Osmosis pathology

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Osmosis

Table of Contents Osmosis Volume 1 1 Cardiovascular System 1.1 ACUTE CORONARY SYNDROMES 1.2 ACYANOTIC DEFECTS 1.3 ANEURYSMS & DISSECTION 1.4 BRADYCARDIA & HEART BLOCK 1.5 CARDIAC TUMORS 1.6 CARDIOMYOPATHY 1.7 CORONARY ARTERY DISEASE 1.8 CYANOTIC DEFECTS 1.9 HEART FAILURE 1.10 HEART VALVE DISEASE 1.11 HYPERTENSION & HYPOTENSION 1.12 INFECTIONS & INFLAMMATION OF THE HEART 1.13 LYMPHATIC DYSFUNCTION 1.14 PERICARDIAL DISEASE 1.15 PERIPHERAL ARTERY DISEASE 1.16 PRE–EXCITATION DISORDERS 1.17 PREMATURE CONTRACTION 1.18 SHOCK 1.19 SUDDEN CARDIAC DEATH 1.20 SUPRAVENTRICULAR TACHYCARDIA 1.21 VASCULAR COMPRESSION SYNDROMES 1.22 VASCULAR MALFORMATIONS 1.23 VASCULAR STEAL SYNDROMES 1.24 VASCULAR TUMORS 1.25 VASCULITIS 1.26 VENOUS DYSFUNCTION 1.27 VENTRICULAR TACHYCARDIA 2 Gasterointestinal System 2.1 BILIARY TRACT DISEASES 2.2 COLORECTAL POLYP CONDITIONS 2.3 ESOPHAGEAL DISEASE 2.4 GASTRIC DISEASE 2.5 GASTROINTESTINAL CANCERS 2.6 INFLAMMATORY BOWEL DISEASE 2.7 INTESTINAL DISEASES 2.8 LIVER & GALLBLADDER CONGENITAL CONDITIONS 2.9 LIVER DISEASES 2.10 LOWER GASTROINTESTINAL CONGENITAL MALFORMATIONS 2.11 MALABSORPTION CONDITIONS 2.12 ORAL DISEASE

8 9 9 9 14 23 29 37 41 49 51 63 72 87 93 103 105 113 119 125 130 135 141 149 153 161 165 170 184 193 202 202 215 223 236 245 263 271 291 297 324 335 342

2.13 PANCREATITIS 2.14 PERITONEAL PATHOLOGY 2.15 RECTAL & ANAL PATHOLOGY 2.16 UPPER GASTROINTESTINAL CONGENITAL MALFORMATIONS 3 Hematology 3.1 CONGENITAL ANEMIA 3.2 DYSPLASTIC & PROLIFERATIVE DISORDERS 3.3 HYPERCOAGULABLE DISORDERS 3.4 HYPOCOAGULABLE DISORDERS 3.5 LEUKEMIAS 3.6 LYMPHOMAS 3.7 MACROCYTIC ANEMIA 3.8 METHEMOGLOBINEMIA 3.9 MICROCYTIC ANEMIA 3.10 NORMOCYTIC ANEMIA (DECREASED PRODUCTION) 3.11 NORMOCYTIC ANEMIA (INCREASED HEMOLYSIS) 3.12 PLASMA CELL DYSCRASIAS 3.13 PLATELET DISORDERS 3.14 PORPHYRIA 3.15 SPLEEN PATHOLOGY 3.16 THROMBOCYTOPENIA 3.17 THYMUS NEOPLASIA 4 Neurology 4.1 ADULT PRIMARY BRAIN TUMORS 4.2 AUTONOMIC DISEASES 4.3 BALANCE DISORDERS 4.4 BRAIN ISCHEMIA 4.5 CEREBRAL CORTEX NERVOUS SYSTEM INFECTIONS 4.6 CEREBROSPINAL MALFORMATIONS 4.7 CHILDHOOD PRIMARY BRAIN TUMORS 4.8 CNS DEMYELINATING DISORDERS 4.9 CONGENITAL MYOPATHIES 4.10 CORTICAL DISORDERS 4.11 CRANIAL NERVE INJURY 4.12 DEMENTIA 4.13 EAR PATHOLOGY 4.14 ENCEPHALOPATHY 4.15 EPILEPSY & SEIZURES 4.16 EYE INFECTIONS 4.17 GLOBE PATHOLOGY 4.18 HEAD INJURY 4.19 HEADACHES 4.20 HEARING LOSS 4.21 INCREASED INTRACRANIAL PRESSURE 4.22 MOTOR NEURON DISEASES

353 359 363 368 376 376 381 391 397 402 410 417 421 423 429 433 446 452 455 459 463 469 472 472 481 484 490 508 521 534 544 552 555 560 563 572 580 584 593 606 619 624 630 636 640

4.23 MOVEMENT DISORDERS 4.24 NEUROCUTANEOUS DISORDERS 4.25 NEUROMUSCULAR JUNCTION DISEASES 4.26 NEUROPATHIES 4.27 PNS DEMYELINATING DISORDERS 4.28 SPINAL CORD INJURY 4.29 VISION DISORDERS 5 Psychology 5.1 ANXIETY DISORDERS 5.2 COGNITIVE & DISSOCIATIVE DISORDERS 5.3 DEPRESSIVE & BIPOLAR DISORDERS 5.4 ELIMINATION DISORDERS 5.5 FACTITIOUS DISORDERS 5.6 FEEDING & EATNG DISORDERS 5.7 NEURODEVELOPMENTAL DISORDERS 5.8 OBSESSIVE-COMPULSIVE DISORDERS 5.9 PERSONALITY DISORDERS: CLUSTER A 5.10 PERSONALITY DISORDERS: CLUSTER B 5.11 PERSONALITY DISORDERS: CLUSTER C 5.12 SCHIZOPHRENIA & PSYCHOTIC DISORDERS 5.13 SEXUAL DYSFUNCTION 5.14 SLEEP & SLEEP-WAKE DISORDERS 5.15 SUBSTANCE USE & RELATED DISORDERS 5.16 TRAUMA– & ABUSE–RELATED DISORDERS 6 Nephrology 6.1 ACUTE & CHRONIC KIDNEY DISEASE 6.2 BLADDER & URETHRAL CONGENITAL DISORDERS 6.3 BLADDER CANCER 6.4 BLADDER PATHOLOGY 6.5 CONGENITAL KIDNEY CONDITIONS 6.6 HYPERCALCEMIA & HYPOCALCEMIA 6.7 HYPERKALEMIA & HYPOKALEMIA 6.8 HYPERMAGNESEMIA & HYPOMAGNESEMIA 6.9 HYPERNATREMIA & HYPONATREMIA 6.10 HYPERPHOSPHATEMIA & HYPOPHOSPHATEMIA 6.11 KIDNEY DISORDERS 6.12 NEPHRITIC SYNDROME 6.13 NEPHROTIC SYNDROME 6.14 RENAL CANCER 6.15 URINARY & KIDNEY INFECTIONS 6.16 URINARY INCONTINENCE 6.17 VASCULAR RENAL DISEASE 7 Respiratory System 7.1 ACUTE RESPIRATORY DISEASE 7.2 LOWER RESPIRATORY TRACT CONGENITAL MALFORMATIONS

646 656 669 674 684 688 691 697 697 704 708 713 715 716 719 725 728 732 737 741 747 751 756 767 770 770 777 784 789 791 802 808 812 816 820 823 833 843 852 861 866 871 875 875 882

7.3 LOWER RESPIRATORY TRACT INFECTION 7.4 OBSTRUCTIVE LUNG DISEASE 7.5 PERINATAL ACUTE RESPIRATORY DISEASE 7.6 PLEURA & PLEURAL SPACE 7.7 PULMONARY VASCULAR DISEASE 7.8 RESPIRATORY TUMORS 7.9 RESTRICTIVE LUNG DISEASE 7.10 SLEEP–RELATED RESPIRATORY DISEASE 7.11 UPPER RESPIRATORY TRACT 7.12 UPPER RESPIRATORY TRACT CONGENITAL MALFORMATIONS Volume 2 1 Dermatology 1.1 BURNS & FROSTBITE 1.2 DERMATITIS & ECZEMA 1.3 ERYTHEMA MULTIFORME & DRUG ERUPTION 1.4 HAIR–RELATED DISEASES 1.5 MALIGNANT TUMORS 1.6 PAPULOSQUAMOUS DISORDERS 1.7 PIGMENTATION DISORDERS 1.8 SKIN & SOFT TISSUE INFLAMMATION & INFECTIONS 1.9 URTICARIA & ERYTHEMA NODOSUM 1.10 VESICULOBULLOUS DISEASES 2 Endocrinology 2.1 ADRENAL HYPERFUNCTION 2.2 ADRENAL HYPERPLASIA 2.3 ADRENAL HYPOFUNCTION 2.4 DIABETES MELLITUS 2.5 ENDOCRINE TUMORS 2.6 GONADAL DYSFUNCTION 2.7 HYPERPARATHYROIDISM & HYPOPARATHYROIDISM 2.8 HYPERPITUITARISM & HYPOPITUITARISM 2.9 HYPERTHYROIDISM & HYPOTHYROIDISM 2.10 NEUROENDOCRINE TUMORS 2.11 THYROIDITIS 3 Medical Genetics 3.1 CHROMOSOMAL DELETION SYNDROMES 3.2 CONNECTIVE TISSUE DISORDERS 3.3 DNA REPLICATION & REPAIR DISORDERS 3.4 GENETIC MUTATIONS 3.5 IMPRINTING DISORDERS 3.6 SEX CHROMOSOME DISORDERS 3.7 TRINUCLEOTIDE REPEAT EXPANSION DISEASES 3.8 TRISOMIES 4 Immunology 4.1 COMBINED B-CELL & T-CELL DEFICIENCIES

886 894 907 914 920 931 943 951 954 964 967 967 967 976 982 987 990 998 1004 1009 1025 1030 1034 1034 1039 1042 1046 1052 1059 1068 1073 1086 1096 1109 1114 1114 1118 1124 1128 1135 1139 1142 1147 1153 1153

4.2 COMPLEMENT DEFICIENCIES 4.3 HUMORAL & B-CELL DEFICIENCIES 4.4 HYPERSENSITIVITY REACTIONS: MULTIPLE MECHANISMS 4.5 PHAGOCYTE DEFICIENCIES 4.6 T–CELL DEFICIENCIES 4.7 TYPE I HYPERSENSITIVITY REACTIONS 4.8 TYPE II HYPERSENSITIVITY REACTIONS 4.9 TYPE III HYPERSENSITIVITY REACTIONS 4.10 TYPE IV HYPERSENSITIVITY REACTIONS 5 Metabolic Disorders 5.1 AMINO ACID METABOLISM DISORDERS 5.2 CARBOHYDRATE METABOLISM DISORDERS 5.3 CHEMICAL & DRUG TOXICITY 5.4 DYSLIPIDEMIA 5.5 FAT SOLUBLE VITAMINS DEFICIENCY 5.6 GLYCOGEN STORAGE DISEASES (GSD) 5.7 HYPERVITAMINOSIS 5.8 MALNUTRITION 5.9 MINERAL DEFICIENCIES 5.10 MITOCHONDRIAL DISEASE 5.11 MUCOPOLYSACCHARIDOSIS 5.12 PURINE & PYRIMIDINE METABOLISM DISORDERS 5.13 SPHINGOLIPIDOSIS 5.14 WATER SOLUBLE VITAMINS DEFICIENCY 6 Microbiology 6.1 ADENOVIRIDAE 6.2 AEROBIC RODS 6.3 ANAEROBIC RODS 6.4 ARENAVIRIDAE 6.5 BUNYAVIRUSES 6.6 CALICVIRUSES 6.7 CENTRAL NERVOUS SYSTEM INFECTIONS 6.8 CESTODES (TAPEWORMS) 6.9 CHLAMYDIA 6.10 COCCOBACILLI: AEROBES 6.11 COCCOBACILLI: FACULTATIVE ANAEROBES 6.12 COMMA–SHAPED RODS 6.13 CORONAVIRUSES 6.14 CUTANEOUS FUNGAL INFECTIONS 6.15 DIPLOCOCCI: AEROBIC 6.16 ECTOPARASITES 6.17 ENTEROCOCCUS 6.18 FILAMENTS 6.19 FILOVIRUSES 6.20 FLAVIVIRUSES

1156 1161 1171 1178 1183 1185 1189 1192 1194 1197 1197 1204 1207 1222 1229 1233 1240 1242 1246 1249 1253 1258 1261 1267 1274 1274 1276 1282 1291 1293 1296 1298 1304 1308 1311 1315 1324 1330 1332 1335 1341 1346 1348 1354 1357

6.21 GASTROINTESTINAL INFECTIONS 6.22 GENERAL INFECTIONS 6.23 GRAM VARIABLE 6.24 HEMATOLOGIC INFECTIONS 6.25 HEPADNAVIRIDAE 6.26 HERPESVIRUSES 6.27 LEISHMANIA 6.28 MYCOPLASMA 6.29 NEMATODES (ROUNDWORMS) 6.30 NON TUBERCULOUS MYCOBACTERIUM 6.31 OPPORTUNISTIC FUNGAL INFECTIONS 6.32 ORTHOMYXOVIRUSES 6.33 PAPILLOMAVIRUS 6.34 PARAMYXOVIRUSES 6.35 PICORNAVIRUSES 6.36 POLYOMAVIRUS 6.37 POXVIRIDAE 6.38 REOVIRUSES 6.39 RETROVIRUSES 6.40 RHABDOVIRUSES 6.41 RICKETTSIAL DISEASES 6.42 RODS 6.43 SPIROCHETES 6.44 STAPHYLOCOCCUS 6.45 STREPTOCOCCUS 6.46 SYSTEMIC MYCOSES 6.47 TOGAVIRUSES 6.48 TREMATODES (FLATWORMS) 6.49 TRICHOMONA 6.50 TRYPANOSOMA 6.51 TUBERCULOSIS 7 Musculoskeletal 7.1 BONE & JOINT INFECTIONS 7.2 BONE & JOINT PATHOLOGY 7.3 BONE TUMORS 7.4 CARTILAGE TUMORS 7.5 HEAD & NECK MUSCULOSKELETAL DISORDERS 7.6 INFLAMMATORY ARTHRITIS 7.7 INFLAMMATORY CONNECTIVE TISSUE DISORDERS 7.8 INFLAMMATORY MYOSITIS 7.9 JOINT PATHOLOGY 7.10 LOWER LIMB INJURY 7.11 MUSCLE TUMORS 7.12 MUSCULOSKELETAL CONGENITAL MALFORMATIONS 7.13 SKELETAL DYSPLASIA

1365 1371 1375 1377 1383 1388 1398 1400 1402 1424 1426 1438 1441 1444 1450 1457 1460 1462 1464 1474 1477 1486 1503 1511 1515 1521 1528 1533 1539 1541 1546 1550 1550 1554 1570 1579 1583 1587 1602 1615 1621 1628 1640 1642 1655

7.14 SPINAL DISORDERS 7.15 TRAUMA COMPLICATIONS 7.16 UPPER LIMB INJURY 8 Reproductive System 8.1 BREAST MASSES 8.2 DISORDERS OF LABOR 8.3 FEMALE GENITOURINARY CANCERS 8.4 GENITOURINARY TRACT INFECTIONS 8.5 INFERTILITY & FETAL LOSS 8.6 MALE GENITOURINARY CANCERS 8.7 MATERNAL CONDITIONS 8.8 OVARIAN & UTERINE DISORDERS 8.9 PENILE, PROSTATE, & TESTICULAR DISORDERS 8.10 PERINATAL INFECTIONS

1659 1674 1678 1683 1683 1695 1703 1716 1720 1729 1736 1753 1762 1777

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ACUTE CORONARY SYNDROMES

GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Signs and symptoms caused by decreased blood flow in the coronary arteries to the extent that the muscle cannot function properly, or even dies ▪ Acute coronary syndromes are almost always due to atherosclerosis

SIGNS & SYMPTOMS ▪ See individual disorders

DIAGNOSIS ▪ See individual disorders

TREATMENT MEDICATIONS Oxygen as needed Pain control with nitrates and/or morphine Antiplatelets Anticoagulants Nitrates: decreases preload by vasodilation Beta blockers: reduces cardiac demand by decreasing heart rate, BP and contractility (first-line choice: metoprolol) ▪ Statins: HMG-CoA reductase inhibitor that reduces production of cholesterol to improve lipid profile ▪ ▪ ▪ ▪ ▪ ▪

OTHER INTERVENTIONS ▪ Hospital admission with continuous monitoring ▪ Reestablish blood flow via catheterization / revascularization ▪ Lifestyle changes: improve diet (reduce intake of saturated fat), smoking cessation, control blood pressure, strict management of diabetes mellitus, increase exercise, weight loss, improve lipid profile

Figure 1.1 Illustration depicting ST depression and ST elevation seen in myocardial infarctions.

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MYOCARDIAL INFARCTION (MI) osms.it/myocardial-infarction PATHOLOGY & CAUSES ▪ Death of heart muscle cells due to lack of oxygen-rich blood flow ▪ Plaque buildup (fat, cholesterol, proteins, calcium, white blood cells) takes years to form in lumen ▪ Blood platelets adhere to plaque and enhance clotting process, creating blockage ▪ Necrosis of myocardial cells follows series of events ▫ < 24 hrs: early coagulative necrosis, cell debris in blood, edema, wavy fibers and hemorrhage ▫ 1–3 days: extensive necrosis, tissue has acute inflammation with neutrophils ▫ 3–14 days: macrophages and granulation tissue in margins ▫ > 14 days: contracted scar forms

TYPES ST segment elevation myocardial infarction (STEMI) ▪ Coronary artery completely blocked; full thickness of myocardial wall involved ▪ ECG shows ST elevation, possible Q waves Non-ST segment elevation MI (NSTEMI) ▪ Coronary artery not completely blocked, subendocardium may be especially vulnerable to ischemia ▪ ECG shows ST depression

RISK FACTORS ▪ Modifiable risk factors: older age, smoking, high blood pressure, diabetes mellitus, high cholesterol, low levels of physical activity, obesity, excessive alcohol use, illegal drug use (e.g., cocaine, amphetamines), chronic stress ▪ Non-modifiable risk factors: family history, biological male

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COMPLICATIONS ▪ Heart failure: heart muscle fails to compensate for damage; risk related to size/territory of infarct and individual’s baseline cardiac function ▪ Cardiac arrhythmia: may be seen within minutes after MI or years later. If undiagnosed MI, may be cause of death ▪ Left ventricular (LV) failure and pulmonary edema: happens after left ventricular infarction, free wall rupture, ventricular septal defect, papillary muscle rupture with mitral regurgitation ▪ Postinfarction pericarditis, papillary muscle rupture (might lead to acute, severe mitral regurgitation), interventricular septal rupture, ventricular pseudoaneurysm formation, ventricular free wall rupture (might lead to ventricular free wall rupture leading to pericardial tamponade/ventricular pseudoaneurysm), true ventricular aneurysm, Dressler syndrome

MNEMONIC: DARTH VADER Complications of MI Death Arrythmia Rupture (free ventricular wall/ ventricular septum/papillary muscles) Tamponade Heart failure (acute or chronic) Valve disease Aneurysm of ventricles Dressler's syndrome thromboEmbolism (mural thrombus) Recurrence/ mitral Regurgitation

Chapter 1 Acute Coronary Syndromes

SIGNS & SYMPTOMS ▪ Acute chest pain lasting > 20 min, radiating to arm/jaw ▪ Uncomfortable chest/back/neck/ jaw/stomach pain, dyspnea, fatigue, diaphoresis, and/or nausea ▪ Feeling of fullness/indigestion

DIAGNOSIS LAB RESULTS ▪ Usually detected with diagnostic laboratory work for cardiac enzymes ▫ Troponin I, troponin T most specific, sensitive markers: rise apparent within 2–4 hrs, peaking ~24 hrs ▫ CK-MB can detect reinfarction after initial MI: levels increased 4 hrs after infarction, peak at 24 hrs, return to normal after 48 hrs

TREATMENT ▪ STEMI first priority: emergent reperfusion via percutaneous coronary intervention (e.g. catheterization)/thrombolysis ▫ Very time sensitive ▪ NSTEMI: reperfusion via percutaneous coronary intervention (not thrombolysis) ▫ Less time sensitive than in STEMI

MEDICATIONS ▪ Heparin, aspirin + clopidogrel, beta blockers, ACE inhibitors, statins ▪ Control symptoms with morphine and nitroglycerin

OTHER DIAGNOSTICS ECG ▪ Can confirm diagnosis; time sensitive, not accurate after 6 hours ▪ < 30 min: ST segment elevation ▫ Only seen in STEMIs ▫ ST depression/no ST segment deviation would be seen in NSTEMIs ▪ < 24 hrs: T wave inversion ▪ > 24 hrs: Q waves appear

Figure 1.2 A pathology pot containing a heart exhibiting an anterior myocardial infarction, usually the result of left anterior descending artery disease.

Figure 1.3 Gross pathology of a ruptured papillary muscle, a serious complication of myocardial infarction.

Figure 1.4 Histological appearance of the myocardium following a myocardial infarct.

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PRINZMETAL'S ANGINA osms.it/prinzmetals-angina PATHOLOGY & CAUSES ▪ AKA vasospastic angina/variant angina

▪ Coronary artery vasospasms; occur spontaneously even at rest ▪ Vasospasms: constriction of the smooth muscle surrounding the artery, reducing blood flow through the vessel ▫ Cause of vasospasms not well understood; likely due to vasoconstrictors such as platelet thromboxane A2 ▫ Coronary artery vasospasms cause ischemia throughout all of the heart layers

SIGNS & SYMPTOMS ▪ Same as stable angina, except pain may occur at rest ▪ Pain described as pressure, squeezing, burning, or tightness; can radiate to the either/both arms, jaw, shoulders, and back; lasts less than 20 minutes ▪ Other symptoms: Levine’s sign (a clenched fist held over the chest), dyspnea, diaphoresis, fatigue, nausea, and epigastric pain

DIAGNOSIS DIAGNOSTIC IMAGING ▪ Transient ST segment elevation ▪ Illustrates transmural ischemia

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MEDICATIONS Calcium channel blockers

CAUSES

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TREATMENT

Vasodilators ▪ Increases coronary blood flow to heart

Chapter 1 Acute Coronary Syndromes

UNSTABLE ANGINA osms.it/unstable-angina DIAGNOSIS

PATHOLOGY & CAUSES ▪ Episodic chest pain that either ▫ Is new in onset ▫ Occurs at rest unpredictably ▫ Rapidly worsens over time ▫ Occurs within 48 hrs after acute MI ▪ Usually caused by ruptured atherosclerotic plaque → formation of thrombosis on top of plaque → almost complete blockage in blood vessel → ischemia → pain ▪ Medical emergency: high risk of progression to MI ▫ Angina: myocytes still alive ▫ Myocardial infarction: death of myocytes

LAB RESULTS ▪ Serial troponins measured for individuals with unstable angina to rule out myocardial infarction ▪ Troponin released after injury to myocytes is a marker for myocardial injury

OTHER DIAGNOSTICS ECG ▪ Can present with ST segment depression ▫ May also present with T wave inversions ▫ Illustrates subendocardial ischemia

TREATMENT

SIGNS & SYMPTOMS ▪ Same as stable angina, except pain may occur at rest ▪ Pain described as pressure, squeezing, burning, or tightness; can radiate to the either/both arms, jaw, shoulders, and back; lasts less than 20 minutes ▪ Other symptoms: Levine’s sign (a clenched fist held over the chest), dyspnea, diaphoresis, fatigue, nausea, and epigastric pain

▪ Unstable angina, NSTEMIs are indistinguishable at initial evaluation ▫ Elevated troponins indicating myocardial infarction not detectable for hours ▫ Initial management identical

MEDICATIONS Clopidogrel Low-molecular-weight-heparin (LMWH) ▪ Prevents clot formation Enoxaparin ▪ Drug of choice based on empirical evidence

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ACYANOTIC DEFECTS GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Heart defects presenting without cyanosis (blue-tinged skin) ▪ Caused by fetal heart malformation, can lead to heart failure ▪ ASD, PDA, and VSD ▫ All three cause left-to right shunt → oxygenated blood flows redundantly through pulmonary circulation → becomes Eisenmenger syndrome over time

SIGNS & SYMPTOMS ▪ Sometimes asymptomatic, but can lead to heart failure, Eisenmenger syndrome Heart failure ▪ Infants: poor feeding/failure to thrive, fluid retention, pulmonary congestion, hepatomegaly, respiratory distress, elevated jugular venous pressure

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Eisenmenger syndrome ▪ At rest: asymptomatic ▪ With exertion: cyanosis, palpitations dyspnea, chest pain, syncope

DIAGNOSIS DIAGNOSTIC IMAGING

▪ Heart imaging to identify defect type

TREATMENT SURGERY ▪ Rarely

MNEMONIC: P(C)AV

Acyanotic defects Patent ductus arteriosus (Coarctation of the aorta): no shunt Atrial septal defect Ventricular septal defect

Chapter 2 Acyanotic Defects

Figure 2.1 Illustration of blood flow through a ventricular septal defect.

ATRIAL SEPTAL DEFECT (ASD) osms.it/atrial-septal-defect PATHOLOGY & CAUSES ▪ A hole in the heart wall dividing left/right atria (left-to-right shunt) ▪ Blood passes through pulmonary circulation redundantly

SIGNS & SYMPTOMS ▪ Fixed, split S2 and pulmonic ejection murmur (louder with age) ▪ Infants and children ▫ Respiratory infections ▫ Failure to thrive ▪ Adults (before 40) ▫ Palpitations, exercise intolerance, dyspnea, fatigue

Figure 2.2 CT scan in the axial plane showing an atrial septal defect. Note the faint contrast plume as blood flows from the high pressure left system to the low pressure right system. RA; right atrium. LA; left atrium. RV; right ventricle. LV; left ventricle.

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DIAGNOSIS DIAGNOSTIC IMAGING Chest X-ray ▪ Right heart dilation ▪ Prominent pulmonary vascularity Transesophageal echocardiography ▪ Visualize size & location accurately

SURGERY Right heart catheterization ▪ Increased oxygen saturation in: ▫ Right atrium ▫ Right ventricle ▫ Pulmonary artery

Figure 2.3 Intraoperative view of multiple, pinhole atrial septal defects.

TREATMENT SURGERY

▪ Percutaneous surgical closure ▪ Adults: surgery in cases of ▫ Right ventricular enlargement, paradoxical embolism, right-to-left shunt

Figure 2.4 Illustration depecting blood shunting from left to right atrium in atrial septal defect.

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Chapter 2 Acyanotic Defects

COARCTATION OF THE AORTA (CoA) osms.it/coarctation-of-the-aorta PATHOLOGY & CAUSES ▪ Narrowed segment of aorta ▪ Upstream issues ▫ Blood flow increases into aortic branches before coarctation → blood flow, pressure increases in upper extremities, head ▪ Downstream issues ▫ Decreased blood flow, decreased pressure in lower extremities ▫ Kidneys receive less blood → activate renin-angiotensin-aldosterone system (RAAS) → secondary hypertension ▪ Preductal coarctation ▫ Associated with Turner syndrome, PDA ▫ May go unnoticed unless severe. Presents as postductal coarctation ▪ Postductal coarctation ▫ Distal to ligamentum arteriosum ▫ Presents in adulthood ▫ Blood pressure higher upstream, lower downstream ▫ Autoregulatory vasoconstriction/ vasodilation preserves regional blood flow

SIGNS & SYMPTOMS ▪ Depends on presence/severity of PDA ▪ Systolic murmur ▫ Systole: diamond-shaped murmur ▫ Diastole: high-pitched decrescendo murmur Infants ▪ Lower extremity cyanosis ▪ Absent or delayed femoral pulse ▪ Failure to thrive/poor feeding ▪ Blood pressure higher in upper extremities

compared to lower extremities ▪ Secondary hypertension ▪ Severe heart failure, shock if/when PDA closes ▪ Other symptoms may more apparent with age ▫ Chest pain, cold extremities, claudication on exertion ▫ Left ventricular impulse palpable, sustained ▫ Pulsations felt in intercostal spaces Adults ▪ Hypertension (most common) ▪ Hypotension in lower extremities ▪ Bilateral lower extremity claudication ▪ Dyspnea on exertion ▪ Delayed/weak femoral pulses

DIAGNOSIS DIAGNOSTIC IMAGING Angiogram ▪ Visualize narrowing in aorta, anatomy & severity Chest X-ray ▪ Rib notching: 3-sign (narrowed aorta resembles notch of number 3 due to prestenotic of aortic arch & postenotic of descending aorta dilatation) Echocardiograph ▪ Visualize location, size, blood turbulance

OTHER DIAGNOSTICS ECG ▪ Left ventricular hypertrophy, left atrial enlargement

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TREATMENT MEDICATIONS Prostaglandin E ▪ Increases flow to lower extremities

SURGERY

▪ Resection with end-to-end anastomosis ▫ If unfeasible, bypass graft across area of coarctation ▪ Long-segment coarctation: subclavian aortoplasty ▪ Prosthetic patch aortoplasty (rarely) ▪ Balloon angioplasty with possible stent

Figure 2.6 CT scan in the sagittal plane demonstrating coarctation of the aorta.

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Figure 2.5 Illustration showing narrowing of aorta lumen.

Figure 2.7 A chest radiograph demonstrating the figure of three sign seen in coarctation of the aorta.

Chapter 2 Acyanotic Defects

PATENT DUCTUS ARTERIOSUS (PDA) osms.it/patent-ductus-arteriosus PATHOLOGY & CAUSES ▪ Ductus arteriosus remains open after birth ▪ Left-to-right shunt between atria ▪ Sometimes presents with congenital defects (congenital rubella syndrome)

CAUSES Congenital rubella ▪ Mother-fetal transmission of rubella in first trimester → cytopathic damage to blood vessels, ischemia to organs ▪ Prematurity ▪ Perinatal distress, hypoxia

SIGNS & SYMPTOMS Depend on size of PDA ▪ Smaller ▫ Usually asymptomatic ▫ Neonates: holosystolic “machine-line” murmur on auscultation ▫ Infants, children, adults: continuous murmur ▪ Moderate ▫ Exercise intolerance ▫ Continuous murmur ▫ Wide systemic pulse pressure ▫ Displaced ventricular apex ▪ Larger ▫ Infants: leads to heart failure ▫ Children: shortness of breath, fatigability, Eisenmenger syndrome

DIAGNOSIS DIAGNOSTIC IMAGING Echocardiograph ▪ 2D suprasternal echocardiogram Chest X-ray ▪ Normal/cardiomegaly

OTHER DIAGNOSTICS ECG ▪ Left ventricular hypertrophy, left atrial enlargement

TREATMENT ▪ Small asymptomatic PDA: monitor

MEDICATIONS Neonates (10–14 days) ▪ Close PDA using prostaglandin inhibitor Symptomatic moderate/large PDA ▪ During heart failure ▫ Digoxin, furosemide

SURGERY Symptomatic moderate/large PDA ▪ Closure recommended for symptoms of left-to-right shunting, left-sided volume overload, reversible pulmonary arterial hypertension ▫ Children < 5kg/11lbs: surgical ligation ▫ > 5kg/11lbs (including adolescents/ adults): percutaneous occlusion, surgical ligation for large PDA

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Figure 2.8 Illustration depicting location of a patent ductus arteriosus.

Figure 2.9 Volume-rendered CT scan of the heart and great vessels showing a patent ductus arteriosus.

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Chapter 2 Acyanotic Defects

VENTRICULAR SEPTAL DEFECT (VSD) osms.it/ventricular-septal-defect PATHOLOGY & CAUSES ▪ ▪ ▪ ▪

Left-to-right shunt between ventricles Most common congenital heart disease Left-to-right shunt between ventricles Often presents with other defects (e.g. tetralogy of Fallot)

Size of defect ▪ Small: restrictive ▫ Normal pressure maintained between ventricles ▪ Moderate or large: non-restrictive ▫ No pressure difference between ventricles

SIGNS & SYMPTOMS ▪ Asymptomatic in utero ▪ Holosystolic murmur (loud, high-pitched) located at lower left sternal border Size of defect ▪ Small: asymptomatic, murmur ▪ Moderate–large: sweating, poor feeding/ failure to thrive, respiratory infections. Murmur plus thrill, and diastolic rumble in mitral area ▫ Signs of congestive heart failure (dyspnea, persistent cough, pulmonary vascular resistance) ▫ Eisenmenger’s syndrome

DIAGNOSIS DIAGNOSTIC IMAGING Chest X-ray ▪ Unreliable; may indicate left atrial enlargement, right ventricular hypertrophy, left ventricular hypertrophy, or pulmonary artery enlargement Echocardiogram ▪ Determines location and size MRI ▪ Use if echo does not diagnose

SURGERY Cardiac catheterization ▪ Used if echo and MRI did not diagnose, but individual still has pulmonary hypertension

OTHER INTERVENTIONS ECG ▪ Left ventricular hypertrophy ▫ May see right ventricular hypertrophy; left, right atrial enlargement (may see Katz–Wachtel phenomenon)

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TREATMENT ▪ Most small VSDs close on their own

SURGERY

▪ Repair larger shunts by age 2 to prevent pulmonary hypertension

Surgical repair ▪ Patch closure over ventricular septal defect (preferred treatment) Transcatheter closure ▪ Mesh to close VSD (higher risk) Hybrid procedure

Figure 2.10 View of the right side of the heart showing multiple ventricular septal defects.

Figure 2.11 Doppler ultrasound scan demonstrating flow of blood across the interventricular septum in a VSD.

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NOTES

NOTES

ANEURYSMS & DISSECTION

ANEURYSMS osms.it/aneuryms PATHOLOGY & CAUSES ▪ Abnormal dilations in blood vessel; 1.5x larger than normal vessel diameter (> 3.0 cm in aortic and thoracic) ▪ Frequently occurs in areas of high blood pressure: aorta, femoral, iliac, popliteal, and cerebral arteries; can occur in veins (uncommon). Pressure on blood vessel walls increases with diameter of vessel lumen (LaPlace’s law) ▪ 60% of true aortic aneurysms occur in abdominal aorta, 40% in thoracic aorta; most between renal artery branch and aortic bifurcation due to less collagen in this area of aorta Locations ▪ Can occur in any blood vessel; particularly life-threatening in the following locations ▪ Abdominal aortic aneurysm (AAA) ▫ Localized in abdominal aorta (diameter > 3cm/1.12in or > 50% larger than normal) ▫ Caused by atherosclerosis, infection, trauma, arteritis, cystic medial necrosis ▪ Thoracic aortic aneurysm ▫ Localized in thoracic aorta. Less common than abdominal aortic aneurysm ▪ Cerebral aneurysms ▫ Located in brain; particularly threatening in circle of Willis

TYPES True aneurysms ▪ All layers of blood vessel wall dilate ▫ Fusiform aneurysms: blood vessel walls dilate symmetrically ▫ Saccular (berry) aneurysms: asymmetrical ballooning of blood vessel walls due to increased blood pressure on one side of blood vessel wall Pseudoaneurysms ▪ Small hole in blood vessel wall → blood leaks out, pools; resembles fusiform/ saccular aneurysm

CAUSES Ischemia ▪ Ischemia of arteries with vasa vasorum: hyaline arteriolosclerosis decreases blood to large artery walls; decreases smooth muscle in arterial tunica media ▪ Ischemia of arteries without vasa vasorum: plaque from atherosclerosis blocks blood vessel walls from receiving oxygen Infection ▪ Tertiary syphilis: causes inflammation of tunica intima of vasa vasorum, decreasing blood to arterial wall in thoracic artery (endarteritis obliterans) ▪ Mycotic aneurysms: secondary infection in intracranial arteries/visceral arteries/arteries of extremities (bacteria enters vessel wall, weakening it) ▫ Pathogens include: Bacteroides fragilis, Pseudomonas aeruginosa, Salmonella

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Figure 3.1 Illustration depicting differences between types of aneurysms.

species, Aspergillus, Candida, Mucor (also an infective endocarditis complication) Genetic ▪ Connective tissue disorders: Marfan’s syndrome, Ehlers-Danlos syndrome

RISK FACTORS

▪ White biologically-male individuals of European descent, advanced age, smoking, hyperlipidemia, hypertension, family history, Ehlers-Danlos syndrome, Marfan syndrome, syphilis, cystic medial degeneration, bicuspid aortic valve

COMPLICATIONS

▪ High mortality rates ▪ Rupture: internal exsanguination; increased intracranial pressure (if in brain) ▪ Compression to surrounding structures: superior vena cava syndrome, aortic insufficiency ▪ Thrombosis/emboli: stagnant blood in extra lumen space ▪ Abdominal aortic aneurysm ▫ Rupture (bleeding can be retroperitoneal or into abdominal cavity), acute aortic occlusion, aortocaval/aortoduodenal fistulae (connections between

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aorta, inferior vena cava/duodenum, respectively) ▪ Thoracic aortic aneurysm ▫ Dissection, rupture (bleeding into thoracic cavity) ▪ Cerebral aneurysm ▫ Rupture (leads to hemorrhagic stroke or subarachnoid hemorrhage) ▫ If large, aneurysm can place pressure on surrounding cerebral tissue, causing neurological symptoms

SIGNS & SYMPTOMS ▪ Asymptomatic until rupture: severe pain in specific location (abdomen, chest, lower back, groin), pulsating mass, hypotension, syncope ▪ Abdominal aortic aneurysm ▫ On rupture: pain in abdomen/back, pulsating sensation in abdomen, low blood pressure, syncope ▫ Large aneurysms felt by pushing on abdomen

Chapter 3 Aneurysms & Dissection

DIAGNOSIS DIAGNOSTIC IMAGING Ultrasound ▪ Confirms presence, location, size; monitors growth CT scan ▪ Accurately measures; used pre-surgery CTA scan ▪ CT scan + injecting contrast dye shows blood flow; used for surgery

OTHER DIAGNOSTICS ECG ▪ Rules out myocardial infarction

TREATMENT MEDICATIONS

▪ Pharmaceutical treatments for blood pressure management

SURGERY

▪ Repair methods ▫ Surgical clipping: aneurysm clipped at base ▫ Endovascular coiling: platinum wires promote blood clotting, decrease blood flow through aneurysm ▫ Endovascular stenting: wire stent inside aneurysm allows blood to bypass aneurysm

OTHER INTERVENTIONS

▪ Goals, initially ▫ Prevent aneurysm rupture with regular ultrasound monitoring ▪ Goals for individuals receiving surgery for aneurysm ▫ Maintain tissue perfusion, motor and sensory function, prevent complications, i.e. infection/thrombosis ▪ Goals for post-operative individuals ▫ Maintain blood pressure/perfusion, especially renal perfusion ▫ Monitor urine output, peripheral pulses, capillary refill, skin temperature, abdominal girth, intra abdominal pressure, limb sensation and movement ▪ Monitor stent/graft patency

▪ Indications: aneurysms > 5cm/1.96in, 0.5cm/0.2in growth in six months, individual symptomatic

Figure 3.2 Illustration depicting Laplace’s law. Increasing diameter increases pressure on the walls of blood vessel. Similar to how a balloon becomes easier to fill with air as it inflates.

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Figure 3.3 A CT scan of the head in the left parasagittal plane demonstrating a saccular aneurysm of the internal carotid artery.

Figure 3.5 A CT scan of the chest in the coronal plane demonstrating a massive thoracic aortic aneurysm involving the ascending aorta. The aortic valve is faintly visible.

Figure 3.4 Abdominal CT scan in the axial plane demonstrating a ruptured abdominal aortic aneurysm.

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Chapter 3 Aneurysms & Dissection

AORTIC DISSECTION osms.it/aortic_dissection PATHOLOGY & CAUSES PATHOLOGY

▪ Tearing/widening of artery’s internal layer, followed by blood entering vessel wall, causing pain ▫ Typically affects aorta ▪ Tear forms in tunica intima of aorta → high pressure blood flows between tunica intima/tunica media → layer separation → false lumen → dilate aorta ▪ Most aneurysms develop in first 10 cm of aorta ▪ Can present acutely/chronically

TYPES Stanford classification ▪ Type A: dissection involves ascending aorta and/or aortic arch, sometimes descending aorta ▪ Type B: dissection involves descending aorta/aortic arch without involvement of ascending aorta

▪ Blood flow tears tunica media/tunica externa → severe internal bleeding → death ▪ Blood flow tears tunica intima again, return to true lumen (not severe) ▪ Obstruction of arterial branches off aorta, leading to ischemia of individual organs ▪ Blood tunnels, creates false lumen that extends to aortic branch → obstruction

SIGNS & SYMPTOMS ▪ Sudden, intense, tearing chest pain radiating to back, nausea, vomiting, diaphoresis ▪ Chronic dissections painless ▪ Decreased peripheral pulses, asymmetric pulses ▪ Hypertension/hypotension depending on location of dissection ▪ Diastolic decrescendo murmur: ascending aortic dissections → aortic regurgitation ▪ Neurological deficits: stroke, hemiplegia, syncope

CAUSES

▪ Weakness in vessel wall due to chronic hypertension, blood vessel coarctation, connective tissue disorders, aneurysms

RISK FACTORS

▪ Pregnancy, previous open heart surgery, vasculitis, trauma, family history of aortic dissection, Turner’s syndrome, cocaine use ▪ Cystic medial necrosis: familial inherited disorder causing degenerative breakdown of collagen, elastin, smooth muscle; wall weakens, predisposing individual to aneurysm/dissection

COMPLICATIONS

▪ Pericardial tamponade: most common cause of death

Figure 3.6 Gross pathology of an aortic dissection.

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DIAGNOSIS DIAGNOSTIC IMAGING Chest X-ray ▪ Widening of mediastinum consistent with dissection, but inadequate as sole evidence for diagnosis Transesophageal echocardiogram ▪ Best for hemodynamically-unstable individuals ▪ High sensitivity for identifying dissection, complications like aortic regurgitation, cardiac tamponade, involvement of coronary arteries CT angiography ▪ Best for hemodynamically-stable individuals ▪ High sensitivity for identifying dissection, can provide anatomic information useful in planning surgical repair; visualize/locate dissection

OTHER DIAGNOSTICS ECG ▪ Helps rule out alternative diagnostic possibilities, e.g. myocardial infarction

TREATMENT MEDICATIONS

▪ Stanford Type B: lower heart rate, blood pressure ▫ First line: beta-blockers ▫ Second line: calcium channel blockers ▫ Pain management for acute dissection

SURGERY

▪ Stanford type A: medical emergency, surgical repair indicated ▪ Stanford Type B: surgical repair indicated when dissection acute, complications arise, medication ineffective

Figure 3.7 Abdominal CT scan in the axial plane demonstrating an aortic dissection of the descending aorta. Note the media, dissected from the wall of the aorta, demarcating the true and the false lumen.

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NOTES

NOTES

BRADYCARDIA & HEART BLOCK

GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Delay or complete blockage in the electrical conduction system of the heart → abnormal heart rhythm; primarily, bradycardia

SIGNS & SYMPTOMS ▪ If symptomatic, may present as lightheadedness, headache, syncope, palpitations, Stokes–Adams attacks, fatigue, dyspnoea etc.

CAUSES

▪ Can be caused by defect in ▫ Atrioventricular node ▫ Bundle branches ▫ Sinoatrial node ▪ Idiopathic or secondary to ▫ Myocardial ischemia ▫ Fibrosis ▫ Infections ▫ Congenital heart disease ▫ Cardiomyopathies ▫ Iatrogenic (e.g. medication, postsurgery)

COMPLICATIONS

▪ May progress to fatal arrhythmias, heart failure, and/or sudden cardiac death

DIAGNOSIS ▪ ECG-based; see individual disorders

TREATMENT ▪ May not require treatment

MEDICATIONS ▪ E.g. atropine

OTHER INTERVENTIONS ▪ Transcutaneous pacing ▪ Pacemaker implantation

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ATRIOVENTRICULAR BLOCK osms.it/atrioventricular-block PATHOLOGY & CAUSES ▪ Blockage/delay in electrical signal stimulating contraction between atria, ventricles

TYPES

▪ First degree atrioventricular (AV) block ▪ Second degree atrioventricular block ▫ Type I/Mobitz I/Wenckebach ▫ Type II/Mobitz II ▪ Third degree atrioventricular block/complete heart block

CAUSES Congenital heart disease Heart damage ▪ Infiltrative/dilated cardiomyopathies, muscular dystrophy, lyme disease, myocardial ischemia, myocarditis, endocarditis with abscess, hyperkalemia, high vagal tone Iatrogenic causes ▪ Medication (beta blockers, calcium channel blockers, cardiac glycosides), post-cardiac surgery, post-catheter ablation, posttranscatheter aortic valve implantation Lev’s disease/Lenegre-Lev syndrome ▪ Idiopathic fibrosis and calcification of heart’s electrical conduction system, most common in elderly

COMPLICATIONS

▪ Heart failure secondary to bradycardia; third degree AV block risk for sudden cardiac death

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SIGNS & SYMPTOMS ▪ Presence/severity depends on ventricular rate ▫ Lightheadedness, syncope, fatigue, dyspnea

DIAGNOSIS OTHER DIAGNOSTICS ECG ▪ First-degree AV block ▫ Signal delayed; continues to ventricles ▫ PR interval > 200ms due to delayed ventricular contraction ▪ Second degree AV block ▫ Type I/Mobitz I/Wenckebach: PR interval lengthens with each beat until blocked completely (e.g. progressive PR intervals : 200ms → 260ms → 300ms → dropped beat; no QRS). Ventricular escape beat: if ventricle does not receive signal from atrioventricular node after short time, latent pacemaker cells within bundle of His/ventricle kick in, begin pacing heart at slower than normal rate (~20–50bpm) ▫ Type II/Mobitz II: prolonged PR interval (> 200ms). Block commonly in bundle of His → QRS usually wide (> 110ms), intermittent dropped beats (no QRS). Happens randomly; no progressive lengthening of PR interval; every second P wave blocked, may progress to third degree AV block ▪ Third degree AV block/complete heart block ▫ Signal completely blocked every time ▫ Eg. ventricles contract at lower rate than atria (ventricular pacemaker cells establish rate) ▫ No association between P waves, QRS complexes

Chapter 4 Bradycardia & Heart Block

TREATMENT ▪ Depends on type/severity ▫ For all: identify electrolyte imbalances/ medication-induced causes ▪ No treatment: ▫ First degree AV block, asymptomatic type I second degree

MEDICATIONS

MNEMONIC

AV blocks If the R is far from P, then you have a First Degree. Longer, longer, longer, drop! Then you have a Wenckebach. If some P’s don’t get through, then you have Mobitz II. If P’s and Q’s don’t agree, then you have a Third Degree.

▪ Atropine: second degree, third degree

OTHER INTERVENTIONS Permanent pacemaker ▪ Asymptomatic: type II second degree, third degree ▪ Symptomatic: type I & II second degree, third degree Transcutaneous pacing ▪ Symptomatic: type I & II second degree, third degree

Figure 4.1 ECG (lead II) demonstrating first degree atrioventricular block.

Figure 4.2 ECG (lead V1) demonstrating Mobitz I (Wenckebach) second degree atrioventiricular block.

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Figure 4.3 ECG (lead V1) demonstrating Mobitz II second degree atrioventricular block.

Figure 4.4 ECG (lead V1) demonstrating third degree (complete) atrioventricular block.

BUNDLE BRANCH BLOCK osms.it/bundle-branch-block PATHOLOGY & CAUSES ▪ Electrical signal for contraction of left/right ventricle completely blocked or delayed

Intermittent bundle branch block ▪ Occasional block, unrelated to heart rate

TYPES

Rate-related bundle branch block ▪ Block occurs when heart rate is relatively fast, temporarily resolves once heart rate slows down

▪ Either right or left bundle branch blocks can be complete or incomplete ▫ Complete: total blockage of signal transmission ▫ Incomplete: slowed signal transmission

Right bundle branch block (RBBB) ▪ Signal blocked in right bundle branch ▫ Left ventricle contracts first → signal carried to right side via Purkinje fibers → right ventricle contracts Left bundle branch block (LBBB) ▪ Signal blocked in left bundle branch ▫ Right ventricle contracts → left ventricle contracts Bilateral bundle branch block ▪ Caused by disease involving both right/left bundle branches; on ECG, indistinguishable

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from complete heart block and may lead to ventricular asystole

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CAUSES

▪ Fibrosis/scarring, formed acutely/chronically

Acute ▪ Ischemia, myocardial infarction, myocarditis ▪ Sudden increase in right ventricular pressure → pulmonary embolism ▪ Iatrogenic: right heart catheterization/ ethanol ablation of basal ventricular septum Chronic ▪ Gradual remodelling of heart muscle ▫ Hypertension, coronary artery disease, cardiomyopathies ▫ Pulmonary hypertension ▫ Congenital heart disease

Chapter 4 Bradycardia & Heart Block

RISK FACTORS

▪ Increasing age, associated with underlying or advancing heart disease

SIGNS & SYMPTOMS RBBB ▪ Asymptomatic; wide splitting on auscultation LBBB ▪ Asymptomatic; reversed splitting on auscultation

▪ LBBB only ▫ Negative V1, positive V6 (away from V1 towards V6) ▫ V1: QS, or “little r”-rS complex. W shape ▫ V6: large, notched R wave. M shape ▪ RBBB only ▫ Positive V1,negative V6 ▫ V1: large terminal R wave. M shape ▫ V6: slurred S wave, W shape

TREATMENT ▪ No treatment

DIAGNOSIS OTHER DIAGNOSTICS ECG ▪ LBBB and RBBB ▫ Lead II (limb lead) shows long QRS complex > 120ms (normal: 80–120ms) ▫ Longer QRS complex because depolarization starts on time but ends later due to depolarization delay in one ventricle

MNEMONIC: WiLLiaM MaRRoW

ECG of Left BBB W-shape in V1 Left BBB Left BBB has V6 M-shape ECG of Right BBB M-shape in V1 Right BBB Right BBB has V6 W-shape

Figure 4.5 Illustration depicting mnemonic “WiLLiaM MaRRoW.”

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Figure 4.6 ECG demonstrating left bundle branch block.

Figure 4.7 ECG demonstrating right bundle branch block.

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Chapter 4 Bradycardia & Heart Block

Figure 4.8 Illustration depicting wide QRS in bundle branch block.

Figure 4.9 Illustration depicting M-shape and W-shape in bundle branch blocks.

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SICK SINUS SYNDROME osms.it/sick-sinus-syndrome SIGNS & SYMPTOMS

PATHOLOGY & CAUSES ▪ Malfunction in sinoatrial node (SA node) characterized by persistent spontaneous sinus bradycardia, alternating sinus bradycardia and tachyarrhythmia (sometimes called tachycardia-bradycardia syndrome)

▪ Stokes–Adams attacks (fainting due to asystole/ventricular fibrillation), syncope, palpitations, chest pain, dyspnea, fatigue, headache, nausea ▪ Variable ECG findings

DIAGNOSIS

CAUSES

▪ Disorders causing scarring/degeneration/ damage to SA node ▫ Sarcoidosis, amyloidosis, hemochromatosis, Chagas disease, cardiomyopathies ▪ Can be caused/worsened by certain medications ▫ Digoxin, calcium channel blockers, beta blockers, anti-arrhythmics ▪ Congenital ▫ Mutations of SCN5A gene encoding alpha subunit of sodium ion channel

RISK FACTORS ▪ ▪ ▪ ▪

Elderly Coronary artery disease High blood pressure Aortic, mitral valve diseases

COMPLICATIONS

▪ Sinus arrest, sinus node exit block, sinus bradycardia ▫ May be associated with tachycardia (characterized by long pause after tachycardia), e.g. atrial tachycardia, atrial fibrillation ▫ Associated with azygos continuation of interrupted inferior vena cava

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DIAGNOSTIC IMAGING ECG

OTHER DIAGNOSTICS ▪ Tilt table testing ▪ Holter monitor

TREATMENT OTHER INTERVENTIONS Pacemaker implantation ▪ For hemodynamically stable individuals, tachycardia can be treated with medication; can be combined with pacemaker in some cases ▪ For hemodynamically unstable individuals, definitive therapy requires pacemaker implantation; medication plays limited role

NOTES

NOTES

CARDIAC TUMORS GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Abnormal cell growth forms mass in heart

TYPES Primary ▪ Rare ▫ Adults: myxoma ▫ Children: rhabdomyoma Secondary ▪ More common than primary ▪ Metastases from cancer in other areas (lung cancer, lymphoma, breast cancer, leukemia, melanoma, hepatocellular carcinoma, colon cancer) ▫ Lymphogenous/hematogenous dissemination

COMPLICATIONS

▪ Impaired left ventricular structure, filling, ejection caused by tumor ▪ Arrhythmias: tumor disrupts normal nodal/ septal electrical conduction ▪ Heart failure: tumor obstructs inflow/ outflow ▪ Recurrence of tumor after excision (if tumor not completely removed) ▪ Embolism, sudden cardiac death, myocardial infarction

SIGNS & SYMPTOMS ▪ Asymptomatic ▫ Incidental finding on echocardiogram, MRI, CT scan ▪ Dyspnea ▫ Most common symptom ▫ Can progress to orthopnea, paroxysmal nocturnal dyspnea ▪ “Tumor plop” sound upon auscultation with left atrial myxoma ▪ Syncope, presyncope, dizziness, chest pain/ tightness

DIAGNOSIS DIAGNOSTIC IMAGING

▪ MRI, CT scan, ultrasound ▫ Incidental finding ▫ See individual disorders ▪ 2D echocardiogram preferred procedure

LAB RESULTS

▪ Histology conducted on biopsy via surgical excision/fine needle aspiration

TREATMENT SURGERY

▪ Symptomatic: surgical resection

OTHER INTERVENTIONS ▪ Asymptomatic: monitor

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ATRIAL MYXOMA osms.it/atrial-myxoma PATHOLOGY & CAUSES

SIGNS & SYMPTOMS

▪ A benign heart tumor ▪ Most common primary cardiac tumor in adults ▪ Arises in heart’s mesenchymal connective tissue ▪ Most common in left atrium, may cause syncope ▫ Tumor in left atrium → obstructs mitral valve ▪ Histology ▫ Pedunculated (attached to tissue stalk) ▫ Gelatinous due to abundance of ground substance

▪ Asymptomatic: incidental finding on echocardiogram, MRI, CT scan ▪ Dyspnea: most common symptom ▫ Can progress to orthopnea, paroxysmal nocturnal dyspnea ▪ “Tumor plop” sound upon auscultation with left atrial myxoma ▪ Syncope, presyncope, dizziness, chest pain/ tightness

RISK FACTORS

▪ Age 40–60 ▪ More common in biological females ▫ Less pronounced in familial atrial myxoma ▪ Genetic disease

DIAGNOSIS LAB RESULTS Histology ▪ Stellate myxoma cells in myxoid stroma of glycosaminoglycans

TREATMENT SURGERY

▪ Symptomatic: resection

OTHER INTERVENTIONS ▪ Asymptomatic: monitor

Figure 5.1 Surgically excised atrial myxoma. A small piece of myocardium marks the point of attachment.

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Chapter 5 Cardiac Tumors

Figure 5.2 Histological appearance of a myxoma with abundant mucoid matrix (pink background) and scanty, bland spindle cells with low mitotic activity.

Figure 5.3 A sagittal CT scan demonstrating a myxoma in the left atrium.

RHABDOMYOMA osms.it/rhabdomyoma PATHOLOGY & CAUSES ▪ Benign tumor of striated muscle ▪ Most common primary cardiac tumor in infants/children ▪ Arises in ventricles ▪ Presents congenitally ▪ Benign hamartoma (abnormal tissue formation) ▪ Association between rhabdomyoma/ tuberous sclerosis about 30–50% ▪ Often regresses spontaneously ▪ Shrink with age

RISK FACTORS

▪ More common in children ▪ More common in biological males (2.4:1 male-female ratio) ▪ Average presentation age is four years old

▪ Associated with nevoid basal cell carcinoma syndrome ▪ Genetic disease

DIAGNOSIS DIAGNOSTIC IMAGING MRI, CT scan, ultrasound ▪ Incidental finding Ultrasound, MRI ▪ Visualize tumor

LAB RESULTS Histology ▪ Hamartomatous growths surrounded in a glycogen-rich eosinophilic cytoplasm

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SIGNS & SYMPTOMS ▪ Usually present at birth ▪ Tender, painful, benign, slow-growing nodules ▫ Common in neck/mouth/larynx, may cause breathing difficulties

TREATMENT SURGERY

▪ Symptomatic: surgical resection

Figure 5.4 A surgically excised rhabdomyoma.

OTHER INTERVENTIONS ▪ Asymptomatic: monitor

Figure 5.5 Histological appearance of a rhabdomyoma composed of plump, pink skeletal muscle cells.

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NOTES

NOTES

CARDIOMYOPATHY GENERALLY, WHAT IS IT? DIAGNOSIS

PATHOLOGY & CAUSES ▪ Broad term, describes any issue resulting from disease of myocardium ▪ Primary cardiomyopathy: issue develops of its own accord ▪ Secondary cardiomyopathy: issue develops as compensation for another underlying disease

DIAGNOSTIC IMAGING

▪ Chest X-ray ▪ Echocardiogram/cardiac MRI

OTHER DIAGNOSTICS ▪ ECG

TREATMENT

RISK FACTORS

▪ Positive family history

COMPLICATIONS

▫ Heart failure, arrhythmias, sudden cardiac death

SIGNS & SYMPTOMS ▪ Can be asymptomatic ▪ Heart failure signs, symptoms ▪ Heart murmurs

MEDICATIONS

▪ See individual diseases

SURGERY

▪ Implantable cardioverter-defibrillator (ICD) ▪ Heart transplant

OTHER INTERVENTIONS ▪ Lifestyle changes

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DILATED CARDIOMYOPATHY osms.it/dilated-cm PATHOLOGY & CAUSES ▪ Dilation of all four chambers of heart ▪ Most common type of cardiomyopathy ▫ New sarcomeres added in series, creates larger chambers with relatively weak walls, less muscle for contraction → low systolic function ▫ Chambers stretch → valves stretch → blood regurgitates back into atria

CAUSES

▪ Primary dilated cardiomyopathy most often idiopathic

Genetic mutations/conditions ▪ Duchenne muscular dystrophy (DMD), hemochromatosis Myocarditis ▪ Can progress from myocarditis to dilated cardiomyopathy Infection ▪ Coxsackievirus B: leads to myocarditis, heart muscle inflammation ▪ Chagas disease: protozoal infection Linked to alcoholism ▪ Alcohol, metabolites have direct toxic effect on heart muscle Linked to certain drugs ▪ Chemotherapy: doxorubicin, daunorubicin ▪ Cocaine Wet beriberi ▪ Beriberi: illness caused by thiamine (vitamin B1) deficiency ▪ Wet beriberi: affects heart; ↓ thiamine levels impair myocardium energy production Peripartum cardiomyopathy ▪ Can develop in third trimester of pregnancy/ weeks after delivery

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▫ Related to pregnancy-associated hypertension ▫ Half of individuals recover following pregnancy Sarcoidosis ▪ Growth of granulomas in heart → dilation

RISK FACTORS

▪ Alcoholism, past family history of diseases implicated in DMD

COMPLICATIONS

▪ Systolic heart failure ▫ Valve regurgitation: as chambers stretch, so do valves ▪ Arrhythmias: stretching muscle irritates conduction system

MNEMONIC: ID BIG MAPS Causes of Dilated Cardiomyopathy Idiopathic Drugs/Doxorubicin (and cocaine) Beriberi (wet) Infection Genetic Myocarditis Alcoholism Peripartum cardiomyopathy Sarcoidosis

Chapter 6 Cardiomyopathy

TREATMENT

SIGNS & SYMPTOMS ▪ Fatigue, dyspnea ▪ Lateral displaced point of maximum impulse (PMI) ▪ Chest pain on exertion ▪ Holosystolic murmur (mitral valve regurgitation during systole) ▪ S3 sound (blood rushing into, slamming into dilated ventricular wall during diastole)

DIAGNOSIS DIAGNOSTIC IMAGING X-ray ▪ Cardiomegaly, pulmonary edema, pleural effusion

MEDICATIONS

▪ Angiotensin-converting-enzyme (ACE) inhibitor, angiotensin receptor blocker, beta blocker ▫ Slows disease progression

SURGERY

▪ Heart transplant (extreme cases)

OTHER INTERVENTIONS

▪ Left ventricular assist device (LVAD): mechanical pump assists heart in delivering blood to body

OTHER DIAGNOSTICS ECG ▪ Shows ventricular dilation, reduced ejection fraction

Figure 6.1 Gross pathology of dilated cardiomyopathy. Note the large ventricles and thin ventricular walls.

Figure 6.2 A chest radiograph demonstrating enlargement of the heart due to dilated cardiomyopathy. The heart occupies more than half the width of the chest.

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HYPERTROPHIC CARDIOMYOPATHY (HCM) osms.it/hypertrophic-cm PATHOLOGY & CAUSES ▪ Myocardium becomes thick, heavy, hypercontractile ▪ Myocytes become disorganized, new sarcomeres added in parallel to existing ones ▪ Left ventricle most often affected ▫ Muscle growth asymmetrical → interventricular septum grows larger relative to free wall ▪ Hypertrophy → walls taking up more space, ↓ blood fills ventricle ▫ Walls become stiff, less compliant → less filling → low stroke volume → dysfunction in diastolic filling of left ventricle → diastolic heart failure ▪ Arrhythmias: larger muscles require more oxygen, coupled with heart having difficulty delivering blood to tissues → ischemia → arrhythmias

CAUSES Genetic missense mutation, inherited as autosomal dominant trait ▪ Different genetic mutations affect different sarcomere proteins ▪ Friedreich’s ataxia: autosomal recessive neurodegenerative disease Hypertrophic obstructive cardiomyopathy (subtype) ▪ Interventricular septum growth blocks left ventricular outflow tract during systole → blood must flow quickly through small opening, ↓ pressure in this area ( Venturi effect) → low pressure pulls anterior leaflet of mitral valve toward septum → further mitral valve obstruction towards septum → further obstruction overall

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COMPLICATIONS

▪ Arrhythmias, sudden cardiac death

RISK FACTORS

▪ Positive family history of HCM/conditions known to be associated with HCM (e.g. Friedreich’s ataxia)

SIGNS & SYMPTOMS ▪ Many individuals asymptomatic ▪ Auscultation: crescendo-decrescendo murmur ▫ ↑ intensity with ↓ venous return (Valsalva, standing), ↓ in intensity with ↑ venous return (handgrip, squatting) ▪ Symptoms arise as complications arise ▫ Dyspnea: left ventricle stiffening, atrium increasing back pressure into lungs → interstitial lung congestion ▫ Fatigue ▫ Exertional chest pain: ischemia ▫ Syncope with exertion: brain receiving low oxygen ▫ Palpitations: ischemia, arrhythmias ▫ Sudden cardiac death ▪ May exhibit bifid pulse: two pulses felt ▫ Mitral valve moves toward outflow tract → ↑ obstruction mid-systole

Chapter 6 Cardiomyopathy

DIAGNOSIS DIAGNOSTIC IMAGING Echocardiography/cardiac MRI ▪ Enlarged heart chambers/↓ ejection fraction Chest X-ray ▪ ↑ ratio of distance between heart, thoracic cage

LAB RESULTS Genetic testing ▪ Cardiomegaly-implicated gene mutations

OTHER DIAGNOSTICS ECG ▪ Detectable electrical changes, such as left ventricular hypertrophy

TREATMENT MEDICATIONS

Disopyramide ▪ Can be used for its negative inotropic properties Digoxin contraindicated ▪ ↑ force of contraction, can ↑ obstruction

SURGERY

▪ Implantable cardioverter-defibrillator

Surgical septal myectomy ▪ Involves removing portion of interventricular septum, ↓ obstruction Septal ablation ▪ Chemical myomectomy to partially ablate septum Heart transplant ▪ If unresponsive to all other forms of treatment

OTHER INTERVENTIONS Lifestyle change ▪ Cessation of high-intensity athletics

Beta blockers ▪ ↓ heart rate, contractile force Calcium channel blockers ▪ If beta blockers not tolerated ▪ Slows down heart rate

Figure 6.4 The histological appearance of the myocardium in a case of hypertrophic cardiomyopathy. There is complete myocyte disarray. The myocytes display bizarre forms with side to side branching and are arranged in a whorled configuration.

Figure 6.3 Gross pathology of hypertrophic cardiomyopathy. The myocardium has become so enlarged that both ventricles are almost entirely obliterated.

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Figure 6.5 Illustration showing the Venturi effect: low blood pressure pulls the anterior leaflet of the mitral valve towards the septum, creating an obstruction. Blood can’t get through the small opening, leading to a crescendo-descrescendo heart murmur.

RESTRICTIVE CARDIOMYOPATHY osms.it/restrictive-cm PATHOLOGY & CAUSES ▪ Cardiomyopathy: heart wall is rigid, has difficulty stretching, pumping ▪ Ventricles restrict filling, ↓ cardiac output

CAUSES

▪ Infiltrative diseases, storage diseases, endomyocardial diseases.

Amyloidosis ▪ Amyloids are misfolded proteins → insoluble → deposit in tissues, organs → organs less compliant ▪ Familial amyloid cardiomyopathy ▪ Mutant transthyretin (TTR) protein; misfolded deposits preferentially in heart tissue ▪ Senile cardiac amyloidosis; TTR protein/ wild type TTR deposits in heart over time Sarcoidosis ▪ Immune cell collections form granulomas in

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heart tissue Endocardial fibroelastosis ▪ Fibrosis develops in endocardium (inner lining of heart) and subendocardium (layer underneath endocardium) Loffler syndrome ▪ Eosinophils accumulate in lung tissue ▪ Loeffler endocarditis/Loeffler endomyocarditis: eosinophils also accumulate in endocardial layer of heart tissue → inflammation, endocardial fibrosis → restrict heart tissue Hemochromatosis ▫ Iron deposits in heart tissue, contributes to restricted tissue Other causes ▪ Heart tissue radiation ▫ Radiation generates reactive oxygen species → inflammation over time → myocardial fibrosis → tissue stiff,

Chapter 6 Cardiomyopathy restrictive

COMPLICATIONS

▪ Can → diastolic heart failure ▫ Stiff ventricles → cannot stretch → less filling → low cardiac output → heart failure

MNEMONIC: LASHER

Causes of Restrictive cardiomyopathy Loffler syndrome Amyloidosis Sarcoidosis Hemochromatosis Endocardial fibroelastosis post-Radiation

SIGNS & SYMPTOMS ▪ Auscultation: stiff ventricle → S4 heart sound ▪ Presents as congestive heart failure: dyspnea; paroxysmal nocturnal dyspnea; orthopnea; crackles; intraalveolar hemorrhage; fatigue; inability to exercise; appetite loss; abdomen swelling; swelling of feet, ankles; uneven/rapid pulse; chest pain; low urine output; nocturia

Figure 6.6 Histological appearance of the myocardium in a case of cardiac amyloidosis; a cause of restrictive cardiomyopathy. Cardiac myocytes (dark purple) are surrounded by amyloid deposits (light pink).

TREATMENT MEDICATIONS Loop diuretics ▪ ↓ systemic, pulmonary congestion Beta-blocker, calcium channel blocker, angiotensin converting enzyme inhibitors ▪ Slows heart rate, ↑ ventricular-filling time

SURGERY

▪ Heart transplant

DIAGNOSIS OTHER DIAGNOSTICS ECG ▪ Low-amplitude signals: peak to nadir measurement of QRS complex being < 5mm (limb leads)/< 10mm (precordial leads). Low voltage produced due to loss of viable myocardium ▪ Small QRS complexes: QRS complexes represent ventricular contraction, restricted tissue → weaker contraction

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NOTES

CORONARY ARTERY DISEASE

STABLE ANGINA PECTORIS osms.it/stable-angina PATHOLOGY & CAUSES ▪ Episodic chest pain because of inadequate oxygen supply to the heart, most often due to obstruction in the coronary arteries ▪ Most common type of angina ▫ Angina pectoris refers to a specific type of chest pain caused by lack of blood flow to the heart muscle. Pain often presents as pressure, fullness, squeezing pain in the center of the chest ▫ In angina → ischemia in the subendocardium → triggers release of adenosine and bradykinin → pain

CAUSES Atherosclerosis ▪ Causes plaque buildup in vessel; blood flow to heart muscle limited ▫ As plaque becomes larger and blocks more flow, pain arises with lower levels of exertion Tachyarrhythmias ▪ Increased heart rate increases heart’s demand for oxygen that cannot be delivered, thus causing pain Pulmonary hypertension ▪ Left main coronary artery can become compressed by enlarged pulmonary artery trunk, leading to reduced perfusion and pain Increased myocardial oxygen demand ▪ Consequence of increased left ventricular

mass secondary to concentric hypertrophy, and an increased afterload due to the fixed obstruction to left ventricular outflow Genetic hypertrophic cardiomyopathy ▪ Cardiac hypertrophy leads to increased oxygen demand of heart muscle. In times of high exertion, the heart cannot supply enough oxygen and ischemia results

RISK FACTORS

▪ Smoking, hypertension, diabetes, dyslipidemia (high LDL, low HDL, and high triglycerides), obesity, family history of coronary artery disease

Protective factors ▪ Modest alcohol consumption (~one drink/ day), healthy diet (e.g., lots of vegetables, grains, and nuts), and regular exercise

SIGNS & SYMPTOMS ▪ Chest pain coinciding with increased exertion or stress. Pain described as pressure, squeezing, burning, or tightness; can radiate to the either/both arms, jaw, shoulders, and back ▫ Pain usually lasts less than 20 minutes ▪ Other symptoms: Levine’s sign (a clenched fist held over the chest), dyspnea, diaphoresis, fatigue, nausea, and epigastric pain ▫ Angina equivalent: These “other symptoms” felt without chest pain during periods of coronary ischemia (more common in diabetics, biologicallyfemale individuals, elderly)

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DIAGNOSIS ▪ Primarily based on signs/symptoms; “clinical diagnosis”

OTHER DIAGNOSTICS Electrocardiogram (ECG) ▪ Stable angina can present with ST segment depression ▫ May also present with T wave inversions ▫ Illustrates subendocardial ischemia ▫ Dynamic ECG changes: changes in ECG are seen for duration of symptoms, but can reduce in intensity or disappear when symptoms abate (e.g. individual may start with 2mm ST depressions with no chest pain, but then get 4mm ST depressions during an episode of unstable angina at rest, which revert to 2mm ST depressions once episode is concluded) ▪ Other tests may be required to obtain more specific information

TREATMENT MEDICATIONS Sublingual nitroglycerin ▪ The classic regimen for stable angina; as needed, daily aspirin, beta blockers and statin Nitrates and Vasodilator ▪ Nitrates treat immediate pain ▪ Vasodilator causes venodilation, which decreases preload, reducing oxygen demand of the heart ▪ Nitroglycerin ▫ Used to treat immediate pain on asneeded basis ▪ Isosorbide mononitrate ▫ Used for prevention Beta blockers ▪ Reduce myocardial oxygen demand by reducing heart rate and contractility ▪ First line medication for stable angina Statins ▪ Preventative. Lowers low density lipoproteins, improves dyslipidemia Aspirin ▪ Preventative. Prevents thrombosis by blocking platelet activation, reduces chance of stable angina → unstable angina

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NOTES

CYANOTIC DEFECTS GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Heart defects with cyanotic presentation: blue discoloration of skin/mucous membranes, typically seen at fingertips, lips, extremities ▪ Develop in utero ▪ Persistent truncus arteriosus, hypoplastic left heart syndrome, transposition of great vessels can lead to heart failure ▪ Persistent truncus arteriosus, tetralogy of Fallot can lead to Eisenmenger syndrome

SIGNS & SYMPTOMS ▪ Cyanosis ▪ See individual disorders

DIAGNOSIS DIAGNOSTIC IMAGING ▪ Prenatal ultrasound ▪ Echocardiography ▪ Chest X-ray

OTHER DIAGNOSTICS ▪ ECG

TREATMENT MEDICATIONS

▪ See individual disorders

SURGERY

▪ Definitive treatment

OTHER INTERVENTIONS ▪ Lifestyle changes

Figure 8.1 Illustration depicting blood flow in hypoplastic left heart syndrome.

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HYPOPLASTIC LEFT HEART SYNDROME osms.it/hypoplastic-left-heart-syndrome PATHOLOGY & CAUSES

SIGNS & SYMPTOMS

▪ Congenital underdevelopment of left heart

▪ Respiratory distress, poor feeding/failure to thrive, left-sided heart failure

CAUSES

▪ Unknown: primary congenital heart defect may reduce flow through left ventricle/ left outflow tract, affect other heart malformations ▪ Underdeveloped left ventricle, ascending aorta ▫ Aortic/mitral valves may also be affected, narrow, or absent (atresia) ▪ If untreated: left-sided heart failure → cardiogenic shock → death

Atrial septal defect (ASD) and Patent ductus arteriosus (PDA) ▪ ASD/PDA required for post-natal survival in hypoplastic left heart syndrome ▪ With ASD, PDA: right heart function present but impaired; sometimes asymptomatic at birth ▫ Oxygenated blood in left atrium flows into right atrium through ASD → pulmonary artery → PDA → aorta → body ▫ Within one day: ductus arteriosus begins closing → cyanosis ▪ Without ASD, PDA: heart not capable of sustaining life outside womb ▫ Right heart functions normally → oxygenated blood enters left atrium → flow backs up due to small mitral valve, small left ventricle → high pressure in left atrium, blood circulated ineffectively by left ventricle

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DIAGNOSIS DIAGNOSTIC IMAGING Prenatal ultrasound Chest X-ray ▪ Cardiomegaly

OTHER DIAGNOSTICS ECG ▪ Right ventricular hypertrophy ▪ After birth

TREATMENT MEDICATIONS

▪ Prostaglandin E1 keeps ductus arteriosus open until surgery can be performed

SURGERY

▪ Surgical repair/heart transplant based on complexity

Chapter 8 Cyanotic Defects

PERSISTENT TRUNCUS ARTERIOSUS osms.it/truncus_arteriosus PATHOLOGY & CAUSES ▪ Truncus arteriosus fails to divide into aorta/ pulmonary artery ▪ Single giant artery branching off from right, left ventricles which splits into aorta, pulmonary artery ▪ Oxygenated, deoxygenated blood mix ▪ Deoxygenated blood mixes into systemic circulation → cyanosis

CAUSES

▪ Associated with DiGeorge syndrome/22q11.2 deletion syndrome (abnormal tissue formation during development) ▪ Before birth, deoxygenated blood sent to mother, oxygenated blood arrives from mother ▫ Fetal heart sends blood through foramen ovale ▫ Oxygenated, deoxygenated blood mix in truncus arteriosus. Both circulations get same amount of oxygenated, deoxygenated blood ▫ Otherwise normal fetal development ▪ After birth, the baby relies on own lungs → foramen ovale closes ▫ Deoxygenated, oxygenated blood still mixed → cyanosis ▫ Excess blood shunted to pulmonary circuit, as pressure in pulmonary circuit is less than pressure of systemic circuit

RISK FACTORS

▪ Combination of genes, maternal environment ▪ Smoking, excessive alcohol intake, teratogenic medications during pregnancy; gestational diabetes; viral illness during pregnancy (e.g. German measles);

associated with genetic disorders (DiGeorge syndrome)

COMPLICATIONS

▪ Cardiomegaly ▪ Pulmonary hypertension, can progress to permanent lung damage ▪ Respiratory problems ▪ Arrhythmia ▪ Valve regurgitation

SIGNS & SYMPTOMS ▪ Difficulty breathing, pounding heart, weak pulse, poor feeding/failure to thrive, lethargy ▪ With physical exertion (severity varies) ▫ Dizziness, fatigue, palpitations, dyspnea ▪ Impaired growth ▪ Auscultation ▫ Loud systolic murmur along left sternal border due to increased flow through mitral valve ▫ Constant ejection click before S2 (closure of aortic, pulmonic valves) ▫ Diastolic flow murmur at apex when pulmonary blood flow increases

DIAGNOSIS DIAGNOSTIC IMAGING X-ray ▪ Shows heart size, lung abnormalities, possible presence of excess fluid in lungs Echocardiogram ▪ Single large vessel arising from left, right ventricles ▪ Abnormalities of valves between large

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vessel and ventricle it arises from ▪ May show abnormal blood movement between right, left ventricle, and volume of blood flow to lungs

OTHER DIAGNOSTICS

▪ Newborn pulse oximetry screening ▫ Low oxygen saturation ▫ Diagnose before symptoms develop

ECG ▪ Atrial enlargement (notching of P waves/P mitrale) ▪ Ventricular hypertrophy ▪ Abnormal T waves ▪ Right axis deviation

TREATMENT ▪ In rare cases, babies may survive into adulthood without surgical repair

MEDICATIONS Diuretics ▪ Gets rid of excess fluid (e.g. chlorothiazide)

Inotropic agents ▪ Strengthens cardiac contractions (e.g. Digoxin, treats congestive heart failure, slows down heart rate, increases force of contractions) Prophylaxis ▪ Antibiotics during dental/other surgical procedures to avoid infections

SURGERY

▪ Goal: restore normal blood flow through heart ▪ Procedures vary depending on individual anatomy ▫ Close hole between right/left ventricles ▫ Separate large vessel into pulmonary artery, aorta ▫ Reconstruct single large vessel into new, complete aorta ▫ Implant new tube, valve to connect right ventricle with upper part of pulmonary artery, creating new, complete pulmonary artery

OTHER INTERVENTIONS

▪ Lifestyle: possible limitation on intense physical activity ▪ Lifelong monitoring

Figure 8.2 llustration depicting blood flow through the heart in persistent truncus arteriosus.

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Chapter 8 Cyanotic Defects

Figure 8.3 Gross pathology of a persistent truncus arteriosus. Both the left and right ventricles pump blood to both the aorta and pulmonary artery through a quadricuspid truncus valve.

Figure 8.4 Gross pathology of a persistent truncus arteriosus. Both the left and right ventricles pump blood to both the aorta and pulmonary artery through a quadricuspid truncus valve.

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TETRALOGY OF FALLOT osms.it/tetralogy-of-fallot PATHOLOGY & CAUSES

SIGNS & SYMPTOMS

▪ Combination of four congenital heart abnormalities ▪ Right ventricular outflow tract stenosis (pulmonic stenosis): obstructs pulmonary circulation ▪ Right ventricular hypertrophy: compensates for right ventricular outflow tract stenosis ▪ Ventricular septal defect (VSD): hole in wall between ventricles. High pressure in right ventricle → blood shunts from right to left → deoxygenated blood to body ▪ Aorta overrides ventricular septal defect: aorta in abnormal position. Variable presentations

▪ Depend upon severity of stenosis ▪ Less severe right ventricular outflow obstruction often asymptomatic ▪ Cyanosis around lips, fingernails (“blue baby syndrome” ) ▪ Poor feeding/failure to thrive ▪ Harsh holosystolic murmur at left upper sternal border → sounds like pulmonary stenosis ▫ Right ventricular heave ▪ Older infants, children ▫ Clubbed fingers, toes after a few months ▫ Exertional dyspnea ▫ Hypercyanotic episode (tet spell): on exertion, infant’s oxygen demands increase → sudden decrease in oxygen saturation → cyanosis

CAUSES

▪ Arises during cardiovascular development ▪ Most common cause of cyanotic congenital heart defects ▪ Four abnormalities together cause ▫ Mixing oxygenated, deoxygenated blood ▫ Narrowed vessels/valves that increase cardiac workload ▪ Severity of stenosis affects blood flow, changing pressure differentials ▫ Mild stenosis: left-right shunt → oxygenated blood simply goes through pulmonary circulation again ▫ Severe stenosis: right-left shunt → deoxygenated blood enters body circulation → less oxygen to tissues ▪ Leads to pulmonic regurgitation: blood flows backwards into RV, right heart overloads, can cause right-sided heart failure ▪ Associated with alcohol exposure in utero, maternal age 40+ years, poor nutrition or viral illness during pregnancy (e.g. rubella), Down syndrome or DiGeorge syndrome, positive family history of tetralogy of Fallot

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DIAGNOSIS DIAGNOSTIC IMAGING Echocardiography ▪ Pre/postnatal Chest X-ray ▪ “Boot-shaped” heart

MNEMONIC: PROVe

Components of tetralogy of Fallot Pulmonary infundibular stenosis Right ventricle hypertrophy Overriding aorta Ventricular septal defect

Chapter 8 Cyanotic Defects

OTHER DIAGNOSTICS ECG ▪ Right ventricular hypertrophy, right atrial enlargement

TREATMENT MEDICATIONS Prostaglandin E1 analogs (alprostadil) ▪ Severe cases ▪ Keep ductus arteriosus open → improve cyanosis until surgery

Figure 8.5 Digital clubbing in an adult with tetralogy of Fallot.

OTHER INTERVENTIONS

▪ Treat tet spell ▫ Infants squat to reduce cyanosis: kinks femoral arteries → increases vascular resistance → increases systemic pressure → increases pressure in left ventricle to greater than pressure in right ventricle → reverse shunt to leftright → resolve cyanosis

SURGERY

▪ Cardiac repair surgery (first year of life) ▫ VSD patch closure (only oxygenated blood flows from left ventricle into aorta) ▫ Right ventricular outflow tract enlarged

Figure 8.6 A chest radiograph of an infant demonstrating the classic boot-shaped heart seen in tetralogy of Fallot.

Figure 8.7 Illustration depicting blood flow through a heart with Tetralogy of Fallot.

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TOTAL ANOMALOUS PULMONARY VENOUS RETURN osms.it/anomalous-pulmonary-venous PATHOLOGY & CAUSES ▪ Congenital heart defect characterized by anomalous connection of the pulmonary veins and the heart ▪ Occurs during first eight weeks of fetal development; cause unknown

TYPES Supracardiac variant ▪ Most common ▪ Pulmonary veins open into brachiocephalic veins/superior vena cava (SVC) Cardiac variant ▪ Pulmonary veins open into coronary sinus/ right atrium Infradiaphragmatic variant ▪ Pulmonary veins open into portal/hepatic veins Mixed variant ▪ Oxygenated blood travels through pulmonary veins to right atrium/veins → blood does not leave pulmonary circulation → no systemic circulation ▪ Incompatible with life unless foramen ovale/patent ductus arteriosus present → oxygenated and deoxygenated blood mix → established connection between pulmonary and systemic circulation ▪ Anomalous connections often accompanied by pulmonary vein obstruction → pulmonary venous hypertension, severe cyanosis

COMPLICATIONS

▪ Recurrent pulmonary vein stenosis

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SIGNS & SYMPTOMS ▪ Severity of symptoms depend upon presence/degree of obstruction ▪ Cyanosis, tachypnea, tachycardia, dyspnea, failure to thrive, recurrent respiratory infections ▪ In case of infradiaphragmatic variant: liver enlargement

DIAGNOSIS DIAGNOSTIC IMAGING Chest X-ray ▫ Snowman sign (figure of 8): dilated SVC, pulmonary vein, brachiocephalic artery formshead; dilated right atrium forms snowman’s body Echocardiography ▪ Right ventricular and pulmonary artery volume loading ▪ Might show left atrium with no connecting veins

LAB RESULTS

▪ Assess oxygenation and acid-base status: decreased values

OTHER DIAGNOSTICS ECG ▪ Right ventricular hypertrophy Auscultation ▪ Systolic ejection murmur ▪ Increased pulmonary component of S2 ▪ Split S2 ▪ S3 gallop

Chapter 8 Cyanotic Defects

TREATMENT SURGERY

▪ Surgery to establish blood flow from the right atrium to left atrium

▫ If present, pulmonary venous obstruction must be identified and treated promptly

OTHER INTERVENTIONS ▪ Cardiac catheterization

TRANSPOSITION OF THE GREAT VESSELS (TGA) osms.it/transposition_of_great_vessels PATHOLOGY & CAUSES ▪ Abnormal development causes aorta to arise from right ventricle, pulmonary artery to arise from left ventricle ▪ Transposition creates two small circuits of blood flow rather than one large ▫ Right side: right ventricle → aorta → body → right atrium → right ventricle (blood never oxygenated) ▫ Left side: left ventricle → pulmonary artery → lungs → pulmonary veins → left atrium → left ventricle (blood never deoxygenated) ▪ After birth → lungs used for oxygen → foramen ovale, ductus arteriosus close → no exchange between two circuits → cyanosis, death ▪ Sometimes, foramen ovale or ductus arteriosus stay open, or baby has ventricular septal defect (VSD); allows blood to circulate ▪ Different levels of severity of transposition of the great arteries (TGA) ▫ d-TGA: dextro-TGA/complete TGA (dextro = aorta on right) ▫ l-TGA: levo-TGA/congenitally corrected TGA (levo = aorta on left). Ventricles, valves switched. Great vessels in normal orientation, but connected to wrong ventricle. Normal blood flow circuits preserved

RISK FACTORS

▪ During pregnancy: diabetes, rubella, poor nutrition, consumption of alcohol, > 40 years old

SIGNS & SYMPTOMS ▪ In utero: asymptomatic ▪ d-TGA: ▫ Cyanosis, unchanged with supplemental oxygen (less severe if VSD present) ▫ Tachypnea ▫ Acidosis ▪ l-TGA: ▫ Asymptomatic

DIAGNOSIS DIAGNOSTIC IMAGING Echocardiogram ▪ Evaluate heart function, structure Chest X-ray ▪ Classic triad ▫ Heart appears as egg on its side/“egg on a string” appearance ▫ Lung congestion ▫ Cardiomegaly Angiogram ▪ Pre-surgery

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TREATMENT MEDICATIONS

▪ Prostaglandin E: short-term solution. Keeps ductus arteriosus open

SURGERY

▪ Balloon atrial septostomy: short-term solution. Hole created in atrial septum ▪ Surgically switch great vessels ▫ Five year survival rate > 80% ▫ No treatment: one year survival rate 10%

Figure 8.8 Chest radiograph in both a lateral (L) and frontal (R) view, demonstrating the “egg on a string” sign of transposition of the great vessels.

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Chapter 8 Cyanotic Defects

Figure 8.9 Illustration depicting blood flow through a heart with dextro transposition of the great arteries.

Figure 8.10 Illustration depicting blood flow through a heart with levo transposition of the great arteries.

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NOTES

HEART FAILURE GENERALLY, WHAT IS IT? PATHOLOGY & CAUSES ▪ A complex clinical syndrome characterized by the heart’s inability to effectively fill and/ or eject (pump) blood ▪ Stroke volume (SV): volume (mL) of blood pumped by heart per contraction ▪ Cardiac output (CO): volume of blood pumped by heart per minute (L/min) ▫ CO = SV X heart rate ▪ Preload: amount of blood in left ventricle before contraction ▪ Afterload: stress on the ventricular wall during systole ▫ ↑ systemic resistance, ↑ blood viscosity, aortic valve stenosis, ventricular dilation → ↑ afterload ▪ Inotropy: cardiac contractility ▪ Ejection fraction (EF): % of blood leaving heart during each contraction ▫E=

(

stroke volume end diastolic volume

)

x100

▪ Frank–Starling mechanism: loading ventricle with blood during diastole, stretching out cardiac muscles → more forceful contraction; ↑ SV during systole Heart failure (HF) with reduced ejection fraction (HFrEF) ▪ Systolic HF; “pump dysfunction” ▪ Causes: ↓ contractility/force of contraction (e.g. myocardial infarction, myocarditis), ↓ blood supply to the heart (e.g. coronary artery disease), ↑ afterload (e.g. hypertension), impaired mechanical function (e.g. valve disease)

▪ Normal preload, ↓ contractility (inotropy; force of contraction) → inadequate emptying of ventricles during systole → ↓ EF ≤ 40 (HFrEF); often also have some degree of diastolic dysfunction HF with preserved ejection fraction (HFpEF) ▪ Diastolic HF; “filling dysfunction” ▪ Causes: restrictive cardiomyopathy (e.g. amyloidosis, sarcoidosis), valve disease, hypertension ▪ Ventricles noncompliant and unable to fill during diastole → ↑ filling pressures ↓ preload, normal contractility → ↓ SV → preserved EF ≥ 50 (HFpEF)

TYPES

▪ Biventricular heart failure ▫ Left, right failure; systolic/diastolic ▪ Cor pulmonale ▫ Heart failure secondary to any cause of pulmonary arterial hypertension ▪ Left-sided heart failure ▫ Impaired ability of the left ventricle to maintain adequate cardiac output without an increase in left-sided filling pressures ▪ Right-sided heart failure ▫ Impaired ability of the right ventricle to deliver of blood flow to the pulmonary circulation and ↑ right atrial pressure ▪ Classification based on structure and symptoms ▫ ACC/AHA HF Stages, NYHA Classes (see table)

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RISK FACTORS

▪ Cardiac disorders: ischemic heart disease, valvular heart disease, hypertension, LV hypertrophy, peripartum cardiomyopathy, myocarditis, congenital heart disease, chronic tachyarrhythmias ▪ Other chronic diseases: hypertension, diabetes, obesity, chronic lung disease, infiltrative diseases (e.g. amyloidosis) ▪ Toxins: cigarette smoking, ethanol, cardiotoxic medications (e.g. doxorubicin, amphotericin B); illicit drugs (e.g. amphetamines, cocaine) ▪ High-output states: thyrotoxicosis, anemia ▪ ↑ age

COMPLICATIONS

▪ Cardiogenic shock ▪ Biventricular heart failure ▫ Left/right-sided HF precursor/ complication of each other

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▪ ▪ ▪ ▪

Arrhythmias End organ damage: due to lack of perfusion Liver damage (congestive hepatopathy) Exacerbation ▫ See mnemonic ▫ Certain drugs may exacerbate HF; e.g. NSAIDs, excessive doses of beta blockers, calcium channel blockers, cyclophosphamide

MNEMONIC: FAILURE

Exacerbation of Heart failure Forgot medication Arrhythmia/Anemia Ischemia/Infarction/Infection Lifestyle (e.g. too much salt) Upregulation of CO (e.g. pregnancy, hyperthyroidism) Renal failure Embolism (e.g. pulmonary)

Chapter 9 Heart Failure

SIGNS & SYMPTOMS ▪ High filling pressures: pulmonary edema, dyspnea, orthopnea, exercise intolerance, paroxysmal nocturnal dyspnea (PND), basilar crackles, tachypnea, jugular venous distention (JVD), hypoxemia, fatigue, peripheral edema, hepatomegaly, S3 ▪ Low cardiac output: tachycardia, hypotension, cool extremities, ↓ pulse pressure, ↓ urine output, ↓ appetite

OTHER DIAGNOSTICS

▪ History and physical examination identifying characteristic symptoms, evidence of fluid retention and/or hypoperfusion and functional impairment due to cardiac dysfunction

ECG ▪ Identifies contributing rhythm disturbances

DIAGNOSIS DIAGNOSTIC IMAGING Chest X-ray ▪ Detects cardiomegaly, chamber and vessel enlargement, pulmonary congestion, presence of pericardial and pleural effusions Doppler echocardiography ▪ Evaluates hemodynamics related to in valvular and biventricular function Right heart (pulmonary artery) catheterization ▪ Measures CO (cardiac index), filling pressures, pulmonary capillary wedge pressure (PCWP) MRI ▪ Visualizes ventricular volumes, mass, presence of myocardial remodeling

LAB RESULTS

▪ ↑ B-type natriuretic peptide (BNP) and/or N-terminal pro-BNP ▪ ↑ serum creatinine and blood urea nitrogen (BUN) indicates glomerular filtration rate ↓ GFR due to hypoperfusion ▪ ↑ serum total bilirubin and aminotransferase indicates congestive hepatopathy from right-sided HF ▪ ↑ serum lactate if cardiogenic shock ▪ Exercise testing: six-minute walk test and/or a cardiopulmonary exercise test measuring oxygen uptake (Vo2) evaluates exercise capacity

TREATMENT MEDICATIONS

▪ Individualized in accordance with New York Heart Association (NYHA) class, EF, comorbidities ▪ Angiotensin converting enzyme (ACE) inhibitor or angiotensin II receptor blockers (ARB) ▪ Beta-blocker (carvedilol, bisoprolol, metoprolol ER) ▪ Aldosterone agonist ▪ Mineralocorticoid receptor antagonist (HFpEF) ▪ Acute decompensation ▫ See mnemonic

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MNEMONIC: POND

Acute decompensation Position (upright) +/- positive pressure ventilation (e.g. BiPAP) Oxygen Nitrates Diuretics

OTHER INTERVENTIONS

▪ Lifestyle modifications ▫ Low dietary salt, exercise as tolerated, smoking cessation, minimize alcohol intake ▪ Ventricular assist device (VAD) ▪ Implanted defibrillator ▪ Biventricular pacemaker for resynchronization

SURGERY

▪ Heart transplant ▫ Considered in NYHA class of III or IV despite maximized medical and resynchronization therapy

COR PULMONALE osms.it/cor_pulmonale PATHOLOGY & CAUSES ▪ Right ventricular hypertrophy, dilation, and/or dysfunction due to pulmonary hypertension secondary to pulmonary disease (e.g. chronic obstructive pulmonary disease (COPD), pulmonary fibrosis), upper airway obstruction (e.g. obstructive sleep apnea, obesity-hypoventilation syndrome), or chest wall irregularities (e.g. kyphoscoliosis) ▪ Acute cor pulmonale develops in the setting of a sudden volume and/or pressure overload in the right side of the heart; e.g. massive pulmonary embolism ▪ ↑ pulmonary vascular resistance → ↑ pulmonary circuit afterload → ↑ right ventricular workload → right ventricular hypertrophy or dilatation → impaired right ventricular function and failure → ↑ right atrial pressure → fluid back-up into venous circulation → peripheral edema

RISK FACTORS

▪ Presence of parenchymal or vascular lung disease, chronic airway obstruction ▪ Smoking

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▪ Recent surgery, hypercoagulable states (↑ risk of pulmonary embolism)

COMPLICATIONS ▪ RV failure ▪ Liver dysfunction

SIGNS & SYMPTOMS ▪ Dyspnea, chest pain, peripheral edema, jugular venous distension, hepatomegaly

DIAGNOSIS DIAGNOSTIC IMAGING Chest X-ray ▪ Visualizes right ventricular hypertrophy, distended pulmonary vasculature, pulmonary edema Echocardiography ▪ Detects structural and functional changes of right ventricle; estimates right ventricular systolic pressures

Chapter 9 Heart Failure MRI ▪ Visualizes right ventricular hypertrophy, right atrial enlargement, tricuspid valve dysfunction regurgitation, retrograde flow Cardiac catheterization ▪ ↑ elevated central venous pressure, ↑ right ventricular, end-diastolic pressure, evidence of underlying pulmonary disease

SURGERY

▪ Heart-lung transplant for resistant cor pulmonale

OTHER INTERVENTIONS

▪ Treat underlying disease process ▪ Lifestyle ▫ Low dietary salt, exercise as tolerated, smoking cessation

TREATMENT MEDICATIONS

▪ Supplemental oxygen ▪ Loop diuretic

DIASTOLIC HEART FAILURE osms.it/diastolic-heart-failure PATHOLOGY & CAUSES ▪ A clinical syndrome characterized by failure of the heart to pump sufficient blood to meet the metabolic needs of the body due to ↓ ventricular filling ▪ HF with preserved ejection fraction (HFpEF) ▪ Filling dysfunction ▫ Stiff, non-compliant ventricle → ↓ ventricular relaxation → ↑ end diastolic pressure → ↑ resistance to filling → ↓ preload → EF ≥ 50, ↓ SV, ↓ CO → pulmonary congestion

RISK FACTORS

▪ ↑ age, restrictive cardiomyopathy (e.g. amyloidosis, sarcoidosis); hypertrophic cardiomyopathy, long-standing hypertension, valve disease (especially aortic stenosis), CAD, diabetes, obesity

COMPLICATIONS

SIGNS & SYMPTOMS ▪ Fatigue, dyspnea, orthopnea, exercise intolerance, pulmonary rales, JVD

DIAGNOSIS DIAGNOSTIC IMAGING Chest X-ray ▪ Cardiomegaly; pulmonary vascular congestion; enlargement of right atrium, ventricle, and pulmonary arteries Doppler echocardiography ▪ Altered mitral flow velocity, ↑ LVEDP, LV hypertrophy with concentric remodeling, LA enlargement, ↑ pulmonary artery systolic pressure (PASP)

LAB RESULTS

▪ ↑ BNP/NT-proBNP

▪ Arrhythmias, pulmonary embolism, pulmonary hypertension, right ventricular failure

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TREATMENT MEDICATIONS Alleviation of symptoms ▪ Diuretics; antihypertensives ▫ Beta blockers, ACE inhibitors, ARBs, aldosterone antagonists

OTHER INTERVENTIONS

▪ Manage contributing factors and associated conditions ▪ Lifestyle modifications ▫ Smoking cessation, ↓ sodium intake, weight management, ↓ alcohol intake

LEFT HEART FAILURE osms.it/left-heart-failure PATHOLOGY & CAUSES ▪ A clinical syndrome due to an alteration of structure and/or function of the left ventricle (LV) resulting in ↓ cardiac output, pulmonary congestion, and ↓ peripheral perfusion ▪ Categorized according to left ventricular ejection fraction (LVEF) ▫ Systolic HF: ↓ LVEF ≤40 percent (HFrEF) ▫ Diastolic HF: preserved LVEF (HFpEF) ▪ ↓ cardiac output → backup of blood into left atrium → pulmonary circulation → ↑ pressure in pulmonary capillaries → pulmonary edema → ↓ gas exchange, dyspnea ▪ Neurohormonal compensatory mechanisms ▫ RAAS and adrenergic activation → renal salt and water retention + vasoconstriction → ↑ contractility, ↑ circulating volume → ↑ CO, ↑ organ perfusion ▫ Adverse effects of compensation: ↑ afterload, ↑ LV workload, LV remodeling ▫ Natriuretic peptide secretion occurs in response to compensatory mechanisms and atrial stretch → diuresis, natriuresis, partial RAAS inhibition

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RISK FACTORS

▪ Coronary artery disease, infiltrative disease (e.g. amyloidosis, hemochromatosis) → cardiomyopathy ▪ Hypertension, aortic stenosis → ↑ afterload ▪ Mitral or aortic regurgitation → ↑ preload ▪ Exposure to toxins → myocardial damage ▪ Arrhythmias → ↓ filling, ↓ ineffective contractions ▪ age > 60 ▪ Obesity ▪ Diabetes mellitus/metabolic syndrome

COMPLICATIONS

▪ Pulmonary edema, pulmonary hemorrhage (congested capillaries burst), pleural effusion, renal insufficiency

SIGNS & SYMPTOMS ▪ Exertional dyspnea, orthopnea; (PND), pulmonary edema (frothy, pink-tinged sputum), bibasilar rales, cough, nocturia, restlessness, confusion. S3/S4

Chapter 9 Heart Failure Echocardiography ▪ LV hypertrophy with eccentric remodeling, ↑ LVEDP, LA enlargement, ↑ PASP

OTHER DIAGNOSTICS

▪ ECG ▫ Identifies contributing rhythm disturbances

TREATMENT Figure 9.1 The gross pathological appearance of pulmonary edema. Exerting pressure on the lung parenchyma causes frothy white fluid to exude from it.

DIAGNOSIS

MEDICATIONS

▪ Diuretics, beta blockers, ACE inhibitors, ARBs, ARNI, hydralazine/nitrate combination, aldosterone antagonists ▪ Acute decompensation ▫ See mnemonic

MNEMONIC: POND

LAB RESULTS

Acute decompensation Position (upright) +/- positive pressure ventilation (e.g. BiPAP) Oxygen Nitrates Diuretics

▪ ↑ BNP/NT-proBNP

DIAGNOSTIC IMAGING Chest X-ray ▪ Cardiomegaly, pulmonary vascular congestion, enlargement of right atrium, ventricle, and pulmonary arteries

MEDICATIONS

▪ Diuretics, beta blockers, ACE inhibitors, ARBs, ARNI, hydralazine/nitrate combination, aldosterone antagonists ▪ Acute decompensation ▫ See mnemonic

SURGERY

▪ Heart transplant

OTHER INTERVENTIONS

Figure 9.2 A plain chest X-ray image demonstrating pulmonary edema. The vessels at the hila are prominent and there are numerous Kerley B lines.

▪ Manage contributing factors and associated conditions ▪ Lifestyle modifications: smoking cessation, ↓ sodium intake, weight management, ↓ alcohol intake ▪ Cardiac rehabilitation ▪ Implantable cardioverter-defibrillator (ICD) ▪ Ventricular assist device

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Figure 9.3 The histological appearance of pulmonary edema. There is flocculent fluid within the alveolar spaces.

Figure 9.4 Pitting edema in an individual with left-sided heart failure.

RIGHT HEART FAILURE osms.it/right-heart-failure PATHOLOGY & CAUSES ▪ A clinical syndrome due to an alteration of structure and/or function of the right ventricle (RV) leading to suboptimal delivery of blood flow to the pulmonary circulation and/or elevated venous pressures ▪ ↑ venous pressure → systolic volume overload ▪ ↑ RV workload (most often due to pulmonary congestion secondary to LV failure) → RV hypertrophy → ↓ pumping ability

CAUSES

▪ Left-sided heart failure, associated pulmonary edema (most common cause), right ventricular infarction, bacterial endocarditis, pulmonic valve stenosis, cardiomyopathy

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COMPLICATIONS ▪ ▪ ▪ ▪

Eventual failure of left side of heart Tricuspid regurgitation Congestive hepatopathy Cardiac cachexia ▫ Nausea, vomiting, anorexia, and diffuse abdominal pain due to abdominal venous congestion → weight loss

SIGNS & SYMPTOMS ▪ JVD, hepatojugular reflux, fatigue (related to poor gas exchange), exercise intolerance, peripheral edema, hepatosplenomegaly, ascites, S3/S4

DIAGNOSIS DIAGNOSTIC IMAGING Chest X-ray ▪ Cardiomegaly, pulmonary vascular congestion; enlargement of right atrium, ventricle, pulmonary arteries

Chapter 9 Heart Failure Echocardiography ▪ Evaluates RV size and function; detects hemodynamic alterations MRI ▪ Myocardial tissue, ventricular volume, muscle damage Right heart catheterization ▪ ↑ pressure in heart chambers and lungs

LAB RESULTS

▪ ↑ BNP/NT-proBNP ▪ ↑ serum total bilirubin and aminotransferase indicates congestive hepatopathy

OTHER DIAGNOSTICS

▪ Clinical presentation: right heart dysfunction, rule out left heart dysfunction

Figure 9.5 A distended external jugular vein (EJV) in an individual with right heart failure.

ECG ▪ Identifies contributing rhythm disturbances

TREATMENT MEDICATIONS

▪ Loop diuretics ▫ Fluid management ▪ Vasopressors ▫ Circulatory support

OTHER INTERVENTIONS ▪ Treat underlying condition

MNEMONIC: LMNOP

Treatment for Right heart failure Lasix Morphine Nitrites Oxygen VassoPressors

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NOTES

NOTES

HEART VALVE DISEASE GENERALLY, WHAT IS IT? PATHOLOGY & CAUSES ▪ Wear and tear, external factors, varies by type ▪ Older age, smoking, hypertension, hyperlipidemia, diabetes mellitus, connective tissue disorders, endocarditis, heart attack

SIGNS & SYMPTOMS ▪ Normally, heart valves keep blood moving by opening for forward flow and closing to prevent backflow; symptoms evidence of flow alterations ▪ Murmurs, altered heart sounds ▪ Sometimes asymptomatic ▪ Advanced disease → heart failure ▪ Left ventricular failure symptoms ▪ Forward effects ▫ Decreased perfusion to body tissues (e.g. decreased perfusion to brain = syncope; decreased perfusion to coronary arteries = chest pain, angina) ▪ Backward effects ▫ Blood backs up to left atrium, into pulmonary circulation (e.g. pulmonary edema, dyspnea, fatigue, paroxysmal nocturnal dyspnea) ▪ Right ventricular failure symptoms ▪ Backup of blood to venous circulation (e.g. peripheral edema, hepatosplenomegaly)

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DIAGNOSIS ▪ Auscultation → echocardiogram, transesophageal echocardiogram, catheterization

TREATMENT ▪ Lifestyle changes, pharmacotherapeutics, surgical intervention

Figure 10.1 Illustration of phonocardiograms from normal and abnormal heart sounds.

Chapter 10 Heart Valve Disease

AORTIC INSUFFICIENCY osms.it/aortic-insufficiency PATHOLOGY & CAUSES ▪ Widening/insufficiency of aortic valve ▪ Doesn’t close fully, blood flows backwards during diastole ▪ AKA aortic regurgitation

CAUSES Aortic root dilation ▪ Root dilates, pulls apart leaflets ▫ Most root dilations idiopathic; some caused by aortic dissection, aneurysm, Marfan syndrome, Ehlers-Danlos syndrome, syphilis, ankylosing spondylitis, rheumatoid arthritis, systemic lupus erythematosus ▫ Valvular damage: infective endocarditis, rheumatic fever, bicuspid aortic valve ▫ Inflammation → fibrosis → valve can’t seal Acute aortic regurgitation (medical emergency) ▪ Infective endocarditis, trauma, aortic dissection ▫ Acute aortic regurgitation presents with sudden cardiovascular collapse, pulmonary edema ▫ Chronic aortic regurgitation presents less urgently, signs of heart failure

RISK FACTORS

▪ Hypertension, syphilis, genetic disorders (Marfan’s syndrome, Ehlers-Danlos syndrome)

COMPLICATIONS Heart failure ▪ High blood volume left ventricle → left ventricle compensates, adding sarcomeres in series → eccentric left ventricular hypertrophy → left ventricular dysfunction → heart failure

SIGNS & SYMPTOMS Abnormal heart sounds ▪ Early decrescendo diastolic murmur, usually heard at left lower sternal border/apex ▪ Systolic flow murmur may develop in chronic aortic regurgitation; increased blood flow through valve during systole, regardless of stenosis Wide pulse pressure ▪ Increased systolic blood pressure (SBP) and decreased diastolic blood pressure (DBP) = hyperdynamic circulation ▪ Calculation for pulse pressure (PP) ▫ SBP - DBP = PP ▪ Hill’s sign ▫ Exaggerated difference in SBP when comparing upper, lower limbs ▪ Bounding pulses ▫ Evidence of wide PP ▫ Corrigan pulse (water-hammer pulses): bounding pulse, blood hammers against arterial walls Other signs ▪ de Musset’s sign ▫ Head bobs in time with heartbeat ▪ Quincke’s sign ▫ Light compression of capillary bed leads to visible pulsations in fingers

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▪ Traub’s sign ▫ Pistol shot sound head over femoral arteries ▪ Duroziez’s sign ▫ Systolic, diastolic bruit over femoral artery when partially compressed ▪ Landolfi’s sign ▫ Diastolic pupil dilation Acute aortic regurgitation ▪ Severe dyspnea, chest pain, hypotension = left ventricular failure, cardiogenic shock

DIAGNOSIS DIAGNOSTIC IMAGING Echocardiography ▪ Using Doppler flow, observe regurgitation jet through aortic valve during diastole

OTHER DIAGNOSTICS Electrocardiogram ▪ Shows non-specific features of left ventricular hypertrophy

TREATMENT ▪ Goal: improve cardiac output, decrease regurgitant flow volume

MEDICATIONS

▪ Vasodilators to reduce afterload

SURGERY

▪ Surgical valve replacement ▪ Surgical replacement once ejection fraction < 55%

Chest X-ray ▪ Nonspecific, may observe cardiomegaly

AORTIC STENOSIS osms.it/aortic-stenosis PATHOLOGY & CAUSES ▪ Stiffening, thickening/calcification of aortic valve (no longer opens fully during systole) ▪ Valve opening narrows → pressure gradient increases across valve

CAUSES Mechanical stress ▪ Damaged endothelial cells over time → fibrosis and calcification → stiff valve does not open fully Rheumatic heart disease ▪ Repeated inflammation, repair → fibrosis → commissural fusion

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COMPLICATIONS

▪ Heart failure, microangiopathic hemolytic anemia (red blood cells damaged as they squeeze through small valve opening), Heyde’s syndrome

SIGNS & SYMPTOMS Asymptomatic ▪ Due to slow progression; abnormal heart sounds heard on auscultation ▫ Ejection click ▫ Harsh, systolic, crescendo-decrescendo systolic murmur at upper sternal border, radiating to carotids Advanced state aortic stenosis ▪ Classic triad: angina, syncope, exertional dyspnea

Chapter 10 Heart Valve Disease ▪ Additional heart sounds: soft, single S2/paradoxical S2 split; crescendodecrescendo systolic murmur peaks later (the later the peak, the more severe the stenosis); S4 ▪ Pulsus parvus et tardus (pulse weak, delayed) ▪ Narrowed pulse pressure

TREATMENT MEDICATIONS

▪ Venodilators, calcium channel blockers, administer beta blockers with caution

SURGERY

▪ Surgical valve replacement if necessary

MNEMONIC: SAD

Characteristics of Aortic stenosis

Syncope Angina Dyspnea

OTHER INTERVENTIONS

▪ If mild, no exercise restrictions; if severe, reduced physical activity

DIAGNOSIS DIAGNOSTIC IMAGING Transthoracic echocardiogram (TTE) ▪ Observe small aortic orifice during systole, increased pressure gradient across valve, left ventricular hypertrophy, calcification of aortic valve Cardiac catheterization ▪ Useful for surgical planning

OTHER DIAGNOSTICS

Figure 10.2 Gross pathology of severe aortic stenosis as a consequence of previous rheumatic heart disease. The valve leaflets are stiffened and fused resulting in a narrowed lumen.

Electrocardiogram ▪ Shows non-specific features of left ventricular hypertrophy

Figure 10.3 Gross pathology of a nodular bicuspid aortic valve.

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MITRAL INSUFFICIENCY osms.it/mitral-insufficieny PATHOLOGY & CAUSES ▪ Mitral valve prolapses (falls back into atrium) ▪ Most common valvular condition ▪ AKA mitral regurgitation

CAUSES Myxomatous degeneration ▪ Leaflets, connective tissue, surrounding tissue weakened → mitral valve prolapse

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▫ Associated with connective tissue disorders (e.g. Marfan syndrome, Ehlers–Danlos Syndrome) ▫ Causes larger valve leaflet area, elongation of chordae tendineae → mitral valve more prone to rupture (rupture usually happens to chordae tendineae on posterior leaflet, leaflet folds up into left atrium) ▫ Doesn’t always cause mitral regurgitation but often does since blood will leak backwards into left atrium if leaflets don’t form perfect seal

Chapter 10 Heart Valve Disease Damage to papillary muscles ▪ Caused by heart attacks ▫ Papillary muscle dies → can’t anchor chordae tendineae → mitral valve flops back → blood leaks back into left atrium Left-sided heart failure ▪ Left sided heart failure → left ventricle dilates → stretches mitral valve annulus (ring) → blood leaks back into left atrium → ventricular dilation Rheumatic fever ▪ Inflammatory disease affecting heart tissue, leading to chronic rheumatic heart disease ▪ Chronic inflammation → leaflet fibrosis → leaflets cannot form complete seal → blood leaks through Mitral regurgitation ▪ Can also cause left-sided heart failure ▪ Regurgitant flow back into left atrium → increased preload → increased workload on left atrium, ventricle → left eccentric hypertrophy (new sarcomeres added in series to existing ones) → left sided heart failure

RISK FACTORS

▪ Intravenous (IV) drug use (increases likelihood of infective endocarditis) ▪ Congenital bicuspid aortic valve (baby born with aortic valve that has only two instead of three leaflets) ▪ Diabetes, high blood pressure, smoking

COMPLICATIONS

▪ Pulmonary congestion, edema ▫ Constant elevation in blood volume, pressure in left atrium causes dilation → blood backs up into pulmonary circulation ▪ Pulmonary hypertension ▫ Extra blood volume, pressure in left atrium backs up into lung causing higher pressure in pulmonary circulation ▪ Right-sided heart failure ▫ Backup of blood in left atrium, lungs → pulmonary hypertension → right ventricular hypertrophy → right-sided heart failure

▪ Atrial fibrillation ▫ Left atrium dilates → muscle walls stretch, pacemaker cells irritated ▪ Thrombus formation, embolism ▫ Atrial fibrillation → blood stagnates, pools → increased risk of thrombus formation, blood clots → goes to systemic circulation ▪ Dysphagia ▫ E.g. difficulty swallowing solid foods; dilated atrium compresses neighboring esophagus

SIGNS & SYMPTOMS ▪ Clinical manifestations of heart failure (e.g. fatigue, swelling, rapid heartbeat) ▪ Holosystolic murmur ▫ Lasts for duration of systole

DIAGNOSIS DIAGNOSTIC IMAGING Transthoracic echocardiography (TTE) or transesophageal echocardiogram (TEE) ▪ Enlarged left atria/ventricle ▪ Rupture/tear/elongation of mitral valve chordae ▪ Regurgitation (seen as retrograde blood flow on Doppler imaging) ▪ Systolic bowing of mitral leaflet (>2mm beyond annular plane) ▪ May reveal leaflet thickening, flail leaflet, annular dilation Chest X-ray ▪ May demonstrate cardiomegaly secondary to left atrial/ventricular dilation

OTHER DIAGNOSTICS ECG ▪ Abnormal findings often observed in MVP ▫ Early repolarization in inferior leads ▫ ST depression, QTc prolongation ▫ Premature ventricular contractions ▪ Not conclusive; result can be normal in people who have mild mitral valve disease

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TREATMENT MEDICATIONS

Lower high blood pressure (e.g. diuretics) Lower cholesterol (e.g. statins) Prevent arrhythmias (e.g. amiodarone) Prevent clots with blood thinners/ anticoagulants (e.g. heparin, warfarin) ▪ Treat heart failure (e.g. digoxin to increase contractility) ▪ ▪ ▪ ▪

▫ Reshape valve tissue to create tighter seal ▫ Repair tears to increase support at base of valve ▫ Replace with prosthetic valve

SURGERY Replacing/repairing valve ▪ Severe mitral regurgitation or stenosis = valve repair or surgical replacement of valve ▫ Separate fused valve flaps Figure 10.4 Illustration depicting differences in mitral valve shape between mitral valve insuffiency (regurgitation) and mitral stenosis.

MITRAL STENOSIS osms.it/mitral-stenosis PATHOLOGY & CAUSES ▪ Narrowing of mitral valve ▪ Rheumatic fever: inflammation → leaflets fuse together (commissural fusion) → prevents seal formation ▫ Normal mitral valve opening (4–6cm2/1.6–2.4in2) narrows to 2cm2/0.8in2 ▫ Smaller opening → harder for blood to flow from left atrium to ventricle → blood backs up in atrium → higher pressure in left atrium

RISK FACTORS

▪ IV drug use ▫ Increases likelihood of infective endocarditis ▪ Congenital bicuspid aortic valve

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▪ Diabetes, high blood pressure, smoking

COMPLICATIONS

▪ Pulmonary congestion, edema ▫ Constant elevation in blood volume, pressure in left atrium → left atrium dilates → blood backs up into pulmonary circulation ▪ Pulmonary hypertension ▫ Extra blood volume, pressure in left atrium backs up into lung → higher pressure in pulmonary circulation ▪ Right-sided heart failure ▫ Backup of blood in left atrium, lungs → pulmonary hypertension → right ventricular hypertrophy → right-sided heart failure ▪ Atrial fibrillation ▫ Left atrium dilates → muscle walls

Chapter 10 Heart Valve Disease stretch, pacemaker cells irritated ▪ Thrombus formation, embolism ▫ Atrial fibrillation → blood stagnates, pools → increased risk of thrombus formation, blood clots entering systemic circulation ▪ Dysphagia ▫ Dilated atrium compresses neighboring esophagus

SIGNS & SYMPTOMS ▪ Clinical manifestations of heart failure ▪ “Snap” sound after S2 (closure of aortic, pulmonic valves) ▫ Higher pressure flowing through fibrotic valve makes “snap” sound when valve opens ▫ Diastolic rumble following “snap” as blood forced through smaller opening ▪ Dyspnea/difficulty breathing ▫ Pulmonary congestion, pulmonary edema

DIAGNOSIS DIAGNOSTIC IMAGING Echocardiography ▪ Shows abnormal blood flow, narrowed/ insufficient valve

OTHER DIAGNOSTICS ECG ▪ Reveals abnormal electrical activity depending on severity ▫ Not conclusive; result can be normal in people who have mild mitral valve disease

TREATMENT MEDICATIONS

▪ Lower high blood pressure (e.g. metoprolol, lisinopril, diuretics) ▪ Lower cholesterol (e.g. statins) ▪ Prevent arrhythmias (e.g. amiodarone) ▪ Prevent clots with blood thinners/ anticoagulants (e.g. heparin, warfarin) ▪ Treat heart failure (e.g. digoxin to increase contractility)

SURGERY

▪ Replacing/repairing valve: severe mitral regurgitation or stenosis = valve repair or surgical replacement of valve ▫ Separate fused valve flaps ▫ Reshape valve tissue to create tighter seal ▫ Repair tears to increase support at base of valve ▫ Replace with prosthetic valve

Transesophageal echocardiogram (TEE) ▪ Enlarged left ventricle ▪ Enlarged left/right atria ▪ Possible rupture/tear of mitral valve chordae ▪ Possible regurgitation Stress test (echocardiography) ▪ Measure blood pressure pre-, post-test ▪ Record how long individual able to carry out test Chest X-ray ▪ Shows heart size, lung condition

Figure 10.5 Gross pathology of a stenotic mitral valve, viewed from the left atrium.

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MITRAL VALVE PROLAPSE osms.it/mitral-valve-prolapse PATHOLOGY & CAUSES ▪ Floppy mitral valve ▪ Cusps of valve flop into atrium during systole. ▪ Myxomatous degeneration from connective tissue disease (e.g. Ehler–Danlos, Marfan syndromes) ▪ Familial mitral valve prolapse ▫ Autosomal dominant: variable penetrance and expression

RISK FACTORS ▪ ▪ ▪ ▪

Age Hypertension History of rheumatic fever Connective tissue disorders

COMPLICATIONS

▪ Heart failure, arrhythmias, systemic emboli, cardioembolic stroke, chordal rupture, sudden death

SIGNS & SYMPTOMS ▪ Usually asymptomatic ▪ Classic heart murmur: midsystolic click followed by systolic murmur ▪ Murmur: blood leaks backward from left ventricle into left atrium ▪ Click: leaflet folding into atrium, suddenly stopped by chordae tendineae ▫ When an individual squats, click comes later, shorter murmur ▫ Squatting increases venous return → fills left ventricle with more blood → left ventricle gets slightly larger → leaflets have more space → ventricle contracts, gets smaller → takes slightly longer for leaflet to be forced into atrium ▫ When individual stands/performs Valsalva maneuver (forceful exhalation

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against closed airway), click comes sooner, longer murmur ▫ Standing reduces venous return → less blood in ventricle → ventricle is slightly smaller → less room for leaflets → leaflet forced out earlier during contraction ▪ Individual may report palpitations

DIAGNOSIS DIAGNOSTIC IMAGING Chest X-ray ▪ May demonstrate cardiomegaly secondary to left atrial/ventricular dilation Transthoracic echocardiography (TTE) or transesophageal echocardiogram (TEE) ▪ Enlarged left atria/ventricle ▪ Rupture/tear/elongation of mitral valve chordae ▪ Regurgitation (seen as retrograde blood flow on Doppler imaging) ▪ Systolic bowing of mitral leaflet (> 2mm beyond annular plane) ▪ May reveal leaflet thickening, flail leaflet, annular dilation

OTHER DIAGNOSTICS Physical examination ▪ Crescendo murmur in late systole heard over apex ▪ Mid-systolic click (due to rapid tensing of chordae tendineae) ECG) ▪ Abnormal findings often observed in MVP ▫ Early repolarization in inferior leads ▫ ST depression, QTc prolongation ▫ Premature ventricular contractions ▪ Not conclusive; result can be normal in people who have mild mitral valve disease

Chapter 10 Heart Valve Disease

TREATMENT MEDICATIONS

▪ If palpitations present ▫ Beta blockers; avoid smoking, caffeine

SURGERY

▪ Severe prolapse ▫ Valve repair/replacement (esp. when left ventricular systolic function impaired) Figure 10.6 Gross pathology of a mitral valve prolapse (anterior superior leaflet) viewed from the left atrium.

PULMONARY INSUFFICIENCY osms.it/pulmonic-insufficiency PATHOLOGY & CAUSES ▪ Pulmonary valve doesn’t close fully → blood leaks back into right ventricle ▪ AKA pulmonic regurgitation ▪ Blood backflow increases right ventricular blood volume → right ventricle needs to work harder during systole → eccentric ventricular hypertrophy → heart failure

CAUSES

▪ Congenital malformation of the leaflets common ▫ Tetralogy of Fallot (TOF), Noonan’s syndrome, congenital rubella ▪ Infective endocarditis, rheumatic heart disease, systemic disease (e.g. carcinoid disease)

COMPLICATIONS

▪ Right-sided heart failure ▫ Ventricles cannot compensate for increased workload ▪ Microangiopathic hemolytic anemia ▫ Shearing damage to red blood cells forced through smaller valve, leading to hemoglobinuria

SIGNS & SYMPTOMS ▪ Abnormal heart sounds ▫ Crescendo-decrescendo murmur: blood flows through narrow pulmonary valve, causes turbulence that gets louder as more blood flows/quieter as blood flow slows, blood leaks back from pulmonary artery into right ventricle, causes murmur that starts loud, quietens ▪ Signs of right-sided heart failure may be present (e.g. fatigue, swelling, rapid heartbeat)

DIAGNOSIS DIAGNOSTIC IMAGING Echocardiogram ▪ Regurgitation seen on Doppler Chest X-ray ▪ May show enlarged right ventricle

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TREATMENT SURGERY

▪ Valve replacement if symptomatic

Figure 10.7 Illustration depicting decrescendo murmur as blood flows back into the right ventricle.

PULMONARY STENOSIS osms.it/pulmonic-stenosis PATHOLOGY & CAUSES

SIGNS & SYMPTOMS

▪ Pulmonary valve doesn’t open fully; harder for right ventricle to pump blood to lungs ▪ Mechanical stress over time ▫ Damages endothelial cells around valves → fibrosis, calcification → hardens valve, makes it more difficult to open fully ▪ Eccentric right ventricular hypertrophy: right ventricle must compensate for larger amount of blood volume due to backflow of blood

▪ Initially asymptomatic ▪ Diastolic crescendo-decrescendo murmur: abnormal heart sound caused by turbulent blood flow through pulmonary valve that does not close properly; starts loud, quietens ▪ Ejection click: valve resists, then finally snaps open ▪ Appears often as right-sided heart failure

CAUSES

DIAGNOSTIC IMAGING

▪ Congenital malformation of leaflets ▫ Associated with tetralogy of Fallot, Noonan’s syndrome, congenital rubella ▪ Systemic disease (e.g. carcinoid disease)

RISK FACTORS

▪ History of rheumatic heart disease, heart surgery, or infective endocarditis

COMPLICATIONS

▪ Right-sided heart failure ▫ Right ventricle cannot compensate for increased force required to push blood through valve

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DIAGNOSIS Echocardiogram ▪ Thickened leaflets, hard to see location of stenosis

TREATMENT ▪ Balloon valvuloplasty ▪ Valve replacement if symptomatic rightsided heart failure

Chapter 10 Heart Valve Disease

Figure 10.8 Illustration depicting hypertrophy of right ventricle due to increased blood pressure in the right ventricle.

TRICUSPID INSUFFICIENCY osms.it/tricuspid-insufficiency

▪ Cusps of valve prolapse during systole → blood backs up into right atrium. ▪ AKA tricuspid regurgitation

▪ Infective endocarditis ▪ Trauma ▫ Catheter insertion ▫ Endocardial pacemaker insertion ▫ Blunt chest trauma

CAUSES

RISK FACTORS

PATHOLOGY & CAUSES

▪ Rheumatic heart disease ▫ Most common cause ▫ Autoimmune reaction involving valve leaflets → chronic inflammation → leaflet fibrosis → valve unable to form seal ▪ Myocardial infarction ▫ Papillary muscles malfunction → destroyed papillary muscles can’t anchor chordae tendineae → blood flows from right ventricle to right atrium ▪ Pulmonary hypertension ▫ Increase in right ventricular pressure → dilates tricuspid valve → blood flows backward ▪ Congenital causes ▫ Leaflets are displaced → difficult to form seal (e.g. Ebstein anomaly) ▪ Carcinoid syndrome ▫ Fibrous tissue deposited on valves ▪ Myxomatous valve degeneration

▪ Disease processes may cause pulmonary hypertension ▪ IV drug abuse

COMPLICATIONS

▪ Heart failure ▫ Increased ventricular preload → eccentric ventricular hypertrophy → right ventricular failure ▪ Ventricular hypertrophy ▫ Structural change in heart → annulus stretches → more blood leakage → worsens regurgitation

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DIAGNOSIS

SIGNS & SYMPTOMS ▪ Holosystolic murmur ▫ Movement of blood heard throughout systole ▪ Carvallo’s sign ▫ Murmur gets louder with inspiration due to negative pressure in chest, more blood backs up into heart ▪ S3, S4 ▪ Signs of right-sided heart failure

DIAGNOSTIC IMAGING Echocardiogram with Doppler ▪ Shows backflow X-ray ▪ Shows right ventricular enlargement

TREATMENT SURGERY

▪ Surgical repair/replacement if symptomatic

TRICUSPID STENOSIS osms.it/tricuspid-stenosis PATHOLOGY & CAUSES

SIGNS & SYMPTOMS

▪ Valve unable to open completely during diastole. ▪ Valve leaflets fuse (commissural fusion) → narrowing of tricuspid valve → impaired blood flow from right atrium to right ventricle

▪ Ejection click ▫ Fibrotic valve makes distinctive snap ▪ Diastolic rumble ▫ As blood is forced through small valve opening ▪ Increased ventricular preload → right ventricular failure → signs of congestion in venous system ▫ Jugular venous distention (JVD) may cause some individuals to feel uncomfortable fluttering in neck

CAUSES

▪ Rheumatic heart disease ▫ Most common cause ▫ Can occur with mitral regurgitation, aortic valve disease ▪ Congenital atresia, stenosis ▪ Pacemaker-induced fibrosis ▪ Cardiac tumors ▪ Infective endocarditis

COMPLICATIONS

▪ Increased right atrial volume, pressure → atrial dilation → blood backs up into venous circulation ▪ Dilation of right atrium → muscle walls stretch → pacemaker cells become irritable → increases risk of atrial flutter, fibrillation

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DIAGNOSIS DIAGNOSTIC IMAGING Echocardiography ▪ Assess degree of leaflet damage, flow across valve

OTHER DIAGNOSTICS Cardiac catheterization ▪ Measure pressure in right side of heart

Chapter 10 Heart Valve Disease

TREATMENT SURGERY

▪ Balloon valvuloplasty, valve repair/ replacement

Figure 10.9 Illustration depicting differences between tricuspid valve regurgitation and tricuspid valve stenosis.

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NOTES

HYPERTENSION & HYPOTENSION

GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Changes of blood pressure above (hyper-) or below (hypo-) normal (120/80mmHg)

CAUSES

▪ Mostly idiopathic, but can include various causes: impaired regulatory pathways (hormonal/neurologic disorders), heart disease, kidney disease, medications etc.

SIGNS & SYMPTOMS ▪ Can be asymptomatic/include symptoms according to underlying cause, degree of change in blood pressure ▫ Hypertension: range from headache, dyspnea, to blurred vision, oliguria, seizures ▫ Hypotension: range from fatigue, pallor to syncope

DIAGNOSIS OTHER DIAGNOSTICS

▪ Blood pressure cuff (sphygmomanometer) or arterial catheter

TREATMENT ▪ Hypotension: generally requires no treatment ▪ Hypertension: treated according to degree, treat underlying cause if present

MEDICATIONS

▪ Hypertension: beta blockers, diuretics, ACE inhibitors, calcium channel blockers, etc.

Figure 11.1 Illustration depicting endothelial damage caused by hypertension.

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HYPERTENSION osms.it/hypertension PATHOLOGY & CAUSES ▪ Condition in which blood pressure is regulated maladaptively, elevating blood pressure over 140/90mmHg ▪ Isolated systolic hypertension: systolic blood pressure is elevated, diastolic is not ▪ Isolated diastolic hypertension: diastolic blood pressure is elevated, systolic is not

▪ ▪

▪

CAUSES Primary/essential hypertension ▪ Most cases (90%) Secondary hypertension ▪ Known etiology, often reversible ▪ Renovascular hypertension: anything partially obstructing blood flow to kidneys (e.g. atherosclerosis, vasculitis, fibromuscular dysplasia). ▫ Decreased blood flow to kidneys → kidneys secrete renin → renin converts angiotensinogen to angiotensin I → angiotensin converting enzyme converts angiotensin I to angiotensin II (active) → angiotensin II effects: ▫ Vasoconstriction: directly increases blood pressure ▫ Stimulation of sodium reabsorption: increases water reabsorption ▫ Stimulation of adrenal cortex to release aldosterone from adrenal cortex → aldosterone increases reabsorption of sodium + water → increased volume → high blood pressure ▪ Primary hyperaldosteronism: increased aldosterone → increased reabsorption of sodium + water → increased volume → increased blood pressure ▪ Nonsteroidal anti-inflammatory drugs (NSAIDs) → inhibit cyclooxygenase in kidneys → ↓ production of PGE-2 (renal vasodilator) → vasoconstriction of afferent arterioles in kidneys → ↓ renal blood flow,

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▪

glomerular filtration rate → ↓ secretion of sodium + water → ↑ volume → ↑ blood pressure Preeclampsia/eclampsia in pregnancy: mechanism unknown Coarctation of the aorta: low pressure past coarctation → low renal perfusion → activation of renin angiotensin-aldosterone system (RAAS) → secondary hypertension Cushing’s syndrome: combination of several pathophysiological mechanisms (e.g. elevated cortisol) that regulate plasma volume, cardiac output, peripheral vascular resistance Chronic kidney disease: fluid overload, sodium retention

MNEMONIC: RHNECCK Causes of Secondary hypertension Renovascular hypertension 1° Hyperaldosteronism NSAIDs Pre-Eclampsia / Eclampsia Coarctation of the aorta Cushing’s syndrome Kidney Disease (chronic)

RISK FACTORS Primary hypertension ▪ Risk increases with age, biological male, obesity, stress, sedentary lifestyle, family history of hypertension ▪ Race (in decreasing order of risk): African descent > white European descent > Asian descent ▪ Diet: excessive sodium, alcohol intake ▪ Abnormal lipid panel (high low-density lipoproteins, low high-density lipoproteins, high triglycerides)

Chapter 11 Hypertension & Hypotension Secondary hypertension ▪ Atherosclerosis: Elderly biological males ▫ Atherosclerosis → renal stenosis → less blood flow to renal arteries → activation of RAAS → renovascular hypertension

COMPLICATIONS

▪ Increased risk of atherosclerosis, arteriosclerosis ▪ Arteriolar rarefaction: loss of arterioles ▪ Coronary artery disease, left ventricular hypertrophy, atrial fibrillation, stroke, hypertensive nephropathy, retinopathy, aortic dissection, aneurysms

SIGNS & SYMPTOMS ▪ Vast majority of cases asymptomatic ▪ May experience headache, dyspnea ▪ Renal bruit in secondary hypertension due to renal artery stenosis ▪ Hypertensive retinopathy

DIAGNOSIS OTHER DIAGNOSTICS

▪ Non-invasive/invasive blood pressure monitoring ▫ High blood pressure: at least 2 separate measurements with blood pressure > 140/90mmHg

Figure 11.2 Illustration depicting stages of hypertension.

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TREATMENT ▪ Reduce BP 180/120mmHg with signs of acute end organ damage (e.g. encephalopathy, stroke, papilledema, myocardial infarction, heart failure, microangiopathic hemolytic anemia, etc.) ▪ Complication of poorly managed hypertension

RISK FACTORS

▪ Kidney failure, renovascular hypertension, stimulant abuse, medication non-adherence ▪ More common in young adults, particularly those of African descent

COMPLICATIONS

▪ Neurological complications (stroke, seizures), myocardial infarction, kidney failure, permanent blindness, pulmonary edema

SIGNS & SYMPTOMS ▪ Blood pressure > 180/120mmHg, signs of end-organ damage ▫ Blurred vision, altered mental state, chest pain, headache, nausea, vomiting, numbness in extremities, oliguria, seizure, dyspnea, weakness, papilledema

DIAGNOSIS OTHER DIAGNOSTICS

▪ Sphygmomanometer ▫ Blood pressure > 180/120mmHg ▪ Evaluation to identify at-risk target organ ▫ Electrocardiography (heart) ▫ Chest X-ray (heart, lungs) ▫ Urinalysis (kidneys) ▫ Serum electrolytes, serum creatinine (kidneys) ▫ Cardiac enzymes (heart) ▫ CT scan of brain (if brain suspected → neurologic symptoms, retinopathy) ▫ Contrast-enhanced CT scan of chest (if aortic dissection suspected)

TREATMENT ▪ Treatment varies case-by-case, dependent on affected organ

MEDICATIONS

▪ Unwise to lower blood pressure too quickly/ too much, as this can lower cerebral perfusion excessively ▫ Most cases: mean arterial pressure (MAP) should be reduced using intravenous medication 10–20 % in first hour, then 5–15% over the following 23 hrs. Specific medications used dependent on case

OTHER INTERVENTIONS

▪ Exceptions to most cases: acute phase ischemic stroke (not lowered unless specific conditions met) ▫ Acute aortic dissection (rapid lowering), intracerebral hypertension (variable)

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HYPOTENSION osms.it/hypotension PATHOLOGY & CAUSES ▪ Condition in which arterial blood pressure drops below 90/60mmHg ▪ Physiological in some cases (professional athletes); considered pathologic if symptomatic ▪ Not a distinctive disease, but a manifestation of various conditions ▪ Orthostatic hypotension: hypotension caused by standing up from a sitting/lying position

CAUSES Hypovolemia ▪ Fluid loss (hemorrhage, diarrhea, vomiting), low fluid intake (starvation, oligodipsia), endocrine disorders, anemia Heart disease ▪ Cardiomyopathies, heart valve disease (e.g. mitral stenosis), congestive heart failure, myocardial infarction, arrhythmias Medications ▪ Most commonly cause orthostatic hypotension ▪ Excessive use of diuretics, alpha/beta blockers, nitrate preparations, calcium channel blockers, angiotensin II (AT1) receptor blockers, antidepressants Neurological disorders ▪ Spinal cord injury resulting in ↓ sympathetic output or ↑ parasympathetic output ▪ Dysautonomia (intrinsic autonomic system dysfunction), Parkinson’s disease

COMPLICATIONS

▪ Ischemia ▪ If severe, can lead to shock

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SIGNS & SYMPTOMS ▪ Lightheadedness, fatigue, pallor, confusion ▪ Significant hypotension → syncope

DIAGNOSIS OTHER DIAGNOSTICS

▪ Evaluation of blood pressure with sphygmomanometer/arterial catheter ▫ Systolic blood pressure < 90mmHg ▫ Diastolic blood pressure < 60mmHg ▫ Mean arterial pressure < 65mmHg ▪ Orthostatic hypotension ▫ Drop in 20mmHg of systolic pressure/10mmHg of diastolic pressure when standing up from a sitting/lying position

TREATMENT ▪ Asymptomatic hypotension does not require treatment ▪ Treat underlying cause

NOTES

NOTES

INFECTIONS & INFLAMMATION OF THE HEART

GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Heart infections, inflammation (may affect epicardium, myocardium, endocardium) ▪ May include: infective endocarditis, Libman-Sacks endocarditis, myocarditis, rheumatic fever ▪ May cause/be caused by/coexist with other infections

COMPLICATIONS

▪ Heart failure, arrhythmias, fibrosis ▪ Infective, Libman–Sacks endocarditis can cause ▫ Damage to heart valves: dysrhythmias, valve dysfunction ▫ Invasion of myocardium: heart failure, heart block, sepsis ▫ Vegetation can embolize to extremities: infarction/ischemia causing stroke, pulmonary edema, glomerulonephritis

SIGNS & SYMPTOMS ▪ See individual disorders

DIAGNOSIS ▪ See individual disorders

TREATMENT ▪ See individual disorders

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INFECTIVE ENDOCARDITIS osms.it/endocarditis PATHOLOGY & CAUSES ▪ Infection of endocardium, usually with bacteria, may include heart valve ▪ Valves have small blood vessels → damage to valve, vessels → microbes in blood escape into valvular tissue/microbes enter small vessels → infection ▪ Valve endothelial lining damaged ▪ Microbes enter body via: dental/surgical procedures, injection with infected needle/ infected substance, wound/abscess ▪ Vegetation: fibrin, leukocytes, microbes attach to thrombosis → abnormal growth → potential embolism ▪ Often affects left side heart valves ▫ Predisposing conditions: mitral valve prolapse, bicuspid aortic valves

TYPES

▪ Classified by microbial cause ▫ Acute bacterial endocarditis: infection of normal valves, rapid progression ▫ Subacute bacterial endocarditis: indolent infection of abnormal valves (e.g. S. viridans) ▫ Endocarditis in IV drug users: Methicillin-resistant Staphylococcus aureus (MRSA), Pseudomonas, Candida ▫ Prosthetic valve endocarditis: Staphylococcus epidermidis within 60 days of replacement; after 60 days, resembles native valve endocarditis

CAUSES Viridans streptococci (most common) ▪ Low virulence ▪ Found in mouth ▪ Attacks previously damaged valves ▪ Small vegetations: don’t destroy valve Staphylococcus aureus ▪ High virulence

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▪ ▪ ▪ ▪

Found on skin Infects damaged, healthy valves Large vegetations: can destroy valve Most commonly contracted from IV drug use

Staphylococcus epidermidis ▪ Infects prosthetic material (e.g. prosthetic heart valves) ▪ Enters body during valve surgery/infected IV catheter: sticks around valve/catheter ▪ Nosocomial infection (infection in hospital) ▪ Gut flora ▫ Enterococcus faecalis ▫ Streptococcus bovis ▪ Severe colorectal disease (e.g. colorectal cancer/ulcerative colitis): bacteria migrate into bloodstream Coxiella burnetii ▪ Exposure to infected animals (e.g. cows, sheep, goats) ▪ Q fever → months/years later, endocarditis ▪ Affects those at high risk: immunocompromised, pregnant individuals, pre-existing heart valve defect ▪ Diagnosis difficult Candida albicans ▪ Fungal endocarditis ▪ Connected with IV drug use Culture-negative endocarditis ▪ Cannot be linked to bacteria using blood cultures ▪ Aortic vascular infection, persistent low fever, rash ▪ Often caused by Coxiella burnetii HACEK organisms ▪ Haemophilus, Aggregatibacter, Cardiobacterium, Eikenella, Kingella ▪ Gram-negative bacteria ▪ Normal flora of mouth, throat

Chapter 12 Infections & Inflammation of the Heart Nonbacterial thrombotic endocarditis ▪ Damage in valve exposes collagen, tissue factor → platelets, fibrin adhere → form tiny thrombosis → mitral valve regurgitation ▫ Bacteremia → bacterial attach to thrombi → bacterial endocarditis

RISK FACTORS

▪ Valvular problems ▫ Mitral valve prolapse ▫ Bicuspid aortic valves ▫ Prosthetic valves ▫ Valves affected: mitral > aortic, tricuspid ▪ Congenital cardiac defects ▪ Damage to valves due to rheumatic heart disease ▪ IV drug use (esp. tricuspid valve) ▪ Chronic hemodialysis ▪ Poor dentition

SIGNS & SYMPTOMS ▪ Anorexia, weight loss, fatigue ▪ See mnemonic below

DIAGNOSIS DIAGNOSTIC IMAGING Chest X-ray ▪ Enlarged heart, possible pulmonary congestion Echocardiogram ▪ Inflamed heart muscle walls, dilation

LAB RESULTS

▪ Elevated troponin, creatine kinase levels (due to heart muscle damage)

Cardiac muscle biopsy ▪ Definitive diagnosis ▪ Risky procedure, performed only if test results would change treatment plan

OTHER DIAGNOSTICS ECG ▪ Sinus tachycardia (increased heart rate) ▪ T-wave inversions ▪ “Saddle-shaped” ST segment elevations

TREATMENT

MNEMONIC: FROM JANE

Signs & Symptoms Fever Roth spots: antigen-antibody complex deposits in eyes Osler nodes: painful antigenantibody complex deposits in pads of digits Murmur: turbulent blood flow past damaged heart valve Janeway lesions: erythematous lesions due to emboli; small, painless, flat Anemia Nail-bed hemorrhage (splinter hemorrhages): deposition of emboli Emboli: vegetations detach from valve, deposit elsewhere (nail beds, kidneys, spleen, central nervous system)

▪ Viral: improves slowly over time ▪ Arrhythmias resolve as inflammation improves

MEDICATIONS

▪ Antibiotics ▪ Signs of heart failure: managed with medication, fluid balance

SURGERY

▪ Heart transplant in severe cases (e.g. Chagas, giant cell myocarditis)

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Figure 12.2 Bacterial vegetations on the mitral valve in endocarditis. Figure 12.1 Janeway lesions are hemorrhagic macules or nodules that may appear on the palms of the hands or soles of the feet in cases of infective endocarditis.

Figure 12.3 Roth spots seen in the retina.

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Chapter 12 Infections & Inflammation of the Heart

LIBMAN–SACKS ENDOCARDITIS osms.it/endocarditis PATHOLOGY & CAUSES ▪ Autoimmune endocarditis associated with systemic lupus erythematosus (SLE), advanced malignancy, rheumatoid arthritis ▪ AKA nonbacterial thrombotic endocarditis/ verrucous endocarditis

CAUSES

▪ Antigen-antibody complexes settle in endocardium ▫ Arises on valves /chordae tendineae, most often mitral valve ▫ Arises even on atrial/ventricular endocardium ▫ Sterile vegetations: aortic valves

COMPLICATIONS ▪ ▪ ▪ ▪

Damage to heart valves Invasion of myocardium Vegetations may embolize In rare cases, may cause secondary infective endocarditis

SIGNS & SYMPTOMS

DIAGNOSIS ▪ Must exclude infective endocarditis (may coexist)

DIAGNOSTIC IMAGING Transesophageal echocardiogram (TEE) ▪ Small, warty, vegetations on both atrial and ventricular sides of valves ▪ Regurgitation, valve insufficiency

LAB RESULTS

▪ CRP, WBC levels, and antiphospholipid/ anticardiolipin antibody level may aid in differentiation

TREATMENT ▪ Treat underlying SLE

MEDICATIONS Anticoagulants ▪ E.g. heparin, direct thrombin, Xa inhibitors ▪ Address embolic risk

▪ Regurgitant murmurs ▫ Bilateral vegetations on valve leaflets ▪ Clinical manifestations indicate systemic emboli ▫ Kidney: flank pain, hematuria ▫ Skin: rash, digital ischemia ▫ Cardiac/central nervous system (CNS): chest pain, stroke

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MYOCARDITIS osms.it/myocarditis PATHOLOGY & CAUSES ▪ Inflammation of/damage to myocardium ▪ Swelling impairs myocardial contraction → less blood pumped out of heart with each heartbeat

CAUSES Coxsackieviruses A & B infections ▪ Viral infections → lymphocytic myocarditis: B, T cells, water invade interstitial space ▪ Common in North America Trypanosoma cruzii ▪ Single-cell protozoan → Chagas disease ▪ Amastigotes within heart muscle cells (intracellular stage of trypanosomes) → necrosis of heart muscle cells ▪ Common in South America Trichinella ▪ Intestinal roundworm may move into heart → myocarditis Borrelia burgdorferi ▪ Lyme disease bacterium Toxoplasma gondii ▪ Single cell parasite harbored by cats Systemic lupus erythematosus (SLE) ▪ Non-infectious myocarditis ▪ Immune system attacks myocardium Drug-associated/hypersensitivity ▪ Adverse drug reaction inflames heart ▪ Eosinophils enters blood vessels in myocarditis Giant cell ▪ Inflammation of heart from unknown cause ▪ Macrophages fuse to form single giant cell

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RISK FACTORS

▪ Viruses that cause flu-like illnesses, HIV/ AIDS, Lyme disease, strep, staph infections, parasites

COMPLICATIONS

▪ Heart failure, fibrosis, arrhythmias

SIGNS & SYMPTOMS ▪ Clinical manifestations of heart failure (e.g. fatigue, shortness of breath, hepatomegaly, edema) ▪ Acute heart failure → cardiogenic shock ▪ Arrhythmias (e.g. ventricular fibrillation, ventricular tachycardia) → sudden cardiac death ▪ Fever ▪ Positional chest pain, related to pericarditis: better/worse depending on body’s position

DIAGNOSIS DIAGNOSTIC IMAGING Chest X-ray ▪ Enlarged heart, possible pulmonary congestion Echocardiogram ▪ Inflamed heart muscle walls, dilation

LAB RESULTS

▪ Elevated troponin, creatine kinase levels (due to heart muscle damage)

Cardiac muscle biopsy ▪ Definitive diagnosis ▪ Risky procedure, performed only if test results would change treatment plan

Chapter 12 Infections & Inflammation of the Heart

OTHER DIAGNOSTICS ECG ▪ Sinus tachycardia (increased heart rate) ▪ T-wave inversions ▪ “Saddle-shaped” ST segment elevations

MNEMONIC: BCD ST3G Common Causes of Myocarditis Borrelia burgdorferi Coxsackieviruses A and B Drug-associated

TREATMENT ▪ Viral: improves slowly over time ▪ Arrhythmias resolve as inflammation improves

MEDICATIONS

▪ Antibiotics ▪ Signs of heart failure: managed with medication, fluid balance

SURGERY

▪ Heart transplant in severe cases (e.g. Chagas, giant cell myocarditis)

Systemic lupus erythematosus Trypanosoma cruzi Trichinella Toxoplasma gondii Giant cell

Figure 12.4 Histological appearance of myocardium in viral myocarditis.

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RHEUMATIC FEVER osms.it/rheumatic-heart-disease PATHOLOGY & CAUSES ▪ Autoimmune inflammatory disease caused by complication of streptococcal infection ▪ Develops after streptococcal pharyngitis (strep throat) from Group A beta hemolytic streptococcus

CAUSES Molecular mimicry ▪ Antibodies against streptococcal M-protein cross-reacts with proteins on myocardium, heart valves, joints, skin, brain → cytokinemediated inflammatory response ▪ Inflammation results in widespread pathology Pancarditis ▪ Inflammation of endometrium, myometrium, pericardium (three layers of heart tissue) ▪ Myometrium: Aschoff bodies (microscopically viewed nodules caused by inflammation) → leads to fibroid necrosis ▫ Characteristic feature of pancarditis ▫ Anitschkow cells (enlarged macrophages inside Aschoff bodies), caterpillar-like nuclei ▪ Pericardium: pericarditis causes pain, friction rub due to visceral pericardium rubbing against parietal pericardium Chronic rheumatic heart disease ▪ Repeated exposure to group A betahemolytic streptococcus → immune attacks on tissues (esp. heart tissue) ▪ Valves (typically mitral valve, sometimes aortic) develop scar tissue → leaflets thicken, fuse → commissural fusion ▫ Stenosis AKA “fish-mouth”/“buttonhole” stenosis ▫ Regurgitation (blood flows backward) ▪ Chordae tendineae attached to valves thicken

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TYPES

▪ When only a subset of symptoms present, classified as the following

Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS) ▪ Neuropsychiatric symptoms Poststreptococcal reactive arthritis ▪ Joint symptoms

RISK FACTORS

▪ Small number of individuals with strep throat develop rheumatic fever, more likely in children/those in areas of poverty, crowding ▪ Rheumatic fever primarily affects children 5–7 years old, 20 days after infection ▪ One third of cases asymptomatic

SIGNS & SYMPTOMS Acute rheumatic fever ▪ Following symptoms develop 2–4 weeks after streptococcal pharyngitis ▪ Fever ▪ Migratory polyarthritis of joints: temporary inflammation, swelling, joint pain ▪ Erythema marginatum: non-itchy, reddish rash, rings on arms/trunk ▪ Subcutaneous nodules: firm collagen lumps under skin ▫ Reaction to hypersensitivity ▫ Painless ▫ Back of wrist, outside elbow, front of knee ▪ Pancarditis (inflammation of three layers of heart) ▪ Dyspnea, sharp chest pain ▪ Friction rub heard on auscultation due to pericarditis ▪ Impaired ability of heart to contract

Chapter 12 Infections & Inflammation of the Heart (myocarditis) → heart failure, death ▪ Sydenham’s chorea: rapid, jerky movements of face, arms from damage to basal ganglia ▫ Autoimmune reaction on basal ganglia of brain ▫ Appears late (three months after infection) Chronic rheumatic heart disease ▪ Symptoms dependent on type of damage to heart: aortic stenosis, aortic regurgitation, mitral stenosis, mitral regurgitation, pulmonic regurgitation PANDAS ▪ Pediatric, abrupt onset, episodic course of symptoms ▪ Neurologic abnormalities: motoric hyperactivity (fidgeting), choreiform movements in stressed postures (sudden, jerky movements), frank chorea (rapid, irregular, jerks, movements continuous while awake but improve with sleep) ▪ Obsessive-compulsive disorder/tic disorder

▪ Minor criteria ▫ Signs/symptoms: fever (>38.5°C/101.3°F), arthralgia ▫ Laboratory evidence: increased acute phase reactants (↑ erythrocyte sedimentation rate, ↑ C-reactive protein, ↑ leukocytosis) ▫ Electrocardiograph: prolonged PR interval ▪ Evidence of recent infection ▫ Positive throat culture ▫ Positive rapid antigen detection test ▫ Elevated antistreptolysin O titre (ASO) ▪ Exception: Sydenham’s chorea/pancarditis independently may indicate rheumatic fever ▪ Electrocardiogram changes Chronic rheumatic heart disease ▪ Previous repeated cases of rheumatic fever ▪ Diagnosis depends on damage done to heart: aortic stenosis, aortic regurgitation, mitral stenosis, mitral regurgitation, pulmonic regurgitation

Poststreptococcal reactive arthritis ▪ Arthritis occurring after a streptococcal infection

DIAGNOSIS OTHER DIAGNOSTICS Jones criteria for acute rheumatic fever ▪ Evidence of previous group A streptococcus infection plus two major criteria/one major plus two minor criteria

MNEMONIC: JONES

Figure 12.5 Anitschkow cells (enlarged macrophageswith linear nucleoli) in an Aschoff body (a granuloma) in a case of rheumatic myocarditis.

Major criteria Joints: polyarthritis myOcarditis: O = vaguely heart-shaped Nodules: subcutaneous Erythema marginatum Sydenham’s chorea

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TREATMENT MEDICATIONS Rheumatic fever ▪ Goals of treatment: control, eradicate streptococcus, prevent complications, relieve joint pain, relieve fever ▫ Antibiotics: penicillin G ▫ Anti-inflammatory agents: aspirin, non-steroidal anti-inflammatory drugs (NSAIDs), steroids ▫ Antipyretics: NSAIDs ▫ Rest

Rheumatic heart disease ▪ Prevent repeated attacks/acute rheumatic fever, streptococcal infections ▪ History of acute rheumatic fever: prophylactic treatment for extended period (benzathine penicillin G/oral penicillin V, 10 years to life)

OTHER INTERVENTIONS Rheumatic fever ▪ Maintain dental health ▪ Strict long-term, prophylaxis: history of bacterial endocarditis, heart transplant, artificial heart valve, other congenital defect

Figure 12.6 Massive cardiomegaly secondary to aortic and mitral valve disease in a severe case of rheumatic fever.

Figure 12.7 Gross pathology of acute rheumatic endocarditis; there is a line of acute inflammation (valvulitis) along the closure line of the mitral valve.

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NOTES

LYMPHATIC DYSFUNCTION

LYMPHEDEMA osms.it/lymphedema PATHOLOGY & CAUSES ▪ Lymphatic system becomes obstructed, causing protein-rich fluid buildup in tissues ▪ When flow is blocked, lymph gets backed up → drainage stops → fluid accumulates ▪ Inflammatory reaction: macrophages release inflammatory molecules → damages nearby cells → scarring, fibrosis (connective tissues thicken/scar tissue forms) → hardening

CAUSES

▪ Filariasis: most common cause in lowincome countries ▫ Infection with nematode parasites (e.g. Wuchereria bancrofti) ▫ Nematode enters lymphatic system, causes fibrosis, creates a blockage ▪ Cancer, associated treatment: most common cause in high-income countries ▫ Removal of lymph nodes most common cancer treatment-related cause (e.g. axillary lymph nodes removed during mastectomy) ▪ Lymphedema praecox/primary lymphedema: congenital, results from lymphatic system not developing correctly < 35 years old ▪ Lymphedema tarda/primary lymphedema: > 35 years old, associated with genetic disorders (e.g. Turner syndrome)

RISK FACTORS

▪ Older age, obesity, rheumatoid/psoriatic arthritis, Turner syndrome, smoking, cancer/ associated treatment (esp. breast cancer)

Figure 13.1 Gross lymphedema of the left leg.

STAGING

▪ Stage 0: latent stage. Damage to lymphatics but enough lymph still removed. Lymphedema not present ▪ Stage 1: spontaneously reversible. Tissue in pitting stage. Affected area normal/almost normal size in morning, progressively worsens throughout day ▪ Stage 2: spontaneously irreversible. Tissue spongy, non-pitting (bounces back when pressed). Fibrosis starts to develop → limbs harden, increase in size ▪ Stage 3: lymphostatic elephantiasis. Swelling irreversible, limbs large, hard from fibrosis

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COMPLICATIONS

▪ Recurrent cellulitis, limb swelling (esp. lower limbs), erythema, pain

SIGNS & SYMPTOMS ▪ Chronic swelling , one limb larger than other ▪ Usually lower limbs; impairs movement ▪ Fatigue, fever, chills, weakness ▪ More likely to occur with superimposed bacterial/fungal skin infection ▪ Regional edema: begins as soft, pitting edema → progresses into chronic fibrosis without treatment

DIAGNOSIS DIAGNOSTIC IMAGING Lymphoscintigraphy ▪ Nuclear imaging to assess lymphatic flow ▫ Radiotracer injected into affected limb → able to visualize dermal backflow, absent/delayed radiotracer movement, absent/delayed lymph node visualization

TREATMENT ▪ No cure, no medication ▪ Depends on severity, limb fibrosis

SURGERY

▪ Goal: improve drainage/reduce fluid load

OTHER INTERVENTIONS

▪ Therapeutic exercises, self care ▪ Kinesio tape: applied to skin to channel lymph, reduce swelling ▪ Aquatic therapy

Manual lymphatic drainage (MLD) ▪ Pneumatic pumps: substitute for MLD Compression ▪ Multilayer compression bandage: stop fluid accumulation ▪ Compression massages help lymph flow ▪ Compression garments

MRI ▪ Shows severity, distribution of edema, lymphatic channels can be depicted after intracutaneous contrast injection MR venogram ▪ Helps differentiate lymphatic channels from superficial veins CT scan ▪ Assists in localization (subfascial, epifascial), characteristics (skin thickening, honeycomb pattern of edema) Ultrasound ▪ May be used to reveal blockages

Figure 13.2 A plain X-ray of the forearm showing edema of the subcutaneous tissues. The subcutaneous fat shows characteristic streaky densities.

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NOTES

PERICARDIAL DISEASE GENERALLY, WHAT IS IT? PATHOLOGY & CAUSES ▪ Disorders affecting pericardium ▪ Pericardial cavity: space between visceral, parietal layer, normally filled with 15–50ml of plasma filtrate

CAUSES

Infections: mostly viral; bacterial, fungal rare Malignancy, mediastinal radiation Dressler’s syndrome Trauma Drugs, toxins Metabolic disease (e.g. uremic syndrome, myxedema, ovarian hyperstimulation syndrome), connective tissue disease ▪ Immune-mediated disorders

▪ ▪ ▪ ▪ ▪ ▪

COMPLICATIONS

▪ Heart failure, circulatory problems, problems breathing

SIGNS & SYMPTOMS ▪ See individual diseases

DIAGNOSIS DIAGNOSTIC IMAGING ▪ Echocardiogram ▪ X-ray

OTHER DIAGNOSTICS ▪ ECG

TREATMENT ▪ Pericardiocentesis, pericardiectomy

MNEMONIC: CARDIAC RIND

Causes of Pericarditis Collagen vascular disease Aortic aneurysm Radiation Drugs Infections Acute renal failure Cardiac infarction Rheumatic fever Injury Neoplasms Dressler’s syndrome

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ACUTE PERICARDITIS osms.it/acute-pericarditis PATHOLOGY & CAUSES ▪ Pericardial inflammation, myopericarditis ▪ Most common pericardial disorder

CAUSES

▪ Idiopathic, viral (e.g. Coxsackie B), uremic syndrome (toxic to pericardium), Dressler’s syndrome, autoimmune (e.g. rheumatoid arthritis, scleroderma, systemic lupus erythematosus), cancer, radiation, medications (e.g. penicillin, anticonvulsants)

RISK FACTORS

▪ Surgery, cancer, autoimmune disease, connective tissue disorders, immunosuppression

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COMPLICATIONS

▪ Constrictive pericarditis, pericardial effusion, cardiac tamponade

SIGNS & SYMPTOMS ▪ Fever, sharp chest pain worsened with deep breathing, symptoms improve with sitting up and leaning forward ▪ Pericardial friction rub heard on auscultation, like two pieces of leather rubbing together, loudest on left sternal border

Chapter 14 Pericardial Disease

DIAGNOSIS

TREATMENT

DIAGNOSTIC IMAGING

▪ Targeted at etiology

X-ray ▪ “Water bottle sign,” liquid collects at the bottom if effusion present

MEDICATIONS

Echocardiography ▪ Performed to exclude pericardial effusion

OTHER INTERVENTIONS

▪ Clinical presentation suggestive of pericardial effusion

ECG ▪ ST elevation, PR depression, voltage changes, flattened, inverted T wave

MNEMONIC: PSPPS

▪ Treat pain, inflammation ▫ Non-steroidal anti-inflammatory drug (NSAID) + colchicine ▫ Glucocorticoids if NSAID contraindicated ▫ Colchicine important if rheumatoid arthritis, Dressler syndrome involved

SURGERY

▪ Pericardiotomy if high recurrence

OTHER INTERVENTIONS ▪ Rest

Acute pericarditis ECG PericarditiS PR depression in Precordial leads ST elevation

Figure 14.2 Illustration depicting sclerosing of pericardial tissues in cross-section of heart wall. Figure 14.1 A chest radiograph demonstrating the globular cardiac silhouette seen in a case of pericardial effusions secondary to acute pericarditis. This is also known as the water bottle sign.

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Figure 14.4 Histology photomicrograph demonstrating acute pericarditis. The mesothelial cells of the pericardium are surrounded by neutrophils and there is no fibrosis, indicating an acute inflammatory reponse. Figure 14.3 Gross pathology of acute fibrinous pericarditis. The yellow fibrinous exudate is clearly visible on the external surface of the heart.

CARDIAC TAMPONADE osms.it/cardiac-tamponade PATHOLOGY & CAUSES ▪ Buildup of fluid in pericardium, constricts heart ▪ Tamponade = pressure obstructing flow ▪ Heart unable to pump normally → blood flow through chambers obstructed → cardiac output decreases → hypotension → lower tissue perfusion → heart rate increases

CAUSES

▪ Acute onset: trauma, myocardial infarction, aortic dissection, pericardial effusion ▪ Slow onset: cancer, chronic inflammation, uremic pericarditis, hypothyroidism, connective tissue disease

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RISK FACTORS

▪ Individuals with malignancy, tuberculous, purulent pericarditis ≥ those with idiopathic pericarditis ▪ Individuals with fibrinolytic therapy, myocardial infarction

SIGNS & SYMPTOMS ▪ Pulsus paradoxus due to ventricular interdependence ▪ Beck’s triad (see mnemonic) ▪ Tachycardia, coughing, dyspnea, weakness, myocardial ischemia

Chapter 14 Pericardial Disease MNEMONIC: 3Ds

Beck’s triad (Signs & Symptoms) Distant heart sounds Distended jugular veins Decreased arterial pressure

DIAGNOSIS DIAGNOSTIC IMAGING Echocardiography ▪ Excess pericardial fluid, heart “swinging” inside pericardial cavity

Figure 14.5 A CT scan in the axial plane demonstrating a large pericardial effusion, separating the pericardium from the heart itself and increasing the intrapericardial pressure, leading to cardiac tamponade.

SURGERY

TREATMENT

▪ Cardiac catheterization → pressure in all four chambers equal

OTHER INTERVENTIONS ▪ Clinical presentation

ECG ▪ Tachycardia, low QRS complex voltage, electrical alternans (QRS complexes have different heights)

MEDICATIONS ▪ IV fluids

OTHER INTERVENTIONS Pericardiocentesis ▪ Needle inserted into pericardium to drain excess fluid

Figure 14.6 Illustration depicting fluid build up around pericardium, putting pressure on the heart walls and decreasing stroke volume.

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CONSTRICTIVE PERICARDITIS osms.it/constrictive-pericarditis PATHOLOGY & CAUSES ▪ Formation of thick, fibrotic pericardium → compresses heart ▪ Fibroblasts accumulate between pericardial layers → collagen deposits → creates scars → layers become adherent, lose elasticity ▪ Heart filling difficult due to stiffness of pericardium ▫ Ventricular interdependence: lowered heart wall compliance, decreased transpulmonary venous pressure → left ventricular filling decreases → lower volume in left heart → right bends septum towards left to increase volume ▫ Maximal volume diminished, continues to decrease with disease progression ▪ Volume overload, hepatopathy, decreased cardiac output

CAUSES

▪ Idiopathic, viral, radiation, myocardial infarction, collagen disorders, tuberculosis

RISK FACTORS

▪ Acute pericarditis ▪ Cardiac surgery, radiation, connective tissue disorders, bacterial (purulent) infections

COMPLICATIONS

▪ Heart failure, arrhythmias, cardiac tamponade

▪ Edema: part of fluid overload; ascites, hepatosplenomegaly (HSM), cachexia (signs of hepatopathy); dyspnea (consequence of low cardiac output) ▪ Clinical manifestations of pleural effusion

DIAGNOSIS DIAGNOSTIC IMAGING X-ray ▪ Pericardial calcifications Echocardiogram ▪ Stiff serous pericardium restricts heart’s movement CT scan ▪ Anatomical variations, thickness, distribution of scarring

LAB RESULTS Plasma brain natriuretic peptide (BNP) ▪ Differentiate between tamponade, cirrhosis, restrictive cardiomyopathy

OTHER INTERVENTIONS Invasive hemodynamic monitoring ▪ Increased pressure in right atrium, Kussmaul’s sign

SIGNS & SYMPTOMS ▪ Elevated jugular venous pressure (JVP) ▪ Kussmaul’s sign: paradoxical inspiratory JVP ▪ Pericardial knock: heard before S3 on auscultation

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TREATMENT MEDICATIONS

▪ Diuretics, NSAIDs, corticosteroids

SURGERY

▪ Pericardiectomy (for progressive disease)

Chapter 14 Pericardial Disease

Figure 14.7 A chest radiograph demonstrating pericardial calcification secondary to a chronic pericarditis.

DRESSLER'S SYNDROME osms.it/dresslers-syndrome PATHOLOGY & CAUSES ▪ ▪ ▪ ▪

Secondary pericarditis, rare AKA postmyocardial infarction syndrome May or may not involve pericardial effusion ≥ two weeks after myocardial infarction (MI), immune-mediated response to injury → antimyocardial antibodies respond to cardiac antigens → immune complex deposits in pericardium, pleura

SIGNS & SYMPTOMS ▪ Unusual fatigue after cardiac surgery/MI ▪ Persistent fever, tachycardia, pulsus paradoxus ▪ Manifestations of pericarditis: friction rub, symptoms improve in sitting position ▪ Pleural effusion signs: pleuritic pain

DIAGNOSIS DIAGNOSTIC IMAGING Echocardiogram ▪ Evaluate ventricular contractility; effusion, signs of tamponade Chest X-ray ▪ Cardiac effusion

LAB RESULTS

▪ Complete blood count (CBC), CRP, erythrocyte sedimentation rate (ESR); troponin studies show leukocytosis, ↑ CRP, ↑ ESR; anti-heart antibody titer

OTHER INTERVENTIONS ECG ▪ Changes same as acute pericarditis ▪ ST segment elevation, PR depression

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TREATMENT MEDICATIONS

▪ Colchicine recommended after cardiac surgery as preventative measure ▪ High dose aspirin, NSAIDs, corticosteroids

PERICARDIAL EFFUSION osms.it/pericardial-effusion PATHOLOGY & CAUSES ▪ Abnormal accumulation of inflammatory fluid, immune cells → diffuse into interstitium → fluid pools in pericardial space → pericardial dilation → pressure on heart, vena cava → decreased cardiac filling → cardiac tamponade → decreased cardiac output ▪ Types of effusion: serous, serosanguinous, chylous

CAUSES

▪ Aortic dissection, heart failure, hypoalbuminemia, lymphatic obstruction, malignancy, radiation, renal failure, trauma, autoimmune disease, acute pericarditis (viral, bacterial, tuberculous, idiopathic in origin), myxedema, some drugs, iatrogenic, idiopathic

COMPLICATIONS

DIAGNOSIS DIAGNOSTIC IMAGING X-ray ▪ Silhouette pools to bottom of heart, gives classic “water bottle” sign Echocardiogram ▪ Pericardial effusion makes heart looks like it’s dancing within pericardium, “swinging heart”

LAB RESULTS

▪ Elevated markers of inflammation: C-reactive protein (CRP)

OTHER INTERVENTIONS ECG ▪ Low QRS complex voltage, electrical alternans, sinus tachycardia

▪ Cardiac tamponade ▪ Constrictive pericarditis

SIGNS & SYMPTOMS ▪ Clinical presentation nonspecific, related to underlying cause, reflecting impaired cardiac function ▪ Diminished heart sounds ▪ Jugular vein distention ▪ Tachycardia, dyspnea, decreased blood pressure, lightheadedness

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TREATMENT MEDICATIONS

▪ Relieve pain, treat underlying cause of inflammation

SURGERY

▪ Pericardiocentesis

NOTES

NOTES

PERIPHERAL ARTERY DISEASE

GENERALLY, WHAT IS IT? PATHOLOGY & CAUSES ▪ Narrowing of the arteries in peripheral, non-coronary arterial circulation ▪ Vessels of the lower extremities are most commonly affected ▪ ↓ blood flow → arterial insufficiency → tissue ischemia ▫ ↓ gas and nutrient exchange → tissue loss, ulcer formation → poor healing ▫ Embolus formation → acute limb ischemia → tissue loss ▫ Ischemic cells release adenosine → adenosine signals nerves → sensation of pain ▫ Claudication: pain caused by poor circulation; occurs when oxygen demand is greater than oxygen supply ▪ Location of pain is dependent upon artery implicated ▫ Lower aorta or iliac artery = pain in hips and buttocks ▫ Iliac or common femoral artery = pain in thigh ▫ Superficial femoral artery = pain in upper ⅔ of calf ▫ Popliteal artery = pain in lower ⅓ of calf ▫ Tibial or peroneal artery = pain in foot

TYPES Occlusive (most common) ▪ Usually caused by blockage due to atherosclerosis ▪ Buildup of plaque → narrowed artery → ↓ blood flow Functional ▪ Caused by a defect in the normal mechanisms that dilate and constrict arteries (e.g. inherited defects, injuries,

certain drugs) ▪ Intermittent arterial constriction → ↓ diameter → ↓ blood flow

RISK FACTORS ▪ ▪ ▪ ▪ ▪ ▪ ▪ ▪

Smoking High blood pressure Diabetes Hyperlipidemia Metabolic syndrome Age > 60 Obesity ↑ risk in black people of African descent

COMPLICATIONS

▪ ↑ risk of developing coronary artery cerebrovascular disease ▪ Tissue necrosis ▪ Amputation ▪ Pain

SIGNS & SYMPTOMS ▪ Often asymptomatic until significant occlusion develops ▪ Intermittent claudication ▫ Muscle pain due to ↑ oxygen demand and ↓ supply ▪ Rest pain ▫ Pain or burning sensation in forefoot and toes when legs elevated, pain relieved when legs are lowered (gravity assisting blood flow) ▪ ↓ lower peripheral pulses (e.g. pedal, tibial) ▪ Leg/foot ulcers that do not heal normally ▫ Have classic punched out appearance ▫ Often form on toe joints, malleoli, shin, base of heel, pressure points

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▪

▪ ▪ ▪

▫ Painful ▫ Slow healing → ↑ risk of infection Cutaneous color changes ▫ Elevation pallor: foot turns pale when raised due to circulation having to work against gravity as well as narrowed artery ▫ Dependent rubor: foot turns red when lowered as gravity works increases perfusion Skin: cool, dry, shiny, hairless Nails: brittle, hypertrophic, ridged Signs of acute limb ischemia ▫ See mnemonic

MNEMONIC: 5Ps

Signs of acute limb ischemia Pain Pallor Pulselessness Paresthesia Paralysis (a surgical emergency)

DIAGNOSIS DIAGNOSTIC IMAGING Doppler ultrasound ▪ ↓ blood flow

OTHER DIAGNOSTICS Auscultation ▪ Bruit (whooshing sound) heard on auscultation of suspected artery ▫ Usually pulse of leg’s iliac artery ▫ Whooshing sound due arterial narrowing Ankle-brachial index (ABI) ▪ ABI < 0.9: peripheral artery disease ▪ ABI of 0.4–0.9: claudication ▪ ABI of 0.2–0.4: rest pain ▪ ABI of 0–0.4: tissue loss, ulcers, gangrene

TREATMENT MEDICATIONS

▪ Antiplatelet therapy

SURGERY

▪ Angioplasty, stent insertion ▪ Endarterectomy ▪ Bypass surgery to restore blood flow by diverting it around blockage ▪ Amputation

OTHER INTERVENTIONS Figure 15.1 An arterial ulcer on the dorsum of the foot; a consequence of peripheral vascular disease. Note the punched out appearance.

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▪ Modify risk factors; e.g. smoking cessation, healthy eating habits, exercising regularly, managing diabetes ▪ Wound care

Chapter 15 Peripheral Artery Disease

Figure 15.2 Illustration depicting the Ankle-branchial index.

ARTERIOLOSCLEROSIS osms.it/arteriolosclerosis PATHOLOGY & CAUSES ▪ Arteriosclerosis: a general term for diseases where the artery wall becomes thicker, harder, and less elastic ▫ Arteriolosclerosis: a disease of the small arteries and arterioles characterized by stiffening and thickening of the vessel wall due to high blood pressure or diabetes, manifested primarily in the kidneys

TYPES Hyaline arteriolosclerosis ▪ Accumulation of proteins and pink hyaline material → ↑ thickness and stiffening of vessel wall → ↓ compliance → ↓ blood flow → tissue hypoxia ▫ Sustained high-pressure in vessels → serum proteins pushed into blood vessel walls → protein build-up in tunica media ▫ Chronic high blood glucose → endothelial cells become glycosylated → endothelial dysfunction → basement

membrane becomes “leaky” → serum proteins move into endothelial cells and build up into tunica media Hyperplastic arteriolosclerosis ▪ Smooth muscle cell hyperplasia → very small lumen → ↓ blood flow → tissue hypoxia ▫ Malignant hypertension → smooth muscle cells lining arteriole exposed to plasma proteins → concentric layers of smooth muscle cell proliferation (“onionskinning”)

RISK FACTORS

▪ Diabetes mellitus ▪ Chronic hypertension ▪ Malignant hypertension

COMPLICATIONS

▪ Arteriolonephrosclerosis ▪ Formation of intraluminal thrombi ▪ Chronic renal failure

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SIGNS & SYMPTOMS ▪ Clinical manifestations of chronic kidney disease ▫ Anemia (fatigue, activity intolerance, pallor) ▫ Fluid and electrolyte imbalance (edema, muscle weakness, palpitations) ▫ Uremia (anorexia, mental status changes) ▫ Renal osteodystrophy

DIAGNOSIS LAB RESULTS ▪ ▪ ▪ ▪ ▪ ▪ ▪

Signs of arteriolonephrosclerosis ↑ blood urea nitrogen ↑ creatinine ↓ hemoglobin ↓ hematocrit Proteinuria Oliguria

TREATMENT OTHER INTERVENTIONS

▪ Management of diabetes and hypertension; support renal function

ATHEROSCLEROSIS osms.it/atherosclerosis PATHOLOGY & CAUSES ▪ Arteriosclerosis: a general term for diseases where the artery wall becomes thicker, harder, and less elastic ▫ Atherosclerosis: atheromatous plaques on the tunica intima of large and medium vessels ▪ Damage to endothelium → low-density lipoproteins enter endothelial wall → LDL oxidation → uptake of LDL by macrophages → foam cell formation → cytokine and growth factor release from foam cells → formation of thrombogenic fatty streak → platelets release platelet-derived growth factor → migration of smooth muscle cells from vascular media to intima → fibrous cap → atherosclerotic plaque → chronic inflammation ▪ Calcium deposits into plaque → stiffening of arteries

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RISK FACTORS ▪ ▪ ▪ ▪ ▪ ▪

Family history of coronary heart disease Smoking Hypertension Dyslipidemia; especially low HDL Metabolic syndrome Males ≥ 45; females 55 ≥ or premature menopause without hormone replacement therapy

COMPLICATONS

▪ Cardiovascular and coronary heart disease ▫ Myocardial infarction, heart failure, death ▪ Cerebrovascular disease ▫ Transient ischemic attack, stroke ▪ Peripheral artery disease ▫ Leg ulcers, amputation ▪ Aortic aneurysm

Chapter 15 Peripheral Artery Disease

SIGNS & SYMPTOMS ▪ Symptoms vary according to extent and location of blockage ▪ Carotid artery ▫ Weakness, difficulty speaking, dizziness, difficulty walking, blurred vision, numbness of face/arms/legs, severe headaches ▪ Peripheral arteries ▫ Claudication, presence of ulcers ▪ Coronary arteries ▫ Angina ▪ Cerebral arteries ▫ Auscultation of bruit, neurological complaints (e.g. visual changes, facial paresis)

DIAGNOSIS ▪ History and presence of clinical manifestations indicating occlusive disease

DIAGNOSTIC IMAGING Angiography ▪ Vascular calcifications, stenosis, occlusion, collateral circulation Ultrasound ▪ Luminal stenosis, atheromatous calcification (hyperechoic foci producing an acoustic shadow) Magnetic resonance angiography ▪ Thickened arterial wall, heterogeneous signal within vessel wall (lipid rich necrotic core, plaque, fibrous cap)

LAB RESULTS

▪ hs-CRP (high-sensitivity C-reactive protein) test ▫ ↑ CRP indicates “silent atherosclerosis” before cardiovascular event ▪ Fasting lipid profile

Figure 15.3 The abdominal aorta at post mortem showing moderate atherosclerosis.

TREATMENT ▪ Goal: reduce risk of complications with management risk factors; e.g. lipids, blood glucose, hypertension

MEDICATIONS

▪ Antiplatelets ▪ Antilipemic agents ▪ Antihypertensives

SURGERY

▪ Complications: stents, bypass grafts, angioplasty, carotid endarterectomy (CEA)

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Figure 15.4 An atherosclerotic artery. Note how the plaque protrudes into the lumen. It is composed primarily of cholesterol with an outer rim of foamy macrophages.

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NOTES

NOTES

PRE–EXCITATION DISORDERS GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Heart rhythm disturbances due to accessory pathway in conduction system that allows depolarization to bypass atrioventricular node and spread from atria to ventricles ▪ Accessory pathways can promote arrhythmias by two mechanisms ▫ Acting as one limb of a reentrant circuit, with atrioventricular node acting as the other ▫ Bypassing physiologic atrioventricular nodal delay → impulses reaching ventricle not regulated → very rapid ventricular responses in atrial arrhythmia setting such as atrial fibrillation, atrial flutter ▪ If ventricular rate becomes too high → ventricles don’t have time to fill → low cardiac output → shock

SIGNS & SYMPTOMS ▪ Tachyarrhythmias → palpitations, chest discomfort, breath shortness, lightheadedness, syncope

DIAGNOSIS ▪ See individual disorders

TREATMENT ▪ Acute termination of preexicitationassociated arrhythmias ▪ Chronic prevention of preexicitationassociated arrhythmias

MEDICATIONS ▪ Acute termination ▫ Adenosine: short acting; causes transient heart block (↓ rate of diastolic depolarization, ↓ HR) ▫ Diltiazem (Class IV): calcium channel blocker (↓ AV node conduction → ↓ HR) ▪ Chronic prevention ▫ Amiodarone (Class III): slows conduction rate (↑ AP duration, ↑ QT interval) ▫ Procainamide (Class 1A): slows conduction velocity (↑ AP duration, ↑ ventricular refractory period, ↑ QT interval)

OTHER INTERVENTIONS ▪ Acute termination ▫ Vagal maneuver (carotid sinus massage/ Valsalva maneuver) → activates vagus nerve ▫ Electrical cardioversion (if pharmacological treatment ineffective/ fast heart rate is poorly tolerated) ▪ Chronic prevention ▫ Radiofrequency catheter ablation (definitive treatment)

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AV REENTRANT TACHYCARDIA (AVRT) osms.it/av-reentrant-tachycardia PATHOLOGY & CAUSES ▪ Arrhythmia due to accessory pathway between atria and ventricles that allows electrical signal to move backwards Orthodromic atrioventricular reentrant tachycardia (AVRT) ▪ Signal moves downward through atrioventricular node → ventricles contract → upward through accessory pathway → atria contract → moves back down atrioventricular node → etc. Antidromic atrioventricular reentrant tachycardia (AVRT) ▪ Signal moves downward through accessory pathway → ventricles contract → upwards through atrioventricular node → atria contract → moves back down the accessory pathway → etc.

SIGNS & SYMPTOMS ▪ Tachyarrhythmias → palpitations, chest discomfort, breath shortness, lightheadedness, syncope

DIAGNOSIS OTHER DIAGNOSTICS ECG ▪ Orthodromic AVRT ▫ Regular, narrow-complex tachycardia, P waves are typically retrograde in morphology and come after QRS complex ▪ Delta wave is not seen ▪ Antidromic AVRT ▫ Regular, wide-complex tachycardia, P waves often not visible

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TREATMENT MEDICATIONS ▪ Acute termination ▫ Adenosine, Diltiazem (Class III) ▪ Chronic prevention ▫ Amiodarone (Class III), Procainamide (Class 1A)

OTHER INTERVENTIONS ▪ Acute termination ▫ Vagal maneuver ▫ Electrical cardioversion (if pharmacological treatment ineffective/ fast heart rate is poorly tolerated) ▪ Chronic prevention ▫ Radiofrequency catheter ablation

Chapter 16 Pre-excitation Disorders

Figure 16.1 An electrocardiogram demonstrating othodromic AVRT. Note the narrow QRS complexes and absence of a discernible P wave.

Figure 16.2 An ECG demonstrating orthodromic AVRT with regular, narrow-complex tachycardia with retrograde P waves visible just after the QRS complexes, most visible in leads II and V4-V6.

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Figure 16.3 An ECG demonstrating antidromic AVRT. There is a regular, wide complex tachycardia that is usually indistinguishable from VT.

WOLFF–PARKINSON–WHITE SYNDROME osms.it/wolff-parkinson-white-syndrome PATHOLOGY & CAUSES ▪ Congenital accessory pathway conducts electrical signals between atria and ventricles → preexcitation, predisposes individuals to clinically significant arrhythmias up to sudden cardiac death ▫ Though “bundle of Kent” is a common eponym for congenital accessory pathway, several different pathways can occur, most commonly direct atrioventricular connections, but also atriofascicular, nodofascicular, atrioHisian, etc. ▫ Wolff–Parkinson–White pattern: benign asymptomatic form, solely described by compatible electrocardiographic changes

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▪ Most common type of ventricular preexcitation syndrome ▫ 0.1% of individuals have Wolff– Parkinson–White pattern, a small proportion of them develops syndrome

SIGNS & SYMPTOMS ▪ Tachyarrhythmias → palpitations, chest discomfort, breath shortness, lightheadedness, syncope

Chapter 16 Pre-excitation Disorders

DIAGNOSIS OTHER DIAGNOSTICS ECG ▪ Short PR interval (< 120ms) ▪ Delta wave ▫ Slurred upstroke of QRS ▪ Widening of the QRS complex (> 110ms) ▪ Secondary ST segment, T wave changes

TREATMENT MEDICATIONS ▪ Acute termination ▫ Adenosine, Diltiazem (Class III) ▪ Chronic prevention ▫ Amiodarone (Class III), Procainamide (Class 1A)

OTHER INTERVENTIONS ▪ Acute termination ▫ Vagal maneuver ▫ Electrical cardioversion (if pharmacological treatment ineffective/ fast heart rate is poorly tolerated) ▪ Chronic prevention ▫ Radiofrequency catheter ablation

Figure 16.4 ECG pattern in Wolff–Parkinson–White syndrome.

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Figure 16.5 An ECG of an individual with Wolff–Parkinson–White syndrome (sinus rhythm). Delta waves are most visible in the V leads.

Figure 16.6 An ECG demonstrating “pre-excited a-fib” or atrial fibrillation in a person with Wolff–Parkinson–White. It’s an irregularly irregular wide-complex rhythm with no discernible P waves.

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NOTES

NOTES

PREMATURE CONTRACTION GENERALLY, WHAT IS IT? PATHOLOGY & CAUSES ▪ Depolarizing potential from anywhere in heart other than sinoatrial (SA) node → contraction earlier than normal in cardiac cycle ▪ Triggered activity ▫ Cells triggered by preceding action potential after repolarization ▫ Cause: reperfusion therapy after myocardial infarction/digoxin toxicity ▪ Ectopic focus ▫ Cells irritated by electrolyte imbalances, drugs, ischemic damage → increased sympathetic activity → enhanced automaticity → early depolarization ▪ Reentrant loop ▫ Tissue unable to depolarize (e.g. scar tissue, amyloid) → no signal conduction → depolarizing wave obstructed → depolarizing wave circles tissue → abnormal electrical circuit

CAUSES

▪ Often idiopathic ▪ Electrolyte imbalances (hypokalemia, hypercalcemia, hypomagnesemia) ▪ Recreational/prescription drugs (methamphetamines, cocaine, digoxin intoxication)

▪ Alcohol use ▪ Heart dilation: cardiomyopathies, cor pulmonale ▪ Heart scarring: after myocardial infarction, myocarditis

COMPLICATIONS

▪ Rarely atrial/ventricular fibrillation

SIGNS & SYMPTOMS ▪ Usually asymptomatic ▪ In case of frequent premature contractions: lightheadedness, palpitations

DIAGNOSIS OTHER DIAGNOSTICS ▪ ECG ▪ Holter monitor ▪ ZIO patch

TREATMENT ▪ See individual disorders

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PREMATURE ATRIAL CONTRACTION (PAC) osms.it/premature-atrial-contraction PATHOLOGY & CAUSES ▪ Contraction of atria earlier than normal in cardiac cycle ▪ Atrial bigeminy: premature atrial contraction consistently occurs after each normal cardiac cycle ▪ Atrial trigeminy: premature atrial contraction consistently occurs after every two normal cardiac cycles

CAUSES

▪ Heart structural disorders, intoxication, electrolyte imbalances

COMPLICATIONS ▪ Atrial fibrillation

SIGNS & SYMPTOMS ▪ Usually asymptomatic ▪ In case of frequent premature contractions: lightheadedness, palpitations

DIAGNOSIS OTHER DIAGNOSTICS ECG ▪ Early, abnormal P wave ▫ Ectopic focus in bottom of atria → negative P wave ▫ Ectopic focus closer to atrioventricular (AV) node → PR interval shorter ▫ P wave, T wave overlap

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▪ Noncompensatory pause ▫ Premature impulse enters sinoatrial (SA) node → shortens cycle ▫ Distinct from compensatory pause: premature ventricular contraction → premature impulse does not reach SA node → if AV node still refractory, pauses → lengthens cycle ▪ Normal QRS ▫ Premature impulse reaches AV node in refractory → blocked premature atrial contraction → QRS nonexistent ▪ Ashman phenomenon ▫ R-R interval prolongs → increases refractory period of right bundle branch → abnormal conduction of subsequent impulse → right bundle branch block on ECG ▪ Holter monitor ▫ 24h, detect premature contractions

TREATMENT ▪ Typically requires no treatment

MEDICATIONS

▪ If symptomatic: beta blockers/calcium channel blockers ▪ Electrolyte replacement

SURGERY

▪ If triggering atrial fibrillation: radiofrequency catheter ablation

Chapter 17 Premature Contraction

Figure 17.1 Illustration depecting abnormal P wave in atrial bigeminy and trigeminy.

Figure 17.2 Illustration comparing normal ECG tracing vs ECG tracing with premature atrial contraction.

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PREMATURE VENTRICULAR CONTRACTION (PVC) osms.it/premature-ventricular-contraction PATHOLOGY & CAUSES ▪ Contraction of ventricles earlier than normal in cardiac cycle ▪ Ectopic focus ▫ Latent pacemakers: AV node, bundle of His/Purkinje fibers take over SA node’s function of pacemaker ▫ Irritated cardiac muscle cells → early depolarization ▪ Triggered activity ▫ Ventricular repolarization → ventricle cells triggered by preceding action potential ▫ Cause: reperfusion therapy after myocardial infarction/digoxin toxicity ▪ Reentrant loop ▫ Tissue unable to depolarize (e.g. scar tissue, amyloid) → no signal conduction → depolarizing wave obstructed → depolarizing wave circles tissue → abnormal electrical circuit ▪ Ventricular bigeminy: premature ventricular contraction consistently comes after each normal cardiac cycle ▪ Ventricular trigeminy: premature ventricular contraction consistently comes after every two normal cardiac cycles

CAUSES

▪ Heart structural disorders, intoxication, electrolyte imbalances

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RISK FACTORS

▪ Hypertension, smoking, exercise, stress, people of African descent (+30% risk), biological male

COMPLICATIONS

▪ Ventricular tachycardia, ventricular fibrillation, increased risk for sudden cardiac death

SIGNS & SYMPTOMS ▪ Can be asymptomatic ▪ Lightheadedness, palpitations

DIAGNOSIS OTHER DIAGNOSTICS ECG ▪ Wide, bizarre QRS: signal goes through ventricular muscle, not normal conduction pathway → conduction is slower than normal ▪ Ectopic impulse in right ventricle ▫ Left bundle branch block pattern of QRS complex ▫ V1: large negative complex, dominating S wave ▪ Ectopic impulse in left ventricle ▫ Right bundle branch block pattern of QRS complex ▫ V1: large positive complex, dominating R wave

Chapter 17 Premature Contraction ▪ Abnormal ST segments: deviation from isoelectric baseline in opposite direction from QRS complex ▪ Inverted T waves in leads, QRS complex predominantly positive ▪ Nonexistent P wave: covered by wide QRS complex ▫ QRS followed by compensatory pause ▪ Ventricular fusion beat: premature QRS complex occurs during PR segment, combines with normal depolarization wave ▪ R-on-T phenomenon: premature QRS complex occurs at/near T wave apex ▪ Holter monitor

TREATMENT ▪ Typically requires no treatment

MEDICATIONS

▪ If symptomatic: venodilators, calcium channel blockers, administer beta blockers with caution

SURGERY

▪ If triggering ventricular arrhythmias: radiofrequency catheter ablation to destroy ectopic focus/replacement if necessary

OTHER INTERVENTIONS

▪ If mild, no exercise restrictions; if severe, reduced physical activity

Figure 17.3 Illustration comparing premature ventricular contractions that occur during a P wave, during a PR segment, and during a T wave.

Figure 17.4 Illustration comparing ventricular bigeminy and trigeminy.

OSMOSIS.ORG 121

NOTES

NOTES SHOCK

SHOCK osms.it/shock PATHOLOGY & CAUSES ▪ Global inadequate tissue perfusion ▫ Extremely low blood pressure (BP) → end-organ failure

TYPES

▪ Hypovolemic shock, cardiogenic shock, obstructive shock, distributive shock

Hypovolemic Shock ▪ General clinical manifestations ▫ Reduced preload with suspected cause ▪ Variable presentation based on etiology of fluid loss ▪ Hemorrhage, evidence of trauma ▫ Internal bleeding into thoracic/peritoneal/ retroperitoneal space ▪ Nonhemorrhagic fluid loss ▫ Decreased tissue perfusion ▫ Elevated blood urea nitrogen, serum

creatinine concentration (non-specific, i.e. seen in all forms of shock) ▫ Abnormal potassium levels ▫ Metabolic acidosis/alkalosis ▫ Hematocrit, serum albumin concentration → reduction in plasma volume increases concentration Cardiogenic Shock ▪ General clinical manifestations ▫ Hypotension, manifestations of pulmonary edema ▪ Subtypes of cardiogenic shock ▫ Myopathic: find specific cause via ECG/ lab values/chest radiograph ▫ Arrhythmogenic: caused by arrythmia Obstructive Shock ▪ General clinical manifestations ▫ Low preload; obstruction of blood flow outside the heart ▫ Cardiac tamponade, pulmonary embolism, tension pneumothorax

Figure 18.1 Illustration summarizing the causes and effects of hypovolemic, cardiogenic, and distributive shock.

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Chapter 18 Shock Distributive Shock ▪ General clinical manifestations ▫ Hypotension without reduced preload, fluid overload ▪ Subtypes of distributive shock ▫ Septic: caused by infection ▫ Anaphylactic: allergic reaction → respiratory distress, vomiting, abdominal pain, chest pain, dysrhythmia, collapse ▫ Neurogenic: pain at site of spinal fracture, evidence of spinal injury (loss of sensation, paralysis, loss of reflexes) ▫ Endocrine: adrenal crisis (nonspecific symptoms, eg. anorexia, nausea, vomiting, abdominal pain, fatigue, lethargy, weakness, fever, confusion, coma); confirmation of adrenal insufficiency

RISK FACTORS

▪ Dependent upon type ▪ Septic shock most common in United States, followed by cardiogenic, hypovolemic, other forms of distributive/ obstructive shock ▪ Hypovolemic shock from gastrointestinal (GI) losses/dehydration most common in low-income countries

STAGING Initial ▪ Cellular, not clinically apparent Compensatory ▪ Neural, hormonal, biochemical compensation to maintain homeostasis; inadequate perfusion → autonomic nervous system attempts to compensate ▫ Sympathetic nervous system

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vasoconstriction, ↑ contractility ▫ Release of catecholamines, vasopressin, angiotensin II → ↑ vasoconstriction, ↑ retention water, sodium → ↑ SVR, ↑ blood volume → ↑ BP → ↑ perfusion Progressive ▪ Compensation fails, requires aggressive interventions to prevent multiple organ dysfunction syndrome Irreversible ▪ Decreased perfusion (vasoconstriction, decreased cardiac output) → anaerobic metabolism; profound hypotension, hypoxemia, organ failure; recovery unlikely

SIGNS & SYMPTOMS ▪ Altered mental state, decreased peripheral pulse, tachycardia, hypotension ▪ Varies by type and subtype of shock (see table below)

DIAGNOSIS DIAGNOSTIC IMAGING Chest radiography ▪ Clear in hypovolemic/obstructive shock from pulmonary embolism ▪ Pneumonia ▫ Septic shock ▪ Pneumothorax ▫ Obstructive shock ▪ Pulmonary edema ▫ Cardiogenic shock/ARDS Pulmonary artery catheterization ▪ Hemodynamic measurements can be helpful ▪ Measure cardiac output, systemic vascular resistance, pulmonary artery occlusion pressure, right atrial pressure, mixed venous oxyhemoglobin saturation ▪ Rarely necessary to identify etiology of shock Ultrasound/echocardiography ▪ Allows visualization of altered cardiac function

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▪ Preserved/hyperdynamic left ventricle = distributive shock ▪ Point-of-care ultrasond ▫ Examination of heart → cause of cardiogenic shock, obstructive shock Focused assessment and sonography for trauma (FAST) ▪ Fast ultrasound examination for hemopericardium, intra-abdominal bleeding; rule out/in hypovolemic shock Hemodynamic monitoring ▪ Via central venous catheters ▪ Elevated central venous pressure, low mixed venous oxygen saturation = cardiogenic shock

LAB RESULTS Elevated serum lactate ▪ Early indicator, reflective of poor tissue perfusion Renal, liver function tests ▪ Elevated blood urea nitrogen (BUN), creatinine, transaminases indicate endorgan damage ▫ May help point to cause (acute hepatitis, chronic cirrhosis) Coagulation studies, D-dimer level ▪ Elevated fibrin split products, elevated D-dimer level, low fibrinogen level = severe shock Cardiac enzymes, natriuretic peptides ▪ Elevated troponin, creatine phosphokinase, N-terminal pro-brain natriuretic peptide, brain natriuretic peptide = cardiogenic shock due to ischemia/pulmonary embolism Complete blood count, differential ▪ High hematocrit ▫ Hemoconcentration from nonhemorrhagic hypovolemic shock ▪ Anemia, bleeding ▫ Hemorrhagic shock ▪ Elevated eosinophil ▫ Allergy, anaphylactic shock ▪ Leukocytosis ▫ Septic shock, not specific; more common

Chapter 18 Shock in septic shock, may also occur in other types of shock as sign of poor prognosis Coagulation studies, D-dimer level ▪ Elevated prothrombin time, international normalized ratio, activated partial thromboplastin time ▫ Septic shock, other issues (e.g. sepsis, systemic inflammatory response syndrome); elevated D-dimer levels common in septic shock Peripheral O2 sat via pulse oximetry ▪ Hypoxemia ▫ Obstructive, cardiogenic shock Urinalysis ▪ Infection, septic shock Material gram stain from infection sites ▪ Septic shock Blood culture ▪ identifies causative microbe in case of septic shock; directs targeted antibiotic therapy

OTHER DIAGNOSTICS History & physical ▪ Low blood pressure, tachycardia, tachypnea, signs of poor end-organ perfusion (low urine output, confusion, loss of consciousness), weak pulse, cool skin, metabolic acidosis, hyperlactatemia Shock index ▪ Heart rate divided by systolic pressure ▫ Normal range 0.5–0.8 ▫ If index higher, increased suspicion of underlying state of shock ▫ Most useful for isolated hypotension/ tachycardia ECG ▪ Arrhythmia, ST segment changes consistent with ischemia ▪ Low-voltage ECG ▫ Pericardial effusion ▪ Arrhythmia ▫ Arrhythmogenic cardiogenic shock ▪ Ischemia ▫ Myopathic cardiogenic shock

OSMOSIS.ORG 125

MNEMONIC: ABCDE

Treatment for shock Airway: ensure clear airway, possibly intubate Breathing: assist individual in breathing, mechanical ventilation/sedation Circulation: administer fluids (e.g. isotonic crystalloid) Delivery of oxygen: monitor lactate levels Endpoint resuscitation (specific to septic shock)

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TREATMENT ▪ See chart for a detailed summary of treatments for different forms of shock

OTHER INTERVENTIONS Surviving sepsis campaign guidelines ▪ End resuscitation when urine output 0.5ml/ kg/hr, central venous pressure (CVP) 8–12 mmHg, mean arterial pressure (MAP) 65–90mmHg, central venous oxygen concentration > 70%, normalize lactate levels ▫ CVP 8–12mmHg (recent literature shows CVP poorly predicts fluid responsiveness, poor marker of adequate resuscitation)

NOTES

NOTES

SUDDEN CARDIAC DEATH GENERALLY, WHAT IS IT? PATHOLOGY & CAUSES ▪ Abrupt cessation of cardiac activity (cardiac arrest) in someone asymptomatic up until moment of arrest

SIGNS & SYMPTOMS ▪ Asymptomatic

DIAGNOSIS

TREATMENT MEDICATIONS

▪ According to Advanced Cardiac Life Support protocols

OTHER INTERVENTIONS Cardiopulmonary resuscitation (CPR) ▪ Maintains blood flow by mimicking pumping motion heart makes during a medical emergency

▪ Made based on lack of pulse

BRUGADA SYNDROME osms.it/brugada-syndrome PATHOLOGY & CAUSES ▪ Condition with characteristic abnormal electrocardiogram findings → increases risk of sudden cardiac death in healthy individuals ▪ Mixture of normal, abnormal sodium channels within adjacent myocardial tissue can set up heterogenous refractory periods necessary for development of reentrant rhythms → ventricular tachycardia/ fibrillation

▪ 20% associated with SCN5A gene mutation which encodes for sodium ion channel in cell membranes of heart muscle cells

RISK FACTORS

▪ Biological males, more common in Asia than North America, Europe

COMPLICATIONS

▪ Ventricular fibrillation, high risk of sudden cardiac death

CAUSES

▪ Inherited ▫ Autosomal dominant, variable expression

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SIGNS & SYMPTOMS ▪ Brugada pattern ▫ ECG findings, no symptoms ▪ Brugada syndrome ▫ ECG findings, symptoms of sustained ventricular tachycardia (palpitations, syncope, dyspnea, lightheadedness)

DIAGNOSIS

▪ Type I ▫ Right bundle branch block pattern ▫ Gradually descending ST elevations, at least 2mm (0.2mV) in leads V1–V3 ▫ Negative T- wave in leads V1–V3 ▪ Type II ▫ Class IV antiarrhythmic can convert to a Type I Brugada pattern—often needed for diagnosis ▫ Saddle-back pattern with at least 2mm J point elevation, 1mm ST elevation (positive/biphasic T wave)

LAB RESULTS Genetic testing ▪ Confirms diagnosis

OTHER DIAGNOSTICS ECG ▪ Type I/II Brugada electrocardiogram pattern ▫ May present simultaneously, may be induced by certain drugs (e.g. calcium channel blockers), or may resurface due to unknown triggers

TREATMENT ▪ Brugada pattern: none

SURGERY Implanted cardiac defibrillator (ICD) ▪ Brugada syndrome

Figure 19.1 ECG (lead V1) demonstrating Brugada waveforms type I (left) and type II (right).

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Chapter 19 Sudden Cardiac Death

Figure 19.2 Calcium channel blockers can increase the chance of developing Brugada syndrome. The condition is typically associated with right bundle branch block, which makes the heart susceptible to developing a reentrant rhythm, which in turn causes ventricular tachycardia and sometimes ventricular fibrillation.

PULSELESS ELECTRICAL ACTIVITY osms.it/pulseless-electrical-activity PATHOLOGY & CAUSES ▪ Pulseless, despite electrical activity (evident on ECG) typically resulting in pulse ▪ Heart does not contract in spite of electrical activity/does not generate enough cardiac output to cause pulse ▪ Survival ~20%

CAUSES

▪ Abrupt drop in preload ▪ Abrupt pump failure

MNEMONIC: 6Ts & 6Hs

Obstruction to blood flow Tablets/toxins (drug overdose) Cardiac Tamponade Tension pneumothorax Thrombosis (myocardial infarction) Thrombosis (pulmonary embolism) Trauma (hypovolemia - blood loss) Hypovolemia Hypoxia Hydrogen ions (acidosis) Hyperkalemia/hypokalemia Hypoglycemia Hypothermia

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SIGNS & SYMPTOMS ▪ Loss of consciousness ▪ Breathing stops

DIAGNOSIS OTHER DIAGNOSTICS

TREATMENT MEDICATIONS

▪ If cause unclear medicine used similar to asystole ▫ Intravenous/intraosseous line, administer epinephrine 1mg/3–5 minutes

▪ Absence of pulse

ECG ▪ Organized/semi-organized electrical activity

VENTRICULAR FIBRILLATION osms.it/ventricular-fibrillation PATHOLOGY & CAUSES ▪ Ventricular electrical activity disorganized to point that coordinated contraction is impossible ▪ Rapid, irregular electrical activity prevents ventricles from contracting in sync → cardiac output falls to zero ▪ Often due to tissue heterogeneity: heart cells stressed/damaged, tissues of different areas structurally, electrically different ▪ Mechanism: tissue heterogeneity in cardiac electrical system → asynchronous depolarization & contraction → inadequate blood pumped → oxygen deprivation → death ▪ Functional reentry: arrhythmia causes different areas of heart to depolarize & contract out of sync → heart non-functional

CAUSES

▪ Medications causing long QT syndrome ▪ Illicit drugs (e.g. methamphetamine, cocaine) ▪ Congenital arrhythmogenic syndromes (e.g. Brugada, hypertrophic cardiomyopathy, arrhythmogenic right ventricular dysplasia, Wolff-Parkinson-White syndrome, congenital long QT syndrome)

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▪ Electrolyte imbalances: hypokalemia, hyperkalemia ▪ Ischemia to ventricular muscle ▪ Scar tissue from previous myocardial infarction ▪ Anatomical reentry ▪ Electrocution/external electrical stimulation, such as in unsynchronized cardioversion ▪ If heart tissue stimulated during T wave upslope (in an electrocardiogram), can induce fibrillation

SIGNS & SYMPTOMS ▪ Chest pains, dizziness, nausea, rapid pulse, dyspnea

DIAGNOSIS OTHER DIAGNOSTICS ▪ Pulse check: no pulse

ECG ▪ Absence of PQRST waves; instead, fine, coarse fibrillatory waves ▪ Electrocardiogram appears chaotic ▪ Undulating baseline

Chapter 19 Sudden Cardiac Death

TREATMENT SURGERY ICD ▪ Used when cause is unpreventable ▪ Surgically implanted ▪ Constantly monitors electrocardiogram ▪ ICD recognizes ventricular fibrillation, delivers responsive defibrillating shock ▪ Doesn’t fix underlying condition; treats symptom, improves survival ▪ Primary prevention ▫ Individuals with heart failure at risk of ventricular tachycardia/fibrillation ▪ Secondary prevention ▫ Cardiac arrest survivors for whom triggers cannot be treated/prevented

OTHER INTERVENTIONS Cardiopulmonary Resuscitation (CPR) Defibrillation ▪ High energy shock depolarizes large enough portion of tissue (critical mass) that sinus node can take control Electrophysiology study ▪ If individual has had previous MI/has survived cardiac arrest in whom signs are not apparent after routine, non-invasive testing ▫ Evaluate for possible ventricular tachycardia ablation Revascularization ▪ If ventricular fibrillation occurs in setting of myocardial infarction ▫ Cardiac catheterization ▫ CABG

Figure 19.3 Histological appearance of fatal ventricular fibrillation demonstrating broken myocardial fibers and squared-off nuclei.

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Figure 19.4 ECG demonstrating ventricular fibrillation.

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NOTES

NOTES

SUPRAVENTRICULAR TACHYCARDIA

GENERALLY, WHAT IS IT? PATHOLOGY & CAUSES ▪ Abnormally fast heart rhythms due to inappropriate electrical activity in upper portion of heart, atria/atrioventricular (AV) node ▪ Ventricles contract > 100 beats per minute, pathology originates above ventricles ▫ Ventricles protected by gating at AV node

CAUSES

▪ Reentry conductive loops ▪ Increased automaticity ▪ Triggered activity

RISK FACTORS

▪ Cardiac: coronary artery disease, heart failure ▪ Non-cardiac: chronic obstructive pulmonary disease (COPD), pulmonary embolism, alcohol abuse, hyperthyroidism

DIAGNOSIS LAB RESULTS

▪ Electrolytes, thyroid stimulating hormone levels

OTHER DIAGNOSTICS ▪ ECG

TREATMENT ▪ See individual disorders

MEDICATIONS

▪ Calcium channel blockers, beta blockers, anticoagulants

SURGERY

▪ Catheter ablation

SIGNS & SYMPTOMS ▪ Palpitations, chest pain, anxiety, dyspnea, syncope, lightheadedness

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ATRIAL FIBRILLATION osms.it/atrial-fibrillation PATHOLOGY & CAUSES ▪ Rapid, irregular (no discernible rhythm) heart rate ▪ Progression ▫ Paroxysmal: intermittent rhythm, may revert back to sinus rhythm spontaneously ▫ Persistent: > seven days, requires intervention to convert back to sinus rhythm ▫ Permanent: long-standing atrial fibrillation, cardioversion unsuccessful

CAUSES

▪ Disorganized waves of atrial depolarization, exact mechanisms not well understood ▫ Regular impulses of sinus node overwhelmed by rapid electrical discharges from various sources (automatic foci, multiple reentry phenomena) ▫ Arise from left more than right atrium

RISK FACTORS

▪ Old age: affects 4% 60–70, 14% > 80 ▪ Obesity, diabetes mellitus, excessive alcohol consumption, genetic predisposition ▪ Cardiovascular disease: heart failure, hypertension, coronary artery disease, non-rheumatic mitral regurgitation, mitral valve prolapse, rheumatic heart disease, damaged atrial myocytes ▪ Increased catecholamine levels ▪ Lung disease ▪ Hyperthyroidism

COMPLICATIONS

▪ Thromboembolic events, heart failure, hypotensive shock

134 OSMOSIS.ORG

SIGNS & SYMPTOMS ▪ May be asymptomatic ▪ Dyspnea, fatigue, palpitations, lightheadedness, weakness, chest pain, hemodynamic shock

DIAGNOSIS LAB RESULTS

▪ Thyroid stimulating hormone (TSH) levels: exclude hyperthyroidism

DIAGNOSTIC IMAGING Transthoracic echocardiogram ▪ Evaluate atrial, ventricular size; valvular disease; left ventricular function; pericardial disease Transesophageal echocardiogram ▪ Evaluate for atrial thrombi

OTHER DIAGNOSTICS ECG ▪ Absent P waves ▪ Irregularly timed QRS complexes (irregular R-R intervals) ▪ No sawtooth wave in atrial fibrillation

Chapter 20 Supraventricular Tachycardia

TREATMENT MEDICATIONS Anticoagulation ▪ E.g. warfarin, dabigatran, apixaban, rivaroxaban ▪ CHA2DS2-VASc/CHADS2 score ▫ Estimate risk of stroke in non-rheumatic atrial fibrillation; higher score = greater risk of stroke ▫ Score 0 (biological male)/1 (biological female): low risk, no anticoagulation recommended ▫ Score 1 (biological male): moderate risk, consider anticoagulation ▫ Score ≥ 2: high risk, anticoagulation recommended ▫ See table of scores

OTHER INTERVENTIONS Rhythm control ▪ Restore sinus rhythm via cardioversion Electrical cardioversion ▪ Defibrillator for synchronization Catheter ablation ▪ Destruction of heart regions responsible for abnormal impulses

Rate control ▪ < 100 beats per minute ▪ Beta blockers (preferably β1 selective) ▪ Non-dihydropyridine calcium channel blockers (e.g. diltiazem, verapamil) ▪ Digoxin Chemical cardioversion ▪ Administer antiarrhythmic medication ▪ Class Ic antiarrhythmics ▪ Class III antiarrhythmics ▪ Maintenance of sinus rhythm after cardioversion ▫ Class Ic antiarrhythmics ▫ Class III antiarrhythmics

OSMOSIS.ORG 135

Figure 20.1 An ECG demonstrating atrial fibrillation.

ATRIAL FLUTTER osms.it/atrial-flutter PATHOLOGY & CAUSES ▪ Atria depolarize regularly at very high rates (200–350bpm), appear to flutter

TYPES Typical atrial flutter (AKA Type 1 flutter) ▪ More common ▪ Single reentrant circuit, right atrium ▪ Isthmus-dependent: reentry circuit crosses cavotricuspid isthmus ▪ Circles tricuspid annulus (ring), usually counterclockwise (viewed from below) ▪ Cavotricuspid isthmus tissue propagates signal slower than surrounding tissue → circuit loops → slows propagation → surrounding tissue exits refractory period Atypical atrial flutter (AKA Type 2 flutter) ▪ Less common

136 OSMOSIS.ORG

▪ Isthmus-independent ▪ Reentrant circuit develops in either atrium ▪ Associated with variety of reentry loops (common after incomplete atrial ablation procedures, right atrial surgical scars)

CAUSES

▪ Reentrant electrical signal from either atrium ▪ Reentrant signal loops back on itself → overrides normal sinus rhythm → establishes endless loop of stimulation ▪ Underlying disease (e.g. heart failure, valvular disease, hypertension, pulmonary disease) → heart cells less electrically stable → alters refractory periods → increased risk of reentrant circuits ▪ Reentrant circuits initiated by premature atrial contraction (PAC) → partial premature contraction, normal tissue relaxes → wave of stimulation propagates → normal tissue

Chapter 20 Supraventricular Tachycardia contracts, premature tissue recovers → chance of reentrant circuit, stimulation wave doubles back on itself

RISK FACTORS

▪ Diseases that change atrial heart cell properties → differing electrophysiological properties in adjacent areas → reentry circuit ▪ Ischemia, fibrosis, previous myocardial infarction, heart failure, high blood pressure, diabetes, valvular heart disease, obstructive sleep apnea

COMPLICATIONS

▪ Heart failure, thromboembolic events, atrial fibrillation

SIGNS & SYMPTOMS ▪ Palpitations, tachycardia, fatigue ▪ Pain/tightness/discomfort in chest ▪ Heart failure ▫ Exercise intolerance ▫ Difficulty breathing at night/while lying flat ▫ Edema of legs, abdomen

DIAGNOSIS DIAGNOSTIC IMAGING Echocardiogram ▪ Evaluate size of right, left atria, ventricles ▪ Detect pericardial/valvular heart disease ▪ Decreased ejection fraction (% of blood pumped by heart per contraction)

LAB RESULTS

▪ Serum electrolytes ▪ Renal function ▪ Thyroid stimulating hormone (TSH) levels: exclude hyperthyroidism

OTHER INTERVENTIONS ECG ▪ Typical P waves absent ▪ Typical atrial flutter: P waves, saw tooth shape (F waves) localised to leads II, III, aVF ▪ Atypical atrial flutter: atrial activity (sawtooth waves/otherwise) may occur anywhere, dependent on reentrant circuit location ▪ Ventricular rate usually 1/2 atrial flutter rate (even ratios 2:1, 4:1 more common than odd, 3:1, 5:1) ▪ 1:1 atrial: catecholamine excess, presence of accessory bypass tract/class 1A, 1C antiarrhythmic drug therapy

Figure 20.2 An electrocardiogram demonstrating atrial flutter with a 3:1 AV nodal block. The atrial trace demonstrates a characteristic sawtooth pattern.

OSMOSIS.ORG 137

Figure 20.3 An electrocardiogram demonstrating atrial flutter with a 3:1 AV nodal block. The atrial trace demonstrates a characteristic sawtooth pattern.

TREATMENT MEDICATIONS

▪ Anticoagulants (reduce chance of clot formation), beta blockers/calcium channel blockers (control rates of ventricles)

SURGERY Radiofrequency catheter ablation ▪ Cavotricuspid isthmus no longer able to carry electrical signal, prevents reentry

OTHER INTERVENTIONS Electrical cardioversion ▪ Depolarize atrial tissue, resynchronize contraction

138 OSMOSIS.ORG

Chapter 20 Supraventricular Tachycardia

ATRIOVENTRICULAR NODAL REENTRANT TACHYCARDIA (AVNRT) osms.it/av-nodal-reentrant-tachycardia PATHOLOGY & CAUSES ▪ Heart rate disturbance due to accessory pathway in/near AV node ▪ Electric conduction splits into two pathways → forms loop ▫ Alpha pathway: slow conduction, short refractory period ▫ Beta pathway: fast conduction, long refractory period

RISK FACTORS

▪ Biologically-female individuals → 75% of cases, emotional stress → alcohol use disorder, hyperthyroidism, electrolyte disturbances

SIGNS & SYMPTOMS ▪ Palpitations, transient chest pain, bouts of transient tachycardia, transient hypotension, (pre)syncope

TYPES Slow-fast/“typical” AVNRT ▪ Anterograde conduction to ventricles via slow pathway (alpha) ▪ Retrograde to atria conduction via fast pathway (beta) ▪ Depolarization down both pathways → reaches end of beta pathway first → signal splits ▫ Travels to ventricles → contraction ▫ Travels up alpha pathway → meets slow signal → signals cancel each other out ▪ Depolarization wave from premature beat reaches AV node → refractory fast (beta) pathway → signal initially down alpha pathway only → splits ▫ Travels to ventricles → contraction ▫ Travels up beta pathway → signal travels down alpha pathway, beta pathway comes out of refractory period → signal reaches end of alpha pathway →splits back up beta pathway Fast-slow/”atypical” AVNRT ▪ Anterograde conduction via fast pathway, retrograde conduction via slow pathway

DIAGNOSIS LAB RESULTS

▪ Thyroid function ▪ Serum electrolytes

OTHER DIAGNOSTICS ECG ▪ Tachycardia 140–280bpm ▪ Absent P waves ▪ P waves immediately before/after QRS complex ▪ P waves inverted/retrograde ▪ R’ waves (small secondary R waves)

TREATMENT MEDICATIONS

▪ Adenosine, beta blockers, calcium channel blockers to slow AV node conduction

OSMOSIS.ORG 139

OTHER INTERVENTIONS Radiofrequency catheter ablation ▪ Definitive treatment ▪ Ablation of slow alpha pathway

Slow AV node conduction ▪ Vagal maneuver (carotid sinus massage/ Valsalva maneuver) → activates vagus nerve

Figure 20.4 Illustration depicting path of electrical conduction in AV node during slow-fast AVNRT.

Figure 20.5 An ECG demonstrating typical (slow-fast) AVNRT. R waves are best seen in lead V1.

140 OSMOSIS.ORG

NOTES

NOTES

VASCULAR COMPRESSION SYNDROMES

GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Range of congenital/acquired anatomical compressions of vasculature/by vascular structure ▪ Acquired ▫ Rapid changes in weight → changes to fat pad cushioning between vasculature, other structures → compression ▪ Vasculature squeezed between two structures → ischemia (artery)/vascular engorgement (vein) ▪ Vasculature compresses, obstructs another structure → obstruction

SIGNS & SYMPTOMS

DIAGNOSIS DIAGNOSTIC IMAGING ▪ X-ray, CT scan, ultrasound

OTHER DIAGNOSTICS ▪ Physical exam

TREATMENT SURGERY

▪ See individual disorders

OTHER INTERVENTIONS ▪ Weight gain/loss

▪ Vascular obstruction → ischemia ▫ Pain, nausea, vomiting, weakness, cold, pulseless extremity ▪ Organ obstruction ▫ Pain, nausea, vomiting, weight loss

OSMOSIS.ORG 141

NUTCRACKER SYNDROME osms.it/nutcracker-syndrome PATHOLOGY & CAUSES ▪ Left renal vein squeezed between superior mesenteric artery, abdominal aorta ▪ Three unpaired arteries ▫ Celiac, superior mesenteric, inferior mesenteric ▪ Aortomesenteric angle ▫ Between aorta, superior mesenteric artery ▪ Aortomesenteric angle reduced → arteries pinch left renal vein → prevents blood return to heart → blood backs up in left kidney → renal hypertension → small breaks in renal blood vessels → blood in urine ▪ Aortomesenteric angle may decrease to 6º ▪ Blood may back up in left testicle

CAUSES

▪ Young people: reduction of aortomesenteric angle due to normal growth ▪ Adults: extreme weight loss due to severe illness (e.g. HIV/AIDS, cancer, anorexia nervosa), compressing tumors (e.g. pancreatic)

COMPLICATIONS

▪ Varicocele ▫ Left testicular vein drains into left renal vein → blood backs up into left testicle ▪ Ovarian vein syndrome ▫ Dilated ovarian vein compresses ureter → abdominal/back/pelvic pain ▪ Renal vein thrombosis

142 OSMOSIS.ORG

SIGNS & SYMPTOMS ▪ Left flank pain ▪ Hematuria ▪ Nausea, vomiting (compression of splanchnic veins) ▪ Individuals who are biologically male ▫ Scrotal mass → varicocele (engorgement of testicular veins)

DIAGNOSIS DIAGNOSTIC IMAGING Ultrasound, Doppler, CT scan, MRI, conventional angiography ▪ Left renal vein stenosis, reduced aortomesenteric angle ▪ Reduced blood flow through left renal vein on Doppler ▪ Collateral circulation ▪ Dilated testicular veins → varicocele

TREATMENT SURGERY

▪ For tumors ▫ Move vein, place stent

OTHER INTERVENTIONS

▪ Weight gain ▫ Increase mesenteric fat pad → widen aortomesenteric angle → relieve compression

Chapter 21 Vascular Compression Syndromes

Figure 21.1 An illustration demonstrating the pathophysiology and sequelae of nutcracker syndrome.

SUPERIOR MESENTERIC ARTERY SYNDROME osms.it/superior-mesenteric-artery-syndrome PATHOLOGY & CAUSES ▪ Vascular structures compressing another structure ▪ Distal third of transverse section of duodenum compresses between abdominal aorta, superior mesenteric artery ▪ Three unpaired arteries ▫ Celiac, superior mesenteric, inferior mesenteric ▪ Mesenteric fat pad thins out → reduces aortomesenteric angle → aorta, superior mesenteric artery pinch down on transverse duodenum → intestinal obstruction

▪ Post-scoliosis surgery ▪ Congenital anatomic abnormalities ▫ Ligament of Treitz too short ▫ Superior mesenteric artery branches off aorta further down

COMPLICATIONS

▪ Small bowel obstruction ▪ Severe malnutrition, wasting → increases compression, worsens condition

CAUSES

▪ Extreme weight loss ▫ Illness/intentional

OSMOSIS.ORG 143

SIGNS & SYMPTOMS ▪ Gradual/quick onset; may be intermittent ▪ Early satiety; bilious emesis; weight loss; abdominal distention; burping; hypersensitive abdomen; reflux, heartburn ▪ Relieved when in left lateral decubitus (knee-to-chest) position/prone position; with Hayes maneuver (apply pressure below umbilicus towards head, spine)

DIAGNOSIS

TREATMENT SURGERY

▪ E.g. ligament of Treitz → allow duodenum to move freely 

OTHER INTERVENTIONS

▪ Management ▫ Nasogastric tube to decompress stomach, early duodenum; fluids, electrolytes ▪ Weight gain (regrow mesenteric fat pad); may require feeding tube past obstruction

DIAGNOSTIC IMAGING Abdominal X-ray ▪ Dilated fluid/gas-filled stomach, proximal duodenum CT scan with oral contrast/MRI ▪ Vascular compression of third part of duodenum, reduced aortomesenteric angle, collapsed small bowel distal to SMA crossing Abdominal ultrasound ▪ Dilated proximal duodenum, stomach

OTHER DIAGNOSTICS

▪ High-pitched bowel sounds ▪ Succussion splash ▫ Sloshing sound of built-up gas, fluid in distended digestive tract upstream of obstruction

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Figure 21.2 An abdominal CT scan in the axial plane demonstrating superior mesenteric artery compression syndrome. The third part of the duodenum (outlined) is compressed between the superior mesenteric artery and the aorta.

NOTES

NOTES

VASCULAR MALFORMATIONS GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Developmental malformations of the vascular system

SIGNS & SYMPTOMS ▪ Usually asymptomatic ▪ Large malformations can cause obstruction /impair organ functions ▪ Diverts away high volume of blood → heart compensates → high-output heart failure

DIAGNOSIS DIAGNOSTIC IMAGING

▪ Imaging studies usually not needed

OTHER DIAGNOSTICS ▪ History ▪ Physical examination

TREATMENT ▪ Generally no need for treatment unless formations bleed/cause other problems

SURGERY

▪ Surgical/laser therapy considered for skin malformations

Figure 22.1 Illustration depicting changing pressure between normal arteries and veins.

OSMOSIS.ORG 145

ARTERIOVENOUS MALFORMATION osms.it/arteriovenous-malformation PATHOLOGY & CAUSES ▪ Abnormal capillary bed formation between artery and vein ▪ Capillary bed does not form, leaving arteries connected directly to veins → tangling → nidus ▪ Arteriovenous fistula: single artery to single vein direct connection ▪ No capillaries → arteries, veins subjected to high pressures → arteries dilate → veins thicken (fibrosis) ▪ AVM expands over time → compresses surrounding tissues → decreases blood flow ▫ Can cause bruit (whooshing noise heard on auscultation) ▫ Noise can get loud enough that person with the bruit can hear it, causing psychological stress, hearing issues and sleep issues

CAUSES

▪ Possibly congenital/genetic ▪ Osler–Weber–Rendu disease/hereditary hemorrhagic telangiectasia connected to AVM

RISK FACTORS

▪ Biological male, 10–30 years old, genetic conditions (e.g. Osler-Weber-Rendu)

COMPLICATIONS

▪ Ischemia at site, high output heart failure, rupture, haemorrhage

SIGNS & SYMPTOMS ▪ Most are asymptomatic ▪ Depend upon location ▪ Presence of bruit on auscultation

146 OSMOSIS.ORG

Brain ▪ Epilepsy, neurological deficits, abnormal sensations (numbness, tingling, pain) ▪ Sudden onset, severe headache indicates subarachnoid hemorrhage ▪ Difficulty with movement coordination, muscle weakness, paralysis, vertigo ▪ Apraxia (physical difficulties performing actions upon command, though command is understood) Lungs ▪ Asymptomatic 1/3 of time ▪ Dyspnea, cough, clubbing, cyanosis, hemoptysis, chest pain ▪ Platypnea (shortness of breath in upright position, relieved by lying down) ▪ Orthodeoxia (decrease in oxygen saturation by ≥ 2% when rising from lying down to standing) Spine ▪ Muscle weakness, paralysis Pediatric ▪ May present with ▫ Heart failure, macrocephaly, prominent scalp veins

DIAGNOSIS DIAGNOSTIC IMAGING Angiography ▪ Functional anatomy of AVM ▫ Feeding arteries: stenosis ▫ Sharp twisting of veins (ectasia) ▫ Arterial and venous dilatation CT scan/MRI ▪ Anatomy of AVM ▫ Irregular/bulbous masses in brain/ brainstem

Chapter 22 Vascular Malformations

OTHER DIAGNOSTICS ▪ Bruit

TREATMENT ▪ Treat all arteriovenous malformations

SURGERY Radiosurgery ▪ Radiation beams target AVM to close vessels Endovascular embolization ▪ Catheter placed to obstruct vessels

Figure 22.2 CT scan of the head in the axial plane demonstrating an arteriovenous malformation in the left parietal lobe.

CAVERNOUS HEMANGIOMA osms.it/cavernous-hemangioma PATHOLOGY & CAUSES ▪ Benign tumor formed from tangle of unencapsulated, dilated, thin-walled blood vessels ▪ Spherical caverns form from dilatation of vessels separated by fibrous connective tissue ▪ Characteristic “mulberry” presentation

TYPES

RISK FACTORS

▪ Von Hippel–Lindau disease

COMPLICATIONS ▪ ▪ ▪ ▪

Rupture → hemorrhage Obstructive jaundice, clotting disorders Intravascular thrombosis Dystrophic calcifications

SIGNS & SYMPTOMS

Cerebral cavernous malformations

▪ Usually asymptomatic

Liver cavernous hemangioma ▪ Sometimes found in people with previous pregnancies → high estrogen levels thought to be a factor

Brain ▪ Brain tissue compression → seizures, hemorrhages ▪ Stroke, speaking difficulties, memory/ attention difficulties ▪ Headaches, balance issues

Ocular cavernous hemangioma

CAUSES

▪ Genetic mutations ▫ CCM1, CCM2, CCM3

Liver ▪ Pain in right upper quadrant ▪ Gastrointestinal issues: nausea, vomiting, loss of appetite, early fullness after eating

OSMOSIS.ORG 147

Eyes ▪ Double/decreased vision, proptosis

DIAGNOSIS DIAGNOSTIC IMAGING MRI ▪ Seen as popcorn/mulberry shape → pathognomonic ▪ Hepatic cavernous hemangiomas best diagnosed with ▫ Ultrasound ▫ IV contrast CT scan ▪ Can be mistaken for metastatic tumors

Figure 22.3 Abdominal CT scan in the axial plane showing a hemangioma of the liver.

148 OSMOSIS.ORG

TREATMENT ▪ Monitoring usually sufficient

MEDICATIONS

▪ Facial hemangioma growth slowed with steroids ▫ Administered orally/injected at site

Sclerotherapy ▪ Close tumor’s blood supply → tumor shrinks

SURGERY

▪ Prevent damage to healthy tissues

Figure 22.4 A cavernous hemangioma from the liver, composed of large vascular spaces with thin walls. No normal liver is present.

Chapter 22 Vascular Malformations

HEMANGIOMA osms.it/hemangioma PATHOLOGY & CAUSES ▪ Hemangioma/infantile hemangioma (IH): benign vascular skin tumor ▫ Originates from endothelial cells lining blood vessels ▪ Most frequent tumors of infancy ▪ Develop a few days after parturition ▫ If IH appears to be present at birth → not IH

RISK FACTORS ▪ ▪ ▪ ▪

Intrauterine hypoxia Localised hypoxia Biological females more at risk Premature underweight infants

COMPLICATIONS

Usually none Easily infected, start bleeding Possible ulceration → infection Usually psychosocial: mostly appear on highly visible areas (face, neck, etc.) ▪ Multiple IH in newborns can indicate liver hemangiomas ▪ ▪ ▪ ▪

SIGNS & SYMPTOMS ▪ Appear in first weeks of life ▪ Tumors can grow for ≤ six months after birth ▪ Most regress over time, around five years old ▫ Can leave marks: fibroadipose tissue, changes in pigmentations, scars ▪ Resemble red/white patch, blemish; can be found all over body ▪ Superficial lesions: bright red, flat/raised from the skin → papules AKA “strawberry hemangiomas” ▫ Exposed areas: if grazed, can produce

black, crusted, sometimes painful ulceration ▫ > five hemangiomas → ultrasound for hepatic hemangioma ▪ Deeper hemangiomas: bluish lesions, poorly defined ▫ Can proliferate into bigger tumors ▫ Some have superficial capillary counterparts visible over/surrounding affected area ▫ Slower development ▪ Compound hemangiomas: deep IH + superficial IH

DIAGNOSIS DIAGNOSTIC IMAGING

▪ Usually no need for imaging

Doppler ultrasound ▪ High vessel density and high peak arterial Doppler shift, may show peripheral feeding vessels MRI ▪ Multiple high signal intensity lobules (due to cavernous/cystic spaces containing stagnant blood); often heterogeneous

LAB RESULTS

▪ Usually no need for biopsy unless history unclear; used to confirm diagnosis

OTHER DIAGNOSTICS History and physical exam ▪ History of onset, age, growth pattern, duration, treatment

OSMOSIS.ORG 149

TREATMENT ▪ Most do not require treatment, regress in a few years ▪ Exceptions ▫ Functional issues: feeding (laryngeal hemangiomas), obscuring vision ▫ Bleeding ▫ Hepatic/cardiac complications ▫ Permanent scars causing disfigurement Figure 22.5 A capillary hemangioma on the abdomen of an infant.

MEDICATIONS

▪ Beta blockers, oral corticosteroids ▪ Antiangiogenic therapies ▫ Usually intravenous: interferon-alfa 2a, 2b, vincristine

SURGERY

▪ Rarely, surgery/laser therapy

Figure 22.6 Histological appearance of a capillary hemangioma showing multiple small vascular spaces containing red blood cells.

LYMPHANGIOMA osms.it/lymphangioma PATHOLOGY & CAUSES ▪ Benign lymphatic malformations ▪ Composition: lymphatic channels/cysts ▪ May present at birth/develop during first few years of life

TYPES Cystic hygroma (macrocystic) ▪ AKA cavernous lymphangiomas ▪ Composition: cystic masses, dilated lymphatic networks with thin endothelial

150 OSMOSIS.ORG

layer; fluid-filled cavities; indistinct margins ▪ One/more cysts ≥ 2cm3/0.8in3 in size ▪ Tends to develop in deep soft tissues; propensity for rapid growth, local invasion of muscle, bone, underlying tissue Lymphangioma circumscriptum (microcystic) ▪ AKA simple/capillary lymphangioma ▪ Composition: capillary-sized endotheliallined lymphatic networks ▪ One/more cysts < 2cm3/0.8in3 in size ▪ Tend to develop in superficial tissues

Chapter 22 Vascular Malformations Mixed ▪ Contains variously-sized cysts

CAUSES

DIAGNOSIS DIAGNOSTIC IMAGING

▪ Failure to form communication between lymphatic, venous circulation (e.g. jugular lymph sac, internal jugular vein) during fetal development ▪ May be sporadic/associated with genetic mutations (e.g. VEGFR3 germline mutation)

MRI ▪ Multiloculated fluid-filled cystic lesions; identifies lesion’s extent

RISK FACTORS

Histopathology ▪ Cystically dilated channels lined with flat endothelial cells, filled with lymphatic fluid; deeper vessels are large, contain smooth muscle

▪ Chromosomal anomalies ▫ Turner syndrome, Down syndrome, Noonan syndrome (cystic hygroma)

Ultrasound ▪ Prenatal cystic mass detection; ↑ nuchal translucency (hypoechoic space)

COMPLICATIONS ▪ ▪ ▪ ▪

Lymphedema, recurrent cellulitis Disfigurement Lesion recurrence Fetal hydrops, fetal death, obstructed labor, chylous pleural effusion, chylopericardium, airway compression (cystic hygroma)

SIGNS & SYMPTOMS

TREATMENT SURGERY ▪ Resection

OTHER INTERVENTIONS

▪ Image-guided percutaneous chemoablation ▪ Sclerotherapy

Cystic hygroma ▪ Large (up to 15cm/5.9in), poorly-defined soft, fluctuant mass ▫ Commonly located in deeper layers of cervicofacial region, axilla, lateral chest wall ▫ Covered with normal skin Lymphangioma circumscriptum ▪ Slightly elevated lesion ▫ Commonly located in head (oral cavity), trunk, proximal extremities, axillary region ▫ May appear as translucent/hemorrhagic vesicles ▫ Overlying skin may be reddish-purple color secondary to small hemorrhages, thrombus formation/may contain wartlike lesions

Figure 22.7 CT scan in the coronal plane demonstrating a large cystic hygroma on the left side of the neck.

OSMOSIS.ORG 151

Figure 22.8 Histological appearance of a lymphangioma composed of dilated lymphatic spaces, lined by simple endothelium.

152 OSMOSIS.ORG

NOTES

NOTES

VASCULAR STEAL SYNDROMES

GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ AKA steal syndrome ▫ Occlusion → blood follows path of least resistance → abnormal blood flow ▪ Hemodynamics ▫ Length, width of vessel ▪ Obstruction/narrowing of vessel → increased resistance → blood follows path of least resistance → area distal to obstruction/narrowing receives less blood, others receive more blood

TYPES

▪ Coronary steal syndrome ▫ Coronary arteries ▪ Subclavian steal syndrome ▫ Subclavian artery

DIAGNOSIS DIAGNOSTIC IMAGING ▪ Incidental finding

CT angiography ▪ Blood flow/occlusion Doppler ultrasound ▪ Retrograde blood flow

LAB RESULTS

▪ Atherosclerosis, elevated troponin

OTHER DIAGNOSTICS ▪ Nuclear stress test ▪ ECG alterations ▪ Heart catheterization

CAUSES

▪ Narrowing/obstruction of vessel ▪ Atherosclerosis/structural abnormalities

SIGNS & SYMPTOMS ▪ See individual disorders

TREATMENT MEDICATIONS

▪ Pharmacological treatment; see individual disorders

SURGERY

▪ Revascularization of ischemic area ▫ Endovascular methods, bypass surgery, percutaneous transluminal angioplasty

OSMOSIS.ORG 153

CORONARY STEAL SYNDROME osms.it/coronary-steal-syndrome PATHOLOGY & CAUSES ▪ Narrowed/obstructed coronary vessel + vasodilator alters cardiac circulation → blood shunted away from area distal to narrowing/obstruction exacerbating ischemia ▪ AKA cardiac steal syndrome ▪ Artery narrowing/obstruction → dilation of distal arteries to compensate for decreased blood flow → addition of vasodilator → dilation of resistance vessels → blood supplying ischemic zone shunted away to areas of least resistance → more ischemia ▪ Narrowing of coronary arteries + vasodilator (e.g. dipyridamole, adenosine) → blood flows to non-obstructed vessels → exacerbating ischemia ▫ Dipyridamole: antiplatelet, vasodilator → all coronary vessels dilate when in individual with partial obstruction of coronary artery ▫ Vasodilator may steal blood from deprived region distal to obstruction ▪ Dilation of resistance vessels → blood shunted away from coronary vessels

CAUSES

▪ Coronary artery bypass grafting surgery (CABG) ▫ Rare ▫ Due to left internal mammary artery (LIMA) graft ▫ Retrograde flow from LIMA to left subclavian artery

154 OSMOSIS.ORG

▪ Drugs ▫ Dipyridamole, nitroprusside, isoflurane (inhaled anesthetic), vasodilators ▪ Coronary arteriovenous fistula between coronary artery, cardiac chamber

COMPLICATIONS

▪ Recurrent myocardial infarction (MI), ischemia

SIGNS & SYMPTOMS ▪ Cerebrovascular ▫ Presyncope/syncope, vertigo, vision loss, memory loss, weak pulse ▪ Chest pain ▪ Unequal pulses in upper extremities ▪ Blood pressure differences between arms

DIAGNOSIS OTHER DIAGNOSTICS

▪ Cardiac stress test ▫ Vasodilator produces ischemic ECG changes (with/without exercise) ▪ Coronary angiography

TREATMENT SURGERY

▪ Balloon angioplasty, stent insertion, coronary bypass

Chapter 23 Vascular Steal Syndromes

SUBCLAVIAN STEAL SYNDROME osms.it/subclavian-steal-syndrome PATHOLOGY & CAUSES ▪ Stenosis/occlusion in subclavian artery → reversal of blood flow in vertebral artery ▪ Occlusion/narrowing in subclavian artery → blood drawn away from head, flows retrogradely to supply oxygen to upper extremities (e.g. blood to brain stolen to supply left upper limb) ▫ More often on left than right due to anatomical location of left subclavian artery ▪ Narrowing of subclavian artery → short low resistance pathway becomes high resistance ▪ Blood flows up right brachiocephalic → right subclavian → right vertebral artery → basilar artery, left vertebral joins → blockage of left vertebral upstream → blood from right vertebral artery enters left vertebral → left subclavian → flows back to left arm ▪ Rare condition

RISK FACTORS

▪ Smoking, diabetes, obesity, lack of exercise, unhealthy diet, family history ▪ More common in individuals who are biologically male

COMPLICATIONS

▪ Upper limb ischemia, neurological problems

CAUSES

▪ Atherosclerosis (most common) ▫ Narrowing, hardening of arteries due to plaque buildup ▪ Takayasu disease (least common) ▫ Chronic inflammation of aorta, large vessels ▪ Giant cell arteritis ▪ Blalock Taussig shunt ▫ Surgical procedure to increase blood flow to lungs; tube placed between subclavian, pulmonary arteries ▪ Thoracic aortic dissection ▪ Thoracic outlet compression ▪ Interrupted aortic arch ▪ Congenital aortic coarctation

Figure 23.1 An illustration depicting the flow of blood in subclavian steal syndrome. Blood flows around the blockage in the proximal subclavian artery, reversing flow in the internal carotid and “stealing” the blood from the brain.

OSMOSIS.ORG 155

SIGNS & SYMPTOMS ▪ Asymptomatic ▪ Numbness of arm, extends to fingertips (most frequent) ▪ Vertebrobasilar artery insufficiency ▫ Presyncope/syncope, neurologic deficits ▪ Upper extremity claudication ▪ Tingling sensation/numbness in face ▪ Decreased blood pressure on affected side ▪ Transient hemiparesis (weakness) of affected side ▪ Blood pressure (BP) in left arm < BP in right arm ▪ Pulse in left arm < pulse in right arm

DIAGNOSIS DIAGNOSTIC IMAGING ▪ CT angiography ▪ Doppler ultrasound scan

TREATMENT SURGERY

▪ Balloon stenting, angioplasty ▪ Endarterectomy

156 OSMOSIS.ORG

NOTES

NOTES

VASCULAR TUMORS GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Abnormal growths of blood/lymph vessels ▪ Can be benign/malignant, can occur anywhere in body ▪ Vascular tumors are rare, but most commonly found in neonates (e.g. hemangiomas), HIV-positive individuals (e.g. Kaposi’s sarcoma)

DIAGNOSIS DIAGNOSTIC IMAGING

▪ Visual identification, imaging studies (MRI, CT scan, ultrasound with Doppler, biopsy) ▫ Determine location, tumor size, extent of spread

LAB RESULTS

▪ Biopsy for definitive diagnosis

COMPLICATIONS

▪ Metastasis ▪ Complications from chemo/radiation therapy

SIGNS & SYMPTOMS

TREATMENT ▪ Depends on type, location, severity, malignancy; see individual disorders

▪ See individual disorders

ANGIOSARCOMA osms.it/angiosarcoma PATHOLOGY & CAUSES ▪ Rare blood vessel malignancy involving blood vessel endothelial lining ▪ Aggressive, rapidly proliferating → poor prognosis ▪ Can occur anywhere; usually occurs in sunexposed areas (head, neck, breast) ▫ Cutaneous angiosarcomas (occur beneath skin’s surface) most common ▪ Can affect liver blood vessels

CAUSES

▪ Most likely due to lymphedema (fluid buildup causing sweeling), radiation exposure, carcinogens

RISK FACTORS

▪ Biologically male (twice as likely), elderly, sun-exposure, radiation therapy, chronic post-mastectomy lymphedema, frequent exposure to vinyl chloride monomer gas in PVC manufacturing/arsenic insecticides ▫ High-grade: aggressive, fast-growing

OSMOSIS.ORG 157

▫ Low-grade: less aggressive, slowgrowing

COMPLICATIONS

▪ High chance of metastasis, poor prognosis. Better prognosis for individuals with smaller tumors with clearly delineated margins. Low grade breast angiosarcoma has better prognosis than tumors with poorly-defined borders

SIGNS & SYMPTOMS ▪ Lesion resembling non-healing bruise/ wound ▪ Violet color ▪ Soft, visible, tactile lump/swelling ▪ Can form irregular vascular channels that disrupt tissue planes ▪ Fatigue ▪ Bone pain ▪ Anemia

DIAGNOSIS LAB RESULTS

▪ Biopsy, usually diagnosed late after the disease has spread

TREATMENT MEDICATIONS ▪ Chemotherapy

SURGERY

▪ Difficult to resect due to delay in diagnosis

OTHER INTERVENTIONS ▪ Radiation

Figure 24.1 A surgically excised angiosarcoma. Figure 24.2 Histological appearance of an angiosarcoma composed of malignant endothelial cells with vascular spaces containing red blood cells.

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Chapter 24 Vascular Tumors

GLOMUS TUMOR osms.it/glomus-tumor TREATMENT

PATHOLOGY & CAUSES ▪ Benign tumor arising from modified smooth muscle cells of skin’s thermoregulatory glomus bodies ▪ Derives from small vessels/arteriovenous anastomoses in glomus bodies ▪ Malignancy, metastasis rare ▪ Etiology includes loss-of-function mutation of protein glomulin in familial glomangiomas

SURGERY ▪ Resection

RISK FACTORS

▪ Adults: 20–40 years old ▪ Most lesions solitary, localized ▪ Autosomal dominant inheritance pattern

COMPLICATIONS

▪ Good prognosis, low recurrence rate after resection ▪ Malignant glomus tumors rare, have good prognosis when treated with wide excision ▪ Metastasis associated with poor prognosis

Figure 24.3 Homogenous enhancement of a glomus tumor of the nail bed at the ulnar aspect of the left index finger.

SIGNS & SYMPTOMS ▪ Painful, small, red-blue growths ▫ Pain associated with solitary lesions ▫ Younger individuals: multiple tumors, usually asymptomatic ▪ Usually found on distal extremities ▪ Paroxysmal pain depending on temperature, pressure changes ▫ Cold, pressure worsens pain

DIAGNOSIS

Figure 24.4 Histological appearance of a glomus tumor.

OTHER DIAGNOSTICS ▪ Visual inspection ▪ Occasional imaging

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KAPOSI SARCOMA osms.it/kaposi PATHOLOGY & CAUSES

STAGING

TYPES

AIDS-related Kaposi’s sarcoma ▪ Takes three factors into account ▪ Extent/severity of tumor ▫ T0: localized tumor ▫ T1: widespread, multiple lesions that spread to other organs ▪ CD4 cell count (immune status) ▫ I0: CD4 count above 150 cells/mm3 ▫ I1: CD4 count less than 150 cells/mm3 ▪ Presence/absence of systemic illness ▫ S0: no systemic illness/opportunistic infections, and/or B symptoms. B symptoms: systemic fever symptoms, night sweats, weight loss, diarrhea ▫ S1: presence of systemic illness, opportunistic infections, and/or B symptoms

AIDS-related ▪ Most common malignancy in AIDS

COMPLICATIONS

▪ Malignant vascular tumor/lesions of blood vessel endothelial cells ▪ Due to human herpesvirus 8 ▪ Virus penetrates cells, causing uncontrollable replication ▪ May involve visceral organs ▪ Progression, severity of tumor depends on underlying factor ▫ Genetic: usually seen in older Eastern European males; tumor localized to skin ▫ AIDs: tumor spreads (see staging below) ▫ Organ transplant recipients: tumor spreads

Immunocompromised & iatrogenic-related Classic/sporadic Endemic (African) ▪ Burkitt’s lymphoma due to Epstein-Barr virus

RISK FACTORS

▪ Immunocompromised individuals ▫ AIDS ▫ Kaposi’s sarcoma associated human herpesvirus-8 (HHV-8) ▫ Organ transplant ▪ Biologically male ▪ Eastern European ▪ Higher risk: biologically-male individuals engaging in same-sex sexual acts (“MSM“)

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▪ ▪ ▪ ▪ ▪

Lymphedema Bleeding Infection Long term hyperpigmentation Prognosis depends on individual’s immune status, viral load (amount of HIV virus in blood)

SIGNS & SYMPTOMS ▪ Most common symptoms affect skin, also affect mouth, GI tract, respiratory tract ▫ Progresses from flat lesion → plaque → ulcerating nodule ▫ Purple, red lesion similar to bruise that does not blanch ▫ Lesion starts off flat, may become raised, more painful

Chapter 24 Vascular Tumors ▫ Lesions in other tissues (e.g. mouth, nose, throat, lymph nodes, lungs, gastrointestinal tract); Commonly found in mucous membranes (esp. hard palate) ▪ Pulmonary symptoms: pulmonary Kaposi’s sarcoma ▫ Coughing (possibly bloody cough) ▫ Dyspnea

DIAGNOSIS DIAGNOSTIC IMAGING ▪ Bronchoscopy/endoscopy

LAB RESULTS ▪ Biopsy

MEDICATIONS

▪ HIV/AIDS management with antivirals ▫ Control HIV/AIDS → lesions shrink ▪ Removal of drugs (e.g. corticosteroids) allows immune system to recover ▫ Treatment more difficult in immunocompromised individuals ▪ Chemotherapy

SURGERY

▪ Surgically remove affected skin

OTHER INTERVENTIONS

▪ Cryotherapy → freeze affected skin ▪ Radiation

TREATMENT ▪ Depends on ▫ Severity of immunosuppression ▫ Number, location of tumors ▫ Symptoms

Figure 24.5 Kaposi sarcoma of the gingiva in a HIV positive individual. The tumor has replaced the gingiva of the upper right side of the jaw. There is overlying oral candidiasis.

Figure 24.6 A Kaposi sarcoma composed of spindle cells which form slits filled with erythrocytes.

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NOTES

NOTES

VASCULITIS GENERALLY, WHAT IS IT? PATHOLOGY & CAUSES ▪ Inflammation of blood vessels ▪ Vasculitides categorized by blood vessel size: small, medium, large

CAUSES Damaged endothelium ▪ Damaged endothelium → exposed collagen, tissue → increased blood coagulation → weakened, damaged blood vessel walls → aneurysms → vessel wall heals, stiffens as fibrin deposits Autoimmune disease ▪ Direct method: body mistakes endothelial layer of blood vessel for foreign pathogen → attacks ▫ Molecular mimicry: immune system white blood cells (WBCs) mistake normal antigens of endothelial cells for foreign invaders (e.g. bacteria) ▫ Medium, large-vessel vasculitides ▪ Indirect method: immune system attacks healthy cells near vascular endothelium → damages endothelial cells ▫ Small-vessel vasculitides (exception: Henoch-Schönlein purpura)

SIGNS & SYMPTOMS ▪ Inflammatory response symptoms: fever, weight loss, malaise, fatigue ▪ Ischemia ▫ Blood cells clump to exposed collagen inside blood vessels → blood clots → restricted blood flow ▫ Fibrin deposits in vessel wall → wall thickens, bulges into vessel → stenosis → restricted blood flow

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DIAGNOSIS LAB RESULTS

▪ C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), complete blood count (CBC), various autoantibodies ▪ Biopsy vessel segment

TREATMENT MEDICATIONS Reduce inflammatory response ▪ Corticosteroids/immunosuppressive drugs

Chapter 25 Vasculitis

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BEHCET'S DISEASE osms.it/behcets-disease PATHOLOGY & CAUSES ▪ Autoimmune multisystem vasculitis affecting any sized vessel, arterial/venous

RISK FACTORS

▪ Individuals who are 20–30 years old, of Middle Eastern/Asian descent, biologically male

COMPLICATIONS

TREATMENT MEDICATIONS

▪ Skin creams, mouth rinses, eye drops ▪ Corticosteroids: (e.g. prednisone) control inflammation ▪ Medications: (e.g. azathioprine, cyclosporine, or cyclophosphamide) suppress immune system ▪ Medications: (e.g. interferon alfa-2b) alter immune system response

▪ Blindness from untreated uveitis (inflammation in eyes)

SIGNS & SYMPTOMS ▪ Recurrent, painful, sterile oral/genital ulcers (pathergy) ▪ Skin papules indistinguishable from acne ▪ Uveitis, optic neuritis, conjunctivitis iritis ▪ Neurologic involvement (meningoencephalitis, intracranial HTN, stroke, headache) ▪ Arthritis (knees, ankles) ▪ Fever, weight loss

DIAGNOSIS OTHER DIAGNOSTICS Clinical presentation ▪ Recurrent oral ulcers (three in one year) + two of following ▪ Recurrent genital ulcers ▪ Eye lesions, uveitis ▪ Skin lesions ▪ Positive pathergy test ▪ ≥ 2mm papule 24–48 hours after oblique insertion 5mm into skin with 20-gauge needle, often performed on forearm

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Figure 25.1 Mucosal ulcer in an individual with Behcet’s disease.

Chapter 25 Vasculitis

BUERGER'S DISEASE osms.it/buergers PATHOLOGY & CAUSES ▪ Nonatherosclerotic, segmental, inflammatory disease affecting small-, medium-sized veins, arteries of extremities → inflammatory occlusive thrombus → distal extremity ischemia, digit ulcers/ gangrene → autoamputation ▪ AKA thromboangiitis obliterans ▪ Associated with use of tobacco products

RISK FACTORS

LAB RESULTS Biopsy ▪ Definitive; rarely (healing a concern) ▪ Histopathologically, acute-phase lesions show highly cellular, inflammatory thrombus with minimal inflammation of blood vessel

TREATMENT ▪ Immediate smoking cessation

▪ Individuals < 45 years old, who are biologically male, use tobacco ▪ Chronic anaerobic periodontal infection (⅔ of people with Buerger disease)

SIGNS & SYMPTOMS ▪ Ulceration of digits ▪ Ischemic claudication: cold, painful, cyanotic distal extremities ▪ Subcutaneous nodules, superficial thrombophlebitis ▪ Paresthesias of extremities ▪ Raynaud phenomenon

DIAGNOSIS DIAGNOSTIC IMAGING

Figure 25.2 A volume rendered CT angiogram demonstrating obliteration of the right femoral artery secondary to thromboangiitis obliterans. There is also stenosis of the femoral artery on the left.

Angiogram ▪ Lack of atherosclerosis ▪ Collateralization, segments of diseased vessel interspersed: smoking → atherosclerosis + Buerger disease simultaneously

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CHURG–STRAUSS SYNDROME osms.it/churg-strauss-syndrome PATHOLOGY & CAUSES ▪ Small, medium vessel granulomatous vasculitis involving many organ systems (cardiac, gastrointestinal, respiratory, skin, renal, neurologic) in individuals with allergy-related respiratory conditions (esp. asthma) ▪ AKA eosinophilic granulomatosis with polyangiitis (EGPA), allergic granulomatosis ▪ P-ANCA reacting with neutrophilic myeloperoxidase ▪ Etiology unknown

RISK FACTORS

▪ Age 30–50; asthma/nasal issues

SIGNS & SYMPTOMS ▪ Allergies ▫ Asthma, chronic rhinosinusitis, usually precedes vasculitic phase by 8–10 years ▪ Neurological ▫ Peripheral neuropathy (usually mononeuritis multiplex) ▫ Subarachnoid, cerebral hemorrhage, cerebral infarction, cranial nerve palsies ▪ Skin ▫ Palpable purpura, subcutaneous nodules ▪ Cardiac ▫ Damage → heart failure, arrhythmias ▫ Accounts ½ deaths ▪ Other organ systems (renal, gastrointestinal) → symptoms similar to medium-vessel vasculitides

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DIAGNOSIS DIAGNOSTIC IMAGING Chest X-ray ▪ Transient, patchy, symmetrical opacities, often in hilar/peripheral distribution ▪ Pulmonary hemorrhage ▪ Bilateral nodular disease without cavitation High-resolution CT scan ▪ Peribronchial, septal thickening ▪ Widely scattered indistinct opacities Pulmonary function test ▪ Obstructive pattern consistent with asthma Bronchoalveolar lavage ▪ High % of eosinophils

LAB RESULTS

▪ Eosinophilia > 1500/microL, > 10% on differential leukocyte count ▪ P-ANCA/MPO-ANCA antibodies ▪ Acute phase reactants: ↑ ESR, CRP

Lung/skin biopsy ▪ Definitive

TREATMENT ▪ Prognosis poor (five year survival, 25% without treatment; 50% with treatment)

MEDICATIONS

▪ Corticosteroids, immunosuppressive drugs

Chapter 25 Vasculitis

Figure 25.3 Histological appearance of vasculitis in Churg-Strauss syndrome. The background is composed almost entirely of eosinophils.

GIANT CELL ARTERITIS osms.it/giant-cell-arteritis PATHOLOGY & CAUSES ▪ Chronic vasculitis of large-, medium-sized vessels ▪ AKA temporal arteritis ▪ Cranial branches of arteries originating from aortic arch ▫ Temporal branch of carotid artery ▪ Aorta, carotids also affected ▪ Most common systemic vasculitis

CAUSES

▪ Unknown: possibly genetic, environmental, autoimmune-related

RISK FACTORS

▪ Almost always in individuals ≥ 50 ▪ More common in individuals who are biologically female ▪ Strong association with polymyalgia rheumatica (40–50% of GCA individuals)

COMPLICATIONS

▪ Irreversible blindness (if untreated)

SIGNS & SYMPTOMS ▪ New-onset headache (most common): temporal branch of carotid artery ▪ Jaw claudication (pain when chewing) ▪ Transient unilateral vision loss (amaurosis fugax): ophthalmic artery ▪ Carotid bruits, decreased pulses in arms, aortic regurgitation ▪ Tender, palpable nodules, absent temporal pulse ▪ Increased risk of aortic dissection, aortic aneurysm

MNEMONIC: TEMPORAL

Characteristics of Temporal (Giant cell) arteritis Temporal artery tenderness ESR >100 Multinucleated giant cells Pain Onset >50 years old polymyalgia Rheumatica association Amaurosis fugax Lost vision

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DIAGNOSIS LAB RESULTS

▪ Extremely elevated ESR (> 100mm/hr), ↑ IL-6 associated with active disease

Temporal artery biopsy ▪ Tightly packed monocytes/macrophages, as if one giant cell, in internal elastic lamina; segmental pattern; 90% sensitivity

TREATMENT ▪ Corticosteroids

Figure 25.4 A histology photomicrograph demonstrating giant cell arteritis. The external elastic lamina to the right has been completely destroyed by granulomatous inflammation.

GRANULOMATOSIS WITH POLYANGIITIS osms.it/granulomatosis-with-polyangiitis PATHOLOGY & CAUSES ▪ Small-vessel vasculitis involving nasopharynx, lungs, kidneys ▪ AKA Wegener’s granulomatosis ▪ Granulomatous disease of respiratory tract → systemic necrotizing vasculitis ▪ B-cells release cytoplasmic antineutrophil cytoplasmic antibodies (c-ANCA) → binds to proteinase 3 (neutrophil granule) in neutrophils → neutrophils release free radicals → free radicals damage neighboring endothelial cells → vasculitis ▪ Triad ▫ Focal, necrotizing vasculitis ▫ Necrotizing granulomas in upper airway, lungs ▫ Necrotizing glomerulonephritis (renal vasculitis)

RISK FACTORS

▪ Middle aged individuals who are biologically male

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MNEMONIC: 3Cs

“C” drawn from upper respiratory tract to lungs, kidneys (all involved) C-anca Corticosteroids/ cyclophosphamide (treatment)

SIGNS & SYMPTOMS ▪ Chronic pain: oral ulcers, bloody nasal mucus, chronic sinusitis, saddle nose (nose caves in/curls) ▪ Hemoptysis, dyspnea, cough, pleuritic chest pain (inflammation of lung vessels) ▪ Decreased urine production, hypertension, hematuria, red cell casts, proteinuria (glomerular inflammation)

Chapter 25 Vasculitis

DIAGNOSIS DIAGNOSTIC IMAGING Abnormal chest X-ray ▪ Nodules, fixed infiltrates, cavities, bronchial stenosis

TREATMENT ▪ Relapse common if c-ANCA still present

MEDICATIONS

▪ Corticosteroids, cyclophosphamide/ rituximab

LAB RESULTS

▪ c-ANCA in 90%, thrombocytopenia ▪ Abnormal urinary sediment; microscopic hematuria (with/without red cell casts)

Open lung biopsy ▪ Confirm diagnosis; granulomatous inflammation of artery/perivascular area

OTHER DIAGNOSTICS Nasal/oral inflammation ▪ Oral ulcers; painful/painless ▪ Purulent bloody nasal discharge ▪ Chronic sinusitis, saddle nose/destructive sinonasal disease

Figure 25.5 Illustration demonstrating the effects of granulomatosis with polyangiitis.

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HENOCH–SCHÖNLEIN PURPURA osms.it/henoch-schonlein-purpura PATHOLOGY & CAUSES ▪ Small vessel vasculitis secondary to IgA immune complex deposition. ▪ Elevated IgA in blood targets selfendothelial cells: molecular mimicry ▪ Most common systemic vasculitis of childhood ▪ Frequently follows upper respiratory infection ▪ Associated with Berger disease (IgA nephropathy) ▪ Unknown cause; immune-mediated vasculitis triggered by infections/ immunizations ▪ Self-limited disease ▪ Tetrad ▫ Palpable purpura, without coagulopathy/ thrombocytopenia; mainly lower extremities ▫ Arthritis/arthralgias ▫ Renal disease ▫ Abdominal pain

TREATMENT ▪ Self-resolving, may reoccur

MEDICATIONS

▪ Steroids, only if severe

SIGNS & SYMPTOMS ▪ Palpable purpura of buttocks, legs (skin discolouration, as if blood collected under skin surface); abdominal pain; arthritis/ arthralgias; hematuria, decreased kidney function (associated with IgA nephropathy)

DIAGNOSIS LAB RESULTS Biopsy ▪ Definitive, not necessary

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Figure 25.6 The clinical appearance of Henoch-Schönlein purpura.

Chapter 25 Vasculitis

KAWASAKI DISEASE osms.it/kawasaki-disease PATHOLOGY & CAUSES ▪ Coronary arteries: inflammation → aneurysms ▪ AKA mucocutaneous lymph node syndrome ▪ Most common type of vasculitis in children ▪ Usually self-limited

RISK FACTORS

▪ Infants, children < five years old, Asian descent, biologically male

COMPLICATIONS

▪ Coronary artery aneurysm ▪ Decreased myocardial contractility → heart failure ▪ Myocardial infarction (MI) ▪ Arrhythmias ▪ Peripheral artery occlusion

DIAGNOSIS DIAGNOSTIC IMAGING Chest X-ray ▪ Cardiomegaly Echocardiography ▪ Coronary artery aneurysms, pericardial effusions, decreased contractility

LAB RESULTS

▪ ↑ CRP, ESR, platelet count (reactive thrombocytosis)

OTHER DIAGNOSTICS

▪ Four of five CRASH symptoms, high fever lasting five days

ECG ▪ Arrhythmias, abnormal Q waves, prolonged PR, QT intervals

SIGNS & SYMPTOMS MNEMONIC: CRASH & BURN

Signs & Symptoms Conjunctivitis: bilateral, nonexudative Polymorphous Rash: desquamating Cervical lymphAdenopathy Strawberry tongue: cracked red lips, oral mucositis Hand-foot erythema/ desquamation: edema, erythema Fever: “burn”

Figure 25.7 A coronary angiogram demonstrating a massive right coronary artery aneurysm.

OSMOSIS.ORG 171

TREATMENT MEDICATIONS

▪ Intravenous immunoglobulin (IVIG) ▪ Aspirin

MICROSCOPIC POLYANGIITIS osms.it/microscopic-polyangiitis PATHOLOGY & CAUSES ▪ Necrotizing vasculitis: kidney, lung vessels ▪ No granulomas present ▪ Associated with perinuclear anti-neutrophil cytoplasmic antibodies (p-ANCA)/MPOANCA ▪ Pauci-immune glomerulonephritis (minimal immunofluorescent staining for IgG) ▪ Older adults

SIGNS & SYMPTOMS ▪ Similar to granulomatosis with polyangiitis, without nasopharyngeal involvement ▪ Fever, weight loss, fatigue, myalgia, arthralgias ▪ Cough, dyspnea, hemoptysis, pleuritic chest pain ▪ Decreased urine output, hematuria, red cell casts, proteinuria ▪ Skin lesions (especially lower extremities): purpura → focal necrosis → ulceration

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DIAGNOSIS LAB RESULTS

▪ p-ANCA/MPO-ANCA levels; elevated ESR, CRP, anemia, increased creatinine ▪ Protein, red blood cells (RBCs)

TREATMENT ▪ Relapse common

MEDICATIONS

▪ Corticosteroids, cyclophosphamide

Chapter 25 Vasculitis

POLYARTERITIS NODOSA osms.it/polyarteritis-nodosa PATHOLOGY & CAUSES ▪ Immune system forms antibody antigen complex (sometimes associated with hepatitis B) → deposits in vessel wall → immune reaction → invasion of polymorphonuclear leukocytes → segmental, transmural inflammation of muscular arteries → necrosis of three artery layers (tunica intima, media, adventitia) → fibrosis as walls heal (fibrinoid necrosis) → fibrosed vessel wall weakens, prone to aneurysms → fibrotic aneurysms (hard bulges) develop ▪ Different stages of inflammation in different vessels

RISK FACTORS

▪ Individuals > 40 years old, biologically male ▪ Active hepatitis B (HBV)/hepatitis C (HCV) infection ▪ HIV ▪ Prescription/illicit drug exposure, amphetamines

SIGNS & SYMPTOMS

DIAGNOSIS DIAGNOSTIC IMAGING Mesenteric angiogram ▪ “String of beads” pattern along artery, spasms

LAB RESULTS

▪ HBV, HCV serologies, Cr, muscle enzymes, urinalysis

Biopsy

OTHER DIAGNOSTICS Physical exam ▪ Vascular lesions, motor weakness (due to ischemia)

TREATMENT MEDICATIONS

▪ Corticosteroids ▪ Cyclophosphamide: supplement corticosteroids in moderate to severe cases

▪ Systemic: fever, fatigue, weight loss, arthralgia ▪ End organ ischemic damage ▪ Renal arteries: HTN ▪ Mesenteric artery: mesenteric ischemia, severe abdominal pain, gastrointestinal bleeding ▪ Mononeuropathy multiplex: motor, sensory deficits occur in > one nerve throughout body ▪ Skin arteries: skin lesions (e.g. ulcers, erythematous nodules resembling erythema nodosum, purpura, livedo reticularis)

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Figure 25.8 Illustration showing polyarteritis nodosa’s characteristic “string of beads” pattern running along the artery.

TAKAYASU ARTERITIS osms.it/takayasus-arteritis PATHOLOGY & CAUSES ▪ Segmental, patchy granulomatous vasculitis of aortic arch, major branches ▪ Stenosis, thrombosis, aneurysm

CAUSES

▪ Unknown; possibly bacterial (e.g. spirochetes, Mycobacterium tuberculosis, streptococcal) ▪ Genetic

RISK FACTORS

▪ Individuals of Asian descent, < 40 years old, biologically female

COMPLICATIONS

▪ Limb ischemia; aortic aneurysm; aortic regurgitation; stroke; secondary hypertension (HTN) due to renal artery stenosis

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SIGNS & SYMPTOMS ▪ Inflammation ▫ Aortic branches, upper extremities: weak/absent pulse ▫ Aortic branch, head: neurological symptoms (e.g. headaches, syncope, stroke) ▫ Coronary arteries: angina ▫ Renal arteries: HTN ▪ Visual disturbances: ocular vessels/retinal hemorrhage ▪ Constitutional symptoms: fever, night sweats, arthralgias, malaise, fatigue ▪ Ischemia in areas of stenosis

DIAGNOSIS DIAGNOSTIC IMAGING CT angiography (CTA), magnetic resonance angiography (MRA) ▪ Luminal narrowing/occlusion of major aortic branches ▪ Vessel wall thickening ▪ Aortic valve disease (e.g. regurgitation,

Chapter 25 Vasculitis stenosis) ▪ Aneurysmal dilation/pseudoaneurysm formation Ultrasound ▪ Homogeneous and circumferential thickening of arterial wall (contrast to atherosclerotic plaque: non-homogeneous, calcified, irregular walls) ▪ Vascular occlusion due to intimal thickening/secondary thrombus formation ▪ Loss of pulsatility of vessel

LAB RESULTS ▪ ↑ ESR

TREATMENT MEDICATIONS ▪ Corticosteroids ▪ Treat HTN

SURGERY

▪ Angioplasty (when no acute inflammation); bypass grafting if severe

Figure 25.9 An angiogram demonstrating multiple stenosis of the aortic arch vessels, a feature of Takayasu arteritis.

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NOTES

NOTES

VENOUS DYSFUNCTION GENERALLY, WHAT IS IT? PATHOLOGY & CAUSES ▪ Venous system defects affecting blood flow from lower extremities

▪ Localized hyperpigmentation/skin discoloration ▪ Hard, cord-like veins/prominent dilated tortuous veins

DIAGNOSIS

CAUSES

▪ Blood clot partially/completely blocking way/venous valves failing to pump blood against gravity

Virchow’s triad ▪ Hypercoagulability, increased clot formation ▫ Factor V Leiden thrombophilia ▫ Protein C and protein C deficiencies ▪ Venous stasis from prolonged immobilization (e.g. bed rest) ▪ Damage to endothelial lining

RISK FACTORS

▪ Prolonged immobility, hereditary clotting dysfunctions, high estrogen levels, obesity ▪ One venous dysfunction can lead to another

MNEMONIC: PHD

Virchow's Triad Prolonged immobilization (stasis) Hypercoagulability Damage to endothelium

SIGNS & SYMPTOMS ▪ Localized pain, usually lower extremities ▪ Edema ▪ Pruritus

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DIAGNOSTIC IMAGING Doppler ultrasound ▪ Assess vein diameter, thrombi, valve status, blood flow (anterograde vs. retrograde) Venography ▪ X-ray, contrast medium injected into vein ▪ Assess status of vein network, detect thrombi

LAB RESULTS

▪ D-Dimer: High sensitivity (~100%) and negative predictive value (~100%) for detection of venous thromboembolism

TREATMENT MEDICATIONS

▪ Acute manifestation: unfractionated heparin/low-molecular-weight heparins ▪ Long-term management: oral anticoagulants (e.g. warfarin) ▪ Prior DVT ▫ Long term anticoagulation therapy, antiplatelet treatment, parenteral anticoagulants

SURGERY

▪ Vein transplant/repair/removal

Chapter 26 Venous Dysfunction

OTHER INTERVENTIONS

▪ Preventative: calf exercises, compression stockings/devices, raise affected areas to decrease swelling

CHRONIC VENOUS INSUFFICIENCY (CVI) osms.it/chronic-venous-insufficiency PATHOLOGY & CAUSES ▪ Veins cannot push blood back to heart, resulting in blood pooling in leg

CAUSES

▪ Develops from varicosities, DVT, phlebitis ▫ Varicose veins affect superficial veins, but blood sometimes rerouted to collateral veins deep in leg, preventing blood stagnation ▪ When deep veins carry more blood than normal ▫ Deep veins stretch over time, blood pools ▫ Blood flow stagnation in lower extremities causes inflammatory reaction in vessels, tissue, causing fibrosis, venous stasis ulcers

RISK FACTORS

▪ Biological females, inactive standing/sitting for long periods, aging, family history, ligamentous laxity, obesity, smoking, lowextremity trauma, prior venous thrombosis, arteriovenous shunt, pregnancy

SIGNS & SYMPTOMS ▪ Calf/ankle pain (most common symptom) ▪ Worse with prolonged standing/sitting, improves with leg elevation, movement ▪ Brown hyperpigmentation of skin

(hemosiderin deposits) ▪ Pruritus, stasis dermatitis ▪ Painless, wet ulcers, particularly on medial malleolus ▪ Edema ▪ Atrophie blanche: hypopigmented atrophic areas with telangiectasia (clusters of red/ purple capillaries), red dots

DIAGNOSIS DIAGNOSTIC IMAGING Doppler ultrasound imaging ▪ Most common diagnostic ▪ Modified vein diameter (increased = acute thrombus, decreased = chronic thrombus) ▪ Absent color flow: vein completely occluded ▪ Increased flow in surrounding superficial veins Venography ▪ Most effective, but invasive and costprohibitive

TREATMENT SURGERY

▪ Vein transplant/repair/removal

OTHER INTERVENTIONS

▪ Preventative: calf exercises, compression stockings/devices, raise affected areas to decrease swelling

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Figure 26.1 The clinical appearance of mild CVI. Hemosiderin deposition is clearly visible.

Figure 26.2 Illustration of varicose veins that have developed into a case of CVI.

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Chapter 26 Venous Dysfunction

DEEP VEIN THROMBOSIS (DVT) osms.it/deep-vein-thrombosis PATHOLOGY & CAUSES

SIGNS & SYMPTOMS

▪ Blood clotting in deep leg veins (iliofemoral, popliteal, femoral veins) ▪ Arterial clots usually due to artery wall damage; venous clots don’t require vein damage ▪ Valves inside veins can lower blood oxygen levels → venous stasis-associated hypoxemia can activate reactive oxygen species, other hypoxia-inducible factors → tissue factor released into blood ▫ Tissue factor activation → prothrombin turns into thrombin → fibrin fibers form net → traps red blood cells, white blood cells, platelets → venous thrombus

▪ 50% asymptomatic due to venous collateral channels ▪ Localized inflammation around clot ▪ High venous pressure engorges visible superficial veins ▪ If PE occurs: sudden dyspnea, chest pain ▫ Fatal if enough lung tissue affected

CAUSES

▪ Virchow’s triad ▪ Antiphospholipid syndrome ▪ Prolonged immobilization (bed rest, orthopedic casts, long-distance air travel) ▪ Genetic ▫ Antithrombin, protein C, S deficiencies

RISK FACTORS

▪ Pregnancy, oral contraceptives, old age, major surgery (e.g.orthopedic surgery), malignancy, obesity, trauma, heart failure

COMPLICATIONS

▪ Pulmonary embolism (PE) most common ▫ Can cause pulmonary infarction, death ▪ Post-thrombotic syndrome ▫ Develops in 50% of individuals with DVT ▪ Extreme cases: phlegmasia cerulea dolens (blue, painful, swollen leg, possible venous gangrene)

DIAGNOSIS DIAGNOSTIC IMAGING Doppler ultrasound imaging ▪ Most common diagnostic ▪ Modified vein diameter ▫ Increased: acute thrombus ▫ Decreased: chronic thrombus ▪ Absent colour flow: vein completely occluded ▪ Increased flow in surrounding superficial veins Venography ▪ Most effective, but invasive/cost-prohibitive

LAB RESULTS

▪ D-dimers → rule out DVT ▫ Increased level: plasmin dissolves thrombus

OTHER DIAGNOSTICS Wells’ score ▪ Higher score indicates increased chance of DVT (Scale of -2 to 9 points) ▫ High score = high chance: > 2 points ▫ Moderate score = moderate chance: 1–2 points ▫ Low score = low chance: < 1 point

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TREATMENT MEDICATIONS

▪ Acute manifestation: unfractionated heparin/low-molecular-weight heparins ▪ Long-term management: oral anticoagulants (e.g. warfarin) ▪ Prior DVT: long term anticoagulation therapy, antiplatelet treatment, parenteral anticoagulants

OTHER INTERVENTIONS

▪ Preventative: calf exercises, compression stockings/devices, raise affected areas to decrease swelling

Figure 26.3 An IVC filter, used to prevent embolization of the deep vein thrombus into the pulmonary vasculature.

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Figure 26.4 Clinical appearance of a deep vein thrombosis of the right leg. The lower leg is erythematous and swollen.

Chapter 26 Venous Dysfunction

THROMBOPHLEBITIS osms.it/thrombophlebitis PATHOLOGY & CAUSES ▪ Vein inflammation caused by clot in deep leg veins ▪ Increased coagulability (Virchow’s triad) ▪ Potential locations ▫ Upper limbs (usually at site of IV cannula) ▫ Lower limbs (coupled with varicose veins) ▫ Periprostatic venous plexus in biological males ▫ Pelvic venous plexus in biological females ▫ Large veins of cranium, dural sinuses ▫ Portal vein

TYPES Migrating thrombophlebitis ▪ Occurs in several different locations, usually in pancreatic carcinomas due to proclotting factors secreted by tumoral cells Superficial thrombophlebitis ▪ Thrombus develops in vein near skin’s surface ▫ Mondor’s syndrome: thrombophlebitis of subcutaneous veins of breast/arm / penis; presents as lump Suppurative (septic) thrombophlebitis ▪ Infection from IV cannula; possible purulence

CAUSES

▪ Most commonly: needle/catheter ▪ Prolonged immobilization: bed rest, orthopedic casts, long-distance air travel ▪ High estrogen: pregnancy, estrogen replacement therapy, oral contraceptives ▪ Hereditary clotting disorders: protein D/C deficiencies/factor V Leiden mutations ▪ Vasculitis, Behcet’s disease

COMPLICATIONS

▪ DVT, superficial thrombophlebitis, pulmonary embolism

SIGNS & SYMPTOMS ▪ Pain, inflammation/swelling, hard, cord-like veins ▪ Sometimes asymptomatic, can be revealed by applying pressure ▫ Hoffman’s sign (forced dorsiflexion on foot creates soreness behind knee); not 100% accurate

DIAGNOSIS DIAGNOSITC IMAGING Venous duplex ultrasound ▪ Thrombosed veins thickened, poorly compressible ▪ Completely occluded vein = hypoechoic (low level echoes) ▪ No internal flow present distal to clot Imaging studies ▪ Thrombus detection (e.g. CT venography (CTV) with contrast, magnetic resonance (MR) venography) ▪ Blood coagulation tests (e.g. elevated D-dimers)

LAB RESULTS Blood coagulation tests ▪ Elevated D-dimers

OTHER DIAGNOSTICS

▪ Inspection of affected area ▫ Pulse (weak/absent) ▫ Blood pressure (high) ▫ Temperature (high)

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TREATMENT MEDICATIONS

▪ Acute manifestation: unfractionated heparin/low-molecular-weight heparins ▪ Long-term management: oral anticoagulants

OTHER INTERVENTIONS

▪ Preventative: calf exercises, compression stockings/devices, raise affected areas to decrease swelling

Figure 26.5 Illustration showing blood clots discovered via imaging studies.

Figure 26.6 Illustration showing a surgically-implanted filter in the inferior vena cava preventing a pulmonary embolism.

182 OSMOSIS.ORG

Chapter 26 Venous Dysfunction

VARICOSE VEINS osms.it/varicose-veins PATHOLOGY & CAUSES ▪ Enlarged, twisted superficial veins (most commonly in leg) ▪ Downward gravitational pull causes walls of veins to stretch over time, blood leaks backwards → extra blood volume twists veins → veins become varicose ▪ Blood sometimes rerouted to collateral veins deep in leg

TYPES Varicocele ▪ Abnormal enlargement of pampiniform venous plexus in scrotum ▪ Mechanism same as varicose veins ▪ Most common in left testicle ▫ Left testicular vein brings blood to left renal vein at 90º angle → difficult → blood backs up → vein becomes varicose → loops back and forth on itself ▫ “Bag of worms” appearance

CAUSES

▪ Obesity, pregnancy, standing for long periods of time, menopause ▫ Pelvic vein reflux (PVR): ovarian vein reflux, internal iliac vein reflux ▪ Hyperhomocysteinemia destroying structural proteins in vessels ▪ Chronic alcohol use

COMPLICATIONS

▪ Chronic venous insufficiency ▪ Venous ulcers ▫ Can develop into carcinomas, sarcomas over time (rare) ▪ Superficial thrombophlebitis

SIGNS & SYMPTOMS ▪ Twisted superficial veins ▪ Edema, pain (usually in evening) ▪ Pruritus in affected area/stasis dermatitis because of undrained waste in leg ▪ Prolonged bleeding, slowed healing in injuries to adjacent areas ▪ Restless legs syndrome

DIAGNOSIS DIAGNOSTIC IMAGING Doppler ultrasound ▪ Used to discover subcutaneous varicosities, assess saphenofemoral junction ▪ If blood reflux spotted during Valsalva manoeuvre → valve incompetence ▪ Reflux > 1s → surgical intervention

OTHER DIAGNOSTICS Trendelenburg test ▪ Person laid back on flat surface, leg raised above heart, blood will flow towards heart → compress upper thigh with tourniquet (not too tightly) → lower leg onto flat surface → person stands, refilling times assessed ▫ Normal: superficial saphenous vein fills < 30–35s ▫ Faster filling → valvular incompetence below compressed area → deep/ communicating veins ▫ Slower filling → tourniquet released → if filling sudden → incompetent superficial veins

OSMOSIS.ORG 183

TREATMENT SURGERY

▪ Radiofrequency/laser ablation ▪ Sclerotherapy ▪ Ambulatory phlebectomy: removal of surface vein through slits in skin

OTHER INTERVENTIONS

▪ Preventative: compression stockings/ devices, avoid prolonged standing

Figure 26.7 An X-ray image demonstrating varicose veins of the left leg.

Figure 26.8 Illustration of a varicocele in the left testicle.

184 OSMOSIS.ORG

NOTES

NOTES

VENTRICULAR TACHYCARDIA GENERALLY, WHAT IS IT? PATHOLOGY & CAUSES ▪ Depolarization wavefronts originate in ventricles → ventricles pump > 100 beats per minute ↓ stroke volume ▪ Premature ventricular contractions (PVCs): single instance of ventricle contracting prematurely ▫ ≥ three PVCs consecutively defined as ventricular tachycardia (VT)

COMPLICATIONS

▪ Sustained VT may result in sudden cardiac death due to insufficient blood perfusion/ rapid ventricular fibrillation

SIGNS & SYMPTOMS ▪ Chest pain, syncope, dizziness, shortness of breath, palpitations

DIAGNOSIS

TYPES Monomorphic VT ▪ Ventricular contractions have typical, uniform shape ▪ Typical for reentrant circuits ▫ Depolarizations begin from same spot, for focal VT because one area of cells in ventricle is responsible ▫ Often caused by reentry around scar in ventricular wall; e.g. from previous myocardial infarction (MI) Polymorphic VT ▪ > One QRS complex morphology type ▫ Includes Torsades de pointes ▪ Shape of contractions from each beat changes as signal begins in different areas of ventricle ▪ May occur when pacemaker cells stressed, increasing automaticity rates, including from severe hypoxia

RISK FACTORS

▪ Ventricular muscle ischemia, structural heart disease, coronary artery disease (CAD), electrolyte abnormalities

LAB RESULTS

▪ Serum electrolytes ▪ Toxicology studies (therapeutic/recreational drug use) ▫ E.g. digoxin, tricyclic antidepressants, methamphetamine, cocaine

OTHER DIAGNOSTICS ECG ▪ Determines cardiac rhythm

TREATMENT MEDICATIONS

▪ Pharmacotherapy ▫ Depending on cause

SURGERY

▪ Implanted devices

OTHER INTERVENTIONS ▪ Cardioversion, pacing ▪ Correct underlying cause

OSMOSIS.ORG 185

Figure 27.1 Illustration depicting ECG of monomorphic ventricular tachycardia.

Figure 27.2 Illustration depicting focal ventrical tachycardia.

186 OSMOSIS.ORG

Chapter 27 Ventricular Tachycardia

LONG QT SYNDROME (LQTS) osms.it/long-qt-syndrome PATHOLOGY & CAUSES ▪ Cardiac rhythm disorder characterized by prolonged ventricular repolarization ▪ Characterized by abnormally long QT interval ▫ QT interval: total time from ventricular depolarization (QRS complex) to complete repolarization (T wave); measured from beginning of QRS to end of T wave ▫ QTc (corrected) accounts for changes in heart rate: QTc = QT interval ÷ √RR interval (in sec); AKA Bazett formula ▫ Adult normal = 420 ± 20 msec ▪ Results in ↑ risk of polymorphic ventricular arrhythmias (TdP), which can deteriorate into ventricular fibrillation

TYPES Inherited ▪ Caused by mutations in genes associated with cardiac potassium, sodium channels ▪ Triggered by exertion, emotional events, stress, postpartum events, noise ▪ ≥ 13 types identified; associated with mutations in genes encoding myocyte ion channels ▪ KCNQ1, KCNH2, KCNE1, KCNE2 affect potassium channels → ↓ outward potassium current ▪ SCN5A affects sodium channels → ↑ inward sodium current ▫ Two distinct LQT phenotypes due to mutant alleles in same locus: ▫ Romano–Ward syndrome: autosomal dominant; LQTS without hearing loss ▫ Jervell and Lange–Nielsen syndrome: autosomal recessive; LQTS with congenital sensorineural hearing loss

Acquired ▪ Usually caused by certain drugs (e.g. antiinfectives, psychotropics, antiarrhythmics, antineoplastics, bronchodilators, gastric motility agents) ▫ Common mechanism involves blockage of rapidly activating potassium channels (IKr) current in potassium channel encoded by KCNH2 gene

RISK FACTORS

▪ Electrolyte imbalances (e.g. hypokalemia, hypomagnesemia, hypocalcemia) ▪ Underlying heart disease (e.g. HF, hypertrophic left ventricle, history of myocardial infarction) ▪ Bradyarrhythmias ▪ Biological females > biological males ▪ ↑ age ▪ Inherited genetic mutation ▪ Postpartum period ▫ Related to physiologic stress, altered sleep patterns ▪ Anorexia nervosa

COMPLICATIONS

▪ Malignant arrhythmias (TdP, VF), syncope, seizures, sudden death

SIGNS & SYMPTOMS ▪ Palpitations, lightheadedness, hypotension

DIAGNOSIS LAB RESULTS

▪ Serum electrolytes ▫ Hypokalemia, hypomagnesemia, hypocalcemia may be present

OSMOSIS.ORG 187

OTHER DIAGNOSTICS

SURGERY

12-lead ECG ▪ Prolonged QTc (> 470msec in males, > 480msec in females); presence of tachyarrhythmias (TdP); altered T-wave morphology

Congenital LQTS ▪ Left cervicothoracic sympathectomy (LCTS), left cardiac sympathetic denervation; implantable cardioverter-defibrillator (ICD); pacemaker

Bicycle/treadmill stress test ▪ Presence of exercise-associated arrhythmias

Acquired LQTS ▪ Pacemaker → if bradycardia triggers arrhythmia

Catecholamine drug testing ▪ Differentiates etiology ▫ Provocative testing with catecholamine; e.g. epinephrine ▫ Measure effect on QT interval Clinical/family history, physical examination ▪ With compatible findings Genetic testing Schwartz score ▪ Diagnosis of congenital LQTS by scoring QTc, clinical factors, individual history ▪ Scoring: probability of congenital LQTS ▫ ≤ 1: low ▫ 1.5–3: intermediate ▫ ≥ 3.5: high

TREATMENT MEDICATIONS Congenital LQTS ▪ Beta-blockers: blunt adrenergic response ▪ Mexiletine: for sodium-channel mutations ▪ Flecainide: if SCN5A mutation Acquired LQTS ▪ Magnesium sulfate: treatment, prevention of recurrence of long QT-related ventricular ectopic beats ▪ Isoproterenol: increase sinus rate, decrease QT interval ▪ Lidocaine/phenytoin: shorten duration of the action potential

188 OSMOSIS.ORG

OTHER INTERVENTIONS Acquired LQTS ▪ Address underlying cause; e.g. correct electrolyte abnormalities, discontinue offending drug; temporary transvenous overdrive pacing, electrical cardioversion/ defibrillation Lifestyle modifications ▪ Avoidance of triggering drugs, avoidance adrenergic stimuli; e.g. strenuous exercise, emotional stress

Chapter 27 Ventricular Tachycardia

Figure 27.3 ECG trace demonstrating long-QT syndrome.

OSMOSIS.ORG 189

Figure 27.4 ECG trace demonstrating long-QT syndrome.

TORSADES DES POINTES (TdP) osms.it/torsades-de-pointes PATHOLOGY & CAUSES ▪ Literally means “twisting of the points” ▪ The peaks of QRS complex “twist” around isoelectric line on electrocardiogram ▪ Lengthening QT interval → early afterdepolarizations (EADs) → premature ventricular depolarizations → polymorphic VT (TdP) ▫ May resolve spontaneously ▫ Transmural reentry/abnormal automaticity may perpetuate TdP ▫ May degenerate into ventricular fibrillation

RISK FACTORS ▪ ▪ ▪ ▪ ▪

LQTS, drugs associated with LQTS Bradycardia Electrolyte imbalance Biologically female Anorexia nervosa

COMPLICATIONS

▪ Ventricular fibrillation, seizures, sudden cardiac death

190 OSMOSIS.ORG

MNEMONIC: TO4SADE

Drugs that may induce QT prolongation Thiazides O4 - Oanzapine, Opioids, Quinidine, Quinolones Sotalol/SSRIs Antihistamines/antipsychotics AntiDepressants like TCAs Erythromycin (Macrolide antibiotics

SIGNS & SYMPTOMS ▪ Palpitations, lightheadedness, syncope

DIAGNOSIS LAB RESULTS

▪ Serum electrolytes ▫ Hypokalemia, hypomagnesemia, hypocalcemia may be present

Chapter 27 Ventricular Tachycardia

OTHER DIAGNOSTICS

▪ 12-lead ECG ▫ Ventricular rate: 150–300 beats per minute ▫ RR interval: irregular ▫ P wave, PR interval: absent ▫ QRS duration: > 0.12 seconds; changes amplitude, shape, direction

TREATMENT

SURGERY

▪ Left cardio-thoracic sympathectomy

OTHER INTERVENTIONS

▪ Treat underlying cause; e.g. correct electrolyte abnormalities, discontinue offending drug ▪ Temporary pacing, permanent dual chamber pacemaker, implantable cardioverter-defibrillator (ICD)

MEDICATIONS

▪ For acquired LQTS/other causes of TdP ▫ Magnesium sulfate, isoproterenol, lidocaine, phenytoin ▪ For congenital LQTS ▫ Beta-blockers, mexiletine

Figure 27.5 ECG demonstrating torsades de pointes.

OSMOSIS.ORG 191

VENTRICULAR TACHYCARDIA osms.it/ventricular-tachycardia PATHOLOGY & CAUSES ▪ Ventricular arrhythmia originating in ectopic ventricular pacemaker, resulting in ≥ three premature ventricular complexes (PVCs) occurring at ≥ 100 beats/min ▪ Dysrhythmia may be sustained (> 30 seconds)/nonsustained (< 30 seconds)/ paroxysmal ▪ Abnormally fast ventricular contractions → ↓ ability for ventricles to fill → ↓ cardiac output → ↓ perfusion → impaired hemodynamics

TYPES Non-reentrant/focal ventricular tachycardia ▪ Triggered by abnormal automaticity of specific area of ventricle ▫ Ventricular pacemaker cells fire at high rate, preventing pacemaker cells in SA node from firing → heart rate driven by ventricular pacemakers ▫ May be caused by certain medications, illicit drugs (e.g. methamphetamine, cocaine), electrolyte imbalances, myocardial ischemia in ventricles Reentrant ventricular tachycardia ▪ More common than focal VT ▪ Reentry: perpetual electrical signal that occurs due to changes in refractory period length, rate of signal conduction ▫ Cardiomyocytes can be altered when stressed/irritated by external stimuli; e.g. medications/illicit drugs: change conduction speed, refractory period ▫ Dead cells in myocardial tissue create scar tissue → conduction signals go around scar → perpetual signal, AKA reentry

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RISK FACTORS

▪ ↑ age ▪ Cardiac disease ▫ Post-MI, cardiomyopathy, valve disease, HF ▪ Electrolyte imbalance ▪ Cardiac ion channelopathies resulting in long QT syndromes ▪ Infiltrative disease; e.g. amyloidosis ▪ Pericardial inflammation ▪ Blunt chest trauma ▪ Drugs; e.g. cocaine

COMPLICATIONS

▪ Cardiac ischemia, infarction ▪ May degenerate into ventricular fibrillation ▪ Sudden cardiac death

SIGNS & SYMPTOMS ▪ ▪ ▪ ▪ ▪ ▪

Chest pain Shortness of breath Dizziness Syncope Pallor Blood pressure: normal/↓

DIAGNOSIS LAB RESULTS

▪ Serum electrolytes ▫ Hypokalemia, hypomagnesemia, hypocalcemia may be present

OTHER DIAGNOSTICS ECG ▪ Rate: >100 beats per minute, irregular ▪ P waves: may be absent ▫ If present, atrioventricular dissociation common (hallmark of VT)

Chapter 27 Ventricular Tachycardia ▫ May be positive/upright or negative/ inverted in Lead II ▪ PR interval: none ▪ QRS complex: wide ( > 0.12 seconds); ≥ 3 consecutive; distorted shape: may be monomorphic/polymorphic ▪ T-waves: large; polarity may be opposite of major QRS deflection; may be difficult to distinguish

TREATMENT MEDICATIONS

▪ Chronic prevention ▫ Beta blockers, amiodarone, nondihydropyridine calcium channel blockers

OTHER INTERVENTIONS

▪ Acute treatment ▫ Cardioversion ▪ Drug cardioversion ▫ Procainamide, lidocaine, amiodarone frequently used ▪ Electrical cardioversion ▫ Primary treatment for VT associated with hemodynamic instability/when drug cardioversion not immediately available ▪ Radiofrequency catheter ablation ▪ ICD

OSMOSIS.ORG 193

NOTES

NOTES

BILIARY TRACT DISEASES GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Diverse spectrum of diseases affecting biliary system (gallbladder, bile ducts, liver) ▪ Bile stored in gallbladder → stasis/chemical constituents change → precipitate to solid stone → travel down biliary tract → obstruction → decreased bile drainage → symptoms

SIGNS & SYMPTOMS ▪ Symptoms vary, based on location ▫ Pain, jaundice, infection, inflammatory response, sepsis ▪ Right upper quadrant (RUQ) epigastric pain ▪ Jaundice ▪ Nausea, vomiting ▪ Fever, chills → sepsis

DIAGNOSIS DIAGNOSTIC IMAGING

Magnetic resonance cholangiopancreatography (MRCP) ▪ MRI for detailed images of hepatobiliary, pancreatic systems Endoscopic retrograde cholangiopancreatography (ERCP) ▪ Down esophagus, stomach, duodenum, ducts → contrast medium injected into ducts → X-ray shows narrow areas/ blockages ▫ Complications: pancreatitis (most common); intraluminal/intraductal bleeding, hematomas; perforation; infection (cholangitis, cholecystitis); cardiopulmonary complications (cardiac arrhythmia, hypoxemia, aspiration)

LAB RESULTS ▪ See table

TREATMENT MEDICATIONS ▪ Antibiotics

CT scan/ultrasound ▪ Locations of stones, gallbladder wall thickening/inflammation

SURGERY

X-ray ▪ Pigmented gallbladder stones (radiopaque)

OTHER INTERVENTIONS

194 OSMOSIS.ORG

▪ Cholecystectomy

▪ Sepsis management, biliary drainage, ERCP

Chapter 28 Biliary Tract Diseases

ASCENDING CHOLANGITIS osms.it/ascending-cholangitis PATHOLOGY & CAUSES ▪ Acute infection of bile duct caused by intestinal bacteria ascending from duodenum ▪ Bacterial infection of bile duct superimposed on obstruction of biliary tree; due to choledocholithiasis ▪ Gallstones form in gallbladder → slip out → travel through cystic bile duct, lodge in common bile duct → obstruction of normal bile flow → bacteria ascend from duodenum to bile duct → infect stagnant bile, surrounding tissue

▪ Common bacteria: E. coli, Klebsiella, Enterobacter, Enterococcus ▪ Medical emergency

RISK FACTORS

▪ Gallstones (most common) ▪ Stenosis of bile duct due to neoplasm/injury from laparoscopic procedure

OSMOSIS.ORG 195

COMPLICATIONS

▪ Sepsis, septic shock ▫ High pressure on bile duct → obstruction → cells lining ducts widen → bacteria, bile enter bloodstream ▪ Multiorgan failure

LAB RESULTS

▪ Assess infection, jaundice ▫ Increased WBC ▫ Increased serum C-reactive protein (CRP) ▫ Elevated LFTs: ALP, GGT, ALT, AST

SIGNS & SYMPTOMS ▪ Charcot’s triad ▫ RUQ pain, jaundice, fever/chills ▪ Reynold’s pentad ▫ Charcot’s triad + hypotension/shock, altered consciousness ▫ Associated with significant morbidity, mortality

DIAGNOSIS DIAGNOSTIC IMAGING Ultrasound, ERCP ▪ Biliary dilation ▪ Bile duct wall thickening ▪ Evidence of etiology (stricture/stone/stent)

TREATMENT MEDICATIONS

▪ Antibiotics + IV fluids

SURGERY

▪ Cholecystectomy ▫ Avoid future complications

OTHER INTERVENTIONS

▪ ERCP ▫ Removes gallstones ▪ Shockwave lithotripsy ▫ High frequency sound waves break down stone ▪ Stent ▫ Widen bile ducts in areas of stricture

Figure 28.1 The pathophysiology of ascending cholangitis.

196 OSMOSIS.ORG

Chapter 28 Biliary Tract Diseases

BILIARY COLIC osms.it/biliary-colic PATHOLOGY & CAUSES ▪ AKA “gallbladder attack” ▪ Gallstones lodged in bile ducts → temporary severe abdominal pain ▪ After meal, gallbladder contracts → gallstone ejected into cystic duct, lodged → gallbladder contracts against lodged stone → severe abdominal pain ▪ Pain subsides when gallstone dislodged

CAUSES ▪ ▪ ▪ ▪ ▪

Gallstones Narrow bile duct Pancreatitis Duodenitis Esophageal spasms

RISK FACTORS

▪ More common in individuals who are biologically female ▪ Obesity ▪ Pregnancy ▪ Age ≥ 40

COMPLICATIONS

▪ Acute cholecystitis ▫ Inflammation of gallbladder wall ▫ Gallstone doesn’t dislodge from cystic duct

SIGNS & SYMPTOMS ▪ Pain ▫ Severe right upper quandrant pain; radiates to right shoulder/shoulder blades ▫ Intensity increases for 15 minutes, plateaus for few hours (< six), subsides ▫ Starts hours after meal/at night/laying flat ▪ Nausea, vomiting, anorexia

DIAGNOSIS ▪ Recurrent symptoms

DIAGNOSTIC IMAGING Ultrasound ▪ Confirmation of obstruction X-ray, CT scan, MRI

TREATMENT SURGERY

▪ Cholecystectomy ▫ Gallbladder removal ▫ Definitive

OTHER INTERVENTIONS ▪ Pain, symptom management

OSMOSIS.ORG 197

CHOLECYSTITIS (ACUTE) osms.it/acute-cholecystitis PATHOLOGY & CAUSES ▪ Stone lodged in cystic duct/common bile duct → acute inflammation → pain ▫ 90% of acute cholecystitis resolves within month as stone dislodges ▪ Fatty meal → small intestine cholecystokinin (CCK) signals gallbladder to secrete bile → gallbladder contracts → stone lodged in cystic duct → blocks bile flow → irritates mucosa → mucosa secretes mucus, inflammatory enzymes → inflammation, distention, pressure ▪ Cholesterol stones ▫ More potent ability to stimulate inflammation compared to pigment gallstones ▪ Possible progressions ▫ Stone ejected out of cystic duct → cholecystitis subsides, symptoms subside ▫ Stone remains in place → pressure builds → pushes down on blood vessels supplying gallbladder → ischemia → gangrenous cell death → gallbladder walls weaken → perforation/rupture → bacteria seeds to bloodstream → sepsis → medical emergency ▫ Stone lodged in common bile duct → blocks flow of bile out of liver ▪ Bacterial growth (cholangitis) ▫ Cholelithiasis → stone descends to cystic duct → cholecystitis → stone descends from cystic duct, lodges in common bile duct → choledolithiasis → secondary infection due to obstruction → cholangitis ▫ Most commonly E. coli, Enterococci, Bacterioides fragilis, Clostridium

198 OSMOSIS.ORG

Acalculous cholecystitis ▪ Acute inflammation of gallbladder without gallstones/cystic duct obstruction; high morbidity, mortality rate ▪ 5–10% of acute cholecystitis cases ▪ Rare, difficult to diagnose ▪ Multifactorial etiology ▪ Often occurs in critically ill individuals/ following major surgery ▪ Pathogenesis ▫ Gallbladder ischemia, reperfusion injury ▫ Bacterial invasion of ischemic tissue

COMPLICATIONS

▪ Biliary peritonitis (from rupture) ▪ Gallbladder ischemia → rupture → sepsis ▪ Acalculous cholecystitis

Figure 28.2 A CT scan in the coronal plane demonstrating a thickened, oedematous gallbladder, indicative of acute cholecystitis.

Chapter 28 Biliary Tract Diseases

SIGNS & SYMPTOMS ▪ Midepigastric pain → dull right upper quadrant pain radiates to right scapula/ shoulders (esp. after a meal in chronic cholecystitis) ▪ Hypoactive bowel sounds; nausea, vomiting, anorexia; jaundice; low grade fever ▪ Blumberg’s sign/rebound tenderness ▫ RUQ pain when pressure rapidly released from abdomen; peritonitis (secondary to gallbladder perforation/ rupture) ▪ Positive Murphy’s sign ▫ Sudden cessation of inhalation due to pain when inflamed gallbladder reaches examiner’s fingers ▫ Examiner asks individual to exhale → places hand below right costal margin in midclavicular line → individual instructed to breathe in → cessation due to pain ▫ Differentiates cholecystitis from other causes of right upper quadrant pain

Diffusion-weighted MRI ▪ Differentiate between acute, chronic cholecystitis Ultrasound ▪ Gallstones/sludge ▫ Gallbladder wall thickening, distention ▫ Air in gallbladder wall (gangrenous cholecystitis) ▫ Pericholecystic fluid from perforation/ exudate

LAB RESULTS

▪ Elevated ALP ▫ Concentrated in liver, bile ducts ▫ Bile backs up, pressure in ducts increase → cells damaged, die → ALP released ▪ Elevated leukocyte count

TREATMENT MEDICATIONS ▪ Antimicrobials

SURGERY

DIAGNOSIS

▪ Cholecystectomy

DIAGNOSTIC IMAGING Cholescintigraphy/hepatic iminodiacetic acid (HIDA) scan ▪ Radioactive tracer injected into individual → marked HIDA taken up by hepatocytes, excreted in bile → drains down hepatic ducts ▪ Location of blockage

OSMOSIS.ORG 199

CHOLECYSTITIS (CHRONIC) osms.it/chronic-cholecystitis PATHOLOGY & CAUSES ▪ Obstruction of cystic duct (not infection) → inflammation of gallbladder wall ▪ Constant state of inflammation due to gallstones repeatedly blocking ducts ▫ Changes gallbladder mucosa → deep grooves (Rokatansky–Aschoff sinus) ▫ Pain esp. after meal; gallbladder attempts to secrete bile to small intestine for digestion ▪ Fatty meal → small intestine cholecystokinin (CCK) signals gallbladder to secrete bile → gallbladder contracts → stone lodged in cystic duct → blocks bile flow → irritates mucosa → mucosa secretes mucus, inflammatory enzymes → inflammation, distention, pressure ▪ Cholesterol stones ▫ More potent ability to stimulate inflammation compared to pigment gallstones ▪ Possible progressions ▫ Stone ejected out of cystic duct → cholecystitis subsides, symptoms subside ▫ Stone remains in place → pressure builds → pushes down on blood vessels supplying gallbladder → ischemia → gangrenous cell death → gallbladder walls weaken → perforation/rupture → bacteria seeds to bloodstream → sepsis → medical emergency ▫ Stone lodged in common bile duct → blocks flow of bile out of liver ▪ Bacterial growth (cholangitis) ▫ Cholelithiasis → stone descends to cystic duct → cholecystitis → stone descends from cystic duct, lodges in common bile duct → choledolithiasis → secondary infection due to obstruction → cholangitis ▫ Most commonly E. coli, Enterococci, Bacterioides fragilis, Clostridium

200 OSMOSIS.ORG

COMPLICATIONS

▪ Biliary peritonitis (from rupture) ▪ Gallbladder ischemia → rupture → sepsis ▪ Porcelain gallbladder (chronic cholecystitis) ▫ Chronic state of inflammation → epithelial fibrosis, calcification ▫ Bluish discoloration of gallbladder; becomes hard, brittle ▫ Bile stasis → calcium carbonate bile salts to precipitate out → deposit into walls ▫ Increased risk of gallbladder cancer ▪ Acalculous cholecystitis

SIGNS & SYMPTOMS ▪ Midepigastric pain → dull right upper quadrant pain radiates to right scapula/ shoulders (esp. after a meal in chronic cholecystitis) ▪ Hypoactive bowel sounds; nausea, vomiting, anorexia; jaundice; low grade fever ▪ Blumberg’s sign/rebound tenderness ▫ Right upper quadrant pain when pressure rapidly released from abdomen; peritonitis (secondary to gallbladder perforation/rupture) ▪ Positive Murphy’s sign ▫ Sudden cessation of inhalation due to pain when inflamed gallbladder reaches examiner’s fingers ▫ Examiner asks individual to exhale → places hand below right costal margin in midclavicular line → individual instructed to breathe in → cessation due to pain ▫ Differentiates cholecystitis from other causes of right upper quadrant pain

Chapter 28 Biliary Tract Diseases

DIAGNOSIS DIAGNOSTIC IMAGING Cholescintigraphy/hepatic iminodiacetic acid (HIDA) scan ▪ Radioactive tracer injected into individual → marked HIDA taken up by hepatocytes, excreted in bile → drains down hepatic ducts ▪ Location of blockage Diffusion-weighted MRI ▪ Differentiate between acute, chronic cholecystitis Ultrasound ▪ Gallstones/sludge ▫ Gallbladder wall thickening, distention ▫ Air in gallbladder wall (gangrenous cholecystitis) ▫ Pericholecystic fluid from perforation/ exudate

Figure 28.3 Endoscopic retrograde cholangiopancreatography demonstrating gallstones in the cystic duct.

LAB RESULTS

▪ Elevated ALP: concentrated in liver, bile ducts ▫ Bile backs up, pressure in ducts increase → cells damaged, die → ALP released ▪ Elevated leukocyte count

TREATMENT MEDICATIONS ▪ Antimicrobials

Figure 28.4 Histological appearance of cholestasis in the liver. There is build up of bile pigment in the hepatic parenchyma.

SURGERY

▪ Cholecystectomy

OSMOSIS.ORG 201

202 OSMOSIS.ORG

Chapter 28 Biliary Tract Diseases

GALLSTONE osms.it/gallstone PATHOLOGY & CAUSES ▪ Solid stones inside gallbladder composed of bile components ▪ Form based on imbalance of chemical constituents → precipitate out to form solid stone

TYPES

▪ Categorized by location (choledocholithiasis, cholelithiasis) or major composition (cholesterol, bilirubin stones)

Choledocholithiasis ▪ Gallstones in common bile duct → obstruction of outflow tract ▫ Stasis, infection (primary cause) ▫ Affects liver function; may cause liver damage Cholelithiasis ▪ Gallstones in gallbladder ▫ Primary cause: imbalance of bile components ▫ Bile flow out of liver not obstructed; liver function not affected Cholesterol stones ▪ Most common, 80% ▪ Composed primarily of cholesterol ▪ Cholesterol precipitation out of bile: supersaturation; inadequate salts/acids/ phospholipids; gallbladder stasis ▪ Radiolucent (not visible on X-ray) Bilirubin stones (pigmented stones) ▪ Composed primarily of unconjugated bilirubin ▫ Formed from nonbacterial, nonenzymatic hydrolysis of conjugated bilirubin ▪ Occurs when too much bilirubin in bile ▪ Combines with calcium → solid calcium bilirubinate

Figure 28.5 Cholesterol gallstones. ▪ Radiopaque (visible on X-ray) ▪ Can be caused by excessive extravascular hemolysis ▫ Extravascular hemolysis → macrophages consume RBCs → increased unconjugated bilirubin production → too much unconjugated bilirubin for liver to conjugate → unconjugated bilirubin binds to calcium instead of bile salts → precipitate out to form black pigmented stones ▪ Brown pigmented gallstone: gallbladder/ biliary tract infection ▫ Stones enter common bile duct ▫ Brown pigment due to unconjugated/ hydrolyzed bilirubin, phospholipids: infectious organism brings hydrolytic enzymes → hydrolysis of conjugated bilirubin, phospholipids → combine with calcium ions → precipitate out to form stones ▫ Common infections: E. coli, Ascaris lumbricoides, Clonorchis sinensis (trematode endemic to China, Korea, Vietnam) ▫ Commonly seen in Asian populations

OSMOSIS.ORG 203

RISK FACTORS

▪ More common in individuals who are biologically female, who use oral contraceptive ▫ ↑ estrogen → ↑ cholesterol in bile + bile hypomotility → ↑ risk of gallstones ▪ Obesity ▪ Rapid weight loss ▫ Imbalance in bile composition → ↑ risk of calcium-bilirubin precipitation ▪ Total parenteral nutrition (prolonged)

COMPLICATIONS ▪ ▪ ▪ ▪

Cholecystitis (inflammation of gallbladder) Ascending cholangitis Blockage of common, pancreatic bile ducts Gallbladder cancer: history of gallstones → ↑ risk of gallbladder cancer

DIAGNOSIS DIAGNOSTIC IMAGING Ultrasound, CT scan, X-ray, ERCP ▪ Visualize stones

LAB RESULTS

▪ Elevated bilirubin levels ▪ Liver function tests (LFTs) ▫ Elevated gamma-glutamyl transferase (GGT), alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate transaminase (AST)

SIGNS & SYMPTOMS ▪ May be asymptomatic ▪ Sudden, intense abdominal epigastric/ substernal pain; radiates to right shoulder/ shoulder blades ▪ Nausea/vomiting; jaundice; abdominal tenderness, distension; fever, chills; flatulence, belching ▪ See mnemonic for summary

MNEMONIC: 6 Fs

Typical clinical presentation of an individual with gallstones Fat Female Fertile Forty Fatty food intolerance Flatulence

204 OSMOSIS.ORG

Figure 28.6 Abdominal ultrasound demonstrating cholelithiasis. The gallstones cast an acoustic shadow.

TREATMENT ▪ Necessary only if symptomatic

MEDICATIONS

▪ Bile salts ▫ Dissolve cholesterol stones

Chapter 28 Biliary Tract Diseases

SURGERY

▪ Cholecystectomy

OTHER INTERVENTIONS

▪ Pain management ▪ Shock wave therapy (lithotripsy) ▫ High-frequency sound waves fragment stones

Figure 28.7 Numerous gallstones, of mixedtype, in a cholecystectomy specimen. The wall of the gallbladder is thickened and fibrotic, consistent with long-standing disease.

PRIMARY SCLEROSING CHOLANGITIS (PSC) osms.it/primary-sclerosing-cholangitis PATHOLOGY & CAUSES ▪ Autoimmune disorder in which T-cells attack, destroy bile duct epithelial cells in genetically predisposed individuals exposed to environmental stimuli ▫ HLA-B8, HLA-DR3, HLA-DRw52a ▪ Associated with ulcerative colitis, Crohn’s disease ▪ Sclerosis, inflammation of intra-, extrahepatic ducts ▪ Cells around bile ducts inflamed, die → fibrose ▪ Death of epithelial cells lining bile ducts → bile leaks into interstitial space, bloodstream ▪ “Beaded” appearance of bile ducts ▫ Stenosis of affected ducts, dilation of unaffected ducts ▪ Severity depends on bilirubin levels, encephalopathy, presence/absence of ascites, serum albumin level, prothrombin time

COMPLICATIONS

▪ Portal hypertension ▫ Fibrosis builds around bile ducts → constricts portal veins → ↑ pressure ▪ Hepatosplenomegaly ▫ Portal hypertension → backup of fluid, enlargement of spleen, liver ▪ Cirrhosis ▫ Recurrent cycle of inflammation, healing → tissue scarring → fibrosis ▪ ↑ risk of cholangiocarcinoma, gallbladder cancer, hepatocellular carcinoma

SIGNS & SYMPTOMS ▪ May remit, recur spontaneously ▪ Jaundice, RUQ pain, weight loss, pruritus (deposition of bile salts, acids in skin), hepatosplenomegaly ▪ Liver failure ▫ Ascites, muscle atrophy, spider angiomas, increased clotting time, dark urine, pale stool

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DIAGNOSIS DIAGNOSTIC IMAGING MRCP ▪ Intrahepatic and/or extrahepatic bile duct dilation; multifocal or diffuse strictures ERCP ▪ Intrahepatic and/or extrahepatic bile duct dilation; multifocal or diffuse strictures

LAB RESULTS

▪ Liver function tests (LFTs) ▫ Elevated conjugated bilirubin, ALP, GGT ▪ Elevated serum IgM antibody, p-ANCA (targets antigens in cytoplasm/nucleus of neutrophils; 80% of individuals with PSC) ▪ Bilirubinuria ▪ Liver biopsy ▫ Stage disease, predict prognosis

Figure 28.8 Cholangiogram demonstrating multiple biliary strictures in a case of primary sclerosing cholangitis.

OTHER DIAGNOSTICS

▪ Histology ▫ “Onion-skin fibrosis”: concentric rings of fibrosis around bile duct, resembles onion skin

TREATMENT ▪ No effective treatment

MEDICATIONS

▪ Treat symptoms, manage complications, not curative (e.g. antibiotics) ▪ Immunosuppressants, chelators, steroids

SURGERY

▪ Liver transplant ▫ Advanced liver disease

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Figure 28.9 Histological appearance of primary sclerosing cholangitis. There is onion-skin fibrosis of the biliary ducts.

NOTES

NOTES

COLORECTAL POLYP CONDITIONS

GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Colorectal polyps: overgrowths of epithelial cells lining colon/rectum ▪ Usually benign, can turn malignant

TYPES Adenomatous polyps/colonic adenomas ▪ Gland-like polyps caused by tumor suppressor gene mutation in adenomatous polyposis coli (APC) ▪ Characterized by accelerated division of epithelial cells → epithelial dysplasia → polyp formation ▪ No malignant potential by itself; requires mutations in other tumor suppressants (KRAS, p53) ▪ Histologic classification ▫ Tubular: pedunculated polyp, protrudes out in lumen ▫ Villous: sessile, cauliflower-like appearance; more often malignant ▫ Tubulovillous: characteristics of tubular, villous polyps Serrated polyps ▪ Saw-tooth appearance microscopically ▪ Contain methylated CpG islands → silencing of DNA-repair genes, others → more mutations → malignancy ▫ Small polyps (most common): AKA hyperplastic polyps; rarely malignant ▫ Large polyps: often flat, sessile, malignant Hamartomatous polyps ▪ Mixture of tissues; disorganized mass containing tissue found at site of polyp ▪ Occur sporadically/in genetically inherited conditions (Juvenile polyposis, Peutz– Jeghers syndrome)

Inflammatory polyps ▪ Caused by inflammatory bowel diseases ▫ Crohn’s disease, ulcerative colitis ▪ Not malignant

CAUSES

▪ Genetic mutations ▪ Inflammatory conditions (e.g. Crohn’s disease)

RISK FACTORS

▪ Family history ▪ Bowel wall injury (e.g. radiation exposure, smoking, inflammatory bowel disease) ▪ Risk increases with age

COMPLICATIONS

▪ Malignancy ▫ Depends on degree of dysplasia, size of polyp

SIGNS & SYMPTOMS ▪ Often asymptomatic ▪ If ulcerating ▫ Rectal bleeding, anemia symptoms (e.g. fatigue) ▪ If large ▫ Obstruction → abdominal pain, constipation ▪ Malabsorption → diarrhea ▪ Some polyposis syndromes ▫ Extracolonic symptoms

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DIAGNOSIS

TREATMENT

DIAGNOSTIC IMAGING

SURGERY

CT scan, MRI ▪ Hyperdense outpouchings of colonic wall into lumen; detection of metastases

Polyp removal (polypectomy)

Endoscopy (colonoscopy) with biopsy ▪ Type of polyp, malignant potential (degree of dysplasia)

Colonic resection (colectomy) ▪ If multiple polyps associated with polyposis syndromes/polyps with high-grade dysplasia

LAB RESULTS

▪ Iron-deficiency anemia → decreased red blood cell (RBC) count, low mean corpuscular volume (MCV) levels ▪ Iron-deficiency anemia → low ferritin, serum iron, transferrin saturation ▪ APC, RAS, etc. mutations ▪ Assess asymptomatic family members for risk

OTHER DIAGNOSTICS Digital rectal examination ▪ Detection of distal rectal polyps; malignant polyp, hard, irregular; benign polyps, softer, pliable

Figure 29.2 Histological appearance of a villous adenoma, characterised by a surface composed of long villous projections.

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Figure 29.1 The gross pathological appearance of a sessile colorectal polyp.

Figure 29.3 The histological appearance of a tubular adenoma composed of compact glands with variable levels of dysplasia.

Chapter 29 Colorectal Polyp Conditions

FAMILIAL ADENOMATOUS POLYPOSIS (FAP) osms.it/familial-adenomatous-polyposis PATHOLOGY & CAUSES ▪ Inherited condition; hundreds/thousands adenomatous polyps in colon ▪ Autosomal dominant inheritance; 100% penetrance; de novo mutations may occur

TYPES Classic FAP ▪ Most aggressive, frequent; > 100 polyps at diagnosis; early onset Attenuated FAP (AFAP) ▪ < 100 polyps at diagnosis (oligopolyposis); later onset Autosomal recessive FAP

CAUSES

▪ Germline mutation in APC gene (tumor suppressor) → prevention of apoptosis → cell overgrowth → polyps ▪ APC gene nonfunctional in FAP; slightly impaired in AFAP ▪ Autosomal recessive FAP ▫ Mutations of MUTYH gene on chromosome 1

RISK FACTORS ▪ Family history

COMPLICATIONS

▪ Malignancy if untreated ▪ Extracolonic manifestations ▫ Congenital hypertrophy of retinal pigment epithelium (CHRPE) ▫ Fundic gland polyps: sessile polyps in stomach, usually not malignant ▫ Duodenal adenomas: malignant potential

▫ Abdominal mesenchymal desmoid tumors: compress adjacent structures → obstruction/vascular impairment ▫ Other potential malignancies: thyroid, pancreas, brain (glioma), liver (hepatoblastoma)

SIGNS & SYMPTOMS ▪ Usually asymptomatic until malignancy ▪ Colonic manifestations ▫ Palpable abdominal mass; hematochezia (rectal bleeding); pain (esp. abdomen); diarrhea

DIAGNOSIS DIAGNOSTIC IMAGING Endoscopy with biopsy Colonoscopy, flexible sigmoidoscopy: ▪ Detection of ≥ 100 polyps; ~30 polys, AFAP Esophagogastroduodenoscopy (EGD) ▪ Gastric, duodenal adenomas Barium enema (with double contrast) ▪ Filling defects Abdominal CT scan ▪ Hyperdense outpouchings of colonic wall into lumen

LAB RESULTS

▪ Iron-deficiency anemia ▪ ↓ RBC, ↓ MCV ▪ ↓ ferritin, ↓ serum iron, ↓ transferrin saturation ▪ APC mutations

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OTHER DIAGNOSTICS Family history ▪ Cancers, gastrointestinal (GI) tract diseases Digital rectal examination ▪ Palpable mass Ophthalmic examination ▪ CHRPE

TREATMENT MEDICATIONS

▪ Cyclooxygenase 2 inhibitors, other nonsteroidal anti-inflammatory drugs (NSAIDs) ▪ Epidermal growth factor receptor inhibitor: erlotinib ▪ Chemotherapy, if colon cancer

SURGERY

▪ Frequent endoscopic check-ups to detect onset of polyposis every 1–2 years ▫ If polyps detected → surgical removal (colectomy; proctocolectomy)

Figure 29.4 Endoscopic appearannce of the colon in a case of familial adenomatous polyposis. Figure 29.5 A retinal photograph demonstrating hypertrophy of the retinal pigment epithelium in a case of familial adenomatous polyposis.

GARDNER'S SYNDROME (GS) osms.it/gardners-syndrome PATHOLOGY & CAUSES ▪ Variant of FAP with prominent extracolonic manifestations ▪ Inherited condition; numerous adenomatous polyps in colon; extracolonic polyps, tumors

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▪ Tumors outside colon ▫ Fibromas, lipomas, epidermoid cysts, thyroid neoplasms, osteomas, desmoid ▪ Extracolonic polyps can arise in stomach, duodenum, spleen, kidneys, liver, mesentery, small bowel; CHRPE lesions

Chapter 29 Colorectal Polyp Conditions

CAUSES

▪ APC, RAS, TP53 mutation; DCC deletion → furthers carcinogenesis ▪ Autosomal dominant inheritance

COMPLICATIONS

▪ Malignancy in colon, thyroid, liver, kidneys

SIGNS & SYMPTOMS ▪ Colonic manifestations ▫ Rectal bleeding, diarrhea ▪ Extracolonic manifestations ▫ Desmoid tumors (parietal bumps, bleeding) ▫ Dental problems ▫ Epidermoid cysts ▫ Epigastric pain, bleeding, jaundice ▫ Malnutrition → malaise, lethargy, fatigue

DIAGNOSIS

▪ Supernumerary impacted teeth ▪ Multiple jaw osteomas, odontomas Digital rectal examination ▪ Palpable mass Ophthalmic examination ▪ CHRPE ECG ▪ Stomach, duodenum for polyps

TREATMENT ▪ No cure; palliative treatment

SURGERY

▪ Excision of tumors/polyps with wide (8mm) margin ▪ Colectomy

OTHER INTERVENTIONS ▪ Radiotherapy, if recurrent

DIAGNOSTIC IMAGING Endoscopy with biopsy Colonoscopy, flexible sigmoidoscopy ▪ Direct visualization of adenomatous polyps in colon Abdominal CT scan ▪ Hyperdense outpouchings of colonic wall into lumen Head/dental X-ray ▪ Dental abnormalities

LAB RESULTS

▪ Iron-deficiency anemia ▫ ↓ RBC, ↓ MCV ▫ ↓ ferritin, ↓ serum iron, ↓ transferrin saturation ▪ Tumoral markers (e.g. carcinoembryonic antigen) ▪ APC, RAS, TP53 mutations; DCC deletion

OTHER DIAGNOSTICS Physical examination

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JUVENILE POLYPOSIS SYNDROME osms.it/juvenile-polyposis PATHOLOGY & CAUSES ▪ Numerous benign (AKA juvenile) polyps along GI tract ▪ Majority non-neoplastic hamartomas polyps, in colorectum

CAUSES

▪ BMPR1A, SMAD4 mutations ▪ Autosomal dominant inheritance; incomplete penetrance ▪ De novo mutations (25%)

COMPLICATIONS

▪ Increased risk of colorectal/extracolonic adenocarcinoma; intestinal obstruction

SIGNS & SYMPTOMS ▪ Hematochezia, anemia symptoms; abdominal pain; diarrhea/constipation; rectal prolapse

DIAGNOSIS DIAGNOSTIC IMAGING Endoscopic studies ▪ E.g. endoscopy, colonoscopy, sigmoidoscopy ▪ Criteria for diagnosis ▫ > five juvenile polyps in colon/rectum ▫ Multiple juvenile polyps in other areas of GI tract ▫ Family history with any number of polyps ▪ Biopsy, cytology

LAB RESULTS

▪ Iron-deficiency anemia ▫ ↓ RBC, ↓ MCV ▫ ↓ ferritin, ↓ serum iron, ↓ transferrin saturation ▪ BMPR1A, SMAD4 mutations

TREATMENT SURGERY

▪ Polypectomy ▪ Surgical colectomy, proctocolectomy ▫ Malignant, ulcerating polyps

Figure 29.6 A juvenile retention polyp with abundant edematous stroma and dilated cystic spaces filled with mucin. The spaces are lined by cuboidal epithelium.

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Chapter 29 Colorectal Polyp Conditions

PEUTZ–JEGHERS SYNDROME (PJS) osms.it/peutz-jeghers PATHOLOGY & CAUSES ▪ Inherited condition; benign hamartomatous polyps, in small bowel; also in colon, stomach ▪ Associated with hyperpigmented (melanincontaining) macules on skin, mucosa

CAUSES

▪ IV drug use ▫ Increases likelihood of infective endocarditis ▪ Congenital bicuspid aortic valve ▪ Diabetes, high blood pressure, smoking

COMPLICATIONS

▪ Very high risk of extracolonic malignant transformation ▫ Breast, ovarian, cervical, testicular, pancreatic, thyroid cancer ▪ Mild malignant potential of polyps

SIGNS & SYMPTOMS ▪ GI ▫ Ulceration → GI bleeding (hematochezia/melena) → symptoms of anemia ▫ Colicky abdominal pain ▫ Intussusception → bowel obstruction, bowel infarction ▫ Diarrhea, constipation ▪ Pigmented lesions around oral mucosa, nostrils, perianal area of extremities; fade after puberty

DIAGNOSIS DIAGNOSTIC IMAGING Endoscopy, colonoscopy, with biopsy Capsule endoscopy Abdominal CT scan ▪ Hyperdense outpouchings of colonic wall into lumen

LAB RESULTS

▪ Fecal occult blood test ▪ Iron-deficiency anemia ▫ ↓ RBC, ↓ MCV ▫ ↓ ferritin, ↓ serum iron, ↓ transferrin saturation ▪ Tumor markers ▫ CEA, CA-19-9, CA-125 ▪ STK11 (LKB1) mutations

OTHER DIAGNOSTICS Diagnostic criteria ▪ One of following ▫ ≥ two PJ polyps confirmed histologically ▫ ≥ one PJ polyp with family history ▫ PJS-associated mucocutaneous pigmentations Digital rectal examination ▪ Palpable mass

TREATMENT SURGERY

▪ Polypectomy

MEDICATIONS

▪ Cyclooxygenase 2 inhibitors (celecoxib)

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Figure 29.7 Histological appearance of a Peutz-Jegher’s polyp.

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Figure 29.8 Multiple melanotic macules on the skin and oral mucosa of a young boy with Peutz-Jegher’s syndrome.

NOTES

NOTES

ESOPHAGEAL DISEASE GENERALLY, WHAT IS IT? PATHOLOGY & CAUSES ▪ Pathologies of the esophagus ▪ Esophageal motility disorders ▫ Diseases interfering with correct function of esophagus’ various muscular components

DIAGNOSIS ▪ Individual history/clinical features, esophagogastroduodenoscopy (EGD), barium swallow X-ray, esophageal manometry, endoscopic biopsy

TREATMENT

CAUSES

▪ Infections, autoimmune disease, anatomical defects, irritative processes

▪ See individual diseases

SIGNS & SYMPTOMS ▪ Difficulty/pain while swallowing, especially spasm-type pain ▪ Difficulty with food regurgitation

ACHALASIA osms.it/achalasia PATHOLOGY & CAUSES ▪ Esophageal smooth muscle fibres fail to relax → lower esophageal sphincter remains closed/fails to open ▪ AKA esophageal achalasia, achalasia cardiae, cardiospasm, esophageal aperistalsis ▪ Progressive degeneration of ganglion cells in myenteric plexus within esophageal wall → lower esophageal sphincter fails to relax → loss of peristalsis in distal esophagus ▪ Involves smooth muscle layer of esophageal, lower esophageal sphincters

▪ Affected individual lacks nonadrenergic, noncholinergic, inhibitory ganglion cells → imbalanced excitation and relaxation → incomplete lower esophageal sphincter relaxation, increased lower esophageal tone, lack of esophageal peristalsis

CAUSES

▪ Likely caused by underlying autoimmune process triggered by previous viral infection/ genetic predisposition/ neurodegenerative disease/other infective process

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Primary achalasia (most common) ▪ No known underlying cause → failure of distal esophageal inhibitory neurons Secondary achalasia ▪ Esophageal cancer ▪ Chagas disease ▫ Protozoan infection due to Trypanosoma cruzi → loss of intramural ganglion cells → aperistalsis, incomplete lower esophageal sphincter relaxation

SIGNS & SYMPTOMS ▪ Dysphagia to solids/liquids, odynophagia (rarely), heartburn unresponsive to proton pump inhibitor therapy, symptoms worsen progressivelys, regurgitation of undigested food, substernal chest pain, hiccups ▪ Weight loss ▪ Coughing while lying horizontally, aspiration of food → recurrent pulmonary complications

DIAGNOSIS DIAGNOSTIC IMAGING Barium swallow X-ray and continuous fluoroscopy ▪ Normal peristalsis not seen ▪ Acute tapering at lower esophageal sphincter ▪ Narrowing of gastroesophageal junction (bird’s beak/rat’s tail appearance) ▪ Dilated esophagus above narrowing ▪ Air-fluid margin over barium column due to lack of peristalsis Esophageal endoscopy with or without endoscopic ultrasound ▪ May appear normal ▪ Unusually increased resistance to passage of endoscope through esophagogastric junction ▪ Retained food in esophagus on upper endoscopy

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Endoscopic biopsy ▪ Hypertrophic musculature ▪ Absence of specific nerve cells within myenteric plexus

OTHER DIAGNOSTICS Esophageal manometry ▪ Lower esophageal sphincter fails to relax upon wet swallow (< 75% relaxation) ▪ Lower esophageal pressure ▫ Normal < 26mmHg ▫ Achalasia > 100mmHg ▫ Nutcracker achalasia > 200mmHg ▪ Aperistalsis in esophageal body ▪ Relative increase in intraesophageal pressure vs. intragastric pressure

TREATMENT MEDICATIONS

▪ Calcium channel blockers for mild to moderate disease ▪ Nitrates effective before dilatation occurs ▪ Antimuscarinic agents (rarely effective) ▪ Proton pump inhibitors (after surgery/ pneumatic dilatation) to prevent reflux damage

SURGERY Laparoscopic Heller myotomy ▪ Esophageal dilatation via surgical cleaving of muscle ▪ Only cut through outer muscle layers (those failing to relax), leaving inner mucosal layer intact Endoscopic myotomy ▪ Peroral endoscopic myotomy, minimally invasive → incision made through esophageal mucosa, innermost circular muscle layer divided and extended through lower esophageal sphincter, 2cm/0.8in into gastric muscle

Chapter 30 Esophageal Disease

OTHER INTERVENTIONS

▪ Eat slowly, chew well, drink plenty of water with meals, avoid eating near bedtime, raise head off bed when sleeping with pillows (promotes emptying of esophagus with gravity) ▪ Avoid foods that aggravate reflux → ketchup, citrus, chocolate, caffeine

Botox injection ▪ Paralyze muscle keeping lower esophageal sphincter shut (causes scarring of sphincter → may complicate later myotomy) Pneumatic dilatation ▪ Muscle fibres stretched/torn by forceful inflation of balloon placed in lower esophageal sphincter ▪ Lowers basal lower esophageal tone by disruption of muscular ring

Figure 30.1 A barium swallow demonstrating the bird’s beak sign in achalasia. The proximal esophagus is dilated.

BARRETT'S ESOPHAGUS osms.it/barretts-esophagus PATHOLOGY & CAUSES ▪ Premalignant condition; metaplasia of cells lining lower esophagus ▪ Normal stratified squamous epithelium → simple columnar epithelium, goblet cells (usually native to lower gastrointestinal tract) ▪ Chronic acid exposure → reflux esophagitis (chronic irritation) → metaplasia ▪ Bile acids → intestinal differentiation → promotes cancer growth

TYPES

▪ If z-line and gastroesophageal junction coincide → intestinal metaplasia at gastroesophageal junction ▫ Associated with Helicobacter pylori

Long-segment Barrett’s ▪ Distance between z-line and gastroesophageal junction > 3cm/1.2in ▫ Associated with more severe reflux

▫ Upright/supine reflux ▫ Significantly more likely to develop adenocarcinoma Short-segment Barrett’s ▪ Distance between z-line and gastroesophageal junction < 3cm/1.2in ▫ Greater prevalence ▫ Shorter history of heartburn ▫ Usually asymptomatic ▫ Predominantly upright reflux ▫ Less mucosa involved → lower incidence of dysplasia

RISK FACTORS

▪ Bulimia ▪ Central obesity ▪ Previous chemical damage to esophageal epithelium (e.g. swallowing lye) ▪ Smoking ▪ Hiatal hernia

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COMPLICATIONS

TREATMENT

▪ Esophageal adenocarcinoma

SIGNS & SYMPTOMS ▪ Often asymptomatic ▪ Same as reflux, not (initial) cancerous changes ▪ Frequent, prolonged heartburn, dysphagia, hematemesis, epigastric pain, weight loss (due to painful eating)

DIAGNOSIS DIAGNOSTIC IMAGING Esophagogastroduodenoscopy ▪ Fiber optic camera inserted via mouth → examine and biopsy esophagus, stomach, duodenum

LAB RESULTS Biopsy ▪ Specimen from esophagogastroduodenoscopy must contain goblet cells → “intestinal metaplasia” → marker for progression of metaplasia to dysplasia → adenocarcinoma ▪ Immunohistochemical staining assists in diagnosis ▪ Biopsy classification ▫ Nondysplastic ▫ Low-grade dysplasia ▫ High-grade dysplasia ▫ Frank carcinoma

OTHER DIAGNOSTICS Screening ▪ Biological males, > 60 years old, long standing reflux, life expectancy > five years ▪ Anyone with diagnosis of Barrett’s esophagus Esophageal pH studies ▪ Establish efficacy of proton pump inhibitor treatment

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MEDICATIONS Proton pump inhibitors ▪ E.g. omeprazole; manage acid reflux Chemoprevention ▪ Nondysplastic/low-grade lesion ▫ Aspirin, NSAIDS → inhibition of cyclooxygenase (COX-1 & 2) may protect against progression of disease

SURGERY Treatment of dysplastic lesions ▪ Endoscopic mucosal resection, surgical removal of esophagus, radiation therapy, systemic chemotherapy

OTHER INTERVENTIONS Annual endoscopic observation ▪ For nondysplastic/low-grade lesions Management of acid reflux ▪ Avoid/reduce intake of foods known to worsen reflux: chocolate, coffee, tea, peppermint, alcohol, fatty/spicy/acidic foods Treatment of dysplastic lesions ▪ Radiofrequency ablation ▫ Electrical current used to destroy small regions of tissue ▪ Spray cryotherapy ▫ Liquid nitrogen spray applied to small region of tissue → freezing → tissue death ▪ Photodynamic therapy ▫ Chemical photosensitizer → cytotoxicity when stimulated by certain frequency of light

Chapter 30 Esophageal Disease

Figure 30.2 Histological appearance of the squamocolumnar junction in a case of Barrett’s esophagus. The underlying glandular epithelium contains goblet cells, indicating intestinal metaplasia.

BOERHAAVE SYNDROME osms.it/boerhaave-syndrome PATHOLOGY & CAUSES ▪ Rupture through esophagus caused by increased intraesophageal pressure and negative intrathoracic pressure ▪ Vomiting / retching → unrelaxed esophagus, closed glottis → increase in esophageal pressure, slight drop in intrathoracic pressure → spontaneous rupture of esophageal wall → contamination of mediastinum with gastric contents → chemical mediastinitis ▫ Tears commonly occur at left posterolateral aspect (distal esophagus), just above esophageal hiatus of diaphragm ▫ Can be fatal without treatment → sepsis

▫ Chemical mediastinitis → mediastinal necrosis → rupture of overlying pleura → contamination of pleural cavity → pleural effusion ▫ Effort rupture of cervical esophagus → localized cervical perforation ▫ Spread of contamination slow due to attachments of esophagus to prevertebral fascia ▪ Usually occurs in anatomically normal esophagi

RISK FACTORS

▪ Caustic ingestion, pill/medication esophagitis, eosinophilic esophagitis, Barrett’s esophagus, infectious ulcers, stricture dilatation

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SIGNS & SYMPTOMS ▪ Severe vomiting → profound retrosternal chest pain (may radiate to left shoulder) or abdominal pain ▫ Followed by painful swallowing (odynophagia), tachypnea, dyspnea, cyanosis, fever, shock ▪ Mackler’s triad: chest pain, vomiting, subcutaneous emphysema ▪ Hamman’s sign: crunching/rasping sound, synchronous with heartbeat: ▫ Heard over precordium, left lateral position ▫ Caused by mediastinal emphysema ▪ Cervical perforation: neck pain, difficulty swallowing (dysphagia), difficulty speaking (dysphonia), tenderness of sternocleidomastoid ▪ Intra-abdominal perforation: epigastric pain (may radiate to left shoulder), back pain, inability to lie supine, acute abdomen pain

▪ Barium sulfate common contrast material, but spillage into mediastinal and pleural spaces → inflammatory response → fibrosis Endoscopy avoided ▪ May extend tear, introduce air into mediastinum

LAB RESULTS

▪ Hemoglobin and hematocrit ▪ Assess severity of initial bleeding ▪ Pleural effusion fluid may be high in amylase (saliva), low pH ▪ Leukocytosis

DIAGNOSIS ▪ Non-specific symptoms → diagnostic delay, poor outcome ▪ Physical examination often unhelpful; history important

DIAGNOSTIC IMAGING Chest X-ray ▪ Early: free mediastinal air ▪ Hours to days later: pleural effusion, pneumothorax, widened mediastinum, subcutaneous emphysema Chest CT scan ▪ Esophageal wall edema/thickening, extraesophageal air, periesophageal fluid, mediastinal widening, pneumothorax Fluoroscopy ▪ Water soluble contrast (gastrografin) esophagram → location and extent of extravasation of contrast

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Figure 30.3 A contrast swallow in an individual with Boerhaave’s syndrome. The contrast has leaked into and accumulated in the thoracic cavity.

Chapter 30 Esophageal Disease

TREATMENT MEDICATIONS

▪ IV proton pump inhibitor → reduce acidity, irritation ▪ Prophylactic antibiotic therapy

SURGERY

▪ Debride infected/necrotic tissue, repair defect/resection of defect/diversion

OTHER INTERVENTIONS

▪ Parenteral/enteral ( jejunostomy/PEG tube) nutritional support

DIFFUSE ESOPHAGEAL SPASM osms.it/esophageal-spasm PATHOLOGY & CAUSES ▪ Esophageal motility disorder characterized by repetitive, non-peristaltic, spontaneous contractions of the distal esophageal smooth muscle ▪ Sphincter function = normal

CAUSES

▪ Cause relatively unknown ▪ Uncontrolled brain signals and extremely hot/cold beverages can trigger disease

COMPLICATIONS

▪ Leads to difficulty swallowing, impaired advancement of food and/or regurgitation

SIGNS & SYMPTOMS ▪ Intermittent dysphagia ▪ Atypical chest pain that mimics cardiac chest pain; may radiate to jaw, arms, back ▪ Food regurgitation relatively uncommon

DIAGNOSIS DIAGNOSTIC IMAGING Barium swallow x-ray (upper GI) ▪ “Corkscrew” appearance is characteristic Endoscopy ▪ Exclude heart disease, mechanical intraluminal obstruction

OTHER DIAGNOSTICS 24-hour esophageal manometry ▪ Shows uncoordinated esophageal contractions of normal amplitude

TREATMENT ▪ No cure

MEDICATIONS

▪ Nitrates, calcium channel blockers, and/ or botulinum toxin injections to lower esophageal muscle; used to decrease spasms ▪ Antidepressants, anti-anxiety medications

SURGERY

▪ Surgical esophagomyotomy rarely considered

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GASTROESOPHAGEAL REFLUX DISEASE (GERD) osms.it/gastroesophageal-reflux PATHOLOGY & CAUSES ▪ AKA acid reflux ▪ Failure of lower esophageal sphincter → poor closure/inappropriate relaxation (poor tone) of lower esophageal sphincter → stomach contents re-enter esophagus ▪ Commonly associated with decreased esophageal motility, gastric outlet obstruction, hiatal hernia

RISK FACTORS

▪ Obesity, pregnancy, smoking, hiatal hernia ▪ Medications ▫ Antihistamines, calcium channel blockers, antidepressants, hypnotics, glucocorticoids ▪ Zollinger–Ellison syndrome, high blood calcium (increased gastrin production), scleroderma/systemic sclerosis (esophageal dysmotility) ▪ Visceroptosis

COMPLICATIONS

▪ Esophagitis, esophageal strictures, Barrett’s esophagus (premalignant condition), esophageal adenocarcinoma, laryngitis, chronic cough, pulmonary fibrosis, earache, asthma, recurrent pneumonia

SIGNS & SYMPTOMS ▪ Acid taste in mouth, heartburn, retrosternal chest pain, early satiety, regurgitation, odynophagia, increased salivation, postprandial nausea and vomiting, sore throat, sensation of lump in throat, coughing, wheezing

222 OSMOSIS.ORG

▫ Often felt shortly after eating meals (worse after large meals/when lying down) ▪ Halitosis, tooth decay

DIAGNOSIS ▪ Can be diagnosed based on clinical symptoms, history alone

DIAGNOSTIC IMAGING Endoscopy ▪ Used when therapeutic response poor/ concerning symptoms present (dysphagia, anemia, blood in stool, wheezing, weight loss, voice changes) Upper GI series X-rays with barium contrast ▪ Useful to identify complications ▪ Early stages of reflux esophagitis: granular nodular appearance of mucosa in distal third of esophagus with numerous illdefined 1–3mm lucencies ▪ Shallow ulcers and erosions ▫ Collections of barium in distal esophagus near gastroesophageal junction ▫ Identify stricture (tapered area of concentric narrowing in distal esophagus)

LAB RESULTS

▪ 24-hour esophageal pH monitoring in lower esophagus

Chapter 30 Esophageal Disease Biopsy ▪ Edema, basal hyperplasia (non-specific inflammation) ▪ Lymphocytic inflammation (non-specific) ▪ Neutrophilic inflammation (reflux/ Helicobacter gastritis) ▪ Eosinophilic inflammation (usually reflux, if > 20 eosinophils per high-power field extending beyond distal esophagus, more like eosinophilic esophagitis) ▪ Elongation of papillae ▪ Goblet cell intestinal metaplasia ▪ Thinning of squamous cell layer ▪ Dysplasia ▪ Carcinoma

OTHER DIAGNOSTICS

▪ Esophageal manometry (excludes motility disorder) ▪ Short term trial of proton-pump inhibitors

Figure 30.4 The histological appearance of the squamous-lined esophagus in a case of reflux. The papillae become elongated and there is overgrowth of the basal cells (darker blue) known as basal cell hyperplasia.

TREATMENT MEDICATIONS

▪ Antacids neutralise acidity of gastric secretions ▪ H2 receptor blockers decrease acidification of gastric secretions ▪ Proton pump inhibitors decrease acidification of gastric secretions ▪ Prokinetics strengthen lower esophageal sphincter (LES), causing stomach contents to empty faster ▪ Baclofen (GABAB agonist) ▫ Inhibits transient LES relaxations, particularly in postprandial period ▫ Modestly effective, but rarely used due to frequent dosing requirements

Figure 30.5 A contrast X-ray demonstrating gastroesophageal reflux. The contrast medium was injected percutaneously into the stomach and has migrated into the esophagus.

Surface agents and alginates ▪ Sucralfate (aluminium sucrose sulfate) ▫ Adheres to mucosal surface → promotes healing, protects from peptic injury ▪ Sodium alginate ▫ Polysaccharide derived from seaweed → forms a viscous gum that floats within stomach → reduced postprandial acid pocket in proximal stomach

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SURGERY Nissen fundoplication ▪ Upper part of stomach wrapped around lower esophageal sphincter → strengthens sphincter, prevents acid reflux Transoral incisionless fundoplication ▪ Similar procedure to Nissen fundoplication, performed transorally with endoscope LINX reflux management system ▪ Titanium beads with magnetic cores wrapped around weak native lower esophageal sphincter → attractive force between beads closing sphincter → force of peristaltic wave of caused by swallowing can transiently open beads

Figure 30.6 An endoscopic view of an esophageal stricture, a potential consequence of severe, long-standing reflux.

OTHER INTERVENTIONS Lifestyle modifications ▪ Avoid lying down within three hours after eating, wedge pillow when sleeping to elevate head, weight loss, avoid certain foods (coffee, alcohol, chocolate, fatty/ acidic/spicy foods), smoking cessation, moderate exercise

MALLORY–WEISS SYNDROME osms.it/mallory-weiss PATHOLOGY & CAUSES ▪ Severe vomiting → sudden increase in intra-abdominal pressure → partial thickness laceration at gastroesophageal junction → bleeding from mucosa ▪ Also called gastroesophageal laceration syndrome ▪ Laceration known as “Mallory–Weiss tear”, involves mucosa and submucosa, not muscular layer

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CAUSES

▪ Vomiting, straining, coughing, seizures, blunt abdominal injury, nasogastric tube placement, gastroscopy

RISK FACTORS

▪ Alcoholism, bulimia, food poisoning, hiatal hernia, NSAID abuse, biological male sex (80%), hyperemesis gravidarum (severe morning sickness in pregnancy)

Chapter 30 Esophageal Disease

SIGNS & SYMPTOMS

TREATMENT

▪ Hematemesis after episode of violent retching/vomiting ▪ Melena ▪ Bleeding associated symptoms may cease after 24–48 hours ▪ Epigastric, back pain ▪ Signs of hemodynamic instability ▫ Resting tachycardia, hypotension

▪ In absence of comorbidities (esp. portal vein hypertension), significant healing occurs in first 24–48 hours

DIAGNOSIS DIAGNOSTIC IMAGING Endoscopy ▪ Tears appear as red longitudinal breaks in mucosa, may be covered by clot

LAB RESULTS

▪ Hemoglobin, hematocrit (assess severity of initial bleeding)

MEDICATIONS Supportive (persistent bleeding uncommon) ▪ Acid suppression ▫ IV proton pump inhibitor ▪ If nausea and vomiting persistent ▫ Antiemetics

SURGERY Endoscopy (for spurting/oozing tears) ▪ Cauterization, hemoclips (hemostasis of small defects), endoscopic band ligation (with or without epinephrine injection), arterial embolization

Figure 30.7 Endoscopic appearance of a Mallory-Weiss tear.

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PLUMMER–VINSON SYNDROME osms.it/plummer-vinson PATHOLOGY & CAUSES ▪ Triad of iron deficiency anemia, dysphagia, cervical esophageal web ▪ AKA Paterson–Brown–Kelly syndrome, sideropenic dysphagia ▪ Premalignant disease

CAUSES

▪ Exact cause unknown, likely connected to genetic factors, nutritional deficiencies

RISK FACTORS

▪ Postmenopause

COMPLICATIONS

▪ Esophageal/pharyngeal squamous cell carcinoma

DIAGNOSTIC IMAGING Barium esophagography, videofluoroscopy, esophagogastroduodenoscopy ▪ Esophageal web

LAB RESULTS

▪ Anemia ▫ Complete blood cell count, peripheral blood smear, iron study

TREATMENT MEDICATIONS

▪ Iron supplementation, folate, vitamin B12 → correct iron deficiency anemia

SURGERY

▪ Mechanical widening of esophagus

SIGNS & SYMPTOMS ▪ Esophageal signs and symptoms ▫ Esophageal webs, difficult/painful swallowing, Plummer–Vinson syndrome at upper end of esophagus, Schatzki ring lower end of esophagus ▪ Iron deficiency signs and symptoms ▫ Glossitis, cheilosis, angular stomatitis, koilonychia, splenomegaly, dizziness, pallor, dyspnea

DIAGNOSIS ▪ Presence of esophageal web in individual with iron deficiency anemia

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Figure 30.8 An endoscopic view of an esophageal web which is usually associated with Plummer-Vinson syndrome.

Chapter 30 Esophageal Disease

ZENKER'S DIVERTICULUM osms.it/zenkers PATHOLOGY & CAUSES ▪ Diverticulum (outpouching) of pharyngeal mucosa through Killian’s triangle (area of muscular weakness), between transverse fibres of cricopharyngeus muscle and oblique fibres of lower inferior constrictor muscle ▪ AKA pharyngoesophageal diverticulum, pharyngeal pouch, hypopharyngeal diverticulum ▪ Pseudodiverticulum ▫ Does not involve all layers of esophageal wall → contains mucosa, submucosa

CAUSES

▪ Uncoordinated swallowing, impaired relaxation and swallowing, impaired relaxation and spasm of cricopharyngeus muscle → increased pressures in distal pharynx → excessive lower pharyngeal pressures → diverticulum formation

CT scan with oral contrast ▪ Distinct outpouching visible

TREATMENT ▪ Small/asymptomatic diverticula do not require treatment

SURGERY

▪ Neck surgery → cricopharyngeal myotomy, diverticulopexy

OTHER INTERVENTIONS

▪ Non-surgical endoscopic technique ▪ Endoscopic stapling ▪ Endoscopic laser

RISK FACTORS

▪ Biological male > 60 years old

SIGNS & SYMPTOMS ▪ May be asymptomatic ▪ Difficulty swallowing, sense of lump in throat, cervical webs ▪ Food trapping ▫ Regurgitation, cough, halitosis, infection

DIAGNOSIS DIAGNOSTIC IMAGING Barium swallow ▪ Distinct outpouching visible Upper gastrointestinal endoscopy ▪ Pouch visualized

Figure 30.9 A barium swallow demonstrating a Zenker’s diverticulum, outlined on the right of the image.

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NOTES

NOTES

GASTRIC DISEASE GENERALLY, WHAT IS IT? PATHOLOGY & CAUSES ▪ Diseases affecting gastric mucosa, gastric outlet, etc. ▪ Inflammation due to infection; ulceration

SIGNS & SYMPTOMS ▪ May be asymptomatic ▪ Epigastric pain, nausea, vomiting ▪ Anemia; fecal, urinary incontinence; ulcers; bleeding

DIAGNOSIS DIAGNOSTIC IMAGING ▪ Endoscopy

LAB RESULTS ▪ Biopsy

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TREATMENT MEDICATIONS

▪ Proton pump inhibitor (PPI) ▪ Correct fluid, electrolyte deficits ▪ Discontinue nonsteroidal anti-inflammatory drugs (NSAIDs)

SURGERY

▪ Endoscopic ligation/coagulation ▪ Surgical repair

OTHER INTERVENTIONS

▪ Dietary modification; exercise ▪ Avoid smoking

Chapter 31 Gastric Disease

CYCLIC VOMITING SYNDROME osms.it/cyclic-vomiting PATHOLOGY & CAUSES ▪ An uncommon disorder characterized by recurrent episodes of vomiting separated by asymptomatic periods ▪ Median onset age: 5–6 years old

CAUSES

▪ Cause unknown; triggers may include psychological stress (e.g. interpersonal conflict, holidays) or physical stress (e.g. infections, exhaustion), certain foods (e.g. cow’s milk, chocolate, cheese, monosodium glutamate) menses

RISK FACTORS

▪ Children > adults ▫ In children: mitochondrial DNA deletions and polymorphisms ▪ Females > males ▪ Family history of migraines ▪ Autonomic abnormalities (elevated sympathetic tone) ▪ Hypothalamic-pituitary-adrenal activation (Sato variant) ▪ Chronic cannabis use

COMPLICATIONS ▪ ▪ ▪ ▪ ▪

Erosive esophagitis Mallory-Weiss tear Dehydration Electrolyte imbalance Unintended weight loss

SIGNS & SYMPTOMS ▪ Symptoms tend to develop at night, in the early morning hours, or upon awakening ▪ Prodromal period is common ▪ Gastrointestinal: vomiting which may include bile or blood; retching, abdominal pain, diarrhea

▪ Autonomic: lethargy, pallor, excessive salivation, low grade fever ▪ Neurologic: headache, photophobia, phonophobia, vertigo ▪ Social withdrawal

DIAGNOSIS OTHER DIAGNOSTICS

▪ History and physical examination ▫ No identifiable organic cause ▪ Diagnostic criteria (Rome IV criteria) ▫ ≥ three recurrent, discrete episodes of vomiting in the prior year, with two episodes in the past six months occurring at least one week apart ▫ Variable intervals between vomiting episodes and asymptomatic baseline ▫ Stereotypical characteristics regarding timing of onset, symptoms, and duration

TREATMENT OTHER INTERVENTIONS

▪ During cyclic vomiting episodes ▫ IV fluids, antiemetics, sedatives; comfort care in dark, quiet room

Prevention ▪ Prophylactic therapy ▫ H1-antagonists (e.g. cyproheptadine) for children ≤ five years old ▫ Tricyclic antidepressants (e.g. amitriptyline) > years of age ▪ Abortive therapy ▫ Triptans; neurokinin-1 receptor antagonists ▪ Avoidance of triggers

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GASTRIC DUMPING SYNDROME osms.it/gastric-dumping DIAGNOSIS

PATHOLOGY & CAUSES ▪ Iatrogenic post-gastric surgery syndrome; impaired gastric motility → rapid stomach emptying ▪ Surgical intervention → disruption in gastric anatomy, mucosal function, fundus tone, antropyloric regulatory mechanisms, duodenal feedback on motility → rapid emptying of stomach contents into duodenum ▪ 50% of individuals undergoing gastric surgical procedures ▪ More common in individuals who are biologically female

SIGNS & SYMPTOMS ▪ GI: early satiety; abdominal colic; nausea, vomiting; explosive diarrhea; bloating; malabsorption ▪ Vasomotor: diaphoresis; palpitations; vertigo ▪ Early dumping syndrome ▫ 30–60 minutes post-meal ▫ Accelerated stomach emptying → hyperosmolar contents poured into small bowel → osmotic activity → bowel distention, motility stimulated → GI symptoms ▪ Late dumping syndrome ▫ 60–180 minutes post-meal ▫ Accelerated stomach emptying → ↑ carbohydrate concentration in proximal intestine → rapid glucose absorption → rapid, sustained insulin response → hypoglycemia → vasomotor symptoms

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DIAGNOSTIC IMAGING ▪ Endoscopy

LAB RESULTS

▪ Oral glucose challenge test elicits symptoms ▪ Hydrogen breath test after glucose ingestion

OTHER DIAGNOSTICS

▪ Gastric emptying study ▪ Clinical indices ▫ Sigstad’s diagnostic index: > 7 ▫ Visick classification: heart rate variations after oral glucose challenge

TREATMENT MEDICATIONS Acarbose ▪ Interferes with carbohydrate reabsorption Octreotide ▪ Inhibits insulin release

OTHER INTERVENTIONS Dietary modification ▪ Avoid simple sugars, fluid intake during meals; low carbohydrate, high protein diet

Chapter 31 Gastric Disease

GASTRITIS osms.it/gastritis PATHOLOGY & CAUSES ▪ Inflammation of the lining of the stomach ▪ May occur as a short episode or may be of a long duration

TYPES Acute gastritis ▪ Inflammation of gastric mucosa; compare to gastropathy (without active inflammation) ▪ Gastritis, gastropathy ▫ Clinically identical, histologically distinct

▪ Infectious ▫ Most common cause (80%) ▫ H. pylori → chronic gastritis → gastric atrophy → metaplasia → dysplasia → cancer (associated with intestinal-type gastric carcinoma) ▫ Cytotoxin-associated gene A (CagA); carcinogenic virulence factor of H. pylori ▫ Normal gastrin levels, no hypochloridia, no anti-parietal cell/anti-intrinsic factor antibodies (compare to autoimmune atrophic gastritis; hypochloridia, antiparietal/anti- intrinsic factor antibodies) ▫ Gastric ulcers

Atrophic gastritis ▪ AKA chronic gastritis, metaplastic gastritis, gastric atrophy ▪ Chronic inflammation of gastric mucosa → epithelial metaplasia, mucosal atrophy, gland loss ▫ Metaplasia: reversible change of one epithelium into another, response to stress ▫ Intestinal metaplasia: goblet cells

CAUSES Acute gastritis ▪ Certain medications, alcohol, corticosteroids, uremia ▪ NSAIDs block cyclooxygenase → ↓ prostaglandin E2, I2 production → ↓ gastric defense mechanisms (mucus, HCO3 secretion) → mucosal injury ▪ H. pylori infection → gastric mucosa infiltrates antrum, corpus → inflammation involving neutrophil, mononuclear cells ▪ Alcohol, cigarette smoke, caffeine → irritates, erodes stomach mucosa lining ▪ Extreme physiological stress (e.g. shock, sepsis, burns) Atrophic gastritis ▪ Two main causes: infectious and autoimmune

Figure 31.1 A high magnification image of Helicobacter organisms within a gastric crypt. Helicobacter are a common cause of gastritis. ▪ Autoimmune ▫ Most common cause in individuals without H. pylori ▫ Inherited autoimmunity against intrinsic factor, H+/K+ ATPase in parietal cells → inhibition of gastric acid secretion (hypochloridia). ↓ intrinsic factor →

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cobalamin (B12) malabsorption → pernicious anemia ▫ Hypochloridia (impaired iron absorption /G-cell hyperplasia, hypergastrinemia → ↑ neuroendocrine tumor formation) ▫ ↑ gastric adenocarcinoma, neuroendocrine tumors ▫ Damage limited to gastric fundus, body

RISK FACTORS Atrophic gastritis ▪ Infectious ▫ Household crowding; rural areas; poor sanitation ▪ Autoimmune ▫ Associated with HLA-DR3, B8, other autoimmune diseases; more common in biologically-female individuals

SIGNS & SYMPTOMS ▪ ▪ ▪ ▪

May be asymptomatic Epigastric pain, nausea, vomiting Mucosal ulcers Hemorrhage, hematemesis, melena

Autoimmune atrophic gastritis ▪ Iron deficiency anemia ▫ Hypochlorhydria → dietary iron in ferric form → ↓ iron absorption → iron deficiency ▪ Pernicious anemia (symmetrical neuropathy predominantly affecting lower limbs) ▫ Anti-intrinsic factor (IF) antibodies, ↓ cobalamin (B12) absorption → depletion of 5-methyl-tetrahydrofolate → homocysteine cannot convert into methionine → impaired myelin regeneration → subacute combined degeneration of spinal cord posterior columns ▫ Weakness, paraplegia, paresthesias, ataxia, loss of position/vibration sense ▫ Spasticity, clonus; atrophic glossitis; fecal/urinary incontinence; diarrhea; dementia

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DIAGNOSIS LAB RESULTS Endoscopic biopsy ▪ Distinguish gastropathy from gastritis, nonspecific; mucosal erosions, erythema, absence of rugae ▪ Infectious atrophic gastritis ▫ Multifocal atrophy; gastric/duodenal ulcers; erythematous, nodular mucosa; thickened rugal folds in early disease, loss of rugal folds in late disease; damage limited to gastric antrum ▪ Autoimmune atrophic gastritis ▫ Diffuse atrophy, absent rugae, mucosal thinning, visible submucosal blood vessels H. pylori detection ▪ Serology, stool antigen test, urease breath test, biopsy ▪ Atrophic gastritis ▫ H. pylori curved bacilli (hematoxylin, eosin; Giemsa; Warthin-Starry stain); intraepithelial neutrophil, plasma cell invasion Other lab results ▪ Autoimmune atrophic gastritis ▫ Anti-IF antibodies, anti-parietal cell antibodies ▫ ↑ serum gastrin: parietal cell loss → achlorhydria → unrestricted gastrin secretion ▫ ↓ serum pepsinogen: gastric oxyntic mucosa damaged → ↓ chief cells → ↓ serum pepsinogen ▫ Lymphocytosis, eosinophilia, plasma cell invasion; oxyntic gland destruction; metaplasia (intestinal, pyloric, pancreatic)

Chapter 31 Gastric Disease

TREATMENT MEDICATIONS Remove offending agents ▪ NSAIDs, acids/alkalis Eradicate H. pylori ▪ Triple therapy ▫ PPI + clarithromycin + amoxicillin (2 weeks) ▪ Quadruple therapy ▫ PPI + bismuth + metronidazole + tetracycline (1 week)

Figure 31.2 Histological appearance of chronic gastritis. The lamina propria contains numerous plasma cells.

Correct vitamin deficiencies ▪ For Autoimmune atrophic gastritis

Figure 31.3 The histological appearance of intestinal metaplasia, characterized by the presence of goblet cells in the gastric mucosa.

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GASTROPARESIS osms.it/gastroparesis PATHOLOGY & CAUSES ▪ Delayed gastric emptying, no mechanical obstruction

CAUSES

▪ Most common cause ▫ Idiopathic/diabetes ▪ Iatrogenic (post-surgical/medication side effect), post-viral ▪ More common among individuals with T1DM than T2DM secondary to neuropathy

SIGNS & SYMPTOMS ▪ Chronic nausea, vomiting ▪ Early satiety, bloating ▪ Abdominal pain

DIAGNOSIS DIAGNOSTIC IMAGING Endoscopy, CT scan, MRI ▪ Exclude mechanical obstruction Gastric emptying scintigraphy

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Chapter 31 Gastric Disease

TREATMENT MEDICATIONS

OTHER INTERVENTIONS ▪ Exercise; low fat diet

▪ Metoclopramide (gastrointestinal prokinetic) ▪ Remove medications that may delay gastric emptying

PEPTIC ULCER osms.it/peptic-ulcer PATHOLOGY & CAUSES ▪ Chronic mucosal ulceration of stomach/ duodenum extends into muscularis mucosa. ▪ Most common cause of upper gastrointestinal bleeding; proximal duodenum/gastric antrum ▪ Associated with chronic gastritis ▪ ↑ acid secretion, ↓ protective mechanisms → mucosal damage → ulceration

RISK FACTORS

▪ H. pylori infection (most common) ▫ ↑ gastric acid secretion, ↓ duodenal HCO3 secretion ▪ NSAID ▫ Particularly low dose aspirin corticosteroids ▪ Physiologic stress ▫ Cushing’s ulcer (intracranial hypertension), Curling ulcer (severe burns) ▪ Psychological stress ▪ Hyperchlorydia ▪ Smoking ▪ Chronic obstructive pulmonary disease (COPD) ▪ Hypergastrinemia (Zollinger-Ellison syndrome)

Figure 31.4 An endoscopic view of the gastric antrum which displays two discrete ulcers.

SIGNS & SYMPTOMS ▪ Up to 70% asymptomatic ▪ Epigastric burning pain; may mimic myocardial infarction ▫ Usually occurs few hours after meal, worsens at night ▫ Pain characteristically relieved by food/ antacids ▪ Pain may radiate to back, chest, left/right upper abdominal quadrants ▪ Nausea, vomiting, coffee-ground emesis, bloating, weight loss

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▪ Surgical emergency ▫ Hematemesis, melena, positive guaiac test if slow bleed ▫ Acute abdomen; abdominal guarding, peritonitis ▫ GI obstruction ▪ Gastric outlet obstruction, fistula formation

DIAGNOSIS DIAGNOSTIC IMAGING Abdominal CT scan Barium abdominal radiography Endoscopy ▪ Diagnostic, therapeutic

TREATMENT MEDICATIONS

▪ Discontinue NSAIDs, avoid smoking ▪ PPI

SURGERY

▪ Endoscopic ligation/coagulation of bleeding ulcers

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Figure 31.5 A barium study demonstrating the bullseye sign in a case of a gastric ulcer.

NOTES

NOTES

GASTROINTESTINAL CANCERS

GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Tumors arising from cells in gastrointestinal (GI) tract ▪ Multifactorial etiology; generally result from aberrant cellular signaling, unregulated cellular growth ▫ Genetic alterations (e.g. point mutations, amplifications, rearrangements, deletions) ▫ Epigenetic influence (e.g. DNA methylation, chromatin remodeling) ▫ Environmental factors (e.g. exposure to carcinogens, chronic inflammation) ▪ Risk increases with age

SIGNS & SYMPTOMS ▪ Highly variable clinical presentation; see individual disorders ▪ Fatigue, anorexia, weight loss

DIAGNOSIS

▪ Grading, TNM staging for treatment ▫ T: characteristic of primary Tumor (e.g. invasion of nearby tissue) ▫ N: involvement of regional lymph Nodes ▫ M: Metastasis; spread from primary tumor to other body parts

LAB RESULTS Biopsy ▪ Histopathological diagnosis

TREATMENT MEDICATIONS ▪ Chemotherapy

SURGERY

▪ See individual disorders

OTHER INTERVENTIONS ▪ Radiation therapy

DIAGNOSTIC IMAGING Imaging studies ▪ Localization, staging

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CARCINOID TUMOR osms.it/carcinoid-tumor PATHOLOGY & CAUSES ▪ Uncommon, well-differentiated, slowgrowing neuroendocrine tumor; originates in tubular digestive tract; also found in bronchopulmonary system, genitourinary tract ▪ Benign/malignant; tendency for liver metastasis ▪ Carcinoid: tumors of different morphology, less aggressive than GI tract adenocarcinomas; low grade (proliferative activity); low mitotic rate

TYPES

▪ Embryonic origin of GI tract (e.g. foregut, midgut, hindgut)

Foregut tumors (e.g. stomach) ▪ Type I ▫ Most common ▫ Originates from enterochromaffin-like (ECL) cells ▫ In association with high gastrin levels secondary to chronic atrophic gastritis ▫ Small, usually benign ▪ Type II ▫ Originates from ECL cells ▫ In association with high gastrin levels induced by gastrinomas (e.g. Zollinger– Ellison syndrome) in conjunction with multiple endocrine neoplasia type 1 (MEN1) ▫ Often large, indolent; low-grade malignancy ▪ Type III ▫ Not associated with high gastrin levels ▫ Large, aggressive; local lymphatic/ hepatic metastases; produce serotonin (5-HT) Midgut tumors ▪ Small bowel (most common) ▫ Originates from intraepithelial endocrine

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cells ▫ Commonly located in ileum; may arise from Meckel’s diverticulum ▫ Potential for lymph node/hepatic metastasis ▪ Appendix ▫ Originates from subepithelial endocrine cells ▫ Relatively low potential for metastasis Hindgut tumors ▪ Rectum, colon, cecum (most common)

COMPLICATIONS

▪ Depend on tumor’s location, size, local biochemical attributes ▫ Local/distant metastasis ▫ Pain: obstruction, intussusception, bowel ischemia, mechanical pressure from tumor ▫ Desmoplasia: intense, local reaction characterized by overproduction of extracellular matrix proteins + myofibroblast cell proliferation → fibrosis, obstruction ▫ Carcinoid syndrome: tumor-related humoral factors (e.g. serotonin, histamine, etc.) → cutaneous flushing, pruritic rash; excessive lacrimation; wheezing; diaphoresis

SIGNS & SYMPTOMS ▪ Often asymptomatic, discovered incidentally (e.g. imaging, surgery, endoscopy) ▪ Vary according origin site ▫ Nonspecific, vague abdominal pain ▫ Loss of appetite, vomiting, diarrhea, constipation ▪ Desmoplasia (with CT scan)

Chapter 32 Gastrointestinal Cancers

DIAGNOSIS

TREATMENT

DIAGNOSITC IMAGING

MEDICATIONS

CT scan, MRI, labeled somatostatin receptor-based diagnostic imaging ▪ Localization, TNM staging ▪ Presence of hepatic lesions

SURGERY

Endoscopy with biopsy ▪ Tumor visualization ▪ Histopathological analysis, grading

▪ Somatostatin analogues suppress tumor proliferation, decrease symptoms

▪ Surgical removal of tumor

LAB RESULTS

▪ 5-hydroxyindoleacetic acid, chromogranin

Figure 32.2 Gross pathology of carcinoid tumor of the terminal ileum.

