Diabetic Neuropathy and Clinical Practice 9789811524165, 9789811524172

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Diabetic Neuropathy and Clinical Practice Sanjeev Kelkar

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Diabetic Neuropathy and Clinical Practice

Sanjeev Kelkar

Diabetic Neuropathy and Clinical Practice

Sanjeev Kelkar Independent Health Researcher Pune, Maharashtra India

ISBN 978-981-15-2416-5    ISBN 978-981-15-2417-2 (eBook) https://doi.org/10.1007/978-981-15-2417-2 © Springer Nature Singapore Pte Ltd. 2020 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Singapore Pte Ltd. The registered company address is: 152 Beach Road, #21-01/04 Gateway East, Singapore 189721, Singapore

To Mr. Dhananjay Kesheo and Mrs. Sai Dhananjay Kelkar For their significant contribution to the development of The movement for better Diabetic Foot Management in India Through the development of fine instrumentation, Yeoman’s work in Diabetic Footwear That received less recognition than it deserved

Preface

The cornerstone of clinical practice, Communication between the doctor and the patient, the cornerstone of clinical practice, is the greatest casualty in the last two decades. There is a failure to understand the meaning of what the patient is saying, explaining not just the complaints but his concerns. The art and science of history taking, communication through fingers and eyes in examining a patient, about arriving at a primary diagnosis and extending a differential one, pertinence of investigation and rational management, and the various forms of communication are as good as lost today. There are many reasons for this, which have been elaborated in the two volumes on India’s Public Health Care Delivery: Policies for Universal Health Care and India’s Private Health Care Delivery: Critique and Remedies I have written. These two volumes will soon be published by Palgrave Macmillan. In addition, there is a lack or loss of critical clinical reasoning and its articulate, non-jargonistic and empathic articulation in the business of patient care. A more important reason for the genesis of this principally comes from the loss of the grip on the basics of clinical medicine which lie in the nonclinical subjects first taught, viz. anatomy, physiology, biochemistry, and pathology. The direct effect of this loss of grip continues to affect while learning in the clinical branches, pharmacology and therapeutics, continues. There is a disconnection between these clinical and nonclinical subjects. Since the details of mechanisms and basic information are no longer available, the doctors are at loss in explaining anything about the disorder of the patient in an understandable and satisfying manner. For some good reasons, I have been associated with and talking or teaching about diabetic neuropathy since 2000 CE. The numbers taught are really large and widely spread over India, South East Asia, and other places. In doing so I believe I have gained some insight into what needs to be taught and how. A few important elements of this insight are to retain as my primary focus an understanding of the basics of anatomy, physiology, and pathology in dealing with the clinical issues at hand. The second is on developing critical clinical reasoning and its verbal articulation. Unless the clinical skills are combined with the basics, the all-important diagnosis can never be achieved and rational care is impossible. The area of Diabetic Neuropathy is one such area where this could be facilitated for the betterment of

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patients and the professionals. It is widely prevalent but poorly understood; one has to deal with it within a much larger canvas of clinical practice at many levels of complexity. To equip the doctors, this book has been penned. Pune, Maharashtra, India December 2019

Sanjeev Kelkar

Acknowledgments

I am grateful to Novo Nordisk and Novo Nordisk Education Foundation (NNEF) and to the Managing Director and Trustee Dr. Anil Kapur, who recognized the need for an intensive effort to improve the status of Diabetic Foot Care in India for the first time. Dr. Kapur gave it a huge push initially and entrusted me to develop this field. He was also the key figure behind the creation of Diabetic Foot Society of India (DFSI), a unique body in the world, now recognized for its work all over, and has contributed greatly for the betterment of this area. I am grateful to the University of Newcastle Australia and its faculty for including Diabetic Nerve and Foot Disorders as an important component of the Problem-­ Based Learning Courses it conducted with NNEF—Dr. Jean McPherson, Dr. Judith Scott, Dr. Richard Gibson, Dr. Kerry Bowen, and the pro-vice-chancellor Dr. John Marley. This effort gave a great boost to the work of DFSI also. Three sets of people have done a great deal of work in this field to whom I wish to express my gratitude. From NNEF, Mr. M V Prasad’s support in high-quality reference work has simply been incredible for this volume; Mrs. Anandhi Singh, my efficient secretary in NNEF, handled the immensely complicated logistics of these works and relieved me to concentrate on many other aspects like teaching programs, organizing conferences, and formatting support material for learning for this work and for Diabetes Education for professionals intimately connected with it. The staff of the University of Newcastle, Ms. Judy Melville, Mrs. Carolyn Holland, and Mrs. Kathy Byrne, traveled enormous distances every 2 months for five long years to do the work, ever smiling and lifting the burden of these activities. Diabetic neuropathy and foot work has also progressed largely in different parts of the country by those who organized 17 National Conferences in as many years of existence of DFSI. The national and international faculty have contributed to the knowledge process greatly. Last and the most important person I wish to acknowledge is Dr. Arun Bal, premiere diabetic foot surgeon of India, the capacity builder of the army of diabetic foot professionals, honored and awarded by the world bodies, and the founder president of DFSI. I worked all these years as a competent manager under his benign generalship and learned all that I could. He is the brick and mortar of DFSI. There are many others who worked for this cause in DFSI, named and unnamed to whom I extend my gratitude in bringing out this work. ix

Contents

Part I Anatomy and Pathophysiology of Diabetic Nerves 1 Introduction������������������������������������������������������������������������������������������������   3 2 Functional Anatomy of the Cranial, Peripheral, and Autonomic Nerves������������������������������������������������������������������������������   7 2.1 Introduction����������������������������������������������������������������������������������������   7 2.2 Cranial Nerves������������������������������������������������������������������������������������   8 2.2.1 General Features ��������������������������������������������������������������������   8 2.2.2 Afflictions of Optic Tract��������������������������������������������������������   8 2.2.3 Oculomotor Nerves III, IV, and VI in Diabetes����������������������   8 2.2.4 Pupillary Abnormalities����������������������������������������������������������   9 2.2.5 Facial Neuropathy������������������������������������������������������������������   9 2.2.6 Treatment and Prognosis of Facial Neuropathy����������������������   9 2.2.7 Tenth Cranial Nerve Vagus ����������������������������������������������������   9 2.3 Diabetic Peripheral and Autonomic Neuropathies������������������������������  10 2.3.1 Diabetic Sensory Neuropathies����������������������������������������������  10 2.3.2 Diabetic Somatic Motor Neuropathies�����������������������������������  10 2.3.3 Diabetic Autonomic Neuropathies������������������������������������������  10 2.4 Functional Anatomy of Diabetic Somatic Peripheral Neuropathy������������������������������������������������������������������������������������������  11 2.4.1 Diabetic Somatic Sensory Peripheral Neuropathy������������������  11 2.4.2 Classification, Anatomy, and Functions of Sensory Receptors������������������������������������������������������������������  11 2.5 Classification of Nerve Fibers: General����������������������������������������������  12 2.5.1 Alternative Classification Used by Neurophysiologists����������  13 2.6 General Principles and Sensory Physiology ��������������������������������������  14 2.6.1 Adaptation, Accommodation, and Inactivation of the Stimulus and Impulse ��������������������������������������������������  14 2.6.2 Nerve Fibers, Transmission of Different Signals, and Their Physiologic Significance����������������������������������������  14 2.7 Sensory Perception of Touch, Pressure, and Vibration and the Nerve Ending Distribution ����������������������������������������������������  15 2.7.1 Meissner’s Corpuscle��������������������������������������������������������������  15 xi

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2.7.2 Merkel’s Discs������������������������������������������������������������������������  15 2.7.3 Hair End Organ ����������������������������������������������������������������������  16 2.7.4 Ruffini’s End-Organs��������������������������������������������������������������  16 2.7.5 The Pacinian Corpuscles��������������������������������������������������������  16 2.8 Transmission of Tactile Signals in Peripheral Nerve Fibers ��������������  17 2.8.1 Anatomy and the Transmission of the Dorsal Column–Medial Lemniscal System����������������������������������������  17 2.8.2 Signals and Functions Carried in the Dorsal Column–Medial Lemniscal System����������������������������������������  18 2.8.3 Pressure and Vibratory Sensation Through the Dorsal Columns����������������������������������������������������������������������  18 2.8.4 Anatomy and Transmission in the Anterolateral Pathway����������������������������������������������������������������������������������  18 2.8.5 Signals and Functions Carried in the Antero-Lateral System������������������������������������������������������������  19 2.9 Functional Anatomy of Autonomic Nerves����������������������������������������  19 2.9.1 Segmental Distribution of the Sympathetic Nerve Fibers����������������������������������������������������������������������������  19 2.10 Functional Anatomy of Central Autonomic Nervous System������������  20 2.10.1 Sympathetic Nerve Fibers in the Skeletal Nerves������������������  20 2.10.2 Functional Anatomy of the Parasympathetic Nervous System����������������������������������������������������������������������  21 2.10.3 Preganglionic and Postganglionic Parasympathetic Neurons ����������������������������������������������������������������������������������  21 2.10.4 Sympathetic and Parasympathetic “Tone”������������������������������  22 2.10.5 Tone Caused by Basal Secretion of Epinephrine and Norepinephrine by the Adrenal Medullae������������������������  22 2.11 Effect of Loss of Sympathetic or Parasympathetic Tone After Denervation����������������������������������������������������������������������  22 2.11.1 Denervation Super-Sensitivity of Sympathetic and Parasympathetic Organs��������������������������������������������������  23 2.11.2 Sympathetic Stimulation and Skeletal Stimulation����������������  23 2.11.3 Muscarinic and Nicotinic Receptors��������������������������������������  23 3 Pathogenesis of Diabetic Neuropathies����������������������������������������������������  25 3.1 Pathological Hallmarks of Diabetic Neuropathy��������������������������������  25 3.2 Epidemiological Features of Diabetic Peripheral Neuropathy ����������  25 3.2.1 Few Main Clinical Features of Diabetic Sensorimotor Polyneuropathy������������������������������������������������  26 3.2.2 Confirmatory Evidence of Peripheral Neuropathy ����������������  26 3.3 Pathogenetic Mechanisms in Development of Diabetic Neuropathy������������������������������������������������������������������������������������������  26 3.3.1 Hyperglycemia������������������������������������������������������������������������  26

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3.3.2 Generation of Superoxide Radicals and Its Subsequent Effects������������������������������������������������������������������  26 3.3.3 Reactive Oxygen and Nitrogen Species— (ROS and RONS)—Mechanisms of Damage ������������������������  27 3.3.4 RONS and Autonomic Ganglia����������������������������������������������  28 3.3.5 ROS and Synaptic Transmission��������������������������������������������  28 3.3.6 Oxidation and Chromosomal Damage, Vascular Factors, Hypoxia ��������������������������������������������������������������������  28 3.4 Hypoxia in Neuropathies in Diabetes ������������������������������������������������  29 3.4.1 Endoneurial and Epineurial Hypoxia��������������������������������������  29 3.4.2 Some Other Factors of Pathogenic Importance����������������������  30 3.5 Advanced Glycation End Products (AGEs)����������������������������������������  30 3.6 The Polyol Pathways��������������������������������������������������������������������������  31 3.6.1 Mechanism in Detail ��������������������������������������������������������������  31 3.7 Role of Inflammation��������������������������������������������������������������������������  31 3.7.1 Role of TNF Alpha in Inflammation��������������������������������������  32 3.7.2 Role of CD 163 in Inflammation��������������������������������������������  32 3.7.3 Role of Adipose Tissues in Inflammation ������������������������������  32 3.7.4 Other Pathogenic Mechanisms of Inflammation��������������������  33 3.7.5 Clinical Risk Factors for Neuropathy ������������������������������������  33 3.8 Genetic Susceptibility ������������������������������������������������������������������������  34 3.8.1 More Recent Genetic Studies in DPN and Other Microvascular Complications��������������������������������  34 3.8.2 Counterargument for Genetic Susceptibilities������������������������  34 3.9 Paraproteinemic Neuropathy (PPN)���������������������������������������������������  35 3.9.1 Clinical Features of PPN��������������������������������������������������������  35 3.9.2 Associations of PPN with Neuropathy ����������������������������������  36 3.9.3 Prevalence of PPN������������������������������������������������������������������  36 3.10 Key Mechanisms Leading to Neuropathy in Diabetes������������������������  36 3.11 Autoimmune Etiopathogenesis of Diabetic Neuropathies������������������  37 3.11.1 Molecular Mechanisms Involved in Autoimmune Reactions��������������������������������������������������������������������������������  38 3.11.2 Autoimmunity and Axonal Neuropathic Damage������������������  38 3.11.3 Autoimmunity with Reference to T1DM Neuropathies ��������������������������������������������������������������������������  39 3.11.4 Autoimmunity from the Neuropathic Point of View��������������  39 3.12 Chronic Inflammatory Demyelinating Polyradiculoneuropathy in Diabetes Mellitus������������������������������������  40 3.12.1 American Academy of Neurology Research Criteria for the Diagnosis of CIDP ����������������������������������������  40 3.12.2 Conclusions About CIDP in Diabetes Mellitus����������������������  40 3.13 Autoimmunity of the Optic Nerve and Retinal Diseases��������������������  41 3.13.1 The Cerebral Cortex and Autoimmunity��������������������������������  42 References����������������������������������������������������������������������������������������������������  43

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Part II Autonomic Neuropathies in Diabetes 4 Cardiovascular and Cerebral Dysfunction����������������������������������������������  49 4.1 Introduction����������������������������������������������������������������������������������������  49 4.2 Epidemiology of Cardiac Autonomic Neuropathy/Dysfunction in Diabetes��������������������������������������������������  49 4.3 Clinical Profile: Symptoms ����������������������������������������������������������������  50 4.3.1 Clinical Signs of Cardiac Autonomic Neuropathy�����������������  50 4.4 Physiology of Cardiac Innervation ����������������������������������������������������  51 4.4.1 Pathophysiological Basis of Three Events������������������������������  51 4.4.2 Clinical Effects of Autonomous Imbalance����������������������������  52 4.4.3 Degeneration of Sympathetics������������������������������������������������  52 4.5 The Normal Blood Pressure Regulation ��������������������������������������������  52 4.5.1 Baroreflex Sensitivity��������������������������������������������������������������  53 4.6 Clinical Correlates of Cardiac Autonomic Neuropathy����������������������  53 4.6.1 Obstructive Sleep Apnea (OSA) and Cardiac Autonomic Neuropathy����������������������������������������������������������  54 4.6.2 Hypoglycemia Unawareness and Cardiac Autonomic Neuropathy������������������������������������������������������������������������������  55 4.6.3 Impaired Glucose Tolerance (IGT) and Cardiac Autonomic Neuropathy����������������������������������������������������������  55 4.6.4 Diabetic Retinopathy��������������������������������������������������������������  55 4.6.5 Orthostatic Hypotension ��������������������������������������������������������  56 4.6.6 Other Factors��������������������������������������������������������������������������  56 4.6.7 DCCT and Epidemiology of Diabetes Interventions and Complications (EDIC) Studies����������������������������������������  56 4.6.8 Risk Factors Within the Clinical Spectrum����������������������������  56 4.7 Cardiac Autonomic Neuropathy in the Pre, Intra, and Postoperative Course��������������������������������������������������������������������  57 4.7.1 Intraoperative Mortality����������������������������������������������������������  57 4.7.2 Perioperative Mortality ����������������������������������������������������������  57 4.7.3 Mortality due to Cardiac Autonomic Neuropathy������������������  57 4.8 Laboratory Diagnosis of Cardiac Autonomic Neuropathy ����������������  58 4.8.1 Clinical Signs and Symptoms ������������������������������������������������  58 4.8.2 Laboratory Tests and Their Interpretation������������������������������  58 4.8.3 Tests for Parasympathetic Autonomic Neuropathy����������������  58 4.8.4 Tests for Sympathetic Autonomic Neuropathy Control����������  58 4.8.5 Heart Rate Variability (HRV)��������������������������������������������������  59 4.8.6 Response to Standing Up (30:15 ratio)����������������������������������  59 4.8.7 Orthostatic Hypotension ��������������������������������������������������������  59 4.8.8 Sustained Hand Grip ��������������������������������������������������������������  60 4.8.9 The differential diagnosis of cardiac autonomic neuropathy (CAN)������������������������������������������������������������������  60 4.8.10 Electrocardiogram in Cardiac Autonomic Neuropathy: QT Prolongation���������������������������������������������������������������������  60

