cells PB ≥1.5 K eos/μL, 65 yrs • Hemoglobin 25 × 109/L • Circulating blasts >1% • Presence of constitutional symptoms • Red cell transfusion need • Platelet 40 yr

Usually Episodic 40 yr

Insidious

>40 yr

Point of ­shoulder Deep in ­shoulder Over joint

Deltoid region Deltoid region Anterior

Location of Pain

From Hochberg MC: Rheumatology, ed 7, Philadelphia, 2019, Elsevier.

Cervical ­spondylosis Thoracic outlet syndrome

Capsulitis (“frozen shoulder”) Acromioclavicular joint Osteoarthrosis of glenohumeral joint Glenohumeral instability

Calcific tendinitis 30-60 yr Acute

Rotator cuff Any tendinitis Rotator cuff tears >40 yr (chronic) Bicipital tendinitis Any

Diagnosis

TABLE E1  Differential Diagnosis of Shoulder Pain: Clinical and Radiographic Features of Common Causes of Shoulder Pain

Rotator Cuff Disease 1226.e9

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Rotator Cuff Disease

A

1226.e10

B

C

FIG. E7  Oblique coronal fat-suppressed proton density–weighted (A), oblique coronal proton density–weighted (B), and oblique sagittal fat-suppressed T2-weighted (C) magnetic resonance images demonstrate a massive full-thickness rotator cuff tear. Note the retraction of the myotendinous junction to the level of the glenoid (A and B, arrows). There is involvement of the entire supraspinatus and infraspinatus tendons as demonstrated by the complete stripping of the tendons from the greater tuberosity (C, arrowheads). Also note the markedly narrowed acromiohumeral interval. (From Pope TL et al: Musculoskeletal imaging, ed 2, Philadelphia, 2014, WB Saunders.)

• A recent trial showed that older patients with symptomatic, nontraumatic, supraspinatus tears do not benefit from surgery. Patients who underwent surgery and physiotherapy fared no better than those who underwent physiotherapy alone.

RELATED CONTENT Rotator Cuff Pain (Patient Information) Rotator Cuff Tear (Patient Information) Rotator Cuff Tendinitis (Patient Information) Rotator Cuff Tendinosis (Patient Information)

Bursitis (Related Key Topic) AUTHORS: Jeremy E. Raducha, MD, and Manuel F. DaSilva, MD

SUGGESTED READINGS Flores C et al: Efficacy and tolerability of peritendinous hyaluronic acid in patients with supraspinatus tendinopathy: a multicenter, randomized, controlled trial, Sports Med Open 3(1):22, 2017. Hermans J et  al: Does this patient with shoulder pain have rotator cuff disease? The rational clinical examination systematic review, J Am Med Assoc 310(8):837-847, 2013. Hurley ET et al: Nonoperative treatment of rotator cuff disease with platelet-rich plasma: a systematic review of randomized controlled trials, Arthroscopy 35(5):1584-1591, 2019. Karel YHJM et al: Physiotherapy for patients with shoulder pain in primary care: a descriptive study of diagnostic and therapeutic management, Physiotherapy 103(4):369-378, 2017. Karjalainen TV, Jain NB, Page CM et al: Subacromial decompression surgery for rotator cuff disease, Cochrane Database Syst Rev 1:CD005619, 2019. Kukkonen J et  al: Treatment of nontraumatic rotator cuff tears: a randomized controlled trial with two years of clinical and imaging follow-up, J Bone Joint Surg Am 97(21):1729-1737, 2015. Lee DH et  al: Relation between subacromial bursitis on ultrasonography and efficacy of subacromial corticosteroid injection in rotator cuff disease: a prospective comparison study, Arch Phys Med Rehabil 98(5):881-887, 2017. Leong HT et al: Risk factors for rotator cuff tendinopathy: a systematic review and meta-analysis, J Rehabil Med 51(9):627-637, 2019. Lewis J: Rotator cuff related shoulder pain: assessment, management and uncertainties, Man Ther 23:57-68, 2016. Ramme AJ et al: Surgical Versus Nonsurgical Management of Rotator Cuff Tears: A Matched-Pair Analysis, J Bone Joint Surg Am 101:1775-1782, 2019. Seida JC et  al: Systematic review: nonoperative and operative treatments for rotator cuff tears, Ann Intern Med 153:246-255, 2010. Steuri R et  al: Effectiveness of conservative interventions including exercise, manual therapy and medical management in adults with shoulder impingement: a systematic review and meta-analysis of RCTs, Br J Sports Med 51:1340-1347, 2017. Whittle S, Buchbinder R: The clinic. Rotator cuff disease, Ann Intern Med 162:ITC1-ITC15, 2015. Zhang K et al: In-office needle arthroscopy: a systematic review of indications and clinical utility, Arthrosc J Arthrosc Relat Surg 35(9):2709-2721, 2019.

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  Rubella BASIC INFORMATION DEFINITION Rubella is a mild illness caused by the rubella virus that can cause severe congenital problems by in vitro transmission to a fetus when a pregnant woman becomes infected. SYNONYM German measles ICD-10CM CODES B06.9 Rubella without complication B06 Rubella B06.8 Rubella with other complications P35.0 Congenital rubella syndrome Z23 Encounter for immunization B06.00 Rubella with neurological complication, unspecified B06.01 Rubella encephalitis B06.02 Rubella meningitis B06.09 Other neurological complications of rubella B06.81 Rubella pneumonia B06.82 Rubella arthritis B06.89 Other rubella complications B06.9 Rubella without complication Z20.4 Contact with and (suspected) exposure to rubella

EPIDEMIOLOGY & DEMOGRAPHICS • Before vaccination (i.e., before 1969): 1. 28 reported cases per 100,000 person-yr, eight of which were in persons >15 yr. 2.  Four cases of congenital rubella syndrome per 100,000 live births. • Since mass vaccination (i.e., after 1980), most cases have occurred in unimmunized people, with 5 cm, or any deepseated soft tissue mass should be regarded as malignant until proven otherwise. • Bone sarcoma: Patients with unexplained bone pain, persistent bone tenderness, or nonmechanical bone pain (especially when it disturbs sleep or rest) have bone cancer until proven otherwise. • Patients with suspected spontaneous fracture or recurrence of the fracture with minor trauma should be considered as having bone cancer.

TABLE E1  Histologic Classification of Soft Tissue Sarcoma Adipocytic Sarcomas Atypical lipomatous tumor/well-differentiated liposarcoma Dedifferentiated liposarcoma Myxoid liposarcoma Pleomorphic liposarcoma

Fibroblastic and Myofibroblastic Sarcomas Malignant solitary fibrous tumor Inflammatory myofibroblastic tumor Myxoinflammatory fibroblastic sarcoma Infantile fibrosarcomas Adult fibrosarcomas Myxofibrosarcoma (myxoid undifferentiated pleomorphic sarcoma) Low-grade fibromyxoid sarcoma (Evans tumor) Sclerosing epithelioid fibrosarcoma

So-called Fibrohistiocytic Sarcomas Undifferentiated pleomorphic sarcoma (UPS)

Smooth Muscle Sarcomas Leiomyosarcoma

Skeletal Muscle Sarcomas Embryonal rhabdomyosarcoma Alveolar rhabdomyosarcoma Pleomorphic rhabdomyosarcoma

Vascular Sarcomas Epithelioid hemangioendothelioma Angiosarcoma Kaposi sarcoma Solitary fibrous tumor (formerly hemangiopericytoma)

Osseous Sarcomas Extraskeletal osteosarcoma

Sarcomas of Uncertain Differentiation Synovial sarcoma Epithelioid sarcoma Alveolar soft part sarcoma Clear cell sarcoma of soft tissue Extraskeletal myxoid chondrosarcoma Desmoplastic small round cell tumor Extrarenal rhabdoid tumor Extraskeletal Ewing sarcoma Intimal sarcoma

Notochord-derived Tumor Behaving Like Sarcomas Chordoma From Niederhuber JE: Abeloff’s clinical oncology, ed 6, Philadelphia, 2020, Elsevier.

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Sarcoma

ALG

A

1232.e3

B

C FIG. E1  A, Gross photograph of an osteosarcoma of the distal femur. The medullary cavity is filled with tumor, which has replaced the normal marrow contents. The tumor has penetrated and incompletely destroyed the cortex and penetrated the growth plate distally. The Codman triangle, an incomplete host periosteal response, is well demonstrated. Histologically, this would show woven periosteal bone. One also can appreciate how this tumor could enter the joint under the synovium, anteriorly in this case. B, A section from higher in the femur shows where the medullary extent of the tumor ends rather abruptly. There is a margin of normal marrow proximal to the marrow extent. C, Coronal T1-weighted image of this case nicely shows the extent of the tumor in the medullary cavity and the penetration of the growth plate. It corresponds to the preceding findings seen on the gross specimen. (From Niederhuber JE: Abeloff’s clinical oncology, ed 6, Philadelphia, 2020, Elsevier.)

• Referral to a sarcoma treatment center of all patients with a suspected sarcoma is recommended.

IMAGING STUDIES (TABLE E4) • A chest computed tomography (CT) scan (Figs. E2 and E3) is compulsory for staging purposes. Chest spiral CT helps detect lung metastases because hematogenous dissemination to the lungs is the principal form of spread. • The American Joint Committee on Cancer (AJCC) and International Union Against Cancer (IUCC) are widely used for staging classification.

• Soft tissue sarcoma: 1.  Magnetic resonance imaging (MRI) is the initial imaging modality of choice, especially for soft tissue sarcoma of the extremities, trunk, and head and neck. CT with IV contrast is also useful for diagnosis. 2. Ultrasound is used to help differentiate between benign and suspicious lesions. • Bone sarcoma: Radiograph (Fig. E4) is the initial imaging of choice. It helps to rule out bone tumor, shows calcification, and reveals bone erosions. Fig. E5 summarizes radiographic features that may help differentiate benign from malignant lesions. Diagnostic

workup for bone sarcomas is summarized in Table E5. • A multidisciplinary team approach is essential and should include a radiologist, surgeon, pathologist, medical oncologist, and radiation oncologist.

BIOPSY • In nearly all cases a biopsy is needed to establish a tissue diagnosis. Guidelines for biopsy are summarized in Box E1. • Multiple core needle biopsies are usually done. • An excisional biopsy may be used for superficial lesions 50 histologic subtypes of soft tissue sarcoma.

• Newer methods such as immunocytochemistry and cytogenetics can aid diagnosis by identifying tumor lineage. • Sarcomas with complex karyotypes are summarized in Table E6.

TREATMENT Treatment depends on the extent of the disease and falls into several groups.

ACUTE GENERAL Rx • Surgical resection: Most cases are treated by surgery. For example, in most adults soft tissue sarcoma and sarcoma of bone are not very sensitive to chemotherapy. Fig. E6 illustrates a management strategy for soft tissue sarcomas. 1. Surgery must be done by surgeon trained to treat this disease. 2. Wide excision with negative margins is the standard surgical procedure. 3. For bone sarcomas amputation has been the standard procedure. Recent advances

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Sarcoma

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B

A

FIG. E2  A, A 48-yr-old man with retroperitoneal and intraabdominal well-differentiated and dedifferentiated liposarcoma. Axial contrast-enhanced computed tomography (CT) images show a large, heterogeneous mass with foci of calcification, consistent with osteosarcoma divergent differentiation sometimes seen with this form of sarcoma. In this situation, the finding of osteoblasts does not merit the use of chemotherapy for osteosarcoma; the risk of tumor recurrence rests entirely with the dedifferentiated liposarcoma portion of the diagnosis. B, The same patient as in A, with coronal sectioning from data existing from the axial CT scans. This technique is commonly used with both magnetic resonance imaging and CT. (From Niederhuber JE: Abeloff’s clinical oncology, ed 6, Philadelphia, 2020, Elsevier.)

FIG. E3  Contrast-enhanced computed tomography scan of the abdomen demonstrating a retroperitoneal undifferentiated pleomorphic sarcoma. Note the large mass (bottom arrow) between the aorta and inferior vena cava with abutment and displacement of celiac axis and hepatic artery (top arrows). The portal vein (arrowheads) is well visualized, and low-attenuation foci in the liver, which are unopacified hepatic veins, are incidentally visualized. (From Niederhuber JE: Abeloff’s clinical oncology, ed 6, Philadelphia, 2020, Elsevier.)

B Soft tissue mass

Intact bone

A FIG. E4  Fibrosarcoma. A, Anteroposterior plain film of the shoulder of a 40-yr-old woman with a history of an enlarging mass in the right axilla shows an ill-defined mass adjacent to the lateral border of the scapula. B, CT section with contrast enhancement shows the extent of the mass and the lack of bone involvement. The tumor proved to be a fibrosarcoma. (From Skarin AT: Atlas of diagnostic oncology, ed 3, St Louis, 2003, Mosby.)

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Feature

Benign (slow-growing process)

Malignant (aggressive process)

Border

1. Sharply outlined, sclerotic (narrow zone of transition)

2. Poorly defined (wide zone of transition)

Periosteal reaction

3. Solid, uninterrupted

4. Interrupted (sunburst, Codman triangle)

Soft tissue extension/mass

5. Absent or contained by shell of periosteal new bone

6. Frank extension through destroyed periosteum

Type of bone destruction

7. Geographic: Uniformly destroyed area with sharply defined border

8. “Moth-eaten” (likely malignant): Destroyed areas with ragged borders

1 3 5 2 4

7

6

9. Permeative (aggressive/malignant): Ill-defined destruction spreading through marrow space

8

9

FIG. E5  Benign versus malignant bone lesions. The radiographic features illustrated may help differentiate benign from malignant lesions. (From Bullough PG, Vigorita VJ: Atlas of orthopedic pathology, Baltimore/New York, 1984, University Park Press/Gower Medical Publishing; in Skarin AT: Atlas of diagnostic oncology, 4 ed, St Louis, 2010, Mosby.)

TABLE E5  Diagnostic Workup Algorithm for Bone Sarcomas 1. Anteroposterior and lateral radiographs of the bone/joint involved 2. If a malignant bone lesion is suspected, proceed to: • Magnetic resonance imaging (MRI) of the lesion and coronal T1 images of the entire bone • Chest computed tomography (CT) to screen for pulmonary metastases • Radionuclide bone scan to look for “skip” and other bony metastases 3. Review with multidisciplinary team (surgeon, oncologist, radiotherapist, radiologist, and pathologist); decide whether tissue will be needed for cytogenetics or other special biologic studies 4. Plan open or needle biopsy by surgeon or interventional radiologist (after reviewing images with the radiologist who will perform the biopsy) From Niederhuber JE: Abeloff’s clinical oncology, ed 6, Philadelphia, 2020, Elsevier.

BOX E1  Guidelines for Biopsy Needle Biopsy 1. Planning: Biopsy tract must be in line of potential resection. 2. Traverse only one compartment and only one muscle if possible. 3. Avoid contamination of joint. 4. Microbiologic culture. 5. Prolonged gentle pressure for hemostasis. Incisional Biopsy 1. Planning: Plan most appropriate biopsy tract and avoid transverse incisions. 2. Use pneumatic tourniquet after gravity exsanguination. 3. Avoid contamination of joint. 4. Avoid exposure of neurovascular structures. 5. Monitor biopsy with frozen sections. 6. Microbiologic culture if there is question. 7. Maintain integrity of deep tumor-host margin; could extend necessary surgical margin. 8. Absolute hemostasis; thrombogenic agents (e.g., thrombin, Oxycel, Avitene). 9. Hemostatic closure of pseudocapsule. 10. Subcuticular closure. From Niederhuber JE: Abeloff’s clinical oncology, ed 6, Philadelphia, 2020, Elsevier.

TABLE E6  Sarcomas with Complex Karyotypes Type of Sarcoma

Resembles

Fibrosarcoma (other than congenital) Leiomyosarcoma Undifferentiated pleomorphic sarcoma Osteosarcoma Chondrosarcoma (types other than extraskeletal myxoid) Liposarcoma (types other than myxoid) Embryonal rhabdomyosarcoma Malignant peripheral nerve sheath tumor* Angiosarcoma

Fibrous tissue Smooth muscle Poorly differentiated Bone Cartilage Fat Skeletal muscle Nerve sheath Endothelium

*Some have NF1 mutations. From Niederhuber JE: Abeloff’s clinical oncology, ed 6, Philadelphia, 2020, Elsevier.

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Sarcoma

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Mass identified symptomatic/asymptomatic

History and physical examination CT/MRI of primary lesion

Small (5 cm)

Excisional biopsy

Core needle biopsy

Sarcoma

Low grade

High grade

Complete excision with 1–2 cm margin

• Rhabdomyosarcoma or Ewing sarcoma (any size) • >10 cm other HG subtype excluding DDLPS

Limit use of adjuvant therapy even in close/positive margin

• 5–10 cm

Consider enrollment in a clinical trial for adjuvant systemic therapy. Consider adjuvant radiation if: • Tumor >5 cm • Margin is close or positive on pathology and re-excision is not feasible • Recurrence would require morbid resection

Pleomorphic LPS Synovial sarcoma Round cell LPS

No Complete excision with goal of 1–2 cm margin

Yes Consider neoadjuvant chemotherapy

FIG. E6  Management strategy for soft tissue sarcoma. CT, Computed tomography; DDLPS, dedifferentiated liposarcoma; HG, high-grade; LPS, liposarcoma; MRI, magnetic resonance imaging. (From Cameron JL, Cameron AM: Current surgical therapy, ed 12, Philadelphia, 2017, Elsevier.)

permit the avoidance of amputation with limb-sparing surgery followed by reconstruction by endoprosthetic replacement. • Radiotherapy is used often in adjuvant fashion after primary sarcoma resection as a means to decrease local recurrences, e.g., in extremity or retroperitoneal sarcomas. • Chemotherapy is typically used followed by surgery in cases of advanced sarcoma or palliatively in case of metastatic disease. 1. Upfront chemotherapy is used to reduce disseminated micrometastases and to reduce tumor size preoperatively. Recent data support use of chemotherapy combined with hyperthermia in selected soft tissue sarcomas of the extremities before resection. 2.  Systemic chemotherapy regimens for advanced STS typically comprise multiple drugs such as the MAID regimen (mesna, doxorubicin, ifosfamide, dacarbazine) and the AIM regimen (doxorubicin, ifosfamide, mesna). Single-agent therapy with either

doxorubicin or ifosfamide is also appropriate in the palliative setting. 3.  More recently, pazopanib, a tyrosine kinase inhibitor, has been approved for patients with metastatic or recurrent sarcoma. Trabectedin (an agent derived from a marine sponge) and eribulin (a microtubule inhibitor) have now been approved in advanced leiomyosarcoma or liposarcoma after showing an overall survival benefit. 4.  Olaratumab, a monoclonal antibody directed against platelet-derived growth factor (PDGF), had been approved based on early survival data when used in combination with doxorubicin as a first-line option in metastatic soft tissue sarcomas, but the mature survival results did not confirm a survival benefit. • Follow-up of bone sarcoma after treatment includes: 1. Periodic monitoring with radiographs and other imaging modalities. 2. CT scan of the chest.

3. Bone scan. • Follow-up of soft tissue sarcoma (extremities): 1.  Physical exam detects 97% of recurrence. 2. Physical exam is done every 3 to 6 mo for 3 yr, then every 6 mo for the next 2 yr for stage II and III cancers, then annually. 3. Imaging. • Stage I: CXR every 6 to 12 mo. • Stages II and III: Image the primary site with MRI or CT. • Chest x-ray or chest CT every 3 to 6 mo for 5 yr, then annually.

REFERRAL • Sarcomas are relatively uncommon yet comprise a wide variety of different entities; as such, evaluation by multidisciplinary oncology teams with expertise in this field is recommended. • Treatment and follow-up guidelines have been published by the National Comprehensive Cancer Network (www.nccn.org). AUTHOR: Bharti Rathore, MD

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SUGGESTED READINGS Brownstein JM, DeLaney TF: Malignant soft-tissue sarcomas, Hematol Oncol Clin North Am 34(1):161-175, 2020. Demetri GD et al: Efficacy and safety of trabectedin or dacarbazine for metastatic liposarcoma or leiomyosarcoma after failure of conventional chemotherapy: results of a phase III randomized multicenter clinical trial, J Clin Oncol 34(8):786-793, 2016. Harris SJ et al: Current and advancing systemic treatment options for soft tissue sarcomas, Expert Opin Pharmacother 16(13):2023-2037, 2015. Issels RD et al: Effect of neoadjuvant chemotherapy plus regional hyperthermia on long-term outcomes among patients with localized high-risk soft tissue sarcoma: the EORTC 62961-ESHO 95 randomized clinical trial, JAMA Oncol 4(4):483-492, 2018. Ratan R, Patel SR: Chemotherapy for soft tissue sarcoma, Cancer 122(19):29522960, 2016. Schöffski P et al: Eribulin versus dacarbazine in previously treated patients with advanced liposarcoma or leiomyosarcoma: a randomised, open-label, multicentre, phase 3 trial, Lancet 387(10028):1629-1637, 2016. Van der Graaf WT et al: Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised, double-blind, placebo-controlled phase 3 trial, Lancet 379(9829):1879-1886, 2012.

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Scabies BASIC INFORMATION DEFINITION Scabies is a contagious disease caused by the mite Sarcoptes scabiei. ICD-10CM CODE B86 Scabies

PHYSICAL FINDINGS & CLINICAL PRESENTATION • Primary lesions are caused when the female mite burrows within the stratum corneum, laying eggs within the tract she leaves behind; burrows (linear or serpiginous tracts, see Fig. E1) end with a minute papule or vesicle. • Primary lesions (Fig. E2) are most commonly found in the web spaces of the hands, wrists, buttocks, scrotum, penis, breasts, axillae, and knees. They are often confused with eczema (Fig. E3). • Secondary lesions result from scratching or infection. • Intense pruritus, especially nocturnal, is common; it is caused by an acquired sensitivity to the mite or fecal pellets and is usually noted 1 to 4 wk after the primary infestation. • Examination of the skin may reveal burrows, tiny vesicles, excoriations, inflammatory papules. • Widespread and crusted lesions (Norwegian or crusted scabies) may be seen in elderly

ETIOLOGY • Human scabies is caused by the mite S. scabiei, var. hominis (Fig. 5). After impregnation on the skin surface, the gravid female burrows in the stratum corneum within 30 min and gradually extends the tract along the boundary with the stratum granulosum depositing 10 to 25 oval eggs in a 4- to 5-wk period. The eggs hatch in 3 to 5 days, and larvae move to the skin surface and mature in 2 to 3 wk, resuming the cycle. • Clinical manifestations result from a delayed type IV hypersensitivity reaction to the mite, eggs, saliva, or scybala.

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • Pediculosis • Atopic dermatitis • Flea bites • Seborrheic dermatitis • Dermatitis herpetiformis • Contact dermatitis • Nummular eczema • Syphilis • Other insect infestation WORKUP Diagnosis is made on the clinical presentation and on the demonstration of mites, eggs, or mite feces. LABORATORY TESTS • Microscopic demonstration of the organism, feces, or eggs: A drop of mineral oil may be

placed over the suspected lesion before removal (Box 1); the scrapings are transferred directly to a glass slide; a drop of potassium hydroxide is added and a cover slip is applied. • Skin biopsy is rarely necessary to make the diagnosis.

S

TREATMENT NONPHARMACOLOGIC THERAPY Clothing, underwear, and towels used in the 48 hours before treatment must be laundered. ACUTE GENERAL Rx • Permethrin 5% cream is usually effective with one treatment; it should be massaged into the skin from head to soles of feet and applied under fingernails and toenails (it is best if applied in the evening and left overnight to maximize exposure); remove 8 to 14 hr later by washing. Repeat in 1 to 2 wk. Permethrin is safe for children >2 mo old. • A single dose (150 to 200 μg/kg in 6-mg tablets) of ivermectin, an antihelmintic agent, is also effective for the treatment of scabies. It is the best treatment for generalized crusted scabies. Three to seven doses of ivermectin given on days 1, 2, 8, 9, 15, 22, and 28 may be needed for crusted scabies. • Pruritus generally abates 24 to 48 hr after treatment but can last up to 2 wk; oral antihistamines are effective in decreasing postscabietic pruritus. • Topical corticosteroid creams may hasten the resolution of secondary eczematous dermatitis. • If the patient is a resident of an extended care facility, it is important to educate the patients, staff, family, and frequent visitors about scabies and the need to have full cooperation in treatment. Scabicide should be applied to all

Diseases and Disorders

EPIDEMIOLOGY & DEMOGRAPHICS • Scabies is generally acquired by sleeping with or in the bedding of infested individuals. • It is generally associated with poor living conditions and is also common in hospitals and nursing homes.

and immunocompromised patients (Fig. E4). Pruritus may be mild or absent due to impaired host immune response. • Table 1 summarizes the different presenting forms of scabies.

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TABLE 1  Different Presenting Forms of Scabies Presenting Forms of Scabies

Specific High-Risk Populations

Clinical Manifestations

Classic scabies (scabies vulgaris)

Infants and children; sexually active adults; men who have sex with men

Dermatitis herpetiformis, drug reactions, eczema, pediculosis corporis, lichen planus, pityriasis rosea

Scalp scabies

Infants and children; institutionalized older adults; AIDS patients; patients with preexisting crusted scabies Institutionalized older adults; institutionalized developmentally disabled (Down syndrome); homeless, especially HIV-positive; all immunocompromised patients, particularly those with AIDS or positive for HIV or HTLV-1; transplant recipients; patients on prolonged systemic corticosteroids and chemotherapy Sexually active adults; men who have sex with men; HIV-positive men > HIV-positive women

Intense generalized pruritus, worse at night; inflammatory pruritic papules localized to finger webs, flexor aspects of wrists, elbows, axillae, buttocks, genitalia, female breasts; lesions and pruritus spare the face, head, and neck; secondary lesions include eczematization, excoriation, impetigo Atypical crusted papular lesions of the scalp, face, palms, and soles Psoriasiform hyperkeratotic papular lesions of the scalp, face, neck, hands, feet, with extensive nail involvement; eczematization and impetigo common

Contact dermatitis, drug reactions, eczema, erythroderma, ichthyosis, psoriasis

Violaceous pruritic nodules localized to male genitalia, groin, axillae, representing hypersensitivity reaction to mite antigens

Acropustulosis, atopic dermatitis, Darier disease, lupus erythematosus, lymphomatoid papulosis, papular urticaria, necrotizing vasculitis, secondary syphilis

Crusted scabies (Norwegian scabies, scabies norvegica, scabies crustosa)

Nodular scabies

Limited Differential Diagnoses

Dermatomyositis, ringworm, seborrheic dermatitis

AIDS, Acquired immunodeficiency syndrome; HIV, human immunodeficiency virus; HTLV-1, human T-cell lymphotropic virus type 1. From Bennett JE et al: Mandell, Douglas, and Bennett’s principles and practice of infectious diseases, ed 8, Philadelphia, 2015, WB Saunders.

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Scabies patients, staff, and frequent visitors, whether symptomatic or not; symptomatic family members of staff and visitors should also receive treatment. • Table 2 summarizes currently recommended treatment for scabies.

DISPOSITION Refractory cases usually are seen with immunocompromised hosts or patients with underlying skin diseases. Norwegian scabies refers to a highly contagious variant often found in institutions caring for physically and mentally disabled individuals.

FIG. 5  Scabies mite. Note the eggs within the body of the mite. (Live scabies mite, ×40 magnification.) (From Paller AS, Mancini AJ: Hurwitz clinical pediatric dermatology, a textbook of skin disorders of childhood and adolescence, ed 5, Philadelphia, 2016, Elsevier.)

BOX 1  Performing a Mineral-Oil Examination for Scabies

 

1. Apply a drop of mineral oil to the lesion(s) to be scraped. 2. Scrape through the lesion with a number 15 scalpel blade (a small amount of bleeding is expected with appropriately deep scrapings). 3. Smear contents of scraping on a clean glass slide. 4. Add a few more drops of mineral oil. 5. Place cover slip over oil and examine under microscope at low power.

Criteria for a positive mineral oil examination:

Scabies mite. or Ova (eggs). or Scybala (feces).

PEARLS & CONSIDERATIONS COMMENTS • Lindane is potentially neurotoxic and should not be used on infants or pregnant women (permethrin is safe in pregnancy and infants over 2 mo old). • Sexual partners should be notified and treated. SUGGESTED READINGS Available at ExpertConsult.com RELATED CONTENT Scabies (Patient Information)

From Paller AS, Mancini AJ: Hurwitz clinical pediatric dermatology, a textbook of skin disorders of childhood and adolescence, ed 5, Philadelphia, 2016, Elsevier.

AUTHOR: Fred F. Ferri, MD

TABLE 2  Currently Recommended Treatment for Scabies FDA Approved?

Pregnancy Category*

5% Permethrin cream (Actin, Nix, Elimite)

Yes

B

1% Lindane lotion or cream

Yes

B

10% Crotamiton cream or lotion (Eurax)

Yes

C

2%-10% Sulfur in ­petrolatum ointments 10%-25% Benzoyl ­benzoate lotion

No

C

No

0.5% Malathion lotion (Ovide), 1% ­malathion shampoo (unavailable in the U.S.) Ivermectin (Stromectol)

Scabicides

Dosing Schedule

Safety Profile

Contraindications

Apply from neck down; wash off after 8-14 hr; good residual activity, but second application recommended after 1 wk Apply 30-60 ml from neck down; wash off after 8-12 hr; no residual activity; increasing drug resistance Apply from neck down on two consecutive nights; wash off 24 hr after second application Apply for 2-3 days, then wash

Excellent; itching and stinging on application

Prior allergic reactions; infants 20 mg/ day (can precipitate SRC). • Raynaud phenomenon: 1. Keep hands and body warm 2. Avoid smoking and using vasoconstricting drugs 3.  Calcium channel blockers (i.e., longacting dihydropyridines) 4. Peripheral α1-adrenergic blockers 5. Angiotensin II receptor blockers 6. Topical nitrate 7. Phosphodiesterase inhibitors 8. Stellate ganglion blockades 9. Digital sympathectomy 10.  Table E6 summarizes vascular therapies for Raynaud phenomenon • Arthralgias: NSAIDs or low-dose corticosteroids (5-10 mg of prednisone per day)

TABLE 5  Autoantigens and Autoantibodies in Scleroderma Autoantigen

Molecular Structure

Autoantibody Frequency

Scl-70

100-kD native and 70-kD degradation product; DNA topoisomerase I

75% in diffuse scleroderma; 20%-59% in all patients; 13% in CREST

Centromere

Proteins 17, 80, and 140 kD; localized at inner and outer kinetochore plates

57%-82% in CREST; 8% in diffuse form

RNA Pol I

RNA Pol I complex of subunit proteins, 210211 kD

4%-30% in scleroderma; 13% in diffuse form

RNA Pol II

Transcripts mRNA

4%

RNA Pol III

Transcripts 5S rRNA, tRNA

23% in scleroderma; 45% in diffuse form; 6% in CREST

Fibrillarin

Protein 34 kD, component of U3 RNP particle

6%-8%; 5% in diffuse form; 10% in CREST

U1nRNP

Spliceosome complex

2%-5% in all patients; 24% in PM/scleroderma overlap

PM-Scl

Complex of 11 proteins, 110-120 kD

4%-11%; 24% in PM/scleroderma overlap

Ku

DNA-binding protein

1%-14% in scleroderma; 26%-55% in PM/scleroderma overlap

Th/To

Protein 40 kD, complexes with 7S and 8S RNAs

1%-13% in scleroderma; 1%-11% in diffuse form; 8%-19% in CREST; up to 3% in PM/scleroderma overlap

NOR-90

Protein 90 kD, human upstream binding factor, localized in nucleolus organizer region

Rare

CREST, Calcinosis, Raynaud phenomenon, esophageal dysfunction, sclerodactyly, and telangiectasia; DNA, deoxyribonucleic acid; mRNA, messenger RNA; PM, polymyositis; RNA, ribonucleic acid; RNP, ribonucleoprotein; rRNA, ribosomal RNA; tRNA, transfer RNA. From McPherson RA, Pincus MR: Henry’s clinical diagnosis and management by laboratory methods, ed 23, Philadelphia, 2017, Elsevier.

• Myositis: Methotrexate or azathioprine with low-dose corticosteroids • Skin: For skin fibrosis, immunomodulatory drugs have been used, generally started within 3 yr of onset (methotrexate, mycophenolate mofetil). Cyclophosphamide can be used for refractory or rapidly progressive involvement. Table E7 summarizes immunomodulatory and antifibrotic strategies for disease-modifying treatment of systemic sclerosis skin disease • GI tract: Table E8 summarizes treatment of GI tract complications in systemic sclerosis • Esophageal reflux: 1. H2-receptor blockers 2. Proton pump inhibitors • Interstitial lung disease: 1. Mycophenolate mofetil or cyclophosphamide for symptomatic ILD 2. Nintedanib, a small molecule that inhibits several kinases linked to the pathogenesis of interstitial lung diseases (receptor tyrosine kinases and nonreceptor tyrosine kinases), recently received FDA approval for the treatment of ILD associated with systemic sclerosis 3.  Lung transplantation for patients with advanced pulmonary involvement • Pulmonary hypertension: 1. Oxygen 2. Diuretics (with caution) 3.  Prostacyclins (epoprostenol, iloprost, treprostinil) 4. Endothelin-1 receptor inhibitors (bosentan, ambrisentan) 5. Phosphodiesterase 5 inhibitors (sildenafil, tadalafil) 6.  Table E9 summarizes approved therapies for treatment of pulmonary arterial hypertension • Renal involvement: 1. Angiotensin-converting enzyme inhibitors 2. Dialysis 3. Renal transplantation

REFERRAL Rheumatology consultation is indicated. Consider pulmonary, cardiology, or gastrointestinal consultations depending on organ involvement.

PEARLS & CONSIDERATIONS COMMENTS Autologous hematopoietic stem cell therapy (HSCT) has shown some benefit in patients with severe diffuse cutaneous systemic sclerosis, but there was greater treatment-related mortality and morbidity associated with HSCT. SUGGESTED READINGS Available at ExpertConsult.com RELATED CONTENT Scleroderma (Patient Information) AUTHOR: Joanne Szczygiel Cunha, MD

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MANAGEMENT STRATEGIES IN SYSTEMIC SCLEROSIS Systemic sclerosis—diagnosis confirmed

Subset and stage within subset

Immunosuppressive agents

Risk stratification based on stage, subset, autoantibody profile

Organ-based treatments

Gastroesophageal reflux (proton pump inhibitors)

Raynaud phenomenon (vascular therapy, calcium channel blockers)

Antifibrotic (no drugs of proven efficacy)

Diseases and Disorders

Disease-modifying therapy

Screening for organ-based complications

Fibrosing alveolitis (cyclophosphamide)

Myositis (prednisolone, methotrexate)

Pulmonary hypertension (prostacyclins, endothelin receptor antagonist)

Joints, tendons (NSAIDs, analgesic, exercise)

Renal crisis (ACE inhibitors)

Midgut disease (antibiotics)

FIG. 7  Management of scleroderma requires multiple strategies depending on the specific problems that are present in individual patients. ACE, Angiotensin-converting enzyme; NSAID, nonsteroidal antiinflammatory drug. (From Hochberg MC: Rheumatology, ed 7, Philadelphia, 2019, Elsevier.)

I

Scleroderma (Systemic Sclerosis) SUGGESTED READINGS Abou-Raya A et al: Statins: potentially useful in therapy of systemic sclerosisrelated Raynaud's phenomenon and digital ulcers, J Rheumatol 35(9):18011808, 2008. Allanore Y et al: Systemic sclerosis, Nat Rev Dis Primers 1:15002, 2015. Bene MD et al: Autologous fat grafting for scleroderma-induced digital ulcers: an effective technique in patients with systemic sclerosis, Handchir Mikrochir Plast Chir 46(4):242-247, 2014. Bogoch ER, Gross DK: Surgery of the hand in patients with systemic sclerosis: outcomes and considerations, J Rheumatol 32(4):642-648, 2005. Burt RK et al: Autologous non-myeloablative haemopoietic stem-cell transplantation compared with pulse cyclophosphamide once per month for systemic sclerosis (ASSIST): an open-label, randomised phase 2 trial, Lancet 378(9790):498-506, 2011. Chung L et al: MQX-503, a novel formulation of nitroglycerin, improves the severity of Raynaud's phenomenon: a randomized, controlled trial, Arthritis Rheum 60(3):870-877, 2009. Clements PJ et al: High-dose versus low-dose D-penicillamine in early diffuse systemic sclerosis: analysis of a two-year, double-blind, randomized, controlled clinical trial, Arthritis Rheum 42(6):1194-1203, 1999. Clements PJ et al: Cyclosporine in systemic sclerosis. Results of a 48-week open safety study in 10 patients, Arthritis Rheum 36(1):75-83, 1993. Coleiro B et al: Treatment of Raynaud's phenomenon with the selective serotonin reuptake inhibitor fluoxetine, Rheumatology 40(9):1038-1043, 2001. Daoussis D et al: Experience with rituximab in scleroderma: results from a 1-year, proof-of-principle study, Rheumatology 49(2):271-280, 2010. Dees C et al: Stimulators of soluble guanylate cyclase (sGC) inhibit experimental skin fibrosis of different aetiologies, Ann Rheum Dis 74(8):1621-1625, 2015. Distler O et al: Nintedanib for systemic sclerosis-associated interstitial lung disease, NEJM 380:2518-2528, 2019. Dziadzio M et al: Losartan therapy for Raynaud's phenomenon and scleroderma: clinical and biochemical findings in a fifteen-week, randomized, parallel-group, controlled trial, Arthritis Rheum 42(12):2646-2655, 1999. Gliddon AE et al: Prevention of vascular damage in scleroderma and autoimmune Raynaud's phenomenon: a multicenter, randomized, double-blind, placebocontrolled trial of the angiotensin-converting enzyme inhibitor quinapril, Arthritis Rheum 56(11):3837-3846, 2007. Gordon SM et  al: Risk factors for future scleroderma renal crisis at systemic sclerosis diagnosis, J Rheumatol Jul 15, 2018. Granel B et al: Safety, tolerability and potential efficacy of injection of autologous adipose-derived stromal vascular fraction in the fingers of patients with systemic sclerosis: an open-label phase I trial, Ann Rheum Dis 74(12):21752182, 2015. Guillaume-Jugnot P et al: Autologous adipose-derived stromal vascular fraction in patients with systemic sclerosis: 12-month follow-up, Rheumatology 55(2):301-306, 2016. Iorio ML et al: Botulinum toxin A treatment of Raynaud's phenomenon: a review, Semin Arthritis Rheum 41(4):599-603, 2012. Khanna D et al: Safety and efficacy of subcutaneous tocilizumab in adults with systemic sclerosis (faSScinate): a phase 2, randomised, controlled trial, Lancet 387(10038):2630-2640, 2016. Khanna D et al: Autologous hematopoietic stem cell therapy in severe systemic sclerosis: ready for clinical practice? J Am Med Assoc 311:2485, 2014. Knobler RM et al: A randomized, double-blind, placebo-controlled trial of photopheresis in systemic sclerosis, J Am Acad Dermatol 54(5):793-799, 2006. Korn JH et al: Digital ulcers in systemic sclerosis: Prevention by treatment with bosentan, an oral endothelin receptor antagonist, Arthritis Rheum 50(12):3985-3993, 2004. Kowal-Bielecka O et al: Update of EULAR recommendations for the treatment of systemic sclerosis, Ann Rheum Dis 76:1327-1339, 2017. Le CH et al: Minocycline in early diffuse scleroderma, Lancet 352(9142):17551756, 1998.

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Levien TL: Phosphodiesterase inhibitors in Raynaud's phenomenon, Ann Pharmacother 40(7-8):1388-1393, 2006. Mayes MD et al: Minocycline is not effective in systemic sclerosis: results of an open-label multicenter trial, Arthritis Rheum 50(2):553-557, 2004. Matucci-Cerinic M et al: Bosentan treatment of digital ulcers related to systemic sclerosis: results from the RAPIDS-2 randomised, double-blind, placebo-controlled trial, Ann Rheum Dis 70(1):32-38, 2011. Melchor S et al: Validation of the 2013 American College of Rheumatology/European League Against Rheumatism classification criteria for systemic sclerosis in patients from a capillaroscopy clinic, Semin Arthritis Rheum 46:350-355, 2016. Mendoza FA et al: A prospective observational study of mycophenolate mofetil treatment in progressive diffuse cutaneous systemic sclerosis of recent onset, J Rheumatol 39(6):1241-1247, 2012. Nash RA et al: High-dose immunosuppressive therapy and autologous hematopoietic cell transplantation for severe systemic sclerosis: long-term follow-up of the US multicenter pilot study, Blood 110(4):1388-1396, 2007. Poelman CL et al: Intravenous immunoglobulin may be an effective therapy for refractory, active diffuse cutaneous systemic sclerosis, J Rheumatol 42(2):236-242, 2015. Pope JE et al: A randomized, controlled trial of methotrexate versus placebo in early diffuse scleroderma, Arthritis Rheum 44(6):1351-1358, 2001. Pope J et al: Imatinib in active diffuse cutaneous systemic sclerosis: results of a six-month, randomized, double-blind, placebo-controlled, proof-of-concept pilot study at a single center, Arthritis Rheum 63(11):3547-3551, 2011. Postlethwaite AE et al: A multicenter, randomized, double-blind, placebo-controlled trial of oral type I collagen treatment in patients with diffuse cutaneous systemic sclerosis: I. oral type I collagen does not improve skin in all patients, but may improve skin in late-phase disease, Arthritis Rheum 58(6):1810-1822, 2008. Prey S et al: Imatinib mesylate in scleroderma-associated diffuse skin fibrosis: a phase II multicentre randomized double-blinded controlled trial, Br J Dermatol 167(5):1138-1144, 2012. Scorza R et al: Effects of long-term cyclic iloprost therapy in systemic sclerosis with Raynaud's phenomenon: a randomized, controlled study, Clin Exp Rheumatol 19(5):503-508, 2001. Shenoy PD et al: Efficacy of tadalafil in secondary Raynaud's phenomenon resistant to vasodilator therapy: a double-blind randomized cross-over trial, Rheumatology 49(12):2420-2428, 2010. Spiera RF et al: Imatinib mesylate (Gleevec) in the treatment of diffuse cutaneous systemic sclerosis: results of a 1-year, phase IIa, single-arm, open-label clinical trial, Ann Rheum Dis 70(6):1003-1009, 2011. Steen VD et al: D-Penicillamine therapy in progressive systemic sclerosis (scleroderma): a retrospective analysis, Ann Intern Med 97(5):652-659, 1982. Stratton RJ et al: Pilot study of anti-thymocyte globulin plus mycophenolate mofetil in recent-onset diffuse scleroderma, Rheumatology 40(1):84-88, 2001. Sullivan KM et al: Myeloablative autologous stem-cell transplantation for severe scleroderma, N Engl J Med 378:35, 2018. Teh LS et al: Sustained-release transdermal glyceryl trinitrate patches as a treatment for primary and secondary Raynaud's phenomenon, Br J Rheumatol 34(7):636-641, 1995. Thompson AE, Pope JE: Calcium channel blockers for primary Raynaud's phenomenon: a meta-analysis, Rheumatology 44(2):145-150, 2005. van den Hoogen FH et al: Comparison of methotrexate with placebo in the treatment of systemic sclerosis: a 24-week randomized double-blind trial followed by a 24-week observational trial, Br J Rheumatol 35(4):364-372, 1996. Van Laar JM et al: Autologous hematopoietic stem cell transplantation vs intravenous pulse cyclophosphamide in diffuse cutaneous systemic sclerosis: a randomized clinical trial, J Am Med Assoc 311:2490-2498, 2014. https://doi.org/1001/JAMA. 6368. van Laar JM et al: Autologous stem cell transplantation International scleroderma (ASTIS) trial: Hope on the horizon for patients with severe systemic sclerosis, Ann Rheum Dis 64(10):1515, 2005.

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FIG. E1  Sclerodactyly in a patient with systemic sclerosis. (From Hochberg MC, et al.: Rheumatology, ed 5, St Louis, 2011, Mosby.)

A

B

C

D

FIG. E2  Skin involvement in scleroderma is subdivided into “limited” and “diffuse” cutaneous forms. A, Sclerodactyly in limited cutaneous disease. B, Truncal changes in diffuse cutaneous disease. C, Inflammatory signs in early active skin disease. D, Finger contracture in the chronic fibrotic phase of skin involvement in scleroderma. (From Firestein GS, et al.: Kelly’s textbook of rheumatology, ed 9, Philadelphia, 2013, Saunders.)

Scleroderma (Systemic Sclerosis)

A

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C

B

D

FIG.E3  Method used to semi-quantify skin thickness in scleroderma. The modified Rodnan skin score is obtained by clinical palpation of 17 different body areas (fingers, hands, forearms, upper arms, chest, abdomen, thighs, lower legs, and feet) and subjective averaging of the thickness of each specific site: 0 = normal (A); 1 = mild (B); 2 = moderate (C); and 3 = severe (D). The maximum score is 51. (From Firestein GS, et al.: Kelly’s textbook of rheumatology, ed 9, Philadelphia, 2013, Saunders.)

B

A

C

D

FIG. E4  Oral manifestations. A, Perioral skin tightening with decreased oral aperture, furrowing around the lips, and dry membranes. B, Periodontal disease with regression of gum and loosening of teeth. C and D, Telangiectasias on lips and tongue. (From Firestein GS, et al.: Kelly’s textbook of rheumatology, ed 9, Philadelphia, 2013, Saunders.)

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TABLE E1  Overview of Musculoskeletal Complications of Systemic Sclerosis Manifestation

Clinical Features

Serologic Associations

Contractures

Typical feature of dcSSc Associated with ARA positivity Palmar fibrosis Overlap arthritis May resemble RA in overlap Associated with RF positivity and ACPA positivity More with U1RNP reactivity Contributes to deformity and contractures May have Jaccoud pattern but with fixed deformity Minor elevation in CK common, especially in dcSSc Weakness and loss of muscle bulk Severe myositis less frequent Overlap syndromes with myositis most common Serologic associations include anti–PM-Scl, ­anti-U1RNP, anti-fibrillarin More common in environmentally triggered SSc Association with vasculopathy and Raynaud p­ henomenon Possible association with calcinosis

ARA, ATA, RF, ACPA

Tendonitis or tendon friction rubs Arthritis

Myositis

Acro-osteolysis

ARA U1RNP, ACPA, RF

U1RNP, PM-Scl, U3RNP

ACA, ATA

ACA, Anticentromere; ACPA, anti-cyclic citrullinated protein antibody; ARA, anti-RNA polymerase III antibody; ATA, antitopoisomerase; CK, creatine kinase; dcSSc, diffuse cutaneous systemic sclerosis; PM-Scl, anti-polymyositis scleroderma antibody; RA, rheumatoid arthritis; RF, rheumatoid factor; SSc, systemic sclerosis; U1RNP, anti-U1-ribonucleoprotein antibody; U3RNP, anti-U3-ribonucleoprotein antibody. From Hochberg MC: Rheumatology, ed 7, Philadelphia, 2019, Elsevier.

TABLE E2  Patterns of Parenchymal Lung Involvement in Systemic Sclerosis Classification

HRCT Appearance

Frequency (%)

Outcome

Treatment

NSIP

Homogeneous interstitial shadowing with traction bronchiectasis and predilection for bases and subpleural locations

50

Variable depending on extent of disease

UIP

Heterogeneous interstitial shadowing with architectural distortion, traction ­bronchiectasis, and cystic changes

15

Variable depending on extent of disease and may have worse outcome than NSIP but not as much as in IPF

OP

Patchy and asymmetric changes with ­homogeneous appearance and later patchy scarring

5

Potential for improvements and recovery if treated effectively

PF with ­emphysema

Interstitial fibrotic change that may have NSIP or UIP features and is associated with ­airspace enlargement and ­ concurrent emphysematous change

10

Variable depending on extent and severity

Pleuroparenchymal fibroelastosis

Interstitial fibrosis with additional ­ pleural-based dense fibrosis and scarring extending to the upper zones

1

Progressive and difficult to treat with poor outcome

Aspiration ­pneumonia

Asymmetric changes often associated with esophageal dilatation; leaves patchy ­ scarring

20

Potential for i­mprovements and recovery if treated effectively; may be a­ ggravated by ­immunosuppression

Supportive Antireflux MMF or CYC RTX Experimental agents Supportive Antireflux MMF or CYC RTX Experimental agents Steroids and anti-infective ­treatment MMF or CYC if associated with significant fibrosis Supportive Antireflux MMF or CYC RTX for fibrosis Manage airway disease ­according to severity and responsiveness Supportive Antireflux MMF or CYC RTX for fibrosis Vigorous antireflux and acid suppressive therapy Prophylactic antibiotics and prompt treatment of ­intercurrent infection

CYC, Cyclophosphamide; IPF, idiopathic pulmonary fibrosis; MMF, mycophenolate mofetil; NSIP, nonspecific interstitial pneumonia; OP, organizing pneumonia; PF, pulmonary fibrosis; RTX, rituximab; UIP, usual interstitial pneumonia. From Hochberg MC: Rheumatology, ed 7, Philadelphia, 2019, Elsevier.

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MANIFESTATIONS OF SSc AFFECTING THE GI TRACT

Baseline assessment

SSc manifestations

History, trial of PPI therapy, endoscopy, manometry, MUST evaluation

Distention and bloating

GAVE or anemia

Weight loss and malnutrition Constipation Common comorbidities

Gastroesophageal reflux and dysphagia

Orodental complications

Exocrine pancreatic insufficiency Anorectal incontinence

Barrett metaplasia

Diverticular disease

Diarrhea

Rectal prolapse

Sigmoid volvulus

FIG. E5  Manifestations of systemic sclerosis within the gastrointestinal (GI) tract are frequent and require careful assessment. The major features are summarized for the upper, mid-, and lower GI tract along with important comorbidities that may need additional assessment and treatment. GAVE, Gastric antral vascular ectasia; MUST, Malnutrition Universal Screening Tool; PPI, proton pump inhibitor. (From Hochberg MC: Rheumatology, ed 7, Philadelphia, 2019, Elsevier.)

ASSESSMENT AND TREATMENT OF CARDIAC INVOLVEMENT IN SSc Suspected cardiac disease Syncope Hypotension ECG abnormality Chest pain (pericarditic) Troponin T, Nt-pro BNP

Background therapy; consider: Role of CCBs uncertain Diastolic dysfunction: diuretics Systolic dysfunction: ACEi, ?carvedilol, ?selective beta blocker LVEF less than 50% Left heart catheter, endomyocardial biopsy Elevated troponin Immunosuppression (cyclophosphamide, MMF) Dual-chamber pacemaker

Consider implantable loop recorder

Echocardiogram 24-hour tape Cardiac catheterization Cardiac MRI Endomyocardial biopsy

Significant ventricular arrhythmia Reduced systolic function and ICD Significant bradycardia Pacemaker

FIG. E6  Cardiac manifestations of systemic sclerosis (SSc) are common but can be challenging to diagnose and manage. This is because minor changes in rate or imaging may not be significant, and other manifestations can be unpredictable. Cardiac involvement should be investigated systematically, and hemodynamically significant disease may be treated as outlined in the figure. The use of loop recording reveal devices in cases with suspected sporadic significant arrhythmias may be considered to identify patients who may benefit from an implantable defibrillator (ICD). ACEI, Angiotensin-converting enzyme inhibitor; CCB, calcium channel blocker; ECG, electrocardiogram; LVEF, left ventricular ejection fraction; MMF, mycophenolate mofetil; MRI, magnetic resonance imaging; Nt-pro BNP, N-terminal pro b-type natriuretic peptide. (From Hochberg MC: Rheumatology, ed 7, Philadelphia, 2019, Elsevier.)

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TABLE E6  Vascular Therapies for Raynaud Phenomenon Treatment

Examples

Comments

Nondrug

Hand warmers, ­protective clothing Evening primrose oil Fish oil capsules Antioxidant vitamins

Universally helpful

Nutritional

Pharmacologic Agents for Raynaud Phenomenon Calcium channel blockers Nifedipine, ­amlodipine, diltiazem Angiotensin-converting enzyme inhibitors (quinapril) Angiotensin receptor blockers Losartan Selective serotonin reuptake Fluoxetine inhibitor Topical nitrates Nitroglycerin patch MQX-503, topical nitroglycerin Treatment for Ulcers Phosphodiesterase inhibitors

Sildenafil, tadalafil

Parenteral vasodilators

Iloprost, ­prostaglandin E1, treprostinil

Endothelin receptor antagonists

Bosentan

Statins Local management of ulcers

Surgical Procedures Radical microarteriolysis, d­ igital sympathectomy Autologous adipose–derived ­stromal injections and fat grafting Botulinum toxin A (Botox) ­“sympathectomy” Debridement, amputation

Reference

Grade*

Variable and differential response to different agents; slow titration of dose reduces the severity of adverse effects No evidence of effectiveness

1

A

2

A

Effective in clinical trial but limited effectiveness in practice Readily available; clinically less effective but fewer adverse ­vasodilatory effects than calcium channel blockers Long-acting patch helpful but many side effects; multiple studies new agent with significant results but not approved by FDA

3 4

A A

5, 6

A

Clinical trials show improvement in Raynaud manifestations and ulcer healing Effective in healing ulcers and reducing severity and f­requency of Raynaud attacks; expensive with limited long-term benefit (not available in U.S.) Clinical trials show decrease in new ulcers but no effect on healing (approved for prevention of ulcers in Europe but not in U.S.) Single study showing decreased occurrence of ulcers Wound-healing techniques, topical antibiotics, soaking, occlusion, debridement; systemic antibiotics as necessary; adequate ­analgesia (including narcotics if necessary)

7, 8

A

9

C

10, 11

A

12

A

Division of adventitia of digital arteries; sometimes termed digital sympathectomy. Useful treatment for i­ndividual critically ischemic digits; experimental treatment ­showing improved pain and mobility; phase 3 trial of adipose-derived stromal injections ongoing

13

B

14-16

B

Small studies promising but clinical trials needed

17

C

Symptoms improve Symptoms improve only in primary Raynaud, not scleroderma Theoretical benefit but no controlled trial evidence

Autoamputation is best to allow maximum preservation of healthy tissue. Surgery should be conservative and reserved for cases of infection or intractable pain.

*Findings of studies include these types of evidence: Level A: Randomized controlled clinical trial, cohort study. Level B: Retrospective cohort, exploratory cohort, outcomes research, case-control study; or extrapolations from level A studies. Level C: Case-series study or extrapolations from level B studies. Level D: Expert opinion without explicit critical appraisal; or based on physiology, bench research, or first principles. FDA, Food and Drug Administration. From Hochberg MC: Rheumatology, ed 7, Philadelphia, 2019, Elsevier. (1)Thompson AE, Pope JE: Calcium channel blockers for primary Raynaud's phenomenon: A meta-analysis. Rheumatology (Oxford) 44(2):145–150, 2005. (2)Gliddon AE, et al.: Prevention of vascular damage in scleroderma and autoimmune Raynaud's phenomenon: A multicenter, randomized, double-blind, placebo-controlled trial of the angiotensinconverting enzyme inhibitor quinapril. Arthritis Rheum 56(11):3837–3846, 2007. (3)Dziadzio M, et al.: Losartan therapy for Raynaud's phenomenon and scleroderma: Clinical and biochemical findings in a fifteen-week, randomized, parallel-group, controlled trial. Arthritis Rheum 42(12):2646–2655, 1999. (4)Coleiro B, et al.: Treatment of Raynaud's phenomenon with the selective serotonin reuptake inhibitor fluoxetine. Rheumatology (Oxford) 40(9):1038–1043, 2001. (5)Teh LS, et al.: Sustained-release transdermal glyceryl trinitrate patches as a treatment for primary and secondary Raynaud's phenomenon. Br J Rheumatol 34(7):636–641, 1995. (6)Chung L, et al.: MQX-503, a novel formulation of nitroglycerin, improves the severity of Raynaud's phenomenon: A randomized, controlled trial. Arthritis Rheum 60(3):870–877, 2009. (7)Levien TL: Phosphodiesterase inhibitors in Raynaud's phenomenon. Ann Pharmacother 40(7-8):1388–1393, 2006. (8)Shenoy PD, et al.: Efficacy of tadalafil in secondary Raynaud's phenomenon resistant to vasodilator therapy: A double-blind randomized cross-over trial. Rheumatology (Oxford). 2010;49(12):2420–2428. (9)Scorza R, et al.: Effects of long-term cyclic iloprost therapy in systemic sclerosis with Raynaud's phenomenon: A randomized, controlled study. Clin Exp Rheumatol 19(5):503–508, 2001. (10)Korn JH, et al.: Digital ulcers in systemic sclerosis: Prevention by treatment with bosentan, an oral endothelin receptor antagonist. Arthritis Rheum 50(12):3985–3993, 2004. (11)Matucci-Cerinic M, et al.: Bosentan treatment of digital ulcers related to systemic sclerosis: Results from the RAPIDS-2 randomised, double-blind, placebo-controlled trial. Ann Rheum Dis 70(1):32– 38, 2011. (12)Abou-Raya A, et al.: Statins: Potentially useful in therapy of systemic sclerosis-related Raynaud's phenomenon and digital ulcers. J Rheumatol 35(9):1801–1808, 2008. (13)Bogoch ER, Gross DK: Surgery of the hand in patients with systemic sclerosis: Outcomes and considerations. J Rheumatol 32(4):642–648, 2005. (14)Granel B, et al.: Safety, tolerability and potential efficacy of injection of autologous adipose-derived stromal vascular fraction in the fingers of patients with systemic sclerosis: An open-label phase I trial. Ann Rheum Dis 74(12):2175–2182, 2015. (15)Bene MD, et al.: Autologous fat grafting for scleroderma-induced digital ulcers: An effective technique in patients with systemic sclerosis. Handchir Mikrochir Plast Chir 46(4):242–247, 2014. (16)Guillaume-Jugnot P, et al.: Autologous adipose-derived stromal vascular fraction in patients with systemic sclerosis: 12-month follow-up. Rheumatology (Oxford) 55(2):301–306, 2016. (17)Iorio ML, et al.: Botulinum toxin A treatment of Raynaud's phenomenon: A review. Semin Arthritis Rheum 41(4):599–603, 2012.

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TABLE E7  Evidence-Based Review of Immunomodulatory and Antifibrotic Strategies for Disease-modifying Treatment of Systemic Sclerosis Skin Disease Agent Immunomodulatory Agents Methotrexate Mycophenolate Rituximab

Immunoablation

Cyclosporine Intravenous immunoglobulin Extracorporeal photopheresis Oral induction of tolerance to type I collagen Anti–IL-6, tocilizumab

Clinical Trial Data

Reference

Grade*

Placebo-controlled trial, 30 patients; significant improvement in skin score Larger North American study; inconclusive results Favorable outcomes in skin, lung, and survival rate in uncontrolled trials and o­ bservational cohorts Small, open, randomized trial showed favorable skin and lung outcomes, but p­ rospective open study found no effect on skin Observational cohort study found positive effect on joints, skin, and PFTs Observational experience marked improvement in skin Small, short-term study comparing stem cell transplantation with high-dose i­ntravenous cyclophosphamide (Cytoxan); very favorable results ASTIS controlled trial with improved skin and survival Open study, 10 patients; improvement in skin score Improved skin and joint status in open study First study suggested benefit but later evaluation equivocal Favorable pilot data; trial results positive for late-stage disease

18 19 20, 21

A A B

22, 23

B

24 25 26

A B A

27 28 29 30 31

A C C A A

Phase 2 trial with improved skin and less loss of lung function

32

A

Antifibrotic Agents d-Penicillamine

Uncontrolled studies with positive effects but controlled trial without evidence of response

Minocycline

Small, open study with cured patients but larger uncontrolled study showing no effect

Tyrosine kinase

Variable effects in several uncontrolled inhibitor trials showing increased toxicity and a controlled trial that was negative

33 34 35 36 37, 38, 39

B A C B B

A

*Findings of studies include these types of evidence: Level A: Randomized controlled clinical trial, cohort study. Level B: Retrospective cohort, exploratory cohort, outcomes research, case-control study; or extrapolations from level A studies Level C: Case-series study or extrapolations from level B studies Level D: Expert opinion without explicit critical appraisal; or based on physiology, bench research, or first principles ASTIS, Autologous Stem Cell Transplantation International Scleroderma Trial; IL-6, interleukin-6; PFT, pulmonary function test. From Hochberg MC: Rheumatology, ed 7, Philadelphia, 2019, Elsevier. (18)van den Hoogen FH, et al.: Comparison of methotrexate with placebo in the treatment of systemic sclerosis: a 24-week randomized double-blind trial followed by a 24-week observational trial. Br J Rheumatol 35(4):364–372, 1996. (19)Pope JE, et al.: A randomized, controlled trial of methotrexate versus placebo in early diffuse scleroderma. Arthritis Rheum 44(6):1351–1358, 2001. (20)Stratton RJ, et al.: Pilot study of anti-thymocyte globulin plus mycophenolate mofetil in recent-onset diffuse scleroderma. Rheumatology (Oxford) 40(1):84–88, 2001. (21)Mendoza FA, et al.: A prospective observational study of mycophenolate mofetil treatment in progressive diffuse cutaneous systemic sclerosis of recent onset. J Rheumatol 39(6):1241–1247, 2012. (22)Daoussis D, et al.: Experience with rituximab in scleroderma: results from a 1-year, proof-of-principle study. Rheumatology (Oxford) 49(2):271–280, 2010. (23)Spiera RF, et al.: Imatinib mesylate (Gleevec) in the treatment of diffuse cutaneous systemic sclerosis: results of a 1-year, phase IIa, single-arm, open-label clinical trial. Ann Rheum Dis 70(6):1003– 1009, 2011. (24)Pope J, et al.: Imatinib in active diffuse cutaneous systemic sclerosis: results of a six-month, randomized, double-blind, placebo-controlled, proof-of-concept pilot study at a single center. Arthritis Rheum 63(11):3547–3551, 2011. (25)van Laar JM, et al.: Autologous Stem Cell Transplantation International Scleroderma (ASTIS) trial: hope on the horizon for patients with severe systemic sclerosis. Ann Rheum Dis 2005;64(10):1515, 2005. (26)Khanna D, et al.: Safety and efficacy of subcutaneous tocilizumab in adults with systemic sclerosis (faSScinate): a phase 2, randomised, controlled trial. Lancet 387(10038):2630-2640, 2016. (27)van Laar JM, et al.: Autologous hematopoietic stem cell transplantation vs intravenous pulse cyclophosphamide in diffuse cutaneous systemic sclerosis: a randomized clinical trial. JAMA 311(24):2490–2498, 2014. (28)Clements PJ, et al.: Cyclosporine in systemic sclerosis. Results of a 48-week open safety study in 10 patients. Arthritis Rheum 36(1):75–83, 1993. (29)Poelman CL, et al.: Intravenous immunoglobulin may be an effective therapy for refractory, active diffuse cutaneous systemic sclerosis. J Rheumatol 42(2):236–242, 2015. (30)Knobler RM, et al.: A randomized, double-blind, placebo-controlled trial of photopheresis in systemic sclerosis. J Am Acad Dermatol 54(5):793–799, 2006. (31)Burt RK, et al.: Autologous non-myeloablative haemopoietic stem-cell transplantation compared with pulse cyclophosphamide once per month for systemic sclerosis (ASSIST): an open-label, randomised phase 2 trial. Lancet 378(9790):498–506, 2011. (32)Dees C, et al.: Stimulators of soluble guanylate cyclase (sGC) inhibit experimental skin fibrosis of different aetiologies. Ann Rheum Dis 74(8):1621–1625, 2015. (33)Steen VD, et al.: D-Penicillamine therapy in progressive systemic sclerosis (scleroderma): a retrospective analysis. Ann Intern Med 97(5):652–659, 1982. (34)Clements PJ, et al.: High-dose versus low-dose D-penicillamine in early diffuse systemic sclerosis: analysis of a two-year, double-blind, randomized, controlled clinical trial. Arthritis Rheum 42(6):1194–1203, 1999. (35)Le CH, et al.: Minocycline in early diffuse scleroderma. Lancet 352(9142):1755–1756, 1998. (36)Mayes MD, et al.: Minocycline is not effective in systemic sclerosis: results of an open-label multicenter trial. Arthritis Rheum 50(2):553–557, 2004. (37)Prey S, et al.: Imatinib mesylate in scleroderma-associated diffuse skin fibrosis: a phase II multicentre randomized double-blinded controlled trial. Br J Dermatol 167(5):1138–1144, 2012. (38)Postlethwaite AE, et al.: A multicenter, randomized, double-blind, placebo-controlled trial of oral type I collagen treatment in patients with diffuse cutaneous systemic sclerosis: I. oral type I collagen does not improve skin in all patients, but may improve skin in late-phase disease. Arthritis Rheum 58(6):1810–1822, 2008. (39)Nash RA,et al.: High-dose immunosuppressive therapy and autologous hematopoietic cell transplantation for severe systemic sclerosis: long-term follow-up of the US multicenter pilot study. Blood 110(4):1388–1396, 2007.

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TABLE E8  Treatment of Gastrointestinal Tract Complications in Systemic Sclerosis Site

Disorder

Symptom

Investigation

Treatment

Mouth

Tight skin Dental caries Sicca syndrome Dysmotility or esophageal spasm Reflux esophagitis Stricture

Cosmetic Toothache Dry mouth Dysphagia Heartburn Dysphagia

None Dental radiograph Salivary gland biopsy Barium swallow Esophageal scintigraphy Manometry, endoscopy

Stomach

Gastroparesis

Anorexia, nausea, early satiety

Scintigraphy

Pain Severe anemia, silent blood loss Weight loss

Endoscopy, barium UGI Endoscopy

Small bowel

NSAID-related ulcer Gastric antral vascular ectasia or watermelon stomach Hypomotility

Facial exercises Dental treatment Artificial saliva PPIs Minimize NSAID and CCB use Elevate head of bed, avoid late meals Erythromycin (as motility agent), metoclopramide, domperidone, PPIs PPIs Laser coagulation

Stasis

Postprandial bloating

14C

Bacterial overgrowth

Malabsorption

NSAID enteropathy Pseudo-obstruction

Jejunal aspiration Fecal microscopy Plain abdominal r­ adiography Plain abdominal r­ adiography

Barium enema, CT of a­ bdomen Plain abdominal r­ adiography Rectal manometry

Esophagus

Large bowel

Hypomotility

Steatorrhea Abdominal pain Distention Diarrhea with blood, benign pneumoperitoneum Alternating constipation and diarrhea

Anus

Colonic pseudodiverticula Pseudo-obstruction Sphincter involvement

Rare perforation Abdominal pain, distention Fecal incontinence

Pneumatosis intestinalis

Barium follow-through

glycocholate or h­ ydrogen breath tests Breath tests

Barium enema, CT of a­ bdomen

Rotational antibiotics, metronidazole, ciprofloxacin, rifaximin, octreotide (low dose) for severe disease; TPN in rare cases

Domperidone, metoclopramide, rotational antibiotics, metronidazole, ciprofloxacin, rifaximin Oral nutritional supplements Parenteral nutritional support Conservative management Dietary manipulation, stool expanders for constipation, loperamide for diarrhea Resection as a last resort Conservative management Kegel exercises, protective measures, sacral nerve stimulation

CCB, Calcium channel blocker; CT, computed tomography; NSAID, nonsteroidal antiinflammatory drug; PPI, proton pump inhibitor; TPN, total parenteral nutrition. From Hochberg MC: Rheumatology, ed 7, Philadelphia, 2019, Elsevier.