Figure 32.1 Histological appearance of a carcinoid tumor of the lung.

MNEMONIC: CARCinoid

Carcinoid syndrome components Cutaneous flushing Asthmatic wheezing Right-sided valvular heart lesions Cramping and diarrhea

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CHOLANGIOCARCINOMA osms.it/cholangiocarcinoma PATHOLOGY & CAUSES ▪ Rare bile duct cancers; arise from epithelial cells of intrahepatic, extrahepatic bile ducts (not including gallbladder, ampulla of Vater) ▪ High fatality due to late diagnosis; highly proliferative ▪ Mostly adenocarcinomas; minority squamous cell carcinomas

TYPES

▪ Determined by location (Bismuth–Corlette)

Type I ▪ Located below confluence of left, right hepatic ducts Type II ▪ Located at confluence Type IIIa ▪ Occludes common hepatic duct Type IIIb ▪ Occludes right/left hepatic duct Type IV ▪ Multicentric

(IDH1) ▪ Risk increases with age ▪ Slightly more common in individuals who are biologically male

COMPLICATIONS

▪ Metastasis ▫ Liver, lymph nodes, peritoneum, bone, etc. ▪ Bowel perforation, bleeding

SIGNS & SYMPTOMS ▪ Often asymptomatic initially; malaise, weight loss, abdominal pain ▪ Extrahepatic disease (when bile drainage obstructed) ▫ Right upper quadrant pain, jaundice, pruritus, dark urine, clay-colored stools, weight loss ▪ Intrahepatic disease ▫ Dull right upper quadrant pain, malaise, weight loss ▪ Other findings ▫ Hepatomegaly, palpated mass

RISK FACTORS

▪ Primary ▫ Existing liver, gallbladder disease: primary sclerosing cholangitis (PSC); chronic liver disease (e.g. viral hepatitis, cirrhosis) ▪ Congenital abnormalities of biliary tree ▪ Genetic disorders ▫ Lynch syndrome; multiple biliary papillomatosis ▪ Obesity ▪ Liver fluke infection (undercooked fish) ▪ Intrahepatic cholangiocarcinomas ▫ Associated with mutations in gene encoding isocitrate dehydrogenase 1

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Figure 32.3 Histological appearance of a cholangiocarcinoma. There are normal hepatocytes in the top left of the image, with the tumour occupying the bottom right of the image.

Chapter 32 Gastrointestinal Cancers

DIAGNOSIS ▪ History, physical examination ▫ Consistent with hepatobiliary disease

DIAGNOSTIC IMAGING MRI, CT scan, PET, etc. ▪ Detailed evaluation of lesion TNM staging Transabdominal/endoscopic ultrasound (EUS) with biopsy ▪ Biliary obstruction, dilation of intrahepatic ducts ▪ Histolopathological analysis, grading

LAB RESULTS

▪ Tumor markers ▫ Carbohydrate antigen (CA) 19-9; carcinoembryonic antigen (CEA) ▪ Liver function tests ▫ Consistent with biliary obstruction, cholestasis ▫ Elevated transaminases, gammaglutamyl transpeptidase, alkaline phosphatase ▫ Prolonged prothrombin time/elevated INR ▫ Elevated bilirubin

Figure 32.4 Histological appearance of a cholangiocarcinoma. This image shows the tumor edge, with normal hepatocytes on the right and tumor on the left. The tumor cells form tubular structures and are surrounded by fibrosis.

TREATMENT MEDICATIONS

▪ Fluoropyrimidine-based chemoradiotherapy ▪ Chemotherapy

SURGERY ▪ Resection

OTHER INTERVENTIONS ▪ Radiation

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COLORECTAL CANCER osms.it/colorectal-cancer

▪ Common malignancy of large bowel/rectum ▪ Third most common cancer worldwide ▪ Often arises from colonic epithelial tissue → adenomatous polyp formation → adenocarcinoma ▪ High metastatic potential after penetrating muscularis mucosa

▪ Black people of African descent ▫ Highest rates in United States ▪ More common in individuals who are biologically male ▪ Risk increases with age ▪ Protective factors ▫ Physical activity; regular use of aspirin, other nonsteroidal anti-inflammatory drugs (NSAIDs)

RISK FACTORS

COMPLICATIONS

PATHOLOGY & CAUSES

▪ Hereditary ▫ Familial adenomatous polyposis; Lynch syndrome, MUTYH-associated polyposis ▪ Inflammatory bowel disease ▪ Lifestyle ▫ Smoking, physical inactivity ▪ Dietary ▫ High alcohol consumption; processed red meat; low consumption of fruits, vegetables ▪ Obesity ▪ Diabetes mellitus, insulin resistance ▪ Low socioeconomic status ▪ History of abdominal radiation ▪ Lack of screening colonoscopy

▪ ▪ ▪ ▪ ▪

Iron-deficiency anemia (due to bleeding) Local, distant metastasis Bowel obstruction Cachexia Bowel perforation → peritonitis

SIGNS & SYMPTOMS ▪ May be asymptomatic initially ▪ Vague constitutional symptoms ▫ Fatigue, anorexia, weight loss ▪ Change in bowel habits ▫ Narrowing of stool, constipation, diarrhea ▪ Rectal bleeding ▫ Frank/occult ▪ Rectal pain, tenesmus (feeling of incomplete defecation) ▪ Nausea, vomiting ▫ Bowel obstruction from advanced malignancy

DIAGNOSIS DIAGNOSTIC IMAGING

Figure 32.5 Gross pathology of an exophytic colorectal carcinoma.

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Colonoscopy/flexible sigmoidoscopy; biopsy, CT colonography ▪ Tumor visualization, histopathological analysis, grading, TNM staging, potential for resection

Chapter 32 Gastrointestinal Cancers

TREATMENT MEDICATIONS ▪ Chemotherapy

SURGERY

▪ Polypectomy with clear margins ▪ Surgical resection ▪ Sessile polyps: colectomy

Figure 32.6 Histological appearance of adenocarcinoma of the colon. The tumor is composed of malignant cells which continue to form glandular structure. The left side of the image displays normal colonic mucosa.

OTHER INTERVENTIONS ▪ Chemoradiation therapy

LAB RESULTS

▪ Tumor marker: CEA ▪ Stool guaiac testing ▫ Positive for occult blood

OTHER DIAGNOSTICS Digital rectal exam ▪ Palpable mass if distal rectal mass

Figure 32.7 A CT scan in the axial plane demonstrating a tumor in the cecum.

Figure 32.8 Positron emission tomography with high levels of tracer accumulation in the pelvis (rectal tumor) as well as the liver and kidneys (metastases).

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ESOPHAGEAL CANCER osms.it/esophageal-cancer PATHOLOGY & CAUSES

SIGNS & SYMPTOMS

▪ Rare malignancy of esophageal epithelium ▪ Squamous cell carcinoma (most common)/ adenocarcinoma ▪ Commonly diagnosed when disease advanced ▪ Tendency for rapid metastasis

▪ Asymptomatic initially; dysphagia; pyrosis; retrosternal pain; weight loss ▪ Late symptoms ▫ Coughing, chest discomfort when swallowing; hiccups if spread to diaphragm

CAUSES

▪ Chronic exposure to irritants → metaplasia → dysplasia → malignant transformation

RISK FACTORS

▪ Smoking ▪ Alcohol (esp. combined with smoking) ▪ Gastroesophageal reflux disease (GERD); reflux esophagitis, Barrett esophagus ▪ Hiatal hernia ▪ More common in individuals who are biologically male ▪ Risk increases with age

MNEMONIC: ABCDEF

DIAGNOSIS DIAGNOSTIC IMAGING EUS guided biopsy, CT scan, PET, integrated fluorodeoxyglucose (FDG) ▪ Tumor visualization, histopathological analysis, grading, TNM staging, potential for resection Bronchoscopy ▪ In carina identifies potential lung involvement

OTHER DIAGNOSTICS

▪ Palpable supraclavicular lymphadenopathy

Esophageal cancer risk factors Achalasia Barret’s esophagus Corrosive esophagitis Diverticulitis Esophageal web Familial

COMPLICATIONS

▪ Esophageal obstruction; regurgitation → aspiration → aspiration pneumonia; metastasis

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Figure 32.9 Endoscopic appearance of an esophageal tumor. The tumor sits at the gastroesophageal junction and is viewed from above.

Chapter 32 Gastrointestinal Cancers

TREATMENT MEDICATIONS ▪ Chemotherapy

SURGERY

▪ Resection of primary tumor, associated nodes

OTHER INTERVENTIONS ▪ Radiation

Esophageal stenting ▪ Therapeutically enlarges esophageal lumen, reduces dysphagia

Figure 32.10 A barium swallow demonstrating a tumor distorting the normal outline of the esophagus.

GALLBLADDER CANCER osms.it/gallbladder-cancer PATHOLOGY & CAUSES ▪ Uncommon malignancy; most frequently diagnosed cancer of biliary tract ▪ High fatality rate due to typically late diagnosis ▪ Most gallbladder cancers arise within fundus ▪ May obstruct bile flow at common bile duct/ duodenum

RISK FACTORS

▪ Chronic gallbladder inflammation

▪ ▪ ▪ ▪ ▪

▫ Cholelithiasis (gallstones), primary sclerosing cholangitis, porcelain gallbladder, gallbladder polyps, biliary cysts; chronic infection (e.g. Salmonella typhi, Helicobacter bilis) More common in individuals who are biologically female Obesity Cigarette smoking Occupational exposure to carcinogens: textile, oil, paper, chemical industries, radon (mining) Genetic predisposition

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COMPLICATIONS

▪ Biliary fistula ▪ Local/nodal/distant metastases

SIGNS & SYMPTOMS ▪ Often asymptomatic in early stages; malignancy discovered incidentally after symptoms mimic benign gallbladder disease ▪ Non-specific symptoms ▫ Malaise, pain, anorexia, nausea, vomiting, weight loss ▪ Clinical manifestations (when bile drainage obstructed) ▫ Jaundice, dark urine ▪ Palpable gallbladder

DIAGNOSIS DIAGNOSTIC IMAGING EUS guided/percutaneous biopsy, CT scan, MRI, PET, MRCP ▪ Tumor visualization, histopathological analysis, grading, TNM staging, potential for resection

LAB RESULTS

▪ Tumor markers: CA 19-9; CEA ▪ Liver function tests ▫ Consistent with biliary obstruction, cholestasis ▫ Elevated transaminases, gammaglutamyl transpeptidase, alkaline phosphatase ▫ Elevated bilirubin

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Figure 32.11 Histological appearance of gallbladder adenocarcinoma. The tumor cells show increased nuclear size, prominent nucleoli and are forming tubular structures.

TREATMENT MEDICATIONS ▪ Chemotherapy

SURGERY

▪ Simple/radical cholecystectomy

OTHER INTERVENTIONS ▪ Radiation

Chapter 32 Gastrointestinal Cancers

HEPATOBLASTOMA osms.it/hepatoblastoma PATHOLOGY & CAUSES ▪ Common primary childhood hepatic malignancy; arises from primitive hepatic cells ▪ Usually occurs in right lobe of liver ▪ Morphologically diverse tumor: composed of many cell types including embryonal hepatocytes, tissues (e.g. bone, striated muscle) ▪ Extramedullary hematopoiesis may occur in sinusoids ▪ Usually present during first two years of life

DIAGNOSIS DIAGNOSTIC IMAGING Ultrasound, percutaneous biopsy, CT scan with/without contrast, MRI ▪ Diagnostic workup for tumor visualization, histopathological analysis, grading, pretreatment staging system (PRETEXT); potential for resection

LAB RESULTS

▪ Elevated alpha-fetoprotein (AFP) ▪ Genetic testing

RISK FACTORS ▪ ▪ ▪ ▪ ▪ ▪

Beckwith Wiedemann syndrome Trisomies 18, 21 Familial adenomatous polyposis Type Ia glycogen storage disease Li–Fraumeni syndrome More common in individuals who are biologically male

COMPLICATIONS

▪ Ectopic gonadotropin → precocious puberty (uncommon) ▪ Fatal hepatic hemorrhage, rupture ▪ Metastasis: commonly lungs

Figure 32.12 Histological appearance of a hepatoblastoma, a tumor of immature hepatocytes.

SIGNS & SYMPTOMS ▪ Children ▫ Abdominal mass; discomfort ▪ Anorexia, weight loss, precocious puberty

TREATMENT MEDICATIONS ▪ Chemotherapy

SURGERY ▪ Resection

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HEPATOCELLULAR CARCINOMA osms.it/hepatocellular-carcinoma PATHOLOGY & CAUSES ▪ Hepatic malignancy commonly diagnosed in presence of chronic liver disease

RISK FACTORS

▪ Hepatitis B/C infection, coinfection with hepatitis D ▪ Hereditary hemochromatosis ▪ Cirrhosis ▪ Smoking; frequent alcohol consumption ▪ Obesity ▪ Alpha-1 antitrypsin deficiency ▪ Gallstones ▪ Chronic exposure to aflatoxin (mycotoxin found in peanuts, soybeans, corn) ▪ More common in individuals who are biologically male

SIGNS & SYMPTOMS ▪ Often no symptoms aside from those of chronic liver disease ▪ Epigastric pain; appetite, weight loss ▪ Palpable abdominal mass; manifestations of decompensated cirrhosis (e.g. splenomegaly, ascites, jaundice); hepatic bruit

COMPLICATIONS

▪ Paraneoplastic syndrome: watery diarrhea, hypoglycemia, hypercalcemia, erythrocytosis; cutaneous lesions (e.g. pemphigus foliaceus) ▪ Extrahepatic metastasis: commonly lymph nodes, lungs, adrenal gland

MNEMONIC: ABC

Hepatocellular carcinoma etiology Aflatoxins Hep B Cirrhosis Hepatocellular carcinoma features AFP increased: classic marker Bile-producing: DDx from cholangiocarcinoma Most Common primary liver tumor

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Figure 32.13 An abdominal CT scan in the axial plane demonstrating a massive hepatocellular carcinoma.

DIAGNOSIS DIAGNOSTIC IMAGING Ultrasound with biopsy, CT scan, MDCT, arteriography, portography, MRI ▪ Tumor visualization, histopathological analysis, grading, TNM staging, potential for resection MRI angiography ▪ 3D characterization of lesion, hepatic circulation

Chapter 32 Gastrointestinal Cancers

LAB RESULTS

▪ Elevated aminotransferases, alkaline phosphatase, gamma-glutamyl transpeptidase; hyperbilirubinemia; hypoalbuminemia ▪ Elevated alpha-fetoprotein (most common serum marker)

Figure 32.14 Gross pathology of hepatocellular carcinoma.

TREATMENT MEDICATIONS

Figure 32.15 Histological appearance of a hepatocellular carcinima. The cells show high nuclear variation, thickened nuclear envelopes and occasional prominent nucleoli. The cells also have abundant eosinophilic cytoplasm.

▪ Chemotherapy ▪ Systemic molecularly targeted therapy; sorafenib, nivolumab

SURGERY

▪ Partial hepatectomy ▪ Liver transplant

OTHER INTERVENTIONS

▪ Radiofrequency ablation ▪ Percutaneous ablation with ethanol/acetic acid ▪ Transarterial chemoembolization ▪ Cryoablation ▪ Radiation therapy; stereotactic body radiation therapy

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ORAL CANCER osms.it/oral-cancer PATHOLOGY & CAUSES ▪ Oral cavity malignancy; arises from mucosal surfaces ▫ Lips, buccal mucosa, anterior tongue, mouth floor, hard palate, gingiva, retromolar trigone ▫ Most often: squamous cell carcinoma ▪ May arise from normal mucosa/ premalignant lesions (e.g. erythroplakia, leukoplakia); undergo malignant transformation

COMPLICATIONS

▪ Surgical resection → airway, speech, mastication, cosmetic complications ▪ Metastasis

SIGNS & SYMPTOMS ▪ ▪ ▪ ▪

Asymptomatic initially Pain/burning sensation Lump/ulcer visualized, palpated Hard, fixed lymph nodes

DIAGNOSIS

RISK FACTORS

▪ Tobacco (esp. with alcohol) ▪ Alcohol ▪ Human papillomavirus (HPV) infection: oropharynx ▪ Periodontal disease ▪ Chronic oral candidiasis ▪ Betel quid chewing ▪ Immunosuppression ▪ Hepatitis C infection ▪ Genetic polymorphisms: cytochrome P450 1A1 (CYPIA 1); glutathione S-transferase mu 1 (GSTM1); alcohol dehydrogenase 3 genotype → oropharyngeal cancers ▪ More common in individuals who are biologically male

DIAGNOSTIC IMAGING CT scan/MRI ▪ Local spread/location of additional primary tumors

LAB RESULTS

▪ Fine needle biopsy; histopathological diagnosis

OTHER DIAGNOSTICS

▪ Palpation and visualization ▫ Of mucous membranes, oral cavity, lymph nodes ▪ Flexible laryngoscopy ▫ Back of throat, vocal cords

MNEMONIC: PATH LAB

Oral cancer risks Plummer-vinson syndrome Alcohol Tobacco Human papilloma virus Leukoplakia Asbestos Bad oral hygiene

TREATMENT MEDICATIONS ▪ Chemotherapy

SURGERY ▪ Resection

OTHER INTERVENTIONS ▪ Radiation

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Chapter 32 Gastrointestinal Cancers

PANCREATIC CANCER osms.it/pancreatic-carcinoma PATHOLOGY & CAUSES ▪ Highly lethal malignancy of exocrine pancreas ▪ Usually unresectable at presentation

RISK FACTORS

▪ Chronic pancreatitis ▪ Malignant transformation of pancreatic intraductal papillary mucinous neoplasm (IPMN) ▪ Genetic mutations (e.g. BRCA-1, BRCA-2, ATM, PALB2, CDKN2A, MLH1) ▪ Smoking; obesity; sedentary lifestyle

COMPLICATIONS

▪ Hypercoagulability with possible venous/ arterial thromboembolism ▪ Paraneoplastic manifestations ▫ Bullous pemphigoid; nodular fat necrosis (pancreatic panniculitis) ▪ Metastasis

SIGNS & SYMPTOMS ▪ Recent onset of diabetes mellitus ▪ Clinical presentation ▫ Tumor location ▪ Pain ▫ Epigastric, abdominal, may radiate to the back, may worsen after eating/when lying down; asthenia: ▪ Physical weakness, loss of strength; anorexia, nausea; weight loss; jaundice, dark urine ▪ Hepatomegaly; right upper quadrant mass; Courvoisier’s sign (nontender, palpable gallbladder at right costal margin); cachexia; metastasis: left supraclavicular/periumbilical lymphadenopathy, ascites, abdominal mass

DIAGNOSIS DIAGNOSTIC IMAGING Transabdominal ultrasound ▪ Detects degree of biliary tract dilation, obstruction ERCP ▪ Increased visibility of pancreaticobiliary tree MRCP ▪ Visualization of liver parenchyma, vascular structures Laparoscopy ▪ Determines resectability Abdominal CT scan; contrast-enhanced CT scan, EUS guided/percutaneous biopsy ▪ Tumor visualization, histopathological analysis, grading, TNM staging

LAB RESULTS

▪ Tumor marker: CA 9-19 ▪ Hyperbilirubinemia (mostly conjugated); elevated alkaline phosphatase

OTHER DIAGNOSITCS Cardiac catheterization ▪ Measure pressure in right side of heart

TREATMENT MEDICATIONS

▪ Chemotherapy with/without chemoradiotherapy

SURGERY

▪ Resection (e.g. pancreaticoduodenectomy) ▫ Only curative treatment

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Figure 32.16 Cytological preparation of a pancreatic fine needle aspirate which demonstrates pancreatic adenocarcinoma. The group on the left is the cancer, with large, pleomorphic nuclei, which overlap with one another. Contrast these with the smaller, regularly spaced pancreatic ductal epithelial cells on the right.

Figure 32.17 Histological appearance of pancreatic adenocarcinoma. The tumor cells form acini, small sack like spaces surrounded by malignant glandular cells.

STOMACH (GASTRIC) CANCER osms.it/stomach-cancer PATHOLOGY & CAUSES ▪ Aggressive adenocarcinoma arising from gastric mucosa

TYPES Diffuse type (G-DIF): undifferentiated ▪ Impairment/lack of adhesion molecule E-cadherin ▪ Genetic mutation (germline, somatic, epigenetic methylation) of CDH1 gene → inactivation of CDH1 → nonfunctional E-cadherin → unregulated division (impaired tumor suppressor function); increased ability to spread, invade adjacent structures ▫ Autosomal dominant inheritance pattern ▫ More aggressive than G-INT Intestinal type (G-INT): well-differentiated ▪ Due to environmental factors; more

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common in high-risk populations ▪ Intercellular adhesion molecules → adherence of tumor cells → arrangement in glandular formations

RISK FACTORS

▪ Primary cause (G-INT) ▫ H. pylori infection ▪ Family history of gastric cancer ▪ Autoimmune atrophic gastritis ▪ Lifestyle ▫ Smoking, alcohol consumption ▪ Diet ▫ Nitrates, nitrosamines, highly-salted foods; pickled/smoked foods ▪ Obesity ▪ Risk increases with age ▪ More common in individuals who are biologically male

Chapter 32 Gastrointestinal Cancers ▪ Protective factors ▫ Intake of fruit, vegetables, fiber, folate

COMPLICATIONS

▪ Metastasis to liver, peritoneum, lymph nodes, etc. ▪ Paraneoplastic manifestations ▫ Seborrheic keratoses, polyarteritis nodosa, Trousseau’s syndrome (spontaneous, recurrent, migratory venous thrombosis)

DIAGNOSIS DIAGNOSTIC IMAGING Esophagogastroduodenoscopy with biopsy, barium studies, abdominopelvic CT scan ▪ Tumor visualization, histopathological analysis, grading, TNM staging, potential for resection

OTHER DIAGNOSTICS Physical examination ▪ Enlarged supraclavicular, anterior axillary, periumbilical lymph nodes ▪ Palpable abdominal mass

Figure 32.18 Gross pathology of gastric carcinoma. The stomach has been pinned flat. The tumor is found in the antrum.

SIGNS & SYMPTOMS ▪ Asymptomatic initially ▪ Early symptoms ▫ Vague constitutional symptoms (e.g. malaise, loss of appetite, dyspepsia) ▪ With disease progression ▫ Epigastric pain, nausea, vomiting, dysphagia, weight loss ▪ If GI bleeding ▫ Anemia, melena, coffee-ground hematemesis ▪ Pseudoachalasia syndrome (difficulty moving food, liquids from esophagus to stomach) ▫ If tumor extends to Auerbach’s plexus/obstruction occurs near gastroesophageal junction

Figure 32.19 The histological appearance of a well-differentiated gastric adenocarcinoma of intestinal type. The tumor is composed of disordered glands, the cells of which have large, hyperchromatic nuclei.

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TREATMENT MEDICATIONS Chemotherapy ▪ G-INT, G-DIF differ in susceptibility to chemotherapeutic agents ▪ Eradication of H pylori infection

SURGERY ▪ Resection

OTHER INTERVENTIONS ▪ Chemoradiotherapy

WARTHIN'S TUMOR osms.it/warthins-tumor PATHOLOGY & CAUSES ▪ Uncommon benign tumor; arises from salivary gland ▪ AKA papillary cystadenoma lymphomatosum ▪ May involve submandibular/sublingual/ parotid gland (most common) ▪ Unilateral/bilateral, slow-growing

RISK FACTORS

▪ Smoking ▪ Risk increases with age ▪ More common in individuals who are biologically male

COMPLICATIONS

▪ Malignant transformation (rare)

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SIGNS & SYMPTOMS ▪ Development of painless nodular mass, usually near mandible angle

DIAGNOSIS OTHER DIAGNOSTICS ▪ Easily palpable tumor

Fine needle aspiration ▪ Histopathological diagnosis

TREATMENT SURGERY

▪ Local resection/parotidectomy

NOTES

NOTES

INFLAMMATORY BOWEL DISEASE

GENERALLY, WHAT IS IT? PATHOLOGY & CAUSES

DIAGNOSIS

▪ Immune-mediated inflammatory bowel conditions ▪ More common in White people of Jewish descent ▪ Usually presents in young people, 15–35 ▪ Up to 25% of people with inflammatory bowel disease have affected first-degree relative

DIAGNOSTIC IMAGING

CAUSES

MEDICATIONS

▪ Gut microbiome alterations ▪ “Western” style diet: high processing/ sugar/fat content

RISK FACTORS

▪ Crohn’s disease: smoking ▫ Smoking may be protective for Ulcerative colitis

▪ Endoscopy

LAB RESULTS ▪ Biopsy

TREATMENT ▪ Anti-inflammatory medications; antibiotics; immunosuppressants

SURGERY

▪ Surgical resection

OTHER INTERVENTIONS ▪ Dietary changes

SIGNS & SYMPTOMS ▪ ▪ ▪ ▪

Chronic diarrhea, frequently bloody/mucous Abdominal pain Fever, weight loss, anemia Extraintestinal manifestations ▫ Arthritis, uveitis

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CROHN'S DISEASE osms.it/crohns-disease PATHOLOGY & CAUSES ▪ AKA Crohn disease, regional enteritis ▪ Chronic, immune-related disorder → excessive immune response to unknown trigger → transmural inflammation anywhere along gastrointestinal (GI) tract, mouth to anus ▪ Compare to ulcerative colitis ▫ Only affects colon, rectum; superficial lesions; autoimmune disorder where tissue is directly attacked by immune system ▪ Frameshift mutation in nucleotide-binding oligomerization domain-containing protein 2 (NOD2)/ caspase recruitment domaincontaining protein 15(CARD15) ▫ Excessive inflammatory response → tissue damage ▪ Unknown immune response trigger → T helper (Th) 1 cells release inflammatory cytokines ▫ Interferon (IFN) gamma, tumor necrosis factor (TNF) alpha → inflammatory response → cytokines recruit macrophages → further inflammatory mediators released (proteases, platelet activating factor, free radicals) → further inflammation → healthy tissue destroyed → inflammatory cells invade intestinal mucosa → ulcer, granuloma form → transmural inflammation → intestinal lumen; fistula formation, narrowing ▪ Fistula, stricture formation ▫ Serosal layer involvement → fistula ▫ Most common: enterovesical, enterocutaneous, enterovaginal, enteroenteric fistulae ▪ Scattered inflammation → cobblestone appearance ▪ Most commonly affects terminal ileum, colon

CAUSES

▪ Unclear; mycobacterium paratuberculosis, pseudomonas, listeria implicated

SIGNS & SYMPTOMS ▪ Unpredictable patterns of flares, remissions ▪ Abdominal pain; most common in right lower quadrant (ileal inflammation) ▪ Fatigue, fever, nausea, vomiting ▪ Chronic diarrhea; may/may not be bloody ▫ Gross bleeding rare; upon microscopy, bleeding common ▪ Malabsorption, weight loss, vitamin deficiencies ▪ Up to 20% of cases present with inflammatory eye, skin, joint lesions ▫ Uveitis, erythema nodosum, pyoderma gangrenosum, cholelithiasis (impaired bile reabsorption), arthritis ▪ Perianal abscesses, phlegmon, fistulae ▫ Perianal fistulas (up to 30%) ▫ Enterovesical fistulae → recurrent UTI, pneumaturia ▫ Enteroenteric fistulae → asymptomatic ▫ Enterovaginal fistulae → passage of fecal matter through vagina ▫ Enterocutaneous fistulae → draining of bowel contents unto skin ▪ Intestinal obstruction (up to 30%)

Figure 33.1 Pyoderma gangrenosum on the leg of an individual with Crohn’s disease.

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Chapter 33 Inflammatory Bowel Disease MNEMONIC: CHRISTMAS

Features of Crohn’s disease Cobblestones High temperature Reduced lumen Intestinal fistulae Skip lesions Transmural: all layers, may ulcerate Malabsorption Abdominal pain Submucosal fibrosis

Figure 33.3 Gross pathology of a resected colon involved by Crohn’s disease. The severe and prolonged inflammation has led to a cobblestone appearance of the colonic mucosa.

DIAGNOSIS DIAGNOSTIC IMAGING ▪ Endoscopy

LAB RESULTS

▪ Biopsy ▫ Cobblestone appearance, intermittent lesion pattern, pseudopolyps, aphthous ulcers

OTHER DIAGNOSTICS ▪ Barium enema

TREATMENT MEDICATIONS

▪ Anti-inflammatory medications → sulfasalazine ▫ For colonic symptom management ▪ Antibiotics → metronidazole ▫ Reduce bacterial overgrowth, antiinflammatory effect ▪ Immunosuppressants → prednisone, azathioprine ▫ Only if no response to antibiotics ▪ Antidiarrheals ▪ Methotrexate, anti-TNF agents ▫ Refractory disease

SURGERY

▪ Surgical removal of affected tissue ▫ High relapse rate ▫ Short bowel syndrome: complication of resection

OTHER INTERVENTIONS

▪ Nutritional supplementation, support

Figure 33.2 Histological appearance of Crohn’s disease. The lamina propria is expanded by chronic inflammatory cells and there is a non-caseating granuloma present.

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MICROSCOPIC COLITIS osms.it/microscopic-colitis DIAGNOSIS

PATHOLOGY & CAUSES ▪ Idiopathic chronic inflammation of colon → watery diarrhea ▪ Associated with celiac disease, autoimmune diseases, NSAIDs, smoking ▪ More common in individuals who are biologically female ▪ Unknown trigger → abnormal collagen metabolism → dysfunctional epithelium → alteration in barrier function → mucosal inflammation → decreased sodium absorption, increased chloride secretion → secretory diarrhea

TYPES Collagenous ▪ More common in older individuals who are biologically female ▪ Dense subepithelial collagenous layer; increased intraepithelial lymphocytes, inflammatory infiltrate in lamina propria Lymphocytic ▪ Increased intraepithelial lymphocytes, inflammatory infiltrate in lamina propria

SIGNS & SYMPTOMS ▪ ▪ ▪ ▪ ▪

Abdominal pain Chronic watery diarrhea No weight loss Fecal urgency, incontinence Anemia

DIAGNOSTIC IMAGING Endoscopy ▪ Non-specific findings, normal mucosa

LAB RESULTS

▪ Biopsy of colonic mucosa ▫ Inflammatory changes in lamina propria, intraepithelial lymphocytic infiltration, dense subepithelial collagenous layer ▪ Elevated inflammatory markers (nonspecific) ▫ Erythrocyte sedimentation rate, myeloperoxidase ▪ Autoantibodies ▫ Anti-thyroid peroxidase (TPO), antinuclear (ANA), antineutrophil cytoplasmic (ANCA), anti Saccharomyces cerevisiae (ASCA), rheumatoid factor (RF)

TREATMENT MEDICATIONS

▪ Avoid NSAIDs, other medications associated with microscopic colitis ▪ Antidiarrheals ▫ Loperamide, bismuth salicylate ▪ Corticosteroids ▫ Budesonide, prednisone ▪ Bile acid sequestrants ▫ Cholestyramine

SURGERY

▪ Surgical resection (ileostomy)

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Chapter 33 Inflammatory Bowel Disease

Figure 33.4 Histological appearance of collagenous colitis. The subepithelial basement membrane is markedly thickened.

Figure 33.5 Histological appearance of lymphocytic colitis. There is an increase in the number of intraepithelial lymphocytes (>20/100 epithelial cells).

PROTEIN LOSING ENTEROPATHY osms.it/protein-losing-enteropathy PATHOLOGY & CAUSES

SIGNS & SYMPTOMS

▪ Inflammatory GI conditions → loss of serum proteins into GI tract ▪ Mucosal injury → epithelial inflammation, → mucosal permeability → protein exudates across epithelium → proteins in GI tract degraded into amino acids (AA) ▪ Lymphatic obstruction/venous stasis → increased hydrostatic pressure in lymphatics → lymph leaks into intestinal lumen → reduced chylomicron reabsorption → decrease in fat soluble vitamins → protein deficiency

▪ Hyponatremia, peripheral edema, ascites ▪ Serosal effusions (pleural and pericardial) ▫ Dyspnea, cough, chest pain ▪ Steatorrhea, bloating, flatulence, abdominal pain ▪ Weight loss, chronic diarrhea

CAUSES

▪ Inflammatory bowel disease ▫ Crohn’s disease, ulcerative colitis ▪ Malabsorptive diseases ▫ Tropical sprue, celiac sprue ▪ Infectious diseases ▫ C. difficile → pseudomembranous colitis ▪ GI malignancies

DIAGNOSIS LAB RESULTS

▪ Consider in individuals with edema, hypoalbuminemia ▪ Increase in alpha-1 antitrypsin clearance ▪ Exclude other causes of hypoproteinemia ▫ Renal disease → proteinuria ▫ Hepatic disease → impaired protein synthesis ▫ Malnutrition

TREATMENT OTHER INTERVENTIONS

▪ Low fat, high protein diet; supplement medium chain triglycerides (MCT)

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ULCERATIVE COLITIS osms.it/ulcerative-colitis PATHOLOGY & CAUSES ▪ Autoimmune disease → superficial ulcer formation; continuous, circumferential inflammation in colonic, rectal mucosa ▪ Most common inflammatory bowel disease; may present at any age ▪ Compare to Crohn’s disease ▫ Usually affects young people, affects entire GI tract; causes transmural inflammation; patches of inflamed mucosa, cobblestone appearance ▪ CD8+ cell activation → destruction of cells in mucosal, submucosal colonic layers ▫ Associated with perinuclear antineutrophil cytoplasmic antibodies (p-ANCAs) ▪ Multifactorial origin ▫ Environmental stimuli + excessive sulfide-producing bacteria + genetic predisposition ▪ More common among white people, especially of Eastern European descent ▪ More common in young individuals who are biologically female

CAUSES

▪ Unclear; autoimmune reaction against colonic flora, molecular mimicry, increased sulfide production implicated ▪ Environmental factors contribute to acute flares

COMPLICATIONS

▪ Toxic megacolon, anal fissures, perirectal abscess

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MNEMONIC: ULCERATIONS

Features of Ulcerative colitis Ulcers Large intestine Carcinoma (risk of) Extraintestinal manifestations Remnants of old ulcers (pseudopolyps) Abscesses in crypts Toxic megacolon (risk of) Inflamed, red, granular mucosa Originates at rectum Neutrophil invasion Stool is bloody

SIGNS & SYMPTOMS ▪ Acute flares, remissions; gradual onset ▫ Risk of relapse related to person’s age at diagnosis ▪ Severity determined by frequency of bowel movements, degree of inflammation, systemic symptoms ▪ Colicky, left lower quadrant pain ▪ Diarrhea; frequently grossly bloody, mucous ▪ Rectal tenesmus, incontinence, urgency, bleeding ▫ Tenesmus: Latin teinesmos; to strain ▪ Fever, fatigue, weight loss, anemia, dehydration ▪ Extraintestinal manifestations ▫ Arthritis (most common); uveitis; erythema nodosum; pyoderma gangrenosum; primary sclerosing cholangitis; arterial, venous thromboembolisms

Chapter 33 Inflammatory Bowel Disease

DIAGNOSIS ▪ > four weeks active diarrhea + inflammatory findings on endoscopy + chronic inflammatory changes on biopsy ▪ Biopsy ▫ Crypt abscesses

LAB RESULTS

▪ Anemia ▪ Elevated inflammatory markers ▫ Erythrocyte sedimentation rate (ESR), C-reactive protein (CRP)

Figure 33.6 A pancolectomy specimen from an individual with ulcerative colitis.

OTHER DIAGNOSTICS

▪ Clinical diagnosis; exclude other causes of colitis ▫ Infections (e.g. parasites, Clostridium difficile), STIs, radiation, medications

TREATMENT MEDICATIONS

▪ Anti-inflammatory medications ▫ Sulfasalazine, mesalamine ▪ Immunosuppressors ▫ Corticosteroids, azathioprine, cyclosporine ▪ TNF blocking agent

SURGERY

▪ Colectomy only if disease localized

Figure 33.7 Abdominal radiograph demonstrating toxic megacolon, a complication of ulcerative colitis.

Figure 33.8 The clinical appearance of erythema nodosum; a cutaneous manifestation of inflammatory bowel disease.

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Figure 33.9 Histological appearance of active ulcerative colitis in a colonic biopsy. There is active inflammation causing crypt destruction. Cryptitis and crypt abscesses are also present.

262 OSMOSIS.ORG

NOTES

NOTES

INTESTINAL DISEASES GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Diseases preventing adequate digestive system function ▫ Often involve inflammation, stasis, obstruction, necrosis ▪ Various structural, functional etiologies

SIGNS & SYMPTOMS ▪ Abdominal symptoms etiologicallydependent ▪ Abdominal pain, distension, constipation, bowel-habit change, hematochezia, nausea, vomiting ▪ Bulging abdominal mass (in hernia)

DIAGNOSIS DIAGNOSTIC IMAGING

TREATMENT ▪ See individual diseases

MNEMONIC: APPENDICITIS

Right lower-quadrant pain common differential Appendicitis/ Abscess Pelvic inflammatory disease (PID)/ Period pancreatitis Ectopic/ Endometriosis Neoplasia Diverticulitis Intussusception Crohn’s Disease/ Cyst (ovarian) IBD Torsion (ovary) Irritable Bowel Syndrome Stones

▪ CT scan, MRI, ultrasound

OTHER DIAGNOSTICS

▪ Right lower-quadrant pain common differential (see mnemonic)

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APPENDICITIS osms.it/appendicitis PATHOLOGY & CAUSES

SIGNS & SYMPTOMS

▪ Lumen obstruction → vestigial vermiform appendix inflammation ▪ Located at cecum base (near ileocecal valve) ▪ Obstruction → intraluminal content stasis → ↑ luminal, intramural pressure → thrombosis, occlusion small vessels, lymphatic flow stasis → ischemia, necrosis ▪ Excessive multiplication (gut flora) behind obstruction → immune system response → fibropurulent reaction → parietal peritoneum irritation ▪ Visceral nerve fiber stimulation → abdominal pain

▪ Abdominal pain ▫ Often begins in umbilical area → McBurney’s point (abdomen’s right lower-quadrant; one-third distance from anterior superior iliac spine, umbilicus) → progressive inflammation ▫ Rovsing’s sign: left lower-quadrant palpated → right lower-quadrant pain ▫ Psoas sign: right leg extended in leftside position → retrocecal appendix ▫ Obturator sign: right leg internally rotated in supine position → pelvic appendix ▪ Fever, anorexia, nausea, vomiting, diarrhea/ constipation ▪ In case of peritonitis ▫ Rebound tenderness at McBurney’s point ▫ Abdominal guarding (peritoneal irritation)

CAUSES

▪ Obstruction ▫ Lymphoid hyperplasia (adolescence, viral infection), fecalith, foreign body (e.g. undigested seeds), pinworm infection, tumor (benign, malignant)

RISK FACTORS

▪ 10–30 years old, family history, biologicallymale, cystic fibrosis comorbidity (children)

COMPLICATIONS

▪ Appendix-supplying vessel compression → ischemia → appendix wall necrosis → bacterial invasion (wall) → appendix rupture → bacterial invasion (peritoneum) → peritonitis ▪ Periappendiceal abscess, subphrenic abscess, pylephlebitis, portal venous thrombosis, sepsis

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DIAGNOSIS DIAGNOSTIC IMAGING CT scan with IV contrast ▪ Increased appendix diameter ▪ Increased wall enhancement ▪ Severe ▫ Visible abscess, pus spillage Ultrasound (pregnancy, children) ▪ Visible, noncompressible, dilated appendix ▪ ↑ blood flow in appendix wall ▪ Visible appendicolith ▪ Right iliac fossa fluid collection

Chapter 34 Intestinal Diseases

LAB RESULTS

▪ Neutrophilic leukocytosis ▫ ↑ with progression ▪ Mildly elevated serum bilirubin ▫ Perforation marker

TREATMENT MEDICATIONS

▪ Antibiotics ▪ IV fluids, no food/water orally (NPO)

SURGERY

▪ Removal (appendectomy) ▪ Abscess drainage

Figure 34.1 Camera view of a laparoscopic appendicectomy being performed. The appendicectomy has been performed and the stump is visible on the right of the image, with the severed appendix reflected laterally.

DIVERTICULITIS osms.it/diverticulitis PATHOLOGY & CAUSES ▪ Inflamed diverticula; microperforation of diverticulum

CAUSES

▪ Increased intraluminal pressure → erosion → inflammation, focal necrosis → micro/ macro perforation

RISK FACTORS

▪ Diverticula present

COMPLICATIONS

▪ Stricture, intestinal obstruction ▪ Diverticulum perforation ▫ Abscess, peritonitis ▪ Fistula formation ▫ Bladder communication ▫ Other organ communication (vagina, skin, other parts of bowel) ▫ Vesicoenteric fistula: pneumaturia (air in urine), fecaluria (stool in urine)

SIGNS & SYMPTOMS ▪ Left lower-quadrant pain (often sigmoid colon); palpable abdominal mass; diarrhea/ constipation; nausea; vomiting; fever; urinary urgency/frequency/dysuria (inflamed sigmoid colon → bladder irritation)

DIAGNOSIS DIAGNOSTIC IMAGING CT scan with contrast ▪ Inflammation → hyperdense tissue Abdominal X-ray ▪ Bowel obstruction ▪ Bowel perforation ▫ Free air

LAB RESULTS ▪ Leukocytosis

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TREATMENT MEDICATIONS

▪ Uncomplicated ▫ Antibiotics, fluids, no food/water orally (NPO)

SURGERY

▪ Resection ▫ Severe case/recurrence/complication

OTHER INTERVENTIONS ▪ High-fiber diet ▫ Prevents recurrence

Figure 34.2 Gross pathology of sigmoid diverticulosis. Notice how the diverticula appear either side of the longitudinal muscle.

DIVERTICULOSIS osms.it/diverticulosis

▪ Diverticulum (plural diverticula): outpouching of hollow anatomical structure wall ▫ Most frequent in large intestine (particularly sigmoid colon) ▪ Diverticulosis: multiple diverticula present

(some areas) → mucosa/submucosa herniation predisposed → diverticulum formation ▫ Sigmoid colon: smallest diameter → highest pressure (Laplace’s Law: P∝1/D), most common location ▪ Outpouching: tend to form where intestinal wall-supplying blood vessels (i.e. vasa recta) traverse muscle layer

TYPES

RISK FACTORS

PATHOLOGY & CAUSES

True diverticulum ▪ All organ wall layers included (e.g. Meckel’s diverticulum) False (pseudo-) diverticulum ▪ Only mucosa, submucosa layers included ▫ Most common ▫ Colonic diverticula

CAUSES

▪ Multifactorial pathogenesis from abnormal colonic motility ▪ Abnormal/exaggerated smooth muscle contractions → unequal intraluminal pressure distribution → high pressure

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▪ Lifestyle: low-fiber diet, constipation; fatty food, red meat-rich diet; inactivity; smoking ▪ ↑ age ↑ risk ▪ Biologically-male ▪ Family history ▪ Obesity ▪ Connective tissue disorders ▫ Marfan syndrome ▫ Ehlers–Danlos syndrome ▫ Autosomal dominant polycystic kidney disease

Chapter 34 Intestinal Diseases

COMPLICATIONS

▪ Blood vessel surrounding weakened outpouching ruptures → large intestine blood loss → bloody stool ▪ Inflammation (diverticulitis) ▪ Segmental colitis

SIGNS & SYMPTOMS ▪ ▪ ▪ ▪ ▪

Often asymptomatic Vague abdominal pain, tenderness, bloating Occasional cramping Altered bowel habit (diarrhea/constipation) Rectal bleeding (hematochezia—fresh blood in stool)

TREATMENT SURGERY

▪ Resection (if complications develop)

OTHER INTERVENTIONS

▪ Lifestyle changes ▫ Diet (↑ fiber intake), avoid constipation, ↑ physical activity, smoking cessation

DIAGNOSIS ▪ Often found incidentally

DIAGNOSTIC IMAGING X-ray with barium enema ▪ Lower gastrointestinal series ▪ Directly shows pouches CT scan ▪ Visualization of colonic diverticula, thickening of the bowel wall thickening (> 4mm), an increase in soft tissue density within pericolonic

Figure 34.3 Barium study demonstrating multiple diverticula.

OTHER DIAGNOSTICS Colonoscopy, sigmoidoscopy ▪ Visible outpouching

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FEMORAL HERNIA osms.it/femoral-hernia PATHOLOGY & CAUSES ▪ Intestinal projection across femoral canal associated with femoral artery, vein; below inguinal ligament, lateral to pubic tubercle

▪ Abdominal contents enter hernia → may precipitate intestinal obstruction ▫ Most common cause worldwide ▫ Incarcerated/strangulated; severe abdominal pain, tenderness, erythema, fever, nausea, vomiting

CAUSES

▪ Congenital, acquired ▪ Weakness/abnormal fascial opening in abdominal wall ▪ Usually includes properitoneal fat/omentum edge/small bowel loop

RISK FACTORS

▪ Biologically-female, congenital disorder (embryological development → processus vaginalis obliteration failure), hernia (family history), obesity, pregnancy, frequent heavy lifting

DIAGNOSIS DIAGNOSTIC IMAGING Ultrasound ▪ Variable echogenicity of tissue; movement of intra-abdominal structures in an inferior direction through the femoral canal CT scan ▪ Visualization of characteristic funnelshaped neck; protrusion through femoral ring

COMPLICATIONS

▪ Narrow femoral canal ▫ ↑ incarceration/strangulation risk ▪ Compression of femoral vein ▪ Bowel obstruction

SIGNS & SYMPTOMS ▪ Asymptomatic (commonly) ▪ Can manifest intestinal obstruction symptoms ▫ Bulging mass, pain, discomfort ▫ Supine: may resolve ▫ Valsalva maneuver (coughing/straining): worsens

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TREATMENT SURGERY

▪ Repair ▫ Open/laparoscopic (case-dependent) ▪ Early/elective repair ▫ Uncomplicated, asymptomatic hernia ▪ Urgent repair ▫ Complicated hernia (may require bowel resection)

Chapter 34 Intestinal Diseases

GALLSTONE ILEUS osms.it/gallstone-ileus PATHOLOGY & CAUSES ▪ Gastrointestinal motility (peristalsis) disruption → impaired bowel content propulsion ▪ Blockage → progressive intestine dilation blockage-proximal, decompression blockage-distal ▪ Gas accumulation (swallowed air, bacterial fermentation) → ↑ bowel distention ▪ Bowel wall edema → ↓ bowel content absorption → luminal fluid sequestration ▪ ↑ capillary permeability → transudative fluid loss from intestinal lumen into peritoneal cavity ▪ Emesis → fluid, electrolyte (Na, K, H, Cl) loss → metabolic alkalosis, hypovolemia ▪ Bowel dilation continues → ↓ intestinal wall tissue perfusion → ischemia, necrosis, bowel perforation

TYPES Onset ▪ Acute: factors such as torsion, intussusception → sudden onset ▪ Chronic: factors such as tumor growth → prolonged onset ▪ Recurrent: often caused by adhesions → intermittent obstructions Extent ▪ Partial: some of intestinal lumen remains open ▪ Complete: total lumen obstruction Location ▪ Intrinsic: obstruction within bowel wall—e.g. inflammatory stricture, edema, hemorrhage, foreign body (ingested, parasite accumulation, large biliary calculus) ▪ Extrinsic: obstruction outside bowel wall— e.g. torsion, compression (hernia)

Effect on intestinal wall ▪ Simple: no blood supply impairment ▪ Strangulated: blood supply cut off to bowel section ▪ Closed loop: obstruction occurs at each end of bowel section Type of factor ▪ Mechanical: obstruction caused by gallstone, neoplasm, adhesion, stricture, hematoma, meconium (in cystic fibrosis), medical device migration (PEG tube) ▪ Functional: intestinal musculature paralysis caused by trauma (surgery, blunt abdominal trauma), peritonitis, medication (opiates, anticholinergics)

RISK FACTORS

▪ Surgery; bowel manipulation, anesthesia, postoperative opioids ▪ Hernia, neoplasm history, abdominal/pelvic irradiation, chronic inflammation, abdominal trauma

COMPLICATIONS

▪ Fluid/electrolyte/acid-base imbalance; bowel strangulation, necrosis; perforation; sepsis

SIGNS & SYMPTOMS ▪ Abdominal distension, cramping pain, constipation, nausea, vomiting ▪ Dehydration: tachycardia, dry mucous membranes, ↓ urine output ▪ Bowel sounds ▫ High-pitched “tinkling” sound auscultated: acute mechanical bowel obstruction ▫ Muffled, hypoactive bowel sounds: significant bowel distention association ▪ Abdominal percussion: hyperresonance/ tympany

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DIAGNOSIS DIAGNOSTIC IMAGING X-ray ▪ Small intestine, colon distension

TREATMENT SURGERY

▪ Surgical intervention: e.g. release adhesions, complete obstructions, repair bowel

OTHER INTERVENTIONS

▪ No food/water orally (NPO) ▪ Fluid, electrolyte replacement ▪ Parenteral feeding → nasogastric decompression

Figure 34.4 A CT scan of the abdomen and pelvis in the coronal plane demonstrating a gallstone in the terminal ileum. If so large that it is unable to pass through the ileocecal valve, the gallstone will cause small bowel obstruction.

GASTROENTERITIS osms.it/viral-gastroenteritis PATHOLOGY & CAUSES ▪ Gastrointestinal tract viral infection (lasts 12 hours–3 days) ▪ Primary transmission ▫ Oral–fecal route ▪ Viruses → epithelium damage → osmotic diarrhea (> three stools daily), vomiting

CAUSES

▪ Children: rotavirus (most common) ▪ Adult: norovirus (most common), astrovirus, adenoviruses

RISK FACTORS

▪ ↑ morbidity ▫ Children, elderly, immunocompromised individuals

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▪ Viral contact ▫ E.g. daycare center, cruise ship, closed community outbreak; contaminated food/water

COMPLICATIONS

▪ Severe dehydration → altered mental status, weight loss

SIGNS & SYMPTOMS ▪ Watery diarrhea; nausea; vomiting; abdominal cramps, pain; fever; malaise; dehydration (dry lips, skin turgor, tachycardia)

Chapter 34 Intestinal Diseases

DIAGNOSIS LAB RESULTS

▪ Stool sample ▫ Excludes bacterial/parasitic etiology ▪ ↑ C-reactive protein (CRP), ↑ leukocytes ▪ Polymerase chain reaction (PCR) ▫ Stool, vomit: enzyme-linked immunosorbent assay (ELISA) performed for rotavirus

TREATMENT Figure 34.5 A scanning electron micrograph of a cluster of Norwalk virus capsids.

OTHER INTERVENTIONS ▪ Fluid replacement

Prevention ▪ Hygiene practices, rotavirus vaccine

INGUINAL HERNIAS osms.it/inguinal-hernias PATHOLOGY & CAUSES Direct inguinal hernia ▪ Peritoneal sac; projects directly through inguinal triangle (AKA Hesselbach’s triangle) ▪ Projects medially to inferior epigastric vessels, lateral to rectus abdominis, pierces parietal peritoneum ▪ Hesselbach’s triangle composition: inguinal ligament (AKA Poupart’s ligament), rectus abdominis muscle (lateral border), inferior epigastric vessels ▪ Covered by external spermatic fascia Indirect inguinal hernia ▪ Most common hernia ▪ Intestinal projection through internal inguinal ring ▫ Location: spermatic cord (biologicallymale), round ligament (biologicallyfemale) exit the abdomen

▫ Testicular descent path: covered by three layers of spermatic fascia (three layers); external spermatic fascia (external oblique muscle fascia continuation); cremasteric muscle fascia; internal spermatic fascia (internal oblique muscle fascia continuation)

CAUSES Indirect inguinal hernia ▪ Processus vaginalis closure failure (i.e. internal inguinal ring and processus vaginalis obliteration failure)

RISK FACTORS Direct inguinal hernia ▪ Acquired, affects transversalis fascia ▫ Chronic intra-abdominal pressure ↑ (e.g. obesity, chronic cough, constipation, heavy lifting—occupational/recreational) ▪ Abdominal wall musculature atrophy

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(aging) ▪ Older, biologically-male individuals Indirect inguinal hernia ▪ Biologically-male individuals > biologicallyfemale individuals ▫ Biologically male: late right testicle descent ▫ Biologically female: asymmetric pelvis

COMPLICATIONS Direct inguinal hernia ▪ Incarceration/strangulation potential Indirect inguinal hernia ▪ Can form hydrocele ▪ May precipitate intestinal obstruction ▪ Most common cause worldwide

SIGNS & SYMPTOMS ▪ May be asymptomatic ▪ Bulging mass (indirect inguinal hernia, mass in groin), pain, discomfort ▫ Valsalva maneuver cessation/prone: may resolve ▪ Valsalva maneuver: worsens projection ▫ Coughing/straining

DIAGNOSIS DIAGNOSTIC IMAGING Ultrasound ▪ Direct inguinal hernia ▫ Variable echogenicity of tissue; movement of intra-abdominal structures in an anterior direction through the Hesselbach triangle ▪ Indirect inguinal hernia ▫ Visualization through abdominal wall in biologically-female individuals CT scan ▪ Direct inguinal hernia ▫ Visualization of a protrusion with compressing inguinal canal contents; inguinal canal pushed into a semicircle of tissue that resembles a moon crescent ▪ Indirect inguinal hernia ▫ Identifies occult hernia/complications; hernia neck visualized superolateral to the inferior epigastric vessels

OTHER DIAGNOSTICS

▪ Indirect inguinal hernia ▫ History, clinical exam; sufficient for majority of suspected inguinal hernias

Direct inguinal hernia ▪ May precipitate intestinal obstruction ▫ Most common cause worldwide ▫ Incarcerated/strangulated: severe abdominal pain, tenderness, erythema, fever, nausea, vomiting Indirect inguinal hernia ▪ Visible bulge ▫ May be unapparent in biologicallyfemale individuals ▪ Incarcerated/strangulated ▫ Severe abdominal pain, tenderness, erythema, fever, nausea, vomiting Figure 34.6 Intraperitoneal view of an inguinal hernia during a laparoscopic hernia repair. The peritoneal cavity extends into the inginal canal, lateral to the epigastric vessels, making this an indirect hernia.

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Chapter 34 Intestinal Diseases

TREATMENT SURGERY Repair ▪ Open/laparoscopic (case-dependent) ▪ Elective repair ▫ Symptomatic hernias ▪ Direct inguinal hernia (asymptomatic) ▫ Monitor, surgical repair preferred

Figure 34.7 Clinical appearance of a hernia in the groin. It is often not possible to distinguish between a direct and indirect hernia on clinical examination alone.

Figure 34.8 A CT scan in the coronal plane demonstrating an indirect inguinal hernia. The proximal bowel is dilated, indicating a strangulated hernia causing obstruction.

INTESTINAL ADHESIONS osms.it/intestinal-adhesions PATHOLOGY & CAUSES ▪ Fibrous tissue bands form physical attachment between intestines → ↓ intestinal motility ▪ Formed from scarred, post-trauma tissue ▪ Tissue injury → inflammation → fibrin deposits → fibrin connects parts left (similar to reconstructive “glue”) ▪ Adhesions extend between tissue if both parts have been injured, close proximity ▪ Initial fibrous adhesions dissolved by fibrinolytic enzymes

▪ Injury prevents enzyme secretion → macrophages, fibroblasts deposit collagen into adhesion → permanent

CAUSES

▪ Surgery (most common), inflammation (cholecystitis, pancreatitis, peritonitis), endometriosis, pelvic inflammatory disease

COMPLICATIONS

▪ Bowel obstruction, intestinal wall volvulus/ ischemia

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SIGNS & SYMPTOMS ▪ Abdominal pain, vomiting, bloating, constipation

DIAGNOSIS DIAGNOSTIC IMAGING X-ray ▪ Detect obstruction; small intestine dilation CT scan, ultrasound ▪ Exclude other obstructive causes

Figure 34.9 Intraoperative view of abdominal adhesions.

TREATMENT SURGERY

▪ Surgical/laparoscopic adhesion excision

INTUSSUSCEPTION osms.it/intussusception PATHOLOGY & CAUSES ▪ Condition that occurs when part of intestine folds into adjacent section → obstruction ▪ Ileocecal region most commonly affected ▪ May be idiopathic/caused by abnormal structure (causes pathological lead point) → peristalsis causes one part of bowel to move ahead of adjacent section → bowel telescoping → ↑ pressure, impaired venous return → bleeding, bowel ischemia, infarction

CAUSES

▪ Adults: abnormal growth (e.g. polyp, tumor) ▪ Infants: post-infection lymphoid hyperplasia (Peyer’s patches), Meckel’s diverticulum

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RISK FACTORS

▪ Most common < 24 months old, intestinal malrotation history, previous intussusception, intussusception in sibling, biologically male

COMPLICATIONS ▪ Peritonitis, sepsis

SIGNS & SYMPTOMS ▪ Intermittent abdominal pain (worsens with peristalsis) ▪ Guarding ▪ Straining efforts, draw knees toward chest ▪ Vomiting ▪ Sausage-like abdominal mass ▪ “Red currant jelly” stool (blood, mucus)

Chapter 34 Intestinal Diseases

DIAGNOSIS

TREATMENT

DIAGNOSTIC IMAGING

SURGERY

Ultrasound, X-ray, CT scan ▪ Telescoped intestine: visualized as classic bull’s-eye image ▪ Intestinal obstruction signs

OTHER INTERVENTIONS

OTHER DIAGNOSTICS

▪ Free telescoped intestine portion → clear obstruction → remove necrotic tissue

▪ Reduction by air/hydrostatic contrast material enema (e.g. saline, barium)

▪ May be felt during digital rectal examination (children)

IRRITABLE BOWEL SYNDROME (IBS) osms.it/IBS PATHOLOGY & CAUSES ▪ Chronic functional gastrointestinal system disorder; recurrent abdominal pain, impaired bowel motility ▫ No microscopic, macroscopic irregularities ▫ Constipation/diarrhea

CAUSES

▪ Pathology not completely understood; likely multifactorial ▫ Visceral hypersensitivity: altered stimuli response ▫ Fecal flora alterations; bacterial overgrowth ▫ Food sensitivity: short-chain carbohydrates; ↑ water in bowel → smooth muscle spasm, diarrhea; metabolized by bacteria → gas → bloating, spasm, pain ▫ Psychosocial influence ▫ Genetic factor

RISK FACTORS

▪ Biologically-female (region-dependent),

previous gastroenteritis, stress

SIGNS & SYMPTOMS ▪ Impaired bowel motility → diarrhea/ constipation ▪ Recurrent abdominal pain ▫ Bowel movement → improvement ▪ Bloating, nausea, mucus in stool

DIAGNOSIS OTHER DIAGNOSTICS

▪ Based on predominant consistency of stool ▫ Diarrhea predominant, constipation predominant, mixed stool pattern, unclassified ▪ Organic disease exclusion

“Rome IV” diagnostic criteria ▪ Abdominal pain ≥ one day weekly in last three months, associated with two/more of following ▫ Defecation → lessened pain ▫ Change in stool frequency ▫ Change in stool consistency

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TREATMENT ▪ No definitive cure

MEDICATIONS

▪ Symptom-guided therapy ▫ Diarrhea predominant: drugs (e.g. loperamide) ▫ Constipation predominant: fiber supplementation, adequate fluid intake, osmotic laxatives ▫ Spasm, pain: antispasmodics

OTHER INTERVENTIONS

▪ Stress management ▪ Diet modification ▫ Low fermentable oligo-, di-, monosaccharides/polyols diet (low FODMAPs diet) ▫ Avoid gas-producing food (caffeine, alcohol) ▫ Probiotics ▫ Physical activity

ISCHEMIC COLITIS osms.it/ischemic-colitis PATHOLOGY & CAUSES ▪ Inflammatory, ischemic condition; affects colon, most often splenic flexure, rectosigmoid junction ▪ Sudden blood flow ↓ → insufficient perfusion, oxygen/nutrient delivery to bowel → compromised cellular metabolism → ischemia, inflammation, infarction, necrosis → possible perforation ▪ Damaged, gangrenous mucosa promotes fluid/electrolyte loss → dehydration, shock, metabolic acidosis

CAUSES

▪ Ischemia causes may be occlusive (embolic, thrombotic)/nonocclusive (↓ mesenteric circulation → severe hypotension, vasospasm) ▫ Usually acute, may be chronic disorder for marathon runners

RISK FACTORS

▪ Any cause of ↓ perfusion/mesenteric arterial embolism, thrombosis/vasoconstriction ▫ Risk ↑ with age/comorbidities

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▫ Hypercoagulable states (e.g. factor V Leiden) ▫ Biologically-female individuals ▫ Impaired perfusion (e.g. aortic surgery, myocardial infarction, hemodialysis) ▫ Vasculopathy ▫ Certain drugs (e.g. vasopressors)

COMPLICATIONS

▪ Gangrenous bowel, stricture, pancolitis, colonic perforation, peritonitis, sepsis, shock, metabolic acidosis, multisystem organ failure, reperfusion injury, potentially fatal

SIGNS & SYMPTOMS ▪ Symptomatology may be self-limiting ▪ Localized abdominal cramping, tenderness (usually left side) ▪ Loose, bloody stools, hematochezia ▪ ↓ bowel sounds ▪ Guarding, rebound tenderness ▪ Fever ▪ May develop shock signs (e.g. hypotension)

Chapter 34 Intestinal Diseases

DIAGNOSIS

▪ Stool culture ▪ Identifies infectious etiology

DIAGNOSTIC IMAGING X-ray/CT scan ▪ Abdominal; visualizes obstruction, perforation, pneumonitis ▫ Thumbprinting: segmented bowel edema/thickening pattern ▫ Double-halo pattern: mucosa, muscularis hyperdensity ▫ Pneumatosis coli, pneumoperitoneum indicates perforation

TREATMENT MEDICATIONS

▪ Antibiotics ▫ Perforation/infection

SURGERY

▪ Bowel resection ▫ Necrotic tissue

Colonoscopy ▪ Visualizes ischemia: edema, erythema, friable mucosa ▪ Single-stripe sign: linear ulcer seen along longitudinal axis ▪ Submucosal hemorrhage: bluish nodules ▪ Biopsy: transmural fibrosis, mucosal atrophy

LAB RESULTS

▪ Leukocytosis, thrombocytopenia, ↓ hemoglobin ▪ ↑ serum lactate, lactate dehydrogenase (LDH), creatine phosphokinase (CPK), amylase indicates tissue damage

Figure 34.10 The endoscopic appearance of the colon in a case of ischemic colitis. There is mucosal edema and patchy erythema.

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OTHER INTERVENTIONS ▪ Circulatory support ▫ IV fluids, electrolytes ▪ Supplemental oxygen ▪ Bowel rest

Figure 34.11 Histological appearance of the colon in an individual with ischemic colitis. There is mucosal necrosis, a sign that the condition is in its early stages at the time of biopsy.

NECROTIZING ENTEROCOLITIS (NEC) osms.it/necrotizing-enterocolitis PATHOLOGY & CAUSES ▪ Severe intestinal disorder: inflammation, ischemic necrosis ▫ Terminal ileum, colon (most often affected) ▪ Multifactorial pathology ▪ Preterm infants ▫ Immature gastrointestinal tract characterized by ↓ intercellular junction integrity + ↓ mucosal barrier → triggering event → normal intestinal microbiome dysbiosis → ↑ pathogenic bacterial growth → exaggerated immune system response → release of host cytokines, chemokines → tissue injury → necrosis ▪ Term infants ▫ Usually underlying condition adversely affecting intestinal perfusion

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RISK FACTORS

▪ Gestational age < 32 weeks ▪ Low birth weight < 2kg/4.41lbs ▪ Dysbiosis-contributing interventions ▫ Antibiotics, acid-reducing agents, feeding bovine milk formula ▪ Human milk promotes commensal bacteria growth, supports mucosal integrity ▪ Infections, gas-forming organism presence ▪ Underlying conditions ▫ Term infants (e.g. fetal growth restriction, perinatal hypoxia, congenital heart disease, gastrointestinal disorders, sepsis)

COMPLICATIONS

▪ Bowel perforation, ileus, septic shock, metabolic acidosis, coagulopathy, respiratory failure ▪ Surgical complications

Chapter 34 Intestinal Diseases ▫ Strictures, short bowel syndrome ▪ ↑ impaired neurodevelopmental development risk ▪ High mortality rate

SIGNS & SYMPTOMS ▪ Abrupt feeding tolerance change ▪ Abdominal distension, tenderness ▪ Erythema, crepitus, induration may also be present ▪ ↑ gastric residuals ▪ Vomiting (often bilious), bilious drainage from enteral feeding tubes ▪ Hematochezia ▪ Nonspecific findings ▫ Temperature instability, lethargy, apnea

OTHER DIAGNOSTICS Surgery ▪ Through surgical/postmortem specimens ▫ Gross examination: gangrenous necrosis, hemorrhage, subserosal gas collection ▫ Histological examination: edema, hemorrhage, transmural necrosis, bacterial infiltration

TREATMENT MEDICATIONS

▪ Empirical antimicrobial therapy

SURGERY

▪ Exploratory laparotomy, bowel resection ▪ Primary peritoneal drainage (PPD) → ↓ intra-abdominal pressure

OTHER INTERVENTIONS

Figure 34.12 Gross pathology of necrotizing enterocolitis.

▪ Address complications (e.g. metabolic correction/hematologic abnormalities) ▪ Bowel rest with nasogastric intubation decompression ▪ Supplemental oxygen/mechanical ventilation ▪ Fluid replacement ▪ Inotropic support ▪ Total parenteral nutrition (TPN)

DIAGNOSIS DIAGNOSTIC IMAGING Abdominal radiography, ultrasound ▪ Pneumatosis intestinalis, pneumoperitoneum/hepatobiliary gas

LAB RESULTS

▪ Positive blood culture, ↓ platelets, ↓ red blood cells, disseminated intravascular coagulopathy evidence, ↑ serum lactate

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SMALL BOWEL ISCHEMIA & INFARCTION osms.it/ischemia-and-infarction PATHOLOGY & CAUSES ▪ Serious small bowel condition; reduced blood flow, subsequent infarction; AKA mesenteric ischemia ▫ Collateral circulation network → small bowel especially vulnerable to widespread ischemic injury ▫ Hypoxia, subsequent reperfusion → tissue injury ▪ ↓ blood flow may be acute/chronic ▫ Acute: sudden ↓ small intestine perfusion ▫ Chronic: episodic ↓ digestion perfusion (often related to mesenteric atherosclerosis) ▪ Insufficient perfusion, oxygen/nutrient delivery to bowel → compromised cellular metabolism → ischemia, inflammation, transmural infarction, necrosis → bacterial transmigration + possible perforation ▪ Damaged, gangrenous mucosa promotes fluid/electrolyte loss → dehydration, shock, metabolic acidosis

CAUSES

▪ Ischemia causes ▫ Occlusive (arterial/venous): embolic, thrombotic, tumor, volvulus, intussusception, hernia, atherosclerosis ▫ Nonocclusive: severe hypotension, vasospasm → ↓ mesenteric circulation

RISK FACTORS

▪ Any cause of ↓ perfusion/mesenteric arterial embolism, thrombosis/vasoconstriction ▪ Cardiac disorders (e.g. arrhythmia, valvular disease → arterial emboli formation from heart; ↓ cardiac output, peripheral hypoperfusion) ▪ Procedures (e.g. cardiac catheterization,

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▪ ▪ ▪ ▪ ▪

cardiopulmonary bypass surgery, hemodialysis → ↓ intestinal perfusion) Coagulative disorders Atherosclerotic occlusive disease Hypovolemia (e.g. dehydration, hemorrhage) Bowel strangulation (e.g. volvulus, incarcerated hernia) Vasoconstriction medications

COMPLICATIONS

▪ Ileus, shock, metabolic acidosis, multisystem organ failure, high mortality

SIGNS & SYMPTOMS ▪ Severe abdominal pain (often postprandial); nausea, vomiting; distended abdomen; guarding, rebound tenderness (develops later); ↓ bowel sounds; fever; feculent breath odor; rectal bleeding; may exhibit shock signs (e.g. hypotension)

DIAGNOSIS DIAGNOSTIC IMAGING CT/magnetic resonance (MR) angiography ▪ Detects acute mesenteric ischemia Abdominal X-ray/CT scan ▪ Dilated bowel loops, bowel wall thickening, thumbprinting, intestinal pneumatosis, free intraperitoneal air

LAB RESULTS

▪ Leukocytosis with left shift, ↑ hematocrit (dehydration, hemoconcentration) ▪ ↑ serum lactate, amylase, alkaline phosphatase

Chapter 34 Intestinal Diseases

OTHER DIAGNOSTICS

SURGERY

▪ Laparotomy ▫ Abdominal exploration

▪ Resection

OTHER INTERVENTIONS

TREATMENT

▪ Pain management ▪ Bowel rest with decompression

MEDICATIONS

▪ Antibiotics ▪ Circulatory support ▫ IV fluids, electrolytes, inotropic medications

VOLVULUS osms.it/volvulus PATHOLOGY & CAUSES ▪ Intestinal obstruction ▫ Intestinal twisting/looping

TYPES

▪ Classified by location

Sigmoid volvulus (most common) ▪ Usually middle-aged/elderly individuals ▪ Causes include pregnancy, chronic constipation (e.g. Hirschsprung’s disease), intestinal adhesions Cecal volvulus ▪ Causes include impaired abdominal mesentery development, pregnancy, chronic constipation Midgut volvulus ▪ Usually infants/young children ▪ Caused by anomalous intestinal development (e.g. intestinal malrotation)

COMPLICATIONS

SIGNS & SYMPTOMS ▪ Abdominal tenderness, pain, distension, bilious vomiting, constipation, fever, auscultation (abnormal bowel sounds, often decreased), percussion (tympany), hematochezia (may indicate bowel ischemia, necrosis)

DIAGNOSIS DIAGNOSTIC IMAGING X-ray ▪ Asses volvulus shape ▫ Bent inner tube sign (“coffee bean” sign) Barium enema ▪ May show “bird’s beak” shape (point of twisted bowel) ▪ Perforation suspected → barium contrast contraindicated CT scan ▪ Twisted mesentery (“whirlpool” sign)

▪ Mesenteric artery compression → intestinal wall ischemia, infarction ▪ Intestinal wall perforation, infection (e.g. diffuse peritonitis)

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TREATMENT SURGERY

▪ In case of midgut volvulus/ischemia/ necrosis; surgical resection if necessary

OTHER INTERVENTIONS

▪ IV fluid replacement ▪ Bowel decompression ▫ Sigmoid volvulus: sigmoidoscopy ▫ Cecal volvulus: colonoscopy

Figure 34.13 Abdominal radiograph demonstrating a massively dilated sigmoid colon in a case of sigmoid volvulus.

Figure 34.14 3D CT virtual colonoscopy demonstrating sigmoid volvulus.

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NOTES

NOTES

LIVER & GALLBLADDER CONGENITAL CONDITIONS

GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES

DIAGNOSIS

▪ Inherited metabolic/congenital structural anomalies, affect hepatobiliary system → hyperbilirubinemia

DIAGNOSTIC IMAGING

COMPLICATIONS

LAB RESULTS

▪ ▪ ▪ ▪

Kernicterus Recurrent cholangitis, cirrhosis Portal hypertension Metabolic problems, impaired growth

SIGNS & SYMPTOMS ▪ Jaundice, dark urine, light stools ▪ Impaired liver function ▪ Neurologic alterations

▪ Ultrasound ▪ Oral cholecystogram

▪ Conjugated vs. unconjugated bilirubin, liver function tests ▪ Biopsy

TREATMENT ▪ See individual disorders

BILIARY ATRESIA osms.it/biliary-atresia PATHOLOGY & CAUSES ▪ Congenital anomaly of extrahepatic duct fibrosis, obstruction of bile flow ▪ Infections, environmental toxins, immune dysregulation, genetic mutations → perinatal injury to biliary system ▪ Bile prevented from entering duodenum → impaired fat digestion, absorption + cholestasis, distension of gallbladder, ducts

TYPES

▪ Biliary atresia only; not accompanied by other anomalies (most common) ▪ Biliary atresia + laterality malformations (left-right axis patterning/malpositioning of organs) ▫ Dextrocardia, situs inversus, asplenia/ polysplenia, interrupted inferior vena cava ▫ Related CFC1 gene mutation ▪ Biliary atresia + intestinal atresia, imperforate anus, kidney anomalies

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COMPLICATIONS

▪ Liver cirrhosis, portal hypertension, hepatic encephalopathy ▪ Recurrent cholangitis, cirrhosis ▪ Metabolic problems, impaired growth (associated with malabsorption)

SIGNS & SYMPTOMS ▪ Neonates asymptomatic at birth; stools gradually become acholic, clay-colored ▪ Persistent jaundice ▫ Skin gradually turns yellow, greenishbronze ▪ Dark urine ▫ Increased bilirubin concentration ▪ Portal hypertension ▫ Splenomegaly, ascites, enlarged abdominal veins ▪ Impaired liver function → decreased coagulation factors, bleeding tendencies ▫ Impaired coagulation also related to decreased vitamin K absorption

DIAGNOSIS DIAGNOSTIC IMAGING Ultrasound ▪ Abnormal gallbladder size, shape, contractility; absent common bile duct; “triangular cord” sign (triangle-shaped echogenic density above porta hepatis) Hepatobiliary scintigraphy ▪ Decreased/absent patency of extrahepatic biliary tree

LAB RESULTS

▪ Increased conjugated serum bilirubin, aminotransferases

Liver biopsy ▪ Identifies obstruction-related histological changes

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Figure 35.1 Intraoperative photography of extra-hepatic biliary atresia. The underside of the liver displays only connective tissue in the gallbladder fossa.

TREATMENT MEDICATIONS

▪ Ursodeoxycholic acid (hydrophilic bile acid)

SURGERY

▪ Type indicated by blood chemistry, imaging, biopsy

Intraoperative cholangiogram ▪ Gold standard for confirming obstruction, diagnosis Hepatoportoenterostomy (Kasai HPE) ▪ Restores bile flow from liver; may need subsequent revision Liver transplant ▪ If Kasai procedure unsuccessful

OTHER INTERVENTIONS Diet ▪ Fat-soluble vitamin supplements; high protein diet, medium-chain triglyceride supplements

Chapter 35 Liver & Gallbladder Congenital Conditions

CRIGLER–NAJJAR SYNDROME osms.it/crigler-najjar-syndrome PATHOLOGY & CAUSES ▪ Rare inherited metabolic disorder; nonhemolytic hyperbilirubinemia ▪ Autosomal recessive inheritance pattern ▪ AKA congenital nonhemolytic jaundice with glucuronosyltransferase deficiency

TYPES

COMPLICATIONS

▪ Kernicterus (Type I), if not promptly addressed

SIGNS & SYMPTOMS ▪ Persistent jaundice in first few days of life ▪ Neurological symptoms as kernicterus develops

Type I ▪ Severe jaundice, bilirubin encephalopathy, possible kernicterus-associated neurologic impairment

LAB RESULTS

Type II ▪ Lower serum bilirubin concentration; no neurologic impairment

Unconjugated hyperbilirubinemia ▪ Type I: 20–50 mg/dL ▪ Type II: < 20 mg/dL

CAUSES

▪ Mutation in coding area of UGT gene, encodes for bilirubin-conjugating enzyme UGT1A1 (bilirubin-uridine diphosphate glucuronosyltransferase) → structurally abnormal enzyme → decreased/absent conjugation of bilirubin

DIAGNOSIS

Stool color ▪ Type I: pale yellow, low fecal urobilinogen (significantly decreased bilirubin conjugation) ▪ Type II: normal Normal liver histology, liver function tests

RISK FACTORS ▪ Consanguinity

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TREATMENT MEDICATIONS Phenobarbital ▪ Useful in Type II, induces residual UGT activity

SURGERY

OTHER INTERVENTIONS Phototherapy ▪ In first years of life; effectiveness decreases over time Exchange transfusion Plasmapheresis + albumin infusions ▪ Removes bilirubin tightly bound to serum albumin

Liver transplant ▪ Definitive treatment for Crigler-Najjar syndrome Type I

DUBIN–JOHNSON SYNDROME osms.it/dubin-johnson-syndrome PATHOLOGY & CAUSES ▪ Inherited metabolic disorder; mild, fluctuating elevations in conjugated (predominantly), unconjugated bilirubin, no evidence of hemolysis ▪ Autosomal inheritance pattern ▪ MRP2 (ABCC) gene mutation → impaired hepatic excretion of non-bilesalt organic anions, bilirubin into bile via canalicular membrane → cholestasis → hyperbilirubinemia

SIGNS & SYMPTOMS ▪ Mild jaundice; evident during physiological stress (e.g. illness)/hormonal fluctuations (e.g. pregnancy, oral contraceptives) ▪ Constitutional ▫ Vague abdominal pains, weakness ▪ Occasional hepatosplenomegaly

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DIAGNOSIS DIAGNOSTIC IMAGING Oral cholecystogram ▪ Gallbladder may not be visualized

LAB RESULTS

▪ Hyperbilirubinemia, normal liver function tests ▪ Total urinary coproporphyrin normal; majority, coproporphyrin I

Liver biopsy, histological exam ▪ Brown, black discoloration ▫ Pigment accumulates in lysosomes

TREATMENT ▪ None required

Chapter 35 Liver & Gallbladder Congenital Conditions

GILBERT'S SYNDROME osms.it/gilberts-syndrome PATHOLOGY & CAUSES

SIGNS & SYMPTOMS

▪ Benign, inherited metabolic disorder; recurring unconjugated hyperbilirubinemia, jaundice ▪ Autosomal recessive inheritance pattern ▪ AKA Meulengracht disease, familial nonhemolytic jaundice ▪ Serum bilirubin increases during physiologic stress (e.g. illness, dehydration, fasting, overexertion, menses) ▪ Differs from other forms of non-hemolytic hyperbilirubinemia ▫ Genetic mutation in promoter region of UGT gene → structurally normal enzyme → impaired genetic expression of hepatic UGT with decreased activity → decreased conjugation of bilirubin

▪ Asymptomatic between episodes, jaundice evident during physiological stress ▪ Clinical manifestations ▫ During adolescence, with effects of sex steroids on bilirubin metabolism

DIAGNOSIS ▪ Exclude other causes of unconjugated hyperbilirubinemia

TREATMENT ▪ None required

ROTOR SYNDROME osms.it/rotor-syndrome PATHOLOGY & CAUSES

SIGNS & SYMPTOMS

▪ Rare benign inherited disorder; chronic conjugated, unconjugated hyperbilirubinemia; no hemolysis ▪ SLCO1B1, SLCO1B3 gene mutations (code for transporter proteins 1B1, 1B3 responsible for bilirubin re-uptake by hepatocytes) → alters bilirubin re-uptake → increases bilirubin in plasma

▪ Mild jaundice; during physiological hormonal fluctuations (e.g. pregnancy, oral contraceptive use)

DIAGNOSTIC IMAGING

COMPLICATIONS

Oral cholecystogram ▪ Normal gallbladder opacification

▪ Impaired 1B1 activity → significant drug toxicities (e.g. statin-associated myopathy)

DIAGNOSIS

LAB RESULTS

▪ Hyperbilirubinemia, normal liver function tests

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▪ Total urinary coproporphyrin markedly increased; majority coproporphyrin I Liver biopsy, histological exam ▪ Normal

TREATMENT ▪ None required

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NOTES

NOTES

LIVER DISEASES GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Diseases affecting hepatic parenchymal tissue or vasculature ▪ Variable insults ▫ Impairment in function of/destruction of liver parenchyma → inflammation → scarring (cirrhosis) → liver failure ▫ Obstruction or restriction of blood flow through liver → hypertension in portal circuit producing secondary systemic effects ▫ Diseases caused by anomalies in absorbing, storing, converting or detoxification → accumulation of substances in the liver and other tissues causing damage

SIGNS & SYMPTOMS ▪ Early stages generally asymptomatic ▪ Non-specific symptoms ▫ Weakness, weight loss, fatigue Portal hypertension ▪ Abdominal distension (ascites) ▪ Splenomegaly ▪ Esophageal varices → trouble swallowing, hematemesis, dark stools ▪ Caput medusae ▫ Dilated periumbilical collateral veins ▪ Cruveilhier–Baumgarten murmur ▫ Venous hum heard in epigastric region with stethoscope Liver cellular dysfunction ▪ Decreased hepatic albumin production ▫ Decreased osmotic pressure → edema ▫ Increase in levels of free circulating compounds normally bound to albumin

(e.g. increase in free calcium) ▪ Decreased hepatic metabolism of circulating estrogens → hyperestrogenism ▫ Spider nevi: vascular lesions, central arteriole surrounded by smaller vessels ▫ Palmar erythema ▫ Gynecomastia ▪ Fetor hepaticus (breath odor due to increased dimethyl sulfide levels) ▪ Jaundice (cellular necrosis → reduced hepatic ability to metabolize, excrete bilirubin → buildup of unconjugated bilirubin in the blood) ▪ Decreased production of coagulation factors → easy bruising, bleeding ▪ Hepatic encephalopathy ▫ Ammonia, related nitrogenous substances not cleared from blood → accumulate in brain → impaired cerebral function

MNEMONIC: ABCDEFGHIJ

Common signs of liver disease Asterixis, Ascites, Ankle edema, Atrophy of testicles Bruising Clubbing/ Color change of nails (leukonychia) Dupuytren’s contracture Encephalopathy / palmar Erythema Fetor hepaticus Gynecomastia Hepatomegaly Increase size of parotids Jaundice

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MNEMONIC: 3Cs & 3Cs

▫ Neglect of personal appearance ▫ Unresponsive, forgetful, trouble concentrating ▫ Changes in sleeping habits ▫ Psychosis ▫ Asterixis (bilateral asynchronous flapping of outstretches, dorsiflexed hands) ▪ Decreased metabolism of active compounds → increased sensitivity to certain medications ▪ Pruritus

DIAGNOSIS DIAGNOSTIC IMAGING

▪ CT scan with contrast, MRI, ultrasound, radionuclide imaging

LAB RESULTS

▪ Complete blood count (CBC) ▪ Liver function tests ▫ Tests of synthetic function: serum albumin level, international normalized ratio (INR) ▫ Hepatocellular enzymes: aspartate transaminase (AST), alanine transaminase (ALT), total bilirubin, direct bilirubin ▫ Ductal enzymes: alkaline phosphatase (ALP), gamma glutamyl transpeptidase (GGT) ▪ Hepatitis virus serology ▫ Hepatitis A: anti-hepatitis A IgM, antihepatitis A IgG ▫ Hepatitis B: hepatitis B surface antigen, anti-hepatitis B core/surface antibodies,

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Hepatomegaly common causes Cirrhosis Carcinoma Cardiac failure

Hepatomegaly rare causes Cholestasis Cysts Cellular infiltration anti-hepatitis B core IgM ▫ Hepatitis C: hepatitis C antibody, hepatitis C RNA ▫ Hepatitis D & E: IgM, IgG antibodies ▪ Autoimmune panel ▫ Rheumatoid factor (RF), anti-cyclic citrullinated peptide antibody (CCP), anti-nuclear antibody (ANA), antidouble stranded DNA (anti-dsDNA), anti-extractable nuclear antigen (antiENA), antineutrophil cytoplasmic antibody (ANCA) ▪ Liver biopsy

TREATMENT ▪ Initially disease-specific; see individual disorders

SURGERY

▪ Advanced disease → liver transplant

Chapter 36 Liver Diseases

ALCOHOLIC LIVER DISEASE osms.it/alcoholic-liver-disease PATHOLOGY & CAUSES ▪ Abnormal lipid retention in hepatocytes (steatosis) → large triglyceride fat vacuoles accumulate in liver cells → fatty liver ▪ Fat content of liver exceeds 5–10% by weight ▪ Can be accompanied by progressive inflammation (hepatitis) → steatohepatitis

RISK FACTORS

▪ Glycogen storage diseases, acute fatty liver during pregnancy, malnutrition, obesity, HIV, hepatitis C

Alcohol ▪ Most common cause ▪ Chronic alcohol use → production of toxic metabolites (e.g. aldehydes) ▫ Damages mitochondria, cellular structures → impaired cellular energy mechanisms ▫ Alcohol metabolised to aldehyde hepatic enzymes (reaction facilitates conversion of NAD+ → NADH; lower NAD+ concentration → less fatty acid oxidation → fatty acids accumulate → steatosis)

STAGING

▪ Stages of intracytoplasmic accumulation of triglycerides → fatty change

Initial stage ▪ Hepatocytes contain small fat vacuoles (liposomes) around nucleus (microvesicular fatty change) Late stage ▪ Vacuoles enlarge → nucleus pushed to cell periphery → signet ring appearance (macrovesicular fatty change) ▪ Vesicles well-delineated, optically empty ▫ Fats dissolve during tissue processing

▪ Large vacuoles coalesce → fatty cysts → irreversible lesions ▪ Macrovesicular steatosis most commonly associated with alcohol, diabetes, obesity, corticosteroids ▪ Severe fatty liver may be accompanied by inflammation, steatosis → steatohepatitis ▫ Steatohepatitis → hepatocyte ballooning, necrosis → liver cell death, inflammatory response → hepatic stellate cell activation → fibrosis → cirrhosis

COMPLICATIONS

▪ Hepatocellular carcinoma

SIGNS & SYMPTOMS ▪ Fatigue, malaise, dull right-upper-quadrant pain, mild jaundice (rare), significant damage → hepatomegaly, ascites

DIAGNOSIS DIAGNOSTIC IMAGING Ultrasound ▪ Steatosis → bright liver with increased echogenicity ▪ Fibrosis → coarse echo pattern ▪ Cirrhosis → nodules → irregular outline of liver surface CT scan ▪ Lower density than spleen on CT scan MRI ▪ Fat → bright on T1 and T2-weighted images

LAB RESULTS Liver function tests ▪ Serum aminotransferases normal/

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moderately elevated ▫ AST usually more elevated than ALT in alcoholic fatty liver disease ▫ GGT often elevated in alcoholic fatty liver disease

TREATMENT ▪ Hepatic steatosis reversible, nonprogressive if underlying cause controlled (e.g. cease alcohol use)

Secondary causes of steatosis ▪ Hepatitis C virus antibodies ▪ Hepatitis A IgG ▪ Hepatitis B surface antigen, surface antibody, core antibody ▪ Plasma iron, ferritin, total iron-binding capacity Biopsy ▪ Early changes ▫ Accumulation of membrane bound large droplet steatosis (Large macrovesicular drops → alcoholic steatosis; small microvesicular droplets → acute fatty liver of pregnancy, tetracycline toxicity, Reye’s syndrome) ▫ Proliferation of smooth endoplasmic reticulum ▫ Gradual distortion of mitochondria ▪ Steatohepatitis ▫ Presence of neutrophils → alcoholic steatohepatitis, unusual in chronic viral hepatitis ▫ Mallory-Denk bodies (clusters of intracellular cytoskeletal protein aggregates) ▪ Advanced changes ▫ Fibrosis: accumulation of scar tissue or extracellular matrix, potentially reversible if individual stops drinking alcohol, not true cirrhosis characterized by presence of regenerative nodules (irreversible)

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Figure 36.1 A Mallory–Denk body is a feature of many liver pathologies including alcoholic hepatitis and alcoholic cirrhosis.

Figure 36.2 Histological appearance of fatty liver. The numerous white spaces represent the accumulation of lipid.

Chapter 36 Liver Diseases

AUTOIMMUNE HEPATITIS osms.it/autoimmune-hepatitis DIAGNOSIS

PATHOLOGY & CAUSES ▪ Inflammation of the liver tissue caused by autoimmunity

TYPES

▪ Type 1: 80% of cases ▪ Type 2: most common in young biologically-female individuals ▪ Type 3: different antibodies but presents as Type 1 ▪ Type 4: no detectable antibodies

CAUSES

▪ Combination of environmental triggers and genetic predisposition

RISK FACTORS

▪ Young biologically-female individuals; presence of HLA-DR3.DR4

COMPLICATIONS

▪ Acute liver failure, chronic liver failure, hepatocellular carcinoma, long term immunosuppression can lead to malignancies

LAB RESULTS

▪ ↑↑ALT, ↑ AST, ↓ albumin, ↑ prothrombin time ▪ Type 1 ▫ Antinuclear antibodies (ANAs), antibodies against smooth muscle proteins, or (ASMAs) ▪ Type 2 ▫ Antibodies to the microsomes of the liver or kidney (ALKM-1), liver cytosol antigen (ALC-1) ▪ Type 3 ▫ Soluble liver antigen positive

TREATMENT MEDICATIONS Immunosuppressants ▪ Corticosteroids, azathioprine

SURGERY Liver transplantation ▪ If resistant to drug therapies

SIGNS & SYMPTOMS ▪ Wide spectrum of presentation, from asymptomatic to cirrhosis and liver failure ▪ Common moderate symptoms ▫ Fever, jaundice, and hepatosplenomegaly ▪ Chronic disease symptoms ▫ Coagulation disturbance, impaired immunity ▪ Type 2 is associated with other diseases (Hashimoto’s thyroiditis, Grave’s disease)

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Figure 36.3 The histological appearance of autoimmune hepatitis. There is an infiltration of lymphocytes and plasma cells at the interface between the hepatic lobule and the portal tract i.e. lymphoplasmacytic interface hepatitis.

BUDD–CHIARI SYNDROME osms.it/budd-chiari-syndrome PATHOLOGY & CAUSES ▪ Congestive hepatic disease caused by obstruction of hepatic venous outflow ▪ Usually > one hepatic vein or hepatic section of vena cava ▪ Venous congestion leads to ▫ Ischemia and centrilobular necrosis ▫ Increased pressure in portal system → portal hypertension

CAUSES

▪ Occlusion (primary) ▫ Thrombosis (most common) ▪ Compression (secondary) ▫ Tumor mass, granuloma

RISK FACTORS

▪ Myeloproliferative and hematologic disorders (e.g. polycythemia vera) ▪ Hypocoagulative disorders ▪ Tumors ▪ Infections (e.g. tuberculosis) ▪ Inflammatory diseases

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▪ Trauma ▪ Pregnancy ▪ Contraceptive therapy

COMPLICATIONS

▪ Cirrhosis and liver failure ▪ Esophageal, gastric and rectal varices ▪ Kidney dysfunction (hepatorenal syndrome)

SIGNS & SYMPTOMS ▪ Can present acutely or chronically ▪ Classic triad ▫ Hepatomegaly ▫ Abdominal pain ▫ Ascites ▪ Jaundice ▪ Fever ▪ Other signs and symptoms of portal hypertension (e.g. splenomegaly, encephalopathy)

Chapter 36 Liver Diseases

DIAGNOSIS DIAGNOSTIC IMAGING Doppler ultrasound ▪ Thrombus ▪ Alteration of hepatic venous outflow ▪ ‘Spider web’ formation around the obstruction duto collateral vessels proliferation Venography CT scan, MRI

LAB RESULTS

▪ Elevated aminotransferases ▪ Liver biopsy

TREATMENT ▪ Treat the underlying cause

MEDICATIONS

▪ Usually insufficient ▪ Anticoagulants ▪ Diuretics

SURGERY Liver transplantation ▪ In case of fulminant liver failure Portosystemic shunt ▪ Divert the flow away from the obstruction ▪ Transjugular intrahepatic portosystemic shunt (TIPS) ▪ Surgical shunt

OTHER INTERVENTIONS Thrombolytic therapy ▪ Dissolve clots ▪ Balloon angioplasty

Figure 36.4 An abdominal CT scan in the axial plane demonstrating hypoperfusion of the right lobe of the liver secondary to BuddChiari syndrome.

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CHOLESTATIC LIVER DISEASE osms.it/cholestatic-liver-disease PATHOLOGY & CAUSES ▪ Cholestasis: decrease in bile flow through bile ducts into duodenum ▪ Hepatic retention, spillage into systemic circulation of cholesterol, bile salts → incorporation into biological membranes → altered membrane fluidity → injury to biological membranes, impaired function of membrane channels → bile secretion impaired in liver ▪ No bile reaches small intestine → intestinal malabsorption → nutritional deficiencies of fat soluble vitamins (A, D, E, K)

CAUSES Hepatocellular cholestasis ▪ Impaired secretion of bile by hepatocytes ▫ Intracellular accumulation of bile acids → ↓ regulation of bile synthesis → ↓ total bile production/secretion → accumulation of bile components (e.g. conjugated bilirubin) → diffuse/ exocytose into interstitium → diffuse into blood Elevated levels of estrogen ▪ Breakdown of cholesterol → cholic acid (bile acid) ▪ ↑ estrogen → inhibition of export pump → estrogen-induced cholestasis ▪ Risk factors ▫ Oral contraceptives (increase estrogen exposure), pregnancy (pregnancyinduced cholestasis), anabolic steroids (similar in structure to estrogen) ▪ Extrahepatic cholestasis ▫ Physical obstruction blocks bile flow ▫ Ductal obstruction → bile accumulates in liver → ↑ pressure in bile ducts → bile leaks through tight junctions between hepatocytes → enters serum, interstitial space ▫ Causes: cholelithiasis (gallstones),

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malignancy (biliary tree/head of pancreas), strictures, cystic fibrosis (impaired secretory function of biliary epithelium), primary sclerosing cholangitis (immune system attacks bile ducts → inflammation, scar tissue), biliary atresia (≥ one newborn infant’s bile ducts narrow/blocked/absent) ▫ Complications: prolonged obstruction → biliary cirrhosis; subtotal/intermittent obstruction → ascending cholangitis (secondary bacterial infection of biliary tree) → sepsis, if untreated

SIGNS & SYMPTOMS ▪ Jaundice ▫ Individual components of bile enter serum (e.g. conjugated bilirubin) ▪ Pain ▫ Right upper quadrant (RUQ) pain, radiates to right shoulder, minutes to hours in duration (often after fatty meal) ▪ Pruritus ▫ Systemic accumulation of bile salts/ endogenous opioids/lysophosphatidic acid ▪ Skin xanthomas ▫ Focal accumulations of cholesterol (common in obstructive jaundice) ▪ Pale stools/dark urine ▫ Absence of bile in gut → conjugated bilirubin (water soluble) not excreted with bile, excreted via kidneys

Chapter 36 Liver Diseases

TREATMENT

DIAGNOSIS

MEDICATIONS

LAB RESULTS Liver function tests (LFTs) ▪ Elevated membrane-bound enzymes (sensitive to hepatocyte damage) → ↑ serum alkaline phosphatase (ALP), gammaglutamyl transpeptidase (GGT) Histology ▪ Individual hepatocytes take on brownishgreen stippled appearance (due to trapped bile), canalicular bile plugs form between individual hepatocytes/bile ducts (excreted bile cannot travel further due to obstruction) ▫ Under sufficient pressure, canalicular plugs may rupture → spillage of bile into surrounding tissue → hepatic necrosis

▪ Associated vitamin deficiency ▫ Fat-soluble vitamin supplementation ▪ Children ▫ Ursodeoxycholic acid → increased bile formation

SURGERY

▪ Extrahepatic obstruction ▫ Surgical correction of obstruction (e.g. cholecystectomy; if gallstone obstructing common bile duct, removal of gallbladder)

OTHER INTERVENTIONS

▪ Pregnancy-induced cholestasis ▫ Early delivery (around week 36 of gestation)

CIRRHOSIS osms.it/cirrhosis PATHOLOGY & CAUSES ▪ Hepatic parenchyma replaced by scar tissue → scar tissue blocks portal flow of blood through liver → raised blood pressure and disturbance of function ▪ Reversible phase → hepatitis/fatty liver (steatosis) often precedes cirrhosis ▪ Long term accumulation of liver damage → disruption of liver architecture → functional impairment ▪ Develops over months to years ▪ Damage to parenchyma → activation of stellate cells (sit between sinusoids and hepatocytes in perisinusoidal space) → secretion of ▫ TGF-β1 → production of myofibroblasts → increased fibrosis, proliferation of connective tissue ▫ TIMP 1 & 2 (matrix metalloproteinase inhibitors) → prevents breakdown of

fibrotic material in extracellular matrix ▪ Fibrotic cascade → formation of fibrous septa → separation of hepatocyte nodules → distortion of liver architecture → decrease blood flow throughout → splenic congestion → hypersplenism, splenic sequestration of platelets ▪ Injured liver cells group together → regenerative nodules (clumps of cells between fibrotic tissue, collagen) → bumpy cirrhotic liver

RISK FACTORS

▪ Chronic alcohol use, chronic hepatitis C infection, chronic hepatitis B (+/- hepatitis D) infection, autoimmune hepatitis, hereditary hemochromatosis, Wilson disease, alpha 1-antitrypsin deficiency, medications

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COMPLICATIONS

▪ Portal hypertension, hepatic encephalopathy, increased blood levels of estrogens, hepatocellular carcinoma

MNEMONIC: HEPATIC

Causes of Cirrhosis Hemochromatosis (primary) Enzyme deficiency (alpha-1anti-trypsin) Post hepatic (infection + drug induced) Alcoholic Tyrosinosis Indigenous people in America (galactosemia) Cardiac/ Cholestatic (biliary)/ Cancer/ Copper (Wilson’s)

SIGNS & SYMPTOMS ▪ Early stages generally asymptomatic ▫ Liver may be enlarged, shrinks as cirrhosis progresses ▫ Non-specific symptoms: weakness, weight loss, fatigue ▪ Portal hypertension ▪ Liver cellular dysfunction ▪ Nail changes (Muehrcke’s lines, Terry’s nails, clubbing) ▪ Hypertrophic osteoarthropathy ▪ Dupuytren’s contracture

DIAGNOSIS DIAGNOSTIC IMAGING Ultrasound ▪ Small nodular liver (advanced cirrhosis), increased echogenicity, irregular- looking areas, widening fissures, splenomegaly, imaging of blood flow in portal vein Endoscopy ▪ Esophagogastroduodenoscopy (EGD) ▫ Exclude esophageal varices ▪ Imaging of bile ducts (endoscopic retrograde cholangiopancreatography

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(ERCP) /magnetic resonance cholangiopancreatography (MRCP)) Diagnostic paracentesis ▪ Determine ascitic fluid origin ▪ Portal hypertension ▪ Suspected spontaneous bacterial peritonitis ▫ Cell count, gram stain, culture ▫ Serum: ascites albumin gradient (SAAG) > 1.1 g/dL → portal HTN

LAB RESULTS

▪ AST, ALT moderately elevated, AST > ALT ▪ ALP 2–3x normal ▪ GGT very high in chronic alcoholic liver disease ▪ Bilirubin increases as cirrhosis worsens ▪ Albumin decreases as synthetic function declines ▪ Prothrombin time increases as synthetic function declines ▪ Hyponatremia from inability to excrete free water (high levels of antidiuretic hormone, aldosterone) ▪ Serum biomarkers correlate with degree of liver damage in variety of liver diseases ▪ A2-macroglobulin, haptoglobin, apolipoprotein A1, bilirubin, GGT, age, biological sex

Histology ▪ Macroscopic appearance ▫ Surface irregular, consistency firm ▫ Yellow color (in steatosis) ▫ Nodular ▪ Liver biopsy ▫ Microscopic appearance of hepatocytes (regenerating nodules) and fibrosis/ connective tissue deposits between nodules ▪ Cause specific abnormalities ▫ Chronic hepatitis B: infiltration of liver parenchyma with lymphocytes ▫ Cardiac cirrhosis: erythrocytes, greater amount of fibrosis in tissue surrounding hepatic vein ▫ Primary biliary cholangitis: fibrosis around bile duct, presence of granulomas, pooling of bile ▫ Alcoholic cirrhosis: neutrophilic infiltration

Chapter 36 Liver Diseases

OTHER DIAGNOSTICS Child-Pugh score ▪ Grading of cirrhosis ▫ Class A (5–6 points): one year survival 100%, two year survival 85% ▫ Class B (7–9 points): one year survival 81%, two year survival 57% ▫ Class C (10–15 points): one year survival 45%, two year survival 35%

TREATMENT

Figure 36.5 Gross pathology of micronodular liver cirrhosis.

MEDICATIONS

▪ Antiviral medication (e.g. interferon) ▫ For hepatitis B, C ▪ Corticosteroids ▫ For autoimmune hepatitis ▪ Diuretics, antibiotics, laxatives, enemas, thiamine, steroids, acetylcysteine, pentoxifylline ▫ For decompensation (compensated cirrhosis—no jaundice, ascites, variceal bleeding, hepatic encephalopathy; development of any of above → decompensated)

OTHER INTERVENTIONS

▪ Abstain from alcohol ▫ For alcoholic hepatitis ▪ Chelation therapy (e.g. penicillamine) ▫ For Wilson disease ▪ Dissolve gallstones ▫ Blockage of bile ducts

Figure 36.6 Histological appearance of liver cirrhosis (trichrome stain). The blue highlights the bands of fibrosis between islands of hepatocytes.

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FITZ–HUGH–CURTIS SYNDROME osms.it/fitz-hugh-curtis-syndrome PATHOLOGY & CAUSES ▪ Pelvic inflammatory disease (PID) → inflammation of local structures → anterior liver capsule inflammation (perihepatitis) → patchy purulent, fibrinous exudate → adhesions form

CAUSES

▪ Etiology of inflammation poorly understood ▪ Thinning of cervical mucus → bacteria colonizing vagina enters uterus, fallopian tubes → infection, inflammation → possibly spreads via ▫ Direct intraperitoneal spread from initial pelvic inflammation and infection ▫ Bacterial seeding via lymphatic bloodstream ▫ Autoimmune response to PID

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▪ Causative organisms ▫ Commonly: Chlamydia trachomatis, Neisseria gonorrhoeae, Mycobacterium tuberculosis (endemic areas) ▫ Reported: Trichomonas vaginalis, Ureaplasma urealyticum, Mycoplasma hominis, Bacteroides spp., Gardnerella vaginalis, E. coli and Streptococcus spp.

RISK FACTORS

▪ Biological females of reproductive age

SIGNS & SYMPTOMS ▪ Vomiting, nausea, hiccupping, headaches ▪ Acute onset right upper quadrant abdominal pain; aggravated by breathing, coughing, laughing (pleuritic pain), may refer to right shoulder, tenderness to

Chapter 36 Liver Diseases palpation, tenderness to percussion of overlying ribs ▪ Fever, chills, night sweats, malaise, vaginal discharge, lower abdominal pain, cervical motion tenderness

DIAGNOSIS ▪ History of pelvic inflammatory disease

TREATMENT MEDICATIONS

▪ Organism-specific antibiotics ▪ Pain management ▫ Appropriate analgesia ▫ Laparoscopy for lysis of adhesions for refractory pain

DIAGNOSTIC IMAGING Abdominal ultrasound ▪ Typically normal Abdominal CT scan with contrast ▪ Perihepatic ▫ Subtle enhancement of liver capsule, inflammatory stranding and fluid along right paracolic gutter and perihepatic region, gallbladder wall thickening, pericholecystic inflammatory change ▪ Pelvic ▫ Possible tubo-ovarian abscess

Figure 36.7 A laparoscopic view of intra abdominal adhesions caused by Fitz-HughCurtis syndrome.

LAB RESULTS

▪ Liver function tests ▫ Typically normal ▪ D-dimer ▫ Markedly raised ▫ Often ordered due to pleuritic chest pain ▪ Endocervical/low vaginal swab ▫ Culture causative organism

OTHER DIAGNOSTICS Laparoscopy ▪ “Violin string” adhesions of parietal peritoneum to liver/diaphragm

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HEMOCHROMATOSIS osms.it/hemochromatosis PATHOLOGY & CAUSES ▪ Excessive iron absorption in the intestine → iron deposited in organs and tissues → free radical generation → cellular damage → cell death → tissue fibrosis

TYPES Primary (hereditary: autosomal recessive) ▪ Variety of possible mutations (C282Y being the most common) in HFE gene on chromosome 6 regulating iron absorption from food → most of the iron in the food is absorbed by enterocytes in the gut and pass into the bloodstream → iron overload Secondary (not genetic) ▪ Multiple blood transfusions → erythrocytes contain iron bound to the hemoglobin → heme is released in bloodstream when erythrocytes die after 120 days ▪ Chronic hemolytic anemias ▪ Excessive iron intake (very rare)

COMPLICATIONS

▪ Caused by deposition of iron in tissues ▫ Liver: cirrhosis, cancer ▫ Pancreas: altered endocrine and exocrine function ▫ Skin: bronze pigmentation ▫ Heart: cardiomyopathy, arrhythmias ▫ Gonads (related to impaired pituitary function): amenorrhea in biologicallyfemale individuals, testicular atrophy in biologically-male individuals ▫ Adrenal gland: gland insufficiency ▫ Joints: degenerative joint disease

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SIGNS & SYMPTOMS ▪ Initially asymptomatic ▫ Biogically male: symptoms appear around age 50 ▫ Biologically female: eliminate iron through menstrual bleeding → symptoms appear 10-20 years after menopause ▪ Signs and symptoms of liver disease ▪ Altered glucose homeostasis (hyper/ hypoglycemia) ▪ Fatigue ▪ Arthralgia ▪ Sexual dysfunction ▪ Abdominal pain ▪ Cardiac arrhythmias

DIAGNOSIS LAB RESULTS ▪ ▪ ▪ ▪

High levels of serum iron Elevated ferritin High transferrin saturation Decreased total iron binding capacity

Liver biopsy ▪ Iron can be seen as brown spots inside hepatocytes → it becomes blue with a Prussian blue stain

OTHER DIAGNOSTICS

▪ Genetic analysis and screening of family members

Chapter 36 Liver Diseases

TREATMENT MEDICATIONS Deferoxamine ▪ Chelating agent binds iron molecules → deferoxamine excreted by kidneys → urine excretion → decreases iron load

SURGERY Figure 36.8 Iron deposition (hemosiderosis) in the liver parenchyma in a case hemochromatosis. There is associated hepatocyte damage.

▪ Advanced liver damage → transplantation

OTHER INTERVENTIONS

▪ Phlebotomy ▪ Dietary changes to reduce iron absorption

Figure 36.9 Prussian blue stain on a liver biopsy highlights iron deposits in a case of hemochromatosis.

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HEPATITIS B osms.it/hepatitis PATHOLOGY & CAUSES ▪ Infection of the liver caused by hepatitis B virus (HBV) ▪ DNA virus from the hepadna group ▪ Incubation is 1–6 months, long term carrier state established after, transmitted through blood or semen ▪ Immune system attacks infected hepatocytes

RISK FACTORS

▪ Intravenous drug users, unprotected sexual intercourse, blood transfusions; hemodialysis

COMPLICATIONS

▪ Liver cirrhosis, hepatocellular carcinoma

SIGNS & SYMPTOMS ▪ General infection ▫ Low grade fever, malaise, lethargy, anorexia ▪ Liver related ▫ Fatty stool, dark urine, jaundice, hepatomegaly, scleral icterus, pruritus, right upper quadrant tenderness

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DIAGNOSIS LAB RESULTS

▪ HBV virions found in blood serum, proves viral replication ▪ ↑ ALT, ↑ AST ▪ ↑ CRP, ↑ ESR, ↑ WBC ▪ HBsAg (surface antigen); present in acute infection then cleared in recovery; if present over six months → chronic infection; used to create vaccine ▪ Anti-HBc IgM (core antigen); present in active infection for six months; if present longer individual is carrier; used for screening because present most of the time ▪ Anti-HBc IgG develop after IgM, lifelong secretion indicates individual is immune ▪ Anti-HBe secreted core antigen, appears during viral replication, indicates active infection ▪ Bilirubin normal to increased

OTHER DIAGNOSTICS

▪ Physical exams shows hepatomegaly

TREATMENT MEDICATIONS

▪ Interferon alpha, nucleoside reverse transcriptase inhibitors (NRTI) ▪ Post exposure prophylaxis available with HBV immunoglobulins ▪ Vaccine available

Chapter 36 Liver Diseases

HEPATITIS C osms.it/hepatitis DIAGNOSIS

PATHOLOGY & CAUSES ▪ Viral hepatitis caused by hepatitis C virus (HCV) ▪ RNA virus from the class of flaviviridae ▪ Incubation is 6–7 weeks, lifelong infectious carrier state ▪ Virus mutates often to bypass the host immune system ▪ Minority of individuals develop acute hepatitis symptoms, due to this majority progress to chronic infection

RISK FACTORS

▪ Intravenous drug use, sexual contact, from mother to child in neonatal period (vertical transmission); chronic hemodialysis

COMPLICATIONS

▪ Cirrhosis, hepatocellular carcinoma, renal dysfunction (HCV immune complexes involved in pathogenesis)

SIGNS & SYMPTOMS ▪ General infection ▫ Low grade fever, malaise, lethargy, anorexia ▪ Liver related ▫ Fatty stool, dark urine (iron), jaundice, hepatomegaly, icterus, pruritus

LAB RESULTS

▪ Enzyme-linked immunosorbent assay (ELISA) used to detect antibodies in chronic cases, may be false negative in immunosuppressed ▪ Specific hepatitis C antigens immunoassay ▪ HCV RNA test with PCR ▪ ↑ ALT ▪ ↑ CRP, ↑ ESR, ↑ WBC

OTHER DIAGNOSTICS

▪ Physical exam shows enlarged liver

TREATMENT MEDICATIONS

▪ Interferon alfa, ribavirin ▪ Screen for HBV, HIV and HAV; vaccinate against HBV and HAV if tests are negative ▪ No HCV vaccine available

SURGERY

▪ Liver transplant in case of liver failure

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HEPATITIS E osms.it/hepatitis PATHOLOGY & CAUSES ▪ Viral hepatitis caused by hepatitis E virus (HEV) ▪ RNA virus from the class hepeviridae ▪ Transmitted via fecal-oral route

RISK FACTORS

▪ Consuming contaminated food and water in endemic areas, blood transfusions, from mother to child in neonatal period

DIAGNOSIS LAB RESULTS

▪ Anti - HEV IgM assay in acute infection, PCR in chronic cases ▪ ↑ ALT ▪ ↑ CRP, ↑ ESR, ↑ WBC

OTHER DIAGNOSTICS

▪ Physical exam shows enlarged liver

TREATMENT

COMPLICATIONS

▪ Rare but if present then cholestatic hepatitis, chronic infection in immunosuppressed individuals, liver failure, high mortality rate in pregnant individuals

SIGNS & SYMPTOMS ▪ General infection ▫ Low grade fever, malaise, lethargy, anorexia ▪ Liver related ▫ Fatty stool, dark urine (iron), jaundice, hepatomegaly, icterus, pruritus ▪ Other ▫ Diarrhea, arthralgia, urticarial rash

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MEDICATIONS

▪ Ribavirin used in immunosuppressed individuals

SURGERY

▪ Liver transplant in case of liver failure

Chapter 36 Liver Diseases

HEPATOCELLULAR ADENOMA osms.it/hepatocellular-adenoma DIAGNOSIS

PATHOLOGY & CAUSES ▪ Rare, benign liver tumor ▪ Formed from hepatic epithelial cells, often in healthy liver ▫ Enlarged, nonfunctional epithelial cells ▫ More glycogen, lipids than expected ▫ Surrounding tissue highly vascularized ▫ Bile ducts, portal triads absent

CAUSES

▪ Exact mechanisms unknown; associated with estrogen-based drugs: oral contraceptives, anabolic steroids ▪ Genetic diseases ▫ Glycogen storage disease type I (von Gierke’s disease): glucose cannot be generated from glycogen via gluconeogenesis

DIAGNOSTIC IMAGING

▪ Often incidental finding on abdominal imaging

Ultrasound ▪ Solitary well-demarcated heterogeneous mass with variable echogenicity CT scan ▪ Well-marginated isoattenuating hepatic lesions; fat content → hypoattenuation

LAB RESULTS Histology (definitive) ▪ Well-circumscribed nodules ▫ Sheets of hepatocytes with bubbly vacuolated cytoplasm ▪ Lack portal tracts/central veins

RISK FACTORS

TREATMENT

▪ Diabetes, metabolic syndrome, obesity

COMPLICATIONS

▪ Rupture, bleeding; malignant transformation (rare)

SIGNS & SYMPTOMS ▪ Usually asymptomatic ▪ Abdominal pain (esp. epigastric/RUQ), palpable mass ▪ If adenoma ruptures, bleeds ▫ Hypotension, tachycardia, diaphoresis

SURGERY

▪ Surgical resection

OTHER INTERVENTIONS

▪ Estrogen-associated ▫ Cessation of estrogen-based medication → adenoma regression ▪ Von Gierke’s disease ▫ Strict dietary management → adenoma regression

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Figure 36.10 Intraoperative photograph of a large, well-circumscribed hepatocellular adenoma of the left lobe of the liver. There is a rim of normal liver surrounding the adenoma. The right lobe of the liver is just visible to the left of the image.

NEONATAL HEPATITIS osms.it/neonatal-hepatitis PATHOLOGY & CAUSES ▪ Inflammation of liver in newborns (usually 1–2 months after birth)

CAUSES

▪ Viruses (20%) ▫ Infect mother during pregnancy/baby shortly after birth ▫ Rubella; Cytomegalovirus (CMV); hepatitis A,B,C ▪ Idiopathic (80%) ▫ Unknown origin ▫ Viral ▫ Neonatal cholestasis ▫ Newborn bile production immature → ↓ bile production ▫ Developing liver more sensitive to injury → ↓ bile synthesis, flow ▪ Genetic ▫ Alpha 1-antitrypsin deficiency: malformation → cannot be transported out of hepatocytes → accumulation within cells → cell death → hepatitis

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COMPLICATIONS

▪ If untreated > six months ▫ Chronic liver disease → hepatic cirrhosis → liver failure

SIGNS & SYMPTOMS ▪ Jaundice, pruritus, rashes, dark urine, pale stools, hepatomegaly (due to liver inflammation) ▪ Decreased intestinal bile flow → impaired fat digestion, vitamin absorption → failure to grow

DIAGNOSIS DIAGNOSTIC IMAGING Ultrasound ▪ Check bile ducts for obstruction, correct development

Chapter 36 Liver Diseases

LAB RESULTS Liver biopsy ▪ Multinucleated giant cells ▫ Arise from combination of neighboring cells (hepatocytes) ▫ Signs of cholestatic liver disease Blood tests ▪ ↑ serum bilirubin

TREATMENT MEDICATIONS

▪ Ursodeoxycholic acid ▫ Increase bile formation

SURGERY

▪ Cirrhotic liver disease/liver failure requires liver transplant

OTHER INTERVENTIONS

▪ Optimize nutrition/vitamin supplementation

NON-ALCOHOLIC FATTY LIVER DISEASE osms.it/non-alcoholic-fatty-liver PATHOLOGY & CAUSES ▪ Disease due to fat accumulation in liver, associated inflammation

TYPES Non-alcoholic fatty liver (NAFL) ▪ Steatosis without inflammation Non-alcoholic steatohepatitis (NASH) ▪ Steatosis with hepatic inflammation, indistinguishable from alcoholic steatohepatitis Subtype ▪ Liver steatosis without evident secondary cause (e.g. chronic alcohol use/persistent viral infection) ▫ Liver large, soft, yellow greasy ▫ Bloating, hepatocyte necrosis ▫ Mallory–Denk bodies ▫ Damage attracts neutrophils → more inflammation ▫ Inflammation → hepatic stellate cells activate → fibrosis → cirrhosis

NAFL → NASH ▪ Second hit hypothesis ▫ Initial fatty change benign → oxidative stress, hormonal imbalances, mitochondrial abnormalities → progression ▪ Hepatocytic fat vulnerable to degradation ▫ Unsaturated fatty acids: ≥ one double bond, hydrogen atoms vulnerable to initiators (e.g. reactive oxygen species) ▫ Process damages cell lipid membranes → mitochondrial dysfunction → cell death → inflammation → steatohepatitis (NASH)

RISK FACTORS

▪ NAFL → NASH ▫ Age > 50 ▫ BMI ≥ 28kg/m2 (5.7lbs/ft2) ▫ Diabetes mellitus ▫ Elevated serum aminotransferases ▫ Ballooning degeneration, Mallory–Denk bodies or fibrosis on biopsy ▪ NAFL (general) ▫ Insulin resistance, metabolic syndrome, ▫ ≥ Three of: obesity, hypertension,

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▪ Typically diagnosed as incidental finding on liver function panel

Liver biopsy ▪ > 5% fat content → NAFL ▪ Iron deposits ▪ NAFL ▫ Steatosis alone ▫ Steatosis with lobular/portal inflammation without hepatocyte ballooning ▫ Steatosis with hepatocyte ballooning but without inflammation ▪ NASH ▫ Hepatocyte ballooning degeneration, hepatic lobular inflammation, apoptotic bodies, mild chronic portal inflammation, perisinusoidal collagen deposition → zone 3 accentuation (chicken wire pattern), portal fibrosis without perisinusoidal or pericellular fibrosis, cirrhosis (macronodular or mixed), Mallory–Denk bodies, megamitochondria, vacuolated nuclei in periportal hepatocytes

DIAGNOSTIC IMAGING

OTHER DIAGNOSTICS

diabetes, hypertriglyceridemia, hyperlipidemia, excessive soft drink consumption (high concentration of fructose), diet rich in saturated fats, medications (corticosteroids)

COMPLICATIONS

▪ Liver cirrhosis, hepatocellular carcinoma

SIGNS & SYMPTOMS ▪ Usually asymptomatic ▪ Fatigue, malaise, dull right upper quadrant pain, mild jaundice (rare), significant liver damage → hepatomegaly, ascites

DIAGNOSIS

▪ Identify fatty infiltrates

Ultrasound ▪ Increased echogenicity → bright appearing liver → diffuse fatty infiltration CT scan ▪ Decreased hepatic attenuation MRI ▪ Increased fat signal

LAB RESULTS

▪ Destruction of hepatocytes → increase in liver enzymes AST/ALT ▪ Serum ALT > AST level = NAFL

▪ Alcohol consumption > 25 ml/day pure ethanol excludes diagnosis

TREATMENT OTHER INTERVENTIONS Dietary changes ▪ Avoid high fructose-corn syrup, trans-fats ▪ Omega 3 fatty acid supplementation → improvement in liver fat deposition ▪ Coffee and olive oil consumption may be protective Treat insulin resistance ▪ Weight-loss ▪ Insulin sensitizers Treat hyperlipidemia ▪ Statins

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Chapter 36 Liver Diseases

PORTAL HYPERTENSION osms.it/portal-hypertension PATHOLOGY & CAUSES ▪ Elevation of blood pressure in the portal venous system above 5mmHg

CAUSES Prehepatic causes ▪ Portal vein obstruction (e.g. thrombosis) Intrahepatic causes ▪ Cirrhosis (most common of all causes) ▪ Schistosomiasis ▪ Sarcoidosis Posthepatic causes ▪ Right-sided heart failure ▪ Constrictive pericarditis ▪ Budd–Chiari syndrome

COMPLICATIONS

▪ Portosystemic shunts and development of collateral channels ▫ Esophageal varices ▫ Hemorrhoids ▫ Caput medusae (distension of abdominal wall veins) ▪ Increased hydrostatic pressure and hypoalbuminemia → ascites ▪ Splenomegaly (blood drainage backs up to spleen due to high pressure portal system) → sequestration of blood elements → anemia, thrombocytopenia, leukopenia ▪ Liver disease and blood shunting away from liver → decreased blood detoxification → increased ammonia in the blood → encephalopathy ▪ Spontaneous bacterial peritonitis

SIGNS & SYMPTOMS ▪ GI bleeding (secondary to esophagogastric varices) → most life-threatening complication ▫ Hematemesis ▫ Melena ▪ Jaundice ▪ Ascites ▪ Periumbilical caput medusae ▪ Signs and symptoms of encephalopathy ▫ Altered level of consciousness ▫ Lethargy ▫ Hand tremor when the wrist is extended (aka asterixis) ▫ Seizure, coma and death

DIAGNOSIS DIAGNOSITC IMAGING Liver ultrasound ▪ Nodules in case of cirrhosis CT scan, MRI ▪ Ascites ▪ Cirrhosis ▪ Splenomegaly ▪ Vascular alteration such as inferior vena cava dilatation

LAB RESULTS

▪ Full blood count ▪ Liver enzymes and serology ▪ Perform emergent upper GI endoscopy, to diagnose/treat varices

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OTHER DIAGNOSTICS Diagnostic paracentesis ▪ Will determine if ascites is due to portal HTN or other etiology ▪ Serum ascites albumin gradient (SAAG) > 1.1 mg/dL ▫ Portal HTN is likely

TREATMENT ▪ Prevent and treat the complications

MEDICATIONS

▪ Beta-blockers ▫ → decrease portal venous pressure ▪ IV octreotide ▫ If bleeding, non-selective beta blockers (prophylaxis), antibiotics (prophylaxis for spontaneous bacterial peritonitis) ▫ For esophageal varices ▪ Diuretics and sodium restriction ▫ For ascites

SURGERY

Figure 36.11 Ascites as a consequence of portal hypertension caused by cirrhosis of the liver.

▪ Transjugular intrahepatic portosystemic shunt ▫ Communication between portal vein and hepatic vein → blood bypasses the liver circulation → reduced intrahepatic pressure ▪ Balloon tamponade, sclerotherapy, variceal ligation/banding ▫ For esophageal varices

MNEMONIC: ABCDE

Features of Portal hypertension Ascites Bleeding (haematemesis, piles) Caput medusae Diminished liver Enlarged spleen

Figure 36.12 Barium swallow demonstrating esophageal varices.

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Chapter 36 Liver Diseases

Figure 36.13 Endoscopic appearance of esophageal varices.

PRIMARY BILIARY CIRRHOSIS osms.it/primary-biliary-cirrhosis PATHOLOGY & CAUSES ▪ Autoimmune disease of liver → progressive destruction of cells lining small intrahepatic bile ducts → leakage of bile, toxins into liver parenchyma, blood → inflammation, fibrosis → cirrhosis ▪ AKA primary biliary cholangitis

CAUSES

▪ Failure of immune tolerance against mitochondrial pyruvate dehydrogenase complex (PDC-E2), other hepatic proteins → destruction of cells lining bile ducts → autoimmunity

RISK FACTORS

▪ Biological female, family history of disease, extrahepatic autoimmune disease ▫ Previous infection with environmental gram-negative Novosphingobium aromaticivorans → cross-reaction between bacterial antigens, hepatic mitochondrial proteins

COMPLICATIONS

▪ Osteoporosis, hyperlipidemia, fat soluble vitamin deficiencies

SIGNS & SYMPTOMS ▪ Fatigue, pruritus, jaundice, right upper quadrant pain ▪ Loss of bone density → fractures ▪ Hypercholesterolemia → xanthelasma, xanthoma ▪ Liver cirrhosis → ascites, splenomegaly, esophageal varices, hepatic encephalopathy

DIAGNOSIS DIAGNOSTIC IMAGING Abdominal ultrasound/MRCP/CT scan ▪ Rule out bile duct obstruction

LAB RESULTS

▪ Antimitochondrial antibodies (most individuals)

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▪ Other autoantibodies may be present ▫ Antinuclear antibody, antiglycoprotein-210 antibodies, anti-p62 antibodies (suggests more severe disease → liver failure), anticentromere antibodies (correlates with developing portal hypertension), anti-np62 and anti-sp100 ▪ Elevated IgM, total cholesterol, HDL, GGT, ALP (released from damaged bile ducts), bilirubin = advanced disease Liver biopsy (percutaneous/laparoscopic) ▪ Interlobular bile duct destruction, bile duct inflammation (intraepithelial lymphocytes), periductal epithelioid granulomas

TREATMENT MEDICATIONS

▪ Ursodeoxycholic acid ▫ Reduces intestinal absorption of cholesterol → reduces cholestasis, improves liver function tests ▪ Cholestyramine ▫ Bile acid sequestrant → reduces bile acid absorption in gut → relieves itching due to bile acids in circulation ▪ Modafinil ▫ For fatigue

OTHER INTERVENTIONS ▪ Cease all alcohol intake

Figure 36.14 The histological appearance of primary biliary cirrhosis. The bile duct is surrounded by epithelioid macrophages which in turn are surrounded by a rim of lymphocytes, indicative of granulomatous inflammation.

WILSON'S DISEASE osms.it/wilsons-disease PATHOLOGY & CAUSES ▪ Autosomal recessive mutation in ATP7B gene → defect in ATP7B transport protein action in the hepatocyte ▪ AKA hepatolenticular degeneration ▪ Reduced copper incorporation into apoceruloplasmin and reduction of its copper-bound form (ceruloplasmin)

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▪ Reduced copper elimination in the bile ▪ Copper accumulation in hepatocytes → free radical generation → hepatocyte damage → spilling of free copper into the blood → copper accumulation in organs and tissues → free radical generation → tissues damage

Chapter 36 Liver Diseases

COMPLICATIONS

▪ Liver: cirrhosis, liver failure ▪ Brain: movement disorders, dementia, and psychiatric issues ▪ Kidney: renal disease ▪ Eye: Kayser–Fleischer’s ring, sunflower cataract ▪ Blood: hemolytic anemia

SIGNS & SYMPTOMS ▪ Presents at a young age (< 30 years old) ▪ Signs and symptoms of cirrhosis and portal hypertension (e.g. hepatosplenomegaly, jaundice, ascites, esophageal varices) ▪ Signs of renal dysfunction ▪ Parkinsonian-like movement disorders ▫ Tremors ▫ Rigidity ▪ Psychiatric illness ▫ Depression ▫ Personality changes ▫ Psychosis ▫ Cognitive dysfunctions ▪ Kayser–Fleischer ring ▫ Ring of copper deposition in the cornea (Descemet’s membrane) ▫ Appears to encircle the iris

DIAGNOSIS LAB RESULTS

▪ Signs of liver dysfunction (e.g. high liver enzymes) ▪ Low serum ceruloplasmin ▪ High 24-hour copper excretion

TREATMENT MEDICATIONS

▪ Chelating agents → make it easier to excrete copper ▫ Penicillamine (penicillin metabolite without antibiotic properties) ▫ Trientine hydrochloride ▪ Agents that block intestinal absorption of copper ▫ Ammonium tetrathiomolybdate ▫ Zinc

SURGERY

▪ Advanced liver damage → transplantation

OTHER INTERVENTIONS

▪ Eliminate copper-rich food (e.g. mushrooms, nuts, shellfish)

Figure 36.15 Copper deposition in Descemet’s membrane of the sclera results in a Kayser–Fleischer ring.

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NOTES

NOTES

LOWER GASTROINTESTINAL CONGENITAL MALFORMATIONS

GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Lower gastrointestinal tract structural/ functional anomalies during embryonic development; present at birth ▪ Malformations from duodenum to anus

DIAGNOSIS DIAGNOSTIC IMAGING

▪ Prenatal ultrasound, MRI, CT scan/ radiography ▪ Avoid X-ray due to teratogenicity

CAUSES

TREATMENT

▪ Genetic, environmental factors

SIGNS & SYMPTOMS

SURGERY

▪ See individual disorders

▪ At birth: may be asymptomatic ▪ Malformations: relatively benign (nausea, vomiting, difficulty passing stool) to life incompatibility

GASTROSCHISIS osms.it/gastroschisis PATHOLOGY & CAUSES ▪ Extrasomatic protrusion of intestines through hole in abdominal wall near umbilicus ▪ Hernia: affected organs exit cavity ▪ Week 4 of gestation: lateral folds fail to fuse → hole in abdominal wall → organs protrude ▪ Most common on right side ▪ Usually small intestine ▪ Stomach, liver may also protrude (rare)

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CAUSES

▪ Genetic, environmental factors

RISK FACTORS

▪ Mother’s young age ▪ Exposure to teratogenic substances (alcohol, tobacco)

COMPLICATIONS

▪ Intestinal inflammation due to intrauterine exposure to amniotic fluid, malabsorption, infarction of intestinal tube due to compressed blood vessels, infection

Chapter 37 Lower Gastrointestinal Congenital Malformations

SIGNS & SYMPTOMS ▪ During fetal life: asymptomatic ▪ At birth: difficulty feeding/passing stool

DIAGNOSIS DIAGNOSTIC IMAGING Intrauterine ultrasound, MRI X-ray, CT scan ▪ Post-op evaluation

LAB RESULTS

▪ Increased maternal serum alphafetoprotein (MSAFP)

OTHER DIAGNOSTICS

Figure 37.1 An abdominal X-ray of a newborn with gastroschisis. The abdominal contents are clearly visible outside the abdominal wall.

▪ Defect visible at birth

TREATMENT ▪ Fatal if untreated

MEDICATIONS

▪ Antibiotics for existing/potential infection ▪ IV fluid/nutrients

SURGERY

▪ Surgical repositioning of organs back into abdominal cavity, closure of abdominal wall defect ▪ Usually requires multiple surgeries

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HIRSCHSPRUNG'S DISEASE osms.it/hirschsprungs-disease PATHOLOGY & CAUSES ▪ Myenteric (Auerbach), submucosal (Meissner) plexuses absent from intestinal wall in distal bowel ▪ AKA congenital aganglionic megacolon ▪ Absent plexuses (regulate bowel function) → intestine muscles permanently constricted → passing stool difficult, impossible

CAUSES

▪ Failure of neuroblasts to migrate from neural crest to intestine, form plexuses ▪ Genetic: RET proto-oncogene, EDNRB, etc. ▪ RET proto-oncogene: sporadic/autosomal dominant (familial) cases; associated with Down syndrome ▪ Isolated: sporadic/autosomal dominant ▪ Present within syndrome: Down syndrome, multiple endocrine neoplasia II, etc.

DIAGNOSIS DIAGNOSTIC IMAGING

▪ Barium assisted radiography

LAB RESULTS

▪ Rectal suction biopsy

OTHER DIAGNOSTICS ▪ Digital rectal exam

TREATMENT SURGERY

▪ Surgical resection of intestine, subsequent fusion of remaining healthy tissue (pullthrough technique)

COMPLICATIONS

▪ Constipation/obstipation, malnutrition, enterocolitis, intestinal perforation, megacolon

SIGNS & SYMPTOMS ▪ At birth: asymptomatic ▪ Can be diagnosed in adulthood ▪ First sign: baby’s inability to pass meconium, 48 hours postpartum ▪ Vomiting, abdominal distension, colics

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Figure 37.2 Immunohistochemical staining for acetylcholinesterase in the colon of an individual with Hirschprung’s disease. Ganglia are absent resulting in overstimulation of nerves and increased levels of acetylcholinesterase.

Chapter 37 Lower Gastrointestinal Congenital Malformations

IMPERFORATE ANUS osms.it/imperforate-anus DIAGNOSIS

PATHOLOGY & CAUSES ▪ Narrowed anal opening (anal stenosis)/ complete atresia ▪ AKA anal atresia ▪ Anus completely closed → colon ends in blind pouch in pelvis/opens into other pelvic structures (bladder, vagina) via fistulae ▪ All pelvic structures open into same channel → persistent cloaca ▪ Nerve, muscle tissue of missing parts of anus, rectum missing/malformed

DIAGNOSTIC IMAGING

CAUSES

SURGERY

▪ Mostly unknown genetic cause ▪ HLXB9 gene: only when imperforate anus is present within Currarino syndrome

MRI, ultrasound, X-ray/CT scan ▪ Determine internal extent of defect, plan corrective surgery

OTHER DIAGNOSTICS

▪ Physical exam at birth, defect visible

TREATMENT ▪ Anoplasty if possible, colostomy if not

COMPLICATIONS

▪ Megacolon, intestinal rupture, septic shock, incontinence/constipation (even after surgery)

MNEMONIC: VACTERL

Group of malformations with common, unknown cause Vertebral anomalies Anal atresia Cardiovascular anomalies Tracheoesophageal fistula Esophageal atresia Renal anomalies Limb defects

Figure 37.3 A lateral X-ray of a neonate demonstrating an imperforate anus. The rectum is dilated and the anal canal is absent.

SIGNS & SYMPTOMS ▪ Constipation (if anus narrowed), obstipation (if anus non-existent) ▪ Vomiting, abdominal distension

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INTESTINAL ATRESIA osms.it/intestinal-atresia PATHOLOGY & CAUSES ▪ Congenital malformation resulting in closed/ absent part of small/large intestine ▪ Different from intestinal stenosis; in stenosis the passageway exists, and is just narrowed

TYPES

▪ Named according to affected portion of intestine: duodenal, jejunal, ileal, colonic ▪ Divided into duodenal/non-duodenal intestinal atresia due to different mechanism of origin ▪ Duodenal intestinal atresia is caused by failure in duodenal vacuolization ▫ During fetal development duodenal epithelium proliferates rapidly → complete duodenal obstruction (AKA solid phase of vacuolization)→ apoptosis of excess cells → formation of small vacuoles which fuse → reestablish duodenal passageway (AKA recanalization phase)

CAUSES

▪ Duodenal intestinal atresia ▫ Strongly associated with trisomy 21 (Down syndrome) ▪ Non-duodenal intestinal atresias ▫ Intrauterine ischemic injury (small part of duodenum, entire jejunum, ileum, colon receive vascularization from superior mesenteric artery)

COMPLICATIONS

▪ Distension of stomach and duodenum caused by accumulated amniotic fluid which has nowhere to go ▪ Polyhydramnios (accumulation of amniotic fluid in amniotic sac) ▫ Fetus swallows less fluid due to intestinal obstruction → more fluid accumulates in amniotic sac ▪ Intestinal perforation and pneumoperitoneum/meconium peritonitis

SIGNS & SYMPTOMS ▪ Bilious vomiting, abdominal pain, malnutrition

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Chapter 37 Lower Gastrointestinal Congenital Malformations

DIAGNOSIS DIAGNOSTIC IMAGING Prenatal ultrasound ▪ To assess signs of obstruction; detectable in the third trimester ▫ Duodenal atresia: dilated fluid-filled stomach adjacent to dilated duodenum ▫ Non-duodenal intestinal atresia: Dilated fluid-filled bowel loops ▫ Polyhydramnios Postnatal X-ray ▪ Duodenal atresia: Double bubble sign (dilated stomach adjacent to dilated duodenum) ▪ Non-duodenal intestinal atresia: dilated bowel loops with air-fluid levels proximal to the obstruction

Figure 37.5 A plain abdominal radiograph of a neonate demonstrating the double bubble sign of duodenal atresia.

OTHER DIAGNOSTICS

▪ Physical examination ▫ Apple peel (spiral) shape of intestines upon visual examination during surgery ▪ Amniocentesis to determine possible trisomy 21

TREATMENT SURGERY

▪ Gastric decompression: removal of fluid from stomach ▪ IV fluid compensation ▪ Surgical reattachment of functional portions of intestines ▫ In case of duodenal intestinal atresia → duodenoduodenostomy

Figure 37.4 A plain abdominal radiograph of a neonate demonstrating the triple bubble sign of jejunal atresia.

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INTESTINAL MALROTATION osms.it/intestinal-malrotation DIAGNOSIS

PATHOLOGY & CAUSES ▪ Improper rotation of midgut during embryogenesis ▪ Rapid midgut growth in restricted space → herniation into umbilical coelum → rotation 270° around SMA → error occurs = final anatomy description ▫ Small intestine lodges into left abdominal cavity → cecum in lower right quadrant, first two thirds of colon lodge into right side over small intestine ▪ Due to error, several organs in incorrect anatomical position ▫ Small intestine in right side ▫ Coecum in epigastrium ▫ Appendix follows coecum ▫ Ladd’s bands span over vertical duodenum, compressing from outside ▫ Suspensory muscle of duodenum further right ▫ Mesentery of small intestine narrower root

DIAGNOSTIC IMAGING MRI/CT scan/barium-assisted radiography ▪ Detect improper organ position

TREATMENT SURGERY

▪ Surgical repositioning of intestines, resection of Ladd’s bands to remove duodenal obstruction ▪ Preventive appendectomy

COMPLICATIONS

▪ Omphalocele, volvulus (part of intestine rotates around itself/part of mesenterium → blocks passage of intestinal content → compresses blood vessels → obstructs blood flow), ileus, ischemic bowel, malnutrition, hernias

SIGNS & SYMPTOMS ▪ May be asymptomatic ▪ Colic, bilous regurgitation, abdominal distension

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Figure 37.6 An abdominal X-ray with bowel contrast demonstrating intestinal malrotation. The entire small bowel is situated on the right side of the abdomen.

Chapter 37 Lower Gastrointestinal Congenital Malformations

MECKEL'S DIVERTICULUM osms.it/meckels-diverticulum DIAGNOSIS

PATHOLOGY & CAUSES ▪ Abnormal pouch on antimesenteric side of ileum ▪ True diverticulum (contains all three layers of intestinal wall) ▪ Early fetal life: nutrients received from yolk sac into ileum via omphalomesenteric duct until it obliterates (week 5–6 of pregnancy) ▪ If omphalomesenteric duct obliterates improperly: Meckel’s diverticulum ▪ May contain ectopic epithelia, omphalomesenteric duct lined with pluripotent cells

COMPLICATIONS

▪ Diverticulitis, ulcers from HCl secretion if gastric mucosa present, perforation of diverticulum, food impaction, lithiasis, peritonitis, peritoneal adhesions, intussusception, volvulus, neoplasms

MNEMONIC

DIAGNOSTIC IMAGING Abdominal ultrasound/CT scan ▪ Incidental finding Angiography

OTHER DIAGNOSTICS Meckel’s scan ▪ In children; technetium-99m procedure, detects gastric mucosa in diverticulum Surgery ▪ Incidental finding

TREATMENT SURGERY

▪ Uncomplicated: resection of diverticulum ▪ Complicated: resection of diverticulum, intestine

Meckel's Rule of 2s Symptomatic presentation before 2 years of age 2% of population Approximately 2 feet from ileocecal valve 2 inches in length 2 types of ectopic mucosa (pancreatic, gastric)

SIGNS & SYMPTOMS ▪ Usually asymptomatic ▪ Abdominal pain/distension, melena, vomiting, constipation

Figure 37.7 Intraoperative photograph of a Meckel’s diverticulum.

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Figure 37.8 A CT scan in the axial plane demonstrating a Meckel’s diverticulum.

Figure 37.9 Histological appearance of a Meckel’s diverticulum containing ectopic gastric mucosa.

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Chapter 37 Lower Gastrointestinal Congenital Malformations

OMPHALOCELE osms.it/omphalocele DIAGNOSIS

PATHOLOGY & CAUSES ▪ Persistent, pathological, herniation of intestines into umbilical cord ▪ Midgut herniates through umbilicus → pulls layer of peritoneum into umbilical cord in order to properly develop (grow, rotate) due to insufficient space in abdominal cavity → returns into abdomen ▪ Midgut doesn’t return: omphalocele ▪ High mortality rate

DIAGNOSTIC IMAGING Intrauterine ultrasound MRI

LAB RESULTS

▪ Blood test for MSAFP ▪ Amniocentesis

TREATMENT

CAUSES

▪ Genetic, environmental factors ▪ Associated with: trisomy 13 (Patau syndrome), trisomy 18 (Edward’s syndrome), trisomy 21 (Down syndrome), Beckwith–Wiedemann syndrome

SURGERY

▪ Surgical repositioning of protruding organs

RISK FACTORS

▪ Consumption of alcohol/tobacco during pregnancy, certain medications (SSRIs), obesity

COMPLICATIONS

▪ Abdominal cavity malformation, volvulus, ischemic bowel

SIGNS & SYMPTOMS ▪ Intrauterine: asymptomatic ▪ At birth: visible defect Figure 37.10 An MRI scan in the sagittal plane demonstrating a large omphalocele. The abdominal organs are clearly visible outside the abdominal wall.

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NOTES

NOTES

MALABSORPTION CONDITIONS GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Impaired ability of gastrointestinal tract to absorb nutrients ▪ Malabsorption may be ▫ Global → impaired function of intestinal cells ▫ Partial → external agent interferes with absorption ▪ Manifestation of underlying illness; may be congenital/acquired/infectious

CAUSES

▪ Defects in absorption process of intestinal cells (e.g. change to bowel surface area) ▪ Impaired nutrient digestion (e.g. altered digestive enzymes)

SIGNS & SYMPTOMS ▪ Abdominal distention, pain ▪ Chronic diarrhea, malabsorption, dehydration ▪ Weight loss ▪ Clinical manifestations of nutritional deficiencies (e.g. paresthesias from cobalamin deficiency)

DIAGNOSIS DIAGNOSTIC IMAGING

▪ Abdominal ultrasound, colonoscopy, intestinal biopsy, serological markers

LAB RESULTS

▪ D-xylose test ▫ Test for carbohydrate malabsorption ▪ Fecal fat testing ▪ Complete blood count (CBC) ▫ Look for for infection, anemia

OTHER DIAGNOSTICS

▪ Individual history ▫ Pancreatitis ▫ Recent surgeries ▫ Symptoms of vitamin deficiency ▫ Family history

TREATMENT ▪ See individual disorders

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CELIAC DISEASE osms.it/celiac-disease PATHOLOGY & CAUSES ▪ Autoimmune disorder of small intestine ▪ AKA gluten-sensitive enteropathy/ nontropical sprue

CAUSES

▪ Triggered by foods containing gliadin, a peptide found in foods containing gluten (e.g. grains: wheat, barley, rye, oats) ▫ Gluten consumption → degradation into peptides in small intestine → secretory IgA binds to gliadin in duodenum → IgA-gliadin complex binds to transferrin receptor → IgA-gliadin complex travels across enterocyte into lamina propria → tissue transglutaminase deaminates gliadin → macrophages uptake, present deaminated gliadin in MHC-2 molecules HLA-DQ 2, 8 → CD4+ activation → inflammatory cytokines released (interferon gamma, tumor necrosis factor) → damage/destruction of intestinal villi → B cell activation → antigliadin, anti-tissue transglutaminase, antiendomysial antibodies released → CD8+ cell activation → tissue destruction ▪ On microscopy ▫ Villous atrophy, mucosal inflammation, intestinal crypt hyperplasia ▪ Presence of anti-gliadin, anti-endomysium IgA = pathognomonic

SIGNS & SYMPTOMS ▪ Abdominal distention, chronic diarrhea (steatorrhea) ▪ Failure to thrive (children) ▪ Dermatitis herpetiformis ▫ Circulating IgA antibodies attack dermal papillae → generalized rash

DIAGNOSIS LAB RESULTS

▪ Anti-gliadin IgA/IgG ▪ Anti-endomysium IgA ▪ Anti-tissue transglutaminase IgA ▫ Tissue transglutaminase: endomysial enzyme released in response to cellular stress ▫ More sensitive, specific

Duodenal biopsy ▪ Showing lymphocytic infiltration, villous atrophy, crypt hyperplasia

TREATMENT OTHER INTERVENTIONS

▪ Correct nutritional deficiencies related to malabsorption

Preventative ▪ Gluten-free diet

RISK FACTORS

▪ Northern European ancestry, genetic component

MNEMONIC: Grains are BROWn

Grains to avoid with Celiac disease Barley Rye Oats Wheat

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Chapter 38 Malabsorption Conditions

Figure 38.1 Histological appearance of a duodenal biopsy in an individual with celiac disease. There is villous blunting, an expansion of the lamina propria by chronic inflammatory cells and an increase in crypt length. A higher magnification would reveal an increase in lymphocyte count in the surface epithelium.

Figure 38.2 Clinical appearance of dermatitis herpetiformis. Individual with celiac disease are at increased risk of this condition.

LACTOSE INTOLERANCE osms.it/lactose-intolerance PATHOLOGY & CAUSES

SIGNS & SYMPTOMS

▪ Decreased ability to digest lactose ▪ Lactose consumption → lactase deficiency/ inactivity → ↑ undigested lactose → fermentation by colonic flora → gas, osmotically active substances produced → bloating, diarrhea

▪ Occur after consuming lactose (e.g. milk, cheese) ▪ Abdominal pain, cramping in lower quadrants ▪ Abdominal distention, flatulence, vomiting, diarrhea (more common in children)

CAUSES

▪ Most often acquired due to physiologic weaning off of milk

RISK FACTORS

▪ Non-European ancestry (most common) ▪ Increases with age ▪ May be congenital ▫ Rare, autosomal recessive disorder ▪ May be developmental ▫ Most common among premature infants ▪ Underlying intestinal disease

DIAGNOSIS ▪ Based on above symptoms

LAB RESULTS

▪ Unabsorbed carbohydrates → high stool osmotic gap ▪ Bacterial lactose fermentation → acidic stool pH

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Preventative ▪ Lactose-free diet ▫ Compensate with lactase

TREATMENT OTHER INTERVENTIONS

▪ Optimize calcium, vitamin D intake

SMALL BOWEL BACTERIAL OVERGROWTH SYNDROME osms.it/sbbos PATHOLOGY & CAUSES ▪ Excessive colonic bacteria colonizing small intestine ▪ Often occurs secondary to conditions limiting intestinal motility, gastric acid and bile secretion and IgA deficiencies

CAUSES

▪ Alteration of factors regulating intestinal flora → aerobic bacteria proliferation → changes in aerobic microclimate of small intestine → migration of colonic anaerobic bacteria → damage to intestinal surface → maldigestion, malabsorption → symptoms ▫ ↑ bacteria → ↑ carbohydrate metabolism → ↑ gas production → bloating ▫ ↑ bacteria → bile acid inactivation → ↑ fat in colon → osmotic effect → diarrhea ▫ ↑ bacteria → intrinsic factor degradation → impaired B12 absorption → B12 deficiency

RISK FACTORS

▪ Increases with age

▪ Altered mental status after high carbohydrate meal ▪ Failure to thrive (children)

DIAGNOSIS LAB RESULTS

▪ Signs/symptoms of vitamin, electrolyte abnormalities ▫ Weakness, ataxia, paresthesias → B12 deficiency ▫ Perioral numbness, feet paresthesias, muscle cramping → calcium deficiency ▪ Anemia ▫ Macrocytic → B12 deficiency ▫ Microcytic → chronic bleeding ▪ Fecal fat testing ▪ Lactulose/glucose breath testing ▪ Jejunal aspirate, culture ▫ > 103 colony forming units

OTHER DIAGNOSTICS

▪ Individual history ▫ Chronic pancreatitis, intestinal surgery, GI neuropathy

SIGNS & SYMPTOMS ▪ Abdominal pain/distention, chronic diarrhea, flatulence ▪ Tympanitic abdomen upon percussion

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TREATMENT MEDICATIONS ▪ Antibiotics

Chapter 38 Malabsorption Conditions

TROPICAL SPRUE osms.it/tropical-sprue DIAGNOSIS

PATHOLOGY & CAUSES ▪ Gastrointestinal disease of uncertain etiology resulting in nutrient malabsorption

DIAGNOSTIC IMAGING

CAUSES

Barium swallow ▪ Shows intestinal wall thickening

▪ Acute intestinal infection (viral/bacterial/ protozoan) → damaged intestinal lining → inflammation → enteroglucagon secretion → decreased intestinal motility → increased intestinal transit time → overgrowth of Klebsiella, E. coli, Enterobacter → production of toxic fermentation byproducts → further inflammation → villous atrophy → malabsorption → depletion of folate, B12 → intestinal villi can’t function normally → further intestinal injury, megaloblastic anemia

RISK FACTORS

▪ Most common in individuals living in tropical regions

Endoscopy

LAB RESULTS

▪ Fecal fat test ▪ D-xylose test ▪ Jejunal biopsy ▫ Shows villous atrophy, inflammation

TREATMENT MEDICATIONS

▪ Antibiotics → reduce bacterial overgrowth ▪ Replace folate, B12

SIGNS & SYMPTOMS ▪ Diarrhea, weight loss, dehydration, abdominal pain, fatigue, megaloblastic anemia

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WHIPPLE'S DISEASE osms.it/whipples-disease PATHOLOGY & CAUSES ▪ Rare, malabsorptive infectious disease caused by Tropheryma whipplei ▪ Pathognomonic finding → lamina propria displays numerous macrophages with periodic acid-Schiff (PAS) positive intracellular material

CAUSES

▪ Tropheryma whipplei ▫ Gram-positive, non-acid fast, PAS positive bacillus; ubiquitous in environment ▫ Fecal-oral transmission ▪ Readily spreads throughout body, causing multisystem effects ▫ Evades immune response → allows for accumulation of bacilli in tissues ▪ Current hypothesis suggests host immunodeficiency as predisposing factor

RISK FACTORS

▪ Middle-aged biological males of European ancestry; exposure to fecal matter (sewage workers, farmers)

MNEMONIC: WHIPPLES

Features of Whipple’s disease Weight loss Hyperpigmentation of skin Infection with tropheryma whippelii PAS positive granules in macrophage Polyarthritis Lymphadenopathy Enteric involvement Steatorrhea

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SIGNS & SYMPTOMS ▪ Four cardinal signs ▫ Diarrhea, weight loss, abdominal pain, arthralgias ▪ Endocarditis, pericarditis, myocarditis ▪ Skin hyperpigmentation ▪ Pleural disease

DIAGNOSIS LAB RESULTS

▪ Biopsy ▫ Shows copious PAS positive macrophages invading lamina propria in intestine ▪ ≥ two positive PCR/PAS tests ▪ Immunohistochemistry for T. whipplei ▪ Laboratory findings suggesting chronic inflammation, nutritional deficits

TREATMENT MEDICATIONS

▪ Start with IV antibiotics → ceftriaxone/ penicillin G ▪ Trimethoprim-sulfamethoxazole (1 year)

Chapter 38 Malabsorption Conditions

Figure 38.3 Histological appearance of the duodenum in a case of Whipple’s disease. The lamina propria is occupied by numerous foamy macrophages. Electron microscopy would reveal numerous membrane bound bacilli.

Figure 38.4 Histological appearance of a duodenal biopsy with the special stain DPAS (diastase periodic acid-Schiff). This stain highlights diastase resistant mucin within the foamy macrophages residing in the lamina propria. The mucin within goblet cells is also positively stained.

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NOTES

NOTES

ORAL DISEASE GENERALLY, WHAT IS IT? PATHOLOGY & CAUSES ▪ Infectious, inflammatory diseases; affect oral cavity, associated structures

RISK FACTORS

▪ Poor oral hygiene, dehydration, concomitant illness, malnutrition

DIAGNOSIS DIAGNOSTIC IMAGING X-ray ▪ See individual diseases CT scan ▪ Soft tissue inflammation extension

SIGNS & SYMPTOMS ▪ Inflammation ▫ Redness, swelling, pain, loss of function, warmth ▪ Infection ▫ Fever, malaise, localized pain

TREATMENT MEDICATIONS

▪ Nonsteroidal anti-inflammatory drugs (NSAIDs) for pain ▫ For inflammation ▪ Antibiotics, antifungal medications ▫ For infection

APHTHOUS ULCERS osms.it/aphthous-ulcers PATHOLOGY & CAUSES ▪ Painful lesions inside mouth; benign, noninfectious; AKA canker sores

TYPES Minor ▪ Small (3–4mm), last 7–10 days, recur 3–4 times/year; if recurrent, > 4 times/year Major ▪ Lesions > 1cm, last 10–30 days

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Herpetiform ▪ Coalesce, recur frequently

CAUSES

▪ Idiopathic; likely multifactorial; may be part of TH1 autoimmune response, hormonal factors influence epithelium thickness, connected to vitamin B12 deficiencies

RISK FACTORS

▪ Stress, systemic autoimmune disorders (e.g. celiac), nutritional deficiencies, stopping smoking, oral cavity trauma (e.g. biting lips, dentures)

Chapter 39 Oral Disease

COMPLICATIONS

▪ Recurrent aphthous stomatitis (Mikulicz ulcers), infection; may interfere with eating/ drinking

SIGNS & SYMPTOMS ▪ Round/oval ulcerations in oral mucosa, white/yellow sharply demarcated center covered with fibrous membrane cap, surrounded by red erythematous margins; yellowish exudate ▪ Inside of cheeks, lips; under tongue; painful swallowing, if in back of throat Minor ▪ Small, mildly painful, annoying, round/ oval, disappear within seven days, resolve spontaneously, no scarring; more common on non-keratinized epithelium

DIAGNOSIS OTHER DIAGNOSTICS ▪ Recurrence of ulcers

TREATMENT MEDICATIONS

▪ Vitamin B12 supplementation ▪ Topical analgesics, corticosteroids, sucralfate suspension ▪ Anti-tumor necrosis factor (TNF)-alpha agents ▫ Recalcitrant, recurrent ulcers

OTHER INTERVENTIONS ▪ Avoid triggers

Major ▪ Larger, painful, recur more often, may scar Herpetiform ▪ Not herpes virus connected, vesicles coalesce into patches

Figure 39.1 The clinical appearance of aphthous ulcers.

OSMOSIS.ORG 335

DENTAL CARIES DISEASE osms.it/dental-caries DIAGNOSIS

PATHOLOGY & CAUSES ▪ Odontogenic infections; tooth decay caused by acids produced by bacteria. ▪ Bacteria → plaque → ↓ pH → demineralization → caries

CAUSES

▪ Streptococcus mutans, Streptococcus sabrinus, Lactobacillus spp. ▫ Metabolically produce acids

RISK FACTORS

▪ Prolonged bottle use (baby bottle tooth decay), poor oral hygiene, sugar-rich foods, diabetes mellitus (DM), salivary gland disorders (e.g. Sjogren’s), medications that decrease salivation

COMPLICATIONS

▪ Hematogenous spread of bacteria to heart valves, joints, implanted prosthetics ▪ Spread from enamel to tooth pulp, alveolar bone ▪ Abscesses ▪ Soft tissue infections in extraoral perforation ▪ Deep head, neck infections ▪ Jaw osteomyelitis ▪ Tooth loss

DIAGNOSTIC IMAGING Odontogram ( jaw X-ray) ▪ Examine depth of lesions CT scan ▪ If widespread, soft tissue infection

OTHER DIAGNOSTICS Clinical presentation ▪ Teeth discoloration, changes

TREATMENT MEDICATIONS

▪ Topical/systemic antibiotics

SURGERY

▪ Extraction of infected material, replacement with fillings

OTHER INTERVENTIONS

▪ Dietary counselling, hygiene improvement

SIGNS & SYMPTOMS ▪ Yellow/black teeth staining, enamel softening; appearance of pits, cracks ▪ If severe: tooth collapse ▪ If pulp affected: dull pain exacerbated by cold, soft food ▪ If root caries: lower, where teeth close together, food difficult to extract; more difficult to diagnose

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Figure 39.2 A dental cavity in the tooth of a ten-year-old boy.

Chapter 39 Oral Disease

Figure 39.3 An orthopantomogram demonstrating dental cavities of the left mandibular second and third molar teeth.

GINGIVITIS osms.it/gingivitis PATHOLOGY & CAUSES ▪ Type of periodontal disease; inflammation of gums ▪ Pathogenic bacteria tunnel between microcolonies on tooth to surface in order to bring in steady supply of food → form hard mass (dental calculus) → bacterial plaque formation → enter gingival sulcus → gingivitis ▪ Immune response delivers blood to damaged tissue → provides nutrients for bacteria → immune response activates osteoclasts → dissolves bone → tooth loosening ▪ Non-infectious systemic factors → gingival overgrowth, inflammation ▫ Hormonal shifts (e.g. during pregnancy) ▫ Drug-induced (e.g. phenytoin, calcium channel blockers) ▫ Malnutrition-induced (e.g. vitamin C deficiency) ▫ Non-plaque-induced (rare, associated with genetics, allergy, trauma)

COMPLICATIONS

▪ Periodontitis, tooth loss, receding gums

SIGNS & SYMPTOMS ▪ Redness, swelling, bleeding after brushing/ flossing ▪ May be asymptomatic in early infection

DIAGNOSIS DIAGNOSTIC IMAGING X-ray ▪ Evaluate bone level, sulcus becomes deeper as periodontal pocket expands

OTHER DIAGNOSTICS Physical exam ▪ Swollen/bleeding gums, probe gingival sulcus to determine depth

RISK FACTORS

▪ Poor dental hygiene, older age

OSMOSIS.ORG 337

TREATMENT MEDICATIONS

▪ Antibiotics for severe infections

SURGERY

▪ Removal of infected tissue if severe

Figure 39.4 An individual with a severe case of gingivitis. The gums are swollen and hemorrhagic. There is visible plaque covering the free gingival margin of both maxillary incisors.

LUDWIG'S ANGINA osms.it/ludwigs-angina PATHOLOGY & CAUSES ▪ Bilateral infection of submandibular space (sublingual, submylohoid)

CAUSES

▪ Spread from infection of 2nd/3rd mandibular molars, pericoronitis, parotitis, peritonsillar abscess ▪ Mandibular fracture, piercings ▪ Causative agents polymicrobial from mouth flora, dominated by Streptococcus viridans; staphylococci, bacteroides also common

RISK FACTORS

▪ DM, hypertension, HIV infection, immunosuppression

COMPLICATIONS

▪ Airway obstruction, mediastinitis, necrotizing cellulitis, sepsis, asphyxia

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SIGNS & SYMPTOMS ▪ Infection ▫ Fever, chills, malaise, pain ▪ Stiff neck, dysphagia, individual leans forward to expand airway, no lymphadenopathy, bilateral, sudden aggressive spread, enlarged tongue, drooling ▪ Critical symptoms ▫ Stridor, cyanosis ▪ No abscess formation

DIAGNOSIS DIAGNOSTIC IMAGING CT scan ▪ Rule out abscess formation (occurs late in disease) ▪ Chest CT scan ▫ Mediastinitis

Chapter 39 Oral Disease

LAB RESULTS

TREATMENT

▪ Blood culture

MEDICATIONS

OTHER DIAGNOSTICS

▪ Ultrasound-guided needle aspiration

▪ Empiric broad-spectrum antibiotics with beta-lactamase activity

SURGERY

▪ Surgical drainage, if abscess identified on CT scan

OTHER INTERVENTIONS Airway management ▪ Fiberoptic nasal intubation, emergent tracheostomy may be necessary

ORAL CANDIDIASIS osms.it/oral-candidiasis PATHOLOGY & CAUSES ▪ Opportunistic infection of oral mucosal membranes by Candida spp. (e.g. Candida albicans) ▪ AKA thrush

TYPES Pseudomembranous ▪ Whitish plaques on oral mucosa (most common); can be scraped off to reveal erythematous surface Atrophic (denture stomatitis) ▪ Red lesions without plaques Hyperplastic (rare) ▪ Non-scrapable plaques

RISK FACTORS

COMPLICATIONS

▪ Spread into pharynx, disseminated candidiasis

SIGNS & SYMPTOMS ▪ ▪ ▪ ▪ ▪ ▪

May be asymptomatic Cottony feeling in mouth; lesions Pain/tenderness in oral cavity Painful swallowing (odynophagia) Decreased sense of taste Angular cheilitis

DIAGNOSIS LAB RESULTS

▪ Microbiological analysis of scrapings; Gram stain; KOH preparation; biopsy

▪ Young age, dentures, xerostomia, antibiotics, DM, malnutrition ▪ Immunosuppression due to corticosteroids, chemotherapy, HIV/AIDS

OSMOSIS.ORG 339

TREATMENT MEDICATIONS

▪ Topical antifungal agents (e.g. nystatin suspension, clotrimazole troches, systemic fluconazole)

Figure 39.5 Oral candidiasis in a child who had taken antibiotics.

PAROTITIS osms.it/parotitis PATHOLOGY & CAUSES ▪ Parotid gland inflammation ▪ Salivary stasis → seeding of parotid (Stensen) duct by microorganisms → infection, inflammation

CAUSES

▪ Bacterial: S. aureus, most common ▪ Viral: mumps, influenza, coxsackie, Epstein– Barr virus (EBV) ▪ Autoinflammatory: sarcoidosis as part of Mikulicz syndrome

RISK FACTORS

▪ Surgery, dehydration, salivary gland stones, poor oral hygiene, medications that decrease salivation (e.g. anticholinergic,

340 OSMOSIS.ORG

sympathomimetics)

COMPLICATIONS

▪ Spread to deep head, neck structures; septic jugular thrombophlebitis; septic osteomyelitis; sepsis; respiratory obstruction; facial nerve palsy

SIGNS & SYMPTOMS ▪ Systemic manifestations ▫ Fever, chills ▪ Periauricular, mandibular pain, swelling; trismus, dysphagia; purulent drainage ▪ Viral ▫ No discharge, prodrome followed by swelling lasting 5–10 days

Chapter 39 Oral Disease

DIAGNOSIS DIAGNOSTIC IMAGING

▪ Sample purulent exudate, ultrasound guided needle aspiration; culture, Gram stain

Ultrasound ▪ Increased blood flow through gland, enlargement, nodules CT scan ▪ Extension of inflammation to surrounding tissues

LAB RESULTS

▪ Complete blood count (CBC) ▪ Increased amylase without underlying pancreatitis ▪ Viral shows leukocytosis, increased IgM against mumps

Figure 39.6 The clinical appearance of parotitis of the left parotid gland. There is a marked swelling just anterior to the left ear.

TREATMENT MEDICATIONS

▪ Hydration; IV antibiotics ▪ Vaccination ▫ Mumps prevention

PERIODONTITIS osms.it/periodontitis PATHOLOGY & CAUSES ▪ Inflammation, destruction of supporting structures around teeth, wasting of bone ▪ Dysbiosis (disturbed bacterial symbiosis) more extreme than in gingivitis ▪ Orange-complex of bacteria (Fusobacterium nucleatum, Prevotella intermedia), red-complex of bacteria (Tannerella forsythia, Treponema denticola, Porphyromonas gingivalis) → immune response → more blood flow to damaged tissue → provides nutrients for bacteria → more damage to gingiva, periodontal ligament → activated osteoclasts in bone

→ tooth loosening ▪ Severity based on ligament loss ▪ Porphyromonas gingivalis impairs immune cells, kills bacteria → pathogenic bacteria overgrow ▪ Necrotizing ulcerative periodontitis (NUP) ▫ Extreme loss of periodontal attachment, alveolar bone; associated with immunosuppression (e.g. HIV/AIDS; chemotherapy, severe malnutrition); may be associated with enteric bacteria, yeast

OSMOSIS.ORG 341

CAUSES

▪ Poor oral hygiene; red-, orange-complex bacteria

RISK FACTORS

OTHER DIAGNOSTICS

▪ Clinical exam ▫ Probe teeth pockets, test for bleeding, depth

TREATMENT

▪ DM, smoking, Ehler–Danlos syndrome

COMPLICATIONS

▪ Tooth loss, infection spread to soft tissues of head, neck, sinusitis; hematogenous dissemination to heart valves (prosthetic/ native), joints, etc.

SIGNS & SYMPTOMS ▪ ▪ ▪ ▪ ▪

Redness, swelling, tender to palpation Halitosis Bleeding during teeth brushing Teeth loosening Periodontal pockets widen

MEDICATIONS

▪ Systemic antibiotics (if severe)

SURGERY

▪ Removal of infected tissue (if severe)

OTHER INTERVENTIONS

▪ Prevent plaque formation ▫ Daily brushing, flossing; antimicrobial agents (e.g. mouthwash) ▪ Scaling, root planing ▫ Remove plaque ▪ Topical fluoride

DIAGNOSIS DIAGNOSTIC IMAGING Panoramic dental X-ray ▪ Bone loss around tooth

SIALADENITIS osms.it/sialadenitis PATHOLOGY & CAUSES ▪ Inflammation of salivary glands ▫ Parotid (most common), sublingual, submandibular; unilateral ▪ Decreased flow of saliva → deposits settle in walls of salivary duct → duct blocked → flow of saliva slowed → deposits of calcium, phosphorous, etc. precipitate → form small concretions (microsialoliths) → grow into sialoliths → stones block duct → bacteria moves from mouth up, around blockage, into salivary duct →

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inflammation, tissue swelling

CAUSES

▪ Bacterial: Staphylococcus aureus (most common), Streptococcus viridans, Haemophilus influenzae ▪ Viral: mumps, HIV

RISK FACTORS

▪ Decreased salivary flow (dehydration, illness, anticholinergic medications, Sjogren’s syndrome) ▪ Risk increases with age

Chapter 39 Oral Disease

LAB RESULTS

▪ Lab culture of pus ▫ Gentle compression of gland

OTHER DIAGNOSTICS ▪ Clinical presentation

TREATMENT MEDICATIONS ▪ Antibiotics

SURGERY Figure 39.7 An individual holding their own salivary duct stone following surgical removal. Salivary duct stones predispose individuals to sialadenitis.

▪ Surgical gland removal ▫ If disease recurrent

OTHER INTERVENTIONS

▪ Hydration, warm compress, glandular massage, sialogogues

SIGNS & SYMPTOMS ▪ Acute sialadenitis ▫ Fever, chills, abscess formation ▫ Pain, swelling, redness of skin overlying affected gland ▫ Less saliva → dry mouth → bad taste (pus leaking out of affected duct) ▫ Severe: painful to open mouth ▪ Chronic sialadenitis ▫ Less painful, gland enlarges following meals, no overlying redness of the skin ▫ Associated with conditions linked to chronic decreased salivary flow (e.g. Sjogren’s syndrome), due to inflammation, salivary duct fibrosis, altering glandular tissue, composition of saliva

DIAGNOSIS

Figure 39.8 A submandibular sialogram demonstrating a salivary duct stone; a risk factor for sialadenitis.

DIAGNOSTIC IMAGING Ultrasound ▪ Abscess, salivary stone, tumor

OSMOSIS.ORG 343

Figure 39.9 The histological appearance of sialadenitis at low power. The acini are surrounded by dense fibrosis and display patchy lymphocytic infiltrates.

344 OSMOSIS.ORG

NOTES

NOTES

PANCREATITIS GENERALLY, WHAT IS IT? PATHOLOGY & CAUSES ▪ Inflammation of pancreas

SIGNS & SYMPTOMS ▪ Upper abdominal pain radiating to back; nausea; vomiting

TYPES

DIAGNOSIS

▪ Acute, chronic

DIAGNOSTIC IMAGING

CAUSES

▪ Acute ▫ Gallstones, alcoholism, direct trauma, infections (mumps) ▪ Chronic ▫ Recurrent acute pancreatitis, chronic alcoholism, cystic fibrosis

▪ Abdominal CT scan; ultrasound

LAB RESULTS

▪ Clinical, lab findings; see individual disorders

TREATMENT

RISK FACTORS ▪ Smoking

OTHER INTERVENTIONS

▪ Dietary modifications, symptomatic treatment

PANCREATIC PSEUDOCYST osms.it/pancreatic-pseudocyst PATHOLOGY & CAUSES ▪ Localized fluid collection of pancreatic enzymes, necrotic debris and blood encapsulated by non-epithelialized wall (hence the name pseudocyst) composed of fibrous and granulation tissue ▪ Usually take up to 4–6 weeks to develop, unlike acute fluid collections ▪ Occurs due to disruption of pancreatic duct → accumulation of pancreatic fluid →

hemorrhagic fat necrosis → inflammatory reaction → encapsulation of fluid by fibrous and granulation tissue

CAUSES

▪ Arises as complication of acute/chronic pancreatitis/abdominal trauma

COMPLICATIONS

▪ Infection; hemorrhage ▪ Compression of the gastrointestinal/urinary/

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biliary tract ▪ Rupture → spilling of enzymes and debris into abdominal cavity → diffuse peritonitis

SIGNS & SYMPTOMS ▪ Abdominal discomfort, indigestion, anorexia, abdominal mass

DIAGNOSIS DIAGNOSTIC IMAGING CT scan ▪ Large cyst cavity of low attenuation surrounded by well-defined enhancing wall within, around pancreas ▪ Calcifications ▪ If present, complications may be visualized Ultrasound ▪ Visualization of hypoechoic/anechoic cystic fluid collections MRI ▪ Not necessary, but useful for distinguishing from organized necrosis

LAB RESULTS Cyst fluid analysis ▪ To distinguish from tumor ▫ ↓ carcinoembryonic antigen (CEA) ▫ ↑ cmylase ▫ ↓ cluid viscosity

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Figure 40.1 A CT scan in the axial plane demonstrating a pancreatic pseudocyst.

TREATMENT ▪ Initially ▫ Bowel rest, total parenteral nutrition (TPN), observation

SURGERY

▪ If symptoms do not improve ▫ Surgical drainage to establish connection which drains pseudocystic fluid into small intestine (cystojejunostomy), stomach (cystogastrostomy), or duodenum (cystoduodenostomy) ▪ Endoscopic drainage

Chapter 40 Pancreatitis

PANCREATITIS (ACUTE) osms.it/acute-pancreatitis PATHOLOGY & CAUSES ▪ Sudden inflammation of pancreas due to autodigestion → reversible pancreatic injury.

TYPES Mild ▪ Inflammation, parenchymal edema, peripancreatic fat necrosis Severe ▪ Parenchymal necrosis, hemorrhage

CAUSES

▪ See mnemonic for summary of causes

MNEMONIC: I GET SMASHED

Causes of Acute pancreatitis Idiopathic Gallstones Ethanol abuse Trauma Steroids Mumps infection Alcohol abuse Scorpion sting Hypertriglyceridemia, hypercalcemia Endoscopic retrograde cholangiopancreatography Drugs: sulfa drugs, reversetranscriptase inhibitors, protease inhibitors

Alcohol ▪ Increases zymogen secretion; decreases fluid, bicarbonate production → pancreatic juices become thick, viscous → pancreatic duct blocked ▪ Stimulates release of inflammatory cytokines ▪ Oxidative metabolism produces free radicals Gallstones ▪ Lodge at Oddi sphincter → pancreatic duct blocked Alcohol and gallstones ▪ Pancreatic duct blocked → pancreatic juices back up → pressure increases → zymogen granules fuse with lysosomes → trypsinogen transforms into activated trypsin → digestive enzyme activation, autodigestion

RISK FACTORS

▪ Biologically male to biologically female, 1:3 ▪ Smoking

COMPLICATIONS

▪ Most often ▫ Acute pseudocyst, intra-abdominal infection, pancreatic abscess, disseminated intravascular coagulation (DIC), internal pancreatic fistula ▪ Severe manifestations ▫ Acute respiratory distress syndrome (ARDS), acute renal failure, hemorrhage, hypotensive shock

OSMOSIS.ORG 347

TREATMENT

SIGNS & SYMPTOMS ▪ Abdominal pain; loss of appetite; palpable, tender mass ▪ Cullen’s sign ▫ Periumbilical region bruising ▪ Grey Turner’s sign ▫ Bruising along flank

MEDICATIONS

▪ Pain management, hydration, electrolytes ▪ Hyperbaric oxygen therapy, antibiotics

SURGERY

▪ Necrosectomy

OTHER INTERVENTIONS

▪ Total restriction of food intake, alcohol cessation ▪ Endoscopic retrograde cholangiopancreatography (ERCP)

Figure 40.2 Cullen’s sign. Individual presented with a four-day history of abdominal pain following an alcohol binge.

DIAGNOSIS DIAGNOSTIC IMAGING CT scan ▪ Visualization of inflammation, necrosis, abscess, pancreatic pseudocysts Ultrasound ▪ Gallstones

LAB RESULTS

▪ Elevated serum amylase, lipase, bilirubin

OTHER DIAGNOSTICS Histology ▪ Microvascular edema; fat tissue necrosis; acute inflammation; destruction of parenchyma, blood vessels; interstitial hemorrhage

348 OSMOSIS.ORG

Figure 40.3 A CT scan in the axial plane demonstrating acute pancreatitis. There is diffuse enlargement of the pancreas associated with peripancreatic fluid.

Chapter 40 Pancreatitis

PANCREATITIS (CHRONIC) osms.it/chronic-pancreatitis PATHOLOGY & CAUSES ▪ Persistent, chronic inflammation of pancreas due to autodigestion → irreversible injury of exocrine, endocrine pancreas ▪ Fibrosis, calcification ▫ Prolonged inflammation produces fibrogenic cytokines, transforming growth factor beta (TGF-beta), plateletderived growth factor (PDGF) → activates myofibroblasts → collagen production, fibrosis ▫ Early stages: Langerhans islets not affected ▫ Advanced: atrophy, fibrosis of islets

CAUSES

▪ See mnemonic for summary of causes ▪ Genetic ▫ Hereditary chronic pancreatitis: autosomal-dominant disease due to mutations in cationic trypsinogen gene ▫ Cystic fibrosis: cystic fibrosis transmembrane conductance regulator (CFTR) mutation → decreased bicarbonate secretion → pancreatic duct plugged, obstructed ▪ Autoimmune ▫ Distinct form of chronic pancreatitis → manifestation of immunoglobulin G (IgG) related disease

COMPLICATIONS

▪ Pancreatic pseudocyst; ascites; pancreatic insufficiency; diabetes mellitus; vitamins A, D, E, K deficiency; pancreatic cancer

MNEMONIC: TIGAR-O

Causes of Chronic pancreatitis Toxins: chronic alcoholism Idiopathic Genetic Autoimmune Recurrent acute pancreatitis Obstruction: gallstones, pancreatic head tumor

SIGNS & SYMPTOMS ▪ Severe abdominal pain radiates to back; nausea; vomiting; steatorrhea; weight loss; edema due to malabsorption

DIAGNOSIS DIAGNOSTIC IMAGING CT scan ▪ Visualization of pancreatic ducts dilatation, calcifications, atrophy, pseudocysts Ultrasound ▪ Hyperechogenicity (fibrosis), pseudocysts, pseudoaneurysms, ascites ERCP/magnetic resonance cholangiopancreatography (MRCP) ▪ Visualization of pancreatic ducts; chain-oflakes pattern due to alternating stenosis, dilation

LAB RESULTS

▪ Mildly elevated serum amylase, alkaline phosphatase, bilirubin

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OTHER DIAGNOSTICS Histology ▪ Dilatation of pancreatic ducts; acinar cell atrophy; fibrosis; chronic inflammatory infiltrate; protein plugs, calcifications

TREATMENT MEDICATIONS

▪ Pain management ▪ Pancreatic enzyme replacement

SURGERY Endoscopy, surgery ▪ Resectional/drainage procedures for pseudocyst, fistula, ascites

OTHER INTERVENTIONS

▪ Alcohol cessation, dietary modifications (low-fat)

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Figure 40.4 The histological appearance of pancreatic fat necrosis in a case of severe pancreatitis.

NOTES

NOTES

PERITONEAL PATHOLOGY GENERALLY, WHAT IS IT? PATHOLOGY & CAUSES ▪ Conditions affecting peritoneal cavity (e.g. serosal membrane inflammation, gas)

CAUSES Peritonitis ▪ Spontaneous bacterial peritonitis ▪ Leakage of gastrointestinal (GI) contents ▪ Presence of foreign material ▫ Bile, blood, contrast material ▪ Endometriosis ▪ Peritoneal dialysis Pneumoperitoneum ▪ Perforation of anterior duodenal ulcer ▪ Iatrogenic ▪ Increased intrathoracic pressure

SIGNS & SYMPTOMS Peritonitis ▪ Fever, chills, tachycardia ▪ Ascites, abdominal distention, abdominal rigidity, spider angiomata, jaundice ▪ Anorexia, nausea, vomiting, diarrhea ▪ Encephalopathy; delirium, confusion, cognitive decline ▪ Absent bowel sounds, ileus Pneumoperitoneum ▪ Abdominal pain, rigidity ▪ Absent bowel sounds, ileus

DIAGNOSIS DIAGNOSTIC IMAGING X-ray ▪ Peritonitis ▫ Supine, upright abdominal films ▪ Pneumoperitoneum ▫ Upright chest radiography ▫ Subdiaphragmatic free gas; cupola sign ▫ Rigler’s sign, football sign ▫ Lateral decubitus X-ray CT scan ▪ Pneumoperitoneum ▫ Small quantities of air

LAB RESULTS Paracentesis ▪ Peritonitis ▫ If ascites present Complete blood count (CBC) Blood chemistry

TREATMENT MEDICATIONS

▪ Systemic antibiotics

SURGERY

▪ Exploratory laparotomy

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PERITONITIS osms.it/peritonitis PATHOLOGY & CAUSES

DIAGNOSIS

▪ Inflammation of serosal membrane lining abdominal cavity, organs (AKA peritoneum). ▪ Neutrophilic infiltration, formation of fibrinopurulent exudate

DIAGNOSTIC IMAGING

CAUSES

LAB RESULTS

▪ Spontaneous bacterial peritonitis ▫ Bacterial migration from GI lumen; more common in people with ascites/cirrhosis ▫ E. coli, Klebsiella, Pseudomonas, Proteus, Gram-negatives ▪ Leakage of GI contents; most common; perforated viscera ▫ Proximal GI tract perforation → Grampositive bacteria ▫ Distal GI tract perforation → Gramnegative bacteria ▪ Foreign material ▫ Bile, blood, contrast material ▪ Endometriosis ▪ Peritoneal dialysis

Supine, upright abdominal films ▪ Subhepatic/subdiaphragmatic free air, abscesses in case of perforated viscus

▪ Leukocytosis, acidosis

Paracentesis ▪ If ascites present ▪ Serum ascites albumin gradient (SAAG) ▫ > 1.1 in spontaneous bacterial peritonitis ▪ Neutrophil count > 250 cells/microliter

TREATMENT MEDICATIONS Systemic antibiotics ▪ Third generation cephalosporins/quinolones

SIGNS & SYMPTOMS ▪ Fever, chills, tachycardia ▪ Ascites, abdominal distention, abdominal rigidity, spider angiomata, jaundice ▪ Anorexia, nausea, vomiting, diarrhea → hypovolemia, renal failure ▪ Absent bowel sounds, ileus ▪ Early stages ▫ Dull, poorly localized abdominal pain ▪ Late stages ▫ Severe, localized abdominal pain; acute abdomen ▪ Encephalopathy; delirium, confusion, cognitive decline

352 OSMOSIS.ORG

Figure 41.1 The histological appearance of tuberculous peritonitis, a rare kind of peritonitis. There are numerous epithelioid macrophages and giant cells infiltrating the peritoneal biopsy.

Chapter 41 Peritoneal Pathology

Figure 41.2 An abdominal CT scan with oral contrast in the axial plane demonstrating severe peritonitis. There is diffuse peritoneal thickening and large amounts of radiodense fluid. On laparotomy this was discovered to be pus.

PNEUMOPERITONEUM osms.it/pneumoperitoneum PATHOLOGY & CAUSES ▪ Abnormal collection of gas within peritoneal cavity.

CAUSES

▪ Most common ▫ Perforation of anterior duodenal ulcer secondary to peptic ulcer disease ▪ Iatrogenic ▫ Abdominal surgery; resolves spontaneously ▪ Increased intrathoracic pressure (mechanical ventilation, chest compressions)

SIGNS & SYMPTOMS ▪ Abdominal pain, rigidity ▪ Absent bowel sounds, ileus

DIAGNOSIS DIAGNOSTIC IMAGING CT scan ▪ Small quantities of air Upright chest radiography ▪ Subdiaphragmatic free gas; Cupola sign (free intraperitoneal air, well-defined superior border formed by diaphragm) Supine abdominal X-ray ▪ Rigler’s sign (double wall sign): both sides of abdominal wall visible ▪ Football sign (massive pneumoperitoneum): ellipsoid shape of abdominal cavity outlined by gas Lateral decubitus X-ray ▪ Free gas between liver, abdominal wall

OSMOSIS.ORG 353

TREATMENT SURGERY Exploratory laparotomy ▪ Repair perforated viscus

Figure 41.3 A CT scan in the axial plane demonstrating air in the peritoneal cavity. The air has also tracked along an umbilical hernia.

Figure 41.4 An erect chest radiograph demonstrating a sub-diaphragmatic air bubble, diagnostic of pneumoperitoneum.

354 OSMOSIS.ORG

NOTES

NOTES

RECTAL & ANAL PATHOLOGY GENERALLY, WHAT IS IT? PATHOLOGY & CAUSES ▪ Diseases affecting rectum and anal region

COMPLICATIONS

▪ Discomfort during defecation, itching, pain, bleeding

SIGNS & SYMPTOMS

DIAGNOSIS ▪ History, physical examination

TREATMENT ▪ Change dietary/defecation habits, pharmacological, surgical

▪ Visible abnormalities

ANAL FISSURE osms.it/anal-fissure PATHOLOGY & CAUSES ▪ Anal mucosa linear fissure ▪ Hard bowel movement → anal mucosa stretches → acute fissure → internal anal sphincter spasms → blood flow reduces → difficult healing → chronic fissure ▪ Midline, anteriorly/posteriorly

RISK FACTORS

Low fiber diet Diarrhea Previous anal surgery Anal trauma Abnormalities in internal anal sphincter Sexually transmitted infections (STIs) ▫ Human papillomavirus (HPV), herpes, chlamydia ▪ Inflammatory bowel disease (IBD)

▪ ▪ ▪ ▪ ▪ ▪

COMPLICATIONS

▪ Fecal bacteria infection

SIGNS & SYMPTOMS ▪ Midline tear ▪ Pain during bowel movements → fear of defecation → constipation → harder stool → more pain ▪ Blood on toilet paper/stool

DIAGNOSIS ▪ History, examination of anal region/rectum

OSMOSIS.ORG 355

TREATMENT MEDICATIONS

▪ Stool softeners ▪ Topical nitrates/calcium channel blocker (e.g diltiazem)

SURGERY

▪ Sphincterotomy

OTHER INTERVENTIONS

▪ Proper anal hygiene ▪ Warm bath (AKA sitz bath) ▪ Muscle relaxation → increase healing mechanisms ▪ Fiber supplementation

Figure 42.1 The clinical appearance of an anal fissure affecting the posterior anal mucosa.

ANAL FISTULA osms.it/anal-fistula PATHOLOGY & CAUSES ▪ Abnormal communication between anal canal, perianal skin ▫ Fistula: Latin (pipe, catheter), from findo (cleave, divide, split) ▪ Foreign material in anal crypts → anal glands ducts blocked → anal abscess → pus travels to skin through tract

Extrasphincteric ▪ Rectum/sigmoid colon → levator muscle ani → skin

SIGNS & SYMPTOMS ▪ Skin excoriations, pus/serous fluid/feces draining from skin-opening, bleeding, itching, pain, redness, swelling

TYPES Intersphincteric ▪ Internal anal sphincter → space between internal, external anal sphincters (AKA intersphincteric plane) → skin Transsphincteric (U-shaped fistula) ▪ Internal anal sphincter → intersphincteric plane → external anal sphincter → skin Suprasphincteric ▪ Internal anal sphincter → puborectalis muscle → space between puborectalis, levator ani muscle → skin

356 OSMOSIS.ORG

DIAGNOSIS OTHER DIAGNOSTICS

▪ Anal examination → delineate course of fistula

TREATMENT SURGERY

▪ Drain infection → eradicate fistulous tract → preserve anal sphincter function → avoid recurrences

Chapter 42 Rectal & Anal Pathology

Figure 42.2 Surgical wound following removal of an anal fistula.

HEMORRHOID osms.it/hemorrhoid PATHOLOGY & CAUSES ▪ Anal cushions hypertrophy due to supportive tissue deterioration

TYPES Internal ▪ Affecting hemorrhoidal venous cushions above dentate line ▫ Grade I: bleed but not prolapse ▫ Grade II: prolapse on straining but reduce spontaneously ▫ Grade III: prolapse on straining, require manual reduction ▫ Grade IV: spontaneous, irreducible prolapse External ▪ Affecting hemorrhoidal venous cushions below dentate line

RISK FACTORS

▪ Constipation (low fiber diet), strenuous defecation, diarrhea, prolonged sitting, aging, increased intra-abdominal pressure, pregnancy, intra-abdominal mass, ascites, portal hypertension

COMPLICATIONS Internal hemorrhoids ▪ Bleeding with bowel movements ▪ Prolapsing ▪ Incarceration, strangulation → pain ▪ Mucus deposits on perianal tissue → itching External hemorrhoids ▪ Bleeding ▪ Acute thrombosis → acute pain ▪ Itching ▪ Hygiene difficulties

SIGNS & SYMPTOMS ▪ Itching ▪ Bleeding associated with bowel movement → bright red blood on toilet paper ▪ Pain ▪ Mucous discharge ▪ Perianal mass in case of prolapse

OSMOSIS.ORG 357

DIAGNOSIS DIAGNOSTIC IMAGING

▪ Anoscopy for internal hemorrhoids

OTHER DIAGNOSTICS

TREATMENT MEDICATIONS

▪ Stool softeners ▪ Topical, systemic analgesics

SURGERY

▪ Anal, perianal inspection ▪ Digital rectal examination

▪ Sclerotherapy, rubber band ligation, infrared coagulation

OTHER INTERVENTIONS ▪ Increase fiber, fluid intake

Figure 42.3 The histological appearance of an excised hemorrhoid. There is fibromuscular hyperplasia and numerous dilated vascular spaces. Figure 42.4 External appearance of grade 2 hemorrhoids.

RECTAL PROLAPSE osms.it/rectal-prolapse PATHOLOGY & CAUSES ▪ Partial/total slip of rectal tissue through anal orifice

RISK FACTORS

▪ Constipation, diarrhea, pregnancy, pelvic floor damage

COMPLICATIONS

▪ Mucous discharge, bleeding, fecal incontinence, constipation, rectal ulceration

358 OSMOSIS.ORG

SIGNS & SYMPTOMS ▪ Mass protruding through anus ▫ After defecation; when sneezing/ coughing; when walking → pain, rectal bleeding, incontinence

Chapter 42 Rectal & Anal Pathology

DIAGNOSIS OTHER DIAGNOSTICS

▪ Physical examination ▫ Prolapse clearly evident

TREATMENT SURGERY

▪ Sutures/mesh slings to anchor rectum to posterior wall of pelvis (sacrum) ▫ Open or laparoscopic ▪ Rectosigmoidectomy ▫ Part of rectum and sigmoid pulled through anus and removed, reanastomosis of remaining rectum to colon ▫ Usually reserved for severe prolapse/ non-candidates for open/laparoscopic procedure

OTHER INTERVENTIONS Figure 42.5 A complete rectal prolapse.

▪ High fiber diet, enemas, suppositories (to avoid constipation/straining) ▪ Kegel exercises may help limit progression

OSMOSIS.ORG 359

NOTES

NOTES

UPPER GASTROINTESTINAL CONGENITAL MALFORMATIONS

GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Upper gastrointestinal tract structural/ functional anomalies during embryonic development; present at birth

CAUSES

DIAGNOSIS DIAGNOSTIC IMAGING

▪ Prenatal ultrasound; MRI ▪ X-ray/CT scan ▫ Avoid if possible due to teratogenicity

▪ Genetic, environmental factors

SIGNS & SYMPTOMS ▪ May be asymptomatic/complete dysfunction of gastrointestinal (GI), life incompatibility

TREATMENT SURGERY

▪ See individual disorders

OTHER INTERVENTIONS ▪ Nasogastric intubation

CLEFT LIP & PALATE osms.it/cleft-lip-and-palate PATHOLOGY & CAUSES ▪ Group of congenital malformations in upper lip, oral cavity roof ▪ Result of improper fusion of facial bones, associated tissues

TYPES

▪ Based on severity

Cleft lip (CL, cheiloschisis) ▪ Unilateral, bilateral “hare lip” Cleft palate (CP, palatoschisis) ▪ Commonly uvula also split

360 OSMOSIS.ORG

Combination (CLP, cheilopalatoschisis) ▪ Most severe forms; split alveolar ridge, uvula (cheilognathopalatoschisis)

RISK FACTORS

▪ Other inherited genetic disorders (e.g. Patau syndrome, Stickler syndrome) ▪ Environmental teratogenic factors (e.g. intrauterine hypoxia, pesticides, anticonvulsant medication, folate deficiency)

COMPLICATIONS

▪ Speech impediments, hearing issues/ recurrent otitis media, difficulty eating

Chapter 43 Upper Gastrointestinal Congenital Malformations

SIGNS & SYMPTOMS ▪ Velopharyngeal insufficiency ▫ Inability to temporarily stop physical communication between oral, nasal cavities ▪ Dysphonia ▫ Air leaks to nasal cavity → hypernasal vocalization ▪ Dysarthria ▫ Abnormal structure increases speech difficulty → distorted word structure ▪ Nasal cavity infection ▫ Food trapped in nasal cavity → predisposes infection

OTHER INTERVENTIONS

▪ Temporary prosthetic implants, until surgery ▪ Speech-language therapy ▪ Folate supplementation during pregnancy decreases risk

DIAGNOSIS DIAGNOSTIC IMAGING

Figure 43.1 A cleft hard palate in an infant.

Prenatal ultrasound ▪ Evaluation of integrity of nares, upper lip, hard and soft palate ▪ 3D reconstruction and surface rendering allow for better diagnosis and help parents prepare psychologically MRI ▪ Evaluation of associated extra/intracranial abnormalities ▪ Prenatal MRI aids in confirmation and characterization/integrity of maxillary arch CT scan/X-ray ▪ Not typically used; 3D reconstructions can aid in surgical planning

OTHER DIAGNOSTICS ▪ Clinically evident at birth

TREATMENT SURGERY

▪ Surgical closure of cleft lip by three months of age ▪ Timing for surgical closure of palate is variable; usually done by one year of age

Figure 43.2 A child with a unilateral, incomplete cleft lip.

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CONGENITAL DIAPHRAGMATIC HERNIA (CDH) osms.it/congenital-diaphragmatic-hernia PATHOLOGY & CAUSES ▪ Protrusion of abdominal viscera into chest cavity ▪ Results from abnormal development of diaphragm in utero ▪ High mortality rate ▪ Incomplete diaphragm formation → abdominal organs protrude into chest cavity → physical obstruction of heart, lung formation/function → pulmonary hypoplasia, surfactant deficiency, pulmonary hypertension, arrhythmia

TYPES Bochdalek hernia ▪ Posterolateral diaphragmatic hernia; most common CDH ▫ Viscera protrude through posterolateral segment of diaphragm ▫ Left kidney, perinephric fat, stomach, small intestine Morgagni hernia ▪ Retrosternal, parasternal diaphragmatic hernia ▫ Viscera protrude through foramina of Morgagni (form sternocostal angle)

CAUSES

▪ Genetic, environmental factors

SIGNS & SYMPTOMS ▪ Dyspnea, tachypnea, central cyanosis, tachycardia, retractions, nasal flaring, decreased/absent breath sounds on affected side, scaphoid abdomen

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MNEMONIC: 5Bs

Bochdalek hernia features Bochdalek hernia Big Back and medial, usually left side Baby Bad: associated with pulmonary hypoplasia

DIAGNOSIS DIAGNOSTIC IMAGING Prenatal ultrasound ▪ Polyhydramnios ▪ Cardiomediastinal shift with possible abnormal cardiac axis ▪ Lack of visualization of normal stomach bubble ▪ Absent bowel loops in abdomen; stomach and small bowel in thorax ▪ Intrathoracic herniation of liver (seen in 85%, poor prognosis) ▪ Peristaltic bowel movements in thorax ▪ Reduced abdominal circumference X-ray ▪ indistinct diaphragm, opacification of hemithorax (typically left-sided) MRI ▪ Helpful in further assessment of pulmonary hypoplasia ▪ Measurement of fetal lung volumes

Chapter 43 Upper Gastrointestinal Congenital Malformations

TREATMENT SURGERY

▪ Surgical repair of hernia

OTHER INTERVENTIONS

▪ Planned delivery after week 37 of gestation → immediate intubation, mechanical ventilation ▪ Inhaled nitric oxide for severe pulmonary hypertension ▪ Nasogastric, pulmonary intubation

Figure 43.3 A plain X-ray of a newborn demonstrating visible bowel loops in the thoracic cavity.

ESOPHAGEAL WEB osms.it/esophageal-web PATHOLOGY & CAUSES ▪ Rare narrowing of esophagus due to thin membrane of esophageal tissues (mucosa, submucosa) ▪ Most commonly appear in lower third of esophagus ▪ Can be congenital/acquired ▪ May occur as solitary disease

RISK FACTORS

▪ Plummer–Vinson syndrome ▫ Sideropenic dysphagia, iron-deficiency anemia, glossitis, cheilosis, esophageal webs

COMPLICATIONS

▪ Food impaction, perforation by solid food/ esophageal probe insertion

SIGNS & SYMPTOMS ▪ ▪ ▪ ▪

May be asymptomatic (if small) Dysphagia: difficulty in swallowing Odynophagia: painful swallowing Retrosternal pain: can be mistaken for angina pectoris

DIAGNOSIS OTHER DIAGNOSTICS Fluoroscopy/barium swallow ▪ Visualized when esophagus is fully distended with contrast ▪ “Jet effect” of contrast being ejected distally from web

TREATMENT OTHER INTERVENTIONS

▪ Endoscopic dilation via inflated balloon

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HYPERTROPHIC PYLORIC STENOSIS osms.it/hypertrophic-pyloric-stenosis PATHOLOGY & CAUSES ▪ Constriction of pylorus due to pyloric sphincter hypertrophy → gastric outflow obstructed ▪ Autosomal dominant/multifactorial

RISK FACTORS

▪ Firstborn, biologically male, parents had hypertrophic pyloric stenosis, macrolide exposure

COMPLICATIONS

▪ Dehydration, malnourishment, acid-base imbalance

Fluoroscopy ▪ Delayed gastric emptying ▪ Elongated pylorus with narrow lumen ▪ Entrance to pylorus may be beak shaped

TREATMENT SURGERY

▪ Pyloromyotomy

OTHER INTERVENTIONS

▪ Rehydration ▪ Regulate acid-base status, correct electrolyte abnormalities

SIGNS & SYMPTOMS ▪ Projectile nonbilious vomiting at/soon after birth ▪ Visible peristalsis ▪ Dehydrated, undernourished

DIAGNOSIS DIAGNOSTIC IMAGING X-ray ▪ Distended stomach, minimal intestinal gas Ultrasound ▪ Modality of choice; but cannot exclude midgut volvulus ▪ Pyloric muscle thickness

OTHER DIAGNOSITCS

▪ Abdominal olive palpable on physical examination

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Figure 43.4 An abdominal radiograph demonstrating a grossly dilated stomach, secondary to obstructive pyloric stenosis.

Chapter 43 Upper Gastrointestinal Congenital Malformations

THYROGLOSSAL DUCT CYST osms.it/thyroglossal-duct-cyst PATHOLOGY & CAUSES ▪ Benign cyst; epithelium of unclosed thyroglossal duct ▪ Thyroid cells migrate from foramen cecum downward → leave thyroglossal duct → thyroid duct stays open → fills with mucus → cyst forms

COMPLICATIONS

OTHER DIAGNOSTICS

▪ Fluctuant mass palpable at a anterior midline/paramedian location ▪ Draining sinus may be visible

TREATMENT SURGERY

▪ Surgical excision (Sistrunk procedure)

▪ Infection (spread from respiratory system), inflammation, discharging sinus with skin (secondary to inflammation/trauma), thyroid gland malformation (if thyroid cells remain in thyroglossal duct/cyst), extrathyroid thyroid carcinoma (from leftover thyroid cells)

SIGNS & SYMPTOMS ▪ Painless mass in front of neck, moves when swallowing; inflammation, pain; dysphagia; dyspnea

Figure 43.5 The clinical appearance of a thyroglossal duct cyst. There is a vague, fluctuant swelling in the midline of the neck.

DIAGNOSIS DIAGNOSTIC IMAGING Ultrasound ▪ Fluctuant mass filled with anechoic fluid, thin walled, without vascularity CT scan ▪ Thin-walled, well-defined homogeneous, fluid dense lesions, anterior midline/ paramedian location ▪ May demonstrate capsular enhancement ▪ Sternocleidomastoid muscle may be displaced posteriorly/posterolaterally ▪ May be embedded in infrahyoid muscles

Figure 43.6 A CT scan of the head and neck in the sagittal plane demonstrating a thyroglossal duct cyst adjacent to the hyoid bone.

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TRACHEOESOPHAGEAL FISTULA osms.it/tracheoesophageal-fistula PATHOLOGY & CAUSES ▪ Pathologic communication between trachea, esophagus ▪ Results from tracheoesophageal ridge fusion failure ▪ Occurs as congenital malformation/surgery complication (later in life) ▪ VACTERL association; see mnemonic

COMPLICATIONS

▪ Atresia (due to hydrochloric acid accumulation), gastroesophageal reflux, dysphagia, frequent respiratory infections

SIGNS & SYMPTOMS ▪ Hypersalivation/drooling, choking, vomiting, central cyanosis upon feeding

DIAGNOSIS

MNEMONIC: VACTERL

Group of malformations with common, unknown cause Vertebral anomalies Anal atresia Cardiovascular anomalies Tracheoesophageal fistula Esophageal atresia Renal anomalies Limb defects

TYPES Type A ▪ Middle esophageal segment missing Type B ▪ Proximal esophagus communicates with trachea Type C (most common) ▪ Distal esophagus communicates with trachea, proximal esophagus atresia Type D ▪ Proximal, distal esophageal segments communicate with trachea, middle segment atresia Type E (AKA Type H) ▪ Complete esophagus, additional part communicates with trachea

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DIAGNOSTIC IMAGING Chest X-ray ▪ Nasogastric tube coiled in proximal esophagus (usually sufficient for diagnosis) Fluoroscopy/Barium swallow ▪ If difficult to diagnose, may require contrast swallow study to visualize contrast passing into tracheobronchial tree ▫ Barium is contrast medium of choice (ionic iodinated medium can cause chemical pneumonitis) CT scan ▪ Useful for preoperative planning

OTHER DIAGNOSTICS

▪ Inability to pass gastric tube ▪ Neonates drool, choke, vomit during first feeding

TREATMENT SURGERY

▪ Surgical closing of pathologic communication, fusion of esophageal buds

Chapter 43 Upper Gastrointestinal Congenital Malformations

Figure 43.7 An acquired tracheo-esophageal fistula.

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NOTES

NOTES

CONGENITAL ANEMIA GENERALLY, WHAT IS IT? PATHOLOGY & CAUSES ▪ Inherited macrocytic-normochromic anemias ▫ Diamond–Blackfan anemia ▫ Fanconi anemia

COMPLICATIONS

▪ Congenital anomalies, ↑ blood malignancy risk, solid tumor cancers

SIGNS & SYMPTOMS ▪ See individual disorders

DIAGNOSIS ▪ See individual disorders

TREATMENT ▪ See individual disorders

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Chapter 44 Congenital Anemia

DIAMOND–BLACKFAN ANEMIA (DBA) osms.it/diamond-blackfan-anemia PATHOLOGY & CAUSES ▪ Autosomal dominant ribosomopathy resulting in inherited bone-marrow failure syndrome, macrocytic-normochromic anemia, associated congenital anomalies ▪ Genetic mutation → ribosomopathy → impaired hematopoiesis → red blood cell aplasia → macrocytic-normochromic

anemia ▫ No other significant cytopathies evident ▫ Sporadic, unpredictable penetrance → high degree of genotypic heterogeneity → variety of possible congenital anomalies

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COMPLICATIONS

▪ Genetic predisposition to malignancies like myelogenous leukemia, myelodysplastic syndrome, solid tumors ▪ Congenital anomalies increase complication risk

SIGNS & SYMPTOMS ▪ Anemia often present at birth → signs and symptoms of impaired oxygen-carrying capacity (e.g. pallor, tachycardia, apnea, lethargy) ▪ Low birth weight, evidence of growth restriction usually present Congenital anomalies ▫ Craniofacial: low-set ears, micrognathia, high-arched/cleft palate, broad nasal bridge ▫ Neck: short, may be webbed ▫ Ophthalmological: congenital glaucoma, cataracts, strabismus ▫ Thumbs: duplex/bifid; flat thenar eminence ▫ Urogenital: absent/horseshoe kidney ▫ Cardiac: ventricular/atrial septal defect, coarctation of the aorta

DIAGNOSIS ▪ DBA usually diagnosed within first month of life

DIAGNOSTIC IMAGING Renal imaging/echocardiography ▪ Find internal congenital anomalies

LAB RESULTS

▪ Complete blood cell count (CBC) with red blood cell indices ▫ ↓ red blood cell count, hemoglobin, hematocrit ▫ Reticulocytopenia ▫ ↑ mean corpuscular volume (MCV) ▫ Normal mean corpuscular hemoglobin (MCH), white blood cell, platelet counts ▪ Bone marrow aspirate normal, except few/

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no erythroid precursors ▪ Serum erythropoietin, fetal hemoglobin (HbF) increased secondary to stress hematopoiesis ▪ Elevated erythrocyte adenosine deaminase (eADA)

OTHER DIAGNOSTICS

▪ Classical physical congenital anomalies associated with DBA ▪ Genetic testing, family history

TREATMENT ▪ 25% chance of spontaneous remission

MEDICATIONS Corticosteroids ▪ Hemoglobin ↑ observed after steroid therapy initiation ▪ Weigh dose, duration of steroid treatment against adverse effects (e.g. growth disturbances, adrenal suppression, immunosuppression, pathological fractures)

SURGERY Curative ▪ Allogeneic hematopoietic stem cell transplant

OTHER INTERVENTIONS

▪ Monitor for development of malignancies ▪ Specialist care (e.g. cardiology, nephrology, urology) ▪ Family support, genetic counseling

Transfusions ▪ Packed red blood cells ▫ Maintain Hgb ≥ 8g/dL ▫ Must be leukocyte poor to decrease transmission of cytomegalovirus ▫ Monitor for iron overload, hemosiderosis

Chapter 44 Congenital Anemia

FANCONI ANEMIA (FA) osms.it/fanconi-anemia PATHOLOGY & CAUSES ▪ Autosomal recessive/X-linked disorder of chromosome fragility causing inherited bone marrow failure syndrome, macrocyticnormochromic anemia, pancytopenia Physical abnormalities ▪ Short stature, malformations associated with the VACTERL-H (vertebral, anal, cardiac, tracheoesophageal, renal, limb and hydrocephalus) association ▫ Microcephaly, congenital heart disease, imperforate anus, conductive deafness, hypogenitalia, cafe-au-lait spots

CAUSES

▪ Mutation of several genes responsible for DNA repair ▫ Impaired cellular repair of DNA crosslinks → impaired regulation of cell cycle, genomic instability → hematopoietic stem cell loss → macrocyticnormochromic anemia → bone marrow aplasia → pancytopenia ▫ Predisposition for development of blood/ solid tumor malignancies ▪ Bone marrow biopsy usually normocellular at birth ▪ Macrocytic-normochromic anemia and other cytopenias develop gradually → usually diagnosed within first eight years of life

COMPLICATIONS

▪ Neutropenia: life-threatening infections ▪ Thrombocytopenia: bleeding tendencies ▪ Malignancies: e.g. myelogenous leukemia, myelodysplastic syndrome, solid tumors ▪ Endocrine derangements: hypothalamicpituitary axis disruption during fetal development ▪ Congenital anomalies

SIGNS & SYMPTOMS ▪ Cytopenias develop → clinical manifestations → increased bruising/ bleeding, frequent infections ▪ Symptomatic anemia related to impaired oxygen-carrying capacity develops late in disease

DIAGNOSIS ▪ History, physical examination

LAB RESULTS

▪ CBC assessment, bone marrow examination

FA testing indicators ▪ Evidence of single-/multilineage cytopenias with no other identified cause ▫ ↓ absolute neutrophil count, platelet count, absolute reticulocyte count, hemoglobin ▪ Hypocellular bone marrow (without evidence of malignancy/other known cause) ▪ Congenital anomalies ▪ Family history: people of Ashkenazi Jewish descent have ↑ carrier frequency FA-specific testing ▪ Chromosome DEB assay ▫ Laboratory test for chromosomal breakage performed on leukocytes (indicates chromosome instability syndrome; not FA-specific) ▪ Cytometric flow analysis ▫ Examines cellular growth, division; cytometry following DNA crosslinking shows cells unable to repair DNA damage, cellular arrest in cell cycle G2 phase ▪ Chromosomal breakage test positive → FA gene sequencing recommended

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TREATMENT MEDICATIONS Growth factors ▪ Granulocyte colony-stimulating factor (GCSF) ▪ Granulocyte-macrophage-stimulating factor (GM-CSF) ▪ Thrombopoietin mimetics (e.g. romiplostim) Androgen therapy ▪ (e.g. oxymetholone) sometimes ↑ blood cell count

SURGERY Bone marrow failure ▪ Allogeneic hematopoietic stem cell transplant

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OTHER INTERVENTIONS

▪ Screen, monitor for malignancies ▪ Specialist care (e.g. cardiology, nephrology, endocrinology) ▪ Family support, genetic counselling

Transfusions ▪ Leukoreduced, irradiated packed red blood cells ▫ Symptomatic anemia ▫ Hemodynamic instability ▪ Platelet transfusions ▫ Platelet count < 10,000/microL ▫ Evidence of severe bruising, bleeding

NOTES

NOTES

DYSPLASTIC & PROLIFERATIVE DISORDERS

GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Acquired disorders caused by defective hematopoiesis

CAUSES

▪ Mostly idiopathic ▪ Gene mutations ▫ JAK2 gene in most myeloproliferative disorders

COMPLICATIONS

▪ Can progress to serious conditions ▫ Acute myelogenous leukemia (AML)

SIGNS & SYMPTOMS ▪ Can be asymptomatic ▪ When symptomatic, depends on cell line affected

DIAGNOSIS LAB RESULTS

▪ Complete blood count (CBC) ▫ Cell line levels ▪ Peripheral blood smear ▫ Morphology ▪ Bone marrow aspiration/biopsy ▫ Morphology, cellularity (normal, hypo, hyper), % of blasts ▪ Cytogenetic studies ▫ Chromosomal abnormalities ▪ Molecular tests ▫ Gene mutations

TREATMENT OTHER INTERVENTIONS

▪ Blood transfusion ▪ Hematopoietic stem cell transplant

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ESSENTIAL THROMBOCYTOSIS osms.it/essential-thrombocytosis PATHOLOGY & CAUSES ▪ Chronic myeloproliferative neoplasm due to overproduction of megakaryocytes in bone marrow ▪ AKA essential thrombocythemia ▪ ↑ platelets, abnormally shaped; ↓ platelet survival ▪ Thromboses; bleeding episodes may occur; other cell lines may be affected ▪ JAK2 mutation (50%), MPL (5–10%)/ calreticulin ▪ “Spent phase” of myelofibrosis/AML (rarely)

SIGNS & SYMPTOMS ▪ Primary symptomatic manifestations due to thrombosis → potential ischemia in various organs, extremities (e.g. stroke, erythromelalgia) ▪ Headache, dizziness, fatigue, vision loss, abdominal pain, nausea ▪ Less frequently, paradoxical bleeding ▫ Epistaxis, bleeding gums, ecchymoses ▪ Splenomegaly

DIAGNOSIS LAB RESULTS

▪ Platelets > 450 × 103/µL for ≥ two months; anisocytosis ▪ ↑ bleeding time

Bone marrow aspiration/biopsy ▪ Normal cellularity Genetic testing ▪ JAK2 mutation

OTHER DIAGNOSTCS

▪ History of thrombosis, bleeding, vasomotor symptoms, first trimester fetal loss

TREATMENT MEDICATIONS

▪ Low risk for thrombosis ▫ Antiplatelet drugs (aspirin, anagrelide) ▪ High risk for thrombosis ▫ Hydroxyurea, interferon-alpha

SURGERY

▪ In severe conditions ▫ Plateletpheresis (removal of platelets from blood)

Figure 45.1 A peripheral blood smear from an individual with essential thrombocytosis. There are a higher than normal number of platelets visible.

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Chapter 45 Dysplastic & Proliferative Disorders

LANGERHANS CELL HISTIOCYTOSIS (LCH) osms.it/langerhans-cell-histiocytosis PATHOLOGY & CAUSES

SIGNS & SYMPTOMS

▪ Rare, proliferative disorder affecting Langerhans cells (type of dendritic cells), myeloid progenitor cells in bone marrow ▪ AKA histiocytosis X ▪ Osteolytic bone lesions infiltrated with histiocytes; histiocytes, lymphocytes, macrophages, eosinophils infiltrate organs: skin, lymph nodes, bones, lungs, liver, spleen, central nervous system (CNS)

▪ Lytic bone lesions may be asymptomatic/ cause localized pain ▪ Skin lesions ▫ Brown to purplish papules pustular, purpuric, petechial, vesicular, papulonodular; eczema-like rash ▪ Mucous membranes ▫ Gingivitis, mucosal mass/ulcers, loose teeth ▪ Lymphadenopathy ▪ Liver, spleen ▫ Hepatic lesions, hepatosplenomegaly ▪ Lungs ▫ Recurrent spontaneous pneumothorax, dyspnoea, chest pain ▪ CNS ▫ Diabetes insipidus, neurological deficits ▪ Systematic symptoms ▫ Fever, lethargy, weight loss

Proliferating cells ▪ Functionally immature ▪ Immunohistochemistry ▫ CD1a, S100 positive ▪ Abundant, foamy cytoplasm ▪ Folded, grooved nuclei ▪ Birbeck granules, “tennis racket”/rodshaped cytoplasmic organelles

RISK FACTORS

▪ Usually affects children; also present in adults ▪ Mutations detected; most common (55– 60%) activates BRAF gene

COMPLICATIONS

▪ CNS ▫ Pituitary gland → diabetes insipidus, pons, basal ganglia; cerebellum → cognitive deficits, neuromotor dysfunction ▪ Liver, spleen ▫ Worse prognosis; sclerosing cholangitis may require liver transplant

DIAGNOSIS DIAGNOSTIC IMAGING MRI ▪ CNS involvement

LAB RESULTS

▪ Accumulation of inflammatory cells, Langerhans cells (large, mononuclear cells with prominent nuclear groove), few cytoplasmic vacuoles, pale eosinophilic cytoplasm

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TREATMENT ▪ Spontaneous regression can occur

MEDICATIONS

▪ Systemic corticosteroids ▪ Chemotherapeutic agents ▫ Alkylating agents, antimetabolites, vinca alkaloids

SURGERY

▪ Surgial excision

OTHER INTERVENTIONS ▪ Radiation therapy

Figure 45.3 An MRI scan of the head in the sagittal plane demonstrating a subcutaneous soft-tissue mass, destroying the frontal bone. The diagnosis was confirmed as Langerhans histiocytosis on biopsy.

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Figure 45.2 The histological appearance of Langerhans cell histiocytosis. There are numerous clonal dendritic cells (light pink) with associated eosinophils (red).

Chapter 45 Dysplastic & Proliferative Disorders

LEUKEMOID REACTION osms.it/leukemoid-reaction PATHOLOGY & CAUSES ▪ Excessive, reactive leukocytosis (WBCs: 40,000–100,000/mL), resembling leukemia, with increase in neutrophil precursors, “left shift” (e.g. myeloblasts, promyelocytes, myelocytes) in peripheral blood ▪ Cytoplasmic toxic granulation, Dohle bodies, blue-gray inclusions in peripheral cytoplasm of neutrophils ▪ Lymphocytic reaction can occur

COMPLICATIONS

▪ Severe/chronic infections ▫ Clostridium difficile infection (CDI), Mycobacterium tuberculosis, Bordetella pertussis, Epstein–Barr virus (EBV) ▪ Sepsis ▪ Non-infectious inflammation ▫ Burns, postoperative state, acute asthma attack, acute episodes of gout ▪ Severe hemolysis ▪ Acute hemorrhage ▫ Peritoneal cavity ▪ Tissue necrosis ▫ Hepatic necrosis, ischemic colitis ▪ Metastatic cancer ▪ Paraneoplastic syndrome ▫ Lung carcinoma, renal cell carcinoma

▪ Drugs ▫ Sulfonamides, dapsone, glucocorticosteroids, granulocyte-colony stimulating factor (G-CSF) ▪ Asplenia ▪ Metabolic ▫ Diabetic ketoacidosis, preeclampsia, uremia

SIGNS & SYMPTOMS ▪ Fatigue, weakness, high fever

DIAGNOSIS LAB RESULTS

▪ ↑↑↑ WBCs ▪ Rule out blood malignancies ▫ Mature neutrophil precursors, unlike immature cells in acute leukemia (blasts < 20%); toxic granulation, Döhle bodies unlike chronic myelogenous leukemia (CML) ▫ Serum leukocyte alkaline phosphatase (LAP) score normal/elevated, unlike CML ▫ Confirm CML by Philadelphia chromosome with BCR/ABL fusion gene + FISH/PCR ▫ Bone marrow aspiration/biopsy

TREATMENT ▪ Treatment of underlying condition

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MYELODYSPLASTIC SYNDROMES (MDS) osms.it/myelodysplastic-syndrome PATHOLOGY & CAUSES ▪ Group of malignant hematopoietic stem cell disorders ▪ Abnormal, ineffective hematopoiesis → peripheral cytopenia Dysplastic cells ▪ Pseudo Pelger–Huët cells ▫ Bilobed neutrophils ▪ Ring sideroblasts ▫ Erythroblasts with granules of iron accumulated in mitochondria ▪ Megaloblastoid maturation ▪ Nuclear budding abnormalities ▪ Pawn ball megakaryocytes ▫ Discrete nuclear lobes/multinucleation

CAUSES

▪ Can be idiopathic/secondary to exposure ▫ Toxins, genotoxic drugs, immunosuppressive agents, chemotherapy, radiation therapy (tMDS, therapy related MDS) ▪ Genetic defects due to ▫ Epigenetic factors, RNA splicing factors, transcription factors ▫ 5q (5q-) deletion most common ▪ Affects elderly individuals; mean age of onset is 70 years

COMPLICATIONS

▪ MDS = pre-leukemias, high risk of conversion to AML ▪ % of blasts (1–20%) ▫ How close individual is to AML (> 20%) ▪ Progresses slowly → most succumb to bleeding, infections before AML

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▪ Functional defects in red (RBCs), white blood cells (WBCs), platelets → anemia, infections, bleeding

SIGNS & SYMPTOMS ▪ Asymptomatic in early stages ▪ Fatigue (anemia), infections (neutropenia), bleeding (thrombocytopenia)

DIAGNOSIS LAB RESULTS

▪ Low RBCs, WBCs, platelets, normal/mildly elevated mean corpuscular volume (MCV), increased red cell distribution width (RDW) ▪ Low reticulocyte count, dysplastic RBCs, WBCs, normal platelets, 1–20% blasts ▪ Dysplastic cells, increased blasts ▪ Chromosomal abnormalities, gene mutations

TREATMENT MEDICATIONS

▪ Tumor necrosis factor (TNF) inhibitors (e.g.lenalidomide, thalidomide), DNA methylation inhibitors

OTHER INTERVENTIONS Allogeneic hematopoietic stem cell transplant ▪ Only curative option, for young individuals ▪ If transplant not an option → blood product transfusions, infection control (supportive)

Chapter 45 Dysplastic & Proliferative Disorders

Figure 45.4 A neutrophil from a in the peripheral blood smear of an individual with myelodysplastic syndrome. The neutrophil is hypogranulated and has a hypolobated nucleus, known as a pseudo Pelger–Huët nucleus.

POLYCYTHEMIA VERA (PCV) osms.it/polycythemia-vera PATHOLOGY & CAUSES ▪ Chronic myeloproliferative neoplastic disease ▪ Hematopoietic stem cell disorder → erythroid, granulocytic, megakaryocytic lineages proliferate ▪ Increased ▫ RBCs, independent of erythropoietin (EPO); platelets; basophils; eosinophils; cell turnover → hyperuricemia ▪ Polycythemia → increased blood viscosity; increased total blood volume → abnormal blood flow ▪ Abnormal blood flow, defective platelet function → vein thrombosis, infarcts, bleeding ▪ PCV may evolve to “spent phase” ▫ Myelofibrosis, extramedullary hematopoiesis in liver, spleen

RISK FACTORS

▪ Occurs in all ages; median age at diagnosis 60 years ▪ Genetic ▫ JAK2V617F mutation (95% of cases)

COMPLICATIONS

▪ Hypertension, Budd–Chiari syndrome, deep vein thrombosis, arterial thrombosis, myocardial infarction (MI), gout (high cell turnover, hyperuricemia), PCV → AML (rare) ▪ If untreated ▫ Thrombotic, hemorrhagic complications → death within months

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SIGNS & SYMPTOMS ▪ Symptoms due to ↑ in RBCs → blood viscosity ▫ Headache, fatigue, dizziness, dyspnea, plethora, cyanosis ▪ Symptoms due to ↑ in basophils → histamine release ▫ Pruritus (intense itching, especially after hot shower), gastric ulcers ▪ Thrombosis ▫ Deep vein thrombosis, MI, Budd–Chiari syndrome (portal vein thrombosis), erythromelalgia (hyperemic and inflamed extremities due to microvascular occlusion of vessels) ▪ Bleeding ▫ Bleeding gums, epistaxis, ecchymoses, GI bleed ▪ Hepatosplenomegaly, splenomegaly ▪ Hypertension

DIAGNOSIS LAB RESULTS

▪ Exclude secondary polycythemia (hypoxia, renal cell, hepatocellular carcinoma); ↑ EPO serum ▪ CBC ▫ ↑ RBCs, hematocrit, hemoglobin; ↑ platelets/WBCs ▪ ↑ Lactate dehydrogenase ▪ ↓ serum EPO ▪ Bone marrow aspiration/biopsy confirms diagnosis ▪ Genetic testing ▫ JAK2 mutation

Figure 45.5 The clinical appearance of erythromelalgia; a sign of numerous diseases, including polycythemia vera.

TREATMENT MEDICATIONS

▪ Hydroxyurea ▫ ↓ RBC production ▪ Interferon-alpha ▫ ↑ RBC destruction ▪ Aspirin ▫ ↓ risk of thrombosis

OTHER INTERVENTIONS ▪ Phlebotomy ▫ ↓ hematocrit, hemoglobin

Figure 45.6 The clinical appearance of erythromelalgia; a sign of numerous diseases, including polycythemia vera.

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Chapter 45 Dysplastic & Proliferative Disorders

PRIMARY MYELOFIBROSIS (PM) osms.it/myelofibrosis PATHOLOGY & CAUSES ▪ Chronic myeloproliferative disease of hematopoietic stem cells resulting in bone marrow fibrosis ▪ AKA essential thrombocythemia ▪ Overproduction of megakaryocytes in bone marrow ▪ Increased platelets, abnormally shaped; decreased platelet survival ▪ Thromboses; bleeding episodes may occur; other cell lines may be affected ▪ JAK2 mutation (50%), MPL (5–10%)/ calreticulin ▪ “Spent phase” of myelofibrosis/AML (rarely)

SIGNS & SYMPTOMS ▪ May be asymptomatic ▪ When symptomatic, thrombosis, potential ischemia in various organs ▫ Headache, dizziness, fatigue, numbness in extremities, erythromelalgia, vision loss, abdominal pain, nausea ▪ Less frequently, bleeding ▫ Epistaxis, bleeding gums, bruises ▪ Splenomegaly

DIAGNOSIS LAB RESULTS

▪ ↓ RBCs, platelets ▪ Leukoerythroblastosis, dacryocytes

OTHER INTERVENTIONS Bone marrow aspiration ▪ Dry tap, no sample (accumulation of collagen fibers)

Figure 45.7 The histological appearance of the bone marrow in an individual with myelofibrosis. The fibrosis is seen as fine silver strands upon staining with reticulin.

TREATMENT MEDICATIONS

▪ Low risk for thrombosis ▫ Antiplatelet drugs (aspirin, anagrelide) ▪ High risk for thrombosis ▫ Hydroxyurea, interferon-alpha

SURGERY

▪ In severe conditions ▫ Plateletpheresis (removal of platelets from blood)

Bone marrow biopsy ▪ Hypocellularity, fibrosis

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NOTES

NOTES

HYPERCOAGULABLE DISORDERS

GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Unregulated activation of coagulation cascade → vascular thrombosis

CAUSES

▪ Inherited/acquired ▪ Secondary to liver disease, autoimmune systemic disorders, renal failure, acute thrombosis, exposure to toxins, anticoagulation therapy

COMPLICATIONS

▪ Venous, arterial thrombosis, obstetric

SIGNS & SYMPTOMS ▪ Deep vein thrombosis (DVT) → pulmonary embolism (PE)

DIAGNOSIS ▪ Family history of thrombophilia, thrombosis under age of 50 years, thrombosis in unusual location (e.g. portal veins), recurrent thromboembolic episodes

LAB RESULTS

▪ Assays for specific proteins/factors, antibodies ▪ Genetic testing

TREATMENT MEDICATIONS

▪ Anticoagulants/thrombolysis ▫ If symptomatic ▪ Prophylactic anticoagulation when high risk for thrombosis ▫ E.g. perioperatively/in postpartum period ▫ If asymptomatic

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ANTIPHOSPHOLIPID SYNDROME (APS) osms.it/antiphospholipid-syndrome PATHOLOGY & CAUSES ▪ Acquired autoimmune multisystem disorder; associated underlying disorders, systemic lupus erythematosus (SLE) ▪ AKA lupus anticoagulant syndrome ▫ May be idiopathic; may appear after exposure drugs/infectious agents ▪ Antiphospholipid antibodies (aPL) bind to targets → induce hypercoagulable state ▪ Pathways ▫ Thromboembolic episodes/pregnancy morbidity ▫ Increase in atherosclerosis, fetal loss, neurological damage; aPL-associated increase in vascular tone ▪ Catastrophic APS (rare) ▫ Widespread thrombosis → multiorgan failure

COMPLICATIONS Pregnancy complications ▪ Spontaneous abortions; fetal death ▪ Premature birth due to preeclampsia/placental insufficiency Cutaneous complications ▪ Livedo reticularis (most common) ▫ Obstruction of microvasculature → netlike purplish discolouration of skin ▪ Cutaneous ulcers Ocular complications ▪ Retinal venous/arterial circulation occlusion; anterior ischemic optic neuropathy

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SIGNS & SYMPTOMS ▪ Recurrent venous thromboses ▫ DVT → PE → pulmonary hypertension ▫ Superficial thrombophlebitis ▫ Hepatic/portal vein thrombosis → BuddChiari syndrome, hepatic infarction, portal hypertension, cirrhosis ▫ Adrenal vein thrombosis → hemorrhagic infarction ▪ Recurrent arterial thromboses (less common) ▫ Stroke/transient ischemic attack ▫ Myocardial infarction ▫ Bowel infarction ▫ Multiple capillary, arterial thromboses → renal microangiopathy → renovascular hypertension

DIAGNOSIS LAB RESULTS

▪ ≥ one antiphospholipid antibodies ▫ Lupus anticoagulant, AKA lupus antibody ▫ Anticardiolipin antibody ▫ Anti-beta2 glycoprotein I ▪ ≥ one clinical feature ▫ Vascular thrombosis/pregnancy morbidity ▪ Moderate thrombocytopenia ▪ Prolonged PT, aPTT ▫ Not corrected by plasma transfusions ▪ False positive in venereal disease lab test, rapid plasma reagin test for syphilis ▫ Cardiolipin phospholipid as major reagent

Chapter 46 Hypercoagulable Disorders

TREATMENT MEDICATIONS

▪ Aspirin/anticoagulants (e.g. warfarin) ▫ To stabilize coagulation pathways ▫ Lifelong systemic therapy with antiplatelet medications

ANTITHROMBIN III DEFICIENCY osms.it/antithrombin-III-deficiency PATHOLOGY & CAUSES ▪ Endogenous serine protease inhibitor in coagulation cascade; inactivates thrombin (factor IIa), factor Xa.

CAUSES

▪ Inherited ▫ Autosomal dominant gene mutation; variable penetrance ▪ Acquired ▫ Defective synthesis; liver disease, therapy with vitamin K antagonists (e.g. warfarin) ▫ Loss in urine; renal failure/nephrotic syndrome ▫ Depletion in acute thrombosis/ disseminated intravascular disease (DIC)

COMPLICATIONS

▪ Venous thromboembolism ▪ Heparin resistance

SIGNS & SYMPTOMS ▪ Deep vein thrombosis → pulmonary embolism

DIAGNOSIS LAB RESULTS Genetic testing Functional assay ▪ Reduced plasma antithrombin III activity ▪ PT/aPTT/thrombin time ▫ No change + aPTT → diminished increase following heparin

TREATMENT MEDICATIONS

▪ Treat deep vein thrombosis / pulmonary embolism ▫ Anticoagulants with vitamin K antagonists/direct oral anticoagulants (DOACS) ▪ If ≥ two thromboembolic events occur → lifelong anticoagulant therapy (e.g. vitamin K antagonists/ DOACs) ▪ Prophylactic antithrombin replacement ▫ High-risk thrombophilic situations (e.g. surgery/pregnancy)

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FACTOR V LEIDEN (FVL) osms.it/factor-v-leiden PATHOLOGY & CAUSES ▪ Inherited thrombophilia ▪ Mutant form of coagulation factor V, lacks Arg506 cleavage site

CAUSES

▪ FVL → resistance to degradation by activated protein C (aPC) → unregulated activation of coagulation cascade → hypercoagulable state → venous thromboembolism (VTE)

RISK FACTORS

▪ FVL homozygosity ▪ Coinheritance with other thrombophilia disorders ▪ Pregnancy (physiologic hypercoagulability) ▪ Oral hormonal contraceptives

SIGNS & SYMPTOMS ▪ VTE ▪ DVT/thrombosis in superficial veins of lower extremities/cerebral, portal, hepatic veins ▪ Possible fetal loss

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DIAGNOSIS LAB RESULTS

▪ Genetic testing ▫ FVL mutation (direct analysis of genomic DNA) ▫ Functional aPC resistance assay (individual’s plasma mixed with factor V-deficient plasma)

OTHER DIAGNOSTICS

▪ Family history of thrombophilia ▪ VTE at young age/in unusual location

TREATMENT MEDICATIONS

▪ Anticoagulants/thrombolysis ▫ Treat for DVT/PE ▫ If ≥ two thromboembolic events → lifelong anticoagulant therapy ▪ Prophylactic anticoagulation ▫ High risk thrombophilic situations (e.g. surgery, pregnancy)

Chapter 46 Hypercoagulable Disorders

PROTEIN C DEFICIENCY osms.it/protein-c-deficiency PATHOLOGY & CAUSES ▪ Protein C deficiency → familial thrombophilia ▪ Protein C ▫ Vitamin K-dependent inhibitor of factors V, VIII ▫ Protein C deficiency → unregulated activation of coagulation cascade → increased thrombotic risk

TYPES

▪ Type I ▫ Reduced protein C levels ▪ Type II ▫ Normal protein C levels, reduced function

CAUSES

▪ Autosomal dominant inherited disorder ▪ Acute thrombosis, disseminated intravascular coagulation, liver disease, vitamin K antagonist anticoagulants

COMPLICATIONS

▪ Due to treatment ▫ Warfarin-induced thrombotic skin necrosis

SIGNS & SYMPTOMS

DIAGNOSIS LAB RESULTS Functional assay ▪ Reduced protein C

OTHER DIAGNOSTICS

▪ Monitor if recurrent VTE, family history of VTE, thrombosis in unusual location/at young age

TREATMENT MEDICATIONS

▪ Anticoagulants/thrombolysis ▫ Treat deep vein thrombosis/VTE ▪ Prophylactic protein C concentrate ▫ Asymptomatic individuals (e.g. perioperatively/in postpartum period)

Warfarin-induced skin necrosis ▪ Stop warfarin; start vitamin K, heparin, protein C concentrate/fresh frozen plasma administration

MNEMONIC

Proteins C & S C and S inhibit coagulation: they are Clot Stoppers

▪ Venous thromboembolism (VTE) ▪ In homozygotes, neonatal purpura fulminans

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PROTEIN S DEFICIENCY osms.it/protein-s-deficiency PATHOLOGY & CAUSES ▪ Deficiency of protein S → familial thrombophilia ▪ Protein S ▫ Cofactor of protein C ▫ Protein S deficiency → decreased protein C activity → enhanced activity of coagulation cascade → increased thrombotic risk

TYPES

▪ Type I (classic) ▫ Reduced total protein S, free protein S, protein S function ▪ Type II (rare) ▫ Normal total, free protein S, reduced function ▪ Type III ▫ Reduced free protein S, protein S function; normal total protein S

CAUSES

▪ Autosomal dominant inherited condition ▫ Most individuals heterozygous for PROS1 gene mutation ▪ Pregnancy, oral hormonal contraceptive, disseminated intravascular coagulation (DIC), acute thrombosis, HIV infection, nephrotic syndrome, liver disease

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SIGNS & SYMPTOMS ▪ VTE ▪ In homozygotes, neonatal purpura fulminans

DIAGNOSIS ▪ Monitor if recurrent venous thromboembolism (VTE), family history of VTE, thrombosis at young age/in unusual location

LAB RESULTS ▪ Protein S assay

TREATMENT MEDICATIONS

▪ Anticoagulants/thrombolysis ▫ Treat deep vein thrombosis ▪ If asymptomatic, avoid drugs that predispose to thrombosis (e.g. oral contraceptives) ▪ Prophylactic anticoagulation (e.g. preoperatively/in postpartum period)

NOTES

NOTES

HYPOCOAGULABLE DISORDERS

GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Acquired, inherited disorders; defects in coagulation cascade

SIGNS & SYMPTOMS ▪ Bleeding ▪ Thrombosis, only disseminated intravascular disease (DIC)

DIAGNOSIS LAB RESULTS ▪ ▪ ▪ ▪ ▪ ▪

Platelet count Levels of clotting factors Prothrombin time (PT) Partial thromboplastin time (aPTT) Fibrin degradation products Genetic testing

TREATMENT OTHER INTERVENTIONS ▪ Supportive therapy

DISSEMINATED INTRAVASCULAR COAGULATION (DIC) osms.it/disseminated-intravascular-coagulation PATHOLOGY & CAUSES ▪ Acquired, paradoxical process of thrombosis, bleeding ▪ Release of procoagulants, tissue factors, bacterial components, enzymes/major endothelial injury → excessive activation of coagulation cascade → thrombosis of small/medium blood vessels → activation of fibrinolysis to resolve clots → fibrin degradation products released into circulation → interfere with platelet aggregation, clot formation ▪ Depletion of platelets, fibrin, coagulation factors → consumption coagulopathy

CAUSES

▪ Complication of underlying conditions ▪ Obstetric complications (e.g. preeclampsia, obstetric hemorrhage, retained dead fetus) ▪ Critical illness (individuals in intensive care unit) ▪ Malignancy ▫ Mucin-secreting adenocarcinoma (e.g., lungs, pancreas, stomach, prostate, ovaries) ▫ Acute promyelocytic leukemia (APL) ▪ Infection/sepsis, especially gram-negative bacteria ▪ Massive tissue injury due to trauma,

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surgery, burn, fracture ▪ Intravascular hemolysis due to blood type incompatibility ▪ Shock ▪ Snakebites

COMPLICATIONS

▪ Widespread thrombosis, ischemia, necrosis of brain, heart, kidneys, liver, lungs, adrenals, spleen → organ dysfunction ▪ Microangiopathic hemolytic anemia (MAHA) ▪ Paradoxical tendency to life-threatening bleeding, due to consumption of procoagulatory factors

MNEMONIC: DIC TEAR

Common causes of DIC Delivery TEAR: obstetric complications Infections: gram negative)/ Immunological Cancer: prostate, pancreas, lung, stomach Obstretrical complications Toxemia of pregnancy Emboli (amniotic) Abruptio placentae Retain fetus products

SIGNS & SYMPTOMS ▪ Acute: bleeding episodes (e.g. ecchymoses, petechiae, purpura, blood oozing from gingival/oral mucosa, sites of trauma, catheters, intravenous lines) ▪ Chronic: thromboembolism, tissue hypoxia, infarctions

DIAGNOSIS LAB RESULTS

↓ Platelets ↓ Fibrinogen ↓ Clotting factors ↑ Prothrombin time (PT) ↑ Partial thromboplastin time (aPTT) ↑ D-dimers (fibrin degradation product) Schistocytes, damaged red blood cells (RBCs) due to MAHA ▪ Physiologic compensation → lab results normal ▫ For chronic (solid tumors, large aortic aneurysms) ▪ ▪ ▪ ▪ ▪ ▪ ▪

TREATMENT MEDICATIONS

▪ Oxygen, IV fluids

OTHER INTERVENTIONS

▪ Replace clotting factors with fresh frozen plasma (FFP), cryoprecipitate, fibrinogen ▪ Platelet transfusions, if platelet count < 30,000 ▪ RBC transfusions for severe bleeding

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Chapter 47 Hypocoagulable Disorders

HEMOPHILIA A osms.it/hemophilia-a PATHOLOGY & CAUSES ▪ Most common inherited clotting factor deficiency; classic hemophilia ▪ X-linked recessive disorder ▪ Mutated gene F8 on X chromosome

CAUSES

▪ Quantitative/qualitative deficiency of factor VIII → insufficient activation of the intrinsic pathway → defect in common coagulation pathway → increased tendency for bleeding ▪ Peritoneal dialysis

RISK FACTORS

▪ More common in individuals who are biologically male; individuals who are biologically female more likely to be carriers

SIGNS & SYMPTOMS ▪ Varies according to mutation, factor VIII activity ▪ Asymptomatic/spontaneous bleeding ▪ < 10% factor VIII ▫ Easy bruising ▫ Prolonged bleeding, after injury/surgery ▫ Hematomas (e.g. muscle hematomas, hemophilic pseudotumors) ▫ Gastrointestinal (GI) bleeding ▫ Hematuria ▫ Severe epistaxis ▫ Painful hemarthrosis → progressive joint irregularity, disability (knee most common) ▫ Intracerebral hemorrhage

DIAGNOSIS LAB RESULTS

▪ Normal platelet count ▪ Normal prothrombin time (extrinsic pathway not affected) ▪ Prolonged partial thromboplastin time (intrinsic pathway affected) ▪ Factor VIII clotting assay ▪ Genetic testing

TREATMENT MEDICATIONS Desmopressin (DDAVP) ▪ For mild quantitative hemophilia A ▫ → stimulates von Willebrand factor (vWF) release → promotes stabilization of residual factor VIII

OTHER INTERVENTIONS

▪ Recombinant factor VIII infusions ▪ If severe deficiency, immune system may perceive supplemental factors as foreign → production of antibodies (inhibitors) → elimination of injected factors/anaphylaxis ▪ Avoid sports, trauma, medications that promote bleeding ▪ Local measures ▫ Treat hemarthrosis, hematomas (e.g. resting of affected part, application of ice)

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Figure 47.1 An abdominal MRI scan in the coronal plane demonstrating a hematoma of the right psoas muscle in an individual with hemophilia.

Figure 47.2 An MRI scan of the knee demonstrating hemarthrosis. Individuals with hemophilia are at increased risk of hemarthrosis.

HEMOPHILIA B osms.it/hemophilia-b PATHOLOGY & CAUSES

DIAGNOSIS

▪ Mutated gene F9 on X chromosome ▪ AKA Christmas disease ▪ Qualitative/quantitative deficiency of coagulation factor IX → insufficient activation of intrinsic coagulation pathway → impaired hemostasis ▪ Less common

LAB RESULTS

SIGNS & SYMPTOMS

MEDICATIONS

▪ Spontaneous bleeding, delayed bleeding after trauma, hemarthrosis, hematomas, epistaxis, intracranial, GI/genitourinary tract bleeding

▪ Normal platelet count, prothrombin time (intrinsic pathway affected) ▪ Factor IX clotting assay/genetic mutation testing

TREATMENT DDAVP ▪ Not helpful in hemophilia B; stimulates vWF → stabilizes only factor VIII, not IX

OTHER INTERVENTIONS

▪ Infusions of recombinant factor IX

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Chapter 47 Hypocoagulable Disorders

VON WILLEBRAND DISEASE osms.it/von-willebrand-disease PATHOLOGY & CAUSES ▪ Most common inherited bleeding disorder of primary hemostasis ▪ Defective platelet function with normal platelet count ▪ Quantitative/qualitative deficiency of vWF → impaired platelet aggregation, adhesion, dysfunction of factor VIII → deficiency in coagulation cascade → bleeding tendency ▪ Hemostatic pressure (e.g. surgery/trauma)

TYPES Type I ▪ Most common ▪ Autosomal dominant, partial quantitative deficiency Type II ▪ Autosomal dominant, qualitative deficiency Type III ▪ Autosomal recessive, severe quantitative deficiency

SIGNS & SYMPTOMS

DIAGNOSIS LAB RESULTS

Abnormal PFA-100 test ↓ factor VIII activity ↓ vWF PTT prolonged ↓ platelet aggregation, presence of ristocetin ▪ Collagen-binding function reduced ▪ Platelet count normal ▪ ▪ ▪ ▪ ▪

TREATMENT MEDICATIONS

▪ DDAVP ▫ Type I, Type II ▪ Factor VIII/vWF concentrates ▫ After major injury; during operation; Type III, II not responding to DDAVP ▪ High-purity vWF concentrates

OTHER INTERVENTIONS

▪ Local measures, tranexamic acid for mild bleeding

▪ Typically asymptomatic ▪ Surgery/trauma provoke clinical manifestation ▪ Spontaneous mucosal, cutaneous bleeding (e.g. epistaxis, easy bruising, excessive bleeding from wounds, bleeding gums) ▪ Menorrhagia ▪ GI bleeding ▪ Internal/joint bleeding (Type III)

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NOTES

NOTES

LEUKEMIAS GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Malignant neoplastic monoclonal proliferation of hematopoietic blood cells ▪ Abnormal blood cells/precursors accumulate in bone marrow → physical suppression → prevent maturation

TYPES Acute ▪ Acute lymphoid leukemia ▪ Acute myeloid leukemia Chronic ▪ Chronic lymphoid leukemia ▪ Chronic myeloid leukemia

RISK FACTORS

▪ Numerical, structural chromosomal aberrations ▪ Ionizing radiation, chemotherapy ▪ Benzene exposure

COMPLICATIONS

▪ Infections, bleeding → death

SIGNS & SYMPTOMS Cellular maturation absent ▪ Anemia → fatigue, shortness of breath, pallor ▪ Thrombocytopenia → bruising, petechiae, epistaxis ▪ Neutropenia → bacterial infections → fever, pneumonia, sepsis

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Neoplastic infiltration ▪ Bone marrow ▫ Bone pain ▪ Thymus ▫ Palpable mass, airway compression ▪ Liver and spleen ▫ Hepatosplenomegaly ▪ Lymph nodes ▫ Lymphadenopathy ▪ Meningeal infiltration ▫ Headaches, vomiting, nerve palsies, nuchal rigidity

DIAGNOSIS LAB RESULTS ▪ ▪ ▪ ▪

Blood count Blood smear Bone marrow smear Immunophenotyping

TREATMENT MEDICATIONS ▪ Chemotherapy

SURGERY

▪ Bone marrow transplantation

OTHER INTERVENTIONS ▪ Radiation therapy

Chapter 48 Leukemias

ACUTE LYMPHOID LEUKEMIA (ALL) osms.it/acute-lymphoid PATHOLOGY & CAUSES ▪ Neoplastic monoclonal proliferation of lymphoid stem cells (lymphoblasts) in bone marrow ▪ Immature lymphoblasts accumulate in bone marrow → physical suppression → prevent maturation

TYPES B cell acute lymphoblastic leukemia (B-ALL) ▪ Most common (85%) ▪ Origin ▫ Pre-B cells of bone marrow ▪ Associated with translocations t(12,21), t(9,22) T cell acute lymphoblastic leukemia (T-ALL) ▪ Origin ▫ Pre-T cells in thymus ▪ Associated with NOTCH1 mutation

RISK FACTORS

▪ Young age (most common leukemia in children) ▫ B-ALL: peak incidence at three years old ▫ T-ALL: peak incidence at 15–20 years old ▪ Down syndrome (after age five) ▪ Radiation exposure

SIGNS & SYMPTOMS ▪ Abrupt onset Cellular maturation absent ▪ Anemia → fatigue, shortness of breath, pallor ▪ Thrombocytopenia → bruising, petechiae, epistaxis

▪ Neutropenia → bacterial infections → fever, pneumonia, sepsis Neoplastic infiltration ▪ Bone marrow ▫ Bone pain ▪ Thymus ▫ Palpable mass, airway compression ▪ Liver and spleen ▫ Hepatosplenomegaly ▪ Lymph nodes ▫ Lymphadenopathy ▪ Meningeal infiltration ▫ Headaches, vomiting, nerve palsies, nuchal rigidity

DIAGNOSIS LAB RESULTS Blood count, smear of peripheral blood ▪ ↑ lymphoblasts ▪ ↑ white blood cells Bone marrow smear ▪ Hypercellular bone marrow, lymphoblast domination (> 20%) ▪ T-ALL ▫ “Starry sky” pattern produced by phagocytosing macrophages ▪ Mitotic figures Immunophenotyping ▪ Terminal deoxynucleotidyl transferase (TdT) ▫ Positive nuclear staining, distinguish from acute myeloid leukemia (AML) ▪ B-ALL ▫ Express tumor markers CD10, CD19, CD20 ▪ T-ALL ▫ Express tumor markers CD1, CD2, CD5, CD7, CDH

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TREATMENT MEDICATIONS

▪ Aggressive chemotherapy with prophylactic injections to scrotum, cerebrospinal fluid (CSF) ▫ 95% complete remission, 75% cure rate ▫ More successful in children > two years old ▪ If spread to brain ▫ Intrathecal chemotherapy/radiation therapy ▪ Tyrosine-kinase inhibitors

MNEMONIC: ABCDE

Characteristics of Acute leukemias Acute: Blasts predominate Children Drastic course Elderly Few WBC’s (+ Fevers)

Figure 48.1 A bone marrow film from an individual with acute lymphoid leukemia.

ACUTE MYELOID LEUKEMIA (AML) osms.it/acute-myeloid PATHOLOGY & CAUSES ▪ Neoplastic monoclonal proliferation of myelogenous stem cells (myeloblasts) in bone marrow ▪ Immature myeloblasts accumulate in bone marrow → physical suppression → prevents maturation

TYPES Acute promyelocytic leukemia ▪ Associated with translocation t(15,17) → disruption of retinoic acid receptor → promyelocytes accumulate Acute monocytic leukemia

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Acute megakaryocytic leukemia

RISK FACTORS ▪ ▪ ▪ ▪

Adults age; peak at 60 Radiation, chemotherapy Myeloproliferative disorders Down syndrome (before age five)

COMPLICATIONS

▪ Disseminated intravascular coagulation (DIC)

SIGNS & SYMPTOMS ▪ Abrupt onset

Chapter 48 Leukemias Cellular maturation absent ▪ Anemia → fatigue, shortness of breath, pallor ▪ Thrombocytopenia → bruising, petechiae, epistaxis ▪ Neutropenia → bacterial infections → fever, pneumonia, sepsis Neoplastic infiltration ▪ Symptoms less common in AML than ALL ▪ Bone marrow ▫ Bone pain ▪ Thymus ▫ Palpable mass, airway compression ▪ Liver and spleen ▫ Hepatosplenomegaly ▪ Lymph nodes ▫ Lymphadenopathy ▪ Meningeal infiltration ▫ Headaches, vomiting, nerve palsies, nuchal rigidity Neoplastic infiltration ▪ Symptoms more common in AML than ALL ▪ Skin ▫ Leukemia cutis ▪ Gums ▫ Swelling (classic)

SURGERY

▪ Bone marrow transplantation

Figure 48.2 The histological appearance of a myeloid sarcoma, also known as a chloroma. The tumor is an extramedullary manifestation of acute myeloid leukemia.

DIAGNOSIS LAB RESULTS Blood count, blood smear ▪ ↑ leukocytes, anemia Bone marrow smear ▪ ↑ myeloblasts > 20% ▪ Myeloblasts containing Auer rods (aggregates of myeloperoxidase)

TREATMENT MEDICATIONS

Figure 48.3 A CT scan of the head in the axial plane demonstrating a myeloid sarcoma, or chloroma, of the occiput. The tumor is extradural and destroying the overlying bone.

▪ Chemotherapy ▪ All-trans retinoic acid treatment ▫ For promyelocytic leukemia

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MNEMONIC: ABCDE

Characteristics of Acute leukemias Acute: Blasts predominate Children Drastic course Elderly Few WBC’s (+ Fevers)

CHRONIC LYMPHOID LEUKEMIA (CLL) osms.it/chronic-lymphoid PATHOLOGY & CAUSES ▪ Neoplastic monoclonal proliferation of mature, functionally abnormal B lymphocytes in bone marrow, blood ▪ Mature B lymphocytes accumulate in bone marrow → physical suppression → prevent maturation

CAUSES

▪ Chromosomal abnormalities ▪ Mutation of proteins involved in tyrosine kinase pathway (e.g. Bruton’s tyrosine kinase)

RISK FACTORS

▪ Adult age; most common leukemia in adults ▪ Family history ▪ Agent Orange exposure

COMPLICATIONS

▪ Abnormal Ig secretion ▫ Hypogammaglobulinemia, autoimmunity (e.g. autoimmune hemolytic anemia) ▪ Richter syndrome ▫ Progresses into aggressive lymphoma (e.g diffuse large B cell lymphoma)

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SIGNS & SYMPTOMS ▪ Late onset Cellular maturation absent ▪ Anemia → fatigue, shortness of breath, pallor ▪ Thrombocytopenia → bruising, petechiae, epistaxis ▪ Neutropenia → bacterial infections → fever, pneumonia, sepsis Neoplastic infiltration ▪ Symptoms less common in AML than ALL ▪ Bone marrow ▫ Bone pain ▪ Thymus ▫ Palpable mass, airway compression ▪ Liver and spleen ▫ Hepatosplenomegaly ▪ Lymph nodes ▫ Lymphadenopathy ▪ Meningeal infiltration ▫ Headaches, vomiting, nerve palsies, nuchal rigidity

Chapter 48 Leukemias

DIAGNOSIS LAB RESULTS Blood count, blood smear ▪ Lymphocytosis > 5,000 per mm3 ▪ Smudge cells: disruption of fragile cell membranes of abnormal lymphocytes Immunophenotyping ▪ CD5, CD20, CD23

OTHER DIAGNOSTICS Surgery ▪ Lymph node biopsy ▫ ↑ small, round lymphocytes infiltration ▫ Proliferation centers (pathognomic)

TREATMENT

Figure 48.4 The gross pathological appearance of the spleen in a case of chronic lymphoid leukemia. The lymph nodes at the hilum of the spleen are also involved.

MEDICATIONS

▪ Chemotherapy ▪ Immunotherapy

SURGERY

▪ Bone marrow transplant

OTHER INTERVENTIONS ▪ Radiation therapy

Figure 48.5 The histological appearance of chronic lymphocytic leukemia. There is a proliferation centre (also known as a pseudofollicle) composed of malignant lymphocytes with bigger, larger nuclei. This proliferation centre is surrounded by small, darker staining lymphocytes.

Figure 48.6 A CT scan in the coronal plane demonstrating splenomegaly as a consequence of chronic lymphoid leukemia.

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CHRONIC MYELOID LEUKEMIA (CML) osms.it/chronic-myeloid PATHOLOGY & CAUSES ▪ Neoplastic monoclonal proliferation of mature granulocytes/precursors ▪ Mature granulocytes accumulate in bone marrow → physical suppression → prevent maturation ▪ Associated with Philadelphia chromosome t(9, 22) → BCR-ABL1 fusion → chimeric protein with strong tyrosine kinase activity (> 90% of individuals)

RISK FACTORS

▪ Adult age (> 40 years), radiation exposure, benzene exposure

SIGNS & SYMPTOMS ▪ Classified by clinical signs, lab results

▪ Increasing anemia, thrombocytopenia, basophilia ▪ Bone pain, fever ▪ Significant splenomegaly

DIAGNOSIS LAB RESULTS Blood count, blood smear ▪ ↑ granulocytes (basophils, eosinophils, neutrophils) Bone marrow biopsy ▪ Hypercellularity (cells of myeloid cell line/ precursors) ▪ Karyotypic analysis ▫ Fluorescent in situ hybridization (FISH), PCR: BCR-ABL1 gene mapping ▪ Mild fibrosis

Chronic phase (85% at time of diagnosis) ▪ Leukocytosis (predominantly neutrophils) ▪ Asymptomatic/non-specific symptoms ▫ Fatigue, weight loss, loss of energy, fever Accelerated phase ▪ > 20% basophils in blood/bone marrow ▪ 10–19% myeloblasts in blood/bone marrow ▪ Anemia ▪ Splenomegaly, hepatomegaly, lymphadenopathy ▪ Recurrent infections ▪ Bleeding, petechiae, ecchymoses ▪ Treatment less effective Blast crisis ▪ Terminal phase; rapid progression, low survival rate ▪ > 20% myeloblasts/lymphoblasts in blood/ bone marrow

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Figure 48.7 A bone marrow smear demonstrating a small, hypolobated megakaryocyte, typical of chronic myelogenous leukemia.

Chapter 48 Leukemias

TREATMENT MEDICATIONS

▪ Tyrosine kinase inhibitors

SURGERY

▪ Bone marrow transplantation

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NOTES

NOTES

LYMPHOMAS GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Lymphocytic tumors ▪ Nodal lymphomas: develop in lymph nodes ▪ Extranodal lymphomas: develop in/spread to other organs/tissues ▪ Neoplastic B cells do not produce antibodies ▪ Attract non-neoplastic inflammatory cells (e.g. T cells) via chemokines ▪ Activate fibroblasts to make collagen, eosinophils

▪ Metastasis to bone marrow → crowds out normal marrow progenitor cells → decreases healthy erythrocytes/leukocytes/ platelets

SIGNS & SYMPTOMS ▪ B (systemic) symptoms: fever, night sweats, weight loss, fatigue, loss of appetite, chills

DIAGNOSIS

TYPES

DIAGNOSTIC IMAGING

Hodgkin’s lymphomas ▪ Spread contiguously (to nearby lymph nodes; rarely extranodal) ▫ Prognosis better for Hodgkin’s: contiguous spread allows direct, targeted treatment ▪ Reed–Sternberg cells

CT scan, positron emission tomography (PET) scan ▪ Stage of lymphoma

Non-Hodgkin’s lymphomas ▪ Spread non-contiguously

LAB RESULTS Lymph node biopsy ▪ Confirmation, type

TREATMENT

▪ No Reed–Sternberg cells

CAUSES

▪ Genetic mutation in lymphocytes → no apoptosis → cell divides → becomes neoplastic cell ▪ Possible link between viruses (e.g. HIV, EBV), lymphomas

COMPLICATIONS

▪ Metastasis to spinal cord → spinal cord compression → sensory/motor deficits

▪ Depends on extent, stage, category; age, health of individual; coexisting diseases

MEDICATIONS ▪ Chemotherapy

SURGERY

▪ Stem cell transplant

OTHER INTERVENTIONS ▪ Radiation therapy

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Chapter 49 Lymphomas

HODGKIN'S LYMPHOMA osms.it/hodgkins PATHOLOGY & CAUSES ▪ B-cell tumors; Reed–Sternberg cells: large mononuclear, neoplastic cells; two cells fused, two nuclei (resemble owl eyes)

TYPES Classical Hodgkin’s lymphoma (CHL) ▪ More common ▪ Reed–Sternberg cells express CD45/CD20; not CD15/CD30 ▪ Histological subtypes: background inflammatory cells, fibrosis

Histological CHL subtypes ▪ Nodular sclerosis Hodgkin’s lymphoma ▫ Most common; esp. in young adults ▫ Neoplastic, inflammatory cells surrounded by collagen from fibroblasts forming nodules ▫ Lacunar cells (Reed–Sternberg cells with shrunken cytoplasm, nucleus appears as if in middle of lacuna/lake) ▫ Good prognosis ▪ Mixed cellularity ▫ Second most common; more common in older adults ▫ Prevalent in HIV-positive individuals ▫ Mixed inflammatory background

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composed of eosinophils, neutrophils, plasma cells, histiocytes surrounding Reed–Sternberg cells ▪ Lymphocyte-rich ▫ Reed-Sternberg cells surrounded by lymphocytes ▫ Best prognosis, caught early ▪ Lymphocyte-depleted ▫ Rarest; median age: 30–37 years ▫ No reactive lymphocytes, abundance of Reed–Sternberg cells ▫ Prevalent in HIV-positive individuals ▫ Worst prognosis, advanced stage diagnosis Nodular lymphocyte predominant Hodgkin’s lymphoma ▪ More common in individuals who are biologically male ▪ Abnormal B cells express CD20/CD45; not CD15/CD30 ▪ Lymphocyte-predominant cells; no Reed– Sternberg cells ▫ Large groups of lymphocytes form nodules around lobulate-nucleated “popcorn” cells (variant of Reed– Sternberg cells) ▪ Slow-growing, highly curable ▪ Small risk of transformation to aggressive non-Hodgkin’s lymphoma

SIGNS & SYMPTOMS ▪ Painless cervical lymphadenopathy ▫ Mediastinal lymphadenopathy: nodular sclerosis subtype ▪ Cytokine release: fever, drenching night sweats, weight loss ▫ Rarely present with nodular lymphocyte predominant Hodgkin’s lymphoma ▪ B symptoms ▫ Nodular sclerosis: about 50% ▫ Mixed cellularity: common ▫ Lymphocyte-rich: rare ▫ Lymphocyte-depleted: common

DIAGNOSIS DIAGNOSTIC IMAGING ▪ CT scan, PET scan

LAB RESULTS

▪ Lymph node biopsy

STAGING

▪ Stage 1: limited to one lymph node group/ group of adjacent lymph nodes ▪ Stage 2: ≥ two lymph node regions on same side as diaphragm ▪ Stage 3: lymph nodes on both sides (superior, inferior) of diaphragm ▪ Stage 4: lymph nodes superior, inferior to diaphragm; liver/spleen/lungs/bone marrow ▪ Subdivisions ▫ Category A: no symptoms ▫ Category B: B symptoms present ▫ Category E: organs/tissues beyond lymph system

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Figure 49.1 A CT scan of the chest in the coronal plane demonstrating a large mediastinal mass. The mass is a focus of Hodgkin’s lymphoma.

Chapter 49 Lymphomas

TREATMENT MEDICATIONS Rituximab ▪ For nodular lymphocyte predominant Hodgkin’s lymphoma ▪ Monoclonal antibody, binds CD20, induces complement-mediated lysis → apoptosis Figure 49.2 The histological appearance of Hodgkin’s lymphoma. Reed–Sternberg cells are pathognomonic of this disease.

Figure 49.3 The gross pathology of a spleen that has been infiltrated by Hodgkin’s lymphoma.

NON-HODGKIN'S LYMPHOMA osms.it/non-hodgkin PATHOLOGY & CAUSES ▪ B/T cell tumors, no Reed–Sternberg cells

TYPES B cell lymphomas ▪ More common ▪ Neoplastic B cells: CD20 on surface ▪ Rate of growth: slow/aggressive/highly aggressive B cell lymphoma subtypes ▪ Diffuse large B cell lymphoma ▫ Aggressive ▫ Most common ▪ Follicular lymphoma

▫ Slow growing ▫ Chromosomal translocation: t(14,18) → BCL2 gene placed after Ig heavy chain promoter → overexpression of BCL2 → inhibition of apoptosis → cell proliferation ▫ BCL2 promotes cell viability, blocks apoptosis ▪ Burkitt lymphoma ▫ Highly aggressive ▫ “Starry sky” appearance under microscope ▫ Stars: tingible bodies (macrophages) with phagocytosed dead neoplastic cells ▫ Sky: dark neoplastic lymphocytes ▫ Chromosomal translocation: t(8,14) → Myc gene moved adjacent to IgH

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promoter sequence → upregulation of Myc gene → Myc gene stimulates cell growth, metabolism → increased cell division ▫ Variant in individuals of African descent: extranodal involvement of jaw, associated with EBV infection ▫ Variant in individuals of non-African descent: extranodal involvement of abdomen (e.g. at ileocecal junction), less frequently associated with EBV infection ▪ Mantle cell lymphoma ▫ Aggressive ▫ Chromosomal translocation: t (11,14) → BCL1 gene moved to Ig promoter → upregulation of BCL1 gene → stimulation of cell growth

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▪ Marginal zone lymphoma ▫ Indolent ▫ Most common type ▫ Associated with mucosa-associated lymphoid tissue (extranodal) in cases of chronic inflammation of stomach lining (e.g. chronic H. pylori infection) ▫ May occur in lymph nodes (nodal marginal zone lymphoma)/spleen (splenic marginal zone lymphoma) ▪ Lymphoplasmacytic lymphoma ▫ Indolent ▫ Bone marrow, lymph nodes, spleen ▫ Waldenstrom macroglobulinemia: neoplastic cells produce M proteins (IgM) in high levels → IgM released into

Chapter 49 Lymphomas blood → increases blood viscosity T cell lymphomas ▪ Adult T cell lymphoma ▫ AKA leukemia: abnormal leukocytes in bloodstream ▫ Possibly cause: human T-lymphotropic virus (HTLV) ▫ HTLV infects T cells → becomes incorporated into T cell DNA → genetic mutation → adult T cell lymphoma ▪ Mycosis fungoides ▫ T cell lymphoma of of skin, resembles fungal infection ▫ Neoplastic cells: CD4+ helper T cells circulate in blood → Sezary syndrome (erythroderma)

SIGNS & SYMPTOMS ▪ Painless lymphadenopathy ▪ B symptoms: release of cytokines ▪ Extranodal involvement of GI tract: bowel obstruction ▪ Extranodal involvement of bone marrow: fatigue, easy bruising, recurrent infections ▪ Extranodal involvement of spinal cord: motor/sensory deficits (esp. legs)

Figure 49.4 A PET scan in the coronal plane demonstrating gross lymphadenopathy in the axillary, para-aortic and inguinal chains. The underlying cause is a Non-Hodgkin lymphoma.

DIAGNOSIS DIAGNOSTIC IMAGING ▪ CT scan, PET scan

LAB RESULTS

▪ Lymph node biopsy

TREATMENT MEDICATIONS Rituximab ▪ CD20-positive B cell non-Hodgkin lymphomas

Figure 49.5 A diffuse large B-cell lymphoma in a cytology specimen.

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Figure 49.6 The histological appearance of mantle cell lymphoma at low power. This lymph node has been infiltrated by the malignant lymphocytes which have a vaguely nodular architecture.

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Figure 49.7 A diffuse large B-cell lymphoma in a cytology specimen.

NOTES

NOTES

MACROCYTIC ANEMIA GENERALLY, WHAT IS IT? PATHOLOGY & CAUSES ▪ Bone marrow produces larger than normal erythrocytes AKA red blood cells (RBCs)

CAUSES

▪ Multifactorial: nutritional deficits, genetics, substance exposure (e.g. certain drugs, alcohol)

SIGNS & SYMPTOMS ▪ Fatigue, dyspnea, weight loss, pallor, impaired concentration/memory, diarrhea, onychoschizia (brittle nails)

DIAGNOSIS LAB RESULTS ▪ ▪ ▪ ▪ ▪

Complete blood count Peripheral blood smear analysis Blood chemistry Iron studies Genetic testing

TREATMENT ▪ Address underlying causes

MEGALOBLASTIC ANEMIA osms.it/megaloblastic-anemia PATHOLOGY & CAUSES ▪ Macrocytic, normochromic anemia characterized by formation of large RBCs

CAUSES Cobalamin and/or folate deficiency ▪ Impaired DNA synthesis during erythropoiesis → uncoordinated maturation of cytoplasm and nuclei in erythroblasts (nuclear-cytoplasmic asynchrony) → abnormally large RBCs (macrocytosis) + defective cells with fragile membranes → RBCs die prematurely → anemia

B12 deficiency ▪ Insufficient diet (e.g. vegan diet without B12 supplements, alcoholism, systemic/mental illness, food insecurity) ▪ Malabsorption ▫ Lack of intrinsic factor → pernicious anemia ▫ Surgical: gastrectomy, bariatric surgery → lack of absorptive surface → pernicious anemia ▫ Pancreatic insufficiency → impaired binding of B12 to intrinsic factor → pernicious anemia ▫ Medications that interfere with absorption: e.g. biguanides, H2 receptor blockers, proton-pump inhibitors, neomycin

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▫ Fish tapeworm (Diphyllobothrium latum) → competes with host for B12 Folate deficiency ▪ Insufficient diet ▪ Adequate diet but increased requirements (e.g. pregnancy, lactation, chronic hemolysis, exfoliative skin disease) ▪ Malabsorption (e.g. celiac disease, inflammatory bowel disease, gastric surgery) ▪ Metabolic interference from medications (e.g. methotrexate, phenytoin, trimethoprim) ▪ Alcoholism Less common causes of macrocytosis ▪ Thiamine-responsive megaloblastic anemia syndrome, congenital anemias (Fanconi anemia, Diamond–Blackfan anemia), myelodysplastic syndromes, pure RBC aplasia, lipid abnormalities (e.g. liver disease), thyroid disease, copper deficiency ▪ Impaired DNA synthesis also causes formation of giant metamyelocytes → neutrophils with hypersegmented nuclei

SIGNS & SYMPTOMS ▪ From decreased number of functional RBCs in circulation → decreased RBC oxygencarrying capacity → tissue hypoxia ▫ Fatigue ▫ Activity intolerance ▫ Pallor ▫ Compensatory mechanisms: increased heart rate, bounding pulse ▪ From increased rate of hemolysis, destruction of defective cells ▫ Jaundice: hemolysis → increased serum bilirubin ▫ Splenomegaly: increased reticuloendothelial activity secondary to extravascular hemolysis ▪ From neuronal demyelination (if B12 decreased): numbness, tingling, weakness, possible neuropsychiatric symptomatology

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DIAGNOSIS LAB RESULTS

▪ Peripheral blood cell analysis ▫ Increased mean corpuscular volume (MCV) ▫ Increased mean corpuscular hemoglobin (MCH) ▫ Normal mean corpuscular hemoglobin concentration (MCHC) ▫ Hypersegmented neutrophils ▫ Anisocytosis (different sizes of RBCs) ▫ Poikilocytosis (abnormally-shaped RBCs) ▫ Macroovalocytes (large oval-shaped cells) ▪ Decreased RBC count secondary to increased hemolytic destruction of defective erythrocytes ▪ Decreased reticulocyte count → formation impaired in anemias caused by defective DNA synthesis ▪ Mild leukopenia and/or thrombocytopenia caused by defective DNA synthesis ▪ Decreased serum hemoglobin and hematocrit related to decreased number of circulating RBCs ▪ Markers of hemolysis ▫ Increased lactate dehydrogenase (LDH) ▫ Increased serum unconjugated bilirubin ▫ Decreased haptoglobin ▪ Decreased serum B12 and/or folate levels ▪ Increased homocysteine or methylmalonic acid are also evidence of B12 deficiency

TREATMENT MEDICATIONS

▪ Supplementation: increased dietary vitamin B12 and/or folate when indicated ▫ Parenteral vitamin B12 if pernicious anemia ▫ Dietary vitamin B12 found in animal products ▫ Folate found in both plant, animal products, esp. dark green leafy vegetables

Chapter 50 Macrocytic Anemia

Figure 50.1 A hyperlobated neutrophile in a peripheral blood smear; a characteristic feature of megaloblastic anemia.

Figure 50.2 An erythrocyte displaying a Cabot ring and basophilic stippling. These features represent disordered erythropoiesis and are seen in many conditions, including megaloblastic anemias.

SIDEROBLASTIC ANEMIA osms.it/sideroblastic-anemia PATHOLOGY & CAUSES ▪ Anemias caused by altered mitochondrial function and defects in heme synthesis within erythroid cells

TYPES Congenital forms ▪ Involve inheritance patterns affecting nuclear/mitochondrial genes encoding for erythrocyte synthesis—X-linked/autosomal recessive/mitochondrial inheritance patterns ▫ Syndromic: presents with clinical manifestations of anemia along with effects on other organ systems (e.g. exocrine pancreatic insufficiency, sensorineural deafness, hepatic/renal failure, myopathy) ▫ Non-syndromic: main features associated with anemia, iron overload

Acquired forms ▪ Clonal: myelodysplastic syndromes/ myeloproliferative neoplasms alter erythrocytes, granulocytes, platelets ▪ Reversible (metabolic): caused by exposure to a substance (e.g. excessive alcohol/drugs such as isoniazid, chloramphenicol; copper deficiency/zinc overload) Both congenital & acquired ▪ Impaired erythropoiesis, hemoglobin synthesis → reduced iron in RBCs + defective RBCs undergo apoptosis within bone marrow + fewer functional RBCs in circulation → anemia ▪ Circulating RBC morphology: microcytic/ dimorphic (normocytic-to-macrocytic)

COMPLICATIONS

▪ Systemic effects of heme synthesis defects include impaired utilization of iron → accumulation in mitochondria → systemic iron overload → complications from hemochromatosis (e.g. diabetes, cardiac

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▪ ▪ ▪ ▪

pathology) ▫ Repeated blood transfusions add to iron overload Anemia-induced acceleration of erythropoiesis → erythroid hyperplasia of bone marrow Increased risk of infection Acute leukemia develops in some cases Infection possibly fatal

Complete blood count ▪ Decreased serum hemoglobin ▪ Decreased RBC count ▪ Decreased/low reticulocyte count—related to ineffective erythropoiesis Iron studies ▪ Hemochromatosis Genetic testing

SIGNS & SYMPTOMS ▪ Presentation variable depending on cause ▪ Clinical manifestations of decreased oxygen-carrying capacity of RBCs and hypoxia (e.g. fatigue, dyspnea, palpitations, pallor; mild jaundice if hemolysis significant) ▪ Erythropoietic hemochromatosis will manifest as varying degrees of iron overload (e.g. hepatosplenomegaly, cardiac arrhythmias, heart failure)

DIAGNOSIS LAB RESULTS Bone marrow aspirate smear ▪ Presence of sideroblasts confirms diagnosis ▫ Prussian blue stain reveals iron ring around nucleus

TREATMENT ▪ If sideroblastic anemia acquired, cause is reversible with treatment

MEDICATIONS

▪ X-linked sideroblastic anemia: vitamin B6 (pyridoxine)

SURGERY

▪ Reduce organ damage secondary to iron overload ▫ Mild anemia: therapeutic phlebotomy

OTHER INTERVENTIONS

▪ Reduce organ damage secondary to iron overload ▫ Mild anemia: therapeutic phlebotomy ▫ Chelation therapy (e.g. deferoxamine)

RBC indices ▪ Low MCH ▪ MCV may be low/normal/high ▫ Acquired sideroblastic anemias often produce macrocytic erythrocytes ▫ Hereditary sideroblastic anemias produce microcytic erythrocytes Blood smear analysis ▪ Anisocytosis ▪ Poikilocytosis ▪ Micro/macrocytosis ▪ Hypochromic erythrocytes ▪ Iron-containing inclusions (Pappenheimer bodies) may be present

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Figure 50.3 An erythrocyte displaying a Cabot ring and basophilic stippling. These features represent disordered erythropoiesis and are seen in many conditions, including megaloblastic anemias.

NOTES

NOTES

METHEMOGLOBINEMIA

METHEMOGLOBINEMIA osms.it/methemoglobinemia PATHOLOGY & CAUSES ▪ ↑ methemoglobin levels in blood > 10% ▫ Normal methemoglobin level < 1% ▪ Methemoglobin ▫ Hemoglobin form: contains ferric (Fe3+) iron → ↓ oxygen affinity ▫ Overwhelming oxidative stress (in red blood cells) → iron oxidation within heme (Fe2+ → Fe3+) → hemoglobin converted to methemoglobin ▫ Oxygen binding → ↑ affinity in remaining heme sites that may have been in ferrous (Fe2+) state in heme tetramer → left shift in oxygen curve → overall oxygen to tissue release ability ↓ → tissue hypoxia ▪ Healthy cells ▫ Spontaneous methemoglobin conversion rapidly ↓ by protective enzymes ▫ Nicotinamide adenine dinucleotidereduced (NADH) methemoglobin reductase (diaphorase I) ▫ Nicotinamide adenine dinucleotide phosphate (NADPH) methemoglobin reductase ▫ Ascorbic acid ▫ Glutathione enzyme system

TYPES

▪ Industrial chemicals ▫ Aniline dyes, chlorates, bromates, nitrates Congenital methemoglobinemia ▪ Recessive gene → enzyme diaphorase I deficiency → inefficient methemoglobin ↓ → accumulation ▪ Abnormal hemoglobin variants (HbM/HbH) → hemoglobin not enzymatic-reduction amenable ▪ Diaphorase I cofactor deficiency ▫ Impaired upstream enzymes → insufficient diaphorase I cofactors production → impaired enzymatic reduction ▫ Pyruvate kinase deficiency ▫ Glucose-6-phosphate dehydrogenase deficiency

SIGNS & SYMPTOMS ▪ Arterial blood may develop bluish/ chocolate-brown tinge ▪ Healthy individuals ▫ Symptoms may only manifest at methemoglobin levels > 15% ▫ Cyanosis → dyspnea, mental status change, headache, fatigue, exercise intolerance, dizziness ▪ Severe methemoglobinemia (> 50%) → seizure, coma, death

Acquired methemoglobinemia ▪ ↑ methemoglobin formation ▪ Drugs ▫ Antibiotics, local anesthetics, antiemetics

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DIAGNOSIS DIAGNOSTIC IMAGING

TREATMENT MEDICATIONS

Co-oximetry ▪ Analyses blood-spectrum absorption → methemoglobin peak absorbance at 631nm

▪ Specific ▫ Methylene blue: intravenous reducing agent → reduces heme group from methemoglobin → hemoglobin

LAB RESULTS

OTHER INTERVENTIONS

▪ Arterial blood gas ▫ Clinical cyanosis in normal arterial PO2 presence ▪ Enzyme assays ▫ Enzyme assays for specific enzymes involved in maintaining hemoglobin in reduced state may be utilized

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▪ Supplemental oxygen ▪ Vitamin C (ascorbic acid) may improve cyanosis in chronic cases

NOTES

NOTES

MICROCYTIC ANEMIA GENERALLY, WHAT IS IT? PATHOLOGY & CAUSES ▪ Inherited/acquired anemias, small erythrocytes, varying hemoglobin content

SIGNS & SYMPTOMS ▪ Decreased oxygen to tissues → fatigue, pallor, dyspnea, activity intolerance

MNEMONIC: Find Those Small Cells Last

DIAGNOSIS LAB RESULTS

▪ Complete blood count (CBC), peripheral blood smear analysis, blood chemistry, iron studies

TREATMENT OTHER INTERVENTIONS

▪ Nutrient replacement, packed red blood cell transfusions

Microcytic anemias Fe deficiency Thalassemia Sideroblastic Chronic disease Lead poisoning

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IRON-DEFICIENCY ANEMIA osms.it/iron-deficiency-anemia PATHOLOGY & CAUSES ▪ Microcytic, hypochromic anemia, small erythrocytes, decreased hemoglobin ▪ Insufficient iron → decreased iron for hemoglobin synthesis → impaired erythropoiesis → production of microcytic, hypochromic erythrocytes ▫ Insufficient iron to synthesize hemoglobin during erythropoiesis (most common cause of anemia worldwide)

CAUSES Insufficient intake/absorption ▪ Decreased intake ▫ Eating disorders (e.g. pica, anorexia, bulimia); self-imposed dietary restrictions (e.g. vegan diet); food insecurity ▪ Decreased absorption ▫ Celiac disease, surgical resection of gastrointestinal (GI) tract, bariatric surgery, excessive dietary calcium, tannates, oxalates Increased need ▪ Increased need ▫ Pregnancy, lactation ▪ Increased growth ▫ Infants, children, adolescents Increased loss ▪ Overt blood loss ▫ Hematemesis, trauma-related hemorrhage, heavy menses, hematuria, multiple blood donations ▪ Occult ▫ GI bleed (e.g. peptic ulcer, tumor); vascular lesions (e.g. hemorrhoids); hookworm/other helminthic infections

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COMPLICATIONS

▪ High-output heart failure, angina, cardiorespiratory failure ▪ Infants, young children ▫ Impaired growth, development

SIGNS & SYMPTOMS Decreased oxygen to tissues ▪ Pallor ▪ Fatigue, activity intolerance, exertional dyspnea, angina ▪ Compensatory mechanisms ▫ Palpitations, increased pulse, increased cardiac output, tachypnea, selective shunting of blood to vital organs (e.g. skin to kidneys) Effects on epithelial tissues ▪ Glossitis ▫ Smooth, “beefy red” tongue ▪ Cheilosis ▫ Scaling, fissuring; dryness; lip scaling ▪ Koilonychia ▫ Spoon-shaped, concave nails ▪ Esophageal stricture ▪ Gastric atrophy ▪ Blue sclerae ▪ Pagophagia ▫ Obsessive consumption of ice

DIAGNOSIS LAB RESULTS ▪ ▪ ▪ ▪

↓ red blood cell count Low/normal reticulocytes ↓ hemoglobin, hematocrit Hypochromic-microcytic erythrocytes ▫ Decreased: mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC)

Chapter 52 Microcytic Anemias ▫ Blood smear analysis: erythrocytes with increased central pallor (> ⅓ diameter, anisocytosis (anisto = unequal), poikilocytosis (poikilo = irregular), target cells (resemble target; center stain with pallor ring, outside stain ring) ▪ Iron studies ▫ Decreased serum iron, ferritin (stores cellular iron) ▫ Decreased transferrin saturation (major iron transport protein) ▫ Increased total iron binding capacity

OTHER DIAGNOSTICS

▪ History, physical examination (e.g. colonoscopy for GI bleed)

TREATMENT MEDICATIONS

▪ PO iron supplements (e.g. ferrous sulfate) ▪ Parenteral iron ▫ Severe, persistent anemia ▫ Intolerance of PO iron ▫ Nonadherence to PO supplements/ dietary changes

OTHER INTERVENTIONS

▪ Increase dietary iron ▫ Heme iron (e.g. meat) absorbed better than non-heme iron (e.g. eggs, legumes, nuts) ▫ Vitamin C increases absorption; calcium decreases absorption ▪ Blood transfusion

LEAD POISONING-RELATED ANEMIA osms.it/lead-poisoning PATHOLOGY & CAUSES ▪ Lead exposure, toxicity → anemia ▪ Lead absorbed through lungs/skin/GI tract ▫ Interferes with enzymatic steps in heme pathway → decreased hemoglobin synthesis, microcytosis ▫ Impairs sodium/potassium ATPase in erythrocyte cell membrane → hemolysis

RISK FACTORS

▪ Water contaminated with industrial waste/ from pipes made of lead/that contain lead solder ▪ Exposure to leaded paint/paint dust/chips (esp. children); increased risk in older homes (built before 1978, lead in paint since banned)

▪ Exposure to soil/dust contaminated with lead ▪ Breathing industrial emissions containing lead (e.g. smelters, refineries, battery manufacturing, recycling) ▪ Food/ beverages from lead-glazed ceramics

SIGNS & SYMPTOMS ▪ Small, hypochromic red blood cells → hypoxemia → decreased oxygen to tissues → tissue hypoxia → fatigue, dyspnea, activity intolerance ▪ Lead toxicity ▫ Abdominal pain, headache, difficulty concentrating, muscle/joint pain, confusion, ataxia

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DIAGNOSIS

TREATMENT OTHER INTERVENTIONS

LAB RESULTS ▪ ▪ ▪ ▪ ▪

↑ serum blood lead level (BLL) Basophilic stippling ↓ or normal MCV ↓ mean MCH Hemolysis ▫ ↑ indirect bilirubin, LDH ▫ ↓ haptoglobin

▪ Eliminate exposure ▪ Chelation therapy ▫ Dimercaptosuccinic acid (DMSA, AKA succimer), CaNa2EDTA

THALASSEMIA osms.it/thalassemia PATHOLOGY & CAUSES ▪ Thallas = sea; emia = blood ▪ Inherited hemoglobinopathies; most common in individuals with Mediterranean, Middle Eastern, Southeast Asian, African genetic descent ▪ Hemoglobin synthesis with insufficient globin chains → impaired erythropoiesis, malfunctioning erythrocytes ▪ Autosomal recessive inheritance; wide range of phenotypes, clinical syndromes ▪ Deficient alpha/beta chains → imbalanced beta chain to alpha chain ratio → globin chains aggregate, precipitate in erythroid precursors → unstable hemoglobin tetramer ▫ Impaired erythropoiesis ▫ Intramedullary hemolysis and apoptosis ▫ Small, hypochromic cells → decreased oxygen to tissues ▫ Production of few microcytic, hypochromic erythrocytes with rigid, less deformable membranes → extravascular hemolysis, phagocytosis by reticuloendothelial macrophages

TYPES Alpha-thalassemia ▪ Deletion of ≥ one gene(s) encoding alpha

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globin chains → absent/ reduced chains ▪ One gene missing: alpha-thalassemia minima ▫ Benign carrier state ▪ Two genes missing: alpha-thalassemia minor, alpha thalassemia trait ▫ Mild anemia ▪ Three genes missing: hemoglobin H (HbH) disease ▫ Mild anemia/may require periodic transfusions (variable presentation) ▪ Four genes missing: alpha-thalassemia major, hydrops fetalis, hemoglobin Barts ▫ Incompatible with extrauterine life due to inability to form normal hemoglobin; death occurs before/shortly after birth ▫ Only hemoglobin Barts (Hb Barts) is produced; tetramers of gamma globulin, oxygen not delivered to fetal tissues ▫ Severe anemia during fetal development → hydrops fetalis → heart failure, hepatomegaly, ascites, death Beta-thalassemia ▪ Genetic mutations of one/both genes → absent/reduced beta chains ▪ Mutation in one beta globin chain: betathalassemia minor, thalassemia trait ▫ Asymptomatic carrier state/mild anemia ▪ Mutation in two beta globin chains: reduced beta globin production → betathalassemia intermedia

Chapter 52 Microcytic Anemias ▫ Heterogeneous presentation ▫ May become transfusion-dependent later in life ▪ No beta globin chains produced: betathalassemia major ▫ Transfusion dependent

COMPLICATIONS

▪ Hemolytic, microcytic, hypochromic anemia ▫ Chronic tissue hypoxia ▫ Leg ulcers ▫ High output heart failure ▫ Hypermetabolic state → nutritional deficiencies (children: growth impairment) ▪ Extrameduallary hematopoiesis → bone marrow hyperplasia, bone marrow widens, structural malformations (e.g. facial irregularity, osteoporosis, premature fusion of epiphysis in children) ▪ Hemolysis → increased bilirubin → gallstones ▪ Iron overload, deposition in tissue ▫ Myocardium → arrhythmias, restrictive cardiomyopathy, heart failure ▫ Pancreas, other endocrine glands → endocrinopathies (e.g. diabetes, thyroid dysfunction) ▫ Liver → cirrhosis, hepatocellular cancer ▫ Kidneys → renal insufficiency (metabolic load from high hematopoietic cell turnover) ▪ Hydrops fetalis ▫ Alpha thalassemia major only ▪ Treatment-related complications ▫ Transfusions, chelation therapy

SIGNS & SYMPTOMS ▪ With exception of alpha-thalassemia major, mild compared to beta-thalassemia ▪ Decreased oxygen to tissues ▫ Systemic: pallor, fatigue, activity intolerance ▫ Cardiac: altered hemodynamics, e.g. tachycardia, low blood pressure, arrhythmias

▪ Chronic hemolysis ▫ Jaundice, dark urine, hepatosplenomegaly

DIAGNOSIS LAB RESULTS

▪ ↓ serum hemoglobin ▪ Decreased/normal/increased reticulocyte count → degree of impaired erythropoiesis ▪ White blood cells, platelets normal ▪ Red blood cell indices ▫ Hypochromic-microcytic erythrocytes ▫ MCHC increased related to erythrocyte dehydration ▫ Decreased MCV ▫ High red cell distribution width (RDW) ▪ Blood smear analysis ▫ Poikilocytosis (dacrocytes, i.e. teardropshaped cells) ▫ Anisocytosis ▫ Erythroblasts (nucleated red blood cells) ▫ Target cells ▫ Inclusions (precipitated globin chains) ▪ Blood chemistry indicative of hemolysis ▫ Increased lactate dehydrogenase (LDH) ▫ Increased indirect (unconjugated) bilirubin ▫ Decreased haptoglobin ▪ Iron studies ▫ Increased serum iron, transferrin saturation (TSAT), serum ferritin ▪ Diagnostics to determine organ involvement (e.g. cardiac MRI, thyroid hormone, glucose levels, bone mineral density) ▪ Hemoglobin analysis using highperformance liquid chromatography (HPLC)/hemoglobin electrophoresis, genetic testing (confirmation)

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TREATMENT ▪ According to phenotype

MEDICATIONS

▪ Folic acid supplements: support erythropoiesis

SURGERY

▪ Splenectomy

OTHER INTERVENTIONS

▪ Blood transfusions ▪ Chelation therapy ▪ Allogeneic hematopoietic cell transplantation (beta-thalassemia major) ▪ Consultation with cardiology, other specialties: organ involvement ▪ Ongoing monitoring: individuals with high impairment (e.g. blood, iron studies; liver studies; growth, development in children)

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NOTES

NOTES

NORMOCYTIC ANEMIA (DECREASED PRODUCTION)

GENERALLY, WHAT IS IT? PATHOLOGY & CAUSES ▪ Insufficient production of erythrocytes AKA red blood cells (RBCs)

CAUSES

▪ Chronic diseases most common cause (e.g. kidney disease, cancer, rheumatoid arthritis)

SIGNS & SYMPTOMS ▪ Variable depending on degree of hypoxia, pallor; fatigue; dyspnea; activity intolerance; cardiorespiratory compromise

DIAGNOSIS LAB RESULTS ▪ ▪ ▪ ▪ ▪

Complete blood count (CBC) Peripheral blood smear analysis Blood chemistry Iron studies Genetic testing (rarely)

TREATMENT MEDICATIONS

▪ Dietary changes

OTHER INTERVENTIONS

▪ Supplementation (address iron deficiency)

ANEMIA OF CHRONIC DISEASE (ACD) osms.it/anemia-of-chronic-disease PATHOLOGY & CAUSES ▪ Deficient RBC production due to chronic diseases (e.g. infection, inflammation, malignancy) ▪ AKA anemia of chronic inflammation

CAUSES

▪ Inflammatory processes in iron homeostasis ▪ Systemic inflammation → ↑ circulation cytokines, interleukin 1 (IL1), interleukin

6 (IL6), tumor necrosis factor alpha (TNF alpha), interferon beta (IFN beta), interferon gamma (IFN gamma) ▫ ↑ hepcidin secretion by liver → ↓ iron absorption from gastrointestinal (GI) tract, ↓ iron sequestration in reticuloendothelial system → ↓ iron available for erythropoiesis ▫ ↓ secretion of erythropoietin ▫ Direct inhibition of erythropoiesis ▫ ↓ erythrocyte lifespan

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RISK FACTORS

▪ Advanced age, physical trauma

SIGNS & SYMPTOMS ▪ Hypoxia, pallor; fatigue; dyspnea; activity intolerance; cardiorespiratory compromise ▪ Variable depending on degree of hypoxia

DIAGNOSIS

▪ ▪ ▪ ▪ ▪ ▪ ▪

(ESR), C-reactive protein (CRP), IL6 Decreased serum iron levels High ferritin Decreased serum transferrin saturation Decreased total iron binding capacity Low serum erythropoietin concentration Decreased reticulocyte count Bone marrow examination ▫ Increased iron in macrophages (related to actions of hepcidin), erythroid precursors

LAB RESULTS

▪ RBCs normochromic, normocytic ▪ Microcytic, hypochromic RBCs (rarely) ▪ Leukocytosis ▫ Underlying disorder ▪ Normal/low mean corpuscular hemoglobin (MHC), mean corpuscular volume (MCV) ▪ Normal mean corpuscular hemoglobin concentration (MCHC) ▪ Normal/increased red cell distribution width (RDW) normal/increased ▪ Erythrocyte hypoproliferation ▫ Decreased RBC count ▫ Mild to moderate decrease in hemoglobin ▪ Elevated erythrocyte sedimentation rate

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TREATMENT MEDICATIONS

▪ Supplemental iron ▫ IV more effective than oral iron for systemic inflammation ▪ Erythropoiesis-stimulating agents (e.g. epoetin alfa, darbepoetin alpha) ▫ For severe anemia

OTHER INTERVENTIONS ▪ Transfusion of packed RBCs ▫ For severe anemia

Chapter 53 Normocytic Anemia (Decreased Production)

APLASTIC ANEMIA osms.it/aplastic-anemia PATHOLOGY & CAUSES ▪ Pancytopenia due to bone marrow hypoplasia/aplasia ▪ Idiopathic/inherited/acquired

CAUSES

▪ Inherited ▫ Fanconi anemia; Shwachman–Diamond syndrome; familial aplastic anemias; reticular dysgenesis ▪ Acquired ▫ Immune processes (e.g. systemic lupus erythematosus, graft-versushost disease, paroxysmal nocturnal hemoglobinuria) ▫ Drugs (e.g. cytotoxic cancer chemotherapy, carbamazepine, phenytoin, indomethacin, sulfonamides, chloramphenicol) ▫ Viruses (e.g. Epstein–Barr, HIV, hepatitis, herpes) ▫ Toxic chemicals (e.g., solvents, benzene, pesticides) ▫ Ionizing radiation ▪ Acquired or idiopathic ▫ Insidious onset of bone marrow hypoplasia/aplasia, hematopoietic cell loss → ↓ production of cell lineages (thrombocytes, leukocytes, erythrocytes) → peripheral pancytopenia

COMPLICATIONS

▪ Impairment of blood’s immunity, hemostasis, oxygen-carrying capacities

SIGNS & SYMPTOMS ▪ Deficient thrombocytes, leukocytes ▫ Shorter lifespan ▪ Neutropenia ▫ Increased frequency/severity of

infections ▫ Neutropenia-related sepsis common cause of death ▪ Thrombocytopenia ▫ Mucosal hemorrhage (e.g. gingival, nares, ecchymosis, petechiae, heavy menstrual flow, occult blood in stool, intracranial hemorrhage) ▪ Anemia ▫ Pallor, fatigue, dyspnea, activity intolerance, cardiorespiratory compromise

DIAGNOSIS LAB RESULTS

Prolonged bleeding time Decreased hemoglobin, hematocrit Absolute neutrophil count decreased Platelet count decreased Reticulocyte count decreased ▫ Normal erythrocyte morphology ▪ Bone marrow biopsy ▫ Some lymphocytes, plasma cells, stromal elements (e.g. blastoid cells) ▫ No increase in blasts/dysplasia

▪ ▪ ▪ ▪ ▪

TREATMENT ▪ Treat underlying cause ▫ Discontinue offending drug treatment ▪ Varies by age, severity of symptoms, likelihood of finding donor match

MEDICATIONS

▪ Manage cytopenias ▪ Antimicrobials for infections ▫ Medical emergency: fever + low absolute neutrophil count ▪ Growth factors ▫ Granulocyte colony-stimulating factor

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(G-CSF): frequent/severe infections ▫ Thrombopoietin (TPO) receptor agonists with immunosuppressive therapy ▫ Hematopoietic growth factors (rarely) ▪ Immunosuppressive therapy (IST) ▫ Consists of antithymocyte globulin (ATG) + cyclosporin A ▫ Administer glucocorticoid with ATG: steroid reduces risk of serum sickness; immunosuppressive properties ▫ Cyclosporin A: immunosuppressive ▫ Eltrombopag (thrombopoietic agent) to increase platelet count

OTHER INTERVENTIONS

▪ Hematopoietic stem cell transplant ▫ Curative if effective ▪ Transfusions ▫ Platelets, packed red blood cells ▫ Increased risk of alloimmunization, graft rejection after bone marrow transplant

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Figure 53.1 A bone marrow biopsy from an individual with aplastic anemia. The bone marrow spaces contain large amounts of fat and minimal hematopoietic tissue is present.

NOTES

NOTES

NORMOCYTIC ANEMIA (INCREASED HEMOLYSIS)

GENERALLY, WHAT IS IT? PATHOLOGY & CAUSES ▪ Inherited/acquired disorders resulting in premature destruction of normal red blood cells (RBCs)

SIGNS & SYMPTOMS ▪ If hematopoietic compensation insufficient, anemic symptoms (e.g. pallor, fatigue, activity intolerance) ▪ Intravascular hemolysis → hemoglobinuria, iron deficiency ▪ Extravascular hemolysis → jaundice, splenomegaly, gallstone formation

DIAGNOSIS LAB RESULTS

▪ Complete blood count (CBC) ▪ Peripheral blood smear analysis ▪ Measure plasma for hemolysis indicators ▫ Bilirubin, lactate dehydrogenase (LDH), haptoglobin ▪ Measure specific indicators of hemolysis in urine ▫ Hemoglobin, bilirubin, hemosiderin

TREATMENT ▪ See individual disorders

AUTOIMMUNE HEMOLYTIC ANEMIA (AHA) osms.it/autoimmune-hemolytic-anemia PATHOLOGY & CAUSES ▪ Anemia caused by immune destruction of red blood cells by autoantibodies against antigens on RBCs surface ▪ AKA AIHA

TYPES Warm AIHA ▪ Most common ▪ “Warm” because optimum temperature for antibody to react with RBCs = normal body

temperature (37°C/98.6°F) ▪ Predominant autoantibody: IgG (IgA and IgM may also be involved) ▪ Predominant RBC antigen: Rh ▪ Associated with immune deficiencies, malignancies, certain drugs ▪ Antibody fixes complement + binds to RBC membrane → antibody-coated RBCS destroyed in spleen ▫ Usual site of hemolysis: extravascular, by macrophages in spleen, liver

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Cold AIHA ▪ “Cold” because optimum temperature for antibody to react with RBCs = below normal body temperature (4°C/39.2°F) ▪ Predominant autoantibody: IgM ▪ Predominant RBC antigen: I, i, P ▪ Antibodies activate direct complement system attack ▪ Usual site of hemolysis: intravascular, complement-mediated ▪ Paroxysmal cold hemoglobinuria ▫ Most common in children ▫ Caused by Donath–Landsteiner antibody ▫ Associated with viral (e.g. measles, varicella) or bacterial (e.g. mycoplasma, H. influenza) infections ▪ Cold agglutinin syndrome ▫ Most common in adults > 70 years old ▫ Primarily biologically-female individuals ▫ Associated with lymphoproliferative disorders, autoimmune disorders, mycoplasma infections

COMPLICATIONS

▪ Depend on type/degree of hemolysis ▪ Anemia, venous thromboembolism, cholelithiasis, renal insufficiency ▪ Older individuals: increased risk of cardiac complications

SIGNS & SYMPTOMS ▪ Onset insidious/acute ▪ If hematopoietic compensation insufficient, anemic signs and symptoms (e.g. pallor, fatigue, activity intolerance) ▪ If severe anemia/underlying cardiac disease, a hyperdynamic state (e.g. bounding pulses, tachycardia, pulmonary congestion) ▪ Cold AIHA ▫ Hemoglobinuria after exposure to cold temperatures ▪ Paroxysmal cold hemoglobinuria ▫ Jaundice, hemoglobinuria, anemia after infection; pain in legs, back following exposure to cold ▪ Cold agglutinin syndrome ▫ Anemia, acrocyanosis, or Raynaud’s phenomenon

DIAGNOSIS LAB RESULTS

RISK FACTORS

▪ Exposure to cold ▪ Administration of offending drug ▪ Development of associated diagnosis ▫ Infection, malignancy, autoimmune disorder

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▪ Evidence of hemolysis ▫ Increased lactate dehydrogenase (LDH) ▫ Increased indirect bilirubin ▫ Decreased haptoglobin ▪ Increased mean corpuscular volume (MCV) ▪ Low hemoglobin, hematocrit ▪ Reticulocytosis ▪ Direct antibody (DAT) ▫ Warm: positive for IgG/IgG + C3d ▫ Cold: positive for C3d ▪ Partial macrophage phagocytosis → spherocytosis

Chapter 54 Normocytic Anemia (Increased Hemolysis)

TREATMENT ▪ Cold AIHA: often no treatment required

MEDICATIONS

▪ Corticosteroids ▪ Monoclonal antibody: rituximab ▪ Immunosuppressants

SURGERY

▪ Splenectomy (reduces hemolysis)

OTHER INTERVENTIONS

Figure 54.1 A peripheral blood smear from an individual with warm autoimune hemolytic anemia. There are numerous spherocytes present due to degradation of the red cell membrane by macrophages.

▪ Eliminate triggers (e.g. cold, drugs) ▪ Correct anemia ▫ Folic acid supplements to support erythropoiesis ▫ Blood transfusion

GLUCOSE-6-PHOSPHATE DEHYDROGENASE DEFICIENCY osms.it/G6PD PATHOLOGY & CAUSES ▪ Hematological enzymopathy where deficient glucose-6-phosphate dehydrogenase (G6PD) causes premature hemolysis ▪ Inherited, X-linked mutation of G6PD gene ▪ Hemolysis can be acute/intermittent/chronic (rare) ▪ Inadequate G6PD, GSH → oxidative stress → build-up of free radicals, peroxides → precipitation of hemoglobin → disruption of cell membrane → increased cellular rigidity → extravascular hemolysis, accelerated removal of damaged RBCs by reticuloendothelial system in spleen; intravascular hemolysis may also occur ▪ Hemolysis precipitated by sources of oxidative damage that trigger hemolysis. ▫ RBCs with deficient G6PD have a

decreased lifespan ▫ Certain drugs (sulfa drugs, antimalarials) and chemicals (e.g. henna compounds, aniline-based dyes, naphthalene) interact with hemoglobin + oxygen → hydrogen peroxide (H2O2), other oxidizing radicals within cell → hemoglobin precipitation ▪ Infections → possible generation of hydrogen peroxide by leukocytes/exposure to neutrophil produced oxidants → hemoglobin precipitation ▪ Ingestion of fava beans (favism) W.H.O. Classifications ▪ Based on degree of enzyme deficiency, resulting hemolysis ▪ Class I: G6PD < 10% of normal; chronic hemolytic anemia ▪ Class II: G6PD < 10% of normal; intermittent hemolysis when exposed to

OSMOSIS.ORG 427

oxidative stress ▫ G6PD Mediterranean: majority of RBCs hemolyze in setting of oxidative stress; half-life of G6PD especially short (measured in hours) ▪ Class III: G6PD 10–60% of normal; intermittent hemolysis when exposed to trigger ▫ G6PD A- : only oldest RBCs hemolyze in setting of oxidative stress; G6PD halflife = 13 days (normal = 62 days)

▪ ▪ ▪

▪

TYPES

▪ Acute hemolysis ▫ May be mild/severe (life-threatening) ▪ Kernicterus ▫ G6PD-related neonatal jaundice → kernicterus if not promptly treated ▪ Renal failure

RISK FACTORS

▪ Most common in people of African, Asian, Mediterranean descent

SIGNS & SYMPTOMS ▪ Generally asymptomatic until exposed to oxidative stress ▪ Acute hemolysis ▫ Pallor, jaundice, dark urine ▫ Abdominal/back pain due to increased splenic activity ▫ Renal insufficiency (severe hemolysis) ▪ Favism (potentially fatal acute hemolysis)

DIAGNOSIS LAB RESULTS

▪ Decreased hemoglobin ▪ Heinz bodies ▫ Caused by precipitation of oxidized, denatured hemoglobin ▪ Bite cells ▫ Cells have bitten appearance where macrophages have removed bits of precipitated hemoglobin from RBC ▪ Blood chemistry demonstrates evidence of hemolysis

428 OSMOSIS.ORG

▪

▫ Elevated indirect bilirubin ▫ Elevated lactate dehydrogenase (LDH) ▫ Decreased haptoglobin Reticulocytosis Hemoglobinuria, hemosiderinuria G6PD assay ▫ Directly measures G6PD activity in RBCs; false-negative if testing done during/immediately after acute hemolytic episode Screening tests ▫ Fluorescent spot test: glucose6-phosphate + NADP added to hemolysate of individual’s RBCs → fluorescence of NADPH ▫ Methemoglobin reduction test: methylene blue measures transfer of hydrogen ions from NADPH to methemoglobin → indirectly estimates NADPH generation ▫ Newborn screening: blood analyzed for biochemical, genetic markers of G6PD, other inherited disorders Confirmatory test to assay NADPH formation performed after positive screening test/as initial test ▫ Spectrophotometric analysis of RBC hemolysate + glucose-6-phosphate + NADP measures NADPH generation rate

TREATMENT MEDICATIONS

▪ Folic acid supplements (support erythropoiesis)

OTHER INTERVENTIONS

▪ Eliminate triggers ▪ Manage acute hemolytic episodes ▫ Hydration ▫ Transfusions ▪ Phototherapy, exchange transfusion ▫ Neonatal jaundice

Chapter 54 Normocytic Anemia (Increased Hemolysis)

HEMOLYTIC DISEASE OF THE NEWBORN osms.it/hemolytic-disease-of-the-newborn PATHOLOGY & CAUSES ▪ Anemia caused by hemolytic destruction of fetal/neonatal erythrocytes by maternal antibodies ▪ AKA alloimmune HDFN/erythroblastosis fetalis

CAUSES

▪ Fetomaternal hemorrhage exposes maternal circulation to antigens present on fetal RBCs → maternal sensitization → formation of maternal IgG antibodies against fetal RBCs → IgG antibodies small enough to cross placenta → antibody attachment to fetal cells → agglutination (clumping) → microcirculatory impairment → hemolysis, destruction of RBCs by macrophages in reticuloendothelial system ▫ Involves Rhesus (Rh) blood group/A, B, AB, O blood groups ▪ Causes of maternal sensitization include normal delivery, spontaneous/induced abortion, chorionic villus sampling, amniocentesis, antenatal hemorrhage, maternal trauma, idiopathic ▫ Small amount (0.1mL) of fetal blood needed to induce maternal immune response ▪ Rh incompatibility ▫ Rh negative mother exposed to Rh positive fetal RBCs → maternal anti-D antibodies formed ▫ Usually will not affect first pregnancy when initial exposure occurs; adversely affects subsequent pregnancies ▫ Decreasing occurrence due to availability of Rh(D) immune globulin prophylaxis ▪ ABO incompatibility ▫ More common, less severe morbidity, mortality than with Rh incompatibility

▫ Occurs in type O mother with naturallyoccurring Anti-A and Anti-B antibodies + Type A/Type B fetus ▫ Can occur in first and all subsequent pregnancies

RISK FACTORS

▪ Blood group incompatibility, fetomaternal hemorrhage

COMPLICATIONS

▪ Anemia, hyperbilirubinemia, kernicterus ▪ Growth restriction, hydrops fetalis, erythroblastosis fetalis ▫ Increased immature RBCs in fetal circulation

SIGNS & SYMPTOMS ▪ Hemolytic disease caused by ABO incompatibility ▫ Mild to moderate hyperbilirubinemia within first 24h of life ▫ Mild to moderate anemia ▪ Hemolytic disease caused by Rh incompatibility (more severe) ▫ Hyperbilirubinemia, kernicterus: possible ▫ Symptomatic anemia: pallor, lethargy, tachycardia, tachypnea ▫ Hydrops fetalis: related to severe anemia-induced hypoxia; subcutaneous edema, pleural/pericardial effusion, ascites, signs and symptoms of shock ▪ Antenatal presentation ▫ Intrauterine growth restriction signals problems with ongoing hemolysis, hypoxia

OSMOSIS.ORG 429

DIAGNOSIS DIAGNOSTIC IMAGING Doppler ultrasound ▪ Antenatal (maternal testing) ▪ Notes growth restriction/presence of hydrops

LAB RESULTS

▪ Antenatal (maternal testing) ▫ Positive indirect antiglobulin test: IAT, indirect Coombs test; demonstrates IgG antibodies in maternal serum ▫ Kleihauer–Betke test: positive if fetomaternal hemorrhage has occurred ▫ Percutaneous umbilical blood sampling (PUBS): measures hemoglobin, hematocrit, identifies fetal blood type ▫ Spectrophotometric amniotic fluid analysis: increased bilirubin if significant hemolysis has occurred ▪ Postnatal (neonatal testing) ▫ Blood typing: confirm incompatibility of maternal, neonatal blood types ▫ Positive direct antiglobulin test: DAT, direct Coombs test; evidence of maternal antibodies on RBC surface ▫ Positive indirect antiglobulin test: IAT, indirect Coombs test; evidence of maternal antibodies in serum ▫ Transcutaneous bilirubin (TcB), serum bilirubin: increased ▫ CBC: decreased RBCs, reticulocytosis, decreased hemoglobin and hematocrit ▫ Peripheral blood smear analysis: evidence of hemolysis; polychromasia, microspherocytosis (seen in ABO incompatibility)

430 OSMOSIS.ORG

TREATMENT MEDICATIONS

▪ Hematopoietic agents (epoetin alfa/ darbepoetin), iron supplements ▫ Anemia

OTHER INTERVENTIONS

▪ RBC transfusion ▫ Anemia, hydrops fetalis ▪ Exchange transfusion ▫ Hyperbilirubinemia, hydrops fetalis ▪ Phototherapy ▫ Hyperbilirubinemia ▪ Intravenous immunoglobulin (IVIG) ▫ Hyperbilirubinemia ▫ Reduces hemolysis, bilirubin production ▪ Pericardiocentesis, paracentesis, thoracentesis ▫ Hydrops fetalis; as indicated for pericardial effusion, pleural effusion, ascites ▪ Intrauterine RBCl transfusion ▫ Hydrops fetalis if diagnosed antenatally

Chapter 54 Normocytic Anemia (Increased Hemolysis)

HEREDITARY SPHEROCYTOSIS osms.it/hereditary-spherocytosis PATHOLOGY & CAUSES ▪ Inherited RBC membrane defect causing destabilization of cellular membrane, resulting in chronic, premature extravascular hemolysis ▪ Autosomal dominant (75%) or autosomal recessive (25%) ▪ Mutations of genes encoding for proteins that secure RBC membrane skeleton to plasma membrane → membrane destabilization → rigidity, resistance to deformability → hemolysis

TYPES Mild (20–30%) ▪ Mild anemia, splenomegaly, jaundice; modest reticulocytosis; normal hemoglobin ▪ Adolescents/adults most commonly diagnosed Moderate (60–70%) ▪ Moderate anemia, reticulocytosis, hyperbilirubinemia ▪ Require occasional transfusions ▪ Infants/children most commonly diagnosed Severe (5%) ▪ Marked anemia, hyperbilirubinemia, splenomegaly ▪ Regular transfusions needed

RISK FACTORS

▪ Most common in people of Northern European descent

COMPLICATIONS

▪ Transient aplastic crisis caused by infections (e.g. parvovirus B19) ▪ Megaloblastic anemia related to folate deficiency ▪ Neonatal icterus; non-immune hydrops fetalis with fetal death if disease = severe

SIGNS & SYMPTOMS ▪ Jaundice ▪ Anemic signs and symptoms (e.g. pallor, fatigue, activity intolerance) ▪ Splenomegaly

DIAGNOSIS LAB RESULTS

▪ Decreased hemoglobin ▪ Reticulocytosis ▪ Spherocytosis ▫ Morphology = sphere-shaped (normal = biconcave) ▪ Presence of schistocytes (RBC fragments) ▪ Slightly decreased to normal MCV ▫ Spherocytes: decreased MCV ▫ Reticulocytes: increased MCV ▪ Elevated mean cell hemoglobin concentration (MCHC) ▫ Secondary to dehydration, loss of cellular membrane ▪ Elevated red cell distribution width (RDW) ▪ Evidence of hemolysis ▫ Elevated indirect bilirubin ▫ Elevated lactate dehydrogenase (LDH) ▫ Decreased haptoglobin ▪ Osmotic fragility test, acidified glycerol lysis test (AGLT) ▫ Identifies spherocytes which lyse in hypotonic solutions at higher rate than normal RBCs ▪ Cryohemolysis test ▫ Uses hypertonic solution, temperature manipulation to identify spherocytes which lyse at higher rate than normal RBCs ▪ Eosin-5-maleimide (EMA) binding test ▫ Flow cytometric test to observe cell membrane protein interaction with eosin-5-maleimide dye

OSMOSIS.ORG 431

▪ Osmotic gradient ektacytometry ▫ Measures surface area to volume, cell hydration, membrane deformability

TREATMENT SURGERY

▪ Splenectomy

OTHER INTERVENTIONS

▪ Blood transfusions ▪ Phototherapy, exchange transfusions ▫ Neonatal hyperbilirubinemia ▪ Folic acid supplements ▫ Support hematopoiesis

Figure 54.2 A peripheral blood smear demonstrating sphere shaped erythrocytes in an individual with hereditary spherocytosis. The erythrocytes have lost their biconcave shape.

PAROXYSMAL NOCTURNAL HEMOGLOBINURIA (PNH) osms.it/paroxysmal-nocturnal-hemoglobinuria PATHOLOGY & CAUSES ▪ Inherited, X-linked hematologic stem cell disorder resulting in nocturnal hemolysis, hemolytic anemia, bone marrow failure, thrombosis

CAUSES

▪ Mutation of PIGA gene in hematopoietic stem cells ▫ PIGA required for synthesis of glycosylphosphatidylinositol (GPI) protein on cell surface ▫ GPI anchors glycoproteins on erythrocyte surface, protecting cell from lysis by attenuating activity of complement ▪ GPI protein absence or deficiency → ↑

432 OSMOSIS.ORG

susceptibility to complement activity → complement-mediated intravascular hemolysis ▪ Three phenotypes of RBCs categorized according to amount of GPI-anchored proteins on cell surface ▫ Type I: normal ▫ Type II: decreased ▫ Type III: absent

RISK FACTORS

▪ Hemolysis in PNH cases increases in setting of increased complement activation ▫ Infections ▫ Surgery ▫ Blood transfusions ▫ Strenuous exercise ▫ Excessive alcohol use

Chapter 54 Normocytic Anemia (Increased Hemolysis)

COMPLICATIONS

▪ Intravascular, extravascular hemolysis → anemia ▪ Consequences of hemoglobin-mediated nitric oxide scavenging ▫ Intravascular hemolysis → free hemoglobin → ↑ consumption of nitric oxide → smooth muscle dystonia, vasospasm (abdominal pain, esophageal spasm, erectile dysfunction) ▪ Venous, arterial thrombosis ▫ Multifactorial etiology related to proinflammatory complement activity, decreased availability of nitric oxide with resulting vasoconstriction, endothelial cell activation, associated platelet aggregation/clot formation ▫ Hepatic vein thrombosis (Budd–Chiari syndrome) → hepatomegaly, jaundice, ascites, gastric and/or esophageal varices ▫ Intestinal vein thrombosis → ischemic colitis ▫ Cerebral vein thrombosis → headache, neurologic effects ▪ Microvascular hemolysis + iron deposits in renal tubules → chronic kidney disease ▪ Bone-marrow failure, aplastic anemia related to hematopoietic stem cell injury ▪ Eculizumab treatments associated with Increased risk of life-threatening neisserial infections

SIGNS & SYMPTOMS ▪ Variable according to degree of GPIanchored protein loss → hemolysis ▪ Intermittent episodes (paroxysms) of hemoglobinuria ▫ Dark urine ▫ Hemolysis during night ▪ Clinical manifestations of anemia; e.g. pallor, fatigue, exertional dyspnea

DIAGNOSIS LAB RESULTS

▪ Range from normal to abnormal according to degree of GPI-anchored protein loss, resulting hemolysis ▪ RBCs normal morphologically (pancytopenia may be evident in setting of bone marrow failure) ▪ Occasional poikilocytosis, anisocytosis ▪ Normochromic ▪ Normal to extremely decreased serum hemoglobin ▪ Reticulocyte count ranges from normal to decreased ▪ Evidence of hemolysis ▫ Elevated bilirubin ▫ Decreased haptoglobin ▫ Elevated LDH ▪ Direct antiglobulin (DAT/Coombs) positive ▪ Hemoglobinuria, hemosiderinuria

OTHER INTERVENTIONS

▪ Bone marrow examination may indicate hypocellularity ▪ Flow cytometry

TREATMENT MEDICATIONS

▪ Eculizumab ▫ Monoclonal antibody, reduces complement-mediated hemolysis ▫ Vaccinate against Neisseria meningitidis ▪ Iron, folic acid supplements support erythropoiesis ▪ Therapeutic anticoagulation and/or thrombolysis, as indicated for thrombosis ▪ Immunosuppressive therapy if aplastic anemia present

SURGERY

▪ Allogeneic hematopoietic stem cell transplant

OTHER INTERVENTIONS

▪ Red blood cell transfusions as needed

OSMOSIS.ORG 433

PIRUVATE KINASE DEFICIENCY osms.it/piruvate-kinase-deficiency PATHOLOGY & CAUSES ▪ Hematological enzymopathy caused by deficient pyruvate kinase, resulting in chronic, premature hemolysis of RBCs, hyperactive erythropoiesis ▪ Inherited, autosomal recessive mutation of (PK-LR) pyruvate kinase-LR (liver-red cell) gene ▫ Homozygous for single PK-LR mutation/ heterozygous for two mutations ▪ Hemolysis primarily extravascular (within spleen); intravascular hemolysis variable ▪ Pyruvate kinase ▫ Tetramer enzyme, catalyzes transphosphorylation of phosphoenolpyruvate into pyruvate, ATP during glycolysis ▫ Pyruvate kinase deficiency-related block in glycolysis → accumulation of 2,3-bisphosphoglycerate (2,3-BPG) → shifts oxyhemoglobin dissociation curve to right → improved oxygen delivery to tissues → better tolerance of hemolytic anemia

CAUSES

▪ Hemolytic mechanism is unclear; possibly ▫ ATP deficiency ▫ Apoptosis of erythroid progenitors in spleen (ineffective erythropoiesis)

RISK FACTORS

▪ Most common in white people of Northern European descent, Asian people of Chinese descent, genetically-isolated communities of Swiss/German descent

COMPLICATIONS

▪ Pigmented gallstone formation ▪ Iron overload-associated organ damage ▪ Megaloblastic anemia related to folate deficiency

434 OSMOSIS.ORG

▪ Accelerated hemolysis during pregnancy/ with oral contraceptive use ▪ Neonatal icterus/non-immune hydrops fetalis ▪ Transient aplastic crisis induced by infections (e.g. parvovirus B19)

SIGNS & SYMPTOMS ▪ Variable presentation ranging from compensated disease to transfusiondependent anemia ▪ Anemic signs and symptoms ▫ Pallor, shortness of breath, activity intolerance ▪ Jaundice, splenomegaly

DIAGNOSIS LAB RESULTS

Decreased RBC count, reticulocytosis Increased serum glycolytic 2,3-BPG Hemoglobinuria, hemosiderinuria Evidence of hemolytic anemia with one or both of ▫ Low levels of erythrocytic PK enzymatic activity ▫ PK-LR gene mutation ▪ Evidence of hemolysis ▫ Elevated indirect bilirubin ▫ Elevated lactate dehydrogenase (LDH) ▫ Decreased haptoglobin

▪ ▪ ▪ ▪

OTHER DIAGNOSTICS

▪ Clinical evidence of hemolysis ▫ Jaundice, pigmented (bilirubin) gallstones

Chapter 54 Normocytic Anemia (Increased Hemolysis)

TREATMENT SURGERY

▪ Splenectomy ▫ Reduces hemolysis ▪ Allogeneic hematopoietic cell transplantation ▫ May be curative

OTHER INTERVENTIONS

▪ RBC transfusions ▫ Often chronic ▪ Chelation therapy ▫ Reduces iron-related organ damage ▪ Folic acid supplementation ▫ Supports erythropoiesis ▪ Phototherapy, exchange transfusion ▫ Treats neonatal jaundice

SICKLE-CELL ANEMIA osms.it/sickle-cell-anemia PATHOLOGY & CAUSES ▪ Hemolytic anemia caused by sickle-cell disease (SCD) ▪ A group of inherited hemoglobinopathies caused by point mutation of beta globin gene → produces hemoglobin S (HbS) ▪ RBCs containing HbS tend to polymerize, deform into sickle/crescent-shaped forms when deoxygenated ▫ Triggers for deoxygenation: cold, dehydration, insomnia, alcohol consumption, stressful situations, overexertion, hormonal changes ▫ Deoxygenation may be idiopathic ▪ Sickled cells less deformable than normal RBCs ▫ Decreased lifespan due to hemolysis

TYPES HbSS ▪ Sickle-cell disease ▫ Homozygous for HbS ▫ Chronic hemolytic anemia HbSC ▪ Milder form of sickle-cell disease ▫ Heterozygous for HbS + abnormal hemoglobin C

HbSA ▪ Sickle-cell trait/benign carrier state ▫ Heterozygous for HbS + hemoglobin A (normal hemoglobin) HbS beta thalassemia ▪ Heterozygous for HbS + one beta thalassemia gene HbSD, HbSE, HbSO ▪ Rare ▪ Heterozygous for HbS + one other abnormal hemoglobin (D, E, or O)

COMPLICATIONS

▪ Affect all body systems ▪ Hematologic ▫ Anemia related to aplastic crisis involving temporary arrest of erythropoiesis ▪ Pain ▫ Vaso-occlusion, tissue ischemia, infarction; dactylitis (acute pain in small bones of hands/feet especially in children) ▪ Increased risk of infection ▫ Related to hyposplenism/asplenism, decreased tissue perfusion ▪ Central nervous system ▫ Ischemic/hemorrhagic stroke; transient ischemic attack, seizures

OSMOSIS.ORG 435

▪ Cardiovascular ▫ Myocardial infarction, dysrhythmias, cardiomyopathy, heart failure, venous thromboembolism, leg ulcers, sudden death ▪ Respiratory ▫ Acute chest syndrome (fever, chest pain, hypoxemia, wheezing, cough, respiratory distress), pulmonary hypertension, disordered breathing during sleep with nocturnal hypoxemia ▪ Genitourinary, reproductive ▫ Priapism, erectile dysfunction; pregnancy complications, fetal/neonatal or maternal (e.g. intrauterine growth restriction, fetal death, low birthweight; preeclampsia, thromboembolic events) ▪ Endocrine ▫ Delayed growth, development ▪ Skeletal ▫ Osteoporosis, bone infarction ▪ Sensory ▫ Proliferative retinopathy, retinal detachment ▪ Systemic ▫ Multiorgan failure related to ischemia and/or infarction

SIGNS & SYMPTOMS ▪ Mild to moderate anemia (e.g. fatigue, activity intolerance, extertional dyspnea) ▪ Hypersplenism ▪ Pain from acute vaso-occlusive crisis

DIAGNOSIS ▪ Findings variable depending on inheritance pattern, degree of hemolysis ▪ Pain indicates cell sickling, vaso-occlusion

LAB RESULTS

▪ Vaso-occlusion, hemolysis, splenic sequestration → decreased hemoglobin, hematocrit, RBC count ▪ Reticulocytosis ▪ Increased white blood cell (WBC) count ▪ Peripheral blood smear analysis

436 OSMOSIS.ORG

▪ Mostly normochromic, normocytic cells; polychromasia may be present secondary to reticulocytosis ▪ Sickled cells present in SCD but not sicklecell trait ▪ Canoe-shaped (partially sickled) RBCs ▪ Howell Jolly bodies ▫ Related to hyposplenia ▪ Normal-to-increased mean corpuscular volume (MCV) ▪ Target cells ▪ Diagnostic tests to determine organ damage (e.g. urinalysis → hematuria, albuminuria from renal papillary damage) ▪ Evidence of hemolysis ▫ Elevated unconjugated bilirubin ▫ Elevated lactate dehydrogenase (LDH) ▫ Low haptoglobin ▪ Positive solubility test (Sickledex) ▪ Hemoglobin electrophoresis provides definitive diagnosis (90–95% HbS)

TREATMENT ▪ Prevent/reduce occurrence of crises (e.g. immunizations to prevent infection, manage stress, prevent deoxygenation)

MEDICATIONS

▪ Hydroxyurea ▫ Increases cell deformability, decreases RBC endothelial adhesion, increases hemoglobin F levels; reduces sickling ▪ L-glutamine ▫ Reduces sickling ▪ Pain management ▫ Analgesics, adjunctive, nonpharmacological therapies

SURGERY

▪ Hematopoietic cell transplantation

OTHER INTERVENTIONS ▪ Blood transfusions ▪ Folic acid supplements ▪ Manage iron deficiency

Chapter 54 Normocytic Anemia (Increased Hemolysis)

Figure 54.3 A recoloured scanning electron micrograph demonstrating a sickled erythrocyte.

Figure 54.4 An abdominal CT scan in the axial plane demonstrating autosplenectomy in an individual with sickle cell disease. The splenic remnant is densely calcified.

Figure 54.5 A peripheral blood smear containing sickled erythrocytes in an individual with sickle cell disease.

OSMOSIS.ORG 437

NOTES

NOTES

PLASMA CELL DYSCRASIAS GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Acquired/inherited disorders ▫ Impaired platelet function, decreased platelet count, sequelae ▪ Accelerated destruction/consumption → decreased platelets

SIGNS & SYMPTOMS ▪ Mucocutaneous bleeding (e.g. epistaxis, gingival bleeding, petechiae, purpura)

DIAGNOSIS LAB RESULTS

▪ Complete blood count (CBC) ▪ Peripheral blood smear analysis ▪ Platelet function tests

TREATMENT OTHER INTERVENTIONS

▪ Mitigate complications of deranged platelet function

MONOCLONAL GAMMOPATHY OF UNDETERMINED SIGNIFICANCE (MGUS) osms.it/monoclonal-gammopathy PATHOLOGY & CAUSES ▪ Asymptomatic premalignant plasma cell proliferative disorder; M protein < 3g/dL ▪ Most common plasma cell dyscrasia ▪ M protein ▫ IgM, IgA, IgG of free light chains ▪ 25% progress to multiple myeloma, early stage

TYPES

▪ Non-IgM MGUS (IgG, IgA, IgD MGUS) ▪ IgM MGUS

438 OSMOSIS.ORG

CAUSES Genetic mutations ▪ t(14,11) ▫ Translocation between Ig heavy chain gene on chromosome 14, oncogene (cyclin D1) on chromosome 11 ▪ t(14,6) ▫ Translocation between Ig heavy chain gene on chromosome 14, oncogene cyclin D3 on chromosome 6 ▪ Deletion of gene TP53 tumor suppressor locus on chromosome 17

Chapter 55 Plasma Cell Dyscrasias

RISK FACTORS

▪ More commons in individuals who are biologically male; increased incidence with age ▪ Agent Orange exposure

COMPLICATIONS

▪ Multiple myeloma (IgA, IgG MGUS), Waldenström macroglobulinemia, AL amyloidosis, light chain deposition disease (IgM MGUS) ▪ Venous thromboembolism (VTE), fractures, infections

SIGNS & SYMPTOMS

DIAGNOSIS LAB RESULTS

▪ Monoclonal proteins < 3mg/dL ▪ Plasma cells CD38+, CD56+, CD19-

Bone marrow biopsy ▪ Mild hypercellularity ▫ Plasma cells < 10%

TREATMENT OTHER INTERVENTIONS

▪ No treatment ▪ Regular observation; assess progression

▪ Mostly asymptomatic ▪ Rash, paresthesias, hypoesthesia

MULTIPLE MYELOMA osms.it/multiple-myeloma PATHOLOGY & CAUSES ▪ Neoplasm of plasma cells (myeloma cells) in bone marrow ▫ Overproduction of M protein ▪ M protein ▫ IgG, IgA, free light chains ▪ Bone marrow cells, myeloma cells secrete cytokines, interleukin 6 (IL6), NF-κB → promote proliferation, survival of myeloma cells

MNEMONIC: CRAB

Features of Multiple myeloma Calcium elevated Renal disease Anemia Bone lesions

Calcium (elevated) ▪ Increased bone resorption → hypercalcemia Renal disease ▪ Monoclonal free light chains (к, λ) ▫ Low molecular mass, filter easily in renal glomeruli → Bence Jones proteins in urine, toxic to proximal tubules → proximal tubular necrosis ▫ Bence Jones, Tamm-Horsfall proteins, albumin form obstructive proteinaceous casts in distal convoluted tubules, collecting ducts ▫ Hypercalcemia, hypercalciuria → nephrocalcinosis Anemia ▪ Neutropenia, thrombocytopenia ▪ Bone marrow infiltration by myeloma cells, cytokines → inhibits hematopoiesis Bone lesions (osteolytic) ▪ Neoplastic cells secrete cytokines (IL1β, TNFɑ) → activate osteoclasts → increase bone resorption → hypercalcemia,

OSMOSIS.ORG 439

pathologic fractures ▪ Axial skeleton (skull, spinal vertebrae, ribs, pelvic bones), long bones ▪ Pathologic fractures along vertebrae → spinal cord compression

SIGNS & SYMPTOMS

Symptomatic multiple myeloma

▪ Hypercalcemia ▫ Confusion, somnolence, constipation, nausea, thirst ▪ Anemia, neutropenia, thrombocytopenia ▫ Fatigue, pallor, fever, infections, bleeding ▪ Bone lesions ▫ Pain, pathologic fractures; spinal cord compression → neuropathies (hypoesthesia, paresthesia)

Non-secretory multiple myeloma ▪ Less common (3%)

DIAGNOSIS

TYPES Smoldering multiple myeloma (SMM) ▪ Asymptomatic

CAUSES

DIAGNOSTIC IMAGING

Genetic mutations ▪ t(14,11) ▫ Translocation between Ig heavy chain gene on chromosome 14, oncogene (cyclin D1) on chromosome 11 ▪ t(14,6) ▫ Translocation between Ig heavy chain gene on chromosome 14, oncogene cyclin D3 on chromosome 6 ▪ Deletion of gene TP53 tumor suppressor locus on chromosome 17

X-ray (skeletal survey) ▪ Multiple rounded lytic bone lesions in skull, long bones, spine

RISK FACTORS

▪ Alcohol consumption, obesity, radiation exposure, family history

COMPLICATIONS

▪ Free light chains deposit in kidneys, heart, other organs → immunoglobulin light chain amyloidosis (AL amyloidosis) ▪ Renal failure ▪ Infection → death ▫ Most common, urinary tract infections (UTIs); pneumonia ▪ Hyperviscosity syndrome

440 OSMOSIS.ORG

CT scan ▪ Radiodense bone lesions; in advanced disease, lesions in spleen, lymph nodes, lungs, etc. MRI ▪ Radiodense lesions in thoracic, lumbar vertebrae Fluorescent in situ hybridization (FISH) ▪ Detection of chromosomal mutations (translocations, deletions)

LAB RESULTS

▪ Cormocytic, normochromic anemia, thrombocytopenia, leukopenia ▪ Increased monoclonal proteins (free light chains, ↑IgG > 3mg/dL, ↑IgA) ▪ Monoclonal protein measurement with densitometer ▪ Calcium blood test ▫ > 2.7mmol/L ▪ Bence Jones proteins (> 6mg/dL) ▪ Quantification of Bence Jones proteins ▪ Proteinuria greater than 1g/24hr ▪ Myeloma cells CD36+, CD56+, CD138+, CD319+

Chapter 55 Plasma Cell Dyscrasias Bone marrow biopsy ▪ Neoplastic infiltration → hypercellularity (> 30% plasma cells) ▪ Cytology ▫ Plasma cells: 2–3 times larger, eccentric nuclei, perinuclear halo (prominent Golgi apparatus) ▫ Other variants: mott cells (multiple grapelike cytoplasmic inclusions), flame cells (fiery red cytoplasm)

TREATMENT ▪ Treatable, incurable ▫ If untreated, survival 5–12 months; with treatment, 48% survival for five years

Figure 55.1 An X-ray image of the skull displaying numerous lytic lesions caused by myelomatous deposits. This radiological presentation is commonly known as a pepper pot skull.

MEDICATIONS

▪ Chemotherapy ▫ Bortezomib, lenalidomide– dexamethasone, melphalan ▪ Immunomodulators ▫ Thalidomide, lenalidomide ▪ Bisphosphonates: prevent bone loss ▪ Antibiotics: infections ▪ Glucocorticoids: hypercalcemia

OTHER INTERVENTIONS

▪ Autologous hematopoietic stem-cell transplantation (ASCT) ▪ Allogeneic stem cell transplantation with chemotherapy, glucocorticoids

Figure 55.2 A histological section of the kidney from an individual with multiple myeloma. The myeloma cast colors a light pink on PAS stain.

Figure 55.3 An X-ray image of the forearm demonstrating multiple lytic lesions in an individual with multiple myeloma. Figure 55.4 The histological appearance of a plasmacytoma, an aggregate of malignant plasma cells found in the soft tissues or axial skeleton.

OSMOSIS.ORG 441

WALDENSTRÖM MACROGLOBULINEMIA osms.it/waldenstrom-macroglobulinemia PATHOLOGY & CAUSES ▪ Neoplasm of plasma cells, lymphoplasmacytoid cells; high levels of M protein as IgM antibodies ▪ AKA lymphoplasmacytic lymphoma ▪ Preceded by MGUS ▪ Neoplastic plasma, lymphoplasmacytoid cells infiltrate, crowd out normal hematopoietic cells → anemia ▪ High levels of IgM antibodies aggregate ▫ Hyperviscosity syndrome ▫ Cryoglobulinemia: IgM proteins become insoluble at reduced temperatures

CAUSES

▪ Somatic mutations of MYD88, CXCR4 genes

RISK FACTORS

▪ Autoimmune diseases mediated by antibodies ▪ HIV, hepatitis, rickettsiosis ▪ Pesticides exposure

COMPLICATIONS

▪ Autoimmune hemolysis, raynaud phenomenon secondary to cryoglobulinemia ▪ Amyloidosis of heart, kidney, liver, lungs, joints

SIGNS & SYMPTOMS ▪ Infiltration of neoplastic plasma cells ▫ Splenomegaly, hepatomegaly, lymphadenopathy ▪ Anemia ▫ Weakness, fatigue, weight loss

442 OSMOSIS.ORG

Hyperviscosity syndrome triad ▪ Retinopathy ▫ Stasis + venous congestion, distention, hemorrhage of retinal veins → vision loss ▪ Neurologic symptoms ▫ Venous congestion of cerebral veins → hypoperfusion → headache, vertigo, hearing loss, parestesias, ataxia, stupor ▪ Mucosal bleeding ▫ IgM antibodies interfere with coagulation → gum bleeding, epistaxis, rectal bleeding, menorrhagia

DIAGNOSIS DIAGNOSTIC IMAGING CT scan ▪ Hepatomegaly, splenomegaly

LAB RESULTS

▪ Normocytic, normochromic anemia ▪ IgM ≥ 3000mg/dL

TREATMENT ▪ If asymptomatic, observation

MEDICATIONS

▪ Chemotherapy ▪ Plasmapheresis for hyperviscosity syndrome

OTHER INTERVENTIONS

▪ Rarely autologous stem cell transplantation

Chapter 55 Plasma Cell Dyscrasias

Figure 55.5 A peripheral blood film demonstrating rouleaux formation. Rouleaux may be seen in many infections, autoimmune conditions and plasma cell diseases, including Waldenstrom macroglobulinemia.

OSMOSIS.ORG 443

NOTES

NOTES

PLATELET DISORDERS GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Platelet dysfunction, impaired hemostasis, bleeding

RISK FACTORS

DIAGNOSIS LAB RESULTS

▪ Complete blood count (CBC) ▪ Clotting studies (e.g. bleeding time) ▪ Platelet function tests

▪ Children of parents who are close relatives (consanguineous)

COMPLICATIONS

▪ Mild to severe hemorrhage

SIGNS & SYMPTOMS ▪ Mucocutaneous bleeding ▪ Excessive bruising/bleeding after minor trauma ▪ Immediate, excessive bleeding with invasive procedures

TREATMENT ▪ Manage spontaneous/trauma-related bleeding episodes

MEDICATIONS ▪ ▪ ▪ ▪

Anti-fibrinolytic therapy Platelet transfusions Avoid antiplatelet medications Corticosteroids, immunosuppressants

BERNARD–SOULIER SYNDROME (BSS) osms.it/bernard-soulier-syndrome PATHOLOGY & CAUSES ▪ Rare, inherited clotting disorder; mild thrombocytopenia, macrothrombocytopenia (giant platelets), platelet dysfunction, bleeding

CAUSES

▪ Autosomal recessive inheritance pattern

444 OSMOSIS.ORG

▪ Platelets lack essential glycoprotein Ib-IX-V complex (GPIb) → impaired hemostasis → bleeding

RISK FACTORS

▪ Prevalence in individuals of Mediterranean descent ▪ Children of parents who are close relatives (consanguineous)

Chapter 56 Platelet Disorders

SIGNS & SYMPTOMS ▪ Mucocutaneous bleeding ▫ Epistaxis; gingival bleeding; petechiae, purpura (coalesced petechiae); GI bleeding; genitourinary bleeding (e.g. hematuria); menorrhagia ▪ Excessive bruising/bleeding after minor trauma; bruises linger ▪ Immediate, excessive bleeding with invasive procedures ▪ Asymptomatic until adulthood

DIAGNOSIS LAB RESULTS

▪ CBC ▫ Low platelet count ▪ Peripheral blood smear analysis ▫ Giant platelets (accelerated platelet turnover)

▪ Clotting studies ▫ Bleeding time prolonged (PT, aPTT normal) ▪ Flow cytometry ▫ Deficient/absent GPIb-IX-V complex

OTHER DIAGNOSTICS ▪ Physical examination ▫ Purpura ▫ Ecchymoses

TREATMENT MEDICATIONS

▪ Avoid antiplatelet medications ▪ Anti-fibrinolytic therapy (e.g. tranexamic acid)

OTHER INTERVENTIONS

▪ Platelet transfusions (e.g. prophylaxis before invasive procedures) ▫ HLA matching/leukocyte reduced platelets reduces risk of allo-antibody formation

GLANZMANN'S THROMBASTHENIA (GT) osms.it/glanzmanns-thrombasthenia PATHOLOGY & CAUSES ▪ Inherited bleeding disorder, defect in platelet surface receptor αIIbβ3 ▪ Platelet-mediated hemostasis ▫ Binding of platelets to exposed components of injured endothelium through glycoprotein (GP) receptors on platelet surface (e.g. GPIb/IX, GPIa/IIa, integrin αIIbβ3) ▪ Integrin αIIbβ3 defect → impaired platelet clot retraction, altered hemostasis

CAUSES

▪ Autosomal recessive inheritance pattern ▪ Rarely, allo-/auto-antibodies to platelet αIIbβ3 produced by autoimmune conditions (e.g. systemic lupus erythematosus, immune thrombocytopenia, myelodysplastic syndrome) during pregnancy/with use of platelet integrin αIIbβ3 antagonists (abciximab, eptifibatide)

RISK FACTORS

▪ Slightly more common in individuals who are biologically female ▪ Children of parents who are close relatives

OSMOSIS.ORG 445

▪ Conditions requiring frequent platelet transfusion ▫ Platelet alloimmunization

COMPLICATIONS

▪ Fatal bleeding ▫ Risk increases during childbirth (maternofetal bleeding, primary/ secondary postpartum hemorrhage)

SIGNS & SYMPTOMS ▪ Mucocutaneous bleeding ▫ Epistaxis; gingival bleeding; petechiae, purpura (coalesced petechiae); gastrointestinal (GI) bleeding; genitourinary bleeding (e.g. hematuria); menorrhagia ▪ Excessive bruising/bleeding after minor trauma ▪ Immediate, excessive bleeding with invasive procedures ▪ Infants ▫ Leukocytosis, delayed separation of umbilical cord, purpura, spontaneous bruising, mucocutaneous bleeding

DIAGNOSIS LAB RESULTS

▪ CBC ▫ Platelet count normal ▪ Clotting studies ▫ Bleeding time prolonged (PT, aPTT normal) ▪ Light transmission aggregometry (LTA) ▫ Determines degree of platelet aggregation ▫ Decreased or absent in GT ▪ Platelet function analyzer (PFA) ▫ Measures flow rate as platelets form platelet plug within capillary tube ▫ Formation of platelet plug prolonged in GT

446 OSMOSIS.ORG

▪ Flow cytometry ▫ Deficient/absent αIIbβ3 platelet receptors ▫ Mutation analysis through genomic DNA sequencing

OTHER DIAGNOSTICS ▪ Physical examination ▫ Purpura ▫ Ecchymoses

TREATMENT ▪ Avoid antiplatelet medications, punctures, invasive procedures

MEDICATIONS

▪ Individuals who are biologically female, of childbearing age ▫ Metrorrhagia: oral contraceptives (suppress menstrual periods); iron supplementation; hysterectomy (if bleeding severe) ▫ Childbirth: prophylaxis with recombinant factor VIIa + antifibrinolytic agent ▪ Rituximab, corticosteroids, immunosuppressants (e.g. cyclophosphamide)

OTHER INTERVENTIONS

▪ Manage bleeding episodes ▫ Compression, fibrin sealants, gelatin sponges, nasal packing, topical thrombin, anti-fibrinolytic therapy (e.g. tranexamic acid), recombinant factor VIIa ▪ Platelet transfusions (e.g. prophylaxis before invasive procedures) ▫ HLA matching/administration of leukocyte reduced platelets reduces allo-antibody formation ▪ Oral hygiene mitigates gingival bleeding ▪ Hematopoietic cell transplantation (if bleeding severe, recurrent)

NOTES

NOTES

PORPHYRIA GENERALLY, WHAT IS IT? PATHOLOGY & CAUSES ▪ Metabolic diseases; accumulation of heme precursors ▫ Porphyrin; neurologic/cutaneous disorders ▪ Mostly hereditary ▫ Porphyria cutanea tarda (most common) ▫ Acute intermittent porphyria ▫ Aminolevulinic acid dehydratase deficiency porphyria (AKA Doss porphyria) ▫ Hereditary coproporphyria ▫ Variegate porphyria ▫ Congenital erythropoietic porphyria

CAUSES

▪ Sporadic/inherited enzyme mutations in heme production → porphyrin accumulates in tissues

RISK FACTORS

▪ Smoke, alcohol, hormonal changes, fasting, stress, certain drugs, sunlight exposure, lead poisoning

COMPLICATIONS ▪ Paralysis, seizures

Chronic ▪ E.g. porphyria cutanea tarda, erythropoietic porphyria ▪ Skin manifestations ▪ Photosensitivity ▫ Pain, discomfort, burning of sunlightexposed areas ▪ Vesiculo-erosive manifestations (e.g. erosions, blistering) ▪ Increased skin fragility

DIAGNOSIS LAB RESULTS

▪ Blood, urine tests ▫ Increased levels of porphobilinogen in urine ▪ Genetic testing

TREATMENT MEDICATIONS

▪ Acute intermittent porphyria (AIP) ▫ Hospitalization during acute attack, intravenous hemin, etc. ▪ Porphyria cutanea tarda (PCT) ▫ Phlebotomy, chloroquine/ hydroxychloroquine sulfate, etc.

SIGNS & SYMPTOMS Acute ▪ Resolve once attack passes (e.g. acute intermittent porphyria, doss porphyria) ▪ Abdominal pain, vomiting, hypertension, tachycardia, neurological/psychiatric symptoms (e.g. seizures, neuropathy, anxiety, confusion, hallucinations), red urine

OSMOSIS.ORG 447

ACUTE INTERMITTENT PORPHYRIA (AIP) osms.it/acute-intermittent-porphyria PATHOLOGY & CAUSES ▪ Neurovisceral disease ▫ Acute, recurrent attacks of abdominal pain + other clinical manifestations (neuropsychiatric, gastrointestinal, urinary)

CAUSES

▪ Autosomal dominant mutation of hydroxymethylbilane synthase (HBMS) gene → alterated codification of enzyme hydroxymethylbilane synthase (AKA porphobilinogen deaminase/ uroporphyrinogen I synthase) → impaired heme production → accumulation of metabolites: porphobilinogen (PBG), aminolevulinic acid (ALA)

RISK FACTORS

▪ Drugs (e.g. barbiturates, antiepileptics, rifampin) ▪ Alcohol ▪ Exposure to tobacco smoke ▪ Hormonal fluctuations (e.g. menstruation) ▪ Dietary changes (e.g. reduced caloric intake) ▪ Stress (e.g. illness, psychological stress)

COMPLICATIONS

▪ Hypertension, kidney failure, neuromuscular respiratory failure, hepatocellular carcinoma

448 OSMOSIS.ORG

SIGNS & SYMPTOMS ▪ Acute episodes lasting several hours to few days ▫ Severe, diffuse abdominal pain ▫ Palpitations, sweating ▫ GI: nausea, vomiting, constipation ▫ Neurological: seizure, peripheral neuropathy (e.g. tingling sensations in limbs), muscle weakness ▫ Psychiatric: irritability, anxiety, hallucinations ▫ Urinary: dysuria, urinary retention, discolored (reddish, red-brown) urine

MNEMONIC: 5Ps

Features of Acute intermittent porphyria Pain in the abdomen Polyneuropathy Psychological abnormalities Pink urine Precipitated by drugs: including barbiturates, oral contraceptives, sulfa drugs

DIAGNOSIS LAB RESULTS

▪ Elevation of heme precursor in urine (PBG) ▪ Genetic testing

Chapter 57 Porphyria

TREATMENT MEDICATIONS

▪ Intravenous hemin ▪ Symptomatic treatment (e.g. antiemetics, pain medications)

Figure 57.1 The urine of an individual with porphyria (right).

PORPHYRIA CUTANEA TARDA (PCT) osms.it/porphyria-cutanea-tarda PATHOLOGY & CAUSES ▪ Blistering cutaneous lesions of sunlightexposed skin

TYPES

▪ PCT Type I: acquired disease ▪ PCT Type II: autosomal dominant disease

CAUSES

▪ Impaired function of uroporphyrinogen decarboxylase (UROD) enzyme → porphyrins overproduction, accumulation → photosensitizing porphyrins in skin damage proteins, lipids, basement membrane → cutaneous lesions

RISK FACTORS ▪ ▪ ▪ ▪ ▪

Alcohol Exposure to tobacco smoke Hormonal imbalances Infectious disease (e.g. HIV, hepatitis C) Hemochromatosis, iron overloading

COMPLICATIONS

▪ Cirrhosis, hepatocellular carcinoma

SIGNS & SYMPTOMS ▪ Increased mechanical fragility after sunlight exposure → painful vesicles, blisters on hands/face (minor trauma) ▪ Increased facial hair growth (e.g. hypertrichosis) ▪ Hardened yellow skin lesions (e.g. scleroderma-like plaques) ▪ Hypermelanosis (brownish skin pigmentation) ▪ Abnormal urine color

DIAGNOSIS LAB RESULTS

▪ Elevated porphyrins level (orange-red fluorescence on Wood lamp) ▪ Elevated porphyrins level in stool ▪ UROD activity in blood cells

Skin biopsy of lesions ▪ Subepidermal bullae, inflammation ▪ Immunofluorescence ▫ Immunoglobulins at dermal-epidermal junctions

OSMOSIS.ORG 449

TREATMENT MEDICATIONS

▪ Low doses of chloroquine/ hydroxychloroquine sulfate

OTHER INTERVENTIONS

▪ Avoid sunlight exposure ▪ Discontinue aggravating substances (alcohol, estrogen) ▪ Blood removal (e.g. phlebotomy) ▫ Decrease body iron load ▪ Limit iron-rich food

450 OSMOSIS.ORG

Figure 57.2 Skin lesions on the dorsum of both hands in a case of porphyria cutanea tarda.

NOTES

NOTES

SPLEEN PATHOLOGY GENERALLY, WHAT IS IT? PATHOLOGY & CAUSES ▪ Injuries/medical procedures/illnesses ▫ Impair splenic function/lead to spleen removal

SIGNS & SYMPTOMS ▪ Asplenia → frequent infections ▪ Traumatic rupture → shock, referred pain to left shoulder

DIAGNOSIS

OTHER DIAGNOSTICS Enlarged spleen ▪ Palpable (increased risk of rupture)

TREATMENT MEDICATIONS Asplenia ▪ Immunization/antibiotic prophylaxis

SURGERY

DIAGNOSTIC IMAGING

Splenic rupture ▪ Splenectomy ▫ If hemodynamically unstable

Ultrasound/CT scan ▪ Splenic rupture, asplenia

OTHER INTERVENTIONS

LAB RESULTS

Splenic rupture ▪ Strict bed rest, 1–3 days ▫ Conservative; if hemodynamically stable

▪ Impaired blood filtration

OSMOSIS.ORG 451

ASPLENIA osms.it/asplenia PATHOLOGY & CAUSES ▪ Absence of normal spleen → immunodeficiency ▪ Splenic macrophages loss → inability to clear opsonized bacteria from blood ▪ T-cell independent antibodies deficiency ▪ Increased infection risk, severity from polysaccharide encapsulated bacteria ▫ Haemophilus influenzae type b, Streptococcus pneumoniae, Neisseria meningitidis, Group B streptococcus, Klebsiella pneumoniae, Salmonella typhi

TYPES Acquired asplenia ▪ Splenectomy ▫ Surgical procedure, spleen partially/ completely removed (following trauma, cancer, hemoglobinopathies, massive enlargement) ▪ Auto-splenectomy ▫ Underlying disease → focal venous occlusion → repeated infarction → gradual perivascular fibrosis → loss of function (e.g. sickle-cell disease, pneumococcal septicaemia, systemic lupus erythematosus) Congenital asplenia (rare) ▪ Heterotaxy syndrome (situs ambiguus) → disruption to splenic development during embryogenesis → no spleen/formation of multiple ineffective spleens → functional asplenia ▪ Isolated congenital asplenia → ribosomal mutation → failure of spleen development Functional asplenia ▪ Splenic tissue present, functionally impaired (e.g. sickle-cell disease, isolated congenital asplenia) Hyposplenism

452 OSMOSIS.ORG

▪ Reduced splenic function, less severe

SIGNS & SYMPTOMS ▪ Recurrent infection ▪ Sickle cell disease ▫ Enlarged palpable spleen

DIAGNOSIS DIAGNOSTIC IMAGING

▪ Abdominal ultrasound, CT scan/MRI ▪ Radionuclide scan ▫ Assess for function

LAB RESULTS

▪ Thrombocytosis (elevated platelet count), leukocytosis (elevated white cell count) ▪ Howell–Jolly bodies ▫ Erythrocytes containing basophilic DNA fragments ▪ Target cells ▫ Erythrocytes with increased ratio of surface membrane area to volume

TREATMENT MEDICATIONS Antibiotics ▪ Antibiotic prophylaxis (penicillins) ▪ Early antibiotic prescription at first sign of infection (common/otherwise) Vaccination ▪ Pneumococcal polysaccharide vaccine ▪ Haemophilus influenzae type b vaccine ▪ Meningococcal conjugate vaccine ▪ Influenza vaccine

Chapter 58 Spleen Pathology

Figure 58.1 A peripheral blood smear with erythrocytes containing Howell–Jolly bodies. Howell-Jolly bodies represent a damaged or absent spleen which has failed to filter these red blood cells.

Figure 58.2 A peripheral blood smear containing target cells; erythrocytes that have become derformed and damaged, yet have not been cleared by an absent spleen.

RUPTURED SPLEEN osms.it/ruptured-spleen PATHOLOGY & CAUSES ▪ Splenic rupture → break in splenic structural integrity → large amount of blood leaks into abdomen → shock → death

CAUSES Traumatic ▪ Significant force to spleen → rupture ▪ Blunt trauma to abdomen ▪ Penetrating trauma (e.g. gunshots/ stabwounds) Non-traumatic ▪ Splenomegaly → capsule thins, decreases structural integrity ▪ Infectious diseases ▫ Malaria, infectious mononucleosis ▪ Medical procedures ▫ Colonoscopy ▪ Hematological disease ▫ Non-Hodgkin’s lymphoma, acute lymphoblastic leukemia ▪ Malignancy ▫ Angiosarcoma

▪ Medications ▫ Anticoagulants ▪ Pregnancy ▪ Enlarged spleens more vulnerable to traumatic rupture

SIGNS & SYMPTOMS ▪ Abdominal pain, epigastric tenderness, pain in left flank ▪ Kehr’s sign ▫ Blood in peritoneal cavity → irritation of surrounding tissues → pain referred to tip of left shoulder ▪ Hypovolemic shock ▫ Tachycardia, hypotension, tachypnea, pallor, anxiety

DIAGNOSIS DIAGNOSTIC IMAGING Emergency ultrasound ▪ Free blood in peritoneum

OSMOSIS.ORG 453

CT scan with contrast ▪ Free blood in peritoneum ▪ Spleen → inhomogeneous hypodense regions

OTHER DIAGNOSTICS Procedural ▪ Peritoneal lavage → free blood drawn from peritoneum

Figure 58.3 An abdominal CT scan in the axial plane demonstrating a large perisplenic hematoma. This hematoma has formed as a result of splenic rupture, most likely as a result of trauma.

454 OSMOSIS.ORG

TREATMENT SURGERY Splenectomy ▪ Hemodynamically unstable/emergency/ grade IV, V injury

OTHER INTERVENTIONS Strict bed rest, 1–3 days ▪ Conservative (hemodynamically stable) ▪ Follow-up CT scan in seven days

Figure 58.4 The gross pathology of a spleen ruptured by trauma. The capsule is torn, revealing the dark red splenic parenchyma.

NOTES

NOTES

THROMBOCYTOPENIA GENERALLY, WHAT IS IT? PATHOLOGY & CAUSES ▪ Acquired/inherited disorders: impaired platelet function, decreased platelet count, sequelae ▪ Accelerated destruction/consumption → decreased platelets

SIGNS & SYMPTOMS ▪ Mucocutaneous bleeding (e.g. epistaxis, gingival bleeding, petechiae, purpura)

DIAGNOSIS LAB RESULTS

▪ Complete blood count (CBC) ▪ Peripheral blood smear analysis ▪ Platelet function tests

TREATMENT OTHER INTERVENTIONS

▪ Mitigate complications of deranged platelet function

HEPARIN-INDUCED THROMBOCYTOPENIA (HIT) osms.it/heparin-induced-thrombocytopenia PATHOLOGY & CAUSES ▪ Acquired platelet disorder ▫ Accelerated thrombosis in arteries, veins → consumptive thrombocytopenia. ▫ Occurs in individuals exposed to unfractionated heparin/low molecular weight heparin (LMWH) ▫ AKA heparin-induced thrombocytopenia thrombosis (HITT) ▪ Exposure to heparin/LMWH → IgG autoantibodies formed against heparin → platelet factor 4 (PF4) binds to heparin → antibody-heparin-PF4 complex → increased platelet activation → thrombosis formation in arteries, veins

▪ Increased consumption of platelets for clotting + removal of antibody-heparinPF4 complexes by macrophages of reticuloendothelial system → thrombocytopenia ▫ Thrombocytopenia usually not sufficient to cause significant bleeding ▪ Classified by severity, timing, degree of drop in platelet count drop, antibody mediation

RISK FACTORS

▪ 5% individuals exposed to unfractionated/ LMWH ▫ Unfractionated > LMWH

OSMOSIS.ORG 455

▪ Dose ▫ Prophylactic dose > therapeutic doses > intermittent heparin flushes ▪ More common in individuals who are biologically female

COMPLICATIONS

▪ Venous thromboembolism (VTE) ▪ Occlusion of large lower limb arteries by platelet rich “white clots” → limb ischemia, necrosis, gangrene, loss of limbs ▪ Skin necrosis ▪ Organ infarction ▫ Kidney, myocardial infarction; cerebrovascular insult ▪ Adrenal hemorrhage ▫ Adrenal vein thrombosis ▪ Heparin-induced anaphylactoid reactions

SIGNS & SYMPTOMS ▪ Skin necrosis at injection site ▪ Acute systemic reaction after IV heparin bolus ▫ Fever with chills, tachycardia, hypertension, dyspnea ▪ Limb ischemia, organ infarction

456 OSMOSIS.ORG

DIAGNOSIS LAB RESULTS HIT antibody testing ▪ HIT immunoassay ▫ ELISA for anti-PF4 antibodies ▫ PF4 antibodies in individual’s serum ▫ Colorimetric change: optical density (OD), HIT antibody concentration ▫ Higher OD = higher antibody titer = HIT ▪ Functional assay ▫ Serotonin release assay (SRA) ▫ Serotonin release from platelets, ability of HIT antibodies from individual’s serum to activate test platelets ▫ Release of serotonin + therapeutic heparin concentration ▪ Heparin-induced platelet aggregation (HIPA) assay ▫ Platelet aggregation with no heparin, low/high heparin concentration ▫ Minimal platelet aggregation with no heparin, high heparin concentrations; strong aggregation with low heparin concentrations

OTHER DIAGNOSTICS

▪ History of exposure to unfractionated heparin ▪ New venous/arterial thrombosis

MNEMONIC: 4Ts

Diagnosis of Thrombocytopenia Thrombocytopenia: CBC, fall in platelet count Timing: fall in platelet count, 5–10 days after heparin initiation Thrombosis: venous/arterial thrombosis, sequelae OTher: no other explanations

Chapter 59 Thrombocytopenia

TREATMENT MEDICATIONS

▪ Immediate discontinuation of heparin ▪ Administration of non-heparin anticoagulant (e.g. fondaparinux, argatroban)

▫ Transition to warfarin/other outpatient anticoagulant after stabilization

SURGERY Thromboembolectomy ▪ If severe limb ischemia, high risk for amputation

IDIOPATHIC THROMBOCYTOPENIC PURPURA (ITP) osms.it/idiopathic-thrombocytopenic-purpura PATHOLOGY & CAUSES ▪ Acquired thrombocytopenia; accelerated immune platelet destruction → bleeding ▪ AKA, immune thrombocytopenic purpura, autoimmune thrombocytopenic purpura ▪ B cells produce IgG autoantibodies against platelet glycoproteins (e.g. IIb/IIIa, Ib/ IX complexes) → platelets coated with antibodies recognized as “non-self” by splenic macrophages → platelet destruction ▫ Contributing factors: impaired platelet production, cell-mediated platelet destruction

malignancy, chronic lymphocytic leukemia ▫ Alter immune homeostasis ▫ Alterations in T cell-mediated cytotoxicity/suppression of megakaryocyte production, maturation Drug-induced immune thrombocytopenia (DITP) ▪ Triggered by drug-dependent platelet antibodies ▪ Quinidine, phenytoin, valproic acid, rifampin, trimethoprim-sulfamethoxazole, sulfonamides ▪ Reaction due to drug/metabolites

TYPES

Severe ITP ▪ Platelet counts < 10,000–20,000/microL; significant bleeding requires treatment

Primary ITP ▪ Idiopathic

Refractory ITP ▪ Severe ITP, fails to respond to/relapses after splenectomy

▪ Classifed by cause, duration, severity

Secondary ITP ▪ Caused by systemic condition ▪ Viral infections (most common) ▫ HIV, hepatitis C, cytomegalovirus ▫ Antibodies against viral antigens cross-react with platelet antigens via molecular mimicry ▪ Bacterial lipopolysaccharides attach to platelet surfaces → increase phagocytosis of platelets ▪ Systemic lupus erythematosus, lymphoid

RISK FACTORS

▪ Age; genetic/acquired factors

OSMOSIS.ORG 457

COMPLICATIONS

▪ Potentially severe hemorrhage (uncommon) ▫ Intracranial bleeding, subarachnoid hemorrhage, gastrointestinal (GI) hemorrhage, hematuria, severe menorrhagia

SIGNS & SYMPTOMS ▪ Bruising easily after minor trauma ▪ Mucocutaneous bleeding ▫ Petechiae, purpura, epistaxis, gingival bleeding

DIAGNOSIS LAB RESULTS

▪ CBC ▫ Low platelet count ▪ Peripheral blood smear analysis ▫ Scarce platelets ▪ Flow cytometry-based assays ▫ Drug-dependent platelet antibodies

OTHER DIAGNOSTICS

▪ History of drug implicated in DITP

TREATMENT MEDICATIONS Raise platelet count ▪ High dose glucocorticoids (dexamethasone; prednisone) ▪ Immune globulin (IVIG) If no response to above medications ▪ Rituximab ▫ Monoclonal antibody reduces antibodydependent cytotoxicity, complementmediated lysis of platelets ▪ Thrombopoietin (TPO) receptor agonists (e.g. eltrombopag) ▫ Increases platelet production by stimulating production of megakaryocytes ▪ Immunosuppressive agents ▫ Danazol, azathioprine, cyclosporine Medications to avoid ▪ Antiplatelet agents ▫ Aspirin, other nonsteroidal antiinflammatory drugs (NSAIDs)

SURGERY

▪ If no response to medication

Splenectomy ▪ Reduces platelet destruction

OTHER INTERVENTIONS

▪ Platelet transfusions ▫ Clinically significant bleeding

Figure 59.1 Multiple petechiae present in the skin of an individual with ITP. The platelet count was < 5 x 109/L.

458 OSMOSIS.ORG

Chapter 59 Thrombocytopenia

THROMBOTIC THROMBOCYTOPENIC PURPURA (TTP) osms.it/thrombotic-thrombocytopenic PATHOLOGY & CAUSES ▪ Thrombotic microangiopathy (TMA) caused by deficient activity of ADAMTS13 protease ▪ ADAMTS13 breaks von Willebrand factor (vWF) molecules into smaller multimers, prevents excessive accumulation on endothelial surfaces in microvasculature ▪ Excessive vWF on endothelial surfaces → increased propensity for platelets to attach, accumulate (esp. in high pressure areas with shearing stress) + endothelial damage → platelet-rich thrombi in microcirculation → tissue ischemia, organ dysfunction, microangiopathic hemolytic anemia (MAHA), thrombocytopenia ▪ Thrombocytopenia consumptive ▫ Increased need for platelets from cyclical clot formation, dissolution ▪ MAHA ▫ Red blood cell (RBC) mechanical fragmentation in microthrombi, damaged vessels → schistocytes ▪ Organs most affected by TTP in microcirculation ▫ Brain, heart, adrenal glands, pancreas, kidneys

CAUSES

▪ ADAMTS13 deficiency ▫ Acquired inhibitory autoantibody (IgG) to ADAMTS13; inherited mutation of ADAMTS13 gene (minority)

RISK FACTORS

▪ Increased prevalence in individuals who are biologically female, of African

ancestry, diagnosed with systemic lupus erythematosus (SLE) ▪ Sepsis, liver disease, pancreatitis, cardiac surgery ▫ Reduce activity of ADAMTS13 ▪ Pregnancy ▫ Decrease in ADAMTS13, increase in vWF, 2nd–3rd trimesters

COMPLICATIONS

▪ Organ damage ▫ Renal insufficiency, focal neurologic/ mental status anomalies, arrhythmias

SIGNS & SYMPTOMS ▪ Classic TTP pentad ▫ Thrombocytopenia, MAHA, renal dysfunction, neurologic impairment (e.g. headache, confusion, seizures, coma), fever ▪ Mucocutaneous bleeding ▫ Petechiae, purpura (coalesced petechiae), epistaxis, gingival bleeding ▪ Intravascular hemolysis → dark urine ▪ Lightheadedness, abdominal pain, easy bruising, nausea/vomiting

MNEMONIC: RAFT'N

Common signs of Thrombotic thrombocytopenia purpura Renal problems Anemia: MAHA associated Fever Thrombocytopenia Neurologic dysfunction

OSMOSIS.ORG 459

DIAGNOSIS LAB RESULTS

▪ CBC ▫ Decreased platelet count ▫ Increased reticulocyte count ▫ Decreased hemoglobin, hematocrit ▪ Peripheral blood smear analysis ▫ Schistocytes, spherocytes ▪ Hemolysis ▫ Elevated lactate dehydrogenase (LDH) ▫ Elevated indirect bilirubin ▫ Reduced haptoglobin ▪ Elevated creatinine ▫ Renal insufficiency

OTHER DIAGNOSTICS

▪ ADAMTS13 assay ▫ Gel electrophoresis of VWF multimers measures degradation by ADAMTS13 ▪ ADAMTS13 inhibitor assay ▫ Autoantibody titer ▪ Genetic testing ▫ ADAMTS13 gene mutation, if hereditary TTP suspected

TREATMENT MEDICATIONS

▪ Glucocorticoids ▪ Monoclonal antibody

OTHER INTERVENTIONS ▪ Plasma exchange (PEX)

460 OSMOSIS.ORG

NOTES

NOTES

THYMUS NEOPLASIA GENERALLY, WHAT IS IT? PATHOLOGY & CAUSES ▪ Tumors in thymus (anterior mediastinum)

TYPES

▪ Classified by cell from which tumors arise

Thymoma, thymic cancers (most common) ▪ Thymic epithelial cells Neuroendocrine tumors ▪ Carcinoids Others ▪ Thymic hyperplasia, cysts, thymolipoma

COMPLICATIONS

DIAGNOSIS DIAGNOSTIC IMAGING ▪ Chest X-ray, CT scan

LAB RESULTS

▪ Fine needle aspiration/core biopsy

TREATMENT MEDICATIONS

▪ Chemotherapy/radiation therapy/both

SURGERY ▪ Resection

▪ Bioactive substances → paraneoplastic syndromes

SIGNS & SYMPTOMS ▪ Can be asymptomatic ▪ Chest pain, cough, dyspnea, paraneoplastic syndromes

OSMOSIS.ORG 461

THYMOMA osms.it/thymoma PATHOLOGY & CAUSES ▪ Rare tumor from epithelial cells (thymus) ▪ Benign/malignant ▪ Localization ▫ Anterior superior mediastinum (most frequently) ▫ Atypical position (neck, thyroid, pulmonary hilum) ▪ Macroscopic characteristics ▫ Lobulated ▫ Firm ▫ Gray-white ▫ Containing cystic spaces/calcifications/ hemorrhages

TYPES

▪ Extension (Masaoka staging systems)

Type I ▪ Encapsulated (non-invasive) Type II ▪ Invasion through capsula Type III ▪ Invasion into adjacent organs Type IV ▪ Local and distant implantations (metastases)

COMPLICATIONS

▪ Mass effect (e.g. cardiac tamponade, respiratory problems); humoral effects (e.g. paraneoplastic syndromes), metastases, recurrences

SIGNS & SYMPTOMS ▪ Asymptomatic; found incidentally during imaging studies ▪ Weight loss

462 OSMOSIS.ORG

▪ Fatigue ▪ Compression of mediastinal structures ▫ Esophagus → dysphagia ▫ Airways → cough, dyspnea ▫ Recurrent laryngeal nerve → hoarseness ▫ Superior vena cava (SVC) → SVC syndrome (face, arms edema; venous distension in neck, chest, arms) ▫ Chest pain Paraneoplastic syndromes ▪ Myasthenia gravis (most frequent, 30%) ▫ Muscle weakness ▫ Drooping eyelid (ptosis), double vision (diplopia) ▫ Dysphagia (difficulty swallowing) ▪ Pure red cells aplasia ▪ Hypogammaglobulinemia ▪ Graves disease ▪ Pernicious anemia ▪ Systemic lupus erythematosus ▪ Sjogren syndrome ▪ Dermatomyositis-polymyositis ▪ Cushing syndrome

DIAGNOSIS DIAGNOSTIC IMAGING Chest X-ray ▪ Hyperdense mediastinal mass, calcifications CT scan ▪ Well-defined attenuation, cystic components, calcifications MRI, nuclear medicine studies

LAB RESULTS

▪ Fine-needle aspiration/core biopsy

Chapter 60 Thymus Neoplasia

TREATMENT MEDICATIONS

▪ Surgical resection of thymus (thymectomy)

OTHER INTERVENTIONS

▪ Pre/post-operative chemotherapy/ radiotherapy (advanced Masaoka stages)

Figure 60.1 A CT scan in the axial plane demonstrating a large thymoma occupying the superior and anterior mediastinum.