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4.9 Autoregulation of Cerebral Blood Flow ��������������������������������������������  61 4.9.1 Maintenance of Normal Cerebral Perfusion Pressure������������  61 4.9.2 Changes in the Regulation of Cerebral Circulation and Blood Pressure����������������������������������������������  61 4.10 Profiling Clinical Autonomic Symptom Profile: Questionable Questionnaires��������������������������������������������������������������  62 References����������������������������������������������������������������������������������������������������  63 5 Gastrointestinal and Urinary Dysfunction����������������������������������������������  65 5.1 Introduction����������������������������������������������������������������������������������������  65 5.1.1 Correlations of Autonomic Neuropathy����������������������������������  65 5.1.2 Prevalence of Diabetic Autonomic GI Neuropathies��������������  65 5.2 Organization and Function of the Enteric Nervous System (ENS) ����������������������������������������������������������������������  66 5.2.1 Autonomic Innervation of the Digestive Tract������������������������  66 5.2.2 Autonomic Innervation and Reflexes of Gastrointestinal Tract��������������������������������������������������������������  66 5.2.3 Non-spinal Reflex Pathways ��������������������������������������������������  67 5.3 Intramural Nerve Plexuses of the Gastrointestinal System����������������  67 5.4 Diabetic Enteropathy: Pathogenesis���������������������������������������������������  68 5.4.1 Hyperglycemia and Intracellular Biochemical Changes����������������������������������������������������������������������������������  68 5.4.2 Diabetes-Induced Marked Structural Remodeling of GI Tract Wall��������������������������������������������������  68 5.4.3 Role of Entero Glial Cells (EGCs)�����������������������������������������  69 5.5 Autonomic Nervous System Disturbances in Gastrointestinal Tract��������������������������������������������������������������������������  69 5.5.1 Parasympathetic Nervous System and the Gut ����������������������  69 5.5.2 Clinical Features and Effects of Accelerated/Rapid Gastric Emptying��������������������������������������������������������������������  70 5.5.3 Clinical Effects of Disturbances in Sympathetic Innervation on Gut������������������������������������������������������������������  70 5.5.4 Main GI Effects����������������������������������������������������������������������  71 5.6 Laboratory Diagnosis of GI Autonomous Disorders��������������������������  72 5.6.1 Preconditions��������������������������������������������������������������������������  72 5.6.2 Diagnosis of Gastroparesis, Intestinal, and Colonic Abnormalities��������������������������������������������������������������������������  72 5.6.3 Scintigraphy in Gastroparesis, Intestinal, and Colonic Transit Time��������������������������������������������������������  73 5.6.4 Disadvantages of Scintigraphy�����������������������������������������������  73 5.6.5 Radiopaque Markers for GI Motility��������������������������������������  73 5.6.6 Gastric Emptying Breath Testing��������������������������������������������  73 5.6.7 Wireless Motility Capsule for GI Motility Studies����������������  74 5.6.8 Transit Time Detection and Diagnosis������������������������������������  74

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5.6.9 Manometric Measurements of GI Tract: Esophageal Evaluation������������������������������������������������������������  75 5.7 Treatment of Diabetic Neuropathy of GI Tract����������������������������������  75 5.7.1 The Variables of Planning and Monitoring Therapy��������������  76 5.8 Gastrointestinal Organ-Specific Management in Diabetic Autonomic Neuropathy��������������������������������������������������������  76 5.8.1 General Remarks��������������������������������������������������������������������  76 5.9 Esophageal Disorders in Diabetes������������������������������������������������������  76 5.9.1 Investigation of Esophageal Disorders�����������������������������������  77 5.10 Gastroesophageal Reflux Disease ������������������������������������������������������  77 5.10.1 Esophageal Complications of GERD�������������������������������������  77 5.10.2 Prevalence of GERD and Diabetes ����������������������������������������  77 5.10.3 Treatment of GERD����������������������������������������������������������������  77 5.11 Diabetic Gastroparesis: Clinical Profile and Management Issues����������������������������������������������������������������������  78 5.11.1 Systematic Record of Upper GI Symptomatology: An Extension to History Taking����������������������������������������������  78 5.11.2 Management and Treatment of Gastroparesis������������������������  78 5.11.3 Non-Pharmacological Management���������������������������������������  79 5.11.4 Pharmacologic Management of Gastroparesis�����������������������  79 5.11.5 Metoclopramide����������������������������������������������������������������������  79 5.11.6 Domperidone��������������������������������������������������������������������������  80 5.11.7 Erythromycin��������������������������������������������������������������������������  80 5.11.8 Other (Experimental) Drugs Used in Gastroparesis ��������������  80 5.11.9 Acute Diabetic Gastroparesis��������������������������������������������������  81 5.12 Abnormal Bowel Function: Diarrhea and Constipation ��������������������  82 5.12.1 Pathophysiology of Diarrhea��������������������������������������������������  82 5.12.2 The Differential Diagnosis������������������������������������������������������  82 5.12.3 Treatment of Diabetic Diarrhea����������������������������������������������  82 5.13 Diabetic Constipation��������������������������������������������������������������������������  83 5.13.1 Treatment of Refractory Constipation������������������������������������  83 5.13.2 Treatment of Abdominal Pain in Diabetic Autonomic Neuropathy of GI Tract����������������������������������������  83 5.14 Autonomic Dysfunction of the Urinary Tract������������������������������������  84 5.14.1 Functional Anatomy of Autonomic Innervation ��������������������  84 5.14.2 Diabetic Cystopathy����������������������������������������������������������������  84 5.14.3 Laboratory Investigation of Diabetic Cystopathy ������������������  84 5.14.4 Detrusor Hyperreflexia������������������������������������������������������������  85 5.14.5 Electromyography Testing������������������������������������������������������  85 References����������������������������������������������������������������������������������������������������  86 6 Dysfunction of Sexual and Accessory Sex Organs����������������������������������  91 6.1 Introduction����������������������������������������������������������������������������������������  91 6.2 Neurophysiology of Penile Erection��������������������������������������������������  91

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6.2.1 Penile Erection: Role of the Parasympathetic Nerves ������������������������������������������������������������������������������������  92 6.2.2 Lubrication, a Parasympathetic Function ������������������������������  92 6.2.3 Emission and Ejaculation: Function of the Sympathetic Nerves����������������������������������������������������������  92 6.3 Clinical Factors Leading to Erectile Dysfunction (ED)in Diabetes����������������������������������������������������������������������������������  93 6.3.1 Factors Responsible at Organ Level ��������������������������������������  94 6.3.2 Molecular Mechanisms Involved in ED ��������������������������������  94 6.4 Hormonal Changes������������������������������������������������������������������������������  95 6.4.1 Testosterone����������������������������������������������������������������������������  95 6.4.2 Causes of Testosterone Deficiency in Diabetes����������������������  95 6.4.3 Testosterone and ED: Newer Evidence����������������������������������  95 6.4.4 Testosterone and Cardiovascular Risks/Benefits��������������������  96 6.4.5 Other Incidental Factors����������������������������������������������������������  97 6.5 Erectile Dysfunction and Cardiovascular Disease������������������������������  97 6.5.1 Smooth Muscle Abnormalities in Penile Cavernosa��������������������������������������������������������������������������������  98 6.6 Symptomatology and Physical Examination��������������������������������������  98 6.6.1 Physical Examination�������������������������������������������������������������  98 6.7 Laboratory Diagnosis��������������������������������������������������������������������������  99 6.7.1 Penile Tumescence Test����������������������������������������������������������  99 6.7.2 Bulbocavernous Reflex ����������������������������������������������������������  99 6.7.3 Vascular Evaluation����������������������������������������������������������������  99 6.7.4 Hormonal Testing��������������������������������������������������������������������  99 6.8 Treatment of Erectile Dysfunction������������������������������������������������������  99 6.8.1 Lifestyle Changes������������������������������������������������������������������� 100 6.8.2 Hormonal Changes����������������������������������������������������������������� 100 6.8.3 Antidepressants ���������������������������������������������������������������������� 100 6.9 Phosphodiesterase Type 5 Inhibitors PDE5i�������������������������������������� 100 6.9.1 Sildenafil �������������������������������������������������������������������������������� 101 6.9.2 Tadalafil���������������������������������������������������������������������������������� 101 6.9.3 Verdenafil�������������������������������������������������������������������������������� 101 6.9.4 Avanafil ���������������������������������������������������������������������������������� 101 6.9.5 Mirodenafil and Udenafil�������������������������������������������������������� 102 6.9.6 Pharmacokinetics and Efficacy of All Phosphodiesterase 5 Inhibitors ���������������������������������������������� 102 6.9.7 Cardiovascular Assessment and PDE 5i Use�������������������������� 102 6.9.8 Other Pharmacological Agents ���������������������������������������������� 103 6.9.9 Alprostadil������������������������������������������������������������������������������ 103 6.9.10 Papaverine and Phentolamine ������������������������������������������������ 103 6.9.11 Vacuum Erection Devices ������������������������������������������������������ 104 6.9.12 Penile Prosthesis �������������������������������������������������������������������� 104 6.9.13 Low-Intensity Shock Wave Therapy �������������������������������������� 104

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6.10 Female Sexual Dysfunction (FSD) ���������������������������������������������������� 105 6.10.1 Salient Features Affecting FSD���������������������������������������������� 105 6.10.2 Patterns of FSD ���������������������������������������������������������������������� 105 6.10.3 Factors Affecting Female Sexual Dysfunction in Diabetes������������������������������������������������������������������������������ 106 6.10.4 Molecular Basis of FSD in Diabetes�������������������������������������� 107 6.10.5 Drugs Affecting Various Components of FSD������������������������ 108 6.10.6 Treatment of Female Sexual Dysfunction������������������������������ 108 6.10.7 Therapeutic Options���������������������������������������������������������������� 108 6.10.8 Choosing Between the Two���������������������������������������������������� 109 6.10.9 A Word About Hormone Therapy������������������������������������������ 110 6.11 Diabetic Autonomic Neuropathy, Seminal Vesiculitis, and Infertility�������������������������������������������������������������������������������������� 110 6.11.1 USG Diagnosis of Individual Organs ������������������������������������ 111 6.11.2 Ultrasonography (USG) in MAGI������������������������������������������ 112 6.11.3 Abnormalities of the Semen Examination������������������������������ 112 6.11.4 Innervation of Prostate, Seminal Vesicles, and Epididymis with Disease Association������������������������������ 113 References���������������������������������������������������������������������������������������������������� 114 7 Sudomotor Dysfunction and Histopathology in Diabetic Neuropathy������������������������������������������������������������������������������ 121 7.1 Sudomotor Dysfunction���������������������������������������������������������������������� 121 7.1.1 Introduction���������������������������������������������������������������������������� 121 7.1.2 Physiology of Sudomotor Function���������������������������������������� 121 7.1.3 Thermoregulation�������������������������������������������������������������������� 122 7.1.4 Neural Architecture of Sudomotor Function of the Sweat Glands���������������������������������������������������������������� 122 7.1.5 Causes for Sudomotor Dysfunction���������������������������������������� 123 7.1.6 Sweating and the Plantar Skin in Diabetes ���������������������������� 123 7.2 Laboratory Tests for Sudomotor Function������������������������������������������ 124 7.2.1 Thermoregulatory Sweat Testing (TST) �������������������������������� 124 7.2.2 Quantitative Sudomotor Axon Reflex Sweat Test (QSART) for Postganglionic Sudomotor Function���������������������������������������������������������������������������������� 124 7.2.3 Electrochemical Skin Conductance (ESC) ���������������������������� 124 7.2.4 Normal Values of ESC������������������������������������������������������������ 125 7.2.5 Correlations for Electrochemical Skin Conductance�������������� 125 7.2.6 Correlations, Sensitivities: QSART, ESC, TST���������������������� 126 7.3 Histology in Diabetic Neuropathy������������������������������������������������������ 126 7.4 Skin Biopsy���������������������������������������������������������������������������������������� 126 7.4.1 General Remarks�������������������������������������������������������������������� 126 7.4.2 Demonstrable Skin Biopsy Findings�������������������������������������� 127

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7.4.3 Skin Biopsy Findings in Diabetes and Impaired Glucose Tolerance (IGT)�������������������������������������������������������� 127 7.4.4 Some Other Concerns ������������������������������������������������������������ 127 7.4.5 IENFD, Thermal Thresholds, and Nerve Conduction Studies (NCS)������������������������������������������������������ 128 7.5 Other Histopathology Study Methods������������������������������������������������ 128 7.5.1 Pathological Assessment of Teased Longitudinal Fibers�������������������������������������������������������������������������������������� 129 7.5.2 Histopathological Changes in Diabetic Peripheral Nerves: Detailed Description�������������������������������������������������� 129 7.6 Corneal Confocal Microscopy������������������������������������������������������������ 130 7.6.1 The Place of CCM in Investigating Diabetic Neuropathy������������������������������������������������������������������������������ 130 7.6.2 Human Corneal Innervation���������������������������������������������������� 130 7.6.3 Capture and Storage of CCM Image�������������������������������������� 131 7.6.4 CCM Image Quantification���������������������������������������������������� 131 7.6.5 CCM in Diabetic Peripheral Neuropathy�������������������������������� 132 7.6.6 Correlations Between CNFD and IENFD������������������������������ 132 7.6.7 Other Correlations������������������������������������������������������������������ 132 7.6.8 Prognostic Significance of CCM�������������������������������������������� 133 7.6.9 CCM Beyond Diabetic Neuropathy���������������������������������������� 133 7.6.10 The Downside of Sophisticated Investigations ���������������������� 134 References���������������������������������������������������������������������������������������������������� 134 Part III Diabetic Peripheral Neuropathies 8 Clinical and Laboratory Measurements in Diabetic Neuropathies���������������������������������������������������������������������������������������������� 141 8.1 Introduction���������������������������������������������������������������������������������������� 141 8.2 Difficulties in the Diagnosis of Diabetic Peripheral Neuropathies (DPN)���������������������������������������������������������������������������� 142 8.2.1 Early Diagnosis���������������������������������������������������������������������� 142 8.2.2 A Diagnosis of Exclusion ������������������������������������������������������ 142 8.2.3 Prevalence of DPN������������������������������������������������������������������ 143 8.3 Classification of Diabetic Peripheral Neuropathies���������������������������� 143 8.4 Assessment of Peripheral Sensory Neuropathy���������������������������������� 144 8.4.1 History������������������������������������������������������������������������������������ 144 8.4.2 Neuropathic Sensations���������������������������������������������������������� 144 8.4.3 Symptomatic Progression ������������������������������������������������������ 145 8.4.4 Pruritis or Itching�������������������������������������������������������������������� 145 8.4.5 History of any Kind of Foot Care ������������������������������������������ 145 8.4.6 Injurious Practices������������������������������������������������������������������ 146 8.4.7 End of the Day Edema������������������������������������������������������������ 146 8.4.8 Sensation of Pain in Particular������������������������������������������������ 146

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8.4.9 Weakness or Malfunctions in Hands, Pelvic and Leg Muscles���������������������������������������������������������� 146 8.4.10 Skin Changes of Sensory Neuropathy������������������������������������ 147 8.4.11 Inspection and Palpation of Limbs ���������������������������������������� 147 8.5 Instrumentation in Clinical Practice of Diabetic Neuropathy������������ 148 8.5.1 Preamble �������������������������������������������������������������������������������� 148 8.5.2 The Purpose���������������������������������������������������������������������������� 148 8.5.3 Facilitating Communication���������������������������������������������������� 148 8.5.4 An Important Clarification������������������������������������������������������ 148 8.6 Neuropathy Scores—An Extension to Clinical Examination������������ 149 8.6.1 Challenges of Systematic Study of Symptoms in DPN������������������������������������������������������������������������������������ 149 8.6.2 Neuropathy Scores in Practice������������������������������������������������ 150 8.6.3 Validated Neuropathy Scores�������������������������������������������������� 150 8.6.4 NSS and NDS ������������������������������������������������������������������������ 151 8.6.5 Neuropathy Deficit (or Disability) Score (NDS) of Boulton ������������������������������������������������������������������������������ 151 8.6.6 Neuropathy Impairment Score (NIS)�������������������������������������� 151 8.6.7 Neuropathy Symptom Score Lower Limb (NIS-LL) and NIS (LL) +7 ���������������������������������������������������� 152 8.6.8 Nis-LL +7 ������������������������������������������������������������������������������ 152 8.6.9 Neuropathy Symptom and Change Score—NSC ������������������ 153 8.6.10 Neuropathic Pain Questionnaire �������������������������������������������� 153 8.6.11 painDETECT�������������������������������������������������������������������������� 153 8.6.12 ID Pain������������������������������������������������������������������������������������ 153 8.6.13 Neuropathic Pain Symptom Inventory������������������������������������ 153 8.6.14 Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) Pain Scale���������������������������������������������� 154 8.6.15 Subjective Peripheral Neuropathy Screen Questionnaire (SPNSQ)���������������������������������������������������������� 154 8.6.16 Douleur Neuropathique (DN) 4 Questionnaire���������������������� 154 8.6.17 Neuropathic Pain Symptom Inventory (NPSI) ���������������������� 154 8.6.18 Sheehan Disability Scale (SDS)��������������������������������������������� 155 8.6.19 Patient Global Impression-Improvement (PGI-I) ������������������ 155 8.6.20 Utah Early Neuropathic Pain�������������������������������������������������� 155 8.7 Basic to Sophisticated Methods of Clinical Testing �������������������������� 155 8.7.1 Introduction���������������������������������������������������������������������������� 155 8.7.2 The Well-Trained Paramedics: A Must for Laboratory Testing������������������������������������������������������������������������������������ 155 8.7.3 Standard Practices in Testing�������������������������������������������������� 156 8.7.4 Meaning and Significance of the Thresholds and Deficits ���������������������������������������������������������������������������� 157 8.8 Qualitative and Quantitative Sensations �������������������������������������������� 157 8.8.1 The Monofilament (MF) Testing�������������������������������������������� 157 8.8.2 Number of Sites to Be Tested ������������������������������������������������ 158 8.8.3 The Method of Using Monofilament�������������������������������������� 158