Scleroderma (Systemic Sclerosis)

1241.e9

TABLE E9 Approved Therapies for Treatment of Pulmonary Arterial Hypertension Class of Drug

Drug

Route of Administration

Main Adverse Effects

Comments

Endothelin receptor antagonists

Bosentan

Oral twice a day

Nonselective ETA and ETB blockade

Ambrisentan

Oral daily dose

Macitentan

Oral daily dose

Sildenafil, PDE5 inhibitor

Oral: 3 times a day

Tadalafil, PDE 5 inhibitor

Oral: Once daily

LFT abnormalities in up to 10% ­(bosentan); reduces oral ­anticoagulant efficacy (bosentan); potentially t­eratogenic; fluid retention and anemia Potentially teratogenic; fluid retention and anemia Potentially teratogenic; fluid retention and anemia Headache, visual disturbance, epistaxis; generally well tolerated Headache, visual disturbance, epistaxis

Riociguat, guanylin cyclase stimulator

Oral: Twice a day

Headache, hypotension, bleeding

Epoprostenol

Continuous IV infusion

Treprostinil

SC or IV infusion Nebulized inhaled: 4 times a day Oral: 3 times a day

Iloprost

Nebulized inhaled: 6-9 times a day Oral: 60 μg a day Oral: Twice a day

Headaches, muscle cramps, diarrhea; severe worsening if infusion interrupted; sepsis and other risks from IV administration Headaches, muscle cramps, diarrhea; worsening if infusion interrupted but less immediate than with epoprostenol; sepsis and other risks from IV administration; severe local site pain from SC infusion Headaches, muscle cramps, diarrhea

Nitric oxide ­stimulation

Prostacyclin ­analogues

Beraprost Selexipag, prostacyclin receptor stimulator

Headaches, muscle cramps, diarrhea Headaches, muscle cramps, diarrhea

Partially selective ERA with specificity for ETA Nonselective ETA and ETB blockade (more tissue-specific) Different formulation licensed for erectile dysfunction Generally well tolerated; longer duration of action than sildenafil Cannot be used with PDE5 inhibitors reserved for severe disease Reserved for severe ­disease; Side effects for all ­prostacyclins are similar and often limit dose

Inhaled drug PAH Licensed only in Japan Recently approved; will need to see if as effective as IV drugs

ERA, Endothelin receptor antagonist; ETA, endothelin receptor type A; ETB, endothelin receptor type B; IV, intravenous; LFT, liver function test; PAH, pulmonary arterial hypertension; PDE5, phosphodiesterase type 5; SC, subcutaneous. From Hochberg MC: Rheumatology, ed 7, Philadelphia, 2019, Elsevier.

1242

Scoliosis

ALG

BASIC INFORMATION DEFINITION Scoliosis is a three-dimensional spine deformity characterized by lateral and rotational curvature of the spine. The two main types are adolescent idiopathic scoliosis (AIS) and adult degenerative scoliosis (ADS), which are distinguished by age of onset. Scoliosis may be classified as either structural (fixed, nonflexible) or nonstructural (flexible, correctable, and secondary to nonspinal pathology). Scoliosis is often detected on physical examination (Adams forward bend test) and confirmed radiographically. ICD-10CM CODES M41 Scoliosis M41.0 Infantile idiopathic scoliosis M41.1 Juvenile idiopathic scoliosis M41.20 Other idiopathic scoliosis, site unspecified M41.3 Thoracogenic scoliosis M41.40 Neuromuscular scoliosis, site unspecified M41.80 Other forms of scoliosis, site unspecified Q67.5 Congenital deformity of spine

EPIDEMIOLOGY & DEMOGRAPHICS (IDIOPATHIC FORM) PREDOMINANT SEX: The incidence of AIS is similar in males and females; however, females have up to a tenfold greater risk of curve progression. Females are roughly seven times as likely to require orthopedic surgical intervention for idiopathic scoliosis. ADS has an equal gender distribution. PREVALENCE: 1.5% to 3% of adolescents PREDOMINANT AGE: • Onset variable • Most curves found in adolescents (age ≥11 yr) PHYSICAL FINDINGS & CLINICAL PRESENTATION • Typical presentation involves postural complaints rather than pain or neurologic symptoms. • Record patient age (in yrs plus mos) and height.

A

B

C

• Perform neurologic examination to rule out neuromuscular disease. • Inspect the shoulders and iliac crests to determine if they are level. • Palpate the spinous processes to determine their alignment. • Have the patient bend forward at the waist to approximately 45 degrees with the arms hanging free (Adams position); observe from the back to detect whether one side of the back appears higher than the other (Fig. 1). • May repeat forward bending test in a sitting position to eliminate leg length inequality.

ETIOLOGY • 90% unknown, referred to as idiopathic (genetic) • Congenital spine deformity • Neuromuscular disease • Leg-length inequality • Local inflammation or infection • Acute pain (disk disease) • Chronic degenerative disk disease with asymmetric disk narrowing Curves of an idiopathic nature or those accompanying congenital deformity or neuromuscular disease are associated with structural changes. The nonstructural types (leg-length discrepancy, muscle spasm, inflammation, or acute pain) disappear when the offending disorder is corrected.

DIAGNOSIS WORKUP • Curvatures associated with congenital spine abnormalities, neuromuscular disease, and other less common forms of scoliosis can usually be identified by history or associated radiographic or physical findings. • The diagnosis of scoliosis is suspected on the basis of physical examination and confirmed by radiography performed while the patient is in a standing position. Physical examination with the Adams forward bend test and scoliometer measurement can identify scoliosis, and the radiologic testing for Cobb angle measurement can confirm the diagnosis. The Cobb angle is measured on a thoraco-lumbar radiograph and is defined as the intersecting angle between lines drawn parallel to the endplates of the two

D

FIG. 1  Structural changes in idiopathic scoliosis. A, As curvature increases, alterations in body configuration develop in both the primary and compensatory curve regions. B, Asymmetries of shoulder height, waistline, and the elbow-to-flank distance are common findings. C, Vertebral rotation and associated posterior displacement of the ribs on the convex side of the curve are responsible for the characteristic deformity of the chest wall in scoliosis patients. D, In the school screening examination for scoliosis, the patient bends forward at the waist. Rib asymmetry of even a small degree is obvious.

vertebrae with the greatest amount of tilt. The Risser grade measures ossification of the iliac apophysis. It consists of five grades ranging from 25% ossification in grade 1 to full ossification of the apophysis in grade 5. Lower Risser scores are associated with higher spinal growth potential. Patients with Risser scores of 0 or 1 are at greatest risk of scoliosis curve progression. Scoliosis screening is described in Fig. 2.

IMAGING STUDIES • PA, lateral, and side-bending radiographs of the entire spine and pelvis. • There is high potential for repeated radiation exposure in adolescents evaluated for scoliosis. Use breast and gonadal shielding whenever possible. If you are referring to a specialist that will be unable to view the images obtained, instruct the patient’s family to bring a printed copy to their visit. • Diagnosis of idiopathic scoliosis is confirmed by a Cobb angle greater than 10 degrees as measured on a radiograph. • Severity of the curve is measured in degrees, usually by the Cobb method (Fig. 3). • MRI is usually not indicated unless there is pain, neurologic deficit, or a left thoracic curve (which is often associated with an underlying spinal disorder).

TREATMENT ACUTE GENERAL Rx • Treatment or correction of cause if curve is nonstructural • Early detection is key in treating genetic (idiopathic) curve • Regular observation for curves 45 degrees in patients with an immature skeleton DISPOSITION • The larger the curve at detection, the greater the chance of progression. • Progression is more common in young children who are beginning their growth spurt. • Curves in females are more likely to progress. • Curves 50% of the time. • Failure to diagnose and treat these curves may allow progressive deformity, pain, and cardiopulmonary compromise to develop. • Spinal deformities >50 degrees in adults may progress and eventually become painful or compromise pulmonary function. • There is no difference in the rate of back pain in the general population and patients with adolescent idiopathic scoliosis. REFERRAL Refer for orthopedic consultation if structural curve >20 degrees is present or if structural curve 4° C or >40° F • Risk factors for more severe reaction 1. Immunocompromised 2. Patients with preexisting chronic pulmonary conditions 3.  Medications that inhibit metabolism of histamine 4. Chronic diseases impairing normal cardiac response to hypotension PHYSICAL FINDINGS & CLINICAL PRESENTATION • Typically within 30 min to 1 hour after ingestion, patients will experience symptoms of overwhelming levels of histamine that include: 1. Metallic or peppery taste 2. Cutaneous flushing 3. Urticarial rash 4. Perioral burning or edema 5. Tachycardia/palpitations 6. Dizziness 7. Headache 8. GI symptoms: Abdominal pain, nausea, vomiting, diarrhea 9. Hypotension • Rarer symptoms 1. Bronchospasm 2. Cardiac arrhythmias 3. Shock ETIOLOGY There are certain types of fish whose flesh naturally has high levels of histidine. When they are not stored properly, bacteria (generally gram-

negative Enterobacteriaceae) can grow and metabolize histidine into histamine. Once histamine is present, cooking, freezing, smoking will NOT destabilize it. Extent of poisoning is related to the quantity of histamine ingested, which is dependent on the growth of bacteria producing histamine and the amount of fish ingested. Fish known to cause scombroid poisoning include: • Scombridae family 1. Tuna 2. Mackerel 3. Bonito • Other examples 1. Mahi-mahi 2. Anchovies 3. Sardines 4. Albacore 5. Marlin 6. Herring • Cheese 1. Most notably, Swiss cheese

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • Allergic reaction/anaphylaxis • Asthma exacerbation • Serum sickness • Angioedema • Ciguatera poisoning • Table 1 summarizes marine biotoxins WORKUP • Unnecessary for diagnosis, however can obtain: 1. Plasma levels of histamine 2. Urine levels of histamine metabolites 3.  Plasma levels of tryptase: Should be negative in scombroid cases LABORATORY TESTS Not generally indicated unless there is a suspicion of intentional overdose IMAGING STUDIES Generally not indicated

TREATMENT • Supportive care • Antihistamines (PO if patient can tolerate) 1. H1 blocker: Benadryl 2. H2 blocker: Ranitidine, cimetidine, famotidine 3. Can have patients take H1/H2 blockers scheduled after initial symptoms resolve to prevent recurrence • If patient becomes anaphylactic, may need crystalloids, steroids, and epinephrine • Hypotensive patients requiring fluids or epinephrine should be observed as an admit

NONPHARMACOLOGIC THERAPY Fluids, no known benefit of crystalloid type ACUTE GENERAL Rx H1 and H2 blocker (PO or IV)

DISPOSITION • Supportive care is normally sufficient. Symptoms should resolve in 1 to 2 days, and most patients can be discharged home if they have no airway compromise or hypotension during their stay and are observed to be improving. There is no standard of care for length of observation. • In cases of patients with preexisting illnesses or medications that predispose them to a more severe manifestation of the illness: 1. The duration of illness may be prolonged. 2. May need admission for observation until toxicity has resolved. REFERRAL The local health department should be notified when a scombroid case is suspected.

PEARLS & CONSIDERATIONS COMMENTS This is not a true allergy. Histamine already is present in the fish or cheese consumed, as opposed to a Type I hypersensitivity reaction, in which the patient’s immune system reacts to the fish’s antigens and generates histamine. In the case of scombroid, only the histamine consumed is part of the reaction. PREVENTION Store fish immediately after it is caught to prevent bacterial growth and conversion of histidine in dark meat into histamine (65 yr of age account for 60% of all cases of sepsis. GENETICS: • Familial disposition: A great variety of congenital immunodeficiency states and other inherited disorders may predispose to septicemia. • Neonatal infection: Incidence is high in neonatal period.

ICD-10CM CODES A41.9 Sepsis, unspecified organism A41.50 Gram-negative sepsis, unspecified A41.2 Sepsis due to unspecified ­Staphylococcus A41.4 Sepsis due to anaerobes A41.51 Sepsis due to Escherichia coli [E. coli] A41.52 Sepsis due to Pseudomonas A54.86 Gonococcal sepsis B37.7 Candidal sepsis A32.7 Listerial sepsis A40.0 Sepsis due to streptococcus, group A A40.1 Sepsis due to streptococcus, group B A40.3 Sepsis due to Streptococcus ­pneumoniae A40.8 Other streptococcal sepsis A40.9 Streptococcal sepsis, unspecified A41.01 Sepsis due to Methicillin susceptible Staphylococcus aureus A41.02 Sepsis due to Methicillin resistant Staphylococcus aureus

PHYSICAL FINDINGS & CLINICAL PRESENTATION • Fever or hypothermia • Hypotension • Tachycardia • Tachypnea • Altered mental status • Bleeding diathesis • Skin rashes • Symptoms that reflect primary site of infection: Urinary tract, GI tract, CNS, respiratory tract • Table 3 describes some clinical signs and symptoms of sepsis

EPIDEMIOLOGY & DEMOGRAPHICS INCIDENCE (IN U.S.): • Sepsis occurs in 6% of hospitalized patients; approximately half require ICU admission. • More than 1 million cases of sepsis occur each yr in the U.S. 15% of sepsis patients die in the hospital; 6% are discharged to hospice. PREDOMINANT SEX: Males are slightly more commonly affected than females.

ETIOLOGY • Disseminated infection with a great variety of bacteria: 1. Gram-negative bacteria: a.  Escherichia coli b.  Klebsiella spp. c.  Pseudomonas aeruginosa d.  Proteus spp. e.  Neisseria meningitides 2. Gram-positive bacteria: a.  Staphylococcus aureus (including MRSA) b.  Streptococcus spp. c.  Enterococcus spp. • Less common infections: 1. Fungal

TABLE 1  Proposed New Definitions of Sepsis Term

Definition

Criteria

Notes

Sepsisa

Life-threatening organ dysfunction caused by a dysregulated host response to infection

Organ dysfunction is identified as an acute change in the SOFA score, ≥2 points from the baseline consequent to the infection.

Septic shock

It is a subset of sepsis in which the underlying circulatory and ­cellular/metabolic ­abnormalities are profound enough to ­substantially increase mortality.

A clinical construct of sepsis with p­ ersisting hypotension requiring v­ asopressors to maintain MAP ≥65 mm Hg and having a serum lactate level ≥2 mmol/L despite adequate volume resuscitation

qSOFA (quick Sequential Organ Failure Assessment) Prolonged ICU stay or in-hospital mortality can be identified at the bedside with qSOFA. 1. Respiratory rate ≥22 breaths/min 2. Acute mental status change 3. Systolic blood pressure ≤100 mm Hg An increase in SOFA of ≥2 predicts a 10% mortality in the general hospital population. Presume a baseline SOFA of 0 unless the patient has known (acute or chronic) organ dysfunction before the onset of infection. Septic shock portends hospital mortality in excess of 40%.

­(previously severe sepsis)

aNote

that the proposed new definitions abandon the previous term “severe sepsis” to describe infection-induced organ dysfunction and now use “sepsis” in its place. The previous condition called “sepsis” is now just called “infection,” and when infection is not associated with organ dysfunction, there is no differentiation between infection with or without systemic manifestations. MAP, Mean arterial pressure. From Parrillo JE, Dellinger RP: Critical care medicine, principles of diagnosis and management in the adult, ed 5, Philadelphia, 2019, Elsevier.

1249

S

Diseases and Disorders

DEFINITION Sepsis is an exaggerated inflammatory response to an infectious stimulus. It is usually caused by generalized bacterial or fungal infection and characterized by evidence of infection, fever or hypothermia, hypotension, and evidence of end-organ compromise. The Sepsis Definitions Task Force in 2016 updated definitions for sepsis and septic shock (Table 1). A major change in the definitions is the elimination of mention of SIRS*. According to the new definitions, sepsis is now defined as evidence of infection plus life-threatening organ dysfunction, clinically codified by an acute change in 2 points or greater in the SOFA score (Table 2). The new clinical criteria for septic shock include sepsis with fluid, unresponsive hypotension, serum lactate level greater than 2 mmol/L, and the need for vasopressors to maintain mean arterial pressure of 65 mm Hg or greater.1,2

SYNONYMS Septicemia Sepsis syndrome Severe sepsis Systemic inflammatory response syndrome Septic shock

Sepsis

I

Sepsis

1250

ALG

TABLE 2  The Sequential Organ Failure Assessment (SOFA) Score Score

0

1

2

3

4

>400

≤400

≤300

≤200 With respiratory support

≤100

>150

≤150

≤100

≤50

≤20

204)

No hypotension

MAP 5 or epinephrine ≤0.1 or norepinephrine ≤0.1*

Dopamine >15 or epinephrine >0.1 or norepinephrine >0.1*

15

13-14

10-12

6-9

50,000 cells/mm3 with >80% polymorphonuclear cells. 2.  Counts are highly variable, with similar findings in gout, pseudogout, or rheumatoid arthritis. Lower WBC counts can occur in joint replacement, disseminated gonococcal disease, and peripheral leukopenia. 3. Synovial fluid glucose or protein is not helpful because results are not specific for septic arthritis. The differential diagnosis of synovial fluid abnormalities is described in Section IV. 4. PCR testing: Useful for detection of uncommon organisms (e.g., Lyme disease). 5. Crystal analysis: Septic arthritis can coexist with crystal arthropathy; therefore, the presence of crystals does not preclude a diagnosis of septic arthritis. • Blood cultures: Positive in 25% to 50% of patients with septic arthritis. • Culture of possible extraarticular sources of infection. • Elevated peripheral WBC count, ESR (nonspecific), C-reactive protein (CRP) (nonspecific). When elevated, ESR and CRP may be useful to monitor therapeutic response. • If gonococcus is suspected, perform nucleic acid amplification tests (NAATs) on synovial fluid.

IMAGING STUDIES • Radiograph of the affected joint (Fig. E3): Useful to rule out osteomyelitis, fractures, chondrocalcinosis, or inflammatory arthritis • MRI: Findings that suggest an acute intraarticular infection include the combination of bony erosions with marrow edema • CT scan: Useful for early diagnosis of infections of the spine, hips, and sternoclavicular and sacroiliac joints • Ultrasound: Can be useful for detecting effusions in joints that are more difficult to examine (e.g., hip)

TREATMENT NONPHARMACOLOGIC THERAPY • Affected joints aspirated daily to remove necrotic material and to follow serial WBC counts and cultures • If no resolution with IV antibiotics and closed drainage: Open debridement and lavage, particularly in nongonococcal infections • Prevention of contractures: 1. After acute stage of inflammation, rangeof-motion exercises of the affected joint 2. Physical therapy helpful ACUTE GENERAL Rx • IV antibiotics immediately after joint aspiration and Gram stain of the synovial fluid. Empiric antibiotic therapy (Table E1) is based on organism found on Gram stain of synovial fluid: 1. Gram-positive cocci: Vancomycin: 15 to 20 mg/kg IV q8 to 12h. Keep trough levels at 15 to 20 mcg/ml. Alternatives include daptomycin and linezolid 2. Gram-negative cocci: Ceftriaxone: 1 to 2 g IV q day in adults (children: 50 to 100 mg/ kg IV q day). Alternative includes cefotaxime 3. Gram-negative rods: Ceftriaxone, cefepime: 1 to 2 g IV q8 to 12h in adults (children: 100 to 150 mg/kg/day divided in q8h dosing), piperacillin-tazobactam: 3.375 g IV to 4.5 g IV q6h. Aztreonam or fluoroquinolones can be used in patients with allergy to penicillin or cephalosporins 4. Negative Gram stain: Vancomycin plus either cefepime or a carbapenem such as meropenem: 1 g IV q8h in adults (children: 60 mg/kg/day divided in q8h dosing) or ertapenem The optimal duration of antibiotic use in septic arthritis has traditionally been 3 to 6 wk usually following surgical drainage. Recent trials (Gjika et al, Ann Rheum Dis Aug 2019, 78: 1114) support a 2-wk course in conjunction with surgery. SUGGESTED READINGS Available at ExpertConsult.com RELATED CONTENT Septic Arthritis (Patient Information) AUTHOR: Glenn G. Fort, MD, MPH

ALG

Septic Arthritis

Diagnostic arthrocentesis: (always try to tap the joint dry) • Note which joint • Total volume of synovial fluid • Gross description of fluid, • bloody or nonbloody

S

Nonbloody fluid: Note color, turbidity, and viscosity

Diseases and Disorders

Bloody fluid: Consider the following differential diagnosis of hemarthrosis: • Trauma with or without fracture • Over-anticoagulation • Hemophilia • Other bleeding disorders • Pigmented villonodular synovitis or other tumors • Traumatic tap

1255

I

Synovial fluid WBC 50,000 WBC/mm3

Positive

Negative

Markedly inflammatory fluid: Consider empiric antibiotic therapy pending culture results

Noninflammatory to moderately inflammatory fluid: Consider a broad differential diagnosis from OA to RA. However, septic arthritis is less likely but still possible

Crystals? Under polarized light

Negative

Positive

Inflammatory arthritis not due to crystals

Gout or pseudogout at least

Gram stain and/or culture positive?

Gram stain and/or culture positive?

Negative

Positive Positive

Negative

Markedly inflammatory fluid not due to crystals or infection: Consider the other possibilities of pseudoseptic arthritis

Septic arthritis

Crystal-induced arthritis defined by the nature of the crystals

FIG. 2  Algorithm for synovial fluid analysis in septic arthritis. OA, Osteoarthritis; RA, rheumatoid arthritis; WBC, white blood cell count. (From Harris ED et al: Kelley’s textbook of rheumatology, ed 7, Philadelphia, 2005, Saunders.)

Septic Arthritis

1255.e1

1 – The hematogenous route. 2 – Dissemination from osteomyelitis. 3 – Spread from an adjacent soft tissue infection. 4 – Diagnostic or therapeutic measures. 5 – Penetrating damage by puncture or trauma.

1 2

4

5 3

FIG. E1  Routes by which bacteria can reach the joint. (From Hochberg MC et al: Rheumatology, ed 5, St. Louis, Mosby, 2011.)

A

B

C

FIG. E3  Septic arthritis (x-ray and magnetic resonance imaging [MRI]). A, X-ray in anteroposterior view of sacroiliac joints shows destruction of the right sacroiliac joint as part of septic arthritis (arrows). B, In another patient, short tau inversion recovery (STIR) coronal MRI through sacroiliac joints shows erosive changes in the right sacroiliac joint with extensive bone marrow edema. C and D, Tuberculous spondylitis. C, X-ray of the lumbar spine in lateral view shows disk space narrowing at the L3-L4 level with destructive changes involving the superior end plate of the L4 vertebral body (arrow). D, Coronal STIR MRI of the lumbar spine of the same patient confirms focal destruction of the L4 vertebral body (arrow). Enlargement of both psoas muscles (P) with increased signal is noted, owing to paraspinal extension of the infection. (From Firestein GS et al: Kelly’s textbook of rheumatology, ed 9, Philadelphia, 2013, Saunders.)

Septic Arthritis

1255.e2

TABLE E1  Recommended Empiric Therapy for Adult Native Joint Bacterial Arthritis Gram Stain

Preferred Antibiotic*

Gram-positive cocci

Vancomycin, 15-20 mg/kg (ABW) daily every 8-12

Gram-negative cocci§ Gram-negative rods¶

Ceftriaxone, 1 g every 24 hr Ceftazidime, 2 g every 8 hr or cefepime, 2 g every 8 hr or piperacillin-tazobactam, 4.5 g every 6 hr Vancomycin plus ceftazidime or cefepime

Gram stain negative¶

Alternative Antibiotic hr†

Daptomycin, 6-8 mg/kg daily™™ or linezolid, 600 mg IV or PO every 12 hr‡ Cefotaxime, 1 g every 8 hr║ Aztreonam, 2 g every 8 hr or fluoroquinolone or carbapenem Daptomycin‡ or linezolid‡ plus piperacillin-tazobactam or aztreonam or fluoroquinolone** or carbapenem

*Unless noted otherwise, dosages are IV for persons with normal renal function. †Therapeutic monitoring should target a serum trough of 15-20 mg/L. ‡For patients allergic to, or intolerant of, vancomycin. §Equivocal gram-negative morphology should be considered as gram-negative rods. ║ Gram-negative cocci with epidemiology or history suggestive of gonococcal infection should be initially treated per Centers for Disease Control and Prevention Sexually Transmitted Disease Guidelines. Alternative therapies have not been suggested for patients with a history of a Stevens-Johnson syndrome or severe IgE-mediated allergy to β-lactam antibiotics. Possible empiric options for penicillin-allergic patients, pending culture sensitivities, include azithromycin, ciprofloxacin, tobramycin, gentamicin, and spectinomycin (not available in U.S.). ¶For patients with risk factors for resistant gram-negative pathogens (significant health care exposure, immunosuppression, or history of extended-spectrum β-lactamase gram-negative infection or colonization), drug selection should consider regional or local antibiograms. **Ciprofloxacin, 400 mg IV q8h or 750 mg PO q12h or levofloxacin, 750 mg IV or PO q24h. Bennett JE et al: Mandell, Douglas, and Bennett’s principles and practice of infectious diseases, ed 8, Philadelphia, 2015, WB Saunders.

SUGGESTED READINGS Arnold JC, Bradley JS: Osteoarticular infections in children, Infect Dis Clin North Am 29:557-574, 2015. Costales C, Butler-Wu SM: A real pain: diagnostic quandaries and septic arthritis, J Clin Microbiol 56(2):e01358-17, 2018. Gjika E et  al: Two weeks versus four weeks of antibiotic therapy after surgical drainage for native joint bacterial arthritis: a prospective, randomized, noninferiority trial, Ann Rheum Dis 78(8):1114-1121, 2019. Hassan AS et  al: Peripheral bacterial septic arthritis: review of diagnosis and management, J Clin Rheumatol 23:435-442, 2017. Lim SY et  al: Septic arthritis in gout patients: a population-based cohort study, Rheumatology (Oxford) 54:2095-2099, 2015.

1256

Serotonin Syndrome BASIC INFORMATION DEFINITION Serotonin syndrome (SS) is a potentially lifethreatening condition resulting from excessive serotonergic stimulation of 5-HT1A and 5-HT2A receptors in the CNS and PNS. SS is a druginduced disorder that is classically characterized by mental status changes, neuromuscular hyperactivity, and autonomic dysfunction. SYNONYMS SS Hyperserotonemia Serotonergic syndrome Serotonin toxicity ICD-10CM CODES Y49 Adverse effects due to psychotropic drugs Y49.0 Adverse effects due to tricyclic and tetracyclic antidepressants Y49.1 Adverse effects due to monoaminooxidase-inhibitor antidepressants Y49.2 Adverse effects due to other and unspecified antidepressants Y49.3 Adverse effects due to phenothiazine antipsychotics and neuroleptics G25.89 Other specified extrapyramidal and movement disorders

EPIDEMIOLOGY & DEMOGRAPHICS • The true incidence of SS is not known, as clinical manifestations may go unnoticed or be attributed to another condition. • SS is seen in all age groups. • SS classically occurs in patients receiving two or more serotonergic drugs, but it can also occur with monotherapy—selective serotonin reuptake inhibitor (SSRI) monotherapy has an incidence of 0.5 to 0.9 cases of SS per 1000 patient-mo. Although there is an FDA alert, it has been argued that there is a lack of sufficient evidence showing that SSRIs and triptans cause serious SS. • Concomitant use of an SSRI with a monoamine oxidase inhibitor (MAOI) poses the greatest risk of developing SS. • Combination of SSRIs with other ­serotonergic drugs (e.g., tryptophan, illicit drugs like cocaine and MDMA, “Ecstasy”) or drugs with serotonergic properties (e.g., methylene blue, lithium, meperidine, triptans, linezolid) may also lead to SS. PHYSICAL FINDINGS & CLINICAL PRESENTATION • Findings of clonus with hyperreflexia in the setting of recent (38° C (100° F) to severe hyperthermia 3. Altered mental status: Anxiety, agitation, confusion, coma

ETIOLOGY • Hyperstimulation of the brain stem and spinal cord serotonin receptors leading to the neuromuscular and autonomic symptoms. • Psychopharmacologic drugs—in particular, fluoxetine and sertraline co-administered with MAOI (e.g., tranylcypromine and phenelzine)—have been cited as a common cause of SS. Triptans (serotonin-receptor agonists used in the treatment of migraines) may also precipitate the SS when used in combination with SSRIs and serotonin-norepinephrine reuptake inhibitors (SNRIs). Box 1 describes classes of medications that produce SS. BOX 1  Classes of Medications That Produce Serotonin Syndrome in Psychiatric Patients Selective serotonin reuptake inhibitors Monoamine oxidase inhibitors Atypical antipsychotics Heterocyclic antidepressants Trazodone Dual-uptake inhibitors Psychostimulants Buspirone Mood stabilizers Analgesics Antiemetics Cough suppressants Dietary supplements Linezolid From Goldman L, Schafer AI: Goldman-Cecil medicine, ed 24, Philadelphia, 2012, Saunders.

DIAGNOSIS • SS is a clinical diagnosis. There are no specific laboratory tests for SS. A high index of suspicion along with a detailed medication history is the mainstay of diagnosis. • Diagnostic criteria: Most accurate is Hunter Serotonin Toxicity Criteria (sensitivity 84%, specificity 97%, confirmation by toxicologist). Sternbach diagnostic criteria (Table 1) are also commonly used. • To fulfill Hunter criteria a patient must have consumed a serotonergic drug and have one of the following: 1. Spontaneous clonus 2. Inducible clonus plus agitation or diaphoresis 3. Ocular clonus plus agitation or diaphoresis 4. Tremor and hyperreflexia 5. Temperature >38° C (100° F) plus hypertonia plus ocular clonus or inducible clonus

DIFFERENTIAL DIAGNOSIS • Neuroleptic malignant syndrome (NMS), substance abuse (e.g., cocaine, amphetamines), anticholinergic toxicity, malignant hyperthermia, thyroid storm, infection (e.g., meningitis, encephalitis), alcohol and opioid withdrawal. • Classic features in differentiation of NMS from SS are that SS develops over 24 hr, involves neuromuscular hyperactivity (hyperreflexia, myoclonus), and begins to resolve within 24 hr with appropriate therapy, whereas NMS develops gradually over days to wks, involves sluggish neuromuscular response, and resolves over an average period of 1 wk to 10 days. WORKUP • Because SS is a clinical diagnosis, there is no laboratory test that confirms the diagnosis, and serum serotonin concentration does not correlate with the clinical picture. Other causes

TABLE 1  Criteria to Determine Serotonin Syndrome and Toxicity Sternbach diagnostic criteria for serotonin syndrome

Hunter criteria for serotonin toxicity (context of serotonergic medications)

1 . Recent addition or increase of proserotonergic medication 2. At least three of the following: 1. Agitation 2. Ataxia 3. Diaphoresis 4. Diarrhea 5. Hyperreflexia 6. Hyperthermia 7. Mental status changes 8. Myoclonus 9. Shivering 10. Tremor 3. Neuroleptic agent not added or dose increased before the onset of symptoms 4. Diagnosis of infections, withdrawal, and other poisoning or metabolic disruptions excluded 1. If patient has spontaneous clonus, serotonin toxicity present 2. If no spontaneous clonus, one of the following needed for a diagnosis of serotonin toxicity: 1. Inducible clonus and agitation or diaphoresis 2. Ocular clonus and agitation or diaphoresis 3. Tremor and hyperreflexia 4. Temperature >38° C and ocular clonus or inducible clonus

From Adams JG et al: Emergency medicine, clinical essentials, ed 2, Philadelphia, 2013, Elsevier.

Serotonin Syndrome are described in “Differential Diagnosis.” Thus, all patients should have blood tests and diagnostic imaging studies to rule out infectious, toxic, and metabolic causes. • Additional laboratory tests are performed to exclude complicating features of SS (e.g., renal failure secondary to rhabdomyolysis).

IMAGING STUDIES Imaging studies are not specific in the diagnosis of SS and are only ordered to exclude other causes with similar clinical presentations as SS.

TREATMENT • Once a diagnosis of SS is established, consultation with a medical toxicologist, clinical pharmacologist, and/or poison control center should be considered • Management includes: 1. Discontinue use of all potential precipitating drugs. 2. Provide supportive management. 3. Control agitation. 4. Administer serotonin antagonists. 5. Control autonomic instability. 6. Control hyperthermia. 7. Reassess the need to resume the use of the serotonergic agent once the symptoms have resolved.

NONPHARMACOLOGIC THERAPY • Discontinuation of the drug is the mainstay of therapy.

ACUTE GENERAL Rx • Benzodiazepines for control of agitation are preferred to physical restraints. 1. Lorazepam 1 to 2 mg IV every 30 min has been used effectively in treating agitation, muscle rigidity, myoclonus, and seizure complications. 2. Diazepam is an alternative choice. • Blood pressure management with short-acting agents such as esmolol and nitroprusside. • Serotonin antagonists should be titrated to clinical effectiveness in patients for whom nonpharmacologic therapy and benzodiazepines are not achieving adequate response, although substantial and rigorous data are lacking. 1. Cyproheptadine 4 mg tablet or 2 mg/5 ml syrup is given 12 mg initially followed by 2 mg every 2 hr until therapeutic response is achieved in adults (up to 32 mg/day); children ages 7 to 14 should receive 4 mg every 6 hr (up to 16 mg/ day), children ages 2 to 6 should receive 2 mg every 6 hr (up to 12 mg/day), and children younger than 2 yr should receive a maximum of 0.25 mg/kg/day as 0.06 mg/kg every 6 hr. 2. Atypical antipsychotic agents with serotonin antagonist properties (e.g., olanzapine 10 mg SL) have been tried with some success. 3. Chlorpromazine 50 to 100 mg IM may be considered in severe cases, but intravenous fluid loading is essential to prevent hypotension.

CHRONIC Rx For patients not requiring hospital admission, cyproheptadine and lorazepam can be given in an oral dose on a prn basis with close follow-up. DISPOSITION • SS is a potentially life-threatening condition if not recognized early, although it does exist on a spectrum. • Prompt diagnosis and withdrawal of the medication result in improvement of symptoms within 24 hr. • Seizures, rhabdomyolysis, hyperthermia, ventricular arrhythmia, respiratory arrest, and coma are all complicating features of SS. REFERRAL All cases of SS secondary to psychotropic medications should be referred to a psychiatrist. PREVENTION Modify prescription practices by avoiding multidrug regimens.

PEARLS & CONSIDERATIONS The combined use of SSRIs and MAOIs is contraindicated.

COMMENTS • The use of SSRIs and other serotonergic agents is not an absolute contraindication; however, prompt withdrawal of the medication is recommended if any symptoms suggesting SS occur. • SS is usually found in patients being treated for depression, bipolar disorders, obsessivecompulsive disorder, attention deficit disorder, and Parkinson disease. SUGGESTED READINGS Available at ExpertConsult.com AUTHORS: Neal Bucher, MD, and J. Richard Walker III, MD, MS, FACEP

S

Diseases and Disorders

LABORATORY TESTS • CBC with differential when considering sepsis • Urine and blood cultures • Electrolytes, BUN, and creatinine to rule out acidosis and renal failure • Coagulation studies to rule out disseminated intravascular coagulation • Blood and urine toxicology screen, including acetaminophen and salicylate levels if overdose was intentional • Thyroid function tests • C reatine-phosphokinase (CPK) with isoenzymes • ECG because ventricular rhythm disturbance is a potentially fatal complication • CSF studies to rule out meningitis

• Treatment is supportive: Maintaining oxygenation and blood pressure and monitoring respiratory status. Hypotensive patients may require both IV fluids and vasopressor therapy. • Patients who are severely hyperthermic with temperatures >41° C (106° F) should be given IV sedation, paralyzed, and intubated. Cooling blankets can be used for patients with mild to moderate hyperthermia. There is no role for acetaminophen here. • Intubation is recommended for patients unable to protect their airways as a result of mental status changes or seizures.

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Serotonin Syndrome SUGGESTED READINGS Ables AZ, Nagubilli R: Prevention, recognition, and management of serotonin syndrome, Am Fam Physician 181(9):1139-1142, 2010. Buckley NA et al: Serotonin syndrome, BMJ 348:g1626, 2014. Evans RW et  al: The FDA alert on serotonin syndrome with the use of triptans combined with selective serotonin reuptake inhibitors: American Headache Society position paper, Headache 50(6):1089-1099, 2010. Gillman PK: Triptans, serotonin agonists, and serotonin syndrome (serotonin toxicity): a review, Headache 50(2):264-272, 2010.

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Sexual Assault  BASIC INFORMATION DEFINITION Sexual assault is any sexual act performed against someone who has not freely given their consent or who is unable to give consent. SYNONYM Rape ICD-10CM CODES Y05  Sexual assault by bodily force Z04.41  Encounter for examination and observation following alleged adult rape Z04.42 Encounter for examination and observation following alleged child rape

EPIDEMIOLOGY & DEMOGRAPHICS INCIDENCE: 19% of women, 3% of men PEAK INCIDENCE: As high as 25% PREVALENCE (IN U.S.): 23 million women, 2.8 million men PREDOMINANT SEX AND AGE: Female, ages 12 to 34 RISK FACTORS: Alcohol/drug consumption, prior history of being sexually/physically abused, multiple sexual partners, involvement in sex work, poverty, incarceration/institutionalization, intellectual disability PHYSICAL FINDINGS & CLINICAL PRESENTATION • Extragenital trauma: 70%: Erythema, bruises, abrasions, lacerations, or fractures on thigh, arms, face, neck • Anogenital trauma: 27%: Injury to breasts, external genitalia, vagina, anus, rectum • Other: Pregnancy (5%), bullet wounds, death Physical findings more likely if examined within 72 hr of event, if event occurred outdoors, and if perpetrator was unknown

DIAGNOSIS WORKUP Preliminary issues and strategies in preparing for taking the history from a sexual assault victim (SAV) are described in Box E1. Consent issues are summarized in Box E2. • History: 1. Circumstances of assault: Date, time, location 2. Physical description of perpetrator 3. Areas of trauma, specifically details of oral, vaginal, anorectal contact, or penetration 4. Condom use 5. Ejaculation: Presence or absence 6. Presence of bleeding in victim or perpetrator 7. Recent consensual sexual activity 8. Showering, bathing, changing of clothes since event

• Physical examination: 1. Ideally performed by individual trained to perform sexual assault examinations, i.e., SANE (Sexual Assault Nurse Evaluation) providers: www.sane-sart.com 2. Physical exam can take 3 to 6 hr to complete 3. Components: a. Physical examination of entire body b. Forensic evidence collection c. STD evaluation and treatment d. Pregnancy risk evaluation e. Care of injuries 4. General physical exam components: a. Documentation of any physical trauma, including photographs b. Colposcopy: May reveal areas of minor genital trauma c. Wood’s light: To reveal foreign debris or semen 5. Forensic evaluation: Not required, but should be offered; written informed consent needed: a. Commercially made specimen collection kits available: Once completed, kits need to be sealed and handled according to kit instructions b. U.S.: States required to provide free specimen collection c.  Samples of blood, saliva, mucosal swabs: Buccal/vaginal/rectal, fingernail scrapings/clippings, hair specimens d. Clothing: If unchanged since event • Box E3 summarizes potential specimens to be gathered for forensic evidence collection.

• Fig. E1 describes an algorithm for emergency department management of patients after sexual assault.

LABORATORY TESTS • Laboratory evaluation of sexual assault is summarized in Table E1 • Pregnancy test (if applicable) • STD testing: 1. GC/CT: Recommended for all, may be excluded if individual elects prophylactic treatment 2.  Wet mount or vaginal swab for Trichomonas 3. Baseline HIV/hepatitis/syphilis testing: Individual basis 4. Retest for HIV/syphilis at 6 wk, 3 mo, and 6 mo from incident IMAGING STUDIES Use of imaging studies as dictated by other injuries sustained for diagnosis/treatment of fractures, soft tissue, and other traumatic injuries

TREATMENT NONPHARMACOLOGIC THERAPY Acute crisis counseling: To support mental health needs of victim in immediate post-assault period ACUTE GENERAL Rx • Post-exposure prophylaxis (PEP) for acute sexual assault victims is summarized in Table E2 • Sexually transmitted infections:

BOX E1  Preliminary Issues and Strategies in Preparing for Taking A Patient History From a Sexual Assault Victim (SAV) Provide a quiet, confidential, safe environment. Briefly review the interview and examination process in private with the SAV. Explain the sensitive, personal, embarrassing nature of questions and the right to be interviewed in private. Show concern for the SAV’s immediate comfort (e.g., if thirsty, take oral swabs first so SAV may drink). Provide advocacy. Try to conduct the interview the same way. Leave difficult questions until the end; some may need to be repeated during appropriate parts of the physical examination. Explain why you are asking the question and the possible responses. Explain that all questions will be asked. From Marx JA et al: Rosen’s emergency medicine, ed 8, Philadelphia, 2014, WB Saunders.

BOX E2  Consent Issues in Sexual Assault Cases Consent should specify that the sexual assault victim’s signature acknowledges the following: • That hospitals and health care professionals are mandated reporters and that an anonymous Jane Doe report can be made • Receipt of information about victim compensation funds • Specific understanding of examination and evidence collection procedures • Specific understanding of the use of photography in documenting physical and genital injuries • That information collected will be sent to law enforcement and is obtainable by defense counsel • That data without patient identity can be collected for valid educational and scientific purposes • That consent may be withdrawn at any time • That there is no charge for the examination, whether reported to law enforcement or not From Marx JA et al: Rosen’s emergency medicine, ed 8, Philadelphia, 2014, WB Saunders.

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BOX E3  Potential Specimens to Be Gathered for Forensic Evidence Collection Clothing • Each article of clothing should be packaged in a separate paper bag to avoid crosscontamination. • If the patient has changed her clothing, only underwear should be collected. Known blood sample • Crime laboratory assesses for secretor status and blood type of the patient. • Toxicology testing (urine and blood) • For use in cases in which drug-facilitated sexual assault is suspected • Collect for evaluation less than 72 to 96 hr after the assault (the time varies by crime laboratory). Oral swabs and smears • Collect for evaluation up to 24 hr after the assault. Head hair combings Fingernail scrapings Foreign material collection Swabs of bite marks or areas where the assailant’s mouth touched the patient Pubic hair combings External genital swabs Vaginal swabs and smears • Cervical sampling should be considered for evaluation between 96 and 120 hr after the assault. Perianal swabs Anorectal swabs and smears • Collect for evaluation up to 24 hr after the assault. Forensic photography • Three views per injury, one with a ruler for scale. From Adams JG et al: Emergency medicine: clinical essentials, ed 2, Philadelphia, 2013, Elsevier.

1. Empiric treatment recommended secondary to poor follow-up rates 2. Gonorrhea: Ceftriaxone 250 mg IM or cefixime 400 mg PO 3.  Chlamydia: Azithromycin 1 g (single dose) or doxycycline 100 mg bid × 7 days 4. Trichomoniasis: Metronidazole 2 g PO (single dose) • Hepatitis B: 1. If perpetrator is known to be infected: HBIG + Hep B vaccination. 2. If perpetrator disease status unknown: Hep B vaccination alone.

3. If victim has already been vaccinated with documented immunity: No treatment necessary. • HIV: 1. Use of antiretrovirals after sexual assault is controversial. 2. Overall risk of acquiring HIV is unknown but higher in certain situations: a. Male-on-male rapists b. Assault occurring in area with high local prevalence c. Multiple assailants d. Anal sexual assault



e. P resence of trauma, bleeding, or genital lesions in either victim/assailant 3. Antiretroviral drugs should be offered in all situations. 4. Ideally, antiretrovirals are initiated within 4 hr; should not start if >72 hr. • Pregnancy: 1. Pregnancy risk is estimated to be 5% per rape in women age 12 to 45. 2.  Emergency contraception should be offered in all cases. a. Levonorgestrel: 0.75 mg q12h for two doses or 1.5 mg single dose b. Yuzpe regimen: 100 mcg ethinyl estradiol + 0.5 mg levonorgestrel, repeated in 12 hr c. Ulipristal (selective progesterone receptor modulator): Preferred method when >72 hr from assault 3. Antiemetics: EC + antibiotics for STD prophylaxis commonly causes nausea.

CHRONIC Rx • No chronic prescriptions. • Long-term psychiatric counseling may be needed. REFERRAL Mental health professional SUGGESTED READINGS Available at ExpertConsult.com RELATED CONTENT Chlamydia Genital Infections (Related Key Topic) Contraception (Related Key Topic) Gonorrhea (Related Key Topic) Syphilis (Related Key Topic) Human Immunodeficiency Virus (Related Key Topic) AUTHORS: Yaneve Fonge, MD, and Sarah L. Chisholm, MD

Sexual Assault TABLE E1  Laboratory Evaluation of Sexual Assault Within 8-12 hr (if indicated by history) Urine and blood for date rape drugs (GHB, Rohypnol, ketamine) Within 24 hr (if indicated by history) Blood for comprehensive toxicology screen (for other classes of drugs) Within 72 hr (or up to 96 hr depending on the protocol used) Forensic evidence kit Pregnancy test Hepatitis B screen (hepatitis B surface antigen, surface antibody, and core antibody) Syphilis (rapid plasma reagin [RPR], Venereal Disease Research Laboratories [VDRL]) HIV infection Bacterial vaginosis (BV) and candidiasis: Point-of-care testing and/or wet mouth with measurement of vaginal pH and KOH application for whiff test Trichomonas vaginalis: Nucleic acid amplification tests (NAATs) by urine or vaginal specimen or point-of-care testing (DNA probes) from vaginal specimen Chlamydia and Neisseria gonorrhoeae: Nucleic acid amplification testing (NAATs) at sites of penetration or possible penetration: 1. N. gonorrhoeae: Oropharynx, rectum, urine* 2. Chlamydia: Urine,* rectum *Dirty urine sample may be used as alternate for genital swab. From Centers for Disease Control and Prevention: Sexually transmitted diseases: Treatment guidelines 2015, MMWR Recomm Rep 64(RR3):1–140, 2015, and Updated guidelines for antiretroviral postexposure prophylaxis after sexual, injection drug use, or other nonoccupational exposure to HIV—United States, 2016. In Kliegman, RM: Nelson textbook of pediatrics, ed 21, Philadelphia, 2020, Elsevier.

TABLE E2  Postexposure Prophylaxis (PEP) for Acute Sexual Assault Victims Routine Recommended Regimen for STI Prophylaxis Ceftriaxone 250 mg intramuscularly plus Azithromycin 1g orally in a single dose plus Metronidazole 2 g orally in a single dose or Tinidazole 2 g orally in a single dose Pregnancy Prophylaxis* Levonorgestrel (Plan B) 1.5 mg orally in a single dose or Ulipristal acetate (Ella) 30 mg is effective for up to 120 hr. Human Papillomavirus (HPV) Assess HPV vaccine history; to the unimmunized, administer initial vaccine at initial exam, with 2 follow-up doses at 1 to 2 mo and at 6 mo if >15 yr old or a single follow-up dose at 6-12 mo if ≤15 yr old. As Indicated All persons offered PEP should be prescribed a 28-day course of a two- or three-drug antiretroviral regimen. Human Immunodeficiency Virus (HIV)† Preferred regimen: Tenofovir 300 mg and fixed-dose combination emtricitabine, 200 mg (Truvada) once daily plus Raltegravir 400 mg twice daily or Dolutegravir 50 mg daily‡ Hepatitis B Virus (HBV) Specific indications for vaccine, immunoglobulin and/or Booster dependent upon assailant’s status *Provided for patients with negative urine pregnancy screen. In addition, antiemetic (Compazine, Zofran) can be prescribed for patients receiving emergency contraception. †HIV PEP is provided for patients with penetration and when the assailant is known to be HIV-positive or at high risk because of a history of incarceration, intravenous drug use, or multiple sexual partners. If provided, laboratory studies must be drawn before administration of medication (HIV, CBC, LFTs, BUN/Cr, amylase, lipase), and follow-up must be arranged. ‡Dolutegravir has been associated with neural tube defects if exposure occurs within the first trimester of pregnancy. Therefore, it should be avoided in pregnant patients or those at risk for becoming pregnant. U.S. Department of Health and Human Services, U.S. Food & Drug Administration. Juluca, Tivicay, Triumeq (dolutegravir): FDA to evaluate potential risk of neural tube birth defects. May 18, 2018. In Kliegman, RM: Nelson textbook of pediatrics, ed 21, Philadelphia, 2020, Elsevier.

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Sexual Assault

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Identify and treat traumatic injuries

Notify victim advocate and police with patient’s permission

Obtain written consents

Urine pregnancy test No

5 days since assault

Yes HIV counseling

High risk of HIV

Yes

CBC, BUN/Cr, LFTs, ID consultation

Yes

No History

nPEP

History

History

Physical exam

Physical exam

Physical exam

Evidence collection

Evidence collection

Undress on sheet if still wearing clothing worn during assault

Emergency contraception

STD prophylaxis

STD prophylaxis

STD prophylaxis or genital cultures and full treatment for symptomatic patients

Follow up

Follow up

Follow up

FIG. E1  Emergency department management of patients after sexual assault. BUN, Blood urea nitrogen; CBC, complete blood count; Cr, creatinine; HIV, human immunodeficiency virus; ID, infectious disease; LFTs, liver function tests; nPEP, nonoccupational postexposure prophylaxis; STD, sexually transmitted disease. (From Adams JG et al: Emergency medicine, clinical essentials, ed 2, Philadelphia, 2013, Elsevier.)

SUGGESTED READINGS American College of Obstetricians and Gynecologists: Committee on health care for underserved women: Committee opinion no. 499: sexual assault, Obstet Gynecol 118(2 Pt 1):396-399, 2014. American College of Obstetricians and Gynecologists: Sexual assault. ACOG Committee opinion No. 777, Obstet Gynecol 133:e296-302, 2019. Bates CK et  al: Evaluation and management of adult sexual assault victims. Available at www.uptodate.com. CDC: MMWR: Sexually Transmitted Diseases Treatment Guidelines 64, 2015. No. 3. Fisher BS et al: The sexual victimization of college women. Department of Justice, National Institute of Justice, Publication No. NCJ 182369: Washington, DC. Senn CY et  al: Efficacy of a sexual assault resistance program for university women, N Engl J Med 372:2326-2335, 2015. Tjaden P, Thoennes N: Extent, nature, and consequences of rape victimization: findings from the National Violence against Women Survey, Department of Justice, 2006. Available at: www.ncjrs.gov/pdffiles1/nij/210346.pdf.

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Sexual Dysfunction in Women BASIC INFORMATION DEFINITION A sexual dysfunction in a woman is any disorder that interferes with female sexuality and that causes marked distress to that person. The DSM-5 reclassified these disorders into the following categories: • Female sexual arousal disorder (FSIAD): Hypoactive sexual desire disorder (HSDD) and female sexual arousal disorder (FSAD) were merged into this category • Female orgasmic disorders • Genito-pelvic pain/penetration disorder (GPPD): Combines the diagnoses of dyspareunia and vaginismus • Sexual dysfunction due to secondary causes (e.g., medication, substance abuse, medical conditions) Female sexual dysfunction is also further categorized as lifelong (primary) or acquired (secondary—present for 6 mo or more). The updated classification system has a high rate of false negatives due to the elimination of individuals reporting mild-to-moderate symptoms. The symptoms must also cause significant distress to the individual. The change in criteria was established to avoid overmedicalization of normal sexual function. SYNONYMS Female sexual dysfunction Hypoactive sexual desire disorder (HSDD) ICD-10CM CODES (note: The new classification categories will be included in the ICD-11) R37 Sexual dysfunction, unspecified F52.0 Hypoactive sexual desire disorder F52.22 Female sexual arousal disorder F52.31 Female orgasmic disorder N94.1 Dyspareunia N94.81 Vulvodynia

EPIDEMIOLOGY & DEMOGRAPHICS INCIDENCE: According to the National Health and Social Life Survey, in 1999, ∼20% to 50% of women reported some form of sexual dysfunction during their lifetimes. One third of women reported a decrease in sexual interest, and one fourth reported an inability to achieve orgasm. PREVALENCE (TABLE E1): A more recent survey of women 18 yr of age and older found an age-adjusted prevalence of any sexual problem to be ∼43%. PREDOMINANT AGE: Sexually related personal distress was more common in middle-aged women (aged 45 to 64) than in younger or older women. RISK FACTORS: • Correlates of distressing sexual problems include poor self-assessed health, low education level, depression, anxiety, thyroid conditions, and urinary incontinence. • Higher insomnia scores and shorter sleep duration are associated with decreased sexual function. • Obesity and overweight body status have been associated with lower sexual satisfaction and desire. • Comorbid conditions such as arthritis, diabetes mellitus, hypertension, malignancy, neuromuscular disorders, renal failure, and gynecologic (e.g., chronic pelvic pain) and dermatologic conditions (e.g., lichen sclerosis, psoriasis) can contribute to sexual dysfunction. • Aging is associated with decreased sexual responsiveness, sexual activity, and libido. • Decreased hormonal levels associated with menopause can cause decreased vaginal lubrication and dyspareunia. PHYSICAL FINDINGS & CLINICAL PRESENTATION • History: Important to obtain the patient’s definition of the dysfunction, including its

onset and duration; to determine whether the dysfunction is situational or global; and to determine whether more than one dysfunction exists and the interrelationship among the dysfunctions. Dysfunction is diagnosed if the symptoms are causing distress to the patient. • Related medical and gynecologic conditions (including prior gynecologic surgery) • Psychosocial factors, including sexual abuse, sexual orientation, depression and anxiety, status of current relationships and sexual activity, personal and family beliefs about sexuality • Current medications including OTC and herbal preparations; alcohol, tobacco, and drug use; and birth control method, substance use/misuse • Physical examination: 1. The gynecologic examination can aid in identifying signs of decreased estrogen and androgen levels, infection, endometriosis, pelvic floor dysfunction, and systemic disease 2. Cotton swab test when concern exists for provoked vulvodynia 3. Other body systems as indicated (e.g., cardiovascular, thyroid)

ETIOLOGY • Chronic medical conditions (e.g., diabetes, coronary vascular disease, arthritis, urinary incontinence). • Medication induced (e.g., antihypertensives, narcotics, hormonal preparations, antihistamines, amphetamines, psychotropic medications). SSRIs are the most common medications linked to sexual dysfunction. • Gynecologic conditions (e.g., cystitis, posthysterectomy, gynecologic cancers, breast cancer [femininity/self-image issues; chemotherapy effects], postpregnancy, postmenopausal). Premenopausal BSO is associated with a higher risk of HSDD.

TABLE E1  Prevalence and Definition of Female Sexual Dysfunctions Prevalence*

Definition†

Hypoactive sexual desire/low libido

9%-60%

Sexual arousal disorder/sex not pleasurable Difficulty with genital lubrication

5%-51% 8%-60%

Persistent genital arousal disorder

∼1%

Female orgasmic disorder

7%-65%

Sexual pain disorders

4%-42%

Anxiety about sexual performance

6%-16%

Diminished feelings of sexual interest or desire, absence of sexual thoughts, and/or lack of receptivity to sexual activity‡ Genital Female Sexual Arousal Disorder (GFSAD): Disruption of clitoral erection, vaginal vasocongestion, vaginal lubrication Psychological Female Sexual Arousal Disorder (PFSAD): Absent or markedly ­diminished feelings of excitement or pleasure in response to sexual stimuli Mixed Female Sexual Arousal Disorder: GFSAD and PFSAD Persistent, recurrent, intrusive, and/or distressing sensations of genital arousal not related to sexual stimulation and that do not resolve after orgasm Lack of experience of orgasm or diminished orgasm intensity despite high sexual arousal after a period of sufficient sexual stimulation and arousal Dyspareunia: Persistent/recurrent pain with attempted/complete vaginal entry with a penis, finger, or other object Vaginismus: Vaginal spasm or pain in response to penetration with a penis, finger, or other object despite a desire for penetration to occur‡ N/A

*Laumann et al, 1999; Nicolosi et al, 2005, 2006a, 2006b; Shifren et al, 2008; West et al, 2008; Witting et al, 2008; Garvey et al, 2009. †Waldinger et al, 2009; Basson et al, 2010b. ‡The term vaginismus is no longer preferred, as it includes significant semantic baggage as a psychological disorder.

Sexual Dysfunction in Women Orgasm

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Female

Plateau

Male

Excitement

Resolution

A

ACUTE GENERAL Rx NSAIDs before intercourse for sexual pain disorders

Multiple reasons for sex

Original goals fulfilled —increased emotional intimacy, well-being

Initial/spontaneous sexual desire (variable)

Sexual satisfaction

B

Sexual stimuli in appropriate context

Biological factors The mind’s information processing

More arousal triggered desire Subjective arousal +ANS response

Psychological factors

FIG. E1  A, The four phases of the human sexual response cycle as postulated by Masters and Johnson. Because the resolution phase is prolonged considerably in men, men can experience refractoriness to further stimulation for varying lengths of time before they can achieve another orgasm. As discussed in the text, understanding of the human sex response cycle has evolved substantially since the publication of this work. B, The circular human response cycle of overlapping phases. It is increasingly recognized that the human sexual response involves much more complexity, circularity, and flexibility than is reflected in Masters and Johnson’s original model. “Desire” may or may not be present initially; it can be triggered during the experience. Arousal and desire overlap. Multiple psychologic and biologic factors influence the information processing of sexual stimuli. Underlying this processing may be the individual’s unique tendency for excitation versus inhibition. ANS, Autonomic nervous system. (From Melmed S: Williams textbook of endocrinology, ed 12, Philadelphia, 2011, Saunders.)

• Psychosocial (e.g., religion, taboos, identity conflicts, guilt, relationship problems, abuse, rape, life stressors). • Fig. E1 illustrates the four phases of the human sexual response as postulated by Masters and Johnson.

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • Depression • Psychosocial stressors • Medical disease (e.g., thyroid dysfunction) • Menopausal status can be assessed using STRAW + 10 tool LABORATORY TESTS • Cervical cultures and vaginal swabs for infectious disease • Cervical cancer screening as per current guidelines • Appropriate laboratory tests if comorbid or chronic disease is suspected

• Activities to enhance stimulation and eliminate routine • Distraction techniques • Noncoital behavior • Position changes (e.g., female astride) • Lubricants (e.g., nonpetroleum based). There are several over-the-counter lubricants and massage oils, some of which are hypoallergenic, that can be safely applied to female genitalia • Physical therapy may be useful for patients with pelvic floor dysfunction and pain • Eros clitoral therapy device: An FDA-approved device for targeting symptoms of FSAD

• Measurement of prolactin, thyroid function tests, estrogen, progesterone, LH, testosterone, and sex hormone binding globulin is indicated only if a hormonal etiology is suspected from history

IMAGING STUDIES Appropriate imaging studies if comorbid or chronic disease is suspected

TREATMENT NONPHARMACOLOGIC THERAPY • Treat genital arousal and pelvic pain symptoms before addressing HSDD • Education including a discussion of normal sexual behavior • Stress management • Behavioral therapy (e.g., cognitive-behavioral therapy) and mindfulness-based ­interventions can treat low sexual desire and arousal disorders • Counseling (individual or couples) for relationship issues

CHRONIC Rx • Treat underlying medical, gynecologic, or psychological conditions. • Reduce comorbidities, including weight loss. • Increase physical activity (associated with increased satisfaction and sexual engagement). • For medication-induced conditions, decrease dose or change medication. • For postmenopausal women or those with hypoestrogenism, try estrogen replacement therapy with or without progesterone. Local vaginal estrogen therapy is preferred over systemic therapy. Transdermal estradiol is superior to oral estradiol for improving sexual function because oral estradiol increases circulating sex hormone-binding globulin (SHBG) and lowers free testosterone, thus effecting libido adversely. Estrogen replacement is associated with improvements in dyspareunia and vaginal dryness. • For postmenopausal vaginal and/or vulvar atrophy, ospemifene has been associated with improved sexual function. • Transdermal testosterone therapy: Results show increase in satisfying sexual activity and sexual desire. Must weigh risks (hirsutism, acne, virilization, and cardiovascular complications) vs. benefits of use. Monitoring of testosterone levels to avoid supraphysiologic therapy is recommended. • Sildenafil (evidence from RCTs for use in patients with neurodegenerative disease and antidepressant-induced FSD after traditional therapy has failed). Data are conflicting. Phosphodiesterase inhibitors may increase blood flow to the genitalia but generally appear to have little benefit in treating arousal disorders. Sildenafil has been helpful in patients with SSRI-induced sexual dysfunction. • Bupropion 300 to 400 mg/day was shown to increase sexual arousal and orgasm completion in a recent trial. In addition, adjunctive treatment with bupropion significantly improved key aspects of sexual function in women with SSRI-induced sexual dysfunction. • Flibanserin (Addyi): A nonhormonal treatment for HSDD. It is an agonist at serotonin 5-HT receptors and an antagonist at 5-HT2A receptors. Its mechanism of action in treating HSDD is unknown. The recommended dose is

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TABLE E2  Investigational Pharmacotherapy for Women’s Sexual Dysfunctions Sexual Dysfunction Sexual interest/ desire disorder

Mechanisms of Dysfunction Loss of brain’s ­arousability to sexual stimuli

Subjective arousal disorder Combined arousal disorder Genital arousal ­disorder: Estrogen deplete

Genital arousal disorder despite estrogen replete Serotoninergic antidepressant–­ associated orgasmic disorder

Drug Type Drugs with specific ­serotonin receptor ­subtype or agonist/ antagonist profile Melanocortin agonists

Dopamine agonists

Loss of genital ­vasocongestion in response to sexual stimulation

Loss of genital ­vasocongestion in response to sexual stimulation Former orgasmic response absent or extremely delayed

Off-Label and Investigational Drugs

Comments

Flibanserin: 5-HT1A agonist Flibanserin is now FDA approved for and 5-HT2A antagonist, treatment of hypoactive sexual desire weak partial D4 agonist disorder Bremelanotide: Synthetic peptide, α-MSH analog agonist at MC1R, MC3R, MC4R Bupropion

To provide local ­substrate for estrogen and ­testosterone intracrine synthesis Selective tissue estrogenic activity regulator with androgenic and ­progestogenic properties

Local vaginal DHEA

To enhance the action of NO–PDEIs

Sildenafil, tadalafil, vardenafil

PDEIs

Sildenafil

Tibolone

Small RCT showed benefit for women’s arousal disorder with in-home use of nasal drug 45 min before sex. Sponsor has discontinued trials. One small 4-mo study in nondepressed premenopausal women showed increased arousability and sexual response, no increase in initial desire. Phase 3 RCT showed increased maturation of vaginal epithelium, lower pH, and sexual benefit in all domains of response from local vaginal DHEA for 12 wk. RCT of dysfunctional women showed tibolone marginally superior to 50 μg/140 μg combined transdermal estradiol/norethisterone. Major problem is distinguishing the subgroup of women with genital arousal disorder who have reduced genital vasocongestion. Small RCTs in diabetes and MS showed only modest benefit from sildenafil.

8-wk RCT with very strict entry criteria showed benefit from 50-100 mg sildenafil.

D4, Dopamine 4 receptor; DHEA, dehydroepiandrosterone; 5-HT, serotonin; ISSWSH, International Society for the Study of Women’s Sexual Health; MC1R, melanocortin-1 receptor; MS, multiple sclerosis; MSH, melanocyte-stimulating hormone; NO, nitric oxide; PDEIs, phosphodiesterase inhibitors; RCTs, randomized controlled trials.

100 mg once daily at bed time. Side effects include hypotension, syncope, and CNS depression. Consumption of alcohol increases risk of side effects and is contraindicated. It is mostly effective with approximately 10% of women reporting “much” or “very much” improvement in HSDD symptoms. • Ospemifene: A selective estrogen receptor agonist/antagonist (SERM). Clinical trials demonstrated a significant improvement in sexual pain, arousal, and desire.

• Table E2 summarizes investigational pharmacotherapy for women’s sexual dysfunctions.

REFERRAL • Gynecologic referral for conditions that may be amenable to surgical therapy (e.g., pelvic floor disorders) • Psychological referral for conditions (e.g., depression, abuse) that may benefit from counseling or psychotherapy • Social services referrals for active abuse issues

SUGGESTED READINGS American College of Obstetricians and Gynecologists Committee on Practice Bulletins-Gynecology: ACOG Practice Bulletin No. 119: female sexual dysfunction, Obstet Gynecol 117:996, 2011. Clayton AH et al: The International Society for the Study of Women's Sexual Health process of care for the management of hypoactive sexual desire disorder in women, Mayo Clin Proc 93:467-487, 2018. Clayton AH et  al: Female sexual dysfunction, Med Clin North Am 103:681-698, 2019.

RELATED CONTENT Female Sexual Dysfunction (Patient Information) Hypoactive Sexual Desire Disorder (Related Key Topic) AUTHOR: Anngene Anthony, MD, MPH, FAAFP

Faubion SS et al: Sexual dysfunction in women: a practical approach, Am Fam Phys 92(4):281-288, 2015. Lorenz T et al: Antidepressant-induced female sexual dysfunction, Mayo Clin Proc 91(8):1280-1286, 2016. Taylor HS et al: Effects of oral vs transdermal estrogen therapy on sexual function in early postmenopause: ancillary study of the Kronos early estrogen prevention study (KEEPS), JAMA Intern Med 177(10):1471-1479, 2017.

Shaken Baby Syndrome BASIC INFORMATION DEFINITION Shaken baby syndrome is a potentially lifethreatening and severe form of abuse in which an infant or child is violently shaken. Intracranial injury is caused by rapid acceleration and rotation of the cranium (sometimes associated with impact on a solid object which leads to rapid angular deceleration). The classic injury pattern associated with shaking includes diffuse subdural hemorrhage, retinal hemorrhages, and diffuse brain injury (Fig. E1). The diagnosis is often difficult to make because the clinical manifestations are nonspecific, perpetrators are unlikely to report a history of trauma, and there may be little to no external signs of injury. SYNONYMS Shaken infant syndrome Abusive head trauma Nonaccidental head injury ICD-10CM CODES T74.1 Physical abuse T74.4 Shaken infant syndrome, initial encounter T74.4XXD Shaken infant syndrome, subsequent encounter T74.4XXS Shaken infant syndrome, sequela

EPIDEMIOLOGY & DEMOGRAPHICS INCIDENCE: Most common cause of death or serious neurologic injury resulting from child abuse. It is specific to infancy, when children have unique anatomic features. A populationbased study conducted in the U.S. showed an incidence of abusive head trauma in children 1 yr postsurgery) a. Recruit bypassed bowel b. Bowel-lengthening procedure (Bianchi or STEP) c. Monitor for development of TPN-associated complications, and refer for transplant before recurrent sepsis, thrombosis, or end-stage liver disease STEP, Serial transverse enteroplasty; TPN, total parenteral nutrition. From Cameron JL, Cameron AM: Current surgical therapy, ed 10, Philadelphia, 2011, Saunders.

PROGNOSIS • Directly dependent on the extent of the bowel resection and in the case of Crohn disease by the underlying illness. • Whether the colon remains in continuity with the small bowel is an important factor in the patient’s ability to adapt after significant small bowel resection. RELATED CONTENT Short Bowel Syndrome (Patient Information) Malabsorption (Related Key Topic) AUTHOR: Fred F. Ferri, MD

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Component

Short Bowel Syndrome

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Short Bowel Syndrome

ALG

Jejunoileal anastomosis, no colon present

Jejunoileal anastomosis

End jejunostomy

Re-anastomosis of colon, if possible

≥100 cm small intestine + colon

≥100 cm residual small intestine

$5 billion/yr RISK FACTORS: Underlying spinal disease can predispose to SCI: • Inflammatory spondyloarthropathies, especially ankylosing spondylitis • Diffuse idiopathic skeletal hyperostosis (DISH) • Congenital spinal disorders • Preexisting spinal canal stenosis or compromise • Atlantoaxial instability • Osteoporosis • Rheumatoid arthritis (cervical spine) PHYSICAL FINDINGS & CLINICAL PRESENTATION Clinical features reflect the amount of spinal cord involvement: • Weakness, sensory changes (dependent on level of compression/lesion/injury). • Myelopathy if cord involvement, radiculopathy if nerve root involvement (may involve both).