Figure 60.2 The gross pathology of a thymoma.

OSMOSIS.ORG 463

NOTES

NOTES

ADULT PRIMARY BRAIN TUMORS

GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Diverse central nervous system cell neoplasms ▫ Benign/malignant

RISK FACTORS

▪ Genetic predisposition ▪ Ionizing radiation exposure ▪ Dietary N-nitroso compounds (NOCs)

COMPLICATIONS

▪ Mass effect: hydrocephalus, ↑ intracranial pressure, herniation ▪ Neurocognition, motor dysfunction, death

SIGNS & SYMPTOMS ▪ Vary depending on tumor type ▪ May be asymptomatic; headache; visual, hearing deficits; nausea; vomiting; altered level of consciousness (LOC)

DIAGNOSIS DIAGNOSTIC IMAGING CT scan/MRI ▪ Visualizes tumor mass

464 OSMOSIS.ORG

LAB RESULTS

▪ Biopsy: histopathologic, molecular examination

OTHER DIAGNOSTICS

▪ Tumor grades: World Health Organization (WHO) grading system

TREATMENT ▪ Dependent on tumor stage, grade

MEDICATIONS

▪ Steroids ▪ Monoclonal antibodies ▫ Avastin ▪ Chemotherapy

SURGERY ▪ Resection

OTHER INTERVENTIONS ▪ Radiation

Chapter 61 Adult Primary Brain Tumors

GLIOBLASTOMA MULTIFORME (GBM) osms.it/gllioblastoma-multiforme PATHOLOGY & CAUSES ▪ Highly malignant, aggressive glial cell tumor ▪ Location: usually hemispheric white matter ▫ Mass with grayish periphery, necrosed yellow center, multiple bleeding zones ▪ World Health Organization (WHO) grade IV tumor

TYPES Histology ▪ Giant-cell glioblastoma ▫ Multinuclear, giant cells ▪ Gliosarcoma ▫ Combined astrocytic, sarcoma-like components; squamous/gland-like structures → possible differentiation into other tissue ▪ Epithelioid glioblastoma ▫ Eosinophilic cytoplasm in large epithelioid cells Development-based ▪ Correlated with Isocitrate dehydrogenase (IDH) gene mutation ▪ Primary ▫ Spontaneous development, individuals aged > 50 ▫ AKA IDH wild-type: no IDH gene mutation ▪ Secondary ▫ Individuals aged < 50 ▫ Low-grade astrocytoma (WHO grade II) ▫ Anaplastic astrocytoma (WHO grade III) Subtypes: molecular characteristics ▪ Classic ▫ Molecular changes resemble primary type

▪ Proneural ▫ Secondary type gene mutations ▪ Neural ▪ ↑ expression of NEFL, GABRA1, SYT1, SLC12A5 tumor markers ▪ Mesenchymal ▫ ↓ NF1 gene, ↑ TNF and NF-κB pathway genes expression

CAUSES

▪ Genetic alterations

Primary GBM ▪ Epidermal growth factor receptor (EGFR) gene mutation → overexpression, constant receptor activation → uncontrolled cell proliferation ▪ Heterozygosity loss commonly affects long arm of chromosome 10 ▪ Phosphatase, tensin homologue (PTEN) gene mutation → tyrosine phosphatase activity loss → overactivated signaling pathways → ↑ proliferation Secondary GBM ▪ IDH1/IDH2 gene mutation → 2-hydroxyglutarate (2-HG) overproduction → impaired DNA methylation due to 2-HG ▪ TP53 mutation → tumor suppression function lost ▪ Heterozygosity loss on long arm of chromosomes 13, 19, 22 ▪ Platelet-derived growth factor (PDGF) gene mutation with overexpression → ↑ PDGF receptor binding → ↑ proliferation

RISK FACTORS

▪ White, biologically-male individuals of Jewish descent, aged 45–70 ▪ Genetically-inherited diseases ▫ Li–Fraumeni syndrome, tuberous sclerosis, neurofibromatosis

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▪ ▪ ▪ ▪

Radiation exposure Tobacco use Pesticide exposure Viruses ▫ Simian virus 40, Human herpesvirus 6, Cytomegalovirus

COMPLICATIONS

▪ Extension to ventricular wall ▪ Meningeal gliomatosis ▫ Malignant cell spread to spinal cord via cerebrospinal fluid (CSF) ▪ Recurrence ▪ Multifocality ▪ Mass effect ▫ Obstructive hydrocephalus, ↑ intracranial pressure, herniation ▪ Seizures ▫ Supratentorial glioblastoma

OTHER DIAGNOSTICS Histology ▪ Inadequate astrocyte differentiation with atypical nuclei, uncontrolled cell proliferation with shape/size cell variation ▪ Immunostaining ▫ Commonly positive glial fibrillary acidic protein (GFAP)

SIGNS & SYMPTOMS ▪ Severe morning headache, attenuates throughout day → focal symptomatology ▫ Motor (gradual), sensory, vision loss; aphasia ▪ Mental changes ▫ Altered mood, personality; impaired comprehension, concentration, memory

Figure 61.1 An MRI scan of the head in the coronal plane demonstrating glioblastoma of the left temporal lobe.

DIAGNOSIS DIAGNOSTIC IMAGING CT scan ▪ Hypodense central area, irregular ring-like edge enhancements MRI ▪ T1: hypointense center ▪ T2: hyperintense center, peripheral lowattenuated vasogenic edema Magnetic resonance spectroscopy (MRS) ▪ ↑ choline, lactate, lipid peaks ▪ ↓ N-acetylaspartate, myo-inositol peaks Positron emission tomography (PET) ▪ ↑ glucose metabolism

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Figure 61.2 The histological appearance of a glioblastoma multiforme. The tumor is composed of malignant glial cells with marked nuclear pleomorphism. The tumor demonstrates necrosis and is forming microvascular channels.

Chapter 61 Adult Primary Brain Tumors

TREATMENT MEDICATIONS

▪ Avastin (common)

SURGERY

▪ Total/subtotal tumor resection

OTHER INTERVENTIONS

▪ Adjuvant chemotherapy, radiation therapy

HEMANGIOBLASTOMA osms.it/hemangioblastoma PATHOLOGY & CAUSES ▪ Benign tumor; vascular cell proliferation, new blood vessel formation ▪ Cherry red cystic/solid mass structure in cerebellum, spinal cord, brainstem ▪ WHO grade I tumor

CAUSES Sporadic ▪ Usually solitaire, cerebellum most commonly affected Von Hippel–Lindau (VHL) disease ▪ Gene impairment with HL protein dysfunction → hypoxia inducing factor (HIF) build up → ↑ production of angiogenic factors, vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), transforming growth factor (TGF) → stimulation of angiogenesis ▪ Small, multiple lesions ▪ Common spinal cord affection, retinal hemangiomas also occurs

COMPLICATIONS

▪ Acute hemorrhage ▫ Intracerebral: brainstem compression/ tonsillar herniation, obstructive hydrocephalus ▫ Spinal: acute quadriplegia ▪ Tumor mass effect → ↑ intracranial pressure ▪ Local structure compression: neurologic deficits (e.g. oculomotor nerve dysfunction, motor weakness, sensory deficits) ▪ Paraneoplastic erythrocytosis → polycythemia

SIGNS & SYMPTOMS ▪ Tumor location-dependent ▫ Brainstem: visual, sensory impairment; motor weakness ▫ Cerebellum: ataxia ▫ Spinal cord: pain, sensory impairment ▪ In von Hippel–Lindau disease (VHL) ▫ Effect on retina → vision loss

RISK FACTORS

▪ Biologically-male individuals, aged 20–50

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DIAGNOSIS DIAGNOSTIC IMAGING MRI ▪ T1 hypointense/T2 hyperintense mass with defined edges CT scan ▪ Hypodense mass Ultrasound ▪ Hyperechoic zones amid surrounding tissue Angiography ▪ Preoperative tumor visualization

Figure 61.4 The histological appearance of a hemangioblastoma. The tumor is composed of numerous, closely-packed, thin-walled capillaries with underlying neoplastic stromal cells.

OTHER DIAGNOSTICS Histology ▪ Two components ▫ Endothelial: small endothelial cells with sparse cytoplasm ▫ Stromal: cells with eosinophilic cytoplasm, numerous vacuoles

TREATMENT MEDICATIONS

▪ Antiangiogenic treatment ▫ ↓ EDGF production

SURGERY

▪ Excision ▪ Stereotactic radiosurgery

Figure 61.3 Immunohistochemical staining of a hemangioblastoma with CD31 highlights the endothelial component of the tumor (dark brown).

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Chapter 61 Adult Primary Brain Tumors

MENINGIOMA osms.it/meningioma PATHOLOGY & CAUSES ▪ Tumor arising from dome-shaped meningeal arachnoid cells with base on meninges ▪ Intracranial (usual), spinal (occasional) ▪ WHO grade I, II, III (morphologydependent)

CAUSES

COMPLICATIONS

▪ Recurrent meningiomas ▪ Mass effect ▫ Obstructive hydrocephalus, ↑ intracranial pressure, herniation ▪ Bone abnormalities ▫ Reactive sclerosis, bone invasion/erosion possible (meningioma located on skull base) ▪ Seizures

Sporadic ▪ TNF-receptor associated factor 7 (TRAF7) mutation Genetic predisposition ▪ Long arm of chromosome 22 loss → NF2 tumor suppressor gene impairment ▪ SMARCB1 tumor suppressor gene mutation ▪ MEN1 tumor suppressor gene mutation

RISK FACTORS Genetically-inherited diseases ▪ Neurofibromatosis type 2 ▫ Intracranial localization (usual), spinal meninges (occasional) ▫ Associated with multiple meningiomas ▪ Schwannomatosis ▪ Multiple endocrine neoplasia type I (MEN I) Ionizing radiation ▪ Radiation exposure, dental radiographs, diagnostic CT scan (children) Other risk factors ▪ Obesity ▪ Black, biologically-female individuals of African descent more prone, ↑ incidence in later age

Figure 61.5 An MRI scan of the head in the coronal plane demonstrating a meningioma.

SIGNS & SYMPTOMS ▪ May be asymptomatic; very slow growth ▪ Symptoms tumor location-dependent Visual impairment ▪ Sella turcica vicinity ▫ One-sided papilledema, optic atrophy of other eye (Foster–Kennedy syndrome) ▪ Cavernous sinus meningiomas ▫ Compression of cranial nerves supplying extraocular muscles → muscles

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weakness, double vision ▪ Optic nerve meningiomas ▫ Gradual, monocular, vision loss

DIAGNOSTIC IMAGING

Impaired hearing and smell ▪ Cerebellopontine angle meningiomas ▫ Sensorineural deafness ▪ Olfactory groove meningiomas: anosmia

MRI ▪ T1 hypointense/T2 hyperintense duralbased mass, dural thickening with tail-like structure (“tail sign”)

Behavioral changes ▪ Apathy, impaired attention, impulsivity ▪ Usually subfrontal meningiomas

CT scan ▪ Isodense mass, brain tissue compression

Muscle weakness ▪ Parasagittal meningiomas ▫ Contralateral leg weakness ▪ Foramen magnum meningiomas ▫ Lesion-side arm weakness → ipsilateral leg progression → contralateral leg affection → contralateral arm weakness ▪ Spinal cord meningiomas ▫ One-sided plegia of extremities, sensory loss on other side (Brown–Séquard syndrome)

DIAGNOSIS

PET ▪ ↑ uptake of 18F-Fluorodeoxyglucose

OTHER DIAGNOSTICS Histology ▪ WHO Grade I ▫ Benign, not classified ▪ WHO grade II ▫ Atypical, needs to have at least three of ↑ nucleus-cytoplasm ratio, ↑ cellularity, prominent nucleus, unorganized growth, focal necrosis ▪ WHO grade III ▫ Malignant; ↑ mitotic index with atypical cells, brain tissue infiltration, multifocal necrosis

TREATMENT ▪ Monitoring ▫ Lesions small, asymptomatic

Figure 61.6 The histological appearance of a meningioma showing a typical whorled architecture.

SURGERY

▪ Resection ▫ Large symptomatic/asymptomatic tumors ▪ Stereotactic radiosurgery ▫ Hard-to-reach/smaller than 3cm/1.18in lesions

OTHER INTERVENTIONS

▪ Radiotherapy ▫ Primary management/adjuvant therapy

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Chapter 61 Adult Primary Brain Tumors

OLIGODENDROGLIOMA osms.it/olligodendroglioma PATHOLOGY & CAUSES

SIGNS & SYMPTOMS

▪ A tumor derived from oligodendrocytes ▪ Supratentorial in frontal/temporal white matter (usual); spinal cord (occasional) ▪ Genetic alteration combination → oligodendroglioma grade II development → oligodendroglioma grade III progression ▪ Oligodendroglioma grade III can develop without oligodendroglioma grade II

▪ May be asymptomatic; slow tumor growth ▪ Seizures ▫ Focal/secondarily generalized ▪ Focal symptomatology ▫ Frontal lobe: one-sided muscle weakness, impaired sensory perception, impaired memory ▫ Temporal lobe: impaired language

TYPES WHO classification ▪ Grade II ▫ Low-grade, low mitotic index with atypical nuclei ▪ Grade III ▫ High-grade (anaplastic), ↑ cellular density, ↑ mitotic index with atypical nuclei, microvascular proliferation ▪ Oligodendroglioma not-other-specified (NOS) ▫ Tumors with appropriate histologic characteristics without 19p-1q chromosomes co-deletion or IDH1/IDH2 gene mutation

CAUSES

▪ IDH1/IDH2 gene mutation ▪ 19p-1q chromosomes co-deletion due to unbalanced translocation

RISK FACTORS

▪ Biologically-female > biologically-male individuals, aged 25–45, most commonly affected

DIAGNOSIS DIAGNOSTIC IMAGING MRI ▪ T1 hypointense/T2 hyperintense mass CT scan ▪ Hypodense, delineated tumor mass with calcification present

LAB RESULTS

▪ Genetic testing ▫ IDH gene mutation, 19p-1q detection

OTHER DIAGNOSTICS Histology ▪ Needed for diagnosis ▫ Diffuse infiltrative tumors ▫ Large nuclei with perinuclear halo— “fried egg” appearance ▫ ↑ capillary branching—“chicken wire” appearance

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TREATMENT MEDICATIONS ▪ Chemotherapy

SURGERY ▪ Resection

OTHER INTERVENTIONS Figure 61.7 The histological appearance of an oligodendroglioma. The tumor is composed of monomorphic malignant glial cells with perinuclear halos and visible nucleoli.

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▪ Radiation therapy

NOTES

NOTES

AUTONOMIC DISEASES GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Autonomic nervous system (ANS) disorders (dysautonomia) ▪ Normative autonomic function ▫ Balanced impulses of sympathetic, parasympathetic ANS ▫ One/both components fail → symptoms ▪ Etiology ▫ Genetic, environmental factors

CAUSES

▪ Primary ▫ Pure autonomic failure, familial dysautonomia, multiple system atrophy, postural orthostatic tachycardia syndrome (POTS) ▪ Secondary (neuropathy) ▫ Alcoholism, diabetes mellitus, trauma, HIV infection, multiple sclerosis, Lyme disease, Parkinson’s disease, porphyria, nerve compression (tumor), drug toxicity (vincristine)

SIGNS & SYMPTOMS ▪ Breadth of autonomic function → wide symptomatic variation ▪ Common autonomic disease symptoms ▫ ↑↓ heart/respiration rate ▫ ↑↓ blood pressure ▫ Bowel/bladder/erectile dysfunction ▫ Hypohidrosis/hyperhidrosis ▫ Syncope

DIAGNOSIS DIAGNOSTIC IMAGING ▪ See individual diseases

LAB RESULTS

▪ Nerve biopsy ▫ Neuropathy detection

OTHER DIAGNOSTICS

▪ Autonomic function test battery ▫ Monitor heart rate, autonomic functions for pathological changes ▪ Valsalva maneuver ▫ ↑ intraspinal pressure → neuropathic symptom exacerbation ▪ Quantitative sudomotor axon reflex test (QSART) test ▫ Electrical current → sweat gland stimulation ▪ Tilt table test ▫ Individual lies on table → table tilted upright → detects sudden blood pressure change

TREATMENT ▪ Treat underlying cause if possible ▪ Mostly symptomatic treatment

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HORNER'S SYNDROME osms.it/horners-syndrome PATHOLOGY & CAUSES ▪ AKA oculosympathetic paresis ▪ Clinical syndrome ▫ Damaged sympathetic neural pathways to eye, associated structures ▪ Sympathetic innervation to eye ▫ Three neurons comprise pathway ▫ 1st order neurons: in posterolateral hypothalamus, preganglionic fibers ▫ 2nd order neurons: in ciliospinal center (Budge’s center) in intermediolateral segment of spinal column (C8–T2) → preganglionic fibers travel to superior cervical ganglion (SCG) → synapse with 3rd order neurons ▫ 3rd order neurons: in SCG, postganglionic fibers follow different paths upon leaving SCG → flushing, absent sweating not mandatory signs ▪ Manifests ipsilaterally

SIGNS & SYMPTOMS ▪ Classic triad: ptosis, anhydrosis, miosis ▪ May present with anhidrosis (if 2nd order neurons affected), flushing (impaired vasoconstriction), apparent enophthalmos (ptosis)

MNEMONIC: PAM

Signs & symptoms of Horner’s syndrome Ptosis Anhidrosis Miosis

CAUSES

▪ Condition manifests following pathway interruption ▪ Congenital/acquired ▫ Congenital: may present with heterochromia iridis as eye pigmentation under sympathetic innervation during development ▪ Classification based on lesion’s level ▫ 1st order neuron lesion: Arnold–Chiari malformation, cerebrovascular insult, basal skull tumor ▫ 2nd order neuron lesion: trauma, cervical rib, Pancoast tumor, neuroblastoma, aorta dissection ▫ 3rd order neuron lesion: herpes zoster, internal carotid artery dissection, cluster headache

Figure 62.1 An individual with Horner’s syndrome demonstrating ptosis and miosis of the left eye.

DIAGNOSIS DIAGNOSTIC IMAGING X-ray ▪ Detects Pancoast tumor, shoulder trauma MRI ▪ Detects aneurysm, dissection

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Chapter 62 Autonomic Diseases

LAB RESULTS

▪ Vanillylmandelic acid (VMA) level ▫ Detects neuroblastoma

OTHER DIAGNOSTICS

▪ Neurological exam ▪ Pharmacological diagnostics ▫ Disorder detection, lesion level determination ▫ Cocaine drops: norepinephrine missing from synaptic cleft → absent mydriasis

▫ Apraclonidine: upregulation of α1 receptors (↑ apraclonidine sensitivity) → mydriasis occurs ▫ Hydroxyamphetamine: 1st or 2nd order neuron lesion → mydriasis occurs (postganglionic fibers undamaged); 3rd order neuron lesion → weaker/absent mydriasis in affected eye

TREATMENT ▪ Treat the underlying cause if possible

ORTHOSTATIC HYPOTENSION (OH) osms.it/orthostatic-hypotension PATHOLOGY & CAUSES ▪ Sudden, sustained systolic blood pressure (> 20mmHg)/diastolic blood pressure (> 10mmHg) drop within three minutes upon standing/ tilting head upright ≥ 60° ▪ Delayed/lowered lower-body vasoconstriction ▪ Lower-body blood accumulation while seated/supine → lower-body vasoconstriction delayed upon standing → ↓ cardiac output → ↓ cerebral perfusion → dizziness, blurred vision, syncope

CAUSES

▪ Neuropathy impairs vasoconstriction ▪ Baroreceptor reflex impairment (α1 blockers inhibit vasoconstriction) ▪ Hypovolemia (absolute/relative); atherosclerosis; diabetes mellitus; Addison’s disease; Parkinson’s disease; anorexia nervosa; alcohol, THC intoxication; medication (MAOI) ▪ Occurs in elderly/postpartum individuals

COMPLICATIONS

▪ Postural orthostatic tachycardia syndrome (compensatory mechanism for chronic ↓ cardiac output), syncope, injury (falling)

SIGNS & SYMPTOMS ▪ Pale skin, vertigo, blurred vision, nausea, heart palpitations

DIAGNOSIS LAB RESULTS

▪ Measure blood pressure ▫ Confirm sudden drop

OTHER DIAGNOSTICS ▪ Tilt table test ▫ Provokes OH episode

TREATMENT MEDICATION

▪ Corticosteroids ▪ Antihypotensives ▪ Supplemental measures (caffeine)

OTHER INTERVENTIONS

▪ Increase blood pressure via increased fluid/ salt intake ▪ Treating underlying cause

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NOTES

NOTES

BALANCE DISORDERS GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES

DIAGNOSIS

▪ Disorders of inner ear (vestibular portion) → disequilibrium (balance loss)

DIAGNOSTIC IMAGING

CAUSES

OTHER DIAGNOSTICS

▪ Inner ear infections, injuries; genetic disorders, others

SIGNS & SYMPTOMS ▪ Vertigo ▫ Spinning sensation of oneself/ surroundings ▪ Hearing loss, tinnitus

▪ CT scan, MRI

▪ Audiometric test ▪ Neurologic examination ▪ Clinical manifestation

TREATMENT MEDICATIONS

▪ Antibiotics (causitive) ▪ Antihistamines, antiemetics, anticholinergics (symptomatic)

SURGERY

▪ Causative treatment

OTHER INTERVENTIONS

▪ Vestibular rehabilitation therapy

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Chapter 63 Balance Disorders

LABYRINTHITIS osms.it/labyrinthitis PATHOLOGY & CAUSES ▪ Inner ear (labyrinth) inflation ▪ Damage of auditory, vestibular-end organs responsible for hearing, retaining balance (rotational, linear-motion sensation)

CAUSES

▪ Viral infection (rubella virus, cytomegalovirus, mumps virus) ▪ Bacterial infection ▫ Streptococcus pneumoniae, Haemophilus influenzae, Neisseria meningitidis; most commonly meningitis/ otitis media complication ▪ Head injury, stress, allergy, medication

RISK FACTORS

▪ Upper respiratory tract infection

COMPLICATIONS

▪ Permanent hearing loss

SIGNS & SYMPTOMS ▪ Severe vertigo (oneself/surroundings seem spinning), associated symptoms ▪ Fatigue, nausea, vomiting ▪ Rotational motion signalization impairment → nystagmus ▪ Tinnitus, hearing loss ▪ Gait impairment

DIAGNOSIS OTHER DIAGNOSTICS

▪ Head, neck examination ▫ Nystagmus ▪ Neurologic examination ▫ Positive Romberg’s test: inability to maintain postural control ▫ Abnormal tandem gait: inability to walk in straight line with one foot in front of other (heel-to-toe) ▪ Head impulse, Nystagmus, and Test of skew (HiNTs) examination ▫ Positive head-thrust test: inability to maintain visual fixation when head turned rapidly toward side of lesion by examiner ▫ Negative test of skew ▫ Direction-changing nystagmus

TREATMENT MEDICATIONS

▪ Inflammation ▫ Corticosteroids ▪ Bacterial infection ▫ Antibiotics ▪ Symptomatic treatment ▫ Antihistamines, antiemetics, anticholinergics

OTHER INTERVENTIONS

▪ Self-limiting ▫ Recovery in 1–6 weeks ▪ Vestibular rehabilitation therapy ▫ Head, eye movement, postural change, walking exercise

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MENIERE'S DISEASE osms.it/menieres-disease PATHOLOGY & CAUSES ▪ Idiopathic inner-ear disorder ▫ Vertigo, progressive hearing loss

CAUSES

▪ Exact cause unknown ▫ Likely abnormal fluid, ion homeostasis in inner ear (endolymphatic hydrops) ▪ Possibly due to endolymphatic sac/ duct blockage, viral infection, vestibular aqueduct hypoplasia, vascular constriction

RISK FACTORS

▪ Children ▫ Congenital inner-ear malformations ▪ Family history (10% familial)

SIGNS & SYMPTOMS ▪ Spontaneous vertigo episodes (last 20 minutes–24 hours), associated symptoms (fatigue, nausea, vomiting); tinnitus, progressive hearing loss ▪ Less common ▫ Drop attack (sudden fall with preserved consciousness)

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DIAGNOSIS OTHER DIAGNOSTICS

▪ Diagnostic criteria ▫ Two/more unprovoked vertigo episodes (each last > 20 minutes) ▫ Audiometrically-confirmed sensorineural hearing loss in affected ear on at least one occasion before/during/after vertigo episode ▫ Tinnitus/fullness feeling in ear

TREATMENT MEDICATIONS

▪ Symptomatic treatment ▫ Antihistamines, antiemetics, anticholinergics

SURGERY

▪ Symptoms do not improve ▫ Surgical decompression of endolymphatic sac

OTHER INTERVENTIONS

▪ Sodium restriction, diuretics may alleviate symptoms (unknown efficacy)

Chapter 63 Balance Disorders

SCHWANNOMA osms.it/schwannoma PATHOLOGY & CAUSES ▪ Benign nerve-sheath Schwann cell tumor ▪ Involves any peripheral nerve ▫ Most commonly affects head, neck nerves; vestibular nerve (vestibular schwannoma) ▪ Associated with neurofibromatosis type II (presents with bilateral schwannomas) ▫ Caused by loss-of-function mutation in neurofibromin 2 (NF2) gene that encodes tumor-suppressor protein merlin (schwannomin)

RISK FACTORS

▪ Childhood radiation treatment

OTHER DIAGNOSTICS

▪ Neurologic examination ▫ Cranial nerve deficit ▪ Audiometry ▫ Confirms sensorineural hearing loss

TREATMENT SURGERY ▪ Excision

OTHER INTERVENTIONS

▪ Radiation therapy ▫ Stereotactic radiosurgery, stereotactic radiotherapy, proton beam therapy

COMPLICATIONS

▪ Very rarely become malignant (neurofibrosarcoma degeneration) ▪ Left untreated ▫ Brainstem compression, cerebellar tonsil herniation, hydrocephalus

SIGNS & SYMPTOMS ▪ Cochlear nerve involvement → hearing loss, tinnitus ▪ Vestibular nerve involvement → walking disequilibrium ▪ Trigeminal nerve involvement → facial paresthesia, hypoesthesia, pain ▪ Facial nerve involvement → facial paresis, gustatory disturbances; xerophthalmia, paroxysmal lacrimation, xerostomia

Figure 63.1 The histological appearance of a Schwannoma demonstrating characteristic Antoni A and Antoni B areas.

DIAGNOSIS DIAGNOSTIC IMAGING MRI ▪ Mass detection

Figure 63.2 The gross pathology of an excised schwannoma.

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VERTIGO osms.it/vertigo PATHOLOGY & CAUSES

SIGNS & SYMPTOMS

▪ Sensation that oneself/surroundings are spinning ▫ Symptom, not disease ▪ Labyrinth, vestibular nerve, vestibular centers (in brainstem) damage/dysfunction

▪ Peripheral vertigo ▫ Mild–moderate disequilibrium (dizziness, lightheadedness) ▫ Spinning sensation; fatigue, nausea, vomiting; hearing loss, tinnitus, fullness, ear pain ▪ Central vertigo ▫ Severe disequilibrium ▫ Less prominent spinning sensation, nausea than peripheral vertigo ▫ May be accompanied by neurologic deficits, nystagmus

CAUSES

▪ Peripheral vertigo ▫ Calcified otoliths in posterior semicircular canal (canalithiasis) → benign paroxysmal positional vertigo (most common) ▫ Labyrinthitis, Ménière disease, herpes zoster oticus ▪ Central vertigo ▫ Vestibular migraine; brainstem ischemia; cerebellar infarction, hemorrhage; multiple sclerosis

MNEMONIC: VOMITS

Causes of vertigo Vestibulitis: labyrinthitis or vestibular neuronitis Ototoxic drugs Meniere’s disease Injury Tumor Spin: benign paroxysmal positional vertigo

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DIAGNOSIS DIAGNOSTIC IMAGING MRI/CT scan ▪ Suspected central vertigo ▫ Central nervous system abnormalities

OTHER INTERVENTIONS Vestibular system function tests ▪ Differentiate vertigo from other dizziness causes ▪ Electronystagmography ▪ Dix–Hallpike maneuver ▫ Individual sits, head rotated 45° towards ear being tested → individual lowered to supine past bed’s end, extends neck 20° below horizontal → vertigo, nystagmus reproduced → test positive ▪ Head-thrust test ▫ Individual fixates on target while head is rotated quickly → catch-up saccades, nystagmus → test positive

Chapter 63 Balance Disorders ▪ Rotation test ▫ Individual accelerates, decelerates in rotating chair → analyze postrotatory nystagmus → test positive ▪ Caloric reflex test ▫ Cold/warm water/air irrigation into external auditory canal Audiometry ▪ Assess hearing loss

TREATMENT MEDICATIONS

▪ Vestibular migraines (underlying cause) ▫ Anticonvulsants, beta blockers ▪ Symptomatic treatment ▫ Antihistamines, antiemetics, anticholinergics, benzodiazepines

OTHER INTERVENTIONS

▪ Vestibular rehabilitation therapy

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NOTES

NOTES

BRAIN ISCHEMIA GENERALLY, WHAT IS IT? PATHOLOGY & CAUSES

DIAGNOSIS

▪ Impaired brain function due to lack of blood

DIAGNOSTIC IMAGING

TYPES

CT scan ▪ Visualize trauma, bleeding, skull fracture

Focal ischemia ▪ Occlusion of blood vessel → ↓ perfusion → affected regions damaged ▪ ↓ oxygen → ischemic stroke ▪ Blood vessel rupture → hemorrhagic stroke; bleeding inside parenchyma/between brain membranes Global ischemia ▪ Cardiac arrest → whole brain hypoperfusion → brain damage

CAUSES

Atherosclerotic plaque/thrombosis/emboli Hypertension Blood vessel malformation Cardiac arrest, tachycardia, congenital heart problems ▪ Tumors ▪ ▪ ▪ ▪

SIGNS & SYMPTOMS ▪ Altered consciousness; weakness; problems with vision, hearing, swallowing; dizziness, vertigo ▪ See mnemonic for common symptoms

MRI ▪ Visualize hypointense, hyperintense blood clot MR/CT angiography ▪ Visualize occlusions, aneurysms

TREATMENT MEDICATIONS

▪ Antiplatelet medications (e.g. aspirin/ clopidogrel) ▪ IV tissue plasminogen activator (tPA) ▪ Mannitol, other osmotic diuretics ▫ ↑ intracranial pressure treatment

SURGERY

▪ Evacuation of blood clot ▪ ↑ intracranial pressure treatment

OTHER INTERVENTIONS

▪ Manage conditions that worsen prognosis (e.g. hyperglycemia, fever)

MNEMONIC: FAST

Common stroke symptoms Facial drooping Arm weakness Speech difficulties Time: reminder to call emergency services

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Chapter 64 Brain Ischemia

EPIDURAL HEMATOMA osms.it/epidural_hematoma PATHOLOGY & CAUSES ▪ Nervous tissue compression due to accumulation of blood in epidural space ▪ Head trauma → skull fracture → damage of blood vessels through dura mater → extradural blood accumulation → rapid, limited expansion of hematoma due to tight dura adherence at cranial sutures → brain tissue compression → neurological decline

TYPES Intracranial ▪ Frontal injuries ▫ Anterior ethmoidal artery ▪ Temporoparietal (most common) ▫ Middle meningeal artery ▪ Occipital ▫ Transverse, sigmoid sinus ▪ Vertex ▫ Superior sagittal sinus Spinal ▪ Venous plexus of lumbar, thoracic regions

CAUSES

▪ Neurosurgical procedures complication ▪ Trauma

Intracranial epidural hematoma ▪ Head trauma → pterion skull fracture (most common) ▪ Blood vessel malformations Spinal epidural hematoma ▪ Trauma (e.g. lumbar puncture/epidural anesthesia)

RISK FACTORS

▪ More common in individuals who are biologically male, between 2–60 years ▪ Pregnancy

▫ Spontaneous spinal hematoma (very rare) ▪ Systemic lupus erythematosus ▫ Vasculitis, associated with immune system reaction ▪ Coagulopathies, bleeding diathesis, sickle cell anemia

COMPLICATIONS

▪ ↑ intracranial pressure ▪ Supratentorial herniation → compression of arteries → ischemic stroke ▪ Infratentorial herniation → brainstem compression → heart, respiratory arrest ▪ Paralysis/sensory loss ▪ Seizures

SIGNS & SYMPTOMS ▪ Initial loss of consciousness, lucid state if blood slowly accumulating; delayed neurological deterioration consequence of enlarging hematoma compression ▪ Intracranial epidural hematoma ▫ Broken skull with hematoma ▫ Otorrhea/rhinorrhea ▫ Altered consciousness ▪ ↑ intracranial pressure ▫ Headache ▫ Nausea with vomiting ▫ Cushing reflex (↑ blood pressure, ↓ heart rate, irregular breathing) ▫ Focal signs (weakness of extremities on opposite side; dilated pupil on injured side due to compression of CN III) ▪ Spinal epidural hematoma ▫ Radicular back pain (resembles pain from herniated discus) ▫ Sensory defects ▫ Urinary, fecal incontinence

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MRI ▪ T2-WI: acutely ▫ Hypointense blood clot due to deoxyhemoglobin ▪ T1, T2-WI: in following weeks ▫ Deoxy → methemoglobin; hyperintense blood clot ▪ T1-WI: months later ▫ Methemoglobin → hemosiderin; hypointense mass

TREATMENT MEDICATIONS Figure 64.1 A CT scan of the head in the axial plane demonstrating a large epidural hematoma with a classical biconvex shape.

DIAGNOSIS DIAGNOSTIC IMAGING X-ray ▪ Skull fracture CT scan ▪ Hematoma: typically presents as a biconvex, relatively heterogeneous, high density mass in the space between skull, brain; does not cross sutures ▪ Swirl sign: bleeding into blood clot, diverse hypoattenuated foci ▪ Assess hematoma volume ▪ Skull fracture

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▪ Mannitol, other osmotic diuretics ▫ ↑ urine excretion, ↓ intracranial pressure ▪ Anticoagulation reversal ▫ Individuals undergoing surgery, on anticoagulation therapy

SURGERY

▪ Craniotomy ▫ Evacuation of blood mass ▪ Embolization/ligation of damaged blood vessel ▪ Trephination (burr-hole) ▫ In acute EDH, if neurosurgical procedure delayed ▪ Laminectomy ▫ ↓ blood in spinal epidural hematoma

OTHER INTERVENTIONS

▪ Observation, nonoperative management ▫ Awake, conscious individuals ▫ If hematoma volume < 30cm3, thickness < 15mm, midline shift < 5mm

Chapter 64 Brain Ischemia

INTRACEREBRAL HEMORRHAGE osms.it/intracerebral-hemorrhage PATHOLOGY & CAUSES ▪ Condition characterized by blood vessels rupture → intraparenchymal blood accumulation ▪ Blood vessel trauma, rupture → creates pool of blood → tissue, surrounding blood vessel compression → hypoxia in downstream tissue → damage due to compression, oxygen lack

CAUSES Hypertension ▪ Most common ▪ Leads to ▫ Atherosclerosis in large arteries ▫ Hyaline arteriolosclerosis → focal arterioles necrosis → small wall ruptures → subclinical microbleeds ▫ Charcot–Bouchard aneurysms (microaneurysms) ▪ Basal ganglia; thalamus; midbrain; pons; cerebellum primarily affected Vascular abnormalities ▪ Cerebral amyloid angiopathy ▫ Deposition of amyloid in blood vessel walls → vessels more prone to rupture ▫ Lobar localization: parietal, occipital lobes ▫ Blood vessels: leptomeningeal, cerebral cortical arterioles ▪ Arteriovenous malformations ▫ Usually affect children ▪ Aneurysm, vasculitis, vascular tumours (e.g. hemangioma) Other causes ▪ Secondary to ischemic stroke ▫ Blood flow blockage → reperfusion → ↑ chance of blood vessel rupture → bleeding into dead tissue (hemorrhagic conversion)

▪ Posttraumatic ▪ Coagulopathies ▪ Sickle cell disease

RISK FACTORS

▪ Individuals who are biologically male of Asian descent ▪ Black individuals who are biologically male of African descent ▪ Heavy alcohol use; amphetamines, cocaine abuse, antithrombotic medications; ↓ LDL, cholesterol, triglycerides; previous cerebrovascular insult

COMPLICATIONS

▪ Hemorrhage enlargement ▫ In hemorrhage border ▫ Poor prognosis ▪ Intraventricular, subarachnoid expansion ▪ Hydrocephalus

SIGNS & SYMPTOMS ▪ Begin slowly, worsen gradually ▪ Enlargement of hematoma within few hours, ↑ intracranial pressure ▫ Altered consciousness, headache, nausea, vomiting, unequal pupil size ▪ Fever Area of brain affected ▪ Anterior/middle cerebral artery: numbness, sudden muscle weakness ▪ Posterior cerebral artery: impaired vision ▪ Broca’s area: slurred speech ▪ Wernicke’s area: difficulty understanding speech Focal neurological signs ▪ Basal ganglia manifestation: loss of contralateral sensory, motor functions; homonymous hemianopsia ▪ Thalamus: contralateral loss of

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sensory, motor functions; homonymous hemianopsia; aphasia if dominant/neglect if nondominant; narrowed pupils unreactive to light ▪ Lobar manifestation: homonymous hemianopsia; if frontal region, contralateral leg plegia/paresis; seizures ▪ Pons: coma within few minutes of hemorrhage; quadriplegia, miosis/deafness; speaking difficulties when awake ▪ Cerebellum: ataxia; same side face weakness; loss of face, body sensory function; occipital headache, neck stiffness

DIAGNOSIS DIAGNOSTIC IMAGING CT scan ▪ Hyperdense blood mass acutely; isodense, ring enhancement appearance in subsequent weeks; hypodense chronically ▪ Trauma ▫ Multifocal bleedings ▪ Coagulum retracts, edema develops ▫ Confused with hemorrhagic infarction CT angiography ▪ Spot sign: unifocal/multifocal enhancement of contrast; ↑ risk of hematoma expansion MRI (T2-WI) ▪ Hyperacute (first 24 hours) ▫ Hyperintense center of mass ▫ Hypointense periphery, border ▪ Subacute ▫ Hypointense in > three days: intracellular methemoglobin ▫ Hyperintense in > seven days: lysis of red blood cells; extracellular methemoglobin ▫ Chronic: hypointense; after two weeks

486 OSMOSIS.ORG

MR angiography ▪ Vasculitis, arteriovenous malformations, other blood vessel pathology

LAB RESULTS

▪ Prothrombin time (PT), activated partial thromboplastin time (aPTT), platelet count ▫ If cause for bleeding diathesis unclear

TREATMENT MEDICATIONS

▪ Vitamin K, unactivated prothrombin ▫ With anticoagulant usage ▪ Protamine sulfate ▫ For heparin users ▪ Antipyretics ▫ Fever reduction ▪ Osmotic diuretics (e.g. mannitol) ▫ Regulation of ↑ ICP ▪ Saline ▫ Fluid replacement ▪ Nicardipine/nitroprusside/enalapril/ nitroglycerin ▫ Hypertension ▪ Phenytoin/levetiracetam ▫ Seizures

SURGERY

▪ Ventriculostomy ▫ Regulation of ↑ intracranial pressure ▪ If hemorrhage > 3cm/1.2in/lobar of young persons/brainstem compression ▫ Craniotomy with clot removal ▫ Stereotactic aspiration ▫ Endoscopic evacuation

Chapter 64 Brain Ischemia

Figure 64.2 A CT scan of the head in the axial plane demonstrating a right-sided, periventricular, intracerebral hemorrhage.

ISCHEMIC STROKE osms.it/ischemic-stroke PATHOLOGY & CAUSES ▪ Decreased blood supply in specific brain area due to blood vessel obstruction → hypoperfusion, tissue hypoxia, infarction ▪ ↓ blood flow → lack of oxygen, glucose in brain → ↓ adenosine triphosphate (ATP) production, electrochemical gradient → cell death Two mechanisms of cell death ▪ Sodium buildup: water follows sodium → cell swelling, death ▪ Calcium buildup: creates oxygen radicals → damages mitochondrial, lysosomal lipid membrane → seeping of degradative enzymes, apoptosis-inducing factors → cell death Two zones ▪ Ischemic core ▫ Brain tissue dies from ischemia within

few minutes of stroke ▫ Blood flow < 10ml/100g tissue/minute ▪ Ischemic penumbra ▫ Periphery of affected region preserved due to collateral circulation; chance of survival if blood restored quickly ▫ Blood flow < 25ml/100g tissue/minute ▫ Infarction zone spreads if blood supply not restored quickly

TYPES Five subtypes (TOAST classification) ▪ Large artery atherosclerosis ▪ Small artery strokes ▪ Cardioembolic infarction ▫ Formation of emboli in heart → lodging in brain arteries ▪ Other determined pathology ▪ Undetermined pathology

OSMOSIS.ORG 487

CAUSES Thrombosis ▪ May lead to obstruction inside blood vessel ▪ Narrowing of blood vessel due to atherosclerotic plaque → gradual ↓ blood flow ▪ Damage to atherosclerotic fibrous cap → platelet, clotting cascade activation → thrombus formation with sudden stop of blood flow Embolism ▪ Four classes based on emboli origin ▫ Cardiac emboli: atrial fibrillation, rheumatic valve disease, infective endocarditis, dilated cardiomyopathies, left atrial myxoma ▫ Possible cardiac/aortic emboli: calcification of mitral valve annulus, patent foramen ovale, atheroma in ascending/arch of aorta, atrial septal aneurysm ▫ Arterial emboli: detachment of blood clot (e.g. atherosclerotic plaque in bigger upstream artery) → emboli travels through blood → lodges in smaller downstream artery ▫ Cryptogenic: unknown origin of emboli Lacunar infarct ▪ Affects small blood vessels of distal vertebral, basilar artery, middle cerebral artery, circle of Willis ▫ Lipohyalinosis: buildup of hyaline in arterioles wall → hypertrophy of tunica media → progressive narrowing of arterioles until blood flow stops ▫ Microatheromatoma: narrowing of blood vessel due to debris accumulation within wall Hypoperfusion ▪ Lack of blood reaching brain due heart failure, ↓ cardiac output ▪ Most vulnerable ▫ Spaces between supply of two arteries (watershed regions) Inflammation of blood vessel wall ▪ E.g. Takayasu/giant cell arteritis

488 OSMOSIS.ORG

Moyamoya disease ▪ Progressive stenosis of cerebral arteries → ischemia Dissection of artery wall

RISK FACTORS

▪ Age (esp. > 55) ▪ More common in individuals who are biologically male ▪ More common in black individuals of African descent ▪ Migraine headaches with aura ▪ Genetics; specific gene loci associated with stroke subtypes ▫ ABO loci: all subtypes ▫ HDAC9: large vessel stroke ▫ PITX2, ZFHX3: cardioembolic stroke ▪ Hematologic disorders ▫ Multiple myeloma, sickle cell disease, polycythemia vera; esp. in younger individuals ▪ Hypertension, diabetes mellitus, heart diseases, dyslipidemia, hyperhomocysteinemia, smoking, physical inactivity, cocaine abuse

COMPLICATIONS

▪ Blood reaches infarcted regions through collateral blood vessel/dissolution of occlusive embolus/thrombus; first week

Hemorrhagic transformation ▪ Ischemia → impaired cellular, metabolic functions of affected region; ↑ permeability of damaged blood vessels → resolved cause of ischemia → restored blood flow → blood extravasation ▪ Gray matter more commonly affected; large number of collateral vessels worsen reperfusion injury ▪ Massive cerebral infarction; hyperglycemia; ↓ cholesterol, LDL, IV recombinant tissue plasminogen activator (rtPA): higher risk of hemorrhagic transformation Cerebral edema ▪ ↑ intracranial pressure with possible herniation ▫ Cytotoxic: defective ATP pump, swelling of brain cellular elements due to water

Chapter 64 Brain Ischemia accumulation ▫ Vasogenic: ↑ permeability of blood-brain barrier → ↑ extracellular fluid volume due to ↑ passing of proteins, other macromolecules Liquefactive necrosis ▪ First 48 hours: edema, paleness of affected region ▪ 2–10 days: affected area gelatinous; noticeable border between healthy, damaged tissue ▪ 3–21 days: liquefaction of tissue; fluid-filled cavity Seizures ▪ Brain injury → ↑ irritability of nervous tissue with neuronal discharges Deep vein thrombosis ▪ Esp. immobilized individuals Pneumonia ▪ Swallowing mechanism impairment → aspiration pneumonia ▪ Intubation/ventilatory support → ↑ risk for pneumonia Dysphagia ▪ Due to damage of cortex, subcortical structures responsible for swallowing Dementia ▪ Altered memory, cognition, behavior due to brain damage

SIGNS & SYMPTOMS Thrombosis ▪ Neurological defects Embolism ▪ Sudden start of symptoms; maximum defects Lacunar stroke ▪ Contralateral, mostly motor/sensory defects; four syndromes ▫ Pure motor stroke: internal capsule lesion ▫ Pure sensory stroke: thalamus lesion ▫ Ataxic hemiparesis ▫ Dysarthria: speech, swallowing

difficulties; facial weakness; hand weakness, clumsiness (clumsy hand syndrome) Anterior cerebral artery ▪ Contralateral hemiparesis (esp. leg, face), sensory deficit; inability to understand, produce speech (left hemisphere); impaired judgment; incontinency Middle cerebral artery ▪ Contralateral paresis (esp. face, arm), sensory deficit; inability to understand, produce speech (left hemisphere); hemispatial neglect (right hemisphere); homonymous hemianopsia; deviation of eye to damaged side Posterior cerebellar artery ▪ Homonymous hemianopsia ▪ Cortical blindness (bilateral lesion) ▪ Midbrain ▫ Oculomotor, trochlear palsy → dilated pupil ▪ Thalamus ▫ Sensory loss, impaired memory, altered consciousness ▪ Posterior cerebellar artery syndrome (PICA) ▫ AKA “Wallenberg” syndrome ▫ Dizziness, nystagmus; speech, swallowing difficulties ▫ Ipsilateral: facial sensory loss, Horner’s sign, ataxia ▫ Contralateral: loss of pain, temperature sensation in limbs Basilar, vertebral arteries ▪ Dizziness; gait, vision disorders; dysarthria, dysphagia ▪ Locked-in syndrome ▫ Thrombosis/embolism of basilar artery ▫ Plegia of head, body muscles, except eye; only blinking, vertical eye movement possible

DIAGNOSIS DIAGNOSTIC IMAGING ▪ If applicable

Noncontrast CT scan ▪ First few hours

OSMOSIS.ORG 489

▫ Affected tissue appears normal ▪ Later ▫ Loss of differentiation between white, grey matter ▫ Hypodense parenchyma with sulcal effacement ▫ Loss of insular ribbon sign CT perfusion ▪ Detection of core, ischemic penumbra CT angiography ▪ Find thrombus, embolus in blood vessel/ intra-arterial thrombolysis MRI ▪ T1, T2 weighted imaging (see table) ▪ Diffusion-weighted imaging ▫ Shows ischemic stroke early; differentiation from acute, chronic ▪ Fluid-attenuated inversion recovery (FLAIR) sequence ▫ Hyperintense signal within 12 hours Transcranial Doppler ultrasound ▪ Visualization of occlusion in middle cerebral artery/intracranial carotid/vertebrobasilar artery Conventional angiography ▪ Visualize occlusion; for confirmation of CTA, MRA findings

LAB RESULTS

▪ Blood tests ▫ ↑ cardiac markers in heart disease ▫ ↑ erythrocytes in polycythemia vera ▫ Toxicology screening (individual suspected of sympathomimetics abuse) ▫ ↑ blood glucose level

OTHER DIAGNOSTICS

▪ Symptoms, neurological changes scoring ▪ Based on National Institute of Health stroke scale (NIHSS)

ECG ▪ Detection of myocardial ischemia/atrial fibrillation

490 OSMOSIS.ORG

Figure 64.3 A CT scan of the head in the axial plane demonstrating a large ischemic stroke in territory of the middle cerebral artery. The scan was performed three days after the onset of symptoms.

TREATMENT MEDICATIONS

▪ Establishment of blood flow in ischemic penumbra ▫ Thrombolytic enzymes: rtPA; alteplase given within 4.5 hours; after hemorrhagic stroke ruled out ▫ Antiplatelet therapy: aspirin (325mg orally within 48 hours); other drugs (e.g. clopidogrel/aggrenox) ▪ Hypertension treatment ▫ IV labetalol/nicardipine: only if systolic pressure > 220, diastolic > 120 mmHg; except in individuals with vital indications for lowering blood pressure (acute myocardial infarction, kidney failure, dissection of aorta) ▪ Cerebral edema management ▫ Antipyretic: if temperature ≥ 40°C/ 100.4ºF ▫ IV insulin: hyperglycemia; keep glucose between 140–180 mg/dl (7.8–10 mmol/L)

Chapter 64 Brain Ischemia ▪ Prevention ▫ Anticoagulant medications: emboli prevention (e.g. warfarin, aspirin)

SURGERY

▪ Establishment of blood flow in ischemic penumbra ▫ Mechanical embolus removal in cerebral ischemia (MERCI) retriever ▫ Penumbra system (aspiration, extraction) ▫ Solitaire revascularization device, Trevo (stent-retriever systems) ▪ Cerebral edema management ▫ Craniectomy

OTHER INTERVENTIONS

▪ Cerebral edema management ▫ Hyperbaric oxygen therapy: ↑ pure oxygen supply in damaged regions ▫ Fluid management: isotonic saline without dextrose ▪ Protection of airwaves, prevention of aspiration ▫ Head elevation by 30%, nothing by mouth/nil per os (NPO) status ▪ Prevention ▫ Control risk factors (for atherosclerosis): e.g. smoking, hypertension, diabetes, aspirin use; carotid endarterectomy ▫ Lifestyle alteration: exercising, appropriate diet

PSYCHOTHERAPY

▪ If applicable ▪ Type of psychotherapy (e.g. group therapy, exposure therapy) with goal of psychotherapy

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SACCULAR ANEURYSM osms.it/saccular-aneurysm PATHOLOGY & CAUSES ▪ Asymmetrical ballooning of blood vessel wall ▪ Bifurcation of arteries common place esp. on circle of Willis due to weakness of wall, turbulent blood flow ▫ Anterior communicating (most common); posterior communicating; middle cerebral; internal carotid; basilar artery tip

TYPES Type A ▪ Blood vessel wall with endothelium, linear smooth muscle Type B ▪ Disorganization of smooth muscle, thickening of wall Type C ▪ Hypocellular wall with thickening of intima/ luminal thrombosis Type D ▪ Hypocellular wall coated with thin thrombosis layer

CAUSES

▪ Inborn defect of arteries, lack of external lamina, tunica media → hemodynamic stress over years → gradual ballooning of blood vessel wall, thickening of intima, adventitia

RISK FACTORS

▪ More common in individuals who are biologically female, > 50 years (due to estrogen deficiency) ▪ Diseases associated with aneurysm ▫ Ehler–Danlos syndrome, pseudoxanthoma elasticum, lupus, autosomal dominant polycystic kidney

492 OSMOSIS.ORG

disease (ADPKD), bacterial endocarditis, fibromuscular dysplasia ▪ Familial predisposition; smoking; alcohol, cocaine use; hypertension; trauma

COMPLICATIONS

▪ Warning leaks ▫ May precede aneurysm rupture; strong headaches, photophobia, nausea/ vomiting ▪ Rupture → subarachnoid hemorrhage ▫ Apex of aneurysm/atheromatous plaque edge ▫ ↑ risk in smokers, individuals with migraines, elderly, affection of posterior circulation, larger size ▪ Ischemia ▫ Thrombus forms within aneurysm → detachment of small particles (emboli) → emboli lodges → ischemia of downstream tissue ▪ Multiple aneurysms

SIGNS & SYMPTOMS ▪ May be asymptomatic if small ▪ Mass effect symptoms due to size ▫ Anterior communicating artery: both leg weakness with positive Babinski sign ▫ Posterior communicating, internal carotid artery: headaches with palsy of oculomotor nerve ▫ Left middle cerebral artery: inability to understand, produce speech ▫ Right middle cerebral artery: contralateral field vision loss

Chapter 64 Brain Ischemia

DIAGNOSIS DIAGNOSTIC IMAGING CT/MR angiography ▪ Detect aneurysms > 2mm

TREATMENT SURGERY

▪ Endovascular management ▫ Aneurysmal coiling with thrombosis → endothelialization across aneurysm neck → prevents rebleeding, regrowth ▫ In development: stent-assisted, balloonassisted coiling; disruptors, flow diverters ▪ Surgical clipping

OTHER INTERVENTIONS

▪ Regular monitoring with CTA/MRA ▪ Avoid smoking, alcohol, drugs, excessive strain

SUBARACHNOID HEMORRHAGE (SAH) osms.it/subarachnoid-hemorrhage

▪ Bleeding into space between pia mater, arachnoid membrane ▪ Injury/spontaneous event → rupture of blood vessel in subarachnoid space → release of blood into cerebrospinal fluid (CSF) → rapid ↑ intracranial pressure

▪ Smoking; hypertension; alcohol, cocaine abuse ▪ Diseases associated with saccular aneurysm (e.g. blood vessel disorders, Ehlers–Danlos syndrome, Marfan syndrome, polycystic kidney disease) ▪ Sickle cell disease ▪ Coagulopathies

CAUSES

COMPLICATIONS

PATHOLOGY & CAUSES

▪ Traumatic: head injury (e.g. bridging vein tear) ▪ Spontaneous: arterial origin (more common) ▫ Rupture of saccular “berry” aneurysms (e.g. anterior half of circle of Willis) ▫ Arteriovenous blood vessel malformations

RISK FACTORS

▪ More common in individuals who are biologically female, elderly

▪ Vasospasm ▫ Delayed ischemia; 4–11 days after SAH ▫ Blood clot lysis → release of spasmogenic substances (e.g. endothelin), ↓ production of nitric oxide → vasospasm due to smooth muscle contraction → brain ischemia ▪ Hydrocephalus ▫ Clogging of CSF drainage ▪ Rebleeding ▫ May occur two weeks after SAH ▫ ↑ tendency in individuals with

OSMOSIS.ORG 493

▪

▪ ▪

▪ ▪ ▪

hypertension, anxiety, seizures postSAH ▫ Associated with ↑ mortality, neurological damage Sympathetic hyperactivity due to ↑ intracranial pressure, SAH (“sympathetic surge”) → sudden, life-threatening ↑ of blood pressure due to vasoconstriction ↑ plasma adrenaline levels due to sympathetic hyperactivity → arrhythmias Over-action of sympathetic nervous system → pulmonary vasoconstriction → ↑ capillary permeability, pressure → neurogenic pulmonary edema Hyponatremia Meningitis (irritation from presence of blood) Seizures

SIGNS & SYMPTOMS ▪ Area of brain ▫ Anterior/middle cerebral artery: numbness, sudden muscle weakness ▫ Broca’s area: slurred speech ▫ Wernicke’s area: difficulty understanding speech ▪ ↑ intracranial pressure ▫ Thunderclap headache: “worst ever” headache; may be only symptom ▫ Nausea, vomiting ▪ Altered consciousness; coma, confusion, seizures ▪ Meningeal irritation: bleeding into subarachnoid space filled with CSF → blood degradation → irritation of meninges, development of aseptic meningitis ▫ Neck pain, stiffness ▫ Positive meningeal signs: Kernig’s (pain generated by knee extension from 90º); Brudzinski’s (forced neck flexion → spontaneous knee, hip flexion) ▫ Photophobia ▪ Focal neurological signs ▫ Posterior communicating artery aneurysm rupture/brain herniation due to ↑ intracranial pressure → oculomotor nerve paralysis → ipsilateral ptosis; eye pointed down, out; mydriasis, loss of pupillary light reflex

494 OSMOSIS.ORG

▫ ↑ intracranial pressure → abducens nerve paralysis → eye pointing out → diplopia

DIAGNOSIS DIAGNOSTIC IMAGING Noncontrast CT scan ▪ Fisher scale grading ▫ Group 1: no hemorrhage ▫ Group 2: blood depositions < 1mm, without blood clots ▫ Group 3: blood depositions > 1mm, with localized clots ▫ Group 4: diffuse/lack of subarachnoid hemorrhage with extension to ventricles, brain parenchyma ▪ Hydrocephalus ▫ “Mickey Mouse” ventricular system appearance MRI ▪ Visualize arteriovenous malformations (not detected by angiography) Digital-subtraction cerebral/CT/MR angiography ▪ Visualize aneurysm

LAB RESULTS

▪ Identify hematologic abnormalities ▪ PT, aPTT: identify coagulopathies ▪ ↑ troponin, if heart abnormalities present

OTHER DIAGNOSTICS

▪ Lumbar puncture ▫ ↑ erythrocytes in all three samples ▫ CSF centrifugation: yellow coloration due to erythrocytes breakage, release of heme (“xanthochromia”); positive 3–4 weeks after SAH ▪ Physical examination ▫ Characteristic neurological presentation; fever; tachycardia; fundoscopy (optic disc swelling, retinal hemorrhages)

ECG ▪ ↑ QRS, QT intervals; ↓ PR intervals; U waves; dysrhythmias

Chapter 64 Brain Ischemia

TREATMENT MEDICATIONS

▪ Antihypertensive therapy: beta-blockers; hydralazine, calcium channel blockers; ACE inhibitors ▪ Intracranial pressure treatment: osmotic, loop diuretics ▪ Prior all procedures: IV midazolam (initial treatment) ▪ Vasoconstriction treatment: calcium channel blocker (e.g. nimodipine), recombinant tissue plasminogen activator ▪ Seizure treatment: phenytoin/phenobarbital ▪ Pulmonary edema treatment: diuretics, dobutamine

SURGERY

Figure 64.4 A CT scan of thea head in the sagittal plane demonstrating high signal in the sulci of the frontal lobe, consistent with a subarachnoid hemorrhage.

▪ Aneurysm treatment: endovascular coiling (with aneurysm obliteration), craniotomy (with aneurysm neck clipping, coiling) ▪ Vasoconstriction: aspiration/irrigation of blood clot during clipping process, CSF drainage, transluminal balloon angioplasty ▪ Hydrocephalus: temporary/serial lumbar puncture for CSF drainage, permanent ventricular shunt, ventriculostomy

OTHER INTERVENTIONS

▪ Vital sign stabilization ▪ Intubation if comatose, heart monitoring (initial treatment) ▪ Keep blood pressure < 140mmHg to avoid rebleeding

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SUBDURAL HEMATOMA (SDH) osms.it/subdural-hematoma PATHOLOGY & CAUSES ▪ Intracranial bleeding with blood accumulation between dura mater, arachnoid membrane ▪ Head trauma → tearing of venous blood vessels/small cortical arteries → blood accumulation → limited blood mass expansion due to adherent dural attachments → brain tissue compression

TYPES Acute ▪ Slow blood outflow into subdural space due to low pressure in bridging veins Subacute ▪ Combination of fluid, clotted blood Chronic ▪ Caused by minor trauma/inflammation ▪ More common in elderly ▪ Head trauma with small bleeding, dural border cell damage → inflammation, unsuccessful attempt to repair border cells with formation of granulation tissue → encapsulation; development of blood vessels within new membrane → erythrocytes, plasma exudation from leaky capillaries to encapsulated space → recurrent bleeding with expansion

CAUSES

▪ Head trauma (most common) ▪ Acceleration-deceleration (coupcontrecoup injury) ▪ cceleration of body → sudden stop with forwarding momentum carrying brain → impacts front of skull → backward brain movement → impacts back of skull → bridging veins tear ▪ Intracranial hypotension ▫ ↓ CSF due to lumbar puncture/ lumboperitoneal shunt → ↑ traction

496 OSMOSIS.ORG

of brain on surrounding structures → bridging veins tear ▪ Shaken baby syndrome ▪ Spontaneous ▫ Vascular malformations ▪ Neurosurgical procedure complication

RISK FACTORS

▪ Brain atrophy elderly ▫ ↑ bridging veins stretch ▪ Infants, alcohol abusers ▫ Thinner wall of bridging veins ▪ Epilepsy, anticoagulant drugs, thrombocytopenia

COMPLICATIONS

▪ Liquefaction of granulation tissue in chronic subdural hematoma (subdural hygroma) → ↑ protein → expansion of mass due to water drawn by osmotic pressure → mass effect brain injuries ▪ ↑ intracranial pressure → supratentorial, infratentorial herniation of brain ▪ Progressive dementia in chronic subdural hematoma

SIGNS & SYMPTOMS ▪ Loss of consciousness after trauma/in ensuing days due to hematoma expansion ▪ Bleeding characteristics ▫ Hemispheric: most common ▫ Interhemispheric: altered consciousness, headache, hemiparesis ▪ Physical examination ▫ Broken basilar skull: periorbital ecchymosis (raccoon eyes), retroauricular ecchymosis (Battle’s sign) ▫ CSF rhinorrhea/otorrhea ▪ Acute subdural hematoma ▫ Neurological presentation in 48–72 hours

Chapter 64 Brain Ischemia ▫ May be comatose/awake ▫ Sudden, severe headache with nausea, vomiting; unequal pupils; difficulties in speech, swallowing; palsies of cranial nerves ▪ Subacute ▫ Presents 2–14 days ▪ Chronic ▫ Present 14 days after injury ▫ Impaired cognitive skills, altered consciousness, headaches, contralateral/ ipsilateral hemiparesis (depends on hematoma location), hemianopsia, optic disc swelling

DIAGNOSIS DIAGNOSTIC IMAGING CT scan ▪ Acute: crescent-shape hyperdense blood collection ▪ Subacute/chronic: isodense/hypodense crescentic mass MRI ▪ T2-WI (acutely): hypointense blood clot due to deoxyhemoglobin ▪ T1, T2-WI (in following weeks): bright appearance; deoxy → methemoglobin ▪ T1-WI (months later): hypointense clot due to hemosiderin remains MR/CT angiography ▪ Spontaneous SDH

Figure 64.5 A CT scan in the axial plane demonstrating a large, right-sided, subdural hematoma. The hematoma has a classical crescentic shape.

TREATMENT MEDICATIONS

▪ Diuretics ▫ ↓ intracranial pressure ▪ Vitamin K/factor VIII inhibitor activity bypassing agent (FEIBA)/frozen plasma ▫ Anticoagulation reverse; ↓ risk of hematoma enlargement; individuals undergoing surgery

SURGERY

▪ If clot thickness > 10mm, midline shift > 5mm, intracranial pressure > 20mmHg ▫ Burr hole, craniotomy, decompressive craniectomy, blood vessel ligation

OTHER INTERVENTIONS

▪ Nonsurgical treatment based on Glasgow coma score (GCS); clot thickness (< 10mm); neurological examination; stable/ deteriorated condition; comorbidities, associated injuries; age

OSMOSIS.ORG 497

TRANSIENT ISCHEMIC ATTACK (TIA) osms.it/transient-ischemic-attack PATHOLOGY & CAUSES ▪ Short-lasting neurological dysfunction due to transient focal ischemia, without infarction ▪ Blood vessel occlusion/stenosis → ↓ blood flow in affected region → neurological dysfunction

CAUSES

▪ Adults: thrombosis, hypoperfusion, emboli ▪ Children: congenital heart defects with thrombosis, coagulopathies, idiopathic progressive arteriopathy of childhood (Moyamoya disease)

RISK FACTORS

▪ More common in black individuals of African descent who are biologically male; ↑ risk with age ▪ Family history, hypertension, diabetes, obesity, obstructive sleep apnea, ↑ lowdensity lipoprotein (LDL), ↓ high-density lipoprotein (HDL), atherosclerosis, cocaine abuse, smoking

COMPLICATIONS ▪ Recurrent TIA ▪ Ischemic stroke

SIGNS & SYMPTOMS ▪ Duration: few minutes to one hour ↓ flow in large arteries (few minutes) ▪ Numbness/paresis ▫ Face, cheek, tongue, arm, hand, leg ▪ Aphasia ▫ If dominant hemisphere affected ▪ Hemispatial neglect

498 OSMOSIS.ORG

▫ If nondominant hemisphere affected ▪ Distal vertebral artery ▫ Dizziness, difficulty speaking, double vision ▪ Mid-basilar artery ▫ Dizziness, paresis affecting both legs/ arms Embolic TIA (> one hour) ▪ Anterior cerebral circulation ▫ Symptoms depend on blood vessel lodged ▫ Middle cerebral artery: contralateral hemiplegia; aphasia if dominant hemisphere; hemispatial neglect if nondominant ▫ Branches of middle cerebral artery: numbness/motor function loss; face, arm, leg ▫ Ophthalmic artery: amaurosis fugax; transient monocular/binocular vision loss ▪ Posterior cerebral circulation ▫ Dizziness, focal hearing loss, speech difficulties, double vision, hemi/ quadrantanopia, face/body numbness ▫ Basilar artery: thalamus, subthalamus, medial midbrain, reticular activating system → stupor/coma

DIAGNOSIS DIAGNOSTIC IMAGING CT/MR/conventional catheter angiography ▪ Occlusion within blood vessel Diffusion-weighted MRI ▪ Ischemic regions corresponding to neurologic symptomatology ▪ Changes seen within first few hours of symptoms

Chapter 64 Brain Ischemia Perfusion-weighted MRI ▪ ↓ tissue blood flow Neck Doppler ultrasound ▪ Evaluate carotid stenosis

LAB RESULTS

▪ Hypoglycemia, hyponatremia, thrombocytosis: rule out conditions that mimic TIA

OTHER DIAGNOSTICS

▪ See mnemonic ▫ ABCD2 score: evaluate risk for possible ischemic stroke (can occur two days after TIA)

MNEMONIC: ABCD2

Evaluating ischemic stroke risk Age Blood pressure Clinical features Duration of symptoms Diabetes

TREATMENT MEDICATIONS

▪ Antiplatelet (noncardioembolic TIA) ▫ Aspirin/extended-release dipyridamole/ aspirin + clopidogrel ▪ Anticoagulation ▫ Atrial fibrillation: low-molecular-weight heparin ▫ Heart thrombus: in acute myocardial infarction/rheumatic mitral valve; warfarin + direct acting oral anticoagulants (e.g. apixaban) ▪ Diuretics, angiotensin-converting enzyme (ACE) inhibitors ▫ Blood pressure control ▪ Statins ▫ Cholesterol management

SURGERY

▪ Same side carotid stenosis/TIA ▫ Carotid endarterectomy

OTHER INTERVENTIONS ▪ Mediterranean diet

OSMOSIS.ORG 499

NOTES

NOTES

CEREBRAL CORTEX NERVOUS SYSTEM INFECTIONS

GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Infection, inflammatory disorders of central nervous system (CNS), surrounding tissues

CAUSES

▪ Bacteria (most common), viruses, fungi, parasites, prions, aberrant immune responses, reactions to medications

RISK FACTORS

▪ Immunocompromised individuals (e.g. HIV, diabetes, chemotherapy, corticosteroid use)

SIGNS & SYMPTOMS ▪ ▪ ▪ ▪

Fever Headache Focal neurological symptoms Altered level of consciousness

DIAGNOSIS DIAGNOSTIC IMAGING Brain CT scan/MRI ▪ With contrast: bright ring with dark center indicates brain abscess; underlying sinusitis, thickening of superior ophthalmic vein, irregular filling defects indicate cavernous sinus thrombosis; fluid collections in epidural space indicate epidural abscesses ▪ Focal/diffuse diffusion-restriction, cerebellar atrophy indicates Creutzfeldt–Jakob disease (CJD)

LAB RESULTS

▪ Lumbar puncture (if not contraindicated) ▫ Culture, biochemical analysis of fluid ▪ Blood cultures

TREATMENT MEDICATIONS

▪ Empiric antibiotic therapy followed by targeted therapy once cause identified ▪ Corticosteroids to manage inflammation/ cerebral edema

500 OSMOSIS.ORG

Chapter 65 Cerebral Cortex Nervous System Infections

BRAIN ABSCESS osms.it/brain-abscess PATHOLOGY & CAUSES ▪ Localized focal necrosis of brain tissue with inflammation, usually caused by bacterial infection ▪ Rare (de novo within brain; primary infection typically arises elsewhere, spreads to brain) Sources of infection ▪ Direct implantation ▫ Traumatic inoculation (e.g. head trauma → skull fracture with broken skin → bacterial contamination) ▫ Iatrogenic: contamination through invasive procedures ▪ Local extension from adjacent foci of infection ▫ Ear infection, dental abscess, paranasal sinusitis, mastoiditis, epidural abscess ▪ Hematogenous spread ▫ Distant sources of infection (e.g. organ infection) ▫ Congenital heart disease with right-toleft shunt → loss of pulmonary filtration of microorganisms → abscesses in distribution of middle cerebral artery ▪ Common causative bacterial organisms (abscesses often polymicrobial) ▫ Staphylococcus aureus, Streptococcus, Bacteroides, Enterobacteriaceae, Pseudomonas ▪ Immunocompromised hosts may develop viral/fungal abscesses, commonly caused by poliovirus, Toxoplasma gondii, Cryptococcus neoformans

RISK FACTORS

▪ Right-to-left cardiac shunts, bronchiectasis, immunosuppression

SIGNS & SYMPTOMS ▪ Classic triad (20% of cases) ▫ Fever, progressively worsening focal neurology, headache ▫ Increased intracranial pressure (ICP) while supine → worse headache early morning, at night/increased ICP stimulates medullary center, area postrema → morning vomiting ▪ Mental status change, seizures, nausea, vomiting, papilledema

DIAGNOSIS DIAGNOSTIC IMAGING MRI/CT scan with contrast ▪ Initial immature lesions without capsule: difficult to distinguish from spaceoccupying lesions/infarcts ▪ 4–5 days after initial infection: formation of capsule around necrotic focus → ringenhancing appearance ▫ Intravenous contrast material cannot pass through capsule → accumulation around lesion → bright ring with dark center

LAB RESULTS

▪ Lumbar puncture ▫ If intracranial pressure not significantly raised ▫ ↑ white cell count, ↑ protein concentration, normal glucose content ▪ Abscess aspirate ▫ Sample obtained via imaging-guided aspirate/during surgical drainage; culture of causative organism → specific treatment

COMPLICATIONS

▪ Ischemia/necrosis of pituitary → pituitary insufficiency → Addisonian crisis

OSMOSIS.ORG 501

TREATMENT MEDICATIONS

▪ Targeted antibiotic therapy ▫ Penetration through abscess wall poor, typically accompanies surgical management ▪ Hyperbaric oxygen therapy ▫ Reduces intracranial pressure, bacteriostatic, enhances oxidative immune function ▪ Corticosteroids in complicated cases with pituitary insufficiency

SURGERY

▪ Drainage ▪ Removal of any foreign material

Figure 65.1 A CT scan of the head in the axial plane demonstrating a abscess in the left frontal lobe. This example developed five weeks following a repair of a depressed skull fracture.

CAVERNOUS SINUS THROMBOSIS osms.it/cavernous-sinus-thrombosis PATHOLOGY & CAUSES Cavernous sinuses ▪ Irregularly shaped, trabeculated, blood filled cavities, acts as venous channel between endosteum, dura mater at base of skull ▪ Numerous important structures pass through cavernous sinuses ▫ Internal carotid artery ▫ Cranial nerves III, IV, V (branches V1, V2), VI ▪ Drain into internal jugular vein Infection ▪ Infection → formation of blood clot within cavernous sinus ▪ Infection often arises via contiguous spread from nearby infection (e.g. nasal furuncle, sphenoidal/ethmoidal sinusitis/dental infection) ▫ Commonly associated organisms: Staphylococcus aureus, Streptococcus

502 OSMOSIS.ORG

RISK FACTORS

▪ Immunosuppression (e.g. uncontrolled diabetes, corticosteroid use, cancer, chemotherapy) ▪ Thrombophilia ▪ Obesity ▪ Severe dehydration

COMPLICATIONS

▪ Dural venous, cavernous system valveless → communication with dural sinuses, cerebral, emissary veins → meningitis, dural empyema, brain abscess ▪ Spread via jugular vein to pulmonary vasculature → septic emboli, pulmonary abscesses, pneumonia ▪ Carotid artery narrowing → stroke ▪ Ischemia/direct infectious spread → hypopituitarism

Chapter 65 Cerebral Cortex Nervous System Infections

SIGNS & SYMPTOMS ▪ Local compression, inflammation of cranial nerves (III–VI) → several partial/complete cranial neuropathies ▫ Diplopia, limited eye abduction, nonreactive pupil, numbness/paresthesia around eyes, nose, forehead, facial pain ▪ Decreased drainage from facial vein, superior, inferior ophthalmic veins → periorbital edema, chemosis (conjunctival swelling), proptosis, headache

DIAGNOSIS DIAGNOSTIC IMAGING CT scan ▪ Non-contrast: high-density thrombus in cavernous sinus ▪ With contrast: underlying sinusitis, thickening of superior ophthalmic vein, irregular filling defects in cavernous sinus

MRI ▪ T1, T2: absent flow void, abnormal signal characteristics of affect cavernous sinus ▪ Contrast venogram: deformity of internal carotid artery in cavernous sinus, signal hyperintensity in thrombosed vascular sinuses

TREATMENT MEDICATIONS

▪ Broad spectrum empiric antibiotic therapy until primary agent, source identified

SURGERY

▪ Sinus drainage (e.g. drainage, sphenoidotomy if primary infection arises from sphenoidal sinuses)

CREUTZFELDT–JAKOB DISEASE osms.it/creutzfeldt-Jakob-disease PATHOLOGY & CAUSES ▪ Universally fatal prionopathy; spongiform encephalopathy → rapidly progressive dementia ▪ Native prions play role in long-term memory, neuronal repair ▪ Infectious prions composed entirely of protein, folded in structurally abstract conformations; able to pass on “misfolded” conformation ▫ Infectious prions propagate by inducing misfolding of native host prion proteins → formation of new infectious prions ▫ Malformed prion proteins extremely stable (resistant to denaturation by enzymes) → accumulation in infected neuronal tissue → formation of amyloid sheets → eventual tissue damage, death

→ holes form where nerves died → sponge-like appearance on microscopy

TYPES

▪ Sporadic (sCJD) ▫ Majority (> 85%) of cases occur spontaneously ▪ Familial (fCJD) ▫ Minority (< 10%) transferred via autosomal dominant inheritance ▪ Variant (vCJD) ▫ Bovine-to-human transmission of bovine spongiform encephalopathy ▪ Iatrogenic (iCJD) ▫ Exposure to brain/spinal tissue from infected individual (e.g. cadaveric human pituitary hormone)

OSMOSIS.ORG 503

RISK FACTORS

▪ Exposure to harvested human brain products (e.g. corneal grafts, dural grafts, human growth hormone), ingestion of infected bovine products, cannibalism

COMPLICATIONS

▪ Progressive neurodegeneration → dysphagia → aspiration pneumonia common

TREATMENT MEDICATIONS

▪ Sedatives/antidepressants/antipsychotics ▫ Palliative, relief of psychiatric symptoms ▪ Benzodiazepines/antiepileptics ▫ Palliative, relief of movement disorders (e.g. myoclonic jerks)

SIGNS & SYMPTOMS ▪ Rapidly progressive dementia: memory loss, personality change, hallucinations ▪ Movement disorders: myoclonus, ataxia, rigid posture ▪ Psychiatric: anxiety, depression, psychosis

DIAGNOSIS DIAGNOSTIC IMAGING MRI ▪ Diffusion-weighted MRI ▫ Focal/diffuse diffusion-restriction involving cerebral cortex/basal ganglia ▪ Fluid-attenuated inversion recovery (FLAIR)/T2-weighted ▫ Hyperintense signal changes in basal ganglia, thalamus, cortex ▪ Cerebellar atrophy

LAB RESULTS

▪ Cerebrospinal fluid (CSF) ▫ Elevated concentration of 14-3-3 protein ▪ Tissue biopsy ▫ Prion deposits in brain (definitive diagnosis) skeletal muscle, tonsils, spleen; classical histological appearance → spongiform change in gray matter

OTHER DIAGNOSTICS

▪ Electroencephalography (EEG) ▫ Generalized periodic sharp wave pattern

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Figure 65.2 A section of the brain demonstrating a prion plaque. This individual displayed the symptoms of variant CJD.

Chapter 65 Cerebral Cortex Nervous System Infections

ENCEPHALITIS osms.it/encephalitis PATHOLOGY & CAUSES

SIGNS & SYMPTOMS

▪ Acute inflammatory brain disease due to direct invasion/pathogen-initiated immune response → inflammation of brain parenchyma (often with meningitis) ▫ Peripheral nerves conduits to brain parenchyma for viral infection—rabies, herpes simplex virus (HSV) ▫ Hematogenous spread → transfer of infections from distant sites

▪ Fever, chills, malaise ▪ Meningeal involvement → meningism ▫ Nuchal rigidity (inability to flex neck forward passively due to increased muscle tone, stiffness), headache, photosensitivity ▪ Parenchymal involvement → focal neurological signs, seizures, altered mental state

CAUSES

▪ Viral (most common): HSV-1 (most common), arbovirus (e.g. West Nile virus), enterovirus (e.g. Polio), varicella zoster virus (VSV), Epstein Barr virus (EBV), HIV, influenza ▪ Bacterial: Listeria monocytogenes, mycobacteria, spirochetes (e.g. syphilis) ▪ Parasites: protozoa (e.g. Toxoplasma), malaria ▪ Fungi: cryptococcus ▪ Non-infectious, autoimmune: acute disseminated encephalomyelitis, anti-Nmethyl-D-aspartate (NMDA) receptor encephalitis, T-cell lymphoma

RISK FACTORS

▪ Immunosuppression ▪ Travel to low-income nations ▪ Exposure to disease vectors in endemic areas

COMPLICATIONS

▪ Seizures, syndrome of inappropriate secretion of antidiuretic hormone (SIADH), increased ICP, coma

DIAGNOSIS DIAGNOSTIC IMAGING Brain CT scan (with/without contrast) ▪ Complete prior to lumbar puncture to exclude significantly increased ICP, obstructive hydrocephalus, mass effect Brain MRI ▪ Increased T2 signal intensity in frontotemporal region → viral (HSV) encephalitis

LAB RESULTS Blood tests ▪ Blood, CSF cultures ▫ Bacterial pathogens ▪ Blood glucose ▫ Comparison with CSF glucose; exclude confusion due to hypoglycemia ▪ Toxoplasma serology CSF ▪ CSF chemistry ▫ Lymphocytosis (> 5WBC/mL) with normal glucose → viral encephalitis ▪ CSF polymerase chain reaction (PCR) ▫ Diagnosis of specific viral cause ▪ Specific antibody testing for EBV, arbovirus

OSMOSIS.ORG 505

Tissue analysis ▪ Tzanck smear (from base) of suspicious skin lesions → identify presence of VZV/HSV ▪ Brain biopsy (definitive diagnosis) ▫ Cowdry type A inclusions (HSV, VZV, CMV) ▫ Hemorrhagic necrosis in temporal, orbitofrontal lobes (HSV)

OTHER DIAGNOSTICS

▪ EEG ▫ Temporal lobe discharges → viral (HSV) encephalitis

TREATMENT MEDICATIONS

▪ Viral encephalitis ▫ HSV encephalitis: acyclovir ▫ CMV encephalitis: ganciclovir/foscarnet ▫ Most viral infections lack specific antiviral agent ▪ Bacterial encephalitis ▫ Targeted antibiotics

Figure 65.3 An MRI scan of the head demonstrating increased signal in the left temporal lobe. HSV encephalitis was later confirmed by PCR of the cerebrospinal fluid.

Figure 65.4 A histological section of the brain demonstrating a lymphocytic infiltrate in an individual with encephalitis.

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Chapter 65 Cerebral Cortex Nervous System Infections

EPIDURAL ABSCESS osms.it/epidural-abscess PATHOLOGY & CAUSES ▪ Collection of pus, infectious material in epidural space of CNS

TYPES Intracranial epidural abscess ▪ Dura mater (tough outermost layer of meninges) directly in contact with skull ▪ Puss, granulation tissue accumulate between dura mater, cranial bone ▪ Dura adheres tightly to skull → limits expansion → dangerously increases ICP ▪ Typically caused by Staphylococci/ Streptococci reaching dural space ▫ Direct extension from local infection (e.g. ear/paranasal sinuses) → osteomyelitis → abscess formation ▫ Hematogenous seeding from distant infection ▫ Iatrogenic spread due to invasive procedures ▪ Risk factors: prior craniotomy, head injury, sinusitis, otitis media, mastoiditis ▪ Complications: seizures, increased ICP → uncal/tonsillar herniation, hemorrhage into abscess, septic shock Spinal epidural abscess ▪ Spinal epidural space ▫ Outermost space within spinal canal (formed by vertebrae, lying outside dura mater) ▫ Contains lymphatics, spinal nerve roots, connective tissue, fat, vasculature ▪ Collection of pus/inflammatory granulation tissue between dura mater, vertebral column → spinal epidural abscess → physical compression, inflammation of surrounding tissues, spinal cord → local ischemia

▪ Loose association between dura, vertebral bodies → extension of spinal epidural abscess to multiple spinal levels → extensive neurological findings ▪ Typically caused by Staphylococcus aureus, enteric gram-negative bacilli (e.g. E. coli), coagulase-negative Staphylococci reaching dural space ▫ Direct extension of local infection; vertebral osteomyelitis, psoas abscess, soft-tissue infection ▫ Hematogenous seeding from distant infection ▫ Iatrogenic spread due to invasive procedures ▪ Risk factors: old age, invasive spinal procedures, immunocompromised states, intravenous drug use, most common in thoracolumbar area (epidural space larger, contains more fat tissue) ▪ Complications: recurrent sepsis, spinal cord injury → bladder dysfunction

SIGNS & SYMPTOMS ▪ Fever, malaise ▪ Cranial epidural abscess ▫ Pain/tenderness over abscess site, pus draining from ear/sinuses, neck stiffness, headache, nausea, vomiting ▪ Spinal epidural abscess (staging follows clinical progression) ▫ Back pain, tenderness, fever ▫ Radicular pain, reflex abnormalities ▫ Sensory abnormalities, motor weakness, loss of bowel/bladder control ▫ Paralysis (progresses to irreversible paralysis without rapid surgical intervention)

OSMOSIS.ORG 507

DIAGNOSIS DIAGNOSTIC IMAGING CT scan with contrast ▪ Fluid collections in epidural space MRI with contrast ▪ Homogeneous enhancement of abnormal area, liquid abscess surrounded by inflammatory tissue showing varying degrees of peripheral enhancement X-ray ▪ Osteomyelitis, vertebral collapse

LAB RESULTS

▪ Blood cultures ▫ May culture causative organism ▪ Lumbar puncture contraindicated ▫ Risk of spreading infection to subarachnoid space ▪ CT-guided aspirates/surgically-obtained fluid ▫ Culture causative organism

TREATMENT MEDICATIONS

▪ Initial empirical antibiotic therapy, broadspectrum coverage for gram-positive, gram-negative organisms ▫ Vancomycin (Gram-positive coverage), third-generation cephalosporins (Grampositive, Gram-negative) ▪ Targeted antibiotics specific to isolated organisms

SURGERY

▪ Intracranial ▫ Craniotomy → removal of infected bone, surgical decompression ▪ Spinal ▫ Decompressive laminectomy (CTguided drainage)

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Figure 65.5 A histological section of the brain demonstrating a lymphocytic infiltrate in an individual with encephalitis.

Chapter 65 Cerebral Cortex Nervous System Infections

MENINGITIS osms.it/meningitis PATHOLOGY & CAUSES ▪ Inflammation of meninges surrounding brain, spinal cord

CAUSES Bacteria, viruses, fungi, parasites, noninfectious causes ▪ Non-infectious: e.g. medications, autoimmune disease, malignancy ▪ “Aseptic meningitis” ▫ Don’t culture on typical bacterial media (e.g. viruses, fungi, parasites, noninfectious causes) ▪ Acute illness ▫ Onset: hours, days ▫ Likely viral/bacterial causes ▪ Chronic meningitis ▫ Onset: weeks, months ▫ Likely mycobacteria, fungi, Lyme disease, parasitic causes ▪ Pyogenic meningitis ▫ Most likely bug by age group ▫ Mnemonic: Explaining Big Hot Neck Stiffness (in order from birth to death)

MNEMONIC: Explaining Big Hot Neck Stiffness

Causative microorganisms in meningitis by age group E. coli, Group B streptococcus (infants) Haemophilus influenzae (older infants, kids) Neisseria meningitidis (young adults) Streptococcus pneumoniae (elderly)

Figure 65.6 A sample of cerebrospinal fluid taken from an individual with bacterial meningitis. Microbial spread to CNS ▪ Hematogenous spread (from distant site of infection) ▪ Retrograde transport along cranial/ peripheral nerves (viral illness) ▪ Contiguous spread from local infections of sinuses, ears, overlying bone ▫ Infectious agents colonize nasopharynx/ respiratory tract ▫ Preceding viral infection → breakdown of normal nasal mucosal barrier → colonizing bacteria enter bloodstream → seeding of subarachnoid space in areas where blood-brain barrier vulnerable (e.g. choroid plexus) ▪ Traumatic inoculation Other sources of inflammation ▪ Significant inflammation not directly due to bacterial action ▪ Presence of bacterial antigens (e.g. cell wall products) in CNS → recognition by astrocytes, microglia → cytokine release → inflammation ▪ Inflammation → increased blood-brain barrier permeability → vasogenic cerebral edema

OSMOSIS.ORG 509

▪ Extravasation of white blood cells, plasma into CSF → interstitial edema ▪ Immune cell activity (e.g. further cytokine release, oxidative burst) → inflammation of walls of blood vessels → cerebral vasculitis → decreased blood flow → cytotoxic edema ▪ Collectively edema subtypes → raised intracranial pressure ▪ Administration of antibiotics → greater amounts of bacterial antigens (from dead bacteria) enter CSF → worsening inflammation (initially)

RISK FACTORS

▪ Immunocompromised individuals, unvaccinated individuals (S. pneumoniae, H. influenzae Type B) ▪ Penetrating head trauma ▪ Anatomical meningeal defects (CSF leaks) ▪ Contact with colonized/infected individuals

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COMPLICATIONS

▪ Cerebral edema, cerebral herniation, deafness, epilepsy, hydrocephalus, cognitive deficits

SIGNS & SYMPTOMS ▪ Neonates, children ▫ Fever, lethargy, irritability, vomiting, poor feeding ▪ Adults ▫ Classic triad (< 50% of cases): sudden onset headache, fever, nuchal rigidity ▫ Photophobia, phonophobia (discomfort with loud sounds), confusion, vomiting, papilledema ▫ Brudziński’s sign: passive neck flexion → pain, involuntary flexion of hips, knees ▫ Kernig’s sign: resistance to knee extension when hip flexed to 90º

Chapter 65 Cerebral Cortex Nervous System Infections ▫ Jolt accentuation of headache: headache worsens if individual asked to “jolt” head from side to side in horizontal plane ▪ Meningococcal meningitis ▫ Petechial rash; non-blanching when pressure applied; trunk, lower extremities

TREATMENT MEDICATIONS Prevention ▪ Immunization with meningococcal, mumps, pneumococcal, Hib vaccines

DIAGNOSIS LAB RESULTS

▪ Lumbar puncture ▫ Gram stain; bacterial culture, susceptibility; WBC count, differential; RBC count; glucose, protein concentration ▫ Acid-fast bacilli stain in TB endemic areas/if suspected exposure ▫ HSV/enterovirus PCR

▪ Preemptive treatment to any close contacts of individuals with meningococcal meningitis is a single dose of ceftriaxone/ rifampin Acute bacterial meningitis ▪ Empiric antibiotic therapy based on age ▫ If immediate lumbar puncture performed, obtain sample prior to antibiotics

OSMOSIS.ORG 511

▫ < one week: penicillin (e.g. ampicillin) + third-generation cephalosporin (e.g. cefotaxime)/aminoglycoside ▫ 1 week–3 months: third-generation cephalosporin + vancomycin ▫ > three months: vancomycin ▫ Targeted antibiotic therapy ▫ Corticosteroids: inflammation, cerebral edema (dexamethasone) Aseptic meningitis ▪ HSV, VZV meningitis: acyclovir ▪ Fungal meningitis (cryptococcal meningitis): amphotericin B, flucytosine

Figure 65.7 The brain of an individual at post mortem following death from meningitis. Removal of the dura mater reveals pus surrounding the brain.

Figure 65.8 Post mortem histology of the brain and meninges of an individual who died from acute bacterial meningitis. The zoomed in area demonstrates numerous neutrophils infiltrating the meninges.

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NOTES

NOTES

CEREBROSPINAL MALFORMATIONS

GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Disorders affecting normative central nervous system (CNS) development/ function ▪ Varying severity, intensity

CAUSES

▪ Primary ▫ Genetic mutation/idiopathic ▪ Secondary ▫ E.g. trauma, infection, neoplasm, environmental factors

RISK FACTORS

▪ Cerebral ischemia, delivery trauma, premature birth, teratogenic substance exposure (prenatal) ▪ Supportive structure (bone, connective tissue) malformation → physically obstructs CNS development

SIGNS & SYMPTOMS ▪ Developmental milestones ▫ Not met ▪ Motor dysfunction ▫ Ataxia, paresis, unsteady gait, speech impairment, poor coordination ▪ Dysautonomia ▪ Intellectual disability ▫ Learning/memory issues ▪ Dementia

DIAGNOSIS DIAGNOSTIC IMAGING ▪ CT scan, MRI

OTHER DIAGNOSTICS ▪ Neurological exam

TREATMENT ▪ Mostly supportive

SURGERY

▪ In some cases; see individual disorders

OSMOSIS.ORG 513

ARNOLD–CHIARI MALFORMATION osms.it/arnold-chiari-malformation PATHOLOGY & CAUSES

SIGNS & SYMPTOMS

▪ Insufficient posterior fossa growth → developmental cerebellum, brainstem, craniocervical junction malformation ▪ Affects cerebellar structure, position ▪ AKA Chiari malformation type II (types I, III, IV—no specific name) ▪ Chiari malformations: similar presentations, different mechanism development ▪ Accompanying findings: aqueductal stenosis, upward cerebellar displacement, cerebellar dysplasia ▪ Cerebellar tonsil protrusion through foramen magnum ▪ Associations: lumbosacral myelomeningocele, Pierre Robin syndrome, neurofibromatosis type I, Noonan syndrome ▪ Commonly accompanies spina bifida

▪ Nausea, vertigo, nystagmus, unsteady gait ▪ Lumbosacral/thoracic myelomeningocele presence ▪ Medulla oblongata compression → dysautonomia (↓ ↑ heart/breathing rate, neurogenic bladder, sleep apnea, pupillary dilation, etc.) ▪ Paralysis/dysesthesia below spinal compression ▪ Valsalva maneuver → symptoms worsen (increased intracranial pressure)

RISK FACTORS

▪ Hydrocephalus (congenital/acquired) ▪ Ehlers–Danlos syndrome, Marfan syndrome → craniocervical joint instability → cerebellar tonsil displacement ▪ Posterior cranial fossa malformation (agenesia, craniosynostosis, osteopetrosis) ▪ Posterior cranial fossa pathology (tumor, abscess, cyst, hematoma)

COMPLICATIONS

▪ Aqueductal stenosis → impaired CSF flow → non-communicating hydrocephalus → lateral, third ventricle dilatation ▪ Fourth ventricle obstruction → noncommunicating hydrocephalus → aqueduct dilatation; lateral, third ventricles ▪ Brainstem, spinal cord compression ▪ Syringomyelia (hydrocephalus → distention, dilation of spinal cord’s central canal)

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DIAGNOSIS DIAGNOSTIC IMAGING CT scan, MRI ▪ Findings include presence of myelomeningocele, cerebellar tissue (downward displacement) through foramen magnum, small fourth ventricle, tectal beaking, atlas assimilation

OTHER DIAGNOSTICS ▪ Neurological exam

TREATMENT SURGERY

▪ Open neural tube defect closure ▪ Shunt placement (relieves hydrocephalus) ▪ Bone removal (↓ brain structure pressure)

OTHER INTERVENTIONS

▪ Address complications: neurogenic bowel, bladder; neonatal feeding difficulty; respiratory failure, apnea

Chapter 66 Cerebrospinal Malformations

Figure 66.1 An MRI scan of the head in the sagittal plane of an individual with an Arnold-Chiari malformation. There is a small posterior fossa and partial descent of the brainstem and the cerebellar tonsils through the foramen magnum.

CEREBRAL PALSY (CP) osms.it/cerebral-palsy PATHOLOGY & CAUSES ▪ Wide disorder group; non-progressive cerebral lesions impair motor, postural function/muscle tone ▪ Most common motor disorder, 2.1 per 1000 babies affected, ages 0–3 years ▪ Varying severity, complexity ▪ Often accompanied by mental function impairment, epilepsy

MNEMONIC: PALSY

Main characteristcs of CP Paresis Ataxia Lagging motor development Spasticity Young

CAUSES

▪ Primary: genetic (autosomal recessive glutamate decarboxylase-1 deficiency) ▪ Secondary: preterm birth (most common cause), CNS injury, intrauterine growth restriction, intrauterine infection, antepartum hemorrhage, severe placental pathology, multiple pregnancy

RISK FACTORS

▪ Prenatal/perinatal ▫ CNS trauma (pregnancy/birth) ▫ Cerebrovascular insult (infarction, thrombosis, hypoxic-ischemic injury) ▫ CNS infection ▫ Radiation exposure ▫ Methylmercury/alcohol (prenatal exposure) ▫ Maternal smoking/obesity ▫ Infections during pregnancy

OSMOSIS.ORG 515

▪ Postnatal ▫ Stroke, CNS trauma, hypoxia (drowning), sepsis/meningitis, kernicterus

SIGNS & SYMPTOMS ▪ Motor symptoms (type-dependent) ▫ Paresis, ataxia, spasticity, irregular posture, orthopedic contracture, scoliosis, seizure, neurogenic bladder/ bowel, impaired vision/speech, difficulty feeding/swallowing

DIAGNOSIS DIAGNOSTIC IMAGING CT scan, MRI ▪ Type-dependent ▫ Hypoxic-ischemic lesions (e.g. periventricular leukomalacia/basal ganglia lesions); cortical malformation; hydrocephalus Ultrasound ▪ In young infants with open anterior fontanelle

OTHER DIAGNOSTICS

▪ Neurological exam ▪ Diagnostic tests ▫ Differentiate from other motor dysfunction disorders (e.g metabolic disorders, stroke, hydrocephalus, hematomas)

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TREATMENT ▪ No definitive treatment

MEDICATIONS

▪ Benzodiazepines → myorelaxation, anxiety relief ▪ Spasmolytics → muscle-spasticity relief ▪ Anticonvulsants → seizure treatment, prevention ▪ Pain medication

SURGERY

▪ Posture correction

OTHER INTERVENTIONS

▪ Physical, occupational, speech therapy ▪ Posture correction ▫ Braces/other orthotic devices

Chapter 66 Cerebrospinal Malformations

DANDY–WALKER SYNDROME (DWS) osms.it/dandy-Walker-malformation PATHOLOGY & CAUSES ▪ Neurodevelopmental disorders; affect cerebellar vermis, fourth ventricle ▪ Classical triad ▫ Vermis hypoplasia/agenesis, cystic dilatation (fourth ventricle), posterior fossa enlargement ▪ Accompanying disorders (wide range) ▫ Cortical dysplasia, syringomyelia, schizencephaly, corpus callosum dysgenesis, cleft palate, etc. ▪ Associated with posterior fossa malformations–hemangiomas– arterial anomalies–cardiac defects– eye abnormalities–sternal cleft and supraumbilical raphe syndrome (PHACES)

MNEMONIC: DWS

Components of DWS Dilated 4th ventricle Water on the brain Small vermis

CAUSES

▪ Genetic, environmental factors ▫ Meckel syndrome ▫ Chromosomal aneuploidy (e.g. 45X, triploidy) ▫ Rubella infection/warfarin exposure during pregnancy ▫ Maternal alcohol consumption ▫ Congenital heart defect ▫ Neural tube defect ▫ Holoprosencephaly

COMPLICATIONS

▪ Foramina (Magendie, Luschka) atresia → hydrocephalus

SIGNS & SYMPTOMS ▪ Macrocephaly, developmental milestones not met (mental, motor), impaired motor coordination, unsteady gait, seizure, lower limb spasticity, eye/ear involvement (rarely)

OSMOSIS.ORG 517

DIAGNOSIS DIAGNOSTIC IMAGING MRI, prenatal ultrasound ▪ Characteristic findings ▫ Cerebellar vermis agenesis/hypoplasia, cystic dilatation (fourth ventricle), posterior fossa enlargement; hydrocephalus, absent corpus callosum may also be present

LAB RESULTS ▪ Amniocentesis

Figure 66.2 An MRI scan of the head in the sagittal plane demonstrating a Dandy-Walker malformation in a one-year-old boy. There is accompanying gross hydrocephalus.

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TREATMENT ▪ No definitive treatment

SURGERY Ventricular-peritoneal shunt ▪ Manages hydrocephalus

OTHER INTERVENTIONS

▪ Physical, occupational therapy

Chapter 66 Cerebrospinal Malformations

NORMAL PRESSURE HYDROCEPHALUS (NPH) osms.it/normal-pressure-hydrocephalus PATHOLOGY & CAUSES ▪ Cerebrospinal fluid (CSF) accumulation → progressive lateral ventricle enlargement ▪ AKA Hakim’s syndrome ▪ Intracranial pressure (ICP) not normal (name is misnomer)

OTHER DIAGNOSTICS

▪ High-volume lumbar puncture/lumbar drain trial ▫ Improved functionality with CSF removal ▪ Neurological exam

TREATMENT SURGERY

CAUSES

▪ Slight–moderate elevation → classical ↑ ICP symptoms (nausea, vomiting, photophobia, neck pain, stiffness) not evident ▪ ↑ CSF → ↑ ICP → lateral ventricle dilation → pressure on corona radiata ▫ Urinary incontinence), brainstem structure (magnetic gait), periventricular limbic system (dementia) ▪ Idiopathic/secondary ▫ Cerebrovascular insult, meningitis, trauma, tumor

▪ In some situations

Ventriculoperitoneal shunt ▪ ↑ ICP relief

RISK FACTORS

▪ Prevalence largest among elderly (common onset approx. 60 years old)

SIGNS & SYMPTOMS ▪ Unsteady gait ▫ Described as magnetic or “glue-footed” ▪ Urinary incontinence ▪ Cognitive impairment

DIAGNOSIS

Figure 66.3 An MRI scan of the head in the sagittal plane demonstrating hydrocephalus. There is a prominent flow void in the sylvian aqueduct, suggesting a normal-pressure hydrocephalus.

DIAGNOSTIC IMAGING MRI/CT scan ▪ Ventriculomegaly, enlarged Sylvian fissures, enlarged sulci with no cortical atrophy

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RETT SYNDROME osms.it/rett-syndrome PATHOLOGY & CAUSES

RISK FACTORS

▪ Rare neurological disorder, impairs motor function (eating, walking, talking, breathing) ▪ AKA cerebroatrophic hyperammonemia ▪ Associated with prolonged QT syndrome

▪ Young, individuals who are biologically female ▪ Extraordinarily, individuals who are biologically male with Klinefelter syndrome (XXY), otherwise fatal for biologically-male (XY) individuals

CAUSES

COMPLICATIONS

▪ X-linked autosomal dominant MeCP2 gene mutation (spontaneous) ▪ MeCP2 protein involved in forming neuronal connections, when only one gene is mutated, the other one can compensate to a degree

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Growth failure Seizure Fractures (related to ↓ bone mineralization) Cardiac abnormalities; e.g. prolonged QTc interval ▪ Autonomic nervous system dysfunction ▪ Sleep disturbances ▪ Behavioral issues; e.g. clapping, “pill-rolling” (due to extrapyramidal motor defects) ▪ ▪ ▪ ▪

Chapter 66 Cerebrospinal Malformations

TREATMENT

SIGNS & SYMPTOMS ▪ Manifests after six months old → later, divided into four stages

DIAGNOSIS LAB RESULTS

▪ No definitive treatment

MEDICATIONS

▪ SSRI (behavioral issues)

OTHER INTERVENTIONS

▪ Genetic test ▫ MeCP2 mutation

▪ Occupational, speech, physical therapy ▪ Nutritional support for fracture reduction

OTHER DIAGNOSTICS

▪ Clinically diagnosed (characteristic findings) ▫ Loss of acquired purposeful hand skills, spoken language ▫ Gait abnormalities ▫ Stereotypic hand movements

SEPTO-OPTIC DYSPLASIA (SOD) osms.it/septo-optic-dysplasia PATHOLOGY & CAUSES ▪ Congenital malformation triad ▫ Underdeveloped optic nerve, hypopituitarism, absent septum pellucidum ▪ AKA de Morsier syndrome ▪ Most individuals have two of three components, some present with all three ▪ May also have encephalomalacia, schizencephaly, ectopic pituitary tissue

CAUSES

▪ Genetic ▫ Spontaneous/inherited HESX1, OTX2, SOX2, PAX6 mutation ▪ In utero sodium valproate, cocaine exposure

SIGNS & SYMPTOMS Nystagmus Visual impairment Intellectual impairment Seizure Growth hormone deficiency → short stature, hypoglycemia, micropenis (if biologically-male) ▪ Vasopressin deficiency → diabetes insipidus ▪ Hyperprolactinemia ▪ Hyperbilirubinemia → jaundice ▪ ▪ ▪ ▪ ▪

DIAGNOSIS DIAGNOSTIC IMAGING MRI ▪ Optic nerve hypoplasia, septum pellucidum, corpus callosum agenesis

OSMOSIS.ORG 521

LAB RESULTS Genetic testing ▪ HESX1, OTX2, SOX2, PAX6 mutations

OTHER DIAGNOSTICS ▪ Neurological exam

TREATMENT MEDICATIONS

▪ Hormone replacement therapy ▪ Anticonvulsants → seizure treatment, prevention

OTHER INTERVENTIONS

▪ Treat complications ▫ Ophthalmic, physical, and occupational therapy

Figure 66.4 An MRI scan of the head in the coronal plane of an individual with septooptic dysplasia. The septum pellucidum, which normally separates the two lateral ventricles, is absent.

SPINA BIFIDA osms.it/spina-bifida PATHOLOGY & CAUSES ▪ Congenital spinal column, meninges malformation ▪ Most common neural tube defect ▪ Improper vertebrae formation allows meninges/spinal cord to protrude dorsally out of spinal canal ▪ Occurs in fourth week of pregnancy ▪ Usually manifests in lumbar part of spinal column (can occur elsewhere) ▪ Most individuals with spina bifida have latex allergy (complicates medical procedures) ▪ Some individuals with spina bifida have intellectual impairment ▪ Can present with Arnold–Chiari malformation ▪ Associated with malformed corpus callosum, cerebellum, cerebral cortex

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RISK FACTORS

▪ Multifactorial ▫ Genetic, environmental factors ▪ Pregnancy ▫ Folate deficiency, anticonvulsant use ▪ Obesity ▪ Poorly-managed diabetes mellitus

COMPLICATIONS

▪ Meningitis; neurogenic bladder, bowel; nerve damage paralysis; tethered cord syndrome; cognitive impairment; pressure ulcer; seizure; hydrocephalus; orthopedic problems

SIGNS & SYMPTOMS ▪ Lower-back pain, hip dysplasia, dysesthesia (below lesion), leg weakness, nystagmus, clubfoot, scoliosis

Chapter 66 Cerebrospinal Malformations

DIAGNOSIS DIAGNOSTIC IMAGING Prenatal ultrasound

OTHER INTERVENTIONS

▪ Resolve complications ▫ Seizure, hydrocephalus, orthopedic problems ▪ Physical therapy

X-ray, CT scan, MRI ▪ Show improper vertebral formation

LAB RESULTS

▪ ↑ alpha-fetoprotein ▫ Spina bifida occulta does not show ↑ ▪ Genetic tests

OTHER DIAGNOSTICS

▪ Visual examination ▫ Visible meningocele, myelomeningocele at birth

TREATMENT SURGERY

▪ Reposition meninges, spinal cord into spinal canal

Figure 66.5 An individual with spina bifida and a an associated myelomeningocoele, also known as spina bifida cystica.

OSMOSIS.ORG 523

SYRINGOMYELIA osms.it/syringomyelia PATHOLOGY & CAUSES ▪ Cerebrospinal fluid-filled cyst around spinal cord’s central canal ▪ Cyst in nerve tissue (syrinx); spinal cord (myelia) ▫ E.g. brainstem syrinx (syringobulbia) ▪ As cyst forms, grows → fluid collects within spinal cord tissue → ↑ pressure within spinal cord → damage ▪ Symptoms progress slowly, often adult diagnosis

TREATMENT SURGERY

▪ Cyst drainage; flow restoration

RISK FACTORS

▪ Congenital: Arnold–Chiari malformation, genetic mutation ▪ Acquired: trauma; spinal cord tumor, bleeding; scoliosis

SIGNS & SYMPTOMS ▪ Various locations, syringomyelia severity ▪ Chronic pain, dysesthesia, paresis/paralysis ▪ Suspended sensory level ▫ Sensory perception defect only on body parts innervated by syringomyeliaaffected structures

DIAGNOSIS DIAGNOSTIC IMAGING MRI ▪ Syrinx visualization in spine

OTHER DIAGNOSTICS Neurological exam ▪ For suspended sensory level

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Figure 66.6 An MRI scan of the head and neck in the sagittal plane demonstrating syringomyelia extending from approximately the level of C4 to T3. There is also a Chiari I malformation.

Chapter 66 Cerebrospinal Malformations

TETHERED SPINAL CORD SYNDROME (TCS) osms.it/tethered-spinal-cord-syndrome PATHOLOGY & CAUSES ▪ Pathological spinal cord fixation to spinal canal wall ▪ AKA occult spinal dysraphism sequence ▪ Spinal cord movement restricted ▫ Normally, spinal cord floats freely in CSF ▫ TCS: restricted movement → physical strain → spinal cord damage

CAUSES

▪ Primary: congenital short filum terminale ▪ Secondary: surgery/trauma → scar tissue attachment; (myelo)meningocele

SIGNS & SYMPTOMS ▪ Lower-back pain, scoliosis, clubfoot, neurogenic bladder, bowel, paresis/ paralysis below lesion

DIAGNOSIS DIAGNOSTIC IMAGING Spinal MRI ▪ Conus medullaris located below the normal L2–3 level

Figure 66.7 An MRI scan of the spine in the sagittal plane demonstrating a tethered spinal cord associated with a lipoma of the filum terminale.

TREATMENT SURGERY

▪ Relieve spinal cord strain (if possible) ▪ Corrective orthopedic surgery

OTHER INTERVENTIONS ▪ Physical therapy

OTHER DIAGNOSTICS ▪ Neurological exam

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NOTES

NOTES

CHILDHOOD PRIMARY BRAIN TUMORS

GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Most common solid tumor in children < 15 years old ▪ 20% of all childhood cancer ▪ Most pediatric brain, spinal cord tumors are primary tumors; originate from central nervous system (CNS) cells ▪ Most common types ▫ Astrocytomas, medulloblastomas, ependymomas, brainstem gliomas ▪ Better prognosis (generally) than adult brain tumors

RISK FACTORS

▪ Biologically-male > biologically-female individuals ▪ Varies with tumor type

COMPLICATIONS

▪ Dependent on tumor type, location, grade, child’s age ▪ Dependent on size, location, malignant potential of tumor; lesion’s mass effect → complications ▫ Increased intracranial pressure (ICP) → headache, nausea, vomiting ▫ Vision, balance, gait disturbance (common) ▫ May be mental changes, normal growth/ development disturbance

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SIGNS & SYMPTOMS ▪ May be subtle (slow-onset)/progress quickly ▪ Headache, nausea/vomiting ▫ Morning often worse (waking up) ▫ Cough, exercise, body-position change may exacerbate headache ▪ Mental change ▫ Personality/behaviour change, concentration difficulty ▪ Other associated symptoms ▫ Balance/gait disturbance; visual disturbance/loss; hearing/speech difficulty; weakness; numbness

DIAGNOSIS DIAGNOSTIC IMAGING CT scan/MRI ▪ Head ▫ Identify lesion’s size, location

LAB RESULTS Biopsy ▪ Open surgery/stereotactic biopsy (definitive diagnostic tool) ▪ Determine type, stage, grade ▫ Grade: degree of differentiation (tumor cells) ▫ Stage: extent of spread (tumors cells)

Chapter 67 Childhood Primary Brain Tumors Lumbar puncture ▪ Cerebrospinal fluid (CSF) analysis → malignant cell detection

OTHER DIAGNOSTICS

▪ Visual field examination ▫ ↑ ICP → mass effect/swelling → detect central/peripheral vision defects ▪ Childhood primary brain tumor grades ▫ Based on World Health Organization (WHO) grading system (see table)

TREATMENT ▪ Depends on tumor size/location, child’s age ▪ Goals ▫ Eliminate tumor, relieve symptoms, restore brain function

MEDICATIONS

▪ Chemotherapy ▫ Residual tumor/metastasis ▪ Corticosteroids, diuretics ▫ Reduce swelling, alleviate associated ↑ ICP symptoms ▪ Pain management

SURGERY ▪ Resection

OTHER INTERVENTIONS

▪ Radiation ▫ Residual tumor/metastasis

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CRANIOPHARYNGIOMA osms.it/craniopharyngioma PATHOLOGY & CAUSES ▪ Rare benign non-glial epithelial CNS tumor ▫ Often within sellar/suprasellar space ▪ Hypothesis ▫ Derived from Rathke’s cleft/squamous cell crests along craniopharyngeal duct ▪ Gross pathology ▫ Cholesterol crystals in “motor oil”-like fluid within tumor, homogeneous

TYPES

DIAGNOSIS DIAGNOSTIC IMAGING CT scan/MRI ▪ Mass visualization ▪ Other common findings ▫ Suprasellar region calcification, one/ more supra/parasellar region cysts Histopathology ▪ Cysts with stratified squamous epithelium, cholesterol crystals, keratin pearls

▪ Adamantinomatous ▫ Primarily children, often single/multiple cysts ▪ Papillary ▫ Adults (almost exclusively), solid lesions

RISK FACTORS

▪ Bimodal age distribution ▫ 5–14 years old (children), 50–70 years old (adults)

COMPLICATIONS

▪ Hypopituitarism, hydrocephalus, ↑ ICP

SIGNS & SYMPTOMS ▪ Headache, nausea, vomiting ▪ Visual disturbance/loss (i.e. bitemporal hemianopia) ▪ Endocrine abnormality ▫ Affects growth, thyroid/adrenal function, diabetes insipidus ▪ Behavioral change (ie. hypersomnia)

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Figure 67.1 An MRI scan of the head in the sagittal plane demonstrating a craniopharyngioma, adamantinomatous subtype. The tumor has clear solid and cystic components with abundant calcification.

Chapter 67 Childhood Primary Brain Tumors

TREATMENT MEDICATIONS

▪ Endocrine replacement therapy: specific endocrine deficiency-dependent

SURGERY ▪ Resection

OTHER INTERVENTIONS ▪ Radiotherapy

Figure 67.2 A histological section of a craniopharyngioma, adamantinomatous type. The tumor is composed of cystic spaces, calcifications and keratin.

EPENDYMOMA osms.it/ependymoma PATHOLOGY & CAUSES ▪ Uncommon glial tumor ▫ Arises from ependymal cells lining ventricular system, spinal cord’s center ▪ Located intracranially (children), within spinal canal (adults) ▪ Often form ependymal pseudorosettes ▫ Tumor cells arranged around vessels, fibrils pointing towards vessel

TYPES

▪ Five subtypes: WHO grade classification ▫ Subependymoma: grade I ▫ Myxopapillary ependymoma: grade I ▫ Ependymoma: grade II ▫ RELA fusion–positive ependymoma: grade II/grade III (with RELA gene change) ▫ Anaplastic ependymoma: grade III

RISK FACTORS

▪ Neurofibromatosis type II (NF2)-diagnosed individuals (more common)

COMPLICATIONS

▪ Fourth ventricle blockage → hydrocephalus → headache, nausea, vomiting ▪ Tumor mass effect

SIGNS & SYMPTOMS ▪ Headache, visual disturbance/loss, nausea, vomiting, ataxia (gait, balance disturbance), vertigo, papilledema, cranial-nerve palsy, seizure/focal neurologic deficit, back pain, limb numbness/weakness

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DIAGNOSIS

TREATMENT

DIAGNOSTIC IMAGING

MEDICATIONS

CT scan ▪ Hyperdense with enhancement, commonly see cysts, calcifications

SURGERY

MRI ▪ Hypointense lesion, extension into Luschka foramen may be seen

▪ Chemotherapy

▪ Resection

OTHER INTERVENTIONS ▪ Adjuvant radiotherapy

LAB RESULTS Histological examination ▪ Cells with round/oval nuclei, dense fibrils forming canal structure ▪ Perivascular pseudorosettes ▫ Cells arranged around vessels with thin ependymal processes directed inwards ▪ Immunohistochemical markers include glial fibrillary acid protein, epithelial membrane antigen CSF cytology ▪ Guides tumor staging

Figure 67.4 An MRI scan of the head of a child demonstrating an ependymoma in the posterior fossa, compressing the cerebellum.

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Figure 67.3 The histological appearance of an ependymoma. The tumor is composes of monomorphic cells which form ependymal rosettes, with a central clearing.

Chapter 67 Childhood Primary Brain Tumors

MEDULLOBLASTOMA osms.it/medulloblastoma PATHOLOGY & CAUSES ▪ Most common pediatric malignant primary brain tumor ▫ Arises from cerebellum’s primitive neuroepithelial cells ▪ Usually forms midline mass along roof of fourth ventricle (between brainstem/ cerebellum) ▪ WHO grade IV classification

TYPES

▪ Categorized as desmoplastic, classic, largecell, anaplastic, variants ▪ Gene expression profiling recognizes four molecular subgroups

Wingless (WNT) ▪ Excellent prognosis ▪ 1:1 biologically male/biologically female ratio ▪ 10–12 years old (peak incidence) ▪ Classic histology (majority) ▪ Often CTNNB1 gene (encodes betacatenin) mutation Sonic Hedgehog (SHH) ▪ Intermediate prognosis ▪ 1:1 biologically male/biologically female ratio ▪ Infants < four years old, adults > 16 years old ▪ Classic, large-cell, anaplastic, desmoplastic, with extensive nodularity Group 3 ▪ Poor prognosis ▪ 2:1 biologically male/biologically female ratio ▪ 4–16 years old ▪ Classic/large-cell anaplastic histology, associated with Myc amplification, poorly-defined lesions (better contrast enhancement than group 4 lesions)

Group 4 ▪ Poor prognosis ▪ 2:1 biologically male/biologically female ratio ▪ 4–16 years old ▪ Classic histology, well-defined lesions (limited contrast enhancement)

RISK FACTORS

▪ 2:1 biologically male/biologically female ratio ▪ 3–8 years old ▪ Certain inherited familial syndromes ▫ Ataxia-telangiectasia, Rubinstein–Taybi syndrome, Gorlin syndrome, Turcot’s syndrome, Li–Fraumeni syndrome

COMPLICATIONS

▪ Frequent metastasis → other brain, spinal cord parts ▪ Fourth ventricle blockage → hydrocephalus → headache, nausea, vomiting ▪ Tumor’s mass effect

SIGNS & SYMPTOMS ▪ Headache; nausea; vomiting; ataxia (gait/ balance disturbance), falls; diplopia; papilledema; positional dizziness, nystagmus; bulging anterior fontanelle; visual disturbance/loss

DIAGNOSIS DIAGNOSTIC IMAGING CT scan ▪ Often appear as vermis mass → fourth ventricle effacement → obstructive hydrocephalus ▪ Hyperdense, +/- cysts, +/- calcifications

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MRI ▪ Heterogeneous mass; calcification, necrosis, cyst formation ▪ May see surrounding edema

LAB RESULTS Histological examination ▪ Variable cellular atypia ▪ Homer Wright rosette; dark tumor cells spherically arranged around pale eosinophilic neurofibrils ▪ INI1-positive (tumor suppressor gene marker) Lumbar puncture ▪ CSF analysis ▫ Malignant cell detection

TREATMENT

Figure 67.5 An MRI scan of a child in the sagittal plane demonstrating a medulloblastoma. In childhood, they commonly arise in the posterior fossa at the roof of the fourth ventricle.

MEDICATIONS ▪ Chemotherapy

SURGERY

▪ Tumor resection

OTHER INTERVENTIONS ▪ Radiotherapy

Figure 67.6 A medulloblastoma forming Homer–Wright rosettes, with no central clearing.

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Chapter 67 Childhood Primary Brain Tumors

PILOCYTIC ASTROCYTOMA osms.it/pilocytic-astrocytoma PATHOLOGY & CAUSES ▪ Primary tumor ▫ Arises from astrocytes ▫ AKA juvenile pilocytic astrocytoma/ cystic cerebellar astrocytoma ▪ Mainly occurs in children (majority 0–30 years old) ▪ Often arises in cerebellum, hypothalamic region, along optic pathway ▪ Tumors slow growing, benign (WHO grade I) ▪ Associated with cyst formation, often wellcircumscribed ▪ Strong neurofibromatosis type I (NF-1) association ▪ Microscopic appearance ▫ Elongated hair-like projections, Rosenthal fibers (characteristic feature)

▪ Spectroscopy/perfusion MRI head ▫ Determines tumor grade

LAB RESULTS Biopsy ▪ Mass ▫ Heterogeneous/homogeneous/mixed; cystic; solid; with/without hemorrhage, necrosis

OTHER DIAGNOSTICS

▪ Ophthalmological evaluation/visual field testing ▫ May detect visual field deficit

SIGNS & SYMPTOMS ▪ Altered mental status; headache, nausea, vomiting; gait disturbance, ataxia; weakness; seizure; visual disturbance, nystagmus, papilloedema; aphasia/ dysphasia

DIAGNOSIS DIAGNOSTIC IMAGING CT scan ▪ Lesion (hypodense), calcification/ hemorrhage area (hyperdense) MRI (head) ▪ Range of appearances ▫ Cystic component(s) with mural nodule (enhancing, nonenhancing cyst wall); heterogeneous, mixed solid; homogeneous solid

Figure 67.7 A brain biopsy smear from a pilocytic astrocytoma demonstrating malignant astrocytes with pleomorphic, hyperchromatic nuclei. In addition there is an eosinophilic granular body, commonly seen in such tumors.

TREATMENT MEDICATIONS ▪ Chemotherapy

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SURGERY

▪ Resection (location often prohibits total resection)

OTHER INTERVENTIONS

▪ Radiotherapy ▪ Observation (when asymptomatic)

Figure 67.8 The histological appearance of a pilocytic astrocytoma. There are bipolar neoplastic cells arranged in fascicles with elongated hair-like processes.

PINEALOMA osms.it/pinealoma PATHOLOGY & CAUSES ▪ Rare tumor that arises from cells in the pineal region ▪ May result in endocrine disruption, obstructive hydrocephalus, and compression of adjacent structures (cerebellum, brainstem) ▪ Occurs any age; malignancy more common in children (< eight years old)

TYPES

▪ Four pinealoma types ▫ Germ cell tumors ▫ Papillary tumors ▫ Pineal parenchymal cell tumors ▫ Glial cell tumors ▪ Other miscellaneous tumors and cysts in the pineal region

RISK FACTORS

▪ RB1 gene inheritance ▪ Previous radiation exposure

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COMPLICATIONS

▪ Precocious puberty ▫ Homeostatic hypothalamic-pituitary axis disruption → puberty onset in biologically-male individuals (< nine years old), biologically-female individuals (< eight years old) ▫ ↓ melatonin production (may result) → impaired circadian rhythm regulation ▪ Physical ventricular system obstruction → ↑ ICP → hydrocephalus

SIGNS & SYMPTOMS ▪ Parinaud’s syndrome (upward gaze paralysis, pupillary areflexia), pseudo-Argyll Robertson pupils, convergence-retraction nystagmus, eyelid reaction (Collier’s sign) ▪ Headache; nausea; vomiting; visual, balance, gait disturbance; fatigue/ irritability; insomnia

Chapter 67 Childhood Primary Brain Tumors

DIAGNOSIS DIAGNOSTIC IMAGING Head CT scan/MRI ▪ May appear cystic/partially cystic ▪ Often lobulated, seen as heterogeneous mass ▪ Usually 2.5–4 cm/1–1.6in wide, well circumscribed in pineal region; contrastenhanced rim in cystic forms

TREATMENT SURGERY

▪ Resection +/- shunt (drain excess CSF)

OTHER INTERVENTIONS

▪ Adjuvant radiotherapy (malignant tumors)

LAB RESULTS

▪ Hormonal evaluation ▫ Melatonin (indicates pineal gland pathology) ▪ Lumbar puncture ▫ CSF analysis for detection of malignant cells ▫ α-fetoprotein/β-HCG tumor markers indicate germinal origin ▪ Biopsy ▫ Determines type, stage; open surgery/ stereotactic biopsy

OTHER DIAGNOSTICS

▪ Visual field examination ▫ Defect detection: central, peripheral vision; swelling around optic nerve (↑ ICP sign)

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NOTES

NOTES

CNS DEMYELINATING DISORDERS

GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES

DIAGNOSIS

▪ Disorders affecting brain, spinal cord; damage to oligodendrocytes → loss of myelin, axons ▪ Damage mostly caused by autoimmune reaction ▫ Inflammatory cells release cytotoxic molecules/engulf cells ▪ Trigger unknown

DIAGNOSTIC IMAGING

RISK FACTORS

OTHER DIAGNOSTICS

▪ Genetic predisposition ▪ Environmental factors (e.g. infections)

SIGNS & SYMPTOMS ▪ Motor: weakness, tremors, paraparesis/ quadriparesis ▪ Sensory: abnormal sensations, numbness, visual problems ▪ Autonomic: sphincter, sexual dysfunction

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CT scan, MRI ▪ Abnormal signals in white matter regions

LAB RESULTS

▪ Cerebrospinal fluid (CSF) ▫ ↑ cell count, ↑ protein level

▪ Neurologic symptoms

TREATMENT MEDICATIONS

▪ Reduce inflammation (e.g. corticosteroids)

OTHER INTERVENTIONS ▪ Plasma exchange ▪ Manage symptoms

Chapter 68 CNS Demyelinating Disorders

ACUTE DISSEMINATED ENCEPHALOMYELITIS osms.it/acute-diss-encephalomyelitis PATHOLOGY & CAUSES ▪ Autoimmune disease characterized by sudden inflammation of brain, spine; destruction of myelin sheath at multiple locations Type IV hypersensitivity reaction ▪ Cell-mediated ▪ T-cells penetrate blood brain barrier, activated by myelin antigens (myelin basic protein, proteolipid protein, myelin oligodendrocyte protein) → release of cytokines (IL-1, IL-6, TNF-alpha, interferongamma) ▫ Direct damage to oligodendrocytes, myelin ▫ Blood brain barrier expresses more receptors → attracts more immune cells (B-cells, macrophages) → blood vessel dilatation ▪ B-cell activation → production of autoantibodies against myelin proteins ▪ Macrophages look for antibody marked oligodendrocytes, destroy them

CAUSES

▪ Antigen mimicry ▫ Antibodies aimed against pathogen antigens bind to myelin proteins

RISK FACTORS

▪ Genetic predisposition ▪ Infections ▫ Viral (measles, mumps, rubella); bacterial (Mycoplasma pneumoniae, beta-hemolytic Streptococci) ▪ Vaccination ▫ Measles-mumps-rubella (MMR) vaccination ▪ Usually affects children

SIGNS & SYMPTOMS ▪ Sudden onset of symptoms 1–3 weeks after interaction with pathogen ▪ Systemic inflammation (fever, headache, nausea, vomiting) ▪ Sensory, visual deficits ▪ Seizures, confusion, drowsiness ▪ Motor deficits, weakness, ataxia ▪ Oculomotor deficits, nystagmus, dysarthria ▪ Coma

DIAGNOSIS DIAGNOSTIC IMAGING MRI ▪ Multiple lesions in white matter regions of central nervous system (CNS) ▪ Open ring sign with contrast enhancement ▪ Edema CT scan ▪ Emergency cases ▪ Low density lesions in white matter region

LAB RESULTS

▪ Lumbar puncture ▫ ↑ protein, ↑ cell count (lymphocytes), high level of antibodies, CSF culture

OTHER DIAGNOSTICS

▪ Clinical ▫ Polyfocal neurologic symptoms, encephalopathy ▪ Microscopically ▫ All lesions similar, preserved axons with myelin loss, mononuclear infiltration, foamy macrophages

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TREATMENT MEDICATIONS

▪ Corticosteroids ▫ Reduce inflammation ▫ E.g. glucocorticoids ▪ Cyclophosphamide ▫ Cell cycle inhibition

OTHER INTERVENTIONS

▪ Intravenous immune globulins ▫ Neutralize antibodies ▪ Plasma exchange

Figure 68.1 An MRI scan of the head of an individual with acute disseminated encaphalomyelitis. There are bilateral, asymmetrical, tumefactive lesions of the cerebral white matter.

CENTRAL PONTINE MYELINOLYSIS osms.it/central-pontine-myelinolysis PATHOLOGY & CAUSES ▪ Destruction of myelin sheath around nerve cells in pons due to rapid osmotic changes (osmotic demyelination syndrome) ▪ ↓ sodium level in serum → water leakage through blood brain barrier → ↑ brain volume ▪ Activation of defense mechanisms ▫ After few minutes: ↑ intracranial pressure pushes excess water, sodium into CSF → ↓ brain volume ▫ After few hours: astrocytes release organic solutes → release of excess intracellular water → evening osmolarity with serum ▫ After two days: fully adapted to altered osmolarity ▪ Sudden correction of hyponatremia in already adapted brain

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▫ Potassium, sodium surge back into astrocytes → ↑ cation concentracion ▫ Shrinkage of endothelial cells → distortion of blood brain barrier → complements, cytotoxic elements form blood leak into brain ▪ Damage astrocytes, induce apoptosis ▫ Interruption of myelin-making process in oligodendrocytes ▫ Release of cytokines ▫ Activation of microglia

RISK FACTORS

▪ Sodium level < 120meq/L ▪ Hyponatremia lasts > two days ▪ Syndrome of inappropriate diuretic hormone (SIADH) ▫ Kidneys retain too much water ▪ Alcoholism, malnutrition

Chapter 68 CNS Demyelinating Disorders

COMPLICATIONS

▪ Respiratory failure, aspiration pneumonia, coma, death

SIGNS & SYMPTOMS

TREATMENT OTHER INTERVENTIONS

▪ Correcting serum sodium slowly ▪ 6–8 weeks; endotracheal intubation, ventilator support

▪ Movement disorders ▪ Paraparesis/quadriparesis ▪ Severe cases ▫ “Locked-in” syndrome (conscious, paralyzed; can only move eyes, blink) ▪ Dysarthria, dysphagia, diplopia ▪ Seizures, confusion, lethargy, coma

DIAGNOSIS DIAGNOSTIC IMAGING MRI ▪ Earliest changes seen in diffusion weighted imaging (DWI) ▫ Restriction in pons region ▪ Later changes ▫ High T2, low T1 signal ▫ “Trident sign” (trident spear-shaped lesion in pons) CT scan ▪ Low sensitivity; low attenuation signal in pons

Figure 68.2 An MRI scan of the head and neck in the sagittal plane demonstrating a hypointense lesion in the pons of an individual with central pontine myelinolysis.

PET ▪ Initial high uptake

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MULTIPLE SCLEROSIS (MS) osms.it/multiple-sclerosis PATHOLOGY & CAUSES ▪ Autoimmune demyelinating disease of nerve cells in brain, spinal cord characterized by various neurological disorders ▪ Cell-mediated (Type IV) hypersensitivity reaction ▫ T cells, B cells, macrophages T cells ▪ Break through blood brain barrier → activated by myelin proteins (myelin basic protein) ▪ Th17 cells produce cytokines → attract other leukocytes ▪ Th1 cells produce interferon gamma → activation of macrophages ▪ Produce cytokines (IL-1, IL-6, TNF-alpha) ▫ Oligodendrocytes damaged ▫ Blood brain barrier expresses more receptors for other leukocytes ▫ Blood vessels dilate; easier passage for other leukocytes B cells ▪ Produce antibodies that bind to myelin proteins, mark them Macrophages ▪ Recognize marked oligodendrocytes, engulf them ▪ Attacks ▫ Early: regulatory T cells reduce inflammation → oligodendrocytes heal, renew myelin (remyelination) ▫ Later: repetitive extensive damage → death of oligodendrocytes → loss of myelin → damage, loss of axons

TYPES

▪ Relapsing-remitting multiple sclerosis (RRMS) ▫ Bouts of autoimmune attacks, months/

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years apart ▫ Improvement after attack ▫ Residual permanent damage accumulates ▫ Disabilities do not increase between bouts ▪ Secondary progressive multiple sclerosis (SPMS) ▫ Starts as RRMS ▫ Over time attacks become constant → progression of disabilities ▪ Primary progressive multiple sclerosis (PPMS) ▫ One constant attack → progression of disabilities over lifetime ▪ Progressive-relapsing multiple sclerosis (PRMS) ▫ One constant attack ▫ Superimposed bouts → faster progression of disabilities

RISK FACTORS

▪ Genetic ▫ Individuals who are biologically female twice as susceptible ▫ Polymorphisms of certain alleles of major histocompatibility complex (e.g. HLA-DR2; identifying, binding of foreign molecules) ▪ Environmental ▫ Infections (e.g. Epstein–Barr virus infection) ▫ Vitamin D deficiency ▪ Usually affects young adults

MNEMONIC: MS MS

Pathology of multiple sclerosis Multiple Sclerosis affects Myelin Sheath

Chapter 68 CNS Demyelinating Disorders

SIGNS & SYMPTOMS ▪ Charcot’s neurologic triad ▫ Dysarthria, nystagmus, intention tremor ▪ Lhermitte’s sign ▫ Bending neck forward → electric shock runs down back, radiates to limbs ▪ Higher order activities ▫ Poor concentration, critical thinking; depression, anxiety Plaque location ▪ Brainstem ▫ Conscious movements (e.g. difficulty talking/eating) ▫ Unconscious movements (e.g. difficulty swallowing) ▪ Eye nerves ▫ Optic neuritis (e.g. loss of vision) ▫ Eye movement nerves (e.g. double vision) ▪ Motor pathways ▫ Muscle weakness, spasms, tremors, ataxia, paralysis ▪ Sensory pathways ▫ Numbness; pins, needles; paresthesias (tingling, itching, burning) ▪ Autonomic nervous system ▫ Constipation, urinary incontinence, sexual dysfunction

OTHER DIAGNOSTICS

▪ Clinical ▫ Neurologic symptoms with relapsingremitting course ▪ Visual evoked potential ▫ Measure response to visual stimuli

Figure 68.3 An MRI scan of the head in the sagittal plane demonstrating multiple demyelinating plaques adjacent to the corpus callosum. This radiological sign is known as Dawson’s fingers and is specific for multiple sclerosis.

DIAGNOSIS DIAGNOSTIC IMAGING MRI ▪ Hypointense T1, hyperintense T2 lesions ▪ ≥ one lesions in periventricular, juxtacortical, infratentorial, spinal cord ▪ Gadolinium-enhanced, nonenhanced lesions simultaneously ▪ Dawson’s fingers ▫ Plaques radiating outwards from corpus callosum in sagittal images

LAB RESULTS

▪ CSF ▫ High levels of antibodies

Figure 68.4 An MRI scan of the head in the axial plane demonstrating the multiple demyelinating plaques present in the brain of an individual with multiple sclerosis.

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TREATMENT MEDICATIONS

▪ RRMS ▫ Corticosteroids, cyclophosphamide, intravenous immunoglobulin

▪ Progressive MS ▫ Manage symptoms (e.g. urinary incontinence), physical therapy, cognitive rehabilitation therapy, vitamin D

OTHER INTERVENTIONS

▪ RRMS ▫ Plasmapheresis: removing antibodies ▫ Immunosuppressants

TRANSVERSE MYELITIS osms.it/transverse-myelitis PATHOLOGY & CAUSES

SIGNS & SYMPTOMS

▪ Rare immune disorder affecting spinal cord; causes acute motor, sensory, autonomic defects ▪ Perivascular inflammation (monocytes, lymphocytes) → damage to oligodendrocytes → loss of myelin sheath around axons → loss of axons, neurons

▪ Motor: extremity weakness → paraparesis ▪ Sensory: abnormal sensations, numbness, pain ▪ Autonomic: sphincter, sexual dysfunction

TYPES

DIAGNOSTIC IMAGING

▪ Acute partial ▫ Asymmetric dysfunctions ▫ 1–2 segments involved ▪ Acute complete ▫ Symmetric dysfunctions ▫ 1–2 segments involved ▪ Longitudinally extensive ▫ Symmetric/asymmetric dysfunctions ▫ > two segments involved

RISK FACTORS

▪ CNS, systemic infections ▪ CNS disease (e.g. multiple sclerosis)

DIAGNOSIS MRI ▪ Hypointense/isointense T1, hyperintense T2 signal ▪ Abnormal contrast enhanced signal on ≥ one segment ▪ Spinal cord swelling

LAB RESULTS

▪ CSF ▫ ↑ cell count (lymphocytes), ↑ protein level

OTHER DIAGNOSTICS

▪ Clinical ▫ Motor, sensory, autonomic defects

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Chapter 68 CNS Demyelinating Disorders

TREATMENT OTHER INTERVENTIONS ▪ Intravenous glucocorticoids ▪ Plasma exchange

Figure 68.5 An MRI scan of the spine in the sagittal plane demonstrating increased T2 signal uptake in the spinal cord, typical of transverse myelitis, extending from C7 downwards and ending at T12 (not shown).

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NOTES

NOTES

CONGENITAL MYOPATHIES GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES

SIGNS & SYMPTOMS

▪ Inherited, progressive myopathic disorders caused by genetic dystrophin gene mutation (dystrophinopathies) ▪ Duchenne and Becker’s muscular dystrophy (most common types) ▫ X-linked recessive inheritance pattern ▪ Dystrophin protein ▫ Normally links intracellular actin, dystrophin-associated protein complex to extracellular matrix to stabilize sarcolemma ▪ Genetic defect → misshapen/absent dystrophin protein → weak sarcolemma, cell damage → creatine kinase escapes from/calcium enters damaged cell → cell death → muscle degeneration → progressive weakness

▪ Motor development milestone delays (e.g. walking) ▪ Progressive limb, girdle weakness ▪ Gowers’ sign ▫ Weak hips, upper legs → using arms to help stand ▪ Waddling gait ▪ Musculoskeletal abnormalities (e.g. calf pseudohypertrophy, scoliosis, contracture) ▪ Progressive mobility impairment

DIAGNOSIS ▪ See individual myopathies

TREATMENT ▪ See individual myopathies

BECKER'S MUSCULAR DYSTROPHY osms.it/beckers-dystrophy PATHOLOGY & CAUSES ▪ Caused by misshapen dystrophin gene due to missense mutation ▫ See mnemonic: BMD

COMPLICATIONS

▪ Rapidly progressive heart failure, arrhythmia

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MNEMONIC: BMD

Cause of Becker’s Muscular Dystrophy Badly Made Dystrophin (truncated protein)

Chapter 69 Congenital Myopathies

TREATMENT

SIGNS & SYMPTOMS ▪ Milder form, later onset than Duchenne muscular dystrophy ▪ Symptoms appear 10–20 years old ▪ Intellectual disability, contractures not as common/severe as Duchenne muscular dystrophy ▪ Cardiac fibrosis may be predominant presentation feature ▫ Starting with right ventricular involvement, left ventricular dysfunction later

▪ No cure

MEDICATIONS

▪ Glucocorticoids to slow muscle degeneration

OTHER INTERVENTIONS

▪ Vitamin D, calcium supplements support bone health ▪ Physical therapy, conditioning ▪ Complication management

DIAGNOSIS LAB RESULTS

▪ ↑ serum creatine kinase ▪ Mutations in dystrophin by DNA test/ Western blot ▪ Muscle biopsy ▫ Stain for dystrophin

DUCHENNE MUSCULAR DYSTROPHY osms.it/duchenne_muscular_dystrophy PATHOLOGY & CAUSES ▪ Caused by absent dystrophin gene due to nonsense/frameshift mutation ▫ See mnemonic: DMD

MNEMONIC: DMD

Cause of Duchenne Muscular Dystrophy Doesn’t Make Dystrophin

COMPLICATIONS

▪ Wheelchair needed for mobility → scoliosis ▫ Scoliosis → poor pulmonary function ▪ Weak diaphragm → respiratory failure (may develop) ▪ Fibrosis progression in dilated cardiomyopathy → mitral regurgitation (may develop) ▪ Dilated cardiomyopathy (late stages) → heart failure, arrhythmias (may develop) ▪ Falling → arm, leg fractures ▫ Vertebral compression fractures with glucocorticoid therapy ▪ Respiratory insufficiency/cardiomyopathy → death (late teens, early twenties)

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SIGNS & SYMPTOMS ▪ More severe dystrophinopathy form ▪ Symptoms appear by five years old; weakness usually occurs 2–3 years old ▪ Walking begins later in childhood; may have slow, ungainly run; difficulty jumping, walking up steps ▪ Proximal-limb muscle weakness before distal, lower extremities before upper ▪ Gowers’ sign ▪ Waddling gait, calf pseudohypertrophy ▪ Decreased mobility ▫ May lead to independent ambulation impairment, wheelchair-use by 12 years old (usually) ▪ Primary dilated cardiomyopathy, conduction abnormalities

Figure 69.1 A muscle biopsy from an individual in the later stages of Duchenne muscular dystrophy. The myocyte hypertrophy is even more pronounced and there is marked fatty replacement of the muscle.

TREATMENT ▪ No cure

MEDICATIONS

▪ Glucocorticoids to slow muscle degeneration

OTHER INTERVENTIONS

▪ Vitamin D, calcium supplements support bone health ▪ Physical therapy, conditioning ▪ Complication management

Figure 69.2 A muscle biopsy from an individual in the early stages of Duchenne muscular dystrophy. There is variation in myocyte size with small atrophic myocytes juxtaposed with large, rounded hypertrophic myocytes. There is intervening fibrosis.

DIAGNOSIS LAB RESULTS

▪ ↑ serum creatine kinase ▪ Mutations in dystrophin by DNA test/ Western blot ▪ Muscle biopsy ▫ Stain for dystrophin

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Figure 69.3 A histological section of muscle showing complete fibrofatty replacement in end stage Duchenne muscular dystrophy.

NOTES

NOTES

CORTICAL DISORDERS GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Cortical structure damage in brain → functional regional-specific impairment

CAUSES

▪ Stroke (common), hemorrhage, infection, tumor, trauma, surgery, degenerative disease (e.g. Broca’s aphasia, Wernicke’s aphasia, Klüver–Bucy syndrome)

SIGNS & SYMPTOMS ▪ Affected brain region dependent ▪ Broca’s aphasia ▫ Expressive nonfluent aphasia ▪ Wernicke’s aphasia ▫ Receptive fluent aphasia ▪ Klüver–Bucy syndrome ▫ Amnesia, compulsive eating, hypersexuality

DIAGNOSIS DIAGNOSTIC IMAGING

▪ CT scan, MRI, single-photon emission computerized tomography (SPECT), positron emission tomography (PET)

LAB RESULTS

▪ Cerebrospinal fluid (CSF) analysis

OTHER DIAGNOSTICS ▪ Functional assessment ▪ Neurological exam

TREATMENT OTHER INTERVENTIONS ▪ Address underlying cause

MNEMONIC: MD vs. DPM Cortical brain Memory Discrimination

Subcortical brain Devoid of seizure Primary sensation through thalamus Movement disorders (most)

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BROCA'S APHASIA osms.it/brocas-aphasia PATHOLOGY & CAUSES ▪ Aphasia ▫ Language loss/defect (speaking, fluency, reading, writing, comprehension) ▫ Injury to brain’s language centers → different aphasia types ▫ Most lesions involve dominant hemisphere (left in 95% of right-handed individuals, right in 50% of left-handed individuals) ▪ Broca’s aphasia ▫ Broca’s area: responsible for language comprehension ▫ Damage to Broca’s area → expressive nonfluent aphasia (trouble expressing language → “individuals know what they want to say, but cannot get it out”)

CAUSES

▪ Stroke (superior division of left-middle cerebral artery), traumatic brain injury, brain tumor, cerebral hemorrhage

SIGNS & SYMPTOMS ▪ Slowed, effortful speech ▪ Short sentences without grammatical construction (content appropriate, meaningful) ▪ Individual with Broca’s aphasia may describe trip to barber for haircut as follows ▫ “Yes... errr... Tuesday... er... Dad and Kevin T... (his own name), and Dad.... er... the mall... and ah... Tuesday... Tuesday, ten o’clock... and.. oh barber... one... um’ barber... and er... hair...” ▪ Written, spoken language comprehension intact (or mildly impaired) ▪ Self-monitoring speech (generally still capable) → awareness of speech deficit

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▪ Broca’s area: anterior to primary motor cortex, damage to adjacent areas → individual may have associated contralateral hemiparesis, hemisensory loss

DIAGNOSIS DIAGNOSTIC IMAGING

▪ Findings vary by underlying aphasia cause ▫ May include evidence of bleeding/ hypodensities (stroke); mass effect, overt tumors (cancer) ▫ Functional imaging will reveal regional perfusion deficits

Brain CT scan ▪ With/without contrast MRI ▪ Standard MRI ▪ Diffusion tensor imaging (images white matter tracts) ▪ Functional MRI (images neurological activity) SPECT/PET ▪ Images neurological activity

OTHER DIAGNOSTICS

▪ Language assessment, screening tools

TREATMENT ▪ Treat underlying cause ▪ Most individuals improve/recover spontaneously within one month

OTHER INTERVENTIONS

▪ Speech therapy (early initiation)

Chapter 70 Cortical Disorders

KLÜVER–BUCY SYNDROME osms.it/kluver-Bucy_syndrome PATHOLOGY & CAUSES ▪ AKA bilateral temporal lobe disorder ▪ Caused by bilateral lesions to medial temporal lobe ▫ Hippocampus, surrounding structures including amygdala; vital for declarative, long-term memory

CAUSES

▪ Trauma/lobectomy, herpes simplex encephalitis, stroke, Pick's disease, Alzheimer’s disease

SIGNS & SYMPTOMS ▪ Amnesia (profound antero-, retrograde amnesia), inappropriate things/compulsive eating, inappropriate object insertion into mouth, hypersexuality, visual agnosia (inability to recognize familiar objects/ people), docility (diminished fear/aggression response)

DIAGNOSIS ▪ Three/more symptoms present (most commonly placidity, hyperorality, dietary changes)

DIAGNOSTIC IMAGING CT scan/MRI ▪ Temporal lobe lesions

LAB RESULTS

▪ If viral encephalitis underlying cause → CSF analysis, serology ▪ CSF fluid analysis ▫ Normal/mild protein ↑, normal/low glucose content, normal/raised red cell count, lymphocytosis ▪ CSF serology ▫ CSF antibodies compared to serumspecific antibodies ▫ 4x rise in virus specific IgG/positive IgM ▪ CSF polymerase chain reaction (PCR) → specific virus identification

TREATMENT MEDICATIONS

▪ Herpes simplex encephalopathy → antivirals

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WERNICKE'S APHASIA osms.it/wernickes-aphasia PATHOLOGY & CAUSES ▪ Wernicke’s aphasia ▫ Wernicke’s area: assigns speech sounds meaning ▫ Damage to Wernicke’s area → receptive, fluent aphasia (trouble interpreting language)

CAUSES

▪ Typically stroke (left middle cerebral artery), traumatic brain injury, brain tumor, cerebral hemorrhage

SIGNS & SYMPTOMS ▪ Impaired written, spoken language comprehension ▪ Unaware of speech error, meaninglessness ▪ Speech-specific symptoms ▪ Jargon: neologisms, real words used meaninglessly; structurally intact speech, typical intonation but lacks content ▫ Literal (phonemic) paraphasia: substitution, addition, rearrangement of sounds → errors sound like intended word( e.g. “nog” instead of “dog”) ▫ Verbal (semantic) paraphasia: related word instead of intended word (e.g “spoon” instead of “fork”) ▫ Neologism: made-up non-word instead of intended word (e.g. “fluparp” for “kettle”) ▫ Circumlocution: describe intended word (e.g. “it’s pointed, thin, you write with it”, in reference to a pen) ▫ Run-on speech: verbalized idea stream related to topic (e.g. asked what do you do at the pet store: “The pet store is a place, it is a place with many pets, and pet food, my favourite animals are dogs, at the pet store I buy food for my dog, there are also fish at the pet store…”)

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DIAGNOSIS DIAGNOSTIC IMAGING

▪ Findings vary by aphasia cause ▫ May include evidence of bleeding/ hypodensities (stroke); mass effect, tumor (cancer) ▫ Functional imaging reveals regional perfusion deficits

Brain CT scan ▪ Vary by aphasia cause ▪ With/without contrast MRI ▪ Vary by aphasia cause ▪ Standard MRI ▪ Diffusion tensor imaging ▪ Functional MRI SPECT/PET ▪ Vary by aphasia cause

OTHER DIAGNOSTICS

▪ Language assessment, screening tools

TREATMENT OTHER INTERVENTIONS

▪ Most individuals improve/recover spontaneously within one month ▪ Speech, comprehension therapy (early initiation)

Chapter 70 Cortical Disorders

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NOTES

NOTES

CRANIAL NERVE INJURY GENERALLY, WHAT IS IT? PATHOLOGY & CAUSES ▪ Brain/cranial nerves injury → neurological dysfunction

CAUSES

▪ Trauma (accidental, inflicted), autoimmune, infectious, idiopathic

SIGNS & SYMPTOMS ▪ Varies widely ▫ Area-dependent

DIAGNOSIS DIAGNOSTIC IMAGING CT scan/MRI ▪ Specific, focused neurological functioning tests

TREATMENT ▪ Symptomatic complications, treat underlying causes

BELL'S PALSY osms.it/bells-palsy PATHOLOGY & CAUSES ▪ Lower motor neuron weakness of cranial nerve VII (facial nerve) → acute, peripheral facial palsy ▪ Adversely affects facial motor activity; lacrimal, salivary glands (parasympathetic fibers); taste (afferent fibers on anterior two-thirds of tongue); external auditory canal, pinna (somatic afferents) ▪ Etiology unknown ▫ Potentially viral-associated ischemia, demyelination (e.g. herpes zoster, herpes simplex (HSV), Epstein–Barr virus, Lyme disease)

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RISK FACTORS

▪ Age (peak incidence > 50), diabetes mellitus, pregnancy (third trimester), early postpartum

COMPLICATIONS

▪ Corneal exposure → keratitis, motor regeneration → oral incompetence, reinnervation “miswiring” → synkinesis (involuntary muscle movement) ▪ Incomplete sensory regeneration ▫ Dysesthesia (unpleasant/abnormal touch), dysgeusia (distorted taste), ageusia (decreased taste)

Chapter 71 Cranial Nerve Injury

SIGNS & SYMPTOMS ▪ Unilateral facial weakness evolves rapidly over 48 hours ▫ Eyebrow sags, eye won’t close, mouth corner droops (drooling, difficulty eating/ drinking), decreased tear production → ocular dryness, hyperacusis (↓ everyday sound tolerance), ageusia (decreased taste sensation) ▪ Prodromal symptoms (pre-onset) ▫ Ear pain, dysacusis (sound distortion) ▪ See mnemonic: BELL’S Palsy

MNEMONIC: BELL'S Palsy

Symptoms of Bell’s palsy Blink reflex abnormal Ear sensitivity Lacrimation: deficient, excess Loss of taste Sudden onset Palsy: CN VII nerve muscles (All symptoms are unilateral)

DIAGNOSIS LAB RESULTS

▪ Serologic testing if viral infection suspected

OTHER DIAGNOSTICS

▪ House–Brackmann facial nerve dysfunction classification ▫ Grades facial muscle impairment degree ▫ Normal, mild, moderate, moderatelysevere, severe, total paralysis ▪ Palpebral-oculogyric reflex (Bell phenomenon) ▫ Attempted eyelid closure → upward eye deviation ▪ Stethoscope loudness test ▫ Individual listens to tuning fork through stethoscope ▫ Hyperacusis indicates paralyzed stapedius muscle on affected side ▪ ↓ pinprick sensation in posterior auricular area ▪ ↓ taste ▫ Sweetness, saltiness, acidity ▪ Motor nerve conduction studies (NCS) ▫ Estimates axonal loss degree

TREATMENT MEDICATIONS

▪ Corticosteroids ▫ Symptom onset → begin within 3–4 days

OTHER INTERVENTIONS

▪ Artificial tears, eye patching ▫ Reduce corneal damage risk ▪ Physical therapy (e.g. facial exercise, neuromuscular retraining) ▪ May resolve spontaneously within three weeks

Figure 71.1 An individual with Bell’s palsy affecting the right side of the face.

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TRIGEMINAL NEURALGIA osms.it/trigeminal-neuralgia PATHOLOGY & CAUSES

DIAGNOSIS

▪ AKA tic douloureux; stimulating facial trigger zone → intense, stabbing, paroxysmal pain in trigeminal nerve (cranial nerve V—usually V2/V3 subdivisions) ▫ Triggers: touching/moving tongue, lips, face; chewing; shaving; brushing teeth; blowing nose; hot/cold drinks

DIAGNOSTIC IMAGING

TYPES

OTHER DIAGNOSTICS

▪ Classic ▫ Most common; unknown etiology, artery/vein compressing cranial nerve (CN) V root may → pain ▪ Secondary ▫ Nonvascular lesion compressing nerve → pain

RISK FACTORS

▪ Biological sex (female > male) ▪ Age (peak incidence 50–60) ▪ Demyelinating disorders (e.g. multiple sclerosis) ▪ Postherpetic trigeminal neuropathy ▪ Acoustic neuroma ▪ Saccular aneurysm ▪ Vestibular schwannoma

SIGNS & SYMPTOMS ▪ Pain paroxysms ▫ Last one–several seconds; may repeat; usually unilateral ▪ Dull pain between paroxysms ▪ Facial muscle spasms/autonomic symptoms (e.g. lacrimation, diffuse conjunctival injection, rhinorrhea)

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CT scan/MRI ▪ May identify lesion/vascular compression ▪ Electromyographyrigeminal reflex testing ▫ Measures muscles’, controlling nerves’ electrical activity

▪ Classic trigeminal neuralgia ▫ No clinically evident neurologic deficit, no better explanation via another diagnosis, ≥ three attacks of unilateral facial pain fulfilling criteria A and B ▫ A: Occurs in ≥ one trigeminal nerve divisions, no radiation beyond trigeminal distribution ▫ B: Pain has three or more of the following four characteristics: recurring paroxysmal attacks (< two minutes); severe intensity; shock-like, shooting, stabbing, sharp pain; stimulating affected facial side → > two attacks (other attacked may be spontaneous)

TREATMENT MEDICATIONS

▪ Pain management

SURGERY

▪ Microvascular decompression ▪ Neuroablation ▫ Rhizotomy with radiofrequency thermocoagulation/mechanical balloon compression/chemical (glycerol) injection ▫ Radiosurgery ▫ Peripheral neurectomy, nerve block

NOTES

NOTES

DEMENTIA GENERALLY, WHAT IS IT? PATHOLOGY & CAUSES ▪ Acquired, progressive cognitive impairment ▪ Involving one/more cognitive functions ▫ Memory, concentration, language, learning, praxis, judgment, executive functions, social cognition ▪ Previous functional-level deterioration; consciousness remains intact

CAUSES

▪ Increasing age; most important risk factor ▪ Alzheimer disease ▪ Vascular dementia including multi-infarct dementia, Binswanger’s disease ▪ Lewy body dementia (DLB) ▪ Frontotemporal dementia (e.g. Pick disease)

COMPLICATIONS

▪ Inability to function independently in everyday life ▪ Debilitated state infections (death secondary) ▪ See mnemonic for summary

MNEMONIC: DEMENTIA

Common causes of Dementia Diabetes Ethanol Medication Environmental (eg CO poisoning) Nutritional Trauma Infection Alzheimer’s

SIGNS & SYMPTOMS ▪ Memory loss, difficulty retaining new information ▪ Language impairment ▪ Executive dysfunction ▫ Difficulty in handling complex tasks, concentration loss, poor judgement ▪ Visuospatial ability impairment ▪ Apraxia (inability to perform an action) ▪ Behavioral disturbance ▪ Personality change

DIAGNOSIS DIAGNOSTIC IMAGING CT scan ▪ Reveals microinfarcts indicative of vascular dementia

OTHER DIAGNOSTICS

▪ Mental status examination ▫ Identify cognitive impairment with standardized mental status scales ▪ Montreal cognitive assessment (MoCA), mini-mental state examination (MMSE) ▪ Neuropsychological testing ▫ Quantitate cognitive impairment degree/ domains involved (e.g. animal-naming test) ▪ Post-autopsy brain biopsy

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TREATMENT ▪ Treatment/control of reversible causes

MEDICATIONS

▪ Acetylcholinesterase inhibitors ▫ ↑ acetylcholine (brain’s primary

neurotransmitter) levels; used for Alzheimer disease, DLB ▪ Memantine ▫ N-methyl-D-aspartate (NMDA) receptor antagonist (neuroprotective, diseasemodifying drug) for advanced dementia

ALZHEIMER'S DISEASE (AD) osms.it/alzheimers-disease PATHOLOGY & CAUSES ▪ Neurodegenerative disease; beta amyloid plaque, neurofibrillary tangle formation → impaired neuronal signaling, neuron apoptosis ▪ Most common form of dementia ▪ Sporadic (95% of cases), typically > 60 years old ▫ Early AD onset unusual, mostly familial ▪ Amyloid precursor protein (APP) ▫ Normally located in neuronal membrane ▫ Growth, neuron-repair contributor ▫ Abnormal APP degradation via beta secretase (normally degraded by gamma, alpha secretase) → APP cut into insoluble fragments → create beta amyloid plaque → AD results ▫ Beta amyloid plaque pathology: signalling obstruction → deposits around vessels (amyloid angiopathy), ↑ hemorrhage risk → initiates inflammatory response ▪ Tau proteins ▫ Intracellular microtubule-associated proteins ▫ In AD, Tau proteins become pathologically hyperphosphorylated → aggregate, stop supporting microtubules → form neurofibrillary tangles → obstruct neuronal signaling → neuron apoptosis

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RISK FACTORS

▪ ↑ age (> 60 years old → risk doubling every five years) ▪ Family history ▪ Trisomy 21 (Down syndrome) ▪ Gene mutations affecting APP, presenilin 1 and 2 (gamma secretase subunits) ▪ Apolipoprotein E-e4 alleles (ApoEe4) ▫ ApoE normally breaks down beta amyloid, e4 alleles encode less effective ApoE ▪ History of hypertension, dyslipidemia, cerebrovascular disease, altered glucose metabolism, brain trauma

COMPLICATIONS

▪ Complete debilitation, dependence on others ▪ Debilitation → dehydration, malnutrition, infection ▪ Death occurs 5–10 years after symptoms onset

MNEMONIC: RONALD

Features of AD Reduction of Ach Old age Neurofibrillary tangles Atrophy of cerebral cortex (diffuse) Language impairment Dementia (MC in elderly)/ Down’s syndrome

Chapter 72 Dementia

SIGNS & SYMPTOMS ▪ Insidious onset, symptom progression Early stages ▪ Initial symptom ▫ (Commonly) recent memory impairment; inability to acquire, remember new information ▪ Executive dysfunction ▫ Impaired reasoning, handling complex tasks, concentration/motivation loss, difficulty making/executing plans, poor judgement ▫ Impaired visuospatial skills ▫ Reduced insight into cognitive deficit (anosognosia) ▫ Sleep disturbance Intermediate/later stages ▪ Behavioral, psychological symptoms ▫ Apathy, social disengagement, irritability, agitation, aggression, wandering, psychosis (hallucination, delusion) ▪ Motor task completion ▫ Difficulty (dyspraxia)/inability (apraxia) ▫ Impaired language function (e.g. wordfinding deficit) ▫ Remote memory loss ▫ Seizure ▫ Motor signs (e.g. pyramidal signs)

MNEMONIC: ALZHEIMER'S Characteristics of AD Anterograde amnesia Life expectancy increase in population shows increased prevalence Zapped (loss of) acetylcholinergic neurons Hereditary disease Entire hippocampus affected Identified by neurofibrillary tangles Mutation in amyloid genes Entorhinal areas degenerate first Retrograde amnesia Senile plaques at synapse

OTHER DIAGNOSTICS

▪ Mental status scale clinical assessment (e.g., MoCA, MMSE) ▪ Neuropsychological testing ▫ Confirm cognitive impairment diagnosis ▪ Post-autopsy brain biopsy ▫ Shows characteristic beta-amyloid plaque, neurofibrillary tangle

Advanced ▫ Complete debilitation, dependence on others, urinary/fecal incontinence

DIAGNOSIS ▪ Diagnosis of exclusion

DIAGNOSTIC IMAGING CT scan/MRI ▪ Exclude other dementia causes ▪ Brain scans show diffuse cortical (especially hippocampus) atrophy, gyri narrowing, sulci widening, ventricle enlargement

Figure 72.1 An MRI scan in the axial plane demonstrating prominent sulci and gyri in an individual with Alzheimer’s disease.

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TREATMENT ▪ No cure

MEDICATIONS

▪ Acetylcholinesterase inhibitors ▪ Vitamin E supplementation may provide benefit ▪ Memantine (advanced stages) Figure 72.2 A histological section of the hippocampus from an individual with Alzheimer’s disease demonstrating a neurofibrillary tangle.

Figure 72.3 A histological section of brain from an individual with Alzheimer’s disease demonstrating multiple amyloid plaques.

LEWY BODY DEMENTIA osms.it/lewy-body-dementia PATHOLOGY & CAUSES ▪ Degenerative disease ▫ Early dementia, visual hallucinations onset; later parkinsonian clinical feature onset, presence of Lewy bodies ▪ Occurs at 50–85 years old (typically) ▪ More rapid cognitive decline than AD

CAUSES

▪ Alpha-synuclein protein aggregation in neurons (particularly cortex, substantia nigra) forming Lewy bodies, → apoptosis

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COMPLICATIONS

▪ Persistent psychotic symptoms, especially visual hallucinations ▪ Depression ▪ Complete debilitation, dependence on others ▪ Debilitation infection often → death; life expectancy ↓ ▪ Neuroleptic-agent sensitivity ▫ Adverse effects (parkinsonism) ↑ severity, symptom exacerbation

Chapter 72 Dementia

TREATMENT

SIGNS & SYMPTOMS Early stages ▪ Progressive, fluctuating cognitive function impairment ▫ Attention, executive, visuospatial functions; memory affected later ▪ Visual hallucination, disorganized speech, depression Later stages ▪ Motor symptoms mimic Parkinson’s disease ▫ Resting tremor, stiffness, slow movement, reduced facial expressions

▪ No cure

MEDICATIONS Alleviate symptoms ▪ Acetylcholinesterase inhibitors ▫ Cognitive symptoms ▪ Dopamine analogue ▫ Motor symptoms ▪ Atypical neuroleptic agents ▫ Persistent disabling hallucinations, psychotic features (used very cautiously)

Other clinical features ▪ Rapid eye movement (REM) sleep behavior disorder ▫ Sleep disturbance (sleep walking, talking) ▪ Autonomic nervous system dysfunction ▫ Orthostatic hypotension, syncope, urinary incontinence/retention, constipation, impotence ▪ Repeated falls (parkinsonism), cognitive fluctuation/orthostatic hypotension ▪ Neuroleptic sensitivity

DIAGNOSIS ▪ Exclude other dementia causes

Figure 72.4 A histological section of the brain demonstrating a Lewy body. They are caused by the abnormal deposition of the protein alpha synuclein.

DIAGNOSTIC IMAGING Single-photon emission computerized tomography (SPECT) scanning ▪ Dopamine transporter ligand ioflupane I-123 (DaTSCAN) shows ↓ transporter perfusion

OTHER DIAGNOSTICS

▪ Neuropsychological testing ▫ Confirms cognitive-impairment diagnosis ▪ Mental status scale assessment (e.g. MoCA, MMSE) ▪ Post-autopsy brain biopsy ▫ Shows Lewy bodies as eosinophilic intracytoplasmic inclusions in cortical neurons

Figure 72.5 Immunohistochemical tain for the protein alpha synuclein highlights the Lewy bodies in the brain tissue of an individual with Lewy body dementia.

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FRONTOTEMPORAL DEMENTIA (FTD) osms.it/frontotemporal-dementia PATHOLOGY & CAUSES

SIGNS & SYMPTOMS

▪ Heterogeneous degenerative frontal/ temporal lobe disease ▫ Presents with personality/behavioral disturbances/aphasia ▪ Occurs < 65 years old (typically) ▫ Memory loss develops later ▪ Inherited/sporadic ▪ Associated with specific-protein cellular inclusions ▫ Tau proteins (Pick disease) ▫ TAR DNA-binding protein 43 (TDP43) ▪ Protein buildup → stop neuronal signaling, lead neurons to apoptosis ▪ Concomitant motor disease: 15–20% (e.g. parkinsonism, motor neuron disease)

▪ Frontal lobe involvement → behavior/ emotional changes ▪ Disinhibition, emotional blunting, apathy/ empathy-loss, hyperorality, compulsive behavior, family/friend dissociation (argumentative/hostile behavior) ▪ Temporal lobe involvement → language impairment, emotional disturbance ▪ Difficulty finding correct word, progressive aphasia, impaired word comprehension, emotional impairment (anxiety/irrational fear), sarcasm-recognition difficulty ▪ Later stages → cognitive decline ▪ Worsening memory, inability to learn new things, concentration loss

TYPES Pick disease ▪ Specific pathological FTD subtype characterized by presence of Pick bodies (tangles of abnormal Tau proteins—3R tau isoforms) ▫ 3R tau isoforms (particular amino-acid sequence repeated three times) are hyperphosphorylated, stop supporting microtubules, tangle into round silverstaining inclusion bodies (Pick bodies)

Figure 72.6 An MRI scan of the head in the axial plane demonstrating frontotemporal volume loss.

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Chapter 72 Dementia

DIAGNOSIS ▪ Exclude other dementia causes ▫ Laboratory, imaging tests

DIAGNOSTIC IMAGING MRI ▪ Structural imaging ▪ Unilateral frontal/temporal atrophy, may → both hemispheres, ventricle enlargement SPECT/perfusion-MRI/PET ▪ Functional imaging ▪ Affected-lobe hypometabolism, hypoperfusion

LAB RESULTS Genetic testing ▪ Familial FTDs Pick disease-specific biopsy findings ▪ Pick bodies ▫ Round/oval, Tau-positive, neuronal cytoplasmic inclusions ▪ Pick cells ▫ Swollen (ballooned) neurons

TREATMENT ▪ No cure

MEDICATIONS Symptom alleviation ▪ Antidepressants ▫ Severe behavioral symptoms ▪ Atypical antipsychotic drugs have significant side effects ▪ Cholinesterase inhibitors ▫ No convincing evidence of benefit

OTHER INTERVENTIONS

▪ Physical exercise; physical, occupational, speech therapy; ↑ supervision

MNEMONIC: PICK

Features of Pick disease Progressive degeneration of neurons Intracytoplasmic Pick bodies Cortical atrophy Knife edge gyri

OTHER DIAGNOSTICS

▪ Neuropsychological tests ▫ Normal in early stages ▪ Mental status scale assessment (e.g. MoCA, MMSE) ▪ Post-autopsy brain biopsy shows characteristic microscopic findings ▫ Microvacuolation, neuronal loss, swollen neurons, myelin loss, astrocytic gliosis, abnormal protein inclusions

Figure 72.7 A brain at post mortem with frontotemporal degeneration.

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VASCULAR DEMENTIA osms.it/vascular-dementia PATHOLOGY & CAUSES ▪ Heterogenous dementia ▫ Results from multiple cerebrovascular events/chronic ischemia ▪ Second most common dementia cause in elderly ▪ High Alzheimer disease comorbidity ▪ Multiple, bilateral, cortical, subcortical infarcts/chronic ischemia → ↓ brain blood supply → stepwise cognitive function decline, gait abnormality, focal neurological deficits ▫ Prominent executive function deficit ▫ Late-onset memory impairment ▪ Binswanger’s disease ▫ Large subcortical white matter areas involved

CAUSES

▪ Cerebral artery atherosclerosis ▪ Carotid artery/heart embolization ▪ Chronic hypertension → cerebral arterioles sclerosis ▪ Vasculitis

RISK FACTORS

▪ Smoking, hypertension, diabetes, insulin resistance, hyperlipidemia, hyperhomocysteinemia

SIGNS & SYMPTOMS ▪ Progressive, stepwise cognitive function impairment (affected cortical areadependent) ▫ Frontal: executive dysfunction (frontal) ▫ Left parietal: aphasia, apraxia, agnosia ▫ Right parietal: hemineglect, confusion, agitation, visuospatial, constructional difficulty ▫ Temporal: anterograde amnesia

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▪ Deficits due to subcortical infarcts ▫ Focal motor signs ▫ Gait disturbance ▫ Urinary frequency/urgency ▫ Personality, mood change ▫ Relatively mild memory deficit ▫ Improvements may occur between cerebrovascular events

DIAGNOSIS DIAGNOSTIC IMAGING MRI/CT scan ▪ Show multiple cortical, subcortical infarcts ▪ Microinfarcts identified ▫ Initiate evaluation to define etiology ▫ Carotid Doppler ultrasound: reveal carotid plaques ▫ Echocardiogram: reveal cardiogenic emboli

OTHER DIAGNOSTICS

▪ Neuropsychological testing ▫ Detects cognitive impairment, domains involved ▫ Similar language, construction, memory registration deficits with AD, but more impaired executive functioning ▪ Microinfarcts identified ▫ Initiate evaluation to define etiology ▫ Holter monitor (detect arrhythmias) ▫ Risk factor screening

Chapter 72 Dementia

TREATMENT ▪ No cure

MEDICATIONS

▪ Vascular risk factor control ▫ Antihypertensive drugs, antidiabetic agents, statins, antiplatelet agents ▪ Acetylcholinesterase inhibitors/memantine

OTHER INTERVENTIONS ▪ Vascular risk factor control ▫ Lifestyle changes

Figure 72.8 An MRI scan in the axial plane of the head of an individual with cognitive impairment. There are multiple small white matter infarcts and an absence of cortical atrophy.

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NOTES

NOTES

EAR PATHOLOGY GENERALLY, WHAT IS IT? PATHOLOGY & CAUSES ▪ Structural, functional pathology affecting different ear components ▪ Outer ear: auricle, pinna, ear canal ▫ Inflammation/infection → otitis externa ▪ Outer ear, middle ear: separated by tympanic membrane (eardrum); normally no air passage/fluids between two compartments ▫ Perforated eardrum → communication through tympanic membrane ▪ Middle ear: tiny chamber; contains functional ear bones (malleus, incus, stapes) ▫ Inflammatory middle ear disease → otitis media ▪ Eustachian tube: connects middle ear to nasopharynx ▫ Failure to open/close, remove secretions → Eustachian tube dysfunction

SIGNS & SYMPTOMS ▪ Hearing loss ▪ Ear pain ▪ Ear discharge

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DIAGNOSIS DIAGNOSTIC IMAGING

▪ Otoscopy ▫ Tympanic membrane visualization

OTHER DIAGNOSTICS

▪ Outer ear inspection ▪ Hearing screening tests (Weber, Rinne tests) ▫ Distinguishes between conductive, sensorineural hearing loss

TREATMENT MEDICATIONS

▪ Topical otic drops/systemic agents ▪ Antihistamines/corticosteroids/ decongestants (guided by specific diagnosis)

SURGERY

▪ Drain fluid accumulation/debride granulation tissue/repair defect

Chapter 73 Ear Pathology

EUSTACHIAN TUBE DYSFUNCTION osms.it/eustachian-tube-dysfunction PATHOLOGY & CAUSES ▪ Any primary Eustachian tube function failure ▪ Failure to equalize/dilatory dysfunction ▫ Eustachian tube may not open → tympanic membrane stretches → pain Patulous dysfunction (chronic patency) ▪ Normal Eustachian tube is two-way valve (opens to equalize pressure, closed at rest) ▪ Persistent opening → irritant/bacteria entering middle ear Ciliary dyskinesia ▪ Tiny cilia line Eustachian tube, clear out middle ear mucus secretion ▪ Ciliary dysfunction/dyskinesia: cilia fail to clear section → stagnant secretion → complications (e.g. otitis media)

CAUSES Failure to equalize/dilatory dysfunction ▪ Functional: inflammation (viral infection— e.g. common cold, allergy) → Eustachian tube swelling, secretion accumulation → Eustachian tube mechanical blockage → equalization failure ▪ Anatomical: regional mass pressure (e.g. tumour) or previous trauma scar/medical procedure Patulous dysfunction (chronic patency) ▪ Weight-loss (> 6 lbs/2.7 kg) → tissue atrophy (e.g. chronic illness) ▪ Chronic allergy/gastric-content reflux → mucosal atrophy ▪ Chronic gum-chewing → repeated musclefacilitated Eustachian tube opening ▪ Short, floppy Eustachian tubes (in children) → provide little resistance against middleear reflux during ↑ positive pressure on nasopharyngeal end of tube (e.g. crying/ nose blowing)

Ciliary dyskinesia ▪ Acquired: toxins → ciliary damage, paralysis → mucociliary elevator failure ▫ Cilia can’t flick back and forth (e.g. cigarette smoke) ▪ Congenital: cystic fibrosis → very thick secretions not adequately cleared

COMPLICATIONS

▪ Conductive hearing loss, otitis media, tympanic membrane perforation, cholesteatoma

SIGNS & SYMPTOMS ▪ Affected ear is clogged, muffled ▪ Ear pain ▪ Autophony (hearing one’s own voice, breathing) ▫ Encountered primarily in patulous dysfunction ▪ If inner ear affected → balance problems

DIAGNOSIS DIAGNOSTIC IMAGING CT scan / MRI ▪ Contrast in persistent effusion cases ▫ Neoplasm may cause Eustachian tube obstruction Nasal endoscopy ▪ Inflammation, secretion, allergic manifestation signs ▫ Eustachian tube opening quality (assessed through yawn, swallowing maneuvers) Otoscopic ear examination ▪ Normal tympanic membrane appears shiny, translucent

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▪ Examine for abnormality (e.g. retraction, effusion, perforation) ▫ Dull bluish-gray/yellowish coloration denotes effusion behind membrane; reddish coloration, engorged vessels signal inflammation ▪ Pneumatic examination ▫ Fluid-filled ear minimizes tympanic membrane excursion with insufflation

OTHER DIAGNOSTICS

▪ Hearing tests for conductive hearing loss ▫ Weber test: sound lateralized to affected ear ▫ Rinne test: BC > AC

TREATMENT MEDICATIONS

▪ Dilatory dysfunction ▫ Upper respiratory tract inflammation (viral infection, allergy) → short intranasal/systemic decongestant, corticosteroid course ▪ Patulous dysfunction ▫ Avoid decongestants/corticosteroids

SURGERY

▪ Dilatory dysfunction ▫ Tympanostomy tubes: hollow tubes inserted into eardrum → create direct opening between middle, outer ear → allow easy pressure equilibration, accumulated debris drainage

OTHER INTERVENTIONS

▪ Patulous dysfunction ▫ Hydration, nasal saline drops/irrigation

OTITIS EXTERNA osms.it/otitis-externa PATHOLOGY & CAUSES ▪ AKA “swimmer’s ear” ▪ Outer ear canal irritation

CAUSES

▪ Outer ear canal microbial infection (primary cause) ▫ Bacterial (90%): Pseudomonas aeruginosa, Pseudomonas vulgaris, E. coli, S. aureus ▫ Fungal: Candida albicans, Aspergillus niger ▪ Dermatological conditions ▫ Allergic contact dermatitis, psoriasis, atopic dermatitis

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RISK FACTORS

▪ Frequent swimming ▪ Mechanical cleaning/irritation (cotton swabs/scratching) ▪ Ear canal occlusion (hearing aid, headphone) ▪ Diabetes

SIGNS & SYMPTOMS ▪ Acute (< six weeks) ▫ Pinna traction → aggravated pain ▫ Otorrea: sticky yellow discharge) ▫ Swelling, purulent debris → external canal obstruction → conductive hearing loss, +/- aural fullness ▫ Posterior auricular lymphadenopathy

Chapter 73 Ear Pathology ▫ Complicated otitis externa: periauricular soft tissue erythema, swelling ▪ Chronic (> three months) ▫ External ear canal pruritus; epidermis atrophy, scaling; otorrhea; normal tympanic membrane

DIAGNOSIS LAB RESULTS

▪ Discharge ▫ Gram stain, culture

OTHER DIAGNOSTICS

▪ Note physical outer ear change (discharge, erythema, scaling) ▪ Hearing tests for conductive hearing loss ▫ Weber test: sound lateralized to affected ear ▫ Rinne test: BC > AC

TREATMENT MEDICATIONS

▪ General ▫ Burow’s solution: topical drops application (buffered aluminum sulfate, acetic acid mixture) ▪ Bacterial ▫ Antipseudomonal otic drops/topical steroid drops/combination ▫ 3% acetic acid solution → acidify ear canal (bacteriostatic acidic pH) ▫ Systemic antibiotics (lymphadenopathy/ cellulitis) ▪ Fungal ▫ Topical antifungal preparation (e.g. gentian violet, boric acid) ▪ Chronic otitis externa (pruritus without obvious infection) ▫ Corticosteroid otic drops alone

OTHER INTERVENTIONS

▪ General ▫ Clean ear under magnification → irrigation, suction, dry-swabbing ▪ Fungal ▫ Debridement

Figure 73.1 An individual with otitis externa of the left ear.

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OTITIS MEDIA osms.it/otitis-media PATHOLOGY & CAUSES ▪ Inflammatory middle ear diseases

TYPES Acute otitis media ▪ Acute middle ear compartment infection (< three weeks) ▪ Acute infection/allergies → nasopharyngeal mucous membrane inflammation → Eustachian tube dysfunction → secretion reflux/aspiration from nasopharynx to middle ear (normally sterile) → infection Otitis media with effusion ▪ Fluid presence in middle ear, with/without infection signs ▪ Eustachian tube dysfunction → trapped fixed gas volume in middle ear → surrounding tissue slowly absorbs gas → ↓ middle-ear pressure ▫ Sufficient ↓ middle-ear pressure → surrounding tissue fluid drawn into middle ear cavity → middle-ear effusion (transudate) ▪ Most common pediatric hearing loss cause Chronic suppurative otitis media ▪ Acute otitis media complication → chronic suppurative otitis media ▪ Perforated tympanic membrane with persistent drainage (> 6–12 weeks) ▪ Acute otitis media → prolonged inflammatory response → middle ear mucosal oedema; tympanic membrane ulceration, perforation → chronic middle ear, mastoid cavity inflammation → persistent discharge from middle ear through perforated tympanic membrane ▪ Persistent infection/inflammation → granulation tissue → polyps within middleear space → inflammation, ulceration, infection, granulation tissue formation cycle → eventual surrounding bony structure destruction

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CAUSES

▪ Bacteria ▫ S. pneumoniae, H. influenzae, M. catarrhalis, group A streptococcus, S. aureus) ▪ Virus ▫ Respiratory syncytial virus, influenza, parainfluenza, adenovirus) ▫ Often viral/bacterial coinfection

RISK FACTORS

Smoke, air-pollution exposure Immunosuppression Pacifier use; daycare Down syndrome Recent upper-respiratory tract viral infection ▪ Craniofacial malformation (cleft lip/palate, microcephaly) ▪ Cystic fibrosis ▪ ▪ ▪ ▪ ▪

Figure 73.2 A tympanic mebrane bulging as due to the accumulation of pus in the middle ear of an individual with otitis media.

Chapter 73 Ear Pathology

COMPLICATIONS

▪ Tympanic membrane perforation, mastoiditis, cholesteatoma, bacterial meningitis, dural sinus thrombosis, conductive/sensorineural hearing loss

SIGNS & SYMPTOMS ▪ Acute otitis media ▫ Otalgia, fever, conductive hearing loss (triad) ▫ Children: ear pulling, crying, poor sleep, irritability ▫ Crying → small blood vessel distension on tympanic membrane → mimics otitis media redness (confounds diagnosis) ▪ Otitis media with effusion ▫ Ear fullness, conductive hearing loss +/tinnitus, no pain/fever ▪ Chronic suppurative otitis media ▫ Perforated tympanic membrane; otorrhea; hearing loss; no pain/ discomfort; fever, vertigo, pain → danger signs (possible complications)

DIAGNOSIS DIAGNOSTIC IMAGING CT scan/MRI ▪ Acute otitis media ▫ Severe cases with hearing loss/high fever) ▫ Excludes more serious complications (e.g. bony destruction/meningitis) Otoscopy ▪ Acute otitis media ▫ Tympanic membrane ↓ mobility, hyperemia, bulging membrane (pus behind tympanic membrane), landmark loss (malleus handle, long process not visible) ▪ Otitis media with effusion ▫ Amber/dull grey tympanic membrane discoloration; meniscus fluid level ↑ ↓, air bubbles behind tympanic membrane; air insufflation → immobile tympanic membrane

▪ Chronic suppurative otitis media ▫ Perforated tympanic membrane; otorrhea; visible granulation tissue (medial canal/middle-ear space); middle ear mucosa (through perforation) may be edematous, polypoid, pale, erythematous

OTHER DIAGNOSTICS Otitis media with effusion ▪ Hearing tests for conductive hearing loss ▫ Weber test: sound lateralized to affected ear ▫ Rinne test: BC > AC ▪ Audiological investigation ▫ Flat audiogram, tympanogram

TREATMENT MEDICATIONS

▪ Acute otitis media ▫ Analgesics ▫ Systemic antibiotics if severe/persistent (> three days) ▪ Otitis media with effusion ▫ Avoid antihistamines, decongestants → secretions thicken ▪ Chronic suppurative otitis media ▫ Corticosteroid drops → ↓ granulation tissue ▫ Antibiotics (topical/drops) ▫ Granulation tissue control: granulation tissue prevents affected-site topical medication penetration

SURGERY

▪ Acute otitis media ▫ Frequent recurrence: tympanostomy tubes ▪ Otitis media with effusion ▫ Severe cases: tympanostomy tubes, myringotomy (tiny eardrum incision) +/ventilating-tube insertion

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OTHER INTERVENTIONS

▪ Otitis media with effusion ▫ Watchful waiting: 90% of children clear fluid in three months without intervention ▫ Minor cases: may resolve spontaneously; manual autoinflation (manually pinch nasal passage, close back of pharynx → forceful diaphragm contraction)

▪ Chronic suppurative otitis media ▫ Mechanical/irrigative debris clearing: aural toilet (mechanical removal of mucoid exudates, desquamated epithelium, associated debris prior to medication administration); aural irrigation (50% acetic acid/sterile water ear-rinse solution)

PERFORATED EARDRUM osms.it/perforated-eardrum PATHOLOGY & CAUSES ▪ Tympanic membrane communication between middle ear, external environment

CAUSES

▪ Otitis media ▪ Trauma ▪ Explosive/percussive force, exceptionally loud noise ▪ Iatrogenic, sudden pressure ↑ ↓ (with blocked Eustachian tubes)

COMPLICATIONS

▪ Chronic infection → permanent hearing loss

SIGNS & SYMPTOMS ▫ Hearing loss ▫ Tinnitus ▫ Ear-ache (infection association) ▫ Otorrhea ▫ Nausea/vomiting

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DIAGNOSIS DIAGNOSTIC IMAGING Otoscopy ▪ Perforation visualization

OTHER DIAGNOSTICS

▪ Hearing tests: conductive hearing loss ▫ Weber test: sound lateralized to affected ear ▫ Rinne test: BC > AC ▪ Audiometry: conductive hearing loss

TREATMENT MEDICATIONS

▪ Avoid otic drops containing gentamicin, neomycin sulfate, tobramycin ▫ Ototoxicity → permanent hearing loss ▪ Otorrhea control ▫ Topical: fluoroquinolone otic drops ▫ Systemic: antibiotics covering respiratory flora

Chapter 73 Ear Pathology

SURGERY

▪ Tympanoplasty: surgical repair

OTHER INTERVENTIONS

▪ Watchful waiting ▫ Perforations may heal in weeks/months

Figure 73.3 A partial perforation of the ear drum.

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NOTES

NOTES

ENCEPHALOPATHY GENERALLY, WHAT IS IT? PATHOLOGY & CAUSES ▪ Abnormal brain structure/function ▪ Permanent/reversible brain injury due to direct injury/other illness

SIGNS & SYMPTOMS ▪ Altered mental status ▫ Irritability, agitation, confusion, somnolence, stupor, coma, psychosis, delirium ▪ Seizure, myoclonus, asterixis, ataxia, tremor

DIAGNOSIS DIAGNOSTIC IMAGING Brain imaging (CT scan, MRI, etc.) ▪ Changes indicative of Wernicke–Korsakoff syndrome (e.g. shrunken mammillary bodies)

LAB RESULTS Blood studies ▪ Complete blood count (CBC),

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comprehensive metabolic panel (CMP) ▫ ↑ ammonia, ↑ transaminases, ↑ prothrombin time, hyper/hypoglycemia Cerebrospinal fluid (CSF) ▪ Determine underlying cause, rule out other causes

OTHER DIAGNOSTICS Electroencephalogram (EEG) ▪ High-amplitude low-frequency, triphasic waves

TREATMENT MEDICATIONS

▪ Anticonvulsants ▫ Individuals with seizures due to encephalopathy

OTHER INTERVENTIONS

▪ Careful monitoring, supportive measures (e.g. IV fluids, nutritional support)

Chapter 74 Encephalopathy

BERIBERI osms.it/beriberi PATHOLOGY & CAUSES ▪ Thiamine (vitamin B1) deficiency ▫ Decreased intake/inability to absorb thiamine

RISK FACTORS

▪ Common in individuals who are alcoholic, malnourished, elderly

COMPLICATIONS

▪ “Wet beriberi” ▫ Cardiomegaly, cardiomyopathy, heart failure

SIGNS & SYMPTOMS ▪ Nystagmus, ataxia, ophthalmoplegia (triad of Wernicke–Korsakoff syndrome), confusion ▪ Wet beriberi: tachycardia, dyspnea, edema ▪ Dry beriberi: peripheral neuropathy, confusion, pain; AKA Wernicke–Korsakoff syndrome

DIAGNOSIS DIAGNOSTIC IMAGING CT scan/MRI ▪ Changes indicative of Wernicke–Korsakoff syndrome (e.g. shrunken mammillary bodies)

OTHER DIAGNOSTICS

▪ History ▫ Alcoholism/low nutritional state

TREATMENT MEDICATIONS

▪ IV thiamine supplementation ▫ Avoid glucose before thiamine if alcoholic; can precipitate encephalopathy

HEPATIC ENCEPHALOPATHY osms.it/hepatic-encephalopathy PATHOLOGY & CAUSES ▪ Brain injury due to toxic metabolites; not removed by liver due to liver dysfunction ▪ Accumulation of toxic metabolites (e.g. ammonia), byproduct of nitrogen metabolism ▪ Ammonia detoxification in astrocytes → glutamine accumulation → osmotic stress → swelling

▪ Other injuries (e.g. alkalosis, metabolic abnormalities, medications, bleeding, infection) → hepatic encephalopathy

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SIGNS & SYMPTOMS ▪ Mental status: confusion, poor concentration, stupor, coma ▪ Neuromuscular: asterixis, rigidity, hyperreflexia ▪ Graded by severity ▫ Grade I: mild; short attention span; mood, sleep problems ▫ Grade II: moderate; decreased energy, slurred speech, tremors ▫ Grade III: severe; confusion, stupor, anxiety ▫ Grade IV: coma

DIAGNOSIS DIAGNOSTIC IMAGING T1-weighted MRI ▪ Hyperintensity of globus pallidus

LAB RESULTS

OTHER DIAGNOSTICS

▪ Psychometric tests ▫ Inhibitory control test (ICT); mental status changes ▪ History ▫ Liver disease, altered mental status

EEG ▪ High-amplitude low-frequency, triphasic waves

TREATMENT MEDICATIONS

▪ Lactulose ▫ Decrease absorption of ammonia ▪ Rifaximin ▫ Kill bowel flora that produce ammonia

OTHER INTERVENTIONS ▪ Nutritional support ▫ Limit protein intake

▪ Blood tests ▫ ↑ ammonia

REYE SYNDROME osms.it/reye-syndrome PATHOLOGY & CAUSES ▪ Encephalopathy, liver failure associated with salicylate use in children with viral illness ▪ Rare syndrome in children ages 4–12; associated with aspirin use during viral infection (e.g. varicella, influenza A/B) ▪ Uncoupling of oxidative phosphorylation reactions ▪ Oxidative phosphorylation in mitochondria fails → liver damage → nitrogen-containing toxins not removed from blood → ammonia accumulates in blood → crosses blood-

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brain barrier → swelling, oxidative damage to astrocytes → brain inflammation, edema → encephalopathy

SIGNS & SYMPTOMS ▪ Five stages 1. Quiet, sleepy, vomiting 2. Stupor, seizures, decorticate response, intact pupillary reflex 3. Possible coma, decerebrate response, absence of pupillary reflex 4. Coma, absence of deep tendon reflex 5. Death

Chapter 74 Encephalopathy

DIAGNOSIS LAB RESULTS

▪ Blood studies ▪ ↑ ammonia, ↑ transaminases, ↑ prothrombin time, hyper/hypoglycemia

OTHER INTERVENTIONS

▪ Hyperventilation ▫ Manage cerebral edema ▪ Careful monitoring, supportive measures (e.g. IV fluids)

OTHER DIAGNOSTICS

▪ History ▫ Viral illness, aspirin use

TREATMENT MEDICATIONS

▪ Mannitol, glycerol ▫ Manage cerebral edema

Figure 74.1 The histological appearance of the liver of a child who died from Reye syndrome. The hepatocytes have accumulated fat droplets which causes a pale appearance.

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NOTES

NOTES

EPILEPSY & SEIZURES GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Seizure: brain neurons → abnormal, excessive, synchronized electrical activity period ▫ Clusters of brain neurons temporarily impaired (seconds-minutes) → paroxysmal electrical discharges → disordered awareness, behavior, movement ▫ → too much excitatory, too little inhibitory activity

CAUSES

▪ Many unknown causes; some known causes (e.g. brain infection): ▫ ↑ excitation: long-lasting/fast activation of NMDA receptor via glutamate ▫ ↓ inhibition: genetic mutations → dysfunctional GABA receptors ▪ Causation → classification

Provoked seizures ▪ Triggers → abnormal brain activity; subside once trigger removed ▪ Medication ▫ Aminophylline, bupivacaine, bupropion, butyrophenones ▪ Recreational drugs ▫ Amphetamines, cocaine, methylphenidate, psilocybin, psilocin ▪ Alcohol consumption/ withdrawal ▪ Flashing lights ▫ Photosensitive epilepsy ▪ Fever ▫ Febrile seizures Epileptic seizures ▪ Recurring, unpredictable seizures; brain dysfunction → abnormal brain activity; seizures triggered

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▪ Idiopathic seizures/epilepsy disorder ▫ Most common ▪ Disorders ▫ Brain injury, brain abscess, brain tumors, eclampsia, encephalitis, Angelman syndrome ▪ Cerebrovascular disease ▫ Intracranial bleeding; perinatal hypoxia, ischemia; ischemic stroke ▪ Systemic disorders ▫ Uremic encephalopathy, hepatic encephalopathy, electrolyte imbalances, hypoglycemia, thiamine deficiency, vitamin B12 deficiency Nonepileptic seizures ▪ → fainting spell, psychological conditions, stress, not epileptic brain activity

SIGNS & SYMPTOMS ▪ Subtle signs ▫ Spacing out, unusual sensations, brief muscle jerks ▪ Life-threatening ▫ Generalized muscle contractions > five minutes

DIAGNOSIS DIAGNOSTIC IMAGING MRI/CT scan ▪ Detects structural brain abnormalities (brain tumors or vascular disorders)

LAB RESULTS

▪ Electrolytes; blood glucose; complete blood cell count; liver, renal function; serum calcium; urinalysis

Chapter 75 Epilepsy & Seizures MNEMONIC: SICK DRIFT3R

▫ Assess possible underlying infection, genetic condition, metabolic disorder, other causes

Differential diagnosis for seizures Substrates: sugar, oxygen Isoniazid Cations: Na, Ca, Mg Kids: pregnancy/eclampsia Drugs Rum: alcohol withdrawal Illnesses: chronic Fever Trauma 3 “antis”: antihistamine, antidepressant, anticonvulsants Rat poison

OTHER DIAGNOSTICS Electroencephalogram (EEG) ▪ Detects abnormal, epileptiform brain electrical activity Clinical history ▪ Assess type of seizure; differentiate between primary, secondary seizures Neurological exams ▪ Assess behavior, motor abilities, mental functions → underlying seizure cause, type

TREATMENT MEDICATIONS Epilepsy ▪ Antiepileptic medication ▫ Depends on type of seizures, age, lifestyle, and comorbidities

OTHER INTERVENTIONS Provoked seizures ▪ Address trigger

ABSENCE SEIZURE osms.it/absence-seizure PATHOLOGY & CAUSES ▪ Formerly called petit mal seizures ▪ Generalized seizure; brief loss of awareness/responsiveness; sudden onset, termination; usually no postictal state ▪ Most common in children; can occur 50–100 times/day; often misdiagnosed as inattentiveness, daydreaming

CAUSES

▪ Cause → abnormal neuronal activity unknown

COMPLICATIONS

▪ May progress into generalized tonic-clonic seizures ▪ Learning difficulties ▪ Behavior problems

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(e.g. lip smacking, chewing motions, eyelid flutters) ▪ Possible sign of coexisting seizure types ▪ No recollection of seizure

DIAGNOSIS DIAGNOSTIC IMAGING MRI/CT scan ▪ To rule out brain abnormalities

OTHER DIAGNOSTICS

Figure 75.1 An EEG taken from an individual having an absence seizure.

EEG ▪ Shows generalized spike-and-slow wave discharges ▪ Easily induced by hyperventilation (most reliable test)

TREATMENT

SIGNS & SYMPTOMS ▪ Sudden loss of awareness, responsiveness → from few seconds-half a minute ▪ Blank stare ▪ Preceding activity ceases ▪ Ends abruptly or followed by automatisms

▪ Usually resolves as child ages

MEDICATIONS Anticonvulsant medication ▪ Valproic acid (drug of choice in case of other coexisting types of seizures), ethosuximide (only for absence seizures)

EPILEPTIC SEIZURE osms.it/epileptic-seizure PATHOLOGY & CAUSES ▪ Recurrent, unprovoked seizures → epilepsy symptoms

TYPES Focal (partial) seizures ▪ Affect one brain hemisphere ▫ Subcategories: Focal aware seizure; focal impaired awareness seizure

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Generalized seizures ▪ Affect both brain hemispheres ▫ Subcategories: tonic seizures, atonic seizures, clonic seizures, tonic-clonic seizures, myoclonic seizures, absence seizures

CAUSES

▪ Seizures genetic/idiopathic ▪ Cerebrovascular disease ▫ Intracranial bleeding; perinatal hypoxia,

Chapter 75 Epilepsy & Seizures ischemia; cerebrovascular insult ▪ Neurological disorder/illness ▫ Brain tumors, metastases; brain injury; brain abscess; encephalitis; eclampsia; Angelman syndrome; multiple sclerosis; systemic lupus erythematosus ▪ Systemic disorders ▫ Uremic encephalopathy; hepatic encephalopathy; electrolyte imbalances (hypercalcemia, hyponatremia); hypoglycemia, hyperglycemia; thiamine, pyridoxine, vitamin B12 deficiency

COMPLICATIONS

▪ Injury → falling, drowning, car crash during attack ▪ Pregnancy complications → seizures during pregnancy; → antiepileptic medication → teratogenic effects ▪ Status epilepticus ▫ Continuous seizure activity > five minutes → permanent brain damage, death ▪ Sudden unexpected death in epilepsy (SUDEP) → frequent tonic-clonic seizures, inadequate antiepileptic treatment

SIGNS & SYMPTOMS Focal seizures ▪ Focal aware seizure ▫ No awareness impairment; motor, sensory, autonomic, psychological sensations ▪ Focal impaired awareness seizure ▫ May include automatisms (e.g. lip smacking, chewing, swallowing, unpurposeful walking, etc.) Generalized seizures ▪ Tonic seizures ▫ Sudden, continuous muscle contractions; causes falling, often backwards ▪ Atonic seizures ▫ Sudden muscle relaxation; causes falling, often forwards ▪ Clonic seizures ▫ Rhythmic muscle contractions (convulsions)

▪ Tonic-clonic seizures ▫ Tonic phase → muscles suddenly stiffen; clonic phase → muscles rapidly contract, relax ▪ Myoclonic seizures ▫ Short, one/multiple muscle twitches over short time ▪ Absence seizures ▫ Loss of awareness/responsiveness; staring spell Generalized seizures often → postictal state ▪ Confusion, drowsiness, sleepiness, total amnesia for hours Todd’s paralysis or paresis ▪ May follow; affects arms/legs, usually limited to one side ▫ Lasts about 15 hours; temporary, but severe suppression of brain activity in seizure-affected area

DIAGNOSIS DIAGNOSTIC IMAGING MRI/CT scan ▪ Detect structural brain abnormalities (brain tumors, vascular disorders)

LAB RESULTS

▪ Electrolytes, blood glucose and calcium levels ▫ Assess possible underlying infection, genetic condition, metabolic disorder, other causes

OTHER DIAGNOSTICS

▪ ≥ two unprovoked seizures required for epilepsy diagnosis

EEG ▪ Detect abnormal, epileptiform electrical brain activity Neurological exam ▪ Assess behavior, motor abilities, mental functions → underlying cause, type of seizure

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TREATMENT MEDICATIONS Anticonvulsant medications ▪ Depends on type of seizures, age, lifestyle, comorbidities ▫ Focal epilepsy: lamotrigine, oxcarbazepine, carbamazepine ▫ Generalized epilepsy: valproate, lamotrigine, ethosuximide (only for absence seizures)

▫ If unsure: broad spectrum anticonvulsants (effective for all types): valproate, lamotrigine, topiramate

SURGERY

▪ Surgical resection in certain cases (e.g. brain tumors or vascular disorders)

FEBRILE SEIZURE osms.it/febrile-seizure PATHOLOGY & CAUSES ▪ Triggered by fever ▪ Exact mechanism unknown; proposed explanations ▫ ↑ body temperature during fever → ↑ excitability of neurons ▫ Hyperventilation during fever → ↓ CO2 levels → respiratory alkalosis → ↑ neuronal excitability ▫ ↑ cytokine levels during fever → enhancement of NMDA receptors → ↑ neuronal excitability

TYPES Simple febrile seizure (most common) ▪ Affects whole body (tonic-clonic seizures) ▪ Lasts < 15 minutes ▪ Does not repeat within 24 hours Complex febrile seizure ▪ If 1/3 criteria met ▫ Affects specific body part corresponding to specific brain part ▫ Lasts > 15 minutes ▫ Repeats within 24 hours

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RISK FACTORS

▪ Genetic susceptibility ▪ Age 6 months–5 years ▪ Infections ▫ Usually common infections, e.g. otitis media

SIGNS & SYMPTOMS ▪ High body temperature: >38° C/100.4° F ▪ Simple febrile seizure ▫ Presents as tonic-clonic seizures ▫ Tonic phase (muscles stiffen, go rigid) → clonic phase (muscles rapidly contract, relax) → convulsions ▫ Followed by postictal state, residual arm/leg weakness

DIAGNOSIS LAB RESULTS

▪ Laboratory studies ▪ Lumbar puncture to distinguish from other underlying causes of fevers, seizures (e.g. encephalitis, meningitis)

Chapter 75 Epilepsy & Seizures

TREATMENT ▪ Simple febrile seizures usually resolve by themselves

MEDICATIONS

▪ Anticonvulsant ▫ Complex febrile seizures ▪ Antipyretic medications (ibuprofen, acetaminophen) ▫ Fever management

FOCAL SEIZURE osms.it/focal-seizure PATHOLOGY & CAUSES ▪ Seizure that initially stems from localized brain region; limited to one hemisphere

TYPES Focal aware seizure ▪ Affects small brain area ▪ Individual awake, alert; remembers seizure Focal impaired awareness seizure ▪ Unilaterally affects larger area of one cerebral hemisphere ▪ Individual loses awareness, responsiveness; does not remember seizure ▪ May develop into a secondary generalized seizure (focal onset bilateral tonic-clonic seizure)

SIGNS & SYMPTOMS Focal aware seizures ▪ Symptoms may be subtle, last ≥ two minutes, vary by affected lobe ▫ Preserved consciousness ▪ Motor symptoms ▫ Twitching, muscle jerking ▪ Sensory symptoms ▫ Unusual auditory, gustatory, tactile, olfactory sensations ▪ Autonomic symptoms ▫ Sweating, piloerection, dilation of pupils, incontinence, unusual feelings of nausea

▪ Psychological symptoms ▫ Sudden unusual feeling of sadness, happiness, fear, anger; feelings of derealization (environment is not real) or depersonalization (dissociation from the environment or self); feeling of déjà vu ▪ Speech difficult/impossible Focal impaired awareness seizure ▪ Impaired consciousness ▪ Often preceded by aura (symptoms of focal aware seizure) ▪ May involve automatisms (e.g. lip smacking, chewing, swallowing, unpurposeful walking, etc.) ▪ Amnesia (no recollection of seizure)

DIAGNOSIS DIAGNOSTIC IMAGING MRI/CT scan ▪ Identify structural brain abnormalities (brain tumors, vascular disorders)

LAB RESULTS

▪ Blood tests ▫ Detect possible underlying infection, genetic condition, metabolic disorder, other causes

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OTHER DIAGNOSTICS EEG ▪ Detect epileptiform, abnormal electrical brain activity Neurological exam

TREATMENT MEDICATIONS

▪ Anticonvulsant medications ▫ E.g. lamotrigine, oxcarbazepine, carbamazepine

SURGERY

▪ Treat underlying cause ▫ E.g. brain tumors, vascular disorders → surgical resection

MYOCLONIC SEIZURE osms.it/myoclonic-seizure PATHOLOGY & CAUSES ▪ Type of generalized seizure; presents with myoclonus ▫ Sudden, brief, involuntary muscle jerks lasting 1–2 seconds ▪ Epileptic; non-epileptic, e.g. physiologic while falling asleep, waking up; myoclonic jerks → nervous system disorders, metabolic abnormalities, etc. ▪ Associated with epileptic syndromes: ▫ Juvenile myoclonic epilepsy ▫ Progressive myoclonus epilepsy ▫ Myoclonic epilepsy with ragged-red fibers (MERRF) ▫ Lafora disease ▫ Unverricht–Lundborg disease ▫ Neuronal ceroid lipofuscinosis

COMPLICATIONS

▪ May become generalized tonic-clonic seizures

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SIGNS & SYMPTOMS ▪ Brief body jerks; most commonly facial muscles, limbs ▪ Preserved consciousness, recollection of seizure

DIAGNOSIS OTHER DIAGNOSTICS EEG ▪ Detect abnormal, epileptiform electrical brain activity

TREATMENT MEDICATIONS

▪ Anticonvulsant medication ▫ Clonazepam, valproate, levetiracetam; carbamazepine, oxcarbazepine, pregabalin, others contraindicated

Chapter 75 Epilepsy & Seizures

STATUS EPILEPTICUS osms.it/status-epilepticus PATHOLOGY & CAUSES ▪ Medical emergency involving one acute prolonged seizure ≥ five minutes or multiple seizures occurring close together without recovery between

TYPES

▪ Convulsive status epilepticus (CSE) ▪ Nonconvulsive status epilepticus (NCSE)

CAUSES

▪ Epilepsy ▫ Usually triggered by medication change/ inadequate treatment ▪ Alcohol consumption/fasting while on anticonvulsant ▪ Acute cerebral injury ▪ Brain disorders ▫ Brain tumors, brain injury, brain abscess, encephalitis ▪ Systemic process/illness ▫ Uremic encephalopathy, hepatic encephalopathy ▪ Cerebrovascular disease ▫ Intracranial bleeding, cerebrovascular insult ▪ Eclampsia

COMPLICATIONS

▪ Delayed treatment → irreversible neurological damage ▪ Prolonged muscle activity → hyperpyrexia, acidosis

SIGNS & SYMPTOMS ▪ CSE ▫ Prolonged/repeated tonic-clonic seizures ▫ Tonic phase (muscles stiffen and go

rigid), followed by clonic phase (muscles rapidly contract, relax) → convulsions ▪ NCSE ▫ Prolonged/repeated absence or focal impaired awareness seizure ▫ Long-lasting stupor, staring; unresponsiveness

DIAGNOSIS ▪ Continuous seizure lasting > five minutes or recurrent seizures without regaining consciousness in between them for > five minutes

DIAGNOSTIC IMAGING MRI/CT scan ▪ Detect structural brain abnormalities

LAB RESULTS

▪ Identify underlying cause

OTHER DIAGNOSTICS EEG ▪ Detect abnormal, epileptiform electrical brain activity

TREATMENT MEDICATIONS

▪ Immediate application of benzodiazepines followed by antiseizure drug phenytoin ▪ If uneffective ▫ Valproic acid, phenobarbital, propofol, or ketamine

OTHER INTERVENTIONS ▪ Oxygen, intravenous fluids

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TONIC-CLONIC SEIZURE osms.it/tonic-clonic-seizure PATHOLOGY & CAUSES ▪ Formerly called grand mal seizure ▪ Characterized by tonic (rigid) stage and clonic (convulsion) stage ▪ Most common seizure type ▪ May occur as one or multiple episodes as part of epilepsy disorder ▪ Can initiate in both brain hemispheres (generalized tonic-clonic seizure) or initiate in one and spread to both (focal to bilateral tonic-clonic seizure) ▪ Episode > five minutes → status epilepticus

DIAGNOSTIC IMAGING

SIGNS & SYMPTOMS

OTHER DIAGNOSTICS

▪ May be preceded by unusual sensations, e.g. visual, auditory, olfactory hallucinations; dizziness (called an aura) ▪ Characterized by two phases ▫ Tonic phase: rigid, stiffening muscles; contracting chest muscles → cry/groan; biting of tongue, cheeks ▫ Clonic phase: muscles rapidly, rhythmically contract, relax; elbows, hips, knees bend, relax; urinary/fecal incontinence ▪ Tonic-clonic seizure → postictal state ▫ Confusion, drowsiness, sleepiness, total amnesia for hours after seizure ▪ May be followed by Todd paralysis/paresis for minutes–hours following seizure

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DIAGNOSIS MRI/CT scan ▪ Detect structural brain abnormalities (brain tumors, vascular disorders)

LAB RESULTS

▪ Electrolytes; blood glucose, calcium levels ▫ Identify possible underlying infection, genetic condition, metabolic disorder, other causes

EEG ▪ Detect abnormal epileptiform electrical brain activity

TREATMENT MEDICATIONS

▪ Antiepileptic medication ▫ Valproate, lamotrigine, topiramate, phenytoin

SURGERY

▪ Surgical resection for brain tumors, vascular disorders

NOTES

NOTES

EYE INFECTIONS GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Ocular disorders with infectious, noninfectious etiologies → inflammation, damage to eye structures

RISK FACTORS

DIAGNOSIS DIAGNOSTIC IMAGING ▪ Fundoscopy

CT scan/MRI ▪ Orbits, sinuses

▪ Immunocompromised state, contact with infectious agent, ocular trauma, certain systemic diseases

LAB RESULTS

COMPLICATIONS

OTHER DIAGNOSTICS

▪ Range from benign, self-limiting to visionthreatening infections

SIGNS & SYMPTOMS ▪ Structural damage, functional impairment

▪ Giemsa/Gram stains; cultures

▪ Snellen chart

TREATMENT MEDICATIONS ▪ Antimicrobials

OTHER INTERVENTIONS ▪ Address comorbidities

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CHALAZION osms.it/chalazion PATHOLOGY & CAUSES ▪ Firm, painless lipogranulomatous inflammatory lump in eyelid; caused by blockage of ocular sebaceous glands ▫ Deep chalazion: inflammation of meibomian sebaceous glands ▫ Superficial chalazion: inflammation of Zeis sebaceous glands ▪ Gland obstruction → impissation (decreased flow of secretions) → granulomatous inflammatory response → lipogranuloma inflammation → lesion forms on upper (most common)/lower eyelid ▪ Slow growing; may persist for weeks/ months; deeper within eyelid than hordeolum (stye)

RISK FACTORS

▪ Rosacea, seborrhea, blepharitis, inflamed hordeolum

may demonstrate diffuse inspissation of yellowish contents from eyelid margin orifices

Figure 76.1 A chalazion of the left upper eyelid.

COMPLICATIONS

▪ If large chalazion presses on cornea → visual changes ▪ Recurring chalazion: may signal carcinoma (rare)

SIGNS & SYMPTOMS ▪ Eyelid erythema; swelling; firm, nodular, rubbery consistency

DIAGNOSIS OTHER DIAGNOSTICS

▪ Clinical history, physical examination ▪ Histological examination: chalazia may indicate eyelid carcinoma

Slit-lamp ▪ Determine status of meibomian glands;

586 OSMOSIS.ORG

Figure 76.2 The histological appearance of a chalazion. There is granulomatous inflammation with giant cells, numerous macrophages as well as neutrophils and eosinophils surrounding a nidus of lipid.

Chapter 76 Eye Infections

TREATMENT MEDICATIONS

▪ Recalcitrant chalazia: intralesional steroid injection

SURGERY

▪ Recalcitrant chalazia: incision, curettage

OTHER INTERVENTIONS

▪ Warm, wet compresses encourage drainage ▪ Ocular cleansing pads applied to eyelid margin ▪ Treat comorbidities (e.g. blepharitis, rosacea) ▪ Small chalazion may resolve on own

CHORIORETINITIS osms.it/chorioretinitis PATHOLOGY & CAUSES ▪ Inflammation of choroid, retina; AKA posterior uveitis

CAUSES Infectious ▪ Bacterial: tuberculosis, syphilis ▪ Viral: cytomegalovirus, West Nile virus, herpes simplex virus (HSV) 1 ▪ Parasitic: toxoplasmosis, onchocerciasis ▪ Fungal: Candida albicans Noninfectious ▪ Sarcoidosis, Behçet’s disease, traumatic chorioretinitis

RISK FACTORS

▪ Immunodeficiency, contact with infectious agent, traumatic eye injury, systemic disease associated with chorioretinitis

COMPLICATIONS

▪ Retinal hemorrhage/detachment, visual impairment with macular involvement

SIGNS & SYMPTOMS ▪ Floaters (vitritis), blurred vision, impaired color/night vision, ocular pain, photophobia, excessive lacrimation

DIAGNOSIS DIAGNOSTIC IMAGING Fluorescein angiography ▪ Irregularities Fundoscopy ▪ Creamy white/yellow/gray lesions; keratic precipitates; retinal edema, necrosis; chorioretinal atrophy, neovascularization; cotton-wool infiltrates (Candida-associated chorioretinitis); polymorphic retinochoroidal scars (toxoplasmosis-associated chorioretinitis)

OTHER DIAGNOSTICS

▪ Clinical history, physical examination

TREATMENT MEDICATIONS

▪ Corticosteroids/antimicrobials

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Figure 76.3 A retinal photograph displaying the features of chorioretinitis. There are numerous, patchy, cream-colored lesions and retinal edema.

CONJUNCTIVITIS osms.it/conjunctivitis PATHOLOGY & CAUSES ▪ Inflammation of conjunctiva, transparent mucous membrane covering inside of eyelids (tarsal conjunctiva), globe (bulbar conjunctiva) ▫ Non-keratinized epithelium containing goblet cells, highly vascularized substantia propria ▫ Turns pink/red when inflamed: diffuse conjunctival injection ▪ Infection, inflammation → dilatation of conjunctival vessels → conjunctival hyperemia, edema → inflammatory discharge

TYPES Infectious (bacterial) ▪ Highly contagious; spread by direct contact

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▪ Common causes: Staphylococcus aureus, Streptococcus pneumoniae, Haemophilus influenzae ▪ Hyperacute bacterial conjunctivitis ▫ Causes: Neisseria gonorrhoeae (most common)/Neisseria meningitidis ▫ Oculogenital disease: usually transmitted from genitals to eyes via hands ▫ Vision-threatening ▪ Chlamydial ▫ Caused by Chlamydia trachomatis ▫ Adult inclusion conjunctivitis: chronic, indolent ▫ Trachoma: infectious blindness cause worldwide; active trachoma caused by serotypes A, B, Ba, C (low-income country-endemic, mostly in children); initial follicular inflammation progresses in severity → cicatricial disease, vision loss

Chapter 76 Eye Infections Infectious (viral) ▪ Highly contagious; spread by direct contact ▪ Causes: adenovirus (most common), HSV (in children), varicella zoster virus (VZV) ▫ Ocular manifestation of systemic infection ▫ Epidemic keratoconjunctivitis (EKC): caused by adenovirus 8, 19, 37; fulminant conjunctivitis, keratitis (epithelium of conjunctiva, cornea); corneal inclusions degrade visual acuity Noninfectious (allergic) ▪ Caused by airborne allergens (seasonal, perennial) ▪ Immunoglobulin E (IgE)-mediated → local mast cell degranulation Noninfectious (nonallergic) ▪ Caused by mechanical/chemical insult

RISK FACTORS

▪ Exposure to causative agent, immunocompromised state, atopy (allergic conjunctivitis) ▪ Contact lens wear: common source of mechanical injury, nonallergic, infectious conjunctivitis

COMPLICATIONS

▪ Cornea: keratitis (inflammation), ulcer, perforation, scarring ▪ Dacryocystitis (bacterial infection of lacrimal sac) ▪ Vision loss

SIGNS & SYMPTOMS ▪ Appearance: unilateral/bilateral inflammation; pinkish-red eye; eyelid edema; chemosis (conjunctival edema); excessive lacrimation ▪ Discharge ▫ Bacterial: purulent/mucopurulent; white/ yellow/green ▫ Gonococcal: hyper-purulent, profuse ▫ Viral: watery; stringy ▫ Allergic: watery, mucoid ▫ Nonallergic: mucoid

▪ Infected eye “stuck” shut from morning crusting; gritty, burning sensation (viral); itching (allergic); photophobia (corneal involvement); transient visual impairment ▪ Preauricular lymphadenopathy

Figure 76.4 The clinical appearance of conjunctivitis.

DIAGNOSIS LAB RESULTS

▪ Adenoviral conjunctivitis: rapid point-ofcare adenovirus antigen test ▪ Recalcitrant conjunctivitis: conjunctival biopsy (rule out neoplasm)

Giemsa/gram stains ▪ Confirm identity of organism in suspected infectious cause

OTHER DIAGNOSTICS

▪ Clinical history, physical examination

TREATMENT MEDICATIONS

▪ Ocular lubricant drops/ophthalmic ointment ▪ Allergic conjunctivitis: antihistamine drops ▪ Adult inclusion conjunctivitis: systemic therapy to eradicate Chlamydia infection (antibiotics) ▪ Bacterial conjunctivitis: Topical antibiotic drops/ointment ▪ Epidemic keratoconjunctivitis (EKC): topical glucocorticoids

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OTHER INTERVENTIONS

▪ Warm, wet compresses encourages drainage ▪ Hyperacute conjunctivitis, EKC: immediate specialized ophthalmologist referral ▪ Viral conjunctivitis: self-limiting; usually resolves in 2–3 weeks

KERATITIS osms.it/keratitis PATHOLOGY & CAUSES ▪ Cornea inflammation → corneal tissue destruction ▪ Inflammatory response → stromal damage from infection, host response → edema, infiltrates, necrotic ulceration, focal thinning, perforation

CAUSES Infectious ▪ Bacteria: Staphylococcus aureus, Pseudomonas aeruginosa, coagulasenegative Staphylococcus, diphtheroids, Streptococcus pneumoniae ▪ Viruses: HSV, herpes zoster ▪ Fungi: Candida supp., Aspergillus supp., Fusarium supp. ▪ Parasites: Acanthamoeba Noninfectious ▪ Corneal inflammation with no known infectious etiology

RISK FACTORS

▪ Corneal epithelium disruption ▫ Contact lenses (contact lens-related keratitis); esp. improper use (e.g. overnight wear, poor hygiene) ▫ Recent keratoplasty, trauma, corneal exposure (e.g. Graves’ ophthalmopathy, Bell’s palsy)

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▪ Immunocompromised state ▪ Topical (ocular) corticosteroid use ▪ Contributing disorders: rosacea; keratoconjunctivitis sicca (dry eye syndrome); neurotrophic keratitis (lesion on cranial nerve V); autoimmune diseases (e.g. rheumatoid arthritis, cicatricial pemphigoid)

COMPLICATIONS

▪ Endophthalmitis (interior eye inflammation), intraocular damage, vision loss, keratolysis (corneal melting)

SIGNS & SYMPTOMS ▪ Erythema ▪ Preauricular lymphadenopathy ▪ Discharge: mucopurulent (bacterial), watery (viral) ▪ Corneal opacity, stromal infiltrate (immune complex deposits), ulcer ▫ Bacterial keratitis: yellow infiltrates ▫ Fungal keratitis: white infiltrates, feathery borders ▫ Acanthamoeba: Wessely ring infiltrate ▪ Hypopyon (layer of white cells in anterior chamber): fulminant bacteria ▪ Foreign body sensation; difficulty keeping eye open; photophobia; pain; decreased visual acuity, blurred vision; blepharospasm

Chapter 76 Eye Infections Penlight ▪ Visualizes infiltrate/ulcer (> 0.5mm); round, white spot (bacterial keratitis)

Figure 76.5 An individual with sterile keratitis of the left eye.

DIAGNOSIS DIAGNOSTIC IMAGING Fundoscopy ▪ Slit beam; examine contour abnormalities of cornea, lens, retina; small corneal infiltrates; faint branching grey opacity (viral keratitis)

Fluorescein dye ▪ Corneal uptake of dye ▫ Visualize loss of epithelial cells, ulceration ▫ Green glow under cobalt blue light ▫ Diffuse white opacity/dull corneal light reflex ▫ Seidel sign (leaking aqueous humor → fluorescein streaming): penetrating trauma Snellen chart ▪ ↓ visual acuity

TREATMENT MEDICATIONS

▪ Topical antimicrobials for infectious etiology

LAB RESULTS

▪ Corneal scrapings, cultures: suspected infectious etiology

OTHER DIAGNOSTICS

▪ Clinical history, physical examination

OTHER INTERVENTIONS

▪ Control of associated comorbidities ▪ Temporary discontinuation of wearing contact lenses

ORBITAL CELLULITIS osms.it/orbital-cellulitis PATHOLOGY & CAUSES ▪ Serious infection involving contents of orbit (ocular muscles, surrounding fat; not globe)

CAUSES

▪ Entry of microorganisms into orbital space ▫ Via anatomical perforations of nerves, blood vessels in paranasal sinuses (e.g. ethmoid) ▫ Migration from surrounding tissues (e.g. face, eyelids) after local trauma/surgery ▫ Inflammatory response → tissue destruction

RISK FACTORS

▪ More common in children ▪ Migration from other infections ▫ Bacterial rhinosinusitis: Staphylococcus aureus, streptococci (common); fungal rhinosinusitis (rare) ▫ Dacryocystitis: lacrimal sac infection ▫ Infected mucocele: mucus-containing cystic lesion of salivary gland ▫ Infections involving teeth, middle ear, face ▪ Direct inoculation: ophthalmic surgical procedures; orbital trauma with fracture/ foreign body

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COMPLICATIONS

▪ Extraorbital extension: epidural/subdural empyema; brain abscess; meningitis; cavernous sinus thrombosis; dural sinus thrombosis; involvement of cranial nerves III, IV, V, VI; optic neuritis ▪ Endophthalmitis: interior eye inflammation ▪ Vision loss ▪ Potentially fatal if sepsis develops

SIGNS & SYMPTOMS Systemic ▪ Fever; severe headache, vomiting, mental status changes (intracranial complications) Ocular ▪ Red, swollen eyelids; chemosis (conjunctival edema); pain (esp. with eye movement); ophthalmoplegia (paralysis of eye muscles); proptosis (abnormal displacement of eye); impaired visual acuity, color vision; abnormal pupillary light reflex

DIAGNOSIS DIAGNOSTIC IMAGING CT scan/MRI ▪ Orbits, sinuses; detects abscess, intracranial changes Dilated fundoscopy ▪ Determines optic neuropathy/retinal vascular occlusion

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LAB RESULTS Complete blood count (CBC) ▪ Leukocytosis; ↑ absolute neutrophil count (ANC) Blood/orbital/subperiosteal aspirates cultures ▪ Identify causative organism

OTHER DIAGNOSTICS

▪ Clinical history, physical examination ▪ Ocular motility: pain with movement ▪ Pupillary light reflex: sluggish/absent reflex → optic nerve involvement ▪ Exophthalmometry: measures degree of proptosis ▪ Asses color vision acuity: determines optic nerve involvement ▪ Intraocular pressure measurement (↑)

TREATMENT MEDICATIONS ▪ Antimicrobials

SURGERY

▪ External (through orbit)/endoscopic transcaruncular approach

Chapter 76 Eye Infections

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PERIORBITAL (PRESEPTAL) CELLULITIS osms.it/periorbital-cellulitis PATHOLOGY & CAUSES ▪ Mild infection of superficial tissues of anterior eyelid (tissues anterior to orbital septum); more common than orbital cellulitis

CAUSES

▪ Introduction/migration of microorganisms into preseptal space: Staphylococcus aureus, Streptococcus pneumoniae, other streptococci, anaerobes

RISK FACTORS

▪ More common in children ▪ Migration from other infections: sinusitis; upper respiratory tract infection; dacryocystitis; bacteremia (rare) ▪ Direct inoculation: trauma (e.g. insect bites, animal bites, introduction of foreign bodies); ophthalmic surgical procedures

COMPLICATIONS ▪ Orbital cellulitis

SIGNS & SYMPTOMS ▪ Ocular pain, eyelid swelling, erythema, fever, lymphadenopathy

DIAGNOSIS DIAGNOSTIC IMAGING Contrast-enhanced CT scan (orbits, sinuses) ▪ Distinguishes between preseptal, orbital cellulitis; associated sinusitis

LAB RESULTS CBC ▪ Leukocytosis Cultures (abscess contents, paranasal sinus secretions) ▪ Identify causative agent

OTHER DIAGNOSTICS

▪ Clinical history, physical examination

TREATMENT MEDICATIONS ▪ Oral antibiotics

Figure 76.6 An individual with left-sided periorbital cellulitis.

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Chapter 76 Eye Infections

STYE (HORDEOLUM) osms.it/stye PATHOLOGY & CAUSES ▪ Blockage, purulent inflammation of upper/ lower eyelid

SIGNS & SYMPTOMS ▪ Tenderness; fluctuant pustule; localized swelling, erythema; excessive lacrimation; photophobia

CAUSES

DIAGNOSIS

▪ Sterile/bacterial (e.g. Staphylococcus aureus, Staphylococcus epidermidis)

Internal ▪ Meibomian sebaceous gland; points toward conjunctival side of lid → conjunctival inflammation External ▪ Zeiss/Moll sebaceous glands; points toward skin surface of eyelid

RISK FACTORS

▪ Touching eyes with contaminated hands, chronic blepharitis, seborrhea, improper contact lens hygiene, sleeping with eye makeup, immunocompromised state

COMPLICATIONS

▪ Hardens → chalazion

DIAGNOSTIC IMAGING Slit lamp, fundoscopy ▪ Determine infection extension to other tissues

OTHER DIAGNOSTICS

▪ Clinical history, physical examination ▪ Visual acuity assessment

TREATMENT MEDICATIONS

▪ Topical antibiotic ointment

SURGERY

▪ Incision, curettage: if progresses to chalazion

OTHER INTERVENTIONS

▪ Warm compresses encourage drainage ▪ Usually self-limiting with spontaneous resolution

Figure 76.7 A stye on the right lower eye lid.

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UVEITIS osms.it/uveitis PATHOLOGY & CAUSES ▪ Inflammation of uveal tract (choroid, ciliary body, iris); unilateral/bilateral ▪ Onset: rapid/insidious ▪ Course: acute/recurrent/chronic ▪ Duration: persistent (> three months)/ limited (≤ three months)

TYPES Anterior (most common) ▪ Anterior uveal tract; iritis, iridocyclitis (inflammation of ciliary body) Panuveitis ▪ Anterior chamber, vitreous body, retina/ choroid Posterior uveitis ▪ Retina/choroid

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Chapter 76 Eye Infections Intermediate uveitis ▪ Vitreous body; chorioretinal inflammation

CAUSES

Bacterial: tuberculosis, syphilis Viral: cytomegalovirus, HSV Fungal: candidiasis, Pneumocystis jirovecii Parasitic: Acanthamoeba, toxoplasmosis Noninfectious systemic: Crohn’s disease, ankylosing spondylitis ▪ Conditions confined to eye: trauma, acute retinal necrosis ▪ ▪ ▪ ▪ ▪

RISK FACTORS

▪ Systemic infectious, inflammatory conditions

COMPLICATIONS

▪ Intraocular hypertension, glaucoma; increased intraocular pressure; posterior synechiae (iris adheres to lens); band keratopathy (corneal calcium deposits); cataract; vision loss

SIGNS & SYMPTOMS ▪ Ocular erythema ▪ Impaired vision ▪ Pain, photophobia, vision distortion, floaters (vitritis), photopsia (flashing lights)

DIAGNOSIS

LAB RESULTS Microscopy, cytology, culture, polymerase chain reaction (PCR) ▪ Fluid sampling/biopsy; identify presence of infectious agent

OTHER DIAGNOSTICS

▪ Clinical history, physical examination

Snellen chart ▪ ↓ visual acuity Pupillary light reflex ▪ Sluggish pupillary reaction to light → synechiae Intraocular pressure ▪ No change if uncomplicated uveitis; ↑ in acute uveitis-induced glaucoma

TREATMENT MEDICATIONS

▪ Corticosteroids: topical, local injection, implantable, systemic ▪ Recalcitrant uveitis: immunomodulatory agents (if corticosteroid response inadequate) ▪ Recalcitrant uveitis: tumor necrosis factor (TNF) inhibitor (if resistant to treatment) ▪ Posterior synechiae prevention: mydriatic/ cycloplegic medications ▪ Viral-associated uveitis: antivirals

DIAGNOSTIC IMAGING Fluorescein/indocyanine green angiography (posterior uveitis) ▪ Evaluate status of retinal vascular circulation; identify choroidal disease Fundoscopy ▪ Ciliary flush: perilimbal redness ▪ Keratic precipitates: inflammatory deposits on cornea ▪ Hypopyon: white blood cells settle on bottom of anterior chamber ▪ Haziness of aqueous humor: protein accumulation

Figure 76.8 An individual with a hypopyon of the left eye as a result of severe anterior uveitis.

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NOTES

NOTES

GLOBE PATHOLOGY GENERALLY, WHAT IS IT? PATHOLOGY & CAUSES ▪ Disorders affecting eye structures; if untreated → severe visual impairment ▪ Due to damage to cornea, retina, lens, optic nerve ▪ Inherited/acquired

COMPLICATIONS

▪ Impaired vision, blindness

SIGNS & SYMPTOMS ▪ Early stages often asymptomatic ▪ Visual changes

DIAGNOSIS DIAGNOSTIC IMAGING Direct/indirect fundoscopy ▪ Visualize retina

OTHER DIAGNOSTICS

▪ Clinical presentation: history; visual acuity, field loss

Slit lamp ▪ Visualize sclera, conjunctiva, iris, lens, cornea

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TREATMENT MEDICATIONS

▪ Corneal ulcer ▫ Antimicrobial, steroid eye drops; analgesics ▪ Age-related macular degeneration (ARMD)/ diabetic retinopathy (DR) ▫ Intravitreal injections of vascular endothelial growth factor (VEGF) antagonists ▪ Glaucoma ▫ Beta blockers, alpha agonists

SURGERY

▪ Cataract ▫ Small incision; removal of opacified lens ▫ Alternative: leaving lens capsule intact (extracapsular cataract extraction), eye without lens (aphakic eye) ▪ DR ▫ Laser photocoagulation of peripheral retina, vitrectomy ▪ Glaucoma ▫ Laser surgery, trabeculectomy, peripheral iridotomy

OTHER INTERVENTIONS

▪ ARMD ▫ Vitamin, antioxidant supplements; smoking cessation ▪ DR ▫ Glucose, blood pressure control

Chapter 77 Globe Pathlogy

AGE-RELATED MACULAR DEGENERATION (ARMD) osms.it/macular-degeneration PATHOLOGY & CAUSES ▪ Acquired degenerative disease of macula → loss of central vision; peripheral vision preserved; most common cause of severe visual impairment in older adults in highincome countries ▪ Results from damage to photoreceptors of macula ▪ Unilateral/bilateral; contralateral eye at high risk

TYPES Nonexudative ARMD ▪ AKA dry/atrophic; most common ▪ Drusen: extracellular deposits between Bruch membrane, retinal pigment epithelium (RPE) ▫ ↑ size, number of soft drusen → ↑ risk of progression to advanced ARMD ▪ RPE changes: geographic atrophy, detachments, subretinal clumping Exudative ARMD ▪ AKA wet/neovascular; less common ▪ Neovascularization: abnormal vessel formation under retina originating from choroidal circulation, penetrating through Bruch membrane beneath RPE → leakage of serous fluid, blood → collections, fibrosis

RISK FACTORS

▪ ↑ age; > 65 most common ▪ Family history: associated with polymorphisms in complement regulatory genes, esp. complement factor H (CFH) ▪ More common in individuals who are biologically female, white people of Ashkenazi Jewish descent ▪ Smoking, intense light exposure, heavy alcohol use, obesity, hypertension,

hyperlipidemia

COMPLICATIONS

▪ Severe visual impairment: impacts functional status, quality of life; complete loss of vision rare

SIGNS & SYMPTOMS ▪ Early stages: often asymptomatic; blurred vision; metamorphopsia (straight lines seen curved) ▪ Loss of central vision; gradual progression in nonexudative, rapid over weeks/months in exudative

DIAGNOSIS DIAGNOSTIC IMAGING Fluorescein dye retinal angiography ▪ Fluorescein leaks from abnormal vessels Optical coherence tomography ▪ Retinal edema/subretinal fluid Amsler grid ▪ Individual holds grid at 36–41cm/14–16in, looks at center dot ▫ Curvy lines, blurry spots, scotomas Direct/indirect fundoscopy ▪ Nonexudative ARMD ▫ Drusen: white-yellowish, round/oval deposits ▫ Retinal atrophy: round patches of depigmentation ▫ RPE clumping: increased pigmentation ▪ Exudative ARMD ▫ Neovascularization: gray discoloration ▫ Subretinal fluid/hemorrhage

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OTHER DIAGNOSTICS

▪ Clinical presentation: history; ↓ visual acuity, visual fields (central vision loss)

TREATMENT MEDICATIONS

▪ Exudative ARMD ▫ Intravitreal injections of VEGF antagonists to reduce neovascularization ▫ Alternative: photodynamic therapy; injection of photosensitive dye verteporfin → damages neovascular endothelium; application of photoactivating laser

Figure 77.1 Drusen in the macula of individual with age-related macular degeneration.

OTHER INTERVENTIONS

▪ No curative method; therapy aimed at slowing progression ▪ Vitamin, antioxidant supplements ▪ Nonexudative ARMD ▫ Smoking cessation

CATARACT osms.it/cataract PATHOLOGY & CAUSES ▪ Painless, gradual decline in vision due to opacification of lens ▪ Proteins deposit on lens → reduce transmission of light to retina → decrease in vision ▪ Often bilateral but asymmetrical; congenital/ acquired

TYPES Nuclear ▪ Opacification of lens nucleus ▪ Slow progression of vision loss Cortical ▪ Opacification of lens fibers surrounding

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nucleus (cortex) ▪ Mild degradation of vision Posterior subcapsular ▪ Opacification in posterior cortical layer under lens capsule ▪ Rapid progression

RISK FACTORS

▪ Age-related cataract; usually > 60 ▪ Smoking, excessive alcohol use, prolonged drug use (esp. glucocorticoids), exposure to UV light, eye trauma/infections, radiation of intraocular tumor, trisomies (13, 18, 21) ▪ Metabolic diseases: diabetes mellitus, Wilson disease, galactosemia, myotonic dystrophy

Chapter 77 Globe Pathlogy

COMPLICATIONS

▪ Blindness (if untreated) ▪ Secondary posterior subcapsular cataract due to migration of lens epithelium posterior cortical layer

Secondary glaucoma ▪ Phacolytic ▫ Lysed lens proteins clog trabecular meshwork → ↑ pressure ▪ Phacoanaphylactic ▫ Autoimmune reaction to proteins → ↑ pressure ▪ Phacomorphic ▫ Swollen lens → closed angle glaucoma Surgery ▪ Residual lens epithelial cells migrate over capsule → opacification, reduction in vision ▪ Endophthalmitis, bullous keratopathy, intraocular lens dislocation, cystoid macular edema, retinal detachment ▪ Toxic anterior segment syndrome ▫ Inflammation of anterior segment due to noninfectious contaminants of surgical equipment

SIGNS & SYMPTOMS ▪ Painless visual impairment; progresses slowly over many years ▪ Myopic shift: improvement in nearsightedness before decline in vision; lens sclerosis → increase in refractive power ▪ Blurry vision, poor vision at night, dullness of colors ▪ Glare, halos around bright lights; predominant in cortical cataract

DIAGNOSIS DIAGNOSTIC IMAGING Slit lamp ▪ Loss of lens transparency Indirect/direct fundoscopy ▪ Degree of lens opacity ▪ Obscuration of fundus details ▪ Darkening of normal red reflex from fundus

OTHER DIAGNOSTICS

▪ Clinical presentation: history; ↓ visual acuity

TREATMENT SURGERY

Figure 77.2 The eye of a 50-year-old male with a cataract.

▪ Small incision ▫ Phacoemulsification of lens, implantation of synthetic intraocular lens ▪ Removal of opacified lens (alternative) ▫ Leaving lens capsule intact (extracapsular cataract extraction), eye without lens (aphakic eye)

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CORNEAL ULCER osms.it/corneal-ulcer PATHOLOGY & CAUSES

TREATMENT

▪ Inflammatory condition of cornea; usually infectious → dissolution of corneal stroma ▪ Presents as open corneal sore ▪ AKA ulcerative keratitis ▪ Exudate, cells leak into anterior chamber → form hypopyon if sufficient quantity

MEDICATIONS

CAUSES

SURGERY

▪ Bacteria, fungi, viruses (esp. herpes simplex, zoster), protozoa (e.g. Acanthamoeba)

▪ Antimicrobial eye drops ▪ Analgesics for pain control ▪ Steroid eye drops after treatment of infection to reduce swelling, prevent scarring

▪ Corneal transplantation to replace damaged cornea if scarring decreases vision

RISK FACTORS

▪ Improper usage of contact lens, corneal abrasions, eye burns, xerophthalmia (i.e. dry eye), eyelid disorders, steroid eye drops, vitamin A deficiency

SIGNS & SYMPTOMS ▪ Red eye, severe pain, soreness, discharge (tearing, pus), eyelid swelling, blurred vision, vision loss, photophobia

DIAGNOSIS DIAGNOSTIC IMAGING

▪ Slit lamp ▪ Reveals corneal ulcer/hypopyon ▪ Fluorescein dye ▫ Ulcer margins (absorbed by exposed corneal stroma, appears green) ▪ Herpes simplex ulcers ▫ Typical dendritic/geographic pattern

OTHER DIAGNOSTICS

▪ Clinical presentation: history; ↓ visual acuity

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Figure 77.3 A corneal ulcer caused by herpes simplex keratitis viewed with fluorescein under a UV lamp. The ulcer has a classical dendritic pattern.

Chapter 77 Globe Pathlogy

DIABETIC RETINOPATHY (DR) osms.it/diabetic-retinopathy PATHOLOGY & CAUSES ▪ Type of retinopathy affecting individuals with diabetes mellitus → vision loss ▪ Long-standing diabetes mellitus/poor glycemic control → chronic hyperglycemia → retinal vascular changes (e.g. abnormal vascular permeability, vascular occlusions) → ischemia → production of VEGF → formation of abnormal blood vessels (neovascularization)

microaneurysms, microocclusions, exudates, nerve-fiber layer infarcts (cotton wool spots), intraretinal hemorrhage, macular edema

OTHER DIAGNOSTICS

▪ Ophthalmologic screening: annual screening suggested for individuals with diabetes ▪ Clinical presentation: ↓ visual acuity

TYPES Proliferative DR ▪ Presence of neovascularization Nonproliferative DR ▪ Absence of neovascularization; majority of cases; can progress to proliferative; hypertension, fluid retention exacerbate condition

COMPLICATIONS

▪ Visual loss due to ▫ Macular edema (most common); vitreal hemorrhage from neovascularization; retinal detachment; neovascular glaucoma

Figure 77.4 A retinal photograph demonstrating proliferative diabetic retinopathy. There are cotton wool spots and as well as neovascularisation of the retina.

SIGNS & SYMPTOMS ▪ Usually asymptomatic until late stages ▪ Decreased/fluctuating vision; presence of floaters, flashes of lights (photopsias); scotomas

DIAGNOSIS DIAGNOSTIC IMAGING Direct/indirect fundoscopy ▪ Thickening of basement membrane,

TREATMENT MEDICATIONS

▪ Intravitreal VEGF inhibitors for proliferative DR, significant macular edema

SURGERY

▪ Laser photocoagulation of peripheral retina ▪ Vitrectomy for vitreous hemorrhage/ severe proliferative DR nonresponsive to photocoagulation

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OTHER INTERVENTIONS

▪ Glucose, blood pressure control to reduce progression of nonproliferative DR

GLAUCOMA osms.it/glaucoma PATHOLOGY & CAUSES ▪ Group of eye disorders; intraocular hypertension damages optic nerve → progressive peripheral visual field loss ▪ Aqueous humour drainage pathway becomes partially/completely blocked → fluid cannot easily drain out → pressure of anterior chamber builds up → intraocular hypertension (pressure > 21mmHg/2.8kPa) → affects eye structures → atrophy of outer rim of optic nerve → peripheral vision loss ▪ Intraocular pressure increases → continued damage to optic nerve → ganglion cell loss → loss of central vision

TYPES Open Angle Glaucoma ▪ Angle between cornea, iris; most common ▪ Increased aqueous production/decreased outflow ▪ Secondary to uveitis, vitreous hemorrhage, retinal detachment Closed Angle Glaucoma ▪ Narrowing/closure of anterior chamber angle → inadequate drainage of aqueous humor → increased intraocular pressure → optic nerve damage ▪ Acute: rapid buildup of pressure Normal Tension Glaucoma ▪ Genetic hypersensitivity to intraocular pressures in normal range

RISK FACTORS Open angle ▪ ↑ age, black people of African descent,

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family history Closed angle ▪ ↑ age, family history, biologically-female individuals of Asian descent, hyperopia, medications (e.g. mydriatic eye drops), pseudoexfoliation

COMPLICATIONS

▪ If untreated, blindness

SIGNS & SYMPTOMS Open angle ▪ Asymptomatic Closed angle ▪ Chronic: often asymptomatic, peripheral vision loss ▪ Acute (ophthalmic emergency): abrupt onset of severe eye pain, redness, blurry vision/vision loss, headache, nausea, halos around lights, fixed mid-dilated pupil, conjunctival redness, corneal edema

DIAGNOSIS DIAGNOSTIC IMAGING Tonometry ▪ ↑ intraocular pressure Direct/indirect fundoscopy ▪ Cupping: hollowed-out appearance of optic nerve (thinning of outer rim) ▪ Increased cup-to-disc ratio; > 0.5 suggestive of glaucoma Slit lamp ▪ Special lens to visualize angle (gonioscopy)

Chapter 77 Globe Pathlogy

OTHER DIAGNOSTICS

▪ Clinical presentation: history, ↓ visual acuity, visual field (peripheral vision loss; central loss at late stages)

TREATMENT MEDICATIONS Open angle ▪ Beta-adrenergic receptor antagonists, carbonic anhydrase inhibitors, alpha adrenergic agonists ▫ ↓ production of aqueous humor ▪ Prostaglandin analogs, alpha adrenergic agonists ▫ ↑ outflow of aqueous humor

▫ Open trabecular meshwork, increase aqueous outflow (trabeculoplasty); destroy humor producing cells; create new channel for aqueous humour drainage ▪ Surgical trabeculectomy ▫ Create alternate drainage pathway Acute closed angle ▪ Peripheral iridotomy with laser ▫ Small hole through iris for aqueous humor drainage

Acute closed angle ▪ Eye drops (e.g. beta-blockers, alpha agonists); systemic (e.g. acetazolamide, urea, mannitol, glycerol)

SURGERY Open angle ▪ Laser surgery

Figure 77.5 A photograph of the eye of an individual with acute angle closure glaucoma. There is ciliary flush and a hazy cornea.

RETINAL DETACHMENT (RD) osms.it/retinal-detachment PATHOLOGY & CAUSES ▪ Separation of retinal photoreceptors from underlying retinal pigment epithelium (RPE), choroid; if untreated leads → vision loss ▪ Detachment of neurosensory retinal layer from underlying layers → ischemia, progressive degeneration of photoreceptors → vision loss

TYPES Rhegmatogenous ▪ Most common ▪ Full thickness retinal break → vitreous fluid passes into subretinal space → retinal detachment ▪ Causes ▫ Posterior vitreous detachment: most common, age 50–75, separation of

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posterior vitreous membrane from retina due to natural age-related liquefaction of vitreous → retinal breaks can occur in areas of strong vitreoretinal attachment ▫ Ocular trauma Nonrhegmatogenous ▪ Vitreous traction ▫ Abnormally strong vitreoretinal adhesion → contraction → detachment; proliferative diabetic retinopathy, retinopathy of prematurity ▪ Exudative ▫ Fluid accumulation between layers; inflammatory conditions, choroidal neoplasms

RISK FACTORS Rhegmatogenous ▪ High myopia; lattice degeneration (thinning of retinal periphery); family history; history of retinal detachment; ocular trauma; previous intraocular surgery (e.g. cataract surgery)

COMPLICATIONS

▪ Vision loss, proliferative retinopathy

SIGNS & SYMPTOMS ▪ Sudden onset: floaters/flashes of light; if preceded by posterior vitreous detachment ▪ Monocular vision loss: curtain drawn over vision field

▪ Tractional: smooth concave retinal surface; minimal shifting with eye movements ▪ Exudative: smooth retinal surface, shifting fluid

LAB RESULTS

▪ Diabetes: traction, exudative RD; find underlying cause

OTHER DIAGNOSTICS

▪ Clinical history, physical examination

TREATMENT SURGERY

▪ Laser photocoagulation/cryoretinopexy: seal retinal breaks, prevent retinal detachment ▪ Rhegmatogenous RD ▫ Pneumatic retinopexy: intraocular injection of gas to tamponade retinal break (along with laser or cryoretinopexy) ▫ Scleral buckles: silicone bands placed are sewed to sclera under rectus muscles (along with laser or cryoretinopexy) ▫ Vitrectomy: removal of vitreous body to reduce the effect of vitreous traction to retina ▪ Tractional RD ▫ Vitrectomy with scleral buckling

DIAGNOSIS DIAGNOSTIC IMAGING ▪ ↓ visual acuity

Ocular ultrasound ▪ E.g. choroidal masses ▪ Traction, exudative RD; find underlying cause Direct/indirect fundoscopy ▪ Rhegmatogenous: wavy appearance, changes with eye movements, changes in vessel direction

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Figure 77.6 An MRI scan of the head in the axial plane demonstrating detachment of the right retina.

Chapter 77 Globe Pathlogy

RETINOBLASTOMA osms.it/retinoblastoma PATHOLOGY & CAUSES ▪ Intraocular malignant tumor; affects children; presents as leukocoria ▪ Most common primary intraocular malignancy of childhood; usually < two years ▪ Associated with intracranial tumor ▫ Pinealoblastoma (trilateral retinoblastoma) ▪ Mutational inactivation of both alleles of retinoblastoma (RB1) gene located in chromosome 13

▫ Blood → lungs, bones, liver ▫ Lymphatic vessels → conjunctiva, eyelids, extraocular tissue ▪ Heritable retinoblastoma ▫ Secondary malignancy (e.g. bone, soft tissue sarcomas)

TYPES Heritable (40%) ▪ Germline mutations: inherited/de novo ▪ Presents at early age; bilateral/multifocal; 50% risk of passing to offspring Nonheritable (60%) ▪ Somatic mutations in both alleles; negative family history ▪ Presents later in life; unilateral

Figure 77.7 The gross pathological appearance of a retinoblastoma.

RISK FACTORS

▪ Family history ▪ 13q14 deletion syndrome ▫ Microdeletions in region 1 band 4 located in large arm (q) of chromosome 13

COMPLICATIONS

▪ Fatal if untreated; with prompt treatment, survival > 95% ▪ Spreads via ▫ Choroid → sclera, orbit → destruction of globe → vision loss ▫ Optic nerve → brain ▫ Subarachnoid space → contralateral optic nerve, brain

Figure 77.8 A child with retinblastoma causing whitening of the right pupil known as leukocoria.

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SIGNS & SYMPTOMS ▪ Leukocoria (abnormal white reflexion from retina) ▪ Strabismus, nystagmus, red eye

DIAGNOSIS DIAGNOSTIC IMAGING MRI (brain, orbits) ▪ T1-weighted: bright ▪ T2-weighted: dark compared to vitreous ▪ Detect optic nerve involvement, associated intracranial tumor Direct/indirect fundoscopy ▪ Well-circumscribed, translucent, white intraretinal mass Ocular ultrasound ▪ Normal globe size, calcification

LAB RESULTS

Figure 77.9 An MRI scan of the head in the axial plane demonstrating a retinoblastoma of the left globe.

▪ Genetic testing ▫ Estimate risk in family members, future offspring

OTHER DIAGNOSTICS

▪ Metastasis evaluation (e.g. bone marrow aspiration, lumbar puncture)

TREATMENT MEDICATIONS

▪ Local/systemic chemotherapy ▫ Preserve vision, optimize survival

SURGERY

▪ Cryopexy, laser photoablation, enucleation ▫ Preserve vision, optimize survival

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Figure 77.10 A retinoblastoma as seen on fundoscopy.

Chapter 77 Globe Pathlogy

RETINOPATHY OF PREMATURITY osms.it/retinopathy-of-prematurity PATHOLOGY & CAUSES ▪ AKA retrolental fibroplasia ▪ Proliferative retinopathy, occurs in preterm infants; if untreated → vision loss ▪ Common cause of childhood blindness ▪ Premature birth interrupts development → ↑ risk of vascular insult ▪ Supplemental oxygen administration → disruption of normal angiogenesis → abnormal growth of blood vessels, fibrous tissue affecting temporal part of retinal periphery ▪ Regress spontaneously in most cases

RISK FACTORS

▪ Gestational age < 30 weeks; birth weight ≤ 1.5kg/3.3lbs; excessive oxygen therapy; supplemental oxygen

COMPLICATIONS

▪ Retinal bleeding, scarring ▪ Contraction of fibrovascular tissue → retinal detachment → blindness ▪ Refractive errors: myopia, anisometropia ▪ Squint/strabismus ▪ Glaucoma

SIGNS & SYMPTOMS ▪ Blindness due to retinal detachment, if untreated

▪ Classification ▫ Location: three concentric zones from optic disc to periphery ▫ Extent: retina divided in 12 parts (hours of a clock) ▫ Stage I: thin white demarcation line separating vascularized from avascular retina ▫ Stage II: ridge of fibrous tissue into vitreous between vascularized, avascular retina ▫ Stage III: abnormal growth of fibrovascular tissue on ridge; extension into vitreous ▫ Stage IV: partial retinal detachment ▫ Stage V: total retinal detachment ▫ Plus disease: increased venous dilation, tortuosity of posterior retinal vessels, vitreous haze

OTHER DIAGNOSTICS

▪ Screening of preterm infants

TREATMENT MEDICATIONS

▪ Intravitreal injection of VEGF antagonists

SURGERY

▪ Ablation of retina with laser photocoagulation

DIAGNOSIS DIAGNOSTIC IMAGING Fundoscopy ▪ Direct/indirect following pupil dilation ▫ Disorganized growth of vessels, fibrous tissue

OSMOSIS.ORG 609

Figure 77.11 A CT scan of the head in the axial plane demonstrating increased density and asymmetry of the globes in a one year old biologically-female individual. The increase in density is caused by retinal detachment and subsequent fibrous reorganisation of the vitreous.

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NOTES

NOTES

HEAD INJURY GENERALLY, WHAT IS IT? PATHOLOGY & CAUSES ▪ External force to head → brain injury (stretching, compression, impact, rotational) → cellular dysfunction

SIGNS & SYMPTOMS ▪ ▪ ▪ ▪ ▪ ▪ ▪

Mental-status change Consciousness loss Headache Irritability Lethargy Vomiting Seizure

DIAGNOSIS DIAGNOSTIC IMAGING

▪ Concussion ▫ Neuro-imaging rules out more extensive injury

▪ Shaken baby syndrome ▫ Fundoscopy (retinal hemorrhage), neuro-imaging reveals characteristic intracranial injury (intracranial hemorrhage, edema)

OTHER DIAGNOSTICS

▪ Concussion ▫ Functional assessment

TREATMENT SURGERY

▪ Significant injury ▫ Drain ventricle if needed ▫ Drain intracranial hemorrhage if required

OTHER INTERVENTIONS

▪ Mild injury ▫ Rest ▪ Significant injury ▫ Monitor intracranial pressure (ICP)

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CONCUSSION osms.it/concussion PATHOLOGY & CAUSES ▪ AKA mild traumatic brain injury ▪ Direct blow to head, face, neck, other body part transmitting to head → acute, mildly traumatic brain injury → mental status alteration, potential consciousness loss ▪ Concussion alters cellular functioning ▫ Physical trauma → nerve cell membrane disruption → intracellular ion migration (potassium, calcium) to extracellular space → unregulated glutamate release → depolarization ▫ Ion shifts at axon level/axonal rupture → disrupted cellular oxidative metabolism → cell death → functional disturbance → temporary (normal function) brain impairment ▫ Ion regulation loss → ↑ membrane pump activity (e.g. sodium-potassium ion channels) → ↑ ATP, glucose utilization ▫ Paradoxical ↓ cerebral blood flow → cellular energy crisis → susceptible ↑ further injury ▫ Excitatory neurotransmitters released (e.g. acetylcholine, glutamate, aspartate) + free-radical generation generation → secondary injury ▫ Initial ↑ glucose utilisation → ↓ energy-use metabolic state; neuronal suppression may persist weeks postinjury

CAUSES

▪ Traumatic head injury (e.g. motor vehicle crash, combat, contact sport) ▪ Force transmission (head/body injury) → diffuse neuronal-level brain injury → temporary (reversible) brain-function loss → mental status alteration, +/consciousness loss with little/no resultant imaging change ▪ Coup-contrecoup injury ▫ Coup injury: compressive force at

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impact point → brain injury at contact point ▫ Contrecoup injury: brain may collide with skull opposite initial impact sight during rebound ▪ Torque injury ▫ Rotational force → different rotational velocity dependent on variable distance from rotation’s center, differing grey/ white matter density → neuron stretching (more severe injury → shearing) ▫ Brain regions most affected: midbrain, diencephalon ▫ Injury disrupts normal cellular activity in reticular activating system → consciousness loss

RISK FACTORS

▪ Biologically-male ▪ Contact sport, cycling injury, combatrelated traumatic brain injury (TBI) ▪ Hospital-admission history (intoxicationrelated) ▪ Low socioeconomic status ▪ Lower cognitive function

COMPLICATIONS

▪ Seizure, intracranial hemorrhage, skull fracture, dementia pugilistica, ↑ further concussion risk ▪ Second-impact syndrome (SIS) ▫ Further head injury (post-concussion period) during ↓ blood supply → rapid cerebral edema ▪ Postconcussive syndrome (PCS) ▫ Persistent post-concussive neurocognitive symptoms ▪ Repeated concussion → ↑ later-life risk of chronic traumatic encephalopathy (tau protein accumulation in neurons → neuronal death → brain atrophy), Parkinson’s disease, depression

Chapter 78 Head Injury

SIGNS & SYMPTOMS ▪ Develop after initial injury, may continue developing days afterwards ▪ Physical ▫ Headache; dizziness; vomiting; nausea; concussive convulsion (immediately post-injury); light/sound sensitivity; tinnitus; cranial nerve impairment (extraocular muscle weakness, vertigo, nystagmus); incoordination ▪ Cognitive ▫ Blunted affect, confusion, difficulty focusing attention, consciousness loss, pre-/post-traumatic amnesia, sleepingpattern change, slow answering questions, memory deficit ▪ Emotional ▫ Irritability, anhedonia, tearfulness, restlessness

DIAGNOSIS DIAGNOSTIC IMAGING Contrast-CT scan/MRI ▪ Concussion → normal findings without other injury ▪ Contusion, hemorrhage → abnormality

OTHER DIAGNOSTICS

Neuropsychological testing ▪ Assess functional impairment (also assesses recovery) ▫ Standardized Assessment of Concussion (SAC) ▫ Post-Concussion Symptom Scale and Graded Symptom Checklist ▫ Sport Concussion Assessment Tool (SCAT5) ▫ Westmead post-traumatic amnesia scale

TREATMENT MEDICATIONS

▪ Analgesia ▫ Paracetamol, NSAIDS ▫ Avoid narcotics (prevent further consciousness-clouding)

OTHER INTERVENTIONS

▪ Physical, cognitive rest (1–2 days) → gradual full-function return ▫ Delay return to contact sport until complete symptom resolution ▪ 24 hour observation period for neurological deterioration (diagnostic findings → outpatient/in-hospital) ▪ Functional single concussion recovery (usually 48–72 hours), headaches (over 2–4 weeks)

Diagnostic criteria ▪ Consciousness loss: < 30 minutes ▪ Memory loss: < 24 hours ▪ Glasgow Coma Scale: score 13–15 (eye opening, verbal/motor/orientation response) ▪ More severe symptoms → moderate/severe traumatic brain injury

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SHAKEN BABY SYNDROME osms.it/shaken-baby-syndrome PATHOLOGY & CAUSES ▪ AKA abusive head trauma/shaking-impact syndrome ▪ Child head injury caused by another person ▪ Traumatic shaking → child’s head flung violently back/forth (may strike surrounding surfaces/objects) → acceleration– deceleration, rotational force → bridging vessels tear (subdural hematoma), diffuse axonal injury, oxygen deprivation, brain swelling, ↑ ICP ▪ Infant anatomy → ↑ neurological-injury risk from shaking ▫ Large head:body ratio, weak cervical paraspinal muscles → accelerationdeceleration force movement ▫ Thin, pliable infant skull → ↑ force transfer across subarachnoid space ▫ Relatively flat skull base → ↑ brain movement with deceleration force ▫ Soft infant brain (↑ water content compared to adult), incompletelymyelinated infant neurons → ↓ blood flow autoregulation

RISK FACTORS

▪ Age (often first year of life), abusive caregiver; caregivers hold unrealistic expectations of child; emotional stress; aggression; biological sex (male > female); perinatal illness (e.g. premature birth, difficult labor, hospitalization, congenital conditions); incessant crying ▪ Family/individual factors ▫ Family dysfunction history (abuse, neglect; domestic violence; drug/alcohol abuse) ▫ Young/single parent, parental depression, low socioeconomic status (financial stress), limited education, biologically-male > -female (stepfather/ maternal boyfriend)

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COMPLICATIONS

▪ Retinal hemorrhage (diffuse, multilayered); subdural hemorrhage; diffuse brain injury; global hypoxia, ischemia; increased intracranial pressure, herniation; skull fracture; spinal cord/paraspinal injury; hemorrhagic shock open fontanelle, (cranial sutures allow large blood accumulation)

SIGNS & SYMPTOMS ▪ Trauma signs may be invisible ▪ Retinal hemorrhage; long bone, rib fracture; soft-tissue scalp swelling; bruising; irritability; poor feeding; lethargy, coma; vomiting; seizure; bulging fontanel (↑ ICP) ▪ Late, severe neurologic deterioration signs ▫ Bradycardia, pupillary change

DIAGNOSIS DIAGNOSTIC IMAGING Brain CT scan/MRI ▪ Intracranial hemorrhage ▫ Hematoma; subarachnoid, subdural (most common), epidural hemorrhage; intraparenchymal bleeding ▪ Cerebral contusion/edema ▪ Uncal, subfalcine, transtentorial herniation ▪ Hypoxia/ischemia ▫ Loss of grey-white distinctions ▪ Skull fracture ▪ Appendicular, axial skeleton survey ▫ Detects additional injuries Fundoscopy ▪ Retinal hemorrhage (before intracranial pathology evident) X-ray ▪ Limb X-ray → metaphyseal fractures ▪ Chest X-ray → rib fractures

Chapter 78 Head Injury

OTHER DIAGNOSTICS

▪ Diagnostic triad ▫ Subdural, subarachnoid hemorrhage ▫ Metaphyseal fractures (extremities flail uncontrollably during shaking) ▫ Retinal hemorrhage

TREATMENT SURGERY

▪ Monitor ICP → cerebral ventricle drainage may be required ▪ Intracranial hematoma → drain blood collection (when indicated)

OTHER INTERVENTIONS

▪ Many countries have mandatory suspected child abuse reporting laws → report incident

Figure 78.1 An MRI scan in the coronal plane of an three month old female with head injury secondary to abuse. There is intraparenchymal hemorrhage as well as sub-falcine and transtentorial herniation of the brain.

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NOTES

NOTES

HEADACHES GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Cranial pain, disturbs everyday life

TYPES Primary ▪ Migraine, tension headache, cluster headache Secondary ▪ Headaches caused by other disorders

CAUSES

▪ Genetic, environmental factors; stress

SIGNS & SYMPTOMS ▪ Unilateral/bilateral, localized/diffuse head pain ▪ Nausea, vomiting, aura/autonomic symptoms

DIAGNOSIS DIAGNOSTIC IMAGING CT scan/MRI ▪ Used to exclude other diseases ▫ Unusual neurological symptomatology; headache accompanied by ↑ body temperature, stiff neck; new headache in individual with HIV/cancer

TREATMENT MEDICATIONS

▪ Prophylactic management ▫ Prevention of further attacks ▪ Symptomatic treatment ▫ Pain, symptom-management medications

CLUSTER HEADACHE osms.it/cluster-headache PATHOLOGY & CAUSES ▪ One-sided headache in ophthalmic nerve distribution region with autonomic symptomatology ▪ Hypothalamus involvement ▫ Episodic occurrence of cluster attacks ▪ Posterior hypothalamic activation → secondary trigeminal stimulation →

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afferents travel to nucleus caudalis ▫ Projection to thalamus, sensory cortex → perception of pain ▫ Hyperactivation of parasympathetic pterygopalatine ganglion → autonomic symptoms ▪ Cavernous sinus walls inflammation → ↓ venous flow → injury of internal carotid artery sympathetic fibers

Chapter 79 Headaches

TYPES Episodic ▪ Daily episodes over 6–12 weeks; “clusters” followed by remission period up to 12 months Chronic ▪ Episodes without substantial remission period

CAUSES

▪ Unknown; possibly genetic

RISK FACTORS

▪ More common in individuals who are biologically male ▪ Stressful periods, allergic rhinitis, sexual intercourse, tobacco, excessive alcohol use

COMPLICATIONS

▪ Progresses episodic → chronic

SIGNS & SYMPTOMS ▪ Headache ▫ One-sided sharp, stabbing, burning orbital/supraorbital/temporal head pain ▪ Autonomic ▫ Ipsilateral conjunctival hyperemia with lacrimation, nasal discharge, miosis, edema, drooping eyelid ▪ Episodes ▫ 1–8 per day; lasts five minutes to three hours ▪ Restlessness, agitation, suicidal ideation

DIAGNOSIS DIAGNOSTIC IMAGING CT scan/MRI ▪ Exclude possible cranial lesions

OTHER DIAGNOSTICS

▪ Requires each of following ▫ Five unilateral/orbital/supraorbital/ temporal attacks; 1–8 episodes daily, ≤ three hours ▫ Agitation/restlessness ▫ ≥ one autonomic symptom on same side as headache

TREATMENT MEDICATIONS Acute management ▪ Supplemental oxygen/intranasal sumatriptan/zolmitriptan ▫ Initial treatment ▪ Intranasal lidocaine/oral ergotamine/IV dihydroergotamine ▫ If initial treatment not effective Prophylaxis ▪ Verapamil ▫ Episodic attacks > two months/chronic cluster headaches ▪ Glucocorticoids (e.g. prednisone); can be used together with verapamil ▪ Lithium ▫ If other medications contraindicated

SURGERY

▪ Block greater occipital nerve ▪ Percutaneous radiofrequency ablation of pterygopalatine ganglion ▪ Gamma knife radiosurgery ▪ Stimulation of pterygopalatine ganglion ▪ Posterior hypothalamus deep brain stimulation

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MIGRAINE osms.it/migraine PATHOLOGY & CAUSES ▪ Disease characterized by one-sided head pain ▪ Probable mechanism ▫ ↑ neuronal hyperexcitability → cortical spreading depression wave across cortex → release of proinflammatory cytokines, matrix metalloproteinases (MMP), nitric oxide (NO), glutamate, adenosine triphosphate (ATP), potassium ions from neurons/glial/ vascular cells → alters blood-brain barrier → activates perivascular trigeminal nociceptors ▫ Release of substance P, calcitonin gene-related peptide, neurokinin A → neurogenic inflammation with meningeal blood vessels dilatation, protein exudation → further nociceptor stimulation ▫ Projection of afferents to trigeminal nucleus-pars caudalis → fibers relay to thalamus, sensory cortex → perception of pain ▪ Trigeminal nociceptors innervate anterior head region, upper cervical dorsal roots innervate posterior head region → converge in trigeminal nucleus caudalis → characteristic pain distribution affecting anterior, posterior head region ▪ Aura likely caused by depression spreading to areas where perceived consciously ▪ Serotonin receptors possibly involved in migraine pathogenesis ▫ Directly acting on blood vessels/ affecting pain pathways ▪ If nociceptors stimulated too frequently → neuronal sensitization, cutaneous allodynia phenomenon (nociceptive response to nonnociceptive stimuli)

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TYPES Migraine with aura ▪ Typical aura migraine with/without headache ▪ Brainstem aura migraine ▪ Hemiplegic migraine ▫ Familial; types I, II, III ▫ Sporadic ▪ Ocular migraine Migraine without aura ▪ Menstrual migraine ▫ Develops ≤ two days before, continues ≤ three days after menstrual period ▪ Chronic migraine ▫ ≥ 15 headaches per month for ≥ three months ▫ Analgesics, nonsteroidal antiinflammatory drugs (NSAIDs) overuse biggest risk factor Probable migraine ▪ Attacks similar to migraine without one feature needed for migraine diagnosis

CAUSES

▪ Inheritance ▫ ↑ neuronal excitability ▪ Familial hemiplegic migraine (FHM) ▫ Type I: CACNA1A gene mutation ▫ Type II: ATP1A2 gene mutation ▫ Type III: SCN1A gene mutation

RISK FACTORS

▪ Individuals who are biologically female, age 30–39 ▪ Stress, hormone oscillations, irregular eating/sleeping, weather, light, alcohol, tobacco, odors ▪ Syndromes associated with migraine ▫ Recurrent gastrointestinal (GI) disturbance; benign paroxysmal vertigo, torticollis

Chapter 79 Headaches

COMPLICATIONS

▪ Status migrainosus ▫ Migraine lasting ≥ 72 hours without spontaneous resolution ▪ Persistent aura without infarction ▫ ≥ one week ▪ Migrainous infarction ▫ Preceded by migraine attack with aura symptoms ≥ one hour; retinal migraine → permanent blindness ▪ Migraine aura-triggered seizure ▪ Rebound headache due to medication overuse

SIGNS & SYMPTOMS ▪ One-sided, pulsatile headache worsened by physical activity, with maximum pain at supraorbital location; followed by nausea, vomiting, hypersensitivity to light and sounds ▫ May be accompanied by cutaneous allodynia phenomenon ▪ Prodromal symptoms (appear hours/days before attack) ▫ ↑ irritability to light, sound, smells; yawning, food cravings, mood changes, constipation/diarrhea ▪ Postdrome symptoms ▫ Lasting approx. one day after headache; sudden movements → short-lasting pain in previously affected regions; exhaustion/tiredness/euphoria Aura ▪ Negative features (areas of vision loss) ▫ Hemianopia/quadrantanopia, peripheral vision loss, spot-like scotomas, blurriness/blindness ▪ Positive features ▫ Scintillating scotoma: glimmering geometric shapes (e.g. zigzag line) appearing centrally with expansion to periphery; visual hallucinations ▫ Visual: most common ▫ Sensory: tingling sensations beginning from one hand → arm, face → shortlasting numbness ▫ Motor: facial/extremities weakness ▫ Language: progresses from mild speech

impairment to aphasia ▪ Subtypes ▫ Brainstem aura: dizziness, double vision, tinnitus, speech difficulties, altered consciousness ▫ Hemiplegic: aura usually includes onesided motor weakness; vision, sensory defects, ↑ body temperature, seizures, coma ▫ Ocular: loss of vision/scotomas in one eye; headache

DIAGNOSIS LAB RESULTS

▪ ↓ serum N-acetyl-aspartate levels

OTHER DIAGNOSTICS Non-aura migraine ▪ Requires each of following ▫ ≥ five attacks: lasting 4–72 hours ▫ ≥ two of the following: one-sided, throbbing quality, moderately severe pain, worsening with physical activity ▫ ≥ one of following with headache: nausea/vomiting; light, sound sensitivity Migraine with aura ▪ Requires each of following ▫ Aura symptoms: visual, sensory, motor, speech ▫ ≥ two of following: ≥ one aura symptom lasting ≥ five minutes, followed by other aura symptomatology; auras lasting five minutes–one hour; one aura, one-sided; aura precedes headache that occurs within 60 minutes ▫ ≥ two attacks: with listed characteristics

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TREATMENT MEDICATIONS Mild/moderate ▪ NSAIDs (e.g. aspirin, naproxen, diclofenac, ibuprofen) ▪ Paracetamol Moderate/severe ▪ Triptans ▫ Serotonin agonists; constrict blood vessels, alter pain pathways ▫ Sumatriptan, zolmitriptan, naratriptan, eletriptan ▫ Oral/nasal/subcutaneous administration ▫ Triptan, NSAID combination; more effective than individual medications (e.g. sumatriptan, naproxen) ▫ Ergots (ergotamine) ▪ IV triptans ▪ Dopamine antagonists ▫ IV metoclopramide; IV/IM chlorpromazine ▪ Ergots (e.g. dihydroergotamine)

▪ Dexamethasone ▫ Combined with symptomatic therapy → ↓ early headache recurrence rate ▪ Antihypertensives ▫ Beta blockers (propranolol/metoprolol/ timolol) ▫ Calcium channel blockers (verapamil/ nifedipine) ▫ Angiotensin-converting enzyme inhibitors (ACEI)/angiotensin II receptor blockers (ARBs); e.g. lisinopril/ candesartan respectively ▪ Antidepressants ▫ Tricyclic antidepressants (amitriptyline, nortriptyline, doxepin) ▫ Serotonin-norepinephrine reuptake inhibitors (SNRIs) (e.g. venlafaxine) ▪ Anticonvulsants ▫ Topiramate/valproate

OTHER INTERVENTIONS

▪ Complementary, alternative medicine ▫ Herbs: butterbur (Petasites hybridus), feverfew (Tanacetum parthenium) ▫ Supplementation: riboflavin, coenzyme Q10, magnesium

TENSION HEADACHE osms.it/tension-headache PATHOLOGY & CAUSES ▪ Bilateral, “tightening” headache (most common headache type) ▫ ↑ tenderness of pericranial myofascial structures → activation of vasculaturesurrounding nociceptors → episodic TH → prolonged nociceptor stimulation → pain pathway sensitization with hyperalgesia → chronic TH

TYPES Episodic ▪ Rare (≤ one headache monthly)

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▪ Common (≤ 14 headaches monthly) Chronic ▪ ≥ 15 headaches monthly

CAUSES

▪ ↑ muscle tenderness ▪ Combination of genetic, environmental factors ▫ Episodic TH ▪ Multifactorial inheritance ▫ Chronic TH

RISK FACTORS

▪ White individuals who are biologically

Chapter 79 Headaches female of Ashkenazi Jewish descent ▪ Age ≥ 40 ▪ Stress, anxiety, depression, poor posture

COMPLICATIONS

▪ Rebound headache ▪ Progresses episodic → chronic

SIGNS & SYMPTOMS ▪ Moderate, bilateral, non-pulsating head pain ▫ Band-like distribution, without worsening during physical activity, few minutes to one week ▪ Photophobia/phonophobia ▪ Stiffness/tenderness of head, neck, shoulder muscles

DIAGNOSIS OTHER DIAGNOSTICS Requires each of following ▪ Absence of nausea, vomiting ▪ Light/sound hypersensitivity without other aura symptoms ▪ ≥ two of following ▫ Both sides of head affected ▫ Non-throbbing quality ▫ Moderate intensity ▫ No worsening during physical activity

TREATMENT MEDICATIONS Immediate symptoms ▪ Analgesics ▫ NSAIDs ▫ Paracetamol ▪ Caffeine ▪ Butalbital ▫ If contraindication for NSAIDs/caffeinecombined analgesics Prophylactic management ▪ Antidepressants ▫ Tricyclic antidepressants (amitriptyline, nortriptyline/protriptyline) ▫ Mirtazapine/venlafaxine ▪ Anticonvulsants ▫ Topiramate/gabapentin

PSYCHOTHERAPY

▪ Behavioral, cognitive-behavioral, biofeedback therapy

OTHER INTERVENTIONS

▪ Acupuncture, heating/icing, resting for immediate symptoms

OSMOSIS.ORG 621

NOTES

NOTES

HEARING LOSS GENERALLY, WHAT IS IT? PATHOLOGY & CAUSES ▪ Decrease in ability to perceive sound ▪ Variable etiology ▫ External, middle, inner ear, associated neurological input/processing structures

SIGNS & SYMPTOMS ▪ Hearing loss ▪ Balance issues, headache, tinnitus

DIAGNOSIS OTHER DIAGNOSTICS

▪ Bedside (otoscopy to Rinne) and formalized (audiogram) testing

Otoscopy Whisper test ▪ Examiner speaks in whispered voice 0.61m/2ft away → individual covers far ear with hand → examiner whispers word/ phrase → individual repeats word/phrase Finger rub ▪ Examiner speaks closer to pinna → individual indicates if sound heard

Weber ▪ Distinguishes between conductive, sensorineural hearing loss ▪ Examiner places vibrating tuning fork (128Hz) at apex of head → individual indicates loudest side ▫ One ear preferred/louder indicative of possible hearing loss Rinne ▪ Compares air, bone conduction of sound ▪ Examiner places vibrating tuning fork (512Hz) at mastoid process → individual indicates when vibration heard → examiner moves vibrating tuning fork outside of pinna → individual indicates if vibration heart ▫ Bone conduction (mastoid placement of tuning fork) > air conduction (i.e. individual cannot hear vibration after first step complete) indicative of possible hearing loss Audiogram ▪ Pure tones of varying frequencies (Hz) at varying volume of sound ▪ Plot individual’s 50% correct response rate (dependent on volume) for each frequency

TREATMENT ▪ Specific to underlying etiology; some etiologies irreversible

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Chapter 80 Hearing Loss

CONDUCTIVE HEARING LOSS osms.it/conductive-hearing-loss PATHOLOGY & CAUSES ▪ Disability of sound waves ▫ Unable to be amplified, transmitted by external/middle ear

CAUSES Bony outgrowth ▪ Exostoses: form at suture lines of external auditory canal bony suture lines; associated with repeated cold water exposure (e.g. swimmers) ▪ Osteomas: form at tympanosquamous suture line Cerumen impaction ▪ ↑ Incidence in elderly Congenital ▪ Microtia: malformation/absence of auricle; 1st, 2nd branchial arch derivative; mildmoderate conductive hearing loss ▪ External auditory canal atresia: associated with craniofacial diseases (e.g. Treacher Collins syndrome, Robin sequence, Crouzon syndrome) ▪ Commonly of ossicular chain (most commonly malformation of stapes) → inability to reverberate → ↓ sound wave transmittance to oval window

Eustachian tube dysfunction ▪ Results in abnormal pressure/reflux/ clearance of middle ear contents ▪ Shorter eustachian tubes in children → ↑ reflux of nasopharynx contents → otitis media ▫ Higher incidence in children with abnormal craniofacial anatomy (e.g. Down syndrome, Treacher Collins syndrome) Otitis externa ▪ AKA swimmer’s ear ▪ Commonly bacterial ▫ Pseudomonas aeruginosa (most common pathogen) ▪ Chronic/repeated infections → polyps (can occlude external auditory canal) Otitis media ▪ Infection → effusion → poor transmittance of sound wave in middle ear → hearing loss ▪ Highest incidence ▫ 6–18 months of age ▪ Microbiology: Staphylococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis ▪ Risk factors: daycare, bottle feeding ▪ Complications: mastoiditis, cholesteatoma, permanent hearing loss → deafness

OSMOSIS.ORG 623

Otosclerosis ▪ Bony overgrowth of stapes to oval window → inability to vibrate → inability to conduct sound waves; can be autosomal dominant with variable penetrance Trauma ▪ Complete external auditory canal occlusion Tumors of middle ear ▪ Cholesteatomas (most common overall) ▫ Desquamated, stratified, squamous epithelium in middle ear space ▫ Accumulation → erosion of middle ear contents (ossicular chain) → surrounding structures: external auditory canal (EAC), mastoid bone ▪ Squamous cell carcinoma (most common malignant tumor) Tympanic membrane perforation ▪ Common; due to trauma/barotrauma to ear/ face

SIGNS & SYMPTOMS ▪ Decreased perception of sound ▫ Especially poor perception of lowfrequency sound ▫ Overcome by volume of stimulus

DIAGNOSIS OTHER DIAGNOSTICS

▪ History, associated symptoms ▪ Otoscopy ▪ Special testing ▫ Weber (localization of vibration to affected ear) ▫ Rinne (abnormal; bone conduction > air conduction) ▪ Audiogram ▫ Universal/low-frequency deficit in pure tone discrimination

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TREATMENT ▪ Specific to underlying etiology

MEDICATIONS

▪ External ear ▫ Mild: topical acidifying agent, glucocorticoid ▫ Moderate/severe: topical/oral antibiotics ▪ Middle ear ▫ Pain control (e.g. ibuprofen, acetaminophen), antibiotics

SURGERY

▪ External ear ▫ If repeat infections/↑ size ▪ Middle ear ▫ Tissue graft ▫ Surgical removal

OTHER INTERVENTIONS

▪ External ear ▫ Cerumenolytics/irrigation/manual removal ▫ Repeat infections/↑ size: EAC occlusion ▪ Middle ear ▫ Hearing aids

Chapter 80 Hearing Loss

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SENSORINEURAL HEARING LOSS osms.it/sensorineural-hearing-loss PATHOLOGY & CAUSES ▪ Disability of inner ear (cochlea/CN VIII) to transduce sound waves → viable neurologic input → brain

CAUSES Central nervous system (CNS) ▪ Acoustic neuroma (CN VIII; AKA vestibular neuroma) ▫ ↑ size → compress cerebellum → ataxia ▪ Meningitis ▫ Infection (via cerebrospinal fluid) → cochlea → cochleitis → direct damage to inner hair cells ▪ Meningioma ▪ Acoustic nerve neuritis ▫ Multiple sclerosis, syphilis Congenital ▪ Spontaneous/genetic ▪ Acquired ▫ Toxoplasmosis, other (syphilis, varicella-zoster, parvovirus B19), rubella, cytomegalovirus (CMV), herpes (TORCH) infections Drug-induced ▪ Aminoglycoside antibiotics (most common); cisplatin ▪ Aspirin (high-dose 6–8g/day), quinidine, loop diuretics (e.g. furosemide, ethacrynic acid) → reversible hearing loss, tinnitus Inner ear infection ▪ Labyrinthitis (inflammation, spinning, ringing) Menière’s disease ▪ Rare

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▪ Unilateral, episodic loss concurrent with tinnitus, vertigo ▫ Pathogenesis: unknown; possible infection, autoimmune, vascular constriction, congenital malformation → endolymphatic hydrops (e.g. overproduction of endolymph, distension of endolymphatic space) Noise-induced ▪ Cause: chronic exposure to loud (> 85dB) auditory stimuli ▪ Pathogenesis: overstimulation of hair cells in organ of Corti → nitric oxide, free radical release → damage, death of hair cells ▪ ↓ Mg2+ → ↓ Ca2+ intracellular concentration → ↑ cell damage, death Presbycusis ▪ Most common ▪ Gradual, symmetric hearing loss in elderly ▪ More significant loss with higher frequencies ▪ Pathogenesis: degeneration of hair cells at base of cochlea Trauma ▪ Skull fracture → injury to CN VIII/cochlea

SIGNS & SYMPTOMS ▪ Decreased perception of sound (esp. highpitched sounds, speech discrimination)

DIAGNOSIS DIAGNOSTIC IMAGING MRI ▪ Identifies causes such as acoustic neuroma, perilymphatic fistula

Chapter 80 Hearing Loss

OTHER DIAGNOSTICS

▪ History, associated symptoms ▪ Otoscopy ▫ Rules out causes of conductive hearing loss ▪ Special testing ▫ Weber: lateralization of sound to unaffected ear ▫ Rinne: air, bone conduction (AC > BC) ▪ Audiogram ▫ Identifies deficit in high-pitched pure tone discrimination

TREATMENT

▪ Antibiotics ▫ Meninges

SURGERY

▪ Surgical resection ▫ Acoustic nerve

OTHER INTERVENTIONS

▪ Hearing aids ▫ Hair cells of organ of Corti ▪ Dietary changes (↓ Na+) ▫ Endolymph of labyrinthine systems ▪ Radiotherapy ▫ Acoustic nerve

▪ Specific to underlying etiology

MEDICATIONS

▪ Antiemetics, vestibular suppressants (e.g. benzodiazepines), diuretics ▫ Endolymph of labyrinthine systems

OSMOSIS.ORG 627

NOTES

NOTES

INCREASED INTRACRANIAL PRESSURE

GENERALLY, WHAT IS IT? PATHOLOGY & CAUSES ▪ Abnormal ↑ intracranial pressure ▫ Normal: 10–15mmHg (adults); 5–20mmHg (infants) Monro-Kellie hypothesis ▪ Fixed cranial volume in skull ▪ Three main components ▫ Cerebrospinal fluid (CSF), blood, brain tissue Intracranial compliance (ICC) ▪ Changes in intracranial content volume and changes in intracranial pressure (ICP) ▪ Slight ↑ volume → compensatory mechanisms → slight ↑ ICP ▫ CSF displacement into thecal sac ▫ Venoconstriction/extracranial drainage → ↓ cerebral venous blood volume ▪ Drastic volume increase → ↓ ICC → ↑ ICP ↑ ICP ▪ → compression of blood vessels → ↓ brain perfusion → brain ischemia → edema → ↑↑ ICP ▫ Cerebral perfusion pressure (CPP) = mean arterial pressure (MAP)−ICP ▫ ↓ CPP → ↑ systemic blood pressure/ vasodilation → ↑ cerebral blood volume → ↑ ICP → ↓ ↓ CPP Nerve compression ▪ → impaired brain function

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CAUSES

▪ Cerebral edema (e.g. acute hypoxic ischemic encephalopathy, trauma) ▪ Intracranial space occupying lesion (e.g. tumor, aneurysm, hemorrhage, etc.) ▪ ↑ CSF production ▪ Obstructive hydrocephalus ▪ ↓ CSF absorption ▪ Venous outflow obstruction ▪ Idiopathic intracranial hypertension

SIGNS & SYMPTOMS ▪ Deteriorating level of consciousness (early sign) ▪ Headache ▪ Nausea ▪ Vomiting ▪ Ocular palsies ▪ Mydriasis (dilated pupils) ▪ Papilledema ▪ Dyspnea ▪ Back pain ▪ Decorticate/decerebrate posturing

DIAGNOSIS DIAGNOSTIC IMAGING CT scan ▪ Mass lesions, midline shift, basilar cisterns effacement

Chapter 81 Increased Intracranial Pressure

OTHER DIAGNOSTICS

▪ ICP monitoring ▫ Intraventricular catheter (gold standard) ▫ Intraparenchymal fiberoptic catheter

TREATMENT MEDICATIONS

▪ Sedation (propofol), osmotic diuretics, prophylactic anticonvulsants

SURGERY

▪ Surgical removal of space-occupying lesion ▪ Decompressive craniectomy ▪ Extraventricular drain (EVD)

OTHER INTERVENTIONS

▪ Target → ICP < 20mmHg, MAP > 90mmHg, CPP > 65mmHg ▪ Elevate head (30°) → maximize venous outflow ▪ Airway, breathing, and circulation (ABCs), maintain adequate oxygenation ▪ Treat shock (if applicable): hypertonic saline (HTS) (e.g 7.5%) to treat edema; HTS maintains high serum osmolality → reduces cerebral edema (> 280 mOsm/L); ↑ serum osmolarity prevents intravascular fluid leakage to brain tissue; ↑ serum osmolarity draws excess water from brain tissue → ↓ ICP ▪ Hyperventilation

BRAIN HERNIATION osms.it/brain-herniation site (craniectomy) → decortication of herniated gyrus

PATHOLOGY & CAUSES ▪ Brain tissue displacement: through skull opening or dural fold ▪ Damages associated with herniated section

TYPES Supratentorial herniation ▪ Cingulate/subfalcine ▫ Gyrus forced under falx cerebri → cerebral artery compression → cerebral ischemia then edema → ↑ ICP ▪ Uncal/transtentorial ▫ Cranial nerve (CN) compression in nerves III, IV, posterior cerebral artery → ipsilateral visual cortex ischemia → homonymous hemianopsia ▪ Central ▫ Temporal lobes squeezed through notch in tentorium cerebelli → basilar artery stretched → tearing, bleeding (Duret hemorrhage) ▪ Transcalvarial ▫ Brain herniates through fracture/surgical

Infratentorial herniation ▪ Tonsillar ▫ Cerebellar tonsils herniate in foramen magnum → brainstem, spinal cord compression

CAUSES ▪ ↑ ICP

SIGNS & SYMPTOMS ▪ ▪ ▪ ▪ ▪ ▪ ▪ ▪

Decorticate/decerebrate posturing Seizures ↓ level of consciousness, coma Glasgow Coma Scale (GCS) 3–5 Mydriasis (dilated pupils) Irregular/slow pulse Respiratory/cardiac arrest Loss of brainstem reflexes (blinking, gagging, pupillary reflex)

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DIAGNOSIS DIAGNOSTIC IMAGING Head CT scan/MRI ▪ Depending on the cause, results show mass lesions (e.g. tumor, aneurysm, infarction, hemorrhage etc.) and subsequent displacement of the brain away from the mass, depending on localization

TREATMENT MEDICATIONS

Osmotic diuretics Paracetamol (manage fever) Sedation/paralytic agents ↓ metabolism → ↓ O2 consumption + ↓ CO2 production → no systemic vasodilation → ↓ cerebral blood volume → ↓ ICP ▪ Prophylactic anticonvulsants

▪ ▪ ▪ ▪

Figure 81.1 An MRI scan of the head in the coronal plane demonstrating herniation of the cerebellar tonsils secondary to hypoxic brain injury.

SURGERY

▪ Decompressive craniectomy

OTHER INTERVENTIONS

▪ HTS boluses → support circulation ▫ HTS → ↑ serum osmolarity → draw excess water from brain tissue → ↓ ICP ▪ Hyperventilation ▫ Helps avoid ↑ PaCO2 or hypoxemia → systemic vasodilation → ↑ ↑ cerebral blood volume → ↑ ICP

Figure 81.2 A CT scan of the head in the axial plane demonstrating a right sided acute subdural hemorrhage. The pressure effect has pushed the medial aspect of the right cerebral hemisphere underneath the falx cerebri, known as sub-falcine herniation.

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Chapter 81 Increased Intracranial Pressure

IDIOPATHIC INTRACRANIAL HYPERTENSION (IIH) osms.it/idiopathic-intracranial-hypertension TREATMENT

PATHOLOGY & CAUSES ▪ AKA pseudotumor cerebri ▪ Chronic ↑ ICP, no obvious cause

CAUSES

▪ ↑ ICP → CN II compression → visual impairment

RISK FACTORS

▪ Overweight, biologically female, fertile individuals

SIGNS & SYMPTOMS ▪ Papilledema ▪ Visual field loss ▪ CN palsies, typically CN VI (long intracranial course) ▪ Headache ▪ Pulsatile tinnitus ▪ Photopsia (seeing flashes of light) ▪ Diplopia (double vision) ▪ Temporary visual disturbance ▪ Retrobulbar pain ▪ Back pain

▪ Goal: treat symptoms/preserve vision

MEDICATIONS

▪ Carbonic anhydrase inhibitor (acetazolamide) → ↓ CSF production ▫ Contraindication: pregnancy ▪ Loop diuretics (furosemide) → ↓ papilledema and ↓ mean CSF pressure ▫ Contraindication: pregnancy

SURGERY

▪ Optic nerve sheath fenestration (ONSF)

OTHER INTERVENTIONS ▪ Weight loss

DIAGNOSIS OTHER DIAGNOSTICS

▪ Headache & papilledema with ▫ No secondary cause of ↑ ICP: normal neuroimaging (MRI, contrast CT scan), normal CSF composition ▫ No malignant hypertension: mimics IIH ▫ Lumbar puncture: ↑ opening pressure

Figure 81.3 A retinal photograph demonstrating an expanded optic disc caused by intracranial hypertension.

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NOTES

NOTES

MOTOR NEURON DISEASES GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Group of degenerative motor neuron diseases ▫ Progressive muscle weakness, disability

CAUSES

▪ Mainly genetic

SIGNS & SYMPTOMS ▪ Muscle weakness, fatigue → disability

DIAGNOSIS OTHER DIAGNOSTICS

▪ History, physical examination (upper, lower motor neuron signs) ▪ Muscle biopsy ▪ Electromyography (EMG)

TREATMENT MEDICATIONS

▪ Emerging disease-modifying agents (limited efficacy)

OTHER INTERVENTIONS ▪ Primarily supportive care

AMYOTROPHIC LATERAL SCLEROSIS (ALS) osms.it/amyotrophic-lateral-sclerosis PATHOLOGY & CAUSES ▪ Progressive, degenerative motor neuron disease; upper, lower motor neuron signs ▫ AKA Lou Gehrig’s disease ▪ Genetic associations in familial ALS provide insight to pathogenesis ▪ Protein aggregation → neuronal injury, death → retrograde neuronal degeneration → gliosis ▪ Superoxide dismutase 1 (SOD1): antioxidant protein encoded on

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chromosome 9; 20% of familial ALS ▫ Gain-of-function mutation → misfolding → protein aggregation → direct neuronal injury, unfolded protein response → death ▫ Interference with organelle autophagy, proteasome function ▫ Interference with axonal transport, mitochondrial function ▫ Further protein sequestration within protein aggregate ▪ C9orf72: protein of unknown significance; 40% of familial ALS

Chapter 82 Motor Neuron Disease ▫ Hexanucleotide repeat expansion → long 5’ end of RNA transcript → abnormal transcription, novel protein production → aggregation ▫ Unknown specific pathogenesis ▫ Accumulated, novel proteins; dead neurons ▪ TDP-43, FUS: RNA-binding genes ▫ Abnormal RNA processing → abnormal protein accumulation → neuronal injury ▫ Pathway not completely known ▪ Inflammatory response ▫ Cerebral inflammatory response primarily mediated by microglia, astrocytes ▫ Natural killer, peripheral T-cells, monocytes infiltrate, contribute to inflammation ▫ Microglial response → nitric oxide, oxygen radical, cytokine, glutamate release → motor neuron cell death ▫ SOD1 mutations especially susceptible to pathologic inflammatory response

TYPES Progressive motor atrophy ▪ Predominant lower motor neuron degeneration Primary lateral sclerosis ▪ Predominant upper motor neuron degeneration

COMPLICATIONS

▪ Frontotemporal lobar dementia (FTLD) ▫ Disinhibition, compulsivity, loss of empathy ▫ Pseudobulbar affect (PBA): common; inappropriate, labile, expressive emotions (e.g. crying, yawning) ▪ Neuromuscular respiratory failure ▪ Dysphagia → pneumonia

SIGNS & SYMPTOMS ▪ Early symptoms ▫ Asymmetric hand weakness → dropping of objects (e.g. glasses of water) ▫ Cramping of upper extremities (common) ▫ Dysarthria, dysphagia, dysphonia develop later ▪ Atrophy → ↓ strength → ↓ muscle bulk, abnormal tone → fasciculations ▫ Weakness → inability to ambulate → wheelchair use ▪ Late symptoms ▫ Respiratory weakness → dyspnea → respiratory infection ▫ Recurrent bouts of cough, fever, chill → pneumonia

DIAGNOSIS

Progressive bulbar palsy (AKA bulbar ALS) ▪ Affected cranial nerves → abnormal deglutition, phonation → ventilator support required ▪ Poor prognosis ▫ Mortality rate > 50% at two years

LAB RESULTS

CAUSES

▪ El Escorial criteria (all three required) ▫ Evidence of lower motor neuron (LMN) disease by clinical/electrophysiologic/ neuropathic examination ▫ Evidence of upper motor neuron (UMN) disease by clinical examination ▫ Progressive spread of signs/symptoms within/outside of body region, as determined by history/examination ▪ Family history

▪ May be sporadic ▪ Familial (5–10%) ▫ Multiple genes (e.g. SOD1)

RISK FACTORS

▪ Family history, age, cigarette smoking

▪ ↑ creatinine kinase (due to muscle atrophy) ▪ Heavy-metal levels, lyme disease ▫ Negative

OTHER DIAGNOSTICS

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▪ Neurological ▫ Upper, lower motor neuron signs ▪ Psychiatric ▫ Mental status examination → apathy, disinhibition, PBA in FTLD individuals EMG ▪ Helps differentiate from other neuromuscular junction diseases ▪ Acute denervation ▫ Fibrillations of muscle fibers → active denervation → improper neuronal discharge → small-amplitude baseline variance ▪ Chronic denervation ▫ Large amplitude, long duration, complex motor potentials ▫ Denervation injury → ↑ muscle fiber recruitment, ↓ neuronal innervation

OTHER INTERVENTIONS

▪ Nothing curative, management of symptom progression, severity ▪ Symptom management ▫ Multidisciplinary approach: neurologists, physical therapists, speech therapists, dietitians ▫ Respiratory management: ↓ aspiration event → ↓ rate of progression to tracheostomy, ventilator-dependence ▫ Respiratory evaluation every three months after diagnosis

TREATMENT MEDICATIONS Disease-modifying agents ▪ New to market, mild/modest benefit ▪ Riluzole ▫ Indicated for mild-moderate disease of < five year duration ▫ Mechanism of action: ↓ any excitotoxic interplay by glutamate in neuronal toxicity → ↓ rate of neuron degeneration, symptom progression ▪ Edaravone ▫ Mechanism of action: free-radical scavenger → ↓ oxidative stress → ↓ rate of neuronal death, symptom progression ▪ Symptom management ▫ Muscle spasms: quinine ▫ Muscle spasticity: muscle relaxants

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Figure 82.1 Amyotrophic lateral sclerosis is also known as Lou Gehrig’s disease. Gehrig played for the Yankee’s and died of ALS at the age of 37.

Chapter 82 Motor Neuron Disease

SPINAL MUSCULAR ATROPHY osms.it/spinal-muscular-atrophy PATHOLOGY & CAUSES ▪ Genetically-mediated degenerative neurologic disease of childhood ▫ Lower motor neuron weakness, muscular atrophy ▪ Survival of motor neuron-1 (SMN1) lossof-function mutation → ↓ motor neuron survival → loss of alpha motor neurons (even in utero) → degeneration of anterior horn cells → denervated skeletal muscle → hypotonia, muscle atrophy

CAUSES SMN1 loss-of-function mutation ▪ Autosomal recessive ▪ Encoded on chromosome 5q ▪ Multiple physiologic roles ▫ Spliceosome assembly: ↓ nuclear expression of SMN1 in spinal muscular atrophy (SMA) ▫ Inhibition of caspase system: ↓ SMN1 expression → disinhibition of caspase → ↑ caspase expression → cellular apoptosis ▫ Unclear role in alpha motor neuron (patho)physiology

SMN2 pseudogene point mutation ▪ Encodes similar protein as SMN1 ▫ Difference: exon 7 (c.840C>T) ▫ ↑ susceptibility for protein degradation → ↓ functional protein at baseline ▪ SMN1 deficient → SMN2 responsible for SMN protein production → poor production of viable protein → motor neuron cell death ▫ Copy number variation correlates with clinical presentation

RISK FACTORS ▪ Family history

COMPLICATIONS

▪ Sleep disturbance ▪ Cardiac arrhythmias (esp. SMA 1, 2, 3) ▪ Restrictive respiratory disease (esp. SMA 0,1) ▫ Diaphragmatic involvement → respiratory collapse ▪ Dysphagia → aspiration → pneumonia ▪ Poor ambulation → delayed gastric emptying → gastrointestinal (GI) reflux, constipation

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SIGNS & SYMPTOMS ▪ Lower motor neuron signs ▫ Proximal limb severity (more common than distal), ↓ muscle strength, tone; ↓/absent DTRs, muscle atrophy, fasciculations

DIAGNOSIS OTHER DIAGNOSTICS

▪ Neurological ▫ Fasciculations; ↓ muscle strength, tone; DTRs ▪ Muscle testing ▫ EMG ▫ Abnormal spontaneous activity, fibrillations, positive sharp waves ▪ Muscle biopsy ▫ Large zones of severely atrophic myofibers ▫ Remaining innervated fibers → unchanged/hypertrophied size

Figure 82.2 A muscle biopsy demonstrating neurogenic atrophy as would be seen in motor neurone diseases like spinal muscular atrophy. Denervated muscle fiber bundles are small and atrophied whilst those that remain innervated retain their normal size.

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TREATMENT MEDICATIONS Experimental disease-modifying therapy ▪ Nusinersen ▫ Antisense oligonucleotide → binds SMN2 mRNA → ↓ exon 7 splicing → ↑ levels of functional SMN protein ▫ Limited effectiveness

OTHER INTERVENTIONS

▪ Pulmonary ▫ Secretion management → ↓ aspiration events → ↓ pneumonia ▫ Ventilator support (SMA 0,1) ▪ Nutrition, GI ▫ Manage food consistency → ↓ aspiration ▫ Gastrostomy tube placement in SMA 1 ▫ Encourage ambulation → ↓ gastric emptying time → ↓ constipation, GI reflux ▪ Orthopedic, musculoskeletal ▫ Physical therapy ▫ Spinal bracing → ↓ scoliosis → ↓ incidence of restrictive lung disease

Chapter 82 Motor Neuron Disease

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NOTES

NOTES

MOVEMENT DISORDERS GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Disorders causing abnormal movement ▫ Increased voluntary/involuntary movement (hyperkinetic disorders); reduced movement (hypokinetic disorders)

TYPES Acute fulminant episodes ▪ Reaction to trigger, medication (neuroleptic malignant syndrome) Benign chronic conditions ▪ Restless legs syndrome (RLS), essential tremor Progressive chronic syndromes ▪ Parkinson’s disease (PD), Friedreich’s ataxia

CAUSES

▪ Often idiopathic; genetic mutations, medication

SIGNS & SYMPTOMS ▪ Mild, unpleasant sensations, intention/ action tremors; rigidity, catatonia

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▪ Motor abnormality ▫ Hypokinesia: ↓ amplitude ▫ Bradykinesia: ↓ speed ▫ Dyskinesia: unwanted, characterized motor movement ▫ Tremor: rhythmic motor movement; resting, action, postural ▫ Rigidity: abnormal, uncoordinated muscle tone across joint

DIAGNOSIS OTHER DIAGNOSTICS

▪ Neurologic examination ▫ Observation of spontaneous movement, strength testing, tone evaluation, reflex exam

TREATMENT MEDICATIONS

▪ Beta blockers, anti-epileptics, benzodiazepines; dopamine replacement, agonists

OTHER INTERVENTIONS

▪ Avoid caffeine, nicotine, etc. ▪ Educational, supportive therapy

Chapter 83 Movement Disorders

ESSENTIAL TREMOR osms.it/essential-tremor PATHOLOGY & CAUSES ▪ Most common movement disorder; involuntary, rhythmic shaking ▪ Usually affects hands, fingers; sometimes head, vocal cords ▪ Action tremor (occurs during muscle effort) ▫ Postural/intention tremor

CAUSES

▪ Unknown; may be familial with autosomal dominant inheritance pattern

RISK FACTORS

▪ Meat consumption ▫ Exposure to heterocyclic amines (e.g. harmane, harmaline) ▪ Associated with dystonia (cervical, spasmodic, cranial dystonia, writer's cramp), parkinsonism

SIGNS & SYMPTOMS ▪ Rhythmic, symmetrical tremor ▫ Hands, head, vocal cords, neck, face, leg, tongue, trunk ▪ High frequency tremor (4–12Hz) exacerbated by muscle contraction ▪ Inability to perform precise tasks ▪ Intention tremor ▫ Intensifies upon touching nose with finger ▪ Postural tremor ▫ During outstretched arms ▪ Walking difficulties ▪ ↓ tremor with alcohol intake

DIAGNOSIS OTHER DIAGNOSTICS

▪ Postural/action tremor of hands/head; duration ≥ three year ▪ Alleviation with alcohol intake

Physical examination ▪ Fine postural, action tremor in hands, head/ voice ▪ Asymmetric/symmetric: cogwheel rigidity, resting tremor, dystonia (esp. head)

TREATMENT MEDICATIONS

▪ If disabling, symptomatic treatment ▫ Beta blockers ▫ Anti-epileptics ▫ Benzodiazepines ▫ Botulinum toxin (head tremors not responsive to medication)

OTHER INTERVENTONS ▪ Avoid caffeine, nicotine, etc. ▪ Get enough sleep

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FRIEDREICH'S ATAXIA osms.it/friedreichs-ataxia PATHOLOGY & CAUSES ▪ Genetic disorder; causes progressive central nervous system (CNS) damage, movement problems ▪ Predominantly affects CNS; also affects heart, pancreas ▪ ↓ frataxin → ↓ mitochondrial oxidative phosphorylation → cell damage, death ▪ ↓ frataxin → ↑ free iron → ↑ oxidative stress → cell damage, death ▪ Neuronal cell death affects posterior columns of spinal cord, distal corticospinal tracts, spinocerebellar tracts, brain stem, cerebellum ▪ Gene silencing → no frataxin synthesized → iron accumulates in cell, reacts with oxygen → unstable oxygen radicals → cell death

CAUSES

▪ Trinucleotide repeat GAA expansion (chromosome 9q13) → ↓ production of mitochondrial inner membrane protein, frataxin ▫ Autosomal recessive inheritance pattern ▫ ↑ repeats → ↑ severity, ↓ age of onset

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▫ 600–1200 trinucleotide repeats → Friedreich’s ataxia

COMPLICATIONS Progressive loss of cells ▪ In CNS, heart, pancreas ▪ Limb, gait ataxia → wheelchair bound → bedridden ▪ Dysphagia, dysarthria → aspiration → gastric bacteria insult to respiratory parenchyma ▪ Hypertrophic cardiomyopathy (secondary to myocardial cell death) ▫ Fibrosis → arrhythmia, hypertrophic cardiomyopathy → heart failure ▫ Most common cause of death in affected individuals (age 40–50) ▪ Diabetes mellitus ▫ Loss of beta cells of pancreas ▪ 25% of affected individuals ▪ Musculoskeletal abnormalities ▫ Muscle denervation → abnormal forces about joints → abnormalities ▪ Kyphoscoliosis ▫ Severe → ↓ total lung capacity → restrictive lung disease

Chapter 83 Movement Disorders ▪ Pes cavus ▫ Similar restrictive lung disease in severe cases ▪ Hammer toes

SIGNS & SYMPTOMS ▪ Ataxia ▫ Falling/staggering while walking, widebased gait ▫ Gait ataxia most common (age 0–10); most individuals progress to wheelchair dependence within 11–25 years ▪ Loss of vibratory sense, proprioception ▪ Muscle weakness, chest pain, dyspnea, heart palpitations, absence of tendon reflexes in legs, involuntary eye movements, action tremor, hand clumsiness, dysarthria, fatigue

DIAGNOSIS LAB RESULTS Genetic testing ▪ Confirms diagnosis ▪ GAA repeats; examine first intron in frataxin gene

OTHER DIAGNOSTICS

▪ Symptom progression, family history ▪ Neurological exam ▫ Ataxia (gait, hand); ↓ vibratory sensation, proprioception; ↓ deep tendon reflexes, nystagmus

Electromyogram ▪ Absent/reduced sensory nerve action potentials ▪ Normal/only slightly decreased motor nerve conduction velocities ▪ Abnormal auditory, visual, somatosensoryevoked responses

TREATMENT OTHER INTERVENTIONS

▪ Occupational, physical therapy ▫ Balance, ataxic progression ▪ Cardiology ▫ Annual electrocardiogram, echocardiogram ▪ Severe scoliosis ▫ Orthopedic referral ▪ Annual diabetes screening ▪ Genetic, psychological counseling services

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NEUROLEPTIC MALIGNANT SYNDROME osms.it/neuroleptic-malignant-syndrome PATHOLOGY & CAUSES ▪ Life-threatening idiosyncratic reaction to antipsychotic drugs; muscle rigidity, fever, altered mental status, autonomic dysfunction ▪ Dopamine blockade theory ▫ Central dopamine blockade → hypothalamus → hyperthermia, dysautonomia ▫ Nigrostriatal dopamine blockade → tremor, rigidity ▪ Peripheral muscle theory ▫ Direct toxic effect of neuroleptics → mitochondria of skeletal muscle → rigidity, fever ▪ Sympathetic nervous system theory ▫ ↓ dopamine inhibitors → ↑ sympathetic output ▫ ↑ sudomotor, vasomotor activity → fever

CAUSES Reaction to medications ▪ First-generation neuroleptic (most common) ▫ Haloperidol, fluphenazine, chlorpromazine ▪ Second-generation neuroleptic medication ▫ Clozapine, risperidone, olanzapine ▪ Antiemetic ▫ Metoclopramide, promethazine, droperidol ▪ Withdrawal of L-Dopa/dopamine agonist therapy (Parkinson disease)

RISK FACTORS

▪ Increase in dose/change of neuroleptic medication ▪ Abrupt cessation/reduction of dopaminergic medication

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▪ Lithium/alcohol/psychoactive substance use ▪ Previous episode of neuroleptic malignant syndrome ▪ Acute injury (e.g. trauma, surgery, infection) ▪ Psychiatric conditions (e.g. acute catatonia, severe agitation) ▪ Lewy body dementia

COMPLICATIONS

▪ Rhabdomyolysis, renal failure ▪ Seizures ▫ Due to hyperthermia, metabolic imbalances ▪ Encephalopathy, stupor, coma ▪ Cardiac arrhythmias (e.g. torsades de pointes, cardiac arrest) ▪ Disseminated intravascular coagulation

SIGNS & SYMPTOMS Altered mental status ▪ Agitated delirium with confusion (initial symptom); coma Muscular abnormalities ▪ Generalized muscular rigidity (“lead-pipe rigidity”) ▫ Associated dysphonia, dysarthria ▪ Catatonic signs ▪ Extrapyramidal symptoms ▫ Tremor, chorea, akinesia ▪ Less common ▫ Dystonic movements (e.g. opisthotonos, trismus, blepharospasm), mutism, dysarthria, dysphagia Hyperthermia ▪ Temperatures > 38–40°C/100.4–104°F

Chapter 83 Movement Disorders Autonomic dysfunction ▪ Tachycardia, labile/elevated blood pressure, tachypnea, sialorrhea, profuse diaphoresis (sweating), flushing, incontinence

DIAGNOSIS LAB RESULTS

▪ Severe ↑ creatine kinase (CK) ▫ Correlates with rigidity severity → 1–100k international units/L ▪ Mild ↑ lactate dehydrogenase, alkaline phosphatase, liver transaminases ▪ Electrolyte imbalances ▫ ↓ Ca2+, ↓ Mg2+, ↓ Na+/↑ Na+, ↑ K+, metabolic acidosis ▪ ↑ white blood cell count (leukocytosis) 10–40k ▪ Myoglobinuria ▪ ↓ serum iron concentration

OTHER DIAGNOSTICS

▪ Clinical presentation ▫ Altered mental status → hyperthermia, rigidity → autonomic dysfunction

TREATMENT MEDICATIONS

▪ Discontinue offending neuroleptic agent ▪ Dantrolene (skeletal muscle relaxant), bromocriptine (dopamine agonist); both (if severe) to reduce muscle rigidity, hyperthermia

OTHER INTERVENTIONS

▪ Maintain cardiorespiratory stability ▫ Intubation, mechanical ventilation ▪ Temperature reduction ▫ Cooling blankets, ice water gastric lavage, ice packs in axilla; acetaminophen/aspirin ▪ Correct fluid, electrolyte imbalance ▫ ↓ CK damage/accumulation; replete insensible losses from diaphoresis ▫ Benzodiazepines: ↓ uncontrollable agitations ▪ Electroconvulsive therapy ▫ If not responsive to medical therapy in first week; if severe/lethal catatonia

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PARKINSON'S DISEASE osms.it/parkinsons-disease PATHOLOGY & CAUSES ▪ Degeneration of dopaminergic neurons in substantia nigra → tremor, rigidity, akinesia, postural instability ▪ Most common neurological disorder; onset after age 50 ▪ Degeneration of neurons in substantia nigra → dopamine depletion from basal ganglia → disruption of connection to thalamus, motor cortex → Parkinsonism ▪ Exact mechanism unknown; build-up of abnormal proteins into Lewy bodies in neurons; accompanied by death of astrocytes, significant increase in microglia of substantia nigra ▪ Protein (e.g. alpha-synuclein) accumulation in neuron → abnormal intracellular transit → neuronal damage, death → motor symptoms ▫ Asymptomatic neuronal degeneration: brainstem (locus coeruleus) ▫ Symptomatic neuronal degeneration: basal ganglia; dopaminergic substantia nigra pars compacta neurons diseased, die → dennervate striatum → dysfunctional basal ganglia → hypo/ bradykinetic motor output ▫ Late degeneration: cerebral cortex; leads to cognitive impairment

CAUSES

▪ Usually idiopathic ▪ Mutation of PINK1, parkin, alpha synuclein genes ▪ Toxicity in recreational drug MPPP (synthetic opioid); rare

RISK FACTORS

▪ Family history, previous head injuries, pesticides exposure ▪ Protective factors ▫ Caffeine, nicotine

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COMPLICATIONS

▪ Freezing phenomenon ▫ Progressive hypokinesia, bradykinesia → (akinetic) pauses in movement; common when walking; tend to occur at thresholds (e.g. door frames) ▪ Falls ▫ Secondary to postural instability, poor movement amplitude ▪ Dystonia ▫ Abnormal tone across joints → disfiguring, painful posturing; universal flexion of joints → severely kyphotic posturing → poor ability to ambulate, ventilate ▪ Dementia ▫ Common after prolonged, primarily motor disease (in contrast to Lewy body dementia); psychosis, hallucinations (severe)

SIGNS & SYMPTOMS ▪ Psychiatric ▫ Depression, anxiety, mood disturbances; impairment of cognitive function, dementia (advanced stages) ▪ Sleep disturbances ▫ Wild dreams ▪ Autonomic dysfunction ▫ Orthostatic hypotension, constipation, increased sweating ▪ ↓ olfactory sense ▫ Common first symptom; history of ↓ / changed sense of taste, smell prior to motor symptoms ▪ Micrographia

Chapter 83 Movement Disorders MNEMONIC: TRAPS

Parkinson’s disease symptoms Tremor (resting tremor) Rigidity Akinesia Postural changes (stooped) Stare (serpentine stare)

DIAGNOSIS OTHER DIAGNOSTICS

▪ Clinical presentation ▫ Resting tremor, rigidity, bradykinesia ▫ Dopaminergic medication response ▪ Postmortem autopsy ▫ Loss of pigmented dopaminergic neurons of substantia nigra pars compacta ▫ Lewy bodies (intracytoplasmic eosinophilic inclusions), neurites

TREATMENT MEDICATIONS

▪ Symptomatic treatment; see mnemonic

MNEMONIC: SALAD

Common Parkinsonism treatments Selegiline Anticholinergics: trihexyphenidyl, benzhexol, orphenadrine L-Dopa + peripheral decarboxylase inhibitor: carbidopa, benserazide Amantadine Dopamine postsynaptic receptor agonists: bromocriptine, lisuride, pergolide Dopamine replacement ▪ Precursor to dopamine → ↑ dopamine synthesis → ↑ synaptic dopamine → ↓ motor symptoms ▪ Commonly formulated with carbidopa (peripheral decarboxylase inhibitor) ▫ Carbidopa-mediated inhibition of liver, systemic carboxylation → levodopa cross blood brain barrier (BBB) → ↑ dopamine formation ▪ Adverse effects ▫ On/off phenomena: return of symptoms prior to next dose; due to half life of levodopa (approx. 90 minutes) ▫ Dyskinesia, dystonia: abnormal, repetitive movement (dyskinesia), abnormal sustained muscle contraction (dystonia); head, neck (e.g. tardive dyskinesia of tongue, cervical torticollis); ↑ incidence with ↑ dosing, duration of disease ▫ Neuroleptic malignant syndrome: when discontinued abruptly/high, multiple doses missed Dopamine agonists ▪ ↑ dopaminergic stimulation of postsynaptic receptors → ↓ motor symptoms ▪ Adverse effects ▫ Dyskinesia ▫ Impulse control disorder: ↑ risk-taking behavior (e.g. pathologic gambling; compulsive sexual behavior, shopping)

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Monoamine oxidase B (MAO-B) inhibitors ▪ ↓ MAO-B-related dopamine metabolism → ↑ synaptic dopamine → ↓ motor symptoms ▪ Most effective for mild-moderate symptoms Anticholinergic ▪ Improves neurochemical imbalance in basal ganglia ▪ Most useful in young (< 70) individuals with tremor as primary symptom; less useful for rigidity, bradykinesia ▪ Anticholinergic side effects common Amantadine ▪ Antiviral drug ▫ Known NMDA receptor agonist; ↓ neurotransmitter imbalance i ▪ Most useful in mild disease

SURGERY

▪ Deep brain stimulation (DBS) ▫ Direct neural stimulation of basal ganglia (either subthalamic nucleus of globus pallidus interna) → ↑ motor output of basal ganglia → ↓ motor symptoms ▫ Severe/medication nonresponsive disease

OTHER INTERVENTIONS

▪ Education, support ▫ Physical, emotional aspect of degenerative, debilitating disease ▪ Physical therapy ▫ Exercise → ↓ incidence of falls

Catechol-O-methyltransferase (COMT) inhibitors ▪ ↓ dopamine, levodopa metabolism → ↑ synaptic dopamine → ↓ motor symptoms ▪ Rarely used as monotherapy

RESTLESS LEG SYNDROME osms.it/restless-legs-syndrome PATHOLOGY & CAUSES ▪ Uncontrollable urge to move legs, relieved by movement ▪ Affects legs, feet bilaterally; less commonly affects arms

CAUSES

▪ Unknown ▪ CNS ▫ ↓ iron, dopamine ▪ Peripheral nervous system ▫ Abnormal A fibers, peripheral nerve microvasculature

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TYPES Primary RLS ▪ Idiopathic; runs in families; onset < 45 years old; progressive, worsens over time Secondary RLS ▪ Associated with underlying medical conditions, medications; onset > 45 years

RISK FACTORS

▪ Pregnancy, iron deficiency/anemia, smoking, caffeine, Parkinson’s disease, family history, renal failure, obesity ▪ Peripheral neuropathy (due to diabetes, alcoholism, rheumatoid arthritis, etc.)

Chapter 83 Movement Disorders ▪ Medications ▫ Antidepressants, antiemetics, antipsychotics, antihistamines, calcium channel blockers ▪ More common in individuals who are biologically female

COMPLICATIONS

▪ Insomnia → daytime drowsiness

SIGNS & SYMPTOMS ▪ Strong urge to move legs while resting; unpleasant sensations (e.g. tingling, burning, crawling, itching, aching) ▪ Relief by movement; worsening of symptoms in evening/night → insomnia ▪ Nighttime leg twitching while asleep Aggravating factors ▪ Antihistamines ▫ Commonly used for sleep assistance ▪ Dopamine antagonists ▪ Psychiatric medications ▫ Selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs)

TREATMENT MEDICATIONS

▪ If other interventions not effective ▪ Dopamine agonists (e.g. pramipexole, ropinirole) ▪ Alpha-2-delta calcium channel ligands (e.g. pregabalin, gabapentin) ▪ Benzodiazepine ▫ Individuals with intermittent symptoms ▪ Iron replacement ▫ ↓ symptom severity when low (< 75ng/ ml) serum iron levels repleted

OTHER INTERVENTIONS

▪ Lifestyle changes ▫ Avoid aggravating factors/situations, ↓ caffeine intake ▪ Mental alert activities ▫ Distract individual in times of symptoms

DIAGNOSIS OTHER DIAGNOSTICS Clinical Presentation ▪ Urge to move limbs with/without unpleasant sensations ▪ Improvement with activity ▪ Worsening at rest/in evening

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NOTES

NOTES

NEUROCUTANEOUS DISORDERS

GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Various disorders, primarily affecting skin, nervous system ▫ Characterized by inherited/de novo tumor suppressor gene mutations → ↑ tumor formation incidence ▪ Tumor suppressor gene mutation → abnormal/absent protein → loss of control over important cell cycle regulators; cell growth, proliferation; intercellular communication → tumor formation

DIAGNOSIS DIAGNOSTIC IMAGING MRI, CT scan ▪ See individual disorders

LAB RESULTS

▪ Genome testing

OTHER DIAGNOSTICS ▪ Eye examination

RISK FACTORS

TREATMENT

▪ Parents with germline mutation

SIGNS & SYMPTOMS ▪ Various neurologic signs (lesion sitedependent) ▪ Eye, visual problems ▪ Mental, cognitive problems ▪ Skin lesions ▪ Benign, malignant nervous/other organsystem tumors

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SURGERY

▪ See individual disorders

OTHER INTERVENTIONS

▪ No current underlying mutation treatment ▪ Surveillance ▪ Symptom management

Chapter 84 Neurocutaneous Disorders

ATAXIA-TELANGIECTASIA osms.it/ataxia-telangiectasia PATHOLOGY & CAUSES ▪ Rare autosomal recessive disorder ▫ Involves defective DNA repair ▫ Characterized by progressive neurological abnormalities, most noticeably ataxia, oculocutaneous telangiectasias (superficial, dilated blood vessels of skin), immune deficiency, malignancy ▪ Mutation in ataxia-telangiectasia mutated (ATM) gene on chromosome 11; believed to be DNA surveillance (looks for damage → stops cell cycle to repair it/activates apoptosis) Abnormal ATM protein ▪ Unable to phosphorylate ▫ Tumor suppressor protein p53 → cell-cycle slowing/apoptosis absence → DNA repairing absence → mutation accumulation → malignant transformation → ↑ cell susceptibility to ionizing radiation ▫ Tumor suppressor BRCA1 → ↑ breast cancer susceptibility ▫ eIF-4E binding protein 1 controls protein synthesis when insulin present → probable cause of insulin resistance, disturbed growth ▪ Loses ribonucleotide reductase control → abnormal mitochondrial DNA synthesis, repair → probable cause of neurodegeneration, premature aging ▪ → chromosomal translocation, lymphocyte inversion → ↑ tendency of leukemias, lymphomas Histology ▪ Central nervous system (CNS) ▫ Brain atrophy, Purkinje cell loss in cerebellum (contributes to ataxia) ▪ Peripheral nervous system (PNS) ▫ Malformed nuclei in Schwann cells

▪ Thymus hypoplastic ▫ Fewer lymphocytes, Hassall’s corpuscle absence

COMPLICATIONS

▪ Dysphagia → aspiration ▪ Pulmonary disease (chronic infection, restrictive interstitial lung disease) ▪ Malignancies ▪ Infection (due to T cell deficiency, inability to produce some antibodies, etc.)

SIGNS & SYMPTOMS ▪ Telangiectasias (blood vessel dilation in skin of face, neck, bulbar conjunctiva) ▪ Skin lesions (e.g. café au lait spots—flat, lightly-brown pigmented birthmarks) ▪ Immune deficiency in cellular, humoral immunity Neurologic ▪ Abnormal gait, stance ▪ Ataxia (tremors, lack of voluntary coordinated movement) ▪ Dystonia (muscle contractions → repetitive movement/abnormal posture) ▪ Oculomotor apraxia (inability to coordinate head, eye movements) ▪ Nystagmus, acquired strabismus, reading problems ▪ Problems with speaking, chewing, swallowing can → aspiration ▪ Cognitive impairment Pulmonary disease ▪ Respiratory muscles weakness ▪ Aspiration ▪ Interstitial lung disease

OSMOSIS.ORG 649

DIAGNOSIS ▪ Neurological symptom presence (e.g. progressive cerebellar ataxia)

LAB RESULTS

▪ Genetic testing ▫ Mutation identification in both ATM gene copies ▪ Laboratory studies ▫ ↑ alpha-fetoprotein in serum ▫ ↓ ATM protein ▫ ↓ immunoglobulins in serum (usually IgA, IgG) ▫ Cell culture exposed to radiation (e.g. X-ray) → ↑ cell, chromosomal breakage

Figure 84.1 An ocular telangiectasia in an individual with ataxia telangiectasia.

TREATMENT OTHER INTERVENTIONS

▪ Occupational, physical therapy (functional deficits) ▪ Monitor, treat main mortality causes ▫ Infections, dysphagia, pulmonary disease, malignancy

NEUROFIBROMATOSIS TYPE I (NF1) osms.it/neurofibromatosis-type-i PATHOLOGY & CAUSES ▪ Rare autosomal dominant disorder ▫ Characterized by ↑ tumor incidence ▫ AKA von Recklinghausen disease, NFI ▪ Mutation in neurofibromin 1 gene (NF1) on chromosome 17 → abnormal/absent neurofibromin 1 protein (usually acts as tumor suppressor) → unable to control RAS pathway (stays trapped in active form) → loss of cell growth, division control

TYPES

▪ Small mutations in one NF1 gene copy → mild phenotypes

650 OSMOSIS.ORG

▪ Deletion of one NF1 gene → more severe phenotypes ▪ New mutation appearing in postzygotic stage → some cells have normal NF1 genes, some have mutations → segmental neurofibromatosis ▪ Both NF1 genes mutated → complete NF1 protein production loss

COMPLICATIONS

▪ Cognitive/learning disability, seizure, hypertension

Chapter 84 Neurocutaneous Disorders

SIGNS & SYMPTOMS ▪ ≥ six café au lait macules Freckling ▪ Similar to cafe au lait macules but smaller, appearing later in groups with tendency for inguinal, axillary region Lisch nodules (NF1-specific) ▪ Lifted tan-colored iris hamartomas Neurofibromas ▪ Peripheral ▫ Benign peripheral nerve sheath tumors; consist of many cells (primarily Schwann cells) ▫ Location: skin, along nerve, nerve root next to spine ▪ Plexiform (leading morbidity cause) ▫ Superficial, deep/mixed nerve overgrowth ▫ Can compress adjacent structures (e.g. airways), invade surrounding tissue, become malignant ▪ Nodular ▫ Superficial/deep hard lesions ▫ Usually not invading tissue but can become malignant Optic pathway glioma (OPG) ▪ Proptosis, visual problems Malignant peripheral nerve sheath tumor (MPNST) ▪ Swelling in extremity; pain; numbness, burning sensation; extremity movement difficulty Neurologic manifestations ▪ Speech, language delays; attention deficit hyperactivity disorder (ADHD) Bone abnormalities ▪ Long bone dysplasia (anterolateral bowing) ▫ Narrowed medullary canal, cortical thickening, pathologic fractures ▪ Pseudoarthrosis ▫ Fake joint forming at previous fracture site ▪ Scoliosis; osteoporosis ▪ Short stature

Figure 84.2 Lisch nodules in the iris of an individual with neurofibromatosis. Hamartomata of the iris constitute part of the diagnostic criteria for neurofibromatosis.

DIAGNOSIS DIAGNOSTIC IMAGING MRI ▪ Bright spots (areas of ↑ signals in T2 imaging) Neuroimaging ▪ Megalencephaly (↑ brain volume)

LAB RESULTS

▪ Genetic testing (diagnosis confirmation)

OTHER DIAGNOSTICS

▪ Clinically ▫ Neurology, genetics, ophthalmology evaluation ▫ Parent, sibling history, examination helpful ▪ At least two following features needed for diagnosis ▫ ≥ six café au lait macules ▫ ≥ two neurofibromas ▫ Freckling ▫ Optic glioma ▫ ≥ two Lisch nodules ▫ Characteristic bony lesion ▫ First-degree relative diagnosed with NF1

OSMOSIS.ORG 651

treatment → volume shrinkage MPNSTs / OPGs ▪ Chemotherapy Neurologic abnormalities ▪ Stimulants

SURGERY Mass effect tumors ▪ Surgical removal Figure 84.3 Numerous cutaneous neurofibromata on the skin of an individual with type I neurofibromatosis.

MPNSTs ▪ Surgical excision with radiation therapy

PSYCHOTHERAPY

TREATMENT MEDICATIONS Mass effect tumors ▪ Selumetinib ▫ MEK 1/2 inhibitor; orphan drug for NF1

Neurologic abnormalities ▪ Speech, occupational therapy

OTHER INTERVENTIONS ▪ Orthopedic interventions

Neurologic abnormalities ▪ Physical therapy

NEUROFIBROMATOSIS TYPE II (NF2) osms.it/neurofibromatosis-type-ii PATHOLOGY & CAUSES ▪ Uncommon autosomal dominant disorder ▫ Characterized by ↑ neural tumor incidence (schwannomas, meningiomas) ▪ Mutations in neurofibromin 2 (NF2) gene on chromosome 22 → abnormal NF2 protein (i.e. merlin) ▫ Cell membrane protein acts as tumor suppressor → loss of contact inhibition (likely) → ↑ tumor development risk ▪ Usually appears in young adulthood

652 OSMOSIS.ORG

TYPES

▪ Phenotype is mutation type-dependent ▫ Nonsense, frameshift → severe phenotypes ▫ Missense, inframe deletions → mild phenotypes

COMPLICATIONS ▪ ▪ ▪ ▪ ▪

Vestibular schwannoma Meningiomas (intracranial, spinal) Neuropathies (facial, polyneuropathy) Gliomas Eye lesions (e.g. cataracts, retinal hamartomas)

Chapter 84 Neurocutaneous Disorders ▪ Other non-neoplastic lesions (e.g. meningioangiomatosis—benign leptomeninges lesions with good vascularization) ▪ Visual impairment

DIAGNOSIS DIAGNOSTIC IMAGING MRI ▪ Nervous system ▫ For individuals with first-grade relatives diagnosed with NF2

LAB RESULTS

▪ Molecular testing for mutation ▫ For individuals with first-grade relatives diagnosed with NF2

OTHER DIAGNOSTICS

Figure 84.4 An MRI scan of the head in the axial plane demonstrating bilateral acoustic Schwannomas in an individual with type II neurofibromatosis.

SIGNS & SYMPTOMS ▪ Skin lesions (cutaneous, subcutaneous tumors) Neurologic disorders ▪ Vestibular schwannomas (may be bilateral) ▫ Progressive hearing loss, balance problems, tinnitus ▪ Meningiomas ▫ Extremity weakness, double vision, incontinence, seizure ▪ Gliomas ▫ Headache, vomiting, visual loss ▪ Spinal tumors ▫ Muscle pain, weakness; paresthesias

▪ At least one of following needed ▫ Bilateral vestibular schwannomas < 70 years old ▫ Unilateral vestibular schwannoma < 70 years of age + first degree relative with NF2 ▫ Neurofibroma, meningioma, glioma, non-vestibular schwannoma, cataract or cerebral calcifications + first degree relative with NF2/unilateral vestibular schwannoma without schwannomatosis gene mutations ▫ Multiple meningiomas + unilateral vestibular schwannoma/two of neurofibroma, glioma, cerebral calcification, cataract, non-vestibular schwannoma ▫ NF2 gene mutation from blood/detecting same mutation in two different tumors ▪ Skin, eye examination ▫ For individuals with first-grade relatives diagnosed with NF2

OSMOSIS.ORG 653

TREATMENT MEDICATIONS

▪ Monoclonal antibodies against vascular endothelial growth factor (VEGF) → hearing improvement, tumor shrinkage

SURGERY

▪ Removal ▫ Vestibular schwannomas; meningioma (surveillance until symptomatic)

OTHER INTERVENTIONS

▪ Stereotactic radiosurgery, radiotherapy ▫ Vestibular schwannomas; meningioma (surveillance until symptomatic)

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Figure 84.5 An MRI scan of the head in the axial plane demonstrating bilateral acoustic Schwannomas in an individual with type II neurofibromatosis.

Chapter 84 Neurocutaneous Disorders

STURGE–WEBER SYNDROME osms.it/sturge-Weber-syndrome PATHOLOGY & CAUSES ▪ Uncommon congenital disorder affecting blood vessels on face, brain, eyes ▪ GNAQ gene mutation → abnormal guanine nucleotide binding protein → loss of some intracellular signal pathway control → capillary angiomatosis development → hypoxia, venous stasis, thrombosis (probable tissue damage cause) ▪ Mutation occurrence ▫ Early embryogenesis stages → probably affect more vascular cell precursors → Sturge–Weber syndrome (SWS) ▫ Later embryogenesis stages → believed to affect endothelial cell precursors → nonsyndromic port wine stains (malformed facial capillaries)

COMPLICATIONS

▪ Intellectual disability ▪ Hydrocephalus (probably due to venous stasis, thrombosis) ▪ Glaucoma (↑ intraocular pressure)

SIGNS & SYMPTOMS Port wine stain ▪ Newborns ▫ Flat pink lesions ▪ Grows bulging out, turns to red wine color as individual ages ▪ Dilated blood vessels injury-prone → superficial bleeding → hypertrophy, nodularity ▪ Usually appears on forehead, upper eyelids

Seizures (epilepsy) ▪ Affect young children ▪ Usually start as focal → become generalized Hemiparesis ▪ Affects extremities contralateral to brain lesion ▪ ↓ motor function Ophthalmologic problems ▪ Visual defects when brain’s occipital region affected ▪ Choroid hemangiomas → ↑ intraocular pressure ▪ Episcleral, conjunctival hemangiomas Endocrine problems ▪ Growth hormone deficiency ▪ Central hypothyroidism

DIAGNOSIS DIAGNOSTIC IMAGING MRI ▪ Contrast enhancement ▪ Presence, position, range of malformed capillaries, veins CT scan ▪ Calcifications

OTHER DIAGNOSTICS

▪ Characteristic neurologic, ophthalmic, skin manifestations

Leptomeningeal vascular malformation ▪ Big malformed intracerebral veins, usually drain in deep venous system ▪ Venous stasis → chronic ischemia → atrophied brain parenchyma, calcific deposits

OSMOSIS.ORG 655

TREATMENT MEDICATIONS

▪ Antithrombotic therapy ▪ Topical medications ▫ Managing intraocular pressure ▪ Anticonvulsants ▫ Manage seizure

SURGERY

▪ Epileptogenic tissue removal ▫ Manage seizure ▪ Hemispherectomy (disabling half of brain) ▫ Manage seizure

OTHER INTERVENTIONS

▪ Photothermolysis (laser produced heat) ▫ Skin lesions

Figure 84.6 A CT scan of the head in the axial plane of an individual with SturgeWeber syndrome. There is calcification and volume loss of the cerebral cortex on the right side.

TUBEROUS SCLEROSIS osms.it/tuberous-sclerosis PATHOLOGY & CAUSES ▪ Autosomal dominant disorder ▫ Characterized by hamartoma, benign neoplasm development involving many organ systems ▪ Mutation in one/both genes ▫ TSC1 on chromosome 9 → abnormal/ absent hamartin ▫ TSC2 on chromosome 16 (more commonly mutated) → abnormal/absent tuberin ▪ Abnormal hamartin, tuberin can not form/ form inactive complex → control loss over kinase mechanistic target of rapamycin (mTOR) ▫ Anabolic metabolism, cell size regulator → giant-cell tumors

656 OSMOSIS.ORG

▪ Mutation range-dependent ▫ One copy mutated → cortical, subependymal tubers ▫ Both copies mutated → subependymal giant-cell astrocytomas ▪ ↑ malignancy risk

COMPLICATIONS ▪ ▪ ▪ ▪ ▪

Seizure (leading morbidity cause) Autism spectrum disorders Intellectual disability Pneumonia Heart, renal failure

Chapter 84 Neurocutaneous Disorders

SIGNS & SYMPTOMS Skin lesions ▪ Ash-leaf spots (hypomelanotic macules) ▪ Angiofibromas on cheeks ▪ Ungual fibromas (small tumors growing under nails) ▪ Shagreen patches (thick, pigmented, dimpled skin lesion usually on lower back) ▪ Characteristic brown plaques on infant forehead Brain lesions ▪ Glioneuronal hamartomas, subependymal nodules ▫ Seizure, intellectual disability ▪ Subependymal giant-cell tumors ▫ Hydrocephalus → headaches, vomiting, visual problems, depression, appetite loss ▪ White matter lesions Cardiovascular lesions ▪ Cardiac rhabdomyoma (benign heart tumor) ▫ Blood flow obstruction, cardiac murmurs Renal lesions (angiomyolipomas) ▪ Pain, irregular renal function

LAB RESULTS Genetic testing ▪ Mutation identification in TSC1/TSC2 genes of healthy tissue cells ▫ Can establish diagnosis without clinical manifestation ▪ Clinically uncertain diagnosis confirmation ▪ Prenatal diagnosis

OTHER DIAGNOSTICS

▪ Presents with at least two major symptoms ▪ Presents with one major, two/more minor symptoms ▫ “Confetti” skin lesions (small hypomelanotic macules) ▫ ≥ three dental enamel pits ▫ ≥ two intraoral fibromas ▫ Retinal achromic patch ▫ Multiple renal cysts ▫ Nonrenal hamartomas ▪ Full parental evaluation once child diagnosed ▪ Skin, neurologic, ophthalmic examination ▪ Vogt triad ▫ Seizure, facial angiofibroma, intellectual disability

Pulmonary lesions ▪ Diffuse interstitial fibrosis/ lymphangioleiomyomatosis (systemic disease → cystic lung destruction) ▫ Dyspnea, pneumothorax Ophthalmic lesions ▪ Retinal hamartomas (flat, translucent lesions); eyelid angiofibromas

DIAGNOSIS DIAGNOSTIC IMAGING

Figure 84.7 Numerous facial angiofibromas in an individual with tuberous sclerosis.

MRI ▪ With, without contrast enhancement ▫ Cortical glial hamartomas ▫ Subependymal nodules/giant-cell tumor ▫ White matter lesions ▫ Renal angiomyolipomas/cysts

OSMOSIS.ORG 657

TREATMENT MEDICATIONS Seizure management, monitoring ▪ Infantile seizures: corticotropin (ACTH)/ vigabatrin ▪ Partial seizures: many drugs (such as oxcarbazepine) ▪ Refractory epilepsy ▫ Everolimus (mTOR inhibitor) Tumor management ▪ Medical therapy (e.g. everolimus)

SURGERY Seizure management, monitoring ▪ Refractory epilepsy ▫ Epilepsy surgery Tumor management ▪ Surgical removal if possible ▪ Angiomyolipoma embolization

Lungs ▪ Lung transplantation

PSYCHOTHERAPY Cognitive, behavioral problems ▪ Special needs educational programs ▪ Occupational therapy ▪ Social support ▪ Psychiatric therapy

OTHER INTERVENTIONS Seizure management, monitoring ▪ Refractory epilepsy ▫ Ketogenic diet ▫ Vagus nerve stimulation Skin lesions ▪ Sun protection ▪ Laser therapy ▪ Dermabrasion (wearing away of skin) Lungs ▪ Pleurodesis ▫ Adhesion of two pleurae → pneumothorax prevention

VON HIPPEL–LINDAU DISEASE osms.it/von-hippel-lindau PATHOLOGY & CAUSES ▪ Autosomal dominant disorder ▫ Characterized by formation of many different benign, malignant tumors (hemangioblastomas, renal cell carcinoma, pheochromocytoma) ▪ Mutation affects von Hippel–Lindau (VHL) tumor suppressor gene on chromosome 3 → abnormal VHL protein ▫ Lost ability to deactivate hypoxia induced factor 1 alpha (HIF1A), 2 alpha (HIF2A) → HIF1A starts continuously producing erythropoietin while HIF2A produces VEGF → cellular metabolism,

658 OSMOSIS.ORG

growth dysregulation → highly vascular tumor formation ▫ Cilia centrosome, microtubules dysregulation → cyst formation in pancreas, liver, kidneys ▫ Dysregulation of extracellular matrix → malignant behavior ▪ Affected people usually have one inherited mutated allele but development requires other allele mutation/deletion/inactivation

TYPES

▪ Two types of VHL disease (based on pheochromocytoma development risk)

Chapter 84 Neurocutaneous Disorders Type 1 ▪ ↓ risk ▪ Usually associated with large deletions, frameshift, nonsense mutations Type 2 ▪ ↑ risk ▪ Usually associated with missense mutations

SIGNS & SYMPTOMS Hemangioblastomas ▪ Usually affect cerebellum, spinal cord, retina ▫ Benign, well defined tumors ▫ Highly vascular ▫ Can pressure adjacent structures/bleed Retinal capillary hemangioblastomas ▪ Visual loss ▪ Retinal detachment ▪ Glaucoma Renal cell carcinomas (RCC) ▪ Haematuria ▪ Flank pain (between ribs, hips) ▪ Abdominal mass Pheochromocytomas ▪ Headaches ▪ High blood pressure, ↑ heart rate ▪ Skin sensations Pancreatic tumors ▪ Usually asymptomatic ▫ Epigastric pain ▫ Diarrhea Endolymphatic sac tumors of middle ear (ELSTs) ▪ Hearing loss ▪ Tinnitus ▪ Vertigo

DIAGNOSIS DIAGNOSTIC IMAGING CT scan ▪ Tumor visualization ▪ ELSTs ▫ Retrolabyrinthine calcifications MRI ▪ Tumor visualization ▪ ELSTs ▫ Hyperintense T1, heterogeneous T2 focal signals

LAB RESULTS

▪ Pheochromocytomas ▫ Serum testing: ↑ normetanephrine to metanephrine ratio ▪ Genome testing ▫ Southern blotting ▫ Genome sequencing ▪ Prenatal diagnosis ▫ Amniocentesis ▫ Chorionic villus sampling

OTHER DIAGNOSTICS ▪ Retinal examination ▪ ELSTs ▫ Auditory tests ▪ Genetic counseling

TREATMENT MEDICATIONS

▪ Pheochromocytomas ▫ Alpha-adrenergic blockade

SURGERY

▪ CNS hemangioblastomas, pancreatic tumors, ELSTs ▫ Removal (when symptomatic) ▫ Cochlear implants: individuals with hearing loss

OSMOSIS.ORG 659

▪ RCC ▫ Partial nephrectomy ▪ Pheochromocytomas ▫ Removal

OTHER INTERVENTIONS

▪ CNS hemangioblastomas, pancreatic tumors, ELSTs ▫ Stereotactic radiosurgery, radiation therapy

660 OSMOSIS.ORG

▪ Retinal capillary hemangioblastomas ▫ Laser photocoagulation ▫ Cryotherapy ▪ RCC ▫ Cryotherapy ▫ Radiofrequency ablation ▪ Pheochromocytomas ▫ Catecholamines production surveillance

NOTES

NOTES

NEUROMUSCULAR JUNCTION DISEASES

GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Disorders impairing neuromuscular transmission lead to muscle fatigability, weakness

CAUSES

▪ Autoantibody production ▫ Targeted against neuromuscular transmission pathway proteins ▪ Myasthenia gravis (MG) ▪ Lambert–Eaton myasthenic syndrome (LEMS) ▪ Transient acquired neonatal myasthenia ▪ Genetic mutation ▫ Affecting pathway components (e.g., congenital myasthenia)

COMPLICATIONS

▪ Respiratory muscles involved → potentially fatal respiratory failure

SIGNS & SYMPTOMS ▪ Primary clinical manifestation ▫ Painless muscle weakness without significant muscle atrophy ▫ Ocular, extraocular, oropharyngeal, bulbar, neck, limb, respiratory muscles

DIAGNOSIS DIAGNOSTIC IMAGING CT scan ▪ Thymoma (MG) ▪ Small-cell lung carcinoma (LEMS)

LAB RESULTS

▪ Serologic test for specific antibodies

OTHER DIAGNOSTICS Electrophysiologic study ▪ Repetitive nerve stimulation ▫ Decremental response/improvement ▪ Electromyogram ▫ ↓ muscle action potential Pulmonary function test (PFT) ▪ Periodically ▫ Detect respiratory muscle involvement in forced vital capacity (FVC) ↓

TREATMENT ▪ Treat underlying cause (e.g. LEMS malignancy)

MEDICATIONS

▪ Acetylcholinesterase inhibitors ▫ Inhibit acetylcholine degradation → ↑ acetylcholine concentration in neuromuscular junction (symptomatic therapy) ▪ Immunomodulating agents ▫ ↓ autoantibody production ▫ Individuals with poor acetylcholinesterase inhibitor response ▫ Corticosteroids/other immunosuppressive agents ▪ If above fails/emergency (e.g., myasthenic crisis) ▫ Plasmapheresis/intravenous immunoglobulin (IVIG)

OSMOSIS.ORG 661

LAMBERT–EATON MYASTHENIC SYNDROME (LEMS) osms.it/lambert-eaton-myasthenic PATHOLOGY & CAUSES ▪ Rare autoimmune disorder ▫ Autoantibodies inhibit presynaptic calcium channels on motor neurons → reduced acetylcholine release in neuromuscular junction ▪ Muscle weakness ▫ Improves temporarily after repeated muscle use (no significant muscle atrophy) ▪ Mostly affects somatic nervous system, can also affect autonomic nervous system’s parasympathetic part ▪ Middle-aged adults (most cases)

CAUSES Type II hypersensitivity reaction ▪ B cells produce antibodies that target, block voltage-gated calcium channels located presynaptically on motor neurons → only few unbound channels available to open, allow calcium in → ↓ calcium within neuron (insufficient to trigger acetylcholine release) → ↓ acetylcholine release in neuromuscular junction → attached muscle fiber does not contract ▪ Repeated stimulation by brain’s electrical impulses → enough calcium might get through remaining unbound calcium channels → acetylcholine release → muscle contraction

RISK FACTORS

▪ Malignancy ▫ Strong small-cell lung cancer association; stimulus for antibody production is same calcium channel expression in neoplastic cells ▫ Other associated malignancies include

662 OSMOSIS.ORG

lymphoproliferative disorders (e.g., Hodgkin’s lymphoma) ▪ Autoimmune diseases ▫ Hashimoto’s thyroiditis, diabetes mellitus type 1, vitiligo

COMPLICATIONS

▪ Respiratory muscle involvement → respiratory failure ▪ Underlying malignancy → can lead to death

SIGNS & SYMPTOMS ▪ Progressive, symmetrical proximal muscle weakness (e.g., shoulders, hips, thighs) → difficulty climbing stairs/standing when seated ▫ Paraneoplastic LEMS: more rapidly progressive course ▪ Warming-up phenomenon ▫ Repeated muscle use → weakness temporarily relieved ▪ Reflex strength ↓ ▫ Muscle activation → reflex recovery/ improvement ▪ Small minority ▫ Ocular, oropharyngeal muscle involvement ▪ Advanced stages ▫ Possible respiratory muscles involvement → respiratory failure (myasthenic crisis) ▪ Autonomic symptoms ▫ Dry mouth (most common), constipation, blurry vision, erectile dysfunction, urinary problems, syncope

Chapter 85 Neuromuscular Junction Disorders

DIAGNOSIS DIAGNOSTIC IMAGING CT scan ▪ Chest ▫ Detect underlying small-cell lung cancer ▪ Abdomen, pelvis also recommended ▪ Negative initial malignancy evaluation ▫ Periodical screening recommended

LAB RESULTS

▪ Serological tests ▫ Detect antibodies against the voltagegated calcium channels

OTHER DIAGNOSTICS

▪ Electrophysiologic studies ▫ Repetitive nerve stimulation: ↑ muscle action potential amplitude ▫ Electromyogram: ↑ muscle action potential amplitude after exercise ▪ PFT ▫ ↓ FVC → respiratory muscle involvement

TREATMENT MEDICATIONS

▪ Symptomatic therapy ▫ Acetylcholinesterase inhibitors: minimal effect ▫ Aminopyridines: block potassium channels → prolonged nerve membrane depolarization → ↑ calcium entry → ↑ acetylcholine release in neuromuscular junction ▪ If above methods fail ▫ Immunomodulating agents can be used (corticosteroids, other immunosuppressive agents)

OTHER INTERVENTIONS

▪ Occasionally treated with IVIG/ plasmapheresis ▫ More severe cases

MYASTHENIA GRAVIS osms.it/myasthenia-gravis PATHOLOGY & CAUSES ▪ Autoimmune disorder; significant skeletal muscle weakness ▫ Decreased acetylcholine receptor function → worsens with muscle use ▫ Most common neuromuscular junction disorder ▪ Type II hypersensitivity reaction ▫ B cells produce antibodies against postsynaptic nicotinic acetylcholine receptors of neuromuscular junction/ receptor-associated proteins ▫ Autoantibodies targeted against muscle-specific receptor tyrosine kinase

▪ ▪

▪

▪

(MuSK) → ↓ in acetylcholine receptor function Acetylcholine cannot bind → normal action potentials cannot be generated (adjacent muscle Complement activated → inflammatory response initiation → postsynaptic membrane damage → acetylcholine receptor destruction Bimodal onset age ▫ 20–30 years old (biologically-female predominance) ▫ 60–70 years old (biologically-male predominance) Associated with thymic abnormality; thymus considered antigen source

OSMOSIS.ORG 663

promoting autoantibody production (most cases) ▪ Neonatal myasthenia gravis ▫ Transient myasthenia form (newborn from individual with myasthenia gravis) ▫ Maternal antibodies → transplacental passage → neuromuscular junction function interference ▪ Rare non-immune mediated forms ▫ E.g. congenital myasthenia gravis ▫ Mutations affecting neuromuscular transmission

COMPLICATIONS

▪ Myasthenic crisis ▫ Decreased respiratory muscle function → life-threatening respiratory failure (requires mechanical ventilation) ▫ Occurs spontaneously/precipitated (e.g. surgery, infection, medication, immunosuppressive-agent withdrawal)

SIGNS & SYMPTOMS ▪ Fluctuating muscle weakness ▫ Exacerbated by repetitive muscle use throughout day/after exertion/repetitive movement ▪ Improves with rest ▪ Progression ▫ Symptoms continuously present, fluctuate from mild–severe ▪ Sensation, reflexes preserved Clinical MG forms ▪ Ocular myasthenia ▫ Limited (eyelid, extraocular muscle); individuals (50%) with ocular myasthenia will → generalized myasthenia (< two years) ▪ Generalized myasthenia ▫ Ocular, bulbar, facial, limb, respiratory muscle ▪ Ocular muscles ▫ Eyelid (ptosis), extraocular (binocular diplopia) ▪ Bulbar muscle ▫ Jaw closure (prolonged chewing → weakness), oropharyngeal (dysarthria,

664 OSMOSIS.ORG

▪ ▪

▪ ▪

dysphagia), palatal (nasal tone, prolonged speech → hypophonia) Facial muscle ▫ Facial weakness, facial expression loss Neck muscle ▫ Cannot keep head up (“drooped head syndrome”) Limb muscle ▫ Proximal, asymmetric muscle weakness Respiratory muscle ▫ Respiratory failure (myasthenic crisis)

DIAGNOSIS DIAGNOSTIC IMAGING CT scan ▪ Chest scan to detect associated thymic abnormalities ▫ Abnormal thymus (most cases) ▫ Thymoma

LAB RESULTS

▪ Serologic test ▫ Acetylcholine receptor antibodies (AChR-Abs)/muscle-specific receptor tyrosine kinase antibodies (MuSK-Abs) ▫ Most specific tests ▫ Seronegative for AChR-Abs, MuSK-Abs

OTHER DIAGNOSTICS

▪ Electrophysiologic studies ▫ Repetitive nerve stimulation studies: progressive decline in muscle action potential amplitude (decremental response) ▫ Single-fiber electromyography: increased jitter ▪ Tensilon test ▫ Edrophonium: acetylcholinesterase inhibitor with rapid onset, short acting duration ▫ Prolongs acetylcholine presence in neuromuscular junction → marked improvement ▫ Easy to perform/limited utility; high false-positive rate, possible complications from muscarinic effects

Chapter 85 Neuromuscular Junction Disorders (especially older adults, e.g. bradycardia, bronchospasm) ▪ PFTs ▫ Periodical FVC monitoring; FVC ↓ reveals respiratory muscle involvement ▪ Ice pack test ▫ Ice pack application (2–5 minutes) → MG-affected muscles ▫ Neuromuscular transmission improvement in low temperature

SURGERY

▪ Thymectomy, especially for thymoma; myasthenia often improves/disappears ▪ Rapidly worsening myasthenia/myasthenic crisis ▫ Intubation ▫ Plasmapheresis/intravenous immunoglobulin (IVIG) ▫ Long-acting immunotherapy (e.g., corticosteroids, azathioprine)

MNEMONIC

Edrophonium vs. pyridostigmine eDrophonium for Diagnosis pyRIDostigmine is to get RID of symptoms

Figure 85.1 A biologically-female individual with myasthenia gravis demonstrating ptosis of the right eye before treatment (above) and after treatment (below) with edrophonium.

TREATMENT ▪ No curative method

MEDICATIONS

▪ Avoid MG-exacerbating drugs (e.g. aminoglycosides, tetracyclines, betablockers, quinidine) ▪ Acetylcholinesterase inhibitors ▫ Symptomatic therapy ▪ Immunomodulating agents ↓ autoantibody production ▫ Individuals with poor acetylcholinesterase inhibitor response ▪ Corticosteroids, other immunosuppressive agents

OSMOSIS.ORG 665

NOTES

NOTES

NEUROPATHIES GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Peripheral nervous system (PNS) disorders caused by neuronal damage

SIGNS & SYMPTOMS ▪ Impairment/loss of motor/somatosensory function; “pins and needles” sensation (paresthesia)

DIAGNOSIS ▪ History: characteristic symptoms, sometimes preceding injury

DIAGNOSTIC IMAGING

▪ Imaging for some conditions

OTHER DIAGNOSTICS

▪ Electromyography (EMG), nerve conduction studies (NCS)

TREATMENT MEDICATIONS

▪ For neuropathic pain

SURGERY

▪ Surgery to relieve nerve compression

666 OSMOSIS.ORG

OTHER INTERVENTIONS

▪ Physiotherapy ▫ Helps restore muscle function (if nerves are not severed → may help motor function with partial lesions) ▪ Splinting (e.g. wrist, ankle)

MNEMONIC: DANG THERAPIST

Peripheral neuropathies common differential diagnosis Diabetes Amyloid Nutritional (e.g. B12 deficiency) Guillain-Barre Toxic (e.g. amiodarone) Hereditary (Charcot-MarieTooth) Endocrine Recurring (10% of Guillain– Barre) Alcohol Pb (lead) Idiopathic Sarcoid Thyroid

Chapter 86 Neuropathies

CARPAL TUNNEL SYNDROME osms.it/carpal-tunnel-syndrome PATHOLOGY & CAUSES

SIGNS & SYMPTOMS

▪ Nerve entrapment disorder → compression of wrist’s median nerve ▫ Median nerve passes through carpal tunnel ▪ Carpal tunnel ▫ Floor: carpal arch ▫ Roof: flexor retinaculum (transverse carpal ligament) ▫ Contains nine flexors, median nerve ▪ Repetitive stress injury in susceptible people → inflammation → edema → fluid in narrow space compresses structures → nerve injury, impaired neuronal transport/ vessel compression, nerve ischemia

▪ Usually unilateral symptoms ▪ Individual may awake with numbness, tingling (after day of use → worsens at night) ▪ Initially dull ache, discomfort; paresthesia, sharp pain extending to forearm ▪ Pain, numbness, tingling in thumb, index finger, middle finger, thumb side of ring finger on palmar side of hand ▪ Clumsiness, dropping small objects ▪ No sensation loss in palm’s central region ▫ Palmar branch of median nerve innervates it, branches off before going through carpal tunnel

CAUSES

▪ Tendonitis, edema, repetitive stress injury (typing)

RISK FACTORS

▪ Obesity, pregnancy, other underlying conditions (rheumatoid arthritis), trauma, genetic predisposition, occupation

COMPLICATIONS

▪ Thenar muscle atrophy

MNEMONIC: TRAMP

Carpal tunnel syndrome common causes Trauma (occupational) Rheumatoid arthritis Acromegaly Myxoedema Pregnancy

DIAGNOSIS OTHER DIAGNOSTICS EMG ▪ Identifies neuropathic changes (sharp waves, ↑ insertional activity) NCS ▪ ↓ response amplitude Physical exam ▪ Findings that support diagnosis ▫ Phalen maneuver: pressing of upper hands together while flexing wrists induces pain ▫ Tinel’s sign: tapping on wrist over median nerve elicits pain ▫ Durkan’s test: pressing of median nerve for 30 seconds worsens symptoms ▫ Thenar eminence atrophy

OSMOSIS.ORG 667

MNEMONIC: WRIST

TREATMENT

Carpal tunnel syndrome treatment Wear splints at night Rest Inject steroid Surgical decompression Take diuretics

MEDICATIONS

▪ Corticosteroid injections → ↓ inflammation

SURGERY

▪ If symptoms persist, cut transverse ligament to relieve pressure

OTHER INTERVENTIONS

▪ Behavior modification (e.g. adjusting typing position, weight loss) ▪ Wrist supports, splints ▪ Physical therapy ▫ Helps relieve wrist strain, ↓ symptom severity

Figure 86.1 Relative wasting of the right thenar eminence in a case of carpal tunnel syndrome.

ERB–DUCHENNE PALSY osms.it/erb-duchenne-palsy PATHOLOGY & CAUSES ▪ Type of neonatal brachial plexus palsy ▫ Caused by upper part of brachial plexus injury ▫ AKA Erb’s palsy ▫ Brachial plexus: group of nerves provide movement, feeling to shoulder, arm, hand, fingers; roots included in plexus are C5–T1 forming superior, middle, inferior trunks which form lateral, posterior, medial cords ▪ Nerves affected ▫ Axillary ▫ Musculocutaneous (biceps brachii, brachioradialis) ▫ Suprascapular

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▪ Upper brachial plexus stretching → nerve damage

TYPES

▪ Brachial plexus injuries ▫ Neuropraxia (most common, nerve stretched but not torn) ▫ Avulsion (most severe, roots torn from spinal cord) ▫ Rupture (nerve torn) ▫ Neuroma (nerve torn → healed, scar puts pressure on injured nerve)

RISK FACTORS

▪ Shoulder dystocia, macrosomia, malpresentation, maternal obesity, cephalopelvic disproportion, prolonged/

Chapter 86 Neuropathies difficult labor, precipitous delivery

COMPLICATIONS

▪ Affected arm grows shorter than other ▪ Limited range of motion ▪ Muscle weakness

SIGNS & SYMPTOMS ▪ “Waiter’s tip” ▫ Hanging arm rotated medially, extended forearm, fixed wrist ▪ Affected arm may be held against body; flaccid, flexed at elbow ▪ Lateral part of forearm sensation loss, circulatory disturbances, paralysis ▪ Asymmetric Moro reflex ▫ Infant spreads only one arm (instead of two) when it feels like it’s falling

DIAGNOSIS DIAGNOSTIC IMAGING X-ray ▪ Rule-out fracture Ultrasound ▪ May show shoulder dislocation

OTHER DIAGNOSTICS

▪ Neurological exam ▫ Difficult due to limited child movement ▫ Involves evaluation of arm range of movement, motility

Electromyoneurography (EMNG) ▪ Shows damage extent

TREATMENT SURGERY

▪ Nerve repair/reconstruction

OTHER INTERVENTIONS

▪ Physical therapy ▫ Promotes muscle strengthening, normal function

Figure 86.2 An illustration of the “waiter’s tip” position.

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KLUMPKE PARALYSIS osms.it/klumpke-paralysis PATHOLOGY & CAUSES ▪ Type of brachial plexus palsy affecting lower brachial plexus nerve roots C8–T1 ▪ Abducted arm during childbirth → arm traction, pulling → nerve stretching in inferior brachial plexus area → brachial plexus damage

CAUSES

▪ Obstetric injury in adulthood ▫ Caused by grabbing things when falling from height

RISK FACTORS

▪ Birth injury ▫ Macrosomia, cephalopelvic disproportion, shoulder dystocia, prolonged/difficult labor, precipitous delivery, abnormal presentations ▪ Adult trauma ▫ Car crashes, falls, contact sports

COMPLICATIONS

▪ Severe pain, arm immobility

SIGNS & SYMPTOMS ▪ Claw hand ▫ Intrinsic hand muscle atrophy → flexion of interphalangeal, extension of metacarpophalangeal joints ▪ Sensation loss in appropriate dermatome (medial side of arm), upper-arm weakness Horner’s syndrome ▪ Ptosis (drooping eyelid) ▪ Enophthalmos (deep-set eye) ▪ Miosis (constricted pupil) ▪ ↓ sweating on one side of face

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Figure 86.3 An illustration of the claw hand position.

DIAGNOSIS OTHER DIAGNOSTICS

▪ Clinical diagnosis through neurological exam ▫ Testing mobility, sensation, Horner’s syndrome symptoms

EMG/NCS ▪ Confirms lesion location, assesses severity

TREATMENT OTHER INTERVENTIONS

▪ Physiotherapy, electrical nerve stimulation, occupational therapy ▪ Repositioning, splinting (extreme damage cases)

Chapter 86 Neuropathies

SCIATICA osms.it/sciatica PATHOLOGY & CAUSES

SIGNS & SYMPTOMS

▪ Type of neuralgia following sciatic nerve along its distribution path ▪ Lumbosacral radiculopathy (spinal nerve root disorder) → radicular (radiating, shooting) pain ▪ Most commonly caused by spinal disc disease → narrowing of neural foramen/ intraspinal space → disc profusion outside spinal column border → lumbar/sacral nerve root compression → nerve irritation

▪ Sudden shooting pain onset radiating from lumbar spine → down leg → areas innervated by sciatic nerve (side, back) ▫ Mostly unilateral ▪ Pain may involve lower back, hip, foot ▪ Numbness, muscle weakness, burning sensation

CAUSES

DIAGNOSTIC IMAGING

▪ Spinal disc herniation (most common) ▪ Spinal stenosis (spinal canal narrowing) ▪ Piriformis syndrome ▫ Rare variation of sciatic nerve passing through piriformis muscle → symptoms ▪ Pregnancy ▫ Due to ligament loosening, shifting of center of gravity pressure on nerve ▪ Nerve tumors (schwannoma), trauma ▪ Younger individuals ▫ Infection

DIAGNOSIS X-ray, MRI ▪ Confirms disc herniation, stenosis, tumors as etiology; determines management

OTHER DIAGNOSTICS

▪ Clinically diagnosed ▫ Straight leg raise test: passive straight leg raising between 30–70° while lying down, produces Lasègue’s sign (positive if pain present); not very specific ▫ Crossed straight leg raising test: has higher specificity, not very sensitive

RISK FACTORS

▪ Preexisting spinal disorders ▪ Age: ↑ risk ▪ Biologically-male individuals

COMPLICATIONS

▪ Nerve damage, muscle atrophy, immobility, permanent sensation loss

TREATMENT MEDICATIONS

▪ Pain management (nonsteroidal antiinflammatory drugs (NSAIDs), opioids)

SURGERY

▪ Spinal disc repair (severe symptoms)

OTHER INTERVENTIONS ▪ Recommend normal activity

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THORACIC OUTLET SYNDROME osms.it/thoracic-outlet-syndrome PATHOLOGY & CAUSES ▪ Compression of neurovascular bundle in space between clavicle, first rib; traverses thoracic outlet ▫ Can result from combination of developmental abnormalities, injuries, physical activities that predispose neurovascular compression

TYPES Structures involved ▪ Neurogenic ▫ Brachial plexus compressed ▫ Most common ▪ Venous ▫ Subclavian vein ▪ Arterial ▫ Subclavian artery Obstruction areas ▪ Anterior scalene ▫ Inflammation/structural anomaly (multiple attachments) → scalene muscle presses down onto structures, brachial plexus compressed ▫ Most common ▪ Cervical rib ▫ Congenital abnormality of additional rib, subclavian vein compressed ▫ More common in biologically-female individuals ▪ Costoclavicular ▫ All structures may be involved ▫ Second most common

CAUSES

▪ Repetitive motion → chronic inflammation ▪ Congenital ▫ Cervical rib, supernumerary muscle insertions ▪ Neck hyperextensions

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RISK FACTORS

▪ Coagulation disorders, pregnancy, tumors, trauma ▪ Repetitive movement sports (swimming, handball)

COMPLICATIONS

▪ Stroke (arising from retrograde thrombi); deep venous thrombosis; arterial thromboembolism; atrophy; neural damage, paralysis; limb ischemia

SIGNS & SYMPTOMS ▪ Differ according to structure involved, unilateral presentation more common ▪ Neurogenic ▫ Pain, numbness, paresthesia (tingling), weakness when raising arm, muscle atrophy (thumb muscles) ▪ Venous ▫ Swollen, painful, cyanotic (blue) arm; spontaneous edema, may cause paresthesia ▪ Arterial ▫ Cold, painful, pale arm; ↓ systolic blood pressure in affected arm, diminished distal pulses, aneurysmal change in artery after compression may → thrill over subclavian artery; thromboembolism → worsening symptoms, ischemia

DIAGNOSIS DIAGNOSTIC IMAGING Upper-extremity ultrasound, angiography ▪ Shows blood clot formation in vessels; distinguishes between arterial, venous etiology

Chapter 86 Neuropathies Chest X-ray ▪ Identifies bone abnormalities

TREATMENT

CT scan ▪ Identifies compression areas in greater detail MRI ▪ Identifies brachial plexus compression, contrast displays vessel occlusion level

OTHER DIAGNOSTICS Physical exam ▪ Examine limbs for signs of neural, venous/ arterial insufficiency ▪ Blood pressure difference between arms indicates arterial involvement ▪ Adson test: raising arms above head induces further compression → distal pulse diminishment

MEDICATIONS

▪ Local corticosteroid, anesthetic injections (symptom relief) ▪ Thrombolysis (in vascular clot cases)

SURGERY

▪ Decompression techniques

OTHER INTERVENTIONS ▪ Physical therapy ▫ Stretching, exercise

EMNG ▪ Confirms neurological dysfunction

ULNAR CLAW osms.it/ullnar-claw PATHOLOGY & CAUSES ▪ Two medial fingers (fourth, fifth) become flexed at interphalangeal level, extended at metacarpophalangeal level ▫ Due to ulnar nerve damage, hand resembles “claw” ▪ Prolonged ulnar nerve pathway pressure → nerve injury → hand muscle wasting (except thenar, two lateral lumbricals); flexor carpi ulnaris, flexor digitorum profundus → fourth, fifth finger flexion at interphalangeal joint, extension at metacarpophalangeal joint Injury level ▪ Low ▫ Wrist, damage usually more severe ▫ Lesion site of nerve within wrist area doesn’t influence symptoms

▫ Cause: usually trauma/repetitive movement ▪ High ▫ Cause: regularly leaning against elbows

CAUSES

▪ Prolonged pressure on Guyon’s canal (where ulnar nerve passes) ▪ Trauma

RISK FACTORS

▪ Biologically-male individuals: ↑ BMI ▪ Biologically-female individuals: ↓ BMI ▪ Cubitus valgus (forearm at pathological angle) ▪ Cycling ▪ Leaning against desk

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▪ Tool use requiring downward pressure (musical instruments)

COMPLICATIONS ▪ Nerve palsy

SIGNS & SYMPTOMS ▪ Range in severity from mild intermittent paresthesia to complete sensation loss, atrophy ▪ Flexion at interphalangeal joints, extension at metacarpophalangeal ▪ Weakness, dexterity loss

DIAGNOSIS DIAGNOSTIC IMAGING Ultrasound ▪ Identifies local inflammation in Guyon’s canal (where ulnar nerve passes) MRI ▪ Identifies nerve thickening

OTHER DIAGNOSTICS Clinical exam ▪ Identify injury level ▫ Elbow has different muscles involved (flexor carpi ulnaris, flexor digitorum profundus) ▫ Froment’s sign: card gripped using interphalangeal joints (abductor pollicis weak) ▫ Finger abduction, pressing hands together causes one side to collapse EMNG ▪ Identifies neural damage level in fingers

TREATMENT SURGERY

▪ Severe injury ▫ Nerve decompression at level of Guyon’s canal

OTHER INTERVENTIONS

▪ Lighter injury ▫ Physical therapy, occupational therapy ▪ Splints, avoiding exacerbation

Figure 86.4 A left hand demonstrating an ulnar claw.

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Chapter 86 Neuropathies

WINGED SCAPULA osms.it/winged-scapula PATHOLOGY & CAUSES

DIAGNOSIS

▪ Abnormal scapula protrusion from back of chest wall, usually unilateral ▫ AKA scapula alata ▪ Caused by muscle weakness ▫ Serratus anterior: damage either to brachial plexus, long thoracic nerve (most common) ▫ Trapezius: damage to accessory nerve ▫ Rhomboid: damage to dorsal scapular nerve ▪ Nerve damage, irritation/muscular dystrophy → muscle weakness → scapula elevation from thoracic wall → scapula winging

DIAGNOSTIC IMAGING

RISK FACTORS

OTHER INTERVENTIONS

Neck lymphadenectomy Neuromuscular disorder Idiopathic Traumatic ▫ Neck injury, repetitive movement, backpack straps, sleeping in bad position, surgery ▪ Non-traumatic ▫ Viral neuritis (influenza), allergy, toxic; neuromuscular disorders (facioscapulohumeral muscular dystrophy)

▪ ▪ ▪ ▪

X-ray ▪ Confirms absence of fractures, structural irregularities

OTHER DIAGNOSTICS

▪ Scapular asymmetry, winging

TREATMENT SURGERY

▪ Nerve transfer, scapular fixation

▪ May resolve spontaneously ▪ Massage therapy ▫ Muscle relaxation ▪ Physical therapy ▫ Improves shoulder weakness

COMPLICATIONS

▪ Compensatory back muscle imbalance

SIGNS & SYMPTOMS ▪ ▪ ▪ ▪

Fatigue Neck, shoulder pain Scapular winging, shoulder asymmetry Muscle weakness, difficulty lifting objects, difficulty raising arm above head

Figure 86.5 Winged scapula in an individual with a long thoracic nerve palsy.