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8.8.4 Inquiry������������������������������������������������������������������������������������ 159 8.8.5 “Don’ts” for Monofilament Testing���������������������������������������� 160 8.8.6 Reusability������������������������������������������������������������������������������ 160 8.8.7 The Inference of a Negative Monofilament Test�������������������� 160 8.9 Tests for Vibration Detection/Perception Thresholds—VDT or VPT������������������������������������������������������������������ 160 8.9.1 Neurothesiometer�������������������������������������������������������������������� 161 8.9.2 The VibraTip™ ���������������������������������������������������������������������� 161 8.9.3 NerveCheck���������������������������������������������������������������������������� 161 8.10 Indian Vibration Perception Threshold Sensitometer (VPT)�������������� 161 8.10.1 Calibration and Qualities of Sensitometer������������������������������ 161 8.10.2 The Probe and the Motor�������������������������������������������������������� 162 8.10.3 Testing Vibration Perception�������������������������������������������������� 163 8.10.4 Interpretation of the First-Time Reading�������������������������������� 164 8.10.5 Interpretation of Second-Time Reading���������������������������������� 164 8.10.6 Vibration Threshold Detection and its Correlations �������������� 164 References���������������������������������������������������������������������������������������������������� 166 9 Small Fiber and Painful Neuropathy ������������������������������������������������������ 169 9.1 Introduction���������������������������������������������������������������������������������������� 169 9.2 Small Fiber Neuropathies ������������������������������������������������������������������ 169 9.2.1 Symptoms of Small Fiber Neuropathy ���������������������������������� 169 9.2.2 Small Fiber Neuropathies and Autonomic Dysfunction���������������������������������������������������������������������������� 170 9.2.3 Causes of Small Fiber Neuropathy ���������������������������������������� 170 9.3 Generation and Flows of Painful Neural Impulses ���������������������������� 171 9.3.1 Generation of Pain—At the Nerve Fiber and Cellular Levels ���������������������������������������������������������������� 172 9.3.2 Pain Generation at the Cell Body�������������������������������������������� 172 9.3.3 Perception of Pain ������������������������������������������������������������������ 173 9.3.4 Nonadaptive Nature of Pain Receptors ���������������������������������� 173 9.3.5 Rate of Tissue Damage as a Stimulus for Pain ���������������������� 174 9.3.6 Tissue Ischemia as a Cause of Pain���������������������������������������� 174 9.3.7 Localization of Fast Pain in the Body������������������������������������ 174 9.3.8 The Slow-Chronic Pain���������������������������������������������������������� 174 9.3.9 Paleospinothalamic Pathway for Transmitting Slow-­Chronic Pain������������������������������������������������������������������ 175 9.3.10 Substance P, the Probable Slow-Chronic Neurotransmitter of Type C Nerve Endings��������������������������� 175 9.3.11 Chronic Pain Signals into the Brain Stem and Thalamus�������������������������������������������������������������������������� 175 9.3.12 Physiologic Mitigation of Pain ���������������������������������������������� 176 9.3.13 Some Clinical Abnormalities of Pain and Other Somatic Sensations������������������������������������������������ 176 9.3.14 Surgical Interruption of Pain Pathways���������������������������������� 177

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9.4 Clinical and Laboratory Correlates of Small Fiber Neuropathy Diabetes (SFN) and Diabetes�������������������������������� 177 9.5 Laboratory Assessment of Pain���������������������������������������������������������� 179 9.5.1 The SET Device�������������������������������������������������������������������� 179 9.5.2 Quantitative Sensory Testing by NerveCheck���������������������� 180 9.5.3 Quantitative Sensory Testing—Some More Aspects������������ 181 9.6 Details for Laboratory Measurement of Thermal Sensations ������������ 181 9.6.1 The Thermal Receptors�������������������������������������������������������� 181 9.6.2 Stimulatory Effects of Rising and Falling Temperature—Adaptation of Thermal Receptors���������������� 183 9.6.3 Mechanism of Stimulation of Thermal Receptors���������������� 183 9.6.4 Rate of Change of Temperature and its Physiology�������������� 183 9.6.5 Physiological Ranges of Thermal Sensations in Normal Individuals ���������������������������������������������������������� 184 9.6.6 Tissue Damage under Thermal Stimuli�������������������������������� 184 9.7 Thermal Threshold Measuring Instrument and the Process��������������� 184 9.8 Components of Heat and Cold Perception Sensitometer�������������������� 185 9.8.1 Methods of Generating the Heat Quanta������������������������������ 185 9.8.2 Issues about the Probe Tip���������������������������������������������������� 185 9.8.3 Accuracy and Traceability���������������������������������������������������� 185 9.8.4 Method of Testing for Temperature Perception�������������������� 185 9.8.5 Interpretation������������������������������������������������������������������������ 186 9.9 Details about Heat and Cold Perception (HCP) Sensitometer���������������������������������������������������������������������������������������� 186 9.9.1 The Programs������������������������������������������������������������������������ 186 9.10 Steps for Cool Testing as a General Example������������������������������������ 187 9.10.1 First Part of Operation���������������������������������������������������������� 187 9.10.2 Second Part of Operation������������������������������������������������������ 187 9.10.3 The Nine Programs �������������������������������������������������������������� 188 9.10.4 Program 1������������������������������������������������������������������������������ 188 9.10.5 Program 2������������������������������������������������������������������������������ 189 9.10.6 Program 3������������������������������������������������������������������������������ 190 9.10.7 Program 4������������������������������������������������������������������������������ 190 9.10.8 Programs 5 and 6������������������������������������������������������������������ 190 9.10.9 Program 7 and 8�������������������������������������������������������������������� 190 9.10.10 Base Temperatures���������������������������������������������������������������� 191 9.10.11 The Report���������������������������������������������������������������������������� 191 References���������������������������������������������������������������������������������������������������� 191 10 Motor Neuropathy and Diabetic Hand Syndrome���������������������������������� 195 10.1 Introduction�������������������������������������������������������������������������������������� 195 10.2 The Basic Pathophysiological Mechanisms�������������������������������������� 195 10.2.1 The Pathophysiology of Diabetic Foot—The Ligaments ���������������������������������������������������������� 196 10.2.2 The Pathophysiology of Diabetic Foot—The Muscles�������� 197 10.3 Anatomy of the Foot ������������������������������������������������������������������������ 198

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10.3.1 Anatomy of the Ligaments��������������������������������������������������� 198 10.3.2 Anatomy of the Muscles of the Foot������������������������������������ 198 10.4 Examination of Motor Neuropathy�������������������������������������������������� 199 10.4.1 Deformities of the Toes�������������������������������������������������������� 200 10.4.2 Deformities of Hallux and the Toes�������������������������������������� 200 10.4.3 Assessment of Motor Function �������������������������������������������� 201 10.4.4 Foot Pressure Studies in Diabetic Motor Neuropathy���������������������������������������������������������������������������� 201 10.5 Proximal Motor Neuropathy ������������������������������������������������������������ 202 10.5.1 General Features ������������������������������������������������������������������ 202 10.5.2 Differential Diagnosis ���������������������������������������������������������� 203 10.5.3 Pathological Changes������������������������������������������������������������ 204 10.5.4 Diabetic Ischemic Changes�������������������������������������������������� 204 10.5.5 (Auto)Immune-Mediated Changes �������������������������������������� 204 10.5.6 Other Changes���������������������������������������������������������������������� 205 10.5.7 Detecting Other Abnormalities �������������������������������������������� 205 10.6 Electrophysiological Changes in Diabetic Amyotrophy������������������ 205 10.6.1 Imaging Muscles������������������������������������������������������������������ 206 10.7 Treatment of Diabetic Amyotrophy�������������������������������������������������� 206 10.7.1 Pain in Amyotrophy�������������������������������������������������������������� 206 10.7.2 Other Pain Treatments���������������������������������������������������������� 206 10.7.3 Exercise�������������������������������������������������������������������������������� 207 10.7.4 Methylprednisolone�������������������������������������������������������������� 207 10.8 Diabetic Hand Neuropathy and Other Changes�������������������������������� 207 10.8.1 Introduction�������������������������������������������������������������������������� 207 10.8.2 Stiff Hand Syndrome������������������������������������������������������������ 207 10.8.3 Carpal Tunnel Syndrome (CTS, Entrapment Neuropathy)�������������������������������������������� 208 10.8.4 Dexterity of Hands in Diabetic Hand Neuropathies ������������ 209 10.8.5 Quality of Life Study������������������������������������������������������������ 209 10.8.6 Purdue Pegboard Test������������������������������������������������������������ 209 10.8.7 Michigan Hand Outcomes Questionnaire���������������������������� 209 10.8.8 Diabetes-39 �������������������������������������������������������������������������� 210 References���������������������������������������������������������������������������������������������������� 210 11 Electrophysiology in Diabetic Neuropathy���������������������������������������������� 213 11.1 Introduction�������������������������������������������������������������������������������������� 213 11.1.1 Terminology�������������������������������������������������������������������������� 213 11.1.2 Diagnosis of an Abnormality������������������������������������������������ 214 11.1.3 Electrophysiological Testing in Clinical Practice ���������������� 214 11.1.4 What Is and What Is Not Tested by Electrophysiological Studies (EPS)? ������������������������������ 214 11.1.5 Referring for EPS������������������������������������������������������������������ 215 11.1.6 The Detectable Abnormalities in DPN �������������������������������� 215 11.1.7 Frequencies of Various Abnormalities Detected by NCS and EMG ���������������������������������������������������������������� 216 11.2 Electrophysiology of Nerves—General Features ���������������������������� 216

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11.3 Description of some Common Terms and their Meaning As Used in EPS������������������������������������������������������������������ 220 11.3.1 F Waves ������������������������������������������������������������������������������ 220 11.3.2 H Reflexes �������������������������������������������������������������������������� 220 11.3.3 Fasciculations���������������������������������������������������������������������� 221 11.3.4 Fibrillations ������������������������������������������������������������������������ 221 11.3.5 Recruitment ������������������������������������������������������������������������ 221 11.4 EPS in Diabetes�������������������������������������������������������������������������������� 221 11.4.1 Asymptomatic Patients�������������������������������������������������������� 222 11.4.2 Moderately Symptomatic Symmetric Peripheral Neuropathy Patients ������������������������������������������ 222 11.4.3 Mixed Motor and Sensory Neuropathies���������������������������� 223 11.4.4 Differential Diagnosis of Motor Neuropathy from CTS���������������������������������������������������������������������������� 223 11.4.5 Painful Neuropathies in Diabetes and EPS ������������������������ 224 11.4.6 EPS in Autonomic Neuropathy ������������������������������������������ 224 11.4.7 Limitations of Electrodiagnostic Studies���������������������������� 224 11.4.8 Correlations ������������������������������������������������������������������������ 225 11.4.9 Differentiation from Nondiabetic Neuropathies������������������ 225 11.5 Focal or Entrapment Neuropathies (EN)������������������������������������������ 225 11.5.1 Entrapment in the Upper and Lower Extremities���������������� 225 11.5.2 Pathological Changes in Nerves Leading to Entrapment�������������������������������������������������������������������������� 226 11.5.3 Pathogenic Involvement of Median Nerves in Entrapment�������������������������������������������������������������������������� 226 11.5.4 Symptomatic Profile of Entrapment Neuropathies�������������� 226 11.5.5 Imaging in Diagnosis of Entrapment—Ultrasonography ������������������������������������������ 227 11.5.6 Magnetic Resonance Imaging (MRI)���������������������������������� 227 11.5.7 Prevalence of Entrapment Neuropathies ���������������������������� 227 11.5.8 Diagnosis of CTS/MNW and Ulnar Nerve ������������������������ 228 11.5.9 Treatment of Carpal Tunnel Syndrome ������������������������������ 228 11.5.10 Surgery in CTS�������������������������������������������������������������������� 228 11.5.11 UNE and Ulnar Entrapment Neuropathy at the Wrist (UNW) ������������������������������������������������������������ 229 11.5.12 Peroneal Nerve Entrapment������������������������������������������������ 229 11.5.13 Entrapment of the Tibialis Nerve���������������������������������������� 230 11.5.14 Surgery on Entrapped Nerves and its after Effects������������� 230 11.6 Critical Review of Surgical Treatment of Entrapment Neuropathy���������������������������������������������������������������������������������������� 230 11.6.1 Claims for the Success of Decompression�������������������������� 231 11.6.2 The Answer������������������������������������������������������������������������� 232 11.7 Other Electrophysiological Diagnostic Modalities�������������������������� 232 11.7.1 Laser-Evoked Potentials (LEPs), Nociceptive Functions Not Tested by Standard EPS������������������������������ 232

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11.7.2 Contact Heat-Evoked Potential Stimulator (CHEPS) �������� 233 11.7.3 Neurometer and Contact Heat-Evoked Potentials (CHEPS)������������������������������������������������������������������������������ 233 References���������������������������������������������������������������������������������������������������� 234 Part IV Therapeutics of Diabetic Neuropathies 12 Treatment of Painful Diabetic Neuropathy �������������������������������������������� 241 12.1 Introduction�������������������������������������������������������������������������������������� 241 12.2 The Ad Hoc Panel on Endpoints for Diabetic Neuropathy�������������� 242 12.2.1 The Burden of Disappointment and Psychological Support�������������������������������������������������������������������������������� 242 12.2.2 The Sequence of Discussion Followed�������������������������������� 242 12.3 Treatment of Painful Polyneuropathy in Diabetes���������������������������� 243 12.3.1 Tricyclic Antidepressants (TCAs) �������������������������������������� 243 12.3.2 Amitriptyline ���������������������������������������������������������������������� 244 12.3.3 Important Clinical Considerations�������������������������������������� 244 12.4 Pregabalin����������������������������������������������������������������������������������������� 245 12.4.1 Mechanism of Action—Animal Studies ���������������������������� 245 12.4.2 Pharmacodynamics and Pharmacokinetics ������������������������ 245 12.4.3 Efficacy of Pregabalin �������������������������������������������������������� 245 12.4.4 Clinical Efficacy—Pregabalin �������������������������������������������� 246 12.4.5 Gabapentin�������������������������������������������������������������������������� 246 12.5 Duloxetine and Others���������������������������������������������������������������������� 247 12.5.1 Background ������������������������������������������������������������������������ 247 12.5.2 Analysis of some Major Studies������������������������������������������ 247 12.5.3 Mechanism of Action���������������������������������������������������������� 247 12.5.4 Trials and Tribulations of Duloxetine���������������������������������� 248 12.5.5 Venlafaxine Hydrochloride�������������������������������������������������� 248 12.6 Mexiletine ���������������������������������������������������������������������������������������� 249 12.7 Opioids in Painful Neuropathy �������������������������������������������������������� 249 12.7.1 Opioids and Tramadol �������������������������������������������������������� 249 12.7.2 Tramadol����������������������������������������������������������������������������� 249 12.8 Miscellaneous Drugs������������������������������������������������������������������������ 250 12.8.1 Strong Opioids and Botulinum Toxin A������������������������������ 250 12.8.2 Oromucosal Cannabinoids�������������������������������������������������� 250 12.8.3 Topical Lidocaine���������������������������������������������������������������� 251 12.8.4 Capsaicin Patches���������������������������������������������������������������� 251 12.8.5 Interventional Treatments���������������������������������������������������� 251 12.8.6 Oral Treatment with Alpha-Lipoic Acid������������������������������ 251 12.9 Experimental Drugs�������������������������������������������������������������������������� 253 12.9.1 Ruboxistaurin Mesylate������������������������������������������������������ 253 12.9.2 Rationale of Using RBX in Diabetic Neuropathy �������������� 253 12.9.3 Efficacy and Related Issues for Ruboxistaurin Mesylate (RBX)������������������������������������������������������������������ 254