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DEFINITION • Spinal cord compression is characterized by direct compression of the spinal cord within the spinal canal. This may result in loss of neurologic function from compression of the spinal cord in the cervical, thoracic, and upper lumbar spinal canal. Compression may also occur at the cauda equina in the lower lumbar spinal canal, which is anatomically below the level of the spinal cord. Fig. 1 illustrates a schematic demarcation of principal dermatomes shown as distinct segments. Depending on the underlying etiology, symptoms may develop gradually or acutely and may result in complete or incomplete deficits. Neurologic deficits related to compression of the cord itself are referred to as myelopathy, whereas deficits caused by compression on nerve roots are described as radiculopathy. • Signs and symptoms of myelopathy: 1. Upper motor neuron signs (Hoffman sign, inverted radial reflex, Babinski sign, spasticity, hyperreflexia, clonus) in chronic cases 2. Weakness 3. Sensory deficits 4. Clumsiness, difficult ambulation, ataxic gait (secondary to loss of proprioception in legs) • Signs and symptoms of radiculopathy: 1. Lower motor neuron signs (hyporeflexia, hypotonicity, fasciculations, muscle atrophy) 2. Weakness 3. Sensory deficits

Incomplete spinal cord lesions may classically present in distinct syndromic patterns (Table 1), for example, as follows: • Anterior cord syndrome • Central cord syndrome (most common) • Cauda equina syndrome (not a true example of spinal cord compression but rather of cauda equina compression, affecting lower motor neurons in lumbosacral nerve roots) • Conus medullaris syndrome • Brown-Séquard syndrome

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Spinal Cord Compression TABLE 1  Spinal Cord Syndromes Sphincter Involvement

Syndrome

Sensory

Motor

Central cord syndrome Brown-Séquard syndrome

Variable

Upper extremity weakness, distal > proximal Motor loss ipsilateral to cord lesion

Variable

Motor loss or weakness below cord level

Variable

Loss of voluntary motor function below cord level Weakness may be of lower motor neuron type

Sphincter control lost

Ipsilateral position and vibration sense loss Contralateral pain and temperature sensation loss Loss of pin and touch sensation Vibration, position sense preserved Loss of sensation below level of cord injury

Anterior cord syndrome Transverse cord syndrome— complete Cauda equina syndrome

Saddle anesthesia may be present, or sensory loss may range from patchy to complete transverse pattern

Variable

Sphincter control impaired

From Marx JA et al: Rosen’s emergency medicine, ed 8, Philadelphia, 2014, WB Saunders.

TABLE 2  Physical Examination Findings Associated with Vertebral Fractures and Spinal Cord Injuries

Injury Vertebral fracture

Physical Examination Area Spine Neurologic Chest Abdomen/pelvis

Extremity

Spinal cord injury

Neurologic, motor (anterior column) Neurologic, sensory (spinothalamic tract) Neurologic, sensory (dorsal column) Neurology, deep tendon reflex Anogenital

Head-to-toe examination

Associated Findings Tenderness of the neck and/or back. Examine the entire spine because vertebral fractures may occur in multiples. See “Spinal cord injury” later. Thoracic spine fractures: Check for chest tenderness, unequal breath sounds, and arrhythmia, which are suggestive of an associated intrathoracic injury or myocardial contusion. Thoracolumbar and lumbar spine fractures: Check for abdominal or pelvic tenderness. A transverse area of ecchymosis on the lower abdominal wall (seat belt sign) increases the chance of an abdominopelvic injury. Thoracolumbar and lumbar spine fractures: Check for calcaneal tenderness because 10% of calcaneal fractures are associated with a low thoracic or lumbar fracture. Mechanistically, these areas are fractured as a result of axial loading. Assess motor function on a scale of 0 to 5. The motor level is defined as the most caudal segment with at least 3/5 strength. Injuries to the first eight cervical segments result in tetraplegia (previously known as quadriplegia); lesions below the T1 level result in paraplegia. Assess sensory function via pinprick and light touch on the following scale: 0 = absent; 1 = impaired; 2 = normal. The sensory level is defined as the most caudal segment of the spinal cord with normal sensory function. The highest intact sensory level should be marked on the patient’s spine to monitor for progression. Assess vibratory sensory function on a scale of 0 to 2 by using a tuning fork over bony prominences. Assess position sense (proprioception) by flexing and extending the great toe. On a scale of 0 to 4, assess the deep tendon reflexes in the upper (biceps, triceps) and lower (patellar, Achilles) extremities. Assess rectal tone, sacral sensation, signs of urinary or fecal retention or incontinence, and priapism. Also check the anogenital reflexes. An anal wink (S2-S4) is present if the anal sphincter contracts in response to stroking the perianal skin area. The bulbocavernosus reflex (S3-S4) is elicited by squeezing the glans penis or clitoris (or pulling on an inserted Foley catheter), which results in reflexive contraction of the anal sphincter. A spinal cord injury may mask a patient’s ability to perceive and localize pain. Imaging of high-risk areas, such as the abdomen, and areas of bruising or swelling may be required to exclude occult injuries.

From Adams JG et al: Emergency medicine, clinical essentials, ed 2, Philadelphia, 2013, Elsevier.

• Central cord syndrome (most common incomplete spinal cord injury): Motor impairment greater in upper than in lower extremities, variable degree of sensory loss below the injury level. Weakness and poor hand dexterity are especially common. Classically occurs after mild trauma including cervical hyperextension in the setting of preexisting cervical spondylosis. • Anterior cord syndrome (worst prognosis of incomplete spinal cord injury): Affects the anterior or ventral two thirds of the spinal cord, sparing the dorsal columns. May be caused by a vascular injury to the anterior spinal artery or by a flexion/compression injury. Impairment usually is worse in the lower extremities than upper extremities. Physical manifestations include motor, pain, and temperature loss below the lesion. Proprioception and vibratory sense may be preserved as dorsal columns are preserved. • Brown-Séquard syndrome: Rare in isolation. Caused by injury to half of the spinal cord and resulting in the loss of motor function, position, vibration, and light touch on the side of injury, as well as loss of pain and temperature sense on the contralateral side. Typically, secondary to a knife wound. • Conus medullaris syndrome: Results in variable motor loss in the lower extremities with loss of bowel and bladder function. In general, more bowel and bladder is affected earlier than motor. • Cauda equina syndrome: Low back pain, weakness in bilateral lower extremities, saddle anesthesia, and loss of voluntary bladder and/or bowel control, often presenting as bladder retention and/or bowel incontinence.

ETIOLOGY • Trauma (most SCIs result from high-speed motor vehicle accidents, falls, sports injuries, or violence) • Tumor • Infection (e.g., epidural abscess) • Inflammatory processes • Degenerative disk disease with associated spinal stenosis • Acute disk herniation • Cystic abnormalities • Ankylosing spondylitis, DISH. Patients with underlying DISH or ankylosing spondylitis are at high risk of SCI with otherwise relatively minor fractures of the spine • Table 2 summarizes physical examination findings associated with vertebral fractures and spinal cord injuries

DIAGNOSIS DIFFERENTIAL DIAGNOSIS See “Synonyms or Related Terms.” WORKUP • Signs and symptoms of spinal cord or cauda equina compression often indicate urgent surgical conditions and thus require urgent imaging and early referral for assessment by a spine specialist.

Spinal Cord Compression

IMAGING STUDIES • Signs and symptoms of spinal cord compression in most cases will mandate advanced imaging, often including CT and CT myelogram and/or MRI. • Plain x-rays may be helpful; however, normal plain films do not negate the need for further advanced imaging in the setting of signs and symptoms of spinal cord compression or spinal cord injury. This is especially true in the setting of ankylosing spondylitis or DISH. • In the trauma setting, after primary and secondary surveys, fine-cut helical CT scans with axial, coronal, and sagittal reconstructions have replaced plain cervical radiographs in most trauma centers as the initial evaluation of choice in detecting fractures of the cervical spine. • Detection of injury to any part of the spine during trauma evaluation mandates full imaging evaluation of the entire spine, as noncontiguous injuries are common. • While CT scan is excellent at imaging bony structures and detecting fractures, MRI provides more detailed imaging of the softtissue structures, including neural structures,

discoligamentous structures, the posterior ligamentous complex, and paraspinal soft tissues. MRI is very sensitive for detecting ligamentous injury, spinal cord edema, spinal cord compression from soft-tissue structures, epidural hematoma, diskitis, osteomyelitis, and epidural abscess. Of note, gadolinium contrast may increase the sensitivity of the MRI study for the detection of tumors or infections.

TREATMENT • Depending on the etiology of spinal cord compression as well as the specific signs and symptoms during physical examination and history-taking, urgent surgical decompression and/or stabilization may be indicated. Referral to a spine specialist is indicated in most cases of spinal cord compression. • Corticosteroids: Controversial in cases of acute spinal cord injury. Methylprednisolone was thought to reduce the amount of secondary injury that occurs after SCI and was previously used in many trauma centers. However, current evidence is insufficient to support corticosteroids for this use, and most spine trauma centers no longer utilize steroids in cases of acute spinal cord injury. Vasopressors: Current evidence supports the use of vasopressors in cases of spinal cord injury to maintain spinal cord perfusion and to prevent ischemic damage to the cord. The ideal mean arterial pressure and duration of treatment are yet to be defined. Both the treatment modality and the injury itself mandate admission to ICU level of care in most cases for close monitoring.

DISPOSITION Indicators regarding prognosis: • Patients with acute traumatic SCI need monitoring in the ICU and evaluation for potential

life-threatening complications, including cardiovascular instability and respiratory failure. • In general, the greater the distal motor and sensory sparing, the greater the expected recovery. • In most cases of spinal cord compression and/or spinal cord injury, the primary goal of surgical decompression and/or stabilization should be to spare the remaining functional levels and to prevent worsening of the injury. Return of function should not be guaranteed. • Prophylaxis against deep vein thrombosis and pulmonary embolism should always be provided. In acute injuries to the spine or postoperatively, this may consist of mechanical prophylaxis including TEDs and SCDs. Pharmacologic deep vein thrombosis/pulmonary embolism prophylaxis is often held initially to prevent development of epidural hematoma. The optimal timing for initiation of pharmacologic prophylaxis is controversial, and no strict guidelines are currently in place.

REFERRAL Signs and symptoms of spinal cord or cauda equina compression often indicate urgent surgical conditions and thus require urgent imaging and early referral for assessment by a spine specialist. SUGGESTED READINGS Available at ExpertConsult.com RELATED CONTENT Spinal Stenosis (Patient Information) Lumbar Disk Syndrome (Related Key Topic) Spinal Epidural Abscess (Related Key Topic) Spinal Stenosis, Lumbar (Related Key Topic) AUTHORS: Daniel Brian Carlin Reid, MD, MPH, and Shyam A. Patel, MD

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Diseases and Disorders

• In cases of acute trauma in which spinal cord injury is suspected, patient should undergo full trauma evaluation following advanced trauma life support protocol in emergency room setting. With suspected injury to the cervical spine, the patient should be immobilized in a hard cervical collar or in-line traction at all times during evaluation. Logroll precautions may be indicated as well to immobilize the spine during acute injury evaluation. • Inflammatory labs will usually be elevated both in cases of trauma and infectious processes. Laboratory tests ordered should be specific to the suspected etiology or differential diagnosis for spinal cord compression.

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Spinal Cord Compression SUGGESTED READINGS Eltorai AEM et  al: Recent developments in the treatment of spinal epidural abscesses, Orthop Rev 9(2):7010, 2017. Martin AR et al: Can microstructural MRI detect subclinical tissue injury in subjects with asymptomatic cervical spinal cord compression? A prospective cohort study, BMJ Open 8(4):e019809, 2018. O'Phelan KH: Emergency neurologic life support: spinal cord compression, Neurocrit Care 27(Suppl 1):144-151, 2017. Ropper AE, Ropper AH: Acute spinal cord compression, N Engl J Med 376:1358-1369, 2017.

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Spinal Epidural Abscess BASIC INFORMATION DEFINITION A spinal epidural abscess (SEA) is a focal suppurative infection occurring in the spinal epidural space. SYNONYM SEA ICD-10CM CODE G06.1  Intraspinal abscess and granuloma

EPIDEMIOLOGY & DEMOGRAPHICS INCIDENCE (IN U.S.): • 2 to 25 cases/100,000 hospitalized patients/yr • May be increasing over the past 3 decades PREDOMINANT AGE: • Median age of onset approximately 50 yr (35 yr in intravenous drug users) • Peak incidence in seventh and eighth decades of life PHYSICAL FINDINGS & CLINICAL PRESENTATION • The presentation of SEA can be nonspecific. • Fever, malaise, and back pain are the most consistent early symptoms. • Pain is often focal. It may initially be mild but can progress to become severe. • As the disease progresses, root pain can occur, followed by motor weakness, sensory changes, bladder and bowel dysfunction, and paralysis. • Physical findings may be limited to fever or spinal tenderness. • The evolution to neurologic deficits can occur as quickly as a few hours, or over wks to mos. • Once paralysis occurs, it may quickly become irreversible without the appropriate intervention. ETIOLOGY • SEA most commonly results from hematogenous dissemination. • Pyogenic bacteria account for the majority of cases in the U.S. Immigrants from TB-endemic areas may present with tuberculous SEAs. Fungi and parasites can also cause this condition. The most common causative organism is Staphylococcus aureus. Gram-negative bacilli and anaerobes may be seen if the infection has a urinary or GI source. • Most posterior SEAs are thought to originate from distant focus (e.g., skin and soft tissue infections), while anterior SEAs are commonly associated with diskitis or vertebral osteomyelitis. No source was found in approximately one third of cases. • Associated predisposing conditions include diabetes mellitus, alcoholism, cancer, AIDS, and chronic renal failure, or following epidural anesthesia, spinal surgery or trauma, prolonged epidural catheter placement, paraspinal glucocorticoid or analgesic injections, acupuncture, or IV drug use. No predisposing condition is found in approximately 20% of patients.

ALG

• Damage to the spinal cord can be caused by direct compression of the spinal cord, vascular compromise, bacterial toxins, and inflammation.

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • Herniated disk • Vertebral osteomyelitis and diskitis • Metastatic tumors • Meningitis LABORATORY TESTS • WBC may be normal or elevated. • ESR and C-reactive proteins are usually elevated.

• Blood cultures are positive in approximately 60% of patients with SEA and should be obtained prior to starting antibiotics. • CSF cultures are positive in 19%, but lumbar puncture is unnecessary, and may be contraindicated. • Once imaging is done, CT-guided aspiration or open biopsy should be done to determine causative organism. Abscess content culture is positive in 90% of patients.

IMAGING STUDIES • MRI with gadolinium is the imaging modality of choice (Fig. 1); CT scan with contrast may show the abscess (Fig. 2) but is less sensitive than MRI. • CT with myelography is more sensitive for cord compression.

cauda equina CSF (white) dura mater (dark gray line)

A

fluid (white) and air (black) in spinal canal, concerning for epidural abscess

B

FIG. 1  Same patient as in Fig. 2, in whom noncontrast computed tomography showed air in the spinal canal, concerning for epidural abscess. Magnetic resonance imaging (MRI) of the lumbar spine without contrast was performed, as the patient was in acute renal failure. A, This T2-weighted sagittal MRI provides useful information even without gadolinium contrast. B, Close-up. On T2-weighted MRI sequences, fluid including cerebrospinal fluid (CSF) appears white. Fat-containing tissues such as bone marrow and the spinal cord or cauda equina appear dark gray. Calcified bone appears nearly black due to an absence of resonating protons. Air appears completely black for the same reason. The midline sagittal image shows the cauda equina to be impinged upon by an epidural fluid collection containing air—an epidural abscess. The dura mater is visible as a thin, dark-gray line parallel to the spinal cord. It is indented in the region of the epidural abscess. (From Broder JS: Diagnostic imaging for the emergency physician, Philadelphia, 2011, WB Saunders.)

lamina surgically absent

A

Air in spinal canal, concerning for epidural abscess

Air in vertebral body, concerning for vertebral osteomyelitis

B

Air in paraspinous soft tissues

Air in spinal canal, concerning for epidural abscess

C

FIG. 2  This 67-yr-old female presented with delirium and fever. 3 mo prior, she had undergone lumbar laminectomy, and her wound had been treated with a wound VAC dressing. Magnetic resonance imaging was not initially available, so noncontrast computed tomography (CT) was performed. Noncontrast CT is excellent at delineating air, which appears black on bone windows. A, The midsagittal view demonstrates air (black) in the spinal canal at the L2 and L3 levels. On the axial views (B, C), air is visible in the spinal canal, in paraspinal soft tissues, and within the vertebral body. These findings are concerning for a paraspinal infection that has developed into an epidural abscess with vertebral osteomyelitis. (From Broder JS: Diagnostic imaging for the emergency physician, Philadelphia, 2011, WB Saunders.)

ALG TREATMENT

Management of Patients with Spinal Epidural Abscess Syndrome (Acute onset of back pain and spinal tenderness plus fever.) (Higher integrative functions are intact, but neck stiffness may be present.) Acute onset or acute exacerbation of back pain, spinal tenderness, and fever

2 hours

Obtain MRI of spine Epidural mass present consistent with abscess?

Evaluate for other causes of back pain

Yes Begin antimicrobials directed against most likely pathogens* Neurologic deficit?

No Aspiration to obtain samples for microbiology Consider conservative observation only if:

Yes Emergent neurosurgical intervention to decompress lesion and obtain samples for microbiology

No neurologic deficit is present and Microbiologic etiology is firmly established and WBC and ESR fall rapidly on antibiotics and Excruciating pain resolves and Paraspinous fluid collections have been drained percutaneously (or if surgery is absolutely contraindicated for other reasons)

FIG. 3  Algorithm for the management of patients with spinal epidural abscess syndrome. If magnetic resonance imaging (MRI) cannot be performed, myelography, high-contrast computed tomography (CT), or CT-myelography may be an acceptable alternative to localize an epidural abscess. *If abscess drainage can be performed promptly, antimicrobial drugs may be withheld until specimens for microbial analysis are obtained. ESR, Erythrocyte sedimentation rate; MRI, magnetic resonance imaging; WBC, white blood cell. (From Vincent JL et al: Textbook of critical care, ed 6, Philadelphia, 2011, WB Saunders.)

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CHRONIC Rx Neurologic deficits may remain despite aggressive treatment. DISPOSITION Irreversible paralysis and death can occur in up to 25% of patients. REFERRAL All cases should be referred to a neurosurgeon and an infectious disease specialist.

 EARLS & P CONSIDERATIONS • Follow-up imaging with MRI is not necessary unless patient develops new neurologic signs or symptoms, has poor clinical response, or has persistent elevation of inflammatory markers. • It is critically important to recognize this process early; the prognosis is generally excellent if treatment is initiated while symptoms are localized and before evidence of myelopathy develops. • The likelihood of success postsurgery is low in patients who have developed complete paralysis for longer than 36 hours.

Obtain baseline blood cultures, WBC, and ESR

No

IV q6h) or carbapenem such as meropenem (1 to 2 g IV q8h) or imipenem. The regimen can be adjusted according to culture results. Therapy should continue for at least 4 to 6 wk.

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SUGGESTED READINGS Available at ExpertConsult.com AUTHOR: Glenn G. Fort, MD, MPH

Diseases and Disorders

NONPHARMACOLOGIC THERAPY • Surgical decompression is the mainstay of treatment. Decompression within the first 24 hr has been related to an improved prognosis. • Nonsurgical treatment is effective in some patients, but failure rate may be excessive. This approach should not be considered and should only be attempted in the absence of signs of compressive myelopathy and with very careful follow-up.

ACUTE GENERAL Rx • In addition to surgery, antibiotics directed at the most likely organism should be initiated. Fig. 3 describes an algorithm for the management of patients with SEA. • If the organism is unknown, broad coverage against staphylococci, streptococci, and gram-negative bacilli should be initiated. Empiric antimicrobial intravenous therapy typically includes vancomycin (loading dose: 25 to 30 mg/kg, then 15 to 20 mg/kg q8-12h, aiming for trough levels of 15 to 20) plus an antipseudomonal cephalosporin such as piperacillin/tazobactam at high dose (4.5 g

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Spinal Epidural Abscess SUGGESTED READINGS Shah AA et  al: Nonoperative management of spinal epidural abscess: development of predictive algorithm for failure, J Bone Joint Surg Am 100(7):546-555, 2018. Vakili M, Crum-Cianflone NF: Spinal epidural abscess: a series of 101 cases, Am J Med 130:1458-1463, 2017.

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Spinal Stenosis, Cervical Spine BASIC INFORMATION DEFINITION Cervical spinal stenosis is defined as any abnormal narrowing of the cervical spinal canal. Radiographically, absolute cervical stenosis is defined as a canal diameter less than 10 mm, and relative stenosis is defined as a canal diameter between 10 and 13 mm. Stenosis of any part of the spinal canal (cervical, thoracic, or lumbar) may be congenital or, more commonly, acquired. Congenital spinal stenosis is due to a skeletal hypoplasia, whereas acquired stenosis is a multifactorial process that usually evolves with advanced age and as a result of degenerative disease. Symptoms arising from cervical spinal stenosis are due to compression of the exiting nerve root or on the spinal cord itself. SYNONYMS Cervical myelopathy Cervical radiculopathy Degenerative disease of the spine Spinal foramina narrowing ICD-10CM CODES M47.12 Other spondylosis with myelopathy—cervical region M47.22 Other spondylosis with radiculopathy—cervical region M47.812 Cervical spondylosis without myelopathy or radiculopathy M48.02 Spinal stenosis in cervical region M50.0 Cervical disc disorder with myelopathy M50.1 Cervical disc disorder with radiculopathy

EPIDEMIOLOGY & DEMOGRAPHICS PEAK INCIDENCE: In acquired cases, >50 yr PREVALENCE: 1:1000 persons >65 yr old and 5:1000 persons >50 yr old PREDOMINANT SEX AND AGE: Males and females affected equally; age depends on etiology (congenital vs. acquired); in acquired cases, most common between 20 and 65 yr of age

GENETICS: Genetic factors play a role in degenerative disease of the vertebrae and disc desiccation, but no one associated gene has been identified. RISK FACTORS: Systemic diseases, rheumatoid arthritis, osteoarthritis; degenerative disc disease, repetitive microtrauma (spear tackler’s spine), poor ergonomics

PHYSICAL FINDINGS & CLINICAL PRESENTATION • Neurologic symptoms related to cervical stenosis may include: 1. Chronic neck pain 2. Unilateral or bilateral upper limb pain, often radiating 3. Numbness of hands 4. Arm or hand clumsiness 5. Loss of hand dexterity 6. Progressive loss of fine motor function of the hands 7. Weakness of the upper extremities and proximal lower extremities 8. Decreased sensation of the arm or hands 9. Gait disturbances 10. Hyperreflexia • A positive Hoffman sign has somewhat low sensitivity but can be specific for cervical myelopathy in the context of other signs and symptoms. • Central cord syndrome should be considered if a patient with existing cervical stenosis falls and develops weakness greater in the upper extremities than lower extremities. ETIOLOGY • Congenital or developmental cervical spinal stenosis is associated with skeletal hypoplasia resulting in diminished space within the spinal canal. Possible causes include: 1. Vertebral segmentation failure 2. Achondroplasia 3. Incomplete vertebral arch fusion 4. Anterior vertebral wedging or beaking 5. Thoracolumbar kyphosis 6. Early vertebral arch ossification • Acquired stenosis accounts for the majority of cases; most arise from degenerative changes at the disk space level. It is a complex process that can also involve systemic,





traumatic, and iatrogenic etiologies (Fig. E1). Several causes include: 1. Facet joint and ligamentum flavum hypertrophy 2. Stenosis from herniated disks 3. Ossification of the posterior longitudinal ligament 4. Spondylolisthesis 5. Previous spinal fusions 6. Paget disease 7. Acromegaly 8. Ankylosing spondylitis

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • Ankylosing spondylitis • Rheumatoid arthritis • Diffuse idiopathic skeletal hyperostosis (DISH) • Epidural, subdural, or intradural abscess • Metabolic diseases (osteomalacia, vitamin B12, or folate deficiency) • Vascular disease (peripheral with claudication) • Lumbar muscle strain • Thoracic outlet syndrome • Metastatic disease, Paget disease • Conversion disorder, malingering • Various intracranial processes WORKUP • Imaging modalities are of greatest utility in diagnosing cervical stenosis 1. AP and lateral cervical spine x-rays 2. Cervical spine CT scan can be helpful to describe the bony architecture 3. Cervical spine MRI immediately if neurologic deficit or if pain >4 wk; most useful diagnostic test (Fig. E2) 4. CT myelography if MRI is contraindicated (pacemaker) • Consider nerve conduction studies if imaging equivocal

Osteophytes Osteophytes

Buckled ligamentum flavum Intervertebral discs Spinal cord

FIG. E1  Illustration of cervical spinal stenosis with associated causes (disc protrusion, osteophyte formation, hypertrophied ligamentum flavum). (From Frontera WR et al: Essentials of physical medicine and rehabilitation, Philadelphia, 2015, Elsevier.)

FIG. E2  T2 magnetic resonance image of the cervical spine demonstrating stenosis within the canal at the C4 to C5 and C5 to C6 level. (From Crowley P, Oxon BA: Neuroimaging of spinal canal stenosis, MRI Clin N Am 24:523-539, 2016.)

Spinal Stenosis, Cervical Spine LABORATORY TESTS Appropriate blood tests or CSF examination to rule out conditions on differential diagnosis

TREATMENT Management of cervical spinal stenosis is geared toward symptom relief, preservation of function, and prevention of further neurologic decline. The decision between conservative or operative treatment depends on symptom severity, chronicity, and presence of neurologic deficits.

NONPHARMACOLOGIC THERAPY • Physical/occupational therapy • Mechanical measures (soft collar, heat, firm pillow) for pain relief • Lifestyle changes • Cervical traction PHARMACOLOGIC THERAPY • Analgesics • Antiinflammatory agents: 1. Use of PO or IV steroids 2. Epidural steroid injections • Antispasmodics

• M embrane stabilizing anticonvulsants (e.g., gabapentin) for neuropathic/radicular pain

DISPOSITION • Nonoperative management of symptomatic patients is usually a temporizing measure; however, physicians must exhaust all nonsurgical options before referral for surgery in the absence of major neurologic deficits or progressive decline. • Between 5% and 25% of patients with cervical stenosis will require surgery, with 33% of those experiencing favorable outcomes. • Surgical intervention often involves decompression of the spinal cord/canal and fusion of the bony elements for stabilization. Laminoplasty, in which the spine is decompressed but the posterior processes are not resected, may be an option for eligible patients to retain motion. REFERRAL • Physical therapy • Orthopedic or neurosurgical spine specialist for possible surgical decompression and fusion

SUGGESTED READINGS Aljuboori Z, Boakye M: The natural history of cervical spondylotic myelopathy and ossification of the posterior longitudinal ligament: a review article, Cureus 11(7):e5074, 2019. Clarencon F et al: The degenerative spine, Magn Reson Imaging Clin N Am 24(3):495–513, 2016. Crowley P, Oxon BA: Neuroimaging of spinal canal stenosis, Magn Reson Imaging Clin N Am 24:523-539, 2016. Gutierrez GJ, Chirumamilla D: Cervical spinal stenosis. In Desai M, O'Brien J, (eds): The spine handbook, New York, 2018, Oxford University Press, pp. 132-146. Lund T, Santos de Moraes OJ: Cervical, thoracic and lumbar stenosis. In Winn HR et al: Youmans and Winn neurological surgery, Philadelphia, 2017, Elsevier, pp. 2373-2383. Meleger AL, Egyhazi R: Cervical spinal stenosis. In Frontera WR et al (eds): Essentials of physical medicine and rehabilitation, Philadelphia, 2015, Elsevier, pp. 35-39. Toledano M, Bartleson JD: Cervical spondylotic myelopathy, Neurol Clin 31:287305, 2013.

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 EARLS & P CONSIDERATIONS COMMENTS As the population ages, cervical spinal stenosis will increase in prevalence. In general, treatment is initiated when the patient becomes symptomatic. The majority of patients can be treated conservatively, and in the primary care setting, immediate intervention for asymptomatic cervical stenosis is not necessary. However, any patient presenting with a neurologic deficit should be referred urgently to a spine specialist. PREVENTION Measures to strengthen neck musculature, improve the ergonomics of one’s work environment, as well as avoiding chronic repetitive trauma may play a role in prevention of acquired cases. PATIENT & FAMILY EDUCATION Patient information on cervical spinal stenosis is available at www.spine-health.com/ conditions/spinal-stenosis. AUTHORS: Lindsay R. Kosinski, MD, and Shyam A. Patel, MD

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Spinal Stenosis, Lumbar

ALG

• Primary stenosis (congenital or developmental narrowing): 1. Idiopathic 2. Achondroplasia 3. Morquio-Ullrich syndrome • Secondary stenosis (acquired): 1. Degenerative (hypertrophy of the articular processes, disk degeneration, ligamentum flavum hypertrophy, spondylolisthesis) 2. Fracture/trauma 3. Postoperative (postlaminectomy) 4. Paget disease 5. Ankylosing spondylitis 6. Tumors 7. Acromegaly

BASIC INFORMATION DEFINITION Lumbar spinal stenosis (LSS) is an anatomical impairment characterized by narrowing of the spinal canal or nerve root foramen (Fig. E1). SYNONYMS Central spinal stenosis Lateral spinal stenosis Spondylosis Lumbar spinal stenosis LSS ICD-10CM CODE M48.06  Spinal stenosis, lumbar region

• Ultrasound of the spinal canal has also been used. • CT scan of the lumbosacral spine: Sensitivity (75% to 85%), specificity (80%). • MRI of the lumbosacral spine (Fig. E4): Sensitivity (80% to 90%), specificity (95%). • Myelogram: Sensitivity (77%), specificity (72%). Absolute stenosis is defined as the anterior-posterior (AP) diameter of the spinal canal 50 yr),

ETIOLOGY Several of the SCAs are the result of polyglutamine CAG repeat expansions; this leads to the accumulation of mutant proteins inside neurons, which is thought to cause neuronal dysfunction and cell death. Higher numbers of repeats are correlated with an earlier onset of symptoms, and anticipation in subsequent generations may be present. Other types of repeat expansions and point mutations have been found with several SCAs; for others, the affected gene has not been identified.

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • Structural cerebellar abnormality: Includes cerebellar tumor, inflammation (e.g., multiple sclerosis), stroke, or hemorrhage; the time course for these causes is typically more acute or subacute than chronic. • Endocrine dysfunction: Hypothyroidism or hypoparathyroidism can uncommonly cause ataxia. • Alcoholic cerebellar degeneration: Caused by heavy alcohol use; gait ataxia predominates. • Other toxin-induced ataxias: Antiepileptic medications, lithium, heavy metals (lead, manganese, mercury, bismuth), and chemotherapeutic agents. • Creutzfeldt-Jakob disease: Rapidly progressive ataxia, dementia, and myoclonus. • Paraneoplastic cerebellar degeneration: Found in association with primary malignancies (e.g., small cell lung cancer, breast cancer); subacute-onset ataxia that progresses rapidly.

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1–58y

2–56y

3–54y

4–55y

21/69 50y

1–30y

II 37y

2–33y

3–33y

4–32y

5–29y III

22/69 21/70

25/67 29y

25y 2–4y

1–11y

67/72

3–8y IV

4y

FIG. E1  Family pedigree of proband (IV-1). Age at onset of spinocerebellar ataxia type 3 symptoms is given beneath symbols (italics). Above the symbols, the actual age of the members of the family is given. If tested, the number of CAG repeat units of the ATXN3 allele pair is also given (underscored italics). (From Daniel RC et al: Homozygosity enhances severity in spinocerebellar ataxia type 3, Pediatri Neurol 38[4]:296-299, 2008.)

These proofs may contain color figures. Those figures may print black and white in the final printed book if a color print product has not been planned. The color figures will appear in color in all electronic versions of this book.

Spinocerebellar Ataxia tremor, and sometimes parkinsonism; MRI often shows T2 hyperintensities in the middle cerebellar peduncle. • Episodic ataxias: Autosomal dominant, transient ataxia lasting seconds to days depending on the mutation; pediatric onset in most; ataxia may be responsive to acetazolamide. • Spastic ataxias: Distinguished by prominent, symmetric spasticity, particularly of the lower extremities. Most of these conditions have an autosomal recessive pattern of inheritance and include autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS), hereditary spastic paraplegia (HSP), and cerebrotendinous xanthomatosis. • Box E1 shows the classification of the various causes of ataxia.

LABORATORY TESTS • Rule out acquired causes of ataxia, depending on the clinical scenario, with thyroid studies, toxicology screening, and the determination of the vitamin E level or presence of paraneoplastic antibodies. • For pediatric patients, screen for ataxia telangiectasia with serum alpha-fetoprotein (AFP). • Screen for Wilson disease with ceruloplasmin and, if indicated, a 24-hour urinary copper determination. • Genetic testing is commercially available for many but not all of the SCAs (SCA 1, 2, 3, 5, 6, 7, 8, 10, 12, 13, 14, 17, 28, DRPLA).

1289.e9 IMAGING STUDIES • MRI of the brain should be performed to exclude structural abnormalities. • Cerebellar or brain stem atrophy can be seen with several of the SCA subtypes.

TREATMENT NONPHARMACOLOGIC THERAPY • Speech therapy for dysarthria and dysphagia • Physical therapy • Occupational therapy CHRONIC Rx Treatment is symptomatic and supportive. In some cases, parkinsonism can respond to levodopa. Clonazepam can be helpful if tremor is prominent. Spasticity can be treated with baclofen or tizanidine. Focal spasticity or dystonia may benefit from botulinum toxin injections. DISPOSITION All SCA disorders are progressive, although the speed is variable from subtype to subtype and from patient to patient. On average, patients become wheelchair bound 15 yr after the onset of ataxia, and death can occur after 20 to 25 yr.

 EARLS & P CONSIDERATIONS COMMENTS • Genetic testing can have consequences for both the patient and the family. These issues should be discussed during the informed consent process. Patients who desire asymptomatic testing as a result of a relevant family history should undergo genetic counseling before testing. • In symptomatic patients with a family history of dominantly inherited ataxia, the diagnostic process is relatively straightforward. Genetic testing that is directed toward likely mutations by phenotype and ethnic origin should be the first step, rather than an extensive workup for other causes. PATIENT & FAMILY EDUCATION Patient educational materials, as well as contact information for support and advocacy groups, are available through the National Ataxia Foundation: http://www.ataxia.org. AUTHORS: Andrew P. Duker, MD, and Jennifer E. Vaughan, MD

REFERRAL Referral to a general neurologist or to a movement disorders center is appropriate.

SUGGESTED READINGS Bird TD: Hereditary ataxia overview. Available at www.ncbi.nlm.nih.gov/books/NB K1138/ Accessed January 3, 2020. Rossi M et al: Movement disorders in autosomal dominant cerebellar ataxias: a systematic review, Mov Disord Clin Pract 1:154-160, 2014. Verbeek DS, van de Warrenburg BPC: Genetics of the dominant ataxias, Semin Neurol 31:461-469, 2011.

BOX E1  Classification of Ataxia Congenital Ataxias Hereditary Ataxias Autosomal Recessive Ataxias • Friedreich ataxia • Ataxia–telangiectasia • Ataxia with oculomotor apraxia type 1 • Ataxia with oculomotor apraxia type 2 • Autosomal recessive spastic ataxia of Charlevoix-Saguenay • Abetalipoproteinemia • Ataxia with isolated vitamin E deficiency • Refsum disease • Cerebrotendinous xanthomatosis • Marinesco-Sjögren syndrome • Autosomal recessive ataxia with known gene locus • Early-onset cerebellar ataxia X-Linked Ataxias • Fragile X tremor ataxia syndrome Autosomal Dominant Ataxias • Spinocerebellar ataxias • Dentatorubral-pallidoluysian atrophy • Episodic ataxias

Nonhereditary Degenerative Ataxias • Multiple system atrophy, cerebellar type • Sporadic adult-onset ataxia of unknown etiology Acquired Ataxias • Alcoholic cerebellar degeneration • Ataxia as a result of other toxic causes (e.g., antiepileptic medications, lithium, solvents) • Paraneoplastic cerebellar degeneration (e.g., anti-Hu, anti-VGKC, antiCV2) • Other immune-mediated ataxias (e.g., gluten ataxia, ataxia associated with anti-glutamic acid decarboxylase antibodies) • Acquired vitamin E deficiency • Hypothyroidism • Ataxia as a result of physical causes (e.g., heat stroke, hyperthermia)

From Goetz CG: Textbook of clinical neurology, ed 3, Philadelphia, 2007, WB Saunders.

These proofs may contain color figures. Those figures may print black and white in the final printed book if a color print product has not been planned. The color figures will appear in color in all electronic versions of this book.

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Spondyloarthropathies BASIC INFORMATION DEFINITION Spondyloarthropathies (SpAs) are a group of interrelated systemic autoinflammatory conditions that are serologically negative for rheumatoid factor, connected by an underlying genetic risk with similar patterns of inflammation. This group encompasses ankylosing spondylitis, psoriatic arthritis, reactive arthritis, enteropathic arthritis, and undifferentiated spondyloarthritis (Table 1). SpAs are broadly classified by axial versus peripheral joint involvement, with or without radiographic progression. SYNONYMS Spondyloarthritis Spondylopathy Spondylitis Spondylosis SPAs ICD-10CM Codes M46.80 Other specified inflammatory spondylopathies, unspecified site M46.82 Other specified inflammatory spondylopathies, cervical region M46.83 Other specified inflammatory spondylopathies, cervicothoracic region M46.86 Other specified inflammatory spondylopathies, lumbar region M46.87 Other specified inflammatory spondylopathies, lumbosacral region M46.89 Other specified inflammatory spondylopathies, multiple sites M46.81 Other specified inflammatory spondylopathies, occipito-atlantoaxial region M46.88 Other specified inflammatory spondylopathies, sacrococcygeal region M46.84 Other specified inflammatory spondylopathies, thoracic region M46.85 Other specified inflammatory spondylopathies, thoracolumbar region

EPIDEMIOLOGY & DEMOGRAPHICS PREVALENCE: Worldwide prevalence of SpA is 0.2% to 1.6%, with over 1% of the U.S. population affected. Varies regionally with prevalence of HLA-B27. PREDOMINANT SEX AND AGE: Males younger than age 45 yr are predominantly affected. Previously, male:female ratio was thought to be 10:1; more recently, about 3:1. Patients older than 45 yr may present with chronic, severe disease due to diagnostic delays. GENETICS: Association with the HLA-B27 allele is the strongest known genetic risk factor. RISK FACTORS: HLA-B27 allele*, male sex*, smoking*, ethnic background, family history of SpA, and certain infections (*Associated with more severe disease)

PHYSICAL FINDINGS & CLINICAL PRESENTATION • History: 1. Inflammatory low back pain may be the primary presenting symptom: a. Pain and stiffness in low back or buttocks that is worst in the morning, may awaken the patient from sleep, and improves with exercise b.  Morning stiffness generally lasting longer than 1 hour c. Improvement with NSAIDs d.  Sensitivity up to 90% and positive likelihood ratio up to 2.2 for axial SpA 2.  Symptoms of systemic and peripheral inflammation are additional clues that can be elicited in a comprehensive review of systems: a. Uveitis: Painful ocular inflammation b. Psoriasis: Chronic skin inflammation with red patches and silvery scales c.  Inflammatory bowel disease: Crohn disease and ulcerative colitis d. Synovitis: Inflammation of the synovial membrane of joints e.  Enthesitis: Inflammation at the site of tendon or ligament insertion onto bone f. Dactylitis: Tenosynovitis of the digits causing classic sausage-like appearance • Physical exam: 1. Axial joints: Spine and sacroiliac (SI) joints 2. Inspect curvature, palpate for tenderness, and evaluate range of motion for cervical, thoracic, and lumbar spine. Measure degree of axial involvement with occiput wall, thoracic expansion. Patients with SpA may have an abnormal Schober test result (Fig. E1). This test is performed by having the patient stand erect and marking the distance between the midpoint of the posterior superior iliac spines (“dimples of Venus”) and 10 cm above that point. The patient is then asked to maximally flex forward while the more caudal spot is kept

stationary. The more cephalad point on the tape measure should demonstrate at least 5 cm of excursion. This abnormality also can be seen with lumbar degenerative disk disease. Test for sacroiliitis with Patrick and Gaenslen tests 3.  Peripheral joints: Lower extremity predominance 4. Inspect for signs of inflammation, including dactylitis, synovitis, and enthesitis 5. Evaluate for systemic involvement manifesting as anterior uveitis and psoriasis: a.  Slit lamp is necessary to diagnose anterior uveitis b.  Full skin exam is critical to detect occult psoriasis; look for nail changes • Musculoskeletal manifestations commonly affect weight-bearing joints with high mechanical stress; thus, it is particularly important to examine the lumbar spine, SI joints, and lower extremities • Degree of axial involvement can be measured via specialized exam techniques, which are used to track disease activity and response to treatment over time

ETIOLOGY • Genetic: 1. The HLA-B27 allele has a strong association with SpA, through mechanisms not fully understood. • Environmental: 1. Microbial infections, disruptions in barrier defense mechanisms (skin and intestinal mucosa), and mechanical articular stressors may trigger an inflammatory response, which then develops into signs and symptoms specific to each type of SpA. • Autoinflammatory: 1.  Key components of the inflammatory cascade involved in the pathogenesis of SpA are TNF, IL-12, IL-17, IL-23, and prostaglandins. Success in treatment with targeted therapies to each of these molecules has helped us understand their role in the etiology of SpA.

TABLE 1  Comparison of Ankylosing Spondylitis and Related Disorders Feature Sex (male:female) Age of onset Sacroiliitis or spondylitis (%) Symmetry of sacroiliitis Peripheral arthritis (%) Distribution HLA-B27 positivity (%) Uveitis

Ankylosing Spondylitis

Psoriatic Arthritis

Reactive Arthritis

Enteropathic Arthropathy

2-3:1 250/mm3 • Presence of bacteria on Gram stain • pH 32 mg/dl • Protein 50 mg/dl • Lactate dehydrogenase 1.1 g/dl, the patient has portal hypertension, with 97% accuracy. If the difference is 30 mg/dl, serum creatinine >1 mg/ dl, bilirubin >4 mg/dl. PROPHYLAXIS • Ciprofloxacin 500 mg PO qd or levofloxacin 250 mg PO qd. • Alternative therapy: TMP-SMX one doublestrength tablet PO qd. • Rifaximin 1200 mg a day was shown in a recent study to be superior to norfloxacin. • Prophylaxis should be continued until disappearance of ascites or until liver transplantation. DISPOSITION The overall mortality rate from an episode of SBP is 20%, and following an episode, the 1-yr mortality rate approaches 70%. Patients that develop SBP should be considered for liver transplantation.

PEARLS & CONSIDERATIONS COMMENTS • Renal failure is a major cause of morbidity in cirrhotic patients with SBP. The use of IV albumin (1.5 g/kg at the time of diagnosis and 1 g/kg on day 3) may lower the rate of renal failure and mortality in patients with SBP. • The criteria for the diagnosis of SBP require that abdominal paracentesis be performed and ascitic fluid be analyzed before a diagnosis of SBP can be made. • Culturing ascitic fluid as if it were blood (with bedside inoculation of at least 10 ml of ascitic fluid directly into blood culture bottles at the bedside) has been shown to significantly increase the culture positivity of the ascitic fluid in the 80% to 100% range. • Avoid therapeutic paracenteses during active infection. • Positive blood cultures in an individual with ascites require exclusion of a peritoneal source by paracentesis. • Follow-up paracentesis is indicated only in selected cases (worsening clinical status, nosocomial SBP, infection with atypical organism, recent β-lactam exposure). SUGGESTED READINGS Available at ExpertConsult.com AUTHOR: Glenn G. Fort, MD, MPH

S

Diseases and Disorders

DEFINITION Spontaneous bacterial peritonitis (SBP) is an inflammatory reaction of the peritoneum secondary to the presence of bacteria or other microorganisms. More specifically, SBP is defined as an ascitic fluid infection without an evident intraabdominal surgically treatable source occurring primarily in patients with advanced cirrhosis of the liver.

DIAGNOSIS

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Spontaneous Bacterial Peritonitis SUGGESTED READINGS Dever JB, Sheikh MY: Review article: spontaneous bacterial peritonitis—bacteriology, diagnosis, treatment, risk factors and prevention, Aliment Pharmacol Ther 41:1116-1131, 2015. Ekser B, Mangus RS: Spontaneous bacterial peritonitis, Lancet S0140S6736(16):30782-30786, 2016. Elfert A et al: Randomized-controlled trial of rifaximin versus norfloxacin for secondary prophylaxis of spontaneous bacterial peritonitis, Eur J Gastroenterol Hepatol 28:1450-1454, 2016. Narula N et al: Should albumin be used in all patients with spontaneous bacterial peritonitis? Can J Gastroenterol 25(7):373-376, 2011.

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Sporotrichosis BASIC INFORMATION DEFINITION Sporotrichosis is a granulomatous/pyogenic disease commonly caused by pathogenic strains of the dimorphic fungus Sporothrix schenckii, although at least six other pathogenic Sporothrix species exist in various geographic regions, such as Sporothrix brasiliensis. SYNONYMS Lymphocutaneous sporotrichosis Cutaneous sporotrichosis Pulmonary sporotrichosis ICD-10CM CODES B42.0 Pulmonary sporotrichosis B42.1  Lymphocutaneous sporotrichosis B42.7 Disseminated sporotrichosis B42.8 Other forms of sporotrichosis B42.9 Sporotrichosis, unspecified

EPIDEMIOLOGY & DEMOGRAPHICS PREDOMINANT SEX: The most common form, lymphocutaneous sporotrichosis, occurs equally in both sexes. Males predominate in both pulmonary and osteoarticular sporotrichosis. PREDOMINANT AGE: Generally, lymphocutaneous sporotrichosis occurs in people 35 yr of age or younger, usually through occupation or hobbies such as landscaping or gardening. Pulmonary sporotrichosis occurs in people between the ages of 30 and 60 yr, often alcoholic men with COPD and diabetics. Those with HIV are at risk for disseminated infection. GENETICS: Neonatal infection: At least one case of transmission from the cheek lesions of the mother to the skin of the infant has been reported. PHYSICAL FINDINGS & CLINICAL PRESENTATION • Cutaneous disease: 1. Arises at the site of inoculation, often the site of soil exposure (Fig. E1) 2. Initial lesion usually located on the distal part of an extremity (Fig. E2), although any area may be affected, including the face 3.  Variable incubation period of approximately 3 wk once introduced into the skin 4. Granulomatous reaction provoked 5. Lesion becomes papulonodular, erythematous, elastic, variable in size 6.  Subsequently, nodule becomes fluctuant, undergoes central necrosis, breaks down, discharges mucoid pus from which fungus may be isolated 7. Indolent ulcer with raised erythematous or violaceous borders 8. Secondary lesions: a.  Develop along superficial lymphatic channels b. Evolve in the same manner as the primary lesion, with subsequent inflammation, induration, and suppuration • Fixed, or plaque form: 1.  Erythematous verrucous, ulcerated, or crusted lesions



2. Does not spread locally 3. Does not involve lymphatic vessels 4. Rarely undergoes spontaneous resolution 5. More often persists for yrs without systemic symptoms and within a setting of normal laboratory examinations • Osteoarticular involvement: 1. Most common extracutaneous form 2. Usually presents as monoarticular arthritis 3. Left untreated, may progress to: a. Synovitis b. Osteitis c. Periostitis d.  All involving elbows, knees, wrists, and ankles 4. Joint inflamed: a. Associated with an effusion b. Painful on motion • Early pulmonary disease: 1. Usually associated with a paucity of clinical findings: a. Low-grade fever b. Cough c. Fatigue d. Malaise e. Weight loss







2. Untreated: a. Cavitary pulmonary disease b. Frank pulmonary dysfunction c. Hemoptysis d. Mimics tuberculosis 3. Meningitis: a.  Uncommon except perhaps in the immunocompromised patient b. Presents with few signs or symptoms of neurologic involvement, usually headache 4. Few reported cases: a. Infection of the ocular adnexa b.  Endophthalmitis without antecedent trauma c. Infection of the testes and epididymis d.  Certain strains favor cooler body areas such as the scrotum, lower extremities

ETIOLOGY • Sporothrix schenckii: 1. Global in distribution 2. Often isolated from soil, plants, and plant products

FIG. E1  Sporotrichosis. Erythematous papules and nodules on the plantar surface with early lymphangitic (sporotrichoid) spread. (From Paller AS, Mancini AJ: Hurwitz clinical pediatric dermatology, a textbook of skin disorders of childhood and adolescence, ed 5, 2016, Elsevier.)

FIG. E2  Sporotrichosis of the fifth finger in a gardener. Three nodular lesions are visible on the hand and arm. (From Mandell GL et al: Principles and practice of infectious diseases, ed 7, Philadelphia, 2010, WB Saunders.)

Sporotrichosis 3. Majority of case reports from tropical and subtropical regions of the Americas • Occupational or recreational exposure: 1. Hay 2. Straw 3. Sphagnum moss 4. Timber 5. Thorny plants (e.g., roses and barberry bushes) • Animal contact: 1. Armadillos 2. Cats 3. Squirrels • Tattooing

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • Fixed, or plaque, sporotrichosis: 1. Bacterial pyoderma 2. Foreign body granuloma 3. Tularemia 4. Anthrax 5. Other mycoses: Blastomycosis, chromoblastomycosis • Lymphocutaneous sporotrichosis: 1.  Nocardia brasiliensis 2.  Leishmania braziliensis 3.  Atypical mycobacterial disease: Mycobacterium marinum, Mycobacterium kansasii • Pulmonary sporotrichosis: 1. Pulmonary TB 2. Histoplasmosis 3. Coccidioidomycosis • Osteoarticular sporotrichosis: 1. Pigmented villonodular synovitis 2. Gout 3. Rheumatoid arthritis 4. Infection with Mycobacterium tuberculosis 5. Atypical mycobacteria: Mycobacterium marinum, Mycobacterium kansasii, Mycobacterium avium-intracellulare • Meningitis: 1. Histoplasmosis 2. Cryptococcosis 3. TB WORKUP • The diagnosis should be considered in individuals who are occupationally exposed to soil, decaying plant matter, and thorny plants (gardeners, horticulturists, farmers) who present with chronic nonhealing ulcers or lesions with or without associated arthritis or pulmonary symptoms. • Diagnosis is made by culture: 1. Pus 2. Joint fluid 3. Sputum 4. Blood 5. Skin biopsy • Isolation of the fungus from any site is considered diagnostic of infection. • Saprophytic colonization of the respiratory tract has been described. • A positive blood culture may indicate infection in an immunocompromised host.

1295.e3 • Increasingly sensitive laboratory culturing systems may detect the fungus in the normal host. • Biopsy specimens are diagnostic if characteristic cigar-shaped, round, oval, or budding yeast forms are seen. • Despite special staining, the yeast may remain difficult to detect unless multiple sections are examined, as organisms are rare. • No standard method of serologic testing is available.

LABORATORY TESTS • CBCs and serum chemistries are generally normal. • Elevated ESR is seen with extracutaneous disease. • CSF analysis in meningeal disease reveals: 1. Lymphocytic pleocytosis 2. Elevated protein 3. Hypoglycorrhachia • Nested polymerase chain reaction (PCR) assay represents a future clinical modality to rapidly detect Sporothrix schenckii. • Matrix-assisted laser desorption ionizationtime of flight (MALDI-TOF) has been used to identify Sporothrix grown in culture to the species level. IMAGING STUDIES • Chest x-ray examination: Unilateral or bilateral upper lobe cavitary or noncavitary lesions • Radiographic findings of affected joints: 1. Loss of articular cartilage 2. Periosteal reaction 3. Periarticular osteopenia 4. Cystic changes

TREATMENT NONPHARMACOLOGIC THERAPY Local heat and prevention of bacterial superinfection in cutaneous or plaque form. This treatment is important for pregnant women as azoles are teratogenic. ACUTE GENERAL Rx CUTANEOUS AND LYMPHOCUTANEOUS SPOROTRICHOSIS: • Itraconazole at doses of 200 mg/day is the drug of choice and should be given for 2 to 4 wk after the lesions have resolved. • Alternative treatment: Use saturated solution of potassium iodide (SSKI) 5 to 10 drops PO tid or 1.5 ml PO tid, gradually increasing to 40 to 50 drops PO tid or 3 ml PO tid after meals. • Maximum tolerated dose should be continued until cutaneous lesions have resolved, approximately 6 to 12 wk. • Adjunctive therapy with heat is useful and occasionally curative. • Side effects of SSKI: 1. Nausea 2. Anorexia 3. Diarrhea 4. Parotid or lacrimal gland hypertrophy 5. Acneiform rash DEEP-SEATED MYCOSES (OSTEOARTICULAR, NONCAVITARY PULMONARY DISEASE): • Itraconazole:

1. Appropriate initial chemotherapy 2. Less toxic than amphotericin B 3. 200 mg PO bid for 1 to 2 yr with continued lifelong suppressive therapy in selected patients 4. Absence of relapses from 40 to 68 mo has been documented when at least 200 mg/day administered for 24 mo 5. Insufficient data for use in disseminated disease (e.g., fungemia and meningitis) 6.  Drug levels should be monitored to assess absorption • Parenteral amphotericin B, total course of 2 to 2.5 g or more, results in cure in approximately two thirds of cases. Lipid AmB 3 to 5 mg/kg/ day is also recommended and less toxic. 1. Relapses are common. 2.  Amphotericin B-resistant isolates of Sporothrix schenckii have been reported. 3. Remains the drug of choice for severely ill patients with disseminated disease. 4.  In cavitary pulmonary disease, given perioperatively as an adjunct to surgical resection. 5. When patient is improved, can continue treatment with itraconazole 200 mg PO bid. 6. Treat for at least 12 mo. 7. The latest IDSA guidelines recommend fluconazole only as an alternative treatment for lymphocutaneous disease. 8.  Requires daily doses of 400 mg/day for lymphocutaneous disease and 800 mg/day for visceral or osteoarticular disease. 9.  Fluconazole much less effective than itraconazole. 10. All azoles are teratogenic in pregnancy.

CHRONIC Rx For lymphocutaneous and visceral disease, therapy with itraconazole 200 mg/day for periods of 24 mo or greater. Sporothrix is resistant to voriconazole. It is sensitive in vitro to posaconazole, but existing data are very limited at present. DISPOSITION • Prognosis for cutaneous disease is good. • Prognosis is less satisfactory for extracutaneous disease, especially if associated with abnormal immunologic states or other underlying systemic diseases. REFERRAL • To surgeon; with an established diagnosis of pulmonary sporotrichosis, cavitary lesions require resection of involved tissue and possible pretreatment with amphotericin • To infectious disease physician

PEARLS & CONSIDERATIONS COMMENTS • In patients with underlying immunosuppression (e.g., hematologic malignancy or infection with HIV), progression of the initial infection may develop into multifocal extracutaneous sporotrichosis.

Sporotrichosis • In this subset of patients, dissemination of cutaneous lesions is accompanied by hematogenous spread to lungs, bone, mucous membranes, CNS. • Osteoarticular and pulmonary manifestations predominate with the development of polyarticular arthritis and osteolytic bone lesions. • In the absence of therapy, the infection is ultimately fatal. • Patients with underlying immunosuppressive states should be carefully evaluated

1295.e4 even when presenting with single cutaneous lesions. • Diagnostic modalities should include: 1. Radiographic examination of chest 2. Technetium pyrophosphate bone scan 3. Culture of synovial fluid, blood, skin lesion(s) • In patients with AIDS, itraconazole appears to be the drug of choice, although meningitis and pulmonary disease may warrant the use of amphotericin B.

SUGGESTED READINGS Aung AK et al: Pulmonary sporotrichosis: case series and systematic analysis of literature on clinico-radiological patterns and management outcomes, Med Mycol 51(5):534, 2013. Barros MB et al: Sporothrix schenckii and sporotrichosis, Clin Microbiol Rev 24:633, 2011. Bernardos-Engemann AR et al: Validation of a serodiagnostic test for sporotrichosis: a follow-up study of patients related to the Rio de Janeiro zoonotic outbreak, Med Mycol 53:28, 2015. Bonifaz A et al: Cutaneous and extracutaneous sporotrichosis: current status of a complex disease, J Fungi (Basel) 3, 2017. Bunce PE et al: Disseminated sporotrichosis in a patient with hairy cell leukemia treated with Ampho B and posaconazole, Med Mycol 50:197, 2012. Da Rosa AC et al: Epidemiology of sporotrichosis; a study of 304 cases in Brazil, J Am Acad Dermatol 52(3 Pt 1):451, 2005. De Lima Barros MB et al: Treatment of cutaneous sporotrichosis with itraconazole-study of 645 patients, Clin Infect Dis 52:e200, 2011. Espinel-Ingroff A et al: Multicenter international study of MIC/MEC distributions for definition of epidemiological cutoff values for Sporothrix species identified by molecular methods, Antimicrob Agents Chemother 61; e01057-17, 2017. Freitas DF et al: Sporotrichosis in HIV-infected patients: report of 21 cases of endemic sporotrichosis in Rio de Janeiro, Med Mycol 50:170, 2012. Freitas DF et al: Zoonotic sporotrichosis in Rio de Janeiro, Brazil: a protracted epidemic yet to be curbed, Clin Infect Dis 50(3):453, 2010.

• In patients with AIDS, lifetime suppressive therapy with itraconazole should follow initial therapy because of the potential for relapse and dissemination. Treatment may be terminated when CD4 counts exceed 200 for more than 1 yr. • Disseminated cases have been reported with the use of TNF-alpha inhibitors. AUTHOR: Patricia Cristofaro, MD

Gutierrez-Galhardo MC et al: Disseminated sporotrichosis as a manifestation of immune reconstitution inflammatory syndrome, Mycosis 53(1):78, 2010. Hessler C et al: The upside of bias: a case of chronic meningitis due to Sporothrix schenckii in an immunocompetent host, Neurohospitalist 7(1):30, 2017. Kauffman CA et al: Clinical practice guidelines for the management of sporotrichosis: 2007 update by the Infectious Diseases Society of America, CID 45:1255, 2007. Liu X et al: Rapid identification of Sporothrix schenckii in biopsy tissue by PCR, J Eur Acad Dermatol Venereal 27(12):1491, 2013. Oliveira MM et al: Development and optimization of a new MALDI-TOF protocol for the identification of the Sporothrix species complex, Res Microbiol 166:102, 2015. Rangel-Gamboa et al: Update of phylogenetic and genetic diversity of Sporothrix schenckii sensu lato, Med Mycol 54:248, 2016. Soto R, et al: Sporotrichosis among children of a hyperendemic area in Peru: an 8 year retrospective study, Int J Dermatol 56:868, 2017. Rodrigues AM et al: Genetic diversity and antifungal susceptibility profiles in causative agents of sporotrichosis, BMC Infect Dis 14:219, 2014. Rodrigues AM et al: Molecular diagnosis of pathogenic Sporothrix species, PLoS Negl Trop Dis 9:e0004190, 2015. Rodrigues AM et al: Emergence of pathogenicity in the Sporothrix schenckii complex, Med Mycol 51:405, 2013. Rudramurthy SM et al: Sporotrichosis: update on diagnostic techniques, Curr Fungal Infect Rep 11:134, 2017. Tiwari A et al: Primary pulmonary sporotrichosis: case report and review of the literature, Infect Dis Clin Pract 20:25, 2012.

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Squamous Cell Carcinoma BASIC INFORMATION DEFINITION Squamous cell carcinoma (SCC) is a malignant neoplasm of keratinocytes. SYNONYMS SCC Skin cancer ICD-10CM CODES C44.5 Malignant neoplasm of skin of trunk C44.4 Malignant neoplasm of skin of scalp and neck D04 Carcinoma in situ of skin C44.9 Malignant neoplasm of skin, unspecified C44.0 Malignant neoplasm of skin of lip C44.2 Malignant neoplasm of skin of ear and external auricular canal C44.3 Malignant neoplasm of skin of other and unspecified parts of skin C44.02 Squamous cell carcinoma of skin of lip C44.121 Squamous cell carcinoma of skin of unspecified eyelid, including canthus C44.122 Squamous cell carcinoma of skin of right eyelid, including canthus C44.129 Squamous cell carcinoma of skin of left eyelid, including canthus C44.221 Squamous cell carcinoma of skin of unspecified ear and external auricular canal C44.222 Squamous cell carcinoma of skin of right ear and external auricular canal C44.229 Squamous cell carcinoma of skin of left ear and external auricular canal C44.320 Squamous cell carcinoma of skin of unspecified parts of face C44.321 Squamous cell carcinoma of skin of nose C44.329 Squamous cell carcinoma of skin of other parts of face C44.42 Squamous cell carcinoma of skin of scalp and neck C44.520 Squamous cell carcinoma of anal skin C44.521 Squamous cell carcinoma of skin of breast C44.529 Squamous cell carcinoma of skin of other part of trunk C44.621 Squamous cell carcinoma of skin of unspecified upper limb, including shoulder C44.622 Squamous cell carcinoma of skin of right upper limb, including shoulder C44.629 Squamous cell carcinoma of skin of left upper limb, including shoulder C44.721 Squamous cell carcinoma of skin of unspecified lower limb, including hip C44.722 Squamous cell carcinoma of skin of right lower limb, including hip C44.729 Squamous cell carcinoma of skin of left lower limb, including hip C44.82 Squamous cell carcinoma of overlapping sites of skin

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EPIDEMIOLOGY & DEMOGRAPHICS • SCC is the second most common cutaneous malignancy, comprising 20% of all cases of nonmelanoma skin cancer. • Incidence is highest in lower latitudes (e.g., southern U.S., Australia). • Male:female ratio is 2:1. • Incidence increases with age and sun exposure. • In black patients, SCC are 20% more common than basal cell carcinomas (BCC). • Average age at diagnosis is 66 yr. PHYSICAL FINDINGS & CLINICAL PRESENTATION • SCC frequently begins at the site of actinic keratosis and commonly affects the scalp, neck region, back of hands (Fig. E1), superior surface of the pinna, and the lip (Fig. E2). On the lower lip, SCC often develops on actinic cheilitis. A history of smoking is a significant predisposing factor. • Bowen disease refers to SCC in situ (Fig. E3). • SCC lesions may have a scaly, erythematous macule or plaque (Fig. E4). • Telangiectasia, central ulceration may also be present. The ulcer may be superficial and hidden by a crust. Removal of the crust may reveal a well-defined papillary base. • Most SCCs present as exophytic lesions that grow over a period of mo. • Although most SCCs are relatively slow growing and nonaggressive, some (2% to 5%) can exhibit rapid growth and metastases. Aggressive tumors are more common in immunocompromised patients and when arising from scars, burns, or prior injury (Marjolin ulcer). Presence of SCC on ears, lips, or size >2 cm are high-risk features of SCC. ETIOLOGY Risk factors include ultraviolet B radiation, immunosuppression (kidney transplant recipients have a significantly increased risk), arsenic exposure, HPV infection, medications (azathioprine, sorafenib, tumor necrosis factor [TNF] inhibitors), discoid LE, erosive lichen planus, chronic ulcers, prior radiation exposure, and tobacco abuse.

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • Keratoacanthomas • Actinic keratosis • Amelanotic melanoma • Basal cell carcinoma • Benign tumors • Healing traumatic wounds • Spindle cell tumors • Warts WORKUP Diagnosis is made by full-thickness skin biopsy (incisional or excisional).

TREATMENT ACUTE GENERAL Rx • Electrodesiccation and curettage for small SCCs (6 mm - Perineural invasion of nerve ≥0.1 mm in diameter - Poorly differentiated histology

- Mohs surgery or excision with complete histologic margin evaluation - Consider sentinel lymph node biopsy - Consider adjuvant radiation therapy - Consider imaging - Multidisciplinary management - Surgery, if possible - Primary or adjuvant radiation therapy - Consideration for clinical trials, systemic therapy

SCC in situ

Low risk SCC

Diseases and Disorders

- Locally advanced / surgically unresectable SCC - Tumor in regional lymph nodes - Metastatic tumor

I - Mohs surgery* or - Wide excision with histologic margin control - Selected cases of small, superficially invasive, well-differentiated SCC may be managed as SCC in situ

- EDC - Cryosurgery - PDT - Imiquimod - Topical 5-FU - Excision - Mohs surgery*

- If tumor invades bone - If sentinel lymph node is positive - If tumor free plane cannot be achieved

*If lesion meets appropriate use criteria for Mohs surgery. Note: For nonsurgical candidates (> 60 years), radiation therapy may be considered regardless of tumor characteristics.

FIG. 5  Treatment algorithm for squamous cell carcinoma (SCC). EDC, Electrodesiccation and curettage; 5-FU, 5-fluorouracil; PDT, photodynamic therapy. (From Niederhuber JE: Abeloff’s clinical oncology, ed 6, Philadelphia, 2020, Elsevier.)

TABLE 1  Risk Factors for Metastasis of Invasive Squamous Cell Carcinoma Tumor thickness: >2 mm (high risk: tumor thickness >6 mm) Diameter: >2 cm Location: Ear, lips, and mucosae, including tongue, vulva, and penis (perineural growth may be an additional risk factor in these locations) Arising within a scar (e.g., burn, radiation) Histopathologic features: Poorly differentiated or undifferentiated, acantholytic,* developing within Bowen disease Immunosuppression *Recently questioned Ogawa T et al: Acantholytic squamous cell carcinoma is usually associated with hair follicles, not acantholytic actinic keratosis, and is not “high risk”: diagnosis, management, and clinical outcomes in a series of 115 cases, J Am Acad Dermatol 76:327-333, 2017. Based in part on Brantsch KD et al: Analysis of risk factors determining prognosis of cutaneous squamous-cell carcinoma: a prospective study, Lancet Oncol 9:713-720, 2008.

• Oral retinoids may be useful as a preventive strategy in patients with immunosuppression. • Nicotinamide (500 mg bid, available over the counter) mitigates some of the deleterious effects of UV radiation and has been reported to lower the incidence of nonmelanoma skin cancer (NMSC0) by 23%.2

RELATED CONTENT Squamous Cell Carcinoma (Patient Information) AUTHOR: Fred F. Ferri, MD 2 Chen

AC et al: A phase 3 randomized trial of nicotinamide for skin cancer chemoprevention, N Engl J Med 373:1618, 2015.

Squamous Cell Carcinoma

FIG. E1  Squamous cell carcinoma. (From James WD et  al: Andrews’ diseases of the skin, ed 12, Philadelphia, 2016, Elsevier.)

A

B FIG. E2  Squamous cell carcinoma of the lip. The lower lip (A) is a relatively commonly affected site. Smoking is a risk factor for this site, and the prognosis is poorer compared to similar-sized lesions at other sunexposed sites. Treatment is usually by wedge excision or with radiotherapy. By contrast, the upper lip margin (B) is a relatively uncommon site. The chronic trauma from the patient’s only three teeth may have been relevant. (From White GM, Cox NH [eds]: Diseases of the skin, a color atlas and text, ed 2, St Louis, 2006, Mosby.)

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C

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D FIG. E3  Squamous cell carcinomas in situ, Bowen disease type. A, Scaly red plaque on the chest with skip areas and background photodamage. B, Larger broken-up pink plaque with scale-crust in the pubic region, a sun-protected site. This type of lesion often is misdiagnosed as dermatitis or psoriasis and treated with topical corticosteroids. C, Bright red, well-demarcated plaque on the proximal nail fold with associated horizontal nail ridging; the possibility of HPV infection needs to be considered. D, Dermoscopic findings of tiny dotted vessels in the upper half of the lesion combined with superficial scales. E, Extensive involvement of the finger that was misdiagnosed clinically as an inflammatory dermatosis and treated for yrs with corticosteroid creams. (From Bolognia J: Dermatology, ed 4, Philadelphia, 2018, Elsevier. B, Courtesy Kalman Watsky, MD; D, Courtesy, Iris Zalaudek, MD)

FIG. E4  Squamous cell carcinoma in situ, erythroplasia of Queyrat type. Large, eroded erythematous plaque with well-demarcated borders. The lesion began on the shaft of the penis. (From Bolognia J: Dermatology, ed 4, Philadelphia, 2018, Elsevier.)