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NOTES

NOTES

PNS DEMYELINATING DISORDERS

GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Progressive peripheral nervous system (PNS) disorders; destruction of myelin, disruption of motor, sensory function

TYPES Charcot–Marie–Tooth disease ▪ Genetic mutations → defective myelin sheath, impaired neuronal mitochondrial function Guillain–Barré syndrome ▪ Acute triggering event (e.g. infection) → aberrant autoimmune response → myelin sheath destruction

COMPLICATIONS Charcot–Marie–Tooth disease ▪ Muscle atrophy, impaired ambulation, foot irregularities Guillain–Barré syndrome ▪ Respiratory failure, cardiac arrhythmias, quadriplegia

SIGNS & SYMPTOMS ▪ ↓/absent deep tendon reflexes, paresthesia, muscle weakness, ↓ touch sensation

DIAGNOSIS DIAGNOSTIC IMAGING Gadolinium-enhanced MRI ▪ Guillain–Barré ▫ Intrathecal spinal nerve root thickening

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LAB RESULTS

▪ Guillain–Barré ▫ Albuminocytologic dissociation in cerebrospinal fluid (CSF)

OTHER DIAGNOSTICS

▪ Electromyography (EMG), nerve conduction studies (NCS) ▫ ↓/blocked nerve conduction velocity ▪ History, physical examination

TREATMENT MEDICATIONS

▪ Guillain–Barré ▫ Intravenous immunoglobulin (IVIG)

SURGERY

▪ Charcot–Marie–Tooth ▫ Correction of severe skeletal irregularities

OTHER INTERVENTIONS

▪ Charcot–Marie–Tooth ▫ Genetic testing, orthotics, physical/ occupational therapy ▪ Guillain–Barré ▫ Plasmapheresis; supportive care (e.g. respiratory/hemodynamic support) ▪ Pain management ▫ Acetaminophen, nonsteroidal antiinflammatory drugs (NSAIDs), gabapentin, carbamazepine

Chapter 87 PNS Demyelinating Disorders

CHARCOT–MARIE–TOOTH DISEASE osms.it/Charcot-Marie-Tooth PATHOLOGY & CAUSES ▪ Group of hereditary, progressive neurological disorders; disruption of PNS processes, impaired sensory/motor function ▪ Genetic mutations → defective structure, function of proteins in myelin sheath/ neuron’s axon ▪ Classification: Types I-VII; Type X (X-linked) ▫ Subtypes based on associated genes and phenotypes

TYPES

SIGNS & SYMPTOMS ▪ Onset in first to third decade of life, depending on type ▪ Progressive distal muscle weakness; atrophy of hands, feet ▪ Distal sensory loss, paresthesias, loss of proprioception ▪ ↓ deep tendon reflexes, areflexia ▪ Foot irregularities ▫ Foot drop, high arches (pes cavus), hammer toes, flail foot, cavovarus foot ▪ Unsteady gait, toe-walking

Charcot–Marie–Tooth I (CMT1) ▪ Demyelinating form ▫ Caused by mutations in PMP22, MPZ genes (encode for myelin sheath proteins) → ↓ nerve conduction velocity ▫ Autosomal dominant/sporadic inheritance CMT2 ▪ Axonal form ▫ Caused by mutations in MFN2 gene (encodes for mitofusin-2 protein in neuronal mitochondria) → neuronal death ▫ Autosomal dominant/recessive inheritance

RISK FACTORS

▪ Inheritance of defective gene(s)

COMPLICATIONS

▪ Muscle atrophy, loss of ambulation; deafness, intellectual disability, optic neuropathy, feeding difficulties, hip dysplasia

Figure 87.1 An MRI scan of the foot of an individual with Charcot-Marie-Tooth disease. There is wasting of the plantar muscles and prominent pes cavus as well as a hammer irregularity of the great toe.

OSMOSIS.ORG 677

DIAGNOSIS OTHER DIAGNOSTICS

▪ NCS, EMG ▫ ↓ nerve conduction velocity ▪ History, physical examination (e.g. age of onset) ▪ Genetic testing

OTHER INTERVENTIONS

▪ Physical/occupational therapy ▫ Strengthening, range of motion, balance, maintenance of mobility, activities of daily living ▪ Orthotics

TREATMENT MEDICATIONS

▪ Pain management ▫ Acetaminophen, NSAIDs, gabapentin, carbamazepine

SURGERY

▪ Correction of severe skeletal irregularities Figure 87.2 A section of a peripheral nerve from an individual with Charcot–Marie–Tooth disease.

GUILLAIN–BARRÉ SYNDROME osms.it/guillain-barre-syndrome PATHOLOGY & CAUSES ▪ Acute, progressive demyelinating PNS disease; sensory, motor, cognitive deficits ▪ AKA acute inflammatory demyelinating polyneuropathy ▪ Abnormal autoimmune response ▫ Myelin autoantigen picked up by antigen-presenting cells (e.g. dendritic) → antigen presented to helper T-cells → production of cytokines → activation of B-cells and macrophages → B-cells make antibodies, mark autoantigens; macrophages use antibody markers to attack myelin sheath on peripheral neurons → ↓/blocked nerve conduction velocity; axonal degeneration

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Variants ▪ Acute inflammatory demyelinating polyradiculoneuropathy (AIDP) ▪ Miller–Fisher syndrome ▫ Affects cranial nerves (CN) III, IV, VI ▪ Acute motor axonal neuropathy (AMAN) ▪ Acute sensorimotor axonal neuropathy (AMSAN)

CAUSES

▪ Molecular mimicry between microbe, nerve antigens ▫ Most commonly associated with Campylobacter jejuni, Mycoplasma pneumoniae, cytomegalovirus, Epstein– Barr, influenza A, Zika, HIV

Chapter 87 PNS Demyelinating Disorders

RISK FACTORS

▪ Acute infection ▪ ↑ age ▪ More common in individuals who are biologically male

COMPLICATIONS

▪ Acute ▫ Ileus, urinary retention, cardiac arrhythmias, pneumonia, respiratory failure, quadriplegia ▪ Long-term ▫ Chronic fatigue, chronic pain, relapses

SIGNS & SYMPTOMS ▪ Variable presentation, depending on affected nerve ▪ Bilateral, flaccid, ascending weakness of limbs, peaking ≤ four weeks ▪ ↓ deep tendon reflexes, areflexia, touch sensation ▪ Paresthesia ▪ Diaphragmatic weakness → breathing difficulties (e.g. hypoventilation, requires mechanical ventilation) ▪ Autonomic involvement ▫ Hypertension/hypotension/postural hypotension, bradycardia ▪ CN involvement ▫ Blurred vision, dysarthria, abnormal pupillary response to light

DIAGNOSIS DIAGNOSTIC IMAGING Gadolinium-enhanced MRI (spine) ▪ T1-weighted images ▫ Thickening of intrathecal spinal nerve roots

LAB RESULTS

▪ CSF ▫ Albuminocytologic dissociation (high levels of protein without increase in cell counts) ▪ Serum immunoglobulin G (IgG) antibodies to ganglioside Q1b (GQ1b) ▫ Miller–Fisher

OTHER DIAGNOSTICS

▪ EMG, NCS ▫ ↓/blocked nerve conduction velocity ▪ History, physical examination

TREATMENT MEDICATIONS

▪ IVIG ▪ Gabapentin/carbamazepine ▫ Pain management

OTHER INTERVENTIONS

▪ Plasmapheresis ▪ Respiratory/hemodynamic support

OSMOSIS.ORG 679

NOTES

NOTES

SPINAL CORD INJURY GENERALLY, WHAT IS IT? PATHOLOGY & CAUSES ▪ Damage/inflammation of spinal cord → loss of function, sensation

RISK FACTORS

DIAGNOSIS DIAGNOSTIC IMAGING MRI ▪ Secondary compression of spinal cord

▪ Traumatic spine injury, tumours, inflammatory disease

SIGNS & SYMPTOMS ▪ Brown–Sequard syndrome (BSS) ▫ Contralateral loss of pain, temperature; ipsilateral hemiparesis ▪ Cauda equina syndrome (CES) ▫ Severe back pain, sciatica, saddle anesthesia, incontinence, sexual dysfunction

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TREATMENT SURGERY

▪ Decompression surgery

OTHER INTERVENTIONS

▪ Stabilize vitals, immobilize acute injuries

Chapter 88 Spinal Cord Injury

BROWN–SÉQUARD SYNDROME (BSS) osms.it/brown-sequard-syndrome PATHOLOGY & CAUSES ▪ AKA spinal hemiparaplegia ▪ Spinal cord hemisection (damage limited to one half) → paralysis on side of lesion; loss of sensation on opposite side ▪ Neurological fallout from damage to spinal tracts ▫ Corticospinal tract: loss of upper motor neuron innervation → ipsilateral spastic paralysis, below level of lesion; damage to lower motor neuron at level of spinal injury → ipsilateral flaccid paralysis of muscles supplied at spinal level ▫ Dorsal column (medial lemniscus): ipsilateral loss of vibration, proprioception, fine touch ▫ Spinothalamic tract: contralateral loss of pain, temperature sensation; 1–2 levels below lesion

COMPLICATIONS

▪ Progression to complete paralysis

SIGNS & SYMPTOMS ▪ Contralateral pain, temperature loss; ipsilateral hemiparesis, proprioception/ vibration sense loss

DIAGNOSIS DIAGNOSTIC IMAGING MRI ▪ Unilateral spinal cord pathology/ hemisection of spinal cord

TREATMENT OTHER INTERVENTIONS

CAUSES

▪ Spinal fractures, gunshot wounds, stab wounds, crush injury, tumours, inflammatory diseases

▪ Traumatic injuries ▫ Cervical spine/lower dorsal vertebra immobilization

CAUDA EQUINA SYNDROME (CES) osms.it/cauda-equina-syndrome PATHOLOGY & CAUSES ▪ Simultaneous compression of multiple lumbosacral nerve roots below level (L2) of conus medullaris (distal bulbous part of spinal cord) → neuromuscular, urogenital symptoms

CAUSES

▪ Lower back disc herniation, spinal stenosis, cancer, trauma, epidural abscess/ hematoma

OSMOSIS.ORG 681

COMPLICATIONS

▪ Paraplegia, persistent bowel/bladder problems, sexual dysfunction, loss of sensation

SIGNS & SYMPTOMS ▪ Red flags (urgent investigation/treatment required) ▫ Severe back pain; saddle anesthesia; incontinence/sexual dysfunction ▪ Muscle weakness in lower leg with absent/ reduced deep tendon achilles/patellar reflex ▪ Gait disturbance ▪ Sciatica-like pain in one/both legs: low back pain, radiates down leg ▪ Numbness in saddle distribution ▫ Anesthesia/paresthesia of S3–S5 dermatomes → anesthesia/paresthesia perineum, external genitalia, anus, perianal region ▪ Loss of bowel/bladder control ▪ Absent anal reflex, bulbocavernosus reflex ▪ Decreased tone of urinary, anal sphincters ▪ Detrusor weakness → urinary retention/ post-voiding residual incontinence ▪ Sexual dysfunction

TREATMENT SURGERY

▪ Surgical decompression (e.g. laminectomy)

OTHER INTERVENTIONS Sudden onset CES ▪ Medical emergency ▫ Early treatment (< 48hrs) of compressive lesions → significantly better outcomes, prevents progression to paraplegia

DIAGNOSIS DIAGNOSTIC IMAGING Spine MRI (with gadolinium contrast) ▪ Compression of S2–S4 nerve roots by mass/herniation Bladder ultrasound ▪ Post-void residual > 250ml

OTHER DIAGNOSTICS Clinical examination ▪ Regional anesthesia, muscle weakness, abnormal reflexes, abnormal gait

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Figure 88.1 An MRI scan of the spine in the sagittal plane demonstrating a L4/L5 intervertebral disc prolapse compressing the cauda equina. The individual presented with symptoms of cauda equina syndrome.

NOTES

NOTES

VISION DISORDERS GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Vision deficit disorders ▪ Correlate with anatomical lesions along visual pathway ▫ Light → cornea → lens → media → retina → optic nerve → chiasmal decussation → optic radiations (parietal, temporal paths) → primary visual cortex in occipital lobe

DIAGNOSIS OTHER DIAGNOSTICS

▪ History ▪ Physical/neurologic examination ▪ Cranial nerve (CN) testing ▫ CN II: visual fields and acuity ▫ CN II/III: pupillary reflex ▫ CN III/IV/VI: ocular movement

TREATMENT

CAUSES

▪ Mass effect → impingement of structures ▪ Vascular → brain parenchyma infarction along visual pathway

SIGNS & SYMPTOMS

MEDICATIONS

▪ Vascular: thrombolytics

SURGERY

▪ Masses: resection

▪ Impaired vision

OSMOSIS.ORG 683

BITEMPORAL HEMIANOPSIA osms.it/bitemporal_hemianopsia PATHOLOGY & CAUSES ▪ Visional deficit: lateral vision loss ▫ Optic chiasm lesions (commonly) ▪ Pathogenesis: ↑ sellar mass size → presses optic chiasm → impinges decussating visual fibers (most medial) → bitemporal hemianopsia

CAUSES

▪ Pituitary enlargement ▫ Hyperplasia (i.e. pregnancy or lactation); adenoma (specific, hormone-secreting pituitary hyperplasia); cyst; abscess ▪ Craniopharyngioma ▪ Meningioma (in sella turcica) ▪ Saccular aneurysm (anterior communicating artery) ▪ Primary malignancy ▫ Germ cell tumor (AKA ectopic pinealoma); chordoma; central nervous system (CNS) lymphoma

COMPLICATIONS

▪ ↑ size → further impinges surrounding structures ▫ Cavernous sinus impingement → CN III, IV, VI → diplopia → ophthalmoplegia ▪ Dorsal extension of mass → dorsal midbrain impingement → Parinaud’s syndrome ▫ Upgaze paralysis ▫ Pinealomas (posterior, common)

SIGNS & SYMPTOMS ▪ Vision loss ▫ Lateral fields, both eyes (may go unnoticed; chronic, progressive) ▪ Headache ▪ Diplopia

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▪ Ophthalmoplegia (especially large mass lesions, pinealomas) ▪ Hormonal deficiency/excess (if pituitary growth is functional)

DIAGNOSIS DIAGNOSTIC IMAGING MRI ▪ Visualize mass at area of optic chiasm; gadolinium-enhanced images aid elucidating pituitary tissue (↑ gadolinium uptake in pituitary) CT scan ▪ Less diagnostic; may reveal sellar calcification, mass

TREATMENT MEDICATIONS

▪ Smaller, hormone-responsive adenomas (prolactinomas → dopamine agonists firstline therapy)

SURGERY

▪ Neurosurgery: nasal aperture, posterior nasopharynx, sublabial (upper lip) incision accesses inferior aspect of cerebrum ▫ Fluoroscopic visualization: navigation, pituitary visualization ▪ First-line therapy for all other pituitary adenomas, sellar masses with meaningful visual field impingement/other symptom severity

Chapter 89 Vision Disorders

COLOR BLINDNESS osms.it/color-blindness PATHOLOGY & CAUSES ▪ Altered color perception ▪ Pathogenesis ▫ Atypical cone type(s) function → altered color hue → limited color discrimination (commonly) ▫ Optic nerve/other retinal lesions (uncommon)

CAUSES Congenital ▪ Three cone types (opsins) ▫ Red, green opsins (X-chromosome): most inherited color blindness X-linked recessive → predominantly biologicallymale individuals ▫ Blue opsin (VII-chromosome): blue wavelength deficiency, very rare ▪ Associated with Turner syndrome Acquired ▪ Optic neuropathies ▫ Optic neuritis: persistent color blindness after visual deficit restoration; early multiple sclerosis symptom ▫ Diabetic retinopathy: neoproliferation, microvascular disease → retinal dysfunction (glaucoma) ▪ Bilateral, ventral occipital stroke → cerebral achromatopsia (rare)

SIGNS & SYMPTOMS ▪ Limited color discrimination

DIAGNOSIS ▪ Family, medication history

OTHER DIAGNOSTICS

▪ Ishihara plates: visual stimuli, colors offer wavelength-specific stimulation for three cone types ▫ Inability to perceive numbers/letters on plate → reveal cone type deficit(s)

TREATMENT OTHER INTERVENTIONS

▪ No curative therapy ▪ Acquired disease ▫ Glaucoma: regular eye examinations ▫ Diabetes: glycemic control → ↓ microvascular disease; regular eye examinations ▪ Individual education → lifestyle adaptation → proper visual cue interpretation ▫ Unable to perceive red vs. green light difference on traffic signals → location discrimination education → top vs. bottom light interpretation

Iatrogenic ▪ Ethambutol → poor red-green discrimination ▪ Digoxin → yellowish hue disturbance ▪ Other ▫ Ibuprofen, quinine, acetaminophen, sildenafil citrate, tobacco

COMPLICATIONS

▪ Nyctalopia: limited night vision

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CORTICAL BLINDNESS osms.it/cortical-blindness PATHOLOGY & CAUSES ▪ Acquired blindness: bilateral lesions to visual cortex in occipital lobe Pathogenesis ▪ Vascular occlusion ▫ Bilateral, distal posterior cerebral artery (PCA) occlusion; commonly embolic ▫ Basilar artery occlusion → ↓ blood flow in bilateral distal PCAs ▪ Vascular flow dysregulation → posterior reversible encephalopathy syndrome (PRES)

CAUSES

▪ Primary visual cortex lesions (calcarine fissure in occipital lobe) ▫ Neighboring lesions → similar anopsia

COMPLICATIONS

▪ Anton–Babinski syndrome (visual anosognosia) ▫ Individual unable to perceive vision → blindness denial ▫ Image confabulation common

SIGNS & SYMPTOMS ▪ Inability to perceive visual input ▪ CN testing: II/III preserved pupillary light reflex

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DIAGNOSIS DIAGNOSTIC IMAGING MRI ▪ Some cases, detects cause (e.g. vascular occlusion, infarction)

OTHER INTERVENTIONS History, physical examination ▪ Assess non-cortical functions: normal pupillary light reflex ▫ Limited/no visual response with intact pupillary light reflex → blindness neurological not ocular Fundoscopy ▪ Normal

TREATMENT MEDICATIONS

▪ Vascular occlusion: thrombolysis ▪ PRES: emergent antihypertensives

OTHER INTERVENTIONS

▪ Spontaneous recovery ▫ Visual defects may persist (e.g. prosopagnosia—inability to recognize faces)

Chapter 89 Vision Disorders

HEMIANOPSIA osms.it/hemianopsia PATHOLOGY & CAUSES ▪ Individual loses half of visual field, commonly due to retrochiasmatic lesion of visual tract Pathogenesis ▪ Vascular ▫ Middle cerebral artery (MCA): complete contralateral hemianopia ▫ Unilateral posterior cerebral artery (PCA): contralateral hemianopia with macular sparing ▪ Mass ▫ Visual pathway compression

CAUSES

▪ Unilateral optic tract lesion ▪ Large (complete) unilateral optic radiation lesion ▪ Quadrantanopia: sub-complete lesion, corresponds to lesioned optic radiation ▫ Upper outer-quadrant deficit (“pie-inthe-sky” defect) → temporal lobe loop lesion ▫ Lower inferior quadrant deficit → parietal lobe lesion ▪ Large, unilateral primary visual cortex lesion ▫ Macular visual field spared ▪ Bilateral upper/lower visual cortex lesion → altitudinal hemianopia ▫ Upper/lower field visual defect

COMPLICATIONS

▪ Vascular/mass effect territory-dependent ▪ PCA distribution ▫ Diplopia, dizziness, balance issues ▪ Anterior cerebral artery (ACA)/MCA distribution ▫ Ipsilateral motor and sensory symptoms ▪ Parietal lobe involvement → contralateral neglect

▫ Lesion to non-dominant lobe → Gerstmann syndrome (finger agnosia, acalculia, agraphia, right-left visualization) ▪ Temporal lobe involvement → seizure

SIGNS & SYMPTOMS ▪ Visual field loss ▫ Unilateral hemianopia: contralateral optic tract lesion (homonymous hemianopia); large, contralateral optic radiation lesion ▫ Superior quadrantanopia: contralateral temporal lobe lesion of optic radiation loop ▫ Inferior quadrantanopia: contralateral parietal lobe lesion of optic radiation loop ▪ Neurologic examination ▫ CN II testing: visual field ▫ Motor/sensory testing for concomitant symptoms

DIAGNOSIS ▪ History, physical examination

DIAGNOSTIC IMAGING MRI ▪ Mass lesions/old stroke (preferred method) CT scan ▪ Mass lesion and acute, hemorrhagic stroke

TREATMENT SURGERY

▪ Resection: mass compressing the visual pathway

OSMOSIS.ORG 687

OTHER INTERVENTIONS

▪ Peripheral prism spectacles ▫ High-power prism segments in regular spectacle lens → expands visual field up to 30° ▪ Saccadic eye movement training (scanning therapy) ▫ Individual makes compensatory saccadic eye movements to side with lost visibility without moving head → ↑ function, injury prevention

HOMONYMOUS HEMIANOPSIA osms.it/homonymous-hemianopsia PATHOLOGY & CAUSES ▪ Lesion in optic tract → vision loss in each eye (corresponding halves of visual field) ▪ Pathogenesis ▫ Vascular: large MCA/smaller anterior choroidal artery stroke ▫ Mass effect: tumor, cyst, arteriovenous malformation (AVM)

CAUSES

DIAGNOSIS ▪ History, physical examination

DIAGNOSTIC IMAGING MRI ▪ Mass lesions/old stroke (preferred method) CT scan ▪ Mass lesion/acute, hemorrhagic stroke

▪ Unilateral optic tract lesion

SIGNS & SYMPTOMS ▪ Half of visual field lost ▫ Not relieved by monocular vision (vision deficit persists despite closing one eye)

TREATMENT SURGERY

▪ Resection: mass compressing the visual pathway

OTHER INTERVENTIONS

▪ Peripheral prism spectacles ▪ Saccadic eye movement training (scanning therapy)

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NOTES

ANXIETY DISORDERS GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Mental disorders characterized by excessive, unreasonable fear, distress ▪ May be omnipresent/in response to particular stimulus ▪ Awareness of condition often causes more distress

CAUSES

▪ May be genetic, environmental ▪ Often associated with other mental disorders (mood, substance-related)

SIGNS & SYMPTOMS ▪ Persistent fear/distress ▪ Nausea, difficulty sleeping, headache

DIAGNOSIS ▪ ▪ ▪ ▪ ▪

Excessive, unreasonable fear/distress Struggle to control symptoms Lasts > six months Affects day-to-day functioning Not explained by other condition/substance

TREATMENT MEDICATIONS

▪ Selective serotonin reuptake inhibitors (SSRIs), other antidepressants, benzodiazepines

PSYCHOTHERAPY

▪ E.g. cognitive behavioral therapy ▫ Identify, explain thoughts/feelings, change flawed ones ▫ Better long-term prognosis; no side effects, no dependency

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AGORAPHOBIA osms.it/agoraphobia PATHOLOGY & CAUSES

DIAGNOSIS

▪ Fear, avoidance of public places ▪ Individuals refuse to leave “safety” of home

▪ Unreasonable fear/anxiety associated with public places ▪ Caused by underlying fear of feeling trapped, unable to receive help ▪ Resulting avoidance of public places ▪ Lasts > six months ▪ Distress affects day-to-day functioning ▪ Not explained by other condition/substance

CAUSES

▪ May be genetic, environmental ▪ Associated with other anxiety disorders, e.g. panic disorder

SIGNS & SYMPTOMS ▪ Fast heartbeat, dizziness, trembling ▪ Thinking about/avoidance of public places causes distress

TREATMENT MEDICATIONS

▪ SSRIs, benzodiazepines

PSYCHOTHERAPY

▪ E.g. cognitive behavioral therapy, systematic desensitization

Figure 90.1 Illustration showing how other disorders can lead to agoraphobia. If someone with panic disorder has panic attacks outside frequently, they may develop agoraphobia and avoid going outdoors altogether.

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Chapter 90 Anxiety Disorders

GENERALIZED ANXIETY DISORDER osms.it/generalized-anxiety-disorder PATHOLOGY & CAUSES ▪ Excessive, unreasonable, persistent fear, distress

CAUSES

▪ May be genetic, environmental; higher in some groups ▪ Associated with depressive disorders

SIGNS & SYMPTOMS ▪ Restlessness, difficulty concentrating, irritability ▪ Muscle tension (→ aching and soreness), fatigue, insomnia (→ chronic fatigue)

DIAGNOSIS ▪ Excessive, unreasonable anxiety ▪ Struggle to control anxiety ▪ Persistent fear/distress, nausea, difficulty sleeping, headache ▪ > three symptoms listed above (children > one year old) ▪ Lasts > six months ▪ Distress affects day-to-day functioning ▪ Not explained by other condition/substance

TREATMENT MEDICATIONS

▪ SSRIs, antidepressants, benzodiazepines

PSYCHOTHERAPY

▪ E.g. cognitive behavioral therapy

Figure 90.2 Illustration of the different levels of anxiety.

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PANIC DISORDER osms.it/panic-disorder PATHOLOGY & CAUSES

DIAGNOSIS

▪ Recurrent panic attacks → sudden periods of intense fear/discomfort ▪ Attacks unpredictable

▪ Recurrent, unpredictable panic attacks (> two) ▪ Distress affects day-to-day functioning ▪ Behavioral changes to avoid further attacks ▪ Presence of > four symptoms ▪ Not explained by other condition/substance

CAUSES

▪ May be genetic, environmental; higher in some groups ▪ Associated with major depressive disorder, social and generalized anxiety disorders, obsessive-compulsive disorder

SIGNS & SYMPTOMS ▪ Feelings of choking, derealization, fear of losing control/dying ▪ Elevated heart rate, chest pain/discomfort, sweating, trembling, shortness of breath, nausea, dizziness, chills, numbness

TREATMENT MEDICATIONS

▪ SSRIs and other antidepressants, benzodiazepines ▪ Antiseizure medications

PSYCHOTHERAPY

▪ E.g. cognitive behavioral therapy

Figure 90.3 Illustration showing possible causes for panic disorder, and avenues to treatment.

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Chapter 90 Anxiety Disorders

PHOBIAS osms.it/phobia PATHOLOGY & CAUSES ▪ Excessive, unreasonable, persistent fear resulting in avoidance of particular object/ situations (phobic stimulus)

TYPES

▪ As listed in the DSM-5 ▫ Fear of animals ▫ Fear of natural environment ▫ Fear of blood, needles ▫ Situational fears ▫ “Other” fears (AKA none of the above)

CAUSES

▪ May be genetic, environmental ▪ Associated with anxiety, mood, substance use disorders

DIAGNOSIS ▪ Unreasonable fear/anxiety associated with phobic stimulus ▪ Resulting avoidance (which may itself cause distress) of phobic stimulus ▪ Lasts > six months ▪ Distress affects day-to-day functioning ▪ Not explained by other condition/substance

TREATMENT MEDICATIONS

▪ SSRIs, benzodiazepines

PSYCHOTHERAPY

▪ E.g. cognitive behavioral therapy, systematic desensitization

SIGNS & SYMPTOMS ▪ Response to phobic stimulus: elevated heartbeat, dizziness, trembling ▪ Excessive thinking about/avoidance of phobic stimulus causes distress

Figure 90.4 Illustration of different specific phobias making someone feel powerless.

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SEPARATION ANXIETY DISORDER osms.it/separation-anxiety-disorder PATHOLOGY & CAUSES

DIAGNOSIS

▪ Excessive, unreasonable, persistent fear of being separated from individual/location

▪ Excessive, unreasonable, persistent fear of being separated from individual/location ▪ Adults: lasts > six months ▪ Children: lasts > four weeks ▪ Not explained by other condition/substance

CAUSES

▪ May be genetic, environmental ▪ Associated with all other anxiety disorders

SIGNS & SYMPTOMS ▪ Distress caused by thought of experiencing separation ▪ Nightmares, headaches, nausea

TREATMENT MEDICATIONS

▪ SSRIs, benzodiazepines

PSYCHOTHERAPY

▪ E.g. cognitive behavioral therapy

SOCIAL ANXIETY DISORDER osms.it/social-anxiety-disorder PATHOLOGY & CAUSES ▪ Excessive, unreasonable, persistent fear of being judged ▪ Avoidance of social situations

CAUSES

▪ May be genetic, environmental; higher in some groups ▪ Associated with mood disorders, substance-related disorders, eating disorders, obsessive-compulsive disorders

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SIGNS & SYMPTOMS ▪ Trembling, blushing, derealization ▪ Excessive thinking about/avoidance of social situations/circumstances, associated distress

DIAGNOSIS ▪ Excessive, unreasonable, persistent fear of being judged ▪ Avoidance of social situations/ circumstances, associated distress ▪ Fear of others judging anxious feelings ▪ Lasts > six months ▪ Distress affects day-to-day functioning ▪ Not explained by other condition/substance

Chapter 90 Anxiety Disorders

TREATMENT MEDICATIONS

▪ SSRIs, antidepressants, benzodiazepines

PSYCHOTHERAPY

▪ E.g. cognitive behavioral therapy

Figure 90.5 Illustration of the possible causes of social anxiety disorder, which are still unclear, as well as the DSM-5’s criteria for a diagnosis of the condition.

OSMOSIS.ORG 695

NOTES

NOTES

COGNITIVE & DISSOCIATIVE DISORDERS

GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Cognitive disorders: involve cognitive decline ▪ Dissociative disorders: involve detachment from past/present versions of oneself/the world

SIGNS & SYMPTOMS ▪ See individual disorders

DIAGNOSIS ▪ See individual disorders

CAUSES

▪ Past trauma/stress may cause/worsen condition

TREATMENT ▪ See individual disorders

COMPLICATIONS

▪ Personality changes, depression

AMNESIA osms.it/amnesia PATHOLOGY & CAUSES ▪ Acute loss of memory

TYPES Anterograde amnesia ▪ Inability to form new memories ▪ Associated with encoding and consolidation phases of memory ▪ Usually involves damage to prefrontal cortex/hippocampus Retrograde amnesia ▪ Inability to recall old memories (may result in creation of false memories)

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▪ Associated with storage and retrieval phases of memory ▪ Usually involves damage to cortex

CAUSES

▪ Head trauma, infection, neurodegenerative diseases (e.g. dementia/Alzheimer’s), brain tumours, thiamine deficiency (causing Wernicke–Korsakoff syndrome), benzodiazepines, electroconvulsive therapy

COMPLICATIONS

▪ Range of potential complications (e.g. confusion, loss of identity)

Chapter 91 Cognitive & Dissociative Disorders

TREATMENT

SIGNS & SYMPTOMS ▪ Acute memory loss, affects memories created before/after an event (or onset of illness)

PSYCHOTHERAPY

▪ Occupational and cognitive therapies to enhance memory

OTHER INTERVENTIONS

DIAGNOSIS

▪ Often temporary (address cause) ▪ Mobile phones and digital devices as workarounds to memory loss

DIAGNOSTIC IMAGING MRI/CT scan ▪ Brain damage/abnormalities

LAB RESULTS

▪ Nutritional deficiencies/infections

DELIRIUM osms.it/delirium PATHOLOGY & CAUSES ▪ Fast decline in attention/consciousness, thinking ▪ Sometimes accompanied by symptoms of hyper/hypoactivity

RISK FACTORS

▪ Disease (e.g. dementia, constipation, pneumonia, UTIs) ▪ Post-surgical complications ▫ Medications (e.g. narcotic pain medications, benzodiazepines, hypnotics, anticholinergics) ▫ Altered metabolic homeostasis (e.g. electrolyte or imbalance), chronic fatigue ▪ Increases risk of falling over → broken bones, head injuries, bruises, bleeds → longer hospitalizations, more complications, higher mortality rates

SIGNS & SYMPTOMS ▪ Difficulties with attention span, concentration, remaining conscious ▪ Disorganized/delayed thinking ▪ Hyperactive symptoms ▫ Agitated/aggressive ▫ Delusions/hallucinations ▪ Hypoactive symptoms ▫ Sluggish, drowsy ▫ Less reactive, withdrawn

DIAGNOSIS ▪ Issues with attention/consciousness and cognition, developing over short time (several days or fewer) ▫ Difficulties with attention span, concentration, remaining conscious ▫ Disorganized/delayed thinking ▪ Not explained by pre-existing neurocognitive condition ▪ Explained by other medical condition and/or exposure to/withdrawal from a substance

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TREATMENT MEDICATIONS Severe symptoms ▪ Haloperidol/second generation antipsychotics

OTHER INTERVENTIONS Preventative ▪ Make high-risk targets feel oriented, comfortable (reducing excess noise/ stimulation; make sure glasses, hearing aids are used if needed; encourage daily routine) ▪ Avoid opiates, other causative medications; avoid restraints

DISSOCIATIVE DISORDERS osms.it/dissociative-disorders PATHOLOGY & CAUSES ▪ Characterized by disruptions or breakdowns of memory, awareness, identity, or perception.

TYPES

▪ Three types on scale of severity

Low severity: depersonalization/derealization disorder ▪ Depersonalization: feeling detached from own body/mind (e.g. feeling one’s body is a robot/ feeling of watching self) ▪ Derealization: feeling of world not being fully real (e.g. feeling outside world not real/ lacks lucidity) Middle severity: dissociative amnesia ▪ Inability to recall significant information about oneself (e.g. location of childhood home, what mother looked like) ▪ Four categories of amnesia ▫ Localized: trouble recalling traumatic event (and surrounding period) ▫ Generalized: trouble recalling significant portion of one’s past ▫ Systematized: trouble recalling specific category of information ▫ Continuous: trouble recalling events after they occur ▪ Can involve dissociative fugue (individual becomes confused about identity, starts sudden travel/ wandering)

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▪ Worsens under stress High severity: dissociative identity disorder ▪ Feeling of having multiple identities which act/think/perceive differently, thus impairing ability to recall everyday/important information about oneself ▪ Two categories of dissociative identity disorder ▫ Covert: individual aware of identity shifts, struggles to manage them ▫ Overt: individual completely assumes different identities while unaware ▪ Can involve dissociative fugue (individual becomes confused about identity, starts sudden travel/ wandering)

CAUSES

▪ Thought to be primarily caused by psychological trauma; associated with sexual abuse, post-traumatic stress disorder, depression, substance abuse, borderline personality, somatoform conditions ▪ More common in biologically-female indiviudals

SIGNS & SYMPTOMS Depersonalization/derealization disorder ▪ Explicit thoughts/behaviors related to depersonalization/derealization ▪ Emotional/physical numbness; weak sense of self

Chapter 91 Cognitive & Dissociative Disorders ▪ ▪ ▪ ▪ ▪

Deadpan speech Altered sense of time Brain fog/lightheadedness Prone to rumination, anxiety Severe symptoms: difficulty recognizing familiar places, people, objects

Dissociative amnesia & Dissociative identity disorder ▪ Inability to recall significant information about oneself ▪ Altered consciousness (e.g. depersonalization, derealization) ▪ Depression, suicidal ideation

DIAGNOSIS

TREATMENT MEDICATIONS

▪ Antidepressants (like selective serotonin reuptake inhibitors) ▪ Mood stabilizers ▪ Neuroleptics

PSYCHOTHERAPY

▪ E.g., psychodynamic, cognitive, cognitive behavioral, supportive

OTHER INTERVENTIONS

▪ Memory aids: alarms, reminders, media (e.g. photos/videos/recordings) ▪ Occupational therapy

Depersonalization/derealization disorder ▪ Presence of depersonalization/derealization ▪ Symptoms affect day-to-day functioning ▪ Not caused by other condition/substance Dissociative amnesia ▪ Inability to recall significant information about oneself, beyond everyday forgetting ▪ Symptoms affect day-to-day functioning ▪ Not caused by other condition/substance Dissociative identity disorder ▪ Feeling of having multiple identities which act/think/ perceive differently ▪ Inability to recall significant information about oneself, beyond everyday forgetting ▪ Symptoms affect day-to-day functioning ▪ Not described by cultural/religious practices, nor by play (e.g. imaginary friends) ▪ Not caused by other condition/substance

OSMOSIS.ORG 699

NOTES

NOTES

DEPRESSIVE & BIPOLAR DISORDERS

GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES Mental disorders involving mood changes ▪ Often involve depression, sometimes mania/hypomania (see below)

CAUSES

▪ Genetic (especially between close relatives) ▪ Linked to neurotransmitter regulation (norepinephrine, serotonin, dopamine) ▪ High comorbidity with other mental disorders

COMPLICATIONS

▪ Self-harm/suicide ▪ Social consequences (e.g. losing friends)

SIGNS & SYMPTOMS ▪ Manic episodes featuring a mood disturbance, increased energy/activity, and ≥ three of following for ≥ one week, affecting day-to-day functioning ▪ Hypomanic (“less than manic”) episodes featuring a mood disturbance, increased energy/activity, and ≥ three of the above during a period > four days, not affecting day-to-day functioning ▪ Major depressive episodes featuring ≥ five of following in a two week period ▪ Other mood changes, including more mild depression; see individual disorders

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DIAGNOSIS ▪ ▪ ▪ ▪ ▪

Excessive, unreasonable fear/distress Struggle to control symptoms Lasts > six months Affects day-to-day functioning Not explained by other condition/substance

TREATMENT MEDICATIONS

▪ Antidepressants, lithium

PSYCHOTHERAPY

▪ See individual disorders

OTHER INTERVENTIONS

▪ Lifestyle changes ▫ Improved diet, more exercise, more sunlight

Chapter 92 Depressive & Bipolar Disorders

BIPOLAR I DISORDER osms.it/bipolar-I PATHOLOGY & CAUSES Bipolar disorder characterized by extreme mood swings with combination of manic, hypomanic, depressive episodes

CAUSES ▪ ▪ ▪ ▪

Genetic (especially between close relatives) Medications (e.g. SSRIs) Often no particular trigger High comorbidity with other mental disorders

MNEMONIC: DIG FAST

Characteristics of manic episode Distractibility Indiscretion: excessive involvement in pleasurable activities Grandiosity Flight of ideas Activity increase Sleep deficit/decreased need for sleep Talkativeness/pressured speech

SIGNS & SYMPTOMS ▪ Mood swings ▪ Manic episodes ▪ Usually, hypomanic and depressive episodes

DIAGNOSIS ▪ ≥ one manic episode ▪ Symptoms affect day-to-day functioning ▪ Not caused by other condition/substance

TREATMENT MEDICATIONS

▪ Atypical antipsychotics (e.g. olanzapine), in combination with mood stabilizers (esp. lithium)

PSYCHOTHERAPY

▪ E.g. cognitive behavioral therapy, interpersonal

OTHER INTERVENTIONS

▪ Electroconvulsive therapy (ECT)

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BIPOLAR II DISORDER osms.it/bipolar-II DIAGNOSIS

PATHOLOGY & CAUSES Bipolar disorder characterized by mood swings with hypomanic, depressive episodes.

CAUSES ▪ ▪ ▪ ▪

Genetic (especially between close relatives) Medications (e.g. SSRIs) Often no particular trigger High comorbidity with other mental disorders

SIGNS & SYMPTOMS ▪ Mood swings ▪ Hypomanic, depressive episodes

▪ ▪ ▪ ▪

≥ one hypomanic episode ≥ one major depressive episode Symptoms affect day-to-day functioning Not caused by other condition/substance

TREATMENT MEDICATIONS

▪ Atypical antipsychotics (e.g. olanzapine), in combination with mood stabilizers (esp. lithium)

PSYCHOTHERAPY

▪ E.g. cognitive behavioral therapy, interpersonal

MAJOR DEPRESSIVE DISORDER osms.it/major-depressive-disorder PATHOLOGY & CAUSES Depressive disorder characterized by one or more episodes of a strongly depressed mood ▪ Episodes interfere with day-to-day life in activities such as eating, working, and sleeping

CAUSES

▪ Exact cause unknown; runs in families, especially between close relatives; linked to neurotransmitter regulation (norepinephrine, serotonin, dopamine); high comorbidity with other mental disorders

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SIGNS & SYMPTOMS ▪ Major depressive episodes

DIAGNOSIS ▪ One or more major depressive episodes ▪ The symptoms cause distress in other areas of life ▪ The disturbance is not better explained by or accounted for by another medical condition or substance ▫ There has not been a manic or hypomanic episode

Chapter 92 Depressive & Bipolar Disorders MNEMONIC: SIG ED CAPS

Diagnostic criteria for Major depressive disorder Sleep: increased or decreased Interest: decreased Guilt/worthlessness Energy: decreased or fatigued Depressed mood most of the day Concentration/difficulty making decisions Appetite and/or weight increase or decrease Psychomotor activity: increased or decreased Suicidal ideation/ thoughts of death

TREATMENT MEDICATIONS

▪ Antidepressants (SSRIs, SNRIs, NDRIs)

PSYCHOTHERAPY

▪ E.g., cognitive behavioral therapy, interpersonal

OTHER INTERVENTIONS

▪ Improved diet, more exercise, more sunlight

PREMENSTRUAL DYSPHORIC DISORDER osms.it/premenstrual-dysphoric-disorder PATHOLOGY & CAUSES ▪ Depressive disorder characterized by mood changes during menstrual cycle

CAUSES

▪ Unknown; possible sensitivity to hormonal changes

SIGNS & SYMPTOMS ▪ Emotional ▫ Affective lability ▫ Irritability/anger ▫ Anxiety/angst ▪ Other symptoms ▫ Diminished interest/pleasure ▫ Decreased concentration ▫ Fatigue ▫ Weight loss/gain

▫ Inability to sleep/oversleeping ▫ Feelings of being overwhelmed ▫ Mild physical symptoms (e.g. tenderness/swelling)

DIAGNOSIS ▪ Mood changes ≤ one week before menses, as evidenced by presence of ≥ five of symptoms (≥ one from each category), resolving within one week post-menses ▪ Must occur during majority of menstrual cycles over past year ▪ Symptoms affect day-to-day life ▪ Not caused by other condition/substance

OSMOSIS.ORG 703

TREATMENT MEDICATIONS

▪ SSRIs, oral contraceptives

PSYCHOTHERAPY

▪ E.g. cognitive behavioral therapy, interpersonal

OTHER INTERVENTIONS

▪ Lifestyle changes: improved diet, more exercise, more sunlight

SEASONAL AFFECTIVE DISORDER osms.it/seasonal-affective-disorder PATHOLOGY & CAUSES ▪ Depressive disorder characterized by one or more episodes of a strongly depressed mood ▪ Episodes interfere with day-to-day life in activities such as eating, working, and sleeping ▪ Occurs most commonly in seasons of lower light, like winter

CAUSES

▪ Exact cause unknown; runs in families, especially between close relatives; linked to neurotransmitter regulation (norepinephrine, serotonin, dopamine); high comorbidity with other mental disorders

SIGNS & SYMPTOMS ▪ Major depressive episodes

DIAGNOSIS ▪ One or more major depressive episodes ▪ The symptoms cause distress in other areas of life ▪ The disturbance is not better explained by or accounted for by another medical condition or substance ▫ There has not been a manic or hypomanic episode

TREATMENT MEDICATIONS

▪ Antidepressants (SSRIs, SNRIs, NDRIs)

PSYCHOTHERAPY

▪ E.g. cognitive behavioral therapy, interpersonal

OTHER INTERVENTIONS

▪ Improved diet, more exercise, more sunlight

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NOTES

ELIMINATION DISORDERS GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES

DIAGNOSIS

▪ Repeated voluntary/involuntary passage of feces/urine into inappropriate places ▫ Encopresis: feces ▫ Enuresis: urine ▪ Disorders can be functional; often explained by/causing distress

▪ Repeated voluntary/involuntary passage of feces/urine into inappropriate places ▪ > five years old ▪ Not caused by other condition/substance

CAUSES

MEDICATIONS

▪ Genetic, environmental

TREATMENT ▪ Laxatives, desmopressin, to manage elimination

SIGNS & SYMPTOMS ▪ Repeated voluntary/involuntary passage of feces/urine into inappropriate places

PSYCHOTHERAPY

▪ E.g. cognitive behavioral therapy

ENCOPRESIS osms.it/encopresis PATHOLOGY & CAUSES ▪ Repeated voluntary/involuntary passage of feces into inappropriate places ▪ Often functional, caused by overflow due to withholding feces (e.g. fear of defecation); constipation-related ▪ When feces deposited in abnormal places, may be neurodevelopmental/induced by fear of toilets

CAUSES

▪ Genetic, environmental ▪ Often associated with psychiatric comorbidities

SIGNS & SYMPTOMS ▪ Repeated passage, voluntary or uncontrolled, of feces into inappropriate places

DIAGNOSIS ▪ Repeated passage, voluntary or uncontrolled, of feces into inappropriate places ▪ Occurs at least once a month for three months in a row

OSMOSIS.ORG 705

▪ Age: > four years old ▪ Not caused by other condition/substance (except constipation)

TREATMENT MEDICATIONS

▪ Daily laxatives (stool softeners: 1g/kg polyethylene glycol per day)

OTHER INTERVENTIONS Dietary ▪ Avoid constipating foods ▪ Adequate hydration ▪ Increase fiber intake; fiber tablets Remove fecal impaction ▪ Polyethylene glycol/mineral oil ▪ Rectal enema

PSYCHOTHERAPY

▪ Behavioral therapy ▫ Encourage toilet usage, normalize bowel movements

ENURESIS osms.it/enuresis PATHOLOGY & CAUSES

DIAGNOSIS

▪ Repeated voluntary/involuntary passage of urine into inappropriate places ▪ Can be nocturnal, diurnal, both ▪ Can involve poor bladder control (physiological developmental reasons)/ exceeding bladder capacity

▪ Repeated voluntary/involuntary passage of urine into inappropriate places ▪ “Clinically significant”: occurs > two times per week for > three consecutive months or affects day-to-day life ▪ Age: > five years old ▪ Not caused by other substance

CAUSES

▪ Genetic, environmental; stress-related ▫ Often associated with psychiatric comorbidities ▫ More common in biological males

SIGNS & SYMPTOMS ▪ Repeated voluntary/involuntary passage of urine into inappropriate places

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TREATMENT MEDICATIONS

▪ Desmopressin (reduce urine production)

PSYCHOTHERAPY

▪ Behavioral therapy (e.g. bedtime alarm therapy), bladder program

NOTES

NOTES

FACTITIOUS DISORDERS

MUNCHAUSEN SYNDROME osms.it/munchausen-syndrome PATHOLOGY & CAUSES ▪ Fabricating/exaggerating physical/ psychological symptoms in oneself/another ▪ Both types motivated by desire for sympathy/attention

TYPES Munchausen syndrome ▪ Faking/exaggerating symptoms in oneself ▫ AKA factitious disorder Munchausen syndrome by proxy ▪ Purposefully inducing symptoms in another (e.g. a child, elder, family member, pet) ▫ AKA factitious disorder by proxy/ factitious disorder imposed on another

CAUSES

▪ High comorbidity with mood/personality disorders

SIGNS & SYMPTOMS Munchausen syndrome ▪ Feigned symptoms Munchausen syndrome by proxy ▪ Purposefully inducing symptoms in another ▪ High level of perceived interest in victim/ victim’s condition (if applicable)

DIAGNOSIS Munchausen syndrome ▪ Fabricating/exaggerating physical/ psychological symptoms ▪ Seeks self to be treated as ill/impaired/ injured Munchausen syndrome by proxy ▪ Purposefully inducing symptoms in another ▪ Seeks victim to be treated as ill/impaired/ injured ▪ Diagnosis for perpetrator, not victim Both ▪ Behavior occurs even without obvious rewards (e.g. insurance claim) ▪ Not caused by other condition ▪ Can occur once, multiple times

TREATMENT PSYCHOTHERAPY

▪ Various psychotherapy methods

Munchausen syndrome by proxy ▪ Family therapy helpful ▪ Separate perpetrator, victim ▪ Treat victim for induced illness/injury/ emotional trauma

Both types ▪ Limited but highly-relevant medical knowledge

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FEEDING & EATNG DISORDERS

GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Psychological disorders causing unhealthy relationship with food, body image ▪ Often begin in teens/early adulthood

CAUSES

▪ Genetic, environmental ▪ High comorbidity with obsessivecompulsive disorder, depression, anxiety

COMPLICATIONS

▪ Refeeding syndrome (refeeding → secretion of insulin → cells take in electrolytes from already low serum levels → even lower serum electrolyte levels → cardiac arrhythmia/death)

SIGNS & SYMPTOMS ▪ Unhealthy relationship with food (physically, mentally) ▪ Distorted view of body, belief that body weight/appearance crucial for self-worth ▪ Restrictive food intake/compensatory behaviors (purging/excessive exercise)

DIAGNOSIS ▪ See individual disorders

TREATMENT PSYCHOTHERAPY

▪ E.g. cognitive behavioral therapy

OTHER INTERVENTIONS ▪ Careful weight gain

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Chapter 95 Feeding & Eating Disorders

ANOREXIA NERVOSA osms.it/anorexia-nervosa PATHOLOGY & CAUSES ▪ Eating disorder characterized by restrictive food intake (leading to significantly low body weight), fear of weight gain, distorted view of body ▪ Often begins in teens/early adulthood

TYPES Atypical anorexia nervosa ▪ Label for individuals with anorexia symptoms without significantly low body weight Restricting anorexia nervosa ▪ Individual loses weight only by via highly restricted food intake/excessive exercise Binge-eating/purging anorexia nervosa ▪ Individual loses weight by purging (e.g. vomiting, use of laxatives/diuretics/enemas)

CAUSES

▪ Genetic (e.g. abnormalities in hunger signals), environmental (e.g. peer pressure/ forces of popular culture) ▪ High comorbidity with obsessivecompulsive disorder, depression, anxiety

COMPLICATIONS

▪ Refeeding syndrome, difficulty breathing, heart failure, brain damage, suicidal ideation, death

SIGNS & SYMPTOMS ▪ Fear of weight gain → restrictive food behaviors, purging, excessive exercise, weight checks, food rituals ▪ Restrictive food intake → electrolyte abnormalities, vitamin deficiencies, muscle loss, low creatinine levels, fatigue → brain damage, weakened bones, dry/scaly skin,

hair falls out, menstruation stops, difficulty breathing, slow heartbeat, hypotension, congestive heart failure, edema (especially in feet), bone marrow shuts down (→ dampened immune response, low energy levels, easier bleeding/bruising) ▪ If purging by vomiting: enamel erosion, parotid gland swelling, bad breath, bruised/ calloused knuckles (Russell’s sign), stomach tearing, fast heartbeat, depletion of electrolytes

DIAGNOSIS ▪ Restrictive food intake (leading to significantly low body weight) ▫ If body weight cannot be described as significantly low, diagnosis = atypical anorexia nervosa ▪ Fear of weight gain ▪ Distorted view of body ▪ Restricting type: individual has not repeatedly binge-eaten or purged over ≤ three months (instead, attempts to lose weight by restricting food intake/exercising excessively) ▪ Binge-eating/purging anorexia nervosa: repeated binge-eating/purging over ≤ three months Specify severity ▪ Mild: BMI > 17 ▪ Moderate: BMI 16–17 ▪ Severe: BMI 15–16 ▪ Extreme: BMI < 15

TREATMENT PSYCHOTHERAPY

▪ E.g. cognitive behavioral therapy

OTHER INTERVENTIONS ▪ Careful weight gain

OSMOSIS.ORG 709

BULIMIA NERVOSA osms.it/bulimia-nervosa PATHOLOGY & CAUSES ▪ Eating disorder characterized by repeated binge-eating, compensatory behaviors to prevent weight gain, belief that body weight/appearance crucial for self-worth ▪ Compensatory behaviors/”purges”: vomiting, use of laxatives/diuretics/enemas ▪ Attempts to conceal behaviors ▪ Often begins in teens/early adulthood

CAUSES

▪ Genetic (e.g. abnormalities in hunger signals), environmental (e.g. peer pressure/ forces of popular culture) ▪ High comorbidity with obsessivecompulsive disorder, depression, anxiety

COMPLICATIONS

▪ Refeeding syndrome, diabetes mellitus, fast heartbeat, suicidal ideation, death

SIGNS & SYMPTOMS ▪ Binge-eating, compensatory behaviors (usually purposeful vomiting) ▪ Endocrine changes → menstruation stops/ never starts, increased risk of diabetes mellitus ▪ If purging by vomiting: enamel erosion, parotid gland swelling, bad breath, bruised/ calloused knuckles (Russell’s sign), stomach tearing, fast heartbeat, depletion of electrolytes

▪ Compensatory behaviors to prevent weight gain, concurrent with binge-eating ▪ Distorted view of body, belief that body weight/appearance crucial for self-worth Specify severity ▪ Mild: 1–3 compensatory behaviors/week ▪ Moderate: 4–7 compensatory behaviors/ week ▪ Severe: 8–13 compensatory behaviors/ week ▪ Extreme: > 14 compensatory behaviors/ week

TREATMENT MEDICATIONS

▪ Antidepressants (e.g. selective serotonin reuptake inhibitors)

PSYCHOTHERAPY

▪ E.g. cognitive behavioral therapy

OTHER INTERVENTIONS ▪ Careful weight gain

DIAGNOSIS ▪ Must occur exclusive of anorexia nervosa ▪ Repeated binge-eating over ≤ three months ▪ Binge-eating classification requires sense of loss of control

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Figure 95.1 Erosion of the enamel of the mandibular teeth of an individual with bulimia nervosa.

NOTES

NOTES

NEURODEVELOPMENTAL DISORDERS

GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Mental disorders causing difficulties in everyday activities/skills (e.g. communication, learning), occurring over an extended period, beginning during development ▪ Often causes social isolation/anxiety → depression

SIGNS & SYMPTOMS ▪ See individual disorders

DIAGNOSIS ▪ See individual disorders

TREATMENT

CAUSES

▪ Genetic, environmental

▪ Not curative ▪ See individual disorders

COMPLICATIONS

▪ Reduced success in various areas of life (esp. social, academic)

ATTENTION DEFICIT HYPERACTIVITY DISORDER (ADHD) osms.it/ADHD PATHOLOGY & CAUSES ▪ Developmental disorder characterized by inattentiveness/hyperactivity/impulsiveness, lasting for > six months

TYPES

▪ Inattentive, hyperactive/impulsive, or both

CAUSES

▪ Genetic, environmental ▪ Associated with neurotransmitter activity (low amounts of dopamine/norepinephrine)

COMPLICATIONS

▪ Reduced success in various areas of life (esp. social, academic)

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SIGNS & SYMPTOMS ▪ Inattentiveness (careless mistakes, not listening, easily distracted) ▪ Hyperactivity/impulsiveness (restlessness) ▪ Developmental delay (e.g. in linguistic/ social/ motor skills)

DIAGNOSIS ▪ For inattentive diagnosis, ≥ six of following (≥ five if age > 16) ▫ Makes careless mistakes/overlooks details ▫ Struggles to stay focused ▫ Doesn’t appear to listen ▫ Doesn’t follow instructions ▫ Has poor organizational skills ▫ Avoids mentally-engaging tasks ▫ Often loses things ▫ Is easily distracted ▫ Is forgetful ▪ For a hyperactive/impulsive diagnosis, ≥ six of following (≥ five if age > 16) ▫ Often fidgets

▫ Struggles to stay seated ▫ Restless ▫ Struggles to keep quiet ▫ Likes to keep moving ▫ Talks before others have finished ▫ Doesn’t like waiting ▫ Interrupts/bothers others ▪ Symptoms for either category must ▫ Persist > six months ▫ Present < 12 years old ▫ Present in multiple settings ▫ Affect day-to-day functioning ▫ Not caused by other condition

TREATMENT MEDICATIONS

▪ Stimulants to slowly release neurotransmitter (e.g. amphetamines = Adderall/ methylphenidate = Ritalin)

PSYCHOTHERAPY

▪ Behavioral therapy focused on decreasing distractions/improving time management, organizational skills

AUTISM SPECTRUM DISORDER (ASD) osms.it/autism PATHOLOGY & CAUSES ▪ Developmental disorder characterized by difficulties with social interaction/ communication as well as restricted/ repetitive behaviors, interests, activities ▪ Encompasses autism, Asperger syndrome, childhood disintegrative disorder, and PDDNOS (pervasive developmental disorder not otherwise specified)

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CAUSES

▪ Genetic, environmental

COMPLICATIONS

▪ Reduced success in various areas of life (esp. social, academic)

Chapter 96 Neurodevelopmental Disorders

SIGNS & SYMPTOMS ▪ Difficulties with social interaction, communication (doesn’t understand others’ emotions/respond to them, struggles to make friends) ▪ Restricted/repetitive nature regarding particular behaviors/interests/activities

DIAGNOSIS ▪ Struggles with social interaction/ communication ▫ Poor emotional reciprocity (doesn’t respond to/communicate emotions, thoughts) ▫ Poor non-verbal communication (especially poor understanding thereof) ▫ Impaired joint attention (doesn’t share interests with others) ▫ Difficulty in developing/maintaining relationships

▪ Restricted/repetitive behaviors, interests, or activities, with ≥ two of following ▫ Repetition of particular movements/ phrases ▫ Specific routines/rituals, resistant to change ▫ Restricted interests (e.g. highly specific knowledge in a subject) ▫ Highly sensitive to/interested in surroundings ▪ Symptoms must have been present in development, and affect day-to-day functioning ▪ Not caused by other condition

TREATMENT PSYCHOTHERAPY

▪ Educational programs, behavioral therapy tailored to individual

DISRUPTIVE, IMPULSE CONTROL, AND CONDUCT DISORDERS osms.it/conduct-disorder PATHOLOGY & CAUSES ▪ Mental disorders characterized by impulsive behaviors or a general lack of self-control ▪ No underlying motives for resulting behaviors ▪ Tend to start in childhood and persist into adulthood ▪ Includes ▫ Conduct disorders ▫ Intermittent explosive disorder ▫ Oppositional defiant disorder ▫ Pyromania ▫ Kleptomania

CAUSES

▪ Generally unknown (genetic + environmental); tend to run in families

MNEMONIC

Conduct disorders are seen in Children Antisocial personality disorder is seen in Adults

OSMOSIS.ORG 713

SIGNS & SYMPTOMS ▪ Persistent, aggressive or harmful behaviors ▫ May involve aggression or harm towards other individuals or animals ▫ May involve damage to or stealing physical property

DIAGNOSIS ▪ Multiple impulsive behaviors observed over an extended period of time

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TREATMENT PSYCHOTHERAPHY

▪ Focused on therapy, not medications ▪ Cognitive behavioral therapy, social skills training, anger management, parent management training

Chapter 96 Neurodevelopmental Disorders

LEARNING DISABILITY osms.it/learning-disability PATHOLOGY & CAUSES ▪ Difficulty with learning/developing certain skills

TYPES

▪ Dyslexia: difficulty reading ▪ Dysgraphia: difficulty writing ▪ Dyscalculia: difficulty with mathematics

CAUSES

▪ Genetic, environmental ▪ Not due to lack of intelligence/desire to learn/education

COMPLICATIONS

▪ Reduced success in various areas of life (esp. academic)

SIGNS & SYMPTOMS ▪ Difficulty with learning/developing certain skills ▫ Dyslexia: slow, effortful reading/poor understanding ▫ Dysgraphia: poor spelling, grammar, handwriting ▫ Dyscalculia: poor arithmetic ▪ Often comorbid with anxiety, depression

DIAGNOSIS ▪ ≥ one of following for at ≥ six months ▫ Poor reading skills ▫ Poor reading comprehension ▫ Difficulties with spelling ▫ Other difficulties with written language ▫ Trouble with mathematics ▫ Trouble with mathematical reasoning ▪ Academic skills significantly lower than what would otherwise be expected, as confirmed by testing ▫ Learning difficulties must begin during school years but may not be problematic until later ▪ Not caused by other condition/ environmental factor

TREATMENT OTHER INTERVENTIONS

▪ Modified approaches to education (e.g. one on one tutoring) ▪ Specific techniques/workarounds dependent on symptoms (e.g. using specific fonts to alleviate dyslexia)

OSMOSIS.ORG 715

TOURETTE SYNDROME osms.it/tourette-syndrome PATHOLOGY & CAUSES

DIAGNOSIS ≥ two motor tics, ≥ one vocal tic Must last ≥ one year from first tic Must start < 18 years old Not caused by other condition/substance

▪ Developmental disorder characterized by tics (rapid, repeated, involuntary, often inappropriate movements/vocalizations) ▫ Simple: short, involving particular body part ▫ Complex: comprised of multiple simultaneous tics

▪ ▪ ▪ ▪

TYPES

MEDICATIONS

▪ Motor tics: repeating movements of others (echopraxia), making obscene gestures (copropraxia) ▪ Vocal tics: repeating same words/ phrases (echolalia, palilalia), blurting out inappropriate language (coprolalia)

CAUSES

▪ Genetic, environmental

COMPLICATIONS

▪ Often comorbid with anxiety, depression

SIGNS & SYMPTOMS ▪ Simple/complex tics of either/both types

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TREATMENT ▪ Antipsychotics/epilepsy medications (only in severe cases) ▪ Botox injections may decrease appearance of facial tics

PSYCHOTHERAPY

▪ Cognitive behavioral therapy ▪ Habit reversal training

NOTES

NOTES

OBSESSIVE-COMPULSIVE DISORDERS

GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Mental disorders characterized by obsessions and/or compulsions ▪ Obsessions: recurrent, intrusive thoughts (often causing anxiety) ▪ Compulsions: repeated, purposeful, ritualistic behaviors (often attempts to alleviate anxiety from obsessions) ▪ Obsessions/compulsions give feelings of gratification but affect day-to-day life

CAUSES

▪ Genetic, often associated with psychiatric comorbidities ▪ Can lead to depressive/substance use disorders

DIAGNOSIS ▪ Presence of obsessions, compulsions ▪ Not caused by other condition/substance

TREATMENT MEDICATIONS

▪ Selective serotonin reuptake inhibitors (SSRIs), other antidepressants

PSYCHOTHERAPY

▪ E.g. cognitive behavioral therapy

SIGNS & SYMPTOMS ▪ Obsessions, compulsions causing distress

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BODY DYSMORPHIC DISORDER osms.it/BDD PATHOLOGY & CAUSES

DIAGNOSIS

▪ Characterized by an obsessive belief that one’s appearance is flawed ▪ Can cause compulsive behaviors (e.g. excessive grooming)

▪ Not caused by other condition/substance

CAUSES

▪ No consensus on optimal treatment

▪ Genetic, environmental; linked to issues with serotonin neurotransmitters

SIGNS & SYMPTOMS ▪ Obsessive belief that one’s appearance is flawed ▪ Compulsive behaviors in response ▪ Distress affects day-to-day functioning

TREATMENT

MEDICATIONS

▪ SSRIs and other antidepressants

PSYCHOTHERAPY

▪ Cognitive behavioral therapy

BODY FOCUSED REPETITIVE DISORDERS osms.it/repetitive-disorders PATHOLOGY & CAUSES TYPES Excoriation disorder ▪ Characterized by compulsive skin-picking ▪ Can lead to infection/tissue damage Trichotillomania ▪ Characterized by compulsive hair-pulling

CAUSES

▪ High comorbidity with other mood disorders; stress-related ▪ Trichotillomania: genetic

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SIGNS & SYMPTOMS ▪ Purposeful skin-picking (excoriation) or hair-pulling (trichotillomania) with associated damage ▪ Causes distress in other areas of life

DIAGNOSIS ▪ Not explained by any other condition/ substance

Chapter 97 Obsessive-Compulsive Disorders

TREATMENT ▪ No consensus on optimal treatment

MEDICATIONS

▪ SSRIs and other antidepressants

PSYCHOTHERAPY

▪ Cognitive behavioral therapy

OTHER INTERVENTIONS

▪ Physical prevention (e.g. covering exposed skin or hair)

Figure 97.1 An individual with excoriation syndrome and numerous, small skin sores caused by constant skin scratching and picking.

OBSESSIVE–COMPULSIVE DISORDER osms.it/OCD PATHOLOGY & CAUSES ▪ Characterized by obsessions and/or compulsions ▪ Obsessions, compulsions vary in scope, type

CAUSES

▪ Genetic, environmental; linked to issues with serotonin neurotransmitters

SIGNS & SYMPTOMS ▪ Obsessions (e.g. with germs, unsafeness) and/or compulsions (e.g. repeated handwashing, checking stove burner) ▪ Distress affects day-to-day functioning

DIAGNOSIS ▪ Obsessions and/or compulsions ▫ Must be time consuming (affecting dayto-day life) ▫ Must not be caused by effects of a substance or other medical condition ▪ Not explained by other condition/substance

TREATMENT MEDICATIONS

▪ SSRIs, other antidepressants

PSYCHOTHERAPY

▪ E.g. cognitive behavioral therapy (exposure and response therapy)

OSMOSIS.ORG 719

NOTES

NOTES

PERSONALITY DISORDERS: CLUSTER A

GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Deviations from cultural expectations → worsens day-to-day life, relationships. ▪ Paranoid, schizoid, schizotypal personality disorders

TREATMENT PSYCHOTHERAPY

▪ Focused on supporting individual, not challenging beliefs ▫ Challenging beliefs often elicits negative responses, affects treatment

CAUSES

▪ May be genetic, environmental ▪ Linked to schizophrenia (esp. schizotypal)

SIGNS & SYMPTOMS ▪ Unusual behavior ▪ Poor relationships

DIAGNOSIS ▪ Unusual behaviors/traits ▪ Not explained by other condition/substance

Figure 98.1 Illustration depicting different types of cluster A personality disorders.

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Chapter 98 Personality Disorders: Cluster A

PARANOID PERSONALITY DISORDER osms.it/paranoid-personality-disorder PATHOLOGY & CAUSES

DIAGNOSIS

▪ Overlaps with schizotypal personality disorder ▪ Generally distrustful of others; demands loyalty of family, friends ▪ Individual harbors grudges if feeling lied to/ slighted ▪ Suspiciousness damages relationships

▪ ≥ four of following ▫ Irrational belief that others are harmful/ deceptive ▫ Doubts trustworthiness of close individuals ▫ Reluctance to confide in others, fearing it may be used against oneself ▫ Sees hidden threats in everyday scenarios ▫ Holds prolonged grudges ▫ Constantly feels attacked ▫ Suspicion of partner’s fidelity ▫ Not explained by other condition/ substance

CAUSES

▪ May be genetic, environmental

SIGNS & SYMPTOMS ▪ Excessive distrust of others ▪ Prolonged grudges, superficial relationships, isolation

TREATMENT PSYCHOTHERAPY

▪ Aimed at improving social understanding; can be challenging due to trust issues

Figure 98.2 Illustration depicting thoughts and symptoms of paranoid personality disorder.

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SCHIZOID PERSONALITY DISORDER osms.it/schizoid-personality-disorder PATHOLOGY & CAUSES

DIAGNOSIS

▪ Overlaps with negative symptoms of schizophrenia (blunted emotions/flat affect) ▪ Disinterested in, avoids social interaction ▫ Not caused by paranoia/social anxiety ▪ Dislikes physical contact

▪ ≥ four of following ▫ Does not want/enjoy close relationships ▫ Prefers solitude ▫ Lack of interest in sexual activities ▫ Hard to please ▫ Lacks close friends ▫ Unbothered by others’ comments ▫ Flat affect/emotional blunting ▫ Not explained by other condition/ substance

CAUSES

▪ May be genetic, environmental

SIGNS & SYMPTOMS ▪ ▪ ▪ ▪

Flat affect/blunted emotions Lack of desire for intimacy Chooses solitary activities Takes pleasure in few activities

TREATMENT PSYCHOTHERAPY

▪ Aimed at improving social understanding; can be challenging due to trust issues

Figure 98.3 Illustration depicting thoughts and symptoms of schizoid personality disorder.

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Chapter 98 Personality Disorders: Cluster A

SCHIZOTYPAL PERSONALITY DISORDER osms.it/schizotypal-personality-disorder PATHOLOGY & CAUSES

DIAGNOSIS

▪ Overlaps with paranoid personality disorder ▪ Excessive magical thinking (linking unrelated events) ▪ Ideas of reference (believes everything relates to personal destiny) ▪ Beliefs cause overconfidence, self-centered thinking ▪ Poor at gauging how others perceive them ▪ Maintain desire for relationships (unlike schizoid) ▫ schizoiD = “Distant” ▫ schizoTypal = “magical Thinking”

▪ ≥ five of following ▫ Ideas of reference ▫ Magical thinking that changes behavior ▫ Altered perception ▫ Unusual thinking/talking ▫ Suspiciousness/paranoia ▫ Inappropriate/flat affect ▫ Eccentric/unusual behavior ▫ Lack of close friends ▫ Social anxiety (related to paranoia, not fear of judgment) ▪ Not explained by other condition/substance

CAUSES

▪ May be genetic, environmental ▪ Linked to schizophrenia

SIGNS & SYMPTOMS

TREATMENT PSYCHOTHERAPY

▪ Aimed at improving social understanding; can be challenging due to trust issues

▪ Ideas of reference ▪ Altered perception ▪ Unusual thinking/talking (vague, not incoherent) ▪ Paranoia/anxiety

Figure 98.4 Illustration depicting thoughts and symptoms of schizotypal personality disorder.

OSMOSIS.ORG 723

NOTES

NOTES

PERSONALITY DISORDERS: CLUSTER B

GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES

DIAGNOSIS

▪ Antisocial, borderline, histrionic, narcissistic personality disorders ▪ Deviations from cultural expectations → affects day-to-day life, relationships ▪ Linked to depressive, substance use disorders

▪ Unusual behaviors/traits ▪ Not explained by other condition/substance

CAUSES

▪ May be genetic, environmental

SIGNS & SYMPTOMS

TREATMENT MEDICATIONS

▪ Antidepressants

PSYCHOTHERAPY

▪ See individual disorders

▪ Unusual behavior ▪ Poor relationships

Figure 99.1 Illustration depicting the four cluster B personality disorders: antisocial personality disorder, borderline personality disorder, histrionic personality disorder, and narcissistic personality disorder.

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Chapter 99 Personality Disorders: Cluster B

ANTISOCIAL PERSONALITY DISORDER osms.it/antisocial-personality-disorder PATHOLOGY & CAUSES

DIAGNOSIS

▪ Uses charisma to manipulate others. ▪ Disregard for moral values, societal norms, rights of others ▪ Poor impulse control, lacks empathy ▪ Willing to hurt others for own benefit → aggressive, unlawful behavior → often given “sociopath”/“psychopath” label ▪ Associated with substance use disorders, overrepresented in prisons

▪ ≥ three of following ▫ Does not conform to societal norms ▫ Deceitful ▫ Impulsive ▫ Irritable/aggressive ▫ Reckless ▫ Irresponsible ▫ Unremorseful ▪ Age > 18, conduct disorder since age < 15 ▪ Not explained by other condition

CAUSES

▪ May be genetic, environmental; more common in biological males

SIGNS & SYMPTOMS ▪ Outwardly normal behavior ▪ Hidden hostility, callousness, disregard for others

MNEMONIC: CC/AA

Conduct disorder/antisocial personality disorder Conduct disorder is seen in children Antisocial personality disorder is seen in adults

TREATMENT PSYCHOTHERAPY ▪ E.g. self help groups

Figure 99.2 Illustration depicting thoughts and symptoms of antisocial personality disorder.

OSMOSIS.ORG 725

BORDERLINE PERSONALITY DISORDER osms.it/borderline-personality-disorder PATHOLOGY & CAUSES ▪ Unstable moods (intense joy ← → rage) ▪ Intense relationships that sour over time ▪ “Stable instability” (consistent pattern of instability) ▪ Splitting (extreme perspectives: things seen as completely good/completely bad) ▪ Fear of abandonment

CAUSES

▪ May be genetic, environmental

SIGNS & SYMPTOMS ▪ ▪ ▪ ▪

Unstable mood Fear of abandonment (real/imagined) Splitting Suicidal/self-harming behavior

DIAGNOSIS ▪ ≥ five of following ▫ Frantic avoidance of abandonment ▫ Unstable, intense relationships ▫ Unstable self-image ▫ Self-destructive impulsivity ▫ Suicidal/self-harming behavior ▫ Emotional instability ▫ Feeling empty ▫ Anger management issues ▫ Transient paranoid thinking ▫ Not explained by other condition

TREATMENT MEDICATIONS

▪ Antipsychotics, antidepressants

PSYCHOTHERAPY

▪ E.g. dialectical behavior therapy, mentalization-based therapy, transferencefocused therapy

Figure 99.3 Illustration depicting thoughts and symptoms of borderline personality disorder.

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Chapter 99 Personality Disorders: Cluster B

HISTRIONIC PERSONALITY DISORDER osms.it/histrionic-personality-disorder

▪ ▪ ▪ ▪

PATHOLOGY & CAUSES

DIAGNOSIS

Attention-seeking, excessive emotionality. Manipulative tendencies Superficial relationships Shallow, flighty, egocentric

▪ ≥ five of following ▫ Must be center of attention ▫ Inappropriate (e.g. provocative) interactions ▫ Fast changing, shallow emotions ▫ Uses appearance to draw attention ▫ Vague speech ▫ Exaggerated manner ▫ Easily affected by others/situations ▫ Mistakes relationships as more intimate ▪ Not explained by other condition

CAUSES

▪ May be genetic, environmental

SIGNS & SYMPTOMS ▪ Exaggerated thoughts, feelings (e.g. tantrums) ▪ Superficial relationships ▪ Excessively seductive behavior ▪ Attention-seeking behavior

TREATMENT PSYCHOTHERAPY

▪ Psychoanalytic therapy

Figure 99.4 Illustration depicting thoughts and symptoms of histrionic personality disorder.

OSMOSIS.ORG 727

NARCISSISTIC PERSONALITY DISORDER osms.it/narcissistic-personality-disorder PATHOLOGY & CAUSES ▪ ▪ ▪ ▪ ▪ ▪ ▪

Grandiose self-image Demands special treatment Thinks ideas are best, should be supported Fragile self-esteem, lashes out if slighted Lacks empathy Exploitative of others Only involved in what advances personal agenda

CAUSES

▪ May be genetic, environmental

SIGNS & SYMPTOMS ▪ ▪ ▪ ▪

Sense of entitlement Arrogant behavior Vulnerable to criticism Exploitative of others

DIAGNOSIS ▪ ≥ five of following ▫ Grandiose self-image ▫ Fantasies of grandiosity ▫ Believes they are “special” ▫ Seeks admiration ▫ Entitled ▫ Exploitative ▫ Thoughtless ▫ Envious/jealous ▫ Arrogant ▪ Not explained by other condition

TREATMENT MEDICATIONS

▪ Lithium, SSRIs, other antidepressants

PSYCHOTHERAPY

▪ Psychoanalytic therapy, group therapy

Figure 99.5 Illustration depicting thoughts and symptoms of narcissistic personality disorder.

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NOTES

NOTES

PERSONALITY DISORDERS: CLUSTER C

GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Avoidant, obsessive-compulsive and dependent personality disorder ▪ Deviations from cultural expectations → worsens day-to-day life and relationships

CAUSES

▪ May be genetic, environmental ▪ Linked to anxiety disorders

SIGNS & SYMPTOMS

DIAGNOSIS ▪ Unusual behaviors/traits ▪ Not explained by other condition/substance

TREATMENT MEDICATIONS

▪ Antidepressants

PSYCHOTHERAPY

▪ E.g. behavioral therapy, group therapy, assertiveness training

▪ Unusual behavior ▪ Poor relationships

Figure 100.1 Illustration depicting the three cluster C personality disorders: avoidant personality disorder, obsessive-compulsive personality disorder, and dependent personality disorder.

OSMOSIS.ORG 729

AVOIDANT PERSONALITY DISORDER osms.it/avoidant-personality-disorder PATHOLOGY & CAUSES

DIAGNOSIS

▪ Shyness, social inhibition, low self-esteem ▪ Wants close relationships, but doesn’t take social risks ▪ Hypersensitive to rejection, criticism ▪ Overlap with dependent personality disorder, others from clusters A, B

▪ ≥ four of following ▫ Avoids social situations ▫ Unwillingness to interact ▫ Limits intimate relationships ▫ Preoccupation with rejection, criticism ▫ Low self-esteem ▫ Fears embarrassment associated with social risk-taking ▪ Not explained by other condition/substance

SIGNS & SYMPTOMS ▪ Hypersensitivity to rejection, criticism ▪ Resulting timidness ▪ Desire for relationships

TREATMENT MEDICATIONS

▪ Beta blockers, selective serotonin reuptake inhibitors (SSRIs)

PSYCHOTHERAPY

▪ E.g. group therapy, assertiveness training

Figure 100.2 Illustration depicting thoughts/symptoms typical of avoidant personality disorder.

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Chapter 100 Personality Disorders: Cluster C

OBSESSIVE-COMPULSIVE PERSONALITY DISORDER osms.it/obessive-complusive PATHOLOGY & CAUSES ▪ Obsessed with orderliness, perfection, need to be in control ▪ Inflexible, easily stressed, inefficient (because of excessive planning) ▪ Rigid beliefs → “stubborn” label ▪ OCD ego-dystonic; OCPD ego-syntonic

SIGNS & SYMPTOMS ▪ ▪ ▪ ▪

Preoccupation with rules, details, perfection Rigid, inflexible behavior Lacking sense of humor Indecisive (for fear of making wrong decision)

DIAGNOSIS ▪ ≥ four of following ▫ Preoccupation with details ▫ Disruptive perfectionism ▫ Work eclipses personal life ▫ Rigid, loud beliefs (religious, ethical) ▫ Tendency to hoard possessions ▫ Refuses to delegate ▫ Excessively frugal ▫ Stubbornness ▪ Not explained by other condition/substance

TREATMENT MEDICATIONS

▪ SSRIs, benzodiazepines

PSYCHOTHERAPY

▪ Cognitive behavioral therapy, group therapy

Figure 100.3 Illustration depicting differences between obsessive compulsive disorder and obsessive compulsive personality disorder.

OSMOSIS.ORG 731

DEPENDENT PERSONALITY DISORDER osms.it/dependent-personality-disorder

▪ ▪ ▪ ▪ ▪ ▪

PATHOLOGY & CAUSES

DIAGNOSIS

Excessive fear of separation/rejection Overly dependent on others Lack self-confidence Overly indecisive Possessive of individuals they depend on Overlap with avoidant personality disorder, others from clusters A, B

▪ ≥ five of following ▫ Can’t make everyday decisions ▫ Overly dependent on others ▫ Scared to disagree with others ▫ Lack of self-motivation ▫ Craves approval ▫ Uncomfortable/afraid of being alone ▫ Quick to replace lost relationships ▪ Not explained by other condition/substance

SIGNS & SYMPTOMS ▪ Dependent, submissive ▪ Overly indecisive ▪ Clings onto others

TREATMENT MEDICATIONS

▪ SSRIs, benzodiazepines

PSYCHOTHERAPY

▪ E.g. insight oriented, behavioral, family, group, assertiveness training

Figure 100.4 Illustration depicting thoughts/symptoms typical of dependent personality disorder.

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NOTES

NOTES

SCHIZOPHRENIA & PSYCHOTIC DISORDERS

GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Mental disorders characterized by fragmented patterns of thinking ▪ Feature positive, negative symptoms

CAUSES

▪ Multiple factors: genetic vulnerability, physiological/biochemical dysfunction, psychosocial stressors

SIGNS & SYMPTOMS Positive (psychotic) symptoms ▪ Delusions ▫ False beliefs remaining even when opposing evidence presented (e.g. delusions of control/reference) ▪ Hallucinations ▫ Perceptual experiences occurring without sensory stimuli (e.g. visual, auditory, tactile hallucinations) ▪ Disorganized speech (e.g. word salad) ▪ Disorganized behavior (e.g. wearing warm clothes on a hot day; may include catatonic behavior; e.g. resistant movement/ unresponsiveness)

Negative symptoms ▪ Impairment of normal functioning in emotional expression, communication, purposeful activities ▫ Flat affect (less emotional response) ▫ Alogia (lack of content in speech) ▫ Avolition (decrease in motivation) Cognitive symptoms ▪ Difficulties with memory, learning, understanding Mood-related symptoms ▪ Sometimes

DIAGNOSIS ▪ Based on symptoms’ presence over certain time period (varies by disorder) ▪ Affects day-to-day functioning (e.g. social, occupational, academic) ▪ Not caused by other condition/substance

TREATMENT MEDICATIONS ▪ Antipsychotics

PSYCHOTHERAPY

▪ E.g. individual/group therapy, rehabilitation

OSMOSIS.ORG 733

Figure 101.1 Illustration depicting positive, negative, and cognitive syjmptoms.

DELUSIONAL DISORDER osms.it/delusional-disorder PATHOLOGY & CAUSES ▪ Mental disorder characterized by persistent delusions ▪ Delusions may be bizarre (impossible)/nonbizarre (possible, but still wrong) ▪ Delusions remain even when opposing evidence presented

SIGNS & SYMPTOMS Delusions ▪ Of control ▫ Others control one’s actions/thoughts ▪ Of thought broadcasting ▫ Others can hear one’s thoughts ▪ Of thought withdrawal ▫ One’s thoughts are being stolen ▪ Nihilistic ▫ World/self doesn’t exist

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Non-bizarre delusions ▪ Persecutory ▫ Others conspiring against/following oneself ▪ Jealous ▫ One’s partner unfaithful ▪ Of guilt/sin ▫ One wrongly feels guilty ▪ Of reference ▫ One believes messages directed at them/are especially significant ▪ Somatic ▫ One’s body is diseased/changed ▪ Erotomanic ▫ Another is in love with oneself ▪ Grandiose ▫ One believes they have special talents/ abilities ▪ Religious ▫ Involving spiritual aspect

Chapter 101 Schizophrenia & Psychotic Disorders

DIAGNOSIS ▪ ≥ one delusion, over ≥ one month period, without meeting other criteria for schizophrenia ▫ Hallucinations may occur in some cases of delusional disorder ▪ Affects day-to-day functioning ▪ Not caused by other condition/substance

TREATMENT MEDICATIONS

▪ Antipsychotics, antidepressants

PSYCHOTHERAPY

▪ E.g. individual/group therapy, rehabilitation

SCHIZOAFFECTIVE DISORDER osms.it/schizoaffective-disorder PATHOLOGY & CAUSES

TREATMENT

▪ Mental disorder characterized by symptoms of schizophrenia + a mood disorder

▪ Treat depressive, schizophrenic symptoms separately

SIGNS & SYMPTOMS ▪ Positive symptoms ▫ Delusions, hallucinations, disorganized speech, disorganized behavior ▪ Negative symptoms ▫ Flat affect, alogia, avolition ▪ Mood-related symptoms ▫ Depression, suicidal ideation ▫ Manic episodes (e.g. euphoria, grandiosity, hyperactivity)

MEDICATIONS

▪ Antipsychotics, antidepressants

PSYCHOTHERAPY

▪ Dialectical behavior therapy, mentalizationbased therapy, transference-focused therapy

DIAGNOSIS ▪ ≥ two of following (+ at least one of first three) + a mood disorder ▫ Delusions ▫ Hallucinations ▫ Disorganized speech ▫ Disorganized or catatonic behavior ▫ Negative symptoms ▪ Delusions/hallucinations last ≥ two weeks beyond mood episode ▪ Not caused by other condition/substance

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SCHIZOPHRENIA osms.it/schizophrenia PATHOLOGY & CAUSES

DIAGNOSIS

▪ Mental disorder characterized by fragmented patterns of thinking for > six months ▪ Individuals cycle through three phases, normally in order ▫ Prodromal phase: socially withdrawn; blunted affect ▫ Active phase: severe positive, negative symptoms ▫ Residual phase: cognitive symptoms; periods of remission

▪ ≥ two of following (+ at least one of first three), over one month ▫ Delusions ▫ Hallucinations ▫ Disorganized speech ▫ Disorganized or catatonic behavior ▫ Negative symptoms ▪ Other signs of disturbance (with prodromal, residual symptoms) persist ≥ six months ▪ Affects day-to-day functioning ▪ Not caused by other condition/substance

CAUSES

TREATMENT

▪ Success of treatment with dopamine antagonists suggests link to increased dopamine levels ▪ Genetic; more common in biological males

MEDICATIONS

RISK FACTORS

PSYCHOTHERAPY

▪ Suicidal ideation → death

SIGNS & SYMPTOMS ▪ Positive symptoms ▫ Delusions, hallucinations, disorganized speech, disorganized behavior ▪ Negative symptoms ▫ Flat affect, alogia, avolition ▪ Cognitive symptoms ▫ Difficulties with memory, learning, understanding

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▪ Antipsychotics

▪ E.g. individual/group therapy, rehabilitation

Chapter 101 Schizophrenia & Psychotic Disorders

Figure 101.1 Illustration depicting positive, negative, and cognitive syjmptoms.

SCHIZOPHRENIFORM DISORDER osms.it/schizophreniform-disorder PATHOLOGY & CAUSES ▪ Mental disorder characterized by fragmented patterns of thinking over reduced period (1–6 months) ▪ Similar to active phase of schizophrenia (severe positive, negative symptoms), minus prodromal phase

SIGNS & SYMPTOMS ▪ Positive symptoms ▫ Delusions, hallucinations, disorganized speech, disorganized behavior ▪ Negative symptoms ▫ Flat affect, alogia, avolition ▪ Cognitive symptoms ▫ Difficulties with memory, learning, understanding

DIAGNOSIS ▪ ≥ two of following (+ at least one of first three), over one month ▫ Delusions ▫ Hallucinations ▫ Disorganized speech ▫ Disorganized or catatonic behavior ▫ Negative symptoms ▪ Other signs of disturbance (with prodromal, residual symptoms) do not persist ≥ six months (if ≥ six months, diagnosis = schizophrenia) ▪ Affects day-to-day functioning ▪ Not caused by other condition/substance

TREATMENT MEDICATIONS ▪ Antipsychotics

PSYCHOTHERAPY

▪ E.g. individual/group therapy, rehabilitation

OSMOSIS.ORG 737

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NOTES

NOTES

SEXUAL DYSFUNCTION GENERALLY, WHAT IS IT? PATHOLOGY & CAUSES

SIGNS & SYMPTOMS

▪ Sexual function disturbances, often causing distress ▪ May be lifelong/acquired, mild/moderate/ severe, generalized/situational

▪ Sexual dysfunction ▫ E.g. ↓/absent orgasmic function, altered libido ▪ Anxiety, distress

Associated factors ▪ Medical diagnoses ▫ E.g. diabetes mellitus, thyroid dysfunction ▪ Relationship issues ▫ E.g. impaired interpersonal communication, intimate partner violence ▪ Cultural/religious factors ▫ E.g. negative attitudes/prohibitions regarding sexual activity ▪ Individual vulnerabilities ▫ E.g. history of abuse, psychiatric comorbidity—anxiety, depression, intrapsychic conflict, psychosocial stressors ▪ Partner issues ▫ E.g. mental, physical, sexual health issues

DIAGNOSIS OTHER DIAGNOSTICS

▪ Based on specific sexual-disturbance presence ▫ Causing individual distress ▫ Not better explained/accounted for by another medical condition, non-sexual psychological disorder, interpersonal stress, substance

TREATMENT MEDICATIONS

▪ See individual disorders

PSYCHOTHERAPY

▪ See individual disorders

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FEMALE SEXUAL INTEREST/ AROUSAL DISORDER osms.it/female-arousal-disorder PATHOLOGY & CAUSES ▪ Disorder characterized by either absence or ↓ frequency/intensity of sexual/erotic activity or thoughts in biological females

SIGNS & SYMPTOMS ▪ Self-reported ↓/absent sexual pleasure, genital/nongenital sensations, ↓ vaginal lubrication → anxiety/distress

DIAGNOSIS OTHER DIAGNOSTICS

▪ Absence of/↓ frequency/intensity of at least three of following; persisting for ≥ six months → distress; not better explained by non-sexual factors ▫ Interest in sexual activity

▫ Sexual/erotic thoughts ▫ Sexual activity initiation; partner initiation receptivity ▫ Pleasure/excitement during ≥ 75% of sexual encounters ▫ Interest/arousal in sexual/erotic-cue settings ▫ Genital/non-genital sensation during ≥ 75% of sexual encounters

TREATMENT MEDICATIONS

▪ Flibanserin, bupropion

PSYCHOTHERAPY

▪ Cognitive-behavioral and/or psychosexual therapy

GENITO-PELVIC PAIN AND/OR PENETRATION DISORDER osms.it/genito-pelvic-pain PATHOLOGY & CAUSES ▪ Disorder characterized by difficulty with intercourse due to vulvovaginal/pelvic pain, anticipatory fear of pain during penetration, pelvic floor muscle tension during penetration ▪ Penetration concerns may be related to vaginal intercourse/other situations

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(gynecological exams, tampon insertion) Associated factors ▪ Medical conditions ▫ E.g. anatomic anomalies, atrophic vaginitis, obstetric perineal injury (e.g. episiotomy) ▪ Sexually-transmitted disease history ▪ Vulvodynia (persistent idiopathic vulvar pain)

Chapter 102 Sexual Dysfunction ▪ Low estrogen levels

SIGNS & SYMPTOMS ▪ Dyspareunia ▫ Pain described as superficial/deep; throbbing, shooting, burning ▪ Pelvic floor muscle guarding, reflexive spasms ▪ Avoidance of intimate sexual activity/ recommended gynecological exams ▪ Resulting anxiety/distress

DIAGNOSIS OTHER DIAGNOSTICS

▪ Recurring one/more difficulties persisting for ≥ six months → distress, not better explained by non-sexual factors ▫ Vaginal penetration during intercourse ▫ Vulvovaginal/pelvic pain during

intercourse/penetration attempts ▫ Fear/anxiety in anticipation of, during, after penetration ▫ Pelvic floor muscle tensing during penetration attempts

TREATMENT PSYCHOTHERAPY

▪ Cognitive-behavioral and/or psychosexual therapy

OTHER INTERVENTIONS

▪ Pelvic physical therapy ▪ Address underlying cause ▫ E.g. ospemifene for dyspareunia (vulvovaginal atrophy)

MALE HYPOACTIVE SEXUAL DESIRE DISORDER osms.it/male-hypoactive-desire PATHOLOGY & CAUSES ▪ ↓/non-existent sexual desire, interest, arousal in biological males, persisting for ≥ six months → distress, not better explained by non-sexual factors Associated factors ▪ Medical conditions ▫ E.g. impaired erectile/ejaculatory function; diabetes mellitus; hyperprolactinemia; low testosterone levels ▪ Psychological/social conditions ▫ E.g. depression, stress, substance abuse

SIGNS & SYMPTOMS ▪ Persistent, ↓/non-existent sexual desire, interest, arousal → anxiety/distress

DIAGNOSIS OTHER DIAGNOSTICS

▪ Absence of/↓ frequency/intensity of sexual desire or sexual/erotic thoughts; persisting for ≥ six months → distress; not better explained by non-sexual factor

OSMOSIS.ORG 741

TREATMENT MEDICATIONS ▪ Bupropion

PSYCHOTHERAPY

▪ Cognitive-behavioral/psychosexual therapy

ORGASMIC DYSFUNCTION osms.it/orgasmic-dysfunction PATHOLOGY & CAUSES ▪ Orgasmic sensation absence, infrequency, ↓ intensity, delay Female ▪ Female orgasmic disorder: difficulty experiencing normal orgasmic function Male ▪ Erectile dysfunction (ED): persistent inability to obtain/maintain erection ▪ Abnormal ejaculation (premature, delayed)

Male ▪ ED: presence of one of following symptoms experienced during ≥ 75% of sexual activity; persisting for ≥ six months → distress; not better explained by nonsexual cause ▫ Difficulty obtaining erection ▫ Difficulty maintaining erection ▫ ↓ erectile rigidity ▪ Abnormal ejaculation ▫ Delayed ejaculation ▫ Ejaculation infrequency/absence ▫ Premature ejaculation

SIGNS & SYMPTOMS ▪ Reported impaired orgasmic function during sexual activity ▪ Low self-esteem, ↓ sense of sexual self → depressed affect

DIAGNOSIS OTHER DIAGNOSTICS Female ▪ Presence of one of following symptoms experienced during ≥ 75% of sexual activity; persisting for ≥ six months → distress; not better explained by nonsexual cause ▫ Orgasm delay, infrequency, absence (specify if orgasm never experienced) ▫ ↓ orgasmic intensity

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TREATMENT MEDICATIONS ▪ Sildenafil

PSYCHOTHERAPY

▪ Cognitive-behavioral/psychosexual therapy

NOTES

NOTES

SLEEP & SLEEP-WAKE DISORDERS

GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Mental disorders impacting normal sleep

SIGNS & SYMPTOMS ▪ See individual disorders

CAUSES

DIAGNOSIS

▪ Stress, substance use, medical conditions

▪ See individual disorders

COMPLICATIONS

▪ Affects quantity/quality of sleep, causing lack of restorative sleep → irritability, anxiety, depression

TREATMENT ▪ See individual disorders

BRUXISM osms.it/bruxism PATHOLOGY & CAUSES

SIGNS & SYMPTOMS

▪ Repeated teeth grinding/clenching ▪ Nocturnal (sleep bruxism) or diurnal (awake bruxism) ▪ Awake variant more associated with stress

▪ Dental abfraction/attrition → hypersensitivity ▪ Tooth fractures/loosening/loss ▪ Tongue biting → crenated/scalloped tongue ▪ Cheek biting → canker sores ▪ Sleep bruxism: jaw pain in morning ▪ Awake bruxism: jaw pain increases throughout day

CAUSES

▪ Obstructive sleep apnea, misaligned teeth, stress, dehydration, medication side effects, illicit drugs

COMPLICATIONS

▪ Can cause temporomandibular joint disorder

DIAGNOSIS OTHER DIAGNOSTICS

▪ Persistent grinding/clenching of teeth ▪ Not caused by other condition

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TREATMENT MEDICATIONS

▪ Avoid stimulants, depressants

OTHER INTERVENTIONS

Figure 103.1 Bruxism causes flattening of the occlusal surfaces as seen here.

▪ Sleep bruxism: mouth guards, occlusal splints, dental plates, muscle relaxants, oral surgery ▪ Awake bruxism: behavior modification ▪ Minimize chewing

INSOMNIA osms.it/insomnia PATHOLOGY & CAUSES ▪ Repeated difficulty falling asleep, waking up throughout night, waking up too early ▪ Affects quantity/quality of sleep, causing lack of restorative sleep ▪ Individuals often self-medicate with alcohol/benzodiazepines

CAUSES

▪ Stress, stimulants, depressants, psychiatric/ physical conditions (e.g. pulmonary disease)

RISK FACTORS

▪ Heightened cortisol levels/ sensitivity ▪ Reduced levels of estrogen/progesterone ▪ Increases with age

SIGNS & SYMPTOMS ▪ Excessive time spent falling asleep ▪ Repeated waking up during night ▪ Daytime sleepiness, fatigue → irritability, anxiety, depression

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DIAGNOSIS OTHER DIAGNOSTICS

▪ Poor sleep quantity/quality, associated with ▫ Difficulty falling asleep ▫ Difficulty maintaining sleep (waking up/ being unable to fall back to sleep) ▫ Waking up too early, being unable to fall back to sleep ▪ Affects day-to-day functioning ▪ Difficulty with sleep ≥ three nights a week for ≥ three months ▪ Must have sufficient opportunity to sleep

TREATMENT MEDICATIONS

▪ Melatonin agonists, non-benzodiazepine sedatives, occasionally benzodiazepines

OTHER INTERVENTIONS

▪ Improve sleep hygiene ▫ Regular sleep schedule, exercise; reduce alcohol, caffeine, smoking (esp. in evening); avoid daytime naps and going to sleep hungry ▪ Stimulus control ▫ Use bed only to sleep; remove bright

Chapter 103 Sleep & Sleep-Wake Disorders lights, minimize noise ▪ Don’t force sleep (try for 20 min, then stop) ▪ Behavior therapy

NARCOLEPSY osms.it/narcolepsy PATHOLOGY & CAUSES ▪ Recurrent sleep phenomena (e.g. sleepiness/dreaming) during wakefulness ▪ Associated with a lack of orexin (neuropeptide) ▪ Orexin (A and B) increases state of wakefulness when binding with postsynaptic neurons ▪ Individuals fall asleep faster and enter REM faster

CAUSES

▪ Damage to orexin-transporting neurons ▫ By autoimmune process/injury)

RISK FACTORS

▪ Genetic factors, low levels of histamine, infections, autoimmune diseases

DIAGNOSIS OTHER DIAGNOSTICS

▪ Recurrent feelings of sleepiness during daytime > three times/week ≥ three months ▪ ≥ one of following ▫ Cataplexy ▫ Hypocretin deficiency ▫ Short rapid eye movement (REM) sleep ▪ Not caused by other condition/substance

TREATMENT MEDICATIONS

▪ Selective serotonin reuptake inhibitors (SSRIs), stimulants (e.g. modafinil)

SIGNS & SYMPTOMS ▪ Daytime sleepiness ▪ Cataplexy (strong emotions cause muscle weakness) ▪ Hallucinations ▫ Hypnagogic: happen when falling asleep ▫ Hypnopompic: happen when waking up ▪ Sleep paralysis ▫ Regaining consciousness while body’s muscles are paralyzed during sleep

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NIGHT TERROR osms.it/night-terror PATHOLOGY & CAUSES ▪ Repeated night/sleep terrors ▫ Periods of intense fear occurring at night ▪ Usually occur during deep non-REM sleep

CAUSES

▪ Linked to past traumatic events, sleep deprivation

DIAGNOSIS OTHER DIAGNOSTICS ▪ ▪ ▪ ▪ ▪

Presence of night terrors No recollection of imagery during episode Incomplete/absent memory of episode Affects day-to-day life Not caused by other condition/substance

TREATMENT

RISK FACTORS

▪ Most common in children (3–8 years old)

SIGNS & SYMPTOMS

OTHER INTERVENTIONS

▪ Reduce stress, follow nighttime routine ▪ Often resolves spontaneously (esp. in children)

▪ Night terrors ▫ Begins with sharp scream → individual sits up → unresponsive → when awoken, individual confused, has no memory of episode

NOCTURNAL ENURESIS osms.it/nocturnal-enuresis PATHOLOGY & CAUSES ▪ Repeated, uncontrolled passage of urine into bed/clothes, during nighttime ▪ Often occurs during REM sleep

CAUSES

▪ Poor bladder control (for physiological developmental reasons)/simply exceeding bladder capacity ▪ Genetic, environmental ▫ Comorbid with other mental disorders ▫ More common in biological males

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SIGNS & SYMPTOMS ▪ Repeated, uncontrolled passage of urine into bed/clothes during the nighttime

DIAGNOSIS OTHER DIAGNOSTICS

▪ Repeated, uncontrolled passage of urine into bed/clothes during the nighttime ▪ “Clinically significant” ▫ Occurs ≥ two times/week for ≥ three consecutive months or affects day-to-

Chapter 103 Sleep & Sleep-Wake Disorders day functioning ▪ ≥ five years old ▪ Not caused by other condition/substance

TREATMENT ▪ Often resolves spontaneously

MEDICATIONS

▪ Desmopressin → reduces urine production

PSYCHOTHERAPY

▪ Behavioral therapy ▫ Esp. bedwetting alarm therapy ▫ Moisture-detecting alarm wakes individual up during enuresis

OTHER INTERVENTIONS ▪ Bladder program ▫ To build good habits

OSMOSIS.ORG 747

NOTES

NOTES

SUBSTANCE USE & RELATED DISORDERS

GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Maladaptive pattern of substance use ▪ Dependence: inability to feel “normal” without using substance ▪ Addiction: compulsive substance use to achieve reward stimuli, despite negative effects ▪ Continued consumption causes tolerance ▫ Receptors become less sensitive, or neurons have fewer receptors (downregulation) ▫ Must consume more of substance to feel desired effect (positive reinforcement) ▪ Stopping use causes withdrawal ▫ Body predictively counters consumption symptoms; no consumption = nothing to counter ▫ Must consume more to avoid discomfort (negative reinforcement) ▪ Possibly fatal complications (e.g. cancer, heart attack, overdose)

SIGNS & SYMPTOMS ▪ Increased tolerance ▪ Upon withdrawal ▫ Anxiety, depression, irritability, fatigue, tremors, palpitations, clammy skin, dilated pupils, sweating, headaches, difficulty sleeping, vomiting, seizures, changes in vital signs

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DIAGNOSIS OTHER DIAGNOSTICS

▪ ≥ two of following ▫ Consuming more of a substance than intended ▫ Inability to cut down ▫ Use takes up a lot of time ▫ Cravings ▫ Use affects responsibilities ▫ Using in spite of social problems caused ▫ Use replaces important activities ▫ Using in physically dangerous situations ▫ Using even if it worsens a problem ▫ Developing tolerance ▫ Feeling withdrawal symptoms ▪ Mild = 2–3 symptoms, moderate = 4–5 symptoms, severe = ≥ 6 symptoms

TREATMENT MEDICATIONS

▪ To reduce cravings, mimic substance, or change its effects

PSYCHOTHERAPY

▪ E.g. motivational interviewing, cognitive behavioral therapy, peer-support programs

Chapter 104 Substance Use & Related Disorders

ALCOHOL USE DISORDER osms.it/alcohol-use-disorder PATHOLOGY & CAUSES ▪ Inability to feel “normal” without alcohol ▪ Alcohol use disorder: maladaptive pattern of alcohol consumption ▪ Alcohol = depressant ▪ Develop alcohol tolerance ▫ GABA, glutamate, dopamine, serotonin receptors become less sensitive/neurons have fewer receptors (downregulation) ▫ Must drink more to feel euphoric (positive reinforcement) ▪ Withdrawal

COMPLICATIONS

▪ Heart damage (dilated cardiomyopathy, arrhythmias, stroke), liver damage (steatosis, steatohepatosis, fibrosis, cirrhosis), pancreatitis, cancers (mouth, esophagus, throat, liver, breast), death by overdose (cardiac, respiratory depression)

SIGNS & SYMPTOMS ▪ Increased alcohol tolerance ▪ Upon withdrawal ▫ Anxiety, depression, irritability, fatigue, tremors, palpitations, clammy skin, dilated pupils, sweating, headaches, difficulty sleeping, vomiting, seizures ▫ Delirium tremens (high fever, hallucinations, intense agitation)

MNEMONIC: CANs of beer Wernicke-Korsakoff triad Confusion Ataxia Nystagmus

DIAGNOSIS OTHER DIAGNOSTICS

▪ ≥ two of following ▫ Consuming more alcohol than intended ▫ Inability to cut down ▫ Alcohol use takes up a lot of time ▫ Cravings to use alcohol ▫ Alcohol use affects responsibilities ▫ Using alcohol despite social problems ▫ Giving up important activities for alcohol ▫ Using alcohol in dangerous situations ▫ Using alcohol even if worsens a problem ▫ Becoming tolerant to alcohol ▫ Withdrawal symptoms ▪ Mild = 2–3 symptoms, moderate = 4–5 symptoms, severe = ≥ six symptoms

TREATMENT MEDICATIONS

▪ Naltrexone (reduces cravings), acamprosate (stabilizes withdrawal), disulfiram (increases ethanol sensitivity)

PSYCHOTHERAPY

▪ Motivational interviewing, cognitive behavioral therapy, peer-support programs

MNEMONIC: COAT RACK

Wernicke’s encephalopathy Confusion Ophthalmoplegia Ataxia Thiamine tx. Korsakoff’s psychosis Retrograde amnesia Anterograde amnesia Confabulation Korsakoff’s psychosis

OSMOSIS.ORG 749

Figure 104.1 Illustration showing alcohol’s effects on the hypothalamus, pituitary glands, and medulla.

Figure 104.2 Illustration showing the effects of alcohol withdrawal.

CANNABIS DEPENDENCE osms.it/cannabis_dependence PATHOLOGY & CAUSES ▪ Inability to feel “normal” without cannabis ▪ Cannabis use disorder: maladaptive pattern of cannabis use ▪ Cannabis = depressant/stimulant

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▪ Continued cannabis use causes tolerance ▫ Cannabinoid receptors become less sensitive/neurons have fewer receptors (downregulation) ▫ Must consume more to feel euphoric (positive reinforcement) ▪ Withdrawal

Chapter 104 Substance Use & Related Disorders

COMPLICATIONS

▪ Anxiety, depression, psychotic disorders (e.g. schizophrenia), hyper-inflated lungs (when smoking cannabis), chronic bronchitis, respiratory infections, heart attacks, strokes ▪ Teenagers at higher risk (developing brain more sensitive)

SIGNS & SYMPTOMS ▪ Increased cannabis tolerance ▪ Upon withdrawal ▫ Cravings, irritability, anxiety, difficulty sleeping

▫ Giving up important activities for cannabis ▫ Using cannabis in dangerous situations ▫ Using cannabis even if it worsens a problem ▫ Becoming tolerant to cannabis ▫ Withdrawal symptoms ▪ Mild = 2–3 symptoms, moderate = 4–5 symptoms, severe = ≥ six symptoms

TREATMENT PSYCHOTHERAPY

▪ Motivational interviewing

DIAGNOSIS OTHER DIAGNOSTICS

▪ ≥ two of following ▫ Consuming more cannabis than intended ▫ Inability to cut down ▫ Cannabis use takes up a lot of time ▫ Cravings to use cannabis ▫ Cannabis use affects responsibilities ▫ Using cannabis despite social problems

Figure 104.3 Illustration showing the stimulant effects of tetrahydrocannabinol (THC) versus the depressant effects of cannabidiol (CBD). CBD’s properties mean it can be used medicinally in some cases.

OSMOSIS.ORG 751

Figure 104.4 Illustration showing the potential physical and mental effects of severe cannabis dependence.

COCAINE DEPENDENCE osms.it/cocaine-dependence PATHOLOGY & CAUSES ▪ Inability to feel “normal” without cocaine ▪ Stimulant use disorder: maladaptive pattern of stimulant use ▪ Cocaine = stimulant ▪ Continued cocaine use causes tolerance ▫ Dopaminergic receptors become less sensitive/neurons have fewer receptors (downregulation) ▫ Must consume more to feel euphoric (positive reinforcement) ▪ Withdrawal

COMPLICATIONS

▪ Hyperthermia, seizures, stroke, brain hemorrhage, heart attack, death by overdose

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SIGNS & SYMPTOMS ▪ Increased cocaine tolerance ▪ Upon withdrawal ▫ Depression, anxiety, fatigue, reduced concentration, cravings, tiredness, increased appetite, excessive sleeping, vivid dreaming, suicidal ideation, nausea, vomiting, hallucinations

DIAGNOSIS OTHER DIAGNOSTICS

▪ ≥ two of following ▫ Consuming more stimulants than intended ▫ Inability to cut down ▫ Stimulant use takes up a lot of time ▫ Cravings to use stimulants ▫ Stimulant use affects responsibilities

Chapter 104 Substance Use & Related Disorders ▫ Using stimulants despite social problems ▫ Giving up important activities for stimulants ▫ Using stimulants in dangerous situations ▫ Using stimulants even if they worsen a problem ▫ Becoming tolerant to stimulants ▫ Withdrawal symptoms ▪ Mild = 2–3 symptoms, moderate = 4–5 symptoms, severe ≥ six symptoms

TREATMENT MEDICATIONS

▪ Modafinil (stimulates, reduces cravings)

PSYCHOTHERAPY

▪ Motivational interviewing, peer-support programs

Figure 104.6 An individual with a perforated nasal septum secondary to cocaine abuse. Cocaine causes vasoconstriction and ischemic necrosis. The hole has been closed with a translucent silicone button to provie structural support.

Figure 104.5 Illustration showing the symptoms of cocaine withdrawal.

OSMOSIS.ORG 753

Figure 104.7 Illustration showing some of the recommended approaches to immediate treatment of someone experiencing a cocaine overdose.

OPIOID DEPENDENCE osms.it/opioid-dependence PATHOLOGY & CAUSES ▪ Inability to feel “normal” without opioid use ▪ Opioid use disorder: maladaptive pattern of opioid use ▪ Opioids = depressants ▪ Continued opioid use causes tolerance ▫ Opioid receptors become less sensitive, /neurons have fewer receptors (downregulation) ▫ Must use more to feel euphoric (positive reinforcement) ▪ Withdrawal

COMPLICATIONS

▪ Disease transmission from shared needles, death by overdose (cardiac, respiratory depression)

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SIGNS & SYMPTOMS ▪ Increased opioid tolerance ▪ Upon withdrawal ▫ Anxiety, shivering, tremors, yawning, body aches, sweating, runny nose, abdominal cramps, diarrhea, vomiting, increased heart rate, blood pressure

DIAGNOSIS OTHER DIAGNOSTICS

▪ ≥ two of following ▫ Consuming more opioids than intended ▫ Inability to cut down ▫ Opioid use takes up a lot of time ▫ Cravings to use opioids ▫ Opioid use affects responsibilities

Chapter 104 Substance Use & Related Disorders ▫ Using opioids despite social problems ▫ Giving up important activities for opioids ▫ Using opioids in dangerous situations ▫ Using opioids even if they worsen a problem ▫ Becoming tolerant to opioids ▫ Withdrawal symptoms ▪ Mild = 2–3 symptoms, moderate = 4–5 symptoms, severe = ≥ six symptoms

TREATMENT MEDICATIONS

▪ Naloxone (blocks opioids), naltrexone, methadone (opioid for maintenance/ tapering consumption), buprenorphine

PSYCHOTHERAPY

▪ Motivational interviewing, peer-support programs, cognitive behavioral therapy

Figure 104.8 Illustration with examples of endogenous and exogenous opioids.

Figure 104.9 Illustration showing the ways opioids are most commonly self-administered by people with opioid use disorder.

OSMOSIS.ORG 755

TOBACCO DEPENDENCE osms.it/tobacco-dependence PATHOLOGY & CAUSES ▪ Inability to feel “normal” without tobacco use (nicotine) ▪ Tobacco use disorder: maladaptive pattern of tobacco use ▪ Tobacco = depressant, stimulant ▪ Continued tobacco use causes tolerance ▫ Nicotinic receptors become less sensitive/neurons have fewer receptors (downregulation) ▫ Must use more to feel euphoric (positive reinforcement) ▪ Withdrawal

▫ Using tobacco in dangerous situations ▫ Using tobacco even if it worsens a problem ▫ Becoming tolerant to tobacco ▫ Withdrawal symptoms ▪ Mild = 2–3 symptoms, moderate = 4–5 symptoms, severe = ≥ six symptoms

COMPLICATIONS

▪ Heart attack, stroke, peripheral vascular disease, pulmonary disease, cancer (mouth, throat, lungs, bladder, pancreas, uterus)

SIGNS & SYMPTOMS ▪ Increased tobacco tolerance ▪ Upon withdrawal ▫ Cravings, irritability, anxiety, anger, poor concentration, restlessness, impatience, increased appetite, weight gain, insomnia

DIAGNOSIS

Figure 104.10 An individual with tar stained fingers caused by tobacco smoking.

OTHER DIAGNOSTICS

▪ ≥ two of following ▫ Consuming more tobacco than intended ▫ Inability to cut down ▫ Tobacco use takes up a lot of time ▫ Cravings to use tobacco ▫ Tobacco use affects responsibilities ▫ Using tobacco despite social problems ▫ Giving up important activities for tobacco

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TREATMENT MEDICATIONS

▪ Nicotine replacement therapies (gum, sprays, patches) to taper dose ▪ Bupropion (antidepressant; reduces cravings, withdrawal symptoms), varenicline (reduces cravings, enjoyment of tobacco)

Chapter 104 Substance Use & Related Disorders

PSYCHOTHERAPY

▪ Motivational interviewing, peer-support programs

OTHER INTERVENTIONS

▪ Switch to electronic cigarettes

Figure 104.11 Illustration showing the effects of nicotine on the brain after binding to nicotinic receptors.

Figure 104.12 Illustration showing the half-life of nicotine, which can lead to chain smoking.

OSMOSIS.ORG 757

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NOTES

NOTES

TRAUMA– & ABUSE–RELATED DISORDERS

GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Mental disorders caused by/associated with past traumatic/stressful event ▪ Abuse: intentional mistreatment of others; may be directed at anyone; often features children or the elderly ▫ Increases risk of the target developing a mental disorder; generally results in depression or aggressiveness; may incite posttraumatic stress disorder ▪ Psychological symptoms → behavioral changes ▪ Individuals might self-medicate with substance use

SIGNS & SYMPTOMS

DIAGNOSIS ▪ See individual disorders

TREATMENT MEDICATIONS

▪ See individual disorders

PSYCHOTHERAPY

▪ Abuse-related: cognitive behavioral therapy

OTHER INTERVENTIONS ▪ Manage substance use

▪ Anxiety/fear associated with traumatic/ stressful stimuli ▪ Reduced pleasure, self-acceptance; depression; anger, aggressiveness; dissociation (detachment from present in cognitive/sensory capacity); etc.

PHYSICAL & SEXUAL ABUSE osms.it/physical_and_sexual_abuse PATHOLOGY & CAUSES ▪ Intentional injuring of others, which may include hitting, burning, or even poisoning ▪ Sexual abuse: forced or otherwise inappropriate (e.g. in age difference) sexual behavior with others

COMPLICATIONS

▪ Increases risk of the target developing a mental disorder; generally results in depression or aggressiveness; may incite posttraumatic stress disorder ▪ Severe abuse may cause prolonged or irreversible damage to the body

OSMOSIS.ORG 759

TREATMENT

SIGNS & SYMPTOMS ▪ Bruising, cuts, sores, burns or rashes; fractured or broken bones; damage to internal organs; failure to thrive ▪ Anxiety related to the abuse ▪ Dissociative reactions ▪ Depression ▪ Aggressiveness ▪ PTSD ▪ Sexual abuse ▫ Fear of or anxiety towards sexual activity ▫ Increased risk of suicide ▫ If appropriate, physical symptoms (e.g. physical trauma, STIs, UTIs)

MEDICATIONS

▪ Sexual abuse: may require emergency contraceptives or STD prophylactics

PSYCHOTHERAPY

▪ Focus on screening and prevention; may include symptomatic treatment or psychotherapy (esp. cognitive behavioral therapy)

OTHER INTERVENTIONS

▪ Medical intervention, as needed ▪ Referral to protective services for legal/ social support

DIAGNOSIS OTHER DIAGNOSTICS

▪ Based on individual history and presence of above symptoms

POSTTRAUMATIC STRESS DISORDER (PTSD) osms.it/PTSD

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PATHOLOGY & CAUSES

SIGNS & SYMPTOMS

▪ Memory of past traumatic event → recurrent mental, physical stress ▫ E.g. car crashes; sexual abuse; military service; natural disasters ▪ Psychological symptoms → behavioral changes ▪ Individuals might self-medicate with substance use ▪ Neurological factors ▫ Dysfunctions in hypothalamic-pituitaryadrenal axis/endogenous opioid system; deficits in arousal, sleep regulation; family history

▪ Psychological ▫ Nightmares, flashbacks, intrusive thoughts ▪ Behavioral ▫ Avoidance of situations/environments, hypervigilance, hyperarousal → trouble sleeping, general irritability, emotional outbursts ▪ Children less likely to show distress; often use play to express memories

Chapter 105 Trauma- and Abuse-Related Disorders

DIAGNOSIS OTHER DIAGNOSTICS

▪ Exposure to traumatic event ▪ Intrusive symptoms ▫ Recurrent, distressful memories, dreams ▫ Dissociative reactions ▫ Distress/physiological reactions in response to stimuli ▪ Avoidance of associated stimuli, psychological (e.g. memories)/tangible (e.g. places) ▪ Negative changes in thoughts, feelings ▪ Increased sensitivity to event, associated stimuli ▪ Disturbance lasts > one month → distress in other areas of life

▪ Disturbance cannot be better explained by another condition/substance

TREATMENT MEDICATIONS

▪ Antidepressants, esp. selective serotonin reuptake inhibitors (SSRIs); anti-anxiety; sleep aids

PSYCHOTHERAPY

▪ Exposure, group therapy

OTHER INTERVENTIONS ▪ Manage substance use

SOMATIC SYMPTOM DISORDER osms.it/somatic-symptom-disorder PATHOLOGY & CAUSES ▪ Extended periods of unexplainable physical symptoms ▪ Individuals not faking symptoms (unlike factitious disorder) ▪ Thinking about physical symptoms → cognitive symptoms (e.g. stress/anxiety) ▪ Cause unknown; affected individuals sensitive to physical changes → everyday experiences misinterpreted ▪ High comorbidity with depressive, anxiety disorders

SIGNS & SYMPTOMS ▪ Somatic symptoms (e.g. pain, sexual, gastrointestinal problems); change over time ▪ Cognitive symptoms (e.g. worry, anxiety)

DIAGNOSIS OTHER DIAGNOSTICS

▪ ≥ one somatic symptoms → distress in other areas of life, last > six months ▪ Changes in behavior/thinking, related to somatic symptoms ▫ Excessive thought about severity of symptoms ▫ Anxiety about symptoms/health ▫ Devotion of time/energy to symptoms/ health ▪ Severity determined by changes in behavior/thinking ▫ Mild = one change ▫ Moderate = ≥ two changes ▫ Severe = ≥ two changes + multiple physical symptoms/one severe symptom

TREATMENT PSYCHOTHERAPY

▪ Improve cognitive symptoms (e.g. cognitive-behavioral/group therapy)

OSMOSIS.ORG 761

NOTES

NOTES

ACUTE & CHRONIC KIDNEY DISEASE

GENERALLY, WHAT IS IT? PATHOLOGY & CAUSES

DIAGNOSIS

▪ Decline of kidney function

DIAGNOSTIC IMAGING

TYPES

Ultrasound, CT scan ▪ Obstructive renal failure

Acute kidney injury (AKI) ▪ Decline over < three months ▪ Divided by cause ▫ Prerenal azotemia: kidney hypoperfusion ▫ Intrarenal azotemia: injury within kidney ▫ Postrenal azotemia: obstructed urine outflow distally Chronic kidney disease (CKD) ▪ Decline over > three months ▪ Any etiology causing decreased kidney function

SIGNS & SYMPTOMS ▪ Electrolyte imbalance (e.g. ↑ K+, ↓ Na+, ↓ Ca2+) ▪ Decreased waste elimination (azotemia/ uremia) ▪ Fluid retention

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LAB RESULTS ▪ Urine electrolytes, osmolality, cellular casts, proteinuria, hematuria ▪ Acid-base status, electrolytes, protein levels ▪ Blood urea nitrogen (BUN)-to-creatinine ratio (BUN:Cr) ▫ Prerenal azotemia: > 20:1 ▫ Renal azotemia: < 15:1 ▫ Postrenal azotemia: > 15:1; over time, < 15:1

TREATMENT MEDICATIONS ▪ Correct acid-base status, electrolytes, volemia

OTHER INTERVENTIONS ▪ Hemodialysis (not used for prerenal azotemia)

Chapter 106 Acute & Chronic Kidney Disease

CHRONIC KIDNEY DISEASE osms.it/chronic-kidney-disease PATHOLOGY & CAUSES ▪ Gradual decline of kidney function over ≥ three months ▪ Affects all physiologic roles of kidney ▪ ↓ Glomerular filtration rate (GFR) → ↓ waste products excretion → build-up of nitrogenous compounds → ↑ BUN, Cr, urea (azotemia/uremia) ▫ Inflammation (e.g uremic pericarditis) ▫ Interferes with neurotransmitter metabolism → encephalopathy ▫ Platelet dysfunction → bleeding (platelet adhesion, aggregation) ▫ Excess urea through eccrine glands → crystallizes on skin → uremic frost ▪ ↓ reabsorption, secretion → impaired electrolyte homeostasis ▫ ↑ K+, ↓ Na+, ↓ HCO3-, ↓ Ca2+ ▪ Impaired hormone secretion ▫ ↓ erythropoietin → anemia ▫ ↓ GFR → ↑ renin → hypertension ▫ ↓ vitamin D activation → ↓ intestinal absorption of Ca2+ → hypocalcemia

CAUSES ▪ Hypertension (most common) ▫ ↑ blood pressure → hypertrophy/ sclerosis of renal arteries → hypoperfusion, ischemic injury → growth factor secretion by macrophages → mesangial cells regress to mesoangioblasts, secrete extracellular matrix → glomerulosclerosis, loss of function ▪ Diabetic nephropathy ▫ ↑ blood glucose → non-enzymatic glycosylation of efferent arterioles → initial hyperinflation → mesangial cells secrete structural matrix → nodular glomerulosclerosis, loss of function

▪ Less common ▫ Glomerulonephritis (e.g. lupus nephritis); rheumatoid arthritis; HIV nephropathy; long term medication use (e.g. NSAIDs); polycystic kidney disease

RISK FACTORS ▪ Family history ▪ Reflux nephropathy ▪ Other congenital kidney disorders

COMPLICATIONS ▪ Uremic fibrinous pericarditis, uremic gastroenteritis ▪ Renal osteodystrophy → increased risk of skeletal fractures; caused by secondary hyperparathyroidism (compensatory parathyroid hormone release due to lack of vitamin D) ▪ Renovascular hypertension ▫ Development/exacerbation of hypertension due to increased RAAS ▪ Congestive heart failure ▪ Coma, death by severe encephalopathy

SIGNS & SYMPTOMS ▪ Less advanced stages usually asymptomatic ▪ Oliguria ▫ Urine output < 400mL in 24 hour ▪ ↑ fluid volume ▫ Peripheral edema ▪ Azotemia/uremia ▪ Skin ▫ Uremic pruritus, excoriations ▪ GI tract ▫ Ulcerations, bleeding, diarrhea, vomiting ▪ Encephalopathy ▫ Fatigue, somnolence, appetite loss, asterixis, confusion

OSMOSIS.ORG 763

▪ ↑ K+ (> 5.5mEq/L) ▫ Cardiac arrhythmias ▪ Anemia ▫ Low erythropoietin production by kidneys

DIAGNOSIS DIAGNOSTIC IMAGING Ultrasound ▪ Etiological investigation; polycystic kidney disease (PCKD), renal artery stenosis, hydronephrosis, etc.; decreased kidney volume

LAB RESULTS ▪ Iron deficiency anemia ▪ Metabolic acidosis, ↑ PO3-, ↑ K+, ↓ Na+, ↓ HCO3-, ↓ Ca2+ ▪ Biopsy ▫ Glomerulosclerosis/interstitial fibrosis

OTHER DIAGNOSTICS ▪ Rise of serum Cr over months/years ▪ Increased blood urea nitrogen:creatinine (BUN:Cr) ▪ Cr clearance to assess glomerular filtration rate (GFR) ▫ Stage I: kidney damage with normal/

increased GFR (> 90mL/min/1.73m2) ▫ Stage II: mild reduction in GFR (60– 89mL/min/1.73m2) ▫ Stage IIIa: moderate reduction in GFR (45–59mL/min/1.73m2) ▫ Stage IIIb: moderate reduction in GFR (30–44mL/min/1.73m2) ▫ Stage IV: severe reduction in GFR (15–29mL/min/1.73m2) ▫ Stage V: end stage kidney failure (GFR < 15mL/min/1.73m2 or dialysis)

TREATMENT MEDICATIONS ▪ ACE inhibitors, angiotensin II receptor antagonists (ARBs)

SURGERY ▪ Kidney transplantation ▫ Severe (e.g. Stage V CKI)

OTHER INTERVENTIONS ▪ Dialysis ▫ Severe (e.g. Stage V CKI) ▪ Hemodialysis ▫ Remove excess waste products, fluids via artificial kidney (dialyzer) ▪ Peritoneal dialysis ▫ Remove excess waste products, fluids via peritoneal membrane

POSTRENAL AZOTEMIA osms.it/postrenal-azotemia PATHOLOGY & CAUSES ▪ Acute kidney injury due to obstructed urine outflow distally → ↑ nitrogenous compounds in blood ▪ Obstruction of urine outflow → reversal of Starling forces → pressure backs up to kidneys, tubules → reduced pressure gradient between arterioles, tubules →

764 OSMOSIS.ORG

↓ GFR

CAUSES ▪ Compression ▫ Ureters (e.g. intra abdominal tumors); urethra, benign prostatic hyperplasia (BPH) ▪ Obstruction ▫ Ureters; urethra, kidney stones

Chapter 106 Acute & Chronic Kidney Disease ▪ Congenital abnormalities ▫ Vesicoureteral reflux

COMPLICATIONS ▪ Hydronephrosis; urinary tract infection (UTI), obstruction, urosepsis

SIGNS & SYMPTOMS ▪ Normotensive/hypertensive ▪ Renal colic ▫ Acute complete obstruction, dysuria, urgency, overflow incontinence, frequent urination ▪ Abdominal distention ▫ Urinary retention ▪ Costovertebral angle tenderness ▪ Pain ▫ Bladder distention, secondary infection, stones, masses ▪ Decreased urine output, hematuria ▫ Stones

DIAGNOSIS DIAGNOSTIC IMAGING Renal ultrasound ▪ Detect obstruction; hydronephrosis, stones > 3mm ▫ Echogenic foci, acoustic shadowing

CT scan ▪ Confirmation ▪ Hyperdense foci; dilation of ureter

LAB RESULTS ▪ Urinalysis ▫ UNa+ < 20 mEq/L; over time > 40mEq/L ▫ FENa > 1%; severe: FENa > 2% ▫ Uoms > 500mOsm/kg; over time 350mOsm/kg

OTHER DIAGNOSTICS ▪ Physical exam ▫ Palpable bladder ▪ Digital rectal examination ▫ Enlarged prostate

TREATMENT SURGERY ▪ Percutaneous nephrostomy, lithotripsy ▫ Obstruction by stones

OTHER INTERVENTIONS ▪ Short term hemodialysis (severe) ▪ Placement of Foley catheter, ureteral stent/ nephrostomy

OSMOSIS.ORG 765

PRERENAL AZOTEMIA osms.it/prerenal-azotemia PATHOLOGY & CAUSES ▪ Acute renal injury ▫ Kidney hypoperfusion → increased nitrogenous compounds in blood (BUN, Cr) ▪ Decreased blood flow to kidney → ↓ glomerular filtration rate (GFR), accumulation of waste products (BUN, Cr) in blood → azotemia ▪ ↓ GFR → renin–angiotensin–aldosterone system (RAAS) activation → aldosterone secretion → Na+, water retention → urea follows Na+ → ↑ BUN:Cr (> 20:1)

CAUSES ▪ Absolute fluid loss ▫ Burns, dehydration, long term vomiting, diarrhea, hemorrhage ▪ Relative fluid loss ▫ Congestive heart failure, distributive shock ▪ Renal artery stenosis/embolus ▪ Liver failure ▫ Portal hypertension → systemic, splanchnic vasodilation → ↓ effective blood volume, ↑ sequestration in peritoneal cavity (ascites) → relative hypovolemia → ↓ renal perfusion

RISK FACTORS ▪ Gastrointestinal (GI) tract disorders (e.g. diarrhea, vomiting) ▪ Liver disease ▪ Congestive heart failure

SIGNS & SYMPTOMS ▪ Oliguria: urine output < 400mL in 24 hours ▪ Azotemia: confusion, lethargy, asterixis, appetite loss, nausea, bleeding (platelet dysfunction), uremic frost

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▪ Dehydration: dry mucous membranes, skin turgor loss, thirst, xerostomia (dry mouth), tachycardia, orthostatic hypotension ▪ Congestive heart failure: jugular vein distention, edema ▪ Underlying liver failure: ascites

DIAGNOSIS DIAGNOSTIC IMAGING Doppler renal ultrasound ▪ Renal artery stenosis/embolus

LAB RESULTS ▪ Absolute fluid loss ▫ ↑ Na+, ↑ Ca2+, ↑ hematocrit, ↑ HCO3, ↑ protein/albumin ▪ Relative fluid loss ▫ ↓ Na+, ↓ protein/albumin ▪ Urine sodium (UNa+) < 20mEq/L ▪ Fraction of sodium excreted to sodium filtered (FENa) < 1% ▪ Urine osmolality (Uoms) > 500mOsm/kg

OTHER DIAGNOSTICS ▪ BUN:Cr > 20:1

TREATMENT MEDICATIONS ▪ Diuretics, angiotensin-converting enzyme (ACE) inhibitors, beta blockers, nitrates, positive inotropic agents ▫ Congestive heart failure

OTHER INTERVENTIONS ▪ Correct fluid, electrolyte imbalances with IV fluids ▫ Crystalloid solutions: isotonic solutions containing electrolytes, small organic molecules (e.g. isotonic saline, Ringer’s

Chapter 106 Acute & Chronic Kidney Disease lactate); most common ▫ Colloid solutions: hypertonic solutions containing larger molecules; albumin, hyperoncotic starch (e.g. glucose, dextrose) ▫ Blood transfusion: in case of hemorrhage

Figure 106.1 The clinical appearance of uremic frost in an individual with azotemia.

RENAL AZOTEMIA osms.it/renal-azotemia PATHOLOGY & CAUSES ▪ Acute renal injury caused by problem within kidney → increased nitrogenous compounds in blood ▪ Kidney injury → ↓ GFR → accumulation of waste products in blood → azotemia

CAUSES Glomerular injury ▪ Glomerulonephritis ▫ Inflammation of glomeruli (e.g. poststreptococcal glomerulonephritis, Goodpasture’s syndrome, Wegener’s granulomatosis, IgA nephropathy) ▫ Deposition of immune complexes on glomerular basement membrane → activation of complement system → chemoattraction of macrophages, neutrophils → mediator release → inflammation, podocyte damage → protein, blood cell leakage → reduces pressure gradient between arterioles, tubules → ↓ GFR, oliguria Tubular injury ▪ Acute tubular necrosis: damage to tubular epithelial cells; shedding of tubular cells,

granular casts in urine ▫ Ischemic tubular necrosis: caused by prerenal issues (hypoperfusion due to absolute, relative fluid loss) ▫ Nephrotoxic tubular necrosis: caused by nephrotoxins, like organic solvents (carbon tetrachloride), heavy metal poisoning (lead, mercury), ethylene glycol, radiocontrast agents, certain medications (aminoglycosides) ▪ Shedded tubular cells, granular casts obstruct tubule → ↑ tubular pressure → reduces pressure gradient between arterioles, tubules → ↓ GFR → oliguria Interstitial injury ▪ Acute interstitial nephritis ▫ Caused by Type I, IV hypersensitivity due to nonsteroidal anti-inflammatory drugs (NSAIDs)/penicillin/diuretics ▫ Inflammation of interstitium → renal papillary necrosis → hematuria ▪ Bilateral pyelonephritis Glomerular endotheliopathy ▪ Thrombotic microangiopathy, hyaline arteriolosclerosis, scleroderma

OSMOSIS.ORG 767

RISK FACTORS

OTHER DIAGNOSTICS

▪ Family history of congenital/systemic diseases (e.g. diabetes, hypertension, systemic lupus erythematosus, hepatitis B, C)

▪ BUN:Cr < 15:1 ▪ Interstitial nephritis ▫ Hypersensitivity, acute interstitial nephritis ▫ ↑ IgE: Type I ▫ Skin test: T-cell mediated Type IV ▫ Eosinophilia

SIGNS & SYMPTOMS ▪ Oliguria, hematuria, flank pain, livedo reticularis (lace-like purplish skin discoloration) ▪ Fluid build-up ▫ Hypertension, hypertensive retinopathy, edema ▪ Azotemia ▫ Confusion, lethargy, asterixis, loss of appetite, nausea, bleeding (platelet dysfunction) ▪ Hypersensitivity ▫ Rash, fever, joint swelling/tenderness

DIAGNOSIS LAB RESULTS UNa+ > 40mEq/L FENa < 2% Uoms > 350mOsm/kg Erythrocyte, leukocyte, epithelial casts: glomerulonephritis ▪ Pigmented muddy brown granular/tubular epithelial cells cylinders: acute tubular necrosis

▪ ▪ ▪ ▪

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TREATMENT MEDICATIONS ▪ Glomerulonephritis; treat according to etiology (e.g. corticosteroids) ▪ Pyelonephritis ▫ Antibiotics

OTHER INTERVENTIONS ▪ Avoid nephrotoxins/allergens ▪ Glomerulonephritis; treat according to etiology (e.g. plasmapheresis) ▪ Hemodialysis

NOTES

NOTES

BLADDER & URETHRAL CONGENITAL DISORDERS

GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Congenital abnormalities in bladder, urethra ▪ Benign/kidney failure/systemic involvement

CAUSES

▪ Interferences in fetal development

SIGNS & SYMPTOMS

DIAGNOSIS DIAGNOSTIC IMAGING Prenatal ultrasound ▪ Diagnosis difficult

OTHER DIAGNOSTICS

▪ Bladder exstrophy, hypospadias, epispadias: visible at birth

TREATMENT

▪ May be asymptomatic until complications develop

SURGERY

▪ See individual disorders

BLADDER EXSTROPHY osms.it/bladder-exstrophy the mesenchymal tissue towards midline → rupture of cloacal membrane → herniation of lower abdominal components through the lower abdominal wall surface

PATHOLOGY & CAUSES ▪ Congenital disorder, inside-out bladder protruding out of abdomen ▪ Part of the exstrophy-epispadias complex (EEC) that includes epispadias and cloacal exstrophy ▪ Bladder fails to fully form anteriorly, pushed through front anterior abdomen wall

CAUSES

▪ Occurs during embryological development: overdevelopment of cloacal membrane disrupts development of the lower abdominal wall → prevents migration of

RISK FACTORS ▪ ▪ ▪ ▪

Genetic predisposition Biological males > biological females Firstborn > subsequent births Infants born to white parents

COMPLICATIONS

▪ Urinary and/or fecal incontinence, UTIs, abnormal gait, hip dysplasia, rectal prolapse; inguinal hernia, uterine prolapse

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SIGNS & SYMPTOMS ▪ Observable changes in pelvis, pelvic floor, genitalia ▫ Exposed bladder and urethra ▫ Low-set umbilicus ▫ Abnormalities of the pelvic bone, vertebral column, and spinal cord ▫ Flattened puborectal sling, anus anteriorly displaced ▫ Biological males: epispadias, absent dorsal foreskin, open prostate, shortened penis ▫ Biological females: vagina wider, shorter, more vertically oriented; displaced, narrowed vaginal orifice; bifid clitoris; divergent labia ▫ Epispadias

DIAGNOSIS DIAGNOSTIC IMAGING

Figure 107.1 A newborn baby with a severe case of bladder exstrophy. The genitals are also grossly irregular.

TREATMENT SURGERY

▪ Performed within first weeks of life ▪ Staged surgeries required over months/ years

CT scan ▪ CT scan detects skeletal abnormalities Ultrasound and MRI ▪ Often made by prenatal ultrasound, can be confirmed by MRI

OTHER DIAGNOSTICS

▪ Clinically recognizable at time of delivery

Figure 107.2 Illustration of the bladder pushing through the symphysis pubis and abdominal wall during bladder exstrophy.

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Chapter 107 Bladder & Urethral Congenital Disorders

Figure 107.3 A plain pelvic radiograph demonstrating a wide symphysis pubis in a case of bladder exstrophy.

HYDRONEPHROSIS osms.it/hydronephrosis PATHOLOGY & CAUSES ▪ Dilation of renal pelvis, calyces associated with kidney atrophy ▪ Severe, long-standing hydronephrosis → kidney failure ▪ Urinary tract obstruction/compression → build up of urinary pressure → progressive dilation ▪ Dilation starts at blockage, continues up towards kidneys ▫ Hydroureter: dilation of ureter ▫ Hydronephrosis/hydroureteronephrosis: dilation of ureter, renal pelvis, calyces ▪ Grading ▫ 0: no dilation ▫ I: dilation of renal pelvis ▫ II: dilation of renal pelvis, calyces ▫ III: moderate dilation of renal pelvis, calyces; mild cortical thinning, flattening of papillae ▫ IV: severe renal dilation; cortical thinning

CAUSES

▪ Fetus: antenatal hydronephrosis ▫ Often unknown, may disappear on own ▫ Congenital malformation: ureteropelvic junction obstruction, vesicoureteral reflux ▪ Children: ▫ Congenital malformation: ureterocele, posterior urethral valves ▪ Adults: ▫ Acquired disease: kidney stones (most common cause), benign prostatic hyperplasia, blood clot, contiguous malignant diseases (prostate/bladder/cervix cancer, retroperitoneal lymphoma), contiguous inflammation (prostatitis, ureteritis, urethritis, retroperitoneal fibrosis), tissue scarring from injury/surgery, uterus enlargement during pregnancy

OSMOSIS.ORG 771

MNEMONIC: SIP BaN

Causes of acquired hydronephrosis Stones Inflammation Prostate hypertrophy Baby (pregnancy) / Blood clot Neoplasm

SIGNS & SYMPTOMS

TREATMENT SURGERY

▪ Restore urine flow: upper blockage ▫ Acute: nephrostomy tube ▫ Chronic: ureteric stent/pyeloplasty

OTHER INTERVENTIONS

▪ Restore urine flow: lower blockage ▫ Urinary or suprapubic catheter

▪ Acute with sudden onset: intense pain in flank, called Dietl’s crisis ▪ Nausea, vomiting

DIAGNOSIS DIAGNOSTIC IMAGING Abdominal ultrasound ▪ Dilation of renal calyces ▪ Increased anteroposterior diameter ▪ Dilated ureter, if obstruction is distal Prenatal ultrasound ▪ Oligohydramnios if bilateral obstruction Intravenous (IV) urography/pyelography ▪ Demonstrates distal obstruction

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Figure 107.4 An abdominal CT scan in the coronal plane demonstrating severe hydronephrosis of the left kidney.

Chapter 107 Bladder & Urethral Congenital Disorders

POSTERIOR URETHRAL VALVE osms.it/posterior-urethral-valve PATHOLOGY & CAUSES ▪ Congenital disorder, posterior urethra obstructed by membranous folds/tissue flap ▪ Most common cause of bladder outlet obstruction in infants who are biologically male ▪ Obstruction increases bladder pressure → bladder wall hypertrophy → decreases bladder compliance → repeats ▪ Obstruction increases bladder pressure → ureterovesical junction dysfunction → vesicoureteral reflux ▪ Urine retention by obstruction → urine backs up → bilateral hydronephrosis ▪ Severe obstructions in utero → oligohydramnios → Potter syndrome ▫ Limb irregularities, facial anomalies, kidney failure, pulmonary hypoplasia

Antenatal ultrasound ▪ Hydronephrosis (10% may be normal) ▪ Trabeculated and thick-walled bladder with elongation and dilation of posterior urethra ▪ Valve may be seen as echogenic line Voiding cystourethrogram (VCUG) ▪ Dilation and elongation of posterior urethra ▪ Vesicoureteral reflux (in half of instances) ▪ Bladder trabeculation or diverticula ▪ Radiolucent linear band (representing valve)

TREATMENT SURGERY

▪ Surgical ablation of membrane ▪ Prenatal surgery

CAUSES

▪ Unknown; theory: abnormal integration of Wolffian duct → large plicae colliculi fuse anteriorly

SIGNS & SYMPTOMS ▪ Posterior urethra obstructed by membranous folds/tissue flap

DIAGNOSIS DIAGNOSTIC IMAGING Prenatal ultrasound ▪ Generally seen > 26 weeks gestation ▪ Noticeable distension and hypertrophy of bladder ▪ Possitlbe hydronephrosis and hydroureter ▪ Keyhole sign: distended proximal urethra and thick-walled bladder, resembles keyhole

Figure 107.5 A lateral view of a micturating cystourethrogram demonstrating a proximally dilated urethra in case of posterior urethral valve.

OSMOSIS.ORG 773

VESICOURETERAL REFLUX osms.it/vesicoureteral-reflux PATHOLOGY & CAUSES ▪ Retrograde flow of urine from the bladder into the ureters and kidneys ▪ Grading ▫ Grade I: urine goes into ureters ▫ Grade II: urine fills entire ureter, renal pelvis ▫ Grade III: urine fills, stretches ureter, renal pelvis ▫ Grade IV: ureter swollen, curvy; renal pelvis, calyces swollen, distorted ▫ Grade V: urine fills ureter, pelvis, calyces; swell completely ▪ Primary vesicoureteral reflux (most common type): due to congenital defect at ureterovesical junction (congenital absence/ shortening of intravesical portion of ureter) ▫ Inadequate closure of the ureterovesical junction → urine builds up in bladder → ureter fails to act as valve → urine returns to ureters ▪ Secondary vesicoureteral reflux: due to failure of the ureterovesical junction to close during bladder contraction; often due to a blockage in urinary tract ▫ Pressure increases in urinary tract → urine follows path of least resistance, back into ureters

RISK FACTORS ▪ ▪ ▪ ▪

Genetic predisposition Neonates: prenatal hydronephrosis Children: febrile UTIs Individuals of white, Northern European descent

COMPLICATIONS

▪ Recurrent UTIs, pyelonephritis, renal scarring/fibrosis, hypertension, kidney failure ▪ Infants: asymptomatic, fever, lethargy, poor appetite

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▪ Children: discomfort with urination; bowel and bladder dysfunction

SIGNS & SYMPTOMS ▪ Infants: asymptomatic, fever, lethargy, poor apetite ▪ Children: discomfort with urination

DIAGNOSIS DIAGNOSTIC IMAGING Abdominal ultrasound ▪ Assesses renal parenchyma for scarring or anatomical abnormalities ▪ Presence of hydronephrosis VCUG ▪ Should be performed on first UTI in child < six years old ▪ Used for grading ▪ Presence of other anatomical abnormalities

TREATMENT SURGERY

▪ Primary vesicoureteral reflux ▫ Surgery to repair valve at ureterovesical junction ▫ Infants, children: no intervention; child grows → ureters lengthens → valve function improves ▪ Secondary vesicoureteral reflux ▫ Surgery to remove blockage

Chapter 107 Bladder & Urethral Congenital Disorders

Figure 107.6 A voiding cystourethrogram demonstrating bilateral vesicoureteric reflux.

OSMOSIS.ORG 775

NOTES

NOTES

BLADDER CANCER GENERALLY, WHAT IS IT? PATHOLOGY & CAUSES ▪ Cellular cancers in bladder lining/wall

TYPES

▪ Non-urothelial ▪ Transitional cell carcinoma (AKA urothelial)

RISK FACTORS

▪ Irritants, carcinogens (e.g. smoking)

DIAGNOSIS LAB RESULTS

▪ Cystoscopy-guided biopsy (definitive diagnosis)

TREATMENT ▪ See individual disorders; depends on tumor stage, grade, location; kidney condition; localized/regional/metastatic

SIGNS & SYMPTOMS ▪ Hematuria, pain

NON-UROTHELIAL BLADDER CANCERS osms.it/non-urothelial-bladder PATHOLOGY & CAUSES ▪ Bladder cancers that do not arise from the urothelium ▪ More invasive, poorer prognosis; may arise from urothelial layer but cells differentiate ▪ Squamous cell metaplasia: cells of urothelium → pancake-like appearance of squamous cells → differentiate into squamous cell carcinoma ▫ Grow in multiple locations ▫ Cause extensive keratinization ▫ Caused by chronic irritation (e.g. recurrent urinary tract infections, long-

776 OSMOSIS.ORG

standing kidney stones, infection with Schistosoma haematobium, a type of flatworm) ▪ Primary adenocarcinomas ▫ Frequently metastasize ▫ Derive from glandular tissue → produce a lot of mucin ▫ Primary form of bladder tumor associated with bladder exstrophy ▫ Can develop as complication of Schistosoma haematobium infection ▪ Adenocarcinomas of urachus ▫ Similar to bladder adenocarcinomas ▫ Arises from urachus (fibrous tissue

Chapter 108 Bladder Cancer sitting at dome of bladder)

RISK FACTORS

▪ Chronic urinary tract infections (UTIs)

COMPLICATIONS

DIAGNOSIS LAB RESULTS

▪ Cystoscopic biopsy ▫ Definitive diagnosis based on cellular morphology

▪ Metastasis

SIGNS & SYMPTOMS ▪ Bladder irritation ▪ Pain (location determined by tumor size/ extent—flank, suprapubic, perineal, abdominal, etc.) ▪ Hematuria ▪ Adenocarcinomas secrete mucin → mucusuria ▪ Urachal adenocarcinomas → abdominal mass

TREATMENT SURGERY

▪ Transurethral resection, small tumors resected with cystoscope ▪ Radical cystectomy, complete bladder removal, dissection of surrounding lymph nodes ▪ Urachal adenocarcinomas → remove dome of bladder, urachal ligament, umbilicus

Figure 108.1 Histological appearance of Schistosoma haematobia eggs in a bladder biopsy.

OSMOSIS.ORG 777

Figure 108.2 Illustration of a cytoscopy being performed. A tissue sample will be collected and tested to determine if the tumor is the result of a squamous cell carcinoma or an adenocarcinoma.

TRANSITIONAL CELL CARCINOMA osms.it/transitional-cell-carcinoma PATHOLOGY & CAUSES ▪ Most common form of lower urinary tract cancer (bladder, urethra) ▪ AKA urothelial cell carcinoma ▪ Can also affect upper urinary tract (e.g. renal pelvis, ureter) ▪ Usually due to bladder urothelium ▪ Mutations in tumour suppressor protein p53 → horizontally growing, flat tumours (invasive) ▫ p53 independent mutations → outward facing finger-like projections (noninvasive, less aggressive) ▪ Tumours often multifocal ▫ Field effect: entire urothelial field exposed to carcinogens, all cells bathed in urine ▫ Implantation theory: tumour cells detach from one site, implant at another

778 OSMOSIS.ORG

RISK FACTORS

▪ Advanced age, heavy alcohol use, human papillomavirus (HPV) infection, more common in individuals who are biologically male, chronic extended dwell times (not voiding bladder for long periods)

COMPLICATIONS ▪ Metastasis

MNEMONIC: P-SAC

Risk factors: exposure to carcinogens Phenacetin: banned analgesic, once common Smoking: primary risk factor Aniline: compound used in rubber/dye manufacturing Cyclophosphamide: cytotoxic medicine, cancer/autoimmune conditions

Chapter 108 Bladder Cancer

TREATMENT

SIGNS & SYMPTOMS ▪ Hematuria (typically intermittent, painless, present throughout urination) ▪ Pain (location determined by size/extent of tumor: flank, suprapubic, perineal, abdominal, etc.) ▪ Constitutional symptoms (severe disease) ▪ Dysuria; frequent/urgent urination

DIAGNOSIS DIAGNOSTIC IMAGING Cystoscopy

LAB RESULTS

▪ Depends on tumor stage, grade, location; kidney condition; localized/regional/ metastatic

MEDICATIONS Chemotherapy ▪ Non-aggressive: localised via catheter ▪ Aggressive: systemic

SURGERY

▪ Non-aggressive: transurethral resection via cystoscopy (localized, non-invasive tumors) ▪ Aggressive: complete removal of prostate, bladder (cystoprostatectomy)

▪ Identify presence of blood in urine ▪ Cystoscopy-guided biopsy of tumour (definitive diagnosis)

Figure 108.3 Histological appearance of muscle-invasive transitional cell carcinoma of the bladder.

OSMOSIS.ORG 779

Figure 108.4 An MRI scan in the axial plane demonstrating a transitional cell carcinoma of the bladder.

Figure 108.5 Transitional cell carcinoma can occur anywhere from the renal pelvis to the distal urethra. This coronal CT scan demonstrated a transitional cell carcinoma of the mid ureter.

Figure 108.6 Immunohistochemical staining with compound CK20 demonstrating urothelial carcinoma in situ. The urothelium has undergone malignant transformation but has not yet begun to invade surrounding tissue.

780 OSMOSIS.ORG

NOTES

NOTES

BLADDER PATHOLOGY

NEUROGENIC BLADDER osms.it/neurogenic-bladder PATHOLOGY & CAUSES ▪ Impaired control of bladder emptying due to nerve damage ▪ Bladder fills → damaged S2-S3 nerves → impaired signal transmission, lack of voluntary control → incontinence Overflow incontinence ▪ Bladder reaches maximum capacity, releases urine involuntarily all at once ▪ Results from impaired capacity to detect bladder filling Urge incontinence ▪ Small amount of urine initiates micturition reflex involuntarily ▪ Results from impaired capacity to inhibit micturition reflex

CAUSES Overflow incontinence ▪ Diabetes mellitus (most common); ischemic, metabolic, endothelial damage ▪ Syphilis → tabes dorsalis; inflammation, scarring of dorsal root nerves ▪ Herpesvirus → latent in dorsal nerve roots ▪ Spinal injury → micturition center (S2-S3 level) affected ▫ Once shock resolves → normal micturition reflex ▫ May also lead to urge incontinence; impaired transmission of inhibitory signal for micturition reflex

Urge incontinence ▪ Multiple sclerosis (MS) → autoimmune damage to nerve myelin sheath in S2-S3 level in spinal cord ▪ Spinal shock ▪ Stroke ▪ Chronic processes affecting central nervous system (CNS): Parkinson’s disease, brain tumor

RISK FACTORS

▪ Any disease affecting central, peripheral nervous system ▫ Diabetes, syphilis, herpes, spinal birth defects, spinal cord injuries, stroke, traumas

COMPLICATIONS

▪ Rashes/skin infections ▪ Recurrent urinary tract infections (UTIs)

SIGNS & SYMPTOMS ▪ Depends on nerves damaged, extension ▪ Urge, overflow incontinence

OSMOSIS.ORG 781

DIAGNOSIS LAB RESULTS

▪ Post-voiding residual measuring: amount of urine in bladder after urination ▪ Pressure, flow of urine measurements

TREATMENT MEDICATIONS

▪ Urge incontinence: anticholinergic drugs to relax detrusor muscle

OTHER INTERVENTIONS

▪ Overflow incontinence: catheter to drain urine

Figure 109.1 Illustration of syphilis and herpes viruses attacking the nerves of the bladder, which ultimately leads to overflow incontinence.

Figure 109.2 Illustration of causes of overflow incontinence. Spinal injuries can temporarily impair bladder functioning, while chronic conditions affecting the nervous system, like Parkinson’s disease, have more permanent effects.

782 OSMOSIS.ORG

NOTES

NOTES

CONGENITAL KIDNEY CONDITIONS

GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES

DIAGNOSIS

▪ Kidney abnormalities present at birth ▪ Polycystic kidney disease, multicystic dysplastic kidney, horseshoe kidney, renal agenesis

DIAGNOSTIC IMAGING

Developmental phases ▪ Pronephros → mesonephros → migrate upwards into abdomen → separate into two kidneys

LAB RESULTS

COMPLICATIONS

OTHER DIAGNOSTICS

▪ Progressive renal damage, renal failure

Ultrasound, CT scan, intravenous urethrogram, MRI

▪ Evaluate renal function; blood urea nitrogen (BUN), creatinine, estimated glomerular filtration rate (eGFR), serum electrolytes

▪ Visible at birth: bladder exstrophy, hypospadias, epispadias

RISK FACTORS

▪ More common in individuals who are biologically male ▪ Pregnancy: high BMI, alcohol abuse, smoking, teratogenic medication ▪ Genetics

SIGNS & SYMPTOMS ▪ Potter sequence (epicanthal folds, low-set ears, flat nose, recessed chin)

TREATMENT MEDICATIONS

▪ Support renal function ▫ Diuretics, erythropoietin (EPO), medication for electrolyte imbalances, angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers

SURGERY

▪ Kidney transplant

OTHER INTERVENTIONS Dialysis ▪ If kidney(s) no longer functional, machine performs kidney function; filtering, purifying blood by removing waste, excess fluid

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HORSESHOE KIDNEY osms.it/horseshoe-kidney PATHOLOGY & CAUSES

SIGNS & SYMPTOMS

▪ AKA renal fusion, congenital disorder; two kidneys fuse during fetal development → one large, horseshoe-shaped kidney ▪ Week 7–8 ▫ Horseshoe-shaped kidney tries to migrate from pelvis up into abdomen → gets hooked around inferior mesenteric artery → remains low in abdomen

▪ Mostly asymptomatic, sweating, nausea, vomiting; hematuria; fever, chills; cloudy urine

CAUSES

DIAGNOSTIC IMAGING

Mechanical fusion ▪ Metanephros stage (gestation week 5) ▪ Flexion/growth of developing spine, pelvic organs → pushes kidneys together → lower poles of kidneys fuse → fibrous isthmus forms ▫ Isthmus made of connective tissue

Ultrasound ▪ Periodic monitoring for early Wilms’ tumor detection

Teratogenic event ▪ Posterior nephrogenic cells (help form part of kidney) migrate to wrong spot → parenchymal isthmus forms → connects kidneys ▫ Isthmus made of kidney cells

RISK FACTORS

▪ More common in individuals who are biologically male ▪ Chromosomal disorders (e.g. Turner syndrome, trisomy 13, 18, 21) ▪ Neural tube defects

COMPLICATIONS

▪ Hydronephrosis, kidney stones, infection, kidney cancer (especially Wilms’ tumor, carcinoid tumor), obstruction, vesicoureteral reflux, infection, polycystic kidney disease

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DIAGNOSIS ▪ Usually incidental

CT scan ▪ 3D scanning: evaluate anatomy, collecting system MRI ▪ Provide anatomical information ▪ Evaluate arterial anatomy before surgery ▪ Check renal artery stenosis in hypertensive people

LAB RESULTS

▪ BUN, creatinine, glomerular filtration rate (GFR), serum studies, 24-hour kidney stone risk assessment

TREATMENT MEDICATIONS

▪ For renal disease (e.g. erythropoietin, ACE inhibitors)

SURGERY

▪ Possibly corrective surgery

Chapter 110 Congenital Kidney Conditions

Figure 110.1 An abdominal CT scan in the axial plane demonstrating a horseshoe kidney. There is renal tissue connecting the right and left kidneys.

Figure 110.2 A 3D-reconstruction MRI in an anterior view in an individual with a horseshoe kidney.

MEDULLARY CYSTIC KIDNEY DISEASE (MCKD) osms.it/mdullary-cystic-kidney-disease PATHOLOGY & CAUSES ▪ A group of autosomal dominant kidney diseases that cause progressive renal failure ▪ AKA autosomal dominant tubulointerstitial kidney disease (ADTKD)

TYPES Uromodulin kidney disease (UKD) ▪ Caused by UMOD gene mutations ▪ Encodes uromodulin (Tamm–Horsfall protein), a non-ciliary protein ▫ Maintains integrity of the thick ascending limb of the loop of Henle ▪ Intracellular abnormal uromodulin accumulation → tubular cell atrophy → progressive renal failure + ↓ urate excretion → hyperuricemia, gout

ADTKD due to REN mutations: REN (ADTKD-REN) ▪ Caused by REN gene mutations ▪ Encodes renin, a key hormone in the RAAS pathway ▪ Intracellular pre-prorenin accumulation → structural damage, apoptosis of reninproducing cells → progressive renal failure + ↓ renin production → ↓ blood pressure, anemia Mucin-1 kidney disease (MKD) ▪ Caused by MUC1 gene mutations ▪ Encodes mucin-1 ▪ Pathophysiology not completely understood; results in progressive renal failure

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COMPLICATIONS

▪ Gout, chronic kidney disease, end-stage renal disease (ESRD), low blood pressure, anemia

SIGNS & SYMPTOMS ▪ Clinical manifestations of chronic kidney disease UKD ▪ Gout occurs at early age ADTKD-REN ▪ Low/low-normal blood pressures, anemia (occurs in childhood; resolves in adolescence from the influence of sex hormones), mild hyperkalemia MKD ▪ ↑ serum creatinine, hyperuricemia and gout occurring later in life

DIAGNOSIS DIAGNOSTIC IMAGING Ultrasound ▪ Small to normal kidneys with occasional cysts

UKD (presumptive diagnosis factors) ▪ All three of the following ▫ Strong family history of kidney disease ▫ Family history of gout ▫ Urinalysis: bland urinary sediment; absence of proteinuria or hematuria ADKTD-REN (presumptive diagnosis factors) ▪ Family history of chronic kidney disease, plus one of the following ▪ Unexplained anemia out of proportion to ↓ glomerular filtration rate ▪ Evidence of acute kidney injury; bland urinary sediment ▪ Chronic kidney disease + hyperkalemia, low or low-normal blood pressure, and hyperuricemia MKD (presumptive diagnosis factors) ▪ Presentation chronic kidney disease plus each of the following findings ▫ Urinalysis: bland urinary sediment; little or no proteinuria ▫ Absence of symptoms associated with UKD (precocious gout) or ADKTD-REN (childhood anemia, hyperkalemia, and hyperuricemia)

TREATMENT

LAB RESULTS

MEDICATIONS

Urinalysis ▪ See presumptive diagnosis factors for each subtype

UKD ▪ Gout: allopurinol

Biopsy ▪ Interstitial fibrosis

OTHER DIAGNOSTICS

▪ Confirmed through genetic testing

ADTKD-REN ▪ Symptomatic anemia: erythropoietin ▪ Low blood pressure, hyperkalemia: fludrocortisone ▪ Avoid NSAIDs

SURGERY

▪ Treat progressive renal failure; kidney transplantation

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Chapter 110 Congenital Kidney Conditions

MEDULLARY SPONGE KIDNEY (MSK) osms.it/medullary-sponge-kidney PATHOLOGY & CAUSES ▪ Rare congenital disorder characterized by ectasia (dilation) of the renal collecting ducts ▪ Genetic basis for developmental abnormality is incompletely understood; may involve embryonic disruption of the ureteral-bud and the metanephric blastema ▪ Renal collecting duct dilation, distension → urinary stasis → medullary cyst formation → impaired acidification in the terminal collecting duct → ↑ urine pH → nephrocalcinosis

RISK FACTORS

▪ Associated conditions include hemihypertrophy, Beckwith–Wiedemann syndrome

COMPLICATIONS

▪ Urinary tract infections ▪ Nephrocalcinosis ▪ Renal calculi (calcium phosphate, calcium oxalate) ▪ Chronic kidney disease

SIGNS & SYMPTOMS

DIAGNOSIS ▪ Often discovered incidentally during investigations for another indication

DIAGNOSTIC IMAGING Intravenous pyelography ▪ Cystic dilatations have brushlike appearance; enlarged pyramids; clusters of stones CT scan ▪ Medullary nephrocalcinosis

LAB RESULTS

▪ Hypercalciuria, hyperuricosuria, hypocitraturia, and hyperoxaluria

TREATMENT MEDICATIONS Treat complications ▪ Urinary tract infection: antibiotics ▪ Recurrent stone formation: potassium citrate, thiazide diuretics, ↑ fluid intake, ↓ sodium in diet

▪ Often asymptomatic, flank pain, renal colic, hematuria, dysuria, nocturia

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Figure 110.3 An X-ray image of the kidney, ureters and bladder. The dilated collecting ducts of the nephron give a paintbrush effect to each renal calyx.

MULTICYSTIC DYSPLASTIC KIDNEY (MCDK) osms.it/dysplastic-kidney PATHOLOGY & CAUSES ▪ Congenital disease, one/both kidneys do not form correctly → urine does not drain properly, builds up in kidneys, forms multiple fluid-filled sacs (cysts) ▪ Result of abnormal induction of metanephric blastema by ureteric bud ▫ Possibly due to malformation of mesonephric duct/ureteric bud/both ▪ Ureteric bud fails to produce ureters, renal calyces, collecting ducts, collecting tubules ▫ Urine cannot exit kidney, builds up → forms fluid-filled cysts ▫ Fluid-filled cysts composed of abnormal connective tissue replace normal kidney tissue → kidney function decreases

CAUSES

▪ Mostly sporadic ▪ Potential link to medication during pregnancy ▫ ACE inhibitors, illicit drugs (e.g. cocaine) ▪ Without treatment → kidney involutes (shrinks due to inactivity)

RISK FACTORS

▪ More common in individuals who are biologically male, genetic syndromes (papillorenal syndrome; error in genes EYA1, SIX1, PAX2)

COMPLICATIONS Bilateral MCDK ▪ Potter sequence Unilateral MCDK ▪ Uncommon, risk of chronic kidney disease

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Chapter 110 Congenital Kidney Conditions

TREATMENT

SIGNS & SYMPTOMS Unilateral MCDK ▪ Asymptomatic/palpable flank mass Bilateral MCDK ▪ Potter sequence

DIAGNOSIS ▪ May go undiagnosed if unilateral, no palpable flank mass, remaining kidney compensating fully

DIAGNOSTIC IMAGING Antenatal ultrasound ▪ Most common ▪ Visualize kidney containing multiple large, peripheral cysts Ultrasound ▪ Performed on neonate if health professionals detect palpable flank mass

SURGERY Mild bilateral MCDK ▪ Dialysis, kidney transplant ▪ Newborn requires dialysis/kidney transplant

OTHER INTERVENTIONS Unilateral MCDK ▪ Observation ▫ Affected kidney involutes ▪ Follow-up ▫ Serial ultrasound evaluation at birth, four weeks, two years, five years, 10 years of age; blood pressure, urinalysis (for proteinuria), renal function studies Severe bilateral MCDK ▪ Provide support for Potter sequence ▪ Newborns generally don’t survive

Figure 110.4 Pathological features of multicystic dysplastic kidney.

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POLYCYSTIC KIDNEY DISEASE (PKD) osms.it/polycystic-kidney PATHOLOGY & CAUSES ▪ Genetic disease, kidneys fill with hundreds of cysts → become larger, unable to function ▪ Cysts in outer layer (cortex), inner layer (medulla) of kidneys ▪ Cysts lined with renal tubular epithelium, become larger ▪ Cysts make kidneys larger over time → compress blood vessels of neighboring healthy nephrons → starve neighboring nephrons of oxygen → poor perfusion of kidneys activates renin-angiotensinaldosterone system → retain fluid → hypertension ▪ Large cysts → compress collecting system → urinary stasis → kidney stones

TYPES Autosomal dominant ▪ AKA adult PKD; usually manifests in adulthood ▪ Polycystin 1 (PKD1), polycystin 2 (PKD2) ▫ Necessary for inhibition of cell proliferation; if absent, cells proliferate abnormally, water moves to cyst lumen ▪ PKD1 gene mutation → more severe, earlier onset ▪ PKD2 gene mutation → less severe, later onset Autosomal recessive ▪ AKA infantile PKD; usually manifests in infancy ▫ Possible renal failure before birth → trouble producing urine → low amniotic

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fluid (oligohydramnios) ▪ Inherited mutation on both copies of polycystic kidney hepatic disease 1 (PKHD1) gene, fibrocystin protein ▫ Fibrocystin co-localizes with PKD2 regulation pathway, calcium signaling similar to autosomal dominant

RISK FACTORS Autosomal dominant ▪ One parent passes along PKD1/PKD2 mutation Autosomal recessive ▪ Both parents pass along PKHD1 mutation

COMPLICATIONS

▪ Renal insufficiency → renal failure ▪ Kidney stones

Autosomal dominant ▪ Cerebral artery berry aneurysms ▪ Mitral valve prolapse ▪ Benign hepatic cysts ▪ Heart failure (due to aortic root dilation) Autosomal recessive ▪ Congenital hepatic fibrosis → portal hypertension ▪ Ascending cholangitis (due to obstructed biliary tree)

SIGNS & SYMPTOMS ▪ Flank pain, high blood pressure, hematuria (blood in urine), renal insufficiency, renal failure, fetal oligohydramnios in autosomal recessive PKD

Chapter 110 Congenital Kidney Conditions

DIAGNOSIS DIAGNOSTIC IMAGING Prenatal ultrasound ▪ For autosomal recessive polycystic kidney disease ▪ Bilaterally large kidneys with cysts, oligohydramnios

LAB RESULTS

▪ Complete blood count (CBC), urinalysis, urine culture

TREATMENT MEDICATIONS

▪ Hypertension: ACE inhibitors, angiotensin receptor blockers ▪ Cholestasis: ursodiol (slows down rate of cholesterol absorption by intestines)

SURGERY

▪ Kidney transplant

Portal hypertension ▪ Portocaval shunt → bypasses liver, connects portal vein to inferior vena cava; liver transplant

OTHER INTERVENTIONS ▪ Dialysis

Figure 110.5 Histological appearance of renal parenchyma in a case of polycystic kidney disease.

Figure 110.6 A CT scan in the coronal plane demonstrating innumerable cysts in the kidneys and liver in autosomal dominant polycystic kidney disease. Figure 110.7 The gross pathological appearance of polycystic kidneys.

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RENAL AGENESIS osms.it/renal-agenesis PATHOLOGY & CAUSES ▪ Ureteric bud fails to induce metanephric blastema to develop → one/both kidneys don’t form

TYPES Unilateral renal agenesis (URA) ▪ One kidney does not develop ▫ Usually asymptomatic if other kidney healthy, able to compensate ▫ Predisposes individuals to more serious renal problems Bilateral renal agenesis (BRA) ▪ Neither kidney develops ▫ Incompatible with life outside womb ▫ Usually fatal within first few days after birth; no treatment

SIGNS & SYMPTOMS ▪ Oligohydramnios/anhydramnios (no amniotic fluid) ▪ Symptoms at birth include high blood pressure, protein/blood in urine, swelling of face/extremities URA ▪ Bsually asymptomatic if other kidney healthy BRA ▪ Babies ill at birth, usually do not live ▫ Widely separated eyes with epicanthal folds ▫ Low set ears ▫ Flat, broad nose ▫ Small chin ▫ Underdeveloped lungs

CAUSES

▪ Combination of genetic/in utero environmental factors (toxins, infections)

RISK FACTORS

▪ More common in individuals who are biologically male

COMPLICATIONS URA ▪ Hypertrophy of remaining kidney, infections, kidney stones, hypertension, renal failure BRA ▪ Oligohydramnios, pulmonary hypoplasia, Potter sequence

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DIAGNOSIS DIAGNOSTIC IMAGING Prenatal ultrasound/MRI ▪ Confirm diagnosis

OTHER DIAGNOSTICS

▪ Oligohydramnios/anhydramnios

TREATMENT SURGERY

▪ Kidney transplant

OTHER INTERVENTIONS ▪ Routine monitoring ▪ Dialysis

Chapter 110 Congenital Kidney Conditions

Figure 110.8 A 3D reconstruction of a CT scan demonstrating left-sided renal agenesis.

Figure 110.9 An MRI scan in the coronal plane demonstrating right-sided renal agenesis.

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NOTES

NOTES

HYPERCALCEMIA & HYPOCALCEMIA

GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Calcium concentrations in the blood falling outside of the normal reference range ▪ Hypocalcemia: < 8.5mg/dL ▪ Hypercalcemia: > 10.5mg/dL

SIGNS & SYMPTOMS ▪ Variations that are mild, or slow in onset, usually asymptomatic ▪ Hypercalcemia → less excitable neurons and associated symptoms across multiple systems ▪ Hypocalcemia → more excitable neurons and associated symptoms across multiple systems

DIAGNOSIS LAB RESULTS

▪ Blood calcium levels ▪ Determination of underlying cause (blood tests for levels of) ▫ Parathyroid hormone, vitamin D, albumin, phosphorus, magnesium

OTHER DIAGNOSTICS ECG ▪ Identify associated organ dysfunction

TREATMENT MEDICATIONS Hypercalcemia ▪ Lower blood calcium levels ▫ Rehydrate, loop diuretics, glucocorticoids, bisphosphonates or calcitonin, dialysis Hypocalcemia ▪ Raise calcium levels ▫ Calcium gluconate ▫ Vitamin D supplementation

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Chapter 111 Hypercalcemia & Hypocalcemia

HYPERCALCEMIA osms.it/hypercalcemia PATHOLOGY & CAUSES ▪ High blood calcium (> 10.5mg/dL) ▪ True hypercalcemia due to elevation of free ionized calcium (not protein-bound, which is 40–45% of total calcium)

CAUSES Excessive bone resorption ▪ Hyperparathyroidism ▫ Most common cause ▫ Increased osteoclastic bone resorption ▫ Overactive parathyroid → releases more parathyroid hormone → stimulates osteoclasts → osteoclasts break down bone → release calcium into blood ▪ Thyrotoxicosis ▫ Thyroid hormone mediated increase in bone reabsorption ▪ Malignant tumors ▫ Can secrete parathyroid hormonerelated protein (PTHrP) ▫ Can cause osteoblast cells to die ▫ Can also cause overstimulation of osteoclasts → lytic bone lesions ▫ Can directly invade bone ▪ Uncommon causes ▫ Immobilisation, Paget disease of bone, anti-oestrogen treatment, hypervitaminosis A (retinoic acid → dose dependent increase in bone resorption)

▫ Thiazide diuretics (increase calcium reabsorption in distal tubule of kidney) ▫ Lithium (increase calcium reabsorption from the loop of Henle, also interferes with normal hypercalcemic feedback on the parathyroid gland) ▫ Calcium carbonate supplementation ▪ Milk-alkali syndrome ▫ Extra calcium from diet, alkali found in antacids) ▫ Hypercalcemia, metabolic alkalosis, renal insufficiency Insufficient excretion ▪ Adrenal insufficiency (e.g. Addisonian crisis) ▪ Adrenal failure (e.g. rhabdomyolysis) False hypercalcemia / pseudohypercalcemia ▪ Hyperalbuminemia → ↑ albumin → ↑ protein-bound calcium → ↑ total calcium ▫ Free ionized calcium concentrations remain the same (hormonal regulation) ▫ Total calcium high, free ionized calcium normal ▫ Rare cause: dehydration

COMPLICATIONS

▪ Calcium oxalate kidney stones (hypercalciuria, fluid loss) ▪ Osteoporosis (depletion of calcium stores in bone) ▪ Renal failure ▪ Cardiac arrhythmias ▪ Confusion, dementia, coma

Excessive calcium absorption ▪ Excess vitamin D ▫ Stimulates active intestinal absorption, resorption from bone and increased renal reabsorption ▪ Diet or excessive supplementation ▫ When intake exceeds 2 grams daily, passive transport may also lead to hypercalcemia ▪ Medications

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SIGNS & SYMPTOMS ▪ Many individuals asymptomatic ▪ Slow chronic onset, better tolerated ▪ Neurological ▫ Neurons less excitable ▫ Blurred vision, slow or absent reflexes ▫ Central nervous system: fatigue, anxiety, confusion, hallucinations, stupor ▪ Cardiovascular ▫ Arrhythmias, shortened QT interval, bradycardia, hypertension ▪ Musculoskeletal ▫ Generalized muscle weakness, bone pain, weak bones ▪ Gastrointestinal ▫ Anorexia, nausea and vomiting, constipation ▪ Renal ▫ Hypercalciuria, polyuria, polydipsia, kidney stones, distal renal tubular acidosis, nephrogenic diabetes insipidus, renal insufficiency

DIAGNOSIS LAB RESULTS

▪ High calcium levels in blood > 10.5mg/dL ▪ Calcium levels must be corrected for albumin levels or measure free ionized calcium ▫ Albumin: may be ↑ in pseudohypercalcemia ▪ Parathyroid hormone: ↑ or ↓ ▪ PTH-related hypercalcemia: primary hyperparathyroidism and familial hyperparathyroidism ▪ Non-PTH-related hypercalcemia: primary malignancy, intoxication of vitamin D, granulomatosis ▪ PTH-related peptide: may ↑ in certain malignancies

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▪ Vitamin D: may be ↑ in intoxication ▪ Phosphate: ↑ or ↓ depending if PTHdependent (high in renal insufficiency, hypoparathyroidism, low in vitamin D deficiency) ▪ Magnesium: hypercalcemia may ↓ Mg levels

OTHER DIAGNOSTICS ECG ▪ Bradycardia ▪ Atrioventricular block ▪ Shortening of QT interval ▪ Osborn wave (positive deflection at junction between QRS complex and ST segment)

TREATMENT MEDICATIONS

▪ Main goal: lower calcium levels in blood ▪ Rehydrate: increases urinary excretion of calcium ▪ Loop diuretics: inhibit calcium reabsorption, so more is excreted ▪ Glucocorticoids: decrease gastrointestinal calcium absorption ▪ Bisphosphonates or calcitonin: inhibit osteoclasts, prevent bone resorption ▪ Dialysis: if renal failure is present, consider hemodialysis or peritoneal dialysis

MNEMONIC

The effects of hypercalcemia Stones: renal or biliary calculi Bones: bone pain Groans: abdominal pain/ nausea Thrones: polyuria Psychiatric overtones: depression, anxiety, coma, insomnia

Chapter 111 Hypercalcemia & Hypocalcemia

Figure 111.1 Illustration of the potential sequelae of hypercalcemia.

HYPOCALCEMIA osms.it/hypocalcemia PATHOLOGY & CAUSES ▪ Low blood calcium (< 8.5mg/dL)

CAUSES Less calcium entering blood ▪ Most common cause ▪ Low vitamin D: deficient diet, malabsorption, cirrhosis, lack of sunlight, chronic renal failure ▪ Hypoparathyroidism: low levels or low activity of parathyroid hormone ▫ Hypomagnesemia (Mg serum concentration < 1mg/dL) can facilitate parathyroid hormone resistance via suppressing secretion ▪ Pseudohypoparathyroidism type 1A: kidney unresponsive to parathyroid hormone ▫ Pseudohypoparathyroidism: end-organ parathyroid hormone resistance ▪ Inhibition of bone resorption (uncommon) ▫ Medications such as bisphosphonates, calcitonin and denosumab

▫ Often occurs in setting of vitamin D deficiency, hypoparathyroidism and parathyroid hormone resistance Too much calcium leaving blood ▪ Kidney failure: nephron doesn’t effectively reabsorb calcium ▪ Tissue injury: burns, rhabdomyolysis, tumor lysis syndrome ▪ Acute pancreatitis: free fatty acids bind to ionized calcium ▪ Inflammatory processes (eg. sepsis and severe illness) ▫ Up to 90% of critically-ill individuals, or those that have had major surgery develop hypocalcemia ▪ Too many blood transfusions → additives bind to ionised calcium → additives in blood (citrate, ethylenediaminetetraacetic acid (EDTA) chelate (bind) to calcium → complexed calcium, an inactive molecule ▪ Hyperphosphatemia: results in calcium being deposited in bone and extraskeletal tissue ▪ Calcium complex formation: formation of complexes → reduced availability of ionized

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calcium for cellular processes ▫ Foscarnet, drug for treatment of refractory herpes and cytomegalovirus ▫ Fluoride poisoning, causes hypocalcemia partially due to formation of fluorapatite False hypocalcemia / pseudohypocalcemia ▪ Hypoalbuminemia (low albumin): loss of bound calcium ▫ Hormonal regulation means free ionized calcium concentrations stay essentially the same ▫ Less overall calcium due to less bound calcium, but free ionized calcium levels remain the same

COMPLICATIONS

▪ Osteopenia, osteoporosis, cardiovascular collapse, vasogenic shock (calcium required in vascular smooth muscle contraction), cardiac arrhythmias, seizures, tetany, basal ganglia calcification, parkinsonism, hemiballismus, choreoathetosis

Figure 111.2 Trousseau’s sign of latent tetany.

SIGNS & SYMPTOMS ▪ Neurological → neurons hyperexcitable ▫ Involuntary contraction of muscles ▫ Chvostek’s sign (facial muscles twitch after facial nerve lightly finger tapped 1cm/0.39in below zygomatic process) ▫ Trousseau’s sign (blood pressure cuff occludes brachial artery → pressure makes nerve fire → muscle spasm makes wrist and metacarpophalangeal

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joints flex) ▫ Muscle cramps ▫ Abdominal pain ▫ Perioral tingling (tingling around mouth) ▫ Paresthesias (abnormal sensation felt on skin, eg. tingling, tickling, prickling, numbness, burning) ▫ Carpopedal spasm (spasmodic contraction of muscles in hands, feet, ankles, wrists) ▫ Hyperactive deep tendon reflexes ▫ Seizures (extreme cases) ▪ Cardiovascular: decrease in rate, strength of contractions ▫ Hypotension ▫ Heart failure ▫ Arrhythmias

DIAGNOSIS LAB RESULTS

▪ Low level of calcium in blood (< 8.5mg/dL) ▪ Calcium levels must be corrected for albumin levels or measure free ionized calcium ▫ Albumin may be low in pseudohypocalcemia ▪ PTH-related hypocalcemia ▫ ↓ : hypoparathyroidism ▫ ↑ : kidney disease, vitamin D deficiency, pseudohypoparathyroidism ▪ Non-PTH-related hypocalcemia: hypomagnesemia ▪ Autosomal dominant hypocalcemia: mutation in calcium-sensing receptor gene ▪ PTH ▫ ↑ in kidney disease, vitamin D deficiency, pseudohypoparathyroidism ▫ ↓ in hypoparathyroidism ▪ Vitamin D ▫ Hypocalcemia may be caused by ↓ vitamin D (which ↑ PTH secretion) ▪ Phosphate ▫ ↑ in hypoparathyroidism (in absence of kidney disease) or pseudohypoparathyoidism (PTH resistance) ▫ ↓ in secondary hyperparathyroidism

Chapter 111 Hypercalcemia & Hypocalcemia ▫ Normal in setting of hypocalcemia: hypomagnesemia/mild vitamin D deficiency ▪ Magnesium: ↓ levels can cause hypocalcemia

OTHER DIAGNOSTICS ECG ▪ Prolonged QT segment ▪ Prolonged ST segment ▪ Arrhythmias (torsades de pointes, atrial fibrillation)

TREATMENT MEDICATIONS

▪ Main goal: normalize calcium levels ▫ Calcium gluconate ▫ Vitamin D supplementation

Figure 111.3 Hypocalcemia can can cause tetany, seen here in the face of this individual.

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NOTES

NOTES

HYPERKALEMIA & HYPOKALEMIA

GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Imbalances of potassium levels in blood ▪ Etiologies influence potassium intake, excretion, transcellular shift

SIGNS & SYMPTOMS ▪ Mild variations usually asymptomatic, severe imbalances may be fatal

TREATMENT MEDICATIONS

▪ Discontinue medication that aggravates potassium homeostasis ▪ Low serum K+ ▫ Oral K+ can be supplemented ▪ High serum K+ ▫ Agents/procedures that remove extracellular K+, into cells/↑ secretion from body

DIAGNOSIS LAB RESULTS

▪ Blood potassium levels; further tests useful to establish underlying cause

HYPERKALEMIA osms.it/hyperkalemia PATHOLOGY & CAUSES ▪ High potassium levels in blood > 5.5 milliequivalents/liter (mEq/L)

CAUSES Decreased kidney excretion ▪ Decreased glomerular filtration rate in acute/chronic kidney disease ▪ Adrenal insufficiency → primary hypoaldosteronism ▫ Principal cells secrete less potassium ▪ Drugs

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▫ Renin inhibitors, angiotensin converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, potassium-sparing diuretics, nonsteroidal anti-inflammatory drugs (NSAIDs), cyclosporine, trimethoprim-sulfamethoxazole Transcellular shift ▪ Uncontrolled Type I diabetes ▫ Lack of insulin → decreases sodium/ potassium pump action ▪ Acidosis ▫ Excess hydrogen ions move into cells via ion transporters that exchange hydrogen ions for potassium ions ▫ Respiratory acidosis; metabolic acidosis

Chapter 112 Hyperkalemia & Hypokalemia

▪

▪

▪

▪

from organic acids are two exceptions Hyperosmolarity ▫ Gradient pulls water out of cells → intracellular concentration potassium goes up → potassium pushed out Massive cell lysis ▫ E.g. tumor lysis syndrome, rhabdomyolysis, massive hemolysis ▫ Intracellular potassium released into bloodstream (98% of K+ found within cells) Drugs ▫ Beta2-adrenergic antagonists, digoxin toxicity Exercise ▫ Cellular ATP consumed → potassium channels open ▫ Shift usually small, can exacerbate condition in individuals with hyperkalemia

Increased intake ▪ Excessive potassium oral intake ▫ Unusual, can exacerbate condition in individuals with hyperkalemia ▪ Rapid, excessive potassium infusion (rare)

MNEMONIC: MURDER

Signs & symptoms of Hyperkalemia Muscle weakness Urine: oliguria, anuria Respiratory distress Decreased cardiac contractility EKG changes: peaked T waves; QRS widening Reflexes: hyperreflexia or areflexia (flaccid)

DIAGNOSIS LAB RESULTS

▪ Potassium levels in blood > 5.5mEq/L

OTHER DIAGNOSTICS ECG ▪ Prolonged PR interval, tall, peaked T-waves with narrow base, shortened QT interval, depressed ST segment ▪ Severe ▫ Small/indiscernible P wave, widened QRS complex → strip mimics sine wave

SIGNS & SYMPTOMS ▪ Mostly asymptomatic ▪ Severe/rapid-onset hyperkalemia ▫ Muscle weakness, flaccid paralysis (starts in lower extremities, moves upward) → respiratory failure ▫ Decreased deep tendon reflexes ▫ Arrhythmias, cardiac arrest ▫ Nausea, vomiting, intestinal colic, diarrhea

Figure 112.1 An ECG demonstrating the changes of hyperkalemia, including elevated T waves, bizarre, broad QRS complexes and a prolonged QT interval.

OSMOSIS.ORG 801

TREATMENT MEDICATIONS

▪ Initial treatment (individuals with ECG changes) ▫ Calcium to stabilize myocardial cell membranes

MNEMONIC: C BIG K DROP Treatment of Hyperkalemia Calcium gluconate Beta 2 agonist Insulin + Glucose Kayexalate Diuretics/Dialysis

▪ Insulin with dextrose + beta2-adrenergic agonists ▫ Increase potassium shift into cells ▪ Kayexalate ▫ Bind potassium → decrease potassium absorbed from gastrointestinal (GI) tract ▪ Loop diuretics ▫ Increase potassium excretion in kidneys

OTHER INTERVENTIONS

▪ Severe hyperkalemia/renal failure ▫ Hemodialysis (most rapid, effective way to lower serum K+)

Figure 112.2 The ECG features found in hyperkalemia.

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Chapter 112 Hyperkalemia & Hypokalemia

HYPOKALEMIA osms.it/hypokalemia PATHOLOGY & CAUSES ▪ Low potassium levels in the blood < 3.5mEq/L

CAUSES

▪ Increased kidney excretion ▫ Hyperaldosteronism; drugs (e.g. loop, thiazide diuretics, amphotericin B, cisplatin); renal tubular defects (e.g. Bartter syndrome); hypomagnesemia ▪ Increased gastrointestinal excretion ▫ Vomiting (direct loses minimal, causes metabolic alkalosis); diarrhea ▪ Increased sweat production ▫ Relevant for individuals who exercise in hot climate ▪ Shift from extracellular to intracellular space ▫ Insulin overdose in Type I diabetes; excess insulin → increases sodium/ potassium pump action ▪ Alkalosis ▫ Hydrogens move out of cells using ion transporter that exchanges with potassium ions ▫ Respiratory alkalosis an exception ▪ Drugs ▫ Beta2-adrenergic agonists

Other causes ▪ Low dietary intake (e.g. prolonged fasting, anorexia, ketogenic diet) ▪ Insulin administration ▪ Antibiotics (TMP-SMX/amphotericin B) ▪ Epinephrine (beta 2-agonists) ▫ Slightly more than half of trauma cases present with hypokalemia (increased epinephrine levels)

SIGNS & SYMPTOMS ▪ Mostly asymptomatic ▪ Severe/rapid-onset hypokalemia ▫ Constipation, paralytic ileus ▫ Muscle weakness, cramps, flaccid paralysis ▫ Decreased deep tendon reflexes ▫ Arrhythmias (prolong cardiac conduction), cardiac arrest ▫ Polyuria, polydipsia, nausea, vomiting ▫ Exacerbates digitalis toxicity

DIAGNOSIS LAB RESULTS

▪ Blood potassium level < 3.5mEq/L

OTHER DIAGNOSTICS ECG ▪ Flattened/inverted T waves, U waves, ST depression, prolonged PR interval ▫ Prominent U waves fused to T waves, mimic prolonged QT ▪ Atrial, ventricular tachyarrhythmias

TREATMENT MEDICATIONS

▪ Replenish potassium with supplementation ▫ In acute coronary ischemia, active arrhythmias ▪ Oral KCl administration (safest) ▪ IV administration for individuals taking nil per os ▫ 10mEq KCl increases K+ by 0.1MEq/L ▪ Magnesium replacement ▪ If diuretic therapy needed ▫ Potassium-sparing diuretic

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NOTES

NOTES

HYPERMAGNESEMIA & HYPOMAGNESEMIA

GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Abnormal levels of magnesium in the blood ▪ Hypomagnesemia: < 1.7mg/dL ▪ Hypermagnesemia: > 2.4mg/dL

SIGNS & SYMPTOMS ▪ Mild variations are usually asymptomatic, severe imbalances may result in potentially fatal arrhythmias and neurological complications

DIAGNOSIS LAB RESULTS

▪ Assessment of blood magnesium levels ▪ Further tests are useful to establish underlying cause

TREATMENT MEDICATIONS

▪ Identify and treat any underlying causes ▪ Hypermagnesemia ▫ Administer calcium gluconate → competes for magnesium binding sites ▪ Hypomagnesemia ▫ Supplemental magnesium

HYPERMAGNESEMIA osms.it/hypermagnesemia PATHOLOGY & CAUSES ▪ Blood magnesium levels above 2.4mg/dL

CAUSES

▪ Renal failure ▫ Kidneys unable to efficiently excrete magnesium (most common cause) ▪ Excessive intake ▫ Ingesting larger amounts of magnesium than the kidneys are able to excrete (supplements or medication e.g. magnesium hydroxide, often used for heartburn or constipation)

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▫ Excessive IV administration (e.g. treatment of preeclampsia) ▪ Cellular breakdown (excessive release) ▫ Tumour lysis syndrome, rhabdomyolysis

COMPLICATIONS

▪ Impaired signal transmission across neuromuscular junction → muscle weakness (magnesium inhibits calcium influx at neuromuscular junction), inhibition of parathyroid hormone release, hypocalcemia, cardiac bradyarrhythmias

Chapter 113 Hypermagnesemia & Hypomagnesemia

SIGNS & SYMPTOMS ▪ Nausea ▪ Drowsiness ▪ Tingling sensation in the face (facial paresthesia) ▪ Progressive loss of deep tendon reflexes (earliest sign) ▪ Coma ▪ Muscular paralysis ▪ Respiratory failure ▪ Cardiac arrest

DIAGNOSIS ▪ ECG changes similar to those of hyperkalemia, increased PR interval, widened QRS complex, bradyarrhythmias

LAB RESULTS

TREATMENT MEDICATIONS

▪ Calcium gluconate injection ▫ Calcium and magnesium compete for binding sites ▫ Reserved for severe, symptomatic hypermagnesemia ▪ Loop diuretics increases the urinary excretion of magnesium

OTHER INTERVENTIONS

▪ Identify and stop the source of excessive intake ▫ If normal renal function, with relevant history or possible iatrogenic cause, cessation of excessive intake sufficient treatment ▪ Hemodialysis ▫ In severe cases magnesium can be externally filtered from the blood

▪ Blood free magnesium level > 2.4mg/dL ▪ Renal function testing ▫ Urea, creatinine clearance test (levels increase with renal failure)

OTHER DIAGNOSTICS

▪ Thorough examination of individual’s history often reveals cause

Figure 113.1 Illustration depicting calcium channel inhibition due to hypermagnesemia, causing delayed muscle contraction.

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HYPOMAGNESEMIA osms.it/hypomagnesemia PATHOLOGY & CAUSES ▪ Low levels of magnesium in the blood, sodium loss ▪ Extrarenal water loss ▫ Skin losses (sweating when hot, exercising, fever), gastrointestinal (GI) losses (vomiting, drainage, diarrhea) ▪ Hypothalamic lesions ▫ Antidiuretic hormone (ADH) ↓ → dilute water loss ▫ Thirst center loss (insufficient intake), ↑ serum sodium ▫ Both ▪ Renal water loss (e.g. nephrogenic diabetes insipidus)

Chapter 114 Hypernatremia & Hyponatremia Sodium ↑ ▪ ↑ sodium intake, kidney dysfunction ▪ Iatrogenic ▫ Intravenous (IV) sodium-containing solutions administered too quickly/too high concentration

RISK FACTORS

▪ Uncontrolled diabetes, underlying polyuria disorder, diuretic therapy, inability to act on thirst impulse, age extremes (elderly/ neonate), mental/physical impairment, nursing home residency, hospitalization

COMPLICATIONS

▪ Acute hypernatremia ▫ Demyelinating brain lesions, rapid brain volume ↓ → blood vessel rupture → cerebral haemorrhage

SIGNS & SYMPTOMS ▪ Dehydration ▫ Thirst, sunken orbits, dry mucous membranes, reduced skin turgor, postural hypotension, tachycardia ▪ Acute hypernatremia ▫ Lethargy, weakness, irritability, twitching, seizure, coma ▪ Long-standing hypernatremia ▫ Fewer symptoms, cells adjust

MNEMONIC: FRIED SALT

Hypernatremia Signs & Symptoms Fever (low), Flushed skin Restless (irritable) Increased fluid retention, Increased blood pressure Edema (peripheral, pitting) Decreased urinary output, Dry mouth Skin flushed Agitated Low-grade fever Thirst

DIAGNOSIS LAB RESULTS

▪ Measure blood sodium ▫ Hypernatremia: > 145mEq/L

Intravascular volume hypovolemic ▪ Drinking too little/losing too much water ▫ Urine osmolality: > 600 milliosmoles per kilogram (mOsm/kg) ▫ Urine sodium: < 20mEq/L ▪ Kidneys losing sodium ▫ Urine sodium: > 20mEq/L ▫ Kidney disease, medications (e.g. osmotic,loop diuretics) ▪ Euvolemic ▫ Urine osmolality: < 300mOsm/kg ▫ Urine sodium: < 20mEq/L ▫ Kidneys losing water (diabetes insipidus)

TREATMENT OTHER INTERVENTIONS

▪ ↓ sodium concentration ▪ ↑ water intake ▫ Extrarenal water loss ▫ Diabetes insipidus, normal thirst mechanism ▪ Monitor serum sodium, glucose ▫ Dextrose water hydration, isotonic to plasma, electrolyte free ▫ Overly dextrose water infusion → hyperglycemia → osmotic diuresis, counteracting rehydration efforts ▪ Chronic cases ▫ Slower correction ▪ IV 5% dextrose water → lowers sodium ▫ Hypernatremia correction with IV fluids → practice care to avoid cerebral edema ▪ Rapid overcorrection ▫ Administer sodium-containing IV fluids (e.g. saline, Ringer’s lactate) ▪ Concomitant extracellular fluid depletion presenting with severe hypernatremia, hypovolemia signs ▫ Isotonic sodium containing fluids

OSMOSIS.ORG 809

HYPONATREMIA osms.it/hyponatremia PATHOLOGY & CAUSES ▪ Low sodium concentration in extracellular fluid ▫ < 135mEq/L

TYPES Hypervolemic hyponatremia ▪ Significant total body water ↑, small sodium ↑ ▪ Congestive heart failure, hepatic cirrhosis, nephrotic syndrome, water lost to extracellular space → circulating volume ↓ → ADH, aldosterone released → pure water retention ↑, sodium retention ↑ (further pure water retention ↑) Hypovolemic hyponatremia ▪ Small total body water, large sodium ↓ ▪ Diarrhea, vomiting, medications (e.g. diuretics) → sodium actively pumped into GI tract ▪ Cerebral salt wasting, intracranial injury/ infection disrupts kidney sympathetic stimulation → ↑ sodium loss Euvolemic hyponatremia ▪ ↑ body water, no body sodium change ▪ Dilute urine ▫ Adrenal insufficiency, hypothyroidism, polydipsia (excessive water drinking), potomania (excessive beer drinking) ▪ Concentrated urine ▫ Syndrome of inappropriate antidiuretic hormone secretion (SIADH) False hyponatremia/pseudohyponatremia ▪ No water, sodium level changes ▪ Hypertriglyceridemia (excessive lipid concentration), multiple myeloma (excessive protein concentration) → affect lab equipment → false sodium reading

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CAUSES

▪ Sodium loss > water loss ▪ Water gain > sodium gain

COMPLICATIONS

▪ Sudden/severe hyponatremia → water shifts into brain cells → swelling → ↑ intracranial pressure → ischaemia/ herniation → respiratory center damage → death ▪ Excessively rapid sodium-level correction → cerebral pontine myelinolysis (rapid sodium, water shifts → myelin-loss in pons)

SIGNS & SYMPTOMS ▪ Nausea, vomiting, muscle cramps, confusion, seizure, coma

DIAGNOSIS LAB RESULTS

▪ Measure serum sodium concentration ▫ 100mOsm/kg → SIADH ▪ Dilute urine ▫ < 100mOsm/kg → excessive fluid intake ▪ Urine sodium ▫ > 20–40mEq/L → SIADH, cerebral salt wasting ▪ Urine sodium ▫ < 20mEq/L → hypovolemia

Chapter 114 Hypernatremia & Hyponatremia

TREATMENT OTHER INTERVENTIONS

▪ SIADH ▫ Fluid restriction ▪ Hypovolemia ▫ Fluids ▪ Hyponatremia ▫ Hypertonic saline (slowly—prevents cerebral pontine myelinolysis)

Figure 114.1 An MRI scan in the sagittal plane demonstrating central pontine myelinolysis. There is faint, but well demarcated, hypoattenuation in the centre of the pons.

OSMOSIS.ORG 811

NOTES

NOTES

HYPERPHOSPHATEMIA & HYPOPHOSPHATEMIA

GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Phosphate imbalances in blood ▫ Hyperphosphatemia: > 4.5mg/dL ▫ Hypophosphatemia: < 2.5mg/dL ▪ Phosphate intake; absorption through gastrointestinal (GI) tract; kidney excretion; transcellular shift; balance between uptake, release by bone tissue

DIAGNOSIS LAB RESULTS

▪ Assess blood phosphate levels

TREATMENT ▪ See individual disorders

SIGNS & SYMPTOMS ▪ Mild: usually asymptomatic ▪ Severe: may be fatal

Figure 115.1 Illustration depicting parathyroid hormone preventing reabsorption of phosphate and promoting reabsorption of calcium.

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Chapter 115 Hyperphosphatemia & Hypophosphatemia

HYPERPHOSPHATEMIA osms.it/hyperphosphatemia 1cm/0.39in below zygomatic process) ▫ Trousseau’s sign (blood pressure cuff occludes brachial artery, pressure on nerve leads to muscle spasm, flexing wrist, metacarpophalangeal joints) ▫ Hyperreflexia ▫ Tingling around mouth ▫ Seizures ▫ Bone pain

PATHOLOGY & CAUSES ▪ High phosphate levels in blood > 4.5mg/dL ▪ 70% of individuals with advanced chronic kidney disease ▫ Individuals with chronic kidney disease, hyperphosphatemia → secondary hyperparathyroidism, renal osteodystrophy → bones thin, weak ▪ Risk of metastatic calcification (e.g. kidney stones, nephrocalcinosis)

CAUSES

▪ Decreased kidney excretion ▫ Decreased glomerular filtration rate in acute/chronic kidney disease ▫ Hypoparathyroidism ▫ Pseudohypoparathyroidism ▫ Vitamin D intoxication: increased phosphate absorption through Gl tract ▪ Increased phosphate intake ▫ Only acute phosphate load (e.g. too much phosphate-based laxative) ▪ Transcellular shift ▫ Massive cell death (e.g. tumor lysis syndrome, rhabdomyolysis, crush injuries, massive hemolysis— intracellular phosphate released into bloodstream) ▫ Acidosis

COMPLICATIONS

▪ Metastatic calcification ▪ Renal calcinosis

SIGNS & SYMPTOMS ▪ Mild: asymptomatic ▪ Severe: hypocalcemia ▫ Tetany ▫ Chvostek’s sign (facial muscles twitch after facial nerve lightly finger tapped

DIAGNOSIS LAB RESULTS ▪ ▪ ▪ ▪ ▪

↑ phosphate ↓ calcium ↑ vitamin D ↓ parathyroid hormone ↑ urinary phosphate excretion

OTHER DIAGNOSTICS

▪ History, physical examination

TREATMENT MEDICATIONS

▪ Decrease phosphate absorbed from GI tract ▫ Phosphate binders (e.g. aluminium salts, calcium carbonate) ▪ Increase phosphate excretion ▫ Healthy kidneys: forced diuresis, intravenous (IV) saline, loop diuretic (furosemide) → overwhelm proximal convoluted tubule of nephron → unable to effectively reabsorb solutes (e.g. phosphates) ▫ Life-threatening hyperphosphatemia: dialysis

OTHER INTERVENTIONS

▪ Decrease phosphate intake; avoid highphosphate foods (e.g. dairy, meat, soda)

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HYPOPHOSPHATEMIA osms.it/hypophosphatemia PATHOLOGY & CAUSES ▪ Low phosphate levels in blood < 2.5mg/dL

CAUSES

▪ Increased kidney excretion ▫ Primary hyperparathyroidism ▫ Fanconi syndrome: proximal convoluted tubule loses capacity to reabsorb solutes (e.g. phosphates) ▪ Decreased intake, absorption through GI tract ▫ Low intake dietary phosphate (unusual) ▫ Medications impair absorption (e.g. antacids with aluminum/calcium/ magnesium) ▫ Alcohol use disorder → low dietary phosphate intake, vitamin D deficiency ▪ Transcellular shift ▫ Refeeding syndrome in severely malnourished individuals → hypokalemia, cardiac arrhythmias, neurologic problems ▫ Insulin treatment in diabetic ketoacidosis; insulin makes phosphate move from the bloodstream inside the cells ▫ Respiratory alkalosis

RISK FACTORS

▪ Alcoholism, diabetes, sepsis

COMPLICATIONS

▪ Rhabdomyolysis, kidney damage ▪ Chronic hypophosphatemia ▫ Osteomalacia (adults), rickets (children)

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SIGNS & SYMPTOMS ▪ Mild: asymptomatic ▪ Severe: ▫ Muscle weakness, respiratory/cardiac insufficiency ▫ Altered mental status ▫ Seizures

DIAGNOSIS LAB RESULTS ▪ ▪ ▪ ▪

↓ phosphate ↑ calcium ↓ vitamin D ↑ parathyroid hormone

OTHER DIAGNOSTICS

▪ History, physical examination

TREATMENT MEDICATIONS

▪ Replenish phosphates ▫ Oral administration, diet alone may suffice ▫ IV for life-threatening hypophosphatemia

OTHER INTERVENTIONS

▪ Avoid refeeding syndrome by gradually increasing caloric intake, supplements over several days

NOTES

NOTES

KIDNEY DISORDERS GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Group of diseases involving renal system, commonly due to systemic disease/ iatrogenic factors (medications, fluid management) ▪ Common complication of hospitalized individuals, esp. elderly with chronic disease ▪ Kidneys sensitive to any systemic change due to high metabolic demand ▪ Classification: pre-, intra-, post-renal causes; based on location of pathology in urinary system

SIGNS & SYMPTOMS ▪ Widely variable, universally includes urine abnormalities (amount, composition, color) ▪ May be easily evident (hematuria)/indolent (oliguria)

DIAGNOSIS LAB RESULTS

▪ Blood urea nitrogen (BUN)-to-creatinine (BUN:Cr) ratio ▫ Filtration/reabsorptive function ▪ Glomerular filtration rate (GFR) ▫ Estimated value, correlates to filtration function

▪ Urinalysis ▫ Physical, chemical, microscopic data; compare to serum concentration Urine microscopy ▪ Cell/substance accumulation in tubules → casts → molds to tubular form → excreted as tubular-shaped mass ▪ Eosinophils, epithelial cells, erythrocytes

OTHER DIAGNOSTICS

▪ Medical history ▫ Medication, exposure ▪ Physical examination ▫ Systemic signs of disease ▫ Limited for renal-specific disease; identify gross abnormalities of lower urinary tract

TREATMENT ▪ Goal: achieve adequate volume, composition

OTHER INTERVENTIONS

▪ Treat underlying systemic disease ▫ Withdrawal of offending agent (e.g. medication)

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ACUTE TUBULAR NECROSIS osms.it/acute-tubular-necrosis PATHOLOGY & CAUSES ▪ Disease of tubular epithelial cell death; most common cause of acute kidney injury (AKI) in hospitalized individuals; potential for permanent kidney failure ▪ AKA acute tubular injury (ATI) ▪ Death of tubular epithelial cells → disruption of basolateral cell surface → sloughing, obstruction of tubules → ↑ tubular hydrostatic pressure → ↓ GFR → filtration/reabsorption → ↓ urine output → oliguria → azotemia

MNEMONIC: LIFELESS

Differences between apoptosis and necrosis Leaky membranes Inflammatory response Fate Extent Laddering Energy dependent Swell or shrink Stimulus

CAUSES Ischemia ▪ Death of tubular epithelial cells due to insufficient oxygen to meet metabolic demand ▫ Most common in proximal, thick ascending tubules; most metabolically active sites across nephron due to high amounts of active sodium reabsorption ▫ ↓ blood delivery to tubular epithelial cells → hypoxia → ischemia

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▫ ↓ blood flow → endothelial cell, ↑ vasoconstrictor release; endothelin + ↓ vasodilators release; nitric oxide (NO), prostacyclin (PGI2) → net effect of afferent arteriole constriction → ↓ glomerular filtration rate (GFR) ▪ Ischemic conditions/diseases ▫ Shock; heart failure; renal artery stenosis; excessive gastrointestinal (GI) fluid loss; malignant hypertension; microangiopathies ▫ Systemic disease associated with thrombosis: hemolytic-uremic syndrome (HUS), thrombotic thrombocytopenic purpura (TTP), disseminated intravascular coagulation (DIC) ▫ Microscopic polyangiitis ▫ Surgical procedures, esp. cardiac, abdominal aortic aneurysm (AAA) repair Nephrotoxins ▪ Direct tubular epithelial cell injury due to toxins encountered by kidney ▪ Most common in proximal convoluted tubule; first tubular site in nephron for filtered toxin ▪ Pathophysiology ▫ Direct toxic renal epithelial tubular cell injury; death ▪ Endogenous toxins ▫ Myoglobin, hemoglobinuria; uric acid (tumor lysis syndrome); monoclonal light chains (multiple myeloma) ▪ Exogenous toxins ▫ Medications: aminoglycosides (most common), cisplatin, amphotericin B, nonsteroidal anti-inflammatory drugs (NSAIDs) ▫ Heavy metals (lead); ethylene glycol; radiocontrast agents; organic solvents

Chapter 116 Kidney Disorders

TREATMENT OTHER INTERVENTIONS Hydration ▪ Return to euvolemic fluid status/eliminate offending nephrotoxin ▪ 1–2 weeks for epithelial cells to regenerate Figure 116.1 Histological appearance of acute tubular necrosis. The tubular epithelial cells are poorly demarcated and there is loss of nuclei, consistent with necrosis.

SIGNS & SYMPTOMS ▪ Onset: triggering event ▪ Oliguric phase (10–14 days): may advance to anuria if unrecognized, untreated ▪ Diuretic phase (> 500ml urine per day): due to regeneration of functional tubular epithelial cell growth, outflow of fluid overload during oliguric phase, osmotic diuresis from retained solutes ▪ Recovery phase (normal urine output, concentration): parallels full recovery of tubular epithelial cell function

Prevention ▪ Identification of nephrotoxins, elimination/ limitation of use ▪ Identification of high-risk individuals, situations for acute ↓ renal blood flow, ensure adequate intravascular volume status ▪ Add allopurinol in tumor lysis syndrome (TLS) cases ▫ Prophylactic/therapeutic

DIAGNOSIS LAB RESULTS ▪ ▪ ▪ ▪ ▪ ▪

Intrarenal AKI ↓ BUN:Cr ratio: < 15 ↑ FeNa: > 2% Dilute urine: ↓ Uosm; < 500mOsm/kg ↑ K+ Urinalysis: brown granular casts ▫ Sloughed-off epithelial cells in tubules, excreted as mass)

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KIDNEY STONES osms.it/kidney-stone PATHOLOGY & CAUSES ▪ AKA nephrolithiasis ▪ Stones form in kidney when solutes precipitate out as crystals in urine ▪ Solute supersaturated with crystalline constituents → precipitate out of solution → form crystals → further precipitation → more solutes deposit, build up → stones ▪ Occurs when ↑ solute, ↓ solvent, combination of both (e.g. dehydration) ▪ Some stones < 5mm can be passed through urinary stream within hours without intervention

TYPES Calcium stones ▪ Calcium oxalate (most common) ▫ Black/dark brown ▫ Positively-charged calcium ion binds to negatively-charged oxalate ion in medullary interstitium ▫ More likely in acidic urine ▫ Pathology: primary hyperoxaluria (autosomal recessive disorder → excessive hepatic oxalate production); acquired hyperoxaluria (e.g. enteric oxaluria; → excessive absorption of oxalate in gut) ▪ Calcium phosphate ▫ Dirty white ▫ Calcium binds to negatively charged phosphate group ▫ More likely in alkaline urine ▫ Pathology: alteration in calcium absorption in gut/renal reabsorption → hypercalciuria Uric acid stones ▪ Red brown ▪ Physiologic pH uric acid, proton loss → urate ion → binds sodium → forms monosodium urate → crystallizes → stones

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▪ Uric acid: breakdown product of purines ▪ Pathology: excessive dietary purine → ↑ uric acid as metabolite → hyperuricosuria Struvite stones (infection/triple stones) ▪ Dirty white ▪ Composite of magnesium, ammonium, phosphate ▪ Urea-splitting bacteria (e.g. Proteus vulgaris, Staphylococci) convert urea to ammonia → urine more alkaline → favors precipitation of magnesium, ammonium, phosphate ▪ Often form largest stones; can form staghorn calculi, branch into renal calyces ▪ Pathology: ammonium ions from ureaseproducing bacteria + alkaline urine → precipitation Cystine stones (less common) ▪ Yellow/light pink ▪ Composed of amino acid cystine ▪ Pathology: autosomal recessive/dominant disorder → defective renal transport of cystine → ↓ renal reabsorption + increased urinary cystine excretion → cystinuria Xanthine stones (rare) ▪ Brick red ▪ Composed of xanthine, usually found in xanthinuria ▪ Pathology ▫ Hereditary xanthinuria: autosomal recessive disorder → ↓ xanthine oxidase → ↓ conversion of xanthine to uric acid → ↑ urinary excretion of xanthine ▫ Acquired: xanthine oxidase inhibitors (e.g. allopurinol) or liver disease → ↓ xanthine oxidase

RISK FACTORS

▪ Genetic predisposition ▫ Positive family history; genetic mutations (e.g. primary hyperoxaluria)

Chapter 116 Kidney Disorders ▪ Renal/urinary tract disorders ▫ Vesicoureteral reflux; urinary tract infections (UTIs); congenital urinary tract malformations (e.g. horseshoe kidney); cystic kidney diseases; neurogenic bladder ▪ Factors associated with hyperuricemia; diet high in purines (e.g. red meat, organ meat, shellfish, anchovies); cellular depletion (e.g. leukemia, cytotoxic medications); gout ▪ Factors associated with increased serum calcium ▫ Primary hyperparathyroidism; inflammatory bowel disease; diets high in calcium oxalate (beer, chocolate, nuts); excessive calcium supplementation ▪ Excessively salty foods; low fluid intake, dehydration; ↑ BMI/obesity; more common in individuals who are biologically male

COMPLICATIONS

▪ Gout ▫ May exacerbate existing gout/cause new onset gout ▪ Infections ▫ UTIs; pyelonephritis; urosepsis; abscess ▪ Scarring, stenosis; urinary fistula; obstruction of ureter → hydronephrosis; renal failure

Figure 116.2 A single calcium oxalate kidney stone.

SIGNS & SYMPTOMS ▪ Dull, localized flank pain in mid, lower back; one/both sides ▫ Pain caused by dilation, stretching, spasm due to obstruction of ureter ▫ Subsides once stone reaches bladder ▪ Renal colic ▫ Intense bouts of pain caused by smooth muscle peristalsis against obstruction ▫ Caused by sharp stone moving through ureter ▪ Pain on urination (dysuria); cloudy, red/ brown urine ▪ Fever, chills (infection); nausea, vomiting

DIAGNOSIS DIAGNOSTIC IMAGING X-ray ▪ Radiopaque ▫ Calcium oxalate, phosphate ▪ Radiolucent ▫ Uric acid stones, struvite stones, cystine stones, xanthine stones CT scan ▪ Abdomen, pelvis (preferred) ▪ Performed without contrast (contrast ↓ sensitivity for stones < 3mm) ▪ Accurately detects size, location ▪ Density, location, appearance determines category; cannot identify type of calcium stones (e.g. oxalate/phosphate) Ultrasound ▪ Preferred initial modality for pregnant individuals ▪ Reliably detects hydronephrosis (if stone obstructive) ▪ Stones detected as echodensities (with shadow effect); less sensitive than CT scan

OSMOSIS.ORG 819

Figure 116.3 An abdominal CT scan in the axial plane demonstrating a stone in the renal pelvis. There is prominent hydronephrosis.

Figure 116.4 Scanning electron micrograph of the surface of a calcium oxalate stone.

OTHER DIAGNOSTICS History ▪ Prior stones, colicky episodes of flank pain, passage of stone/gravel in urine Physical exam ▪ Ancillary findings support etiologies/risk factors (e.g. hypovolemia, podagra of gouty arthritis)

TREATMENT MEDICATIONS

Figure 116.5 A plain abdominal radiograph demonstrating a staghorn calculus of the left kidney. Intravenous pyelography (IVP) ▪ Less common ▪ Radiographic imaging ▫ IV iodinated contrast administration ▪ Reliable for hydronephrosis; less sensitive, specific than CT scan for stone detection

LAB RESULTS

▪ Microscopic/gross hematuria ▪ Crystals may be present

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▪ Analgesics ▫ Treat pain ▪ Potassium citrate treatment ▫ Makes urine alkaline, ↓ salt crystallization, ↓ stone formation ▪ Alpha-adrenergic blockers, calcium channel blockers ▫ ↓ spasms, help stones pass through relaxed ureters, ↓ pain ▪ Magnesium, citrate ▫ Inhibit crystal growth, aggregation; prevent kidney stones forming ▪ Shockwave lithotripsy ▫ Noninvasive treatment; acoustic pulses travel through body to break up kidney stones into smaller fragments

Chapter 116 Kidney Disorders

SURGERY

▪ Surgery, endoscopic stent placement ▫ For larger stones

OTHER INTERVENTIONS

▪ Hydration ▫ Reverse precipitation, facilitate passage

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RENAL PAPILLARY NECROSIS osms.it/renal-papillary-necrosis PATHOLOGY & CAUSES ▪ Damage to renal papillary tissue, severe enough to result in cell death; multiple etiologies ▪ Located within renal medulla near end of vasa recta → ↑ susceptibility to ischemic damage when vascular blood supply impaired ▪ Both kidneys usually involved

CAUSES

▪ Acute interstitial nephritis, phosphate nephropathy; severe, acute pyelonephritis; renal tuberculosis (rare)

COMPLICATIONS

▪ Obstruction due to sloughed-off papillary necrotic tissue ▪ Further complicated by UTI; worsens AKI

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SIGNS & SYMPTOMS ▪ Recent infection/immune challenge may trigger symptoms ▪ Colicky flank pain

DIAGNOSIS DIAGNOSTIC IMAGING CT scan/X-ray ▪ Calcifications ▫ Variable, due to underlying etiology Kidney ultrasound ▪ Calcifications appear echodense

LAB RESULTS

▪ Hematuria; proteinuria (foamy urine); flecks of tissue in urine; sterile pyuria

Chapter 116 Kidney Disorders

TREATMENT SURGERY

▪ Remove obstruction

OTHER INTERVENTIONS

▪ Specific to underlying etiology: withdraw offending analgesic; control RBC sickling

RENAL TUBULAR ACIDOSIS (RTA) osms.it/renal-tubular-acidosisPATHOLOGY & CAUSES ▪ Group of disorders; renal tubular cell defects unable to acidify urine → metabolic acidosis

CAUSES RTA I (AKA distal RTA) ▪ Unable to secrete H+ ▪ Cells involved ▫ Alpha-intercalated cells in distal tubule, collecting duct ▪ Genetic mutations ▫ H+ ATPase, H/K ATPase on apical surface: unable to actively secrete H+ into tubular lumen ▫ HCO3/Cl antiporter on basolateral cell surface: unable to transport HCO3 to bloodstream ▪ Medications ▫ Lithium/amphotericin B ▫ Makes cells permeable for H+ to leak across into cell RTA II ▪ Unable to resorb HCO3; lost in urine ▪ Cells involved: brush border cells in proximal tubule ▪ Genetic mutations ▫ Na/HCO3 cotransporter on basolateral surface: ↓ HCO3 transport → imbalance in H+ → acidemia

▪ Fanconi syndrome ▫ Reabsorptive disease of proximal tubular cells ▫ Results in prophosphaturia, glycosuria, aminoaciduria, uricosuria, proteinuria ▫ Due to genetic disease, medication (e.g. tetracyclines) ▪ May be no change in urinary pH ▫ Intact distal tubular cell function, ability to acidify urine RTA III (rare) ▪ Cells involved: proximal, distal tubule ▪ Etiology mostly unknown ▪ Congenital carbonic anhydrase deficiency; defect of carbonic anhydrase needed to convert HCO3 + H+ → H2CO3; associated with osteopetrosis (carbonic anhydrase for bone remodeling) RTA IV (AKA hyperkalemic acidosis) ▪ Cells involved: distal tubular cells (alphaintercalated, principal cells) ▪ Aldosterone deficiency (e.g. Addison disease) ▫ ↓ aldosterone-induced secretion of H+ via apical transporters in alphaintercalated cells → ↑ cellular H+ → H+ moves down gradient to peritubular capillaries → acidemia ▪ Aldosterone resistance ▫ Genetic mutation of ENac (apical cell surface of principal cells)

OSMOSIS.ORG 823

▪ Severe hypovolemia ▫ ↓ intracellular Na → altered Na/K exchange → ↑ intracellular K+ → peritubular capillaries → ↑ serum K+ and ↓ serum Na+ → acidemia ▪ Systemic lupus erythematosus (SLE) ▫ Rare complication ▪ Medications (e.g. lithium, amphotericin B) ▫ H+ diffuses across cell into blood → acidemia

COMPLICATIONS

▪ Shock ▫ Metabolic acidosis → dilation of peripheral arterioles → ↓ afterload, preload → ↓ effective circulating volume → distributive shock → inadequate perfusion to vital organs ▪ Nephrolithiasis ▫ Alkalotic urine environment (pH > 6; esp. in RTA I) → hypercalciuria → precipitation of calcium stones

SIGNS & SYMPTOMS ▪ GI ▫ ↓ appetite, vomiting, abdominal pain ▪ Shock ▫ Tachycardia; flushing; Kussmaul breathing → ↓ CO2 serum levels ▪ Nephrolithiasis (potential complication) ▫ Colicky pain; hematuria; urinary frequency/hesitancy

DIAGNOSIS LAB RESULTS

▪ Blood studies ▫ Metabolic acidosis: pH < 7.35, < HCO3 ▫ ↑ Cl▫ ↑ K+ (in RTA IV) ▪ Urinalysis ▫ Urinary anion gap (above 20mEq/L) ▫ Acidity ▫ RTA I, II (acutely): alkalotic (pH > 6) ▫ RTA III: not characteristically defined ▫ RTA IV: acidic (pH < 6)

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Figure 116.6 A plain kidney-ureter-bladder (KUB) X-ray demonstrating medullary calcinosis, a complication of renal tubular acidosis.

TREATMENT MEDICATIONS

▪ RTA I, II: eplenish HCO3, correct hypokalemia with potassium citrate ▫ RTA II: thiazide diuretics → water loss, ↑ HCO3 reabsorption ▪ RTA IV: treat hypoaldosteronism ▫ Fludrocortisone, loop diuretics → ↑ Na+ delivery to collecting duct → ↑ K/H exchange

NOTES

NOTES

NEPHRITIC SYNDROME GENERALLY, WHAT IS IT? PATHOLOGY & CAUSES ▪ Diseases caused by inflammation, damage to glomeruli of kidney; become more permeable, allow red blood cells (RBCs) into urine → hematuria

CAUSES

▪ Children/adolescents: IgA nephropathy, post-streptococcal glomerulonephritis, hemolytic uremic syndrome ▪ Adults: systemic lupus erythematosus, Goodpasture’s syndrome, rapidly progressive glomerulonephritis

COMPLICATIONS

▪ Acute kidney failure

SIGNS & SYMPTOMS ▪ Damaged, permeable glomeruli → hematuria, proteinuria ▪ Decreased glomerular filtration rate → edema, hypertension ▪ Less waste product excreted → uremia

DIAGNOSIS LAB RESULTS

▪ Protein/blood, RBC casts in urine ▪ Decreased glomerular filtration

Kidney biopsy ▪ Changes under light/electron microscope, immunofluorescence

TREATMENT MEDICATIONS

▪ Edema ▫ Diuretics (furosemide), medical nutrition therapy ▪ Blood pressure control ▫ Angiotensin converting enzyme inhibitors (ACE) inhibitors

OTHER INTERVENTIONS

▪ Reduce salt, potassium intake

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ACUTE PROLIFERATIVE GLOMERULONEPHRITIS osms.it/proliferative-glomerulonephritis PATHOLOGY & CAUSES

SIGNS & SYMPTOMS

▪ Inflammation of glomeruli, complication of bacterial infection ▪ AKA poststreptococcal glomerulonephritis ▫ Commonly arises several weeks after group A beta-hemolytic streptococcus infection ▪ Type III hypersensitivity reaction ▫ IgG/IgM antibodies bind to bacterial antigens, form immune complexes → complexes travel through bloodstream to glomerulus, deposit in glomerular basement membrane ▪ Immune complex/complement deposits trigger immune reactions ▫ Activate complement system → enzyme cascade → formation of membrane attack complex → damage to podocytes, mesangial cells ▫ Recruit inflammatory cells → proteases, oxidants release → basement membrane damage → hematuria, proteinuria → nephritic syndrome

▪ Nephritic syndrome: hematuria, oliguria, edema, hypertension ▪ Fever, headache, malaise, anorexia, nausea

CAUSES

▪ Group A beta-hemolytic streptococcus infection

RISK FACTORS

▪ Most commonly in children (who are biologically male) ▫ Six weeks after impetigo, 1–2 weeks after throat infection

COMPLICATIONS

▪ Rapidly progressive glomerulonephritis, renal failure

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DIAGNOSIS LAB RESULTS

▪ Protein/blood in urine ▪ Antibodies against group A streptococcus (e.g. anti-DNase B antibodies, antiStreptolysin O antibody) ▪ Decreased complement levels

Renal biopsy ▪ Light microscopy ▫ Mesangial proliferation → hypercellular glomerulus ▪ Electron microscopy ▫ Subepithelial deposits of immune complexes, “humps” ▪ Immunofluorescence ▫ “Starry sky,” granular deposition of IgG, complement in basement membrane, mesangium

TREATMENT ▪ Usually supportive

Chapter 117 Nephritic Syndrome

Figure 117.1 The effect of crescentic glomerulonephritis on the nephron.

Figure 117.2 The constituent parts of the crescent seen in crescentic glomerulonephritis.

Figure 117.3 Histological appearance of the glomerulus in post-infective glomerulonephritis. The glomerulus is expanded and compressed due to infiltration of neutrophils and other inflammatory cells.

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GOODPASTURE'S SYNDROME osms.it/goodpasture-syndrome PATHOLOGY & CAUSES ▪ AKA anti-GBM antibody disease; damage of basement membrane in lungs, kidneys; mostly composed of Type IV collagen ▪ Damaged by Type II hypersensitivity reaction ▫ IgG antibodies (rarely IgM/IgA) bind to alpha 3 folded chain → activate complement system → damage collagen fibers of basement membrane

RISK FACTORS

▪ Bimodal distribution with peak incidence age 20–30 (biologically male), 60–70 (biologically female) ▪ Genetic: predisposition for genes that code for HLA-DR15 (immune molecule; identifies, binds to foreign molecules) ▪ Environmental: infection, smoking, oxidative stress, hydrocarbon-based solvents

DIAGNOSIS LAB RESULTS Renal biopsy ▪ Light microscopy ▫ Crescentic glomerulonephritis ▪ Electron microscopy ▫ Diffuse thickening of glomerular basement membrane ▪ Immunofluorescence ▫ Linear deposition along basement membrane

TREATMENT MEDICATIONS

▪ Corticosteroids, cyclophosphamide, plasmapheresis to filter plasma/fluid of blood (reduces risk of chronic renal failure)

COMPLICATIONS

▪ Chronic renal failure; require dialysis/kidney transplant; hemoptysis

SIGNS & SYMPTOMS ▪ Pulmonary manifestations usually occur before renal ones; minority (20–40%) with only renal manifestations ▫ Damaged lung alveoli → cough, hemoptysis, dyspnea ▫ Kidney filtration problems (e.g. hematuria, proteinuria) → nephritic syndrome

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Figure 117.4 Histological appearance of the kidney in a case of crescentic glomerulonephritis caused by Goodpasture’s syndrome.glomerulonephritis on the nephron.

Chapter 117 Nephritic Syndrome

Figure 117.5 Immunofluorescence with positive signal for antibodies to IgG. In addition the IgG deposition is linear. These features are consistent with Goodpasture’s syndrome.

HEMOLYTIC-UREMIC SYNDROME osms.it/hemolytic-uremic-syndrome PATHOLOGY & CAUSES ▪ Small blood clots in tiny blood vessels, mostly in kidneys → RBCs break down, kidney function decreases → urea levels in blood increase ▪ Triggered by bloody diarrhea ▫ Diarrhea-positive/D+ hemolytic uremic syndrome (HUS/typical HUS) Atypical hemolytic uremic syndrome ▪ D-hemolytic uremic syndrome ▫ No preceding diarrhea ▪ Damage to endothelial cell lining of glomerular capillaries from infections not related to diarrhea, medication, autoimmune causes ▪ Infants, children ▫ Streptococcus pneumoniae presents as pneumonia/meningitis ▪ Familial forms ▫ Genetically increased tendency for endothelial cell damage

CAUSES

▪ Escherichia coli (E. coli) from contaminated food/drink ▫ Enterohemorrhagic E. coli (EHEC, serotype O157:H7); may be caused by other strains ▫ E. coli attaches to intestinal wall → secretes Shiga-like toxin → absorbed by intestinal blood vessels → attaches to immune cells → toxins from white blood cells (WBCs) bind to endothelial cells of glomerular capillaries → inhibition of protein synthesis → apoptosis → many tiny blood clots form in kidneys

RISK FACTORS

▪ Children < five years old, people 75+ years old, genetic predisposition to endothelial cell damage

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SIGNS & SYMPTOMS ▪ Bloody diarrhea ▪ Weakness, fatigue, lethargy, jaundice due to red blood cell destruction ▪ Fever, blood clots: affect brain blood supply → visual disturbances, altered mental status, seizures, stroke → death

DIAGNOSIS

TREATMENT MEDICATIONS Typical, D+ hemolytic uremic syndrome ▪ Shiga-like toxin clears in days to weeks, antibiotics not recommended as dead bacteria potentially release more toxins Atypical hemolytic uremic syndrome ▪ Identify underlying cause

LAB RESULTS

▪ Requires thrombocytopenia, microangiopathic hemolytic anemia (MAHA), acute renal failure ▪ Proteinuria, hematuria ▪ Schistocytes/helmet cells ▪ D+ hemolytic uremic syndrome ▫ Shiga toxin (ELISA), gene encoding Shiga toxin (PCR) ▪ Differential diagnosis ▫ Thrombotic thrombocytopenic purpura (TTP) hemolytic uremic syndrome: measure ADAMTS13 activity in plasma ▫ Disseminated intravascular coagulation (DIC): DIC panel (e.g. pTT, INR, d-dimer, fibrinogen)

Figure 117.6 90% of hemolytic-uremic syndrome cases are a result of a prior infection with Shiga toxin producing E. coli.

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Figure 117.7 Histological appearance of acute thrombotic microangiopathy which is the pathological mechanism of renal failure in hemolytic uremic syndrome. Endothelial damage caused thrombus formation in small capillaries.

Chapter 117 Nephritic Syndrome

IgA NEPHROPATHY osms.it/IgA-nephropathy PATHOLOGY & CAUSES ▪ AKA Berger’s disease; abnormal IgA forms, deposits in kidneys → kidney damage ▪ Abnormal post-translational modification of IgA → development of IgA immune complexes preferentially deposited in mesangium → alternative complement pathway activated → cytokines released → macrophages migrate to kidney → glomerular injury → RBCs leak into urine ▪ Associated with gastrointestinal (GI)/ respiratory tract infections

RISK FACTORS

▪ Most common nephropathy worldwide; usually presents in childhood ▪ Highest prevalence in people of East Asian/ European ancestry ▪ Family history of chronic nephritis, alcohol consumption, recurrent infections

DIAGNOSIS LAB RESULTS

▪ RBCs, RBC casts

Renal biopsy ▪ Light microscopy ▫ Mesangial proliferation, immune complexes deposited in mesangium ▪ Electron microscopy ▫ Immune complexes deposited in mesangium ▪ Immunofluorescence ▫ Mesangial IgA deposits, +/- IgA, +/- IgM

TREATMENT MEDICATIONS

▪ Corticosteroids ▫ Prevent immune system making defective IgA1, anti-glycan IgG

COMPLICATIONS

▪ Nephrotic syndrome, chronic kidney disease

SIGNS & SYMPTOMS ▪ Episodic hematuria ▫ Sometimes accompanying upper respiratory tract infections ▪ Asymptomatic microscopic hematuria ▫ With subnephrotic proteinuria ▪ Classic nephrotic syndrome/kidney injury (minority)

Figure 117.8 Immunofluorescence with positive signal for antibodies to IgA immunoglobulin. The pattern of deposition in the glomerulus is granular.

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RAPIDLY PROGRESSIVE GLOMERULONEPHRITIS osms.it/progressive-glomerulo PATHOLOGY & CAUSES ▪ Inflammation of kidney’s glomeruli → crescent-shaped proliferation of cells in Bowman’s capsule → renal failure within weeks/months ▪ Inflammation damages glomerular basement membrane → inflammatory mediators, complement proteins, fibrin, monocytes macrophages pass into Bowman’s space → expansion of parietal layer of cells into thick, crescent-moon shape → may undergo sclerosis/scarring

TYPES Primary ▪ Idiopathic Secondary ▪ Type I: anti-GBM antibodies ▫ Goodpasture syndrome ▪ Type II: immune complexes ▫ Poststreptococcal glomerulonephritis, systemic lupus erythematosus, IgA nephropathy, Henoch-Schonlein purpura ▪ Type III: anti-neutrophilic cytoplasmic antibodies (ANCA) ▫ Cytoplasmic ANCA (C-ANCA): Wegener’s granulomatosis ▫ Perinuclear ANCA (P-ANCA): microscopic polyangiitis, Churg-Strauss syndrome

COMPLICATIONS

▪ If untreated: rapid progression to acute renal failure

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SIGNS & SYMPTOMS ▪ Nephritic syndrome ▫ Hematuria, oliguria, edema, hypertension

DIAGNOSIS LAB RESULTS Kidney biopsy ▪ Light microscopy: crescent-shaped glomeruli Immunofluorescence ▪ Type I: linear, antibodies bind to collagen of glomerular basement membrane ▪ Type II: granular, immune complex deposition in subendothelium ▪ Type III: negative (pauci-immune) ▫ Type III associated with ANCAs in blood

TREATMENT MEDICATIONS

▪ Pulse methylprednisolone, then prednisone/cyclophosphamide/rituximab/ plasmapheresis

OTHER INTERVENTIONS ▪ If renal failure irreversible ▫ Dialysis/kidney transplant

Chapter 117 Nephritic Syndrome

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NOTES

NEPHROTIC SYNDROME GENERALLY, WHAT IS IT? PATHOLOGY & CAUSES ▪ Collection of diseases caused by inflammation, damage to glomeruli of kidney; glomeruli become more permeable, allow proteins from blood into urine → proteinuria Proteinuria ▪ Hallmark of nephrotic syndromes ▫ Loss of protein (mostly albumin) → hypoalbuminemia; lowers oncotic pressure in blood → water moves out of vessels into interstitium → edema ▫ ↓ proteins → ↑ lipids → hyperlipidemia; ↑ lipids filtered in glomeruli → lipiduria; fatty casts, foamy urine

CAUSES

▪ Immune-mediated, metabolic, hemodynamic disturbances ▪ Primary: kidney lesion ▫ Minimal change disease, focal segmental glomerulosclerosis, membranous glomerulonephritis, membranoproliferative glomerulonephritis ▪ Secondary: systemic disease ▫ Diabetic nephropathy, lupus nephritis

COMPLICATIONS

▪ Loss of proteins (e.g. anticoagulants, ironcarrying proteins): thromboembolism, renal vein thrombosis, microcytic hypochromic anemia, infections, hypocalcaemia

SIGNS & SYMPTOMS ▪ Proteinuria, hypoalbuminemia, edema, hyperlipidemia, lipiduria, hypercoagulability

DIAGNOSIS LAB RESULTS

▪ Protein/blood in urine ▪ Decreased glomerular filtration rate: estimated from serum creatinine clearance

Kidney biopsy ▪ Changes under light/electron microscope, immunofluorescence ▪ Blood test: albumin, cholesterol levels

TREATMENT MEDICATIONS

▪ Edema ▫ Diuretics (furosemide), medical nutrition therapy ▪ Blood pressure control ▫ Angiotensin converting enzyme (ACE) inhibitors ▪ Hyperlipidemia ▫ Reduce cholesterol, saturated fat intake ▪ Hypercoagulability ▫ Heparin ▪ Infections ▫ Antibacterial drugs ▪ Immunosuppressants ▫ Cyclophosphamide, prednisone

MNEMONIC: Protein LEAC

Nephrotic syndrome findings Proteinuria Lipid up Edema Albumin down Cholesterol up

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DIABETIC NEPHROPATHY osms.it/diabetic-nephropathy PATHOLOGY & CAUSES ▪ Kidney damage caused by Type I, Type II diabetes

CAUSES Excess glucose in blood ▪ Overrides renal threshold for glucose (160–180mg/dl) → glycosuria ▪ Non-enzymatic glycation of proteins → basement membranes thicken → hyaline arteriosclerosis ▪ Hyaline arteriosclerosis, arteriole dilatation increases pressure in glomerulus → increased glomerular filtration rate (first stage) ▪ Thickening of basement membrane → glomerulus expands, filtration slits widen → increased permeability ▪ High-pressure state → supportive mesangial cells secrete more structural matrix → Kimmelstiel–Wilson nodules ▪ Damage glomeruli → decreased glomerular filtration rate (second stage)

Figure 118.1 Histological appearance of the glomeruli in a case of diabetic nephropathy. There is diffuse sclerosis of the glomerulus.

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RISK FACTORS

▪ Family history; poor control of diabetes, duration of diabetes (more common if developed at younger age); poor control of hypertension; obesity

SIGNS & SYMPTOMS ▪ Mostly asymptomatic

DIAGNOSIS LAB RESULTS

▪ Microalbuminuria (30–300mg/day), macroalbuminuria (> 300mg/day)

TREATMENT MEDICATIONS

▪ Control hyperglycemia ▪ ACE inhibitors/angiotensin receptor blockers: reduce constriction of efferent arteriole → lower pressure in glomerulus

Chapter 118 Nephrotic Syndrome

FOCAL SEGMENTAL GLOMERULOSCLEROSIS osms.it/focal-segmental PATHOLOGY & CAUSES ▪ Histologic finding of glomerular damage, not distinct disease. ▪ Affects parts (segmental) of some (focal) glomeruli of nephron; damage, scarring → proteinuria ▪ Foot processes of podocytes damaged → plasma proteins, lipids permeate glomerular filter ▪ Proteins, lipids trapped → build up inside glomeruli → hyalinosis (hyaline/ glassy view on histology) → scar tissue (glomerulosclerosis)

CAUSE

▪ Primary: unknown ▪ Secondary: result of underlying cause ▫ Sickle cell disease, HIV, renal hyperfiltration (e.g. unilateral renal agenesis), heroin abuse ▪ Genetic forms: FSGS 1–6

RISK FACTORS

▪ More common in black people of African descent/people of Latin American descent ▪ Morbid obesity ▪ Chronic kidney disease (congenital malformation)

DIAGNOSIS LAB RESULTS

▪ Protein in urine > 3.5g/L

Kidney biopsy: most definitive ▪ Light microscopy: segmental sclerosis, hyalinosis of glomeruli ▪ Electron microscope: effacement of foot processes of podocytes ▪ Immunofluorescence: nonspecific focal deposits of IgM, complement proteins not always seen (sometimes trapped in hyalinosis)

TREATMENT MEDICATIONS

▪ Blood pressure reduction ▫ ACE inhibitors ▪ Edema ▫ Diuretics ▪ Prednisone/calcineurin inhibitors ▫ Depend on nephrotic-range proteinuria, likelihood of reversibility

COMPLICATIONS

▪ End-stage renal failure: inconsistent response with treatment; adults—more involved segments of kidney’s glomeruli → kidney failure

SIGNS & SYMPTOMS ▪ Proteinuria, hypoalbuminemia, edema, hyperlipidemia, lipiduria, hypercoagulability

Figure 118.2 Histological appearance of focal segmental glomerulosclerosis. There is sclerosis and hyalinosis of only one part of the glomerulus, in this case the hilar part. The more distal part is normal.

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LUPUS NEPHRITIS osms.it/lupus-nephritis PATHOLOGY & CAUSES ▪ Inflammation of kidney due to systemic lupus erythematosus. ▪ Focal (nephrons in one area)/diffuse (all nephrons in both kidneys) ▪ Caused by antinuclear antibodies (antidsDNA): bind to nuclear antigens, form antigen-antibody complexes ▪ Antigen-antibody complexes deposit in capillary walls, basement membrane, Bowman’s space → initiate inflammatory response → Type III hypersensitivity reaction

DIAGNOSIS LAB RESULTS Kidney biopsy ▪ Microscopic presentation depends on class of lupus nephritis

TYPES Class I ▪ Minimal mesangial glomerulonephritis Class II ▪ Mesangial proliferative glomerulonephritis Class III ▪ Focal glomerulonephritis Class IV ▪ Diffuse proliferative nephritis Class V ▪ Membranous glomerulonephritis Class VI ▪ Advanced sclerosing lupus nephritis

COMPLICATIONS

▪ Renal vein thrombosis, pulmonary embolism, rapidly progressive glomerulonephritis

SIGNS & SYMPTOMS ▪ Nephrotic, nephritic syndrome ▪ Nephritic syndrome: hematuria, hypertension, edema, proteinuria, oliguria

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Figure 118.3 Gross pathological appearance of a kidney in case of lupus nephritis. The renal capsule has a characteritic flea-bitten appearance.

Chapter 118 Nephrotic Syndrome

TREATMENT MEDICATIONS

▪ Immunosuppressants ▫ Corticosteroids; mycophenolate, cyclophosphamide

Figure 118.4 Histological appearance of the glomerulus in a case of lupus nephritis. There is global mesangial cell proliferation and abundant mesangial matrix.

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MEMBRANOPROLIFERATIVE GLOMERULONEPHRITIS osms.it/membrano-golmerulonephritis PATHOLOGY & CAUSES ▪ Type of nephrotic syndrome; inflammation of glomerular basement membrane, mesangium → decreased kidney function, proteinuria ▪ Immune complex/complement deposits trigger immune reactions ▫ Activates complement system → enzyme cascade → membrane attack complex → damage to podocytes, mesangial cells ▫ Recruits inflammatory cells → proteases, oxidants release → basement membrane damage → proteins leak into urine → nephrotic syndrome

TYPES

▪ Appearance under light microscopy ▫ Type I, II, II ▫ All three can present as nephrotic, nephritic syndrome ▪ Immunofluorescence: immune complexmediated MPGN, complement-mediated MPGN

CAUSES Type I ▪ Chronic infection (e.g. hepatitis B, hepatitis C) ▫ Antigens released → bind antibodies in blood → immune complexes deposit in glomerular basement membrane → activate classical complement pathway → complement protein + immune complex deposits ▪ Inappropriate activation of alternative pathway of complement ▫ Mutation in proteins that regulate pathway

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▫ Presence of autoantibodies against proteins that regulate pathway ▪ Nephritic factor (C3NeF) ▫ IgG antibody, binds to C3 convertase → C3 convertase more stable, active longer ▫ Only complement deposits, no immune complex deposits ▫ Autoimmune diseases: systemic lupus erythematosus, scleroderma, Sjögren syndrome, sarcoidosis ▫ Cancer: leukemia, lymphoma Type II ▪ Nephritic factor (C3NeF) ▫ IgG antibody binds to C3 convertase → C3 convertase more stable, active longer Type III ▪ Idiopathic

RISK FACTORS

▪ Dysregulation of complement system

COMPLICATIONS

▪ Chronic renal failure, hypertension

SIGNS & SYMPTOMS ▪ Nephrotic syndrome ▫ Proteinuria, peripheral edema, foamy urine, hyperlipidemia, lipiduria ▪ Nephritic syndrome (more common) ▫ Hematuria, oliguria (low production of urine), hypertension

Chapter 118 Nephrotic Syndrome

DIAGNOSIS LAB RESULTS Kidney biopsy Electron microscopy ▪ Type I ▫ Subendothelial deposits ▫ Thickening of basement membrane ▫ Mesangial interposition: mesangial cells reach cytoplasmic arms through thick basement membrane, split lengthwise → duplicate basement membrane → “tram-track” appearance

▪ Type II ▫ Complement deposits along basement membrane of glomeruli, tubules, Bowman’s capsule ▪ Type III ▫ Subepithelial deposits in mesangium, subendothelial space

TREATMENT MEDICATIONS

▪ Treatment of underlying cause (e.g. antiviral therapy for hepatitis B virus) ▪ If underlying cause ruled out/nephrotic range proteinuria ▫ Immunosuppressive therapy (steroids)

MEMBRANOUS GLOMERULONEPHRITIS osms.it/membranous-glomerulonephritis PATHOLOGY & CAUSES ▪ Inflammation of glomerular basement membrane triggered by immune complex deposits → increased permeability, proteinuria → nephrotic syndrome ▪ Glomerular basement membrane damaged by immune complex deposits; sandwiched between epithelial cells of podocytes, glomerular basement membrane (subendothelial deposits) ▪ Autoantibodies target glomerular basement membrane ▫ Two major antigen targets on podocytes: M-type phospholipase A2 receptor, neural endopeptidase ▪ Complexes outside kidney, carried through blood, deposit in basement membrane ▫ Possible antigens: cationic bovine serum albumin (cow’s milk, beef protein) ▪ Immune complex deposits → immune reactions ▫ Activates complement system →

enzyme cascade → membrane attack complex → damage to podocytes, mesangial cells ▫ Recruits inflammatory cells → proteases, oxidants release → basement membrane damage → proteins leak into urine → nephrotic syndrome ▪ Often benign ▫ Spontaneous complete remission: 5–30% at five years ▫ Spontaneous partial remission: 25–40% at five years

CAUSES Primary ▪ Mostly idiopathic ▪ Associated with human leukocyte antigen (HLA) alleles (e.g. HLA-DQA1)

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Secondary ▪ Auto-antibodies generated in response to underlying conditions ▪ Infections ▫ Hepatitis B virus, hepatitis C virus, syphilis ▪ Medications ▫ NSAIDs, penicillamine, gold ▪ Autoimmune ▫ Systemic lupus erythematosus ▪ Malignancy

RISK FACTORS

▪ White people of European descent ▪ Increase risk of end-stage renal disease ▫ Older age at onset (> 50 years), individuals who are biologically male, nephrotic-range proteinuria (> 8–10g/ day), increased serum creatinine

COMPLICATIONS

▪ Chronic kidney failure, if untreated + nephrotic range proteinuria

SIGNS & SYMPTOMS ▪ Often asymptomatic, discovered incidentally ▪ Proteinuria, hypoalbuminemia, edema, hyperlipidemia, lipiduria, hypercoagulability; develop gradually over months

DIAGNOSIS LAB RESULTS ▪ Proteinuria

Renal biopsy ▪ Light microscopy ▫ Diffuse thickening of glomerular basement membrane ▪ Electron microscopy ▫ “Spike and dome” appearance due to glomerular basement matrix on top of subepithelial deposits; effacement of podocytes ▪ Immunofluorescence ▫ Deposits appear granular throughout glomerular basement membrane ▪ If kidney biopsy not an option ▫ Serum: assayed for antibodies associated with membranous glomerulonephritis (anti-PLA2R antibody)

TREATMENT MEDICATIONS Primary cause ▪ Diuretics (furosemide), ACE inhibitors, heparin, antibacterial drugs ▫ Symptomatic therapy ▪ Close observation, no immunosuppression ▫ If at low risk of end-stage renal disorder (i.e. proteinuria < 3.5g/day) ▪ Prednisone + calcineurin inhibitor (e.g. tacrolimus, cyclosporine)/cytotoxic agent (e.g. cyclophosphamide) ▫ If at moderate/high risk of end-stage renal disorder ▪ Rituximab Secondary cause ▪ Treat underlying condition

Figure 118.5 Histological appearance of membranous glomerulonephritis. The basement membrane of the glomerulus is markedly thickened.

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OTHER INTERVENTIONS

▪ Lifestyle changes ▫ Medical nutrition therapy, reduce cholesterol, saturated fat intake

Chapter 118 Nephrotic Syndrome

MINIMAL CHANGE DISEASE osms.it/minimal-change-disease PATHOLOGY & CAUSES ▪ Type of glomerulonephritis; podocytes in glomeruli damaged by T cells cytokines ▪ Foot processes of podocytes damaged, flattened (AKA effacement) → lose function as barrier → albumin permeates, bigger proteins cannot get through (selective proteinuria)

CAUSES

▪ Unknown; T cells release cytokines, may cause effacement of podocytes

RISK FACTORS

▪ Recent infection; immunization; immune stimulus; medications: nonsteroidal antiinflammatory drugs (NSAIDs) ▪ Hematologic malignancies (e.g. Hodgkin’s lymphoma) ▪ Most common nephrotic syndrome in children

DIAGNOSIS LAB RESULTS

▪ Protein in urine > 3.5g/day

Kidney biopsy ▪ Corticosteroid resistant patients ▪ Light microscopy ▫ Glomeruli appear normal, hence “minimal change disease” ▪ Electron microscopy ▫ Effacement of foot processes. ▪ Immunofluorescence ▫ Negative (no immune complex deposition)

TREATMENT MEDICATIONS

▪ Prednisone therapy ▫ Excellent response, more quickly in children than adults; potential relapse

COMPLICATIONS

▪ Relatively benign, does not affect kidney function

SIGNS & SYMPTOMS ▪ Proteinuria, hypoalbuminemia, edema, hyperlipidemia, lipiduria, hypercoagulability ▪ Onset more rapid (days to weeks) than other nephrotic syndromes

Figure 118.6 An illustration demonstrating the pathophysiology of minimal change disease.

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NOTES

RENAL CANCER GENERALLY, WHAT IS IT? PATHOLOGY & CAUSES ▪ Abnormal cell growth → kidney mass (malignant/benign), caused by genetic mutation of tumor suppressor gene ▪ Angiomyolipoma: most common benign renal tumor ▪ Renal cell carcinoma: most common malignant renal tumor in adults ▪ Wilms tumor: most common malignant renal tumor in children

COMPLICATIONS

▪ Spontaneous hemorrhage, kidney highly vascular ▪ Malignant ▫ Distant metastasis

SIGNS & SYMPTOMS ▪ Often asymptomatic initially ▪ Unilateral abdominal mass ▪ Flank pain, hematuria, systemic symptoms (e.g. fever, appetite loss) ▪ Ectopic hormone production: renin, erythropoietin (EPO), adrenocorticotropic hormone (ACTH), parathyroid hormonerelated peptide (PTHrP) → paraneoplastic syndromes

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DIAGNOSIS DIAGNOSTIC IMAGING CT scan/MRI/ultrasound ▪ See individual disorders

LAB RESULTS ▪ Tissue biopsy

TREATMENT MEDICATIONS

▪ Malignant: chemotherapy

SURGERY

▪ Malignant: surgical resection

OTHER INTERVENTIONS

▪ Angiomyolipoma: embolization, surgery not suitable ▪ Malignant: radiotherapy

Chapter 119 Renal Cancer

ANGIOMYOLIPOMA osms.it/angiomyolipoma PATHOLOGY & CAUSES ▪ Most common benign kidney tumor ▪ Also found in liver (common), reproductive organs (rare) ▪ Made of blood vessels (angio), smooth muscle (myo), fat (lipo) ▪ Type of hamartoma: cellular tumor, disorganized architecture ▪ Genetic mutation in tumor suppressor gene tuberous sclerosis 1 (TSC1) for hamartin/ tuberous sclerosis 2 (TSC2) for tuberin ▫ Usually sporadic ▫ Associated with tuberous sclerosis (multiple, bilateral angiomyolipomas) ▪ Perivascular epithelioid cell tumor family (PEComa): epithelial-like cells around blood vessels on microscopy ▪ More common in right kidney

RISK FACTORS

▪ Individuals who are biologically female ▪ Tuberous sclerosis

COMPLICATIONS

▪ Spontaneous hemorrhage risk ▫ Dysregulated angiogenesis → weak blood vessels → aneurysms

SIGNS & SYMPTOMS ▪ Small: often asymptomatic ▪ Large: mass effect on healthy kidney tissue → chronic kidney disease ▪ Extreme cases: end-stage renal disease (dialysis needed)

DIAGNOSIS DIAGNOSTIC IMAGING Ultrasound ▪ Fat appears hyperechogenic MRI ▪ Small lesions with wedge-shaped pattern which grow outward as tumor enlarges; fat appears bright on T1-weighted images, intermediate-dark on T2-weighted images

Figure 119.1 Histological appearance of an angiomyolipoma. The tumor is composed primarily of myoid cells with areas of mature adipose tissue and numerous vessels.

LAB RESULTS

▪ Image-guided percutaneous needle biopsy and histological analysis

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TREATMENT ▪ Surgery unlikely to be useful, highly vascular tumors with high bleeding risk

OTHER INTERVENTIONS Embolization ▪ Synthetic emboli released into tumor vessels → vessel occlusion → tumor necrosis → tumor shrinkage, haemorrhage less likely ▪ Adverse effects ▫ Postembolization syndrome, fever, flank pain, malaise

Figure 119.2 An abdominal CT scan in the axial plane demonstrating an angiomyolipoma of the left kidney.

RENAL CELL CARCINOMA (RCC) osms.it/renal-cell-carcinoma PATHOLOGY & CAUSES ▪ Most common malignant kidney tumor in adults ▪ “Silent cancer,” may be asymptomatic until late stage, poor prognosis ▪ Spontaneous: solitary upper pole tumors ▪ Inherited: young adults; multiple, bilateral tumors ▫ Von Hippel–Lindau (VHL) disease: inherited RCC

TYPES Clear cell carcinoma ▪ Epithelial cells in proximal convoluted tubule in renal cortex ▫ Polygonal epithelial cells: clear cytoplasm, full of carbohydrate, fat ▫ Fat in tumor cells → yellow tumor Papillary carcinoma Chromophobe carcinoma

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RISK FACTORS

Individuals who are biologically male Advanced age Lifestyle factors (e.g. smoking, obesity) Hypertension Environmental exposures (e.g. asbestos, heavy metals) ▪ Existing kidney disease ▫ Acquired renal cystic disease, long-term dialysis, renal transplant ▪ Genetic mutations in chromosome 3p common in spontaneous, inherited ▪ ▪ ▪ ▪ ▪

STAGING

▪ Tumor, nodes, metastasis (TNM), scored 0–4 ▫ T: size, sites invaded (e.g. renal vein) ▫ N: degree of spread to retroperitoneal lymph nodes ▫ M: presence of distant metastasis

Chapter 119 Renal Cancer

SIGNS & SYMPTOMS Flank pain Hematuria Palpable mass in abdomen/lower back Systemic symptoms (e.g. fever, weight loss, night sweats, weakness, malaise) ▪ Ectopic hormone secretion → paraneoplastic syndromes ▫ Erythropoietin: polycythemia → hyperviscosity symptoms ▫ Renin: hypertension ▫ PTHrP → hypercalcemia ▫ ACTH → cortisol release → Cushing syndrome ▪ Left varicocele (testicular swelling) ▫ RCC in left kidney → obstructs left renal vein → drains left testicular vein ▪ Lung/bone presentations ▫ RCC invades renal vein/inferior vena cava (IVC) → quick metastasis ▪ ▪ ▪ ▪

SURGERY Resection ▪ If localized

Figure 119.3 Histological appearance of renal cell carcinoma. The tumor is of the clear cell subtype.

DIAGNOSIS DIAGNOSTIC IMAGING

▪ Some of newly diagnosed individuals ▫ Metastases on radiology, esp. lungs/ bones

CT scan of chest/abdomen with contrast ▪ CT scan chest to evaluate metastasis Ultrasound

TREATMENT

Figure 119.4 A CT scan in the axial plane demonstrating a renal cell carcinoma (RCC) of the left kidney.

▪ Chemotherapy/radiotherapy resistant

MEDICATIONS

▪ Immunomodulatory drugs ▫ Activate immune system to attack tumor; interferon, interleukin-2 (IL-2), monoclonal antibodies (nivolumab) ▪ Molecular targeted drugs ▫ Inhibit growth receptors; everolimus, temsirolimus

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Figure 119.5 Histological appearance of a papillary renal cell carcinoma. The tumor is composed of numerous clusters of malignant cells arranged around fibrovascular cores.

WAGR SYNDROME osms.it/WAGR-syndrome PATHOLOGY & CAUSES ▪ Genetic disorder affecting children predisposed to Wilms tumor ▫ Wilms’ tumor ▫ Aniridia (total/partial absence of iris) ▫ Genitourinary anomalies ▫ Intellectual disability (previously mental Retardation) ▪ Sporadic mutation → autosomal dominant inheritance

TYPES WAGRO (O for obesity) subtype ▪ Additional deletion of brain-derived neurotrophic factor (BDNF) gene → obesity

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CAUSES Contiguous gene deletion syndrome ▪ Heterozygous deletion of several genes beside each other on p arm of chromosome 11 ▫ Deletion of WT1 → Wilms’ tumor, genitourinary malformations ▫ Deletion of PAX6 protein → aniridia ▫ Genetic basis for intellectual disability unclear

COMPLICATIONS

▪ Streak ovaries in individuals who are biologically female; gonadoblastoma

Chapter 119 Renal Cancer

TREATMENT

SIGNS & SYMPTOMS ▪ Few patients with WAGR exhibit all symptoms ▪ Wilms’ tumor (nephroblastoma) ▫ Only ⅓ of individuals with WAGR ▪ Aniridia (since birth) ▫ Most common feature ▫ Blurry vision, photophobia ▪ Genitourinary anomalies ▫ In individuals who are biologically male: cryptorchidism (undescended testes), hypospadias (urethra opens onto underside of penis, not tip) ▫ In individuals who are biologically female: streak ovaries (undeveloped ovaries; increased risk of gonadoblastoma) ▫ Ambiguous genitalia ▪ Intellectual disability ▫ Not always present, often associated with autism/attention deficit hyperactivity disorder (ADHD) ▪ Other features ▫ Progressive kidney failure ▫ Growth retardation, small head size, obesity ▫ Cataracts, glaucoma, nystagmus

▪ Each symptom addressed independently

MEDICATIONS Chemotherapy ▪ Wilms’ tumor

SURGERY Nephrectomy ▪ Wilms’ tumor

OTHER INTERVENTIONS Radiotherapy ▪ Wilms’ tumor Tinted lenses ▪ Photophobia from aniridia Medical surveillance ▪ Wilms’ tumor ▫ Renal ultrasound, blood pressure ▪ Genitourinary ▫ Pelvic US for gonadoblastoma in individuals who are biologically female

DIAGNOSIS LAB RESULTS Fluorescence in situ hybridization (FISH) ▪ DNA mixed with fluorescently-labeled DNA probe ▪ Genetic deletion on one chromosome → only one bright spot

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WILMS' TUMOR osms.it/wilms-tumor PATHOLOGY & CAUSES ▪ Most common malignant kidney tumor in children, typically ages 2–5 ▪ AKA nephroblastoma (metaphrenic blastemal cells) ▪ Wilms’ tumor typically appears in otherwise healthy children ▫ Beta-catenin mutations in 10% of sporadic Wilms’ tumors ▪ Tumors composed of metanephric blastemal cells ▫ Abortive/partly-developed structures of nephron ▫ Triphasic blastoma: tumor composed of blastemal, stromal, epithelial cells

CAUSES Genetic mutations ▪ Chromosome 11, short arm p, region 1, band 3 ▪ Loss-of-function mutation in Wilms’ Tumor 1 (WT1); may be part of wider developmental syndrome with additional abnormalities ▫ WAGR syndrome: genetic disorder affecting children predisposed to Wilms’ tumor ▫ Denys–Drash syndrome: WT1 mutation → Wilms’ tumor, earlyonset nephrotic syndrome, male pseudohermaphroditism ▪ Wilms’ Tumor 2 (WT2) mutation → developmental syndromes (e.g. Beckwith– Wiedemann syndrome) ▪ Majority of cases not associated with WT1/ WT2 mutations, developmental syndromes

RISK FACTORS

▪ Ages 2–5 ▪ Developmental syndromes: WAGR, Beckwith–Wiedemann, Denys–Drash ▪ Family history of Wilms’ tumor

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COMPLICATIONS

▪ Distant metastasis to brain, lungs, liver, bones ▪ Paraneoplastic syndrome ▫ Renin secretion → high blood pressure → decreased kidney function

SIGNS & SYMPTOMS ▪ Large, palpable, unilateral flank mass (bilateral tumors) ▪ Abdominal pain ▪ Constipation (due to kidney hemihypertrophy) ▪ Hematuria ▪ Systemic symptoms (e.g. loss of appetite, fever, nausea, weakness) ▪ Renin secretion → hypertension

Figure 119.6 A CT scan in the axial plane demonstrating a Wilms’ tumor of the right kidney.

Chapter 119 Renal Cancer ▪ Developmental syndromes ▫ Denys–Drash syndrome: Wilms’ tumor, early-onset nephrotic syndrome, male pseudohermaphroditism ▫ Beckwith–Wiedemann syndrome: Wilms’ tumor, macroglossia, organomegaly, hemihypertrophy

DIAGNOSIS ▪ Never palpation ▫ Risk of tumor rupture, metastasis Abdominal ultrasound ▪ Presence of mass, renal vein infiltration Abdominal contrast-enhanced CT scan/MRI ▪ Tumor staging; lymph node metastasis penetration of capsule Chest CT scan ▪ Detects metastasis

LAB RESULTS

▪ Image-guided percutaneous needle biopsy and histologic analysis

TREATMENT ▪ Depends on genetic mutations, tumor aggressiveness, unilateral/bilateral

MEDICATIONS ▪ Chemotherapy

SURGERY

▪ Nephrectomy

OTHER INTERVENTIONS

▪ Radiation ▫ Used with care, risk of secondary cancers

Figure 119.7 Histological appearance of Wilms’ tumor. The tumor is triphasic, composed of blastema, stroma and immature epithelial elements (glomeruli and tubules).

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Figure 119.9 Illustration of the signs and symptoms of Wilms’ tumor, which most commonly affects children who were otherwise healthy.

Figure 119.8 Gross pathological appearance of a nephrectomy specimen in a patient with Wilms’ tumor.

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NOTES

URINARY & KIDNEY INFECTIONS

GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Infections involving kidneys, ureters, bladder, urethra (UTI)

TYPES Upper UTIs (kidneys) ▪ Pyelonephritis

SIGNS & SYMPTOMS Lower UTIs ▪ Dysuria (painful urination), frequent urination/urgency Upper UTIs ▪ Flank pain, fever, chills, nausea, vomiting, malaise, lower UTI symptoms

Lower UTIs (bladder, urethra) ▪ Cystitis, urethritis

CAUSES Bacterial infection (most common) ▪ Gram negative bacteria: Escherichia coli (E. coli), 80% of cases; Klebsiella; Proteus; Enterobacter; Citrobacter ▪ Gram positive bacteria: Enterococcus; Staphylococcus saprophyticus (S. saprophyticus), second most common, esp. in young individuals who are biologically female, sexually active Ascending infection ▪ Bacteria move from rectal area → urethra → bladder → kidney Descending infection ▪ Bacteria starts in blood/lymph → kidney → bladder, urethra

COMPLICATIONS

▪ Urosepsis, septic shock

DIAGNOSIS DIAGNOSTIC IMAGING Renal scintigraphy, dimercaptosuccinic acid (DMSA), radionuclide/DMSA scan ▪ Kidney scarring

LAB RESULTS

▪ Pyuria (white blood cells in urine) ▪ > 105 colony-forming units/mL ▪ Leukocyte esterase (enzyme created by white blood cells)

TREATMENT MEDICATIONS

▪ Antibiotic treatment (e.g. trimethoprimsulfamethoxazole, nitrofurantoin, penicillin) to dialysis ▪ Pain medications

SURGERY

▪ Kidney transplantation

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PYELONEPHRITIS osms.it/pyelonephritis PATHOLOGY & CAUSES ▪ Inflamed kidney; result of bacterial infection; affects tubules, interstitium, renal pelvis ▪ Interstitial abscesses filled with pus ▪ Tubules damaged, contain neutrophil casts Chronic pyelonephritis ▪ Repeated episodes of acute pyelonephritis. ▪ Leads to fibrosis, renal interstitium scarring, renal tubules atrophy ▪ Localized in upper, lower poles of kidney ▪ Xanthogranulomatous pyelonephritis (XGP) ▫ Rare type of chronic pyelonephritis ▫ Infected kidney stone forms granulomatous tissue ▫ Can be mistaken for kidney tumors on imaging

RISK FACTORS

▪ Urinary tract abnormalities, indwelling urinary catheter, diabetes, immunocompromised status, enlarged prostate

SIGNS & SYMPTOMS ▪ ▪ ▪ ▪

May be asymptomatic Hematuria, polyuria/nocturia Flank pain Inflammatory response ▫ Leukocytosis; fever; chills; nausea, vomiting; gerontologic (e.g. altered mental status)

Chronic pyelonephritis ▪ Same as acute pyelonephritis ▪ Hypertension

DIAGNOSIS LAB RESULTS

▪ Urine culture, bacteria ▪ Pyuria, hematuria, bacteriuria, leukocyte casts ▪ Leukocyte esterase, nitrites, hematuria

CAUSES Chronic pyelonephritis ▪ Vesicoureteral reflux (VUR) ▫ Most common cause ▫ VUR → predisposed to recurrent infections ▫ Failure of vesicourethral orifice → urine moves backward up urinary tract from bladder ▫ Increases risk of ascending upper UTI ▫ May result from primary congenital defect, bladder outlet obstruction Figure 120.1 A CT scan in the coronal plane demonstrating perinephric fat stranding and cortical rim loss seen in acute pyelonephritis.

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Chapter 120 Urinary & Kidney Infections

TREATMENT MEDICATIONS ▪ Antibiotics targeted to bacterial infection

SURGERY

Figure 120.2 The histological appearance of the kidney in a case of acute pyelonephritis. There are neutrophils present in the interstitium and within the tubular lumina.

Chronic pyelonephritis ▪ Correct kidney obstruction/VUR ▪ Nephrectomy: removal of part/all of damaged kidneys ▪ Kidney transplant

OTHER INTERVENTIONS

▪ Ensure individual well hydrated

Chronic pyelonephritis ▪ Dialysis: machine works for kidneys too damaged to function

Figure 120.3 A CT scan of the abdomen in the axial plane demonstrating a subcapsular abscess secondary to pyelonephritis of the right kidney.

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URINARY TRACT INFECTIONS osms.it/UTI PATHOLOGY & CAUSES ▪ UTI; bladder inflammation due to bacterial/ fungal infection, chemical irritants, foreign bodies, trauma ▪ AKA cystitis

CAUSES

▪ Most common: bacterial infections (e.g. E. coli, S. saprophyticus) ▫ Ascending infection → bacteria move from rectal area → urethra → bladder ▫ Descending infection → bacteria starts in blood/lymph → kidney → bladder, urethra

DIAGNOSIS DIAGNOSTIC IMAGING Renal ultrasound ▪ Children with kidney malformation Voiding cystourethrogram (VCUG) ▪ Individual given radiocontrast liquid, fluoroscopy (real-time X-rays); healthcare provider monitors urination ▪ Children with severe/recurrent UTIs, to detect vesicoureteral reflux (retrograde movement of urine from bladder back up into ureters, kidneys)

LAB RESULTS

RISK FACTORS

▪ Positive for nitrites ▫ Gram negative organisms (e.g. E. coli) convert nitrates to nitrites ▪ > 105 colony-forming units/mL from clean catch urine sample ▪ < 105 colony-forming units/mL, infection still possible ▪ Sterile pyuria (pyuria, urine culture without bacteria) → urethritis (urethra inflammation) ▫ Neisseria gonorrhoeae, Chlamydia trachomatis: most common causes, sexually transmitted infections (STIs)

COMPLICATIONS

Pyuria ▫ Cloudy urine ▫ > five white blood cells, high-powered field on microscopy, > 10 white blood cells/mL on hemocytometer ▫ Hematuria

▪ Young individuals who are biologically female (shorter urethra → shorter distance for ascending bacteria) ▪ Sexual intercourse; penile foreskin ▪ Postmenopause (decreased estrogen levels → decreased vaginal flora) ▪ Indwelling catheter ▪ Diabetes mellitus (hyperglycemia inhibits neutrophil diapedesis) ▪ Impaired bladder emptying/urinary stasis

▪ Pyelonephritis ▪ Urosepsis ▪ Septic shock

SIGNS & SYMPTOMS ▪ Suprapubic pain, dysuria, frequent urination/urgency, urine voids small in volume ▪ Infants: fussy, fever, difficulties feeding ▪ Elderly individuals: fatigue, incontinence, altered mental status

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Dipstick test ▪ Leukocyte esterase

Chapter 120 Urinary & Kidney Infections

TREATMENT MEDICATIONS

▪ Antibiotics: trimethoprim-sulfamethoxazole, ciprofloxacin, ceftriaxone, azithromycin, penicillin ▪ Pain medications

OTHER INTERVENTIONS ▪ Increase fluid intake

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NOTES

NOTES

URINARY INCONTINENCE GENERALLY, WHAT IS IT? PATHOLOGY & CAUSES ▪ Inability to maintain micturition control → involuntary urine leakage ▪ Chronic urinary incontinence: important geriatric issue, affecting personal hygiene, social life

TYPES

▪ Urge, stress, mixed (combination of stress, urge), overflow, functional

SIGNS & SYMPTOMS ▪ Involuntary urine leakage

DIAGNOSIS

OTHER DIAGNOSTICS

▪ History (e.g. voiding diary) ▪ Physical examination; urine leakage easily established ▪ Urodynamic studies

TREATMENT MEDICATIONS

▪ See individual disorders

SURGERY

▪ See individual disorders

OTHER INTERVENTIONS

▪ Behavioral therapy, lifestyle changes, catheterization, incontinence undergarments

DIAGNOSTIC IMAGING Abdominal ultrasound

LAB RESULTS ▪ Urinalysis ▪ Renal function

Figure 121.1 Illustration of somebody with urinary incontinence. This condition can negatively affects one’s personal hygiene and social life.

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Chapter 121 Urinary Incontinence

OVERFLOW INCONTINENCE osms.it/overflow-incontinence PATHOLOGY & CAUSES ▪ Urinary retention → bladder pressure increases, exceeds urethral resistance

CAUSES Urinary flow blockage ▪ Benign prostatic hypertrophy, prostate cancer, urethral strictures, severe constipation with fecal impaction, cystocele, prolapsed uterus Ineffective detrusor muscle ▪ Disorders affecting autonomic innervation of bladder (e.g. diabetes mellitus, spinal cord injury, cauda equina syndrome, spinal cord anomalies), anticholinergics

SIGNS & SYMPTOMS ▪ Frequent loss of small amount of urine; hesitancy; weak/intermittent urinary stream

DIAGNOSIS DIAGNOSTIC IMAGING Abdominal ultrasound

LAB RESULTS ▪ Urinalysis ▪ Renal function

OTHER DIAGNOSTICS

▪ History (e.g. voiding diary) ▪ Urine leakage easily established ▪ Urodynamic studies

TREATMENT MEDICATIONS

▪ Cholinergic agents (e.g. bethanechol, increases bladder muscle tone), alpha blockers (e.g. prazosin, tamsulosin, relaxes smooth muscle in bladder neck)

SURGERY

▪ Anterior colporrhaphy/colposuspension

OTHER INTERVENTIONS

▪ Intermittent self-catheterization

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Figure 121.2 Illustration of overflow incontinence’s causes and possible avenues to treatment.

STRESS INCONTINENCE osms.it/stress-incontinence PATHOLOGY & CAUSES

DIAGNOSIS

▪ Pelvic floor laxity → urethra loses support → increase in intra-abdominal pressure → overwhelms sphincter muscles

DIAGNOSTIC IMAGING

RISK FACTORS

LAB RESULTS

▪ Most prevalent in individuals who are biologically female, < 70 years old ▪ Menopause, multiparity/childbirth-related trauma, pressure on bladder during pregnancy, obesity, urologic/retropubic surgery

SIGNS & SYMPTOMS ▪ Spurts of urine when intra-abdominal pressure increases (e.g. sneeze, cough, laugh, exercise)

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Abdominal ultrasound

▪ Urinalysis ▪ Renal function

OTHER DIAGNOSTICS

▪ History (e.g. voiding diary) ▪ Urine leakage easily established ▪ Urodynamic studies

TREATMENT MEDICATIONS

▪ Estrogen replacement therapy (only for stress incontinence caused by menopause)

Chapter 121 Urinary Incontinence

OTHER INTERVENTIONS

▪ Lifestyle changes (e.g. weight loss) ▪ Kegel exercises to strengthen external sphincter, pessaries, electrical stimulation ▪ Sling procedures

Figure 121.3 Illustration of stress incontinence’s causes and possible avenues to treatment.

URGE INCONTINENCE osms.it/urge-incontinence PATHOLOGY & CAUSES ▪ Overactive bladder: uninhibited detrusor muscle contracts randomly

CAUSES

▪ Urinary tract infections (UTIs) ▪ Central nervous system (CNS) disorders: stroke, Parkinson’s disease (PD), multiple sclerosis (MS)

RISK FACTORS

▪ Most prevalent in elderly individuals

SIGNS & SYMPTOMS ▪ Sudden/great urine leakage, strong/ immediate urge to void; frequency; nocturnal wetting

DIAGNOSIS DIAGNOSTIC IMAGING Abdominal ultrasound

LAB RESULTS ▪ Urinalysis ▪ Renal function

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OTHER DIAGNOSTICS

▪ History (e.g. voiding diary) ▪ Urine leakage easily established ▪ Urodynamic studies

TREATMENT MEDICATIONS

▪ Anticholinergic agents → inhibit detrusor overactivity by blocking muscarinic receptors ▪ Tricyclic antidepressants (TCAs) → anticholinergic properties

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SURGERY

▪ Injections with botulinum toxin → prevent acetylcholine release, decrease detrusor muscle activity

OTHER INTERVENTIONS

▪ Lifestyle changes (e.g. avoid alcohol, diuretics) ▪ Kegel exercises ▪ Bladder/toilet training ▫ Relaxation techniques ▪ Sling procedures

NOTES

NOTES

VASCULAR RENAL DISEASE GENERALLY, WHAT IS IT? PATHOLOGY & CAUSES

DIAGNOSIS

▪ Variety of diseases affecting renal arteries, veins → abnormal renal circulation

DIAGNOSTIC IMAGING

RISK FACTORS

CT scan/MRI

▪ Age, atherosclerosis, smoking, diabetes, high cholesterol

Doppler ultrasound

Renal arteriogram

LAB RESULTS

COMPLICATIONS

▪ Renal atrophy, kidney failure

SIGNS & SYMPTOMS ▪ Impaired renal function → urine output disorders ▪ Blood pressure disorders

▪ Excess nitrogen waste products ▫ Blood urea nitrogen (BUN), creatinine ▪ Proteinuria, hematuria, cell casts ▪ Biopsy ▫ Rare

TREATMENT ▪ Conservative, angioplasty, bypass surgery, hemodialysis

RENAL ARTERY STENOSIS osms.it/renal-artery-stenosis PATHOLOGY & CAUSES ▪ Progressive narrowing of renal artery → decrease in renal blood flow ▪ Stimulates renin release by juxtaglomerular cells → production of angiotensin II, aldosterone → vasoconstriction, increased reabsorption of sodium, water ▪ Contraction of blood vessels, increase in blood volume → blood pressure (BP) elevation

CAUSES

▪ Atherosclerosis (most cases) ▪ Fibromuscular dysplasia (in individuals who are biologically female)

COMPLICATIONS

▪ Secondary hypertension, AKA renovascular hypertension ▪ If severe, persistent: renal blood flow decreases → prerenal azotemia ▪ Renal atrophy, fibrosis

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SIGNS & SYMPTOMS ▪ Sudden onset of hypertension ▫ Severe, refractory to medical therapy; headaches, blurry vision ▪ Impaired renal function ▪ Upper abdominal bruit on auscultation, caused by turbulence of blood flow through stenosis

DIAGNOSIS DIAGNOSTIC IMAGING Renal arteriogram ▪ Localize stenotic lesion Megnetic resonance angiogram (MRA) ▪ Individuals with impaired renal function, at risk for contrast-induced renal failure

Figure 122.1 A 3D-reconstructed CT scan demonstrating the renal vasculature. The left renal artery (on the right of this image) is completely stenosed and the left kidney is poorly perfused as compared to the right.

Doppler ultrasound of renal arteries ▪ Initial screening test CT scan with contrast ▪ Alternative

LAB RESULTS

▪ High BUN to creatinine ratio

TREATMENT MEDICATIONS Antihypertensive medication ▪ Angiotensin converting enzyme (ACE) inhibitors, calcium channel blockers

SURGERY

▪ Percutaneous transluminal renal angioplasty (PTRA) ▪ If PTRA not successful ▫ Bypass surgery

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Figure 122.2 A contrast CT scan demonstrating stenosis of the right renal artery. The right kidney is small and shows minimal contrast uptake when compared to the left.

Chapter 122 Vascular Renal Disease

RENAL CORTICAL NECROSIS osms.it/renal-cortical-necrosis PATHOLOGY & CAUSES ▪ Rare, irreversible prerenal kidney injury; sudden decrease in blood perfusion to renal cortex ▪ AKA diffuse cortical necrosis ▪ Reduced blood supply to renal tubules → acute tubular necrosis ▪ Lack of anastomoses among cortical radial arteries (end arteries) ▪ High demand for blood of nephron (e.g. proximal tubule, thick ascending loop of Henle) ▪ If ischemia persists → irreversible necrotic injury of renal cortex → renal cortical necrosis

CAUSES

DIAGNOSIS DIAGNOSTIC IMAGING CT scan with contrast ▪ Non-enhancing renal cortex, thin rim of enhancement may occur (cortical rim sign) Ultrasound ▪ Hypoechoic areas in renal cortex

LAB RESULTS

▪ BUN, creatinine ▪ Hyperkalemia, metabolic acidosis ▪ Hematuria, proteinuria, tubular cell casts

Biopsy ▪ Patchy necrosis, atrophy of renal cortex

▪ Obstruction of blood flow ▫ Blood clots/vasospasms ▪ Pregnancy complications → disseminated intravascular coagulation → widespread blood clots → renal cortical necrosis ▫ Placental abruption, prolonged intrauterine fetal death, infected abortion, severe eclampsia, septic shock

COMPLICATIONS

▪ Acute kidney failure

SIGNS & SYMPTOMS ▪ Sudden decrease in urine output ▫ Oliguria/anuria ▪ Flank pain at costovertebral angle ▫ Renal edema stretching renal capsule

Figure 122.3 The histological appearance of renal cortical necrosis. The cells which comprise the glomeruli and the renal tubules have a fuzzy outline and have lost their nuclei, indicative of necrosis.

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TREATMENT OTHER INTERVENTIONS

▪ Increase blood perfusion to renal cortex ▫ Intravenous (IV) fluids ▪ If severe ▫ Hemodialysis

Figure 122.4 An abdominal CT scan in the axial plane demonstrating bilateral renal cortical necrosis. The low-signal renal cortex surrounding the relatively high-signal renal medulla is known as cortical rim sign.

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NOTES

NOTES

ACUTE RESPIRATORY DISEASE

GENERALLY, WHAT IS IT? DIAGNOSIS

PATHOLOGY & CAUSES ▪ Acute respiratory disorders induced by changes in atmospheric pressure/direct communication between atmosphere, vasculature/pulmonary conditions, diseases (e.g. pulmonary trauma, pneumonia, sepsis, severe burns) ▪ Impaired alveolar gas exchange → hypoxemia ▪ Can lead to potentially fatal conditions

SIGNS & SYMPTOMS ▪ Hypoxemia: dyspnea, tachypnea, chest pain

DIAGNOSTIC IMAGING ▪ Medical imaging

OTHER DIAGNOSTICS

▪ Clinical presentation, history ▪ Arterial blood gases

TREATMENT OTHER INTERVENTIONS ▪ Oxygen therapy ▪ Mechanical ventilation

ACUTE RESPIRATORY DISTRESS SYNDROME (ARDS) osms.it/ards PATHOLOGY & CAUSES ▪ Acute lung condition ▪ Widespread diffuse inflammation → increased vascular permeability, loss of pulmonary tissue ▪ Triggered by pulmonary conditions, diseases (e.g. pulmonary trauma, pneumonia, sepsis)

PATHOLOGY

▪ Refractory hypoxemia, reduced pulmonary compliance, pulmonary edema without

cardiovascular cause (noncardiogenic pulmonary edema) ▪ Alveolar barrier cells damaged → alveolar sacs flooded → impairs air exchange ▫ Pro-inflammatory cytokines released: tumor necrosis factor (TNF), interleukins ▫ Interleukins (IL-1, IL-6, IL-8) → neutrophil activation → toxic substances (reactive oxygen species) released → alveolar and capillary damage → oncotic gradient lost → no fluid resorption → fluid in interstitium ▪ Damaged Type II pneumocytes → surfactant layer malfunction

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▪ Acute inflammatory response → abnormal extravascular fibrin deposition ▫ Increased activity of extrinsic coagulation pathway ▫ Impaired fibrinolysis

CAUSES

▪ Systemic infections/septic shock ▪ Acute lung injury ▫ Compromises ability to regulate gas exchange → lungs fill up with fluid in interstitium, alveoli ▪ Gastric contents aspiration ▪ Severe pneumonia ▪ Serious burns ▪ Mechanical (e.g. near drowning) ▪ Inflammatory (e.g. pancreatitis)

SIGNS & SYMPTOMS ▪ Usually begin within first few hours, 1–2 days ▪ Dyspnea, tachypnea, tachycardia, diaphoresis, low blood oxygenation → cyanosis, diffuse crackles on lung auscultation

DIAGNOSIS DIAGNOSTIC IMAGING Chest X-rays ▪ Bilateral alveolar infiltrate, pulmonary edema with no cardiovascular cause CT scan ▪ Bilateral airspace opacities Ultrasound ▪ Subpleural consolidations, pleural line irregularities, no lung gliding

LAB RESULTS

▪ Respiratory alkalosis → respiratory acidosis

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Figure 123.1 A chest radiograph demonstrating diffuse, bilateral, coalescent opacities resembling ground glass.

OTHER DIAGNOSTICS 2012 Berlin definition ▪ Acute pulmonary injury within week of clinical consultation ▪ Bilateral opacities on chest X-ray/CT scan unexplained by other pulmonary pathologies (e.g. pleural effusion, lung collapse) ▪ Respiratory failure without heart failure (noncardiogenic) ▪ Minimum positive end expiratory pressure (PEEP) of 5cmH20 ▪ Reduced oxygen in arteries, reduced partial pressure arterial oxygen/fraction of intake of oxygen (PaO2/FiO2) ratio ▫ Mild: 201–300mmHg ▫ Moderate: 101–200mmHg ▫ Serious: < 100mmHg

TREATMENT MEDICATIONS

▪ Antibiotic therapy ▫ After microbiological culture, determines appropriate course of antibiotics ▪ Diuretics ▫ Manage fluid output

Chapter 123 Acute Respiratory Disease

OTHER INTERVENTIONS

Figure 123.2 The histological appearance of diffuse alveolar damage, the pathological correlate of ARDS. There is a diffuse inflammatory cell infiltrate and pink, hyaline membranes in the alveolar spaces.

Mechanical ventilation ▪ Maintain gas exchange to meet metabolic demands ▪ Endotracheal intubation/tracheostomy (prolonged intubations) ▪ Monitor parameters ▫ PEEP: keep alveoli from collapsing, improve oxygenation ▫ Mean airway pressure: recruit alveoli to open ▫ Plateau pressure: monitor alveoli for overdistension ▪ Extracorporeal membrane oxygenation (ECMO) ▫ Removes blood from body, artificially removes CO2, oxygenates red blood cells

Figure 123.3 The gross pathological appearance of ARDS. There is a diffuse, vaguely nodular infiltrate, most easily visible at the apices.

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ALTITUDE SICKNESS osms.it/altitude-sickness PATHOLOGY & CAUSES ▪ Reaction to exposure to low oxygen concentrations when traveling to high altitude ▫ AKA high altitude illness (HAI), acute mountain sickness (AMS) ▪ Partial pressure of oxygen of inspired air calculated by PiO2 (mmHg) = FiO2 (%) x [Pb (mmHg) - 47mmHg] ▫ FiO2: fraction of inspired oxygen, not affected by altitude, remains unchanged in 21% ▫ Pb: barometric pressure ▫ 47mmHg: vapor pressure of water at 37°C/98.6°F ▪ In high altitudes, ↓ Pb → ↓ PiO2 ▪ Partial pressure of alveolar oxygen (PAO2) ▫ Pressure in alveolar space after equilibration with blood ▪ PAO2 lower than PiO2 ▫ Air enters lungs, humidified by upper airway, partial pressure of water vapor reduces partial pressure of oxygen ▫ Continual uptake of oxygen from alveoli by pulmonary capillaries ▫ Continual diffusion of CO2 from capillaries into alveoli ▪ ↓ PiO2 → ↓ PAO2, ↓ PaO2 → hypoxemia ▪ HAI starts at 1.5km/5,000ft, symptoms noticeable above 2.4km/8,000ft Adaptive mechanisms ▪ Hypoxemia → hyperventilation → ↑ expiration of CO2 by lungs → ↓ PCO2 → ↑ pH (respiratory alkalosis) ▪ ↓ PCO2 , ↑ pH inhibit central, peripheral chemoreceptors, decrease ventilation rate ▪ Within several days ↑ HCO3-, ↓ H+ kidney excretion → ↓ pH → stimulation of respiratory center to further increase ventilation ▪ ↑ erythropoietin production → ↑ red blood

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cell production ▪ ↑ 2,3 BPG synthesis → ↓ hemoglobin affinity for O2 → ↑ release of oxygen to tissues Measures to avoid HAI ▪ Acclimatization: ascending slowly to high altitudes, to adjust to decreasing oxygen levels ▪ Preventative medications: acetazolamide (diuretic); increases bicarbonate kidney excretion

RISK FACTORS ▪ ▪ ▪ ▪

History of HAI episodes Prior exercise/alcohol consumption Rapid ascent to high altitude Comorbidities that affect breathing (e.g. asthma)

COMPLICATIONS

▪ Can lead to potentially fatal conditions ▫ High altitude cerebral edema (HACE), high altitude pulmonary edema (HAPE)

SIGNS & SYMPTOMS ▪ Usually appear within 6–12 hours of ascent ▪ Headache, dizziness, fatigue, nausea, vomiting, loss of appetite, sleep disturbance ▪ Often improves with time if person does not ascend to higher altitude ▪ HACE ▫ Excessive fatigue, confusion, neurologic deficits (e.g. ataxia, altered mental state) ▪ HAPE ▫ Dry cough, dyspnea

Chapter 123 Acute Respiratory Disease

DIAGNOSIS LAB RESULTS

▪ Arterial blood gases ▫ ↓ PaO2, ↑ PaCO2, respiratory alkalosis

OTHER DIAGNOSTICS

▪ Clinical presentation, history of living at low altitude, recent ascent at high altitude

TREATMENT MEDICATIONS

▪ Symptom relief ▫ E.g. analgesics for headache, antiemetics for nausea ▪ Carbonic anhydrase inhibitors (e.g. acetazolamide) ▫ Increase HCO3- excretion; treat respiratory alkalosis

Figure 123.4 A chest radiograph demonstrating acute pulmonary edema in an individual who ascended to 2700m.

OTHER INTERVENIONS

▪ Rest ▪ Descent ▪ Symptom relief ▫ E.g. oxygen to improve breathing ▪ HACE, HAPE ▫ Medical emergencies; require immediate descent/oxygen administration

DECOMPRESSION SICKNESS (DCS) osms.it/decompression_sickness PATHOLOGY & CAUSES ▪ Gas embolism, occurs when individuals experience sudden decreases in atmospheric pressure ▫ AKA diver’s disease ▪ Air breathed at relatively high pressure (e.g. diver descends from water surface) → inspired gases compressed to higher pressure of surrounding water → ↑ partial

pressure of oxygen, nitrogen → ↑ oxygen, nitrogen dissolved in blood, loaded in body tissues ▫ Henry’s law: at constant temperature, amount of gas dissolved in liquid directly proportional to partial pressure ▪ If oxygen, nitrogen quantities high enough → oxygen toxicity/nitrogen narcosis, respectively

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▪ Pressure drops too rapidly (e.g. ascent to water surface) → sum of gas tensions in tissue exceeds ambient pressure → liberation of free gas from tissues due to excess dissolved gases → gas bubbles → vessels blocked, tissues compressed, clotting cascade, inflammation ▪ Occurs in scuba, deep sea divers, underwater construction workers; during rapid ascent of an unpressurized aircraft ▪ Caisson disease (chronic decompression sickness) ▫ Tunnel workers, moving from caisson to atmospheric pressure

RISK FACTORS

▪ Right-to-left shunt (e.g. patent foramen ovale/atrial/ventricular septal defect) ▪ Air travel after diving ▪ More common in individuals who are biologically male

SIGNS & SYMPTOMS ▪ Usually develop within one hour of surfacing ▪ Excessive fatigue, headache ▪ Depend upon size, location of gas bubbles Type I DCS ▪ Skeletal muscles, joints ▫ Painful condition, AKA “the bends”; arching of back, posture reminiscent of Grecian bend ▪ Skin ▫ Itching, rash Type II DCS (more severe) ▪ Nervous system ▫ Paresthesia, amnesia, weakness, paralysis ▪ Lungs ▫ Edema, hemorrhage, atelectasis, emphysema → respiratory distress, AKA “the chokes”; cough, chest pain, dyspnea ▪ Can progress to permanent injuries/fatal damage

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DIAGNOSIS OTHER DIAGNOSTICS

▪ Clinical presentation, history of exposure to sudden decreases in atmospheric pressure ▪ Confirmed if symptoms relieved after recompression

TREATMENT OTHER INTERVENTIONS

▪ Hyperbaric oxygen therapy in recompression chamber ▫ Under high pressure gas bubbles forced back into solution; slow decompression permits gradual gas elimination via lungs, prevents obstructive bubbles reforming

Chapter 123 Acute Respiratory Disease

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NOTES

NOTES

LOWER RESPIRATORY TRACT CONGENITAL MALFORMATIONS

GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES

DIAGNOSIS Prenatal ultrasound, radiography, CT scan, MRI

▪ Structural anomalies of lung during embryonic development

TREATMENT

SIGNS & SYMPTOMS

▪ Surgical resection, respiratory support

▪ Asymptomatic/respiratory distress

CONGENITAL PULMONARY AIRWAY MALFORMATION osms.it/cpam PATHOLOGY & CAUSES ▪ Congenital pulmonary airway malformation (CPAM) ▪ AKA congenital cystic adenomatoid disorder → part of/entire lung lobe replaced by non-functional cysts ▪ Result of abnormalities in branching morphogenesis of lung ▪ Rare in general; most common congenital lung malformation

TYPES

▪ CPAM Type 0: rare; multiple small cysts composed of cartilage, mucus cells; lethal anomaly ▪ CPAM Type 1: most common; large (> 2cm/0.78in) multiloculated cysts; good prognosis ▪ CPAM Type 2: small uniform cysts;

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associated with other congenital malformations (e.g. esophageal atresia with esophageal fistula); poor prognosis ▪ CPAM Type 3: large; not true cysts; communicates with surrounding parenchyma; “adenomatoid” type; more common in individuals who are biologically male ▪ CPAM Type 4: rare

CAUSES

▪ Possibly, in utero airway obstruction/atresia; definitive cause unknown

RISK FACTORS

▪ Occurs sporadically ▪ Not related to maternal factors ▪ No genetic predisposition except Type 4 (associated with familial pleuropulmonary blastoma syndrome)

Chapter 124 Lower Respiratory Tract Congenital Malformations

COMPLICATIONS

▪ Pulmonary hypoplasia ▪ Mediastinal shift, putting pressure against heart ▪ Respiratory infections ▪ Rapid growth → venous outflow obstruction, cardiac failure, hydrops fetalis, death ▪ Longstanding CPAMs → cancer

diaphragm, absence of visible lung tissue MRI/CT scan ▪ Delineate pathology

TREATMENT SURGERY ▪ Minimally invasive surgical resection (thoracoscopy)

SIGNS & SYMPTOMS

▪ Large cysts: in utero placement of Harrison thoracoamniotic shunt

▪ 75% of individuals: asymptomatic ▪ 25% of individuals: cyanosis, pneumothorax, respiratory distress, tachypnea, intercostal retractions, grunting ▪ Hyperresonance on percussion, diminished vesicular murmur, asymmetrical thorax

▪ Rare: fetal surgery in utero; surgical delivery, ex utero intrapartum treatment (EXIT) procedure

Figure 124.1 Illustration depicting continuous pulmonary airway malformation.

Figure 124.2 A fetal MRI demonstrating a congenital pulmonary airway malformation.

DIAGNOSIS ▪ Definitive diagnosis usually not possible without surgical resection, histopathological evaluation

DIAGNOSTIC IMAGING Prenatal ultrasound ▪ Echogenic mass appearing in the chest, displacement of heart, flat/everted

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Figure 124.3 The histological appearance of a congenital cystic type II malformation. There are multiple small cystic spaces lined by immature respiratory tissue.

Figure 124.4 A CT scan of the chest demonstrating a pulmonary congenital cystic adenomatoid malformation, Type I, presenting as a single cyst of middle lobe in an adult.

PULMONARY HYPOPLASIA osms.it/pulmonary_hypoplasia PATHOLOGY & CAUSES ▪ Underdevelopment of lungs → low number/ size of bronchopulmonary segments/alveoli ▪ Typically occurs prior to/after pseudoglandular stage (6–16 weeks gestation)

TYPES

▪ Primary ▫ Idiopathic, not associated with maternal/ fetal abnormalities; rare ▪ Secondary ▫ Due to fetal abnormalities disrupting lung development ▫ Associated with bilateral renal agenesis, congenital diaphragmatic hernia, congenital cystic adenomatoid malformation, fetal hydronephrosis,

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caudal regression syndrome, mediastinal tumor, dextrocardia, sacrococcygeal teratoma ▫ Bilateral renal agenesis → oligohydramnios → decreased lung expansion, decreased mechanical stretching → decreased growth factors lung synthesis → pulmonary hypoplasia

RISK FACTORS

▪ Decreased amniotic fluid: severe oligohydramnios, mid-trimester rupture of membranes ▪ Disruption of signaling pathways involved in growth: sonic hedgehog (SHH) signaling pathway ▪ Aberrant expression growth factors: vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), fibroblast growth factor (FGF) ▪ Early delivery

Chapter 124 Lower Respiratory Tract Congenital Malformations

COMPLICATIONS

▪ Respiratory distress, chronic respiratory failure, bronchopulmonary dysplasia, pneumothorax, secondary scoliosis, impaired cardiac function ▪ Survival depends on degree of hypoplasia, cause of restricted growth

SIGNS & SYMPTOMS ▪ Prenatal: poor fetal movement, amniotic fluid leakage, oligohydramnios ▪ Postnatal: asymptomatic/severe respiratory distress, apnea, cyanosis ▪ Small, bell-shaped chest; heart displacement; decreased/absent breath sounds

TREATMENT OTHER INTERVENTIONS

▪ Amnioinfusion: instilling isotonic fluid into amniotic cavity ▪ Amniopatch: intra-amniotic injection of platelets, cryoprecipitate → seal amniotic fluid leak ▪ Treatment of underlying condition; respiratory support; in severe cases, fetal surgery

DIAGNOSIS DIAGNOSTIC IMAGING 3D ultrasound ▪ Total lung volume measurement Doppler ultrasound/magnetic resonance angiography ▪ Shows lack of blood supply CT scan/MRI ▪ Shows loss of lung volume Radiography

Figure 124.5 A chest X-ray demonstrating a volume defect of the right thoracic cavity caused by pulmonary hypoplasia.

LAB RESULTS

▪ Renal function (serum creatinine, blood urea, electrolyte levels) ▫ Oligohydramnios

OTHER DIAGNOSTICS

▪ Lung weight, lung weight to body weight ratio, mean radial alveolar count (RAC), lung DNA

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NOTES

NOTES

LOWER RESPIRATORY TRACT INFECTION

GENERALLY, WHAT IS IT? PATHOLOGY & CAUSES ▪ Infections involving trachea, bronchi, bronchioles, lungs

RISK FACTORS

▪ Smoking, compromised immunity, age (children, elderly), comorbidities

DIAGNOSIS LAB RESULTS

▪ Complete blood count (CBC)

Microbe identification ▪ Blood culture, sputum culture; Gram stain, polymerase chain reaction (PCR)

TREATMENT

COMPLICATIONS

▪ Respiratory compromise, infection spread, sepsis

SIGNS & SYMPTOMS ▪ Cough, dyspnea, fatigue, fever

MEDICATIONS ▪ Antimicrobials

OTHER INTERVENTIONS ▪ Ventilatory support

BACTERIAL TRACHEITIS osms.it/bacterial_tracheitis PATHOLOGY & CAUSES ▪ Rare, potentially life-threatening exudative infection ▫ Characterized by mucosal ulceration, pseudomembrane formation, airway obstruction risk (due to edema, exudative sloughing) ▪ Common infective agents: Staphylococcus aureus, Moraxella catarrhalis, Streptococcus pneumoniae, H. influenzae

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RISK FACTORS

▪ Antecedent viral infections, especially croup ▪ Commonly affects children

COMPLICATIONS

▪ Pneumonia, septicemia, pneumothorax, pneumomediastinum, hypoxia (secondary to airway obstruction), cardiorespiratory arrest

Chapter 125 Lower Respiratory Tract Infections

TREATMENT

SIGNS & SYMPTOMS ▪ Prodromal respiratory viral infection presentation → acute onset of fever, hoarseness, sore throat, stridor ▪ Productive, barky cough with copious tracheal secretions, retrosternal pain ▪ Progressive respiratory distress ▫ Dyspnea, retractions, fatigue, ↓ level of consciousness

DIAGNOSIS

MEDICATIONS

▪ Broad antibiotic coverage

OTHER INTERVENTIONS

▪ Ventilatory support ▫ Humidified supplemental oxygen, intubation, endoscopic tracheal debridement ▪ Fluid management

DIAGNOSTIC IMAGING Chest X-ray ▪ Upper tracheal narrowing (“steeple sign”) ▪ Tracheal pseudomembranes (irregular shadows)

LAB RESULTS

▪ CBC: leukocytosis, left shift

Microbe identification ▪ Positive tracheal culture, Gram stain

OTHER DIAGNOSTICS

▪ Laryngoscopy: subglottic edema; tracheal lumen narrowing; presence grayish exudate; slough, pus; friable tracheal mucosa

Figure 125.1 The endoscopic appearance of bacterial tracheitis in a nine-year-old boy.

BRONCHIOLITIS osms.it/bronchiolitis PATHOLOGY & CAUSES ▪ Viral small airway respiratory infection ▪ Viral spread through respiratory secretions, contaminated hands → infects lower respiratory tract cells → natural killer cells attack → cytokines released → epithelial cells produce mucus, vessels vasodilate → fluid leaks, walls swell → airway narrows (more severe in children)

▪ Dead cells, mucus slide into airway → form mucus plugs → trap air → airways collapse (atelectasis)

CAUSES

▪ Respiratory syncytial virus (RSV): most common, especially during winter months ▪ Adenovirus, human bocavirus, human metapneumovirus ▪ Mycoplasma pneumoniae

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RISK FACTORS

▪ Young age (children < two years old), previous infection, daycare attendance, decreased immunity, neuromuscular disorders, premature birth, cardiovascular malformations, airway malformations, exposure to smoking

COMPLICATIONS

▪ Hypoxemia, sepsis

SIGNS & SYMPTOMS ▪ Congestion, pharyngitis, sore throat, cough ▪ Hypoxia → tachycardia, tachypnea, exhaustion ▪ If severe: dyspnea, wheezing, central apnea (brief periodic breathing arrest), nasal flaring, retractions, cyanosis, fever, poor feeding, ↓ activity

Figure 125.2 A plain chest radiograph in a child with bronchiolitis demonstrating bilateral hilar fullness.

DIAGNOSIS DIAGNOSTIC IMAGING X-ray ▪ Patchy infiltrates, atelectasis

LAB RESULTS

▪ Positive rapid viral testing (RT-PCR): suggests viral infection

TREATMENT OTHER INTERVENTIONS Immunoprophylaxis ▪ Palivizumab: monoclonal antibody against RSV given monthly throughout RSV season for prematurely-born infants, chronic lung disease, congenital heart disease ▪ Heated, humidified supplemental oxygen (high-flow nasal cannula/continuous positive airway pressure (CPAP)), fluids, nasal suctioning ▪ Intubation (if hypoxia continues despite intervention)

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Figure 125.3 A CT scan of the chest in the axial plane in an individual with severe bronchiolitis. Both lung fields demonstrate the tree-in-bud pattern.

Chapter 125 Lower Respiratory Tract Infections

COMMUNITY–ACQUIRED PNEUMONIA osms.it/community-acquired_pneumonia PATHOLOGY & CAUSES ▪ Pneumonia acquired outside hospital/ healthcare setting ▪ Viral pneumonia may → superimposed bacterial infection Spread ▪ Respiratory: from host to host ▪ Hematogenous: from another infection with same pathogen (e.g. cellulitis) Causative organisms ▪ S. pneumoniae, S. aureus, H. influenzae, group A streptococci, influenza virus, respiratory syncytial virus (RSV), parainfluenza

Resolution ▪ Approx. day 8, can continue for three weeks ▫ Exudate digested by enzymes, ingested by macrophages, coughed up

COMPLICATIONS

▪ Meningitis, sepsis, pleural effusions

SIGNS & SYMPTOMS ▪ High fever, cough, hemoptysis, pleuritic chest pain, tachypnea, tachycardia, dyspnea, muscle pain, fatigue ▪ Crepitation on palpation, dullness on percussion

RISK FACTORS

▪ Advanced age, lowered immunity, smoking, alcohol abuse, malnutrition, chronic lung disease

STAGING Congestion ▪ Between days 1–2 ▫ Blood vessels, alveoli start filling with excess fluid Red hepatization ▪ Between days 3–4 ▫ Exudate (contains red blood cells, neutrophils, fibrin) starts filling airspaces → solidifies them → lungs develop liverlike appearance Gray hepatization ▪ Approx. days 5–7 ▫ Lungs remain firm but color changes → red blood cells in exudate start to break down

Figure 125.4 A plain chest radiograph demonstrating patchy peri-bronchial shadowing in an individual with bronchopneumonia.

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DIAGNOSIS DIAGNOSTIC IMAGING X-ray ▪ Interstitial infiltrates; consolidation; may show pleural effusion

Prevention ▪ 23-valent vaccine (Pneumovax) available against pneumococcus ▫ Recommended in splenectomised, immunocompromised individuals

LAB RESULTS

▪ ↓ oxygen saturation ▪ CBC: leukocytosis ▪ Organism identification: sputum Gram stain, culture; C-reactive protein test (CRP), PCR for typical viruses ▪ Positive urine for S. pneumoniae

TREATMENT MEDICATIONS ▪ Antibiotics

OTHER INTERVENTIONS ▪ Supplemental oxygen, fluids

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Figure 125.5 A plain chest radiograph demonstrating consolidation of the right middle lobe in an individal with lobar pneumonia.

Chapter 125 Lower Respiratory Tract Infections

Figure 125.6 The histological appearance of acute pneumonia. In the affected part of the lung (right) the alveoli are filled with neutrophils.

CROUP osms.it/croup PATHOLOGY & CAUSES

SIGNS & SYMPTOMS

▪ Acute respiratory condition ▫ Characterized by laryngotracheitis ▪ Immune response to epithelial viral infection ▫ Upper bronchi: larynx, trachea narrow due to swelling ▫ Lower bronchi: terminal bronchioles, viral pneumonia

▪ Progressive respiratory symptoms; sore throat, hoarse voice (due to laryngeal involvement) ▪ Respiratory symptoms ▫ “barking” cough ▫ Tachypnea ▫ Grunting (attempt to increase endexpiratory pressure) ▫ Prominent inhalation, inspiratory stridor, apnea

CAUSES

▪ RSV, parainfluenza, adenoviruses ▪ Historically: Corynebacterium diphtheriae (vaccine development → ↓ incidence)

RISK FACTORS

▪ Most common in children < six years old

COMPLICATIONS

▪ Hypoxia, respiratory failure ▪ Secondary bacterial infections → ↑ mortality

DIAGNOSIS DIAGNOSTIC IMAGING X-ray ▪ “Steeple sign,” narrowing below epiglottis

LAB RESULTS

▪ CBC: normal ↑ with left shift, or ↓

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OTHER DIAGNOSTICS

▪ Severity: Westley scale 0–17 ▫ 3-7: moderate ▫ 8-11: severe ▫ 12 and above: indicates respiratory failure

TREATMENT MEDICATIONS

▪ Dexamethasone, epinephrine (nebulized)

OTHER INTERVENTIONS

▪ Humidified supplemental oxygen, fluids, antipyretics ▪ Intubation (if impending respiratory failure)

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Figure 125.7 A plain X-ray image demonstrating the steeple sign in an infant with croup.

Chapter 125 Lower Respiratory Tract Infections

NOSOCOMIAL PNEUMONIA osms.it/nosocomial-pneumonia PATHOLOGY & CAUSES

SIGNS & SYMPTOMS

▪ Hospital-acquired pneumonia ▫ AKA healthcare-associated pneumonia ▫ Includes ventilator-associated pneumonia ▪ Involves microaspiration of organisms from oropharyngeal tract/sometimes from gastrointestinal tract ▪ Severity varies depending on offending organism, individual’s immune system status

▪ Nonspecific symptoms (malaise, lethargy), fever, productive cough

CAUSES

▪ MRSA, Klebsiella pneumoniae, Pseudomonas aeruginosa, Acinetobacter ▪ Often polymicrobial

RISK FACTORS

▪ Intubation, poor staff hygiene, contaminated equipment contact

COMPLICATIONS

▪ Meningitis, sepsis, pleural effusions

DIAGNOSIS DIAGNOSTIC IMAGING Chest X-ray ▪ Shows infiltrates

LAB RESULTS

▪ CBC: leukocytosis, ↑ CRP ▪ Positive sputum culture

TREATMENT MEDICATIONS ▪ Antibiotics

OTHER INTERVENTIONS ▪ Supplemental oxygen, fluids

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NOTES

NOTES

OBSTRUCTIVE LUNG DISEASE

GENERALLY, WHAT IS IT? PATHOLOGY & CAUSES ▪ Obstruction of airflow from lungs ▪ Increased resistance to airflow → airtrapping ▪ Classifications ▫ Narrowing of lumen wall (e.g. asthma, chronic bronchitis) ▫ Increasing pressure external to airway/loss of lung parenchyma (e.g. emphysema) ▫ Obstruction of airway lumen (e.g. bronchiectasis, chronic bronchitis)

COMPLICATIONS

▪ Cor pulmonale, right ventricular hypertrophy

SIGNS & SYMPTOMS ▪ Cough, thick mucus, dyspnea, wheezing

DIAGNOSIS DIAGNOSTIC IMAGING Chest X-ray/CT scan

LAB RESULTS

▪ Sputum culture ▪ Arterial blood gas (ABGs)

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OTHER DIAGNOSTICS Spirometry/pulmonary function test (PFTs) ▪ Tidal volume (TV) ▫ Volume of air inspired, expired during quiet breathing ▪ Residual volume (RV) ▫ Volume of air left in lung after maximal expiration ▪ Forced vital capacity (FVC) ▫ Maximum volume of air that can be expired after maximal inspiratory effort ▪ Forced expiratory volume (FEV) ▫ Volume of air forcibly exhaled per unit of time ▪ Peak expiratory flow rate (PEFR) ▫ During FEV, maximum flow of expiration ▪ Functional residual capacity (FRC) ▫ Volume of air left in lungs after quiet expiration

TREATMENT ▪ See individual diseases

Chapter 126 Obstructive Lung Disease

ALPHA 1-ANTITRYPSIN (A1AT) DEFICIENCY osms.it/a1at-deficiency PATHOLOGY & CAUSES ▪ Autosomal dominant (codominant) genetic disorder ▫ Decreased production/absence of A1AT → overaction of proteases → damaged alveoli → damaged lungs, liver ▪ Lungs ▫ Damaged alveoli inflammation → neutrophils secrete elastase → absence of/decreased A1AT → elastase overacts, inflames → increased breakdown of elastin → alveoli lose elasticity, integrity → chronic obstructive pulmonary disease (COPD) ▪ Liver ▫ Genetic mutation → misfolded A1AT build up in endoplasmic reticulum of hepatocytes → kill hepatocytes → cirrhosis

CAUSES

▪ Smoking ▫ Earlier onset of COPD in individuals with A1AT deficiency ▪ Genetics ▫ Serine protease inhibitor, clade A, member 1 (SERPINA1) encodes A1AT protein, located on long arm of chromosome 14 ▪ Pi*M ▫ Normal allele ▪ Pi*Z (most common) ▫ Mutated/diseased allele ▫ Misfolded A1AT proteins aggregate → stick in endoplasmic reticulum of hepatocytes → kill hepatocytes ▪ PiMZ ▫ Heterozygous (one normal allele, one diseased allele) ▫ Mutated gene contributes 10% normal

amounts A1AT proteins ▫ Heterozygous individuals have 60% normal levels (enough to protect lungs in non-smokers) ▫ Increased risk of lung/liver disease ▪ PiZZ ▫ Homozygous ▫ Individuals only have 15–20% normal levels ▫ Much higher risk of lung/liver disease ▫ Can live without lung/liver disease if environmental exposures minimal ▫ Infants can develop liver failure during first years of life ▫ Individuals with no production of A1AT = no liver disease

COMPLICATIONS

▪ COPD (emphysema, bronchiectasis, chronic bronchitis), hepatocellular carcinoma, liver cirrhosis, chronic hepatitis

SIGNS & SYMPTOMS ▪ COPD: shortness of breath, wheezing, mucus production, chronic cough ▪ Liver damage, cirrhosis, impaired liver function: inability to make coagulation factors, hepatic encephalopathy, portal hypertension, esophageal varices, jaundice, hepatocellular carcinoma

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DIAGNOSIS DIAGNOSTIC IMAGING Liver ultrasound Chest X-ray/CT scan ▪ Hyperinflated/damaged lungs, basilar emphysema, panlobular emphysema ▫ Smoking: apically distributed emphysema

LAB RESULTS

▪ Serum A1AT levels ▪ Family history, genetic testing ▪ Liver biopsy

OTHER DIAGNOSTICS

▪ PFT ▫ Measure rate air exits lungs ▪ Periodic acid-Schiff (PAS) ▫ Diastase-resistant pink globules in liver biopsy ▫ Stains A1AT pink

TREATMENT MEDICATIONS

▪ Augmentation therapy ▫ Intravenous (IV) infusions of A1AT protein from plasma donors ▫ Not curative, only slows progression ▪ Inhalers, supplemental oxygen ▫ COPD ▪ Lactulose ▫ Prevent hepatic encephalopathy ▫ For liver cirrhosis

SURGERY

▪ Liver transplant ▫ Esp. homozygous infants, liver failure during first years ▪ Lung transplant

Figure 126.2 A CT scan of the chest in the axial plane demonstrating panlobular emphysema as a consequence of alpha 1-antitrypsin deficiency. Figure 126.1 The histological appearance of the liver in an individual with alpha 1-antitrypsin deficiency. There are globular inclusions within periportal hepatocytes.

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Chapter 126 Obstructive Lung Disease

ASTHMA osms.it/asthma PATHOLOGY & CAUSES ▪ Hyperresponsiveness disorder, reversible airflow obstruction ▪ Chronic inflammation, narrowing of airways ▪ Acute (Type 1 hypersensitivity reaction) ▫ Initial sensitization to allergen → production of cluster of differentiation 4 (CD4), T helper 2 (Th2) cells → release interleukin 4 (IL4), interleukin 5 (IL5) → environmental trigger → eosinophils, mast cells release inflammatory mediators in bronchial walls (e.g. histamine, leukotrienes) → degradation of lipids, proteins, nucleic acids → tissue destruction → strong inflammatory reaction in bronchiolar walls → smooth muscle of bronchioles spasm, mucus in narrow airways increases → difficulty breathing ▫ Vasodilation of pulmonary vasculature, increased capillary permeability → edema ▫ Increased mucus production by goblet cells → impaired mucociliary function ▪ Chronic inflammation → scarring, fibrosis → thickening of epithelial basement membrane → permanently narrows airway ▪ Th2 cells release IL5 → attract, activate eosinophils ▪ Neutrophils release cytokines ▫ Interleukin 8 (IL8) ▫ More severe for individuals with neutrophilic asthma ▪ Triggers ▫ Air pollution, cigarette smoke, dust, pet dander, cockroaches, mold, pollen, medications (e.g. aspirin, beta-blockers)

TYPES Extrinsic ▪ Type 1 hypersensitivity reaction triggered by extrinsic allergens (e.g. dust, mold)

▪ Individuals with atopic family history to allergies ▪ Atopic triad ▫ Asthma, atopic dermatitis, allergic rhinitis Intrinsic ▪ Nonimmune ▪ Viral infections, stress, exercise, smoking

SIGNS & SYMPTOMS ▪ Coughing, chest tightness, dyspnea, difficulty breathing, wheezing, whistling during expiration ▪ Curschmann spirals in sputum ▫ Spiral-shaped mucus plugs ▫ Casts from small bronchi ▫ Blocks air exchange, inhaled medications from reaching inflammation ▪ Charcot–Leyden crystals in sputum ▫ Needle-shaped, formed from breakdown of eosinophils

DIAGNOSIS OTHER DIAGNOSTICS

▪ Trigger test, spirometry, peak air flow ▪ Classifications based on frequency of symptoms (esp. night/morning), forced expiratory volume in one second (FEV1), PEFR, frequency of medication use (intermittent, mild persistent, moderate persistent, severe persistent)

TREATMENT OTHER INTERVENTIONS

▪ No cure; treatments manage symptoms, prevent asthma attack ▪ Avoid triggers

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Chapter 126 Obstructive Lung Disease

Figure 126.3 A chest radiograph demonstrating hyperinflation in an individual with chronic asthma. There is a pneumothorax in the right lower zone.

BRONCHIECTASIS osms.it/bronchiectasis PATHOLOGY & CAUSES ▪ Chronic inflammation → permanent dilation of bronchi, bronchioles → destruction of airways ▫ Damage to mucociliary “elevator” → mucus, bacteria accumulates

CAUSES Chronic inflammation ▪ Primary ciliary dyskinesia ▫ Absence of dynein arm in cilia → cilia move abnormally → mucus stuck in airways → bacteria in mucus multiply → pneumonia → chronic inflammation ▪ Cystic fibrosis (most common) ▫ Mucus too sticky → hard for cilia to sweep → mucus accumulates → recurrent pneumonias → chronic inflammation, infection

Airway obstruction ▪ E.g. tumor inside/outside airway, lodged foreign object ▪ Blockage prevents mucociliary escalator from clearing mucus → recurrent pneumonias → chronic inflammation Infections ▪ E.g. aspergillosis, tuberculosis, adenovirus, Haemophilus influenzae, Staphylococcus aureus; hypersensitivity response → inflammation ▫ Chronic inflammation → immune cells, cytokines damage cilia, elastin fibers → airways dilated, clogged with mucus → fibroblasts deposit collagen → loss of elastin, buildup of collagen → lungs less elastic → more difficult for air to move smoothly → lung function declines → hypoxia → pulmonary arterioles constrict to divert blood away from damaged areas of lung → increased

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pulmonary vascular resistance → right ventricular hypertrophy → cor pulmonale → inflammation of pleura

SIGNS & SYMPTOMS ▪ Wheezing, productive cough, foul smelling mucus, dyspnea, hemoptysis, recurrent/ persistent pneumonia, basilar crackles ▪ Long term hypoxia ▫ Digital clubbing

DIAGNOSIS DIAGNOSTIC IMAGING CT scan ▪ Dilated bronchi/bronchioles Chest X-ray ▪ Increased bronchial markings at lung periphery

LAB RESULTS ▪ Sputum culture ▪ Genetic testing

Figure 126.4 The gross pathological appearance of the lungs in a case of severe bronchiectasis.

OTHER DIAGNOSTICS

▪ Spirometry ▫ FEV1 decreased, FEV1/FVC ratio decreased ▪ Sweat test

TREATMENT MEDICATIONS

▪ Bronchodilators; beta-2 agonists (e.g. albuterol) ▪ Inhaled corticosteroids (e.g. fluticasone ▪ Antibiotics ▫ Recurrent pneumonias

OTHER INTERVENTIONS

▪ Percussion, postural drainage ▫ Recurrent pneumonias ▪ Pulmonary hygiene ▪ Adequate hydration

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Figure 126.5 The histological appearance of bronchiectasis complicated by fungal colonisation. There is a heavily dilated bronchus containing an aggregation of fungus known as an aspergilloma.

Chapter 126 Obstructive Lung Disease

CHRONIC BRONCHITIS osms.it/chronic-bronchitis PATHOLOGY & CAUSES ▪ Preventable, progressive pulmonary disease ▫ Chronic airway inflammation, limited airflow ▫ Bronchial tubes in lungs inflame → productive cough ▪ Subset of COPD ▪ Exposure to irritants → hypertrophy/ hyperplasia of bronchial mucous glands, goblet cells in bronchioles, cilia less mobile → increased mucus production, less movement → mucus plugs → obstruction in bronchioles → air-trapping → productive cough ▪ Blocked airflow, air-trapping → increased partial pressure of CO2 in lungs → less O2 reaches blood → cyanosis (if severe); individuals referred to as “blue bloaters”

RISK FACTORS

▪ Smoking (primary cause), cystic fibrosis, sulfur, nitrogen dioxide, dust, silica, family history, genetic predisposition

COMPLICATIONS

▪ Pulmonary hypertension, increased workload of right ventricle, cor pulmonale, infections distal to mucus blockages, fibrosis of terminal bronchioles, compensatory polycythemia

SIGNS & SYMPTOMS ▪ Wheezing (due to mucus, narrow airway), crackles/rales (small airways pop open during air movement due to narrow passageway) ▪ Hypoxemia, hypercapnia (due to mucus plugs blocking air flow) → cyanosis → tissue hypoxia

DIAGNOSIS DIAGNOSTIC IMAGING Chest X-ray ▪ Large, horizontal heart, increased bronchial markings

LAB RESULTS

▪ ABGs ▫ Respiratory acidosis (arterial PCO2 > 45mmHg, bicarbonate > 30mEq/L)

OTHER DIAGNOSTICS

▪ Productive, mucinous cough ▫ At least three months over two consecutive years ▪ PFTs ▫ Increased TLC, air-trapping; decreased FVC1/FVC ratio ▪ Postmortem measurement ▫ Reid index (measure ratio of thickness of bronchial mucinous glands, total thickness of airway, epithelium to cartilage) ▫ > 40% (due to hyperplasia, hypertrophy of glands)

TREATMENT MEDICATIONS

▪ Supplemental oxygen, bronchodilators, inhaled steroids, antibiotics ▫ Manage symptoms ▪ Prophylactic vaccination against influenza, Streptococcus pneumoniae (S. pneumoniae)

OTHER INTERVENTIONS

▪ Smoking cessation, pulmonary rehabilitation

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CYSTIC FIBROSIS (CF) osms.it/cystic-fibrosis PATHOLOGY & CAUSES ▪ Autosomal-recessive multisystem disorder ▫ Affects lungs, digestive system, reproductive system, sweat glands ▪ Caused by CFTR gene defect (located on long arm of chromosome 7) ▫ Encodes cyclic adenosine monophosphate–regulated chloride channel cystic fibrosis transmembrane conductance regulator (CFTR) ▫ Various mutations: including lack of protein production; protein trafficking defect, degradation within cellular endoplasmic reticulum, Golgi body ▪ Genetic defect → impaired sodium, chloride transport across epithelial cell surface → thick, tenacious secretions ▫ Classic triad: ↑ sweat chloride levels, chronic sinopulmonary disease, pancreatic insufficiency ▪ Bronchi effects ▫ Goblet cell hyperplasia, submucosal gland hypertrophy → production of viscous mucus, mucus plugging → airway inflammation → elastase released from neutrophils → tissue destruction → ↑ thickness of airway walls, bronchiectatic cysts, ventilationperfusion mismatch → hypoxemia

RISK FACTORS

▪ Family CF history; especially carrier parents ▪ ↑ incidence in white people of Northern, Central European descent

COMPLICATIONS

▪ Chronic respiratory tract infections ▫ Common bacteria: Pseudomonas aeruginosa, Staphylococcus aureus, Haemophilus influenzae (especially younger children) ▫ Invasive fungal disease may occur → allergic bronchopulmonary aspergillosis

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(ABPA) ▪ Sinusitis ▫ Related to chronic inflammation ▪ Significant hemoptysis ▫ Related to enlarged, tortuous bronchial arteries ▪ Bronchiectasis ▫ Due to mucus plugging ▪ Pneumothorax ▫ Related to ruptured emphysematous bullae ▪ Secondary pulmonary hypertension ▫ Related to small pulmonary artery hypertrophy ▪ Nasal polyps ▫ Related to chronic inflammation ▪ Respiratory failure ▪ Non-pulmonary complications ▫ Cirrhosis; gallstones; pancreatitis; heat exhaustion, dehydration; hypochloremic alkalosis (excessive salt-loss in sweat); rectal prolapse; infertility (azoospermia); fat-soluble vitamin deficiency; anemia; nail clubbing

SIGNS & SYMPTOMS ▪ Highly variable presentation ▫ Related to specific mutation, gene penetrance, environmental factors ▪ Specific pulmonary manifestations ▫ Chronic, productive cough; dyspnea; ↑ anterior-posterior chest diameter; digital clubbing; basilar crackle; expiratory wheeze; generalized hyperresonance

Chapter 126 Obstructive Lung Disease

DIAGNOSIS DIAGNOSTIC IMAGING Prenatal ultrasound ▪ May detect hyperechogenic bowel, meconium peritonitis Chest X-ray ▪ Hyperinflation, air trapping, atelectasis, flattened diaphragm, peribronchial thickening, bronchovascular markings, peribronchial cuffing, parallel lines (related thickened bronchial walls—”tram tracks”) CT scan ▪ Inspissated bronchial secretions; detects degree of bronchiectasis

LAB RESULTS

▪ Genetic testing ▪ CFTR mutation identification ▪ Sweat chloride test ▫ ↑ sweat chloride concentration ▫ Pilocarpine administered → stimulate sweat; collected, analyzed for chloride content

Figure 126.6 A plain chest radiograph demonstrating tram-track opacities and ring shadows in an individual with cystic fibrosis. They are particularly well demonstrated in the left upper zone.

OTHER DIAGNOSTICS

▪ Newborn screening ▫ Detects CF in neonatal period; initiate early intervention ▪ Pulmonary function tests ▫ ↓ FEV1 FEV1/FVC ▫ ↑ residual volume to total lung capacity (RV/TLC) ratio ▫ ↓ total lung capacity ▫ ↓ vital capacity

TREATMENT MEDICATIONS

Figure 126.7 A CT scan of the chest in the coronal plane demonstrating bilateral widespread bronchiectasis in a twenty five year old female with cystic fibrosis.

▪ CFTR modulators ▪ Medications to clear respiratory secretions; inhaled hypertonic saline ▪ Anti-inflammatory medications (e.g. glucocorticoids) ▪ Antibiotics ▫ Infections ▪ Bronchodilators ▫ ↓ airflow obstruction ▪ Prevention ▫ Annual influenza vaccine; pneumococcal vaccine

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SURGERY

▪ Lung transplantation ▪ Respiratory support ▫ Respiratory failure → invasive ventilation

OTHER INTERVENTIONS

▪ Address complications ▪ Chest physiotherapy ▫ Mobilize retained secretions ▪ Respiratory support ▫ Supplemental oxygen ▫ Positive-pressure ventilation

EMPHYSEMA osms.it/emphysema PATHOLOGY & CAUSES ▪ COPD subset ▫ Exposure to irritants → degrades elastin in alveoli, airways → air-trapping, poor gas exchange. ▪ Irritants (e.g. cigarette smoke) → attraction of inflammatory cells → release leukotrienes, chemical mediators (e.g. B4; IL8; TNF alpha/proteases, elastases/ collagenases) → destroy collagen, elastin → lose elasticity → low pressure during expiration pulls walls of alveoli inward → collapse → air-trapping distal to collapse → septa breaks down → neighboring alveoli coalesce into larger air spaces → decreased surface area available for gas exchange ▫ Loss of elastin → lungs more compliant (lungs expand, hold air) ▫ Alveolar air sacs permanently enlarge, lose elasticity → exhaling difficult

TYPES Centriacinar/centrilobular emphysema ▪ Most common ▪ Damage to central/proximal alveoli of acinus sparing distal alveoli ▫ Individuals who smoke (irritants can’t reach distal alveoli); upper lobes of lungs Panacinar emphysema ▪ Entire acinus uniformly affected ▫ A1AT deficiency; lower lobes of lungs

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Paraseptal emphysema ▪ Distal alveoli most affected ▫ Lung tissue on periphery of lobules near interlobular septa ▫ Ballooned alveoli on lung surface rupture → pneumothorax

CAUSES

▪ Smoking, A1AT deficiency

COMPLICATIONS

▪ Hypoxic vasoconstriction → cor pulmonale ▫ Poor gas exchange → vessels vasoconstrict to shunt blood to better gas exchange → pulmonary hypertension → increased workload for right heart → right ventricular hypertrophy → cor pulmonale ▪ Hypoxemia ▪ Pneumothorax

SIGNS & SYMPTOMS ▪ Barrel chest (air-trapping, hyperinflation of lungs), apparent respiratory distress with use of accessory muscles, tripod positioning, weight loss, exhaling slowly through pursed lips (“pink puffers”), hyperventilation ▪ Pursing lips increases pressure in airway → keeps airway from collapsing → weight loss ▪ Dyspnea, cough (with less sputum)

Chapter 126 Obstructive Lung Disease

DIAGNOSIS DIAGNOSTIC IMAGING Chest X-ray ▪ Increased anterior-posterior diameter, flattened diameter, increased lung field lucency (air-trapping)

OTHER DIAGNOSTICS

▪ Increased TLC ▪ FVC decreased (esp. FEV1)

TREATMENT MEDICATIONS

▪ Bronchodilators ▪ Inhaled steroids ▪ Combination inhalers ▫ Bronchodilators + inhaled steroids ▪ Oral steroids ▫ Adverse effects: oral candidiasis, weight gain, diabetes, osteoporosis ▪ Antibiotics (e.g. azithromycin prevents exacerbations) ▪ Supplemental oxygen

Figure 126.8 The gross pathological appearance of emphysema. There are numerous dilated airspaces in a peripheral distribution.

SURGERY

▪ Lung volume reduction ▫ Removal of areas of damaged lung tissue to create extra space in chest cavity for healthy lung tissue to expand ▫ Can improve quality of life and prolong survival ▪ Lung transplant ▪ Bullectomy ▫ Removal of bullae (large air spaces) to improve air flow

OTHER INTERVENTIONS

▪ Pulmonary rehabilitation program ▫ Customized education plan consisting of exercising training, nutrition advice, and lifestyle counseling

Figure 126.9 The histological appearance of emphysema There are numerous hyperexpanded alveoli.

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MNEMONIC: P vs. B

Emphysema vs. Bronchitis EmPhysema: Pink Puffer Chronic Bronchitis: Blue Bloater

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NOTES

NOTES

PERINATAL ACUTE RESPIRATORY DISEASE

GENERALLY, WHAT IS IT? PATHOLOGY & CAUSES ▪ Respiratory problems in newborns/infants; dyspnea to sudden death

SIGNS & SYMPTOMS ▪ Respiratory distress ▫ Cyanosis, bradypnea, tachypnea, etc.

OTHER DIAGNOSTICS

▪ Pulse oximetry, arterial blood gases

ECG ▪ Congenital heart defects

TREATMENT OTHER INTERVENTIONS

▪ Supplemental oxygen therapy, assisted ventilation

DIAGNOSIS DIAGNOSTIC IMAGING Chest X-ray

MECONIUM ASPIRATION SYNDROME (MAS) osms.it/meconium-aspiration-syndrome PATHOLOGY & CAUSES ▪ Respiratory condition caused by aspiration of amniotic fluid contaminated by meconium (fetal stool) before/during birth ▪ Bile pigments ▫ Meconium with black-green color ▪ MAS in approx. 10% of neonates exposed to meconium ▪ Meconium in airways ▫ Airway obstruction: atelectasis

▫ Surfactant deactivation, synthesis inhibition ▫ Chemical pneumonitis: irritates air pathways ▫ Persistent pulmonary hypertension of newborn (PPHN): hypertrophy of pulmonary vessels due to chronic distress ▫ Medium for bacterial growth + reduces antibacterial activity → increases risk of infection

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CAUSES

▪ Initiated by fetal distress due to perinatal complications (e.g. maternal hypertension, preeclampsia, placental insufficiency, oligohydramnios, infection, acidosis, maternal drug abuse) ▫ Hypoxia → increased vagal stimulation → gastrointestinal (GI) tract peristalsis + sphincter relaxation → meconium release ▫ Hypoxia → fetus gasping, aspiration of meconium-stained amniotic fluid

RISK FACTORS

▪ Term/post-term gestation (> 40 weeks); perinatal complications → fetal hypoxia, stress

COMPLICATIONS

▪ Pneumothorax, pulmonary hypertension, neonatal infection, infant respiratory distress syndrome, acidosis

SIGNS & SYMPTOMS ▪ Meconium spotting during labor ▫ Green-yellow colour of amniotic fluid, infant’s skin, umbilical cord ▪ Low APGAR score ▫ Appearance, Pulse, Grimace, Activity, Respiration ▪ Respiratory distress ▫ Labored breathing, tachypnea, bradycardia, intercostal/subcostal/ substernal retractions, cyanosis, nasal flaring ▪ Blood gas ▫ Hypoxemia, hypercarbia, acidosis

Figure 127.1 A plain chest radiograph of a neonate demonstrating bilateral, diffuse, coarse opacities secondary to meconium aspiration.

DIAGNOSIS DIAGNOSTIC IMAGING Chest X-ray ▪ Patchy atelectasis, consolidation areas ▪ Hyperexpansion due to airway obstruction ▪ Pneumomediastinum due to air leak Ultrasound ▪ ECG to assess pulmonary hypertension

OTHER DIAGNOSTICS Meconium ▪ In amniotic fluid, on infant, in trachea (if intubation required) Respiratory distress Pulse oximetry ▪ Low oxygen saturation Auscultation ▪ Crackles, rhonchi sounds

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Chapter 127 Perinatal Acute Respiratory Disease

TREATMENT MEDICATIONS

▪ Antibiotics ▪ Maintain circulatory volume; correct existing metabolic imbalances ▫ IV fluids; electrolytes, glucose; correct acidosis

OTHER INTERVENTIONS

▪ Transfer to neonatal intensive care unit (NICU)

Amnioinfusion ▪ Intrauterine saline infusion ▪ If meconium-stained amniotic fluid, preventative measures Maintain oxygenation, ventilation ▪ Neutral thermal environment ▪ Decreased oxygen consumption ▪ Supplemental oxygen ▪ Mechanical ventilation ▪ If PPHN ▫ Inhalation of nitric oxide (iNO), phosphodiesterase inhibitors ▪ If severe ▫ ECMO

Figure 127.2 Flowchart depicting the pathophysiology of MAS.

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Figure 127.3 A histology photomicrograph of the fetal membranes containing meconium laden macrophages.

NEONATAL RESPIRATORY DISTRESS SYNDROME osms.it/neonatal-resp-distress PATHOLOGY & CAUSES Respiratory disease in neonates: loss of lung compliance (distensibility) due to lack of surfactant. ▪ AKA neonatal respiratory distress syndrome/surfactant deficiency disorder (SDD) ▪ Surfactant deficiency → ↑ surface tension → ↓ lung compliance → alveoli collapse upon expiration (microatelectasis) → V/Q mismatch → intrapulmonary shunting + extrapulmonary shunting (e.g. through patent ductus arteriosus) → hypoxemia

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CAUSES

▪ Surfactant production inhibition by insulin due to maternal diabetes ▪ Genetic mutations affect production of surfactant proteins ▪ Surfactant inactivation by meconium ▪ Pulmonary inflammation, edema may complicate respiratory distress

RISK FACTORS

▪ Premature delivery, cesarean delivery, maternal diabetes, intrauterine asphyxia, meconium aspiration syndrome

Chapter 127 Perinatal Acute Respiratory Disease

COMPLICATIONS Acute ▪ Acidosis, hypoglycemia, hypotension, infection, diffuse atelectasis, respiratory failure, death Chronic ▪ Intracranial hemorrhage, retinopathy of prematurity, bronchopulmonary dysplasia, pulmonary hemorrhage, neurologic impairment

SIGNS & SYMPTOMS ▪ Respiratory distress ▫ Tachypnea, tachycardia, intercostal/ subcostal/substernal retractions, cyanosis, nasal flaring, expiratory grunting ▪ Ventilatory failure (↑ blood CO2), apnea

DIAGNOSIS DIAGNOSTIC IMAGING Chest X-ray ▪ Low lung volume ▪ Bilateral, diffuse granular/”ground glass” appearance ▪ Air bronchograms ▫ Pulmonary edema secondary to inflammation, atelectasis

TREATMENT OTHER INTERVENTIONS

▪ Reduce oxygen consumption ▪ Radiant warmer, intravenous (IV) fluids with glucose

Assisted ventilation ▪ If symptoms do not subside ▪ Endotracheal intubation with synthetic/ animal exogenous surfactant therapy Prevention ▪ Fetal lung maturity test (if preterm delivery anticipated) ▫ Assess surfactant levels by amniocentesis; administer corticosteroids, promote lung maturity Continuous positive airway pressure (CPAP) If severe ▪ Extracorporeal membrane oxygenation (ECMO) INSURE ▪ INtubation-SURfactant-Extubation

LAB RESULTS

▪ Oxygen saturation monitor ▫ ↓ SaO2, consider influence of preductal/ postductal gradients ▪ Metabolic acidosis, hypoxia

OTHER DIAGNOSTICS Physical examination ▪ Lung auscultation (decreased breath sounds); respiratory distress Post-mortem histopathology ▪ Lungs interspersed with hyper-distended alveolar ducts, collapsed alveoli ▪ Hyaline membranes lining/filling alveoli

Figure 127.4 A plain chest radiograph of a neonate with infant respiratory distress syndrome. Both lung fields are granular in appearance.

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SUDDEN INFANT DEATH SYNDROME (SIDS) osms.it/sids PATHOLOGY & CAUSES ▪ Sudden unexplainable death of infants < one year old despite thorough death scene investigation, analysis of perinatal history, autopsy ▪ Leading cause of death in infants < one year old; peak incidence, 8–16 weeks

CAUSES Triple risk model ▪ Triggering event ▫ Sleeping prone, infection ▪ Underlying vulnerability ▫ Genetic polymorphisms involving autonomic nervous system function, cardiac conduction channels, altered cerebral serotonin (5-HT) signaling ▪ Developmental vulnerability ▫ Immature neuroregulation of cardiorespiratory control, delayed immune functionality

RISK FACTORS

▪ Previous loss of infant from SIDS ▪ Periconceptional/postnatal smoking, substance abuse ▪ Teenage (< 20 years) pregnancy ▪ Inadequate prenatal care ▪ Premature birth ▪ Low birth weight ▪ Intrauterine growth restriction ▪ Infant of genetically male sex ▪ Sleep environment ▫ Prone position (strongest modifiable risk factor); soft sleeping surface; loose blankets, pillows, stuffed toys; overheating; bed sharing

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SIGNS & SYMPTOMS ▪ Infant fed, put to bed without sign of distress; found unresponsive

DIAGNOSIS OTHER DIAGNOSTICS

▪ Diagnosis of exclusion ▪ Forensic autopsy, clinical history, death scene investigation

TREATMENT OTHER INTERVENTIONS

▪ Emergency responders ▫ Attempt cardiopulmonary resuscitation; document scene ▪ Transport to healthcare facility ▫ Resuscitation attempt continued ▪ Physical examination, lab tests documented ▪ Interview of family members ▫ When was infant last seen alive; who found infant, when; history of illnesses; sleeping environment ▪ Protective factors ▫ Prone sleeping position, elimination of environmental risk factors; breastfeeding, room-sharing, not bedsharing, immunizations

Chapter 127 Perinatal Acute Respiratory Disease

TRANSIENT TACHYPNEA OF THE NEWBORN osms.it/newborn-transient-tachypnea PATHOLOGY & CAUSES ▪ Respiratory condition; presents in first hours of life, periods of non-acute rapid breathing ▪ AKA “quiet tachypnea”

CAUSES

▪ Delayed reabsorption of alveolar fluid through epithelial aquaporin channels → increased alveolar fluid → decreased pulmonary compliance, partial collapse of small airways, air trapping → hypoxemia, hypercapnia

RISK FACTORS

▪ Cesarean delivery without labor; maternal diabetes, asthma, smoking during pregnancy; pulmonary immaturity; surfactant deficiency

SIGNS & SYMPTOMS ▪ Symptoms present immediately after birth in response to excessive fluid in lungs ▪ Tachypnea (> 60 breaths/minute), nasal flaring, expiratory grunting, intercostal/ subcostal/substernal retractions ▪ Hypoxemia → hypoxia, cyanosis

DIAGNOSIS DIAGNOSTIC IMAGING Lung sonography Chest X-ray ▪ Radiopaque levels of fluid in horizontal fissure of lungs; hyperinflated lungs; diaphragm flattening

OTHER DIAGNOSTICS

▪ Pulse oximetry ▪ Arterial blood gas assessment ▫ Evaluate gas exchange, monitor acidbase balance

TREATMENT OTHER INTERVENTIONS

▪ Commonly resolves during first three days of life ▪ Supplemental oxygen therapy; nasal CPAP if additional support required ▪ Neutral thermal environment: decrease oxygen consumption ▪ Orogastric feedings/IV fluids with glucose if PO feedings avoided due to increased respirations ▪ Antibiotics, if infection suspected

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NOTES

NOTES

PLEURA & PLEURAL SPACE GENERALLY, WHAT IS IT? DIAGNOSIS

PATHOLOGY & CAUSES ▪ Conditions that adversely affect the function of the chest wall, pleura, and lungs resulting in impaired ventilation and oxygenation ▫ Pleural effusion: abnormal accumulation of fluid in the potential space between the visceral and parietal pleura (pleural space) ▫ Pneumothorax: presence of air or gas in the space between the thoracic wall and the lung (pleural cavity)

DIAGNOSTIC IMAGING

COMPLICATIONS

SURGERY

▪ Mediastinal shift → impaired cardiovascular function

SIGNS & SYMPTOMS ▪ See individual disorders

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Chest X-ray, CT scan, thoracic ultrasound

LAB RESULTS

▪ Pleural effusion ▫ Analysis of pleural fluid confirms etiology

TREATMENT ▪ Pleural effusion ▫ Thoracentesis ▪ Pneumothorax ▫ Needle chest decompression, chest tube

Chapter 128 Pleura & Pleural Space

PLEURAL EFFUSION osms.it/pleural-effusion PATHOLOGY & CAUSES ▪ Excess fluid accumulates in pleural space ▪ Lung expansion limited → impaired ventilation Origin ▪ Hydrothorax (serous fluid), hemothorax (blood), urinothorax (urine), chylothorax/ lymphatic effusion (chyle), pyothorax (pus, AKA empyema) Pathophysiology ▪ Transudative pleural effusion ▫ Pressure driven filtration: ↑ hydrostatic pressure/↓ oncotic pressure → force imbalance, fluid extravasation → fluid leaks across intact capillary membranes ▫ Alteration in Starling forces ▪ Exudative pleural effusion ▫ Local inflammatory processes → leaky capillaries

DIAGNOSIS DIAGNOSTIC IMAGING Chest X-ray ▪ Fluid occupies space between visceral, parietal pleural ▪ Area of whiteness on standard posteroanterior (PA) chest X-ray ▪ Blunted costophrenic angles ▪ Greater density than rest of lung → gravitates towards dependent regions ▫ ↑ fluid on upright X-ray or lateral decubitus X-ray Lung ultrasound ▪ Confirms presence of effusion and detects pleural fluid septations

CAUSES

▪ Transudative ▫ Congestive heart failure, liver cirrhosis, severe hypoalbuminemia, nephrotic syndrome, acute atelectasis, myxedema, peritoneal dialysis, Meigs syndrome, obstructive uropathy, end-stage renal disease ▪ Exudative ▫ Infection, malignancy, trauma, pulmonary infarction, pulmonary embolism, autoimmune processes, pancreatitis, ruptured esophagus

SIGNS & SYMPTOMS ▪ Asymptomatic (if small) ▪ Pleuritic chest pain ▪ Dyspnea ▫ Worse when lying down (orthopnea)

Figure 128.1 A plan chest radiograph demonstrating a large left sided pleural effusion, in this case as a consequence of metastatic melanoma. There is notable tracheal deviation.

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▫ Rheumatoid factor, antinuclear antibody, complement: collagen vascular disease ▫ Triglycerides: chylothorax from thoracic duct leakage (trauma, cancer, lymphoma)

OTHER DIAGNOSTICS ▪ Medical history

Figure 128.2 A CT scan of the chest in the coronal plane demonstrating a right sided pleural effusion.

LAB RESULTS Thoracentesis ▪ Needle inserted through chest wall, 5th– 8th intercostal space, midaxillary line → pleural space → withdraw fluid ▪ Trial diuresis for three days in heart failure before thoracentesis ▪ Effusion analysis ▫ Amylase: pancreatitis, esophageal perforation, malignancy ▫ Blood: traumatic, malignancy, pulmonary embolism with infarction, tuberculosis ▫ Cholesterol: chylous (lymphatic fluid) vs. chyliform effusion (chyle-like fluid from chronic disease) ▫ Cytology: malignancy, infection (reactive effusion) ▫ Differential cell count: lymphocytic effusion in tuberculosis, cancer, lymphoma ▫ Glucose (low): rheumatoid arthritis, tuberculosis, empyema, malignancy ▫ Microscopy, culture: microorganisms ▫ ↓ pH: empyema, tuberculosis, mesothelioma ▫ Protein, LDH: transudative/exudative

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Clinical examination ▪ ↑ fluid on affected side ▫ ↓ chest expansion ▫ Stony dullness to percussion ▫ Diminished breath sounds ▫ ↓ vocal resonance, fremitus ▫ Tracheal deviation away from effusion ▪ If lung compressed above effusion ▫ Bronchial breathing, egophony Light’s criteria ▪ Classification of transudative/exudative effusion ▪ Transudative ▫ Difference between albumin in blood, pleural fluid > 1.2g/dL ▪ Exudative ▫ Ratio of pleural fluid protein to serum protein > 0.5 ▫ Ratio of pleural fluid LDH to serum LDH > 0.6 ▫ Pleural fluid LDH > 0.6, ⅔ times lab specific upper limit for serum

Figure 128.3 The cytological appearance of a benign pleural effusion. There are numerous bland mesothelial cells mixed with lymphocytes.

Chapter 128 Pleura & Pleural Space

TREATMENT SURGERY

▪ Therapeutic aspiration ▪ Insertion of intercostal drain ▪ Repeated effusions ▫ Surgical pleurodesis: obliteration of pleural space; prevents fluid accumulation

OTHER INTERVENTIONS

▪ Supplemental oxygen ▪ Repeated effusions ▫ Chemical pleurodesis: obliteration of pleural space; prevents fluid accumulation (talc, bleomycin, tetracycline/doxycycline) ▪ Pleural catheter ▫ User-operated daily draining ▪ Treat underlying cause

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PNEUMOTHORAX osms.it/pneumothorax PATHOLOGY & CAUSES ▪ Abnormal collection of air in pleural cavity ▪ Air enters through damage to chest wall/ lung/gas-producing microorganisms ▫ Positive pressure in pleural space if air enters → lung partial/complete collapse

TYPES Primary pneumothorax ▪ No clear cause/no preexisting lung disease ▫ Secondary to ruptured blebs (small sacs of air on lung surface) Secondary pneumothorax ▪ Occurs with existing lung disease Tension pneumothorax ▪ One-way valve formed by damaged tissue → air enters, can’t escape → intrathoracic pressure builds up → impaired cardiac, respiratory function Traumatic pneumothorax ▪ Follows physical trauma to chest (e.g. blast injury); result of medical procedure (e.g. iatrogenic pneumothorax)

RISK FACTORS

▪ Smoking, chronic obstructive pulmonary disease (COPD), asthma, tuberculosis ▪ More common in individuals who are biologically male ▪ Changes in atmospheric pressure ▪ Family history of pneumothoraces

SIGNS & SYMPTOMS ▪ ▪ ▪ ▪ ▪ ▪ ▪ ▪ ▪ ▪

Sharp chest pain (one-sided) Dyspnea Tachycardia Cyanosis Hypercapnia → confusion, coma Diminished/absence of breath sounds (affected side) Hyperresonance to percussion ↓ vocal, tactile fremitus Trachea displaced away from affected side Tension pneumothorax ▫ ↓ blood pressure ▫ ↓ oxygen saturation ▫ Epigastric pain ▫ Displaced apex beat ▫ Distended neck veins

DIAGNOSIS DIAGNOSTIC IMAGING Chest X-ray/CT scan ▪ Identifies atypical collections of gas, changes in lung markings, presence of mediastinal shift and/or tracheal deviation; lucent/dark lung field, deep sulcus sign (a deep costophrenic angle) Ultrasound ▪ Reverberation echoes of the pleural line, absence of lung sliding at the pleural line

OTHER DIAGNOSTICS

▪ Clinical history, physical examination

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Chapter 128 Pleura & Pleural Space

Figure 128.4 A CT scan of the chest in the coronal plane demonstrating a right-sided pneumothorax.

TREATMENT SURGERY Pleurodesis/pleurectomy ▪ Repeated pneumothoraces Tension pneumothorax: needle chest decompression ▪ AKA needle thoracostomy ▪ Emergency procedure ▪ Not definitive, improves cardiopulmonary function

▪ Large bore intravenous catheter needle inserted into pleural space ▫ Midclavicular line: second/third intercostal space ▫ Anterior/mid axillary line: fifth intercostal space ▫ Listen for air escaping ▫ Remove needle, leave catheter in place ▪ May cause injury, reserve for ▫ Mechanism of injury suggestive of pneumothorax ▫ Clinical signs of respiratory distress, persistently low oxygen saturation despite supplemental oxygen ▫ Hemodynamic instability ▫ Prolonged transport time

OTHER INTERVENTIONS

▪ Supplemental oxygen ▫ Improves rate of pneumothorax reabsorption ▪ Small pneumothoraces may resolve spontaneously ▪ If wound present, cover with dressing ▫ Dressing secured on three sides to create “vent dressing” ▪ Chest tube (connected to water-seal drainage system) ▫ Inserted into “safe triangle,” damage to internal organs avoided ▫ Horizontal line, nipple to lateral chest well; between latissimus dorsi, pectoralis major

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NOTES

NOTES

PULMONARY VASCULAR DISEASE

GENERALLY, WHAT IS IT? PATHOLOGY & CAUSES ▪ Diseases affecting blood flow through pulmonary vasculature, or fluid flow from vasculature ▪ Can be caused by process within lungs/ elsewhere in body

SIGNS & SYMPTOMS

DIAGNOSIS X-ray, chest CT scan, spirometry, ultrasound, echocardiogram, ECG

TREATMENT ▪ Supportive, treat underlying disease, optimize organ function (heart, lungs)

▪ Dyspnea, poor effort tolerance, chest pain, tachypnea

Figure 129.1 Chronic thromboembolic pulmonary hypertension is an example of a pulmonary vascular disease that originates outside the lungs. In this case, an embolism blocks the pulmonary vessels, causing pulmonary blood pressure to rise beyond normal levels.

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Chapter 129 Pulmonary Vascular Disease

PULMONARY EDEMA osms.it/pulmonary-edema PATHOLOGY & CAUSES ▪ Alteration in Starling forces → build up of fluid within interstitial space, air spaces of lung

CAUSES Cardiogenic (heart disease) ▪ Left sided heart failure → inefficient pumping of blood from heart by left ventricle → blood backs up into left atrium → pulmonary circulation → pulmonary hypertension (raised hydrostatic pressure) → more fluid in lung interstitium → pulmonary edema ▫ Severe systemic hypertension (> 180/110mmHg) → left ventricle cannot pump effectively against extreme afterload → blood backs up into left atrium → pulmonary circulation → pulmonary edema Non-cardiogenic (damage to pulmonary capillaries or alveoli) ▪ Direct damage to alveoli/vasculature → inflammatory response → leaky capillaries ▫ Pulmonary infection, toxin inhalation, chest trauma, pulmonary vein occlusion, burns ▫ Sepsis → systemic inflammation → global edema ▫ Insufficient circulation of osmotically active proteins, e.g. albumin → low oncotic pressure in capillaries ▪ Malnutrition ▪ Liver failure ▪ Excessive protein loss (nephrotic syndrome, protein losing enteropathies)

COMPLICATIONS

▪ Impaired gas exchange: oxygen/carbon dioxide must diffuse through wide layer of fluid → blood unable to fully saturate

▪ Free fluid predisposes to secondary infection

SIGNS & SYMPTOMS ▪ Dyspnea, productive cough (pink frothy sputum), excessive sweating, anxiety, tachycardia, end-inspiratory crackles, dullness to percussion, cyanosis (decreased hemoglobin saturation) ▪ Pulmonary edema in heart failure may also include ▫ Orthopnea (shortness of breath worse when lying flat) ▫ Paroxysmal nocturnal dyspnea (episodes of severe sudden breathlessness at night) ▫ Peripheral pitting edema ▫ Raised jugular venous pressure ▫ Hepatomegaly

DIAGNOSIS DIAGNOSTIC IMAGING Chest X-ray ▪ Kerley B lines (thickened subpleural interlobular septa, usually seen at base of lung) ▪ Increased vascular shadowing → batwing perihilar pattern ▪ Upper lobe diversion (prominent upper lobe pulmonary veins) ▪ Pleural effusion (if edema severe) Non-contrast high resolution chest CT scan ▪ Airspace opacity ▪ Smooth thickening of interlobular septae Chest ultrasound ▪ Detection of small amounts of fluid ▪ Echo-free space between visceral and parietal pleura ▪ Septations in pleural fluid → underlying

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infection, chylothorax/hemothorax Echocardiograph ▪ Evaluation of cardiac function, can demonstrate left ventricular failure

LAB RESULTS ▪ ▪ ▪ ▪ ▪

Serum electrolytes Renal function Inflammatory markers Low oxygen saturation Increased carbon dioxide

TREATMENT MEDICATIONS

▪ If cardiogenic ▫ Preload reduction: nitroglycerin, diuretics, morphine sulphate ▫ Afterload reduction: ACE inhibitors, angiotensin II receptor blockers, nitroprusside ▪ If non-cardiogenic ▫ Manage illness (e.g. treat infection)

OTHER INTERVENTIONS

▪ Continuous positive airway pressure (CPAP) ▪ Intubation: mechanical ventilation if level of consciousness compromised

Figure 129.2 A CT scan of the chest in the coronal plane demonstrating the peribronchovascular distribution of acute pulmonary edema. Figure 129.3 A plain chest radiograph demonstrating pulmonary edema. There is interstitial edema, represented by fine stranded opacities known as Kerley B lines, as well as alveolar edema, represented by confluent nodular opacities.

Figure 129.4 Illustration depicting pulmonary edema.

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Chapter 129 Pulmonary Vascular Disease

Figure 129.5 The histological appearance of pulmonary edema.

PULMONARY EMBOLISM osms.it/pulmonary-embolism PATHOLOGY & CAUSES ▪ Blockage of pulmonary artery by a substance brought there via bloodstream ▪ Thrombus in remote site embolizes → lodges in pulmonary vascular tree → “pulmonary embolism” ▪ Obstruction of blood flow distal to embolism → increased pulmonary vascular resistance → increased pulmonary artery pressure → increased right ventricular pressure → cor pulmonale (if severe obstruction) ▪ Regional decrease in lung perfusion → dead space (ventilation, but no perfusion) → hypoxemia → tachypnea Source of embolus ▪ Lower extremity deep vein thrombosis ▫ Most arise from deep veins above knee, iliofemoral deep vein thrombosis ▫ Can arise from pelvic deep veins ▫ Pelvic thrombi tend to advance to more proximal veins before embolizing ▪ Upper extremity deep veins (rarely) ▪ Uncommon embolic material: air, fat, amniotic fluid

RISK FACTORS

▪ Virchow’s triad: endothelial injury, stasis of blood flow, blood hypercoagulability ▪ > 60 years old, malignancy, history of deep vein thrombosis/pulmonary embolism, hypercoagulable states, genetic disorders (e.g. Factor V Leiden thrombophilia), dehydration, prolonged immobilization (bed rest, travel), cardiac disease, obesity, nephrotic syndrome, major surgery, trauma, pregnancy, estrogen-based medication (e.g. oral contraceptives) ▪ Increased risk of fat embolism with bone fractures (e.g. hip, femur)

SIGNS & SYMPTOMS ▪ Dyspnea, pleuritic chest pain, cough, hemoptysis ▪ Signs, symptoms of deep vein thrombosis ▫ Tender, swollen, erythematous extremity ▪ Syncope ▪ Often asymptomatic (in the case of small emboli)

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MNEMONIC: TOM SCHREPFER

Risk factors for Pulmonary embolism Trauma Obesity Malignancy Surgery Cardiac disease Hospitalization Rest (bed-ridden) Elderly Past history Fracture Estrogen (pregnancy, postpartum) Road trip

Figure 129.6 A CT pulmonary angiogram demonstrating a pulmonary embolus and subsequent right middle lobe infarct.

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▪ Low SpO2, tachypnea, rales, tachycardia, S4 heart sound, increased P2 (closure of pulmonary valve), shock, low-grade fever, decreased breath sounds, percussion dullness, pleural friction rub, sudden death (pulmonary saddle embolism)

DIAGNOSIS Wells’ score ▪ Used to assess probability of pulmonary embolism (multiple different probability tests available) ▫ Score > 4: pulmonary embolism likely, consider diagnostic imaging ▫ Score ≤ 4: pulmonary embolism unlikely, consider D-dimer test to rule out

Chapter 129 Pulmonary Vascular Disease

DIAGNOSTIC IMAGING Chest X-ray ▪ Typically normal CT pulmonary angiography ▪ Definitive test ▪ Visualize decreased blood supply Venous duplex ultrasound ▪ Of lower extremities ▫ May reveal origin of pulmonary embolism ▫ Negative result does not exclude pulmonary embolism Ventilation-perfusion scan ▪ Normal scan rules out pulmonary embolism

LAB RESULTS

▪ D-dimer (high negative predictive value) ▫ Positive result does not prove pulmonary embolism ▫ Negative result rules out pulmonary embolism ▪ Arterial blood gas ▫ ↓ PaO2 → hypoxemia ▫ Hyperventilation → ↑ PaCO2 → ↑ pH → respiratory alkalosis ▫ A-a gradient elevated (indicated V/Q mismatch) ▪ Tests for causes of secondary pulmonary embolism ▫ Full blood count, clotting profile, erythrocyte sedimentation rate, renal function, liver function, electrolytes

OTHER DIAGNOSTICS ECG ▪ Excludes other causes of chest pain ▪ ECG features of pulmonary embolism (or any pulmonary hypertension) include ▫ Sinus tachycardia ▫ Right bundle branch block ▫ Right ventricular strain pattern: T wave inversion in right precordial (V1–V4), and inferior leads (II, III, aVF) ▫ Right atrial enlargement (P pulmonale) ▫ Right atrial dilatation → right axis deviation

▫ Dominant R wave in V1 ▫ S1Q3T3 pattern: Deep S wave in lead I, Q wave in lead III, negative wave in lead III ▪ Nonspecific ST segment, T wave changes ▪ Pulmonary embolism can be excluded if ▫ SaO2 exceeds 95% ▫ Age < 50 ▫ No unilateral leg swelling, hemoptysis, history of deep vein thrombosis/ pulmonary embolism, recent surgery/ trauma, hormone use (or estrogenbased medications), tachycardia

TREATMENT MEDICATIONS Anticoagulation ▪ Acute phase (days–weeks) ▫ Prevent further thromboembolic events ▫ Unfractionated heparin, low molecular weight heparin, fondaparinux ▪ Long-term (vitamin K antagonists) ▫ Warfarin, acenocoumarol, phenprocoumon Thrombolysis ▪ Used for massive pulmonary embolism causing hemodynamic instability ▪ Carries risk of secondary hemorrhage ▪ Thrombolytics used to break up clots ▫ Streptokinase, staphylokinase, urokinase, anistreplase ▫ Recombinant tissue plasminogen activators (alteplase, reteplase, tenecteplase)

SURGERY Pulmonary thromboendarterectomy ▪ Surgical removal of a chronic thromboembolism ▪ Rare Inferior vena cava filter ▪ Vascular filter inserted into inferior vena cava to prevent life-threatening pulmonary emboli ▪ Indications: anticoagulant therapy contraindicated, major embolic event

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despite anticoagulation

OTHER INTERVENTIONS Preventative measures ▪ Unfractionated heparin, low molecular weight heparin ▪ Factor Xa inhibitor ▪ Long-term low-dose aspirin ▪ Anti-thrombosis compression stockings/ intermittent pneumatic compression

Figure 129.7 A plant chest radiograph of the same individual, demonstrating the pulmonary infarct which is visible as a wedge shaped opacity in the lateral art of the right lung field.

Figure 129.8 The gross pathological appearance of a pulmonary embolus.

Figure 129.9 The ECG changes associated with a pulmonary embolism. There is a right bundle branch block, sinus tachycardia and T-wave inversions in leads V1-3 and III.

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Chapter 129 Pulmonary Vascular Disease

PULMONARY HYPERTENSION osms.it/pulmonary-hypertension PATHOLOGY & CAUSES ▪ Increased blood pressure in pulmonary circulation ▪ Mean pulmonary arterial pressure > 25mmHg (normal ~15mmHg) ▪ Pulmonary hypertension → excess fluid in pulmonary interstitium (pulmonary edema) → impaired gas exchange ▪ Pulmonary hypertension → strain on right heart → hypertrophy → right heart oxygen demand eventually exceeds supply → right-sided heart failure ▫ Right heart failure caused by lung disease → cor pulmonale → backup of blood in venous system → signs, symptoms of right heart failure ▪ Raised jugular venous pressure ▪ Fluid build up in liver → hepatomegaly ▪ Fluid build up in legs → leg edema ▪ Left ventricle receives less blood → compensation → pumps harder, faster (tachycardia)

TYPES Group I ▪ Pulmonary arterial hypertension, pulmonary veno-occlusive disease, pulmonary capillary hemangiomatosis ▪ Abnormal increase in pulmonary arteriolar resistance → increased strain on right heart (pumping fluid through narrower pipe) ▪ Damage to endothelial cells lining pulmonary arteries → release of endothelin-1 serotonin, thromboxane, produce less nitric oxide and prostacyclin → constriction of arterioles, hypertrophy of smooth muscle → pulmonary hypertension ▪ Over time affected vessels become stiffer, thicker (fibrosed) due to vasoconstriction, thrombosis, vascular remodeling → greater increase in blood pressure in lungs, more strain on right heart

▪ Idiopathic, inherited, drug/toxin associated causes connective tissue disease, HIV infection, portal hypertension congenital heart disease (shunting) Group II ▪ Pulmonary hypertension secondary to left heart disease ▪ Pulmonary hypertension due to left heart disease (heart failure, valvular dysfunction) → left heart fails to pump blood efficiently → backup of blood in pulmonary veins, capillary beds → increased pressure in pulmonary artery → pulmonary edema, pleural effusion ▪ Raised back pressure may trigger secondary vasoconstriction → increased right heart strain ▪ Common causes include ▫ Left ventricular systolic/diastolic dysfunction ▫ Valvular heart disease ▫ Congenital/acquired in/out-flow tract obstruction ▫ Congenital cardiomyopathy ▫ Pulmonary venous stenosis Group III ▪ Pulmonary hypertension due to lung disease/chronic hypoxia ▪ Low oxygen levels in alveoli pulmonary arteries constrict ▪ Chronic lung disease → region of diseased lung → inefficient/total lack of gas exchange → hypoxic vasoconstriction (pulmonary arterioles) → shunting of blood away from damaged areas ▪ Prolonged alveolar hypoxia across wide portion of pulmonary vascular bed → increase in pulmonary arterial pressure → thickening of pulmonary vessel walls → greater effort required from right heart → sustained pulmonary hypertension ▪ Causes include ▫ COPD

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▫ Interstitial lung disease ▫ Mixed restrictive/obstructive pattern disease ▫ Sleep-disordered breathing ▫ Alveolar hypoventilation ▫ Chronic exposure to high altitude Group IV ▪ Chronic arterial obstruction/ thromboembolic disease ▪ Recurrent blood clots in pulmonary vasculature ▪ Blockage/narrowing of pulmonary vessel with unresolved obstruction (e.g. clot) → increased pressure, shear stress (turbulence) in pulmonary circulation → vessel wall remodelling → sustained pulmonary hypertension ▪ Causes endothelium to release histamine, serotonin → constriction of pulmonary arterioles → rise in pulmonary blood pressure → chronic thromboembolic pulmonary hypertension ▪ Other causes of arterial obstruction ▫ Angiosarcoma, arteritis, congenital pulmonary artery stenosis, parasitic infection Group V ▪ Unclear/multifactor mechanisms ▪ Hematologic disease (e.g. hemolytic anemia) ▪ Systemic disease (e.g. sarcoidosis, vasculitis) ▪ Metabolic disorders (e.g. glycogen storage disease, thyroid disease) ▪ Other (e.g. microangiopathy, chronic kidney disease)

RISK FACTORS

▪ Family history, prior pulmonary embolic events, HIV/AIDS, sickle cells disease, cocaine use, COPD, sleep apnea, living at high altitude, mitral valve pathology

SIGNS & SYMPTOMS ▪ Dyspnea, syncope, fatigue, chest pain, poor effort tolerance, loss of appetite, lightheadedness, orthopnea (left-sided heart failure) ▪ Tachycardia, cyanosis, parasternal heave ▪ Signs of systemic congestion/right heart failure: ▫ Loud pulmonic component of second heart sound (P2) ▫ Jugular venous distension ▫ Ascites ▫ Hepatojugular reflux ▫ Lower limb edema

DIAGNOSIS DIAGNOSTIC IMAGING Chest X-ray ▪ Enlarged pulmonary arteries ▪ Lung fields may or may not be clear, dependent on underlying cause Echocardiogram ▪ Increased pressure in pulmonary arteries, right ventricles → dilated pulmonary artery ▪ Dilatation/hypertrophy of right atrium, right ventricle ▪ Large right ventricle → bulging septum Ventilation/perfusion scan ▪ Identity / exclude ventilation-perfusion mismatches

OTHER DIAGNOSTICS Right heart catheterisation (gold standard) ▪ Catheter into right heart → most accurate measure of pressures ECG ▪ Right heart strain pattern: T wave inversion in right precordial (V1–V4), and inferior leads (II, III, aVF) Spirometry ▪ Unidentified underlying cause

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Chapter 129 Pulmonary Vascular Disease

TREATMENT MEDICATIONS

▪ Pulmonary hypertension secondary to left ventricular failure → optimize left ventricular function ▫ Diuretics (cautiously—individuals may be preload dependent) ▫ Digoxin ▫ Anticoagulants ▪ Cardiogenic pulmonary arterial hypertension ▫ Relax smooth muscle (promote vasodilation), reduce vascular remodelling, improve exercise capacity

with prostanoids, phosphodiesterase inhibitors, endothelin antagonists ▪ Pulmonary arterial hypertension ▫ Endothelin receptor antagonists ▫ Prostanoids

SURGERY

▪ Lung transplant ▪ Repair/replace damaged valves to optimize left ventricular function

Figure 129.10 The gross pathological appearance of the pulmonary arteries in a case of pulmonary hypertension. The underlying pathological process is similar to atherosclerosis found elsewhere in the cardiovascular system.

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Figure 129.11 A CT scan of the chest in the axial plane demonstrating enlargement of the pulmonary trunk as a consequence of pulmonary hypertension.

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Figure 129.12 The histological appearance of a pulmonary artery in a case of pulmonary hypertension. There is marked thickening of both the intima and the media.