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Contents

12.9.4 Adverse Reactions�������������������������������������������������������������� 254 12.9.5 Remarks������������������������������������������������������������������������������ 254 12.10 Vitamins Minerals and Diabetic Polyneuropathy ���������������������������� 255 12.10.1 Vitamin C and E������������������������������������������������������������������ 255 12.10.2 Vitamin D���������������������������������������������������������������������������� 256 12.10.3 Vitamin E in Diabetic Neuropathy�������������������������������������� 256 12.10.4 Vitamin B 12 ���������������������������������������������������������������������� 257 12.10.5 Replacement of B 12 in Deficiency������������������������������������ 258 12.11 Experimental Electrical Studies to Reduce Painful DPN ���������������� 258 12.11.1 High-Frequency External Muscle Stimulation (HF) ���������� 259 12.11.2 Frequency-Modulated Electromagnetic Neural Stimulation�������������������������������������������������������������� 259 12.11.3 Monochromatic Infrared Energy (MIRE) �������������������������� 260 12.11.4 Botulinum Toxin A�������������������������������������������������������������� 260 References���������������������������������������������������������������������������������������������������� 260 13 Insulin and Diabetic Peripheral Nerve Pathologies�������������������������������� 265 13.1 Introduction�������������������������������������������������������������������������������������� 265 13.2 New Evidences about Insulin Effects on Nervous Tissues�������������������������������������������������������������������������������� 265 13.2.1 Animal Evidence ���������������������������������������������������������������� 265 13.2.2 Insulin in Humans �������������������������������������������������������������� 266 13.2.3 Insulin and Diabetic Neuropathy���������������������������������������� 268 13.2.4 Diabetic Neuropathy and Insulin in Clinical Practice������������������������������������������������������������������ 269 13.3 Chronic Intermittent Intravenous Insulin Therapy (CIIIT)�������������� 270 13.3.1 Improvement in Autonomic Neuropathy Function������������� 270 13.3.2 Other Benefits of CIIIT ������������������������������������������������������ 270 13.3.3 Method Used in CIIIT �������������������������������������������������������� 271 13.4 Other Situations of Improvement in Diabetic Polyneuropathy �������������������������������������������������������������������������������� 271 13.4.1 Pancreatic Transplant with or without Kidney Transplant �������������������������������������������������������������� 271 13.4.2 Reduction of Polyneuropathy in Critically Ill Patients������������������������������������������������������������ 271 13.4.3 C-Peptide in Neuropathy ���������������������������������������������������� 272 13.5 An Uncommon Cause of Painful Neuropathy—Insulin Neuritis���������������������������������������������������������������������������������������������� 272 13.5.1 Symptom Profile and Temporal Progression���������������������� 272 13.5.2 Mechanism of Genesis�������������������������������������������������������� 273 References���������������������������������������������������������������������������������������������������� 273 14 Treatment of Cardiac Autonomic Neuropathy���������������������������������������� 279 14.1 Introduction�������������������������������������������������������������������������������������� 279 14.2 Pharmacologic Treatment ���������������������������������������������������������������� 280 14.2.1 Antioxidants������������������������������������������������������������������������ 280

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14.2.2 Aldose Reductase Inhibitors������������������������������������������������ 280 14.2.3 The ACE Inhibitors�������������������������������������������������������������� 281 14.2.4 Beta Blockers���������������������������������������������������������������������� 281 14.2.5 Sodium Glucose Transporter 2 Inhibitors, SGLT2i�������������������������������������������������������������������������������� 284 14.2.6 C-Peptide���������������������������������������������������������������������������� 284 14.2.7 Additional Treatment Methods for CAN���������������������������� 285 14.3 Treatment of Orthostatic Hypotension���������������������������������������������� 285 14.3.1 Non-pharmacological Interventions������������������������������������ 286 14.3.2 Drugs Enhancing Orthostatic Hypotension������������������������ 286 14.4 Pharmacotherapy of Orthostatic Hypotension���������������������������������� 286 14.4.1 Midodrine���������������������������������������������������������������������������� 287 14.4.2 Fludrocortisone�������������������������������������������������������������������� 287 14.4.3 Somatostatin and its Analog Octreotide������������������������������ 287 14.4.4 Erythropoietin���������������������������������������������������������������������� 287 14.4.5 Desmopressin Acetate �������������������������������������������������������� 287 14.4.6 Pyridostigmine Bromide ���������������������������������������������������� 287 14.4.7 Future Strategies������������������������������������������������������������������ 288 14.5 Prevention and Mitigation of Cardiac Autonomic Neuropathy���������������������������������������������������������������������������������������� 288 14.5.1 Treatment of Cardiac Autonomic Neuropathy�������������������� 288 References���������������������������������������������������������������������������������������������������� 288

About the Author

Sanjeev Kelkar received his MD from the University of Mumbai in January 1980. He has worked in various fields of health care, including tribal/rural health, for 10 years. He has also worked at specialist institutes, multinational pharmaceutical companies, and been involved in innovative postgraduate teaching programs in diabetes and internal medicine in collaboration with foreign universities. Further, he has worked extensively with international bodies, setting up and developing different models of health care. He was the Founder Secretary of the unique Diabetic Foot Society of India, (DFSI) which has achieved a Guinness world record for the most diabetic foot screenings in a day. He has received prestigious awards, including from the Australian Government and Australian industry for best international collaboration and from the Lite for Life Foundation for his essay on Tuberculosis Control in India. For several years, he worked in rural West Bengal and Tripura, helping establish hospitals with modern facilities and intensive care units. Thanks to his broad experience, he had gained a comprehensive overview of health care and the issues plaguing it. He has edited several widely acclaimed books on diabetic foot care and has written one on diabetes and surgery that is used as a reference guide by Indian practitioners in the field.

xxix

Part I Anatomy and Pathophysiology of Diabetic Nerves

1

Introduction

This book is about Diabetic Neuropathy AND Clinical Practice and not Diabetic Neuropathy IN clinical practice. The title first places any neuropathic elements with or without diabetes which must be attended to. This in itself is a large area even without diabetes. If the Great Peter Dyck has to be quoted “40% of all neuropathies is likely to have an autoimmune origin,” eclipsing the toxic-, alcohol-, and vitamin deficiency-induced neuropathies with other neuropathies associated with neurological syndromes. Managing neuropathy with close listening to the symptoms, an examination, diagnosis, investigation, explanation, and therapeutics are rudimentary in today’s practice. A detailed clinical examination even at the specialty level today may have got transferred to an Electromyography and Nerve conduction studies, foraying into the evoked potentials at times. Such recordings not corresponding with disordered nerves, imperfect conclusions, and confusions with no particular benefit to the patient to understand of his problems or to the specialist in terms of diagnosis. The same problems will get more confusing if diabetic neuropathies get added to the above scenario. Thus it is not a strong element in practice. A title of Diabetic Neuropathy IN Clinical Practice would have limited the scope and would have taken the learning and practice away from the rest of the non diabetic spectrum. Diabetic Neuropathy also placed within the same clinical practice, has in itself a much larger spectrum and scope than consciously recognized by the physicians. The foundational ideas of these depressing and fatiguing conditions are far from clear in their minds. That the physician thus needs to pay special attention to it while dealing with diabetes is wanting. The big issues in diabetes—glucose, heart, and kidneys, sometimes eyes dominated the era from nineties till middle of the first decade of the new millennium. Promptly, the burden of being abreast with these systems was gleefully shared by the referral culture of today’s practice with unenviable results. Lately it is the diabetic foot movement which has caught up well with much less understanding and hence without engagement with diabetic neuropathy as a whole. If at all diabetic neuropathy is clearly defined in practice, from clinical to final well laid out diagnosis, separating the nondiabetic nerve involvement from diabetic © Springer Nature Singapore Pte Ltd. 2020 S. Kelkar, Diabetic Neuropathy and Clinical Practice, https://doi.org/10.1007/978-981-15-2417-2_1

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1 Introduction

nerve involvement in practice is still more crucial. That is because at least 10% people with diabetes will have this dual pathology. Treating them in an undifferentiated way leads to many unsavory clinical situations. Unfortunately, the complex diabetes disorder has come to be equivalent to a sugar-only problem, the management of which is far from optimal. Even after so many advances if it comes to any surgery, including foot, the pandemonium over it breaks lose. Diabetic Neuropathy and its relationship to the symptoms it produces are considered somewhat complex to understand and explain or diagnose. If the basic pathophysiology and anatomy is well understood, it is quite dimple. This negative attitude or belief results in inadequate or unsatisfactory explanation to the patients about the situation. The potential and limitations of treatment remain unclear. There is a need to understand the pathogenetic mechanisms in broad terms also so that the treatment will have a well-calibrated approach. This approach reduces the anxiety and relieves their depression common in severe forms of Diabetic Neuropathy. More often than not this remains an unmet need. The spectrum of symptoms arising from many organ systems, its pathogenesis, and evaluation methods admittedly is large. However a unifying approach, over which this book is built the matters will be far simpler to understand and manage. As important as evaluating diabetic foot at risk of ulceration are other forms of neuropathies commonly met with in clinical practice if one pays attention to. The treatment options also therefore are many. The diabetes consultant or physician who manages it therefore needs a complete picture of this disorder. These two factors point to a need to have a usable, sufficiently detailed, and easily available single volume on this subject to fulfill this need. It is with this purpose this monograph is prepared. Before going in to the details of the book, one question that looks legitimate and should be answered is—how much should a specialist know and undertake about so many complex disorders with so much advanced knowledge available? Why should she get burdened by it when subspecialists are abundantly available, particularly if one’s own practice is quite busy? The answer is as much more as possible. When any patient comes for consultation, the detailed definition of all problems must be made by spending time for it and communicating more immediate elements and what is required to be done. It is a skill to impart more details of less urgency over time in repeat visits. Once this is done, the rest of the time one needs to spend with the patient in follow-up visits is much less and far more meaningful. This is possible when any issue that concerns either the physician or the patient is understood in anatomical and pathophysiological basis. There is another reason for undertaking this burdensome-looking exercise. The less one refers the more unified and unitary the treatment becomes with numerous benefits following it. Today if an internist tries to do as less as possible and depend on the specialties all the time, a time will come when he will become the post office directing all the mail to this or that place never dealing with anything at all. The enormous consequences of this type of practice are detailed in the two volumes mentioned earlier. The last and not the least are to understand correctly and as less frequently as possible when a person needs institutional support and matters cannot be handled in the office.

1 Introduction

5

Turning to the book itself it may be said that it is constructed and written to precisely overcome all the objections, limitations, and for physician benefits in understanding this subject. The book covers the entire spectrum of diabetic neuropathy with sufficient detail which can be remembered without feeling burdened over it. The author has long believed that medicine is not to be practiced by remembering ten million random data points. It should be practiced by using a framework of logic for every organ, organ system, and the whole body as such. It is possible to do so by retaining some basics of cellular physiology and anatomy of tissues. The second and the third chapters, Functional Anatomy of the Peripheral, Autonomic, and Cranial Nerves and Pathogenesis of Diabetic Neuropathy, cover the most relevant information precisely in this manner. Once this basic logic is consolidated, the door to proper diagnosis and evaluation of the neuropathic element opens in a well-lit manner. This also gives an ability to think of diseases or disorders as they affect the cells and tissues and then organs, etc. The section that follows next is the Dysfunctions of the Diabetic Autonomic Neuropathy. This is the least understood part of the diabetic spectrum and within the Diabetic Neuropathy itself. These neuropathic abnormalities are also loaded with troublesome and debilitating symptomatic elements for which little explanations are offered by the clinicians, often pushing these aside as functional disorders without any organic basis. Considerable work and awareness have developed about the sensory neuropathies. Hence what is likely to be new and beneficial to the internist is first placed here. No doubt this will give so much information that a much better assessment of this spectrum will improve the diagnosis and the communication to alleviate the anxieties even if there is no possibility of completely eliminating the hardships in all cases. The sections Diabetic Peripheral Neuropathy with Clinical and Laboratory Measurements, Small Fiber and Painful Neuropathy, Motor Neuropathy, and Diabetic Hand Syndrome followed by Electrophysiology in Diabetic Neuropathy will bring the internist to a more familiar ground systematizing the logic-based understanding. These chapters like the earlier sections are closely connected and well separated for the clarity of understanding. The next section, Therapeutics of Diabetic Neuropathies, once again will bring enhancement and precision for the ideas of how to reduce the patient burden of the neuropathy itself and postpone or prevent altogether the disastrous consequences arising there from. Treatment of Painful Neuropathy essentially discusses the oral medications and other physical methods of treating this depressing condition with as great a success as possible. What is particularly interesting in this section is the chapter on Insulin which plays a great role in the preservation of integrity of function and structure of the diabetic nerves. This information surely brings home the judicious, early use of this wonderful and purely anabolic hormone to great benefit of people suffering from diabetes and its complications. The chapter on Treatment of Cardiovascular Autonomic Dysfunction is purposely separated from the discussions of its pathophysiology so that all aspects of therapeutics hang together. It may be mentioned that one cannot do much about causal cure of Cardiovascular Autonomic Dysfunction, but much can be achieved

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1 Introduction

by mitigating the high frequency of cardiovascular deaths in diabetes, by reducing the consequences of the same. Every bit of information provided in this volume is aimed at improving the communication from the doctor to the patient about what is the issue, its cause, effects on the body and life, the investigation—necessary and unnecessary, the treatment and its potential for cure, and limitations thereof. The author hopes that this aspect is kept in mind while going through the book. Let us move on to the book.

2

Functional Anatomy of the Cranial, Peripheral, and Autonomic Nerves

2.1

Introduction

System entails classification. In science information is consolidated to make it understandable and easier to refer to. One of the main instruments used for that is classification. In this volume a formal classification is partially set aside and presented as descriptive functional anatomy for many reasons. The diabetic neuropathy is essentially quite varied as it relates to many types of nerves, all in the same human body. The target organs, the functions regulated by each type, the physical, biochemical, and electrophysiological characteristics are different for each set. Within each set there are at least two divisions. The development of abnormalities in each set and different types of many such sets also affect a single organ system or participate in affecting other, different systems with an overlap. This cannot be viewed in isolation from each other and in the context and perspective of varied pathophysiological changes it brings about in the body. In addition, the changes in one or all subgroups in one set can and do occur in temporally separated sequences. In most cases not just one set but several sets of neural networks are present simultaneously, with varying degrees of abnormalities, appearing at various times and affecting each other or working in concert with each other, the effects of which are composite. In view of this the author considers that a formal and somewhat rigid system of classification of diabetic neuropathy would be more an academic and conventional way of starting a monograph on this subject, of little practical significance. Instead a descriptive functional anatomical approach would be more helpful in understanding the neuropathic symptom/signs/effects, and pathologies emanating from it. The three main divisions are the Cranial Neuropathies, the Somatic Neuropathies, and the Autonomic Neuropathies. In cranial neuropathies dominant segments which subserve autonomic functions along with the other sensory motor function are also present. The noncranial Somatosensory and Somatomotor neuropathies subserve the rest of the body. This system also offers the delicate autonomic nerves (see later) an anatomical support pathway till these reach their target organ or nearby it. © Springer Nature Singapore Pte Ltd. 2020 S. Kelkar, Diabetic Neuropathy and Clinical Practice, https://doi.org/10.1007/978-981-15-2417-2_2

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2  Functional Anatomy of the Cranial, Peripheral, and Autonomic Nerves

Cranial Nerves

2.2.1 General Features Wide variations on incidence/prevalence are reported. There is little universally applicable hard data about prevalence, or gender ratios. It is generally agreed that some of the palsies or neural afflictions are commoner in diabetes or at times highly specific to it. Near complete recovery over few days to few months is a definitive characteristic, but recurrence is frequent. In somatic nerves during axonal regeneration after injury or praxis or disruption of axons, aberrant regeneration is common. Aberrant regeneration of cranial nerve fibers is uncommon, except in case of Bell’s palsy, considered more frequent to occur in diabetes (discussed later). Laboratory findings, all cranial imaging, and CSF are mostly normal. Nerve conduction velocity studies however do offer some clues discussed later. Hence it is important to make an astute diagnosis of cranial neuropathies in diabetes and avoid unnecessary, essentially fruitless and expensive investigations. This will be repeated elsewhere also in the context of other neuropathies. Treatment consists of good diabetes control, pain relief, stopping smoking, vasodilators, omega fatty acids, anticonvulsants, or antidepressants, antioxidants. One EPS finding in the brain stem detectable is the interrupted R1 and R2 reflex arcs in the pontine region in brain stem strokes which are far more frequent than in persons without diabetes. Evoked potentials from the scalp have also been recorded. Visual and auditory evoked potentials have also been recorded but are found to be normal. Some abnormalities may be detectable in long duration of diabetes but mostly recordings are normal.