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Statin-Induced Muscle Syndromes BASIC INFORMATION DEFINITION Statin-induced muscle syndromes (SIMS) include myopathy, myalgia, myositis, and rhabdomyolysis. Definitions for these syndromes are inconsistent in the medical literature. • Myopathy: A general term defined as any disease of muscles. • Myalgia: Muscle weakness or pain without serum creatinine kinase elevation. • Myositis: Muscle weakness or pain with an increased serum creatinine kinase level. • Rhabdomyolysis: Muscle weakness or pain and a marked serum creatinine kinase level usually greater than 10× the upper limit of normal and serum creatinine elevation as well as signs of brown urine and elevated urine myoglobin. A rare immune-mediated necrotizing myopathy (IMNM), also known as statin-associated autoimmune myopathy, has also been associated with the use of statins with symptoms persisting after discontinuation of the drug. This condition presents with symmetric proximal arm and leg weakness and severe elevations of muscle enzymes. SYNONYMS SIMS Statin-induced myopathies Statin-induced myositis Statin-induced myalgias Statin-induced rhabdomyolysis Statin-associated autoimmune myopathy ICD-10CM CODES M60.9 Myositis, unspecified M62.82 Rhabdomyolysis G72.2 Myopathy due to other toxic agents G72.9 Myopathy, unspecified G72.81 Critical illness myopathy G72.89 Other specified myopathies M60.89 Other myositis, multiple sites

EPIDEMIOLOGY & DEMOGRAPHICS INCIDENCE: Risk of statin-induced rhabdomyolysis is 1.2 per 10,000 persons/yr. Rhabdomyolysis risk of death is 0.15 deaths per 1 million prescriptions. SIMS most commonly occur in people aged 51 to 75, which may reflect the pattern of statin use. Statin-associated autoimmune myopathy occurs in an estimated 2 or 3 of every 100,000 patients treated with statins. PEAK INCIDENCE: Patients on high-dose statins have a 0.9% incidence of statin-induced rhabdomyolysis. PREVALENCE: The prevalence of statin-induced myalgias is about 1% to 5%, similar to placebo in clinical trials, although observational studies have suggested a prevalence of 10% or higher. Statins may cause elevated transaminases (ALT, AST) at a prevalence of 0.5% to 2.0% and rhabdomyolysis ∼0.08%. PREDOMINANT SEX AND AGE: The mean age of hospitalized patients with statin-induced myopathy or rhabdomyolysis was 64 yr old and was slightly more common in women (56%).

GENETICS: Interpatient variability exists in the activity of the CYP3A4 gene for the metabolism of simvastatin, atorvastatin, and lovastatin. Homozygous carriers of CYP2D6 (poor metabolizers) had a higher rate of discontinuation of simvastatin due to muscle syndromes compared with the CYP2D6 wild-type genotype; patients taking atorvastatin and having a muscle event were more likely to have the CYP2D6*4 allele. SLCO1B1 polymorphisms encode for the organic anion transport of statins into the liver cells. The variant C allele may increase the risk of the SLCO1B1 statin–induced myopathy. Simvastatin-induced myopathy is more likely to be associated with SLO1B1 genotype and not ABCB1 genotype. However, a statin-associated autoimmune myopathy has shown a link to class II HLA allele DRB1*11:01 in the development of anti-HMG CoA reductase antibodies, leading to an increase in expression of the antibodies in the muscles of patients exposed to statins. Deficiencies in ubiquinone (coenzyme Q10) may exist in patients with a mutation in the COQ2 gene. The EYS gene can affect neuromuscular tissue and may have a role. In addition, RYR1 and CACNA1S genetic variants may be associated with statin-induced muscle syndromes and elevated CK levels. RISK FACTORS: Small body frame; age over 80 yr; women, particularly frail elderly women; patients taking multiple drugs, especially gemfibrozil, niacin, cyclosporine, itraconazole, ketoconazole, erythromycin, clarithromycin, verapamil, amiodarone; renal or liver impairment; pharmacogenetic variability; hypothyroidism; excessive alcohol intake; vigorous exercise; severe infections; excessive grapefruit juice ingestion; low vitamin D levels; inherited defects of muscle metabolism such as carnitine palmityl transferase II deficiency, McArdle disease, and myoadenylate deaminase deficiency; acquired myopathies such as postpoliomyelitis syndrome; lipophilic statins (simvastatin, atorvastatin, lovastatin); multiple conditions such as diabetes; renal impairment, and prior elevated CK; and drugs of abuse (amphetamines, heroin, cocaine, phencyclidine).

PHYSICAL FINDINGS & CLINICAL PRESENTATION • Myopathy can occur at any time, although it is more common within the first 4 wk of therapy; statin-associated necrotizing myopathy may occur after mos of using statins • Proximal generalized muscle aches, body aches, and pains, and may be mild or severe • Dark-colored urine • Muscle cramps, spasms, tenderness, or stiffness • Unusually tired or weak • Nocturnal cramping • Tendon pain ETIOLOGY • History of current statin use. • May be explained by one of three deficiencies of end products of the 3-hydroxy-3-methylglutaryl-coA reductase pathway: cell signaling and apoptosis, mitochondrial function and ubiquinone concentrations, and cholesterol concentrations and cell membrane integrity.

• The risk may be enhanced by drug interactions that interfere with hepatic metabolism and gut wall transport of interacting medications and by pharmacodynamic effects. • Underlying metabolic muscle disorder may predispose a patient to develop myopathy. • Patients with statin-associated autoimmune myopathy have been found to have antiHMG-CoA reductase antibodies even prior to exposure to statin therapy.

DIAGNOSIS DIFFERENTIAL DIAGNOSIS Bursitis, tendinitis, radiculopathy, osteoarthritis, muscle strain, myofascial pain, hypothyroidism, proton pump inhibitor–induced polymyositis, viral illness, polymyositis, idiopathic inflammatory myositis, and polymyalgia rheumatica WORKUP Workup consists of a thorough history, including exercise history, urine color, medication history, and physical exam to palpate tenderness and obtain blood tests to evaluate muscle and kidney damage. LABORATORY TESTS If severe myopathy or rhabdomyolysis is suspected: • Elevated CPK, positive serum myoglobin, elevated BUN, serum creatinine, AST, ALT, LDH, and potassium • Urine creatinine, positive casts, and hemoglobin in urine with absence of red blood cells • Anti-3-hydroxy-3-methylglutaryl-conenzyme A (anti-HMG-CoA) antibody • Consider electrocardiogram and assessment of calcium, phosphate, and uric acid If mild to moderate myopathy is suspected: • Monitor TSH and CPK levels; CPK may only be elevated when sudden severe myopathy occurs. • If the patient has brown or dark urine or elevated CPK, monitor BUN and serum creatinine. • In statin-associated autoimmune myopathy, the creatine kinase level is usually ≥10 times the upper limit of normal. In these patients, muscle biopsy specimens will be positive for autoantibodies against HMG-CoA reductase and may have necrosis. IMAGING STUDIES • Not recommended. • In statin-associated autoimmune myopathy, electromyography shows small-amplitude motor-unit potentials with increased spontaneous activity characteristic of an active myopathic process. Muscle edema is evident on MRI.1 • Statin Intolerance Tool: 1. The American College of Cardiology has created a tool to assess statin muscle symptoms and to guide clinicians that can be of value: http://tools.acc.org/stati nintolerance/#!/ 1Mammen

AL: Statin-associated autoimmune myopathy, N Engl J Med 374:664-669, 2016.

Statin-Induced Muscle Syndromes TREATMENT NONPHARMACOLOGIC THERAPY Treatment of rhabdomyolysis is generally supportive in nature (see “Rhabdomyolysis” topic).

CHRONIC Rx • After stopping the statin and symptom or CPK resolution, which may take up to 4 mo, consider the same statin at a lower dosage or a different statin at an equivalent or lower dosage. • When restarting therapy, consider statins such as low-dose rosuvastatin; pravastatin; and alternate-day dosing of rosuvastatin or atorvastatin. • If patient had rhabdomyolysis secondary to statin therapy, consider nonstatin treatments. • If the patient develops myopathy after a second trial of therapy, statin treatment should be permanently discontinued and nonstatin cholesterol-lowering therapy initiated. • For IMNM (statin-associated autoimmune myopathy and idiopathic inflammatory myositis), immunosuppressive therapy with prednisone (1 mg per kg of body weight per day) and at least one agent (methotrexate, azathioprine, or mycophenolate mofetil) have been used. In resistant cases, IV immune

INTEGRATIVE MEDICINE • The effect of coenzyme Q10 on reducing or preventing SIMS remains controversial; although it may be effective in reducing muscle pain, weakness, cramps, and tiredness, it has no effect on lowering CK levels. Given its safety, coenzyme Q10 can be recommended if the actions listed under “Chronic Rx” are insufficient to continue the use of the statin and if the muscle symptoms have been limited to myalgias. Use coenzyme Q10 with caution in patients taking warfarin, as its anticoagulant effect may be decreased. • A 2015 meta-analysis of observational studies reported that vitamin D levels were lower in patients with statin-induced myalgias than in individuals who did not have these symptoms. • In a study of 282 patients with vitamin D levels less than 32 ng/ml and with myalgiamyositis from statins, vitamin D supplementation (median 50,000 IU D3/wk) for 6 mo improved symptoms and statin tolerance in 74% to 85% of patients; another study showed that replacement of vitamin D in patients with low-serum vitamin D may be able to maintain or restart previously failed statin therapy. DISPOSITION • Usually resolves within 1 wk up to 4 mo after discontinuing statin therapy. • Once the patient has a full recovery, an alternative statin can be tried. • Statins should not be restarted in IMNM or idiopathic inflammatory myositis. REFERRAL If rhabdomyolysis is suspected, immediate referral for hospitalization is suggested.

PEARLS & CONSIDERATIONS COMMENTS SIMS are usually mild and will resolve within a few wk after discontinuing statin therapy. However, such syndromes may progress to rhabdomyolysis.

PREVENTION • Follow the 2013 AHA/ACC treatment guidelines and the 2017 ACC focused update on nonstatin therapies for LDL cholesterol and limit the concomitant use of fibrates with statins. • Discontinue statin therapy prior to and during surgical procedures. • If patient requires a short-term therapy with an interacting medication such as an azole antifungal, temporarily discontinue statin therapy until interacting therapy is completed. • If statin–fibric acid therapy is warranted, fenofibrate is preferred over gemfibrozil to decrease risk of myopathy. • Baseline liver function testing before initiation of statin therapy and only if clinically indicated thereafter. PATIENT & FAMILY EDUCATION • Inform patients to promptly report muscle weakness, unexpected muscle pain, or brownish urine. • Ensure that the pharmacist and/or primary care physician checks for drug-drug interactions with every new prescription, including those from dentists and physicians from other specialties. • Coenzyme Q10 may lessen milder muscle symptoms from statins, but patients should inform their physician and pharmacist if they decide to use this supplement. • A recent clinical trial comparing lipid-lowering efficacy for two nonstatin therapies, ezetimibe and evolocumab, among patients with statin intolerance revealed that evolocumab resulted in a significantly greater reduction in LDL-C levels after 24 wk. Further studies are needed to assess long-term efficacy and safety. SUGGESTED READINGS Available at ExpertConsult.com RELATED CONTENT Rhabdomyolysis (Related Key Topic) AUTHORS: Lisa Cohen, PharmD , and Anne L. Hume, PharmD

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ACUTE GENERAL Rx • Stop statin therapy immediately if muscle symptoms occur. Check history, potential drug-drug interactions, CPK, TSH, renal function, hepatic function, and urinalysis. • If patients have suspected rhabdomyolysis, they should be hospitalized and treated with supportive therapy and monitoring of complications. • If CPK 10× ULN with an elevation in serum creatinine or need for intravenous hydration therapy), statin therapy should be stopped. Intravenous hydration therapy in a hospital should be instituted if indicated for patients experiencing rhabdomyolysis. Once patients recover, risk versus benefit of statin therapy should be carefully reconsidered. CK, Creatine kinase; PCP, phencyclidine; ULN, upper limit of normal. From McKenney JM et al: Final conclusions and recommendations of the National Lipid Association Statin Safety Assessment Task Force, Am J Cardiol 97(suppl 8A):89C94C, 2006.

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Status Epilepticus

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BASIC INFORMATION DEFINITION Status epilepticus is a medical neurologic emergency. It is historically defined as 30 min of continuous seizure activity or two or more seizures without full recovery of consciousness between seizures. However, in practice a continuous seizure that lasts >5 min is treated as status epilepticus. SYNONYMS Convulsive status epilepticus Nonconvulsive status epilepticus ICD-10CM CODES G41 Status epilepticus G40.301 Generalized idiopathic epilepsy and epileptic syndromes, not intractable, with status epilepticus

EPIDEMIOLOGY & DEMOGRAPHICS INCIDENCE: 40 to 100 cases per 100,000 persons PEAK INCIDENCE: It is most common among children younger than 1 yr and adults older than 60 yr. PREDOMINANT SEX AND AGE: No gender preference PHYSICAL FINDINGS & CLINICAL PRESENTATION • Patients can present with repetitive tonicclonic movements of the body (convulsive status epilepticus); other patients are comatose and nonresponsive (nonconvulsive status epilepticus). • Patients may also present with lethargy, intermittent confusion, and involuntary movements. ETIOLOGY • Status epilepticus can be the result of an acute neurologic injury, such as stroke, meningitis, brain tumor, etc. Table 1 summarizes causes of status epilepticus in adults presenting in the community. • In patients with epilepsy, abrupt discontinuation of antiepileptic drugs can result in status epilepticus.

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • Convulsive syncope • Encephalopathies: Metabolic, infectious, toxic, etc. • Nonepileptic spells WORKUP • ABCs • ICU admission • Emergent electroencephalogram (EEG) • Continuous video EEG in refractory cases

• Table 2 describes a suggested timetable for emergency diagnosis and treatment of status epilepticus. A treatment approach is summarized in Table 3 and Fig. 1.

LABORATORY TESTS • Routine blood workup (CBC, CMP, glucose, electrolytes) TABLE 1  Causes of Status Epilepticus in Adults Presenting from the Community Previous Seizures

No Previous Seizures

Common Subtherapeutic anticonvulsant Ethanol-related Intractable epilepsy

Ethanol-related Drug toxicity CNS infection Head trauma CNS tumor

Less Common CNS infection Metabolic aberration Drug toxicity Stroke CNS tumor Head trauma

Metabolic aberration Stroke

CNS, Central nervous system. From Vincent JL et al: Textbook of critical care, ed 7, Philadelphia, 2017, Elsevier.

• Urine drug screen • Lumbar puncture and CSF analysis in patients with suspected infectious meningitis or encephalitis or suspected autoimmune or paraneoplastic encephalitis

IMAGING STUDIES • Immediate CT scan of the head. • MRI of the brain with and without contrast should be performed once the patient is in a stable condition.

TREATMENT • Patients with continuous seizure activity over 3 min need intravenous lorazepam 0.1 mg/kg at 2 mg/min (or diazepam 0.2 mg/kg at 5 mg/ min only when lorazepam is not available). • In the absence of intravenous access, intramuscular administration of midazolam 10 mg in an adult is a superior alternative. • Failure of response to lorazepam or midazolam is referred to as established status epilepticus and should be followed by secondline therapy of intravenous fosphenytoin 20 mg/kg (PE) at a rate not greater than 150 mg/ min, phenytoin 20 mg/kg IV at up to 50 mg/ min as tolerated, intravenous valproic acid 40 mg/kg IV, or intravenous levetiracetam 60 mg/kg IV. Vital signs should be monitored during the infusion. • If seizures continue, an additional infusion of intravenous valproate, levetiracetam, lacosamide, or brivaracetam or continuous

TABLE 2  Suggested Timetable for Emergency Diagnosis and Treatment of Status Epilepticus Time

Exam/Intervention

Testing

Initial presentation: 0 min

Airway, breathing, circulation, IV access, monitoring Neurologic exam Administer antiepileptic drugs Lorazepam, 0.1 mg/kg IV Phenobarbital, 20 mg/kg IV Normal saline maintenance IV Reduce fever Evaluate treatment results Second-line antiepileptic drug if seizure persists Fosphenytoin, 20 mg/kg IV, or phenytoin, 20 mg/kg IV Intubation and mechanical ventilation Titrate antiepileptic drug to burst suppression Pentobarbital, 10 mg/kg IV given over 30 min, then 5 mg/kg every hour for 3 doses, then 1 mg/kg/h; titrate to effect Midazolam, 0.15 mg/kg IV, then 1-2 μg/kg/min, titrate to effect Phenobarbital, 5-10 mg/kg IV every 20 minutes to achieve burst suppression, then every 12 hours Evaluate need for vasopressors

Glucose, oxygenation via pulse oximetry ± blood gas analysis Electrolytes, renal and liver function, ammonia, anticonvulsant levels, toxicology, complete blood cell count, urinalysis

Primary survey: 5 min

Secondary survey: 15-30 min

Status epilepticus: >30 min Refractory status epilepticus: >60 min

Patient-specific: Cranial imaging (CT vs. MRI), lumbar puncture, EEG, ECG

Continuous EEG Neurologic consultation Consider anesthesia consultation for treatment with inhaled anesthetic

CT, Computed tomography; ECG, electrocardiogram; EEG, electroencephalogram; IV, intravenous; MRI, magnetic resonance imaging. From Vincent JL et al: Textbook of critical care, ed 7, Philadelphia, 2017, Elsevier.

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Status Epilepticus

TABLE 3  Treatment Approach to Status Epilepticus

From Vincent JL et al: Textbook of critical care, ed 7, Philadelphia, 2017, Elsevier.

Patient in clinical status epilepticus (SE)

Patient in confirmed NCSE

Patient in possible NCSE

Emergent EEG; assume patient is in NCSE until proven otherwise

Critical care/diagnostic evaluation

• Observe patient • Prevent SE recurrence • Manage underlying causes

Seizures stop Emergent initial therapy Lorazepam 0.1 mg/kg, or Midazolam 0.2 mg/kg IM/IV, or Diazepam 0.15 mg/kg Seizures persist Urgent control therapy Fosphenytoin/phenytoin 20 mg PE/kg IV, or Valproic acid 20-40 mg/kg IV, or Levetiracetam 1000-3000 mg IV, or Phenobarbital 20 mg/kg IV, or Lacosamide 200-400 mg IV, or Midazolam 0.2 mg/kg IV, then 0.05-2 mg/kg/hr continuous infusion

top

Seizures stop off infusion

ss

re izu

Se

r

cu

re

izu

Se

e sr

Seizures persist

Wean continuous infusion Seizures stop × 24 h

Refractory therapy Midazolam 0.2 mg/kg IV, then 0.052 mg/kg/hr continuous infusion, or Propofol 1-2 mg/kg, then 20 mcg/kg/min continuous infusion, or Pentobarbital 5-15 mg/kg then 0.55 mg/kg/h continuous infusion

FIG. 1  Management algorithm for status epilepticus. EEG, Electroencephalogram; IM, intramuscular; IV, intravenous; NCSE, nonconvulsive status epilepticus; SE, status epilepticus. (From Vincent JL et al: Textbook of critical care, ed 7, Philadelphia, 2017, Elsevier.)

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1. Appropriate critical care treatment should be provided as soon as possible and simultaneously with emergent initial therapy for seizures. Treatment should be escalated quickly until seizures are controlled. 1a. Critical care treatment (dictated by clinical circumstances): a. Intubation for airway protection and mechanical ventilation b. Vital sign monitoring c. Peripheral IV access d. Treatment of hypotension with vasopressors e. Finger stick blood glucose f. Nutrient resuscitation (thiamine before dextrose) g. Hypertension may be related to ongoing seizure activity, and termination of status epilepticus often substantially corrects it. Additionally, many agents used to terminate status epilepticus can produce hypotension. 1b. Emergent initial therapy with benzodiazepines: a. Lorazepam 0.1 mg/kg up to 4 mg per dose, may repeat after 5-10 min b. Midazolam 0.2 mg/kg IM/IV up to 10 mg c. Diazepam 0.15 mg/kg up to 10 mg per dose, may repeat after 5 min 2. Urgent control therapy—antiseizure drugs available in IV formulations: a. Fosphenytoin/phenytoin 20 mg PE/kg IV, may repeat bolus of 5 mg/kg IV: b. Valproic acid 20-40 mg/kg IV, may repeat bolus of 20 mg/kg IV c. Levetiracetam 1000-3000 mg IV d. Phenobarbital 20 mg/kg IV, may repeat bolus of 5-10 mg/kg e. Lacosamide 200-400 mg IV f. Midazolam bolus 0.2 mg/kg IV, followed by 0.05-2 mg/kg/h continuous infusion 3. Refractory therapy–continuous infusion of antiseizure drugs, titrated to either seizure cessation, suppression-burst, or complete suppression on EEG: a. Midazolam bolus 0.2 mg/kg IV, followed by 0.05-2 mg/kg/h continuous infusion b. Propofol bolus 1-2 mg/kg, followed by 20 mcg/kg/min continuous infusion, titrate up to 30-200 mcg/kg/min c. Pentobarbital 5-15 mg/kg, may repeat bolus of 5-10 mg/kg, followed by 0.5-5 mg/kg/h continuous infusion 4. Treat complications. 5. Complications of status epilepticus are numerous and can involve multiple organ systems. In particular, convulsive status epilepticus is associated with cardiac complications such as hypertension and tachycardia, as well as rhabdomyolysis and hyperthermia. Respiratory complications, including respiratory failure, hypoxia, and neurogenic pulmonary edema, may be seen. Status epilepticus is associated with neuronal damage and cerebral edema with increased intracranial pressure, which may require intracranial pressure monitoring and aggressive treatment with hypertonic agents.

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TABLE 4  Treatment Alternatives for Refractory and Super-Refractory Status Epilepticus Comments

Adverse Events

Thiopental

Metabolized to pentobarbital

Ketamine

Mechanism of action particularly well-suited to treat refractory and super-refractory SE (NMDA receptor antagonist) High rate of complications Needs closed system (gas recovery)

Hypotension Respiratory depression Cardiac depression High intracranial pressure Hypotension Hallucinations

Inhaled anesthetics Ketogenic diet

Lidocaine Hypothermia Resective surgery

Relatively safe (no respiratory and cardiocirculatory instability) Slow onset of action Requires skilled dietician Minor respiratory depression compared with other drugs Only transitory control (cannot be a prolonged therapy) Long-term treatment of seizures Not all patients are eligible

Hypotension Infection Paralytic ileus Gastroesophageal reflux Constipation Acidosis Hypertriglyceridemia Cardiocirculatory instability Possible induction of seizures Hypotension Cardiovascular instability Impaired coagulation (bleeding risks) Surgical risks

NMDA, N-methyl-D-aspartate; SE, status epilepticus. From Swaiman KF et al: Swaiman’s pediatric neurology, principles and practice, ed 6, Philadelphia, 2017, Elsevier. See original table for references.

infusions of phenobarbital, midazolam, and propofol are alternatives. Many of these drugs remain under investigation, and superiority of any one agent is not established. Treatment alternatives for refractory and super-refractory status epilepticus are summarized in Table 4.

NONPHARMACOLOGIC THERAPY None GENERAL Rx It is important to find out the etiology of the status epilepticus (e.g., metabolic disturbance, infection). The appropriate treatment/understanding of the underlying cause of the status epilepticus will impact successful treatment. CHRONIC Rx • Chronic treatment of status epilepticus depends on underlying etiology.

• Patient with status epilepticus due to epilepsy will need chronic treatment.

COMPLEMENTARY & ALTERNATIVE MEDICINE Not applicable DISPOSITION • Response to treatment depends on the etiology of the status epilepticus. • When there is no CNS injury as a cause or result of the status epilepticus, the prognosis is good. • No driving until seizure freedom in accordance with local laws and regulations. REFERRAL Status epilepticus is a neurologic emergency; therefore immediate inpatient neurologic consultation is warranted.

COMMENTS • Status epilepticus is a medical emergency that carries a high risk of mortality. Mortality among patients who present in status epilepticus is 15% to 22%. Among those who survive, functional ability will decline in 25% of cases. • Continuous video EEG is crucial in the treatment of these patients because some of them may not be clinically seizing (convulsing) but electrographically they may still have subclinical repetitive seizures or subclinical status epilepticus. • In the context of benzodiazepine-refractory convulsive status epilepticus, the anticonvulsant drugs levetiracetam, fosphenytoin, and valproate each led to seizure cessation and improved alertness by 60 min in approximately half the patients, and the three drugs were associated with similar incidences of adverse events.1 PREVENTION Medication compliance is crucial in patients with epilepsy. PATIENT & FAMILY EDUCATION • Patients with epilepsy have normal lives. • The goal of treatment is no seizures and no side effects to medications. • Patient education and information can be obtained at the Epilepsy Foundation: www.ep ilepsyfoundation.org • Pregnant women with epilepsy should visit the Antiepileptic Drug Pregnancy Registry website for information and assistance: www.aedpregnancyregistry.org • Patients with ongoing seizures are forbidden from driving; check state regulations and laws regarding driving and epilepsy. AUTHORS: Patricio Sebastian Espinosa, MD, MPH, and Corey Goldsmith, MD

1Kapur

J et al: Randomized trial of three anticonvulsant medication for status epilepticus, N Engl J Med, 381:2103-13, 2019

  Stevens-Johnson Syndrome BASIC INFORMATION DEFINITION Stevens-Johnson syndrome (SJS) is a rare, severe vesiculobullous form of erythema multiforme (EM) affecting the skin, mouth, eyes, and genitalia. SJS is defined as affecting 30% of BSA. Table E1 provides a classification of SJS and TEN. SYNONYMS SJS Herpes iris Febrile mucocutaneous syndrome ICD-10CM CODE L51.1 Stevens-Johnson syndrome

EPIDEMIOLOGY & DEMOGRAPHICS • SJS affects predominantly children and young adults. • Male:female ratio is 2:1. • Prevalence: 1:100,000 for SJS and 1:1,000,000 for TEN PHYSICAL FINDINGS & CLINICAL PRESENTATION • The cutaneous eruption generally occurs within 4 wk of drug initiation and is generally preceded by vague, nonspecific symptoms of low-grade fever and fatigue (influenza-like symptoms) occurring 1 to 14 days before the skin lesions. Cough is often present. Fever may be high during the active stages. The acute phase of the disease lasts 1 to 2 wk. • Enlarging red-purple macules (Fig. E1) or papules and bullae generally occur on the conjunctiva, mucous membranes of the mouth (Fig. E2), nares, and genital regions. Lesions rapidly spread to their maximum extent usually within 2 days. • Corneal ulcerations may result in blindness. • Ulcerative stomatitis results in hemorrhagic crusting (Fig. E3). • Nikolsky sign (shearing off of epidermis with pressure on skin) can be present. • Flat, atypical target lesions or purpuric maculae may be distributed on the trunk or be widespread. • The pain from oral lesions may compromise fluid intake and result in dehydration. • Thick, mucopurulent sputum and oral lesions may interfere with breathing. • Box E1 summarizes features of SJS and TEN. ETIOLOGY • Drugs (see Box E2). Upper respiratory tract infections (e.g., Mycoplasma pneumoniae) and HSV infections have also been implicated. • Increased rash of SJS with HLA-B*1502 and HLA-B*5801, HIV, kidney disease, and unconfirmed autoimmune diseases.

TABLE E1  Classification of Stevens-Johnson Syndrome, Toxic Epidermal Necrolysis, and Stevens-Johnson Syndrome–Toxic Epidermal Necrolysis Overlap SJS

SJS-Ten

Ten

Lesional morphology

Targetoid lesions, dusky red macules, bullae

Targetoid lesions, dusky red macules, bullae

Targetoid lesions, dusky erythematous macules and plaques; detachment of epidermis

Localization of skin lesions

May be scattered and isolated; may be confluent, especially on the trunk and face

May be scattered and isolated; often confluent

Usually extensive involvement with widespread confluence

Involved skin

30%

Biopsy features

More interface dermatitis

Significant interface dermatitis + necrolysis

Predominantly necrolysis

Mucosal changes

Prominent

Prominent

May be less than in SJS

Systemic involvement

Often present

Always present

Always present

SJS, Stevens-Johnson syndrome; TEN, toxic epidermal necrolysis. From Paller AS, Mancini AJ: Hurwitz clinical pediatric dermatology, a textbook of skin disorders of childhood and adolescence, ed 5, 2016, Elsevier.

FIG. E1  Stevens-Johnson syndrome (SJS). Intensely erythematous macules are nearly confluent on the palms of this boy with SJS from carbamazepine. (From Paller AS, Mancini AJ: Hurwitz clinical pediatric dermatology, a textbook of skin disorders of childhood and adolescence, ed 5, 2016, Elsevier.)

FIG. E2  Stevens-Johnson syndrome. Purpuric macules became bullous. Note the inflammation of the conjunctivae and lips. (From Paller AS, Mancini AJ: Hurwitz clinical pediatric dermatology, a textbook of skin disorders of childhood and adolescence, ed 5, 2016, Elsevier.)

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Stevens-Johnson Syndrome

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FIG. E3  Stevens-Johnson syndrome. Mucous membrane involvement with severe swelling and hemorrhagic crusting of the lips. (From Paller AS, Mancini AJ: Hurwitz clinical pediatric dermatology, a textbook of skin disorders of childhood and adolescence, ed 5, 2016, Elsevier.)

BOX E1  Features of StevensJohnson Syndrome and Toxic Epidermal Necrolysis Constitutional Fever Dehydration Mucocutaneous Stomatitis with hemorrhagic crusts Oral and genital erosions Dysphagia Purulent conjunctivitis with photophobia Occasionally esophageal and pulmonary mucosal sloughing Dusky erythematous macules, targetoid lesions, bullae, and skin sloughing Visceral Lymphadenopathy Hepatosplenomegaly with hepatitis Uncommonly: Pneumonitis, arthritis, myocarditis, and nephritis

Laboratory abnormalities

Increased erythrocyte sedimentation rate (100%) Leukocytosis (60%) Eosinophilia (20%) Anemia (15%) Elevated hepatic transaminase levels (15%) Leukopenia (10%) Proteinuria, microscopic hematuria (5%)

From Paller AS, Mancini AJ: Hurwitz clinical pediatric dermatology, a textbook of skin disorders of childhood and adolescence, ed 5, 2016, Elsevier.

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • Toxic erythema (drugs or infection) • Pemphigus • Pemphigoid • Urticaria • Hemorrhagic fevers • Serum sickness • Staphylococcus scalded-skin syndrome

BOX E2  Most Common Pharmacologic Triggers of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis Allopurinol Barbiturates Carbamazepine Lamotrigine NSAIDs Penicillins Phenytoin Sulfonamides NSAIDs, Nonsteroidal antiinflammatory drugs. From Paller AS, Mancini AJ: Hurwitz clinical pediatric dermatology, a textbook of skin disorders of childhood and adolescence, ed 5, 2016, Elsevier.

• Behçet syndrome

WORKUP • Diagnosis is generally based on clinical presentation and characteristic appearance of the lesions. • Skin biopsy is generally reserved for when classic lesions are absent and diagnosis is uncertain. Biopsy reveals epidermal necrolysis but cannot distinguish between SJS, TEN, and EM. LABORATORY TESTS CBC with differential, cultures in cases of suspected infection IMAGING STUDIES Chest x-rays may show patchy changes in patients with pulmonary involvement.

TREATMENT NONPHARMACOLOGIC THERAPY • Withdrawal of any potential drug precipitants • Careful skin nursing to prevent secondary infection

SUGGESTED READING Wetter DA, Camilleri MJ: Clinical, etiologic, and histopathologic features of Stevens-Johnson during an 8-year period at Mayo Clinic, Mayo Clin Proc 85(2):131-138, 2010.

ACUTE GENERAL Rx • Treatment of associated conditions (e.g., acyclovir for HSV infection, azithromycin for Mycoplasma infection) • Antihistamines for pruritus • Treatment of the cutaneous blisters with cool, wet Burow compresses • Relief of oral symptoms by frequent rinsing with lidocaine (Xylocaine Viscous) • Liquid or soft diet with plenty of fluids to ensure proper hydration • Treatment of secondary infections with antibiotics • Corticosteroids: Use remains controversial and there is a clear risk of sepsis; they should be used only in severe cases early in the disease; when used, prednisone 20 to 30 mg bid until new lesions no longer appear, then rapidly tapered • Topical steroids: May use to treat papules and plaques; however, should not be applied to eroded areas • Vitamin A: May be used for lacrimal hyposecretion • Consider IVIG in severe cases DISPOSITION • Prognosis varies with severity of disease. It is generally good in patients with limited disease; however, mortality rate may approach 10% in patients with extensive involvement. A severity of illness score known as SCORETEN that incorporates increased glucose level (>252 mg/dl), increased BUN (>28 mg/dl), electrolytes (serum bicarbonate 40 yr), immunosuppression (presence of cancer), involvement >10% of BSA, and increased heart rate (>120 beats/min) can be used to calculate mortality risk. • Oral lesions may continue for several mo. • Scarring and corneal abnormalities may occur in 20% of patients. REFERRAL • Management of SIS is similar to those with extensive burns. Hospital admission in a unit used for burn care is recommended in severe cases. • Urethral involvement may necessitate catheterization. • Ocular involvement should be monitored by an ophthalmologist. SUGGESTED READING Available at ExpertConsult.com RELATED CONTENT Stevens-Johnson Syndrome (Patient Information) Toxic Epidermal Necrolysis (Related Key Topic) AUTHOR: Fred F. Ferri, MD

Stomatitis/Mucositis BASIC INFORMATION DEFINITION Stomatitis is inflammation involving the oral mucous membranes. Mucositis is inflammation and ulceration of the mucous membranes. It is most commonly seen in the mouth but can occur anywhere in the GI, genitourinary (GU), or respiratory tract. It is most often due to side effects of chemotherapy or radiation therapy (Fig. E1) in cancer patients. SYNONYM Heterogeneous grouping of unrelated illnesses, each with its own designation(s) ICD-10CM CODES A69.0 Necrotizing ulcerative stomatitis B08.4 Enteroviral vesicular stomatitis with exanthem B08.61 Bovine stomatitis B37.0 Candidal stomatitis K12 Stomatitis and related lesions K12.0 Recurrent oral aphthae K12.1 Other forms of stomatitis K12.30 Oral mucositis (ulcerative), unspecified K12.31 Oral mucositis (ulcerative) due to antineoplastic therapy K12.32 Oral mucositis (ulcerative) due to other drugs K12.33 Oral mucositis (ulcerative) due to radiation K12.39 Other oral mucositis (ulcerative) K13.0 Other and unspecified lesions of oral mucosa

PHYSICAL FINDINGS & CLINICAL PRESENTATION WHITE LESIONS: • Candidiasis (thrush) 1.  Caused by yeast infection (Candida albicans) 2. Examination: White, curdlike material (Fig. E2) that, when wiped off, leaves a raw, bleeding surface 3. Epidemiology: Seen in the very young and the very old, those with immunodeficiency (AIDS, cancer), persons with diabetes, and patients treated with antibacterial agents • Other: 1.  Leukoedema: Filmy opalescent-appearing mucosa, which can be reverted to normal appearance by stretching. This condition is benign. 2. White sponge nevus: Thick, white corrugated folds involving the buccal mucosa. Appears in childhood as an autosomal dominant trait. Benign condition. 3.  Darier disease (keratosis follicularis): White papules on the gingivae, alveolar mucosa, and dorsal tongue. Skin lesions also present (erythematous papules). Inherited as an autosomal dominant trait. 4. Chemical injury: White sloughing mucosa. 5. Nicotine stomatitis: Whitened palate with red papules.

6.  Lichen planus: Linear, reticular, slightly raised striae on buccal mucosa. Skin is involved by pruritic violaceous papules on forearms and inner thighs. 7.  Discoid lupus erythematosus: Lesion resembles lichen planus. 8.  Leukoplakia: White lesions that cannot be scraped off; 20% are premalignant epithelial dysplasia or squamous cell carcinoma. 9. Hairy leukoplakia: Shaggy white surface that cannot be wiped off; seen in HIV infection, caused by Epstein-Barr virus. RED LESIONS: • Candidiasis may present with red lesions instead of the more frequent white. Median rhomboid glossitis is a chronic variant. • Benign migratory glossitis (geographic tongue): Area of atrophic depapillated mucosa surrounded by a keratotic border. Benign lesion, no treatment required. • Hemangiomas. • Histoplasmosis: Ill-defined, irregular patch with a granulomatous surface, sometimes ulcerated. • Allergy. • Anemia: Atrophic reddened glossal mucosa seen with pernicious anemia. • Erythroplakia: Red patch usually caused by epithelial dysplasia or squamous cell carcinoma. • Burning tongue (glossopyrosis): Normal examination; sometimes associated with denture trauma, anemia, diabetes, vitamin B12 deficiency, psychogenic problems. DARK LESIONS (BROWN, BLUE, BLACK): • Coated tongue: Accumulation of keratin; harmless condition that can be treated by scraping • Melanotic lesions: Freckles, lentigines, lentigo, melanoma, Peutz-Jeghers syndrome, Addison disease • Varices • Kaposi sarcoma: Red or purple macules that enlarge to form tumors; seen in patients with AIDS

RAISED LESIONS: • Papilloma • Verruca vulgaris • Condyloma acuminatum • Fibroma • Epulis • Pyogenic granuloma • Mucocele • Retention cyst BLISTERS: • Primary herpetic gingivostomatitis (Fig. E3) 1. Caused by herpes simplex virus type 1 or, less frequently, type 2 2.  Typical course of herpetic gingivostomatitis: Day 1: Malaise, fever, headache, sore throat, cervical lymphadenopathy; days 2 and 3: appearance of vesicles that develop into painful ulcers of 2 to 4 mm in diameter; duration of up to 2 wk 3. Recurrent intraoral herpes: Rare; recurrences typically involve only the keratinized epithelium (lips). Table E1 summarizes distinctions between aphthous and herpetic oral ulcers • Pemphigus and pemphigoid • Hand-foot-mouth disease: Caused by coxsackievirus group A • Erythema multiforme • Herpangina: Caused by echovirus • Traumatic ulcer • Primary syphilis • Perlèche (or angular cheilitis) • Recurrent aphthous stomatitis (canker sores): Most common oral mucosa lesion; may be associated with many systemic diseases • Behçet syndrome (aphthous ulcers, uveitis, genital ulcerations, arthritis, and aseptic meningitis) • Reiter syndrome (conjunctivitis, urethritis, and arthritis with occasional oral ulcerations) 1. Unknown cause 2. Solitary or multiple painful ulcers may develop simultaneously and heal over 10 to 14 days. The size of the lesions and the frequency of recurrences are variable.

FIG. E1  Oral mucositis caused by radiation therapy. (From Keefe ZDM, Logan R: Oral complications of cancer and its treatment. In Walsh TD et al [eds]: Palliative medicine, Philadelphia, 2008, WB Saunders.)

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Stomatitis/Mucositis

A

C

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B

D

E

F FIG. E2  Stomatitis and mucositis. A, Marked stomatitis in a patient receiving methotrexate. B, Aphthous stomatitis related to severe granulocytopenia after chemotherapy. The ulcers may be due to herpes simplex or other infection. C, Mucositis in a patient receiving combination chemotherapy for head and neck cancer. D, Marked ulcer of the tongue in a 32-yr-old man receiving induction chemotherapy for acute leukemia. E, Mucositis of the tongue due to Monilia infection (thrush) in a patient receiving corticosteroids for brain metastases. F, Marked oral mucositis due to mixed infection in a patient receiving chemotherapy for acute leukemia. (From Skarin AT: Atlas of diagnostic oncology, 4 ed, St Louis, 2010, Mosby.)

Stomatitis/Mucositis

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DIAGNOSIS WORKUP • White lesions: Candidiasis (thrush) diagnosis—ovoid yeast and hyphae seen in scrapings treated with KOH culture • Blisters: 1. Exfoliative cytology 2. Viral culture 3. Immunofluorescence for herpes antigen

TREATMENT FIG. E3  Herpetic gingivostomatitis, extensive erosions of the oral mucosa. (James WD et al: Andrews’ diseases of the skin, ed 12, Philadelphia, 2016, WB Saunders.)

TABLE E1  Distinctions between Aphthous and Herpetic Oral Ulcers Condition

Mucosa

Location

Aphthous ulcers

Unkeratinized

Herpetic ulcers

Keratinized

Lateral tongue, floor of the mouth, labial and buccal mucosa, soft palate, pharynx Gingiva, hard palate, dorsal tongue

From Feldman M et al: Sleisenger and Fordtran’s gastrointestinal and liver disease, ed 10, Philadelphia, 2016, Elsevier.

A

B FIG. E4  A, Multiple minor aphthous ulcers. B, A major aphthous ulcer. (From Feldman M et al: Sleisenger and Fordtran’s gastrointestinal and liver disease, ed 10, Philadelphia, 2016, Elsevier.)

White lesions: Candidiasis (thrush) treatment: • Topical with nystatin or clotrimazole • Systemic with ketoconazole or fluconazole Blisters: • Supportive • Consider acyclovir Recurrent intraoral herpes/aphthous ulcerations (Fig. E4): Topical corticosteroids (dexamethasone ointment applied to the identified ulcer tid) or systemic steroids for severe cases.

RELATED CONTENT Stomatitis (Patient Information) AUTHOR: Fred F. Ferri, MD

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Strabismus  BASIC INFORMATION DEFINITION Strabismus is a condition of the eyes in which the visual axes of the eyes are not aligned. The misalignment may be constant or intermittent, and it may vary depending on the gaze direction (comitant or incomitant). SYNONYMS Esotropia Exotropia Heterotropia Hypertropia Hypotropia Restrictive eye movement Crossed eyes Walleye Squint Lazy eye Floating eye ICD-10CM CODES H50.0 Convergent concomitant strabismus H50.1 Divergent concomitant strabismus H50.2 Vertical strabismus H50.3 Intermittent heterotropia H50.4 Other and unspecified heterotropia H50.5 Heterophoria H50.6 Mechanical strabismus H50.8 Other specified strabismus H50.9 Strabismus, unspecified H51.9 Unspecified disorder of binocular movement

EPIDEMIOLOGY & DEMOGRAPHICS INCIDENCE (IN U.S.): 2% of the population PEAK INCIDENCE: Childhood PREDOMINANT SEX: None PREDOMINANT AGE: Variable depending on type, but more common in childhood GENETICS: Most childhood forms suggest polygenic inheritance patterns with variable penetrance, although certain types (i.e., accommodative esotropia, intermittent exotropia) show a definite hereditary predisposition. PHYSICAL FINDINGS & CLINICAL PRESENTATION • Conjugate gaze loss with the eyes fixing independently • Diplopia in acquired adult-onset strabismus • Decreased range of eye movements in paralytic and restrictive forms • Compensatory head posture

• Amblyopia (a decrease in best-corrected visual acuity in an otherwise structurally healthy eye) may occur with untreated strabismus with a childhood onset

ETIOLOGY • Often obscure in childhood strabismus. • Many cases of esotropia are infantile, or present in first yr of life • Accommodative esotropia occurs later, with the peak incidence between 2 and 4 yr of age • Higher risk with neurologic disease, vision loss, or severe refractive errors • Orbital or ocular trauma and/or surgery • Thyroid disorders or other orbital inflammatory disease

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • Evaluation of eye position and movement • Vision testing • Refractive errors • Central nervous system (CNS) tumors • Orbital tumors • Brain and CNS dysfunction • Thyroid disease • Myasthenia gravis WORKUP • Eye examination: Fig. E1 illustrates diagnostic tests that help differentiate between common causes of strabismus. Strabismus is classified according to the type and magnitude of misalignment. Esotropia refers to an inward deviation of the nonfixing eye and exotropia to the outward deviation of the nonfixing eye. Hypertropia is a vertical deviation in which the nonfixing eye is higher, and hypotropia is a vertical deviation in which the nonfixing eye is lower. • Measurement of deviation: The Hirschberg test (Fig. E2) gives a rough estimate of the angle of a manifest strabismus and is especially useful in young or uncooperative patients or when fixation in the deviating eye is poor. • Visual field testing. • MRI or CT to rule out tumors or other intracranial pathology in paralytic strabismus. • Thyroid function tests in acquired restrictive strabismus. • Myasthenia gravis workup in acquired, unstable strabismus.

LABORATORY TESTS • Generally not needed, except in suspected myasthenia gravis where blood testing for acetylcholine receptor antibodies may be helpful, or thyroid function tests in suspected thyroid related eye disease. • Single-fiber EMG in suspected myasthenia gravis. IMAGING STUDIES Necessary only if other neurologic findings are found.

TREATMENT THERAPY • Glasses • Surgery • Prisms • Occlusion to relieve diplopia • Orthoptic exercises • Botulinum toxin • Pharmacologic treatment, i.e., pyridostigmine in myasthenia gravis–induced strabismus CHRONIC Rx • Glasses • Prisms • Ocular occluding devices for intractable diplopia caused by strabismus • Botulinum toxin DISPOSITION Glasses, prisms, and/or surgery may reestablish normal or improved ocular alignment and recover binocular single vision. REFERRAL • Early for full evaluation and rehabilitation of functional and cosmetic ocular alignment • To an ophthalmologist for management (usually) RELATED CONTENT Strabismus (Patient Information) AUTHORS: David Robbins Tien, MD, and Alexandra Meyer Tien, MD

Strabismus

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Strabismus

Examination Define characteristics

Incomitant

Comitant

Forced duction test

Negative

Positive

Tensilon test

Restrictive disease • Dysthyroid • Orbital pseudotumor • Orbital mass • Trauma

Negative

Positive

Ocular myopathy Cranial neuropathy Internuclear ophthalmoplegia Supranuclear disorder

Myasthenia gravis

Acquired

Present since childhood

Vergence paresis • Divergence • Convergence Skew deviation

Congenital strabismus

FIG. E1  Diagnostic tests that help differentiate between common causes of strabismus. (From Goldman L, Ausiello D [eds]: Cecil textbook of medicine, ed 23, Philadelphia, 2008, WB Saunders.)

Strabismus

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A

B

C FIG. E2  Hirschberg test. A, The right corneal reflex is near the temporal border of the pupil, indicating an angle of about 15 degrees. B, The left corneal reflex is at the limbus, indicating an angle of about 45 degrees. C, The right corneal reflex is at the limbus in a divergent squint. (A, Courtesy J. Yanguela. From Kanski JJ, Bowling B: Clinical ophthalmology, a systematic approach, ed 7, Philadelphia, 2010, WB Saunders.)

  Stroke, Acute Ischemic BASIC INFORMATION DEFINITION Ischemic stroke is the sudden onset of a focal neurologic deficit as a result of cerebral ischemia resulting in cell death. The purpose of this chapter is to help the provider make decisions about the management of the acute stroke patient within the first several hours of symptoms; this is the crucial time for definitive treatment interventions.

ICD-10CM CODES I63 Cerebral infarction I63.3 Cerebral infarction due to thrombosis of cerebral arteries I63.4 Cerebral infarction due to embolism of cerebral arteries I63.5 Cerebral infarction due to unspecified occlusion or stenosis of cerebral arteries I63.6 Cerebral infarction due to cerebral venous thrombosis, nonpyogenic I63.8 Other cerebral infarction I63.9 Cerebral infarction, unspecified I67.89 Other cerebrovascular disease

EPIDEMIOLOGY & DEMOGRAPHICS INCIDENCE: • ∼795,000 new or recurrent strokes occur each yr in the U.S. • Stroke is the number five cause of death (165,000 deaths every yr) and the leading cause of long-term disability in the U.S. PREVALENCE: There are ∼4.5 million stroke survivors in the U.S. RISK FACTORS: Hypertension, dyslipidemia, diabetes mellitus, and smoking are the four major modifiable risk factors. Other risk factors include age, gender, atrial fibrillation (most common cause of cardioembolic stroke), mechanical heart valve, patent foramen ovale, recent myocardial infarction, metabolic syndrome, carotid artery stenosis, vertebral artery stenosis, intracranial artery stenosis, hypercoagulable states, subclinical atrial tachyarrhythmias without clinical atrial fibrillation, sickle cell disease, and obesity. GENETICS: Multifactorial PHYSICAL FINDINGS & CLINICAL PRESENTATION When a patient presents with an acute ischemic stroke acutely, the most important considerations are determination of the time the patient was last known normal, the etiology (ischemic or hemorrhagic), and the severity, because these aspects will determine acute treatment. The time last known normal was when the patient was last seen normal (by themselves or by someone else). If they awoke with the deficits, the time last seen normal was when they went to bed. Clinical presentation varies with the artery and region of CNS affected. Clinical presentation

• Small arteries: Lacunar syndromes; no cortical signs are present in lacunar syndromes. 1. Pure motor hemiparesis: Typically due to an ischemic lesion in either the internal capsule or pons. 2. Pure hemisensory loss: Typically due to an ischemic lesion of the thalamus. 3. Ataxic hemiparesis: Ataxia out of proportion to the hemiparesis; typically due to an ischemic lesion of either the internal capsule or pons. 4. Sensorimotor stroke: Typically due to ischemic lesion involving both the thalamus and internal capsule. 5. Dysarthria–clumsy hand syndrome: Multiple localizations possible but typically the pons; facial weakness, dysarthria, and mild clumsiness and weakness of the hand.

ETIOLOGY Etiologies include atherosclerosis, cardioembolism, artery-to-artery embolism, small-vessel lipohyalinosis, arteritis, arterial dissection, and vasospasm.

DIAGNOSIS DIFFERENTIAL DIAGNOSIS The differential diagnosis of acute ischemic stroke includes hemorrhagic stroke (intracerebral hemorrhage), subarachnoid or subdural hemorrhage, seizure with postictal paralysis, migraine with hemiparesis or other aura, syncope, hypoglycemia, hypertensive encephalopathy, and conversion disorder.

BOX 1  Immediate Diagnostic Studies: Evaluation of a Patient with Suspected Acute Ischemic Stroke All Patients Noncontrast brain computed tomographic scan (magnetic resonance imaging, if available) Blood glucose level Serum electrolyte and renal function tests Electrocardiography Markers of cardiac ischemia Complete blood count, including platelet count Prothrombin time/international normalized ratio Activated partial thromboplastin time Oxygen saturation Selected Patients CT angiogram head and neck or MR angiogram head and neck CT or MR perfusion Hepatic function tests Toxicology screen Blood alcohol level Pregnancy test Arterial blood gas tests (if hypoxia is suspected) Chest radiography (if lung disease is suspected) Lumbar puncture (if subarachnoid hemorrhage is suspected and computed tomography scan is negative for blood) Electroencephalogram (if seizures are suspected) CT, Computed tomography; MR, magnetic resonance. From Christensen H et al: Abnormalities on ECG and telemetry predict stroke outcome at 3 months, J Neurol Sci 234:99-103, 2005.

S

Diseases and Disorders

SYNONYMS Stroke Brain attack Cerebrovascular accident (this is a nonspecific term and should not be used)

cannot reliably distinguish between hemorrhagic and ischemic causes, and so imaging must be done. Below is a noncomprehensive list of common stroke syndrome presentations based on the cerebral vascular territory affected. Please note that this list is not comprehensive and that all findings for a particular syndrome may not be listed here. • Large- to medium-sized arteries: 1. Dominant middle cerebral artery (MCA): Dominant face and arm > leg weakness and sensory loss with aphasia (expressive, receptive, or both); possible hemianopia 2. Nondominant MCA: Nondominant face and arm > leg weakness and sensory loss with hemineglect; possible hemianopia 3. A nterior cerebral artery (ACA): Contralateral leg weakness and sensory loss 4. Internal carotid artery: Combination of contralateral MCA and ACA 5. Basilar artery: Typically an acute loss of consciousness preceded by vertigo, nausea, vomiting, and diplopia; quadriparesis or quadriplegia may be seen, including “locked-in” syndrome 6. Posterior cerebral artery: Unilateral hemianopia; blindness with anosognosia (Anton syndrome) if bilateral 7. Posterior inferior cerebellar artery: Lateral medullary (Wallenberg) syndrome— ipsilesional loss of pinprick and temperature on the face and contralateral loss of pinprick and temperature on the body; ipsilesional Horner syndrome and ipsilesional palatal weakness with resulting dysphagia, dysarthria. Also with vertigo, nystagmus, ataxia.

1303

I

1304

Stroke, Acute Ischemic TABLE 1  National Institutes of Health Stroke Scale 1A. Level of Consciousness (LOC) 0 = Alert 1 = Not alert, but arousable 2 = Not alert, obtunded 3 = Coma

1C. LOC Commands

1B. LOC Questions Ask the month and his/her age. 0 = Answers both correctly 1 = Answers one correctly 2 = Answers neither correctly

Open and close the eyes. Open and close the nonparetic hand. 0 = Performs both tasks correctly 1 = Performs one task correctly 2 = Performs neither task correctly

2. Best Gaze (Horizontal)

3. Visual Fields

4. Facial Palsy

0 = Normal 1 = Partial gaze palsy 2 = Forced deviation or total gaze paresis

0 = No visual loss 1 = Partial hemianopia 2 = Complete hemianopia 3 = Bilateral hemianopia

0 = Normal 1 = Minor paralysis 2 = Partial paralysis (total or near total paralysis of lower face) 3 = Complete paralysis of upper and lower face

5. Motor Arm

6. Motor Leg

7. Limb Ataxia

Right Arm extended with palms down 90 degrees (if sitting) or 45 degrees (if supine) for 10 s 0 = No drift 1 = Drift; limb drifts down from position and does not hit bed or support in 10 s 2 = Some effort against gravity 3 = No effort against gravity 4 = No movement Left

Right Leg extended at 30 degrees, always tested supine for 5 s 0 = No drift 1 = Drift; limb drifts down from position and does not hit bed or support in 5 s 2 = Some effort against gravity 3 = No effort against gravity 4 = No movement Left

The finger-nose-finger and heel-shin tests 0 = Absent 1 = Present in one limb 2 = Present in two limbs

8. Sensory

9. Best Language

10. Dysarthria

To Pinprick or Noxious Stimuli 0 = Normal 1 = Mild to moderate sensory loss 2 = Severe to total sensory loss

0 = No aphasia, normal 1 = Mild-to-moderate aphasia 2 = Severe aphasia 3 = Mute, global aphasia, coma

0 = Normal 1 = Mild-to-moderate 2 = Severe (including mute/anarthric due to aphasia) Do not score if intubated.

11. Extinction and Inattention

Total Score:

0 = No abnormality 1 = Present 2 = Profound (two modalities) From Vincent JL et al: Textbook of critical care, ed 7, Philadelphia, 2017, Elsevier.

LABORATORY TESTS • Immediate (Box 1): Complete blood count, metabolic panel that includes blood glucose and renal function, PT/INR, aPTT, troponin I, and urinalysis. Blood glucose is the only test required before initiation of IV tPA • National Institutes of Health Stroke Scale (Table 1): A brief, focused neurologic examination aimed at providing a numeric estimate of the severity of stroke; can be performed by any health care provider trained in its use; may increase the likelihood of the correct assessment of stroke • ECG and telemetry monitoring • Echocardiogram to look for potential cardiogenic source of embolism, infective endocarditis, and intracardiac shunts IMAGING STUDIES • Immediate (Fig. 1): Computed tomography (CT) of the head without contrast to rule out hemorrhage. • CT angiogram of the head and neck is necessary acutely in selected patients if deficits are severe to assess whether there is a thrombus that is amenable to intervention as

well as CT head perfusion to assess for the degree of salvageable tissue (Table 2). • MRI of the brain with stroke protocol to assess the extent of stroke (because CT typically will not show an ischemic stroke for several hours), but it is rarely needed in the hyperacute setting to determine appropriateness of reperfusion strategy. Cross reference: See “Transient Ischemic Attack” for general workup, which is identical to that for ischemic stroke.

TREATMENT NONPHARMACOLOGIC THERAPY GENERAL CONSIDERATIONS: • Airway and breathing should be maintained. • Supplemental oxygen should be provided to keep the oxygen saturation at ≥92%. • Pneumatic compression devices or pharmacologic means should be applied to help prevent deep venous thrombosis. • Avoid any and all oral intake until swallowing is evaluated and found to be unimpaired; this helps to avoid aspiration pneumonia. • Early mobilization for rehabilitation is desirable.

• Consider neurosurgical intervention for craniectomy in select cases. Typical cases in which craniectomy may be performed include cerebellar ischemia with compression of the brain stem and/or the fourth ventricle as well as large middle cerebral artery ischemia. Available evidence suggests that it may be better to perform early hemicraniectomy (220 mm Hg systolic blood pressure); there is evidence of hypertension-induced organ damage; or thrombolysis is being considered, in which case the blood pressure needs to be reduced (if it can be safely accomplished) to 110 mm Hg) • Evidence of active bleeding or acute trauma (fracture) on examination • Taking an oral anticoagulant or, if taking anticoagulant, INR ≥1.7 is a contraindication • If receiving heparin in previous 48 hours, aPTT must be in normal range • Platelet count ≤100,000 mm3 • Blood glucose concentration ≥50 mg/dl (2.7 mmol/L) • Seizure with postictal residual neurologic impairments • CT shows a multilobar infarction (hypodensity >1⁄3 cerebral hemisphere) aPTT, Activated partial thromboplastin time; CT, computed tomography; INR, international normalized ratio. From Hoffman R et al: Hematology, basic principles and practice, ed 7, Philadelphia, 2018, Elsevier.

BOX 2  Management of Suspected Intracerebral Hemorrhage after Use of Tissue Plasminogen Activator Discontinue the tPA infusion if it remains in progress. Obtain noncontrast CT scan of the head stat. Order PT, PTT, platelet count, fibrinogen level, type and cross-match stat. In event of hemorrhage, consult hematology and neurosurgery. Give 6 to 8 units of cryoprecipitate, then 6 to 8 units of platelets. Administer aminocaproic acid 4 to 5 gm IV over 1 hour, followed by 1 gm PO or IV per hour. Check fibrinogen every 4 hours and give cryoprecipitate to keep fibrinogen >150 mg/dl. Monitor blood pressure every 15 min. Periodically repeat CBC, PT, PTT. Consider repeat head CT. CBC, Complete blood cell count; CT, computed tomography; IV, intravenous; PO, oral; PT, prothrombin time; PTT, partial thromboplastin time; stat, immediately; tPA, tissue plasminogen activator. From Parrillo JE, Dellinger RP: Critical care medicine, principles of diagnosis and management in the adult,ed 5, Philadelphia, 2019, Elsevier.

TABLE 4  AHA Recommendations for Endovascular Therapy in Patients with Acute Ischemic Stroke Patients should receive endovascular therapy with a stent retriever if they meet all of the following criteria (class I; level of evidence, A): 1. Prestroke modified Rankin score 0 to 1 (functionally independent) 2. Acute ischemic stroke receiving intravenous recombinant tissue plasminogen activator within 4.5 hours of onset according to guidelines from professional medical societies 3. Causative occlusion of the internal carotid artery or proximal middle cerebral artery 4. Age 18 years or older 5. National Institutes of Health Stroke Scale (NIHSS) score of 6 or greater 6. Alberta Stroke Program Early CT Score (ASPECTS) of 6 or greater 7. Treatment can be initiated (groin puncture) within 6 hours of symptom onset CT, Computed tomography. From Zipes DP: Braunwald’s heart disease, a textbook of cardiovascular medicine, ed 11, Philadelphia, 2019, Elsevier.

ANTIPLATELET THERAPY: Oral, rectal, or feeding tube administration of aspirin (325 mg/day) within 48 hours of stroke onset is advised to decrease the likelihood of a repeat ischemic stroke. Other oral antiplatelet regimens approved for secondary stroke prophylaxis (e.g., clopidogrel, aspirin plus extended-release dipyridamole)

may also be used. Patients who have received t-PA cannot be given antithrombotic or anticoagulant agents within the first 24 hr after administration. In patients with acute ischemic stroke and atrial fibrillation, full dose anticoagulation with heparin infusion or low molecular weight heparin should be avoided in the acute setting,

as this could potentially harm the patient by causing symptomatic intracranial hemorrhage, and there is very little evidence to suggest any benefit. However, chronic anticoagulation is indicated after the acute period has passed.

DISPOSITION Patients with acute ischemic stroke should be cared for in a stroke unit or an intensive care unit. Nurses with skills in stroke care and telemetry monitoring should be routine. Once the patient is stable and the workup is complete, rehabilitation should be arranged. REFERRAL Patients with acute ischemic stroke should be transported to a hospital in which providers are skilled in stroke care. Depending on the severity and duration of symptoms, the patient may qualify for immediate endovascular intervention at a comprehensive stroke center, even if he or she is not a candidate for IV tPA. If complications from brain edema develop, further evaluation by a neurosurgeon may be helpful during the acute phase.

PEARLS & CONSIDERATIONS PREVENTION • The prevention of acute ischemic stroke depends on the aggressive management of risk factors in individual patients. • Cross reference: Stroke, secondary prevention. • Paroxysmal atrial fibrillation is common in patients with cryptogenic stroke. A recent study found that noninvasive ambulatory ECG monitoring for 30 days significantly improved the detection of atrial fibrillation by a factor of >5 and nearly doubled the rate of anticoagulant treatment compared to the standard practice of short-duration ECG monitoring. PATIENT & FAMILY EDUCATION Patients and families need to be taught about ways to reduce the risk for recurrent stroke, including lifestyle modifications. Education about rehabilitation goals, when appropriate, should also be accomplished. SUGGESTED READINGS Available at ExpertConsult.com RELATED CONTENT Stroke (Patient Information) Stroke, Secondary Prevention (Related Key Topic) Transient Ischemic Attack (Related Key Topic) Atrial Fibrillation (Related Key Topic) AUTHORS: Corey Goldsmith, MD, and Prashanth Krishnamohan, MBBS, MD

Stroke, Acute Ischemic

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SUGGESTED READINGS Albers GW et  al: Thrombectomy for stroke at 6 to 16 hours with selection by perfusion imaging, N Engl J Med 378:708-718, 2018. Broderick JP et al: Endovascular therapy after intravenous t-PA versus t-PA alone for stroke, N Engl J Med 368:893-903, 2013. Bushnell C: McCullough: Stroke prevention in women: synopsis of the 2014 American Heart Association/American Stroke Association guideline, Ann Intern Med 160:853-857, 2014. Gladstone DJ et al: Atrial fibrillation in patients with cryptogenic stroke, N Engl J Med 370:2467-2477, 2014. Healey JS et al: Subclinical atrial fibrillation and the risk of stroke, N Engl J Med 366:120-129, 2012. Jovin TG et al: Thrombectomy within 8 hours after symptom onset in ischemic stroke, N Engl J Med 372:2286-2306, 2015. Juttler G et al: Hemicraniotomy in older patients with extensive middle-cerebralartery stroke, N Engl J Med 370:1091-1100, 2014. Nogueira RG et  al: Thrombectomy 6 to 24 hours after stroke with a mismatch between deficit and infarct, N Engl J Med 378:11-21, 2018. Parsons M et al: A randomized trial of tenecteplase vs. alteplase for acute ischemic stroke, N Engl J Med 366:1099, 2012. Powers WJ et al: Guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association, 2018. Association: American Stroke Association, Stroke, 2018. Prabhakaran S et al: Acute stroke intervention: a systematic review, J Am Med Assoc 313(4):1451-1462, 2015. Saver JL et al: Stent-retriever thrombectomy after intravenous t-PA vs. t-PA alone in stroke, N Engl J Med 372:2285-2295, 2015. Saver JL et al: Time to treatment with endovascular thrombectomy and outcomes from ischemic stroke: a meta-analysis, J Am Med Assoc 316(12):1279-1288, 2016. van den Berg et  al: Two year outcome after endovascular treatment for acute ischemic stroke, N Engl J Med 376:1341-1349, 2017. Wechsler LR: Intravenous thrombolytic therapy for acute ischemic stroke, N Engl J Med 364:2138-2146, 2011.

A

B

FIG. E2  A, A catheter angiogram showing left middle cerebral artery occlusion, which caused severe stroke symptoms for several hours. B, The artery was opened with the Merci clot retrieval system, and this resulted in normal flow.

Stroke, Acute Ischemic

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FIG. E3  A, A diffusion-weighted magnetic resonance image of the same patient as shown in previous figure, this time showing only mild left cerebral ischemia after intervention. The patient was clinically normal. B, Thrombi removed from the middle cerebral artery using the Merci clot retrieval system.

  Stroke, Hemorrhagic BASIC INFORMATION DEFINITION Hemorrhagic stroke is the sudden onset of a focal neurologic deficit caused by hemorrhage into or around the brain.

ICD-10CM CODES I61 Intracerebral hemorrhage I61.0 Intracerebral hemorrhage in hemisphere, subcortical I61.1 Intracerebral hemorrhage in hemisphere, cortical I61.2 Intracerebral hemorrhage in hemisphere, unspecified I61.3 Intracerebral hemorrhage in brainstem I61.4 Intracerebral hemorrhage in cerebellum I61.5 Intracerebral hemorrhage, intraventricular I61.6 Intracerebral hemorrhage, multiple localized I61.9 Nontraumatic intracerebral ­hemorrhage, unspecified

EPIDEMIOLOGY & DEMOGRAPHICS INCIDENCE: There are approximately 795,000 new or recurrent strokes per yr in the U.S., of which approximately 10% are hemorrhagic.1 RISK FACTORS: • Hypertension • Anticoagulant use • Thrombolysis • Alcoholism • Illicit drug use (e.g., cocaine) • Cerebral amyloid angiopathy • Increased age • African American race • Low cholesterol, low-density lipoprotein, and triglycerides • Minuscule increase in absolute risk from antiplatelet therapy • Questionable effect of chronic kidney disease and selective use of serotonin reuptake inhibitors GENETICS: Multifactorial

1Chatterjee

S et al: New oral anticoagulants and the risk of intracranial hemorrhage: traditional and Bayesian meta-analysis and mixed treatment comparison of randomized trials of new oral anticoagulants in atrial fibrillation, JAMA Neurol 70(12):14861490, 2013.

ETIOLOGY • Rupture of vessels • Aneurysm • Arteriovenous malformation • Brain tumor • Amyloid angiopathy

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • Ischemic stroke • Seizure with postictal paralysis • Syncope • Migraine with hemiparesis • Conversion disorder LABORATORY TESTS • Complete blood count, metabolic panel including blood glucose and renal function, prothrombin time/international normalized ratio, activated partial thromboplastin time, urinalysis, and toxicology screens • ECG and telemetry monitoring IMAGING STUDIES • Immediate: CT scan of the head without contrast is highly sensitive for hemorrhage (Fig. 1). • CT or MR angiogram to rule out an underlying vascular malformation. CT spot sign on the CTA has been shown to be a reliable early predictor of hematoma expansion.

TABLE 1  Correlation between Levels of Brain Function and Clinical Signs Structure

Function

Clinical Sign

Cerebral cortex

Conscious behavior

Brainstem activating and sensory pathways (reticular activating system)

Sleep-wake cycle

Brainstem motor pathways

Reflex limb movements

Midbrain CN III

Innervation of ciliary muscle and certain extraocular muscles Connects pontine gaze center with CN III nucleus

Speech (including any sounds) Purposeful movement Spontaneous To command To pain Eye opening Spontaneous To command To path Flexor posturing (decorticate) Extensor posturing (decerebrate) Pupillary reactivity

Pontomesencephalic MLF Upper pons CN V CN VIII Lower pons CN VIII (vestibular portion) connects by brainstem pathways with CN III, IV, VI Pontomedullary junction pressure Spinal cord

S

Internuclear ophthalmoplegia

Facial and corneal Facial muscle innervation

Corneal reflex-sensory Corneal reflex-motor response Blink Grimace

Reflex eye movements

Doll’s eyes Caloric responses

Spontaneous breathing Maintained blood pressure

Breathing and blood pressure do not require mechanical or chemical support Deep tendon reflexes Babinski response

Primitive protective responses

CN, Cranial nerve; MLF, medial longitudinal fasciculus. Parrillo JE, Dellinger RP: Critical care medicine, principles of diagnosis and management in the adult, ed 4, Philadelphia, 2014, Elsevier.

Diseases and Disorders

SYNONYMS Intracerebral hemorrhage (ICH) Intracranial hemorrhage Cerebrovascular attack (this is a nonspecific term and should not be used) The term subarachnoid hemorrhage refers to a specific location for hemorrhage, which commonly occurs as a result of a ruptured aneurysm. Please see “Subarachnoid Hemorrhage” for additional information.