NOTES

NOTES

RESPIRATORY TUMORS GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Uncontrolled division of epithelial cells lining respiratory tract → formation of solid tumor ▪ Mutated cells become cancerous ▫ Resist inhibitory signals, evade immune surveillance ▪ Malignant tumors invade basement membrane ▫ Carcinoma in situ ▪ Metastasis ▫ Malignant tumors establish secondary tumors at distant site; lung cancer metastasizes quickly ▫ Common sites: mediastinum, hilar lymph nodes, lung pleura, breasts, liver, adrenal glands, brain, bones

TYPES Small-cell ▪ Small, immature, neuroendocrine cells; divide rapidly, spread quickly Non-small-cell (most common) ▪ Large cells; divide, spread slowly ▫ Adenocarcinoma (goblet cells) ▫ Squamous cell carcinoma (squamous cells) ▫ Large cell carcinoma ▫ Carcinoid tumors (mature neuroendocrine cells) Nonspecific classification ▪ Small-cell carcinoma with poorer prognosis

RISK FACTORS

▪ Age ▫ Malignancy more common in older individuals ▪ Smoking ▫ Direct, linear positive correlation between pack years, risk of lung cancer ▪ Asbestos exposure, radon exposure, ionizing radiation exposure ▪ Chronic obstructive pulmonary disease (COPD) ▪ Tuberculosis

MNEMONIC: ABCDE

Presentation of lung cancers Bronchial Airway disruption → pneumonia Blood: hemoptysis Cough Distribution: mestastasis whEEzing

SIGNS & SYMPTOMS ▪ Asymptomatic in early disease ▪ Nonspecific, wide overlap with other noncancerous lung conditions ▪ Constitutional symptoms: loss of appetite, weight loss, weakness ▪ If located in certain areas (e.g. upper lobe of lung) → compressive symptoms ▫ Nerve compression: hoarseness (recurrent laryngeal nerve), Horner’s syndrome (sympathetic chain), diaphragmatic paralysis (phrenic nerve) ▪ Paraneoplastic syndromes ▫ Digital clubbing, muscle weakness, syndrome of inappropriate antidiuretic

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hormone secretion (SIADH), ectopic adrenocorticotropic hormone (ACTH) secretion, ectopic parathyroid hormone (PTH)-like secretion, hypertrophic pulmonary osteoarthropathy, Eaton– Lambert syndrome ▫ Mostly small cell carcinoma (neuroendocrine cells secrete hormones with systemic effects)

LAB RESULTS

▪ Sputum sample ▫ Diagnosis of central (near to main bronchus) tumors, not peripheral tumors ▪ Fine needle aspiration ▫ Histopathologic diagnosis using cytology ▪ Endoscopic biopsy

TREATMENT

DIAGNOSIS

MEDICATIONS

DIAGNOSTIC IMAGING

▪ Simple analgesics, opioids (if severe) ▫ Pain management

Chest X-ray ▪ Coin lesion CT scan ▪ Asymmetrical, expanding nodule; used for staging; can demonstrate extent of metastasis (e.g. hilar lymph node involvement) PET ▪ Areas of higher glucose turnover ▪ Bronchoscope ▪ Diagnosis of central (near to main bronchus) tumors, not peripheral tumors

SURGERY

▪ Intraoperative frozen section if diagnosis of malignancy uncertain ▪ If malignancy confirmed, wedge resection performed for small tumors ▪ Lobectomy performed for larger tumors/ after wedge resection if margins positive

OTHER INTERVENTIONS

▪ Chemotherapy, immunotherapy, radiation therapy

MESOTHELIOMA osms.it/mesothelioma PATHOLOGY & CAUSES ▪ Cancer of mesothelium; most commonly lungs, chest wall pleural lining (composed of mesothelial cells); sometimes pericardium ▪ Commonly associated with asbestos exposure ▪ Asbestos fibers ▫ Mineral used as construction, insulation material ▫ Jagged in shape, very fine ▫ Increases risk of lung cancer, malignant mesothelioma

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▪ Asbestos fibers inhaled → phagocytic cells attempt to phagocytose fibers → unable to destroy fibers → apoptosis of phagocytic cells → release of tumor promoting factors → mesothelial cells of pleura inflamed → DNA damage → mesothelial cells divide uncontrollably → tumor formation ▪ Mesothelial plaques cover visceral, parietal pleura; extend around chest cavity ▪ Asbestos fibers can be found in stomach (via swallowing of saliva/mucus containing asbestos) ▪ Mesothelioma can theoretically affect any organ with mesothelial cells, most commonly found in thoracic cavity

Chapter 130 Respiratory Tumors

TYPES Malignant ▪ Prognosis is poor, unless caught early; extremely resistant to treatment; spread to multiple organs Benign ▪ Prognosis is excellent; surgery for isolated lesions usually curative

SIGNS & SYMPTOMS

TREATMENT MEDICATIONS ▪ Chemotherapy

SURGERY ▪ Excision

OTHER INTERVENTIONS ▪ Radiation

▪ Angina, dyspnea, recurrent pleural effusions, weight loss, cough ▪ If tumor invades blood vessel ▫ Blood-tinged sputum

DIAGNOSIS DIAGNOSTIC IMAGING Chest X-ray, CT scan ▪ Visualize mesothelioma lesions

LAB RESULTS Biopsy ▪ Video assisted thoracoscopic surgery (VATS) ▪ Tissue sample immunostained with antibody that reacts to calretinin ▫ Calretinin: calcium-binding protein that regulates calcium levels inside cells ▫ Distinguishes mesotheliomas from other tumors ▪ Cancerous cells have “fried egg” appearance

Figure 130.1 A CT scan of the chest in the coronal plane demonstrating a mesothelioma occupying the lower thoracic cavity.

Figure 130.2 Immunohistochemical staining with calretinin reveals the architecture of this pleural mesothelioma.

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Figure 130.3 The histological appearance of epithelioid mesothelioma. The malignant cells are cuboidal, have moderate amounts of cytoplasm and display conspicuous nucleoli. Figure 130.4 The gross pathology of a large mesothelioma of the thoracic cavity. The tumor completely encases the normal lung tissue (outlined).

NASOPHARYNGEAL CARCINOMA osms.it/nasopharyngeal-carcinoma PATHOLOGY & CAUSES ▪ Cancer of nasopharynx (upper throat, behind nose) ▪ Most common malignant tumor of nasopharynx ▪ Can be clinically silent for long periods, difficult to detect early ▪ Often metastasizes to cervical lymph nodes ▪ Associated with Epstein–Barr virus (EBV) ▪ Prognosis ▫ Five year survival rate, 60% (all types)

TYPES Keratinized squamous cell carcinoma ▪ Worst prognosis, least radiosensitive Nonkeratinized squamous cell carcinoma ▪ Best prognosis

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MNEMONIC: NASOPharyngeal

Types of Nasopharyngeal malignant cancers Nasopharyngeal Adenocarcinoma Squamous cell carcinoma Olfactory neuroblastoma Plasmacytoma Undifferentiated/basaloid carcinoma (lymphoepithelioma) ▪ Most radiosensitive

RISK FACTORS

▪ More common in individuals who are biologically male, < 55 years ▪ Family history ▪ Common in Asia, Africa (esp. children); in southern China, common in adults, rare in children

Chapter 130 Respiratory Tumors ▪ Diets high in nitrosamines (fermented foods), alcohol ▪ Smoking, certain chemical fumes, formaldehyde

COMPLICATIONS

▪ Radiation ▫ Death of healthy tissue, brain stem injury, blindness, xerostomia

SIGNS & SYMPTOMS ▪ Altered vision, recurrent ear infections, headache, tinnitus, nosebleeds, sore throat, facial paresthesia ▪ Lump in neck, epistaxis, nasal obstruction

DIAGNOSIS DIAGNOSTIC IMAGING

TREATMENT MEDICATIONS

▪ Monoclonal antibodies ▫ Synthetic antibodies, target epidermal growth factor receptors (EGFRs); adverse effects (Type III hypersensitivity infusion reaction, rash, fatigue, headache, fever, diarrhea)

SURGERY

▪ Surgical resection

OTHER INTERVENTIONS

▪ Intensity-modulated radiation therapy (standard) ▫ High-precision radiation, minimizes damage to surrounding tissues; better outcome, less adverse effects than conventional radiation therapy

CT scan, MRI, PET, X-ray, nasopharyngoscopy/nasal endoscopy ▪ Visualize carcinoma

LAB RESULTS Biopsy ▪ Squamous cell carcinoma/undifferentiated

OTHER DIAGNOSTICS ▪ Physical exam ▫ Neck swelling

Figure 130.5 An MRI scan of the head in the sagittal plane demonstrating a large nasopharyngeal carcinoma blocking the choanae and invading the skull base.

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NON-SMALL-CELL LUNG CARCINOMA osms.it/nsclc PATHOLOGY & CAUSES ▪ Lung cancers not of small-cell type ▪ Grow, spread more slowly

TYPES Squamous-cell carcinoma ▪ Centrally located, strongly associated with smoking Adenocarcinoma ▪ Develops peripherally in bronchiole/alveolar sac, no link to smoking Large-cell carcinomas ▪ Found throughout lungs; centrally, peripherally ▪ Diagnosis of exclusion; if criteria for adenocarcinoma/squamous-cell carcinoma not met Bronchial carcinoid tumor ▪ Low-grade malignancy of neuroendocrine cells ▪ Same cell of origin as small-cell carcinoma; malignant potential low

DIAGNOSIS LAB RESULTS Fine needle aspiration (lung) ▪ Cells demonstrate cardinal features of malignancy ▫ Variation in nuclear size, shape; irregularly distributed nuclear chromatin; large prominent nucleoli

TREATMENT SURGERY

▪ Contraindicated in cases of metastasis outside of chest ▪ Recurrence likely even after complete resection

OTHER INTERVENTIONS ▪ Radiation, chemotherapy

SIGNS & SYMPTOMS ▪ ▪ ▪ ▪ ▪ ▪

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Cough Hemoptysis Hoarseness Chest pain Weight loss Neurologic symptoms (brain metastasis is common)

Figure 130.6 A cytological preparation of a bronchial washing containing malignant squamous cells.

Chapter 130 Respiratory Tumors

Figure 130.8 The histological appearance of squamous cell carcinoma of the lung. The tumor cells have large amounts of eosinophilic cytoplasm, have irregular nuclear forms and are forming islets. The surrounding lung demonstrates a chronic inflammatory cell reaction.

Figure 130.7 The gross pathological appearance of squamous cell carcinoma of the lung. There is a large primary tumor in the upper lobe with intrapulmonary metastases in the lower lobe.

Figure 130.9 The histological appearance of adenocarcinoma of the lung. The tumor is forming slit like spaces called acini, which are lined by malignant cells.

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PANCOAST TUMOR osms.it/pancoast-tumor PATHOLOGY & CAUSES ▪ Pulmonary neoplasm located in lung apices ▪ Location enables them to impinge nerves, vessels ▪ Majority ▫ Non-small-cell lung tumors (adenocarcinoma/squamous cell carcinoma) ▪ Structures most vulnerable to compression/ invasion ▫ Cervical sympathetic nerves, brachial plexus, laryngeal nerves, superior vena cava (SVC)

MNEMONIC: Horner has a MAP of the Coast PanCoast → Horner’s syndrome, including: Miosis Anhidrosis Ptosis

SIGNS & SYMPTOMS ▪ Cough, angina, dyspnea, hemoptysis, wheezing ▪ Recurrent pneumonia ▪ Constitutional symptoms ▫ Loss of appetite, weight loss, weakness Local inflammation and compression ▪ Tumor causes local inflammation, invasion of nearby nerves/vessels, direct compression ▪ Pain, upper extremity weakness due to brachial plexus impingement ▪ Compression ▫ Cervical sympathetic nerves: Ipsilateral Horner syndrome (ptosis, miosis, anhidrosis)

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▫ Brachial plexus: ipsilateral paresthesia ▫ Laryngeal nerves: voice hoarseness ▫ SVC: SVC syndrome (facial flushing, edema, dyspnea)

DIAGNOSIS DIAGNOSTIC IMAGING CT scan/chest X-ray ▪ Tumor in lung apex

LAB RESULTS Biopsy ▪ Confirm tumor type

OTHER DIAGNOSTICS ▪ Physical examination

TREATMENT ▪ Impingement of important nerve /vessel; shrink tumor before resection

MEDICATIONS

▪ Chemotherapy ▫ Late stages: chemotherapy alone; prophylactic radiation to decrease chance of brain metastases

SURGERY

▪ Surgical resection

OTHER INTERVENTIONS

▪ Radiation ▫ Early stages: used with chemotherapy

Chapter 130 Respiratory Tumors

Figure 130.10 The gross pathological appearance of squamous cell carcinoma of the lung. There is a large primary tumor in the upper lobe with intrapulmonary metastases in the lower lobe.

Figure 130.11 A CT scan of the chest in the coronal plane demonstrating a pancoast tumor at the apex of the right lung.

SMALL-CELL LUNG CANCER osms.it/sclc PATHOLOGY & CAUSES ▪ Uncontrolled proliferation of small, immature, neuroendocrine cells ▪ Strongly associated with smoking ▪ Usually develops centrally in lung, near main bronchus ▪ Grows fastest, rapidly metastasizes to other organs; intrapulmonary metastasis also common ▪ Secretes hormones → paraneoplastic syndromes ▫ Cushing’s syndrome: excretion of cortisol from adrenal glands → elevated blood glucose, high blood pressure ▫ SIADH: release of antidiuretic hormone (ADH) from tumor → water retention → high blood pressure, edema, concentrated urine ▫ Eaton–Lambert myasthenic syndrome (Type II hypersensitivity): small-cell

carcinoma stimulates production of autoantibodies → destroy neurons

TYPES Limited ▪ Contained within one lung, supraclavicular nodes (no extension to cervical/axillary nodes) ▪ Prognosis ▫ Five year survival, 10% (median survival 15–20 months) Extensive ▪ Spreads beyond one lung, supraclavicular nodes ▪ Prognosis ▫ Five year survival, 1% (median survival 8–13 months)

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SIGNS & SYMPTOMS ▪ ▪ ▪ ▪

Dyspnea Wheezing Cough Hemoptysis

DIAGNOSIS LAB RESULTS

▪ Histology ▫ Large cells with limited cytoplasm, nuclear moulding

Figure 130.12 The histological appearance of small cell carcinoma. The cells have minimal cytoplasm and moulded nuclei.

TREATMENT SURGERY

▪ Usually not curative

OTHER INTERVENTIONS

▪ Limited ▫ Combination of chemotherapy, radiation therapy ▪ Extensive ▫ Chemotherapy, prophylactic radiation

Figure 130.13 A PET-CT scan in the coronal plane demonstrating high-uptake in the left upper lobe, corresponding with a small cell carcinoma of the lung. The left ventricle also demonstrates high uptake, but this is normal.

Figure 130.14 A cytology specimen demonstrating the characteristic features of small cell carcinoma; nuclear moulding, salt and pepper chromatin and minimal cytoplasm.

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Chapter 130 Respiratory Tumors

SUPERIOR VENA CAVA SYNDROME osms.it/svc-syndrome PATHOLOGY & CAUSES

SIGNS & SYMPTOMS

▪ Constellation of signs, symptoms when blood flow through SVC obstructed ▪ Obstruction → increase in venous pressure behind obstruction → blood rerouted through collateral vessels → blood drains into inferior vena cava, right atrium → dilation of collateral veins → venous pressure decreases with full dilation of collateral veins ▪ Collateral vessels ▫ Azygos vein, internal mammary vein, lateral thoracic vein, esophageal venous systems

▪ Edema of face, neck; inspiratory stridor; voice changes; flushed appearance (backup of blood, venous stasis); dilated neck, chest veins; dyspnea (blockage of SVC → decreased return of blood to heart → less blood pumped to lungs); hoarseness of voice (compression of laryngeal nerve/ muscles of larynx from excess fluid)

CAUSES

▪ Obstruction (external/internal) ▫ Tumor invasion, mass effect (inflammation, swelling) ▫ Lung cancer most common (e.g. Pancoast tumor), tumor of lymph nodes (e.g. lymphomas) ▫ Blood clot (develops in individuals with long-term device; e.g. indwelling central venous catheter)

COMPLICATIONS

▪ Edema, dysphagia, cerebral ischemia ▪ Severe cerebral edema → compression of blood vessels in brain → cerebral ischemia

DIAGNOSIS DIAGNOSTIC IMAGING Chest X-ray/CT scan/venous angiography ▪ Visualize tumors, collateral vessel dilation, obstruction

LAB RESULTS Biopsy ▪ Evaluate tumor; determine type, staging

TREATMENT MEDICATIONS

▪ Steroids ▫ Reduce swelling around tumor ▪ Anticoagulants ▫ Treat blood clot

OTHER INTERVENTIONS

▪ Combination of surgery, chemotherapy, radiation therapy ▪ Keep head above level of heart to help drain fluid from head, neck to heart

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NOTES

NOTES

RESTRICTIVE LUNG DISEASE GENERALLY, WHAT IS IT? PATHOLOGY & CAUSES

DIAGNOSIS

▪ Inflammatory disorders of lung parenchyma ▪ Restricts lung expansion → decreases lung volume, ventilation, gas exchange → difficulty breathing

DIAGNOSTIC IMAGING

RISK FACTORS

▪ Lung biopsy

▪ Exposure to occupational, biological dusts

SIGNS & SYMPTOMS ▪ Dyspnea, cough

High resolution chest CT scan

LAB RESULTS OTHER INTERVENTIONS

▪ Spirometry ▫ ↓ Vital capacity ▫ ↓ Total lung volume ▫ ↓ Forced expiratory volume in one second (FEV1) ▫ ↓ Diffusion capacity of carbon monoxide ▪ Bronchopulmonary lavage

TREATMENT SURGERY

▪ Lung transplant (definitive)

Figure 131.1 Illustration depicting the various criteria examined during a spirometric test.

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IDIOPATHIC PULMONARY FIBROSIS osms.it/idiopathic-pulmonary-fibrosis PATHOLOGY & CAUSES ▪ Abnormal pulmonary healing process: pulmonary insult heals → excess deposits of collagen, fibrotic tissue → progressive scarring of lung tissue → loss of lung compliance → dyspnea worsens, lung function declines → hypoxemia ▪ Affects pulmonary interstitium: tissue between alveoli, airspaces, peripheral airways, vessels ▪ Chronic, irreversible, ultimately fatal disease

CAUSES

▪ Overproliferation of type 2 pneumocytes → excessive myofibroblast population → excessive collagen production → collagen accumulates → interstitial layer thickens between alveoli, capillary → poor ventilation/gas exchange, lung parenchyma stiffens → restricted lung expansion (restrictive lung disease)

RISK FACTORS

▪ Ages 50–70, history of smoking, more common in individuals who are biologically male, exposure to occupational dusts (e.g. metal, wood, coal, silica, stone), biologic dusts (e.g. hay, molds, spores, agricultural products, livestock), gastroesophageal reflux disease, genetic

SIGNS & SYMPTOMS ▪ Worsens over time, coughing (dry nonproductive cough, worse on exertion), dyspnea (progressive exertional), cyanosis, digital clubbing, dry inspiratory bibasilar crackles on auscultation, significant respiratory failure with increasing tissue loss

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DIAGNOSIS ▪ Exclude known causes of interstitial lung disease (e.g. hypersensitivity pneumonitis, pulmonary Langerhans cell histiocytosis, asbestosis, collagen vascular disease)

DIAGNOSTIC IMAGING High-resolution chest CT scan ▪ Usual interstitial pneumonia (UIP) pattern ▫ Honeycombing with well-defined walls ▫ Reticular opacities with/without traction bronchiectasis (ground glass opacities, honeycombing, cystic spaces) ▫ Subpleural, basal lung fields ▫ Absence of features inconsistent with UIP (mid to upper predominance; peribronchovascular predominance; extensive ground glass appearance; profuse micronodules; discrete cysts away from areas of honeycombing; diffuse air-trapping) ▫ Bronchopulmonary consolidation ▪ Thickening of interstitial walls ▫ Fibrotic changes ▫ Bases, periphery

LAB RESULTS Biopsy ▪ Taken from three different areas, large enough to show underlying lung architecture (bronchoscopic biopsies insufficient; thoracotomy/thoracoscopy prefered) ▪ Histology ▫ Interstitial fibrosis in patchwork pattern; interstitial scarring; honeycomb changes; fibroblastic foci (dense collections of myofibroblasts, scar tissue)

Chapter 131 Restrictive Lung Disease

OTHER INTERVENTIONS Broncheolar lavage ▪ Cytology ▫ Exclude alternative diagnoses (e.g. malignancy, infection, eosinophilic pneumonia, histiocytosis X, alveolar proteinosis) ▪ Lymphocytes > 30% ▫ Exclude idiopathic pulmonary fibrosis

TREATMENT MEDICATIONS

▪ Antifibrotic medication ▫ Slows progression ▪ Seasonal influenza vaccine

SURGERY

▪ Lung transplant (definitive)

Spirometry ▪ Restrictive pattern decreased ▫ Total lung capacity ▫ Forced vital capacity (FVC) ▫ FEV1 ▪ Decreased diffusing capacity of lungs for carbon monoxide

Figure 131.2 The clinical appearance of digital clubbing as seen in a case of idiopathic pulmonary fibrosis.

Figure 131.3 A CT scan of the chest in the axial plane demonstrating marked honeycombing of the lung and a collection of subpleural cysts in an individual with idiopathic pulmonary fibrosis.

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SARCOIDOSIS osms.it/sarcoidosis PATHOLOGY & CAUSES ▪ Disease involving formation of noncaseating granulomata (clumps of inflammatory cells) ▪ Can affect any organ system ▫ Accumulation of monocytes, epithelioid macrophages, activated T-lymphocytes ▫ Macrophages may aggregate to form multinucleated giant cells (AKA Langhans giant cells) ▫ Increased production of inflammatory mediators (Th-1 mediated) ▫ Cytokines released from activated immune cells → systemic effects

CAUSES

▪ Unknown; may be triggered by immune reaction in genetically predisposed individuals

RISK FACTORS

▪ Genetic, previous episode of sarcoidosis, biological females, 20–50 age group

COMPLICATIONS Paradoxical effect on immune reactivity ▪ Increased macrophage and CD4 helper T-cell activation → accelerated inflammation ▪ But antigen challenges, e.g. tuberculin skin test are suppressed ▪ This paradoxical hyper-/hypo-activity is immunological anergy → increased risk of infections, cancer Pulmonary pathology ▪ > 90% of affected individuals ▪ Bilateral hilar lymphadenopathy (up to 90% of affected individuals) ▪ Predominantly upper lobe parenchymal infiltration

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▪ Airway involvement → airway hyperresponsiveness (increased sensitivity to inhaled triggers) ▪ Pulmonary hypertension → cor pulmonale Ocular pathology ▪ Up to 25% ▪ Significantly more common in Asian people of Japanese descent (>70%) ▪ Anterior uveitis ▪ Uveoparotitis (inflammation of uvea, parotid gland) ▪ Retinitis Cardiac pathology ▪ 5% symptomatic, autopsy reports 25–70% subclinical involvement ▪ Significantly more common in Asian people of Japanese descent ▪ Conduction defects ▫ Asymptomatic conduction abnormalities ▫ Fatal ventricular arrhythmias ▫ Complete heart block ▫ Sudden cardiac death ▪ Cardiac fibrosis, interstitial fluid accumulation, heart failure, valvular dysfunction, pericardial disease Nervous system pathology ▪ ~5% ▪ AKA neurosarcoidosis ▪ Variable presentation ▫ Cranial nerves most commonly affected ▫ Neuroendocrine changes ▫ Chronic meningitis Endocrine/exocrine pathology ▪ Sarcoidosis of anterior pituitary ▫ Deficiency of adrenocorticotropic hormone, thyroid-stimulating hormone, follicle-stimulating hormone, luteinizing hormone, insulin-like growth factor 1 ▪ Hypothalamic dysfunction ▫ Hypersecretion of prolactin

Chapter 131 Restrictive Lung Disease ▪ Increase in 1,25-dihydroxyvitamin D (active form of vitamin D) ▫ Hydroxylation usually occurs in kidney; in sarcoidosis it may occur in sarcoid granulomata due to activated macrophages → hypercalcemia → hypercalciuria Hepatic pathology ▪ Liver granulomata very common (70%) ▪ Only 20–30% have detectable aberrant liver function ▪ Liver granlomata → cholestatic pattern → raised alkaline phosphatase, mildly elevated bilirubin, aminotransferases Nephrological pathology ▪ < 5% ▪ Can cause nephritis, but renal injury from hypercalcemia more common ▪ Nephrocalcinosis, nephrolithiasis

SIGNS & SYMPTOMS ▪ Varies by organ. May be asymptomatic. General ▪ Peripheral lymphadenopathy, fatigue (not relieved by sleep), weight loss, arthralgia, dry eyes Lower respiratory manifestations ▪ Wheezing, cough, dyspnea, chest pain, hemoptysis, crackles Upper respiratory sarcoidosis (uncommon) ▪ Laryngeal sarcoid: involves supraglottis, occasionally subglottis ▫ Subglottis: dysphagia, dyspnea, cough, hoarseness ▪ Nasal and sinus sarcoidosis: nasal obstruction, nasal crusting, anosmia, epistaxis, nasal polyposis

Gynecological/Urological ▪ Uncommonly epididymis, tesicles, prostate, ovaries, fallopian tubes, uterus or vulva may be affected ▪ Biological males → infertility Hematological ▪ Sequestration of lymphocytes into areas of inflammation → lymphopenia ▪ Anemia ▪ Leukopenia ▫ May reflect bone marrow involvement or redistribution of T-cells to disease sites ▪ Monocytosis ▪ Polyclonal hypergammaglobulinemia Rheumatological ▪ 10% ▪ Acute polyarthritis ▪ Enthesitis ▫ Inflammation at sites where tendons or ligaments insert into bone ▪ Chronic sarcoid arthritis ▫ Diffuse organ involvement ▫ Periosteal bone resorption

Figure 131.4 The clinical appearance of cutaneous sarcoidosis. Skin ▪ Erythema nodosum ▫ Inflammation of subcutaneous adipose tissue → painful nodules ▫ Affects anterior surface of lower extremities ▪ Plaques ▫ Often seen in chronic forms ▫ Affects shoulders arms, back and buttocks ▪ Maculopapular eruptions ▫ Common manifestation

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▫ Affects alae, nares, lips, eyelids, forehead, nape of neck, sites of previous trauma ▪ Subcutaneous nodules ▫ Affects face, trunk, extensor surfaces ▪ Lupus pernio ▫ Violaceous or erythematous indurated papules, plaques/nodules ▫ Primarily affects nose, cheeks, chin, ears Ocular involvement ▪ Photophobia, blurred vision ▪ Increased tearing or dry eyes ▪ Loss of visual acuity → blindness ▪ Heerfordt syndrome: anterior uveitis, parotitis, cranial nerve VII palsy, fever Cardiac involvement ▪ Palpitations, dizziness, chest pain Nervous system ▪ Hearing abnormalities, headache, altered consciousness level, changes in peripheral sensation Endocrine & exocrine changes ▪ General: changes in body temperature, mood alterations, swelling of salivary/ parotid glands ▪ Biological females: amenorrhea, galactorrhea, nonpuerperal mastitis, changes in menstrual cycle ▪ Biological males: hypogonadism ▪ Other clinical manifestations of hypopituitarism, e.g. diabetes insipidus, hypothyroidism, adrenal insufficiency Hepatic ▪ Hepatomegaly Nephrological ▪ Reduced creatinine clearance ▪ Proteinuria ▪ Signs and symptoms of renal calculi

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Hematological ▪ Signs and symptoms of anemia, immunodeficiency ▪ Splenomegaly ▪ Immunological abnormalities ▫ Allergies to test antigens, e.g. candida or purified protein derivative Rheumatological ▪ Acute polyarthritis ▪ Symmetric involvement of ankle joints ▪ Usually periarthritis not true arthritis ▪ May be present in isolation or as part of Löfgren syndrome ▪ Löfgren syndrome ▫ Acute form of sarcoidosis ▫ 95% specificity for sarcoidosis ▫ Predominantly occurs in biological females of Scandinavian, Irish, and Puerto Rican descent ▫ Bilaterally enlarged hilar lymph nodes ▫ Erythema nodosum (tender red nodules, typically pretibial surface) ▫ Arthritis most commonly occurring in ankles > knees > wrists > elbows > metacarpophalangeal joints; usually not true arthritis, but periarthritis affecting soft tissue around joints ▫ Enthesitis (inflammation sites where tendons/ligaments insert into the bone) ▪ Chronic sarcoid arthritis ▫ Diffuse organ involvement ▫ Ankles, knees, wrists, elbows, hands may be affected (polyarticular pattern) ▫ Dactylitis (inflammation of entire digit) ▫ Pain, stiffness

Chapter 131 Restrictive Lung Disease MNEMONIC: SARCOIDOSIS

Features of Sarcoidosis Schaumann calcifications Asteroid bodies/ACE increase/ Anergy Respiratory complications/ Renal calculi/Restrictive lung disease/Restrictive cardiomyopathy Calcium increase in serum and urine/CD4 helper cells Ocular lesions Immune mediated noncaseating granulomas/Ig increase Diabetes insipidus/D vit. increase/Dyspnea Osteopathy Skin: subcutaneous nodules, erythema nodosum Interstitial lung fibrosis/IL-1 Seventh CN palsy

▫ Noncaseating granulomata ▫ Tuberculin skin test (tuberculosis, sarcoidosis share many clinical features) ▫ Exclusion of other granulomatous causes

DIAGNOSTIC IMAGING X-ray, CT scan ▪ Staged according to extent of lung involvement (Siltzbach classification system) ▫ Stage 0: normal lung at presentation ▫ Stage I: bilateral hilar lymphadenopathy only (60% resolution within 1–2 years) ▫ Stage II: bilateral hilar lymphadenopathy with pulmonary infiltrates (46%) ▫ Stage III: pulmonary infiltrates without bilateral hilar lymphadenopathy (12%) ▫ Stage IV: pulmonary fibrosis ▪ CT scan-/ultrasound-guided biopsy/fineneedle aspiration of mediastinal lymph nodes ▫ Flow cytometry ▫ Microscopy and staining ▫ Culture PET scan ▪ Lamba sign → gallium uptake in paratracheal, hilar lymph nodes ▪ Panda sign → lacrimal, parotid, submandibular glands with normal nasopharyngeal uptake ▪ Combination of two specific for sarcoidosis

LAB RESULTS

Figure 131.5 A giant cell containing an asteroid body in a case of pulmonary sarcoidosis.

▪ High blood calcium (normal parathyroid level) ▪ Elevated angiotensin converting enzyme (level correlates with total granuloma load) ▫ Can be used for monitoring treatment and disease progression

OTHER DIAGNOSTICS

DIAGNOSIS ▪ Diagnosis of exclusion ▪ Usually dependent on biopsy of organ involved

Lung function testing ▪ Determine level of function ▪ Monitor course of disease ▪ Typically reveals restrictive pattern (reduced vital/total lung capacity)

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▪ Endobronchial sarcoid may lead to impairment of airflow, obstructive pattern Diffusion of carbon monoxide (DLCO) ▪ Most sensitive test for interstitial lung disease Bronchoscopy ▪ Biopsy ▪ Bronchoalveolar lavage ▫ CD4/CD8 T cell ratio in bronchoalveolar lavage is raised > 3.5 (can be normal/ low) Ophthalmological exam ECG

symptoms ▫ Topical/local therapy preferred for organ-confined disease

MEDICATIONS Anti-inflammatory drugs ▪ NSAIDS ▫ Up to 75% of individuals may achieve sufficient symptomatic control on these alone ▪ Corticosteroids ▫ If long course required, consider steroidsparing agents Antimetabolites ▪ Methorexatem, chloroquine, azathioprine

TREATMENT ▪ May resolve spontaneously over years ▪ Dermatological involvement typically resolves without treatment ▪ Acute disease ▫ No therapy is a viable option for mild

Immunosuppressants ▪ Cyclophosphamide, cladribine, chlorambucil, cyclosporine ▪ Anti-tumor necrosis factor treatment ▫ These agents have also been reported to cause sarcoidosis-like illness

Figure 131.6 The histological appearance of pulmonary sarcoidosis. There are large numbers of giant cells visible.

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NOTES

NOTES

SLEEP–RELATED RESPIRATORY DISEASE

GENERALLY, WHAT IS IT? PATHOLOGY & CAUSES ▪ Impaired capacity to breathe

SIGNS & SYMPTOMS ▪ Apneic episodes (variable duration); fatigue; hypoxemia; hypercapnia

DIAGNOSIS OTHER DIAGNOSTICS

snoring, airflow, end tidal CO2, oxygen saturation, cardiac rhythm, body positioning ▫ Electroencephalography: sleep pattern ▫ Electrooculography: REM ▫ Electromyography: neck muscle tonicity ▫ Electrocardiography: heart rhythm ▫ Video monitoring: body positioning

TREATMENT OTHER INTERVENTIONS

▪ Supportive, lifestyle modification

Polysomnography ▪ Measure sleep patterns, rapid eye movements (REM), tonicity of neck muscles,

APNEA OF PREMATURITY osms.it/apnea-of-prematurity PATHOLOGY & CAUSES ▪ Most common cause of apnea in preterm neonates ▪ Developmental disorder associated with decreased responsiveness to carbon dioxide ▪ Respiratory pauses of ≥ 20 seconds/shorter pause with bradycardia (< 100/minute), cyanosis, pallor, oxygen desaturation in neonates < 37 weeks gestational age (GA)

CAUSES

▪ Immaturity of fetal brain areas responsible for breathing ▪ Incidence increases with degree of prematurity ▫ Most neonates < 28 weeks GA ▫ > ½ neonates 28–36 weeks GA

SIGNS & SYMPTOMS ▪ Apneic episodes ≥ 20 seconds in first 72 hours post-birth ▫ Frequency increases 14–21 days postbirth

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▪ Bradycardia ▪ Hypoxemia

TREATMENT DIAGNOSIS

OTHER DIAGNOSTICS

▪ Monitor premature neonates ▫ Cardiorespiratory monitors, pulse oximetry ▪ Exclude other causes for apnea ▫ Metabolic disorders, neurological disorders, infections, antepartum drugs (e.g. opiates)

▪ Resolves spontaneously after 37 weeks postmenstrual age ▫ Postmenstrual age = postnatal age + GA age

MEDICATIONS

▪ Methylxanthines ▫ Improve sensitivity to carbon dioxide, increase ventilations/minute, decrease periodic breathing events

OTHER INTERVENTIONS ▪ Nasal CPAP

SLEEP APNEA osms.it/sleep-apnea PATHOLOGY & CAUSES ▪ Irregular breathing patterns, shallow breathing and snoring during sleep. ▪ Apnea: momentary: pause in breathing ▪ Can last several seconds to several minutes ▪ More than five episodes an hour must occur ▪ Hypopnea: abnormally shallow breathing event

TYPES Central sleep apnea ▪ Sudden failure of brain respiratory center’s generation of spontaneous breathing efforts ▪ Damage to brain respiratory centers→ ↑ respiratory drive → hyperventilation → CO2 (hypocapnia) → apnea → ↑ ↑ CO2(hypercapnia) → ↑ respiratory drive → hyperventilation ▪ Associated with Cheyne–Stokes respiration Obstructive sleep apnea ▪ Intermittent airway obstruction → 20–30

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second apnea → individual wakes from sleep ▪ Most common form of sleep apnea; peripheral problem; obstruction at oropharynx

CAUSES Obstructive sleep apnea ▪ Obesity (most common) ▪ Hypertrophic adenoid glands/palatine tonsils ▪ Micrognathia (small chin, AKA underbite) ▪ Sedatives (excessive muscle relaxation— alcohol, sleeping pills) ▪ Allergies ▪ Hypothyroidism (obesity, less muscle tone)

RISK FACTORS

▪ More common in individuals who are biologically male ▪ Incidence increases with age

Chapter 132 Sleep-Related Respiratory Disease

COMPLICATIONS Obstructive sleep apnea ▪ Systemic hypertension ▪ Diabetes ▪ Anginal chest pain, arrhythmias, heart failure ▪ Pulmonary hypertension, cor pulmonale, respiratory failure

SIGNS & SYMPTOMS ▪ Sleep deprivation, excessive daytime fatigue ▪ Headache, difficulty concentrating ▪ Morning headaches Central sleep apnea ▪ Nocturia ▪ Stress-induced insomnia ▪ Nocturnal anginal chest pain Obstructive sleep apnea ▪ Loud snoring ▪ Hypopnea ▪ Repeated arousals from sleep ▪ Decreased libido

DIAGNOSIS OTHER DIAGNOSTICS ▪ Polysomnography

TREATMENT MEDICATIONS

▪ Central sleep apnea: respiratory stimulants (acetazolamide, theophylline)

SURGERY

▪ Obstructive sleep apnea: micrognathia, hypertrophic adenoids/tonsils

OTHER INTERVENTIONS

▪ Continuous positive airway pressure (CPAP) ▪ Central sleep apnea: supplemental oxygen during sleep ▪ Obstructive sleep apnea: custom mouthpieces, weight loss

Figure 132.1 A CT scan of the head and neck in the sagittal plane. The soft palate is elongated, thickened and abutts the posterior pharynx, leading to obstructive sleep apnea.

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NOTES

NOTES

UPPER RESPIRATORY TRACT GENERALLY, WHAT IS IT? DIAGNOSIS

PATHOLOGY & CAUSES ▪ Upper-airway infection (e.g. nasal cavity, pharynx, larynx) with pathogenic microbes

RISK FACTORS

▪ Compromised immunity; genetic, congenital malformations; concomitant infection

LAB RESULTS

▪ Cultures, complete blood count (CBC) ▫ Bacterial involvement

OTHER DIAGNOSTICS

▪ Clinical presentation, physical exam

COMPLICATIONS

TREATMENT

▪ Airway obstruction, infection spread, sepsis

SIGNS & SYMPTOMS ▪ Stridor; fever (if bacterial infection); discharge; difficulty swallowing

MEDICATIONS ▪ Antimicrobials

SURGERY

▪ Surgical interventions

OTHER INTERVENTIONS

▪ Respiratory support, intubation (if severe respiratory obstruction)

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Chapter 133 Upper Respiratory Tract

BACTERIAL EPIGLOTTITIS osms.it/bacterial-epiglottitis PATHOLOGY & CAUSES ▪ Inflammation of epiglottis, nearby supraglottic structures ▪ Fluid, inflammatory-cell accumulation → rapid, progressive swelling of epiglottis, adjacent structures (supraglottic larynx) → airway narrows, ball-valve curling → airway obstruction

CAUSES

▪ Bacteria from posterior nasopharynx, Haemophilus influenzae (most common in children), Streptococcus pneumoniae, Staphylococcus aureus

RISK FACTORS

▪ Unimmunized status ▪ Mucosal trauma ▫ E.g. burns, caustic substance/foreign body ingestion ▪ Most common in children 6–12 years old ▪ Comorbidities (adults) ▫ E.g. diabetes mellitus, substance abuse, BMI > 25

COMPLICATIONS ▪ ▪ ▪ ▪

Airway obstruction Oropharyngeal secretion aspiration Cardiopulmonary arrest High mortality rate

anterior neck tenderness, anxiety

DIAGNOSIS DIAGNOSTIC IMAGING Laryngoscopy ▪ Swollen, red epiglottis X-ray ▪ Shadow of enlarged epiglottis (“thumb” sign); ballooning of hypopharynx

LAB RESULTS

▪ CBC: ↑ white blood cells (WBCs) ▪ ↑ C-reactive protein (CRP), positive throat culture

TREATMENT MEDICATIONS

▪ Empiric antimicrobial therapy ▫ E.g. third generation cephalosporin for Haemophilus influenzae colonization

OTHER INTERVENTIONS

▪ Airway management with humidified supplemental oxygen

Prevention ▪ Haemophilus Influenzae Type b (Hib) vaccine

SIGNS & SYMPTOMS ▪ Children: abrupt “3Ds” onset: dysphagia, drooling, distress ▪ Respiratory: stridor, retractions, tachypnea, cyanosis ▪ Behavioral: individual refuses to lie down; assumes tripod posture ▪ Voice: aphonia, muffled ▪ Other: sore throat, fever, odynophagia,

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LARYNGITIS osms.it/laryngitis PATHOLOGY & CAUSES ▪ Inflammation of larynx ▫ Acute: < three weeks ▫ Chronic: > three weeks

CAUSES Acute ▪ Viral ▫ Rhinovirus, influenza virus, parainfluenza, adenovirus ▪ Bacterial ▫ Moraxella catarrhalis, H. influenzae, S. pneumoniae ▪ Fungal ▫ Candida in immunosuppressed ▪ Trauma, nerve damage Chronic ▪ Acid reflux, smoke exposure, allergies, rheumatoid arthritis, autoimmune disease

SIGNS & SYMPTOMS ▪ Flu-like ▫ Fever, cough, malaise, enlarged lymph nodes ▪ Stridor, hoarseness, pain, odynophagia, lump in throat

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DIAGNOSIS DIAGNOSTIC IMAGING Laryngoscopy ▪ Swollen, red vocal folds; biopsy

LAB RESULTS ▪ Blood culture

TREATMENT MEDICATIONS

▪ Simple analgesics ▪ Non-steroidal anti-inflammatory drugs (NSAIDs) ▪ If bacterial infection, antibiotics

OTHER INTERVENTIONS ▪ Voice rest

Chapter 133 Upper Respiratory Tract

NASAL POLYPS osms.it/nasal-polyps PATHOLOGY & CAUSES ▪ Overgrowths of epithelial tissue lining nasal cavity, paranasal sinuses ▪ Most commonly formed in maxillary/ ethmoid sinus ▪ Results in airflow obstruction, mucus drainage blockage

DIAGNOSIS DIAGNOSTIC IMAGING Endoscopy ▪ Direct visualization of nasal polyp CT scan ▪ Hyperdense outpouching in nasal cavity

CAUSES

▪ Unknown; associated with long-term inflammatory sinus conditions ▫ Seasonal allergies, frequent asthma exacerbations, chronic sinusitis, aspirin sensitivity

RISK FACTORS

▪ Cystic fibrosis, primary ciliary dyskinesia

COMPLICATIONS

▪ Mucus drainage obstruction; sinusitis → recurrent infections

TREATMENT MEDICATIONS Topical steroids ▪ Nasal spray to shrink polyp; ↓ inflammation, swelling Nasal saline lavage ▪ Underlying allergy treatment

SURGERY

▪ Endoscopic sinus surgery if unresponsive to steroids

SIGNS & SYMPTOMS ▪ May be asymptomatic ▪ Bacterial infection ▫ Blocked mucus drainage ▫ Fever, headache ▪ Obstructed air flow ▫ ↓ sense of smell, snorting, sleep apnea, cyanosis (in infants)

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Figure 133.1 The histological appearance of a nasal polyp. There is loose, myxoid stroma lined by respiratory epithelium. Figure 133.2 A trans-nasal view of a polyp in the posterior nasal passage.

RETROPHARYNGEAL & PERITONSILLAR ABSCESS osms.it/rp-and-pt-abscess PATHOLOGY & CAUSES ▪ Abscesses of the upper respiratory tract

TYPES Retropharyngeal abscess ▪ Abscess formation in retropharyngeal space ▫ Between buccopharyngeal fascia, alar fascia ▪ Bacteria of nasopharynx enter weakened mucosa → white blood cells (WBCs) follow, create pus → mass grows, pushes into airway Peritonsillar abscess ▪ Pus in potential space between pharyngeal muscles, palatine tonsils

CAUSES Retropharyngeal abscess ▪ Bacterial ▫ S. aureus, group A beta-hemolytic bacteria, H. parainfluenzae ▪ Trauma, upper respiratory tract infections Peritonsillar abscess ▪ Streptococcus pyogenes (most common) → acute tonsillitis ▪ Staphylococcus, Haemophilus, anaerobes of mouth flora (less common)

COMPLICATIONS Retropharyngeal abscess ▪ Spread beyond retropharyngeal space, mediastinitis, pericarditis; pharyngitis, airway obstruction; sepsis Peritonsillar abscess ▪ Retropharyngeal abscess, cellulitis of head and neck, sepsis

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Chapter 133 Upper Respiratory Tract

SIGNS & SYMPTOMS ▪ Fever, lethargy, swelling, sore throat Retropharyngeal abscess ▪ Neck pain/stiffness, pharyngeal obstruction, difficulty swallowing, dyspnea, cough, stridor Peritonsillar abscess ▪ Asymmetric tonsillar swelling with uvular displacement; lymph node enlargement ▪ Muffled voice, trismus, sleep disturbance (difficult breathing), snoring, halitosis

DIAGNOSIS DIAGNOSTIC IMAGING Contrast CT scan ▪ Tissue swelling

Figure 133.3 Clinical appearance of a right sided peritonsillar abscess which shows swelling of the palatopharyngeal arch.

Ultrasound ▪ Differentiate Peritonsillar abscess from Cellulitis

LAB RESULTS

▪ Systemic spread in CBC, throat culture, blood culture

OTHER DIAGNOSTICS Clinical presentation ▪ Swollen pharyngeal space tissues ▪ Redness, asymmetry

TREATMENT MEDICATIONS ▪ IV antibiotics

Figure 133.4 A CT scan of the head in the axial plane demonstrating a peritonsillar abscess.

SURGERY

▪ Surgical drainage of abscess ▪ Peritonsillar abscess ▫ If airway obstruction, immediate tonsillectomy/incision, drainage

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SINUSITIS osms.it/sinusitis PATHOLOGY & CAUSES ▪ Inflammation of sinuses, usually due to infection

LAB RESULTS

▪ CBC, leukocytes often normal ▪ Swabs, cannulation contraindicated due to high likelihood of sample contamination

TREATMENT

CAUSES

▪ Influenza, parainfluenza, rhinoviruses, adenoviruses; bacteria of nasopharynx

RISK FACTORS

▪ Upper respiratory tract infections, allergies, teeth infections (spread to maxillary sinus), tumors, adenitis, nasotracheal/nasogastric tubes, genetic disorders (Kartagener, cystic fibrosis), deformation of bone

COMPLICATIONS

▪ Meningitis, cavernous sinus thrombosis, orbital/periorbital cellulitis, abscesses

SIGNS & SYMPTOMS

MEDICATIONS Antibiotics ▪ If bacterial ▪ First line treatment, penicillin (amoxicillin with clavulanic acid); second line, fluoroquinolones Corticosteroids (topical/systemic) ▪ Alleviate allergies

OTHER INTERVENTIONS Steam treatments ▪ Dislodge secretions

▪ Bacterial ▫ Fever, headache, immediately previous upper respiratory infection, feeling of draining fluid, pain when leaning forward, voice change, last > 10 days ▪ Viral ▫ Self-limiting, painful sinuses (esp. leaning forward), discharge, last < 10 days

DIAGNOSIS DIAGNOSTIC IMAGING ▪ Rare

CT scan ▪ Screen for complications

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Figure 133.5 A CT scan of the head in the coronal plane demonstrating left maxillary sinusitis.

Chapter 133 Upper Respiratory Tract

UPPER RESPIRATORY TRACT INFECTION osms.it/upper-resp-tract-infection PATHOLOGY & CAUSES Pharyngitis ▪ Clinical syndrome characterized by sore throat, cervical lymphadenopathy; sore throat worsens with swallowing; typically accompanied by reactive enlargement of tonsils ▪ Inflammation of nasopharyngeal mucosa with reactive inflammation of lymph nodes, tonsils The common cold ▪ Mild self-limiting viral infection characterized by nasal congestion, rhinorrhea, sore throat, nonproductive cough, low grade fever ▪ Most common upper respiratory tract infection ▪ Hand contact/inhalation of airborne droplets from infected individual → viral inoculation → deposition on nasal mucosa → viral replication → cytokines release from infected cells → immune response initiates → inflammation, congestion of nasal cavity mucous membranes ▪ Resolves within one week, symptoms last up to 10–14 days; esp. in young children < six ▪ No cross immunity between serotypes ▫ Possible reinfection with milder symptoms, shorter duration

CAUSES Pharyngitis ▪ Infectious ▫ Most common pathogens: respiratory viruses (rhinovirus, echovirus, adenovirus, coronavirus), Group A Streptococcus pyogenes (GAS) ▫ Less common pathogens: bacteria

(Staphylococcus aureus; Group C, G Streptococcus; Arcanobacterium haemolyticum; Fusobacterium necrophorum; Mycoplasma pneumoniae; Chlamydia pneumoniae; Corynebacterium diphtheriae; Neisseria gonorrhoeae; Treponema pallidum); viruses (respiratory syncytial viruses; influenza A, B; HIV; Epstein–Barr virus; cytomegalovirus; herpes simplex virus; parainfluenza; enteroviruses) ▪ Noninfectious ▫ Allergic rhinitis ▫ Irritative pharyngitis (due to dry air, esp. in winter) ▫ Medications (e.g. angiotensinconverting enzyme inhibitors) ▫ Kawasaki disease ▫ Periodic fever, aphthous stomatitis, pharyngitis, adenitis (PFAPA) syndrome The common cold ▪ Viruses ▫ Most common: rhinoviruses (50% of all cases) ▫ Coronaviruses, parainfluenza viruses, RSV, influenza, adenoviruses, coxsackie viruses

RISK FACTORS The common cold ▪ Age, usually children < six; malnutrition; underlying diseases; immunodeficiency disorders; smoking; stress; sleep disturbances; weather, high prevalence in fall, winter

COMPLICATIONS Pharyngitis ▪ Severe pharyngeal inflammation, abscess formation, tonsillar hypertrophy → upper

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airway obstruction ▪ Post streptococcal ▫ Suppurative (spread of infection beyond pharynx): otitis media; peritonsillar cellulitis/abscess; retropharyngeal abscess; sinusitis; meningitis; bacteremia; necrotizing fasciitis; jugular vein septic thrombophlebitis ▫ Non suppurative (immune mediated): acute rheumatic fever, which can progress to rheumatic heart disease; post streptococcal glomerulonephritis; reactive arthritis; scarlet fever (delayed skin reactivity to erythrogenic toxin produced by GAS; requires prior exposure to GAS; characteristic scarlet rash, white with red enlarged papillae aka “strawberry tongue”); streptococcal toxic shock syndrome; pediatric autoimmune neuropsychiatric disorder associated with streptococcus (PANDAS) ▪ Lemierre syndrome: suppurative thrombophlebitis of jugular vein caused by Fusobacterium necrophorum The common cold ▪ Secondary bacterial infection ▫ Acute otitis media, sinusitis, pneumonia ▪ Asthma exacerbation

SIGNS & SYMPTOMS Pharyngitis ▪ Reddening; edema of pharyngeal mucosa; sore throat, worsens when swallowing ▪ Neck pain/swelling due to reactive lymphadenopathy ▫ Not prominent in viral pharyngitis ▫ Prominent, tender, anterior cervical lymphadenopathy in bacterial pharyngitis ▪ Constitutional symptoms ▫ Fever (low grade in viral pharyngitis, high grade in bacterial pharyngitis) ▫ Headache, fatigue, malaise ▪ Swollen, reddened tonsils with white spots of exudate from tonsillar crypts ▪ Suggestive of ▫ Viral pharyngitis: cough, nasal congestion, conjunctivitis, coryza, oral

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ulcer, viral exanthem ▫ Bacterial pharyngitis: sudden onset of symptoms, high grade fever, tonsillopharyngeal edema, tonsillar exudates, painful cervical lymphadenopathy ▪ Symptoms resolve within 3–5 days in viral pharyngitis; 5–7 days in bacterial pharyngitis The common cold ▪ Immune response to infection ▪ Nasal features ▫ Congestion; clear, purulent, yellow/green discharge; sneezing; erythema, nasal mucosa swelling ▪ Nonproductive cough ▪ Sore throat ▪ Low grade fever ▫ Predominant in young children; uncommon in older children, adults ▪ Headache, malaise, abnormal middle ear pressure, conjunctivitis

DIAGNOSIS LAB RESULTS Pharyngitis ▪ If suggestive of GAS pharyngitis (AKA strep throat) ▫ Rapid strep test (RST): detects GAS antigens on swab sample of tonsils, posterior pharynx ▫ Throat culture: more accurate than RST, takes 24 hours. If RST negative, but clinical suspicion of GAS pharyngitis; beta hemolytic, bacitracin sensitive, pyrrolidonyl arylamidase (PYR) positive colonies ▫ Polymerase chain reaction (PCR)-based assays: more sensitive, rarely available ▫ Serological tests: (antistreptococcal antibodies: anti-streptolysin (ASO), antihyaluronidase, anti-streptokinase, antinicotinamide adenine dinucleotidase, anti-DNase; ↑ titres suggestive of recent GAS infection; useful for detecting post streptococcal complications

Chapter 133 Upper Respiratory Tract

OTHER DIAGNOSTICS Pharyngitis ▪ Oropharyngeal examination ▪ Centor criteria: predict possibility of GAS pharyngitis ▫ 1 point each: fever, tonsillar exudates, tender anterior cervical lymphadenopathy, absence of cough, age < 15; subtract 1 point if age > 44 ▫ -1, 0, 1: no testing ▫ 2, 3: testing required ▫ 4, 5: empirical antibiotic treatment The common cold ▪ Clinical presentation ▪ Re-evaluation if symptoms worsen/exceed expected recovery time

TREATMENT

▫ Chronic tonsillitis unresponsive to antibiotics ▫ Tonsil enlargement causing airway obstruction ▫ Complications of pharyngotonsillitis ▫ PFAPA syndrome

OTHER INTERVENTIONS Pharyngitis ▪ Viral pharyngitis often self-limited ▪ Symptomatic ▫ Rest ▫ Adequate fluids to loosen secretions, prevent airway obstruction The common cold ▪ Symptomatic ▫ Rest ▫ Adequate fluids

MEDICATIONS Pharyngitis ▪ Antipyretics/analgesics ▫ Aspirin, acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs); for fever, pain control ▪ Salt water gargling ▪ GAS pharyngitis: antibiotics to prevent complications, reduce symptoms, prevent transmission ▫ First line treatment: penicillin (penicillin V/amoxicillin) ▫ Alternatives: cephalosporins, clindamycin, macrolides ▫ If recurrent/persistent: repeat 10 day course of antibiotics The common cold ▪ Topical saline/nasal suction/combination of nasal decongestant with antihistamines ▪ Antipyretics/analgesics ▪ Dextromethorphan/codeine to suppress cough

SURGERY Pharyngitis ▪ Tonsillectomy ▫ Recurrent infections

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UPPER RESPIRATORY TRACT CONGENITAL MALFORMATIONS

CHOANAL ATRESIA osms.it/choanal-atresia PATHOLOGY & CAUSES ▪ Congenital narrowing or blockage of the nasal passage (choana) by abnormal bony or soft tissue ▪ Most common nasal abnormality in newborns; more than 50% have other congenital conditions ▪ ⅔ present unilaterally, ⅓ bilaterally ▪ Cause unknown: can be associated with conditions that cause depression of the nasal bridge or midface retraction (craniosynostosis syndromes)

MNEMONIC

In context of CHARGE association Coloboma Heart defects Atresia of choanae Retardation (physical, mental) Genitourinary abnormalities Ear defects

RISK FACTORS

▪ Possible association with: low thyroid hormone levels; smoking; coffee consumption; high maternal zinc and B12 intake; exposure to agricultural chemicals; anti-infective urinary tract medications

COMPLICATIONS

▪ Aspiration while feeding ▪ Respiratory arrest

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▪ Re-narrowing of the area after surgery

SIGNS & SYMPTOMS ▪ Variance of presentation depends on unilateral or bilateral defect ▪ Newborns are obligate nasal breathers → difficulty breathing unless crying ▪ Unilateral choanal atresia may not be detected for years → newborn uses healthy nostril to breathe; distress may be intermittent ▪ Bilateral choanal atresia can be lifethreatening; causes acute breathing problems and cyanosis ▪ Marked chest retraction ▪ Inability to nurse and breathe at the same time ▪ Persistent one-sided mucous discharge ▪ Cyanosis

DIAGNOSIS DIAGNOSTIC IMAGING CT scan Endoscopy of the nose Sinus radiography

OTHER DIAGNOSTICS

▪ Inability to pass a catheter through nasal passage

Chapter 134 Upper Respiratory Tract Congenital Malformations

Figure 134.1 A CT scan of the head in the axial plane demonstrating membranous atresia of the right choana.

Figure 134.2 A CT scan of the head in the axial plane demonstrating bilateral osseous choanal atresia.

TREATMENT ▪ Temporarily: oral airway placement; place infant prone

SURGERY

▪ Definitive: surgical correction of the atresia

LARYNGOMALACIA osms.it/laryngomalacia laryngeal muscle tone

PATHOLOGY & CAUSES ▪ Congenital malformation of the larynx where the aryepiglottic folds are shorter than normal ▪ Short aryepiglottic folds cause folding of epiglottis in a characteristic omega shape that prolapses during inspiration ▪ Arytenoid cartilages are enlarged and softer than normal, so they flop into the airway ▪ Most common cause of congenital stridor and most common congenital lesion of the larynx ▪ Cause is unknown; associated with weak

COMPLICATIONS

▪ Impaired growth and development caused by hypoventilation (hypoxemia) ▪ Associated with gastroesophageal reflux ▪ Swallowing dysfunction and choking

SIGNS & SYMPTOMS ▪ ▪ ▪ ▪

High-pitched stridor Noisy respirations Breathing difficulties Gastroesophageal reflux

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DIAGNOSIS DIAGNOSTIC IMAGING Laryngoscopy or bronchoscopy ▪ Confirms diagnosis

OTHER DIAGNOSTICS

▪ History and physical exam

TREATMENT ▪ Can resolve spontaneously as throat muscles strengthen by age two

MEDICATIONS

▪ If hypoxemic → supplemental oxygen

Figure 134.3 A laryngoscopic view of the larynx in an individual with laryngomalacia in which there is an omega-shaped epiglottis.

SURGERY

▪ If laryngomalacia persists, surgical treatment is necessary (tracheotomy or supraglottoplasty)

Figure 134.4 Illustration of unique shape of larynx seen in laryngomalacia.

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BURNS & FROSTBITE GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Damage to skin, underlying structures due to overexposure to harmful conditions ▪ Burn/frostbite injury → loss of skin function ▫ Impaired thermoregulation → loss of body heat ▫ Impaired fluid retention → large water, protein losses from skin, affected tissues ▫ Loss of microbial barrier function → high risk of infection

SIGNS & SYMPTOMS ▪ Pain, erythema, blistering, skin layers slough off

DIAGNOSIS OTHER DIAGNOSTICS

▪ Clinical presentation ▫ Nature of exposure, appearance of wound, depth of damage

TREATMENT MEDICATIONS ▪ Analgesia

SURGERY

▪ Debridement of dead tissue

ACTINIC KERATOSIS osms.it/actinic_keratosis PATHOLOGY & CAUSES ▪ Repeated prolonged sun exposure → small, ill-defined, rough, scaly patches of skin ▪ Once initial lesions develop, more may follow without additional sun exposure ▪ UVB radiation → damage to keratinocytes → accumulation of oncogenic changes (e.g. p53 gene mutation) → unchecked proliferation of dysplastic keratinocytes → precancerous lesion

RISK FACTORS

▪ Fair-skinned individuals; facial distribution, sun-exposed limbs; increased age;

immunosuppression; albinism; xeroderma pigmentosum; human papillomavirus (HPV) infection

COMPLICATIONS

▪ Malignant transformation to squamous cell carcinoma (0.03–20% likelihood)

SIGNS & SYMPTOMS ▪ Small, rough, scaly skin lesions ▪ Sandpaper-like sensation felt on palpation ▪ Induration, tenderness, bleeding → possible malignant transformation

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DIAGNOSIS LAB RESULTS

▪ Skin biopsy ▫ Exclude malignancy

TREATMENT MEDICATIONS Figure 1.1 The clinical appearance of an actinic keratosis.

▪ Topical pharmacotherapy: 5-Fluorouracil, imiquimod, ingenol mebutate

SURGERY

▪ Scraping, excision

OTHER INTERVENTIONS Prevention ▪ Avoid excessive sun exposure, use sunscreen Dermatologic ▪ Cryotherapy (liquid nitrogen), photodynamic therapy, electrodessication Figure 1.2 The histological appearance of actinic keratosis. There is full thickness epidermal atypia with hyperchromatic basal cells and nuclei in the stratum corneum (parakeratosis).

BURNS osms.it/burns PATHOLOGY & CAUSES ▪ Tissue destruction due to exposure ▫ Heat, electricity, chemicals, radiation ▪ Burn injury → loss of skin function ▪ Impaired thermoregulation → loss of body heat ▪ Impaired fluid retention → large water, protein losses from skin, affected tissues ▪ Loss of microbial barrier function → high risk of infection

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▪ Cell survival favoured by moist environment, aseptic conditions, good blood supply

TYPES Thermal burns ▪ Contact with heat/heated objects, fluids ▪ > 44°C/111.2°F ▫ Proteins denature, break down → cell damage ▪ Amount of tissue destruction determined

Chapter 1 Burns & Frostbite by temperature, duration → injury diminishes outwards as heat disperses around central site ▪ Zone of coagulation (ischemia): area of maximal damage; no remaining tissue perfusion → irreversible cell damage → coagulative necrosis ▪ Zone of stasis (edematous): surrounds coagulation area, microvascular sludging, thrombosis → decreased perfusion → progressive tissue necrosis; cellular death within 24–48 hours without treatment; early intervention may save significant amounts of tissue ▪ Zone of hyperemia: surrounds zone of stasis; inflammation → vasodilation, increased capillary permeability → erythema; tissues still viable → recovery likely Chemical burns ▪ Exposure to corrosive substances (e.g. acids, bases, oxidizing/reducing agents, solvents, alkylants, chemical weapons) ▪ Severity ▫ Alkali > acid; warmer temperature; greater volume, concentration, contact duration; specific mechanism of chemical action; degree of tissue penetration ▪ Occur immediately on contact, may continue to progress for some time ▪ May not be immediately evident ▪ May diffuse to deeper structures without initial damage to skin surface Electrical burns ▪ Passage of electricity through tissue → rapid injury ▪ Subdermal damage significantly greater than superficial injury ▪ Extent of injury determined by ▫ Current: higher current → increased lethality/tissue damage ▫ Voltage: higher voltage → more damage; higher voltage → dielectric breakdown of skin → lowered resistance, greater current flows

▫ Frequency: very high frequencies → tissue burning; doesn’t penetrate deep enough to affect heart ▫ Duration: longer duration → more tissue damage ▫ Pathway: current flowing through heart → lethal ▫ Tissue resistance (pathway, depth dependant): nerves < blood vessels < muscle < skin < tendon < fat < bone Radiation burns ▪ Excessive exposure to radiation ▫ Ultraviolet (UV) light: sunlight most common cause of radiation, superficial burns ▫ Ionizing radiation (e.g. radiation therapy, X-rays, radioactive fallout): skin effects vary from hair loss at 3Gy to necrosis at 30Gy ▫ Microwave burns

Figure 1.3 An adult male with superficial partial thickness burns to the arms and torso, secondary to sun overexposure.

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RISK FACTORS

▪ Complicated injury ▫ Age (< 3, > 60), location (e.g. face, neck, hands, feet, perineum), inhalational injury, associated injuries (e.g. fractures), comorbid disease (e.g. chronic renal failure)

COMPLICATIONS

▪ Wound contracture/hypertrophic scarring, infection ▫ Most common organisms: S. aureus, P. aeruginosa, C. albicans ▪ Systemic effects of severe burns ▫ Large burns > 30% of total body

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surface area → significant inflammatory response → impaired organ perfusion → gastrointestinal (GI) bleeding, renal failure, progressive pulmonary insufficiency ▫ Increased levels of catecholamines, cortisol → hypermetabolism. immunosuppression ▪ Additional injury ▫ Singeing of airways → inflammation → eventual compromised airway ▫ Carbon monoxide inhalation

Chapter 1 Burns & Frostbite

DIAGNOSIS OTHER DIAGNOSTICS

▪ % of total body surface area (TBSA) affected ▫ Doesn’t include areas with first degree/ superficial burns ▫ Palm size estimation: size of individual’s hand print (palm, fingers) 1% of TBSA ▫ Wallace rule of nines: each major body part assigned value corresponding to approx. proportion of body surface area

American Burn Association severity classification ▪ Minor ▫ < 2% full thickness burn ▫ < 10% TBSA (young/old < 5% TBSA) ▪ Moderate ▫ 2–5% full thickness burn ▫ 10–20% TBSA (young/old 5–10% TBSA) ▫ high voltage injury, possible inhalation injury, circumferential burn, comorbidities ▪ Major ▫ > 5% full thickness burn ▫ > 20% TBSA (young/old > 10% TBSA) ▫ high voltage burn, known inhalation injury, significant burns to face/joints/ hands/feet, associated injuries

Figure 1.4 A full-thickness superficial burn to the hand.

TREATMENT OTHER INTERVENTIONS Intravenous (IV) fluids ▪ Parkland formula ▫ Estimated IV fluid replacement required over initial 24 hours ▫ Volume required in 24 hours = 4 x mass (kg) x (% TBSA x 100) ▫ Half of requirement given over first eight hours; remainder over following 16 hours Wound care ▪ First degree: maintain moist skin barrier with antimicrobial burn dressings ▪ Second degree: daily burn dressing change with topical antimicrobial, leave blisters intact unless circulation impaired/overlying joint, inhibiting movement ▪ Deep second degree: prevention of sepsis → antibiotics

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▪ Remove dead tissue ▫ Surgical debridement, excise to viable (bleeding) tissue Chemical burn ▪ Remove contaminated clothing, brush off dry powder ▪ Irrigate with water for 1–2 hours under low pressure; if elemental metal burn (e.g. sodium, potassium, magnesium, lithium) avoid exothermic reaction with water, soak in mineral oil instead ▪ Acid ▫ Water irrigation, followed by dilute solution of sodium bicarbonate Electrical burn ▪ Debride non-viable tissue, repeat every two days ▪ Monitor for cardiac complications

Figure 1.5 A full thickness burn to the medial aspect of the foot.

FROSTBITE osms.it/frostbite PATHOLOGY & CAUSES ▪ Exposure to low temperatures for significant periods of time, subsequent rewarming → tissue damage Freezing ▪ Temperatures < −4°C/24.8°F → formation of ice crystals within tissues → damage to cellular membranes, small blood vessels ▪ Cooling → vasoconstriction, impaired circulation → further cooling, warm blood unable to effectively perfuse freezing extremities Thawing ▪ Rewarming → vasodilation → edema ▪ Poor blood flow through damaged

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capillaries → ischemia, inflammation, blood coagulation → tissue death ▪ Thawing → formation of blood clots in small vessels

RISK FACTORS

▪ Frequently exposed/thermally vulnerable skin (e.g. hands, feet, face); occupational/ hobby exposure to low temperature environments (e.g. winter sports enthusiasts, military personnel); circulationimpairing disorders (e.g. Raynaud’s phenomenon, diabetes), substance use (e.g. smoking)

COMPLICATIONS

▪ Hypothermia, compartment syndrome

Chapter 1 Burns & Frostbite

SIGNS & SYMPTOMS ▪ Numbness prior to thawing ▪ White/bluish discolouration of skin ▪ Swelling/blistering after treatment

DIAGNOSIS ▪ Clinical presentation: physical assessment, classification

DIAGNOSTIC IMAGING

Figure 1.6 The clinical appearance of frostbitten fingers.

▪ Technetium (Tc)-99m scintigraphy (SPECT scan)/CT scan ▪ Assess salvageable tissue; earlier debridement of nonviable soft tissue ▪ Perfusion/metabolic imaging identifies viable bone, tissue/location autoamputation likely to occur

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activator, heparin for risk of amputation ▫ Blood vessel dilator: iloprost ▫ Sympatholytic drugs → counteract peripheral vasoconstriction ▫ High risk of infection → antibiotic prophylaxis (e.g. penicillin G)

SURGERY

▪ Debride dead tissue ▪ Escharotomy: release restrictive eschars ▪ Fasciotomy: compartment syndrome

Figure 1.7 Toes three weeks following frost bite.

TREATMENT MEDICATIONS Initial thawing ▪ Analgesia ▫ Nonsteroidal anti-inflammatory drugs (NSAIDs)/opioids ▪ Pharmacological adjuvants (severe cases, grade 2+) ▫ Antithrombotics: tissue plasminogen

OTHER INTERVENTIONS General measures ▪ Do not rewarm if possibility of refreezing exists (worse tissue damage) ▪ Do not walk on frostbitten feet/rub frostbitten hands (worse tissue damage) ▪ Avoid using stoves/fires to reheat insensate limbs (avoid thermal damage) Initial thawing ▪ Temperature: immerse in 37–39°C/98.6– 102.2°F agitated water; maintain steady temperature ▪ Duration: 10–30 min with povidone iodine/ chlorhexidine antiseptic

SUNBURN osms.it/sunburn PATHOLOGY & CAUSES ▪ Radiation burn of living tissue due to excessive exposure to UV radiation ▫ Burning may occur in 15 minutes of sunlight exposure in high UV radiation areas/seconds of non-shielded welding arcs ▪ UV light radiation overexposure ▫ Initial direct DNA damage (formation of thymine dimer) → activates cellular response mechanisms → DNA repair/ inflammatory response, cell death via apoptosis

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▫ Within one hour mast cells degranulate → release of histamine, serotonin, tumor necrosis factor (TNF) → prostaglandin, leukotriene synthesis → neutrophilic, lymphocytic infiltrate → further inflammation ▪ UV exposure → activation of genes to produce melanin → absorbs UV wavelength light → acts as photoprotectant

RISK FACTORS

▪ Outdoor work/sports, fair skin, very young/ old age, genetic defects in DNA repair, use of photosensitizing medication

Chapter 1 Burns & Frostbite

COMPLICATIONS

▪ Increased risk of skin cancers (e.g. melanoma; basal-cell, squamous-cell carcinoma)

SIGNS & SYMPTOMS ▪ Initial erythema, heat given off by increased blood flow to area due to vasodilation ▪ Pain proportional to severity of exposure ▪ Blistering, swelling, edema, peeling skin, fever, chills

DIAGNOSIS OTHER DIAGNOSTICS

▪ Clinical presentation (similar to thermal burn) ▫ Superficial (first degree) → affects only epidermis (erythematous) ▫ Superficial partial thickness (second degree) → affects dermis (forms blisters)

TREATMENT MEDICATIONS Analgesia ▪ hydrocortisone cream, NSAIDs

OTHER INTERVENTIONS

▪ Protect burnt skin with loose fitting clothing when outside to prevent further damage

Analgesia ▪ Cool baths/showers, soothing skin moisturizers Figure 1.8 Desquamation (peeling) of the skin following sunburn.

Prevention ▪ Avoid peak UV radiation intervals (10:00 AM to 4:00 PM), wear appropriate clothing (e.g. long-sleeved shirts, long trousers, wide-brimmed hats, sunglasses), broadspectrum sunscreen on any exposed skin

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DERMATITIS & ECZEMA GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Inflammatory skin disorders ▪ Immune-mediated skin damage

SIGNS & SYMPTOMS ▪ Rashes ▫ Pruritus (itching), burning, pain

OTHER DIAGNOSTICS

▪ Rash ▫ Appearance, distribution

TREATMENT MEDICATIONS

▪ Corticosteroids ▪ Immunosuppressants

DIAGNOSIS LAB RESULTS

▪ Skin biopsy, blood tests

ATOPIC DERMATITIS (ECZEMA) osms.it/atopic-dermatitis

▪ Allergic, inflammatory skin condition ▪ Common for children; may affect adults ▪ Associated with elevated serum IgE levels ▫ Atopy: predisposition to IgE antibody release after trigger exposure

Type 4 hypersensitivity ▪ Primary immune dysfunction ▫ T cell subset imbalance → Th2 predominance → increased inflammatory cytokine production (IL-4, 5, 13) → increased release of IgE from plasma B-cells, recruitment of mast cells, eosinophils

TYPES

RISK FACTORS

PATHOLOGY & CAUSES

Type 1 hypersensitivity ▪ Epidermal barrier dysfunction ▫ Skin barrier defects (e.g. filaggrin mutation) → antigen entry → inflammatory cytokines

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▪ Family history of atopy (eczema, asthma, allergic rhinitis) ▪ Environmental allergen sensitivities ▪ Loss of function mutation in filaggrin gene (skin barrier function)

Chapter 2 Dermatitis & Eczema ▪ Higher incidence in urban populations, high-income countries ▪ Low levels of early life exposure to endotoxin (immunogenic component of gram-negative bacteria)

COMPLICATIONS

▪ Skin infections ▫ Staphylococcus aureus common commensal organism → impetigo ▪ Eczema herpeticum ▫ Rapid spread of herpes simplex virus on affected skin ▪ Social stigma, anxiety

SIGNS & SYMPTOMS ▪ Acute ▫ Pruritic erythematous papules, vesicles with exudate, crusting ▪ Chronic ▫ Dry, excoriated erythematous papules with scaling; lichenification (hyperplasia) ▪ Dry skin ▪ Pruritus → chronic scratching → skin thickening, increased infection risk ▪ Cutaneous hyperreactivity to environmental antigens/stimuli (e.g. stress) ▪ 0–2 years old ▫ Erythematous, pruritic, scaly, crusted lesions +/- vesicles, serous exudate ▫ Extensor surfaces, cheeks, scalp ▪ 2–16 years old ▫ Lichenified plaques (thickened epidermis) ▫ Flexural distribution (e.g. antecubital, popliteal fossae); volar aspect of wrists, ankles, neck ▪ Adults ▫ Localized lichenified plaques ▫ Flexural surface involvement ▫ Uncommonly involves face/neck/hands

DIAGNOSIS LAB RESULTS

▪ Elevated level of Serum IgE

OTHER DIAGNOSTICS

▪ Morphology, distribution of lesions

United Kingdom working group atopic dermatitis criteria ▪ Mandatory ▫ Evidence of pruritic skin with rubbing/ scratching ▪ ≥ three following criteria ▫ Skin crease involvement (antecubital fossa, popliteal fossae, neck, around eyes, ankles) ▫ History/first degree relative with asthma/hay fever ▫ Dry skin in past year ▫ < two years old before symptoms arose (not applicable to children < four years old) ▫ Visible dermatitis of flexural surfaces (< four years old → examine cheeks, forehead, outer aspects of extremities)

Figure 2.1 Atopic dermatitis affecting the flexural surfaces of the forearms.

TREATMENT MEDICATIONS

▪ Control pruritus ▫ Antihistamines ▫ Topical calcineurin inhibitors (tacrolimus ointment, pimecrolimus cream) ▫ Antibiotics to treat associated skin infections ▪ Immune suppression ▫ Topical → systemic corticosteroids

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▫ Topical calcineurin inhibitors ▫ Oral cyclosporine ▫ Dupilumab (IL-4 receptor antagonist)

OTHER INTERVENTIONS

▪ Reduce exposure to environmental allergens ▪ Avoid triggers ▫ Heat, low humidity ▪ Manage stress/anxiety

▪ Maintain skin hydration ▫ Thick, unscented creams with low water content/ointments without water ▫ Apply after bathing/hand washing ▫ Avoid lotions with high water/low oil content (evaporation dries out skin, triggers outbreak) ▪ Control pruritus ▫ Prevent scratching; keep fingernails short (esp. young children)

CONTACT DERMATITIS osms.it/contact-dermatitis PATHOLOGY & CAUSES ▪ Inflammation of skin after contact exposure to allergens/irritants ▪ Localized ▪ Exposure to foreign substance triggers immune response ▪ Most common form: irritant contact dermatitis

CAUSES

▪ Exposure to irritant (irritation may be mechanical/chemical/physical) ▫ Acute: strong irritant ▫ Chronic: recurring exposure to weak irritant ▪ Detergents, surfactants, extreme pH, organic solvents, water ▫ Altered epidermal barrier function: Fat emulsion → defatting of dermal lipids → cellular damage to epithelium → DNA damage, transepidermal water loss → cytotoxic cell damage → cytokine release from keratinocytes → activation of innate immunity ▪ Plants with spines/irritant hairs ▪ Low humidity ▫ Skin loses moisture more easily

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Allergic contact dermatitis ▪ Anacardiaceae family plants ▫ Poison ivy, poison oak, poison sumac ▪ Nickel, fragrances, dyes ▫ Induction phase: immune system primed for allergic response to antigen ▫ Elicitation phase: contact allergens are typically haptens → small, can cross stratum corneum of skin to associate with epidermal proteins → form complete reactive antigen → dendritic cells recognise antigen → internalise antigen, transport to lymph nodes → present to T lymphocytes → trigger immune response → cell mediated immune response (Type IV delayed hypersensitivity) → memory cells remain within skin. Future exposure → triggers memory cells → immune response (cytokines, chemokines, TNF, lymphocytes, granulocytes migrate)

RISK FACTORS

▪ Age ▫ Infants: highest risk ▫ > 65 years old: lowest risk ▪ Body site exposure ▫ Difference in thickness of stratum corneum, barrier function ▫ Face, dorsum of hands, finger webs are prone to irritation ▪ Atopy

Chapter 2 Dermatitis & Eczema ▫ Chronically impaired barrier function ▪ Occupational exposure ▫ Continuous moisture exposure, repeated cycles of wet-to-dry from frequent handwashing ▪ Allergic contact dermatitis ▫ Occupation (health professionals, chemical industry, beauticians, hairdressers, machinists, construction) ▫ Increases with age ▫ History of atopic dermatitis

SIGNS & SYMPTOMS ▪ Erythematous rash (can develop ≤ 72hrs after exposure) ▪ Vesicles/bullae/wheals occur at exposure site ▪ Glaze/parched/scaled presentation ▪ Scaling, hyperkeratosis, fissuring ▪ Itching (favors allergic etiology); burning (favors irritant)

TREATMENT MEDICATIONS

▪ Pruritus ▫ Calamine lotion ▪ Mild topical corticosteroid (hydrocortisone) ▪ Oral antihistamine ▪ Allergic contact dermatitis ▫ High potency topical corticosteroids ▫ Oral corticosteroids ▫ Topical calcineurin inhibitors (tacrolimus/ pimecrolimus) ▫ Systemic immunosuppression (azathioprine, mycophenolate mofetil, cyclosporine)

OTHER INTERVENTIONS

▪ Remove/avoid trigger ▪ Treat blistering ▫ Cold compress ▪ Avoid scratching ▪ Retain moisture, protect skin ▫ Barrier cream (e.g. zinc oxide) ▪ Irritant contact dermatitis ▫ Mild acidic solutions (e.g. acetic acid) may neutralize alkali irritants/vice versa ▫ Emollients (e.g. Aquaphor) ▫ Gloves ▪ Allergic contact dermatitis ▫ Phototherapy (narrow band UVB radiation)

Figure 2.2 Contact dermatitis secondary to poison ivy exposure.

DIAGNOSIS OTHER DIAGNOSTICS

▪ History of possible exposure to irritant/ allergen ▪ Patch allergen testing

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SEBORRHOEIC DERMATITIS osms.it/seborrhoeic-dermatitis PATHOLOGY & CAUSES ▪ Sebaceous gland-centered skin inflammation ▪ Response to fungal antigens/irritants ▪ Chronic/relapsing ▪ Typically mild form of dermatitis

CAUSES

▪ Occurs in sites with greater density of sebaceous glands ▪ Not a disease of sebaceous glands, nor increased sebum production ▪ Suspected connection to lipid-dependent fungal genus Malassezia ▫ Immune response to fungus ▫ Local irritants produced by fungus ▪ Children ▫ Nutritional deficiencies of biotin, pyridoxine (vitamin B6), riboflavin (vitamin B2)

Distribution ▪ Areas containing significant number of sebaceous glands ▫ External ear, center of face, upper trunk, areas where skin rubs together ▪ Scalp ▫ Infants: aka cradle cap; self-resolving ▫ Adults: aka dandruff (pityriasis sicca); mildest form ▫ Fine, white scaliness without erythema +/- pruritus ▫ Severe cases: inflammation; patchy orange plaques with yellow, oily scales (pityriasis steatoides); may progress to oozing/crusting fissures affecting outer canal, concha of ear (vulnerable to superinfection) ▪ Face ▫ Forehead, eyebrows, glabella, nasolabial folds; may affect cheeks/malar area in butterfly distribution ▫ Frequently affects areas of facial hair distribution

RISK FACTORS

▪ Age (biphasic incidence: 2–12 months of age to adolescence; adulthood: peaks 30s–40s) ▪ Hyperandrogenism ▪ Biological males > biological females ▪ HIV ▪ Parkinson’s ▪ Stress ▪ Cold, dry weather ▪ Sleep deprivation ▪ Poor general health

SIGNS & SYMPTOMS ▪ Scaling erythematous plaques ▪ Scales yellow, oily in appearance Figure 2.3 Seborrhoeic dermatitis affecting both nasal folds.

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Chapter 2 Dermatitis & Eczema ▪ Periocular ▫ Blepharitis, free margin redness ▫ Yellow crusting between lashes ▫ Can occur in isolation/part of larger distribution ▪ Trunk (five distinct patterns of distribution) ▫ Moist, skin-contact regions: axillae, inframammary folds, umbilicus, genitocrural ▫ Petaloid pattern: fine, scaling plaques over sternum/interscapular ▫ Annular/arcuate: round, scaly plaques, may have hypopigmented central clearing ▫ Pityriasiform pattern: mimics pityriasis rosea, 5–15mm oval, scaly lesions along lines of skin tension ▫ Psoriasiform pattern: large, rounded erythematous plaques with thick scales

DIAGNOSIS OTHER DIAGNOSTICS

▪ History, appearance, distribution

TREATMENT MEDICATIONS ▪ ▪ ▪ ▪ ▪ ▪

Topical antifungals Antifungal shampoo Topical corticosteroids Topical calcineurin inhibitors Oral antifungals Antiandrogens ▫ Reserved for individuals for whom feminization/male infertility is unproblematic ▫ Sexually-active, uterus-bearing people: combine with contraception to avoid risk to fetus

OTHER INTERVENTIONS

▪ Cradle cap ▫ Apply emollient (petroleum jelly, vegetable oil, baby oil) to scalp overnight to loosen scales → remove scales with soft toothbrush ▫ Frequent shampooing with mild, nonmedicated baby shampoo → remove scales with soft toothbrush ▫ Extensive/persistent cases → medical therapy ▪ Topical ▫ Coal tar shampoo/ointment

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ERYTHEMA MULTIFORME & DRUG ERUPTION

GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES

DIAGNOSIS

▪ Skin, mucous membrane conditions ▪ Associated with medication use/infection

LAB RESULTS

CAUSES

OTHER DIAGNOSTICS

▪ Exact mechanism unclear, severe immune reaction against foreign antigen

▪ Skin biopsy

▪ Clinical history

TREATMENT

COMPLICATIONS

▪ Initial rash may → epidermal layer loss

▪ Identify/remove/treat offending agent/ infection

SIGNS & SYMPTOMS ▪ Desquamating skin, mucous membrane rash

ERYTHEMA MULTIFORME osms.it/erythema-multiforme PATHOLOGY & CAUSES ▪ Immune-mediated, acute, self-limiting skin condition ▪ Type IV hypersensitivity

CAUSES

▪ Suspected deposition of primarily IgMbound immune complexes in superficial skin, oral mucous membranes

Infection (most) ▪ Viral ▫ Herpes simplex primary cause

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▪ Bacterial ▫ Hemolytic Streptococci, Legionella, Mycobacterium, Mycoplasma pneumoniae, Neisseria meningitidis, Pneumococcus, Salmonella, Staphylococcus ▪ Parasitic ▫ Trichomonas, Toxoplasma gondii Drugs (rarely) ▪ Non-steroidal anti-inflammatories (NSAIDs), sulfonamides, phenytoin, barbiturates, phenylbutazone, penicillin, allopurinol

Chapter 3 Erythema Multiforme & Drug Eruption Physical factors ▪ Sunlight, radiotherapy, cold Autoimmune disease ▪ Vasculitides Hematological malignancy ▪ Non-Hodgkin lymphoma, leukemia, myeloid metaplasia

RISK FACTORS

▪ < 20 years old ▪ ↑ frequency in biological males

SIGNS & SYMPTOMS ▪ “Multiforme” denotes wide associated lesion variety ▪ Target lesions ▫ Initially round erythematous papules → dusky central area/blister, surrounded by dark red inflammation, surrounded by pale edematous ring, erythematous region on periphery ▪ Pruritus in affected area ▪ Painful lesions ▪ If severe ▫ Fever, weakness, malaise

Erythema multiforme minor ▪ Often herpes simplex ▪ Involves skin (little/no mucous membrane involvement) ▪ Favors skin of extremities, face ▪ Symmetrical circular lesions ▪ Lesions become classic “target” lesions (red border, small white center) ▪ Rash spreads towards body center Erythema multiforme major ▪ Often drug-related ▪ Epidermal detachment/skin loss progression ▪ Erythematous, confluent, bullous lesions ▪ Involves mucous membranes ▪ Nikolsky’s sign (lightly rub skin with firm object for few seconds → blister forms)

DIAGNOSIS LAB RESULTS

▪ Biopsy to exclude other skin disorders

OTHER DIAGNOSTICS

▪ Identify offending agent/infection ▫ Identification: target lesions, symmetrical distribution

TREATMENT ▪ Often self-resolving in 1–2 weeks

MEDICATIONS

▪ Control primary cause ▫ Treat/remove identifiable causes ▫ Herpes simplex suspected: oral acyclovir/valaciclovir/famciclovir ▫ Eliminate possible offending drugs

Figure 3.1 The abdomen of a child displaying numerous target lesions in a case of erythema multiforme.

Mild disease ▪ Topical corticosteroids ▪ Antihistamines Severe Disease ▪ Glucocorticoids ▪ In severe cases, prednisone considered

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Recurrent disease ▪ Systemic antivirals (up to 6 months) ▪ Immunosuppression if antivirals fail

STEVENS–JOHNSON SYNDROME & TOXIC EPIDERMAL NECROLYSIS osms.it/stevens-johnson_syndrome osms.it/toxic-epidermal-necrolysis PATHOLOGY & CAUSES ▪ Same underlying pathology (severity spectrum) ▫ Stevens–Johnson syndrome (lower end), toxic epidermal necrolysis (upper end) ▪ Severity, classification ▫ Body surface involvement % ▪ Severe mucocutaneous reaction → epidermal detachment

COMPLICATIONS

▪ Dehydration, sepsis, pneumonia, multiple organ failure, renal tubular necrosis, acute renal failure, phimosis, vaginal synechiae (adhesions), inside eyelid-tissue scarring → corneal vascularisation → vision loss

CAUSES

▪ Cytotoxic T cell mediated destruction of keratinocytes expressing foreign antigen

Medications ▪ Most common ▪ Allopurinol, sulfa drugs (e.g. sulfonamide antibiotics), lamotrigine, carbamazepine, nevirapine, phenylbutazone, thiacetazone, oxicam NSAIDS Infections ▪ Mycoplasma pneumoniae most common infective agent

RISK FACTORS

HIV/AIDS Systemic lupus erythematosus > 40 years old Genetic carbamazepine interaction predisposition (HLA-B*15:02, HLAA*31:01 alleles) ▪ ↑ frequency in biological females ▪ ▪ ▪ ▪

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Figure 3.2 An individual with Stevens– Johnson syndrome.

Chapter 3 Erythema Multiforme & Drug Eruption

DIAGNOSIS

SIGNS & SYMPTOMS Systemic ▪ Before skin eruptions occur ▪ Fever, sore throat, fatigue, cough Mucocutaneous ▪ Burning eyes, skin ▪ Red-purple macules → skin blisters → peels, forms painful raw areas ▪ Mucous membranes (often) → painful crusts, erosions ▪ Starts on trunk → rest of body ▪ Spontaneous ulceration of skin, mucous membranes (often eyes/lips) ▪ Conjunctivitis (often accompanied by purulent discharge) ▪ Round ulcerating lesions (approx. 2.5cm/1in diameter) ▫ Arise on face, trunk, arms, legs, soles of feet (scalp spared) ▪ Nikolsky’s sign

▪ Stevens–Johnson syndrome: < 10% skin involvement ▪ SJS/TEN overlap: 10–30% ▪ Toxic epidermal necrolysis: > 30%

LAB RESULTS ▪ Skin biopsy

OTHER DIAGNOSTICS

▪ Clinical history, suspected agents

TREATMENT MEDICATIONS

▪ Analgesics (non-opioid for non-severe, opioids for severe pain) ▪ Antihistamines ▪ Intravenous immunoglobulin

Infection control ▪ Culture-specific antibiotic initiation

OTHER INTERVENTIONS ▪ ▪ ▪ ▪

Transfer to burn/intensive care unit Fluid support Oral feeding, nasogastric tube Room temperature 30–32°C/86–90°F (minimize heat loss)

Infection control ▪ Sterile handling ▪ Skin disinfection ▫ Antiseptic solution ▪ 48 hourly skin, blood, indwelling line culture

Figure 3.3 An individual with toxic epidermal necrolysis ten days after the onset of symptoms.

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Figure 3.4 A histological section of skin demonstrating epidermal necrolysis. The epidermis is detached from the dermis and the keratinocytes have undergone necrosis. This can be seen in erythema multiforma, Stevens-Johnson syndrom and toxic epidermal necrolysis.

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HAIR–RELATED DISEASES GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Conditions affecting either total number of hairs/thickness of hair on body ▪ Scalp most commonly affected

SIGNS & SYMPTOMS ▪ See individual diseases

DIAGNOSIS ▪ See individual diseases

TREATMENT ▪ See individual diseases

ALOPECIA AREATA osms.it/alopecia-areata PATHOLOGY & CAUSES ▪ Chronic localized hair loss, generally on scalp; autoimmune-related ▪ May occur at any age, but > 30 years old in most cases; lifetime prevalence 2%

CAUSES

▪ Exact mechanism unclear; hypothesized ▫ T cells release cytokines, chemokines → normal hair cycle disrupted → hair loss ▪ Spontaneous regrowth of hair possible, often within one year

RISK FACTORS

▪ Genetic ▫ Close family members, history of autoimmune conditions

SIGNS & SYMPTOMS ▪ Usually smooth, circular patches of hair loss, but can be any shape ▪ Can be accompanied by nail changes ▫ Nail pitting, roughening/longitudinal fissuring of nail plate ▪ Associated with other autoimmune conditions ▫ Psoriasis, vitiligo, thyroid disease

DIAGNOSIS LAB RESULTS

▪ Biopsy (unclear cases) ▫ Peribulbar lymphocytic inflammatory infiltrates characteristic ▫ Follicular edema, cellular necrosis, microvesiculation, pigment incontinence

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OTHER DIAGNOSTICS

▪ Based on timeline of events, physical examination (exclamation point hairs) ▫ Short, broken hairs around area of hair loss ▫ Narrower proximal than distal end ▫ Dermatoscope may make hairs easier to spot

TREATMENT ▪ Treatment unreliable, temporary; no cure

MEDICATIONS

▪ Intralesional steroid injections of triamcinolone acetonide ▪ Topical agents including 5% minoxidil solution/topical steroids

Figure 4.1 The clinical appearance of the scalp in a case of alopecia areata.

TELOGEN EFFLUVIUM osms.it/telogen-effluvium PATHOLOGY & CAUSES ▪ Periodic episodes of increased hair thinning/shedding due to altered follicle growth cycle ▫ Occurs during follicles’ telogen (resting) phase

CAUSES

▪ May be related to ▫ Recent stressor (e.g. major illness/ surgery) ▫ Drugs/toxins ▫ Nutritional deficiencies

SIGNS & SYMPTOMS ▪ Non-scarring, diffuse < 50% hair loss ▪ Nail changes ▫ Deep grooved lines running from side to side may be present

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DIAGNOSIS OTHER DIAGNOSTICS

▪ Determine timeline of stressors, recent events, drug/medication usage, course/ characteristics of hair loss ▪ Hair-pull test ▫ Grasp 50–60 hairs → tug lightly ▫ If > 6–10 hairs extracted, test = positive ▫ Telogen hairs confirmed by microscopic examination

TREATMENT ▪ Sometimes self-correcting

OTHER INTERVENTIONS

▪ Reduce stressors, improve diet, handle hair carefully

Chapter 4 Hair-related Diseases

Figure 4.2 The clinical appearance of the nails in a case of telogen effluvium.

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MALIGNANT TUMORS GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Malignant cutaneous lesions due to abnormal/uncontrolled growth of epithelial cells

SIGNS & SYMPTOMS ▪ ≥ one multiple visible cutaneous tumors ▪ Melanoma can present noncutaneously (e.g. ocular, mucosal)

DIAGNOSIS TREATMENT

LAB RESULTS Histological analysis ▪ Confirms diagnosis, establishes tumor grade

MEDICATIONS

Biopsy ▪ Confirms diagnosis, establishes tumor grade

SURGERY

OTHER DIAGNOSTICS

OTHER INTERVENTIONS

▪ Dermatological examination with dermatoscope, TNM staging ▪ Breslow thickness ▫ Distance of tumor cell from basal layer of epidermis

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▪ Immunomodulators

▪ Surgical excision ▪ Electrodesiccation, curettage of lesion

▪ Radiation therapy

Chapter 5 Malignant Skin Tumors

BASAL-CELL CARCINOMA osms.it/basal-cell_carcinoma PATHOLOGY & CAUSES

CAUSES

▪ Most common type of skin cancer; emerges from basal cells found in lower epidermis ▪ Slow growing, can infiltrate surrounding tissue, rarely metastasizes

▪ UV radiation: direct DNA damage (pyrimidine dimers) → alters DNA structure → mutations, carcinogenesis if tumor suppressor gene involved ▪ Gorlin syndrome: numerous basal cell carcinomas due to mutation of PTCH1 gene

TYPES

RISK FACTORS

Nodular ▪ Pearly circular cystic pigmented nodule Infiltrative ▪ Invades dermis Micronodular ▪ Solid white-coloured lesion Morpheaform ▪ Flat white-yellowish waxy lesion Superficial ▪ Erythematous plaque, usually on upper trunk

▪ Arsenic exposure; immunodeficiency; fair skin, albinism; xeroderma pigmentosum; risk increases with age; high exposure to UV radiation

SIGNS & SYMPTOMS ▪ Presents on face, periocular, neck, scalp (i.e. sun-exposed areas) ▪ Newly discovered lesion ▫ Pearly elevated patch of skin ▪ Does not heal within four weeks ▪ Dimpled at midpoint ▪ Grows slowly ▪ May bleed (esp. when poked/knocked) ▪ Painless, may itch ▪ Dilated blood vessels (telangiectasia) ▪ Ulcerated lesion ▫ Brown-black pigmentation in crater of lesion

DIAGNOSIS LAB RESULTS Figure 5.1 The clinical appearance of a basal-cell carcinoma on the nose of an elderly individual. The tumor is nodular with central ulceration and pearly borders.

Skin biopsy/histopathology ▪ Basal cells form clusters called islands with peripheral palisading nuclei

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TREATMENT MEDICATIONS

▪ Topical 5-fluorouracil/imiquimod

SURGERY

▪ Electrodesiccation, curettage; complete surgical excision; cryosurgery; Mohs surgery

Figure 5.2 The histological appearance of a basal-cell carcinoma. Malignant darkstaining, basaloid cells infiltrate the dermis. There is clefting at the junction between the tumor and the dermis.

OTHER DIAGNOSTICS

▪ Radiation, photodynamic therapy

OTHER DIAGNOSTICS

▪ Dermatoscopy ▫ Scattered vascular pattern, telangiectasias, hemorrhage-ulceration, hypopigmented areas with blue-grey ovoid nests, red dots/globules

MELANOMA osms.it/melanoma PATHOLOGY & CAUSES ▪ Malignant skin cancer, arises from melanocytes ▪ Occurs most commonly on skin ▫ Rarely: mouth, eyes, gastrointestinal (GI) tract ▪ Can arise from ▫ Preexisting mole ▫ De novo lump: nodular melanoma (most dangerous) Variants ▪ Superficial spreading melanoma ▪ Lentigo maligna melanoma ▪ Nodular melanoma ▪ Acral lentiginous melanoma

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Figure 5.3 A malignant melanoma exhibiting pigment production.

Chapter 5 Malignant Skin Tumors Growth phases ▪ Radial growth phase (< 1mm thick) ▫ Grows laterally along epidermis, superficial dermis; does not spread ▫ Rarely metastasizes; good prognosis if detected ▪ Vertical growth phase (> 1mm thick) ▫ Grows deeper into dermis, beyond ▫ Invasive, able to metastasize through lymph/blood vessels

CAUSES

▪ DNA damage caused by ultraviolet (UV) light exposure (e.g. sun, tanning beds) ▪ Genetic mutations in MC1R, CDKN2A, BRAF genes

RISK FACTORS

Immunosuppression Numerous moles Family history of melanoma Syndromes ▫ Dysplastic nevus syndrome, xeroderma pigmentosum, albinism, Gorlin syndrome ▪ Exposure/overexposure to UV light (e.g. sun, tanning beds) ▫ Esp. if blistering/occurring early in life; more common in people with fair skin

▪ ▪ ▪ ▪

▫ See tables: American Joint Committee on Cancer Guideline for TMN staging of melanoma ▪ Histopathological evaluation for tumor grade

OTHER DIAGNOSTICS

▪ Dermatological examination using dermatoscope ▫ Classic melanoma: mnemonic ABCDE ▫ Nodular melanoma: mnemonic EFG

MNEMONIC: ABCDE

Appearance of classic melanoma Asymmetry Border irregularities Color variation Diameter: 6 mm Enlargement

MNEMONIC: EFG

Appearance of nodular melanoma Elevated Firm to touch Growing

COMPLICATIONS

▪ Metastazes most commonly to lymph nodes, skin, subcutaneous tissue → lungs, liver, brain

SIGNS & SYMPTOMS ▪ New skin lesion/change pre-existing lesion: color, shape, size irregularities; ulcerations, pruritus, bleeding ▪ Nausea, vomiting, loss of appetite, fatigue

DIAGNOSIS LAB RESULTS

Figure 5.4 The clinical appearance of a malignant melanoma. It is darkly pigmented with an irregular border.

Full-thickness, sentinel node biopsy ▪ Tumor staging

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TREATMENT MEDICATIONS

▪ Immunotherapy in case of metastases

SURGERY

▪ Surgical excision ▫ Wide margin excision (1–3cm of normal tissue depending on depth of invasion) ▪ Excision if sentinel node biopsy is positive

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OTHER INTERVENTIONS

▪ Early detection for good prognosis (depends directly on depth of invasion) ▪ Radiation/chemotherapy in case of metastases

Chapter 5 Malignant Skin Tumors

Figure 5.5 The gross pathology of the heart in a case of metastatic melanoma.

SQUAMOUS-CELL CARCINOMA (SCC) osms.it/squamous-cell_carcinoma PATHOLOGY & CAUSES ▪ Second most common type of skin cancer ▪ Epidermal keratinocytes acquire antiapoptotic properties → frequent mitosis

RISK FACTORS

▪ Immunosuppression, chronic UV exposure, fair skin, albinism, xeroderma pigmentosa, tobacco use (increases risk of lip/oral SCC), arsenic exposure (rare)

CAUSES

▪ UV radiation (e.g. sun, tanning beds) ▪ HPV infection ▪ Genetic mutations ▫ Deletion of tumor progression locus 2 (Tpl2) gene ▪ Preceding skin lesions (e.g. actinic keratosis, other melanomas) ▫ Actinic keratosis: precancerous skin lesion; rough, scaly patch caused by chronic, long-term sun exposure ▪ Bowen’s disease (AKA squamous cell carcinoma in situ)

Figure 5.6 An ulcerated squamous cell carcinoma on the nose of a middle-aged individual.

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COMPLICATIONS

▪ Significant risk of metastasis

SIGNS & SYMPTOMS ▪ Most commonly found on sun-exposed areas (e.g. head, nose, neck) ▪ Small rough scaly nodule (slow growing) ▫ Nodule expands → center necroses → evolves into ulcer covered by red growing plaque → frequently scales, easily bleeds ▪ Chronic draining sinuses

DIAGNOSIS DIAGNOSTIC IMAGING CT scan ▪ Assess surrounding tissue invasion (soft tissue, bones, lymph nodes), metastasis Dermatoscopy, excisional/incisional biopsy of subcutaneous tissue ▪ Microscopic features: hyperkeratosis, nuclear atypia ▪ See tables: American Joint Committee on Cancer Guideline for TMN staging of cutaneous squamous-cell carcinoma MRI ▪ Evaluate vital structures (neural, vascular invasions)

TREATMENT MEDICATIONS

▪ Topical immunomodulators

SURGERY

▪ Surgical excision ▪ Mohs surgery: microscopic procedure removing thin layers of affected tissue, examining under microscope until cancerfree tissue reached ▪ Electrodessication, curettage

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OTHER INTERVENTIONS

▪ Chemotherapy, radiotherapy, photodynamic therapy

Chapter 5 Malignant Skin Tumors

Figure 5.7 The histological appearance of well-differentiated squamous cell carcinoma of the skin. It is composed of polygonal cells with eosinophilic cytoplasm which produce keratin pearls.

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PAPULOSQUAMOUS DISORDERS

GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Heterogeneous skin disorders; scaly papules, plaques ▫ Papule: circumscribed, solid elevation of skin < 1cm/0.39in ▫ Plaque: broad papule/confluence of papules ≥ 1cm/0.39in ▫ Scale: dry/greasy laminated masses of keratin

CAUSES

▪ Inflammation

SIGNS & SYMPTOMS ▪ See individual disorders

DIAGNOSIS OTHER DIAGNOSTICS ▪ Rash patterns

TREATMENT ▪ May spontaneously resolve

MEDICATIONS

▪ Topical (e.g. corticosteroids), nonsteroidal anti-inflammatory drugs (NSAIDs), antihistamines ▪ Immunosuppressants, retinoids (e.g. acitretin)

OTHER INTERVENTIONS ▪ Phototherapy, colloid baths

LICHEN PLANUS osms.it/lichen-planus PATHOLOGY & CAUSES ▪ Self-limiting chronic dermatosis ▪ Multifactorial pathogenesis ▫ Environmental factors → genetic aberrations of immune system ▫ CD8+ T cells respond to altered antigens in basal epidermidis/ dermoepidermal junction ▫ Causal agent identified: lichenoid reaction (e.g. drugs)

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▪ Chronic inflammation in mucosal lesions → squamous cell carcinoma

SIGNS & SYMPTOMS ▪ Shiny, flat-topped, pink-purple, polygonal papules coalesce, form plaques with red scales ▪ Wickham striae (pathognomonic) ▫ Interspersed grey-white lace-like pattern of lines

Chapter 6 Papulosquamous Disorders ▪ Symmetrical peripheral distribution, esp. on flexural surfaces (e.g. wrists, elbows, ankles, shins) ▪ Severe pruritus ▪ Koebner phenomenon ▫ Skin lesions induced by local trauma ▪ Nail involvement ▫ 10% of individuals; subungual thickening/hyperpigmentation, thinning/ ridging/ grooving of nail plate, pterygium formation, onycholysis ▪ Mucosal involvement ▪ Oral mucosa ▫ Asymptomatic/burning sensation,severe pain ▫ Mostly bilateral, inner cheeks ▫ Various types may coexist; oral variant of Wickham’s striae, erosive/ulcerative, papular, plaque-like, atrophic, bullous ▫ Possible secondary Candida infections ▪ Esophageal mucosa ▫ Dysphagia/odynophagia ▪ Genital mucosa (glans penis, vulva/vagina) ▫ Lower urinary tract symptoms, dyspareunia, itching in individuals who are biologically female

MNEMONIC: 6 Ps

▫ Basal keratinocytes degenerate, appear like stratum spinosum cells (squamatization)/undergo necrosis, become incorporated into inflamed papillary dermis (Civatte bodies)

OTHER DIAGNOSTICS

▪ Rash pattern distinctive at skin examination ▪ Skin biopsy ▫ Rule out secondary malignancies

TREATMENT ▪ Cutaneous lesions spontaneously resolve in nine months, longer for mucosal lesions ▫ Leaves area of hyperpigmentation

MEDICATIONS

▪ Reduce symptoms, shorten duration ▪ Antihistamines (pruritus), corticosteroids ▪ Retinoids, immunosuppressants

OTHER INTERVENTIONS ▪ Occlusive dressings ▪ Phototherapy ▫ Ultraviolet A radiation

Clinical presentation of lichen planus Planar Purple Polygonal Pruritic Papules Plaques

DIAGNOSIS LAB RESULTS

▪ Typical microscopic features ▫ Acanthosis: epidermidis thickening ▫ Interface dermatitis: continuous infiltrate of lymphocytes along dermoepidermal junction → sawtoothing (dermoepidermal interface with zig-zag contour)

Figure 6.1 Lesions on the shins of an individual with lichen planus.

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Figure 6.2 The histological appearance of lichen planus. There is a lymphocytic infiltrate at the junction between the dermis and epidermis which is known as interface dermatitis.

PITYRIASIS ROSEA osms.it/pityriasis-rosea PATHOLOGY & CAUSES ▪ Self-limiting acute dermatosis ▪ Unknown etiology; may be viral in origin, related to human herpesvirus 7 (HHV7)

SIGNS & SYMPTOMS ▪ Upper respiratory tract infection may precede rash ▪ “Herald patch” ▫ Solitary oval red plaque, usually located on trunk ▫ First skin lesion ▫ Spreads with central clearing, fading in 2–10 days ▪ 1–2 weeks after herald patch, multiple round/oval pink (white individuals of European descent)/dark brown (black individuals of sub-Saharan African descent) plaques with central scale appear

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▪ Trunk, neck, upper arms, thighs; “Christmas tree” progression ▫ Across chest, then rib-line ▪ Pruritus ▪ Systemic ▫ Low-grade fever, headache, nausea, fatigue

Figure 6.3 A herald patch is often seen at the onset of pityriasis rosea. It is a slightly raised, erythematous patch with superficial scaling.

Chapter 6 Papulosquamous Disorders

DIAGNOSIS LAB RESULTS

▪ Skin biopsy (rare) ▪ Microscopic features ▫ Dyskeratosis: abnormal premature keratinization ▫ Extravasated erythrocytes within dermal papillae

OTHER DIAGNOSTICS

▪ Rash pattern ▫ Distinctive at skin examination

TREATMENT ▪ May spontaneously disappear in 6–8 weeks Figure 6.4 The clinical appearance of pityriasis rosea on the torso of an adult male.

MEDICATIONS

▪ Antihistamines for pruritis

OTHER INTERVENTIONS

▪ May spontaneously disappear in 6–8 weeks ▪ Colloid baths for pruritis

PSORIASIS osms.it/psoriasis PATHOLOGY & CAUSES ▪ Chronic dermatosis of skin, nails, joints ▪ Multifactorial pathogenesis ▫ Environmental factors → genetic abnormalities of immune system ▫ CD4+ TH1, TH17, CD8+ T cells collect in epidermis, secrete cytokines (e.g. IFN-gamma, TNF-alpha, IL-17, IL22), growth factors → abnormal microenvironment (“cytokine soup”) accelerates keratinocyte proliferation → defective keratinization, epidermal thickening ▪ Unpredictable progression with

spontaneous remissions, sudden exacerbations (e.g. may worsen in winter— lack of sun, humidity) ▫ Skin abrasion, infection, drugs (e.g. lithium, beta blockers, chloroquine), psychosocial stress → exacerbations ▪ 10–15% of individuals develop psoriatic arthritis ▫ Inflammatory cells in joint tissue → synoviocyte proliferation ▫ Surrounding connective tissue also involved (e.g. enthesitis)

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TYPES

▪ Plaque psoriasis, AKA vulgar psoriasis; 90% ▪ Guttate (eruptive), inverse (flexural), pustular, erythrodermic

SIGNS & SYMPTOMS ▪ Plaque ▫ Pink, salmon-colored papules/plaques covered by loosely adherent silver-white scales ▫ Any area of body, esp. extensor surfaces (e.g. knees, elbows), lumbosacral area, scalp, glans penis ▫ Itching is mild/absent ▪ Nail involvement in 30% of individuals ▫ Subungual thickening ▫ Yellow-brown discolorations of nail plate (resembling oil slicks) ▫ Crumbling/ridging/pitting of nail plate ▫ Onycholysis: separation of nail plate from bed ▪ Guttate (eruptive) ▫ Drop-like appearance, associated with group A streptococcus ▪ Inverse (flexural) ▫ Skin folds ▪ Pustular ▫ Blisters filled with non-infectious pus ▪ Erythrodermic ▫ Total body inflammation, skin exfoliation, severe itching, swelling, pain; ability to regulate temperature, perform barrier functions impaired; possibly fatal ▫ May develop from any type (e.g. plaque during corticosteroid rebound phenomenon) ▪ Auspitz sign ▫ Pinpoint bleeding appears when scale removed ▪ Koebner phenomenon ▫ Characteristic skin lesions induced by local trauma ▪ Psoriatic arthritis ▫ Inflammatory arthritis: pain, red overlying area, swelling, hot to touch ▫ Frequently occurs after onset of rash ▫ Asymmetric peripheral oligoarthritis;

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joints of hands, feet most affected, followed by sacroiliac bone, spine ▫ Fusiform swelling of digits (dactylitis); aka “sausage digits” ▫ Aggressive disease with joint damage, malformations not common

DIAGNOSIS DIAGNOSTIC IMAGING ▪ For psoriatic arthritis

X-ray ▪ Erosive changes, “fluffy” periostitis, presence of new bone formation MRI ▪ Inflammation in adjacent bone marrow and soft tissues

LAB RESULTS

▪ Skin biopsy (rare) ▪ Acanthosis ▫ Epidermidis thickening ▪ Parakeratosis ▫ Keratinization (retention of nuclei in stratum corneum) ▪ Neoangiogenesis with tortuous blood vessels below stratum corneum ▪ Accumulation of neutrophils in superficial epidermis (spongiform pustules), in stratum corneum (Munro microabscesses) ▪ Clinical diagnosis ▫ Psoriasis features, clinical pattern of joint involvement ▪ Confirmation ▫ Elevated inflammatory markers, negative rheumatoid factor (RF), anticyclic citrullinated peptide antibody (anti-CCP)

OTHER DIAGNOSTICS

▪ Rash pattern ▫ Distinctive at skin examination ▪ Differentiation from rheumatoid arthritis ▫ Minority show polyarthritic pattern with no skin lesions; note asymmetry, distal interphalangeal joint involvement, mild joint destruction

Chapter 6 Papulosquamous Disorders

TREATMENT ▪ No definitive cure ▪ Avoid triggers

MEDICATIONS

▪ Topical corticosteroids → antiinflammatory, antiproliferative ▪ Vitamin D derivatives (calcipotriene, calcipotriol) → limit keratinocyte proliferation ▪ Anthralin → suppresses proliferation ▪ Combination therapy is most effective (e.g. betamethasone dipropionate + calcipotriene) ▪ Affected area > 10%, unsuccessful topical treatment, involves face, hands, genitals ▪ Immunosuppressant ▫ Methotrexate, cyclosporine ▪ Systemic retinoids ▫ Acitretin → inhibits pro-inflammatory cytokines ▪ Biologic therapy ▫ Anti-TNF (infliximab, etanercept, adalimumab), T-cells (alefacept), IL12/23 (ustekinumab) ▪ NSAIDs, immunosuppressant/biologic therapy ▫ For psoriatic arthritis

Figure 6.5 A large psoriatic plaque on the upper limb.

OTHER INTERVENTIONS

▪ Topical ▫ Coal tar → inhibits cellular mitotic activity, proliferation ▫ Moisturizers, emollients ▪ Phototherapy ▫ Ultraviolet A radiation ▫ Often combined with topical tar/ systemic acitretin/psoralen/methoxsalen ▫ Immunosuppressive, antiproliferative

Figure 6.6 Psoriasis affecting the hand.

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NOTES

NOTES

PIGMENTATION DISORDERS GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Skin loses pigment, becomes lighter/darker ▪ Pigment-producing cells (melanocytes) ▫ Expected number, overproduce pigment (melanin) ▫ Higher in number, produce expected melanin ▫ Destroyed, no melanin produced

DIAGNOSIS LAB RESULTS ▪ Skin biopsy ▪ Genetic testing

OTHER DIAGNOSTICS

▪ Dermatological physical examination (e.g. dermoscopy)

CAUSES

▪ Autoimmune disorders → melanocyte destruction ▪ Long periods of sun exposure ▪ Genetic mutations

SIGNS & SYMPTOMS ▪ Changes in skin pigmentation only symptom ▪ Some disorders (esp. produced by sun overexposure) heighten risk of skin cancer

TREATMENT ▪ Usually no cure

MEDICATIONS

▪ Topical medication ▫ Most respond to steroids ▫ Depigmentation agents effective for hyperpigmentation disorders

SURGERY

▪ For some lesions

OTHER INTERVENTIONS

▪ Sun avoidance, if caused by ultraviolet (UV) overexposure

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Chapter 7 Pigmentation Disorders

ALBINISM osms.it/albinism PATHOLOGY & CAUSES

SIGNS & SYMPTOMS

▪ Congenital condition; skin, eyes, hair partially (hypomelanistic albinism)/ completely (amelanistic albinism) devoid of pigment ▪ Lack of pigment → dermatological problems ▫ Increased risk of sunburn, skin cancer

▪ Complete/partial absence of skin pigmentation ▪ Light yellow/white hair ▪ Light eye colour ▫ Light blue (partial pigment production) ▫ Pink (complete absence of pigment production) ▪ Visual problems ▫ Visual development in fetus highly dependent on melanin production; abnormal arrangements in optic nerves fibres (e.g. abnormal optic chiasm) ▫ Severe sensitivity to light ▫ Poor visual acuity due to foveal hypoplasia ▫ Amblyopia/nystagmus: poor coordination between eye, brain

TYPES Oculocutaneous albinism (OCA) ▪ Eyes, skin; possibly hair ▪ Autosomal recessive transmission ▪ Seven different subtypes; OCA1, OCA2 most common ▫ OCA1: defect in gene for enzyme tyrosinase (TYR) ▫ OCA2: defect in P gene (membrane transporter, moves amino acid tyrosine) ▪ Rufous oculocutaneous albinism ▫ Specific subtype of OCA ▫ Common in people of sub-Saharan African descent Ocular albinism (OA) ▪ Only eyes ▪ OA1 most common subtype (AKA Nettleship–Falls syndrome) ▫ X-linked recessive inheritance ▫ Lack of pigment in retinal epithelium

DIAGNOSIS LAB RESULTS

▪ Genetic testing ▫ Identify defective gene, allotype

OTHER DIAGNOSTICS ▪ Physical examination ▪ Family history

CAUSES

▪ Hereditary/genetic ▫ Autosomal/X-linked ▫ Recessive inheritance pattern → defect leading to lack/absence of enzyme in melanin synthesis pathway → hypopigmentation/depigmentation ▪ Chediak–Higashi syndrome ▫ Rare; malfunctions in lysosomal trafficking regulator gene (CHS1/LYST)

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TREATMENT ▪ No cure

SURGERY

▪ Manage strabismus, nystagmus

OTHER INTERVENTIONS

▪ Lifestyle management ▫ Avoid sunburn ▫ Regular dermatological, ophthalmological check-ups ▫ Visual rehabilitation ▫ Glasses/contact lenses

Figure 7.1 A baby with albinism.

PITYRIASIS ALBA osms.it/pityriasis-alba PATHOLOGY & CAUSES ▪ Common, irregularly hypopigmented skin condition: slightly scaly patches, macules ▫ Lesion diameter: 0.5–5cm/0.2–2in ▫ Irregular borders ▫ Most common on face, neck, shoulders, upper arms ▫ May resolve spontaneously after puberty

CAUSES

▪ Unknown etiology: eczema-related postinflammatory hypopigmentation (possible relation)

RISK FACTORS ▪ ▪ ▪ ▪ ▪

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Atopy Sun exposure Frequent bathing Biologically male Children/adolescents > adults

COMPLICATIONS ▪ Benign condition

SIGNS & SYMPTOMS ▪ Often asymptomatic, may itch/burn

DIAGNOSIS OTHER DIAGNOSTICS

▪ Wood’s lamp examination: hypomelanosis patches ▪ Microscopy: ↓ melanocyte number, size

TREATMENT MEDICATIONS

▪ Hydrocortisone (topical), calcineurin inhibitors, emollients

Chapter 7 Pigmentation Disorders

VITILIGO osms.it/vitiligo PATHOLOGY & CAUSES ▪ Pigmentation disorder; parts of skin, hair lose pigment ▪ Melanocytes destroyed → white patches of depigmented skin ▫ Sharp margins on depigmented patches ▪ May be autoimmune condition

SIGNS & SYMPTOMS ▪ Depigmented skin patches only symptom, usually on extremities ▪ Patches grow over time (non-segmental subtype) ▪ Can be associated with alopecia

DIAGNOSIS

TYPES Segmental ▪ Areas innervated by dorsal roots of spinal cord ▪ Unilateral; stable over time Non-segmental ▪ Symmetrical; appearance of new patches ▪ Multiple subtypes ▫ Vitiligo universalis: most severe, almost no pigmented skin remains ▫ Generalized: most common ▫ Focal: smaller, localised patches ▫ Acrofacial: hands, face ▫ Mucosal: only mucous membranes

CAUSES

▪ Autoimmune disorder → melanocyte destruction

RISK FACTORS

▪ Medical/family history of autoimmune conditions ▫ Hashimoto’s thyroiditis ▫ Type I diabetes mellitus ▫ Systemic lupus erythematosus ▫ Celiac disease ▫ Addison’s disease

▪ Rule out autoimmune/inflammatory disorders

OTHER DIAGNOSTICS

▪ Ultraviolet light (Wood’s lamp): lesions; vitiligo turns blue

TREATMENT ▪ No cure

MEDICATIONS

▪ Topical immune system suppressing medication ▪ Glucocorticoids ▪ Calcineurin inhibitors

OTHER INTERVENTIONS

▪ Ultraviolet light therapy (phototherapy) ▪ Skin camouflage (e.g. makeup)

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Figure 7.2 The clinical appearance of vitiligo affecting the hands.

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NOTES

NOTES

SKIN & SOFT TISSUE INFLAMMATION & INFECTIONS

GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES

DIAGNOSIS

▪ Inflammation of epidermis, dermis, underlying tissues

LAB RESULTS

CAUSES

OTHER DIAGNOSTICS

▪ Infections, autoimmune response

RISK FACTORS ▪ ▪ ▪ ▪ ▪

Impaired skin barrier Pressure Friction Exposure to infectious agents Immunosuppression

COMPLICATIONS

▪ Infection ▫ Local or systemic disease

▪ Tissue cultures, Gram stain

▪ Mostly clinical, based on presentation

TREATMENT MEDICATIONS

▪ Infections: antimicrobials

OTHER INTERVENTIONS ▪ Dressings, ointments ▪ Cryotherapy ▪ Curettage

SIGNS & SYMPTOMS ▪ See individual disorders

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ACNE VULGARIS osms.it/acne_vulgaris PATHOLOGY & CAUSES ▪ Common inflammatory skin disorder affecting hair follicles, sebaceous glands ▪ May involve comedones, papules, pustules, cysts, scars ▪ Especially affects individuals who are ▫ Biologically male, with hormonal disorders producing androgens (e.g. polycystic ovarian syndrome), adolescent ▫ Symptoms decrease with age

TYPES Mild ▪ Occasional, comedones, inflammatory papules, pustules

▪ Infection ▫ Follicle colonization by Propionibacterium acnes ▪ Medications ▫ Lithium, glucocorticoids, anabolic steroids ▪ Polycystic ovarian syndrome ▪ Stress

COMPLICATIONS

▪ Cosmetic ▫ Scars, hyperpigmentation, pyogenic granulomas, osteoma cutis ▪ Psychiatric ▫ Low self esteem, depression

Moderate ▪ Multiple pustules, nodules occur on trunk Severe ▪ Cystic, large nodules predominant, with persistent involvement of trunk; scarring

CAUSES

▪ Androgen stimulates sebaceous follicles to overproduce sebum → follicles become blocked ▪ Hyperkeratinization of epithelium → accumulation → follicular blocking → debris accumulates further → skin follicles rupture ▪ Propionibacterium acnes replicates within follicle → releases lipase → sebum converted to free fatty acids → release of cytokines → inflammation

RISK FACTORS

▪ Genetic predisposition ▪ Oil-based skin products ▪ Hormonal imbalance

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Figure 8.1 Acne vulgaris affecting the face of an adolescent male.

Chapter 8 Skin & Soft Tissue Inflammation & Infections

SIGNS & SYMPTOMS ▪ Papules, pustules, painful nodules (cysts) on face, neck, chest, back ▪ Closed comedones ▪ Erythema

DIAGNOSIS

▪ In case of comedonal acne, use azelaic acid, salicylic acid as anti-inflammatory, antibacterial, antiproliferative agent Mild to moderate ▪ Benzoyl peroxide, retinoid ▪ Add topical antibiotic (clindamycin) for synergistic effect with benzoyl peroxide Severe ▪ Oral isotretinoin decreases sebum production, bacterial proliferation, inflammation ▪ Avoid using tetracycline due to sun sensitivity

OTHER DIAGNOSTICS ▪ Clinical presentation

TREATMENT

OTHER INTERVENTIONS

MEDICATIONS

▪ Target sebum production, inflammation, bacterial/follicular proliferation

Mild ▪ Benzoyl peroxide treats Propionibacterium acnes ▪ Add topical retinoids to prevent follicular proliferation

▪ Clean skin with gentle agents ▪ Comedones extraction ▪ Pigmentation ▫ Topical retinoid, azelaic acid, chemical peels ▫ Photodynamic treatment with lasers (removes superficial layers of skin) ▫ Dermabrasion (treatment of scars; may irritate skin)

CELLULITIS osms.it/cellulitis PATHOLOGY & CAUSES ▪ Non-necrotizing inflammation of dermis, subcutaneous tissue, typically caused by streptococci (S. aureus, S. pyogenes); usually unilateral ▪ Skin breach: trauma; dry, fissuring skin; ulcers → bacteria invade skin, subcutaneous tissue ▪ Common locations: face, legs; may affect arms ▪ Other locations: causes vary ▫ Orbital cellulitis: originates from trauma, sinuses, hematogenous spread

▫ Abdominal wall cellulitis: morbid obesity causes bacteria to enter skin sores ▫ Buccal cellulitis: spread from tooth infection ▫ Perianal cellulitis: affects all demographics

TYPES

▪ Purulent ▫ Furuncles (inflamed follicles), carbuncles (accumulation of furuncles), abscesses, cysts ▪ Non-purulent ▫ Superficial cellulitis, erysipelas

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RISK FACTORS

▪ Skin inflammation ▫ Abrasion: wounds, eczema, radiation, broken skin between toes ▪ Lowered immunity ▫ Diabetes mellitus, alcohol abuse, HIV, older age ▪ Skin infection ▫ Tinea, impetigo, varicella, rash ▪ Edema ▫ Lymphatic obstruction, venous insufficiency ▪ Obesity

DIAGNOSIS DIAGNOSTIC IMAGING Ultrasound ▪ Subcutaneous fat separates into lobules ▫ Cobblestone appearance

COMPLICATIONS

▪ Recurrence, abscess formation, necrotizing fasciitis, osteomyelitis, sepsis

SIGNS & SYMPTOMS ▪ Fever, chills ▪ Localized inflammation ▫ Swelling ▫ Warmth ▫ Erythema with unclear borders (contrast to erysipelas—clear demarcations) ▫ Often painful ▪ Enlarged lymph nodes ▪ Purulent cellulitis associated with S. aureus infection

Figure 8.2 An ultrasound scan of the right lower limb demonstrating the cobblestone appearance of subcutaneous edema, in this case secondary to cellulitis.

LAB RESULTS

▪ Complete blood count (CBC) ▫ ↑ inflammatory markers: ↑ C-reactive protein (CRP), ↑ erythrocyte sedimentation rate (ESR), ↑ WBC count ▪ Wound, blood cultures ▫ Identify causative microbe

OTHER DIAGNOSTICS

▪ Clinical presentation ▫ Spreading inflammation of skin/ subcutaneous tissues

TREATMENT MEDICATIONS

Figure 8.3 An individual with cellulitis of the left leg.

▪ Antibiotics: second generation penicillins, first generation cephalosporins; vancomycin for MRSA

OTHER INTERVENTIONS

▪ Immobilization, elevation, dressings ▪ Drain abscess

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Chapter 8 Skin & Soft Tissue Inflammation & Infections

ERYSIPELAS osms.it/erysipelas PATHOLOGY & CAUSES ▪ Acute, non-necrotizing infection of upper dermis, superficial lymphatics; usually unilateral ▪ Well-defined demarcation between normal, infected tissue; non-purulent ▪ Usually caused by streptococci; most often Streptococcus pyogenes

▪ Elevated, warm, painful rash called “forest fire rash” (because it’s reddest at border) ▪ Vesicles may be present; may be bright, salmon red ▪ Inflammation of regional lymph nodes, lymphangitis in chronic infection

RISK FACTORS

▪ Very young/old age ▪ Breaks in skin ▫ Abrasions, trauma, eczema, radiation, bites ▪ Lowered immunity ▫ Diabetes mellitus, alcohol abuse, HIV, older age ▪ Skin infection ▫ Tinea, impetigo, varicella, rash ▪ Edema ▫ Lymphatic obstruction, venous insufficiency ▪ Obesity

COMPLICATIONS

▪ Lymphedema due to impaired lymphatic drainage ▪ Necrosis ▪ If spread hematogenously to other areas ▫ Arthritis, osteomyelitis, necrotizing fasciitis, glomerulonephritis

SIGNS & SYMPTOMS ▪ Initially, general infection symptoms ▫ Fever, chills, headache, fatigue ▪ Lesions ▫ Mostly on legs, but may be found on face, arms, fingers, toes

Figure 8.4 Erysipelas affecting the face of an elderly individual.

DIAGNOSIS LAB RESULTS

▪ Blood test ▫ CBC: ↑ CRP, ↑ ESR, ↑ WBCs; antistreptolysin titer O shows streptococcal involvement ▪ Wound, blood culture

OTHER DIAGNOSTICS ▪ Clinical presentation

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TREATMENT MEDICATIONS

▪ Antibiotics: oral penicillins/macrolides, vancomycin for MRSA, intravenous (IV) route in severe infection

FOLLICULITIS osms.it/folliculitis PATHOLOGY & CAUSES ▪ Hair follicle inflammation (pyoderma), usually infectious cause ▪ May also be due to persistent trauma (mechanical folliculitis) ▪ Pathogen enters hair follicle → inflammatory inflammatory response → infection causes a perifollicular infiltrate of lymphocytes, neutrophils, macrophages → pustule formation

CAUSES

▪ Bacterial ▫ S. aureus, Pseudomonas aeruginosa (hot-tub folliculitis) ▪ Viral ▫ Herpes simplex virus (HSV) ▪ Fungal ▫ Tinea barbae ▪ Rarely ▫ Autoimmune; oily skin in factory workers

RISK FACTORS

▪ Swimming pools, hot tubs ▪ Shaving against hair growth, tight clothes causing friction, profuse sweating (hyperhidrosis) ▪ Use of antibiotics, acne medication, topical corticosteroids ▪ Upper respiratory presence of S. aureus

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COMPLICATIONS

▪ Recurrence ▪ Furunculosis ▫ Deep infection of hair follicle → evolves into swollen nodule, may coalesce into carbuncles

SIGNS & SYMPTOMS ▪ Many small pustules, papules in areas of hair growth (e.g. face, legs, arms, back) ▫ Typical in groin, armpits ▫ Gram-negative infections more common on the face (areas of acne) ▫ Methicillin resistant S. aureus (MRSA) more common on the front trunk ▪ Itching, redness; often tender ▪ Does not appear in areas without hair growth (palms of hands, soles of feet) ▪ Sycosis vulgaris ▫ Multiple pustules on chin, upper lip; caused by S. aureus infection after shaving

DIAGNOSIS LAB RESULTS

▪ Gram stain, wound culture performed for treatment-resistant individuals ▪ Skin biopsy ▫ Differentiation from other skin disorders in persistent folliculitis

Chapter 8 Skin & Soft Tissue Inflammation & Infections

OTHER DIAGNOSTICS

▪ History ▫ Risk behavior/predisposition ▪ Clinical presentation

TREATMENT MEDICATIONS

▪ Topical antibiotics: mupirocin, clindamycin ▪ Oral antibiotics: tetracycline, cephalosporin ▫ Used in extensive involvement ▪ MRSA treatment: trimethoprim/ sulfamethoxazole, clindamycin, tetracycline ▪ Fungal treatment: fluconazole, itraconazole ▪ Viral treatment: acyclovir, valacyclovir, famciclovir

Figure 8.5 The clinical appearance of folliculitis.

OTHER INTERVENTIONS

▪ May resolve spontaneously ▪ Warm compress with antiseptic use ▪ Loose fitting clothing; avoiding shaving

HIDRADENITIS SUPPURATIVA osms.it/hidradenitis-suppurativa PATHOLOGY & CAUSES ▪ Chronic, pus-producing dermatological disorder ▫ AKA acne inversa ▪ Dysfunctional hair follicles/apocrine sweat glands → pore clogging → inflammation → painful abscesses

CAUSES Environmental ▪ Skin/clothes friction, hormonal changes, sweating, humidity Genetic ▪ Apocrine gland dysfunction, cellular disorders

RISK FACTORS

▪ Obesity, tight clothes, smoking, deodorant use, shaving ▪ More common for biologically-female individuals

COMPLICATIONS

▪ Scarring, bacterial infection, interstitial keratitis, sinus formation, fistula formation; squamous cell carcinoma (chronic lesions); depression

SIGNS & SYMPTOMS ▪ Red inflamed areas, painful bumps that drain with pus ▪ Presence of double comedones ▪ Mostly in axilla, groin, under breasts

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DIAGNOSIS

TREATMENT

OTHER DIAGNOSTICS

MEDICATIONS

Clinical presentation ▪ Sartorius/Hurley’s staging systems (determines severity; guides treatment) ▫ Stage I: solitary/multiple isolated abscess formation without scarring/ sinus tracts ▫ Stage II: recurrent abscesses; lesions may be single/multiple, widely separated; sinus tract formation ▫ Stage III: diffuse, regional involvement across; multiple interconnected sinus tracts, abscesses

▪ Corticosteroids, anti-androgen medication, oral antibiotics, tumor necrosis factor (TNF) inhibitors to ↓ inflammation

SURGERY

▪ Incision, drainage; sinus tract opening

OTHER INTERVENTIONS

▪ Clean affected area ▪ Laser treatments remove lesions, scarring

Behavioral ▪ Smoking cessation, weight loss

IMPETIGO osms.it/impetigo PATHOLOGY & CAUSES ▪ Highly infectious skin infection; affects superficial epidermis ▫ Commonly affects children ▫ Skin-to-skin spread possible ▪ Contact with carrier → pathogen enters intact/non-intact skin → incubation → lesion formation, spread over body through scratching ▪ Commonly caused by S. aureus, S. pyogenes

TYPES

▪ Nonbullous ▪ Bullous ▪ Ecthyma

RISK FACTORS

▪ Higher incidence in warm, humid climates ▪ Eczema, HSV, diabetes mellitus, malnutrition ▪ School, daycare

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COMPLICATIONS

▪ Cellulitis, poststreptococcal glomerulonephritis

SIGNS & SYMPTOMS ▪ Nonbullous ▫ Most common ▫ Red bump → blister → blisters rupture, ooze, form crusts → characteristic yellow scab formation ▪ Bullous ▫ Bullae on limbs, trunk ▫ Not painful ▫ Ruptured bullae become covered with thin, brown crust ▪ Ecthyma ▫ Deeper nonbullous impetigo appears on limbs ▫ Painful ▫ Evolves into yellow scabs ▪ Fever (rare); blisters may be painful, itchy

Chapter 8 Skin & Soft Tissue Inflammation & Infections

DIAGNOSIS LAB RESULTS

▪ Lesion culture ▫ Identify pathogen, adjust treatment

OTHER DIAGNOSTICS ▪ History ▪ Physical exam

TREATMENT MEDICATIONS

▪ Topical antibiotic ▪ Penicillins ▪ In case of MRSA, use trimethoprim/ sulfamethoxazole

OTHER INTERVENTIONS

▪ Clean with antiseptic to prevent spreading ▪ Topical antibiotic ▫ Penicillins ▫ In case of MRSA use trimethoprim/ sulfamethoxazole

Figure 8.6 Impetigo on the back of the neck of an adult male.

NECROTIZING FASCIITIS osms.it/necrotizing_fasciitis PATHOLOGY & CAUSES ▪ Potentially life-threatening infection ▫ Progressive destruction of deep soft tissue (subcutaneous fat, muscle fascia) ▪ Bacteria spread via subcutaneous tissue → release exotoxins → tissue destruction spreads along fascial planes

TYPES Type I: polymicrobial ▪ Causes: combination of aerobic, anaerobic bacteria ▫ Most common anaerobes: Bacteroides,

Clostridium, Peptostreptococcus ▫ Enterobacteriaceae: Escherichia coli, Klebsiella, Proteus, Enterobacter ▫ Facultative anaerobic streptococci ▪ Common sites ▫ Perineum (Fournier’s gangrene): impaired gastrointestinal/urethral mucosal integrity → spreads to anterior abdominal wall; gluteal muscles; scrotum, penis (in biological male); labia (in biological female) ▫ Cervical (head, neck): impaired oropharynx mucosa (often related to dental/odontogenic infection) → spreads to face, neck, mediastinum

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Type II: monomicrobial ▪ Causes: Group A Streptococcus, other beta-hemolytic streptococci, Staphylococcus aureus Type III: saltwater infection ▪ Cause: Vibrio vulnificus ▪ Rare Type IV: fungal infection

RISK FACTORS

▪ Immunosuppression ▫ HIV, diabetes, cirrhosis, corticosteroid use ▪ Peripheral vascular disease ▪ Trauma ▫ Injury, surgery ▪ IV drug abuse ▪ Childbirth ▪ Exposure of open wound to fresh/salt water, swimming pools, hot tubs ▪ Ludwig’s angina (submandibular region infection) ▪ Lemierre syndrome (septic thrombophlebitis located in jugular vein)

COMPLICATIONS ▪ Shock ▪ Organ failure ▪ Potentially fatal

SIGNS & SYMPTOMS Overlying skin ▪ May appear normal initially ▪ Later ▫ Warmth, erythema/violet/purple (violaceous), woody induration, edema, necrosis ▪ Bullae; may fill with serosanguinous fluid ▪ Subcutaneous emphysema (if infection with anaerobes) Systemic findings ▪ Pain ▫ Often out of proportion to exam findings ▪ Fever ▪ ↑ pulse ▪ ↓ perfusion (motling, pallor, altered level of consciousness) ▪ Hemodynamic instability (↓ BP)

DIAGNOSIS DIAGNOSTIC IMAGING CT scan ▪ Subcutaneous gas visualized in fascial planes

LAB RESULTS Blood ▪ ↑ WBCs, left shift; ↑ creatine phosphokinase; ↓ hemoglobin, ↑ glucose, ↓ sodium Urine ▪ Proteinuria Gram stain, cultures of skin ▪ Debrided tissue identifies organism(s)

Figure 8.7 Necrotizing fasciitis on the left leg. The dark areas represent progression to necrosis.

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OTHER DIAGNOSTICS

▪ Laboratory Risk Indicator for Necrotizing Fasciitis (LRINEC) score ▫ Score = 6: ↑ suspicion of necrotizing fasciitis ▫ Score = 8: strongly predictive

Chapter 8 Skin & Soft Tissue Inflammation & Infections

Figure 8.9 A histological section of subcutaneous tissue in a case of necrotizing fasciitis showing an inflammatory infiltrate in the fascia leading to necrosis.

TREATMENT MEDICATIONS

Figure 8.8 A CT scan in the coronal plane demonstrating the presence of gas in the fascial planes of the leg, consistent with a diagnosis of necrotizing fasciitis.

▪ Empiric IV antibiotics ▫ Carbapenem/beta-lactam-betalactamase inhibitor + vancomycin/ linezolid + clindamycin ▪ Hemodynamic support ▫ Fluids, vasopressors

SURGERY

▪ Direct surgical examination of skin, subcutaneous tissue, fascial planes, muscle → debridement of all devitalized, necrotic tissue ▪ Fasciotomy

OTHER INTERVENTIONS ▪ Hyperbaric oxygen

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ONYCHOMYCOSIS osms.it/onychomycosis PATHOLOGY & CAUSES ▪ Chronic fungal infection ▫ Nail bed, matrix, plate of toes/fingers ▪ Infection spread by direct contact from people, animals, soil, fomites (upholstery, hairbrushes, hats) ▪ Causative agents ▫ Dermatophytes (tinea unguium): most commonly Trichophyton rubrum ▫ Nondermatophyte molds: Aspergillus spp. ▫ Yeasts: most commonly Candida albicans ▪ Dermatophyte hyphae penetrate stratum corneum of skin, nails → manufacture keratinolytic proteases → invade living cells ▪ Spores of nondermatophyte (e.g. Aspergillus) lodge under nail/at lateral nail folds → colonization, spread toward cuticle Candida spp. → infect soft tissue around nail, penetrate nail plate

TYPES

Mixed pattern ▪ Combination of other types

RISK FACTORS

↑ age Biological male > female Communal showers, swimming pools Contributory/predisposing factors ↑ warmth, humidity Occlusive footwear Occupational ▫ Jobs that involve frequent hand washing; dishwashers, housekeepers ▪ Immunocompromised state (HIV, diabetes) ▪ Living with others affected by onychomycosis ▪ Chronic mucocutaneous fungal infection

▪ ▪ ▪ ▪ ▪ ▪ ▪

COMPLICATIONS ▪ ▪ ▪ ▪

Pain ↑ risk of bacterial coinfection, cellulitis Nail disfigurement Recurrence

Distal lateral subungual ▪ Initially affects distal corner of nail; eventually spreads toward cuticle ▪ Most common Proximal subungual ▪ Affects nail plate near cuticle; extends distally ▪ Sign of severely immunocompromised state White superficial ▪ Affects nail surface; may spread to cover entire nail Endonyx ▪ Affects interior of nail plate Total dystrophic ▪ Nail plate is completely destroyed

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Figure 8.10 Onychomycosis of the toe nails.

Chapter 8 Skin & Soft Tissue Inflammation & Infections

TREATMENT

SIGNS & SYMPTOMS ▪ Distal lateral subungual ▫ Yellow, brown, white discoloration; subungual hyperkeratosis; mild inflammation; onycholysis ▪ Proximal subungual ▫ Diffuse patches/transverse striate of white to yellow patches on nail plate ▪ Endonyx ▫ Discoloration, onycholysis ▪ White superficial ▫ Soft white spots on nail surface ▪ Total dystrophic ▫ Keratotic debris on thick, rigid nail bed ▪ Other associated features ▫ Coexisting tinea pedis infection (common) ▫ Chronic paronychia (proximal/lateral fold inflammation) ▫ Dermatophytoma (linear, yellow/white band of dermatophyte hyphae) ▫ Fungal melanonychia (black/brown discoloration; caused by pigmentproducing molds, fungi)

MEDICATIONS

▪ Topical triazole ▫ Efinaconazole ▪ Systemic ▫ Terbinafine (dermatophyte infections); itraconazole (yeast, non-dermatophyte infections) ▪ Coexisting tinea capitis ▫ Griseofulvin ▪ Keratolytic (urea) ▫ Reduces nail thickening

SURGERY

▪ Nail removal in some cases (nail avulsion)

OTHER INTERVENTIONS ▪ Laser (Nd:YAG) ▪ Photodynamic therapy

DIAGNOSIS LAB RESULTS

▪ Potassium hydroxide (KOH) microscopy ▫ Identifies fungal elements (e.g. fungal hyphae, pseudohyphae, yeast) ▪ Histopathological analysis using periodic acid-Schiff (PAS) stain ▫ Identifies fungal elements ▪ Fungal culture (e.g. dermatophyte test medium/DTM) ▫ Identifies organism

OTHER DIAGNOSTICS

▪ History, physical examination with characteristic findings

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PRESSURE ULCER osms.it/pressure-ulcer PATHOLOGY & CAUSES ▪ Localized skin, underlying-tissue injury ▫ Caused by unrelieved pressure/pressure in combination with friction, shearing forces ▪ AKA bedsores/decubitus ▪ Blood flow diminishes ▫ Pressure → ischemia → necrosis ▪ Bony prominences most commonly affected ▫ Sacrum, heels, hips, elbows

RISK FACTORS

▪ Reduced mobility ▫ Chronic/acute disease (e.g. hip fracture, stroke, Parkinson disease) ▫ Central/peripheral neural damage, altered level of consciousness, advanced age ▪ Reduced perfusion ▫ Atherosclerosis, peripheral vascular disease, hypotension, smoking ▪ Factors affecting skin structure ▫ Malnutrition, protein deficiency, skin moisture (incontinence, sweating) ▪ Diabetes mellitus

STAGING

▪ Stage I: nonblanchable erythema; skin intact, localized ▪ Stage II: partial thickness dermis loss; red wound bed; serum-filled blister; no skin sloughing ▪ Stage III: full thickness tissue loss; visible subcutaneous fat; raised wound edges (epibole); skin sloughs ▪ Stage IV: full thickness tissue loss; bone, muscle, tendon exposed; raised wound edges; skin sloughs/eschar formation

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▪ Unstageable: if filled with sloughed skin, scabs; diagnosis difficult ▪ Deep tissue injury: nonblanchable erythema, skin separation; no skin disruption

COMPLICATIONS

▪ Biofilm formation on wound → inflammation → delayed healing → wound dehiscence ▪ Wound, bone, joint infection; sepsis; fistulas; gangrene ▪ Malignant transformation rare

SIGNS & SYMPTOMS ▪ Ulceration (skin in contact with underlying surface) ▪ Fever, foul odor (if complicated by infection) ▪ May be painful

DIAGNOSIS LAB RESULTS

▪ Swab culture ▫ May help determine treatment in healing-resistant ulcers

OTHER DIAGNOSTICS ▪ Clinical presentation

TREATMENT MEDICATIONS

▪ Topical sulfadiazine cream

OTHER INTERVENTIONS

▪ Debridement of biofilm, dressing replacement, negative pressure therapy

Chapter 8 Skin & Soft Tissue Inflammation & Infections Prevention ▪ If bedridden, reposition at least every two hours (reduces chance of ulcer development) ▪ Use of special mattresses

ROSACEA osms.it/rosacea PATHOLOGY & CAUSES ▪ Chronic inflammatory cutaneous disorder ▫ Usually affects face (may extend to neck, upper chest, ears) ▫ Ocular involvement: dry, burning, itching, foreign-body sensation ▪ Typical onset: 30–50 years ▪ Defining features ▫ Persistent central facial erythema; intensity may be intermittent ▫ Phymatous changes (irregular, nodular skin), usually affecting nose (biologically-male > biologically-female individuals) ▪ Hyperactive vascular response, may extend to eyes (ocular rosacea) ▪ Triggered by warm weather, alcohol, certain foods, sun, stress

CAUSES

▪ Unknown ▪ May be innate immune system dysfunction; response to bacteria, UV → chronic inflammation

COMPLICATIONS

▪ Skin thickening, scarring, rhinophyma, ocular rosacea (blepharitis)

RISK FACTORS

▪ Genetic predisposition ▪ More common in biologically-female individuals, especially of Celtic/NorthernEuropean descent

SIGNS & SYMPTOMS ▪ Telangiectasia with erythema, papules, pustules ▪ Flushing Characteristics of different types ▪ Papulopustular ▫ Similar to acne, no comedones ▪ Phymatous ▫ Thick oily skin; mostly on nose, in biologically-male individuals ▪ Ocular (common) ▫ Conjunctivitis, keratitis, tearing, burning, telangiectasias ▪ Granulomatous ▫ Papules around eyes, cheeks ▪ Pediatric (rare) ▫ Never phymatous ▪ Neurogenic ▫ Pain, neurologic symptoms

DIAGNOSIS OTHER DIAGNOSTICS

▪ History; clinical exam with characteristic findings

TREATMENT MEDICATIONS

▪ Antibiotic (topical metronidazole) ▪ Topical azelaic acid ▪ Oral doxycycline

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OTHER INTERVENTIONS

▪ Avoid exacerbating factors (e.g. spicy food, alcohol, sun, stress) ▪ Regular sunscreen use ▪ Laser therapy ▫ Telangiectasia ablation

STAPHYLOCOCCAL SCALDED SKIN SYNDROME (SSS) osms.it/SSS PATHOLOGY & CAUSES ▪ Infectious, superficial skin disorder ▫ Skin blistering, desquamation ▪ AKA Ritter’s disease

CAUSES

▪ S. aureus produces epidermolytic exotoxin → enters skin → breaks down desmosomes between cells → peeling skin

COMPLICATIONS ▪ Cellulitis, sepsis

RISK FACTORS ▪ ▪ ▪ ▪

S. aureus infection Immunocompromised state Immature renal function/kidney disease Affects children < six years

SIGNS & SYMPTOMS ▪ Tender erythema with large desquamation areas, moist patches ▪ Nikolsky sign: skin peels at gentle touch ▪ Fever, malaise, appetite loss

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DIAGNOSIS DIAGNOSTIC IMAGING Chest X-ray ▪ Check for pneumonia as infectious cause; lobar infiltrates

LAB RESULTS Biopsy ▪ Epidermal splitting in stratum granulosum near skin surface Blood culture ▪ S. aureus

OTHER DIAGNOSTICS ▪ Clinical presentation

TREATMENT MEDICATIONS ▪ Antibiotics

NOTES

NOTES

URTICARIA & ERYTHEMA NODOSUM

GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Vascular reaction of the skin triggered by allergic reaction, irritation, or infection ▪ Vasodilation, increased vascular permeability → fluid leaks into interstitium → swelling/edema ▪ Possible elicitation of hypersensitivity reaction (immune system involved) ▪ Can be acquired (e.g. medications), associated with underlying illness (e.g. malignancies, autoimmune disorders), or have genetic predisposition

SIGNS & SYMPTOMS ▪ Range of dermatological manifestations: ▫ Erythema ▫ Swelling

▫ Urticaria, pruritus ▫ Raised or flat lesions

DIAGNOSIS ▪ Physical examination ▫ Based on appearance ▪ Patch testing to confirm and determine the allergy ▪ Screening for autoimmune or neoplastic etiologies

TREATMENT ▪ Identify/avoid triggers ▪ Address underlying cause ▪ Symptomatic management

ERYTHEMA NODOSUM osms.it/erythema-nodosum PATHOLOGY & CAUSES ▪ Acute skin eruption due to inflammation in the subcutaneous adipose tissue ▫ Most common form of acute panniculitis ▪ Chronic or recurrent forms are rare but may occur ▪ Presumably caused by a delayed hypersensitivity type IV reaction to a variety of antigens

CAUSES

▪ 30–50% unknown etiology ▪ Infections: Streptococcus spp., M. tuberculosis complex, M. leprae, M. pneumoniae, Yersinia spp., Histoplasma capsulatum, Coccidioides immitis ▪ Autoimmune disorders: inflammatory bowel disease, sarcoidosis, Behçet’s disease, medium-vessel vasculitis ▪ Medications: sulfonamides, oral contraceptives, amiodarone

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▪ Malignancies: hematological malignancies, carcinoid tumours, pancreatic cancer

SIGNS & SYMPTOMS ▪ Pre-eruptive phase ▫ Fever, malaise, and arthralgia ▪ Eruptions of red, painful, poorly defined plaques and nodules, most commonly located on shins, knees, arms, thighs, and torso → skin lesions gradually get softer and smaller until they completely disappear over the course of about two weeks

DIAGNOSTIC IMAGING Chest X-ray ▪ Additional evaluation to determine the underlying cause

TREATMENT MEDICATIONS

▪ Potassium iodide, corticosteroids and colchicine can be used in severe refractory cases

OTHER INTERVENTIONS

▪ Address underlying cause ▪ Symptomatic management ▫ Bedrest, leg elevation, compressive bandages, wet dressings, and nonsteroidal anti-inflammatory agents

Figure 9.1 A single area of erythema nodosum.

DIAGNOSIS ▪ Observation of typical skin lesions

LAB RESULTS

▪ Biopsy in uncertain cases ▪ Additional evaluation to determine the underlying cause ▫ Complete blood count, erythrocyte sedimentation rate, antistreptolysin-O titer, throat culture, urinalysis, intradermal tuberculin test, venereal disease research laboratory (VDRL), and cultures, as appropriate

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Figure 9.2 Erythema nodosum affecting the shins; a common site for this disease.

Chapter 9 Urticaria & Erythema

HEREDITARY ANGIOEDEMA (HAE) osms.it/hereditary-angioedema PATHOLOGY & CAUSES ▪ Small but important number of all cases of angioedema ▫ Increased vasodilation and vascular permeability → fluid leakage from deep blood vessels → angioedema ▫ Urticaria and pruritus are not present

▪ Attacks begin during childhood and become increasingly frequent and severe ▪ Frequency of attacks differs greatly, varying from weekly episodes to intervals longer than a year; discrepancies can occur among different individuals and at different times in the same individual

CAUSES

▪ Inherited in an autosomal dominant manner involving mutation of genes associated with C1-inhibitor (C1INH) that inhibits the complement pathway and is associated with coagulation factor XII ▫ Results in unregulated levels of bradykinin and other vasoactive substances → inflammation, vasodilation, and cellular injury ▫ Attack triggers may include minor trauma, mood and temperature changes, but often no obvious inciting event can be established

SIGNS & SYMPTOMS ▪ Recurrent attacks of angioedema ▪ Painless, nonpruritic, nonpitting swelling of extremities, genitalia, buttocks, eyelids, lips, tongue, larynx or gastrointestinal tract ▫ Gastrointestinal tract → nausea, vomiting, intense colicky abdominal pain, diarrhea, dehydration, and intense exhaustion → mimics a surgical emergency and unnecessary surgery could be performed ▫ Larynx → life-threatening airway obstruction → without treatment, death by asphyxia occurs in about 25% ▪ Tightness, tingling, or erythema marginatum corresponding to the affected area may precede the swelling ▪ Each episode usually resolves within 72 hours

Figure 9.3 Angioedema of the lips.

DIAGNOSIS DIAGNOSTIC IMAGING

▪ Imaging studies may be useful during attacks of gastrointestinal edema

LAB RESULTS

▪ Complement testing to assess alterations in the system

TREATMENT MEDICATIONS

▪ Management of attacks ▫ Intravenous C1-inhibitor concentrates, kallikrein inhibitors (ecallantide), bradykinin B2 receptor antagonists (icatibant) or, if those are unavailable, fresh-frozen plasma as an alternative

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▪ More than one episode in a month or high risk of developing laryngeal edema → longterm prevention ▫ Danazol (an androgen that increases levels of C4) ▫ C1-inhibitor concentrates

OTHER INTERVENTIONS

▪ Avoid specific stimuli that have previously led to attacks ▪ Avoid medications associated with attacks ▫ ACE inhibitors; medications containing estrogen

URTICARIA (HIVES) osms.it/urticaria PATHOLOGY & CAUSES ▪ Acute (< six weeks) or, rarely, chronic (> six weeks) skin eruption ▪ Acute form most common dermatologic disorder seen in emergency department ▫ Most often benign and self-limiting, though may rarely progress to lifethreatening angioedema or anaphylactic shock; strong tendency to recur ▪ Hypersensitivity reaction → mast cell degranulation and release of inflammatory mediators → increased vascular permeability → fluid leakage from superficial blood vessels → cutaneous lesion

TYPES

▪ Acute urticaria ▫ Single lesions usually last less than 24 hours ▪ Chronic urticaria ▫ May last six weeks or more

▪ Precipitants include psychological and physical stress, cold or hot temperature, pressure or vibration ▪ Physical urticaria is urticaria is induced by an exogenous physical stimulus such as scratching or firm stroking of the skin ▫ The most common type of physical urticaria is called a dermatographism

SIGNS & SYMPTOMS ▪ Wheals: skin eruption characterized by itchy, burning or stinging, red, raised plaques with well-defined erythematous margins and pale centers ▫ Individual lesions may coalesce ▫ New lesions may appear as others resolve ▪ Can occur anywhere, but common sites are areas exposed to pressure (e.g., trunk, distal extremities, ears)

CAUSES

▪ Assessment for potential causes includes “5 Is” ▫ Infection (bacterial/viral/fungal/parasitic) ▫ Injection of a drug/insect venom ▫ Inhaled substances (pollen, mold, dust) ▫ Ingestion of foods, drugs, chemicals ▫ Internal disease process such as an autoimmune disorder ▪ Vasculitis urticaria associated with autoimmune and malignant diseases

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Figure 9.4 Urticaria of the forearm.

Chapter 9 Urticaria & Erythema

DIAGNOSIS ▪ Typically based on appearance ▪ Patch testing to confirm and determine the allergy

LAB RESULTS

▪ Complete blood count ▪ Erythrocyte sedimentation rate ▪ Thyroid-stimulating hormone (rule out thyroid disease) ▪ Autoimmune screening

TREATMENT ▪ Avoid triggers ▪ Symptomatic management ▫ Antihistamines ▫ In severe cases, corticosteroids or leukotriene inhibitors ▫ Monoclonal antibodies and immunosuppressants may be used in refractory cases

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NOTES

NOTES

VESICULOBULLOUS DISEASES

GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Chronic skin blistering diseases; associated with underlying autoimmune, genetic pathology ▪ Destruction/malfunction of structural, anchoring proteins of skin

SIGNS & SYMPTOMS ▪ Skin blistering ▪ Mucosal erosions pruritus

DIAGNOSIS LAB RESULTS

▪ Skin biopsy ▪ Immunofluorescence testing

TREATMENT MEDICATIONS ▪ Corticosteroids

OTHER INTERVENTIONS ▪ Lifestyle modifications

BULLOUS PEMPHIGOID osms.it/bullous-pemphigoid PATHOLOGY & CAUSES ▪ Autoimmune skin disease; bubble-like blisters ▫ Bulla- = blister, pemphig- = bubble, oid= similar ▪ Chronic, relapsing, remitting, autoimmune subepithelial blistering disease ▫ Epithelial lesions (unlike pemphigus vulgaris) ▫ Can affect mucous membranes ▪ Presents with cutaneous bullae, mucosal erosions ▪ Rare disease, most common autoimmune blistering disorder

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CAUSES

▪ Autoantibodies against hemidesmosomal proteins ▫ Bullous pemphigoid antigen 2 (BPAg2) ▫ Collagen type XVII ▪ Autoantibodies may develop in response to certain drugs/infections ▪ Autoantibody activation → abnormal IgG/complement deposition in basement membrane zone → separation of dermis, epidermis → inflammatory reaction → formation of blisters, inflammatory mucosal erosions

RISK FACTORS

▪ More common in individuals > 60 years

Chapter 10 Vesiculobullous Diseases

SIGNS & SYMPTOMS ▪ Trunk, skin folds, extremities most affected ▪ May exhibit prodromal phase ▫ Pruritic papular lesions, resemble eczema ▪ Oral, ocular mucositis ▪ Blisters with inflammatory/noninflammatory base ▪ Unlike pemphigus vulgaris, bullae tense, difficult to rupture → negative Nikolsky sign ▪ After rupture, scarring uncommon

TREATMENT MEDICATIONS

▪ Topical/systemic corticosteroids ▫ Decrease blister formation, promote blister healing, improve quality of life

DIAGNOSIS LAB RESULTS

▪ Histopathological studies (confirm) ▫ Skin biopsies, immunofluorescent staining techniques ▪ Complete blood count (CBC) ▫ Eosinophilia ▪ ↑ IgG antibodies

Figure 10.1 The histological appearance of the skin in a case of bullous pemphigoid. In contrast to pemphigus vulgaris, the bullae are subepithelial. The bullae contain an infiltrate of eosinophils.

EPIDERMOLYSIS BULLOSA osms.it/epidermolysis-bullosa PATHOLOGY & CAUSES ▪ Skin breakdown → blisters ▫ Epidermo- = skin, lysis- = breakdown, bullosa- = blistering ▪ Rare condition, inherited group of disorders; blisters, erosions after minor skin trauma due to fragility of epithelial tissue ▪ May also affect mucous membranes, nails

CAUSES

▪ Mutations in structural proteins of skin responsible for tissue integrity ▫ Keratin, desmosomes, cell junctions, intermediate filaments, etc. ▫ Presence of some or all → determine

disease severity, clinical presentation

RISK FACTORS

▪ Genetic inheritance

SIGNS & SYMPTOMS ▪ Localized/systemic ▪ Skin blistering following minor trauma/ friction ▪ Nail dystrophy, loss (common) ▪ Oral lesions

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DIAGNOSIS LAB RESULTS

▪ Skin biopsy ▪ Immunofluorescence testing

OTHER DIAGNOSTICS ▪ Family history

TREATMENT ▪ No specific therapy

OTHER INTERVENTIONS

Figure 10.2 The hands of an individual with epidermolysis bullosa. Numerous consecutive bullae have caused scarring and induration of the skin, leading to contractures.

▪ Symptomatic care, wound care, infection prophylaxis, pain management

PEMPHIGUS VULGARIS osms.it/pemphigus-vulgaris PATHOLOGY & CAUSES ▪ Autoimmune, life-threatening blistering disorders of skin, mucous membranes ▪ Epithelial lesions ▫ Unlike bullous pemphigoid, which presents with subepithelial lesions ▪ Acantholysis: defining mechanism (acanthus- = thorny, lysis- = breakdown) ▫ Impaired adhesion between cells in spinous layer of epidermis

CAUSES

▪ Autoantibodies against desmoglein ▪ Autoantibody activation → attack of adhesion molecules → breakdown of intercellular adhesion → inflammatory reaction → blister formation

RISK FACTORS

▪ Adults ▪ Jewish people of Middle Eastern origin

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SIGNS & SYMPTOMS ▪ Oral mucosa (most common); can affect all mucosal surfaces ▪ Nikolsky sign → blister ruptures with pressure/friction ▫ Unlike bullous pemphigoid, where blisters difficult to rupture ▪ Easily-eroding painful blisters over erythematous skin ▪ No pruritus

DIAGNOSIS LAB RESULTS

▪ Skin biopsy ▪ Immunofluorescent staining ▪ Serum antibodies

Chapter 10 Vesiculobullous Diseases

TREATMENT MEDICATIONS

▪ Systemic steroids ▪ Immunosuppressive agents

Figure 10.3 A histological section of the skin in a case of pemphigus vulgaris. There is intraepidermal bulla formation in the superficial epidermis and characteristic tombstoning of the dermoepidermal junction.

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NOTES

NOTES

ADRENAL HYPERFUNCTION GENERALLY, WHAT IS IT? PATHOLOGY & CAUSES ▪ Overproduction of ≥ one adrenal hormones → complex systemic disorders

CAUSES

▪ Pituitary/adrenal endocrine tumors ▪ Idiopathic, iatrogenic ▪ Increased aldosterone → hyperaldosteronism ▪ Increased cortisol → Cushing syndrome

SIGNS & SYMPTOMS

DIAGNOSIS DIAGNOSTIC IMAGING CT scan/MRI ▪ Image tumors

LAB RESULTS

▪ Blood/urine tests; measure hormone levels

TREATMENT ▪ See individual disorders

▪ Diffuse systemic symptoms due to systemic endocrine effects

CONN'S SYNDROME osms.it/conns-syndrome PATHOLOGY & CAUSES ▪ Type of primary hyperaldosteronism

CAUSES

▪ Adrenal glands produce too much aldosterone due to benign tumor (adrenal adenoma) ▫ Forms in zona glomerulosa in adrenal gland

RISK FACTORS

▪ Individuals who are biologically female, 20–60 years old, with family history

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SIGNS & SYMPTOMS ▪ Headache, facial flushing (due to hypertension) ▪ Constipation, muscle weakness, arrhythmias (if severe, due to hypokalemia) ▫ Low potassium, high blood pressure (BP); unresponsive to treatment

Chapter 11 Adrenal Hyperfunction

DIAGNOSIS DIAGNOSTIC IMAGING CT scan ▪ Abdominal CT scan to differentiate tumor from idiopathic hyperaldosteronism

LAB RESULTS

▪ Adrenal vein sampling (CT scans do not detect lesions < 1cm/0.39in)

TREATMENT SURGERY

▪ Unilateral adrenalectomy

Figure 11.1 The gross pathological appearance of an adrenal cortical adenoma in an individual with Conn’s syndrome.

CUSHING'S SYNDROME osms.it/cushings-syndrome PATHOLOGY & CAUSES ▪ Endocrine disorder caused by increased cortisol ▪ Can be endogenous (caused by cortisol production inside body)/exogenous (iatrogenic) ▪ Pseudo Cushing’s syndrome: estrogencontaining oral contraceptive pills → increased cortisol-binding globulin → increased total cortisol ▫ Active hormone total free cortisol levels found in a 24-hour urine sample normal

CAUSES Primary ▪ Tumor in zona fasciculata of adrenal gland secretes cortisol ▪ Adenoma (benign)/adenocarcinoma (malignant) Secondary ▪ Iatrogenic

▫ Glucocorticoid steroid medications to treat inflammatory, autoimmune disorders (e.g. asthma, rheumatoid arthritis, eczema, immunosuppression); most common ▪ Pituitary adenoma (benign) ▫ Leads to excess adrenocorticotropic hormone (ACTH), adrenal cortisol secretion ▪ Adrenal Cushing’s disease ▫ Adrenal gland tumors/hyperplastic adrenal glands/nodular adrenal hyperplasia of adrenal glands produce excess cortisol ▪ Ectopic ACTH ▫ Increased ACTH secreted from benign bronchial carcinoid tumors/malignant oat-cell carcinoma

COMPLICATIONS

▪ Metabolic syndrome, diabetes, infection due to immunosuppression, fragility fractures due to osteoporosis

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SIGNS & SYMPTOMS ▪ Fat redistribution due to glucose release → insulin release ▪ Muscle, bone, skin breakdown due to protein breakdown ▪ Hypertension due to corticosteroids crossreacting with mineralocorticoid receptors ▪ High cortisol → feedback inhibition of GH-releasing hormone (GRH) → disrupts ovarian, testicular function

DIAGNOSIS DIAGNOSTIC IMAGING CT scan ▪ Adrenal glands (primary Cushing’s) ▪ Chest, abdomen, pelvis (ectopic ACTH production) MRI ▪ Pituitary gland (Cushing’s disease)

LAB RESULTS

▪ ↑ free cortisol in 24-hour urine sample ▪ Cortisol blood/saliva test: ↑ cortisol ▫ Performed in evening when cortisol levels are normally low

OTHER DIAGNOSTICS

Figure 11.2 Abdominal striae in an individual with Cushing’s syndrome.

MNEMONIC: BAM CUSHINGOID

Signs & symptoms of Cushing’s syndrome Buffalo hump: fat redistribution Amenorrhea Moon face: fat redistribution Psychosis/agitation: previously, Crazed Ulcers Skin changes: acne, purple striae/stretch marks Hypertension Infection: due to immunosuppression Necrosis of femoral head Glaucoma Osteoporosis: causing fragility fractures Immunosuppression Diabetes

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Dexamethasone suppression test ▪ Differentiates endogenous, exogenous Cushing’s syndrome ▪ Measure cortisol change after dexamethasone (exogenous steroid) ▪ Endogenous Cushing’s syndrome: cortisol unchanged, negative feedback cycle broken by autonomous endocrine tumor in pituitary, adrenal, etc. (ectopic ACTH) ▪ Positive dexamethasone test ▫ High ACTH: ACTH-producing tumor ▫ Low ACTH: adrenal tumor, causing pituitary ACTH suppression Long dexamethasone suppression test ▪ If high ACTH ▪ Differentiates ACTH-producing pituitary tumor, ectopic ACTH-producing tumor (e.g. small cell lung cancer) ▫ Cushing’s disease (pituitary adenoma): cells partly responsive to negative feedback → cortisol decrease ▫ Ectopic ACTH-producing tumor: no negative feedback → cortisol unchanged

Chapter 11 Adrenal Hyperfunction

TREATMENT MEDICATIONS

▪ Cortisol inhibitors ▫ Esp. if surgery ruled out by ectopic ACTH production/metastatic adrenal carcinoma ▪ Wean steroid medications ▫ For Iatrogenic Cushing’s ▫ Sudden withdrawal → adrenal crisis

SURGERY

▪ Transphenoidal resection of pituitary gland ▫ For Cushing disease ▪ Surgical resection ▫ For adrenal adenoma

Figure 11.3 A large fat deposit at the upper back in an individual with Cushing’s syndrome.

HYPERALDOSTERONISM osms.it/hyperaldosteronism PATHOLOGY & CAUSES ▪ Adrenal gland produces excess aldosterone → hypertension (high blood pressure), hypokalemia (decreased blood potassium) ▪ Increased aldosterone → sodium, water retention → increased blood volume → hypertension

TYPES Primary ▪ Idiopathic (2/3 of cases): overproduction from both adrenal glands ▪ Conn’s syndrome (1/3 of cases): benign adrenal tumor → excess aldosterone ▪ Familial hyperaldosteronism: rare genetic condition, adrenocorticotropic hormone (ACTH) → adrenal aldosterone, renin secretion

angiotensin-aldosterone axis activation → hyperaldosteronism ▪ Decreased blood flow to kidneys (e.g. renal stenosis) ▪ Renal-secreting neoplasms

COMPLICATIONS

▪ Hypertension, hypokalemia ▫ Heart disease (ischemic heart disease, arrhythmias), vascular disease, renal disease, stroke, alkalosis (due to increased hydrogen ion excretion)

SIGNS & SYMPTOMS ▪ Headache, facial flushing (due to hypertension) ▪ Constipation, muscle weakness, arrhythmias (if severe, due to hypokalemia)

Secondary ▪ Hypotension (e.g. congestive heart failure, cor pulmonale, hypoalbuminemia, cirrhosis, ascites, coarctation of aorta) → renin-

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DIAGNOSIS LAB RESULTS

▪ Renin, aldosterone levels in blood and urine ▪ Primary ▫ Increased aldosterone, decreased renin; potassium decreased/normal ▫ Metabolic acidosis secondary to hypokalemia ▪ Secondary ▫ Increased renin, aldosterone in blood

OTHER DIAGNOSTICS ▪ Increased blood pressure

TREATMENT ▪ Goal: prevent complications of hyperaldosteronism on organs (e.g. ventricular hypertrophy, heart failure, stroke, myocardial infarction, atrial fibrillation, metabolic syndrome)

MEDICATIONS

▪ Potassium-sparing diuretic/aldosterone antagonist ▫ Spironolactone ▪ Additionally ▫ Thiazide diuretics, angiotensin converting enzyme inhibitors (ACE) inhibitors, calcium channel antagonists, angiotensin II blockers

OTHER INTERVENTIONS

▪ Control BP via lifestyle ▫ Sodium restriction, weight management, regular exercise ▪ Second-line ▫ Thiazide diuretics, ACE inhibitors, calcium channel antagonists, angiotensin II blockers

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NOTES

ADRENAL HYPERPLASIA

CONGENITAL ADRENAL HYPERPLASIA osms.it/congenital-adrenal-hyperplasia PATHOLOGY & CAUSES ▪ Congenital adrenal hyperplasia (CAH) is a group of autosomal-recessive metabolic disorders characterized by defects in certain genes resulting in a partial/total lack of an enzyme involved in steroidogenesis within the adrenal cortex ▫ ↓ steroid hormone production → compensatory ↑ ACTH → adrenal hyperplasia ▫ ↓ cortisol → cortisol precursor accumulation → steroid precursors shunted to overproduction of other ACTH-dependent adrenal steroids

TYPES 21-hydroxylase deficiency ▪ Defective gene: CYP21A2 ▪ Most common type of CAH ▫ Classic: neonatal/early infancy genital ambiguity in females, adrenal insufficiency; classic non-salt-losing (simple virilizing): female fetus virilization; classic salt-losing ▫ Non-classic (late onset): presents later in life (child-adult) with androgen excess signs; non-salt-losing 17-alpha hydroxylase deficiency ▪ Defective gene: CYP17A1 ▪ Rare ▪ Steroid precursors for testosterone, cortisol synthesis shunted to aldosterone

11-beta-hydroxylase deficiency ▪ Defective gene: CYP11B1 ▪ 7% of CAH cases ▪ Lack of enzyme prevents conversion of 11-deoxycortisol to cortisol ▪ 11-deoxycortisol (aldosterone precursor) has mild mineralocorticoid effect → biphasic effect on mineralocorticoid balance

SIGNS & SYMPTOMS 21-hydroxylase deficiency ▪ Varies by subtype 17-alpha hydroxylase deficiency ▪ ↓ cortisol → corticosterone presence prevents adrenal crisis ▪ Mineralocorticoid excess → secondary hypertension; hypokalemic alkalosis ▪ Gonadocorticoid deficiency (males: mildly underdeveloped genitalia, hypergonadotropic hypogonadism; females: abnormal pubertal sexual development, infertility) 11-beta-hydroxylase deficiency ▪ Androgen excess → external genitalia virilization, sexual ambiguity (females) ▪ Biphasic mineralocorticoid balance → possible salt-wasting crisis in early infancy; secondary hypertension and hypokalemia in childhood and adult life

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TREATMENT MEDICATIONS

Figure 12.1 Clitoromegaly with normal labia and introitus in a biologically female individual with 21-hydroxylase deficiency.

DIAGNOSIS ▪ Clinical presentation ▫ Steroid imbalance evidence ▪ Most cases identified via newborn screening

SURGERY

LAB RESULTS

▪ Address complications (e.g., fluid, electrolyte imbalance) ▪ Monitor ▫ Serum 17-hydroxyprogesterone, renin, electrolytes ▫ Blood pressure ▫ Bone age and density ▫ Tanner staging ▫ Weight ▫ Growth velocity

Serum hormone levels ▪ 21-hydroxylase deficiency ▫ ↓ sodium (salt-losing type), ↑ potassium (salt-losing type) ▫ Serum markers: ↑↑ serum 17-hydroxyprogesterone, ↑ 21-deoxycortisol) ▪ 17-alpha hydroxylase deficiency ▫ ↑ sodium, ↓ potassium ▫ Serum markers: ↑ pregnenolone, ↑ progesterone, ↑ 11-deoxycorticosterone, ↑ 11-deoxycortisol ▪ 11-beta-hydroxylase deficiency ▫ ↑ sodium, ↓ potassium ▫ Serum markers: ↑ 11-deoxycorticosterone, ↑ 11-deoxycortisol) Genetic testing Prenatal diagnosis ▪ By chorionic villus sampling at 10–12 weeks

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▪ 21-hydroxylase deficiency ▫ Exogenous glucocorticoid (hydrocortisone), mineralocorticoid (fludrocortisone) ▪ 11-beta-hydroxylase deficiency ▫ Exogenous glucocorticoid (hydrocortisone), antihypertensives ▪ 17-alpha hydroxylase deficiency ▫ Exogenous glucocorticoid (hydrocortisone), sex steroid replacement beginning at puberty, antihypertensives ▪ If CAH diagnosed prenatally ▫ Dexamethasone

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▪ Potential atypical genitalia correction

OTHER INTERVENTIONS

Chapter 12 Adrenal Hyperplasia

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NOTES

ADRENAL HYPOFUNCTION GENERALLY, WHAT IS IT? PATHOLOGY & CAUSES ▪ Disorders of adrenal cortex resulting in loss of essential steroid hormones (corticosteroids, mineralocorticoids, androgens)

CAUSES

▪ Addison’s disease ▫ Multiple causes; primarily autoimmune ▪ Waterhouse–Friderichsen syndrome (WFS) ▫ Primarily caused by meningococcal infection, sepsis

COMPLICATIONS

▪ Adrenal crisis ▫ Addison’s, WFS ▪ Disseminated intravascular coagulation ▫ WFS

SIGNS & SYMPTOMS ▪ Hypoglycemia, hypotension, electrolyte imbalance ▪ Adrenal crisis: dehydration, electrolyte imbalance, shock

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DIAGNOSIS DIAGNOSTIC IMAGING Ultrasound, CT scan ▪ Visualizes enlarged, calcified, solid/ hemorrhagic glands

OTHER DIAGNOSTICS

▪ Rapid adrenocorticotropic hormone (ACTH) test confirms adrenal hypofunction

TREATMENT MEDICATIONS

▪ Hormone replacement: hydrocortisone, fludrocortisone ▫ Dehydroepiandrosterone (DHEA) in some cases

OTHER INTERVENTIONS ▪ Treat underlying cause

Chapter 13 Adrenal Hypofunction

ADDISON'S DISEASE osms.it/addisons-disease PATHOLOGY & CAUSES ▪ Endocrine disorder characterized by primary adrenal insufficiency due to bilateral adrenal cortex destruction ▪ Adrenal cortex destruction → ↓ production of adrenocortical hormones → glucocorticoid, mineralocorticoid, androgen deficiency ▫ Adrenals only source of androgens in biologically-female individuals; testicles supply androgens in biologically-male individuals ▪ ↓ cortisol → ↓ adrenal medullary epinephrine synthesis → ↓ serum epinephrine, compensatory norepinephrine production

CAUSES

▪ Autoimmune destruction (e.g. polyglandular autoimmune syndrome type 2) ▪ Infection (e.g. tuberculosis, fungal infections) ▪ Adrenal hemorrhage (e.g. WFS) ▪ Adrenal vein thrombotic infarction ▪ Metastatic infiltration ▪ Drugs that inhibit cortisol biosynthesis (e.g. ketoconazole, suramin)

norepinephrine ▪ Hyponatremia ▫ Mineralocorticoid deficiency → sodium loss + ↓ volume due to ↑ vasopressin secretion secondary to ↓ cortisol ▪ Hyperkalemia, mild hyperchloremic acidosis due to mineralocorticoid deficiency ▪ Hypoglycemia due to ↓ gluconeogenesis ▪ Gastrointestinal ▫ Abdominal pain, anorexia, nausea, vomiting → weight loss ▪ Intolerance of temperature extremes ▪ Hyperpigmentation due to ACTH stimulation of melanocyte activity ▪ Vitiligo due to autoimmune destruction of melanocytes ▪ Salt cravings due to hyponatremia ▪ ↓ libido, ↓ pubic, axillary hair in biologicallyfemale individuals due to ↓ adrenal androgens ▪ Psychiatric symptoms (e.g. confusion, depression) ▪ Addisonian crisis triggered by stress ▫ Hypoglycemia ▫ Vasomotor/circulatory collapse; shock may be unresponsive to vasopressors due to ↓↓ cortisol, potentially fatal

COMPLICATIONS

▪ Addisonian crisis precipitated by physiologically stressful events (e.g. surgical procedures, trauma, infection, dehydration)

SIGNS & SYMPTOMS ▪ Fatigue, weakness are common initial symptoms ▪ Hypotension, postural hypotension, syncope ▫ ↓ glucocorticoids → ↓ vascular responsiveness to angiotensin II and

Figure 13.1 An example of increased skin pigmentation in an individual with Addison’s disease (left) and resolution post-treatment (right).

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▪ ↑ serum ACTH ▪ Plasma renin activity ▫ ↑ renin, compensatory to ↓ aldosterone ▪ ↓ serum sodium, ↑ serum potassium, mild hyperchloremic acidosis

OTHER DIAGNOSTICS

Figure 13.2 Hyperpigmentation of the gums in an individual with Addison’s disease.

DIAGNOSIS DIAGNOSTIC IMAGING Abdominal CT scan ▪ Enlarged adrenal glands with tuberculosis/ malignant mass; small if autoimmune adrenalitis/advanced tuberculosis; calcifications if infectious cause ▪ Visualizes adrenal gland hemorrhage/ thrombosis Abdominal X-ray ▪ Adrenal calcifications if infectious cause

LAB RESULTS

▪ ↓ serum cortisol ▫ Blood draw in AM when cortisol levels should peak

▪ History, physical examination with characteristic findings ▪ Rapid ACTH test ▫ Administer 250µg synthetic ACTH (cosyntropin) intravenous (IV)/ intramuscular (IM) → insufficient/no cortisol produced in response

TREATMENT MEDICATIONS

▪ Life-long glucocorticoid replacement; e.g. hydrocortisone, mineralocorticoid replacement ▫ E.g. fludrocortisone ▪ Biologically-female individuals may need low dose dehydroepiandrosterone (DHEA) ▪ Addisonian crisis ▫ Glucocorticoids, epinephrine, glucose, isotonic fluids ▪ Stress dose of glucocorticoid during any surgical intervention/significant trauma ▫ Premedication/induction-maintenancegradual titration to baseline dose

WATERHOUSE–FRIDERICHSEN SYNDROME osms.it/waterhouse-friderichsen PATHOLOGY & CAUSES ▪ Uncommon, severe syndrome characterized by adrenal failure related to overwhelming infection, adrenal gland hemorrhage

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▪ Bacterial infection → septicemia → release of bacterial endotoxins → endothelial dysfunction → seeding of bacterial emboli into adrenals → bleeding into one/both

Chapter 13 Adrenal Hypofunction adrenal glands → hemorrhagic necrosis → adrenocortical insufficiency → adrenal crisis

CAUSES

▪ Associated with sepsis caused by organisms (e.g. Neisseria meningitidis (80% of cases), Streptococcus pneumoniae, Neisseria gonorrhoeae, Escherichia coli, Haemophilus influenzae, Staphylococcus aureus)

COMPLICATIONS

▪ Disseminated intravascular coagulation (DIC) ▪ Profound shock ▪ Potentially life-threatening

SIGNS & SYMPTOMS ▪ Initial presentation: malaise, fever, chills, headache, vomiting ▪ Signs of shock (e.g. hypotension, tachycardia, tachypnea) ▪ Widespread petechial lesions → purpura → plaques ▪ Cyanosis, AKA dusky gray color of skin

DIAGNOSIS

OTHER DIAGNOSTICS

▪ History, physical examination with characteristic findings ▪ Rapid ACTH test ▫ Insufficient/no cortisol produced indicates adrenal insufficiency

TREATMENT MEDICATIONS

▪ Adrenal insufficiency ▫ IV glucocorticoids ▪ Infection ▫ Antibiotics (e.g. IV penicillin, cefotaxime/ ceftriaxone if meningococcal infection) ▪ Shock ▫ IV fluids, vasopressors, supplemental oxygen ▪ DIC ▫ Packed red blood cells (RBCs), cryoprecipitate, fresh frozen plasma, platelets

OTHER INTERVENTIONS

▪ Prevention ▫ Routine vaccination against meningococcal disease

DIAGNOSTIC IMAGING CT scan ▪ Identifies blood collection within adrenals Ultrasound ▪ Adrenal hemorrhage appears solid, diffusely echogenic

LAB RESULTS

▪ Blood culture ▫ Identifies causative organism ▪ Adrenal insufficiency ▫ ↓ serum sodium, ↓ glucose, ↑ potassium, ↓ serum cortisol ▪ DIC ▫ ↑ fibrinogen degradation products, ↑ D-dimer levels, prolonged PT, aPTT

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NOTES

DIABETES MELLITUS GENERALLY, WHAT IS IT? PATHOLOGY & CAUSES ▪ A group of chronic disorders characterized by abnormal glucose metabolism resulting in elevated blood glucose levels

CAUSES

▪ Genetic predisposition, lifestyle factors

COMPLICATIONS

▪ Hyper/hypoglycemia, diabetic ketoacidosis, hyperosmolar hyperglycemic state (HHS), vascular and neurological pathology, renal disease

SIGNS & SYMPTOMS ▪ Symptomatic hyperglycemia

DIAGNOSIS LAB RESULTS Urinalysis ▪ Albuminuria, glycosuria Blood tests ▪ ↑ Non-fasting/fasting glucose tests ▪ ↑ HbA1c ▪ Diabetic ketoacidosis (DKA) ▫ Glucose > 250mg/dL ▪ Hyperosmolar hyperglycemic state (HHS) ▫ Glucose >600mg/dL

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OTHER DIAGNOSTICS Physical examination ▪ Fundoscopic exam ▫ Cotton wools spots, flare hemorrhages ▪ Monofilament testing ▫ ↓ sensation ▪ Lower extremities ▫ ↓ pedal pulses, presence of ulcers

TREATMENT MEDICATIONS

▪ Diabetes mellitus type I ▫ Insulin ▪ Diabetes mellitus type II ▫ Oral antidiabetic agents, insulin

OTHER INTERVENTIONS

▪ Metabolism regulation with diet ▪ Weight loss, exercise ▪ Smoking cessation

Chapter 14 Diabetes Mellitus

DIABETES MELLITUS TYPE 1 osms.it/diabetes-mellitus-type-1 PATHOLOGY & CAUSES ▪ Chronic metabolic disease; destroys pancreatic beta cells → insulin deficiency, hyperglycemia ▪ Diabetes (going through) mellitus (honey/ sweet) ▪ ↓ insulin → glucose unable to enter cells → hyperglycemia ▫ Cells “starve” due to no glucose for energy generation → polyphagia, fatigue ▫ Glucose exceeds renal threshold → glycosuria → osmotic diuresis → polyuria → hypovolemia ▫ ↑ serum osmolality + hypovolemia → polydipsia ▫ Endothelial glycosylation (endothelial cells unable to downregulate glucose transport in setting of extracellular hyperglycemia) → damage to endothelial cells → microvascular damage + accelerated atherosclerosis in large vessels ▫ Narrowing of vascular lumens → ↓ microcirculation → tissue ischemia, cellular loss ▫ ↓ blood supply to nerves → segmental demyelination → slowing of nerve conduction neuropathy

Latent autoimmune diabetes ▪ Progressive form of autoimmune diabetes ▪ Onset at > 30 years old

RISK FACTORS

▪ Genetic predisposition ▪ Multiple gene polymorphisms associated with DM Type I ▫ HLA-DQalpha, HLA-DQbeta, HLA-DR, PTPN22 gene, CTLA-4

COMPLICATIONS

▪ ↑ risk of infection, delayed wound healing; ↑ risk of amputations ▪ Diabetic ketoacidosis ▫ Hyperglycemia (> 250mg/dL), ketonemia, metabolic acidosis ▪ Neuropathy ▫ Autonomic, somatic

Microvascular ▪ Retinopathy, nephropathy, erectile dysfunction Macrovascular ▪ Cardiovascular, cerebrovascular, and peripheral vascular disease

TYPES Type IA: immune-mediated diabetes ▪ Most common ▪ Autoimmune destruction of pancreatic beta-cells ▪ Type IV hypersensitivity response Type IB: idiopathic diabetes ▪ No evidence of autoimmunity ▪ Varying degrees of low insulin, episodes of ketoacidosis

Figure 14.1 A retinal photograph of an individual who has received laser treatment for proliferative retinopathy as a consequence of diabetes mellitus.

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DIAGNOSIS LAB RESULTS Non-fasting/random glucose test ▪ 200mg/dL Fasting glucose test ▪ Prediabetes: 110–125mg/dL ▪ Diabetes: ≥ 126mg/dL HbA1c glycated hemoglobin test ▪ Indicates glucose level control over prolonged period ▪ Prediabetes: 5.7–6.4% HbA1c ▪ Diabetes: > 6.5% HbA1c Urinalysis ▪ Albuminuria, glycosuria

Figure 14.2 An individual with diabetes mellitus and charcot arthropathy of the left ankle. Lack of sensation to the joint causes results in repetitive microtrauma which eventually leads to bony destruction and joint malformation.

SIGNS & SYMPTOMS ▪ Classic presentation: polyuria, polydipsia, polyphagia (3Ps) ▫ Dehydration → dry mucous membranes/ decreased skin turgor ▪ Fatigue, lethargy ▪ Blurred vision ▪ Gastroparesis → constipation ▪ Paresthesias ▪ Unexplained weight loss ▪ Mild hyperglycemia, may be asymptomatic ▪ Volume depletion: symptomatic moderate to severe hyperglycemia ▫ Dry mucous membranes, hypotension, poor skin turgor

Differentiation from Type II diabetes ▪ Autoantibodies against beta cells: glutamic acid decarboxylase autoantibodies (GADA), insulinoma-associated-2 autoantibodies (IA-2A), islet cell autoantibodies, insulin autoantibodies (IAA), zinc transporter 8 (ZnT8Ab) ▪ C-peptide: insulin low

OTHER DIAGNOSTICS Physical examination ▪ Fundoscopic exam: cotton wools spots, flare hemorrhages ▪ Monofilament testing: ↓ sensation ▪ Lower extremities: ↓ pedal pulses, presence of ulcers

Figure 14.3 A neuropathic ulcer on the heel of an individual with diabetes mellitus.

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Chapter 14 Diabetes Mellitus

TREATMENT MEDICATIONS

▪ Lifelong insulin therapy (short-acting insulin/insulin pump)

Figure 14.4 The histological appearance of a glomerulus in an individual with diabetes mellitus. The glomerular basement membrane is thickened and there is mesangial proliferation leading to the appearance of a Kimmelstiel–Wilson nodule.

DIABETES MELLITUS TYPE II osms.it/diabetes-mellitus-type-2 PATHOLOGY & CAUSES ▪ Metabolic disorder; varying degrees of resistance to insulin ▪ Most common type of diabetes in adults (90–95%)

CAUSES

▪ Insulin resistance (inherited, acquired) → beta cell hyperplasia, hypertrophy → ↑ beta cell secretion of insulin + amylin production → hyperinsulinemia, amyloid deposits within beta cells → beta cell exhaustion, dysfunction, atrophy → ↓ insulin production → hyperglycemia ▪ Genetic polymorphisms associated with DM Type II ▫ TCF7L2, GCK, HNF1B, WFS1, KCNJ11, PPARG, IRS1

▪ Family history, physical inactivity, poor diet, obesity, > 45 years old, history of gestational diabetes, prediabetes, polycystic ovary syndrome (PCOS), medications that adversely affect glucose tolerance/↑ blood glucose levels (e.g. glucocorticoids, atypical antipsychotics, thiazide diuretics)

COMPLICATIONS

▪ ↑ risk of cardiovascular, peripheral artery disease

Hyperosmolar hyperglycemic state (HHS) ▪ Profound hyperglycemia (>600mg/dL) → ↑ plasma osmolarity (>320mOsm/kg) → systemic, cellular dehydration ▪ Mental status changes; thrombotic events; polyuria; mild ketonemia, acidosis; high mortality rate

RISK FACTORS

▪ Multifactorial; interaction between genetic, environmental, behavioral factors

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SIGNS & SYMPTOMS ▪ Polyuria, polydipsia, polyphagia; glycosuria, weakness, unexplained weight loss, blurred vision; acanthosis nigricans (hyperpigmented cutaneous patches) related to insulin resistance

DIAGNOSIS LAB RESULTS Non-fasting/random glucose test ▪ 200mg/dl Fasting glucose test ▪ Prediabetes: 110–125mg/dl ▪ Diabetes: 126mg/dl Oral glucose tolerance test ▪ Prediabetes: 99–140mg/dl ▪ Diabetes: ≥ 200 HbA1c glycated hemoglobin ▪ Prediabetes: 5.7–6.4% ▪ Diabetes: > 6.5%

Differentiation from Type I ▪ Autoantibodies ▫ Absent ▪ C peptide ▫ Normal/elevated

OTHER DIAGNOSTICS Physical examination ▪ Fundoscopic exam: cotton wool spots, flare hemorrhages ▪ Monofilament testing: ↓ sensation ▪ Lower extremities: ↓ pedal pulses, presence of ulcers

TREATMENT MEDICATIONS

▪ Metformin; sulfonylureas, meglitinides ▪ Long/short-acting insulin

OTHER INTERVENTIONS

▪ Weight loss, exercise, diet management

DIABETIC KETOACIDOSIS osms.it/diabetic-ketoacidosis PATHOLOGY & CAUSES ▪ Medical emergency due to cell starvation → altered mental status ▪ Arises with stress/infection, individuals with poorly regulated glucose levels ▪ Epinephrine → glucagon → lipolysis → free fatty acids → ketone bodies, acetoacetic, hydroxybutyric acid → ↑ blood acidity ▪ Occurs in Type I, long-standing Type II DM when body completely stops producing insulin

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COMPLICATIONS

▪ Acute cerebral edema ▫ High glucose → osmotic shift of water to extracellular fluid ▪ Hyperkalemia due to H+/K+ exchange mechanisms in regulating acidosis → arrhythmias

RISK FACTORS

▪ Infection, stress, irregular insulin use

Chapter 14 Diabetes Mellitus

SIGNS & SYMPTOMS ▪ Anion gap metabolic acidosis, bicarbonate low → insulin stops letting potassium into cells, potassium acts as buffer by letting hydrogen into cells → hyperkalemia → ultimately lost in urine ▪ Dehydration (individual extremely thirsty), nausea, vomiting, mental status change ▪ Kussmaul respiration ▫ Deep, labored breathing to move carbon dioxide out of blood ▪ Acetone breath ▫ Ketone bodies break down into acetone → excrete as gas through lungs

DIAGNOSIS LAB RESULTS

▪ Hyperkalemia (> 5.2mg/dl), initially with hypokalemia (< 3.5mg/dl) ▪ Glucose > 250mg/dL

TREATMENT MEDICATIONS Insulin ▪ Lower blood glucose ▪ Monitor carefully ▫ Rapid decrease in serum glucose → osmotic shift of water intracellularly → risk for cerebral edema → increased ICP ▪ Treat cerebral edema with hypertonic solution (3% saline, mannitol) Fluid, electrolyte replacement ▪ 0.9% normal saline + potassium (KCl); serum K+ levels drop as insulin shifts potassium intracellularly → risk for hypokalemia ▪ Bicarbonates ▫ Reverse acidosis

OTHER INTERVENTIONS ▪ Fluids, rehydration

Acid base status ▪ Ketones present in urine; arterial gas, bicarbonates measured; pH < 7.3

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NOTES

ENDOCRINE TUMORS GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Tumors arising from endocrine gland tissue ▪ May be functional (excess secretion of one/ more hormones); nonfunctional (clinically silent)

LAB RESULTS

▪ Measure hypersecretion degree

OTHER DIAGNOSTICS

▪ History, physical examination with characteristic findings

TREATMENT

SIGNS & SYMPTOMS ▪ Depends on degree of hypersecretion, mass effect

DIAGNOSIS DIAGNOSTIC IMAGING CT scan/MRI ▪ Tumor visualization, staging

MEDICATIONS

▪ Chemotherapy ▪ Hormone replacement/suppression

SURGERY ▪ Resection

OTHER INTERVENTIONS ▪ Radiation therapy ▪ Address complications

ADRENAL CORTICAL CARCINOMA osms.it/adrenal-cortical-carcinoma PATHOLOGY & CAUSES ▪ Rare, malignant adrenal cortex tumor ▪ Usually functional, with excess hormone secretion ▫ Glucocorticoids → Cushing’s syndrome ▫ Androgens → virilization (biologicallyfemale individuals), feminization (biologically-male individuals) ▫ Aldosterone (rare) → hyperkalemia

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RISK FACTORS

▪ Biologically female ▪ Bimodal distribution: ages 0–5, 40–50 ▫ Adults: more aggressive ▪ Associated with hereditary cancer syndromes (e.g. MEN1, Li–Fraumeni syndrome)

COMPLICATIONS

▪ Metastasis (renal vein, para-aortic nodes, lungs), diabetes

Chapter 15 Endocrine Tumors

SIGNS & SYMPTOMS ▪ Rapidly progressing hypercortisolism signs ▫ ↑ weight, muscle wasting, fat redistribution, skin atrophy ▪ Hyperandrogenism ▫ Female: hirsutism, male-pattern baldness, oligomenorrhea ▫ Male: gynecomastia, testicular atrophy, erectile dysfunction ▪ Mass effect ▫ Abdominal, flank pain; nausea; vomiting

DIAGNOSIS DIAGNOSTIC IMAGING CT scan ▪ Usually unilateral, irregular shape, heterogeneous; presence of necrosis, calcification; tumor staging (local invasion/ distant metastases)

LAB RESULTS

▪ Measure hypersecretion degree ▫ Fasting blood glucose, potassium, basal cortisol, corticotropin (ACTH), 24-hour urinary free cortisol, sex hormones (e.g. dehydroepiandrosterone, androstenedione, testosterone, 17-hydroxyprogesterone, 17-betaestradiol)

TREATMENT MEDICATIONS ▪ Chemotherapy

SURGERY ▪ Resection

OTHER INTERVENTIONS ▪ Radiation therapy

PITUITARY ADENOMA osms.it/pituitary-adenoma PATHOLOGY & CAUSES ▪ Benign anterior pituitary tumor arising from specific cell types ▫ Eventual normal pituitary tissue destruction → hypopituitarism ▪ Associated with genetic mutations ▫ Loss-of-function mutations (MEN1) ▫ Activating mutation in guanine nucleotide stimulatory protein (Gsalpha) ▫ Overexpression of pituitary tumor transforming gene (PTTG) ▫ Expression of truncated form of fibroblast growth factor receptor (FGF4) ▪ Monoclonal tumor formation → adjacent structure compression (e.g. meninges,

optic nerve/chiasm) + specific hormone hypersecretion Classification ▪ Microadenoma: < 1cm/0.4in ▪ Macroadenoma: > 1cm/0.4in ▪ Functional, non-functional

TYPES

▪ Gonadotroph adenomas usually nonsecreting/may cause hypogonadism ▪ Prolactinomas → hyperprolactinemia, galactorrhea, hypogonadism ▫ Lactotroph/somatotroph adenoma (rare plurihormonal adenomas) secrete prolactin, growth hormone (GH) ▪ Somatotroph adenomas secrete GH → acromegaly (adults); gigantism (children) ▪ Corticotropin (adrenocorticotropic hormone

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[ACTH])-secreting adenomas → Cushing’s syndrome ▪ Thyrotropin-secreting tumors → hyperthyroidism

RISK FACTORS

▪ Genetic predisposition, sporadic development

SURGERY

▪ Transsphenoidal tumor resection ▪ Stereotactic radiosurgery (gamma knife)

OTHER INTERVENTIONS ▪ Radiation therapy

COMPLICATIONS

▪ Mass effect, pituitary apoplexy (hemorrhage into pituitary), sella turcica erosion, hormone-related disease development (e.g. Cushing syndrome), panhypopituitarism

SIGNS & SYMPTOMS ▪ Adjacent structure compression ▫ Visual changes (e.g. diplopia, bitemporal hemianopsia), headache

DIAGNOSIS DIAGNOSTIC IMAGING

Figure 15.1 An MRI scan of the head in the sagittal plane demonstrating a large pituitary adenoma.

Gadolinium-enhanced MRI ▪ Delineates tumor boundary; proximity to optic chiasm, cavernous sinus; tumor consistency; hemorrhage/cystic lesion presence ▫ T1-weighted: hypointense ▫ T2-weighted: hyperintense

LAB RESULTS

▪ Pituitary hormone hyper-/hyposecretion

TREATMENT MEDICATIONS

▪ Replacement hormones (e.g. hydrocortisone, synthroid for hypopituitarism) ▪ Hormone suppression (e.g. somatostatin analogs for GH-secreting hormones; dopamine agonists for lactotrophs)

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Figure 15.2 The histological appearance of a pituitary adenoma. The finely granular eosinophilic cytoplasm seen here is characteristic of a growth hormone producing adenoma. The lobular architecture of normal pituitary tissue is lost.

Chapter 15 Endocrine Tumors

PROLACTINOMA osms.it/prolactinoma PATHOLOGY & CAUSES

DIAGNOSIS

▪ Functional, usually benign lactotroph cell tumor in anterior pituitary → prolactin (PL) secretion, prolactinemia ▫ Rarely: tumors arise from both lactotroph, somatotroph cells → secrete growth hormone (GH), and PL ▫ Malignant pituitary PRL-secreting carcinomas (rare) ▪ Monoclonal tumor formation → adjacent structure compression (e.g. meninges, optic nerve/chiasm) + prolactin hypersecretion → milk production stimulation; secondary gonadal function effects

DIAGNOSTIC IMAGING

Classification ▪ Microadenoma: < 1cm/0.4in ▪ Macroadenoma: > 1cm/0.4in

MEDICATIONS

RISK FACTORS

▪ Biologically female ▪ Peak incidence during childbearing years ▪ May be associated with MEN1

COMPLICATIONS

Gadolinium-enhanced MRI ▪ Delineates tumor boundary; proximity to optic chiasm, cavernous sinus; tumor consistency; hemorrhage/cystic lesion presence

LAB RESULTS

▪ ↑ serum prolactin

TREATMENT ▪ Dopamine agonists

SURGERY

▪ Transsphenoidal resection ▪ Stereotactic radiosurgery (gamma knife)

OTHER INTERVENTIONS ▪ Radiation therapy

▪ Hypothalamic-pituitary stalk compression → hypopituitarism ▪ Gonadal steroidogenesis impairment → infertility ▪ Hypogonadism-induced ↓ bone-mineral density → osteoporosis (biologically-female individuals) ▪ Male/female infertility

SIGNS & SYMPTOMS ▪ Microprolactinomas may be asymptomatic ▪ Biologically-female individuals: galactorrhea, amenorrhea, vaginal dryness ▪ Biologically-male individuals: gynecomastia, erectile dysfunction ▪ Mass effects → visual problems, headaches

Figure 15.3 The histological appearance of a prolactinoma. The cells have moderate amounts of eosinophilic cytoplasm and finely granular nuclear chromatin.

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THYROID CANCER osms.it/thyroid-cancer PATHOLOGY & CAUSES ▪ Uncommon thyroid gland carcinoma ▪ Predominance: biologically-female adults ▪ Derived from thyroid’s follicular epithelium ▫ Except medullary thyroid carcinoma → functional parafollicular C cells

TYPES Papillary thyroid ▪ Most common, least aggressive ▪ Multiple projections arise from follicular cells growing towards blood vessels, lymphatics; papillae = small projection/ outgrowth ▫ Lymphatic spread to cervical lymph nodes ▪ May be part of inherited syndrome (Cowden syndrome, Gardner syndrome) ▪ Light microscopy ▫ Cells with empty nuclei, AKA “Orphan Annie eyes”

Figure 15.5 The gross pathological appearance of an anaplastic thyroid carcinoma which has replaced an entire thyroid lobe.

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Figure 15.4 The cytological appearance of papillary thyroid carcinoma following fine needle aspiration. There are large cell clusters in a papillaroid configuration. The cell nuclei are of variable size.

Figure 15.6 The histological appearance of thyroid papillary carcinoma at high magnification demonstrating nuclear inclusion bodies and pale chromatin with a dark nuclear envelope giving the classic orphan Annie appearance.

Chapter 15 Endocrine Tumors

Figure 15.7 An ultrasound image of the left lobe of the thyroid demonstrating a papillary carcinoma. The tumor is well circumscribed and hypoechoic with visible microcalcifications. Follicular thyroid ▪ AKA follicular adenocarcinoma; second most common ▪ Follicular cell invasion of thyroid capsule → blood vessel invasion → hematogenous spread to bone, liver, brain, lungs ▫ Distant metastasis in some cases ▪ Well-circumscribed single nodules with colloid filled follicles; may be calcified, have central fibrosis ▪ May present with eosinophilic cells with granular cytoplasm; AKA Hürthle cells

Figure 15.9 The histological appearance of follicular thyroid carcinoma. The tumor cells form vague follicular structures and there is abundant central necrosis.

Medullary thyroid carcinoma ▪ Arises from functional parafollicular C cells; in upper ⅓ of gland ▫ Calcitonin secretion → breakdown → deposits in extracellular thyroid space → amyloid ▪ ⅓ familial, ⅓ sporadic, ⅓ associated with MEN 2A, 2B ▪ Germline RET mutations → abnormal receptor activation → cancer ▪ Light microscopy ▫ Spindle shaped cells; myloid deposits Anaplastic/undifferentiated carcinomas

Figure 15.8 The histological appearance of a spindled anaplastic thyroid carcinoma.

Figure 15.10 The histological appearance of medullary thyroid cancer. The nuclear chromatin displays a classic salt and pepper pattern.

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SIGNS & SYMPTOMS ▪ Large, solitary, painless, thyroid nodule (hard consistency, fixed) ▪ May impair thyroid hormone production → hypothyroidism ▫ Weight gain, fatigue, cold intolerance ▪ Mass effect ▫ Hoarseness, trouble swallowing

DIAGNOSIS DIAGNOSTIC IMAGING

Figure 15.11 The gross pathological appearance of medullary carcinoma of the thyroid gland. The tumor is well circumscribed occupying a single thyroid lobe with a fleshy cut surface.

CAUSES

▪ Gain-of-function mutations in growth factor signaling pathways ▫ Except medullary thyroid carcinoma

Ultrasound ▪ Thyroid ▫ Solid vs. cystic thyroid nodule (most cancers solid)

LAB RESULTS

▪ Thyroid hormone levels

Fine needle aspiration ▪ Confirm diagnosis (benign vs. malignant) Thyroid scan ▪ When fine needle aspiration indeterminate

RISK FACTORS Papillary thyroid ▪ Childhood ionizing radiation exposure: ionizing radiation → RET + BRAF protooncogene activation → cancer Follicular thyroid ▪ Iodine deficiency: RAS, PIK3CA protooncogene activation + PTEN tumor suppressor gene inactivation → cancer

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TREATMENT SURGERY

▪ Resection, adjuvant treatment

Chapter 2 Acyanotic Defects

NOTES

GONADAL DYSFUNCTION GENERALLY, WHAT IS IT? PATHOLOGY & CAUSES ▪ Disturbance in gonadal development/ function due to gonadal disorder/ hypothalamic-gonadal axis dysfunction

CAUSES

▪ Impaired gonadal hormone production due to enzyme deficiency/receptor disturbance/ exogenous hormone use ▪ Hypogonadotropic hypogonadism (AKA central/secondary hypogonadism) ▫ Deficient gonadal hormone production due to decreased gonadotropin production ▫ Gonadotropins, gonadal hormone levels low ▪ Hypergonadotropic hypogonadism (AKA peripheral/primary hypogonadism) ▫ Deficient gonadal hormone production due to disease of gonads ▫ Gonadotropin levels high, gondal hormone levels low

RISK FACTORS

▪ Genetic (autosomal dominant disease), history (gestational diabetes) ▪ Environment (e.g. obesity, lack of physical exercise, steroid use)

COMPLICATIONS

▪ Most commonly leads to infertility

SIGNS & SYMPTOMS ▪ Individuals who are biologically male ▫ Primary sex characteristic dysfunction: small penis, testes; improper testicular descent; low sperm count ▫ Secondary sex characteristic dysfunction: lack of facial, body hair; low muscle mass; failure of voice mutation ▪ Individuals who are biologically female ▫ Primary sex characteristic dysfunction: amenorrhea (absence of menstruation), oligomenorrhea (irregular menstrual cycle) ▫ Secondary sex characteristic dysfunction: lack of breast development, pubic hair

DIAGNOSIS LAB RESULTS

▪ Blood tests ▫ Gonadotropic, gonadal hormone levels

OTHER DIAGNOSTICS

▪ Tanner scale ▫ Identify delayed development ▫ Development of primary, secondary sex characteristics divided into five stages based on pubic hair, testicular volume, breast development

TREATMENT OTHER INTERVENTIONS

▪ Hormone replacement therapy ▪ Infertility treatments

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5-ALPHA-REDUCTASE DEFICIENCY osms.it/5-alpha-reductase_deficiency PATHOLOGY & CAUSES ▪ Autosomal recessive sex-limited genetic mutation in SRD5A2 gene (encodes enzyme 5 alpha reductase) ▪ Defective/absent ▪ Affects only individuals who are biologically male ▪ Defective 5 alpha reductase → ↓ testosterone to dihydrotestosterone conversion → impaired secondary sexual characteristics development

COMPLICATIONS

▪ Infertility; inflammation, infection of gonads due to malformation

SIGNS & SYMPTOMS Pre-puberty ▪ Male internal sex organs present, external genitalia with female appearance ▫ Phallus doesn’t fully elongate; resembles something between clitoris, penis ▫ Bifid scrotum: scrotum remains split ▫ Hypospadias: urethral opening remains on underside of penis ▫ Ambiguous genitalia: external genitalia does not look clearly male/female Puberty ▪ ↑ testosterone → despite no testosterone conversion, phallus, scrotum grow larger → male appearance, deepening of voice, muscle growth, development of facial, body hair

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DIAGNOSIS LAB RESULTS

▪ Genetic testing ▫ Karyotyping to ensure individual genetically male; confirm enzyme deficiency ▪ Normal serum testosterone level, ↓ dihydrotestosterone levels, ↑ testosterone to dihydrotestosterone ratio

OTHER DIAGNOSTICS

▪ Suspected in newborns with ambiguous genitalia

TREATMENT MEDICATIONS

▪ Hormone replacement therapy ▫ Male/female sex hormones according to gender role adopted by individual

SURGERY

▪ Surgical procedures to help restore external genitalia to nonambiguous appearance

OTHER INTERVENTIONS

▪ Assisted reproduction techniques ▫ Internal genitalia do not produce ova, may produce sperm

Chapter 16 Gonadal Dysfunction

ANDROGEN INSENSITIVITY SYNDROME osms.it/androgen-insensitivity PATHOLOGY & CAUSES ▪ Genetic disorder of defective androgen receptor gene ▪ Person with XY genotype unresponsive to androgens ▪ Inherited in X-linked recessive pattern

TYPES

▪ Complete androgen insensitivity ▫ Completely nonfunctional receptor; cells do not respond to androgens at all ▪ Partial androgen insensitivity ▫ Some remaining function of androgen receptor; cells, tissues partially sensitive to androgens ▪ Mild androgen insensitivity ▫ Masculinization of external genitalia

CAUSES

▪ Defect in androgen receptor on external genitalia, genital ducts, testes itself

COMPLICATIONS

▪ Infertility (most cases) ▪ Risk of testicular cancer due to cryptorchidism in complete androgen insensitivity

SIGNS & SYMPTOMS Complete androgen insensitivity ▪ Cryptorchidism ▫ Without effects of androgens, testes fail to descend into scrotum, remain in abdomen/pelvis ▪ Ineffective spermatogenesis ▫ Epididymis, vas deferens, seminal vesicles do not develop normally

▪ Development of female secondary sex characteristics ▫ Excess testosterone converted into estrogen → breast growth, widening of hips, female fat distribution ▪ Failed development of internal female organs ▫ Testes still produce anti-Müllerian hormone → uterus, fallopian tubes do not develop, vagina ends in blind pouch → female appearance without menstrual cycles Partial androgen insensitivity ▪ Appearance of external genitalia, secondary sex characteristics varies widely Mild androgen insensitivity ▪ Masculinization of external genitalia, some female secondary sex characteristics

DIAGNOSIS DIAGNOSTIC IMAGING Ultrasound ▪ Absence of uterus, ovaries; cryptorchidism

LAB RESULTS

▪ ↑ serum testosterone, dihydrotestosterone ▪ Genetic testing ▫ Karyotype; visualize sex chromosomes, ensure individual genetically male

OTHER DIAGNOSTICS

▪ Diagnosed in infants with cryptorchidism ▪ Can remain undiagnosed until puberty

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TREATMENT MEDICATIONS

▪ Hormone replacement therapy ▫ Male/female sex hormones according to gender role adopted by individual; testosterone/dihydrotestosterone if male, estrogen if female

SURGERY

▪ Surgical removal of testes (esp. in cryptorchidism) to reduce cancer risk ▪ External genitalia correction

DELAYED PUBERTY osms.it/delayed-puberty PATHOLOGY & CAUSES ▪ Onset of puberty after age 13 in individuals who are biologically female, after 14 in individuals who are biologically male

TYPES Primary/hypergonadotropic hypogonadism ▪ Dysfunction of gonads due to unresponsiveness to luteinizing hormone (LH), follicle-stimulating hormone (FSH)/lack of testosterone/estrogen, progesterone production in gonads → no negative feedback on hypothalamus → overproduction of LH, FSH ▪ Causes of acquired ▫ Radiation therapy, chemotherapy, trauma to gonads ▪ Causes of congenital ▫ Klinefelter syndrome: two X chromosomes in individuals who are biologically male → small testes, sterility ▫ Turner syndrome: X chromosome missing in individuals who are biologically female → dependence on hormonal treatment to develop secondary sex characteristics Secondary/ hypogonadotropic hypogonadism ▪ Hypothalamus/pituitary gland dysfunction; inability to produce gonadotropin-releasing hormone (GnRH)/LH, FSH; suppression

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from other hormones (e.g. prolactin, thyroid hormone) ▪ Causes of acquired ▫ Radiation therapy, chemotherapy, trauma to gonads, tumor of pituitary gland, hypothalamus ▪ Causes of congenital ▫ Kallmann syndrome, panhypopituitarism ▪ General causes ▫ Chronic illness (e.g. cystic fibrosis, celiac disease), excessive exercise, malnutrition/obesity, stress; affect hypothalamus, pituitary release of hormones Constitutional delay ▪ Temporary delay in puberty; doesn’t typically result in infertility ▪ Lack of GnRH, not pathologic → naturally slowed rate of maturation ▪ Onset of puberty occurs naturally, at later age; typically genetic component

COMPLICATIONS

▪ Permanent infertility if puberty never begins/fails to complete, sexual maturity never reached

SIGNS & SYMPTOMS ▪ Delayed primary, secondary sexual characteristics

Chapter 16 Gonadal Dysfunction

DIAGNOSIS LAB RESULTS

▪ Blood hormone levels ▫ Indicate type of hypogonadism; ↓ testosterone, estrogen in low gonad activity; ↓ FSH, LH in suppressed pituitary activity

OTHER DIAGNOSTICS

TREATMENT MEDICATIONS

▪ Hormone replacement therapy

OTHER INTERVENTIONS

▪ Constitutional delay can resolve on own with natural onset of puberty ▪ Infertility treatments

▪ Medical history ▫ Evaluate underlying medical conditions, family history for constitutional delay ▪ Tanner scale ▫ Estimates puberty development

KALLMANN SYNDROME osms.it/kallmann-syndrome PATHOLOGY & CAUSES ▪ Type of hypogonadotropic hypogonadism; delayed/absent puberty with impaired sense of smell (anosmia) ▪ Pituitary failure → ↓ sex hormones → hypogonadotropic hypogonadism → failure to start/complete puberty ▪ Defect in migration of neurons from olfactory placode ▫ Olfactory neurons: hyposmia/anosmia (reduced sense of smell) ▫ GnRH neurons: ↓ GnRH → ↓ LH, FSH

COMPLICATIONS

▪ Infertility, osteopenia, osteoporosis

SIGNS & SYMPTOMS

foot, teeth underdevelopment, cleft palate ▪ Neurological sensory, motor ▫ Hearing impairment, colour blindness, dyskinesias, cerebral ataxia

DIAGNOSIS LAB RESULTS

▪ Blood hormone levels ▫ ↓ GnRH, LH, FSH, sex hormones ▪ Genetic tests ▫ Gene mutation in FGFR1, PROKR2, PROK2, CHD7, FGF8; associated with Kallmann syndrome

OTHER DIAGNOSTICS ▪ Smell test, sperm count

▪ Underdevelopment of primary, secondary sex characteristics; anosmia; long arms in proportion to body (eunuchoid body); osteoporosis; kidney agenesis ▪ Skeletal ▫ Scoliosis, short middle finger, split hand/

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TREATMENT MEDICATIONS

▪ Hormone therapy ▫ Stimulate puberty, development of secondary sex characteristics

▪ Calcium, vitamin D ▫ Osteopenia

OTHER INTERVENTIONS ▪ Infertility treatments

POLYCYSTIC OVARY SYNDROME osms.it/polycystic-ovary PATHOLOGY & CAUSES ▪ Excessive androgen production by ovaries; primarily testosterone

CAUSES Hyperinsulinemia ▪ Aids LH overproduction ▪ Theca cells in ovary express insulin receptors → excess insulin induces growth, division of theca cells → ↑ LH receptors → hypothalamus ↑ rate of GnRH pulses → ↑ LH secretion Anterior pituitary produces excessive LH ▪ Theca cells produce excess amounts of androstenedione → converted into estrone by aromatase in adipose tissue → negative feedback signal → blocks anterior pituitary from releasing FSH, LH → no LH surge → no dominant follicle to break away from ovary → remains in ovary as cyst/ degenerates with other follicles → no ovulation Excessive adipose tissue ▪ Aromatase in adipose tissue converts androgens to estrogens → ↑ androgens

RISK FACTORS

▪ Genetic: autosomal dominant disease ▪ Obesity, lack of physical exercise ▪ History of gestational diabetes

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COMPLICATIONS

▪ Diabetes mellitus, hyperinsulinemia, infertility, increased risk of endometrial cancer

SIGNS & SYMPTOMS ▪ High levels of androstenedione → virilization ▫ Excessive hair growth on chin, upper lip, chest, back (hirsutism) ▫ Thinning of hair, from crown of head (male-pattern baldness) ▫ Acne on face, chest, back ▫ Lack of ovulation → oligomenorrhea, amenorrhea → infertility ▪ Insulin resistance ▫ Overweight/obese; dark, velvety patches in creases of neck, groin, underarms (acanthosis nigricans)

DIAGNOSIS DIAGNOSTIC IMAGING Ultrasound ▪ Follicles on one/both ovaries, appear like small cysts

LAB RESULTS

▪ Blood tests ▫ ↑ LH to FSH ratio; ↑ androstenedione

Chapter 16 Gonadal Dysfunction

TREATMENT MEDICATIONS

▪ Oral contraceptives ▫ Regulate menstrual cycle ▪ Clomiphene citrate ▫ Induce ovulation ▪ Metformin ▫ Increase insulin sensitivity

Figure 16.1 An abdominal ultrasound scan demonstrating a polycystic ovary. The cysts are are represented by the well circumscribed hypoechoic areas within the ovary.

OTHER DIAGNOSTICS

▪ Rotterdam criteria (2 of 3) ▫ Lack of ovulation, excessive androgens, polycystic ovaries on ultrasound ▪ Oral glucose tolerance test (OGTT) ▫ Establish insulin resistance

SURGERY

▪ Ovarian drilling ▫ Puncturing cystic ovary; induces ovulation; can damage ovary, doesn’t resolve overall hormonal imbalance

OTHER INTERVENTIONS

▪ Incurable condition, treatment symptoms ▪ Weight loss, low glycemic index diet reduces insulin resistance, improves symptoms

PRECOCIOUS PUBERTY osms.it/precocious-puberty PATHOLOGY & CAUSES ▪ Onset of puberty at earlier age than average ▫ ≤ eight in individuals who are biologically female, ≤ nine in individuals who are biologically male

TYPES Central/gonadotropin-dependent precocious puberty ▪ Early maturation of hypothalamic-pituitarygonadal axis → early release of LH, FSH → ↑ sex hormones ▪ Cause ▫ Dysfunctional hypothalamus/pituitary gland: tumor releases GnRH/human

chorionic gonadotropin (hCG); infection; cyst; radiation damage to brain → impairs negative feedback system in hypothalamic-pituitary-gonadal axis ▫ Idiopathic precocious puberty: most common; normal variation; depends on weight, genetics Peripheral/gonadotropin-independent precocious puberty ▪ Abnormal overproduction of sex hormones by testes/ovaries ▪ Cause ▫ Ovarian/testicular cyst/tumor; genetic conditions (e.g. McCune–Albright syndrome); dysfunction of other glands (thyroid/adrenal gland); exogenous sex hormones from medications, creams

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SIGNS & SYMPTOMS ▪ Child starts progressing through Tanner scale before 95% of other children at same age ▪ Early sexual maturation

DIAGNOSIS

LAB RESULTS

▪ Gonadotropin hormone levels ▫ Distinguish gonadotropin-dependent/ independent causes

OTHER DIAGNOSTICS

▪ Physical exam ▫ Assess growth compared to age; Tanner scale

DIAGNOSTIC IMAGING MRI ▪ Structural abnormalities in brain Ultrasound ▪ Screening of gonads X-ray ▪ Estimates bone maturation

TREATMENT MEDICATION

▪ Hormone therapy ▫ GnRH analogues → suppress hypothalamic-pituitary-gonadal axis hormones, bind to GnRH receptor on pituitary gland → decrease release of LH, FSH → slow puberty

SURGERY

▪ Surgical removal of tumor/cyst from ovaries/ testicles

PREMATURE OVARIAN FAILURE osms.it/premature-ovarian-failure PATHOLOGY & CAUSES ▪ AKA primary ovarian insufficiency ▪ Loss of function of ovaries before age 40; not caused by menopause ▪ Follicles stop responding to pituitary LH, FSH → disrupted ovulation → ↓ estrogen, progesterone, androstenedione → amenorrhea, hypogonadotropism, hypoestrogenism ▪ Around half of biologically-female individuals maintain some intermittent ovarian function ▪ Usually no clear cause; associated with ▫ Acquired: chemotherapy, radiotherapy, autoimmune destruction ▫ Genetic: Turner syndrome, fragile X syndrome, BRCA1 mutations →

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gonadal dysgenesis ▪ Two mechanisms ▫ No remaining follicles: ovary started off with few/rapid degeneration ▫ Follicles dysfunctional: hypergonadotropic hypogonadism; estrogen-low pituitary increases LH, FSH production

COMPLICATIONS

▪ Infertility, cardiovascular disease, osteoporosis, hypothyroidism, Addison’s disease

Chapter 16 Gonadal Dysfunction

SIGNS & SYMPTOMS ▪ Absence of ovulation; low levels of estrogen, progesterone ▪ Normal puberty with regular periods before disorder develops ▪ Infrequent menstrual periods → difficulty conceiving/infertility ▪ Lack of hormones: hot flashes, night sweats, vaginal dryness → dyspareunia (pain during sex) ▪ ↓ estrogen: cardiovascular disease, osteoporosis, decreased bone density ▪ Symptoms mimic natural menopause; some biologically-female individuals still able to get pregnant due to intermittent ovarian function

DIAGNOSIS

LAB RESULTS

▪ ↓ ovarian hormones (estrogen), ↑ LH, FSH ▪ If autoimmune cause suspected ▫ Test for steroid cell antibodies/ sulfoxythiocarbamate alkynes (STCAs) ▪ Genetic testing ▫ Karyotype, chromosomal abnormalities; evaluate for genetic disease

TREATMENT MEDICATIONS

▪ Hormone replacement therapy ▫ Estrogen, progesterone

OTHER INTERVENTIONS ▪ In-vitro fertilization ▫ Treat infertility

DIAGNOSTIC IMAGING Ultrasound ▪ Shrunken ovaries

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NOTES

NOTES

HYPERPARATHYROIDISM & HYPOPARATHYROIDISM

GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ An imbalance of parathyroid hormone (PTH) due to overproduction or underproduction by the parathyroid gland resulting in impaired regulation of calcium and other electrolytes Hyperparathyroidism ▪ ↑ PTH → ↑ bone resorption and ↑ renal reabsorption of calcium → ↑ serum calcium levels → asymptomatic or symptomatic hypercalcemia Hypoparathyroidism ▪ ↓ PTH → ↓ serum calcium → symptomatic hypocalcemia

RISK FACTORS

▪ Hyperparathyroidism ▫ Genetic mutations, chronic kidney disease, ↓ vitamin D intake/absorption, hyperplasia of parathyroid glands ▪ Hypoparathyroidism ▫ Most commonly iatrogenic cause due to accidental removal or damage to parathyroid blood supply during thyroid surgery

COMPLICATIONS

▪ Hyperparathyroidism ▫ Osteoporosis, osteitis fibrosa cystica, nephrolithiasis, keratopathy, symptomatic hypercalcemia (e.g. hypertension, cardiac arrhythmias) ▪ Hypoparathyroidism ▫ Symptomatic hypercalcemia (e.g. respiratory paralysis, cardiac arrhythmias)

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SIGNS & SYMPTOMS ▪ See individual disorders

DIAGNOSIS LAB RESULTS

▪ Measure serum PTH, calcium, phosphate, magnesium, 25-hydroxyvitamin D, urine calcium

OTHER DIAGNOSTICS ▪ Genetic testing

TREATMENT MEDICATIONS

▪ Hyperparathyroidism ▫ Vitamin D analogs, calcimimetics, bisphosphonates ▪ Hypoparathyroidism ▫ IV calcium gluconate (acute), vitamin D analogs, synthetic PTH, thiazide diuretics (↓ renal calcium excretion)

SURGERY

▪ Hyperparathyroidism ▫ Partial/complete parathyroidectomy; radiofrequency ablation

OTHER INTERVENTIONS

▪ Hyperparathyroidism ▫ Physical activity to ↓ bone resorption, maintain hydration to ↓ nephrolithiasis, vitamin D supplements ▪ Hypoparathyroidism ▫ Calcium, magnesium, and vitamin D supplements

HYPERPARATHYROIDISM

NOTES

osms.it/hyperparathyroidism PATHOLOGY & CAUSES TYPES Primary ▪ Parathyroid gland creates PTH independently of calcium levels, does not respond to normal feedback mechanisms Secondary ▪ Parathyroid gland hyperplasia, excess parathyroid hormone secreted in response to chronic hypocalcemia ▪ Impaired kidney function; kidneys do not filter phosphate properly into urine, make insufficient calcitriol ▫ AKA renal osteodystrophy (bone pain, fracture) ▪ Altered calcium, phosphate levels → increased parathyroid hormone levels → bone resorption Tertiary ▪ Develops in individuals with secondary hyperparathyroidism for many years, often due to hyperplasia of parathyroid glands ▪ Autonomous secretion of PTH separately from blood calcium levels ▫ Even if causes of secondary hyperparathyroidism (e.g. renal transplant) corrected, increased PTH persists

RISK FACTORS Primary ▪ Genetic mutations ▫ Multiple endocrine neoplasia (MEN) syndrome

COMPLICATIONS Primary ▪ Brown tumors, large bone cysts (due to high osteoclast activity)

SIGNS & SYMPTOMS ▪ “Stones, thrones, bones, groans, and psychiatric overtones”; see mnemonic Primary, tertiary ▪ Slower muscle contractions caused by less excitable neurons secondary to hypercalcemia Secondary ▪ Bone resorption/renal osteodystrophy; calcification of blood vessels, soft tissues

MNEMONIC

Signs and symptoms of hyperparathyroidism Stones: calcium-based kidney stones, gallstones Thrones: toilet; polyuria (frequent urination) from impaired sodium, water reabsorption Bones: pain from chronic hormone-driven demineralization Groans: constipation, muscle weakness Psychiatric overtones: depressed mood, confusion

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DIAGNOSIS LAB RESULTS Primary ▪ High total serum calcium (hypercalcemia), low phosphate (hypophosphatemia), high PTH valve during diastole ▪ Hypercalciuria from excess calcium loss through urine, may cause dehydration ▪ Serum 25-hydroxyvitamin D ▫ Determine type Secondary ▪ Low calcium, high phosphate, low vitamin D Tertiary ▪ Normal-high calcium, high PTH, low vitamin D

Figure 17.1 An ultrasound of the neck demonstrating a large parathyroid adenoma situated posteriorly and to the right of the right thyroid lobe. The skin surface is at the top of the image.

TREATMENT MEDICATIONS Primary, tertiary ▪ Calcimimetics ▫ Drugs that imitate calcium by attaching to CaSR on parathyroid cells ▫ If surgery not an option Secondary ▪ Hyperphosphatemia ▫ Phosphate binders ▪ Vitamin D supplements ▫ Increase calcium absorption, reduce PTH synthesis ▪ Calcitriol, vitamin D analogs (doxercalciferol, paricalcitol) ▫ Suppress PTH levels ▪ Calcimimetics ▫ Modulate CaSR → increase sensitivity of serum calcium → decrease PTH levels Tertiary

SURGERY

▪ Remove abnormal parathyroid glands

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Figure 17.2 A X-ray image of the forearm demonstrating a brown tumor of the distal radius in an individual with hyperparathyroidism.

Chapter 17 Hyperparathyroidism & Hypoparathyroidism

HYPOPARATHYROIDISM osms.it/hypoparathyroidism PATHOLOGY & CAUSES

SIGNS & SYMPTOMS

▪ Underproduction of parathyroid hormone (PTH); hypo- = under/low ▪ No parathyroid hormone → ↓ bone resorption, ↓ renal calcium reabsorption, ↓ intestinal calcium reabsorption → hypocalcemia, hyperphosphatemia → ↑ cell excitability → tetany, paresthesias, seizures, arrhythmias

▪ Asymptomatic/life-threatening ▫ Degree, duration of hypocalcemia ▫ Muscular dysfunction → respiratory paralysis → death ▪ ECG changes ▫ Prolonged QT, ST ▫ Torsades des pointes ▫ Atrial fibrillation

CAUSES

Acute ▪ Muscular spasms/cramps → tetany → Chvostek, Trousseau signs ▪ Perioral numbness, paresthesias, seizures

Autoimmune disorders Magnesium deficiencies Latrogenic ▪ Most common ▪ Thyroid/parathyroid surgery/radiation Hereditary abnormalities ▪ DiGeorge syndrome (DGS) ▪ Autosomal dominant hypoparathyroidism ▪ Albright hereditary osteodystrophy (pseudohypoparathyroidism) ▫ Kidney resistance to PTH, increased PTH

Chronic ▪ Extrapyramidal movements → basal ganglia calcifications ▫ Dystonias, parkinsonism, athetosis, hemiballismus, oculogyric crisis ▪ Cataracts ▪ Dermatologic manifestations ▫ Dry, coarse skin; brittle nails; patchy alopecia

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Figure 17.3 Dry, brittle nails are a dermatologic manifestation of chronic hypoparathyroidism.

DIAGNOSIS LAB RESULTS

▪ Hypocalcemia, low serum PTH ▪ Hypercalciuria

OTHER DIAGNOSTICS

▪ Medical history of thyroid surgery/radiation

TREATMENT MEDICATIONS ▪ ▪ ▪ ▪

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IV calcium gluconate (severe cases) Oral calcium (mild-moderate cases) Vitamin D supplementation Synthetic PTH

Chapter 2 Acyanotic Defects

NOTES

HYPERPITUITARISM & HYPOPITUITARISM

GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Disorders caused by excess/insufficient pituitary hormones, disruption in hypothalamic-pituitary axis function

CAUSES Hyperpituitarism ▪ Genetic inheritance ▪ Secreting tumors (intracranial, ectopic) Hypopituitarism ▪ Intracranial tumors, bleeding, infarction ▪ Neurosurgery, head trauma, infection ▪ Idiopathic

SIGNS & SYMPTOMS ▪ Disruption in growth, regulation; depends on affected hormones ▪ If pituitary adenoma, sequence of loss: “Go Look For The Adenoma” (see mnemonic)

MNEMONIC: Go Look For The Adenoma

Pituitary adenoma sequence of loss Growth hormone (GH) Luteinizing hormone (LH) Follicle-stimulating hormone (FSH) Thyroid-stimulating hormone (TSH) Adrenocorticotropic hormone (ACTH)

DIAGNOSIS DIAGNOSTIC IMAGING X-ray, CT scan, MRI ▪ Intracranial, ectopic tumors; bleeding, infarction

LAB RESULTS

▪ Altered levels of pituitary, target tissue hormones

OTHER DIAGNOSTICS

▪ History, physical examination

TREATMENT MEDICATIONS Hyperpituitarism ▪ Somatostatin + dopamine agonists; GH receptor antagonists Hypopituitarism ▪ Hormone replacement (e.g. glucocorticoids, thyroid hormone)

SURGERY

▪ Surgical excision of tumor

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ACROMEGALY osms.it/acromegaly PATHOLOGY & CAUSES ▪ GH hypersecretion in adulthood after epiphyseal closure → enlargement of extremities, face

CAUSES

▪ Pituitary adenoma produces excess GH ▪ Nonpituitary tumors (pancreatic, lung, adrenal gland) produce ectopic GH

COMPLICATIONS

▪ Glucose intolerance to Type II diabetes, high blood pressure, respiratory problems, carpal tunnel syndrome, heart/kidney failure

SIGNS & SYMPTOMS ▪ Soft tissue, bone swelling ▫ Hands, feet ▫ Skull: jaw protrusion, enlargement (macrognathia), increased spacing of teeth; forehead, brow protrusion ▫ Organomegaly: heart, kidneys; vocal cords → slow, deep voice ▪ Joint pain, headache, vision problems, thickened skin ▪ Excess sweating, hair growth, pigmentation

LAB RESULTS Blood tests ▪ Acromegaly ▫ ↑ insulin-like growth factor-1 (IGF-1) / somatomedin C ▪ Oral glucose tolerance test (OGTT) ▫ Hyperglycemia

TREATMENT MEDICATIONS

▪ Somatostatin agonists ▫ Stop GH production ▪ Dopamine agonists, alternative to somatostatin agonists ▫ For tumors that affect prolactin levels ▪ GH receptor antagonists ▫ Blocks GH binding to receptors

SURGERY

▪ Transsphenoidal tumor resection

OTHER INTERVENTIONS ▪ Tumor radiation

DIAGNOSIS DIAGNOSTIC IMAGING MRI of sella turcica with gadolinium ▪ Somatotroph adenoma; tumoral location CT scan of chest/abdomen ▪ Ectopic tumors

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Figure 18.1 The clinical appearance of acromegaly. The facial features are coarse and mandibular overgrowth has lead to prognathism.

Chapter 18 Hyperpituitarism & Hypopituitarism

Figure 18.2 The appearance of the hands in the case of acromegaly. The acromegalic right hand is larger with expanded soft tissues and thickened, stubby fingers.

CONSTITUTIONAL GROWTH DELAY osms.it/constitutional-growth-delay PATHOLOGY & CAUSES ▪ Normal variation in rate of growth → temporary delay during early childhood, puberty ▪ Eventual adult height within normal range

CAUSES

▪ Alterations in hormones critical for growth, development ▪ GH axis: regulates bone, muscle growth ▪ ↓ GH → ↓ production of IGF-1/ somatomedin C (prevents cell death), ↑ cellular metabolism, cell division, differentiation throughout body ▪ Hypothalamic-pituitary-gonadal axis: regulates sexual maturation ▪ ↓ gonadotropin-releasing hormone (GnRH) → ↓ anterior pituitary production of gonadotropins (LH, FSH) → ↓ production of sex hormones by gonads (estrogen, progesterone in individuals who are biologically female, testosterone in individuals biologically male) → delayed development of sex organs, secondary sexual characteristics

RISK FACTORS

▪ Family history of delayed growth

COMPLICATIONS

▪ Psychosocial stress

SIGNS & SYMPTOMS ▪ Normal size at birth ▪ Short preadolescent stature ▪ Delayed pubertal development, skeletal age

DIAGNOSIS DIAGNOSTIC IMAGING X-ray ▪ Delayed bone development

OTHER DIAGNOSTICS

▪ History, physical examination ▪ Height growth curve below, parallel to third percentile ▪ Delayed Tanner scale staging

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TREATMENT OTHER INTERVENTIONS

▪ Provide reassurance regarding eventual normal growth, development

DIABETES INSIPIDUS (DI) osms.it/diabetes-insipidus PATHOLOGY & CAUSES ▪ Disorder of fluid balance characterized by defect in urine concentration → excretion of large volumes of dilute urine ▪ Diabetes = to pass through; insipidus = tasteless

TYPES Neurogenic (central) DI ▪ DI caused by absence/↓ secretion/ production of antidiuretic hormone (ADH) by posterior pituitary Nephrogenic DI ▪ Kidneys unresponsive to ADH secreted by posterior pituitary

▪ Damage of renal tubules from systemic disease (e.g. polycystic kidney disease, pyelonephritis, amyloidosis) ▪ Lithium toxicity ▫ Interferes with aquaporin function

SIGNS & SYMPTOMS ▪ Polyuria ▫ Neurogenic: urine amount varies depending on degree of ADH production/secretion ▫ Nephrogenic: daily output of > 3L in adults; > 2L/m2 in children ▪ Nocturia, polydipsia, dehydration, hypotension ▪ Neurogenic DI ▫ Lack of other pituitary hormones

CAUSES Neurogenic DI ▪ Idiopathic (most common) ▪ Damage to hypothalamus/pituitary/ supraoptico-hypophyseal tract (e.g. head trauma, pituitary adenoma), neurosurgery, infection (e.g. tuberculosis), infiltrative disease (e.g. Langerhans cell histiocytosis), hypoxic encephalopathy, ischemia ▪ Familial (familial neurohypophyseal DI) ▫ Autosomal dominant gene mutation ▪ Congenital (e.g. septo-optic dysplasia) Nephrogenic DI ▪ Hereditary ▫ Defect in genes encoding for ADH receptor/aquaporin function

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DIAGNOSIS DIAGNOSTIC IMAGING Cranial MRI (neurogenic DI) ▪ Hyperintensities, pituitary stalk thickening identifies signs of hypothalamic/pituitary dysfunction

LAB RESULTS ▪ ▪ ▪ ▪

↓ ADH levels (neurogenic), urine osmolarity ↑ plasma osmolarity Hypernatremia Water deprivation test (ADH stimulation test): fluid deprivation → ADH (vasopressin) administered subcutaneously

Chapter 18 Hyperpituitarism & Hypopituitarism ▫ ↑ urine osmolality: confirms neurogenic DI ▫ Little/no ↑ urine osmolality: confirms nephrogenic DI

TREATMENT MEDICATIONS Neurogenic DI ▪ Desmopressin (dDAVP) (synthetic vasopressin) ▪ Chlorpropamide ▫ Enhances renal response to low levels of ADH

Neurogenic/nephrogenic DI ▪ Nonsteroidal anti-inflammatory drugs (NSAIDs) (e.g. indomethacin) ▫ ↑ renal concentration of urine ▪ Thiazide diuretics (e.g. hydrochlorothiazide) + low sodium diet ▫ ↓ polyuria (↑ water permeability to collecting tubules)

OTHER INTERVENTIONS

▪ Fluid replacement ▪ Diet ▫ Low solute (low sodium, low protein)

GIGANTISM osms.it/gigantism PATHOLOGY & CAUSES ▪ GH hypersecretion during childhood → rapid, excessive linear growth

CAUSES ▪ ▪ ▪ ▪

Excessive secretion of GH, GHRH, IGF-1 Tumor in pituitary gland Tumors outside pituitary, secrete GH Hereditary ▫ Gene mutation (e.g. McCune Albright syndrome, multiple endocrine neoplasia Type I)

COMPLICATIONS

▪ Cardiovascular conditions: hypertension in children ▪ Bone conditions: osteoarthritis ▪ Diabetes mellitus: insulin resistance

SIGNS & SYMPTOMS

▪ Overgrowth of face, extremities ▪ Headaches ▪ Maxilla/mandible protrusion

DIAGNOSIS DIAGNOSTIC IMAGING MRI ▪ Pituitary tumors CT scan ▪ Tumors in other organs, might secrete GH/ GHRH X-ray ▪ Assess bones

LAB RESULTS Blood tests ▪ OGTT ▫ Hyperglycemia ▫ Elevated IGF-1

▪ Height significantly above standard deviations ▪ Obesity

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TREATMENT MEDICATIONS

▪ Somatostatin agonists ▫ Shrink pituitary tumors, stop GH production ▪ Dopamine agonists ▫ If somatostatin agonists not effective ▫ Effective in tumors producing hyperprolactinemia ▪ Somatostatin + dopamine agonists ▪ GH receptor antagonists

SURGERY

▪ For small pituitary adenomas ▫ Transsphenoidal surgical approach

OTHER INTERVENTIONS

▪ Radiation (not recommended for children) ▫ Can produce panhypopituitarism (decreased secretion in most pituitary hormones) → learning disabilities, obesity Figure 18.3 The worlds tallest ever recorded man, Robert Wadlow, was diagnosed with from gigantism as a consequence of pituitary hyperplasia. He stood at 2.27m/8ft 11in and wore a size 37 shoe.

GROWTH HORMONE DEFICIENCY (GHD) osms.it/growth-hormone-deficiency PATHOLOGY & CAUSES ▪ Conditions caused by decreased production of GH (AKA somatotropin) ▪ Partial/complete, permanent/transient

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CAUSES

▪ Hypothalamic/pituitary dysfunction ▫ Tumors (e.g. pituitary/parasellar adenomas); radiation; traumatic injury; autoimmune disease; genetic mutations (e.g. PROP1); congenital structural defects of brain (e.g. Prader–Willi, Turner syndrome); idiopathic

Chapter 18 Hyperpituitarism & Hypopituitarism

SIGNS & SYMPTOMS ▪ Newborns ▫ Hypoglycemia, micropenis, excessive jaundice ▪ Children ▫ Stunted growth/short stature, delayed puberty ▫ Nystagmus, hypoglycemia, retinal defects, midfacial defects (e.g. cleft lip) ▫ Severe cases: delayed basic motor skills (e.g. standing, walking) ▫ Moderately overweight (rare—severely obese) ▪ Adults ▫ Decreased muscle mass, decreased bone mineral density, high 5-alpha reductase, baldness, cardiac conditions ▫ Psychological issues (memory problems, social issues, depression)

▪ Serum IGF-1 ▫ More accurate assessment of GH secretion; not affected by external factors ▫ Less than standard gender-specific levels → confirms diagnosis ▪ Insulin tolerance test ▫ Regular insulin administered via intravenous (IV) → measure blood at 30 minute intervals ▫ Subnormal increase in serum GH confirms diagnosis

TREATMENT MEDICATIONS

▪ Daily injections with recombinant growth hormone (rGH) ▫ Childhood: GH daily injections; stature monitoring throughout growth period ▫ Adulthood: 25% treatment for children

DIAGNOSIS LAB RESULTS

▪ Serum GH levels < 1ng/mL ▫ Nonspecific test for GH deficiency: affected by circadian rhythms, food intake, stress

HYPERPITUITARISM osms.it/hyperpituitarism PATHOLOGY & CAUSES ▪ Disorders caused by pituitary hormones hypersecretion

CAUSES

▪ Pituitary adenoma (most common) ▪ Genetic mutation from single cell (monoclonal) → tumorigenesis → tumor secretes hormones ▫ Prolactin → prolactinoma ▫ ACTH → Cushing’s disease

▫ GH → acromegaly (occurs during adulthood after epiphyseal closure), gigantism (during childhood before epiphyseal closure)

SIGNS & SYMPTOMS ▪ Diaphoresis; visual field problems; headaches; lethargy; excessive hair growth; larger organs, extremities, facial components

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DIAGNOSIS DIAGNOSTIC IMAGING X-ray ▪ Sella turcica, pituitary glands

LAB RESULTS

▪ Elevated hormone levels in serum

TREATMENT MEDICATIONS

▪ Dopamine agonists: gonadal dysfunctions ▫ Inhibit prolactin secretion ▫ Inhibitors of tumoral cells division

SURGERY

▪ Total/partial removal of pituitary/tumor ▫ Endonasal transsphenoidal surgery (most common)

HYPERPROLACTINEMIA osms.it/hyperprolactinemia PATHOLOGY & CAUSES ▪ Disorder caused by high blood levels of pituitary hormone prolactin ▪ Prolactin: secreted by lactotroph cells in anterior segment of pituitary

CAUSES

▪ Prolactinoma/lactotroph adenoma (prolactin-secreting tumor) ▪ Pregnancy ▪ Damage to hypothalamic-pituitary stalk ▪ Disorders affecting hypothalamus ▪ Drugs, medication, heavy metal poisoning ▫ Inhibits dopamine production ▫ Dopamine receptor antagonists, synthesis inhibitors → pituitary overproduces prolactin ▪ Renal failure ▪ Primary hypothyroidism

SIGNS & SYMPTOMS ▪ Individuals who are biologically male ▫ Impaired genital activity (hypogonadism) → infertility, impotence ▫ Decreased libido

114 OSMOSIS.ORG

▫ Overdevelopment of mammary glands (gynecomastia) ▫ Spontaneous secretion, flow of breast milk (galactorrhea) ▪ Individuals who are biologically female ▫ Irregular menstrual cycles: sometimes complete lack of menstruation (amenorrhoea); no ovulation → infertility ▫ Galactorrhea ▫ Painful breasts ▪ Visual impairment, headaches when pituitary adenoma presses on optic nerve

DIAGNOSIS DIAGNOSTIC IMAGING Head MRI/CT scan ▪ Tumors/lesions in hypothalamic-pituitary area: if none + high serum levels: idiopathic hyperprolactinemia

LAB RESULTS

▪ High serum prolactin levels

OTHER DIAGNOSTICS

▪ Lower bone density ▪ Pregnancy/hypothyroidism

Chapter 18 Hyperpituitarism & Hypopituitarism

TREATMENT MEDICATIONS

SURGERY

▪ Surgical removal of tumor ▫ High rate recurrence

▪ Tumor: dopamine agonist (inhibit prolactin production, secretion) ▫ Bromocriptine/cabergoline

HYPOPITUITARISM osms.it/hypopituitarism PATHOLOGY & CAUSES ▪ Disorders caused by complete/partial lack of pituitary hormone production, secretion

CAUSES

▪ Tumors ▫ Pituitary adenomas → compression → intracranial pressure → destruction of pituitary ▫ Brain (e.g. metastatic cancer) ▫ Body ▪ Traumatic injury, shock, stroke → ischemia ▪ Vascular ▫ Hemorrhages (e.g. aneurysms, subarachnoid hemorrhage) ▪ Radiation ▪ Infections ▫ Brain (e.g. meningitis) ▫ Abnormal brain cells/substance infiltrations (e.g. hemochromatosis) ▫ Autoimmune disorders (e.g. autoimmune hypophysitis) ▪ Congenital (defect in transcription factors) ▫ PROP1 gene mutation → hormone deficiency (most common) ▫ Pituitary transcription factor 1 (PIT1) mutation → GH, prolactin, TSH deficiencies ▪ Hypothalamic dysfunction, decrease in releasing hormones

SIGNS & SYMPTOMS ▪ Occur when ≥ 75% of anterior pituitary nonfunctional ▪ Vary depending on hormone affected ▪ Sequence of loss: “Go Look For The Adenoma” (see mnemonic) ▪ If tumor present ▫ Pressure on optic chiasm → visual disturbances ▫ Increased intracranial pressure → headache

MNEMONIC: Go Look For The Adenoma

Pituitary adenoma sequence of loss Growth hormone (GH) Luteinizing hormone (LH) Follicle-stimulating hormone (FSH) Thyroid-stimulating hormone (TSH) Adrenocorticotropic hormone (ACTH)

DIAGNOSIS LAB RESULTS

▪ Blood tests ▫ Serum thyroid levels (T3/T4) ▫ ACTH secretion (measure serum cortisol in the morning)

OSMOSIS.ORG 115

TREATMENT MEDICATIONS

▪ Hormone replacement ▫ ACTH deficiency: hydrocortisone ▫ TSH deficiency: levothyroxine

▫ FSH/LH deficiency: testosterone (for individuals who are biologically male); estrogen-progestin (for premenopausal individuals who are biologically female)

SURGERY

▪ Surgical excision of tumors

HYPOPROLACTINEMIA osms.it/hypoprolactinemia PATHOLOGY & CAUSES ▪ Low serum prolactin levels due to damaged lactotroph cells in anterior pituitary

CAUSES

▪ Sheehan’s syndrome ▫ Postpartum hemorrhage → hypotension, decreased circulation to pituitary, ischemia, damaged lactotroph cells ▪ Medications ▫ Dopamine, dopamine agonists; inhibit prolactin release ▪ Tumors ▫ Pressure on pituitary/hypothalamus → damage lactotroph cells

SIGNS & SYMPTOMS ▪ Individuals who are biologically female and breastfeeding ▫ Decreased lactation (agalactorrhea)

116 OSMOSIS.ORG

DIAGNOSIS DIAGNOSTIC IMAGING MRI ▪ Tumor confirmation

LAB RESULTS

▪ Low prolactin levels despite receiving thyrotropin-releasing hormone (TRH) ▫ Individuals who are biologically female: < 3µg/L ▫ Individuals who are biologically male: < 5µg/L

TREATMENT MEDICATIONS

▪ Dopamine antagonists ▫ Oppose dopamine in individuals who want to breastfeed

SURGERY

▪ Surgical removal of tumor

Chapter 18 Hyperpituitarism & Hypopituitarism

PITUITARY APOPLEXY osms.it/pituitary-apoplexy PATHOLOGY & CAUSES

DIAGNOSIS

▪ Pituitary function impaired due to hemorrhage into gland ▪ Hemorrhage → blood collects within pituitary interstitium → swelling → infarction, loss of pituitary function → compression of surrounding structures

DIAGNOSTIC IMAGING

RISK FACTORS

▪ ↓ pituitary hormone levels, target tissue hormones

▪ Intracranial tumors, head trauma, neurosurgery, Sheehan’s syndrome (postpartum pituitary necrosis)

COMPLICATIONS

▪ Hypopituitarism, neuronal damage

SIGNS & SYMPTOMS ▪ Meningeal stretching ▫ Severe headache ▪ Optic chiasm compression ▫ Diplopia, bitemporal hemianopia ▪ Parenchymal compression ▫ Mental status changes ▪ Clinical manifestations of hypopituitarism (e.g. ↓ ACTH → ↓ cortisol → hypoglycemia, hypotension, adrenal crisis)

CT scan/MRI ▪ Enlarged pituitary gland; hyperintense blood-filled center

LAB RESULTS

TREATMENT MEDICATIONS

▪ Hormone replacement ▫ Glucocorticoids (emergent), levothyroxine

SURGERY

▪ Surgical decompression ▪ Transphenoidal resection of pituitary gland

OSMOSIS.ORG 117

SHEEHAN'S SYNDROME osms.it/sheehans-syndrome PATHOLOGY & CAUSES

DIAGNOSIS

▪ AKA postpartum pituitary gland necrosis ▪ Destruction of lactotroph cells of anterior pituitary in setting of postpartum hemorrhage

DIAGNOSTIC IMAGING

CAUSES

LAB RESULTS

▪ Pituitary increases in size during gestation → metabolic activity of lactotrophs increase, blood supply does not → pituitary vulnerable to perfusion decrease → hypovolemia, hypotension, shock → pituitary infarction, necrosis

SIGNS & SYMPTOMS

MRI ▪ Pituitary ring sign (halo around empty sella)

▪ Pituitary hormone levels

OTHER DIAGNOSTICS ▪ Obstetric history

TREATMENT MEDICATIONS

▪ Glucocorticoid replacement (emergent) if adrenal insufficiency ▪ Ongoing hormone replacement as needed

▪ Pituitary dysfunction

SYNDROME OF INAPPROPRIATE ANTIDIURETIC HORMONE SECRETION (SIADH) osms.it/SIADH PATHOLOGY & CAUSES ▪ Inappropriate ADH secretion → ↓ water excretion ▫ ADH overproduced, secreted → highly concentrated urine, ↓ volume ▫ ↑ intake of fluids, ADH secretion → water retention → dilutes plasma sodium levels → hyponatremia

118 OSMOSIS.ORG

CAUSES

▪ Central nervous system (CNS) disorders enhance ADH production, release ▫ Trauma, stroke, hemorrhage, infection ▫ Mental illness, though carbamazepine effects ▪ Ectopic production of ADH ▫ Lung malignancies: e.g. small cell carcinoma

Chapter 18 Hyperpituitarism & Hypopituitarism ▫ Nonmalignant lung disorders: pneumonia, tuberculosis, cystic fibrosis (CF) ▪ Medications ▫ Anticonvulsants, opioids, sulfonylureas ▪ Injury/surgical removal of pituitary

SIGNS & SYMPTOMS ▪ Body weakness ▫ Fatigue, dizziness, confusion, nausea, lethargy; anorexia ▪ Muscle cramps ▫ Myoclonus,tremors ▪ Seizures

TREATMENT MEDICATIONS

▪ ADH receptor antagonist (e.g. tolvaptan)

OTHER INTERVENTIONS

▪ Water restriction ▫ < 800mL daily ▫ If SIADH associated with subarachnoid hemorrhage, fluid restriction not recommended ▪ IV hypertonic saline administration for severe cases, oral salt tablets, loop diuretics ▪ Urea administration ▫ Increases urine output

DIAGNOSIS LAB RESULTS

▪ Urinalysis ▫ Highly concentrated urine ▪ Serum tests ▫ Hyponatremia, low plasma osmolarity

OSMOSIS.ORG 119

NOTES

NOTES

HYPERTHYROIDISM & HYPOTHYROIDISM

GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Imbalance in thyroid hormones triiodothyronine (T3), thyroxine (T4) → alterations in metabolism

CAUSES Hyperthyroidism ▪ Thyroid gland hyperfunction → overproduction of thyroid hormones ▫ Primary: dysfunction of thyroid gland ▫ Secondary: ↑ thyroid-stimulating hormone (TSH) secretion by pituitary gland Hypothyroidism ▪ Thyroid hormone deficiency ▫ Primary: dysfunction of thyroid gland ▫ Central (secondary): pituitary/ hypothalamic gland dysfunction → ↓ thyrotropin-releasing hormone (TRH)/ TSH

COMPLICATIONS

▪ Hyperthyroidism: thyroid storm ▪ Hypothyroidism: myxedema, cretinism (infants, young children)

SIGNS & SYMPTOMS ▪ Hyperthyroidism: hypermetabolic state, related to sympathetic nervous system stimulation ▪ Hypothyroidism: hypometabolic state

120 OSMOSIS.ORG

DIAGNOSIS DIAGNOSTIC IMAGING Radioiodine uptake scan (RAIU) ▪ Measures thyroid function ▫ Ability to absorb radioactive iodine (123I) Ultrasound ▪ Size of thyroid; characteristics of nodules/ cysts Color flow Doppler sonography (CFDS) ▪ Thyroid blood flow velocity, vascularity

LAB RESULTS

▪ Serum levels of TSH, total T4, free (unbound) T4, total T3, thyroid-stimulating immunoglobulins (TSI), TSH-receptor antibodies (TRAb)

TREATMENT MEDICATIONS Hyperthyroidism ▪ Antithyroid medication ▪ Beta blockers for symptomatic thyrotoxicosis Hypothyroidism ▪ Exogenous thyroid hormone replacement

SURGERY

▪ Hyperthyroidism ▫ Radioactive thyroid ablation ▫ Thyroidectomy

Chapter 19 Hyperthyroidism & Hypothyroidism

EUTHYROID SICK SYNDROME osms.it/euthyroid-sick-syndrome PATHOLOGY & CAUSES ▪ Older term; describes acquired, transient central hypothyroidism in severely sick ▫ Thought to be euthyroid despite ↓ T3 +/T4 concentrations ▫ Transient central hypothyroidism coincident with peripheral T3 metabolism/production abnormalities ▪ ↓ 5’-monodeiodinase activity → ↓ peripheral (skeletal muscle, liver, kidney) T4 → T3 conversion → ↓ T3 serum concentration ▪ ↑ 5’-monodeiodinase (D3) activity → ↑ conversion of T3 → rT3 → ↓ T3 serum concentration (↑ rT3, T2 breakdown products)

CAUSES

▪ Poor caloric intake ▪ High endogenous serum cortisol in setting of exogenous glucocorticoid therapy ▪ Circulating inhibitors of deiodinase activity (e.g. free/nonesterified fatty acids) ▪ Medications (e.g. amiodarone; propranolol, in high doses) ▫ Inhibit 5’-monodeiodinase activity ▪ Cytokines ▫ Tumor necrosis factor (TNF), interferonalpha (IFN-α), nuclear factor kappa-beta (NF-kB), interleukin 6 (IL-6) ▪ Impaired peripheral T4 uptake → ↓ T3 production

SIGNS & SYMPTOMS ▪ Similar to hypothyroidism, not attributable to critical illness ▫ Fatigue, cold intolerance, weight loss/ gain, constipation, muscle cramps, headache, hair loss/brittleness, menstrual irregularities

DIAGNOSIS LAB RESULTS

▪ Serum TSH (required for diagnosis) ▫ Detects TSH suppression

TREATMENT OTHER INTERVENTIONS

▪ Standard replacement therapy (e.g. levothyroxine) ▫ No benefit, unless diagnosis of preceding hypothyroidism/progression to myxedema coma

RISK FACTORS

▪ Severe illness, intensive care unit (ICU) hospitalization

COMPLICATIONS ▪ Myxedema coma

OSMOSIS.ORG 121

GRAVES' DISEASE osms.it/graves-disease PATHOLOGY & CAUSES ▪ Autoimmune disease; production of antibodies against TSH receptor ▪ Most common cause of hyperthyroidism (80%) ▪ Thyroid-stimulating immunoglobulin (TSI) antibody binds to TSH receptors, acts as analog

▫ Exophthalmos dries eyes → corneal ulcers; weakens muscles controlling eye, upper lid ▪ Infiltrative dermopathy ▫ Glycosaminoglycan builds up → pretibial myxedema → non-pitting edema ▪ Pretibial myxedema

RISK FACTORS

▪ Genetic; polymorphisms in CTLA4, PTPN22, HLA-DR3 allele ▪ Peak incidence occurs at 20–40 years old ▪ Individuals who are biologically female affected 10 times more often

COMPLICATIONS

▪ Congestive heart failure, osteoporosis ▪ Thyroid storm ▪ Autoimmune conditions ▫ Rheumatoid arthritis, systemic lupus erythematosus, pernicious anemia, diabetes mellitus Type I ▪ Radioiodine treatment → hypothyroidism

SIGNS & SYMPTOMS ▪ Effects of TSI ▫ Thyroid hypertrophy, hyperplasia → diffuse goiter ▫ Increased synthesis, release of T3, T4 ▫ Follicular cells express molecules on surface, attract nearby T cells → T cells bind to follicular cells, infiltrate interstitium of thyroid tissue ▫ TSI stimulation of fibroblasts in eye orbit → increased production of glycosaminoglycans → local inflammation, swelling → exophthalmos, lid retraction

122 OSMOSIS.ORG

Figure 19.1 The clinical appearance of Graves’ disease. There is proptosis and lid retraction bilaterally.

DIAGNOSIS DIAGNOSTIC IMAGING

▪ Radioiodine scans, measurements of iodine uptake ▫ Diffusely increased

LAB RESULTS

▪ ↓ TSH, ↑ T3, ↑ T4, ↑ TSI

TREATMENT MEDICATION

▪ Antithyroid medication ▫ Thioamides ▪ Beta-blockers

Chapter 19 Hyperthyroidism & Hypothyroidism

SURGERY

▪ Thyroidectomy ▪ Radioiodine radioisotope surgery ▫ Partially/completely destroy thyroid gland with radiation

OTHER INTERVENTIONS

▪ Ophthalmopathy ▫ Steroids, radiation and surgery

Figure 19.2 The histological appearance of scalloped colloid within a hyperplastic thyroid follicle; a classic sign of Graves’ disease.

Figure 19.3 The histological appearance of the thyroid gland in Graves’ disease. There are enlarged thyroid follicles lined by hyperplastic follicular epithelium. The epithelium demonstrates papillary infolding.

HYPERTHYROIDISM osms.it/hyperthyroidism PATHOLOGY & CAUSES ▪ Disorder caused by excessive amount of thyroid hormone produced by overactive thyroid gland ▪ ↑ thyroid hormone synthesis, secretion → thyrotoxicosis (↑ circulating thyroid hormones)

CAUSES

▪ Autoimmune ▫ Graves’ disease (most common cause) ▪ TSH-related disease ▫ TSH-secreting pituitary adenoma;

stimulation of TSH receptors due to excess hCG (e.g. trophoblastic tumors, hyperemesis gravidarum) ▪ Solitary autonomous adenoma ▪ Excessive iodine ingestion

RISK FACTORS

▪ More common in individuals who are biologically female ▪ Smoking, genetic inheritance (Graves’ disease)

COMPLICATIONS ▪ Thyroid storm

OSMOSIS.ORG 123

DIAGNOSIS

SIGNS & SYMPTOMS ▪ Thyroid ▫ Normal/enlarged, with/without palpable nodules (may be diffusely firm, tender) ▪ Cardiovascular ▫ Bounding, rapid pulse; hypertension; palpitations ▪ Respiratory ▫ Tachypnea, dyspnea on exertion ▪ Gastrointestinal (GI) ▫ ↑ appetite/↓ weight; hyperdefecation ▪ Integumentary ▫ Warm, flushed, moist skin; patchy hair loss; thyroid acropachy (digital clubbing); infiltrative dermopathy (pretibial myxedema) ▪ Musculoskeletal ▫ Osteoporosis (↑ bone resorption); skeletal muscle atrophy ▪ Neurological ▫ Heat intolerance, fine tremor, agitation, insomnia ▪ Reproductive ▫ Menstrual irregularities, ↓ libido, infertility ▪ Ocular changes (Graves’ disease) ▫ Wide, staring gaze; lid lag, exophthalmos

DIAGNOSTIC IMAGING RAIU ▪ ↑ 123I uptake confirms hyperthyroidism CFDS ▪ ↑ blood flow due to thyroid hyperactivity Ultrasound ▪ Benign/malignant nodules (e.g. microcalcifications, hypoechogenicity in malignant nodules)

LAB RESULTS

▪ ↓ TSH, ↑ free T4, total/free T3 ▫ Confirms hyperthyroidism with suppressed TSH ▪ ↑ TSH, free T4, total/free T3 ▫ Confirms TSH-induced hyperthyroidism ▪ ↑ TRAb/TSI

TREATMENT MEDICATIONS

▪ Antithyroid drugs

SURGERY

▪ Thyroidectomy

OTHER INTERVENTIONS ▪ Radioactive thyroid ablation

124 OSMOSIS.ORG

Chapter 19 Hyperthyroidism & Hypothyroidism

HYPOTHYROIDISM osms.it/hypothyroidism PATHOLOGY & CAUSES ▪ Hypometabolic state caused by underproduction of thyroid hormones T3, T4 ▪ ↓ availability of thyroid hormone → general slowing of thyroid hormone-induced cell metabolism ▪ Accumulation of matrix glycosaminoglycans in interstitial space → myxedema

TYPES Primary hypothyroidism (thyroid gland dysfunction) ▪ Iodine deficiency ▪ Autoimmune: Hashimoto’s thyroiditis ▫ Autoantibodies against thyroglobulin (Tg), thyroid peroxidase (TPO), TSH receptor → bound antibodies facilitate T-cell, complement-mediated immune destruction of thyroid cells; steric hindrance at TSH receptor ▪ Congenital ▫ Inborn errors of thyroid hormone metabolism ▫ Thyroid agenesis/hypoplasia ▪ Iatrogenic ▫ Treatment of hyperthyroidism, thyroid neoplasm (radiation, surgical) ▪ Medication-induced ▫ Overdose of antithyroid drugs (propylthiouracil, methimazole) ▫ Agents ↓ T4 absorption (cholestyramine, iron salts) ▫ Agents ↓ T4 → T3 conversion (amiodarone) ▫ Agents ↓ clearance of T4 (phenytoin, carbamazepine) ▫ Others: lithium carbonate, interferon alpha, IL-2, tyrosine kinase inhibitors (esp. sunitinib), P-aminosalicylic acid

Secondary, tertiary hypothyroidism (central hypothyroidism) ▪ Disorder of pituitary/hypothalamus/ hypothalamic-pituitary communication → ↓ TSH/TRH ▫ Hypopituitarism: surgical resection/ radiation for adenoma, trauma, postpartum pituitary necrosis (Sheehan’s syndrome), infiltrative disease ▫ Hypothalamic damage: radiation, granulomas, neoplasms

RISK FACTORS

▪ ↑ age ▪ More common in individuals who are biologically female

COMPLICATIONS

▪ Myxedema coma ▫ Common in older individuals who are biologically female with longstanding hypothyroidism; precipitated by acute event (e.g. trauma, infection, myocardial infarction) ▪ Dyslipoproteinemias ▪ Dilated cardiomyopathy; ↓ thyroid hormone → dysregulation of myocardial enzymes → ↓ myocardial contractility ▪ Anemia ▫ Hypoproliferative (normochromic, normocytic)/pernicious anemia (most common in chronic autoimmune thyroiditis) ▪ Hyperprolactinemia → galactorrhea ▪ ↓ clearance of drugs (e.g. antiepileptic, anticoagulant, opioids) in setting of hypothyroidism → ↑ accumulation of drugs → potential drug toxicity ▪ Congenital hypothyroidism ▫ Failure to thrive, intellectual disability

OSMOSIS.ORG 125

SIGNS & SYMPTOMS ▪ Fatigue, cold intolerance, constipation, muscle weakness, headache, weight gain, brittle hair/loss of eyebrow hair, menstrual irregularities, goiter (primary hypothyroidism) ▪ Neurologic manifestations ▫ Difficulty concentrating, poor memory, peripheral neuropathy, carpal tunnel syndrome, ↓ deep tendon reflexes ▪ Myxedema (nonpitting edema) ▫ Periorbital edema, tongue enlargement, puffy facies ▪ Myxedema coma ▫ Altered mental status, hypothermia, multi-organ failure, hypotension, bradycardia, hyponatremia, hypoglycemia, hypoventilation

Figure 19.4 Myxedema of the hands in an individual with hypothyroidism.

DIAGNOSIS LAB RESULTS

▪ Primary hypothyroidism ▫ ↑ TSH, ↓ free T4 ▪ Central hypothyroidism ▫ ↓ free T4, ↓/↔/↑ TSH ▪ Autoimmune autoantibody detection (Hashimoto’s thyroiditis) ▫ ↑ ↑ anti-TPO/Tg/TSH receptor antibodies

OTHER DIAGNOSTICS

▪ History, physical examination

TREATMENT MEDICATIONS

▪ Synthetic T4 (levothyroxine) replacement therapy

126 OSMOSIS.ORG

Figure 19.5 Pretibial myxedema in an individual with hypothyroidism.

Chapter 19 Hyperthyroidism & Hypothyroidism

THYROID STORM osms.it/thyroid-storm PATHOLOGY & CAUSES

DIAGNOSIS

▪ Severe, acute, life-threatening complication of hyperthyroidism

LAB RESULTS

CAUSES

OTHER DIAGNOSTICS

▪ Abrupt termination of hyperthyroidism therapy ▪ Complication of hypothyroid treatment ▪ Diabetic ketoacidosis ▪ Stressors (surgery, infection, trauma, childbirth) ▪ Increased sensitivity of tissues to thyroid hormone, catecholamines

COMPLICATIONS

▪ Myocardial infarction (MI), heart failure; coma, death

SIGNS & SYMPTOMS

▪ ↓ TSH, ↑ T3, ↑ T4

ECG ▪ Confirmation

TREATMENT MEDICATION

▪ Beta blockers ▪ Thyroid hormones reduction ▫ Thioamides, iodine preparations, glucocorticoids, bile acid sequestrants

OTHER INTERVENTIONS ▪ Plasmapheresis

▪ Exaggerated hyperthyroidism symptoms ▫ Heat intolerance → fever ▫ Hyperactivity, anxiety → agitation, confusion, seizures, coma ▫ Tachycardia → cardiac arrhythmias, high-output heart failure

OSMOSIS.ORG 127

TOXIC MULTINODULAR GOITER osms.it/toxic-multinodular-goiter PATHOLOGY & CAUSES ▪ Excess thyroid hormone production from multiple autonomous thyroid nodules, without stimulation of TSH ▪ Second most common cause of hyperthyroidism; AKA Plummer’s disease ▪ Starts as non-toxic multinodular goiter caused by chronic lack of dietary iodine ▫ Lack of iodine → low levels of thyroid hormones→ anterior pituitary releases TSH → thyroid hypertrophy, hyperplasia → some parts of thyroid gland more responsive to TSH than others → uneven growth → most responsive follicular cells grow quickly, develop into nodule → multiple nodules appear ▫ More follicular cells compensate for low thyroid hormone production → euthyroid state ▪ Non-toxic multinodular goiter becomes toxic when genetic mutation for TSH receptor occurs in one of dividing follicular cells → cell becomes constitutively active without TSH → overstimulation of thyroid to divide, produce thyroid hormone → toxic multinodular goiter

COMPLICATIONS ▪ Malignancy (rare)

SIGNS & SYMPTOMS ▪ Increased synthesis, release of T3, T4 → hyperthyroidism ▫ Increased basal metabolic rate, catabolism of proteins, carbohydrates, bone resorption ▫ Exacerbation of sympathetic nervous system ▫ Impairment of reproductive system

128 OSMOSIS.ORG

▪ Thyroid hypertrophy, hyperplasia → goiter ▫ Difficulty swallowing, airway obstruction ▫ Compression of recurrent laryngeal nerve → hoarse voice ▫ Superior vena cava syndrome → facial, arm swelling

Figure 19.6 The clinical appearance of a goiter.

DIAGNOSIS DIAGNOSTIC IMAGING

▪ Radioiodine scans, measurements of iodine uptake ▫ Uneven (“hot” autonomous nodules)

LAB RESULTS

▪ ↓ TSH, ↑ T3, ↑ T4

TREATMENT MEDICATION

▪ Beta blockers ▪ Antithyroid medication ▫ Thioamides ▫ If radioiodine therapy, surgery not appropriate

Chapter 19 Hyperthyroidism & Hypothyroidism

SURGERY

▪ Thyroidectomy ▪ Radioiodine radioisotope surgery ▫ Partially/completely destroy thyroid nodules with radiation

OTHER INTERVENTIONS ▪ Inject ethanol into nodules

Figure 19.7 A CT scan of the head and neck in the sagittal plane demonstrating a massive goiter extending from the mandible to the suprasternal notch.

OSMOSIS.ORG 129

NOTES

NOTES

NEUROENDOCRINE TUMORS GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Tumors arising from cells of neuroendocrine origin; most are functional with hormonesecreting capacity ▪ Can be sporadic; most associated with genetic syndromes

SIGNS & SYMPTOMS ▪ Mass effect ▪ Depends on secreted hormone

DIAGNOSIS DIAGNOSTIC IMAGING

▪ Location; tumor, lymph node, metastasis (TNM) staging

130 OSMOSIS.ORG

LAB RESULTS

▪ Hormone level plasma measurement

OTHER DIAGNOSTICS

▪ History, physical examination ▪ Histopathological analysis, tumor grading

TREATMENT MEDICATIONS

▪ Chemotherapy; hormonal agonists, antagonists

SURGERY ▪ Resection

OTHER INTERVENTIONS ▪ Radiotherapy

Chapter 20 Neuroendocrine Tumors

CARCINOID SYNDROME osms.it/carcinoid-syndrome PATHOLOGY & CAUSES ▪ Signs, symptoms caused by tumor arising from neuroendocrine cells secreting serotonin ▪ ⅓ metastasize, ⅓ associated with secondary malignancy, ⅓ multiple tumors ▪ Most commonly arises from gastrointestinal (GI) tract; followed by lungs, liver, ovaries, thymus ▫ Most common small intestine malignancy ▫ Appendix most common GI tract site ▫ Liver most common site for metastasis; from ileal tumors

DIAGNOSIS DIAGNOSTIC IMAGING CT scan ▪ Locate tumors

LAB RESULTS

▪ Niacin deficiency

Urinalysis ▪ ↑ 5-hydroxyindoleacetic acid

SIGNS & SYMPTOMS ▪ Usually asymptomatic until liver metastasis; symptoms develop occasionally ▫ GI tract tumor → hormone secretion → enter into enterohepatic circulation → liver inactivates hormones → no symptoms ▫ Liver tumor → hormone secretion → released into circulation + liver dysfunction → symptoms ▪ Cutaneous flushing ▪ ↑ intestinal motility, diarrhea ▪ Collagen fiber thickening, fibrosis ▫ Heart valve dysfunction → tricuspid regurgitation, pulmonary stenosis (both right-sided) ▪ Bronchoconstriction, asthma, wheezing ▪ Pellagra (niacin/B3 deficiency) ▫ ↑ serotonin synthesis → ↓ tryptophan → ↓ niacin/B3 synthesis ▫ Dermatitis, diarrhea, dementia, death

Figure 20.1 The gross pathology a lung carcinoid tumor. The cut surface is firm and yellowish brown. The tumor has obstructed a nearby bronchus, leading to an obstructive pneumonia.

OSMOSIS.ORG 131

TREATMENT MEDICATIONS

▪ Somatostatin analogues ▪ Niacin supplementation ▪ Chemotherapy (if malignant)

SURGERY ▪ Resection

Figure 20.2 The histological appearance of a carcinoid tumorlet. The tumor cells form discrete nests.

MULTIPLE ENDOCRINE NEOPLASIA 1 (MEN1) osms.it/multiple-endocrine-neoplasia-1 PATHOLOGY & CAUSES ▪ Autosomal dominant disorder ▫ Characterization: predisposition for endocrine tumor development ▪ Tumors may be functional/non-functional (NF); benign/malignant; may affect one/ more tissues simultaneously

TYPES Parathyroid ▪ Most common Pancreas, duodenum ▪ Gastrinoma (ZES), insulinoma, glucagonoma, VIPoma Anterior pituitary adenoma ▪ Prolactinoma ▪ Other: corticotroph (ACTH) secreting, thyroid-stimulating hormone (TSH) secreting, growth hormone (GH) secreting, NF

132 OSMOSIS.ORG

Carcinoid ▪ Thymic, lung, gastric enterochromaffin-like tumor (NF) Adrenal cortical tumor ▪ NF

CAUSES

▪ Mutation of MEN1 gene located on chromosome 11 (11q13) ▫ Encodes protein menin (endocrine organ tumor suppressor) ▫ Menin function disruption/inactivation → clonal proliferation → somatic heterozygosity loss of remaining functional allele → endocrine neoplasia formation → primarily affects parathyroid, pituitary, pancreas (3Ps)

RISK FACTORS

▪ Mutant MEN1 inheritance

COMPLICATIONS

Chapter 20 Neuroendocrine Tumors ▪ Hyperparathyroidism: ↓ bone mineral density, nephrolithiasis ▪ Pituitary adenoma: mass effects (e.g. headache, diplopia, visual field defects), Cushing disease, acromegaly ▪ Gastrinoma: peptic ulcer disease, gastrointestinal bleeding ▪ Glucagonoma: necrolytic migratory erythema (NME) ▪ Metastasis, tumor recurrence

SIGNS & SYMPTOMS Clinical hormone imbalance, affected organ manifestations ▪ Hyperparathyroidism ▫ Hypercalcemia (e.g. muscle weakness, constipation) ▪ Pituitary adenoma ▫ Prolactinoma: menstrual irregularities, galactorrhea, ↓ libido, infertility ▫ ↑ GH: excessive bone, soft tissue growth; arthralgias ▫ ↑ ACTH: fat redistribution, plethoric facies, thin skin, striae ▫ ↑ TSH: hyperthyroidism (e.g. palpitations, tremulousness) ▪ Pancreatic tumors ▫ Glucose dysregulation (insulinomas, glucagonomas); watery diarrhea, hypokalemia, achlorhydria (WDHA) (VIPoma); steatorrhea (somatostatinoma), abdominal pain, gastroesophageal reflux (gastrinoma) ▪ Carcinoid tumors ▫ Dyspnea, wheezing (lung), nausea, vomiting, abdominal pain (gastrointestinal), clinical manifestations of Cushing’s syndrome (↑ ACTH from thymic tumor) Cutaneous manifestations ▪ Facial angiofibroma, lipoma, collagenoma

DIAGNOSIS DIAGNOSTIC IMAGING MRI/CT scan ▪ Identifies tumor, metastasis, organ structure

changes; TNM staging Upper GI endoscopy ▪ Identifies gastric, duodenal carcinoid tumors, peptic ulcers; allows biopsy Endoscopic ultrasound, somatostatin receptor scintigraphy ▪ Detects pancreatic neuroendocrine neoplasms (PanNETs)

LAB RESULTS Blood studies ▪ Parathyroid tumors ▫ ↑ basal serum calcium, ↑ serum PTH, hypercalciuria ▪ Anterior pituitary adenomas ▫ ↑ prolactin, ↑ ACTH, ↑ cortisol, ↑ GH ▪ PanNETs ▫ ↑ fasting gastrin, ↑ insulin, ↑ ↓ glucose, ↑ VIP

OTHER DIAGNOSTICS

▪ History, physical examination ▫ Occurrence of ≥ two primary MEN1 tumor types; identification of firstdegree relatives with similar findings ▪ MEN1 gene-mutation testing

TREATMENT MEDICATIONS

▪ Hyperparathyroidism ▫ Calcimimetic agents ▪ Prolactinoma ▫ Dopamine agonists ▪ Gastromas ▫ Proton pump inhibitors (PPIs) ▪ Glucagonomas, insulinomas, somatostatinoma, VIPoma ▫ Somatostatin analogue, antihyperglycemic agents ▪ Insulinoma ▫ Diazoxide

SURGERY

▪ Parathyroid tumor ▫ Parathyroidectomy, ethanol ablation

OSMOSIS.ORG 133

▪ Pituitary adenoma ▫ Gamma knife stereotactic radiosurgery, transsphenoidal surgical resection ▪ Glucagonoma, somatostatinoma, gastrinoma, insulinoma, VIPoma, carcinoid ▫ Tumor resection

OTHER INTERVENTIONS

▪ Correction of fluid, electrolyte, glucose, nutritional abnormalities ▪ Radiation therapy (e.g. pituitary adenoma)

MULTIPLE ENDOCRINE NEOPLASIA 2 (MEN2) osms.it/multiple-endocrine-neoplasia-2 PATHOLOGY & CAUSES ▪ Autosomal dominant disorder ▫ Characterization: predisposition for medullary thyroid carcinoma (MTC), pheochromocytoma, primary parathyroid hyperplasia

TYPES MEN 2A ▪ Most common type, AKA Sipple syndrome ▪ Variants ▫ Classic MEN2A with MTC, pheochromocytoma, primary hyperparathyroidism (milder than MEN1) (MEN2A with cutaneous lichen amyloidosis (CLA); MEN2A with Hirschsprung disease (HD)) ▫ Familial medullary thyroid carcinoma (FMTC) MEN 2B ▪ Variants ▫ MTC ▫ Pheochromocytoma ▫ Other features: mucosal neuromas (eyelid, lip, tongue), intestinal ganglioneuromas, marfanoid habitus, medullated corneal nerve fibers

CAUSES

▪ Defect in RET proto-oncogene located on

134 OSMOSIS.ORG

chromosome 10 (10q11.2) ▪ Encodes transmembrane tyrosine kinase receptor RET protein (integral to intracellular signalling that regulates cellular differentiation, proliferation) ▪ Mutation → RET activation → disulfidelinked RET dimerization → intracellular substrate phosphorylation → clinical syndromes

RISK FACTORS

▪ RET mutation presence

COMPLICATIONS

▪ MTC ▫ Hypercalcemia, cardiac arrhythmias, nephrolithiasis ▪ Parathyroid hyperplasia ▫ Hyperparathyroidism, nephrolithiasis, osteoporosis ▪ Pheochromocytoma ▫ Hypertension (therapy-resistant) ▪ HD ▫ Functional bowel obstruction, megacolon, enterocolitis ▪ Intestinal ganglioneuromas ▫ Bowel obstruction ▪ Metastasis

Chapter 20 Neuroendocrine Tumors

SIGNS & SYMPTOMS ▪ MTC/FMTC ▫ Palpable neck mass, cervical lymphadenopathy, facial flushing (peptide secretion by tumor), diarrhea (gastrointestinal fluid, electrolyte secretion from excess calcitonin); clinical Cushing’s syndrome manifestations (ectopic corticotropin (ACTH) production) ▪ Parathyroid hyperplasia ▫ Fatigue, muscle weakness, altered mental status, bone pain (↓ bone density), flank pain (nephrolithiasis), nausea, vomiting, thirst, frequent urination ▪ Pheochromocytoma ▫ Hypertension, paroxysms of palpitations, tachycardia, excessive sweating, facial flushing, tremors, anxiety (↑ catecholamines) ▪ HD ▫ Vomiting, abdominal distension, constipation ▪ CLA ▫ Scaly, papular, pigmented, lesions in either interscapular region/extensor surface extremities ▪ Intestinal ganglioneuromas ▫ Abdominal pain, gaseous distension ▪ Dysmorphic facies ▫ E.g. upper-eyelid margin thickening, eversion; nodules on tongue, vermilion border of lips

DIAGNOSIS DIAGNOSTIC IMAGING CT scan/MRI ▪ Tumor identification, TNM staging Thyroid, neck ultrasound ▪ MTC ▫ Calcification presence

LAB RESULTS

▪ MTC ▫ ↑ carcinoembryonic antigen (CEA), ↑

serum calcitonin, pentagastrin/calcium stimulation test (↑ serum calcitonin) ▪ Parathyroid hyperplasia ▫ ↑ basal serum calcium, ↑ serum PTH, hypercalciuria ▪ Pheochromocytoma ▫ ↑ plasma fractionated metanephrines, ↑ 24-hour urine metanephrine

OTHER DIAGNOSTICS

▪ Medical history, family history, physical examination ▫ MEN 2A: ≥ two characteristic neoplasias in individual/close family members ▫ MEN 2B: mucosal neuromas of lips, tongue; marfanoid habitus; medullated corneal nerve fibers; gut ganglioneuromatosis; MTC ▫ FMTC ≥ four MTC cases in families without pheochromocytoma/ hyperparathyroidism ▪ Fine-needle aspiration (FNA) thyroid biopsy ▫ Histological analysis: MTC with large, pleomorphic, ↑ C cell number ▪ Rectal biopsy ▫ Absent ganglion cells (HD) ▪ Ophthalmic slit-lamp examination ▫ Detects thickened, medullated corneal nerve fibers ▪ Genetic RET mutation testing

TREATMENT MEDICATIONS

▪ Tyrosine kinase inhibitors ▪ Post-surgical hormone replacement ▪ Hyperparathyroidism ▫ Bisphosphonates/calcimimetics (cinacalcet) ▪ Cutaneous lichen amyloidosis ▫ Intralesional steroids, antihistamines, ultraviolet light/laser therapy

SURGERY

▪ Tumor resection (e.g. thyroidectomy, adrenalectomy, partial/cortex-sparing adrenalectomy) ▪ Lymphadenectomy

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▪ HD ▫ Resect affected colon segment

NEUROBLASTOMA osms.it/neuroblastoma PATHOLOGY & CAUSES ▪ Neural crest cell tumor arising in adrenal gland/spinal cord ▪ Fetal development → oncogene, tumor suppressor gene mutation → adequate cellular differentiation failure → tumor formation ▪ Most common infant cancer; most occur in age < five; better prognosis ▪ Releases chemokines (esp. CXCL12) → stimulates cell growth, migration → metastasis ▪ Half metastasize to bone

▪ Abdominal mass Bone metastasis ▪ Pain, pathologic fractures ▪ Skull base fractures → battle, “racoon eyes” sign ▪ Myelosuppression → anemia, thrombocytopenia, leukopenia → fatigue, easy bruising, frequent infections

TYPES

▪ Three types: differentiation level

Undifferentiated ▪ Neural crest cells, AKA small blue round cells; contains nerve fibers, AKA neuropil Poorly differentiated ▪ Partially displays characteristics of differentiated, undifferentiated Differentiated ▪ Surrounded by myelin, AKA Schwannian stroma; better prognosis

SIGNS & SYMPTOMS ▪ Related to chemokine release; unspecific ▪ Fever; weight loss; sweating; fatigue Mass effect ▪ Horner syndrome → ptosis, miosis, anhidrosis ▪ Spinal cord compression syndromes → limb weakness, incontinence

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Figure 20.3 The histological appearance of a neuroblastoma demonstrating Homer-Wright rosettes.

DIAGNOSIS DIAGNOSTIC IMAGING CT scan ▪ Renal mass/mass adjacent to spinal nerve roots; confirm diagnosis

LAB RESULTS

▪ Catecholamine breakdown products: VMA, HMA

Complete blood count (CBC)

Chapter 20 Neuroendocrine Tumors

SURGERY

▪ Anemia, leukopenia

TREATMENT MEDICATIONS

▪ Localized ▫ Resection ▪ Metastatic ▫ Resection, bone marrow transplant

▪ Metastatic ▫ Chemotherapy

PANCREATIC NEUROENDOCRINE NEOPLASMS osms.it/pancreatic-ne-neoplasms PATHOLOGY & CAUSES ▪ AKA PanNETs ▫ Functional tumors arising from pancreatic neuroendocrine cells ▪ Unregulated hormone secretion → effect on target organs → hormone-related clinical syndrome

TYPES Insulinoma ▪ Rare functional tumor ▫ Arises from insulin producing pancreatic beta cells ▪ Most common functioning PanNET ▪ Usually benign, indolent, small (< 2cm/0.8in), solitary lesions; rarely malignant ▪ ↑ insulin secretion → hyperinsulinemia → ↓ hepatic gluconeogenesis → hyperinsulinemic hypoglycemia VIPoma ▪ Rare functional tumor ▫ Arises from pancreatic D-1 cells that produce vasoactive intestinal polypeptide (VIP) ▫ AKA Verner–Morrison syndrome/ pancreatic cholera syndrome ▪ Malignancy: 50% ▪ ↑ VIP secretion ▫ Cellular adenylate cyclase, cAMP

production by intestinal epithelial cells → secretion of fluid, sodium, chloride into intestinal lumen → high-volume secretory diarrhea Glucagonoma ▪ Rare functional tumor ▫ Arises from pancreatic glucagonproducing alpha cells ▪ Usually malignant ▪ Excessive glucagon ▫ ↑ liver’s catabolic action → ↑ amino acid oxidation, gluconeogenesis from amino acid substrates → glucagonoma syndrome (amino acid deficiency, ↑ blood glucose, glucose intolerance) ▫ Co-secretion of gastrin, VIP, serotonin, calcitonin → diarrhea Somatostatinoma ▪ Very rare somatostatin-secreting tumor ▫ Arises from pancreatic D-cells ▪ Commonly located within head of pancreas; may also arise from ampulla, periampullary region of duodenum; rarely in jejunum, liver, colon, rectum ▪ Usually malignant ▫ ↑ somatostatin → digestive organ inhibition → clinical syndrome

RISK FACTORS Insulinoma

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▪ Multifocal insulinomas associated with MEN 1 VIPoma, glucagonoma ▪ Associated with MEN 1 Somatostatinoma ▪ Associated with MEN1, neurofibromatosis type 1 (NF1)

COMPLICATIONS Insulinoma ▪ Hypoglycemia, seizures, rarely metastasis Vipoma ▪ Dehydration, electrolyte imbalances, metastasis Glucagonoma ▪ NME, weight loss (secondary to hyponutrition) ▪ Diabetes, chronic diarrhea, venous thrombosis (deep vein thrombosis, pulmonary embolism) ▪ Neuropsychiatric complications (e.g. depression, psychosis, agitation, paranoid delusions) ▪ Metastasis Somatostatinoma ▪ Cholelithiasis, diabetes mellitus, metastasis

SIGNS & SYMPTOMS Insulinoma ▪ Whipple’s triad: hypoglycemia, hypoglycemia signs, intravenous (IV) glucose → symptom resolution ▫ Neuroglycopenic manifestations: visual disturbances, weakness, confusion ▫ Sympathetic/adrenergic manifestations: diaphoresis, tremors, palpitations, hunger VIPoma ▪ WDHA; stools tea-colored, odorless ▪ ↑ potassium secretion into large bowel → hypokalemia ▪ ↓ gastric acid secretion → hypochlorhydria ▪ ↑ glycogenolysis → hyperglycemia ▪ ↑ bone resorption → hypocalcemia

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▪ ↑ vasodilation → flushing Glucagonoma ▪ Hyperglycemia, weight loss ▪ NME ▫ Erythematous, sometimes painful rash with papules/plaques on face, perineum, extremities; hair loss, nail dystrophy ▫ If mucous membranes affected: glossitis, angular cheilitis, stomatitis, blepharitis Somatostatinoma ▪ Classic syndrome ▫ ↓ cholecystokinin → colelithiasis ▫ ↓ pancreatic enzyme, ↓ intestinal lipid absorption → steatorrhea ▫ ↓ gastrin → hypochlorhydria ▫ ↓ insulin → diabetes mellitus ▪ Abdominal pain ▪ Weight loss

MNEMONIC: 6 Ds

Glucagonoma symptoms Dermatitis Diabetes Diarrhea Deep Venous Thrombosis Decreased Weight Depression

DIAGNOSIS DIAGNOSTIC IMAGING Endoscopic ultrasound ▪ Insulinoma, VIPoma, glucagonoma, somatostatinoma ▫ Detects small tumors, establishes local disease extent, allows for needle biopsy CT scan/MRI ▪ Insulinoma, VIPoma, glucagonoma, somatostatinoma ▫ Tumor localization, TNM staging CT scan ▪ VIPoma ▫ Homogeneous, well-circumscribed

Chapter 20 Neuroendocrine Tumors lesions; may have cystic regions ▪ Glucagonoma ▫ May appear solid/contain central lowattenuation areas ▪ Somatostatinoma ▫ Isodense; may be cystic MRI ▪ VIPoma, glucagonoma, somatostatinoma ▫ Low signal intensity on T1-weighted images, high signal intensity on T2weighted images

hyperchromasia, mitotic activity

TREATMENT MEDICATIONS Insulinoma ▪ Diazoxide: inhibits insulin release, enhances glycogenolysis VIPoma ▪ Somatostatin analogue

GLP-1 scintigraphy ▪ Insulinoma ▫ Identifies insulinoma via radiolabeled GLP-1 receptor imaging

Glucagonoma, somatostatinoma ▪ Somatostatin analogue ▪ Anti-hyperglycemic agents

Somatostatin receptor scintigraphy ▪ VIPoma, glucagonoma, somatostatinoma ▫ Detects metastases via radiolabeled form of somatostatin analog octreotide (Indium-111 [111-In]) pentetreotide

SURGERY

Functional PET imaging with 68-Ga DOTATATE ▪ Glucagonoma, somatostatinoma ▫ Detects small tumors

LAB RESULTS Insulinoma ▪ Overnight fasting plasma levels/72 hour fast test (inpatient) ▫ ↓↓ glucose, ↑ insulin, ↑ proinsulin, ↑ C-peptide VIPoma ▪ Hormonal assay: ↑ plasma VIP ▪ ↓ stool osmotic gap ( basal levels ▪ If other cause of hypergastrinemia ▫ Gastrin inhibition

OTHER DIAGNOSTICS ▪ MEN1 screening

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MEDICATIONS

▪ Chemotherapy ▫ Metastatic disease

SURGERY ▪ Resection

OTHER INTERVENTIONS

▪ Proton pump inhibitors ▫ ↓ gastric acid ▪ Somatostatin analog ▫ ↓ gastrin levels; may slow tumor growth

Chapter 2 Acyanotic Defects

NOTES

THYROIDITIS GENERALLY, WHAT IS IT? DIAGNOSIS

PATHOLOGY & CAUSES ▪ Group of autoimmune disorders resulting in inflammation, destruction, and functional impairment of the thyroid gland

SIGNS & SYMPTOMS ▪ Hypothyroidism ▫ Weight gain despite reduced appetite, constipation ▫ Cold intolerance, fatigue, lethargy, weakness ▫ Brittle hair and nails, dry skin, hair loss (alopecia) ▫ Mental slowness (bradypsychia) ▫ Voice hoarseness → compression of recurrent laryngeal nerve ▫ Enlarged thyroid gland (goiter)

▪ Suspect based on clinical presentation

LAB RESULTS

▪ Serum antibody levels against thyroid components ▪ Thyroid biopsy via fine needle aspiration

TREATMENT MEDICATIONS

▪ Thyroid hormone replacement → levothyroxine

SURGERY

▪ Surgical removal if adjacent structures are affected

HASHIMOTO'S THYROIDITIS osms.it/hashimotos-thyroiditis PATHOLOGY & CAUSES ▪ Chronic autoimmune disorder leading to inflammation, gradual destruction and functional impairment of the thyroid gland resulting in hypothyroidism and increased risk of thyroid cancer ▪ Most common cause of hypothyroidism in areas where dietary iodine is sufficient ▪ Cause unclear; related to HLA-DR3 and HLA-DR5 genes; may occur in combination with Graves' disease; may be influenced by

environmental factors ▪ Hürthle cells ▫ Enlarged follicular cells with an eosinophilic, granular cytoplasm ▪ Gene mutation → B cell dysfunction → B cell thyroid invasion → B cell germinal centers established within thyroid → B cell activation and autoantibody production → NK cells signaled to destroy thyroid follicular cells + CD4+ cells produce inflammatory cytokines + CD8+ cells attack thyroid follicular cells → release of stored T3 and T4 → transient hyperthyroidism

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→ burnout → hypothyroidism → compensatory increase in thyroidstimulating hormone (TSH), thyrotropinreleasing hormone (TRH) ▪ Chronic inflammation → connective tissue buildup → enlarged gland ▪ B cells have the potential to become malignant → B cell lymphoma of the thyroid ▫ Rare; usually in females over 70 with history of Hashimoto’s

SIGNS & SYMPTOMS Hypothyroidism ▪ Weight gain despite reduced appetite, constipation ▪ Brittle hair and nails, dry skin, hair loss (alopecia) ▪ Cold intolerance, fatigue, lethargy, weakness ▪ Mental slowness (bradypsychia) ▪ Enlarged, nodular thyroid gland (goiter) ▫ Non-tender, firm ▫ Voice hoarseness → compression of recurrent laryngeal nerve ▫ Stridor → tracheal compression ▪ Menstrual abnormalities, galactorrhea ▪ ↑ TRH → ↑ prolactin levels ▪ Myxedema ▫ Nonpitting edema caused by mucopolysaccharide deposition in upper skin layers ▫ Most common around tibial area, may also occur around eyes and feet ▪ Rapidly growing goiter suggests B cell lymphoma of the thyroid

▪ Perform fine needle aspiration (FNA) if B cell lymphoma of the thyroid suspected

TREATMENT MEDICATION

▪ Thyroid hormone replacement → levothyroxine

SURGERY

▪ Goiter affecting adjacent structures → surgical removal

Figure 21.1 The histological appearance of Hashimoto’s thyroiditis. The normal thyroid follicles are on the right. The lymphocytic infiltrate has replaced the normal thyroid tissue on the left.

DIAGNOSIS ▪ Suspect based on clinical presentation

LAB RESULTS

▪ ↓ T3 and T4 ▪ ↑ TSH and TRH ▪ Autoantibodies against thyroid peroxidase (anti-TPO) and against thyroglobulin (antiTG)

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Figure 21.2 A low power image of Hashimoto’s thyroditis, showing the lymphoycytic infiltrate forming germinal centres.

Chapter 21 Thyroiditis

POSTPARTUM THYROIDITIS osms.it/postpartum-thyroiditis PATHOLOGY & CAUSES ▪ Autoimmune destruction of the thyroid gland occurring within one year after after parturition, resulting in transient thyroid dysfunction and thyroid hormone imbalance ▪ Related to normal fluctuations in maternal immune function in the setting of subclinical autoimmune thyroid disease ▪ Autoimmune-related thyroid inflammation (1–4 months postpartum) → damage to thyroid follicles and thyroglobulin → ↑ ↑ thyroxine (T4) and triiodothyronine (T3) release into the blood → hyperthyroidism (last 2–8 weeks) ▫ T4/T3 stores eventually used up + TSH-induced cessation of new thyroid hormone synthesis → transient hypothyroidism ▫ Resolution of inflammation → follicle regeneration → return to normal thyroid levels

RISK FACTORS

▪ Prior history of postpartum thyroiditis ▪ Pre-existing hypothyroidism (e.g. Hashimoto’s thyroiditis with remaining functional thyroid hormone) ▪ Type 1 diabetes mellitus ▪ Familial predisposition (possible inheritance pattern)

COMPLICATIONS

▪ Chronic hypothyroidism

SIGNS & SYMPTOMS ▪ Symptoms of hyper- and hypothyroidism are usually mild ▪ Hyperthyroid phase (↑ metabolic rate) ▫ Anxiety ▫ Heat intolerance ▫ Tachycardia, palpitations ▫ Tremor ▫ Fatigue ▫ Weight loss ▫ Diffuse, painless goiter ▪ Hypothyroid phase (↓ metabolic rate) ▫ Impaired concentration ▫ Cold intolerance ▫ Sluggishness ▫ Constipation ▫ Dry skin

DIAGNOSIS DIAGNOSTIC IMAGING

▪ Radioactive iodine uptake ▫ Profoundly suppressed (test is contraindicated if breastfeeding)

LAB RESULTS

▪ Blood studies ▫ Hyperthyroid phase: ↑ T4, T3; ↓ TSH ▫ Hypothyroid phase: ↓ free T4, ↑ TSH ▫ ↑ antithyroid peroxidase antibodies ▪ Thyroid biopsy ▫ Lymphocytic thyroiditis - infiltration of lymphocytes, follicular destruction

OTHER DIAGNOSTICS

▪ History and physical examination

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TREATMENT ▪ Mild symptoms require no treatment

MEDICATIONS

▪ Symptomatic hyperthyroidism: betablocker ▪ Symptomatic hypothyroidism: levothyroxine

RIEDEL'S THYROIDITIS osms.it/riedels-thyroiditis PATHOLOGY & CAUSES ▪ Rare autoimmune disorder leading to inflammation, fibrotic infiltration, gradual destruction, and functional impairment of the thyroid gland ▪ May be related to a systemic autoimmune fibrotic disease process ▪ Component of IgG4-related disease ▫ May also cause fibrosis of salivary glands, kidneys, pancreas and lungs ▪ IgG4 attacks thyroid follicular cells → T cells release inflammatory cytokines → abnormal fibroblast activation within thyroid stroma → stromal fibrosis replaces damaged follicles → gland enlarges and hardens → fibrosis spreads to neck structures (parathyroid glands, blood vessels, trachea, muscles, nerves)

SIGNS & SYMPTOMS ▪ Hardened, wood-like, fixed, painless and enlarged thyroid gland (goiter) ▪ Hypothyroidism ▫ Weight gain despite reduced appetite, constipation ▫ Brittle hair and nails, dry skin, hair loss (alopecia) ▫ Cold intolerance, fatigue, lethargy, weakness

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▫ Mental slowness (bradypsychia) ▫ Bradycardia ▪ Other neck structures affected by compression ▫ Tracheal fibrosis → shortness of breath (dyspnea) ▫ Recurrent laryngeal nerve fibrosis → voice hoarseness ▫ Esophageal fibrosis → dysphagia ▫ Parathyroid gland fibrosis → hypocalcemia and tetany (hypoparathyroidism)

DIAGNOSIS ▪ Suspect based on clinical presentation

LAB RESULTS

▪ Autoantibodies against thyroid components (anti-TPO) ▪ ↓ T3 and T4 ▪ ↑ TSH and TRH ▪ Tissue biopsy ▫ Predominant fibrous tissue and collagen + lymphocyte infiltration

Chapter 21 Thyroiditis

TREATMENT MEDICATIONS

▪ Corticosteroids ▪ Tamoxifen may decrease goiter size ▪ Thyroid hormone replacement → levothyroxine

SURGERY

▪ Debulking or surgical removal if goiter affects adjacent structures

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NOTES

NOTES

CHROMOSOMAL DELETION SYNDROMES

GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Congenital syndromes: genetic deletions during parental gamete formation ▪ Mutation: permanent DNA change

TYPES Numerical ▪ Entire chromosome deletion (aneuploidy) Structural ▪ Structural change due to chromosome break → separated portion rearrangement ▫ Balanced rearrangement: without genetic material gain/loss; not associated with phenotypic anomaly ▫ Unbalanced rearrangement: with genetic material gain/loss; associated with phenotypic anomaly ▪ Deletion size: proportional to clinical severity

CAUSES

▪ Chromosomal breakage mechanism ▫ Endogenous: defect in DNA replication, transcription, recombination, repair ▫ Exogenous: radiation, chemical substances → DNA damage

RISK FACTORS

▪ Parental genetic defect

COMPLICATIONS

▪ Congenital heart defect; recurrent infection (e.g. urinary tract infections, otitis media); gastrointestinal abnormalities; severe constipation; impaired development; intellectual disability

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SIGNS & SYMPTOMS ▪ Atypical facial features, short stature, noise sensitivity, additional organ defect-related signs/symptoms

DIAGNOSIS ▪ History, clinical examination

LAB RESULTS

▪ Genetic tests ▫ e.g. karyotyping, fluorescent in-situ hybridization (FISH)

TREATMENT OTHER INTERVENTIONS

▪ Early intervention education ▪ Physical, language, occupational therapy ▪ Associated condition treatment

Chapter 22 Chromosomal Deletion Syndromes

CRI DU CHAT SYNDROME osms.it/cri-du-chat PATHOLOGY & CAUSES ▪ Chromosomal deletion syndrome: physical, neurological congenital anomalies ▫ Caused by partial/total macrodeletion in short arm of chromosome 5 (5p-) ▫ AKA cat cry syndrome, 5p- syndrome, Lejeune’s syndrome ▫ Cri-du-chat: “cat’s cry” ▪ Inheritance pattern: mostly sporadic ▫ Paternal origin (most): sporadic chromosome breakage during male gamete formation ▫ Inherited Cri du chat syndrome (rare): parent with balanced translocation → child with unbalanced translocation (rearrangement with genetic material loss) in 5p ▪ Most due to terminal deletions

CAUSES

▪ Deletion ▫ 5p15.2: major clinical features (e.g. dysmorphism, intellectual impairment) ▫ 5p15.3: altered larynx anatomy, central nervous system (CNS) dysfunction → cat-like cry, high-pitched voice, speech delay ▪ CTNND2 gene loss: severe mental disability

RISK FACTORS

▪ Parental genetic defect ▪ Biologically-female individuals (more common)

COMPLICATIONS

gastrointestinal/genitourinary abnormalities

SIGNS & SYMPTOMS ▪ Cat-like cry, high-pitched voice: may resolve during infancy ▪ Poor feeding ▪ Facial features: microretrognathia (hypoplastic, posteriorly displaced mandible); round face; epicanthus (prominent eye folds); downslanting eyelids; hypertelorism (widely-spaced eyes); wide nasal bridge; low-set ears ▫ Physical signs become less prominent with age ▪ Body features: muscular hypotonia, short stature, short neck, small hands, single palmar crease, scoliosis, prenatal-growth deficiency, low birth weight ▪ Ocular: myopia, strabismus, cataracts ▪ Neurologic: noise sensitivity (hyperacusis); behavior alterations (e.g. aggression, hyperactivity, repetitive movement) ▪ Adulthood: small testes, premature hair graying (age ≥ 15), constipation ▫ Physical signs become less prominent with age

DIAGNOSIS LAB RESULTS

▪ Cytogenetic tests: FISH, karyotyping, chromosomal analysis ▪ Molecular genetics tests: heteroduplex analysis; single strand conformation analysis; whole genome sequencing; Southern, northern blotting

▪ Low birth weight; postnatal failure to thrive; microcephaly; developmental, mental disability; pneumonia; congenital heart defects; craniofacial dysmorphism; respiratory distress syndrome; hydrocephalus; chronic otitis media;

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TREATMENT OTHER INTERVENTIONS

▪ Early intervention education; physical, language, occupational therapy ▪ Associated condition treatment (e.g. heart defect repair)

Figure 22.1 The facial appearance of a child with Cri du chat syndrome.

WILLIAMS SYNDROME osms.it/williams-syndrome PATHOLOGY & CAUSES ▪ Chromosomal deletion syndrome: affects most organ systems ▫ AKA Williams–Beuren syndrome ▪ 26–28 genes involved ▪ Inheritance pattern: sporadic (mutation during gamete formation)

CAUSES

▪ Hemizygous microdeletion in long arm of chromosome 7 (7q11.23) ▫ Most chromosomal breaks in medial, centromeric duplicons (gene clusters organized in low-copy repeat blocks) ▪ May include elastin gene (ELN) deletion: involved in supravalvular aortic stenosis

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RISK FACTORS

▪ Parental genetic defect (e.g. Williams syndrome)

COMPLICATIONS

▪ Hypercalcemia/hypercalciuria; nephrocalcinosis; dysfunctional voiding; chronic kidney disease; urinary tract congenital anomalies; gastrointestinal conditions (e.g. chronic constipation, cholelithiasis); diabetes mellitus; diabetic nephropathy; progressive valvular stenosis; joint limitations; systemic arterial stenosis (esp. supravalvular aortic stenosis); hypothyroidism; type I Chiari malformation (cerebellar tonsils extend to foramen magnum); recurrent otitis media

Chapter 22 Chromosomal Deletion Syndromes

SIGNS & SYMPTOMS ▪ “Elfin”/pixie-like facies: flat nasal bridge, short upturned nose, long medial cleft, periorbital puffiness, full lips, wide mouth, broad forehead, medial eyebrow flare ▫ More distinctive with age ▪ Hoarse voice, high-tone sensorineural hearing loss, noise sensitivity (hyperacusis) ▪ Short stature ▪ Dental: small/abnormally shaped teeth, malocclusion ▪ Psychiatric: friendly, “cocktail party” personality; cognitive impairment; weak visuospatial/visuomotor skills; strong language skills; development delay; anxiety, phobias; obsessive-compulsive traits ▪ Neurologic: hyperreflexia; clonus; extrapyramidal signs (e.g. tremor, bradykinesia, dystonia); cerebellar signs (e.g. incoordination) ▪ Ocular: strabismus, amblyopia ▪ Gastrointestinal: constipation, gastroesophageal reflux, rectal prolapse ▪ Hypertension ▪ Hypercalcemia: irritability, ↓ appetite, constipation, hypotonia

DIAGNOSIS DIAGNOSTIC IMAGING Ultrasound, echocardiogram ▪ Urinary tract abnormalities (e.g. bladder diverticula, renal aplasia) ▪ Cardiovascular: supravalvular aortic stenosis, “hourglass” aorta, left ventricular hypertrophy (occasionally)

LAB RESULTS

▪ Lab tests: altered thyroid function, hypercalcemia, hypercalciuria, ↑ serum creatinine ▪ Cytogenetic tests: FISH ▪ Comparative genomic hybridization

OTHER DIAGNOSTICS

▪ Audiologic tests: high-tone sensorineural hearing loss

TREATMENT OTHER INTERVENTIONS

▪ Early intervention education: physical, language, occupational therapy ▪ Associated condition treatment: e.g. aortic stenosis surgical repair, hypertension treatment

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NOTES

NOTES

CONNECTIVE TISSUE DISORDERS

GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Genetic disorders affecting synthesis of connective tissue components (e.g. fibrillin, collagen) ▪ Genetic mutation → dysfunctional protein (e.g. ↓ function fibrillin/collagen) → ↓ supportive function connective tissue → ↓ function of various organs, tissues ▪ Common disorders ▫ Marfan syndrome (fibrillin 1 mutation) ▫ Ehler–Danlos syndrome (various etiologies) ▫ Osteogenesis imperfecta (collagen Type I mutation) ▫ Alport syndrome (collagen Type IV mutation) ▪ Vary from dominant to recessive, range in severity

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SIGNS & SYMPTOMS ▪ May affect all organ systems containing connective tissue; esp. musculoskeletal, ocular, cardiovascular systems

DIAGNOSIS OTHER DIAGNOSTICS

▪ Standardized criteria ▪ Genetic testing (confirmation)

TREATMENT OTHER INTERVENTIONS

▪ Supportive due to the genetic basis of disease, not curable

Chapter 23 Connective Tissue Disorders

ALPORT SYNDROME osms.it/alport-syndrome PATHOLOGY & CAUSES ▪ Rare disorder caused by mutations in genes encoding for chains of Type IV collagen → abnormal basement membranes of kidney glomerulus, eye, cochlea ▫ AKA hereditary nephritis ▪ Mutation substitutes glycine with different amino acid → triple-helix unable to form → impaired basement membrane structure ▫ Glomerular basement membrane progressively hardens as abnormal Type IV collagen accumulates → thin glomerular basement membrane nephropathy ▫ Impaired ability of hair cells attached to basement membrane in organ of Corti (in cochlea) to generate nerve signals ▫ Thinning of lens capsule → disruption of lens shape → anterior lenticonus

TYPES X-linked ▪ COL4A5 on X-chromosome ▪ Presents early, most common form Autosomal recessive/dominant ▪ COL4A3, COL4A4 mutations Thin basement membrane nephropathy ▪ Mild mutations in COL4A3, COL4A5 ▪ Microscopic hematuria (sole symptom)

RISK FACTORS ▪ Family history

COMPLICATIONS

▪ End-stage renal disease, sensorineural hearing loss, changes in visual acuity, aortic aneurysms

SIGNS & SYMPTOMS ▪ Generally appear in early childhood/ adolescence ▪ Renal ▫ Progressive renal insufficiency, hypertension ▪ Eye ▫ Corneal abrasions, lens opacity, ocular pain ▪ Ear ▫ Initial high-frequency hearing loss → loss of normal speech

DIAGNOSIS LAB RESULTS Urinalysis ▪ Hematuria, proteinuria, ↑ creatinine

OTHER DIAGNOSTICS Clinical exam ▪ Renal failure with deafness, with no other apparent cause Ophthalmic examination ▪ Slit lamp examination of eye ▫ “Oil droplet” reflex ▪ Fundoscopy ▫ White/yellow granulations in retina (fleck retinopathy) Kidney/skin biopsy (confirmation) ▪ Immunohistochemistry (labelled antibody applied to biopsy, viewed on slide) ▫ Label usually identifies collagen alpha chains ▫ Misfolded collagen degraded; does not stain

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▪ Electron microscopy ▫ Early disease: thinning of glomerular basement membrane ▫ Later disease: glomerular basement membrane thin, thick, abnormal segments, split lamina densa (appears as woven basket) Gene testing ▪ Gene testing for COL4A genes ▫ Diagnostic procedure of choice due to noninvasive nature, accuracy

TREATMENT MEDICATIONS

▪ Renal ▫ Angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers prevent progression to kidney failure, dialysis, kidney transplant

SURGERY

▪ Anterior lenticonus ▫ Replacement of lens

OTHER INTERVENTIONS

▪ Hearing loss may benefit from hearing aids

EHLERS–DANLOS SYNDROME (EDS) osms.it/ehlers-danlos_syndrome PATHOLOGY & CAUSES ▪ Defective collagen synthesis → group of rare connective tissue disorders → tissue fragility ▫ Single gene disorders ▫ Autosomal dominant/recessive ▫ 30 types of collagen may be affected ▫ 13 different Ehler–Danlos syndromes classified on distribution of tissue involvement

CAUSES

▪ Gene mutation (specific gene varies depending on type) → defective fibrous proteins/enzymes → ↑ elasticity of tissues, structure, ↓ strength of tissues ▪ Minor injuries → gaping defects → repair difficult due to low tensile strength

RISK FACTORS ▪ Family history

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COMPLICATIONS

▪ Colon, large artery, corneal rupture; retinal detachment, diaphragmatic hernias, premature arthritis; pregnancy complications (e.g. cervical insufficiency, premature rupture of membranes)

SIGNS & SYMPTOMS ▪ Skin ▫ Hyperextensive, fragile, vulnerable to trauma; easy bruising; atrophic scars ▪ Ligament laxity ▫ Hypermobile joints; joint dislocation predisposition (diagnosed by Beighton hypermobility scale); spinal malformations (e.g. scoliosis); osteochondrosis, arthritis; pain in muscles, joints ▪ Bones, joints ▫ Pes planus, pectus excavatum, high arched palate; islocations ▪ Cardiovascular

Chapter 23 Connective Tissue Disorders ▫ Spontaneous artery dissection; valvular disorders; arterial rupture; Raynaud’s phenomenon; impaired platelet aggregation ▪ Spontaneous organ rupture ▪ Cerebrovascular rupture

DIAGNOSIS OTHER DIAGNOSTICS

▪ Clinical exam ▫ Typical presentation (e.g. lens dislocation, cardiovascular incidents, hypermobility) ▫ Beighton score (evaluates hypermobility): nine criteria, four needed to establish hypermobility ▪ Ehler–Danlos specific genetic panel (confirmation) ▪ Skin biopsy

TREATMENT MEDICATIONS

▪ According to type ▫ Pain medication: nonsteroidal antiinflammatory drugs (NSAIDs) for arthralgia, myalgia

SURGERY

▪ According to type ▫ Joint surgery for severe arthritis

OTHER INTERVENTIONS

▪ According to type ▫ Education, counseling ▫ Physical therapy to prevent joint damage ▫ Casting/orthoses to stabilize joints ▫ Regular cardiovascular monitoring

Figure 23.1 Hypermobility at the wrist and metacarpophalangeal joints in an individual with Ehlers–Danlos syndrome.

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MARFAN SYNDROME osmosis.org/learn/marfan_syndrome PATHOLOGY & CAUSES ▪ Genetic disorder of defective connective tissue

CAUSES

▪ Fibrillin 1 structural protein dysfunction due to FBN1 gene mutation (locus 15q21) ▫ Autosomal dominant ▫ Compromised extracellular matrix (e.g. elastic fibers) ▫ Fibrillin loss → ↑ transforming growth factor beta (TGF-β) → ↓ vascular muscle, extracellular matrix → compromises strength, elasticity → Marfanoid appearance ▪ Skeleton, heart, blood vessels, eyes, lungs; most commonly affects aorta, ligaments, ciliary zonules supporting lens

▪ Hyperextensibility with inability to extend elbows 180º ▪ Scoliosis ▪ Pes excavatum, pigeon chest ▪ Arachnodactyly (long fingers) ▫ Thumb sign: thumb protrudes beyond ulnar margin when fist clenched ▫ Wrist sign: entire fingernail of fifth finger covered by thumb when wrapped around wrist ▪ Dolichocephaly ▫ Narrow skull

RISK FACTORS ▪ Family history

COMPLICATIONS

▪ Lens dislocation, aortic rupture, pneumothorax

SIGNS & SYMPTOMS ▪ Vary in severity, rarely present at birth (neonatal Marfan syndrome) Eyes ▪ Bilateral cranial, temporal dislocation of lens (ectopia lentis); highly specific ▪ Retinal detachment ▪ Downward slant of palpebral fissures Skeleton ▪ Tall, slim with long (↑ arm span to height ratio); slender limbs ▪ Narrow, arched palate

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Figure 23.2 An adolescent female with Marfan syndrome. She is taller than average and thin, with long arms and legs. Arachnodactyly is also seen. Heart ▪ Aortic root dilation, floppy valve syndrome (mitral valve), aortic dilation causes aortic valve insufficiency Lungs ▪ Blebs, bullae (dilated spaces filled with air predisposing to spontaneous pneumothorax)

Chapter 23 Connective Tissue Disorders Blood vessels ▪ Cystic medial necrosis of aorta, aortic incompetence, dissecting aortic aneurysms Skin ▪ Striae (stretch marks)

DIAGNOSIS OTHER DIAGNOSTICS

▪ History, physical exam ▫ Ghent nosology criteria: scale using major, minor indicators to establish Marfan diagnosis, max 20 points; includes family history, skeletal, vascular, ocular, pulmonary/skin symptoms (e.g. ectopic lens and aortic dissection) ▪ Genetic testing ▫ Confirmation of FBN1 mutation

TREATMENT MEDICATIONS

▪ Beta blockers (slow aortic dilation) ▪ Angiotensin receptor blockers (decrease TGF-β signalling, slow aortic dilation)

SURGERY

▪ Valve, lens replacement; aortic dissection repair

OTHER INTERVENTIONS

▪ Physiotherapy ▫ Restrict high-intensity exercise, scoliosis treatment ▪ Routine aortic, heart, ophthalmic screening

Figure 23.3 A contrast CT scan of the chest in the sagittal plane demonstrating aortic root dilation in an individual with Marfan syndrome.

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NOTES

NOTES

DNA REPLICATION & REPAIR DISORDERS

GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Group of rare, inherited disorders; mutations in DNA maintenance, repair genes → spectrum of cancers (typically early-onset cancer diagnosis)

SIGNS & SYMPTOMS ▪ See individual conditions

DIAGNOSIS LAB RESULTS

▪ Genetic sequencing

OTHER DIAGNOSTICS ▪ Family history

TREATMENT OTHER INTERVENTIONS

▪ Adequate malignancy surveillance ▪ Minimize sun, radiation exposure

BLOOM SYNDROME osms.it/bloom-syndrome PATHOLOGY & CAUSES ▪ Rare autosomal recessive disease; extreme susceptibility to DNA damage, immune deficiency, cancer Pathogenesis ▪ Instability of DNA duplexes during recombination, repair, replication → DNA mutation → oncogenesis

CAUSES

▪ Mutation in BLM gene on chromosome 15q26.1 ▫ Encodes RecG helicase (AKA Bloom syndrome protein): helps maintain stability of DNA when duplexes

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unwound during recombination, repair, replication

RISK FACTORS

▪ Individuals of Ashkenazi Jewish descent

COMPLICATIONS

▪ Infertility (more common in individuals who are biologically male) ▪ Dehydration due to reflux, vomiting, diarrhea in infancy ▪ Immunodeficiency → secondary infection, early predisposition to cancer ▪ Limited intellectual ability ▪ Fetal intrauterine growth restriction

Chapter 24 DNA Replication & Repair Disorders

SIGNS & SYMPTOMS ▪ Microcephaly with proportionate small stature ▪ Sparse subcutaneous adipose tissue ▪ Integument: childhood rash (erythematous on nose, cheeks; worsens after sun exposure; persists 1–2 years); cafe-au-lait spots; hypopigmented skin lesions ▪ Facial anomalies

DIAGNOSIS LAB RESULTS

▪ Karyotype analysis ▪ Genetic testing (mutated BLM gene) ▪ ↓ immunoglobulins (IgM, IgA deficit > IgG), effector memory T-cells, memory B-cells

OTHER DIAGNOSTICS Physical examination ▪ Typical facies; body habitus; integument examination (erythematous rash, hyper/ hypopigmented lesions)

TREATMENT OTHER INTERVENTIONS ▪ No therapeutic options

Management ▪ Minimize radiation exposure (MRI/ ultrasound for diagnostic imaging); protect face from sun; IgG replacement for severe hypogammaglobulinemia; monitor fluid levels in infants Figure 24.1 A male child with Bloom syndrome. He has telangiectatic facial erythema, typical of the condition.

LI–FRAUMENI SYNDROME osms.it/li-fraumeni_syndrome PATHOLOGY & CAUSES ▪ Syndrome caused mutation of guardian of genome (TP53) → wide array of malignancies Pathogenesis ▪ Abnormal TP53 function → abnormal checkpoint inhibition, tumor suppression → damaged DNA cell proliferation → malignant transformation

▪ Abnormal TP53 function → dysregulated apoptosis signaling → proliferation of DNAdamaged cells → malignant transformation Diseases ▪ Sarcoma, leukemia, breast cancer, brain tumors (e.g. medulloblastomas, choroid plexus carcinomas), adrenocortical carcinoma

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CAUSES

▪ Autosomal dominant mutation on gene TP53, located on 17p3.1 chromosome (mostly missense mutations in exons 5, 8)

COMPLICATIONS

▪ Radiation-associated cancers

SIGNS & SYMPTOMS Sarcomas ▪ Growing, painless mass (arises with compression of surrounding structures) Osteosarcoma ▪ Localized pain for several months; soft tissue mass tender to palpation, commonly of long bones (e.g. femur, humerus) Breast cancer ▪ Breast mass (most common) Brain tumors ▪ Focal neurologic deficit Adrenocortical carcinomas ▪ Abdominal mass; hormone excess syndrome (e.g. Cushing, hyperaldosteronism, virilization, feminization)

DIAGNOSIS LAB RESULTS

▪ Genetic conformational testing ▪ ↑ hormonal levels in functional adrenocortical carcinoma, alkaline phosphatase in osteosarcoma setting

OTHER DIAGNOSTICS History ▪ Presence of malignancy ▪ Family history (diagnosis requires all three) ▫ Sarcoma diagnosed before age 45 ▫ First-degree relative with any cancer before age 45 ▫ First/second-degree relative with any cancer before age 45/sarcoma at any age

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TREATMENT SURGERY Resection ▪ Choroid plexus carcinoma (malignancyspecific therapy) Mastectomy + radiation therapy ▪ Breast cancer (malignancy-specific therapy)

OTHER INTERVENTIONS

▪ Management: surveillance of individuals, family members of diagnosed individuals ▫ Annual skin examination ▫ Noninvasive breast cancer screening at 18–20 years ▫ Regular diagnostic testing begins at 20–25 ▫ Colorectal cancer screening every 2–5 years, starting at 25 ▫ Whole body MRI recommended by American Association for Cancer Research ▪ Screening for ▫ Individuals with breast cancer < 31 years ▫ Individuals with adrenocortical carcinoma, regardless of age/family history ▫ Individuals with choroid plexus carcinoma ▫ Individuals with childhood sarcoma (except Ewing sarcoma)

Chapter 24 DNA Replication & Repair Disorders

XERODERMA PIGMENTOSUM osms.it/xeroderma-pigmentosum PATHOLOGY & CAUSES ▪ Rare autosomal recessive disease of nucleotide excision repair (NER) gene; extreme photosensitivity, early development of skin cancer ▪ Pathogenesis: UV light in setting of mutated NER gene → cross-linking of pyrimidine residues → inability for removal of covalently-linked pyrimidine residues → epithelial DNA mutation → ↑ oncogenesis risk

TREATMENT OTHER INTERVENTIONS

▪ No curative therapy ▪ Avoid sun ▪ Sunscreen, proper clothing (minimize photoreactivity, mitigate cancer risk) ▪ Basal, squamous cell cancer surveillance: annual skin examination

CAUSES

▪ Autosomal recessive mutation of NER gene on chromosome 9q22

COMPLICATIONS

▪ Basal, squamous cell carcinomas; melanoma ▪ Ocular: keratitis, opacification of cornea, iritis with synechiae formation, melanoma of choroid ▪ Neurologic abnormalities: primary neuronal degeneration ▪ Radiation complications: chromosome breakage → oncogenesis

SIGNS & SYMPTOMS ▪ Extreme photosensitivity to sunlight, abnormal pigmentation, xerosis (abnormal dryness of skin), telangiectasia, skin atrophy

Figure 24.2 A female child with xeroderma pigmentosum. There are numerous hyperkeratoses on the face as well as innumerable solar lentigines. Corneal scarring is also present.

DIAGNOSIS OTHER DIAGNOSTICS

▪ Clinical diagnosis: family history, photoreactivity history, physical examination (e.g. integument, ocular examination; xerosis, skin fragility, ocular complications)

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NOTES

NOTES

GENETIC MUTATIONS GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Permanent alterations of DNA sequence → clinically significant syndrome ▪ Germ cell mutations inherited ▪ Somatic cell mutations due to environmental factors (e.g. radiation) ▪ Physiologic, pathologic processes: evolution, immune system development, cancer Inheritance patterns ▪ Autosomal dominant: one genetic copy mutated ▪ Autosomal recessive: both genetic copies mutated ▪ X-linked (dominant/recessive): mutation in X chromosome; no transmission from father to son; individuals who are biologically male more frequently/severely affected ▪ Y-linked: mutation in Y chromosome; passed from father to son ▪ Codominant: two alleles affect same trait (e.g. ABO blood group) ▪ Mitochondrial: mutation in mitochondrial DNA; maternal inheritance

CAUSES Error during DNA replication ▪ Point mutation within coding sequences: substitution of single base; may occur as transition (e.g. purine → purine)/ transversion (e.g. purine → pyrimidine) ▫ Silent: codes same amino acid, no phenotypic change ▫ Missense: codes different amino acid, may cause phenotypic change (e.g. sickle cell anemia) ▫ Nonsense: early stop codon, produces nonfunctional protein, may cause

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▪

▪ ▪

▪ ▪

phenotypic change (e.g. adrenal gland hyperplasia) Point mutation within noncoding sequences: mutation of promoter/ enhancer sequences → reduced/abolished transcription Deletion: removal of bases Insertion: addition of bases ▫ Splice site mutation: altered splicing of mRNA ▫ Frameshift: shifted reading frame Trinucleotide-repeat mutation: ↑ trinucleotide repeats Disorders of imprinting: one gene copy silenced by methylation (e.g. Prader–Willis syndrome)

TYPES Mendelian disorder ▪ Single gene mutation, large effects Chromosomal disorder ▪ Numerical: insertion/deletion of entire chromosome (e.g. trisomies, aneuploidies) ▪ Structural: change in genetic sequence Complex multigenic disorder (polymorphism) ▪ Genes increase risk of disease, no gene capable of causing disease on own (e.g. hypertension, diabetes mellitus)

RISK FACTORS

▪ Parental genetic defect ▪ Exposure to radiation, carcinogens

COMPLICATIONS

▪ Spontaneous abortion; severe organ defects (e.g. tetralogy of Fallot, renal dysplasia); visual/hearing disturbances;

Chapter 25 Genetic Mutations growth deficiency; intellectual disability; cancer

SIGNS & SYMPTOMS ▪ Abnormal physical features ▪ Organ defect-related signs/symptoms

LAB RESULTS

▪ Altered blood tests, hormones, liver enzymes

OTHER DIAGNOSTICS

▪ History, physical examination ▪ Genetic tests

TREATMENT

DIAGNOSIS DIAGNOSTIC IMAGING X-ray, CT scan ▪ Evidence of organ defects (e.g. fibrous dysplasia, cardiac malformations)

SURGERY

▪ Surgical repair of significant defects

ALAGILLE SYNDROME (ALGS) osms.it/alagille-syndrome PATHOLOGY & CAUSES ▪ Autosomal dominant disorder → liver, skeletal, ocular, cardiac, renal defects ▪ AKA arteriohepatic dysplasia, Alagille– Watson syndrome ▪ Variable penetrance; severity related to size of deletion ▪ Sometimes associated with somatic/ germline mosaicism ▪ Individuals susceptible to additional mutations

CAUSES

▪ Mutation/deletion related to notch signalling pathway (involved in angiogenesis, cell proliferation, differentiation) ▫ 95% involve JAG1 gene (chromosome 20p12) ▫ NOTCH2 gene (chromosome 1p.13); related to renal malformations ▪ Results in absence of intrahepatic bile ducts → ↑ risk of progressive liver disease → chronically elevated bilirubin, cholesterol

COMPLICATIONS ▪ ▪ ▪ ▪

Malabsorption Pancreatic insufficiency Abnormal vertebral segmentation Vascular anomalies (e.g. basilar artery aneurysm; ↑ risk of intracranial bleeding)

Liver ▪ Chronic cholestasis (95%), cirrhosis, liver failure Cardiac ▪ Peripheral pulmonary artery stenosis, tetralogy of Fallot Ocular ▪ Shallow anterior chamber, keratoconus, embryotoxon (prominent Schwalbe’s ring), Axenfeld anomaly (embryotoxon + attached iris strands), pigmentary retinopathy, cataracts Renal ▪ Dysplasia, renal tubular acidosis

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SIGNS & SYMPTOMS ▪ Intellectual disability, learning difficulties ▪ Hepatosplenomegaly Cholestasis ▪ Jaundice, pruritus, xanthomas (cholesterol deposits in skin) Facial features ▪ Triangular face, prominent forehead, hypertelorism (widely-spaced eyes), deepset eyes, upslanting eyelids, long nose with bulbous tip, large ears, prominent mandible, pointed chin; more prominent with age Growth deficiency ▪ Short stature

DIAGNOSIS DIAGNOSTIC IMAGING Spinal X-ray ▪ Butterfly-shaped vertebrae, hemivertebrae, spina bifida occulta

LAB RESULTS

▪ ↑ bilirubin (total, conjugated), ↑ liver enzymes, ↑ cholesterol ▪ Liver biopsy: intrahepatic bile duct paucity, portal inflammation

OTHER DIAGNOSTICS

▪ History, clinical examination ▪ Genetic tests

TREATMENT MEDICATIONS

▪ Choleretic agents: ursodeoxycholic acid + cholestyramine/rifampin/naltrexone

SURGERY

▪ Biliary diversion/liver transplantation ▪ Heart defect surgical repair

OTHER INTERVENTIONS ▪ Nutritional support

Abdominal ultrasound ▪ Kidneys: small, echogenic, presence of cysts, ureteropelvic obstruction

MCCUNE–ALBRIGHT SYNDROME osms.it/mccune-albright_syndrome PATHOLOGY & CAUSES ▪ Genetic disorder characterized by fibrous dysplasia (FD), endocrinopathy, unilateral café-au-lait skin spots ▪ Occurs most commonly in skull base/ proximal femur; most lesions appear < age 15 ▪ External beam radiotherapy: ↑ risk of malignant transformation ▪ More common among individuals who are biologically female

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▪ Post zygotic mutation in GNAS1 gene (20q.13.1-13.2) ▫ Encodes Gs alpha protein → G protein/ cAMP/adenylate cyclase signaling pathway ▪ Somatic mosaicism: some somatic cells mutated

COMPLICATIONS

▪ Pathologic fractures; osteosarcoma; osteomalacia; visual/hearing disturbances (due to nerve compression); severe pain; scoliosis; ovarian cysts; acromegaly,

Chapter 25 Genetic Mutations gigantism; Mazabraud syndrome (fibrous dysplasia + intra/juxtamuscular myxoma); liver disease; higher risk of thyroid, testicular, breast cancer

LAB RESULTS

SIGNS & SYMPTOMS

GH excess ▪ ↑ GH, ↑ prolactin

Clinical triad ▪ Bone fibrous dysplasia ▫ Limp, pain, dysmorphism ▪ Hyperfunctioning endocrinopathy ▫ Hyperthyroidism: change in appetite, insomnia, fatigue, palpitations ▫ Cushing’s syndrome: moon facies, plethora, hirsutism ▫ Growth hormone (GH) excess: enlarged facial/body features, excessive sweating, thickened skin ▫ Renal phosphate wasting: usually asymptomatic; weakness, pain, altered mental status ▫ Precocious puberty: early vaginal bleeding, breast development in individuals who are biologically female; early testicular/penile enlargement, scrotal rugae, body odor, pubic/axillary hair, sexual behaviour in individuals who are biologically male ▪ Café-au-lait skin spots ▫ Brown macules, irregular borders (“coast of Maine”); mostly on lower back, buttocks

DIAGNOSIS DIAGNOSTIC IMAGING X-ray, radionuclide bone scan ▪ Long bones: expansile, lytic lesions; endosteal scalloping (focal resorption of cortex inner layer), cortex thinning, “ground-glass” appearance of medulla; epiphysis usually spared ▫ Proximal femur: “shepherd’s crook” malformation ▪ Skull: sclerotic lesions, “ground-glass” appearance, cyst-like lesions

Hyperthyroidism ▪ ↓ thyroid stimulating hormone (TSH), ↑ triiodothyronine (T3)

Cushing’s syndrome ▪ ↑ 24-hour urinary free cortisol Renal phosphate wasting ▪ ↑ urinary phosphate, ↓ serum phosphate Precocious puberty ▪ ↑ testosterone/estradiol, ↓ luteinizing hormone (LH), ↓ follicle-stimulating hormone (FSH) Bone tissue biopsy ▪ Absence of lamelation pattern, “Chinese writing” pattern, areas of unmineralized osteoid

OTHER DIAGNOSTICS

▪ History, physical examination ▪ Genetic tests (e.g. polymerase chain reaction, next-generation sequencing)

TREATMENT MEDICATIONS

▪ Bisphosphonate treatment for pain management (no effect on disease progression) ▪ Medication for endocrine disorders (e.g. gonadotropin releasing hormone analogues, tamoxifen, thionamides)

SURGERY

▪ Surgical management of fibrous dysplasia (e.g. intramedullary devices, bone grafting)

OTHER INTERVENTIONS

▪ Physical exercise (e.g. cycling, swimming) ▫ ↑ bone support → ↓ fracture risk

Thyroid ultrasound ▪ Presence of cystic areas

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PRIMARY CILIARY DYSKINESIA osms.it/primary-ciliary-dyskinesia PATHOLOGY & CAUSES ▪ Congenital disease; defect in cilia motility → impaired mucociliary clearance, decreased fertility ▪ AKA immotile-cilia syndrome ▪ Affects cilia of respiratory tract, fallopian tubes, sperm flagella ▪ Inheritance pattern: autosomal recessive

CAUSES

▪ Defect in proteins of cilia structure → absent/altered motion (e.g. clockwise rotation) ▪ Genetic mutations ▫ DNAH5, DNAI1: encode axonemal outer dynein arms ▫ RSPH4A, RSPH9: encode radial spokes

COMPLICATIONS

▪ Chronic sinusitis; Kartagener’s syndrome (situs inversus, chronic sinusitis, and bronchiectasis); hydrocephalus; transposition of great vessels; epispadias; pectus excavatum; chronic secretory otitis media; conductive hearing loss

SIGNS & SYMPTOMS ▪ Recurrent upper/lower respiratory tract infections: chronic cough, mucopurulent sputum; symptoms increase during course of day ▪ Newborns: present with mild respiratory distress (tachypnea, mild hypoxemia) ▪ Bronchiectasis: crackles, wheezes ▫ Exacerbation: dark sputum, dyspnea, pleuritic pain ▪ Rhinosinusitis: runny nose, constant congestion, nasal polyps, altered sense of smell ▪ Fatigue, headaches

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▪ Infertility ▪ ↓ aerobic fitness

DIAGNOSIS DIAGNOSTIC IMAGING Chest X-ray, CT scan ▪ Pulmonary hyperinflation, peribronchial thickening, atelectasis, bronchiectasis; situs inversus

LAB RESULTS

▪ Reduced/absent nasal nitric oxide (also present in some cases of cystic fibrosis)

Cell culture ▪ Inferior concha epithelium: tissue culture → cilia shed → emergence of new, immotile cilia → diagnosis confirmation

OTHER DIAGNOSTICS

▪ Spirometry: obstructive pattern ▪ Genetic tests

Ciliary motion, ultrastructure ▪ High speed video microscopy analysis (HSVA): live examination of respiratory epithelial cells; after air-liquid interface/ cooling → assessment of motion pattern, beat frequency ▪ Transmission electron microscopy (TEM): observation of ciliary ultrastructure defects

TREATMENT MEDICATIONS

▪ Bronchiectasis ▪ Antibiotics, airway hydration (e.g. nebulized hypertonic saline), mucolytic agents

Chronic rhinitis ▪ Nasal saline lavage + intranasal glucocorticoids

Chapter 25 Genetic Mutations

SURGERY Chronic rhinitis ▪ Polyp removal

OTHER INTERVENTIONS

▪ Smoking cessation ▪ Pneumococcus, influenza vaccination

Bronchiectasis ▪ Daily chest physiotherapy

TREACHER COLLINS SYNDROME osms.it/treacher-collins-syndrome PATHOLOGY & CAUSES ▪ Severe genetic disorder of craniofacial development ▪ AKA mandibulofacial dysostosis, Franceschetti–Zwahlen–Klein syndrome ▪ Inheritance pattern: autosomal dominant, variable penetrance; 60% spontaneous

CAUSES

▪ TCOF1 gene mutation (chromosome 5q32) → treacle protein (ribosome biogenesis regulator) insufficiency → neuroepithelial cell apoptosis → ↓ neural crest cells → first, second branchial arch anomalies → cranioskeletal hypoplasia ▪ Other genetic mutations: POLR1C (6q21.2), POLR1D (13q12.2); involved in ribosome biogenesis

COMPLICATIONS

▪ Perinatal death; bilateral conductive hearing loss; speech problems; airway compromise; feeding difficulties; visual loss; brachycephaly; choanal atresia; congenital heart defects; intellectual disability; renal malformation

SIGNS & SYMPTOMS ▪ Facial bone hypoplasia (esp. mandible, zygomatic bone): retrognathia, sunken cheeks ▪ Facial asymmetry ▪ Projection of scalp hair to lateral cheek ▪ Dental: high/arched/cleft palate; malocclusion, tooth agenesis, enamel opacities ▪ Ocular: downslanting eyelids, lower eyelid coloboma, paucity of eyelashes medial to notch, hypertelorism (widely spaced eyes) ▪ Malformation of external ear, external auditory canals, middle ear ossicles

DIAGNOSIS DIAGNOSTIC IMAGING Cranial X-ray, orthopantomogram, CT scan ▪ Facial bone hypoplasia, altered middle ear ossicles, external auditory canal stenosis

OTHER DIAGNOSTICS

▪ History, clinical examination ▪ Prenatal: amniocentesis, chorionic villus sampling

OSMOSIS.ORG 167

TREATMENT SURGERY

▪ Reconstructive surgery ▪ Tracheostomy (severe airway obstruction at birth) ▪ Glossopexy (tongue-lip adhesion) ▪ Corrective surgery for cleft lip/palate/ choanal atresia ▪ Gastrostomy tube placement

OTHER INTERVENTIONS

▪ Supportive treatments (e.g. hearing aid, speech therapy)

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Figure 25.1 The face of a female child with Treacher Collins syndrome.

Chapter 2 Acyanotic Defects

NOTES

IMPRINTING DISORDERS GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Genetic, epigenetic mutations/defects within imprinting controlling regions of genes ▪ Disruption of methylation of cytosine bases in CpG dinucleotides of DNA

RISK FACTORS

▪ Increased incidence in individuals conceived using assisted reproductive technology

SIGNS & SYMPTOMS ▪ Angelman syndrome ▫ Seizures, severe intellectual disability, jerky/tremulous limbs, characteristic facial appearance (e.g. large mouth, protruding tongue, prominent nose), excitability, impaired speech ▪ Beckwith–Wiedemann syndrome ▫ Premature birth, abdominal wall defects, embryonal tumors ▪ Prader–Willi syndrome ▫ Infancy: poor feeding, low muscle tone, weak cry, diminished reflexes ▫ Early childhood obesity, developmental delay, behavioral problems ▫ Dysmorphic facial features

DIAGNOSIS OTHER DIAGNOSTICS

▪ History, clinical examination ▪ Fluorescence in situ hybridization (FISH), genotyping, methylation DNA testing ▪ Methylation-sensitive multiplex ligation probe analysis (MS-MLPA)

TREATMENT MEDICATIONS

▪ Angelman syndrome: antiepileptic therapy ▪ Prader–Willi syndrome: thyroid, sex hormone replacement therapy

OTHER INTERVENTIONS

▪ Angelman syndrome: speech therapy ▪ Beckwith–Wiedemann syndrome: tumor surveillance, abdominal wall repair ▪ Prader–Willi syndrome: food restriction, vitamin D/calcium supplements

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ANGELMAN SYNDROME osms.it/angelman-syndrome PATHOLOGY & CAUSES ▪ Genetic neurological disorder; severe developmental delay, intellectual disability, absence of speech, ataxia, dysmorphic features, unprovoked episodes of laughter

CAUSES

▪ Maternal 15q11-q13 deletion ▪ Loss of function of UBE3A ▪ Paternal uniparental disomy 15 (both copies of chromosome 15 from father)

SIGNS & SYMPTOMS ▪ Seizures, severe intellectual disability ▪ Ataxia, toe-walking, jerky/tremulous limbs ▪ Hypopigmentation, microcephaly, maxillary hypoplasia, large mouth, protruding tongue, prominent nose, wide-spaced teeth ▪ Inappropriate laughter (“happy puppet”), excitability, impaired speech

170 OSMOSIS.ORG

DIAGNOSIS OTHER DIAGNOSTICS

▪ FISH, genotyping, methylation DNA testing

TREATMENT MEDICATIONS

▪ Antiepileptic therapy for seizures

OTHER INTERVENTIONS

▪ Speech therapy; emphasis on nonverbal methods of communication

Chapter 26 Imprinting Disorders

BECKWITH–WIEDEMANN SYNDROME osms.it/beckwith-wiedemann_syndrome PATHOLOGY & CAUSES ▪ Pediatric overgrowth syndrome; visceromegaly, predisposition to tumors

CAUSES

▪ Error in imprinted gene expression in chromosome 11p15.5 region ▪ Usually sporadic, may be inherited in autosomal dominant fashion

SIGNS & SYMPTOMS Fetal macrosomia, premature birth Macroglossia Renal medullary hyperplasia Abdominal wall defects ▫ Omphalocele, umbilical hernia, diastasis recti ▪ Hypoglycemia due to islet cell hyperplasia ▪ Puberty, episeal fusion (early symptoms) ▪ Embryonal tumors (e.g. Wilms tumor, hepatoblastoma, neuroblastoma, rhabdomyosarcoma)

▪ ▪ ▪ ▪

DIAGNOSIS OTHER DIAGNOSTICS

▪ Clinical diagnosis ▪ MS-MLPA ▫ Detect majority of epigenetic, genetic etiologies

TREATMENT OTHER INTERVENTIONS

▪ Tumor surveillance with abdominal MRI/CT scan ▪ Abdominal wall repair for omphalocele ▪ Assess, treat airway insufficiency; feeding evaluation in presence of macroglossia ▪ Assess, treat hypoglycemia for neonates

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PRADER–WILLI SYNDROME osms.it/prader-willi_syndrome PATHOLOGY & CAUSES ▪ Genetic multisystem disorder; weak muscle tone; delayed growth, development; behavioral abnormalities (e.g. insatiable hunger)

CAUSES

▪ Paternal 15q11-q13 deletion (maternal gene unchanged) ▪ Maternal uniparental disomy 15 (both copies of chromosome 15 from mother) ▪ Defects in imprinting center controlling chromosome 15 activity of genes ▪ Associated with dysregulation of hypothalamic-pituitary axis

COMPLICATIONS

▪ Sleep apnea (central/obstructive), scoliosis, osteoporosis, hypothyroidism, Type II diabetes

SIGNS & SYMPTOMS ▪ Infancy ▫ Poor feeding, low muscle tone, weak cry, diminished reflexes ▪ Overeating (hyperphagia), early childhood obesity ▪ Developmental delay ▫ Intellectual disability; delayed motor, language development ▪ Behavioral problems ▫ Inflexibility, obsessive-compulsive characteristics ▪ Low sex hormones in childhood, hypogenitalism/hypogonadism; cryptorchidism in individuals who are biologically male

172 OSMOSIS.ORG

▪ Dysmorphic facial features in childhood ▫ Almond-shaped eyes, narrow forehead, thin upper lip ▪ Small hands/feet, short stature

DIAGNOSIS OTHER DIAGNOSTICS

▪ History, clinical examination ▪ Fluorescence in situ hybridization (FISH), genotyping, methylation DNA testing

TREATMENT MEDICATIONS

▪ Human recombinant growth hormone therapy ▫ Decrease body weight/fat, increase muscle mass ▪ Address complications ▫ Thyroid, sex hormone replacement therapy

OTHER INTERVENTIONS

▪ Food restriction ▪ Address complications ▫ Vitamin D, calcium supplements

Chapter 2 Acyanotic Defects

NOTES

SEX CHROMOSOME DISORDERS

GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Disorders caused by numeric abnormalities (addition/loss)/structural damage of one/ both sex chromosomes (X, Y) ▪ Occur in approx. 1/448 live births ▪ Phenotypes less severe than autosomal defects due to X chromosome inactivation, low gene content of Y chromosome

SIGNS & SYMPTOMS ▪ Delay in puberty onset, absence of menstruation, ambiguous genitalia, infertility

DIAGNOSIS LAB RESULTS

▪ Prenatal fetus chromosomal analysis ▫ Amniocentesis, chorionic villi sampling of placenta

TREATMENT MEDICATIONS

▪ Hormone replacement therapy

OTHER INTERVENTIONS

▪ No corrective treatment available

KLINEFELTER'S SYNDROME osms.it/klinefelters-syndrome PATHOLOGY & CAUSES ▪ Extra copy of X chromosome in individuals who are biologically male due to sex chromosome nondisjunction during maternal/paternal meiotic division ▪ Most common ▫ 47, XXY karyotype ▪ Less common ▫ Greater/lesser numbers of X chromosome 48,XXXY, 49,XXXXY, 46,XY/4,XXY mosaicism karyotypes ▪ Greater number X chromosomes → greater phenotypic abnormalities ▪ Most common sex chromosome abnormality; occurs in approx. 1/1000 live

births ▪ Leads to primary hypogonadism, impaired cognitive development

COMPLICATIONS

▪ Increased risk for psychiatric disorders, autism ▪ Problems with social interactions ▪ Delayed speech, language competence

Predisposition to diseases ▪ May result in death ▪ Pulmonary ▫ Chronic bronchitis, emphysema ▪ Thromboembolic cancers ▫ Germ cell tumors, breast cancer

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(morbidity much higher in individuals with Klinefelter), non-Hodgkin lymphoma ▪ Leg ulcers ▪ Diabetes mellitus

SIGNS & SYMPTOMS ▪ Newborns who are biologically male, phenotypically normal (e.g. with male external genitalia) ▪ Tall stature with decreased upper to lower extremity ratio due to decreased levels of testosterone, unsuppressed folliclestimulating hormone (FSH), luteinizing hormone (LH) ▪ Decreased testes size ▪ Increased levels of serum FSH, LH ▪ Variably decreased levels of serum testosterone → breast enlargement (increased risk of breast cancer); reduced facial, body hair; infertility

DIAGNOSIS LAB RESULTS

▪ Blood/urine test ▫ Abnormal hormone levels ▪ Karyotype analysis

OTHER DIAGNOSTICS

▪ Postnatally, observe signs of physical clinical manifestations ▫ Evaluation for infertility, enlarged breast tissue ▫ May present with cryptorchidism (undescended testes)

TREATMENT MEDICATIONS

▪ Testosterone replacement therapy; stimulate changes that typically occur during puberty (e.g. facial, body hair growth; increased muscle mass, penis size; improved bone density)

SURGERY

▪ Breast tissue removal

PSYCHOTHERAPY

▪ Psychological counseling

OTHER INTERVENTIONS

▪ Sex chromosome changes can’t be corrected ▪ Supportive therapy minimizes adverse effects, improves quality of life ▫ Speech therapy ▫ Fertility treatment

Figure 27.1 The body habitus of an individual with Klinefelter’s syndrome. The body type is rounded with prominent gynecomastia.

174 OSMOSIS.ORG

Chapter 27 Sex Chromosome Disorders

TURNER SYNDROME osms.it/turner-syndrome PATHOLOGY & CAUSES

SIGNS & SYMPTOMS

▪ Completely/partially missing X chromosome in individuals who are biologically female ▫ Monosomy 45,X karyotype (most common) ▫ Mosaic X chromosome monosomy: 45,X/46,XX, 45,X/46,XY ▫ X chromosome abnormalities

▪ Newborns ▫ Congenital lymphedema (hands, feet), webbed neck, short fourth metacarpal ▪ Short stature, broad chest with widely spaced nipples, low hairline

COMPLICATIONS

DIAGNOSTIC IMAGING

▪ Primary hypogonadism ▪ Predisposition to several diseases, may result in death ▫ Cardiovascular: typically involves left outflow, coarctation of aorta (e.g. aortic valve abnormalities, elongated transverse aortic) ▫ Congenital renal anomalies: system, positional malformations ▪ Hearing loss, hypothyroidism, liver function abnormality incidences increase with age ▪ Low bone mineral density (BMD) ▫ Prone to fractures ▪ Ovarian insufficiency, infertility: premature oocyte death, degeneration of ovarian tissue ▪ Increased risk for learning disabilities, attention-deficit/hyperactivity disorder (ADHD)

DIAGNOSIS Fetal ultrasound ▪ Cardiac/renal abnormalities, short femur

LAB RESULTS

▪ Karyotype analysis

TREATMENT MEDICATIONS

▪ Growth hormone therapy ▫ Promote height and bone growth ▪ Estrogen therapy ▫ Promote breast, uterine development

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NOTES

NOTES

TRINUCLEOTIDE REPEAT EXPANSION DISEASES

GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Group of genetic diseases; mutations characterized by increased number of 3 base pair repeats ▫ C, G nucleotides: loci at which repeats expanded ▪ Mechanism of disease ▫ Loss-of-function: transcriptional silencing ▫ Toxic, gain-of-function: may occur at mRNA, translational level/protein structure level

RISK FACTORS

SIGNS & SYMPTOMS ▪ See individual diseases

DIAGNOSIS LAB RESULTS

▪ Genetic testing for number of repeats

OTHER DIAGNOSTICS

▪ Family history, physical examination (disease-specific, pathognomonic findings)

TREATMENT

▪ Family history

OTHER INTERVENTIONS

COMPLICATIONS

▪ Anticipation ▫ More severe, earlier-onset of disease as mutation passed down

▪ No curative treatment currently available ▪ Symptom management (hallmark of therapy)

FRAGILE X SYNDROME osms.it/fragile-x-syndrome PATHOLOGY & CAUSES ▪ Autosomal recessive, X-linked disease; intellectual disability, typical facies, macroorchidism

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▪ Inherited defect in 5’ untranslated region (UTR) of familial mental retardation-1 (FMR1) gene → trinucleotide expansion → abnormal length → ↑ methylation → promoter region methylation → ↓ transcription of FMR1 gene → ↓ familial mental retardation protein (FMRP) synthesis → clinical phenotype

Chapter 28 Trinucleotide Repeat Expansion Diseases FMRP ▪ High concentration in testes, brain ▪ mRNA transport protein ▫ ↓ FMRP → ↓ transport of neuronal proteins from perinuclear space → dendritic spines → dysregulated synaptic function ▪ Translation regulator ▫ ↓ FMRP → via ↑ metabotropic glutamate receptor activity → ↑ translation of bound mRNA at synaptic junction → dysregulated synaptic activity → intellectual disability

CAUSES Trinucleotide (CGG) repeat expansion ▪ Trinucleotide (CGG) repeat expansion on 5’ UTR FMR1 gene at Xq27.3 locus ▫ 45–54: intermediate expansion repeat number ▫ 55–200: carrier/premutation individual repeat number ▫ 200–4,000: affected individual repeat number Inheritance ▪ Autosomal recessive (some caveats) ▪ Mutations occur/worsen during oogenesis, not spermatogenesis → abnormal autosomal recessive expression ▫ 20% of disease-genotype individuals who are biologically male: asymptomatic, carriers ▫ 30–50% of genotypically carrier individuals who are biologically female: symptomatic (preferential X-chromosome inactivation → inconsistent mutation expression → variable symptom presentation) ▪ Anticipation ▫ Genetic mutations continue through pedigree → ↑ length of expansion → ↑ severity of disease

RISK FACTORS

▪ Genotype-phenotype correlation ▫ Repeat size, methylation mosaicism: ↑ % cells with same expression/methylation amount → ↑ phenotype penetrance

COMPLICATIONS Behavioral features ▪ Autism, attention-deficit hyperactivity disorder (ADHD), anxiety disorders Seizures ▪ Simple/complex; occurs commonly in childhood, resolves in adulthood Fragile X tremor/ataxia ▪ Observed in carrier/premutation individuals ▪ Tremor/ataxia → parkinsonism ▫ Short-term memory loss, executive dysfunction (common) ▫ Individuals who are biologically female: ovarian insufficiency; early menopause (age ≤ 40) ▪ Pathogenesis ▫ Mild CGG repeat expansion → mild ↑ methylation (not including promoter region) → adequate transcription → RNA product → poor translation → abnormal protein → nuclear accumulation → aggregation of mRNAbinding protein → toxic effects to cell function → neurodegeneration

SIGNS & SYMPTOMS Impaired cognitive function ▪ Developmental delay: delayed attainment of language, motor milestones ▫ Delayed milestones: sit alone (10 months), walk (18 months), clear spoken words (20 months) ▪ Intellectual disability: IQ range of 20–60 Physical features ▪ Prominent in adulthood; more common in individuals who are biologically male ▪ Facies ▫ Prominent forehead, jaw; long, narrow face; large ears ▪ Macroorchidism ▪ Connective tissue ▫ Joint hyperlaxity, arched palate, flat feet, mitral valve prolapse (benign) ▪ Behavioral features ▫ Hyperactivity, inattention, gaze aversion, stereotypic movements (e.g. handflapping, unusual speech patterns)

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TREATMENT MEDICATIONS

▪ Symptom-directed management

Behavioral features ▪ ADHD presentation ▫ < 5 years old: non-stimulant therapy (e.g. guanfacine, clonidine) ▫ > 5 year old: stimulant prescription (e.g. methylphenidate) Anxiety/mood disorders ▪ Selective serotonin reuptake inhibitors (SSRIs) Figure 28.1 A child with fragile X syndrome.

DIAGNOSIS LAB RESULTS DNA testing (obtained prenatally) ▪ Chorionic villus sampling (11–13 weeks of gestation) ▫ Degree of methylation variable in later development ▪ Amniocentesis (> 15 weeks of gestation) Complete prenatal screening ▪ DNA testing ▪ Fluorescent polymerase chain reaction (PCR) ▫ Identify degree of methylation ▪ AGG trinucleotide genotyping ▫ Determine risk in premutation/ carrier expansion individuals who are biologically female

OTHER DIAGNOSTICS History Physical examination ▪ Phenotypic characteristics on musculoskeletal, genitourinary examination ▪ Neurological ▫ Mental status (intellectual, behavioral deficits)

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Seizures ▪ Anticonvulsants Premature ovarian insufficiency ▪ Estrogen replacement therapy

PSYCHOTHERAPY

▪ Symptom-directed management

Behavioral features ▪ Counseling, psychotherapy

OTHER INTERVENTIONS ▪ No curative therapy

Symptom-directed management ▪ Intellectual disability ▫ Speech/language therapy, early intervention, special education Prevention ▪ Genetic preconception counseling ▫ Preconception reproductive options (e.g. use of donor gametes from unaffected donor)

Chapter 28 Trinucleotide Repeat Expansion Diseases

HUNTINGTON'S DISEASE osms.it/huntingtons-disease PATHOLOGY & CAUSES ▪ Autosomal dominant, neurodegenerative disease; chorea, dementia ▫ Average age of onset is 40 ▪ Medium spiny striatal (GABAergic) neuronal cell death → dysregulation of basal ganglia circuitry → unchecked dopamine, glutamate-mediated basal ganglia activity → ↑ motor output → hyperkinetic movement ▪ Cortical cell death → cognitive impairment

CAUSES Trinucleotide repeat (CAG) expansion ▪ Trinucleotide repeat (CAG) expansion of first exon in huntingtin (HTT) gene on chromosome 4p16.3 ▫ Intermediate repeat number: 27–35 (rarely causes disease) ▫ Disease repeat number: 36–39 (incomplete penetrance) ▫ Disease repeat numbers: > 40 (complete penetrance ↑ repeat number → ↓ age of onset) ▪ Repeat CAG expansion in first exon of HTT → expansion of polyglutamine region at N terminus of HTT protein → gain-of-function ▪ Physiologic role of HTT protein unknown (high levels found in brain tissue) Possible pathophysiologic roles of HTT protein ▪ Aggregation of protein → cellular dysfunction ▫ Aggregation → uptake by neurons → neuronal death; akin to prionlike pathogenesis; most prominent aggregation (neuronal death) in caudate, putamen (AKA neostriatum) ▫ Aggregation → ↑ proteasomal, autophagic degradation pathways → dysregulated cell injury, death ▪ Transcriptional dysregulation

▫ Abnormal HTT protein → binding of various transcriptional regulators → ↓ mitochondrial oxidative stress protective genes → susceptibility of oxidative damage → neuronal death ▪ Altered levels of brain-derived neurotrophic factors Role of ras homolog enriched in striatum (Rhes) ▪ Avidly bind with mutant huntingtin ▪ Protein selectively expressed in striatum ▪ Rhes → mediates covalent attachment of small ubiquitin-like modifier (SUMO) to HTT → ↑ HTT aggregation → neurotoxicity Inheritance ▪ Autosomal dominant ▪ Anticipation ▫ Repeat expansion occurs during spermatogenesis → paternal transmission associated with early age of onset

COMPLICATIONS

▪ Depression → suicide ▪ Dysphagia → aspiration pneumonia (common cause of death)

SIGNS & SYMPTOMS ▪ Motor symptoms (movement inhibition; excessive, involuntary movements) ▫ Hypotonia with hyperreflexia (early symptom), chorea (e.g. face, head, neck, tongue, trunk, extremities), athetosis, dystonia, eye movement slows, gait abnormalities (unsteady, irregular → bradykinesia, rigidity in late disease) ▪ Psychiatric ▫ Apathy, irritability, depression, delusions, aggression, disinhibition, paranoia

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▪ Cognitive ▫ Progressive dementia, inflexibility of thought; ↓ insight, concentration; memory loss ▪ Weight loss, cachexia

DIAGNOSIS DIAGNOSTIC IMAGING MRI ▪ Atrophy of head of caudate nuclei

LAB RESULTS

▪ Genetic testing for CAG repeat in HTT (> 36 repeats)

OTHER DIAGNOSTICS

▪ History ▪ Physical examination ▪ Neurological ▫ Motor, mental status examination

TREATMENT MEDICATIONS Chorea (symptomatic therapy) ▪ Presynaptic VMAT2 (vesicular monoamine transporter Type II) inhibitors: tetrabenazine/deutetrabenazine ▫ ↑ synaptic metabolism of dopamine → ↓ dopamine → ↓ basal ganglia output → ↓ hyperkinetic output ▫ May exacerbate parkinsonism symptoms ▫ As late symptom (e.g. chorea abates), periodic review of dosing recommended ▪ Neuroleptics: haloperidol/chlorpromazine ▫ Dopamine receptor antagonists → ↓ dopaminergic input → ↓ basal ganglia output → ↓ hyperkinetic output ▫ Similar parkinsonism side effects/ exacerbation of symptoms ▪ Psychosis: quetiapine (dopamine, serotonin antagonist properties)

PSYCHOTHERAPY

▪ Chorea (symptomatic therapy) ▫ Counseling, techniques to ↓ anxiety, stress

OTHER INTERVENTIONS

▪ No curative therapy ▫ Palliative, advance care planning ▪ Symptomatic therapy ▫ Chorea (severe cases): assistive equipment (e.g. helmets, padded reclining chairs, low beds) ▫ Dysphagia: thickened liquids ▫ Speech, language problems: physical therapy ▫ Gait impairment: hip protectors → ↓ hip fractures → ↓ morbidity

Figure 28.2 An MRI scan in the coronal plane of the head of an individual with Huntington’s disease. There is atrophy of both caudate nuclei which has led to hydrocephalus ex vacuo. There is also generalized cortical atrophy.

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NOTES

NOTES

TRISOMIES GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES

DIAGNOSIS

▪ Genetic disorders: trisomies (three copies of particular chromosome) → severe multiorgan defects (cardiac, gastrointestinal, genitourinary), debilitating dysmorphic features

DIAGNOSTIC IMAGING

CAUSES

LAB RESULTS

RISK FACTORS

OTHER DIAGNOSTICS

▪ Meiotic nondisjunction (most common, > 90%) ▪ Mutation (e.g. translocation) ▫ Mitotic nondisjunction → mosaicism

▪ Advanced maternal age

Ultrasound ▪ Prenatal diagnosis ▫ Nuchal translucency, organ defects

▪ Prenatal diagnosis ▫ Chorionic villus sampling, amniocentesis ▪ Postnatal diagnosis ▫ Karyotyping

▪ Postnatal diagnosis ▫ Clinical identification of dysmorphic features

COMPLICATIONS

▪ Widespread organ dysfunction

SIGNS & SYMPTOMS ▪ Depend on trisomy, affected organs

TREATMENT OTHER INTERVENTIONS ▪ Genetic counseling

DOWN SYNDROME osms.it/down-syndrome PATHOLOGY & CAUSES ▪ Autosomal trisomy of chromosome 21 ▪ Most common chromosomal abnormality in live births, cause of intellectual disability

▪ Range of dysmorphic features, congenital anomalies (e.g. congenital heart, otolaryngeal, gastrointestinal, hematologic, endocrine, urogenital defects)

CYTOGENETIC TYPES

▪ Meiotic nondisjunction in one parent (most common) → trisomy 21 (47 XY, +21)

OSMOSIS.ORG 181

▪ Chromosome 21 involved in Robertsonian translocation ▪ Trisomy 21 mosaicism due to mitotic nondisjunction ▫ Some cells unchanged (46 XY), others (47 XY, +21) ▫ Duodenal atresia/stenosis, tracheoesophageal fistula, cervical spine instability, hematologic disorders

RISK FACTORS

▪ Advanced maternal age, previous child with trisomy 21, parental consanguinity

COMPLICATIONS

▪ Cardiac ▫ Valve disease (e.g. mitral valve prolapse) ▪ Developmental delay, intellectual disability (IQ: 20–75) ▪ Endocrine ▫ Hypothyroidism, obesity ▪ Gastrointestinal ▫ Delayed dental eruption, duodenal atresia, celiac disease ▪ Genitourinary ▫ Cryptorchidism, infertility (in individuals who are biologically male) ▪ Hematologic ▫ Anemia, ↑ risk of leukemia ▪ Musculoskeletal ▫ Atlantoaxial instability (↑ mobility of C2 in relation to C1); juvenile idiopathic arthritis, hip dislocation ▪ Neurologic/psychiatric ▫ Early onset dementia (by age 55), major depressive disorder, seizures ▪ Premature aging ▪ Respiratory ▫ Tracheal stenosis, obstructive apnea ▪ Sensory ▫ Congenital cataracts, hearing loss, frequent otitis media

SIGNS & SYMPTOMS ▪ Brushfield spots (small white/grayish spots on periphery of iris)

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▪ Dysmorphic features ▫ Microcephaly, flat occiput, flattened face; epicanthal folds; flat nasal bridge; upward-slanting palpebral fissures; small nose/mouth; protuberant tongue; low-set/small ears; short neck, excessive nuchal skin; shortened extremities; big gap between first toe (hallux), others; single transverse palmar crease; short fifth finger with clinodactyly ▪ Gastrointestinal ▫ Vomiting, constipation, poor appetite, ↓ weight gain ▪ Neuromuscular ▫ Hypotonia, diastasis recti (abnormally large inter-recti distance) ▪ Pale, dry skin; fatigue ▪ Respiratory ▫ Dyspnea, wheezing

Figure 29.1 An eight-year-old boy with Down syndrome.

Chapter 29 Trisomies

DIAGNOSIS DIAGNOSTIC IMAGING Ultrasound ▪ Prenatal diagnosis ▫ Nuchal translucency (weeks 11–14)

LAB RESULTS

▪ Chorionic villus sampling/amniocentesis ▪ Prenatal diagnosis ▫ ↓ pregnancy-associated plasma protein A (PAPP-A), unconjugated estriol (uE3), alpha-fetoprotein (AFP) ▫ ↑ serum beta human chorionic gonadotropin (β-hCG), inhibin A ▫ Quadruple screen ▪ Postnatal diagnosis ▫ Fluorescence in situ hybridization (FISH), karyotyping

OTHER DIAGNOSTICS

▪ Postnatal diagnosis ▫ Clinical identification of dysmorphic features

Figure 29.2 The feet of an individual with Down syndrome. There is a large space between the great and second toes.

TREATMENT OTHER INTERVENTIONS

▪ Prenatal genetic counseling ▪ Supportive management of affected body systems

EDWARDS SYNDROME osms.it/edwards-syndrome PATHOLOGY & CAUSES ▪ Autosomal trisomy of chromosome 18 ▪ Second most common autosomal trisomy in live births

CYTOGENETIC TYPES

▪ Meiotic nondisjunction in one parent (most common) ▫ Trisomy 18 (47 XY, +18) ▪ Translocation of chromosome 18 ▪ Trisomy 18 mosaicism due to mitotic nondisjunction ▫ Some cells unchanged (46 XY), others (47 XY, +18)

RISK FACTORS

▪ Family history, more common in individuals who are biologically female (3:1), advanced maternal age

COMPLICATIONS

▪ ↑ risk of neoplasms (e.g. Wilms’ tumor, hepatoblastoma) ▪ Multi-organ abnormalities (e.g. cardiac septal defects, intestinal malrotation, Meckel’s diverticulum, neurological disorders, horseshoe kidney, hypotonia, pulmonary hypoplasia, cryptorchidism) ▪ Failure to thrive (FTT) ▪ Severe developmental, cognitive impairment

OSMOSIS.ORG 183

▪ ↓ life expectancy (< one year old); up to 50% die within first week

SIGNS & SYMPTOMS ▪ Dyspnea, hypotonia, wheezing, lack of appetite, severe mental disability, poor weight gain ▪ Dysmorphic features ▫ Clenched hand/overlapping fingers; microcephaly, prominent occiput; small mouth, low-set pointy ears; short sternum; ocular hypertelorism; abnormal retinal pigmentation; short nose with upturned nares; clubfeet, rocker bottom feet; scoliosis, narrow pelvis

DIAGNOSIS DIAGNOSTIC IMAGING Abdominal ultrasound ▪ Postnatal diagnosis ▫ Presence of tumors Ultrasound ▪ Prenatal diagnosis ▫ Unchanged inhibin A; nuchal translucency (weeks 11–14)

LAB RESULTS

▪ Prenatal diagnosis ▫ Amniocentesis/chorionic villus sampling (CVS), ↓ PAPP-A, serum β-hCG, uE3, AFP, quadruple screen ▪ Postnatal diagnosis ▫ Fluorescence in situ hybridization (FISH), karyotyping

OTHER DIAGNOSTICS

▪ Prenatal ▫ Growth restriction: umbilical cord with two vessels; persistent clenched/ overlapping fingers; heart defects; cystic hygroma; polyhydramnios, oligohydramnios; intrauterine growth delay; omphalocele; hydrocephalus; agenesis of corpus callosum; Dandy– Walker abnormality; diaphragmatic hernia ▪ Postnatal ▫ Clinical identification: dysmorphic features

TREATMENT OTHER INTERVENTIONS

▪ Treat life-threatening/disabling conditions (e.g. infections, cardiac/gastrointestinal defects) ▪ Prenatal genetic counseling ▪ Psychosocial management

PATAU SYNDROME osms.it/patau-syndrome

▪ Autosomal trisomy of chromosome 13

▪ Trisomy 13 mosaicism due to mitotic nondisjunction ▫ Some cells unchanged (46 XY), others (47 XY, +13)

CYTOGENETIC TYPES

RISK FACTORS

PATHOLOGY & CAUSES

▪ Meiotic nondisjunction in one parent ▫ Trisomy 13 (47 XY, +13) ▪ Translocation of chromosome 13

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▪ Family history, advanced maternal age

Chapter 29 Trisomies

COMPLICATIONS

▪ Intrauterine growth restriction ▪ Multi-organ congenital anomalies (e.g. severe intellectual disability, capillary hemangioma, cardiac septal defects, cryptorchidism bicornuate uterus, intrauterine growth retardation, cerebral hypoplasia) ▪ High mortality ▫ Most fetuses die in utero/stillborn; neonates die shortly after birth (median survival is seven days)

OTHER DIAGNOSTICS

▪ Postnatal ▫ Clinical identification of dysmorphic features

SIGNS & SYMPTOMS ▪ Anophthalmia, microphthalmia, cyclopia, colobomas ▪ Holoprosencephaly (formation of single forebrain with single ventricle) ▪ Microcephaly, neural tube defects, deafness ▪ Cleft palate/lip, cutis aplasia, omphalocele, post-axial polydactyly, prominent heel (rocker-bottom feet), dextroposition, absent philtrum

Figure 29.3 An adolescent femal with Patau syndrome.