2.2.2 Afflictions of Optic Tract It is afflicted by certain autoimmune abnormalities not necessarily in diabetes which will be discussed in the section on autoimmunity in Pathogenesis of Diabetic Peripheral Neuropathies. The garden variety of diabetic retinopathy does have much to do with neuropathic abnormalities since these appear together too often.

2.2.3 Oculomotor Nerves III, IV, and VI in Diabetes The symptoms of oculomotor nerve afflictions are acute ipsilateral head ache which is refractory to analgesics and diplopia that occurs on account of the oculomotor nerve lesions giving rise to muscle palsies. Ptosis is caused by total ophthalmoplegia or selective damage to the orbicularis oculi muscle and is unilateral, unlike myasthenia gravis where it is bilateral. In both diabetic and nondiabetic population, the VIth nerve is often affected leading to reduced unilateral lateral eye ball movement, whereas the IVth nerve causing medial movement of the eye ball probably is less common.

2.2 Cranial Nerves

9

2.2.4 Pupillary Abnormalities These are a part of the autonomic nerve supply to the pupillomotor muscle component. The ciliac ganglion is close to the pupillary muscle, characteristics of parasympathetic nerve supply. Ipsilateral pupil is smaller; it is a tonic small-sized pupil with reduced light reflex. A self-limiting often detected abnormality of eye movements occurs in small embolic/ischemic lesion in the medial lemniscus in the midbrain pontine area with characteristic abducting eye nystagmus, not necessarily a diabetic abnormality.

2.2.5 Facial Neuropathy Bell’s is a complete paralysis reportedly more common in diabetes, with clinical unilateral weakness on the face, both upper and lower. In facial palsies not involving the nucleus but on account of an upper pyramidal lesion, the upper face remains mobile, an important point of differentiation. Sensory symptoms in ear, pain and hyperacusis, are present much less often. There is often a lagophthalmos which may result in exposure keratopathy and dry cornea. Gustatory disturbances are variable. The facial nerve recovery more often results in aberrant regeneration of the axons which may innervate different axonal sheaths to give rise to unilateral sweating of face due to its stimulation while eating.

2.2.6 Treatment and Prognosis of Facial Neuropathy It consists of control of diabetes. Steroids do not help but merely destabilize diabetes control. Dry cornea should be treated with appropriate lubrication; night eye taping is advisable to prevent injuries during sleep. In severe cases a marginal tarsorrhaphy is undertaken till recovery, to prevent dryness as well as injuries. Assumed to be due to Herpes like nuclear affliction, it is also treated with anti-retroviral drugs. Prognosis is proportional to the initial deficit; recovery is nearly complete in 80–90% cases although some residual damage may be seen.

2.2.7 Tenth Cranial Nerve Vagus A large nerve trunk is populated with large numbers of parasympathetic fibers which has widespread effects on the body as a whole and will be discussed at many places in this monograph.

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2.3

2  Functional Anatomy of the Cranial, Peripheral, and Autonomic Nerves

Diabetic Peripheral and Autonomic Neuropathies

2.3.1 Diabetic Sensory Neuropathies The sensory nerves have nerve fibers of varying sizes each of which carry out specific sensory function/s in all parts of the body except those served by the cranial nerves for somatic sensations. The most prevalent is the distal symmetric sensory polyneuropathy involving lower limbs. Within it, the spectrum consists of distal but asymmetric sensory polyneuropathy to start with, which may or may not become fully symmetric. The sequence in which different fibers may get affected varies temporally. The smallest unmyelinated C or thinly myelinated A delta fibers are now known to precede the abnormalities in larger and thicker fibers. These sensory neuropathies are also not necessarily the first to appear as compared to the diabetic (somatic) motor neuropathies which may as well precede these or develop with these. The symptom spectrum thus is extremely wide and difficult to group into any one type.

2.3.2 Diabetic Somatic Motor Neuropathies These are common, may precede the sensory neuropathies or coexist with them. The maximum pathological effects are seen in diabetic foot where deformities are caused and alter the dynamics of walking greatly leading to diabetic ulcers, deep spreading infections and often fatality. These abnormalities also affect large muscle groups, sometimes symmetrically and sometimes asymmetrically, from various known or unknown etiologies with variable prognosis and management. All of these will be discussed in the separate chapter on Motor Neuropathy and Diabetic Hand Syndrome in this volume.

2.3.3 Diabetic Autonomic Neuropathies These fall in the third major group which is paid much less attention to, in clinical practice, are widely prevalent as will be discussed throughout this volume and often have unseen or undiagnosed serious consequences. These neuropathies also do not necessarily occur separately without the others described above, rather with them. Anatomically and functionally the two major divisions are the Sympathetic and the Parasympathetic Nervous Systems under direct governance of hypothalamus most of the times, with strong cerebral influence intermittently. These two systems are partially antagonistic to each other thereby regulate all the autonomic functions in a balanced manner. Generally one of the two systems will degenerate more than the other and will dominate the symptom complex arising there from in diabetes. Hence a proper diagnosis of which one is dominantly affected and how it relates to the symptoms and what therapeutics should be applied must be clearly worked out. Both these systems innervate all the organs, the functions of which are generally unnoticed, until the cerebral cortex intervenes. The principle organ systems

2.4 Functional Anatomy of Diabetic Somatic Peripheral Neuropathy

11

discussed in this volume are the cardiovascular, gastrointestinal, genitourinary, and the sudomotor (sweating) systems. Each of these has profound effects on the quality of life and prognosis in a patient with diabetes. In addition to above, the type of nerve fibers these two systems consist of are the thin unmyelinated small nerve fibers which are also present in the somatic sensory nerves. As a result, sensations like pain are shared by these two. Hence, considering these factors it is probably easier to group the diabetic neuropathies separately but manage them together rather than worrying about classifying them with all the structural and functional overlaps discussed above.

2.4

 unctional Anatomy of Diabetic Somatic Peripheral F Neuropathy

2.4.1 Diabetic Somatic Sensory Peripheral Neuropathy It has different kinds of peripheral cutaneous receptors to detect various sensations. From the impulse generated at the receptor level, mostly skin or mucous membranes in limited areas or in muscles themselves, it is carried by sensory nerves to the spinal cord and from there to different parts of brain stem and cerebral cortex. These fibers are called the afferent fibers. These action impulses are carried back to the motor organs through the motor or efferent fibers mainly through the anterior horn cells of the spinal cord. This sensory motor arc is governed by both reflex and conscious mechanisms. The differences arise because of the physical characters of the receptors, sensory nerves, their ganglionic connections, and projections.

2.4.2 C  lassification, Anatomy, and Functions of Sensory Receptors 1. Mechanoreceptors carry superficial skin tactile sensibilities from epidermis and dermis. These have free nerve endings as well as Spray endings, Ruffini’s endings and expanded tip endings like Merkel’s discs with other variants. 2. Deep tissue sensibilities also have free nerve endings, expanded tip endings, spray endings, and Ruffini’s endings. The fibers with expanded tip with encapsulations are the Meissner’s corpuscles, Krause’s corpuscles, and Pacinian corpuscles with some variants. 3. Hair end-organs are supplied with a pilo-erector muscle stimulated by emotions or application of chemicals to a skin area. 4. Muscle spindles and Golgi tendon receptors are essentially sensory and will be described later in motor neuropathy. 5. Thermoreceptors for Cold, Cold pain, Warm, and Hot pain. 6. Nociceptors for pain, free nerve endings will be discussed under the section of small fiber neuropathy. 7. Two-point discrimination is a test that is carried out by touching two nearby points on skin by an opened-up clip. It is a mixed sensation of very light touch

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2  Functional Anatomy of the Cranial, Peripheral, and Autonomic Nerves

and sight pressure. This sensation is most acute in fingertips and tips that are extremely sensitive areas of the body and can be within a couple of millimeters, whereas on dorsal back it may get detected 5 or even 10 cm apart. 8. The importance of this sensation lies in fact that many parietal strokes may cause a loss of it or that of proprioception. It is also said that the closer the area of two points, the higher is the mobility of it. This element in general has not been investigated for any potential benefit for diagnosis or treatment.

2.5

Classification of Nerve Fibers: General

In the general classification, the fibers are divided into types A and C. C fibers correspond to the fibers which carry sensations of cold, cold pain, warmth and hot pain, and other pain sensations. Type C fibers are the small unmyelinated nerve fibers that conduct impulses at low velocities. The C fibers constitute more than one half of the sensory fibers as well as all the postganglionic autonomic fibers in most peripheral nerves. Type A fibers are the typical large and medium-sized myelinated fibers of spinal nerves. The type A fibers are further subdivided into alpha, beta, and delta fibers and g fibers (discussed later). The different nerve fiber types are given in Fig. 2.1. Type A alpha are motor and carry the sensations of the touch, vibration, and position sense as well. A simplified view of the peripheral nervous system. GIT, gastrointestinal tract. Motor

Myelinated

Sensory

Myelinated

Aα

Aα/β

Thinly myelinated

Autonom

Unmyelinated

Aδ

C

Thinly myelinated

Unmyelinated

Aδ

C LARGE Muscle control

Touch, vibration, position perception

SMALL Cold perception, pain

Warm perception, pain

Heart rate, blood pressure, sweating, GIT function 2

Fig. 2.1  Peripheral and autonomic nerve fiber morphology. (Courtesy: Diabetic Foot Society of India from National Guidelines for Diabetic Foot Management 2nd edition 2017)

2.5 Classification of Nerve Fibers: General

13

A delta and C fibers carry the sensation of pain and thermal stimuli. A delta fibers are also important since these with the autonomic fibers, both sympathetic and parasympathetic, are responsible for the regulation or modulation of organs with smooth muscle fibers like heart, gastrointestinal, and genitourinary tract and sweating, a vital function for thermoregulation. The motor nerve fibers are the thickest. The axonal diameter is larger and the myelin sheaths are also thicker than others. The velocities of these fibers are as high as 120  m/s. Conversely, the smallest fibers which are unmyelinated with much smaller axonal diameter transmit impulses as slowly as 0.5 m/s, requiring about 2 s traveling from the big toe to the spinal cord. The velocities are thus proportional to both the diameter and the myelination. The uniform diameter myelin sheaths constrict at many places called the nodes of Ranvier. The sensory or the motor impulses carried by these fibers have a Saltatory conduction. It jumps from one Ranvier node to the next which is why these impulses travel so fast. This mechanism is not available to C fibers hence their velocities being purely axonal are slower. The anatomical pathways and significance of each function and its neural distribution will be discussed later. Thus, the more critical sensory signals, precise localization on the skin, minute gradations of intensity, or rapid changes in sensory signal intensity are all transmitted in more rapidly conducting types of sensory nerve fibers.

2.5.1 Alternative Classification Used by Neurophysiologists Much refined techniques for action potential recordings separate the type A alpha fibers as A alpha and Ag fibers. Therefore, the following classification is frequently used by sensory physiologists: • Group I A alpha fibers arise from the annulospiral endings of muscle spindles embedded in the contractile muscle itself. It has an average diameter of 17 μm. These are type A fibers in the general classification carrying other sensations as well. • Group I beta fibers arise from the Golgi tendon organs with an average of 16  μm diameter; these also are like type A alpha fibers from the general classification. • Group II fibers arise from most discrete cutaneous tactile receptors as well as from the flower-spray endings of the muscle spindles. These average about 8  μm in diameter; these are beta and g-type A fibers in the general classification. • Group III fibers carrying temperature, crude touch, and pricking pain sensations average about 3  μm in diameter; these are the A delta fibers in the general classification. • Group IV unmyelinated fibers carrying pain, itch, temperature, and crude touch sensations have 0.5–2 μm diameter; (these are type C fibers in the general classification).

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2.6

2  Functional Anatomy of the Cranial, Peripheral, and Autonomic Nerves

General Principles and Sensory Physiology

Intense stimulation of any sensory receptor leads to the continual reduction in the frequencies and magnitude of large action potentials once generated within it initially. The receptor thereby becomes sensitive even to weak stimulations without reaching the maximum action potential firing rate till the stimulation becomes extremely intensive. That facilitates the receptor recognition and response from weak to intense stimuli. The Pacinian corpuscle is a viscous and elastic structure which can instantly transmit any distorting force to the sensory fiber and recovers itself in just a few milliseconds to be able to generate another response as it has elicited before in the nerve fiber.

2.6.1 A  daptation, Accommodation, and Inactivation of the Stimulus and Impulse In case of continuous significant stimulation, the initial response also withers away in a few milliseconds. This leads to adaptation to the continued sensory stimuli which in its turn do not bombard the central system unnecessarily. Otherwise there will be chaos. This is quick adaptation. The second adaptive mechanism is much slower. It occurs in the nerve fiber itself. Even if the central core fiber remains distorted, the tip of the nerve fiber slowly accommodates itself and inactivates response by the tip of the nerve fiber itself, gradually becomes “accommodated” to the stimulus. This probably results from progressive “inactivation” of the sodium channels stopping the sodium current.

2.6.2 N  erve Fibers, Transmission of Different Signals, and Their Physiologic Significance Some signals must be rapidly transmitted due to fast changing body situation as in running. Unless the instantaneous position of the legs is not transmitted back and the motor order comes back equally fast, such activity will become unbalanced or uncoordinated. The sensory inputs in this example will be the pressure and position sense. These sensations are typically transmitted by the thickly myelinated sensorimotor nerve fibers with a velocity of 120 m/s. Prolonged, aching pain sensations need not be transmitted fast. These sensations are thus transmitted by slowly conducting fibers. It will take even longer to reach the central system. The relevance of this will be clear in testing methods for heat cold hat pain and cold pain sensations in a later chapter. Type C unmyelinated fibers transmit impulses at velocities from a fraction of a meter up to 2  m/s. Type A delta thinly myelinated fibers conduct impulses at velocities of only 5–30 m/s.

2.7 Sensory Perception of Touch, Pressure, and Vibration and the Nerve Ending…

2.7

15

 ensory Perception of Touch, Pressure, and Vibration S and the Nerve Ending Distribution

Touch, pressure, and vibration are frequently considered as separate sensations. But all these are detected by the same types of receptors. The touch sensation generally results from stimulation of tactile receptors in the epidermis and dermis. Pressure sensation generally results from deformation of deeper tissues. The vibration sensation results from rapidly repetitive sensory signals in which instantaneous vibrations are like alternating pressure sensation. It causes deformation and reformation in the split second variation. The receptors used therefore are of the same type for touch and pressure. In different areas even if there is a single type of sensory nerve distribution, it can sense different sensations. For example, in cornea there are only fine nerve endings present for pain; yet these can sense the touch as well as pressure even with a light touch.

2.7.1 Meissner’s Corpuscle This is highly sensitive to touch sensation. These corpuscles are present in the non-­ hairy parts of the skin and are particularly abundant in the fingertips, lips, and other areas of the skin where one’s ability to discern spatial locations of touch sensations is highly developed. It is actually an elongated encapsulated nerve ending of large A beta type of myelinated nerve fiber. Inside the capsulation are many branching terminal nerve filaments. Meissner’s corpuscles adapt in a fraction of a second (see above) after they are stimulated. It is considered as being particularly sensitive to movement of objects over the surface of the skin as well as to low frequency vibration. Low frequency vibrations from 2 up to 80 cycles per second, in contrast, stimulate other tactile receptors also.

2.7.2 Merkel’s Discs The fingertips and other areas have numerous Meissner’s corpuscles. These areas also have large numbers of Merkel’s discs. These are expanded tipped tactile receptors from the same type A beta single nerve fiber. The hairy skin also contains moderate numbers of these expanded tip receptors but hardly any Meissner’s corpuscles. Merkel’s discs are quick adapters to a strong stimulus (as discussed above) and continue to send weaker signals with continued stimulation with slower adaption. This is how a steady-state signal is transmitted that allows the perception of continuous touch of objects against the skin. A group of Merkel’s discs often protrudes underside of the epithelium of the skin to form domes on it. These domes are extremely sensitive receptors. With Meissner’s corpuscles, the domes play an extremely important role in localizing touch sensations to specific surface skin areas and determine the texture of what is felt.