PHYSICAL FINDINGS & CLINICAL PRESENTATION The presentation varies with the region of the brain that is affected. Table 1 summarizes correlation between levels of brain function and clinical signs. There is no clinical way to distinguish between a primary cerebral hemorrhage and an ischemic stroke; therefore imaging is required. Imaging can also help determine if the diagnosis is ischemic stroke with hemorrhagic conversion versus primary hemorrhage. The following are common locations for hypertensive hemorrhage: • Basal ganglia • Cerebellum • Pons Lobar hemorrhage in an older adult is likely due to amyloid angiopathy. A systematic, detailed examination is necessary when approaching a comatose patient (Box 1). The ICH score is a widely used grading scale to estimate mortality based on CT scan results. Parameters used to calculate the ICH score include Glasgow Coma Scale (GCS) (0 to 2 points) at presentation, patient age ≥80 (1 point), ICH volume ≥30 ml (1 point), presence of intraventricular blood (1 point), and infratentorial origin of blood (1 point). Scores range from 0 to 6, with a score of 0 conferring 0% mortality and a score of 6 with estimated 100% mortality.

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Stroke, Hemorrhagic BOX 1  Neurologic Profile: A Modified Glasgow Coma Scale Verbal Response Oriented speech Confused conversation Inappropriate speech Incomprehensible speech No speech Eye Opening Spontaneous Response to verbal stimuli Response to noxious stimuli None Motor Response Obeys Localizes Withdraws (flexion) Abnormal flexion None Pupillary Reaction Present Absent

Spontaneous Eye Movement Orienting Roving conjugate Roving disconjugate Miscellaneous abnormal movements None Oculocephalic Response Normal (unpredictable) Full Minimal None Oculovestibular Response Normal (nystagmus) Tonic conjugate Minimal or disconjugate None Deep Tendon Reflexes Normal Increased Absent

From Parrillo JE, Dellinger RP: Critical care medicine, principles of diagnosis and management in the adult, ed 4, Philadelphia, 2014, Elsevier.

H

3 2

3 2

1

1

B

A

C

FIG. 1  Hemorrhage. Axial computed tomography image (A) demonstrates a large area of acute hemorrhage (H) in right temporal lobe. T1-weighted (B) and T2-weighted (C) magnetic resonance imaging scans demonstrate the hemorrhage in various stages of breakdown. Center of lesion is dark on T1- and T2-weighted images, indicating oxyhemoglobin (1). Intermediate zone is bright on T1-weighted image and gray on T2-weighted image, indicating intracellular methemoglobin (2). Outer rim is bright on both T1- and T2-weighted images, indicating extracellular methemoglobin (3). (From Vincent JL et al: Textbook of critical care, ed 6, Philadelphia, 2011, Saunders.)

• MRI of the brain with a gradient echo sequence is also highly sensitive for hemorrhage, including intracerebral microhemorrhages that may not be visible with computed tomography scanning. MRI may also help to identify underlying brain tumors or vascular malformations, especially if the bleeding occurs at atypical sites. In the acute setting the MRI may show only the hematoma, but repeat MRI approximately 6 weeks after initial hemorrhage may help exclude these other etiologies.

TREATMENT NONPHARMACOLOGIC THERAPY • Urgent neurosurgical evaluation is needed in many cases either for evacuation of the hematoma or for relieving raised intracranial

pressure by procedures such as EVD placement or decompressive surgeries. • Surgery should be performed promptly for cases of cerebellar hemorrhage of >3 cm when the patient is deteriorating clinically, showing brain stem edema or hydrocephalus. • Surgery for lobar or deep brain clots may be considered for select cases, although the level of evidence for efficacy is not high. Currently, guidelines recommend standard craniotomy for patients with lobar clots >30 ml within 1 cm of the cerebral cortex. • Recent innovative surgical techniques, such as instillation of thrombolytic agents for intraventricular hemorrhage and minimally invasive surgery for hematoma evacuation, appear to be promising. Clinical trials are currently in progress to assess whether these approaches improve mortality and neurologic outcomes.

ACUTE GENERAL Rx The cornerstones of medical management of acute intracerebral hemorrhage include: • Control of hypertension • Correction of coagulopathy • Management of elevated intracranial pressure • Treatment of seizures HYPERTENSION (BOX 2): Blood pressure should be quickly lowered by 15% and then gradually and safely brought to the individual patient’s target range. In theory, this may diminish the expansion of the hematoma. More aggressive control of systolic blood pressure (SBP) to 140 or less in the acute setting has been shown to be safe in clinical trials (INTERACT2 trial) with nonsignificant improvement in outcomes compared to less aggressive BP control (target SBP 220 mm Hg, it may be reasonable to consider aggressive reduction of BP with a continuous intravenous infusion and frequent BP monitoring. CORRECTION OF COAGULOPATHY: • Early hematoma expansion has been associated with poor outcome. • Protamine sulfate is used to treat cases of heparin-induced intracerebral hemorrhage. Protamine dosage is 1 mg IV for every 100 units of heparin administered in the previous 2 to 3 hours (maximum dose is 50 mg). • Prothrombin concentrate complex (PCC) is now recommended for reversal of warfarinassociated ICH. FFP may also be used for this purpose, although it carries the disadvantage of administering more volume, potentially leading to complications such as pulmonary edema and slightly longer times to reversal of coagulopathy compared to PCC. Vitamin K should be administered IV along with flash-frozen plasma (FFP)/PCC for sustained effects. Routine use of recombinant factor VII concentrates is not recommended due to insufficient evidence and concern for increased risk of thromboembolic events. • Idarucizumab (Praxbind) is a humanized monoclonal antibody fragment that can be used for urgent reversal of the anticoagulant effect of the direct thrombin inhibitor ­dabigatran (Pradaxa).

Stroke, Hemorrhagic BOX 2  Suggested Recommended Guidelines for the Treatment of Elevated Blood Pressure in Patients with Spontaneous Intracerebral Hemorrhage

BP, Blood pressure; ICP, intracranial pressure; MAP, mean arterial pressure; SBP, systolic blood pressure. Modified from Broderick J et al: Guidelines for the management of spontaneous intracerebral hemorrhage in adults: 2007 update, Stroke 38:2001-2023, 2007.

• Andexanet alfa, a recombinant modified human factor X2 decoy protein, has been effective for reversion of the anticoagulant effect of apixaban (Eliquis), rivaroxaban (Xarelto), and edoxaban (Savaysa). • Recommendations for thrombolytic-associated intracerebral hemorrhage treatment include the consideration of the infusion of platelets and cryoprecipitate. • Hemostatic therapy has not been shown convincingly to improve outcomes, despite reducing hematoma expansion. Efforts are under way to identify patients at high risk of early hematoma expansion by using clinical and radiographic information to determine who may benefit from more aggressive hemostatic intervention. • Platelet transfusion for patients experiencing ICH while on aspirin appears to result in worse outcomes than no platelet transfusion according to the PATCH trial. The odds of death or dependence at 3 mo were significantly higher in the transfused group as compared to the nontransfused group. ELEVATED INTRACRANIAL PRESSURE: This condition should be treated with a graded approach, which may include the elevation of the head of the bed, analgesia/sedation, hyperventilation, and osmotic therapy. In patients clinically suspected to have elevated ICP or with GCS 150 mm Hg: Consider the aggressive reduction of BP with continuous intravenous infusion, with BP monitoring every 5 min. 2. SBP of >180 mm Hg or MAP of >130 mm Hg with evidence or suspicion of elevated ICP: Consider ICP monitor and reducing BP with intermittent or continuous intravenous medications to keep cerebral perfusion pressure >60 to 80 mm Hg. 3. SBP of >180 mm Hg or MAP of >130 mm Hg without evidence or suspicion of elevated ICP: Consider a modest reduction of BP (e.g., MAP of 110 mm Hg or target blood pressure of 160/90 mm Hg) with intermittent or continuous intravenous medications, and clinically reexamine the patient every 15 min.

Depending on the severity and duration of symptoms, the patient may require neurosurgical intervention.

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Stroke, Hemorrhagic SUGGESTED READINGS Anderson CS et al: Rapid blood-pressure lowering in patients with acute intracerebral hemorrhage, N Engl J Med 368:2355-2365, 2013. Baharoglu MI et al: Platelet transfusion versus standard care after acute stroke due to spontaneous cerebral haemorrhage associated with antiplatelet therapy (PATCH): a randomised, open-label, phase 3 trial, Lancet 387(10038):26052613, 2016. Chatterjee S: New oral anticoagulants and the risk of intracranial hemorrhage: traditional and Bayesian meta-analysis and mixed treatment comparison of randomized trials of new oral anticoagulants in atrial fibrillation, JAMA Neurol 70(12):1486-1490, 2013. Demchuk AM et al: Prediction of haematoma growth and outcome in patients with intracerebral haemorrhage using the CT-angiography spot sign (PREDICT): a prospective observational study, Lancet Neurol 11:307-314, 2012. Frontera JA et al: Guideline for reversal of antithrombotics in intracranial hemorrhage: executive summary. A statement for healthcare professionals from the Neurocritical Care Society and the Society of Critical Care Medicine, Crit Care Med 44:2251, 2016. Hackam DG, Mrkobrada M: Selective serotonin reuptake inhibitors and brain hemorrhage: a meta-analysis, Neurology 79(18):1862-1865, 2012. Hemphill 3rd JC et al: The ICH score: a simple, reliable grading scale for intracerebral hemorrhage, Stroke 32:891-897, 2012. Hemphill 3rd JC et al: Guidelines for the management of spontaneous intracerebral hemorrhage: a guideline for healthcare professionals from the American Heart Association/American Stroke Association, Stroke 46(7):2032-2060, 2015. Jauch E et  al: Emergency neurological life support: intracerebral hemorrhage, Neurocritical Care1-11, 2015. Morgenstern LB et al: Guidelines for the management of spontaneous intracerebral hemorrhage: a guideline for healthcare professionals from the American Heart Association/American Stroke Association, Stroke 41(9):2108-2129, 2012. Mozaffarian D et al: Heart disease and stroke statistics—2015 update: a report from the American Heart Association, Circulation e29- e322, 2015. Qureshi AI et al: Intensive blood pressure lowering in patients with acute cerebral hemorrhage, N Engl J Med 375:1033-1043, 2016.

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Stroke, Secondary Prevention BASIC INFORMATION DEFINITION Secondary prevention of stroke involves preventing the recurrence of a cerebral vascular ischemic or hemorrhagic stroke after a primary event (including transient ischemic attack) and early rehabilitation. SYNONYMS Brain attack Stroke Cerebral thrombosis Cerebral hemorrhage Brain infarct ICD-10CM CODES I65.2 Occlusion and stenosis of carotid artery I65.0 Occlusion and stenosis of vertebral artery I65.9 Occlusion and stenosis of unspecified precerebral artery I66 Occlusion and stenosis of cerebral artery, not resulting in cerebral infarction I65.1 Occlusion and stenosis of basilar artery

EPIDEMIOLOGY & DEMOGRAPHICS Stroke is the fifth leading cause of death in the U.S. and the leading cause of disability. Each yr, there are a total of 795,000 strokes, of which 185,000 are recurrent strokes. Thus, secondary prevention of ischemic stroke remains good treatment strategy. Secondary prevention is specifically targeted toward modifiable risk factors. RISK FACTORS: Age is the most important nonmodifiable risk factor. Modifiable risk factors include hypertension, hyperlipidemia, cigarette smoking, excessive alcohol consumption, physical inactivity, obesity (i.e., a body mass index of >25 kg/m2), obstructive sleep apnea, illegal drug use (amphetamines, cocaine), and diabetes mellitus. GENETICS: Multifactorial and strong family correlation if idiopathic strokes occur in parents 2, and therefore anticoagulation is recommended. Two first-line drug therapies can be recommended: direct oral anticoagulants (DOACs) such as apixaban, dabigatran, edoxaban, and rivaroxaban; and warfarin with an international normalized ratio (INR) between 2.0 and 3.0. DOACs have been shown to result in a lower rate of intracerebral hemorrhage. Although more expensive than warfarin, DOACs do not require monitoring, do not have the dietary issues associated with warfarin, and have fewer drug-drug interactions. However, patients on enzyme-inducing medications such as phenytoin or HIV patients on protease inhibitors cannot use DOACs. Warfarin is still preferred in patients with marked renal impairment (see specific information available from the FDA about renal impairment and dosing for each DOAC) and in patients with mechanical heart valves or valvular causes of atrial fibrillation. Reversible therapies for some of the DOACs have recently been made available. A patient on a DOAC experiencing a recurrent stroke should only receive tissue plasminogen activator (t-PA) if the patient has been off the medication for at least 48 hr. For patients on warfarin, an INR of less than 1.7 allows for administration of t-PA. There is no evidence that aspirin monotherapy is helpful in reducing cardioembolic events. The Active-A trial suggested that a combination of aspirin and clopidogrel is slightly better than aspirin alone for those unable to tolerate warfarin,

Stroke, Secondary Prevention therapy (e.g., aspirin, clopidogrel, Aggrenox) may be considered in all cases of intracerebral hemorrhage where there is a definite indication. Consider a neurology consultation in these cases. • Antiplatelet therapy is recommended in cases of cryptogenic strokes. A consultation with a neurologist should be considered for young stroke patients and for patients with no obvious cause or with stroke from unusual causes (e.g., hypercoagulable states, dissections).

PREVENTING LONG-TERM COMPLICATIONS AFTER A STROKE • Evaluation by a physical, occupational, and speech therapist will reduce the long-term disability that can follow a stroke event. The American Stroke Association 2014 guideline recommends a multidisciplinary approach to rehabilitation. Studies have shown an improved survival and recovery. Home-based rehabilitation can be considered after discussion with the rehabilitation specialist. • Depression rates are high after an ischemic stroke, and patients should be screened. RISK FACTOR MODIFICATION • Hypertension: Antihypertensive treatment is recommended for both the prevention of recurrent stroke and the prevention of other vascular events in persons who have had an ischemic stroke or a TIA. Absolute target blood pressure level and reduction should be individualized, but a target of 50 yr of age. Mean age of presentation is 68.8 yr. RISK FACTORS: SC can be triggered by severe medical illness, intense emotional psychosocial stress or physical stress (death of loved ones, domestic abuse, fierce arguments, financial hardships, severe pain, natural disasters, etc.), or chronic stress/distress. A positive life event (happy heart syndrome) also can cause SC. Familial case series have raised the possibility of a genetic predisposition. PHYSICAL FINDINGS & CLINICAL PRESENTATION • Acute substernal chest pain, dyspnea, and syncope are the most common presenting complaints (International Takotsubo Registry study). • On physical examination, a systolic ejection murmur (due to left ventricular outflow tract obstruction and mitral regurgitation) may be present. • SC can manifest as heart failure (30%), ventricular arrhythmias, cardiogenic shock (10%), or sudden cardiac death.

ETIOLOGY The proposed mechanisms for SC include the following: • In postmenopausal women, estrogen deficiency leads to endothelial vasomotor dysfunction. Lack of endothelial-dependent vasodilation causes excessive coronary vasoconstriction. • Increased catecholamine from an acute event can be directly toxic to the myocardium. The increased density of betaadrenoreceptors in the apex makes it more sensitive to catecholamine and accounts for the apical ballooning. • Impaired microvascular perfusion resulting in ischemic stunning. • Fig. 1 depicts the interplay among triggers, pathogenic factors, and predisposing factors in SC.

WORKUP • A high index of suspicion is required when a postmenopausal woman presents with ACS after intense stress. • Cardiology consult should be immediately obtained. • Obstructive coronary artery disease needs to be ruled out. LABORATORY TESTS • Cardiac biomarkers (troponin, CK-MB) are often modestly elevated. • Cardiac natriuretic peptide (brain natriuretic peptide [BNP] and pro-BNP) levels are also commonly elevated. IMAGING STUDIES • ECG: ST elevation in precordial leads (reciprocal changes typically absent), T-wave inversions (which may be dramatic) in the anterior or lateral leads, QT prolongation, and abnormal Q waves. • Echocardiography (ECHO) typically shows the characteristic apical ballooning. Contrast ECHO is quite useful to exclude apical thrombus. • Obstructive coronary artery disease should be excluded with a coronary angiogram. • Cardiac magnetic resonance imaging (Fig. 3) can show the absence of late gadolinium enhancement (seen in MI). • Coronary computed tomography angiography may help evaluate for stenosis in epicardial coronary arteries in specific clinical settings (e.g., poor MRI acoustic windows).

DIAGNOSIS Mayo Clinic proposed criteria (2008) for diagnosis of SC: All four criteria required to make diagnosis. • Transient wall motion abnormalities that extend beyond a single epicardial vascular distribution (Fig. 2). A stressful trigger is often, but not always, present • Absence of obstructive coronary disease or angiographic evidence of acute plaque rupture • New ECG abnormalities (ST-segment elevation and/or T-wave inversion) or modest elevation in cardiac troponins • Absence of pheochromocytoma or myocarditis

COMPLICATIONS • Approximately 20% have in-hospital complications including heart failure, cardiogenic shock requiring mechanical support, lifethreatening arrhythmias, acute mitral regurgitation, LV outflow tract (LVOT) obstruction, free wall rupture, and death. • Due to the Venturi effect, mitral valve systolic anterior motion could cause LVOT obstruction and mitral regurgitation (14% to 45% of patients), which further impede LV systolic function.

DIFFERENTIAL DIAGNOSIS • Acute coronary syndrome • Cardiac syndrome X/microvascular angina • Prinzmetal angina • Acute myocarditis • Cocaine cardiomyopathy • Cardiomyopathy associated with pheochromocytoma

A

Triggers

B

Pathogenic factors

C

Predisposing factors

Emotional stressors

Physical stressors

Increased catecholamine levels

Cardiovascular risk factors

Iatrogenic stressors

and/or

and/ or

Neurologic triggers

Coronary vasomotor abnormalities leading to myocardial ischemia

Endothelial dysfunction

and/ or

Co-morbidities

Takotsubo syndrome

FIG. 1  The interplay among triggers, pathogenic factors, and predisposing factors in Takotsubo disease. (From Pelliccia F et al: Takotsubo syndrome [stress cardiomyopathy]: an intriguing clinical condition in search of its identity, Am J Med 127:699-704, 2014.)

Takotsubo Cardiomyopathy TREATMENT Initially, patients should be treated for presumptive acute coronary syndrome until this is excluded.

A

B

LV

FIG. 3  Takotsubo cardiomyopathy. The patient was a 58-yr-old woman who was referred for cardiovascular magnetic resonance (CMR) after a coronary angiogram revealed no obstructive disease despite the presence of ST-segment elevations on electrocardiogram and positive biomarker assays. A diagnosis of Takotsubo cardiomyopathy was made on the basis of the CMR image, which shows LV apical akinesis and ballooning (arrow). LV, Left ventricle. (From Mann DL et al: Braunwald’s heart disease, ed 10, Philadelphia, 2015, Elsevier.)

• Arrhythmias (25%) include supraventricular tachycardia and ventricular arrhythmias. • Systemic thromboembolism and increased risk of stroke. • Intramyocardial hemorrhage and rupture.

ACUTE GENERAL Rx • Hemodynamically stable: Treat with diuretics, vasodilators, and venodilators (nitroglycerin, nitroprusside). • Cardiogenic shock without LVOT obstruction: Vasopressor (phenylephrine, vasopressin) and inotropic support (dobutamine, milrinone, dopamine) may be required. When treatment is refractory to medical therapy, percutaneous and surgical mechanical circulatory support will be required. • Cardiogenic shock with LVOT obstruction: Increase preload by leg elevation and fluid resuscitation if no significant pulmonary congestion. Avoid inotropic agents, since increased basal contractility will increase the LVOT obstruction. Beta blockers can improve the obstruction. Phenylephrine should be used cautiously because it could increase the after-load and thus increase the gradient. CHRONIC Rx • 3 to 6 mo of guideline-directed medical therapy for heart failure with reduced ejection fraction (beta blockers, ACE inhibitors, angiotensin II receptor blocker, aldosterone antagonist, angiotensin receptor-neprilysin inhibitor) • Repeat ECHO (in 4 to 6 wk) to ensure normalization of systolic function. • 3 mo of anticoagulation is suggested if an intraventricular thrombus is detected.

REFERRAL Follow up with a cardiologist.

PEARLS & CONSIDERATIONS COMMENTS • The term takotsubo is the Japanese name for an octopus trap (tako-tsubo), which has a similar shape of the LV in systole during a left ventriculogram (see Fig. 2). • Patients with takotsubo cardiomyopathy have a higher prevalence of neurologic or psychiatric disorders than those with an acute coronary syndrome. PREVENTION Minimizing stress may reduce incidence but no data to support this. SUGGESTED READINGS Available at ExpertConsult.com AUTHORS: Mostafa Ghanim, MD, and Maxwell Eyram Afari, MD

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FIG. 2  A and B, Left ventriculogram showing apical ballooning characteristic of stress-induced cardiomyopathy. (From Mitsuma W et al: JACC 51[1]: cover, 2008.)

NONPHARMACOLOGIC THERAPY Supportive care such as the elimination of the physical or emotional trigger is important.

DISPOSITION • Carries a favorable prognosis compared to STEMI or NSTEMI; in-hospital mortality is up to 5%. The recurrence rate is around 2% to 4% per yr. • In a Medicare cohort, patients ≥85 yr of age had higher in-hospital, 30-day, 1-yr mortality, and 30-day readmission rates; hence, the need for good discharge planning is key.

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Takotsubo Cardiomyopathy SUGGESTED READINGS Deshmukh A et al: Prevalence of Takotsubo cardiomyopathy in the United States, Am Heart J 164:66-71, 2012. Ghadri JR et  al: Happy heart syndrome: role of positive emotional stress in Takotsubo syndrome, Eur Heart J 37:2823-2829, 2016. Jesel L et al: Ventricular arrhythmias and sudden cardiac arrest in Takotsubo cardiomyopathy: incidence, predictive factors, and clinical implications, Heart Rhythm 5:1171-1178, 2018. Kim H et al: Natural history and predictors of mortality of patients with Takotsubo syndrome, Int J Cardiol 267:22-27, 2018. Kosuge M et al: Simple and accurate electrocardiographic criteria to differentiate Takotsubo cardiomyopathy from anterior acute myocardial infarction, J Am Coll Cardiol 55(22):2514-2516, 2010. Medina H et al: Stress cardiomyopathy diagnosis and treatment: JACC State-ofthe-Art Review, J Am Coll Cardiol 72(16):1955-1971, 2018. Murugiah K et al: Trends in short- and long-term outcomes for Takotsubo cardiomyopathy among Medicare fee-for-service beneficiaries, 2007 to 2012, JACC Heart Fail 4(3):197-205, 2016. Pelliccia F et  al: Pathophysiology of Takotsubo syndrome, Circulation 135(24):24262441, 2017. Singh K et al: Meta-analysis of clinical correlates of acute mortality in Takotsubo cardiomyopathy, Am J Cardiol 419:1420-1428, 2014. Templin C et al: Clinical features and outcomes of Takotsubo (stress) cardiomyopathy, N Engl J Med 373:929-938, 2015.

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Tapeworm Infestation PREDOMINANT SEX: Equal sex distribution PREDOMINANT AGE: • T. saginata, T. solium, D. latum: 20 to 39 yr of age • H. nana in setting of institution outbreaks: Children

BASIC INFORMATION DEFINITION Four species of adult tapeworm (cestodes) may infect humans as the definitive host: Taenia saginata (beef tapeworm), Taenia solium (pork tapeworm), Diphyllobothrium latum (fish tapeworm), and Hymenolepis nana (dwarf tapeworm). In addition, several tapeworms (T. solium, T. crassiceps, T. multiceps) can infect human tissue in their larval form, resulting in cysticercosis. Others infect in their intermediate forms, resulting in hydatid disease (see “Echinococcosis” in Section I). Table 1 describes common cestode parasites of humans, their typical vectors, and their usual symptoms. SYNONYM Cysticercosis (larval infection by T. solium) ICD-10CM CODES B68.0 Taenia solium taeniasis B68.1 Taenia saginata taeniasis B68.9 Taeniasis unspecified B70.0 Diphyllobothriasis B71.0 Hymenolepiasis B71.9 Cestode infection, unspecified

PHYSICAL FINDINGS & CLINICAL PRESENTATION Adult worms: • Attach to bowel mucosa via suckers, hooks, or grooves depending on species • Feed and grow, producing digestive/body/ reproductive segments called proglottids • Cause minimal or no symptoms or sequelae but occasionally can cause nausea, anorexia, or epigastric pain Cysticercosis: Larval infection by T. solium: • Mass lesions of brain (neurocysticercosis), soft tissue, viscera • Neurocysticercosis may cause seizures, hydrocephalus (due to ventricle obstruction) Prolonged infection with D. latum: • Vitamin B12 deficiency • Megaloblastic anemia

EPIDEMIOLOGY & DEMOGRAPHICS INCIDENCE (IN U.S.): • Diagnosed primarily in immigrants, particularly those from Latin America and Southeast Asia • Varies widely by country of origin and dietary practices PREVALENCE (IN U.S.): • T. saginata: 450,000/ml) in peripheral blood. It is caused by overproduction of platelets (reactive thrombocytosis) or clonal expansion of megakaryocytes (clonal thrombocytosis). Reactive thrombocytosis is driven by excessive cytokines induced by various stimuli, such as trauma or inflammation. Clonal thrombocytosis is defined as chronic myeloproliferative neoplasms (MPNs), of which four subgroups are well characterized: chronic myelogenous leukemia (CML), polycythemia vera (PV), primary myelofibrosis (PMF), and essential thrombocythemia (ET). In addition, platelet count can be spuriously elevated in some conditions (see “Differential Diagnosis”). Extreme thrombocytosis is defined as platelet count >1 million/ml. SYNONYMS Thrombocythemia Essential thrombocythemia ET ICD-10CM CODES D47.3 Essential (hemorrhagic) thrombocythemia D75.89 Other specified diseases of blood and blood-forming organs D75.9 Disease of blood and blood-forming organs, unspecified D77 Other disorders of blood and bloodforming organs in diseases classified elsewhere

EPIDEMIOLOGY & DEMOGRAPHICS Reactive thrombocytosis is much more frequent than clonal thrombocytosis (70% vs. 22% in one series). Epidemiology for essential thrombocythemia: INCIDENCE: 1.2 to 3.0 per 100,000 population/yr PREVALENCE: Estimated as 24 cases/100,000 population PREDOMINANT SEX AND AGE: The median age at diagnosis is 58 yr. Female:male ratio is 2:1. PHYSICAL FINDINGS & CLINICAL PRESENTATION • Regardless of the cause, a high platelet count may be associated with vasomotor symptoms such as headache, visual disturbances, dizziness, atypical chest pain, acral dysesthesia, and erythromelalgia. • Thrombotic and bleeding complications can occur. • Symptoms and complications are much more likely to occur in association with clonal thrombocytosis than reactive thrombocytosis. • The degree of thrombocytosis does not predict the likelihood of clonal thrombocytosis and does not generally correlate to the risk of thrombosis. • Splenomegaly is common with MPNs.

• Coexistent leukocytosis and erythrocytosis are common with CML and PV. • Disease transformation from ET to PV, PMF, and acute myeloid leukemia (AML) is uncommon. In patients with ET, the 20-yr rate of leukemic transformation is estimated at 5%.

ETIOLOGY • Essential thrombocytosis, a myeloproliferative neoplasm, is a clonal disorder of a multipotent hematopoietic progenitor cell. • Abnormality in JAK2-STAT pathway (including JAK2, CALR, and MPL gene mutations) may play a role in pathogenesis of MPN.

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • Spurious thrombocytosis: 1. Mixed cryoglobulinemia—precipitated cryoglobulin particles are counted as platelets by automatic counters; generally occurs at low temperatures. 2.  Circulating cytoplasmic fragments miscounted as platelets—seen mainly in patients with leukemia, lymphoma, severe hemolysis, or burns • Reactive thrombocytosis: 1. Benign hematologic disorders 2. Acute hemorrhage, iron deficiency anemia, hemolytic anemia 3. Chronic infection, such as tuberculosis 4. Acute and chronic inflammatory disorders 5. Rheumatologic disorders 6. Inflammatory bowel disease 7. Celiac disease 8. Functional and surgical asplenia 9. Tissue damage 10. Trauma, thermal burn 11. Myocardial infarction



12. Acute pancreatitis 13. Recent surgery 14. Renal failure, nephrotic syndrome 15. Exercise 16.  Medications, such as vincristine, epinephrine • Clonal thrombocytosis: 1. CML 2. PV 3. PMF 4. Myelodysplastic syndrome (5q-syndrome) 5. AML with inv(3), t(3;3) 6. Essential thrombocytosis (Box 1)

WORKUP • Comprehensive history and physical examination to exclude many of the common causes of reactive thrombocytosis: History and physical examination suggestive of acute blood loss, iron deficiency, acute or chronic infection/inflammation, medication use, asplenia, malignancy, and trauma should be evaluated. Fig. E1 describes a diagnostic algorithm for thrombocytosis. The diagnosis of ET requires platelet counts >450 × 103/ ml on two separate occasions >4 weeks apart, absence of Philadelphia chromosome, and exclusion of secondary causes of thrombocytosis. • Repeat CBC with peripheral blood smear and bone marrow biopsy (Figs. E2 and E3) to exclude spurious thrombocytosis. LABORATORY TESTS • CBC with peripheral blood smear: HowellJolly bodies and target cells are present in patients with asplenia; nucleated RBC, teardrop RBC and WBC precursors in patients with PMF. • Serum ferritin level: Low ferritin level suggests iron deficiency.

BOX 1  World Health Organization Diagnostic Criteria for Essential Thrombocythemia Diagnosis requires that all of the following criteria be met: • Sustained platelet count ≥450 × 109/L* • Bone marrow biopsy specimen showing proliferation mainly of the megakaryocytic lineage, with increased numbers of enlarged, mature megakaryocytes; no significant increase or left shift of neutrophil granulopoiesis or erythropoiesis • Failure to meet the WHO criteria for polycythemia vera,† primary myelofibrosis,‡ BCRABL1–positive chronic myelogenous leukemia,§ myelodysplastic syndrome,¶ or other myeloid neoplasms • Demonstration of JAK2 V617F or other clonal marker; or, in the absence of JAK2 V617F, no evidence of reactive thrombocytosis¶ WHO, World Health Organization. *Sustained during the workup process. †Requires the failure of iron replacement therapy to increase the hemoglobin level to the polycythemia vera range in the presence of decreased serum ferritin. Exclusion of polycythemia vera is based on hemoglobin and hematocrit levels; red cell mass measurement is not required. ‡ Requires the absence of relevant reticulin fibrosis, collagen fibrosis, peripheral blood leukoerythroblastosis, or markedly hypercellular marrow accompanied by megakaryocyte morphology typical for primary myelofibrosis— small to large megakaryocytes with an aberrant nuclear-to-cytoplasmic ratio and hyperchromatic, bulbous, or irregularly folded nuclei and dense clustering. §Requires the absence of BCR-ABL1. ¶Requires the absence of dyserythropoiesis and dysgranulopoiesis. ¶ Causes of reactive thrombocytosis include iron deficiency, splenectomy, surgery, infection, inflammation, connective tissue disease, metastatic cancer, and lymphoproliferative disorders. From Swerdlow SH et al (eds): WHO classification of tumours of haematopoietic and lymphoid tissues, Lyon, France, 2008, IARC Press.

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TREATMENT No therapies are known to alter survival or leukemic transformation in ET. Reactive thrombocytosis has been rarely associated with thrombosis or bleeding and generally does not require specific therapy.

ACUTE GENERAL Rx • Vasomotor symptoms easily manageable with low-dose aspirin (1,000,000/uL [1000×109/L]), acquired von Willebrand disease may occur. Immediate definitive

therapy with a platelet-lowering agent is essential in this instance. Platelet pheresis should be reserved for cases of acute thrombosis or bleeding. • Thrombosis: 1. Arterial or venous thrombosis occurs in 20% to 30% of patients. 2.  If the platelet count is >800,000/ml, platelet apheresis coupled with a platelet-lowering agent should be considered with the goal of platelet count 20% suggest the presence of other diagnoses.

DIAGNOSIS

ICD-10CM CODE M31.1 Thrombotic microangiopathy

EPIDEMIOLOGY & DEMOGRAPHICS • About 90% of new TTP cases are seen in adults (mostly females between 18 and 50 yr). • The incidence of new TTP is 3 to 11 cases per million population per yr. The prevalence is ∼10 cases per million population. • There is increased incidence in HIV/AIDS and during pregnancy. PHYSICAL FINDINGS & CLINICAL PRESENTATION • The disease often begins as a flulike illness ultimately followed by clinical and laboratory abnormalities. • Most patients present with nonspecific constitutional symptoms (weakness, nausea, abdominal pain, vomiting). • Purpura (secondary to thrombocytopenia). • Jaundice, pallor (from hemolysis). • Mucosal bleeding. • Fever. • Fluctuating levels of consciousness (caused by thrombotic occlusion of the cerebral vessels). However, one third of patients have no neurologic abnormalities. • Renal failure and neurologic events are usually end-stage features. ETIOLOGY • Acquired TTP is an autoimmune disorder caused by autoantibody inhibition of

DIFFERENTIAL DIAGNOSIS It is challenging to differentiate TTP from other thrombotic microangiopathies given the significant overlap in clinical presentation, but this distinction is critical in selecting an appropriate therapy for patients. • Disseminated intravascular coagulation (DIC) • Malignant hypertension • Vasculitis • Eclampsia or preeclampsia • Hemolytic-uremic syndrome (HUS) and atypical HUS • Gastroenteritis as a result of a serotoxinproducing serotype of Escherichia coli WORKUP A comprehensive history, physical examination, and laboratory evaluation usually confirm the diagnosis (Fig. 1). LABORATORY TESTS • Severe anemia and thrombocytopenia (platelet count 50% reduction from previous counts) • Peripheral blood smear (Fig. E2, Fig. E3) reveals numerous red cell fragments (schistocytes) • Elevated blood urea nitrogen and creatinine • Evidence of hemolysis: Elevated reticulocyte count, indirect bilirubin, lactate dehydrogenase, decreased haptoglobin • Urinalysis: Hematuria (red blood cells [RBCs] and RBC casts in urine sediment) and proteinuria • Peripheral smear: Severely fragmented RBCs (schistocytes). More than 4% RBC fragments in the peripheral blood

TREATMENT ACUTE GENERAL Rx • Discontinue potential offending agents. Initiate ADAMTS13 replacement by plasma infusion in patients with hereditary TTP. • Current therapy for TTP is built on two complementary pillars: therapeutic plasma exchange (TPE) and immunosuppression. • Daily TPE with replacement of 1.0 to 1.5 times the predicted plasma volume of the patient is standard therapy for TTP. TPE should be continued for a minimum of 2 days after the platelet count returns to normal (>150,000 cells/m3). • High-dose plasma infusion (25 ml/kg/day) may be useful only if TPE cannot be promptly started and for patients with very severe or refractory disease between plasma exchange sessions. High-dose plasma infusions can cause volume overload in patients with renal insufficiency. • Patients with hereditary TTP who experience severe plasma allergic reactions have been effectively treated with plasma-derived factor VIII concentrate that contains ADAMTS13. • Immunosuppression with the use of corticosteroids (prednisone 1 to 2 mg/kg/day) typically is administered concomitantly with TPE for a period of 3 to 4 wk. • The monoclonal anti-CD20 antibody rituximab has been traditionally used for treatment of suboptimally responsive TTP and results in remissions in the majority of patients. Frontline use of rituximab results in shorter hospitalization with fewer relapses but is likely resulting in overtreatment in many cases.

TABLE 1  Etiology, Epidemiology, and Pathogenesis of TTP, HUS, and ADAMTS13–Related Parameters Congenital TTP Etiology Epidemiology Pathogenesis ADAMTS13 antigen ADAMTS13 activity Inhibitor against ADAMTS13

ADAMTS13 mutation

Acquired TTP

Antibody to ADAMTS13, endothelial cell activation 5-10 cases per yr per million ≤1 case per yr per million Defective cleavage of vWF multimers, massive secretion of ultra-large vWF multimers, increased platelet deposition under shear condition, occlusion of blood vessels in microcirculation Very low or absent Low or variable ≤5%-10% ≤5%-10% or variable No Mostly yes

HUS Escherichia coli or other microorganisms 1-5 cases per yr per million, mainly in children Intoxication with Shiga-like toxin, damage of endothelial cells, enterohemorrhagic colitis, renal disorder Normal or moderately decreased 30%-100% No

ADAMTS13, A disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13; HUS, hemolytic uremic syndrome; TTS, thrombotic thrombocytopenic purpura; vWF, von Willebrand factor. From McPherson RA, Pincus MR: Henry’s clinical diagnosis and management by laboratory methods, ed 23, Philadelphia, 2017, Elsevier.

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DEFINITION Thrombotic thrombocytopenic purpura (TTP) is a rare autoimmune disorder characterized by thrombocytopenia and microangiopathic hemolytic anemia that can be associated commonly with other hallmarks such as neurologic impairment, renal dysfunction, and fever. The laboratory hallmark of TTP is a severe deficiency of the ADAMTS13 factor (activity 2 cm but 4 cm in patient >45 yr of age • Stage IV: Distal spread in patient >45 yr of age

TREATMENT ACUTE GENERAL Rx • Papillary carcinoma: 1.  Total thyroidectomy is indicated if the patient has: a. Extrapyramidal extension of carcinoma. b. Papillary carcinoma limited to thyroid but a positive history of irradiation to the neck. c. Lesion >2 cm. 2. Lobectomy with isthmectomy may be considered in patients with intra-thyroid papillary carcinoma 40 yr Heart rate >120 bpm Cancer/hematologic malignancy BSA involved more than 10% on day 1 Serum urea level >28 mg/dl Serum bicarbonate level 252 mg/dl

1 1 1 1 1 1 1

0-1 2 3 4 >5

3.2 12.1 35.8 58.3 90

BSA, Body surface area; SCORTEN, SCORe of Toxic Epidermal Necrosis.

LABORATORY TESTS In addition to the skin biopsy, no specific laboratory test is available to diagnose TEN. Standard chemistry to monitor electrolyte and fluid balance and organ function (e.g., serum urea, bicarbonate, glucose; see Table E2) should be monitored as in burn patients. IMAGING STUDIES N/A





TREATMENT Withdrawing the offending drug reduces the risk of death by 30% per day and is the single most important measure in the management of TEN.

NONPHARMACOLOGIC THERAPY • Symptomatic treatment: 1. SCORTEN >1: Transfer to intensive care unit/burn unit 2. Fluid replacement 3. Peripheral venous access (preferably in non-involved areas) 4.  Increased environmental temperature (30°C; 86° F)



5. Air-fluidized bed 6. Early nutritional support through nasogastric tube 7.  Aseptic procedures, frequent culturing of skin, blood, urine specimens 8. No prophylactic antibiotics 9. Prophylactic anticoagulation 10. Nonadhesive wound dressings, porcine xenografts, human allografts, autologous skin grafts, skin substitutes 11. Daily ophthalmologic exam/consultation; artificial tears, antibiotic eyedrops every 2 hours; early mechanical disruption of synechia 12. Regular mouth washes with antiseptic/ antifungal solutions

ACUTE GENERAL Rx There is no consensus for the optimal pharmacologic treatment of TEN. • High-dose steroids may be effective in the initial course of the disease, but probably increase mortality later on due to infectious complications (sepsis). • Administration of high-dose IVIG over 3 to 4 days may reduce TEN-associated mortality (e.g., by blocking Fas-FasL interaction).

SUGGESTED READINGS Ng QX et  al: A meta-analysis of cyclosporine treatment for SJS/TEN, J Inflam Research 11:135-142, 2018. Paradisi A et al: Etanercept therapy for TEN, J Am Acad Dermatol 71:278-283, 2014. Scarf JM et al: Population prevalence of tourette syndrome: a systematic review and meta-analysis, Mov Disord 30(2):221-228, 2015. Schwartz RA et al: Toxic epidermal necrolysis: Part I. Introduction, history, classification, clinical features, systemic manifestations, etiology, and immunopathogenesis, J Am Acad Dermatol 69(2):173.e1-13, 2013. Schwartz RA et al: Toxic epidermal necrolysis: Part II. Prognosis, sequelae, diagnosis, differential diagnosis, prevention, and treatment, J Am Acad Dermatol 69(2):187.e1-16, 2013. Villano JH, Lovell EO: Mixed signals: toxic epidermal necrolysis, Am J Med 128(3):254-256, 2015.

• Newer studies have found that cyclosporine offers a greater mortality benefit and decreases morbidity because the mean duration of re-epithelialization and duration of hospital stay was significantly lower (e.g., by targeting granulysin). • Several reports in the literature suggest efficacy of TNF-α inhibitors, notably infliximab and etanercept. • Other agents that may also be effective in the treatment of TEN include cyclophosphamide, plasmapheresis, and N-acetylcysteine.

DISPOSITION Late withdrawal of the causative drug is associated with a less favorable outcome/increased mortality. If he/she survives, the patient may suffer debilitating and disfiguring scars and contractures, requiring extensive physical therapy and/or surgical interventions.

PEARLS & CONSIDERATIONS COMMENTS Early recognition and prompt discontinuation of the culprit drug saves lives. PREVENTION In order to prevent recurrences, it is of pivotal importance that patients are never again exposed to the drug that caused TEN. This also includes chemically related medications. Avoiding any drugs that have caused less severe drug reactions in the past is important for primary prevention of TEN. RELATED CONTENT Erythema Multiforme-Major (Related Key Topic) Steven-Johnson Syndrome (Related Key Topic) AUTHOR: Ganary Dabiri, MD, PhD

ALG BASIC INFORMATION DEFINITION Toxic megacolon is a rare but severe complication of colonic inflammation, usually inflammatory bowel disease (IBD). It is characterized by total or segmental nonobstructive colonic distention (>6 cm) associated with systemic toxicity of inflammatory or infectious etiology.

ICD-10CM CODES A04.7 Megacolon due to Clostridium difficile K59.3 Megacolon, not elsewhere classified

EPIDEMIOLOGY & DEMOGRAPHICS INCIDENCE: Varies depending on etiology. Incidence in patients with ulcerative colitis (UC) is approximately 10% and nearly 5% in patients with Crohn disease. Clostridium difficile infections may be complicated by toxic megacolon in up to 3% of cases. PEAK INCIDENCE: N/A PREVALENCE: N/A PREDOMINANT SEX AND AGE: With increasing rates of Clostridium difficile (C. diff) infections, patients ages 65 and older are at higher risk for developing toxic megacolon as a result of C. diff infection. GENETICS: There are no known genetic factors that predispose patients to developing toxic megacolon associated with an inflammatory or infectious etiology. RISK FACTORS: Major risk factors include inflammatory, infectious, and ischemic conditions of the colon, especially in individuals who are immunocompromised. Other risk factors include hypokalemia, use of narcotics or antidiarrheal agents, pregnancy, and recent instrumentation (such as colonoscopy). PHYSICAL FINDINGS & CLINICAL PRESENTATION • Patients with toxic megacolon usually appear severely ill. Clinical symptoms are similar to those of IBD and acute colitis and may include abdominal pain, diarrhea (usually bloody) and vomiting. • Physical exam findings may include a distended, tender, and tympanic abdomen with reduced or absent bowel sounds. The patient may also present with signs of shock such as fever, tachycardia, mental status changes, and hypovolemia. Older patients are less likely to demonstrate a peritoneal abdominal examination. • Laboratory findings may include leukocytosis, lactic acidosis, anemia, and electrolyte abnormalities such as hypokalemia and hypoalbuminemia. ETIOLOGY • Most common etiologies are inflammatory conditions such as UC, Crohn disease, and Behçet disease.

DIAGNOSIS DIFFERENTIAL DIAGNOSIS Ischemic colitis, Crohn disease, ulcerative colitis WORKUP • General principles of workup include physical examination to evaluate for an acute abdomen, laboratory testing and radiography to evaluate for colonic dilation. • Clinical criteria for toxic megacolon, proposed by Jalan et al in 1969, are still used. A diagnosis can be made if radiographic evidence of colonic distention >6 cm is present with at least three of the following: Fever >38° C (100.4° F), heart rate >120, leukocytosis >10.5, or anemia. In addition, at least one of the following must also be present: Dehydration, altered level of consciousness, electrolyte abnormalities, or hypotension. • Patients with suspected toxic megacolon should be triaged emergently to an emergent care setting to facilitate rapid diagnosis and treatment.

and for surgical planning (Fig. 2). It can also be helpful when differentiating between the various etiologies of toxic megacolon and to assess for complications such as intraabdominal hemorrhage or abscess.

BOX 1  Disorders Associated with Toxic Megacolon • Inflammatory bowel disease 1. Ulcerative colitis 2. Crohn disease • Infectious colitis 1. Salmonella, Shigella, amoebic colitis 2. Clostridium difficile 3. Cytomegalovirus colitis 4. HIV infection • Cancer chemotherapy • Ischemia HIV, Human immunodeficiency virus. From Vincent JL et al: Textbook of critical care, ed 6, Philadelphia, 2011, WB Saunders.

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TREATMENT Treatment includes both medical and surgical options. Principles of initial management include treating the underlying cause, managing shock, analgesia, and early surgical and gastroenterology consultation.

NONPHARMACOLOGIC THERAPY • Surgery may be required in up to 50% of patients with toxic megacolon who do not show clinical improvement within 24 to 48 hr. The preferred first-line surgical treatment is subtotal colectomy with an end ileostomy. Other options include total proctocolectomy or colon decompression via the Turnbull method. • Timing of surgical treatment is still controversial, with many advocating for aggressive medical treatment and observation before surgical intervention. Definitive indications for early surgical treatment include perforation, persistent colonic hemorrhage, or rapid clinical deterioration.

LABORATORY TESTS Initial testing should include a CBC, full chemistry panel, lactic acid, coagulation panel, liver function panel, and a type and screen. IMAGING STUDIES • All patients should initially receive a plain abdominal radiograph (Fig. 1) to assess for colonic dilation. Common findings include mucosal irregularity, loss of haustrations, “thumb printing” due to bowel wall edema, and thickening of the colonic wall with a continuous segment of air-filled colon >6 cm in diameter. The transverse or right colon is usually the most dilated segment seen. • Computed tomography (CT) has been increasingly used to assess disease extent

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FIG. 1  Toxic megacolon secondary to ulcerative colitis. The smooth indentations seen along the margin of the colon represent pseudopolyps. (From Marx JA et al [eds]: Rosen’s emergency medicine: concepts and clinical practice, ed 7, Philadelphia, 2010, Elsevier.)

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FIG. 2  Toxic megacolon. In a young patient with severe ulcerative colitis, coronal computed tomography demonstrates marked dilation of the colon (c) with thinning of its walls. The diameter of the lumen of the colon exceeds 7 cm. This finding places the patient at high risk of colon perforation. (From Webb WR et al: Fundamentals of body CT, ed 4, Philadelphia, 2015, WB Saunders.)

Diseases and Disorders

SYNONYM Toxic dilation of the colon

• Infections such as C. diff, Salmonella, Shigella, E. coli, cytomegalovirus, and Entamoeba can also be complicated by toxic megacolon. • Other less common etiologies include ischemic colitis, malignancy such as lymphoma, and Kaposi sarcoma. In general, toxic megacolon is more likely to be associated with pancolitis than segmental colitis (Box 1).

Toxic Megacolon

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ACUTE GENERAL Rx • Medications that impact colonic motility such as anticholinergics, opioids, and antidiarrheal agents should be discontinued and avoided. • Electrolyte abnormalities, dehydration, and anemia are common clinical findings and should be addressed early. Fluid resuscitation with an isotonic solution and correction of electrolyte disturbances (especially hypokalemia) can help prevent worsening atony of the colonic wall. Patients with anemia from colonic hemorrhage should receive blood transfusion(s). • Patients with toxic megacolon should receive broad-spectrum antibiotics as soon as possible. Infections due to C. diff should be treated with vancomycin (oral or rectal) or metronidazole (oral or IV). Toxic megacolon due to cytomegalovirus should be treated with ganciclovir IV. • Patients with inflammatory etiologies such as UC or Crohn should receive high-dose IV steroids, either hydrocortisone 100 mg IV or methylprednisolone 60 mg IV. Steroids should not be used in patients with a confirmed infectious etiology. • There are currently no data to support empiric treatment of toxic megacolon due to IBD with cyclosporine or infliximab. These treatment options should be reserved for patients who are not steroid responsive and should be limited to one attempt at clinical improvement so as not to delay surgical intervention. • A management algorithm for toxic megacolon is outlined in Fig. 3. CHRONIC Rx Patients with IBD will need continued treatment for the underlying disease process once the acute processes associated with toxic megacolon have resolved. COMPLEMENTARY & ALTERNATIVE MEDICINE N/A DISPOSITION All patients with toxic megacolon will require admission, possibly to the intensive care unit, depending on their clinical presentation. REFERRAL • Patients with suspected toxic megacolon presenting outside an emergency department should be referred there immediately. • Surgical consultation in all cases.

Fulminant colitis/Toxic megacolon (TM)

Start supportive management immediately: • Bowel rest • Fluid and electrolyte resuscitation • Stop inciting medication • VTE prophylaxis • Gastric ulcer prophylaxis

IBD-associated TM • High-dose intravenous steroid • Broad-spectrum antibiotics

CDAD • Discontinue antibiotic that is causing Clostridium difficile • Start oral vancomycin and/or oral metronidazole, IV metronidazole

Frequent clinical assessment and close monitoring: • Serial complete blood count, electrolyte level, and abdominal x-ray (every 12 hours) Improvement

Deterioration

Continue medical treatment

Emergent surgery: Total abdominal colectomy with ileostomy

FIG. 3  Management algorithm for toxic megacolon. CDAD, C. difficile-associated disease; IBD, inflammatory bowel disease; VTE, venous thromboembolism. (From Cameron JL, Cameron AM: Current surgical therapy, ed 12, Philadelphia, 2017, Elsevier.)

• All patients with toxic megacolon due to newly diagnosed IBD who are discharged from the hospital should be referred to a gastroenterologist for continued treatment.

 EARLS & P CONSIDERATIONS COMMENTS • Early recognition and treatment of toxic megacolon is critical given the associated high morbidity and mortality. • Anticholinergic medications, antidiarrheal agents, and opioids can precipitate or worsen toxic megacolon. • Management includes medical and surgical treatment with inpatient hospitalization and treatment of the underlying cause.

PREVENTION Prevention focuses on treatment of underlying causes of colitis to prevent complications such as toxic megacolon. SUGGESTED READINGS Available at ExpertConsult.com RELATED CONTENT Clostridium difficile Infection (Related Key Topic) Crohn Disease (Related Key Topic) Small Bowel Obstruction (Related Key Topic) Ulcerative Colitis (Related Key Term) AUTHORS: Steven Rougas, MD, MS, FACEP, and Rory Merritt, MD, MEHP

Toxic Megacolon SUGGESTED READINGS Autenrieth DM, Baumgart DC: Toxic megacolon, Inflamm Bowel Dis 18:584-591, 2012. Strong SA: Management of acute colitis and toxic megacolon, Clin Colon Rectal Surg 23:274-284, 2010.

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Toxic Shock Syndrome BASIC INFORMATION

SYNONYM TSS ICD-10CM CODE A48.3 Toxic shock syndrome

EPIDEMIOLOGY & DEMOGRAPHICS • Case reported incidence peak: 14 cases per 100,000 menstruating women annually in 1980; has since fallen to 1 case per 100,000 persons • Occurs most commonly between ages 10 and 30 yr in healthy, young, menstruating white females • Case fatality ratio of 3% PHYSICAL FINDINGS & CLINICAL PRESENTATION • Fever (>38.0° C; 100.4° F) • Diffuse macular erythrodermatous rash that involves both skin and mucous membranes, resembles sunburn, and also involves the palms and soles. The rash then desquamates 1 to 2 wk after disease onset in survivors • Orthostatic hypotension • Gastrointestinal symptoms: Vomiting, diarrhea, abdominal tenderness • Constitutional symptoms: Myalgia, headache, photophobia, rigors, altered sensorium, conjunctivitis, arthralgia • Respiratory symptoms: Dysphagia, pharyngeal hyperemia, strawberry tongue • Genitourinary symptoms: Vaginal discharge, vaginal hyperemia, adnexal tenderness • End-organ failure • Severe hypotension and acute renal failure • Hepatic failure • Cardiovascular symptoms: Disseminated intravascular coagulation, pulmonary edema, acute respiratory distress syndrome (ARDS), endomyocarditis, heart block ETIOLOGY • Menstruation-associated TSS: 45% of cases associated with tampons, diaphragm, or vaginal sponge use. There has been a decline in these cases and in the case-fatality ratio. • Non–menstruation-associated TSS: 55% of cases associated with puerperal sepsis, post-cesarean section endometritis, mastitis, sinusitis, wound or skin infection, septorhinoplasty (nasal packings), pelvic inflammatory disease, respiratory infections following

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • Staphylococcal food poisoning • Septic shock • Mucocutaneous lymph node syndrome • Scarlet fever • Rocky Mountain spotted fever

• Meningococcemia • Toxic epidermal necrolysis • Kawasaki syndrome • Leptospirosis • Legionnaires’ disease • Hemolytic-uremic syndrome • Stevens-Johnson syndrome • Scalded skin syndrome • Erythema multiforme • Acute rheumatic fever

WORKUP Broad-spectrum syndrome with multiorgan system involvement and variable but acute clinical presentation, including the following diagnostic criteria for staphylococcal toxic shock syndrome: • Fever (>38° C; 100.4° F) • Classic desquamating rash (1 to 2 wk) • Hypotension/orthostatic systolic blood pressure ≤90 mm Hg • Syncope • Negative throat and cerebrospinal fluid cultures • Negative serologic test for Rocky Mountain spotted fever, rubeola, and leptospirosis • Clinical involvement of three or more of the following: 1. Cardiopulmonary: ARDS, pulmonary edema, endomyocarditis, second- or third-degree atrioventricular block 2. Central nervous system: Altered sensorium without focal neurologic findings 3. Hematologic: Thrombocytopenia (platelets 20 kg (see text) 5-20 mg 3 times weekly 1 mg/kg/day divided twice daily 2 mg/kg per day for 2 days, then 1 mg/kg/day for 6 mo, then 3 times weekly (M-W-F) for 6 mo 100 mg/kg per day divided twice daily 5-10 mg 3 times weekly 1 mg/kg/day divided twice daily

Pregnant women—acute infection first 21 wk of gestation

Spiramycin

3 g/day divided twice daily without food

Pregnant women—fetal infection confirmed (amniotic fluid PCR positive)

Pyrimethamine plus

100 mg/day divided twice daily for 2 days, then 50 mg/day 3 g/day divided twice daily 5-20 mg/day

Folinic acid

Sulfadiazine plus

Congenital

Folinic acid plus Prednisone Pyrimethamine plus

Sulfadiazine plus Folinic acid

4-6 wk or 2 wk after symptoms resolve Prednisone should be continued until resolution of sight-threatening active chorioretinitis

1 yr

Until resolution of elevated CSF protein level or sight-threatening active chorioretinitis Until fetal infection documented or excluded at 21 wk of gestation; if fetus infected, change to pyrimethamine plus sulfadiazine plus folinic acid until delivery Until delivery

AIDS, Acquired immunodeficiency syndrome; CSF, cerebrospinal fluid; PCR, polymerase chain reaction. aFor more detailed recommendations for patients with human immunodeficiency virus infection/AIDS, see http://aidsinfo.nih.gov/guidelines. From Cherry JD et al: Feigin and Cherry’s pediatric infectious diseases, ed 8, Philadelphia, 2019, Elsevier.

CHRONIC Rx Maintenance therapy in AIDS patients because of the high risk (80%) of relapse: • Pyrimethamine 25 mg PO qid • Sulfadiazine 500 mg PO qid • Leucovorin 10 to 20 mg PO qid DISPOSITION • Prognosis: 1. Excellent in the immunocompetent host 2. Good in ocular infection (although re­lapses are common) • Treatment of acute infection in pregnancy: 1. Reduces incidence and severity of congenital toxoplasmosis • Treatment of congenital infection: 1. Improvement in intellectual function 2. Regression of retinal lesions • AIDS: 1. 70% to 95% response to therapy

REFERRAL • To infectious disease expert: 1. Immunocompromised hosts 2. Pregnant women 3. Difficulty in making a diagnosis or deciding on treatment • To pediatric infectious disease expert: 1. Congenital infection • To obstetrician: 1. Pregnant seronegative mother 2. Acute seroconversion • To ophthalmologist: 1. Congenital infection 2. Any case of ocular infection

PEARLS & CONSIDERATIONS COMMENTS • Prevention of toxoplasmosis is most important in seronegative pregnant women and immunocompromised hosts.

• Patient instructions: 1. Cook meat to 66° C (150.8° F). 2. Cook eggs. 3. Do not drink unpasteurized milk. 4.  Wash hands thoroughly after handling raw meat. 5. Wash kitchen surfaces that come in contact with raw meat. 6. Wash fruits and vegetables. 7. Avoid contact with materials potentially contaminated with cat feces.

SUGGESTED READINGS Available at ExpertConsult.com RELATED CONTENT Toxoplasmosis (Patient Information) AUTHORS: Tara C. Bouton, MD, MPH, TM, Philip A. Chan, MD, MS, and Glenn G. Fort, MD, MPH

Toxoplasmosis

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Tissue cysts Cat

Rodents

Birds

Oocysts in feces Contaminated food, water or soil

Tissue cysts Oocysts

Oocysts

Transfusion

Humans

Transplantation Food animals

Tissue cysts

Vertical transmission Congenital infection

FIG. E1  Life cycle of Toxoplasma gondii. (From Kanski JJ, Bowling B: Clinical ophthalmology, a systematic approach, ed 7, Philadelphia, 2010, Saunders.)

SUGGESTED READINGS Maldonado YA, Read JS: Committee on infectious diseases: diagnosis, treatment, and prevention of congenital toxoplasmosis in the United States, Pediatrics 139(2):e20163860, 2017. Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents: Guidelines for the prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from the Centers for Disease Control and Prevention, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. Available at: http://aidsinfo.nih.gov/contentfiles/lvguidelines/adult_oi.pdf.

FIG. E4  Toxoplasmic encephalitis in a person who has acquired immunodeficiency syndrome. A cranial computed tomography scan shows bilateral contrast-enhanced ring lesions with peripheral edema and mass effect. (From Cohen J, Powderly WG: Infectious diseases, ed 2, St Louis, 2004, Mosby.)

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Tracheitis BASIC INFORMATION DEFINITION Bacterial tracheitis is an acute infectious disease affecting the trachea and large conducting airways. Tracheal inflammation may be caused by a large number of inhaled stimuli, but bacterial infection is a life-threatening illness associated with purulent secretions and subglottic edema. SYNONYMS Bacterial tracheobronchitis Pseudomembranous croup Membranous laryngotracheobronchitis ICD-10CM CODES J04.1 Acute tracheitis J04.10 Acute tracheitis without obstruction J04.11 Acute tracheitis with obstruction

EPIDEMIOLOGY & DEMOGRAPHICS INCIDENCE (IN U.S.): • Uncommon • May be the most common cause of acute upper airway obstruction requiring admission to pediatric ICUs PEAK INCIDENCE: Three fourths of cases reported in winter PREDOMINANT SEX: Boys > girls in one series PREDOMINANT AGE: • 1 mo to 8 yr • Almost all 100 ml/hr until hypotension is corrected and hemoglobinuria clears. IV furosemide may be necessary to maintain adequate renal flow. • The addition of mannitol may prevent renal damage (controversial). Mannitol, if chosen,

TABLE 1  Signs and Symptoms of Acute Adverse Reactions to Blood Transfusion Reaction

Fever

Chills/ Rigors

Nausea/ Chest Vomiting Discomfort/Pain

Facial Wheezing/ Back/ Flushing Dyspnea Lumbar Pain

Discomfort at Infusion Site

Hypotension

Acute hemolytic Febrile nonhemolytic Nonimmune hemolysis Acute lung injury Allergic Massive transfusion ­complications Anaphylaxis Passive cytokine infusion Hypervolemia Bacterial sepsis Air embolus

X X

X X

X

X X

X

X

X

X X X

X X

X X

X X

X

X

X

X

X

From Goldman L, Bennett JC (eds): Cecil’s textbook of medicine, ed 22, Philadelphia, 2004, Saunders.

X

X

X

X

X X X X

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X

X

X

X

X

X

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Transfusion Reaction, Hemolytic TABLE 2  Types of Acute Transfusion Reactions Reaction Type

Presenting Signs and Symptoms

Acute hemolytic

Fever, chills, dyspnea, vomiting, hypotension, tachycardia, infusion site pain, back pain, hemoglobinuria, hemoglobinemia, indirect hyperbilirubinemia, renal failure, DIC Fever, chills, rigors Urticaria, pruritus, flushing, angioedema, dyspnea, bronchospasm stridor, hypotension, tachycardia, abdominal cramping Dyspnea, tachycardia, hypertension, headache, jugular venous distention Fever, chills, hypotension, tachycardia, vomiting Dyspnea, hypoxemia, fever, hypotension

Febrile reaction Allergic Hypervolemic Septic Transfusion-related acute lung injury

DIC, Disseminated intravascular coagulation. From Hoffman R et al: Hematology, basic principles and practice, ed 7, Philadelphia, 2018, Elsevier.

DISPOSITION Mortality rate is 3% to 10% in severe transfusion reactions.

PEARLS & CONSIDERATIONS

TABLE 3  Immediate Investigations in the Case of an Acute Transfusion Reaction Check for hemolysis. Perform visual examination of patient’s plasma and urine (plasma and urine hemoglobin can be checked, but this is not essential). Blood film may show spherocytosis. Bilirubin and lactate dehydrogenase (LDH) levels will be raised. Check for incompatibility. Check the documentation and the patient’s identity. Repeat ABO group of patient on pretransfusion and posttransfusion samples and of the donor unit(s). Screen the patient for red cell antibodies pretransfusion and posttransfusion. Repeat crossmatch with pretransfusion and posttransfusion samples. Direct antiglobulin test (DAT) on pretransfusion and posttransfusion samples. Eluate from patient’s red cells. Check for disseminated intravascular coagulation. Perform blood count and film, coagulation screen, and fibrin degradation products (or D-dimers). Check for renal dysfunction. Check blood urea, creatinine, and electrolytes. Check for bacterial infection. Take blood cultures from the patient and donor unit including immediate Gram stain. From Bain BJ, Bates I, Laffan MA: Dacie and Lewis practical haematology, ed 12, Philadelphia, 2017, Elsevier.

TABLE 4  Hemolytic Transfusion Reactions: Serologic Presentation

Type

Antibody Detectable Initially

Primary Antibody Type

Degree of Complement Binding

Example

Acute intravascular Acute extravascular Delayed intravascular Delayed extravascular

Yes Yes No No

IgM IgG IgG IgG

Full (C1-9) None/partial Full (C1-9) None/partial

ABO system Rh system Kidd system Duffy system

From Hoffman R et al: Hematology, basic principles and practice, ed 7, Philadelphia, 2018, Elsevier.

must be used with caution; if acute tubular necrosis occurs before mannitol infusion, pulmonary edema may occur as a result of the acute increase in intravascular volume secondary to fluid expansion. • Monitor for the presence of disseminated intravascular coagulation. PT, aPTT, and fibrinogen levels should be closely monitored. • If sepsis is suspected, culture as appropriate.

COMMENTS Hemolysis caused by minor antigen systems is generally less severe and may be delayed 1 to 10 days after transfusion. SUGGESTED READINGS Available at ExpertConsult.com AUTHOR: Joseph Sweeney, MD, FACP, FRCPath

Transfusion Reaction, Hemolytic SUGGESTED READINGS Hendrickson JE et  al: ncidence of transfusion reactions: a multicenter study utilizing systematic active surveillance and expert adjudication, Transfusion 56:2587-2596, 2016. Panch SR: Hemolytic transfusion reactions, N Engl J Med 381:150–162, 2019.

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Transient Global Amnesia BASIC INFORMATION DEFINITION A clinical syndrome lasting up to 24 hours of sudden onset, severe anterograde and variable retrograde amnesia without loss of other neurologic function. SYNONYM TGA

EPIDEMIOLOGY & DEMOGRAPHICS INCIDENCE (IN U.S.): 3.4 to 10.4 per 100,000 people. PEAK INCIDENCE: Most between ages 50 to 70 and equally common in men and women. In population older than 50 the incidence increases to 23.5 per 100,000 per year. TGA is also more common in individuals with migraine.1 RECURRENCE RATE: 2.9% to 23.8% PHYSICAL FINDINGS & CLINICAL PRESENTATION2 • Cannot recall novel episodic information, repeatedly asking the same questions • No impairment in consciousness or nonmemory cognitive domains, no focal neurologic deficit • Complex procedural memory is often preserved (i.e., driving) • Triggers include Valsalva maneuver, immersion in cold or hot, sexual intercourse, emotional stress • Typically a single attack that is self-limited, with amnestic gap of the duration of episode • Those with recent head injury or epilepsy diagnosis are excluded 1 Arena

JE et al: Transient global amnesia, Mayo Clin Proc 90(2):264-272, 2015. 2 Arena JE et al: Long-term outcome in patients with transient global amnesia: a population-based study, Mayo Clin Proc 92(3):399-405, 2017.

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • Posterior cerebral artery transient ischemic attack: Can be associated with confusion or memory loss. Commonly with vascular risk factors and other focal neurologic signs (homonymous hemianopsia, aphasia, hemiparesis, hemisensory loss, hemi-body pain, oculomotor nerve palsy or vertical gaze palsy). • Transient epileptic amnesia: Epilepsy syndrome, consisting of atypical TGA or recurrent attacks of amnesia, often less than one hour and upon waking, responsive to antiepileptic medications. Associated with olfactory hallucinations or oral automatisms. Interictal EEG may be abnormal. Hippocampal atrophy on MRI may be seen. • Dissociative fugue, or transient dissociative amnesia: Extensive retrograde amnesia, loss of personal identity may occur, unlike in TGA where such is preserved. • Hypoglycemia: Metabolic dysfunction can cause impairment in consciousness, focal signs, or prolonged cognitive impairment unlike TGA. WORKUP • Largely a clinical diagnosis, workup should focus on exclusion of vascular or epileptic source of symptoms. • Collateral history of witnessed event and exclusion of prior event. • Cognitive examination with evaluation of registration, delayed recall, and orientation. • Careful cranial nerve examination to exclude posterior circulation stroke.

LABORATORY TESTS • Complete blood count with erythrocyte sedimentation rate and C-reactive protein • Serum chemistries, including lipid profile • Troponins and electrocardiogram DIAGNOSTIC STUDIES • MRI of the brain may show reversible T2 hyperintensity or diffusion restriction exclusive to the hippocampi. • Electroencephalogram (EEG) to exclude epileptiform activity.

TREATMENT NONPHARMACOLOGIC THERAPY Self-limited, not requiring specific pharmacologic or nonpharmacologic treatment ACUTE GENERAL Rx Investigate as an emergency. CHRONIC Rx • Does not lead to long-term sequela of memory loss. Complete recovery of cognitive function has been reported 5 days to 6 mo after the episode. • Low risk of subsequent ischemic cerebral stroke or seizures though possible increased risk of future dementia DISPOSITION Due to the benign nature of transient global amnesia, rarely is continued followup necessary. REFERRAL Referral to a neurologist is necessary when the diagnosis is uncertain or with atypical features of the clinical presentation. SUGGESTED READINGS Available at ExpertConsult.com AUTHOR: Rituparna Das, MD

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Diseases and Disorders

ICD-10CM CODE G45.4 Transient global amnesia

ETIOLOGY • Several proposed mechanisms of pathophysiology: 1. Hypoperfusion or arterial ischemia of the hippocampi 2. Internal jugular venous flow reversal causing venous hypertension to the medial temporal lobe 3. Migraine phenomena with cortical spreading depression

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Transient Global Amnesia SUGGESTED READINGS Arena JE, Rabinstein AA: Transient global amnesia, Mayo Clin Proc 90(2):264272, 2015. Mangla A, Navi BB: Transient global amnesia and the risk of ischemic stroke, Stroke 45(2):389-393, 2014. Nicastro N, Picard F: Transient global amnesia mimics: transient epileptic amnesia, Epilepsy Behav Case Rep 2:100-101, 2014. Noël A, Quinette P: The still enigmatic syndrome of transient global amnesia: interactions between neurological and psychopathological factors, Neuropsychol Rev 25(2):125-133, 2015. Szabo K: Transient global amnesia, Front Neurol Neurosci 34:143-149, 2014, https://doi.org/10.1159/000356431. Epub 2014 Apr 16. Sugiyama A, Kobayashi M: Transient global amnesia with a hippocampal lesion followed by transient epileptic amnesia, Seizure 31:141-143, 2015.