DIAGNOSIS DIAGNOSTIC IMAGING Prenatal ultrasound ▪ Unchanged inhibin A ▪ Nuchal translucency (weeks 11–14) ▫ Holoprosencephaly; ventriculomegaly; microcephaly; corpus callosum agenesis; cleft lip, palate; neural tube defects; omphalocele; single umbilical artery; radial aplasia; polydactyly

LAB RESULTS

▪ Prenatal diagnosis ▫ Amniocentesis/chorionic villus sampling (CVS): ↓ PAPP-A, serum β-hCG, uE3, AFP, quadruple screen ▪ Postnatal diagnosis ▫ Fluorescence in situ hybridization (FISH), karyotyping

Figure 29.4 An infant with a more severe case of Patau syndrome demonstrating cyclopia and a proboscis.

OSMOSIS.ORG 185

TREATMENT SURGERY

▪ Intensive treatment ▫ Surgical repair of cardiac defect, cleft lip/ palate

OTHER INTERVENTIONS

▪ Prenatal genetic counseling ▪ Noninterventional paradigm ▫ Palliative, supportive management

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Chapter 2 Acyanotic Defects

NOTES

COMBINED B-CELL & T-CELL DEFICIENCIES

GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Group of disorders characterized by impaired cellular, humoral immunity ▪ Diverse genetic causes ▪ Leads to immunodeficiency, increased susceptibility to recurrent, potentially fatal infections

SIGNS & SYMPTOMS ▪ Recurrent infections, chronic diarrhea, failure to thrive (FTT), skin rashes

DIAGNOSIS LAB RESULTS

▪ Low T lymphocyte, natural killer (NK) cell count ▪ Normal B lymphocyte count, low immunoglobulins ▪ Genetic testing to find defect

TREATMENT OTHER INTERVENTIONS

▪ Measures to prevent serious infections (e.g. antimicrobial prophylaxis, isolation)

Hematopoietic stem cell transplantation (HSCT) ▪ If HSCT fails ▫ Genetic therapy

ADENOSINE DEAMINASE DEFICIENCY osms.it/adenosine-deaminase-deficiency PATHOLOGY & CAUSES ▪ Absence of ADA → intracellular accumulation of metabolites (e.g. deoxyadenosine), toxic to lymphocytes (esp. T cells) ▪ Reduction of T, B lymphocytes, NK cell count → combined immunodeficiency ▪ Autosomal recessive pattern of inheritance

COMPLICATIONS

▪ Progresses to severe combined immunodeficiency (SCID)

SIGNS & SYMPTOMS ▪ Presents as SCID early in life ▪ Neurologic abnormalities (cognitive deficits, behavioral problems, gait abnormalities)

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DIAGNOSIS

TREATMENT OTHER INTERVENTIONS

LAB RESULTS

▪ Measures to prevent infections, HSCT ▪ Gene therapy, enzyme replacement therapy (less effective)

▪ SCID ▫ Decreased ADA blood levels

OTHER DIAGNOSTICS ▪ Genetic testing

SEVERE COMBINED IMMUNODEFICIENCY (SCID) osms.it/SCID PATHOLOGY & CAUSES ▪ Rare genetic syndrome; disturbance in cellmediated, humoral immunity ▪ Combined defects in T, B lymphocyte development, function → severe immunodeficiency

CAUSES

▪ Underlying causes vary in different forms of SCID ▪ Cytokine receptor defects, adenosine deaminase (ADA) deficiency (most common) ▪ Cytokine receptor defects (50–60% of cases) ▫ Mutation in gene encoding common γ-chain subunit of interleukin (IL) receptors (IL-2 receptor gamma/IL-2Rγ) ▪ Impaired interleukin signaling required for survival, development, proliferation of lymphocytes (esp. T lymphocytes) ▪ Profound decrease in lymphocyte count (esp. T, NK-cells) ▪ B lymphocyte count can be normal, immunoglobulin synthesis defective due to lack of T helper cells

188 OSMOSIS.ORG

RISK FACTORS

▪ X-linked recessive pattern of inheritance, more common in individuals who are biologically male

COMPLICATIONS

▪ Susceptibility to recurrent, severe infections by wide range of microorganisms ▫ Candida albicans, Pneumocystis jiroveci, Pseudomonas, cytomegalovirus, varicella ▪ Without HSCT, death may occur within first year due to fatal infections

SIGNS & SYMPTOMS ▪ Recurrent infections ▪ Oral candidiasis presenting with prominent thrush ▪ Chronic diarrhea → malabsorption, failure to thrive ▪ Extensive rash ▪ Morbilliform rash due to reaction of maternal T cells against fetus → graft versus host disease (GVHD)

Chapter 30 Combined B-Cell & T-Cell Deficiencies

DIAGNOSIS DIAGNOSTIC IMAGING Chest X-ray ▪ Hypoplasia of lymphoid tissues ▫ Absence of thymic shadow; thymic hypoplasia

LAB RESULTS

▪ Complete blood count (CBC), manual differential ▫ Total lymphocyte count, ↓ T cell count, normal B cell count, ↓ immunoglobulin levels ▪ Polymerase chain reaction (PCR) ▫ Measure concentration of T cell receptor excision circles (TRECs); indicative of T cell maturation → decreased levels in SCID

▪ Genetic testing to find the specific defect ▪ Lymph node biopsy ▫ Hypoplasia of lymphoid tissues where lymphocytes develop ▫ Absence of germinal centers

TREATMENT OTHER INTERVENTIONS Prevention ▪ Isolation to prevent serious infections; “bubble baby disease” ▪ Avoidance of live vaccines ▪ Antimicrobial prophylaxis ▪ Immunoglobulin replacement therapy HSCT ▪ Curative therapy for most cases ▪ If HSCT fails ▫ Genetic therapy (less effective)

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NOTES

NOTES

COMPLEMENT DEFICIENCIES GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Genetic diseases: a protein of the 30+ in complement system missing → abnormal inflammatory/immune response-prone individual

SIGNS & SYMPTOMS ▪ Recurrent bacterial infection (i.e. pneumonia, tonsillitis, otitis), especially encapsulated bacteria ▪ Rheumatologic/autoimmune disorders ▫ Can be systemic lupus erythematosus (SLE)-like (fever, rash, arthritis, glomerulonephritis)

DIAGNOSIS LAB RESULTS

▪ Screening based on recurrent infection/ autoimmune familial/individual history ▫ Genetic screening ▫ Total hemolytic complement (THC/ CH50) testing < 11% (measures individual serum’s ability to lyse sheep red blood cells (RBCs) coated with antiRBC rabbit antibody → activates serum complement proteins; AH50 alternative pathway evaluation test)

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▪ Complement component serum levels ▫ Level ↓ correlates with specific protein deficiency ▫ Overactive pathway consumption → protein level ↓ (i.e. decreased C2/ C4 ↓ indicates classical pathway overactivation—as in C1 inhibitor deficiency)

TREATMENT MEDICATIONS

▪ Bacterial infection prevention: vaccination ▫ Meningococcal, pneumococcal, Haemophilus influenzae b (Hib) vaccines (conjugated vaccines preferred for Hib pneumococcal) ▪ Bacterial infection-suspicious symptoms → swift antibiotic management

Chapter 31 Complement Deficiencies

C1 ESTERASE INHIBITOR DEFICIENCY osms.it/complement_deficiency PATHOLOGY & CAUSES ▪ Autosomal dominant disorder: C1 inhibitor protein missing → clinical hereditary angioedema (HAE) syndrome ▪ C1 esterase inhibitor role: inhibits C1 protein cleavage in complement cascade ▫ C1 esterase inhibitor deficiency → overactive C1 cleavage → ↑ classical complement pathway activation → proinflammatory, ↑ immune responsive state → ↑ downstream anaphylatoxin production (C2a, C4a) ▪ C1 esterase inhibitor also mediates bradykinin production → hereditary angioedema (HAE) ▫ C1 esterase inhibitor absence → ↑ kallikrein, factor XII → unchecked bradykinin production → vasodilation → severe angioedema

SIGNS & SYMPTOMS Angioedema episodes ▪ Commonly last 24–72 hours, without urticaria/pruritis ▫ Frequent prodromal symptoms: fatigue, nausea, gastrointestinal (GI) symptoms, myalgias present ▫ Individuals may report stress (physical/ mental) as episode triggers Edematous episodes ▪ Nondependent areas, non-pitting ▫ Most common locations: upper respiratory/GI tract skin/mucosal tissue ▫ GI bowel edema → nonspecific GI distress symptoms (abdominal pain, colic) ▫ Laryngeal edema most feared → closed airway → asphyxiation

DIAGNOSIS LAB RESULTS

▪ Low C1 esterase inhibitor, C4 levels

OTHER DIAGNOSTICS History ▪ Recurrent, self-resolving angioedema episodes with/without colicky, abdominal pain ▪ No concurrent angiotensin-converting enzyme (ACE) inhibitors/nonsteroidal antiinflammatory drug (NSAIDs) use ▪ Positive angioedema family history Physical examination ▪ Nondependent (i.e. head/neck), non-pitting edema areas without urticaria/pruritis

TREATMENT MEDICATIONS

▪ Therapies: purified C1 inhibitor concentrate, kallikrein inhibitor, bradykinin-B2-receptor antagonist ▪ If above targeted therapy interventions unavailable → fresh frozen plasma ▪ Avoid angiotensin-converting-enzyme (ACE) inhibitors

SURGERY

▪ Acute episodes → intubation for airway management

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C2 DEFICIENCY osms.it/complement_deficiency PATHOLOGY & CAUSES ▪ Autosomal recessive disorder: involves C2 protein absence in classical complement cascade ▫ Most common complement deficiency disorder ▫ Symptoms commonly present in early childhood ▪ Associated with IgG deficiency

SIGNS & SYMPTOMS ▪ Individuals sometimes present with SLElike symptoms ▫ Fever, rash, arthritis, glomerulonephritis ▪ ↑ infection risk from encapsulated bacteria ▫ Streptococcus pneumoniae, Haemophilus influenza type b, Neisseria meningitidis

DIAGNOSIS LAB RESULTS

▪ Recurrent SLE-like episodes: CH50 testing

OTHER DIAGNOSTICS

▪ Clinical/family recurrent, bacterial infection history

TREATMENT MEDICATIONS

▪ Bacterial infection vigilance: prompt antibiotic therapy ▪ SLE-like episodes: corticosteroids, other immunosuppressants

C3 DEFICIENCY osms.it/complement_deficiency PATHOLOGY & CAUSES ▪ Autosomal recessive disorder: involving protein C3 (vital protein connecting three complement activation pathways— classical, alternative, lectin—to final, common pathway) ▫ Presents with severe infections shortly after birth ▫ Rarest complement deficiency disorder ▪ Cleavage product: C3b (major opsonin) ▫ Inability to effectively opsonize without C3b → antigen-antibody complex unable to be phagocytosed → excess immune complex formation, deposition

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→ type III hypersensitivity reaction ▫ Inability to opsonize underlies frequently encountered sinopulmonary diseases (see bacterial infections below) ▪ Inability to form C5 convertase → deficient membrane attack complex (MAC) formation ▫ Inability to complete complement cascade underlies (primarily meningitisrelated) septic presentation ▪ Abnormal C3 protein levels → abnormal three complement pathway activation → abnormal pathway byproduct concentrations (i.e. anaphylatoxins C2a, C4a) → abnormal immune cell response to immune insult → abnormal neutrophil response → abscess formation

Chapter 31 Complement Deficiencies

SIGNS & SYMPTOMS ▪ Severe, recurrent encapsulated bacterial infections shortly after birth ▫ Particularly Streptococcus pneumoniae ▪ Children who survive severe infections develop problems secondary to immune complex deposition, reaction ▫ Especially membranoproliferative glomerulonephritis

TREATMENT MEDICATIONS

▪ Bacterial infection vigilance: prompt antibiotic therapy ▪ Bacterial infection prophylaxis: vaccination ▫ Pneumococcal vaccination ▫ Meningococcal vaccination (for resulting dysfunctional C5–C9 MAC formation)

DIAGNOSIS LAB RESULTS

▪ Clinical/family history of recurrent, bacterial infections (especially Streptococcus pneumoniae) → CH50 testing

C5-C9 DEFICIENCY osms.it/complement_deficiency PATHOLOGY & CAUSES

DIAGNOSIS

▪ Autosomal recessive disorder group: involving any protein (C5–C9) involved in MAC formation (part of final, common complement pathway) ▪ MAC-forming inability: precludes ability to create osmotic gradient for cellular lysis

LAB RESULTS

SIGNS & SYMPTOMS

MEDICATIONS

▪ Frequent, recurrent bacterial infection ▫ Propensity for Neisseria gonorrhoeae, meningitidis infections (thin cell walls → especially complement destructionvulnerable)

▪ Clinical recurrent, bacterial infection history (especially Neisseria species) → CH50 testing

TREATMENT ▪ Bacterial infection vigilance: prompt antibiotic therapy ▪ Severe bacterial infection mitigation: meningococcal vaccination

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PAROXYSMAL NOCTURNAL HEMOGLOBINURIA (PNH) osms.it/pnh PATHOLOGY & CAUSES ▪ Acquired genetic disorder: hematopoietic stem cells produce cells that lack cellmembrane protein CD55 (AKA decayaccelerating factor (DAF)) or CD59 that predispose cells to complement-mediated lysis ▫ Involved gene (on X chromosome) is phosphatidylinositol glycan complementation group A (PIGA) ▫ Biologically-male individuals in early 20s (most common) ▪ CD59: anchor protein for glycosylphosphatidylinositol (GPI), a marker of ‘self’ antigenicity on erythrocytes, leukocytes ▫ CD59 deficiency → cells sensitive to complement-mediated lysis → intravascular hemolysis ▫ Nocturnal: relative hypoventilation during sleep → slightly ↑ serum CO2 → slightly acidic serum pH → ↑ complement activity → ↑ nighttime hemolysis

COMPLICATIONS

▪ Potentially fatal venous (Budd–Chiari syndrome), arterial thrombosis ▪ Aplastic anemia, myelodysplasia, myelofibrosis, acute leukemia evolution

SIGNS & SYMPTOMS ▪ Episodic crises triggers include infection, dietary iron supplementation, menstruation ▪ Nocturnal hemoglobinuria (upon waking) ▪ Lumbar, abdominal, general musculoskeletal pain

194 OSMOSIS.ORG

▪ Splenomegaly may present in severe hemolysis setting ▪ Venous, arterial thrombosis

DIAGNOSIS LAB RESULTS

▪ Normochromic, normocytic anemia; pancytopenia; ↑ lactate dehydrogenase (LDH) tests

Sugar water test ▪ Serum mixed in sucrose (isotonic solution, low ionic strength) → predisposes to complement-mediated lysis → CD55/59deficient cells hemolyze Acid hemolysis test (Ham test) ▪ Alternative complement cascade triggered in acidified serum conditions → CD55/59deficient cells hemolyze CD55/59 protein flow cytometry ▪ Most sensitive, specific test

TREATMENT MEDICATIONS

▪ Glucocorticoids (prednisone; typically poor response) ▪ Eculizumab: monoclonal antibody binds C5 cleavage → prevents MAC formation, complement-mediated cell lysis

SURGERY

▪ Bone marrow transplantation

Chapter 2 Acyanotic Defects

NOTES

HUMORAL & B-CELL DEFICIENCIES

GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES

DIAGNOSIS

▪ Ineffective B-cell function → impaired antibody production, cellular immunity intact → recurrent, severe upper/lower respiratory tract infections, encapsulated bacteria

LAB RESULTS

CAUSES

▪ Clinical presentation

▪ Familial/sporadic, specific mutations

SIGNS & SYMPTOMS ▪ Mostly asymptomatic ▪ Infections, recurrent fever, autoimmune diseases, allergic reactions, chronic diarrhea, hepatosplenomegaly, failure to thrive (FTT)

▪ Evaluate levels of immunoglobulins (Ig), specific antibodies, B-cells

OTHER DIAGNOSTICS

TREATMENT OTHER INTERVENTIONS ▪ Replacement of Ig

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COMMON VARIABLE IMMUNODEFICIENCY osms.it/common-variable-immunodeficiency PATHOLOGY & CAUSES ▪ Immune disorder characterized by hypogammaglobulinemia ▫ IgG,IgM, IgA; inherited/sporadic ▪ Defect in B-cell differentiation → impaired lymphocyte activation, function

CAUSES

▪ Unclear ▪ Intrinsic defects in B-cells → antibody deficiency ▫ Impaired T-cell mediated activation ▫ Impaired differentiation into plasma cells → ↓ immunoglobulins ▪ Mutations in genes encoding B-cell activating factor (BAFF) cytokine receptor/ inducible costimulator (ICOS)

COMPLICATIONS

▪ Autoimmune disorders ▫ Rheumatoid arthritis, autoimmune hemolytic anemia (AHA) ▪ Lymphoid malignancy, gastric cancer ▪ Bronchiectasis secondary to recurrent infections ▪ Granulomatous infiltration ▪ Poor immune response to immunizations

SIGNS & SYMPTOMS ▪ Usually presents > two years old ▪ Variable presentation secondary to antibody deficiencies → recurrent infections (e.g. sinopulmonary pyogenic, meningoencephalitis)

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DIAGNOSIS LAB RESULTS

▪ Decreased serum IgG levels, marked decrease in IgM/IgA ▪ Lack of antibody immune response to protein antigens/immunization ▪ Genetic testing for mutations

OTHER DIAGNOSTICS

▪ > four years old ▪ History of recurrent infections, positive family history ▪ Physical examination ▫ Peripheral lymphadenopathy ▪ Exclusion of other causes of hypogammaglobulinemia (e.g. X-linked agammaglobulinemia)

TREATMENT MEDICATIONS

▪ Immunosuppressants to control autoimmune clinical features ▪ Antibiotics to treat chronic lung infections

OTHER INTERVENTIONS ▪ Ig replacement therapy

Chapter 32 Humoral & B-Cell Deficiencies

HYPER IGM SYNDROME osms.it/hyper-IgM-syndrome PATHOLOGY & CAUSES

DIAGNOSIS

▪ Immune disorder; elevated levels of IgM; low to absent IgG, IgA, IgE ▫ X-linked/autosomal recessive ▪ Defect in B-cell antibody class switching → defective lymphocyte activation, function ▪ Predisposition to certain infections ▪ IgM antibodies can react with blood cells → autoimmune hemolytic anemia, thrombocytopenia, neutropenia ▪ In elderly, proliferation of plasma cells producing IgM can infiltrate gastrointestinal (GI) tract mucosa

LAB RESULTS

CAUSES

MEDICATIONS

▪ Genetic defects ▫ Type 1 (most common): X-linked disease of CD40 ligand (CD40L) gene → affects T cell ability to stimulate, activate B cells ▫ Other subtypes: affect class switching, autosomal recessive diseases

SIGNS & SYMPTOMS ▪ Recurrent severe pyogenic/opportunistic infections early in life ▪ Related to cause of infection ▫ Fungi: Pneumocystis jiroveci → pneumonia ▫ Protozoa: Cryptosporidium → infects biliary tract → diarrhea, malabsorption ▫ Viruses: Cytomegalovirus (CMV) → viral pneumonia/hepatitis ▫ Encapsulated bacteria: Streptococcus pneumoniae → otitis media, sinusitis, bacterial pneumonia

▪ No serum IgA, IgE, extremely low IgG ▪ Normal/elevated IgM ▪ Flow cytometry/genetic test ▫ Confirm mutation in CD40L

OTHER DIAGNOSTICS

▪ History of recurrent infections, positive family history

TREATMENT ▪ Prophylactic treatment with trimethoprim/ sulfamethoxazole for Pneumocystis jiroveci

OTHER INTERVENTIONS

▪ Ig replacement therapy ▪ Individuals with persistent neutropenia may require granulocyte colony stimulating factor (G-CSF) ▪ Hematopoietic stem cell transplantation (HSCT) → bone marrow transplant (BMT)/ cord blood stem cell transplant

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HYPERIMMUNOGLOBULIN E SYNDROME osms.it/hyper-IgE-syndrome PATHOLOGY & CAUSES ▪ Rare immunodeficiency; recurrent skin, respiratory infections, eczema, elevated serum IgE levels ▪ AKA Job syndrome ▪ Mostly sporadic

DIAGNOSIS LAB RESULTS

▪ Markedly elevated serum IgE levels

OTHER DIAGNOSTICS ▪ Clinical presentation

TYPES Autosomal dominant (AD-HIES) ▪ More common Autosomal recessive (AR-HIES) ▪ Increased risk of developing fatal complications, infections, malignancies, autoimmune disorders

SIGNS & SYMPTOMS ▪ Primary characteristics ▫ Newborn rash/eczema, first manifestation; impetigo, boils ▫ Recurrent staphylococcal skin abscesses, without typical signs of inflammation (“cold abscesses”) ▫ Recurrent respiratory infections → formation of lung cavities, pneumatoceles ▪ Ear, sinus infections; mucocutaneous candidiasis; facial, skeletal findings (e.g. hyperextensibility of joints, retained primary teeth, due to connective tissue, skeletal abnormalities); susceptibility to malignancies (esp. lymphomas), autoimmune diseases

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TREATMENT MEDICATIONS

▪ Prophylactic administration of trimethoprim-sulfamethoxazole ▪ Limited use of steroids for eczema

SURGERY

▪ Incision, drainage for skin/lung abscesses

OTHER INTERVENTIONS

▪ Skin care, antisepsis (prevent infections); prompt treatment of skin, respiratory infections; control of pulmonary complications; moisturizing creams ▪ HSCT

Chapter 32 Humoral & B-Cell Deficiencies

IGG SUBCLASS DEFICIENCY osms.it/IgG-subclass-deficiency PATHOLOGY & CAUSES ▪ Decrease in serum concentration of ≥ one subclasses of IgG ▫ IgG1, IgG2, IgG3, IgG4 while total IgG concentration remains unchanged ▫ IgG1 accounts for 60–70% of total IgG; IgG1 deficiency presents with low total IgG ▫ IgG2/IgG3 deficiencies most common ▫ Low IgG4 alone insufficient evidence of antibody deficiency disorder ▪ IgG subclass deficiency ▫ Integral component of other primary immunodeficiency diseases (e.g. Wiskott–Aldrich syndrome) ▪ Individuals with IgG subclass deficiency have recurrent ear/sinus/lung infections ▪ In many children, deficiency resolves with age ▪ May develop into common variable immunodeficiency (CVID)

DIAGNOSIS LAB RESULTS

▪ ≥ one low IgG subclasses with normal total IgG ▪ History of recurrent sinopulmonary infections ▪ Inadequate response to vaccination

TREATMENT MEDICATIONS

▪ Antibiotic prophylaxis

OTHER INTERVENTIONS

▪ Treatment of conditions predisposing to recurrent infections (e.g. asthma) ▪ Immunization with conjugate vaccines ▪ Long-term Ig replacement therapy

SIGNS & SYMPTOMS ▪ Mostly asymptomatic ▪ Recurrent ear/sinus/pulmonary infections with encapsulated bacteria (e.g. Streptococcus pneumoniae, Haemophilus influenzae) ▪ Increased incidence of atopic disease, chronic airway disease, autoimmune disease (e.g. vasculitis)

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ISOLATED PRIMARY IMMUNOGLOBULIN M DEFICIENCY osms.it/isolated-primary-IgM-deficiency PATHOLOGY & CAUSES ▪ Rare immune disorder; decreased IgM antibodies in bloodstream ▪ AKA selective IgM immunodeficiency (SIgMD) ▪ Unclear etiology ▫ Rapid degradation of B cells after being secreted ▫ B cells unable to mature, produce free IgM ▪ Associated with recurrent infections, allergic conditions, Bloom’s syndrome, celiac disease, systemic lupus erythematosus (SLE), malignancy

COMPLICATIONS

▪ Infections may progress to meningitis, sepsis

SIGNS & SYMPTOMS ▪ Start in infancy, vary widely ▫ May be asymptomatic; recurrent severe infection (e.g. sinusitis, diarrhea, skin infections); allergic reactions (e.g. atopic dermatitis)

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DIAGNOSIS LAB RESULTS

▪ Decreased levels of IgM antibodies

OTHER DIAGNOSTICS

▪ History of recurrent infections

TREATMENT MEDICATIONS

▪ Prophylactic antibiotics for severe recurrent infections ▪ Antibiotics to treat infections

Chapter 32 Humoral & B-Cell Deficiencies

SELECTIVE IMMUNOGLOBULIN A DEFICIENCY osms.it/selective-IgA-deficiency PATHOLOGY & CAUSES ▪ Most common primary immunodeficiency; isolated deficiency of IgA in blood, secretions ▪ IgA deficiency (primarily in mucosal surface secretions) → infections, GI disorders, autoimmune diseases, allergic reactions ▪ Unknown etiology; associated with several non-causative genetic alterations

RISK FACTORS

▪ Family history of IgA deficiency/CVID

SIGNS & SYMPTOMS ▪ May be asymptomatic; may present significant clinical problems (less common) ▪ Susceptibility to infections (e.g. sinopulmonary, ear infections) ▪ Autoimmune diseases ▫ Rheumatoid arthritis, systemic lupus erythematosus, immune thrombocytopenic purpura ▪ GI disorders (e.g. diarrhea); Giardia lamblia infections ▪ Allergic disorders (e.g. asthma) ▪ Anaphylactic reactions to blood products

DIAGNOSIS LAB RESULTS

▪ Individual > four years old ▫ Undetectable levels of IgA

OTHER DIAGNOSTICS

▪ Clinical presentation ▪ Exclude other causes of hypogammaglobulinemia, IgA deficiency secondary to medications

TREATMENT MEDICATIONS

▪ Antibiotics to treat infections/long-term antibiotic prophylaxis to prevent them ▪ Anti-inflammatory drugs, steroids, monoclonal antibodies for autoimmune diseases ▪ Antihistamines, anti-inflammatory drugs, steroids for allergies

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TRANSIENT HYPOGAMMAGLOBULINEMIA OF INFANCY osms.it/infant/hypogammaglobulinemia PATHOLOGY & CAUSES ▪ Temporary decrease in circulating Ig during first months of life ▫ Maternal IgG pass fetus through placenta in sixth month of pregnancy → maternal IgG slowly diminishes, disappears six months after birth ▫ By 3–6 months of age, healthy infants begin making IgG as maternal IgG levels fall ▫ If severe/prolonged beyond six months of age → THI ▪ More common in individuals who are biologically male (2:1) ▪ Most individuals with THI have adequate antibody responses to infections/ immunizations → usually not susceptible to infections ▪ Serum Ig levels should return by age four years, may persist for few more years ▪ Severe, life-threatening infections rare

SIGNS & SYMPTOMS ▪ Usually asymptomatic ▪ Recurrent infections ▫ Upper respiratory, ear, sinus ▪ Atopic manifestations ▫ Asthma, eczema, food allergy ▪ GI difficulties

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DIAGNOSIS LAB RESULTS

▪ IgG level < two standard deviations below age-appropriate mean, with/without diminished levels of other serum Ig, on at least two occasions ▪ Ig must normalize during childhood/rarely during adolescence

OTHER DIAGNOSTICS

▪ Diagnosis of exclusion; other permanent forms of hypogammaglobulinemia must be excluded first

TREATMENT MEDICATIONS

▪ Antibiotics ▫ If persistent infections occur

OTHER INTERVENTIONS

▪ Immunoglobulin replacement therapy if infections severe/persistent

Chapter 32 Humoral & B-Cell Deficiencies

WISKOTT–ALDRICH SYNDROME osms.it/wiskott-aldrich_syndrome PATHOLOGY & CAUSES ▪ Rare syndrome; classic triad of microthrombocytopenia, eczema, recurrent pyogenic infections ▪ AKA eczema-thrombocytopeniaimmunodeficiency syndrome ▪ X-linked recessive inheritance pattern; can also result from spontaneous DNA mutation affecting hematopoietic cells ▪ Most commonly presents in individuals who are male, > two years old ▪ Progressive loss of T lymphocytes in peripheral blood, lymph nodes → impairment of T-cell mediated, humoral immunity

CAUSES

▪ Mutation in Wiskott–Aldrich syndrome protein (WASP) gene at Xp11.23 ▫ Encodes for hematopoietic cellular proteins involved in cytoskeletal architecture

COMPLICATIONS

▪ Increased risk of infections, bleeding, autoimmune disease, malignancy

SIGNS & SYMPTOMS ▪ Thrombocytopenia → petechiae, bruising, epistaxis, severe bleeding ▪ Eczema, atopic symptoms ▪ Recurrent sinopulmonary/opportunistic infections caused by ▫ Encapsulated bacteria (e.g. Streptococcus pneumoniae, Haemophilus influenzae, Neisseria meningitidis) ▫ Fungi (e.g. Pneumocystis jirovecii, Candida albicans) ▫ Viruses (e.g. molluscum contagiosum, varicella zoster, cytomegalovirus)

DIAGNOSIS LAB RESULTS

Low to normal IgG, IgM High IgA, IgE Decreased number, function of T cells Peripheral blood smear ▫ Fewer, smaller platelets secondary to cytoskeletal remodeling ▪ Genomic DNA sequencing ▪ Flow-cytometry ▫ Screening test, determine presence of WASP

▪ ▪ ▪ ▪

OTHER DIAGNOSTICS

▪ History of bleeding, recurrent infections, eczema ▪ Clinical presentation, positive family history

TREATMENT MEDICATIONS

▪ Prophylactic antimicrobials ▪ IVIG for recurrent infections

SURGERY

▪ Splenectomy for severely low platelets

OTHER INTERVENTIONS

▪ Platelet transfusions for severely low platelets ▪ Blood transfusions for severe bleeding ▪ HSCT ▫ Potentially curative

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X-LINKED AGAMMAGLOBULINEMIA osms.it/x-linked_agammaglobulinemia PATHOLOGY & CAUSES

SIGNS & SYMPTOMS

▪ Immunodeficiency disorder; severe hypogammaglobulinemia, deficiency of all classes of antibodies → increased susceptibility to infection ▪ AKA Bruton’s disease ▪ Familial/sporadic mutation in BTK gene on X-chromosome → X-linked recessive genetic condition ▫ Manifests as disease in individuals who are biologically male ▫ Individuals who are biologically female only carriers ▪ Ineffective Bruton’s tyrosine kinase (BTK) enzyme → B-lymphocyte precursors fail to mature into B lymphocytes, plasma cells → differentiation stops at pre-B cell stage → absence of B-cells in circulation → deficiencies of all Ig → high risk of developing infections ▫ Bacterial (e.g. acute/chronic pharyngitis, sinusitis, otitis media, bronchitis, pneumonia), viral (e.g. enteroviruses, polio, coxsackievirus), protozoal intestinal parasitosis (e.g. giardia lamblia) ▪ T-cell mediated immunity remains intact; some viral, fungal, protozoal infections still cleared

▪ Newborns typically asymptomatic; after six months transplacentally-delivered Ig no longer present → prone to develop infections ▪ Infections frequently occur at mucous membranes, can also involve bloodstream, spread to internal organs, bones, joints, brain (e.g. otitis media, pharyngitis, bronchitis) ▪ Small/absent tonsils, lymph nodes

DIAGNOSIS LAB RESULTS

▪ Serum Ig levels ▫ All Ig markedly reduced/absent ▪ Number of B-cells in peripheral blood ▫ Nearly absent (most characteristic finding)

OTHER INTERVENTIONS

▪ Clinical presentation ▫ Any child with recurrent/severe bacterial infections ▪ Genetic testing ▫ Absence of BTK protein/presence of BTK mutation

TREATMENT OTHER INTERVENTIONS

▪ Lifelong IVIG can be given to replace missing Ig ▪ Complete, prompt treatment of infections ▪ Avoid live viral vaccines (e.g. polio vaccine)

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Chapter 2 Acyanotic Defects

NOTES

HYPERSENSITIVITY REACTIONS: MULTIPLE MECHANISMS

GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Hypersensitivity (intolerance): undesirable reactions produced by immune system (e.g. allergies, autoimmunity) ▪ Range from minor (e.g. swelling, itching) to tissue-damaging, fatal ▪ Multiple mechanisms indicates the presence of two or more of the four types of hypersensitivity reaction ▫ Type I: allergy, acute hypersensitivity ▫ Type II: antibody-dependent cytotoxicity ▫ Type III: immune complex disease ▫ Type IV: delayed type hypersensitivity/ cell-mediated immune memory response ▫ Tissue specific antibody response: autoimmune disease/organ rejection Common Hypersensitivity reactions with multiple mechanisms ▪ Hypersensitivity pneumonitis ▪ Transplant rejection ▪ Latex allergy (I+IV) ▪ Sjögren syndrome ▪ Autoimmune hepatitis Autoimmune polyendocrine syndrome (APS1, APS2) ▪ Autoimmune adrenalitis ▪ Systemic autoimmune disease

SIGNS & SYMPTOMS ▪ Non-specific flu-like symptoms (e.g. fever, chills, malaise, cough, joint pains) ▪ Multiple mechanisms varies by location; see individual disorders

DIAGNOSIS LAB RESULTS

▪ Acute (Type I) hypersensitivity ▫ Spirometry/pulmonary function, skin tests (exposure to specific allergens provokes skin reaction), radioallergosorbent tests (quantify allergen specific IgE levels) ▪ Type II–IV hypersensitivity ▫ Identify organ/cell component specific antibodies

Biopsy (Type II–IV hypersensitivity) ▪ Immune cell infiltration of organ ▪ Compromise of normal organ anatomy

TREATMENT MEDICATIONS Acute (Type I) hypersensitivity ▪ General ▫ Withdraw offending agent, H1 receptor blockers ▪ Anaphylaxis ▫ Hypertension: epinephrine, intravenous fluids, vasopressors (e.g. dopamine) ▫ Bronchoconstriction: nebulized B2 agonists (e.g. salbutamol) ▫ Late-phase reaction, corticosteroids Type II–IV hypersensitivity ▪ Immunosuppression

SURGERY Type II–IV hypersensitivity ▪ Irreversible organ damage/rejection → transplant of new organ

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OTHER INTERVENTIONS Type II–IV hypersensitivity ▪ Support organ function

HYPERSENSITIVITY PNEUMONITIS osms.it/hypersensitivity-pneumonitis PATHOLOGY & CAUSES ▪ AKA (extrinsic) allergic alveolitis ▪ Reaction to antigens usually 1–5 micrometers in size; fungal, bacterial, mycobacterial, animal, chemical sources ▫ Type III (antibody complex mediated) and IV hypersensitivity (delayed cellmediated) ▫ Inhaled antigen → forms haptens → inflammation of alveoli, small distal airways within lung ▫ Histological changes: inflammation of bronchi, peribronchiolar tissue; diffuse interstitial inflammatory infiltrate; poorly defined granulomas, associated giant cells within lung interstitium/alveoli ▫ Long-standing disease → pulmonary fibrosis, emphysematous changes → ↓ lung capacity, alveolar gas exchange → hypoxemia ▪ > 200 common causative agents identified, often given eponymous names (e.g. farmer’s lung, bird fancier’s lung, etc.)

RISK FACTORS

▪ Farming, ventilation, water-related exposure; poultry, bird handling; veterinary work, animal handling; grain, flour processing; grain dust; mold contamination; milling, construction; plastic manufacturing; painting; electronics industry, other chemical industries; textile workers

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SIGNS & SYMPTOMS Acute ▪ Fever, chills, malaise, cough, chest tightness, dyspnea, rash, headache ▪ Resolves 12 hours to several days after cessation of exposure Sub-acute ▪ Productive cough, dyspnea, fatigue, anorexia, weight loss, pleurisy, mild hypoxemia ▪ Lesser severity, longer duration ▪ Resolves weeks to months after cessation of exposure Chronic ▪ Insidious onset cough, progressive dyspnea, fatigue, weight loss, clubbing, tachypnea, respiratory distress, inspiratory crackles (lower lung fields) ▪ Emphysematous component ▪ May have irreversible component, even if antigen removed

DIAGNOSIS DIAGNOSTIC IMAGING Bronchoscopy/bronchoalveolar lavage ▪ Marked lymphocytosis; ↑ IgG, IgA, IgM Chest X-ray ▪ Subacute hypersensitivity ▫ Micronodular/reticular opacification in middle to lower lung zones ▪ Chronic hypersensitivity ▫ Progressive fibrotic changes, loss of lung volume (esp. upper lobes)

Chapter 33 Hypersensitivity Reactions: Multiple Mechanisms High-resolution chest CT scan ▪ Subacute hypersensitivity ▫ Diffuse micronodules, ground-glass opacification, focal air trapping/ emphysematous changes, mild fibrosis ▪ Chronic hypersensitivity ▫ Interstitial inflammation, alveolar destruction, dense fibrosis, features of emphysema (centrilobular nodules), ground glass opacification, subpleural honeycombing

Figure 33.1 A high resolution CT scan in the axial plane of an individual with hypersensitivity pneumonitis. There are multiple centrilobular ground glass nodules and anterior subpleural reticulation.

LAB RESULTS

▪ Lung biopsy ▫ Loose, poorly-defined noncaseating granulomas in vicinity of small airways ▫ Focal fibrotic changes ▪ Immunoassay ▫ Detect antibodies against specific antigens ▫ Chemical labels accumulate in response to specific antigen-antibody reactions/ enzymes bind to specific markers → catalyze color-changing reaction ▫ Known antigens: identify specific antibodies in blood sample

OTHER DIAGNOSTICS Diagnostic criteria: acute hypersensitivity ▪ Definite hypersensitivity pneumonitis: 2 and 3, plus one other ▪ Probable disease: 1, 2A, 3 ▪ Subclinical disease: 1, 3A ▪ Previous sensitization: 1 only 1. Known exposure ▪ History of exposure ▪ Aerobiological/microbiological investigation of environment → confirmed exposure ▪ Specific IgG antibodies against identified antigen 2. Compatible clinical, radiographic, physiologic evidence ▪ Respiratory signs: crackles, weight loss, cough, breathlessness, fever, wheezing fatigue, esp. hours after exposure ▪ Radiographic: reticular, nodular, ground glass pattern ▪ Lung function: spirometry (restrictive, obstructive, mixed); diffusion capacity for carbon monoxide (reduced, altered gas exchange) 3. Bronchoalveolar lavage ▪ Lymphocytosis ▪ Positive specific immune response to antigen 4. Inhalation challenge testing ▪ Worsening clinical condition after exposure to environment ▪ Worsening clinical condition after exposure to specific antigen in hospital setting 5. Histopathology ▪ Poorly formed noncaseating granulomas ▪ Mononuclear cell infiltrate Lung function ▪ Subacute ▫ Restrictive pattern ▪ Chronic ▫ Restrictive pattern, hypoxemia at rest, desaturates with exercise, ↓ carbon monoxide diffusion capacity

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TREATMENT MEDICATIONS

▪ Glucocorticoids ▫ Subacute, chronic hypersensitivity ▪ Immunosuppression ▫ Refractory disease

SURGERY

▪ Lung transplant ▫ Advanced chronic lung disease

OTHER INTERVENTIONS

▪ Identify allergen, reduce/eliminate exposure → disease generally self-limiting (if acute) ▪ Occupational measures ▫ Reduce antigenic burden, moisture control, ventilation, personal protective devices (respirator masks)

Figure 33.2 A section of the lung of an individual with hypersensitivity pneumonitis. The alveolar septa are thickened and contain numerous lymphocytes.

TRANSPLANT REJECTION osms.it/transplant-rejection PATHOLOGY & CAUSES ▪ Transplanted tissue rejected (attacked) by new host’s immune system → destruction of transplanted tissue Timescale of rejection ▪ Hyperacute rejection ▫ Minutes after transplant ▫ Initiated by humoral immunity ▫ If tissue left implanted → systemic inflammatory response syndrome ▫ Often caused by preexisting anti-human leukocyte antibodies (HLA) ▪ Acute rejection ▫ Highest risk window one week to three months after transplant ▫ Mediated by cellular immunity ▫ Occurs in nearly all transplants if recipient inadequately immunosuppressed

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▫ Highly vascularised tissue (e.g. kidney, liver) esp. vulnerable ▫ Can be treated prior to organ failure; multiple episodes → chronic rejection ▪ Chronic rejection ▫ Months to years after transplantation ▫ Fibrosis of blood vessels → long term loss of function in transplanted organs Multiple divisions of immune system involved in rejection ▪ Innate immunity → attraction, activation of phagocytes ▪ Humoral immunity → activation of B cells → antibody secretion ▪ Adaptive response → cellular immunity → killer T cells induce apoptosis Cellular markers influencing rejection ▪ Blood group, major histocompatibility (MHC) antigens ▫ Most intense graft rejection reactions

Chapter 33 Hypersensitivity Reactions: Multiple Mechanisms (hyperacute rejection) occur due to differences between donor, recipient ABO blood-groups, MHC antigens ▫ Blood-group antigens expressed on red blood, epithelial, endothelial cells → donor, recipient must be ABO compatible ▫ Minor blood group exposure (e.g. Kell antigen) following allogeneic blood transfusion/trauma during pregnancy may also prime recipient’s humoral immunity against future transplants ▫ MHC compatibility assessed via molecular assay using sequencespecific primers (“tissue typing”) → determination of which HLA alleles expressed by donor, recipient

STAGING

▪ Of acute graft rejection

Sensitization ▪ Recipient antigen-reactive lymphocytes proliferate in response to alloantigens on graft ▪ Dendritic cells migrate to peripheral lymphoid tissue → present donor’s “self” peptides to recipient’s lymphocytes → presentation of antigen to T cells (helper, killer subclasses), B cells → specific immunity directed at donor self peptides/

▫ Presence of preformed antibodies to HLA alloantigens must be evaluated to reduce risk of rejection ▪ Minor histocompatibility locus ▫ Short variable proteins, 9–12 amino acids in length, bound to MHC class I, II proteins ▫ Provoke less vigorous immune response, may still lead to slow graft rejection ▫ Potential for graft rejection even if ABO, MHC antigens match ▪ Donor cell debris ▫ Damage-associated molecular patterns by pattern recognition receptors (e.g. toll-like receptors on phagocytes) → further secretion of proinflammatory cytokines, phagocyte chemotaxis

donor major histocompatibility complex/ both ▪ CD4+ (T helper), CD8+ (T killer) T cells recognize alloantigen (major, minor histocompatibility complex) on foreign graft cells → proliferation ▫ Direct presentation: donor MHC directly recognised as foreign ▫ Indirect presentation: donor peptides residing in cleft of recipient MHC recognised ▪ T helper (Th) cells activate when they interact with antigen presenting cells

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(APCs) that express appropriate antigenicligand/MHC-molecule complex, provide costimulatory signal ▫ Dendritic cells found in most tissue, express high levels of class II MHC → activated dendritic cells mediate direct presentation in grafts/draining lymph nodes ▫ APCs of host origin migrate into grafts, endocytose foreign alloantigens → indirect presentation of alloantigen ▫ Langerhans, endothelial cells present alloantigen to recipient’s immune system Effector phase ▪ Influx of immune cells into graft ▪ Most common rejection mechanism: cell mediated immunity ▪ Less common: antibody-mediated complement lysis, antibody-dependent cellmediated cytotoxicity ▪ Th cell cytokines play central role → Th1 cells secrete interleukin (IL) 2, interferon (IFN) gamma → T cell proliferation, delayed type hypersensitivity response, IgG synthesis by B cells → complement activation ▪ Cytokines → increased expression of MHC class I, II; IFN, tumor necrosis factor (TNF) ▪ Elevated levels of IL-4, 5, 13, 17 → B-cell activation, eosinophil accumulation within grafts ▪ Antibody-mediated rejection ▫ Antibodies directed against donor HLA molecules/endothelial antigens ▫ Dependent on T cell maintenance of alloreactive B cells → antibody production → activation of complement, deposition of C4d among cells lining graft capillaries

TYPES Autograft ▪ Transplant of “self” tissue; surplus tissue that can regenerate/tissue moved from one site to another (e.g. skin, ligament grafts) Isograft ▪ Transplant of tissue between two genetic identical members of same species (e.g.

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transplant between two identical twins) Allograft ▪ Transfer of tissue between genetically non-identical members of same species; non-identical grafts recognised by immune system, destroyed Xenograft ▪ Transplant from one member of species to another (e.g. porcine heart valve transplant)

SIGNS & SYMPTOMS ▪ Fever, chills, dizziness, nausea, malaise, night sweats ▪ Specific to transplanted organ: failure of associated organ

DIAGNOSIS LAB RESULTS Tissue biopsy ▪ T cell infiltration, accompanied by eosinophils, plasma cells, neutrophils ▪ Structural compromise of tissue anatomy ▪ Blood vessel injury

Figure 33.3 A biopsy from a transplanted lung showing a prominent perivascular lymphocytic infiltrate, consistent with rejection. There are numerous background macrophages and eosinophils.

Chapter 33 Hypersensitivity Reactions: Multiple Mechanisms

TREATMENT MEDICATIONS Generalized immunosuppression ▪ Mitotic inhibitors (antiproliferatives) ▫ Suppression of B, T cell proliferation; antimetabolites, DNA alkylating agents, fungal metabolites (also suppress T-cell cytokine expression) ▪ Corticosteroids ▫ Anti-inflammatory, potent immunosuppressives at higher doses Specific immunosuppression ▪ Targeted to specific antigens ▪ Monoclonal antibodies ▫ Soluble ligands, bind specific cellsurface molecules → can be used to deplete recipient of particular cell population/block specific steps in cellular signalling ▫ Modern monoclonal antibodies carry toxins (e.g. diphtheria) → target cell internalizes toxin → cell death ▫ Cellular markers expressed only by activated T cells kill cell lines activated after transplant ▫ Cytokines targeted as well; neutralized cytokine no longer stimulates target (e.g. costimulatory signals needed to activate T-helper cells)

SURGERY

▪ Removal of transplanted tissue (hyperacute rejection) ▪ Bone marrow transplant (acute rejection) ▫ Recipient bone marrow replaced with donor marrow; risk of graft vs host disease ▪ New transplant (chronic rejection)

OTHER INTERVENTIONS

▪ Prevent rejection ▫ Total lymphoid irradiation; X-rays eliminate lymphocytes prior to transplant (e.g. bone marrow transplantation)

For acute rejection ▪ Extensive immunosuppressive regimens: corticosteroids, calcineurin inhibitors, antiproliferatives, mTOR inhibitors ▪ Antibody-based treatment ▫ Monoclonal anti-IL-2R alpha receptor antibodies (e.g. basiliximab), polyclonal anti-T cell antibodies (e.g. antithymocyte globulin, antilymphocyte globulin), monoclonal anti-CD20 antibodies (e.g. rituximab)

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NOTES

NOTES

PHAGOCYTE DEFICIENCIES

GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Inherited immunodeficiency disorders: mutations in genes that code immune-cell functioning ▪ Impaired immune function: recurrent, often severe, life-threatening infections

SIGNS & SYMPTOMS ▪ Recurrent infection history

DIAGNOSIS

LAB RESULTS

▪ Complete blood count (CBC) ▪ Peripheral blood smear analysis ▪ Genetic testing

TREATMENT MEDICATIONS

▪ Infection prophylaxis/treatment

OTHER INTERVENTIONS

▪ Hematopoietic cell transplantation

▪ Characteristic findings upon physical examination

CHEDIAK–HIGASHI SYNDROME osms.it/chediak-higashi_syndrome PATHOLOGY & CAUSES ▪ Rare, inherited immunodeficiency disorder; impaired leukocyte lysosomal granules function in phagocytes, NK cells → recurrent pyogenic infections ▪ Autosomal recessive; lysosomal trafficking regulator gene CHS1/LYST defect ▫ Trafficking: protein movement within cell ▪ Genetic mutation → impaired trafficking → absent/partially functioning CHS1/LYST protein → large, abnormal intracellular granules → decreased phagocytosis → infections primarily affect skin, mucous

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membranes, respiratory tract ▪ Accelerated disease phase: profound lymphohistiocytic organ infiltration, worsening immunodeficiency

RISK FACTORS

▪ Parental consanguinity

COMPLICATIONS

▪ Related to impaired intracellular trafficking ▫ Oculocutaneous albinism (reduced skin, eye pigment) ▫ Neurologic abnormalities ▫ Coagulation defects

Chapter 34 Phagocyte Deficiencies ▫ Hemophagocytic lymphohistiocytosis (disorder resembles lymphoma) ▫ If bone marrow transplant unsuccessful → childhood death from infection usually occurs

SIGNS & SYMPTOMS ▪ Presents in infancy: frequent/severe bacterial, viral, fungal infections ▪ Neurological: nystagmus, ataxia, peripheral neuropathy, seizures, Parkinsonian-like features may develop ▪ Coagulation defect presents as easy bruising ▪ Photosensitivity ▪ Hair has silvery tint

DIAGNOSIS LAB RESULTS

▪ Microscopic hair examination: pigmentation clumping ▪ CBC: neutropenia ▪ Peripheral blood smear analysis: giant intracellular granules ▪ Bone marrow aspiration: large inclusion bodies in precursor cells ▪ Genetic testing

TREATMENT MEDICATIONS

▪ Prophylactic antibiotics ▪ Prompt, aggressive infection treatment

OTHER INTERVENTIONS

▪ Hematopoietic cell transplant; cord blood transplant ▫ Does not address debilitating neurological manifestations/albinism

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CHRONIC GRANULOMATOUS DISEASE (CGD) osms.it/chronic-granulomatous-disease PATHOLOGY & CAUSES

SIGNS & SYMPTOMS

▪ Rare immune-system disorder; affects neutrophils, monocytes, macrophages → serious, life-threatening infections (bacterial/fungal), granuloma formation ▫ X-linked: CYBB encoded ▫ Autosomal recessive form common with consanguinity—CYBA encoded ▫ De novo mutations also occur ▪ Mutations: genes encoding for phagocyte nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, which catalyzes lysosomal reactive oxygen species ▪ Impaired NADPH → phagocytes unable to effectively phagocytize, destroy certain microbes → ↑ infection susceptibility; especially catalase-positive bacteria/fungi

▪ History of disorder-characteristic recurrent infections, granulomatous lesions ▪ Fever, leukocytosis, lymphadenopathy, abnormal wound healing, diarrhea, chronic disease anemia, growth failure (children)

Host immune system response ▪ Recruiting additional phagocytes, activating T cells ▪ Immune cells collect around microbe → granulomas form ▪ Childhood/adulthood diagnosis (underlying mutation-dependent) Frequent infection sites ▪ Lung, skin, lymph nodes, liver Common infections ▪ Pneumonia, bacteremia, fungemia, impetigo, cellulitis, granulomatous lesions (skin, organs), gingivitis, gastroenteritis, otitis Inflammation manifestations ▪ Esophageal/urethral strictures, colitis, cystitis, interstitial pneumonitis, dermatosis

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DIAGNOSIS LAB TESTS

▪ ↑ inflammation markers: erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) ▪ Immune stimulation → hypergammaglobulinemia ▪ Neutrophil function tests: e.g. dihydrorhodamine (DHR) 123 test measure neutrophils ability to produce oxidative burst ▪ Genetic testing

TREATMENT MEDICATIONS

▪ Antimicrobial prophylaxis using combination of therapies ▫ Antibacterial: TMP/SMX ▫ Antifungal: itraconazole ▫ Immunomodulatory: interferon-gamma ▪ Aggressive acute infection treatment ▪ Inflammatory manifestations: oral glucocorticoids ▪ Avoid live bacterial vaccines

OTHER INTERVENTIONS

▪ Hematopoietic cell transplantation: curative if successful

Chapter 34 Phagocyte Deficiencies

LEUKOCYTE ADHESION DEFICIENCY (LAD) osms.it/leukocyte-adhesion-deficiency PATHOLOGY & CAUSES ▪ Rare, inherited immunodeficiency disorders; mutations in genes encoding leukocyte adhesion molecules → impaired leukocyte function, deficient immunological response (foreign antigens), ↓ inflammatory response to injury ▫ Autosomal recessive inheritance ▪ Leukocyte adhesion cascade initiated in response to infection/injury ▫ Involves adhesion molecule-activation on vascular endothelial cells which bind to glycoproteins on leukocyte surface ▪ Stepwise adhesion, activation process ▫ Capture: temporary leukocyte to endothelial cell tethering ▫ Rolling: leukocyte rolls along endothelial cells (weak, reversible initial adherence) ▫ Slow rolling: endothelial cell ligands interact with leukocyte selectins → slow movement along vessel wall ▫ Firm adhesion: leukocyte integrins bind to endothelial intercellular adhesion molecules (ICAMs) → leukocyte stops (arrest) on endothelial surface ▫ Transmigration: leukocyte movement between endothelial cells, into interstitium/infected tissue

TYPES

▪ Categorization: specific genetic defects ▪ LAD I: integrin beta-2 gene mutation (ITGB2) encoding CD18 subunit → CD18 requires activation before endothelial ligand adhesion can occur ▫ Integrins: glycoproteins that mediate firm adhesion, transmigration along endothelium (via endothelial cell counter-receptors) ▫ LAD I defect prevents leukocyte bloodstream → interstitium migration

▪ LAD II: guanosine diphosphate (GDP)fucose transporter gene (SLC35C1) mutation → absent ligands for selectins ▫ Selectins: endothelial, leukocyte adhesion glycoproteins that mediate margination, leukocyte rolling (slows velocity → allows endothelial ligand adhesion) ▫ Fucose (monosaccharide; cellular glycans, glycolipids component) metabolism defect → absent fucosylated endothelial ligands for selectins ▪ LAD III: mutations in CalDAG-GEF1, kindlin-3; FERMT3 genes → defects all beta integrins (e.g. 1, 2, 3) activation ▫ Integrin glycoproteins remain inactivated, unable to adhere to endothelial ligands ▫ Beta-3 defect impairs platelet aggregation → severe bleeding tendency ▫ Also involves natural killer (NK) cell activity impairment

COMPLICATIONS

▪ Specific mutation dependent ▫ Poor wound healing ▫ Bleeding tendencies (may involve neonatal cerebral hemorrhage, gastrointestinal tract bleeding) ▫ Developmental delay ▫ Decreased lifespan (e.g. infection)

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SIGNS & SYMPTOMS

DIAGNOSIS ▪ High index of suspicion at birth with delayed umbilical cord separation, leukocytosis, along with additional findings ▫ LAD I: recurrent soft tissue infections ▫ LAD II: psychomotor impairment, Bombay blood group presence ▫ LAD III: bleeding complications from birth

LAB RESULTS

▪ White blood cell count with differential: elevated leukocyte count ▫ Leukocytes unable to leave bloodstream → persistent leukophilia (basal) + ↑↑ during infection (especially neutrophils) ▪ Flow cytometry ▫ LAD I: CD18, alpha subunit molecules (CD11a, CD11b, CD11c) absence

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▫ LAD-II: SLeX expression (CD15a) absence ▪ LAD-II: genetic testing confirms defect of gene that encodes for guanosine diphosphate (GDP)-fucose transporter ▪ LAD III: impaired integrin activation

TREATMENT MEDICATIONS

▪ Antibiotics: mild–moderate infections

OTHER INTERVENTIONS

▪ Control periodontitis: scrupulous oral hygiene, dental care ▪ Bacterial infection treatment: mitigate severity ▪ Fucose supplementation (LAD II) ▪ Hematopoietic cell transplantation

NOTES

NOTES

T–CELL DEFICIENCIES GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Impaired function of T lymphocytes due to thymic hypoplasia → deficiency of cell-mediated immunity → high risk of infections ▪ Two main causes of thymic hypoplasia ▫ DiGeorge syndrome (DGS)/22q11.2 deletion syndrome ▫ Ataxia-telangiectasia (AT) syndrome (see Chapter 84 in Volume 1) ▪ Inherited, due to genetic defects ▪ Associated with other congenital abnormalities

SIGNS & SYMPTOMS ▪ Recurrent infections; usually viral ▪ Depend on cause of thymic hypoplasia

DIAGNOSIS LAB RESULTS Blood tests ▪ T cell numbers, function ▪ Calcium levels ▫ Hypocalcemia → DGS, eucalcemia → AT

OTHER DIAGNOSTICS

▪ Genetic testing ▫ Identify genetic defect

TREATMENT MEDICATIONS

▪ Management of symptoms ▫ Antibiotic therapy/prophylaxis for infections

SURGERY

▪ Thymus transplantation

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DIGEORGE SYNDROME (DGS) osms.it/digeorge-syndrome PATHOLOGY & CAUSES ▪ AKA 22q11.2 deletion syndrome ▪ Genetic condition; q11.2 portion of DNA on chromosome 22 deleted → deletion of TBX gene on chromosome 22 → impaired development of pharyngeal pouches 3, 4 → hypoplasia of thymus, inferior parathyroid gland ▫ Deficiency in mature T cells, adaptive immune response: complete thymic aplasia can be fatal in first year of life ▫ Parathyroid hypoplasia → low levels of parathyroid hormone → hypocalcemia ▪ 22q11.2 region encodes genes that affect other organs/tissues → congenital cardiac defects; facial, developmental abnormalities; behavioral, mental health conditions

SIGNS & SYMPTOMS ▪ Characteristic facial appearance: long face, small teeth, broad nose ▪ Developmental abnormalities (e.g. cleft palate) ▪ Cardiac defects (e.g. truncus arteriosus, tetralogy of Fallot) ▪ Thymus gland abnormalities → underdevelopment of cellular immune system → susceptibility to recurrent sinopulmonary infections/severe combined immunodeficiency (SCID) ▪ Learning difficulties/mental health conditions (e.g. schizophrenia) ▪ Hypoparathyroidism → hypocalcemia → seizures, tetany, osteoporosis

DIAGNOSIS LAB RESULTS Blood tests ▪ Reduced T cell number, function ▪ Hypocalcemia ▪ Low levels of parathyroid hormone

OTHER DIAGNOSTICS ▪ Genetic testing

TREATMENT MEDICATIONS

▪ Management of symptoms ▫ Antibiotics for infections

SURGERY

▪ Thymus transplantation

OTHER INTERVENTIONS

▪ Vitamin D, calcium supplements for hypocalcemia

Figure 35.1 A child with DiGeorge syndrome.

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NOTES

NOTES

TYPE I HYPERSENSITIVITY REACTIONS

GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Exaggerated immune reaction mediated by IgE antibodies (atopy) triggered by harmless antigen (allergens) Sensitization phase ▪ Allergen → antigen presenting cells (APCs) → B-cell, Th2 cells assist in IgE production → bind via Fc region to mast cells → mast cells sensitized Re-exposure/effector phase ▪ Cytotropic/IgE receptor binding; allergens bind to Fab region of IgE on sensitized cells → activates mediator release ▪ Early phase reactions (within minutes) ▫ Primarily mast cell-release of preformed mediators (e.g. histamine, proteases, chemotactants); causes vasodilation, capillary leak, increased secretions, bronchial smooth muscle contraction ▪ Late phase reactions (8–12 hours) ▫ Mediators require synthesis (e.g. interleukins 4, 5, 10; leukotrienes); increases early downstream effects, prolongs inflammatory response Common Type I hypersensitivity reactions ▪ Ingested allergens ▫ Foods, dander, bee stings, mold, drugs/ medications, pollen ▪ Other allergens ▫ Latex, lotions, soaps, penicillin ▪ Atopic eczema ▪ Allergic urticaria ▪ Allergic rhinitis (Hay fever) ▪ Allergic asthma ▪ Anaphylaxis ▪ Eosinophilic esophagitis

CAUSES

▪ Causes of hyper/overactive re-exposure/ effector phase unclear; environmental exposure (esp. in early childhood), genetic factors ▪ “Atopic march”: multiple atopic (IgEmediated) diseases occur over lifetime

SIGNS & SYMPTOMS ▪ Range from mild, local (e.g. urticaria, rhinorrhea, itching) to life-threatening anaphylactic reaction (e.g. cardiac arrhythmia, shock, bronchospasm, laryngeal obstruction)

DIAGNOSIS LAB RESULTS

▪ Skin allergen testing, variable sensitivities ▪ Eosinophilia

OTHER DIAGNOSTICS

▪ History of symptoms, frequency, triggers

TREATMENT MEDICATIONS

▪ Symptom-based ▫ Antihistamines (e.g. H1 blockers), corticosteroids, epinephrine

OTHER INTERVENTIONS

▪ Hypo/de-sensitization ▫ Escalating doses of allergen subcutaneously injected over course of years; variable effectiveness, more severe reactions less responsive

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ACUTE RHINITIS osms.it/acute-rhinitis PATHOLOGY & CAUSES ▪ IgE-mediated immune response upon re-exposure of airborne allergens to eyes, nose ▪ AKA hay fever ▪ Local mast cells of eye, nose mucosa degranulate, release immediate mediators (e.g. histamine)

CAUSES

▪ Hay, pollen (seasonal due to flowering plants), dust, animal hair, mold spores

SIGNS & SYMPTOMS ▪ Due to increased fluid in eyes, nasal cavity ▫ Conjunctival injection, eyelid edema; sneezing; rhinorrhea, nasal obstruction; edematous bluish-red nasal turbinates

DIAGNOSIS LAB RESULTS

▪ Skin allergen tests ▫ Subdermal introduction of defined amount of allergen to volar surface of forearm; observe for “wheal-and-flare” reaction at specific site

OTHER DIAGNOSTICS

▪ Clinical presentation ▫ History of symptoms, frequency, triggering events

TREATMENT MEDICATIONS

▪ Oral antihistamine (e.g. H1 blockers) ▪ Nasal corticosteroids

OTHER INTERVENTIONS

▪ Nasal irrigation ▪ Environmental control (to avoid antigen) ▪ When severe, hypo/desensitization to allergen

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Chapter 36 Type I Hypersensitivity Reactions

ANAPHYLAXIS osms.it/anaphylaxis PATHOLOGY & CAUSES ▪ Generalized, life-threatening allergic response ▪ Systemic release of large quantities of immune mediators; symptoms most severe at site of greatest mediator concentration Immune mediators ▪ Histamine (ubiquitous systemic concentration) ▫ Vasodilator, immune system modulator ▫ H1 receptor → tachycardia, pruritus, rhinorrhea, bronchospasm ▫ H2 receptor → flushing, hypotension ▪ Tryptase (high skin concentration) ▫ Activate complement, coagulation pathways, kallikrein–kinin systems ▫ Angioedema, hypotension, disseminated intravascular coagulation (DIC) ▪ Leukotriene C4, prostaglandin D2 (in high lung concentration) ▫ Bronchoconstriction, increased mucus secretion

CAUSES

▪ Drugs (e.g. beta-lactam antibiotics, insulin) ▪ Foods (e.g. nuts, eggs, seafood) ▪ Proteins (e.g. blood transfusions, tetanus antitoxin) ▪ Latex

SIGNS & SYMPTOMS ▪ Generalized, mild-moderate ▫ Flushing, feeling of doom, tachycardia, urticaria, incontinence ▪ Generalized, severe ▫ Syncope, shock, hypoxia, cardiorespiratory collapse

DIAGNOSIS OTHER DIAGNOSTICS

▪ Clinical presentation ▫ Symptoms indicate allergic reaction

TREATMENT MEDICATIONS

▪ Immediate, necessary ▫ Epinephrine intravenously (IV) (1:10,000)/intramuscularly (IM) (1:1,000), repeat every 30 minutes with potential epinephrine infusion after bolus(es) ▪ Adjunct therapy ▫ H1, H2 receptor blockers, IV corticosteroids ▪ IV fluids, O2 supplementation ▪ Critical care ▫ Intubation, vasopressors if necessary

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FOOD ALLERGY osms.it/food-allergy PATHOLOGY & CAUSES ▪ Adverse food reaction; immune response to ingested antigens ▪ Distinct from non-immunologic adverse food reactions ▫ Enzyme deficiency (e.g. lactase), toxin ingestions (e.g. staphylococcal toxin), intolerance (e.g. caffeine)

TYPES IgE-mediated ▪ Rapid onset (minutes to couple hours after ingestion); immune mediator release from tissue mast cells, circulating basophils; common allergens include peanuts, soy, milk, wheat, fish Non-IgE mediated ▪ Symptoms subacute to chronic in nature; leukocytosis; local, lymphocytic destruction of gastrointestinal (GI) tissue; celiac disease, food protein-induced enterocolitis syndrome (FPIES) Mixed IgE/non-IgE-mediated ▪ Variable immune response, acute responses involving IgE-mediation, others favoring leukocytes (e.g. eosinophils, lymphocytes); atopic dermatitis, eosinophilic esophagitis, eosinophilic gastroenteritis

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SIGNS & SYMPTOMS ▪ Dermatologic (e.g. pruritus, erythema, urticaria), GI (e.g. nausea, vomiting, abdominal pain, diarrhea), anaphylactic (e.g.cardiac/respiratory reactions) ▪ Non-IgE-mediated food allergies ▫ Nonspecific, subacute/chronic GI symptoms; distinct dermatologic vesicular, papular eruptions; dermatitis herpetiformis in celiac disease

DIAGNOSIS LAB RESULTS

▪ Skin allergen testing

OTHER DIAGNOSTICS ▪ Food elimination trials

TREATMENT MEDICATIONS

▪ Antihistamines ▫ May be of little value unless urticaria, angioedema present

OTHER INTERVENTIONS

▪ Elimination of offending food from diet; mild disease may remit with time

NOTES

NOTES

TYPE II HYPERSENSITIVITY REACTIONS

GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Antibody-mediated hypersensitivity reactions; tissue-specific, broad spectrum of disease manifestations ▪ Disorder due to self-reactive B cells that produce antibodies (e.g. IgM, IgG) that bind antigens on host cells, form antigenantibody complex at tissue site ▫ Defective central tolerance → autoantibodies against self/intrinsic antigens ▫ Embedded outside/extrinsic antigens into normal cell surface alter cell antigenicity Common Type II hypersensitivity reactions ▪ Hemolytic disease of the newborn ▪ Autoimmune hemolytic anemia ▪ Immune thrombocytopenic purpura ▪ Bullous pemphigoid ▪ Pemphigus vulgaris ▪ Rheumatic fever ▪ Goodpasture syndrome ▪ Guillain–Barré syndrome ▪ Graves’ disease ▪ Myasthenia gravis ▪ Pernicious anemia

TYPES

▪ Four pathologic mechanisms

Activation of complement system ▪ IgM/IgG antibody binds fixed antigen on cell → C1 binds Fc portion of IgM/IgG → classical pathway C2–C9 cleavage/ activation → C3a–C5a anaphylatoxin production ▫ Chemoattract promote degranulation of neutrophils, basophils, mast cells

(granules of lysosomal contents of leukocytes fuse, degrade target cell → cell death; mast cell degranulation contents include histamine → promote further immune cell response) ▫ Promote macrophage, monocytes pro-inflammatory cytokine release; interleukin (IL1), 6 (e.g. Goodpasture’s syndrome, antibodies against Type IV collagen in lung, kidney) ▪ Membrane attack complex (MAC) formation (C5b–C9) → insertion into, disruption of cell membrane → impaired osmotic gradient → cell lysis (e.g. ABO mismatch in transfusion reaction, hyperacute transplantation reaction) Opsonization, phagocytosis ▪ Antigen-opsonin C3b/IgG complex circulate ▫ To spleen → fixed macrophages recognize IgG-bound antigens → phagocytosis ▫ To liver → Kupffer cells recognize C3b-bound antigens → phagocytosis (Autoimmune hemolytic anemia (AIHA), ABO, Rh-hemolytic disease of newborn) Antibody-dependent cell-mediated cytotoxicity (ADCC) ▪ Natural killer cells bind Fc portion of antibody-antigen complex → release perforins, granzymes, granulysin → apoptotic cell death Antibody-mediated cellular dysfunction (only non-cytotoxic mechanism) ▪ Physical presence of antibody at receptor binding site impairs physiologic function ▫ Activate: thyroid hormone receptor in Graves’ disease ▫ Inhibit: acetylcholine receptor in Myasthenia gravis (MG)

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SIGNS & SYMPTOMS ▪ Acute hemolytic transfusion reactions ▫ Fevers, chills; nausea/vomiting; flank, chest pain; dyspnea ▪ Autoimmune hemolytic anemia ▫ Fatigue, jaundice, hepatosplenomegaly (HSM) ▪ Bullous pemphigoid ▫ Abdominal, groin, extremity blistering ▪ Erythroblastosis fetalis ▫ Kernicterus, death in fetus ▪ Goodpasture syndrome ▫ Dyspnea, hemoptysis, hematuria ▪ Graves’ disease ▫ Tremor, insomnia, irritability, weight loss, tachycardia ▪ Guillain–Barre syndrome ▫ Ascending paralysis ▪ Idiopathic thrombocytopenic purpura ▫ Petechiae, skin ecchymoses ▪ Myasthenia gravis ▫ Weakness, ptosis, diplopia, dysphagia ▪ Pemphigus vulgaris ▫ Blistering of oral mucosa ▪ Pernicious anemia ▫ Fatigue, glossitis, B12 deficiency sequelae ▪ Rheumatic fever ▫ Migratory polyarthritis, fever, +/- cardiac involvement

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DIAGNOSIS LAB RESULTS

▪ Coombs testing ▫ Direct: detects Fc region of bound antibodies on red blood cells (RBCs) (e.g. ABO incompatibility) ▫ Indirect: detects circulating serum antibodies against known antigen (e.g. anti-D) ▪ RBC antigen testing ▪ Immunohistochemistry (IHC) ▪ Diffuse radioactive iodine (RAI) uptake

OTHER DIAGNOSTICS

▪ Clinical presentation of disease-specific symptoms

TREATMENT MEDICATIONS

▪ Corticosteroids ▪ Severe reactions may require plasmapheresis/immunosuppressants

Chapter 37 Type II Hypersensitivity Reactions

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NOTES

NOTES

TYPE III HYPERSENSITIVITY REACTIONS

GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Hypersensitivity reaction mediated by immune complexes ▫ Antibodies (IgG) binding to soluble antigens → antigens not bound to cell surfaces ▪ Formation of immune complexes → complement activation (esp. C3a, C4a, C5a) ▫ Anaphylatoxins → increase vascular permeability → edema ▫ Chemokins → recruitment of phagocytes, neutrophils, mast cells → degranulation of lysosomal enzymes, reactive oxygen species → inflammation, tissue necrosis (fibrinoid necrosis) ▫ May also elicit systemic inflammation ▪ Common sites of immune complex accumulation ▫ Blood vessel walls → vasculitis ▫ Kidneys → glomerulonephritis ▫ Joints → arthritis ▪ If triggered by single exposure to antigen, resolves after catabolism of immune complexes → acute serum sickness ▪ If repeated/prolonged exposure → chronic serum sickness ▫ Systemic erythematosus lupus (SLE), polyarteritis nodosa, poststreptococcal glomerulonephritis, reactive arthritis Common Type III hypersensitivity reactions ▪ Henoch–Schönlein purpura ▪ Hypersensitivity vasculitis ▪ Reactive arthritis ▪ Farmer’s lung ▪ Post-streptococcal glomerulonephritis ▪ Serum sickness ▪ Arthus reaction

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▪ Systemic lupus erythematosus ▪ Subacute bacterial endocarditis ▪ Rheumatoid arthritis

SIGNS & SYMPTOMS ▪ ▪ ▪ ▪ ▪ ▪

Fever, fatigue, weight loss Skin: rash, urticaria Kidney: proteinuria Joints: arthralgias Mucosa: ulcers Serosa: pleuritis, pericarditis

DIAGNOSIS LAB RESULTS

▪ Antibody testing ▪ Histopathology to observe fibrinoid necrosis ▫ Necrosis of vessel wall with infiltration of neutrophils, eosinophils, complement, plasma proteins; staining pattern reminiscent of fibrin

Figure 38.1 A vessel displaying fibrinoid necrosis in Churg–Strauss syndrome, which is a type III hypersensitivity reaction.

Chapter 38 Type III Hypersensitivity Reactions ▪ Immunofluorescence microscopy to visualize immune complexes ▪ Complement levels in blood ▫ Track disease progression

TREATMENT MEDICATIONS

▪ SLE ▫ Administration of anti-inflammatory, corticosteroids, cytotoxic medications to decrease inflammatory activity

SERUM SICKNESS osms.it/serum-sickness PATHOLOGY & CAUSES ▪ Systemic Type III hypersensitivity reaction against foreign antibodies in serum ▪ Exposure to foreign serum → triggers B cells to become plasma cells, produce IgG antibodies against foreign antibodies → immune complexes formed, deposited in basement membrane → complement activation, immune cells recruitment → lysosomal enzymes, reactive oxygen species, cytokines produced → local, systemic inflammatory response ▪ Initial exposure ▫ 4–10 days to develop reaction ▪ Second exposure ▫ Faster, more potent reaction ▪ Resolves after withdrawal of culprit agent

CAUSES

▪ Medications (e.g. cefaclor, anti-seizure medications); infections (e.g., hepatitis B); vaccines

SIGNS & SYMPTOMS ▪ Allergy-like response ▪ Present within 1–2 weeks if initial exposure, 12–36 hours if second exposure ▫ General malaise, erythema, itching, arthralgia ▪ Fever > 38.5°C/101.3°F, rash, lymphadenopathy, polyarthritis, proteinuria

DIAGNOSIS LAB RESULTS

▪ Complete blood count (CBC) ▫ Neutropenia, increase in lymphocytes ▪ Elevation of erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) ▪ Urinalysis ▫ Mild proteinuria (50%)

OTHER DIAGNOSTICS

▪ Clinical presentation; suspected when allergy-like symptoms present after administration of potential responsible agent (e.g. antivenom serum after bitten by snake) ▪ Testing to exclude infections (e.g. hepatitis B)

TREATMENT MEDICATIONS

▪ Relieve symptoms with antihistamines, analgesics ▪ Glucocorticoids for individuals with severe clinical features (e.g. very high fever, severe arthritis, extensive rashes)

OTHER INTERVENTIONS

▪ Discontinue, avoid offending agent

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NOTES

NOTES

TYPE IV HYPERSENSITIVITY REACTIONS

GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Delayed, T cell-mediated (antibodyindependent) hypersensitivity reaction ▪ 24–72 hour delayed nature due to stepwise sensitization-response progression ▫ Antigen presentation by antigen presenting cells (APCs) → naive T-cells recognition → T-cells, macrophages migration, response Role of CD4+ (helper) T cells, macrophages ▪ CD4+ (helper) T cells ▫ APC displays antigen on MHC II receptor → naive CD4+ T cell binds MHC II via T cell receptor, CD4 coreceptor → T cell expresses CD28 → binds APC B7 → cobinding stimulates APC cytokine secretion ▫ Interleukin (IL) 12 produced → TH1 cell maturation → TH1 secrete IL-2, IFN𝛄 → proliferation of TH1 response, macrophage recruitment, activation ▫ IL-6, TGF-beta produced → TH17 cell maturation → TH17 secrete IL-17 → recruit neutrophils ▪ Macrophages ▫ Secrete TNF-alpha, IL-1, IL-6 → promote inflammation, leaky endothelium → edema, fever; secrete lysosomal enzymes, complement, and reactive oxygen species (ROS) → tissue damage ▪ Pathophysiology in inflammatory bowel disease (IBD), multiple sclerosis (MS), rheumatoid arthritis (RA) Role of CD8+ (AKA cytotoxic, effector, killer) T cells ▪ Altered host cell MHC I signal → CD8+ T cell receptor → activate CD8+ T cells

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▪ Secrete perforins, granzymes → create membrane pores, induce cellular apoptosis ▪ Pathophysiology in Type I diabetes mellitus (DM), against islet cells; Hashimoto’s thyroiditis, against epithelial cells; immune response to some tumor cells Common Type IV hypersensitivity reactions ▪ Allergic contact dermatitis ▪ Mantoux test ▪ Diabetes mellitus type I ▪ Hashimoto’s thyroiditis ▪ Multiple sclerosis ▪ Coeliac disease ▪ Giant-cell arteritis ▪ Postorgasmic illness syndrome ▪ Reactive arthritis ▪ GVHD ▫ Transfusion-associated graft versus host disease

TYPES Contact hypersensitivity ▪ Molecules covalently alter major histocompatibility complex (MHC) I receptors to neo-self antigens; nickel, urushiol (poison ivy molecule) Chronic, delayed hypersensitivity ▪ Agents unusually resistant to elimination by immune system; tuberculosis (TB), leprosy, silicosis, sarcoidosis

COMPLICATIONS

▪ Granuloma formation in chronic, delayedtype hypersensitivity reactions ▪ Due to hyperactive macrophages, surrounding inflammatory reaction “walls off” offending agent (e.g. sarcoidosis, tuberculosis, silicosis)

Chapter 39 Type IV Hypersensitivity Reactions

SIGNS & SYMPTOMS ▪ Local inflammatory reaction → erythema, warmth, edema, fever ▪ Sequelae of organ-specific cell destruction ▫ Islet cell destruction in pancreas → insulin-deficient (e.g. lethargy, seizure, coma) ▪ Chronic inflammation → granuloma formation → organ failure

DIAGNOSIS OTHER DIAGNOSTICS

▪ Exposure history of molecule/agent at site of symptoms ▪ Contact hypersensitivity ▫ Patch test (adhesive-mounted patches with miniscule amounts of allergen imbued in tape) ▫ Evaluate in 48–96 hours for local skin reaction

▪ Tuberculosis ▫ Tuberculin skin test (TST)/purified protein derivative (PPD) test ▫ Intradermal injection of tuberculin protein → pre-sensitized T-cells react to antigen → measure induration size at 48–72 hours ▫ Positive test (induration size) inversely related to TB exposure risk of individual

TREATMENT MEDICATIONS

▪ Corticosteroids for inflammatory control ▫ Systemic for severe, generalized reactions; otherwise, site-specific (e.g. topical for contact dermatitis; inhaled for hypersensitivity pneumonitis)

GRAFT-VERSUS-HOST DISEASE (GvHD) osms.it/graft-versus-host-disease PATHOLOGY & CAUSES ▪ Type of transplant rejection caused by immunocompetent, donor T cells reacting against recipient MHC I “foreign” antigens ▫ Variable time course of symptoms ▫ Common targets: skin, liver, intestine epithelial tissue ▪ Donor CD4+ T cell → recognize recipient MHC II as foreign → activated donor CD4+ T cells → cytokine release → recipient macrophage, CD4+ recruitment → exacerbate cytokine response ▫ Tumor necrosis factor (TNF) alpha: possible cause of “metabolic wasting”

▪ Donor CD8+ T cell → recognize recipient MHC I as foreign → activated CD8+ T cells → Fas, perforin-mediated cytotoxicity ▫ Majority of tissue destruction occurs via CD8+ T cells ▪ Similar graft-versus leukemia reaction (GvL) beneficial in individuals with leukemia due to ability to help eliminate recipient’s hematopoietic cancer cell line

RISK FACTORS

▪ Liver, bone marrow transplants (rich in lymphocytes) ▪ T cell immunodeficient individuals, newborns

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SIGNS & SYMPTOMS ▪ Metabolic wasting/failure to thrive, maculopapular rash, jaundice, bloody diarrhea, hepatosplenomegaly

DIAGNOSIS LAB RESULTS

▪ Histological analysis of easily biopsied tissue in individual with history of transplantation ▫ Liver, skin, gastrointestinal (GI) tract; most helpful in chronic, indolent disease

OTHER DIAGNOSTICS

▪ Clinical presentation ▫ Constellation of symptoms

TREATMENT MEDICATIONS

▪ Prophylaxis (e.g. cyclosporine, methotrexate) ▪ Site-directed corticosteroids ▫ Topical for primary skin manifestation; non-absorbable (e.g. budesonide, beclomethasone) for GI involvement

Figure 39.1 A CT scan in the coronal plane of the abdomen of an individual with graftversus-host disease. The gastrointestinal tract, including the stomach and small bowel, is grossly edematous.

OTHER INTERVENTIONS Prevention ▪ Proper donor, recipient human leukocyte antigen (HLA), MHC, minor histocompatibility (MiHA) matching; irradiation of transfused blood products Figure 39.1 A colonic biopsy taken from an individual with graft-versus-host disease. There is florid cryptitis (neutrophils infiltrating the crypt wall) and apoptotic debris at the crypt bases.

230 OSMOSIS.ORG

NOTES

NOTES

AMINO ACID METABOLISM DISORDERS

GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Inherited disorders of amino acid metabolism, transportation, excretion ▪ Impaired enzymes → reactant accumulation → toxicity ▪ Inherited autosomal/X-linked recessive

SIGNS & SYMPTOMS ▪ See individual disorders

DIAGNOSIS LAB RESULTS

▪ Amino acids levels in blood, urine

CAUSES

▪ Gene mutation

TREATMENT

RISK FACTORS

▪ Infants with central nervous system (CNS) disorders most commonly affected

OTHER INTERVENTIONS ▪ Modified diet

ALKAPTONURIA osms.it/alkaptonuria PATHOLOGY & CAUSES ▪ Inherited autosomal recessive disorder of tyrosine, phenylalanine metabolism with build-up of degradation product (homogentisic acid) in connective tissues ▪ Homogentisic acid transforms into polymer → deposition of polymer into collagen fibers of connective tissues (e.g. cartilage) → ochronosis

CAUSES

▪ Mutation of homogentisic oxidase gene (HDG) → deficit of homogentisate oxidase → ↑ homogentisic acid

COMPLICATIONS

▪ Coronary artery disease ▪ Arthritis ▪ Renal stones

SIGNS & SYMPTOMS ▪ Usually asymptomatic in childhood/ adolescence ▪ In infants, urine in diapers darkens due to oxidation of homogentisic acid; “black nappies” ▪ Bluish pigmentation of sclera, ear, etc. ▪ Pain in spine, hip, knee joints

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DIAGNOSIS DIAGNOSTIC IMAGING Radiology ▪ Calcification of multiple intervertebral discs

LAB RESULTS

▪ Dark brown/black color of urine on prolonged air exposition ▪ Chromatography ▫ ↑ homogentisic acid

TREATMENT MEDICATIONS

▪ Herbicide nitisinone → inhibits enzyme which converts tyrosine to homogentisic acid → ↓ homogentisic acid

OTHER INTERVENTIONS

▪ Tyrosine, phenylalanine restriction → ↓ homogentisic acid excretion

Figure 40.2 Alkaptonuria leads to the accumulation of homogentisic acid giving the clinical appearance known as ochronosis.

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Figure 40.1 An X-ray image demonstrating calcification of the intervertebral discs in an individual with ochronosis.

Chapter 40 Amino Acid Metabolism Disorders

CYSTINURIA osms.it/cystinuria PATHOLOGY & CAUSES ▪ Autosomal recessive disorder; high levels of cystine in urine → kidney, ureter, bladder stones

CAUSES

▪ Mutation of SLC3A1, SLC7A9 gene → defect of intestinal, renal amino acid transporter affecting positively charged amino acids (e.g. cysteine, arginine, ornithine)

COMPLICATIONS

▪ Hydronephrosis, pyelonephritis, frequent urinary tract infections (UTIs)

SIGNS & SYMPTOMS ▪ May be asymptomatic ▪ Flank pain, hematuria

DIAGNOSIS LAB RESULTS

▪ Sodium cyanide-nitroprusside test ▫ Determination of cystine concentration ▪ Urinalysis ▫ Pathognomonic hexagonal crystals ▪ Stone analysis

TREATMENT MEDICATIONS

▪ Chelation therapy with penicillamine ▫ Forming soluble disulfide complex

OTHER INTERVENTIONS

▪ Sufficient hydration; urine alkalization ▪ Protein, sodium restriction ▪ Formed stones ▫ Renal: extracorporeal shock wave lithotripsy (ESWL) ▫ Ureteric: intracorporeal lithotripsy ▫ Bladder: cystolitholapaxy

HARTNUP DISEASE osms.it/hartnup-disease PATHOLOGY & CAUSES ▪ Inherited autosomal recessive metabolic disorder affecting neutral amino acids (esp. tryptophan)

CAUSES

▪ Intestinal, renal deficiency of neutral amino acid transporters → ↓ absorption from

intestines, ↓ reabsorption from kidneys → less amino acids available to build proteins

COMPLICATIONS

▪ Drop of tryptophan to niacin conversion → decrease of nicotinamide, NAD+ → pellagra-like symptomatology ▪ Hyper/hypopigmentation in repeated sunlight exposure

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SIGNS & SYMPTOMS Pellagra-like symptoms Photosensitivity Diarrhea Nervous system symptoms (e.g. ataxia, tremor, headaches; intellectual disability, mental abnormalities) ▪ Ocular manifestations (e.g. nystagmus, double vision) ▪ ▪ ▪ ▪

DIAGNOSIS LAB RESULTS

▪ Urine chromatography ▫ Increased levels of neutral amino acids (e.g. aminoaciduria)

TREATMENT OTHER INTERVENTIONS

▪ High-protein diet, nicotinic acid supplements, sunlight protection

HOMOCYSTINURIA osms.it/homocystinuria PATHOLOGY & CAUSES ▪ Autosomal recessive disorder; high levels of homocysteine in blood, urine due to impaired methionine metabolism

TYPES

▪ Type I ▫ Deficiency of cystathionine synthase ▪ Type II ▫ Deficiency of methionine synthase ▪ Type III ▫ Cystathionine synthase impairment → decreased affinity for pyridoxal phosphate

COMPLICATIONS

▪ Increased risk for thrombotic strokes

SIGNS & SYMPTOMS ▪ Ocular anomalies (e.g. myopia, ectopia lentis) ▪ Marfan-like presentation ▪ Intellectual disability ▪ Cardiovascular defects ▪ Osteoporosis

234 OSMOSIS.ORG

DIAGNOSIS DIAGNOSTIC IMAGING CT scan, MRI ▪ Large-vessel/lacunar stroke

LAB RESULTS

▪ Blood, urine quantitative test for homocystinuria ▪ Cyanide nitroprusside test ▫ Urine screening test for amino acids containing sulfur ▪ Measurement of cystathionine synthase activity in cultured fibroblasts

TREATMENT OTHER INTERVENTIONS

▪ Vitamin B6, B12, folate acid supplements in cystathionine synthase deficiency ▪ Methionine in methionine synthase deficiency ▪ Cysteine, high doses of vitamin B6 in decreased affinity of cystathionine synthase for pyridoxal phosphate

Chapter 40 Amino Acid Metabolism Disorders

MAPLE SYRUP URINE DISEASE osms.it/maple-syrup-urine-disease PATHOLOGY & CAUSES ▪ Disease caused by impaired metabolism of branched amino acids (e.g. isoleucine, leucine, valine); AKA branched-chain ketoaciduria ▪ Autosomal recessive inheritance ▪ Impaired metabolism → accumulation of byproducts with toxicity in brain, other organs

TYPES Classic MSUD ▪ Most common; occurs soon after birth Non-classic MSUD ▪ Later onset, less severe symptoms

CAUSES

▪ Mutation of genes BCKDHA, BCKDHB, DBT → dysfunction of enzyme complex

COMPLICATIONS

DIAGNOSIS LAB RESULTS

▪ Plasma amino acid test ▫ Alloisoleucine detection ▪ Prenatal diagnostic by measuring enzyme activity in cultured amniocytes

OTHER DIAGNOSTICS

▪ Genetic testing ▫ BCKDHA, BCKDHB, DBT ▪ Physical examination, newborn screening

TREATMENT SURGERY

▪ Liver transplant

OTHER INTERVENTIONS

▪ Regular metabolism check ▪ Regulation of isoleucine, leucine, valine intake

▪ Possible permanent brain damage ▪ Fatal if not treated in first five months

SIGNS & SYMPTOMS ▪ Sweet (maple syrup-like) smelling urine Classic MSUD ▪ Healthy-looking infants at birth, quick deterioration; feeding difficulties, failure to thrive (FTT), vomiting, seizures Non-classic MSUD ▪ Vomiting, diarrhea, rapid neurological decline, ataxia, seizures, coma

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ORNITHINE TRANSCARBAMYLASE DEFICIENCY osms.it/OTC-deficiency PATHOLOGY & CAUSES

DIAGNOSIS

▪ X-linked disorder affecting ornithine transcarbamylase enzyme ▪ Disorder of urea cycle → accumulation nitrogen in form of ammonia ▪ Defect of ornithine transcarbamylase enzyme → carbamoyl phosphate accumulation → conversion of carbamoyl phosphate into orotic acid ▪ Presents often in neonatal form, may present later

LAB RESULTS

RISK FACTORS

▪ Ornithine transcarbamylase only expresses in liver; liver biopsy needed to confirm diagnosis ▪ Newborn screening

▪ Individuals who are biologically male fully affected due to X-recessive transmission ▪ Individuals who are biologically female usually asymptomatic

SIGNS & SYMPTOMS ▪ Neonatal form ▫ Lethargy, irritability, poor feeding, seizures, impaired thermoregulation; hyperventilation → respiratory alkalosis; cerebral edema, possible progression into coma, death ▪ Later presentation ▫ Headaches, nausea, vomiting, psychiatry disorders

236 OSMOSIS.ORG

▪ Plasma, urine amino acid analysis ▫ Elevated arterial/venous ammonia (hallmark finding), orotic acid, glutamine ▫ Decreased blood urea nitrogen (BUN), citrulline concentrations ▪ Urine organic acid analysis ▫ Orotic acid in urine

OTHER DIAGNOSTICS

TREATMENT SURGERY

▪ Liver transplant

OTHER INTERVENTIONS

▪ Low-protein diet ▪ Nitrogen scavenging agents ▫ Sodium benzoate, arginine

Chapter 40 Amino Acid Metabolism Disorders

PHENYLKETONURIA osms.it/phenylketonuria PATHOLOGY & CAUSES

DIAGNOSIS

▪ Genetic disorder characterized by high levels of phenylalanine ▪ Autosomal recessive inheritance

LAB RESULTS

CAUSES

Chromatography/tandem mass spectrometry ▪ ↑ phenylalanine

▪ PAH gene mutation → hepatic phenylalanine hydroxylase deficiency → defect in metabolism of phenylalanine → activation of alternative pathways → accumulation of phenylalanine, byproducts ▪ Mutation of HPABH4 genes → impairment in synthesis, recycling of tetrahydrobiopterin cofactor (BH4) → impaired function of phenylalanine hydroxylase enzyme

COMPLICATIONS

▪ If untreated ▫ Severe intellectual disability ▪ Seizures ▪ Increased risk of anxiety, inattention, depression, other neuropsychiatric disorders ▪ Phenylalanine embryopathy ▫ Inappropriate diet during pregnancy in individuals with phenylketonuria → elevated levels of phenylalanine concentration in serum → teratogenic effects of phenylalanine passing placenta → newborn with microcephaly, mental disorders, congenital heart defects

SIGNS & SYMPTOMS ▪ Skin, hair pigmentation disorders (lack of melanin pigment) ▪ Eczema ▪ Musty odor

Cranial magnetic resonance spectrometry ▪ Brain phenylalanine levels

Guthrie test ▪ Formerly used; replaced with tandem mass spectrometry Ferric chloride urine test ▪ Rarely used; results may be negative in first months of life

OTHER DIAGNOSTICS ▪ Newborn screening

Figure 40.3 The heelprick test is performed on all newborn babies and screens for phenylketonuria.

TREATMENT MEDICATIONS ▪ Sapropterin

OTHER INTERVENTIONS

▪ Lifelong low-phenylalanine diet with tyrosine supplements ▪ Avoid artificial sweeteners containing phenylalanine (e.g. aspartame)

OSMOSIS.ORG 237

NOTES

NOTES

CARBOHYDRATE METABOLISM DISORDERS

GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Inherited disorders of carbohydrate metabolism (fructose, glucose, galactose) ▪ Determined by exposure to external triggers (e.g. dietary factors) ▪ Disruption in certain metabolic pathways → accumulation of byproducts → systemic alterations, organ failures

SIGNS & SYMPTOMS ▪ See individual disorders

DIAGNOSIS LAB RESULTS

▪ Enzymatic dosage

OTHER DIAGNOSTICS ▪ Genetic testing

TREATMENT OTHER INTERVENTIONS ▪ Avoid triggers

ESSENTIAL FRUCTOSURIA osms.it/essential-fructosuria PATHOLOGY & CAUSES ▪ Benign disease; impaired fructose metabolism → increased excretion in urine

CAUSES

▪ Autosomal recessive mutation in fructokinase, AKA ketohexokinase (KHK) ▫ First enzyme in fructose metabolism ▪ Intake of fructose-rich food/fructose-related sugar (e.g. sucrose, sorbitol) → increase of fructose in blood → excretion of fructose in urine

SIGNS & SYMPTOMS ▪ Asymptomatic

238 OSMOSIS.ORG

DIAGNOSIS LAB RESULTS

▪ Positivity for reducing substances in urine

TREATMENT OTHER INTERVENTIONS ▪ No treatment necessary

Chapter 41 Carbohydrate Metabolism Disorders

GALACTOSEMIA osms.it/galactosemia PATHOLOGY & CAUSES ▪ Disease characterized by altered metabolism of galactose

CAUSES

▪ Autosomal recessive disorder

SIGNS & SYMPTOMS ▪ ▪ ▪ ▪ ▪

FTT Vomiting, diarrhea with lactation Jaundice, hepatomegaly Cataract Intellectual disability, lethargy, speech disorder, altered muscle coordination (ataxia)

Three possible mutations ▪ Galactose-1-phosphate uridyl transferase (GALT) deficiency (most common) ▫ Accumulation of galactose-1-phosphate + alternative metabolic pathway activation → accumulation of galactose metabolites (galactitol, galactonate) ▪ Galactokinase deficiency (uncommon) ▫ Less severe, often asymptomatic ▪ Uridine diphosphate (UDP) galactose-4epimerase deficiency (uncommon)

LAB RESULTS

COMPLICATIONS

OTHER INTERVENTIONS

▪ Metabolites accumulate in ▫ Eyes: increasing osmotic pressure → water attraction → opacification of lens (cataract) ▫ Liver: fatty alteration, cirrhosis ▫ Brain: cell damage, edema, gliosis ▫ Kidney: prevent amino acid reabsorption → aminoaciduria ▪ Altered neutrophil activity → increased risk of sepsis from E.coli ▪ Gonadal failure, hemolysis, coagulopathy

DIAGNOSIS ▪ Routinely screened in newborns ▫ Dosage of enzymes involved in galactose metabolism

TREATMENT ▪ Elimination of galactose from diet

OSMOSIS.ORG 239

HEREDITARY FRUCTOSE INTOLERANCE osms.it/hereditary-fructose-intolerance PATHOLOGY & CAUSES ▪ Disease characterized by alteration of fructose metabolism

CAUSES

▪ Autosomal recessive mutation in liver aldolase (aldolase B) ▪ Aldolase B deficiency → fructose 1-phosphate buildup → ▫ Local fructose toxicity → liver cell death ▫ Hypoglycemia ▫ Adenosine triphosphate (ATP), phosphate depletion → inhibition of protein synthesis → hepatic, renal damage

SIGNS & SYMPTOMS ▪ Avoidance of foods containing fructose (e.g. fruit, juice) ▪ Acute ingestion of fructose/compounds which contain fructose (e.g. sucrose, sorbitol) → nausea, vomiting; restlessness; pallor; sweating, trembling; lethargy, apathy; convulsions; coma ▪ Repeated ingestion of fructose → failure to thrive (FTT); liver disease (e.g. jaundice, hepatomegaly); kidney disease

240 OSMOSIS.ORG

DIAGNOSIS OTHER DIAGNOSTICS

▪ Nutritional history, clinical presentation ▪ Genetic testing

TREATMENT OTHER INTERVENTIONS

▪ Elimination of fructose from diet

Chapter 2 Acyanotic Defects

NOTES

CHEMICAL & DRUG TOXICITY

GENERALLY, WHAT IS IT? PATHOLOGY & CAUSES ▪ Variety of disorders caused by excessive exposure to harmful substances ▪ Adverse effects of exposure ▫ Direct damage to DNA, disruption of metabolic processes, organ dysfunction ▪ Excessive exposure to offending agent ▫ Intentional/unintentional, acute/chronic

SIGNS & SYMPTOMS ▪ See individual disorders

DIAGNOSIS ▪ See individual disorders

TREATMENT MEDICATIONS

▪ Administer available antidote

OTHER INTERVENTIONS

▪ Removal of offending agent ▪ Address comorbidities, complications

ACUTE RADIATION SYNDROME (ARS) osms.it/acute-radiation-syndrome PATHOLOGY & CAUSES ▪ Group of organ system toxicities caused by excessive exposure to ionizing radiation of whole body/significant part of body ▪ Ionizing radiation ▫ Composed of particles, short electromagnetic waves with potential to damage biological tissues; displaces electrons from orbits → creates unstable atoms → ionization occurs as free electrons collide with other atoms ▫ Causes damage to tissues by direct impact on DNA, proteins, cell membrane lipids, generating free radicals; rapidly dividing cells most vulnerable due to

DNA damage; mutagenic, carcinogenic, teratogenic effects Types of ionizing radiation ▪ X-rays, gamma rays ▫ Medical, industrial, military applications (e.g. medical imaging, radiosurgery) ▪ Alpha particles ▫ Unable to penetrate skin, harmful if ingested/inhaled (e.g. plutonium-236, uranium-238) ▪ Beta particles ▫ Penetrate subcutaneous tissues, also harmful if ingested/inhaled (e.g. strontium-90, cesium-137)

OSMOSIS.ORG 241

Measurement ▪ Radiation dose: measured in grays (Gy) ▫ Amount of energy deposited into mass of tissue; 1Gy = 1 joule of absorbed energy per kilogram of biological matter ▪ Effective dose: measured in sieverts (Sv) ▫ Type of radiation + variable tissue sensitivity; adjusts relative biologic effect of different radiation types on different tissues (e.g. 1Gy of alpha radiation more dangerous than 1Gy of gamma radiation) ▪ Nuclear medicine procedures: mSv; 1mSv = 1mGy ▪ Typical threshold dose for whole-body/ significant partial-body irradiation ▫ ≥ 1Gy delivered at relatively high dose rate

STAGING

Four organ-system toxicities ▪ Neurovascular/cerebrovascular ▫ Caused by localized central nervous system (CNS) changes ▪ Gastrointestinal (GI) ▫ Caused by loss of intestinal crypt cells, breakdown of mucosal barrier, loss of epithelium ▪ Hematopoietic ▫ Caused by impairment of mitotically active hematopoietic precursors ▪ Cutaneous ▫ Caused by damage to epidermis, dermis, hair follicles, subcutaneous tissues

▪ Malnutrition, cognitive impairment, hemorrhage, permanent skin/hair loss, malignancies, infertility, congenital malformations, radiation pneumonitis, multiorgan failure, high mortality

RISK FACTORS

▪ Occupational exposure (e.g. medical imaging technicians) ▫ Especially with insufficient shielding ▪ Injurious incident (e.g. nuclear power plant, transportation, overtreatment during medical therapy) ▪ Detonation of nuclear bomb/radiological dispersal device (dirty bomb) ▪ ↑ dose, rate of dose; ↓ distance from radiation source, type of radiation ▪ Individuals < 12 years , > 60 more sensitive to radiation

242 OSMOSIS.ORG

▪ Prodromal ▫ 0–2 days post-exposure; fever, tachycardia, nausea, vomiting, headache, fatigue ▪ Latent phase ▫ 2–20 days post-exposure; partial functionality ▪ Manifest illness ▫ 21–60 days post-exposure; progression to organ-system syndromes ▪ Recovery/death ▫ Death may occur days after exposure to high amounts of radiation/ weeks, months after low exposure; death inevitable if doses > 10–12Gy

COMPLICATIONS

SIGNS & SYMPTOMS ▪ Neurovascular/cerebrovascular ▫ Meningeal inflammation, cerebral edema → ↑ intracranial pressure, hemorrhage ▪ GI ▫ Abdominal cramping, pain; loose stools, vomiting → fluid, electrolyte imbalance; bleeding → anemia; bowel ulceration, necrosis, perforation ▪ Hematopoietic ▫ Pancytopenia; bone marrow hypoplasia, aplasia ▪ Cutaneous ▫ Erythema; edema; dry, moist desquamation; ulceration (subcutaneous tissue, muscle, bone); blisters, bullae

Chapter 42 Chemical & Drug Toxicity

DIAGNOSIS DIAGNOSTIC IMAGING CT scan ▪ GI ▫ Segmental inflammation, bowel thickening, fibrosis, bowel obstruction ▪ Neurovascular/cerebrovascular ▫ Cranial edema, swelling

LAB RESULTS

▪ Serial complete blood counts (CBCs) ▫ Demonstrate changes in bone marrow function ▪ Peripheral blood sample ▫ Cytogenetic biodosimetry analyzes chromosomal aberrations in lymphocytes; correlation with radiation dose

OTHER DIAGNOSTICS

▪ Geiger counter/alpha-radiation detection device ▫ Determines degree of contamination ▪ Medical Treatment Protocols for Radiation Accident Victims (METREPOL) ▫ During first 48 hours

TREATMENT MEDICATIONS

▪ Nonradioactive potassium iodide (KI) ▫ Take within first hours of exposure; inhibits corporation of radioactive isotopes of iodine into thyroid gland ▪ External decontamination ▫ Wounds, body orifices

▪ Internal decontamination ▫ Minimize absorption, maximize excretion ▫ Chelating agents: diethylene-triaminepentaacetic acid (DTPA) ▫ Oral ferric hexacyanoferrate (Prussian blue): traps radioactive materials in intestines → prevents reabsorption ▪ Sodium bicarbonate ▫ ↓ risk of renal tubular necrosis ▪ Pain management ▪ Anxiolytics Organ-based management ▪ Hematopoietic: cytokine therapy (e.g. granulocyte colony-stimulating factor); recombinant human erythropoietin, antimicrobials ▪ GI: antiemetics (e.g. selective 5HT3 receptor antagonists), antidiarrheals

SURGERY Organ-based management ▪ Hematopoietic: stem cell transplant

OTHER INTERVENTIONS

▪ Address injuries (e.g. fractures, burns) ▪ Fluid, electrolyte replacement ▪ Lung lavage, mechanical ventilation

Organ-based management ▪ Hematopoietic: blood products ▪ Neurovascular: address increased intracranial pressure; comfort care (outcome likely fatal with neurovascular syndrome) ▪ Cutaneous: debridement, wound care

OSMOSIS.ORG 243

244 OSMOSIS.ORG

Chapter 42 Chemical & Drug Toxicity

ARSENIC POISONING osms.it/arsenic-poisoning PATHOLOGY & CAUSES ▪ Excessive exposure (acute/chronic) to arsenic → disruption of metabolic processes ▫ Naturally-occurring metalloid element, organic/inorganic compounds (organic— relatively low toxicity, inorganic—high toxicity) ▫ Present in soil, groundwater in certain areas; in gaseous state (arsine); tasteless, odorless ▪ Arsenic taken up by red blood cells → distributed to all body tissues, penetrates blood-brain barrier → interacts with intracellular compounds ▫ Interferes with metabolic processes (e.g. binds to sulfhydryl groups → impairs enzymatic reactions, interferes with cellular respiration) ▫ Concentrates in keratin-rich tissues (e.g. skin, hair, nails) ▫ Excreted in urine

RISK FACTORS

▪ Ingestion ▫ Contaminated groundwater: natural leaching from soil/agricultural, industrial pollution ▫ Foods (e.g. rice) grown in water containing arsenic ▫ Certain Asian homeopathic compounds ▪ Inhalation ▫ Arsenic-containing gas/dust from melting, refining, coal-fired power plants ▪ Occupational exposure ▫ Glass manufacturing, metallurgy, mining, semiconductor manufacturing (e.g. gallium arsenide), pressure-treated wood products using chromated copper arsenate (CCA) ▪ Potential toxicity when administered therapeutically (e.g. arsenic trioxide for leukemia)

COMPLICATIONS

▪ Skin pigmentation, structural changes → squamous cell carcinoma ▪ Fluid, electrolyte imbalance, shock → common cause of death ▪ Blocks cardiac potassium channels → conduction disturbances ▪ Respiratory distress syndrome ▪ Hepatotoxicity ▪ Intravascular hemolysis → renal failure ▪ Peripheral vascular disease, gangrene (“black foot”) ▪ Encephalopathy ▪ Bone marrow depression, pancytopenia ▪ Malignancies ▫ Lung, liver, kidney bladder, colon; basal/ squamous cell carcinoma ▪ Crosses placenta → ↑ risk for spontaneous abortions, stillbirths, preterm births

SIGNS & SYMPTOMS ▪ GI ▫ Abdominal cramping, nausea, vomiting, hematemesis, diarrhea ▪ Cardiovascular ▫ Tachycardia, hypotension ▫ Conduction disturbances: QT prolongation, ventricular dysrhythmias (e.g. torsades de pointes) ▪ Neurological ▫ Peripheral neuropathy (“stocking-glove” distribution), diminished vibratory sensation, decreased deep tendon reflexes, delirium, seizures ▪ Skin ▫ Plantar/palmar hyper/hypopigmentation, “raindrop on dusty road” pigmentation, hyperkeratosis, Mees lines on nails (transverse leukonychia) ▪ Breath ▫ Garlic odor

OSMOSIS.ORG 245

OTHER DIAGNOSTICS

▪ History of exposure, physical examination ▪ Analysis of hair/fingernails ▫ Degree of chronic exposure

ECG ▪ Dysrhythmias

TREATMENT MEDICATIONS Figure 42.1 Mee’s lines appear on the nails after an episode of acute arsenic poisoning.

DIAGNOSIS LAB RESULTS

▪ 24-hour urinary arsenic excretion ▫ Methylated metabolites of inorganic arsenical compounds ▪ ↑ LFTs, hyperbilirubinemia ▪ CBC: anemia, leukopenia, thrombocytopenia ▪ ↑ blood urea nitrogen (BUN), creatinine

▪ Chelation therapy ▫ Dimercaprol, AKA British anti-Lewisite (BAL); meso-2,3-dimercaptosuccinic acid (DMSA)

OTHER INTERVENTIONS

▪ Chronic exposure ▫ Remove source, protective equipment for occupational exposure ▪ Fluid, electrolyte administration, correction of imbalances

CYANIDE POISONING osms.it/cyanide-poisoning PATHOLOGY & CAUSES ▪ Excessive exposure to cyanide → arrest of cellular respiration, death ▫ Highly toxic chemical compound ▫ Contains carbon triple-bonded to nitrogen—cyano group (C≡N) ▫ Organic, inorganic, salt, liquid forms ▫ Hydrogen cyanide: distinctive odor of bitter almonds ▫ Cyanogenic compounds found in some fruit seeds (e.g. apricots, peaches) ▫ Seed capsule broken, exposed to

246 OSMOSIS.ORG

intestinal beta-glucosidase → cyanide formed ▫ Also produced by certain bacteria, fungi, algae ▫ Sodium nitroprusside: contains five cyanide groups ▪ Rapidly absorbed into body via all routes → 60% bound to protein → metabolized in liver → thiocyanate → eliminated via urine, lungs ▪ Toxic effect ▫ Blocks mitochondrial electron transport → halts aerobic cellular respiration → cellular hypoxia → metabolic switch to

Chapter 42 Chemical & Drug Toxicity anaerobic pathway → lactic acidosis

RISK FACTORS

▪ Industrial exposure ▫ Metal industries (e.g. extraction, plating), plastics, textiles ▪ Inhalation of smoke from burning synthetic materials ▪ Pediatric risk ▫ Consumption of acetonitrile-containing false fingernail remover ▪ High rate of sodium nitroprusside administration ▪ Rare cases of poisoning from peach, apricot, chokecherry pits

COMPLICATIONS

▪ Lactic acidosis, hypoxia → cardiac failure → death

SIGNS & SYMPTOMS ▪ Respiratory ▫ Hyperpnea, apnea, pulmonary edema; musty almond odor ▪ Cardiovascular ▫ Hypertension (early), tachycardia, dysrhythmias, asystole ▪ Neurological ▫ Altered level of consciousness, seizures, coma ▪ Mucocutaneous ▫ Flushing (cherry-red), cyanosis ▪ Constitutional ▫ Headache ▪ Exposure to small amounts → weakness, nausea, lacrimation, rhinorrhea

DIAGNOSIS LAB RESULTS ▪ ▪ ▪ ▪

Urine cyanide, thiocyanate level ↓ oxygen saturation Arterial blood gas (ABG): lactic acidemia Bright red appearance of blood

OTHER DIAGNOSTICS ECG ▪ Dysrhythmias

TREATMENT OTHER INTERVENTIONS

▪ Remove source of exposure ▪ Supplemental oxygen ▪ Hydroxocobalamin (vitamin B12a ) ▫ Cyanokit: each hydroxocobalamin molecule binds with one cyanide ion → forms vitamin B12 → excreted in urine ▪ Cyanide antidote kit ▫ Amyl nitrate, sodium nitrate, sodium thiosulfate ▫ Nitrates form methemoglobin ▫ Sodium thiosulfate converts cyanide to thiocyanate → excretion in urine

OSMOSIS.ORG 247

ETHYLENE GLYCOL POISONING osms.it/ethylene-glycol-poisoning PATHOLOGY & CAUSES ▪ Ingestion of ethylene glycol → accumulation of toxic metabolites, metabolic acidosis, cellular dysfunction, organ damage ▪ Found in antifreeze, deicing solution, brake fluid, engine coolant, etc. ▪ Metabolism of ethylene glycol → generation of toxic metabolites ▫ Ingestion → absorbed rapidly from GI system → metabolized in liver by alcohol dehydrogenase → converted into glycolaldehyde → aldehyde dehydrogenase converts glycolaldehyde to glycolic acid (later converted into oxalic acid) → metabolic acidosis ▫ Concurrent ingestion of ethanol delays generation of toxic metabolites

STAGING Stage I ▪ Neurologic (30 minutes–12 hours postexposure) ▫ Osmolal gap: direct effect of ethylene glycol ▫ Mimics inebriation (e.g. stupor, euphoria, vomiting) ▫ More severe CNS effects as ethylene glycol metabolized (e.g. nystagmus, seizures) Stage II ▪ Cardiopulmonary (12–24 hours postexposure) ▫ Toxic metabolite accumulation → metabolic acidosis, oxalate crystals in heart, lungs, vasculature ▫ Pulmonary edema → dyspnea; Kussmaul respirations (due to metabolic acidosis) ▫ Impaired cardiac function (e.g. heart failure, circulatory collapse)

248 OSMOSIS.ORG

▫ CNS derangements (e.g. cerebral edema) ▫ Death likely Stage III ▪ Renal (24–72 hours post-exposure) ▫ Renal accumulation of calcium oxalate in kidneys + direct effects of toxic metabolites → acute tubular necrosis, renal failure

RISK FACTORS

▪ Ingestion of products containing ethylene glycol (unintentional/intentional)

COMPLICATIONS

▪ Metabolic acidosis ▪ Hypocalcemia, calcium oxalate crystalluria, renal failure ▪ Hypomagnesemia (cofactor for metabolism of glycolic acid) ▪ Cerebral edema, seizures, coma, death

SIGNS & SYMPTOMS ▪ Dizziness, headache, lethargy, slurred speech, nausea/vomiting, tachycardia, tachypnea, hyperpnea

DIAGNOSIS LAB RESULTS

▪ Urinalysis: calcium oxalate crystals; hematuria; blood, protein casts ▪ ↑ osmolal gap (soon after ingestion) → marker for ethylene glycol ▪ ↑ anion gap metabolic acidosis (later) → marker for toxic metabolites ▪ Hypocalcemia ▪ ↑ BUN, creatinine ▪ Serum ethylene glycol ▪ CBC: leukocytosis

Chapter 42 Chemical & Drug Toxicity

OTHER DIAGNOSTICS

▪ History of exposure, physical examination

ECG ▪ Dysrhythmias secondary to hypocalcemia

TREATMENT MEDICATIONS

▪ Fomepizole: inhibits alcohol dehydrogenase ▪ Ethanol: competitive inhibitor of alcohol dehydrogenase

Address acute complications ▪ Fluids, sodium bicarbonate: metabolic acidosis

▪ Benzodiazepines: seizures ▪ Calcium gluconate: hypocalcemia ▪ Magnesium sulfate: hypomagnesemia

OTHER INTERVENTIONS

▪ Gastric aspiration ▫ Within 60 minutes of ingestion ▪ IV isotonic fluids → facilitate urinary excretion of metabolites ▪ Respiratory support ▪ Hemodialysis ▫ Significant metabolic acidosis, renal failure, hemodynamic instability

FETAL ALCOHOL SYNDROME (FAS) osms.it/fetal-alcohol-syndrome PATHOLOGY & CAUSES ▪ Prenatal exposure to alcohol → dysmorphic craniofacial features, growth deficits, neurobehavioral impairment, CNS dysfunction ▪ Embryo, early fetus have underdeveloped hepatic enzymes needed for ethanol metabolism → ↓ ethanol metabolism → ↑ ethanol concentration → teratogenic effects ▪ Degree of alcohol-related teratogenesis influenced by stage of development, dosage, duration of exposure ▫ Vulnerability continues throughout all three trimesters, all organ systems at risk

RISK FACTORS

▪ Maternal alcohol consumption ▫ No safe amount of alcohol consumption during pregnancy ▪ Low socioeconomic status ▪ Poor psychological indicators ▪ Sibling diagnosed with FAS

COMPLICATIONS

▪ Cardiac ▫ Atrial/ventricular septal defect ▪ Musculoskeletal ▫ Flexion contractures, scoliosis ▪ Auditory ▫ Conductive/neurosensory hearing loss ▪ Ophthalmologic ▫ Optic nerve hypoplasia, strabismus ▪ Renal ▫ Aplastic/dysplastic/hypoplastic kidneys, horseshoe kidney ▪ Mental health disorders ▫ Attention-deficit/hyperactivity disorder, mood impairment ▪ Neurological ▫ Seizure disorder ▪ Intellectual, cognitive deficits ▪ Developmental delay

OSMOSIS.ORG 249

SIGNS & SYMPTOMS ▪ Sentinel dysmorphic features ▪ Growth restriction (intrauterine/postnatal) ▪ Functional, behavioral issues ▫ Poor impulse control, poor judgment, attention problems, hyperactivity; deficits in learning, speech, memory

TREATMENT OTHER INTERVENTIONS

▪ Early intervention ▫ Occupational, speech, behavioral therapy; specialized education; parenting training

DIAGNOSIS OTHER DIAGNOSTICS

▪ Documentation of maternal alcohol consumption

Four features required ▪ Two of three sentinel craniofacial anomalies ▫ Short palpebral fissures ▫ Smooth philtrum ▫ Thin vermilion border of upper lip ▪ Pre/postnatal growth deficiencies ▫ Height/weight ≤ 10th percentile (racially/ ethnically-appropriate standard growth curve) ▪ Deficient brain growth, abnormal morphogenesis, abnormal neurophysiology, including ≥ one ▫ Head circumference ≤ 10th percentile ▫ Structural brain anomalies visualized through imaging ▫ Recurrent nonfebrile seizures (other causes of seizures ruled out) ▪ Neurobehavioral impairment ▫ Children ≥ three years old: cognitive/ behavioral impairment ▫ Children < three years old: developmental delay

250 OSMOSIS.ORG

Figure 42.2 The face of a baby diagnosed with fetal alcohol syndrome. There is a smooth philtrum, a thin upper lip and small eye openings.

Chapter 42 Chemical & Drug Toxicity

FETAL HYDANTOIN SYNDROME osms.it/fetal-hydantoin-syndrome PATHOLOGY & CAUSES ▪ Prenatal exposure to phenytoin/metabolites → spectrum of congenital anomalies, growth deficiencies ▪ Teratogenic mechanism unclear; may be related to phenytoin-associated impairment of folate absorption

RISK FACTORS

▪ Prenatal exposure to phenytoin/ metabolites; no safe amount of phenytoin during pregnancy

▪

▪

▪ ▪

(bowed upper lip; broad alveolar ridge; cleft lip, palate) Limbs ▫ Stiff, tapered fingers; digit, nail hypoplasia; hip dislocation Mild/moderate growth deficiencies ▫ Prenatal onset, continues through postnatal life Mild/moderate mental deficiencies Short neck, umbilical/inguinal hernia, pilonidal sinus, low-set hairline

DIAGNOSIS OTHER DIAGNOSTICS

COMPLICATIONS

▪ Microcephaly, congenital heart defects, growth deficiency, systemic abnormalities (e.g. nervous, renal, GI systems)

SIGNS & SYMPTOMS ▪ Craniofacial anomalies ▫ Wide anterior fontanel; ocular hypertelorism, epicanthal folds; nasal (short; flat, broad nasal bridge); mouth

▪ History of maternal ingestion of phenytoin during pregnancy, physical examination

TREATMENT OTHER INTERVENTIONS

▪ Early intervention ▫ Occupational, speech, behavioral therapy; specialized education

MERCURY POISONING osms.it/mercury-poisoning PATHOLOGY & CAUSES ▪ Excessive exposure to mercury → neurotoxicity, widespread interruption of cellular processes, teratogenesis ▪ Naturally occurring metal found in various forms in environment ▫ Organic, inorganic, methylmercury (MeHg)

Sources ▪ Medical preservative (thiomersal) ▪ Thermometers (phased out) ▪ Dental amalgam ▪ Dietary: inorganic mercury from industrial waste → transformed to methylmercury by soil, marine organisms → bio-amplified in tissues of predatory fish (e.g. tuna) ▪ Household items (e.g. fluorescent bulbs,

OSMOSIS.ORG 251

batteries, paint) ▪ Fungicides, pesticides ▪ Some homeopathic folk remedies Properties ▪ Lipid soluble; easily crosses cellular membranes ▫ Disrupts cellular physiology by binding to functional groups (e.g. sulfhydryl, carboxyl, phosphoryl) ▫ Crosses blood-brain barrier → neurotoxic effects (impairs synthesis of proteins, nucleic acids; disrupts neurotransmitter synthesis, uptake) ▫ Crosses placenta → concentrates in fetus → teratogenic effects ▪ High affinity for sulfhydryl groups in red blood cells (RBCs) → distributed throughout body ▪ Other organ toxicities ▫ Concentrates in kidneys → oxidative damage; pulmonary, GI ▪ Eliminated in feces, urine

RISK FACTORS

▪ Occupational (e.g. dentists, hygienists, miners, ceramic workers, taxidermy)

COMPLICATIONS

▪ Minamata disease ▫ Neurotoxicity caused by severe methylmercury poisoning ▪ Renal, respiratory failure; hemorrhagic colitis; fetal anomalies, death

SIGNS & SYMPTOMS ▪ Acute exposure ▫ Cough, dyspnea, circulatory collapse, vomiting, bloody diarrhea ▪ Chronic inhalation exposure (classic triad) ▫ Tremor (e.g. intentional tremor, tetanus mercurialis)

252 OSMOSIS.ORG

▫ Neuropsychiatric problems (e.g. fatigue, memory loss, mental instability) ▫ Gingivostomatitis ▪ Chronic ingestion exposure ▫ Nervous system: tremor, headache, dysarthria, paresthesia, irritability, psychosis ▫ Cardiovascular: hypo/hypertension ▫ Hematologic: cytopenias ▫ Ocular: conjunctivitis; corneal opacities, ulcers

DIAGNOSIS LAB RESULTS

▪ Mercury, anemia in urine/blood; leukocytosis ▪ Renal tubular damage ▫ N-acetyl-beta-D-glucosaminidase (NAG), albuminuria, epithelial cell casts, oliguria

TREATMENT MEDICATIONS

▪ Chelation therapy: oral DMSA, intravenous (IV) dimercaprol (contraindicated with methylmercury, may shift mercury to brain)

OTHER INTERVENTIONS

▪ Remove source of exposure; IV fluids, electrolytes; respiratory support

Chapter 42 Chemical & Drug Toxicity

PARACETAMOL TOXICITY osms.it/paracetamol-toxicity PATHOLOGY & CAUSES ▪ Excessive ingestion of paracetamol (acetaminophen) → fulminant hepatic failure, coma, death ▪ Acetaminophen metabolization in liver ▫ 90% conjugated via glucuronic acid → nontoxic compounds → excreted in urine ▫ 2% excreted unchanged in urine ▫ Remainder metabolized by cytochrome P450 system → toxic intermediary N-acetyl-p-benzoquinone imine (NAPQI) conjugated by hepatic glutathione → further metabolized → excreted in urine ▫ Glutathione rapidly depleted in acute overdose → accumulation NAPQI → binds to cellular proteins → hepatic necrosis

STAGING Stage I ▪ 0–24 hours post-ingestion; nonspecific indications of toxicity Stage II ▪ 24–72 hours post-ingestion; onset of hepatotoxicity, deterioration of renal function Stage III ▪ 72–96 hours post-ingestion; fulminant hepatic failure Stage IV ▪ hepatic recovery; regeneration of liver if individual survives Stage III

RISK FACTORS

▪ Acute overdose of acetaminophen (intentional/unintentional) ▪ Chronic ingestion of supratherapeutic doses

▪

▪ ▪ ▪

▫ Multiple acetaminophen-containing products, acetaminophen Concomitant ingestion of certain drugs ▫ Hepatic enzyme inducers (e.g. CYP2E1 inducers isoniazid, rifampin, phenobarbital), drugs that deplete glutathione (e.g. zidovudine, trimethoprim-sulfamethoxazole) Decreased hepatic glucuronidation capacity (e.g. chronic alcohol use) Existing hepatic disease (e.g. alcoholic liver disease, hepatitis) Genetic ▫ Gilbert syndrome (inherited deficiency in glucuronidation), cytochrome P450 polymorphisms

COMPLICATIONS

▪ Liver failure; death related to liver, multiorgan failure

SIGNS & SYMPTOMS ▪ May be asymptomatic/demonstrate nonspecific findings (e.g. nausea, vomiting, malaise) ▪ Progressive liver damage ▫ Right upper quadrant (RUQ) pain, jaundice, hypoglycemia, coagulopathy, hepatic encephalopathy, impaired renal function, metabolic acidosis

DIAGNOSIS LAB RESULTS

▪ Urinalysis: renal damage ▪ Serial blood draws for serum acetaminophen concentration ▫ Plot on the Rumack–Matthew nomogram if time of ingestion known ▪ LFTs ▫ ↑ transaminases: AST, ALT

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▫ ↑ bilirubin, lipase ▪ Metabolic panel ▫ ↑ BUN, creatinine, ammonia; ↓ glucose ▪ Coagulation ▫ ↓ prothrombin time, INR ▪ ABG ▫ ↓ pH; anion gap

OTHER DIAGNOSTICS

SURGERY

▪ Liver transplant

OTHER INTERVENTIONS

▪ Activated charcoal: adjunctive treatment for GI decontamination ▪ Address complications ▫ Hemodialysis: renal failure ▫ Fresh frozen plasma: coagulopathy

▪ History of acetaminophen use, physical examination (liver toxicity)

TREATMENT MEDICATIONS

▪ Acetylcysteine: most effective if administered within eight hours of ingestion; replenishes glutathione, detoxifies NAPQI

SEROTONIN SYNDROME osms.it/serotonin-syndrome PATHOLOGY & CAUSES ▪ Potentially life-threatening disorder ▫ Excessive presence of serotonin (5-hydroxytryptamine/5-HT), overactivation of central serotonin receptors → clinical manifestations related to mental status, neuromuscular excitation, autonomic excitation ▪ May be caused by therapeutic use of single serotonergic drug, overdose, drug interactions between ≥ two drugs 5HT increase ▪ ↑ serotonin synthesis ▫ Phentermine, L-tryptophan ▪ ↑ serotonin release ▫ Amphetamines/amphetamine derivatives; dopamine agonists ▪ ↑ activation of serotonergic receptors ▫ Certain antidepressants (buspirone); triptans; prokinetic agents (e.g.

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metoclopramide); ergot alkaloid derivatives; lithium ▪ ↓ serotonin reuptake ▫ Selective serotonin reuptake inhibitors (SSRIs); serotonin noradrenergic reuptake inhibitors (SNRIs); tricyclic antidepressants (TCAs); 5HT3, receptor antagonists; certain opiates (e.g. methadone, tramadol), drug abuse (e.g. ecstasy); Saint John’s wort ▪ ↓ serotonin metabolism ▫ Monoamine oxidase inhibitors (MAOIs); triptans ▪ ↓ activity of certain CYP450 enzymes ▫ Dextromethorphan

RISK FACTORS

▪ Therapeutic use of serotonergic drug ▪ Polypharmacy (increases likelihood of drug interaction)

Chapter 42 Chemical & Drug Toxicity

COMPLICATIONS

▪ Ventricular dysrhythmias ▪ Rhabdomyolysis, myoglobinuria (due to hyperthermia) → renal failure ▪ Metabolic acidosis ▪ Acute respiratory distress syndrome

SIGNS & SYMPTOMS ▪ Neuromuscular excitation ▫ Hyperreflexia, tremors, clonus, muscle rigidity, bilateral Babinski sign ▪ Autonomic nervous system hyperactivity ▫ Vomiting, diarrhea, hypertension, tachycardia, dysrhythmias, tachypnea diaphoresis, hyperthermia, mydriasis ▪ Altered mental status ▫ Anxiety, agitation, confusion

TREATMENT MEDICATIONS

▪ Antidote (if supportive measures insufficient) ▫ Cyproheptadine (H1, 5-HT2 antagonist effects) ▪ Benzodiazepines, short-acting antihypertensives ▫ Address symptomatology

OTHER INTERVENTIONS

▪ Discontinue serotonergic drug ▪ Cooling measures, IV fluids, supplemental oxygen ▫ Address symptomatology

DIAGNOSIS LAB RESULTS

▪ ↑ white blood cell count, creatine phosphokinase; ↓ serum bicarbonate

OTHER DIAGNOSTICS Hunter Serotonin Toxicity Criteria ▪ History of taking serotonergic agent + any one of following clinical features ▫ Spontaneous clonus ▫ Inducible clonus + agitation/diaphoresis ▫ Ocular clonus + agitation/diaphoresis ▫ Tremor + hyperreflexia ▫ Hypertonia + temperature > 38°C/100°F + ocular/inducible clonus

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NOTES

NOTES

DYSLIPIDEMIA GENERALLY, WHAT IS IT? PATHOLOGY & CAUSES ▪ Metabolic disorders: abnormal lipid levels, with ↑ cardiovascular, other disease risk ▪ Lipids: water-insoluble organic molecules contribute to normal metabolic process ▫ Building blocks for cell membranes ▫ Energy source ▫ Fat-soluble vitamin absorption (needed) ▫ Key molecule components (e.g. steroids, prostaglandins, bile acid) ▫ Fat storage ▪ Lipoproteins: triacylglycerol (TAG), cholesterol, phospholipids, apolipoproteins ▪ Classified according physicochemical characteristics ▫ Lipid density, the apolipoproteins types contained (↓ density → ↑ lipid relative to protein) ▪ Lipoprotein types: chylomicrons, very low-density lipoprotein (VLDL), lowdensity lipoprotein (LDL), and high-density lipoprotein (HDL) ▪ Optimal lipid levels ▫ Total cholesterol: 75–169mg/dL (ages ≤ 20 years); 100–199mg/dL (ages > 21 years) ▫ LDL: < 70mg/dL (cardiovascular disease/ very high risk individuals), < 100mg/dL (individuals with multiple cardiovascular disease risk-factors), < 130mg/dL (low cardiovascular disease risk individuals) ▫ HDL: > 40mg/dL ▫ Triglycerides: < 150mg/dL

TYPES

▪ Types organized by Fredrickson classification

Type I ▪ ↑ triglycerides > 99th percentile; ↑

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chylomicron level Type IIa ▪ Total cholesterol level > 90th percentile; ↑ LDL level; familial hypercholesterolemia Type IIb ▪ Total cholesterol/triglyceride level > 90th percentile; ↑ LDL, VLDL levels; combined hyperlipoproteinemia Type III ▪ Total cholesterol, triglyceride levels > 90th percentile; ↑ VLDL remnants, chylomicron levels; familial dysbetalipoproteinemia Type IV ▪ Total cholesterol level > 90th percentile, triglyceride level > 90th percentile likely; ↑ VLDL, low HDL level; endogenous hyperlipidemia Type V ▪ Triglyceride level > 99th percentile; ↑ VLDL, chylomicron levels; familial hypertriglyceridemia

RISK FACTORS

▪ Western diet (e.g. ↑ refined carbohydrate, ↑ calorie, ↑ dietary fat levels) ▪ Physical inactivity ▪ Risk ↑ with age ▪ Genetic/epigenetic influence

COMPLICATIONS

▪ Atherosclerosis → cardiovascular, cerebrovascular disease; pancreatitis, cholelithiasis (some cases)

Chapter 43 Dyslipidemia

SIGNS & SYMPTOMS ▪ Asymptomatic until atherosclerosis progresses, produces complications ▪ Abdominal adiposity ▫ Dyslipidemia correlation ▪ Lipid-related skin eruptions (e.g. xanthomas) ▪ Corneal arcus ▫ Lipid deposition in peripheral cornea ▪ Clinical presentation suggests lipid-related vascular disease

DIAGNOSIS

OTHER DIAGNOSTICS

▪ Pooled risk calculation: lipid levels + variables (age, sex, blood pressure, blood glucose level, smoking status)

TREATMENT MEDICATIONS

▪ Hyperlipidemia ▪ Low, moderate, high statin therapy based on risk ▪ Non-statin therapy (bile acid sequestrants, fibrates)

OTHER INTERVENTIONS

▪ Risk reduction (hyperlipidemia)

LAB RESULTS

▪ Genetic testing as indicated

Blood studies ▪ Lipid profile

ABETALIPOPROTEINEMIA osms.it/abetalipoproteinemia PATHOLOGY & CAUSES ▪ Rare autosomal-recessive disorder ▫ MTTP gene mutation in encoding microsomal triglyceride transfer protein (MTP) ▫ AKA Bassen–Kornzweig disease ▪ MTP: required for hepatic, intestinal assembly of apolipoprotein B (apo B), lipids → ↓ serum apo B-containing lipoproteins (e.g. chylomicrons, LDL, VLDL) → impaired fat-soluble vitamin (A, D, E, K) transport ▫ Vitamin E most susceptible to deficiency ▫ Normally transported from small intestine to liver by chylomicrons, delivered to peripheral tissues via VLDLs

COMPLICATIONS

▪ Malabsorption, failure to thrive; retinal degeneration, ophthalmoplegia; peripheral neuropathy; cerebellar dysfunction (Friedreich-type spinocerebellar ataxia)

SIGNS & SYMPTOMS ▪ Impaired fat absorption ▫ Initially presents (infancy) with gastrointestinal symptoms ▫ e.g. poor feeding/weight gain, failure to thrive, gastrointestinal problems (e.g. nausea, abdominal distension, steatorrhea) ▪ Neurological (related to vitamin E malabsorption) ▫ ↓ deep tendon reflexes, progressive ataxia, dysarthria, neuropathy, lowerextremity spasticity

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▪ Ocular (related to vitamin A malabsorption) ▫ Vision impairment, retinitis pigmentosa; strabismus, nystagmus, ophthalmoplegia (eye muscle paralysis)

DIAGNOSIS LAB RESULTS

▪ ↓ ↓ triglycerides ▪ ↓ ↓ total cholesterol ▪ Lipoprotein electrophoresis → abetalipoproteinemia ▪ Peripheral blood-smear analysis → ↑ ↑ acanthocytes (red blood cell (RBC) with spiked membranes); normocytic anemia ▪ ↓ ↓ alpha-tocopherol, gamma-tocopherol (vitamin E) ▪ ↑ transaminases (present hepatic steatosis)

OTHER DIAGNOSTICS

▪ Sensory nerve conduction studies ▫ Reduced nerve action potential amplitude; normal conduction velocity

TREATMENT OTHER INTERVENTIONS

▪ Address neurological symptoms ▫ Vitamin E ▪ Address gastrointestinal symptoms ▫ Reduced fat-intake ▪ Supplement fat-soluble vitamins ▫ A, D, K

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Figure 43.1 Accumulation of lipids in the enterocytes of an individual with abetalipoproteinemia leads to a clear appearance.

Chapter 43 Dyslipidemia

FAMILIAL HYPERCHOLESTEROLEMIA osms.it/familial-hypercholesterolemia PATHOLOGY & CAUSES ▪ Autosomal dominant disorder → ↑ ↑ low density lipoprotein cholesterol (LDL-C) levels → early-onset atherosclerotic disease ▫ Caused by receptor-mediated LDL-C catabolism-encoding gene mutation ▫ Individuals often still experience ↑ LDL-C levels despite ↑ lipid-lowering therapy ▫ LDL receptor mutation classes involve altered receptor synthesis/function ▪ LDL-mediated atherscelerotic plaque formation ▫ Abnormal lipid metabolism → hyperlipidemia (LDL; especially those containing B-100 apolipoproteins) → subendothelial LDL retention → LDL oxidation → ↑ LDL by macrophages → foam cell formation → cytokine, growth factor release from foam cells → smooth muscle cell migration from vascular media to intima, fibrous cap formation, chronic inflammation → atherosclerotic plaque → cardiovascular, cerebrovascular, other sequelae potential

COMPLICATIONS

▪ Coronary artery calcification ▪ alvular cholesterol deposits → aortic stenosis ▪ Accelerated athersclerotic placque formation → myocardial infarction → sudden cardiac death ▫ Homozygous FH: possible sudden cardiac death before age 20

SIGNS & SYMPTOMS ▪ Evidence of atherosclerotic cardiovascular disease (e.g. angina) ▪ Evidence of aortic stenosis, left ventricular outflow obstruction (e.g. exertional dyspnea) ▪ Xanthoma presence (usually before age 10) ▫ Tendon xanthomas: Achilles tendon (commonly) ▫ Cutaneous xanthomas: planar xanthomas on palms, soles of hands/ feet (may be painful)

TYPES Heterozygous FH ▪ LDL-C ≥ 160mg/dL (children); ≥ 190mg/dL adults (one first-degree relative diagnosed with premature coronary artery disease/ similar LDL-C levels) ▪ Positive genetic testing for LDL-C receptor defect Homozygous FH ▪ LDL-C ≥ 400mg/dL, (one/both parents clinically diagnosed with FH) ▪ Positive genetic testing for LDL-C receptor defect

Figure 43.2 Numerous tendinous xanthomata on the hand of an individual with familial hypercholesterolemia.

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▪ Xanthelasmas: soft, yellow, cholesterolfilled plaques (usually appear on eyelid’s medial aspect) ▪ Corneal arcus: white/grey ring around cornea

DIAGNOSIS ▪ Positive family history ▪ Characteristic findings upon physical examination

LAB RESULTS

▪ Genetic testing ▪ ↑ total cholesterol, LDL-C (LDL > 90th percentile for age/sex) ▪ Normal/↓ HCL-C

TREATMENT MEDICATIONS Figure 43.3 Xanthelasmata around the eyes of an individual with familial hypercholesterolemia.

▪ High-intensity statin therapy ▪ Cholesterol-absorption inhibitors ▫ Monotherapy or in conjunction with statin therapy ▪ PCSK9 inhibitor/monoclonal antibodies ▫ Binds to PCSK9 → inhibits hepatic LDL receptor-binding → ↑ LDL receptors available to clear LDL → ↓ LDL-C levels

HYPERLIPIDEMIA osms.it/hyperlipidemia PATHOLOGY & CAUSES ▪ ↑ serum total cholesterol, LDL-C ▪ Lipids enter circulation via exogenous pathway via gut/endogenous pathway (hepatic synthesis) → lipoproteins transport circulating lipids to various tissues

CAUSES

▪ Primary: genetic abnormalities (e.g. familial hypercholesterolemia), defective apoprotein B (familial) ▪ Secondary: Cushing syndrome, excessive alcohol intake, uncontrolled diabetes mellitus, chronic kidney/liver disease, certain drugs (glucocorticoids, beta blockers, thiazide diuretics, HIV

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antiretroviral regimens, oral estrogen replacement)

RISK FACTORS

▪ Genetic predisposition ▪ Diet/other lifestyle factors (e.g. physical inactivity, high-fat diet) ▪ Pregnancy temporarily increases serum cholesterol ▪ Biologically-male > biologically-female individuals (premenopausal)

COMPLICATIONS

▪ Cardiovascular disease (e.g. angina, myocardial infarction) ▪ Cerebrovascular disease (e.g. stroke)

Chapter 43 Dyslipidemia ▪ Peripheral vascular disease ▪ Cholelithiasis ▪ Pancreatitis (triglycerides > 500mg/dL)

SIGNS & SYMPTOMS ▪ Cardiovascular/cerebrovascular disease evidence ▪ Xanthomas: cutaneous/found/along tendon sheaths (tendinous xanthoma) ▪ Corneal arcus

DIAGNOSIS ▪ Physical examination → presence of risk factors/cardiovascular disease symptoms ▪ History of cardiovascular diseasecharacteristic symptoms

LAB RESULTS

▪ Fasting lipid profile: ↑ total cholesterol, ↑ triglycerides, ↑ LDL, ↓ HDL

TREATMENT ▪ Address secondary hyperlipidemia causes

MEDICATIONS ▪ Statin therapy

OTHER INTERVENTIONS

▪ Non-statin therapy ▫ E.g. fibrates, fish oil supplements containing eicosapentaenoic acid/ docosahexaenoic acid concentrate; nicotinic acid (not as monotherapy) Figure 43.4 Blood drawn from an individual with hyperlipidemia.

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HYPERTRIGLYCERIDEMIA osms.it/hypertriglyceridemia PATHOLOGY & CAUSES ▪ Elevated serum triglyceride levels

CAUSES Primary: genetic mutation (primary) ▪ Familial hypertriglyceridemia ▪ Familial combined hyperlipidemia ▪ Chylomicronemia ▪ Dysbetalipoproteinemia (APOE mutations) ▪ Lipoprotein lipase deficiency ▪ Apolipoprotein C-II deficiency (APOC2 mutations) ▪ Apolipoprotein A-V variants (APOA5 mutations) Secondary: consequence of disease states ▪ Diabetes (especially poor glycemic control) ▪ Obesity ▪ ↑ refined carbohydrate diet ▪ Nephrotic syndrome ▪ Chronic renal failure ▪ Hypothyroidism ▪ Pregnancy (temporarily increased serum triglycerides) ▫ Certain drugs (glucocorticoids, beta blockers, thiazide diuretics, HIV antiretroviral regimens, retinoids, oral estrogen replacement)

RISK FACTORS

▪ Influence of diet/other lifestyle factors (e.g. physical inactivity, ↑ fat diet) ▪ Genetic predisposition

COMPLICATIONS

▪ ↑ atherosclerotic plaque formation risk → cardiovascular, cerebrovascular events ▪ Pancreatitis (serum triglycerides > 1000mg/ dL)

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SIGNS & SYMPTOMS ▪ Clinical atherosclerosis manifestations ▫ May not be evident until complications develop ▪ Xanthomas, xanthelasmas ▫ Usually associated with hereditary forms ▪ Lipemia retinalis: creamy appearance within retinal blood vessels ▫ May be seen with severe hypertriglyceridemia

DIAGNOSIS ▪ Physical examination → presence of risk factors/cardiovascular disease symptoms ▪ History of cardiovascular disease symptoms

LAB RESULTS

▪ Fasting lipid profile: ↑ triglycerides ▫ Normal: 886mg/dL

TREATMENT ▪ Address secondary causes

MEDICATIONS ▪ Statin therapy

OTHER INTERVENTIONS

▪ Non-statin therapy ▫ E.g. fibrates, fish oil supplements containing eicosapentaenoic acid/ docosahexaenoic acid concentrate; nicotinic acid (not as monotherapy)

NOTES

NOTES

FAT SOLUBLE VITAMINS DEFICIENCY

GENERALLY, WHAT IS IT? PATHOLOGY & CAUSES ▪ Insufficient plasma concentrations of fat soluble vitamins required for normal metabolic processes

RISK FACTORS

▪ Reduced intake, impaired absorption, increased elimination

DIAGNOSIS ▪ See individual disorders

TREATMENT OTHER INTERVENTIONS

▪ Increased dietary intake; supplementation

SIGNS & SYMPTOMS ▪ See individual disorders

VITAMIN D DEFICIENCY osms.it/vit-d-deficiency PATHOLOGY & CAUSES ▪ Body’s metabolic needs not met as there is insufficient 25-hydroxyvitamin D ▪ Liver, kidneys hydroxylate physiologically inert vitamin D ▫ Precursor molecule (7-dehydrocholesterol) exposed to ultraviolet light/dietary vitamin D → D3/D2 released into blood → first hydroxylation in liver → second hydroxylation in kidneys → metabolically active calcitriol (1,25-dihydroxyvitamin D) ▪ Insufficient vitamin D → ↓ intestinal absorption of calcium → ↓ serum calcium → ↑ serum PTH → ↑ intestinal calcium absorption + ↑ osteoclastic activity,

calcium resorption from bones + ↑ renal conservation of calcium → normalization of serum calcium

CAUSES

▪ Insufficient dietary, supplementary intake ▪ Increased need, but insufficient intake ▫ Pregnancy, lactation ▪ Obesity, vitamin D sequestration in adipose tissue ▪ Impaired absorption ▫ Small bowel disease; bariatric surgery; gastrectomy; pathology of hepatobiliary tree, pancreas; abetalipoproteinemia ▪ Decreased synthesis in skin ▫ Insufficient sun exposure; dark skin

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(large amounts of melanin in epidermal layer); excessive sunscreen ▪ Impaired liver, kidney hydroxylation ▫ Cirrhosis, renal failure ▪ Altered vitamin D metabolism from drugs ▫ Phenobarbital, phenytoin, rifampin, isoniazid, carbamazepine, ketoconazole Genetic mutations ▪ 1-alpha-hydroxylase deficiency: mutations in CYP27B1; previously called vitamin D-dependent rickets type 1A ▪ 25-hydroxylase deficiency: mutations in CYP2R1; previously called vitamin D-dependent rickets type 1B ▪ Hereditary resistance to vitamin D: mutations in VDR (vitamin D receptor gene); previously called vitamin D-dependent rickets type 2

RISK FACTORS

▪ Risk increases with age ▪ Gastrointestinal tract, liver, kidney conditions ▪ Medications that interfere with vitamin D metabolism ▪ Decreased ultraviolet light exposure ▫ Cold climate/high latitudes, institutionalization/incarceration

Perinatal factors (↓ neonatal vitamin D stores) ▪ Exclusively breastfed infants ▫ Maternal vitamin D status dictates amount vitamin D in milk ▪ Premature birth ▫ Low stores of vitamin D ▪ Low maternal vitamin D during gestation

COMPLICATIONS

▪ Related to accompanying hypocalcemia ▫ Osteoporosis ▫ Increased risk of fractures ▫ Osteomalacia ▫ Ricketts (children) ▫ Secondary hyperparathyroidism

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SIGNS & SYMPTOMS SIGNS & SYMPTOMS ▪ ▪ ▪ ▪ ▪

Mild deficiency may be asymptomatic Decreased bone density, osteoporosis Fractures Dental enamel hypoplasia Severe deficiency ▫ Hypocalcemia-related osteomalacia symptoms ▫ Bone tenderness/pain ▫ Muscle weakness, cramping, numbness/ tingling, positive Trousseau sign, Chvostek’s sign ▫ Bone malformations: difficulty ambulating, waddling gait

DIAGNOSIS DIAGNOSTIC IMAGING X-ray ▪ High-stress areas ▫ Fractures; vertebral compression fractures ▪ Radiolucent bands (indicate pseudofractures) ▪ Codfish vertebrae ▫ Biconcave vertebral discs ▪ Children ▫ Epiphyseal plate widening; osteopenic/ malformed long bone shafts, pathological fractures Dual-energy X-ray absorptiometry (DEXA) ▪ Decreased bone density

LAB RESULTS

▪ Decreased serum 25-hydroxyvitamin D (calcidiol) level ▪ Elevated alkaline phosphatase (bone turnover marker) ▪ Decreased serum calcium ▪ Increased parathyroid hormone (PTH)

Chapter 44 Fat Soluble Vitamin Deficiency

TREATMENT OTHER INTERVENTIONS

▪ Vitamin D3 supplementation ▫ Dietary: fish, egg yolk, fortified foods

▫ Supplementation ▫ Ultraviolet light/natural sunlight exposure ▪ Increase calcium intake

VITAMIN K DEFICIENCY osms.it/vit-k-deficiency PATHOLOGY & CAUSES ▪ Body’s metabolic needs not met; insufficient vitamin K ▫ Coagulation function ▫ Bone biology ▫ Vascular biology ▪ Dietary vitamin K1 (phylloquinone) → bile salts make fat soluble vitamin soluble → incorporated into gastrointestinal tract’s micelles → absorbed by small intestine → integrated into chylomicrons → transported to portal circulation → liver uses to synthesize coagulation factors, other essential proteins

TYPES Infancy: vitamin K-deficiency bleeding (VKDB) ▪ Early-onset VKDB: occurs within first 24 hours of life; caused by immature liver function, low stores of vitamin K at birth, sterile gut, exclusive breastfeeding (breastmilk low in vitamin K), medications present in maternal circulation interfering with vitamin K (anticonvulsants, warfarin) ▪ Classic VKDB: occurs between 1–4 weeks; prevented by vitamin K1 prophylaxis at birth ▪ Late-onset VKDB: occurs between 3 weeks–8 months; associated with lack of vitamin K1 prophylaxis at birth, exclusive breastfeeding (breastmilk low in vitamin K)

▫ Diseases of small intestines, liver, gallbladder, pancreas

RISK FACTORS Infants ▪ No vitamin K1 prophylaxis at birth ▪ Immature liver uses vitamin K inefficiently ▪ Low vitamin K stores ▪ Sterile gut ▪ Maternal ingestion of coumarin-like anticoagulants/some anticonvulsants/ antibiotics during gestation ▪ Antibiotic administration (destroys developing gut flora) Adults ▪ Prolonged diarrhea ▪ Use of broad-spectrum antibiotics, low intake of vitamin K ▪ TPN administration without added vitamin K

COMPLICATIONS

▪ Most common ▫ Bleeding, ranging from mild (mucocutaneous) to severe (intracranial hemorrhage most common in late onset VKDB) ▪ Impaired bone mineralization ▪ Vascular calcium deposits

Later childhood, adulthood ▪ Fat absorption and vitamin K metabolism disorders

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SIGNS & SYMPTOMS ▪ Low bone density signs Impaired coagulation ▪ Mucocutaneous bleeding: gingival, nasal, easy bruising ▪ Gastrointestinal bleeding: melena ▪ Genitourinary bleeding: hematuria ▪ Neonatal bleeding: umbilical stump/ circumcision site ▪ Intracranial hemorrhage: vomiting, seizures

DIAGNOSIS DIAGNOSTIC IMAGING DEXA ▪ Low bone mineralization

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LAB RESULTS

▪ Coagulation studies ▪ Prolonged prothrombin time (PT), partial thromboplastin time (PTT), International Normalized Ratio (INR) ▪ Elevated serum undercarboxylated proteins (proteins induced by vitamin K absence)

TREATMENT OTHER INTERVENTIONS

▪ Administer Vitamin K ▫ Subcutaneous phytonadione ▪ ↑ dietary vitamin K ▫ Liver, green leafy vegetables (broccoli, spinach, kale)

NOTES

NOTES

GLYCOGEN STORAGE DISEASES (GSD)

GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Metabolism disorders → pathological intracellular accumulation of glycogen/ metabolic products ▪ AKA dextrinoses/glycogenoses ▪ Impaired glycogen metabolism → cells without energy between meals → cell dysfunction, death ▪ Tissues most dependent on carbohydrates most affected ▫ Liver, heart muscle, brain, skeletal muscle

CAUSES

▪ Enzyme deficiency in glycogen synthesis/ breakdown ▪ Genetic, environmental factors

COMPLICATIONS

▪ Rhabdomyolysis; cardiomyopathy; atrioventricular block (AV) block; renal failure (myoglobin from dead muscle cells impairs renal function); lactic acidosis due to energy being generated from triglycerides, protein; hyperuricemia, gout (lactic, uric acid excreted via same renal transport mechanism)

DIAGNOSIS LAB RESULTS

▪ Cell count, hormones, metabolites

Muscle/liver biopsy ▪ With periodic acid-Schiff stain ▪ Detects glycogen

OTHER DIAGNOSTICS ▪ Genetic testing

Fasting test for clinical orientation ▪ Hypoglycemia

TREATMENT OTHER INTERVENTIONS

▪ Corrective diet ▪ Symptomatic therapy (cell growth factors) ▪ Enzyme replacement therapy for symptom relief

SIGNS & SYMPTOMS ▪ Symptomatic at birth/early adulthood ▪ Hypoglycemia, hyperlipidemia (compensatory mechanism for hypoglycemia), fatigue, hypotonia (floppy baby), hepato/splenomegaly, hypoglycemia → seizures, metabolic acidosis → hyperventilation, vomiting

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GLYCOGEN STORAGE DISEASE TYPE I (GSD I) osms.it/GSD-I PATHOLOGY & CAUSES ▪ AKA von Gierke disease ▪ Pathological intracellular accumulation of glucose-6-phosphate (G6P) due to impaired glycogenolysis, gluconeogenesis ▪ Final product of both mechanisms: G6P ▪ Most common glycogen storage disease

TYPES GSD Ia ▪ Mutation of G6PC gene GSD Ib ▪ Mutation of G6PT1 gene GSD Ic ▪ Mutation of SLC17A3 gene

CAUSES

▪ G6P deficiency → G6P trapped inside cell (too polar to pass through cell membrane) → severe hypoglycemia ▪ Autosomal recessive mutations

COMPLICATIONS

▪ Hepatomegaly; kidney enlargement; atherosclerosis due to hyperlipidemia; growth, development disorders; gout, kidney damage due to hyperuricemia

SIGNS & SYMPTOMS Fasting hypoglycemia ▪ Blood glucose level regulation impaired (esp. between meals) → low insulin → high cortisol, glucagon Metabolic acidosis ▪ Lactate cannot convert into pyruvate due to

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accumulation of G6P (lactate + pyruvate → G6P via gluconeogenesis) → compensatory hyperventilation, vomiting Hypertriglyceridemia ▪ Compensate for chronically low insulin Hyperuricemia ▪ Excess G6P in pentose phosphate pathway → high blood concentrations of uric acid → competes with other organic acids (e.g. lactic acid) for excretion in kidneys

DIAGNOSIS DIAGNOSTIC IMAGING Ultrasound ▪ Enlarged liver, kidneys

LAB RESULTS Liver biopsy with periodic acid-Schiff stain ▪ Glycogen detection

OTHER DIAGNOSTICS ▪ Genetic testing

Fasting test ▪ Hypoglycemia, doesn’t respond to glucagon injection

TREATMENT OTHER INTERVENTIONS

▪ Diet consisting of frequent meals high in carbohydrates ▪ Regulation of metabolic complications

Chapter 45 Glycogen Storage Diseases

GLYCOGEN STORAGE DISEASE TYPE II (GSD II) osms.it/GSD-II PATHOLOGY & CAUSES

DIAGNOSIS

▪ AKA Pompe disease ▪ Pathological accumulation of glycogen in lysosome ▪ Mainly affects skeletal muscles, heart; also liver, nervous system

DIAGNOSTIC IMAGING

TYPES

▪ ↑ creatine kinase, lactic dehydrogenase, alanine transaminase, aspartate transaminase

Early/infantile onset ▪ Few months after birth, typically 4–8; progression much faster Late onset ▪ > two years; as late as 50–60

CAUSES

▪ Autosomal recessive disease caused by mutation on chromosome 17 ▪ Acid alpha-glucosidase deficiency → glycogen cannot break down, accumulates in lysosome → lysosome bursts → glycogen, lysosomal enzymes leak into cytoplasm → cell dysfunction, death

X-ray ▪ Cardiomegaly

LAB RESULTS

Muscle biopsy ▪ Glycogen detection

OTHER DIAGNOSTICS ECG ▪ Arrhythmia, cardiomyopathy

TREATMENT OTHER INTERVENTIONS

▪ Enzyme replacement therapy

COMPLICATIONS

▪ Rhabdomyolysis, completely impaired motor function, respiratory/heart failure, development disorders

SIGNS & SYMPTOMS ▪ Progressive muscle weakness, respiratory insufficiency due to weakened diaphragm function, arrhythmia, cardiomegaly, cardiomyopathy, hepatomegaly, hypotonia, recurrent chest infections

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GLYCOGEN STORAGE DISEASE TYPE III (GSD III) osms.it/GSD-III PATHOLOGY & CAUSES ▪ AKA Cori’s disease, Forbes disease, limit dextrinosis ▪ Intracellular pathological accumulation of incompletely broken down glycogen → buildup of dextrins (intermediate products of glycogen breakdown) → osmotic pressure of cell increases → pulls water in, damages cell ▪ Affects liver, skeletal muscles, heart

TYPES GSD IIIa ▪ Liver, muscles GSD IIIb ▪ Liver GSD IIIc ▪ Liver, muscles

CAUSES

▪ Autosomal recessive disease ▪ Deficiency of glycogen debranching enzyme (GDE): amylo-alpha-1,6glucosidase, 4-alpha-glucanotransferase

COMPLICATIONS

▪ Hepatosplenomegaly, cardiomegaly, developmental disorders, liver failure

SIGNS & SYMPTOMS ▪ Hypoglycemia, hypotonia, arrhythmia, cardiomyopathy, rhabdomyolysis, musclerelated symptoms (later in life), may resemble GSD I

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DIAGNOSIS DIAGNOSTIC IMAGING Ultrasound ▪ Hepatosplenomegaly

LAB RESULTS Liver/muscle biopsy with periodic acid-Schiff stain ▪ Glycogen detection

OTHER DIAGNOSTICS ▪ Genetic analysis

TREATMENT OTHER INTERVENTIONS ▪ High glucose, protein diet

Chapter 45 Glycogen Storage Diseases

GLYCOGEN STORAGE DISEASE TYPE IV (GSD IV) osms.it/GSD-IV PATHOLOGY & CAUSES ▪ AKA Andersen’s disease ▪ Intracellular accumulation of abnormally formed glycogen ▪ Improper glycogen synthesis → buildup of polyglucosan bodies (unbranched long chains of glucose) → precipitation of polyglucosan bodies → foreign body reactions, increased osmotic pressure → cell damage

CAUSES

▪ Autosomal recessive mutation of GBE1 gene on chromosome 3 ▪ Deficiency of 1,4-alpha-glucan branching enzyme (GBE)

SIGNS & SYMPTOMS ▪ Fatal perinatal neuromuscular ▫ Fetal hydrops, hydramnion; hypotonia; reduced infant mobility; cardiomyopathy present at birth; death approx. one month after birth ▪ Childhood neuromuscular ▫ Variable intensity, life expectancy; manifests in childhood; myopathy, cardiomegaly ▪ Progressive hepatic ▫ Failure to thrive (FTT); liver cirrhosis; portal hypertension; ascites; death few months after birth ▪ Non-progressive hepatic ▫ Similar to progressive hepatic type, symptoms less intense; cirrhosis not present; can live into adulthood ▪ Congenital muscular ▫ Manifests shortly after birth; cardiomegaly; life expectancy few months

DIAGNOSIS DIAGNOSTIC IMAGING Prenatal ultrasound ▪ Fetal hydrops, hydramnion ECG ▪ Heart abnormalities

LAB RESULTS Liver/muscle biopsy with periodic acid-Schiff stain ▪ Glycogen detection

OTHER DIAGNOSTICS ▪ Genetic analysis

Echocardiography ▪ Heart abnormalities

TREATMENT OTHER INTERVENTIONS

▪ Only symptomatic treatment available

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GLYCOGEN STORAGE DISEASE TYPE V (GSD V) osms.it/GSD-V PATHOLOGY & CAUSES ▪ AKA McArdle’s disease ▪ Intracellular pathological accumulation of glycogen in muscle tissue ▪ Cannot release glucose-1-phosphate → ↓ glycolysis, cell energy status, Na+/K+ ATPase function → osmotic cell imbalance → cell damage ▪ Affects only muscle tissue

TYPES Early onset ▪ More severe symptoms, progression Adult onset ▪ Less severe symptoms, progression

CAUSES

▪ Autosomal recessive disease ▪ Deficiency of myophosphorylase (musclespecific isoform of glycogen phosphorylase)

COMPLICATIONS

▪ Renal failure due to myoglobinuria from rhabdomyolysis ▪ Muscle contractures due to fibrosis caused by extensive damage

SIGNS & SYMPTOMS ▪ Exercise intolerance, fatigue, rhabdomyolysis, muscle fibrosis ▪ ‘’Second wind’’ phenomenon: shift in metabolism during exercise → sudden burst of energy, despite being out of breath

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DIAGNOSIS LAB RESULTS Muscle biopsy ▪ With periodic acid-Schiff stain ▪ Glycogen detection

OTHER DIAGNOSTICS ▪ Genetic analysis

TREATMENT OTHER INTERVENTIONS

▪ Only symptomatic treatment available

Chapter 45 Glycogen Storage Diseases

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HYPERVITAMINOSIS GENERALLY, WHAT IS IT? PATHOLOGY & CAUSES ▪ Toxic effects due to increased ingestion/ storage of vitamins, most often fat soluble vitamins (vitamins A, D, E, K) ▫ Fat-soluble vitamins stored in fatty tissues, liver; remain in body for longer periods of time than water-soluble vitamins

RISK FACTORS

DIAGNOSIS ▪ See individual disorders

TREATMENT OTHER INTERVENTIONS

▪ Discontinue consumption of vitamin supplements/food containing high levels of vitamins

▪ Increased ingestion of vitamin supplements/food containing high levels of vitamins

EXCESS VITAMIN A osms.it/excess-vitamin-a PATHOLOGY & CAUSES ▪ Condition caused by excessive amounts of vitamin A in body ▪ Acute toxicity ▫ Occurs in adults when > 200,000mcg (> 660,000IU) consumed in single dose ▫ Occurs in infants < six months when > 6,000mcg (> 20,000IU) consumed < one month ▪ Chronic toxicity ▫ Long-term ingestion of high doses of vitamin A

CAUSES

▪ Most likely by increased ingestion of synthetic “preformed” vitamin A, approximately 10 times the Recommended

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Dietary Allowance (RDA) ▫ Proforms of vitamin A (e.g. carotenoids) generally not toxic ▪ Teratogenic effects ▫ Effects on fetus during first trimester of pregnancy

SIGNS & SYMPTOMS ▪ May compromise bone metabolism, health ▪ Acute toxicity ▫ Nausea, vomiting, blurry vision ▫ In extremely high doses: drowsiness, vomiting ▪ Chronic toxicity ▫ Ataxia, hair loss, bone/muscle pains, vision changes, liver damage, dry skin,

Chapter 46 Hypervitaminosis nausea, headache, hepatomegaly, increased risk of osteoporotic fractures ▪ Teratogenic effects ▫ Can cause spontaneous fetal death, facial/cardiac malformations (e.g. microcephaly)

DIAGNOSIS DIAGNOSTIC IMAGING Bone X-rays ▪ Weakness/damage

▪ Liver function tests (LFTs): mild elevation of liver enzymes ▫ Liver biopsy: enlarged hepatocytes, increased fibrosis in chronic hypervitaminosis A

TREATMENT OTHER INTERVENTIONS

▪ Discontinue consumption of vitamin A supplements/foods containing high levels of vitamin A, esp. containing natural vitamin A (e.g. kidney, liver, egg yolks)

LAB RESULTS

▪ Most vitamin A stored in liver, circulating concentrations not always accurate indicator

EXCESS VITAMIN D osms.it/excess-vitamin-d PATHOLOGY & CAUSES ▪ Toxicity caused by excessive amounts of vitamin D ▫ Vitamin D increases circulating levels of calcium ▫ Most often caused by excessive intake ▪ Maximum tolerable intake 100mg for children > nine years old, adults, pregnant/ lactating individuals; lower for younger children ▪ Main consequence is hypercalcemia

SIGNS & SYMPTOMS ▪ Acute intoxication (often due to hypercalcemia) ▫ Confusion, excessive thirst, nausea, vomiting

▪ Chronic intoxication ▫ Bone demineralization, pain; nephrocalcinosis; kidney damage

DIAGNOSIS LAB RESULTS

▪ Serum concentration of 25(OH)D > 150ng/ mL (374nmol/L)

TREATMENT OTHER INTERVENTIONS

▪ Discontinue consumption of vitamin D supplements; restrict dietary intake of calcium, dairy products (milk, cheese, yogurt), almonds

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MALNUTRITION GENERALLY, WHAT IS IT? PATHOLOGY & CAUSES ▪ Supply/demand imbalance of nutrients, energy required for growth, maintenance, function ▪ Disease spectrum ▫ Kwashiorkor: inadequate protein intake with adequate total caloric intake ▫ Marasmus: inadequate protein, caloric intake ▪ Malnutrition impairs immune function → ↑ infection likelihood → ↑ nutritional demand → further malnutrition ▫ Malnutrition → atrophy of lymph glands, tonsils, thymus → impaired cellular immunity, delayed hypersensitivity loss ▫ Protein insufficiency → ↓ immunoglobulins, ↓ complement → impaired phagocytosis ▫ Acute-phase immune response loss → typical infection signs loss (leukocytosis, fever) ▪ Refeeding syndrome ▫ Metabolic disturbance: excessivelyrapid nutrition reintroduction to severely malnourished individual ▫ Rapid nutrient reintroduction → glycogen, fat, protein synthesis → serum potassium, magnesium, phosphorus consumption → mineral imbalance → cardiac, pulmonary, neurological sequelae (cardiac arrhythmias, cardiac failure, confusion, convulsions, coma)

SIGNS & SYMPTOMS ▪ Kwashiorkor ▫ Bilateral pitting edema, distended abdomen, hair thinning, skin/hair depigmentation, dermatitis

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▪ Marasmus ▫ Emaciated appearance (“wizened” facies), severe muscle wasting, subcutaneous-fat loss

DIAGNOSIS DIAGNOSTIC IMAGING Chest X-ray ▪ Infection workup: respiratory distress

LAB RESULTS

▪ Hypoglycemia ▪ Anemia (normochromic-normocytic or hypochromic-microcytic/macrocytic) ▪ Electrolyte levels (calcium, phosphate, magnesium, serum albumin, urea) → various deficiencies

Infection workup ▪ Blood culture ▪ Common endemic infection tests (e.g. HIV, malaria, parasites)

OTHER DIAGNOSTICS Anthropometry ▪ Body weight < 62.36% expected body weight for age ▪ Weight-for-height Z-score < -3 standard deviations → severe wasting ▪ Mean upper-arm circumference < 11.5cm/4.53in → severe wasting

Chapter 47 Malnutrition

TREATMENT World Health Organisation (WHO) 10 steps for severe malnutrition management ▪ Treat/prevent hypoglycemia (blood glucose < 3mmol/L) ▫ Prevention: urgent small frequent feeds ▫ Treatment: dextrose water ▪ Treat/prevent hypothermia (rectal/oral temperature < 35.5°C/95.9°F) ▪ Treat/prevent dehydration ▫ Prevention: oral rehydration (sunken eyes, no urine passed for 12 hours, thirst) ▫ Treatment: intravenous fluid infusion (lethargy/consciousness loss) ▪ Correct electrolyte imbalances ▫ Total-body sodium excess (likely in severe malnourishment) avoid high sodium solutions, feeds ▫ Specialized refeeding milk feeds contain

▪

▪

▪

▪

▪ ▪

necessary electrolytes Treat infection ▫ Broad-spectrum antibiotics ▫ In endemic regions: children < one year of age, assume presence of parasitic infection → mebendazole Correct micronutrient deficiencies ▫ Supplements: multivitamin, vitamin A, potassium, magnesium, iron, folic acid, zinc, copper Start cautious feeding ▫ WHO recommended starter formula “F-75” Achieve catch-up growth ▫ WHO recommended catch-up formula “F-100” ▫ Reintroduce normal meals Provide sensory stimulation, emotional support Prepare for discharge, post-recovery follow-up

KWASHIORKOR osms.it/kwashiorkor PATHOLOGY & CAUSES

SIGNS & SYMPTOMS

▪ Sufficient calorie intake, severely inadequate protein intake ▪ AKA “the sickness the baby gets when the new baby comes” ▫ Older children in food-scarce environments weaned off breast milk → carbohydrate rich diet ▪ Characterization ▫ Inadequate adaptation; insufficient dietary nutrient intake ▫ Extreme protein deficiency → ↓ liver protein synthesis → osmotic imbalance → edema, abdominal distension ▫ ↓ lymphatic function → ↓ fluid recovery, low lipid absorption → further abdominal distension

▪ Bilateral pitting edema, distended abdomen (rarely ascites; typically weak abdominal musculature, hepatomegaly) ▪ Hepatomegaly (with fatty infiltration) ▪ Muscle wasting ▪ Integumentary change (thinning hair, skin/ hair depigmentation, dermatitis) ▪ Irritability, listless affect

DIAGNOSIS DIAGNOSTIC IMAGING Chest X-ray ▪ Infection workup: respiratory distress

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LAB RESULTS

▪ Hypoglycemia ▪ ↓ blood lipids ▪ Hypoalbuminemia, hypoproteinemia (transferrin, essential amino acids, lipoprotein) ▪ Anemia (normochromic-normocytic/ hypochromic microcytic/macrocytic) ▪ Electrolyte depletion → hypocalcemia, hypophosphatemia, hypomagnesemia, hypokalemia

Infection workup ▪ Blood culture ▪ Common endemic infection tests (e.g. HIV, malaria, parasites)

OTHER DIAGNOSTICS Anthropometry ▪ Body weight < 62.36% expected body weight for age ▪ Weight-for-height Z-score < -3 standard deviations → severe wasting ▪ Mean upper arm circumference < 11.5cm/4.53in → severe wasting

TREATMENT MEDICATIONS

▪ Prophylactic antibiotics ▫ Malnutrition-induced immunodeficiency compensation

OTHER INTERVENTIONS

▪ Correct glycemic, electrolyte, hydration abnormalities ▪ Protein refeeding, gradually ↑ protein amount ▫ Excessively-rapid protein refeeding → protein catabolism → urea accumulation → may overwhelm already-impaired liver → liver failure

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Figure 47.1 A child with kwoshiorkor.

Chapter 47 Malnutrition

MARASMUS osms.it/marasmus PATHOLOGY & CAUSES ▪ Severe malnutrition: inadequate calorie/ protein intake ▪ Insufficient energy balance → evolving adaptation ▫ ↓ intake, ↑ loss (e.g. emesis, diarrhea, burns), ↑ energy expenditure → negative energy balance ▫ Negative energy balance adaptations: ↓ physical activity, lethargy, ↓ basal metabolic rate, growth retardation, weight loss

SIGNS & SYMPTOMS ▪ Emaciated appearance (“wizened” facial appearance), head (compared to body) appears disproportionately large ▪ Severe muscle wasting → redundant skin folds ▪ Subcutaneous fat loss ▪ Irritability, weakness, lethargy

DIAGNOSIS DIAGNOSTIC IMAGING Chest X-ray ▪ Infection workup: respiratory distress

Infection workup ▪ Blood culture ▪ Common endemic infection tests (e.g. HIV, malaria, parasites)

OTHER DIAGNOSTICS Anthropometry ▪ Body weight < 62.36% expected body weight for age ▪ Weight-for-height Z-score < -3 standard deviations → severe wasting ▪ Mean upper arm circumference < 11.5cm/4.53in → severe wasting

TREATMENT MEDICATIONS

▪ Prophylactic antibiotics ▫ Malnutrition-induced immunodeficiency compensation

OTHER INTERVENTIONS

▪ Correct glycemic, electrolyte, hydration abnormalities ▪ Protein refeeding, gradually ↑ protein amount ▫ Excessively-rapid protein refeeding → protein catabolism → urea accumulation → may overwhelm already impaired liver → liver failure

LAB RESULTS

Hypotension Hypothermia Hypoglycemia Anemia (normochromic-normocytic/ hypochromic microcytic/macrocytic) ▪ Hyponatremia +/- non-specific electrolyte imbalances ▪ ▪ ▪ ▪

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MINERAL DEFICIENCIES GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Inadequate dietary minerals (vital for normal health/function) ▪ Minerals ▫ 5% of average diet

CAUSES

▪ Poor diet/required mineral absorption ▪ Macrominerals ▫ Calcium, phosphorus, potassium, sulfur, sodium, chloride, magnesium ▫ Adults > 100mg/day/< 1% of total body weight required ▪ Trace minerals/elements ▫ Iron, zinc, copper, manganese, iodine, fluoride, cobalt, selenium ▫ Adults 1–100mg/day/ 12 years old: 150μg/day ▫ Pregnant, lactating: 250μg/day

CAUSES Malnutrition ▪ Body does not create iodine; diet only source ▪ High deficiency rates ▫ Europe, Africa, Asia ▪ Low deficiency rates ▫ Industrialized countries (most water, salt, bread iodized)

RISK FACTORS

▪ Pregnant/nursing, children, vegan/glutenfree individuals

SIGNS & SYMPTOMS Goiter ▪ Thyroid enlarges because ↑ TSH ▫ Compensation strategy: decreased thyroid hormone production → goiter formation ▪ Low iodine levels → ↓ T4, T3 production → ↑ thyroid stimulating hormone (TSH) attempts restoration of T4, T3 production → TSH stimulates thyroid growth

▪ Often, goiter diffuse initially; eventually may develop nodules (can enlarge, calcify over time) ▪ If large → choking, difficulty swallowing/ breathing Hypothyroidism ▪ ↓ thyroid hormone levels (iodine necessary for production) ▪ Fatigue, constipation, weight gain, muscle weakness Pregnancy ▪ Miscarriages, premature delivery, fetal congenital abnormalities ▪ Child’s physical growth, mental development decrease Cretinism ▪ Infants, children: untreated iodine deficiency → cretinism (permanent intellectual disability, developmental deficiency)

DIAGNOSIS LAB RESULTS

▪ Iodine concentration in urine; site of ~90% ingested iodine, good site for current iodine nutrition measurement ▫ Mild iodine deficiency: 50–99μg/day ▫ Moderate deficiency: 20–49μg/day ▫ Severe deficiency: < 20μg/day

OTHER DIAGNOSTICS

▪ Thyroid size measurements (reflect iodine nutrition over extended periods)

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TREATMENT OTHER INTERVENTIONS

▪ Iodine supplementation, iodine enriched foods ▫ Dairy: cheese, milk, yogurt ▫ Meat/alternatives: shellfish, saltwater fish, eggs

ZINC DEFICIENCY osms.it/zinc-deficiency PATHOLOGY & CAUSES ▪ Insufficient zinc intake ▪ Recommended doses ▫ Oral intake: 4–15mg/day ▫ Dietary intake: 8mg/day (children), 11mg/day (biologically male), 9mg/day (biologically female)

CAUSES

▪ Malnutrition ▪ Malabsorption diseases (chronic inflammatory bowel disease) ▫ Poor zinc absorption; absorbed in small intestine ▪ Prolonged breastfeeding ▫ Individual’s breast milk contains low zinc levels, infant exclusively breastfed ▪ Acrodermatitis enteropathica ▫ Autosomal, recessive, inherited intestinal zinc absorption (partial) defect

SIGNS & SYMPTOMS ▪ Skin, nails, hair ▫ Skin lesions, acne, eczema, alopecia, compromised wound healing ▪ Immune dysfunction → respiratory, gastrointestinal infections ▪ Delayed growth/development ▪ Impaired vision, smell, taste ▪ Delayed sexual maturation ▪ Appetite loss

DIAGNOSIS LAB RESULTS

▪ Measure zinc biomarkers ▫ Red blood cell linoleic acid to dihomo-ylinolenic acid (LA:DLGA) ratios

TREATMENT OTHER INTERVENTIONS

▪ Zinc supplementation, zinc enriched foods ▫ Fortified cereals, whole grains, nuts, meats (oysters, beef, lamb)

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NOTES

MITOCHONDRIAL DISEASE GENERALLY, WHAT IS IT? PATHOLOGY & CAUSES ▪ Impaired mitochondrial activity → disorder

CAUSES

▪ Nuclear, mitochondrial DNA mutations

SIGNS & SYMPTOMS ▪ Muscle weakness, visual/hearing problems, neurological signs/symptoms, heart, kidney, respiratory disorders

DIAGNOSIS DIAGNOSTIC IMAGING

LAB RESULTS

▪ Molecular genetic testing ▫ Southern blot (deletions/duplications) ▫ Sequencing ▫ Polymerase chain reaction (PCR) ▪ Serum tests ▪ ↑ levels metabolites made by shunt pathways

TREATMENT MEDICATION

▪ Enzyme stimulation

OTHER INTERVENTIONS ▪ Supplementation ▪ Diet

MRI ▪ Brain lesions

MITOCHONDRIAL MYOPATHY osms.it/mitochondrial-myopathy PATHOLOGY & CAUSES ▪ Mitochondrial disorders ▫ Inability to produce ATP ▪ Muscles and brain: require high levels of ATP ▫ Only muscles: myopathy ▫ Muscles, brain: encephalomyopathy ▪ Variable clinical phenotypes with myopathy as main/minor feature; phenotypes can overlap

Isolated myopathy ▪ Nuclear DNA mutations ▫ Respiratory chain defects, coenzyme Q10 deficiency ▪ Rarely caused by mtDNA mutations Chronic progressive external ophthalmoplegia, Kearns–Sayre syndrome ▪ Autosomal dominant/autosomal recessive/ maternal inheritance ▪ Nuclear DNA, mtDNA mutations can cause same clinical presentation

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Encephalomyopathy ▪ Infants, children Myopathy with diseases of multiple systems ▪ Barth’s syndrome ▫ X-linked inheritance; TAZ gene mutation; associated with cardiomyopathy, muscle weakness, neutropenia ▪ Myoclonic epilepsy with ragged red fibers (MERRF) ▫ mtDNA mutation → maternally inherited ▪ Mitochondrial encephalomyopathy, lactic acidosis, stroke-like episodes (MELAS) ▫ mtDNA mutation → maternally inherited

CAUSES

▪ Nuclear/mitochondrial DNA (mtDNA) mutation

RISK FACTORS

▪ Mitochondrial DNA maternally inherited; only biological females can pass mutations to children

SIGNS & SYMPTOMS Isolated myopathy ▪ Fatigue, myalgia, chronic progressive extraocular ophthalmoplegia (CPEO), progressive extraocular muscles paresis, bilateral ptosis Kearns–Sayre syndrome ▪ Chronic progressive extraocular ophthalmoplegia ▪ Retinal pigment degeneration ▪ Onset < 20 years old Encephalomyopathy in infants, children ▪ Hypotonia, respiratory muscle weakness, poor feeding, seizures Barth’s syndrome ▪ Underdeveloped, weak muscles; delayed growth; MERRF ▪ Myoclonus (visible muscle spasms) ▪ Neurological defects ▪ Usually begins after normal early development

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MELAS ▪ Stroke-like episodes ▪ Lactic acidosis ▪ Hearing, weight loss

DIAGNOSIS DIAGNOSTIC IMAGING MRI ▪ Lesion within deep gray matter in both hemispheres, cerebrum/cerebellum atrophy, lesions similar to stroke

LAB RESULTS

▪ Serum ▫ ↑ lactate and pyruvate, ↑ alanine, ↑ creatine kinase ▪ Urine analysis ▫ Tests for organic acids (↑ Krebs cycle intermediates) ▫ Myoglobinuria (in isolated myopathy) ▪ Muscle biopsy ▫ Mitochondrial buildup in subsarcolemmal area of affected muscle → ragged red fibers ▪ Histochemical studies ▫ Gomori trichrome stain: ragged red fibers ▫ Succinate dehydrogenase: ragged blue fibers ▪ Biochemical analysis ▫ ↓ respiratory chain complex function

OTHER DIAGNOSTICS Electromyography (EMG) ▪ Short-lasting, polyphasic motor unit potentials

Chapter 49 Mitochondrial Disease

TREATMENT OTHER INTERVENTIONS

▪ Aerobic exercises ▪ Coenzyme Q10, L-carnitine, creatine supplementation ▪ MELAS ▫ Intravenous arginine hydrochloride with saline, fluids with dextrose ▪ Avoid ▫ Valproic acid, tetracyclines, barbiturates, chloramphenicol, aminoglycosides, metmorfin

PYRUVATE DEHYDROGENASE DEFICIENCY osms.it/PDH-deficiency PATHOLOGY & CAUSES ▪ X-linked disease characterized by abnormal pyruvate metabolism

CAUSES

▪ E1 alpha gene mutation ▫ Pyruvate dehydrogenase E1 alpha subunit deficiency → ↓ production of acetyl-coenzyme A (CoA) → limited citrate production → citric acid cycle (Krebs cycle) impairment ▪ Impaired Krebs cycle ▫ Energy production disorder; brain needs energy from Krebs cycle → neurological symptoms ▫ Pyruvate accumulation → transformation to lactate, alanine → lactate buildup → lactic acidosis → metabolic symptoms ▪ Residual activity of enzyme determines clinical presentation ▫ Severe deficiency → congenital brain malformations

▫ Moderate deficiency → neurological symptoms onset in infancy/later childhood

COMPLICATIONS

▪ Intellectual disability, microcephaly, blindness ▪ Leigh syndrome ▫ Gray matter degeneration, capillary proliferation, focal necrosis

SIGNS & SYMPTOMS ▪ Metabolic disorders ▫ Lethargy, poor feeding, mental/ psychomotor delay ▪ Neurological symptoms ▫ Ataxia, hypotonia, progressive encephalopathy, abnormal eye movements, seizures, dystonia ▪ Acidosis respiratory symptoms ▫ Dyspnea, Cheyne–Stokes breathing, respiratory failure

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DIAGNOSIS DIAGNOSTIC IMAGING Magnetic resonance spectroscopy ▪ ↑ lactate levels MRI ▪ Cerebral atrophy ▪ Corpus callosum absence ▪ Medullary pyramids absence

LAB RESULTS

▪ Pyruvic acid test ▫ ↑ lactate, pyruvate levels in blood, cerebrospinal fluid ▪ Serum, urine analysis ▫ ↑ alanine in serum, urine

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TREATMENT OTHER INTERVENTIONS

▪ Thiamine, carnitine, lipoic acid cofactor supplementation ▪ Ketogenic diet ▫ Controls lactic acidosis ▪ Dichloroacetate ▫ Stimulation of pyruvate dehydrogenase

NOTES

NOTES

MUCOPOLYSACCHARIDOSIS GENERALLY, WHAT IS IT? PATHOLOGY & CAUSES ▪ Metabolic disorder: dysfunction of lysosomal enzymes involved in glycosaminoglycans (GAG) breakdown ▪ Lysosomal storage disease ▪ Impaired glycosaminoglycans metabolism → GAGs (heparan, dermatan, keratan, chondroitin sulfate) accumulation within lysosomes → damage of cells, tissues, organs ▫ Heparan (in nervous tissue): decline of neurological function ▫ Keratan (in skeletal system): skeletal abnormalities ▫ Dermatan (in skin, lungs, heart valves): skin changes, mitral valve damage, lung diseases

▪ Residual enzyme activity determines life expectancy MPS VI: Maroteaux–Lamy syndrome ▪ Dermatan, chondroitin sulfate accumulation ▪ Mild to severe forms MPS VII: Sly syndrome ▪ Heparan, dermatan, chondroitin sulfate accumulation ▪ Mild to severe forms MPS IX: Natowicz syndrome (rarest type) ▪ Hyaluronidase deficit → hyaluronan accumulation

CAUSES

▪ Inherited autosomal recessive, except for MPS II (X-linked)

TYPES

COMPLICATIONS

MPS I: Hurler syndrome ▪ Attenuated MPS I ▪ Severe MPS I ▫ Associated with progressive intellectual disability, earlier onset

▪ ▪ ▪ ▪ ▪ ▪ ▪

MPS II: Hunter syndrome ▪ Mild to severe forms MPS III: Sanfilippo syndrome ▪ Four forms: A, B, C, D ▪ Early life clinical presentation ▪ Lack of appropriate enzymes → accumulation heparan sulfate → neurological damage → adolescent death MPS IV: Morquio syndrome ▪ Two forms: A, B ▪ Keratan, chondroitin sulfate accumulation

Hearing, vision loss Skeletal abnormalities, limited movement Valve dysfunction Recurrent respiratory infections Joint stiffness Behavioral problems, intellectual disability C1-C2 subluxation → cord compression → central apnea ▪ Hydrocephalus

SIGNS & SYMPTOMS MPS III: Sanfilippo syndrome ▪ Three stages ▫ Mental, motor skills delays (usually between ages two–six) ▫ Sleep disorders, hyperactivity with aggressiveness, dementia ▫ Inability to walk until age of ten

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▪ Visual, hearing problems; CNS degeneration; intellectual disability; excessive hair growth MPS IV: Morquio syndrome ▪ Skeletal abnormalities, joint stiffness, blurry cornea, common ear infections, hearing loss, breathing difficulties ▪ Severe forms: life expectancy of four decades ▪ Mild forms: life expectancy up to seven decades MPS VI: Maroteaux–Lamy syndrome ▪ Large head, tongue; rough facial features; corneal cloudiness; heart, hearing problems; short growth; progressive, limiting skeletal disorders; spinal cord damage from spinal stenosis ▪ Mild form: slower progression MPS VII: Sly syndrome ▪ Hydrops fetalis; skeletal, soft tissue abnormalities MPS IX: Natowicz syndrome ▪ Pain, swelling nodular masses of soft tissue around joints

DIAGNOSIS DIAGNOSTIC IMAGING CT scan/MRI ▪ Maroteaux–Lamy: spinal canal stenosis, cord compression X-ray ▪ Sanfilippo syndrome: dysostosis multiplex ▪ Morquio syndrome: dysostosis multiplex, vertebra flattening, pectus carinatum, odontoid dysplasia ▪ Sly syndrome: flared ribs, pectus carinatum

LAB RESULTS

▪ Prenatal diagnosis: enzyme activity measurement in amniotic cells ▪ Enzyme test: ↓ activity

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Urine analysis ▪ ↑ glycosaminoglycans ▫ Sanfilippo syndrome: ↑ heparan sulfate ▫ Morquio syndrome: ↑ keratan sulfate ▫ Maroteaux-Lamy syndrome: ↑ dermatan sulfate ▫ Sly syndrome: ↑ dermatan, heparan sulfate

TREATMENT OTHER INTERVENTIONS ▪ ▪ ▪ ▪ ▪ ▪

No definitive cure Enzyme replacement therapy Hematopoietic bone marrow transplant Home exercises Gene therapy in development Treat associated complications

Chapter 50 Mucopolysaccharidosis

HUNTER SYNDROME osms.it/hunter-syndrome PATHOLOGY & CAUSES ▪ X-linked disorder ▫ Impaired metabolism of glycosaminoglycans (GAG) → heparan, dermatan sulfate accumulation

TYPES MPS II A (severe form) ▪ Affects children in early life MPS II B (mild form) ▪ Symptoms later in life; life expectancy up to seventy years

CAUSES

▪ Mutation of IDS gene → enzyme iduronate2-sulfatase dysfunction → ineffective breakdown of GAG in lysosomes → accumulation; cell, tissue, organ damage

COMPLICATIONS MPS II A ▪ Carpal tunnel syndrome ▪ Airway obstruction ▪ Heart problems ▫ Heart valve leaflet dysfunction; thickening of the myocardium → coronary blood vessel compression ▪ Intellectual disability ▪ Seizures MPS II B ▪ Valvular heart disease, hydrocephalus

SIGNS & SYMPTOMS ▪ Death due to heart and lung problems ▪ Lack of blurry cornea differentiates Hunter syndrome from Hurler syndrome

MPS II A ▪ Early life ▫ Rough facial features (enlarged head, flat bridge of nose, bulging forehead) ▫ Skeletal abnormalities, stiff joints, limited movement ▫ Intellectual disability ▫ Skin (ivory colored lesions) ▪ Later life ▫ Progressive neurological decline ▫ Hydrocephalus ▫ Seizures MPS II B ▪ Later onset: milder symptoms ▪ Rough facial features ▪ Rigid joints ▪ Hearing, pulmonary disorders

DIAGNOSIS DIAGNOSTIC IMAGING X-ray ▪ Skeletal abnormalities CT scan/MRI ▪ Cord compression level, odontoid hypoplasia assessment

LAB RESULTS

▪ Prenatal diagnosis ▫ ↓ enzyme activity in amniocytes ▪ Enzyme-linked immunosorbent assay (ELISA) ▫ ↑ heparan, dermatan sulfate in blood, urine ▪ Enzyme activity test on leucocytes/ fibroblasts ▫ ↓ activity ▪ Bone marrow cells histology ▫ Alder–Reilly granulations

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OTHER DIAGNOSTICS

▪ Physical examination ▫ Characteristic findings

ECG, pulmonary testing ▪ Determination of functions

TREATMENT OTHER INTERVENTIONS

▪ No definitive cure ▪ Address complications ▪ Recombinant human iduronate sulfatase ▫ dursulfase; enzyme replacement therapy ▪ Hematopoietic bone marrow transplant

HURLER SYNDROME (MPS I) osms.it/hurler-syndrome PATHOLOGY & CAUSES ▪ Autosomal recessive disorder; glycosaminoglycans buildup ▪ Alpha-L iduronidase deficiency → heparan sulfate accumulation in lysosomes → cell, tissue, organ damage

TYPES Attenuated form ▪ Better prognosis ▪ Presentation: age two–adolescence ▪ Life expectancy: twenties–middle age Severe form ▪ Presentation: within first two years ▪ Life expectancy: about 10 years

CAUSES

▪ IDUA gene mutation

COMPLICATIONS

▪ Carpal tunnel syndrome ▪ Heart valve abnormalities → heart failure ▪ Thick secretions → frequent sinopulmonary infections ▪ Enlargement of tonsils, adenoids → airway obstruction → sleep apnea ▪ Vision, hearing loss

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▪ C1-C2 subluxation → spinal cord compression → central apnea ▪ Hydrocephalus

SIGNS & SYMPTOMS ▪ Developmental delays; in severe form, progressive intellectual disability ▪ Attenuated form; normal intelligence ▪ Rough facial features ▫ Enlarged head, nose, cheeks, lips, tongue ▪ Repeated ear, respiratory infections ▪ Retinal degeneration, corneal blurriness ▪ Hepatosplenomegaly ▪ Hernias (umbilical, inguinal) ▪ Rib, hip, pelvis, vertebral abnormalities ▪ Stiff joints, claw-like hands ▪ Long bones thicken ▪ Thickened skin, short neck

DIAGNOSIS DIAGNOSTIC IMAGING X-ray ▪ Enlargement of skull, frontal bulging ▪ Lumbar, thoracic vertebral hypoplasia ▪ Pelvis hypoplasia, small femoral heads ▪ Metacarpals narrow proximally, widen distally

Chapter 50 Mucopolysaccharidosis

LAB RESULTS

▪ Enzyme activity in fibroblasts ▫ ↓alpha-L iduronidase ▪ ↑ heparan sulfate

OTHER DIAGNOSTICS

▪ Physical examination ▫ Characteristic findings

TREATMENT SURGERY

▪ Hand, foot abnormalities

Figure 50.1 An X-ray image of the head of an infant with Hurler syndrome, showing a J-shaped sella turcica.

OTHER INTERVENTIONS

▪ No definitive cure ▪ Address complications ▪ Recombinant human alpha-L-iduronidase ▫ Laronidase (replaces missing enzyme) ▪ Bone marrow transplant

Figure 50.2 X-ray image of the hands of an infant with Hurler syndrome. The metacarpals are pointed at the proximal ends.

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NOTES

PURINE & PYRIMIDINE METABOLISM DISORDERS

GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Enzymatic disorders in biochemical pathways crucial for biosynthesis of nucleobases → impaired nucleotide formation ▫ Adenosine triphosphate (ATP), guanosine monophosphate (GMP) ▪ Inherited conditions

SIGNS & SYMPTOMS ▪ Disease-specific ▪ Lesch–Nyhan syndrome ▫ Kidney stones, hematuria, urinary tract infections (UTIs), arthritis, tophi ▫ Spasticity, chorea, hyperactive reflexes, grimacing, dystonia ▫ Intellectual impairment, developmental delay, self mutilation, lack of speech, compulsions ▪ Orotic aciduria ▫ Glossitis, growth failure, developmental delay, intellectual disability, congenital malformation, immunodeficiency

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DIAGNOSIS LAB RESULTS

▪ No activity in one enzyme, excess in one metabolite

OTHER DIAGNOSTICS

▪ Clinical evaluation, genetic testing

TREATMENT MEDICATIONS

▪ Lesch–Nyhan syndrome ▫ Xanthine oxidase inhibitors, benzodiazepines, baclofen, gabapentin, neuroleptics

OTHER INTERVENTIONS

▪ Lesch–Nyhan syndrome ▫ Lithotripsy, protecting devices ▪ Orotic aciduria ▫ Pyrimidine replacement therapy

Chapter 51 Purine & Pyrimidine Metabolism Disorders

LESCH–NYHAN SYNDROME osms.it/lesch-nyhan_syndrome PATHOLOGY & CAUSES ▪ Rare disease; excess of uric acid

CAUSES

▪ Behavioural, cognitive ▫ Intellectual impairment, developmental delay, self-mutilation (e.g. finger, lip biting), lack of speech, compulsions (e.g. spitting)

▪ X-linked recessive mutation in HPRT gene → lack of enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRT) ▪ Decreased HGPRT activity, recycling of cell waste products → increased transformation of cell waste products into uric acid → increased uric acid

LAB RESULTS

COMPLICATIONS

OTHER DIAGNOSTICS

▪ Uric acid precipitation in urine → urate stones in kidney, ureter, bladder → renal failure ▪ Uric acid deposition in joints → gout-like arthritis (AKA juvenile gout) ▪ Central nervous system (CNS) alterations, may be due to ▫ Uric acid accumulation → oxidative damages ▫ Decreased nucleotide production → decreased dopamine production → lesions in striatal dopaminergic pathways ▪ Insufficient vitamin B12 → megaloblastic anemia

SIGNS & SYMPTOMS

DIAGNOSIS ▪ HGPRT activity in blood, other tissues ▪ Increased urate-to-creatinine ratio in urine ▪ Hyperuricosuria, hyperuricemia

▪ Clinical evaluation, genetic testing

TREATMENT MEDICATIONS

▪ Xanthine oxidase inhibitors to reduce production of uric acid ▪ Benzodiazepines, baclofen for neurological issues ▪ Benzodiazepines, gabapentin, neuroleptics for behavioural issues

OTHER INTERVENTIONS

▪ Lithotripsy for kidney stones ▪ Protecting devices for behavioural issues

▪ Uric acid hyperproduction ▫ Urate precipitation in urinary tract: “orange sand” deposits in diapers of infants; kidney stones → hematuria, UTIs ▫ Arthritis, tophi ▪ Neuromuscular ▫ Spasticity, chorea, hyperactive reflexes, grimacing, dystonia

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OROTIC ACIDURIA osms.it/orotic-aciduria PATHOLOGY & CAUSES ▪ Extremely rare disease; alteration in pyrimidine synthesis → excessive excretion of orotic acid (intermediate metabolite) in urine

CAUSES

▪ Autosomal recessive disease ▪ Defect in activity of uridine monophosphate synthetase (UMPS) → decreased UTP production and increased dihydroorotate accumulation ▫ Type 1: both enzymes affected; orotidine monophosphate decarboxylase (OMP-decarboxylase), orotate phosphoribosyltransferase (OPRT) ▫ Type 2: only OMP-decarboxylase affected

COMPLICATIONS

▪ Decreased production of pyrimidin, cofactors needed for erythropoiesis → megaloblastic anemia unresponsive to vitamin B12 supplementation, folic acid

SIGNS & SYMPTOMS ▪ ▪ ▪ ▪ ▪ ▪

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Glossitis Growth failure Developmental delay Intellectual disability Congenital malformation Immunodeficiency

DIAGNOSIS LAB RESULTS

▪ Anemia ▪ Orotic acid dosage in urine

OTHER DIAGNOSTICS ▪ Clinical evaluation

TREATMENT OTHER INTERVENTIONS

▪ Pyrimidine replacement therapy ▫ Uridine monophosphate

NOTES

NOTES

SPHINGOLIPIDOSIS GENERALLY, WHAT IS IT? PATHOLOGY & CAUSES ▪ Lysosomal storage diseases ▪ Metabolic disorders characterized by dysfunctional metabolism of sphingolipids ▪ Sphingolipids accumulate within various tissues’ cell lysosomes → affected organ damage ▪ Causes genetic defects → lysosomal enzyme deficiency ▪ Inheritance mode autosomal recessive, except in Fabry disease (X-linked recessive)

SIGNS & SYMPTOMS ▪ Vary depending on organs affected, sphingolipid storage extent

DIAGNOSIS ▪ Clinical presentation, family history ▪ Enzymatic assays ▪ Mutation analysis

TREATMENT ▪ Enzyme replacement therapy ▪ Gene therapy

FABRY DISEASE osms.it/fabry-disease PATHOLOGY & CAUSES ▪ Lysosomal enzyme alpha galactosidase A (a-GAL A) deficiency ▪ → Accumulation of a sphingolipid, called glycoglobotriaosylceramide (Gb3/ceramide trihexoside), within lysosomes ▪ Gb3 most commonly deposits in vessels, ganglions, kidneys, heart ▪ X-linked recessive inheritance pattern

COMPLICATIONS

SIGNS & SYMPTOMS ▪ Early presentation ▫ Acroparesthesias (severe peripheral neuropathic pain in extremities) ▫ Angiokeratomas (painless red to blue papules with hyperkeratosis), Telangiectasias (dilated vessels) presenting on the skin ▫ Gastrointestinal symptoms (e.g. abdominal pain, nausea, vomiting) ▫ Corneal opacities

▪ Affected organ dysfunction, vascular occlusions, infarctions

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▪ Later symptoms ▫ Progressive renal failure, cardiovascular disease, heat/cold intolerance, hypohidrosis (decreased sweat production), hearing loss

DIAGNOSIS LAB RESULTS

▪ Enzymatic assay for alpha galactosidase ▪ Genetic testing

TREATMENT OTHER INTERVENTIONS Figure 52.1 Numerous angiokeratomas on the skin of an individual with Fabry disease.

▪ Symptom management (e.g., analgesics) ▪ Enzyme replacement therapy ▪ Gene therapy

GAUCHER'S DISEASE osms.it/gauchers-disease PATHOLOGY & CAUSES ▪ Most common lysosomal storage disease ▪ Lysosomal enzyme glucocerebrosidase deficiency ▪ → Accumulation of sphingolipid glucocerebroside in cellular lysosomes, particularly macrophages resembling crumpled tissue paper (AKA Gaucher cells) ▪ Glucocerebroside also deposits in liver, spleen, bone marrow, bones, kidneys, lungs, central nervous system (CNS) ▪ Autosomal recessive pattern of inheritance

TYPES

▪ Three types based upon CNS involvement ▫ Type I: absence of CNS involvement ▫ Type II: acute neuronopathic form ▫ Type III: subacute or chronic neuronopathic form

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COMPLICATIONS

▪ Thrombocytopenia, anemia, bone disease, neurological deficits

SIGNS & SYMPTOMS ▪ Hepatosplenomegaly ▪ Pancytopenia, due to bone marrow infiltration with Gaucher cells, hypersplenism, leads to ▫ Easy bruising (thrombocytopenia) ▫ Fatigue (anemia) ▪ Bone disease (e.g., osteoporosis, aseptic necrosis of various bones); most commonly affects the femur ▪ Neurological complications (e.g. seizures, hypotonia, cognitive/olfactory abnormalities) present only in types II, III

Chapter 52 Sphingolidosis

DIAGNOSIS LAB RESULTS

▪ Enzymatic assay to confirm glucocerebrosidase deficiency ▪ Genetic testing ▫ Prenatal diagnosis available

TREATMENT OTHER INTERVENTIONS

▪ Enzyme replacement therapy

Figure 52.2 A section of bone marrow demonstrating numerous crinkled paper macrophages, or Gaucher cells, in an individual with Gaucher’s disease.

KRABBE DISEASE osms.it/krabbe-disease PATHOLOGY & CAUSES ▪ AKA globoid cell leukodystrophy ▪ Lysosomal enzyme galactocerebrosidase deficiency ▪ Lipids galactocerebroside and psychosine buildup → ▫ Globoid cell formation (multinucleated macrophages) ▫ Oligodendrocyte destruction → demyelination ▪ Autosomal recessive inheritance pattern ▪ Progressive damage to nervous system → fatal

SIGNS & SYMPTOMS ▪ Usually present within first six months of life ▪ Peripheral motor, sensory neuropathy, loss of sensation, muscle atrophy in extremities

▪ Central nervous system dysfunction ▫ Irritability, developmental delay, spasticity, optic atrophy, seizures, weakness

DIAGNOSIS LAB RESULTS

▪ Enzymatic assay to measure galactocerebrosidase activity in leukocytes ▪ Microscopy shows demyelination, characteristic globoid cells (i.e, multinucleated macrophages containing ↑periodic acid-Schiff (PAS) positive materials) ▪ Genetic testing

TREATMENT OTHER INTERVENTIONS

▪ Affective therapy not yet available ▪ Hematopoietic stem cell transplantation is beneficial, especially in early onset of symptoms

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METACHROMATIC LEUKODYSTROPHY osms.it/metachromatic-leukodystrophy PATHOLOGY & CAUSES ▪ Lysosomal enzyme arylsulfatase A (ARSA) deficiency → ↑ cerebroside sulfate storage in various tissues, progressive demyelination ▪ Metachromatic leukodystrophy (MLD) also caused by saposine deficiency (i.e. protein that normally stimulates ARSA) ▪ Autosomal recessive inheritance pattern

COMPLICATIONS

▪ Central, peripheral nervous system dysfunction, paralysis, coma ▪ If untreated, fatal in 5–6 years

SIGNS & SYMPTOMS ▪ Usually develops in late infancy, but can also present later in life ▪ Infantile onset ▫ Gait difficulties ▫ Developmental delay

▫ Muscle tone, strength abnormalities ▫ Ataxia ▫ Peripheral neuropathy ▫ Progressive vision loss ▪ Late onset ▫ Behavioral difficulties ▫ Psychiatric disorder ▫ Dementia

DIAGNOSIS LAB RESULTS

▪ Enzymatic assay for ARSA ▪ Sulfatides measurement in urine to confirm diagnosis ▪ Genetic testing

TREATMENT OTHER INTERVENTIONS

▪ Hematopoietic stem cell transplantation ▪ Gene therapy ▪ Enzyme replacement

NIEMANN–PICK DISEASE osms.it/niemann-pick_disease PATHOLOGY & CAUSES ▪ Group of disorders caused by defects in sphingomyelin storage ▪ Types A, B are characterized by enzyme acid sphingomyelinase deficiency → sphingomyelin accumulation in macrophage lysosomes in various tissues

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▪ Type C is characterized by impaired cellular processing, low-density lipoprotein (LDL)cholesterol transport ▪ Autosomal recessive inheritance pattern

Chapter 52 Sphingolidosis

COMPLICATIONS

▪ Progressive neurodegeneration, developmental delay, interstitial lung disease

SIGNS & SYMPTOMS ▪ Hepatosplenomegaly, hypersplenism → thrombocytopenia ▪ Various neurologic deficits ▫ Ataxia, dysarthria, dysphagia, dystonia ▪ Developmental delay ▪ Interstitial lung disease, recurrent respiratory infections ▪ Lipid abnormalities ▪ Dementia/depression/bipolar disease/ schizophrenia (in adults) ▪ Macular cherry red spot seen on fundoscopy examination ▫ Fovea appears bright red compared to rest of retina where lipids are accumulated

TREATMENT ▪ No treatment proven to modify onset/ progression of disease

MEDICACTIONS

▪ Miglustat (glycosphingolipids biosynthesis inhibitor) may be beneficial for type C

OTHER INTERVENTIONS

▪ Physical/occupational therapy, nutritional assessments

DIAGNOSIS LAB RESULTS

▪ Types A, B ▫ Enzymatic assay for sphingomyelinase ▪ Type C ▫ Impaired response to LDL-cholesterol in cultured fibroblasts ▪ Histology shows large lipid laden macrophages in reticuloendothelial system (AKA foam cells) ▪ Genetic testing

Figure 52.3 Numerous lipid-laden macrophages in the spleen of an individual with Niemann–Pick disease.

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TAY–SACHS DISEASE osms.it/tay-sachs_disease PATHOLOGY & CAUSES ▪ Hexosaminidase A deficiency → glycolipid GM2 ganglioside buildup in neuronal lysosomes ▪ Autosomal recessive inheritance pattern

TREATMENT OTHER INTERVENTIONS

▪ Symptom reduction/infection prevention

COMPLICATIONS

▪ Progressive neurodegeneration ▪ Mental/physical ability deterioration ▪ Death at ages 2–5, primarily → pneumonia

SIGNS & SYMPTOMS ▪ Typically presents at 2–6 months of age ▪ Progressive motor skill loss with hyperreflexia, hypotonia ▪ Physical ability deterioration ▫ Blindness, deafness, dysphagia, dysarthria ▪ Milder symptoms in late onset Tay–Sachs disease ▪ Cherry red spot macula sign a characteristic finding on fundoscopy

DIAGNOSIS LAB RESULTS

▪ Enzymatic assay for hexosaminidase A ▪ Genetic testing

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Figure 52.4 A cherry red spot on the retina of an individual with Tay–Sachs disease.

NOTES

NOTES

WATER SOLUBLE VITAMINS DEFICIENCY

GENERALLY, WHAT IS IT? PATHOLOGY & CAUSES ▪ Vitamin: micronutrient that participates in essential cellular function

SIGNS & SYMPTOMS ▪ See individual disorders

DIAGNOSIS

CAUSES

▪ Insufficient water-soluble vitamin intake → ↑ demand, malabsorption, loss → insufficient for body’s metabolic needs

COMPLICATIONS

▪ Chronic water-soluble vitamin deficiency → specific clinical disorders

OTHER DIAGNOSTICS

▪ History, clinical presentation

TREATMENT OTHER INTERVENTIONS

▪ ↑ dietary intake ▪ Synthetic formulation supplementation ▪ Address complications

FOLATE (VITAMIN B9) DEFICIENCY osms.it/folate-(vitamin-b9)-deficiency PATHOLOGY & CAUSES ▪ Insufficient folate (pteroylglutamic acid) for body’s metabolic needs ▪ Body cannot synthesize, normally maintains low stores ▪ Folate must be obtained in diet; lack for several weeks → deficiency ▪ Folate deficiency → impaired DNA synthesis during erythropoiesis (cell cycle S-phase delay) → uncoordinated cytoplasm, nuclei maturation in erythroblasts (nuclear-cytoplasmic asynchrony) → ineffective hematopoiesis

→ ↑ erythroid apoptosis + abnormally large erythrocytes (macrocytosis) → defective cells with fragile membranes → ↓ red blood cell (RBC) lifespan → anemia Sources of folate ▪ Present naturally in plant (especially dark green leafy vegetables), animal products (especially liver) ▪ Folic acid available in dietary supplements, fortified foods (e.g. cereals) Recommended dietary allowances (RDAs) ▪ Folate RDAs listed as micrograms of dietary folate equivalents (DFEs), reflect

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▪ ▪ ▪ ▪

higher bioavailability in food vs. supplement Child 9–13: 300mcg DFE 14+: 400mcg DFE Pregnancy: 600mcg Lactation: 500mcg

RISK FACTORS Insufficient diet ▪ Alcohol abuse ▫ Impairs folate absorption, metabolism; accelerates breakdown ▪ Chronic systemic disease; mental illness; advanced age ▪ Food insecurity ▪ Self-imposed dietary restrictions (e.g. vegan) ▪ ↓ vitamin C (cofactor for folate metabolism) Adequate diet but increased requirements ▪ Pregnancy, lactation, malignancy ▪ Disease state with ↑ cellular turnover (e.g. chronic hemolysis, exfoliative skin disease) Malabsorption ▪ E.g. celiac disease, inflammatory bowel disease, gastric surgery, achlorhydria Metabolic interference from medication ▪ E.g. methotrexate (folate antagonist), phenytoin, trimethoprim Hereditary forms ▪ Hereditary folate malabsorption (HFM) ▫ Loss-of-function mutation of PFCT gene encoding for proton-coupled folate transporter (rare, autosomal recessive disorder) ▪ Infantile cerebral folate deficiency ▫ Autoantibody against folate receptor in choroid plexus → prevents folate transport across blood-brain barrier

COMPLICATIONS

▪ Megaloblastic anemia ▪ Insufficient folate during gestation → ↑ neural tube defect risk ▪ Developmental delay, neurological disorders (child)

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SIGNS & SYMPTOMS ▪ Megaloblastic anemia ▫ Hypoxemia, tissue hypoxia → fatigue, activity intolerance, pallor, ↑ heart rate ▪ ↑ hemolysis → jaundice ▪ Atrophic glossitis, angular stomatitis, anorexia, nausea, diarrhea ▪ Hereditary folate malabsorption ▫ Manifests at age 1–3 months ▫ Failure to thrive, neurologic deterioration, megaloblastic anemia ▪ Infantile cerebral folate deficiency ▫ Manifests at age 4–6 months ▫ Irritability, ↓ sensorineural hearing, seizure, developmental delay, sleep disturbance → visual disturbance/loss

DIAGNOSIS LAB RESULTS

▪ ↓ RBC count; ↓ reticulocyte count; evidence of megaloblastic anemia (↑ mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH)) ▪ Macrocytosis, anisocytosis, poikilocytosis, hypersegmented neutrophils ▪ ↑ hemolysis markers ▫ ↓ indirect bilirubin, ↓ lactate dehydrogenase, ↓ haptoglobin ▪ ↓ serum folate ▪ Hypercellular bone marrow ▪ Infantile cerebral folate deficiency ▫ Cerebrospinal fluid (CSF) assay shows ↓ 5-methyltetrahydrofolate ▫ Serum, RBC folate normal

TREATMENT OTHER INTERVENTIONS

▪ Address complications (e.g. neurologic manifestation) ▪ ↑ dietary folate intake ▪ Folic acid supplementation (synthetic formulation)

Chapter 53 Water Soluble Vitamins Deficiency

NIACIN (VITAMIN B3) DEFICIENCY osms.it/niacin-(vitamin-b3)-deficiency PATHOLOGY & CAUSES ▪ Insufficient niacin (nicotinic acid, nicotinamide) for body’s metabolic needs ▫ Niacin obtained in diet ▫ Liver converts tryptophan to niacin (60g tryptophan = 1mg niacin) ▪ Active forms ▫ Nicotinamide adenine dinucleotide (NAD+), nicotinamide adenine dinucleotide phosphate (NADP+) ▪ Moderate/↑ doses of niacin supplement → ↓ total/low-density lipoprotein (LDL) cholesterol Sources of niacin ▪ Present in plant, animal products (e.g. dairy products, meat, grain (↓ corn), legumes, seeds) ▪ Dietary supplement; enriched grain, cereal, milk

Metabolic defects ▪ E.g. carcinoid syndrome → impaired tryptophan metabolism Accelerated niacin depletion ▪ Prolonged isoniazid use → ↓ pyridoxal phosphate (active form of vitamin B6) → ↑ tryptophan synthesis Tryptophan-to-niacin conversion nhibited by medication ▪ E.g. phenobarbital, chloramphenicol, pyrazinamide

COMPLICATIONS ▪ Pellagra

RDAs ▪ Children 9–13: 12mg ▪ 19+ male: 16mg; 19+ female: 14mg ▪ Pregnancy: 18mg ▪ Lactation: 14mg

RISK FACTORS Insufficient niacin/tryptophan intake ▪ Alcohol abuse ▪ Self-imposed dietary restrictions ▪ Chronic systemic disease; mental illness; advanced age ▪ Food insecurity ▪ Corn-based diet (unless corn treated with alkali, e.g. tortillas) Malabsorption ▪ E.g. bariatric surgery, malabsorptive disease states ▪ Hartnup disorder: defective tryptophan absorption

Figure 53.1 A desqauamating rash on the skin of an individual who presented with diarrhea and confusion. The diagnosis was confirmed as pellagra.

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SIGNS & SYMPTOMS ▪ Dermatitis ▫ Photosensitive, pigmented ▪ Diarrhea ▫ Potentially also vomiting ▪ Dementia ▫ Potentially also anxiety, disorientation ▪ Death ▫ Untreated pellagra potentially fatal

DIAGNOSIS LAB RESULTS

▪ ↓ N-methylnicotinamide (niacin metabolism product)

TREATMENT OTHER INTERVENTIONS ▪ Niacin supplementation ▪ ↑ dietary niacin/tryptophan ▪ Address complications

VITAMIN B12 DEFICIENCY osms.it/vitamin-b12-deficiency PATHOLOGY & CAUSES ▪ Insufficient B12 for body’s metabolic needs ▪ Active cobalamin (coenzyme) forms: methylcobalamin, 5-deoxyadenosylcobalamin ▪ Dietary cobalamin in food protein → gastric hydrochloric acid, protease-free cobalamin → cobalamin + intrinsic factor complex → distal ileum absorption ▪ Cobalamin essential for metabolic reactions involving hematopoiesis; protein, DNA, RNA, myelin synthesis; gastrointestinal tract mucosa maintenance ▫ Methylcobalamin: methionine synthase (folate-dependent enzyme) cofactor → methionine synthase catalyzes homocysteine remethylation to form methionine (essential amino acid for tissue growth/repair; hormone, protein, purine, pyrimidine synthesis) ▫ 5-deoxyadenosylcobalamin: L-methylmalonyl-coenzyme A conversion to succinyl CoA → enters citric acid cycle → lipid, protein energy production ▪ Impaired DNA synthesis during erythropoiesis (e.g. cell cycle S-phase delay) → uncoordinated cytoplasm,

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nuclei maturation in erythroblasts (nuclear-cytoplasmic asynchrony) → ineffective hematopoiesis → ↑ erythroid apoptosis, abnormally large erythrocytes (macrocytosis) → defective cells with fragile membranes → ↓ RBC lifespan → anemia Sources of cobalamin ▪ Animal products (meat, egg, dairy) ▪ Supplements, enriched food RDAs ▪ Child 9–13: 1.8mcg ▪ 14+: 2.4mcg

RISK FACTORS Insufficient intrinsic factor ▪ Pernicious anemia ▫ Autoimmune condition destroys parietal cells → ↓ intrinsic factor production → cobalamin not absorbed ▪ Gastrectomy, bariatric surgery ▪ Gastric atrophy Malabsorption ▪ Achlorhydria (acid promotes gastric mucosa absorption) ▫ ↑ age → ↑ risk ▫ ↓ acid due to medication (e.g. antacid,

Chapter 53 Water Soluble Vitamins Deficiency H2 receptor blocker, proton pump inhibitor) ▫ Ileal resection, disease (e.g. celiac disease) Insufficient diet ▪ Alcohol abuse ▪ Chronic systemic disease, mental illness, advanced age ▪ Food insecurity ▪ Self-imposed dietary restrictions (e.g. vegan) Adequate diet but increased requirements ▪ Pregnancy, lactation, malignancies ▪ Disease states with ↑ cellular turnover (e.g. chronic hemolysis, exfoliative skin disease) Medication interfering with absorption ▪ E.g. Metformin, cycloserine, isoniazid, neomycin Fish tapeworm Diphyllobothrium latum infestation ▪ Competes for absorption in ileum Imerslund–Gräsbeck syndrome ( juvenile megaloblastic anemia) ▪ Autosomal recessive disorder ▪ Vitamin B12-intrinsic factor receptor defect cblD inborn error of cobalamin metabolism ▪ MMADHC gene mutation → MMADHC protein defect (cobalamin transporter)

COMPLICATIONS

▪ Macrocytic anemia ▪ Neurodegenerative disorder

▪ ↑ hemolysis → jaundice ▪ ↓ gastrointestinal tract mucosa integrity → atrophic glossitis, angular stomatitis, anorexia, nausea, diarrhea ▪ Impaired myelin production → cognitive impairment, paresthesias, impaired proprioception, gait disturbance, slowed cognition

DIAGNOSIS LAB RESULTS Blood study ▪ ↓ cobalamin ▪ CBC ▫ ↓ RBC count; ↓ reticulocyte count; megaloblastic anemia (↑ MCV, ↓ MCH) ▪ Blood smear analysis ▫ Macrocytosis, oval macrocytes; anisocytosis; poikilocytosis; hypersegmented neutrophils ▪ ↑ hemolysis markers ▫ Elevated indirect bilirubin, lactate dehydrogenase, ↓ haptoglobin Hypercellular bone marrow

TREATMENT OTHER INTERVENTIONS

▪ ↑ dietary cobalamin ▪ Supplementation (cyanocobalamin) ▫ Pernicious anemia → parenteral cobalamin ▪ Address complications

SIGNS & SYMPTOMS ▪ High body stores → 1–2 years insufficient intake → symptoms (adult/child) ▪ B12-deficient mothers → infant cobalamin deficiency sequelae at age 6–18 months ▪ Megaloblastic anemia ▫ Hypoxemia, tissue hypoxia → fatigue, activity intolerance, pallor, ↑ heart rate

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VITAMIN C DEFICIENCY osms.it/vitamin-c-deficiency PATHOLOGY & CAUSES

SIGNS & SYMPTOMS

▪ Insufficient vitamin C for body’s metabolic needs ▪ Body cannot synthesize, must obtain in diet ▪ Active form: L-ascorbic acid

▪ ↓/no intake → symptoms within one month ▪ Mucocutaneous signs ▫ Spongy gums → loose teeth ▫ Capillary fragility → petechiae, ecchymoses, perifollicular hemorrhage, subperiosteal hemorrhage ▫ Hair structure changes → corkscrew hair ▪ Inability to maintain bone matrix ▫ Arthralgias, bone structure changes ▪ Anemia ▫ Fatigue, malaise ▪ Impaired wound healing

RDA ▪ 9–13 years old: 45mg ▪ 14–18 years old: 75 mg (biologically-male); 65mg (biologically-female) ▪ 19+ years old: 90 mg (biologically-male); 75mg (biologically-female) ▪ Pregnancy: 85mg ▪ Lactation: 120mg ▪ Smokers: ↑ 35mg/day

RISK FACTORS Insufficient diet ▪ Food insecurity ▪ Self-imposed dietary restrictions ▪ Chronic systemic disease, mental illness, advanced age ▪ Feeding infants evaporated/boiled cow’s milk ↑ oxidative stress ▪ Smoking, secondhand smoke

COMPLICATIONS

▪ Scurvy, related sequelae (e.g. periodontal disease; bone, joint disorders) ▪ Impaired wound healing ▪ Weakened immune system ▪ Depression ▪ Microcytic anemia

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DIAGNOSIS DIAGNOSTIC IMAGING MRI ▪ Sclerotic, lucent metaphyseal bands, soft tissue edema

TREATMENT OTHER INTERVENTIONS

▪ ↑ dietary/supplementation vitamin C ▫ Present in many fruits, vegetables (especially citrus, tomatoes, broccoli, bell peppers, potatoes) ▫ Supplements, enriched grains ▪ Address complications

Chapter 53 Water Soluble Vitamins Deficiency

Figure 53.2 An X-ray of the leg of a child with scurvy. There is a dense zone of provisional calcification at the epiphysis, known as a Frankel line, with underlying radiolucency known as a Trümmerfeld zone.

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ADENOVIRIDAE

ADENOVIRUS osms.it/adenovirus PATHOLOGY & CAUSES ▪ Seven subgroups, 52 serotypes ▪ Directly invades human epithelial cells (several organs) → multiple cytopathic effects, usually within 2–7 days postinfection ▪ Responsible for variety of upper, lower respiratory tract; gastrointestinal; genitourinary infections ▪ Common clinical syndromes ▫ Upper respiratory disease, pharyngoconjunctival fever, coryza, pneumonia, gastroenteritis, hepatitis, hemorrhagic cystitis, interstitial nephritis, epidemic keratoconjunctivitis Genetic material ▪ Double-stranded DNA virus Taxonomy ▪ Adenoviridae family Morphology ▪ Non-enveloped icosahedral nucleocapsid ▪ Unique ▫ Fiber-like projections (hemagglutinins) protrude from capsid’s 12 vertices Transmission ▪ Aerosol droplets ▪ Fecal-oral route ▪ Neonates ▫ Infected cervical secretion exposure ▪ Solid organ transplant

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▪ Fomite contact ▫ Survives on environmental surfaces for long periods; inactivated by heat, formaldehyde, bleach

RISK FACTORS

▪ Close living space (e.g. military barracks, daycare centers) ▪ Summer camps (especially with swimming pools/lakes) ▪ Healthcare facilities ▪ Immunocompromised status (especially cell-mediated immunity deficiency)

COMPLICATIONS

▪ Secondary bacterial infection; meningoencephalitis; myocarditis; disseminated intravascular coagulation; myositis, rhabdomyolysis; hypogammaglobulinemia ▪ Disseminated adenovirus infection ▫ Affects multiple organs, immunocompromised individuals especially; high mortality rate

SIGNS & SYMPTOMS ▪ Varies with clinical syndrome ▪ Upper respiratory ▫ Sore throat, nasal congestion, rhinorrhea, dry cough, hoarseness, inflamed tonsils, cervical lymphadenopathy; wheezes/rhonchi on auscultation

Chapter 54 Adenoviridae ▪ Ocular ▫ Conjunctivitis, preauricular, lymphadenopathy ▪ Gastrointestinal ▫ Nausea, vomiting, diarrhea ▪ Systemic ▫ Fever, malaise, headache, myalgia

DIAGNOSIS ▪ History, physical examination ▫ Characteristic findings ▫ Diagnostic test choice based on clinical presentation

DIAGNOSTIC IMAGING Chest X-ray ▪ May show diffuse bilateral pulmonary mononuclear cell infiltration, hyaline membranes, necrosis

LAB RESULTS Microbe identification ▪ Viral culture (e.g. nasopharyngeal swabs, blood, urine, sputum) ▪ Viral assay (e.g. adenovirus-specific enzyme immunoassay (EIA)/ immunofluorescence assay) ▪ Nucleotide amplification test (NAT) ▪ Polymerase chain reaction (PCR)

Serology ▪ Antigen/complement fixation assays ▪ Hemagglutination inhibition/neutralizing antibodies ▪ Restriction endonuclease (RE) analysis Tissue biopsy ▪ Eosinophilic inclusions (early stage) ▪ Basophilic inclusion surrounded by clear intranuclear inclusion Electron microscopy ▪ Icosahedral virions forming intranuclear paracrystalline aggregates

TREATMENT ▪ Usually self-limiting disease

MEDICATIONS Pharmacotherapy ▪ Immunocompromised/severe infection individuals ▫ Antivirals, immunoglobulin (IVIG) Prevention ▪ Infection control measures ▪ Live oral enteric-coated vaccine used for military recruits only

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NOTES

AEROBIC RODS MICROBE OVERVIEW ▪ Gram-positive, rod-shaped, aerobes/ facultative anaerobes

BACILLUS ANTHRACIS (ANTHRAX) osms.it/bacillus-anthracis PATHOLOGY & CAUSES ▪ Etiologic agent of anthrax; nonmotile, nonhemolytic; potential biological weapon ▪ Endospore-forming (centrally located) ▫ Highly adaptable to extreme environmental conditions ▪ Surrounded by protein capsule (composed of poly-D-gamma-glutamic acid) ▫ Prevents phagocytosis

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▪ Transmission (4 Is) ▫ Ingestion ▫ Inhalation ▫ skin Invasion ▫ direct Injection ▪ Anthrax toxin composed of three proteins ▫ Protective antigen (PA): essential for binding, entry to cell ▫ Lethal factor (LF): alteration of signaling pathways → cell death; ↑

Chapter 55 Aerobic Rods proinflammatory cytokines production → inflammation ▫ Edema factor (EF): ↑ cyclic adenosine monophosphate (cAMP) → disordered water, electrolyte balance → edema

RISK FACTORS

▪ Occupational ▫ People who work with animals/ animal products (e.g. veterinarians, livestock producers, butchers); possible bioterrorism (e.g. military personnel); laboratory professionals ▪ Injecting drug users (e.g. heroin contaminated with anthrax spores)

COMPLICATIONS

▪ Hemorrhagic meningitis, mediastinitis; pleural effusion; pneumonia; shock

SIGNS & SYMPTOMS ▪ Respiratory infection ▫ Prodromal phase: flu-like symptoms (e.g. fever, malaise, myalgia), hemoptysis, dyspnea, nausea, chest pain ▫ Fulminant phase: severe dyspnea, hypoxemia, cyanosis, shock, coma ▪ Gastrointestinal (GI) infection ▫ Severe abdominal pain; nausea; vomiting; ascites; ulcerations → GI hemorrhage ▪ Cutaneous infection ▫ Painless, pruritic papule → enlarges, forms central black-colored necrotic ulceration → black eschar ▫ Surrounding edema ▫ Regional lymphadenopathy, lymphadenitis

Figure 55.1 A lesion on the neck caused by Bacillus anthracis.

DIAGNOSIS LAB RESULTS

▪ Identify microbe ▫ Gram stain, culture, direct fluorescent antibody (DFA), polymerase chain reaction (PCR)

OTHER DIAGNOSTICS

▪ History, physical examination

TREATMENT MEDICATIONS ▪ Antibiotics

OTHER INTERVENTIONS

▪ Vaccine (people at high risk of exposure, post-exposure prophylaxis)

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BACILLUS CEREUS (FOOD POISONING) osms.it/bacillus-cereus PATHOLOGY & CAUSES ▪ Common foodborne pathogen; also associated with contaminated medical equipment (e.g. ventilators, dialysis machines), opportunistic infections ▪ Endospore-forming (centrally located) ▫ Highly adaptable to extreme environmental conditions ▪ Motile, catalase positive, beta-hemolytic ▪ Can be transient component of GI microflora Pathogenesis of food poisoning ▪ Production of enterotoxins ▫ Diarrheal toxin (thermolabile) → ↑ cAMP → disordered function of ion pumps → ↑ efflux of ions, water from infected enterocytes → diarrhea ▫ Emetic toxin, cereulide (thermostable) → ↑ afferent vagus nerve stimulation → nausea, vomiting ▪ Two types of food poisoning ▫ Diarrheal syndrome (meat, vegetables, sauces) → toxicoinfection → ingestion of bacteria, production of toxins in digestive tract ▫ Emetic syndrome (rice) → alimentary intoxication → direct ingestion of toxin

RISK FACTORS

▪ Consumption of improperly cooked food

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SIGNS & SYMPTOMS ▪ Abdominal cramps, diarrhea, nausea, vomiting

DIAGNOSIS LAB RESULTS ▪ ▪ ▪ ▪

Stool/contaminated food sample Gram stain Culture (blood agar) PCR

TREATMENT OTHER INTERVENTIONS

▪ Intravenous (IV) fluid, electrolyte replacement

Chapter 55 Aerobic Rods

CORYNEBACTERIUM DIPHTHERIAE (DIPHTHERIA) osms.it/corynebacterium-diphtheriae PATHOLOGY & CAUSES ▪ Infectious agent of diphtheria ▪ Rods with widening at polar regions forming club-like shape ▪ Characteristic “Chinese-letter” arrangement ▪ Nonmotile, non-spore-forming ▪ Stain ▫ Albert’s/Ponder’s; metachromatic granules (e.g. Babes–Ernst, volutin) ▪ Culture ▫ Löffler's medium ▪ Differentiation ▫ Hoyle’s tellurite agar ▪ Types of infection ▫ Respiratory (pharyngeal), cutaneous

RISK FACTORS

▪ Absent/incomplete immunization ▪ Immunocompromised individuals ▪ Citizens, migrants, returning travellers from endemic areas (e.g. African, Asian, South American countries)

COMPLICATIONS

▪ Myocarditis, nerve damage (e.g. demyelinating polyneuropathy, paralysis), renal failure, suffocation (due to pseudomembrane aspiration)

Pathophysiology ▪ Diphtheria toxin → composed of two subunits ▫ A: active, catalytic ▫ B: binding; composed of R (receptor), T (translocation) domains ▪ Bacteria binds to host cell using R domain → endocytosis → acidification inside endosome → T domain transfers to endosomal membrane → translocation of A subunit to cytosol ▪ Subunit A inactivates elongation factor EF2 → inhibition of protein synthesis → cell death ▪ Toxin expression regulated by level of iron ▫ ↑ Fe → ↓ production of toxin ▫ ↓ Fe → ↑ production of toxin Figure 55.2 A pharyngeal pseudomembrane in a child with diphtheria.

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SIGNS & SYMPTOMS ▪ Respiratory infection ▫ Sore throat; malaise; low-grade fever; dysphagia; thick, grey, isolated necrotic tissue → pseudomembrane; massive swelling of tonsils, cervical lymph nodes → “bull neck”; stridor ▪ Cutaneous infection ▫ Lesions, pain, rash, tenderness, erythema, ulceration

DIAGNOSIS LAB RESULTS ▪ ▪ ▪ ▪

Gram stain Culture Elek test (differentiation of toxigenic strains) PCR

OTHER DIAGNOSTICS

▪ History, physical examination

TREATMENT MEDICATIONS

▪ Diphtheria antitoxin ▪ Antibiotic

OTHER INTERVENTIONS

▪ Prophylaxis ▫ Young children: diphtheria-tetanusacellular pertussis (DTaP) vaccine ▫ Adolescents/adults: tetanus-diphtheria (Td)/tetanus-diphtheria-pertussis (Tdap) vaccine

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Figure 55.3 An ulcerating skin lesion on the leg caused by cutaneous diphtheria.

Chapter 55 Aerobic Rods

LISTERIA MONOCYTOGENES osms.it/listeria-monocytogenes PATHOLOGY & CAUSES ▪ Facultative intracellular bacteria, anaerobe; beta-hemolytic ▪ Capable of growing at refrigeration temperatures (0–4°C/32–39.2°F) ▪ Motile ▫ ≤ 30°C/32°F (flagella); body temperature (comet tail structures, polymerized host cells actin) ▪ Foodborne pathogen, common cause of bacterial neonatal meningitis Pathophysiology ▪ Listeria enters host cell via zipper mechanism → bacterial protein internalin binds onto cell membrane protein cadherin → releases listeriolysin O → disruption of vacuolar membrane → invasion of cytosol → actin assembling-inducing protein → polymerisation of cytoskeleton → bacteria gains motility → rapid movement through cytosol, between cells

RISK FACTORS

▪ Mild febrile gastroenteritis ▫ Immunocompetent individuals, ingestion of contaminated food (e.g. raw meat, unpasteurized dairy, seafood) ▪ Cutaneous infection ▫ Direct inoculation of skin (e.g. veterinarians, farmers handling infected animals) ▪ Invasive listeriosis ▫ Immunocompromised individuals, age (neonates, elderly), pregnancy

COMPLICATIONS

▪ Immunodeficient, elderly individuals ▫ Sepsis, meningitis, encephalitis, pneumonia, corneal ulcer

▪ Pregnant individuals ▫ Neonatal meningitis, granulomatosis infantiseptica, miscarriage, stillbirth, premature delivery with chorioamnionitis

SIGNS & SYMPTOMS ▪ Previously healthy individuals ▫ Fever, headache, diarrhea, vomiting, nausea, pustular skin lesions ▪ Individuals with weakened immune system ▫ Stiff neck, confusion, convulsions, loss of balance, cranial nerve palsies ▪ Pregnant individuals ▫ Nonspecific flu-like illness ▪ Newborns ▫ Low birth weight, irritability, fever, poor feeding, circulatory/respiratory insufficiency, pyogranulomatous lesions

DIAGNOSIS LAB RESULTS

▪ Culture ▫ Blood, cerebrospinal fluid (CSF); cervix, amniotic fluid in pregnant individuals; meconium, gastric aspirate, infected tissues (e.g. skin granulomatous lesions) in newborns

OTHER DIAGNOSTICS

▪ History, physical examination

TREATMENT MEDICATIONS

▪ Antibiotics (e.g. ampicillin, penicillin G, gentamicin)

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ANAEROBIC RODS MICROBE OVERVIEW ▪ Rod-shaped (bacilli) bacteria, grampositive, strict anaerobes

CLOSTRIDIUM BOTULINUM (BOTULISM) osms.it/clostridium-botulinum PATHOLOGY & CAUSES ▪ Ubiquitous presence (esp. soil, water); spore-forming; catalase negative, superoxide dismutase positive, subterminal endospore ▪ Fermentation ▫ Carbohydrates ▪ Obligate anaerobe, can tolerate small amounts of oxygen due to superoxide

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dismutase ▪ Potential bioterrorism weapon ▪ Absorption of toxin into bloodstream → spreads to nervous system → binds to presynaptic receptors → endocytosis → cleavage of SNAP-25 protein → lack of acetylcholine with impaired transduction Virulence factors ▪ Seven distinct types of neurotoxins (A–G) ▫ Type A: most potent

Chapter 56 Anaerobic Rods ▪ Heat-resistant ▫ Toxins enduring temperature of 100ºC/212°F for several hours ▪ H-antigen from flagelle Culture ▪ Chopped meat, glucose, starch medium for isolation; egg yolk agar incubation in anaerobic conditions Disease ▪ Causes disease characterized by muscle weakness, nervous system impairment ▪ Infant botulism ▫ Spores ingestion → germination in gastrointestinal (GI) tract → toxin produced in vivo ▪ Foodborne ▫ Ingestion of botulinum toxincontaminated food ▫ Average incubation period is 12–36 hours ▪ Wound botulism ▫ Wound infection with spores → toxin produced in vivo ▫ Average incubation period is 10 days ▪ Adult intestinal toxemia botulism ▫ Colonization of intestines with toxins production ▪ Iatrogenic botulism ▫ Complication of therapeutic use of botulinum neurotoxins ▪ Enteric infectious botulism ▫ C. botulinum colonizes adult GI tract

RISK FACTORS

▪ Infant botulism ▫ Honey consumption in first year of life; ingestion of dust/soil containing C. botulinum spores ▪ Foodborne botulism ▫ Home-canned, improperly preserved food; smoked fish ▪ Wound botulism ▫ IV/subcutaneous drug usage; crush injuries ▪ Enteric infectious botulism ▫ Achlorhydria/other GI diseases → colonization

COMPLICATIONS

▪ Sudden infant death syndrome (SIDS), seizures, ileus, death

SIGNS & SYMPTOMS ▪ General symptoms precede muscle weakness ▫ Abdominal pain, nausea, vomiting, lack of fever (wound botulism only type with fever) ▪ Cranial nerve impairment ▫ Dilated pupil, ptosis; double vision (due to disconjugate eye movement); ophthalmoplegia; dry mouth, difficulty swallowing; loss of facial expressions ▪ Progressive symmetrical muscle weakness descending from head ▫ Hypotonia, hyporeflexia; floppiness in infants ▫ Respiratory muscles: breathing difficulties ▪ Hyperactivation of autonomic system ▫ ↓ salivation, lacrimation, orthostatic hypotension, obstipation, urine retention

DIAGNOSIS LAB RESULTS

▪ Toxin detection/bacteria isolation

Enzyme-linked immunosorbent assay (ELISA), mass spectroscopy, polymerase chain reaction (PCR) ▪ Isolation of C. botulinum from feces, vomitus, food

OTHER DIAGNOSTICS

▪ History, physical examination

Electromyogram (EMG) ▪ Short-lasting motor unit potentials with small amplitude

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TREATMENT MEDICATIONS

▪ IV botulinum immunoglobulin/heptavalent botulinum antitoxin ▫ Manage infection ▪ Antibiotics ▫ Manage secondary infection ▪ Cholinesterase inhibitors

OTHER INTERVENTIONS

▪ Manage infection ▫ Debridement, irrigation of wound ▫ Colon cleansing (enema, cathartics) ▪ Nasogastric tube (feeding), Foley catheter (urinary retention), intubation/mechanical ventilation

Prevention ▪ Pentavalent-botulinum-toxoid (PBT) vaccine ▫ Five dose vaccination with booster dose once per year

CLOSTRIDIUM DIFFICILE (PSEUDOMEMBRANOUS COLITIS) osms.it/clostridium-difficile PATHOLOGY & CAUSES ▪ Ubiquitously present, can be part of “normal” flora; subterminal endospore; motile ▪ Intestinal microbiota disturbance → infection, colonization of gut → produces A, B toxins → binds to receptors on intestinal wall → internalization → fusion with lysosome → toxins exit endosome → damage of cytoskeleton → cell apoptosis → inflammatory response with accumulation of inflammatory cells, fibrin, dead cells → formation of membrane-like structure (pseudomembrane) Virulence factors ▪ Enterotoxin A (TcdA), cytotoxin B (TcdB), H-antigen from flagelle Culture ▪ Agar with cycloserine, cefoxitin, fructose ▪ C. difficile-associated colitis combined with formation of pseudomembranous plaques Transmission ▪ Fecal-oral route by ingestion of spores

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RISK FACTORS

▪ Antibiotic exposure ▫ Disturbance of intestinal microbiota ▪ Previous hospitalization ▫ ↑ risk for infection ▪ Children with neutropenia ▫ More prone to common bacterial infections requiring antibiotics → disturbance of intestinal microbiota ▪ Gastric acid suppression, > 65 years, comorbidities

COMPLICATIONS

▪ Multiple relapses, dehydration (due to excessive diarrhea)

GI complications ▪ Toxic megacolon (due to inflammation damaging muscularis propria, underlying neurons); ileus; colon perforation; intussusception; pneumatosis; ascites; sepsis Extraintestinal complications ▪ Splenic abscess; osteomyelitis

Chapter 56 Anaerobic Rods

SIGNS & SYMPTOMS ▪ Watery diarrhea (most common) with mucus/blood ▪ Abdominal distension, cramps ▪ Malaise ▪ Fever

DIAGNOSIS DIAGNOSTIC IMAGING Sigmoidoscopy/colonoscopy ▪ Visualization of plaques

LAB RESULTS

SURGERY

▪ Colectomy ▫ In persons with acute abdomen, refractory colitis, fulminant colitis

OTHER INTERVENTIONS

▪ End previous antibiotic use ▪ Second relapse: pulse therapy ▪ Recurrent: biological therapies ▫ Fecal microbiota transplant: transplantation of microbiota from healthy individual ▪ Electrolytes, fluids replacement; appropriate nutrition ▪ Prevention of hospital-acquired infection ▫ Infection control protocol, antibiotic stewardship

WBCs ▪ ↑ white blood cells Stool analysis ▪ Presence of blood/mucus ▪ Stool culture ▪ Enzyme immunoassay test ▫ Detection of glutamate dehydrogenase antigen ▪ Toxin detection ▫ Enzyme immunoassay, real-time PCR ▪ Cell culture cytotoxicity assay ▪ Biomarkers ▫ Differentiation between colonization, actual disease; ↑ fecal cytokines, CXCL5, phosphorylated p38

Figure 56.1 The gross pathological appearance of the colonic mucosa in psuedomembranous colitis.

TREATMENT MEDICATIONS

▪ Mild disease: oral metronidazole ▪ Severe disease: oral vancomycin ▪ Complications: combination of oral vancomycin, IV metronidazole ▪ Second relapse: oral vancomycin tapered ▪ Recurrent: probiotics

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CLOSTRIDIUM PERFRINGENS osms.it/clostridium-perfringens PATHOLOGY & CAUSES ▪ Ubiquitous in nature, also part of human microbiota; subterminal endospore; nonmotile Virulence factors ▪ Divided into subtypes A–E ▪ Produces 12 toxins ▪ Alpha ▫ Enzyme lecithinase splits lecithin → ↑ vascular permeability → cell destruction ▫ Responsible for gas gangrene, hemolysis ▪ Beta ▫ Formation of selective pores → ↑ permeability with cell destruction ▫ Responsible for enteritis necroticans; deactivated by trypsin ▪ Epsilon ▫ Pores form on cells → destruction ▪ Iota ▫ AB toxin: enzyme (A), binding (B) domain ▫ Destruction of cells through affection of cytoskeleton Culture ▪ Growth on tryptose sulfite cycloserine agar Clostridial gas gangrene ▪ Saprophytic anaerobic bacteria → clostridial gas gangrene due to tissue infection/food poisoning through ingestion ▪ Disease characterized by necrosis, gangrene due to infection of skin, deep tissues ▪ Bacteria produces gas → characteristic crepitation sound during palpitation ▪ Divided into ▫ Traumatic: wound → spore inoculation → bacteria growth in appropriate anaerobic conditions → production of toxins → destruction of fibroblasts,

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blood cells, muscle cells → necrosis of muscles, subcutaneous fat with blood vessels thrombosis ▫ Postoperative: after interventions on intestinal system ▫ Spontaneous: due to immune system weakness/intestinal diseases Food poisoning ▪ Begins 6–24 hours after ingestion ▪ Infection of food with spores → food standing temperature 30–50ºC/86–122°F → development of vegetative form → ingestion of infected food → toxin production → ↓ glucose absorption, ↑ water, sodium, chloride secretion → damage of intestinal epithelium Enteritis necroticans ▪ Inflammation of jejunum, ileum; type of food poisoning in persons who lack trypsin

RISK FACTORS

▪ Gas gangrene: begins 1–4 days after infection ▫ Traumatic: injury during war/natural disaster; car crash ▫ Postoperative: GI/biliary surgery; septic abortion ▫ Spontaneous: colorectal adenocarcinoma; neutropenic states (e.g. AIDS, chemotherapy); intestinal diseases ▪ Food poisoning: improper food-handling ▪ Enteritis necroticans: improper nutrition (e.g. too many sweet potatoes); trypsin inhibitors → ascariasis

COMPLICATIONS

▪ Disseminated intravascular coagulation; hemodynamic shock, hypotension, renal failure; systemic hemolysis; peritonitis; sepsis; death

Chapter 56 Anaerobic Rods

DIAGNOSIS

SIGNS & SYMPTOMS Gas gangrene ▪ Two types ▫ Cellulitis: infection of necrotic skin; crepitation sounds ▫ Clostridial myonecrosis: infection, destruction of muscles, adjacent tissue ▪ Paleness, serosanguineous exudate, pain, swelling, tenderness at injury site → color changes to bronze → purple bullae with green/black discoloration due to necrosis ▪ Characteristic sweet odor ▪ ↑ heart rate with low-grade fever Food poisoning ▪ If only toxins ingested ▫ Asymptomatic/diarrhea ▪ If vegetative form ingested ▫ Watery diarrhea without blood/mucus; abdominal cramps, last > 24 hours Enteritis necroticans ▪ Abdominal cramps; diarrhea; vomiting; meteorism (excessive gas production in intestines); blood in stool; fever

DIAGNOSTIC IMAGING X-ray ▪ Gas gangrene: detection of gas in softtissue ▪ Enteritis necroticans: small bowel dilatation with presence of gas

LAB RESULTS

▪ Gas gangrene: molecular methods for detection of alpha toxins; ELISA, PCR ▪ Food poisoning: detection of toxins in feces; PCR

Biopsy ▪ Gas gangrene: necrosis of myocytes, connective tissue with small number of neutrophils

OTHER DIAGNOSTICS

▪ Gas gangrene: physical examination; characteristic discoloration, odor, crepitation sound

TREATMENT MEDICATIONS

▪ Gas gangrene: antimicrobial therapy (combination of penicillin G, clindamycin) ▪ Enteritis necroticans: penicillin G/ metronidazole; destruction of bacteria

SURGERY

Figure 56.2 An individual with gas gangrene of the right leg. The causative agent is Clostridium perfringens.

▪ Gas gangrene: removal of dead tissue; hyperbaric oxygen (augments neutrophil, ↓ clostridial exotoxin, spore production); amputation ▪ Enteritis necroticans: resection of necrotic intestinal parts

OTHER INTERVENTIONS

▪ Food poisoning: oral/IV rehydration

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CLOSTRIDIUM TETANI (TETANUS) osms.it/clostridium-tetani PATHOLOGY & CAUSES ▪ Ubiquitously present in soil; resistant to chemical/heat disinfection; terminally present endospore; motile ▪ Anaerobic rod causes nervous system disorder (i.e. tetanus) ▪ Injury → infection with spores → development of vegetative form in appropriate anaerobic conditions → production of exotoxins (tetanospasmin) → blood/lymphatic transmission → spread to neurons through neuromuscular junction → retrograde transport to spinal cord → endocytosis into inhibitory Renshaw cell interneurons → exotoxins protease activity cleaves SNARE proteins → block of glycine, gamma-aminobutyric acid (GABA) neurotransmitter-filled vesicles release at neuromuscular junction → overactivation of muscles → muscle spasms Virulence factors ▪ Two toxins: tetanolysin (relatively unknown function); tetanospasmin (responsible for clinical presentation of tetanus) ▪ H-antigen from flagelle Culture ▪ Oxygen-reduced blood agar with anaerobic incubation

TYPES

▪ Four types of tetanus ▫ Generalized: affects whole musculature, from head downwards ▫ Localized: affects only area near injury ▫ Cephalic: cranial nerves affected due to head/neck injury ▫ Neonatal: tetanus occurring in neonates via infection of umbilical stump

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RISK FACTORS

▪ Deep puncture wounds with/without splinters, crush injuries, middle ear infections, frostbites, burns ▪ IV/subcutaneous drug abuse ▪ Infected diabetic wounds ▪ Septic abortion ▪ Umbilical stump infection via contaminated instruments, hands, cultural practices (e.g. application of cow dung, ghee) ▪ Lack of vaccination/immunization

COMPLICATIONS

▪ Cardiac arrest ▫ Due to ↑ catecholamine levels, brainstem damage ▪ Palsies of phrenic, laryngeal nerves due to toxic effect ▪ Respiratory muscles ▫ Apnea ▪ Vertebral fractures/intramuscular bleeding (due to opisthotonus)

SIGNS & SYMPTOMS Generalized ▪ Masseter muscle spasm → trismus/“lockjaw” → severe generalized muscle contractions ▫ Risus sardonicus: characteristic sarcastic-like facial expression due to facial muscles contraction ▫ Opisthotonus: arched back due to contraction of back muscles ▪ Abdominal respiratory muscles, diaphragm: breathing arrest Localized ▪ Weakness, pain of muscles/extremites in proximity of injury ▪ Stiffness of affected muscles occurring in following days, lasting up to few months ▪ May progress into generalized form

Chapter 56 Anaerobic Rods Cephalic ▪ Palsy of facial nerve ▪ Difficulty swallowing ▪ Weakness of extraocular muscles Neonatal ▪ Sucking difficulty in first days of life ▪ Generalization, opisthotonus may occur Sympathetic overactivity ▪ ↑ heart rate, arrhythmias ▪ Agitation, diaphoresis ▪ ↑/↓ blood pressure ▪ Fever ▫ Due to overactivity/superinfection

TREATMENT MEDICATIONS

▪ Human tetanus immunoglobulin (TIG)/ intravenous immunoglobulins (IVIG) ▫ Neutralization of toxin ▪ Antibiotics ▫ Penicillin, cephalosporins, tetracyclines, metronidazole, vancomycin ▪ Benzodiazepines ▫ Muscle relaxation, sedation ▪ Muscle relaxants ▫ Pancuronium/vecuronium ▪ Labetalol ▫ Autonomic hyperactivity management

OTHER INTERVENTIONS

Figure 56.3 This body posture is known as opisthotonus and is caused by the Clostridium tetani toxin.

▪ Active immunization with tetanus/ diphtheria toxoid (Td) ▪ Respiratory support if needed ▪ Prevention ▫ Primary: vaccination at two months of life, with booster doses at 4, 6, 12–18 months, 4–6, 11–12 years (booster doses every ten years later); passive immunization in immunocompromised ▫ Secondary: vaccination, antitoxin after injury ▫ Tertiary: vaccination, antitoxin after tetanus presentation

DIAGNOSIS OTHER DIAGNOSTICS

▪ History, physical investigation ▪ Spatula test ▫ Touching oropharynx with spatula causes reflex biting due to masseter spasm

EMG ▪ Loss/shortening of silent interval between action potentials with continuous discharge from motor units

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NOTES

ARENAVIRIDAE MICROBE OVERVIEW Taxonomy ▪ Zoonotic virus family ▫ Associated with hemorrhagic fevers, meningoencephalitis ▪ Comprises > 20 viruses ▪ Groups ▫ Old World viruses (e.g. lymphocytic choriomeningitis virus, Lassa, Lujo) ▫ New World viruses (e.g. Junin, Machupo) Morphology ▪ Single-stranded RNA virus ▪ Ribosomes produce sand-like granular appearance under electron microscopy ▫ Latin: arena = sand ▪ Shape varies: pleomorphic–spherical

▪ Enveloped in lipid membrane with glycoprotein spikes ▫ Lipids in membrane → inactivation susceptibility by organic solvents/ detergents ▫ Also inactivated by temperatures > 55°C/131°F, ↑ ↓ pH, UV light, gamma irradiation Transmission ▪ Reservoir ▫ Rodents shed virus in urine, feces, saliva, nasal secretion ▪ Transmission ▫ Ingestion, direct contact, aerosolizedparticle inhalation → entry into cell by GP1 glycoprotein attachment to cellular receptors → systemic dissemination

LYMPHOCYTIC CHORIOMENINGITIS VIRUS (LCMV) osms.it/LCMV PATHOLOGY & CAUSES ▪ Arenavirus ▫ Causes febrile illness with central nervous system (CNS) involvement, congenital infection ▪ Reservoir ▫ Mice (M. musculus/M. domesticus); occasional human disease outbreak related to pet hamster/guinea pig ▪ Transmission ▫ Ingestion, aerosolized-particle

inhalation, transplacentally (infected mother → fetus) ▪ Post-transmission → 7–14 days incubation → replication in lungs → hematogenous dissemination → strong neurotropism (infects meninges, choroid plexus, ventricular ependyma)

RISK FACTORS

▪ Infected rodent contact; dwelling/working in rodent habitats ▪ ↑ risk in substandard housing (e.g. mobile homes, inner-city housing), barns/

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outbuildings ▪ Peak incidence: autumn, winter

COMPLICATIONS

▪ Encephalitis, aseptic meningitis ▪ Transplacental infection: spontaneous abortion, neonatal neurologic deficits, chorioretinitis, seizures, periventricular calcifications, hydrocephalus, microcephaly ▪ Rarely: orchitis, parotitis, myocarditis

SIGNS & SYMPTOMS ▪ May be asymptomatic/mild flu-like symptoms ▪ Prodrome: headache (retro-orbital), nausea, vomiting ▪ Meningitis: fever, rigors, malaise, myalgia, arthralgia anorexia, photophobia ▪ Encephalitis: focal seizures, cranial nerve palsies, papilledema

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DIAGNOSIS LAB RESULTS

▪ Cerebrospinal fluid (CSF) ▫ ↑ lymphocytes, ↑ protein, ↓ glucose, negative Gram stain

Microbe identification ▪ Viral culture, polymerase chain reaction (PCR) Serology ▪ ↑ antibody titer (IgM, IgG)

TREATMENT OTHER INTERVENTIONS Prevention ▪ Rodent control

NOTES

NOTES

BUNYAVIRUSES MICROBE OVERVIEW ▪ Bunyaviruses: RNA virus order ▪ AKA Bunyavirales Genetic material ▪ Negative-sense, single-stranded RNA ▪ Tripartite genome ▫ Large (L) segment (encodes RNApolymerase); medium (M) segment (encodes surface glycoproteins); small (S) segment (encodes nucleocapsid proteins)

Morphology ▪ Enveloped (outer lipid membrane) ▪ Spherical ▪ Size: 90–100nm Replication ▪ Host cytoplasm replication Transmission ▪ Vector-borne, person-to-person, contact with reservoir (species-dependent) ▪ Reservoirs: arthropods, mammals (especially rodents

Figure 58.1 Families of the Bunyavirus order and associated clinical syndromes.

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HANTAVIRUS osms.it/hantavirus PATHOLOGY & CAUSES ▪ Single-stranded RNA virus genus → causes severe renal/pulmonary disease ▪ AKA Orthohantavirus ▪ Hantaviridae family ▪ Reservoir ▫ Rodents (mice, voles, shrews, rats) ▪ Incubation period ▫ 9–33 days ▪ Tissue tropism ▫ Lymphoid organ, heart, lung, kidney vascular endothelium ▪ Hantavirus inhalation → lung phagocytosis → transport to lymph nodes → hantavirus enters epithelial cells using beta-3 integrins → ↑ vascular permeability → dissemination ▪ Immune response ▫ CD4+/CD8+ cytotoxic T cells, dendritic cells ▪ High-prevalence regions ▫ China, Russia, Europe Associated clinical syndromes ▪ Hemorrhagic fever + renal syndrome (“Old World” AKA Asia, Europe)

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▪ ↑ vascular permeability → ↓ blood pressure → kidney endothelial dysfunction ▪ Hantavirus cardiopulmonary/pulmonary syndrome (“New World” AKA North, South America) ▪ ↑ vascular permeability → non-cardiogenic pulmonary edema

CAUSES

▪ Rodents (urine/feces/saliva particle inhalation); person-to-person (rare)

RISK FACTORS ▪ ▪ ▪ ▪

Rural indoor spaces (e.g. barns) Wild rodent exposure Smoking → Puumala virus infection risk ↑ risk among biological males

COMPLICATIONS

▪ Cardiogenic shock, pulmonary edema, arrhythmia, renal insufficiency, acute kidney injury (AKI), coagulopathy, disseminated intravascular dissemination (DIC), hemorrhage; high mortality rate

Chapter 58 Bunyaviruses

SIGNS & SYMPTOMS

Urinalysis ▪ Renal syndrome: proteinuria, hematuria

Pulmonary syndrome ▪ Systemic ▫ Fever, chills, myalgia, headaches, weakness ▪ Nausea, vomiting, diarrhea, abdominal pain, cough, oliguria ▪ Sometimes conjunctivitis, flushing, petechiae

Tissue biopsy ▪ Kidneys: edema, perirenal hemorrhage, tubular destruction ▪ Lungs: edema, mononuclear cell infiltrates, tracheal/pleural fluid, hyaline deposits ▪ Lymphoid organs: mononuclear cell infiltrates

Hemorrhagic fever + renal syndrome ▪ Fever, hypotension, malaise, headache, diffuse hemorrhage (e.g. petechiae, melena, ecchymoses), abdominal/loin pain, nausea/ vomiting, oliguria

TREATMENT

DIAGNOSIS DIAGNOSTIC IMAGING Chest X-ray ▪ Lungs: bilateral pulmonary infiltrates, pleural effusion Abdominal ultrasound ▪ Kidneys: ↑ size, perirenal fluid

LAB RESULTS

MEDICATIONS

▪ Renal syndrome antivirals ▫ Nucleoside analogue

OTHER INTERVENTIONS

▪ ICU monitoring, mechanical ventilation ▪ Severe cases ▫ Extracorporeal membrane oxygenation (ECMO), dialysis, platelet transfusion

Prevention ▪ Potential rodent nesting site removal (e.g. debris, garbage) ▪ Closed spaces ventilation ▪ Avoid rodent contact

▪ Reverse-transcriptase polymerase chain reaction (RT-PCR)

Tests ▪ Diagnostic triad: thrombocytopenia, ↑ immunoblasts (> 10%), left-shifted granulocytic series ▪ ↑ lactate dehydrogenase (LDH), serum lactate ▪ ↑ liver enzymes ▪ ↑ C-reactive protein ▪ Severe ▫ ↑ hemoglobin, hematocrit; ↓ albumin; altered coagulation tests ▪ Renal syndrome ▫ ↑ serum creatinine, ↓ glomerular filtration rate (GFR) Serologic tests ▪ IgM/IgG detection through ELISA, strip immunoblot, Western blot, immunofluorescence

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NOTES

NOTES

CALICVIRUSES MICROBE OVERVIEW Genetic material ▪ Single-stranded RNA viruses

Morphology ▪ Small, icosahedral, non-enveloped

Taxonomy ▪ Genera: Norovirus, Sapovirus, Lagovirus, Nebovirus, Vesivirus

Transmission ▪ Ingestion → small intestine → villi infection → malabsorption → osmotic diarrhea

NOROVIRUS osms.it/norovirus PATHOLOGY & CAUSES ▪ Virus known as viral gastroenteritis agent ▫ AKA Norwalk virus ▪ Classified into seven genogroups ▫ I, II, IV → cause human disease Transmission ▪ Fecal-oral ▫ Infected individual: virus in stool < four weeks ▫ Immunocompetent individual: peak concentration 2–5 days post-infection ▪ Direct person-to-person ▪ Contaminated food, water, fomite ▫ Contaminated water in leafy vegetables, oysters, raspberries ▫ Prepared food → contaminated at point of service (e.g. salads, sandwiches) ▪ Droplet spread from vomitus Pathogenesis ▪ Ingestion → small intestine villi infection → disruption of epithelium, anion transport system → malabsorption of D-xylose, fat → osmotic diarrhea

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Small intestine histopathology ▪ Villous shortening, epithelial vacuolization, crypt hypertrophy, microvilli brush border loss, intercellular space widening, lymphocytic proliferation of lamina propria

RISK FACTORS

▪ Blood group antigens ▫ Viral binding preference for A, B antigens genogroup-determinant ▪ Close-quarter residence (e.g. nursing homes, cruise ships)

COMPLICATIONS

▪ Severe dehydration, malnutrition, persistent disease (immunosuppressed individuals)

SIGNS & SYMPTOMS ▪ 12–48 hour incubation period ▪ Acute onset vomiting ▫ Nonbloody, nonbilious ▪ Watery diarrhea ▫ Nonbloody ▪ Fever, abdominal pain, myalgia, malaise

Chapter 59 Calicviruses

DIAGNOSIS ▪ History ▫ Pathogen contact, contaminated food source

LAB RESULTS

▪ Reverse transcriptase polymerase chain reaction (RT-PCR) ▫ Stool

OTHER INTERVENTIONS

▪ Fluid maintenance, repletion ▫ From oral intake → IV fluids ▪ Electrolyte balance

Prevention ▪ Hand hygiene ▪ Environmental fecal contact decontamination ▪ Limited pathogen contact

TREATMENT ▪ No cure

MEDICATIONS

▪ Antimotility agents ▪ Antiemetics ▫ Reserved for individuals unable to take oral hydration

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NOTES

CENTRAL NERVOUS SYSTEM INFECTIONS

MICROBE OVERVIEW PATHOLOGY & CAUSES ▪ Rare infections of central nervous system (CNS) by ameba, parasites

RISK FACTORS

▪ Immunosuppression (Acanthamoeba, Toxoplasmosis gondii), immersion in infested water (Naegleria fowleri)

SIGNS & SYMPTOMS ▪ Fever, headache, seizures, focal neurological signs, mental status change

DIAGNOSIS LAB RESULTS

▪ Presence of infectious agent via microscopy, culture, polymerase chain reaction (PCR), presence of specific antibodies

Granulomatous amebic encephalitis ▫ Brain biopsy: trophozoites in perivascular space and thick walled cysts, PCR/DNA probes may show Acanthamoeba

Primary amoebic meningoencephalitis ▪ Lumbar puncture ▫ CSF microscopy: motile amebae/ fluorescent antibody staining ▫ CSF PCR: Naegleria fowleri DNA ▫ CSF culture: Naegleria fowleri can be grown on nonnutrient agar coated with Escherichia coli Toxoplasmosis ▪ PCR (blood, CSF): Toxoplasma gondii DNA (inactive cysts may evade detection) ▪ Antibody titres ▫ IgG: evidence of current/previous infection ▫ IgM: occur in weeks after initial infection ▫ Antibody avidity testing: affinity for antigen increases with duration of infection ▪ Sabin–Feldman dye test: high titers → acute infection ▪ Tissue biopsy: tachyzoites in tissues/ smears

TREATMENT MEDICATIONS

▪ Antifungal, antiparasitic agents

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ACANTHAMOEBA osmosis.org/learn/acanthamoeba PATHOLOGY & CAUSES Genus of amebae ▪ Single-celled eukaryotes ▪ Environmentally ubiquitous organisms ▫ Acanthamoeba spp. isolated from soil, air, fresh water, sewage, seawater, chlorinated swimming pools, domestic tap water, bottled water, hospitals, airconditioning units, contact lens cases ▪ Life stages ▫ Metabolically active trophozoite ▫ Dormant stress resistant cyst ▪ Generally free living bacterivores, can cause human infection (acanthamebiasis) Granulomatous amoebic encephalitis ▪ Infection associated with immunosuppression (e.g. diabetes, HIV/AIDS, hematological malignancy, malnutrition, hepatic cirrhosis, chronic renal failure, systemic lupus, chemotherapy) ▪ Parasite enters body through cuts in skin/ inhalation → hematogenous spread to CNS → invasion of connective tissue → inflammatory response → neuronal damage Endosymbiosis, secondary infection ▪ Several human pathogens infect, replicate within Acanthamoeba ▫ Legionella pneumophila, Pseudomonas aeruginosa, some strains of E. coli, Staphylococcus aureus ▪ Replication inside Acanthamoeba → enhanced growth in human macrophages, increased antibiotic resistance → more virulent, fulminant infections

SIGNS & SYMPTOMS ▪ Fever, headache, seizures, focal neurological signs (e.g. cranial nerve palsies), mental status change (e.g.

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confusion), sepsis → progressive worsening over weeks/months → death

DIAGNOSIS DIAGNOSTIC IMAGING Brain CT/MRI ▪ Meningeal exudate, pseudotumoral lesions, multiple space-occupying lesions with ring enhancement

LAB RESULTS Lumbar puncture ▪ Often contraindicated due to risk of herniation associated with mass lesions ▪ Analytical findings generally nonspecific ▫ Intermediate elevations in white blood cell count, elevated protein, decreased glucose levels ▪ Giemsa staining, microscopy ▫ Trophozoites Tissue biopsy ▪ Brain biopsy ▫ Trophozoites in perivascular space, thick-walled cysts on light microscopy; PCR/DNA probes may reveal Acanthamoeba ▫ Immunocompetent host: granulomatous lesions ▫ Severely immunosuppressed host: insufficient CD+ve T-cells to mount granulomatous response → perivascular cuffing with amoebae in necrotic tissue ▪ If other organs involved (e.g. skin, conjunctiva, lungs) ▫ Trophozoites

Chapter 64 Central Nervous System Infections

TREATMENT MEDICATIONS

▪ Current treatment regimes uncertain (based on in vitro studies, case reports) ▫ Antifungal, antiparasitic agents in combination

▫ Empiric antifungal regime: miltefosine, fluconazole, pentamidine isethionate +/- trimethoprim-sulfamethoxazole, metronidazole, macrolide antibiotic

SURGERY

▪ Single cerebral lesions ▫ Surgical resection

NAEGLERIA FOWLERI (PRIMARY AMEBIC MENINGOENCEPHALITIS) osmosis.org/learn/naegleria_fowleri PATHOLOGY & CAUSES ▪ Thermophilic, free-living ameba, found in bodies of warm (stagnant), freshwater

TYPES

▪ Life cycle, three forms 1. Cyst ▫ Immotile, dormant, survival phase ▫ Smooth, single-layered cell wall with single nucleus, naturally resistant to environmental factors ▫ Formation of cysts induced by unfavorable conditions such as food shortage, overcrowding, desiccation, accumulation of waste products, cold temperatures (< 10° celsius) 2. Trophozoite (ameboid) ▫ Feeding, reproductive, infective phase ▫ Transformation into trophozoites occurs around 25° celsius ▫ Reproduction occurs via binary fission (single cell divides into two offspring), optimal temperature 42° celsius 3. Biflagellate (two flagella) ▫ Mobile, infective phase ▫ Pear-shaped body with two flagella ▫ Flagellate phase occurs when ameba encounters change in fluid ionic

concentration → allows movement to suitable environment ▪ In human tissues Naegleria fowleri exists as ameboid trophozoite; flagellate form may be found in CSF/during initial nasal insufflation Primary amoebic meningoencephalitis ▪ AKA naegleriasis ▪ Rare infection, fatality rate > 95% ▪ Mechanism of entry ▫ Insufflated into sinuses during waterbased activities → attaches to olfactory epithelium → follows olfactory axon through cribiform plate → migration to olfactory bulbs → spread throughout brain → diffuse meningoencephalitis ▪ In tissues, Naegleria fowleri feeds via two mechanisms; feeding on neurological tissue → necrosis, bleeding ▫ Phagocytosis of red, white blood cells ▫ Piecemeal consumption of astrocytes, neurons via amoebostome (actin-rich sucking apparatus extended from cell surface)

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SIGNS & SYMPTOMS ▪ Symptoms appear 1–9 days after nasal exposure → death likely follows within two weeks ▪ Change in sensation of taste, smell; headache, fever, nausea, stiff neck, seizures, coma

DIAGNOSIS DIAGNOSTIC IMAGING Brain imaging ▪ Initially unchanged ▫ Reveals associated complications Leptomeningeal enhancement, diffuse subarachnoid hemorrhage, oedema, hydrocephalus, multiple cerebral infarcts

LAB RESULTS

▪ Lumbar puncture ▫ CSF microscopy: motile amebae/ fluorescent antibody staining ▫ CSF PCR: Naegleria fowleri DNA ▫ CSF culture: Naegleria fowleri can be grown on nonnutrient agar coated with E. coli → drop of CSF of infected individual added, incubated at 37° celsius; clearing of E. coli in thin tracks indicative of trophozoite feeding → likely infection

TREATMENT MEDICATIONS:

▪ Amphotericin B +/- fluconazole ▪ Miltefosine

TOXOPLASMA GONDII (TOXOPLASMOSIS) osmosis.org/learn/toxoplasma_gondii PATHOLOGY & CAUSES ▪ Obligate intracellular parasite capable of infecting nearly all warm-blooded animals ▫ Only definitive hosts: biological family Felidae (e.g. house cats) ▪ 30–50% of global population exposed, may be chronically infected Life cycle ▪ Sexual reproduction ▫ Consumes infected animal meal (e.g. mouse) → parasite survives transit through stomach → infects small intestinal epithelial cells → parasites undergo sexual development, reproduction → millions of thick-walled, zygote-containing, oocytes produced ▪ Felid shedding ▫ Infected epithelial cells rupture →

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release oocytes into intestinal lumen → shedding in feces → spread via soil, water, food ▫ Oocysts highly resilient; can survive, remain infective for months in cold, dry climates ▪ Infection of intermediate host ▫ Ingestion of oocysts by warm blooded animals (e.g. humans) → oocyst wall dissolved by proteolytic enzymes in stomach, small intestine → frees sporozoites from within oocyst → parasites invade intestinal epithelium, surrounding cells → differentiation into tachyzoites (motile, quickly-multiplying phase) ▪ Asexual reproduction in intermediate host ▫ Tachyzoites replicated inside specialized vacuoles until host cell dies, ruptures → release, hematogenous spread of tachyzoites to all tissues

Chapter 64 Central Nervous System Infections ▪ Formation of tissue cysts ▫ Host immune response → tachyzoite conversion → bradyzoites (semidormant, slowly dividing stage) → inside host cells known as tissue cysts → can form in any organ; predominantly brain, eyes, striated muscle (including cardiac muscle) ▫ Consumption of tissue cysts in meat from infected animal ▫ Primary means of infection (e.g. pork, lamb) ▫ Tissue cysts maintained in host tissue for remainder of life via periodic cyst rupture, re-encysting

RISK FACTORS

▪ Consumption of raw/undercooked meat; ingestion of contaminated water, soil/ vegetables; previous blood transfusion/ organ transplant; transplacental transmission

COMPLICATIONS

▪ Toxoplasmic chorioretinitis ▫ AKA ocular toxoplasmosis ▫ Common cause of posterior segment infection ▫ Majority of cases acquired; also strongly associated with congenital infection

SIGNS & SYMPTOMS ▪ Initial infection (immunocompetent host) ▫ Mild flu-like symptoms (e.g. swollen lymph nodes, headache, fever, fatigue, muscle aches, pains) ▪ Congenital infection ▫ Chorioretinitis (unilateral decrease in visual acuity), hydrocephalus, seizures, lymphadenopathy, hepatosplenomegaly ▪ Chronic/latent infection ▫ Asymptomatic in healthy hosts ▪ Immunocompromised host ▫ Active infection (toxoplasmosis) ▫ Headache, confusion, poor coordination, seizures, cough, dyspnea ▫ Reactivation of latent infection: worsening of immunosuppression due to progression of underlying disease (e.g. HIV/AIDS, iatrogenic immunosuppression) → loss of immune balance → progression to active infection

DIAGNOSIS DIAGNOSTIC IMAGING CT scan with contrast ▪ Multiple 1–3 cm hypodense regions with nodular/ring enhancement predominantly in basal ganglia, corticomedullary junction T2 weighted MRI ▪ Iso/hyper-intense lesions surrounded by perilesional edema Fundoscopy ▪ Toxoplasmic chorioretinitis ▫ Unifocal area of acute-onset inflammation adjacent to old chorioretinal scar

Figure 8.1 A histological section of the cerebrum demonstrating cerebral toxoplasmosis. There are bradyzoites present and a mixed inflammatory infiltrate which includes eosinophils.

LAB RESULTS PCR (blood, CSF) ▪ Toxoplasma gondii DNA (inactive cysts may evade detection) Antibody titres ▪ IgG (persist for life)

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▫ Evidence of current/previous infection ▪ IgM (acute infection) ▫ Occur in weeks after initial infection, remain detectable for months ▫ Antibody avidity testing may clarify nature of infection; early toxoplasmaspecific IgG has low affinity for toxoplasma antigen; affinity increases with duration of infection ▪ Sabin–Feldman dye test ▫ Requires specialised laboratories (live Toxoplasma gondii required); high titers → acute infection ▫ Patient serum treated with Toxoplasma trophozoites + complement, incubated → methylene blue added (membrane stain) → if anti-toxoplasma antibodies present, complement facilitates lysis of parasite membrane → no staining of lysed membrane ▫ No antibodies in serum → intact membranes → membrane stained blue under microscopy ▪ Tissue (brain/lymph node/muscle) biopsy ▫ Tachyzoites (acute infection) may be demonstrated in tissues/smears

Figure 8.2 An MRI scan of the head in the axial plane demonstrating cerebral toxoplasmosis. There are numerous peripherally enhancing nodules in the basal ganglia.

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TREATMENT MEDICATIONS

▪ Prevention ▫ Trimethoprim/sulfamethoxazole ▪ Acute infection ▫ Antimalarials: pyrimethamine ▫ Antibiotics: sulfadiazine with pyrimethamine, clindamycin, spiramycin ▪ Latent infection ▫ Cysts not sufficiently penetrated by traditional therapy ▫ Atovaquone (antimalarial) +/clindamycin (lincomycin antibiotic) ▪ Toxoplasmic chorioretinitis ▫ Sight-threatening lesions ▫ Triple therapy: pyrimethamine, sulfadiazine, folinic acid ▫ Mono-antibiotic therapy: trimethoprimsulfamethoxazole, clindamycin, spiramycin

NOTES

NOTES

CESTODES (TAPEWORMS) GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Human gastrointestinal tract parasites; AKA tapeworms ▫ Adult tapeworms live in intestines ▫ Larvae live in different tissue (brain, liver, eye, etc.) ▪ Tripartite body ▫ Head/scolex (contain suckers, hooks/ attachment organs) ▫ Thin neck ▫ Trunk (made of numerous proglottids) ▪ Hermaphroditic ▫ Each proglottid has male, female organs ▪ Transmission ▫ Egg/larvae-contaminated water/food ingestion

RISK FACTORS ▪ ▪ ▪ ▪ ▪

Poor hygiene Low socioeconomic status Raw/undercooked fish/meat Livestock exposure Living/travelling in endemic areas

COMPLICATIONS ▪ ▪ ▪ ▪

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Cysticercosis (Taenia) Cyst rupture Intestinal obstruction Malabsorption → vitamin B12 deficiency → megaloblastic anemia

SIGNS & SYMPTOMS ▪ Tapeworm species-dependent ▪ Can be asymptomatic, abdominal pain. nausea/vomiting, weight loss

DIAGNOSIS DIAGNOSTIC IMAGING MRI, CT scan, ultrasound ▪ Cyst presence

LAB RESULTS

▪ Microscopy ▫ Identify eggs/proglottids in stool ▪ Complete blood count (CBC), serology

TREATMENT ▪ Tapeworm species-dependent

MEDICATIONS ▪ Anthelmintics

Chapter 61 Cestodes (Tapeworms)

DIPHYLLOBOTHRIUM LATUM osms.it/diphyllobothrium-latum PATHOLOGY & CAUSES ▪ AKA fish tapeworm ▪ Longest human-infecting tapeworm (4–15m/13–49ft) ▪ Causes diphyllobothriasis in humans ▪ Proglottids ▫ Width > length ▪ Competes for vitamin B12 → vitamin B12 deficiency

CAUSES

▪ Raw/undercooked fish → larvae ingestion

COMPLICATIONS

▪ Tapeworms → mechanical intestinal obstruction ▪ Malabsorption → weight loss ▪ Vitamin B12 deficiency → megaloblastic anemia

SIGNS & SYMPTOMS ▪ Vitamin B12 deficiency ▫ Impaired oxygen delivery: fatigue, activity intolerance, pallor, compensatory mechanisms (↑ heart rate, bounding pulse) ▫ Neuronal demyelination: numbness, tingling, weakness ▪ Weight loss ▪ Abdominal pain

DIAGNOSIS LAB RESULTS

▪ Megaloblastic anemia; e.g. increased mean corpuscular volume (MCV) ▪ Microscopy ▫ Identify eggs/proglottids in stool ▪ ↓ serum vitamin B12

TREATMENT MEDICATIONS ▪ Anthelmintics

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ECHINOCOCCUS GRANULOSUS (HYDATID DISEASE) osms.it/echinococcus-granulosus PATHOLOGY & CAUSES ▪ Parasitic infection caused by E. granulosus ▫ AKA echinococcosis ▪ Produce protoscoleces ▫ Juvenile scolex invaginated in cysts ▫ Tapeworm maturation in definitive host’s intestine ▪ Humans (incidental hosts); herbivores (intermediate hosts); canids (definitive hosts)

CAUSES

▪ Viable parasite egg-containing food consumption

RISK FACTORS

▪ Parasite/egg-contaminated food/water ingestion ▪ Close contact with infected animals

Figure 61.2 The gross pathology of hydatid cysts excised from the lung.

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Figure 61.1 A scolex of the organism Echinococcus granulosus, the causative agent of hydatid disease.

COMPLICATIONS

▪ Arise as cysts migrate, grow in size, rupture ▫ Liver: eosinophilia, pruritus, jaundice, urticaria, liver abscess, anaphylaxis ▫ Peritoneal cavity: peritonitis, pancreatitis ▫ Pleural space: abscess formation → pneumothorax/pleural effusion ▫ Bronchial tree: respiratory distress, hemoptysis ▫ Heart: cardiomegaly/pericardial effusion ▫ Kidney: glomerulonephritis ▪ Large cyst compression effect ▫ Heart: large cyst in liver → compression of right heart ▫ Cerebral/spinal cord (CNS): neurological deficits ▫ Liver/biliary tree cysts: obstructive jaundice/cholangitis; venous drainage obstruction → portal hypertension → Budd–Chiari syndrome (abdominal pain, ascites, hepatomegaly)

Chapter 61 Cestodes (Tapeworms)

SIGNS & SYMPTOMS ▪ Initially asymptomatic ▪ Depend on affected organs ▫ Liver: right upper quadrant pain, hepatomegaly, nausea, vomiting ▫ Lungs: cough, chest pain, dyspnea, hemoptysis ▪ Other organs (rarely affected) ▫ Heart: jugular venous distention, dyspnea ▫ Musculoskeletal: diffuse pain, pathologic fractures ▫ Kidney: hematuria, flank pain ▫ CNS: headache, motor deficit, seizure, coma

▪ Puncture-aspiration-injection-reaspiration (PAIR) ▫ Ultrasound/CT scan-guided cyst puncture ▫ Aspirate cystic fluid ▫ Inject scolicidal solution ▫ Reaspirate cystic solution ▫ Repeat procedure until aspirate clears ▫ Fill cyst with isotonic saline

DIAGNOSIS DIAGNOSTIC IMAGING Ultrasound/MRI/CT scan ▪ Cyst presence

LAB RESULTS

▪ Enzyme-linked immunosorbent assay (ELISA) ▫ Echinococcal antigen detection in cystic fluid ▪ Indirect hemagglutination ▫ Echinococcal antigen detection ▪ Immunodiffusion/immunoelectrophoresis ▫ Echinococcal-specific antibody detection ▪ Biopsy/cyst aspiration

Figure 61.3 A CT scan of the abdomen in the axial plane demonstrating a large hepatic hydatid cyst. The numerous daughter cysts are faintly visible.

TREATMENT MEDICATIONS

▪ Albendazole/ mebendazole ▫ Uncomplicated cases

Figure 61.4 A histological section through a hydatid cyst wall showing a typical laminated structure.

SURGERY

▪ Complicated cases ▫ Rupture, vital structure compression, cysts with diameter > 10cm/3.94in

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NOTES

NOTES

CHLAMYDIA MICROBE OVERVIEW ▪ Gram-negative, obligate intracellular bacteria ▪ AKA “energy parasites”; rely on host cell for adenosine triphosphate (ATP) synthesis ▪ Primarily infects epithelium, mucous membranes Morphology ▪ Coccoid; cell walls don’t contain peptidoglycan

Replication ▪ Intracellular life cycle: infectious stage (spore-like elementary body) attaches to host cell via endocytosis → reorganizes within cellular vacuole into reticulate body (vegetative form) → reproduces, forms multiple reticulate bodies → forms elementary bodies → released from host cell → continues infectious process

CHLAMYDIA SPECIES (PNEUMONIA) osms.it/chlamydia-species PATHOLOGY & CAUSES ▪ Species of chlamydia; primarily causes community-acquired pneumonia ▪ Transmitted via respiratory secretions ▪ Can also infect endothelial cells → atherosclerosis

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RISK FACTORS ▪ ↑ risk with age

COMPLICATIONS

▪ Otitis media, sinusitis, parapneumonic effusions, pericarditis

Chapter 62 Chlamydia

SIGNS & SYMPTOMS ▪ Gradual onset ▪ General malaise, myalgia, fever, chills, pharyngitis, hoarseness, sinusitis, cough ▪ Extra-respiratory manifestations: meningoencephalitis, reactive arthritis, myocarditis

DIAGNOSIS

LAB RESULTS

▪ Microbial identification: serology, polymerase chain reaction (PCR), nasopharyngeal swab culture, direct antigen testing ▪ Complete blood count (CBC): normal white blood cell count

OTHER DIAGNOSTICS

▪ History, physical examination: lung sounds (e.g. crackles, wheezing)

DIAGNOSTIC IMAGING Chest X-ray ▪ Unilateral patchy infiltrates

TREATMENT MEDICATIONS ▪ Antibiotics

CHLAMYDIA TRACHOMATIS osms.it/chlamydia-trachomatis PATHOLOGY & CAUSES ▪ Species of chlamydia; primarily affects eyes, urogenital tract ▪ Different serovars cause diverse disease states ▫ A, B, Ba, C: trachoma ▫ D–K: urogenital infection, conjunctivitis ▫ L1, L2, L2a, L2b, L3: lymphogranuloma venereum

RISK FACTORS

▪ Risky sexual practices (e.g. multiple sex partners, unprotected sex) ▪ Impaired mucous membrane barrier (e.g. cervical friability) ▪ History of sexually transmitted disease ▪ Exposure during birth

COMPLICATIONS

▪ Ocular: ophthalmia neonatorum (conjunctivitis), blindness ▪ Genitourinary: pelvic inflammatory disease (PID), PID-associated ectopic pregnancy, infertility, proctitis, cervicitis, urethritis

▪ Chlamydial pneumonia, bronchitis, perihepatitis (Fitz-Hugh–Curtis syndrome); ↑ risk of acquiring/transmitting HIV due to genital inflammation

SIGNS & SYMPTOMS Trachoma ▪ Chronic, granulomatous inflammation of eye → corneal ulceration, scaring, pannus formation → blindness Adult conjunctivitis ▪ Inclusion (purulent erythematous injection of epithelial surface) conjunctivitis, mucopurulent discharge → keratitis Urogenital infections ▪ Individuals who are biologically female ▫ May be asymptomatic ▫ Bartholinitis, cervicitis (mucopurulent endocervical discharge), endometritis, salpingitis, urethritis (dysuria, pyuria) ▫ PID: uterine/adnexal tenderness ▫ Perihepatitis: right upper quadrant (RUQ) pain

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▪ Individuals who are biologically male ▫ Urethritis: dysuria, watery/mucoid discharge Neonatal conjunctivitis ▪ Eyelid swelling, watery/purulent discharge, red, thickened conjunctiva (chemosis) ▪ Conjunctival scarring, corneal vascularization ▪ ↑ risk of developing C. trachomatis pneumonia Infant pneumonia ▪ Diffuse, interstitial disease; rhinitis, staccato cough

Figure 62.1 Purulent discharge from the cervix of an individual with chlamydia infection.

Lymphogranuloma venereum (LGV) ▪ Anorectal disease: anorectal pain, tenesmus (feeling of incomplete bowel evacuation), rectal bleeding/discharge, constipation ▪ Painless ulcer → inflammation of lymph nodes (preauricular, submandibular, cervical) → progression to systemic symptoms ▪ Population at highest risk: individuals who are biologically male who have same-sex intercourse (MSM)

DIAGNOSIS LAB RESULTS

▪ Microbial identification: nucleic acid amplification test (NAAT)

OTHER DIAGNOSTICS

▪ Clinical presentation, history

TREATMENT MEDICATIONS

▪ Antibiotics ▪ Sexual partners should also be treated

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Figure 62.2 A cervical smear from an individual infected with Chlamydia trachomatis. There are numerous organisms contained within intracellular vacuoles.

Chapter 2 Acyanotic Defects

NOTES

COCCOBACILLI: AEROBES MICROBE OVERVIEW ▪ Intermediate shape between cocci (spherical bacteria), bacilli (rod-shaped bacteria)

▪ Gram-negative, obligate aerobe, nonmotile, non-spore forming

BORDETELLA PERTUSSIS (PERTUSSIS/WHOOPING COUGH) osms.it/bordetella-pertussis PATHOLOGY & CAUSES ▪ Infectious agent, causes pertussis ▪ Strict human pathogen ▪ Tropism to respiratory epithelium Pathophysiology ▪ Bacteria enters upper respiratory tract, releases toxins ▪ Filamentous hemagglutinin, pertactin, agglutinogen ▫ Anchors to epithelial cells

▪ Tracheal cytotoxin ▫ Paralysis of respiratory cilia → ↑ accumulation of mucus in airways → violent cough reflex ▪ Pertussis toxin ▫ Stimulates T cells to divide, blocks them from leaving blood, migrating into tissues → lymphocytosis ▫ ↑ sensitivity of respiratory tissues to histamine → ↑ vascular permeability → fluid leaks into airway tissues → airway edema → dyspnea

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▪ Adenylate cyclase toxin ▫ ↑ conversion of adenosine triphosphate (ATP) to cyclic adenosine monophosphate (AMP) within phagocytes → disbalance in cellular signaling mechanism → phagocytes unable to correctly respond to infection, undergo apoptosis Stages of infection ▪ Catarrhal: follows incubation period (approx. one week); lasts two weeks, very contagious ▪ Paroxysmal: 1–6 weeks ▪ Convalescent: 2–3 weeks

RISK FACTORS

▪ Infants too young to have completed immunization ▪ Unimmunized individuals ▪ Debilitation of immune system

COMPLICATIONS

▪ Apparent life-threatening event (ALTE) ▫ Young infants; gasping, cyanosis, apnea ▪ Hypoxia ▫ Seizures, encephalopathy, death ▪ Pneumonia, pneumothorax

SIGNS & SYMPTOMS ▪ Catarrhal: nasal congestion; mild cough; sneezing; low-grade fever; red, watery eyes (similar to common cold) ▪ Paroxysmal: high-pitched whooping during inhalation; uncontrollable coughing fits → vomiting, fainting, rib fracture, petechiae in face, subconjunctival hemorrhages, hernias ▪ Convalescent stage: coughing improvement; decreased paroxysm, whooping; healing of airways

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DIAGNOSIS LAB RESULTS

▪ Nasopharyngeal swab culture (Bordet– Gengou agar) ▫ Detects microbe; mercury drop colonies ▪ Polymerase chain reaction (PCR) ▫ Detects microbe ▪ Serology ▫ Detects microbe; antibody levels ▪ Complete blood count (CBC) ▫ Leukocytosis (esp. young infants)

OTHER DIAGNOSTICS

▪ History, physical examination ▫ Sudden, dramatic coughing attacks; lung sounds (e.g. whooping)

TREATMENT MEDICATIONS

▪ Prophylactic ▫ Diphtheria, tetanus, acellular pertussis (DTaP) vaccine ▪ Macrolide antibiotics

OTHER INTERVENTIONS

▪ Compulsory isolation of infected individual

Chapter 63 Coccobacilli: Aerobes

FRANCISELLA TULARENSIS (TULAREMIA) osms.it/francisella-tularensis PATHOLOGY & CAUSES ▪ Infectious agent that causes zoonosis tularemia ▪ Facultative, gram-negative intracellular bacteria ▪ Highly infectious, virulent; potential bioterrorism agent Transmission ▪ Direct contact with infected animals (e.g. inoculation of mucous membranes via contaminated hands/infected material) ▪ Ingestion of contaminated water/meat ▪ Airborne spread via contaminated materials (e.g. dust, hay, grass, lab specimens) ▪ Insect vectors ▫ Ticks, mosquitoes, horse flies, fleas, lice Pathophysiology ▪ Francisella tularensis enters body → phagocytosed by macrophages → impairs phagosome-lysosome fusion, rapidly proliferates within macrophage → infected macrophage undergoes apoptosis → bacteria released, infection spread

COMPLICATIONS

▪ Lymph node suppuration, sepsis, renal failure, rhabdomyolysis, hepatitis, pneumonia

SIGNS & SYMPTOMS ▪ Fever, chills, malaise, lethargy, anorexia, chest/muscle soreness ▪ Ulceroglandular: papulo-ulcerative lesion at point of contact with animal/vector; lymphadenopathy ▪ Glandular: lymphadenopathy (no skin lesions) ▪ Oculoglandular: pain/irritation of eye; periorbital edema/erythema; increased tearing; photophobia; regional adenopathy ▪ Oropharyngeal: sore throat; cervical lymph node enlargement; pharyngitis; tonsillitis ▪ Pneumonic: dry cough; breathing difficulties; substernal chest pain ▪ Typhoidal: very high fever; abdominal pain; diarrhea; vomiting; diffuse abdominal tenderness

TYPES

▪ Forms of tularemia: ulceroglandular (75%), glandular, oculoglandular, oropharyngeal, pneumonic, typhoidal

RISK FACTORS

▪ Work-related ▫ Lab workers, farmers, veterinarians, gardeners, hunters, butchers ▪ Skin exposure to vectors (esp. in summer)

Figure 63.1 An ulcer on the skin of an individual with tularemia.

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DIAGNOSIS LAB RESULTS

▪ Culture ▫ Buffered charcoal yeast extract (BCYE) agar ▪ PCR, direct fluorescent antibody (DFA) test ▫ Detects microbe ▪ Serology ▫ IgM, IgG antibodies appear after 2 weeks

OTHER DIAGNOSTICS

▪ History, physical examination

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TREATMENT MEDICATIONS

▪ Antibiotics (e.g. streptomycin, gentamicin, doxycycline)

Chapter 2 Acyanotic Defects

NOTES

COCCOBACILLI: FACULTATIVE ANAEROBES

MICROBE OVERVIEW ▪ Intermediate shape between cocci (spherical bacteria), bacilli (rod-shaped bacteria)

▪ Gram-negative, facultative anaerobes, nonmotile, nonspore-forming

BRUCELLA osms.it/brucella PATHOLOGY & CAUSES ▪ Characteristics ▫ Zoonotic infection ▫ Urease, catalase positive ▫ Facultatively intracellular ▫ Sensitive to heat, ionizing radiation, disinfectants, pasteurization ▪ Virulence factors ▫ Lipopolysaccharide (LPS): promotes cell entry, evasion, intracellular killing ▫ Type IV secretion system (key virulence factor): injection of effector molecules into host cell → modifies endoplasmic reticulum, enables replication ▪ Culture ▫ Isolation specimen: blood, bone marrow, body fluids, tissues ▫ Media: biphasic (solid, liquid) RuizCastaneda blood culture/modern automated blood culture systems (faster, more effective) ▫ Raised, convex colonies with smooth, shiny surface ▪ Causative agent of brucellosis ▪ Most common zoonotic infection to cause disease in humans

Transmission ▪ Contact with infected animals (e.g. sheep, cattle, goats, pigs, etc) ▫ Entry of bacteria through skin lesions, conjunctival inoculation, inhalation of contaminated aerosol ▪ Ingestion of contaminated animal products (e.g. unpasteurized milk, cheese; undercooked meat) ▫ Remains viable up to two days in milk at 8°C/46.4°F, three weeks in frozen meat, three months in goat cheese Pathogenesis ▫ Inoculation of bacteria → ingestion by polymorphonuclears, macrophages → passage to local lymph nodes → bacteria replicates intracellularly → some bacteria avoid intracellular killing by different strategies (e.g. inducing phagocyte apoptosis, inhibiting phagocyte-lysosome fusion) → chronic infection

TYPES Acute infection ▪ Localized infection (30% of cases), can affect any organ

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▫ Skeletal (most common): arthritis, spondylitis, sacroiliitis, osteomyelitis ▫ Pulmonary: bronchitis, interstitial pneumonitis, lobar pneumonia, pulmonary nodules, pleural effusion, empyema, abscesses ▫ Cardiac: endocarditis, myocarditis, pericarditis, endarteritis ▫ Alimentary: cholecystitis, ileitis, colitis, pancreatitis ▫ Reticuloendothelial: reactive hepatitis, granulomas, acute hepatitis with focal necrosis (B. melitensis), formation of noncaseating sarcoidosis-like granulomas (B. abortus), suppurative abscess formation (B. suis) in liver ▫ Genitourinary: orchitis, epididymitis ▫ Hematological: anemia, leukopenia, thrombocytopenia, pancytopenia, disseminated intravascular coagulation ▫ Neurologic: meningitis, encephalitis, myelitis, radiculitis, neuritis, mycotic aneurysms, brain abscess ▫ Ocular: uveitis, keratoconjunctivitis, corneal ulcers, iridocyclitis, nummular keratitis, choroiditis, optic neuritis, papilledema, endophthalmitis ▫ Dermatologic: nonspecific skin eruptions, ulcerations, petechiae, purpura, granumanifestationslomatous vasculitis, abscesses

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Chronic infection ▪ Symptoms persist one year after diagnosis; localized infection, relapse

RISK FACTORS

▪ Occupational exposure ▫ Lab health care workers, farmers, slaughterhouse workers, veterinarians

COMPLICATIONS

▪ Infection during pregnancy → intrauterine infection, premature delivery, spontaneous abortion, miscarriage ▪ Endocarditis damage, destroy heart valves ▪ Leading cause of death by brucellosis ▪ Skeletal ▫ May cause long-term damage, bone/ joint malformations ▪ Neurologic ▫ May lead to permanent brain damage ▪ Ocular ▫ Visual impairment

Chapter 64 Coccobacilli: Facultative Anaerobes

SIGNS & SYMPTOMS ▪ Range from asymptomatic to severe illness ▪ Onset of symptoms can be acute/insidious ▪ Incubation ▫ 1–4 weeks to several months ▪ Acute generalized infection ▫ Acute undulating fever (key sign), arthralgia, myalgia, fatigue, headache, night sweats, malaise, weight loss ▫ Hepatomegaly, splenomegaly, lymphadenopathy ▫ Foul-smelling perspiration (characteristic sign) ▪ Localized infection ▫ Symptoms depend on organ/organ system affected

DIAGNOSIS LAB RESULTS

▪ Rising titers of specific antibodies ▫ Initial rise in IgM class titers, followed in several weeks by predominance of IgG antibodies; both decrease over time with treatment ▪ Anemia, thrombocytopenia

Microbe identification ▪ Positive bodily fluids/tissue culture ▪ Serum agglutination, enzyme-linked immunosorbent assay (ELISA) ▪ Polymerase chain reaction (PCR)

▪ Lysis-centrifugation technique

OTHER DIAGNOSTICS

▪ History of travel, food consumption, occupation

TREATMENT MEDICATIONS

▪ Six-week course of doxycycline plus streptomycin/gentamicin/doxycycline plus rifampin ▪ In children < eight years old ▫ Trimethoprim-sulfamethoxazole (TMPSMX) plus rifampin

SURGERY

▪ Surgical interventions sometimes necessary for osteoarticular manifestations (e.g. pyogenic joint effusions), hepatosplenic granulomas/abscesses, cardiac complications (e.g. valve replacement surgery)

OTHER INTERVENTIONS

▪ Prophylaxis ▫ Biosafety level 3 in laboratories recommended while handling Brucella cultures ▫ No vaccines for humans; live attenuated vaccines containing strains of B. abortus, B. melitensis used for animals

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HAEMOPHILUS DUCREYI osms.it/haemophilus-ducreyi PATHOLOGY & CAUSES ▪ Virulence factors ▫ Lipooligosaccharide ▫ Pili: provides attachment of bacteria ▫ Soluble cytolethal distending toxin, cytotoxic hemolysin, hemoglobinbinding protein, copper-zinc superoxide dismutase, filamentous hemagglutininlike protein, zinc-binding periplasmic protein ▪ Culture ▫ Isolation specimen: genital ulcer swab, lymph node aspirate ▫ Media: enriched growth medium contains factor X (hemin), serum incubated at 33–35ºC/91.4–95°F with CO2; small, heterogenous, gray/ translucent colonies ▪ Causative agent of sexually transmitted genital ulcer called chancroid (AKA ulcus molle), associated inguinal lymphadenopathy ▪ Some strains causes cutaneous ulcers in children in South Pacific, parts of equatorial Africa Transmission ▪ Sexual intercourse (genital ulcers) ▪ Nonsexual transmission (cutaneous ulcers) Pathogenesis ▪ Incubation ▫ 4–10 days ▪ Inoculation through epidermal microabrasions → attachment of bacteria to extracellular matrix in skin via pili,

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lipooligosaccharide → attachment to cells via specific heat shock protein (GroEL) → cytotoxin release, epithelial injury → formation of erythematous papule → evolves into pustule → pustule ruptures, forms ulcer

RISK FACTORS

▪ Uncircumcised individuals, poverty, multiple sexual partners

COMPLICATIONS

▪ Increases risk for HIV contraction

SIGNS & SYMPTOMS ▪ Single/multiple painful genital ulcers on erythematous base, 1–2cm/0.39–0.79in diameter with sharply demarcated borders; base of ulcer covered with purulent exudate, bleeds easily when scraped ▪ Predilection sites ▫ Prepuce, coronal sulcus, glans penis in individuals who are biologically male ▫ Labia, vaginal introitus, perianal area in individuals who are biologically female ▪ Individuals who are biologically female ▫ Dysuria, dyspareunia, vaginal discharge, rectal bleeding, painful defecation ▪ Inguinal lymphadenopathy in approx. 50% of cases (more common in individuals who are biologically male) ▫ Painful fluctuant buboes (swollen lymph nodes); if untreated, may spontaneously rupture, form draining sinus, releases pus

Chapter 64 Coccobacilli: Facultative Anaerobes

DIAGNOSIS LAB RESULTS Microbe identification ▪ Diagnosis of confirmed chancroid ▫ Culture (not widely available) ▪ Nucleic acid amplification tests ▫ Not available outside of clinical research purposes ▪ Polymerase chain reaction (PCR) multiplex ▫ Detection of bacterial DNA ▪ Histologic characteristics of chancroid

OTHER DIAGNOSTICS

▪ Diagnostic criteria for probable chancroid ▫ ≥ one painful genital ulcers ▫ No evidence of Treponema pallidum infection (by darkfield microscopy/ serologic testing) ▫ No evidence of Herpes simplex virus (HSV) infection ▫ Appearance of genital ulcers, regional lymphadenopathy ▪ Purulent exudate in superficial epidermis with perivascular, interstitial mononuclear infiltrate in dermis

Figure 64.1 An ulcer on the glans penis of a male with chancroid. The ulcer is typically painful, unlike the ulcer of primary syphilis.

TREATMENT MEDICATIONS

▪ Single-dose therapy with azithromycin/ ceftriaxone ▪ Alternative ▫ Multiple-dose therapy with ciprofloxacin/erythromycin

OTHER INTERVENTIONS

▪ Fluctuant lymphadenopathy ▫ Needle aspiration, drainage to prevent spontaneous rupture

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HAEMOPHILUS INFLUENZAE osms.it/haemophilus-influenzae PATHOLOGY & CAUSES ▪ Haemophilus: blood loving ▪ Characteristics ▫ Catalase, oxidase positive ▪ Virulence factors ▫ Polysaccharide capsule: prevents phagocytosis; causes ciliostasis, evades mucociliary clearance of bacteria; classified into six serotypes based on capsular antigens (A, B, C, D, E, F); some strains unencapsulated (AKA nontypable); most clinical isolates Haemophilus influenzae type B (Hib)/ nontypable ▫ IgA1 protease, adherence factors, antigenic variation, biofilm formation ▪ Gram stain of exudate shows bacteria arranged in chains (“school of fish”) ▪ Culture ▫ Isolation specimen: cerebrospinal fluid (CSF), urine, serum, synovial fluid ▫ Media: chocolate agar/Fildes medium (hemolyzed erythrocytes) with factor X (hemin), V (nicotinamide adenine dinucleotide) supplementation in aerobic, only factor X supplementation in anaerobic environment ▫ Convex, smooth, grey/transparent colonies ▪ Gram-negative coccobacillus → meningitis, respiratory tract infections ▪ Nontypeable strains colonize nasopharynx of 40–80% children, adults ▪ Hib colonizes 3–5% children

TYPES Hib ▪ Epiglottitis in older children, adults ▪ Cellulitis (most common in young children) ▪ Pneumonia ▫ Sometimes with meningitis, epiglottitis ▪ Meningitis, septic arthritis, osteomyelitis

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Nontypable ▪ Less invasive due to lack of capsule; causes mild localized respiratory tract disease in children, adults ▪ More severe in immunocompromised/ predisposed individuals ▫ Otitis media, sinusitis, purulent conjunctivitis, bacterial pneumonia in children (in low-income countries), neonatal bacteremia ▫ Community-acquired pneumonia in adults with underlying lung disease ▫ Exacerbation of chronic obstructive pulmonary disease (COPD) ▫ Meningitis in individuals with predisposition/conditions causing leakage of CSF fluid (e.g. sinusitis, otitis media, head trauma) Transmission ▪ Direct contact with respiratory tract secretions/airborne respiratory droplets Pathogenesis ▪ Inoculation → passage through upper respiratory tract → adherence to respiratory epithelium, LPS inhibits mucociliary clearance → colonization spreads throughout respiratory tract → sinuses, otitis, pneumonia ▪ IgA1 protease, antigenic variation, paracytosis, biofilm formation → perseverance of bacteria

RISK FACTORS

▪ Viral infection, sickle-cell disease, asplenia, HIV infection, malignancies, congenital deficiencies of complement components

COMPLICATIONS

▪ Nontypable in neonates, immunocompromised individuals → septicemia, meningitis, septic arthritis ▪ Hib meningitis → subdural effusion/ empyema; ischemic/hemorrhagic cortical

Chapter 64 Coccobacilli: Facultative Anaerobes infarction; cerebritis (nonviral parenchymal infection of brain); ventriculitis; intracerebral abscess; hydrocephalus; neurologic sequelae (e.g. permanent sensorineural hearing loss, seizures, intellectual disability) ▪ Hib pneumonia can spread to pericardium → purulent pericarditis

SIGNS & SYMPTOMS Hib ▪ Meningitis ▫ Fever, lethargy, irritability, vomiting, altered mental status ▫ Fulminant course → rapid neurologic deterioration, respiratory arrest ▫ Positive Kernig’s sign: inability to straighten leg when hip flexed to 90º ▫ Positive Brudzinski’s sign: flexing of neck by examiner → flexing of hips, knees ▪ Epiglottitis ▫ Fever, sore throat, difficulty speaking, dyspnea → severe stridor, dysphagia, pooling of secretions, drooling ▫ “Tripod” posture: individual takes sitting position with trunk leaning forward, neck hyperextended, chin thrust forward to get more air through obstructed airway ▪ Cellulitis ▫ Fever; warm, tender area of erythema/ violaceous discoloration on cheek/ periorbital area ▪ Septic arthritis ▫ Fever, pain, swelling, tenderness, decreased mobility of affected joint Nontypeable ▪ Otitis media ▫ Fever, ear pain, irritability, sleep disturbance, otorrhea ▫ Red bulging tympanic membrane with decreased mobility upon pneumatic otoscopy examination ▫ Often conjoined with conjunctivitis ▪ Sinusitis ▫ Fever, persistent purulent nasal discharge or cough > 10 days ▫ Tenderness over involved paranasal sinuses

DIAGNOSIS DIAGNOSTIC IMAGING Laryngoscopy ▪ Red, swollen epiglottis; aryepiglottic folds ▪ Examine with caution; possible laryngeal spasm X-ray ▪ Thumb sign on epiglottis (radiographic corollary of omega sign)

LAB RESULTS Microbe identification ▪ Positive Gram stain, bacterial culture of CSF, synovial fluid, epiglottis, pleural, pericardial, other sterile fluids ▪ Latex agglutination, enzyme immunoassay, coagglutination ▫ Type B capsular antigen detection in CSF, serum, urine ▪ Definitive diagnosis ▫ Culture of fluid obtained by sinus aspiration, tympanocentesis, tracheal/ lung aspiration, bronchoscopy, bronchoalveolar lavage

Figure 64.2 An X-ray image of the chest demonstrating diffuse airway shadows in an individual with bronchopneumonia. H. influenzae is a causative organism of bronchopneumonia.

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TREATMENT MEDICATIONS Prevention ▪ Conjugate Hib vaccines ▫ Routine vaccination of infants of two months ▪ Rifampin chemoprophylaxis ▫ Individuals in close contact with infected; incompletely vaccinated individuals in households with infants/ children < four years old Hib with meningitis ▪ Third generation cephalosporins ▫ Adults: ceftriaxone

▫ Children: ceftriaxone plus dexamethasone (decreases immune response to released LPS upon bacterial death, lowers chance for destruction of neurons, neurologic sequelae) ▪ Epiglottitis (life-threatening condition; prompt treatment paramount) ▫ Ceftriaxone Nontypable ▪ Amoxicillin/clavulanate, broad-spectrum cephalosporins, macrolides (azithromycin/ clarithromycin), fluoroquinolones

SURGERY

▪ Epiglottitis ▫ Placement of artificial airway

PASTEURELLA MULTOCIDA osms.it/pasteurella-multocida PATHOLOGY & CAUSES ▪ Characteristics ▫ Zoonotic infection (e.g. birds, cats, dogs, rabbits, cattle, pigs); oxidase, catalase, nitrate reduction positive ▪ Virulence factors ▫ Polysaccharide capsule: prevents phagocytosis; divided into serogroups based on capsular antigens (A, B, C, D, E) ▫ Lipopolysaccharide: endotoxin ▫ Sialidases, hyaluronidase, surface adhesins, iron acquisition proteins, pasteurella multocida toxin (PMT) ▪ Culture ▫ Isolation specimen: respiratory tract samples, CSF ▫ Media: sheep blood, chocolate, HS, Mueller–Hinton agar at 37ºC/98.6F; opaque/gray colonies 1–2mm in diameter ▪ Medically important subspecies ▫ P. multocida subsp multocida, P.

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multocida subsp septica, P. multocida subsp gallicida Transmission ▪ Most commonly cat/dog bites, scratches, licks

TYPES

▪ Soft tissue infections ▫ Cellulitis at site of inoculation (most common) → abscess, necrotizing soft tissue infections, septic arthritis, osteomyelitis ▪ Respiratory infections ▫ Due to underlying chronic pulmonary disease; glossitis, pharyngitis, sinusitis, otitis media, epiglottitis, tracheobronchitis, pneumonia, empyema, lung abscess ▪ Invasive infection (immunocompromised, infants) ▫ Bacteremia, meningitis, intra-abdominal infections (peritonitis, appendicitis), endocarditis, septic arthritis, ocular infection

Chapter 64 Coccobacilli: Facultative Anaerobes Pathogenesis ▪ Inoculation → attachment of bacteria to ECM, cells soft tissue → PMT secretion → tissue inflammation within 24 hours

LAB RESULTS

COMPLICATIONS

Microbe identification ▪ Culture, PCR, serological testing

▪ Sepsis, septic shock

SIGNS & SYMPTOMS ▪ Soft tissue infections ▫ Wound inflammation, cellulitis with purulent drainage; regional lymphadenopathy ▪ Respiratory tract infections ▫ Fever, malaise, dyspnea, pleuritic chest pain ▪ Sepsis ▫ Purpura fulminans (rash rapidly progresses from petechiae, purpura to gangrene/limb amputation) ▪ Respiratory infection ▫ Wheezing, rhonchi, dullness

DIAGNOSIS

OTHER DIAGNOSTICS

▪ History of animal contact ▫ Cat bites pose higher risk for developing osteomyelitis, septic arthritis

TREATMENT MEDICATIONS ▪ ▪ ▪ ▪

Penicillins Tetracyclines Cephalosporins Quinolones

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NOTES

NOTES

COMMA–SHAPED RODS MICROBE OVERVIEW ▪ Gram-negative, facultative anaerobes, motile, non-spore forming

CAMPYLOBACTER JEJUNI osms.it/campylobacter-jejuni PATHOLOGY & CAUSES Characteristics ▪ Zoonotic disease ▫ Reservoir in wild, domestic mammals, birds (esp. poultry) ▪ Oxidase +; invasive; microaerophilic; sensitive to heat, desiccation, acidity, irradiation, disinfectants Virulence factors ▪ Fimbriae-like filaments ▫ Promote attachment to intestinal

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epithelial cells ▪ Possesses single, unsheathed flagellum in one end (monotrichous)/two flagella each at both ends (amphitrichous) ▫ Provide motility, chemotaxis (mucin is chemoattractant → tropism for ileum, colon, rectum) ▪ Surface proteins (eg, PEB1, CadF) promote colonization, invasion of intestinal epithelial cells ▪ Lipopolysaccharide (LPS) ▫ Plays role in adherence, evasion of host immune response (undergoes antigenic variation)

Chapter 65 Comma-shaped Rods Culture ▪ Isolation specimen: stool, food ▪ Media: blood/charcoal agar with microaerophilic atmosphere (5–10% O2, 3–5% CO2), thermophilic environment (optimal 42°C/107.6°F) ▪ C. jejuni: one of most common bacterial causes of gastroenteritis with acute diarrhea Transmission ▪ Fecal-oral, contaminated water Pathogenesis ▪ Incubation period 1–7 days; tropism for distal ileum, colon, rectum ▪ Inoculation of bacteria → passage through upper GI tract → colonization, adherence to surface epithelium of distal ileum, colon → non-inflammatory secretory diarrhea (exact mechanism unknown) ▪ Invasion of intestinal epithelium, proliferation → release of cytolethal distending toxin → cell damage, inflammatory response → dysentery with fecal leukocytes ▪ Rare: translocates into lamina propria, spreads to mesenteric lymph nodes (mesenteric adenitis) → extraintestinal infections (e.g. meningitis, cholecystitis, UTI) ▫ Occurs mostly in immunocompromised

RISK FACTORS

▪ Consumption of undercooked meat/ unpasteurized milk ▪ Underlying conditions/medications that reduce/buffer gastric acidity (e.g. proton pump inhibitors) ▪ Individuals with HIV/AIDS

COMPLICATIONS

▪ Toxic megacolon, massive bleeding, colonic perforation ▪ Reactive arthritis ▪ Associated with Guillain–Barré syndrome ▫ Sialic acid contained bacterial core oligosaccharide can resemble gangliosides → cross-activation of autoreactive T/B cells (molecular mimicry)

SIGNS & SYMPTOMS ▪ Vary in severity depending upon inoculum concentrations; range from asymptomatic carriage to systemic illness ▫ Most episodes mild, self-limiting (up to one week); rarely persists up to several weeks ▪ Fever, myalgia, malaise, headache (early symptoms, 1–2 days); severe periumbilical abdominal pain, cramping, secretory, inflammatory diarrhea, vomiting ▫ Abdominal pain may mimic acute appendicitis ▫ Secretory diarrhea: more common in children ▫ Inflammatory diarrhea: tenesmus, bloody stools, fecal leukocytes

DIAGNOSIS LAB RESULTS

▪ Stool culture ▪ Rapid diagnosis with carbolfuchsin stain/ phase-contrast/dark-field microscopic examination of fresh stool specimen in case of acute manifestation ▪ PCR-based methods, enzyme immunoassays (EIAs) directly from stool

OTHER DIAGNOSTICS

▪ Clinical manifestations ▪ Histology ▫ Acute mucosal inflammation with edema, cellular infiltration of lamina propria, crypt abscess formation

TREATMENT MEDICATIONS

▪ Antibiotics for severe cases, immunocompromised individuals ▫ Erythromycin/azithromycin

OTHER INTERVENTIONS

▪ Replacement of fluids, electrolytes

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HELICOBACTER PYLORI osms.it/helicobacter-pylori PATHOLOGY & CAUSES Characteristics ▪ Urease +, catalase +, oxidase +; noninvasive ▪ Microaerophilic ▫ Requires oxygen, lower concentrations than present in atmosphere Virulence factors ▪ Possesses 2–7 unipolar sheathed flagella (H-antigen) ▫ Provide motility, chemotaxis (sense pH, move bacteria towards beneficial environment) ▪ Lipopolysaccharide (LPS) ▫ Promotes adherence, causes inflammation ▪ Coccoid form ▫ More resistant form; occurs as adaptation to hostile environment outside human body ▪ Urease ▫ Important for survival, colonization ▪ Mucolytic enzymes ▫ Allow passage through mucus layer to gastric epithelium ▪ Adhesive proteins (Hop proteins) ▪ Vacuolating cytotoxin A (VacA) ▫ Damages epithelial cells; disrupts tight junctions, causes apoptosis ▪ Cytotoxin associated gene CagA (CagA) ▫ Triggers inflammation ▪ Type IV secretion system ▫ Pili-like structure for injection of effectors (e.g. CagA) ▪ Proteases, lipases ▪ Biofilm formation Culture ▪ Isolation specimen: vomitus, diarrheal stools ▪ Media: blood agar/selective Skirrow’s media

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incubated at 37ºC/98.6°F in 5% oxygen; small, uniformly sized, translucent bacterial colonies ▪ H. pylori: causative agent of most common chronic infection in humans; common cause of duodenal, gastric ulcers, chronic gastritis Transmission ▪ Unknown; fecal/oral, oral/oral transmission suggested ▪ Reservoir ▫ Human (majority of cases); found in primates in captivity, domestic cats, sheep ▪ Also found in municipal water in endemic areas of infection with polymerase chain reaction (PCR) techniques Pathogenesis ▪ Bacterial urease hydrolyzes gastric luminal urea to form ammonia → ↑ gastric pH → formation of protective layer around bacteria → survival in hostile gastric environment ▪ ↑ pH → mucin liquefies → H. pylori passes through mucous layer to surface epithelium via bacterial flagella, mucolytic enzymes → attaches to specific gastric epithelial cell receptors via surface adhesins (Hop proteins) → release of proteases (VacA, CagA) + host immune response → inflammation, tissue injury ▪ Disruption of mucous layer → susceptibility to acid peptic damage ▪ Chronic inflammation, tissue injury together with acid peptic damage → chronic gastritis, peptic ulcers (10–20% risk)

RISK FACTORS ▪ ▪ ▪ ▪ ▪

Low socioeconomic status Increased housing density Lack of running water Genetic susceptibility Swimming in pools, rivers, streams

Chapter 65 Comma-shaped Rods

COMPLICATIONS

▪ Gastric carcinoma (1–2% risk): chronic gastritis → atrophic gastritis, intestinal metaplasia, carcinoma ▫ Chronic inflammation, ↑ TNF, ↑ IL-6, ↑ bacterial proteases → excessive tissue damage, cell mutation → intestinal metaplasia → carcinoma ▪ Gastric mucosa-associated lymphomas due to persistent immune stimulation of gastric lymphoid tissue

▫ Omeprazole/pantoprazole + clarithromycin, amoxicillin: in case of penicillin sensitivity, replace amoxicillin with metronidazole

SIGNS & SYMPTOMS ▪ Majority of cases asymptomatic ▪ Acute infection ▫ Upper abdominal pain, nausea, loss of appetite ▪ Chronic infection ▫ Chronic gastritis: upper abdominal pain, nausea, bloating, vomiting/melena (black stool) ▫ Peptic ulcers: stomach pain/ache; occurs with empty stomach, between meals, early morning

Figure 65.1 Helicobacter organisms in a gastric pit.

DIAGNOSIS LAB RESULTS

▪ Blood antibody test ▪ Stool antigen test ▪ Carbon urea breath test ▫ Individual ingests 14C- or 13C-labelled urea, which bacterium metabolizes, yielding labelled carbon dioxide detectable in breath ▪ Urine enzyme-linked immunosorbent assay (ELISA) test

TREATMENT MEDICATIONS

▪ One-week “triple therapy”: antacid/acidreducing drugs (H2-receptor antagonists/ proton pump inhibitors) + two antibiotics ▫ Bismuth salicylate + metronidazole + tetracycline ▫ Ranitidine bismuth citrate + tetracycline + clarithromycin/metronidazole

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VIBRIO CHOLERAE (CHOLERA) osms.it/vibrio-cholerae PATHOLOGY & CAUSES Characteristics ▪ Oxidase +; non-invasive; halophilic; genome consists of two circular chromosomes; sensitive to acid, drying ▪ Reservoir: aquatic environments (saltwater, brackish) ▪ Fermentation: glucose, sucrose Virulence factors ▪ Cholera toxin ▫ Only toxigenic strains; responsible for pathogenesis of massive, watery diarrhea; coded by filamentous bacteriophage (CTXΦ) ▪ Other toxins that increase mucosal permeability ▫ Zona occludens toxin (ZOT), accessory cholera enterotoxin (ACE), WO7 toxin 17 ▪ Lipopolysaccharide (LPS) ▫ > 200 serogroups; O1, O139 associated with cholera epidemics ▪ Motility ▫ Single polar flagellum (H-antigen) ▪ Toxin-coregulated pilus (TCP) ▫ Present only in toxigenic strains; promotes adherence, aggregation of bacteria; coded by genes in Vibrio pathogenicity island (VPI) ▪ Mucinase ▫ Digests mucous layer of gastrointestinal (GI) tract Culture ▪ Isolation specimen: stool, rectal swab ▪ Media: thiosulfate citrate bile salts sucrose (TCBS) agar/taurocholate tellurite gelatin agar (TTGA); large, yellow colonies (2–4mm diameter) with opaque centers, translucent edges

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▪ V. cholerae: diverse species; pathogenic, toxin-producing (toxigenic) variants cause cholera ▪ Cholera characterized by profound secretory diarrhea → rapid, life-threatening dehydration ▪ Transmitted by fecal-oral route/ contaminated food or water Pathogenesis ▪ Inoculation → passage through upper GI tract → rapid movement of bacteria through mucous via flagellum → colonization of small intestine via TCP → releases cholera toxin ▪ Cholera toxin (AB protein toxin) → B subunit binds to GM1 ganglioside on intestinal epithelial cell, allows entry of A subunit → activates G-protein regulated adenylyl cyclase → ↑ intracellular cyclic adenosine monophosphate (AMP) → secretion of chloride, sodium; inhibition of sodium chloride absorption → massive fluid secretion; loss of sodium, chloride, bicarbonate, potassium

TYPES Pathogenic (toxin-producing), nonpathogenic Serological classification: O antigen differences ▪ Serogroup O1 is subdivided into two serotypes (Inaba, Ogawa), two biotypes ▫ El Tor: cause of current global pandemic of cholera ▫ Classical: cause of previous V. cholerae pandemics; now thought extinct ▪ Serogroup O139 ▪ Non-O1/O139

RISK FACTORS

▪ Travel to endemic/epidemic areas ▪ Inadequate access to clean water

Chapter 65 Comma-shaped Rods ▪ Shellfish consumption in areas with sporadic cholera ▪ People with blood group O at higher risk for severe cholera (mechanism unknown)

COMPLICATIONS

▪ If untreated ▫ Dehydration, hypovolemic shock in 4–12 hours, death in 18 hours to several days ▪ Renal failure secondary to hypovolemia ▪ Electrolyte imbalances ▫ Hypokalemia, metabolic acidosis ▪ Pneumonia (esp. in children) due to aspiration of vomit

SIGNS & SYMPTOMS ▪ Incubation period is 28–48 hours ▪ Asymptomatic to severe depending upon strain, inoculum concentration (≥ 108 → severe form) ▪ Abrupt onset of profound watery diarrhea (grey, cloudy, flecked with mucus; “ricewater stool”); painless, without tenesmus; loss of 1 liter of fluid per hour in severe cases ▪ Moderate to severe vomiting, borborygmus, abdominal discomfort ▪ Dehydration ▫ Thirst, dry mucous membranes, decreased skin turgor, sunken eyes, hypotension, weak/absent radial pulse, tachycardia, tachypnea, hoarse voice, oliguria ▪ Altered mental status ▫ Somnolence, restlessness, lethargy

▫ Culture on TCBS agar ▫ Dark field microscopy/dipstick test of stool specimen for rapid confirmation in non-endemic areas (detectable in stool for 1–2 weeks without antimicrobial therapy)

TREATMENT MEDICATIONS

▪ Oral antibiotic treatment reduces duration, severity of disease ▫ Doxycycline for adults ▫ Azithromycin for children, pregnant individuals

OTHER INTERVENTIONS

▪ Prophylaxis ▫ WC-rBS (Dukoral) vaccine: monovalent inactivated oral cholera vaccine containing killed whole cells of V. cholerae O1, additional recombinant cholera toxin B subunit ▫ BivWC (Shanchol) vaccine: bivalent inactivated oral vaccine containing killed whole cells of V. cholerae O1, O139 ▫ CVD 103-HgR/Vaxchora vaccine: attenuated oral vaccine derived from serogroup O1 classical Inaba strain ▪ Rapid, aggressive volume replacement (oral/intravenous fluids) ▪ Adequate nutrition to prevent malnutrition ▪ Correction of electrolyte imbalances ▪ Zinc supplementation reduces duration, severity of disease

DIAGNOSIS LAB RESULTS

▪ Hypoglycemia/hyperglycemia ▪ Hypercalcemia, hypermagnesemia, hyperphosphatemia ▪ ↑ hematocrit due to volume depletion

OTHER DIAGNOSTICS ▪ Clinical presentation ▪ Microbiologic diagnosis

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NOTES

NOTES

CORONAVIRUSES MICROBE OVERVIEW ▪ Causes respiratory infections ▪ OC43, NL63: most common strains of human coronaviruses (HCoV) ▪ Associated clinical syndromes: common cold, pneumonia, bronchitis, Middle East respiratory syndrome (MERS-CoV), severe acute respiratory syndrome (SARS-CoV) Genetic material ▪ Positive-stranded RNA viruses Taxonomy ▪ Corona: crown; named after spiked appearance in electron microscopy ▪ Genera: alpha, beta (human pathogens), gamma, delta

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Morphology ▪ Helical capsid; enveloped (outer lipid membrane) ▪ Structural proteins ▫ Small envelope protein (E) → viral assembly ▫ Hemagglutinin esterase protein (HE) → binds to cell membrane (beta coronaviruses only) ▫ Membrane protein (M) → viral assembly ▫ Nucleocapsid protein (N) → forms nucleocapsid ▫ Spike protein (S) → binds, fuses with host cell membrane

Chapter 66 Coronaviruses

CORONAVIRUS (SARS) osms.it/coronavirus-SARS PATHOLOGY & CAUSES ▪ Causes severe respiratory syndrome (SARS) ▪ B-beta coronavirus: viral pulmonary disease ▪ Viral inoculation of respiratory tract mucosa → cell damage → release of cytokines (interferon-gamma, IL-1, IL-6, IL-12) → inflammation, ↑ secretions ▪ Incubation period: 2–7 days

CAUSES

▪ Direct contact, airborne droplets, fomites

RISK FACTORS

▪ Immunosuppression, healthcare-related occupation, comorbid conditions

COMPLICATIONS

▪ Acute respiratory distress syndrome, multiorgan failure

SIGNS & SYMPTOMS ▪ Prodrome: fever, malaise, headaches, myalgia, chills ▪ Non-productive cough, dyspnea, chest pain ▪ Diarrhea, rhinorrhea, sore throat

▪ Interstitial pulmonary infiltrates

LAB RESULTS Histologic pulmonary tissue observation ▪ Hyaline membranes, edema, fibroblast proliferation Reverse-transcriptase polymerase chain reaction (RT-PCR) ▪ Nasopharyngeal, oropharyngeal, stool, serum samples Serologic tests ▪ Enzyme-linked immunosorbent assays (ELISA) ▪ Fluorescence antigen detection assays Lab tests ▪ Lymphopenia, thrombocytopenia, ↑ lactate dehydrogenase (LDH), ↑ alanine aminotransferase (ALT)

TREATMENT OTHER INTERVENTIONS

▪ Mechanical ventilation in respiratory failure

Prevention ▪ Hand washing ▪ Proper disposal of infected materials (e.g. used tissues) ▪ Mask use within healthcare environment

DIAGNOSIS ▪ Center for Disease Control and Prevention (CDC) ▫ No alternative diagnosis after 72 hours of clinical evaluation ▫ Individual at risk

DIAGNOSTIC IMAGING Chest X-ray

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NOTES

NOTES

CUTANEOUS FUNGAL INFECTIONS

GENERALLY, WHAT ARE THEY? DIAGNOSIS

PATHOLOGY & CAUSES ▪ Noninvasive fungal infections of skin and its annexes ▫ Limited to stratum corneum ▫ Caused by human skin’s commensal flora

LAB RESULTS

▪ Microscopic observation

OTHER DIAGNOSTICS

▪ Clinical findings upon examination

SIGNS & SYMPTOMS ▪ Skin pigmentation changes ▪ Characteristic lesions: macule, patch, scale, plaque ▪ Occasional pruritus

TREATMENT MEDICATIONS ▪ Antifungal

MALASSEZIA (TINEA VERSICOLOR & SEBORRHOEIC DERMATITIS) osms.it/malassezia PATHOLOGY & CAUSES ▪ Genus of yeast-like fungi ▪ Cause cutaneous infections ▪ Cutaneous commensal flora, mostly lipiddependent (thrive on human sebum), saprophytic (nutrients obtained from dead, organic matter), dimorphic (yeast, hyphal/ mycelial forms)

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TYPES Tinea versicolor ▪ Superficial cutaneous mycosis ▪ AKA pityriasis versicolor ▪ Most common causes: M. globosa, M. furfur, M. sympodialis ▪ Fungus produces azelaic acid → tyrosinase activity (activated by sunlight) → skin pigmentation changes → hypopigmented/ hyperpigmented macules, patches, plaques

Chapter 67 Cutaneous Fungal Infections Seborrheic dermatitis ▪ Chronic, inflammatory dermatitis ▫ Tends to flare, relapse ▫ Likely caused by Malassezia spp. ▪ Fungus produces acids, enzymes, oxygen radicals → cell damage → inflammatory response → erythema, greasy, yellowish scaling (range from mild, flaky to coarse, thick lesions)

RISK FACTORS Tinea versicolor ▪ Most common ▫ Adolescents/young adults ▪ Excessive heat, humidity, perspiration, sunlight ▪ Immunosuppression

Figure 67.1 Tinea versicolor on the abdomen.

Seborrheic dermatitis ▪ Biphasic occurrence ▫ Infants (cradle cap), adolescents/adults ▪ Biologically-male > biologically-female individuals ▪ Comorbidities ▫ HIV/AIDS, Parkinson’s disease

SIGNS & SYMPTOMS Tinea versicolor ▪ Characteristic skin changes ▫ Usually located on abundant sebaceous gland areas (torso, proximal extremities, face, neck) ▪ Light brown in light-skinned individuals; dark brown to gray-black in dark-skinned individuals ▪ Mild erythema, pruritus, scaling ▪ Lesions fail to tan with sun exposure Seborrheic dermatitis ▪ Characteristic skin changes ▫ Usually located on trunk (“petaloid pattern”), scalp (dandruff), eyebrows, eyelids, nasolabial folds, external auditory meatus, anogenital area ▪ Pruritus, erythema, blepharitis ▪ Tends to flare during stress, cold weather ▪ Infants: adherent yellowish scales primarily on vertex of scalp

Figure 67.2 Seborrhoeic dermatitis affecting the nasolabial folds.

DIAGNOSIS LAB RESULTS Tinea versicolor ▪ KOH preparation: microscopic observation → “spaghetti and meatballs” ▫ Spaghetti: hyphae ▫ Meatballs: yeast

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OTHER DIAGNOSTICS Tinea versicolor ▪ Wood’s lamp examination: yellow to yellow-green fluorescence Seborrheic dermatitis ▪ Clinical findings upon examination

TREATMENT MEDICATIONS Tinea versicolor ▪ Topical agents: antifungal medications, selenium sulfide, zinc pyrithione ▪ Oral antifungal medications if nonresponsive

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Seborrheic dermatitis ▪ No known cure ▪ Chronic topical agent treatment: antifungal medications, corticosteroids, calcineurin inhibitors ▫ Other topical agents: selenium sulfide, zinc pyrithione, salicylic acid or coal tar (keratolytics) ▪ Oral antifungal agents if non-responsive

Chapter 2 Acyanotic Defects

NOTES

DIPLOCOCCI: AEROBIC MICROBE OVERVIEW ▪ Spherical-shaped bacteria (cocci), appear in pairs as joined cells (diplo) ▪ Gram-negative, aerobes/facultative anaerobes, non-motile, non-spore forming

TYPES Moraxella catarrhalis ▪ Oxidase +, nitrate reduction + (characteristic) ▪ Part of normal respiratory flora, causes opportunistic infections ▪ Virulence factors ▫ Beta-lactamase production → penicillin resistant ▫ DNase production ▪ Culture ▫ Isolation specimen: respiratory secretions, sputum ▫ Media: blood, chocolate agar (round, opaque colonies that turn pink after 48 hours; positive “hockey puck sign”: able to slide colonies across agar with wooden stick without disruption) Neisseria gonorrhoeae ▪ Facultatively intracellular ▪ Oxidase +, catalase + ▪ Fermentation ▫ Glucose; differentiation from N. meningitidis ▪ Virulence factors ▫ LOS/endotoxin: triggers inflammation; undergoes antigenic variation ▫ IgA1 protease: cleaves IgA antibodies; aids in evasion of humoral immune response ▫ Type IV pili: promote adhesion of bacteria to epithelium; undergo phase, antigenic variation

▫ Porins (PorA, PorB): allow movement of ions, nutrients into bacteria, promote invasion into cells ▫ Opa, Opc: promote adhesion, invasion; undergo phase, antigenic variation ▪ Culture ▫ Isolation specimen: urine, vaginal/ endocervical swab, urethral swab; pharyngeal, rectal swab ▫ Media: Thayer–Martin VCN, chocolate agar Neisseria meningitidis ▪ Facultatively intracellular ▪ Oxidase +, catalase + ▪ Fermentation ▫ Maltose, glucose ▪ Present as normal non-pathogenic flora of nasopharynx in 10% of adults ▪ Virulence factors ▫ Capsule: prevents phagocytosis; N. meningitidis subdivided into 13 serogroups based on capsular polysaccharides; A, B, C, W135, Y account for most disease cases ▫ Lipooligosaccharide (LOS)/endotoxin: released in blebs/vesicle-like structures → sepsis, vascular necrosis, hemorrhage into surrounding tissue; levels of LOS closely correlate with prognosis ▫ IgA1 protease: cleaves IgA antibodies; aids in evasion of humoral immune response ▫ Pili: promote adherence of bacteria to nasopharyngeal epithelium; undergo phase, antigenic variation → protect against host immune response, vaccines ▫ Opacity proteins (Opa, Opc): promote adhesion, invasion

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▫ Factor H binding protein: downregulates alternative complement pathway ▪ Culture ▫ Isolation specimen: blood, cerebrospinal fluid (CSF), petechial scrapings ▫ Media: Thayer–Martin vancomycin, colistin, nystatin (VCN), chocolate agar

MORAXELLA CATARRHALIS osms.it/moraxella-catarrhalis PATHOLOGY & CAUSES ▪ Gram-negative diplococcus → respiratory tract infections, otitis media ▪ Infections caused by M. catarrhalis ▫ Respiratory tract infections (bronchitis, rhinosinusitis, laryngitis, bronchopneumonia, communityacquired bacterial pneumonia) ▫ Otitis media in children < three years of age ▫ Exacerbations of chronic obstructive pulmonary disease (COPD)

RISK FACTORS

▪ Immunocompromised individuals ▪ Individuals with chronic respiratory disease

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(e.g. COPD, emphysema) ▪ Children < two years of age, elderly

COMPLICATIONS

▪ Rare: bacteremia, septicemia, urethritis, septic arthritis

SIGNS & SYMPTOMS ▪ Acute bacterial rhinosinusitis: fever, nasal obstruction, purulent nasal discharge, facial pain, headache ▪ Otitis media: fever, ear pain, bulging tympanic membrane ▪ Exacerbations of COPD: increased cough, sputum production/change in color, dyspnea

Chapter 68 Diplococci: Aerobic

DIAGNOSIS OTHER DIAGNOSTICS

▪ Clinical presentation ▫ Sufficient for diagnosis ▪ Microbiologic diagnosis

TREATMENT MEDICATIONS ▪ ▪ ▪ ▪

Amoxicillin-clavulanate Trimethoprim-sulfamethoxazole Third-/second-generation cephalosporins Macrolides (e.g. azithromycin, clarithromycin)

NEISSERIA GONORRHOEAE osms.it/neisseria-gonorrhoeae PATHOLOGY & CAUSES ▪ Gram-negative diplococcus → gonococcal disease (gonorrhea, disseminated gonococcemia, gonococcal ophthalmia neonatorum) ▪ Portal of entry ▫ Unprotected sex (vaginal, oral, anal): bacteria attaches, invades genitourinary, rectal, oral epithelium via Opa, Opc, pili → gonorrhea ▫ Rare: invades bloodstream → disseminated gonococcemia, septic arthritis ▫ Perinatal transmission: birth canal of infected mother → gonococcal ophthalmia neonatorum

TYPES

▪ Gonorrhea ▫ Urethritis, cervicitis, proctitis, pharyngitis ▪ Disseminated gonococcemia ▫ Result of spread, intravascular multiplication of N. gonorrhoeae; joints, skin (dermatitis-arthritis syndrome) ▪ Gonococcal ophthalmia neonatorum ▫ Causes gonococcal conjunctivitis

RISK FACTORS

▪ Unprotected sex ▫ Individuals with multiple sexual

partners, sex between individuals who are biologically male (MSM), recent new sexual partner ▪ Low educational, socioeconomic levels ▪ Substance abuse ▪ History of gonorrhea

COMPLICATIONS Gonorrhea ▪ Epididymitis, prostatitis, penile lymphangitis, urethral strictures in individuals who are biologically male; cervical gonorrhea → pelvic inflammatory disease → infertility in individuals who are biologically female Gonococcal ophthalmia neonatorum ▪ Corneal scarring/perforation, blindness

SIGNS & SYMPTOMS Gonorrhea ▪ Some individuals who are biologically male, most individuals who are biologically female (50–80%) asymptomatic ▪ Urethritis: dysuria, urinary urgency, purulent foul-smelling urethral discharge ▪ Cervicitis: lower abdominal discomfort, dyspareunia (pain during sexual intercourse), vaginal pruritus, purulent foulsmelling vaginal discharge

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▪ Proctitis: anal pruritus, tenesmus, rectal fullness, constipation, purulent anorectal discharge, bleeding ▪ Pharyngitis: sore throat, swollen lymph nodes Disseminated gonococcemia ▪ Fever, chills, generalized malaise ▪ Polyarthralgia (multiple joint pain) ▪ Tenosynovitis (tendon inflammation) ▪ Pustular/vesiculopustular lesions on skin Gonococcal ophthalmia neonatorum ▪ Purulent conjunctival discharge ▪ Swollen eyelids ▪ Conjunctival hyperemia, chemosis

DIAGNOSIS LAB RESULTS Blood tests ▪ ≥ two white blood cells in urethral secretions ▪ ≥ 10 white blood cells on microscopic examination of first void urine ▪ Disseminated gonococcemia ▫ Positive blood culture ▫ Synovial fluid leukocyte count: increased values (50,000 cells/microL) Gram stain ▪ Polymorphonuclear leukocytes with intracellular gram-negative diplococci Nucleic acid amplification testing (NAAT) ▪ For initial diagnosis

TREATMENT MEDICATIONS

Figure 68.1 A neonate with gonococcal ophthalmia neonatorum.

▪ Uncomplicated gonorrhea ▫ Intramuscular injections of ceftriaxone + azithromycin/doxycycline (in case of gonococcal resistance to cephalosporins, potential chlamydia regardless of chlamydial coinfection status)

OTHER INTERVENTIONS

▪ Prophylaxis ▫ No vaccines ▫ Extensive antigenic variations of bacterial components (pili, LOS, opa proteins) prevents development of immunological memory

Figure 68.2 Creamy discharge emanating from the external urethral meatus is typical of genital gonorrhea infection.

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Chapter 68 Diplococci: Aerobic

NEISSERIA MENINGITIDIS osms.it/neisseria-meningitidis PATHOLOGY & CAUSES

SIGNS & SYMPTOMS

▪ Gram-negative diplococcus → meningococcal disease (meningitis, meningococcemia) ▪ Portal of entry ▫ Inhalation of respiratory droplets → bacteria attaches to respiratory epithelium via Opa, Opc, pili → nasopharynx colonization → usually resolves asymptomatically (carriers) ▫ Invades bloodstream → meningococcal disease (rare)

Meningococcemia ▪ Petechial rash caused by destruction of blood vessels, hemorrhage due to endotoxin release; fever, chills; joint, muscle pain

RISK FACTORS

Meningitis ▪ Infants ▫ Early nonspecific: irritability, vomiting, inactivity, poor feeding, temperature instability ▫ Late specific: bulging anterior fontanelle, seizures ▪ Children, adolescents, adults ▫ Early nonspecific: sudden onset of fever, headache, nausea, vomiting, myalgia ▫ Late specific: altered mental status, lethargy, neck stiffness (nuchal rigidity), photophobia ▫ First specific symptoms of sepsis: abnormal skin color (pallor/mottling) which can evolve from nonspecific rash to petechial to hemorrhagic over several hours; cold hands, feet; leg pain ▪ Signs upon physical examination ▫ Positive Kernig’s sign: inability to straighten leg when hip flexed to 90º ▫ Positive Brudzinski’s sign: flexing of neck by examiner → flexing of hips, knees

COMPLICATIONS

Fulminant meningococcemia ▪ Abrupt onset ▪ Rapid enlargement of petechiae/ ecchymoses ▪ Hypotension, tachycardia due to vascular collapse, shock

TYPES

▪ Meningococcemia ▫ Result of intravascular multiplication of N.meningitidis; can occur alone/in conjunction with meningitis ▪ Meningitis ▫ Most common; occurs upon spreading of bacteria to meninges during meningococcemia; usually affects children, adolescents ▪ Fulminant meningococcemia ▫ AKA Waterhouse–Friderichsen syndrome; most severe form of meningococcal sepsis; massive bilateral hemorrhage into adrenal glands

▪ Infants 6–24 months (due to immature immune system, inability to vaccinate) ▪ Living in close quarters (military barracks, dormitories)

▪ Adrenal insufficiency; disseminated intravascular coagulation (DIC); purpura fulminans (cutaneous hemorrhage, necrosis due to vascular thrombosis, DIC); acute respiratory distress syndrome (ARDS); coma, death

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DIAGNOSIS LAB RESULTS

▪ Fulminant meningococcemia ▫ Adrenal insufficiency signs: ↓ blood glucose, ↑ K+, ↓ Na+, adrenocorticotropic hormone (ACTH) stimulation test (low response) ▫ Thrombocytopenia due to DIC ▫ Metabolic acidosis ▪ Meningococcemia and meningitis ▫ Blood culture and CSF analysis

OTHER DIAGNOSTICS

▪ Physical examination ▫ Characteristic findings of meningitis

TREATMENT MEDICATIONS Prophylaxis ▪ Quadrivalent immunization with purified capsular polysaccharides from serogroups A, C, Y, W135 (group B not available)

Figure 68.3 A petechial rash can be seen in the late stages of meningococcal septicemia.

Meningococcal disease ▪ Antibiotics ▫ Third-generation cephalosporins (e.g. cefotaxime, ceftriaxone)/penicillin G ▪ Chloramphenicol ▫ In case of beta-lactam antibiotics hypersensitivity ▪ Chemoprophylaxis of individuals in close contact with the infected ▫ Rifampin of ciprofloxacin ▪ Hydrocortisone ▫ For adrenal insufficiency

SURGERY

▪ Plastic surgery, skin grafting, amputation to treat tissue necrosis

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Figure 68.4 The brain of an individual at post mortem following death from bacterial meningitis. Nesseiria meningitidis is the most common causative organism amongst adolescents and young adults.

NOTES

NOTES

ECTOPARASITES GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Ectoparasites: arthropods that live on outside of host, extract nutrients at host’s expense ▫ Uncommon: viable parasites transferred without direct host contact

RISK FACTORS

DIAGNOSIS OTHER DIAGNOSTICS History ▪ Including close contacts/living quarters Physical examination ▪ Dermatologic examination

▪ Commonly poor hygiene, close living quarters

TREATMENT MEDICATIONS

COMPLICATIONS

▪ Predicated on individual’s immune status, housing situation

▪ Topical neurotoxins, topical/oral parasidal drugs

OTHER INTERVENTIONS

SIGNS & SYMPTOMS ▪ Pruritus, bite marks, visible body parasites

▪ Proper hygiene, household measures, isolation (if necessary)

PEDICULOSIS CORPORIS, CAPITIS, AND PUBIS (LICE) osms.it/lice PATHOLOGY & CAUSES ▪ Infestation of easily transmissible sucking lice species ▫ Commonly in hairy bodily areas, characterized by local pruritus ▪ Sucking lice infection ▫ (Phylum) arthropoda → (class) insecta → (order) phthiraptera → (suborder)

anoplura → (family) pediculidae/ pthiridae

PATHOLOGY

▪ Lice live human hair → suck blood for nutrients ▫ Bite → saliva injection → anticoagulation effect, ↑ histamine release → maculae cerulea (blue/copperhued bite marks); pruritus

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▪ Lice require humans for nutritional source (parasites) ▫ Most climates allow mature louse 24 hours of viable life away from human source Transmission ▪ Physical contact ▫ Ideal location: slow-moving, parallel hair fibers ▫ Louse on one hair fiber → transfer to another individual’s hair → lay nits (eggs) on hair 1–2mm off of scalp → nymphs hatch within one week → mature over one week → female lice lay eggs for one month ▪ Fomites

TYPES

▪ Pediculus humanus capitis → head louse ▫ Can survive 24–48 hours without blood meal/separated from host ▪ Pediculus humanus humanus → body louse ▫ Larger than head louse; can survive < 72 hours without blood meal ▪ Phthirus pubis → pubic louse ▫ AKA crab louse; can spread to body

RISK FACTORS

▪ School-aged children ▪ Homeless population ▪ Refugee population (if living in close quarters)

COMPLICATIONS

▪ Co-infections (also carried by louse) ▫ Bartonella quintana → endocarditis ▫ Epidemic typhus ▫ Louse-borne relapsing fever ▫ Trench fever ▪ Adolescents with pubic lice → ↑ gonorrhea/ chlamydial infection risk ▪ Pruritus → skin excoriation → secondary infection ▫ Commonly staphylococcal infection

SIGNS & SYMPTOMS ▪ Site pruritis (head, body, pubis)

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DIAGNOSIS OTHER DIAGNOSTICS Dermatologic examination ▪ Examination of hair follicles, clothing seams ▪ Nits: more visible than nymphs/lice; most visible (white) after louse released from egg; does not dislodge easily from hair follicle ▪ Body louse → widespread dermatitis ▪ Often linear excoriations ▪ Maculae ceruleae → may have punctal hemorrhages → recent bites ▪ Hyperpigmentation/lichenification → older bites Lymph node examination ▪ Capitis infection → posterior lymphadenopathy

TREATMENT MEDICATIONS Topical benzyl alcohol ▪ Mechanism of action → louse asphyxiation ▫ Difficult for resistance to develop Neurotoxic agents ▪ Resistance develops with ▫ Pyrethrin: botanically-derived neurotoxin ▫ Permethrin: Na+ channel blocker → paralysis → death ▫ Malathion: organophosphate cholinesterase inhibitor

OTHER INTERVENTIONS Hair shaving ▪ Eradicate current infection Mechanical removal ▪ Wet combing → tedious, poor compliance ▫ Pre-treatment: vinegar/formic acid → flattened hair cuticle → better combing efficiency (does not dissolve/loosen nits) Prevention ▪ Proper hygiene

Chapter 69 Ectoparasites ▪ Household ▫ Housemates: examination ▫ Bedmates: prophylactic treatment ▫ Household cleaning: washing > 54°C/130°F; unwashable material → place in sealed plastic bag for two weeks

▪ School ▫ No nit policy (infected children stay home), education, screening during outbreaks

SARCOPTES SCABIEI (SCABIES) osms.it/sarcoptes-scabiei PATHOLOGY & CAUSES ▪ Sarcoptes scabiei mite infection ▫ Elicits strong immune response ▫ Nocturnal pruritus Mite infection ▪ (Phylum) mite → (class) arachnida → (subclass) acari → (order) astigmata → (family) sarcoptidae ▫ Usually obligate human parasite → vars hominis ▫ Sometimes animal mange mites can infest

PATHOLOGY Mite transfer ▪ Direct skin-to-skin contact for 15–20 minutes ▪ Average infested individual carries 5–12 mites ▫ Crusted scabies individuals: > 1000 mites can be shed (transmission through objects more likely) Type IV hypersensitivity reaction ▪ House dust mite cross reactivity ▪ Infestation → ↑ IL-6, vascular epithelial growth factor (VEGF) →TH1-cell activation → IL-2 release → lymphocyte proliferation, differentiation

RISK FACTORS

▪ Overcrowding (including long-term care facilities, prisons), poor hygiene/nutrition, homelessness, dementia, sexual contact

COMPLICATIONS

▪ Infestation → secondary staphylococcal infection ▫ Low-income countries (mostly) ▫ Impetigo → chronic kidney disease ▫ Ecthyma, paronychia, furunculosis

Crusted scabies ▪ AKA Norwegian scabies ▪ Infection commonly scalp, hands, feet → diffuse spread over entire body ▪ Occurs in compromised cellular immunity setting ▫ Acquired immunodeficiency syndrome (AIDS) ▫ Human lymphocytic virus type 1 (HTLV1) ▫ Leprosy ▫ Lymphoma ▫ Long-term topical corticosteroid use ▪ Risk factors: age, Down syndrome ▪ Complications: fissional lesions develop → bacterial entryway → infection ▫ Sepsis, poststreptococcal glomerulonephritis

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SIGNS & SYMPTOMS Classic scabies ▪ Intense, intractable, generalized pruritus ▪ Nodules, pustules at most intense pruritus sites ▪ Common areas → intertriginous spaces ▫ Anterior axillary folds, webs of fingers, volar aspect of hand/wrist, beltline, penis, areolar region (biologically-female individuals)

Dermatologic examination ▪ Serpiginous keratotic lines (1–4mm) → burrow marks ▫ Often with vesicle on end (housing mite)

Nodular scabies ▪ Hypersensitivity reactions → large, persistent, intensely pruritic 5–6mm nodules ▫ Commonly groin, buttock, axillary folds Crusted scabies ▪ Poorly defined, erythematous patches → scale ▫ Untreated → entire integumental spread → warty appearance (especially over bony prominences); lesions crust, fissure develop → malodorous; nail involvement → thickened, dystrophic, discolored

DIAGNOSIS LAB RESULTS Microscopy ▪ Confirmatory scraping: fluorescein stain → highlights fecal material, ova fragments ▫ Epithelial milieu (eosinophils, lymphocytes, histiocytes) ▫ Crusted scabies: mate capture more likely due to disease burden Polymerase chain reaction assays ▪ S. scabiei DNA polymerase

OTHER DIAGNOSTICS History ▪ Close contact commonly present with concurrent symptoms ▪ Infected individual contact history (may be many weeks prior)

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Figure 69.1 A high-magnification photograph of a single mite burrow in the skin of an individual with scabies. The mite is at the end of the burrow at the top right of the image.

TREATMENT MEDICATIONS Classic scabies ▪ Permethrin (5%) → synthetic neurotoxin → Na+ channel blocker → paralysis → death ▪ Precipitated sulfur (6%, 10%) in petroleum ▪ Benzyl benzoate (10%, 25%) ▫ Adverse reactions: allergic dermatitis ▫ Contraindications: pregnancy/lactation (neurotoxicity); children < two years old ▪ Oral ivermectin ▫ One dose (200mcg/kg) repeated in 7–10 days Nodular scabies ▪ Topical steroids ▪ Intralesional steroid injection Crusted scabies ▪ Topical, systemic treatment required ▪ Oral ivermectin, topical permethrin (5%)/ benzyl benzoate (5%) ▫ Two week oral regimen, topical therapy

Chapter 69 Ectoparasites persisting after that twice weekly until cure ▫ Treatment cure → active lesion resolution, nocturnal pruritus absence for one week

OTHER INTERVENTIONS

▪ Isolation for infected ▪ Nail clipping ▫ +/- brushing with scabicidal agent ▪ Thorough personal, household material laundering

Prevention ▪ Monosulfiram soap in communities with ↑ ↑ incidence

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NOTES

NOTES

ENTEROCOCCUS

ENTEROCOCCUS osms.it/enterococcus PATHOLOGY & CAUSES ▪ Gram-positive spherical-shaped bacteria (cocci) ▪ Grow in pairs (diplococci)/short chains ▪ Non-spore forming ▪ Optimal growing conditions: 45ºC/113°F, can withstand up to 60ºC/140°F ▫ Facultatively anaerobic bacteria ▫ 6.5% NaCl, bile-containing media ▪ Characteristics ▫ Catalase negative, pyrrolidonyl arylamidase (PYR) positive ▫ Variable hemolytic activity on blood agar plates; most commonly gamma hemolytic ▪ Common human pathogens: E. faecalis, E. faecium ▪ Important cause of hospital-acquired infections, esp. infective endocarditis, urinary tract infections (UTIs), infections of prosthetic devices (e.g. venus/urinary catheters) ▫ Surface carbohydrates → adherence to cardiac valves → fibrinogen synthesis → valve vegetations → infective endocarditis ▫ Adherence to renal epithelial cells → UTI ▪ Less common associations ▫ Wound, bloodstream, biliary tract, pelvic infections; intraabdominal abscesses

RISK FACTORS

▪ Indwelling medical devices (e.g. central venous, urinary catheterization) ▪ Cardiovascular abnormalities

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▪ Prolonged hospitalization, mechanical ventilation ▪ Prior antibiotic use, immunodeficiency

COMPLICATIONS

▪ Bacteremia ▫ Immunocompromised individuals

SIGNS & SYMPTOMS ▪ UTIs ▫ Cystitis, pyelonephritis; dysuria, frequency, urgency, suprapubic/flank tenderness ▪ Infective endocarditis ▫ Subacute onset of fever, malaise, peripheral signs (e.g. Janeway lesions, Osler’s nodes), cardiac murmurs (usually left-sided), splenomegaly ▪ Infection of prosthetic devices, wounds ▫ Erythema, swelling, tenderness, warmth

DIAGNOSIS DIAGNOSTIC IMAGING Transthoracic echocardiography; abdominal CT scan; ultrasound ▪ Identify organ involvement

LAB RESULTS

▪ Cultures from infected sites (e.g. blood, urine) ▪ Susceptibility testing ▫ Detect antibiotic resistance

Chapter 70 Enterococcus ▪ Complete blood count (CBC) ▫ ↑ polymorphonuclear cells ▪ Urinalysis ▫ UTI → pyuria, proteinuria, hematuria

TREATMENT MEDICATIONS Antimicrobial therapy ▪ Localized infections ▫ Ampicillin/beta lactamase inhibitors (clavulanate/sulbactam) ▫ Alternative: nitrofurantoin ▪ Serious infections with bacteremia, meningitis, endocarditis ▫ Penicillin/ampicillin + aminoglycoside ▫ Alternative: vancomycin, aminoglycoside ▪ Vancomycin-resistant enterococcal (VRE) infection ▫ Linezolid/daptomycin

SURGERY

▪ Drain abscess ▪ Valve replacement

OTHER INTERVENTIONS

▪ Remove venous/urinary catheters

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NOTES

NOTES

FILAMENTS GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES

▪ Gram ⊕ slender bacteria with ⊕ branches (atypical lung disease organisms, capable of affecting any body organ ▪ Atypical organisms → indolent disease → insidious growth → severe disease

RISK FACTORS

▪ Immunodeficiency ▪ Corticosteroid use → iatrogenic immunosuppression

SIGNS & SYMPTOMS ▪ Cough, dyspnea ▫ Indolent course ▫ Common in fever’s absence ▪ Other symptoms ▫ Dependent on organ systems affected by organism

DIAGNOSIS DIAGNOSTIC IMAGING Chest X-ray ▪ Localized alveolar infiltrate ▫ Homogeneous, non-segmental, cavitary appearance

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LAB RESULTS

▪ Tissue biopsy → histological

OTHER DIAGNOSTICS Physical examination ▪ Pulmonary examination ▫ Auscultation: rhonchi (crackles), ↓ breath sounds ▫ Palpation: ↓ tactile fremitus ▫ Percussive dullness

TREATMENT MEDICATIONS ▪ Antibiotics

SURGERY

▪ Resection ▫ Medication non-responsive ▫ Large infections → significant dysfunction

Chapter 71 Filaments

ACTINOMYCES ISRAELII osms.it/actinomyces-israelii PATHOLOGY & CAUSES Microbe characteristics ▪ ⊕ Gram stain ▪ Shape ▫ Filamentous, non-spore-forming, pleomorphic bacilli ▪ Metabolism ▫ Catalase negative, anaerobic/ microanaerobic bacilli ▪ Types ▫ 21 species found in humans ▫ Actinomyces israelii most common ▪ Locations ▫ Normal mouth (by two years old), gastrointestinal (GI) tract, female genitourinary tract flora

PATHOLOGY

Thoracic ▪ Pulmonary → pneumonia ▫ Oropharyngeal content aspiration → bacterial alveoli seeding → immune response, bacterial growth → pneumonia Abdominal & pelvic ▪ Gastrointestinal → appendicitis ▫ Preceding colonic mucosa perforation → unrecognized → months–year course → symptomatic infection ▪ Pelvic → female genitourinary infections ▫ Complicated abortions, infected intrauterine devices (IUDs), endometritis, tubo-ovarian abscess (TOA)

RISK FACTORS

▪ Chronic granulomatous disease

Cervicofacial ▪ Chronic tonsillitis, dental decay, periodontal disease, mastoiditis, otitis media

▪ Uncommon infection source ▪ Mucosal membrane violated → indolent, invasive disease ▫ Commonly co-occurs with another pathogen → micro-O2 Actinomyces environment ▫ Can burrow through soft tissue, bone → small abscesses, drainage tracts ▫ Abscesses: yellow sulfur-containing granules in granulomatous reactive material setting (bacteria found in microfilament tangles, surrounded by neutrophils)

COMPLICATIONS

TYPES

Thoracic ▪ Pneumonitis

Cervicofacial ▪ Osteomyelitis of mandible/maxilla ▫ Resident flora in periodontal pockets, carious teeth, dental plaque, tonsillar crypts

Abdominal & pelvic ▪ Gastrointestinal ▫ Peritoneal, hepatic, pelvic infectious spread

Thoracic ▪ Aspiration history

Cervicofacial ▪ Deep neck tissue infection → retropharyngeal space → mediastinitis ▪ Meningitis → if sinus tracts to posterior neck, spinal cord

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SIGNS & SYMPTOMS Cervicofacial ▪ Lumpy jaw ▫ Usually in fever’s/other infectious signs’ absence ▪ Progression → oral mucosa, trismus sinus tract draining Thoracic ▪ Fever, cough > three day duration ▪ Auscultation ▫ Rhonchi ▫ ↓ breath sounds ▪ Palpation ▫ ↓ tactile fremitus ▪ Percussive dullness Abdominal & pelvic ▪ Gastrointestinal → appendicitis ▫ Asymptomatic colonic mucosa (micro) perforation → months–years prodrome → symptomatic appendicitis ▫ Nonspecific prodrome: chronic fever, weight loss, diarrhea, constipation, night sweats ▫ Appendicitis: nausea, vomiting, anorexia ▪ Pelvic → female genitourinary infections ▫ Painful abdominal, cervical examination ▫ Purulent vaginal discharge

CT scan ▪ Abdominal, pelvic ▫ Disrupted tissue planes Colonoscopy ▪ Abdominal, pelvic ▫ Normal/thickened mucosal appearance, colitis, ulceration, nodular lesion, buttonlike appendiceal orifice elevation Bedside ultrasound ▪ Abdominal, pelvic ▫ TOA evaluation

LAB RESULTS

▪ Cervicofacial ▫ Monoclonal antibody staining ▫ Polymerase chain reaction (PCR) of 16S rRNA

Cultures (needle aspiration) ▪ Cervicofacial ▫ Histology: granulation tissues with neutrophils, foamy macrophages, lymphocytes, plasma cells (with surrounding fibrosis) ▪ Abdominal, pelvic ▫ Histology: granulation tissue surrounding oval, eosinophilic zones

DIAGNOSIS DIAGNOSTIC IMAGING Chest X-ray ▪ Thoracic ▫ Localized alveolar infiltrate: homogeneous; non-segmental, cavitary appearance; can extend past fissure lines → into chest wall Barium enema ▪ Abdominal, pelvic ▫ Luminal narrowing, fistualization, extrinsic compression

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Figure 71.1 Sulphur granules formed by Actinomyces organisms.

Chapter 71 Filaments

OTHER DIAGNOSTICS History ▪ Thoracic ▫ May have community-acquired pneumonia diagnosis, treatment (without relief within 3–5 days) Physical examination ▪ Cervicofacial ▫ Lymphatic examination ▪ Thoracic ▫ Pulmonary examination

TREATMENT MEDICATIONS

▪ Antibiotics ▫ Prolonged (weeks–months) penicillin V (oral)/penicillin G (intravenous) ▫ Amoxicillin (alternative)

SURGERY

▪ Necrotic disease/especially large abscess formation cases

NOCARDIA osms.it/nocardia PATHOLOGY & CAUSES ▪ Microbe characteristics ▪ ⊕ Gram stain ▪ Shape ▫ Filamentous, branch-forming, bacillus ▫ Branches → beaded appearance (delicate nature of stain → cocci/bacilli fragmentation) ▪ Metabolism ▫ Aerobic, catalase ⊕, urease ⊕ ▪ Types ▫ > 80 species ▫ Around 30 disease-causing in humans ▪ Locations ▫ Saprophyte (organic pathogen) → found in soil, house dust, water (fresh/salt), bathing pools

PATHOLOGY

▪ Direct tissue inoculation ▫ Saprophyte → aerosolization common (↑ ↑ pulmonary infections) ▫ Soil/water contamination (contaminated food → GI disease, skin trauma → cutaneous disease, eye trauma → ocular disease)

▪ Facultative intracellular organism → requires innate host defense mechanisms ▫ Inhalation entry: deficient/ineffective mucociliary clearance, host response → bronchopulmonary disease ▫ Skin trauma entry: deficient keratinized skin barrier → local subcutaneous infection; deficient keratinized cornea → ocular infection ▪ Rapid filamentous growth → ↓ phagocytic clearing ▫ Phagocytosed → ↓ lysosomal destruction (phagocyte-lysosome fusion inhibition; catalase, dismutase production → ↓ reactive oxygen species → pathogen survival)

TYPES Pneumonia ▪ Nocardia asteroides (common pathogen) ▪ > 2⁄3 of total disease ▪ Progression ▫ Empyema, pericardial effusion Primary cutaneous infections ▪ Nocardia brasiliensis (common pathogen) ▪ Cellulitis, ulcers, pyoderma, myocetma

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▪ Progression ▫ Abscess/nodular development, lymphangitis

RISK FACTORS

▪ ↓ mucociliary clearance ▫ Cystic fibrosis, asthma, bronchiectasis ▪ Immunosuppression ▫ Iatrogenic (most commonly corticosteroid use); lymphoreticular malignancy; chronic obstructive pulmonary disease; chronic granulomatous disease; dysgammaglobulinemia; HIV infection; bone marrow, organ transplant

COMPLICATIONS

▪ Organ dissemination ▫ Pulmonary infection → hematogenous spread (commonly) ▫ Most common: central nervous system (meningitis, cerebral abscess) ▪ Pulmonary ▫ Empyema, pericardial effusion ▪ Cutaneous ▫ Lymphangitis ▪ Ocular ▫ Endophthalmitis (ocular infection)

SIGNS & SYMPTOMS Pneumonia ▪ Acute, subacute, chronic suppurative course ▫ Symptoms may also relapse/remit ▪ Cough, dyspnea common ▫ Anorexia, weight-loss (uncommon) ▫ Hemoptysis (cavitary disease) ▪ Rhonchi (crackles) ▪ ↓ breath sounds, tactile fremitus, +/egophony Local cutaneous infection ▪ Local erythema, warmth, +/- ulceration, nodular growth Neurologic infection ▪ Meningismus, fever, rigors, seizure

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DIAGNOSIS DIAGNOSTIC IMAGING Chest X-ray ▪ Pulmonary ▫ Homogeneous, non-segmental, cavitary alveolar infiltrate Brain MRI ▪ Neurologic ▫ ↑ T1 imaging intensity → ↑ enhancement (gadolinium)

LAB RESULTS

▪ Tissue biopsy: histology (acid fast stain) ▫ Gram ⊕, branching, beaded filamentous growth

TREATMENT MEDICATIONS Antibiotic monotherapy ▪ Mild/moderate disease ▪ 3–6 months treatment duration ▪ Sulfonamides → trimethoprimsulfamethoxazole (TMP-SMX) ▪ Linezolid ▫ Nocardia 100% sensitive ▫ Limited treatment duration (2–3 weeks) → ineffective monotherapy for complete therapy duration Antibiotic multi-agent therapy ▪ Severe disease ▪ Up to 6–12 months treatment duration ▪ Agents ▫ TMP-SMX + amikacin/carbapenem/ linezolid ▪ Commonly for progressive disease in immunosuppressed individuals/pulmonary, disseminated disease Prevention & vaccine ▪ Daily, full-strength TMP-SMX → secondary prophylaxis ▪ P. jirovecii TMP-SMX prophylaxis (3x/week) → ineffective

Chapter 71 Filaments

SURGERY

▪ Indicated for ▫ Antibiotic-resistant, large cutaneous/ cerebral abscess (craniotomy/aspiration effective) ▫ Empyemas, large fluid collections ▫ Pulmonary nocardiosis → pericarditis (fatal if not performed)

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NOTES

NOTES

FILOVIRUSES MICROBE OVERVIEW Genetic material ▪ Single-stranded negative-sense RNA virus family; causes viral hemorrhagic fever Taxonomy ▪ Genera: Ebolavirus, Marburgvirus, Cuevavirus Morphology ▪ Enveloped virions; filamentous, nonsegmented morphology Replication ▪ Transcription, replication mediated by virus-encoded polymerase in infected cell cytoplasm ▫ Transcription: negative-sense RNA genome transcribed into monocistronic, polyadenylated RNA species using host cell ribosomes, tRNA etc. → translated into seven proteins ▫ Replication: positive-sense antigenome serves as template for negative-sense genomes

Transmission ▪ Zoonotic infection ▫ Natural host: unknown (bats, especially fruit bats considered infection source) ▫ Intermediate host: Often nonhuman primates (gorillas, chimpanzees) Structural proteins ▪ Viral RNA encodes seven structural proteins ▫ Nucleoprotein ▫ Polymerase cofactor (VP35) ▫ Viral proteins VP40, VP24 ▫ Glycoprotein: projecting spikes from lipid bilayer (attachment to host cell receptors) ▫ Transcription activator ▫ RNA-dependent RNA polymerase

EBOLA VIRUS osms.it/ebola-virus PATHOLOGY & CAUSES ▪ Ebola virus: causative agent of severe, often fatal hemorrhagic fever ▪ Species: Zaire, Sudan, Tai Forest, Bundibugyo, Reston ▪ Transmission ▫ Animal-human: direct infected-animal tissue, body-fluid contact; butchering, consuming undercooked meat

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▫ Human-human: direct tissue, body fluid contact with ill/deceased ▫ Potential transmission: contaminated surface/object contact

PATHOLOGY

▪ Inoculation → incubation: 6–12 days average (ranges 2–21 days) ▫ Host cell attachment, virus endocytosis → nucleocapsid release in cytoplasm →

Chapter 72 Filoviruses

▪

▪ ▪

▪

replication → nucleocapsid formation → viral shedding, cell necrosis Initially macrophages, dendritic cells infected → sentinel lymph node spread → bloodstream → many cell types infected (endothelial cells, fibroblasts, hepatocytes, epithelial cells, adrenal-gland cells) with lymphocyte/neuron exception ▫ Although uninfected, inflammatory mediators; support signal loss from dendritic cells → “bystander” apoptosis of lymphocytes Multifocal necrosis in various tissues (e.g. liver, spleen) Systemic inflammatory syndrome: proinflammatory mediator, cytokine release from infected macrophages, dendritic cells, necrotic cell breakdown products, etc. → vasodilation, ↑ vascular permeability → vascular leakage, shock, multiorgan failure Dendritic cell dysfunction, “bystander” lymphocyte apoptosis → impaired adaptive immunity

▪ Spontaneous abortion, vaginal bleeding in infected pregnant individuals (100% third trimester maternal, fetal mortality) ▪ Fatality ranges ▫ 40% to 80–90% (depending upon species)

RISK FACTORS

▪ Healthcare workers without appropriate protective equipment, adequate training ▪ Inadequate infected waste product, corpse handling ▪ Sexual intercourse with person recovering from Ebola in previous three months ▪ Travel to endemic/Ebola epidemic areas ▪ Wild animal contact (mostly nonhuman primates)

COMPLICATIONS

▪ Gastrointestinal dysfunction ▫ Fluid loss, hypotension, acute kidney injury, shock ▪ Neurologic ▫ Meningoencephalitis, meningitis ▪ Coagulopathy ▫ Infected macrophages produce tissue factor (TF), stimulate extrinsic coagulation pathway → disseminated intravascular coagulation (DIC) ▪ Respiratory failure ▪ Coinfection/superinfection ▪ Impaired adaptive immunity → bacterial sepsis

Figure 72.1 A scanning electron micrograph of an ebola virus demonstrating the typical filamentous structure seen in its class, Filoviridae.