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2  Functional Anatomy of the Cranial, Peripheral, and Autonomic Nerves

2.7.3 Hair End Organ The base of the hair entwined by a nerve fiber together is called hair end organ. Each nerve fiber ends in specific neuron of its own. This is also a readily adapting touch receptor and detects movement of an object over the skin or the initial contact with the body.

2.7.4 Ruffini’s End-Organs These multibranched, encapsulated endings are located in the deeper layers of the skin and as well as the still deeper tissues. These endings adapt very slowly. It means that under a continuous state of deformation of tissues, it will continue to transmit the signals like heavy prolonged touch and pressure signals. These are also found in joint capsules and help to signal the degree of joint rotation.

2.7.5 The Pacinian Corpuscles The corpuscle has a central nerve fiber extending through its core. Surrounding this are multiple concentric capsule layers so that compression anywhere on the outside of the corpuscle will elongate, indent, or otherwise deform the central fiber. The tip of the central fiber inside the capsule is unmyelinated, but the fiber become myelinated little before leaving the corpuscle to enter a peripheral sensory nerve. In capsule inclusion of myelin endows the corpuscle with Ranvier’s nodes thereby facilitating the fast conduction. The Pacinian corpuscles lie immediately beneath the skin and deep in the fascial tissues of the body. They are stimulated only by rapid local compression of the tissues because they adapt in a few hundredths of a second. Therefore, they are particularly important for detecting tissue vibration or other rapid changes in the mechanical state of the tissues. Pacinian corpuscles can detect signal vibrations from 30 to 800 cycles per second because they respond extremely rapidly to minute and rapid deformations of the tissues, and they also transmit their signals over type Ab nerve fibers, which can transmit as many as 1000 impulses per second. The cruder types of signals, such as crude pressure, poorly localized touch, and especially tickle, are transmitted by way of much slower, quite small nerve fibers that require much less space in the nerve bundle than the faster myelinated ones. The signals sent by these localize into the spinal cord and lower brain stem, probably subserving mainly the sensation of tickle.

2.8 Transmission of Tactile Signals in Peripheral Nerve Fibers

2.8

17

 ransmission of Tactile Signals in Peripheral Nerve T Fibers

Almost all sensory information from the somatic segments of the body enters the spinal cord through the dorsal roots of the spinal nerves. From there to the brain some signals are carried through the dorsal column–medial lemniscal system or the anterolateral system. These two systems then partially converge in the thalamus.

2.8.1 A  natomy and the Transmission of the Dorsal Column–Medial Lemniscal System On entering the spinal cord through the spinal nerve dorsal roots, the large myelinated fibers from the specialized mechanoreceptors divide almost immediately to form a medial and a lateral branch. The medial branch runs in the dorsal column all the way to the brain. The lateral branch enters the dorsal horn of the cord gray matter, then divides many times to provide terminals that synapse with local neurons in the intermediate and anterior portions of the cord gray matter. Majority fibers arising from these neurons enter the dorsal column to go to the cortex all the way. Many other fibers are short and terminate locally in the gray matter of the spinal cord to regulate the local spinal reflexes, and the remaining ones proceed up in the spino-cerebellar tract. That helps the coordination with the cerebellum and peripheral sensory outputs by connecting these two together. After the nerve fibers synapse in medulla, these cross over to the opposite side in the medulla and continue upward through the brain stem to the thalamus by way of the medial lemniscus. Fibers from areas supplied by cranial nerves are added and from the thalamus these go to the postcentral gyrii of both the parietal lobe. The dorsal column–medial lemniscal system is composed of large, myelinated nerve fibers that transmit signals to the brain at velocities of 30–110 m/s. It has a high degree of spatial orientation of the nerve fibers with respect to their origin. The sensory information that must be transmitted rapidly and with high degree of temporal and spatial accuracy is transmitted mainly in the dorsal column–medial lemniscal system. Thus, the more critical types of sensory signals—those that help to determine precise localization on the skin, minute gradations of intensity, or rapid changes in sensory signal intensity—are all transmitted in more rapidly conducting types of sensory nerve fibers. The dorsal system is limited to discrete types of mechanoreceptive sensations.

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2  Functional Anatomy of the Cranial, Peripheral, and Autonomic Nerves

2.8.2 S  ignals and Functions Carried in the Dorsal Column– Medial Lemniscal System 1 . Touch sensations requiring a high degree of localization of the stimulus 2. Touch sensations requiring transmission of fine gradations of intensity 3. Phasic sensations, such as vibratory sensations 4. Sensations that signal movement against the skin 5. Position sensations from the joints 6. Pressure sensations having to do with fine degrees of judgment of pressure intensity.

2.8.3 P  ressure and Vibratory Sensation Through the Dorsal Columns Pressure is a temporary deformation of the skin which allows the skin to regain its normal state immediately. It can vary in its duration and degree as well. This deformation is sensed as described above in various ways. Vibratory signals are rapid and repetitive. Vibrations up to 700  cycles per second can be detected as vibrations. Higher-frequency vibratory signals originate from the Pacinian corpuscles in the skin and deeper tissues. Lower-frequency signals below about 200 per second originate from Meissner’s corpuscles. These signals are transmitted only in the dorsal column pathway. For this reason, application of vibration as in a “tuning fork” applied to the great toe tests integrity of the sensory nerve and the dorsal columns as well as found in subacute combined degeneration.

2.8.4 Anatomy and Transmission in the Anterolateral Pathway The nerve fibers carried in the anterolateral system, immediately after entering the spinal cord from the dorsal spinal nerve roots, synapse in the dorsal horns of the spinal gray matter, then cross to the opposite side of the cord, and ascend through the anterior and lateral white columns of the cord. They terminate at all levels of the lower brain stem and in the thalamus. The anterolateral system is composed of smaller myelinated fibers that transmit signals at velocities ranging from 6 to 8 m/s up to 40 m/s. The anterolateral system has much less spatial orientation. It however has a special capability that the dorsal system does not have: the ability to transmit a broader spectrum of sensory modalities—pain, warmth, cold, and crude tactile sensations of heat, cold, tickle, itch, and sexual sensations. That is, that sensory information which does not need to be transmitted rapidly or with great spatial fidelity is transmitted mainly in the anterolateral system. The degree of spatial localization of signals carried by the anterolateral columns is poor. The gradations of intensities are also far less accurate and fall between 10 and 20 gradations of strength. In dorsal columns as many as 100 gradations can be

2.9 Functional Anatomy of Autonomic Nerves

19

recognized. Unlike the dorsal column, anterolateral column cannot transmit rapidly changing repetitive stimuli. The anterolateral system is a cruder type of transmission system than the dorsal column–medial lemniscal system.

2.8.5 S  ignals and Functions Carried in the Antero-Lateral System It carries pain, thermal sensations, including both warmth and cold sensations, crude touch and pressure sensations capable only of crude localizing ability on the surface of the body, tickle and itch sensations, and the sexual sensations.

2.9

Functional Anatomy of Autonomic Nerves

From every spinal cord segment, the sympathetic nerves arise from ganglions from the intermediate horn of the spinal cord and travel with the skeletal muscle nerves. Immediately after the spinal nerve leaves the spinal canal, the preganglionic sympathetic fibers leave the spinal nerve and pass through a white ramus into one of the ganglia of the paravertebral sympathetic chain. Some of these fibers synapse with postganglionic sympathetic neurons in it. Some other fibers proceed up or down in the paravertebral sympathetic ganglia chain, chain and synapse in one of the other ganglia. Others proceed for variable distances through radiation outward from the chain along the sympathetic nerves from each ganglion and synapse in a peripheral sympathetic ganglion. After these synaptic connections, the postganglionic fibers innervate the destined organs.

2.9.1 Segmental Distribution of the Sympathetic Nerve Fibers It does not correspond to the segment it originates. It is the embryonic organ development to which it corresponds in the caudal direction. 1. Spinal cord segment Thoracic-1 pass up the sympathetic chain to terminate in the head; 2. Thoracic-2 to terminate in the neck; 3. Thoracic-3, 4, 5, and 6 into the thorax; 4. Thoracic-7, 8, 9, 10, and 11 into the abdomen; 5. T-12, L-1, and L-2 into the legs. There are many segmental overlaps which are quite extensive. 6. The abdominal organs receive most of their sympathetic innervation from the lower thoracic spinal cord segments because most of the primitive gut originated in this area. 7. Sympathetic Nerve Endings in the Adrenal Medullae: the fibers from the intermedio-­lateral horn cells of the spinal cord, pass through the preganglionic

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2  Functional Anatomy of the Cranial, Peripheral, and Autonomic Nerves

sympathetic nerve fibers without synapsing, all the way through the splanchnic nerves, onto adrenal medullae. There they end directly on modified neuronal cells that secrete epinephrine and norepinephrine into the blood stream. These secretory cells are the postganglionic sympathetic neurons.

2.10 F  unctional Anatomy of Central Autonomic Nervous System The autonomic nervous system is activated mainly by centers located in the spinal cord, brain stem, and hypothalamus. Some portions of the cerebral cortex, particularly the limbic cortex, transmit signals to the lower centers and influence autonomic control. Subconscious sensory signals from a visceral organ can enter the autonomic ganglia, the brain stem, or the hypothalamus and then return as subconscious reflex responses directly back to the visceral organ to control its activities. These subconscious efferent autonomic signals are transmitted to the various organs of the body through sympathetic and the parasympathetic nervous system. In many instances, almost all portions of the sympathetic nervous system discharge simultaneously as a complete unit, a phenomenon called mass discharge. This frequently occurs when the hypothalamus is activated by fright or fear or severe pain. The result is a widespread reaction throughout the body called the alarm or stress response. At other times, activation occurs in isolated portions of the sympathetic nervous system. The most important of these are the following: 1. During the process of heat regulation, the sympathetics control sweating and blood flow in the skin without affecting other organs innervated by the sympathetics. 2. Many “local reflexes” involving sensory afferent fibers travel centripetally in the peripheral nerves to the sympathetic ganglia and spinal cord and cause highly localized reflex responses, for example, heating a local skin area causes local vasodilation and enhanced local sweating, whereas cooling causes opposite effects again without affecting the rest of the vessels or the other sweat glands.

2.10.1 Sympathetic Nerve Fibers in the Skeletal Nerves About 8% of the fibers in the average skeletal nerve are sympathetic indicating their importance as these fibers control the diameter of the blood vessels, sweat glands, and piloerector muscles of the hairs. These fibers extend to all parts of the body by way of the skeletal nerves. Some of the postganglionic, very small type C fibers pass back from the sympathetic chain into the spinal nerves through gray rami at all segments of spinal cord.

2.10 Functional Anatomy of Central Autonomic Nervous System

21

2.10.2 Functional Anatomy of the Parasympathetic Nervous System 1. Parasympathetic fibers in the third cranial nerve go to the pupillary sphincter and ciliary muscle of the eye. 2. Fibers from the seventh cranial nerve pass to the lacrimal, nasal, and submandibular glands. And fibers from the ninth cranial nerve go to the parotid gland. 3. The parasympathetic nervous system fibers leave the central nervous system through cranial nerves III, VII, IX, and X. 4. Three-fourths of all parasympathetic nerve fibers are present in the cranial Vagus nerve X. It supplies parasympathetic nerves to the heart, lungs, esophagus, stomach, the entire small intestine, proximal half of the colon, liver, gallbladder, pancreas, kidneys, and upper portions of the ureters. 5. Parasympathetic fibers leave from the lowermost part of the spinal cord through mainly the second and third sacral spinal nerves with a segment above or below. 6. The sacral parasympathetic fibers in the pelvic nerves pass through the spinal nerve-sacral plexus on each side of the cord at the Sacral 2 and 3 levels. These fibers then distribute to the descending colon, rectum, urinary bladder, and lower portions of the ureters. Also, this sacral group of parasympathetics supplies nerve signals to the external genitalia to cause erection. 7. These fibers control the Ileocecal valve, the anal sphincter, and the urinary bladder musculature with detrusor muscle and the trigone.

2.10.3 Preganglionic and Postganglionic Parasympathetic Neurons The parasympathetic system, like the sympathetic, has both preganglionic and postganglionic neurons. However, most preganglionic parasympathetic nerves pass uninterrupted all the way to the organ that is to be controlled. The postganglionic parasympathetic neurons are located in the wall of these organs on which these preganglionic fibers synapse. The postganglionic fibers, fraction of a millimeter to many centimeters long, innervate the tissue. This anatomic arrangement is quite different from the sympathetic outflows. Preganglionic neurons are cholinergic in both the sympathetic and the parasympathetic nervous systems. Either all or almost all of the postganglionic neurons of the parasympathetic system are also cholinergic. Conversely, most of the postganglionic sympathetic neurons are adrenergic. The postganglionic sympathetic nerve fibers to the sweat glands, to the pilo-erector muscles of the hairs, and to a very few blood vessels are cholinergic.

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2  Functional Anatomy of the Cranial, Peripheral, and Autonomic Nerves

2.10.4 Sympathetic and Parasympathetic “Tone” Normally, the sympathetic and parasympathetic systems are continually active, and the basal rates of activity are known, respectively, as sympathetic and parasympathetic tone. The value of tone is that it allows a single nervous system both to increase and to decrease the activity of a stimulated organ. For instance, sympathetic tone normally keeps almost all the systemic arterioles constricted to about half their maximum diameter. The peripheral resistance often talked about resides maximally in these small arterioles. It is directly proportional to the tonic constriction under the sympathetic stimulation. By increasing the degree of sympathetic stimulation above normal, these vessels can be constricted even more; conversely, by decreasing the stimulation below normal, the arterioles can be dilated. If it were not for the continual background sympathetic tone, the sympathetic system could cause only vasoconstriction, never vasodilation.

2.10.5 Tone Caused by Basal Secretion of Epinephrine and Norepinephrine by the Adrenal Medullae The normal resting rate of secretion by the adrenal medullae is about 0.2 mg/kg/min of epinephrine and about 0.05 mg/kg/min of norepinephrine. These quantities are enough to maintain the blood pressure almost up to normal even if all direct sympathetic pathways to the cardiovascular system are removed. Thus, much of the overall tone of the sympathetic nervous system results from basal secretion of epinephrine and norepinephrine, in addition to the tone resulting from direct sympathetic stimulation.

2.11 E  ffect of Loss of Sympathetic or Parasympathetic Tone After Denervation Immediately after a sympathetic or parasympathetic nerve is cut, the innervated organ loses its sympathetic or parasympathetic tone. In the case of blood vessels, for instance, cutting the sympathetic nerves results within 5–30 s in almost maximal vasodilation. However, over minutes, hours, days, or weeks, intrinsic tone in the smooth muscle of the vessels increases. It is affected by smooth muscle in the media of arterial walls, whose contractile force increases. It is the result of chemical adaptations in the smooth muscle fibers. This intrinsic tone eventually restores almost normal vasoconstriction. Essentially the same effects occur in most other effector organs whenever sympathetic or parasympathetic tone is lost. That is, intrinsic compensation soon develops to return the function of the organ almost to its normal basal level.

2.11 Effect of Loss of Sympathetic or Parasympathetic Tone After Denervation

23

However, in the parasympathetic system, the compensation sometimes requires many months. For instance, loss of parasympathetic tone to the heart after cardiac vagotomy increases the heart rate and will not decrease on its own much, especially in diabetes.

2.11.1 Denervation Super-Sensitivity of Sympathetic and Parasympathetic Organs During the first week or so after a sympathetic or parasympathetic nerve is destroyed, the innervated organ becomes more sensitive to injected norepinephrine or acetylcholine, respectively. When the stellate ganglion is removed, the normal sympathetic tone is lost. At first, the blood flow rises markedly because of the lost vascular tone, but over a period of days to weeks the blood flow returns much of the way back toward normal because of progressive increase in intrinsic tone of the vascular musculature itself, thus partially compensating for the loss of sympathetic tone. At this stage the blood flow decreases much more than to a usual Norepinephrine dose, demonstrating that the blood vessels have become about two to four times more sensitive. Occasionally the increase in the response is more than tenfold. This phenomenon is called denervation super-sensitivity. It occurs in both sympathetic and parasympathetic organs.

2.11.2 Sympathetic Stimulation and Skeletal Stimulation One difference about the degree of stimulation to lead to action in the autonomic system and the skeletal system is notable. In muscles the stimulation has to be full for it to contract; else it will not contract at all. It is known as the law of all or none contraction. The autonomic nervous system needs only a low frequency of stimulation for full activation of autonomic effectors. In general, only one nerve impulse every few seconds suffices to maintain normal sympathetic or parasympathetic effect. Full activation occurs when the nerve fibers discharge 10–20 times per second. The skeletal nervous system has to fire at the rate of 50–500 or more impulses per second for full effect. As the number of impulses per second increases more and more, muscle fibers will be “recruited” for action.