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Transient Ischemic Attack BASIC INFORMATION DEFINITION Transient ischemic attack (TIA) is a transient episode of neurologic dysfunction caused by focal brain, spinal cord, or retinal ischemia without acute infarction on MRI. TIA symptoms typically resolve within 60 min and by definition within 24 hours. Despite complete symptom resolution, 20% to 50% of patients clinically suspected to have suffered a TIA have evidence of acute tissue infarction on MRI. SYNONYMS TIA Amaurosis fugax Ophthalmologic TIA “Mini-stroke” Pre-stroke ICD-10CM CODES G45.9 Transient cerebral ischemic attack, unspecified G45.8 Other transient cerebral ischemic attacks and related syndromes Z86.73  Personal history of transient ischemic attack (TIA), and cerebral infarction without residual deficits

EPIDEMIOLOGY & DEMOGRAPHICS INCIDENCE: 70 to 101 cases per 100,000 persons annually PEAK INCIDENCE: After age 60 yr PREVALENCE: 200,000 to 500,000 persons in the United States. The annual risk of stroke after either a TIA or minor stroke is approximately 3% to 4%. PREDOMINANT SEX AND RACE: Males > females; African American > Caucasian RISK FACTORS: Same as for ischemic stroke PHYSICAL FINDINGS & CLINICAL PRESENTATION • TIAs often present with transient neurologic symptoms including ipsilateral transient monocular blindness (amaurosis fugax), contralateral numbness or weakness, contralateral homonymous hemianopsia, and/or aphasia. • Box 1 summarizes carotid artery TIAs. • Vertebrobasilar artery TIAs are described in Box 2. ETIOLOGY Embolic (cardioembolism in 10% to 15%) large vessel atherothrombotic disease (20% to 25%) lacunar disease, hypoperfusion, hypercoagulable state, arteritis

DIAGNOSIS DIFFERENTIAL DIAGNOSIS Seizures, hypoglycemia, hemiplegic migraine, intracranial hemorrhage, mass lesion, vestibular disease, Bell palsy, meningitis, multiple sclero-

ALG

sis, subdural hematoma, brain abscess, cervical or lumbar spine disease, conversion disorder

etc.). Alternatives to this scoring system are being investigated.

WORKUP Given the high risk of stroke within the first 48 hours following TIA (up to 10%), hospital admission for workup is advised. Most of the immediate risk of stroke is secondary to carotid disease. The American Heart Association recommends that the ABCD2 score be used in the evaluation of TIA. It consists of 1 point for age ≥60 yr, 1 point for BP ≥140 mm Hg systolic or ≥90 mm Hg diastolic, clinical features (2 points for unilateral weakness, 1 point for speech impairment), duration of TIA (2 points for duration ≥60 min, 1 point for duration 10-59 min), presence of diabetes mellitus (1 point). According to the guidelines, it is reasonable to hospitalize patients with TIA if they present within 72 hours and have an ABCD2 score ≥3. There is some debate about the usefulness of this scale since it fails to account for changes seen on echocardiogram, carotid Dopplers, or ECG that may place the patient at more imminent risk of stroke (carotid stenosis, Afib, cardiac thrombus,

LABORATORY TESTS Complete blood count, basic metabolic panel, prothrombin time, activated partial thromboplastin time, sedimentation rate, fasting lipid panel, serum glucose and hemoglobin A1c (to detect latent diabetes mellitus), and TSH. IMAGING STUDIES • CT scan should be obtained to exclude hemorrhage; MRI with diffusion-weighted images if immediately available to determine whether infarction occurred. • Imaging of the vessels should be obtained via magnetic resonance angiography (MRA) head and neck, computed tomography angiography (CTA) head and neck, or carotid Doppler/transcranial Doppler (CD/ TCD). If symptoms are localizable to the posterior circulation, MRA or CTA should be obtained in lieu of CD/TCD. • Transthoracic echocardiogram should be obtained.

BOX 1  Carotid Artery Transient Ischemic Attacks Symptoms Contralateral hemiparesis, hemianopsia, hemisensory loss Aphasia, if dominant hemisphere Neglect and hemi-inattention, if nondominant hemisphere Ipsilateral amaurosis fugax Associated findings Carotid bruit Retinal artery emboli Tests Ultrasonography (carotid Doppler studies) Magnetic resonance imaging angiography (MRA) Cerebral arteriography Therapy Medical: Platelet inhibitors (e.g., aspirin) Risk-reduction measures (e.g., control blood pressure, glucose levels, cholesterol) Surgical: Carotid endarterectomy, if stenosis >70% and symptomatic Endovascular: Placement of stent From Kaufman DM, Geyer HL, Milstein MJ: Kaufman’s clinical neurology for psychiatrists, ed 8, Philadelphia, 2017, Elsevier.

BOX 2  Vertebrobasilar Artery Transient Ischemic Attacks Symptoms Vertigo, vomiting, tinnitus Circumoral paresthesias or numbness Dysarthria, dysphasia Drop attacks Associated findings Nystagmus Ataxia Cranial nerve abnormalities Tests Ultrasonography (transcranial Doppler studies) Magnetic resonance imaging angiography (MRA) Cerebral arteriography Therapy Medical: Platelet inhibitors* Risk-reduction measures Surgical: None *See Box 1. From Kaufman DM, Geyer HL, Milstein MJ: Kaufman’s clinical neurology for psychiatrists, ed 8, Philadelphia, 2017, Elsevier.

ALG

TREATMENT NONPHARMACOLOGIC THERAPY • Carotid endarterectomy or carotid stenting should be considered for patients found to have carotid stenosis of ≥50% as the cause for TIA. Efficacy is greatest in the two weeks immediately following a TIA or ischemic stroke. Please refer to the “Carotid Artery Stenosis” chapter for more information. • The practice of intracranial angioplasty and stenting has largely declined following the publication of negative results from clinical trials and is only used in select patients who fail maximal medical management with aggressive platelet inhibition, strict risk factor control such as hyperlipidemia, hypertension, diabetes mellitus, weight loss, treatment of sleep apnea, and smoking cessation among others. ACUTE GENERAL Rx • In the absence of contraindications, patients with atrial fibrillation should be considered for anticoagulation. Choices for anticoagulants include the direct oral anticoagulants (such as dabigatran, rivaroxaban, apixaban, edoxaban, betrixaban) and/or warfarin. In patients with TIA and atrial fibrillation or a

cardiac thrombus, therapeutic anticoagulation should be achieved rapidly. Those who are not candidates for a direct oral anticoagulation and who will need chronic warfarin should first be started on either intravenous heparin or therapeutic anticoagulant doses of Lovenox, along with warfarin, until target INR between 2.0 and 3.0 is achieved, at which point warfarin should be continued as monotherapy. • Although no compelling evidence exists for the use of heparin in the acute treatment of TIAs without cardioembolic source, patients who develop recurrent symptoms within the same vascular territory that increase in duration, severity, and/or frequency (crescendo TIA/stuttering TIA) may benefit from its use pending cardiac and vascular imaging and identification of a possible source.

CHRONIC Rx • Chronic therapy includes antiplatelet or anticoagulation therapy and modifying the four major risk factors: hypertension, dyslipidemia, diabetes mellitus, and smoking cessation. • Antiplatelet therapy should be used to reduce the risk of recurrent TIAs or subsequent stroke. Three antiplatelet agents are commonly used in stroke prevention: aspirin, aspirin/dipyridamole, and clopidogrel. All are reasonable choices, but practitioners should consider their individual patient’s comorbidities when selecting an antiplatelet agent. • A direct oral anticoagulant of dose-adjusted warfarin (INR 2.0 to 3.0) or use of direct oral anticoagulants instead of an antiplatelet is indicated for prevention of future strokes in atrial fibrillation patients.

PEARLS & CONSIDERATIONS • All cause mortality in 1 yr is 25% in patients diagnosed TIA. • Dual antiplatelet therapy in acute TIA and minor stroke is being evaluated. A recent trial revealed that among patients with TIA or minor stroke who can be treated within 24 hours after the onset of symptoms, the combination of clopidogrel and aspirin is superior to aspirin alone for reducing the risk of stroke in the first 90 days but did increase the risk of hemorrhage. Most of the benefit was

concentrated in the first seven to 30 days, so dual antiplatelet therapy may be reasonable in the first 30 days after TIA. • Previous studies conducted between 1987 and 2003 estimated the risk of stroke or an acute coronary syndrome was 12% to 20% during the first 3 mo after a TIA. New data estimate the 1-yr risk to be 6.2%. Multiple infarctions on brain imaging, large-artery atherosclerosis, and an ABCD1 score of 6 or 7 were each associated with more than a doubling of the risk of stroke.2

PREVENTION • A healthy lifestyle and management of cardiovascular risk factors should be encouraged. • Antiplatelet therapy has not been proven efficacious in primary prevention of TIA or stroke but is very beneficial in secondary prevention. PATIENT & FAMILY EDUCATION Patients should be counseled on the early signs of stroke symptoms and instructed to promptly seek medical attention if they develop symptoms concerning for stroke. Patients should be encouraged to pursue a healthy lifestyle to include exercise and smoking cessation. In addition, patients should take an active role in controlling blood pressure and blood glucose. Further educational materials can be found online at http://www.strokecenter.org/. SUGGESTED READINGS Available at ExpertConsult.com RELATED CONTENT Transient Ischemic Attack (TIA) (Patient Information) Carotid Artery Stenosis (Related Key Topic) Atrial Fibrillation (Related Key Topic) Stroke, Acute Ischemic (Related Key Topic) Stroke, Secondary Prevention (Related Key Topic) AUTHORS: Corey Goldsmith, MD, Joseph S. Kass, MD, JD, FAAN, and Prashanth Krishnamohan, MBBS, MD 1 Amarenco

P et al: One-year risk of stroke after transient ischemic attack or minor stroke, N Engl J Med 374:1533-1542, 2016. 2 Kernan WN et al: Pioglitazone after ischemic stroke or transient ischemic attack, N Engl J Med 374:13211331, 2016.

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• An echocardiogram with bubble should be obtained in all patients younger than 50 yr with TIA symptoms. • Electrocardiogram should be obtained to exclude the presence of arrhythmias, namely atrial fibrillation. • A t least 24 hours of heart rhythm monitoring should be accomplished to screen for arrhythmia. Many stroke centers now utilize prolonged ambulatory cardiac rhythm monitoring over several weeks to months to identify paroxysmal atrial fibrillation in select patients when there is a high index of clinical suspicion. • Paroxysmal atrial fibrillation is common in patients with TIA. A recent study found that noninvasive ambulatory ECG monitoring for 30 days significantly improved the detection of atrial fibrillation by a factor of more than five and nearly doubled the rate of anticoagulant treatment as compared with the standard practice of short-duration ECG monitoring.

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Transient Ischemic Attack SUGGESTED READINGS Davis SM, Donnan CA: Secondary prevention after ischemic stroke or transient ischemic attack, N Engl J Med 366:1814-1822, 2012. Easton JD et al: Definition and evaluation of transient ischemic attack: a scientific statement for healthcare professionals from the American Heart Association/ American Stroke Association Council; Council of Cardiovascular Surgery and Anesthesia; Council of Cardiovascular Radiology and Intervention; Council on Cardiovascular Nursing; and the Interdisciplinary Council on Peripheral Vascular Disease, Stroke 40:2276-2293, 2009. Kernan WN et al: Guidelines for the prevention of stroke in patients with stroke and transient ischemic attack: a guideline for healthcare professionals from the American Heart Association/American Stroke Association, Stroke 45:21602236, 2014. Giles MF, Rothwell PM: Systematic review and pooled analysis of published and unpublished validations of the ABCD and ABCD2 transient ischemic attack risk scores, Stroke 41(4):667-673, 2010. Gladstone DJ et al: Atrial fibrillation in patients with cryptogenic stroke, N Engl J Med 370:2467-2477, 2014. Mohr JP et al: Long-term medical management of ischemic stroke and transient ischemic attack due to arterial disease. In Mohr JP, ed: Stroke: pathophysiology, diagnosis, and management, Sudlow & Warlow, Philadelphia, pp 1129-1150. Wang Y et al: Clopidogrel with aspirin in acute minor stroke or transient ischemic attack, N Engl J Med 369:11-19, 2013.

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Transverse Myelitis BASIC INFORMATION DEFINITION Demyelination in a transverse region of the spinal cord due to an inflammatory process that leads to sensory and motor changes below the lesion as well as autonomic dysfunction. The term “transverse myelitis” of late refers to any cause of inflammatory myelopathy, irrespective of severity or degree of structural or functional interruption of pathways through a transverse spinal cord section. Transverse myelitis that extends across three or more segments of the cord is referred to as longitudinally extensive transverse myelitis. The pathologic hallmark of transverse myelitis is the presence of focal collections of lymphocytes and monocytes with varying degrees of demyelination, axonal injury, and astroglial and microglial activation within the spinal cord. SYNONYMS Idiopathic transverse myelitis (ITM) TM ITM ICD-10CM CODES G37.3 Acute transverse myelitis in demyelinating disease of central nervous system G04.89 Other myelitis

EPIDEMIOLOGY & DEMOGRAPHICS INCIDENCE: Annual incidence ranges from 1.3 to 8 cases per million. The incidence increases to 24.6 cases per million annually if causes of acquired demyelination such as multiple sclerosis (MS) or neuromyelitis optic spectrum disorder are included. PREVALENCE: Unknown PREDOMINANT SEX: None, but female preponderance seen in cases associated with multiple sclerosis and neuromyelitis optica spectrum disorder. GENETICS: No genetic predisposition has been shown. PEAK INCIDENCE: Can occur at any age. Bimodal peak in the incidence between 10 to 19 yr and 30 to 39 yr. 20% of cases occur in children with a bimodal peak of incidence between 0 to 2 yr and 5 to 17 yr. RISK FACTORS: Infection, vaccination PHYSICAL FINDINGS & CLINICAL PRESENTATION • Rapid onset of symmetric or asymmetric paraparesis or paraplegia of the lower extremities over a few days, ascending paresthesia, sensory level at the trunk, back pain, sphincter dysfunction, and positive Babinski, which can be bilateral. The arms may also be involved if the cervical cord is involved, but cervical involvement is less common than thoracic involvement. In the acute phase the weakness is flaccid, with diminished deep tendon reflexes mimicking a

peripheral neuropathy such as Guillain-Barré syndrome. • One third to one half of patients present with localizing back pain or a bandlike area of altered sensation, usually at the dermatomal level corresponding to the lesion within the cord. • There is progression to nadir of clinical deficits between 4 hr and 21 days after symptom onset. • Urinary incontinence or retention, GI disturbances (incontinence or constipation), and sexual dysfunction are common. • Acute flaccid myelitis is a subtype of myelitis in which patients present with acute limb weakness and have primarily involvement of gray matter on spinal cord imaging.

ETIOLOGY • The clinical signs are caused by an interruption in ascending and descending sensory, motor, and autonomic pathways in the transverse plane of the spinal cord, resulting in sensory-level weakness and autonomic dysfunction at and below the level of the lesion due to demyelination or inflammation of the spinal cord. • Can be idiopathic demyelination (15% to 30%) that is a monophasic one-time event or demyelination secondary to neurologic or systemic conditions (Box 1). • Secondary causes include postinfection, postvaccination, acute demyelinating

encephalomyelitis (where transverse myelitis tends to be monophasic), and others such as multiple sclerosis, neuromyelitis optica spectrum disorder (NMOSD), connective tissue disorders such as systemic lupus, Sjögren syndrome, antiphospholipid antibody syndrome, sarcoidosis, and paraneoplastic conditions, which can be progressive or relapsing. • Infectious causes of myelitis include HIV, syphilis, varicella zoster (associated with shingles), HTLV-1, Lyme disease, arboviruses such as West Nile virus (typically causing a poliomyelitis-type acute flaccid paralysis), or enteroviruses (typically causing acute flaccid paralysis mainly in children). • About 50% of patients have had a recent upper respiratory infection.

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • MS (Table 1) • Neuromyelitis optica spectrum disorder (NMOSD) • Metastatic disease • Spinal cord tumors • Herniated or slipped discs • Spinal stenosis • Spinal epidural abscess • Vascular malformation

BOX 1  Central Nervous System and Systemic Autoimmune Disorders Associated with Acute Transverse Myelitis Central Nervous System Disorders Acute disseminated encephalomyelitis Multiple sclerosis Neuromyelitis optica Systemic Autoimmune Disorders Antiphospholipid antibody syndrome Behçet disease Mixed connective tissue disorder Neurosarcoidosis Sjögren syndrome Systemic lupus erythematosus From Cherry JD et al: Feigin and Cherry's textbook of pediatric infectious diseases, ed 8, Philadelphia, 2019, Elsevier.

TABLE 1  Distinguishing Acute Transverse Myelitis from Other Central Nervous System Demyelinating Disorders Finding

ATM

ADEM

MS

NMO

Myelitis Acute mental status changes Optic neuritis Abnormal brain MRI CSF oligoclonal bands Serum AQP4-IgG Recurrences

+ − − − − − +/−

+/− + +/− + +/− − +/−

+/− (partial) − +/− + + − +

+ +/− +/− +/− +/− +/− +

+, Always present; +/−, variably present; −, usually absent. ADEM, Acute disseminated encephalomyelitis; AQP, aquaporin 4; ATM, acute transverse myelitis; CSF, cerebrospinal fluid; MRI, magnetic resonance imaging; MS, multiple sclerosis; NMO, neuromyelitis optica. From Cherry JD et al: Feigin and Cherry's textbook of pediatric infectious diseases, ed 8, Philadelphia, 2019, Elsevier.

Transverse Myelitis TABLE 2  Suggested Diagnostic Workup for Recurrent Central Nervous System Demyelinating Disorders and Systemic Autoimmune Disorders Associated with Acute Transverse Myelitis All Patients

Suggestive of Neuromyelitis Optica

Also Consider

Brain MRI with gadolinium CSF oligoclonal bands Antinuclear antibodies Antiphospholipid antibodies Serum AQP4-IgG

Ophthalmology consultation Visual evoked potentials Formal visual field testing

Angiotensin-converting enzyme (serum, CSF) Other autoantibodies Anti-dsDNA Anti-La Anti-Ro Anti-Smith

Blood

Cerebrospinal Fluid

Other

• Blood cultures • Acute and convalescent titers to Borrelia burgdorferi, EBV, Mycoplasma pneumoniae

• Bacterial culture • Viral culture • PCR testing for CMV, EBV, Enterovirus, HSV, M. pneumoniae, VZV

• Viral culture of stool and respiratory secretions • Consider stool ova and parasite testing and serum titers if parasitic infection is suspected

CMV, Cytomegalovirus; EBV, Epstein-Barr virus; HSV, herpes simplex virus; PCR, polymerase chain reaction; VZV, varicella zoster virus. From Cherry JD et al: Feigin and Cherry's textbook of pediatric infectious diseases, ed 8, Philadelphia, 2019, Elsevier.

1. Spinal dural arteriovenous fistula common) 2. Arteriovenous malformation of the cord • Spinal cord infarction due to either rior spinal artery or posterior spinal occlusion

(most spinal anteartery

WORKUP Transverse myelitis (TM) should be suspected in patients with a history of rapid (hours to days) onset of motor weakness and sensory abnormalities with bladder or bowel dysfunction that is referable to the spinal cord. The dysfunction is bilateral (not necessarily symmetric), and there is a clearly defined sensory (dermatomal) level. It is important to distinguish idiopathic TM from TM due to MS or neuromyelitis optica spectrum disorder because idiopathic TM does not relapse and does not require long-term immunomodulatory therapy. A suggested diagnostic workup for recurrent CNS demyelinating disorders and systemic autoimmune disorders associated with acute transverse myelitis is summarized in Table 2. IMAGING STUDIES • Gadolinium-enhanced magnetic resonance imaging (MRI) of brain and MRI of the entire spine (Fig. E1, Fig. E2). This will show demyelinating lesion on T2 with contrast enhancement. In MS there is usually a short segment lesion (less than three vertebral segments) that is dorsally located. Longitudinally extensive transverse myelitis that spans more than three or more segments of the cord is more

typical of NMOSD, postinfectious, vascular, or other inflammatory causes. • Computed tomography (CT) of the spine with and without contrast should be obtained if MRI is unavailable, but CT does not allow for visualization of the spinal cord itself. • CT myelogram may also be obtained if MRI unavailable to evaluate for compression. • Chest CT with and without contrast if sarcoidosis is suspected.

LABORATORY TESTS • Lumbar puncture looking for CSF pleocytosis, oligoclonal bands for MS, or serology and PCR looking for infection (Table 3) such as varicella zoster virus and enterovirus PCR. • ANA, hepatitis B serology, Lyme disease serology, VDRL, SSA, SSB, anticardiolipin antibody, lupus anticoagulant, copper, ceruloplasmin, vitamin B12, RPR. • Serum NMO-IgG and myelin oligodendrocyte glycoprotein (MOG) antibodies to evaluate for neuromyelitis optica spectrum disorder. • If a paraneoplastic etiology is suspected, then appropriate antibodies should be ordered and appropriate cancer screening undertaken.

TREATMENT Corticosteroids (IV methylprednisolone 1 g/day for 3 to 7 days) are the first-line treatment for transverse myelitis.

NONPHARMACOLOGIC THERAPY • Physical therapy • Respiratory and oropharyngeal support

T

Diseases and Disorders

CSF, Cerebrospinal fluid; MRI, magnetic resonance imaging; NMO, neuromyelitis optica. From Cherry JD et al: Feigin and Cherry's textbook of pediatric infectious diseases, ed 8, Philadelphia, 2019, Elsevier.

TABLE 3  Suggested Diagnostic Workup for Infections Associated with Acute Transverse Myelitis

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ACUTE GENERAL Rx • High-dose IV corticosteroid (e.g., methylprednisolone 1000 mg/day for 3 to 7 days) to stop inflammatory damage to the spinal cord. • Rescue therapy with plasma exchange may be helpful in patients who do not respond to corticosteroids. • Combination therapy with plasmapheresis and corticosteroids or other immunosuppressive agents (e.g., rituximab or cyclophosphamide) may also be effective. • Analgesia for pain. CHRONIC Rx • Baclofen or tizanidine for muscle spasms • Gabapentin or pregabalin for neuropathic pain • Low-molecular-weight heparin for DVT prophylaxis in patients with immobility • Need for chronic immunosuppression will depend on underlying etiology DISPOSITION • One third of patients with transverse myelitis will have complete recovery, one third will have fair recovery, and one third have permanent disability and do not recover. Recurrence or relapse is possible, especially if the patient has MS, NMOSD, or sarcoidosis. • Patients who need further care, including those with urinary retention, may need home nursing assistance. Some patients may benefit from rehabilitation, either inpatient or outpatient. REFERRAL • Referral to a neurologist to evaluate need for long-term therapy. • Referral for physical and occupational therapy. • Consider psychiatric consultation (high incidence of long-term mood and anxiety disorders). SUGGESTED READINGS Available at ExpertConsult.com AUTHORS: Padmaja Sudhakar, MBBS, and Corey Goldsmith, MD

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FIG. E1  Patient with clinical picture of transverse myelitis. Sagittal T2-weighted magnetic resonance image of the distal cord shows central T2 hyperintensity within the conus medullaris (arrows) in this case of acute disseminated encephalomyelitis. An acute spinal cord infarct also could have this imaging appearance. (From Fuhrman BP et al: Pediatric critical care, ed 4, Philadelphia, 2011, Saunders.)

D

A

B

C

FIG. E2  Acute transverse myelitis of the cervical cord. (A) Sagittal T1-weighted magnetic resonance imaging (MRI) sequence through the cervical spinal cord demonstrating swelling of the cord. (B) T2-weighted MRI sequence of same patient revealing longitudinally extensive hyperintensity through the cervical cord. (C) T1-weighted MRI sequence with gadolinium revealing patchy enhancement of the cervical cord. (D) T2-weighted axial MRI sequence through the cervical cord revealing hyperintensity of both gray and white matter. (From Cherry JD et al: Feigin and Cherry's textbook of pediatric infectious diseases, ed 8, Philadelphia, 2019, Elsevier.)

Transverse Myelitis SUGGESTED READINGS Frohman EM, Wingerchuk DM: Transverse myelitis, N Engl J Med 363:564, 2010. Wingerchuk DM et al: International consensus diagnostic criteria for neuromyelitis optica spectrum disorders, Neurol 85(2):177-189, 2015.

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Traumatic Brain Injury (TBI) BASIC INFORMATION DEFINITION • Impact to the head resulting in varying levels of cellular and macroscopic changes, detected with clinical examination supplemented by imaging studies. • Mild traumatic brain injury (TBI) is defined as loss of consciousness 24 hours of loss of consciousness with a GCS of 3 to 8 and prolonged posttraumatic amnesia with normal or abnormal imaging. SYNONYMS TBI Head injury Concussion Intracranial contusion ICD-10CM CODES S06.9 X0A Intracranial injury S06.1X7A Traumatic cerebral edema with loss of consciousness of any duration with death due to brain injury prior to regaining consciousness, initial encounter S06.2X9A Diffuse traumatic brain injury with loss of consciousness of unspecified duration, initial encounter S06.300A Unspecified focal traumatic brain injury without loss of consciousness, initial encounter S06.305A Unspecified focal traumatic brain injury with loss of consciousness greater than 24 hours with return to pre-existing conscious level, initial encounter S06.309A Unspecified focal traumatic brain injury with loss of consciousness of unspecified duration, initial encounter

EPIDEMIOLOGY & DEMOGRAPHICS Traumatic brain injury (TBI) is a worldwide leading cause of mortality in young individuals. Urbanization and increasing use of motor vehicles has led to an overall increase in TBI, especially in high-income and developing countries. INCIDENCE: Globally, more than 10 million people suffer TBI resulting in mortality or requiring hospitalization each yr. By 2020, it is projected that TBI will surpass many diseases as the major cause of death and disability worldwide. TBI likely accounts for 9% of global mortality and is a threat to health in every country in the world. The financial burden of TBI has been estimated to be greater than $80 billion per yr in the United States alone. According to estimates

from the CDC, about 2.87 million emergency department visits, including deaths and hospitalizations, were associated with TBI in 2014. PREVALENCE: The prevalence of TBI in the United States has been estimated at approximately 5.3 million. In the European Union with 330 million inhabitants, approximately 7,775,000 new TBI cases occur each yr. According to the CDC, combined rates of TBIrelated hospitalizations, emergency department visits, and deaths have risen from 521/100,000 in 2000 to 823.7/100,000 in 2010. PEAK INCIDENCE: Approximate incidence in the US per CDC data is 103/100,000 population. In the European Union, this is estimated to be at 235/100,000. PREDOMINANT SEX AND AGE: TBI occurs more frequently in young adults, particularly males 15 to 25 yr of age, and has a high cost to society because of life years lost. Hospitalizations and deaths are the highest in older adults >75 yr of age. GENETICS: TBI and Apo E ε4 synergistically are also associated with a tenfold increased risk for Alzheimer disease as well as larger intracerebral hematomas and greater ischemia after TBI. RISK FACTORS: N/A.

PHYSICAL FINDINGS & CLINICAL PRESENTATION TBI patients can present with a spectrum of clinical symptoms including nausea, vomiting, headache, seizures, altered mental status, and/ or coma. Stigmata of trauma, including bruises, scalp lacerations, and periorbital or mastoid ecchymosis suggesting skull base fractures, are telltale signs of possible underlying traumatic brain injury. Box 1 describes risk stratification in patients with minor head trauma. The spectrum of TBI is most commonly assessed using the GCS, which ranges from 3 to 15 and utilizes eye, motor, and verbal exams (Table 1). ETIOLOGY Mechanical falls (35%), motor vehicle accidents (17%), and assaults resulting in direct or indirect trauma to the head are the most common etiologies. The most deaths occur from motor vehicle accidents. An estimated 283,000 children seek care in U.S. emergency departments each yr for a sport- or recreation-related TBI. TBIs sustained in contact sports account for approximately 45% of these visits. Football, bicycling, basketball, playground activities, and soccer account for the highest number of emergency department visits.1

DIAGNOSIS DIFFERENTIAL DIAGNOSIS Differential diagnosis of TBI is quite limited; however, there are several considerations and diagnoses considered as a possibility within 1Sarmiento

K et  al: Emergency Department Visits for Sports- and Recreation-Related Traumatic Brain Injuries Among Children—United States, 2010–2016, MMWR 68;241, 2019.

the realm of TBI. These are enumerated in the imaging section.

WORKUP TBI workup is always a part of the advanced trauma life support (ATLS) protocol. Primary and secondary survey followed by imaging studies constitutes the standardized approach to TBI. Focused TBI workup includes: • History: Including timing of injury, duration of loss of consciousness if applicable, seizures (if any), comorbidities, use of anticoagulants and antiplatelet agents (requires reversal in the event of intracranial blood on imaging). • Neurological examination: Glasgow Coma Scale, cranial nerves, motor/sensory exam. Assess for scalp lacerations, specifically overlying a skull fracture as well as CSF otorrhea or rhinorrhea. BOX 1  Risk Stratification in Patients with Minor Head Trauma High Risk • Focal neurologic findings • Asymmetrical pupils • Skull fracture on clinical examination • Multiple trauma • Serious, painful, distracting injuries • External signs of trauma above the clavicles • Initial Glasgow Coma Scale score of 14 or 15 • Loss of consciousness • Posttraumatic confusion or amnesia • Progressively worsening headache • Vomiting • Posttraumatic seizure • History of bleeding disorder or anticoagulation • Recent ingestion of intoxicants • Unreliable or unknown history of injury • Previous neurologic diagnosis • Previous epilepsy • Suspected child abuse • Age above 60 yr or below 2 yr Medium Risk • Initial Glasgow Coma Scale score of 15 • Brief loss of consciousness • Posttraumatic amnesia • Vomiting • Headache • Intoxication Low Risk • Currently asymptomatic • No other injuries • No focality on examination • Normal pupils • No change in consciousness • Intact orientation and memory • Initial Glasgow Coma Scale score of 15 • Accurate history • Trivial mechanism • Injury less than 24 hours ago • No or mild headache • No vomiting • No preexisting high-risk factors

Traumatic Brain Injury (TBI) TABLE 1  Glasgow Coma Scale (GCS) Adult E 4 3 2 1 M 6 5 4 3 2 1 E 5 4 3 2 1

Eye Opening Spontaneous To speech To pain No response Best Motor Response Normal movements Localizes to pain Withdraws to pain Flexion (decorticate) Extension (decerebrate) No response Best Verbal Response Coos, babbles Cries but consolable Persistently irritable Grunts to pain/restless No response

Mild TBI: GCS 13-15, Moderate TBI: GCS 9-12, Severe TBI GCS 8 or less. GCS can range from 3 to 15. If intubated, then verbal component is replaced by ‘T’. Best possible score if intubated is 10T, and worst is 3T. In obtunded patients, pain stimulus can be central or peripheral. In patients with suspected spinal cord injury and paralysis, central stimulus to elicit facial grimace can be used to assess motor and eye component.

BOX 2  American College of Emergency Physicians Clinical Policy Regarding Neuroimaging in Adults with Mild Traumatic Brain Injury A noncontrast head CT is indicated (level-1 recommendation) in adults with LOC or posttraumatic amnesia only if one or more of the following is present: • Headache • Vomiting • Age >60 yr • Drug or alcohol intoxication • Deficits in short-term memory • Physical evidence of trauma above the clavicle • Posttraumatic seizure • GCS score 50,000) b. Normocytic, normochromic anemia often 2. Rarely helpful diagnostically • ESR usually elevated • Thoracentesis: 1. Exudative effusion: a. Elevated protein b. Decreased glucose c. Elevated WBCs (polymorphonuclear leukocytes early, replaced later by lymphocytes) d. May be hemorrhagic 2. Pleural fluid usually AFB-negative 3. Pleural biopsy often diagnostic—may need to be repeated for diagnosis 4. Culture pleural biopsy tissue for AFB • Bone marrow biopsy is often diagnostic in difficult-to-diagnose cases, especially miliary TB

TREATMENT

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Tuberculosis, Pulmonary BOX 2  Persons in Whom Treatment Should Be Initiated to Prevent Progression to Tuberculosis Household members and other close associates of persons with potentially infectious tuberculosis Contacts of any age with a Mantoux tuberculin skin test reading of 5 mm or greater and no documented history of reaction in the past, or with a positive interferon gamma release assay (IGRA), should be considered recently infected and receive therapy if they have not been treated previously Newly infected people, regardless of age, who have had a tuberculin skin test or IGRA conversion within the past 2 yr People with HIV infection who have a reaction of 5 mm or greater to a Mantoux test or positive IGRA People of any age with past tuberculosis infection who received inadequate treatment People of any age with a positive tuberculin skin test or positive IGRA and an abnormal but stable chest radiograph People with significant tuberculin reactions or positive IGRAs who have special clinical situations, including silicosis, diabetes mellitus, prolonged corticosteroid therapy, immunosuppressive therapy, hematologic malignant disease, or end-stage renal disease All children and adolescents with a positive tuberculin skin test reaction or interferon release assay result Adapted from Cherry JD et al: Feigin and Cherry's textbook of pediatric infectious diseases, ed 8, Philadelphia, 2019, Elsevier.

4. P atients whose fever has not decreased and sputum has not converted to negative in 2 to 4 weeks 5. Patients with overwhelming pulmonary or extrapulmonary TB • To pulmonologist for bronchoscopy or pleural biopsy

PEARLS & CONSIDERATIONS COMMENTS • All contacts (especially close household contacts and infants) should be properly tested for PPD conversions during 3 months following exposure. • Those with positive PPD should be evaluated for active TB and properly treated or given prophylaxis.

• Previous treatment is a common risk factor for XDR and MDR TB. • In treatment of latent TB infections, evidence exists for the efficacy and safety of 6-month isoniazid monotherapy, rifampicin monotherapy, and combination therapies with 3 to 4 months of isoniazid and rifampicin.4 • Left untreated, 5% to 10% of patients with latent TB develop active TB. Updated guidelines from the CDC and the National Tuberculosis Controllers Association5 for latent TB treatment include any of the following regimines: 4Zenner

D et al: Treatment of latent tuberculosis infection, Ann Intern Med 167:248-255, 2017. 5Sterling TR et al: Guidelines for the treatment of latent tuberculosis infection: recommendations from the National Tuberculosis Controllers Association and CDC, 2020, MMWR Recomm Rep 69(1);1-11, 2020.

1. O  nce-weekly isoniazid plus rifapentine for 3 mo administered under direct observation. The guideline recommends this regimen for adults and children (age < 2 yr), including patients who are HIV-positive. 2. Daily rifampin for 4 mo is also recommended strongly, especially for HIVnegative people, and perhaps has the lowest toxicity. 3. Daily rifampin plus isoniazid for 3 mo is another alternative.

SUGGESTED READINGS Available at ExpertConsult.com AUTHORS: Tara C. Bouton, MD, MPH, TM, and Glenn G. Fort, MD, MPH

Tuberculosis, Pulmonary SUGGESTED READINGS Boehme EC et al: Rapid molecular detection of tuberculosis and rifampin resistance, N Engl J Med 363:1005-1015, 2010. Centers for Disease Control and Prevention: Recommendations for use of an isoniazid-rifapentine regimen with direct observation to treat latent Mycobacterium tuberculosis infection, MMWR 60(48):1650-1653, 2011. Centers for Disease Control and Prevention: Updated guidelines for using interferon gamma release assays to detect mycobacterium tuberculosis infection—United States, 2010, MMWR 59(RR-5), 2010. Elkington P, Zumla A: Update in Mycobacterium tuberculosis lung disease in 2014, Am J Respir Crit Care Med 192:793-798, 2015. Horsburgh CR, Rubin EJ: Clinical practice: latent tuberculosis infection in the United States, N Engl J Med 364(15):1441-1448, 2011. Kurz SG, Furin JJ, Bark CM: Drug-resistant tuberculosis: challenges and progress, Infect Dis Clin North Amm 30:509-522, 2016. Kwan CK, Ernst JD: HIV and tuberculosis: a deadly human syndemic, Clin Microbiol Rev 24(2):351-376, 2011. Loddenkemper R et  al: To repeat or not to repeat—that is the question! Serial testing of health-care workers for TB infection, Chest 142(10), 2012. Menzies D et al: Four months of rifampin or nine months of isoniazid for latent tuberculosis in adults, N Engl J Med 379:440-453, 2018.

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Nathanson E et al: MDR tuberculosis—critical steps for prevention and control, N Engl J Med 363:1050-1058, 2010. Nunn AJ et al: A trial of a shorter regimen for rifampin-resistant tuberculosis, N Engl J Med 380:1201-1213, 2018. Perez-Velez CM, Marais BJ: Tuberculosis in children, N Engl J Med 367:348-361, 2012. Reves R, Schluger NW: Update in tuberculosis and nontuberculous mycobacterial infections 2013, Am J Respir Crit Care Med 189(8):894-898, 2014. Sia IG, Wieland ML: Current concepts in the management of tuberculosis, Mayo Clin Proc 86(4):348-361, 2011. Sterling TR et al: Three months of rifapentine and isoniazid for latent tuberculosis infection, N Engl J Med 365:2155-2156, 2011. Stewart RJ et  al: Tuberculosis–United States 2017, MMWR (Morb Mortal Wkly Rep) 67(11):310-323, 2018. Wilson ML: Recent advances in the laboratory detection of Mycobacterium tuberculosis complex and drug resistance, Clin Infect Dis 52(11):1350-1355, 2011. World Health Organization: Global tuberculosis report 2018, Geneva, 2018, WHO. Zumla AI et  al: New antituberculosis drugs, regimens, and adjunct therapies: needs, advances, and future prospects, Lancet Infect Dis 14(4):327-340, 2014. Zumla AI et al: Tuberculosis, N Engl J Med 368:745-755, 2013.

FIG. E1  Tuberculosis case rates (cases per 100,000) by state, 2014. (From Centers for Disease Control and Prevention: Tuberculosis trends—United States, 2014. MMWR 2015;64:265-9.)

FIG. E2  Miliary pattern in tuberculosis consists of numerous nodules of uniform size. (From Grainger RG et al [eds]: Grainger & Allison’s diagnostic radiology, ed 4, Philadelphia, 2001, Churchill Livingstone.)

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Tuberous Sclerosis BASIC INFORMATION DEFINITION Tuberous sclerosis (TS) is an inherited neurocutaneous disorder that is characterized by pleomorphic features involving many organ systems, including multiple benign neoplasms (hamartomas) of the brain, kidney, and skin. SYNONYMS TS TSC Tuberous sclerosis complex ICD-10CM CODE Q85.1  Tuberous sclerosis

EPIDEMIOLOGY & DEMOGRAPHICS INCIDENCE: TS has an estimated incidence of 1 case per 6000 live births. Thus, it is the second most common neurocutaneous syndrome after neurofibromatosis. PREVALENCE: The disorder affects about 1 in 10,000 persons in the general population. PREDOMINANT SEX: TS has no predilection for gender or race. GENETICS: • TS is an autosomal dominant disorder with almost complete penetrance but a wide range of clinical severity. However, only one third of cases are familial. The apparently nonfamilial cases can represent either spontaneous mutations or mosaicism. • Genetic research has identified two TS genes. One is located on chromosome 9 (TSC1 gene) and the other on chromosome 16 (TSC2 gene). About 68% of cases occur as a result of new gene mutations. Because of the genetic transmission and new mutations, antenatal diagnosis is difficult. PHYSICAL FINDINGS & CLINICAL PRESENTATION • Dermatologic manifestations (Figs. E1, E2, and E3) may be the only clues the family physician has to the diagnosis of the disorder, which is also marked by childhood seizures and mental retardation. • The diagnostic criteria for TS were recently revised at a consensus conference. Major and minor features are listed in Table E1. • The classic diagnostic triad of seizures, mental retardation, and facial angiofibromas (Fig. E4) (Vogt triad) occurs in fewer than 50% of patients with TS. • All of the clinical features of TS may not be apparent in the first yr of life. Thus, a child is often initially diagnosed with possible or probable TS, and the diagnosis of definite TS is made after additional features are identified. • Dermatologic manifestations: A careful skin examination of patients at risk for TS continues to be the easiest and most accessible method of establishing the diagnosis (Table E2).

• Neurologic manifestations: These are the leading cause of morbidity and mortality in patients with TS. Brain hamartomas in the form of cortical tubers, subependymal nodules, and subependymal giant cell astrocytomas are often responsible for intractable seizures, most commonly as infantile spasms. Approximately 90% to 96% of TS patients have seizures. Approximately 85% of patients have their first epileptic episode in the first 2 yr of life. Behavioral and cognitive dysfunction, including autism and mental retardation, can be seen in 40% to 50% of patients. • Renal and pulmonary manifestations are strongly associated with TS. • Angiomyolipoma is the most common renal lesion found in TS patients. Clinically evident pulmonary involvement in TS patients is relatively rare, with an estimated incidence of 1% to 6%. The most common lesion is lymphangiomyomatosis (LAM), a progressive cystic lung disease with progressive dyspnea and spontaneous pneumothorax in a childbearing woman.

• Cardiovascular manifestations: These are often the earliest diagnostic findings in patients with TS. Rhabdomyoma is the most common primary cardiac tumor in infants and children. Its incidence in TS patients ranges between 47% and 60%. In fact, 80% to 95% of patients with cardiac rhabdomyomas have TS. • The most common ocular findings in TS are retinal hamartomas, appearing in 40% to 50% of patients.

ETIOLOGY TS is an autosomal dominant disorder.

DIAGNOSIS DIFFERENTIAL DIAGNOSIS Cutaneous manifestations: • Nevus anemicus • Nevus depigmentosus (nevus achromicus) • Vitiligo

FIG. E1  A hypopigmented, ash leaf-shaped spot on the thigh of a patient with tuberous sclerosis. (From Callen JP et al: Dermatological signs of systemic disease, ed 5, Philadelphia, 2017, Elsevier.)

FIG. E2  A periungual fibroma in a patient with tuberous sclerosis. (From Callen JP et al: Dermatological signs of systemic disease, ed 5, Philadelphia, 2017, Elsevier.)

Tuberous Sclerosis

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FIG. E3  An erythematous plaque representative of a connective tissue nevus in a patient with tuberous sclerosis. (From Callen JP et  al: Dermatological signs of systemic disease, ed 5, Philadelphia, 2017, Elsevier.)

TABLE E1  Revised Diagnostic Criteria for Tuberous Sclerosis Complex (TSC) Major Features

1. Facial angiofibromas or forehead plaque 2. Nontraumatic ungual or periungual fibroma 3. Hypomelanotic macule (three or more) 4. Shagreen patch (connective tissue nevus) 5. Multiple retinal nodular hamartomas 6. Cortical tuber 7. Subependymal nodule 8. Subependymal giant cell astrocytoma 9. Cardiac rhabdomyoma, single or multiple 10. Lymphangiomyomatosis 11. Renal angiomyolipoma

Minor Features 1. Multiple, randomly distributed pits in dental enamel 2. Hamartomatous rectal polyps 3. Bone cysts 4. Cerebral white matter radial migration lines 5. Gingival fibromas 6. Nonrenal hamartomas 7. Retinal achromic patch 8. “Confetti” skin lesions 9. Multiple renal cysts Definite TSC: Either two major features or one major feature plus two minor features. Probable TSC: One major plus one minor feature. Possible TSC: Either one major feature or two or more minor features.

WORKUP • The dermatologic manifestations of TS are helpful in diagnosing this disorder. When TS has been inherited in the autosomal dominant form, dermatologic signs are almost universally present in one of the patient’s parents. • No specific prenatal laboratory test is available. • Early recognition of TS is vital because prompt implementation of the recommended diagnostic evaluation (neuroimaging studies, EEG, ECG, renal ultrasonography, brain MRI [Fig. E5] and chest CT) may prevent serious clinical consequences.

• Some findings in TS complex (TSC), notably renal angiomyolipomas and pulmonary lymphangioleiomyomatosis (LAM) emerge later, placing adults with undiagnosed TSC at increased risk for morbidity and mortality.

LABORATORY TESTS • Molecular genetic testing: In recent yr, molecular genetic testing for TS has become clinically available. Such testing identifies mutations in the TSC1 and TSC2 genes by one of several methods, most commonly polymerase chain reaction (PCR) amplification of individual exons followed by DNA sequencing on DNA obtained from a patient’s blood sample. • DNA testing for TS is potentially useful in several settings: 1. It can be helpful in confirming a clinical diagnosis of TS, especially in young patients in whom many clinical signs and symptoms have yet to develop. 2. In many families with a history of TS in which there is a sporadic case of TS in a new child, genetic testing can provide reassurance to parents, children, and other family members that they do not carry the TS gene mutation. 3. DNA testing is useful for prenatal diagnosis.

TREATMENT The management of TSC is presently symptomatic.

include cryosurgery, curettage, dermabrasion, chemical peeling, excision, and laser therapy. • Some patients have been treated successfully with antiepileptic medications; unfortunately, there are multiple cases of intractable seizure in which medical treatment is ineffective. In some cases of intractable epilepsy, neurosurgical intervention becomes a lifesaving option. • In such drug-resistant cases of TS, the early administration of vigabatrin (γ-vinyl-gamma aminobutyric acid), a selective irreversible inhibitor of GABA-transaminase, has been proved to result in 80% to 100% cessation rates of infantile spasms. Vigabatrin is marketed in many European countries but remains unavailable in the U.S. and has not been approved by the FDA. • Embolization and/or renal sparing surgery are treatment options for renal angiomyolipomas. • Oophorectomy, medroxyprogesterone, and tamoxifen have been advocated for patients with LAM, but the therapeutic benefit is unclear. Lung transplantation is reserved for patients with end-stage LAM. • Most rhabdomyomas tend to regress with increasing age, although tumor growth has been documented in some at puberty. Surgery is recommended only for lifethreatening situations, such as hemodynamic compromise. • Oral rapamycin or sirolimus therapy can induce regression of brain astrocytomas associated with TS. Ongoing therapeutic trials with rapamycin in lymphangioleiomyomatosis appear promising. • Neurosurgical resection is the standard treatment for subependymal giant cell astrocytomas in patients with the TSC. Trials with everolimus, which inhibits the mammalian target of rapamycin, a protein regulated by gene products involved in the TSC, have shown marked reduction in volume of subependymal giant cell astrocytomas and seizure frequency.

REFERRAL A multidisciplinary team, including genetics, neurology, ophthalmology, nephrology, dermatology, neurosurgery, and plastic surgery, should evaluate children suspected of having TS.

PEARLS & CONSIDERATIONS

NONPHARMACOLOGIC THERAPY Genetic counseling should be offered to families with affected members even though accurate counseling remains difficult because of the variability of gene expression.

PREVENTION It is speculated that if one could establish the prenatal diagnosis of TS and have the patient begin using rapamycin early, one might prevent the development of TS manifestations.

ACUTE GENERAL Rx & CHRONIC Rx • Treatment methods currently available for patients with disfiguring facial angiofibromas

RELATED CONTENT Tuberous Sclerosis (Patient Information) AUTHOR: Ruby K. Satpathy, MD

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FIG. E4  Multiple facial angiofibromas in a patient with tuberous sclerosis. (From Callen JP et  al: Dermatological signs of systemic disease, ed 5, Philadelphia, 2017, Elsevier.)

TABLE E2  Cutaneous Manifestations Associated with Tuberous Sclerosis Complex Prevalence (%)

Diagnostic Classification

Earliest cutaneous lesion; usually present on buttocks at birth or in infancy Second to fifth yr of life; become more prominent with age Rare during infancy; tend to increase in size and number with age

97.2

Major

74.5

Major

48.1

Major

More common during first decade of life; rare during infancy Common at any age and can be seen at birth or in early infancy Present at puberty or soon after; become more common with age

22.6

Minor

18.9

Major

15.1

Major

Second decade or adulthood

2.8

Minor

Cutaneous Lesions

Descriptions

Age of Onset

Hypomelanotic macules (“ash leaf” spots) or Fitzpatrick patches Facial angiofibromas

Leaf-shaped or polygonal white spots enhanced by Wood lamp examination

Shagreen patches

Molluscum pendulum Fibrous forehead plaque Periungual fibromas

“Confetti-like” macules

Red to pink papules with a smooth surface, symmetrically distributed over the centrofacial areas, sparing the upper lip Slightly elevated patch or plaque, usually found on dorsal body surfaces, especially the lumbosacral area; its rough surface resembles an orange peel; represents a connective tissue nevus, sometimes called collagenoma Multiple soft pedunculated skin growths on neck; rarely in axillae or groin Yellowish-brown or skin-colored plaques of variable size and shape, usually located on the forehead or scalp Skin-colored or reddish nodules seen on the lateral nail groove or nail plate, or along the proximal nail folds; more commonly found on the toes than the fingers Multiple 1 mm to 2-mm white spots, symmetrically distributed over extremities

Tuberous Sclerosis

A

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B

C

FIG. E5  Tuberous sclerosis. A, Computed tomography demonstrating periventricular calcified subependymal nodules. A cortical calcified tuber is also seen in the right frontal region. B, T1-weighted (WI) demonstrating the subependymal nodules (arrows) lining the lateral ventricles (isointense to white matter). C, T2WI demonstrating foci of abnormal SI throughout the subcortical white matter and in the cortex corresponding to cortical tubers. A right frontal tuber (arrows) is probably calcified (low SI). (From Grossman R, Yousem D: Neuroradiology: the requisites, 2003, Mosby. In Grant LA: Grainger & Allison’s diagnostic radiology essentials, ed 2, 2019, Elsevier.)

SUGGESTED READINGS Krueger DA et al: Everolimus for subependymal giant-cell astrocytomas in tuberous sclerosis, N Engl J Med 363:1801-1811, 2010. Seibert D et al: Recognition of tuberous sclerosis in adult women: delayed presentation with life-threatening consequences, Ann Intern Med 154:806-813, 2011.

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Tularemia BASIC INFORMATION DEFINITION Tularemia is a zoonosis caused by the small, facultative gram-negative intracellular coccobacillus Francisella tularensis. Clinical manifestations range from asymptomatic illness to septic shock and death. SYNONYMS Rabbit fever Deerfly fever O’Hara disease ICD-10CM CODES A21.9 Tularemia, unspecified A21.0 Ulceroglandular tularemia A21.1 Oculoglandular tularemia A21.2 Pulmonary tularemia A21.3 Gastrointestinal tularemia A21.7 Generalized tularemia A21.8  Other forms of tularemia

a central eschar (Fig. E2) accompanied by tender lymphadenopathy. Overall mortality rate for this form of tularemia is generally low (55 yr of age PEAK INCIDENCE: June through August and in December

PHYSICAL FINDINGS & CLINICAL PRESENTATION Physical findings: • Incubation period is 3 to 5 days but may range from 1 to 21 days • Most common initial signs and symptoms are abrupt onset of fever and respiratory symptoms. The following signs and symptoms may also be present: 1. Chills 2. Headache 3. Malaise 4. Anorexia 5. Fatigue 6. Cough 7. Myalgias 8. Chest discomfort 9. Vomiting 10. Abdominal pain 11. Diarrhea 12. Conjunctivitis 13. Lymphadenitis Clinical presentation: • Ulceroglandular and glandular: Account for 75% to 80% of cases. Fever and a single erythematous papuloulcerative lesion with

FIG. E1  Reported cases of tularemia in the United States, 2001 to 2010. One dot is placed randomly within the county of residence for each reported case. Cases were reported from 47 states. Six states accounted for 59% of reported cases: Missouri (19%), Arkansas (13%), Oklahoma (9%), Massachusetts (7%), South Dakota (5%), and Kansas (5%). (From Centers for Disease Control and Prevention [CDC]. Tularemia—United States, 2001-2010, MMWR. 2013;62:963-6, In Cherry JD et al: Feigin and Cherry's textbook of pediatric infectious diseases, ed 8, Philadelphia, 2019, Elsevier.)

FIG. E2  Tularemia. (Courtesy of Steve Hess, MD. From James WD et al: Andrews’ diseases of the skin, ed 12, Philadelphia, 2016, Elsevier.)

Tularemia ETIOLOGY • Caused by infection with F. tularensis • Two main biovars of F. tularensis: Types A and B. Type A produces severe disease in humans. Type B produces milder subclinical infection • Transmitted by ticks, tabanid flies, and mosquitoes. Also acquired by inhalation and ingestion • Cases also occur after exposure to animals (wild rabbit, squirrels, birds, sheep, beavers, muskrats, and domestic dogs and cats) or animal products • Laboratory acquisition is possible • Pathogenesis: After inoculation into the skin, the organism multiplies locally within 2 to 5 days; then it produces an erythematous tender or pruritic papule. The papule rapidly enlarges and forms an ulcer with a black base. The bacteria actively inhibit the protective host response by inducing antiinflammatory cytokines and spread to the regional lymph nodes, producing lymphadenopathy, and with bacteremia may spread to distant organs

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • Rickettsial infections • Meningococcal infections • Cat-scratch disease • Infectious mononucleosis • Atypical pneumonia • Group A strep pharyngitis • Typhoid fever • Fungal infection—sporotrichosis • Anthrax • Plague • Bacterial skin infections WORKUP • CBC • Chest radiography • Cultures of blood, lymph node, pleural fluid, wounds, sputum, and gastric aspirate • Antigen detection in urine • Polymerase chain reaction (PCR) • Serology LABORATORY TESTS • Antibodies to F. tularensis demonstrated by tube agglutination, microagglutination,

1404.e7 hemagglutination, and ELISA; definitive serologic diagnosis requires a fourfold or greater rise in titer between acute and convalescent specimens • PCR to facilitate early diagnosis • WBC count and ESR normal or elevated • Rarely seen on Gram-stained smears or tissue biopsies; a tiny gram-negative bacillus

IMAGING STUDIES Chest x-ray examination to show bilateral patchy infiltrate, lobar parenchymal infiltrate, cavitary lesion, pleural effusion, or emphysema

TREATMENT ACUTE GENERAL Rx • Immediate therapy to limit extent of acute illness and complications • Streptomycin 15 mg/kg IV q12h (daily dose should not exceed 2 g) or gentamicin 5 mg/ kg/day in 2 or 3 divided doses for 10 days or in the once-a-day dosing schedule • Doxycycline 100 mg IV or PO bid • Ciprofloxacin 400 mg IV or 750 mg PO bid for 14 to 21 days • Combination antibiotics required for tularemic meningitis—chloramphenicol or doxycycline plus streptomycin • Surgical therapies are limited to drainage of abscessed lymph nodes and chest tube drainage of empyemas PROGNOSIS The mortality rate of severe untreated infection (tularemic pneumonia and typhoidal tularemia) can be as high as 30%. The overall mortality rate associated with tularemia is 2% to 4% with appropriate treatment. Lifelong immunity usually follows tularemia. DISPOSITION Follow up as outpatient PREVENTION • Educate the public in the handling of sick or dead animals. • Use only EPA-registered insect repellents, such as DEET or picaridin sprays. • Remove ticks promptly. • Drink only potable water.

SUGGESTED READINGS Centers for Disease Control and Prevention: Tularemia-United States, 2001-2010, MMWR 62(47):963-966, 2013. Harik NS: Tularemia: epidemiology, diagnosis, and treatment, Pediat Ann 42:288292, 2013. Meagher KE, Decker CF: Other tick-borne illnesses: tularemia, Colorado tick fever, tick paralysis, DM 58(6):370-376, 2012. Sharma N et al: Detection of Francisella tularensis-specific antibodies in patients with tularemia by a novel competitive enzyme-linked immune-sorbent assay, Clin Vaccine Immunol 20:9-16, 2013. Yaglom H et al: Notes from the field: fatal pneumonic tularemia associated with dog exposure, Arizona, June 2016, MMWR 66:891, 2017.

• Adequately cook wild meats. • Tularemia vaccine has been developed but is not commercially available in the U.S.; however, it is available from the CDC. Vaccination of high-risk individuals working with large quantities of cultured organism is recommended. • Avoid skinning wild animals, especially rabbits; wear gloves while handling animal carcasses. • Do not use wells or other water that is contaminated by dead animals. • Hospitalized patients with tularemia do not need special isolation (no person-to-person transmission). Standard universal precautions for contaminated secretion are adequate when handling drainage from wounds. • Laboratory personnel should be notified of potential danger of growing this organism in the laboratory and generation of an infectious aerosol from dried culture media.

REFERRAL • For consultation with infectious diseases specialist in suspected cases. • A cluster of tularemia cases, particularly in an urban area or nonendemic regions, should prompt concern over the possibility of bioterrorism; the local public health authorities should be contacted immediately to investigate the possibility of deliberate release of tularemia as a weapon of terror.

PEARLS & CONSIDERATIONS • Alert the microbiology laboratory to the possibility of tularemia; this is a major biohazard in the laboratory. • Do not use doxycycline or tetracycline in children or pregnant women. • Because of its highly contagious nature with low inoculums, tularemia is considered an agent that could be used by terrorists. It is classified as a category A critical biologic agent by the CDC. AUTHOR: Glenn G. Fort, MD, MPH

ALG BASIC INFORMATION

SYNONYM TLS ICD-10CM CODE E88.3 Tumor lysis syndrome

EPIDEMIOLOGY & DEMOGRAPHICS INCIDENCE: The frequency of TLS is unknown, but it is the most common disease-related emergency encountered by physicians who treat children or adults with hematologic cancers. Incidence depends on cancer mass (greater mass correlates with greater cellular content release at cell death), patient characteristics (e.g., preexisting chronic kidney disease, volume depletion, hypotension), and supportive care. Tumor bulk, proliferation rate, and treatment sensitivity are associated with greater frequency of TLS. PREVALENCE: Variable PREDOMINANT SEX AND AGE: • No sex predilection exists. • Occurs in all age groups. Older adults are more susceptible to TLS due to a decline in glomerular filtration rate with age. GENETICS: No racial predilection RISK FACTORS: • High tumor burden: 1. Large-size tumor 2. LDH >1500 IU/L 3. WBC >25,000/mm3 4. Risk of TLS is further stratified by tumor type: a. High risk: (1) Burkitt lymphoma (2) High-grade non-Hodgkin lymphoma (3) Lymphoblastic lymphoma (4) Acute T-cell leukemia (5) Other acute leukemias b. Moderate risk: (1) Low-grade lymphoma treated with chemotherapy/radiation/corticosteroids (2) Multiple myeloma (3) Breast carcinoma treated with chemotherapy/hormonal therapy (4) Small-cell lung carcinoma



(5) Germ-cell tumors (e.g., seminoma, ovarian) c. Low risk: (1) Low-grade lymphoma treated with interferon (2) Merkel cell carcinoma (3) Adenocarcinoma of the gastrointestinal tract • Administration of certain agents, including: 1. Paclitaxel 2. Hydroxyurea 3. Etoposide 4. Fludarabine 5. Sorafenib • Extensive bone marrow involvement • Elevated pretreatment uric acid, potassium, or phosphorus levels • Tumor highly sensitive to treatment • Volume depletion • Chronic kidney disease • Decreased urine output • Acidic urine • Tumor involvement of the kidney/renal vasculature • Advanced age • Post-transcatheter arterial chemoembolization (TACE), radiofrequency thermal ablation • Chimeric antigen receptor T-cells therapy (CAR-T cell)

ETIOLOGY Most commonly occurs in patients with acute leukemias; bulky, solid tumors; or high-grade lymphomas. The pathophysiology of tumor lysis syndrome is illustrated in Fig. E1. • Can occur spontaneously or after antitumor intervention (chemotherapy, radiation, etc.) • Associated with administration of certain chemotherapeutic agents (whether intravenous, intrathecal, etc.): 1. Paclitaxel 2. Hydroxyurea 3. Etoposide 4. Fludarabine • Spontaneous TLS: 1. Rare 2. Lysis of tumor cells without chemotherapy or in setting of minimal chemotherapy (e.g., steroid monotherapy in case of lymphomas) 3. Related to rapid cell turnover rate

TABLE 1  Classification of Tumor Lysis Syndrome Laboratory tumor lysis syndrome

Clinical tumor lysis syndrome

Two or more of the metabolic abnormalities in the next column present on the same day Occurring within 3 days before initiation of therapy or 7 days after initiation of therapy Assumes the patient receives adequate hydration and a hypouricemic agent Laboratory tumor lysis syndrome plus any of the criteria in the next column (not attributable to other causes)

From Niederhuber JE: Abeloff’s clinical oncology, ed 6, Philadelphia, 2020, Elsevier.

Uric acid ≥476 μmol/L (8 mg/dl) in adults or the upper limits of normal in children Potassium ≥6.0 mmol/L Phosphorus ≥1.5 mmol/L (4.5 mg/dl) in adults or ≥2.1 mmol/L (6.5 mg/dl) in children Calcium ≤1.75 mmol/L (7 mg/dl) or ionized calcium 100,000 colony-forming units per milliliter from a midstream-catch urine sample with no more than two species of organisms and at least one sign or symptom of UTI (urgency, frequency, dysuria, suprapubic tenderness, fever >38.0° C [100.4° F]). In symptomatic patients, a smaller number of bacteria (between 100 and 10,000 colonyforming units per milliliter of midstream urine) is recognized as an infection. ICD-10CM CODES N39.0 Urinary tract infection, site not specified N99.521 Infection of other external stoma of urinary tract N99.531 Infection of other stoma of urinary tract N30.00 Acute cystitis without hematuria N30.30 Trigonitis without hematuria N30.20 Other chronic cystitis without hematuria

CLASSIFICATION • Uncomplicated UTI: Occurs in a normal urinary tract and resolves rapidly with conventional antimicrobials. Patients have a low risk of upper UTI. • Complicated UTI: Occurs in patients with coexisting pathology (strictures, stones, comorbidities [diabetes mellitus, multiple sclerosis, spinal cord injuries]). Patients are considered at high risk for upper UTI. • First infection: The first documented UTI; tends to be uncomplicated and is easily treated. • Unresolved bacteriuria: UTI in which the urinary tract is not sterilized during therapy. Main causes are bacterial resistance, patient noncompliance with medication, mixed bacterial infection, rapid reinfection, azotemia, infected stones, Munchausen syndrome, and papillary necrosis. • Bacterial persistence: UTI in which the urine cultures become sterile during therapy, but a persistent source of infection gives rise to reinfection by the same organism. Causes include infected stone, chronic bacterial prostatitis, atrophic infected kidney, vesicovaginal or enterovesical fistulas, obstructive uropathy, infected pyelocaliceal diverticula, infected ureteral stump after nephrectomy, infected necrotic papillae from papillary necrosis, infected urachal cysts, infected medullary sponge kidney, urethral diverticula, and foreign bodies. • Reinfection: UTI in which a new infection occurs with new pathogens at variable intervals after a previous infection has been eradicated. • Relapse: The less common form of recurrent infection; occurs within 2 wk of treatment

when the same organism reappears in the same site as the previous infection. Relapsing infections of the urinary tract most commonly occur in pyelonephritis, kidney obstruction from a stone, foreign body, and prostatitis.

EPIDEMIOLOGY & DEMOGRAPHICS INCIDENCE: • UTI is the most common bacterial infection encountered in the ambulatory care setting in the U.S. The self-reported annual incidence of UTI in women is 12%, and by age 32 half of all women report having had at least one UTI. • UTIs account for 8 million health care visits per yr and 15% of all outpatient prescriptions. • In neonates: More common in boys as a result of anatomic abnormalities such as the posterior urethral valves. • In preschool children: More common in girls (4.5% vs. 0.5% for boys). • In adulthood: More common in women, with a 1% to 3% prevalence in nonpregnant women. Table 1 describes factors modulating risk for acute uncomplicated UTIs in women. In pregnancy at 12 wk, the incidence of asymptomatic bacteriuria is similar to nonpregnant women, at 2% to 10%. However, 25% to 30% of pregnant women with untreated asymptomatic bacteriuria develop acute pyelonephritis, especially in the second and third trimesters, and have a pyelonephritic recurrence rate of 10%. In adults aged ≥65 yr, at least 10% of men and 20% of women have bacteriuria. PHYSICAL FINDINGS & CLINICAL PRESENTATION • Typical symptoms of UTI include: 1. Urinary frequency, urgency 2. Dysuria 3. Suprapubic pain 4. Gross or microscopic hematuria • The probability of cystitis is greater than 50% in women with any symptom of UTI and greater than 90% in women who have dysuria and frequency without vaginal symptoms. • Clinical symptoms alone can be used to make the diagnosis of uncomplicated UTI in women without a urine culture.

• When negative cultures are associated with significant pyuria, vaginal discharge, or hematuria, infections with Chlamydia trachomatis, Neisseria gonorrhoeae, and Trichomonas vaginalis should be considered. • Acute pyelonephritis presents with fever, flank or abdominal pain, chills, malaise, and vomiting. It is these systemic symptoms that distinguish pyelonephritis from cystitis. Complications of acute pyelonephritis are renal abscess, perinephric abscess, emphysematous pyelonephritis, and pyonephrosis.

ETIOLOGY & PATHOGENESIS • Most UTIs are caused by ascending fecal flora, which can colonize the vaginal and periurethral tissues and eventually enter the bladder. • Other risk factors: Incomplete bladder emptying due to neurologic disease, bladder outlet obstruction or urethral stricture, renal failure, diabetes, vesicoureteral reflux, fistula, urinary diversion, infected stones, age, pregnancy, instrumentation, and poor patient compliance. • Catheters: All patients who require a long-term Foley catheter eventually develop significant levels of bacteriuria. Treatment is reserved for individuals who become symptomatic (leukocytosis, fever, chills, malaise, loss of appetite, etc.) Using prophylactic antibiotics to treat patients who have chronic catheters is not indicated because of the risk of acquiring bacteria resistant to antibiotic therapy. • Once bacteria reach the urinary tract, three factors determine whether symptomatic infection occurs (Box 1). These factors also determine the anatomic level of the UTI: 1. Virulence of the microorganism 2. Inoculum size 3.  Adequacy of the host defense mechanisms • Urinary pathogens: In 90% of UTIs the infecting organism is gram-negative bacilli. Escherichia coli is the most common pathogen (85% of UTI cases). Staphylococcus saprophyticus causes 10% of infections, especially in young women. Other common urinary pathogens include Klebsiella, Enterobacter, Serratia, Proteus, and Pseudomonas. • In contrast, the organisms that commonly colonize the distal urethra and skin of both men and women and the vagina of women

TABLE 1  Factors Modulating Risk for Acute Uncomplicated Urinary Tract Infections in Women Host Determinants

Uropathogen Determinants

Behavioral: Sexual intercourse, use of spermicidal products, recent antimicrobial use, suboptimal voiding habits

Escherichia coli virulence determinants: P, S, Dr, and type I fimbriae; hemolysin; aerobactin; serum resistance

Genetic: Innate and adaptive immune response, enhanced epithelial cell adherence, antibacterial factors in urine and bladder mucosa, nonsecretor of ABO blood group antigens, P1 blood group phenotype, reduced CXCR1 expression, previous history of recurrent cystitis Biologic: Estrogen deficiency in postmenopausal women, micturition From Floege J et al: Comprehensive clinical nephrology, ed 4, Philadelphia, 2010, Saunders.