SIGNS & SYMPTOMS Initial nonspecific symptoms ▪ Fever, chills, fatigue, headache, appetite loss, malaise, sore throat, myalgias, lumbosacral pain Dermatological ▪ Diffuse erythematous; nonpruritic maculopapular/morbilliform rash, especially on torso/face Gastrointestinal ▪ Watery diarrhea (up to 10L/2.2gal); nausea; vomiting; epigastric, abdominal pain; abdominal tenderness

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Hemorrhage ▪ Commonly hematochezia, followed by hematemesis, melena, metrorrhagia, purpura, petechiae, ecchymoses, mucosal bleeding, venipuncture site bleeding ▫ Often occur later in disease course; not all infected individuals develop significant bleeding; host susceptibilitydependent (genetically determined viral immune response difference), different species’ pathogenicity Neurologic ▪ Meningoencephalitis symptoms (altered level of consciousness, hyperreflexia, myopathy, stiff neck, gait instability, seizure) Ocular ▪ Conjunctival injection, uveitis symptoms (blurred vision, photophobia, blindness) Respiratory ▪ Tachypnea, dyspnea Convalescent period ▪ Can persist > two years often followed by symptoms such as arthralgia, blurred vision, retro-orbital pain, hearing loss, alopecia, difficulty swallowing, insomnia ▪ Infectious virus/viral RNA can persist in body fluid (semen, breast milk, urine, cerebrospinal fluid, aqueous humor) < nine months after not detectable in blood → variable transmission risk

DIAGNOSIS ▪ Diagnostic criteria ▫ Clinical manifestation ▫ Travel to endemic/Ebola epidemic areas (within three weeks prior to disease onset) ▫ Infected individual contact during acute disease

LAB RESULTS

▪ Reverse-transcription polymerase chain reaction (RT-PCR) ▫ Detectable Ebola virus in blood samples within three days after symptom onset ▪ Rapid chromatographic immunoassay (ReEBOV)

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▪ Laboratory findings ▫ Leukopenia; thrombocytopenia; ↑ ↓ hematocrit; ↑ aspartate aminotransferase (AST), alanine aminotransferase (ALT) ▫ Prolonged prothrombin (PT), partial thromboplastin time (PTT) ▫ Proteinuria, ↑ blood urea nitrogen, ↑ creatinine ▫ Hyponatremia, hypocalcemia, hyperkalemia

TREATMENT ▪ No cure ▪ Infected individual isolation; placement in negative airflow room advised

MEDICATIONS

▪ Complications treatment ▫ Coinfection/superinfection: empiric antimicrobial therapy with broad spectrum antibiotics ▫ Shock: intravenous fluids, vasoconstrictors ▫ Fever reduction: antipyretic agents

OTHER INTERVENTIONS

▪ Complications treatment ▫ Fluid, electrolyte loss correction ▫ Acute kidney injury: renal replacement therapy (dialysis) ▫ Respiratory failure: supplemental oxygen therapy, mechanical ventilation (if necessary, barotrauma risk) ▪ Prevention ▫ Ervebo: FDA-approved vaccine ▫ Proven highly effective, safe during trial conducted in Guinea (2015)

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FLAVIVIRUSES GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES

▪ Single-stranded, ⊕-sense, enveloped RNA viruses ▪ AKA arboviruses ▪ > 40 types identified Replication ▪ Cell surface attachment → cytoplasm entry → viral protein translation → viral RNA genome replication → virion formation (encapsidation) → cellular release Transmission ▪ Primarily transmitted via arthropod bites

RISK FACTORS

▪ Recent endemic area travel/residence ▪ Poor insect repellant use ▪ Improper skin coverage (e.g. long sleeve clothing)

SIGNS & SYMPTOMS ▪ Mainly asymptomatic ▪ Others commonly have acute-onset flu-like symptoms ▪ Serious complications/sequelae commonly

characterized by neurologic disease (e.g. seizure, encephalopathy) ▫ Fever, nausea/vomiting

DIAGNOSIS LAB RESULTS

▪ Serology ▪ Time-dependent on infection course, immune response ▪ Reverse transcription polymerase chain reaction (RT-PCR) for viral antigens

OTHER DIAGNOSTICS

▪ Endemic area travel/residence ▪ Presence of mosquito bite(s)

TREATMENT ▪ No cure

MEDICATIONS

▪ Variable vaccine availability ▫ Untenable mainly due to antigenic mutations, multiple genotypes

OTHER INTERVENTIONS ▪ Fluid, electrolyte balance

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DENGUE VIRUS osms.it/dengue-virus PATHOLOGY & CAUSES ▪ Viral disease, mosquito transmission ▫ Characterized by febrile illness ▫ AKA break-bone fever ▪ Four serotypes ▫ DENV-1 through DENV-4 ▫ IgG response to specific type → lifetime immunity ▫ Limited, transient cross-protectivity across viral types ▪ Vector ▫ Primarily Aedes aegypti and A. albopictus Pathogenesis ▪ Aedes mosquito bite → dengue virus skin introduction → local infection, response → dissemination → viremia (2–6 days later) → circulating leukocyte infection (especially) monocytes → viral replication, release → fever

RISK FACTORS

▪ Endemic area residence ▪ Recent travel

COMPLICATIONS Severe dengue ▪ AKA dengue hemorrhagic fever ▪ Viremia → local hemorrhage → systemic hemorrhage → hemodynamic collapse → shock ▫ Dengue shock syndrome (rare complication—DENV-2 confers highest risk) ▪ Direct bone marrow infection → hematopoietic stem cell infection → ↓ megakaryocyte differentiation (among all other cell lines) → ↓ platelets formed ▫ ↓ Circulating lifetime: virus-antibody complex → circulating platelet adherence → complement destruction

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▪

▪

▪

▪

of virus-antibody complex → adherent platelet destruction Capillary leak ▫ Direct effect: viral endothelial cell infection → cellular dysfunction → tight junction widening → capillary leak ▫ Indirect: virus-infected monocytes, dendritic cells, mast cells → TNFalpha, IFN-gamma, IL-2, IL-8, vascular endothelial growth factor release, complement activation → ↑ capillary permeability Molecular mimicry ▫ Viral E protein antibody response → plasminogen cross-reaction → inefficient coagulation cascade → hemorrhage Liver failure ▫ Direct viral infection → Kupffer cells, hepatocytes → apoptosis → hepatocellular necrosis, Councilman bodies ▫ Sever disease → shock → liver hypoperfusion → hepatocellular injury, death Central nervous system (CNS) involvement ▫ Rare, direct viral infection of brain parenchyma

SIGNS & SYMPTOMS ▪ High-grade fever (> 38.5°C/101.3°F) ▪ Generalized pain ▫ Abdominal pain/tenderness, headache, joint pain, muscle pain, eye/retro-orbital pain ▪ Nausea/vomiting ▪ Mucosal bleeding ▪ Rash Severe symptoms and signs ▪ Severe bleeding ▪ Fluid accumulation → respiratory distress ▫ Ascites, pleural effusion

Chapter 73 Flaviviruses ▪ Neurologic impairment ▫ Lethargy, seizure, encephalopathy

DIAGNOSIS LAB RESULTS

▪ Leukopenia ▪ Thrombocytopenia ▪ ↑ Hematocrit

TREATMENT MEDICATIONS

▪ No antiviral therapy available ▪ Fever control ▫ Antipyretics

OTHER INTERVENTIONS

Antibody testing ▪ Antigen assay ▫ ⊕ < five days of infection ▪ IgM ▫ ⊕ ≧ three days of infection ▪ IgG ▫ ⊕≧ seven days of infection ▫ May be ⊕ due to prior infection

OTHER DIAGNOSTICS

Positive tourniquet test ▪ Blood pressure cuff insufflation → maintain pressure midway between systolic, diastolic → hold for five minutes → deflate → observe for petechiae ▫ Positive test:10+ petechiae in 2.5cm/1in

▪ Maintain adequate intravascular volume ▪ Shock ▫ Crystalloid fluid resuscitation ▪ Bleeding ▫ Platelet transfusion if severe thrombocytopenia and/or active, uncontrolled bleeding

Prevention ▪ Mosquito control ▫ ↓ Standing water breeding sites ▫ Copepod use (organisms feed on mosquito larvae) ▫ Insecticides ▪ Personal protective measures ▫ Repellant use ▫ Permethrin-treated clothing (Na+ channel blockade → neurotoxicity → paralysis → death; low toxicity in humans)

WEST NILE VIRUS osms.it/west-nile-virus PATHOLOGY & CAUSES ▪ Virus causing mosquito-borne, self-limited disease ▫ Characterized by flu-like symptoms ▫ Potential for severe neurologic sequelae ▪ Vector ▫ Culex mosquito Pathogenesis ▪ Culex mosquito bite → viral replication in skin’s dendritic cells → lymph node migration → further replication →

enters bloodstream → visceral organ dissemination ▫ Complication arise when virus enters bloodstream → crosses blood-brain barrier Transmission ▪ Infected bird (amplifying host) → prolonged viremia → Culex mosquito blood meal → human/other vertebrate bite → blood meal, virus-laden saliva injected→ virus transmission ▪ Viral-load organ/blood donation ▪ Transplacental infection

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RISK FACTORS

▪ Elderly ▪ Immunosuppressed individuals ▪ Malignancy (especially hematologic malignancies) ▪ Chemokine receptor CCR5 deficiency ▫ Chemokine involved in viral infection immune response (especially brain parenchyma)

COMPLICATIONS

▪ Neurological ▫ Meningitis, encephalitis, tremor, flaccid paralysis, Guillain–Barré syndrome ▪ Ocular ▫ Chorioretinitis, uveitis, optic neuritis ▪ Cardiac ▫ Myocarditis, cardiac arrhythmias ▪ Muscular ▫ Myositis, rhabdomyolysis ▪ Other ▫ Pancreatitis, orchitis, hepatitis, central diabetes insipidus

SIGNS & SYMPTOMS ▪ Abrupt-onset fever, headache, myalgias ▫ Usual presentation is self-limited (AKA West Nile Fever) ▪ Abdominal pain, anorexia, nausea/vomiting, diarrhea, maculopapular rash Neurologic complications ▪ Motor ▫ Tremor, flaccid paralysis (Guillain-Barré complications) ▪ Meningoencephalitis ▫ Meningismus, altered mental status

DIAGNOSIS DIAGNOSTIC IMAGING MRI ▪ Neurologic sequelae → ↑ signal in T2 imaging

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Nerve action potentials ▪ Normal sensory conduction velocity ▪ Abnormally ↓motor neuron velocity, potentials

LAB RESULTS

▪ Reverse transcription polymerase chain reaction (RT-PCR) ▪ Viral cultures ▪ Cerebrospinal fluid ▫ Severe cases ▫ If present in CSF → neuroinvasive disease likely ▫ Neutrophilic pleocytosis ( 14 days from onset of symptoms

TREATMENT ▪ No cure

MEDICATIONS ▪ Antipyretics

OTHER INTERVENTIONS Mother ▪ Rest ▪ Fluid management, resuscitation Newborn ▪ Nutritional support ▪ Physical therapy ▪ Specialty referral (especially neurology) Prevention ▪ No vaccine available ▪ Personal protective measures in endemic areas ▪ Consultation with physician prior to travel for pregnant individuals ▪ Safe sexual practice ▫ Biologically-male individuals wait at least six months after endemic-area travel for unprotected sex ▫ Biologically-female individuals wait at least eight weeks after endemic-area travel for unprotected sex ▪ Blood donation ▫ Do not donate for at least six months after endemic-area travel

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GASTROINTESTINAL INFECTIONS

GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Gastrointestinal tract (GIT) inflammation caused by virus, bacteria, other parasites ▪ GIT mucosa inflammation → ulceration → epithelial disruption → edema, bleeding → fluid, electrolyte loss (diarrhea) → dehydration, electrolyte imbalance, anemia (bloody diarrhea) ▪ Mainly fecal-oral transmission

RISK FACTORS

▪ Living/traveling to endemic areas, youth, immunosuppression (e.g. corticosteroid treatment, HIV co-infection), malnutrition, poor hygiene

DIAGNOSIS ▪ Pathogen-dependent

LAB RESULTS ▪ Stool culture

TREATMENT ▪ Rehydration ▪ Antimicrobial therapy (pathogendependent)

SIGNS & SYMPTOMS ▪ Fever, diarrhea, abdominal pain (cramps) ▪ Dehydration ▫ Sunken eyes, dry mouth, decreased urination, dark yellow urine (deep amber—severe), dry skin, syncope

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CRYPTOSPORIDIUM osms.it/cryptosporidium PATHOLOGY & CAUSES ▪ Cryptosporidiosis: diarrheal disease caused by Cryptosporidium (intestinal intracellular protozoan parasite) ▪ Life-cycle can be completed in one host ▫ Immunocompetent hosts: self-limited diarrhea ▫ Immunocompromised hosts: lifethreatening complications

CAUSES

▪ Cryptosporidium oocysts (infective form) transmitted via fecal → oral route ▫ Infected individual/animal feces contaminates food; drinking, swimming water → fecally-contaminated food/ water ingestion ▪ Parasites → intestinal epithelial inflammation → villi structure distortion → ↓ absorption, ↑ secretion → watery diarrhea ▫ Sclerosing cholangitis/acalculous cholecystitis, respiratory cryptosporidiosis, pancreatitis

RISK FACTORS

▪ Endemic-area exposure (tropical countries, Kuwait), immune deficiencies, poor hygiene ▪ Interpersonal transmission: sexual partners, daycare centers, household members

COMPLICATIONS

▪ Dehydration, fluid and electrolyte imbalance

SIGNS & SYMPTOMS ▪ Host’s immune status-dependant

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DIAGNOSIS LAB RESULTS Microscopic oocyte identification ▪ Stool; bile secretion, affected GIT aspirates; affected GIT tissue biopsy; respiratory secretion Polymerase chain reaction (PCR) ▪ More sensitive, specific ▪ Differentiates between Cryptosporidium genotypes Monoclonal antibodies and enzyme immunoassays (EIA) ▪ Monoclonal antibody test against oocyst wall ▪ More sensitive, specific than light microscope

TREATMENT MEDICATIONS

▪ Immunocompetent host: antidiarrheal, antimicrobial agents ▪ Immunocompromised host: antiretroviral therapy (HIV-infected individuals), antimicrobial agents, azithromycin (severe diarrhea)

OTHER INTERVENTIONS

▪ Immunocompetent host: oral/IV fluid/ electrolyte-loss replacement

Chapter 74 Gastrointestinal Infections

Figure 74.1 Cryptosporidium organisms lining the crypt epithelium in an infected individual.

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ENTAMOEBA HISTOLYTICA (AMOEBIASIS) osms.it/entamoeba-histolytica PATHOLOGY & CAUSES

SIGNS & SYMPTOMS

▪ Amebiasis ▫ Caused by Entamoeba histolytica (anaerobic parasitic protozoan) ▪ Trophozoites bind to intestinal epithelial cells in colon, release lytic enzymes (e.g. cysteine proteinases) → epithelial cell lysis → trophozoites lyse inflamed/attracted immune cells → immune cell’s lytic enzymes ↑ release ▫ Intestinal mucosa ulcers → colitis → bowel necrosis → perforation → sepsis ▫ Tissue destruction → mucosa blood vessel injury, malabsorption, ↑ intestinal secretion → bloody diarrhea, amebic dysentery ▫ Blood vessel injury → trophozoites in blood stream → extraintestinal amebiasis (liver, pulmonary, cardiac, brain)

▪ Mostly asymptomatic; bloody diarrhea, mucus in stool (severe dysentery); abdominal pain; fever; weight loss; right upper-quadrant pain, jaundice (liver); cough (pulmonary); dehydration

RISK FACTORS

▪ Endemic-area exposure (Africa, Southern Asia, Central America) ▪ Intimate partner transmission possible ▪ Youth ▪ Malnutrition ▪ Immunodeficiency (e.g. malignancy, corticosteroid treatment, HIV) ▪ Poor hygiene

COMPLICATIONS

▪ Amebic liver abscess rupture ▫ Pericarditis, peritonitis ▪ Toxic megacolon ▪ Cerebral amebiasis → brain abscess → ↑ intracranial pressure ▪ Cutaneous amebiasis ▪ Dehydration

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DIAGNOSIS DIAGNOSTIC IMAGING X-ray ▪ Liver CT scan, MRI, ultrasound ▪ Cystic intrahepatic cavity detection

LAB RESULTS Microscopic identification ▪ Cysts/trophozoites in stool/pus (e.g. liver abscess) Antigen detection ▪ Enzyme-linked immunosorbent assay (ELISA), radioimmunoassay, immunofluorescence PCR ▪ Entamoeba DNA detection Serology ▪ Entamoeba antibodies detection Sigmoidoscopy/colonoscopy ▪ Histological examination biopsies

Chapter 74 Gastrointestinal Infections

TREATMENT MEDICATIONS

▪ Antibacterial agents ▫ Invasive amoebic colitis ▪ Luminal agents ▫ Intraluminal cysts, trophozoites ▪ Metronidazole ▫ Amebic liver abscess ≤ 10cm/3.94in ▪ Broad-spectrum antibiotics ▫ Suspected perforation, bacterial superinfection

SURGERY ▪ ▪ ▪ ▪ ▪

Figure 74.2 Trophozoites of Entamoeba histolytica in a colonic biopsy. The trophozoites have ingested red blood cells.

Massive GIT bleeding Amebic liver abscess > 10 cm/3.94 in Ruptured amebic liver abscess Perforated amebic colitis Toxic megacolon

OTHER INTERVENTIONS ▪ Rehydration

GIARDIA LAMBLIA osms.it/giardia-lamblia PATHOLOGY & CAUSES ▪ Giardiasis ▫ Diarrheal disease caused by Giardia intestinalis/Giardia duodenalis (flagellated protozoan parasite, colonizes small intestine) ▪ Pathogenesis not well understood ▪ Infection causes microvilli shortening → intestinal malabsorption, hypersecretion → diarrhea

CAUSES

▪ Contaminated/untreated water ingestion ▪ Contaminated food (uncommon)

RISK FACTORS

▪ Endemic-area exposure (tropical countries), immunosuppression, comorbidities (e.g. cystic fibrosis), poor sanitation

COMPLICATIONS

▪ Weight loss; dehydration; zinc, disaccharidase deficiency; malabsorption syndrome (adult); growth delay (children)

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SIGNS & SYMPTOMS ▪ Usually asymptomatic Acute giardiasis ▪ 7–14 days after infection exposure ▪ Diarrhea, malaise, abdominal pain, flatulence, nausea/vomiting, malodorous stool, steatorrhea, fever (uncommon) Chronic giardiasis ▪ > 18 days after infection exposure ▪ Loose stools (not typical diarrhea), profound weight loss (occasionally), abdominal pain, borborygmus (moving gas/fluid → GIT gurgling sound), flatulence, burping, malaise, fatigue, depression

Figure 74.3 Giardia lamblia in a cytology specimen.

DIAGNOSIS LAB RESULTS Antigen detection assays ▪ Trophozoite antigen (stool) detection Nucleic acid amplification assays (NAAT) ▪ Giardia DNA detection Stool microscopy ▪ Giardia cyst detection

TREATMENT MEDICATIONS

▪ Antimicrobial therapy ▫ Paromomycin (pregnant/lactating individuals)

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Figure 74.4 A duodenal biopsy demonstrating giardia organisms in the duodenal crypt.

NOTES

NOTES

GENERAL INFECTIONS GENERALLY, WHAT ARE THEY? TREATMENT

PATHOLOGY & CAUSES ▪ Localized, systemic disorders caused by microbial infections

SIGNS & SYMPTOMS

MEDICATIONS ▪ Antimicrobials

OTHER INTERVENTIONS ▪ Drainage

▪ See individual conditions

DIAGNOSIS ▪ See individual conditions

ABSCESSES osms.it/abscesses PATHOLOGY & CAUSES ▪ Localized, circumscribed pus collection surrounded by inflamed tissue ▪ May develop in any body region ▫ Superficial (e.g. skin, soft tissue) ▫ Internal (e.g. lung, liver, brain) ▪ Caused by pyogenic bacteria (e.g. S. aureus, S. pyogenes, S. epidermidis, P. aeruginosa) ▪ Bacterial invasion → local inflammatory response ▫ Suppuration (pus production) ▫ Necrosis, liquefaction ▫ Cellular debris accumulation ▪ Loculation, walling off of abscess by adjacent, healthy cells

RISK FACTORS ▪ ▪ ▪ ▪ ▪

Trauma Foreign body presence (e.g. body piercing) Intravenous (IV) drug use Dermatological conditions (e.g. cellulitis) Anatomical involvement-related risks ▫ Examples: ascending infection → pelvic abscess, hematologic spread → central nervous system (CNS) abscess, local spread → liver abscess

COMPLICATIONS

▪ Spread to other tissue ▪ Fistula formation ▪ Sepsis

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SIGNS & SYMPTOMS ▪ Localized warmth, erythema, swelling, tenderness/pain, induration ▪ Fluctuant mass

DIAGNOSIS ▪ History, physical examination: characteristic findings

DIAGNOSTIC IMAGING CT scan ▪ Central decreased attenuation area with circumferential enhancement ring MRI ▪ T1: central hypointense area ▪ T2: hyperintense ▪ T1, T2: rim is iso- to hypointense Ultrasound ▪ Internal abscess ▫ Homogeneous fluid collection appears as hypoechoic region within tissue ▫ Edema: cobblestone appearance—thin hyperechoic (dark gray) bands, anechoic (black) fluid

Figure 75.1 The clinical appearance of a pilonidal abscess.

LAB RESULTS

▪ Ultrasound-guided needle aspiration ▫ Specimen collection, culture

TREATMENT MEDICATIONS ▪ Antimicrobials

OTHER INTERVENTIONS ▪ Incision, drainage

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Figure 75.2 A CT scan of the brain in the coronal plane demonstrating a cerebral abscess of the left frontal lobe. The abscess shows typical ring enhancement.

Chapter 75 General Infections

SEPSIS osms.it/sepsis PATHOLOGY & CAUSES ▪ Serious, life-threatening, systemic infection reaction ▫ Microbial host barrier breach (skin, mucous membranes) → provokes host dysregulated immune response → proinflammatory mediator release (e.g. TNF-α, interleukins) → detrimental physiological effects, tissue damage ▫ Endothelial damage, dysfunction; ↑ vascular permeability; microvascular dysfunction; coagulopathies

RISK FACTORS

▪ Bacteremia (most common) Gram-positive organisms ▪ Hospital/intensive care unit (ICU) admission → nosocomial infection ▪ Immune system deficiency ▫ E.g. HIV/AIDS, hematologic malignancy, immunosuppressant medication ▪ Recent surgery/hospitalization → altered microbiome ▪ Indwelling medical device presence ▫ E.g. urinary catheter, venous access device ▪ Bimodal age distribution ▫ Infants, adults ≥ 65 ▪ Community-acquired pneumonia ▪ Chronic disease ▫ E.g. diabetes, heart failure (HF), chronic obstructive pulmonary disease (COPD) ▪ Genetic factors

▪ Respiratory failure ▪ Disseminated intravascular coagulation (DIC) ▪ Metabolic acidosis ▪ Stress ulcer ▪ Treatment complications ▫ E.g. ventilator-associated pneumonia, venous thrombosis ▪ Death

SIGNS & SYMPTOMS General presentation ▪ Fever; tachypnea; tachycardia; hypotension; hypoxemia; ↓ urine output; ↓ PaO2; edema; ileus, ↓ bowel sounds ▪ Altered mental status ▫ Malaise, agitation, lethargy, stupor ▪ Signs of shock ▫ E.g. cool skin, cyanosis, ↑ capillary refill, mottling Quick Sequential Organ Failure Assessment (qSOFA) ▪ Score ≥ 2 → ↑ mortality risk ▪ See table

COMPLICATIONS

▪ Severe sepsis → septic shock ▫ Sepsis-induced vasodilation, hypotension ▫ Unresponsive to fluid resuscitation ▪ Multiple organ dysfunction syndrome (MODS)

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DIAGNOSIS ▪ History, clinical presentation, physical examination

LAB RESULTS Blood studies ▪ ↑ white blood cell (WBC) count, left shift ▪ ↑ C-reactive protein (CRP), erythrocyte sedimentation rate (ESR) ▪ Indications of organ hypoperfusion, injury, dysfunction ▫ ↑ lactate, ↓ platelets (may precede DIC), ↑ glucose, ↑ creatinine, ↑ bilirubin ▪ Coagulation studies ▫ ↑ international normalized ratio (INR), activated partial thromboplastin time (aPTT) ▪ Blood cultures ▫ Identify pathogen

TREATMENT MEDICATIONS

▪ Antimicrobials ▫ Initial broad-spectrum antibiotics until pathogen identified ▪ Hemodynamic support ▫ Fluid resuscitation ▫ Vasopressors ▪ Infection prevention ▫ Vaccinations for at risk individuals (influenza, pneumonia) ▪ Complication prevention ▫ Proton pump inhibitor

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SURGERY

▪ Source control ▫ E.g. infected device removal, abscess drainage)

OTHER INTERVENTIONS Hemodynamic support ▪ Invasive monitoring Respiratory support ▪ Supplementary oxygen; mechanical ventilation Infection prevention ▪ Infection control practices ▫ ↓ hospital-acquired infections (ventilator-associated pneumonia, catheter-associated bloodstream infections) Complication prevention ▪ Deep-vein thrombosis prophylaxis ▪ Glycemic control

NOTES

NOTES

GRAM VARIABLE

GARDNERELLA VAGINALIS (BACTERIAL VAGINOSIS) osms.it/gardnerella-vaginalis PATHOLOGY & CAUSES

DIAGNOSIS

▪ Facultative, anaerobic, gram-variable coccobacilli ▪ Microscopically ▫ Very thin gram-positive cell wall appears gram-positive/negative ▪ Non-spore forming, non-motile ▪ Causative agent for bacterial vaginosis (BV) ▫ Disruption of vaginal microbiome ▪ Most common vaginal infection in individuals who are biologically female, age 15–44

LAB RESULTS

RISK FACTORS

OTHER DIAGNOSTICS

▪ Multiple sex partners, douching, smoking

COMPLICATIONS

▪ ↑ risk of contracting HIV, other STDs ▪ Acute cervicitis, endometritis, postabortal infection ▪ During pregnancy ▫ Premature birth, low birthweight

SIGNS & SYMPTOMS ▪ Malodorous (fishy), thin white/gray vaginal discharge ▪ Vaginal pain, itching, burning ▪ Burning with urination

▪ Gram-stain smear of vaginal discharge; using criteria (e.g. Nugent, Hay/Ison) ▪ Affirm VP III ▫ Commercial automated DNA probe assay detects G. vaginalis ▪ OSOM BVBlue test ▫ Chromogenic identifies presence of elevated sialidase enzyme produced by G. vaginalis, other bacteria (e.g. Bacteroides, Prevotella, Mobiluncus)

▪ Requires three of the following Amsel criteria ▫ Characteristic vaginal discharge ▫ pH > 4.5 ▫ Clue cells visible on saline wet mount (vaginal epithelial cells covered with bacteria) ▫ Positive whiff-amine test (combine vaginal discharge sample with 10% KOH → fishy odor)

TREATMENT MEDICATIONS

▪ Antibiotics: metronidazole

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NOTES

HEMATOLOGIC INFECTIONS GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES Taxonomy ▪ Apicomplexan phylum protozoa → infectious hematological diseases Replication/multiplication ▪ Arthropod transmission Transmission ▪ Multiple life cycle stages (host-, vectordependent)

DIAGNOSIS LAB RESULTS

▪ Blood smear: best intra-erythrocyte location diagnosis

TREATMENT ▪ See individual infections

SIGNS & SYMPTOMS ▪ See individual infections

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BABESIA osms.it/babesia PATHOLOGY & CAUSES

RISK FACTORS

▪ Malaria-like parasitic infection ▫ Ixodes tick transmission ▪ Phylum Apicomplexa (same as Plasmodium, Toxoplasmosis) ▪ Common species ▫ Babesia microti most predominant (northeast, upper midwest United States) ▫ B. duncani (Western United States) ▫ B. divergens (Europe)

▪ Endemic area resident ▪ Endemic area travel, especially May– September ▪ Blood transfusion (last six months) ▪ Age > 50 ▪ Biologically male ▪ Asplenia ▪ Decreased immunity (malignancy, HIV/ AIDS infection, immunosuppressive drugs) ▪ Coinfection with Borrelia and/or Anaplasma ▪ Premature birth

CAUSES

COMPLICATIONS

▪ Ixodes scapularis tick: only recognized vector ▫ Same tick transmits Borrelia burgdorferi (→ Lyme disease; concurrently infects ⅔ babesiosis-infected individuals) and Anaplasma phagocytophilum (→ human granulocytic anaplasmosis; concurrently infects ⅓ babesiosis-infected individuals) ▫ Contaminated blood transfusion → rare human-to-human transmission ▪ Life cycle ▫ Two hosts: white-footed mouse, Ixodes tick (definitive) ▫ Blood meal → Babesia-infected tick sporozoites into mouse host → sporozoites directly invade mature mouse erythrocytes → sporogony (asexual reproduction; budding) → in blood, some parasites differentiate into male, female gametes → gametes unite → sporogonic cycle → sporozoites → tick bites human → 1–4 week incubation → sporozoites enter erythrocytes → sporogony ▪ Sporogony ▫ Asynchronous with host → no massive hemolysis (versus malaria) ▪ Tick’s nymph stage is most infectious

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▪ ↑ occurence in anemic/parasitemic individuals ▫ Congestive heart failure ▫ Noncardiac pulmonary edema ▫ Acute respiratory distress syndrome ▫ Splenic infarct ▫ Splenic rupture ▫ Septic shock ▫ Myocardial infarction ▫ Disseminated intravascular coagulation ▫ Death

SIGNS & SYMPTOMS ▪ Mostly asymptomatic, may persist undiagnosed months/years ▪ Blood-stage parasite multiplication → clinical manifestation ▪ Non-specific flu-like symptoms (misdiagnosis common) ▫ Fatigue (gradual onset) ▫ Fever, chills, sweats ▫ Headache, myalgia, arthralgia ▫ Anorexia, nausea ▫ Cough

Chapter 77 Hematologic Infections ▪ Severe manifestations include malaria-like illness (fever, fatigue, malaise) + hemolytic anemia manifestation ▪ B. microti case-fatality rate is 5% ▪ B. divergens infections case-fatality rate is 42% ▫ Disseminated intravascular coagulation, bleeding diathesis ▫ Acute renal failure ▫ Cardiopulmonary complications (e.g. hypotension, poor perfusion, pulmonary edema)

OTHER INTERVENTIONS

▪ Severe disease (parasitemia > 4%) ▫ Antimicrobial + exchange transfusion

Prevention ▪ Personal: avoid endemic areas; long pants, shirts minimize exposed skin ▪ Tick repellant on skin (e.g. DEET) ▪ Post-exposure tick checks ▪ No antibiotic prophylaxis

DIAGNOSIS LAB RESULTS Blood smear ▪ Wright/Giemsa staining ▫ Thin: rapid, ↓ microscopy experience required ▫ Thick: ↑ accurate, ↑ microscopy experience required ▫ Pathognomic tetrad “Maltese cross” visible in erythrocyte Laboratory ▪ Thrombocytopenia ▪ Reticulocytosis ▪ ↓ Hematocrit ▪ ↓ Hemoglobin ▪ ↑ Lactate dehydrogenase ▪ ↓ Haptoglobin ▪ ↑ Liver function tests ▪ ↑ Creatinine Polymerase chain reaction (PCR) ▪ Speciation (useful for low-level parasitemia) Serology ▪ Immunofluorescent antibody testing; species specific

TREATMENT ▪ Asymptomatic: no treatment

MEDICATIONS

▪ Symptomatic disease: azithromycin + atovaquone

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PLASMODIUM SPECIES (MALARIA) osms.it/malaria PATHOLOGY & CAUSES ▪ Anopheles mosquito vector → parasitic hematologic infection ▪ Four major malarial parasite species ▫ Plasmodium falciparum: most lethal, most drug-resistant (sub-Saharan Africa) ▫ P. vivax: widest geographic distribution, relapsing species ▫ P. ovale: relapsing species (western areas of sub-Saharan Africa) ▫ P. malariae: AKA ‘benign’ malaria (mild course) ▪ P. knowlesi: normally infects macaques, recent cause of human malaria cases

▪ Erythrocytic life cycle stage ▫ In erythrocytes → parasites can undergo asexual schizogony/ sexual differentiation (necessary for transmission) → gametocytes ▪ Asexual schizogony ▫ Trophozoites (parasite name once inside erythrocyte) digest host cell hemoglobin (amino acids, energy source) → schizont → undergoes mitosis → differentiates into merozoites → erythrocyte rupture → merozoite bloodstream release → fever, malarial symptoms

CAUSES

▪ Exoerythrocytic (sporogonic; blood) life cycle stage ▫ Blood-stage gametocytes in other host (e.g. human) → female Anopheles mosquito blood meal → mosquito multiplication, growth cycle → 10–18 day incubation → sporozoites in mosquito salivary gland → human bite → sporozoite inoculation → hematogenous translocation to liver → rapid hepatic parenchymal cell invasion → parasites undergo exoerythrocytic schizogony (asexual multiplication) → development, multiplication → 7–14 day incubation → merozoite development → invade erythrocytes → symptomatic stage develops → P. ovale, P. vivax can differentiate into quiescent stage → hypnozoite → can re-enter into schizogony → reemerge to invade erythrocytes ▫ Blood stage → malaria symptoms ▫ Mosquito vector does not have parasite presence

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Figure 77.1 A peripheral blood film taken from an individual with Plasmodium malariae infection. There is a mature schizont, composed of 6-12 merozoites, contained within a red blood cell. ▪ P. malariae ▫ Low-level persistence possible for decades without diagnosis, treatment ▪ P. vivax ▫ Prefers erythrocytes with Duffy blood group antigen (rare in persons from West and Central Africa); prefers reticulocytes but will also invade mature erythrocytes ▪ Others preferentially invade mature erythrocytes

Chapter 77 Hematologic Infections ▪ P. falciparum ▫ Develop ‘knobs’ on infected erythrocytes in late trophozoite stage → parasitized erythrocytes adhere to capillary endothelium → various organ sequestration (notably brain) → cerebral malaria ▪ Most malaria deaths ▫ Children < five years old in hightransmission areas

COMPLICATIONS

Coma Seizure Severe anemia Acute renal failure ▫ Acute tubular necrosis secondary to hypoperfusion, hypovolemia ▪ Acute respiratory distress syndrome ▪ Shock ▪ Septicemia

▪ ▪ ▪ ▪

SIGNS & SYMPTOMS

RISK FACTORS

▪ Poor rural populations in endemic areas ▪ Proximity to standing water ▫ Larvae breeding site (e.g. agriculture, irrigation ditches) ▪ Travel in endemic areas ▪ Blood transfusion (last six months) ▪ Lack of insect repellant, chemoprophylaxis, personal protective measures (long pants, shirts, mosquito nets) ▪ Duffy blood group antigen-positive individuals

Protective factors ▪ P. falciparum protection: sickle cell trait (heterozygotes) ▪ P. vivax: Duffy blood group antigennegative individuals

▪ Febrile paroxysm (hallmark feature) ▫ 10–12 hours of intense rigors, chills → high fever, profuse diaphoresis ▫ Febrile seizure potential ▪ Non-specific complaints ▫ Headache, malaise, myalgia, arthralgia ▪ Abdominal pain, diarrhea, vomiting ▪ Possibly remarkably asymptomatic between episodes ▪ P. falciparum cerebral effects ▫ Significant morbidity, mortality (delirium, confusion, seizures → declining mental status → coma → death) ▪ Parasitemia, cytokine disturbance → hypotension, metabolic acidosis, hypoglycemia ▪ Anemia (high parasitemia → more pronounced) ▪ Sequestration, red blood cell destruction by spleen → hypersplenism

DIAGNOSIS LAB RESULTS Giemsa stain blood smear ▪ Thin: rapid, ↓ microscopy experience required ▪ Thick: ↑ accurate, ↑ microscopy experience required ▪ P. falciparum: red blood cells contain multiple parasites, ring forms, lack of schizonts ▪ Banana-shaped gametocyte form

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Rapid diagnostic test ▪ 15–20 minute results ▪ Histidine-rich protein 2: detects P. falciparum PCR ▪ Supportive laboratory results (nondiagnostic) ▫ Normocytic hemolytic anemia ▫ Thrombocytopenia

TREATMENT MEDICATIONS

▪ Severe malaria ▫ Quinidine + doxycycline/tetracycline/ clindamycin/artesunate (test for G6PD deficiency) ▪ Uncomplicated malaria ▫ Chloroquine-sensitive strain: chloroquine phosphate/ hydroxychloroquine (blocks Plasmodium heme polymerase) ▫ Chloroquine-resistant strain: atovaquone-proguanil, mefloquine, artesunate, quinine-based regimens ▪ P. ovale, P. vivax: + primaquine for hypnozoite (test for G6PD deficiency)

OTHER INTERVENTIONS

Figure 77.2 A histological section of the placenta from an individual infected with malaria. The numerous black dots within the red blood cells are malaria organisms.

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Prevention ▪ Chemoprophylaxis ▪ Avoid outdoors (dusk/dawn) ▪ Reduce exposed skin (long pants, shirts) ▪ Bed netting/mosquito nets ▪ Insect repellent (DEET 30–50%)

NOTES

NOTES

HEPADNAVIRIDAE MICROBE OVERVIEW ▪ Hepadnaviridae: family of DNA viruses, causes liver disease ▪ Produces DNA polymerase with reverse transcriptase, RNAse activity Replication/multiplication ▪ Reverse transcription (RNA intermediate) Structure ▪ Enveloped

▪ Icosahedral capsid ▪ Partially double stranded, partially single stranded circular DNA

COMPLICATIONS

▪ Chronic hepatitis, acute liver failure (fulminant hepatitis), liver cirrhosis, hepatocellular carcinoma (HCC)

HEPATITIS B VIRUS osms.it/hepatitis-b-virus PATHOLOGY & CAUSES ▪ Hepatitis B virus (HBV) ▫ DNA virus: can cause acute/chronic liver disease ▫ Member of Hepadnaviridae family (only human pathogenic species) ▪ Target: hepatocytes, zone I (periportal area) ▪ Incubation period: six weeks to six months Antigens ▪ Hepatitis B surface antigen (HBsAg/ Australia antigen) ▫ Key infection marker ▪ Hepatitis B core antigen (HBcAg) ▫ Not detectable in serum; found in liver with acute/chronic hepatitis B ▪ Hepatitis B e antigen (HBeAg) ▫ Secreted by infected cells; indicates active infection, replication

Transmission ▪ Perinatal (childbirth), parenteral (e.g. IV drug use, blood transfusions), sexual ▪ HBV survives ≥ seven days in environment Highest prevalence ▪ Parts of sub-Saharan Africa, mainly due to perinatal transmission ▪ Lower prevalence areas have greater association with parenteral, sexual transmission

TYPES Acute hepatitis ▪ Liver inflammation for < six months) ▪ HBV penetrates hepatocytes → CD8+ T-lymphocyte activation → cytotoxic killing → hepatocyte apoptosis → liver damage, inflammation ▪ Phases ▫ Early, window (antigens undetectable), recovery

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▪ Acute liver failure progression: < 1% ▪ Chronic hepatitis progression (in adults): < 5% ▪ Acute liver failure ▫ Acute liver injury (severe hepatocyte necrosis), hepatic encephalopathy, coagulopathy ▫ Excessive immune response → massive hepatocyte lysis ▫ Preexisting liver disease absence ▫ Associated with HBV genotype D Chronic hepatitis ▪ HBsAg persistent for > six months ▪ Pathogenesis ▫ HBV penetrates hepatocytes → insufficient CD8+ T-lymphocyte activation → “immune tolerance” → HBV persistence ▪ Progression to HCC ▫ HBV integrates to host DNA → oncogene activation → oncogenesis ▪ Chronicity depends highly on age at time of infection ▫ Younger age, ↑ chronicity risk ▫ Immunosuppressed, elderly people also more susceptible ▪ Phases ▫ Immune tolerant: no liver inflammation/ fibrosis ▫ Immune active: liver damage, inflammation, possible fibrosis ▫ Immune inactive: ↓ inflammation ▫ Reactivation: liver damage, inflammation, possible fibrosis ▫ “Recovery”: occult HBV, HBsAg negative; still infected, disease inactive (best prognosis)

RISK FACTORS

▪ IV drug use ▪ Healthcare workers ▫ Frequent contact with blades, needles, body fluids ▪ High-risk sexual behavior ▪ Anal intercourse ▪ Previous HIV/hepatitis C infection

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COMPLICATIONS

▪ HCC, fulminant hepatitis, liver cirrhosis

Hepatic encephalopathy ▪ Excessive nitrogen load, electrolyte disturbances → altered neurologic functions in individuals with severe liver disease Hepatorenal syndrome ▪ Portal hypertension → splanchnic vasodilation → ↓ effective circulatory volume → ↑ renin-angiotensin-aldosterone system → renal vasoconstriction → hepatorenal syndrome (liver dysfunction → kidney failure) Bleeding diathesis ▪ Hypocoagulability → ↑ hemorrhage risk

SIGNS & SYMPTOMS Acute hepatitis ▪ Can be anicteric (not accompanied by jaundice) with non-specific symptoms (e.g. fever, malaise, nausea, vomiting) ▪ Some progress to icteric hepatitis with hepatomegaly, right upper-quadrant pain, jaundice (30%), dark-colored urine (due to conjugated hyperbilirubinemia), pale stool Chronic hepatitis ▪ Mostly asymptomatic/non-specific symptoms until late disease stages ▪ Exacerbations may present as acute hepatitis ▪ Jaundice, ascites, splenomegaly, encephalopathy (e.g. personality changes, ↓ level of consciousness, intellectual impairment, asterixis) may present ▪ Extrahepatic manifestations (occasionally) ▫ Fever, rash, arthralgia, arthritis, glomerulonephritis

DIAGNOSIS LAB RESULTS

▪ HBV DNA detection ▫ Polymerase chain reaction (PCR), in-situ hybridization, Southern hybridization

Chapter 78 Hepadnaviridae Laboratory testing ▪ ↑ alanine aminotransferase (ALT), aspartate aminotransferase (AST) ▫ ALT > AST ▫ Usually ALT in acute hepatitis > 1000 U/L (may be ↓ in chronic hepatitis) ▫ ALT levels take longer than AST to return to normal ▪ ↑ ALT for > six months indicates chronicity ▪ ↑ alpha-fetoprotein (AFP) in HCC ▪ Liver fibrosis ▫ ↓ leukocytes, platelets ▫ AST/ALT > 1 (normal ≈ 0,8) ▫ ↑ total bilirubin ▫ ↓ serum albumin ▫ Delayed prothrombin time, ↑ international normalized ratio (INR) Serologic marker detection through enzyme immunoassay ▪ Hepatitis B surface antigen (HBsAg) ▫ Indicates infection (acute/chronic) ▪ Hepatitis B surface antibodies (Anti-HBs) ▫ Provides HBV infection immunity appears after vaccination/resolved acute hepatitis

▪ IgM antibodies against hepatitis B core antigen (IgM anti-HBc) ▫ Acute infection/chronic hepatitis reactivation phase ▪ IgG antibodies against hepatitis B core antigen (IgG anti-HBc) ▫ Non-specific antibody; may be ↑ during acute, resolved, chronic hepatitis ▪ Hepatitis B e antigen ▫ Active replication, high infectivity ▪ Hepatitis B e antibodies ▫ Low replication, infectivity Liver biopsy ▪ Acute hepatitis ▫ Mononuclear infiltrate ▫ Pericentral inflammation, necrosis ▫ Eosinophilic hepatocytes ▪ Chronic hepatitis ▫ Fibrosis ▫ Nodule formation ▫ Mononuclear portal infiltrate ▫ Some hepatocytes have uniformly dull cytoplasm due to endoplasmic reticulum swelling (“ground glass” hepatocytes)

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Figure 78.1 Ground glass hepatocytes seen in the liver of an individual with hepatitis B infection.

TREATMENT MEDICATIONS

▪ Antiviral monotherapy ▫ Severe acute hepatitis, pre-existing liver disease, concomitant hepatitis C/D infection, immunocompromised, elderly

Acute hepatitis ▪ Post-exposure prophylaxis ▫ HBV vaccine and immunoglobulin Chronic hepatitis ▪ Combination therapy (e.g. lamivudine, interferon)

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Prevention ▪ HBV vaccine ▪ Recombinant type most commonly used ▫ HBsAg inserted in yeast cells ▪ HBsAg → development of anti-HBsAg → HBV infection immunity ▪ Intramuscular administration ▪ Three doses for coverage (very effective) ▪ Administration regime: 0, 1–2 months, 6–12 months ▫ Infant immunization: first dose at birth ▫ Does not require booster dose (longterm protection)

SURGERY

▪ Acute liver failure ▫ Consider liver transplantation

OTHER INTERVENTIONS

▪ Acute liver failure ▫ Fluid resuscitation, early nutritional support, antiviral therapy (nucleoside/ nucleotide analogues)

Acute hepatitis ▪ Supportive treatment (e.g. fluid therapy, nutrition)

Chapter 78 Hepadnaviridae

HEPATITIS D VIRUS osms.it/hepatitis-d-virus PATHOLOGY & CAUSES

SIGNS & SYMPTOMS

▪ Hepatitis D virus (HDV/delta virus): incomplete RNA virus; contributes to acute liver failure development, chronic hepatitis exacerbation in people coinfected/ previously infected with HBV ▪ HDV not member of Hepadnaviridae family ▪ HDV infection inhibits HBV replication due to HBV, HDAg interaction during viral replication ▫ Coinfected individuals: HDV predominant ▫ ↑ inflammatory response (compared to HBV alone) ▫ Poor response to existing HBV treatment ▪ Incubation period ▫ 6–24 weeks

Coinfection ▪ Biphasic course with acute hepatitis symptoms

Structure ▪ Outer envelope made of HBsAg, inner HDV RNA, delta antigen (HDAg)

LAB RESULTS

Transmission ▪ Parenteral, sexual, perinatal (very rare) Satellite virus ▪ Can only infect if host also infected with HBV ▫ Coinfection: simultaneous infection ▫ Superinfection: HDV infection after established HBV infection; more severe

RISK FACTORS

▪ IV drug use, high-risk sexual behavior, HBV presence

Acute liver failure ▪ Systemic symptoms ▫ E.g. fever, malaise, nausea, vomiting) ▫ Hepatomegaly, right upper quadrant pain; sometimes jaundice, dark colored urine, pale stool ▪ Hepatic encephalopathy ▫ Personality changes, ↓ level of consciousness, intellectual impairment, asterixis

DIAGNOSIS ▪ Serologic marker detection ▫ IgM/IgG anti-HDV ▪ PCR assays ▫ HDV RNA detection

TREATMENT MEDICATIONS

▪ Pegylated interferon alpha ▪ Prevention ▫ HBV vaccine

SURGERY

▪ Consider liver transplantation for chronic hepatitis D, acute liver failure

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HERPESVIRUSES MICROBE OVERVIEW ▪ Large family of DNA viruses Species known to infect humans ▪ Herpes simplex virus (HSV) ▫ HSV-1, HSV-2 ▪ Varicella-zoster virus (VZV) ▪ Epstein-Barr virus (EBV) ▪ Human cytomegalovirus ▪ Human herpesvirus 6 (roseola) ▪ Human herpesvirus 8 (Kaposi’s sarcoma)

Genetic material ▪ Double-stranded, linear DNA genome encoding 84 proteins Morphology ▪ Icosahedral capsid; enveloped virus Life cycle ▪ Obligate intracellular parasites ▪ Can perpetuate in latent phase ▪ Expression of lytic genes → lytic phase→ host cell death → shedding

CYTOMEGALOVIRUS osms.it/cytomegalovirus PATHOLOGY & CAUSES ▪ Primary infection of immunocompetent individuals usually asymptomatic; lifelong latency ▪ Infects mononuclear leukocytes, endothelial cells

CAUSES

▪ Person-to-person transmission ▫ Kissing; intimate, sexual contact ▪ Vertical transmission ▫ Congenital infection ▪ Blood products/transfusion ▪ Organ/stem cell transplant

RISK FACTORS

▪ Immunocompromised ▫ HIV/AIDS; organ transplant; medications (e.g. steroids, chemotherapy)

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COMPLICATIONS

▪ Congenital CMV infection ▫ Cognitive, sensorineural deficits

SIGNS & SYMPTOMS ▪ Usually asymptomatic ▪ Fever, malaise, sore throat, splenomegaly ▪ Individuals with AIDS ▫ Retinitis, colitis, encephalitis, pneumonitis ▪ Individuals with congenital CMV infection ▫ Positive CMV-IgG (if pregnant); intrauterine fetal growth restriction (IUGR), hydrocephalus, microcephaly, intracranial calcification, poly/ oligohydramnios, hepatosplenomegaly

Chapter 79 Herpesviruses

DIAGNOSIS LAB RESULTS

▫ Highly active antiretroviral therapy (HAART) ▫ CMV immunoglobulin G (CMV-IGIV)

▪ Complete blood count ▫ Atypical lymphocytosis, anemia, leukopenia, thrombocytopenia ▪ ↑ serum creatinine, AST, ALT ▪ Serology tests ▫ ↑ CMV-IgM titre; acute infection ▫ ↑ CMV-IgG titre; past infection

TREATMENT ▪ Usually self-limiting

MEDICATIONS

▪ At-risk individuals ▫ Antiviral prophylaxis; IV ganciclovir; oral valganciclovir

Figure 79.1 A colonic biopsy taken from an individual with CMV colitis. The large nuclei that give the virus its name can be clearly seen.

EPSTEIN–BARR VIRUS (INFECTIOUS MONONUCLEOSIS) osms.it/epstein-barr_virus PATHOLOGY & CAUSES ▪ EBV (human herpesvirus 4) ▪ Causes Infectious mononucleosis (glandular fever) ▪ Infection in children ▫ Asymptomatic/mild flu-like symptoms ▪ Infection in adolescents, young adults ▫ Fever, sore throat, enlarged lymph nodes ▪ Lytic, latent life cycle ▫ Lytic in oropharyngeal B cells; latent in lymphocytes

CAUSES

▪ Transmitted through saliva (“kissing” disease), sexual transmission

RISK FACTORS

▪ Multiple sexual partners

COMPLICATIONS

▪ Splenic rupture ▪ EBV infection associated with Hodgkin’s, Burkitt’s lymphoma ▪ Neurologic syndromes (2–4 weeks after initial symptoms) ▫ Guillain-Barré syndrome, cranial nerve palsies (e.g. facial nerve palsy); meningoencephalitis (e.g. aseptic meningitis), transverse myelitis, peripheral neuritis, optic neuritis ▪ EBV can affect, manifest in any organ system ▫ Hepatitis, pneumonia, myocarditis, pancreatitis, acute renal failure, gastric pseudolymphoma

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▪ Classic triad ▫ Fever; cervical/generalized lymphadenopathy; tonsillar pharyngitis (exudative/non-exudative) ▪ Malaise, hepatosplenomegaly, rash, jaundice, myalgia

morphology (large, irregular nuclei) ▪ ↑ hepatic transaminase (50% of infected individuals) ▪ Monospot test ▫ Positive heterophile antibodies (IgM) ▪ Identification of EBV ▫ EBV-specific antibodies, real-time PCR, EBV DNA detection

DIAGNOSIS

TREATMENT

SIGNS & SYMPTOMS

MEDICATIONS

LAB RESULTS

▪ Complete blood count (CBC) ▫ Lymphocytosis (50%) with atypical

▪ Antipyretics, analgesics ▫ Avoid aspirin; may lead to Reye’s syndrome ▪ Corticosteroid for upper airway obstruction (e.g. prednisolone) ▪ Intravenous immunoglobulin (IVIG) for thrombocytopenia

Figure 79.2 Atypical lymphocytes with bizarre nuclear forms in a peripheral blood film from an individual infected with infectious mononucleosis.

HERPES SIMPLEX VIRUS osms.it/herpes-simplex-virus PATHOLOGY & CAUSES ▪ HSV-1, HSV-2 ▫ Members of herpesviridae family ▪ Causes oral, genital, ocular ulcers ▪ Portal of entry ▫ Mucosal surfaces/skin breaks; vertical transmission during pregnancy/ childbirth

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▪ Primary infection often symptomatic; replicates in epidermis of skin → travels down nerve endings, axon→ sensory ganglia ▪ Periodic reactivation, subsequent episodes ▫ Virus becomes active in ganglia → transported via axon to skin → replicates in epidermis → sheds → new sores ▫ Often asymptomatic shedding; may feel tingling, burning sensation

Chapter 79 Herpesviruses

TYPES

▪ Infection types ▫ Primary: first infections; seronegative; symptoms more extensive, systemic; greater viral shedding loads ▫ Non-primary: previously infected individuals; serum antibody, humoral immunity (e.g. genital HSV-2 infection in adulthood after oral mucosa HSV-1 infection in childhood) ▫ Recurrent: previously infected individuals; reactivation episodes (e.g. genital HSV-2 infection in adulthood after genital HSV-2 infection in adolescence) ▪ Herpes labialis (AKA oral herpes) ▫ HSV-1 infection of oral mucosa, lips ▪ Genital herpes ▫ HSV-2, HSV-1 infection of genital area ▫ Healing takes 2–4 weeks

SIGNS & SYMPTOMS ▪ Herpes labialis ▫ Painful ulcers around mouth; high fever; sore throat; pharyngeal oedema; myalgia, cervical lymphadenopathy ▫ Recurrent infection: pain, burning, tingling, vesicle formation ▪ Genital herpes ▫ Genital ulceration, vesicles: vulva, cervix, vagina, penis shaft/glans, perineum, buttocks ▫ Genital pain, dysuria, fever, neuralgia ▫ Constipation, rectal pain, tenesmus, proctitis

CAUSES

▪ Portal of entry ▫ Mucosal surfaces/skin breaks; vertical transmission during pregnancy/ childbirth ▪ Spread person to person; sexual transmission

RISK FACTORS

▪ Genital herpes ▫ Contact with infected individual (producing, shedding virus) ▫ Immunosuppression (e.g. medications, HIV/AIDS) ▫ High-risk sexual behavior (e.g multiple sexual partners, unprotected intercourse, first sexual activity at early age)

COMPLICATIONS

▪ Neonatal HSV infection, meningitis, encephalitis, acute retinal necrosis, uveitis, keratitis, esophagitis

Figure 79.3 Blisters on the lips caused by infection with herpes simplex virus.

DIAGNOSIS LAB RESULTS ▪ ▪ ▪ ▪

Viral culture HSV polymerase chain reaction (PCR) Direct fluorescent antibody (DFA) test Serological HSV-1/HSV-2 specific IgG assay

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TREATMENT MEDICATIONS Herpes labialis ▪ Antivirals (e.g. oral aciclovir, valaciclovir, famciclovir) ▪ Topical antivirals Genital herpes ▪ Antivirals (e.g. oral aciclovir, valaciclovir, famciclovir) ▪ Pregnant: antiviral prophylaxis

OTHER INTERVENTIONS Genital herpes ▪ Pregnant: possible cesarean delivery

Figure 79.4 Blisters on the dorsum of the penis of an individual infected with genital herpes simplex.

HUMAN HERPESVIRUS 6 (ROSEOLA) osms.it/human-herpesvirus-6 PATHOLOGY & CAUSES ▪ Causes roseola (infantum) ▪ Common cause of fever, followed by rash in early childhood, associated with febrile seizures ▪ Incubation period ▫ 1–2 weeks

CAUSES

▪ Asymptomatic contacts ▫ Person-to-person spread by respiratory secretions ▪ Trophic for CD4+ T lymphocytes

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▪ Following acute infection, remains latent in various tissues

RISK FACTORS

▪ More common in young children (six months–two years) ▪ Immunosuppressed ▫ Bone marrow/organ transplant ▫ Reactivation of latent virus

COMPLICATIONS

▪ Afebrile seizures ▪ Associated with chronic fatigue syndrome, multiple sclerosis, systemic lupus erythematosus

Chapter 79 Herpesviruses

SIGNS & SYMPTOMS ▪ 3–5 days of high fever; peak in early evening ▪ Exanthem; morbilliform rash appears with defervescence; 3–5mm pink/red macules, papules along trunk, extremities ▪ Diarrhea, tympanic membrane inflammation, upper respiratory symptoms ▪ Nagayama’s spots: enanthem of red papules on soft palate, uvula ▪ Rare ▫ Seizures, periorbital oedema, bulging anterior fontanelle, cervical/occipital/ postauricular lymphadenopathy

TREATMENT ▪ Usually self-limiting

MEDICATIONS

▪ Immunocompromised ▫ Antiviral compounds (e.g. acyclovir, ganciclovir, cidofovir, foscarnet) ▪ Oral hydration, antipyretics (e.g. paracetamol, ibuprofen) ▪ Avoid aspirin; may lead to Reye’s syndrome

DIAGNOSIS LAB RESULTS

▪ Complete blood count ▫ ↓ white blood cells ▪ Detection of HHV-6B/HHV-7 ▫ Viral culture, specific IgG detection

Figure 79.5 A child with roseola infantum, also known as sixth disease. The most common causative agent is human herpes virus six.

HUMAN HERPESVIRUS 8 (KAPOSI'S SARCOMA) osms.it/human-herpesvirus-8 PATHOLOGY & CAUSES ▪ Causes Kaposi’s sarcoma ▫ Low-grade vasoformative neoplasm associated with human herpesvirus-8 (HHV-8) infection/Kaposi’s sarcoma herpesvirus (KSHV) infection

▪ Lesions on mucocutaneous areas; may involve lymph nodes, viscera ▪ Skin lesions ▫ Patch → plaque → ulcerating tumor nodules ▪ Morphology ▫ spindle-shape, vasoformative cells with vascular proliferation, inflammatory cells

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▪ Spontaneous regression may occur after HAART/immunosuppressive treatment

TYPES

▪ Epidemic AIDS-associated Kaposi’s sarcoma ▫ HIV-positive individuals ▪ Classic sporadic Kaposi’s sarcoma ▫ More common in individuals who are male, older, with Mediterranean/Jewish background ▪ Iatrogenic, transplant-associated Kaposi’s sarcoma ▫ Solid organ transplant individuals ▪ African endemic Kaposi’s sarcoma ▫ More common in central Africa, unrelated to HIV

RISK FACTORS

▪ More common in individuals who are biologically male, > 50 years ▪ Immunosuppression, HIV (co-infection synergistic → aggressive, widespread); drug abuse; immunosuppression therapy

COMPLICATIONS

▪ Secondary skin lesion infection

SIGNS & SYMPTOMS ▪ Skin lesions ▫ Multifocal; asymmetrically distributed; size, colour variation; non-pruritic; papular; nodular; plaque-, bullous-like; indurated; hyperkeratotic ▪ Oral lesions ▫ Hard palate, gingiva, dorsum of tongue ▫ Macules, papules, nodules, exophytic masses ▪ Lymphadenopathy, lymphoedema ▪ Fever, weight loss, night sweats

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Figure 79.6 The skin of an individual with Kaposi’s sarcoma.

DIAGNOSIS DIAGNOSTIC IMAGING Chest X-ray ▪ Nodular/interstitial/alveolar infiltrates; hilar/ mediastinal lymphadenopathy; nodules

LAB RESULTS

▪ HIV test ▪ Positive in AIDS-associated Kaposi’s sarcoma ▪ Fecal occult blood ▫ Positive may indicate intestinal lesions

OTHER DIAGNOSTICS

▪ Lesion, lymph node biopsy of vascular lesion

TREATMENT MEDICATIONS

▪ Delay disease progression ▫ HAART; in HIV infected individuals, HIV suppression may shrink Kaposi’s sarcoma lesions; systemic chemotherapy ▪ Cosmetic ▫ Topical retinoids; intralesional vinblastine

Chapter 79 Herpesviruses

SURGERY

▪ Cosmetic ▫ Surgical excision; cryotherapy; laser therapy (external beam radiation)

Figure 79.7 The histological appearance of a Kaposi sarcoma. The tumor is composed of spindle cells and numerous branching vascular spaces. The occasional spindle cell contains hyaline globules.

VARICELLA ZOSTER VIRUS osms.it/varicella-zoster-virus PATHOLOGY & CAUSES ▪ Double-stranded, linear DNA virus ▫ Causes chickenpox, shingles ▫ Chickenpox: generally benign, selflimited disease in immunocompetent children ▫ Shingles: painful skin rash, can occur in individuals who have recovered from primary VZV infection Primary infection (chickenpox) ▪ Transmission: airborne spread through aerosolized droplets, direct lesion contact ▪ VZV enters respiratory system → lymph node spread → targets skin, mucous membranes → small blood vessel vasculitis → epithelial cell degeneration → fluid-filled vesicles ▫ Incubation period: 14 days ▫ Most infectious: 1–2 days before rash; infectious 3–4 days, until lesions crusted ▫ After symptoms resolve, VZV dormant in nervous system; latent in trigeminal, dorsal root ganglia

Figure 79.8 A child with chickenpox.

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Secondary infection (shingles) ▪ Occurs when dormant VZV reactivates ▫ Reactivation in dorsal root, cranial nerve ganglia → travels down axons → local skin inflammation innervated by ganglion ▫ Prodromal 2–4 day tingling/localized pain before rash onset

RISK FACTORS Chickenpox ▪ More common in children ▫ 1–9 years old (highest risk) ▪ Non-immunized status ▪ Immunocompromised status Shingles ▪ Primary varicella infection history ▪ More common in adults ▫ > 50 years old (highest risk) ▪ Immunocompromised status ▪ Stress

SIGNS & SYMPTOMS Chickenpox ▪ Fever, headache, malaise, sore throat, tachycardia ▪ Rash characteristics ▫ Generalized pruritic, vesicular rash ▫ “Dew drop on rose petal” appearance ▫ Formation: macules → vesicles → rupture → scab ▫ Vesicles on mucous membranes (e.g. nasopharynx, conjunctiva, mouth, vulva) Shingles ▪ Erythematous, maculopapular lesions evolve into painful vesicular rash ▫ Rash follows dermatomal distribution of cranial nerve/dorsal root ganglion ▫ Thoracic, lumbar dermatomes most commonly affected

COMPLICATIONS Chickenpox ▪ Secondary bacterial infection, cutaneous scarring, encephalopathy, varicella pneumonitis/pneumonia ▪ Central nervous system (CNS) complications ▫ Meningitis, encephalitis, intracranial vasculitis ▪ Congenital varicella syndrome ▫ Limb hypoplasia, paresis, microcephaly, ophthalmic lesions Shingles ▪ Ramsay Hunt syndrome ▫ VZV of geniculate ganglion affects facial nerve; hearing loss, facial weakness ▪ Postherpetic neuralgia, superinfection of skin lesions, encephalitis, Mollaret’s meningitis, zoster multiplex/sine herpete, stroke, myelitis ▪ Herpes zoster ophthalmicus (sightthreatening)

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Figure 79.9 Herpes zoster, or shingles, affecting the ophthalmic branch of the trigeminal nerve.

Chapter 79 Herpesviruses

TREATMENT MEDICATIONS Chickenpox ▪ Low risk: usually self-limiting ▪ Moderate risk: oral antiviral therapy ▪ High risk: intravenous antiviral therapy; zoster-immune globulin (ZIG) Figure 79.10 Herpes zoster in a dermatomal distribution on the chest.

DIAGNOSIS LAB RESULTS

▪ Microbe identification ▫ PCR: VZV DNA ▫ Viral culture: positive VZV ▫ DFA: VZV antigen

Shingles ▪ Oral/intravenous antiviral therapy ▪ Analgesics ▫ E.g. paracetamol, ibuprofen; topical; opioid ▪ Calamine lotion ▪ Varicella-zoster immune globulin

OTHER INTERVENTIONS

▪ Prevention ▫ Live attenuated VZV vaccine

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NOTES

LEISHMANIA MICROBE OVERVIEW ▪ Flagellated, parasitic protozoan ▪ Contains kinetoplast (form of mitochondrial DNA) ▪ Hosts: humans, canids, rodents, hyraxes Classification ▪ “Old World” ▫ Usually found in Africa, Asia, Middle East, India ▫ Includes Leishmania infantum, L. donovani, L. tropica, L. aethiopica, L. major ▪ “New World” ▫ Usually found in Central, South America; Mexico ▫ Includes L. braziliensis, L. mexicana, L.

infantum (chagasi), L. amazonensis, L. panamensis, L. guyanensis Life stages ▪ Amastigote ▫ Oval; 3–6µm ▫ Intracellular, nonmotile form (no external flagella) ▫ Found in human circulatory system in mononuclear phagocytes ▪ Promastigote ▫ Spindle-shaped; 15–30µm ▫ Extracellular, motile form (long external flagellum) ▫ Found in alimentary tract of sandflies

LEISHMANIA osms.it/leishmania PATHOLOGY & CAUSES ▪ Causes disease leishmaniasis ▪ Spread by female sandflies of genus Lutzomyia/Phlebotomus ▪ Human leishmaniasis characterized by ulcers (e.g. skin, oral, nasal mucosa), systemic illness ▪ Lipophosphoglycan layer helps it survive immune system

TYPES Cutaneous leishmaniasis (CL) ▪ Most common ▪ Usually caused by L. major, L. tropica, L.

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aethiopica Mucocutaneous leishmaniasis (ML) ▪ Causes mucosal, skin ulcers ▪ Usually caused by L. braziliensis Visceral leishmaniasis (VL) ▪ AKA kala-azar ▪ Most severe, systemic involvement ▪ Usually caused by L. donovani, L. infantum ▪ If recurs post-treatment: post kala-azar leishmaniasis ▪ Resists host’s complement system, prevents natural killer cells ▪ Infected macrophages spread infection ▫ Spleen → splenomegaly ▫ Liver → Kupffer cells with increased size

Chapter 80 Leishmania → liver dysfunction ▫ Bone marrow → hyperplastic → ↓ hematopoiesis → pancytopenia ▫ Lymph nodes → lymphadenopathy

RISK FACTORS

▫ Poverty, malnutrition, poor hygiene; deforestation, urbanization

SIGNS & SYMPTOMS CL ▪ Skin ulcers resembling leprosy lesions ML ▪ Ulcers on oropharyngeal, nose mucosa ▪ Midfacial destruction: nose cartilage/septal granulation, tear; ulcers on palate, uvula, lips ▪ Hoarse voice, gingivitis, periodontitis ▪ Genital mucosal (severe cases) VL ▪ Fever, weight loss, hepatosplenomegaly, pancytopenia, hypergammaglobulinemia, abdominal tenderness

TREATMENT MEDICATIONS CL ▪ Topical paromomycin, miltefosine, pentamidine isethionate, fluconazole, ketoconazole ML ▪ Liposomal amphotericin B, miltefosine, pentamidine VL ▪ Liposomal amphotericin B, miltefosine

OTHER INTERVENTIONS Prevention ▪ Nets treated with insecticide while sleeping; over doors, windows ▪ Insect repellents, insecticide-impregnated dog collars ▪ Treat infected dogs

DIAGNOSIS LAB RESULTS

▪ Enzyme-linked immunosorbent assay (ELISA) ▪ Antigen-coated dipsticks ▪ Direct agglutination test

Light microscope ▪ Amastigotes/Leishman-Donovan body visualization: blood, aspirates from marrow, spleen, lymph nodes, skin lesions ▫ Blood, spleen monocytes ▫ Circulating neutrophils, aspirated tissue macrophages

Figure 80.1 A leishmaniasis ulcer on the leg.

Polymerase chain reaction (PCR) ▪ Detects Leishmania kinetoplast DNA (most sensitive, specific)

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NOTES

MYCOPLASMA MICROBE OVERVIEW ▪ Smallest free living organisms ▪ Prokaryotic with absence of cell wall, presence of flexible cell membrane containing cholesterol ▫ Pleomorphic ▫ Not visible on Gram stain ▫ Resistant to beta lactam, glycopeptide antibiotics

▪ Limited metabolic activity → not culturable on standard culture media, require specialized medium (e.g. Eaton’s agar) with sterols, nutrients provided by natural animal protein (e.g. blood serum) ▪ Can grow under aerobic, anaerobic conditions

MYCOPLASMA PNEUMONIAE osms.it/mycoplasma-pneumoniae PATHOLOGY & CAUSES ▪ Species of mycoplasma; primarily affects respiratory tract; usually causes upper respiratory tract infections; can also cause atypical pneumonia ▪ Transmitted through respiratory droplets after close contact with infected individual → attaches to respiratory epithelium with P1 surface protein → hydrogen peroxide, superoxide radicals synthesized by mycoplasma interact with endogenous toxic molecules synthesized by host cells → oxidative stress in respiratory epithelial cells ▪ Macrophages migrate to site of infection → activation and phagocytosis → initiate inflammatory response → T, B lymphocyte proliferation → antibody production, release of inflammatory cytokines → control infection/initiate immune-mediated lung injury ▪ Extrapulmonary disease (rare) ▫ Due to immune mediated injury/cross reactive antibody mechanism/direct invasion

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▪ Central nervous system (CNS), joints, skin, blood, heart, liver, pancreas affected ▫ CNS is the most common extrapulmonary site; usually encephalitis ▪ Can develop cold agglutinin response (60%) ▫ Autoimmune hemolytic anemia ▫ Coombs positive ▫ Cold (active below 37°C/98.6°F) IgM antibodies against erythrocyte surface antigen due to cross reaction of antigen with mycoplasma antigens → can agglutinate/lyse erythrocytes

RISK FACTORS

▪ Common in children, young adults ▪ Immunocompromised status, smoking, close community living (e.g. nursing homes, dorms)

COMPLICATIONS

▪ Asthma exacerbations ▪ Respiratory failure ▪ CNS involvement

Chapter 81 Mycoplasma ▫ Encephalitis with high mortality rate ▪ Heart involvement ▫ Rhythm disorders, heart failure

SIGNS & SYMPTOMS ▪ Can be asymptomatic ▪ Gradual onset ▫ General fatigue, myalgias, headache, low grade fever, sore throat, cough (worsening, frequent, non-productive), chills ▪ Less common ▫ Sinus/ear pain, wheezing ▪ Chest auscultation ▫ Scattered rales, wheezes, rhonchi, crackles ▪ Sinus tenderness ▪ Erythema of tympanic membrane ▪ Pharyngeal erythema ▪ Pulse-temperature dissociation: normal pulse despite fever indicative of atypical pneumonia

DIAGNOSIS LAB RESULTS

▪ Molecular testing with polymerase chain reaction (PCR); most accurate ▪ Serological tests ▫ ≥ four-fold rise in IgM antibodies titers of acute, convalescent sera 2–3 weeks apart using enzyme immunoassay ▫ High titer of IgM antibodies ▫ Cold agglutinins titer ▪ Isolation with culture ▫ Limited use due to slow growth (2–3 weeks), need for specialized media

DIAGNOSTIC IMAGING Chest X-ray/CT scan/high resolution CT scan ▪ Diffuse reticulonodular pattern indicative of interstitial pneumonia ▪ Areas of airspace consolidation (esp. lower lobes) ▪ Thickening of bronchovascular bundle

OTHER DIAGNOSTICS

▪ Histopathology ▫ Inflammation in trachea, bronchioles, peribronchial tissues ▫ Airspaces filled with purulent exudate with polymorphonuclear cells ▪ Physical examination ▫ Vague symptoms (e.g. fatigue) indicative of atypical/“walking” pneumonia

TREATMENT ▪ Most cases mild, self-limited

MEDICATIONS

▪ Atypical pneumonia ▫ Macrolides (e.g, erythromycin, azithromycin); tetracyclines (e.g. doxycycline); fluoroquinolones (e.g., levofloxacin, moxifloxacin)

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NOTES

NOTES

NEMATODES (ROUNDWORMS) GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ AKA roundworms ▫ Microfilariae: immature worms ▫ Microfilariae: mature worms ▪ Parasites usually enter body cutaneously ▫ Produce gastrointestinal (GI), occasionally cutaneous symptoms, disease

COMPLICATIONS

▪ Loffler syndrome ▫ Transient pulmonary disease during select nematode development (Necator Americanus, Strongyloides, Ascaris Lumbricoides, Toxocara, Ancylostoma duodenale) ▫ Symptoms: irritating, nonproductive cough, substernal burning discomfort, dyspnea, wheezing, fever, blood-tinged sputum production

SIGNS & SYMPTOMS ▪ GI/localized tissue symptoms, organismdependent

DIAGNOSIS LAB RESULTS

▪ Eosinophilia ▪ Gammaglobulinemia abnormalities (↑/↓ depending on organism)

Serology ▪ IgG levels ▪ Enzyme linked immunosorbent assays (ELISA), western blot

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TREATMENT MEDICATIONS

▪ Antihelminthic therapy ▫ Nematode location-dependent

Intestinal nematodes ▪ Mebendazole/albendazole ▫ Bind tubulin colchicine-sensitive sites → inhibit microtubule assembly → inhibited glucose uptake (without human effect) → organism death Systemic nematodes ▪ Diethylcarbamazine (DEC) ▫ Piperazine derivative (uncertain mechanism of action) ▪ Ivermectin ▫ Synthetic lactone → negative-charged ion influx via glutamate-sensitive chloride channels → hyperpolarizes cells → helminth cell death ▫ Not macrofilaricidal, pregnancy contraindication

Chapter 82 Nematodes (Roundworms)

ANCYLOSTOMA DUODENALE & NECATOR AMERICANUS osms.it/ancylostoma-duodenale osms.it/necator-americanus PATHOLOGY & CAUSES ▪ Infectious hookworm species Adult morphology ▪ Ancylostoma duodenale ▫ Two ventral plates on buccal capsule’s anterior margin; two large teeth fused at base (male 8–11mm, female 10–13mm long) ▪ Necator americanus ▫ Two dorsal/ventral cutting plates around buccal capsule’s anterior margin, paired subdorsal/subventral teeth (male 7–9mm, female 9–11mm long) ▪ A. duodenale, Necator americanus: most common hookworm species causing helminth gastrointestinal infection ▫ Light infection (< 100 worms) ▫ Moderate infection (100–500 worms) ▫ Heavy infection (500–1000 worms) ▪ Pathophysiology ▫ Hookworm attachment, hyaluronidase release → intestinal wall degradation, capillary laceration → anticoagulant peptides, inhibits platelet function inhibitor production → bleeding facilitation → extravasated blood ingested (approx. 0.5mL daily) ▫ Moderate–heavy infections → chronic iron-deficiency anemia; protein malnutrition Infectious form ▪ Filariform larva Life cycle ▪ Infectious form maturation ▫ Female A. duodenale lays 10,000– 30,000 eggs daily

▫ Female N. americanus lays 5,000– 10,000 eggs daily ▫ Human feces egge release → soil deposition → eggs hatch (24–48 hours—favorable conditions) → rhabditiform larvae (L1) → transformation to infectious filariform larvae (L3) in 5–10 days ▪ Human stages ▫ Filariform larvae skin penetration → passage through veins to heart, lung → pulmonary alveoli penetration, ascend bronchi to pharynx → coughed up/swallowed into small intestine → maturation → intestinal wall attachment via buccal capsule ▪ Some A. duodenale larvae undergo developmental arrest in gut tissues/muscle ▫ Await more favorable environmental conditions (hypobiotic larvae) ▪ Natural life-span ▫ A. duodenale: approx. one year ▫ N. americanus: 3–5 years Transmission ▪ Contaminated soil contact → percutaneous larval penetration ▪ Oral route ▪ Transmammary route

RISK FACTORS

▪ Inadequate clean-water access ▪ Poor sanitary conditions ▪ Walking barefoot (endemic areas)

COMPLICATIONS

▪ Severe iron-deficiency anemia; protein malnutrition → impaired growth, cognitive

OSMOSIS.ORG 437

development (children); heart failure (adults) ▪ Pregnancy ▫ Low birth weight, maternal anemia, ↑ infant mortality

SIGNS & SYMPTOMS ▪ May be asymptomatic Three phases ▪ Cutaneous phase ▫ Local pruritic dermatitis (ground itch) with papular, sometimes vesicular, focal rash at larval penetration site (usually between toes) ▪ Pulmonary phase ▫ Usually asymptomatic, may involve mild cough, pharyngeal irritation, sore throat, fever ▪ Gastrointestinal phase ▫ Midepigastric pain, appetite loss, nausea, diarrhea, vomiting Heavy infection ▪ Hypoproteinemia → weight loss, anasarca, edema ▪ Anemia → fatigue, mental dullness, dyspnea, pallor ▪ Overt gastrointestinal bleeding

DIAGNOSIS DIAGNOSTIC IMAGING Abdominal X-ray ▪ Intestinal worm visualization

LAB RESULTS

▪ Acute infection ▫ Eosinophelia ▪ Chronic infection ▫ Anemia ▪ Kato–Katz method (thick smear) ▪ Polymerase chain reaction (PCR) test

Direct microscopy ▪ Stool specimen egg visualization

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▫ A. duodenale, N. americanus eggs are morphologically indistinguishable

OTHER DIAGNOSTICS

▪ History ▫ Contaminated-soil skin exposure; endemic-area travel; physical examination

TREATMENT MEDICATIONS

▪ Anthelmintic treatment

Chapter 82 Nematodes (Roundworms)

ANGIOSTRONGYLUS (EOSINOPHILIC MENINGITIS) osms.it/angiostrongylus PATHOLOGY & CAUSES ▪ Parasitic nematode ▫ Causes human GI/CNS disease ▪ Angiostrongylus cantonensis ▫ Medically important species ▫ Causes angiostrongyliasis (most common eosinophilic meningitis cause) Adult morphology ▪ Three outer protective collagen layers; contains fully-developed gastrointestinal tract, simple stomal opening Hosts ▪ Primary intermediate host: snails ▪ Paratenic hosts: fish, frogs, freshwater prawns ▫ Not needed for developmental cycle ▪ Definitive hosts: wild rodents (brown, black rat) ▪ Incidental hosts: humans Life cycle ▪ Infectious form maturation ▫ Worms lay eggs in rat pulmonary artery → spread from lung capillaries to alveoli, larvae hatch → migrate up bronchi, trachea, across epiglottis → swallowed → fecal larvae passage → soil deposition → intermediate-host ingestion ▪ Human stages ▫ Intermediate host larval ingestion (contaminated water/vegetable) → CNS tropism → migration into meningeal capillaries, brain tissue → meningoencephalitis ▪ Larvae usually fail to complete life-cycle, rarely → adult form in human host

Transmission ▪ Intermediate/paratenic host ingestion (raw/undercooked snails, fish, frogs), contaminated vegetables/water Pathophysiology ▪ Post-inoculation, A. cantonensis larvae exhibit neurotropism → meninges, deeper brain tissue invasion → neural-tissue mechanical, toxic byproducts damage; antigen release → meningoencephalitis ▪ Migration to mesenteric arterioles → arteritis, thrombosis, small infarctions ▫ May cause necrotic ulcers → peritonitis, fistula formation

COMPLICATIONS

▪ Long-term encephalitis → permanent nerve damage, intellectual disability, permanent brain damage, death

SIGNS & SYMPTOMS ▪ Incubation period: three weeks–two months ▪ Meninges invasion: meningitis picture ▫ Severe headache, photophobia, stiff neck, fatigue, fever, hyperesthesia, vomiting, paresthesias ▪ Brain parenchyma invasion: encephalitis symptoms (brain location-dependent) ▫ Cognitive impairment, slowed reactions, neuropathic pain, ascending weakness ▫ t quadriparesis, areflexia, respiratory failure, muscle atrophy, death (rare) ▪ Eye invasion: visual impairment, pain, keratitis, retinal edema

OSMOSIS.ORG 439

DIAGNOSIS

TREATMENT

LAB RESULTS

▪ Self-limiting infection (usually)

▪ Cerebrospinal fluid (CSF) ▫ Eosinophilia ▫ ↓ glucose levels (severe meningoencephalitis)

MEDICATIONS

▪ Analgesics, sedatives ▫ Treat headache, hyperesthesia ▪ Corticosteroids ▪ Antihelminthic therapy not advised ▪ Dying parasites, neurologic damage exacerbation → potential inflammatory response

OTHER DIAGNOSTICS

▪ Endemic-area travel history ▪ Physical examination ▪ Clinical presentation

OTHER INTERVENTIONS

▪ CSF drainage ▫ Reduces intracranial pressure, relieve headache

ANISAKIS osms.it/anisakis PATHOLOGY & CAUSES ▪ Zoonotic roundworm ▫ Causes human gastrointestinal, extragastrointestinal disease ▫ Causative anisakiasis agent Adult morphology ▪ Anteriorly-located mouth surrounded by projections; length (2cm/0.8in) Infectious form ▪ L3 larvae Hosts ▪ Natural hosts: marine mammals ▪ Incidental hosts: humans Life cycle ▪ Infectious form maturation ▫ Eggs hatch into larvae (seawater) → larval crustacean ingestion → fish/ squid ingest crustaceans → muscular/ subdermal larval encystation (L3

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larvae) → marine mammals ingest fish → excystation, maturation, nematode reproduction → fecal egg release ▪ Human stages ▫ Larval ingestion (infected fish) → larvae fail maturation, cannot complete lifecycle Transmission ▪ Raw/undercooked fish ingestion Pathophysiology ▪ Infected fish larvae ingestion → larvae burrow into intestinal wall, die → dead organism → inflammatory response → possible allergic reaction, abscess, mechanical obstruction ▪ If parasites pass into large intestine ▫ Eosinophilic granulomatous response → mimic appendicitis/Crohn’s disease

RISK FACTORS

▪ Raw/undercooked seafood ingestion (common in Japan)

Chapter 82 Nematodes (Roundworms)

COMPLICATIONS

▪ Small bowel obstruction ▪ Intestinal perforation ▪ Peritoneal cavity perforation (extraintestinal anisakiasis) ▪ Eosinophilic gastroenteritis/enterocolitis

SIGNS & SYMPTOMS ▪ Gastric anisakiasis ▫ Acute epigastric pain, nausea, vomiting ▪ Intestinal anisakiasis ▫ Severe abdominal pain, abdominal distension, palpable abdominal mass, intestinal obstruction, bloody diarrhea ▪ Allergic reactions ▫ Urticaria, bronchoconstriction, angioedema, anaphylactic shock

DIAGNOSIS DIAGNOSTIC IMAGING

▪ Parasite visualization ▫ Gastroscopic examination, emesis examination

LAB RESULTS ▪ ↑ serum IgE

TREATMENT SURGERY

▪ Parasite removal (endoscopically, surgically)

ASCARIS LUMBRICOIDES osms.it/ascaris-lumbricoides PATHOLOGY & CAUSES ▪ Intestinal roundworm parasite ▫ Causative ascariasis agent ▪ Adult worm size: 15–30cm/5.9–11.8in ▫ Largest intestinal nematode Life cycle ▪ Female A. lumbricoides lays 200,000 eggs daily; begins egg-laying 9–11 weeks postinfection ▪ Infectious-form maturation ▫ Eggs passed in stool → soil deposition → eggs embryonate; infectious after 2–4 weeks; can survive < ten years (favorable conditions) ▪ Human stages ▫ Egg ingestion → larvae hatch → invade intestinal mucosa → portal circulation → systemic circulation → liver → lungs → larvae mature in alveoli (10–14 days) → ascend bronchial tree, pharynx, swallowed → larvae develop into adult

form in small intestine ▪ Life-span: 10–24 months Pathophysiology ▪ Varies upon life-cycle stage ▫ Pulmonary phase (early): caused by larval migration into lungs → pneumonitis ▫ Intestinal phase: manifestations caused by adult-form presence → mechanical obstruction (degree worm-burdendependent)

RISK FACTORS

▪ Egg-contaminated food/water ingestion (especially pig/chicken liver) ▪ Infected soil (children) ▪ Feco-oral route reinfection

COMPLICATIONS

▪ Intestinal obstruction ▫ May → volvulus, ileocecal

OSMOSIS.ORG 441

▪

▪

▪ ▪

intussusception, gangrene, intestinal perforation Children ▫ Malnutrition/malabsorption, impaired growth, cognitive development Hepatobiliary involvement ▫ Biliary colic, biliary strictures, obstructive jaundice, liver abscesses Pancreatic duct obstruction → pancreatitis Aspiration pneumonia during esophageal migration to trachea

SIGNS & SYMPTOMS ▪ Often asymptomatic ▪ Pulmonary phase (Loffler syndrome): develops 4–16 days post-infection ▫ Dry cough, dyspnea, fever, wheezing, substernal discomfort, blood-tinged sputum; symptoms subside after 5–10 days ▪ Intestinal phase: develops 6–8 weeks postinfection ▫ Abdominal discomfort, anorexia, nausea, vomiting, diarrhea

Barium swallow ▪ Intestinal phase ▫ Defects in filling; if worms ingest contrast, tram-track appearance demonstrated Microscopic examination ▪ Pulmonary phase ▪ Eosinophils, Charcot–Leyden crystals in sputum ▪ Intestinal phase ▪ Eggs/adult form stool visualization (KatoKatz/FLOTAC method)

LAB RESULTS

▪ Pulmonary phase ▫ Peripheral eosinophilia

OTHER DIAGNOSTICS

▪ Exposure/endemic-area travel history

DIAGNOSIS DIAGNOSTIC IMAGING Chest X-ray ▪ Pulmonary phase ▫ May show migratory bilateral oval infiltrates, range from several mm– several cm ▪ Intestinal phase ▫ Adult Ascaris worm visualization, intestinal obstruction CT scan ▪ Pulmonary phase ▫ Multiple nodules, “ground-glass” attenuation ▪ Intestinal phase ▫ “Bull’s eye” appearance (worm crosssection)

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Figure 82.1 A barium study demonstrating ascariais. There are numerous worms in the distal part of the duodenum and the ileum.

Chapter 82 Nematodes (Roundworms)

TREATMENT MEDICATIONS

▪ Anthelmintic treatment ▫ Only effective in intestinal phase ▫ Pregnancy: pyrantel pamoate

SURGERY

▪ Complete intestinal obstruction, volvulus, intussusception, appendicitis, perforation cases

OTHER INTERVENTIONS

▪ Endoscopic retrograde cholangiopancreatography (ERCP) ▫ Hepatobiliary-involvement cases

Figure 82.2 Ascaris worms emerging from the two free ends of the small intestine during an operation to remove a length of ischemic bowel.

Figure 82.3 Small bowel packed with Ascaris lumbricoides worms. The bowel is distended so greatly that the visceral peritoneum on the antimesenteric border is split.

OSMOSIS.ORG 443

ENTEROBIUS VERMICULARIS (PINWORM) osms.it/enterobius-vermicularis PATHOLOGY & CAUSES ▪ Small roundworm ▫ May infect human colon, rectum ▫ Causative enterobiasis agent Life cycle ▪ Female E. vermicularis lays > 10,000 eggs daily ▪ Perianal fold egg deposition → autoinfection by scratching; contaminated hand, mouth contact → eggs hatch into larvae (small intestine) → adult-form maturation (cecum, appendix) ▪ Life-span: 2–3 months Transmission ▪ Scratching perianal area (autoinfection) → hand–mouth contact ▪ Contaminated hands (person–person) ▪ Contaminated surface contact ▪ Eggs may become airborne, inhaled

▪ High worm burden → abdominal pain, nausea, vomiting

DIAGNOSIS OTHER DIAGNOSTICS

▪ Pinworm paddle/Scotch tape test ▫ Adhesive clear plastic paddle pressed against perianal areas → placed onto glass slide; reveals eggs upon microscopic examination

TREATMENT MEDICATIONS

▪ Anthelmintic treatment

RISK FACTORS

▪ Crowded living conditions ▪ Children 5–10 years old

COMPLICATIONS

▪ Persistent perianal-area scratching, skin tearing → bacterial dermatitis, folliculitis ▪ Adult worms migrate to extraintestinal sites; cause vulvovaginitis, salpingitis, oophoritis, cervical granuloma, peritoneal inflammation

SIGNS & SYMPTOMS ▪ Mostly asymptomatic ▪ Perianal itching (pruritus ani) occurs nocturnally

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Figure 82.4 Pinworm found incidentally in an appendectomy specimen.

Chapter 82 Nematodes (Roundworms)

GUINEA WORM (DRACUNCULIASIS) osms.it/guinea-worm PATHOLOGY & CAUSES ▪ Water-borne nematode disease ▫ Characterization: rash, GI illness with subcutaneous worm visualization Life cycle/transmission ▪ Infected water → human copepod ingestion → GI, subcutaneous migration, sexual reproduction → pruritus, percutaneous larval eruption upon water-immersion → copepod larval consumption → two molting processes → pathogenic larvae in copepods Pathogenesis ▪ GI symptoms ▫ Ingested copepod death in GI system → larval migration into stomach, intestinal wall → entry into abdominal, retroperitoneal space ▪ Cutaneous symptoms ▫ Larval sexual reproduction → female survival, skin migration → limb waterimmersion → eruption

RISK FACTORS

▪ Rural Eastern-Africa residence/travel

▪ Cutaneous symptoms ▫ Painful papule (2–7cm/0.8–2.8in) → enlarges, ↑ pain → worm emerges through ulceration

DIAGNOSIS DIAGNOSTIC IMAGING X-ray ▪ Calcified dead worm in subcutaneous tissue ▫ If worm does not emerge through skin

OTHER DIAGNOSTICS

▪ Endemic-area travel/residence history ▪ Physical examination ▫ Systemic → cutaneous symptom development

TREATMENT OTHER INTERVENTIONS

▪ Worm extraction; careful extraction protocol ▫ Multiple days (centimeters at a time); keeps worm intact, prevents local pruritic, edematous reaction

COMPLICATIONS

▪ Ectopic site migration → abscess development ▫ Lung, eye, pericardium, spinal cord ▪ Broken worm → intensely painful, edematous local, subcutaneous reaction

SIGNS & SYMPTOMS ▪ Systemic symptoms initially ▫ Fever, urticaria, pruritus, dizziness, nausea/vomiting, diarrhea

Figure 82.5 A match stick being used to extract a guinea worm from an ulcer on the leg.

OSMOSIS.ORG 445

Prevention ▪ Community surveillance, transmission methods education ▪ Safe water precautions ▫ Nylon filters for water filtration, insecticides in drinking water courses, water source covering (prevents infected body-part immersion) ▪ Occlusive dressings applied to papules

LOA LOA (EYE WORM) osms.it/loa-loa PATHOLOGY & CAUSES ▪ Vector-borne filarial nematode endemic in Africa ▫ Characterization: transient swelling episodes, subconjunctival adult worm migration ▪ AKA African eye worm ▪ Allergic reaction ▪ Subconjunctival infiltration ▫ Associated with conjunctivitis, eyelid swelling Life cycle/transmission ▪ Vector ▫ Chrysops (biting deer fly; AKA tabanid fly) ▫ Breed in rainforest canopies, lay eggs in muddy swamps; bite humans during daytime ▪ Tabanid fly human bite → filarial larvae transmission → three month maturation process → microfilarial production → bloodstream release ( ↑ release during daytime) → tabanid blood meal (infected individual) → filarial maturation in tabanid fly

RISK FACTORS

▪ Endemic-area residence/travel ▫ Eastern, Central Africa

446 OSMOSIS.ORG

COMPLICATIONS

▪ Onchocerciasis co-infection ▪ Encephalitis (coincident headache, insomnia, coma may result) ▪ Cardiomyopathy (endomyocardial fibrosis) ▪ Nephropathy ▪ Arthritis ▪ Lymphadenitis ▪ Calabar swelling → entrapment neuropathy

SIGNS & SYMPTOMS Allergic reactions ▪ Calabar swellings ▫ 5–20cm/2–7.9in non-erythematous lesions ▫ Transient, local subcutaneous swelling; face, extremities most common; localized pain, itching prior to swelling episodes ▫ Urticaria, pruritus, asthma Subconjunctival eye infection ▪ Commonly non-painful infiltration of eye subconjunctival area; conjunctivitis may occur (with eyelid swelling) ▪ Worm may be visible

Chapter 82 Nematodes (Roundworms)

DIAGNOSIS LAB RESULTS ▪ ▪ ▪ ▪

Hypergammaglobulinemia ↑ IgE level Worm’s presence (blood smear) Serology ▫ IgG antibodies against L. loa antigens

OTHER DIAGNOSTICS

▪ History, physical examination ▫ Worm detection in subcutaneous tissue, conjunctiva

▫ Onchocerciasis co-infection contraindicated (DEC provokes severe inflammatory skin, eye response; Mazzotti reaction) ▫ Eradication may require multiple treatment rounds ▪ Albendazole ▫ Sterilizes mature worms without microfilarial activity ▪ Antihistamine/corticosteroids ▫ Limits post-treatment immune reactions (e.g. Calabar swelling)

SURGERY

▪ Large worm removal

TREATMENT MEDICATIONS

▪ Diethylcarbamazine (DEC) ▫ Active against L. loa microfilariae, microfilariae (adult worms)

OTHER INTERVENTIONS Prevention ▪ Weekly DEC prophylaxis ▪ Only considered for long-term endemicarea exposure

ONCHOCERCA VOLVULUS (RIVER BLINDNESS) osms.it/onchocerca-volvulus PATHOLOGY & CAUSES ▪ Filarial nematode transmitted by blackflies ▪ Leading preventable blindness cause in sub-Saharan Africa Life cycle/transmission ▪ Simulium blackfly human bite → larvae skin deposited → adult parasite maturation (microfilariae) → subcutaneous/deeper intramuscular tissue migration → fibrous capsule/nodule development → reproduction → microfilarial (immature worm) production, subcutaneous tissue migration → human blackfly bite → microfilarial development into infective larvae (in blackfly)

Ocular onchocerciasis ▪ Common manifestation: West African savanna ▪ Commonly affects anterior eye chamber ▫ Iridocyclitis, glaucoma, uveitis ▪ Posterior chamber may also be affected ▫ Onchochorioretinits, optic atrophy ▪ Ocular involvement degree correlates with symbiotic Wolbachia bacteria quantity Onchocercal skin disease ▪ AKA Leopard/lizard/elephant skin (especially when depigmentation present); common manifestation in African forest areas ▪ Classified by chronicity ▫ Acute/chronic papular onchodermatitis

OSMOSIS.ORG 447

▪ Lichenified onchodermatitis (AKA sowda/ black/dark); epidermal atrophy, elastic fiber breakdown may occur

PATHOLOGY Subcutaneous involvement ▪ Onchocercoma ▪ Dermal O. volvulus → inflammatory response (prostaglandin E2, transforming growth factor-beta-mediated) → nodule formation (onchocercoma); nodules predominate in bony prominence areas, peak inflammatory response occurs upon subcutaneous male O. volvulus death Ocular involvement ▪ Anterior chamber disease ▫ O. volvulus infiltration → immune response, O. volvulus death → Wolbachia release → innate immune response → corneal damage ▪ Posterior chamber disease ▫ O. volvulus infiltration → immune response → cross-reactivity of O. volvulus antigen with retinal pigment epithelial protein → persistent immunologic response → inflammatory limbus, iris, choroid damage

RISK FACTORS

▪ West Africa, Eastern South America travel/ residence ▫ Especially savanna, forest

SIGNS & SYMPTOMS Cutaneous ▪ Pruritus ▪ Nodule development (lymphadenopathy may develop, persist depending on infection duration) ▪ Focal darkening/depigmentation ▪ Epidermal atrophy, hyperpigmentation, hyperkeratosis may be present Ocular ▪ Punctate keratitis → fluffy corneal opacities → eosinophilic infiltrate → sclerosing keratitis → corneal opacification;

448 OSMOSIS.ORG

progressive (eventually irreversible) vision deficit

DIAGNOSIS DIAGNOSTIC IMAGING Ultrasound ▪ Deep ochoceroma detection

LAB RESULTS

▪ Eosinophilia ▪ Hypergammaglobulinemia ▪ PCR assay ▫ O. volvulus

OTHER DIAGNOSTICS

▪ Rheumatologic/dermatologic onchocercoma evaluation

Skin snips ▪ Corneoscleral punch biopsy (ocular involvement)/ disposable razor blade for epidermal sample (cutaneous disease) ▪ 2+ snips taken in areas likely to harbor highest microfilariae concentration ▪ Positive only within 9–15 months postinfection (mature microfilariae produce microfilariae) Patch test ▪ Topical DEC application → local skin reaction assessment ▪ Akin to Mazzotti reaction Fundoscopic and corneal evaluation ▪ Slit-lamp examination reveals wriggling microfilariae ▪ Individuals sit forward for two minutes prior to examination (↑ microfilarial visualization likelihood on chamber examination)

TREATMENT MEDICATIONS

▪ Ivermectin, doxycycline ▫ Ivermectin: kills immature worms only, adult worm repopulate months after treatment

Chapter 82 Nematodes (Roundworms) ▫ Doxycycline: kills Wolbachia (symbiotic bacteria needed for O. volvulus fertility) for 24 months; block reproduction

OTHER INTERVENTIONS Prevention ▪ Protective clothing, insect repellent (especially when blackflies most active— morning/evening)

STRONGYLOIDES STERCORALIS osms.it/strongyloides-stercoralis PATHOLOGY & CAUSES ▪ Filarial disease endemic in tropical areas with characteristic pulmonary infection route, complications include septic shock in immunocompromised individuals ▪ Mild GI, cutaneous, pulmonary inflammation, disease ▫ Dermatitis, urticaria, duodenitis, enterocolitis, pneumonitis ▫ May persist for years Life cycle ▪ Larvae live in fecally-contaminated ground soil → enter human host through broken skin → hematologic spread → pulmonary alveolar sac infiltration, penetration → ascend tracheobronchial tree → swallowed → larval maturation in duodenum, jejunum → larval reproduction, fecal excretion ▪ Autoinfection (single-host life-cycle completion) may occur via larval perianal skin entry

PATHOLOGY

▪ Larvae contaminate skin through breakage → lung migration → inflammation infiltrate → intestinal wall migration → maturation, replication → larval intestinal mucosa penetration → autoinfection

RISK FACTORS

▪ Constipation, diverticula, steroid-use, ↓ bowel motility → ↑ autoinfection likelihood ▪ Hypogammaglobulinemia ▪ Anti-tumor necrosis factor receptor therapy ▪ Organ transplantation, immune suppression

COMPLICATIONS

▪ Hyperinfection (uncontrolled autoinfection → high worm-burden disease) ▫ Immunocompromised individuals ▫ Hematologic parasite spread includes CNS, heart, liver, lungs, endocrine glands ▫ May manifest as septic shock

SIGNS & SYMPTOMS ▪ Immunocompetent individuals ▫ Bloating, diarrhea ▪ Cutaneous ▫ Edema, petechiae, serpiginous/urticarial tracking ▪ Gastrointestinal ▫ Anorexia, nausea, vomiting, epigastric pain (duodenal ulceration cases), malabsorption (chronic enterocolitis) ▪ Pulmonary ▫ Dry cough, throat irritation, dyspnea, wheezing, hemoptysis

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DIAGNOSIS DIAGNOSTIC IMAGING Chest X-ray ▪ Pulmonary disease ▫ Foci of hemorrhage, pneumonitis, pulmonary edema

LAB RESULTS Organism identification ▪ Stool examination ▫ Low sensitivity due to intermittent larval release ▫ Repeat testing ↑ finding’s reliability ▪ ELISA ▫ Immunocompetent individuals

TREATMENT MEDICATIONS

▪ Ivermectin ▪ Albendazole ▫ May combine with ivermectin in hyperinfection/disseminated disease states

OTHER INTERVENTIONS Prevention ▪ Proper shoe wearing ▫ Prevents broken-skin exposure ▪ Serologic evaluation ▫ Solid organ transplant donors

OTHER DIAGNOSTICS

▪ Endemic-area travel history

Endoscopy ▪ Histopathological (biopsy-driven) diagnosis ▫ Stomach, duodenum, colon evaluation of mucosa appearance

Figure 82.6 A duodenal biopsy containing an entire Strongyloides worm, likely an adult female.

450 OSMOSIS.ORG

Chapter 82 Nematodes (Roundworms)

TOXOCARA CANIS (VISCERAL LARVA MIGRANS) osms.it/toxocara-canis PATHOLOGY & CAUSES ▪ Human roundworm disease: dog, cat, pig vectors characterized by cutaneous/ocular disease ▫ Dogs: toxocara canis ▫ Cats: toxocara cati ▫ Pigs: Ascaris suum Life cycle/transmission ▪ Definitive hosts: cats, dogs, pigs ▪ Accidental hosts: humans ▪ Egg-laden stool → soil contamination → definitive host ingestion → GI tract reproduction → larval gut wall penetration → pulmonary migration, penetration → ascend tracheobronchial tree → swallowed → small intestine worm maturation → reproduction, egg excretion in stool ▪ Paratenic host: non-canine, small mammals; egg ingestion → larval gut wall penetration → tissue migration → cyst formation → human paratenic host ingestion → infection Disease ▪ Ocular involvement: inflammatory granuloma of posterior pole, diffuse endophthalmitis, solitary peripheral retinal granuloma

RISK FACTORS

▪ Raw liver/undercooked meat ingestion (e.g. rabbit, chicken, cattle, pork) ▪ Children ▫ Playground, sandbox use

COMPLICATIONS ▪ Hepatitis ▪ Pneumonitis

▪ Cardiac ▫ Pericarditis, myocarditis ▪ CNS involvement ▫ Myelitis, meningoencephalitis, seizure, cerebral vasculitis ▪ Ocular ▫ Retinal detachment, blindness

SIGNS & SYMPTOMS ▪ Visceral larva migrans ▫ Pruritic urticaria, fever, anorexia, malaise, irritability ▪ Ocular larva migrans ▫ Unilateral vision impairment, uveitis, papillitis, endophthalmitis ▪ Hepatomegaly ▪ Respiratory distress

DIAGNOSIS DIAGNOSTIC IMAGING Chest X-ray ▪ Bilateral peribronchial infiltrates CT scan ▪ Chest: multifocal subpleural nodules, “ground-glass” opacities, ill-defined margins ▪ Abdomen: multiple ill-defined lesions in liver parenchyma Ultrasound ▪ Abdomen: may also identify lesions

LAB RESULTS

▪ Leukocytosis ▪ Hypogammaglobulinemia (↑ IgG, IgE) ▪ ELISA

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▫ IgG antibodies against Toxocara excretory/secretory antigens ▫ Does not differentiate Toxocara canis from cati

OTHER DIAGNOSTICS

▪ Endemic-area travel history ▪ Physical examination

TREATMENT MEDICATIONS

▪ Moderate → severe symptoms ▫ Albendazole

▪ Severe inflammatory disease (myocarditis, pneumonitis, CNS involvement) ▫ Prednisone ▪ Ocular larva migrans ▫ Corticosteroids, albendazole

OTHER INTERVENTIONS Prevention ▪ Hand hygiene practice ▪ Pet feces disposal, deworming ▪ Undercooked meat (especially liver) consumption risk education

TRICHINELLA SPIRALIS osms.it/trichinella-spiralis PATHOLOGY & CAUSES

→ female worm release larvae → striated muscle encystation

▪ Roundworm infection (prevalent worldwide) ▫ Raw/undercooked meat with encysted organism consumption ▪ Trichinella: nine species, twelve genotypes ▫ Animal intermediate host-specific ▫ T. spiralis: most common worldwide; variety of carnivorous, omnivorous animals

Disease ▪ Severity correlates with multiple factors ▫ Number of ingested larvae directly correlates with ingested meat cooking temperature ▫ Trichinella species ▫ Incubation period (shorter correlates with ↑ disease severity) ▪ Gastrointestinal involvement ▫ Maturing larvae burrow in intestinal mucosa ▫ Diarrheal illness, nausea, vomiting ▪ Muscular involvement ▫ Adult worm dissemination into skeletal muscle ▫ Symptom resolution occurs with complete worm encystment ▫ Mild subclinical fatigue, post-exercise weakness persists months–years

Life cycle/transmission ▪ Domestic cycle: involves pigs, rodents ▪ Sylvatic cycle: broad animal range ▫ Bear, moose, wild boar most common human infection sources ▪ Trichinella larvae/mature worm ingestion by intermediate host → GI tract maturation → larvae release, migrate from female worms to striated muscles → encyst → intermediate host consumption (inadequate cooking temperature) → larval ingestion → larvae release in stomach (upon gastric acid, pepsin exposure) → small bowel mucosa invasion → adult worm maturation

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RISK FACTORS

▪ Undercooked/raw meat consumption

Chapter 82 Nematodes (Roundworms)

COMPLICATIONS

▪ Myositis, myocarditis ▫ Eosinophil-enriched inflammatory response → life-threatening arrhythmia development ▪ Encephalitis, pneumonia ▫ Direct larval parenchyma infiltration, respiratory muscle disease

SIGNS & SYMPTOMS ▪ Gastrointestinal ▫ Nausea/vomiting, abdominal pain, diarrhea ▪ Muscular ▫ Most severe symptoms ▫ Pain (activity-dependent; ↑ muscle use/ strain correlates with ↑ ↑ pain) ▫ Tenderness, swelling, weakness ▪ Other ▫ High fever, periorbital edema, chemosis, visual disturbance ▫ Retinal hemorrhage on fundoscopic examination

DIAGNOSIS DIAGNOSTIC IMAGING CT scan/MRI ▪ In severe neurologic-involvement cases ▪ Multifocal cerebral cortex, white matter lesions

LAB RESULTS

▪ Serology ▫ ELISA, western blot, immunofluorescence assays ▫ Antibodies only detectable after 2-3 weeks of disease ▫ Eosinophilia ▫ Leukocytosis ▫ ↑ Muscle enzymes, ↑ creatinine kinase, ↑ lactate dehydrogenase ▪ Muscle biopsy ▫ Near tendinous insertion → highest yield obtained

Figure 82.7 A muscle biopsy containing a Trchinella spp. larva.

TREATMENT MEDICATIONS

▪ Mild disease ▫ Self-resolving ▫ Analgesia, antipyretics ▪ Systemic symptoms ▫ Antiparasitic therapy (assists larval burrowing into intestinal mucosa treatment) ▫ Corticosteroids

OTHER INTERVENTIONS Prevention ▪ Postexposure prophylaxis in suspected cases ▫ Mebendazole within six days of exposure ▪ Undercooked/raw meat consumption risk education, safe cooking practices

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TRICHURIS TRICHIURA (WHIPWORM) osms.it/trichuris-trichiura PATHOLOGY & CAUSES ▪ Human intestinal parasite (AKA whipworm) ▪ T. Trichiura causative trichuriasis agent Morphology ▪ Adult ▫ 4 cm/1.6 in in length; made of anterior whip-like esophageal portion, posterior intestine/reproductive organ portion ▪ Egg ▫ Prolate spheroids, polar plugs at each end Life cycle ▪ Female T. Trichiura lays 3000–20,000 eggs daily 60–70 days post-infection ▪ Infectious form maturation ▫ Unembryonated egg passage in stool → soil deposition → eggs embryonate, become infectious in 15–30 days ▪ Human stages ▫ Egg ingestion → eggs hatch into larvae in small intestine → larvae mature into adult worms, embed in cecum, ascending colon ▪ Life-span: 1-3 years

RISK FACTORS

▪ Poor hygiene, sanitary conditions; inadequate human fecal disposal; uncooked/contaminated vegetable ingestion

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COMPLICATIONS

▪ Heavy infection → rectal prolapse ▫ Inflammation, edema caused by high embedded worm quantity in rectum (usually small children) ▪ Persistent blood loss → iron-deficiency anemia ▪ Children ▫ Impaired growth, cognitive development

SIGNS & SYMPTOMS ▪ Mostly asymptomatic ▪ Heavier infection ▫ Abdominal pain, distension, diarrhea, fecal blood/mucus, nocturnal stooling, tenesmus

DIAGNOSIS OTHER DIAGNOSTICS

▪ Kato–Katz thick-smear technique ▫ Eggs in stool visualization

TREATMENT MEDICATIONS

▪ Antihelminthic treatment

Chapter 82 Nematodes (Roundworms)

WUCHERERIA BANCROFTI (LYMPHATIC FILARIASIS) osms.it/wuchereria-bancrofti PATHOLOGY & CAUSES ▪ Mosquito-borne nematode infection ▫ Characterization: lymphatic, subcutaneous involvement → disfigurement, disability ▪ Mosquito species vector geographicspecific (e.g. Culex, Aedes) Life cycle/transmission ▪ Filarial larvae introduction into human skin during mosquito bloodmeal → lymphatic spread → maturation into adult worm → reproduction, microfilarial hematologic release (commonly nocturnal release) → further transmission after infected individual’s mosquito bite Disease ▪ Adenolymphangitis, tropical pulmonary eosinophilia, hydrocele, chronic lymphatic disease

▪ Chyluria ▫ Intestinal lymphatic discharge into pelvis ▫ May → nutritional deficiency (including anemia, hypoproteinemia)

SIGNS & SYMPTOMS ▪ Fever, hydrocele Lymphatic disease ▪ Acute adenolymphangitis ▪ Painful lymphadenopathy, retrograde lymphangitis; self-resolving (4–7 days), may recur multiple times per year ▪ Dilation ▪ Lymphangiectasia ▪ Lymphedema ▫ Pitting edema → non-pitting edema → limb hardening ▫ Hyperpigmentation, hyperkeratosis may occur late in disease

Pathogenesis ▪ Filarial antigens → TH2-type immune response → cytokine production (IL-5, IgE) ▪ Adult worm → mechanical lymphatic disruption → lymphangiectasia, lymphatic dilation ▪ Endosymbiotic bacteria Wolbachia → immune response potentiation

DIAGNOSTIC IMAGING

RISK FACTORS

LAB RESULTS

▪ Sub-Saharan africa, Southeast Africa, India, Pacific island travel/residence

COMPLICATIONS

▪ Lymphedema (AKA elephantiasis) ▫ Chronic lymphatic vessel inflammation → limb swelling

DIAGNOSIS Ultrasound ▪ Lymphatic dilation, lymphangiectasia, adult worms may be visualized

▪ Circulating filarial antigen assays ▫ ELISA: Og4C3 antigen detection ▫ ↑ IgG4 levels indicate active infection ▪ Blood smear ▫ Nocturnal blood draw important to ↑ microfilariae concentration

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OTHER DIAGNOSTICS

▪ Physical examination ▫ Wriggling adult filariae in lymphatic vessels

TREATMENT MEDICATIONS

▪ DEC ▫ Contraindication: onchocerciasis, severe Loa Loa infection, pregnancy ▫ Doxycycline may be added as combination agent for direct larvicidal activity ▫ ↓ lymphedema effectiveness ▫ Proper skin care, topical antimicrobial administration (antifungal, antibacterial agents), extremity elevation, exercise may ↓ edema over time

SURGERY

▪ Hydrocele complications

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Figure 82.8 A histological section of a lymph node which contains a filarial worm. The normal lymph node architecture has been replaced with an inflammatory infiltrate composed largely of eosinophils.

OTHER INTERVENTIONS Prevention ▪ Mass drug administration programs ▪ Insecticide-treated bed nets ▪ Repellant, protective clothing in mosquitoendemic regions

Chapter 82 Nematodes (Roundworms)

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NOTES

NOTES

NON TUBERCULOUS MYCOBACTERIUM

MICROBE OVERVIEW ▪ Pleomorphic acid-fast bacillus; usually rodshaped ▪ Thick waxy coating ▪ Obligate intracellular microorganism ▪ Optimal growing conditions: cool

temperatures (27–33ºC/80.6–91.4°F), aerobic environment ▪ Proliferates slowly; cannot be cultivated in vitro ▪ Appearance: red; Ziehl–Neelsen stain

MYCOBACTERIUM LEPRAE osms.it/mycobacterium-leprae PATHOLOGY & CAUSES ▪ Primarily infects skin, superficial nerves, upper respiratory tract mucosa, eyes ▪ Chronic infection: leprosy; AKA Hansen’s disease ▪ Targets Schwann cells → nerve damage → sensation loss → repeated injuries, infections → gradual destruction of extremities ▪ Infiltration of skin, cutaneous nerves → hypopigmented skin lesions Ridley-Jopling classification ▪ Tuberculoid ▫ ↑ cell-mediated immunity response ▫ AKA paucibacillary (↓ mycobacteria) ▪ Lepromatous ▫ ↓ cell-mediated immunity response ▫ AKA multibacillary (↑ mycobacteria) ▪ Broad disease spectrum ▫ Borderline tuberculoid, mid-borderline, borderline lepromatous, indeterminate

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RISK FACTORS

▪ Close contact with infected individuals (esp. in areas of poverty), armadillos (enzootic in Dasypus novemcinctus) ▪ Older age, genetic factors, immunosuppression

COMPLICATIONS

▪ Lifelong neuropathy → severe disfigurement, disability ▪ Severe ophthalmic injury → vision loss ▪ Social stigma (falsely believed contagious)

SIGNS & SYMPTOMS ▪ Can be asymptomatic for years ▪ ↓ sensation ▫ Glove, stocking pattern → repeated painless injuries ▪ Hypopigmented/reddish skin lesions, heal spontaneously ▫ Tuberculoid: rare, well-demarcated ▫ Lepromatous: numerous, poorly demarcated

Chapter 83 Non Tuberculous Mycobacterium Nodular swelling (face, earlobes) Body hair loss (esp. eyebrows, eyelashes) Tender, thickened peripheral nerves Ocular involvement ▫ Chronic uveitis (common) ▫ Facial nerve paralysis (lagophthalmos) → corneal exposure, dry eye → corneal ulceration ▪ Late stages ▫ Claw fingers, toes ▫ Foot droop (inability to lift front of foot); peroneal nerve infiltration ▫ Nasal septum destruction → nose collapse (saddle nose)

▪ ▪ ▪ ▪

Figure 83.1 A skin lesion on the scalp of an individual with leprosy.

DIAGNOSIS LAB RESULTS

▪ Skin biopsy of active lesion ▫ Mycobacteria in cutaneous nerve ▪ Polymerase chain reaction (PCR) ▫ M. leprae DNA in tissues

OTHER DIAGNOSTICS ▪ Clinical examination

Figure 83.2 The hands of an individual with leprosy. The distal portions of almost all the digits, aside from one, have been lost.

TREATMENT MEDICATIONS

▪ Multidrug therapy to prevent resistance ▫ Tuberculoid: dapsone, rifampicin; six months ▫ Lepromatous: dapsone, rifampicin, clofazimine; 12 months

OTHER INTERVENTIONS

Figure 83.3 Skin changes on the chest of an individual infected with Mycobacterium leprae.

▪ Bacillus Calmette–Guérin (BCG) vaccination ▫ Administered at birth in regions with increased leprosy rates (e.g. Brazil, India, Indonesia)

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NOTES

OPPORTUNISTIC FUNGAL INFECTIONS

GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Range of infections caused by fungi; take advantage of weakened immunity (e.g. HIV/ AIDS, malignancy, immunosuppression), altered microbiota, breached integumentary barriers ▪ Present in environment worldwide → immunocompetent, healthy individuals can be exposed without resulting in disease

RISK FACTORS

▪ Immunosuppression (e.g. HIV/AIDS, neutropenia, chemotherapy, hematologic malignancies, transplant recipients)

SIGNS & SYMPTOMS ▪ Primary local cutaneous, pulmonary infection to dissemination to various internal organs

DIAGNOSIS LAB RESULTS

▪ Direct microscopy with staining, culture, tissue biopsy, bronchoalveolar lavage (sputum sample if pulmonary in origin), polymerase chain reaction (PCR)

TREATMENT MEDICATIONS ▪ Antifungals

ASPERGILLUS FUMIGATUS osms.it/aspergillus-fumigatus PATHOLOGY & CAUSES ▪ Saprophytic fungi species responsible for majority of invasive, chronic aspergillosis ▪ Found in soil, compost ▪ Asexual reproduction → production of green pigmented asexual conidia (spores) → aerosolized → individuals inhale everyday → macrophages attempt to clear conidia → secondary inflammation after conidia germinate into hyphal forms → neutrophil recruitment → activation of

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cellular immunity to kill hyphae ▪ Histopathologically, invasive aspergillosis characterized by progression across tissue planes ▫ Hallmark: vascular invasion → infarction + tissue necrosis ▪ Characteristics of Aspergillus as successful opportunistic pathogen ▫ Ability to grow at 37ºC/98.6°F ▫ Small conidial (2.5–3 micrometers) → buoyant in air for prolonged periods of time → inhaled deeply into lung alveoli

Chapter 84 Opportunistic Fungal Infections ▪ Aspergillus hyphae angioinvasive ▫ Thrombose arteries → hemorrhagic infarcts → abscesses ▪ Suspect in immunocompromised individuals with respiratory distress, fever (despite broad-spectrum antibiotics) ▪ Second most common cause of invasive fungal infections in neutropenic individuals (after Candida species) ▪ Specifically affects pulmonary, sinus, central nervous system (CNS) Diseases ▪ Necrotizing otitis externa ▫ More common in advanced HIV cases ▪ Acute pulmonary aspergillosis ▫ Inhaled conidia ▫ Most common cause of death in persons with chronic granulomatous disease (CGD) ▫ Can spread locally to involve pleura, chest wall, vertebrae → dissemination to other organs

Figure 84.1 Bronchial washing stained with Grocott methenamine silver stain from and individual with pulmonary aspergillosis. The hyphae are uniform, narrow and branch at acute angles. ▪ Cerebral aspergillosis ▫ Occurs in approx. 40% of individuals with invasive aspergillosis ▫ Hematogenous dissemination from extracranial focus (e.g. lung)/direct extension from sinus ▫ Most common brain abscess in stem cell transplant individuals

▪ Pulmonary aspergilloma ▫ Nonsaphrophytic (noninvasive) ▫ Colonization of pre-existing cavities (e.g. tuberculosis, sarcoidosis, bullous emphysema, bronchiectasis) ▫ Occurs in 15–25% of persons with cavitating lung disease from tuberculosis ▫ Lesion impinges on major vessel/airway → massive hemorrhage → hemoptysis ▫ “Fungus ball” ▪ Allergic bronchopulmonary aspergillosis ▫ Exposure to allergens of A. fumigatus → saprophytical growth → colonization of bronchial lumen → persistent bronchial inflammation → IgE-mediated allergic response in airways → hypersensitivity lung disease → bronchial obstruction ▫ Affects those with asthma (1–2%)/cystic fibrosis (1–15%)

RISK FACTORS

▪ Decreased immunity ▫ Malignancy, chemotherapy, transplant (esp. from HLA-mismatched donor), HIV/AIDS, immunosuppressant therapy, neutropenia, prolonged high dose corticosteroid use ▪ Prior pulmonary damage/disease ▪ ↑ age ▪ History of tuberculosis, histoplasmosis, sarcoidosis, bronchiectasis ▪ Cystic fibrosis, asthma (allergic bronchopulmonary aspergillosis)

COMPLICATIONS

▪ Hemorrhage → massive hemoptysis ▪ Widespread bronchiectasis + fibrosis → respiratory failure, death

SIGNS & SYMPTOMS ▪ Acute pulmonary aspergillosis ▫ Unremitting fever in high-risk cases (most common), dry cough, chest pain, dyspnea (more common in persons with diffuse disease), ↑ erythrocyte sedimentation rate (ESR)

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▪ Invasive sinusitis ▫ Ear/facial pain, discharge, swelling; nasal septum/turbinate pallor; epistaxis; orbital swelling, headache; localized areas of frank crusting, ulceration, blackened necrotic areas ▪ Cerebral infection ▫ Headache, nausea, vomiting; altered mental status, confusion, cranial nerve palsies, hemiparesis ▪ Pulmonary aspergilloma ▫ May be asymptomatic; persistent, productive chronic cough, hemoptysis, weight loss ▪ Allergic bronchopulmonary aspergillosis ▫ Manifestations due to immune system response to A. fumigatus antigens; asthma-like symptoms (e.g. wheezing), eosinophilia ▪ Invasive aspergillosis ▫ Acute onset of fever, cough, respiratory distress, diffuse bilateral pulmonary infiltrates

DIAGNOSIS DIAGNOSTIC IMAGING CT scan ▪ Increased sensitivity for radiological diagnosis ▪ Halo sign ▫ Neutropenic individuals (hemorrhagic nodule due to angioinvasion); rim of ground glass opacity surrounding nodule ▪ Air crescent sign ▫ Can develop from halo sign; cavitation → sloughed lung tissue encircled with rim of air MRI ▪ Target sign ▫ Nodule with lower central signal, higher contrast-enhancing signal on periphery; late stage disease ▪ For diagnosis of cerebral aspergillosis; multiple lesions in basal ganglia

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X-ray ▪ Unilateral infiltrates (interstitial, alveolar, mixed), cavitary lesions, multiple nondefined 1–3cm.0.39–1.18in peripheral nodules coalesce into larger masses

LAB RESULTS Tissue biopsy ▪ Not utilized frequently due to invasive nature; ↑ risk of bleeding or secondary infection in immunosuppressed individuals Cultures ▪ Respiratory tract, sputum cultures commonly negative; rarely diagnosed by blood Bronchoalveolar lavage ▪ Approx. 40% diagnostic yield Serology ▪ Useful for diagnosis of aspergilloma, allergic bronchopulmonary aspergillosis in immunocompetent individual; not useful in immunocompromised Galactomannan antigen testing ▪ Enzyme immunosorbent assay recognizes side chains of galactomannan molecule ▫ Positive: invasive disease ▫ High false-positive rate in neutropenic cases Allergic bronchopulmonary aspergillosis ▪ Eosinophilia, ↑ serum IgE

Figure 84.2 A tissue section containing Aspergillus hyphae and fruiting heads.

Chapter 84 Opportunistic Fungal Infections

TREATMENT MEDICATIONS

▪ Invasive aspergillosis ▫ Voriconazole (preferred over amphotericin B)/caspofungin; azoleresistance developing ▪ Local pulmonary aspergilloma ▫ Percutaneous intracavitary instillation of antifungals

▪ Allergic bronchopulmonary aspergillosis ▫ Corticosteroids (attenuate immune system response) ▫ Antifungal therapy: itraconazole (decrease fungal burden, antigen load) ▫ Preventative long term antifungal therapy in immunocompromised individuals

SURGERY

▪ Local pulmonary aspergilloma ▫ Surgical removal (e.g. lobectomy in massive hemoptysis)

CANDIDA osms.it/candida PATHOLOGY & CAUSES ▪ Oval, budding yeast; forms hyphae, pseudohyphae ▪ Nonpathological colonization of humans → overgrowth leads to pathology ▪ Most common cause of invasive fungal infections in immunocompromised individuals (e.g. neutropenic cases) ▫ C. albicans species most common cause of candidiasis ▫ Increasing proportion of fungal infections caused by nonalbicans Candida species (e.g. C. tropicalis, C. parapsilosis, C. kruseim, C. glabrata) Chronic mucocutaneous candidiasis ▪ Persistent infection of mucous membranes, skin, nails ▪ More commonly affects those with defective T-cell mediated immunity Vulvovaginal candidiasis (VVC) ▪ Originates from spread from GI tract, sexual transmission ▪ Occurs in 75% of healthy individuals who are biologically female ▫ 80–90% caused by C. albicans

▫ 10–20% of those with VVC have severe, recurrent infections; usually from nonalbicans species Candida esophagitis ▪ Most common in severely immunocompromised individuals (e.g. HIV individuals) ▪ May occur in absence of thrush ▪ In individuals with AIDS, can occur simultaneously with cytomegalovirus, herpes simplex infection (HSV) Disseminated/invasive candidiasis ▪ Rare in immunocompetent individuals ▪ Development of invasive disease due to interaction between Candida species virulence factors, colonization burden, host immunological status ▪ Candidemia ▫ Isolation of Candida from blood culture ▪ Candida species exhibit tissue tropism → deep organ involvement (e.g. liver, spleen, brain, bone) in absence of prolonged candidemia

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RISK FACTORS

▪ Antibiotic therapy, diabetes mellitus (poorly controlled), immunocompromised state (e.g. immunosuppressive therapy, neutropenia, hematologic malignancy, chemotherapy, transplant), chronic granulomatous disease, Job syndrome, impaired cell-mediated immunity, pregnancy, contraceptive use (hormonal/intravaginal, intrauterine devices)

COMPLICATIONS

▪ ▪ ▪ ▪

hypertension, flank mass, pyelonephritis, acute urinary obstruction from fungal mycetoma → hydronephrosis CNS: altered mental status, characteristic symptoms of meningitis Optic: chorioretinal infections, lens abscess Hepatosplenic: right upper quadrant pain; nausea, vomiting; hepatosplenomegaly Other: endocarditis (may be from central vascular catheters), bone/joint infections

▪ Meningoencephalitis ▫ Obstructive hydrocephalus, calcifications, thrombosis ▪ Renal system ▫ Pyelonephritis ▪ Abscesses in multiple organs ▪ Sepsis, septic shock

SIGNS & SYMPTOMS Mucocutaneous growth (most common) ▪ Mouth, oropharynx ▫ AKA thrush ▫ Thick, pearly white, curd-like plaques on oral mucosa ▫ Painful → dysphagia/odynophagia ▫ Otherwise unexplained → suspect HIV infection ▪ Vagina ▫ Thick, cottage-cheese-like, white vaginal discharge ▫ Painless, pruritic ▫ Dysuria possible ▪ Cutaneous candidiasis ▫ Erythematous pruritic patches + satellite lesions ▫ Individuals who are obese, diabetic ▫ Skin folds, underneath breasts ▪ GI tract ▫ May be asymptomatic ▫ Esophagus → odynophagia Disseminated/invasive candidiasis ▪ Candidemia: nonspecific (hard to distinguish from bacteremia); most commonly manifests as persistent fever despite antibiotic therapy ▪ Renal system: candiduria, rising creatinine,

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Figure 84.3 Oral candidiasis on the tongue of a child who had recently taken oral antibiotics.

DIAGNOSIS LAB RESULTS

▪ Microscopic examination ▫ KOH preparation; visualization of hyphae, pseudohyphae, blastospores ▪ Invasive candidiasis ▫ Blood/tissue culture ▪ PCR ▪ Esophagitis ▫ Tissue biopsy (definitive)

Chapter 84 Opportunistic Fungal Infections

OTHER DIAGNOSTICS

▪ Clinical presentation, history

TREATMENT MEDICATIONS

▪ Oropharyngeal candidiasis ▫ Oral nystatin suspension; clotrimazole troches (dissolves in mouth) ▪ Candida dermatitis ▫ Topical nystatin/miconazole ▪ Vulvovaginal candidiasis ▫ Local miconazole/clotrimazole creams; oral fluconazole

▪ Invasive, systemic candidiasis ▫ Echinocandins; voriconazole, caspofungin (preferred over amphotericin/fluconazole) ▪ Individuals with HIV ▫ Prophylactic antifungals (e.g. oral nystatin, fluconazole)

OTHER INTERVENTIONS

▪ Candida dermatitis ▫ Keep skin dry ▪ Invasive, systemic candidiasis ▫ Immediate removal of all central lines, catheters (Candida can develop rapid biofilms)

CRYPTOCOCCUS NEOFORMANS osms.it/cryptococcus-neoformans PATHOLOGY & CAUSES ▪ Heavily encapsulated, nondimorphic, yeastlike fungus, urease positive ▪ Virulence factors ▫ Grows well in 37ºC/98.6°F environment ▫ Produces polysaccharide capsule, melanin (neurotropism) ▪ Most common cause of fungal meningitis in immunocompromised adults ▪ Found in bird droppings, soil → inhalation of airborne fungi → evident/nonevident pulmonary infection → spreads lymphohematogenously (can affect any organ) → meninges ▪ CNS infection associated with high mortality

COMPLICATIONS

▪ Increased intracranial pressure → herniation → death ▪ May be due to buildup of cryptococcal polysaccharide at arachnoid villi → disruption in cerebrospinal fluid (CSF) reabsorption

RISK FACTORS

▪ Impaired cell-mediated immunity, highdose corticosteroid treatment, hematologic malignancies (e.g. leukemia, lymphoma) ▪ HIV/AIDS (most common immunocompromising state): < 100 cells/ mm3 CD4+ count

Figure 84.4 A histology photomicrograph of the lung.

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SIGNS & SYMPTOMS ▪ Pulmonary manifestations ▫ Asymptomatic in 1/3 of immunocompetent individuals; fever, cough, pleuritic chest pain, dyspnea, weight loss, hemoptysis ▪ Neurologic manifestations (most common) ▫ Acute/insidious; headache, fever, vomiting, nuchal rigidity, mental status changes/seizures, cryptococcal abscesses (e.g. cryptococcomas, not common) ▪ Skin manifestations (10–15%) ▫ Result of direct hematogenous spread/ extension from bone lesion; single/ multiple pustules/papules → ulcer/ abscess ▪ Bone infection (5–10%) ▫ Pain, swelling; joint involvement; often found incidentally

DIAGNOSIS DIAGNOSTIC IMAGING Chest X-ray ▪ Focal/diffuse interstitial infiltrates, hilar lymphadenopathy

LAB RESULTS

▪ CSF ▫ Lymphocytic pleocytosis; ↓ glucose; ↑ protein, opening pressure; results may be unchanged in individuals with AIDS ▪ Direct microscopic analysis of CSF/other body secretions ▫ India ink: capsule visualized with clear halo ▫ Mucicarmine: visualization of red inner capsule ▫ Visualize budding ▪ Culture ▫ Sabouraud glucose agar, incubation up to two weeks ▪ Cryptococcal capsular antigen (serum, CSF, urine, bronchoalveolar lavage) ▫ Most reliable nonculture-based method

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▪ Latex agglutination test ▫ Detects polysaccharide capsular antigen, ↑ specificity

Figure 84.5 Bronchial washings from an immunocompromised individual with pulmonary cryptococcosis. The cryptococcus spores have a characteristically thick capsule.

TREATMENT MEDICATIONS

▪ Amphotericin B, flucytosine ▪ Prevention in HIV cases with CD4+ cell counts < 100 cells/mm3—fluconazole

OTHER INTERVENTIONS

▪ ↑ intracranial pressure complication treatment ▫ Repeat CSF drainage (most important factor in reducing mortality)

Chapter 84 Opportunistic Fungal Infections

MUCORMYCOSIS osms.it/mucormycosis PATHOLOGY & CAUSES ▪ Several genera of family Mucoraceae causing rapidly progressive, invasive mucormycosis in various body systems ▪ Subphylum Mucoromycotina, order Mucorales ▫ Most human infections from members of family Mucoraceae ▫ Six genera: Rhizopus, Mucor, Actinomucor, Rhizomucor, Apophysomyces ▪ Present in decomposing organic matter (e.g. spoiled food items, soil) ▪ Forms broad, aseptate hyphae branching at right angles by sexual reproduction with formation of zygospores ▪ Inhalation of spores → sinuses, lungs primary location of infection ▪ Immunocompetent host → lung macrophages ingest, kill spores → neutrophils kill hyphae ▪ Immunosuppressed individuals → macrophages fail to stop spore germination ▪ Severe neutropenia/diabetic ketoacidotic individuals → abnormal neutrophil function → increased risk of invasive infection ▪ Angioinvasive mold → results in thrombosis, infarction, necrosis of surrounding tissues Diseases ▪ Rhinocerebral mucormycosis ▫ Necrotic lesion in paranasal sinus → orbit, face, palate, brain ▫ Most common in diabetic ketoacidosis ▫ Progresses rapidly ▪ Pulmonary mucormycosis ▫ Most common in severe neutropenic individuals ▪ Gastrointestinal mucormycosis ▫ Rare, occurs in severely malnourished children

▫ Can affect all segments of GI tract (esp. stomach, small/large intestine, esophagus) ▪ Cutaneous mucormycosis ▫ Due to traumatic implantation of spores from soil (e.g. site of surgical incisions, burn wounds) ▫ Extensive necrotic infection → necrotizing cellulitis ▫ Most common in immunocompetent individuals ▪ Disseminated mucormycosis (involves CNS) ▫ Most common in severe neutropenic individuals following pulmonary infection ▫ Brain (most commonly affected), metastatic necrotic lesions can occur in any organ

RISK FACTORS

▪ DM ▪ Diabetic ketoacidosis state ▫ ↑ risk for rhinocerebral mucormycosis ▪ Leukemia, neutropenia, chemotherapy ▫ ↑ risk of rhinocerebral, pulmonary, disseminated disease ▪ Severe malnutrition ▫ GI mucormycosis ▪ Deferoxamine treatment for iron overload state ▪ Recipient of bone marrow transplant ▪ Prolonged use of corticosteroids/other immunosuppressive therapies ▪ Prolonged use of broad-spectrum antibiotics ▪ IV drug use

COMPLICATIONS

▪ Cavernous sinus thrombosis, cranial nerve palsies (e.g. proptosis, ptosis, dilation, fixation of pupil), vision loss,

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brain abscess, necrosis of frontal lobes, GI tract perforation, perirenal abscess, renal infarction

SIGNS & SYMPTOMS ▪ Typical course: rapid onset of necrotic lesion → fulminant course requiring aggressive therapy ▪ Rhinocerebral ▫ Black, necrotic lesion on nasal/palatine mucosa; nasal/sinus congestion, pain; epistaxis; fever; edema, induration, necrosis of perinasal, periorbital tissue ▪ Pulmonary ▫ Nonspecific, pneumonia-like; may involve pleuritic chest pain, cough, fever, hemoptysis ▪ GI ▫ Abdominal pain, bleeding (e.g. hematemesis) ▪ Cutaneous ▫ Painful edema, erythema → raised, indurated lesions with black, necrotic center ▪ Disseminated ▫ Altered mental status (e.g. lethargy, obtunded state, confused)

DIAGNOSIS DIAGNOSTIC IMAGING CT scan, MRI ▪ Thoracic: nodular lesions, cavitations ▪ Head: extension of infection in sinuses → affecting brain tissue

LAB RESULTS

▪ Histopathological identification ▫ Distinct hyphae; broad irregularly branched with rare septations

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Figure 84.6 Bronchial washings stained with Papanicolaou stain from an individual with pulmonary mucormycosis. The mucor hyphae contain no septa, are of variable width and branch at a wide angle.

TREATMENT MEDICATIONS

▪ Aggressive antifungal therapy ▫ Amphotericin B

SURGERY

▪ Infected necrotic tissue ▫ Extensive surgical debridement

OTHER INTERVENTIONS

▪ Adjunctive therapy ▫ Hyperbaric oxygen, immune modulation, white blood cell infusion

Chapter 84 Opportunistic Fungal Infections

PNEUMOCYSTIS JIROVECII (PNEUMOCYSTIS PNEUMONIA) osms.it/pneumocystis-jirovecii PATHOLOGY & CAUSES ▪ Opportunistic yeast-like fungi (originally classified as protozoan) responsible for pneumocystis pneumonia ▪ Formerly known as Pneumocystis carinii ▪ Airborne transmission route; human-tohuman route occurs early in life ▪ Immunocompetent individuals may act as asymptomatic reservoirs ▪ 5–7 micrometer cysts contain up to eight pleomorphic intracystic sporozoites → become excysted → form trophozoites ▪ Reside in alveoli ▪ Disease: pneumocystis pneumonia ▫ Occurs exclusively in immunocompromised individuals ▫ Remains localized in lungs ▫ Clinical manifestations due to inflammatory reaction in alveoli lumen/ septum ▫ Fatal if left untreated

RISK FACTORS

▪ Defects in cell-mediated immunity, HIV/ AIDS, severe combined immunodeficiency syndrome, hematological malignancies, transplant recipients, hyper IgM syndrome

SIGNS & SYMPTOMS ▪ Most infections asymptomatic in immunocompetent individuals ▪ Abrupt onset of tachypnea, fever, cough ▪ Respiratory distress

DIAGNOSIS DIAGNOSTIC IMAGING Chest X-ray/CT scan ▪ Diffuse, bilateral ground glass opacities ▪ First appearing in perihilar area → progresses peripherally, apical regions spared

LAB RESULTS

▪ Microscopic examination with silver stain ▫ Disc-shaped yeast ▪ Open lung biopsy ▪ Bronchoalveolar lavage ▪ PCR of sputum/lavage samples ▪ ↓ PaO2 (reflects severity of disease) ▪ Unchanged WBC count

TREATMENT Figure 84.7 A foamy alveolar cast in a bronchial washing taken from an individual with Pneumocystis pneumonia.

MEDICATIONS

▪ Trimethoprim-sulfamethoxazole ▪ Alternatives ▫ Pentamide, dapsone + trimethoprim, atovaquone

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▪ Prophylactic trimethoprimsulfamethoxazole/pentamide ▫ Individuals with HIV, < 200 CD4+ cells/ mm3

OTHER INTERVENTIONS ▪ Respiratory support

Figure 84.8 A bronchial wash stained with Grocott’s methenamine silver highlighting Pneumocystis spores.

SPOROTHRIX SCHENCKII osms.it/sporothrix-schenckii PATHOLOGY & CAUSES ▪ Chronic subcutaneous thermally dimorphic fungus → sporotrichosis ▪ Found in soil, decomposing vegetation, plant materials (e.g. moss, hay, wood, rose bushes) ▪ Found worldwide, mostly in temperate/ tropical regions (16–22ºC/60.8–71.6°F) ▪ Outside human body grows as filamentous mold; in tissue grows as small budding yeast cells Diseases ▪ Lymphocutaneous sporotrichosis ▫ Follows traumatic inoculation of skin/ subcutaneous tissue (e.g. minor insult from thorns or splinters) → incubation 1–4 weeks → papule develops at site of inoculation → ulceration of primary lesion → nonpurulent, odorless drainage → similar lesions occur along lymphatic channel proximal to primary lesion ▪ Pulmonary sporotrichosis ▫ Following inhalation of Sporothrix conidia ▫ May progress to disseminated disease

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▪ Osteoarticular sporotrichosis ▫ Most commonly affected joints: knee, elbow, wrist, ankle ▫ Chronic infection with progressive decreased range of motion, pain, swelling ▪ Meningeal sporotrichosis ▫ Rare, mostly in individuals with cellular immune defects (e.g. lymphoma, AIDS) ▫ Chronic course ▪ Disseminated cutaneous sporotrichosis ▫ Rare (< 1%) ▫ Numerous small papules/vesicles → necrotic, ulcerated nodules on trunk, limbs ▫ Follows lymphatic spread

RISK FACTORS

▪ Lymphocutaneous ▫ Exposure due to skin trauma (e.g. living in homes with dirt floors) ▫ Individual with outdoor preoccupation ▫ Contact with cats ▪ Pulmonary ▫ Chronic obstructive pulmonary disease (COPD) ▪ Excessive alcohol use

Chapter 84 Opportunistic Fungal Infections

SIGNS & SYMPTOMS ▪ Lymphocutaneous sporotrichosis ▫ Primary papule → ulcerated lesion; similar lesions visualized along lymphatic channel proximally; chronic, fixed cutaneous lesion ▪ Pulmonary ▫ Fever, night sweats, weight loss, fatigue; dyspnea, cough; purulent sputum; hemoptysis ▪ Osteoarticular sporotrichosis; progressive decreased range of motion, pain, swelling in joints ▪ Meningeal sporotrichosis ▫ Chronic (weeks to months) fever, headache

DIAGNOSIS DIAGNOSTIC IMAGING Chest X-ray ▪ Unilateral/bilateral upper lobe cavities ▪ Variable amount of fibrosis ▪ Scattered nodular lesions

LAB RESULTS

▪ Culture (most sensitive) ▫ Tissue biopsy, sputum, body fluid ▫ Sabouraud’s agar at room temperature ▫ Characteristic arrangement of conidia on hyphae ▪ Direct microscopy ▫ Typical oval/cigar-shaped cells ▫ Asteroid bodies of S. Schenckii ▪ CSF analysis ▫ Lymphocytic pleocytosis, ↑ protein, ↓ glucose

OTHER DIAGNOSTICS

▪ Clinical examination, history

Figure 84.10 Sporothrix fungi forming conidia. Figure 84.9 Partially healed skin lesions of sporotrichosis in a typical lymphcutaneous distribution.

TREATMENT MEDICATIONS

▪ Localized: itraconazole ▪ Severe: amphotericin B

OSMOSIS.ORG 471

NOTES

NOTES

ORTHOMYXOVIRUSES GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Associated clinical syndromes: influenza (“the flu”), pneumonia ▪ RNA virus family; causes acute respiratory disease Genetic material ▪ Negative-sense, single-stranded RNA Taxonomy ▪ Genera ▫ Influenza A, Influenza B, Influenza C: infect humans ▫ Influenza D, Isavirus, Thogotovirus, Quaranjavirus ▪ Classified by surface protein ▫ Influenza A, B: hemagglutinin (H) (glycoprotein, allows progeny release); neuraminidase (N) (lectin; binds to host cell through sialic acid residues) ▫ Influenza C: hemagglutinin esterase fusion (F) (binds to host cell) Morphology ▪ Enveloped (outer lipid membrane) ▪ Spherical/filamentous ▪ Size: 50–120nm

472 OSMOSIS.ORG

SIGNS & SYMPTOMS ▪ Fever, malaise, myalgia, sore throat, nonproductive cough

DIAGNOSIS ▪ Clinical examination

DIAGNOSTIC IMAGING X-ray ▪ Chest CT scan

LAB RESULTS

▪ Molecular assays ▪ Viral culture

TREATMENT MEDICATIONS

▪ Antiviral therapy

Chapter 85 Orthomyxoviruses

INFLUENZA VIRUS osms.it/influenza PATHOLOGY & CAUSES ▪ Single-stranded RNA virus; causes acute respiratory disease ▪ AKA “the flu” ▪ Incubation: 1–4 days Pathogenesis ▪ Influenza virus penetrates upper respiratory tract → hemagglutinin binds to epithelial cell sialic acid residue → endocytosis → viral replication → neuraminidase releases progeny → viral infection spreads ▪ Viral shedding (progeny release) ▫ Duration: average 4–8 days ▫ Magnitude: ↑ symptoms = ↑ shedding ▪ Influenza A antigen variations → immune evasion, reinfection ▫ Antigenic shift: major changes in H/N proteins (two different influenza virus genome segments reassort) → epidemic/pandemic ▫ Antigenic drift: minor changes in H/N proteins (mutation in H/N gene) → outbreak Taxonomy ▪ Nomenclature: [type] / [original host] / [location of first identification] / [strain number] / [year of origin] ([subtype]) ▫ Host type, subtype included in influenza A viruses only ▫ E.g. H1N1 type A flu virus of duck origin, found in Alberta, Canada, 35th strain, found in 1976 → A/duck/ Alberta/35/76(H1N1)

Pandemics, associated strains ▪ 1918 “Spanish flu” → H1N1 ▪ 1957 “Asian flu” → H2N2 ▪ 1968 “Hong Kong flu” → H3N2 ▪ 2009 (worldwide) → H1N1

RISK FACTORS

▪ Immunosuppression, age ≥ 65 years, age < six months, nursing/chronic care facility resident, pregnancy, chronic disease, morbid obesity

COMPLICATIONS

▪ Secondary bacterial infection (e.g. pneumonia, sinusitis, otitis media, bronchiolitis), acute respiratory distress syndrome, myositis, rhabdomyolysis, myocarditis, pericarditis, encephalitis ▪ Secondary bacterial infections generally due to Streptococcus pneumoniae

SIGNS & SYMPTOMS Uncomplicated influenza ▪ Systemic: fever, malaise, myalgia, headaches, weakness, dizziness ▪ Respiratory: non-productive cough, sore throat, nasal secretion ▪ Mild cervical adenopathy Complicated influenza ▪ Primary influenza pneumonia: fever, dyspnea, cyanosis ▪ Secondary bacterial pneumonia: fever, cough, purulent sputum

Transmission ▪ Direct contact, airborne droplets, fomites Outbreak ▪ Abrupt ▪ Winter; year-round in tropical regions ▪ Duration: 2–3 months

OSMOSIS.ORG 473

DIAGNOSIS ▪ Clinical examination, during outbreak

DIAGNOSTIC IMAGING X-ray ▪ chest CT scan ▪ Primary influenza pneumonia: bilateral reticular/reticulonodular opacities, sometimes consolidation ▪ Secondary bacterial influenza: pulmonary infiltrates

LAB RESULTS

▪ Respiratory tract specimen molecular assay: reverse-transcriptase polymerase chain reaction (RT-PCR) ▪ Rapid antigen test: immunoassay ▪ Respiratory tract specimen viral culture

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TREATMENT MEDICATION

▪ Severe illness/risk factors → antiviral therapy ▫ Neuraminidase inhibitors; H1N1 commonly resistant ▫ M2 proton channel inhibitors; active against influenza A only ▪ Symptomatic treatment: acetaminophen, non-steroidal anti-inflammatory drugs (NSAID) ▪ Secondary bacterial infection: antibiotics

OTHER INTERVENTIONS ▪ Hydration

Prevention ▪ Vaccine ▫ Inactivated (intramuscular/intradermal)/ live attenuated (intranasal); trivalent/ quadrivalent (2 influenza A antigens + 1/2 influenza B antigens); annual, single-dose application (before winter); age ≥ six years ▪ Antiviral prophylaxis (high-risk individual) ▫ Neuraminidase inhibitors ▪ Infection control ▫ E.g. hand hygiene, face mask

NOTES

NOTES

PAPILLOMAVIRUS

HUMAN PAPILLOMAVIRUS osms.it/human-papillomavirus PATHOLOGY & CAUSES ▪ Human papillomavirus (HPV): virus that causes cutaneous and mucosal infections, resulting in warts (verrucae) ▪ > 200 known types; > 40 transmitted through sexual contact ▪ Humans: only host Genetic material ▪ Small, double-stranded, circular DNA virus Taxonomy ▪ Papillomaviridae family Morphology ▪ Non-enveloped, capsid virus

CAUSES

▪ Transmission ▫ Skin-to-skin contact via breaks in epithelium (autoinoculation causes local spread) ▫ Vaginal, anal, oral sexual intercourse ▫ Vertical transmission (congenital infection) ▪ Cutaneous HPV ▫ Infection of the basal stem cells of keratinized skin → viral genome replicates within proliferating cells → infected cell eventually reaches the upper epithelial layers → hyperkeratotic growth ▪ Mucosal HPV ▫ → infection of epithelium → integration into the host genome → flat, papular, or pedunculated growths → high-grade lesions and cancer may develop

RISK FACTORS

▪ Epithelial trauma ▪ Walking barefoot ▪ Occupational ▫ Meat, poultry, and fish handlers ▪ Use of communal showers ▪ Smoking ▪ Early age of first sexual intercourse ▪ Multiple sexual partners ▪ Uncircumcised males ▪ Immunocompromised state; esp. HIV/AIDS

COMPLICATIONS

▪ Some types have oncogenic potential

SIGNS & SYMPTOMS ▪ Common warts: verruca vulgaris (HPV types 2, 4) ▫ Cauliflower-like raised surface located on hands, feet, elbows, knees, subungual/periungual (under, around fingernail/on cuticle; may be painful) ▫ Common in children, adolescents ▪ Plantar: verruca plantaris (HPV type 1) ▫ Located on soles of feet ▫ May induce pain when walking ▪ Flat: verruca plana (HPV types 3, 20, 28) ▫ Flat warts found on arms, face, forehead ▫ Common in children, adolescents ▪ Anogenital: condyloma acuminatum (HPV types 6, 11 low risk; 15 types have oncogenic potential; types 16 and 18 cause 90% of all genital warts)

OSMOSIS.ORG 475

▫ Cervical cancer: types 16 and 18 70% of all cases ▫ Anal cancer: type 16 is the usual cause ▫ Other cancers; e.g. oropharyngeal, vaginal, vulvar, penile cancers usually caused by type 16 ▪ Laryngeal papillomatosis (HPV types 6, 11) ▫ Larynx, respiratory tract

TREATMENT MEDICATIONS

▪ Cutaneous warts ▫ Topical salicylic acid, fluorouracil 5% ▪ Anogenital warts ▫ External warts: podofilox solution or gel, sinecatechins ointment, imiquimod cream

SURGERY

▪ Anogenital warts ▫ Surgical removal

OTHER INTERVENTIONS

▪ Cutaneous warts ▫ May resolve spontaneously ▫ Cryotherapy (liquid nitrogen) ▪ Anogenital warts ▫ External or internal (vaginal, cervical, intra-anal): cryotherapy, trichloroacetic acid, bichloroacetic acid

Figure 86.1 A giant anal condyloma in an immunocompromised male.

DIAGNOSIS LAB RESULTS

▪ Genetic testing: in situ hybridization/ polymerase chain reaction (PCR) ▫ Real-time PCR (detect HPV viral load) ▪ Immunohistochemistry: biomarker detection ▫ E6, E7 mRNA ▫ p16 cell-cycle protein ▪ Cervical lesions: cytology ▫ If positive for abnormal cells: colposcopy and biopsy

476 OSMOSIS.ORG

Prevention ▪ HPV vaccines ▫ Gardasil (quadrivalent), Cervarix (bivalent), 9-valent ▫ Both vaccines protect against HPV 16, 18; Gardasil also protects against HPV 6, 11 ▫ Administered before primary infection occurs (9–13 years old) ▪ Cervical cancer screening ▫ Pap smear ▪ Effective barrier contraception ▫ Condoms (reduces risk; less protection compared to other STIs) ▪ Decrease number of sexual partners

Chapter 86 Papillomavirus

Figure 86.2 The histological appearance of a condyloma. There is hyperkeratosis and parakeratosis. Numerous keratinocytes demonstrate perinuclear clearing known as koilocytosis.

OSMOSIS.ORG 477

NOTES

NOTES

PARAMYXOVIRUSES MICROBE OVERVIEW ▪ Paramyxoviruses: negative-sense singlestranded RNA virus family ▪ Natural hosts: humans, vertebrates, birds ▪ Replication: occurs in cytoplasm; exits by budding ▪ Transmission: air borne particles

▪ Viral structure: enveloped, linear genomes, spherical/pleomorphic ▪ Pathogenic paramyxoviruses: human parainfluenza virus (HPIV), measles, mumps, respiratory syncytial virus (RSV)

HUMAN PARAINFLUENZA VIRUSES (HPIV) osms.it/human-parainfluenza-viruses PATHOLOGY & CAUSES ▪ Croup (laryngotracheobronchitis): infection usually caused by HPIV ▪ Four distinct HPIV serotypes ▫ HPIV-1: croup ▫ HPIV-2: croup; upper, lower respiratory tract illnesses ▫ HPIV-3: bronchiolitis, pneumonia ▫ HPIV-4: infrequently detected ▪ Common respiratory distress cause (children) ▪ Viral infection → infiltration of histiocytes, lymphocytes, other white blood cells → airway inflammation, edema → upperairway obstruction → ↑ breathing work, barky cough, inspiratory stridor (turbulent, noisy airflow), vocal hoarseness

RISK FACTORS

▪ Age ▫ Six months to three years

478 OSMOSIS.ORG

▪ Biologically-male to biologically-female ratio of 1.4:1 ▪ Previous intubation ▪ Hyperactive airways ▪ Congenital airway narrowing ▪ Late autumn (peak case onset)

COMPLICATIONS

▪ Respiratory failure ▪ Bacterial superinfection ▫ Pneumonia, bacterial tracheitis

SIGNS & SYMPTOMS ▪ Prodrome ▫ Upper respiratory tract infection symptoms (coryza, cough, mild fever) ▪ Acute onset: “barking” cough ▪ Inspiratory stridor; biphasic stridor (severe obstruction sign) ▪ Hoarseness

Chapter 87 Paramyxoviruses ▪ Respiratory distress, ↑ breathing work (e.g. suprasternal, intercostal, subcostal retractions) ▪ Agitation ▪ Symptoms worse at night ▪ Asynchronous chest movement ▪ Severe: fatigue, hypoxia, hypercarbia

DIAGNOSIS

TREATMENT MEDICATIONS

▪ Corticosteroids; dexamethasone for antiinflammatory effects ▪ Nebulized epinephrine in moderate, severe croup; temporary airway obstruction relief

OTHER INTERVENTIONS

▪ Provide comfort, avoid child’s further distress

OTHER DIAGNOSTICS Westley score ▪ Severity classification ▪ Calculated on five factors ▫ Level of consciousness, cyanosis, stridor, air entry, retractions ▫ Score between 0–17 classifies case as mild, moderate, severe croup; impending respiratory failure

MEASLES VIRUS osms.it/measles PATHOLOGY & CAUSES ▪ A paramyxovirus that causes measles, a highly infectious illness ▫ Fever, cough, coryza, conjunctivitis, followed by exanthem ▪ Transmitted via person-to person contact, droplets → infects upper respiratory tract epithelial cells Clinical stages (four) ▪ Incubation ▫ 6–21 days ▫ Virus infects respiratory mucosa/ conjunctiva → local replication → lymphatic tissue spread → disseminates via blood circulation → first virema (infection of endothelial, epithelial, monocyte, macrophage cells) ▫ Usually asymptomatic ▪ Prodrome ▫ 2–4 days

▫ Onset of fever, malaise, anorexia, conjunctivitis, coryza, cough ▪ Exanthem ▫ Onset 2–4 days after fever ▫ Erythematous, maculopapular, blanching rash ▫ Begins on face → trunk → extremities ▪ Recovery ▫ Cough persists 1–2 weeks ▫ Immunity thought to be lifelong

RISK FACTORS ▪ ▪ ▪ ▪ ▪

Measles virus exposure Travel to measles-endemic areas No prior measles immunization Failed measles vaccine response Immunocompromised individuals: AIDS, lymphoma/other malignancy, T cellsuppressive medication

OSMOSIS.ORG 479

COMPLICATIONS

▪ Secondary infection ▪ Diarrhea (most common) ▪ Pneumonia (most common children’s death cause) ▪ Otitis media (younger individuals) ▪ Encephalitis, acute disseminated encephalomyelitis, subacute sclerosing panencephalitis ▪ Subacute sclerosing panencephalitis

SIGNS & SYMPTOMS ▪ Prodrome ▫ Fever onset, malaise, anorexia, conjunctivitis, coryza, cough ▪ Koplik’s spots on buccal mucosa (1–2 days before rash onset) ▫ Red spots on erythematous buccal mucosa ▫ Measles pathognomonic ▪ Maculopapular, blanching, erythematous rash (approx. 14 days after initial infection) ▫ Head → trunk → extremities ▪ Persistent cough after resolution ▪ Modified measles ▫ Measles infection in individual with existing measles immunity ▫ Milder symptoms

▪ Atypical measles ▫ Measles virus infection in individuals immunized with killed virus vaccine ▫ Higher, prolonged fever ▫ Dry cough, pleuritic chest pain may present

DIAGNOSIS ▪ Individual presenting with febrile rash, cough, coryza, conjunctivitis

LAB RESULTS

▪ Measles detection; one of following ▫ Enzyme-linked immunosorbent assay (ELISA): positive measles-specific IgM serology (most common) ▫ Measles IgG antibody: ↑ (between acute, convalescent titers) ▫ Reverse transcription polymerase chain reaction (PCR): measles virus RNA detection ▫ In culture: Measles virus isolation

TREATMENT MEDICATIONS

▪ Antipyretics, bacterial superinfection treatment

OTHER INTERVENTIONS

Figure 87.1 Koplik spots on the oral mucosa of an individual infected with the measles virus.

480 OSMOSIS.ORG

▪ Respiratory support, fluids ▪ Vitamin A supplementation ▫ Vitamin A deficiency plays role in delayed recovery, complications ▪ Prevention ▫ No specific antiviral therapy ▫ MMR (measles, mumps, rubella) vaccine ▫ Infection control (airborne transmission precautions for four days after rash onset)

Chapter 87 Paramyxoviruses

Figure 87.2 The histological appearance of the lungs of an individual with measles pneumonia. There are numerous giant cells, the nuclei of which display inclusions.

MUMPS VIRUS osms.it/mumps PATHOLOGY & CAUSES ▪ Causes mumps; largely preventable by vaccination ▫ Fever, headache, malaise, myalgia, anorexia; followed by parotitis ▪ Transmission ▫ Highly contagious ▫ Transmission via respiratory droplets, direct contact, contaminated fomites ▫ Viral shedding begins before symptoms onset ▪ Incubation period: 14–18 days ▪ Outbreaks: schools, military posts, camps, healthcare settings, workplaces ▪ Replication: occurs in upper respiratory tract epithelium → spread via lymphatics → viremia ▪ Lifelong post-infection immunity

RISK FACTORS

COMPLICATIONS

▪ Orchitis/oophoritis, meningitis, encephalitis, pancreatitis, myocardial involvement, arthritis, deafness

SIGNS & SYMPTOMS ▪ Prodrome ▫ Fever, malaise, headache, myalgias, anorexia ▪ Parotitis ▫ Swelling, inflammation, tenderness of parotid gland(s) ▫ May obscure mandible angle ▫ Unilateral/bilateral ▫ Usually 48 hours after prodrome onset ▫ Commonly children 2–9 years old ▫ Stensen duct orifice: may be erythematous, enlarged ▪ Mastitis

▪ Unvaccinated status, international travel, vaccine failure, immunosuppressed individuals, healthcare workers, closecontact

OSMOSIS.ORG 481

DIAGNOSIS ▪ Diagnosis suspected in individuals with parotitis/other salivary gland swelling, orchitis/oophoritis with prodrome, mumps virus exposure

LAB RESULTS

▪ In parotitis setting, diagnosis established by detection of ▫ Mump virus RNA: reverse-transcription PCR (buccal/oral swab) ▫ Serum mumps IgM (may not be detectable until 5 days after symptom onset) ▪ Full blood count ▫ Leukocytosis may be seen ▪ Lumbar puncture indicated in suspected meningitis/encephalitis

TREATMENT ▪ No specific antiviral therapy

MEDICATIONS

▪ Analgesics, antipyretics, non-steroidal inflammatory agents (orchitis/oophoritis)

OTHER INTERVENTIONS

▪ Prevention ▫ Measles, mumps, rubella (MMR) vaccine ▫ Infection control (isolation with droplet precaution until parotid swelling resolved)

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Figure 87.3 Mumps virus causes parotitis, which presents as swelling at the angle of the jaw, widening the facial outline.

Chapter 87 Paramyxoviruses

RESPIRATORY SYNCYTIAL VIRUS (RSV) osms.it/respiratory-syncytial-virus PATHOLOGY & CAUSES

SIGNS & SYMPTOMS

▪ Most common cause of bronchiolitis: viral infection of the lower respiratory tract, blockage of small airways (bronchioles) ▫ May also be caused by rhinovirus, influenza virus ▪ Terminal bronchiolar epithelial cell viral infection → lung epithelial cell damage/ destruction → small bronchi/bronchioles inflammation → edema, mucus production, inflammation → small airways/atelectasis obstruction ▪ Commonly: children < two years old ▪ Often preceded by upper respiratory tract infection symptoms; rhinorrhea, headache, mild fever

▪ Prodrome ▫ Upper respiratory tract infection (rhinitis, fever) ▪ Cough; tachypnea; expiratory wheeze; ↑ breathing work (nasal flaring, grunting, retractions); crackles heard on auscultation; cyanosis

RISK FACTORS

▪ Infants < 12 weeks old, November–May, prematurity, bronchopulmonary dysplasia/ other chronic lung disease history, tobacco smoke exposure, daycare attendance, impaired airway clearance/function (e.g. cystic fibrosis), congenital heart disease, immunodeficiency

COMPLICATIONS

▪ Bacterial pneumonia, apnea, respiratory failure, dehydration, aspiration pneumonia, asthma

DIAGNOSIS DIAGNOSTIC IMAGING Chest X-ray ▪ If differential diagnosis includes pneumonia

OTHER DIAGNOSTICS Pulse oximetry ▪ ↓ oxygen saturation

TREATMENT MEDICATIONS

▪ Oral corticosteroids: prior wheeze history

OTHER INTERVENTIONS

▪ Supplemental oxygen, hydration, mechanical ventilation ▫ Respiratory symptoms peak on days 3–5, begin to resolve

OSMOSIS.ORG 483

NOTES

NOTES

PICORNAVIRUSES MICROBE OVERVIEW ▪ Have small, cytoplasmic, single-stranded, linear, positive-polarity RNA Taxonomy ▪ Family Picornaviridae; 35 genera (e.g. Enterovirus, Apthovirus, Cardiovirus, Rhinovirus, Hepatovirus)

Morphology ▪ Non-enveloped ▪ Icosahedral capsid ▪ Diameter ▫ 27–30nm(smallest of RNA viruses) ▪ Genome length ▫ About 2500nm Transmission ▪ Hosts: humans, birds, vertebrates

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COXSACKIEVIRUS osms.it/coxsackievirus PATHOLOGY & CAUSES

SIGNS & SYMPTOMS

HFMD (hand, foot and mouth disease) ▪ Clinical syndrome characterized by oral enanthem; maculopapular/vesicular rash of hands, feet ▫ Common exanthem in children and adults ▫ Most commonly caused by coxsackie A virus

HFMD ▪ Mouth, throat pain ▫ Young children may refuse to eat ▪ Mild fever ▪ Lethargy ▪ Oral enanthem: on tongue, buccal mucosa ▫ Erythematous macules → vesicles with halo of erythema ▪ Exanthem: macular, maculopapular, vesicular; nonpruritic, usually not painful ▫ Involves hands (including palms), feet (including soles), buttocks, legs, arms ▫ Palmer and plantar desquamation 1–3 weeks after presentation

Herpangina ▪ Benign clinical syndrome characterized by fever, papulo-vesiculo-ulcerative oral enanthem ▫ Most commonly caused by coxsackie A virus ▪ Transmission person to person via oralfecal route or respiratory aerosols → incubation for 3–5 days → virus replicates in the submucosal lymphoid tissue of pharynx or lower intestine → spread to regional lymph nodes (minor viremia) → dissemination throughout the body → major viremia

RISK FACTORS

▪ Age ▫ Most common in children 40 years ▫ Individuals with chronic liver disease ▫ Allergy to hepatitis A vaccine

OTHER INTERVENTIONS Prevention ▪ Infection control practices ▫ Handwashing; avoid tap water, raw foods in poorly-sanitized areas

MEDICATIONS

▪ Medications known to cause liver damage should be avoided/used with caution

POLIOMYELITIS (POLIO) osms.it/poliomyelitis PATHOLOGY & CAUSES ▪ Infectious disease caused by poliovirus ▪ Characterized by (rare but devastating) cases of muscle weakness, permanent paralysis ▫ Most infections remain asymptomatic ▫ Some experience minor symptoms (e.g. fever, sore throat, headache) ▫ Some may recover from muscle paralysis ▪ Natural host ▫ Humans ▪ Transmitted by fecal-oral route; less commonly via respiratory droplets ▫ Asymptomatic, infected persons may shed virus ▪ Pathogenesis ▫ Oral entry → poliovirus infects cells

490 OSMOSIS.ORG

of mouth, nose, throat → spread to lymphatics → primary replication in tissue of gastrointestinal tract and oropharynx → primary (minor) viremia → invasion of the central nervous system → replication in motor neurons of spinal cord, brain stem, or motor cortex → destruction of motor neurons → secondary (major) viremia and paralysis

RISK FACTORS

▪ Unvaccinated status ▪ Travel to countries endemic for poliovirus

COMPLICATIONS

▪ Post-polio syndrome ▫ Slowly developing muscle weakness similar to initial infection ▪ Bulbar poliomyelitis

Chapter 89 Picornaviruses

▪ ▪ ▪ ▪ ▪ ▪ ▪

▫ Infection of brain stem; may lead to drooling, aspiration pneumonia, respiratory muscle paralysis Skeletal malformations due to muscle paresis, paralysis Equinus foot (club foot) Stunted growth Osteoporosis, bone fractures Urinary tract infections, kidney stones Paralytic ileusv Myocarditis, cor pulmonale

Acute flaccid paralysis ▪ Complete paralysis; spinal, bulbar, bulbospinal ▪ Quadriplegia/respiratory failure ▪ Reflexes absent ▪ Sensation intact

SIGNS & SYMPTOMS Minor illness/minor viremia ▪ Abortive poliomyelitis ▫ Nausea ▫ Vomiting ▫ Abdominal pain ▫ Constipation ▫ Diarrhea ▫ Sore throat ▫ Mild fever ▫ Coryza Major illness/major viremia ▪ Involvement of central nervous system (CNS) ▪ Nonparalytic aseptic meningitis ▪ Headache ▪ Neck, back, abdominal, extremity pain ▪ Fever ▪ Vomiting ▪ Lethargy ▪ Irritability Paralytic disease ▪ Varies from one muscle to muscle group ▪ Reduced tone; often asymmetric ▪ Affects proximal muscles > distal muscles ▪ Affects legs > arms ▪ Worsens over 2–3 days

Figure 89.3 An individual with atrophy of the mucles of the right leg caused by polio.

DIAGNOSIS ▪ Acute-onset flaccid paralysis

LAB RESULTS

▪ PCR detection of poliovirus RNA from cerebrospinal fluid; cerebrospinal fluid (CSF) may also show ↑ leukocytes, ↑ protein ▪ Alternative ▫ Detection by poliovirus isolation, culture (from throat secretions); comparison of viral titers in acute, convalescent sera

OSMOSIS.ORG 491

TREATMENT MEDICATIONS Antiviral therapy ▪ Role remains uncertain Prevention ▪ Passive immunization: gamma globulin; reduces infected individuals’ disease severity ▪ Inactivated poliovirus vaccine ▫ Given in high-income countries ▫ Cannot revert to paralytic form ▪ Live attenuated oral poliovirus vaccine ▫ Inexpensive, easy to administer; given in countries where virus endemic ▫ Risk: attenuated virus reverting to paralysis-causing form

OTHER INTERVENTIONS

▪ Physical therapy; respiratory failure → mechanical ventilation ▪ No effective treatment for restoring motor neuron function

Figure 89.4 An individual with polio inside an iron lung, which provided mechanical ventilation by creating negative pressure.

RHINOVIRUS osms.it/rhinovirus → host inflammatory response to virus → elaboration of inflammatory mediators, recruitment of polymorphonuclear leukocytes → symptoms → illness lasts about 1–2 weeks

PATHOLOGY & CAUSES ▪ The causative agent of most common colds ▪ > 100 serotypes ▪ Most frequent human infectious disease, preferentially infecting the upper respiratory tract ▪ Usually causes mild, self-limiting disease, with increased incidence in early autumn (September–November) and in Spring (March–May) ▪ Predisposes to other infections ▫ Otitis media in children, community acquired pneumonia ▪ Potential to infect the lower respiratory tract → exacerbation of asthma, chronic bronchitis ▪ Inoculation of the nose or conjunctiva → intracellular adhesion molecule-1 (ICAM1) attachment → incubation (2–4 days)

492 OSMOSIS.ORG

Transmission ▪ Airborne droplet nuclei/aerosols (from sneezing, coughing) ▪ Droplet transmission ▪ Direct contact (e.g. hand contact → rubbing eyes, nasal mucosa) ▪ Fomites

RISK FACTORS ▪ ▪ ▪ ▪ ▪

Fatigue (insufficient sleep) Psychological stress Work in daycare/schools Smoking Underlying chronic disease

Chapter 89 Picornaviruses

COMPLICATIONS ▪ ▪ ▪ ▪

Sinusitis Lower respiratory tract disease Asthma exacerbations Acute otitis media

SIGNS & SYMPTOMS ▪ ▪ ▪ ▪ ▪ ▪ ▪ ▪ ▪

Cough Coryza Rhinorrhea (clear/purulent) Sore throat Myalgia Fatigue, malaise Headache Anorexia Fever

DIAGNOSIS DIAGNOSTIC IMAGING

▪ Lower respiratory tract infection → chest radiograph

OTHER DIAGNOSTICS

▪ Nasal cavity examination: swollen, erythematous nasal turbinates

TREATMENT MEDICATIONS

▪ Analgesics ▫ Relieve headache, ear pain, myalgia ▫ E.g. acetaminophen, nonsteroidal antiinflammatory drugs ▪ Antihistamine/decongestant combinations ▪ Cough suppressants

OTHER INTERVENTIONS

▪ Zinc supplements at initial infection may reduce duration

OSMOSIS.ORG 493

NOTES

NOTES

POLYOMAVIRUS MICROBE OVERVIEW ▪ Small DNA virus → central nervous system, urinary system, skin infection ▪ Poly = multiple, oma = tumor → relationship with multiple tumors ▪ Viral DNA replication, virion assembly occurs inside cell nucleus ▪ Primary infection usually asymptomatic → persistent state Taxonomy ▪ Human polyomavirus species ▫ BK virus ▫ JC polyomavirus ▫ Wu polyomavirus ▫ KI polyomavirus ▫ Merkel cell polyomavirus (MCV) ▫ Trichodysplasia spinulosa virus (TSV)

Morphology ▪ Structure ▫ Double-stranded circular DNA ▫ Icosahedral capsid composed of few proteins: VP1 (cell surface binding), VP2, VP3 ▫ Nonenveloped ▪ Non-structural proteins: large, small T antigens ▫ Initiate viral DNA replication ▫ Oncogenic potential Transmission ▪ Probable transmission routes ▫ Fecal-oral, oral, respiratory

RISK FACTORS

▪ Immunodeficiency

BK VIRUS (HEMORRHAGIC CYSTITIS) osms.it/bk-virus PATHOLOGY & CAUSES ▪ Causes hemorrhagic cystitis ▪ BK virus in hematopoietic stem cell transplant recipients → bladder inflammation → bladder mucosa bleeding ▪ Primary infection usually asymptomatic/ mild respiratory infection → urinary tract infection → virus in bladder mucosal lining, kidneys

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▪ Weak immune system → BK viral replication → cells large, round → separate from basal membrane, cell lysis

CAUSES ▪ ▪ ▪ ▪

Radiation Chemotherapy Immunosuppressive drugs Urinary tract infection (e.g. BK virus, adenovirus)

Chapter 90 Polyomavirus

TREATMENT

SIGNS & SYMPTOMS ▪ ▪ ▪ ▪

MEDICATIONS

Frequent urination Dysuria Hematuria Suprapubic pain

▪ Mesna, chemotherapy co-administered ▫ ↓ hemorrhagic cystitis risk

SURGERY

▪ Cystectomy (severe case)

DIAGNOSIS

OTHER INTERVENTIONS

LAB RESULTS

▪ Polymerase chain reaction (PCR) → infection agent fragments in urine ▪ Urinalysis, cytology ▪ Cystoscopy

▪ Bladder irrigation ▫ Water/sodium chloride solution ▪ Pain management ▪ Hyperhydratation ▪ Hyperbaric oxygen, prostaglandins (↓ efficacy)

JC VIRUS (PROGRESSIVE MULTIFOCAL LEUKENCEPHALOPATHY) osms.it/jc-virus PATHOLOGY & CAUSES ▪ Causes progressive multifocal leukoencephalopathy (PML) ▪ Immunocompromised individuals → JC virus → PML (rare demyelinating disease) ▪ Childhood primary asymptomatic infection → latent JC virus in lymphoid organs, kidneys ▪ Immunodeficiency → virus spreads via blood → infects brain oligodendrocytes, astrocytes → viral replication → cell lysis → myelin sheath loss ▪ Triggers ▫ Immunosuppressive drugs (e.g. Natalizumab) ▫ Immune system disorders (e.g. HIV/ AIDS)

SIGNS & SYMPTOMS ▪ ▪ ▪ ▪ ▪

Cognitive, mental dysfunction Gait, coordination problem Hemiparesis, monoparesis Double/blurred vision Seizure

DIAGNOSIS DIAGNOSTIC IMAGING CT scan ▪ Hypodense lesions affect white matter MRI ▪ T1 image decreased signal ▪ T2 image increased signal

OSMOSIS.ORG 495

▪ Affects subcortical, periventricular white matter (usually) ▪ Absent contrast enhancement

LAB RESULTS Brain biopsy ▪ Large oligodendrocyte nuclei with inclusion bodies ▪ Myelin sheath destruction ▪ Abnormal, enlarged astrocytes ▪ Macrophages engulfing myelin ▪ Immunohistochemistry for JC proteins Cerebrospinal fluid (CSF) analysis ▪ PCR detects viral DNA ▪ ↑ white blood cell count (pleocytosis) ▪ ↑ protein level

Figure 90.1 An MRI scan in the coronal place of the head of an individual with progressive mutlifocal leucoencephalopathy.

TREATMENT ▪ No specific treatment; high mortality

MEDICATIONS

▪ HIV-infected individuals ▫ Start/optimize antiretroviral therapy (ART) ▪ No HIV infection ▫ Stop immunosuppressive therapy ▪ Potentially beneficial drugs ▫ Interleukin-2, cytarabine, chlorpromazine, mefloquine

OTHER INTERVENTIONS ▪ Natalizumab-caused PML ▫ Plasma exchange

496 OSMOSIS.ORG

Figure 90.2 Immunohistochemical staining for JC virus protein in the brain of an individual with progressive multifocal leukoencephalopathy. The protein, stained brown, has accumulated in the oligodendrocytes.

Chapter 2 Acyanotic Defects

NOTES

POXVIRIDAE MICROBE OVERVIEW Genetic material ▪ Linear double-stranded DNA

Replication ▪ In host cell cytoplasm

Taxonomy ▪ Poxviridae: family of double-stranded DNA viruses

Associated clinical syndromes ▪ Febrile rash illnesses: smallpox (eradicated), monkeypox ▪ Skin lesions: vesicles, pustules, papules, skin thickening

Morphology ▪ Brick-shaped/ovoid ▪ Enveloped (outer lipid membrane) ▪ Size: 220–450nm

MOLLUSCUM CONTAGIOSUM osms.it/molluscum-contagiosum PATHOLOGY & CAUSES ▪ Molluscum contagiosum virus (MCV): poxvirus; causes papular skin disease ▪ Four subtypes; genotype 1 causes most U.S. cases ▪ Common in children, adolescents ▪ Skin penetration → stratum spinosum replication within keratinocytes → epidermal hypertrophy → papules ▪ Incubation period: 2–6 weeks

COMPLICATIONS

▪ Widespread/refractory lesions in immunosuppressed individuals

CAUSES

▪ Physical contact, autoinoculation, fomites

RISK FACTORS

▪ Contact sports; sexual intercourse with infected individuals; immunosuppression; atopic dermatitis

Figure 91.1 The wart-like lesions caused by molluscum contagiosum infection.

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SIGNS & SYMPTOMS ▪ Dome-shaped, shiny, umbilicated papules (2–5 mm); sometimes polypoid ▪ Lesion distribution: trunk, genitals, intertriginous areas (e.g. axilla, antecubital folds); not on palms, soles ▪ Sometimes pruritus, inflammation, swelling ▪ Molluscum dermatitis: eczematous patches/plaques around papules ▪ Eyelid lesions → keratoconjunctivitis

DIAGNOSIS

Figure 91.2 A histological section through a molluscum wart at low power. There is marked acanthosis and marked hyperplasia causing inversion.

LAB RESULTS

▪ Histologic examination: keratinocyte eosinophilic inclusion bodies (Henderson– Paterson bodies)

OTHER DIAGNOSTICS

▪ Clinical examination: dermoscopy; polylobular, amorphous structures with central umbilication, peripheral blood vessels

TREATMENT ▪ Optional; lesions resolve spontaneously in 6–18 months in immunocompetent individuals

MEDICATIONS Chemical disruption ▪ Topical blistering agent: cantharidin ▪ Antimitotic agent: podophyllotoxin ▪ Topical immunomodulator: imiquimod ▪ Potassium hydroxide (KOH) ▪ Keratinolytic agent: salicylic acid Antiviral treatment ▪ Cidofovir

SURGERY Lesion removal ▪ Cryotherapy, curettage, laser

OTHER INTERVENTIONS Figure 91.3 A histological section through a molluscum wart at high power. The stratum spinosum and granulosum contain eosinophilic inclusions, known as molluscum bodies.

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Prevention ▪ Avoid sharing towels/clothing ▪ Cover lesions with bandage/clothing ▪ Barrier contraception (e.g. condoms)

Chapter 2 Acyanotic Defects

NOTES

REOVIRUSES MICROBE OVERVIEW ▪ Rotavirus: most important Reovirus in clinical practice Genetic Material ▪ RNA viruses with segmented double stranded linear RNA

Morphology ▪ Encapsulated (icosahedral capsid) ▪ Nonenveloped Replication/multiplication ▪ Replicates in cytoplasm

ROTAVIRUS osms.it/rotavirus PATHOLOGY & CAUSES ▪ A major cause of acute diarrhea, especially in children ▫ Most important cause of severe gastroenteritis in infants, young children worldwide ▪ Short incubation period ▫ ↓ activity of brush-border enzymes (such as maltase, lactase) → malabsorption of nutrients → presence of reducing substances in stools → osmotic diarrhea ▫ Direct effects of enterotoxin nonstructural protein 4 (NSP4) on gastrointestinal mucosa (apoptosis of enterocytes) ▫ Activation of enteric nervous system → ↓ absorption of Na+, loss of K+

CAUSES

▪ Transmission by fecal-oral route (ingestion of water/food contaminated by stools) ▫ Spreads easily; minimal infective dose (10 viral particles)

RISK FACTORS

▪ Age ▫ Usually affects children between 6–24 months of age ▪ Cooler months in temperate climates ▪ Hospitalization, long term care facilities, day care centers, kindergartens, college dormitories ▪ Immunodeficiency ▪ Non-immunized status

COMPLICATIONS

▪ Secondary lactase deficiency ▪ Severe dehydration ▫ Shock, multisystem failure ▪ Central nervous system complications ▫ Seizures, encephalopathy ▪ Persistent gastroparesis, diarrhea ▪ Necrotizing enterocolitis ▪ Intussusception ▪ Biliary atresia ▪ Can be fatal

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SIGNS & SYMPTOMS ▪ Average duration: 8 days ▪ Children: watery diarrhea, vomiting, fever ▪ Adults: less severe symptoms

DIAGNOSIS LAB RESULTS Blood tests ▪ ↑ blood urea nitrogen (BUN) ▪ Hyperchloremic acidosis ▪ ↓ serum calcium Stool analysis ▪ Immune based assays ▫ Enzyme linked immunosorbent assay (ELISA), latex agglutination tests (best diagnostic tests); PCR, culture

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TREATMENT OTHER INTERVENTIONS

▪ Most cases are self-limited, do not require pharmacotherapy ▫ Antidiarrheal medications not recommended (they delay elimination of infectious agent from intestines) ▪ ↑ fluid intake; oral rehydration solutions ▪ Good nutrition ▪ If infection is severe ▫ Hospitalization for IV fluids

Prevention ▪ Live attenuated vaccine is indicated routinely for all infants, except for those with history of intussusception/severe combined immunodeficiency (SCID)

Chapter 2 Acyanotic Defects

NOTES

RETROVIRUSES MICROBE OVERVIEW ▪ RNA viruses ▫ Require DNA generation, integration into host DNA → produce viral progeny ▪ Large viral family ▫ Seven genera ▪ Target cells determined by viral glycoprotein spikes on cell membrane → recognized cell surface receptors, coreceptors → viral entry → provirus creation ▫ Viral reverse transcriptase takes singlestranded viral RNA genome → creates linear, double-stranded DNA virus → provirus ▪ Provirus integration (via integrase) into host-cell DNA → viral particle production ▫ Integration stability of provirus, transmission to host-cell progeny determines retroviral infection persistence in host organism Morphology ▪ Lipid-enveloped particles 80–100nm diameter

▪ Protein core ▫ Two linear, ⊕-sense, single-stranded RNA genomes (7–11 kb) ▫ Enzymes (gene locus) needed for viral replication (protease—pol gene, p10 locus; reverse transcriptase—pol gene, p66 locus; integrase—pol gene, p32 locus)

TYPES Human endogenous retroviruses ▪ Proviral DNA/partial genomic sequences integrated into host-genome ▪ Constitutes up to 8% of human DNA ▪ Vertical transmission via germline cells ▪ Translated DNA does not lead to infectious viruses; may → functional proteins Human exogenous retroviruses ▪ Passed horizontally via exposure to blood, sexual secretions, breast milk

HUMAN IMMUNOFEDICIENCY VIRUS osms.it/HIV-(AIDS) PATHOLOGY & CAUSES ▪ HIV: human immunodeficiency virus ▪ Member disease of Lentivirus genus of Retroviridae family ▫ Characterized by immune cell targeting, immunodeficiency

Two pathogenicity targets ▪ Immune system ▫ Mucosal HIV virion infiltration → bloodstream spread → infection of T cells, dendritic cells, macrophages → latency (may be chronic, indolent) → active replication → symptom progression/emergence → further replication→ severe

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immunocompromise, progression to AIDS (acquired immune deficiency syndrome) ▫ HIV infection → targeting, infection of CD4+ cells (e.g. CD4+ T-lymphocytes, monocytes, macrophage) → replication, spread → ↓ CD4+ cells → immunodeficiency ▫ Co-receptor CCR5 important in early infection; persistence ▪ Central nervous system (CNS) ▫ HIV infection → macrophage/microglia infection → abnormal CNS cytokine milieu → neuronal cell death Structure ▪ 110nm diameter spherical virion ▪ Core surrounded by lipid bilayer envelope ▪ Lipid envelope ▫ External glycoprotein gp-120, anchored by gp-41 ▫ Binding sites for host-cell CD4+ receptor (co-receptors—chemokine receptors; especially CCR5, CXCR4) ▪ Core ▫ Two single-stranded RNA copies ▫ Two transfer RNA primers (host-cell origin) ▫ Multiple enzyme copies: reversetranscriptase (RT), integrase, ribonuclease H (RNAse H) ▫ Other proteins: vpr, vif, nef (important in early virion life-cycle) Genome ▪ 9kb ▪ Similar to other retroviruses (six genes—tat, rev, vpr, vpu, vif, nef) ▫ HIV-2 specific: Vpx gene (homologous to gene in simian immunodeficiency virus (SIV); not present in other lentiviruses) Life cycle ▪ Cell contact, fusion: gp-120, CD4+ receptor fusion → gp-120 conformational change → opened gp-120 recognition site → gp-120 binding to host-cell co-receptor (CCR5/CXCR4) → gp-41 conformational change → gp-41 hydrophobic domain exposed → virion lipid bilayer insertion into cell membrane → virus-host-cell membrane

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fusion → viral entry ▪ Viral genome replication: viral RNA transcribed by viral RT in host-cell cytoplasm → HIV provirus production (double-stranded complementary DNA transcript) → transport to nucleus → integrase insertion in cell DNA → viral DNA transcription → viral RNA, protein ▫ Host-cell activation (naive T cells) important factor in determining active vs. latent HIV replication ▫ Antigen/cytokine-mediated T cell activation → NF-KB (nuclear transcription factor) cell stress activation → ↑ NF-KB promoter-associated gene transcription (in HIV proviral DNA) → ↑ viral replication → viral RNA, protein aggregation in cytoplasm → viral protein cleavage (e.g. gag) → viral content assembly → ↑ virion production (↑↑ virion budding → cell death) ▪ Host-cell death: ↑ virion budding → ↑ host-cell plasma membrane permeability; ↑ viral replication → native protein synthesis interference → dysregulated cellular protein concentrations → cell death ▫ Non-cytopathic host-cell HIV infection: HIV infection → inflammasome pathway activation → pyroptosis (inflammatory cytokine, cellular content release) → immune cell recruitment → viral spread (likely plays large role in HIV infection spread) Transmission ▪ HIV-1, HIV-2 ▪ Three transmission modes ▫ Sexual: USA—biologically-male individuals engaging in same-sex sexual contact (MSM) particularly important transmission mode (highest disease incidence → homosexual biologicallymale individuals); global—majority of sexual transmission via heterosexual intercourse; co-existent sexuallytransmitted disease (genital ulceration especially) → ↑ transmission risk during intercourse ▫ Parenteral: non-iatrogenic, intravenous (IV) drug users (shared needles, syringes, other paraphernalia contaminated with HIV ⊕ blood); iatrogenic (hemophiliacs who received

Chapter 93 Retroviruses HIV-contaminated factor VII, IX concentrates; HIV-contaminated blood transfusion recipients; health personnel—e.g. needle-stick injuries) ▫ Vertical, mother-to-infant: in utero, transplacental spread; infected birth canal → delivery → neonatal infection; neonatal HIV ⊕ breast milk ingestion ▪ HIV-2 only ▫ Believed to be zoonosis resulting from SIV cross-speciation infection ▫ Endemic areas correlate with those of sooty mangabey ▫ Less transmissible than HIV-1 Disease ▪ Acute retroviral syndrome ▪ AIDS

AIDS ▪ Persistent fever (> one week); fatigue; weight loss; diarrhea; generalized lymphadenopathy (LAD); serious, opportunistic infection ▪ Secondary neoplasms ▪ Neuropsychiatric disease ▫ Delirium; major depression; mania; schizophrenia; post traumatic stress disorder; substance abuse, addiction (commonly HIV infection risk factor) ▫ Dementia (AKA AIDS dementia complex): cytomegalovirus encephalitis, progressive multifocal leukoencephalopathy, cerebral toxoplasmosis, cryptococcal meningitis, CNS lymphoma

TYPES

▪ Likely related to SIV ▪ Two human virus types ▫ HIV-1, HIV-2

RISK FACTORS

▪ West Africa residence (HIV-2), homosexual/ bisexual biologically-male individuals (USA), IV drug users, hemophiliacs, blood (or component) transfusion recipients, maternal HIV infection

COMPLICATIONS

▪ Opportunistic infections, secondary malignancies, AIDS, neuropsychiatric disease

Figure 93.1 An esophaeal biopsy composed of squamous mucosa with candida hyphae. Esophageal candidiasis is a common opportunitic infection in individual with AIDS.

SIGNS & SYMPTOMS Acute retroviral syndrome ▪ Self-resolving, flu-like syndrome; sore throat; myalgias; fever; weight loss; fatigue Chronic infection ▪ Variable ▫ Asymptomatic → minor infection ▫ Oral/vaginal candidiasis, herpes zoster, mycobacterial tuberculosis (especially Sub-Saharan Africa)

Figure 93.2 The histological appearance of mycobacterium avium intracellulare. There are numerous organisms within the cell cytoplasm.

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Chapter 93 Retroviruses

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DIAGNOSIS

TREATMENT

LAB RESULTS

MEDICATIONS

Serology: enzyme-linked immunoassay (ELISA) ▪ IgG, IgM, p24 antibody testing ▫ Time to positivity: 15–45 days (P24 (viral core protein) earliest positive marker) ▫ May be combined for HIV-1, HIV-2, p24 immunoassay in diagnostic, screening purposes

Highly active antiretroviral therapy (HAART) ▪ Antiretroviral drug combination regimen ▫ Early initiation → ↓ morbidity, ↓ mortality, ↓ transmission risk (regardless of CD4+ count) ▪ Six distinct drug classes ▫ Combination of three drug types used for effective viral load management, combat particular drug class resistance development ▪ Protease inhibitor preferred initial agent ▫ Resistance testing results → narrow therapy ▪ Complications ▫ Immune reconstitution inflammatory syndrome ▫ ↓ in clinical state (symptom return experienced during active viremic phase), despite ↑ CD4+ levels ▫ Believed to be due to reinvigorated host response to high antigenic burden of persistent microbes, remaining viral load

▪ ⊕ Viral RNA level test (> 100,000 copies/ mL) ▫ May be used in indeterminate HIV-1/ HIV-2/ p24 immunoassay ▪ Leukopenia ▫ ↓↓ CD4+ count ▫ CD4+:CD8 ratio < 1

OTHER DIAGNOSTICS ▪ ▪ ▪ ▪

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Flu-like illness Opportunistic infection Needlestick injury with HIV ⊕ individual Unprotected sex with partner of unknown/ HIV ⊕ status

Pre-exposure prophylaxis ▪ Daily tenofovir use can very effectively ↓ transmission

Chapter 93 Retroviruses

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OTHER INTERVENTIONS Monitoring ▪ HIV RNA testing two, four, eight weeks after ART initiation ▫ Continue testing every two weeks until levels below detection limits ▫ Drug resistance testing at 24 weeks if ↑ in RNA viral level/no ↓ in RNA levels ▪ Once viral suppression achieved → repeat testing for RNA levels 3–6 months Screening ▪ One-time for individuals 13–75 years old ▪ Pregnant individuals (even in negative prior pregnancy screening) ▪ Annual/more frequent for high-risk individuals ▫ MSM (USA) ▫ IV drug users ▫ Sex partners of HIV unknown status, HIV ⊕, bisexual, individuals who inject drugs ▪ Blood factor screening ▫ Plasma/recombinant factor hemophiliac recipients

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Opportunistic infection prophylaxis ▪ Determined by CD4+ count ▪ Situational avoidance advised (e.g. cat litter, Toxoplasma exposure) Pre-exposure prophylaxis ▪ Indications ▫ High-risk sexual behavior/drug use ▫ Reliable individual to adhere to daily medication regimen

Chapter 93 Retroviruses

HUMAN T-LYMPHOTROPIC VIRUS osms.it/human_t-lymphotropic_virus PATHOLOGY & CAUSES ▪ Oncogenic retrovirus endemic to certain areas of world → T cell leukemia/lymphoma ▫ AKA HTLV-1 ▫ Genus: Deltaretrovirus ▪ Structure ▫ Enveloped, single-stranded RNA virus ▫ Only human pathogen of oncovirus subfamily ▪ Genome ▫ Contains retrovirus-consistent gag, pol, env, long terminal repeat (LTR) ▫ HTLV-1 specific: tax; encodes protein essential for viral replication; viral RNA transcription stimulation from 5’ LTR ▪ Transmission ▫ Usually via infected T cells (vs. virion particle) ▫ Breastmilk, sexual transmission, blood transfusion, tissue donation, IV drug use, zoonotic transmission (nonhuman primate source) ▪ Disease ▫ Adult T cell leukemia/lymphoma ▫ Myelopathy/tropical spastic paraparesis Targets CD4+ cells ▪ Unlike HIV life cycle, pathogenesis; largely unknown targeting, infection, replication mechanisms ▫ Tumor initiating cell appear to be CD4+ memory T cell with stem-cell-like properties ▪ Distinct from HIV ▫ HTLV-1 → proliferation of T cell population rather than killing of cells

▪ Integrated provirus → mitotic cell division → host cell replication ▫ Low replication rate ▫ Host cell DNA polymerase ensure high transcription fidelity (HTLV-1 genetically stable) Tax-specific oncogenic hallmarks ▪ Inr pro-growth signaling, cell survival ▫ Stimulates AKT (via PI3K), NF-KB, cyclin D2, ↓ CDK inhibitors → ↑ prosurvival, cell growth → polyclonal T cell expansion ▪ Inc genomic instability ▫ Interference with DNA-repair function ▫ Inhibition of cell cycle checkpoints (activated by DNA damage)

RISK FACTORS

▪ Travel/residence in Japan, Caribbean basin, South America, Africa ▫ Sporadic incidence in USA

COMPLICATIONS

▪ Mycosis fungoides ▫ Cutaneous T cell leukemia/lymphoma manifestation ▪ Uveitis ▪ Gastric cancer

Rheumatologic, pulmonary disorders ▪ Chronic inflammatory arthropathy ▫ Shoulder, wrists, knees ▪ Sjögren syndrome ▪ Immune thrombocytopenia

Infectious replication ▪ Integrated provirus re-expression → intracellular virion

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SIGNS & SYMPTOMS Adult T cell lymphotropic leukemia/lymphoma ▪ Skin lesions ▪ Generalized lymphadenopathy ▪ Hepatosplenomegaly Myelopathy/spastic paraparesis ▪ Insidious-onset lower extremity weakness, spasticity ▪ Hyperreflexia, ankle clonus present ▪ ⊕ extensor plantar responses ▪ Lumbar pain ▪ Others ▫ Back pain ▫ Detrusor instability → nocturia, urinary frequency, incontinence ▫ Minor sensory change: paresthesias, ↓ vibrational sense

DIAGNOSIS DIAGNOSTIC IMAGING ▪ Lytic bone lesions

MRI ▪ Tropical spastic paraparesis ▫ Cervical/thoracic cord atrophy ▫ Spinal cord white matter disease

LAB RESULTS

▪ Leukopenia ▪ Hypercalcemia ▪ Histology is variable, with characteristic circulating tumor cells ▫ Medium-sized lymphocytes with condensed chromatin, bizarre hyperlobated nuclei (AKA clover leaf/ flower cells)

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▪ ELISA ▫ Antibody against HTLV-1 virus detection ▪ Western blot ▫ Confirmatory testing for ELISA ▪ Polymerase chain reaction (PCR) ▫ Available for HTLV-1 ▫ Useful with ↑↑ suspicion (ELISA negative) ▪ Flow cytometry ▫ ↑ FoxP3 expression in leukocytes (↑ regulatory T cell-indicative) ▫ Otherwise immunophenotypically mature T lymphocytes

OTHER DIAGNOSTICS

▪ Travel/residence in endemic area

TREATMENT ▪ No therapy proven to benefit affected individuals

MEDICATIONS

▪ Corticosteroid therapy may slow disease course ▪ Antiviral therapy ▫ NRTI zidovudine, IFN-alpha proven beneficial

OTHER INTERVENTIONS Prevention ▪ Endemic area-avoidance when breastfeeding ▪ Blood donor screening ▪ Safe-sex practices ▪ Discourage needle sharing

Chapter 2 Acyanotic Defects

NOTES

RHABDOVIRUSES MICROBE OVERVIEW ▪ Diseases ▫ Rabies encephalitis, vesicular diseases

▪ Genera: Lyssavirus, Vesiculovirus, Sigmavirus, Varicosavirus, Spirivivirus, etc.

Genetic material ▪ Rod-shaped, single-stranded RNA virus

Morphology ▪ Enveloped, bullet-shaped, with helical nucleocapsids, linear genomes

Taxonomy ▪ Order: Mononegavirales ▪ Family: Rhabdoviridae

Transmission ▪ Via bite (infected host’s saliva)

RABIES VIRUS osms.it/rabies-virus PATHOLOGY & CAUSES ▪ Serious central nervous system (CNS) viral zoonotic infection ▪ Virus spreads via nerves (retrograde axoplasmic transport) ▪ Muscle tissue inoculation → incubation (1–3 months), local multiplication → acetylcholine receptor binding → nerve entry → travel via spinal cord axons → brain infection (found in cerebellum Purkinje cells, hippocampal neurons) → encephalitis Advanced-stage ▪ CNS → other organs (salivary glands, cornea, skin, gastrointestinal, etc.) via parasympathetic nervous system

CAUSES

▪ Caused by genus Lyssavirus (multiple species, Rhabdoviridae family)

Transmission ▪ Saliva in virus-infected host bite (dogs, bats, cats, raccoon, foxes, skunks, monkeys, etc.) ▪ Rabies-infected organ/tissue transplantation (rare) ▪ Aerosol transmission (e.g. bat caves) possible

RISK FACTORS

Animal exposure (bite risk) Travel (rabies-endemic Asian/African areas) Age < 15 years Deep bite Head wound (virus → brain transmission risk ↑ ) ▪ No post-exposure prophylaxis ▪ Occupational (laboratory, veterinarian) ▪ Recreational (spelunking → ↑ bat exposure risk) ▪ ▪ ▪ ▪ ▪

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COMPLICATIONS ▪ ▪ ▪ ▪ ▪

Encephalopathy Increased intracranial pressure Coma Permanent neurological deficits Often fatal

SIGNS & SYMPTOMS Prodromal stage ▪ Non-specific symptoms (first week) ▫ Headache; low grade fever, chills; myalgia, weakness, fatigue; malaise, anorexia; nausea/vomiting; sore throat; photophobia (sometimes) ▪ Wound site pain/tenderness/paresthesia/ tingling/itching Encephalitic rabies ▪ AKA furious rabies ▪ Most common form ▪ Involuntary pharyngeal spasms → hydrophobia (fear of water); aerophobia ▪ Fever ▪ Muscle spasms → opisthotonus position ▪ Seizure ▪ ↑ autonomic stimulation ▫ Excess salivation; lacrimation; sweating; mydriasis; impaired temperature homeostasis; tachycardia ▪ Dysphagia ▪ Aggressiveness, agitation, hallucination, confusion ▪ Respiratory distress → coma → respiratory arrest → death Paralytic stage ▪ AKA dumb rabies ▪ Ascending flaccid paralysis ▪ Sphincter atony ▪ Hydrophobia (rare) ▪ Neck stiffness ▪ Cranial nerves palsy ▪ Fasciculations/deep tendon reflex loss ▪ Pharyngeal, diaphragm muscle paralysis → death

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DIAGNOSIS ▪ Clinical Presentation ▫ History of rabid animal bite, rabies infection symptoms/signs

DIAGNOSTIC IMAGING CT scan ▪ Cerebral edema

LAB RESULTS Reverse transcription PCR (RT-PCR) ▪ Saliva ▫ Detects rabies virus RNA Skin punch biopsy ▪ RT-PCR; immunofluorescence staining for viral antigen Cerebrospinal fluid (CSF) ▪ Indirect immunofluorescence, virus neutralization assay ▪ CSF analysis ▫ Pleocytosis, ↑ protein Serum ▪ Anti-rabies virus antibodies in serum appear after first week (if individual not immunized)

OTHER DIAGNOSTICS Post mortem ▪ Brain tissue/other neural tissue examination ▫ Negri bodies, eosinophilic cytoplasmic inclusions in nerve cell cytoplasm (often)

TREATMENT MEDICATIONS

▪ Antivirals ▪ Rabies vaccine ▫ Both post-, pre-exposure prophylaxis ▫ Immunocompetent people: four injections (day 0, 3, 7, 14) ▫ Immunocompromised people: fifth injection (day 28)

Chapter 94 Rhabdoviruses ▫ Previously immunized people: two injections (day 0, 3) ▪ Human rabies immune globulin (HRIG) ▫ Single dose (20 units/kg) injected in, around wound ▫ Remainder administered intramuscular at distant site (e.g. other deltoid)

OTHER INTERVENTIONS Post-exposure prophylaxis (rapid) ▪ Wound cleaning ▫ Water/soap, povidone iodine ▪ Antibiotics/tetanus prophylaxis

Figure 94.1 Multiple Negri bodies in the brain of an individual infected with the rabies virus. The negri bodies form in the Purkinje cells of the cerebellum.

Management ▪ Respiratory (supplemental oxygen, mechanical ventilation), cardiovascular support (fluids) Prevention ▪ Exposed population may receive preexposure prophylaxis ▪ Domestic animal vaccination (especially dogs, cats)

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NOTES

NOTES

RICKETTSIAL DISEASES GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Vector-borne obligate intracellular bacteria; poor Gram staining, rod-shaped structure ▪ Common tropism for endothelial cells → variable amount of hemorrhage, edema, organ dysfunction

SIGNS & SYMPTOMS ▪ Disease-specific; fairly consistent integument manifestations (e.g. rash)

DIAGNOSIS LAB RESULTS

▪ Isolation of Rickettsiae ▫ Inoculation of animal/via cell culture ▪ Serology ▫ Enzyme-linked immunosorbent assay (ELISA), western blot, microimmunofluorescent antibody test (detection of bacterial-specific antigens)

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▪ Immunologic detection in tissue ▫ Isolation in epithelial tissue (from integument involvement) ▫ Requires sophisticated laboratory capability (not common in endemic areas of disease) ▪ Polymerase chain reaction (PCR) ▫ Detection of rickettsial DNA

OTHER DIAGNOSTICS

▪ Clinical presentation (disease-specific)

TREATMENT MEDICATIONS

▪ Prompt antimicrobial therapy ▫ Doxycycline (preferred)

Chapter 95 Rickettsial Diseases

ANAPLASMA osms.it/anaplasma PATHOLOGY & CAUSES ▪ Tick-borne, obligate intracellular bacteria, endemic to wooded areas in North America → self-resolving disease, AKA human granulocytic anaplasmosis (HGA) Vector ▪ Anaplasma phagocytophilum: Ixodes tick ▫ Ixodes scapularis: also transmits Borrelia burgdorferi, Babesia spp. in eastern United States (US) ▫ Ixodes pacificus: main vector in western US ▫ Ixodes ricinus: implicated in European disease Life cycle and transmission ▪ Reservoir hosts: deer, white-footed mice (source of disease, not affected by pathogen) ▪ Vector: Ixodes tick (connects organism from reservoir to target) ▪ Human transmission Pathogenesis ▪ Tick bite → blood circulation → leukocyte infection, membrane attachment → phagocytosis → replication (in early endosome of leukocyte) → dysfunctional vacuolization, immature lysosomal micelles → microcolony (AKA morulae) development → release into extracellular space after cell lysis/exocytosis ▫ P-selectin glycoprotein (identified binding domain for A. phagocytophilum) ▫ Ligand: P-selectin glycoprotein ligand-1 (PSGL-1) required on granulocytes for internalization Disease: HGA ▪ Direct leukocyte cell death ▪ Inflammatory response → perivascular inflammatory infiltrates in multiple organ systems (without organ failure/endothelial damage)

RISK FACTORS

▪ Residence in/travel to wooded areas in North America ▫ Especially during peak tick activity (e.g. spring, summer) ▪ Direct contact with slaughtered deer ▪ Occupational exposure (e.g. military)

COMPLICATIONS

▪ Co-infection with Borrelia burgdorferi, Babesia spp. ▪ Respiratory insufficiency, renal failure, septic shock ▪ Neurological ▫ Demyelinating polyneuropathy, brachial plexopathy ▪ Serious, fatal opportunistic infections ▫ Herpes simplex esophagitis, invasive aspergillosis,

SIGNS & SYMPTOMS ▪ Onset 1–2 weeks after identified tick bite ▪ Fever, malaise, headache ▪ Rash ▫ Typically trunk (sparing hands, feet), maculopapular (more evident in children) ▪ Gastrointestinal (GI) symptoms infrequent ▪ Neurological (rare) ▫ Mental status change, meningismus, clonus

DIAGNOSIS LAB RESULTS

▪ Leukopenia ▫ Specific to disease (neutropenia) ▪ ↑ hepatic enzymes, lactate dehydrogenase

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▪ Serology: indirect IFA ▫ Detection of IgG/IgM antibodies of Anaplasma species ▫ If negative on acute serum testing, repeat with convalescent serum (confirms diagnosis if ↑ fourfold in IgG antibody titer) ▪ Whole blood PCR ▫ Detects epank1 primers on genogroup A. phagocytophilum ▪ Wright stain: morulae of Anaplasma in leukocyte ▫ A. phagocytophila: peripheral blood neutrophils; 25–75% (highest among morulae-producing bacteria)

OTHER DIAGNOSTICS

▪ History ▫ Tick bite in endemic area

TREATMENT MEDICATIONS

▪ Prompt antibacterial management ▫ Doxycycline (if pregnant, rifampin); chloramphenicol

OTHER INTERVENTIONS

▪ Prevention ▫ Avoid tick habitats ▫ Careful inspection after outside activity in wooded areas (esp. in spring, summer); rapid discovery, tick removal < 24–48 hours post bite → effective prophylaxis ▫ Skin application of insect repellants ▫ Proper clothing for outside work/play (light-colored, long pants tucked into socks, long-sleeved shirts)

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Figure 95.1 Mites of the genus Ixodes act as vectors for many rickettsial diseases.

Chapter 95 Rickettsial Diseases

COXIELLA BURNETII (Q FEVER) osms.it/coxiella-burnetii PATHOLOGY & CAUSES ▪ Coxiella burnetii: primarily zoonotic pathogen → febrile illness (after contact with animal amniotic fluid/placental contents) Taxonomy ▪ Order: Legionellales ▪ Family: Coxiellaceae Morphology ▪ Short, pleomorphic rod ▫ Strict intracellular bacterium Life cycle ▪ Source of human infections ▫ Farm animals (e.g. cattle, goats, sheep) ▫ Wild animals (e.g. birds, rabbits, reptiles) ▫ Arthropods (e.g. ticks) ▪ Main reservoir ▫ Ticks Transmission ▪ Inhalation of spores/bacteria ▫ Animal feces, milk, products of conception ▪ Ingestion of contaminated milk ▪ Percutaneous ▫ Crushing of ticks near skin breaks ▪ Vertical spread (transplacental) Pathogenesis ▪ Host cell ▫ Macrophage ▪ Antigenic variation (AKA phase variation) important in virulence ▫ Lipopolysaccharide capsule modifications underly antigenic variation

RISK FACTORS

▪ Occupation involving animal contact (e.g. veterinarian, farmer) ▪ ↑ age ▪ Unpasteurized milk consumption

COMPLICATIONS

▪ Q fever pneumonia, chronic hepatitis, osteomyelitis ▪ Infective endocarditis ▫ Pre-existing heart/valve disease predisposes to endocarditis development ▫ May have secondary, septic embolic manifestation

SIGNS & SYMPTOMS ▪ Q fever (sudden onset) ▫ Fever, headache (often frontal), general malaise, cough, anorexia, myalgia ▪ Pneumonia ▫ Cough, pleural effusion ▪ Hepatitis ▫ Hepatomegaly

DIAGNOSIS LAB RESULTS

▪ ↑ serum hepatic enzymes, leukopenia/ leukocytosis, thrombocytopenia ▪ Immunofluorescent antibody assays: detect IgM/IgG antibodies; differentiate between acute, chronic infection ▫ IgM: detectable 4 days after symptom onset ▫ IgG: detectable 9–14 days after symptom onset ▫ Concentration of serum samples can assist in diagnosis (esp. if vague clinical presentation)

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▪ PCR ▫ Blood/serum detection possible before IgM serology peak ▪ Immunohistochemistry ▪ Culture

OTHER DIAGNOSTICS

▪ History ▫ Animal contact, occupation

▫ Trimethoprim-sulfamethoxazole: pregnant individuals; treat even if asymptomatic ▪ Chronic infection: prolonged therapy ▫ 18 months doxycycline, hydroxychloroquine (monitor serologic response across therapeutic intervention; biannual ophthalmic examinations required)

OTHER INTERVENTIONS

TREATMENT MEDICATIONS

▪ Prompt antimicrobial treatment ▫ Doxycycline: effectiveness of antibacterial agent, severity of complications warrants use despite side effects; shorter therapy for children (14 day course)

▪ Management ▫ Individuals with pre-existing valvulopathy/cardiomyopathy; echocardiogram ▪ Prevention ▫ Whole cell vaccine; recommended for individuals working with farm animals (e.g. farmers, slaughterhouse workers)

EHRLICHIA osms.it/ehrlichia PATHOLOGY & CAUSES ▪ Tick-borne, obligate intracellular bacteria with leukocytic tropism, associated with febrile disease with rare, serious neurologic complication ▫ AKA human monocytic ehrlichiosis (HME) ▪ Characteristics ▫ Small (0.5–1.5 micrometer) gramnegative cocci, (1.8 megabases) genome

TYPES

▪ Ehrlichia ewingii ▫ Southeastern, central United States ▪ Ehrlichia chaffeensis ▫ Northeastern, midwestern United States ▪ Ehrlichia sennetsu ▫ Western Japan

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Vector ▪ Amblyomma americanum (AKA lone star tick) ▫ Ehrlichia ewingii, Ehrlichia chaffeensis Life cycle ▪ Tick bite → blood circulation → leukocyte infection, membrane attachment → phagocytosis → replication (in early endosome of leukocyte) → dysfunctional vacuolization, immature lysosomal micelles → microcolony (AKA morulae) development → release into extracellular space after cell lysis/exocytosis Pathogenesis ▪ Direct leukocyte cell death ▪ Inflammatory response → perivascular inflammatory infiltrates in multiple organ system without organ failure/endothelial damage Disease: Sennetsu fever

Chapter 95 Rickettsial Diseases

RISK FACTORS

▪ Residence in/travel to western Japan ▪ Occupational exposure (e.g. military)

COMPLICATIONS

▪ Co-infection with Babesia spp./B. burgdorferi ▪ Encephalitis, seizure ▫ Associated most with E. chaffeensis ▫ May result in persistent neurologic deficit (rare; seen especially in children) ▪ Heart failure, respiratory insufficiency, renal failure, shock

SIGNS & SYMPTOMS ▪ Sennetsu fever ▫ Abrupt-onset fever, chills, headache, malaise, sore throat, myalgias, arthralgias ▪ Atypical rash ▫ Maculopapular with occasional petechiae; located on trunk (sparing hands, feet) ▪ Generalized lymphadenopathy ▫ Most associated with E. sennetsu; includes hepatosplenomegaly ▪ GI ▫ Associated with E. chaffeensis ▫ Anorexia, diarrhea, nausea, vomiting

▪ Leukopenia, thrombocytopenia, anemia, hyponatremia ▪ Hepatic transaminitis: most common in E. chaffeensis infection ▪ Cerebrospinal fluid (CSF) analysis: pleocytosis (mononuclear cells with morulae), ↑ protein

OTHER DIAGNOSTICS

▪ History ▫ Tick bite in endemic area

TREATMENT MEDICATIONS

▪ Prompt antibacterial management: poxycycline, chloramphenicol

OTHER INTERVENTIONS Prevention ▪ Avoidance of tick habitats ▪ Careful inspection after outside activity (esp. in spring, summer) ▫ Rapid discovery, removal < 24–48 hours after bite → effective prophylaxis ▪ Proper skin application of insect repellants

DIAGNOSIS LAB RESULTS

▪ Serology: indirect IFA ▫ Detection of IgG/IgM antibodies (Ehrlichia species) ▫ If negative on acute serum testing, repeat with convalescent serum (confirms diagnosis if fourfold increase in IgG antibody titer) ▪ Whole blood PCR: detects 16S rRNA gene ▪ Wright stain: morulae (Ehrlichia) in leukocyte ▫ E. ewingii: in peripheral blood granulocyte ▫ E. chaffeensis: in peripheral blood monocyte

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RICKETTSIA RICKETTSII (ROCKY MOUNTAIN SPOTTED FEVER) osms.it/rickettsia-rickettsii PATHOLOGY & CAUSES ▪ Tick-borne, obligate intracellular, Gramnegative bacteria endemic to parts of North America → potentially lethal febrile disease ▪ Characteristics ▫ Weakly gram-negative, nonmotile coccobacillus; 0.7–2.0 micrometers: cannot be visualized by traditional staining methods/direct fluorescent antibody techniques ▫ Bacterial contents: ribosome; single, circular chromosome; microcapsule surrounding cell wall (may be important in pathogenicity) Vectors ▪ Dermacentor variabilis (American dog tick) ▫ Eastern, South-central US ▪ Dermacentor andersoni (Rocky Mountain wood tick) ▫ West of Mississippi River ▪ Rhipicephalus sanguineus (common brown dog tick) ▫ Southwestern US ▪ Virulence of strain depends on tick’s feeding status ▫ ↑ feeds → ↑ incubation at high temperatures → ↑ extracellular slime → ↑ virulence (AKA reactivation phenomenon) Life cycle ▪ Tick bite (requires 6–10 hours of feeding) → proliferates by binary fission ▪ Grows in nucleus, cytoplasm of host cells Pathogenesis ▪ Tropism for endothelial cells, downstream systemic effects as sequelae ▪ Endothelial cell entry: rickettsial outer membrane proteins (rOmps) interact with

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▪

▪

▪

▪

▪

▪

lipopolysaccharides, surface-exposed proteins (SEPs) for entry ▫ rOmps bind Ku70 (membrane protein) → activate Ku70 → recruit ubiquitin ligase → ubiquitination of Ku70 → act upon cAMP receptors protein kinase A, Epac (exchange protein) → rearrangement of host cell actin filaments → rickettsial endocytosis Bacterial spread: R. rickettsii express phospholipase D, tlyC → lyse phagosomal membrane → entry into cytosol → polymerization of host cell monomeric actin filaments → invagination of host cell membranes → passage into neighboring cells Further bacterial spread ▫ Filopodia (from host cell membranes) assist in intercellular movement ▫ Bloodstream, lymphatic spread assist in more distant infection sites Small blood vessel injury (not entirely elucidated) ▫ Associated with phospholipase A activity, protease activity, free radicalinduced lipid peroxidation ▫ Cell necrosis (from other infected cells) → CD8+ T-cell response → endothelial cell injury → immune, phagocytic cellular response → lymphohistiocytic vasculitis Sequelae of small vessel injury: ↑ fluid in interstitial space → exposes brain, lung parenchyma to devastating pathophysiologic consequences Ability to spread cell-to-cell without causing obvious damage ▫ Rarely accumulate in large numbers inside cells Speeds of 4.8m/min ▫ Achieves speed via rapid recruitment, polymerization of host cell actin filaments

Chapter 95 Rickettsial Diseases

RISK FACTORS

▪ Residence in/travel to endemic areas (esp. in spring, summer) ▪ ↑ age (peak: 40–64) ▪ Individuals who are biologically male ▪ Glucose-6-phosphate dehydrogenase (G6PD) deficiency

COMPLICATIONS

▪ Skin necrosis at sites of terminal arterial supply (e.g. fingers, toes, nose, ears, genitals) ▪ Interstitial pneumonitis, myocarditis, encephalitis

SIGNS & SYMPTOMS ▪ Early infection ▫ Fever, headache, malaise, myalgias, arthralgias, nausea (without vomiting), edema (esp. in children) ▪ Rash development (hallmark of infection) ▫ Blanching, erythematous rash ▫ Macules (1–4mm) → petechiae ▫ Ankles, wrist → truncal spread → palms, soles rash (characteristic of late-stage disease) ▪ Confusion, conjunctival erythema, seizures, focal neurologic deficit ▪ Fundoscopic examination ▫ Retinal vein engorgement, arterial occlusion, flame hemorrhage

DIAGNOSIS DIAGNOSTIC IMAGING Chest X-ray ▪ Interstitial infiltrates Echocardiogram ▪ Minimal myocardial dysfunction with normal capillary wedge pressure ▪ Consistent with noncardiogenic nature of pulmonary edema (commonly present)

▪ Advanced disease ▫ Hyponatremia (sign of central nervous system involvement); transaminitis; ↑ bilirubin; azotemia (due to hypovolemia); ↑ prothrombin, partial thromboplastin times ▪ CSF ▫ Pleocytosis (monocytic, polymorphonuclear predominance possible), ↑ protein

OTHER DIAGNOSTICS

▪ History ▫ Residence in/travel to endemic area; recollection of tick bite (only 30% of individuals recollect bite)

TREATMENT MEDICATIONS

▪ Early treatment: prompt, empiric antimicrobial therapy with doxycycline (first-line), chloramphenicol (second-line) ▫ Even if mild symptoms (due to potential lethality of bacterial strain); recommended for pregnant individuals, children ▫ Goal: initiate < five days after symptom onset ▫ Duration: until three days after resolution of febrile illness; minimum seven days ▪ Antiemetics, antimotility agents (individuals intolerant of doxycycline)

OTHER INTERVENTIONS

▪ Hemodynamic monitoring in ICU setting; respiratory support; renal replacement therapy, blood transfusions ▪ Prevention ▫ Vigilant detection, early removal of ticks, proper clothing

LAB RESULTS

▪ Thrombocytopenia (worsens with progression of disease)

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RICKETTSIA TYPHI (MURINE TYPHUS) osms.it/rickettsia-typhi PATHOLOGY & CAUSES ▪ Rat-borne zoonotic disease transmitted to humans via flea; flu-like illness; minority of individuals require ICU-level care ▫ AKA murine, endemic, flea-borne typhus Transmission ▪ Zoonotic reservoir: Rattus typhi ▪ Vector: Xenopsylla cheopis (AKA Oriental rat flea) Life cycle ▪ Flea feeds on infected rodent → lifetime infection → fecal bacterial shedding → human contact with flea feces through breaks in skin barrier/inhalation → human disease ▫ Further human infection occurs via body lice passed human-to-human ▪ Replicates in high titers in yolk sacs of embryonated chicken eggs Pathogenesis (not well elucidated) ▪ Perivascular infiltration with lymphocytes, macrophages, plasma, mast cells (on biopsy) ▪ Vasculitis (rare) ▫ Accompanied by mural/intimal thrombi; heart, lungs, kidneys, central nervous system (CNS) ▪ Disease ▫ Mild, flu-like illness

RISK FACTORS

▪ Warmer climates, seaports, major commercial areas

COMPLICATIONS

▪ Shock, sepsis, myocarditis, renal/respiratory failure, severe hemolysis (associated with

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G6PD deficiency) ▪ Neurological ▫ Meningitis, meningoencephalitis, facial paralysis, hearing loss, ocular abnormalities

SIGNS & SYMPTOMS ▪ Fever (8–16 days after exposure), chills, headache (commonly frontal), myalgia, rash (concurrent with fever; maculopapular, less commonly petechial; spares face, palms, soles), nausea, vomiting

DIAGNOSIS LAB RESULTS

▪ ↑ erythrocyte sedimentation rate (ESR) ▪ Left shifted leukocyte count (absolute neutropenia/lymphopenia possible) ▪ Abnormal hepatic enzymes ▪ Electrolytes ▫ Hyponatremia, hypokalemia, ↑ serum creatinine

TREATMENT MEDICATIONS

▪ Prompt doxycycline antimicrobial therapy ▪ Ciprofloxacin (viable alternative)

OTHER INTERVENTIONS Prevention ▪ Rodent, flea eradication ▪ Rat-proofing homes, food service areas ▪ Protective clothing for occupational exposure to rats

Chapter 2 Acyanotic Defects

NOTES RODS

MICROBE OVERVIEW ▪ Rod shaped bacteria (bacilli), Gramnegative, non-spore forming

BACTEROIDES FRAGILIS osms.it/bacteroides-fragilis PATHOLOGY & CAUSES ▪ Flora of oral cavity, GI tract (primarily large intestine), genitourinary tract of individuals who are biologically female; responsible for variety of infections ▪ Obligately anaerobic, non-motile ▪ Beta lactamase positive → resistance to beta lactam antibiotics ▪ Fastidious → difficult to isolate ▪ Grows in 20% bile ▪ Usually involved in widespread polymicrobial anaerobic Gram-negative bacilli infections (AGNB) ▫ Intra-abdominal, skin/soft tissue, pulmonary

RISK FACTORS

▪ Prior antibiotic use ▪ ↓ blood supply (e.g. trauma, malignancy, surgery, shock, vascular disease) ▪ Tissue necrosis ▪ Disruption of intestinal mucosa ▪ High risk for aspiration pneumonia (e.g. alcoholism, coma, stroke) ▪ Bronchial obstruction → lung abscesses

SIGNS & SYMPTOMS ▪ Foul-smelling discharge, tissue necrosis, formation of abscesses, gas production in tissues/discharges

DIAGNOSIS DIAGNOSTIC IMAGING CT scan ▪ Abscesses/presence of gas in infected site ▫ Highly suggestive of anaerobic infection

LAB RESULTS

▪ Rapid enzymatic test ▪ Polymerase chain reaction (PCR) assays ▪ Direct needle aspiration

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TREATMENT MEDICATIONS

▪ Antimicrobials ▫ Recovered anaerobes mixed with aerobic organisms; clindamycin,

metronidazole, carbapenems, tigecycline, beta-lactam/beta-lactamase inhibitors, cefoxitin

SURGERY

▪ Drain abscesses, relieve obstructions

BARTONELLA HENSELAE osms.it/bartonella-henselae PATHOLOGY & CAUSES ▪ Zoonotic microbe; affects skin (most common), regional lymph nodes, internal organs (e.g. liver, spleen); small, pleomorphic; fastidious, slow growing; requires specific culture conditions; grows in lysis centrifugation tubes; detected with Warthin–Starry (WS)/silver stain ▪ Natural reservoir ▫ Domestic cats, usually young cats ▪ Mode of transmission ▫ Infection follows cat scratch, bite, exposure to cat feces/fleas Commonly associated diseases ▪ Cat-scratch disease (CSD) ▫ Usually affects children ▪ Bacillary angiomatosis (BA) ▫ Rare vasoproliferative disorder; usually occurs in severely immunocompromised individuals (e.g. due to HIV)

COMPLICATIONS CSD ▪ Lymph nodes necrosis; can disseminate, cause life-threatening complications involving visceral organs (e.g. liver, spleen), central nervous system (CNS), eyes BA ▪ Potentially fatal if untreated

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SIGNS & SYMPTOMS ▪ May be asymptomatic CSD ▪ Usually develops 1–3 weeks after inoculation ▪ Regional lymphadenopathy/lymphadenitis (most common) ▫ Usually unilateral; lymph nodes drain site of inoculation; tender, swollen lymph nodes ▪ Rare ▫ Low grade fever, malaise, ↓ appetite, abdominal aches ▪ Cutaneous erythematous lesion at site of inoculation; regresses spontaneously after 1–4 weeks ▪ Visceral organs → hepatomegaly, splenomegaly ▪ Eyes → neuroretinitis, parinaud oculoglandular syndrome ▪ Central nervous system (CNS) → encephalopathy BA ▪ Usually affects skin → red papules, nodules/ subcutaneous masses

DIAGNOSIS LAB RESULTS

▪ Difficult to culture; incubation takes 2–4 weeks ▪ PCR assays

Chapter 96 Rods Biopsy ▪ CSD: granulomatous inflammation of lymph nodes, stellate microabscesses; organisms visualized using WS/silver stain ▪ BA: biopsy of lesions; Bartonella demonstrated with WS stain Serologic test ▪ Indirect immunofluorescence antibody (IFA)/enzyme immunoassay (EIA) Nonspecific findings ▪ ↑ erythrocyte sedimentation rate (ESR), ↑ C-reactive protein (CRP) in CSD

OTHER DIAGNOSTICS

▪ Clinical findings suggestive of Bartonella infection with history of contact with cat

Figure 96.1 The histological appearance of an lymph node excised from an individual with cat-scratch disease. There are numerous neutrophils which form characteristic stellate, or star-shaped, microabscesses.

TREATMENT MEDICATIONS CSD ▪ Usually self-limited within 2–4 months; antimicrobial therapy with azithromycin prevents life-threatening complications; alternative agents include doxycycline, rifampin BA ▪ Erythromycin, doxycycline, tetracycline

Figure 96.2 The histopathological appearance of bacillary angiomatosis. There is a proliferation of small capillaries surrounded by mixed inflammatoru cells, histiocytes and bacterial colonies.

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ENTEROBACTER osms.it/enterobacter PATHOLOGY & CAUSES ▪ Opportunistic microbe; nosocomial, various organ system infections; Enterobacteriaceae family; motile, nonfastidious; fast lactose fermenter, pink colonies on MacConkey agar (lactose containing medium); grows in aerobic, anaerobic conditions, rapidly on selective, nonselective agars; expresses fimbria; hemolysin, urease positive ▪ Commonly isolated species: E. cloacae, E. aerogenes ▪ Natural reservoir ▫ Soil, water, intestinal flora; occasionally respiratory tract ▪ Mode of transmission ▫ Endogenous: transfer from flora to adjacent sterile sites ▫ Exogenous: direct/indirect contact of mucosal surfaces with Enterobacter Commonly associated diseases ▪ Lower respiratory tract infections ▫ Tracheobronchitis, pneumonia, lung abscess, empyema ▪ Urinary tract infections (UTIs) in hospitalized individuals ▫ Cystitis, pyelonephritis, prostatitis ▪ Bloodstream infections (BSI) ▪ Skin, soft tissue infections ▫ Cellulitis, fasciitis, myositis, skin abscesses, wound infections ▪ Intra-abdominal infections ▫ Abscesses, peritonitis following intestinal perforation/surgery ▪ Uncommon ▫ Endocarditis, septic arthritis, osteomyelitis, CNS, ocular infections

RISK FACTORS

▪ More common in neonates, elderly individuals

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▪ Prolonged hospitalization ▪ Invasive procedures (e.g. post-surgery infections) ▪ Prior antibiotic therapy ▪ Invasive devices (e.g. venous catheterization) ▪ Underlying conditions ▫ Malignancy, chronic obstructive pulmonary disease (COPD), diabetes mellitus (DM), burns ▪ Mechanical ventilation ▪ Immunosuppression

COMPLICATIONS ▪ Septic shock

SIGNS & SYMPTOMS ▪ Non-specific, depends upon organ system affected ▪ UTIs ▫ Frequency, urgency of urination, dysuria

DIAGNOSIS DIAGNOSTIC IMAGING Chest X-ray/CT scan ▪ Respiratory infections Abdomen CT scan/ultrasound ▪ Abdominal infections

LAB RESULTS

▪ Urinalysis for UTIs

Microbe identification ▪ Gram staining, culture

Chapter 96 Rods

TREATMENT MEDICATIONS

▪ Antimicrobials ▫ Carbapenems, aminoglycosides, fluoroquinolones, trimethoprimsulfamethoxazole, polymyxins

SURGERY

▪ Drain abscesses

OTHER INTERVENTIONS

▪ Remove invasive devices (e.g. central venous catheters)

ESCHERICHIA COLI osms.it/escherichia-coli PATHOLOGY & CAUSES ▪ Frequent cause of variety of infections; Enterobacteriaceae family; encapsulated, motile; certain strains hemolytic (betahemolytic on blood agar); fast lactose fermenter (pink colonies on MacConkey agar); nonfastidious; beta-galactosidase positive (breaks down lactose into glucose, galactose); iron uptake system ▪ AKA E.Coli ▪ Natural reservoir ▫ Intestinal, vaginal flora ▪ Mode of transmission ▫ Person-to-person contact, contaminated food/water, dislocation from intestinal tract ▪ Growing conditions ▫ On selective media; aerobic, anaerobic; eosin-methylene blue (EMB) agar for isolation (colonies with green metallic sheen); 15–45°C/59–113°F (some strains more heat resistant) ▪ Virulence factors ▫ Fimbriae, K-capsule, lipopolysaccharides (LPS) endotoxin ▪ Pathogenic factors ▫ Fimbriae → cystitis, pyelonephritis ▫ K-capsule → pneumonia, neonatal meningitis ▫ LPS endotoxin → septic shock Commonly associated diseases ▪ Genitourinary tract infections

▫ Leading cause of cystitis, pyelonephritis, prostatitis ▪ Intra-abdominal infections ▫ Enteric infections, abscesses, cholecystitis, spontaneous bacterial peritonitis (E. coli most common cause) ▪ Pneumonia ▪ Meningitis (in neonates)

TYPES Enteroinvasive (EIEC) ▪ Invades intestinal mucosa → necrosis, inflammation → dysentery Enterotoxigenic (ETEC) ▪ Heat-labile toxin (LT) → over-activates adenylate cyclase (cAMP) → ↑ Cl- secretion in gut, water efflux ▪ Heat-stable toxin (ST) → overactivates guanylate cyclase (cGMP) → ↓ resorption of NaCl, water in gut ▪ Produces LT, ST → travellers’ diarrhea (watery), mimics Vibrio cholerae illness Enteropathogenic (EPEC) ▪ Adheres to apical surface, flattens villi, prevents absorption → diarrhea Enterohemorrhagic (EHEC) ▪ Most commonly isolated serotype O157:H7 ▪ Produces Shiga-like toxin → enhances cytokine release ▫ Necrosis, inflammation → dysentery ▫ Endothelial damage → formation of microthrombi → hemolysis

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(microangiopathic hemolytic anemia), platelet consumption (thrombocytopenia), ↓ renal blood flow (acute renal failure) → hemolytic uremic syndrome (HUS) ▫ O157:H7 most common serotype

SIGNS & SYMPTOMS ▪ Depends on organ system affected ▪ Clinical manifestations generally nonspecific, except in enteric infections ▫ EHEC: bloody diarrhea, malaise, fever ▫ EIEC: dysentery, mimics shigellosis; bloody diarrhea, abdominal pain, tenesmus ▫ ETEC: watery diarrhea (travellers’ diarrhea), nausea, abdominal pain ▫ EPEC: fever, watery diarrhea; can last > two weeks; typically affects children

DIAGNOSIS LAB RESULTS

▪ Culture to isolate E. coli, gram staining, ↑ fecal leukocytes (except ETEC), PCR assays ▪ Complete blood count ▫ Leukocytosis ▪ Urinalysis in UTIs ▪ Pyuria ▫ Leukocyte esterase + → evidence of white blood cell (WBC) activity ▪ Proteinuria, bacteriuria ▪ Nitrite test + → ↓ urinary nitrates → marker of infection

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TREATMENT MEDICATIONS

▪ Antimicrobial treatment (UTIs, pneumonia, meningitis, intra-abdominal infections, sepsis) ▫ Third-generation cephalosporins, quinolones, doxycycline, trimethoprim/ sulfamethoxazole (TMP/SMZ) ▪ Antidiarrheal medications ▫ Contraindicated in children, EIEC infections ▪ EHEC ▫ Antibiotics contraindicated; can increase risk of HUS, thrombotic thrombocytopenic purpura (TTP) complications ▪ ETEC ▫ Antibiotics useful; reduce diarrhea duration

OTHER INTERVENTIONS

▪ Most enteric infections self-limited, managed conservatively ▫ Fluid, electrolytes correction

Chapter 96 Rods

KLEBSIELLA PNEUMONIAE osms.it/klebsiella-pneumoniae PATHOLOGY & CAUSES ▪ Causative agent of infections, usually occur in immunocompromised individuals; major cause of hospital-acquired infections; Enterobacteriaceae family, facultative anaerobe, nonmotile; possesses prominent polysaccharide capsule; beta-lactamase positive (resistant to ampicillin, amoxicillin; susceptible to cephalosporins); urease positive, lactose fermenter, iron uptake system ▪ Natural reservoir ▫ Flora of human mouth, intestine; soil, water Commonly associated diseases ▪ Pulmonary infections ▫ Pneumonia, empyema, lung abscesses, bacteremia ▪ UTIs ▫ Cystitis, pyelonephritis, prostatitis, abscesses ▪ Pyogenic liver/splenic abscesses ▪ Infective endocarditis ▪ Spontaneous bacterial peritonitis ▪ Endophthalmitis ▪ CNS infections ▪ Meningitis, brain abscesses ▪ Deep neck infections ▪ Skin, soft tissue infections

COMPLICATIONS

▪ Pneumonia can be fatal regardless of treatment

SIGNS & SYMPTOMS ▪ Pneumonia presents as bronchopneumonia/bronchitis (acute onset of symptoms) ▫ Productive cough (e.g. mucoid; bloody sputum, AKA “currant jelly sputum”), high grade fever, chills, chest pain, dyspnea, tachypnea, crackles ▪ UTIS (frequency, urgency, dysuria)

DIAGNOSIS DIAGNOSTIC IMAGING Chest X-ray ▪ Findings suggestive of pneumonia

LAB RESULTS

▪ Complete blood count ▫ Leukocytosis ▪ Specimen culture ▫ E.g. blood, sputum, urine ▫ Gram stain: Gram-negative, rod-shaped capsule appears as clear space

TREATMENT

RISK FACTORS

▪ Prolonged hospitalization ▪ Prior use of antibiotics ▪ Prolonged use of invasive devices (e.g. catheters) ▪ Underlying medical conditions ▫ Alcoholism, DM, underlying malignancy, hepatobiliary disease, COPD, renal failure ▪ Use of glucocorticoids

MEDICATIONS

▪ Antimicrobial therapy ▫ Beta-lactams with beta-lactamase inhibitors, cephalosporins, fluoroquinolones, aminoglycosides, carbapenems

SURGERY

▪ Drain abscesses ▪ Debride necrotic issues

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LEGIONELLA PNEUMOPHILA osms.it/legionella-pneumophila PATHOLOGY & CAUSES

SIGNS & SYMPTOMS

▪ Gram-negative, facultative intracellular (stain poorly with Gram stain); best visualized by silver stain; appears in specimens as short rod; longer, filamentous in culture; grows best on charcoal yeast extract medium with cysteine, iron; serogroup 1 most commonly associated with human infections ▪ Natural reservoir ▫ Water sources (e.g. air conditioning systems, tubing systems of domestic water supplies, water-cooling towers) ▪ Mode of transmission ▫ Water aerosol inhalation

Legionnaires’ disease ▪ Incubation period ▫ 2–10 days ▪ Atypical pneumonia ▫ Mild cough (may cough bloody mucus), high grade fever, chills, dyspnea, chest pain, rales ▪ GI ▫ Diarrhea, nausea, vomiting, abdominal pain ▪ CNS ▫ Confusion, lethargy, headache, focal neurologic signs, hallucinations

Commonly associated diseases ▪ Legionnaires’ disease ▫ Atypical form of pneumonia ▪ Pontiac fever ▪ Rare self-limited upper respiratory tract infection ▪ Extrapulmonary disease (rare) ▫ Heart most common extrapulmonary site (e.g. myocarditis, endocarditis)

Pontiac fever ▪ Acute onset ▪ Mild, febrile, flu-like syndrome

RISK FACTORS

▪ ↑ age, immunosuppression, smoking, chronic lung disease, organ transplant, renal failure, cardiac disease

COMPLICATIONS

▪ Pneumonia ▫ Progresses rapidly, can be fatal (esp. immunosuppressed individuals) ▪ Renal failure

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DIAGNOSIS DIAGNOSTIC IMAGING Chest X-ray/CT scan ▪ Legionnaires’ disease ▫ Unilateral ▪ Diffuse, patchy inflammation of interstitium → consolidation involving ≥ one lobe

LAB RESULTS

▪ Nonspecific findings ▫ Hyponatremia, thrombocytopenia, leukocytosis, hypophosphatemia ▪ Culture of respiratory specimens ▫ Many neutrophils, few microorganisms ▪ Urinary antigen test using enzyme-linked immunosorbent assay (test of choice along with culture) ▫ Rapid; sensitive, specific; legionella persists in urine for weeks

Chapter 96 Rods ▪ Fluorescent antibody test on sputum specimens ▪ Serological tests ▫ Serum antibodies develop after 8–10 days; fourfold rise in titre/single high titre ▪ PCR using sputum/other specimens (less sensitive than culture)

TREATMENT MEDICATIONS

▪ Atypical pneumonia ▫ Macrolides, tetracyclines. fluoroquinolones, rifampicin

OTHER INTERVENTIONS

▪ Eradication of organism from responsible water source to control disease

NONTYPHOIDAL SALMONELLA osms.it/nontyphoidal-salmonella PATHOLOGY & CAUSES ▪ Causes salmonellosis (foodborne gastroenteritis); Enterobacteriaceae family; motile; encapsulated; facultative intracellular, anaerobes; nonlactose fermenter; oxidase-; possesses type III secretion system, iron uptake system; high infectious dose; H2S production on TSI agar; produces endotoxin ▪ Most common human pathogen ▫ S.enteritidis ▪ Natural reservoir ▫ Humans, animals; poultry, eggs, pets, turtles common sources ▪ Mode of transmission ▫ Food (e.g. undercooked meat, poultry, eggs, milk), fecal-oral route

RISK FACTORS

▪ Age (usually affects young children, older adults); season (peak incidence in summer, fall); low gastric acidity (atrophic gastritis, use of acid-suppressive agents); immunodeficiency; sickle cell disease; hemolytic anemia; alcoholism; cardiovascular dysfunction; malignancies; IV drug use

COMPLICATIONS

▪ Can disseminate via blood → extraintestinal manifestations (e.g. endocarditis, vascular infections, cholecystitis, hepatic/splenic abscesses)

SIGNS & SYMPTOMS ▪ Present 24–48 hours after food ingestion ▪ Loose stools/diarrhea often bloody (can persist for two weeks) ▪ Nausea, vomiting ▪ Fever (resolves within two days) ▪ Abdominal cramps

DIAGNOSIS LAB RESULTS

▪ Stool culture, ↑ fecal leukocytes, blood cultures to detect bacteremia; bone marrow aspiration, culture

TREATMENT MEDICATIONS

▪ Antimicrobial therapy ▫ Generally not required, prolongs duration of fecal shedding of Salmonella, doesn’t shorten duration of symptoms

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▪ Antibiotics ▫ Only indicated in immunocompromised individuals; antimicrobial agents (e.g. ciprofloxacin)

PROTEUS MIRABILIS osms.it/proteus-mirabilis PATHOLOGY & CAUSES ▪ Common cause of community acquired, nosocomial UTIs (e.g. primarily cystitis, pyelonephritis) ▪ Enterobacteriaceae family; highly motile; nonlactose fermenters; oxidase negative; expresses mannose-resistant hemagglutination, calcium dependent/ independent hemolysins; swarming growth in discontinuous manner on agar media; H2S production on TSI agar; resistance to polymyxins, tetracyclines ▪ Urease positive → converts urea to ammonia, CO2 → ↑ urine pH → ammonia combines with magnesium, phosphate → form magnesium-ammonium-phosphate (struvite) stones ▪ Pr. mirabilis causes 90% of infections ▪ Natural reservoir ▫ Intestinal flora ▪ Virulence factors ▫ Fimbria (important for adherence to tissue) Commonly associated diseases ▪ Urethritis, acute prostatitis, pyogenic liver abscesses

RISK FACTORS

▪ Hospitalization; ↑ age (most common in elderly); multiple prior UTIs; prior use of antibiotics; urinary tract surgery; urinary catheterization; structural abnormalities/ obstructions of urinary tract; underlying medical conditions (e.g. DM, chronic kidney disease); neurogenic bladder; frequent sexual activity

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COMPLICATIONS

▪ Abscesses, sepsis, meningitis, chronic pyelonephritis, xanthogranulomatous pyelonephritis (chronic destructive granulomatous process of renal parenchyma)

SIGNS & SYMPTOMS ▪ Nonspecific, disease-dependent: symptoms commonly associated with urethritis, acute prostatitis, pyogenic liver abscesses

DIAGNOSIS DIAGNOSTIC IMAGING Ultrasound/CT scan ▪ Kidneys; indicated if therapy fails X-ray ▪ Struvite stones appear radiopaque

LAB RESULTS

▪ Urine culture to isolate Proteus ▪ Complete blood count ▫ Leukocytosis ▪ Urinalysis ▫ Alkaline urine pH (> 7.0), pyuria, bacteriuria

Chapter 96 Rods

TREATMENT MEDICATIONS

▪ Uncomplicated UTIs ▫ Cystitis: TMP/SMX, nitrofurantoin, quinolones, fosfomycin ▫ Pyelonephritis: quinolone/ampicillin, gentamicin/third-generation cephalosporin ▪ Complicated UTIs ▫ E.g. diabetes, nephrolithiasis, pregnancy, anatomic abnormalities of urinary tract ▫ Therapy should be prolonged

SURGERY

▪ Drainage of collections (e.g. perinephric abscesses) ▪ Removal of struvite renal calculus

Figure 96.3 Proteus species spread in a swarming fashion on an agar plate.

PSEUDOMONAS AERUGINOSA osms.it/pseudomonas-aeruginosa PATHOLOGY & CAUSES ▪ One of most common causes of hospitalacquired infections in immunocompromised individuals; motile; aerobic; nonlactose fermenter (derives energy from carbohydrates by oxidation); nonfastidious; oxidase, catalase, elastase, leukocidin, hemolysin positive; resistant to many antibiotics ▪ Grows on variety of culture media ▫ Colonies greenish-blue due to production of procyanin (blue), pyoverdin (yellow-green); fruity, grapelike odor ▪ Natural reservoir ▫ Water, soil sources (e.g. rivers, ponds), animals, plants, hospital equipment; hospitalized individuals asymptomatic carriers ▪ Mode of transmission ▫ Direct contact with contaminated materials/infected individuals

▪ Virulence factors ▫ Exotoxin A → inactivates elongation factor (EF-2) → inhibition of protein synthesis → death of host cells ▫ Phospholipase C → degrades membranes ▫ Endotoxin → fever, shock ▫ Mucoid exopolysaccharide → biofilm formation → protection from immune system Commonly associated diseases ▪ Pneumonia; sepsis; genitourinary tract infections; skin, soft tissue infections; ear infections (e.g. external otitis, chronic otitis media); eye infections (e.g. keratitis); GI infections; bone, joint infections (usually affects vertebral column); infective endocarditis

RISK FACTORS

▪ Prolonged hospitalization, catheterization, IV drug use, severe burns, contact lenses, eye trauma

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▪ Mechanical ventilation/endotracheal intubation ▫ P. aeruginosa second most common cause of ventilator-associated pneumonia ▪ Cystic fibrosis (CF) → chronic infection with P. aeruginosa ▪ Immune system deficits (e.g. neutropenia, diabetes)

COMPLICATIONS

▪ Sepsis/necrotizing pneumonia can be fatal in immunocompromised individuals ▪ Chronic infections in CF → bronchiectasis, pulmonary fibrosis → pulmonary failure ▪ Disseminated intravascular coagulation due to sepsis ▪ Eye infections → vision loss

SIGNS & SYMPTOMS ▪ Generally nonspecific, depend on organ system ▪ Eye infections (esp. cornea) extremely painful, rapidly destructive ▪ Ecthyma gangrenosum ▫ Due to sepsis, typically appears in immunocompromised individuals ▫ Well-demarcated, black, necrotic cutaneous lesion; rapidly progressive

Figure 96.4 Pseudomonas species will adopt a greenish hue when cultured on cetrimide agar.

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DIAGNOSIS DIAGNOSTIC IMAGING Chest X-ray ▪ Pneumonia ▫ Bilateral bronchopneumonia with nodular infiltrates with/without pleural effusion

LAB RESULTS

▪ Culture (blood/other specimens) on selective media ▫ Enhances production of procyanin ▪ Oxidase test ▪ PCR assays ▪ Complete blood count ▫ Leukocytosis ▪ Serological tests ▫ Only individuals with CF/COPD

TREATMENT MEDICATIONS

▪ Antimicrobial therapy ▫ Extended-spectrum penicillins, betalactamase inhibitors, aminoglycosides, carbapenems, monobactams, polymyxins, fluoroquinolones, third/ fourth-generation cephalosporins

Chapter 96 Rods

SERRATIA MARCESCENS osms.it/serratia-marcescens PATHOLOGY & CAUSES ▪ Opportunistic microbe; uncommon cause of variety of hospital-acquired infections; Enterobacteriaceae family; motile; aerobic; slow, weak lactose fermenter; urease positive (struvite stones in individuals with recurrent UTIs); catalase positive; grows on media at 30–37°C/86–99°F, utilize most carbohydrates with production of acid, gas; produces red pigment (prodigiosin) colonies on agar; often resistant to commonly used antibiotics (e.g. ampicillin, macrolides, firstgeneration cephalosporins) ▪ Natural reservoir ▫ Water, soil sources ▪ Virulence factors ▫ Fimbria, cell surface components, longchain LPS, hemolysin Commonly associated diseases ▪ Respiratory infections (e.g. pneumonia), UTIs, wound infections, CNS infections (e.g. meningitis, cerebral abscesses), intra-abdominal infections, septicemia, endocarditis, otitis externa

RISK FACTORS

▪ Neonates, infants ▪ More common in individuals who are biologically male ▪ Prolonged hospitalization; catheterization (e.g. intravenous, urinary catheters); mechanical ventilation; recent surgery/ obstruction of urinary tract; cardiac valve replacement; IV drug use; immune system deficits (e.g. neutropenia, chronic granulomatous disease, DM); head trauma/ brain surgery; contact lenses

COMPLICATIONS

▪ Septic shock, stroke (due to endocarditis)

SIGNS & SYMPTOMS ▪ Nonspecific, depend upon disease ▪ Symptoms associated with respiratory infections, UTIs, wound infections, CNS infections, intra-abdominal infections, septicemia, endocarditis, otitis externa

DIAGNOSIS DIAGNOSTICS IMAGING Chest X-ray ▪ Pneumonia Abdominal ultrasound/CT scan ▪ Abnormalities of urinary tract, intraabdominal infections, abscesses Echocardiography ▪ Valvular vegetations Brain CT scan ▪ Follow with lumbar puncture in individuals with suspected meningitis

Figure 96.5 Serratia marcessens grows red colonies when cultured on agar.

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LAB RESULTS

▪ Complete blood count ▫ Leukocytosis, ↑ neutrophils with left shift, possible anemia

TREATMENT MEDICATIONS

▪ Antibiotic therapy ▫ Aminoglycosides with antipseudomonal beta-lactam ▫ If infection persists, fluoroquinolones/ carbapenems

SURGERY

▪ Drainage of collections (e.g. abscesses)

SHIGELLA osms.it/shigella PATHOLOGY & CAUSES ▪ Causes acute infectious diarrhea (shigellosis), one of most common causes of bloody diarrhea; Enterobacteriaceae family; facultative anaerobe; nonmotile; nonlactose fermenter; urease, oxidase negative; resistance to low pH of gastric acids; highly virulent; possesses virulence plasmids; invades colonic mucosa via microfold (M) cells of Peyer patches ▪ Natural reservoir ▫ Human only; part of intestinal tract flora ▪ Mode of transmission ▫ Usually fecal-oral route, contaminated water, food; easy person-to-person spread

TYPES

▪ S. dysenteriae: serogroup A ▫ Releases Shiga toxin, causes most severe form of shigellosis ▪ S. flexneri: serogroup B ▪ S. boydii: serogroup C ▪ S. sonnei: serogroup D

COMPLICATIONS

▪ Dehydration (due to fluid loss) ▪ Electrolyte imbalance (e.g. hyponatremia,

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hypokalemia) ▪ Reiter’s syndrome ▫ Reactive arthritis, urethritis, conjunctivitis ▫ Affects HLA-B27+ individuals ▪ Hemolytic-uremic syndrome ▫ Hemolytic anemia, thrombocytopenia, acute renal failure ▫ Usually in infections due to S. dysenteriae ▪ Toxic megacolon ▪ Intestinal obstruction

SIGNS & SYMPTOMS ▪ Incubation period ▫ 2–3 days/one week ▪ Sudden onset ▫ Abdominal pain ▫ Diarrhea that is initially watery, progresses to bloody (bacillary dysentery) in 50% of cases ▫ Tenesmus ▫ Fever, malaise, headache, anorexia ▪ Less common ▫ Nausea, vomiting

Chapter 96 Rods ▪ Subacute presentation in minority of individuals ▫ Several weeks of waxing/waning diarrhea

DIAGNOSIS DIAGNOSTIC IMAGING Colonoscopy ▪ Hemorrhagic, ulcerated mucosa ▪ Most prominent in left colon, ileum also involved ▪ Pseudomembranes

TREATMENT MEDICATIONS

▪ Antimicrobial therapy ▫ Shorten duration of symptoms, reduce fecal shedding of organisms, risk of complications; azithromycin orally, thirdgeneration cephalosporin parenterally ▪ Antidiarrheal medications contraindicated ▫ Delay fecal shedding of Shigella

OTHER INTERVENTIONS

▪ Most cases self limited (resolve within one week), do not require antibiotics

LAB RESULTS

▪ Stool culture ▪ ↑ leukocytes, blood in feces ▪ PCR testing of stools

YERSINIA MARCESCENS osms.it/yersinia-marcescens PATHOLOGY & CAUSES ▪ Enterobacteriaceae family; facultative anaerobe, intracellular; motility depends on temperature (motile at 25°C/77°F, nonmotile at 37°C/99°F); nonlactose fermenter; oxidase negative ▪ Important human pathogens ▫ Y. pestis, Y.enterocolitica ▪ Natural reservoir ▫ Y. pestis: ground squirrels, gerbils, voles, rats ▫ Y. enterocolitica: cattle, deer, pigs, birds, pigs ▪ Virulence factors ▫ Adhesins to bind to host cell beta 1 integrins, endotoxin, coagulase, fibrinolysin, iron uptake system (mediates iron capture, transport)

TYPES Yersinia enterocolitica ▪ Causes yersiniosis ▫ Gastrointestinal infections (e.g. ileum, appendix, right colon) ▪ Common types ▫ Enterocolitis, terminal ileitis, mesenteric lymphadenitis, pseudoappendicitis ▪ Mode of transmission ▫ Pet feces, inadequately cooked foods, contaminated pork, milk, water Yersinia pestis ▪ Causes human plague ▫ Zoonotic infection, highly fatal if untreated ▪ Subtypes ▫ Wild (sylvatic), urban plague (typically transmitted from rats, more severe)

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▪ Clinical forms ▫ Bubonic (more common), septicaemic, pneumonic (least common, high mortality rate) ▪ Mode of transmission ▫ Fleas from rats, other rodents

COMPLICATIONS Yersinia enterocolitica ▪ Reiter’s syndrome, myocarditis, erythema nodosum, kidney disease, mucosal ulceration, bowel necrosis (due to mesenteric vessel thrombosis), septicemia (fatal if untreated) Yersinia pestis ▪ Bubonic plague → sepsis → secondary pneumonic plague/meningitis ▪ Systemic plague → hypotension, disseminated intravascular coagulation, multiorgan failure ▪ Pneumonic plague (rapidly fatal if untreated)

SIGNS & SYMPTOMS Yersinia enterocolitica ▪ Enterocolitis (most common) ▫ Abdominal pain, acute diarrhea, low grade fever, nausea, vomiting ▪ Abdominal tenderness ▫ Right lower quadrant, mimics appendicitis (pseudoappendicitis) ▪ Extraintestinal features of pharyngitis, arthralgia, erythema nodosum (painful, red/ purple lesions, resolve spontaneously) Yersinia pestis ▪ Incubation period ▫ 2–8 days ▪ Bubonic plague (sudden onset) ▫ fever; painful lymphadenopathy (bubos), inguinal lymph nodes frequently involved; chills, fatigue ▪ Septicemic plague ▫ Fever; malaise, GI symptoms (nausea, vomiting, diarrhea)

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▪ Pneumonic plague (sudden onset): ▫ Dyspnea, high grade fever, chest pain, cough with blood-containing sputum

DIAGNOSIS DIAGNOSTIC IMAGING Ultrasound/CT scan ▪ Yersinia enterocolitica: exclude appendicitis Colonoscopy ▪ Yersinia enterocolitica: aphthoid lesions in cecum; elevations, ulcers in terminal ileum Chest X-ray ▪ Yersinia pestis: pneumonic plague

LAB RESULTS Yersinia enterocolitica ▪ Identification of microbe ▪ Stool culture ▫ Cefsulodin-irgasan-novobiocin (CIN) agar ▫ In extraintestinal disease, cultures of lymph nodes/blood may be positive ▪ PCR assays ▪ ↑ leukocytes in stool, blood ▪ Serological tests ▫ Tube agglutination, enzyme-linked immunosorbent assay (ELISA) Yersinia pestis ▪ Nonspecific findings ▫ Leukocytosis, thrombocytopenia ▪ Isolation of organism in blood culture ▫ Positive cultures in individuals with bubonic, septicemic plague ▪ Peripheral blood smear ▫ Wright–Giemsa stain reveals rodshaped bacteria, Wayson stain reveals characteristic “safety pin” appearance ▪ Rapid antigen testing in sputum/serum ▪ Serological tests ▫ Fourfold rise in serum antibody titers between acute, convalescent phase ▪ PCR assays

Chapter 96 Rods

OTHER DIAGNOSTICS Yersinia pestis ▪ Clinical findings suggestive of plague, history of traveling to plague-endemic areas

TREATMENT MEDICATIONS Yersinia enterocolitica ▪ Antimicrobial therapy ▫ TMP/SMX, aminoglycosides ▫ Alternative agents: third-generation cephalosporins, tetracyclines, fluoroquinolones

Figure 96.6 The black, necrotic fingers of a man infected with Yersinia pestis.

Yersinia pestis ▪ Antimicrobial therapy ▫ Aminoglycosides (streptomycin/ gentamicin) ▫ Alternative agents: doxycycline, tetracycline, fluoroquinolones, chloramphenicol

OTHER INTERVENTIONS Yersinia enterocolitica ▪ ↑ fluid intake, good nutrition

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NOTES

NOTES

SPIROCHETES MICROBE OVERVIEW Morphology ▪ Thin-walled, Gram-negative flexible spiral rods ▪ Length: 5–250μm; diameter: 0.1–0.6μm ▪ Unique double membrane separated by periplasmic space

▪ Corkscrew-like motility via axial filament situated lengthwise between inner and outer membranes (endoflagella) Replication ▪ Reproduction: sexual transverse binary fission

BORRELIA BURGDORFERI (LYME DISEASE) osms.it/lyme-disease PATHOLOGY & CAUSES ▪ An obligate parasite that causes Lyme disease, a systemic inflammatory disease ▪ Non-spore forming ▪ Life cycle includes mammals, birds, and ticks (genus Ixodes), principally in North America ▪ Killed when exposed to hypotonic or hypertonic environments, drying, disinfectants (e.g. bleach), or temperatures > 50°C/122°F ▪ Transmission ▫ Via tick bite → enters blood → spreads to tissues and organs; especially joints, heart, nervous system ▪ Infection progresses through three stages 1. Localized disease (occurs 3–30 days after exposure) 2. Disseminated disease (days to months after exposure; multisystem involvement) 3. Late/chronic disease (months to years after exposure)

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RISK FACTORS

▪ Exposure to ticks in endemic areas ▫ Living in areas bordering forests ▫ Outdoor employment, recreation ▪ Most cases occur in late spring to summer

COMPLICATIONS

▪ Meningitis, cranial neuropathy ▪ Lyme carditis ▫ AV block, myopericarditis ▪ Chronic joint inflammation ▪ Post–Lyme disease syndrome

SIGNS & SYMPTOMS Early signs/symptoms of localized disease ▪ Erythema migrans (EM) rash ▫ Non-painful, gradually expanding “bull’s-eye” rash appearing at the site of tick bite; feels warm to palpation; may itch

Chapter 97 Spirochetes ▪ Constitutional ▫ Low grade fever, chills, headache, fatigue, myalgia, arthralgia, lymphadenopathy Disseminated signs/symptoms ▪ Severe headaches and neck stiffness ▪ Formation of additional EM ▪ Joint pain and swelling; especially knees, other large joints ▪ Facial palsy ▪ Palpitations (Lyme carditis) ▪ Episodic dizziness, dyspnea ▪ Pain ▫ Shooting pains, numbness, or tingling in the hands or feet ▪ Short-term memory loss Late/chronic disease ▪ Presence of nonspecific symptoms (e.g. headache, fatigue, joint pain) that persists after treatment for Lyme disease

DIAGNOSIS LAB RESULTS CDC testing criteria ▪ Two tiered testing for lyme disease ▫ First test: enzyme immunoassay (EIA) or immunofluorescence assay (IFA) ▫ Second test (as needed): IgM and/or IgG western blot Other laboratory findings ▪ Blood chemistry ▫ ↑ ESR, serum creatine phosphokinase, aspartate aminotransferase (AST) and/ or alanine aminotransferase (ALT) ▪ Blood studies ▫ Anemia, leukocytosis, thrombocytopenia

OTHER DIAGNOSTICS

▪ History of exposure to ticks in an endemic area and characteristic clinical presentation

TREATMENT MEDICATIONS

▪ Antibiotics ▫ Doxycycline, amoxicillin, or cefuroxime axetil

Figure 97.1 A bulls-eye-shaped rash, known as erythema migrans, at the site of infection with Borellia burgdorferi, the causative agent of Lyme disease.

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BORRELIA SPECIES (RELAPSING FEVER) osms.it/borrelia-species PATHOLOGY & CAUSES ▪ Relapsing fever: bacterial infection caused by Borrelia spirochetes Tick-borne relapsing fever (TBRF) ▪ Endemic ▪ Found in endemic areas ▫ Mountainous areas of North America, plateau regions of Mexico, Central and South America, Mediterranean, central Asia, Africa ▪ Caused primarily by Borrelia hermsii, Borrelia turicatae, Borrelia parkeri in North America ▪ Spread by soft tick species Ornithodoros parkeri and Ornithodoros turicata ▪ Risk factors ▫ Occupying rodent-infested cabins, caves, or other dwellings ▫ Camping near rodent nests ▪ Tick attaches to human host (usually at night during sleep) → bites and feeds on blood → saliva and spirochete enter host’s circulation Louse-borne relapsing fever (LBRF) ▪ Epidemic ▪ Caused by Borrelia recurrentis ▪ Spread person-to-person via body louse ▪ Risk factors ▫ Primarily seen in low resource countries ▫ Famines, wars; causes epidemics among refugees, migrant populations ▫ Homelessness (exposure to lice) ▫ Poor hygiene ▪ B. recurrentis grows in the body cavity Pediculus humanus corporis → human host crushes louse/louse feces with fingers → spirochete enters either through bite site, through breaks in the skin caused by scratching, or through conjunctiva when

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fingers touch eyes After entry into human host ▪ Spirochete divides every 6–12 hours (can number up to 106–108 per mL) → leaves blood and enters tissues: brain, eye, inner ear, liver, heart, testes, and other organs Pattern of intermittent illness ▪ Relapsing fever caused by spirochetemia ▪ Characterized by recurrent episodes of fever and constitutional symptoms with intermittent periods of general well-being ▫ Interval range between fevers is 4–14 days ▫ Pattern of intermittent illness caused by outer membrane lipoproteins called variable major proteins (VMPs) ▫ Employed as multiphasic antigens to evade host adaptive immunity ▫ TBRF: multiple febrile periods last 1–3 days each ▫ LBRF: first episode lasts 3–6 days, followed by a single milder episode Complications ▪ Neurological ▫ Meningitis, subarachnoid hemorrhage, cranial nerve neuritis, Bell’s palsy, hearing loss ▪ Ocular ▫ Iridocyclitis, panophthalmitis, vision loss ▪ Cardiac ▫ Myocarditis, cardiac failure ▪ Respiratory ▫ Bronchopneumonia, acute respiratory distress syndrome ▪ Hematologic ▫ Thrombocytopenia ▪ Other ▫ Hepatitis, splenic rupture ▪ During pregnancy

Chapter 97 Spirochetes ▫ Spontaneous abortion, prematurity, neonatal death ▪ Jarisch–Herxheimer reaction ▫ During treatment with antibiotics → release of proinflammatory cytokines triggered by products released from dead microbes

SIGNS & SYMPTOMS ▪ Characteristics of febrile episodes ▫ Sudden onset of high fever → crisis phase: chills, ↑ ↑ temperature, ↑ HR, ↑ BP → diaphoresis, ↓ fever, ↓ BP ▫ ↑ mortality during crisis and immediate aftermath ▪ Constitutional ▫ Sudden onset of high fever and chills; followed by headache, myalgia, arthralgia, nausea ▪ Neurologic ▫ Dizziness, delirium, stupor, facial palsy ▪ Cardiac ▫ Prolonged QTc interval. ▪ Respiratory ▫ Nonproductive cough, signs of respiratory distress ▪ Hematologic ▫ Epistaxis, petechiae, ecchymoses, blood-tinged sputum ▪ Other ▫ Hepatomegaly, abdominal pain, photophobia, skin rash

DIAGNOSIS LAB RESULTS Visualization of microbe ▪ Blood: thick or thin smears ▫ Giemsa, Wright, or acridine orange stain ▫ Direct or indirect immunofluorescence ▫ Phase contrast or dark field microscopy ▪ PCR, culture, serology ▪ Tissue specimen ▫ Silver stain (e.g. Warthin-Starry, modified Dieterle) ▫ Immunofluorescence

TREATMENT MEDICATIONS

▪ Antibiotics ▫ Penicillin G, ceftriaxone, doxycycline

OTHER INTERVENTIONS Prevention ▪ Avoidance and eradication of vector

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LEPTOSPIRA osms.it/leptospira PATHOLOGY & CAUSES ▪ A spirochete that causes the disease leptospirosis ▫ AKA Weil's disease, Weil–Vasiliev disease, swineherd's disease, rice-field fever, waterborne fever, nanukayami fever, cane-cutter fever, swamp fever, mud fever, Stuttgart disease, canicola fever ▪ Infected mammal excretes microbe in urine which remains viable in stagnant water and wet soil → environmental exposure by humans → microbe usually enters via non-intact skin, mucous membranes, or conjunctivae (rarely via contaminated food, water, or aerosols) ▪ Effects of microbe ▫ Damages blood vessel endothelium → organ damage ▫ Inhibits the Na+-K+-Cl- cotransporter activity in the thick ascending limb of Henle → hypokalemia, hyponatremia

COMPLICATIONS

Electrolyte imbalance, kidney failure Hepatitis, hepatic hemorrhage Aseptic meningitis Pulmonary hemorrhage, acute respiratory distress syndrome (ARDS) ▪ Uveitis, optic neuritis ▪ Myocarditis ▪ Rhabdomyolysis ▪ ▪ ▪ ▪

SIGNS & SYMPTOMS ▪ Variable clinical course ▫ Ranges from mild disease that resolves uneventfully to severe and potentially fatal ▪ Common symptoms ▫ Abrupt onset of fever, chills ▫ Headache

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▫ Nonproductive cough ▫ Pharyngitis ▫ Myalgias, arthralgias ▫ Conjunctival suffusion (redness without exudate) ▫ Lymphadenopathy ▫ Jaundice ▫ Uremia, bacteremia, oliguria, hypokalemia

DIAGNOSIS DIAGNOSTIC IMAGING Chest X-ray ▪ Nodular densities, consolidation; may have a ground-glass appearance

LAB RESULTS

▪ Identification of microbe ▫ PCR, ELISA, microscopic agglutination ▪ Other laboratory studies ▫ Leukocytosis with left shift ▫ Hypokalemia, hyponatremia ▫ ↑ hepatic transaminases, ↑ direct bilirubin ▫ Urinalysis: proteinuria, pyuria, granular casts, hematuria, ↑ creatine kinase ▫ CSF: neutrophilic pleocytosis, ↑ protein

OTHER DIAGNOSTICS

▪ History and physical examination

Chapter 97 Spirochetes

OTHER INTERVENTIONS

TREATMENT MEDICATIONS

▪ Antibiotics ▫ Doxycycline (mild cases), penicillin (severe cases)

▪ Address complications ▪ Prevention ▫ Avoidance of potential infectious sources of infection, domestic animal vaccination

TREPONEMA PALLIDUM (SYPHILIS) osms.it/syphilis PATHOLOGY & CAUSES ▪ The spirochete bacterium that causes syphilis, a localized and systemic disease ▪ Transmission ▫ Sexually: by direct contact with an infectious lesion (primarily) → enters via microscopic abrasions ▫ Perinatally: crosses placenta easily → congenital syphilis ▪ Progresses through stages ▫ Primary: localized sores (chancre) appear after about three weeks at site of infection ▫ Secondary: 2–8 weeks after chancre resolution, hematogenous bacterial dissemination causes systemic symptoms ▫ Latent: asymptomatic ▫ Tertiary (late): organ damage develops 10–30 years after initial infection ▪ Neurosyphilis and ocular syphilis can occur at any stage ▫ Neurosyphilis begins when the microbe invades the CSF

RISK FACTORS

Unprotected sex Multiple sexual partners Biologically male Biologically-male individuals engaging in same-sex sexual contact (MSM) ▪ IV drug use ▪ Existing sexually-transmitted disease, especially HIV ▪ ▪ ▪ ▪

COMPLICATIONS

▪ Cardiovascular: syphilitic aortic aneurysms, dilated aorta, aortic valve regurgitation; coronary artery narrowing ▪ Congenital syphilis: hemolytic anemia, deafness, keratitis, periostitis ▪ Neurosyphilis: dementia, meningitis, brain or spinal cord ischemia/infarction, seizures, ischemic stroke ▪ Ocular syphilis: uveitis, vitritis, retinitis, optic neuropathy, blindness ▪ Otosyphilis: hearing loss, tinnitus

SIGNS & SYMPTOMS Stages ▪ Presentation will vary according to stage of disease ▪ Primary ▫ Chancre: painless ulcers at inoculation site (in contrast to painful lesions seen in genital herpes or chancroid) ▫ Single or multiple; usually firm, round, painless ▫ Heals with or without treatment; treatment prevents progression to secondary stage ▪ Secondary ▫ May be asymptomatic ▫ Rash: diffuse rough, reddish-brown maculopapular on extremities, palms of hands and/or soles of feet, back; raised, gray-whitish lesions on mucous membranes ▫ Condylomata lata

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▫ Myalgia ▫ Fatigue ▫ Lymphadenopathy ▫ Fever ▫ “Moth-eaten” alopecia ▫ Resolves without treatment; treatment prevents progression to latent and tertiary stages ▪ Latent ▫ Positive serology; asymptomatic ▪ Tertiary (late) ▫ Gummas: non-cancerous, granulomatous growths on internal organs, bones, skin; more common in HIV-infected individuals ▫ Evidence of organ involvement; charcot joints, aoritis (due to destruction of vasa vasorum) Complications ▪ Neurosyphilis ▫ Meningitis: headache, nausea and vomiting, stiff neck ▫ Tabes dorsalis: muscle weakness, locomotor ataxia, ↓ proprioception, incoordination ▫ General paresis (paralytic dementia) ▫ Facial and limb hypotonia, intention tremors ▫ Forgetfulness, personality changes ▪ Ocular syphilis ▫ ↓ visual acuity; loss of vision ▫ Argyll Robertson pupil: small pupils that constrict poorly in response to direct light

▪ Serum treponemal tests ▫ Fluorescent treponemal antibody absorption (FTA-ABS) ▫ Treponema pallidum particle agglutination assay (TPPA) ▫ Syphilis enzyme immunoassays (EIAs) ▪ If neurologic symptoms, lumbar puncture and CSF examination ▫ ↑ lymphocytes, ↑ protein ▫ CSF-VDRL reactivity

OTHER DIAGNOSTICS

▪ History and physical examination

Figure 97.2 A painless penile chancre, seen here, is the clinical manifestation of primary syphilis.

Congenital syphilis ▪ Presents with vesicular/bullous rash, rhinitis, hepatosplenomegaly, jaundice, and pseudoparalysis

DIAGNOSIS LAB RESULTS

▪ Identification of microbe ▪ Serum nontreponemal tests (may be nonreactive in late neurosyphilis) ▫ Venereal disease research laboratory (VDRL) ▫ Rapid plasma reagin (RPR)

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Figure 97.3 Condylomata lata, seen here, are the clinical manifestation of secondary syphilis.

Chapter 97 Spirochetes

TREATMENT MEDICATIONS

▪ Parenteral (IM/IV) penicillin G ▫ Doxycycline or tetracycline (PO); ceftriaxone (IM, IV) if penicillin allergy

OTHER INTERVENTIONS

▪ Treat partners ▪ Screening during first prenatal visit (VDRL or RPR)

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NOTES

NOTES

STAPHYLOCOCCUS MICROBE OVERVIEW ▪ Staphylococcus: genus of Gram-positive bacteria responsible for many diseases ▪ Aerobic, facultative anaerobic ▪ Frequent skin colonization: up to half of population Genetic material ▪ All staphylococci are catalase-positive Taxonomy ▪ Staphylo-: cluster; -coccus: berry Morphology ▪ Organized in grape-like clusters ▪ Gram stain: round, Gram-positive (purple)

bacteria; thick peptidoglycan cell wall Antibiotic resistance mechanisms ▪ β-lactamase: hydrolysis of β-lactam antibiotics; some β-lactam antibiotics are resistant to the enzyme (e.g. oxacillin, nafcillin, flucloxacillin) ▪ mecA gene → penicillin binding protein (PBP2a) → reduced affinity for β-lactam antibiotics; present in methicillin-resistant strains ▪ vanA gene → modifies cell wall peptidoglycans → vancomycin cannot bind to bacteria

STAPHYLOCOCCUS AUREUS osms.it/staphylococcus-aureus PATHOLOGY & CAUSES ▪ Staphylococcus aureus: common bacterium, causes infections in most organ systems ▪ Aureus: golden colonies in mannitol salt agar, due to mannitol fermentation ▪ Skin colonization: approx. 30% of population ▫ Primary colonization site: nostrils ▪ Pathogen transmission: direct contact, fomites Virulence factors ▪ Cytolysins: alpha-toxin, Panton–Valentine leukocidin (PVL); both destroy neutrophils ▫ PVL related to severe skin, lung infections

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▪ Hemolysins: form pores in host cells (e.g. erythrocytes, macrophages, lymphocytes) ▪ Superantigens: enterotoxins, toxic shock syndrome toxin-1 (TSST-1) ▫ Superantigens stimulate activation of excessive amount of T-cells → increased production of cytokines → uncontrolled inflammation ▪ Epidermolytic toxins A and B: skin blistering ▪ Coagulase: activates prothrombin → coagulation ▪ Bacterial spread: protease degrades proteins; lipase degrades lipids ▪ Protein A: inactivates immunoglobulins → phagocytosis evasion ▪ Can form biofilms ▫ Biofilm: adherence of cells to polymer

Chapter 98 Staphylococcus surfaces (e.g. catheters) ▫ Properties allow immune evasion

CAUSES

▪ Common cause of infections and toxinmediated diseases acquired from community/healthcare environment ▫ Endocarditis, ocular infections, pneumonia, meningitis, osteomyelitis, septic arthritis, prosthetic device infections, catheter-associated infections

Skin/soft tissue infections ▪ E.g. surgical site infections, abscesses, impetigo, cellulitis, erysipela, fasciitis, mastitis Toxic shock syndrome (TSS) ▪ Mediated by toxic shock syndrome toxin-1; commonly caused by growth of S. aureus in vagina/surgical sites → multiple organ dysfunction Staphylococcal scalded-skin syndrome (Ritter disease) ▪ Mediated by epidermolytic toxins A and B Foodborne illness ▪ Caused by ingestion of S. aureus endotoxins

SIGNS & SYMPTOMS Skin/soft tissue infections ▪ Erythema, swelling, warmth, localized warmth/fever ▫ Staphylococcal scalded-skin syndrome (Ritter disease): fever, erythema, fluidfilled bullae on the skin → skin loss Systemic infections ▪ Joint pain, abdominal pain, headache, CVA tenderness, new onset heart murmur TSS ▪ Fever, hypotension, rash, coagulopathy, tissue necrosis (site of infection) Foodborne illness ▪ Nausea, vomiting, diarrhea, abdominal pain

DIAGNOSIS LAB RESULTS

▪ Culture-based observation ▫ Clustered golden Gram-positive cocci ▫ Catalase-positive; coagulase-positive ▪ Polymerase chain reaction (PCR) amplification ▪ May be guided by further studies depending on site of infection

RISK FACTORS

▪ Immunosuppression, IV drug use, recent invasive procedure, foreign material in body (e.g. prosthetics, catheters, sutures), dialysis

COMPLICATIONS

▪ Sepsis, bacteremia, invasive infection ▪ Antibiotic resistance: all strains resistant to penicillin G; some strains resistant to methicillin (MRSA) or vancomycin (VRSA); some strains have intermediate resistance to vancomycin (VISA) ▫ Resistant strains are common pathogens in nosocomial infections

Figure 98.1 Staphylococcus takes on a golden colour when cultured with mannitol containing media.

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TREATMENT MEDICATIONS Topical antibiotics ▪ Superficial skin infections Oral/IV antibiotics ▪ Treatment based on the pathogen’s antibiotic susceptibility

▫ Oxacillin/nafcillin/cefazolin ▫ MRSA: vancomycin/trimethoprimsulfamethoxazole ▫ VRSA: linezolid

SURGERY

▪ Abscess drainage (if applicable) ▪ Foreign material removal in body (if applicable)

STAPHYLOCOCCUS EPIDERMIDIS osms.it/staphylococcus-epidermidis PATHOLOGY & CAUSES ▪ Staphylococcus epidermidis: bacteria commonly associated with infections of surgical sites, indwelling catheters, and prosthetic devices ▪ Part of skin and mucous membrane natural flora ▪ Does not produce exotoxins

CAUSES

▪ Skin/mucous colonization → barrier rupture → infection ▪ Can form biofilms on foreign materials in body; biofilm properties allow immune evasion ▪ Polymer surface adhesion → extracellular matrix production → polysaccharide intercellular adhesin (PIA) secretion → multi-layered bacteria ▪ Common S. epidermidis infections: catheter-associated infection, intravascular catheter infection, prosthetic joint infection, endocarditis (frequently associated with prosthetic valves), surgical site infection

RISK FACTORS

▪ Immunosuppression, neonates, recent invasive procedure, foreign material in the body (e.g. prosthetics, catheters), dialysis

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COMPLICATIONS

▪ Sepsis, bacteremia ▪ Neonates: pneumonia, urinary tract infections, meningitis, enterocolitis, omphalitis

SIGNS & SYMPTOMS Local ▪ Pain, tenderness, swelling, warmth, erythema, drainage at incisional site Systemic ▪ Fever, hypotension, leukocytosis

DIAGNOSIS LAB RESULTS Culture-based observation ▪ Blood, urine, synovial fluid, surgical site ▫ Clustered Gram-positive cocci ▫ Catalase-positive; coagulase-negative; novobiocin-sensitive PCR amplification

Chapter 98 Staphylococcus

TREATMENT MEDICATIONS

SURGERY

▪ Remove foreign material from body (if applicable)

Oral antibiotics ▪ Empiric treatment: vancomycin ▪ If proven methicillin sensitivity: oxacillin/ nafcillin; may be combined with rifampicin, gentamicin ▪ Fusidic acid for skin infections (if available)

STAPHYLOCOCCUS SAPROPHYTICUS osms.it/staphylococcus-saprophyticus PATHOLOGY & CAUSES

SIGNS & SYMPTOMS

▪ Staphylococcus saprophyticus: bacteria that commonly produces urinary tract infections (UTI) in young, biologicallyfemale individuals ▪ Frequently part of vagina’s natural flora ▪ Tropism for urinary tract: surface fibrillar protein (Ssp) and hemagglutinin/adhesin allow pathogen’s adherence to uroepithelial cells ▪ Does not produce exotoxins ▪ Etiologic agent: community-acquired UTIs (occasionally) ▪ Usually presents as symptomatic cystitis (bladder inflammation)

▪ Dysuria (painful urination), urinary urgency, increased urinary frequency, suprapubic pain, occasional hematuria

RISK FACTORS

DIAGNOSIS LAB RESULTS Urinalysis ▪ Presence of leukocytes, erythrocytes, bacteria, negative urine nitrate Culture-based observation ▪ Clustered Gram-positive cocci ▪ Catalase-positive; coagulase-negative; novobiocin-resistant

▪ Biologically-female (shorter urethra), recent sexual activity (“honeymoon cystitis”), diabetes, immunosuppression, indwelling urinary catheter

Quantitative PCR

COMPLICATIONS

MEDICATIONS

▪ Pyelonephritis

TREATMENT ▪ Oral antibiotics ▪ Symptomatic therapy (e.g. phenazopyridine)

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NOTES

NOTES

STREPTOCOCCUS MICROBE OVERVIEW Morphology ▪ Spherical, Gram-positive bacteria; appear in chains/pairs; catalase, coagulase negative

▪ Produce extracellular substances (e.g. cytolysins, enzymes) → enhance pathogenicity

STREPTOCOCCUS AGALACTIAE (GROUP B STREP) osms.it/streptococcus-agalactiae PATHOLOGY & CAUSES ▪ AKA Group B Streptococcus (GBS) ▪ Encapsulated, facultative anaerobe ▪ Colonizes human genital, gastrointestinal (GI) tracts; upper respiratory tracts of young infants ▪ Beta-hemolytic ▫ Blood agar plates, hemolysins degrade lipid membranes → colonies surrounded by narrow zone of hemolyzed cells → complete (beta-)hemolysis Virulence factors ▪ Complex capsular polysaccharides ▫ Inhibit complement deposition on microbe surface components ▪ Hypervirulent GBS adhesin (HvgA) ▫ ↑ ability to invade blood-brain barrier ▪ Cluster of virulence responder/sensor (CovR/S) mutation ▫ Accelerate failure of amniotic barrier → ↑ ability to penetrate chorioamniotic membranes ▪ Pilins ▫ Act as adhesins → ↑ ability to invade central nervous system, form biofilm

552 OSMOSIS.ORG

▪ Direct cytotoxicity to host phagocytes Common infectious agent ▪ Adults (nonpregnant) ▫ Broad spectrum of infections ▪ Pregnant individuals ▫ Chorioamnionitis ▪ Neonates ▫ GBS infection, sepsis

RISK FACTORS

▪ Adults (nonpregnant) ▫ Chronic disease (e.g. diabetes, liver disease, malignancy; > age 65, esp. residents of nursing homes) ▪ Pregnancy ▪ Neonates ▫ Ascending infection from mother (e.g. rupture of membranes, chorioamnionitis) ▪ Hospitalization ▫ Nosocomial/hospital-acquired infections

Chapter 99 Streptococcus

COMPLICATIONS

▪ Cystitis, pyelonephritis, urethritis, prostatitis; osteomyelitis, septic arthritis; endocarditis; meningitis; pneumonia; sepsis; toxic shock-like syndrome ▪ Neonates ▫ Preterm birth, bacteremia, sepsis, pneumonia, meningitis, neonatal mortality

SIGNS & SYMPTOMS ▪ Fever, chills; malaise; cough ▪ Local tissue infection ▫ Red, warm, swollen, presence of drainage

▪ Hippurate hydrolysis test ▫ Detections hippurate hydrolysis by GBS

OTHER DIAGNOSTICS

▪ Clinical history, physical examination

TREATMENT MEDICATIONS

▪ Antibiotics (e.g. penicillin G, ampicillin)

OTHER INTERVENTIONS ▪ Prenatal screening

DIAGNOSIS LAB RESULTS Identification of microbe ▪ E.g. blood, cerebrospinal fluid ▪ Gram stain, characteristic morphology ▪ Culture ▫ Beta-hemolysis on blood agar ▪ CAMP test ▫ Identifies presence of CAMP factor ▪ Latex agglutination tests ▫ Detects antibodies produced in response to GBS

Figure 99.1 The three classes of streptococcus cultured on a blood agar plate. Alpha (left) shows partial hemolysis, beta (centre) shows complete hemolysis and gamma (right) shows no hemolysis.

STREPTOCOCCUS PNEUMONIAE osms.it/streptococcus-pneumoniae PATHOLOGY & CAUSES ▪ Causative agent for numerous clinical syndromes in children, older adults ▪ Alpha-hemolytic, lancet-shaped diplococci ▪ Lysis by bile (deoxycholate), optochin sensitive ▪ Fastidious; prefers 5% carbon dioxide ▪ Pyogenic

▪ Virulence factors ▫ Resistance to phagocytosis (conferred by 92 polysaccharide serotypes) ▫ Adherence proteins ▫ Biofilm formation ▫ Pneumolysin toxin ▪ Asymptomatic colonization → direct spread from site of colonization,hematogenous spread → clinical syndromes

OSMOSIS.ORG 553

▪ Typical infections caused by S. pneumoniae range from mucosal to invasive diseases ▫ Meningitis ▫ Otitis media ▫ Pneumococcal community-acquired pneumonia ▫ Sinusitis

RISK FACTORS

▪ Age (< 2, ≥ 65 years) ▪ Underlying disease (e.g. liver, kidney, heart, lung, diabetes, malignancies) ▪ Crowded conditions (e.g. daycare centers, military camps, prisons) ▪ Immunodeficiency (e.g. HIV, genetic immune defects, solid organ/bone transplant) ▪ Smoking, alcohol abuse

COMPLICATIONS

▪ Pneumococcal endocarditis, empyema, bacteremia, sepsis

SIGNS & SYMPTOMS ▪ Common clinical presentation ▫ Fever, altered mental status, malaise ▪ Typical findings related to clinical syndrome ▫ Meningitis: headache, neck stiffness ▫ Otitis media: ↓ tympanic membrane mobility/bulging membrane, otorrhea, pain ▫ Pneumonia: cough, bronchial breath sounds, rales ▫ Sinusitis: purulent rhinitis, mucous membrane edema, headache

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DIAGNOSIS DIAGNOSTIC IMAGING Chest X-ray ▪ Infiltration, consolidation (pneumonia)

LAB RESULTS Identification of organism ▪ Gram-positive diplococci, positive culture, polymerase chain reaction (PCR) ▪ Urine antigen analysis (bacteremia)

OTHER DIAGNOSTICS

▪ Clinical history, physical examination

TREATMENT MEDICATIONS

▪ Antibiotics ▫ Pneumonia: beta-lactam antibiotic ▫ Otitis media: amoxicillin-clavulanate (children) ▫ Sinusitis: amoxicillin (amoxicillin– clavulanic acid may be preferable)

OTHER INTERVENTIONS Prevention ▪ Pneumococcal vaccine

Chapter 99 Streptococcus

STREPTOCOCCUS PYOGENES (GROUP A STREP) osms.it/streptococcus-pyogenes PATHOLOGY & CAUSES ▪ AKA Group A Streptococcus (GAS) ▪ Colonizes human skin, mucous membranes ▪ Cell-wall structure ▫ Peptidoglycan backbone + lipoteichoic acid components → structural stability ▪ Beta-hemolytic ▫ Blood agar plates, hemolysins degrade lipid membranes → colonies surrounded by clear zone of hemolyzed cells → complete (beta-) hemolysis ▪ Primarily infects skin, soft tissue Virulence factors ▪ Vary with specific strain ▪ M proteins ▫ Protect microbe from humoral immune surveillance, phagocytosis by polymorphonuclear leukocytes ▪ Binding proteins ▫ Bind to IgG, IgM, IgA → may interfere with complement activation ▫ Protein F: binds to fibronectin → ↑ adherence to epithelial surfaces ▪ Cytolysins ▫ Streptolysins: bind to cholesterol on eukaryotic cell membranes → cell lysis ▫ Hyaluronidase: hydrolyzes hyaluronic acid → facilitates infection spread ▫ Streptokinase: proteolytically converts bound plasminogen to active plasmin → cleavage of fibrin; medically useful as clot-busting drug ▫ Nicotinamide adenine dinucleotidase (NADase): exact function unclear; likely ↑ invasiveness ▫ Deoxyribonuclease: promotes production of anti-deoxyribonuclease (DNase) antibody following pharyngeal/ skin infections

▪ Pyrogenic exotoxins (type A, B, C) ▫ Induce fever, act as superantigens → T-cell proliferation → ↑ cytokine production → promotes shock ▪ Streptococcal inhibitor of complement (SIC) ▫ Inactivates complement membrane attack complex ▪ Opacity factor (OF) ▫ Lipoprotein lipase Causative agent in several disorders ▪ Pyogenic diseases ▫ Pharyngitis, cellulitis (abscess formation in dermis, subcutaneous fat layers), necrotizing fasciitis (progressive destruction of deep soft tissue), impetigo ▪ Toxigenic disease ▫ Scarlet fever, toxic shock syndrome, GAS endometritis (puerperal sepsis) ▪ Immunologic disease ▫ Rheumatic fever (antibodies against streptococcal cell cross-react with cardiac tissue); poststreptococcal glomerulonephritis (immune complexes deposited in glomeruli)

RISK FACTORS

▪ Susceptible host + encounter with streptococcus expressing specific virulence factors

COMPLICATIONS

▪ Local spread (e.g. otitis media, sinusitis, mastoiditis); tissue destruction; valvular, renal disease; sepsis, shock, multiorgan failure; disseminated intravascular coagulation; pediatric autoimmune neuropsychiatric disorder associated with group A streptococci (PANDAS)

OSMOSIS.ORG 555

DIAGNOSIS

SIGNS & SYMPTOMS ▪ Pharyngitis ▫ Acute onset of sore throat, fever, pharyngeal edema, patchy tonsillar exudates ▪ Cellulitis ▫ Erythema, edema, abscess formation ▪ Impetigo ▫ Papules, vesicles, pustules surrounded by erythema pustules → breaks down, forms crusts ▪ Scarlet fever ▫ Erythematous rash ▪ Toxic shock syndrome ▫ Shock, multiorgan failure ▪ GAS endometritis ▫ Postpartum fever, uterine tenderness

LAB RESULTS Identification of microbe ▪ Gram positive cocci ▪ Positive culture ▪ Blood studies ▫ Rapid antigen detection test (RADT) for GAS

OTHER DIAGNOSTICS

▪ Clinical history, physical examination

TREATMENT MEDICATIONS

▪ Antibiotics (e.g. penicillin G, clindamycin)

SURGERY

▪ Surgical debridement

STREPTOCOCCUS VIRIDANS osms.it/streptococcus-viridans infections (e.g. abdominal, central nervous system, lung, skin, soft tissue, sepsis) ▫ Abscess formation ▫ Viridans streptococcal shock syndrome

PATHOLOGY & CAUSES ▪ Heterogeneous collection of alpha/ nonhemolytic streptococci, cause variety of diseases ▪ Some species produce greenish color on blood agar plates ▪ Not bile soluble, optochin resistant ▪ Approx. 30 species classified into six groups ▪ Part of microbiome of oropharynx, GI, genitourinary tract ▪ May be invasive, produce variety of diseases ▫ Dental caries, periodontal disease, maxillofacial infections, exudative pharyngitis, infective endocarditis ▫ Invades circulation → systemic

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RISK FACTORS

Immunocompromised state Periodontal disease More common in children than adults Comorbidities (e.g. mucositis, cystic fibrosis, malignancies) ▪ Altered microbiome ▪ ▪ ▪ ▪

SIGNS & SYMPTOMS ▪ Clinical presentation varies widely depending on infection

Chapter 99 Streptococcus

DIAGNOSIS LAB RESULTS Identification of organism ▪ Gram-positive cocci, positive culture

OTHER DIAGNOSTICS

▪ Clinical history, physical examination

TREATMENT MEDICATIONS

▪ Antibiotics (depending on sensitivity, resistance) ▫ Penicillin + aminoglycoside; broadspectrum cephalosporin, vancomycin

SURGERY

▪ Abscess debridement/drainage

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NOTES

NOTES

SYSTEMIC MYCOSES GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES

DIAGNOSIS

▪ Fungal infections in internal organs (esp. lungs)

DIAGNOSTIC IMAGING

CAUSES

LAB RESULTS

▪ Dimorphic species of fungi ▪ Transmitted by spore inhalation; lymphohematogenous dissemination

SIGNS & SYMPTOMS

▪ X-ray, CT scan, MRI

▪ Culture-based observation, direct microscopy, serologic tests, lab tests (e.g. abnormal blood exams)

TREATMENT MEDICATIONS

▪ Cough, chest pain, fever

▪ Antifungal agents

BLASTOMYCES SPP. osms.it/blastomyces PATHOLOGY & CAUSES ▪ Blastomycosis ▫ Systemic fungal infection caused by Blastomyces dermatitidis, B. gilchristii; usually manifests as chronic pneumonia ▪ Incubation period: 3–6 weeks ▪ Spore inhalation → conversion to yeast in lungs → phagocytosis by macrophages → acute suppurative inflammation ▪ Immune response: mainly cellular, mediated by T-lymphocytes, macrophages ▪ Common sites of infection: primarily lungs (90%); skin, bones, genitourinary tract, central nervous system (CNS)

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Blastomyces spp. ▪ Size: 8–15μm ▪ Broad-based budding (wide connection between two cells before splitting apart during reproduction) ▪ Thermal dimorphism ▫ Mold form (< 37°C/98.6°F): produces spores ▫ Yeast form (37°C/98.6°F): multinucleate; antiphagocytic (e.g. thick cell wall) ▪ Virulence ▫ Thick cell wall: resistance to phagocytosis ▫ BAD-1: cell surface glycoprotein; adhesin ▫ Binds yeast to extracellular matrix, macrophages

Chapter 100 Systemic Mycoses ▫ Blocks production of tumor necrosis factor (TNF) alpha (proinflammatory cytokine) Clinical syndromes ▪ Pulmonary blastomycosis ▫ Pneumonia, mostly chronic ▫ Frequently affects upper lobes ▪ Primary cutaneous blastomycosis ▫ Ulcerative/verrucous skin lesions ▪ Disseminated blastomycosis ▫ Osteomyelitis; prostatitis, epididymoorchitis (inflammation of epididymis/ testicles); meningitis; intracranial abscesses

RISK FACTORS

Outdoor occupations (e.g. farming) Recreational exposure to soil Immunosuppression High prevalence in North America Recent travel to endemic areas (e.g. Ohio, Mississippi river valleys) ▪ Comorbid conditions ▪ ▪ ▪ ▪ ▪

COMPLICATIONS

LAB RESULTS Culture-based observation ▪ tissue, sputum, body fluids ▫ Sabouraud dextrose agar without cycloheximide ▫ Confirmation requires conversion (mold → yeast) at 37°C/98.6°F Direct microscopic examination ▪ Periodic acid–Schiff stain ▪ Differentiation: size, yeast morphology Lab tests ▪ Anemia, leukocytosis, ↑ erythrocyte sedimentation rate Tissue biopsy ▪ Pyogranulomatous response ▪ Skin ▫ Epithelial hyperplasia, intraepidermal abscesses, multinucleated cells ▪ Fungus observation Serologic tests ▪ Polymerase chain reaction (PCR) ▫ Antigen detection assays

▪ Acute respiratory distress, multiorgan disease, chronicity

SIGNS & SYMPTOMS ▪ Cough, fever, weight loss, sputum production, dyspnea, night sweats, chills, hemoptysis, arthralgia, soft tissue swelling ▪ Verrucous skin lesions with irregular borders, ulcerative skin lesions

DIAGNOSIS

TREATMENT MEDICATIONS

▪ Antifungal treatment ▪ Amphotericin B; followed by azole ▫ Liposomal amphotericin B: CNS infections

SURGERY

▪ Resection of abscesses, devitalized bone, empyemas, pericardial effusion

DIAGNOSTIC IMAGING X-ray ▪ Pneumonia ▫ Lobar consolidation, alveolar infiltrates, fibronodular infiltrates, cavitation, nodules, pleural effusion ▪ Osteomyelitis ▫ Well-defined, osteolytic bone lesions

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COCCIDIOIDES SPP. osms.it/coccidioides ▫ Metalloproteinase: inhibits phagocytosis ▫ Alteration of pulmonary surfactant proteins

PATHOLOGY & CAUSES ▪ Coccidioidomycosis ▫ Systemic fungal infection caused by Coccidioides immitis, C. posadasii; usually manifests as acute pneumonia ▪ AKA San Joaquin Valley Fever/“desert rheumatism” (associated with arthralgia) ▪ Arthroconidium inhalation → conversion to spherules → activation of T-lymphocytes → production of cytokines → inflammation → acute pneumonia ▫ In infected tissue, spherules grow, septate → release endospores → infection spreads ▪ Immune response ▫ Mainly mediated by Th1 cells ▫ Interleukin 17, TNF alpha, interferongamma ▪ Incubation period: 1–4 weeks ▪ Common sites of infection: lungs, skin, bones, CNS ▪ High prevalence areas: arid, dry regions in U.S. (e.g. California, Southwest), Mexico, Central America, South America Coccidioides spp. ▪ Size: 20–70μm ▪ Dimorphism ▫ Mold form: found in soil ▫ Yeast form: parasitic ▪ Produces arthroconidia (barrel-shaped, multinucleated spores) ▫ Production stimulated by human sex hormones ▫ Arthroconidia convert to spherules (2–5μm; in infected tissues) ▪ Infectious particles: arthroconidia ▪ Virulence ▫ Enzyme with elastase activity: ↑ infection, inflammation ▫ Cell surface glycoprotein with adhesin activity

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Clinical syndromes ▪ Acute pneumonia ▪ Dermatologic lesions ▫ Wart-like lesions on face ▫ Erythema nodosum/multiforme ▪ Osteomyelitis ▪ Meningitis

RISK FACTORS

▪ Outdoor occupations; recreational exposure to soil (e.g. gardening, camping); immunosuppression; recent travel to endemic areas; comorbid conditions

COMPLICATIONS

▪ Adult respiratory distress syndrome; fatal multilobar pneumonia; pyopneumothorax; meningitis; chronicity

SIGNS & SYMPTOMS ▪ ▪ ▪ ▪ ▪

Mostly mild/asymptomatic Non-specific: fever, malaise Cough, pleuritic pain, hemoptysis, arthralgia Erythema nodosum/multiforme Wart-like lesions on face (e.g. nasolabial folds)

DIAGNOSIS DIAGNOSTIC IMAGING X-ray ▪ Pneumonia ▫ Parenchymal infiltrates, thin-walled cavities ▪ Osteomyelitis ▫ Osteolytic bone lesions

Chapter 100 Systemic Mycoses

LAB RESULTS

TREATMENT

▪ Culture-based observation

Serologic tests ▪ IgM, IgG antibody detection (e.g. enzyme immunoassays) ▪ Antigen detection Direct microscopic observation ▪ Spherules in sputum, blood, body fluid samples Lab tests ▪ ↑ erythrocyte sedimentation rate ▪ Eosinophilia (mostly with dissemination)

MEDICATIONS High risk of dissemination ▪ E.g. immunosuppression, pregnancy ▫ azoles Severe ▪ Amphotericin B

SURGERY

▪ Debridement of abscesses, devitalized bone, pyopneumothorax

Extrathoracic tissue biopsy ▪ Essential for diagnosis of Coccidioides dissemination ▪ Pyogranulomatous inflammation ▪ Presence of spherules Spherulin skin test ▪ Positive after resolution; not available in U.S.

Figure 100.1 Numerous spores in the lungs of an individual with coccidioidomycosis.

OSMOSIS.ORG 561

HISTOPLASMA CAPSULATUM osms.it/histoplasma-capsulatum PATHOLOGY & CAUSES ▪ Histoplasmosis ▫ Systemic fungal infection caused by Histoplasma capsulatum; usually manifests as acute pneumonia ▪ Most frequent systemic mycoses in U.S. ▪ Microconidia inhalation → conversion to yeast form → macrophage phagocytosis → inflammation → pneumonia ▪ Immune response: mainly cellular, mediated by T-lymphocytes, macrophages, TNF alpha, interferon-gamma ▪ Infection sites: primarily lungs; may disseminate to other organs Histoplasma capsulatum ▪ Size: 2–3μm x 3–4μm ▪ Thermal dimorphism ▫ Mold form (< 35°C/95°F); produces microconidia (spores, 2–5μm) ▫ Yeast form (37°C/98.6°F) ▪ Infectious particles: microconidia ▪ Bird, bat fecal material promotes growth Pulmonary histoplasmosis clinical syndromes ▪ Pneumonia: acute (diffuse/localized); chronic ▪ Broncholithiasis Disseminated histoplasmosis clinical syndromes ▪ Progressive disseminated histoplasmosis: excessive reticuloendothelial infection ▪ Adrenal perivasculitis (common) ▪ Endocarditis ▪ Mediastinal granuloma ▪ Mediastinitis ▪ Meningitis ▪ Ocular histoplasmosis (e.g. retinal lesions) ▪ Lesions: intestinal (e.g. ulcers, polyps), skin (e.g. dermatitis, papules)

562 OSMOSIS.ORG

RISK FACTORS

▪ Outdoor occupations (e.g. construction, excavation) ▪ Outdoor activities (e.g. camping) ▪ Immunosuppression ▪ High prevalence regions: U.S. (Ohio, Mississippi river valleys), Mexico, Central America, South America ▪ Recent travel to endemic areas ▪ Comorbid conditions ▪ Extremes of age

COMPLICATIONS

▪ Fatal acute diffuse pneumonia, mediastinal granuloma, mediastinitis, chylothorax, pleural effusion

SIGNS & SYMPTOMS ▪ Mostly asymptomatic Acute pulmonary histoplasmosis ▪ Systemic ▫ Fever, headaches, fatigue ▪ Chest pain (pleuritic/substernal), dry cough, myalgia, arthralgia, erythema nodosum/ multiforme Chronic pulmonary histoplasmosis ▪ Systemic ▫ Fever, fatigue, night sweats, weight loss ▪ Productive cough, hemoptysis, dyspnea ▪ Consolidation: dullness to percussion, crackles

DIAGNOSIS DIAGNOSTIC IMAGING Chest X-ray ▪ Hilar/mediastinal lymphadenopathy, patchy/ nodular pulmonary infiltrates, occasional cavitation

Chapter 100 Systemic Mycoses

LAB RESULTS

▪ Culture-based observation ▪ Direct microscopic observation

Serologic tests ▪ Antibody detection (e.g. immunodiffusion, complement fixation assays) ▪ Antigen detection in urine, sputum, body fluids (e.g. enzyme immunoassays) Lab tests ▪ Anemia, ↑ erythrocyte sedimentation rate, progressive disseminated histoplasmosis (e.g. pancytopenia) Tissue biopsy ▪ Granulomas, lymphohistiocytic aggregates, mononuclear cell infiltrates, fungi visualization

TREATMENT

Figure 100.2 Grocott methenamine silver stain highlights spores in the lung tissue of an immunocompromised individual with histoplasmosis.

MEDICATIONS

▪ Progressive disseminated/prolonged/severe pulmonary histoplasmosis ▫ Corticosteroids: ↓ inflammation ▫ Antifungal treatment: amphotericin B, azoles

PARACOCCIDIOIDES BRASILIENSIS osms.it/paracoccidioides-brasilienses PATHOLOGY & CAUSES ▪ Paracoccidioidomycosis ▫ Systemic fungal infection caused by Paracoccidioides brasiliensis, P. lutzii; usually manifests as chronic lung disease ▪ AKA South American blastomycosis ▪ Spore inhalation → conversion to yeast form in lungs → phagocytosis by macrophages → inflammation → pneumonia ▪ Immune response: mostly cell-mediated ▪ Common sites of infection: mainly lungs;

oral mucosa, skin, adrenal glands, CNS Paracoccidioides spp. ▪ Size: 4–40μm ▪ Thermal dimorphism ▫ Mold form (22–26°C/71.6–78.8°F): present in soil ▫ Yeast form (37°C/98.6°F): “pilot’s wheel” appearance ▪ Stimulated by sex hormones Clinical syndromes ▪ Acute/subacute paracoccidioidomycosis ( juvenile) ▫ Hepatosplenomegaly,

OSMOSIS.ORG 563

lymphadenopathy, skin lesions, pulmonary manifestations (rare) ▪ Chronic paracoccidioidomycosis (adult) ▫ Progressive pulmonary fibrosis (esp. lower lobes), ulcers (mouth, larynx); adrenal involvement

RISK FACTORS

▪ High prevalence regions: Central, South America (80% in Brazil) ▪ Outdoor occupations ▪ Outdoor activities: contact with soil ▪ More common in individuals who are biologically male ▪ Immunosuppression

COMPLICATIONS

▪ Bone marrow, adrenal dysfunction; chronic respiratory failure

SIGNS & SYMPTOMS ▪ Generally asymptomatic (95%) ▪ Non-specific symptoms: fever, weight loss ▪ Cough, dyspnea, hepatosplenomegaly, lymphadenopathies, odynophagia, sialorrhea, skin lesions (ulcers, nodules) ▪ Compressive manifestations: jaundice (bile duct obstruction)

DIAGNOSIS DIAGNOSTIC IMAGING X-ray/CT scan ▪ Acute/subacute paracoccidioidomycosis ▫ Lymph node enlargement ▪ Chronic paracoccidioidomycosis ▫ Pulmonary disease: alveolar/interstitial infiltrates, consolidation, masses/ nodules, cavitation ▫ CNS disease: ring enhancing lesions ▫ Articular disease: effusion, erosions, space narrowing

LAB RESULTS

▪ Direct microscopic observation ▪ Culture-based observation

564 OSMOSIS.ORG

Figure 100.3 A child with numerous lesions on the face caused by Coccidioidomycosis brasiliensis. Serologic tests ▪ Detection of antibodies through immunodiffusion

TREATMENT MEDICATIONS

▪ Antifungal treatment: azoles ▪ Trimethoprim-sulfamethoxazole

NOTES

NOTES

TOGAVIRUSES MICROBE OVERVIEW ▪ Pathogenic viruses in Togaviridae family ▪ Capsid symmetry: icosahedral ▪ RNA structure: linear, positive polarity

EASTERN EQUINE ENCEPHALITIS VIRUS (EEEV) osms.it/eastern-equine-encephalitis PATHOLOGY & CAUSES ▪ Highly pathogenic; causes central nervous system illness in humans, horses (equines) ▪ Genus: Alphavirus ▪ Spherical, approx. 69nm diameter (including glycoprotein spikes) ▪ Enveloped, single-stranded, positive-sense RNA genome ▪ Glycoproteins associated with neurovirulence, cellular apoptosis ▪ Potential bioterrorism agent use (aerosol route) ▪ Range ▫ Atlantic, Gulf-coast states in eastern USA ▪ Four lineages ▫ Group I: endemic in North America, Caribbean (causes most human disease) ▫ Groups IIA, IIB, III: primarily cause equine illness in Central, South America ▪ Viral life-cycle: wild birds, Culiseta melanura mosquito (enzootic vector) ▫ C. melanura rarely bites humans ▫ Human transmission requires other mosquito species (e.g. Aedes,

Coquillettidia, Culex) to bridge between infected birds, humans ▫ Infected mosquito bite → 4–10 day incubation period → prodromal period → neurological symptom development occurs rarely

RISK FACTORS

▪ Rural residence; living in/visiting woodland habitats, swampy areas ▪ Outdoor occupation/recreational activity

COMPLICATIONS

▪ Encephalitis; cerebral edema; coma; residual brain damage (mild–severe, esp. young children); death (some)

SIGNS & SYMPTOMS ▪ May be asymptomatic ▪ Prodromal period: high fever, headache, nausea, vomiting ▪ Neurologic presentation: cranial nerve palsy, seizure, stupor → coma ▪ Infants: fever, bulging fontanel, generalized flaccid/spastic paralysis

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DIAGNOSIS

TREATMENT

DIAGNOSTIC IMAGING

▪ No specific treatment

MRI ▪ Focal lesions in basal ganglia, thalamus, brainstem

MEDICATIONS

LAB RESULTS

▪ Leukocytosis; left shift ▪ Hyponatremia ▪ Serology ▫ IgM antibody presence ▪ Cerebrospinal fluid (CSF) examination ▪ Lymphocytic pleocytosis, ↑ neutrophils; ↑ protein; IgM antibodies (assay); virus isolation

▪ Supportive: anticonvulsants, corticosteroids (↓ inflammation)

OTHER INTERVENTIONS

▪ Supportive: IV fluid, respiratory support, monitor intracranial pressure ▪ Prevention ▫ Insect repellent (DEET, picaridin, IR3535, oil of lemon eucalyptus) ▫ Protective clothing ▫ Vector control

OTHER DIAGNOSTICS Electroencephalography (EEG) ▪ Generalized slowing; disorganized pattern

RUBELLA VIRUS osms.it/rubella-virus PATHOLOGY & CAUSES ▪ Highly communicable virus → German measles ▪ Enveloped, positive-sense, single-stranded RNA virus ▪ Family: Togaviridae ▪ Genus: Rubivirus ▪ Three structural proteins ▫ C: capsid protein surrounding virion RNA ▫ E1, E2: glycosylated proteins forming transmembrane antigenic sites ▪ Humans are the only natural hosts ▪ Transmission: droplet inhalation/direct contact with infectious nasopharyngeal secretion ▪ Viral contact → 12–23 day incubation → nasopharyngeal cell, regional lymph

566 OSMOSIS.ORG

node viral replication → viremia → maculopapular rash eruption → rash resolution (approx. two days) ▫ Contagious via virus shedding before, after rash appears ▫ ↑ contagiousness during rash eruption ▪ Spreads transplacentally

RISK FACTORS

▪ Unvaccinated ▪ Travel (especially abroad) ▪ Contact with febrile rash individuals

COMPLICATIONS

▪ Thrombocytopenic purpura ▪ Encephalitis (rare) ▪ If infected during pregnancy: congenital rubella syndrome (CRS)

Chapter 101 Togaviruses ▫ ↑ risk of miscarriage, fetal death, stillbirth ▫ CRS: A ToRCHeS (see mnemonic) infection; ↑ first trimester risk; extramedullary hematopoiesis (“blueberry muffin” rash), cataract, heart defect, hearing impairment, intellectual disability

MNEMONIC: ToRCHeS

Perinatal infections passed from mother to child Toxoplasmosis, toxoplasma gondii Other infections Rubella Cytomegalovirus Herpes Simplex virus-2/ neonatal herpes simplex

SIGNS & SYMPTOMS

▫ Reverse transcription-PCR (rubella virus RNA performed on amniotic fluid)

OTHER DIAGNOSTICS

▪ Clinical diagnosis ▪ High suspicion index ▫ Febrile rash, unvaccinated status

TREATMENT ▪ No specific antiviral therapy

OTHER INTERVENTIONS

▪ Infection control measures ▫ Prompt isolation for seven days after rash development ▪ Vaccine: live-attenuated measles-mumpsrubella (MMR)/measles-mumps-rubellavaricella (MMRV) ▫ First dose: 12–15 months old ▫ Second dose: 4–6 years old

▪ Maculopapular rash ▫ Pink/light red macules: coalesce to form evenly-colored desquamating rash ▫ Initially: face → generalized rash within 24 hours ▫ Duration: three days ▪ Lymphadenopathy; primarily posterior auricular/suboccipital lymph ▪ Low-grade fever ▪ Mild nonexudative conjunctivitis ▪ Forchheimer spots on soft palate ▪ Arthralgias ▪ Orchitis ▪ Asymptomatic (half of cases)

DIAGNOSIS LAB RESULTS

▪ Polymerase chain reaction (PCR) testing/ molecular typing ▫ Throat, nasal, urine specimens ▪ Serologic testing ▫ Enzyme immunoassay (EIA) detects rubella-specific IgM antibodies ▪ Pregnancy

Figure 101.1 A child with rubella showing a characteristic maculopapular, erythematous rash.

OSMOSIS.ORG 567

WESTERN EQUINE ENCEPHALITIS VIRUS (WEE) osms.it/western-equine-encephalitis PATHOLOGY & CAUSES ▪ Causes central nervous system illness in humans, horses (equines) ▪ Genus Alphavirus ▪ Spherical, approx. 69nm diameter (including glycoprotein spikes) ▪ Enveloped, single-stranded, positive-sense RNA genome ▪ Contain glycoproteins associated with neurovirulence, cellular apoptosis ▪ Range: most commonly US states, Canadian provinces west of Mississippi River ▪ Virus life-cycle: wild birds, other vertebrates, Culex tarsalis mosquito (enzootic vector) ▫ Culex tarsalis (another human vector) ▪ Potential bioterrorism agent use (aerosol route) ▪ Infected mosquito bite → 2–10 day incubation period → sudden onset of severe headache, fever/chills, dizziness, chills, myalgias, malaise, tremor, irritability, photophobia, neck stiffness → rapid neurological manifestation development → recovery ▫ Most adults: no residual neurological effects ▫ Infants, children: ↑ long-term neurologic sequelae risk

RISK FACTORS

▪ Most cases June–September ▪ Bimodal age pattern: < one year; ↑ risk in elderly ▪ Biologically-female ▪ Rural residence ▪ Outdoor occupation/recreational activity

568 OSMOSIS.ORG

COMPLICATIONS

▪ Encephalitis, coma, respiratory failure, death ▪ Infants: intellectual disability, cerebellar damage, spastic paralysis, developmental delay

SIGNS & SYMPTOMS ▪ Neurological manifestations ▫ Generalized weakness; somnolence; hand, tongue, lip tremor; cranial nerve palsy; motor weakness; ↓ deep tendon reflexes ▪ Infants: poor feeding, fussiness, fever, vomiting, tense/bulging fontanelle

DIAGNOSIS LAB RESULTS

▪ Serology ▫ Enzyme-linked immunosorbent assay (ELISA): IgM antibodies ▫ Hemagglutination-inhibition, neutralizing antibody presence ▪ CSF ▫ ELISA: IgM antibodies ▫ Lymphocytic pleocytosis ▫ ↑ protein

TREATMENT ▪ No specific treatment

MEDICATIONS

▪ Supportive: anticonvulsants, corticosteroids

Chapter 101 Togaviruses

OTHER INTERVENTIONS Prevention ▪ Insect repellent (DEET, picaridin, IR3535, oil of lemon eucalyptus) ▪ Protective clothing ▪ Vector control

OSMOSIS.ORG 569

NOTES

NOTES

TREMATODES (FLATWORMS) GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ AKA flukes; parasitic flatworm; infects internal organs ▪ Phylum: Platyhelminthes Characteristics ▪ Adult morphology: flattened oval/elongated ▪ Structures ▫ Tegmentum (outer body covering) ▫ Ventral, oral suckers ▫ Pharynx → esophagus → caeca ▫ Testes, uterus/ovary (hermaphrodites) ▪ Eggs generally operculated (lidded); except schistosomes ▪ Obligate parasites of mollusks, vertebrates Development 1.Egg 2.Miracidium (ciliated, lacks mouth; infects first intermediate host) 3.Sporocyst (elongated sac, produces rediae) 4.Redia (larval stage with oral sucker) 5.Cercaria (larval stage; may be infectant) 6. Metacercaria (encysted cercaria) 7.Adult

SIGNS & SYMPTOMS ▪ See individual trematodes

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DIAGNOSIS DIAGNOSTIC IMAGING

▪ Medical imaging (e.g. ultrasound, CT scan, MRI)

LAB RESULTS

▪ E.g. blood tests ▪ Direct microscopy

OTHER DIAGNOSTICS ▪ Serologic tests

TREATMENT MEDICATIONS ▪ Anthelmintic

Chapter 102 Trematodes (Flatworms)

CLONORCHIS SINENSIS osms.it/clonorchis-sinensis PATHOLOGY & CAUSES ▪ Parasitic fluke; invasion of biliary tree → liver infection ▪ AKA Chinese liver fluke ▪ Morphology ▫ Adult: flat, elongated body; 25 x 5mm ▫ Egg: oval-shaped; 30 x 15μm ▪ Intermediate hosts ▫ First: freshwater snail (e.g. Parafossarulus manchouricus) ▫ Second: freshwater fish/shrimp ▪ Reservoirs: cats, dogs ▪ Transmission ▫ Ingestion of raw/undercooked fish/ shrimp ▪ Infectious form: metacercariae ▫ Ingestion of metacercariae → excyst in duodenum → migration to biliary tract → inflammation, epithelial hyperplasia ▪ Endemic to Eastern Asia (e.g. China, Japan, Philippines, Vietnam)

RISK FACTORS

▪ Recent travel to endemic areas ▪ Consumption of raw/undercooked fish/ shrimp

COMPLICATIONS

▪ Pancreatitis, cholangitis, liver abscesses, cholangiocarcinoma

DIAGNOSIS DIAGNOSTIC IMAGING Ultrasound, CT scan, MRI ▪ Enlarged gallbladder, hepatomegaly, bile duct inflammation, dilated/thickened intrahepatic bile ducts Endoscopy ▪ Visualization of adult organisms

LAB RESULTS

▪ Acute infection ▫ Eosinophilia, ↑ IgE ▪ Chronic infection ▫ ↑ alkaline phosphatase, ↑ bilirubin ▪ Direct microscopy ▫ Detection of Clonorchis eggs in stool samples ▫ Formalin ethyl-acetate concentration technique (FECT) → parasite separation from faeces ▪ Serologic tests ▫ E.g. ELISA ▪ Polymerase chain reaction (PCR)

TREATMENT MEDICATIONS

▪ Anthelmintic (e.g. praziquantel)

SIGNS & SYMPTOMS ▪ Mostly asymptomatic ▪ Acute infection: fatigue, right upper quadrant abdominal pain, indigestion, diarrhea, flatulence ▪ Chronic infection: fatigue, weight loss, abdominal discomfort, diarrhea, dyspepsia, jaundice (severe cases)

Figure 102.1 An adult Clonorchis sinensis worm.

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PARAGONIMUS WESTERMANI osms.it/paragonimus-westermani PATHOLOGY & CAUSES

SIGNS & SYMPTOMS

▪ Parasitic flatworm; causes pulmonary paragonimiasis ▪ AKA Japanese lung fluke ▪ Morphology ▫ Adult: oval-shaped body with spines; 15 x 8mm ▫ Egg: oval-shaped, thick shell; 100 x 55μm ▪ Intermediate hosts ▫ First: freshwater snails (e.g. Semisulcospira spp.) ▫ Second: crustaceans (e.g. crabs, crayfish) ▪ Transmission ▫ Ingestion of raw/undercooked crustaceans (e.g. crab, crayfish) ▪ Infectious form: metacercariae ▫ Ingestion of metacercariae → excyst in duodenum → penetration of peritoneal wall → migration to lungs → encapsulate, mature → inflammation, fibrosis ▪ Endemic to Eastern Asia (e.g. China, Japan, Philippines, Vietnam)

Pulmonary ▪ Early infection ▫ Systemic: fever, malaise ▫ Pulmonary: dyspnea, cough, pleuritic pain ▫ Gastrointestinal: diarrhea, epigastric pain ▪ Late infection ▫ Malaise ▫ Recurrent, chocolate-colored hemoptysis

RISK FACTORS

X-ray, CT scan, MRI ▪ Brain ▫ Skull X-ray: soap-bubble calcifications; calcified cysts ▫ CT/MRI: grape clusters; conglomerated, cystic lesions ▪ Lungs ▫ Pleural effusion, parenchymal cysts/ nodules, cavitary lesions, parasite migration tracts

▪ Poor sanitary conditions ▪ Seafood consumption in endemic areas

COMPLICATIONS

▪ Meningitis, encephalitis, seizures

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Extrapulmonary ▪ Cerebral: headache, fever, vomiting, seizures, papilledema, paresis/paresthesias, visual disturbances (e.g. diplopia) ▪ Abdominal: nausea/vomiting, hematoquezia (bloody stool), pain, hematuria ▪ Subcutaneous: tender, firm, painless, mobile nodules

DIAGNOSIS DIAGNOSTIC IMAGING

Chapter 102 Trematodes (Flatworms)

LAB RESULTS

▪ Eosinophilia, ↑ IgE ▪ Direct microscopy ▫ Detection of eggs in stool, sputum, bronchoalveolar lavage ▪ Serologic tests ▫ Enzyme-linked immunosorbent assay (ELISA), immunoblot

TREATMENT MEDICATIONS

▪ Anthelmintic (e.g. praziquantel, triclabendazole)

SCHISTOSOMES osms.it/schistosomes PATHOLOGY & CAUSES ▪ Blood flukes; parasitize mesenteric veins/ vesical venous plexus → gastrointestinal/ genitourinary tract infections ▪ AKA bilharziasis/snail fever ▪ Morphology ▫ Adult: elongated body, 1–2cm/0.39– 0.79in ▫ Eggs: not operculated ▪ Intermediate host ▫ Snails ▪ Transmission ▫ Contaminated freshwater contact ▪ Infectious form: cercariae ▫ Contact with cercariae in fresh water → skin penetration → schistosomulae → migration to liver through circulation → adult form → migration to mesenteric venules/vesical venous plexus → egg deposits → inflammation → fibrosis ▪ High-prevalence area is sub-Saharan Africa

RISK FACTORS

▪ More common in individuals who are biologically male, rural areas ▪ Recent contact with fresh water bodies in endemic areas

COMPLICATIONS

▪ Bacteremia, infertility, intestinal obstruction, nephrotic syndrome, renal failure, cardiomegaly, acute myelopathy

Figure 102.2 A scanning electron micrograph of a S. japonicum flatworm.

SIGNS & SYMPTOMS Acute infection ▪ Swimmer’s itch ▫ Pruritic papular/urticarial rash, esp. legs/ feet ▪ Acute schistosomiasis syndrome/Katayama fever ▫ Non-specific symptoms (fever, urticaria, chills, arthralgia, myalgia, headaches) ▫ Angioedema, dry cough, abdominal pain, diarrhea Chronic infection ▪ Intestinal: abdominal pain, poor appetite, diarrhea ▪ Hepatosplenic: hepatosplenomegaly, portal

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hypertension (e.g. collateral circulation, gastrointestinal bleeding, ascites) ▪ Pulmonary: dyspnea; pulmonary hypertension → cor pulmonale (enlarged right cardiac chambers) ▪ Urogenital: hematuria, pyuria, dysuria, increased urinary frequency ▪ Neuroschistosomiasis (acute myelopathy): seizures, sensory/motor impairment, cerebellar syndrome (incoordination)

prednisone) ▪ Manageme pruritus (e.g. antihistamines)

OTHER INTERVENTIONS

▪ Prevention ▫ Water sanitation programs ▫ Mass therapy ▫ Control of snails (e.g. molluscicides)

DIAGNOSIS DIAGNOSTIC IMAGING Chest X-ray, CT scan, MRI, abdominal ultrasound ▪ Brain: contrast-enhancing infiltrates ▪ Bladder: wall irregularities/fibrosis ▪ Liver: widened periportal space, periportal fibrosis, collateral pathways ▪ Lungs: patchy infiltrates, miliary nodules ▪ Spinal cord: radicular thickening, intramyelinic lesions

LAB RESULTS

Figure 102.3 Calcified eggs of the flatworm Schistosoma japonicum in the submucosa of the colon of an individual previously treated for schistosomiasis.

▪ Bladder/rectum biopsy ▫ Egg-filled granulomas in mucosa ▪ Direct microscopy ▫ Detection of eggs in stool/urine samples ▫ Kato–Katz method (thick smear) ▫ FLOTAC stool concentration method ▪ Lab tests ▫ Acute infection: eosinophilia ▫ Chronic infections: anemia ▫ Portal hypertension: thrombocytopenia (splenic sequestration) ▫ Urogenital infection: hematuria/ leukocyturia in urinalysis ▪ Serologic testings ▫ E.g. ELISA, indirect hemagglutination

TREATMENT MEDICATIONS

▪ Anthelmintic (e.g. praziquantel, oxamniquine) ▪ Corticosteroids (e.g. prednisolone,

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Figure 102.4 A CT scan of the abdomen and pelvis demonstrating calcification of the bladder secondary to schistosomiasis.

Chapter 102 Trematodes (Flatworms)

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NOTES

NOTES

TRICHOMONA MICROBE OVERVIEW ▪ Trichomonas vaginalis: pear-shaped (pyriform), flagellated protozoa; infects genitourinary tract ▪ Causative agent of trichomoniasis (trich), common sexually transmitted disease (STD) Morphology ▪ Size ▫ 9 x 7 micrometers ▪ Motile via four flagella, undulating membrane

▪ Rigid axostyle runs through cell from anterior to posterior end ▪ Contains hydrogenosomes (unique energyproducing organelles) Replication/Multiplication ▪ Humans only host ▫ Does not survive well in external environments ▫ Multiplies when vaginal pH basic ▫ Incubation period: 5–28 days ▫ No cyst stage

TRICHOMONAS VAGINALIS osms.it/trichomonas-vaginalis PATHOLOGY & CAUSES ▪ Resides in lower genital tract of individuals who are biologically female; urethra, prostate of individuals who are biologically male → trophozoite stage (infective stage) → transmitted sexually → infects squamous epithelium of lower genital tract → replicates by longitudinal binary fission → inflammatory response

RISK FACTORS

▪ Sexual activity with infected partner ▪ Multiple sexual partners ▪ More common in individuals who are biologically female

COMPLICATIONS

▪ ↑ risk of contracting HIV due to genital inflammation

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▪ Pregnancy ▫ ↑ risk of premature rupture of membranes, preterm delivery, low birth weight ▪ Urethritis, cystitis

SIGNS & SYMPTOMS ▪ May be asymptomatic ▪ Individuals who are biologically female ▫ Watery, foul-smelling vaginal discharge; burning; pruritus; dysuria, urinary frequency; lower abdominal pain; dyspareunia; vulvar, vaginal erythema ▪ Individuals who are biologically male ▫ Urethral discharge; pruritus; burning after urination/ ejaculation

Chapter 103 Trichomona

DIAGNOSIS LAB RESULTS Microbe identification ▪ Saline microscopy (wet mount of genital secretions) ▫ Characteristic organism ▫ ↑ polymorphonuclear leukocytes ▪ ↑ vaginal pH (> 4.5) ▪ T. vaginalis assay ▫ Detects species-specific ribonucleic acid (RNA); vaginal swab/urine specimen ▪ Nucleic acid amplification testing (NAAT) ▪ Trichomonas rapid test

TREATMENT MEDICATIONS

▪ Systemic 5-nitroimidazole drugs (e.g. metronidazole, tinidazole) ▫ Treat both partners

OTHER INTERVENTIONS

▪ Rate of transmission decreased with consistent use of condoms, spermicidal agents (e.g. nonoxynol-9)

OTHER DIAGNOSTICS

▪ Speculum exam ▫ Punctate hemorrhages cervix (strawberry cervix)

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TRYPANOSOMA GENERALLY, WHAT ARE THEY? DIAGNOSIS

PATHOLOGY & CAUSES ▪ Genus of flagellated parasitic protozoa Morphology ▪ Elongated body ▪ Flagellum: forms undulated membrane along body ▪ Kinetoplast: functions as mitochondrion Transmission ▪ Through vectors ▪ Incubation period: 1–2 weeks

▪ ▪ ▪ ▪

Direct microscopy Serologic testings Laboratory findings Additional diagnostic tests may be necessary (severity, infection sitedependent)

TREATMENT ▪ See individual pathogens

SIGNS & SYMPTOMS ▪ See individual pathogens

TRYPANOSOMA BRUCEI osms.it/trypanosoma-brucei PATHOLOGY & CAUSES ▪ Protozoan, extracellular parasite → African trypanosomiasis ▪ AKA “sleeping sickness” ▫ Neurologic alterations during meningoencephalitis stage (e.g. somnolence) Virulence factors ▪ Antigenic variation ▫ Changes variant surface glycoprotein (VSG) → immune response evasion ▪ ↑ interferon gamma → ↑ host T. brucei

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susceptibility (mechanism unknown) Morphologic forms (life-cycle) ▪ Epimastigote → procyclic trypomastigote (in tsetse fly midgut) → metacyclic trypomastigote (infectious form) Subspecies ▪ Trypanosoma brucei rhodesiense (acute, more severe disease course) ▪ Trypanosoma brucei gambiense (progressive, milder disease course) Reservoirs ▪ Domestic animals, lions, hyenas, antelopes

Chapter 104 Trypanosoma brucei Vector ▪ Male/female Glossina flies, AKA tsetse flies ▫ Ideal conditions: warm, humid climate (e.g. near river/lake); altitude < 1800m/5905ft Transmission ▪ Saliva inoculation via fly bite; vertical/ parenteral transmission very rare ▪ Endemic regions: sub-Saharan Africa; Democratic Republic of Congo (most cases) Pathogenesis ▪ Glossina bite → subcutaneous metacyclic trypomastigote inoculation → lymph vessels → bloodstream → ↑ tumor necrosis factor (TNF) alpha, interleukin 6 (IL-6), nitric oxide → ↑ capillary permeability → vasculitis → organ invasion, e.g. central nervous system (CNS) Disease stages ▪ Hemolymphatic (early) stage ▪ Meningoencephalitis (late) stage ▪ Symptom severity related to number of organisms in affected tissue (e.g. blood, CNS)

RISK FACTORS

▪ Recent endemic area travel ▪ Dense vegetation near human settlement

COMPLICATIONS

▪ Meningitis ▪ Myocarditis, heart failure ▪ Aspiration → bacterial pneumonia; associated with altered state of consciousness (meningoencephalitis stage)

SIGNS & SYMPTOMS Hemolymphatic stage ▪ Systemic symptoms ▫ Intermittent fever, headache, malaise, weakness, pruritus, rash ▪ Trypanosomal chancre ▫ Rubbery, painful, erythematous, wellcircumscribed lesion at fly bite site approx. one week post-inoculation

▪ Lymphadenopathy ▫ Winterbottom’s sign: enlarged mobile, soft posterior cervical triangle lymph nodes ▪ Hepatosplenomegaly ▪ Dyspnea ▪ Chest pain ▪ Altered thyroid function ▪ Impotence (biologically-male), amenorrhea (biologically-female) ▪ Pain, Kerandel sign (deep hyperesthesia) Meningoencephalitis stage ▪ AKA “Sleeping sickness” ▪ Cachexia ▪ Sleep disturbances (e.g. diurnal somnolence, nocturnal insomnia) ▪ Headaches ▪ Altered state of consciousness ▪ ↓ cognitive function ▪ Personality, behavioral change ▪ Muscle spasms, ataxia, tremor, flaccid paralysis, choreiform movements ▪ Psychiatric manifestations (e.g. psychosis)

DIAGNOSIS DIAGNOSTIC IMAGING MRI ▪ Cerebral ▫ May show multifocal white matter hyperintensity (indicates late-stage disease)

LAB RESULTS Serologic testings ▪ Card agglutination test for trypanosomiasis (CATT) ▫ Blood + drop of reagent with trypanosomal antigen ▪ Immunofluorescence ▪ Enzyme immunoassays Cerebrospinal fluid (CSF) examination ▪ Disease staging essential ▪ ↑ leukocytes ▪ ↑ proteins ▪ IgM/Trypanosoma presence

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▪ Morula/Mott cells (pathognomonic) ▫ IgM-filled plasma cells Direct microscopy ▪ Organism observation in lymph node aspiration, bone marrow, CSF, blood (thin/ thick Giemsa-stained smears) Laboratory findings ▪ Hemolytic anemia; leukocytosis; thrombocytopenia; ↑ erythrocyte sedimentation rate; hypergammaglobulinemia; hypoalbuminemia, hypocomplementemia; ↑ C-reactive protein; coagulation abnormalities Histological observation ▪ Meningoencephalitis stage (CSF sample) ▫ Morula/Mott cells in white matter (pathognomonic), edema, microhemorrhages, perivascular proliferation

OTHER DIAGNOSTICS Electroencephalogram (EEG) ▪ Late stage: abnormal, slow delta waves

TREATMENT MEDICATIONS

▪ Antiprotozoal medication ▫ Hemolymphatic stage: pentamidine, suramin ▫ Meningoencephalitis stage: eflornithine, eflornithine + nifurtimox, melarsoprol

OTHER INTERVENTIONS

▪ Prevention ▫ Vector control, surveillance ▫ Protective clothing

TRYPANOSOMA CRUZI osms.it/trypanosoma-cruzi PATHOLOGY & CAUSES ▪ Protozoan, intracellular parasite ▫ Causes American trypanosomiasis, AKA Chagas disease ▪ Morphologic forms (life cycle) ▫ Amastigote (intracellular, no flagellum) → epimastigote (in triatomine midgut) → trypomastigote (infectious form) ▪ Reservoirs ▫ Opossums, armadillos, canines ▪ Vectors ▫ Triatomine bugs (“kissing bugs”) ▫ Common species: Rhodnius prolixus, Triatoma dimidiata, Triatoma infestans ▫ Characteristics: size (2–3cm/0.79– 1.18in); obligated hematogenous; feeds at night; lives in dark, warm sites (e.g. closets, thatched roofs)

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Transmission ▪ Triatomine bite → fecal wound contamination ▪ Contaminated food/water ingestion (infection through mucous membranes) ▪ Parenteral (e.g. blood transfusion, sharing syringes) ▪ Vertical (mother → fetus) Endemic regions ▪ Rural areas of southern U.S., Latin America Pathogenesis ▪ T. cruzi trypomastigote inoculation → bloodstream → organ invasion (heart, enteric nervous system) → interstitial inflammation → tissue destruction → fibrosis Disease stages ▪ Acute phase: 8–12 weeks ▪ Indeterminate phase: decades

Chapter 104 Trypanosoma brucei ▪ Chronic phase: cardiac/gastrointestinal disease

RISK FACTORS

▪ Recent endemic area travel, immunosuppression, blood transfusion, organ transplant, intravenous drug use

COMPLICATIONS

▪ Heart failure, acute myocarditis, meningoencephalitis, systemic/pulmonary embolism, sudden death

SIGNS & SYMPTOMS Acute phase ▪ Mostly asymptomatic ▪ Systemic: malaise, fever, anorexia, headaches ▪ Chagoma: nodular skin lesion at infection site; usually on face/extremities ▪ Romaña’s sign: unilateral eyelid edema, conjunctivitis, preauricular lymphadenitis; follows conjunctival inoculation ▪ Lymphadenopathy ▪ Hepatosplenomegaly Indeterminate phase ▪ Asymptomatic Chronic phase ▪ Cardiac manifestations: dyspnea, fatigue, palpitation, chest pain, edema, mitral/ tricuspid regurgitation murmur, splitting of S2 ▪ Gastrointestinal manifestations: megacolon (constipation, bloating, abdominal pain); megaesophagus (dysphagia, regurgitation) Congenital disease ▪ Systemic: low birthweight, anasarca, fever ▪ Petechiae ▪ Hepatosplenomegaly ▪ Neurologic abnormalities (e.g. hypotonia, tremor)

DIAGNOSIS DIAGNOSTIC IMAGING

▪ Further studies: stage, clinical syndrome dependent

Figure 104.1 The kissing bug, Triatoma infestans, is found in Central and South America and is a vector for Chagas disease.

Chest X-ray, MRI, echocardiogram ▪ Enlarged cardiac silhouette (cardiomegaly) ▪ Pericardial effusion ▪ Valvular regurgitation ▪ Left ventricular aneurysm Barium studies ▪ Megacolon, megaesophagus

LAB RESULTS

▪ Polymerase chain reaction (PCR)

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▪ Blood culture Direct microscopy ▪ Organism observation in thin/thick blood smears; for acute phase disease (high parasitemia) Serologic testing ▪ E.g. enzyme-linked immunosorbent assay (ELISA), immunofluorescence Xenodiagnosis ▪ Feed laboratory triatomes with person’s blood → examine feces weeks later Cardiac tissue microscopy ▪ Acute disease: intracellular pseudocysts (amastigotes inside myocardiocytes), interstitial inflammation ▪ Chronic disease: mural thrombi, interstitial fibrosis, myocardiocyte necrosis

OTHER DIAGNOSTICS ECG ▪ Arrhythmia evidence: bundle branch/AV block

TREATMENT MEDICATIONS

▪ Antitrypanosomal treatment ▪ Advanced cardiac disease: cardiac arrest prevention, ventricular fibrillation through antiarrhythmic medication

OTHER INTERVENTIONS Prevention ▪ Vector control, treat parasitemia before conception

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Figure 104.2 Trypanosoma species seen on a peripheral blood smear from an individual with Chagas disease.

NOTES

NOTES

TUBERCULOSIS MICROBE OVERVIEW ▪ Tuberculosis (AKA Mycobacterium tuberculosis) mycobacterium that primarily infects lungs but may infect any bodily organ/tissue ▪ Important properties ▫ Curved rod shaped bacteria often wrapped together in cord-like formations ▫ Obligate aerobe ▫ Impervious to Gram staining due to waxy cell wall composed of fatty acids (e.g., mycolic acid)

▪ ▪ ▪ ▪ ▪

▫ Staining: acid-fast stains like Ziehl– Neelsen, fluorescent stains like auramine/rhodamine Clumped colonies Distinctly slow growing (up to 6 weeks for visible growth) Grown on Lowenstein–Jensen media Resistant to weak disinfectants, can survive on dry surfaces for months Can avoid mucus traps, getting into deep airways (alveoli)

MYCOBACTERIUM TUBERCULOSIS osms.it/mycobacterium-tuberculosis PATHOLOGY & CAUSES TYPES Primary tuberculosis Reactivation tuberculosis ▪ In about 5–10% cases of primary TB Extrapulmonary tuberculosis ▪ May involve any organ (most commonly kidneys, meninges, lymph nodes, etc.) ▪ Systemic miliary tuberculosis

STAGING

▪ Transmitted by inhaling infectious aerosol droplets from individual with active TB (e.g. coughing, sneezing, speaking, etc.) ▪ TB enters lungs, gets phagocytized by macrophages → TB produces enzymes that inhibit lysosome and phagocytic vacuole

fusion → bacteria survives, proliferates, creates localized infection → primary tuberculosis development ▫ TB infiltrated macrophage fusion → Langhans giant cells ▫ Cell-mediated immunity activation → granuloma forms within infected area → caseous necrosis inside granuloma → Ghon focus ▫ Lymphatic dissemination of TB → lymph node caseation ▫ Ghon focus + involved lymph node → Ghon complex ▫ Ghon complex fibrosis, calcification → Ranke complex ▪ Primary infection resolution ▫ Mycobacteria killed by immune system ▫ Bacteria walled off in granuloma remains dormant but viable → latent tuberculosis with no further complications in immunocompetent

OSMOSIS.ORG 583

individuals ▪ Compromised immune system → more caseous necrosis areas → cavity formation → reactivation tuberculosis

RISK FACTORS

▪ Immunocompromised states ▫ HIV ▫ Diabetes mellitus ▫ Hematologic malignancy ▫ Chronic lung disease (especially silicosis) ▫ Malnutrition ▫ Aging ▪ Substance abuse ▫ Alcoholism ▫ Injection drug users ▪ Close contact with individuals with active TB infection ▫ Healthcare providers ▫ Incarceration ▪ Lower-income, medically underprivileged countries ▫ Recent immigrants from highprevalence countries

COMPLICATIONS

▪ Bronchopneumonia ▪ Pneumothorax ▪ Extrapulmonary tuberculosis ▫ Kidney → dysuria, pyelonephritis with sterile pyuria ▫ Meninge → meningitis ▫ Lumbar vertebrae → Pott disease ▫ Liver and gallbladder → hepatitis, obstructive jaundice ▫ Lymph nodes → cervical tuberculous lymphadenitis (scrofula) ▫ Peritonitis ▫ Pericarditis ▪ Systemic infection

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Figure 105.1 The gross pathological appearance of a Ghon focus.

SIGNS & SYMPTOMS ▪ Primary tuberculosis ▫ Usually asymptomatic (90-95% of cases) ▫ Mild flu-like illness ▫ Rarely pleural effusion ▪ Reactivation tuberculosis ▫ Constitutional symptoms (fever, chills, night sweats, fatigue, appetite loss, weight loss, pleuritic chest pain) ▫ Cough (dry cough, prolonged cough producing purulent sputum, hemoptysis—suggesting advanced TB) ▫ Crepitations during lung auscultation ▪ Extrapulmonary tuberculosis ▫ Depending on affected organ/tissue ▪ Miliary (disseminated) tuberculosis ▫ Can affect any organ (e.g. choroidal tubercles in eye, granulomas within organs) ▫ Weight loss ▫ Fever, chills ▫ Dyspnea

Chapter 105 Tuberculosis

DIAGNOSIS DIAGNOSTIC IMAGING Chest X-ray ▪ Used in PPD/IGRAs positive ▪ Ranke complex → sign of healed primary TB ▪ Cavities → active TB sign

Antibiotic resistance ▪ Multiple-drug-resistant TB ▫ Resistant to isoniazid and rifampin ▪ Extensively drug-resistant TB ▫ Resistant to both isoniazid and rifampin, any fluoroquinolone, at least one second-line drug

LAB RESULTS PPD intradermal skin test (tuberculin test) ▪ Screening test for people at high risk for TB ▫ Tuberculin injection between dermal layers, induration area measurement within 48–72 hours ▪ Induration area ≥ 5mm: positive in immunocompromised individuals, persons with primary TB radiographic evidence/ close contact with those with active TB ▪ Induration area ≥ 10mm: positive in residents/immigrants from high-prevalence countries, children > four years of age, high risk populations (e.g., medical employees) ▪ Induration area ≥ 15mm: considered positive in individuals with no known risk factors ▪ Cannot be used for differentiation between active and latent TB ▪ PPD result interpretation ▫ Positive → exposure evidence ▫ False-positive → previously immunized with BCG vaccine ▫ Negative → no exposure evidence ▫ False-negative → sometimes seen in individuals with sarcoidosis, malnutrition, Hodgkin’s lymphoma

Figure 105.2 An X-ray image of the chest demonstrating diffuse interstitial granular densities in an individual with milliary tuberculosis.

Sputum testing ▪ Used for definitive diagnosis ▪ Staining, culture, PCR

OTHER DIAGNOSTICS Interferon gamma release assays (IGRAs) ▪ Alternative for PPD ▪ Unlike PPD, doesn’t show false-positive results in BCG vaccinated

Figure 105.3 Multifocal patchy opacities in the right upper lobe of an individual who presented with night sweats, weight loss and persistent cough. The presenting symptoms and radiological appearance are consistent with pulmonary tuberculosis.

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TREATMENT MEDICATIONS

▪ Prophylactics ▫ BCG vaccine (some countries) ▪ Latent TB ▫ Isoniazid for 9 months ▪ Active TB ▫ First line anti-TB drugs: isoniazid, rifampin, pyrazinamide, ethambutol/ streptomycin ▪ Antibiotic resistance ▫ For multiple-drug-resistant TB, treatment requires second-line drugs (amikacin, kanamycin, capreomycin)

OTHER INTERVENTIONS

▪ Active TB ▫ Compulsory isolation (until sputum negative for TB)

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Figure 105.4 The histological appearance of a tuberculosis granuloma. The granuloma is formed of epithelioid macrophages and giant cells with a focus of caseating necrosis at the centre and a rim of lymphocytes at the periphery.

NOTES

NOTES

BONE & JOINT INFECTIONS GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Bacterial invasion and destruction of bone and joint cartilage ▪ Caused by bacteria ▫ E.g. Staphylococcus aureus (S. aureus), Mycobacterium tuberculosis (M. tuberculosis), Pseudomonas aeruginosa (P. aeruginosa)

RISK FACTORS

▪ Trauma/open fractures, diabetes/ atherosclerosis, orthopedic implants, existing infection etc.

COMPLICATIONS ▪ ▪ ▪ ▪

Chronic infections Bone fractures Loss of mobility Dissemination of infection

SIGNS & SYMPTOMS

DIAGNOSIS DIAGNOSTIC IMAGING MRI ▪ Detect bone infections CT scan, X-ray ▪ Detect fractures

LAB RESULTS

▪ Blood tests ▪ Needle aspiration: pathogen detection

TREATMENT MEDICATIONS

▪ Before identifying pathogen → general antibiotics ▪ Known pathogen → specific antibiotics

SURGERY

▪ Surgical cleaning

▪ Pain → individual avoids using infected joint Systemic ▪ Fever, chills, weakness, headache Local ▪ Swollen, painful, warm

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OSTEOMYELITIS osms.it/osteomyelitis PATHOLOGY & CAUSES

▪ Cortical loss ▪ Contrast enhancement of abscess rim

▪ Bacterial infection (S. aureus, M. tuberculosis most common) → bone, bone marrow inflammation ▪ Bacteria → bone via bloodstream, nearby infection, open fractures/orthopedic implants ▪ First week: bacterial reproduction → inflammation → bone necrosis (e.g. sequestrum); if periosteum bursts → abscess ▪ Later: cytokines induce bone resorption → replacement with fibrous tissue → new bone formation around necrotic one (e.g. involucrum)

Nuclear medicine scans ▪ If MRI not attainable: higher radiotracer uptake CT scan, X-ray ▪ not sensitive for 1–2 weeks ▫ Osteopenia (decreased bone density) ▫ Periosteal reaction (thickening of periosteum) ▫ Aggressive infection → Codman’s triangle (lifted periosteum with triangleshaped, ossified edge)

RISK FACTORS

▪ Diabetes, fractures, splenectomy, orthopedic procedures/hardware

COMPLICATIONS

▪ If M. tuberculosis disseminates from joint to vertebra → Pott disease ▪ Inadequate treatment → chronic infection → bone fractures, sepsis

SIGNS & SYMPTOMS Local ▪ Redness, swelling, painful site, sinus connecting to abscess Systemic ▪ Weakness, fever, headache, shivering

DIAGNOSIS DIAGNOSTIC IMAGING MRI ▪ Edema → signal changes

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Figure 106.1 An X-ray image of the tibia demonstrating a radiolucency with a sclerotic border consistent with a Brodie abscess.

Chapter 106 Bone & Joint Infections ▫ Endosteal scalloping (focal resorption of endosteum) ▫ Advanced osteomyelitis → cortical bone breakage ▫ Peripheral sclerosis (increased density at periphery, lower density centrally)

OTHER DIAGNOSTICS Needle aspiration guided with ultrasound ▪ Specific antibiotic therapy

TREATMENT MEDICATIONS

▪ Long-term intravenous antibiotics

SURGERY Figure 106.2 A plain radiograph of the right lower leg of an individual with postoperative osteomyelitis. The surgical wound started discharging pus two weeks post open reduction. There is medial cortical destruction and loss of trabeculations with lateral cortical thickening.

▪ Surgical removal of dead bone ▪ Severe cases → amputation

SEPTIC ARTHRITIS osms.it/septic-arthritis PATHOLOGY & CAUSES ▪ Joint structures: infected, damaged ▪ Pathogen enters the joint via bloodstream, from nearby infection/directly (e.g. open fracture) ▪ Infection of joint → endotoxin production → cytokine release → neutrophil attraction → inflammation, damage of joint structures

CAUSES

▪ Most commonly S. aureus (any age group), Neisseria gonorrhoeae (N. gonorrhoeae; sexual transmission → adults)

RISK FACTORS ▪ ▪ ▪ ▪ ▪ ▪ ▪

Diabetes Joint trauma Artificial joint, surgical procedure Osteomyelitis Chronic arthritis (e.g. rheumatoid arthritis) Immunocompromised HIV

SIGNS & SYMPTOMS ▪ Most commonly affects knee; less commonly ankle, hip, shoulder

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Local ▪ Restricted range of motion; painful, warm, swollen joint Systemic ▪ Fever, weakness

DIAGNOSIS DIAGNOSTIC IMAGING X-ray, CT scan ▪ Normal in early stages ▪ ↑ fluid in synovial part of joint ▪ Narrowing of joint space due to destruction of cartilage ▪ Destruction of bone adjacent to cartilage MRI ▪ Edema around synovium ▪ Assess spread of infection outside the joint Ultrasound ▪ ↑ fluid ▪ Guiding needle for aspiration

Figure 106.3 A red, hot, swollen left knee in an individual with septic arthritis.

TREATMENT MEDICATIONS

Blood test ▪ ↑ white blood cells count (WBC); ↑ sedimentation rate (ESR)

▪ General antibiotics depending on Gram stain of joint fluid ▪ Switch to specific antibiotics once bacteria identified ▪ Pain medications (e.g. NSAIDs, acetaminophen)

Aspiration of joint fluid ▪ → bacterial culture → specific antibiotics

SURGERY

LAB RESULTS

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▪ Surgically drain, cleanse joint fluid

NOTES

NOTES

BONE & JOINT PATHOLOGY GENERALLY, WHAT IS IT? PATHOLOGY & CAUSES ▪ Non-neoplastic disorders affecting bones, joints ▪ Generally result in weakened bones; pathologic fractures, malformations ▪ Include disorders of normal bone structure due to ▫ Impaired bone mineralization (rickets, osteomalacia) ▫ Failure of bone resorption (osteopetrosis, osteosclerosis) ▫ Disorders of bone formation (osteogenesis imperfecta) ▫ Imbalance between bone formation, bone resorption (osteoporosis, Paget’s disease) ▫ Stress injury (Osgood–Schlatter disease) ▫ Impaired vascularization (Legg–Calvé– Perthes disease)

SIGNS & SYMPTOMS ▪ May be asymptomatic ▪ Most common symptoms include ▫ Bone pain, bone tenderness, pathologic fractures, bone malformations, nerve/ tissue compression

LAB RESULTS

▪ Etiology-dependent ▫ Bone specific alkaline phosphatase, creatinine kinase, Ca2+, serum 25(OH)D levels, etc. ▫ Biopsy: microscopic changes

OTHER DIAGNOSTICS ▪ Clinical presentation

TREATMENT ▪ Causative treatment, palliative treatment (management of symptoms with no effect on course of the disease)

MEDICATIONS

▪ Supplementation therapy (vitamin D) ▪ Bisphosphonate therapy

SURGERY ▪ Surgery

OTHER INTERVENTIONS

▪ Fracture management (braces, intramedullary rods, etc.)

DIAGNOSIS DIAGNOSTIC IMAGING X-ray ▪ Lytic/blastic changes ▪ Bone fractures, malformations Bone scan scintigraphy ▪ Extent, distribution of skeletal involvement

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FIBROUS DYSPLASIA OF BONE osms.it/fibrous-dysplasia-of-bone PATHOLOGY & CAUSES

RISK FACTORS

▪ Rare disorder → normal bone tissue replaced by fibrous tissue ▪ → brittle, weak, fracture-prone bones

▪ Sex ▫ ↑ individuals who are biologically male ▪ Age ▫ Symptoms usually occur in teen years

TYPES

COMPLICATIONS

▪ Monostotic ▫ AKA (McCune–Albright syndrome) ▫ Most common; involves one bone ▪ Polyostotic ▫ Involves multiple bones

CAUSES

▪ Post-zygotic activating mutations of guanine nucleotide stimulatory protein (GNAS) gene, which encodes ɑ subunit of the Gs coupled protein receptor → constitutive receptor activation → replacement of bone with fibrous tissue

▪ Pathologic fractures ▫ Repeated pathologic fractures can → “shepherd crook malformation” (varus angulation of the proximal femur) ▪ Severe scoliosis if spine affected

SIGNS & SYMPTOMS ▪ Mostly asymptomatic ▪ During teen years ▫ Pain, swelling, pathologic fractures, malformations ▪ Most commonly affects proximal femur, tibia, ribs, skull ▪ Rare case of optic nerves/auditory canal compression ▫ Vision/hearing loss

DIAGNOSIS DIAGNOSTIC IMAGING

Figure 107.1 The histological appearance of bone in an individual with fibrous dysplasia of bone. Normal bone tissue is on the left. The affected bone is composed of thin disordered trabeculae. The bone marrow spaces are packed with fibrous tissue.

X-ray ▪ Well-circumscribed lytic lesions in metaphysis/diaphysis with “ground glass” appearance ▪ Undulating pattern of cortical bone due to endosteal erosion ▪ “Rind sign”: thick, sclerotic bone layer surrounding lytic lesion ▪ Pathologic fracture → periosteal reaction Total body scintigraphy ▪ Identify extent of bone lesions ▫ Increased Tc99 uptake

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Chapter 107 Bone & Joint Pathology

LAB RESULTS Biopsy ▪ Thin, irregular bony trabeculae; described as “Chinese figures”

OTHER DIAGNOSTICS Clinical presentation ▪ Albright syndrome may present along with endocrine abnormalities; e.g. “café-au-lait” spots, often on neck

TREATMENT

Figure 107.2 An X-ray image of the femurs demonstrating a shepherd’s crook malformation. Both femurs are involved in this case of polyostotic fibrous dysplasia.

▪ Palliative; disease incurable ▪ Asymptomatic: observation ▪ Symptomatic: medications, surgery

MEDICATIONS

▪ Bisphosphonate therapy ▫ Inhibit osteoclast activity, prevent bone loss, decrease bone pain

SURGERY

▪ Curettage; bone grafting; stabilization with plates, screws ▪ Rarely effective; high rate of recurrence

Figure 107.3 A CT scan of the head in the axial plane demonstrating fibrous dysplasia of the squamous temporal bone in a case of monoostotic fibrous dysplasia.

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LEGG–CALVE–PERTHES DISEASE osms.it/legg-calve-perthes_disease PATHOLOGY & CAUSES ▪ Hip disorder characterized by osteonecrosis of proximal femur head due to compromised blood supply ▪ ↓ blood supply to proximal femoral head → osteonecrosis → infiltration of new blood vessels and resorption of necrotic bone → bone mass loss, growth cessation,weakening of bone ▪ Cause of blood supply disruption (ligamentum teres femoris or medial circumflex femoral artery) unknown

RISK FACTORS

▪ Age ▫ Usually affects children 3–12 years ▪ Sex ▫ ↑ individuals who are biologically male ▪ Heredity ▪ Endocrinologic abnormalities ▪ Hemodynamic disorders ▪ Trauma ▪ Steroid use

DIAGNOSIS DIAGNOSTIC IMAGING X-ray ▪ Initial scans often normal; nonspecific effusion of joint (widening of joint space) may be present ▪ As disease progresses ▫ Flattening (coxa plana), fragmentation, demineralization of femoral head with subchondral lucency; proximal femoral neck malformation (coxa magna) Bone scintigraphy ▪ Confirmation and evaluation ▫ Extent of involvement ▪ Focal area of ↓ uptake in femoral head

COMPLICATIONS

▪ Loss of bone mass can → pathologic fractures, malformations (e.g. coxa magna) ▪ ↑ risk of osteoarthritis in adulthood

SIGNS & SYMPTOMS ▪ Intermittent/chronic throbbing hip pain ▪ Referred knee/groin pain exacerbated by movement, especially internal hip rotation, ▪ Soreness, altered gait ▪ Reduced range of motion

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Figure 107.4 X-ray images of the right hip in a child with Legg–Calvé–Perthes disease. The diagnosis was made at six years (left) and by 8.5 years (right) the epiphysis has completely collapsed due to osteonecrosis.

Chapter 107 Bone & Joint Pathology MRI ▪ Confirmation and evaluation ▫ Extent of involvement ▪ Hypointense bone marrow changes, subluxation of femoral head

TREATMENT SURGERY

▪ External fixation to stabilize hip bone, relieve it from carrying body’s weight ▪ Hip replacement is usually required > age 50

OTHER INTERVENTIONS

▪ Traction to remove mechanical pressure, reduce wear ▪ Braces, physiotherapy to restore range of motion ▪ Avoidance of contact sports/games, running, prolonged weight bearing ▫ Swimming, cycling recommended to exercise hip muscles, restore range of motion

OSGOOD–SCHLATTER DISEASE osms.it/osgood-schlatter_disease PATHOLOGY & CAUSES

SIGNS & SYMPTOMS

▪ Traction phenomenon characterized by stress inflammation, stress injury at point of insertion of patellar tendon (apophysitis) on proximal tibial tubercle ▪ AKA apophysitis of tibial tubercle

▪ Swelling, pain at tibial tubercle ▫ Exacerbated by trauma, activity; relieved by rest ▪ Limping; bony prominence of tibial tubercle ▪ Avulsion fracture → acute onset of pain ▪ Usually asymmetric, but often presents bilaterally

CAUSES

▪ Overuse during physical activity ▫ Repetitive quadriceps contraction → traction on tibial tuberosity → microavulsion fractures of tibial tubercle, tendinous inflammation ▪ Severe cases may → complete tibial tubercle avulsion fracture (detachment of tibial tubercle)

RISK FACTORS

▪ Age ▫ ↑ common in 11–14 year olds ▪ Activity level ▫ ↑ common in physically active individuals

DIAGNOSIS DIAGNOSTIC IMAGING

▪ Used only for atypical presentation (pain not related to activity, fever, rash etc.) to exclude other conditions (e.g. osteomyelitis)

X-ray ▪ Elevation of tibial tubercle ▪ Fragmentation of tibial tubercle ▪ Soft tissue swelling ▪ Calcification/thickening of patellar tendon

OTHER DIAGNOSTICS ▪ Clinical presentation

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TREATMENT MEDICATIONS

▪ Short term analgesics/NSAIDs use

SURGERY

▪ Ossicle resection, excision of tibial tuberosity ▫ If everything fails, for individuals with closed growth plates

OTHER INTERVENTIONS

▪ Usually no treatment required ▪ Physical therapy

Figure 107.5 A lateral X-ray image of the knee in an individual with Osgood–Schlatter disease. There is fragmentation of the tibial tuberosity and overlying soft tissue swelling.

OSTEOGENESIS IMPERFECTA osms.it/osteogenesis-imperfecta PATHOLOGY & CAUSES ▪ Disease characterized by brittle bones prone to fractures due to impaired type I collagen synthesis ▪ Type I collagen ▫ Formation: two ɑ1 chains combine with one ɑ2 chain → triple stranded type 1 procollagen → post-translational modification (folding, cross linking) → strong fibrils with enormous tensile strength ▫ Important for structural integrity of bones, joints, eyes, ears, teeth and skin ▪ Affects primarily bones, but also other tissues containing type I collagen → structural abnormalities in affected tissues

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TYPES

▪ Previously classified into nine subtypes based on family history, radiologic, clinical features ▪ Included is modified clinical classification → severity

Mild (type I) ▪ Mild bone fragility ▪ Variable fracture rate; minimal bone fractures before learning to walk ▪ Minimal malformation, normal stature ▪ Adults at higher risk for hearing loss, premature osteoporosis following menopause

Chapter 107 Bone & Joint Pathology Moderate to severe (types III–IX) ▪ Type III ▫ Most severe type compatible with survival ▪ Moderate to severe rate of fractures ▪ Moderate malformations, short stature ▪ Children ▫ Higher risk of hearing loss ▪ Adults ▫ Earlier onset of hearing loss and premature osteoporosis than in mild form Lethal form (type II) ▪ Most cases die in utero/within first year of life ▪ Severe fractures in utero ▪ Severe deformities; short stature ▪ Pulmonary hypoplasia → respiratory failure

CAUSES

▪ Autosomal dominant mutation of COL1A1 or COL1A2 (>90%), other genes encoding ɑ1, ɑ2 chains of type I collagen → misfolding of collagen proteins, loss of function → bone loss, fragility

SIGNS & SYMPTOMS ▪ Highly variable presentation ▪ Pathologic fractures with minimal/no trauma, malformations, short stature, scoliosis ▪ Skull malformations may cause compression, neurologic symptoms ▪ Blue discoloration/translucency of sclera due to decreased collagen, exposure of choroidal veins ▪ Hearing loss due to abnormalities in middle, inner ear ossicles ▪ Dentinogenesis imperfecta ▫ Small, blue/translucent, worn down teeth ▪ Decreased structural integrity, hypermobility of ligaments, joints, skin ▪ Easy bruising

Figure 107.6 Blue sclera in an individual with osteogenesis imperfecta.

DIAGNOSIS DIAGNOSTIC IMAGING Prenatal ultrasound ▪ Lethal form ▫ Severe micromelia (small, undeveloped extremities) ▫ Decreased bone mineralization → skull compression with transducer pressure ▫ Multiple bone fractures Postnatal X-ray skeletal survey ▪ Mild form ▫ Thinning of cortical bone ▫ Wormian bones may be present (small, irregular bones between cranial sutures) ▪ Moderate to severe form ▫ Cystic metaphyses ▫ Severe osteoporosis ▫ Popcorn calcification of metaphysis, epiphysis of long bones ▫ Vertebral/rib fractures common ▪ Lethal form ▫ Beaded ribs ▫ Severe osteoporosis ▫ Multiple fractures, malformations of long bones

LAB RESULTS

▪ ↑ serum alkaline phosphatase in blood ▪ ↑ Ca2+ in the urine

Biopsy ▪ Disorganized bone; decrease of cortical, trabecular width; cancellous bone volume ▪ Increased bone remodeling

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Dermal fibroblast culture ▪ Abnormalities in quality/quantity of collagen synthesis Prenatal DNA mutation analysis ▪ For at-risk pregnancies

OTHER DIAGNOSTICS ▪ Clinical presentation

TREATMENT MEDICATIONS

▪ Bisphosphonate treatment for moderate to severe form (e.g. intravenous pamidronate)

SURGERY

▪ Surgical malformity correction ▪ Fracture management with intramedullary rods placement; telescoping rods for actively-growing individuals

OTHER INTERVENTIONS

Figure 107.7 X-ray images of the arms of an individual with osteogenesis imperfecta. There is generalised osteoporosis as well as multiple fractures and malformations..

▪ Physical therapy → prevent contractures, bone loss due to immobility

OSTEOMALACIA osms.it/osteomalacia PATHOLOGY & CAUSES ▪ Inadequate bone mineralization in adults due to lack of vitamin D, Ca2+/PO3▪ AKA rickets (in children) ▪ ↓ Ca2+ inhibits normal mineralization of newly formed osteoid during bone remodelling → weakening, softening of bones

CAUSES

▪ Vitamin D deficiency → insufficient intestinal absorption of Ca2+ ▫ Most common cause ▫ Insufficient sun exposure → UVB rays

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initiate vitamin D synthesis in the skin ▫ Chronic kidney disease/ liver disease → lack of vitamin D activation ▫ Insufficient intake ▫ Malabsorption syndrome → insufficient intestinal absorption of Ca2+, other minerals ▫ Can occur as adverse effect of long term anticonvulsant use (e.g. phenytoin) ▪ X-linked hypophosphatemia

RISK FACTORS

▪ Limited sun exposure, use of strong sunscreens

Chapter 107 Bone & Joint Pathology ▪ Dietary ▫ Lactose intolerance, vegetarian diet ▪ Darker skin pigmentation

COMPLICATIONS

▪ May → secondary hyperparathyroidism ▪ Prolonged secondary hyperparathyroidism → Ca2+ resorption from bones → osteoporosis

SIGNS & SYMPTOMS ▪ Diffuse bone and joint pain ▪ Proximal muscle weakness ▪ Muscle spasms of hands, feet, tingling/ numbness ▪ Bone fragility, increased risk of fractures with minimal trauma

DIAGNOSIS DIAGNOSTIC IMAGING X-ray ▪ ↓ bone mineral density, AKA osteopenia ▪ Loss of of trabecular bone, thinning of cortical bone ▪ “Looser lines” ▫ Transverse lucencies resembling fractures, AKA pseudofractures ▪ In case of secondary hyperparathyroidism ▫ Subperiosteal resorption of phalanges, bone cysts

LAB RESULTS ▪ ▪ ▪ ▪

↓ Serum 25(OH)D levels ↓ Ca2+, ↓ PO3↑ Parathyroid hormone levels ↑ Alkaline phosphatase due to increased osteoblast activity

Bone biopsy with tetracycline labeling ▪ Rarely done ▪ ↑ unmineralized osteoid volume ▪ ↑ width of osteoid seams ▪ No sign of new bone mineralization

TREATMENT Figure 107.8 An X-ray image of the pelvis of an individual with osteomalacia. There are numerous pseudofractures, or Looser lines, in both the inferior and superior pubic rami.

MEDICATIONS

▪ Oral vitamin D supplementation ▪ Correction of Ca2+ intake

OTHER INTERVENTIONS ▪ Treat underlying cause

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OSTEOPETROSIS osms.it/osteopetrosis PATHOLOGY & CAUSES ▪ Rare genetic disorder characterized by osteoclast dysfunction → hardening of the bone, AKA osteosclerosis ▪ Osteoclasts’ failure to resorb bone → increased density, overgrowth of bones ▪ Despite increased density, bones have disordered architecture, lack flexibility; thus prone to fractures

TYPES Autosomal recessive osteopetrosis, AKA infantile malignant type ▪ Caused by mutations in CA2 gene encoding carbon anhydrase ▪ Deficiency of carbonic anhydrase → inhibition of proton pumping → ↑ pH → osteoclasts fail to resorb bone because acidic environment required → imbalance between bone formation and bone resorption → excess bone formation Autosomal dominant osteopetrosis, AKA adult benign type ▪ Caused by mutations in chloride channel 7 (CLCN7) gene; less severe type ▪ Associated with renal tubular acidosis → deficiency of carbonic anhydrase in kidney

SIGNS & SYMPTOMS Autosomal recessive osteopetrosis ▪ Impaired growth, failure to thrive ▪ Osteomyelitis of mandible ▪ Dental abnormalities ▪ Visual/hearing impairment → sclerosis of skull bones, cranial nerve compression ▪ Hydrocephalus → obstruction of foramen magnum

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▪ Hepatosplenomegaly and hypersplenism ▫ Due to bone marrow replacement and anemia, resulting in extramedullary hematopoiesis ▪ Symptoms of anemia (e.g. weakness, fatigue, pallor) ▪ Symptoms of thrombocytopenia (e.g. bruising, hemorrhage) ▪ Symptoms of leukopenia (e.g. recurrent infections) Autosomal dominant osteopetrosis ▪ Can be asymptomatic; most commonly affects spine, pelvis, base of skull ▪ Vision loss, hearing loss due to sclerosis of skull bones, cranial nerve compression ▪ Pathologic fractures ▪ Osteoarthritis

DIAGNOSIS DIAGNOSTIC IMAGING X-ray ▪ Increased thickness, density of bones ▪ “Bone within bone” appearance ▫ Classical for autosomal dominant osteopetrosis ▪ Sclerotic rings in iliac bones ▪ Widened costochondral junctions ▪ Radiolucent metaphyseal bands ▪ Sandwich vertebrae ▫ Peripheral bony sclerosis with central lucency of vertebral body

LAB RESULTS

▪ Hypocalcemia (due to ↓ reabsorption of Ca2+) ▪ ↑ PTH (secondary hypoparathyroidism) ▪ ↑ acid phosphatase ▫ Released from defective osteoclasts ▪ Creatinine kinase (CK-BB) ▪ Released from defective osteoclasts

Chapter 107 Bone & Joint Pathology

TREATMENT MEDICATIONS ▪ ▪ ▪ ▪

Ca2+, PO3-, vitamin D supplementation Osteomyelitis, other infections → antibiotics Anemia → erythropoietin, corticosteroids Leukopenia → gamma interferon

SURGERY

▪ Mend fractures ▪ Bone marrow transplantation

OTHER THERAPIES

▪ Not curable; treatment is supportive ▪ Fractures → braces ▪ Treat dental abnormalities

Figure 107.9 An X-ray image of a child with osteopetrosis. There is loss of bony corticomedullary differentiation and there are lucent metaphyseal bands. There is an incidental large scrotal hernia.