2.11.3 Muscarinic and Nicotinic Receptors Muscarinic receptors are found on all effector cells that are stimulated by the postganglionic cholinergic neurons of either the parasympathetic nervous system or the sympathetic system. Nicotinic receptors are found in the autonomic ganglia, at the synapses between the preganglionic and postganglionic neurons of both the

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2  Functional Anatomy of the Cranial, Peripheral, and Autonomic Nerves

sympathetic and parasympathetic systems. Nicotinic receptors are also present at many non-autonomic nerve endings—for instance, at the neuromuscular junctions in skeletal muscle. Muscarine activates only muscarinic receptors and will not activate nicotinic receptors; nicotine activates only nicotinic receptors, whereas acetylcholine activates both of them. An understanding of the two types of receptors is especially important because specific drugs are frequently used as medicine to stimulate or block one or the other of the two types of receptors.

3

Pathogenesis of Diabetic Neuropathies

3.1

Pathological Hallmarks of Diabetic Neuropathy

The pathological hallmarks of diabetic neuropathy are microangiopathy of the vasa nervorum, loss of axons and axonal atrophy and demyelination, all of which are the result of a combination of different mechanisms of tissue damage that are common to all long-term complications of diabetes. The other changes are in the myelination of some of the nerves which are composed of various cells and tissues [1]. By definition neuropathy is the presence of symptoms and/or signs of peripheral nerve dysfunction in people with diabetes which may deleteriously affect sensory, motor, and autonomic nerve fibers [1]. Peripheral neuropathy is a diagnosis by exclusion after other likely causes are ruled out.

3.2

 pidemiological Features of Diabetic Peripheral E Neuropathy

1. Peripheral nervous system afflictions are higher in men; the male/female ratio is 2.9 [2, 3]. 2. Diabetic peripheral neuropathy develops earlier in men than in women [4]. 3. Muscle weakness and atrophy also similarly is higher in men [5]. 4. Motor nerve conduction abnormalities and ulnar nerve involvement are also more common in males than in females [5, 6]. 5. As a result, lower amplitudes and conduction velocities and longer latencies are found among men tested by electrophysiology [7]. 6. Neuropathic pain and negative sensory symptoms are observed more frequently in women [5].

© Springer Nature Singapore Pte Ltd. 2020 S. Kelkar, Diabetic Neuropathy and Clinical Practice, https://doi.org/10.1007/978-981-15-2417-2_3

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3  Pathogenesis of Diabetic Neuropathies

3.2.1 F  ew Main Clinical Features of Diabetic Sensorimotor Polyneuropathy 1 . Reduced sensation in lower limbs labeled as a negative symptom 2. Symmetrical reduction in distal sensation 3. Positive neuropathic sensory symptoms which includes burning pain in the distal lower extremities 4. Decreased or absent ankle reflexes.

3.2.2 Confirmatory Evidence of Peripheral Neuropathy 1 . Decreased nerve conduction with signs and symptoms described above. 2. Decreased nerve conduction in the absence of signs or symptoms described above.

3.3

 athogenetic Mechanisms in Development of Diabetic P Neuropathy

There are numerous mechanisms which can be discretely described in parts or substantially, but these also affect each other and produce an orchestrated change in their effectual overlap. Hence in the discussion below this overlap will be seen a few times. Their true separation is nearly impossible and unnecessary.

3.3.1 Hyperglycemia Hyperglycemia is the key factor, which increases cytoplasmic glucose which induces several tissue changes, alters, and leads metabolic pathways into a vicious cycle resulting in chronic tissue damage.

3.3.2 G  eneration of Superoxide Radicals and Its Subsequent Effects 1. Hyperglycemia leads to increased glycolytic load. 2. As the next step in energy production cycle, there is an increased oxidization of pyruvate, a 3-carbon moiety, in mitochondrial citric acid cycle. 3. That results in increased flow of NADH and FADH2. 4. These are electron donors to the electron transport chain within the mitochondria. This is the first metabolic alteration. 5. The mitochondrial intermembrane get a flux of hydrogen ions once the electrons are donated. 6. It increases the voltage gradient across mitochondrial inner membrane lumen.

3.3  Pathogenetic Mechanisms in Development of Diabetic Neuropathy

27

7. Complexes I, III, and IV are responsible for this increased voltage gradient [8]. 8. At a particular height of voltage gradient, the electron transfer of complex III stops. 9. After that the coenzyme Q donates electrons to molecular oxygen, which generates superoxide [8]. 10. Superoxide leads to tissue damage and causes DNA double-strand breaks. 11. This in turn activates DNA repair mechanisms, including the enzyme PARP-1. 12. Activated PARP-1 inhibits the key glycolytic enzyme glyceraldehyde-3-­ phosphate dehydrogenase. 13. This key step directly affects the energy production. 14. This causes the accumulation of glycolytic intermediates. 15. These intermediates are then side tracked into an alternative and from there to finally into the pathogenic pathways [9]. 16. Glyceraldehyde-3-phosphate which accumulates in turn inhibits the key glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase. 17. This leads to de novo synthesis of di-acyl-glycerol (DAG). 18. DAG is known to activate protein kinase C which changes the intracellular phosphorylation levels. 19. These steps then lead to the well-known glycosylation pathways. 20. Glycation primarily occurs on long-lasting proteins like collagen, hemoglobin as well as the various intracellular proteins and lipids also giving rise to advanced glycosilation products (AGEs) 21. AGEs also affect myeloid cells and initiates inflammatory and neurodegenerative process [10]. The mechanisms of polyol pathways are described later. 22. The formation of malondialdehyde (MDA) and thiobarbituric acid reactive substances (TBARS), reduction of glutathione peroxidase (GPx), changes in total antioxidant capacity (TAC), inadequate enhancement in superoxide dismutase (SOD) enzyme are the hallmarks of unmitigated oxidative stress. 23. The adverse physiological effects of oxidative stress are—increase in leaking of cell membranes. It is due to changed structural integrity of membranes or because of the enzymes and surface receptors bound to membranes gets inactivated. The oxidized low density lipoprotein (LDL) may also be involved in these changes.

3.3.3 R  eactive Oxygen and Nitrogen Species— (ROS and RONS)—Mechanisms of Damage 1. Hyperglycemia alters the physical or phenotypic structure of mitochondria. With it, it affects its biological capacity, function, biogenesis, and regenerative capacity [11]. 2. All these changes ultimately result in exhaustion of the adenosine triphosphates (ATPs), the energy-storing molecules. Energy is needed for several functions of the neurons and nerve fibers like neuronal excitation to which ion flux is closely associated as part of all reactions, axonal transport of organelles, and the

28

3  Pathogenesis of Diabetic Neuropathies

p­ lasticity of the whole structure. Plasticity is the adaptive ability of a neural structure especially in reorganizing the axonal and dendritical connections. Compromise of energy metabolism in turn contributes to the distal axonal structural changes of diabetes [12, 13]. 3. Finally, within the cell, there is overproduction of reactive oxygen and nitrogen species (RONS) like superoxide anion radical, peroxynitrite, and hydrogen peroxide in mitochondria. This is the crucial event, the effect secondary to glucose overload characteristic of diabetes. When excess ROS are produced, mitochondrial capacity of electron transfers may get overwhelmed. All of these changes are then responsible for continuing the injury to nerve fibers [14]. 4. RONS in turn also cause DNA damage. RONS also impairs glyceraldehyde-­3-­ phosphate dehydrogenase (GAPDH) with effects described above follow.1

3.3.4 RONS and Autonomic Ganglia Uncontrolled diabetes producing ROS may be responsible for depressing the activity in autonomic ganglia. The depressed activity may be the stage before denervation of the heart. The dampening is considered to be responsible for sudden deaths in diabetes, particularly after myocardial infarction with or without fatal cardiac arrhythmias [9].

3.3.5 ROS and Synaptic Transmission High levels of ROS are likely to depress activity of synaptic transmission in autonomic ganglion similarly leading to sudden death (see above) [9].

3.3.6 O  xidation and Chromosomal Damage, Vascular Factors, Hypoxia It is possible to estimate the oxidative stress at the tissue level. But like glucose it is a single point value within an organ or a tissue. A better pan body measure of it is the excretion of 8-oxo-2′-deoxyguanosine and 8 hydroxyguanine which is increased in multisystem disorders like diabetes where it could be a more pertinent test. 1. Oxidation of DNA and RNA is not diabetes specific. It has been linked to many other diseases where the primary mechanism starts with micro and macrovascular complications. Excretion of these two substances is increased in

1  An animal study model which blocked all the electron transfer complexes I to V clearly demonstrated that the pain is substantially reduced in chronic neuropathic pain models from various pathologies but not diabetes, establishing a role for mitochondrial electron transfer complexes. This has not been pursued later.

3.4  Hypoxia in Neuropathies in Diabetes

29

n­ eurodegenerative diseases, diabetic retinopathy, and nephropathy, but the data on neuropathy is scarce. 2. In case of undiagnosed obstructive sleep apnea or those who do not adhere to the positive pressure ventilation therapy have intermittent hypoxia, increased ROS, and impaired microvascular function. That may be the reason for higher cardiac autonomic neuropathy in OSA.

3.4

Hypoxia in Neuropathies in Diabetes

3.4.1 Endoneurial and Epineurial Hypoxia 1. Endoneurial and epineurial hypoxia well known to be present in diabetes due to closure of small vessels supplying the nerves the vasa nervorum also has a role in producing highly reactive oxygen species. 2. These ROSs react with the lipids and form a perpetuating cycle which is injurious to the nerve tissues which has a high content of lipids in them. Excess RONS overwhelm the capacity of the cells to quench these radicals, in decreased production of nitric oxide which is essential for vasodilation. 3. This sets the stage for a vasoconstrictive milieu. 4. Activation of poly(ADP-ribose) polymerase is another mechanism which becomes operative causing endothelial dysfunction [15]. 5. Microvascular damage itself is also a potent cause as an indirect factor of neuronal dysfunction and apoptosis. 6. Endothelin 1 which causes intense vasoconstriction and 7. Endothelial Nitric Oxide Synthase (eNOS) reduction reduces the ability of small vessels to dilate [16]. 8. Progressive systemic or tissue-level vascular and capillary dysfunction is now considered the putative reason for neuropathies. Since UKPDS times, it is well known that 50% of tissue damage is detected at the time of new diagnosis of diabetes. 9. The probable reason is the long latent period when diabetes exists but is not detected. It is considered to be as long as 5–7 years [17]. 10. Vascular compromise inevitably is followed by hypoxia in the tissue level. The semantics involved here is whether it is the epineurial or whether the endoneurial capillary morphology and vascular reactivity is getting affected leading to hypoxia [17]. 11. Endoneurial capillary morphology and vascular reactivity are present before the development of diabetic neuropathy in humans. The degree of endoneurial hypoxia is found to be corresponding with decreased nerve conduction velocity, in patients with neuropathy in some detectable form. 12. The decreased levels of neurotrophic support, the nerve growth factors, and insulin-like growth factor 1 are claimed to be factors reducing the endoneurial blood flow and neuronal damage [18].

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3  Pathogenesis of Diabetic Neuropathies

13. The epineurial hypoxia is the proposed cause for painful neuropathy [17]. The structural changes take place in axons, endoneurium, Schwann cells, microvascular elements within, and the extracellular matrix [19].

3.4.2 Some Other Factors of Pathogenic Importance 1 . Increase in glutathione (GSH) and myoinositol, 2. Tumor growth factor (TGF) beta, 3. The nicotinamide adenine dinucleotide (NAD), well known as a cofactor in oxidative metabolism, decreases. 4. Protein kinase C (PKC) and hexosamine pathways are enhanced by the impaired cellular milieu, resulting in further production of RONS by means of NADPH oxidase complex, and 5. In transcription of vascular impairment factors, like plasminogen activator inhibitor-­1 (PAI-1), tumor necrosis factor TNF-alpha, tumor growth factor TGF-beta.

3.5

Advanced Glycation End Products (AGEs)

1. Hyperglycemia is directly associated with greater level of advanced glycation end products (AGEs.) AGEs create inflammation and autonomic nerve abnormalities in diabetes. It can lead to cardiac autonomic neuropathy. The autonomic fibers are mostly unmyelinated or are very small thinly myelinated fibers and are the first to get involved as shown in fibers carrying hot and cold sensations [14]. 2. AGEs cause structural and functional alterations in protein in the extracellular matrix as well as in the intracellular space. Glycation occurs on all long-lasting molecules like hemoglobin or collagen or coagulation proteins, depending upon the level of hyperglycemia. The last change decreases plasmin production, thereby decreasing the normal fibrinolytic process becoming prothrombotic. 3. AGEs interact with specific receptors for advanced glycation end products (RAGEs). It results in a chain reaction of complex pro-inflammatory changes which involve interleukin-1 and -6, tumor necrosis factor TNFalpha, tumor growth factor TGF-beta, and vascular cell adhesion molecule (VCAM-1), 4. RAGEs also increase the level of oxidative stress [20, 21]. 5. Advanced glycation end-products, activation of the nuclear factor κ-light chain-­ enhancer of activated B cells, and Protein Kinase C pathways also lead to increased vascular endothelial damage [22]. 6. Advanced glycation end product formations are also a pro-apoptotic signal. The final pathway for apoptosis is the unregulated influx of calcium and its mobilization from the endoplasmic reticulum.

3.7  Role of Inflammation

3.6

31

The Polyol Pathways

1 . Nerves do not have any resistance to glucose entering it. 2. With it the nerves draw extra water in causing edema to various neural structures. 3. Excess glucose overwhelms the capacity of the enzyme sorbitol dehydrogenase and sets the accumulation of sorbitol and then initiates the polyol pathway. 4. This leads to depletion of intracellular NADPH fundamental to the cyclic hydrogenation and dehydrogenation in antioxidant regeneration. 5. This in turn increases the susceptibility of neurons to oxidative damage due to inadequate regeneration of the antioxidant glutathione. 6. In diabetes there is inadequate production of the native defense mechanisms to combat the oxidative stress like superoxide dismutase. 7. This starts a “vicious” cycle [1]. 8. It inhibits the key glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase. 9. Finally the neuronal structural changes and endothelial dysfunction causes neuropathy of diabetes.

3.6.1 Mechanism in Detail 1. Neuronal damage by increased levels of sorbitol changes the nerve impulse formation and its recovery cycle [23, 24]. 2. Increased activation of the polyol pathway may cause a decrease in the activity of Na+/K+ ATPase and may activate diacylglycerol and protein kinase C (PKC) pathways. 3. It then increases the intracellular phospholipase A2 activity and produces a proinflammatory mediator prostaglandin E2 and a cycle of reduction in the Na+/K+/ ATPase action [25, 26]. 4. It will also alter the oxidative state of neuronal cells which is likely to damage DNA, activates PARP a DNA repair enzyme, and inhibits GAPDH and also activates polyol and hexosamine pathways. Polyol accumulation also inhibits Na+/ K+ ATPase, which also interact with protein kinase C pathway. 5. Sorbitol tends to hold more water and makes nerves turgid. The excess water accumulation effect is most notable in the lens which swells, its fibers structure fragments. Whenever the hyperglycemia is controlled and the excess water is lost the shrinking architecture will lead to other changes.

3.7

Role of Inflammation

1. The hall marks of inflammation are Adhesion molecules expression, cytokine overproduction, phagocytic cells infiltration, and innate immune system activation via toll-like receptors (TLR-2 and TLR-4). 2. The secondary neuronal and vascular damage is caused by these and develops a continuous cross talk with the otherwise existing oxidative stress [27, 28].

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3. Many circulating inflammatory markers like C-reactive protein (CRP), IL-6, IL-8, tumor necrosis factor TNF-alpha, and endothelin-1 are elevated in uncontrolled diabetes. 4. Newer markers like the urokinase plasminogen activator receptor (SuPAR) have been detected consistently in several studies on T1DM and T2DM [29]. 5. These markers are considered likely to have predictive value for diabetic complications, especially cardiac autonomic neuropathy [30].