Urinary Tract Infection BOX 1  Bacterial Factors

Pyelonephritis*

Cystitis*

Urine culture

Short-course therapy

1-2 weeks of therapy

No response Urine culture and shortcourse therapy

Clinical cure

Clinical relapse

Clinical cure

Urine culture

Documented relapse‡,§

2 weeks of therapy

Clinical relapse

Consider longer therapy and, if unsuccessful, chronic suppression

Clinical cure

Asymptomatic bacteriuria

Clinical cure Clinical response and recurrence

If therapy indicated, short course†

Urine culture Documented reinfection

Documented relapse

Short-course therapy

1-2 weeks of therapy

Clinical reinfection

Clinical relapse*,‡,§

Short-course therapy

2 weeks of therapy

Frequent reinfections, consider selfRx, precoital prophylaxis or long-term prophylaxis§

Clinical relapse

Clinical cure

Consider longer therapy and, if unsuccessful, chronic suppression

*Consider imaging studies in all men and in women with complicated urinary tract infection. † No therapy except for renal transplant patients or prior to urologic procedures. Follow-up culture only in transplant patients. ‡ Evaluate men for chronic bacterial prostatitis. § Consider imaging studies in women.

FIG. 1  Approach to the management of urinary tract infection in nonpregnant adults. (From Bennett JE et  al: Mandell, Douglas, and Bennett’s principles and practice of infectious diseases, ed 8, Philadelphia, 2015, Saunders.)

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• The size of the inoculum 1. The virulence of the infecting organism 2. Virulence factors a. P-fimbriae facilitate the adherence of bacteria to biologic surfaces. b. K-antigens facilitate adherence and protect the organisms from the host-immune response. c. O-antigens are an important source of systemic reactions such as fever and shock that occur with bacterial infections. d. H-antigens are associated with flagella and are related to bacterial locomotion. e. Hemolysin may potentiate tissue damage and facilitate local bacterial growth. f. Urease alkalinizes the urine and facilitates stone formation, thus potentiating infection. 3. Biofilms harbor bacteria on prosthetic devices and may be a source of recurrent infections. 4. The presence of sialosyl galactosyl globoside on the surface of kidney cells. This compound is a highly powerful receptor for Escherichia coli bacteria. 5. Women with a deficiency in human beta-defensin-1 are at greater risk for urinary tract infection. • Adequacy of host defense mechanisms

are Staphylococcus epidermidis, diphtheroids, lactobacilli, Gardnerella vaginalis, and a variety of anaerobes that rarely cause UTIs. In general, the isolation of two or more bacterial species from a urine culture signifies a contaminated specimen unless the patient is being managed with an indwelling catheter or urinary diversion or has a chronic complicated infection. • Defense mechanisms against cystitis: Low urine pH and high urine osmolarity, mucopolysaccharide glycosaminoglycan (GAG) protective layer, normal bladder that empties completely, and low vaginal pH due to the presence of estrogen and resulting colonization of the genital tract by lactobacillus. According to Walters and Karram, Tamm-Horsfall proteins are secreted in the kidney to help inhibit adherence of bacteria to urothelial cells.

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Urinary Tract Infection • In uncomplicated, nonpregnant patients, cystitis rarely progresses to pyelonephritis or other serious infections such as bacteremia.

DIAGNOSIS (FIG. 1) DIFFERENTIAL DIAGNOSIS • Vaginitis • Urethritis (gonococcal, nongonococcal, Trichomonas) • Interstitial cystitis (painful bladder syndrome) • Pelvic inflammatory disease • Nephrolithiasis • Structural urethral abnormalities such as diverticulum or stricture LABORATORY TESTS • Microscopic urinalysis of clean-catch urine for bacteria and pyuria. The presence of ≥10 leukocytes/μl of unspun urine from a midstream catch indicates possible UTI. The absence of pyuria should call into question the diagnosis of UTI. • Dipstick urinalysis with the presence of nitrites or leukocyte esterase is indicative of UTI. However, dipstick urinalysis may not be useful in symptomatic patients with typical symptoms and a negative dipstick urinalysis does not exclude the diagnosis of UTI such cases; additionally, dipsticks may be falsely positive when the urine is contaminated (dipstick nitrate and leukocyte esterase have a sensitivity of 75% and specificity of 82% in patients with >100,000 CFU/ml). • Urine culture and sensitivity are useful in complicated UTIs and to help guide therapy in women who fail initial therapy. They are generally not needed in uncomplicated UTIs. IMAGING STUDIES • Warranted only if renal infection or genitourinary abnormality is suspected • CT urogram, voiding cystourethrogram, renal ultrasound, and intravenous pyelogram • Specialty examination: Cystoscopy and retrograde pyelography to rule out obstructive uropathy, if suspected urethral diverticulum, suspected mesh, or to rule out cancer in older patients.

TREATMENT NONPHARMACOLOGIC THERAPY Urinary analgesics such as phenazopyridine and aggressive hydration ACUTE GENERAL Rx • First-line antimicrobials for uncomplicated UTI as recommended by the Infectious Disease Society of North America, the American Urologic Society, and ACOG include: Nitrofurantoin bid for 5 days, trimethoprim plus sulfamethoxazole (TMP-SMX) bid for 3 days, or fosfomycin 3-g sachet in a single dose. • Antimicrobial stewardship and drug resistance needs to be considered when choosing antibiotic therapy. Empiric treatment with TMP-SMX is considered appropriate when resistance rates are below 20%. Nitrofurantoin continues to have the lowest rates of antimicrobial resistance. Beta lactam antibiotics may be appropriate in cases of known patient hypersensitivity to conventional first-line agents. 1. Nitrofurantoin may have lower rates of bioavailability in patients >65 yr due to decline in renal function (if Cr Cl < 30 ml/ min) and thus should be avoided, as it may not reach therapeutic concentration in the urine. • High rates of resistance and the potential for serious side effects should limit the use of fluoroquinolone antimicrobials. The U.S. FDA has warned against the use of fluoroquinolone antibiotics for routine infections when suitable alternatives are available. • Pyelonephritis may be treated as an outpatient in stable, well-hydrated patients with close follow-up. Antimicrobial selection is ideally based on urine culture results. Empiric treatment with fluoroquinolone antimicrobials or TMP-SMX is acceptable. Initiation of treatment in the emergency room setting with a single parenteral dose of a long-acting beta lactam or aminoglycoside antibiotic followed by oral treatment with fluoroquinolones or TMP-SMX is an acceptable regimen. Patients should be assessed for a proper response to treatment within 48 hr. Nitrofurantoin and fosfomycin are not indicated for the

treatment of pyelonephritis due to inadequate renal tissue levels. • Inpatient management of pyelonephritis should begin with parenteral antimicrobials followed by transition to oral agents based on clinical response and culture results. • Pyelonephritis requires a total duration of 10 to 14 days of therapy, although evidence exists that 7 to 10 days may be equally effective in low-risk patients.See Table 2.

PEARLS & CONSIDERATIONS COMMENTS • Asymptomatic bacteriuria occurs commonly in postmenopausal women. Treatment of asymptomatic bacteriuria with antimicrobials is discouraged because it seldom resolves and can result in the development of drugresistant organisms. Patients with cloudy or foul-smelling urine should be encouraged to aggressively hydrate to eliminate these symptoms. Postmenopausal women with vaginal atrophy can be treated with vaginal estrogen to reduce the incidence of bacteriuria. Exceptions include immunocompromised patients, patients with structural urinary tract abnormalities, and pregnant patients. • Pregnancy: 25% to 30% of pregnant women with untreated asymptomatic bacteriuria develop pyelonephritis. All pregnant women should be screened for asymptomatic bacteriuria and treated. Nitrofurantoin, TMP-SMX, and beta lactam antibiotics are appropriate first-line choices in pregnancy. • Recurrent UTI: Two or more symptomatic UTIs over a 6-mo period or three or more episodes over a 12-mo period. Causes include unresolved infection, abnormal vaginal colonization by the originally infecting organism, or reinfection with a new strain. Management of recurrent UTI includes antibiotic prophylaxis for 6 months or longer, intermittent self-treatment, and postcoital prophylaxis depending on the circumstances. Patients with recurrent UTIs can be considered for an anatomic evaluation including office cystoscopy and upper urinary tract imaging (renal ultrasound or CT urography).

TABLE 2  Dosage and Toxicity of Antibiotics Commonly Used to Treat Urinary Tract Infections Drug

Oral Dose and Frequency

Minor Toxicity

Major Toxicity

Trimethoprim-sulfamethoxazole Nitrofurantoin macrocrystals Ampicillin

160 mg/800 mg, q12h 100 mg, q12h 250-500 mg, q6h

Allergic GI upset Allergic, candidal overgrowth

Tetracycline

250-500 mg, q6h

Cephalexin Ciprofloxacin

250-500 mg, q6h 250 mg, q12h

GI upset, skin rash, candidal overgrowth Allergic Nausea, vomiting, diarrhea, abdominal pain, headache, skin rash

Serious skin reactions, blood dyscrasia Peripheral neuropathy, pneumonitis Allergic reactions, pseudomembranous colitis Hepatic dysfunction, nephrotoxicity

From Walters M, Karram M: Urogynecology and reconstructive pelvic surgery, ed 4, Philadelphia, 2015, Elsevier.

Hepatic dysfunction Arrhythmias, angina, convulsions, gastrointestinal bleeding, nephritis

Urinary Tract Infection TABLE 3  Spectrum of Antimicrobial Activity against Common Lower Urinary Tract Pathogens Nitrofurantoin

TMP-SMX

Ciprofloxacin

Levofloxacin

Cephalexin

Ampicillin

Fosfomycin

Escherichia coli Pseudomonas Klebsiella Proteus Enterobacter Enterococcus Staphylococcus Serratia marcescens

+ − − ± ± + + −

± − ± ± ± – + ±

+ + + + + − ± +

+ ± + + + ± ± +

+ − + ± − − ± −

± − − + − + + −

+ + + ± ± ± + ±

From Walters M, Karram M: Urogynecology and reconstructive pelvic surgery, ed 4, Philadelphia, 2015, Elsevier.

• Nonantimicrobial strategies to prevent UTI have shown mixed results. Nonantimicrobial agents with antiseptic effects on the lower urinary tract include cranberry supplements with vitamin C, d-mannose, and methenamine. Studies demonstrating clinical effectiveness of these agents show at best modest effects with few side effects. Topical estrogen has been shown to normalize the vaginal flora and may increase the thickness of the urothelium over time and should be used as an adjunct in postmenopausal women with recurrent UTI. Oral probiotics may also be beneficial by decreasing the vaginal pH. ANTIMICROBIAL RESISTANCE: • Because of the overuse of antibiotics, organisms once sensitive to a number of antimicrobial agents are now increasingly resistant, making effective management of UTI and pyelonephritis more difficult and

potentially more dangerous. Most important has been the increasing resistance to trimethoprim plus sulfamethoxazole (TMP-SMX), the current primary care provider drug of choice for acute uncomplicated UTI in women. • Fluoroquinolone use for the treatment of acute cystitis in women should be avoided when suitable alternatives exist. The U.S. FDA has changed the labeling of quinolone antibiotics to reflect this recommendation. • When choosing a treatment regimen, physicians should consider such factors as: 1. In vitro susceptibility 2. Adverse effects on individual patients 3. Adverse effects on the population (stewardship) 4. Cost-effectiveness 5. Resistance rates in their respective communities

• Meropenem (1 g IV every 8 hr) or IV plazomicin (15 mg/kg BW once daily) are effective for the treatment of complicated UTIs and acute pyelonephritis caused by Enterobacteriaceae, including multidrug-resistant strains.See Table 3.

SUGGESTED READINGS Available at ExpertConsult.com RELATED CONTENT Urinary Tract Infection (Patient Information) Urinary Tract Infection (Child) (Patient Information) Pyelonephritis (Related Key Topic) AUTHORS: Matthew J. Fagan, MD, FACOC, and Meagan S. Cramer, MD

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Organism

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Urinary Tract Infection SUGGESTED READINGS Gupta K et  al: International clinical practice guidelines for the treatment of acute uncomplicated cystitis and pyelonephritis in women: a 2010 update by the Infectious Diseases Society of America and the European Society for Microbiology and Infectious Diseases, Clin Infect Dis 52(5):e103-e120, 2011. Gupta K, Trautner B: In the clinic: urinary tract infection, Ann Intern Med 156(5):ITC3-1-ITC3-15, quiz ITC3-16, 2012. Hooton TM: Uncomplicated urinary tract infection, N Engl J Med 366:1028, 2012. Hooton TM: Effect of increased daily water intake in premenopausal women with recurrent urinary tract infections: a randomized clinical trial, JAMA Internal Med 178:1509-1515, 2018. Kodner CM, Gupton TEK: Recurrent urinary tract infections in women: diagnosis and management, Am Fam Physician 82(6):638-643, 2010. McKinnell JA et al: Nitrofurantoin compares favorably to recommended agents as empirical treatment of uncomplicated urinary tract infections in a decision and cost analysis, Mayo Clin Proc 86:840, 2011. Wagenlehner FME et al: Once-daily plazomicin for complicated urinary tract infections, N Engl J Med 380:727-740, 2019. Walters MD, Karram MM: Urogynecology and reconstructive pelvic surgery, ed 4, Philadelphia, PA, Elsevier, 2015.

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Urolithiasis (Nephrolithiasis)  BASIC INFORMATION DEFINITION Urolithiasis is the presence of calculi within the urinary tract. The five major types of urinary stones are calcium oxalate (60% to 70%), calcium phosphate (20%), uric acid (7%), struvite (7%), and cystine (1%) (Table 1). SYNONYMS Kidney stones Kidney calculi Renal stones Renal calculi Ureteral stones Ureteral calculi Nephrolithiasis Ureterolithiasis ICD-10CM CODES N20.0 Calculus of kidney N20.1 Calculus of ureter N20.2 Calculus of kidney with calculus of ureter N20.9 Urinary calculus, unspecified N21.0 Calculus in bladder N21.1 Calculus in urethra N21.8 Other lower urinary tract calculus N21.9 Calculus of lower urinary tract, unspecified

EPIDEMIOLOGY & DEMOGRAPHICS • Urinary stones affect approximately 1 in 11 people in the U.S., with a lifetime prevalence of approximately 10% in males and 7% in females. • Peak incidence is in the fourth to sixth decade of life. • Urolithiasis appears to be more common among whites than Hispanics, Asians, or African Americans. • The incidence of urinary stone disease is increasing, likely due to increased use of cross-sectional imaging and changing dietary and lifestyle factors. • The incidence of symptomatic urolithiasis is greatest during the summer as a result of increased temperature with resulting dehydration and urinary concentration.

ALG

• Annually, between 1 and 2 million emergency department visits are due to kidney stones and renal colic. • Approximately 90% of all urinary stones are radiopaque. Cystine stones are faintly radiopaque. Uric acid stones are radiolucent.

PHYSICAL FINDINGS & CLINICAL PRESEN­TATION Stones may be asymptomatic, or may cause the following signs and symptoms, often from urinary tract obstruction: • Acute, often severe, flank pain (renal colic) • Pain radiating from the flank downward and anteriorly with referred pain to the groin and genitalia (common as the stone progresses down the ureter) • Low back and lower abdominal pain, often ipsilateral to the stone • Nausea and vomiting • Hematuria, gross or microscopic • Inability to find a comfortable position • Urinary urgency and frequency with distal ureteral stones mimicking a urinary tract infection • Fever and chills accompanying acute colic with superimposed infection • Elderly patients, children, and patients with neurologic deficits may present with nonspecific and vague abdominal discomfort and pain ETIOLOGY • Urine composition: Supersaturation of various solutes and stone constituents is the driving force in kidney stone formation. Various metabolic abnormalities such as low or high urine pH, idiopathic hypercalciuria, hypocitraturia, hyperoxaluria, and hyperuricosuria predispose patients to urinary stone formation. • Low urine volume is the most common cause in many stone–formers. • Dietary factors: Diets high in sodium and animal protein increase the risk of urinary stone formation. Very high dietary oxalate consumption and heavy intake of phosphoric acidcontaining carbonated drinks likely increase the risk of stone formation. Foods with high potential renal acid load such as cheese and meats increase the risk of urinary stone formation, while fruits and vegetables with low potential renal acid load may reduce the risk.

TABLE 1  Types of Urinary Tract Stones and Their Etiology Percentage of all stones

Composition

Etiological factors

Calcium oxalate/calcium oxalate mixed with calcium phosphate

An underlying metabolic disorder (e.g. idiopathic hypercalciuria or hyperoxaluria) ▸ in 25% no metabolic abnormality is identified Renal infection

75

Hyperuricemia or hyperuricosuria ▸ it is idiopathic in 50% A renal tubular defect

6

Struvite or matrix calculi (composed of magnesium ammonium phosphate) Uric acid Cysteine

10-15

1-2

Other stones (e.g., xanthine stones, which may be related to a metabolic abnormality, or indinavir stones, which are drug related) are uncommon and account for 1% of calcium phosphate stones) 12. Cystinuria: Autosomal recessive disorder produces 1% of stones • Chronic infections: Urease-producing organisms (e.g., Proteus [most common], Providencia, Pseudomonas, Klebsiella, Staphylococcus) cause alkaline urine favoring struvite or magnesium ammonium phosphate crystal formation (Box 2). • Medications: Protease inhibitors (e.g., indinavir, ritonavir), topiramate, and chronic laxative overuse. BOX 1  Uric Acid Stones Low urine pH (≤5.5) High animal protein diet Diarrhea Insulin resistance (high body mass index, metabolic syndrome, type 2 diabetes) Low Urine Volume Inadequate fluid intake Excessive extrarenal fluid losses Diarrhea Insensible losses (e.g., perspiration) Hyperuricosuria Excessive dietary purine intake Hyperuricemia Gout Intracellular-to-extracellular uric acid shift Myeloproliferative disorders Tumor lysis syndrome Inborn errors of metabolism Lesch-Nyhan syndrome Glucose-6-phosphatase deficiency From Floege J et al: Comprehensive clinical nephrology, ed 4, Philadelphia, 2010, Saunders.

ALG BOX 2  Factors Associated with Struvite Stone Formation

Modified from Floege J et al: Comprehensive clinical nephrology, ed 4, Philadelphia, 2010, Saunders.

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • Urinary tract infection (e.g., cystitis) • Pyelonephritis • Diverticulitis • Appendicitis • Pelvic inflammatory disease • Ovarian pathology, including torsion • Dysmenorrhea • Ectopic pregnancy • Small bowel obstruction • Constipation • Malignancy (primary urinary tract or retroperitoneal lymphadenopathy causing ureteral/ kidney obstruction) • Ureteropelvic junction obstruction • Testicular torsion in children and teenagers • Musculoskeletal back pain • Renal infarction and renal bleeds • Factitious (illicit substance-seeking behavior), often with recurrent stone formers The differential diagnosis of obstructive uropathy is described in Section II. WORKUP • Stone composition of recovered stones should be determined by infrared spectroscopy or x-ray crystallography. Box 3 summarizes indications for a metabolic stone evaluation. • Box 4 describes events in the medical history that may be significant with regard to urolithiasis. LABORATORY TESTS • Urinalysis: Hematuria is often present, but absence of hematuria does not exclude stones. Urine pH may help identify stone type: pH >7.5 is associated with struvite stones; pH 7.5: Infection lithiasis pH 99%. • Culture, when available, is considered the traditional gold standard laboratory test for diagnosis of trichomonas, with sensitivity 75% to 96% and specificity approaching 100%.

both sexes. Treatment of the sexual partner is essential to prevent reinfection. • Alternative regimen: Metronidazole 500 mg PO bid × 7 days. • Alcohol consumption should be avoided during treatment with metronidazole (at least 24 hr after completion of therapy) and tinidazole (at least 72 hr after completion of therapy) to reduce possibility of disulfiram-like reaction. • CDC recommends retesting sexually active women within 3 mo of treatment to assess for possible reinfection.

CHRONIC Rx • For persistent infections, the CDC recommends first trying metronidazole 500 mg PO bid × 7 days. • If treatment is still unsuccessful, proceed with metronidazole or tinidazole 2 g PO daily × 7 days. • Allergy, intolerance, or adverse reactions: Alternatives to metronidazole or tinidazole are not recommended. Patients who are allergic to nitroimidazoles can be managed by desensitization. • Pregnancy: 1. Associated with adverse outcomes (i.e., premature rupture of membranes, preterm delivery), although it is unclear whether treatment decreases the incidence of these outcomes. 2. Treat with metronidazole 2 g PO × 1 day; avoid tinidazole as there is little known about tinidazole in pregnancy. DISPOSITION • Trichomonas infection is considered an STD; therefore, treatment of the sexual partner is necessary. • T. vaginalis infection is associated with twoto threefold increased risk for HIV acquisition. • T. vaginalis infection in pregnancy is associated with premature rupture of membranes, preterm birth, and delivery of low birth weight infants. REFERRAL To obstetrician/gynecologist for recurrence and pregnancy

TREATMENT NONPHARMACOLOGIC THERAPY Condom use: The best way to prevent trichomoniasis is through consistent and correct use of condoms during all penile-vaginal sexual encounters ACUTE GENERAL Rx • Preferred initial treatment: Metronidazole 2 g PO × 1 or tinidazole single 2-g oral dose in

SUGGESTED READINGS Available at ExpertConsult.com RELATED CONTENT Trichomoniasis (Patient Information) Pruritus Vulvae (Related Key Topic) AUTHOR: Margaret R. Hines, MD

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ICD-10CM CODE A59.01 Trichomonal vulvovaginitis

• Fungal vulvovaginitis • Atrophic vulvovaginitis • Vaginal or cervical infection with other sexually transmitted infections such as gonorrhea or chlamydia

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Vaginitis, Trichomonas

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SUGGESTED READINGS Centers for Disease Control and Prevention: 2015 sexually transmitted diseases treatment guidelines: trichomoniasis, Division of STD Prevention, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention. Available at: www.cdc.gov/std/tg2015/trich omoniasis.htm. Herbst de Cortina S et  al: A systematic review of point of care testing for Chlamydia trachomatis, Neisseria gonorrhoeae, and Trichomonas vaginalis, Infect Dis Obstet Gynecol 2016:4386127, 2016. Nye MB et  al: Comparison of APTIMA Trichomonas vaginalis transcription-­ mediated amplification to wet mount microscopy, culture, and PCR for diagnosis of trichomoniasis in men and women, Am J Obstet Gynecol 200(2):188. e1–188.e7, 2009. Patel EU et  al: Prevalence and correlates of Trichomonas vaginalis infection among men and women in the United States, Clin Infect Dis 67(2):211–217, 2018.

TABLE E1  Differential Diagnosis of Vaginitis in Women

pH

White Blood Cells

Microscopy

Symptoms

White, thick, smooth White, thick, curdlike

≤4.5

Absent

Lactobacilli

None

≤4.5

Absent

Mycelia

Trichomoniasis

Frothy or purulent

≥4.5

Present

Mobile trichomonads present Amine odor

Bacterial vaginosis

Thin, white homogeneous

≥4.5

Absent

Paucity of lactobacilli (75% of patients) Amine odor Clue cells

Vulvar pruritus, external or superficial dysuria Vulvar erythema and edema, punctate strawberry lesions on cervix Fishy odor and increased vaginal discharge

Vaginal Discharge Normal Candidiasis

From Wein AJ et al: Campbell-Walsh urology, ed 11, Philadelphia, 2016, Elsevier.

FIG. E1  Trichomonas vaginalis trophozoites stained with Giemsa (left) and iron hematoxylin (right). (From the Centers for Disease Control and Prevention: Laboratory identification of parasites of public health concern, Trichomoniasis.)

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Vaginosis, Bacterial  BASIC INFORMATION DEFINITION Bacterial vaginosis (BV) is a polymicrobial infection in which anaerobic bacteria overgrow and replace the normal hydrogen peroxideproducing lactobacilli, resulting in thin, gray, and malodorous vaginal discharge. SYNONYMS Bacterial vaginosis BV Nonspecific vaginitis Gardnerella vaginalis vaginitis ICD-10CM CODES N76.0 Acute vaginitis N77.1 Vaginitis, vulvitis and vulvovaginitis in diseases classified elsewhere

EPIDEMIOLOGY & DEMOGRAPHICS • Most common cause of vaginal discharge in women of reproductive age. • Most common organisms include Gardnerella vaginalis, Porphyrmonas species, Mycoplasma hominis, Bacteroides species, Peptostreptococcus species, Ureaplasma urealyticum, Fusobacterium species, Prevotella species, and Atopobium vaginae, and other facultative anaerobes. • Women with BV are at increased risk for acquiring other sexually transmitted diseases (STDs) such as HIV, N. gonorrhoeae, C. trachomatis, and HSV-2. BV may contribute to persistent HPV infection. Also associated with pelvic inflammatory disease (PID) and complications after gynecologic surgery. Preoperative evaluation and treatment before planned hysterectomy or abortion decreases the infection complication rate. • May be associated with low birth weight, premature rupture of membranes (PROM), and prematurity. • BV may recur in 30% within the first 3 months after treatment, which may be due to: 1. Persistence of pathogenic bacteria 2.  Reinfection from exogenous sources including sexual partners 3. Failure of the normal lactobacillus-dominant flora to reestablish • Risk factors: Multiple female or male sexual partners, sexually transmitted infections, douching, tobacco use, lack of condom use, and lack of vaginal lactobacilli. PHYSICAL FINDINGS & CLINICAL PRESENTATION • 50% to 75% of patients are asymptomatic. • A thin, dull, and gray homogeneous discharge (Fig. E1) • Characterized by a “fishy” odor from the vagina • Vaginal pH >4.5 • BV alone does not typically cause dysuria or dyspareunia, and presence may suggest concomitant infection with another pathogen • Clue cells on microscopic examination (Fig. E2)

ETIOLOGY • Gardnerella vaginalis detected in 40% to 50% of vaginal secretions. • Increase in vaginal pH secondary to decrease in hydrogen peroxide producing lactobacilli allows predominance of anaerobes that produce amines. • It is unclear how the vaginal floral imbalance occurs and the role sexual activity plays in the pathogenesis of BV. • G. vaginalis may be important in epithelial biofilm formation. • Ethnicity and age may contribute to the vaginal microbial environment.

DIAGNOSIS WORKUP At least three of the Amsel clinical diagnostic criteria: • Sensitivity of 92% and specificity of 77%: 1. Thin, gray, and homogeneous, malodorous discharge that adheres to the vaginal walls. 2. Vaginal pH >4.5. 3. Positive whiff-amine test: a. Conducted by placing wet mount specimen and adding 10% potassium hydroxide, which creates a fishy odor. 4. More than 20% of the epithelial cells are clue cells on microscopy. • Gram staining: Considered the gold-standard laboratory method to determine the concentration of lactobacilli and gram-negative and gram-positive bacteria. • If microscopy is unavailable, other diagnostic tests include Affirm VPIII (Becton Dickinson, Sparks, MD), which is a DNA-hybridization probe test for high concentrations of G. vaginalis, and the OSOM BV Blue test (Sekisui Diagnostics, Framingham, MA), which detects vaginal fluid sialidase activity. A molecular test for the vaginal microbiome for BV, candidiasis, and trichomonas (BD MAX Vaginal Panel) has also shown promising results in early studies. • Cultures are unnecessary. • Pap smear is not a reliable test for BV. • Rule out other causes such as vulvar diseases, STDs, and atrophic vaginitis.

TREATMENT ACUTE GENERAL Rx • Recommended regimens (similar efficacy): 1. Metronidazole 500 mg PO bid for 7 days or 2. Metronidazole 0.75% gel, one full applicator (5 gm) intravaginally daily for 5 days or 3. Clindamycin 2% cream, one full applicator (5 gm) intravaginally at bedtime for 7 days • Alternate regimens: 1. Clindamycin 300 mg PO bid for 7 days or clindamycin 100 mg ovules intravaginally once at bedtime for 3 days. May be associated with antimicrobial resistance. 2. Tinidazole 1g PO once daily for 5 days. Longer half-life than metronidazole (∼12 to 14 hr vs. ∼6 to 7 hr) 3. Secnidazole 2g PO once. Longer half life than metronidazole (∼17 hr vs. ∼8 hr).

Shown to be superior to placebo in phase 3 trial and at least as effective as metronidazole 500 mg PO bid in noninferiority trial. Single 1-g oral dose appears to be effective also. Single dose improves compliance, but more expensive than multidose metronidazole therapy. • Disulfiram-type reactions may occur while taking oral or topical metronidazole and patients should be advised to avoid alcohol while undergoing treatment. • Sexual partners: It is not necessary to treat male partners of affected females; however, females who partner with females need to be aware of the signs and symptoms of BV, and treatment is indicated in this population if symptoms occur. • Follow-up visits after treatment and resolution of symptoms are unnecessary, but patients are advised to return if symptoms recur. • Not enough evidence for or against probiotic use for treatment and prevention. • Clindamycin cream may weaken latex condoms if used together. Avoid treatment of asymptomatic patients. • Treatment in pregnancy: 1. Symptomatic pregnant patients with BV should be treated to relieve bothersome symptoms. 2. Insufficient evidence to recommend routine screening for BV in asymptomatic pregnant women at high or low risk of preterm delivery. 3. Can use oral or topical therapy for symptomatic pregnant women with same regimen as nonpregnant women. 4. There is no evidence that metronidazole or clindamycin have any teratogenic effect during pregnancy. Tinidazole should be avoided in pregnancy. • Recurrent BV: 1. Condom use may help reduce the risk of recurrence. 2. Chronic suppressive therapy has been proven to reduce the development or recurrence of BV.

PEARLS & CONSIDERATIONS • BV is the most common cause of vaginitis in reproductive women. • BV has been associated with PID, postprocedural gynecologic complications, and other STDs. It is reasonable to treat asymptomatic women who are to undergo gynecologic surgery and screen for other STDs. • ACOG, USPSTF, and CDC all agree to not routinely screen and treat all pregnant women with asymptomatic BV to prevent preterm birth.

SUGGESTED READINGS Available at ExpertConsult.com RELATED CONTENT Bacterial Vaginal Infections (Patient Information) AUTHORS: Neha Rana, MD, and Emily Saks, MD, MSSCE

Vaginosis, Bacterial

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SUGGESTED READINGS ACOG Committee on Practice Bulletins–Gynecology: ACOG Practice Bulletin: Clinical management guidelines for obstetrician-gynecologists, Number 72, May 2006: Vaginitis, Obstet Gynecol 107:1195-1206, 2006. Paavonen J, Brunham RC: Bacterial vaginosis and desquamative inflammatory vaginitis, N Engl J Med 379:2246-2254, 2018. Schwebke JR et  al: A Phase 3, double-blind, placebo-controlled study of the effectiveness and safety of single oral doses of secnidazole 2 g for the treatment of women with bacterial vaginosis, Am J Obstet Gynecol 217(6), 2017. 678.e1-678.e9. Workowski KA, Bolan GA, Centers for Disease Control and Prevention: Sexually transmitted diseases treatment guidelines, MMWR Recomm Rep 64(RR-03) :1-137, 2015.

FIG. E1  Bacterial vaginosis. The gray, homogeneous discharge that coats the tissues is characteristic. (From Bennett JE, Dolin R, Blaser MJ: Mandell, Douglas, and Bennett’s principles and practice of infectious diseases, ed 8, Philadelphia, 2015, Saunders.)

A

B FIG. E2  Bacterial vaginosis, seen as dense, evenly distributed collections of rodlike bacterial forms in the squamous cells as seen on a wet prep (A) or Papanicolaou stain (clue cells; B). (From Crum CP et al: Diagnostic gynecologic and obstetric pathology, ed 3, Philadelphia, 2018, Elsevier.)

Vancomycin-Resistant Enterococcus (VRE) BASIC INFORMATION DEFINITION Enterococci are gram-positive, facultative anaerobic organisms usually oval in shape and can be seen as single cells, pairs, or chains. Vancomycin-resistant Enterococcus (VRE) are enterococci that have become resistant to vancomycin and several antibiotics normally used to treat enterococcal infections.

ICD-10CM CODE Z16.39  Resistance to other specified antimicrobial drug

EPIDEMIOLOGY & DEMOGRAPHICS INCIDENCE: VRE may be associated with the use of specific classes of antibiotics. PEAK INCIDENCE: VRE was first reported in Europe in 1986, and there has been a steady rise in the incidence of enterococcal strains resistant to vancomycin. In 2007, 80% of E. faecium isolates and 7% of E. faecalis isolates were resistant to vancomycin. PREVALENCE: Eighty percent of E. faecium are VRE; 69% of E. faecalis are VRE. RISK FACTORS: • Prior antimicrobial therapy, especially vancomycin • Prolonged hospitalization • Chronic medical conditions, renal failure • Invasive devices • ICU stay • Colonization: VRE colonize the gastrointestinal tract; can be found on skin or perirectal swab culture or stool culture PHYSICAL FINDINGS & CLINICAL PRESENTATION Patients may be asymptomatic and have gastrointestinal colonization; it can be associated with diarrhea. In hospitalized patients, infection is associated with colonization and can cause wound infections, bacteremia, abscesses (intraabdominal), and, rarely, pneumonia, urinary tract infections, and endocarditis. ETIOLOGY • The Clinical and Laboratory Standards Institute uses the following MIC definitions for vancomycin susceptibility and resistance in enterococci: 1. Vancomycin susceptible: ≤4 mcg/ml 2. Vancomycin resistant: ≥32 mcg/ml 3. Vancomycin intermediate: 8 to 16 mcg/ml (vancomycin not recommended)

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • Other bacterial pathogens in blood, wounds, or urine. • Once colonized, increased incidence to become infected LABORATORY TESTS • VRE rectal culture • VRE stool culture • Blood, urine, and wound cultures

TREATMENT • For rectal or stool colonization, therapy is not recommended. • Therapy is complicated by the fact that strains exhibit inherent resistance to many commonly used antibiotics. • More than 80% of vancomycin-resistant E. faecium strains are also resistant to ampicillin. • In symptomatic patients, if VRE strains are known to be susceptible, potential therapeutic agents include: 1. Linezolid: 600 mg IV or PO q12h 2. Daptomycin: 4 mg/kg/day IV for nonbacteremia infections and 6 mg/kg/day IV for bacteremias 3. Tigecycline: 100 mg IV load dose, then 50 mg IV q12h. Although not specifically FDA approved for VRE strains, it offers an option for patients intolerant to other agents 4. Quinupristin-dalfopristin (Synercid) only effective for E. faecium strains with no activity for E. faecalis strains: 7.5 mg/kg q8 to 12h. Can cause severe myalgias and arthralgias and venous irritation that

often requires use of a central line, which has limited the use of this antibiotic 5. Salvage regimens for severe VRE infections include: a.  Daptomycin plus gentamicin and/or ampicillin or ceftaroline b. Daptomycin plus tigecycline 6. The Healthcare Infection Control Practices Advisory Committee recommends that three negative stool/rectal cultures be obtained at weekly intervals to remove a patient from contact precautions.

REFERRAL To infectious disease specialist

PEARLS & CONSIDERATIONS COMMENTS • Patients who are colonized with VRE have about an 8% rate of developing a true VRE infection in hospital or after discharge. The rate is higher in immunocompromised and severely ill patients. • Incidence increases with comorbidity and hospitalization. • The number of patients already colonized with VRE in a defined geographic area (colonization pressure) is the most significant factor for predicting new acquisition of VRE. • An association between VRE colonization and Clostridium difficile infection has been reported in patients with hematologic malignancies. PREVENTION • Hand hygiene: Most important and practical method of preventing spread in hospital environment. Soap and water (used as a 30-sec wash) and alcohol-based hand rubs are effective, as is chlorhexidine. • Cohorting and isolation techniques: Use of private rooms and use of gowns and gloves has been shown to decrease the risk of spread of multidrug-resistant bacteria. • Cleaning contaminated objects or surfaces with standard hospital disinfectants, antibiotic management (prudent vancomycin use), and surveillance also help prevent spread. SUGGESTED READINGS Available at ExpertConsult.com RELATED CONTENT Health Care-Related Infections (Related Key Topic) AUTHOR: Glenn G. Fort, MD, MPH

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SYNONYM VRE

• Enterococci are primarily found in the human digestive tract and female genital tract, where they make up a significant portion of the normal bacterial population in healthy people. Enterococci can cause urinary tract, wound, bloodstream, heart valve, and brain infections. In the great majority of cases, VRE infections occur in hospitalized patients who have compromised immune systems. Most cases of VRE are caused by the E. faecium strains that have acquired resistance when they came in contact with other bacteria and shared genetic information. • VRE is most commonly transmitted from one patient to another by health care workers whose hands have become contaminated inadvertently with feces or fluids of a person carrying the organism. VRE are not airborne but can survive on surfaces for several weeks.

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Vancomycin-Resistant Enterococcus (VRE) SUGGESTED READINGS Faron ML et al: Resistance mechanisms, epidemiology, and approaches to screening for vancomycin-resistant enterococcus in the health care setting, J Clin Microbiology 54:2436-2447, 2016. Kohinke RM, Pakyz AL: Treatment of vancomycin-resistant enterococci: focus on daptomycin, Curr Infect Dis Rep 19:33, 2017. Reyes K et al: Vancomycin-resistant enterococci: epidemiology, infection prevention, and control, Infect Dis Clin North Am 30:953-965, 2016.

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Varicella BASIC INFORMATION DEFINITION Varicella is a viral illness caused by varicellazoster virus and characterized by the acute onset of a generalized vesicular rash and fever. SYNONYM Chickenpox ICD-10CM CODES B01.9 Varicella without complication B01.8 Varicella with other complications B01.0 Varicella meningitis B01.11 Varicella encephalitis and encephalomyelitis B01.12 Varicella myelitis B01.2 Varicella pneumonia B01.81 Varicella keratitis B01.89 Other varicella complications Z20.820 Contact with and (suspected) exposure to varicella

EPIDEMIOLOGY & DEMOGRAPHICS • Varicella is extremely contagious. More than 90% of unvaccinated contacts become infected. • The incubation period of chickenpox ranges from 9 to 21 days. • The peak incidence is during the springtime. • The predominant age is 5 to 10 yr. • The infectious period begins 2 days before the onset of clinical symptoms and lasts until all of the lesions have crusted. • Most patients will have lifelong immunity after an attack of chickenpox; protection from the virus after a varicella vaccine is approximately 6 yr. PHYSICAL FINDINGS & CLINICAL PRESENTATION • Findings vary with the clinical course. Initial symptoms consist of fever, chills, backache, generalized malaise, and headache. • Symptoms are generally more severe in adults. • Initial lesions generally occur on the trunk (centripetal distribution) and occasionally on the face; these lesions consist primarily of 3to 4-mm red papules with an irregular outline and a clear vesicle (Fig. E1) on the surface (i.e., the appearance of dewdrops on a rose petal).

FIG. E1  Chickenpox. (From Swartz MH: Textbook of physical diagnosis, ed 7, Philadelphia, 2014, WB Saunders.)

• Intense pruritus generally accompanies the initial stage. • New lesion development generally ceases by the fourth day, with subsequent crusting by the sixth day. • Lesions generally spread to the face and the extremities (i.e., centrifugal spread). • Patients generally present with lesions that are in different stages at the same time. • Crusts generally fall off within 5 to 14 days. Scarring may occur in association with secondary bacterial infections (Figs. E2 and E3). • The fever is usually highest during the eruption of the vesicles; the patient’s temperature generally returns to normal after the disappearance of vesicles. • Skin lesions may become superinfected with Streptococcus pyogenes or Staphylococcus aureus. • Signs of potential complications (e.g., bacterial skin infections, neurologic complications, pneumonia, hepatitis) may be present on physical examination. • Mild constitutional symptoms (e.g., anorexia, myalgias, headaches, restlessness) may be present; these are most common among adults. • Excoriations may be present if scratching is prominent.

ETIOLOGY Varicella-zoster virus (VZV) is a human herpes virus III (HHV-3) that can manifest with either varicella or herpes zoster (i.e., shingles, which is a reactivation of varicella).

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • Other viral infection • Impetigo

• Scabies • Drug rash • Urticaria • Dermatitis herpetiformis • Smallpox

WORKUP The diagnosis is usually made on the basis of the patient’s history and clinical presentation. LABORATORY TESTS • Laboratory evaluation is generally not necessary. • The CBC may reveal leukopenia and thrombocytopenia. • Serum varicella titers (i.e., a significant rise in the serum varicella immunoglobulin G antibody level), skin biopsies, or Tzanck smears are used only when diagnosis is in question.

TREATMENT NONPHARMACOLOGIC THERAPY • Use antipruritic lotions for symptomatic relief. • Avoid scratching to prevent excoriations and superficial skin infections. • Use a mild soap for bathing. • Hands should be washed often. ACUTE GENERAL Rx • Use acetaminophen for fever and myalgias; aspirin should be avoided because of the associated increased risk of Reye syndrome. • Oral acyclovir (20 mg/kg qid for 5 days), valacyclovir, or famciclovir initiated at the earliest sign (i.e., within 24 hr of illness) is useful for healthy, nonpregnant individuals 13 yr old or older to decrease the duration and severity of signs and symptoms. Immunocompromised

FIG. E2  Varicella scarring. Large, deep scars are present in this patient who had secondary bacterial infection of her primary varicella lesions. (From Paller AS et al: Hurwitz clinical pediatric dermatology, a textbook of skin disorders of childhood and adolescence, ed 5, Philadelphia, 2016, Elsevier.)

Varicella

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DISPOSITION • The course is generally benign in immunocompetent adults and children. • Infants who develop chickenpox are incapable of controlling the infection and should be given varicella-zoster immunoglobulin or gamma globulin if VariZIG is not available.

PEARLS & CONSIDERATIONS FIG. E3  Varicella, complicated. Deep, ulcerative lesions occurred in this young girl with underlying immunodeficiency and secondary infection of the skin with Streptococcus pyogenes. (From Paller AS et al: Hurwitz clinical pediatric dermatology, a textbook of skin disorders of childhood and adolescence, ed 5, Philadelphia, 2016, Elsevier.)

hosts should be treated with intravenous acyclovir 500 mg/m2 or 10 mg/kg q8h for 7 to 10 days. • Varicella is most contagious from 2 days before to a few days after the onset of the rash. Varicella vaccine is available for children and adults; protection lasts at least 6 yr. Healthy, nonimmune adults and children exposed to varicella-zoster virus should receive prophylaxis with live attenuated varicella vaccine (Varivax). Patients with HIV or other immunocompromised patients should not receive the live attenuated vaccine.

• Exposed patients with contraindications to varicella vaccine can be treated with varicella-zoster immunoglobulin (VariZIG), which effectively prevents varicella in susceptible individuals. The dose is 12.5 U/kg IM up to a maximum of 625 U. VariZIG must be administered as early as possible after presumed exposure (i.e., within 10 days) for postexposure prophylaxis of varicella. • Pruritus from chickenpox can be controlled with antihistamines (e.g., hydroxyzine 25 mg q6h) and antipruritic lotions (e.g., calamine).

COMMENTS • VariZIG can be obtained from the nearest regional Red Cross Blood Center or the Centers for Disease Control and Prevention in Atlanta. • Varicella immunization is recommended for all who have not had chickenpox; the dosage for adults and adolescents (>13 yr old) is two 0.5-ml doses 4 to 8 wk apart. RELATED CONTENT Chickenpox (Patient Information) AUTHOR: Fred F. Ferri, MD

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Varicocele  40% of infertile men. However, only 10% to 15% of males with varicoceles have fertility problems. RISK FACTORS: There are no reliable data on epidemiologic risk factors for varicocele, such as a family history or environmental exposures.

BASIC INFORMATION DEFINITION A varicocele is a dilation of the testicular vein and pampiniform plexus within the scrotum. SYNONYM Sometimes referred to as “bag of worms” (Fig. E1) ICD-10CM CODE I86.1 Scrotal varices

EPIDEMIOLOGY & DEMOGRAPHICS PREVALENCE: A varicocele is present in up to 20% of all males. It occurs in approximately

PHYSICAL FINDINGS & CLINICAL PRESENTATION • Although most varicoceles are painless, patients may complain of dull, aching pain that is relieved with lying down. They may also complain of testicular atrophy, one testicle being heavier than the other, a swollen testicle, or decreased fertility.

• Patients may report a mass lying posterior to and above the testis. When the patient is supine, dilation of the veins is generally decreased. Dilation and tortuosity of the veins are increased when the patient is upright and when the patient performs a Valsalva maneuver. • The majority of cases (90%) occur more commonly on the left side because the left spermatic vein enters the left renal vein at a 90-degree angle, whereas the right testicular vein drains directly into the vena cava. Bilateral varicoceles occur in 33% of patients. A unilateral right-sided varicocele is very rare and should raise suspicion for an underlying disease causing obstruction of the vena cava. • Physical examination reveals a soft scrotal mass that increases in size when standing and is typically described as a “bag of worms.” • Varicoceles can be graded based on physical exam. Grade 1 is small and is palpable only with Valsalva maneuver. Grade 2 is moderate and nonvisible on inspection but is palpable on standing. Grade 3 is large and visible on gross inspection.

ETIOLOGY Varicoceles are caused by dysfunction of the valves in the spermatic vein, which allows pooling of blood in the pampiniform plexus.

DIAGNOSIS

FIG. E1  Varicocele. (From Swartz MH: Textbook of physical diagnosis, history and examination, ed 7, Philadelphia, 2014, Elsevier.)

DIFFERENTIAL DIAGNOSIS • Hydrocele • Spermatocele • Epididymal orchitis • Testicular tumor • Table E1 describes the differential diagnosis of pediatric scrotal masses and pain

TABLE E1  Age-Based Differential Diagnosis of Pediatric Scrotal Masses and Pain Diagnosis

Age at Onset

Pain

Position of Testes, Tenderness

Systemic Symptoms

Testicular torsion*

All ages; peak onset at 12-18 yr

60% sudden onset; diffuse tenderness

High-riding horizontal lie

Testicular appendix torsion Epididymoorchitis

Prepuberty; average age, 10 yr >16 yr

Acute or gradual; focal tenderness Gradual; posterior tenderness

Normal lie; blue dot Normal lie

Hydrocele

Most common during first yr of life Most common during first yr of life

Painless

Normal lie

Vomiting common; dysuria and fever uncommon Vomiting, dysuria, and fever uncommon Vomiting uncommon; dysuria and fever common None

Pain with incarceration or strangulation

Normal lie

Vomiting, abdominal pain with incarceration or strangulation

10-15 yr

Painless, mild discomfort, “pressure or fullness”

Normal lie

None

Rare; most occur in patients 3 mm in diameter), tortuous conduits (Fig. E1). Reticular veins, often called “feeder veins,” are bluish subdermal veins about 1 to 3 mm in diameter that give rise to telangiectasia. Spider veins or telangiectasias are very small (≤1 mm in diameter) thread veins found commonly in clusters on the surface of the skin. SYNONYM Chronic venous disorder ICD-10CM CODES I83.90 Asymptomatic varicose veins of unspecified lower extremity I83.899 Varicose veins of unspecified lower extremities with other complications

EPIDEMIOLOGY PREVALENCE: One large U.S. cohort study found the biannual incidence of varicose veins was 3% in women and 2% in men. • The prevalence of varicose veins in Western populations was estimated in one study to be about 25% to 30% in women and 10% to 20% in men. RISK FACTORS: • Gender: Female • Genetics: Family history of varicose veins • Increasing age • Multiple pregnancies

vein is involved, large varicose veins are found in posterior knee or calf area. If the anterior accessory of great saphenous vein is involved, large varicose veins are found mainly in anterior or lateral thigh. 2. Perforator: Failure of valves located in perforating vein. Large varicose veins are found most commonly in medial calf and proximal thigh region.

CLASSIFICATION Chronic venous disease can now be classified using the Clinical-Etiology-AnatomyPathophysiology (CEAP) criteria to allow a precise description of the type of venous disease being discussed and provide an orderly framework for decision making (Table E1). ETIOLOGY • The underlying etiology of varicose veins remains uncertain. • Important structural changes that occur: Failure of vein valve function and vein wall dilation from fragmentation of the muscle layer. COMPLICATIONS • Superficial venous thrombophlebitis (SVT): A very common disorder with an incidence of 125,000 new cases/yr in the U.S. The most frequent predisposing risk factors are varicose veins. The clinical findings include the presence of erythema, tenderness, and a palpable cord. Pain, increased warmth, and swelling are also present. Diagnosis is made by ultrasonography, which is useful to identify associated deep vein thrombosis that can occur in approximately 15% of patients. The location of the SVT determines the course of treatment; if the proximal great saphenous vein (GSV) is involved, a 1-mo course of low-molecular-weight heparin plus compression stockings has been found to

SYMPTOMS AND PHYSICAL FINDINGS Leg complaints consistent with chronic venous disease include aching, heaviness, subjective swelling, cramps, itching, tingling, and pain. These symptoms can be exacerbated by menses, heat, and prolonged standing. CLINICAL PRESENTATION • Chronic vein disease is the result of the introduction of high pressures into a normal low-pressure superficial venous system. • This increased pressure or venous hypertension causes superficial veins to distend to such a degree that vein valves fail to close, causing reflux and pooling of blood in surface veins. • Manifested clinically by two syndromes: 1. Junctional: Failure of the terminal valve at the intersection between the saphenous vein trunks and the deep system. If the great saphenous vein is involved, large varicose veins are found mainly above medial knee or calf. When the small saphenous

be more effective than vein ligation. If SVT involves branch varicosities, treatment is usually symptomatic (control of pain). • Bleeding is a more common complication than traditionally suspected. It is associated with thin-walled ectatic veins known as “blue blebs” that are found predominantly in the medial lower calf and ankle region. The best emergency treatment consists of pressure wrapping and not suture ligation, which results in delayed healing of the bleeding site. Sclerotherapy of these veins is the definitive treatment to prevent further bleeding. • Dermal pathology of prolonged chronic venous disease (CEAP classes 4, 5, and 6). 1. Varicose eczema 2. Atrophie blanche 3. Lipodermosclerosis 4. Venous stasis ulcer • Risks for peripheral artery disease and pulmonary embolism are slightly elevated in patients with varicose veins, but the clinical significance is unclear.1

DIAGNOSIS DIFFERENTIAL DIAGNOSIS Other conditions that cause leg pain: • Stress fracture • Arthritis hip/knee joint • Gout • Degenerative disk disease of lower back TABLE E1  CEAP Classification of Chronic Venous Disease C: Clinical C0: No visible or palpable signs of venous disease C1: Telangiectasias or reticular veins C2: Varicose veins C3: Edema C4: Pigmentation or eczema C5: Healed venous ulcer C6: Active venous ulcer E: Etiology c: Congenital p: Primary s: Secondary or post-thrombotic n: No venous cause identified A: Anatomy s: Superficial veins p: Perforator veins d: Deep veins n: No venous location identified P: Pathophysiology r: Reflux o: Obstruction r,o: Reflux and obstruction n: No venous pathophysiology identified CEAP, Clinical-Etiology-Anatomy-Pathophysiology.

FIG. E1  Varicose veins. (From White GM, Cox NH [eds]: Diseases of the skin, a color atlas and text, ed 2, S. Louis, 2006, Mosby.)

1Chang

SL et  al: Association of varicose veins with incident venous thromboembolism and peripheral artery disease, JAMA 319:807-817, 2018.

Varicose Veins • Intermittent claudication secondary to peripheral arterial disease (PAD) • Medications such as allopurinol and statins Other conditions that cause leg swelling: • Cellulitis • Soft tissue injury to leg/ankle/foot • Obesity • Diabetes • Advancing age • Medications such as calcium channel blockers, steroids, monoamine oxidase inhibitors, and tricyclics

WORKUP The diagnosis of chronic venous disorders is predominantly clinical. Initial evaluation consists of a thorough history and physical exam with classification of disease according to the CEAP criteria. LABORATORY TESTS Laboratory tests are not useful in patients with varicose veins. IMAGING STUDIES Duplex ultrasonography: • Gold-standard imaging modality for the diagnosis, prognostic evaluation, pretreatment mapping, and posttreatment assessment of therapeutic intervention. • Duplex ultrasound is used to identify and quantify points of valvular reflux within the superficial venous system. • Assessment of valvular reflux is done with patient in the upright position, which physiologically approximates the condition in which valvular reflux occurs. • Reverse flow of greater than 0.5 sec after distal compression is considered abnormal. Other tests: • Air plethysmography: May be useful in patients who have reflux in both superficial and deep venous systems or in patients with an unusual presentation of leg pain. • Venography: Has been largely replaced by duplex ultrasonography but still retains a critical role in the evaluation of chronic venous insufficiency prior to venous reconstruction.

TREATMENT CONSERVATIVE THERAPY: • Aerobic exercise regularly for 30 min a day. • Elevate legs above heart level to reduce swelling.

1437.e7 • Flex ankles frequently at work and during air travel or long car travel. • Maintain proper weight. • Graduated compression stockings (below knee) to alleviate symptoms in patients who are not candidates or do not desire to undergo treatment of their varicose veins. SCLEROTHERAPY: • Small- to medium-sized varicose veins such as spider veins and reticular varices in the absence of reflux in saphenous trunks are best treated with liquid sclerotherapy. • The three principal sclerosants used in the U.S. are hypertonic saline, sodium tetradecyl sulfate, and the newly FDA-approved solution, polidocanol. • These agents are injected into vessels using 27-gauge or 30-gauge needles at concentrations of 23.4%, 0.1%, or 0.5%, respectively, causing injury to the endothelium with the resultant disappearance of the vein over period of time (usually 8 to 12 wk). AMBULATORY PHLEBECTOMY: • A procedure in which large varicose vein branches are removed with special hook instruments through a small puncture—incisions are made with an 18-gauge needle or No. 11 blade • Performed safely under local anesthesia in an office setting and offers excellent cosmetic results and relief of symptoms • Most commonly performed in conjunction with endovenous ablation procedures ENDOVENOUS ABLATION: • Ablation of diseased saphenous vein trunks, large incompetent tributaries, or perforating veins can be achieved by using: 1. Radiofrequency energy 2. Laser energy 3. Ultrasound-guided foam sclerotherapy • The first two accomplish thermal injury to the vein in situ via an intraluminal catheter or bare-tipped laser wire. Chemical ablation uses a solution (polidocanol or sodium tetradecyl sulfate) that is injected directly into the vein in the form of foam. • Endovenous ablation can be performed in an office setting using local anesthesia. Patients can return to their normal daily activities immediately. • The efficacy of these endovenous ablation procedures has been borne out by numerous published reports with occlusion rates over 95% and reflux free rates over 5-yr follow-up of 86%. A recent trial comparing ultrasoundguided foam sclerotherapy and endovenous

SUGGESTED READINGS Brittenden J et al: A randomized trial comparing treatments for varicose veins, N Engl J Med 371:1218-1227, 2014.

laser ablation revealed that quality of life measures were generally similar among the study groups, with the exception of a slightly worse disease-specific quality of life in the foam group than in the surgery group. Both treatments had similar efficacy, but complications were less frequent after laser treatment and ablation rates were lower after foam treatment.

DISPOSITION • In a recent randomized trial2 of treatments for varicose veins, disease-specific quality of life 5 yr after treatment was better after laser ablation or surgery than after foam sclerotherapy. • It is important that the physician educate the patient to understand that varicose veins are a chronic and progressive disease. • Any treatment is at best palliative, as patients in time will develop varicose veins in other areas. REFERRAL To either a phlebologist, preferably board certified by the newly created American Board of Phlebology, or a residency-trained vascular surgeon RELATED CONTENT Varicose Veins (Patient Information) Thrombophlebitis, Superficial Venous (Related Key Topic) Venous Insufficiency, Chronic (Related Key Topic) AUTHOR: Frank G. Fort, MD, FACS, RPHS

2Brittenden J et al: Five-year outcomes of a randomized trial of treatments for varicose veins, N Engl J Med 381:912-922, 2019.

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Vasculitis, Systemic BASIC INFORMATION DEFINITION Vasculitis refers generically to inflammation occurring within the walls of blood vessels. Blood vessel inflammation can result in either perforation of affected vessels with hemorrhage into adjacent structures or thrombosis with subsequent ischemia and infarction of supplied tissues. Vasculitis can occur as a primary process or secondary to another connective tissue disease, infection, or drug exposure. The systemic vasculitides are a heterogeneous group of disorders (Table 1) characterized by blood vessel inflammation affecting vessels of varying size and location resulting in a wide range of clinical manifestations dictated largely by which vessels are affected (Fig. 1 and Fig. E2). Vasculitis is traditionally classified according to the size of the blood vessels predominantly affected (Table 2). Antineutrophilic cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV) includes granulomatosis with polyangiitis (GPA); microscopic polyangiitis (MPA), including renal-limited vasculitis (RLV); and eosinophilic granulomatosis with polyangiitis (EGPA). All are associated with ANCA and have similar features on renal histology (e.g., a focal necrotizing, and

often crescentic, pauciimmune glomerulonephritis). Several of these are covered in individual topics, including topics on granulomatosis with polyangiitis (GPA), polyarteritis nodosa (PAN), giant cell arteritis (GCA), Takayasu arteritis, and Henoch-Schönlein purpura (HSP). Severity varies between and within specific vasculitides from a relatively benign, self-limited process to severe, life-threatening multisystem organ involvement with significant morbidity and mortality. ICD-10CM CODES M30.0 Polyarteritis nodosa M30.3 Mucocutaneous lymph node syndrome [Kawasaki] M31.30 Wegener granulomatosis without 31 renal involvement M31.5 Giant cell arteritis with polymyalgia rheumatica M31.6 Other giant cell arteritis M31.4 Aortic arch syndrome [Takayasu] D 69.0 Allergic purpura L95.9 Vasculitis limited to the skin, unspecified

EPIDEMIOLOGY & DEMOGRAPHICS • The epidemiology and demographics of the various vasculitides vary by the individual

disease and, where applicable, are covered under the relevant vasculitis disease chapters. • The most common form of systemic vasculitis in the U.S. is giant cell arteritis, with an approximate incidence of 170 cases per 1 million per yr in individuals older than 50 yr. • Antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis is significantly less common with aggregate incidence estimated at approximately 20 per million in the U.S. • Age distribution can demonstrate significant variability between the vasculitides as shown by the fact that GCA generally does not occur before age 50, while 90% of cases of HSP occur in the pediatric population, and 80% of patients with Kawasaki disease are under age 5. • Although genetic factors clearly play a role in disease susceptibility, familial cases of vasculitis are rare.

PHYSICAL FINDINGS & CLINICAL PRESENTATION • Clinical presentation often includes nonspecific constitutional symptoms including fever, malaise, headache, and weight loss.

TABLE 1  Comparing the Vasculitides Disease

Pathophysiology

Classic Features

Giant cell arteritis

Mononuclear cell infiltration and giant cell formation Mononuclear cell infiltration and giant cell formation

Headache, scalp tenderness, ESR CRP biopsy visual disturbance Visual disturbance, chest pain, abdo­ Angiography minal pain, differences in extremity blood pressure and pulses Fever, hypertension, myalgias, ESR, CRP biopsy abdominal pain, hematuria, Angiography CHF, GI bleeding, orchitis

Takayasu arteritis Polyarteritis nodosa

Polymorphonuclear infiltration

Kawasaki disease

Polymorphonuclear infiltration

Cryoglobulinemic vasculitis

Cold precipitable monoclonal or polyclonal immunoglobulins Neutrophilic infiltration Mononuclear and eosinophilic infiltration Polymorphonuclear infiltration

5-day fever, conjunctivitis, oral lesions, rash, red palms and soles, edema, cervical lymphadenopathy Granulomatosis with Granuloma formation Upper and lower respiratory ­polyangiitis (Wegener ­secondary to aggregating symptoms, renal insufficiency, granulomatosis) neutrophils skin lesions, visual disturbance Eosinophilic ­granulomatosis Eosinophilic infiltration Allergic rhinitis, nasal polyps, with polyangiitis ­(ChurgAllergic granulomas asthma Strauss syndrome) Henoch-Schönlein purpura IgA complex deposition Palpable purpura, arthralgias, GI disturbances, glomerulonephritis

Cutaneous leukocytoclastic vasculitis Behçet syndrome

Palpable purpura, glomerulonephritis, myalgias, weakness, peripheral neuropathy Palpable purpura, macules, vesicles, bullae, urticaria Recurrent oral aphthous ulcers, genital ulcers, skin lesions, visual disturbance

Testing

Treatment Prednisone and aspirin Prednisone Surgical or angiographic intervention

Prednisone (mild disease) plus cyclophosphamide (moderate-severe disease) Antiviral therapy if concurrent hepatitis B or C Azathioprine or methotrexate for ­maintenance of remission ESR, CRP Leukocytosis Aspirin plus IV gamma globulin Thrombocytosis Echocardiography ESR CRP c-ANCA Prednisone and methotrexate (mild disease) Cyclophosphamide or rituximab plus ­prednisone (moderate to severe disease) Leukocytosis Prednisone with or without Eosinophilia ESR, ­cyclophosphamide CRP biopsy Leukocytosis Usually self-limited Eosinophilia NSAIDs Ig A elevation, Prednisone if necessary skin biopsy Rituximab (refractory cases) Low complement Rituximab with or without prednisone levels, hepatitis Peg interferon plus ribavirin (HCV infection) C Renal biopsy Skin biopsy Prednisone Colchicine Dapsone ESR, CRP Topical corticosteroids ­leukocytosis Prednisone with azathioprine (end-organ Oral mucosa disease) ­autoantibodies Colchicine (aphthous ulcer and arthritis) Infliximab (refractory disease)

c-ANCA, Cytoplasmic antineutrophil cytoplasmic antibody; CHF, congestive heart failure; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; GI, gastrointestinal; IgA, immunoglobulin A; IV, intravenous. From Adams JG et al: Emergency medicine, clinical essentials, ed 2, Philadelphia, 2013, Elsevier.

Vasculitis, Systemic Vasculitis

Small-vessel vasculitis

Medium-vessel vasculitis Polyarteritis nodosa Kawasaki disease

Immune-complex associated

Microscopic polyangiitis (MPA)

IgA vasculitis (HSP)

GPA (Wegener) EGPA (Churg-Strauss) Drug-induced ANCA-associated vasculitis

Paraneoplastic

Cryoglobulinemic vasculitis

Carcinoma-induced vasculitis

Inflammatory bowel disease vasculitis

Lymphoproliferative neoplasm-induced vasculitis

Anti-GBM (glomerular basement membrane) disease

Myeloproliferative neoplasm-induced vasculitis

Infection-induced immune complex vasculitis (e.g., hepatitis B and C) Serum sickness vasculitis Lupus vasculitis Rheumatoid vasculitis Hypocomplementemic urticarial vasculitis Behçet disease Drug-induced immune-complex vasculitis

FIG. 1  Major categories of noninfectious vasculitis. Not included are vasculitides that are known to be caused by direct invasion of vessel walls by infectious pathogens, such as rickettsial vasculitis and neisserial vasculitis. EGPA, Eosinophilic granulomatous polyangiitis; GPA, granulomatous polyangiitis; HSP, Henoch-Schönlein purpura. (From Freehally J et al: Comprehensive clinical nephrology, ed 6, Philadelphia, 2019, Saunders.)

• Signs and symptoms are generally dictated by the tropism of involved vessels. • Skin manifestations of vasculitis include petechiae, palpable purpura (Fig. E3), subcutaneous nodules, livedo reticularis, ulcerations, and digital ischemia. • Kidney involvement of medium-sized and large vessel vasculitis is often in the form of renovascular hypertension. Glomerulonephritis may be seen in small vessel vasculitis. • Pulmonary small vessel involvement can cause alveolar hemorrhage, which can present with cough, dyspnea, and alveolar hemorrhage. • Mononeuritis multiplex is the characteristic finding of vasculitis affecting the vasa nervorum of the peripheral nervous system. • Gastrointestinal involvement of the mesenteric vasculature can cause postprandial pain, bleeding, and perforation. • Arthritis, while nonspecific, can be present. • Significant clinical variability exists between the various vasculitides, although overlapping symptoms may be seen.

ETIOLOGY Most forms of systemic vasculitis are of unknown etiology. Cryoglobulinemia vasculitis is often secondary to hepatitis C infection, and cutaneous leukocytoclastic vasculitis is often related to a drug exposure.

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • Infective endocarditis • Atrial myxoma • Cholesterol emboli • Malignancy • Hypercoagulopathy • Congenital collagen vascular disorder WORKUP • The diagnosis of most forms of systemic vasculitis relies on the history and physical examination as well as supportive laboratory testing. Table 3 describes differential diagnostic features of selected forms of small vessel vasculitis. • Tissue biopsy is important in establishing an accurate diagnosis; biopsy sites should target affected tissues. • Imaging such as mesenteric angiography can be supportive and may obviate the need for tissue biopsy. LABORATORY TESTS • Laboratory markers of systemic inflammation include elevated erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and anemia of chronic disease. • ANCA targeting myeloperoxidase (MPO) and proteinase 3 (PR3) are frequently found in several small vessel vasculitides, including

• Primary vasculitides • Predominantly large vessel vasculitides • Takayasu arteritis • Giant cell arteritis (temporal arteritis) • Cogan syndrome • Behçet disease* • Predominantly medium-sized vessel vasculitides • Polyarteritis nodosa • Cutaneous polyarteritis nodosa • Buerger disease • Kawasaki disease • Primary angiitis of the central nervous system • Predominantly small vessel vasculitides • Immune complex mediated • Goodpasture disease (anti-glomerular basement membrane disease)† 1. Cutaneous leukocytoclastic angiitis (“hypersensitivity vasculitis”) 2. Henoch-Schönlein purpura 3. Hypocomplementemic urticarial vasculitis 4. Essential cryoglobulinemia‡ 5. Erythema elevatum diutinum • ANCA-associated disorders§ 1. Granulomatosis with polyangiitis (GPA, Wegener granulomatosis)‡ 2. Microscopic polyangiitis (MPA)‡ 3. Eosinophilic granulomatosis with polyangiitis (EGPA, Churg-Strauss syndrome)‡ 4. Renal-limited vasculitis (RLV) • Secondary forms of vasculitis • Miscellaneous small vessel vasculitides • Connective tissue disorders‡ (rheumatoid ­vasculitis, lupus erythematosus, Sjögren ­syndrome, inflammatory myopathy) • Inflammatory bowel disease • Paraneoplastic • Infection • Drug-induced vasculitis: ANCA-associated, other *May involve small, medium-sized, and large blood vessels. †Immune complexes formed in situ, in contrast to other forms of immune complex–mediated vasculitis. ‡Frequent overlap of small and medium-sized blood vessel involvement. §Not all forms of these disorders are always associated with ANCA. ANCA, Antineutrophil cytoplasmic antibody. From Firestein G et al: Kelley’s textbook of rheumatology, ed 8, Philadelphia, 2008, Saunders.

GPA (Wegener), microscopic polyangiitis (MPA), and EGPA (Churg-Strauss). • Hepatitis C antibodies and rheumatoid factor are often present in cryoglobulinemic vasculitis. • Urinalysis in patients with glomerulonephritis due to small vessel ANCA-associated vasculitis will generally demonstrate hematuria with active urinary sediment, with red blood cell casts and proteinuria.

IMAGING STUDIES • CTA, MRA, and angiography can demonstrate vascular narrowing and aneurysm formation in suspected medium-size and large-vessel vasculitis. • Pulmonary and sinus CT scans can demonstrate active pulmonary and upper airway disease in ANCA-associated vasculitis.

V

Diseases and Disorders

Circulating antineutrophil cytoplasmic antibodies (ANCA) associated

Large-vessel vasculitis Giant cell arteritis Takayasu arteritis

TABLE 2  Classification Scheme of Vasculitides According to Size of Predominant Blood Vessels Involved

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Vasculitis, Systemic TABLE 3  Differential Diagnostic Features of Selected Forms of Small Vessel Vasculitis

Features Vasculitic signs and symptoms IgA-dominant immune deposits Cryoglobulins in blood and vessels Antineutrophil cytoplasmic antibodies in blood Necrotizing granulomas Asthma and eosinophils

Microscopic Polyangiitis (MPA)

Granulomatosis with Polyangiitis (GPA)

Eosinophilic Granulomatosis with Polyangiitis

HenochSchönlein Purpura (HSP)

Cryoglobulinemic Vasculitis

+ − − +

+ − − +

+ − − +

+ + − −

+ − + −

− −

+ −

+ +

− −

− −

From Freehally J et al: Comprehensive clinical nephrology, ed 6, Philadelphia, 2019, Saunders.

TREATMENT Treatment of vasculitis depends on the specific type of vasculitis and is tailored to the severity of disease activity. Novel treatments are covered under the relevant vasculitis disease chapters.