Figure 107.10 A plain chest radiograph of a child with osteopetrosis. There is characteristic widening of the costochondral junctions.

OSTEOPOROSIS osms.it/osteoporosis PATHOLOGY & CAUSES ▪ Characterized by imbalance between bone formation, bone resorption → decreased bone density, pathologic fractures ▪ Caused by increased bone loss/decreased bone mass

RISK FACTORS

▪ Postmenopause (↓ estrogen) ▪ Alcohol consumption, smoking ▪ Immobility, malnutrition/malabsorption (↓ Ca2+)

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▪ Hypogonadal states ▫ Turner’s syndrome, hyperprolactinemia, Klinefelter syndrome, hypothalamic amenorrhea, primary/secondary hypogonadism ▪ Endocrine disorders ▫ Cushing’s syndrome, hyperthyroidism, hyperparathyroidism, diabetes mellitus, acromegaly ▪ Inherited disorders ▫ Osteogenesis imperfecta, Marfan’s syndrome, hemochromatosis ▪ Rheumatologic disorders ▫ Rheumatoid arthritis, ankylosing spondylitis, systemic lupus erythematosus ▪ Medications ▫ Corticosteroids, antiepileptics, anticoagulants, L-thyroxine

Figure 107.11 An MRI scan of the spine in the sagittal plane demonstrating a compression fracture of T12 secondary to osteoporosis.

SIGNS & SYMPTOMS ▪ Asymptomatic until fracture occurs ▪ Pathologic fractures; most commonly vertebral column, ribs, hips, wrists ▪ Compression fractures of vertebral column ▫ Signs: loss of height, hunched posture, kyphosis ▫ Symptoms: sudden back pain, radicular pain, spinal cord compression, cauda equina syndrome ▪ Chronic pain; unlikely without fracture

DIAGNOSIS DIAGNOSTIC IMAGING Dual-energy X-ray absorptiometry (DEXA scan) ▪ ↓ bone mineral density (BMD) ≥ 2.5 SD below the young-adult mean

LAB RESULTS

▪ Identification of potential secondary causes ▫ Complete blood cell count ▫ Ca2+, PO3-, creatinine, 25-hydroxyvitamin D levels ▫ Thyroid-stimulating hormone (TSH) ▫ 24-hour urine for calcium and creatinine

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TREATMENT MEDICATIONS

▪ Ca2+, vitamin D supplementation ▪ Oral bisphosphonates (alendronate or risedronate) ▪ Selective estrogen receptor modulators (raloxifene) ▪ Parathyroid hormone/parathyroid hormone-related protein analog for severe osteoporosis

SURGERY

▪ Prompt surgery in case of hip fracture

OTHER THERAPIES

▪ Fracture management ▪ Lifestyle changes ▫ Exercise; smoking, alcohol cessation

Chapter 107 Bone & Joint Pathology

OSTEOSCLEROSIS osms.it/osteosclerosis PATHOLOGY & CAUSES ▪ Abnormal diffuse/patchy hardening of bone, increased bone density due to impaired bone resorption

SIGNS & SYMPTOMS ▪ May be asymptomatic ▪ Generalised bone pain ▪ Pathologic fractures

TYPES Acquired ▪ Paget’s disease ▪ Osteogenic bone metastasis (e.g. prostate, breast cancer) ▪ Myelofibrosis ▪ Chronic osteomyelitis ▪ Hypervitaminosis D ▪ Hypoparathyroidism ▪ Schnitzler syndrome Inherited ▪ Osteopetrosis ▪ Pyknodysostosis ▪ Osteopoikilosis

DIAGNOSIS DIAGNOSTIC IMAGING X-ray ▪ ↑ Bone mineral density ▪ Increased bone thickness, density

TREATMENT MEDICATIONS

▪ Ca2+, PO3-, vitamin D supplementation

OTHER INTERVENTIONS ▪ Fracture management

PAGET'S DISEASE OF BONE osms.it/pagets-disease-of-bone PATHOLOGY & CAUSES ▪ Characterized by localized, disordered bone remodeling ▫ Excessive bone resorption → disorganized compensatory bone formation ▪ Three phases of pathogenesis ▫ Lytic phase: osteoclastic hyperactivity → increased rate of localized bone resorption; bone remodeling increased up to 20x

▫ Mixed lytic-blastic phase: compensatory osteoblastic hyperactivity → accelerated bone formation ▫ Sclerotic phase: results in thick, sclerotic, disorganized bone (“woven bone”) prone to fracture; new bone infiltrated by blood vessels (e.g. hypervascular state)

CAUSES

▪ Unclear; possible causes include ▫ Slow virus infection (e.g.

OSMOSIS.ORG 603

paramyxoviridae) of osteoclasts ▫ Mutations of SQSTM1, RANK genes involved in osteoclasts’ function regulation

COMPLICATIONS

▪ Osteoarthritis ▫ May distort alignment of bone, associated joint → higher mechanical force; rapid wear, degeneration ▪ Heart failure ▫ Rarely, advanced Paget’s disease → excessive demand on heart due to increased hypervascularity, arteriovenous (AV) shunts in affected bone ▪ Neurologic impairments ▫ Neural tissue compression ▪ Rarely, malignant transformation (osteosarcoma)

SIGNS & SYMPTOMS ▪ Involves one or more bones; not generalized ▪ Most commonly affects pelvis, femur, lumbar vertebrae, skull ▪ Bone pain → microfractures, periosteal changes ▪ Pathologic fractures ▪ Bony malformations ▫ Enlarged skull, AKA “increasing hat size”; spinal kyphosis; bowing of long bones ▪ Increased localized temperature → hypervascularity ▪ Arthritis of associated joints ▪ Hearing impairment → sclerosis of the skull bones, cranial nerve compression ▪ Decreased range of motion

DIAGNOSIS DIAGNOSTIC IMAGING X-ray ▪ Osteoporosis circumscripta ▫ Well-defined osteolytic lesions of skull in early course

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Figure 107.12 A CT scan of the head in the sagittal plane. The skull has the typical cotton wool appearance of Paget’s disease of the bone. ▪ “Cotton wool appearance” ▫ Mixed lytic/sclerotic lesions ▪ Looser lines ▫ Transverse lucencies resembling fractures; AKA pseudofractures ▪ Squaring of vertebrae seen on lateral X-ray ▪ Tam O’Shanter sign ▫ Enlarged overriding frontal bone ▪ “Candle flame sign” ▫ Well V-shaped osteolytic lesion; characteristic of lytic phase Bone scan scintigraphy ▪ Focal increased radionuclide uptake

LABORATORY RESULTS Biopsy ▪ Mosaic pattern of lamellar bone ▪ Large, numerous osteoclasts with up to 100 nuclei (normal is 5–10) ▪ Affected bone marrow filled with highly vascular stroma Blood test ▪ ↑ alkaline phosphatase

Chapter 107 Bone & Joint Pathology

TREATMENT MEDICATIONS

▪ Bisphosphonates (zoledronate, risedronate, pamidronate), calcitonin

SURGERY

▪ Correction of fractures, malformations

OTHER INTERVENTIONS Figure 107.13 The histological appearance of bone in the Paget’s disease. Bone formation is increased and highly disordered.

▪ Physical therapy

RICKETS osms.it/rickets PATHOLOGY & CAUSES ▪ Inadequate mineralization of cartilage in children’s growth plates due to lack of vitamin D, Ca2+, or PO3▪ ↓ Ca2+ inhibits normal mineralization of epiphyseal growth plates → accumulation of unmineralized osteoid → softening of the bones, impaired growth and malformations

CAUSES

▪ Most common: vitamin D deficiency → insufficient intestinal absorption of Ca2+ ▪ Insufficient sun exposure → UVB rays initiate vitamin D synthesis in skin ▪ Chronic kidney disease or liver disease → lack of vitamin D activation ▪ Insufficient intake ▫ Malabsorption syndrome → insufficient intestinal absorption of Ca2+ and other minerals ▫ Maternal deficiencies → congenital rickets ▪ X-linked hypophosphatemia

RISK FACTORS

▪ Little sun exposure ▪ Darker pigmented skin ▪ Breastfeeding without vitamin D supplementation

COMPLICATIONS

▪ Bone fractures ▪ Secondary hyperparathyroidism ▪ Increased infection risk

SIGNS & SYMPTOMS ▪ Bone tenderness, pain ▪ Thinned, soft skull bones, AKA craniotabes; delayed closure of fontanelles ▪ Bowed legs or knock knees (genu varum or valgus) ▪ Frontal bossing (enlarged, prominent frontal bone) ▪ Widening of ankles, wrists; bowing of distal radius, ulna ▪ Pigeon chest malformation → Harrison’s groove along thorax’s lower border ▪ Muscle spasms, numbness ▪ Hypoplasia of dental enamel

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LAB RESULTS Blood tests ▪ ↓ Serum 25(OH)D levels ▪ ↓ Ca2+, ↓ PO3▪ ↑ Alkaline phosphatase, ↑ parathyroid hormone levels

Figure 107.14 An X-ray image of both lower limbs demonstrating bowing in an individual with rickets.

DIAGNOSIS DIAGNOSTIC IMAGING X-ray ▪ ↓ bone mineral density, AKA osteopenia ▪ Bowed legs ▪ Widening of epiphyseal growth plate ▪ Thinning of cortical bone ▪ Metaphyseal cupping ▪ Looser lines ▫ Transverse lucencies resembling fractures, AKA pseudofractures ▪ In secondary hyperparathyroidism ▫ Subperiosteal resorption of phalanges, bone cysts

Figure 107.15 An X-ray image of the wrist demonstrating metaphyseal cupping, also known as metaphyseal flaring, in an individual with rickets.

TREATMENT MEDICATIONS

▪ Oral vitamin D supplementation ▪ Correction of calcium intake

OTHER INTERVENTIONS ▪ Treat underlying causes

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NOTES

NOTES

BONE TUMORS GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Abnormal neoplastic bone tissue growth ▪ Benign tumors more common than malignant

TYPES

▪ Primary tumors: originate from bone (more common) ▪ Secondary tumors: originate from other organs

CAUSES

▪ Unknown

RISK FACTORS

▪ Retinoblastoma, Li–Fraumeni syndrome, chronic inflammation, chronic osteomyelitis, Paget’s disease, bone infarcts, radiation

SIGNS & SYMPTOMS ▪ Usual appearance: long bones (e.g. femur/ tibia), pelvis, vertebra, etc. ▪ Benign tumors usually asymptomatic, undetected (early stages), discovered by accident ▪ Pain, swelling, erythema ▪ Palpable mass, structural malformation ▪ Pathological fracture, restricted motion range

DIAGNOSIS DIAGNOSTIC IMAGING X-ray ▪ Benign tumors tend to have more defined edges (circular/oval) CT scan/MRI ▪ Asses relation with other structures Nuclear medicine ▪ Assess skeletal involvement extent, distribution

OTHER DIAGNOSTICS ▪ Biopsy ▫ Histological features

TREATMENT MEDICATIONS ▪ Chemotherapy

SURGERY ▪ Surgery

OTHER INTERVENTIONS ▪ Radiation therapy

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EWING'S SARCOMA osms.it/ewings-sarcoma PATHOLOGY & CAUSES

SIGNS & SYMPTOMS

▪ Rare malignant tumor; bone, soft tissue around bone ▪ Small, round blue-stained cells; believed to have neuroectodermal origin

▪ Pelvis, femur, clavicle, humerus, ribs, spine commonly affected ▪ Intense pain (stronger at night); exacerbated by exercise ▪ Soft palpable mass attached to bone; can compress nerves → function loss (e.g. urinary incontinence if sacrum involved) ▪ Swelling, erythema ▪ Systemic symptoms: fever, weight loss can indicate metastases ▫ Lung metastases: most significant cause of death

CAUSES

▪ Translocation fuses two regions together ▫ Ewing sarcoma gene (EWS): chromosome 22 ▫ Friend leukemia insertion (FLI1): chromosome 11 ▫ Newly-formed EWS-FLI1 protein: abnormal transcription factor → induce cell division, malignant transformation

RISK FACTORS

▪ Usually sporadic; occurs in children, young adults ▪ ↑ risk, Ewing’s sarcoma family history

DIAGNOSIS DIAGNOSTIC IMAGING X-ray/CT scan ▪ Permeative process ▫ Bone appears “moth-eaten” ▪ Periosteal reaction ▫ Rapid tumor growth raises periosteum → laminated “onion skin”-like appearance ▪ Sclerosis MRI ▪ Precise tumor location, size, adjacentstructure relation Positron emission tomography (PET) scan ▪ Metastases search

Figure 108.1 A histological section of a classic Ewing’s sarcoma. The tumor cells are undifferentiated, closely packed and have vague cytoplasmic borders. There are two distinct populations of light and dark cells.

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OTHER DIAGNOSTICS

▪ Tumor biopsy ▫ Small, round, blue cells

Chapter 108 Bone Tumors

TREATMENT MEDICATIONS ▪ Chemotherapy

SURGERY

▪ Tumor removal/limb amputation

OTHER INTERVENTIONS ▪ Radiation therapy

Figure 108.2 An anterior-posterior X-ray of the left shoulder demonstrating a Ewing’s sarcoma of the humeral head.

Figure 108.3 A PET-CT scan in the coronal plane demonstrating a Ewing’s sarcoma of the left proximal femur. The tumor, visible on CT scan corresponds well with the high levels of tracer uptake on the PET scan.

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GIANT-CELL TUMOR OF BONE osms.it/giant-cell_tumor_of_bone PATHOLOGY & CAUSES ▪ Benign tumor ▫ Destructive growth, metastases potential ▪ Tumor mass comprises ▫ Tumor cells: giant multinucleated cells from osteoblastic origin ▫ Non-tumor cells: osteoclasts, their precursors ▪ Tumor cells express RANKL → binds to RANK on osteoclasts, precursors membrane → induce cell division, malignant transformation ▪ ↑ osteoclast number (tumor sometimes called osteoclastoma) + absence of control → bone destruction

SIGNS & SYMPTOMS ▪ Commonly around knee (distal femur/ proximal tibia) ▪ Pain, swelling ▪ Restricted range of motion ▪ Pathological fractures

Figure 108.4 A anterior-posterior radiograph of the wrist demonstrating a giant cell tumor of bone at the subarticular portion of the radius. It has a characteristic soap bubble appearance.

DIAGNOSIS DIAGNOSTIC IMAGING X-ray/CT scan ▪ Lucent mass; cortical thinning/destruction; pathological fracture; mineralization, sclerosis absence

Figure 108.5 The histological appearance of a giant cell tumor of bone. There are numerous multinucleated osteoclastic giant cells surrounded by smaller mononuclear cells.

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MRI ▪ Homogeneous intensity, well-defined edges Nuclear medicine ▪ “Doughnut” sign ▫ ↑ periphery uptake, ↓ center uptake

Chapter 108 Bone Tumors

TREATMENT SURGERY ▪ Resection

OTHER INTERVENTIONS ▪ Radiation therapy

Figure 108.6 The gross pathological appearance of a giant cell tumor of bone affecting the distal femur.

OSTEOBLASTOMA osms.it/osteoblastoma PATHOLOGY & CAUSES ▪ Benign bone tissue-forming tumor; similar to osteoid osteoma ▪ Comprises many osteoid (not yet mineralized bone tissue), fibrous (woven) bone-producing osteoblasts ▪ May break bone cortex, grow to adjacent soft tissue Figure 108.7 The histological appearance of an osteoblastoma. There is abundant osteoid and woven bone forming trabeculae which are lined by a single layer of osteoblasts.

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SIGNS & SYMPTOMS ▪ Commonly affects posterior spine, long bones (e.g. femur, tibia) ▪ Dull pain (exacerbated at night) ▪ Not responsive to salicylates ▪ Structural malformations (e.g. scoliosis) ▪ Spinal cord, nerve compression → pain, function loss ▪ Swelling, tenderness, ↓ range of motion

DIAGNOSIS DIAGNOSTIC IMAGING X-ray/CT scan ▪ Well defined lucent mass ▪ >2cm/0.79in; no periosteal reaction (differs from osteoid osteoma); if arising from cortical bone → thin new bone layer covering ▪ Adjacent sclerosis ▪ Inner calcification MRI ▪ Assess surrounding structure volume, relationship

Figure 108.8 A CT scan of the lower leg in the axial plane demonstrating an osteoblastoma of the fibula.

OTHER DIAGNOSTICS Biopsy ▪ Immature trabeculae with single osteoblast layer ▪ High dilated blood vessel number ▪ Distinguish from osteosarcoma ▫ ↓ mitotic activity ▫ ↓ cell atypia ▫ No cartilaginous matrix ▫ Does not imbue surrounding bone, soft tissue

TREATMENT SURGERY ▪ Excision

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Chapter 108 Bone Tumors

OSTEOID OSTEOMA osms.it/osteoid-osteoma PATHOLOGY & CAUSES ▪ Bone tissue-forming tumor ▫ Benign, similar to osteoblastoma ▪ Tumor mass (nidus) ▫ Good blood supply, comprised of osteoblasts providing osteoid, fibrous bone ▫ Osteoblasts → ↑ prostaglandin E₂ → pain ▪ Nidus produces/envelopes itself in reactive bone

SIGNS & SYMPTOMS ▪ Commonly affects lower-extremity long bones (e.g. femur, tibia), phalanges, spine ▪ Very intense pain (exacerbated at night) ▪ Responsive to salicylates ▪ Painful scoliosis ▪ Swelling, tenderness

DIAGNOSIS DIAGNOSTIC IMAGING X-ray/CT scan ▪ Well-defined lucent nidus ▫ Surrounded by reactive bone, 50 ▪ History of Ollier disease, Maffucci syndrome, Wilms’ tumor, radiotherapy (rare)

COMPLICATIONS

▪ Pathological bone fracture ▪ Metastasis ▫ Most commonly lungs, bones ▪ Neurovascular structure impingement ▫ Ischemia, venous thrombosis, pseudoaneurysm

Chapter 109 Cartilage Tumors

SIGNS & SYMPTOMS ▪ Painful, progressively enlarging mass; localized swelling; limited range of motion; fatigue; weight loss ▪ Neurovascular involvement ▫ Numbness, weakness, skin discoloration, loss of pulse, claudication

DIAGNOSIS Staging ▪ Based on grade, spread ▫ Intracompartmental, extracompartmental, systemic/regional metastasis

DIAGNOSTIC IMAGING CT scan ▪ Matrix calcification, endosteal scalloping

OTHER DIAGNOSTICS Fine needle/core biopsy ▪ Determines histologic grading ▫ Grade 1: moderately cellular; small, round chondrocyte nuclei; abundant hyaline cartilage matrix; absent mitosis ▫ Grade 2: ↑ cellularity; ↓ chondroid matrix; enlarged chondrocyte nuclei; scattered mitosis evidence ▫ Grade 3: ↑ ↑ cellularity, sparse/ absent chondroid matrix; nuclear pleomorphism; mitosis clearly present

TREATMENT SURGERY

▪ Intralesional curettage + local phenolization/ cryotherapy → cementation/bone grafting ▪ Complete resection

MRI ▪ T1: low–intermediate intensity mass ▪ T2: high intensity mass X-ray ▪ Lytic pattern: calcifications, endosteal scalloping

Figure 109.1 An X-ray of an intramedullary lesion with features of a low-grade chondroid lesion, likely a chondrosarcoma.

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OSTEOCHONDROMA osms.it/osteochondroma PATHOLOGY & CAUSES ▪ Benign tumor; outgrowth of tubular bone growth plate ▫ Most common benign bone tumor ▫ Average onset age is 10 years ▫ Capped with hyaline cartilage ▫ Can be pedunculated (with stalk)/sessile (broad base without stalk) ▪ Most common localizations: knee (distal femur/proximal tibia), pelvis, scapula

TYPES

▪ Single sporadic mass ▫ Exostosis ▪ Multiple tumors ▫ Condition known as multiple osteochondromatosis

CAUSES

▪ Mutation of EXT1/EXT2 genes involved in heparan sulfate glycosaminoglycan synthesis → local glycosaminoglycan reduction → disruption of cartilage, normal skeletal growth ▪ Radiation-induced ▪ Idiopathic

COMPLICATIONS

▪ Pathologic fracture, bone malformation, bursitis, malignant transformation (more common in multiple osteochondromatosis) ▪ Neurovascular structure impingement ▫ Ischemia, venous thrombosis, pseudoaneurysm

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Figure 109.2 The gross pathology of an osteochondroma. The surface of the tumor is composed of hyaline cartilage and the centre composed of cancellous bone.

SIGNS & SYMPTOMS ▪ Slow-growing palpable mass, pain, impaired range of motion ▪ Neurovascular involvement ▫ Numbness, weakness, skin discoloration, loss of pulse, claudication

DIAGNOSIS DIAGNOSTIC IMAGING

▪ Often found incidentally (e.g. radiographic exam performed for different reason)

CT scan ▪ Evidence of bony lesion and calcification MRI ▪ Further characterizes tumor morphology, cartilage cap thickness (thick cap → suspect malignancy)

Chapter 109 Cartilage Tumors Ultrasound ▪ Identifies pseudoaneurysms, thrombosis, bursitis X-ray ▪ Dense bony spur

TREATMENT SURGERY

▪ Excision ▫ Symptoms occur/malignant progression signs

OTHER INTERVENTIONS Figure 109.3 An X-ray image of the knee demonstrating a tumor with a cortex continual with normal bone, a characteristic feature of an osteochondroma.

▪ Radiological follow-up ▫ Asymptomatic

Figure 109.4 The histological appearance of an osteochondroma. There is a core of cancellous bone with an overlying cap of hyaline cartilage.

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NOTES

NOTES

HEAD & NECK MUSCULOSKELETAL DISORDERS

GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Disorders of ligaments, muscles, tendons, bones inherent to head, neck

SIGNS & SYMPTOMS ▪ Most commonly pain

TREATMENT MEDICATIONS

▪ Anti-inflammatory/muscle relaxant

SURGERY

▪ In refractory cases

OTHER INTERVENTIONS

DIAGNOSIS

▪ Physical therapy

DIAGNOSTIC IMAGING ▪ For confirmation

OTHER DIAGNOSTICS

▪ History, physical examination

TEMPOROMANDIBULAR JOINT DYSFUNCTION osms.it/TMJ-dysfunction PATHOLOGY & CAUSES ▪ Category of conditions affecting jaw, producing pain and/or dysfunction centred around temporomandibular joint (TMJ)

CAUSES

▪ Jaw clenching ▪ Teeth grinding (bruxism)

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▪

▪ ▪ ▪

▫ Nocturnal/diurnal ▫ Commonly occurs with MDMA use Trauma ▫ Reactive oxygen species produced by inflammation → synovial fluid inflammation → cytokine production → TMJ destruction Arthritis Malocclusion/missing teeth Yawning → joint dislocation

Chapter 110 Head & Neck Disorders ▪ Associated diseases ▫ Rheumatoid arthritis (RA) ▫ Psychiatric disorders → major depressive disorder

SIGNS & SYMPTOMS ▪ Pain: dull, constant ache; waxing, waning intensity (e.g. headaches, toothaches, earaches) ▫ Jaw movement exacerbates (e.g eating, talking) ▫ Manifests anywhere trigeminal nerve (cranial nerve V) innervates ▪ Jaw dysfunction → poor eating/talking ability ▪ Tinnitus ▪ Audible popping/clicking of joint

DIAGNOSIS DIAGNOSTIC IMAGING Panoramic X-ray ▪ May reveal frank dislocation of mandible from TMJ

TREATMENT MEDICATIONS

▪ Short-term NSAIDs ▪ Muscle relaxants second line (e.g. cyclobenzaprine) ▪ Benzodiazepines: nocturnal dosing → ↓ nocturnal bruxism

SURGERY

▪ For refractory disorders ▫ Arthroscopy ▫ Individuals with underlying arthritis → synovial space bone fragment removal

OTHER INTERVENTIONS

▪ Pain control ▫ Moist heat, cold compresses, massage, soft diet, avoid strain ▪ Habit adjustment ▫ ↓ pen chewing, change sleeping position, oral appliance use ▪ Physical therapy ▪ Dislocation → mandible reduction ▪ Bruxism causative → splinting

OTHER DIAGNOSTICS History ▪ Bruxism ▪ Trauma Physical examination ▪ ↓ Range of motion ▪ Palpation ▫ Tenderness to examiner’s finger against TMJ when mouth open ▫ Clicking/popping heard/felt when jaw opened/closed ▪ Abnormal cranial nerve examination ▫ Likely trigeminal (CN V) symptom distribution → muscle weakness and/or sensory disturbance

Figure 110.1 An MRI scan of the head in the parasagittal plane demonstrating an anteriorly dislocated disc in an individual reporting symptoms of temporomandibular joint dysfunction.

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TORTICOLLIS osms.it/torticollis PATHOLOGY & CAUSES ▪ Abnormal posturing of head, neck; various etiologies ▪ AKA cervical dystonia ▪ Sternocleidomastoid (SCM) muscle connect sternums, clavicle (muscle heads) to mastoid process ▪ One/both SCM head shortened/ hypertrophied → contralateral neck flexion, lateral rotation → torticollis

TYPES Congenital ▪ Birthing difficulty → injury → fibroma/ hematoma formation of SCM muscle → abnormal posturing at/soon after birth ▪ Spinal abnormalities ▪ Klippel–Feil syndrome → cervical vertebrae fusion → torticollis ▪ Atlanto-occipital fusion → abnormal articulation/ankylosis of C1, occipital bone → torticollis Iatrogenic ▪ Side effect of dopamine agonist medication (e.g. first-generation antidepressants) Spasmodic ▪ AKA adult-onset/idiopathic ▪ Characterized by tonic/intermittent spasms of cervical muscles in adults

COMPLICATIONS

▪ Permanent musculoskeletal defects ▪ Neurologic defects → spinal cord impingement

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SIGNS & SYMPTOMS ▪ Abnormal posturing of the head and neck ▫ Lateral rotation (laterocollis) ▫ Forward rotation (anterocollis) ▫ Backward rotation (retrocollis) ▪ SCM muscle ▫ Hypertrophied ▫ Nontender

DIAGNOSIS OTHER DIAGNOSTICS

▪ Congenital ▫ Birth trauma/condition ▪ Iatrogenic ▫ Coincide with medication schedule/ change in dosing ▪ Spasmodic ▫ 5% have ⊕ family history ▫ ⅓ have other dystonias

TREATMENT MEDICATIONS Congenital ▪ Muscular etiology → botulinum toxin injections ▫ Botulinum toxin → inhibits zinc endopeptidase → inhibition of neurotransmitter vesicle release → decreased muscle contraction → decreased muscle tone

Chapter 110 Head & Neck Disorders Iatrogenic ▪ Withdrawal/limitation of offending agent ▪ Prescription of a muscle relaxant/ antihistamine Spasmodic ▪ Muscle relaxant ▪ Benzodiazepines ▪ Anticholinergics ▫ Side effects → limited use (dry mouth, blurry vision, urinary retention, tachycardia, nausea, vomiting, anxiety) ▪ Botulinum toxin injections

OTHER INTERVENTIONS Congenital ▪ Muscular etiology → passive neck stretching Spasmodic ▪ Massage ▪ Physical therapy ▪ Behavioral modification ▪ “Sensory trick” ▫ Sensory stimulus (e.g. lightly laying hand on cheek) may relieve muscle contraction

SURGERY Congenital ▪ Vertebral etiology → surgical intervention if severe Spasmodic ▪ Refractory cases → surgical denervation of affected cervical musculature

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NOTES

NOTES

INFLAMMATORY ARTHRITIS GENERALLY, WHAT IS IT? PATHOLOGY & CAUSES ▪ Musculoskeletal disease subset; known immune component underlying disease ▪ Underlying trigger/cause not always understood

SIGNS & SYMPTOMS ▪ Painful, warm, stiff joints ▪ Variable extra-articular symptoms

DIAGNOSIS LAB RESULTS Synovial fluid analysis ▪ Cloudy yellow appearance ▪ White blood cell count (WBC) > 5,000 ▪ Polymorphonuclear neutrophils (PMNs) < 25%

TREATMENT MEDICATION Anti-inflammatory medication ▪ Common NSAIDs ▪ Immunologically-targeted therapy ▫ Anti-cytokine therapy (e.g. adalimumab)

ANKYLOSING SPONDYLITIS osms.it/ankylosing-spondylitis PATHOLOGY & CAUSES ▪ Group: seronegative spondyloarthritides ▪ Characteristics: articular cartilage destruction, bony joint fusion (ankylosis) → primarily spine, sacroiliac joints ▪ AKA rheumatoid spondylitis, Marie– Strümpell disease ▪ Autoimmune self-reactivity believed to underlie pathophysiology ▫ Strong HLA-B27 association (MHC I serotype; positive in 90% of affected individuals)

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▫ Relative risk for HLA-B27 individuals: 100-200x ▫ IL-23 receptor gene also implicated ▫ Abnormal IL-23 cytokine regulation → naive CD4+ T cell → self-reactive Th17 cells ▪ Associated with Crohn’s disease, ulcerative colitis

RISK FACTORS

▪ Biological sex ▫ 3x ↑ individuals who are biologically male

Chapter 111 Inflammatory Arthritis

COMPLICATIONS

▪ Aortic regurgitation ▫ Aortic aneurysm → aortic valve annulus stretched → regurgitation ▪ Uveitis ▪ Enthesitis (tendinous insertion inflammation) ▪ Dactylitis (“sausage fingers”) ▪ Decreased pulmonary function ▪ Thoracic-rib articulation spondylosis → ↓ chest wall expansion across respiratory cycle ▪ Secondary amyloidosis

SIGNS & SYMPTOMS ▪ Symptoms develop teens-20s ▫ Lower back pain, spinal immobility ▪ Peripheral large joints (hips, knees, shoulders) involved in ⅓ of individuals ▪ Morning stiffness; improves throughout day, with exercise ▪ Untreated disease → extenuated kyphosis of spine

DIAGNOSIS DIAGNOSTIC IMAGING Lumbar spine radiograph ▪ Diagnostic → sacroileitis ▪ Progression of early findings ▫ Subchondral erosions (pseudo-widening effect on X-ray) → sclerosis → sacroiliac joint fusion ▪ Late findings (10+ years of disease) ▫ “Bamboo spine”: prominent syndesmophytes (bony growth inside ligaments), diffuse calcification of paraspinal ligaments, spinal osteoporosis

LAB RESULTS

▪ ↑ erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) suggestive, not diagnostic ▪ ⊝ Rheumatoid factor (RF)

Figure 111.1 An X-ray image of demonstrating bamboo spine and the dagger sign in an individual with ankylosing spondylitis.

OTHER DIAGNOSTICS

▪ Family history ▪ Physical examination ▫ ↓ Spine flexion/extension and ↓ lateral range of motion

TREATMENT MEDICATIONS

▪ NSAIDs (maximum daily dosing recommended) ▫ First line for pain, stiffness ▪ TNF-alpha inhibitors ▫ Etanercept: fusion protein (IgG1 Fc region, TNF alpha receptor); intercepts circulating TNF-alpha, competes with body’s TNF alpha receptors ▫ Infliximab, adalimumab, certolizumab: anti-TNF alpha monoclonal antibodies ▫ Sulfasalazine: if TNF-alpha therapy ineffective; recommended for peripheral joint disease

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OTHER INTERVENTIONS

▪ Exercise therapy ▫ Home exercise therapy/formal physical therapy regimens ▪ Tobacco use cessation ▪ Heat, ice packs

Figure 111.2 The skeleton of an individual with ankylosing spondylitis. The lumbar and cervical spine have ossified completely and become fused.

GOUT osms.it/gout PATHOLOGY & CAUSES ▪ Episodic, arthritic disorder ▪ Monosodium urate crystallization in, around joint spaces; when left untreated, can manifest as tophi in chronic arthritic disorder ▪ Monosodium urate (MSU): purine and pyrimidine (nitrogen containing heterocycles; DNA components) → primary sources of uric acid; released when cells broken down ▫ Limited solubility in plasma (only 6.8mg/ dL) ▫ Poorer solubility in joint space → lower temperature, synovial fluid composition favor precipitation

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▫ Sources of nidus (precipitates crystals) include collagen fibers, chondroitin sulfate, proteoglycans, cartilage fragments ▫ Physiologic pH of 7.4 → uric acid loses cation, adds Na+ → MSU crystals ▪ Damage pathway: MSU precipitate into joints → complement cascade activated, cytokines produced → leukocyte recruitment → macrophages phagocytose MSU → inflammasome activates caspase-1 → produce IL-1 and other proinflammatory cytokines → ↑ ↑ ↑ leukocyte recruitment, cytokine production ▪ Classification ▫ 90% primary/idiopathic ▫ 10% secondary

Chapter 111 Inflammatory Arthritis

CAUSES

▪ ↑ production of uric acid, purines (most common) ▪ Diet high in red meat, shellfish, anchovies, organ meat ▪ ↑ cell turnover ▪ Cancer treatment → tumor lysis syndrome ▪ Polycythemia vera (5–10% develop gout) ▪ Lesch-Nyhan syndrome ▫ Hypoxanthine guanine phosphoribosyl transferase (HGPRT) deficiency interrupts purine salvage pathway → ↑ degradation of purines → ↑ uric acid production ▪ Dehydration, alcoholic beverage consumption → ↓ clearance of uric acid ▪ Chronic kidney disease

RISK FACTORS

▪ Age ▫ 20–30+ years of hyperuricemia → ↑ risk ▪ Biological sex (↑ individuals who are biologically male) ▪ Genetic ▫ HGPRT (X-linked); URAT1, GLUT9 (both involved in urate transport/homeostasis) ▪ Heavy alcohol consumption ▪ Obesity ▪ Drugs that ↓ urate excretion/↑ production (e.g. thiazides, aspirin) ▪ Glucose metabolization abnormalities (e.g. diabetes mellitus) ▪ Chronic lead toxicity → saturnine gout ▫ Most common risk factor in U.S. is moonshine consumption → lead-lined stills

Figure 111.3 Urate crystals will display negative birefringence on polarised light microscopy.

COMPLICATIONS

▪ Gravel/stone passage → renal colic ▪ Renal failure → death in 20% individuals with chronic gout ▪ ↓ quality of life, generally not lifespan

SIGNS & SYMPTOMS Acute, episodic arthritis ▪ Nocturnal onset ▫ Awakening with complaints, e.g. “feeling like toe on fire” ▪ Most severe pain remits within first hours; pain can last days–weeks ▪ Painful, warm, erythematous, and swollen joint → ↓ range of motion → disability First episode ▪ Commonly monoarticular; 50% of cases include first metatarsal joint (aka podagra) ▪ Asymptomatic period months–years → subsequent episodes (mono- or polyarticular) ▫ 90% of other joints involved, progressively (ankle > heels > knees > wrists > fingers > elbows) ▫ ↑ episodes, polyarticular effects without treatment

Figure 111.4 Gout of the great toe presenting as erythema of the overlying skin.

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Chronic disease (tophaceous gout) ▪ On average, around 12 years after initial attack ▪ MSU deposition ( joint spaces/affected cartilage) ▪ Painless, pedunculated mass; palpitation may discolor overlying skin ▪ Joint’s range of motion sometimes limited ▪ Kidney complications take one of two forms ▫ Symptoms of colicky flank pain, hematuria → uric acid nephrolithiasis ▫ ↓ urine output, difficulty voiding → urate nephropathy

DIAGNOSIS DIAGNOSTIC IMAGING Radiographic/ultrasound/CT scan ▪ Joint destruction, bony erosions (rarely present on the first acute episode) ▪ Imaging findings become more likely with disease duration X-ray ▪ Radiolucent uric acid nephrolithiasis

LAB RESULTS Synovial fluid analysis ▪ MSUs in context of acute, arthritic episodes Polarized light microscope ▪ Long, slender needle-shaped crystals in synovial fluid, neutrophil cytoplasm ▫ Negatively birefringent; yellow under parallel light, blue under perpendicular light

OTHER DIAGNOSTICS

▪ Histological analysis of chronic tophaceous arthritis ▫ Large aggregations of MSU surrounded by inflammatory reaction of foreign body giant cells ▫ Hyperplastic, fibrotic, thickened synovium → pannus formation → destruction of underlying cartilage, juxta-articular bony erosions

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Figure 111.5 An X-ray image of the foot showing destruction of the first metatarsophalangeal joint by arthritis secondary to gout. There is an overlying gouty tophus. ▪ Histological analysis of gouty nephropathy ▫ MSU (with/without tophi) deposits in medullary interstitium/tubules

TREATMENT MEDICATIONS Acute flare therapy ▪ Anti-inflammatory treatment ASAP within acute flare → rapid, complete resolution faster ▪ Glucocorticoids (oral and/or intra-articular injections) ▪ NSAIDs (i.e. naproxen, indomethacin) ▪ Colchicine (inhibits leukocyte migration) ▪ Biologic agents (IL-1 inhibitors)

Chapter 111 Inflammatory Arthritis Management and prevention ▪ Limit medications that alter urate balance (e.g. thiazides, aspirin) ▪ Initiate medications that ↓ uric acid levels ▪ Xanthine oxidase (XO) inhibitors (allopurinol, febuxostat) ▫ Mechanism of action: directly inhibits enzyme → urate production, stimulates purine base reutilization → ↓ ↓ ↓ urate concentration ▪ Uricosuric medications (probenecid) ▫ ↑ urate excretion at kidney ▪ Uricase medications (rasburicase) ▫ Mimic enzyme that catalyzes urate conversion → allantoin (more soluble purine degradation product); enzyme absent in humans

OTHER INTERVENTIONS

▪ Benefit largely due to ↓ development/ worsening of obesity, cardiovascular disease, diabetes mellitus

▪ Diet modification ▫ Limit/avoid soda, red meat, seafood ▪ Alcohol moderation ▪ ↑ physical activity

Figure 111.6 The histological appearance of a gouty tophus. There is a large aggregate of urate crystals which is associated with granulomatous inflammation.

JUVENILE IDIOPATHIC ARTHRITIS osms.it/juvenile-idiopathic-arthritis PATHOLOGY & CAUSES

SIGNS & SYMPTOMS

▪ Arthritic symptoms of unknown etiology; present < 16 years old for ≥ six weeks ▪ Unknown pathophysiology; appears related to TH1 and TH17 cells → cell mediators ▫ IL-1, IL-17, TNF-gamma

▪ Arthritis ▫ Oligo- or polyarticular involvement; large joints affected > small ▪ Rheumatoid nodules, factor usually absent

RISK FACTORS

▪ HLA and PTPN22 variants

COMPLICATIONS

▪ 10% develop disability in adulthood

DIAGNOSIS LAB RESULTS

▪ Antinuclear antibodies may be ⊕ or ⊝

TREATMENT ▪ Similar to rheumatoid arthritis ▪ Some success with IL-6 R antibody biologic disease-modifying antirheumatic drug (DMARD)

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PSEUDOGOUT osms.it/pseudogout PATHOLOGY & CAUSES ▪ Calcium pyrophosphate (CPP) crystal depositions in articular cartilage ▪ AKA chondrocalcinosis ▪ Unlike gout, hyperuricemia ▫ No known direct substance concentration → ↑ crystal formation ▪ Pathway of joint inflammation, destruction similar to gout ▫ Articular cartilage proteoglycans degraded, serve as nidus for crystal formation around chondrocytes ▫ CPP crystals precipitate around chondrocytes → complement cascade activated, cytokines produced → leukocyte recruitment → macrophages phagocytose MSU (inflammasome activates caspase-1) → produce IL-1, other proinflammatory cytokines → further leukocyte recruitment, cytokine production

CAUSES

▪ Sporadic (idiopathic) ▪ Hereditary ▫ Autosomal dominant version → early manifestation, more severe symptoms ▫ Also associated with osteoarthritis ▫ Mutations in pyrophosphate transport channel ▪ Secondary to previous joint damage, hyperparathyroidism, hemochromatosis, hypothyroidism, ochronosis, diabetes

RISK FACTORS

▪ Age ▫ Usually affects individuals > 50 years; by > 85 years → 30–60% prevalence ▪ ↓ magnesium levels

COMPLICATIONS

▪ Significant joint damage ▫ ≤ 50% of individuals

SIGNS & SYMPTOMS ▪ Episodic joint pain ▫ Knee most commonly affected; followed by wrists → elbows → shoulders → ankles ▪ Duration of several days–weeks ▪ Oligo- or polyarticular ▪ Frequently asymptomatic

DIAGNOSIS OTHER DIAGNOSTICS Histological analysis ▪ Gross ▫ Chalky, white, friable ▪ Microscopic ▫ Aggregates stain as blue/purple, oval ▪ Crystals ▫ Rhomboid, ⊕ birefringent ▪ Crystallization first develops in articular cartilage, menisci, intervertebral discs Physical examination ▪ Acutely painful, inflamed joint; commonly knee

TREATMENT MEDICATIONS Acute flares ▪ NSAIDs ▪ Colchicine ▪ Glucocorticoids Management and prevention ▪ Colchicine

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Chapter 111 Inflammatory Arthritis

OTHER INTERVENTIONS

▪ Treat underlying disorder (if known) ▪ Symptomatic therapy similar to gout treatment

Figure 111.7 A calcium pyrophospahte crystal in joint fluid aspirated from the knee of an individual with pseudogout.

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PSORIATIC ARTHRITIS osms.it/psoriatic-arthritis PATHOLOGY & CAUSES

SIGNS & SYMPTOMS

▪ Group: seronegative spondyloarthritides ▪ Associated with psoriasis ▪ Affects peripheral, axial joints; ligaments, tendons (entheses) ▪ Abnormal T cell response to unknown culprit antigen ▫ TH1, TH17 cells thought responsible → stimulate activated CD8+ T cells → cytokine, growth factor environment change/destroy local tissue ▫ Implicated synovial cell mediators: IL-1, IL-6, TNF-alpha, IL-8 ▫ Synovial fibroblasts interact with immune response → secreting IL-1beta, IL-6, and platelet-derived growth factors (PDGF) ▫ Affected synovia marked with increased vascularity → ↑ leukocytic entryways

▪ Predominantly peripheral arthritis of hands, feet ▪ Distal interphalangeal (DIP) joint first affected, asymmetrically distributed in > 50% of individuals ▪ Sacroiliac joint affected in 20% of individuals ▪ Degree of joint involvement may be mild/ progress → severe, disfiguring disease as in rheumatoid arthritis (RA)

TYPES

▪ Mild: one joint involved/responds to NSAIDs ▪ Moderate-severe: NSAID-resistant ▪ Severe: polyarticular, erosive; functional limitation

CAUSES

▪ Local trauma induces dysregulated immune response → local tissue destruction ▫ AKA Koebner phenomenon ▪ 10% of psoriatic individuals develop arthritis symptoms

RISK FACTORS

HLA-B27 HLA-Cw6 Obesity Associated diseases ▫ Myopathy, enteropathy, AIDS ▪ Age: 30 50 years old

▪ ▪ ▪ ▪

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Figure 111.8 The feet of an individual with psoriatic arthritis. There is inflammation of the ankle and the interphalangeal joints as well as psoriatic nail changes.

DIAGNOSIS DIAGNOSTIC IMAGING

▪ Characteristic “pencil-in-cup” malformation at DIP joint

Chapter 111 Inflammatory Arthritis

OTHER DIAGNOSTICS Histological analysis ▪ Similar to RA, but symptoms not as severe, remissions more frequent, joint destruction less frequent History ▪ 40% of affected individuals have firstdegree relative with psoriatic arthritis Physical examination ▪ Integument examination consistent with psoriasis ▪ Papules, plaques with silver scales on extensor surfaces (fingers, knees, elbows) ▪ Commonly affects scalp, nails (“nail pitting”) ▪ Musculoskeletal examination consistent with arthritis ▪ Asymmetric involvement of both peripheral, axial joints ▪ Commonly affects DIP joints under skin manifestations

Figure 111.9 An X-ray image of the hands of an individual with long-standing psoriatic arthritis which has progressed to arthritis mutilans. Telescoping of the phalangeal joints is visible.

TREATMENT MEDICATIONS Mild disease ▪ NSAIDs Moderate-severe disease ▪ Conventional (DMARD) therapy ▪ Methotrexate (MTX; co-treat with daily folic acid), leflunomide (does not also target skin disease) ▫ Both require eliminating alcohol intake Severe disease ▪ ‘Biologic’ DMARD (e.g. TNF inhibitor) ▪ Etanercept, adalimumab, infliximab, certolizumab ▫ All require latent TB screening before initiation therapy initiation ▪ Anti-IL-17 ‘biologic’ (e.g. secukinumab, ixekizumab, brodalumab)

OTHER INTERVENTIONS

▪ Exercise, physical therapy, occupational therapy ▪ Weight reduction

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REACTIVE ARTHRITIS osms.it/reactive-arthritis PATHOLOGY & CAUSES ▪ Group: seronegative spondyloarthritides ▪ Characterized by triad ▫ Arthritis, nongonococcal urethritis/ cervicitis, conjunctivitis ▪ AKA Reiter syndrome ▪ Hypothesis: autoimmune reaction to prior infection of GU/GI system ▪ Genitourinary triggers: urethritis/cervicitis ▫ Common pathogen: Chlamydia trachomatis ▪ Gastrointestinal triggers: diarrheal illness ▫ Common pathogens: Shigella, Salmonella paratyphi, Yersinia enterocolitica, Campylobacter jejuni ▪ RF ▪ HIV ⊕ ▪ HLA-B27 ⊕ (80+% of affected individuals)

▪ Most asymmetrically affected joints ▫ Ankles, knees, feet; upper extremity involvement less common Other symptoms ▪ Fever, malaise, weight loss, fatigue ▪ Symptoms’ severity waxes, wanes; usually lasts 1.5–6 months ▪ Recurrent arthritic episodes, tendonitis, lumbosacral pain in 50% of individuals ▪ Keratoderma blennorhagicum ▫ Vesiculopustular, waxy lesions on the soles or palms

COMPLICATIONS

▪ Digital tendon sheath synovitis → dactylitis (“sausage” finger/toe) ▪ Tendoligamentous insertion sites ossification → calcaneal spurs, bony outgrowths ▪ Severe spinal disease; becomes indistinguishable from ankylosing spondylitis ▪ Extra-articular involvement ▫ Inflammatory balanitis, conjunctivitis, cardiac conduction abnormalities, aortic regurgitation

SIGNS & SYMPTOMS Arthritic symptoms ▪ Develop several weeks post-initial infection ▪ Common, early symptoms ▫ Joint stiffness, low back pain ▪ Days later ▫ Painful joints, effusion, lack of mobility

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Figure 111.10 Keratoderma blennorhagicum on the feet of an individual with reactive arthritis.

DIAGNOSIS DIAGNOSTIC IMAGING X-ray ▪ Involved joint ▫ No specific diagnostic changes ▪ Negative for stress fractures, other forms of arthritis

Chapter 111 Inflammatory Arthritis

LAB RESULTS Synovial fluid analysis ▪ Absence of joint space infection, crystals Cultures ▪ May be helpful if GI/GU symptoms ongoing → identify well-associated bacteria

OTHER DIAGNOSTICS History ▪ Preceding illness, rapid-onset arthritis/ systemic symptoms ▪ Arthritic presentation often too late for stool/urine culture (for GU/GI trigger) Physical examination ▪ Lower extremity joint involvement as above

TREATMENT MEDICATIONS

▪ NSAIDs ▪ Glucocorticoids; intra-articular, systemic formulation available ▪ Resistant/chronic (> six months) disease ▫ DMARD (e.g. sulfasalazine, MTX, azathioprine) ▪ Antibiotics not recommended ▫ Exception: triggering disease process (GI/GU diarrhea/urethritis/cervicitis) ongoing ▪ Skin involvement (if present) → topical salicylates

OTHER INTERVENTIONS

▪ Conjunctivitis (if present) → ophthalmology referral

RHEUMATOID ARTHRITIS osms.it/rheumatoid-arthritis PATHOLOGY & CAUSES ▪ Systemic, chronic, autoimmune inflammatory disorder involving joint synovium ▪ May progress to disfigurement → cartilaginous, bony damage over time ▪ Dual hit hypothesis (genetics and environment) ▫ Genetics: HLA-DR1 or DR4 genetic predisposition → thought to underlie the immune pathogenesis pathway below ▫ Environment: cigarette smoke, pathogen (i.e. gut bacteria) → may contribute to unknown ‘arthrogenic agent’, trigger immune response

PATHOLOGY

▪ CD4+ T cells: react with arthrogenic agent (unknown; thought to be a microbe/ self-antigen) → cytokine production → IFN-gamma (TH1 product) → activate macrophages and synovial cells → synovial, immune cell proliferation → swollen synovial tissue (also known as pannus formation) → IL-17 (TH17 product) → recruit neutrophils and monocytes → TNF-alpha and IL-1 (macrophage product) → stimulate synovial cells → protease release → hyaline cartilage destruction → ↓ cartilaginous buffer → bone on bone articulation → ↑ bone destruction ▪ RANKL (on T cells): activate osteoclasts’ RANK receptor → bone resorption

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▪ Synovial cells: directly responsible for protease release, contribution to cytokine milieu ▫ Germinal centers within synovium include plasma cells → antibodies against self-antigens, i.e. autoantibodies → specific for citrullinated peptides (CCPs)/arginine residues converted to citrulline ▫ Antibodies against fibrinogen, type II collagen, alpha-enolase, vimentin → form antibody-antigen complexes → deposit into joints ▫ Antibodies (usually IgM or IgA) against Fc regions of IgG antibodies form RF → deposit into joints ▪ Chronic inflammation → angiogenesis → increase inflammatory cell response → further joint involvement Extra-articular involvement ▪ Pyogens (i.e. IL-1) ▫ → Hypothalamus → fever ▪ Skeletal ▫ Protein breakdown ▪ Skin ▫ Macrophage and lymphocytes recruitment → cycle of activation/ recruitment → cells around a central necrotic mass → rheumatoid nodules ▪ Blood vessels ▫ ↑ cytokines and ↑ circulating immune cells → altered endothelial cells → ↑ atheromatous plaques formation ▪ Liver ▫ Under chronic inflammation → ↑ hepcidin production → ↓ iron absorption → anemia ▪ Lung ▫ ↑ fibroblasts → lung fibrosis (AKA Caplan syndrome) → ↓ gas exchange (+/- pleural effusion)

COMPLICATIONS Autoimmune ▪ AA amyloidosis ▪ Sjögren syndrome ▪ Scleritis

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Cardiovascular ▪ ↑ Atheromatous formation → ↑ MI, CVA risk ▪ Pericarditis → ↑ pericardial effusion risk Hematologic ▪ Anemia ▪ Felty syndrome (RA, splenomegaly, neutropenia) Musculoskeletal ▪ Rheumatoid nodules ▫ Can form in any body tissue ▪ Baker (popliteal) cyst formation Neurological ▪ Carpal tunnel syndrome ▪ Mononeuritis multiplex ▪ C1-C2 instability → ↑ risk of subluxation → spinal cord impingement risk → neurologic involvement ▪ Serious complication if unknown at time of intubation Pulmonary ▪ Pleuritis → ↑ risk of pleural effusion (characteristically ↓ glucose, ↓ complement) ▪ Interstitial lung disease ▪ Caplan syndrome

SIGNS & SYMPTOMS Inflammatory polyarthritis ▪ Commonly symmetrically affects multiple (> five) joints ▪ First smaller joints - MCP, PIP, MTP ▪ Avoids DIP joint ▪ Chronic disease → ↑ larger joint involvement Joint characteristics ▪ Warm, red, and painful joints ▪ Morning stiffness (lasting > one hour) Malformation ▪ Ulnar deviation of MCP joints ▪ Boutonniere (buttonhole) malformation ▪ Swan neck

Chapter 111 Inflammatory Arthritis

OTHER DIAGNOSTICS History ▪ Symptoms for > six weeks Physical examination ▪ Inflammatory (warm, stiff, painful) arthritis of > three joints ▪ Characteristic malformations ▫ Ulnar deviation, boutonniere (“buttonhole”) malformation, swan neck malformation

Figure 111.11 Ulnar deviation of the fingers in an individual with rheumatoid arthritis. Extra-articular manifestations ▪ Common, systemic signs ▫ Fever, fatigue, weight loss ▪ Rheumatoid nodules ▫ Commonly arise on extensor surfaces ▪ More varied sequelae in severe and/or chronic disease

DIAGNOSIS DIAGNOSTIC IMAGING X-ray ▪ Soft tissue swelling ▪ Bony erosions ▪ ↓ Bone density ▪ Narrowed joint space (late finding)

LAB RESULTS

▪ RF titers ▫ High titers associated with more severe disease ▫ Eventually present in 80% of affected individuals ▪ Anti-citrullinated peptide/protein antibodies (anti-CCP) ▫ Sensitivity 50–75%; specificity > 90% ▪ ↑ ESR, ↑ CRP ▪ Normocytic anemia (anemia of chronic disease)

Figure 111.12 An X-ray image of the hands of an individual with rheumatoid arthritis. There is destruction of the metacarpophalangeal joints, the carpometacarpal joints and the wrist.

TREATMENT MEDICATIONS

▪ NSAIDs ▪ Short-term, low-dose glucocorticoid ▪ DMARD ▫ Hallmark of RA treatment ▫ Methotrexate (give with folic acid to ↓ side effects) ▫ Others: leflunomide, hydroxychloroquine, sulfasalazine ▪ Biologic DMARDs ▫ Adalimumab, etanercept (intercept), infliximab particularly effective (block TNF-alpha, which is thought to underlie most joint damage)

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▫ Abatacept (suppresses T cells) ▫ Rituximab (suppresses B cells) ▫ Anakinra (blocks IL-1) ▫ Tocilizumab (blocks IL-6)

SURGERY

▪ Only if medication fails ▪ Severe joint malformation ▫ Synovectomy ▪ Severe malformation, disability ▫ Joint replacement

OTHER INTERVENTIONS

▪ Exercise to maintain range of motion and muscle strength

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Figure 111.13 A histological section of a rheumatoid nodule. There is granaulomatous inflammation composed of central fibrinoid necrosis and palisading histiocytes.

NOTES

NOTES

INFLAMMATORY CONNECTIVE TISSUE DISORDERS

GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Chronic autoimmune disorders characterized by inflammation; primarily affect connective tissue ▪ Production of autoantibodies → deposition of immune complexes → complement activation → tissue destruction ▪ Inflammatory cytokines stimulate fibroblasts → increased collagen deposition (fibrosis) ▪ Affects multiple organ systems ▫ Skin, heart, respiratory system, urinary, gastrointestinal (GI) tract

CAUSES

▪ Genetic, environmental factors

COMPLICATIONS

▪ Skin necrosis; renal, cardiac failure; pulmonary insufficiency; GI reflux/bleeding

SIGNS & SYMPTOMS ▪ Constitutional symptoms ▫ Low grade fever, fatigue, weight loss ▪ Specific to disease, organ systems affected ▫ “Butterfly skin rash” specific to systemic lupus erythematosus (SLE)

DIAGNOSIS DIAGNOSTIC IMAGING Barium swallow X-ray ▪ GI involvement

LAB RESULTS

▪ Blood tests ▫ Hematologic abnormalities, increased inflammatory markers, complications (e.g. increased creatinine reflecting renal failure) ▪ Serological tests ▫ Antibodies, confirm diagnosis

OTHER DIAGNOSTICS

▪ Physical examination (e.g. characteristic skin rashes) ▪ Pulmonary function tests ▫ Pulmonary involvement

TREATMENT ▪ Usually symptomatic (e.g. analgesics)

MEDICATIONS

▪ Steroids/other immunosuppressive agents ▫ Reduce inflammation

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CREST SYNDROME osms.it/CREST-syndrome PATHOLOGY & CAUSES

SIGNS & SYMPTOMS

▪ Form of limited systemic sclerosis ▪ Composed of five features; see mnemonic ▫ Calcinosis: deposition of calcium under skin ▫ Raynaud’s syndrome: episodic, dramatic constriction of arteries in hands ▫ Esophageal dysmotility: atrophied muscle in esophagus without significant inflammation/fibrosis ▫ Sclerodactyly: fibrosis of skin of digits ▫ Telangiectasia: dilation of small blood vessels ▪ Caused by chronic autoimmune inflammation triggered mainly by anticentromere antibodies (ACAs) ▪ More benign clinical course than other forms of sclerosis

▪ Calcific nodules under the skin ▪ White-blue-red transitions in skin color in response to triggers (e.g. low temperature, stress) ▪ Dysphagia (due to esophageal dysmotility) ▪ Sclerodactyly ▪ Telangiectasias (esp. hands, face)

MNEMONIC: CREST

Features of CREST syndrome Calcinosis Raynaud’s syndrome Esophageal dysmotility Sclerodactyly Telangiectasia

COMPLICATIONS

▪ Ischemic ulcers, gangrene, predisposition to chronic skin infections (due to sclerosis, severe ischemia of skin) ▪ Upper GI bleeding (due to mucosal telangiectasias)

Figure 112.1 Sclerodactyly in an individual with CREST syndrome.

DIAGNOSIS LAB RESULTS

▪ Serum blood tests ▫ ↑ ANAs: sensitive for systemic sclerosis ▫ ↑ ACAs: highly specific (limited systemic sclerosis); confirm diagnosis

OTHER DIAGNOSTICS

▪ Clinical history, physical examination

TREATMENT MEDICATIONS

▪ Steroids ▪ If sclerosis progresses, stronger immunosuppressants (e.g. cyclosporine)

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Chapter 112 Inflammatory Connective Tissue Disorders

FIBROMYALGIA osms.it/fibromyalgia PATHOLOGY & CAUSES ▪ Chronic condition of central sensitization; hypersensitivity to pain, sleep disturbances ▫ ↓ serotonin (inhibits pain signals) ▫ ↑ substance P, ↑ nerve growth factor (involved in propagating pain signals) ▫ Predominance in individuals who are biologically female

CAUSES

▪ Genetic factors ▪ Environmental factors (child abuse) ▪ Negative emotions (depression, anxiety, negative beliefs) can amplify pain

SIGNS & SYMPTOMS ▪ Low threshold to pain ▪ Widespread muscle pain ▪ Extreme tenderness in various parts of body ▪ Sleep disturbances → fatigue, headache ▪ Difficulty concentrating, remembering things; AKA “fibro fog”

DIAGNOSIS OTHER DIAGNOSTICS Diagnostic Criteria ▪ Pain in ≥ seven areas of body with symptom severity (SS) of ≥ 5 (of 12)/pain in ≥ five areas of body with SS of ≥ 9 (of 12) ▪ Final score between 0–12 ▪ Symptoms present ≥ three months ▪ Pain not due to another disorder

Symptom severity (SS) measures ▪ Fatigue; waking unrefreshed; cognitive symptoms; somatic symptoms ▫ 0: no problem ▫ 1: slight/mild/intermittent ▫ 2: moderate/considerable/often present ▫ 3: severe, continuous, life disturbing

TREATMENT MEDICATIONS

▪ If non-pharmacologic measures fail, drug therapy ▪ Antidepressants ▫ Inhibit pain by elevating levels of serotonin, norepinephrine ▫ Tricyclic antidepressants (TCAs): amitriptyline first line treatment ▫ Serotonin-norepinephrine reuptake inhibitors (SNRIs): milnacipran ▪ Anticonvulsants ▫ Slow nerve impulses, relieve sleep disturbances

PSYCHOTHERAPY

▪ Cognitive behavioral therapy (CBT) ▫ Manage pain, change negative feelings

OTHER INTERVENTIONS

▪ Physical therapy, relaxation techniques, sleep hygiene to reduce pain, fatigue

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MIXED CONNECTIVE TISSUE DISEASE (MCTD) osms.it/mixed-connective-tissue-disease PATHOLOGY & CAUSES

DIAGNOSIS

▪ Overlap autoimmune syndrome; constellation of SLE, systemic sclerosis, polymyositis; may not occur simultaneously ▪ Can evolve into classic SLE/systemic sclerosis

▪ Confirmation requires characteristic clinical presentation

COMPLICATIONS

▪ Pulmonary hypertension; interstitial lung disease; renal disease

SIGNS & SYMPTOMS ▪ Arthralgias (due to polyarthritis) ▪ Myalgias (due to mild myositis) ▪ Swollen hands with puffy fingers (due to synovitis) ▪ Sclerodactyly ▪ Early development of Raynaud phenomenon ▪ Fatigue ▪ Low-grade fevers

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LAB RESULTS

▪ High serum levels of anti-U1 ribonucleoprotein (anti-U1-RNP) antibodies ▪ High ANAs, RF, anti dsDNA, anti Sm, anti Ro

TREATMENT ▪ Depends on predominant autoimmune disease

MEDICATIONS

▪ Corticosteroids ▫ Suppress immune system

Chapter 112 Inflammatory Connective Tissue Disorders

POLYMYALGIA RHEUMATICA (PMR) osms.it/polymyalgia-rheumatica PATHOLOGY & CAUSES ▪ Immune-mediated rheumatic condition affecting joints, sparing muscles ▪ Most commonly affects shoulder, hip joints ▪ Usually occurs in individuals who are biologically female > 50; mean age 70 ▪ Strongly associated with giant-cell arteritis, AKA temporal arteritis ▪ Can regress without treatment after 1–2 years/remain chronic

CAUSES

▪ Genetic defects: specific allele of human leukocyte antigen (HLA)-DR4 ▪ Environmental factors: exposure to adenovirus/human parvovirus B19

SIGNS & SYMPTOMS ▪ Joint pain, stiffness (shoulder, hip joints) ▫ Often starts unilaterally, progresses to bilateral within few weeks ▫ More severe after prolonged inactivity (e.g. morning) ▫ Typically lasts > one hour ▫ Affects nearby nerves in muscle → muscle pain (referred pain)

▪ Constitutional symptoms ▫ Low grade fever (interleukins act as pyrogens) ▫ Fatigue ▫ Loss of appetite → weight loss ▪ If severe headache, jaw pain, vision problems ▫ Temporal arteritis

DIAGNOSIS LAB RESULTS

▪ Increased serum inflammatory markers ▫ Erythrocyte sedimentation rate (ESR) ▫ C-reactive protein (CRP) ▪ Biopsy ▫ Inflammation in joints

OTHER DIAGNOSTICS

▪ Physical examination ▫ Decreased passive range of motion of affected joints

TREATMENT MEDICATIONS

▪ Low dose of corticosteroids ▫ Suppress immune response

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RAYNAUD'S DISEASE osms.it/raynauds-disease PATHOLOGY & CAUSES

SIGNS & SYMPTOMS

▪ Vasospasm of skin arteries in response to triggers, resulting in skin color transitions ▪ Exposure to trigger → stimulation of sympathetic nerves in arteriole walls → vasospasm of arterioles → decrease in blood flow ▪ Usually affects hands, fingers, toes; can affect nose, ears, lips ▪ Common triggers ▫ Emotional stress; low temperatures; nicotine; caffeine; medications that affect sympathetic nervous system (e.g. pseudoephedrine)

▪ Vasospasm → changes in skin color of hands, fingers, toes ▫ White: ischemia ▫ Blue: hypoxia after prolonged ischemia ▫ Red: reactive hyperemia (vasospasm ends, oxygenated blood rushes into tissue) ▪ Raynaud phenomenon ▫ Affects hand fingers, toes symmetrically; severity remains constant ▪ Raynaud syndrome ▫ Asymmetrical; progressive severity ▪ Swelling, numbness, tingling, pain (due to reactive hyperemia)

TYPES Primary: Raynaud phenomenon/disease ▪ Common in pregnant individuals, people who work in jobs involving vibration (e.g. jackhammer) Secondary: Raynaud syndrome ▪ Connective tissue disorders ▫ Systemic lupus erythematosus (SLE), scleroderma, mixed connective tissue disease ▪ Disorders affecting blood vessels ▫ Buerger’s disease, Takayasu’s arteritis, thromboangiitis obliterans ▪ Medications ▫ Beta blockers, nicotine

COMPLICATIONS

▪ Ulceration, infarction, tissue necrosis, gangrene (if severe)

DIAGNOSIS ▪ Based upon description of episodes

DIAGNOSTIC IMAGING

▪ Nailfold capillary microscopy to examine finger capillaries ▫ Normal appearance: Raynaud phenomenon ▫ Damaged appearance: Raynaud syndrome

TREATMENT MEDICATIONS

▪ Vasodilators (e.g. calcium channel blockers)

SURGERY

▪ If severe, surgery to cut sympathetic nerve fibers supplying affected areas

OTHER INTERVENTIONS ▪ Avoid triggers

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Chapter 112 Inflammatory Connective Tissue Disorders

Figure 112.2 A hand with pale fingers caused by Raynaud’s disease.

SCLERODERMA osms.it/scleroderma PATHOLOGY & CAUSES ▪ AKA systemic sclerosis ▪ Chronic inflammatory autoimmune disease, can result in widespread damage to small blood vessels, excessive fibrosis ▫ T helper cells activated by unknown antigen → release cytokines → stimulate inflammatory cells, fibroblasts → chronic inflammation, excessive collagen deposition ▫ Mediators released by inflammatory cells → damage microvasculature → ischemic injuries, scarring ▪ Primarily affects skin, can involve visceral organs ▫ GI tract, kidneys, heart, muscles, lungs

TYPES Limited (80%) ▪ Skin involvement limited to fingers, forearms, face ▪ Late visceral involvement

▪ Some individuals develop CREST syndrome ▫ Calcinosis, Raynaud’s phenomenon, esophageal dysmotility, sclerodactyly, telangiectasia ▪ Associated with anticentromere antibodies ▪ Relatively benign Diffuse (20%) ▪ Widespread skin involvement ▪ Early visceral involvement ▪ Rapid progression ▪ Associated with anti-DNA topoisomerase I antibodies ▪ Poor prognosis

RISK FACTORS

▪ More common in individuals who are biologically female (3:1 ratio) ▪ Average age of onset: 35–50 ▪ Genetic factors ▪ Environmental factors (e.g. viruses, toxins, drugs)

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COMPLICATIONS

▪ Excessive skin fibrosis → painful ulcers, disfigurement, disability ▪ Severe internal organ involvement → renal, cardiac failure; pulmonary insufficiency; intestinal malabsorption

SIGNS & SYMPTOMS ▪ Raynaud phenomenon ▫ Precedes other symptoms, present in almost all individuals ▪ Cutaneous changes of face, extremities ▫ Skin thickening, tightening, sclerosis (most common); edema, erythema (precede sclerosis) ▪ GI involvement ▫ Esophageal fibrosis → dysphagia, GI reflux ▫ Small intestine involvement → abdominal pain, obstructions, constipation, diarrhea, malabsorption syndrome (weight loss, anemia) ▪ Pulmonary involvement with interstitial fibrosis ▫ Right-sided cardiac dysfunction/ pulmonary hypertension ▪ Cardiac involvement ▫ Pericardial effusions, myocardial fibrosis → congestive heart failure, arrhythmias ▪ Renal involvement (diffuse disease) → fatal hypertensive crisis (rare)

Figure 112.3 The finger of an individual with systemic sclerosis showing sclerosis, erythema and ulcer formation.

DIAGNOSIS DIAGNOSTIC IMAGING

▪ Upper endoscopy ▫ Esophageal fibrosis/reflux esophagitis

LAB RESULTS

▪ Serologic tests ▫ ↑ ANAs in almost all individuals with systemic sclerosis; low specificity ▫ ↑ ACAs highly specific (limited) ▫ Anti-topoisomerase I antibodies (antiScl-70) highly specific (diffuse) ▪ Complete blood count (CBC) ▫ Anemia due to malabsorption, increased serum creatinine due to renal dysfunction

OTHER DIAGNOSTICS

▪ Clinical presentation ▫ Skin thickening, swollen fingers, Raynaud’s phenomenon, GI reflux ▪ Pulmonary function tests ▫ Restrictive ventilatory defect due to pulmonary interstitial fibrosis

Figure 112.4 A rash on the back of an individual with a form of localised scleroderma known as morphea.

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Chapter 112 Inflammatory Connective Tissue Disorders

TREATMENT ▪ Depends on disease subset, severity of internal organ involvement

MEDICATIONS

▪ Usually symptomatic ▫ Analgesics for musculoskeletal pain

▫ Proton pump inhibitors for gastroesophageal reflux ▫ Calcium channel blockers for Raynaud’s phenomenon ▫ Angiotensin converting enzyme (ACE) inhibitors for renal hypertensive crisis ▪ Immunosuppressive therapy initiation: diffuse skin/severe internal organ involvement

SJOGREN'S SYNDROME (SS) osms.it/sjogrens-syndrome PATHOLOGY & CAUSES

SIGNS & SYMPTOMS

▪ Chronic autoimmune inflammatory disease; lymphocytic infiltration, destruction of exocrine glands of eyes, mouth ▪ Proposed mechanisms ▫ Immune reactions against antigens of viral infection of exocrine glands ▫ Autoimmune T cell reaction against unknown self antigen expressed in salivary, lacrimal glands ▪ Variety of extraglandular manifestations may occur ▪ Usually occurs in individuals who are biologically female, 50–60 years

▪ Dry eyes ▫ Irritation, itching, foreign body sensation, keratoconjunctivitis ▪ Oral dryness reflecting salivary hypofunction ▪ Salivary gland enlargement (parotid, submandibular, etc.) ▪ Extraglandular manifestations ▫ Musculoskeletal symptoms (arthralgias, arthritis); rashes; interstitial nephritis, vasculitis

CAUSES

▪ Primary: sicca syndrome ▪ Secondary (to other autoimmune diseases): rheumatoid arthritis (most common)

COMPLICATIONS

▪ Periodontal complications; oral infections; mucosal associated lymphoid tissue (MALT) lymphoma

DIAGNOSIS ▪ Clinical presentation: persistent dry eyes/ mouth, parotid gland enlargement

DIAGNOSTIC IMAGING Parotid gland MRI ▪ Honeycomb pattern Salivary gland ultrasound ▪ Multiple hypoechoic areas

LAB RESULTS

▪ CBC ▫ Leukopenia, thrombocytopenia, anemia ▪ ↑ ESR ▪ Urinalysis

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▫ Proteinuria/hematuria reflecting glomerulonephritis ▪ Labial salivary gland biopsy (confirm diagnosis) ▫ Focal lymphocyte foci (collections of tightly aggregated lymphocytes) ▪ Serologic tests (support diagnosis) ▫ ↑ antinuclear antibodies (ANAs) in 95% of individuals ▫ ↑ rheumatoid factor (RF) in 50–75% of individuals with/without rheumatoid arthritis ▫ Anti-Sjögren syndrome A (SSA) (Ro), Anti-Sjögren syndrome B (SSB) (La) specific to SS, found elevated only in 55%, 40% of individuals, respectively

OTHER DIAGNOSTICS Tear deficiency tests ▪ Schirmer test ▫ Measures reflex tear production; wetting of test paper < 5mm indicative of tear deficiency ▫ Ocular surface staining with Rose Bengal stain and slit-lamp examination—assess tear break-up time (TBUT); TBUT < 10 seconds indicative of tear deficiency ▪ Salivary gland tests ▫ Salivary gland scintigraphy: low uptake of radionuclide characteristic of SS ▫ Sialometry: low volume of saliva indicative of salivary gland hypofunction

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Figure 112.5 A lymphocytic infiltrate in a minor salivary gland excised from an individual with Sjögren’s syndrome.

TREATMENT MEDICATIONS

▪ Mild SS ▫ Secretagogues ▫ Local treatment for ocular, oral dryness (e.g. artificial tears) ▪ Moderate to severe SS ▫ Immunosuppressive treatment

Chapter 112 Inflammatory Connective Tissue Disorders

SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) osms.it/systemic-lupus-erythematosus PATHOLOGY & CAUSES ▪ Chronic systemic autoimmune disorder; wide range of clinical, serological features ▪ Periods of flare-ups, remittance ▪ Environmental triggers damage DNA → apoptosis → release of nuclear bodies ▪ Clearance of apoptotic bodies ineffective due to genetic defects → increased amount of nuclear antigens in bloodstream → initiates immune response → production of antinuclear antibodies → bind to antigens, form immune complexes ▪ Complexes deposit in tissues (e.g. kidneys, skin, joints, heart) → Type III hypersensitivity reaction ▪ Individuals may develop antibodies targeting molecules (e.g., phospholipids) of red, white blood cells → marking them for phagocytosis → Type II hypersensitivity reaction

▪ Antiphospholipid syndrome ▫ Hypercoagulable state; individuals prone to develop clots (e.g. deep vein thrombosis, hepatic vein thrombosis, stroke)

SIGNS & SYMPTOMS ▪ Fever, joint pain, rash in sun-exposed areas ▪ Typical rashes ▫ Malar rash (butterfly rash): over cheeks ▫ Discoid rash: plaque-like/patchy redness, can scar ▫ General photosensitivity: typically lasts few days

RISK FACTORS

Genetic defects associated with SLE UV radiation Smoking Viral, bacterial infections Medications (e.g. procainamide, hydralazine, isoniazid, estrogens) ▪ More common in individuals who are biologically female, of reproductive age ▪ ▪ ▪ ▪ ▪

COMPLICATIONS

▪ Cardiovascular disease ▫ Libman–Sacks endocarditis, myocardial infarction (MI) ▪ Serious infections; renal failure; hypertension

Figure 112.6 A butterfly rash on the face of an individual with systemic lupus erythematosus.

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▪ ▪ ▪ ▪

▪ ▪

▪ ▪

Weight loss Ulcers in oral/nasal mucosa Serositis (e.g. pleuritis/pericarditis) Libman–Sacks endocarditis: formation of nonbacterial vegetations on ventricular, atrial valve surfaces; mitral, aortic valves (most common) Myocarditis Renal disorders ▫ Abnormal levels of urine protein, diffuse proliferative glomerulonephritis Neurologic disorders ▫ Seizures, psychosis Hematologic disorders ▫ Anemia, thrombocytopenia, leukopenia

DIAGNOSIS OTHER DIAGNOSTICS Diagnostic criteria (4 of 11) ▪ Malar rash ▪ Discoid rash ▪ General photosensitivity ▪ Oral/nasal ulcers ▪ Serositis ▪ Arthritis in ≥ two joints ▪ Renal disorders ▪ Neurologic disorders ▪ Hematologic disorders ▪ Antinuclear antibodies ▫ Very sensitive, not specific ▪ Other antibodies ▫ SLE specific: anti-Smith, anti-dsDNA ▫ Anti-phospholipid: anticardiolipin (false-positive test for syphilis); lupus anticoagulant (lupus antibody); anti-beta 2 glycoprotein I

TREATMENT ▪ Goal: prevent relapses, limit severity

MEDICATIONS

Figure 112.7 An MRI scan of the head of an individual with SLE who presented with altered mental status and seizures. There a numerous small infarcts suggestive of cerebral vasculitis. The individual improved after treatment with steroids.

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▪ Long term therapy ▫ Antimalarial agents ▪ Mild to moderate manifestations ▫ Non-steroidal anti-inflammatory drugs (NSAIDs), low doses of corticosteroids ▪ Severe/life-threatening manifestations ▫ High doses of corticosteroids, intensive immunosuppressive drugs

OTHER INTERVENTIONS ▪ ▪ ▪ ▪ ▪

Avoid sun exposure Physical exercise Balanced diet Smoking cessation Immunizations

Chapter 112 Inflammatory Connective Tissue Disorders

Figure 112.8 A histological section of a lymph node from an individual with lupus lymphadenopathy. There is necrosis, with an absence of neutrophils, and large numbers of hematoxylin bodies.

Figure 112.9 Histological appearance of the glomerulus in a case of lupus nephritis. There is global mesangial cell proliferation and abundant mesangial matrix.

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NOTES

NOTES

INFLAMMATORY MYOSITIS GENERALLY, WHAT IS IT? PATHOLOGY & CAUSES ▪ Multiple disorders involving autoimmune inflammation, injury of skeletal muscles ▪ Most commonly include polymyositis, dermatomyositis, inclusion body myositis ▫ Dermatomyositis predominantly mediated by humoral immune response; polymyositis, inclusion body myositis by cellular immune response

RISK FACTORS

DIAGNOSIS LAB RESULTS

▪ ↑ muscle enzymes, like creatine kinase (CK) ▪ Muscle biopsy ▫ Dermatomyositis: perivascular, perimysial inflammation ▫ Polymyositis: endomysial inflammation ▫ Inclusion body myositis: endomysial inflammation, intracytoplasmic vacuoles with protein depositions

▪ Age (more common in older population) ▪ Dermatomyositis, polymyositis more common in individuals who are biologically female ▪ Inclusion body myositis more common in individuals who are biologically male ▪ Chronic viral infections: human T cell lymphotropic virus Type I (HTLV-1), HIV ▪ Autoimmune diseases ▪ Malignancies

OTHER DIAGNOSTICS

COMPLICATIONS

▪ Corticosteroids, immunosuppressive agents

▪ Dysphagia, pulmonary involvement ▪ Cardiovascular involvement

SIGNS & SYMPTOMS ▪ Proximal muscle weakness ▪ Inclusion body myositis ▫ Distal muscle weakness ▪ Dermatomyositis ▫ Skin rashes

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▪ Physical examination ▫ Muscle weakness

Electromyography (EMG) ▪ Pathological signals

TREATMENT MEDICATIONS

OTHER INTERVENTIONS ▪ Physical rehabilitation

Chapter 113 Inflammatory Myositis

DERMATOMYOSITIS osms.it/dermatomyositis PATHOLOGY & CAUSES ▪ Autoimmune disorder leading to destruction of small blood vessels in muscles, skin ▪ Unknown factor activates C3 protein (complement component 3) → formation of membrane attack complex (MAC), accumulation in capillaries → destruction of capillary wall → microinfarctions ▪ Juvenile: around seven years; associated with calcinosis (deposition of calcium in skin) ▪ Adult: > 40; associated with malignancy, treating malignancy may cure myositis

Figure 113.1 A heliotrope rash affecting the eyes of an individual with dermatomyositis.

RISK FACTORS ▪ > 60 years ▪ Malignancy

COMPLICATIONS

▪ Respiratory muscle weakness; dysphagia (if esophagus, pharyngeal muscles involved); interstitial pulmonary disease; cardiovascular involvement

SIGNS & SYMPTOMS ▪ Weakness starts in proximal muscles, slowly progresses (e.g. difficulty getting up) ▪ Heliotrope rash ▫ Purplish eyelids with posible periorbital edema ▪ Gottron papules ▫ Scaling erythema of knuckles, elbow, knees ▪ V-shaped rash on chest

Figure 113.2 Gottron’s papules on the extensor surfaces of an individual with dermatomyositis.

DIAGNOSIS DIAGNOSTIC IMAGING CT scan ▪ Malignancy suspected

LAB RESULTS

▪ Blood tests ▫ ↑ CK (muscle cells death) ▫ ↑ aspartate aminotransferase (AST)

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▫ ↑ lactic dehydrogenase (LDH) ▫ Antinuclear antibodies (ANA) ▫ Anti-Mi-2 antibodies (acute phase, better prognosis) ▪ Biopsy ▫ Perivascular, perimysial inflammation ▫ Perifascicular atrophy ▫ “Ghost fibers” (destroyed fibers, can no longer be stained)

OTHER INTERVENTIONS

▪ Physical therapy (preserve muscle strength) ▪ Sunscreen, avoid sun exposure (in skin disease)

OTHER DIAGNOSTICS EMG ▪ Abnormal signals

TREATMENT MEDICATIONS

▪ Corticosteroids (e.g. glucocorticoid) ▪ Immunosuppressive agents (e.g. methotrexate) ▪ IV immune globulins

Figure 113.3 The histological appearance of the skeletal muscle of an individual with dermatomyositis. The perimysium and endomysium have been infiltrated by chronic inflammatory cells, with predilection for the perimysium.

INCLUSION BODY MYOSITIS osms.it/inclusion-body-myositis PATHOLOGY & CAUSES ▪ Idiopathic inflammation of muscles leading to weakness, muscle atrophy ▪ Inflammation, degenerative processes ▪ Unknown factor causes myofibers to present major histocompatibility complex class I (MHC I) → CD8+ T cells gather, recognize MHC I, bind → express perforin → pores form on myofibers membranes → cell degeneration ▪ Accumulation of abnormal amyloidogenic proteins (e.g. beta-amyloid), cytotoxic effect ▫ Causes: misfolding of proteins; damaged/inhibited proteasomes; endoplasmic reticulum stress

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RISK FACTORS

▪ Age > 50 ▪ Chronic viral infections: HTLV-1 ▪ Autoimmune diseases: Sjögren’s syndrome

COMPLICATIONS

▪ Dysphagia (if esophagus, pharyngeal muscles involved)

SIGNS & SYMPTOMS ▪ Slowly progressive muscle weakness, sometimes asymmetric ▫ Proximal leg muscles (difficulty getting up, frequent falls) ▫ Distal arm muscles (weak grip)

Chapter 113 Inflammatory Myositis ▪ As disease progresses ▫ ↑ muscle atrophy ▫ ↓ deep tendon reflexes

DIAGNOSIS LAB RESULTS

▪ Mild ↑ muscle enzymes (e.g. CK) ▪ Muscle biopsy ▫ CD8+ T lymphocytes, macrophages infiltrating non-necrotic myofibers ▫ Vacuoles with amyloides, other protein accumulations (inclusion bodies) ▫ ↑ MHC I on immunostaining

OTHER DIAGNOSTICS ▪ Clinical presentation ▫ Muscle weakness

EMG ▪ Polyphasic motor unit action potentials (MUAPs) with small amplitude, short duration

Figure 113.4 Gomori staining highlights the rimmed vacuoles in inclusion body myositis.

TREATMENT MEDICATIONS

▪ Immunosuppressive therapy ▫ Administered when another systemic autoimmune disease present

OTHER INTERVENTIONS ▪ Physical therapy ▫ Muscle strengthening ▪ Speech therapy ▫ If dysphagia present ▪ Occupational therapy

Figure 113.5 A histological section of muscle showing a myofiber vacuole in an individual with inclusion body myositis.

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POLYMYOSITIS osms.it/polymyositis PATHOLOGY & CAUSES ▪ Inflammatory destruction of muscles leading to muscle weakness ▪ Unknown factor induces CD8+ T cells, macrophages to recognize nuclear, cytoplasmic antigens of muscle cells → immune cells surround nonnecrotic muscle cells → muscle cell destruction

vessels; myofibers surrounded by CD8+ T lymphocytes, macrophages

OTHER DIAGNOSTICS

▪ Physical examination ▫ Muscle weakness, tenderness

EMG ▪ Low amplitude, short duration potential; repetitive discharges

RISK FACTORS

▪ Autoimmune disease ▪ Chronic viral infection (HIV, HTLV-1)

COMPLICATIONS

▪ Aspiration pneumonia ▪ Interstitial lung disease ▪ Dysphagia → malnutrition, anorexia

SIGNS & SYMPTOMS ▪ Symmetrical weakness of proximal leg, arm muscles (e.g. difficulty climbing stairs) ▪ Neck flexor weakness ▪ Mild myalgia, tenderness ▪ Dysphagia (if esophagus, pharyngeal muscles involved)

Figure 113.6 A muscle biopsy from an individual with polymyositis. The lymphocytes penetrate individual myofibers. In this example, the inflammation has progressed to phagocytic destruction by macrophages.

DIAGNOSIS

TREATMENT

DIAGNOSTIC IMAGING Chest X-ray, CT scan ▪ Pulmonary involvement

LAB RESULTS

▪ Blood tests ▫ ↑ CK, aldolase; ANA; antisynthetase antibodies (anti-Jo-1) ▪ Muscle biopsy ▫ Endomysial inflammation; intact blood

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MEDICATIONS

▪ Corticosteroids ▪ Immunosuppressive agents (if nonresponsive to corticosteroids) ▪ IV immune globulins (if severe, lifethreatening)

OTHER INTERVENTIONS

▪ Physical therapy (preserve muscle strength)

Chapter 113 Inflammatory Myositis

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NOTES

NOTES

JOINT PATHOLOGY GENERALLY, WHAT IS IT? PATHOLOGY & CAUSES ▪ Disorders affecting joints ▪ Most commonly caused by trauma

SIGNS & SYMPTOMS ▪ Asymptomatic or pain during rest/ movement

DIAGNOSIS DIAGNOSTIC IMAGING ▪ Radiography ▪ MRI

LAB RESULTS

▪ Synovial fluid analysis

TREATMENT ▪ Treat symptoms pharmacologically ▪ Surgical procedures

BAKER'S CYST osms.it/bakers-cyst PATHOLOGY & CAUSES ▪ Synovial fluid accumulates in popliteal bursa (between medial head of gastrocnemius, semimembranosus muscles) → swelling ▪ Adults: popliteal bursa communicates with synovial sac; underlying knee joint disease main cause ▫ Knee joint disease → ↑ synovial fluid production → synovial fluid squeezes through valve-like formation into bursa → fluid unable to flow backward → bursa enlarges → lump-like structure in the popliteal fossa ▪ Children: noncommunicating cyst; usually arises as primary process

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CAUSES ▪ ▪ ▪ ▪

Chronic knee joint trauma Osteoarthritis Rheumatoid arthritis Meniscal tears

COMPLICATIONS

▪ Cyst enlargement ▫ In popliteal space → obstruction of veins → lower leg swelling ▫ Extension to calf → swelling, redness, bruising, positive Homan’s sign (calf pain during dorsiflexion of the foot) → similar to deep-vein blood clot ▪ Rupture

Chapter 114 Joint Pathology

DIAGNOSIS

SIGNS & SYMPTOMS ▪ May be asymptomatic ▪ Stiffness and pain in the knee → worse with prolonged standing

DIAGNOSTIC IMAGING Ultrasound and MRI ▪ Fluid-filled cyst; differentiation between cyst, blood clot X-ray ▪ Bone, joint pathology associated with cyst

OTHER DIAGNOSTICS

▪ Physical examination ▫ Lump in the back of the knee

TREATMENT SURGERY

▪ Surgical excision

OTHER INTERVENTIONS Figure 114.1 An MRI scan of the knee joint in the sagittal plane demonstrating a Baker’s cyst in the popliteal fossa.

▪ Fluid aspiration, glucocorticoid intraarticular injection → ↓ size and inflammation ▪ Treat complications ▫ Leg elevation, resting, analgesics

BURSITIS osms.it/bursitis PATHOLOGY & CAUSES ▪ Inflammation of bursa (small sac located between muscles, tendons, bone structures) ▪ Inflammation of bursa → ↑ production of synovial fluid → enlargement of bursa → ↑ friction during movement → symptomatology ▪ Most commonly affected bursas ▫ Subacromial, olecranon, trochanteric, prepatellar, infrapatellar

CAUSES

▪ Autoimmune disorders ▫ Rheumatoid arthritis, ankylosing spondylitis, scleroderma, systemic lupus erythematosus → chronic course ▪ Overuse/trauma, gout, bacterial infections (septic bursitis) → acute course

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SIGNS & SYMPTOMS ▪ Joint pain; stiffness of joints; surrounding skin red ▪ Acute bursitis ▫ Tenderness, pain during activation of muscles adjacent to inflamed bursa ▪ Chronic bursitis ▫ Swelling with minimal pain

Figure 114.3 An MRI scan of the elbow demonstrating a high signal fluid collection in the olecranon bursa in an individual with olecranon bursitis. Figure 114.2 An individual with olecranon bursitis.

DIAGNOSIS DIAGNOSTIC IMAGING Ultrasound ▪ Differentiation from Baker’s cyst

LAB RESULTS

▪ Aspiration and analysis of synovial fluid ▫ Infection: ↑ polymorphonuclear leukocytes, proteins, ↓ glucose ▫ Gout: ↑ monosodium urate crystals

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TREATMENT MEDICATION

▪ Non-steroidal inflammatory drugs (NSAIDs) ▪ Injection of steroids, local anesthetics ▪ Septic bursitis ▫ Antibiotics

SURGERY

▪ Surgical excision ▫ Chronic or recurrent bursitis

OTHER INTERVENTIONS ▪ Resting, elevation

Chapter 114 Joint Pathology

OSTEOARTHRITIS osms.it/osteoarthritis PATHOLOGY & CAUSES ▪ Progressive loss of articular cartilage, underlying bone of synovial joints ▪ Articular cartilage damage → chondrocytes replace type II collagen with type I, ↓ proteoglycans → eventual exhaustion, apoptosis of chondrocytes → ↓ elasticity, ↑ cartilage breakdown → clefts in articular surface (fibrillations), “joint mice” in synovial space with inflammation of synovium → bone exposition → rubbing other bone → eburnation (polished ivory look) ▪ Due to damage/inflammation, new bone formation on edges of bone with outward growth → osteophyte (enlargement of the joint with a knob-like look) ▫ Bouchard nodes: proximal interphalangeal finger joints affected ▫ Heberden nodes: distal interphalangeal finger joints affected ▪ Most commonly affected joints ▫ Lower spine, hip, knee, foot and hand joints

CLASSIFICATION

▪ Primary ▫ Usually idiopathic ▪ Secondary ▫ Caused by some other condition (e.g. diabetes, alkaptonuria, hemochromatosis, chronic joint injury)

anabolism of cartilage ▪ Obesity ▫ Excessive load, metabolic disorders affect joints ▪ Genetic disorders ▫ Mutations in cartilage building collagens (types II, IX and XI) ▪ Biological sex ▫ Biologically female more prone ▪ Previous joint injuries ▪ Infection ▪ Neurologic disorders

COMPLICATIONS

▪ Cystic degeneration of subchondral bone ▪ Surrounding ligaments, neuromuscular abnormalities

SIGNS & SYMPTOMS ▪ Sharp pain/burning sensation worsened by prolonged activity ▪ Limited range of motion ▪ Morning stiffness > one hour ▪ No swelling

RISK FACTORS

▪ Aging ▫ Cartilage thinning with ↓ hydratation → protein accumulation, collagen crosslinking → cartilage is more breakable; ↑ calcification of meniscus, cartilage ▪ Inflammation → ↑ proinflammatory cytokines ▫ IL1, IL6, TNF → ↑catabolism/↓

Figure 114.4 Heberden’s node on the distal interphalangeal joint of the right index finger in an individual with osteoarthritis.

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DIAGNOSIS DIAGNOSTIC IMAGING Radiography ▪ Loss of joint space ▪ Subchondral bone sclerosis MRI ▪ Loss of joint space ▪ Subchondral bone sclerosis ▪ Osteophytes ▪ Visualisation of articular cartilage, surrounding soft tissues CT scan ▪ Displacement of foot, ankle, patellofemoral joint Bone scan ▪ Detect abnormalities

LAB RESULTS ▪ Arthrocentesis

Figure 114.5 An X-ray image of the pelvis demonstrating osteoarthritis of the right hip joint. The femoral head is malformed, there is marked loss of joint space and there are numerous subchondral bone cysts.

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TREATMENT MEDICATIONS

▪ Pain management ▫ Acetaminophen, tramadol, topical and oral non-steroidal anti-inflammatory drugs (NSAIDs) ▪ Intra-articular injections ▫ Corticosteroids ▫ Sodium hyaluronate

SURGERY

▪ Osteotomy ▫ Individuals < 60 years with malalignment of hip, knee joint ▪ Arthroplasty ▪ Stem-cell therapy

OTHER INTERVENTIONS ▪ ▪ ▪ ▪

Exercise Weight loss Physical therapy Electromagnetic field stimulation for individuals with knee osteoarthritis

Chapter 114 Joint Pathology

SLIPPED CAPITAL FEMORAL EPIPHYSIS osms.it/slipped-capital-femoral-epiphysis PATHOLOGY & CAUSES ▪ Anterior displacement of femoral head metaphysis, with epiphysis remaining in hip acetabulum ▪ Caused by growth plate (physis) fracture ▪ Example of type I Salter–Harris fracture usually affecting one hip ▪ Hypertrophy of growth plate → abnormal endochondral ossification, cartilage maturation → growth plate weakness → if too much force generated across growth plate → slippage

COMPLICATIONS

▪ Osteoarthritis ▪ Metaphysis slippage → ↓ blood flow → avascular necrosis ▪ Secondary SCFP affecting other hip; usually within a year of first SCFP ▪ Unstable displacement: ↑ complication rate

SIGNS & SYMPTOMS ▪ Hip, groin, knee pain ▪ Duck-like gait ▪ Hip in external rotation, flexion

CLASSIFICATION

▪ Based on disease course ▫ Acute: > three weeks ▫ Chronic: < three weeks ▫ Acute on chronic: chronic with acute exacerbations ▪ Based on lesion stability ▫ Stable: walking possible with/without crutches ▫ Unstable: walking impossible, even with crutches ▪ Displacement of the femoral head from neck; seen on radiography ▫ Type I: slippage < 33% ▫ Type II: 33–50% ▫ Type III: > 50%

RISK FACTORS ▪ ▪ ▪ ▪ ▪

Obesity ↓ thyroid, growth hormone Osteodystrophy Down syndrome Demographics ▫ Adolescent black males of African descent most commonly affected

Figure 114.6 An X-ray image of the pelvis demonstrating a slipped capital femoral epiphysis on the left side.

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DIAGNOSIS DIAGNOSTIC IMAGING X-ray ▪ Anteroposterior X-ray ▫ Melting ice cream cone appearance visible through line of Klein (virtual line parallel to femoral neck’s upper edge) ▪ Frog-leg X-ray ▫ Straight line through center of femoral neck anterior to epiphysis (rather than central)

TREATMENT SURGERY

▪ Fixation with a cannulated screw ▪ Preventive fixation of the other hip ▫ Children with SCFP before the age of 10 ▫ Persons with endocrinopathies ▪ Osteotomy

MRI, CT scan ▪ Accurate measurements of displacement degree

TRANSIENT SYNOVITIS osms.it/transient-synovitis PATHOLOGY & CAUSES ▪ Inflammation of hip joint synovial membrane ▪ Cause relatively unknown, but may be preceded by upper respiratory tract infection ▪ Most commonly seen in male children 3–10 years ▪ Most commonly limited to one side

SIGNS & SYMPTOMS ▪ ▪ ▪ ▪

May be asymptomatic Tenderness/pain during passive movement One-sided pain in the hip, groin, thigh, knee Antalgic limping

DIAGNOSIS ▪ Diagnosis of exclusion

DIAGNOSTIC IMAGING Ultrasound ▪ Fluids in joint capsule

LAB RESULTS ▪ ▪ ▪ ▪

Slightly ↑ white blood cell count ↑ Erythrocyte sedimentation rate ↑ C-reactive protein Needle aspiration ▫ Differentiation between transient synovitis and septic arthritis

OTHER DIAGNOSTICS

▪ Limited abduction and internal rotation

TREATMENT MEDICATIONS ▪ NSAIDs

OTHER INTERVENTIONS ▪ Massage ▪ Rest

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NOTES

NOTES

LOWER LIMB INJURY GENERALLY, WHAT IS IT? PATHOLOGY & CAUSES ▪ Injury to ligaments, tendons, bony structures of lower extremities

CAUSES

▪ Trauma, sport

SIGNS & SYMPTOMS ▪ Pain, swelling in affected region/joint

DIAGNOSIS DIAGNOSTIC IMAGING ▪ Imaging to confirm

TREATMENT MEDICATIONS Acute ▪ Analgesics (NSAIDs)

SURGERY Therapeutic ▪ Surgical intervention (depending on disability, desire to return to sport/ demanding activity)

OTHER INTERVENTIONS Acute ▪ Rest, ice

OTHER DIAGNOSTICS

▪ History: traumatic event, risk factors review ▪ Physical examination: especially provocative (eponymous) musculoskeletal joint evaluation

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ACHILLES TENDON RUPTURE osms.it/achilles-tendon-rupture PATHOLOGY & CAUSES ▪ Acute, complete disruption of achilles tendon ▫ Commonly traumatic, but can be iatrogenic

CAUSES

▪ Recreational Sports: > 80% of achilles tendon ruptures ▫ Increased activity, shear stress on achilles, direct trauma to tendon ▫ Sudden, forced dorsiflexion of ankle outside normal range of motion

RISK FACTORS ▪ ▪ ▪ ▪ ▪

Age: 30–40 years old Biologically-male individuals Obesity Fluoroquinolone use: unknown mechanism Systemic corticosteroid use

▪ Proximal achilles ▫ Likewise collected proximally Physical examination maneuvers ▪ Calf squeeze test (Simmonds/Thompson test) ▫ Squeezing calf of affected leg does not elicit plantar flexion (very high sensitivity, specificity) ▪ Palpable gap test ▫ Posterior leg palpation at level of achilles to palpate gap in tendon ▪ Knee flexion test (Matles test) ▫ Individual is prone with knees flexed at 90° → observe angle of ankle ▫ Ruptured achilles → acute angle (unopposed dorsiflexion of foot by grativity)

COMPLICATIONS

▪ Re-injury: 10% of individuals with rupture have history of previous rupture

SIGNS & SYMPTOMS ▪ Ankle pain ▪ Poor ambulation

DIAGNOSIS OTHER DIAGNOSTICS Physical inspection ▪ History: sudden, painful pop in lower leg; inability to walk; pain immediately after injury ▪ Calf muscles ▫ Soft, lumped together toward knee

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Figure 115.1 A positive Simmond’s test (left) in an individual with a ruptured achilles’ tendon

Chapter 115 Lower Limb Injury

TREATMENT MEDICATIONS Acute ▪ Analgesics (NSAIDs/acetaminophen)

SURGERY Curative ▪ Orthopedic tendon repair

OTHER INTERVENTIONS Acute ▪ Rest, ice

Figure 115.2 A ruptured achilles tendon prior to surgical repair.

ANTERIOR CRUCIATE LIGAMENT INJURY osms.it/ACL-injury PATHOLOGY & CAUSES ▪ Damage/complete tear of anterior cruciate ligament (ACL) in knee; common in deceleration injuries

CAUSES

▪ Common mechanism: twisting knee after planting foot ▫ Typically, non-contact injury ▫ Common athletic injury

RISK FACTORS

▪ Biologically-female individuals ▪ Valgus knee angulation ▪ ↑ traction ability of field of play ▫ Wet surfaces: rotation/shift of gravity results in slipping, rather than biomechanical injury to body

COMPLICATIONS

▪ Segond fracture: avulsion fracture of lateral aspect of tibial plateau; occurs in most ACL tears

SIGNS & SYMPTOMS ▪ Immediate pain ▪ May have popping sensation/sound at time of injury ▪ Immediate knee swelling → hemarthrosis ▫ Diagnostic maneuvers should be performed immediately after injury for clearest results ▪ Post-injury ▫ Knee may “give out” when walking/ standing

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DIAGNOSIS DIAGNOSTIC IMAGING X-ray ▪ Rule out fractures (nondiagnostic for ligament tears) MRI ▪ Preferred modality to evaluate ligament integrity ▪ Very high sensitivity, specificity Knee arthroscopy

OTHER DIAGNOSTICS Physical inspection ▪ History: pivot sign (knee buckling phenomenon, especially at heel strike phase of walking cycle) ▫ Tibia’s ability to travel anteriorly (without intact ACL) when knee is flexed at 0–30°→ snaps back around 40°+ of flexion ▫ Underlying this phenomenon: role of iliotibial band in knee extension, flexion at different degrees of knee position Physical examination maneuvers ▪ Anterior drawer test ▫ Supine individual: affected leg flexes 90°, foot rests on end of bed → examiner sits on foot of affected leg (to stabilize) → grasps around proximal tibia with both hands → pulls anteriorly on tibia → observes anterior movement level ▫ Normal laxity: < 1cm/0.4in anterior tibial subluxation; negative test, likely intact ACL ▫ ↑ Laxity: > 1cm/0.4in; positive test, likely torn ACL ▪ Lachman test ▫ Supine individual: knee flexed around 20° → examiner flexes knee → grasps around proximal tibia with one hand while stabilizing ipsilateral thigh with other hand → pulls anteriorly on tibia → observes anterior movement level

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▫ Similar endpoints to anterior drawer test ▫ Best sensitivity (85%), specificity (94%) compared to other diagnostic tests

TREATMENT MEDICATIONS Acute ▪ NSAIDs

SURGERY

▪ Complete ACL tears ▪ Reconstruction with neighboring patellar ligament/semitendinosus tendon ▪ Eligibility: severity of symptoms, individual’s future athletic ambitions ▪ Majority of individuals elect for surgical repair ▪ Increased risk of osteoarthritis

OTHER INTERVENTIONS

▪ Rehabilitation: intensive physical therapy

Acute ▪ Rest, ice, compression of injured knee

Figure 115.3 An MRI scan of the knee demonstrating partial disruption of the anterior cruciate ligament.

Chapter 115 Lower Limb Injury

ILIOTIBIAL BAND SYNDROME osms.it/IT-band-syndrome PATHOLOGY & CAUSES

DIAGNOSIS

▪ Painful overuse injury: fibrous band of tissue connects muscles of proximal lower extremity to lateral tibia ▪ Common injury for runners

OTHER DIAGNOSTICS

CAUSES

Physical examination maneuvers ▪ Noble compression test (examiner attempts to recreate pain experienced during training) ▫ Individual lays in decubitus position with affected leg above unaffected → examiner puts one thumb proximal to LPE with pressure → examiner uses other hand to passively move affected about the knee from 0–60° flexion → pain → positive test ▪ Ober test ▫ Individual lies on uninvolved side → flexes hip, knee 90° → knee placed in 5° flexion angle → examiner fully abducts lower extremity being tested → allows force of gravity to adduct extremity until hip cannot adduct any further ▪ Palpation of knee (check for no effusion) ▫ Rule out meniscal injury (lateral knee pain, ⊕ effusion)

▪ Iliotibial band (ITB): involved in knee flexion (at < 30°), knee extension at terminal extension (near 0° flexion); very active in heavy activity → overuse causes inflammation ▪ Greatest tension across ITB occurs at 30° ▫ Runners: position of 30° at foot strike → repeat → inflammation, injury ▫ Cyclists: position of 30° at down-pedal position → repeat → inflammation, injury

RISK FACTORS Intrinsic ▪ Weak hip abductors/flexors ▪ Gastrocnemius, soleus inflexibilty ▪ Leg length discrepancy Extrinsic ▪ Sudden training distance/intensity increase ▪ Running: overstriding, foot eversion (poorly fitted/raised shoes) ▪ Cold weather exercise

SIGNS & SYMPTOMS Knee pain ▪ Sharp/burning, worse during exercise at knee flexion of 30° ▪ Beyond exercise, pain may ache more/be deeper ▪ Location: lateral femoral epicondyle (LPE)

Physical inspection ▪ History: Running/cycling with indolent course of lateral knee pain with training

TREATMENT MEDICATIONS Acute ▪ Analgesics (NSAIDs/acetaminophen)

SURGERY

▪ ITB release: individuals who have failed long-term physical therapy program

OTHER INTERVENTIONS

▪ Exercise adjustment ▫ Address extrinsic risk factors

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▫ Correct leg length discrepancy with insole lift ▪ Physical therapy ▫ Address strength of hip abduction/ flexion, calf inflexibility Acute ▪ Rest, ice

Figure 115.4 An MRI scan in the coronal plane of the right knee of individual complaining of iliotibial band syndrome symptoms. The band is inflammed with surrouding edema close to its point of insertion.

MENISCUS TEAR osms.it/meniscus-tear PATHOLOGY & CAUSES ▪ Injury to fibrocartilage (medial/lateral) knee pads (provide cushion, increase stability at tibiofemoral articulation interface)

CAUSES

▪ Pathophysiology: planted foot → twisting force at knee → compressional, rotational, shear stress placed on meniscus → tear ▫ Medial meniscus tears > lateral meniscus tears ▫ Medial meniscus firmly attached to medial collateral ligament (MCL) → ↓ mobility of medial meniscus → ↓ force required to tear fibrocartilage ▫ Poor blood supply to meniscus via geniculate arteries → poor healing/

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regenerative capability post injury Young, healthy athletes ▪ Forceful, sudden, decelerating movement while changing direction Elderly ▪ Chronic injury requires less torsional force at knee

RISK FACTORS

▪ Soccer, basketball, American football

COMPLICATIONS ▪ Osteoarthritis

Chapter 115 Lower Limb Injury

SIGNS & SYMPTOMS ▪ Pain at time of injury ▪ Swelling within 24 hours ▪ Clicking/crepitus with walking/knee extension ▪ Inability to fully extend/lock knee: occurs in anterior meniscus tears > posterior meniscus tears

DIAGNOSIS DIAGNOSTIC IMAGING X-ray ▪ Non-diagnostic; commonly performed to rule out knee fracture MRI ▪ Most sensitive imaging modality for detecting tears ▫ Medial meniscus: very high sensitivity, specificity ▫ Lateral meniscus: high sensitivity, very high specificity ▪ Indicated for surgical evaluation ▫ Prevalence of MRI-positive meniscal tears in asymptomatic population increases with age

▫ Internal rotation → lateral meniscus moves under femoral condyle ▫ Sensitivity (wide range), specificity (high–very high), ⊕ likelihood ratio (LR) (4.0), ⊝ LR (0.6) ▪ Apley grinding test: tests medial meniscus ▫ Individual lays in prone position → examiner flexes affected knee to 90° → rotates foot laterally → while stabilizing thigh/femur (with examiner’s knee), exerts downward force on tibia ▫ Pain: likely medial meniscal tear ▪ Thessaly test: tests medial, lateral meniscus ▫ Individual stands only on affected leg while holding onto examiner for stability → flexes knee to 20° → rotates knee, body externally/internally ▫ Pain/locking/clicking: positive test ▪ Childress duck-waddle test: tests posterior horn of medial/lateral meniscus ▫ Reserved for athletes fit to complete maneuver ▫ Individual squats, walks forward in squatting position → knees are flexed fully → waddling steps exert posterior pressure on knee ▫ Pain/clicking: positive test

OTHER DIAGNOSTICS Physical inspection ▪ Joint line tenderness (at tibial-femoral interface) because synovial capsule/ collateral ligament accompanies injury; less sensitive/specific finding ▪ Joint effusion likely present Physical examination maneuvers ▪ McMurray test: tests medial, lateral meniscus ▫ Individual is supine with affected knee fully flexed → examiner grasps heel with one hand, around tibial prominence with other hand → exerts rotational force while extending leg → evaluates pain/click/palpable crepitus ▫ External rotation → medial meniscus moves under femoral condyle

Figure 115.5 An arthroscopic view of a torn medial meniscus.

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TREATMENT SURGERY

▪ Arthroscopic/open surgery ▪ Meniscectomy/repair determined by amount of viable tissue intraoperatively, individual’s timetable to return to sport/ activity ▫ Meniscectomy: faster timetable to return to baseline activity; long-term ↑ osteoarthritis risk

OTHER INTERVENTIONS

▪ Rest: crutches for severe pain, avoidance of positions/activities that exacerbate pain ▪ If knee commonly gives out: patellar restraining brace; sign of poor quadriceps strength ▪ Physical therapy

Acute ▪ Rest, ice

PATELLAR TENDON RUPTURE osms.it/patellar-tendon-rupture PATHOLOGY & CAUSES ▪ Sudden, forced quadriceps contraction against flexed knee, fixed foot

CAUSES

▪ Most common in individuals < 40 years old involved in heavy training regimens/sport ▫ Landing from high jump, making sudden changes in direction at high speed ▪ Traumatic injury (non-athletic): foot/leg is stuck as individual falls backward ▫ Body weight falls backward → large eccentric force on fixed leg → force transmitted to patellar tendon → rupture ▫ Knee typically fully flexed when injury occurs → exposes tendon to most stress

RISK FACTORS

▪ Recent glucocorticoid injection ▪ Sports with explosive jumping: basketball, weightlifting ▪ Heavy training hours: > 20 per week ▪ Biologically-male individuals

COMPLICATIONS

▪ Tibial tuberosity avulsion fracture ▪ Patellar fracture/avulsion

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SIGNS & SYMPTOMS ▪ Painful, popping sensation ▪ Immediate swelling ▪ Antalgic gait: inability to bear weight on affected leg

DIAGNOSIS DIAGNOSTIC IMAGING Bedside Ultrasound ▪ Assists bedside diagnosis X-ray ▪ Evaluation of patellar positioning, potential fracture/avulsion complication MRI ▪ Reserved for unusual presentations: constitutional signs that raise suspicion of tumor

OTHER DIAGNOSTICS Physical inspection ▪ Observation: upward shift of patella (pathognomonic); swelling distal to patella ▪ Strength: inability to maintain straight leg, raise leg against gravity while supine

Chapter 115 Lower Limb Injury

TREATMENT SURGERY

▪ Recommended within one week of injury for improved outcomes

OTHER INTERVENTIONS

▪ Post-operative physical rehabilitation

Figure 115.6 An MRI scan of the knee in the sagittal plane demonstrating a patellar tendon rupture

PATELLOFEMORAL PAIN SYNDROME osms.it/patellofemoral-pain-syndrome PATHOLOGY & CAUSES ▪ Common overuse disorder ▪ Anterior knee pain that cannot be attributed to intra-articular (meniscus)/peripatellar (patellar tendinopathy) pathology

CAUSES

▪ Multifactorial pathophysiology

Intrinsic, anatomical factors ▪ Leg length discrepancy ▪ Abnormal foot morphology ▪ Hamstring inflexibility ▪ Abnormal patellar mobility ▪ Hallux valgus Extrinsic, athletic factors ▪ Exercise overload

RISK FACTORS

▪ Biologically-female individuals (2:1) ▪ Active individuals; teens–20s ▪ Amount of training (ex. distance run) correlates with incidence of disease

SIGNS & SYMPTOMS ▪ Anterior knee pain ▫ Worsened with training, knee extension, especially with squatting, running exercises ▫ May occur with prolonged sitting ▫ May be present for years ▪ Knee occasionally buckles/gives way ▪ Knee clicks/grinds: most evident when climbing stairs

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DIAGNOSIS

TREATMENT

OTHER DIAGNOSTICS

MEDICATIONS

Physical inspection ▪ History ▫ Absence of traumatic inciting event ▫ Achy/sharp knee pain: typically below patella ▪ Leg length discrepancy > 1cm/0.4in → poor biomechanics when running → predisposes individual to knee injury ▫ < 0.5cm/0.2in leg length discrepancy is common → no increased risk of injury

Acute ▪ NSAIDs (naproxen): short-term use (2–3 weeks) recommended

Physical examination maneuvers ▪ Palpation ▫ Nontender patella, patellar tendon, quadriceps tendon ▪ Tests ▫ Squatting: most individuals experience pain ▫ Patellar glide with extended knee: examiner moves patella laterally ▫ Lateral movement ↑ ¾ patellar width abnormal

OTHER INTERVENTIONS

▪ Lower extremity muscle strengthening ▪ Stretching: especially hamstrings ▪ Patellar bracing/taping

Acute ▪ Pain control: avoidance of painful exercise (stair/hill running); substitution of less stressful exercise (stationary bike exercises)

SPRAINED ANKLE osms.it/sprained-ankle

TYPES

Medial ankle sprain ▪ Infrequent injury ▪ Eversion of foot to medial deltoid ligament complex ▪ Ligament strong enough that medial malleolus fracture is more common than ligament sprain

Lateral ankle sprain ▪ Most common ▪ Inversion of plantar-flexed foot → stretches ankle’s lateral ligament complex ▪ Lateral ligament: anterior talofibular ligament (ATFL), calcaneofibular ligament, posterior talofibular ligament

Syndesmotic sprain ▪ AKA high ankle sprain ▪ Injury to interosseous membrane between tibia, fibula ▫ Foot is dorsiflexed/ankle eversion ▪ Higher rate of injury in contact sports (American football)

PATHOLOGY & CAUSES ▪ Common ankle injury from foot hypereversion/inversion

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Chapter 115 Lower Limb Injury

▪ Higher rate of chronic ankle sprains → recurrent ankle sprains → ossification of interosseous membrane

SIGNS & SYMPTOMS ▪ Pain over lateral/medial ankle (depending on eversion/inversion mechanism) ▪ Swelling hours after inciting event ▪ Inability to ambulate

DIAGNOSIS

▫ Anterior drawer test (ATFL integrity test): individual places affected foot in neutral position (slightly plantar-flexed, inverted) → examiner stabilizes lower leg with one hand → grasps heel with other while foot rests on examiner’s anterior arm → anterior pull of foot → ↑ laxity of joint (vs. unaffected foot) → likely lateral sprain, ATFL instability ▫ Talar tilt test (calcaneofibular integrity test): individual places affected foot in neutral position → examiner grasps foot → passive inverts at ankle → ↑ inversion of ankle (vs. unaffected side) → likely lateral sprain, calcaneofibular instability

DIAGNOSTIC IMAGING X-ray ▪ Evaluate for malleolar, distal fibular, talar dome fracture, syndesmotic separation complication

OTHER DIAGNOSTICS Physical inspection ▪ History ▫ Mechanism of foot inversion/eversion ▫ Prior ankle injuries ▫ Ability to walk after injury: correlates with fracture complication ▪ Observation: swelling/ecchymosis Physical examination maneuvers ▪ Palpation ▫ Fibula, distal tibia: syndesmotic injury ▫ Foot: lateral, medial surface for evaluation of medial, lateral ligament complex pain ▫ Thompson test: rule out achilles pathology ▪ Maneuvers of passive inversion/eversion (replicate pain) ▫ Squeeze test (syndesmotic evaluation): examiner compresses fibular against tibia at level of mid-calf → pain in region of ATFL → likely syndesmotic sprain ▫ External rotation stress test (syndesmotic evaluation): examiner stabilizes leg proximal to ankle → grasps plantar aspect of foot → externally rotated → pain in region of ATFL → likely syndesmotic sprain

TREATMENT MEDICATIONS Acute ▪ NSAIDs

SURGERY

▪ Reserved for ligament rupture in setting of chronic ankle instability

OTHER INTERVENTIONS

▪ Rehabilitation: physical therapy

Acute ▪ Rest: limit weight bearing, use crutches if individual is unable to bear weight ▪ Ice ▪ Early application of compressive wrapping → ↓ swelling ▪ Elevation of ankle → ↓ swelling

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UNHAPPY TRIAD osms.it/unhappy-triad PATHOLOGY & CAUSES ▪ Severe knee injury, typically after trauma, that results in trio of ACL, medial collateral ligament (MCL), lateral meniscus tears

CAUSES

▪ During contact sports, forceful blow to posterolateral aspect of knee, with planted foot (lower body tackle from behind in rugby/American football) ▪ Pathophysiology: posterior force tears ACL → abnormal ↑ anterior glide of tibia relative to femur → medial rotation of tibia → tear of MCL with shearing force → further knee instability → increased rotational force → lateral meniscal tear

COMPLICATIONS ▪ Osteoarthritis

Figure 115.7 An MRI scan of the knee in the coronal plane demonstrating a complete tear of the medial collateral ligament. Injury to the medial collateral ligament is one part of the unhappy triad

SIGNS & SYMPTOMS ▪ Pain ▪ Hemarthrosis ▪ Popping/multiple pops

DIAGNOSIS OTHER DIAGNOSTICS Physical examination maneuvers ▪ ACL maneuvers ▫ Anterior drawer test ▫ Lachman test ▪ MCL maneuvers ▫ Examiner stabilizes affected leg with one hand → exerts valgus stress on lateral aspect of knee → pain and ↑ laxity → likely MCL tear ▪ Lateral meniscus maneuvers ▫ McMurray testing

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TREATMENT MEDICATIONS Acute ▪ NSAIDs

SURGERY

▪ ACL repair: athletes/ individuals who desire return to play/demanding activity ▪ Lateral meniscus repair vs. meniscectomy

OTHER INTERVENTIONS Acute ▪ Rest ▪ Ice ▪ Elevation/compression → ↓ swelling ▪ Knee brace: ACL, MCL recovery; overall knee stability

NOTES

NOTES

MUSCLE TUMORS

RHABDOMYOSARCOMA (RMS) osms.it/rhabdomyosarcoma PATHOLOGY & CAUSES ▪ Highly malignant tumor arising from skeletal muscle cells

TYPES Alveolar Embrional ▪ Most common, frequently children ▫ Botryoid, spindle-cell rhabdomyosarcoma Pleomorphic (anaplastic) ▪ Worst outcome, frequently adults

Figure 116.1 The histological appearance of a rhabdomyosarcoma, alveolar subtype. The cells are small, with little cytoplasm with bland chromatin structures visible.

CAUSES

▪ Genetic translocation determining fusion of two genes which encode two transcription factors ▫ FOXO1, PAX3 ▪ FOXO1-PAX3 fusion protein interferes with differentiation-driven gene expression program → poorer outcome

RISK FACTORS

▪ Syndromes, congenital anomalies (e.g. Li–Fraumeni syndrome, neurofibromatosis type I, Beckwith–Wiedemann syndrome, Costello syndrome)

COMPLICATIONS

Figure 116.2 The histological appearance of a rhabdomyosarcoma, embryonal subtype. The tumor is composed of numerous round or spindled cells, either with minimal or abundant eosinophilic cytoplasm.

▪ Metastasis ▪ Bone marrow involvement: anemia, thrombocytopenia, neutropenia

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TREATMENT

SIGNS & SYMPTOMS ▪ Palpable mass ▫ Localization: head/neck, genitourinary tract, limbs, abdomen ▪ Depending on tumor size ▫ Hematuria, urinary obstruction (genitourinary tract involvement) ▫ Sinusitis, headache, cranial nerve alterations, ear discharge, orbital swelling (head involvement)

MEDICATIONS

▪ Polychemotherapy ▪ Immunotherapy

SURGERY ▪ Resection

OTHER INTERVENTIONS ▪ Radiation therapy

DIAGNOSIS DIAGNOSTIC IMAGING X-ray, CT scan, MRI, ultrasound ▪ Determines local invasion, metastasis

LAB RESULTS

▪ Liver, renal function tests ▪ Complete blood count ▫ Anemia, pancytopenia ▪ Biopsy ▫ Microscopic analysis ▫ Immunohistochemical studies showing muscle tissue-characteristic proteins ▫ Genetic sequencing

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Figure 116.3 The gross pathological appearance of a rahbdomyosarcoma, embryonal subtype. The tumor is poorly circumscribed with a firm texture and is cream to white in color.

NOTES

NOTES

MUSCULOSKELETAL CONGENITAL MALFORMATIONS

GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Soft tissue structure/bone growth/ development errors ▪ Present at birth (often) ▪ Isolated, or + associated anomalies

OTHER DIAGNOSTICS ▪ Clinical evaluation

TREATMENT SURGERY

▪ See individual disorders

SIGNS & SYMPTOMS ▪ Disease-dependent malformations

DIAGNOSIS

OTHER INTERVENTIONS

▪ May resolve with age ▪ Conservative treatment (e.g. occupational therapy, splinting)

DIAGNOSTIC IMAGING E.g. X-ray, CT scan

ARTHROGRYPOSIS osms.it/arthrogryposis PATHOLOGY & CAUSES ▪ Rare, non-progressive congenital disorder ▫ Multiple joint contractures ▫ AKA arthrogryposis multiplex congenita ▪ Decreased fetus movement in utero → fibrous connective, adipose tissue replaces muscle tissue → muscle shortening → joints fixed → affected joints unable to extend, flex ▪ Potential associated syndrome/disease (e.g. pulmonary hypoplasia, cryptorchidism, intestinal atresia, gastroschisis) ▪ Intelligence typically normal

TYPES Amyoplasia ▪ Most common type; sporadic cases ▪ Affects most joints ▪ Four limbs involved symmetrically Distal arthrogryposis ▪ Hands, feet (mainly) ▪ Potential specific gene defect association Syndromic ▪ Primary neurological/muscle disease association

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CAUSES

▪ Neurologic disorder (e.g. anterior horn disease) ▫ 70–80% of cases ▪ Crowding in utero ▫ Uterine malformation (e.g. intrauterine fibroids) ▫ Multiple gestation pregnancy ▪ Oligohydramnios ▫ Amniotic fluid volume low/abnormally distributed ▪ Maternal disorder (e.g. multiple sclerosis) ▪ Genetic disorder (e.g. spinal muscular atrophy type I) ▪ Muscle/connective tissue disorder (e.g. dystrophy, myopathy)

DIAGNOSIS ▪ Physical examination

DIAGNOSTIC IMAGING Ultrasound ▪ 50% of diagnoses prenatal ▫ Low mobility/abnormal fetus position MRI

LAB RESULTS

▪ Test for cause (e.g. chromosomal microarray analysis for chromosomal abnormalities, muscle biopsy for myopathic disorders)

COMPLICATIONS

▪ Can’t walk/delayed walking ▪ Psychosocial effects (e.g. shame, depression, social anxiety)

SIGNS & SYMPTOMS ▪ Congenital malformations present ▪ Typically affects all joints (potentially leg/ arm joints only) ▪ Affected joints contracted (flexion/ extension) ▪ Internal shoulder rotation ▪ Wrist, digit flexion ▪ Elbow, knee extension ▪ Hip dislocation ▪ Club feet ▪ Muscle weakness (especially amyoplasia)

Figure 117.1 Contractures in the hands of an individual with arthrogryposis.

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TREATMENT SURGERY

▪ E.g. wrist surgery

OTHER INTERVENTIONS

▪ No curative method ▫ Increase joint mobility, muscle strength, adaptive use pattern development ▪ Occupational therapy ▫ Joint manipulation, casting ▪ Limb movement-enhancing devices ▪ Splinting

Chapter 117 Musculoskeletal Congenital Malformations

CLUBFOOT osms.it/clubfoot PATHOLOGY & CAUSES ▪ Common congenital malformation; one/ both feet rotated ▫ AKA talipes equinovarus ▪ Talus malformation ▫ Feet, calf, peroneal muscles’ medial side developed abnormally ▪ Isolated or can be associated with developmental dysplasia of hip, Larsen syndrome (+ other hip, knee, elbow malformations), spina bifida, arthrogryposis

TYPES Congenital ▪ Affects bones, muscles, tendons, blood vessels

COMPLICATIONS

▪ Walking difficulty/inability ▪ Post-treatment recurrence ▪ Psychosocial effects

SIGNS & SYMPTOMS ▪ Bilateral (50% of cases) ▪ Three components ▫ Hindfoot equinus ▫ Midfoot varus ▫ Forefoot adduction ▪ Individuals walk on feet sides (typically) ▪ Affected foot potentially smaller

Syndromic ▪ Additional anatomic malformations and/or chromosomal/genetic abnormalities Positional ▪ Fetal position (e.g. breech presentation), often restrictive uterine environment (e.g. oligohydramnios)

CAUSES

▪ Idiopathic (most cases) ▪ Structural anomalies ▪ Chromosomal/genetic abnormalities

RISK FACTORS ▪ ▪ ▪ ▪ ▪ ▪ ▪ ▪

Biologically male (2:1 male:female) Early amniocentesis Genetic factors Family history Multiple gestation pregnancy Oligohydramnios Uterine abnormality Fetal neuromuscular disorders

Figure 117.2 A neonate with club feet.

DIAGNOSIS ▪ Clinical diagnosis at birth

DIAGNOSTIC IMAGING Ultrasound ▪ Prenatal ▫ Abnormal foot positioning

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LAB RESULTS

▪ Amniocentesis ▫ Karyotype detects chromosomal abnormality (e.g. aneuploidy)

OTHER INTERVENTIONS

▪ Conservative therapy ▫ Bracing, proper foot positioning, casting (Ponseti method)

TREATMENT SURGERY

▪ Sometimes required (e.g. Achilles tenotomy → release tightness)

CONGENITAL HIP DYSPLASIA osms.it/congenital-hip-dysplasia PATHOLOGY & CAUSES ▪ Congenital malformation; abnormal acetabulum, proximal femur development → hip joint mechanical instability ▫ AKA developmental hip dysplasia/ congenital hip dislocation ▫ Presents at birth/childhood ▪ Joint ligament laxity/abnormal utero positioning → abnormal development, contact between acetabulum, femoral head ▪ Possible conditions associated (e.g. Ehlers– Danlos, spina bifida)

TYPES Dislocation ▪ Femoral head completely outside acetabulum Subluxation ▪ Femoral head partially outside acetabulum Dislocatable ▪ Femoral head within acetabulum at rest, examination maneuvers dislocate easily (unstable hip joint) Subluxatable ▪ Femoral head loose within acetabulum, examination partially dislocates (mildly unstable hip joint)

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Reducible ▪ Femoral head outside acetabulum at rest, maneuvers can locate within acetabulum Dysplasia ▪ Abnormally-shaped hip joint (usually shallow acetabulum)

RISK FACTORS

▪ Breech presentation ▪ Other anomalies present (e.g. congenital torticollis, congenital foot malformation) ▪ Family history ▪ Swaddling practices ▪ Biologically female ▪ First-born infant ▪ Oligohydramnios ▪ Limited fetal mobility

COMPLICATIONS

▪ Affected leg shorter, painful hip joint ▪ Osteoarthritis ▪ Decreased motion range → restricted hip joint adduction, flexion ▪ Asymmetric gait ▪ Low back pain ▪ Femoral head necrosis ▪ Psychosocial effects

Chapter 117 Musculoskeletal Congenital Malformations

SIGNS & SYMPTOMS ▪ Severity-, age-dependent ▪ Usually unilateral, left hip ↑ affected (20% of cases bilateral) ▪ Hip instability ▫ Ortolani maneuver: infant supine, hips/ knees flexed 90o; hip abducted, pulled anteriorly → dislocated femoral head slides back into acetabulum → palpable/ audible clunk ▫ Barlow maneuver: infant supine, hips/ knees flexed 90o; hip abducted, pushed anteriorly → femoral head slides out of acetabulum → clunk ▪ Asymmetric thigh, groin skin creases ▪ Galeazzi sign ▫ Knee height difference when infant supine (hips flexed, knees bent, feet on examining table) posterior displacement in dysplastic hip → affected side’s knee lower ▪ Adductor spasm → limited hip abduction ▪ Pain (uncommon)

DIAGNOSIS ▪ Clinical evaluation

DIAGNOSTIC IMAGING Hip ultrasound, X-ray ▪ To detect abnormal acetabulum development, femoral head position

Figure 117.3 A plain radiograph of the pelvis of an infant with severe congenital hip dysplasia. There is complete dysplasia of both acetabula and superior dislocation of the femoral heads.

TREATMENT ▪ Early treatment critical ▫ Obtain, maintain concentric hip reduction

SURGERY

▪ Closed/open hip reduction

OTHER INTERVENTIONS

▪ Abduction splinting ▫ Device holds affected hip abducted, externally rotated (e.g. Pavlik harness)

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CRANIOSYNOSTOSIS osms.it/craniosynostosis PATHOLOGY & CAUSES

SIGNS & SYMPTOMS

▪ Premature calvarial suture closure → craniofacial malformation ▪ Abnormal dural attachments → tensile forces prevent bone growth → early suture fusion ▪ Abnormal skull growth ▫ ↓ in perpendicular direction to fused suture ▫ ↑ in parallel direction to accommodate brain growth ▪ Most cases isolated, sporadic; possibly genetic syndrome (e.g. Apert syndrome, Crouzon syndrome)

▪ Phenotypes: variable head shape, facial features (suture-dependent) ▫ Sagittal suture fused → narrow, long skull (scaphocephaly/dolichocephaly) ▫ Coronal/lambdoid sutures fused → diagonal skull malformation, asymmetric orbits (plagiocephaly) ▫ Metopic suture fused → narrow, triangle-shaped forehead + prominent midline ridge (trigonocephaly) ▫ Multiple sutures fused → Kleeblattschädel anomaly/microcephaly ▫ Coronal sutures fused bilaterally → short, broad skull (brachycephaly) ▫ Coronal suture fuses + any other suture → oxycephaly

TYPES

▪ Classified by affected suture ▫ Sagittal (most common) ▫ Coronal ▫ Metopic ▫ Lambdoid ▫ Multiple sutures

RISK FACTORS

▪ Multiple pregnancies ▪ Uterine abnormalities

COMPLICATIONS

▪ ↑ intracranial pressure ▫ Vomiting, papilledema, headache ▪ ↓ brain growth ▪ Vision, hearing, speech, feeding impairments ▪ Neurodevelopmental delay ▪ Obstructive sleep apnea ▪ Abnormal head shape → psychosocial effects Figure 117.4 Facial features of an child with craniosynostosis in Apert syndrome.

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Chapter 117 Musculoskeletal Congenital Malformations

DIAGNOSIS ▪ Physical examination

DIAGNOSTIC IMAGING X-ray, CT scan ▪ Identify fusion, malformation extent

LAB RESULTS

▪ Cephalometry → precisely measure head dimensions ▪ Genetic testing → identify mutations ▪ Funduscopy → detect papilledema

Figure 117.5 Syndactyly seen in an individual with Apert syndrome, which also causes craniosynostosis.

TREATMENT SURGERY

▪ Reconstruct craniofacial structure

FLAT FEET osms.it/flat-feet PATHOLOGY & CAUSES ▪ Common malformation; moderate/complete foot arch flattening ▫ AKA pes planus/fallen arches ▫ Congenital/adult-acquired ▪ Children: abnormal foot muscle, tendon, bone development ▪ Adults: ↑ activity of proteolytic enzymes → break down muscle tendons → foot arch falls

TYPES Rigid pes planus ▪ ↓ tarsal and subtalar joint range of motion + arch does not increase with toe raising

Flexible pes planus ▪ Physiologic or pathologic causes related to associated conditions (e.g. ligamentous laxity, foot muscle motor weakness, bony abnormalities, generalized syndromes) ▪ Type I ▫ Most common type ▫ Calcaneovalgus heel (depressed longitudinal arch that is associated with varying amounts of heel eversion) ▫ Functional flat foot ▪ Type II ▫ Hypermobile flat foot ▫ Lax ligamentous and tight heel cords ▪ Type III ▫ Clinical pes planus ▫ Involves tibialis posterior tendon dysfunction ▫ Often seen in dancers, ice skaters, athletes (e.g. basketball, tennis, soccer, ice hockey)

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RISK FACTORS

▪ Loose connective tissue (e.g. Ehlers–Danlos syndrome) ▪ Neuromuscular conditions (e.g. cerebral palsy) ▪ Tarsal coalition (abnormal tarsal bone connection) ▪ Peroneal spasticity ▪ ↑ physical activity ▪ ↑ stress to foot ▪ Injury ▪ Increasing age (relatively common in biologically-female individuals > 40 years old) ▪ Obesity ▪ Rheumatoid arthritis ▪ Pregnancy (↑ elastin)

COMPLICATIONS ▪ ▪ ▪ ▪

Knee, hip, back pain Progress to high arches (adolescence) Abnormal gait → injuries Tendonitis

SIGNS & SYMPTOMS ▪ Normal foot arch absent (flat) ▪ Foot sole presses ground almost completely ▪ Abnormal gait ▫ ↑ inward foot roll (overpronation) ▪ May involve foot, ankle, knee, hip, back pain

DIAGNOSIS ▪ Clinical evaluation ▪ Wet footprint test ▫ Individual wets feet, stands on paper → footprint with ↑ surface area

DIAGNOSTIC IMAGING Feet X-ray ▪ Talonavicular coverage angle → abnormal lateral rotation ▪ ↓ calcaneus, inferior foot angle (calcaneal pitch) ▪ ↑ long talus axis, first metatarsal bone angle (Meary’s angle) ▪ The anteater nose sign ▫ Anterior tubular elongation of the superior calcaneus; approaches/ overlaps the navicular indicated calcaneonavicular coalition

TREATMENT ▪ Sometimes unnecessary (arch may develop)

SURGERY

▪ Resection of abnormal bridge of bony, cartilaginous, or fibrous tissue (e.g. calcaneonavicular coalition)

OTHER INTERVENTIONS

▪ Conservative treatment ▫ Supportive shoes ▫ Orthotics (insoles stop inward roll) ▫ Casting ▫ Analgesics (e.g. NSAIDs) ▫ Physical therapy

Figure 117.6 Complete collapse of the longitudinal arch has resulted in complete contact of the sole of the foot with the ground.

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Chapter 117 Musculoskeletal Congenital Malformations

GENU VALGUM osms.it/genu-valgum PATHOLOGY & CAUSES ▪ Knee malformation: knees bend towards each other ▫ Typically resolves by age nine ▫ AKA “knock-knees” ▫ Less common than genu varum

CAUSES ▪ ▪ ▪ ▪ ▪ ▪ ▪ ▪ ▪

Physiologic (age 2–5) Poor nutrition Obesity Lower extremity fracture Calcium deficiency Vitamin D deficiency Skeletal dysplasia Neoplasm Idiopathic

COMPLICATIONS ▪ ▪ ▪ ▪

Knee osteoarthritis Injuries Knee chondromalacia Psychosocial effects

SIGNS & SYMPTOMS ▪ Knee malformation ▫ Knee joint’s proximal portion bends inwards ▫ Knee joint’s distal portion bends outwards ▪ Can’t touch knees, feet together ▪ Gait abnormalities ▪ Pain (uncommon)

Figure 117.7 An individual with genu valgum of the left leg secondary to surgery and radiotherapy to treat a synovial sarcoma of the lateral distal femoral epiphysis as a child. The medial epiphysis continued to grow whilst growth of the lateral epiphysis was stunted.

DIAGNOSIS ▪ Clinical evaluation

DIAGNOSTIC IMAGING X-ray ▪ Both legs (hips to feet) in standing position

OSMOSIS.ORG 687

TREATMENT ▪ Treatment of underlying causes (e.g. vitamin D deficiency)

SURGERY

▪ If malformation persists after age 10 ▫ Medial distal femoral epiphysis stapling ▫ Total knee replacement

OTHER INTERVENTIONS ▪ Orthotic devices ▪ Bracing

Figure 117.8 An X-ray image of the affected knee. The medial head is much larger than the lateral head.

GENU VARUM osms.it/genu-varum PATHOLOGY & CAUSES ▪ Most common knee malformation: knees bow ▫ AKA bow-legs

CAUSES

Physiologic (birth to 18 months) Vitamin D deficiency (e.g. rickets) Poor nutrition Other musculoskeletal conditions (e.g. skeletal dysplasia) ▪ Infection/tumors/lower extremity fracture → abnormal leg growth ▪ Blount disease ▪ ▪ ▪ ▪

COMPLICATIONS

▪ Knee osteoarthritis

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▪ Psychosocial effects

SIGNS & SYMPTOMS ▪ Knee malformation ▫ Knee’s distal portion bends inwards ▫ Proximal portion bends outwards (like archer’s bow) ▪ Usually bilateral

DIAGNOSIS ▪ Clinical evaluation

DIAGNOSTIC IMAGING X-ray ▪ Both legs (hips to feet) in standing position

Chapter 117 Musculoskeletal Congenital Malformations

TREATMENT ▪ Treatment of underlying causes (e.g. vitamin D deficiency)

SURGERY

▪ If malformation persists

OTHER INTERVENTIONS ▪ Splinting ▪ Bracing

Figure 117.9 An X-ray image of a child with rickets displaying genu varum.

PECTUS EXCAVATUM osms.it/pectus-excavatum PATHOLOGY & CAUSES ▪ Congenital thoracic wall malformation: chest appears caved-in ▫ Most common anterior chest wall disorder ▫ AKA funnel chest ▪ Abnormal sternum, rib cage growth ▪ Unknown cause ▫ Possibly: increased intrauterine pressure, increased sternum traction, abnormal cartilage development ▪ Usually sporadic

RISK FACTORS

▪ Biologically male (3–5:1 male:female) ▪ Family history ▪ Connective tissue disorders (e.g. Marfan syndrome, Ehlers–Danlos) ▪ Neuromuscular diseases ▪ Genetic conditions (e.g. Noonan syndrome) ▪ Rickets ▪ Congenital diaphragmatic hernia

COMPLICATIONS

▪ Cardiorespiratory function impairments ▪ Psychosocial effects

OSMOSIS.ORG 689

LAB RESULTS

▪ Pulmonary function tests ▫ Normal forced vital capacity ▫ Total lung capacity, residual volume may be abnormal

OTHER DIAGNOSTICS

▪ Cardiology exams (e.g. electrocardiogram, echocardiography) ▫ Abnormalities if heart compression, rotation ▪ Exercise testing ▫ Impairment severity correlates with defect’s degree

Figure 117.10 An individual with pectus excavatum.

SIGNS & SYMPTOMS ▪ Physical ▫ Chest malformation: sternum’s lower end depressed, lower ribs may protrude, narrowed chest wall diameter ▫ Displaced heartbeat ▫ Heart murmurs ▫ Diminished lung sounds ▫ Exercise intolerance ▪ Potential chest/back pain ▪ Respiratory symptoms ▫ Shortness of breath, tachypnea

DIAGNOSIS ▪ Clinical evaluation

DIAGNOSTIC IMAGING Chest CT scan ▪ Determine severity; assess lung, heart effects

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Figure 117.11 A CT scan of the chest in the axial plane demonstrating pectus excavatum.

TREATMENT ▪ Some cases resolve spontaneously (usually worsens in adolescence)

SURGERY

▪ Moderate/severe pectus excavatum

Chapter 117 Musculoskeletal Congenital Malformations

PIGEON TOE osms.it/pigeon-toe PATHOLOGY & CAUSES ▪ Common developmental variation: toe inward rotation ▫ AKA in-toeing ▪ Typically resolves spontaneously ▪ Results from intrauterine molding

CAUSES

▪ Metatarsus adductus (most common in infants < one year old) ▪ Internal tibial rotation (most common between age 1–4) ▪ Increased femoral anteversion (most common in children > three years old)

DIAGNOSIS ▪ Clinical evaluation

DIAGNOSTIC IMAGING X-ray ▪ Assess severity

TREATMENT TREATMENT

▪ Observation ▪ Surgery rarely recommended

COMPLICATIONS

▪ Long-term functional problems (rare)

SIGNS & SYMPTOMS ▪ Abnormal toe rotation when walking/ standing ▫ Metatarsus adductus: inward forefoot rotation ▫ Tibial torsion: inward shin bone twisting ▫ Femoral anteversion: inward femur twisting ▪ Non-flexible/flexible (if malformation can be hand-straightened)

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NOTES

NOTES

SKELETAL DYSPLASIA GENERALLY, WHAT IS IT? PATHOLOGY & CAUSES ▪ Disorders affecting bone development

CAUSES

▪ Inherited/sporadic (de novo) genetic mutation

COMPLICATIONS

▪ Caused by bone malformations, depend upon affected bones

SIGNS & SYMPTOMS ▪ Commonly involve growth impairment, bone malformation

DIAGNOSIS DIAGNOSTIC IMAGING X-ray/CT scan/MRI ▪ Bone malformation, impaired ossification visualization ▪ Bone-age estimation Ultrasound ▪ Prenatal diagnosis

TREATMENT SURGERY

▪ Bone malformation correction if warranted/ desired

ACHONDROPLASIA osms.it/achondroplasia PATHOLOGY & CAUSES ▪ Genetic disorder, causes dwarfism with disproportionate short stature ▪ Relatively normal-sized torso, short limbs, normal–large head (macrocephaly) with prominent forehead (hence “disproportionate dwarfism”) ▪ Average height ▫ Biologically-male: 131cm/4’4’’ ▫ Biologically-female: 123 cm/4’

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CAUSES

▪ Heterozygous “gain-of-function” mutation in fibroblast growth factor receptor 3 (FGFR3) gene on chromosome 4; individuals with homozygous mutation usually do not survive ▫ Mutated receptor displays “constitutive activity” (activated in ligand binding absence) → inhibits chondrocyte proliferation ▫ Endochondral ossification affected → inhibits long bone elongation (e.g. humerus, femur)

Chapter 118 Skeletal Dysplasia ▫ Intramembranous ossification less affected → relatively normal flat bone growth (e.g. skull, ribs) ▪ Autosomal dominant inheritance pattern (20%); sporadic mutation in most cases (80%)

COMPLICATIONS

▪ Eustachian tube narrowing → recurrent middle ear infection ▪ Narrowing of ▫ Lumbar spinal canal → spinal stenosis ▫ Foramen magnum → cervical medullary compression ▪ Venous obstruction at sigmoid sinus → hydrocephalus ▪ Midface retrusion → obstructive sleep apnea ▪ Obesity

▪ Small flat squared iliac wings (“mickey mouse ear”) ▪ Fibular overgrowth ▪ Metaphyseal flaring: diaphysis narrowing, metaphysis widening

LAB RESULTS

▪ DNA test ▫ FGFR3 mutation-positive

TREATMENT SURGERY

▪ Bone malformation correction warranted/ desired

SIGNS & SYMPTOMS ▪ Long bone malformations ▫ Rhizomelic (proximal) limb shortening ▫ Varus/valgus leg malformations ▫ Short metacarpals ▫ Short phalanges (brachydactyly) ▫ Trident hand (fingertips cannot touch) ▪ Flat bone malformations (less common) ▫ Enlarged head ▫ Frontal bossing (prominent forehead) ▫ Flattened nasal bridge (saddle nose malformation) ▫ Narrow foramen magnum ▫ Spinal kyphosis/lordosis

DIAGNOSIS DIAGNOSTIC IMAGING Prenatal ultrasound ▪ Skull width to femur length ratio higher than normal

Figure 118.1 An X-ray image of the knee of an individual with achondroplasia. There is flaring of the distal femoral metaphysis typical of the disease.

X-ray/MRI/CT scan ▪ Large skull with small skull base ▪ Narrow foramen magnum, spinal canal ▪ Short, flattened vertebral bodies

OSMOSIS.ORG 693

CLEIDOCRANIAL DYSPLASIA osms.it/cleidocranial-dysplasia PATHOLOGY & CAUSES ▪ AKA cleidocranial dysostosis ▪ Skeletal dysplasia ▫ Predominantly affects intramembranous ossification-derived bone development ▫ Clavicles (cleido-), skull bones (-cranial) ▪ Abnormal teeth development, delayed cranial fontanelle closure, clavicle underdevelopment/absence, distinctive craniofacial features

CAUSES

▪ Heterozygous runt-related transcription factor 2 (RUNX2) gene mutation (transcription factor involved in osteoblast, chondrocytes differentiation → delayed ossification; 30% of cases are idiopathic) ▪ Autosomal dominant inheritance pattern, can be sporadic

COMPLICATIONS

▪ Osteoporosis (adults)

SIGNS & SYMPTOMS ▪ Dental abnormalities ▫ Supernumerary teeth (up to 13), delayed/failed permanent teeth eruption, abnormal deciduous dentition ▪ Delayed cranial fontanelle closure → soft skull areas ▪ Short stature ▪ Hypoplastic/aplastic clavicles → shoulder hypermobility ▪ Maxilla, mandibular prognathism hypoplasia ▪ Midface hypoplasia, flattened nasal bridge ▪ Frontal/parietal bossing ▪ Abnormal ear ossicles → hearing loss

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Figure 118.2 Retained deciduous teeth in the mouth of an individual with cleidocranial dysplasia.

DIAGNOSIS DIAGNOSTIC IMAGING X-ray ▪ Hypoplastic/aplastic clavicles ▪ Widened fontanelles ▪ Wormian bones (multiple small bones between sutures) ▪ Frontal/parietal bossing ▪ Supernumerary teeth ▪ Supernumerary ribs ▪ Iliac bone hypoplasia ▪ Symphysis pubis widening (diastasis) ▪ Small, highly positioned scapulas

LAB RESULTS

▪ Genetic testing (confirmation)

TREATMENT SURGERY

▪ Bone malformation correction if warranted/ desired

Chapter 118 Skeletal Dysplasia

Figure 118.3 A chest radiograph of a neonate with absent clavicles, consistent with a diagnosis of cleidocranial dysplasia. Figure 118.4 An X-ray image of the skull of a child with cleidocranial dysplasia. There is bitemporal bossing and a widened frontal fontanelle. The posterior lambdoid suture (not visible) contains multiple wormian bones.

OSMOSIS.ORG 695

NOTES

NOTES

SPINAL DISORDERS GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Disorders affecting spinal column ▫ Includes vertebrae, intervertebral discs, surrounding structures

RISK FACTORS

▪ Obesity, extreme exercise/any factor that ↑ spinal column pressure

COMPLICATIONS

DIAGNOSIS DIAGNOSTIC IMAGING MRI ▪ Detects soft tissue involvement ▫ Intervertebral discs, ligaments, nerves X-ray ▪ May show osteoarthritis signs ▫ Joint pain narrowing, bony spurs

▪ Nerve compression, arthritis, progressive degenerative disease

SIGNS & SYMPTOMS ▪ Localized pain, stiffness, limited range of motion ▪ Spine shape irregularities ▪ Compression → pulmonary, cardiac, gastrointestinal disorders ▪ Neurologic signs ▫ Numbness, paresthesia, weakness, tingling (if nerves affected)

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TREATMENT SURGERY

▪ If cause irreversible, condition advanced

OTHER INTERVENTIONS

▪ Malformation ▫ Bracing ▪ Physical rehabilitation, analgesia

Chapter 119 Spinal Disorders

DEGENERATIVE DISC DISEASE osms.it/degenerative-disc-disease PATHOLOGY & CAUSES ▪ Progressive intervertebral disc breakdown ▪ Most common back-pain source ▪ Accrual of factors → intervertebral disc’s nucleus pulposus (mostly water) dehydration → ↓ proteoglycan, collagen → ↓ padding between vertebrae → unable to absorb shock → disc collapse → annular tears, herniation of disc contents into spinal canal → nerve root irritation → nerve impingement → pain

DIAGNOSIS DIAGNOSTIC IMAGING MRI ▪ Evaluates spinal canal, visualizes space available for neural structures ▪ ↑ signal on T2-weighted images indicate disc dehydration ▪ Detects annular tears X-ray ▪ Detects fracture

CAUSES

▪ Multifactorial ▫ Accumulation of natural stress, minor injury throughout life ▫ Genetic predisposition

RISK FACTORS

▪ Genetic predisposition, advanced age, menopause, repeated spinal trauma

COMPLICATIONS

▪ Spine collapse, disc herniation, compression fracture, bony spur growth, neurologic deficit, myelopathy, vertebral artery compression

SIGNS & SYMPTOMS ▪ Back pain (not correlating to damage’s extent), ↓ range of motion ▪ Pain may radiate ▪ Tingling, paresthesia, numbness ▪ Muscle weakness/atrophy ▪ ↓ deep tendon reflexes ▪ Headache, dizziness, vertigo

Figure 119.1 An MRI scan of the spine.

TREATMENT MEDICATIONS

▪ Pain management ▫ Non steroidal anti-inflammatory drugs (NSAIDs), local/epidural corticosteroids

OSMOSIS.ORG 697

SURGERY

▪ Corpectomy ▫ Vertebral portion removal → enlarge intervertebral space ▪ Discectomy ▫ Herniated disc portion removed ▪ Nerve root injection

▪ Intervertebral disc arthroplasty ▫ Degenerated discs replaced with artificial discs ▪ Laminotomy ▫ Lamina removal → relieve nerve root pressure

KYPHOSIS osms.it/kyphosis PATHOLOGY & CAUSES ▪ Exaggerated cervical, thoracic, sacral spinal convex curvature ▪ Greek κυφός kyphos, meaning “hump” ▪ Cobb angle: used to measure extent of curvature ▫ Angle > 45° classified as kyphosis ▪ Damage to vertebrae, intervertebral discs/ supporting ligaments/muscles → weightbearing forces asymmetry → further damage to high-pressure area structures → “wedge-shaped” vertebra → spinal curving

TYPES

▪ May also be caused by trauma/iatrogenic causes (surgery)

Postural ▪ Most common, occurs all ages Structural ▪ Osteoporosis, tumors, tuberculosis (Gibbus malformation), ankylosing spondylitis, fractures, arthritis Congenital ▪ Vertebral malformation/in utero fusion Scheuermann’s kyphosis ▪ Adolescent onset, type of osteochondrosis (disordered cartilage ossification) ▪ Vertebral disc intrudes into end plates in anterior ossification areas (Schmorl’s nodes on X-ray)

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RISK FACTORS

▪ Poor posture, weak back muscles, older age, vertebral fracture, osteoporosis, degenerative disc disease, arthritis ▪ Genetic disease affecting bone, ligaments ▫ Osteogenesis imperfecta, Marfan syndrome, Ehler–Danlos syndrome, mucopolysaccharidosis, glycogen storage disease

COMPLICATIONS

Sternal/vertebral fracture Cardiac disease Imbalance → fall, fracture risk Neurologic ▫ Nerve compressions ▪ Respiratory ▫ ↓ pulmonary function ▪ Gastrointestinal dysfunction ▫ Dysphagia, reflux, hernias

▪ ▪ ▪ ▪

SIGNS & SYMPTOMS ▪ Anterior thoracic pain, dyspnea, limited mobility ▪ Convex spinal curvature ▪ Dysphagia, reflux

DIAGNOSIS ▪ Clinical diagnosis ▫ Curvature measurement using flexicurve ruler

Chapter 119 Spinal Disorders

DIAGNOSTIC IMAGING X-ray ▪ Sagittal plane: > 45° Cobb angle ▫ Lines drawn above first, last deviating vertebra → draw perpendicular lines to those → angle where they close is Cobb angle

TREATMENT SURGERY

▪ Reserved for significant pulmonary/ neurologic impairment cases

OTHER INTERVENTIONS

▪ Milwaukee brace ▫ Improves proprioception, helps support back muscles ▪ Physical therapy strengthens back muscles ▪ Pain management Figure 119.2 A lateral X-ray image of the spine demonstrating marked thoracic kyphosis secondary to Scheuermann’s disease.

LORDOSIS osms.it/lordosis PATHOLOGY & CAUSES ▪ Exaggerated inward curvature of lumbar, cervical spine ▪ Greek lordōsis, from lordos, meaning “bent backward” ▪ Bone/neuromuscular imbalance → weightbearing force asymmetry → further damage to high-pressure area structures/ compensatory muscle spasms → spinal curving

CAUSES

▪ High spine flexibility, lower limb imbalance ▪ Hip imbalance; improper lifting, squatting

▪ Muscle strength imbalance (e.g. weak hamstrings; tight hip flexors) ▪ Obesity ▪ Osteoporosis ▪ Spondylolisthesis, discitis ▪ Temporary lordosis during pregnancy

RISK FACTORS

▪ Poor posture, muscle strength imbalance ▪ Musculoskeletal ▫ Osteoporosis, spondylolisthesis ▪ Genetic ▫ Achondroplasia, Ehler–Danlos syndrome

OSMOSIS.ORG 699

COMPLICATIONS

▪ Degenerative disc disease, nerve compression

SIGNS & SYMPTOMS ▪ Lower-back pain ▪ Apparent ↑ lower-back curvature

DIAGNOSIS ▪ Physical examination reveals ↑ degree of lower-back curvature, muscle tightness

DIAGNOSTIC IMAGING MRI ▪ Detects nerve compression X-ray ▪ Confirms curvature degree ▪ Lamina, neural arch of vertebrae may form divert ‘V’ on anteroposterior lumbar spine radiograph

TREATMENT OTHER INTERVENTIONS

▪ Boston brace ▫ ↓ disc stress, muscle strengthening ▪ Physical therapy to strengthen, balance back muscles ▪ Pain management

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Figure 119.3 A lateral X-ray image of the spine in an individual with hyperlordosis of the lumbar spine.

Chapter 119 Spinal Disorders

SCOLIOSIS osms.it/scoliosis PATHOLOGY & CAUSES ▪ Lateral spinal curvature in coronal plane, commonly coexists with rotational curvature ▪ Bone/neuromuscular imbalance in vertebral/ paravertebral area → weight-bearing force asymmetry → further damage to highpressure area structures → spinal curving ▪ Sometimes associated with kyphosis, lordosis Classification according to etiology ▪ Structural (intrinsic) ▪ Postural (compensatory)

▪ Bone tumors, neuromuscular/neural disorders (e.g. Duchenne muscular dystrophy) ▪ Advanced bone maturity at presentation, biologically-female individuals ▫ More severe progression

COMPLICATIONS

▪ Chest wall abnormalities → respiratory compromise, cardiac complications ▪ Low self-esteem, depression ▪ Spinal nerve damage, hemiplegia

Classification according to shape ▪ C/S shaped ▪ Direction ▫ Projection of curvature apex defined with segment involved (most common right-thoracic with left-lumbar presentation)

CAUSES

▪ Congenital ▪ Idiopathic ▫ Most common; infantile, juvenile, adolescent/early–late onset ▫ Multifactorial (environmental, genetic factors) ▪ Secondary ▫ Osteopathic (Marfan syndrome), neuromuscular, neuropathic (neural palsy), myopathic, neurofibromatosis

RISK FACTORS

▪ Family history ▪ Obesity ▪ Lower limb fracture → limb length difference → compensatory scoliosis ▪ Sudden growth

Figure 119.4 An individual with thoracic and lumbar scoliosis. The uneven position of the scapulae is clearly visible.

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SIGNS & SYMPTOMS ▪ Visible spinal curvature, fanning of ribs on one side, uneven musculature ▪ Back pain ▪ Difficulty breathing ▪ Intestinal compression → gastrointestinal difficulty

DIAGNOSIS DIAGNOSTIC IMAGING X-ray ▪ Cobb angle ▫ Lines drawn above first, last deviating vertebra → draw perpendicular lines to those → Cobb angle > 10°

OTHER DIAGNOSTICS Physical examination ▪ Adams Forward Bend Test ▫ Shows torsion, shoulder, pelvis misalignment, unparallel scapulae

TREATMENT SURGERY

▪ Cobb angle > 45° ▫ Vertebral fusion surgery

OTHER INTERVENTIONS

▪ Cobb angle < 30° ▫ Watchful waiting (frequent check ups estimating curve angle, physical therapy) ▪ Cobb angle > 30° ▫ Boston brace

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Figure 119.5 A plain chest radiograph demonstrating spinal scoliosis.

Chapter 119 Spinal Disorders

SPINAL DISC HERNIATION osms.it/spinal-disc-herniation PATHOLOGY & CAUSES ▪ Middle portion of intervertebral disc (anulus pulposus) herniates through tear in outer portion (anulus fibrosus) of disc ▫ AKA slipped disc ▪ Weakening of intervertebral disc’s outer circle → outer ring tear → inner ring bulging out of spinal column → local nerve compression ▪ Disc protrusion ▫ Outer ring intact but middle portion of disc bulges ▫ May → herniation

RISK FACTORS

▪ Obesity, advanced age, heavy lifting, degenerative disc disease, trauma

DIAGNOSIS DIAGNOSTIC IMAGING MRI ▪ Confirm diagnosis

OTHER DIAGNOSTICS History ▪ History of heavy lifting, bone degenerative disease Clinical exam ▪ Straight leg raise test ▫ Individual lies supine, clinician passively raises leg → pain indicates disc herniation

COMPLICATIONS

▪ Nerve impingement ▪ Sciatica ▪ Cauda equina syndrome (compression of nerve roots controlling bowel, bladder, legs)

SIGNS & SYMPTOMS ▪ Continuous pain in certain position, level dependent on injury extent, often unilateral (may present bilaterally) ▪ Sciatica ▫ Lumbar/sacral nerve root compression → pain radiating down legs ▪ Other symptoms ▫ Sensory: numbness, paresthesia ▫ Motor: chronic atrophy, weakness

Figure 119.6 An MRI scan of the spine in the sagittal plane demonstrating protrusion of the L4/L5 and L5/S1 intervetebral discs.

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TREATMENT MEDICATIONS

▪ Pain, inflammation control ▫ NSAIDs, local corticosteroids

SURGERY

▪ Repair ▫ In neurologic signs, nerve compression cases

OTHER INTERVENTIONS

▪ Physical rehabilitation, weight loss

SPINAL STENOSIS osms.it/spinal-stenosis PATHOLOGY & CAUSES ▪ Common chronic condition characterized by narrowing of spinal canal/intervertebral foramina ▫ More common in cervical, lumbar regions

CAUSES

▪ Aging ▫ Bone spurs grow into canal, ligaments thicken, slipped discs ▪ Skeletal disease (e.g. rheumatoid arthritis, osteoarthritis, Paget disease, ankylosing spondylitis, spondylosis, degenerative disc disease) ▪ Congenital (e.g. achondroplasia, spinal dysraphism) ▪ Other causes ▫ Trauma, fracture, neoplasm, idiopathic

RISK FACTORS

▪ Obesity, advanced age, family history

COMPLICATIONS

▪ Cauda equina syndrome

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▫ Bilateral leg weakness, urinary incontinence ▫ Spinal cord narrowing → nerve root compression (L3–S4) → bowel incontinence/sexual dysfunction ▫ Neurologic emergency (requires immediate surgical decompression)

SIGNS & SYMPTOMS ▪ Canal diameter < 10mm ▪ Neurogenic claudication ▫ Discomfort, sensory loss/leg weakness (buttocks, calves) ▫ Symptomatic when active (e.g. walking, standing); with lumbar extension ▫ Relieved by rest, lying down, waist flexion (squatting, leaning forward) ▫ Back pain may coexist ▪ Radicular pain ▫ Pain radiates along dermatome ▪ Neurologic symptoms ▫ Typically bilateral if nerve compression is involved ▫ Numbness, weakness, paresthesia, limb pain, urinary/bowel incontinence, sexual dysfunction

Chapter 119 Spinal Disorders

DIAGNOSIS DIAGNOSTIC IMAGING CT myelogram ▪ Shows detailed spinal canal contours (if MRI contraindicated) MRI ▪ Spinal canal narrowing, nerve compression

TREATMENT MEDICATIONS

▪ Pain medications (NSAIDs), epidural steroid injections

SURGERY

▪ Decompression (advanced disease, complications)

Figure 119.7 An MRI scan of the cervical spine demonstrating spinal stenosis from C3 to C6 resulting in cord compression.

OTHER INTERVENTIONS

▪ Physical therapy, weight loss

SPONDYLITIS osms.it/spondylitis PATHOLOGY & CAUSES ▪ Chronic vertebrae, vertebral joint inflammation ▪ AKA spondyloarthritis ▪ Autoimmune/infectious agent attacks vertebra → inflammatory cells invade site → inflammation, damage to bone, cartilage; thick paravertebral ossification formation ▪ Spondylodiscitis ▫ Vertebrae, intervertebral disc inflammation

CAUSES

▪ Infectious ▪ E.g. Pott’s disease (osteoarticular tuberculosis); Staphylococcus aureus

▪ Autoimmune ▪ Ankylosing spondylitis, rheumatoid arthritis

RISK FACTORS

▪ Family history ▪ Immunocompromised state ▪ Spinal surgery/invasive intervention history

COMPLICATIONS ▪ ▪ ▪ ▪

Osteoporosis, osteopenia Fractures Neurologic Spinal cord compression, cauda equina syndrome

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SIGNS & SYMPTOMS ▪ Localized pain ▫ Segment-dependent ▪ Gradual symptom onset ▫ Autoimmune disease ▪ Limited movement ▪ Spinal stiffness ▪ Symptoms worse in morning, improve with exercise

DIAGNOSIS DIAGNOSTIC IMAGING MRI ▪ Shows calcifications in column; may reveal erosive disease X-ray ▪ Asymmetric parasyndesmophytes visualization (paravertebral soft-tissue calcifications)

OTHER DIAGNOSTICS

▪ History of joint pain ▪ Positive autoimmune disease/exposure history

TREATMENT MEDICATIONS

▪ Infectious cause ▫ Antibiotics ▪ Autoimmune disease ▫ Disease modifying rheumatoid medications (sulfasalazine, local corticosteroids) ▪ Pain management (NSAIDS, opioids); severity-dependent

SURGERY

▪ Severe cases

OTHER INTERVENTIONS

▪ Physical therapy to strengthen back muscles

LAB RESULTS

▪ Blood tests ▫ Infectious cause ▪ Genetic testing ▫ Autoimmune cause

SPONDYLOLISTHESIS osms.it/spondylolisthesis PATHOLOGY & CAUSES ▪ Spontaneous anterior/posterior vertebral body slippage over one below it ▫ Most commonly affects lumbosacral articulation ▪ Vertebral joint dysfunction → joint instability → vertebral body slipping from original position

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CAUSES

▪ Lytic/isthmic ▫ Most common ▫ Multiple pars interarticularis microfractures; usually affects athletes ▪ Degenerative ▫ Pseudospondylolisthesis, arthritis, osteoporosis ▪ Dysplastic ▫ Congenital posterior spinal dysplasia elements; usually presents with adolescent growth spurt

Chapter 119 Spinal Disorders ▪ Pathologic ▫ Vertebral lesions; neoplastic/infectious infiltration ▪ Traumatic ▫ Facet(s)/pars interarticularis fracture; post-surgical complication

RISK FACTORS

Genetic predisposition Competitive sports (dancing, gymnastics) Extreme growth spurt, muscle weakness Spinal malformation (Scheuermann’s kyphosis) ▪ Biologically-female individuals ▪ ▪ ▪ ▪

COMPLICATIONS

▪ Intervertebral disc degeneration ▪ Spinal stenosis

SIGNS & SYMPTOMS ▪ Chronic back pain/stiffness, posterior leg compartment tightness ▫ Pain ↑ with activity, ↓ with rest ▪ Limited range of motion ▪ Change in gait (often waddling) ▪ Forward flexion with development of transverse abdominal crease ▪ Hip, knee flexion malformations ▪ Sciatic nerve involvement signs (radiating pain down legs)

DIAGNOSIS DIAGNOSTIC IMAGING X-ray or CT scan ▪ Shows altered vertebral body alignment

TREATMENT MEDICATIONS

▪ Pain management (e.g. NSAIDs)

SURGERY

▪ Repair ▫ If persistent pain/neurologic symptoms, vertebral sliding is > 50%

OTHER INTERVENTIONS

▪ Orthoses (lumbar corset) ▫ May help reestablish proprioception, strengthen muscles ▪ Physical therapy to strengthen back muscles

Figure 119.8 A lateral X-ray image of the spine demonstrating spondylolisthesis at L5/ S1.

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Figure 119.9 A CT scan of the spine in the sagittal plane demonstrating spondylolisthesis of the L5/S1 intervertebral joint.

SPONDYLOLYSIS osms.it/spondylolysis PATHOLOGY & CAUSES

SIGNS & SYMPTOMS

▪ Pars interarticularis vertebral defect, mostly lumbar area ▫ May be unilateral/bilateral ▪ Extreme lumbar spine stress → spinal overextension with rotation → vertebral arch fracture/separation

▪ Pain, lumbar spine pressure sensation, focal tenderness ▪ Unilateral pain radiates into corresponding side’s leg ▪ Painful lumbar spine extension ▪ Antalgic gait ▫ Stance phase of gait shorter than swing phase as means of avoiding pain ▪ ↑ lumbar lordosis ▪ Hamstring tightness

CAUSES

▪ Unknown, occasionally appears asymptomatically

RISK FACTORS

▪ Extreme sports during adolescence

COMPLICATIONS

▪ Sciatica, spondylolisthesis, spinal malformations

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Chapter 119 Spinal Disorders

DIAGNOSIS DIAGNOSTIC IMAGING MRI ▪ Used if neurological findings; visualizes soft tissue, neural structures X-ray/CT scan ▪ Lucency in region of pars interarticularis ▪ Description ▫ Collar/“broken neck on the Scotty dog” in lateral oblique view

OTHER DIAGNOSTICS

Figure 119.10 A CT scan of the spine in the sagittal plane demonstrating spondylolisthesis of the L5/S1 intervertebral joint.

▪ Clinical exam ▫ Stork test (ask to stand on one leg, lift the other hip), tenderness on palpation in fracture area

TREATMENT MEDICATIONS

▪ Pain management

OTHER INTERVENTIONS

▪ Boston brace ▪ Physical therapy to strengthen back muscles

Figure 119.11 A plain radiograph of the spine shows the “scotty dog sign” in a case of spondylolysis.

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SPONDYLOSIS osms.it/spondylosis PATHOLOGY & CAUSES ▪ Spinal column degeneration, compression ▪ Spinal osteoarthritis → degeneration of vertebral bodies, joints, foramina → intervertebral space narrowing → compression, damage to nerve roots

CAUSES

▪ Osteoartritis, trauma, postural

RISK FACTORS

▪ Obesity, older age, hyperkyphosis/ hyperlordosis

COMPLICATIONS

▪ Nerve compression, vertebrobasilar insufficiency, spinal disc protrusion, myelopathy

SIGNS & SYMPTOMS ▪ Progressive pain in affected spinal region, ↓ range of motion ▪ If nerves involved ▫ Paresthesia, radiating pain, numbness

DIAGNOSIS DIAGNOSTIC IMAGING MRI ▪ Shows nerve impingement and disc abnormalities

OTHER DIANOSTICS

▪ Clinical exam ▫ Cervical compression test: lateral flexion of head causes pain in neck, shoulder on same side

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TREATMENT MEDICATIONS

▪ Pain management

SURGERY

▪ Alleviate neural impingement

OTHER INTERVENTIONS

▪ Braces ▪ Physical therapy to strengthen back muscles

NOTES

NOTES

TRAUMA COMPLICATIONS GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Disorders following traumas such as fractures, penetrating trauma, crush injuries, lacerations, hemorrhage, etc. ▪ Affected tissue damage → tissue homeostasis disruption ▫ Compartment syndrome: ↑ tissue pressure → blood-flow disruption → tissue ischemia, necrosis ▫ Rhabdomyolysis: damaged tissue contents release into bloodstream

SIGNS & SYMPTOMS

DIAGNOSIS LAB RESULTS

▪ Complete blood count (CBC), metabolic panel, muscle enzymes, urinalysis

OTHER DIAGNOSTICS ▪ Asses injury mechanism

TREATMENT OTHER INTERVENTIONS ▪ Treat underlying cause

▪ Pain, bleeding, tenderness; limb-, lifethreatening conditions

COMPARTMENT SYNDROME osms.it/compartment-syndrome PATHOLOGY & CAUSES ▪ ↑ pressure in closed space compromises space’s blood supply ▪ Any body compartment can be affected (most commonly legs, arms)

TYPES Acute compartment syndrome ▪ Most commonly caused by fractures ▫ Other causes hemorrhage, crush injuries, vascular puncture, penetrating trauma, severe circumferential

burns, intravenous drug injection, revascularization procedures, poorfitting casts ▪ Most commonly affects leg, forearm; also foot, thigh, abdomen, gluteal region ▪ Fracture → hemorrhage, edema, necrotic debris accumulation → ↑ intracompartmental pressure exceeds perfusion pressure (10–30mmHg) → arteriolar collapse → compromised blood flow Chronic compartment syndrome ▪ Repetitive muscle use/exertion during vigorous exercise; most commonly affects leg

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▪ Exercise → ↑ muscle size → ↑ intracompartmental pressure → fluid exudation into interstitial space → compromised blood flow

OTHER DIAGNOSTICS

Acute compartment syndrome ▪ Untreated → irreversible nerve damage (sensory deficits, paralysis); infection; tissue ischemia → necrosis; limb amputation ▪ Volkmann’s contracture ▫ Permanent affected-limb flexion contracture ▪ Rhabdomyolysis, kidney failure

Pressure measurement ▪ Acute compartment syndrome (usually not required ▫ Intracompartmental pressure > 25mmHg ▫ Delta pressure < 20–30mmHg (delta pressure = diastolic blood pressure ‒ measured compartment pressure) ▪ Chronic compartment syndrome ▫ Prior to exercise (≥ 15mmHg); after one minute of exercise (≥ 30mmHg); after five minutes of exercise (≥ 20mmHg) ▫ Diagnosis of exclusion

SIGNS & SYMPTOMS

TREATMENT

COMPLICATIONS

▪ Symptom location depends upon affected compartment Acute compartment syndrome ▪ Rapid signs, symptoms progression ▪ Early signs ▫ Severe deep pain exacerbated by movement, not relieved by analgesics; swelling, tense muscle compartment, paresthesias ▪ Late signs ▫ ↓ pulse/pulselessness, anesthesia, function loss, paralysis Chronic compartment syndrome ▪ Symptoms occur during physical activity, subside when activity stops ▫ Insidious pain, tense muscle compartment, numbness, tingling, cramping, muscle bulging, foot-drop

DIAGNOSIS LAB RESULTS

▪ Lab findings evident in later stages ▪ Acute compartment syndrome ▫ ↑ creatine kinase (CK) ▫ Myoglobinuria

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SURGERY

▪ Acute compartment syndrome ▫ Medical emergency: immediate management required ▫ Fasciotomy: all affected compartments → surgical decompression ▫ Escharotomy: burns ▫ Limb amputation: severe tissue necrosis ▪ Chronic compartment syndrome ▫ Fasciotomy/fasciectomy: moderate– severe cases

OTHER INTERVENTIONS

▪ Chronic compartment syndrome ▫ ↓ exercise volume, physical therapy

Chapter 120 Trauma Complications

Figure 120.1 Surgeons performing a fasciotomy on the lower leg of in an individual with compartment syndrome.

RHABDOMYOLYSIS osms.it/rhabdomyolysis PATHOLOGY & CAUSES ▪ Extensive muscle necrosis, muscle cell content release into bloodstream ▪ Muscle damage → ATP depletion → membrane cell pump dysfunction → ↑ intracellular Ca2+ due to ↓ efflux → Ca2+-dependent protease activation, hydroxylases, nucleases → cell death, muscle cell content release (myoglobin, CK, Ca2+)

CAUSES

▪ Trauma/compression ▫ Crush injury, prolonged immobilization (comatose individuals), acute compartment syndrome, hyperthermia, severe third-degree burns,

▪

▪ ▪ ▪ ▪

postoperative surgical trauma Metabolic/genetic factors ▫ Metabolic myopathies, glycogen storage diseases, mitochondrial disease Infections ▫ Influenza types A, B; HIV; coxsackievirus Medication ▫ Statins, colchicine, propofol Substance abuse ▫ Amphetamines, cocaine, alcohol Others ▫ Electrolyte disorders, exertional activity, snake venom, hyperkinetic states

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COMPLICATIONS

▪ Acute renal injury ▫ Massive myoglobin release exerts toxicity to renal tubules → acute tubular necrosis ▪ Acute compartment syndrome ▪ Hyperkalemia, hypocalcemia, metabolic acidosis ▪ Disseminated intravascular coagulation (DIC) ▪ Electrolyte imbalances → cardiac arrhythmias

TREATMENT OTHER INTERVENTIONS

▪ IV fluids, electrolyte-imbalance correction ▪ Kidney function monitoring ▪ Severe cases ▫ Dialysis/hemofiltration

SIGNS & SYMPTOMS ▪ Severity-dependent ▪ Non-specific symptoms ▫ Fever, nausea, dyspepsia, vomiting ▪ Muscle pain, weakness, affected muscle swelling ▪ Oliguria/anuria (acute renal injury) ▪ Dark urine discoloration

DIAGNOSIS LAB RESULTS

▪ ↑ CK ▫ Most sensitive, nonspecific indicator ▪ Myoglobinuria ▪ Hyperuricemia ▫ Blood urea nitrogen (BUN), creatinine ▪ ↑ Lactate dehydrogenase (LDH) ▪ Electrolyte imbalances ▫ Hyperkalemia, hypocalcemia (early signs)

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Figure 120.2 Urine of an individual with rhabdomyolysis.

NOTES

NOTES

UPPER LIMB INJURY GENERALLY, WHAT IS IT? PATHOLOGY & CAUSES ▪ Upper limb joint damage, dislocation ▪ Weakening/damaging of ligaments, tendons → distortion of normal anatomical joint structure, function loss/impairment

MRI ▪ Damaged ligaments and soft tissue Ultrasound ▪ Soft tissue damage ▪ Tendon dislocations

OTHER DIAGNOSTICS

CAUSES

▪ Trauma, overuse

SIGNS & SYMPTOMS ▪ Pain, swelling, numbness ▪ Reduced range of motion ▪ Visible/palpable malformations

DIAGNOSIS DIAGNOSTIC IMAGING X-ray ▪ Dislocation ▪ Distorted articular spaces ▪ Fractures

▪ Physical examination ▫ Reduced range of motion ▫ Visible dislocation ▫ Swelling

TREATMENT MEDICATIONS

▪ Pain management ▫ Sedation, analgesia

SURGERY

▪ Joint reduction

OTHER INTERVENTIONS ▪ Rest, ice ▪ Physical rehabilitation

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DISLOCATED SHOULDER osms.it/dislocated-shoulder PATHOLOGY & CAUSES ▪ Humeral head detaches from glenoid fossa in glenohumeral joint ▪ Loose ligaments provide high mobility, but are prone to injury in abduction/external rotation

TYPES Anterior dislocation ▪ Most common ▪ Blow to extended, raised, outwardly turned arm → damaged inferior glenohumeral ligament

SIGNS & SYMPTOMS Shoulder feels unstable/like it’s “rolling out” Shoulder pain (can radiate down arm) Limited range of motion Visible displacement Injured/compressed axillary artery: hematoma/weak distal pulse ▪ Stretched axillary nerve: shoulder area numbness ▪ ▪ ▪ ▪ ▪

Posterior dislocation ▪ Strong muscle cramp/electric shock ▪ Associated with tuberosity, surgical neck fractures of humerus Inferior dislocation ▪ Uncommon ▪ Force applied to completely raised arm (e.g. individual falls, tries to grab onto something above) ▪ Highest incidence of axillary nerve, artery injuries

CAUSES

▪ Force from fall/blow → ligaments tear/ stretch → humeral head slips out of position

RISK FACTORS

▪ Previous dislocations ▪ Sports

COMPLICATIONS

▪ Axillary artery, nerve damage from injury/ while performing reduction

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Figure 121.1 An X-ray image of the shoulder demonstrating an anterior dislocation.

DIAGNOSIS DIAGNOSTIC IMAGING X-ray ▪ Two views necessary ▫ Anteroposterior view (AP) ▫ Lateral view ▪ Anterior dislocation: humeral head is in front of glenoid

Chapter 121 Upper Limb Injury ▪ Posterior dislocation: humeral head is in place in AP view ▪ Fractured bones MRI ▪ Damaged ligaments (contrast enhancement for better visualisation) CT angiogram ▪ Arterial damage

TREATMENT ▪ Reduction ▫ Perform as soon as possible for easier reduction, less chance of complications ▫ e.g. Hill–Sachs lesion/compression fractures on humeral head ▪ Immobilisation, rest ▫ Age < 30 → three weeks ▫ Age > 30 → 7–10 days

Figure 121.2 An X-ray image of the left shoulder demonstrating a Hill–Sachs lesion. A Hill–Sachs lesion is a posterolateral compression fracture that occurs as a result of recurrent anterior dislocations of the shoulder.

NURSEMAID'S ELBOW osms.it/nursemaids-elbow PATHOLOGY & CAUSES ▪ Dislocation of radial head in elbow joint ▫ Pulled elbow/radial head subluxation

CAUSES

▪ Pulling extended arm makes annular ligament slip above radial head ▪ Lifting/swinging child ▪ Common in children < six years old

SIGNS & SYMPTOMS

DIAGNOSIS DIAGNOSTIC IMAGING X-ray ▪ When fracture suspected

TREATMENT OTHER INTERVENTIONS

▪ Reduction ▫ Supination, elbow flexion ▫ Hyperpronation (less painful)

▪ Child refuses to bend/use affected arm ▫ Fear of pain ▪ Holds affected arm in prone position, close to body ▪ Inability to supinate

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ROTATOR CUFF TEAR osms.it/rotator-cuff-tear PATHOLOGY & CAUSES ▪ One/more tendons of rotator cuff tear(s) ▫ Supraspinatus, infraspinatus, teres minor, subscapularis comprise the rotator cuff ▪ Most common shoulder problem ▫ Occurs in all age groups

TYPES By course ▪ Acute tears ▫ Strong force damages tendons (e.g. rowing, powerlifting) ▪ Chronic tears ▫ Prolonged repetitive motions (especially overhead moves) ▫ Tendon degeneration: aging, blood supplies worsen ▫ Tendons become irritated, inflamed while passing through narrowed gaps

▪ Weakness, instability, restricted range of motion ▪ Compressed nerves → numbness

DIAGNOSIS DIAGNOSTIC IMAGING X-ray ▪ Anteroposterior view ▫ Sclerosis, cyst formation, smaller gap between acromion, humerus ▪ Lateral view ▫ State of acromion ▪ Axillary view ▫ Humeral head position MRI ▪ Connective tissue visualization ▪ Size, location of damage ▪ Swelling

By amount of damage ▪ Partial thickness tears ▫ Damaged supraspinatus tendon ▪ Full thickness tears ▫ Damaged supraspinatus, infraspinatus, subscapularis, biceps tendon By exterior/interior factors ▪ Exterior factors ▫ Tendon impingement due to curved/ hooked acromion ▪ Interior factors ▫ Small repetitive injuries over prolonged period → tendon degeneration

SIGNS & SYMPTOMS ▪ “Arc of pain” (pain while lowering arm) ▪ Night pain

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Figure 121.3 An MRI scan of the shoulder in a non-orthogonal plane demonstrating a complete tear of the supraspinatus and infraspinatus tendons.

Chapter 121 Upper Limb Injury Ultrasound ▪ Evaluate tear extent ▪ Tendon dislocations

OTHER DIAGNOSTICS Supraspinatus injuries ▪ Active painful arc & drop arm test ▫ Fully raise arm, then steadily lower it back ▫ If pain occurs → positive test ▪ Jobe’s test (aka “empty can”) ▫ Individual raises straight arm 90°, flexes forward 30° with thumb pointing down → resists attempt to depress arm ▫ Pain without weakness → tendinopathy ▫ Pain with weakness → tendon tear Infraspinatus, teres minor injuries ▪ Test external rotation ▫ Individual attempts external rotation of arm, examiner provides resistance Subscapularis injuries ▪ Gerber’s lift-off test ▫ Place hand behind back → push backwards against resistance ▪ Supine Napoleon test ▫ Individual lays down, places hand on abdomen with elbow flexed 90° → attempts to raise elbow while examiner secures hand, shoulder

Impingement test ▪ Neer test ▫ Individual flexes pronated arm (with thumb pointing downwards) above head ▪ Hawkins test ▫ Individual raises arm 90° with halfflexed elbow → examiner attempts to internally rotate shoulder

TREATMENT MEDICATIONS

▪ Pain management ▫ NSAIDs

SURGERY

▪ Small tears → arthroscopically ▪ Large tears → open surgical repair

OTHER INTERVENTIONS

▪ Rest, ice ▫ Pain, inflammation management ▪ Physical therapy ▫ Restore range of motion ▪ Strengthen muscles that support joint ▪ Exercises for preserving neurologic control

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NOTES

NOTES

BREAST MASSES GENERALLY, WHAT ARE THEY? TREATMENT

PATHOLOGY & CAUSES ▪ Diverse breast tissue disorders; often in biologically-female individuals, often benign ▫ Young: ↑ benign masses ▫ Elderly: ↑ breast cancer

CAUSES

▪ Hormonal stimulation ▪ Genetic predisposition

COMPLICATIONS

▪ Possibility that benign mass → breast cancer

SIGNS & SYMPTOMS ▪ Possibly asymptomatic ▪ Breast size/appearance change

DIAGNOSIS ▪ Suggestive physical findings, medical/ family history

DIAGNOSTIC IMAGING Mammogram MRI Ultrasound

LAB RESULTS

▪ Biopsy, histological analysis

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▪ Benign disorders may regress spontaneously

SURGERY

▪ Lumpectomy ▪ Mastectomy

OTHER INTERVENTIONS

▪ Alternatives (e.g. cryoablation, radiation therapy)

Chapter 122 Breast Masses

BREAST CANCER osms.it/breast-cancer PATHOLOGY & CAUSES ▪ Diverse malignant breast lesions with different microscopic features, biologic behavior ▫ ↑ common non-skin malignancy in biologically-female individuals ▫ Rare in biologically-male individuals

TYPES Molecular subtypes ▪ Molecular subtypes classified by estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) expression; protein Ki67 levels (controls cancer cell growth) ▫ Luminal A: ER, PR positive, HER2 negative, ↓ protein Ki67 levels ▫ Luminal B: ER, PR positive, HER2 negative or positive, ↑ protein Ki67 levels ▫ Triple-negative: ER, HER2, PR negative ▫ HER2 enriched: ER, PR negative, HER2 positive ▫ Normal-like: ER, PR positive, HER2 negative, ↓ protein Ki67 levels Most common types ▪ Ductal carcinoma in situ (DCIS) ▫ In ducts → possible invasive ductal carcinoma (usually in same breast) ▪ Lobular carcinoma in situ (LCIS) ▫ In lobules → ↑ cancer risk in either breast ▪ Invasive ductal carcinoma ▫ 70% of all invasive cancers ▫ Subtypes: tubular, medullary, mucinous, papillary, cribriform ▪ Invasive lobular carcinoma ▪ Inflammatory breast cancer ▫ Rare aggressive form ▫ Poor prognosis

Figure 122.1 The gross pathological appearance of breast cancer in a wide local excision specimen.

CAUSES

▪ Genetic aberrations ▪ Hormonal exposure ▪ Inherited susceptibility genes (familial, 10% of cases) ▫ Breast cancer 1 (BRCA1), breast cancer 2 (BRCA2) (80–90% of singlegene familial breast cancers, 3% of all cancers)

RISK FACTORS

Breast cancer prior history ↑ age → ↑ risk Breast cancer in first-degree relatives Individuals who are biologically female Race/ethnicity ▫ Highest incidence in white people of Ashkenazi Jewish descent ▪ Hormonal influence ▫ Estrogen exposure (e.g., menopausal hormone therapy) ▫ Early menarche (< 11 years old) ▫ Late menopause

▪ ▪ ▪ ▪ ▪

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▫ Nulliparity/ > 35 years old at first birth ▫ ↓ breastfeeding duration ▫ Obesity ▪ Toxin exposure ▫ Ionizing radiation ▫ Smoking ▫ ↑ alcohol consumption

Ultrasound ▪ Differentiate cystic/solid masses ▪ Provide procedure guidance ▪ Hypoechoic lesion ▫ Calcifications, shadowing, irregular margins

COMPLICATIONS

▪ Metastasis (bone, lung, liver, brain common) ▪ Treatment complications ▫ Lymph node resection → lymphedema ▫ Cytotoxic chemotherapy → infertility ▫ Chemotherapy, radiation therapy → cardiac disorders (e.g. cardiomyopathy) and/or myeloid neoplasms

SIGNS & SYMPTOMS ▪ Possibly asymptomatic (especially premalignant breast masses) ▪ Palpable mass (hard, nontender, irregular borders, immobile) ▪ Palpable lymph nodes ▫ Axillary, supraclavicular ▪ Skin dimpling (orange peel skin) ▪ Nipple retraction, discharge (usually bloody), eczema-like rash (Paget’s disease of breast) ▪ Inflammatory breast cancer ▫ Presentation mimics inflammation (tenderness, warmth, swelling, erythema) ▫ Orange peel skin over mass

Figure 122.2 An inverted nipple caused by a sub-areolar breast tumor.

DIAGNOSIS DIAGNOSTIC IMAGING Breast MRI ▪ High-risk individuals (with mammography) Mammogram ▪ Ill-defined, spiculated mass ▫ Clustered microcalcifications

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Figure 122.3 A mammogram of the breast demonstrating a well circumscribed tumor.

Chapter 122 Breast Masses

LAB RESULTS

▪ Core biopsy ▫ Histological analysis, tumor grading ▪ Immunohistochemistry analysis ▫ Detect estrogen/progesterone receptor expression; HER2 overexpression ▪ Sentinel lymph node biopsy

OTHER DIAGNOSTICS

▪ Suggestive physical findings, medical/ family history

Figure 122.4 The histological appearance of breast carcinoma, no special type. This subtype can take many forms but in this instance there are cords of pleomorphic, atypical cells with open chromatin and prominent nucleoli.

TREATMENT SURGERY

▪ Lumpectomy/mastectomy ▫ Individual’s choice

OTHER INTERVENTIONS

▪ Radiation therapy ▪ Chemotherapy ▪ Adjuvant hormone therapy/ chemoprevention (some cancers)

Figure 122.5 A fungating tumor of the left breast. The tumor involves almost the entire organ and extends into the axilla where the overlying skin has ulcerated.

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FIBROADENOMA osms.it/fibroadenoma PATHOLOGY & CAUSES ▪ Benign, estrogen-sensitive proliferative breast lesion (from stromal, epithelial components) ▫ ↑ occurence young people (< 35 years old) ▫ Most common benign breast neoplasm ▪ Cause unknown; possibly hormone presence ▫ Pregnancy, pre-menstruation → ↑ proliferation ▫ Regresses with age

TYPES

▪ Giant fibroadenomas ▫ >10cm/3.9in (phylloid tumors appear similar) ▪ Juvenile ▫ Young individuals (10–18 years of age), grow rapidly, ↑ glandularity, ↑ stromal cellularity ▪ Complex fibroadenomas ▫ Proliferative changes (e.g. sclerosing adenosis, calcifications/hyperplasia)

DIAGNOSIS DIAGNOSTIC IMAGING Breast ultrasound ▪ Well-defined, solid, hypoechoic lesion Mammogram ▪ Circumscribed, dense lesion, possible clustered calcifications

LAB RESULTS Biopsy ▪ Definitive diagnostic test ▫ Glandular, fibrous tissue ▪ Excludes breast cancer

OTHER DIAGNOSTICS

▪ Suggestive physical findings

COMPLICATIONS

▪ Size increases → possible infarction/ inflammation ▪ Mildly ↑ breast cancer risk (especially complex fibroadenomas)

SIGNS & SYMPTOMS ▪ Typical presentation: 2–3cm/0.79–1.2in average size, firm, well-circumscribed, round, palpable, mobile, painless (possibly painful during menstrual cycle) ▪ Often multiple, bilateral

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Figure 122.6 The histological appearance of a fibroadenoma. There is overgrowth of both the stroma and the glandular epithelium.

Chapter 122 Breast Masses

TREATMENT ▪ Therapy seldom required; often regress post-menopause

SURGERY

▪ Surgical excision

OTHER INTERVENTIONS ▪ Cryoablation

Figure 122.7 A fine needle aspirate of a fibroadenoma of the breast. Sheets of epithelial cells are arranged in a staghorn pattern.

FIBROCYSTIC BREAST CHANGES osms.it/fibrocystic-breast-changes PATHOLOGY & CAUSES ▪ Common benign breast disease ▪ Bilateral tenderness, multiple lumps related to cyclic ovarian hormonal stimulation ▫ AKA fibrocystic disease, mammary dysplasia, cystic mastitis ▫ Premenopausal individuals (< 35 years old) → ↑ common; 50% of reproductiveage biologically-female individuals ▫ Increased breast cancer risk not associated (non-proliferative breast lesions) ▪ Characteristic changes ▫ Cysts ▫ Adenosis ▫ Stromal fibrosis

TYPES

▪ Epithelial hyperplasia ▫ Cells in terminal ductal/lobular epithelium, atypical cells → ↑ carcinoma risk

COMPLICATIONS

▪ Some subtypes (sclerosing adenosis, atypical hyperplasia) → ↑ increased invasive carcinoma risk (both breasts)

SIGNS & SYMPTOMS ▪ Menstrual cycle-related clinical manifestations ▫ Bilateral breast pain, tenderness ▫ Multiple, smooth, well-defined, mobile lumps (“lumpy bumpy” breasts); usually upper outer quadrant

▪ Sclerosing adenosis ▫ Acini, stromal fibrosis, calcifications associated, slight ↑ cancer risk

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TREATMENT

DIAGNOSIS DIAGNOSTIC IMAGING Mammogram ▪ Dense breasts with cysts Ultrasound ▪ Fluid-filled cysts

LAB RESULTS Aspiration ▪ If mass persistent ▪ Excludes tumor ▪ If clear fluid obtained, mass disappears → fibrocystic breast changes Biopsy ▪ Cysts ▫ Blue serous fluid (“blue dome” appearance), various sizes, calcifications common ▪ Fibrosis ▫ Due to chronic inflammation from cyst rupture, material release to stroma ▪ Adenosis ▫ ↑ acini per lobule

OTHER DIAGNOSTICS

▪ Suggestive physical findings

Figure 122.8 The histological appearance of fibricystic change of the breast. There are numerous small cysts surrounded by fibrous tissue. The cysts are lined with ductal epithelium.

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MEDICATIONS

▪ Conservative measures ▫ Oral contraceptives; analgesics (e.g., nonsteroidal anti-inflammatory agents (NSAIDs))

SURGERY

▪ Surgical intervention often unnecessary; resolves with menopause ▪ Surgical treatment ▫ Complex cysts, if biopsy results atypical/ malignancy revealed

OTHER INTERVENTIONS

▪ Conservative measure ▫ Caffeine elimination ▪ Conservative measures fail → therapeutic aspiration

Chapter 122 Breast Masses

INTRADUCTAL PAPILLOMA osms.it/intraductal-papilloma PATHOLOGY & CAUSES ▪ Rare benign fibroepithelial breast tumor arising from lactiferous duct epithelium

TYPES

▪ Central ▫ Develops near nipple, usually solitary, often arise near menopause ▪ Peripheral ▫ Often multiple, usually in younger individuals

RISK FACTORS

▪ Biologically female, 20–30 years old

COMPLICATIONS

Mammogram ▪ Excludes breast cancer ▪ Intraductal papilloma usually too small to detect Ultrasound ▪ Projections extending from duct wall within lumen; used to diagnose/guide surgical resection

LAB RESULTS Biopsy ▪ Fibrovascular intraductal projections lined by myoepithelial, epithelial cells

OTHER DIAGNOSTICS

▪ Suggestive physical findings

▪ Slightly ↑ breast cancer risk ▪ Peripheral ▫ ↑ risk ▪ ↑ age → ↑ risk

SIGNS & SYMPTOMS ▪ Intermittent bloody/serous nipple discharge (especially premenopausal) ▪ Breast feels full (relieved by discharge passage)

DIAGNOSIS DIAGNOSTIC IMAGING Galactography ▪ Contrast-enhanced mammogram; definitive test but invasive ▪ Filling lactiferous duct defect

Figure 122.9 Breast ductography demonstrating a solitary intraductal papilloma.

TREATMENT ▪ Small, incidental papillomas: treatment may be unnecessary

SURGERY

▪ Breast duct removal

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Figure 122.10 The histological appearance of a papilloma of the breast. There are multiple infolded papillae giving a cribriform pattern. The papillae are lined by benign ductal epithelium.

PAGET'S DISEASE OF THE BREAST osms.it/pagets-disease-of-the-breast PATHOLOGY & CAUSES ▪ Rare cutaneous breast cancer manifestation ▫ Eczema-like skin changes in nipple, areola ▪ Pathogenesis ▫ Epidermotropic theory: underlying mammary carcinoma present (85–88% of cases) → malignant cells migrate through ductal system → nipple epidermis ▫ In situ transformation theory: nipple keratinocyte transformation → malignant cells (independent of other breast pathology)

SIGNS & SYMPTOMS ▪ Typical presentation: unilateral; nipple + adjacent areolar skin; scaly; itching, burning; erythematous

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▪ Less common: bloody nipple discharge, nipple inversion, pain ▪ Palpable mass in 50–60% of cases → worse prognosis

Figure 122.11 The clinical appearance of Paget’s disease of the breast.

Chapter 122 Breast Masses

DIAGNOSIS DIAGNOSTIC IMAGING Mammogram ▪ Identify associated mass, microcalcifications, tissue distortion

LAB RESULTS

▪ Ultrasound-guided mass core biopsy, histopathological analysis ▪ Nipple scrape cytology/full-thickness wedge/punch biopsy ▫ Malignant, intraepithelial adenocarcinoma cells (Paget cells) present

Figure 122.12 The histological appearance of Paget’s disease. There are tumor cells migrating upward toward the skin surface individually and in small groups.

OTHER DIAGNOSTICS

▪ Suggestive physical findings

TREATMENT SURGERY

▪ Mastectomy, breast-conserving surgery

OTHER INTERVENTIONS ▪ Whole breast radiotherapy

PHYLLODES TUMOR osms.it/phyllodes-tumor PATHOLOGY & CAUSES ▪ Rare fibroepithelial breast tumor ▫ Typical phyllodes (leaf-like) projections on pathologic examination ▫ AKA cystosarcoma phyllodes ▪ Generally benign, can become malignant sarcoma ▪ Arises from periductal breast stroma

▪ Associated with acquired chromosomal mutations; most commonly gains in chromosome 1q

COMPLICATIONS

▪ Local recurrence after excision ▪ Local hemorrhage, necrosis ▪ High-grade tumors can give distant hematogenous metastasis; lymphatic spread rare

RISK FACTORS

▪ Biologically female, 30–50 years old

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SIGNS & SYMPTOMS ▪ Mass ▫ Large, palpable, firm, multinodular, wellcircumscribed, mobile, painless ▪ Slow-growing or develops rapidly over entire breast ▪ Overlying skin possibly shiny, stretched ▪ Possible bloody discharge

DIAGNOSIS DIAGNOSTIC IMAGING Breast MRI ▪ Well-circumscribed lesion, ↑ signal intensity on T1-weighted, ↓ signal intensity on T2weighted Mammogram ▪ Smooth, polylobulated mass, resembles fibroadenoma Ultrasound ▪ Solid, hypoechoic, well-circumscribed lesion; possible cystic areas within mass, microcalcifications absent

LAB RESULTS Core needle biopsy ▪ Histologic grading: ↑ cellularity, ↑ mitotic rate, nuclear polymorphism, fibrous stroma overgrowth, leaf-like lobulations, cysts ▫ Cellular pleomorphism indicates malignancy

OTHER DIAGNOSTICS

▪ Suggestive physical findings

TREATMENT SURGERY

▪ Treatment of choice: surgical removal (wide local excision)

OTHER INTERVENTIONS

▪ Large, high-risk/recurrent tumors: adjuvant radiotherapy/chemotherapy

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Figure 122.13 The histological appearance of a Phyllodes’ tumor. Whilst similar in appearance to a fibroadenoma, the stroma is more cellular and constitutes a larger component of the tumor

Chapter 122 Breast Masses

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NOTES

NOTES

DISORDERS OF LABOR

PLACENTA ACCRETA osms.it/placenta-accreta PATHOLOGY & CAUSES

SIGNS & SYMPTOMS

▪ A type of abnormally developed, invasive placenta ▫ Normally a spontaneous, complete placenta separation from uterine wall (myometrium) ▫ Maternal placenta side (decidua) separates from myometrium at stratum basalis layer ▪ Absent/underdeveloped decidua occurs in placenta accreta → adherence of fetal chorionic villi directly to myometrium → placenta fails to fully separate after fetus is delivered ▫ Partial separation → profuse hemorrhage → hemorrhagic shock and coagulopathy ▫ If no separation → hemorrhage is induced when manual separation is attempted

▪ Placenta fails to spontaneously deliver after fetus’s birth ▫ Manual separation attempts unsuccessful, provoke increased bleeding ▪ Severe hemorrhage ▪ Boggy (soft, spongy) uterus unresponsive to uterotonics/uterine massage

TYPES

DIAGNOSTIC IMAGING

▪ Placenta accreta; placenta increta; placenta percreta (based on invasiveness) ▪ Placenta accreta also increases risk of preterm bleeding ▫ Association between placenta accreta, concurrent placenta previa

RISK FACTORS

▪ Previous uterine surgery ▫ Cesarean section (most common), myomectomy, curettage ▫ Scar tissue prevents normal placental implantation ▪ Previous placenta previa

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DIAGNOSIS ▪ Based on clinical presentation of hemorrhage post-delivery; severe hemorrhage after attempted manual placenta delivery ▪ Prenatal diagnosis allows planned management (e.g. cesarean birth, cesarean hysterectomy)

Ultrasound, color Doppler ▪ Evaluate alterations in intraplacental blood flow, status of placental-myometrial interface

LAB RESULTS

▪ Laboratory tests may show ↑ maternal serum alpha fetoprotein

Chapter 123 Disorders of Labor

TREATMENT MEDICATIONS

▪ Circulatory support ▫ Fluids, blood products

SURGERY

▪ Hysterectomy may be needed to control postpartum hemorrhage ▫ Most common life-saving intervention ▪ Cesarean hysterectomy (fetus delivery followed by uterus + placenta removal as one unit) may be planned preoperatively with invasive placenta evidence

Figure 123.1 A uterus removed following cesarian section demonstrating complate invasion through the uterine wall by the placenta, known as placenta percreta.

PLACENTA PREVIA osms.it/placenta-previa PATHOLOGY & CAUSES ▪ Placenta implants in lower uterine segment (placenta previa = placenta first) ▪ Implantation is in lower uterine segment, close to/covering uterine opening (cervical os) → as pregnancy progresses, uterine segment grows → disruption of uterine blood vessels → bleeding (usually after 20 weeks of gestation) ▪ Classified by placenta’s closeness to cervical os ▫ Complete: placenta completely covers cervical os ▫ Partial: placenta partially covers cervical os ▫ Marginal: placenta edge extends to within 2cm/0.79in of cervical os

CAUSES

RISK FACTORS

▪ Multiple placentas or placenta with a larger than normal surface area (e.g. multiple gestation) ▪ Previous cesarean section/any uterine surgery ▪ Multiparity ▪ Intrauterine fibroids ▪ Spontaneous/induced abortion ▪ Placenta accreta ▪ Maternal age ≥ 35 years old ▪ Smoking

COMPLICATIONS

▪ Maternal: hemorrhage ▫ Severity depends on placenta location ▫ Disseminated intravascular coagulation (DIC) if bleeding severe/prolonged ▪ Fetal: hypoxia, preterm birth

▪ Placenta implants lower in uterus when upper uterine endometrium is not well vascularized due to endometrial damage

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SIGNS & SYMPTOMS ▪ Bleeding ▫ Painless ▫ Bright red ▫ Intermittent/continuous ▫ Often increases during labor from uterine contractions, cervical dilation ▪ Uterine hyperactivity ▪ Electronic fetal monitoring tracings may show fetal heart rate deceleration, indicating hypoxia

DIAGNOSIS DIAGNOSTIC IMAGING Prenatal ultrasound ▪ During routine prenatal ultrasound Transabdominal ultrasound ▪ When bleeding occurs during labor, determines placental location

TREATMENT MEDICATIONS

▪ Corticosteroids as indicated to enhance fetal lung maturity

SURGERY

▪ Emergent cesarean delivery if placenta obstructs delivery or hemorrhage is severe

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Figure 123.2 An MRI scan of the abdomen of a pregnant female demonstrating major placenta praevia. The internal cervical os is completely covered by the placenta. ▪ After delivery, measures to control bleeding include ▫ Hysterectomy/interventional radiology (e.g. uterine artery embolization)

OTHER INTERVENTIONS

▪ Manage maternal bleeding; support mother, fetus hemodynamic stability ▫ Transfusion of blood products ▫ IV fluids ▪ Continuous fetal heart rate monitoring

Chapter 123 Disorders of Labor

PLACENTAL ABRUPTION osms.it/placental-abruption PATHOLOGY & CAUSES ▪ Premature separation of all/section of otherwise normally implanted placenta from uterine wall after 20 weeks of gestation wall resulting in hemorrhage

TYPES

▪ Partial/complete: depending on separation degree ▪ Concealed: central separation may cause a pocket of blood to form, concealing bleeding between decidua basalis and uterine wall → hematoma promotes separation ▪ Apparent: bleeding is visualized

CAUSES

▪ Uterine artery degeneration in decidua basalis → diseased vessels rupture → hemorrhage → placenta separation

RISK FACTORS

Previous placental abruption Chronic hypertension Preeclampsia/chronic hypertension Multiparity Rapid uterine decompression (e.g. as with polyhydramnios/multiple gestation) ▪ Trauma (e.g. car crash, fall, domestic violence) ▪ Smoking ▪ Drugs: cocaine, methamphetamine ▪ ▪ ▪ ▪ ▪

SIGNS & SYMPTOMS ▪ Uterus ▫ Pain in abruption area ▫ Abdominal/back pain ▫ Irritability, tachysystole, tetany ▫ Mild to severe vaginal bleeding (evidence of consumptive coagulopathy if severe bleeding) ▪ Fetal hypoxia, bradycardia

DIAGNOSIS ▪ Ultrasound may show retroplacental blood collection ▪ Blood-stained amniotic fluid in vagina ▪ Abruption signs evidenced by fetal heart rate, uterine activity

DIAGNOSTIC IMAGING Electronic fetal monitoring ▪ Decelerations may indicate fetal hypoxia, bradycardia

COMPLICATIONS

▪ Maternal: hypovolemic shock, disseminated intravascular coagulation (DIC), end organ damage (e.g. renal failure, Sheehan syndrome (pituitary necrosis related to hypovolemia)) ▪ Fetal: hypoxia; asphyxia; premature birth, related sequelae; death

Figure 123.3 An ultrasound scan in pregnancy demonstrating a placental abruption. There is a crescent of avascular hypoechoic fluid between the placenta and the uterine wall.

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TREATMENT MEDICATIONS

▪ Corticosteroids as indicated to enhance fetal lung maturity

SURGERY

▪ Emergent delivery ▫ Vaginal/cesarean, as indicated

OTHER INTERVENTIONS

▪ Expectant management for small abruptions ▪ For significant bleeding: support hemodynamic stability of mother, fetus ▪ Blood product transfusion ▪ IV fluids ▪ Continuous fetal heart rate monitoring

POSTPARTUM HEMORRHAGE osms.it/postpartum-hemorrhage PATHOLOGY & CAUSES ▪ Postpartum (post = after; partum = birth) hemorrhage (PPH) is excessive blood loss after giving birth ▪ Defined by estimated blood loss (EBL), mode of birth ▫ > 500mL after vaginal delivery ▫ > 1000mL after cesarean delivery

TYPES

▪ Primary/early: within 24 hours after delivery ▪ Secondary/late: after 24 hours, before six weeks postpartum

CAUSES Four Ts ▪ Tone: soft, boggy uterus (uterine atony) and ineffective uterine contractions that normally cause uterine involution (return of uterus to its pre-pregnancy state) and provide tourniquet-like action on major blood vessels → hemorrhage from placental attachment site ▫ Associated with uterine overdistension: multiple gestation or polyhydramnios (excessive myometrium stretching); uterine fatigue from prolonged labor; full bladder (interferes with contractions); medications (anesthetics, especially halothane)/preterm labor

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drugs (magnesium sulfate, nifedipine, terbutaline) ▪ Trauma: damage to reproductive/genital structures (e.g. uterus, cervix, vagina, perineum) → hemorrhage ▫ Surgical incision: cesarean delivery or episiotomy ▫ Large fetus/fetal malpresentation/ shoulder dystocia (baby’s shoulder impacted against maternal pubic symphysis) → soft tissue damage during descent through vaginal canal ▫ Soft tissue laceration from instruments used in delivery (e.g. use of forceps, vacuum extraction), uterine rupture (lacerations may result in hematoma formation → hidden bleeding → interference with uterine involution → uterine atony → hemorrhage) ▪ Tissue: retained placental fragments, placenta accreta, excessive traction on umbilical cord → interferes with uterine contractions → uterine atony → hemorrhage from placental attachment site ▪ Thrombin: impaired clotting → hemorrhage ▫ Associated with clotting disorders (e.g. von Willebrand disease) ▫ Coagulopathy (e.g. disseminated intravascular coagulation) related to an obstetrical complication (e.g. eclampsia, placenta previa)

Chapter 123 Disorders of Labor

SIGNS & SYMPTOMS ▪ Excessive bleeding visualization ▪ Maternal physiological response to decreased circulating volume ▫ ↑ heart rate ▫ ↓ blood pressure ▫ ↓ pulse pressure ▫ ↓ oxygen saturation ▫ ↓ hematocrit ▫ Delayed capillary refill ▫ Shock signs usually appear when hemorrhage is advanced due to normally ↑ pregnancy blood volume ▪ Soft, “boggy” uterus ▪ Clinical presentation suggesting hematoma

DIAGNOSIS OTHER DIAGNOSTICS

▪ Based on clinical signs, symptoms ▪ Estimated blood loss

TREATMENT MEDICATIONS

▪ Uterotonics: stimulate uterine contractions ▫ Oxytocin ▫ Methylergonovine: ergot derivative ▫ Prostaglandins

SURGERY

▪ Laparoscopic arterial ligation ▪ Hysterectomy

OTHER INTERVENTIONS

▪ Maintain adequate circulating volume; clotting factors, as needed ▫ IV fluids ▫ Blood products ▪ Intrauterine packing/balloon tamponade ▪ Interventional radiology ▫ Uterine artery embolization ▪ Address underlying cause (e.g. repair lacerations, remove retained placental fragments, assess for hematoma; repair ruptured uterus) ▪ Fundal massage ▫ Massaging fundus (upper portion of uterus) often causes entire uterus to contract

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PRETERM BIRTH osms.it/preterm-birth PATHOLOGY & CAUSES ▪ Birth is considered preterm when between 20–37 gestation weeks ▫ Moderate to late preterm: 32–37 weeks ▫ Very preterm: 28–32 weeks ▫ Extremely preterm: < 28 weeks ▪ Worldwide: approximately 15 million babies are born prematurely each year ▫ In the U.S., about 1 in 10 babies are born prematurely ▪ Maternal-fetal unit responds to one or more pathologic risk factors + gene-environment interaction influence → preterm labor, birth ▪ Pathologic processes activate major pathway components to labor, birth ▫ Cervical changes (ripening) include softening, thinning, shortening ▫ Enhanced uterine contractility (myometrial gap-junction formation → synchronized uterine contraction; ↑ oxytocin receptors) ▫ Fetal membrane-maternal decidua interface disruption → preterm premature rupture of membranes (PPROM)

RISK FACTORS Maternal ▪ Obstetric history: previous preterm birth, short interval between pregnancies, conception through assisted reproductive technology (ART)(e.g. in vitro fertilization), previous pregnancy termination, history of stillbirth ▪ Family history of preterm birth: associated genes include FSHR (follicle-stimulating hormone receptor), IGF1R (insulin-like growth factor 1 receptor)

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▪ Obstetric disorders: preeclampsia, placenta previa, placental abruption, uterine or cervical anomalies (e.g. cervical insufficiency—cervix unable to sustain the pregnancy) ▪ Distended uterus: multiple gestation, polyhydramnios ▪ Infections: bacterial vaginosis, sexuallytransmitted infections, urinary tract infections, periodontal disease ▪ Concurrent medical diagnoses: diabetes, pulmonary disease, heart disease, anemia (hemoglobin < 10g/dL) ▪ Socioeconomic/personal factors: low income, lack of prenatal care, ethnic minority, maternal age < 18 or > 40; stressful working conditions, intimate partner violence ▪ Behavioral factors: smoking, substance abuse, poor nutrition, inadequate weight gain, BMI < 19.6 or > 30 Fetal ▪ Intrauterine growth restriction, genetic anomalies, multiple gestation, twin-to-twin transfusion

COMPLICATIONS Maternal ▪ Increased risk of hemorrhage, infection; complications from cesarean section Fetal ▪ Increased fetal/neonatal morbidity, mortality; low birth weight (less than 2.5kg/5.5lbs), lung immaturity, hypoxicischemic encephalopathy, cerebral palsy

Chapter 123 Disorders of Labor

SIGNS & SYMPTOMS ▪ Vaginal discharge before completed gestation ▫ Fluid or blood leak (bloody show) ▫ Ruptured membranes may present as a sudden gush of water ▪ Lower abdominal or pelvic pressure ▪ Low, dull back pain ▪ Onset of contractions every 10 minutes or less ▪ Electronic fetal monitoring may show fetal tachycardia/decelerations (drops in heart rate during contractions)

DIAGNOSIS ▪ Pelvic exam shows cervical changes ▫ Cervical shortening, softening, effacement (thinning) ▫ Opening of cervical os

DIAGNOSTIC IMAGING Transvaginal ultrasound ▪ Shows shortened cervix length

LAB RESULTS

▪ Fetal fibronectin (fFN) test ▫ Glycoprotein that acts like a “glue” between maternal decidua and fetal membrane ▫ Presence of fFN in cervicovaginal secretions indicates preterm labor, birth ▪ Cervical culture for Group B streptococcus if status unknown ▪ Bacterial infection that increases neonatal sepsis, pneumonia, meningitis risks

TREATMENT MEDICATIONS

▪ Tocolytic medications (drugs that interfere with myometrial contractions) may delay birth for up to 48 hours. Allows time for corticosteroids to affect fetal lung development, for transport to a higher level of care if needed ▫ Nifedipine: calcium channel blocker ▫ Indomethacin: prostaglandin inhibitor ▫ Terbutaline: beta 2-adrenergic ▫ Magnesium sulfate: reduces calcium influx into muscle cell, relaxing myometrium; may have fetal neuroprotective benefit (e.g. reducing cerebral palsy risk) ▪ Antibiotics ▫ If bacterial infection suspected/ confirmed ▪ Corticosteroids ▫ To enhance fetal lung maturity, other organ development ▫ Helpful if given between 24–34 gestation weeks

SURGERY

▪ Vaginal/cesarean birth as indicated

OTHER INTERVENTIONS

▪ Cervical cerclage ▫ Stitch application to keep cervix closed, if indicated ▪ Adequate hydration ▫ Dehydration may induce uterine irritability ▪ Lecithin/sphingomyelin (L/S) ratio in amniotic fluid: indication of fetal lung maturity; directes neonate treatment ▪ Continuous ante- and intrapartum surveillance of maternal and fetal status

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NOTES

NOTES

FEMALE GENITOURINARY CANCERS

GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Cancers arising in genitourinary organs of individuals who are biologically female

RISK FACTORS

▪ Genetic mutations, smoking, prolonged use of oral contraceptives, sexually transmitted infections (STIs) (e.g. human papillomavirus), immunodeficiency (e.g. HIV/AIDS)

COMPLICATIONS

▪ Bleeding, metastasis ▪ Tumors produce excess hormones → metabolic disorders ▪ Large tumors → compression/torsion of blood vessels → ischemia

SIGNS & SYMPTOMS ▪ Abnormal vaginal discharge, bleeding; pelvic pain; abdominal pain; dyspareunia

DIAGNOSIS DIAGNOSTIC IMAGING X-ray, CT scan, MRI, ultrasound ▪ Tumor visualisation, staging

LAB RESULTS

▪ Serum tumor markers ▫ ↑ carbohydrate antigen 125 (CA-125), Papanicolaou (Pap) test ▪ Biopsy (definitive diagnosis)

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OTHER DIAGNOSTICS Staging ▪ Tumor, nodes, metastasis (TNM) system: 0–4 ▫ T: size, sites invaded (e.g. only uterus/ extrauterine invasion) ▫ N: degree of spread to regional lymph nodes ▫ M: presence of distant metastasis ▫ V: vascular invasion ▪ FIGO (International Federation of Gynecology and Obstetrics): stages ▫ Stage 0: carcinoma in situ (premalignant lesions) ▫ Stage I: lesions limited to primary ▫ Stage II: nearby organs/tissues affected ▫ Stage III: distant pelvic organs/tissues, nodes ▫ Stage IV: distant metastases out of the pelvis

TREATMENT SURGERY

▪ Tumor debulking, tumor, lymph node, organ resection

OTHER INTERVENTIONS ▪ Chemotherapy, radiotherapy

Chapter 124 Female Genitourinary Cancers

CERVICAL CANCER osms.it/cervical-cancer PATHOLOGY & CAUSES

SIGNS & SYMPTOMS

▪ Cancer arising from cervix ▪ Mainly caused by two strands of human papillomavirus (HPV): 16, 18 ▪ HPV invades two kinds of cells ▫ Immature basal cells of squamous epithelium ▫ Cells of squamocolumnar junction ▪ HPV makes viral proteins E6, E7 → interfere with cell growth regulation ▪ E6, E7 inhibit tumor suppressor proteins (p53) → ↓ DNA repair/↑ cell turn over → ↑ mutations → cancer ▪ Precancerous cervical changes ▫ Cervical dysplasia, cervical intraepithelial neoplasia (CIN), adenocarcinoma in situ (AIS)

▪ Usually asymptomatic in early stage ▪ Irregular/heavy vaginal bleeding, dyspareunia, postcoital bleeding, pelvic/ lower back pain ▪ Watery, mucoid, purulent vaginal discharge ▪ Hematuria, hematochezia

DIAGNOSIS DIAGNOSTIC IMAGING Chest X-ray ▪ Lung metastasis Colposcopy ▪ Cervical lesions

TYPES Squamous cell carcinoma ▪ Most common (85–90%) Adenocarcinoma ▪ Glandular (10–15%)

RISK FACTORS

▪ HPV 16/18 infections, smoking, prolonged use of oral contraceptives, early sexual activity (< 21 years old), multiple sexual partners, STIs, other vaginal/vulvar cancers, immunodeficiency (e.g. HIV/AIDS)

COMPLICATIONS

▪ Hematogenous metastases (e.g. lungs, liver, bone)

Figure 124.1 An MRI scan in the sagittal plane of the abdomen and pelvis. There is carcinoma which has entirely replaced the cervix and invaded the uterus and vagina.

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LAB RESULTS

▪ Pap test ▫ Abnormal cervical cytology ▪ Cervical biopsy (definitive diagnosis)

OTHER DIAGNOSTICS ▪ Staging ▫ TNM ▫ FIGO

TREATMENT SURGERY

▪ CIN ▫ Cryosurgery, laser ablation, loop electrosurgical excision procedure (LEEP)/large loops excision of transformation zone (LLETZ) ▪ Stage IA cancer ▫ Conization, hysterectomy ▪ Stage IB, IIA cancer ▫ Radical hysterectomy + bilateral pelvic lymphadenectomy ▪ Stage IVB, recurrent cancer ▫ Pelvic exenteration

Figure 124.2 A cervical smear stained with Papanicolaou stain demonstrating cervical squamous cell carcinoma. The squamous cells have large dark, irregular nuclei and orangeophilic cytoplasm.

OTHER INTERVENTIONS

▪ Stage IB, IIA cancer ▫ External beam radiation + brachytherapy ▪ Stage IIB, III, IVA cancer ▫ Radiation therapy, brachytherapy ▪ Stage IVB, recurrent cancer ▫ Radiation therapy, systemic chemotherapy, palliative care ▪ Prevention ▫ Pap test, HPV vaccine

Figure 124.3 The appearance of cervical intraepithelial neoplasia at colposcopy. The area of CIN turns “acetowhite” upon application of acetic acid.

Figure 124.4 The cytological appearance of a low grade cervical intraepithelial lesion. The abnormal cells have large, folded nuclei and perinuclear halos. Normal squamous cells are seen on the right for comparison.

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Chapter 124 Female Genitourinary Cancers

CHORIOCARCINOMA osms.it/choriocarcinoma PATHOLOGY & CAUSES

SIGNS & SYMPTOMS

▪ Highly malignant epithelial tumor arising from trophoblastic tissue (e.g. molar pregnancy, abortion, ectopic, preterm/term intrauterine pregnancy) ▪ Germ cell tumor; may arise in ovary/testis (in individuals who are biologically male) ▪ Histology ▫ Anaplastic cytotrophoblasts, syncytiotrophoblasts; no villi ▪ Altered paternal genomic imprinting → excessive expression of paternal genes → excessive proliferation of trophoblastic tissue → gestational trophoblastic disease (GTD) (e.g. choriocarcinoma) ▪ Excessive proliferation of syncytiotrophoblast → ↑ beta human chorionic gonadotropin (β-hCG) in plasma ▪ ↑ β-hCG → ovarian cysts

▪ Depends on metastasized organs ▫ Vagina: profuse vaginal bleeding, vulvar dark blue papules ▫ Lungs: chest pain, dyspnea, hemoptysis ▫ Brain, meninges: headache, dizziness ▫ Hepatic: jaundice, abdominal tenderness

TYPES Diploid ▪ Biparental chromosomes (e.g. after normal gestation) Aneuploid ▪ Only paternal chromosomes (e.g. postmolar)

RISK FACTORS

▪ Complete molar pregnancy; advanced maternal age (> 40); individuals of Asian, indigenous peoples of the Americas ancestry

Figure 124.5 The gross pathological appearance of the lungs containing metastatic choriocarcinoma.

COMPLICATIONS

▪ Highly vascularized tumor → profuse bleeding ▪ Hematogenous metastasis to other organs (e.g. lungs, brain, liver)

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DIAGNOSIS DIAGNOSTIC IMAGING CT scan/MRI/chest X-ray ▪ Metastasis Pelvic ultrasound ▪ Infiltrative myometrial mass

LAB RESULTS

▪ ↑ serum quantitative β-hCG, liver enzymes ▪ Complete blood count (CBC) ▫ Anemia

OTHER DIAGNOSTICS ▪ Staging ▫ FIGO

Figure 124.7 A CT scan of the abdomen and pelvis in the coronal plane demonstrating a uterine choriocarcinoma.

TREATMENT SURGERY

▪ Hysterectomy, lung resection

OTHER INTERVENTIONS ▪ Chemotherapy, radiotherapy

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Figure 124.6 The histological appearance of a choriocarcinoma. Malignant cytotrophoblasts are stained light pink whereas the syncitiotrophoblasts are stained a darker hue.

Chapter 124 Female Genitourinary Cancers

ENDOMETRIAL CANCER osms.it/endometrial-cancer PATHOLOGY & CAUSES ▪ Cancer arising from endometrium (uterine lining)

TYPES Endometrioid ▪ Result from excess estrogen ▪ ↑ estrogen → endometrial hyperplasia → endometrial intraepithelial neoplasia (EIN) → adenocarcinoma ▪ Related to gene mutations ▫ PIK3CA, CTNNB1, PTEN, ARID1A, KRAS ▪ No Tp53 mutations except in Grade III

DIAGNOSIS DIAGNOSTIC IMAGING CT scan ▪ Metastasis Ultrasound ▪ Endometrium > 5mm thick in postmenopausal individuals

LAB RESULTS

▪ Endometrial biopsy

Nonendometrioid ▪ Estrogen-independent ▪ Arising from endometrial atrophy/polyp ▪ Usually involves Tp53 gene mutation ▪ Two types: clear cell, serous ▪ Clear cell ▫ Precancerous lesions: clear cell intraepithelial neoplasia ▫ Hobnail cells ▫ Very aggressive (FIGO grade III) ▪ Serous ▫ Precancerous lesions: endometrial intraepithelial carcinoma (EIC) ▫ Presence of p53 mutations in EIC ▫ May arise after radiotherapy for cervical carcinoma

SIGNS & SYMPTOMS ▪ Postmenopausal vaginal bleeding, abnormal menstruation (frequent, long, heavy), lower abdominal pain, unusual vaginal discharge, pelvic cramping, dyspareunia

Figure 124.8 The gross pathological appearance of endometrial carcinoma of the lower uterine segment.

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TREATMENT SURGERY

▪ Hysterectomy, pelvic/para-aortic lymphadenectomy

OTHER INTERVENTIONS

▪ Chemotherapy, radiotherapy, hormone therapy

Figure 124.9 The histological appearance of endometrioid endometrial carcinoma. This low-grade variant is composed of backto-back glandular structures with minimal underlying stroma.

GERM CELL OVARIAN TUMOR osms.it/germ-cell-ovarian-tumor PATHOLOGY & CAUSES ▪ Tumors that arise from primordial germ cells of ovaries, benign/malignant, produce β-hCG

TYPES Teratomas ▪ Contain all types of tissues (e.g. hair, teeth, neurons) ▪ Immature teratomas ▫ Specifically arise from neuroectoderm cells; usually malignant ▪ Mature cystic teratomas (AKA dermoid cysts) ▫ Arise from any germ layers; common in young individuals who are biologically female Yolk sac tumor (endodermal sinus tumor) ▪ Germ cells differentiate into yolk sac tissue ▪ Most common germ cell tumor in children ▪ Very aggressive ▪ Schiller–Duval Bodies: rings of cells around central blood vessels

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Dysgerminoma ▪ Most common malignant ovarian tumor ▪ Germ cells turn into oocytes → grow uncontrollably → cancer ▪ Central nuclei surrounded by clear cytoplasm

RISK FACTORS

▪ Endometriosis, polycystic ovarian syndrome (PCOS) ▪ Genetic ▫ BRCA-1/BRCA-2 mutations ▪ Lynch syndrome (hereditary nonpolyposis colorectal cancer)

SIGNS & SYMPTOMS ▪ Sister Mary Joseph Nodule (umbilical metastasis) ▪ ↑ β-hCG ▫ Precocious puberty, unusual vaginal bleeding, pregnancy symptoms (e.g. breast tenderness, mood swing, nausea) ▪ Abdominal distension, bowel obstruction, abdominal/pelvic pain, dyspareunia

Chapter 124 Female Genitourinary Cancers

DIAGNOSIS DIAGNOSTIC IMAGING CT scan/MRI ▪ Pelvic masses Pelvic ultrasound ▪ Cystic/solid pelvic masses

LAB RESULTS

▪ Serum tumor markers ▫ ↑ β-hCG, alpha fetoprotein (not always present with immature teratomas), lactate dehydrogenase (in dysgerminomas) ▪ Biopsy (definitive diagnosis)

TREATMENT SURGERY

▪ Resection of affected ovary ▪ Bilateral pelvic, para-aortic lymphadenectomy ▪ Omentectomy

OTHER INTERVENTIONS

Figure 124.10 The histological appearance of a mature cystic teratoma. There is a dermal component (upper section) and a neural component (lower section).

▪ Chemotherapy (if metastasized), radiotherapy

Figure 124.11 A mature cystic teratoma, the most common form of ovarian germ-cell tumor. This specimen contains mature dermal elements which give rise to the hair seen here.

OSMOSIS.ORG 747

KRUKENBERG TUMOR osms.it/krukenberg-tumor PATHOLOGY & CAUSES ▪ Ovarian cancer metastasized from another primary site ▪ Usually metastasizes from gastrointestinal (GI) tract/breast ▪ Likely spreads to ovaries by lymphatics ▪ Involves both ovaries ▪ Mucin-secreting signet ring cells

TREATMENT SURGERY

▪ Remove metastases

OTHER INTERVENTIONS ▪ Chemotherapy

SIGNS & SYMPTOMS ▪ ▪ ▪ ▪ ▪

Pelvic/abdominal pain Bloating Ascites Dyspareunia Vaginal bleeding

DIAGNOSIS DIAGNOSTIC IMAGING CT scan/MRI ▪ Ovarian mass coexisting colic/gastric lesions

LAB RESULTS

▪ Biopsy (definitive diagnosis) ▫ Ovary

OTHER DIAGNOSTICS

▪ Laparotomy ▫ Ovarian mass + tumors in GI tract

748 OSMOSIS.ORG

Figure 124.12 The gross pathological appearance of a Krukenberg tumor. The ovary has been entirely replaced by metastasis.

Chapter 124 Female Genitourinary Cancers

SEX CORD-GONADAL STROMAL TUMOR osms.it/sex_cord-gonadal_stromal_tumor PATHOLOGY & CAUSES ▪ Arise from ovarian follicle cells, stromal/ connective tissue cells ▪ Benign/malignant

TYPES Granulosa-theca cell tumor ▪ Most common malignant stromal tumor in middle-aged individuals who are biologically female ▪ Causes estradiol overproduction → early puberty, uterine bleeding, breast tenderness ▪ Call–Exner bodies ▫ Tiny fluid pockets scattered in tissue

Figure 124.13 The gross pathological appearance of a Sertoli–Leydig cell tumor, a kind of sex cord stromal tumor. The cut surface is yellow and lobulated.

Sertoli-Leydig cell tumors ▪ Similar to testicular sertoli, Leydig cell tumors ▪ Made of primitive gonadal stroma → secretion of testosterone → hirsutism ▪ Reinke crystals (pink, rod-like) Fibroma ▪ Benign ▪ Made of fibroblasts ▪ Needle-like strands (elongated nuclei) under microscope ▪ Associated with ascites, pleural effusion ▪ Compress uterine round ligament → pulling sensation in groin

RISK FACTORS

Figure 124.14 The histological appearance of a Sertoli–Leydig cell tumor. There are two popualtions of cells. The Leydig cells have large amounts of eosinophilic cytoplasm, whereas the Sertoli cells have less cytoplasm which is pale in appearance.

▪ Endometriosis, PCOS ▪ Genetic ▫ BRCA-1/BRCA-2 mutations ▪ Lynch syndrome

OSMOSIS.ORG 749

SIGNS & SYMPTOMS ▪ Uterine bleeding, breast tenderness, early puberty (in young individuals who are biologically female), Sister Mary Joseph Nodule (umbilical metastasis), ascites, abdominal masses, bowel obstruction, abdominal distension, abdominal/pelvic pain, bloating, dyspareunia

DIAGNOSIS DIAGNOSTIC IMAGING

Figure 124.15 The gross pathology of an ovarian fibroma. The tumor has a homogenous, firm, cream-colored surface.

Pelvic ultrasound/CT scan/MRI ▪ Solid/cystic masses

LAB RESULTS

▪ Serum tumor markers ▫ ↑ β-hCG, neural cell adhesion molecule (NCAM) ▪ Biopsy (definitive diagnosis)

TREATMENT SURGERY

▪ If postmenopausal/childbearing completed ▫ Abdominal hysterectomy, bilateral salpingo-oophorectomy ▪ Fertility-sparing with one affected ovary ▫ Unilateral salpingo-oophorectomy for early-stage disease

OTHER INTERVENTIONS

▪ Chemotherapy (if metastasized) ▪ Radiotherapy

750 OSMOSIS.ORG

Figure 124.16 The histological appearance of an ovarian fibroma. The tumor is composed of spindles with interesecting bundles of collagen.

Chapter 124 Female Genitourinary Cancers

SURFACE EPITHELIAL-STROMAL TUMOR osms.it/surface_epithelial-stromal_tumor PATHOLOGY & CAUSES AKA ovarian adenocarcinoma Most common type of ovarian tumor Benign/malignant/borderline Originates from ovarian surface epithelium, fallopian tubes ▪ Mutation in epithelial cells → uncontrollable division → tumors ▪ ▪ ▪ ▪

TYPES Serous ▪ Benign/malignant/borderline ▪ Usually bilateral ▪ Serous cystadenoma if benign ▪ Serous cystadenocarcinoma if malignant ▪ Psammoma bodies → cystadenocarcinomas

Figure 124.17 The histological appearance of an ovarian, high-grade serous carcinoma. There is wild cellular and nuclear pleomorphism, marked atypia and psammomatous calcification.

Endometrioid ▪ Cyst filled with dark blood (chocolate color) ▪ AKA chocolate cysts ▪ Develop from ectopic endometrial cells Mucinous ▪ Usually unilateral ▪ Characterized by lining of tall columnar epithelial cells ▪ Mucinous cystadenoma if benign ▪ Mucinous cystadenocarcinoma if malignant ▪ Can cause pseudomyxoma peritonei ▪ Huge cystic masses (> 25kg/55lbs)

Figure 124.18 The gross pathological appearance of an ovarian mucinos neoplasm. The tumor is composed of innumerable mucin-filled cysts lined by mucin-producing epithelium.

OSMOSIS.ORG 751

RISK FACTORS

▪ Endometriosis, PCOS ▪ Genetic ▫ BRCA-1/BRCA-2 mutations ▪ Lynch syndrome

SIGNS & SYMPTOMS Figure 124.19 The histological appearance of a mucinous neoplasm of the ovary. There are multiple cystic spaces all of which are lined by columnar epithelium.

▪ Uterine bleeding, breast tenderness, early puberty, Sister Mary Joseph Nodule (umbilical metastasis), ascites, abdominal masses, bowel obstruction, abdominal distension, abdominal/pelvic pain, bloating, dyspareunia

DIAGNOSIS

Clear cell ▪ Large epithelial cells with clear cytoplasm ▪ Associated with endometrioid carcinoma of ovaries

DIAGNOSTIC IMAGING

Transitional/Brenner ▪ Resembles bladder epithelium (transitional cells) ▪ Can be associated with endometriosis ▪ Similar to cell carcinoma of endometrium

LAB RESULTS

Pelvic ultrasound, CT scan/MRI ▪ Cystic ovarian masses

▪ Serum tumor markers ▫ ↑ β-hCG ▪ Biopsy (definitive diagnosis)

TREATMENT SURGERY

▪ If postmenopausal/childbearing completed ▫ Abdominal hysterectomy, bilateral salpingo-oophorectomy ▪ Fertility-sparing with one affected ovary ▫ Unilateral salpingo-oophorectomy for early-stage disease

OTHER INTERVENTIONS Figure 124.20 The gross pathological appearance of a Brenner tumor. The tumor is sharply circumscribed, firm and has a pale tan to yellow cut surface.

752 OSMOSIS.ORG

▪ Chemotherapy (if metastasized) ▪ Radiotherapy ▪ Serum CA-125 levels (monitor response to therapy)

NOTES

NOTES

GENITOURINARY TRACT INFECTIONS

GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Infections of genital/urinary tract

CAUSES

▪ Mostly bacteria

RISK FACTORS

▪ Recent sexual activity ▪ High-risk sexual behavior ▪ Previous genitourinary tract infections

COMPLICATIONS

▪ Pelvic inflammatory disease, infertility, pyelonephritis, epididymitis, prostatitis, sepsis, abscesses

SIGNS & SYMPTOMS ▪ Abdominal pain, altered vaginal/urethral discharge, dysuria, fever

DIAGNOSIS LAB RESULTS

▪ Vaginal/urethral discharge microscopy ▪ Nucleic acid amplification tests (NAATs)

OTHER DIAGNOSTICS ▪ Clinical examination

TREATMENT MEDICATIONS

▪ Antibiotic therapy

PELVIC INFLAMMATORY DISEASE osms.it/pelvic-inflammatory-disease PATHOLOGY & CAUSES ▪ Infection, inflammation of upper genital tract (uterus, ovaries, fallopian tubes) in individuals who are biologically female ▪ Common pathogens: Chlamydia trachomatis, Neisseria gonorrhoeae, vaginal flora bacteria (e.g. Gardnerella vaginalis); often polymicrobial ▪ Bacterial vaginosis (alteration in vaginal flora) present in ⅔ of PID cases ▫ Anaerobic bacteria replace lactobacilli

in vagina → enzyme production → degradation of cervical mucus, antimicrobial agents → infections spread ▪ Associated syndromes ▫ Endometritis, salpingitis, oophoritis, peritonitis, perihepatitis (liver capsule inflammation), tubo-ovarian abscess ▪ Vaginal mucosa colonization → disruption of endocervical canal barrier → pathogens ascend to upper genital structures → inflammation

OSMOSIS.ORG 753

RISK FACTORS

▪ More common in individuals who are biologically female, < 25 years old, sexually active ▪ Multiple sexual partners ▪ Partner with sexually transmitted disease (STD) ▪ Personal history of PID/STD ▪ Unprotected sexual intercourse ▪ Cervix instrumentation (e.g. abortion)

COMPLICATIONS

▪ Recurrent PID, hydrosalpinx (fluid-filled fallopian tubes), pyosalpinx (infected fallopian tube filled with purulent matter), chronic pelvic pain, infertility, ectopic pregnancy, ovarian cancer

SIGNS & SYMPTOMS Acute symptomatic PID ▪ Bilateral lower abdominal/pelvic pain ▫ Abrupt onset during/after menstruation ▫ Constant, aching ▫ Worsens during sexual intercourse/ movement ▪ Abdominal/pelvic organ tenderness ▪ Feeling of pelvic fullness ▪ Intermenstrual/postcoital bleeding ▪ Dysuria ▪ Low-grade fever ▪ Rebound tenderness, fever, ↓ bowel sounds (severe) Chronic PID ▪ Low-grade fever, weight loss, abdominal pain Perihepatitis (Fitz-Hugh–Curtis syndrome) ▪ Right upper quadrant pain, tenderness

DIAGNOSIS DIAGNOSTIC IMAGING Pelvic/abdominal ultrasound ▪ Fluid-filled fallopian tubes with cogwheel sign (thickened loops on cross-section) ▪ Endometrium changes (e.g. wall thickening)

754 OSMOSIS.ORG

▪ Tubo-ovarian abscess (thick walls, multilocular cyst)

LAB RESULTS

▪ Vaginal discharge microscopy ▫ Saline microscopy, Gram stain ▫ ↑ leukocytes ▫ Clue cells (epithelial cells surrounded by bacteria) in bacterial vaginosis ▪ Nucleic acids amplification tests (NAATs) ▫ C. trachomatis, N. gonorrhoeae ▪ Tissue biopsy ▫ ↑ plasma cells, neutrophils (inflammation) ▪ Leukocytosis, ↑ C-reactive protein (CRP), ↑ erythrocyte sedimentation rate (severe)

OTHER DIAGNOSTICS

▪ Speculum exam ▫ Mucopurulent cervical discharge (positive swab test)

TREATMENT MEDICATIONS Broad-spectrum antibiotic therapy ▪ Inpatient (parenteral) ▫ Cefoxitin/cefotetan (cephalosporin) + doxycycline (tetracycline) ▫ Clindamycin (lincosamide) + gentamicin (aminoglycoside) ▪ Outpatient ▫ Ceftriaxone/cefoxitin (cephalosporin) + doxycycline (tetracycline) ▪ Pelvic abscess ▫ Clindamycin/metronidazole + doxycycline Antiemetic medication ▪ E.g. metoclopramide Antipyretic medication ▪ E.g. acetaminophen

OTHER INTERVENTIONS

▪ Prevention ▫ Barrier contraception (e.g. condoms) ▫ Abstinence

Chapter 125 Genitourinary Tract Infections

Figure 125.1 An MRI scan of the pelvis in the sagittal plane demonstrating a right-sided pyosalpinx.

URETHRITIS osms.it/urethritis PATHOLOGY & CAUSES ▪ Inflammation of urethra; more common in individuals who are biologically male with sexually transmitted diseases ▪ Common coinfection with other STDs ▪ Incubation period: 4–8 days

CAUSES

▪ Infectious urethritis (most common) ▫ Gonococcal: Neisseria gonorrhoeae ▫ Non-gonococcal: Chlamydia trachomatis (most common), Mycoplasma genitalium ▪ Non-infectious urethritis ▫ Chemical irritation (e.g. soaps, spermicides) ▫ Trauma

RISK FACTORS

▪ Individuals who are biologically male, young ▪ Multiple sexual partners ▪ Partner with sexually transmitted disease (STD) ▪ Unprotected sexual intercourse

COMPLICATIONS

▪ Reactive arthritis related to C. trachomatis, gonococcal conjunctivitis, epididymitis, prostatitis, penile lymphangitis, periurethral abscess

SIGNS & SYMPTOMS ▪ Sometimes asymptomatic ▪ Dysuria ▪ Urethral pruritus, discharge (mucoid, watery, purulent) ▪ Inflammation/edema of urethral meatus

OSMOSIS.ORG 755

DIAGNOSIS LAB RESULTS

▪ Diagnosis criteria (≥ one) ▫ Mucopurulent/purulent urethral discharge ▫ ≥ one leukocyte per oil immersion field in Gram stain of urethral discharge ▫ Positive leukocyte esterase, ≥ 10 leukocytes per high-power field (firstcatch urine) ▪ NAATs ▫ C. trachomatis, N. gonorrhoeae ▪ Urethral discharge microscopy (e.g. Gram stain)

OTHER DIAGNOSTICS

▪ Clinical examination ▫ Gonorrhoea: purulent discharge ▫ Chlamydia: isolated dysuria ▫ Herpes simplex virus (HSV): dysuria + painful genital ulcers

756 OSMOSIS.ORG

TREATMENT MEDICATIONS Antibiotic therapy ▪ Gonococcal urethritis ▫ Ceftriaxone (cephalosporin) + azithromycin (macrolide) ▪ Non-gonococcal urethritis ▫ Azithromycin or doxycycline (tetracycline) ▫ Azithromycin/moxifloxacin (persisent)

OTHER INTERVENTIONS

▪ Prevention ▫ Barrier contraception (e.g. condoms) ▫ Abstinence

NOTES

NOTES

INFERTILITY & FETAL LOSS

GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Disorders that adversely affect the function of the female reproductive system fertility

SIGNS & SYMPTOMS ▪ See individual disorders

DIAGNOSIS DIAGNOSTIC IMAGING ▪ Ultrasound

LAB RESULTS

▪ Serum hormonal levels

OTHER DIAGNOSTICS ▪ Obstetric history

TREATMENT ▪ See individual disorders

AMENORRHOEA osms.it/amenorrhoea PATHOLOGY & CAUSES ▪ Abnormal menstruation cessation/absence in biologically female people of reproductive age, not related to menopause/pregnancy/ lactation

TYPES

▪ Primary amenorrhoea ▫ Failure to reach menarche by age 15 years ▪ Secondary amenorrhoea ▫ Previously regular menses ceases for three months or longer

RISK FACTORS

▪ Hypothalamic-pituitary-gonadal axis does not induce cyclic changes in the endometrium ▫ Hypothalamic dysfunction (e.g. GnRH deficiency, traumatic injury, functional (stress, excessive exercise, eating disorders, systemic illness) ▫ Pituitary dysfunction (e.g. empty sella syndrome, pituitary tumor/infarct) ▫ Ovarian dysfunction (e.g. primary ovarian insufficiency (POI), Turner syndrome, FMR1 mutation) ▪ Psychogenic amenorrhea ▫ Pseudocyesis (false pregnancy)

OSMOSIS.ORG 757

▪ Outflow tract disorders ▫ E.g. Müllerian agenesis (Mayer– Rokitansky–Kuster–Hauser syndrome), intrauterine adhesions (Asherman syndrome) ▪ Other ▫ Polycystic ovary syndrome (PCOS) ▫ Hypo/hyperthyroidism ▫ Hormone receptor abnormalities ▫ Enzyme deficiencies

COMPLICATIONS

▪ Infertility ▪ Osteoporosis ▪ Psychological distress

SIGNS & SYMPTOMS ▪ Menses absent ▪ Clinical presentation of causative disorder

DIAGNOSIS ▪ Evaluate secondary sexual characteristics (Tanner staging) ▪ Discrepancy in Tanner stage and age may indicate constitutional puberty delay, Turner syndrome ▪ ↑ body mass index (BMI) + hyperandrogenism signs (acne, hirsutism) may indicate PCOS

DIAGNOSTIC IMAGING Pelvic ultrasound/hysteroscopy ▪ Detects structural abnormalities Head MRI ▪ Identifies pituitary anomalies

LAB RESULTS

▪ ↑ hGH indicates pregnancy ▪ ↑ serum prolactin indicates pituitary adenoma, prolactinoma ▪ Follicle stimulating hormone (FSH) ▫ ↑ level indicates Turner syndrome, primary ovarian insufficiency (POI)

758 OSMOSIS.ORG

▫ ↓ level indicates functional hypothalamic amenorrhea/hypothalamic-pituitary disorders ▪ ↓ luteinizing hormone level indicates functional hypothalamic amenorrhea/ hypothalamic-pituitary disorders ▪ ↓ estradiol indicates abnormal ovarian function ▪ ↑ free and total testosterone indicates PCOS, ovarian/adrenal tumor

OTHER DIAGNOSTICS

▪ Progesterone challenge test ▫ Oral medroxyprogesterone administered daily for 7–10 days → withdrawal bleeding when hormone stopped indicates adequate endogenous estrogen level, rules out outflow tract abnormality ▫ If no withdrawal bleeding, administer estrogen + progestin daily for 10 days → failure to bleed indicates abnormal endometrium ▪ Karyotype ▫ E.g. Turner syndrome (45,X), Müllerian agenesis (46,XX) ▪ Genetic testing ▫ Fragile X syndrome (FMR1) associated with primary ovarian insufficiency

TREATMENT MEDICATIONS

▪ Hypothalamic dysfunction ▫ Oral contraceptives if pregnancy not desired, gonadotropins if pregnancy desired ▪ Ovarian insufficiency ▫ Estrogen, progesterone replacement

SURGERY

▪ Tumor: surgical resection ▪ Surgically correct anatomic abnormalities preventing outflow

PSYCHOTHERAPY

▪ If functional hypothalamic dysfunction, address underlying cause (e.g. eating disorder)

Chapter 126 Infertility & Fetal Loss

OTHER INTERVENTIONS

▪ Specific treatments for causative morbidities (e.g. PCOS, thyroid disorders) ▪ Treat complications (e.g. estrogen replacement therapy, calcium + vitamin D supplements)

ECTOPIC PREGNANCY osms.it/ectopic-pregnancy PATHOLOGY & CAUSES TYPES

▪ Ectopic pregnancy ▫ Pregnancy in which fertilized ovum is implanted at site other than uterine endometrium ▪ Heterotopic pregnancy (rare) ▫ Concurrent ectopic pregnancy and intrauterine pregnancy

CAUSES

▪ Altered anatomy/function (e.g. impaired tubal motility)

▪ Inflammatory-induced tubal damage, distorted/blocked patency → disrupted blastocyst progress to endometrial implantation site ▪ Ectopic sites ▫ Fallopian tube (most common site, especially ampullary region) ▫ Cervical ▫ Abdominal ▫ Ovarian ▫ Interstitial/cornual (implantation where fallopian tube passes through myometrium) ▫ Uterine cesarean scar

OSMOSIS.ORG 759

RISK FACTORS ▪ ▪ ▪ ▪

▪ ▪ ▪ ▪ ▪ ▪ ▪ ▪ ▪

Previous tubal pregnancy Cesarean section history Endometriosis Infection, pelvic inflammatory disease (e.g. salpingitis) ▫ Chlamydia: damages cilia lining fallopian tube ▫ Gonorrhea: causes clubbed fimbriae, blocked/tortuous tube Previous pelvic surgery Congenital anomalies Tumors Smoking (dose-dependant) Vaginal douching Risk increases with age Intrauterine device (IUD) use (past and present) Use of assisted reproductive technologies (ART) In utero diethylstilbestrol (DES) exposure

COMPLICATIONS

▪ Rupture of fallopian tube or other structures, leading to profound bleeding ▫ May be life-threatening ▪ Pregnancy loss ▪ Infertility ▪ A significant cause of pregnancy-related maternal mortality in first trimester

SIGNS & SYMPTOMS ▪ May be asymptomatic before rupture ▪ Common triad of symptoms ▫ Variable bleeding (spotting/intermittent/ hemorrhage) ▫ Lower abdominal pain/tenderness (abrupt/slow, continuous/intermittent) ▫ Menses absent ▪ Other symptoms ▫ Normal early pregnancy discomforts (e.g. nausea, breast tenderness) ▪ Symptoms of rupture (surgical emergency) ▫ Severe abdominal pain (may refer to shoulder with phrenic nerve irritation; rebound tenderness, guarding indicates peritoneal irritation) ▫ Hemodynamic instability (feeling faint, syncope; tachycardia; hypotension; diaphoresis)

DIAGNOSIS ▪ Pelvic examination ▫ Can identify source of bleeding ▪ Gentle adnexal palpation (light pressure to avoid rupture) ▫ Palpable mass, cervical motion, adnexal, abdominal tenderness

DIAGNOSTIC IMAGING

Figure 126.1 A ruptured cornual ectopic pregnancy following surgical removal. The fallopian tube (left) is distended at the junction with the cornu. The fetus is present on the right with an intact embryonic sac.

760 OSMOSIS.ORG

Ultrasound ▪ Combination of empty uterus on ultrasound with a positive pregnancy test can confirm diagnosis ▪ If hemodynamically unstable ▫ Abdominal Focused Assessment with Sonography for Trauma (FAST): detects peritoneal bleeding, indicates rupture ▪ If stable ▫ Transvaginal ultrasound (TVUS): locates anatomical pregnancy site

LAB RESULTS

▪ ↑ serum human chorionic gonadotropin indicates pregnancy

Chapter 126 Infertility & Fetal Loss

TREATMENT MEDICATIONS

▪ If unruptured ▫ Methotrexate: folic acid antagonist inhibits DNA synthesis, cellular replication

SURGERY

Figure 126.2 A Doppler ultrastound scan of the pelvis demonstrating the ring of fire sign in an individual with a tubal ectopic pregnancy.

▪ If ruptured, laparoscopic surgery ▫ Salpingectomy: fallopian tube removal (standard practice) ▫ Salpingostomy: tubal incision to remove tubal gestation only

OTHER INTERVENTIONS

▪ Stabilization measures if hemodynamic compromise is evident

MISCARRIAGE osms.it/miscarriage PATHOLOGY & CAUSES ▪ Loss of pregnancy < 20 gestation weeks ▫ AKA spontaneous abortion

TYPES

▪ Complete ▫ Spontaneous passage of all products of conception ▪ Incomplete (inevitable) ▫ Bleeding, partially dilated cervix, ruptured membranes, products of conception remain in utero ▪ Threatened ▫ Embryo/fetus jeopardized by bleeding, viable pregnancy, closed cervix ▪ Missed ▫ Intrauterine fetal death that is not expelled ▪ Recurrent ▫ History of ≥ three spontaneous pregnancy losses

RISK FACTORS

Prior miscarriage Multiparity Advanced maternal age Smoking, substance abuse (e.g. cocaine) Chromosomal abnormalities (e.g. aneuploidies) ▪ Structural uterine anomalies (e.g. cervical insufficiency, fibroids) ▪ Maternal infections ▫ Bacterial vaginosis ▫ Toxoplasmosis ▫ Coxsackie virus infection ▫ Paramyxovirus infection (measles, mumps) ▪ Maternal comorbidities ▫ Thrombophilia: ↑ decidual thrombosis risk ▫ Hypothyroidism: thyroid peroxidase autoantibodies → may impair thyroid function during pregnancy ▫ Diabetes mellitus: poor glycemic control ▪ ▪ ▪ ▪ ▪

OSMOSIS.ORG 761

(teratogenic effects of hyperglycemia; maternal vascular disease → uteroplacental insufficiency) ▫ Systemic lupus erythematosus: uteroplacental insufficiency, antiphospholipid antibodies, lupus anticoagulant ▫ Obesity: may be related to insulin resistance ▪ Trauma ▫ Iatrogenic: invasive intrauterine procedures (e.g. chorionic villus sampling, amniocentesis) ▫ Other injuries ▪ Idiopathic

762 OSMOSIS.ORG

COMPLICATIONS

▪ Vaginal blood/clots/fetal tissue passage ▪ Infection (e.g. septic abortion related to infection and retained products of conception) ▪ Disseminated intravascular coagulation (DIC) ▫ Missed abortion → retained products release chemical mediators → coagulopathy

Chapter 126 Infertility & Fetal Loss

SIGNS & SYMPTOMS ▪ Vaginal bleeding ▪ Cramping abdominal/suprapubic pain

DIAGNOSIS ▪ Internal digital examination ▫ Evaluates cervical dilation ▪ Vaginal speculum exam ▫ Determines cervical dilation, characteristics of blood or tissue

DIAGNOSTIC IMAGING Ultrasound ▪ TVUS ▫ < nine gestation weeks ▪ Transabdominal ▫ ≥ nine gestation weeks

LAB RESULTS

▪ Urine ▫ ↑ hCG confirms pregnancy ▪ Complete blood count ▫ Evaluates blood loss degree ▪ Blood type and Rh(D) testing ▫ Determines risk for isoimmunization

TREATMENT MEDICATIONS

▪ Inevitable/incomplete/missed abortion (nonviable pregnancy) ▫ If medically stable: medical evacuation (prostaglandin E1 analog, antiprogesterone); expectant management (allow for natural passage) ▪ Prophylaxis with Rho(D) immunoglobulin as indicated

SURGERY

▪ Inevitable/incomplete/missed abortion (nonviable pregnancy) ▫ If medically unstable: surgical evacuation (dilation and curettage/ vacuum extraction)

OTHER INTERVENTIONS

▪ Complete abortion ▫ No medical intervention ▪ Recurrent abortion ▫ Screening for possible causes ▪ Threatened abortion (viable pregnancy) ▫ Expectant management

MOLAR PREGNANCY osms.it/molar-pregnancy PATHOLOGY & CAUSES ▪ Benign abnormal trophoblastic growth, included in disease group called gestational trophoblastic disease (GTD) ▫ AKA hydatidiform mole (HM) ▪ Premalignant disease with potential to develop into gestational trophoblastic neoplasia (GTN), which includes invasive mole, choriocarcinoma, placental site trophoblastic tumor, epithelioid

trophoblastic tumor

TYPES

▪ Classifications based on histopathology, karyotype

Complete hydatidiform mole ▪ Single sperm fertilizes enucleated egg → paternal DNA duplication ▪ Usually diploid 46,XX/46,XY ▪ Contains paternal genetic material only

OSMOSIS.ORG 763

▪ No fetal cells present ▪ Potential to become invasive → malignant gestational trophoblastic disease (GTD) Partial hydatidiform mole ▪ One (normal) egg fertilized by two sperm ▪ Usually triploid 69,XXX/69,XXY/69XYY ▪ Contains maternal and extra paternal genetic material ▪ Some fetal cells evident (e.g. amnion, RBCs) ▪ Not usually associated with choriocarcinoma (< 5%)

CAUSES

▪ When nonviable fertilized ovum implants in uterus → paternal gene overexpression → trophoblastic proliferation, vesicular placental villi swelling → nonviable pregnancy

RISK FACTORS

▪ Obstetric history ▫ Previous molar pregnancy ▫ Spontaneous abortion ▫ Infertility ▪ Maternal age extremes (≤ 15 and > 35 years old) ▪ Low dietary carotene (vitamin A precursor) and animal fat is associated with partial mole

Figure 126.3 A transvaginal ultrasound scan demonstrating a mass within the uterus. The “bunch of grapes” sign is characteristic of a complete molar preganncy.

▪ ▪

▪ ▪

COMPLICATIONS

▪ Potential for malignancy and metastasis (pulmonary, CNS) ▪ Trophoblastic pulmonary emboli ▪ Complete mole (if diagnosed in second trimester) ▫ ↑ ↑ hCG levels → theca lutein cysts (multiloculated cysts due to ovarian hyperstimulation), hyperthyroidism, preeclampsia ▫ Anemia may also be present

SIGNS & SYMPTOMS ▪ Missed menses ▪ Enlarging uterus, feeling of pelvic pressure ▫ Partial mole: small or normal for gestational age

764 OSMOSIS.ORG

▪

▫ Complete mole: large for gestational age Hyperemesis gravidarum ▫ Associated with ↑ ↑ hCG First trimester uterine bleeding ▫ Evident when molar villi separate from underlying decidua ▫ Complete mole: dark, “prune juice”colored discharge (accumulated, oxidized blood) Spontaneous passage of “grape-like” molar vesicles (hydropic villi) Hyperthyroidism ▫ Tachycardia, warm skin, tremor, heat intolerance Preeclampsia ▫ ↑ blood pressure

DIAGNOSIS ▪ Bimanual examination ▫ Assess uterine size

DIAGNOSTIC IMAGING Transvaginal ultrasound ▪ Complete mole ▫ No embryo, fetus, or gestational sac visualized; absent fetal heartbeat ▫ Absence of amniotic fluid ▫ Numerous anechoic spaces contained

Chapter 126 Infertility & Fetal Loss in a central heterogeneous mass: snowstorm, bunch of grapes, or swiss cheese pattern ▫ Theca lutein cysts ▪ Incomplete mole ▫ A fetus may be identified ▫ Amniotic fluid is present ▫ Chorionic villi echogenicity ▫ Usually no theca lutein cysts Chest X-ray ▪ Screen for metastasis

LAB RESULTS

▪ ↑ ↑ serum hCG ▪ Blood type and Rh(D) testing ▫ Determines risk for isoimmunization ▪ Histopathologic analysis of evacuated material (definitive diagnosis) ▫ Hydropic swelling of chorionic villi (cluster of grapes tissue)

OTHER DIAGNOSTICS

▪ Monitoring hCG levels to assess malignant transformation

Figure 126.4 The histological appearance of a complete mole. The chorionic villi are expanded by loose fibrillar material (hydropic) and the overlying trophoblasts demonstrate marked atypical hyperplasia.

MEDICATIONS

▪ Actinomycin D ▫ Chemoprophylaxis for complete mole ▪ Rh(D) immune globulin if indicated

SURGERY

▪ Hysterectomy ▫ If ≥ 40 years old and/or do not wish further pregnancies

OTHER INTERVENTIONS

▪ Periodic (usually weekly) monitoring of hCG levels at regular intervals + reliable contraception until hCG is undetectable ▫ Persistent elevation indicates postmolar gestational trophoblastic neoplasia

Figure 126.5 A CT scan of the pelvis in the axial plane demonstrating a molar pregnancy. The uterine corpus is distended by heterogenously enhancing mass. There is no evidence of a fetus.

TREATMENT ▪ Uterine evacuation: suction and curettage

Figure 126.6 The histological appearance of a partial mole. In contrast to a complete mole, there will be both normal villi (right of image) and hydropic villi (left of image). Trophoblastic proliferation is minimal.

OSMOSIS.ORG 765

NOTES

NOTES

MALE GENITOURINARY CANCERS

GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Male reproductive, urinary system cancers

CAUSES

▪ Depends on cancer type

RISK FACTORS

▪ Depends on cancer type ▫ Tobacco smoking, increased age, positive family history

COMPLICATIONS

▪ Metastasis, affected part function loss

SIGNS & SYMPTOMS ▪ Depends on cancer type ▫ Dysuria, painful ejaculation, back pain, hematuria/hematospermia, pelvic pain, weight loss, lower back/abdominal pain

DIAGNOSIS DIAGNOSTIC IMAGING ▪ CT scan/MRI/ultrasound ▪ Identify lesions

LAB RESULTS

▪ Serum tumor markers

766 OSMOSIS.ORG

OTHER DIAGNOSTICS ▪ History/physical exam

Biopsy ▪ Grading ▫ GX: grade cannot be assessed (undetermined grade) ▫ G1: well differentiated (low grade) ▫ G2: moderately differentiated (intermediate grade) ▫ G3: poorly differentiated (high grade) ▫ G4: undifferentiated (high grade) Staging ▪ Tumor, nodes, metastasis (TNM) system; scored 0–4 ▫ T: size, sites invaded (e.g. only testis/ extratesticular invasion) ▫ N: degree of spread to regional lymph nodes ▫ M: distant metastasis presence ▫ V: Vascular invasion

TREATMENT MEDICATIONS ▪ Chemotherapy

SURGERY

▪ See individual cancers

OTHER INTERVENTIONS ▪ Radiotherapy

Chapter 127 Male Genitourinary Cancers

PENILE CANCER osms.it/penile-cancer PATHOLOGY & CAUSES ▪ ▪ ▪ ▪

Malignant penis tumor Rare in high-income countries Initial lesions found on prepuce, glans Can invade corpora, shaft of penis → penile autoamputation

TYPES Squamous cell carcinoma (SCC) ▪ Most predominant; melanoma, small-cell carcinoma, Kaposi sarcoma, Meckel cell carcinoma, basal cell carcinoma, etc. ▪ Bowenoid papulosis ▫ SCC form in situ of penis ▪ Erythroplasia of Queyrat ▫ SCC of penis glans, presents as erythroplakia (red patch) Histologic subtypes of SCC ▪ Usual type ▫ Most predominant ▫ Involves corpus spongiosum ▫ Invades perineural, regional lymphovascular system ▪ Papillary carcinoma ▫ Involves superficial erectile tissues ▫ Not associated with human papillomavirus (HPV) ▫ Histology: papillomatosis, hyperkeratosis ▪ Warty tumors ▫ Associated with HPV infection ▫ Histology: irregular stroma with papillary fibrovascular core ▪ Basaloid carcinoma ▫ Associated with HPV ▫ Histology: necrosis, erectile tissue invasion

▪ Verrucous carcinoma ▫ Not aggressive (low metastatic ability) ▫ Histology: straight papillae, surface, interpapillary hyperkeratosis ▪ Sarcomatoid carcinoma ▫ Very rare ▫ Highly aggressive ▫ Histology: SCC, spindle cell carcinoma components

RISK FACTORS

▪ Infection ▫ HPV 16/18 infection, HIV, urinary tract infections (UTIs) ▪ Genital warts, poor hygiene, phimosis/ paraphimosis, tobacco smoking, smegma accumulation, increased age

COMPLICATIONS

▪ Metastasis ▫ Inguinal/femoral lymph nodes; liver, lung, bone, brain (rare) ▪ Penile autoamputation

SIGNS & SYMPTOMS ▪ Painless mass ▪ Ulcer/rash ▪ Penile pain/foul-smelling discharge/ bleeding ▪ Inguinal lymphadenopathy ▪ Penile skin color change (redness)

DIAGNOSIS DIAGNOSTIC IMAGING CT scan/MRI/ultrasound ▪ Regional lymph, distant metastasis assessment

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OTHER DIAGNOSTICS

▪ Obvious suspicious penile lesions ▪ Biopsy ▫ Diagnosis, tumor grading ▪ Staging ▫ TNM

TREATMENT MEDICATIONS ▪ Chemotherapy

SURGERY

▪ Local excision in early stage ▪ Partial/total penectomy if glans/shaft invaded

Figure 127.1 The clinical appearance of a fungating penile tumor, likely a squamous-cell carcinoma. There is visible lymphadenopathy of the left superficial inguinal chain which almost certainly represents metastatic disease.

OTHER INTERVENTIONS ▪ Radiotherapy

PROSTATE CANCER osms.it/prostate-cancer PATHOLOGY & CAUSES ▪ Very common male cancer ▫ Arises in prostate gland ▪ Second leading cancer death cause in biologically-male individuals ▪ Usually associated with BRCA1/BRCA2 gene mutations ▪ Early cancer cells require androgens to survive ▪ Can later become androgen-independent ▪ Usually arise in prostate’s peripheral zone

TYPES Adenocarcinomas ▪ Most common ▪ Arise from glandular tissues; from luminal/ basal cells

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Transitional cell cancer ▪ Arises from prostatic urethra transitional epithelium cells Small cell prostate cancer ▪ Arise from neuroendocrine cells

RISK FACTORS ▪ ▪ ▪ ▪ ▪ ▪

> 40 years old Black people of African descent ↑ risk Positive family history Smoking Obesity Animal-fat rich diet

COMPLICATIONS

▪ Bone osteolysis → hypercalcemia (rare) ▪ Metastasis ▫ Lymph nodes → more metastasis to distant organs (e.g. lungs)

Chapter 127 Male Genitourinary Cancers ▫ Bones (thoracic/lumbar spine, pelvis) → lower back pain, pathologic fractures → spinal cord compression (if spine involved) → neurological deficits (e.g. lower limb pain/weakness, bowel/ urinary bladder control loss, etc.) ▪ Nearby structure compression/invasion ▫ Urinary bladder/prostatic urethra (later stages) → difficulty urinating; bleeding; urination, ejaculation pain

SIGNS & SYMPTOMS ▪ ▪ ▪ ▪ ▪ ▪

Urinary frequency/hesitancy/incontinence Dysuria Painful ejaculation Lower-back/bone pain Hematuria/hematospermia (rare) Neurological deficits (e.g. weakness/lack of lower limb sensation)

DIAGNOSIS Gleason score ▪ 2–4: low grade ▪ 5–7: moderate grade ▪ 8–10: high grade

Figure 127.2 The histological appearance of prostate adenocarcinoma. On the left the tumor forms vague gland like structures (Gleason 4) and on the right is composed of infiltrating single cells (Gleason 5).

DIAGNOSTIC IMAGING Ultrasound ▪ Hypoechoic areas in prostate → suggestive of cancer X-ray/CT scan/MRI ▪ Lesions in prostate, pelvic lymph nodes, bones ▫ Staging: TNM ▪ Bone scan ▫ Bone metastases presence

LAB RESULTS

▪ ↑ prostate specific antigen (PSA) serum levels ▪ ↑ alkaline phosphatase serum levels ▫ Suggestive of bone metastasis ▪ Biopsy used for Gleason scoring

OTHER DIAGNOSTICS

▪ Digital rectal exam (DRE) ▫ Asymmetric prostate enlargement

Figure 127.3 The histological appearance of prostate adenocarcinoma, Gleason grade 3. The tumor is composed of small, compressed glands with only a tiny amount of intervening stroma.

TREATMENT MEDICATIONS

▪ Anti-androgen therapy ▫ ↓ testosterone levels → ↓ cancer cell growth

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SURGERY

▪ Prostatectomy ▪ Cryosurgery ▪ Orchidectomy ▫ ↓ testosterone levels → ↓ cancer cell growth

OTHER INTERVENTIONS

▪ Active surveillance (early stage) ▫ Regular biopsy, PSA monitoring ▪ Radiotherapy

Figure 127.4 An MRI scan of the pelvis in the axial plane demonstrating prostate adenocarcinoma invading the bladder and the rectum.

TESTICULAR CANCER osms.it/testicular-cancer PATHOLOGY & CAUSES ▪ Cancer develops in testicular cells ▫ Unilateral/bilateral ▫ Common in biologically-male individuals (15–35 years old) ▪ High cure rate (very high five year survival rate)

TYPES Germ cell tumors (GCT) ▪ Most common ▪ Seminomas ▫ Very poor prognosis ▫ Syncytiotrophoblastic/spermatocytic seminoma ▫ Histology: “fried egg”-like cells (clear cytoplasm, central nucleus) ▪ Non-seminomas germ cell tumors (NSGCT) ▫ Produce beta human chorionic gonadotropin (β-hCG)

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▫ Yolk sac tumor (AKA endodermal sinus tumor) ▫ Histology: Schiller–Duval bodies (germ cells encircle blood vessel, resemble glomerulus) ▪ Embryonal carcinoma ▫ Histology: prominent nucleoli; necrotic areas; clear, empty-appearing nuclei ▪ Choriocarcinoma ▫ Histology: cytotrophoblasts, syncytiotrophoblasts, hemorrhagic areas ▪ Teratoma ▫ Histology: contains many tissue types (hair, teeth, neurons, etc.) Sex cord/gonadal stromal tumors ▪ Sertoli cells tumor ▫ Histology: dense fibrous stroma, abundant eosinophilic cytoplasm, cells have tubular arrangement ▪ Leydig cells tumors ▫ Histology: Reinke crystals (eosinophilic cytoplasmic inclusion bodies)

Chapter 127 Male Genitourinary Cancers

SIGNS & SYMPTOMS ▪ ▪ ▪ ▪ ▪

Painless/painful testis mass Lower abdominal pain, heaviness Previously atrophied testis → ↑ size Gynecomastia Metastasis evidence (e.g. dyspnea, hemoptysis, palpable lymph nodes, bone pain)

DIAGNOSIS DIAGNOSTIC IMAGING

▪ Tumor identification, TNM staging ▪ Orchidectomy ▫ Biopsy: diagnosis, tumor grading

Chest X-ray ▪ Evaluate pulmonary metastasis CT scan ▪ Asses abdominal, pelvic metastasis Figure 127.5 The gross pathological appearance of a testicular seminoma. The tumor has entirely replaced the normal testicular parenchyma. ▪ Granulosa cell tumor ▫ Histology: Call–Exner bodies (fluid-filled eosinophilic spaces granulosa cells)

MRI ▪ If brain involvement is suspected Ultrasound ▪ Seminoma: smooth echogenic mass ▪ NSGCT: no defined borders, calcified cystic masses

CAUSES

▪ Unknown; chromosome 12p gene mutations usually present

RISK FACTORS

Cryptorchidism (undescended testis) Previous testicular malignancy Family history White individuals Congenital abnormality (hypospadias, inguinal hernias) ▪ Infection (mumps virus → orchitis) ▪ ▪ ▪ ▪ ▪

COMPLICATIONS

▪ Infertility ▪ Lungs, liver, bones, brain metastases

Figure 127.6 A scrotal MRI scan in the coronal plane demonstrating a tumor of the left testicle.

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LAB RESULTS

▪ Serum tumor markers ▫ ↑ alpha fetoprotein (AFP): NSGCT ▫ Normal AFP: pure seminoma, choriocarcinoma ▫ β-hCG: NSGCT ▫ ↑ lactate dehydrogenase (LDH): GCT

TREATMENT MEDICATIONS

▪ Chemotherapy ▪ High-dose chemotherapy + stem cell transplantation

SURGERY

▪ Surgery ▫ Orchidectomy, affected lymph node removal

OTHER INTERVENTIONS

▪ Follow up/surveillance ▫ Regular AFP/β-hCG serum-level monitoring ▪ Radiotherapy for seminomas

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Figure 127.7 The histological appearance of a testicular seminoma, the most common form of testicular cancer. The cells have a fried egg appearance with clear cytoplasm, well-defined nuclei with open chromatin and a well-defined cell border.

NOTES

NOTES

MATERNAL CONDITIONS GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Group of disorders occurring during gestation which potentially have adverse maternal, fetal, neonatal health effects

DIAGNOSIS OTHER DIAGNOSTICS

▪ Preconception, prenatal, obstetric history ▪ Physical examination of mother; assessment of fetal well-being

SIGNS & SYMPTOMS ▪ See individual disorders

TREATMENT OTHER INTERVENTIONS

▪ Interventions focused on pregnancy maintenance, fetal viability, safe delivery, reduced neonatal complications

CERVICAL INCOMPETENCE osms.it/cervical-incompetence PATHOLOGY & CAUSES ▪ The inability of the cervix to retain pregnancy during second trimester → premature cervical os opening, fetal expulsion ▫ In absence of clinical contractions/labor ▪ Usually < 24 weeks of gestation

CAUSES

▪ Exact mechanism not well-understood ▫ Involves structural abnormality presence, factors such as infection, inflammatory processes; weaken cervix integrity

RISK FACTORS

▪ ▪ ▪ ▪ ▪ ▪

▫ Loop electrosurgical excision procedure (LEEP), cone biopsy Spontaneous/induced abortion history Previous forceps/vacuum-assisted birth Uterine anomalies Genetic predisposition Defective cervical collagen (e.g. Ehlers– Danlos syndrome) Idiopathic

COMPLICATIONS

▪ Premature membrane rupture, birth ▫ Fetal loss, morbidity related to prematurity ▪ Chorioamnionitis ▪ Cerclage procedure ▫ Cervical lacerations

▪ Prior cervical surgery

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TREATMENT

SIGNS & SYMPTOMS ▪ Often asymptomatic until pregnancy is lost ▪ Mild symptoms ▫ Pelvic pressure, cramping, backache, vaginal discharge ▪ Signs of painless cervical changes ▫ Shortening, funneling at internal os; cervical canal dilation ▪ Bulging amniotic membranes ▪ Short duration from symptom onset → fetal loss

DIAGNOSIS DIAGNOSTIC IMAGING Serial transvaginal ultrasound ▪ Cervical shortening, funneling, dilation in the absence of significant uterine contractions ▫ Findings unexplained by other preterm birth causes

▪ Treatment aimed at reinforcing cervical structural integrity

MEDICATIONS

▪ Post-cerclage ▫ Indomethacin: enhances fetal lung development ▫ Progesterone: helps maintain pregnancy

SURGERY

▪ Cervical cerclage: concentric suture placement at cervical os (McDonald technique) ▫ 36–37 weeks of gestation → sutures removal ▪ Prior failed cervical cerclage → abdominal cerclage ▫ Circumferential Mersilene tape around uterine isthmus

OTHER DIAGNOSTICS

▪ History of recurrent (≥ two) consecutive pregnancy losses/extremely preterm births ( 35 years

COMPLICATIONS

▪ Status epilepticus (eclampticus), placental abruption, intrauterine asphyxia, maternal/ fetal death

Chapter 128 Maternal Conditions

DIAGNOSIS

SIGNS & SYMPTOMS Seizure ▪ May be preceded by certain signs/ symptoms ▫ May occur in asymptomatic individual ▫ Headache: persistent, frontal, occipital, thunderclap ▫ Visual disturbances: scotoma, cortical blindness, photophobia, blurred vision, visual field defect (e.g. homonymous hemianopsia) ▫ Right upper quadrant (epigastric) pain ▫ Ankle clonus Generalized tonic-clonic seizure onset ▪ Tonic phase ▫ Abrupt consciousness loss; extremities/ chest/back stiffening; possible cyanosis ▪ Clonic phase ▫ Muscle twitching/jerking; frothy/bloody sputum may be present ▪ Postictal phase ▫ Muscle movements stop ▪ Responsiveness resumes (usually) within 10–20 minutes; neurologic findings may include altered mental status, memory/ visual deficits, ↑ deep tendon reflexes Fetal seizure response ▪ Bradycardia → tachycardia + heart rate variability loss → maternal/fetal stabilization → improvement

▪ Clinical diagnosis based on new-onset of seizure in preeclamptic individual

DIAGNOSTIC IMAGING MRI ▪ Can visualize posterior reversible encephalopathy syndrome (PRES) ▪ Patchy T2/FLAIR hyperintensity in subcortical white matter; also in adjacent parietal, occipital lobes’ gray matter ▪ Posterior cerebral hemispheres show localized vasogenic edema

TREATMENT MEDICATIONS

▪ Antihypertensives ▪ Seizure prophylaxis ▫ Magnesium sulfate IV; diazepam/ lorazepam

SURGERY

▪ Prompt delivery ▫ Induced vaginal/cesarean (gestationdependent)

OTHER INTERVENTIONS ▪ Supplemental oxygen

GESTATIONAL DIABETES (GDM) osms.it/gestational-diabetes PATHOLOGY & CAUSES ▪ Glucose intolerance onset during pregnancy → maternal, fetal hyperglycemia ▫ Adverse fetal/neonatal effects depend on glycemic derangement degree/ duration

▪ Normal pregnancy: characterized by progressive insulin resistance, pancreatic β-cell hyperplasia ▫ Hyperplasia: influenced by chorionic somatomammotropin (hCS) AKA human placental lactogen (hPL) ▪ Gestational diabetes develops when insulin resistance overcomes pancreatic β-cell

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ability to maintain normoglycemia ▪ Resistance begins in second trimester, peaks in third (fetal weight gain) ▫ Maternal hormonal, metabolic changes support steady glucose supply for fetal growth, cell proliferation, tissue development, differentiation. ▫ After fetus, placenta delivery → hCS no longer produced → ↓ pregnancyassociated insulin resistance ▪ Maternal hyperglycemia → fetal hyperglycemia → macrosomia (birth weight > 90th percentile on population-appropriate growth chart/> 4kg/8.82lbs) ▫ Hyperinsulinemia → ↓ surfactant production → impaired lung development ▫ ↑ fetal metabolic rate → ↑ oxygen consumption → fetal hypoxemia → metabolic acidosis ▫ ↑ erythropoiesis → polycythemia → hyperviscosity; iron redistribution secondary to accelerated erythropoiesis → ↓ iron available for developing organs → cardiomyopathy, altered neurodevelopment (reactive oxygen species → cardiac remodeling → transient hypertrophic cardiomyopathy)

RISK FACTORS

▪ Respiratory distress ▫ ↓ fetal surfactant development ▪ Hypoglycemia ▫ Hyperinsulinemia + placental glucose delivery loss ▪ Hyperbilirubinemia ▫ Polycythemia, excess red blood cell (RBC) breakdown ▪ ↑ stillbirth risk ▫ Often cardiomyopathy + ↓ ability to tolerate macrosomia-related difficult labor → failure to progress, shoulder dystocia → perinatal asphyxia ▪ ↑ obesity risk (later in life)

SIGNS & SYMPTOMS Maternal ▪ May be asymptomatic ▪ Severe hyperglycemia manifests with polyuria, polydipsia, polyphagia Neonatal (infant of diabetic mother) ▪ Low APGAR score ▪ Large for gestational age; > 4kg/8.82lbs ▪ Plethora ▪ Hypoglycemia (may be jittery on delivery)

DIAGNOSIS

▪ Polygenic influence; age > 25 years; nonwhite people of European descent; BMI > 25kg/m²; polycystic ovary syndrome; hypertension; multiple gestation; personal/ family glucose-intolerance history; previous macrosomic infant/unexplained fetal loss

DIAGNOSTIC IMAGING

COMPLICATIONS

Pulse oximetry ▪ Neonatal: ↓ oxygen saturation

Maternal ▪ ↑ risk of preeclampsia, polyhydramnios, developing type 2 diabetes mellitus Neotatal ▪ Macrosomia/large for gestational age (LGA) ▫ ↑ cesarean delivery risk; ↑ shoulder dystocia risk → ↑ maternal trauma risk (e.g. lacerations, hematoma); fetal birth trauma (brachial plexus injury, facial palsy, clavicular/humeral fractures, cephalohematoma, subdural hematoma)

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Fetal ultrasound ▪ Prenatal: fetal size, weight estimation

LAB RESULTS Prenatal (maternal) ▪ Glucose tests: random capillary glucose, fasting glucose, hemoglobin A1c, oral glucose tolerance testing (OTT) ▪ Serum, urinary ketone bodies

Chapter 128 Maternal Conditions Postnatal ▪ Maternal: serial capillary glucose tests (hyperglycemia initially → resolving after placenta delivery) ▪ Neonatal: blood studies (↓ glucose; ↑ hematocrit; ↑ bilirubin; possible ↓ calcium, magnesium)

OTHER DIAGNOSTICS

▪ Postnatal: neonatal weight, gestational age assessment; physical examination

TREATMENT MEDICATIONS Prenatal ▪ A2 GDM (requires medical management) ▫ Insulin as required to reach blood glucose target (does not cross placenta) ▫ Oral antidiabetic agents (crosses placenta)

Postnatal ▪ Maternal: continue glucose medical management until normalization ▪ Neonatal: supplemental oxygen, oral/ intravenous glucose

SURGERY Prenatal ▪ Elective cesarean delivery (estimated fetal weight ≥4.5kg/9.92lbs)

OTHER INTERVENTIONS Prenatal ▪ Serial nonstress tests, amniotic fluid index (AMI) ▪ A1 GDM (maintains euglycemia via lifestyle modification) ▫ Labor induction: between 40+0–41+0 weeks of gestation ▪ A2 GDM (requires medical management) ▫ Labor induction: 39+0 weeks of gestation (39+0–39+6 if glucose is well-controlled)

GESTATIONAL HYPERTENSION osms.it/gestational-hypertension PATHOLOGY & CAUSES ▪ New hypertension onset; develops ≥ 20 weeks of gestation ▫ Systolic blood pressure (≥ 140mmHg)/ diastolic blood pressure (≥ 90mmHg) ▫ No proteinuria/new end-organ dysfunction evidence ▫ Usually resolves by postpartum week 12 ▫ Exact mechanism unclear

COMPLICATIONS

▪ Preeclampsia development

SIGNS & SYMPTOMS ▪ ↑ blood pressure (≥ 140mmHg)/diastolic blood pressure (≥ 90mmHg) ▪ Severe gestational hypertension (≥ 160mmHg)/diastolic blood pressure (≥ 110mmHg)

RISK FACTORS

▪ ↑ prevalence in primigravidas (first pregnancy) ▪ Genetic factors

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DIAGNOSIS LAB RESULTS

▪ Urine dipstick ▫ Negative/trace protein amounts ▪ Normal platelet count ▪ Creatinine, hepatic transaminases ▫ Normal

OTHER DIAGNOSTICS

▪ Clinical exclusion diagnosis ▫ Established when preeclampsia eliminated as hypertension cause ▪ Focused history ▫ Cerebral/visual disturbance absence; epigastric/right upper quadrant pain absence

Figure 128.3 Histological section of the placenta from an individual with hypertension during pregnancy displaying hypertrophic decidual vasculopathy. There is hypertrophy of the smooth muscle layer and numerous perivascular inflammatory cells. This may also be seen in pre-eclampsia.

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TREATMENT MEDICATIONS

▪ Antihypertensives, antenatal corticosteroids

OTHER INTERVENTIONS

▪ Delivery timed in accordance with individual status ▪ Ongoing maternal monitoring ▫ Blood pressure ▫ Proteinuria ▫ Platelet count, liver enzymes ▪ Ongoing fetal well-being monitoring ▫ Biophysical profile/nonstress test ▫ Measure amniotic fluid index (AFI) ▫ Uterine, umbilical artery doppler velocimetry ▫ Monitor fetal growth signs (placental insufficiency)

Chapter 128 Maternal Conditions

HYPEREMESIS GRAVIDARUM osms.it/hyperemesis-gravidarum PATHOLOGY & CAUSES

DIAGNOSIS

▪ Exaggerated, protracted nausea/vomiting in early pregnancy ▪ Incidence: 1 in 200 pregnancies (Western countries) ▪ Usually between week 4–8 of gestation ▪ May last ≥ 16 weeks

DIAGNOSTIC IMAGING

CAUSES

▪ ↑ Blood urea nitrogen (BUN), creatinine; urea/creatinine ratio > 25:1; ↓ potassium, sodium; ↑ hematocrit, pH ▪ Urinalysis ▫ ↑ specific gravity, ketones

▪ Multifactorial ▫ E.g. pregnancy-induced hormonal changes, pregnancy-related gastric motility ↓ + other individual factors

RISK FACTORS ▪ ▪ ▪ ▪ ▪

Previous hyperemesis gravidarum ↑ human chorionic gonadotropin (hCG) Multiple pregnancy, hydatidiform mole Biologically-female fetus Hyperthyroidism (may be hCG ↑ triggered)

COMPLICATIONS

▪ Dehydration, weight loss, electrolyte imbalance, metabolic alkalosis (HCl loss orally), ketosis, Mallory–Weiss esophageal tear (violent vomiting), intrauterine growth restriction (if prolonged)

SIGNS & SYMPTOMS ▪ Frequent, severe nausea; vomiting ▪ Dehydration ▫ Tachycardia, palpitations, hypotension, postural hypotension, dry mucous membranes, ↓ skin turgor ▪ ↑ smell sensitivity ▪ Malaise ▪ Weight loss ▪ Ketotic odor

Pelvic ultrasound ▪ Excludes molar pregnancy; identifies multiple gestation

LAB RESULTS

OTHER DIAGNOSTICS

▪ Excessive vomiting history ▫ Sufficient to cause clinically-evident dehydration

TREATMENT MEDICATIONS

▪ Antiemetics (off-label for pregnancy) ▪ Vitamin B6 ▫ ↓ nausea ▪ Fluid, electrolyte replacement

OTHER INTERVENTIONS

▪ Trigger avoidance ▫ Consume small, frequent meals ▫ Bland food (avoid spicy/greasy food)

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INTRAUTERINE GROWTH RESTRICTION osms.it/intrauterine-growth-restriction PATHOLOGY & CAUSES ▪ Full fetal growth not accomplished during gestation → ↑ morbidity, mortality risk ▪ AKA fetal growth restriction

TYPES

▪ Symmetric ▫ Effects begin early in gestation ▫ Most commonly intrinsic factors (infection, chromosomal abnormality) ▫ Uniform effect (all organ systems) ▫ Body/head circumference, length, weight restricted proportionally ▪ Asymmetric ▫ Affects fetus in late second/third trimester ▫ Commonly ↓ nutrition delivery to fetus (limits glycogen, fat storage; brain sparing) ▫ Head circumference (normal), length (near normal), weight (significantly affected)

CAUSES

▪ Fetal factors ▫ Genetic (e.g. aneuploidy, single gene mutations) ▫ Infection (e.g. cytomegalovirus (CMV), toxoplasmosis; rubella) ▫ Multiple gestation (e.g. nutrientcompetition by > one fetus) ▪ Placental factors ▫ Ischemic placental disease (e.g. preeclampsia) ▫ Structural anomalies (e.g. single umbilical artery)

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▪ Maternal factors ▫ Chronic disease (e.g. renal, cardiac, pulmonary disease) ▫ Substance use/abuse (e.g. alcohol, cigarettes, illicit drugs) ▫ Poor nutritional status/inadequate weight gain ▪ Environmental factors ▫ Teratogen exposure, pollution ▫ Certain maternal therapeutic medication

COMPLICATIONS

▪ Preterm birth, related sequelae (e.g. necrotizing enterocolitis, respiratory distress syndrome) ▪ Intrauterine asphyxia ▫ ↓ physiological reserve → poor response to temporary hypoxia secondary to uterine contractions ▫ ↑ meconium aspiration risk → pulmonary hypertension ▪ Impaired thermoregulation ▫ ↓ subcutaneous tissue + ↓ catecholamines (used in non-shivering thermogenesis via brown fat) → ↑ cold stress risk → hypoxia, hypoglycemia, metabolic acidosis ▪ Hypoglycemia ▫ ↓ glycogen, fat, protein reserves ▪ Polycythemia ▫ Chronic hypoxia ▪ Impaired immune function ▫ Inadequate nutrition-related ▪ Hypocalcemia ▫ ↑ serum phosphate load from tissue catabolism, ↓ nutrition, renal insufficiency ▪ ↑ mortality risk

Chapter 128 Maternal Conditions

SIGNS & SYMPTOMS ▪ General postnatal appearance ▫ Thin, loose skin; ↓ subcutaneous tissue, skeletal muscle; thin umbilical cord ▪ ↓ weight, length, head, chest circumference ▫ Asymmetric growth restriction (head circumference may be normal; will appear large relative to trunk, extremities)

DIAGNOSIS DIAGNOSTIC IMAGING Ultrasound biometry (prenatal) ▪ Correlate estimated date of confinement (EDC) with fetal parameters ▫ Sonographically-estimated fetal weight (SEFW) ▫ Head: biparietal diameter (BPD), head circumference (HC), transcerebellar diameter (TDC) ▫ Abdominal circumference (AC): AC/HC ratio ▫ Amniotic fluid index (AFI): oligohydramnios present if placental pathology Doppler velocimetry (prenatal) ▪ Measure circulatory status ▫ Vascular resistance, placental/cardiac function)

LAB RESULTS

▪ Blood studies (postnatal) ▫ ↓ capillary glucose level, serum calcium; ↑ hematocrit

OTHER DIAGNOSTICS ▪ Postnatal diagnostics

Ponderal index ▪ Low; asymmetric growth restriction especially ▪ Body weight:length ratio ▫ PI = [weight (in g) x 100] ÷ [length (in cm)]3 Ballard score ▪ Gestational age assessment ▫ Small for gestational age ▪ Includes weight, head, chest circumference; physical maturity, neuromuscular maturity indicators

TREATMENT MEDICATIONS

▪ Glucose ▫ Intravenous/oral/early feeding

OTHER INTERVENTIONS

▪ Maintain neutral thermal environment

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MASTITIS osms.it/mastitis PATHOLOGY & CAUSES ▪ Localized infection: one/more mammary ducts, usually associated with lactation

LAB RESULTS

▪ Leukocytosis ▪ Breast milk culture ▫ Identifies causative microorganism

CAUSES

▪ Infectious ▫ Microorganism introduction: transferred from breastfeeding infant’s mouth/nose (commonly Staphylococcus aureus, Streptococcus spp.) ▪ Noninfectious ▫ Milk stasis: prolonged engorgement, infrequent/inefficient feedings, clogged ducts

RISK FACTORS

▪ Cracked/damaged nipples, poor hygiene, ineffective breastfeeding technique, impaired immunity, diabetes

COMPLICATIONS

▪ Infection progression, abscess formation

SIGNS & SYMPTOMS ▪ ▪ ▪ ▪ ▪

Localized firmness, redness, swelling, heat Palpable lump Breast pain Tender/enlarged axillary nodes Flu-like symptoms ▫ Fever, malaise, myalgias

DIAGNOSIS DIAGNOSTIC IMAGING Ultrasound ▪ Identifies abscess presence

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Figure 128.4 An ultrasound scan of the breast demonstrating a breast abscess, a complication of mastitis.

TREATMENT MEDICATIONS

▪ Analgesics ▪ Antibiotics (if conservative measures ineffective)

OTHER INTERVENTIONS

▪ Ice, cold compress application ▪ Continue breastfeeding/manual extraction ▪ Lactation consultant referral

Chapter 128 Maternal Conditions

OLIGOHYDRAMNIOS osms.it/oligohydramnios PATHOLOGY & CAUSES ▪ ↓ amniotic fluid volume surrounding fetus for gestational age ▫ Can adversely affect fetal development

CAUSES

▪ Amniotic fluid production, movement imbalance ▫ ↓ placental blood flow, ↓ fetal urine production, ↑ amniotic fluid loss → ↓ amniotic fluid volume ▫ ↓ fluid cushioning effect → ↑ umbilical cord compression risk ▫ Restricted fetal movement → ↓ musculoskeletal development ▫ Fetal thorax compression → ↓ pulmonary development ▫ ↓ amniotic fluid bacteriostatic effect → ↑ infection risk

RISK FACTORS Maternal ▪ Hypertensive disorders, diabetes, preeclampsia, abnormal placentation → uteroplacental insufficiency ▪ Premature rupture of membranes (PROM), amniotic fluid leak → fluid loss ▪ Maternal medications (e.g. ACE inhibitors, NSAIDs) ▪ Post-term pregnancy Fetal ▪ Renal/urinary tract anomalies (e.g. renal agenesis), restricted growth, fetal death → ↓ fetal urine production ▪ Congenital anomalies (e.g. aneuploidy, cardiac, preferential perfusion to brain at kidney’s expense)

COMPLICATIONS

▪ Amniotic band syndrome ▫ Adhesions between amnion, fetus → limb malformation, amputation ▪ Limb position defects (e.g. club foot) ▪ Pulmonary hypoplasia → respiratory distress ▪ Multiple anomalies (Potter sequence) ▫ Pulmonary hypoplasia, oligohydramnios, twisted skin/face, extremity malformation, renal agenesis ▪ Chorioamnionitis ▪ Low birth weight ▪ Meconium aspiration syndrome (MAS) ▪ ↑ fetal/neonatal mortality risk

SIGNS & SYMPTOMS ▪ Uterine size/fundal height less than expected for gestational age ▪ Easily palpated fetus ▪ ↓ fetal movement

DIAGNOSIS ▪ Targeted history, physical examination → identify specific cause

DIAGNOSTIC IMAGING Uterine ultrasound ▪ ↓ amniotic fluid index (AFI) ▫ < 5cm/1.97in total; single deepest pocket < 2cm/0.79in ▪ Amniotic fluid measurement in deepest pocket in each uterine quadrant ▪ Sum of each maximum vertical pocket = AFI

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Fetal ultrasound + biophysical profile ▪ Detects fetal anomalies; assesses degree of fetal well-being

LAB RESULTS

▪ Amniotic fluid leak detection: nitrazine, fern tests, AmniSure

TREATMENT OTHER INTERVENTIONS ▪ ↑ intrauterine-fluid volume ▫ Maternal hydration ▫ Amnioinfusion

POLYHYDRAMNIOS osms.it/polyhydramnios PATHOLOGY & CAUSES ▪ Excessive amniotic fluid amount surrounding fetus for gestational age ▪ Can adversely affect fetal development

CAUSES

▪ Amniotic fluid production, movement imbalance ▪ ↑ placental blood flow ▪ ↑ fetal renal perfusion, urine production ▪ ↓ fetal amniotic fluid swallowing/absorption ▪ Idiopathic

RISK FACTORS Maternal ▪ Diabetes; chronic/gestational Fetal ▪ Gastrointestinal anomalies (e.g. duodenal, esophageal, intestinal atresia ) ▪ Central nervous system abnormalities ▪ High cardiac-output state ▪ Twin-twin transfusion syndrome ▪ Nonimmune hydrops ▪ Genetic ▫ Aneuploidy, trisomy 18 or 21

COMPLICATIONS Maternal ▪ Placental abruption, umbilical cord prolapse, postpartum uterine atony → hemorrhage, upward diaphragm pressure → respiratory distress Fetal ▪ Preterm birth, fetal anomalies

SIGNS & SYMPTOMS ▪ Uterine size/fundal height ↑ than expected for gestational age ▪ Difficulty palpating fetal parts

DIAGNOSIS DIAGNOSTIC IMAGING Uterine ultrasound ▪ AFI ≥ 24cm/9.44in ▪ Single deepest pocket ≥ 8cm/3.1in Fetal ultrasound + biophysical profile ▪ Detects fetal anomalies; assesses degree of fetal well-being

OTHER DIAGNOSTICS

▪ Focused history, physical examination → identify specific cause

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Chapter 128 Maternal Conditions

TREATMENT ▪ Treatment determined by gestational age, amniotic fluid excess severity, symptom presence, cause

MEDICATIONS

▪ Indomethacin ▫ Severe polyhydramnios, preterm labor onset ▫ Fetal antidiuretic response via endogenous vasopressin production ▫ Short duration with monitoring → avoids ductus arteriosus constriction

SURGERY

▪ Severe polyhydramnios, preterm labor onset ▫ Amnioreduction (decompression amniocentesis) ▫ Amniotic fluid removal (amniocentesis)

Figure 128.5 A fetal ultrasound scan demonstrating polyhydramnios. There is a large hypoechoic region between the fetus and the maternal abdominal wall. There is also the double-bubble sign of duodenal atresia, which is the underlying cause in this case.

OTHER INTERVENTIONS

▪ Mild polyhydramnios ▫ Expectant management

PRE-ECLAMPSIA osms.it/pre-eclampsia PATHOLOGY & CAUSES ▪ New-onset hypertension, proteinuria/endorgan dysfunction > 20 weeks of gestation ▪ Preeclampsia (severe) characteristics ▫ ↑ ↑ blood pressure; thrombocytopenia; hepatic, renal abnormalities; cerebral/ visual dysfunction; pulmonary edema ▫ Often resolves days/weeks after delivery

CAUSES

▪ Abnormal placentation ▫ Abnormal spiral artery remodeling into shallow, narrow arteries instead of normally deeply implanted, large,

low-resistance arteries → placental, fetal hypoperfusion → gestational age progression → worsening hypoperfusion ▪ Ischemic placenta → release proinflammatory proteins into maternal circulation → generalized endothelial dysfunction → ↑ reactivity to circulating vasoconstrictors + ↓ endogenous vasodilators production + ↑ vascular permeability + abnormal procoagulant expression ▫ Hypertension ▫ Target-organ microangiopathy (kidneys, liver, brain)

OSMOSIS.ORG 787

▫ Intravascular fluid leakage into interstitium ▫ Microangiopathic intravascular hemolysis ▫ Placental thrombosis, sclerosis, infarction

RISK FACTORS

Positive preeclampsia family history Previous pregnancy preeclampsia Nulliparity Age > 40 Biologically-female individuals of AfricanAmerican descent ▪ Chronic disease (e.g. hypertension, diabetes, systemic lupus erythematosus, antiphospholipid syndrome) ▪ ↑ body mass index (BMI) ▪ Assistive reproductive technology use ▪ ▪ ▪ ▪ ▪

COMPLICATIONS Maternal ▪ Cerebral edema/hemorrhage; stroke; hepatic failure; renal failure; hemolysis, elevated liver enzymes, low platelet count (HELLP) syndrome; placental abruption; eclampsia; liver rupture; posterior reversible encephalopathy syndrome (PRES); death Fetal ▪ Intrauterine growth restriction, premature birth, fetal demise

SIGNS & SYMPTOMS ▪ Hypertension ▫ Vasoconstriction ▪ Epigastric pain ▫ Liver capsule swelling (advanced disease sign) ▪ Peripheral edema, dyspnea ▫ ↑ vascular permeability ▪ Oliguria, proteinuria ▫ ↓ glomerular filtration rate (GFR), glomerular damage ▪ Severe headache, altered mental status ▫ Cerebrovascular pathology

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▪ Visual disturbances ▫ E.g. photopsia (flashes of light), scotoma (dark areas/gaps in visual field), blurred vision (retinal arteriolar spasm) ▪ Hyperreflexia, ankle clonus ▫ Neuromuscular irritability ▪ Sudden, rapid weight gain ▫ Fluid retention

DIAGNOSIS DIAGNOSTIC IMAGING Pulse oximetry ▪ ↓ oxygen saturation Ultrasound ▪ Fetal ▫ Intrauterine growth restriction, oligohydramnios ▪ Placenta ▫ Infarction, hematoma, cystic lesion ▪ Uterine, umbilical artery doppler studies ▫ ↑ flow resistance ECG ▪ ↓ left ventricular function; ↑ filling pressure

LAB RESULTS

▪ Proteinuria ▪ ↑ serum creatinine, liver transaminases, indirect bilirubin; ↓ platelet count ▪ Hyperuricemia ▪ Peripheral blood smear ▫ Schistocytes, helmet cells

OTHER DIAGNOSTICS

▪ Low fetal biophysical profile score

TREATMENT MEDICATIONS

▪ Antepartum ▫ Antenatal steroids: promote fetal lung development

Chapter 128 Maternal Conditions ▪ Intrapartum ▫ Intravenous magnesium sulfate: bolus, then continuous infusion (seizure prophylaxis) ▫ Intravenous antihypertensives: maintain normal blood pressure ▪ Postpartum ▫ Continue intravenous magnesium sulfate infusion until stable

SURGERY

▪ Antepartum ▫ Labor induction/cesarean delivery: progressive placental function deterioration, disease advancement (preeclampsia with severe pathological features)

OTHER INTERVENTIONS

▪ Antepartum ▫ Regular maternal status, fetal wellbeing assessments ▪ Intrapartum ▫ Electronic fetal monitoring ▫ Supplemental oxygen

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NOTES

NOTES

OVARIAN & UTERINE DISORDERS

GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Gynecological disorders; adversely affect reproductive function

SIGNS & SYMPTOMS ▪ Pelvic pain ▫ Focal/diffuse ▪ Disorder-specific

OTHER DIAGNOSTICS

▪ Obstetric, gynecologic history ▪ Physical examination

TREATMENT ▪ Considerations: desire to preserve fertility, menopausal/post-menopausal status, presence of malignancy

MEDICATIONS

DIAGNOSIS DIAGNOSTIC IMAGING

▪ Disorder-specific ▫ Hormonal

SURGERY

▪ Disorder-specific

Ultrasound, MRI ▪ See individual disorders

ENDOMETRIOSIS osms.it/endometriosis PATHOLOGY & CAUSES ▪ Inflammatory disorder characterized by ectopic endometrial-like tissue (endometrial glands, stroma) implantation, growth outside uterus ▪ Benign disorder with invasive, disseminating malignancy characteristics ▫ May regress during menopause Common locations ▪ Ovaries (most common); referred to as endometrioma/“chocolate cyst”

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▫ Anterior/posterior cul-de-sac; fallopian tubes; posterior broad, round, uterosacral ligaments ▪ May also implant in non-reproductive sites (bowel, bladder, diaphragm, thorax, brain, skin)

CAUSES

▪ Implantation cause unclear ▫ Multifactorial process involves immune, endocrine, cellular, genetic factors

Chapter 129 Ovarian & Uterine Disorders ▪ Current theories ▫ Metastatic theory: lymphatic/ hematogenous spread, iatrogenic implantation, retrograde menstruation ▫ Metaplastic theory: metaplastic Müllerian remnants changes ▫ Induction theory: undifferentiated mesenchyme stimulated to form endometriotic tissue

TYPES

SIGNS & SYMPTOMS ▪ May be asymptomatic ▪ Symptoms often related to implantation site ▫ Gynecological: dysmenorrhea, pelvic pain, dyspareunia, menorrhagia ▫ Bowel: constipation, hematochezia, obstruction ▫ Bladder: pain, dysuria, hematuria ▫ Thoracic: hemoptysis, bronchospasm

Pelvic ▪ Endometrial tissue within pelvic cavity ▫ Peritoneum, pelvic organs/rectouterine pouch Ovarian ▪ Ovarian cyst lined with endometrial tissue Deeply infiltrating endometriosis ▪ Endometrial tissue extension ≥ 5mm into retroperitoneal space; may exist in several regions

RISK FACTORS

▪ Nulliparity ▪ Prolonged endogenous, physiologic estrogen exposure ▫ Early menarche/late menopause, short menstrual cycles ▪ Menstrual flow obstruction ▪ In utero diethylstilbestrol (DES) exposure ▪ ↓ body mass index (BMI) ▪ ↑ dietary trans-fats ▪ Nucleotide polymorphisms (e.g. rs10965235 in CDKN2BAS gene at locus 9p21.3) ▪ Age ▫ Peak incidence: 25–29 years old

COMPLICATIONS

▪ Infertility ▪ Chronic pain ▪ Endometrioma ▫ ↑ ovarian rupture/perforation/torsion risk ▪ Pneumothorax, hemothorax (thoracic endometriosis) ▪ ↑ epithelial ovarian cancer (EOC) risk

Figure 129.1 An intraoperative photograph of a focus of endometriosis in the parietal peritoneum.

DIAGNOSIS DIAGNOSTIC IMAGING Ultrasound ▪ Abdominal/transvaginal ultrasonography (TVUS) ▪ Endometrioma ▫ Visualization of homogeneous hypoechoic ovarian cyst containing diffuse low-level internal echoes (“ground-glass” echogenicity) ▪ Lesions found elsewhere ▫ Hypoechoic lesions, retroperitoneal tissue thickening; severe endometriosis may demonstrate “kissing ovaries” (ovaries joined behind rectouterine pouch)

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MRI ▪ If ultrasound findings inconclusive ▪ Hemorrhagic “powder burn” areas appear bright on T1 ▪ Solid deep lesions ▫ T1 hyperintense, T2 hypointense ▪ Fibrotic adhesions ▫ Isointense to pelvic muscle on both T1, T2

TREATMENT ▪ No definitive treatment; management options depend on desire to preserve fertility

MEDICATIONS

Laparoscopy ▪ Ectopic endometrial tissue identification ▫ Irregularly-shaped reddish/reddish-blue lesions ▫ Whitish opacifications; occasional hemorrhagic blue-brown areas (“powder burns”) ▫ Nodules, cysts may be present ▫ Fibrous adhesions (severe disease)

▪ Combined norgestimate–ethinyl estradiol cyclic/continuous oral contraceptives ▫ ↓ dysmenorrhea, ↓ endometrioma volume ▪ Gonadotropin-hormone releasing (GnRH) antagonists ▫ Pituitary gonadotropin hormone suppressed → ↓ estrogen ▪ Pain management ▫ Nonsteroidal anti-inflammatory drugs (NSAIDs)

OTHER DIAGNOSTICS

SURGERY

▪ Pelvic exam ▫ Limited motion of ovaries, uterus (fixed uterus) ▫ Adnexal mass palpated; may be tender ▫ Nodules in posterior fornix

Figure 129.2 The histological appearance of endometriosis affecting the ovary. Ovarian stroma is seen on the left and an endometrial deposit on the right.

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▪ Laparoscopic ectopic endometrial tissue removal ▪ Hysterectomy

Chapter 129 Ovarian & Uterine Disorders

OVARIAN CYST osms.it/ovarian-cyst PATHOLOGY & CAUSES ▪ Fluid-filled growth that develops in/on ovary ▫ Usually benign (occasionally malignant) ▪ Majority of cysts occur during reproductive years ▪ Size ▫ 1–10cm/0.4–3.9in ▪ Strenuous physical activity/sexual intercourse → rupture ▫ Contain components that irritate peritoneal cavity upon rupture (cystic serous/mucinous fluid/blood; sebaceous fluid, hair, fat, bone, cartilage from dermoid cysts)

TYPES Functional/physiologic ▪ Abnormally large ovarian components ▫ Follicular cyst ▫ Corpus luteum cyst ▫ Theca-lutein cyst (usually bilateral) Neoplastic ▪ Benign/malignant ▫ Polycystic ovaries ▫ Endometrioma ▫ Serous cystadenoma ▫ Mucinous cystadenoma ▫ Dermoid cyst (benign cystic teratoma)

RISK FACTORS

▪ Early menarche, obesity, infertility, fertility treatments, polycystic ovarian syndrome, hypothyroidism, hyperandrogenism, tamoxifen use, smoking (mucinous cysts)

Figure 129.3 The gross pathological appearance of a large, benign ovarian cyst. The internal lining of the cyst is smooth and would have contained serous fluid prior to opening.

COMPLICATIONS

▪ Rupture, hemorrhage, ovarian torsion

SIGNS & SYMPTOMS ▪ May be asymptomatic ▪ Pelvic pain/lower abdominal pressure sensation ▪ Dyspareunia Ruptured cyst ▪ Sudden severe, sharp pain onset ▪ Pain may be referred to shoulder/upper abdomen (due to subphrenic blood extravasation) ▪ Rebound tenderness/guarding may be present (due to peritoneal irritation) Hemorrhage ▪ Hemodynamic instability signs (e.g. hypotension, tachycardia)

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DIAGNOSIS DIAGNOSTIC IMAGING Ultrasound ▪ TVUS/abdominal ▪ Provides mass characterization ▫ Generally round/oval anechoic mass; smooth, thin walls ▫ Different mass types have unique characteristics MRI ▪ If ultrasound indeterminate for surgical resection evaluation

OTHER DIAGNOSTICS

▪ Obstetric, gynecologic history

Pelvic examination ▪ Adnexal tenderness/palpable mass ▪ Usually unilateral, localized

TREATMENT ▪ Functional/physiologic cysts usually resolve spontaneously

MEDICATIONS

▪ Uncomplicated cyst rupture (hemodynamically stable) ▫ Pain management (e.g. NSAIDs)

SURGERY

Figure 129.4 An ultrasound scan of the pelvis in an individual with a hemorrhagic ovarian cyst. The ovary (outlined) contains a large hypoechoic area which has displaced most of the ovarian parenchyma.

LAB RESULTS

▪ Serum CA-125 (in menopausal, postmenopausal individuals) ▫ Assists in ruling out ovarian cancer

Histopathological examination ▪ Ultrasound-guided aspiration ▪ Histology varies widely, depending on type (e.g. benign mucinous tumor—single layer of columnar epithelial cells with mucinous cytoplasm)

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Laparoscopy/laparotomy ▪ Ongoing hemorrhage, hemodynamic instability, torsion/rupture risk ▪ Ovarian cystectomy ▫ Removal of abnormal tissue only ▪ Unilateral/bilateral oophorectomy ▫ Removal of entire ovary(ies); recommended for menopausal/ postmenopausal individuals, if malignancy confirmed

OTHER INTERVENTIONS

▪ Significant blood loss ▫ Inpatient care: fluid replacement; monitor complete blood count (CBC) ▪ Uncomplicated cyst rupture (hemodynamically stable) ▫ Expectant management

Chapter 129 Ovarian & Uterine Disorders

OVARIAN TORSION osms.it/ovarian-torsion PATHOLOGY & CAUSES ▪ Gynecological emergency caused by rotation of ovary on it’s vascular pedicle ▫ If the fallopian tube twists with the ovary, adnexal torsion occurs ▪ Blood supply from ovarian artery, uterine artery’s ovarian branch pass through mesovarium (suspends ovary between ovarian, suspensory ligaments) → ovarian torsion cuts off ovary’s blood supply → ischemia, infarction, hemorrhage, adnexal necrosis ▫ Venous, lymphatic drainage also impeded → ovarian edema

RISK FACTORS

▪ Ovarian enlargement (e.g. tumor, cyst) ▫ ↑ if > 5cm/2in, though can occur with normal ovary ▪ Strenuous exercise ▪ Sudden ↑ abdominal pressure ▪ Pregnancy ▪ Ovulation induction/hyperstimulation (infertility treatment) ▪ Most cases occur during reproductive years

DIAGNOSIS DIAGNOSTIC IMAGING Pelvic ultrasound ▪ Enlarged, edematous ovary; displaced follicles appear as “string of pearls” ▪ Ovary may be located anterior to uterus (rather than lateral) Doppler imaging ▪ ↓ blood flow to ovary ▪ “Whirlpool” sign ▫ Indicates coiled ovarian vessels ▫ Hypoechoic stripes indicate vascular pedicle twisting MRI ▪ If ultrasound equivocal ▪ Enlarged, edematous ovary, abnormal location; “whirlpool” sign

COMPLICATIONS

▪ Ovarian necrosis, peritonitis, pelvic adhesion formation, hemorrhage

SIGNS & SYMPTOMS ▪ Pelvic pain ▫ Unilateral, severe, sharp ▪ Nausea/vomiting ▪ Fever, ↑ heart rate (HR), ↑ blood pressure (BP) may indicate necrosis Figure 129.5 A CT scan of the abdomen and pelvis in the coronal plane demonstrating whirlpool sign in an individual with torsion of the right ovary.

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OTHER DIAGNOSTICS

▪ Obstetric, gynecologic history

Physical examination ▪ Tender adnexal mass may be palpated ▪ Necrosis present → guarding, rebound tenderness

TREATMENT

Laparoscopic surgery ▪ Confirm torsion (direct visualization) → perform detorsion ▪ Determine ovary’s viability ▫ Preserve viable ovary (may be edematous/hemorrhagic) for premenopausal individuals ▫ Salpingo-oophorectomy (necrotic ovary) for postmenopausal individuals/ suspected malignancy

SURGERY

▪ Ovarian benign mass cystectomy

UTERINE FIBROID osms.it/uterine-fibroid PATHOLOGY & CAUSES ▪ Most common benign pelvic neoplasm in reproductive-age individuals ▫ AKA leiomyoma/myoma ▪ Arises from myometrial smooth muscle cells → forms firm, round smooth muscle, connective tissue tumors ▪ Hormone fluctuation sensitive: ↑ cyclically during menses; ↓ after menopause

Subserosal myoma ▪ FIGO: type 6, 7 ▪ Arise from serosal surface ▪ Pedunculated ▪ Growth may be intraligamentary (between broad ligament folds) Cervical myoma ▪ FIGO: type 8 ▪ Arise from cervix

TYPES

▪ International Federation of Gynecology and Obstetrics (FIGO) classification

Intramural myoma ▪ FIGO type: 3, 4, 5 ▪ Found within uterine wall Submucosal myoma ▪ Arise from cells just below endometrium, extend into uterine cavity ▪ FIGO type: 0, 1, 2 ▫ Type 0: completely within endometrial cavity ▫ Type 1: extend < 50% into myometrium ▫ Type 2: extend ≥ 50% within myometrium

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Figure 129.6 The gross pathological appearance of a uterine fibroid. The specimen has been bisected revealing a firm, whorled cut surface.

Chapter 129 Ovarian & Uterine Disorders

RISK FACTORS ▪ ▪ ▪ ▪ ▪ ▪

▪

▪ ▪ ▪

Family history Nulliparity Early menarche Prenatal exposure to diethylstilbestrol (DES) ↑ (body mass index) BMI Environmental exposures ▫ Phthalates, polychlorinated biphenyl, bisphenol A Dietary factors ▫ Insufficient vitamin D ▫ Significant red meat consumption ▫ Alcohol (especially beer) Hypertension history Physical/sexual abuse history ↑ risk in biologically-female individuals of African descent

COMPLICATIONS

▪ Surrounding structure pressure ▫ Constipation, urinary retention/ frequency ▪ ↑ bleeding → anemia ▪ Pedunculated fibroid torsion (surgical emergency)

Figure 129.7 An MRI scan of the pelvis in the sagittal plane. The uterine corpus is outlined. The many hypodense objects within it are uterine fibroids.

OTHER DIAGNOSTICS Physical examination ▪ Pelvic exam ▫ Lumpy, cobblestone uterus upon palpation

SIGNS & SYMPTOMS ▪ Often asymptomatic ▪ Enlarged/distorted uterus ▪ Abnormal uterine bleeding (e.g. longer/ heavier periods) ▪ Pelvic pain/pressure ▪ Dysmenorrhea ▪ Dyspareunia

DIAGNOSIS DIAGNOSTIC IMAGING MRI ▪ Determines specific fibroid type (e.g. intramural) Transvaginal ultrasound ▪ Visualize fibroids

TREATMENT ▪ Depends on symptomatology degree ▫ Whether/not fertility preservation desired, menopausal status

MEDICATIONS

▪ GnRH agonists ▪ Endometrial atrophy inducement ▫ Oral estrogen-progestin contraceptives ▪ Menstruation suppression (medroxyprogesterone) ▪ Pain management (NSAIDs)

SURGERY

▪ Myomectomy (recurrence possible) ▪ Hysterectomy

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▪ Endometrial ablation ▪ Laparoscopic myolysis ▫ Thermal, radiofrequency, cryoablation

OTHER INTERVENTIONS

▪ Mild cases: expectant management ▫ Annual pelvic exams ▪ Interventional radiology ▫ Uterine artery embolization

Figure 129.8 The histological appearance of a uterine leiomyoma. The tumor is composed of bundles of spindled smooth muscle cells with no atypia.

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NOTES

NOTES

PENILE, PROSTATE, & TESTICULAR DISORDERS

GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Disorders affecting male genitourinary tract

SIGNS & SYMPTOMS ▪ See indiviudal disorders

DIAGNOSIS

LAB RESULTS

▪ Urinalysis, urine culture

TREATMENT ▪ Conservative measures ▫ E.g. decrease fluid intake for benign prostatic hyperplasia ▪ Pharmacological therapy ▪ Surgical therapy

DIAGNOSTIC IMAGING ▪ Ultrasound

BENIGN PROSTATIC HYPERPLASIA osms.it/benign-prostatic-hyperplasia PATHOLOGY & CAUSES ▪ Characterized by nodular prostatic hyperplasia ▪ Not premalignant ▪ Most common prostatic disease in biologically-male individuals > 50 years old

CAUSES

▪ Hyperplasia of prostatic epithelial, stromal cells → formation of nodules in periurethral (transition) zone → narrowing of urethral canal → urine flow constricted ▪ Testosterone, dihydrotestosterone (DHT), estrogens act on stromal, epithelial cells’ androgen receptors → hyperplasia,

inhibition of normal cell death ▪ Dysregulation of stromal growth factors → proliferation, hyperplasia of epithelium ▪ ↑ stem cells

RISK FACTORS

▪ ↑ age ▪ Family history of benign prostatic hyperplasia (BPH) ▪ Heart disease ▪ Beta-blocker use ▪ Obesity ▪ Diabetes ▪ Erectile dysfunction

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COMPLICATIONS

▪ Chronic bladder outlet obstruction ▫ Bladder hypertrophy → formation of bladder diverticula ▫ Urinary retention → bladder calculi ▫ Residual urine can be infection source → recurrent UTIs ▫ Hydronephrosis → renal failure

SIGNS & SYMPTOMS ▪ Urinary ▫ Frequency ▫ Urgency ▫ Nocturia ▫ Dysuria ▫ Emptying bladder feels incomplete ▫ Difficulty starting, stopping urine flow ▫ Weak stream → small amounts of urine lost

DIAGNOSIS DIAGNOSTIC IMAGING Ultrasound ▪ Evaluate bladder size, prostate size, degree of hydronephrosis Cystoscopy ▪ Reveal bladder diverticula/calculi before scheduled invasive treatment

Figure 130.1 An MRI scan of the abdomen and pelvis in the coronal plane demonstrating massive prostatic hypertrophy. The prostate extends past the pelvic brim and into the abdominal cavity.

LAB RESULTS

▪ Urinalysis ▫ Microscopic hematuria may be present ▫ Pyuria, bacteriuria in case of concomitant UTIs ▪ Urine culture ▫ Exclude UTIs ▪ Blood tests ▫ Often ↑ prostate specific antigen (PSA) ▫ Electrolytes, blood urea nitrogen (BUN), and creatinine to evaluate for renal impairment

OTHER DIAGNOSTICS

▪ Digital rectal examination ▫ Enlarged, nodular prostate

Figure 130.2 The histological appearance of benign prostatic hyperplasia. There is a nodule of hyerplastic stromal tissue surrounded by hyperplastic smooth muscle.

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Chapter 130 Penile, Prostate, & Testicular Disorders

TREATMENT MEDICATIONS

▪ Alpha-adrenergic receptor blockers (terazosin, tamsulosin) → decrease prostate, bladder, urethral muscle tone ▪ 5-alpha reductase inhibitors (finasteride) decrease DHT synthesis → reduce prostate gland size ▪ Phosphodiesterase-5 enzyme inhibitors (e.g., tadalafil) → induce smooth muscle relaxation

SURGERY

▪ Transurethral resection of prostate (TURP) ▪ Open prostatectomy

OTHER INTERVENTIONS

▪ Mild cases ▫ Conservative measures; e.g. decrease fluid intake before bedtime/going out; avoid caffeine, alcohol (mild diuretic effects)

CRYPTORCHIDISM osms.it/cryptorchidism PATHOLOGY & CAUSES ▪ Common congenital condition characterized by incomplete/partial descent of testis into scrotal sac ▪ AKA undescended testes ▪ Most cases resolve spontaneously during first year of life

CAUSES

▪ Testicles normally develop in abdomen, descend into scrotal sac before birth ▫ Malpositioned testis usually found in inguinal canal but can be anywhere in descent pathway ▪ Impaired spermatogenesis at temperatures >37°C/98.6°F ▪ Leydig cells remain unaffected → normal testosterone levels ▪ Usually unilateral; bilateral in ¼ of cases ▪ Associated conditions ▫ Malformations of genitourinary tract (e.g. hypospadias), inguinal hernia

RISK FACTORS

Prematurity ↓ birth weight Twining 1st trimester maternal exposure to estrogens ▪ Family history of undescended testes ▪ Genetic syndromes associated with cryptorchidism (e.g. Down syndrome, Klinefelter syndrome) ▪ Disorders of sexual development (e.g. gonadal dysgenesis, ambiguous genitalia) ▪ ▪ ▪ ▪

COMPLICATIONS

▪ Testicular atrophy, dysfunction → infertility ▪ When malpositioned in inguinal canal → prone to trauma, testicular torsion ▪ Left untreated/treatment delayed → germcell tumors, especially seminoma, high risk; contralateral testis also at risk

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SIGNS & SYMPTOMS ▪ Asymptomatic ▪ One/both testes absent from scrotal sac ▪ Undescended testis can be palpable in abdomen

LAB RESULTS

▪ ↑ FSH ▪ ↑ LH ▪ Usually normal testosterone; ↓ in bilateral cryptorchidism

OTHER DIAGNOSTICS

▪ Physical examination ▫ Testis absent from scrotal sac

Figure 130.3 An MRI scan of the abdomen and pelvis in the coronal plane demonstrating bilateral undescended testes.

Figure 130.4 A CT scan of the pelvis in the axial plane demonstrating an undescended testicle in the right inguinal canal that has undergone malignant transformation.

DIAGNOSIS DIAGNOSTIC IMAGING Ultrasound ▪ Used to localize testis

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TREATMENT SURGERY

▪ Treatment of choice ▫ Orchiopexy, preferably at 9–15 months ▫ Testis does not spontaneously descend → placed in scrotal sac

Chapter 130 Penile, Prostate, & Testicular Disorders

EPIDIDYMITIS osms.it/epididymitis PATHOLOGY & CAUSES ▪ Inflammation of epididymis ▫ Due to infectious/non-infectious etiologies ▪ AKA epididymo-orchitis when testicle involved

TYPES

Infectious Non-infectious Idiopathic Acute ▫ < six weeks ▪ Chronic ▫ > six weeks

▪ ▪ ▪ ▪

CAUSES Mechanism of disease ▪ Urinary tract infection → vas deferens/ lymphatics of spermatic cord → epididymitis ▪ Hematogenous spread (rarely) Infectious ▪ Children ▫ Gram negative pathogens (e.g. E. coli) ▪ Adults (35 years of age) ▫ Common urinary tract pathogens (e.g. E.coli, P. aeruginosa), tuberculosis Non-infectious ▪ Trauma ▪ Autoimmune diseases ▪ Vasculitis ▪ Medications (e.g. amiodarone) Idiopathic ▪ Cause unknown

RISK FACTORS ▪ ▪ ▪ ▪

Congenital abnormalities of urinary tract ↑ sexual activity Anal intercourse Urinary tract obstruction

COMPLICATIONS ▪ ▪ ▪ ▪ ▪ ▪

Hydrocele Abscess Fistulization Necrosis Chronic epididymitis Infertility

SIGNS & SYMPTOMS ▪ Gradual onset ▫ Scrotal pain usually unilateral; sometimes radiates to lower abdomen with/without swelling ▫ Fever, chills ▫ Lower urinary tract symptoms (e.g. frequency, urgency, dysuria) ▪ Less common ▫ Urethral discharge, hematuria, hematospermia ▪ Normal cremasteric reflex ▫ Cremasteric muscle contraction → ipsilateral elevation of testicle ▪ Prehn sign ▫ Elevating scrotum relieves pain ▪ Reactive hydrocele can be present

DIAGNOSIS DIAGNOSTIC IMAGING Color Doppler ▪ Enlarged, thickened epididymis with increased blood flow; excludes testicular torsion

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LAB RESULTS ▪ ▪ ▪ ▪ ▪

Leukocytosis Pyuria, bacteriuria Positive urine culture Gram staining of urethral discharge Culture,nucleic acid amplification testing (NAAT) of first-catch urine/urethral swab specimens for C. trachomatis, N. gonorrhoeae

TREATMENT MEDICATIONS Infectious epididymitis ▪ Antimicrobial therapy ▪ Ceftriaxone, doxycycline to cover C. trachomatis, N. gonorrhoeae ▪ Ceftriaxone, quinolone for > 35 years old, individuals that have anal intercourse

SURGERY

▪ Performed when findings are equivocal, testicular torsion cannot be ruled out

OTHER INTERVENTIONS

Figure 130.5 An ultrasound scan of the scrotum demonstrating increased bloodflow in the epididymis, consistent with epididymitis.

Infectious, non-infectious epididymitis ▪ Rest ▪ Analgesia ▫ Hot or cold packs and/or analgesics (e.g. NSAIDs) ▪ Scrotal elevation Non-infectious epididymitis ▪ Treat underlying cause

HYPOSPADIAS & EPISPADIAS osmosis.org/learn/hypospadias osmosis.org/learn/epispadias PATHOLOGY & CAUSES ▪ Congenital malformations characterized by abnormal urethral opening found ventrally (hypospadias), dorsally (epispadias) ▪ Hypospadias more common

TYPES Hyposadias ▪ Glanular: least severe ▪ Midshaft: moderately severe ▪ Penoscrotal: most severe

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Epispadias ▪ Granular: least severe ▪ Penile: moderately severe ▪ Penopubic: most severe

CAUSES Hyposadias ▪ Urethral folds along penile urethra do not close properly → abnormal opening along penile shaft’s ventral surface Epispadias ▪ Genital tubercle grows in posterior direction

Chapter 130 Penile, Prostate, & Testicular Disorders instead of cranial direction → opening along penis’ dorsal surface

RISK FACTORS

▪ Family history of hypospadias/epispadias ▪ Genetic factors causing hormonal disturbances ▪ ↓ androgens ▪ Maternal age > 35 years old ▪ Maternal exposure to environmental toxins (e.g., pesticides on fruits and vegetables)

COMPLICATIONS

▪ Constriction of abnormal opening → urinary tract obstruction ▪ High risk of ascending urinary tract infections ▪ If orifices are situated near base of penis → abnormal ejaculation and insemination → infertility ▪ Psychosocial problems

SIGNS & SYMPTOMS ▪ Depends on location of abnormal urethral opening ▪ Difficulty urinating/incontinence

Figure 130.6 The appearance of subcoronal hypospadias.

DIAGNOSIS DIAGNOSTIC IMAGING Excretory urogram ▪ Series of X-rays used to visualize substances passing through kidneys, bladder, urethra

OTHER DIAGNOSTICS

▪ Clinical examination of newborn infants to reveal abnormal urethral opening

TREATMENT MEDICATIONS

▪ Hormone therapy for additional problems (e.g. low androgen levels → micropenis)

SURGERY

▪ Reconstruction of urethra within first two years of life ▪ Infants with hypospadias should not undergo circumcision → foreskin may be useful for reconstruction

Figure 130.7 A male neonate with epispadias due to non closure of the urethral plate during development. There is also congenital malformation of the external genitalia.

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ERECTILE DYSFUNCTION osms.it/erectile-dysfunction PATHOLOGY & CAUSES

SIGNS & SYMPTOMS

▪ Sexual arousal disorder characterized by inability to obtain, maintain erection during sexual intercourse ▪ AKA impotence

▪ Inability to achieve erection suitable for penetration ▪ ↓ libido ▪ ↓ erection rigidity ▪ Inability to achieve orgasm and/or ejaculation ▪ Early ejaculation ▪ ↓ peripheral pulses ▪ ↓ sensation ▪ Small testicles ▪ Penile abnormalities (e.g. Peyronie’s disease, hypospadias) ▪ Nocturnal erections present in psychogenic erectile dysfunction (ED), absent in organic ED

CAUSES

▪ Cardiovascular disease/peripheral artery disease → abnormal penile vasculature ▪ Drug side effects ▫ Antihypertensives, selective serotonin reuptake inhibitors (SSRIs), antipsychotics, nicotine, ethanol, betablockers, statins ▪ Psychogenic ▫ Performance anxiety, depression ▪ Neurological problems ▫ Prostatectomy surgery trauma, multiple sclerosis ▪ Penile disorders ▫ Peyronie’s disease, priapism

RISK FACTORS ▪ ▪ ▪ ▪ ▪ ▪ ▪

↑ age Hypertension Smoking Hyperlipidemia Diabetes Alcohol/drug abuse Hypogonadism (↓ testosterone levels)

COMPLICATIONS ▪ ▪ ▪ ▪

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↓ sexual activity Inability to satisfy sexual partner(s) Psychosocial problems Infertility

DIAGNOSIS DIAGNOSTIC IMAGING Duplex ultrasound ▪ Measures blood flow before and after injection of vasodilators

LAB RESULTS Hormonal blood tests ▪ ↓ serum testosterone → hypogonadism ▪ Luteinizing hormone (LH) ▫ ↑ LH along with ↓ testosterone → testicular deficit ▫ ↓ LH along with ↓ testosterone → CNS deficit ▫ ↓ prolactin → pituitary dysfunction Other blood tests ▪ Detect risk factors for cardiovascular disease (e.g. glucose, lipids)

Chapter 130 Penile, Prostate, & Testicular Disorders

OTHER DIAGNOSTICS

▪ Nocturnal penile tumescence testing to detect nocturnal erections ▪ Intracavernosal injection of prostaglandin E1 ▫ If adequate vasculature → erection in several minutes ▪ Detailed medical, drug history ▪ Physical examination ▪ Psychological testing

release → penile smooth muscles relax → ↑ penile blood flow → erection ▪ Intracavernosal injections of vasodilators agents ▪ Hormonal replacement (e.g. androgens) in individuals with hypogonadism

SURGERY

▪ Revascularization ▪ Implantation of prosthetic devices

PSYCHOTHERAPY

TREATMENT

▪ Reduce performance anxiety

MEDICATIONS

▪ First line ▫ Phosphodiesterase (PDE) type 5 inhibitors (e.g. sildenafil citrate) ▫ 30–60 minutes before sexual intercourse ▫ Mechanism of action: inhibitions PDE5 → ↑ cGMP levels → ↑ nitric oxide

OTHER INTERVENTIONS

▪ External facilitating devices (e.g. vacuum/ constriction devices) help obtain, maintain erection ▪ Treat underlying causes

ORCHITIS osms.it/orchitis PATHOLOGY & CAUSES ▪ Inflammation of testicle secondary to infection ▪ May occur with epididymitis (epididymoorchitis)

CAUSES

SIGNS & SYMPTOMS ▪ Unilateral/bilateral testicular tenderness, pain, scrotal swelling ▪ Fever ▪ Reactive hydrocele ▪ Inguinal lymphadenopathy

▪ Most cases of isolated orchitis seen in children with viral mumps infection ▪ Viral causes may also include coxsackie B virus ▪ May also be caused by bacterial infections ▫ E.g. E. coli

DIAGNOSTIC IMAGING

COMPLICATIONS

LAB RESULTS

▪ Atrophy ▪ Infertility ▪ Reactive hydrocele

DIAGNOSIS Color Doppler ultrasound ▪ Exclude testicular torsion

▪ Serum immunofluorescence antibody testing → establish diagnosis

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OTHER DIAGNOSTICS

▪ Suggestive clinical findings of mumps/other infections

TREATMENT OTHER INTERVENTIONS

▪ Usually resolves spontaneously after 3–10 days ▪ Conservative measures (e.g. rest, analgesics)

Figure 130.8 The histological appearance of the testicular parenchyma in a case of suppurative orchitis. The seminiferous tubules have been almost completely destroyed and there is a massive neutrophilic infiltrate.

PRIAPISM osms.it/priapism PATHOLOGY & CAUSES ▪ Involuntary, persistent erection unrelated to sexual stimulation, unrelieved by ejaculation ▪ Urologic emergency

TYPES Low flow (ischemic) ▪ Decreased venous outflow; most common High flow (nonischemic) ▪ Increased arterial inflow

CAUSES

▪ Often idiopathic/secondary

Low flow ▪ Hypercoagulable state (e.g. sickle cell anemia, thalassemia) ▪ Neurologic disease (e.g. spinal cord stenosis) ▪ Metastatic disease (e.g. prostate cancer, bladder cancer) ▪ Medications relaxing smooth muscles (e.g.

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prostaglandin, hydralazine) High flow ▪ Penile/perineum trauma → rupture of cavernous artery rupture → fistulas between cavernosal artery, corpus cavernosum

COMPLICATIONS

▪ Hypoxic damage → penile necrosis ▪ Erectile dysfunction ▪ Corporeal fibrosis → loss of penile length

SIGNS & SYMPTOMS ▪ Persistent erection usually lasting 30 minutes to three hours Low flow ▪ Usually painful ▪ Rigid erection ▪ Corporeal aspiration → dark blood

Chapter 130 Penile, Prostate, & Testicular Disorders High flow ▪ Not painful ▪ May be episodic ▪ Trauma evidence

TREATMENT MEDICATIONS Low flow ▪ Intracavernosal injection of sympathomimetic agent ▫ Phenylephrine → pure alpha agonist effects

DIAGNOSIS DIAGNOSTIC IMAGING Doppler ultrasound ▪ Differentiate low/high flow priapism, reveal fistulas CT scan ▪ Detect malignancies

LAB RESULTS

▪ Penile blood gas measurement ▫ Low flow: increased pCO2, decreased pO2, pH less than 7.0 ▪ Complete blood count (CBC) ▫ Detect sickle cell anemia ▪ Selective angiography ▫ Identify exact location of fistulas

SURGERY Low flow ▪ If other measures fail → surgical decompression High flow ▪ Identification, obliteration of fistulas with selective arterial embolization

OTHER INTERVENTIONS Low flow ▪ Treat underlying condition ▪ Corporal aspiration with/without saline irrigation

PROSTATITIS osms.it/prostatitis PATHOLOGY & CAUSES ▪ Prostate gland inflammation; usually → Gram-negative bacterial infection

TYPES Acute bacterial prostatitis ▪ Usually occurs in younger individuals ▪ More serious condition Chronic bacterial prostatitis ▪ Can be bacterial/abacterial ▪ Usually occurs in individuals aged 40–70 years ▪ Chronic bacterial is the most common form

of prostatitis Granulomatous prostatitis ▪ Infectious ▪ Bladder injections of Bacillus Calmette– Guérin (BCG) for treatment of bladder cancer (most common cause) ▪ Fungi in immunocompromised individuals ▪ Noninfectious ▪ Reaction to secretions from prostatic ducts and acini ▪ Acute granulomatous prostatitis ▫ Older adults: Gram bacteria—E.coli (most common), Klebsiella, Proteus, Pseudomonas, Enterobacter, Serratia ▫ Enterococci

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▫ Staphylococci ▫ Young adults: Chlamydia trachomatis, Neisseria gonorrhoeae ▪ Chronic granulomatous prostatitis ▫ Infectious: same causes as acute granulomatous prostatitis ▫ Noninfectious: chemical irritation; secondary to previous infections, nerve problems

CAUSES ▪ ▪ ▪ ▪

Ascending urinary tract infection Spread from rectum (direct/via lymphatics) Hematogenous (rare) May follow catheterization, cystoscopy, urethral dilation, prostate resection procedures

COMPLICATIONS

▪ Urinary retention ▪ Recurrent exacerbations in chronic prostatitis are common ▪ Prostatic abscess; usually in immunocompromised individuals ▪ Urosepsis; can be fatal ▪ Pyelonephritis ▪ Infertility

SIGNS & SYMPTOMS Acute ▪ Fever, chills ▪ Malaise ▪ Urinary symptoms ▫ Frequency, urgency, dysuria ▪ Perineal/low back pain ▪ Digital rectal exam ▫ Boggy, warm, tender, enlarged prostate Chronic ▪ Can be asymptomatic ▪ Intermittent urinary symptoms ▪ History of recurrent UTIs ▪ Perineal/low back pain; suprapubic discomfort ▪ Digital rectal examination ▫ Enlarged, nontender prostate

DIAGNOSIS DIAGNOSTIC IMAGING Ultrasound/CT scan/cystoscopy ▪ For individuals with significant voiding dysfunction/suspected abscesses/ neoplasms

LAB RESULTS

Figure 130.9 The histological appearance of acute prostatitis. There are neutrophils present within the lumina of the prostatic glands.

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▪ Urinalysis ▫ ↑ WBCs in acute ▪ Prostatic secretion ▫ ↑ WBCs in acute and chronic ▪ Urine cultures ▫ Positive in acute, chronic bacterial prostatitis ▫ Negative in chronic abacterial ▪ Blood tests ▫ CBC, blood cultures if clinical findings suggestive of bacteremia ▫ Blood urea nitrogen, creatinine levels for individuals with urinary retention/ obstruction ▫ Serum prostate-specific antigen (PSA) may be elevated

Chapter 130 Penile, Prostate, & Testicular Disorders

TREATMENT MEDICATIONS Acute ▪ Antimicrobial therapy ▫ IV broad-spectrum penicillin, third generation cephalosporin, aminoglycoside, quinolone ▫ PO antibiotics (TMP/SMX or quinolone, doxycycline) ▪ Urinary retention ▫ Alpha-blocking agents/suprapubic catheterization

OTHER INTERVENTIONS Acute ▪ Increase fluid intake ▪ Drain abscesses ▪ Prostatic massage should be avoided to prevent hematogenous spread (sepsis)

Chronic ▪ Antimicrobial therapy ▫ Prolonged course, usually with quinolone ▪ Chronic prostatitis difficult to treat because antibiotics penetrate prostate gland poorly → recurrences common

Figure 130.10 An MRI scan of the pelvis in the coronal plane demonstrating a large prostatic abscess secondary to prostatitis.

TESTICULAR TORSION osms.it/testicular-torsion PATHOLOGY & CAUSES ▪ Vascular disorder of testis characterized by rotation of testicle around spermatic cord ▪ Can lead to testicular infarction ▪ Urologic emergency ▪ Rotation of testicle → thick walled arteries remain patent while thin walled veins become obstructed → congestion → hemorrhagic infarction

RISK FACTORS

▪ Typically occurs in young adolescents; can also occur in neonates/older individuals

▪ Usually → testes’ congenital failure to strongly attach to scrotum ▪ Occasionally → trauma; also → during sleep

COMPLICATIONS

▪ If left untreated/surgery delayed beyond six hours → testicle may not be salvageable → infertility ▪ Recurrent torsions ▪ Contralateral testicle also → torsion risk ▪ Infection ▪ Orchiectomy → cosmetic malformation → psychosocial problems

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SIGNS & SYMPTOMS ▪ Sudden onset of acute, severe pain ▪ Swollen, tender, erythematous scrotum ▪ High riding testis ▫ Moves to a higher scrotal position ▪ Absent cremasteric reflex ▪ Nontender cord

DIAGNOSIS

TREATMENT SURGERY

▪ Immediate surgical detorsion → best within six hours from onset of symptoms ▪ Orchiopexy of testis to scrotum → prevent recurrence ▫ Orchiopexy of contralateral testis also indicated ▪ If testicle non-salvageable → orchiectomy

DIAGNOSTIC IMAGING

▪ Unnecessary if clinical findings are strongly suggestive; surgical detorsion should not be delayed

Color Doppler ultrasound ▪ Absent or decreased blood flow in affected testicle Contrast enhanced MRI ▪ Torsion knot or whirlpool patterns; highly sensitive and specific

LAB RESULTS

▪ Can help exclude alternate diagnosis (e.g. orchiepididymitis)

Figure 130.11 A Doppler ultrasound of the testicles demonstrating complete absence of blood flow on the right side, consistent with testicular torsion.

VARICOCELE osms.it/varicocele PATHOLOGY & CAUSES ▪ Common testicular disorder of young adults characterized by dilatation of pampiniform venous plexus, internal spermatic vein ▪ Most common cause of scrotal enlargement in young adults ▪ Impaired venous drainage → ↑ venous pressure → vein dilatation

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▪ Usually left-sided (> 80%) due to ↑ flow resistance from left testicular vein drainage into left renal vein; right testicular vein drains directly to inferior vena cava (↓ flow resistance)

TYPES Large ▪ Easily identified by inspection as distention

Chapter 130 Penile, Prostate, & Testicular Disorders Moderate ▪ Identified by palpation as “bag of worms” Small ▪ Identified only by bearing down → ↑ abdominal pressure → impeding drainage → ↑ varicocele size

TREATMENT SURGERY

▪ Indicated if varicocele associated with discomfort/pain, testicular atrophy, infertility ▪ Surgical ligation/embolization

CAUSES

▪ Idiopathic ▪ Retroperitoneal pathology (e.g. renal cell carcinoma) → can invade renal vein → leftsided varicocele

COMPLICATIONS

▪ Significant impairments in sperm production, quality due to ↑ heat, ↑ pressure, ↓ oxygen, release of toxins ▫ ↓ sperm concentration ▫ ↓ motility ▫ Abnormal morphology of spermatozoa ▪ Testicular damage, atrophy, poor sperm production, quality → infertility ▪ Contralateral testicle can also be affected

Figure 130.12 A Doppler ultrasound of the scrotum demonstrating avid flow within the spermatic cord; an appearance typical of a varicocele.

SIGNS & SYMPTOMS ▪ Usually asymptomatic ▪ Symptomatic ▫ Scrotal heaviness or scrotal pain

DIAGNOSIS DIAGNOSTIC IMAGING Doppler ultrasound ▪ Characteristic reverse blood flow Ultrasound/ CT scan ▪ May be useful in right-sided varicocele → reveals retroperitoneal pathology

LAB RESULTS

Figure 130.13 The clinical appearance of a varicocele of the right scrotum. There are dilated veins visible on the scrotal surface.

▪ Semen analysis ▫ Impairment in semen parameters (e.g. concentration, motility, morphology)

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NOTES

NOTES

PERINATAL INFECTIONS GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Infections during pregnancy, birth ▫ Teratogenic/other adverse effects on fetus, neonate ▫ Congenital infections cross placenta, infect fetus in utero ▫ Neonatal infections shortly before, during, after delivery

RISK FACTORS

▪ Maternal infection

COMPLICATIONS

▪ Premature birth; intrauterine growth restriction; tissue damage, related sequelae

SIGNS & SYMPTOMS ▪ Self-limiting to life-threatening conditions

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DIAGNOSIS ▪ Maternal prenatal, delivery history; neonatal physical examination ▪ Imaging

LAB RESULTS

▪ Culture, serology testing

TREATMENT ▪ Address complications

MEDICATIONS ▪ Antimicrobials

Chapter 131 Perinatal Infections

CONGENITAL CYTOMEGALOVIRUS INFECTION osms.it/congenital-CMV-infection PATHOLOGY & CAUSES ▪ Clinical syndrome affects developing fetus, neonate ▫ Caused by Cytomegalovirus (CMV) perinatal infection ▫ Herpesvirus family ▪ Enveloped, double-stranded linear DNA, icosahedral viral capsid ▫ Toxoplasmosis, other (syphilis, Varicella zoster, parvovirus B19), rubella, CMV, herpes (TORCH) infection ▫ Tends to become latent, reactivate ▪ Highly-prevalent virus; not very contagious ▫ Infects all ages ▫ Approx. one-third of children are infected with CMV by age five ▫ > half of adults are infected by age 40 ▪ Virus spreads to fetus transplacentally/may be acquired via maternal genital contact during delivery/through breastmilk Maternal infection ▪ Direct infectious body-fluid contact (e.g. saliva, urine, sexually transmitted); blood transfusions; transplanted organs; household contact, close contact with young infected children (e.g. daycare centers) ▫ Usually asymptomatic in adults

RISK FACTORS

▪ Maternal infection

COMPLICATIONS

▪ Fetal/neonatal ▫ Sensorineural hearing loss (SNHL), chorioretinitis, microcephaly, neurodevelopmental disability, seizure, anemia (hemolytic), pneumonitis, dental irregularity

Figure 131.1 Histological sections of chorionic villi demonstrating nuclear inclusions seen in congenital cytomegalovirus infection.

SIGNS & SYMPTOMS ▪ Birth ▫ May be asymptomatic ▪ Small for gestational age, petechial rash, “Blueberry muffin” rash, hypotonia, weak suck, hepatosplenomegaly, jaundice

DIAGNOSIS DIAGNOSTIC IMAGING CT scan/MRI ▪ Neuroimaging ▫ Intracranial calcification, ventriculomegaly, white matter disease, periventricular leukomalacia, corpus callosum dysgenesis, cerebellar hypoplasia Auditory brainstem response (ABR) ▪ Hearing deficit

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Ultrasound ▪ Suggestive prenatal fetal diagnostic findings ▫ Growth restriction, ventriculomegaly, microcephaly, periventricular calcification, hepatic calcification, hydrops/ascites, echogenic bowel

LAB RESULTS

TREATMENT ▪ Address complications

MEDICATIONS

▪ Antiviral therapy ▫ Intravenous (IV) ganciclovir/oral (PO) valganciclovir

▪ Maternal prenatal, delivery history; positive maternal CMV immunoglobulin G (IgG), CMV immunoglobulin M (IgM) antibody; neonatal examination

Microbe identification ▪ Positive culture (urine, saliva) ▪ Polymerase chain reaction (PCR) (blood, urine, saliva) ▪ CMV antigens (pp65) in peripheral leukocytes Blood studies ▪ ↑ liver transaminases ▪ ↑ direct, indirect serum bilirubin ▪ ↓ white blood cells (WBCs), ↓ platelets, ↓ red blood cells (RBCs)

Figure 131.2 Retinal photograph demonstrating the necrotizing retinitis of CMV infection. The retinitis will typically spread in a “brush fire” pattern.

CONGENITAL RUBELLA SYNDROME osms.it/congenital-rubella-syndrome PATHOLOGY & CAUSES ▪ Syndrome caused by fetal rubella virus infection ▫ Enveloped, positive-sense, singlestranded RNA virus ▫ Rubivirus in Togaviridae family ▫ Humans are only natural hosts Maternal infection ▪ Occurs through droplet inhalation/ direct infectious nasopharyngeal secretion contact → maternal viremia → hematogenous transplacental spread to fetus → persistent fetal infection

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throughout gestation → virus-induced impaired cellular division, direct cytopathic effects ▪ Maternal–fetal transmission, congenital defect risk varies in accordance with maternal infection timing ▫ ↑ ↑ risk: inoculation occurs during first ten gestational weeks ▫ ↑ risk: cardiac, eye defects if inoculation occurs before eight gestational weeks ▫ ↑ risk: hearing deficits if inoculation occurs up to 18 gestational weeks ▫ ↓ risk: inoculation occurs after 18–20 gestational weeks

Chapter 131 Perinatal Infections

RISK FACTORS

▪ Maternal non-immunized status, infection

COMPLICATIONS

▪ Fetal growth restriction ▪ Hemolytic anemia, thrombocytopenia

Neurological, sensory defects ▪ Sensorineural hearing loss ▪ Cataracts, congenital glaucoma, pigmentary retinopathy, microphthalmia ▪ Microcephaly, meningoencephalitis, intellectual disability Congenital heart defects ▪ Patent ductus arteriosus ▪ Pulmonary artery stenosis ▪ Coarctation of aorta Vascular defects ▪ Intimal fibromuscular proliferation, arterial sclerosis, systemi345c hypertension (related to renal disease) ▪ May result in adult coronary, cerebral, peripheral vascular disease Late complications ▪ Diabetes, thyroid disease, growth hormone deficiency, progressive rubella panencephalitis

SIGNS & SYMPTOMS ▪ “Blueberry muffin” rash ▫ Purpuric rash indicates cutaneous hematopoiesis ▪ Small for gestational age; low birth weight ▪ Hepatosplenomegaly ▪ Jaundice ▪ Complications present (e.g. cataracts, heart defects)

DIAGNOSIS DIAGNOSTIC IMAGING MRI ▪ Head ▫ Periventricular calcifications; demyelination ▪ Long bones ▫ Radiolucent bone lesions; irregular, alternating longitudinal light, dark bands of density (“celery stalk” appearance)

LAB RESULTS Viral identification ▪ Nasopharyngeal swabs, blood/cord blood, placenta, urine, cerebrospinal fluid (CSF) ▫ PCR/culture: rubella-specific IgM (usually present at birth); persistent IgG Prenatal diagnosis ▪ Viral isolation from amniotic fluid

OTHER DIAGNOSTICS Maternal prenatal history ▪ Rubella exposure ▪ Neonatal exam Figure 131.3 Bilateral cataracts in a newborn baby as a consequence of congenital rubella infection.

TREATMENT ▪ No specific treatment ▪ Address complications Prevention ▪ Maternal MMR vaccination before conception

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CONGENITAL SYPHILIS osms.it/congenital-syphilis PATHOLOGY & CAUSES ▪ Congenital infection caused by Treponema pallidum (spirochete bacterium causes syphilis) Maternal infection ▪ Sexually ▫ Direct infectious lesion contact → enters via microscopic abrasions → crosses placenta easily → fetal spirochetemia → widespread dissemination (almost all fetal organs) → congenital syphilis

RISK FACTORS

▪ Maternal infection → vertical (transplacental) → fetal transmission

COMPLICATIONS ▪ ▪ ▪ ▪

▪ ▪

▪

▪

▪

Stillbirth Premature birth Nonimmune hydrops Neurological ▫ Sensorineural hearing loss, intellectual disability, seizures Hematologic ▫ Hemolytic anemia, thrombocytopenia Renal ▫ Nephrotic syndrome (immune complex mediated) Ophthalmologic ▫ Chorioretinitis, uveitis, cataract, glaucoma, optic atrophy Gastrointestinal ▫ Necrotizing enterocolitis, ileus, malabsorption Skeletal ▫ Long-bone abnormalities, pathologic fractures

Treatment-related complications ▪ Benzathine penicillin G ▫ Jarisch–Herxheimer reaction: release

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of endotoxin-like compounds during penicillin-mediated lysis of T. pallidum → fever/chills, hypotension

SIGNS & SYMPTOMS Early congenital syphilis ▪ General ▫ Low birthweight, fever, hepatomegaly, jaundice, lymphadenopathy, painrelated ↓ extremity movement (pseudoparalysis) ▪ Mucocutaneous ▫ Vesicular (pemphigus syphiliticus)/ maculopapular rash ▫ Contagious, wart-like lesions (condylomata lata) ▫ Syphilitic rhinitis (“snuffles”) ▪ Umbilical cord ▫ Necrotizing funisitis (“barber-pole” appearance) Late congenital syphilis ▪ Onset after two years old ▪ Facial features ▫ Frontal bossing, saddle nose, short maxilla, protuberant mandible ▪ Sensory ▫ Impaired vision/hearing ▪ Oropharynx ▫ Hutchinson teeth (widely-spaced; notched incisors); mulberry molars (small, defective molars; cusps covered with globular enamel growths) ▪ Cutaneous ▫ Gummas ▪ Skeletal ▫ Anterior tibia bowing (saber shins), Higouménakis’ sign (sternoclavicular portion of clavicle enlargement), painless arthritis (Clutton’s joints), scaphoid scapula

Chapter 131 Perinatal Infections

LAB RESULTS

▪ T. pallidum identification ▫ Dark field microscopy ▫ Direct fluorescent antibody (DFA) staining (nasal secretions, placenta, umbilical cord, autopsy tissue) ▫ Reactive venereal disease research laboratory (VDRL), rapid plasma reagin (RPR) ▪ Blood studies ▫ ↓ platelets, ↑ ↓ WBCs ▪ CSF analysis ▫ Reactive VDRL, pleocytosis, ↑ protein, T. pallidum DNA presence (identified by PCR)

TREATMENT Figure 131.4 A newborn baby with a saddle nose malformation and snuffles, both of which are signs of congenital syphilis infection.

DIAGNOSIS DIAGNOSTIC IMAGING Long-bone radiographs ▪ Multiple anomalies ▫ E.g. metaphyseal lucent bands, metaphyseal “sawtooth” serration (Wegener sign), “moth-eaten” appearance

MEDICATIONS

▪ Intramuscular (IM) benzathine penicillin G

Prevention ▪ Screening at first prenatal visit ▫ IM benzathine penicillin G

OTHER INTERVENTIONS Prevention ▪ Characteristic fetal congenital infection features detectable via ultrasound ▫ 18–22 weeks of gestation

Chest X-ray ▫ Diffuse infiltrate/opacification of both lung fields (“pneumonia alba”)

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GROUP B STREPTOCOCCUS (GBS) INFECTION osms.it/group-b-strep-infection PATHOLOGY & CAUSES ▪ Serious neonatal infection caused by Streptococcus agalactiae ▫ Gram-positive, encapsulated diplococcus ▫ Commonly colonizes maternal gastrointestinal, genital tracts ▫ Produces complete (beta hemolysis) on blood agar plates ▪ Acquired via intra-amniotic infection, ascending infection after amniotic membrane rupture/during birth canal passage Classification ▪ GBS onset timing ▫ Early-onset GBS: presents between 24 hours to six days post-delivery (most common) ▫ Late-onset GBS: 4–5 weeks postdelivery ▫ Late, late-onset GBS: presents in infants > three months (most common in infants with immunodeficiency history/born < 28 gestational weeks)

RISK FACTORS

▪ Biologically-female individuals of African descent

COMPLICATIONS

Bacteremia Sepsis; septic shock Pulmonary hypertension (PPHN) Focal infections ▫ Meningitis, pneumonia, endocarditis septic arthritis, osteomyelitis, cellulitis, adenitis ▪ ↑ preterm infant mortality

▪ ▪ ▪ ▪

SIGNS & SYMPTOMS ▪ Lethargy/irritability; poor feeding ▪ Temperature instability ▪ Respiratory symptoms ▫ E.g. tachypnea, grunting, retractions, apnea, hypoxemia/↓ oxygen saturation ▪ Hypotension ▪ Bulging fontanel, nuchal rigidity (GBS meningitis) ▪ ↓ extremity movement/pain with manipulation GBS bone/joint infection

DIAGNOSIS

▪ GBS-positive intrapartum nucleic acid amplification test (NAAT) ▪ Chorioamnionitis ▪ Preterm labor ▪ Premature membrane rupture ≥ 18 hours

DIAGNOSTIC IMAGING

Maternal presentation ▪ Delivery time ▫ Intrapartum fever ≥ 38°C/100.4°F ▫ Delivery < 37+0 gestational weeks ▫ GBS bacteriuria in current pregnancy

LAB RESULTS

Demographic risk factors ▪ Young maternal age

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Chest X-ray ▪ Diffuse alveolar infiltrates, pleural effusion indicate GBS pneumonia

Neonatal blood studies ▪ ↑ ↓ absolute neutrophil count ▪ ↓ platelet count ▪ Positive blood culture

Chapter 131 Perinatal Infections ▪ ↑ C-reactive protein (CRP) Neonatal CSF analysis ▪ ↑ protein level, WBC count ▪ ↓ glucose level ▪ Positive Gram stain, culture results Urinalysis ▪ Gram stain, culture ▫ Presence of nitrates, leukocyte esterase, bacteria

TREATMENT MEDICATIONS

▪ Antibiotics ▫ Penicillin G, ampicillin, nafcillin

Prevention ▪ Vaginal-rectal culture: 35–37 gestational weeks ▫ If positive culture →intrapartum antibiotic prophylaxis ▫ Penicillin, ampicillin, cefazolin

Figure 131.5 Algorithm for GBS screening and prophylaxis.

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Figure 131.6 Group B streptococcus colonies cultured on blood agar.

NEONATAL CONJUNCTIVITIS osms.it/neonatal-conjunctivitis PATHOLOGY & CAUSES ▪ Clinical infection manifestation occurs within first four weeks of life, AKA ophthalmia neonatorum ▫ Most commonly caused by Neisseria gonorrhoeae/Chlamydia trachomatis (coinfection with both microbes common) ▫ Rarely, herpetic conjunctivitis caused by herpes simplex virus (HSV) ▫ Staphylococcus, Streptococcus may also be implicated in some conjunctival infections

COMPLICATIONS ▪ ▪ ▪ ▪

Corneal ulceration, scarring Vision impairment, blindness Systemic sequelae of infection HSV: keratitis, keratouveitis

SIGNS & SYMPTOMS ▪ Eyelid swelling, watery/mucopurulent discharge, chemosis, micropannus (granulation tissue membrane)

Transmission ▪ Primarily via exposure to mother’s infected genital flora during vaginal birth ▪ Ascending infection in case of premature membrane rupture

RISK FACTORS

▪ Maternal infection Figure 131.7 The clinical appearance of severe neonatal conjunctivitis.

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Chapter 131 Perinatal Infections

DIAGNOSIS LAB RESUTS Microbe identification ▪ Conjunctival, nasopharyngeal specimens ▫ Culture ▫ Gram stain ▫ Nucleic acid amplification test (NAAT) ▫ Polymerase chain reaction (PCR) ▫ Direct fluorescent antibody (DFA), enzyme immunoassay (EIA) tests ▫ HSV: Giemsa stain, PCR CBC ▪ ↑ eosinophil count

TREATMENT ▪ Antibiotics ▫ Gonococcal disease: IV/IM ceftriaxone ▫ Chlamydial disease: oral erythromycin, azithromycin ▫ HSV: acyclovir Prevention ▪ Gonococcal conjunctivitis ▫ Routine neonatal prophylaxis with erythromycin 0.5% ointment

OTHER INTERVENTIONS

▪ Treat neonate’s mother, sexual partner ▪ Maternal prenatal screening

OTHER DIAGNOSTICS

▪ Maternal history ▪ No prenatal care; untreated C. trachomatis/N. gonorrhoeae infection; neonatal examination

NEONATAL HERPES SIMPLEX osms.it/neonatal-herpes-simplex PATHOLOGY & CAUSES ▪ Uncommon, serious neonatal infection caused by herpes simplex virus (HSV-1, HSV-2) ▪ Enveloped, double-stranded DNA virus ▫ HSV-2: most neonatal cases ▫ TORCH infection Transmission ▪ Intrauterine/transplacentally is rare ▪ Intrapartum: ascending infection from maternal genitals during delivery/mother’s infected genital flora exposure ▫ Most maternal HSV infections are clinically inapparent ▪ Postnatal via close contact

Inoculation ▪ 2–21 day incubation ▪ Skin, eyes, mouth (SEM) disease ▪ Central nervous system (CNS) disease ▪ Disseminated disease ▫ Multiple organs (e.g. lungs, liver, adrenal, CNS, skin, eye, mouth)

RISK FACTORS Maternal infection ▪ ↑ transmission risk with vaginal delivery, prolonged membrane rupture, delivery instruments that disrupt fetal skin barrier

COMPLICATIONS

▪ Recurring skin lesions throughout childhood

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▪ CNS HSV ▫ Meningoencephalitis ▪ Disseminated HSV ▫ Hepatitis, disseminated intravascular coagulation (DIC), hemorrhagic pneumonitis ▫ High mortality

SIGNS & SYMPTOMS ▪ May be asymptomatic initially ▪ SEM ▫ Mucosal vesiculopustular eruption ▪ CNS HSV ▫ Temperature instability, irritability/ lethargy, bulging fontanelle, seizure ▪ Disseminated HSV ▫ Temperature instability, lethargy, poor feeding, jaundice, hepatosplenomegaly, respiratory distress

DIAGNOSIS LAB RESULTS

▪ Microbe identification ▫ Culture (blood, CSF, urine, mucous membrane fluid) ▫ PCR ▪ CNS analysis ▫ CSF ↑ protein, ↑mononuclear pleocytosis ▪ Lesion analysis ▫ Multinucleated giant cells visualized with Giemsa/Wright stain

TREATMENT MEDICATIONS ▪ IV acyclovir

OTHER INTERVENTIONS

▪ Also treat mother, mother’s partner

Figure 131.8 A neonate with herpes simplex vesicles on the scalp.

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Chapter 131 Perinatal Infections

NEONATAL MENINGITIS osms.it/neonatal-meningitis PATHOLOGY & CAUSES ▪ Severe neurological infection complication ▫ High morbidity, mortality rate ▫ Most often occurs during first week of life ▫ Bacterial, viral, fungal infections ▪ Usually caused by variety of bacteria (e.g. GBS, E. coli, S. pneumoniae, Enterococcus, coagulase-negative staphylococci, S. aureus, L. monocytogenes, H. influenzae)

RISK FACTORS

▪ Premature birth, low birthweight, maternal infection, sepsis

COMPLICATIONS

▪ Cerebral edema/abscess, hydrocephalus, intraventricular hemorrhage, encephalomalacia, cerebral palsy, seizure disorder, auditory/visual sensory deficits

ventriculitis, extracerebral fluid collections MRI/CT scan ▪ Detects cerebral edema, infarction/abscess area, CSF obstruction, encephalomalacia, atrophic tissue (cortical, white matter)

LAB RESULTS

▪ Microbe identification ▫ CSF ▫ Gram stain, culture, PCR, NAAT ▫ Blood culture (may be negative) ▫ Urine culture ▪ Blood studies ▫ ↑↓ WBC count, left shift, ↓ platelets ▪ CSF ▫ ↑ WBCs, ↑ protein, ↓ glucose

SIGNS & SYMPTOMS General ▪ Temperature instability, lethargy, poor feeding, vomiting, diarrhea Neurological ▪ Irritability, hypotonia, tremors, seizures, full/ bulging fontanelle; may have nuchal rigidity Respiratory ▪ Tachypnea, retractions nasal flaring, grunting, apnea

DIAGNOSIS

Figure 131.9 A sample of cerebrospinal fluid from a neonate with meningitis. There are neutrophils present, denoting an acute inflammatory process as well as cocci arranged in groups and pairs. Culture grew Staphylococcus capitis.

DIAGNOSTIC IMAGING Cranial sonography ▪ Assess ventricular size ▫ Detect ventricular hemorrhage,

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TREATMENT MEDICATIONS

▪ Antimicrobials ▫ usually ampicillin + gentamicin + thirdgeneration cephalosporin ▪ Anticonvulsants ▪ IV fluids, vasopressors

NEONATAL SEPSIS osms.it/neonatal-sepsis PATHOLOGY & CAUSES ▪ Serious infection; presents within neonate’s first 30 days; characterized by bacteremia/ meningitis ▪ Characterized by onset ▫ Early-onset sepsis: occurs with first 3–7 days ▫ Late-onset sepsis: occurs between 7–30 days ▪ May be bacterial (most common), viral, fungal (more common in preterm infants) → vertical transmission before/during labor/ delivery

RISK FACTORS

Low birthweight Preterm birth Low Apgar score at five minutes Prolonged membrane rupture Chorioamnionitis Maternal GBS colonization (inadequate intrapartum treatment) ▪ Inborn metabolism errors ▪ Maternal age ≤ 20 ▪ ▪ ▪ ▪ ▪ ▪

COMPLICATIONS

▪ Meningitis, pneumonia, multi-organ failure, necrotizing enterocolitis (NEC), high mortality rate

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SIGNS & SYMPTOMS ▪ May be initially nonspecific ▪ Fever, temperature instability General signs ▪ Lethargy, irritability, poor suck, hypotonia Respiratory distress signs ▪ Tachypnea, grunting, nasal flaring, retractions, apneic periods, cyanosis Hemodynamic instability ▪ Tachycardia/bradycardia, prolonged capillary refill time, hypotension, pallor

DIAGNOSIS ▪ Maternal, intrapartum, neonatal history ▪ Compatible clinical presentation

LAB RESULTS

▪ Blood, CSF culture ▫ Identify causative microbe ▪ CBC ▫ Neutropenia (due to small neutrophil storage pool) ▪ CSF analysis ▫ ↑ WBCs; protein, glucose may also be ↑

Chapter 131 Perinatal Infections

TREATMENT MEDICATIONS ▪ Antibiotics ▪ Vasopressors

OTHER INTERVENTIONS

▪ Supplemental oxygen, mechanical ventilation ▪ IV fluids

TOXOPLASMOSIS osms.it/toxoplasmosis PATHOLOGY & CAUSES ▪ Congenital infection ▫ Caused by protozoa Toxoplasma gondii ▫ TORCH infection ▪ Obligate intracellular parasite ▪ Transplacental transmission to fetus Biphasic life cycle ▪ Sexual cycle ▫ Occurs exclusively in felines (definitive host) ▪ Asexual cycle ▫ Occurs in other animals, including humans Maternal infection routes ▪ Cats consume infective form (cysts) from prey (e.g. intermediate hosts—rodents, birds) → replication within intestines → oocyst formation → fecal excretion → maternal infection via cat fecal exposure (soil, litter box) ▪ Wild game/animals bred for human consumption (e.g. cattle) may ingest environmental oocytes → infection → maternal consumption of raw/undercooked meat, contaminated water/vegetables → maternal infection

RISK FACTORS

▪ Maternal infection ▫ Primary infection during pregnancy/ reactivation in immunocompromised host

COMPLICATIONS

▪ ↑ congenital effect severity when infection occurs early in gestation ▫ Classic triad: chorioretinitis, hydrocephalus, intracranial calcification ▫ Sensorineural hearing loss, microcephaly, intellectual disability, motor/cerebellar dysfunction, growth delay, seizure, pneumonitis, anemia, thrombocytopenia

SIGNS & SYMPTOMS Subclinical infection ▪ Routine assessment reveals no anomalies ▪ Focused examination may reveal infection signs (e.g. ophthalmologic, CNS imaging) Clinically apparent disease ▪ During neonatal period/first few months of life ▫ May be mild/severe, CNS/ocular complications, purpuric rash (“blueberry muffin” rash), fever, jaundice, hepatosplenomegaly, lymphadenopathy, microphthalmia, hypotonia Late infancy, childhood, adolescence ▪ Undiagnosed/untreated infection emergence/relapse ▫ Complication developments (e.g. chorioretinitis, neurosensory hearing loss) ▫ Growth delay, endocrine abnormalities secondary to hypothalamic, pituitary dysfunction

OSMOSIS.ORG 827

DIAGNOSIS DIAGNOSTIC IMAGING ABR ▪ Sensorineural hearing loss CT scan ▪ Neuroimaging ▫ Intracranial calcifications, hydrocephalus (ventriculomegaly), cortical atrophy

LAB RESULTS Confirmatory diagnostics ▪ With any of following ▫ Positive IgG with positive IgM (after five days of life), IgA (after ten days of life) + confirmed maternal serology ▫ Positive CSF PCR + confirmed maternal T. gondii infection during pregnancy, characteristic neonatal clinical findings ▫ Positive IgG beyond 12 months of age demonstrates anti-Toxoplasma IgG persistence Ophthalmic examination ▪ Chorioretinitis Neurologic examination ▪ Lumbar puncture ▫ ↑ protein, mononuclear pleocytosis Blood studies ▪ CBC ▫ ↓ RBCs ↓ platelets, ↑ eosinophils ▪ Liver function tests ▫ Possible ↑ aspartate aminotransferase; alanine aminotransferase; total, direct bilirubin Cytologic placental examination ▪ T. gondii cyst/tachyzoite presence

828 OSMOSIS.ORG

Figure 131.10 Retinal photograph demonstrating the characteristic “headlight in the fog” appearance of toxoplasma retinitis.

TREATMENT MEDICATIONS Neonatal treatment ▪ Antiparasitic therapy ▫ Pyrimethamine + sulfadiazine + folinic acid ▪ Prednisone if ↑ CSF protein Prevention ▪ Maternal antiparasitic therapy ▫ Positive amniotic fluid PCR before 18 gestational weeks ▪ Pyrimethamine + sulfadiazine plus folinic acid until delivery