ACUTE GENERAL Rx • Systemic corticosteroids are generally required to gain initial control of active vasculitis, although mild cases of drug-induced cutaneous leukocytoclastic vasculitis often require cessation of the offending medication and at times, low-dose corticosteroid use. • HSP and vasculitis limited to the skin, including cutaneous PAN, can often be managed without further immunosuppression. • Major organ-threatening disease in systemic vasculitis has traditionally required pulse steroids and oral or intravenous cyclophosphamide for induction of remission. • Studies have demonstrated noninferiority of rituximab compared to cyclophosphamide in ANCA-associated vasculitis with major organ involvement, and it is approved for this use. • Rituximab with prednisone has also recently been shown to be effective in the treatment of relapsing flares of disease activity in ANCA-associated vasculitis. • Similarly, rituximab has been used for maintenance of remission.

• Less severe disease such as granulomatosis with polyangiitis limited to the upper airways can be managed with methotrexate rather than cyclophosphamide. • Trimethoprim/sulfamethoxazole should be used to prevent Pneumocystis carinii infection with concurrent immunosuppressive therapy. • The goal of acute therapy is to induce remission of disease activity and is generally continued for 1 to 2 mo once this is achieved, at which point chronic therapy is used.

CHRONIC Rx • The goal of chronic therapy is to prevent disease relapse and minimize medication side effects. • Steroids are gradually tapered as allowed by disease activity. • Immunomodulatory agents such as methotrexate or azathioprine are commonly used for maintenance therapy in place of cyclophosphamide to reduce side effects. • Cryoglobulinemic vasculitis due to chronic hepatitis C will often improve with treatment of the underlying viral infection. • Rituximab may also be an appropriate remission maintenance agent in ANCA-associated vasculitis, although frequency of dosing and duration of therapy are not yet well characterized.

DISPOSITION Varies widely among the various vasculitides REFERRAL Systemic vasculitis care is generally coordinated by a rheumatologist. Renal, pulmonary, neurologic, and gastrointestinal consultation is often needed when vasculitis involves these organ systems. Isolated cutaneous leukocytoclastic vasculitis is often managed by dermatology. SUGGESTED READINGS Available at ExpertConsult.com RELATED CONTENT Cogan Syndrome (Related Key Topic) Cryoglobulinemia (Related Key Topic) Eosinophilic Granulomatosis with Polyangiitis (Related Key Topic) Giant Cell Arteritis (Related Key Topic) Granulomatosis with Polyangiitis (Related Key Topic) IgA Vasculitis (Related Key Topic) Kawasaki Disease (Related Key Topic) Microscopic Polyangiitis (Related Key Topic) Polyarteritis Nodosa (Related Key Topic) Takayasu Arteritis (Related Key Topic) AUTHORS: Nicole B. Yang, MD, and Anthony M. Reginato, PhD, MD

Vasculitis, Systemic

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CLASSIFICATION OF VASCULITIDES

Behçet disease Giant cell arteritis Takayasu arteritis Polyarteritis nodosa and Kawasaki disease

ANCA-associated vasculitis Granulomatosis with polyangiitis Eosinophilic granulomatosis with polyangiitis Microscopic polyangiitis IgA vasculitis Cutaneous leukocytoclastic angiitis

Vena cava

Aorta

Anti-GBM disease Vein

Venule

Capillary

Medium or

Arteriole

Small size artery

large size artery

FIG. E2  The classification of vasculitides according to vessel size. ANCA, Antineutrophil cytoplasmic antibody; anti-GBM, anti–glomerular basement membrane; IgA, immunoglobulin A. (From Hochberg MC: Rheumatology, ed 7, Philadelphia, 2019, Elsevier.)

SUGGESTED READINGS Elfante E et al: One year in review 2018: systemic vasculitis, Clin Exp Rheumatol 36(Suppl 111):S12-S32, 2018. Kallenberg CG: Key advances in the clinical approach to ANCA-associated vasculitis, Nat Rev Rheumatol 10(8):484-493, 2014. Lyons PA et al: Genetically distinct subsets within ANCA-associated vasculitis, N Engl J Med 367:214-223, 2012. Schmidt WA, Blockmans D: Investigations in systemic vasculitis – the role of imaging, Best prac & Res Clin Rheum 32(1):63-82, 2018. Sharma P et al: Systemic vasculitis, Am Fam Physician 83:556-565, 2011. Specks U et al: Efficacy of remission-induction regimens for ANCA-associated vasculitis, N Engl J Med 369:417-427, 2013. Stone JH et al: Rituximab versus cyclophosphamide for ANCA-associated vasculitis, N Engl J Med 363:211-220, 2010. Stone JH et al: Trial of tocilizumab in giant-cell arteritis, N Engl J Med 377:317328, 2017. Wechsler M et al: EGPA mepolizumab study team. Mepolizumab or placebo for eosinophilic granulomatosis with polyangiitis, N Engl J Med 376:1921-1932, 2017.

FIG. E3  Leukocytoclastic vasculitis, palpable purpura. (From James W et al: Andrews’ diseases of the skin, clinical dermatology, ed 10, Philadelphia, 2005, Saunders.)

ALG BASIC INFORMATION DEFINITION The spectrum of chronic venous disease (CVD) ranges from varicose veins to leg edema and skin manifestations consisting of hyperpigmentation, eczema, lipodermatosclerosis, and venous ulcer. These latter venous-specific skin changes constitute an advanced form of CVD known as chronic venous insufficiency (CVI).

ICD-10CM CODES I87.2 Venous insufficiency (chronic) (peripheral) I87.8 Other specified disorders of veins I87.9 Disorder of vein, unspecified I83.10 Varicose veins of unspecified lower extremity with inflammation

EPIDEMIOLOGY & DEMOGRAPHICS • From 10% to 35% of adults in the United States have some form of CVI. • Venous ulcers are the complication of CVI that results in the greatest morbidity and affects 4% of people over the age of 65. • The population-based costs to the U.S. government for CVI treatment and venous ulcer care have been estimated at >$1 billion/yr. • In addition, 4.6 million workdays/yr are lost to chronic venous-related diseases. PHYSICAL FINDINGS & CLINICAL PRESENTATION The manifestations of CVI can be viewed using the internationally accepted classification system, CEAP (clinical, etiology, anatomy, and pathophysiology) (Table 1). The spectrum of cutaneous changes of CVI in the affected leg include: • Varicose eczema: The most common and earliest sign, this involves the skin above the medial ankle and consists of pruritic, red, and scaly eczematous patches and plaques. • Hyperpigmentation: Caused by the breakdown of red blood cells and leads to hemosiderin deposition and dark staining of the skin (Fig. E1). • Atrophie blanche: Usually presents as hypopigmented white patches with focal red punctate dots or telangiectasia surrounded by hyperpigmentation. Skin in this condition is avascular and prone to ulceration (Fig. E2). • Lipodermatosclerosis: A chronic, brawny induration of the skin and underlying fat that usually involves the skin from medial malleolus up to the lower border of the calf. Progression of the disease leads to an “inverted champagne bottle” appearance. The induration and lack of perfusion of the skin in this area make it susceptible to ulcer formation.

TABLE 1  CEAP Classification Clinical Classification C0 No visible or palpable signs of venous disease C1 Telangiectasias or reticular veins C2 Varicose veins; diameter >3 mm C3 Edema C4 Changes in skin and subcutaneous tissue: Pigmentation, eczema, lipodermatosclerosis, or atrophie blanche C5 Healed venous ulcer C6 Active venous ulcer Each limb is further classified as asymptomatic (A) or symptomatic (S) Etiologic Classification EC Congenital EP Primary ES Secondary (post-thrombotic) EN No venous cause identified Anatomic Classification AS Superficial veins AP Perforator veins AO Deep veins AN No venous location identified Pathophysiologic Classification PR Reflux PR Obstruction PR,O Reflux and obstruction PN No venous pathophysiology identifiable CEAP, Clinical-Etiological-Anatomical-Pathophysiological. From Fillit HM: Brocklehurst’s textbook of geriatric medicine and gerontology, ed 8, 2017, Elsevier.

ETIOLOGY • CVI occurs as a result of sustained venous hypertension in the leg, which can be caused by the following: 1. Primary: Vein valve failure with reflux in the superficial venous system or perforating veins (most common cause of CVI). 2. Secondary: Post-thrombotic syndrome in which a deep vein thrombosis causes outflow obstruction or 3.  Combination of the two previous processes. • This sustained elevation in venous pressure or venous hypertension results in pathologic effects in the skin and subcutaneous tissues such as edema, eczema, hyperpigmentation, fibrosis, and ultimately venous ulceration.

DIAGNOSIS The diagnosis and evaluation of CVI are directed primarily by a detailed history and physical examination.

DIFFERENTIAL DIAGNOSIS • Contact dermatitis • Atopic dermatitis • Cellulitis • Dermatophyte infection • Pretibial myxedema • Nummular eczema

• Xerosis • Asteatotic eczema

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V

WORKUP The primary goal is to identify the cause of sustained venous hypertension. Fig. 3 describes the evaluation and management of chronic venous insufficiency. LABORATORY TESTS Generally not indicated IMAGING STUDIES • Evaluation of the patient is performed in the standing position with duplex ultrasonography to identify reflux in the superficial, deep, and perforating veins as well as obstruction of the deep veins. • No exam of a leg with CVI is complete without palpation of pulses and/or determination of ankle-brachial index (ABI).

TREATMENT NONPHARMACOLOGIC THERAPY • Leg elevation above heart level for 30 min three to four times a day • Weight reduction because obesity is a risk factor for deep vein thrombosis and CVI • Walking exercises to improve calf function • Physical therapy to improve ankle joint mobility • For weeping skin lesions, wet-to-dry dressing changes ACUTE GENERAL Rx • The fundamental role of compression in the treatment of CVI is well recognized and has been validated by randomized controlled trials (RCTs). • The beneficial effects of gradient compression stockings (decrease in edema and control of discomfort) are due to their effect on microvascular hemodynamics and Starling forces. • Below-knee compression stocking with a gradient of at least 20 to 30 mm Hg will control edema, alleviate pain, and improve the quality of life in CVI patients. • Compression stockings are contraindicated in patients with an ABI of 500,000 people suffer from stasis ulcers. RISK FACTORS • Obesity • Increasing age • Family history of chronic venous insufficiency • History of deep venous thromboembolism PHYSICAL FINDINGS & CLINICAL PRESENTATION Venous ulcers are most commonly located in the lower leg just above the ankle (gaiter region). They are a partial-thickness, irregularly shaped wound with well-defined borders with granulation tissue and fibrin present in the ulcer base (Fig. E1). Venous ulcers are relatively painless and are surrounded by brown-stained skin and/or dry, itchy, and reddened skin. In about 50% of patients, there are visible varicose veins in an aching, swollen leg. ETIOLOGY The exact mechanism of the role of venous hypertension in the etiology of venous ulcers is not certain. Hemodynamic forces such as venous hypertension, circulatory stasis, and modified conditions of shear stress appear to play an important role in an inflammatory reaction accompanied by leukocyte activation that clinically leads to fibrosclerotic remodeling of the skin and then to ulceration.

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • Arterial ulcer • Neurotrophic ulcers (located predominantly in the foot)

WORKUP • The history and clinical signs and symptoms of leg ulcers are often misleading and may not differentiate venous ulcers from other leg ulcers; about 30% of leg ulcers are not of venous origin. • Measurement of the ankle-brachial index (ABI) is essential in excluding peripheral arterial disease (PAD), which can be present in 20% of patients and is required before starting compression therapy. Arterial insufficiency is suggested by an ABI 30 msec in V1 or V2 → VT

AV dissociation → VT

Initial R wave in aVR → VT

Any Q in V6 → VT

QRS width >140 msec → VT

>60 msec to S wave nadir in V1 or V2 → VT

Left axis deviation >−30 degrees → VT

Absence of RS complex in all precordial leads → VT Longest R/S interval >100 msec in any precordial lead → VT AV dissociation → VT

Notched downstroke S wave in V1 or V2 → VT

If RBBB morphology, monophasic or biphasic QRS in V1 → SVT or R-to-S ratio of 40 msec in duration → VT Slurred or notched S in V1 or V2 → VT Beginning Q or QS in V6 → VT

aVR with initial r or q >40 msec in duration → VT aVR with a notch on the descending limb of a negative-onset and predominantly negative QRS in aVR → VT In aVR, mV of initial 40 msec divided by terminal 40 msec (vi/vt ≤1) → VT

LBBB, Left bundle branch block; RBBB, right bundle branch block; VT, ventricular tachycardia. †Kindwall KE, Brown J, Josephson ME: Electrocardiographic criteria for ventricular tachycardia in wide complex left bundle branch block morphology tachycardias, Am J Cardiol 61:1279, 1988. ‡Wellens HJ, Bär FW, Lie KI: The value of the electrocardiogram in the differential diagnosis of a tachycardia with a widened QRS complex, Am J Med 64:27, 1978. §Brugada P et al: A new approach to the differential diagnosis of a regular tachycardia with a wide QRS complex, Circulation 83:1649, 1991. ‖Vereckei A et al: New algorithm using only lead aVR for differential diagnosis of wide QRS complex tachycardia, Heart Rhythm 5:89, 2008. From Zipes DP: Braunwald’s heart disease, a textbook of cardiovascular medicine, ed 11, Philadelphia, 2019, Elsevier.

CHRONIC Rx Chronic therapy of patients with VT usually requires multiple therapeutic modalities, including the ICD, antiarrhythmic drugs, catheter ablation, and surgery. An implantable cardioverter-defibrillator (ICD) is indicated for all patients who survive monomorphic VT in the setting of structural heart disease or prior MI, since it indicates the presence of a scar and risk of subsequent arrhythmias. Patients with idiopathic VT and structurally normal hearts generally do not require an ICD, but in cases of syncope associated with VT that cannot be successfully treated with ablation, it may be considered. Management of hemodynamically stable VT in patients with prior MI and normal LVEF remains under debate, but there is a consensus of considering VT ablation as initial therapy before ICD placement. For polymorphic VT, a reversible cause such as ischemia or electrolyte disturbances can sometimes be found, and an ICD may not be appropriate under these circumstances. Chronic therapy with antiarrhythmic medications such as amiodarone, mexiletine, or sotalol may be needed even after ICD implantation if the patient presents with multiple appropriate shocks. No antiarrhythmic drug has shown mortality benefit in patients with monomorphic VT except beta-blockers. Use of antiarrhythmic medications is thus limited as an adjunct to catheter ablation in patients who cannot receive

an ICD or in patients with frequent arrhythmia and ICD shocks. Catheter ablation of VT, particularly if performed early after first appropriate ICD discharge, is also very effective in preventing further ICD discharges and is associated with improved acute and long-term outcomes. For patients with refractory VT, surgical cardiac sympathetic denervation may be beneficial.

DISPOSITION Patients with sustained VT, either monomorphic or polymorphic, should always be managed in an intensive care unit due to the risk of degeneration to a hemodynamically unstable rhythm. An electrophysiologist should be consulted. REFERRAL All patients with VT or NSVT should be referred to a cardiologist or a cardiac electrophysiologist.

PEARLS & CONSIDERATIONS COMMENTS • Use of antiarrhythmic drugs, especially IC agents, to treat NSVT is associated with increased mortality (CAST trial), while beta blockers have been shown to be helpful. • In patients with coronary disease, NSVT has not been shown to have an adverse significance if LVEF is >40%. If the EF is below

40%, the MUSTT trial showed a benefit of EP-guided ICD therapy over antiarrhythmic agents such as mexiletine, propafenone, sotalol, or amiodarone. Patients with LVEF 1.4 or S wave amplitude >1.2 mV “Transition break,” specifically a loss of R from leads V1 to V2 (QS or rS) with prominent R by V3 (suggests near anterior interventricular vein) Tall R wave in the inferior leads Larger Q wave ratio in aVL/aVR Larger R/S amplitude in lead V2 Larger Q wave ratio in aVL/aVR Larger R/S amplitude in lead V2 LBBB morphology and inferior or superior axis R wave in lead I R or r with overall positive polarity in aVL Later precordial transition (>V3) LBBB morphology and inferior axis Large R wave in lead I R wave with flat/positive polarity or “w” pattern in aVL RBBB pattern with concordance in leads V1 to V6 Anterior MAVT: positive QRS polarity in leads II, III, and aVF and negative QRS polarity in leads I and aVL Posterior or posteroseptal MAVT: negative QRS polarity in leads II, III, and aVF and positive QRS polarity in leads I and aVL

Left ventricular outflow tract (LVOT)

Left aortic cusp

Right aortic cusp Aortomitral continuity

Epicardial

Pulmonary artery

Tricuspid annular

Tricuspid inflow or parahisian

Mitral annular (MA)

Fascicular VT Left posterior fascicle

Left anterior fascicle Left septal Papillary Muscle VT Posterior papillary muscle Anterior papillary muscle Crux VT

RBBB and left axis deviation (LAFB pattern) rsR′ in V1 q in I and aVL Narrow QRS ≤140 msec RBBB and right axis deviation (LPFB pattern) Narrow QRS 90 days p revascularization

-adrenergic blocker

-adrenergic blocker Revascularize >40 days p MI

40 days p MI

ARVC

-adrenergic blocker See hypertrophy, cardiomyopathy

Time after 9 mos LVEF 35%

See myocardial infarction

-adrenergic blocker ICD PM if bradycardia Genotype -specific therapy Consider K or Mg supplementation

ICD

LVEF >35%

-adrenergic blocker

See arrhythmogenic ventricular tachycardia topic

See brugada syndrome

FIG. E4  Nonsustained ventricular tachycardia. ARVC, Arrhythmogenic right ventricular cardiomyopathy; CM, cardiomyopathy; CPVT, catecholaminergic polymorphic ventricular tachycardia; EP, electrophysiologic study; HCM, hypertrophic cardiomyopathy; ICD, implantable cardioverter defibrillator; LVEF, left ventricular ejection fraction; MI, myocardial infarction; NSVT, nonsustained ventricular tachycardia; PM, pacemaker. (Modified from Olshansky B et al: Arrhythmia essentials, ed 2, Philadelphia, 2017, Elsevier.)

TABLE E5  Management of Nonsustained Monomorphic and Polymorphic Ventricular Tachycardia Setting

Therapy

Comments

Normal LV function

• No symptoms, no heart disease: No therapy • Young patient with bidirectional (or polymorphic) VT that may be life-threatening (CPVT): beta-adrenergic blocker • Symptoms of palpitations, no heart disease: beta-adrenergic blocker (e.g., acebutolol, 200-800 per day) • Idiopathic LV fascicular tachycardia (RBBB left axis QRS morphology): Verapamil • If LBBB (inferior axis morphology), beta-adrenergic blocker is first line. Other drugs: Sotalol (started in hospital), propafenone, flecainide, amiodarone. • RF ablation is curative for this type of VT in more than 95% if it can be initiated and mapped in the EP laboratory. • CAD, no symptoms: beta-adrenergic blocker, no additional antiarrhythmic therapy • CAD with symptoms, beta-adrenergic blocker, sotalol, amiodarone (started in the hospital) • Polymorphic NSVT 1. In the setting of long QT with syncope, treatment is required. 2. Genotyping is available. 3. Beta-adrenergic blockers are the first choice for long QT type I. 4. ICD is indicated for LQT2 or LQT3 with syncope or family history of sudden death

• Multiple clinical scenarios exist depending on the age of patient, heart disease, and symptoms. • If symptoms persist despite beta-adrenergic blockers or if they are not tolerated, nondihydropyridine calcium channel blockers can be utilized. • Idiopathic VT may occur in repetitive monomorphic variety and be symptomatic. 1. Not life-threatening. 2. Is exacerbated by exercise, mental stress, and catecholamines. • Idiopathic polymorphic VT in the young can be potentially life-threatening. 1. Treat with beta-adrenergic blocker. 2. Consider genotyping for CPVT. • Consider RV cardiomyopathy (dysplasia) with LBBB/ noninferior axis morphology. • Consider ischemia. • The 12-lead morphology is helpful. 1. If LBBB with inferior axis, it is likely from the RV or LV/aortic cusp outflow tract in normal hearts and is ablatable. 2. If QRS is negative in I and aVL, it may be arising from the septum. 3. If it is positive in I and aVL, it may be arising from the free wall and may be adenosine sensitive. 4. VTs may respond to beta-adrenergic blockers, verapamil, and most antiarrhythmic drugs. • If it is a RBBB left axis QRS pattern, it may be a reentrant idiopathic VT from the LV apical septum. 1. Thought to be due to fascicular reentry. 2. Can be cured with RF ablation. 3. Is sensitive to verapamil (only use if known to be this type of VT). • Even patients with normal hearts may be at slightly higher risk for CA compared with the general population, but further evaluation and therapy is not beneficial. • Polymorphic tachycardia may be due to ischemia or infarction and may be transient.

Ventricular Tachycardia

1447.e8

TABLE E5  Management of Nonsustained Monomorphic and Polymorphic Ventricular Tachycardia Setting

Therapy

Comments

Ischemic cardiomyopathy

• For LVEF ≤30%, 40 days after MI or 3 months after revascularization, ICD implantation is indicated for primary prevention • For LVEF ≤35%, NYHA FC II-III, ICD implantation is recommended for primary prevention • For LVEF ≤40%, EP study is recommended, and if sustained VT is induced, ICD should be implanted. • For NYHA FC II-ambulatory IV heart failure, LVEF ≤35%, LBBB and QRS duration ≥130 ms, cardiac resynchronization therapy is recommended after optimal medical therapy for at least 3 months or 40 days after MI. • Beta-adrenergic blockers, ACE inhibitors, and other goal-directed medical therapy for heart failure. • For LVEF ≤35%, NYHA FC II-III, ICD is recommended. • For NYHA FC III-IV heart failure, LVEF ≤35%, and QRS duration >120 ms, cardiac resynchronization therapy is recommended. • Beta-adrenergic blocker, especially if symptomatic • Memory loop event recorders may be beneficial in correlating symptoms with arrhythmias. • No indication for amiodarone or other antiarrhythmic drugs if asymptomatic • Start amiodarone, if symptomatic, in the hospital. • ICD if 1. Septum >30 mm 2. Syncope 3. NSVT 4. Family history of sudden death 5. High-risk genotype 6. If prior CA 7. Sustained VT/VF 8. LV apical aneurysm 9. End-stage HCM with LVEF 50% but with a high rate of long-term recurrence 1. Used as adjunctive therapy to ICD implantation 2. May be used to reduce recurrent ICD shocks • Adjunctive antiarrhythmic drugs include amiodarone or sotalol

• Monomorphic VT 1. May not increase long-term mortality. 2. Can be ischemia induced but this is rare (95%) with chronic VT due to CAD will be inducible in the EP laboratory, but this does not change treatment strategy.

ARVC, Arrhythmogenic right ventricular cardiomyopathy; BP, blood pressure; EP, electrophysiologic; ICD, implantable cardioverter defibrillator; IV, intravenous; LBBB, left bundle branch block; LV, left ventricular; MI, myocardial infarction; MRI, magnetic resonance imaging; RBBB, right bundle branch block; RF, radiofrequency; RV, right ventricular; VF, ventricular fibrillation; VT, ventricular tachycardia. From Olshansky B et al: Arrhythmia essentials, ed 2, Philadelphia, 2017, Elsevier.

Ventricular Tachycardia

1447.e10

Sustained VTAcute Management Stable

Unstable

IV amiodarone IV lidocaine IV procainamide

Shock (anesthetize if awake)

Pace terminate or shock (anesthetize if awake)

Recurrent or refractory

IV amioda rone IV lidocaine IV procainamide IV Mg2+ (especially if LQT) IV epinephrine Correct underlying ischemia

Resolution of VT

Yes

No

Recurrent VT

Shock Consider temporary PM for pace termination of recurrences

Consider additional antiarrhythmic drugs Correct electrolytes Optimize oxygenation, consider sedation, intubation Evaluate for ischemia/MI Correct any proarrhythmic drugs Beta-blockade as tolerated Consider catheter ablation

Resolution of VT

Yes

No

Correct electrolytes Optimize oxygenation, sedation, intubation Evaluate for ischemia/MI Correct any proarrhythmic drugs Beta-blockade as tolerated Consider additional antiarrhythmic drugs Consider mechanical hemodynamic support (e.g., IABP) Consider catheter ablation

FIG. E5  Sustained ventricular tachycardia—acute management. IABP, Intra-aortic balloon pump; IV, intravenous; LQT, long QT interval; MI, myocardial infarction; PM, pacemaker; VT, ventricular tachycardia. (From Olshansky B et al: Arrhythmia essentials, ed 2, Philadelphia, 2017, Elsevier.)

Ventricular Tachycardia SUGGESTED READINGS Al-Khatib SM et  al: 2017 AHA/ACC/HRS Guideline for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: a report of the American College of Cardiology/American heart association Task Force on Clinical Practice Guidelines and the heart rhythm Society, Heart Rhythm 2017. Romero J et al: Early versus late referral for catheter ablation of ventricular tachycardia in patients with structural heart disease: a systematic review and metaanalysis of clinical outcomes, JACC Clin Electrophysiol 4(3):374-382, 2018. Sapp JL et al: Ventricular tachycardia ablation versus escalation of antiarrhythmic drugs, N Engl J Med 375:111-121, 2016. Shivkumar K: V Catheter ablation of ventricular arrhythmias, N Engl J Med 380(16):1555-1564, 2019.

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1448

Vertebral Compression Fractures BASIC INFORMATION DEFINITION Vertebral compression fractures (VCFs) are defined as fractures of spinal vertebrae in which a bony surface is driven toward another bony surface. These fractures are classified as radiographic reductions in vertebral body height of more than 15%. SYNONYMS Thoracolumbar vertebral compression fractures Osteoporotic fractures VCF ICD-10CM CODES M80.0 Post-menopausal osteoporosis with pathologic fracture M80.4 Drug-induced osteoporosis with pathological fracture M80.5 Idiopathic osteoporosis with pathological fracture M80.8 Other osteoporosis with pathological fracture M80.9 Unspecified osteoporosis with pathological fracture S32.009A  Unspecified fracture of unspecified lumbar vertebra, initial encounter for closed fracture S22.009A Unspecified fracture of unspecified thoracic vertebra, initial encounter for closed fracture

EPIDEMIOLOGY & DEMOGRAPHICS Approximately 700,000 VCFs occur in the United States each yr, and they affect up to 25% of postmenopausal women. They are the most common complication of osteoporosis. The prevalence increases with age, reaching a peak of 40% to 50% among women aged >80 yr. Compression fractures are also a major concern among men, although their rates of VCF are lower. RISK FACTORS: • Modifiable: Tobacco or alcohol use, osteoporosis, estrogen deficiency (i.e., early menopause, bilateral oophorectomy, premenopausal amenorrhea for >1 yr), frailty, impaired vision, abusive situations, inadequate physical activity, low body mass index, and deficiency of vitamin D or calcium. • Nonmodifiable: Advanced age, female gender, dementia, Caucasian descent, history of fractures in adulthood and among firstdegree relatives, and falls. PHYSICAL FINDINGS & CLINICAL PRESENTATION • Asymptomatic: Most VCFs are asymptomatic, except for height loss or kyphosis (i.e., dowager’s hump [Fig. 1]), which is often a sign of multiple VCFs and height loss of >6 cm has a sensitivity/ specificity of 94% and 30%, respectively, for VCF. • Symptomatic: When symptomatic, VCFs usually present as acute back pain after activity (e.g., bending, lifting) or coughing; neck strain and radicular rib pain may also be present.

ETIOLOGY • VCFs take place when the combination of bending and the axial load on the spine exceed the strength of the vertebral body. • The primary etiology of VCF is osteoporosis, though a pathologic fracture from an underlying malignancy, typically metastatic disease, must be ruled out.

DIAGNOSIS DIFFERENTIAL DIAGNOSIS • Osteoporosis • Malignancy, most often metastases • Hyperparathyroidism • Osteomalacia • Granulomatous diseases (e.g., tuberculosis) • Hematologic/oncologic diseases (e.g., multiple myeloma, primary bone malignancy) WORKUP • Only one third of VCFs are diagnosed. Guidelines for patient selection for vertebral fractural assessment are described in Box 1. • VCFs can be clinically suspected from the history and physical alone, though they are often diagnosed incidentally by imaging performed for another indication. • There may or may not be a specific injury or a remembered event that led to the VCF. LABORATORY TESTS Tests to rule out infection or cancer may be helpful, such as a complete blood count, an erythrocyte sedimentation rate, an alkaline phosphatase level, and a C-reactive protein level; these tests can be reserved for individuals for whom there is clinical suspicion. IMAGING STUDIES • Plain frontal and lateral radiographs (x-rays) are the initial imaging method and may be sufficient, particularly when no neurologic abnormalities are present. MRI and computed tomography (CT) scans may be

A

uncomfortable or painful for the patient, especially during the acute phase. • Although CT scans are not routinely necessary for the diagnosis, they can be helpful for visualizing fractures that are not seen on plain films, for evaluating the integrity of the posterior vertebral wall, for ruling out other causes of back pain, for detecting spinal canal narrowing, and for assessing instability. • MRI may be useful when spinal cord compression is suspected, if neurologic symptoms are present, or to distinguish malignancy from osteoporosis (e.g., in patients 50,000–100,000/mm3 >75% PMN Gram stain + aerobic, anaerobic culture, and sensitivity studies Blood culture: NGSA: up to 90% + GA: up to 50% + If GA suspected: culture and PCR for N. gonorrhoeae from cervix, urethra, rectum, throat (80% +)

Start antibiotic therapy

FIG. 98  Clinical evaluation of infections of soft tissues, joints, and bone. CBC, Complete blood count; CT, computed tomography; ESR, erythrocyte sedimentation rate; GA, gonococcal arthritis; HIV, human immunodeficiency virus; IV, intravenous; MRI, magnetic resonance imaging; NGSA, nongonococcal septic arthritis; OA, osteoarthritis; PCR, polymerase chain reaction; PET, positron emission tomography; PMN, polymorphonuclear leukocyte; RA, rheumatoid arthritis. (From Goldman L, Schafer AI: Goldman Cecil medicine, ed 25, Philadelphia, 2016, Saunders.)

Pain Swelling Erythema Drainage Fever Risk factors

CBC with differential ESR Blood cultures Imaging: ultrasound, PET, CT, and MRI

If bony involvement present, referral for needle biopsy and aspiration

Culture and sensitivity if positive

Infectious Diarrhea

ICD-10CM # A09 Infectious gastroenteritis and colitis, unspecified

1731

Diarrhea, nausea, or vomiting

Assess: • Duration of symptoms • Severity (dehydration, fever, blood, weight loss, sensorium) • Epidemiologic features (travel, diet, exposures, medications, outbreaks, immunosuppression)

Community-acquired or traveler's diarrhea

Watery diarrhea

Culture or test for: Salmonella Shigella Campylobacter STEC (especially if bloody stool) C. difficile (especially if recent antibiotics) Entamoeba histolytica (if epidemiologic exposure)

Treat symptomatically without further testing unless severe disease or as part of outbreak, such as cholera

Persistent diarrhea, particularly in immunocompromised host

Culture or test for Clostridium difficile Consider noninfectious causes

Culture or test for: Giardia Cryptosporidium Cystoisospora belli Cyclospora cayetanensis Microsporidia (in immunocompromised host) M. avium complex (in immunocompromised host) C. difficile (rare) Consider lactase deficiency, small bowel bacterial overgrowth, and malabsorption syndromes

FIG. 99  Approach to diagnosis of infectious diarrhea. STEC, Shiga toxin-producing Escherichia coli. (From Bennett JE, Dolin R, Blaser MJ: Mandell, Douglas, and Bennett’s principles and practice of infectious diseases, ed 8, Philadelphia, 2015, Saunders.)

Clinical Algorithms

Fever or blood in stool

Nosocomial diarrhea (after 3rd hospital day)

III

1732

IntraabdominalInfection, Suspected INTRAABDOMINAL INFECTION, SUSPECTED

ICD-10CM # A08.5 Other specified intestinal infections

H&P

Peritoneal signs

Localized

Diffuse

RUQ

RLQ

LLQ

U/S

Typical hx of appendicitis

CT scan

Cholecystitis

No

Yes

CT scan

Abx/OR

No

Yes

CT scan

OR

Abscess (Fig. 101)

Upright CXR: Free air

Diverticulitis

Appendicitis

No

Yes

Observe vs. discharge

Abx

Abscess

IR drainage

No

Yes

CT scan

OR

Pathology identified

No Close observation Consider laparoscopy Operate promptly if no improvement

FIG. 100  Algorithm for the diagnosis and management of patients with suspected intraabdominal infection. Abx, Antibiotics; CT, computed tomography; CXR, chest radiograph; H&P, History and physical exam; hx, history; IR, interventional radiology; LLQ, left lower quadrant; RLQ, right lower quadrant; RUQ, right upper quadrant; U/S, ultrasound. (From Cameron JL, Cameron AM: Current surgical therapy, ed 10, Philadelphia, 2011, Saunders.)

A

B

FIG. 101  Axial (A) and coronal (B) postcontrast computed tomographic images showing bilateral tuboovarian abscesses (arrows). (From Fielding JR et al: Gynecologic imaging, Philadelphia, 2011, Saunders.)

Yes Treat accordingly

Joint Effusion

ICD-10CM # M25.40 Effusion, unspecified joint

1733

Joint effusion

Arthrocentesis and analysis of fluid (Table 29)

Suspected gonococcal arthritis

Suspected Lyme disease

Elevated total protein concentration

WBC 200-10,000, PMNs 50%

Lyme titer

Elevated WBC 10,000, PMNs 50% Glucose level 40 mg/dl over serum glucose level

Examination for crystals under polarized light

Noninflammatory Calcium pyrophosphate

Serology testing or Thayer-Martin cultures

Rule out inflammatory or septic arthritis

Monosodium urate, needle-shaped, strongly birefringent

Rule out infectious process

Confirm by negative Gram stain and negative C&S

Pseudogout

Gram stain, C&S

TABLE 29  Indications for Arthrocentesis Undiagnosed Arthritis with Effusion Characterize type of arthritis • Noninflammatory (WBC 2000/mm3) • Septic (WBC >50,000/mm3) • Definitive diagnosis • Gout (urate crystals) • Pseudogout (calcium pyrophosphate dihydrate crystals) • Septic arthritis (Gram stain [rare] or culture) Undiagnosed Arthritis without Effusion May be definitive in gout (knee, first metatarsophalangeal joint) Patient with Known Diagnosis Septic arthritis (repeated taps for adequate drainage) Other types of arthritis for symptomatic relief (with or without injection)* WBC, White blood cells. *Most studies show improved effect if fluid is aspirated before injection. From Firestein GS et al: Kelley’s textbook of rheumatology, ed 9, Philadelphia, 2013, Saunders.

Clinical Algorithms

FIG. 102  Joint effusion. See also Section IV, Arthrocentesis Fluid. C&S, Culture and sensitivity; PMNs, polymorphonuclear leukocytes; WBC, white blood cell count.

Gout

III

1734

Joint Pain and Swelling

ICD-10CM # M25.40 Effusion, unspecified joint

Joint pain and swelling Consider arthrocentesis (see Table 31 for contraindications to arthrocentesis)

Synovial fluid studies Cell counts Crystals Gram stain Culture

Noninflammatory WBC 2000/mm3

Inflammatory WBC 2000/mm3

Other clinical features History Physical findings Laboratory tests Imaging studies

Inflammatory arthritis Differential: Septic arthritis Rheumatoid arthritis Systemic lupus erythematosus Seronegative spondyloarthropathies Crystal-induced arthritis Lyme arthritis

Noninflammatory arthritis Differential: Osteoarthritis Meniscal and/or ligament tears Avascular necrosis

FIG. 103  Diagnostic approach for swollen joints. WBC, White blood cell count. (From Goldman L, Schafer AL [eds]: Cecil textbook of medicine, ed 24, Philadelphia, 2012, Saunders.)

TABLE 30  Clinical and Radiological Findings in Joint Disease Condition

Site of Involvement

Discriminatory Findings

Primary osteoarthritis (F>M • >45 years)

Hands

PIP and DIP joint involvement (Heberden and Bouchard nodes) • no osteopenia Joint space narrowing • subchondral sclerosis • subchondral cysts • marginal osteophytes Degenerative disc disease • spondylosis deformans • apophyseal joint involvement • spinal stenosis • foraminal stenosis PIP and DIP joint involvement • joint ankylosis • ‘gull-wing’ deformities (central erosions and marginal ­osteophytes) Symmetrical arthritis • MCP and PIP joint involvement • periarticular (early) and diffuse (late) osteopenia • marginal erosions • subluxation (swan neck and boutonnière deformities) • periostitis is uncommon Joint space narrowing • marginal erosions • synovial cysts • protrusio acetabulae Atlantoaxial subluxation

Large joints (e.g., hip, knee)

Spine

Erosive osteoarthritis (affects middle-aged females)

Hands

Rheumatoid arthritis (F>M • Rh factor ­positive)

Hand and wrist

Large joints

Spine

Joint Pain and Swelling—cont’d

ICD-10CM # M25.40 Effusion, unspecified joint

1735

TABLE 30  Clinical and Radiological Findings in Joint Disease—cont’d Site of Involvement

Discriminatory Findings

Juvenile idiopathic arthritis (M = F • affects children)

Hands

Joint ankylosis • florid periosteal reaction • osteopenia Abnormalities of growth and maturation • epiphyseal overgrowth and premature closure of the physis • widened intercondylar notch Apophyseal joint fusion • atlantoaxial subluxation “Sausage” digit • DIP joint involvement • terminal tuft erosion • pencil-in-cup deformity • joint ankylosis • arthritis mutilans • periosteal reaction • no osteopenia Asymmetric or unilateral sacroiliitis Coarse syndesmophytes Hallux involvement • periosteal reaction • calcaneal erosions • osteopenia not prominent Coarse syndesmophytes Asymmetric or unilateral sacroiliitis Bilateral symmetrical sacroiliitis • ankylosis Anterior vertebral body squaring • syndesmophytes • paravertebral ossification • bamboo spine “Whiskering” of the iliac crests and ischial tuberosities Symmetrical sacroiliitis MTP joint of the great toe • juxta-articular erosions • punched-out lesions with an overhanging margin • no periarticular osteopenia • tophi Degenerative changes • chondrocalcinosis • paucity of subchondral sclerosis Periarticular calcification

Large joints (e.g., knee) Cervical spine Psoriatic arthritis (M>F • nail changes • HLA-B27 +ve)

Reites syndrome (affects young male adults)

Ankylosing spondylitis (M>F • affects young adults • HLA-B27 +ve in 95%)

Upper extremities (e.g., hands)

SI joints Spine Lower extremities (e.g., foot)

Spine SI joints SI joints Spine

Enteropathic arthropathies Gout (M>F)

Pelvis SI joints Hands and feet (especially the great toe)

CPPD crystal deposition disease (M = F)

Any peripheral joint • predilection for the knee

HA crystal deposition disease (M = F)

Predilection for the shoulder (supraspinatus tendon) Hands

Hemochromatosis (M>F)

Alkaptonuria (ochronosis) (M = F) Systemic lupus erythematosus (F>M • affects young adults) Scleroderma (F>M • affects adults)

Intervertebral discs • SI joints • large joints Hands Hands

Mixed connective tissue disease (overlap syndrome) Multicentric reticulohistiocytosis (F>M)

Hands

Polymyositis/dermatomyositis

Proximal extremities Hands Distal and middle phalanges of the hands and feet

Sarcoidosis

Hands and feet

2nd and 3rd MCP joint involvement (“squared” metacarpal heads) • joint space narrowing • “hooklike” osteophytes • numerous subchondral cysts Degenerative changes: disc calcification • joint space narrowing • periarticular sclerosis Reversible MCP joint subluxation IP joint arthritis • acroosteolysis • soft tissue calcifications PIP joint, MCP joint, mid-carpal involvement • soft tissue swelling, calcifications, or atrophy DIP joint and carpal involvement • soft tissue swelling • articular erosions • no osteopenia Soft tissue calcification DIP joint erosions Punched-out cystlike lesions • “lacelike” appearance

Clinical Algorithms

Condition

III

1736

Joint Pain and Swelling—cont’d

ICD-10CM # M25.40 Effusion, unspecified joint

TABLE 30  Clinical and Radiological Findings in Joint Disease—cont’d Condition

Site of Involvement

Discriminatory Findings

Hemophilic arthropathy (affecting males— but with female carriers)

Predilection for large joints (e.g., knee)

Neuropathic arthropathy

Any joint

Hypertrophic osteoarthropathy

Tubular bones (radius and ulna > tibia and fibula)

Epiphyseal overgrowth • juxtaarticular osteopenia • erosion and cartilage destruction • widened intercondylar and trochlear notches • squared patella 5 “Ds”: normal bone Density • joint Distension • bony Debris • joint Disorganization • Dislocation Diaphyseal and metaphyseal painful periostitis

From Grant LA, Griffin N: Grainger & Allison’s diagnostic radiology essentials, ed 2, Philadelphia, 2019, Elsevier.

TABLE 31  Contraindications to Arthrocentesis and Joint Injection Contraindication

Comment

Established infection in nearby structures (e.g., cellulitis, septic bursitis) Septicemia (theoretic risk of introducing organism into joint) Disrupted skin barrier (e.g., psoriasis) Bleeding disorder (not absolute, but use more care) Septic joint Prior lack of response Difficult-to-access joint

Sometimes gout mimics cellulitis, creating a confusing picture Need to tap suspected septic joints in septic patients Do not tap through lesions Risk of bleeding very low, even in patients taking warfarin Steroid injection contraindicated Relative contraindication Relative contraindication without imaging aid

From Firestein GS et al: Kelley’s textbook of rheumatology, ed 9, Philadelphia, 2013, Saunders.

Limb Ischemia, Acute

ICD-10CM # I73 Other specified peripheral vascular disease

1737

Diagnosis Symptoms

Pain Paresthesia Weakness or paralysis

Signs Absent pulses Pallor Cool skin Decreased sensation Decreased strength Limb blood pressure 60 in RAEB and RARS —

95%. For the differential diagnosis of ascites, refer to Section II. An ascitic fluid polymorphonuclear leukocyte count >500/μl is suggestive of SBP. A blood-ascitic fluid albumin gradient. Box 24 summarizes causes of peritoneal effusions. Useful criteria for evaluation of peritoneal lavage is summarized in Box 25. Recommended tests in peritoneal effusions are summarized in Box 26.

PARATHYROID HORMONE (PTH) Normal: Serum, intact molecule 10-65 pg/ml Plasma 1.0-5.0 pmol/L Elevated in: Hyperparathyroidism (primary or secondary), pseudohypoparathyroidism, anticonvulsants, corticosteroids, lithium, isoniazid (INH), rifampin, phosphates, Zollinger-Ellison syndrome, hereditary vitamin D deficiency Decreased in: Hypoparathyroidism, sarcoidosis, cimetidine, beta-blockers, hyperthyroidism, hypomagnesemia

Laboratory Tests

PARACENTESIS FLUID Testing and evaluation of results: Process the fluid as follows: Tube 1: LDH, glucose, albumin Tube 2: Protein, specific gravity Tube 3: Cell count and differential Tube 4: Save until further notice Draw serum LDH, protein, albumin. Gram stain, acid-fast bacilli stain, bacterial and fungal cultures, amylase, and triglycerides should be ordered only when clearly indicated; bedside inoculation of blood-culture bottles with ascitic fluid improves sensitivity in detecting bacterial growth. If malignant ascites is suspected, consider a carcinoembryonic antigen level on the paracentesis fluid and cytologic evaluation. In suspected spontaneous bacterial peritonitis (SBP) the incidence of positive cultures can be increased by injecting 10 to 20 ml of ascitic fluid into blood culture bottles. Peritoneal effusion can be subdivided as exudative or transudative based on its characteristics (see Section II).

1885

IV

Paracentesis Fluid

Parathyroid Hormone

Partial neurogenic diabetes insipidus Primary polydipsia Partial nephrogenic diabetes insipidus

1400

Urine osmolality (mOsm/kg)

1200

1000 2L 800

4L 6L

600

8L 10 L

400

12 L 200 16 L 0

0.5 1.0

5 10 Plasma vasopressin (pg/mL)

50

>50

FIG. 41  The relationship between urine osmolality (Uosm) and plasma arginine vasopressin (AVP/ADH) in patients with polyuria of diverse causes and severity. Each of the three categories of polyuria is described by its own family of sigmoid curves of differing heights. Differences in height within a family reflect differences in maximum concentrating capacity caused by “washout” of the medullary concentration gradient. They are proportional to the severity of the polyuria (indicated in liters per day at the right end of each plateau). The normal response is depicted in yellow. The three categories of polyuria differ principally in the ascending portion of the dose-response curve. In patients with partial neurogenic diabetes insipidus (DI), the curve lies to the left of normal, reflecting increased sensitivity to the antidiuretic effects of very low concentrations of plasma ADH. In contrast, in patients with partial nephrogenic DI, the curve lies to the right of normal, reflecting decreased sensitivity to ADH. In primary polydipsia, the relationship of Uosm to ADH remains relatively normal. (Redrawn from Bichet DG: Diabetes insipidus and vasopressin. In Moore WT, Eastman RC [eds]: Diagnostic endocrinology, ed 2, St Louis, 1996, Mosby, p 158, with permission.) (McPherson RA, Pincus MR: Henry’s clinical diagnosis and management by laboratory methods, ed 23, St Louis, 2017, Elsevier.)

BOX 23  Urine Osmolality in Common Clinical Situations High Urine Osmolality AKI or when assessing effective circulating volume Prerenal states Volume depletion (GI losses, renal losses, skin losses, third spacing) Heart failure Cirrhosis Hypoalbuminemia Hyponatremia Prerenal states Volume depletion (GI losses, renal losses, skin losses, third spacing) Heart failure Cirrhosis Hypoalbuminemia Syndrome of inappropriate ADH secretion Hypernatremia GI losses (vomiting, diarrhea, nasogastric tube, fistula) Skin losses (fever, exercise, ventilation) Sodium overload (received excess normal saline or sodium ­bicarbonate) Mineralocorticoid excess Seizures (↑ intracellular osmoles → water shifts → transient increase in serum Na) Low Urine Osmolality AKI or when assessing effective circulating volume Euvolemic or hypervolemic Established AKI Chronic kidney disease Hyponatremia In process of correcting hyponatremia Primary polydipsia Extremely low solute intake (tea and toast diet or beer potomania) Hypernatremia Osmotic diuresis (glucose, mannitol, urea) Loop diuretics Nephrogenic DI Central DI ADH, Antidiuretic hormone; AKI, acute kidney injury; DI, diabetes insipidus; GI, gastrointestinal. From Ronco C: Critical care nephrology, ed 3, Philadelphia, 2019, Elsevier.

The serum-ascites albumin gradient (serum albumin level-ascitic fluid albumin level [SAAG]) correlates directly with portal pressure and can also be used to classify ascites. Patients with gradients ≥1.1 g/dl have portal hypertension, and those with gradients ≤1.1 g/dl do not; the accuracy of this method is >95%. For the differential diagnosis of ascites, refer to Section II. An ascitic fluid polymorphonuclear leukocyte count >500/μl is suggestive of SBP. A blood-ascitic fluid albumin gradient. Box 24 summarizes causes of peritoneal effusions. Useful criteria for evaluation of peritoneal lavage is summarized in Box 25. Recommended tests in peritoneal effusions are summarized in Box 26.

PARATHYROID HORMONE (PTH) Normal: Serum, intact molecule 10-65 pg/ml Plasma 1.0-5.0 pmol/L Elevated in: Hyperparathyroidism (primary or secondary), pseudohypoparathyroidism, anticonvulsants, corticosteroids, lithium, isoniazid (INH), rifampin, phosphates, Zollinger-Ellison syndrome, hereditary vitamin D deficiency Decreased in: Hypoparathyroidism, sarcoidosis, cimetidine, beta-blockers, hyperthyroidism, hypomagnesemia

Laboratory Tests

PARACENTESIS FLUID Testing and evaluation of results: Process the fluid as follows: Tube 1: LDH, glucose, albumin Tube 2: Protein, specific gravity Tube 3: Cell count and differential Tube 4: Save until further notice Draw serum LDH, protein, albumin. Gram stain, acid-fast bacilli stain, bacterial and fungal cultures, amylase, and triglycerides should be ordered only when clearly indicated; bedside inoculation of blood-culture bottles with ascitic fluid improves sensitivity in detecting bacterial growth. If malignant ascites is suspected, consider a carcinoembryonic antigen level on the paracentesis fluid and cytologic evaluation. In suspected spontaneous bacterial peritonitis (SBP) the incidence of positive cultures can be increased by injecting 10 to 20 ml of ascitic fluid into blood culture bottles. Peritoneal effusion can be subdivided as exudative or transudative based on its characteristics (see Section II).

1885

IV

1886

Parietal Cell Antibodies Phosphate BOX 24  Causes of Peritoneal Effusions Transudates: Increased Hydrostatic Pressure or Decreased Plasma Oncotic Pressure Congestive heart failure Hepatic cirrhosis Hypoproteinemia (e.g., nephrotic syndrome) Exudates: Increased Capillary Permeability or Decreased Lymphatic Resorption Infections Primary bacterial peritonitis Secondary bacterial peritonitis (e.g., appendicitis, bowel rupture) Tuberculosis Neoplasms Hepatoma Lymphoma Mesothelioma Metastatic carcinoma Ovarian carcinoma Prostate cancer Trauma Pancreatitis Bile peritonitis (e.g., ruptured gallbladder) Chylous Effusion Damage to or obstruction of thoracic duct (e.g., trauma, lymphoma, carcinoma, tuberculosis and other granulomas [e.g., sarcoidosis, histoplasmosis], parasitic infestation) From McPherson RA, Pincus MR: Henry’s clinical diagnosis and management by laboratory methods, ed 23, St Louis, 2017, Elsevier.

BOX 25  Criteria for Evaluation of Peritoneal Lavage Positive Result Aspiration of >15 ml gross blood on catheter placement Grossly bloody lavage fluid RBC >100,000/μL after blunt trauma RBC >50,000/μL after penetrating trauma WBC >500/μL Amylase >110 U/dl Indeterminate Result Small amount of gross blood on catheter placement RBC 50,000-100,000/μL after blunt trauma RBC 1000-50,000/μL after penetrating trauma WBC 100-500/μL Negative Result RBC 25% and platelet count >50 K/microliter for the test to be performed.

Dosage

Asymptomatic Severe Hypophosphatemia Elemental 2.5 mg/kg body weight phosphate Symptomatic Severe Hypophosphatemia Elemental 5 mg/kg body weight phosphate

Administration Phosphate 0.9 mg/ml 1-3 g/day in 4 divided doses 1-3 g/day in 4 divided doses 30-70 ng/kg body weight per day IV over 6 hr IV over 6 hr

IV, Intravenously. From Skorecki et al: Brenner & Rector’s the kidney, ed 10, Philadelphia, 2016, Elsevier.

TABLE 79  Differential Diagnosis of Thrombocytopenia in Suspected Disseminated Intravascular Coagulation Differential Diagnosis DIC Sepsis without DIC Massive blood loss Thrombotic microangiopathy Heparin-induced thrombocytopenia Immune thrombocytopenia Drug-induced thrombocytopenia

Additional Diagnostic Clues Prolonged aPTT and PT, increased FDP, low levels of AT or protein C Positive (blood) cultures, positive sepsis criteria, hematophagocytosis in BM aspirate Major bleeding, low hemoglobin, prolonged aPTT and PT Schistocytes in blood smear, Coombs-negative hemolysis, fever, neurologic symptoms, renal insufficiency, coagulation test results usually normal, ADAMTS13 levels decreased Use of heparin, venous or arterial thrombosis, positive HIT test (usually immunoassay for heparinplatelet factor 4 antibodies), increase in platelet count after cessation of heparin; coagulation tests usually normal Antiplatelet antibodies, normal or increased number of megakaryocytes in BM aspirate, TPO decreased; coagulation tests usually normal Decreased number of megakaryocytes in BM aspirate or detection of drug-induced antiplatelet antibodies, increase in platelet count after cessation of drug; coagulation test results usually normal

ADAMTS13, A disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13; aPTT, activated partial thromboplastin time; AT, antithrombin; BM, bone marrow; DIC, disseminated intravascular coagulation; FDP, fibrin degradation product; HIT, heparin-induced thrombocytopenia; PT, prothrombin time; TPO, thrombopoietin. From Hoffman R: Hematology, basic principles and practice, ed 6, Philadelphia, 2013, WB Saunders.

COL/ADP: 70 to 120 sec COL/EPI: 75 to 120 sec Elevated in: Acquired platelet dysfunction, von Willebrand disease, anemia, thrombocytopenia, use of aspirin and NSAIDs

PLEURAL FLUID Testing and evaluation of results Pleural effusion fluid should be differentiated in exudate or transudate. The initial laboratory studies should be aimed only at distinguishing an exudate from a transudate. Tube 1: Protein, LDH, albumin. Tubes 2, 3, 4: Save the fluid until further notice. In selected patients with suspected empyema, a pH level may be useful (generally ≤7.0). See following for proper procedure to obtain a pH level from pleural fluid. A serum/effusion albumin gradient of ≤1.2 g/dl is indicative of exudative effusions, especially in patients with congestive heart failure (CHF) treated with diuretics.

Laboratory Tests

AD, Autosomal dominant; FGF-23, fibroblast growth factor 23; GM-CSF, granulocyte-­macrophage colony-stimulating factor; HHRH, hereditary hypophosphatemic rickets with hypercalciuria; Na/Pi-II, type II sodium-dependent phosphate cotransporter; PTHrP, parathyroid ­hormone-related peptide; VDDR, vitamin D-dependent rickets; VDR, vitamin D receptor. From Skorecki K et al: Brenner & Rector’s the kidney, ed 10, Philadelphia, 2016, Elsevier.

1889

IV

1890

Pleural Fluid

Potassium

TABLE 80  Antibody-Mediated Thrombocytopenic Disorders Caused by Autoantibodies (Immune Thrombocytopenia), Alloantibodies (Neonatal Alloimmune Thrombocytopenia), or Potentially Both (Posttransfusion Purpura) Immune Thrombocytopenia

Neonatal Alloimmune Thrombocytopenia

Immune reaction

Autoimmune

Alloimmune

Incidence

5 per 100,000 population

Principal antigenic target Nature of the antibody Mode of sensitization Sensitizing event

GPIIb/IIIa Intermittent Autoantibody Mostly unknown; some viral illnesses, chronic infection Uncommon Higher incidence in children and elderly adults; female predominance in early adulthood

40 per 100,000 births (or 1 per 2500) HPA-1a Persistent (past 1 yr) Alloantibody Exposure to fetal platelet antigens early in first pregnancy Common Majority affects fetus or newborn carrying the HPA-1a antigen

Bleeding frequency Epidemiology

Posttransfusion Purpura Features of both allo- and autoimmunity 1 per 100,000 blood transfusions HPA-1a plus autoantigens Persistent often at high titers Features of allo- and autoantibodies Blood transfusion (RBCs or platelets) 5-10 days earlier Very common Almost all are HPA-1bb women sensitized by previous transfusion or pregnancy

GP, Glycoprotein; HPA, human platelet antigen; RBC, red blood cell. From Hoffman R: Hematology, basic principles and practice, ed 7, Philadelphia, 2018, Elsevier.

TABLE 81  Differential Diagnosis of Thrombocytopenia in Newborns Perinatal Hypoxemia Placental Insufficiency Congenital Infection Sepsis Toxoplasmosis Rubella Cytomegalovirus Autoimmune Maternal immune thrombocytopenia Maternal systemic lupus erythematosus Disseminated Intravascular Coagulation Maternal Drug Exposure Congenital Heart Disease Hereditary Thrombocytopenia MYH9 macrothrombocytopenia (including May-Hegglin anomaly) Thrombocytopenia absent radii syndrome Amegakaryocytic thrombocytopenia Wiskott-Aldrich syndrome Fanconi anemia Hemangioma with Thrombocytopenia Kasabach-Merritt syndrome Bone Marrow Infiltration Congenital leukemia From Hoffman R: Hematology, basic principles and practice, ed 7, Philadelphia, 2018, Elsevier.

TABLE 82  Differential Diagnosis of Thrombocytopenia in Pregnancy Incidental thrombocytopenia of pregnancy (gestational thrombocytopenia) Preeclampsia or eclampsiaa DIC secondary to: Abruptio placentae Endometritis Amniotic fluid embolism Retained fetus Preeclampsia or eclampsiaa Peripartum or postpartum thrombotic microangiopathy TTP HssUS DIC, Disseminated intravascular coagulation; HUS, hemolytic uremic syndrome; TTP, thrombotic thrombocytopenic purpura. a Preeclampsia or eclampsia usually is not associated with overt DIC. From Hoffman R: Hematology, basic principles and practice, ed 7, Philadelphia, 2018, Elsevier.

Note the appearance of the fluid: A grossly hemorrhagic effusion can be a result of a traumatic tap, neoplasm, or an embolus with infarction. A milky appearance indicates either of the following: Chylous effusion: Caused by trauma or tumor invasion of the thoracic duct; lipoprotein electrophoresis of the effusion reveals chylomicrons and triglyceride levels >115 mg/dl. Pseudochylous effusion: Often seen with chronic inflammation of the pleural space (e.g., TB, connective tissue diseases). If transudate, consider CHF, cirrhosis, chronic renal failure, and other hypoproteinemic states and perform subsequent workup ­accordingly. If exudate, consider ordering these tests on the pleural fluid: Cytologic examination for malignant cells (for suspected neoplasm). Gram stain, cultures (aerobic and anaerobic), and sensitivities (for suspected infectious process). AFB stain and cultures (for suspected TB). pH: A value 50%) Bacterial pneumonia (parapneumonic effusion) Pulmonary infarction Pancreatitis Subphrenic abscess Early tuberculosis Transudates (>10%) Lymphocytosis (>50%) Tuberculosis Viral infection Malignancy (lymphoma, other neoplasms) True chylothorax Rheumatoid pleuritis Systemic lupus erythematosus Uremic effusions Transudates (≈30%) Eosinophilia (>10%) Pneumothorax (air in pleural space) Trauma Pulmonary infarction Congestive heart failure Infection (especially parasitic, fungal) Hypersensitivity syndromes Drug reaction Rheumatologic diseases Hodgkin disease Idiopathic From McPherson RA, Pincus MR: Henry’s clinical diagnosis and management by laboratory methods, ed 23, St Louis, 2017, Elsevier.

TABLE 86  Features Differentiating Exudative from Transudative Pleural Effusion Feature

Transudate

Exudate

Appearance Leukocyte count pH Protein Ratio of pleural fluid protein to serum Lactate dehydrogenase (LDH) Ratio of pleural fluid LDH to serum Glucose

Serous 7.2 0.5

200 IU/L

0.6

≥60 mg/dl

20

0.20

60% (literature range, >60% to >70%) Can be poured from a pipet in droplets rather than a thick strand

% Normal sperm Viscosity

SED RATE See ERYTHROCYTE SEDIMENTATION RATE SEDIMENTATION RATE See ERYTHROCYTE SEDIMENTATION RATE SEMEN ANALYSIS Table 98 describes semen analysis reference ranges.

MCV, Mean corpuscular volume; RDW, red blood cell distribution width. From Hoffman R et al: Hematology: Basic principles and practice, ed 5, Philadelphia, 2009, Churchill Livingstone.

Motility

1901

SGOT See ASPARTATE AMINOTRANSFERASE SGPT See ASPARTATE AMINOTRANSFERASE SICKLE CELL TEST Normal: Negative Positive in: Sickle cell anemia, sickle cell trait, combination of Hb S gene with other disorders such as alpha-thalassemia, beta-thalassemia. SMOOTH MUSCLE ANTIBODY Normal: Negative Present in: Chronic acute hepatitis, primary sclerosing cholangitis, primary biliary cirrhosis, autoimmune hepatitis, infectious mononucleosis SODIUM (serum) Normal range: 135 to 147 mEq/L (135 to 147 mmol/L [CF: 1; SMI: 1 mmol/L]). Electrolyte concentrations in extracellular and intracellular fluid are summarized in Table 99. HYPONATREMIA See Fig. 54. Common causes of hyponatremia and electrolyte patterns in serum and urine with normal renal function are described in Table 100. Table E101 describes drugs associated with hyponatremia. Sodium and water depletion (deficit hyponatremia) Loss of gastrointestinal secretions with replacement of fluid but not electrolytes

From Ravel R (ed): Clinical laboratory medicine, ed 6, St Louis, 1995, Mosby.

TABLE 99  Electrolyte Concentrations in Extracellular and Intracellular Fluids

Na+

K+ Ca++ Mg++ Cl– HCO3– SO42– P Protein Organic anion +The

INTERSTITIAL FLUID

PLASMA WATER

CELL WATER (MUSCLE)

(mmol/L)

(mmol/L)

(mmol/L)

(mmol/L)

(mmol/L)

(mmol/L)

(mmol/L)

140 4.5 5.0 1.7 104 24 1.0 2.1 15 5

140 4.5 2.5 0.85 104 24 0.5 1.2+ 1 5

145.3 4.7 2.8 1.0 114.7 26.5 1.2 2.1++ 8 5.6

145.3 4.7 1.4 0.5 114.7 26.5 0.6 1.2+ 0.5 5.6

149.8 4.8 5.3 1.8 111.4 25.7 1.1 2.2 16 5.3

149.8 4.8 5.3 0.9 111.4 25.7 0.55 1.25+ 1 5.3

13 140 10–7 7.0 3 10 – 107 40 –

13 140 0.5 × 10–7 3.5 3 10 – 57+++ 2.5* –

calculation is based on the assumption that the pH of the extracellular fluid is 7.4 and the pK of inorganic H2PO4– is 6.8. concentration of P in the interstitial fluid would be increased by the Donnan effect, but reduced by the lower protein-bound phosphate, and these two opposing effects keep interstitial phosphate concentration about equal to that of plasma. +++The intracellular molal concentration of phosphate is calculated with the assumption that the pK of organic phosphates in the cell is 6.1 and the intracellular pH 7.0. *The calculation is based on the assumption that each mmol of intracellular protein has an average of 15 mEq. From McPherson RA, Pincus MR: Henry’s clinical diagnosis and management by laboratory methods, ed 23, St Louis, 2017, Elsevier. ++The

Laboratory Tests

PLASMA (mmol/L)

IV

Sed Rate Sodium TABLE 97  Combining the Reticulocyte Count and Red Blood Cell Parameters for Diagnosis Reticulocyte Count 100,000/μL

Anemia of chronic disease Anemia of chronic disease Chemotherapy/antivirals/ alcohol Aplastic anemia Iron deficiency anemia

Low, High Normal, High

Early iron, folate, vitamin B12 deficiency Myelodysplasia Folate or vitamin B12 ­deficiency Myelodysplasia

High, High

Chronic liver disease Sickle cell-βthalassemia Sickle cell anemia, sickle cell disease Immune hemolytic anemia Chronic liver disease

TABLE 98  Semen Analysis Reference Ranges Color

Grayish white

pH Volume Sperm count

7.3-7.8 (literature range, 7.0-7.8) 2.0-5.0 ml (literature range, 1.5-6.0 ml) 20-250 million/ml (literature range for upper limit varies from 100-250 million/ml) >60% motile 40% to >70%) >60% (literature range, >60% to >70%) Can be poured from a pipet in droplets rather than a thick strand

% Normal sperm Viscosity

SED RATE See ERYTHROCYTE SEDIMENTATION RATE SEDIMENTATION RATE See ERYTHROCYTE SEDIMENTATION RATE SEMEN ANALYSIS Table 98 describes semen analysis reference ranges.

MCV, Mean corpuscular volume; RDW, red blood cell distribution width. From Hoffman R et al: Hematology: Basic principles and practice, ed 5, Philadelphia, 2009, Churchill Livingstone.

Motility

1901

SGOT See ASPARTATE AMINOTRANSFERASE SGPT See ASPARTATE AMINOTRANSFERASE SICKLE CELL TEST Normal: Negative Positive in: Sickle cell anemia, sickle cell trait, combination of Hb S gene with other disorders such as alpha-thalassemia, beta-thalassemia. SMOOTH MUSCLE ANTIBODY Normal: Negative Present in: Chronic acute hepatitis, primary sclerosing cholangitis, primary biliary cirrhosis, autoimmune hepatitis, infectious mononucleosis SODIUM (serum) Normal range: 135 to 147 mEq/L (135 to 147 mmol/L [CF: 1; SMI: 1 mmol/L]). Electrolyte concentrations in extracellular and intracellular fluid are summarized in Table 99. HYPONATREMIA See Fig. 54. Common causes of hyponatremia and electrolyte patterns in serum and urine with normal renal function are described in Table 100. Table E101 describes drugs associated with hyponatremia. Sodium and water depletion (deficit hyponatremia) Loss of gastrointestinal secretions with replacement of fluid but not electrolytes

From Ravel R (ed): Clinical laboratory medicine, ed 6, St Louis, 1995, Mosby.

TABLE 99  Electrolyte Concentrations in Extracellular and Intracellular Fluids

Na+

K+ Ca++ Mg++ Cl– HCO3– SO42– P Protein Organic anion +The

INTERSTITIAL FLUID

PLASMA WATER

CELL WATER (MUSCLE)

(mmol/L)

(mmol/L)

(mmol/L)

(mmol/L)

(mmol/L)

(mmol/L)

(mmol/L)

140 4.5 5.0 1.7 104 24 1.0 2.1 15 5

140 4.5 2.5 0.85 104 24 0.5 1.2+ 1 5

145.3 4.7 2.8 1.0 114.7 26.5 1.2 2.1++ 8 5.6

145.3 4.7 1.4 0.5 114.7 26.5 0.6 1.2+ 0.5 5.6

149.8 4.8 5.3 1.8 111.4 25.7 1.1 2.2 16 5.3

149.8 4.8 5.3 0.9 111.4 25.7 0.55 1.25+ 1 5.3

13 140 10–7 7.0 3 10 – 107 40 –

13 140 0.5 × 10–7 3.5 3 10 – 57+++ 2.5* –

calculation is based on the assumption that the pH of the extracellular fluid is 7.4 and the pK of inorganic H2PO4– is 6.8. concentration of P in the interstitial fluid would be increased by the Donnan effect, but reduced by the lower protein-bound phosphate, and these two opposing effects keep interstitial phosphate concentration about equal to that of plasma. +++The intracellular molal concentration of phosphate is calculated with the assumption that the pK of organic phosphates in the cell is 6.1 and the intracellular pH 7.0. *The calculation is based on the assumption that each mmol of intracellular protein has an average of 15 mEq. From McPherson RA, Pincus MR: Henry’s clinical diagnosis and management by laboratory methods, ed 23, St Louis, 2017, Elsevier. ++The

Laboratory Tests

PLASMA (mmol/L)

IV

Sodium Sodium1901.e1 TABLE E101  Drugs Associated with Hyponatremia* Vasopressin Analogs

Drugs That Potentiate Renal Action of Vasopressin

Desmopressin (DDAVP) Oxytocin

Chlorpropamide Cyclophosphamide Nonsteroidal anti inflammatory agents Acetaminophen (paracetamol) Drugs That Cause Hyponatremia by Unknown Mechanisms Haloperidol Fluphenazine Amitriptyline Thioridazine Fluoxetine Methamphetamine (MDMA or Ecstasy) Sertraline

Drugs That Enhance Vasopressin Release Chlorpropamide Clofibrate Carbamazepine-oxcarbazepine Vincristine Nicotine Narcotics Antipsychotics/antidepressants Ifosfamide

Italics: The common causes. *Not including diuretics. From Johnson RJ, Feehally J: Comprehensive clinical nephrology, ed 2, St Louis, 2000, Mosby.

1902

Sodium Sodium Hyponatremia

Measure serum osmolarity

>290 mOsm/L

20 mEq/L) Adrenal/mineralocorticoid deficiency Diuretics Osmotic diuresis Cerebral salt wasting

20 mEq/L) Renal failure

>100 mOsm/L SIADH Adrenal insufficiency Hypothyroidism

Extrarenal (