3.7.1 Role of TNF Alpha in Inflammation 1. Blocking TNF-alpha in shock has been proposed many years back. Blocking it may have a neuroprotective effect [31]. 2. Blocking RAGE receptors has also been shown to ameliorate these changes. 3. Cytokines are produced by mast cells, Schwann cells, fibroblasts, and sensory neurons. These are involved in the maintenance of homeostasis in whole of the nervous system, peripheral, central, and autonomic. Tumor necrosis factor alpha (TNFα) is a potent systemic pro-inflammatory cytokine, central to the inflammatory response, in immune-mediated inflammatory diseases. TNFα is produced in Schwann cells and has a role in peripheral nerve regeneration and regulation of apoptosis. 4. Elevated concentrations of TNFα has been reported with neuropathy in diabetes T1DM and T2DM [32]. 5. TNFα could be a candidate biomarker for the presence, severity, and progression of diabetic neuropathy. T2DM patients with neuropathy have higher levels of TNFα than those without neuropathy [21].

3.7.2 Role of CD 163 in Inflammation 1. CD163 is an endocytotic receptor expressed in macrophages and monocytes only. It is found to be increased in chronic inflammatory states and reproducibly demonstrated in diabetes [27, 28]. 2. Furthermore, sCD163 has been shown to be associated with insulin resistance in T2DM, an association that is independent of TNFα [29]. sCD163 links the neuropathic and inflammatory processes and could prove to be a biomarker.

3.7.3 Role of Adipose Tissues in Inflammation 1. Adipose tissue is a reservoir of many inflammatory reactions in the body. Studies on dyslipidemia have shown free fatty acids to be important mediators of ­inflammation and oxidative damage. Elevated triglycerides or decreased HDL cholesterol in plasma also seem to correlate with diabetic neuropathy.

3.7  Role of Inflammation

33

2. There is a possibility of bidirectional mutual relationship between the altered lipid levels with diabetic neuropathy. Afferent nerves sense the injury caused by the inflammation and carry the signal through the vagus nerve to the brain stem. This in turn activates the cholinergic anti-inflammatory pathways and reduces the inflammatory response. Increased activity in the vagus nerve supply to the spleen reduces the innate immune response to those antigens which are likely to produce tissue injury. If the vagal tone decreases as is common in diabetic autonomic neuropathy, the inflammation is likely to remain unchecked [20]. CRP, IL6, and TNFα elevated in diabetes and cardiac autonomic neuropathy correlate well.

3.7.4 Other Pathogenic Mechanisms of Inflammation 1. Decline of autonomic indices like heart rate variability (HRV), so important to cardiac functional responses decline in sensory nerve function and mortality at 6-year follow-up also is linked with higher basal levels of superoxide anion, high serum interleukin (IL)-18, soluble intercellular adhesion molecule-1, and soluble E-selectin. Elevated basal levels of interleukin-1 can also predict decline of heart rate variability in type 2 diabetes [22]. 2. Alteration of KIF1A of kinesin family axonal protein affected only in males may be the reason for abnormalities of the pain and analgesia [5] (discussed later) 3. This motor protein mediates the signals arising from sensory nerves from the peripheral nervous system and its transmission in some way [33]. It is essential for the continuance of function of sensory neurons. 4. Axonal protein contents of kinesin family, KF1A and KIF5B, are involved in the axonal transport. The other axonal content from the same family is KIF5B and Myosin Va. The gene expression of all these is affected only in males.

3.7.5 Clinical Risk Factors for Neuropathy 1. The metabolic changes will continue to occur alongside all other changes described above. 2. Higher glycosylated hemoglobin and longer duration of diabetes, 3. Higher levels of total and low-density lipoprotein cholesterol and triglycerides, 4. Higher body-mass index, 5. Higher von Willebrand factor levels, 6. Higher urinary albumin excretion rate, 7. Hypertension and smoking, 8. Higher body-mass index, and smoking remaining independent associations with the incidence of neuropathy, 9. Cardiovascular disease at baseline doubling the risk of neuropathy, independent of cardiovascular risk factors [34].

34

3.8

3  Pathogenesis of Diabetic Neuropathies

Genetic Susceptibility

1. Substantial new evidence is now available to theorize a link between genetic factors and the development of diabetic complications. 2. A genetic predisposition to oxidative stress has been demonstrated in a diabetic population with an increased risk of neuropathy. This develops due to the polymorphism of antioxidant enzymes like superoxide dismutase (SOD), glutathione peroxidase (GPX), and catalase (CAT) (discussed later) 3. Polymorphisms of genes encoding micro RNAs, MIR146a, MIR27a, a variant allele of rs895819, a single nucleotide polymorphism in MIR27A and MIR499, MIR499A GG genotype are considered to be related with cardiac autonomic neuropathy. 4. C allele of rs2910164 single nucleotide polymorphism (SNP) in MIRI146A indicates a potentially lower risk of developing cardiac autonomic neuropathy [35]. 5. The other genes correlating with the development and progressions of diabetic and cardiac autonomic neuropathy are TCF7L2, APOE 3/4 and 4/4, and ACE. 6. MIRI146a, MIR128a, and MIR27a are single nucleotide polymorphic type [36].

3.8.1 M  ore Recent Genetic Studies in DPN and Other Microvascular Complications 1. There is an increased risk with the genes coding for vascular endothelial growth factor (VGEF) in retinopathy, engulfment, and cell motility (ELMO1) in nephropathy, and ADIPOQ in coronary artery disease [37]. 2. Altered and abnormal glycemic pathways have uncovered genes coding for Aldose Reductase Activity Inhibition (AKR1 B1) in diabetic retinopathy and nephropathy [38]. However, no aldose reductase inhibitors have been found to be useful in treating neuropathy. 3. In the pathogenesis of pain in small fiber neuropathy, the role of various sodium channels and mutation in SCN9A leading to gain-of-function is established. Mutations in the vanniloid receptor gene, TRPA1, may lead to episodic familial pain syndromes [39]. 4. Similarly, channelopathies leading to loss of function mutations may cause insensitivity to pain syndromes [40]. 5. Polymorphisms in the adiponectin (ADPN) genes, T45G and G276T, have recently been found to be associated with increased risk of developing DSPN in type 2 diabetes [41]. ADPN is an insulin sensitizer and anti-inflammatory agent. This polymorphism leads to a downregulation of ADPN serum level. The association however is weak and inconsistent without a clear relationship.

3.8.2 Counterargument for Genetic Susceptibilities 1. Some researchers however have argued for an opposite—that there is no genetic susceptibility but only environmental factors as being responsible for diabetic and cardiac autonomic neuropathy [30].

3.9  Paraproteinemic Neuropathy (PPN)

3.9

35

Paraproteinemic Neuropathy (PPN)

1. This is a heterogeneous group of neuropathies which have different pathogenetic mechanisms. Here neuropathy is accompanied by excess of some homogeneous immunoglobulin in the serum which characterizes it. It is due to abnormal clonal proliferation of B-lymphocytes or plasma cells. More often than not cases occur as monoclonal gammopathy of undetermined significance (MUGS) [42]. 2. MGUS is a common, age-related medical condition [43]. Three criteria define MGUS: A monoclonal paraprotein band less than 30 g/L (3 g/dL); plasma cells less than 10% on bone marrow examination, and no evidence of bone lesions, anemia, hypercalcemia, or renal insufficiency [44]. 3. That is to say, hematologic malignancies which produce such excessive immunoglobulin will not be found to produce some symptoms of neuropathy, which may/may not necessarily be connected with diabetes. In these cases, some clinical experience and information from small uncontrolled trials is available where the treatment will be more empirical and without rigor of evidence [45]. This could also occur in patients with diabetes as a superimposed condition. 4. Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) with MGUS has the same clinical and electrodiagnostic characteristics as pure CIDP and has the same treatment choice—standard CIDP treatments, primarily steroids first before immuno-suppression may be considered. These treatments are however are not as effective as in idiopathic CIDP [46].

3.9.1 Clinical Features of PPN PPN occurs typically as a sensorimotor polyneuropathy, directly depending on the length of the fibers as in diabetes. Axonal loss in PPN is significant. Most of the symptoms are positive—(allodynia, hyperpathia, cramps, paresthesias, gait ataxia, dysesthesia and lancinating pain, abnormal sensation in the legs for touch, joint position, and vibration). The negative symptoms may be mild—distal weakness, foot numbness. Symptoms of peripheral neuropathy may precede by years before symptoms of hematologic malignancy actually manifest [47]. PPN may be caused by interaction of antibodies with specific antigenic targets on peripheral nerves or by deposition of immunoglobulins or amyloid. The clinical presentation, treatment, and prognosis of PPN differs based on the subtype and associated disorders. There are three major clinical PPN subtypes: 1 . Distal demyelinating symmetric neuropathy 2. Chronic inflammatory demyelinating polyneuropathy (CIDP)-like 3. Axonal sensorimotor peripheral neuropathy.

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3  Pathogenesis of Diabetic Neuropathies

3.9.2 Associations of PPN with Neuropathy 1. Approximately 10% of patients with a chronic sensorimotor neuropathy of unknown origin have an associated serum monoclonal gammopathy [48]. 2. IgG/A MGUS with neuropathy resembling CIDP is either relapsing or progressive, with symmetrical proximal and distal weakness of the four limbs, sensory involvement, and areflexia. About 80% of patients respond to one of the typical CIDP treatments [49]. 3. Multiple myeloma, cryoglobulinemia, lymphoma, amyloidosis, Waldenstrom macroglobulinemia, and POEMS (polyneuropathy, organomegaly, endocrinopathy, M-protein spike, and skin manifestations) syndrome are the other conditions associated with PPN [50].

3.9.3 Prevalence of PPN 1. Approximately 1% of the general population, 5.3% in individuals over 70 years and up to 10% in people older than 80 years have paraproteinemia. PPN is most commonly observed with IgM gammopathy (48%), followed by IgG (37%) and IgA (15%). African Americans have a higher prevalence of monoclonal gammopathy. 2. Mixed cryoglobulinemia with neuropathy is mainly a multifocal axonal neuropathy and has a pattern resembling mononeuropathy multiplex. This could be secondary to necrotizing vasculitis [51]. 3. 20% of patients with predominately sensory neuropathy of distal lower limbs, and small fiber painful type have primary (AL) amyloidosis coexisting. Autonomic dysfunction is found frequently. 4. Anti-ganglioside antibodies are present in chronic ataxic neuropathy with ophthalmoplegia. Ataxia is very much marked but contrarily the motor power remains relatively unaffected [52]. A predominantly motor neuropathy is associated with IgM antibodies which target the ganglioside [53]. 5. Polyneuropathy, organomegaly, endocrinopathy, M-protein, skin changes, (POEMS) has neuropathy as the main feature. The diagnosis of osteosclerotic myeloma will often develop later. Positive and slowly progressive symptoms found are mainly the distal weakness [54]. 6. Demyelinating isolated radiculopathy, axonal multiple mono-neuropathies are commonly associated with lymphoma [55]. 7. Peripheral neuropathy with sensory loss and unsteady gait is found in up to 47% patients of Waldenstrom macroglobulinemia (WM). Vascular endothelial growth factor, VEGF, in POEMS is markedly elevated with PPN and vasculitis [56].

3.10 Key Mechanisms Leading to Neuropathy in Diabetes 1. Insulin insufficiency will cause many changes at the tissue levels as the metabolism shifts to free fatty acid from glucose. Acidic intracellular molecules, increased oxidative state, mitochondrial dysfunction, and hypo or hyperkalemia

3.11  Autoimmune Etiopathogenesis of Diabetic Neuropathies

37

occur in insulin deficiency or resistance with or without chronic kidney disease. In the presence of cardiac autonomic neuropathy, these changes can lead to fatal arrhythmia in diabetes. Left ventricular hypertrophy if present is an added risk factor. 2. One of the central mechanisms of diabetic and cardiac autonomic neuropathy is a disturbance of the hypothalamic cardiac clock, which is a result of dopamine deficiency. It leads to sympathetic pre-dominance, insulin resistance, and features of the metabolic syndrome [57]. 3. The main stimulus to respiration, hypoxia, and sensitivity to hypercapnia could be considerably reduced due to diabetic autonomic neuropathy. The bronchial innervation is also under sympathetic influence which if reduced can have serious complications in sleep apnea syndrome [58]. 4. Sleep apnea is more preponderant in diabetes particularly in type 1 even when the patients are younger. Its neurological basis could be due to reduced sensitivity to hypoxia or of the response to hypercapnea [59]. 5. Baroreceptor sensitivity gets considerably lowered in T1DM patients with cardiac autonomic neuropathy than those without cardiac autonomic neuropathy [60]. The same mechanism is likely in type 2 diabetes patients also. 6. Patients on chronic metformin therapy develop B 12 deficiency in about 30% of cases. In India the use of protein pump inhibitors is so widespread and chronic that the relative achlorhydria may contribute to this further. Vegetarianism in India is quite prevalent and many believe that could also lead to B 12 deficiency and its neuropathic effects.

3.11 A  utoimmune Etiopathogenesis of Diabetic Neuropathies The immediate understanding of autoimmunity in diabetes is limited to type 1 diabetes. It can occur as a conglomerate of type 2 diabetes with hypothyroid and adrenal dysfunction which is also known. Diabetic neuropathy is complex and variegated and its understanding is vaguer. Autoimmunity as an etiopathogenesis factor for it would be still rarer. The understanding of immunology to autoimmunity is rather superficial and the details are difficult to understand for a clinician. Hence this short discussion is presented here to serve little more than preliminary understanding with some emphasis on diabetic neuropathy. The author met Dr Peter Dyck, the octogenarian researcher and the world authority on Diabetic Neuropathy in Rochester Mayo Clinic toward the end of 2010. Having learnt about the work in diabetic foot in India, the author is connected with intimately, he was pleased, and gave a suggestion that autoimmunity in neuropathy is much less studied and that the author should do it at some time. Dr Dyck further said that as much as 40% of neuropathic diseases could come from autoimmune mechanism, hinting that one of the big trigger for autoimmune phenomenon, the infection is common in India. This section is written as a tribute to the Grand Old Man.

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3  Pathogenesis of Diabetic Neuropathies

3.11.1 Molecular Mechanisms Involved in Autoimmune Reactions 1. Among these are complement cascade activation, recruitment of immune cells via Fc (crystallizable segment) receptors. It starts the antibody-dependent cellular cytotoxicity, opsonization, phagocytosis, damages the tissues, and sets up inflammation. 2. Additional mechanisms like cross-link antigens—immune complex formation and/or endocytosis of antigen which span the cell membrane are also found in autoimmunity. 3. The IgG4 antibodies block enzymatic activity, often related to energy production (as seen above) or protein–protein interactions of the target antigen. 4. Th2 cytokines IL-4 and IL-13. IL-10 stimulates the IgG4 and inhibits IgGE antibodies. IgG4 has a marked anti-inflammatory function. Its levels rise slowly after chronic exposure to antigens [61]. 5. Autoimmune diseases have well-established HLA association, genetic clustering with other autoimmune diseases in the family. Improvement is possible after antibodies are reduced by plasmapheresis and treatment for B cell reduction. 6. Autoimmune reactions are also connected with infection where the pathogenic similarity of body proteins and that of infective agent usually causes antibody development against the self. 7. Overexpression of tumor antigens also trigger an autoimmune response [61].

3.11.2 Autoimmunity and Axonal Neuropathic Damage 1. In patients with peripheral neuropathy, the screening may be expanded to teased nerve fibers to identify antibodies against proteins in the node of Ranvier. The node of Ranvier is a specialized structure to facilitate high-speed jumping transmission of neural impulses in myelinated nerve fibers. 2. In the formation of the axon–myelin junctions, the nodes of Ranvier, many adhesion molecules separate the voltage-gated potassium channels which are susceptible to autoimmune reactions. Para-nodopathies, as they are called, are antibodies against the proteins in the intermodal region of myelinated fibers leading to autoimmune diseases. 3. The clinical presentation is like atypical CIDP or Guillain-Barré-syndrome (GBS), the latter considered to be a disorder with autoimmune basis. Forty percent of these patients with autoimmune basis have antibodies against the myelin sheath or the axons also. 4. Contactin 1 (CNTN1), contactin-associated protein 1 (Caspr1), are cell adhesion molecules at the motor neurons axo-glial junction of myelin sheaths and on intermodal myelin also. These bind with neurofascin 155 on oligo-dendro-glial surface to which facilitate efficient nerve impulse propagation. Antibodies against CNTN1 of IgG4 present in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and are pathogenic causing transverse band loss and intra-nodal loop detachment in the peripheral nerves.

3.11  Autoimmune Etiopathogenesis of Diabetic Neuropathies

39

5. Ganglioside-specific antibodies cause neuropathies such as Guillain-Barre syndrome (GBS), multifocal motor neuropathy (MMN), Miller Fisher syndrome (MFS), acute and chronic form of inflammatory demyelinating poly-radiculo-­ neuropathy (AIDP; CIDP), and various forms of multiple sclerosis (MS) which are immune-mediated [62]. 6. An important cause of neuropathy, as part of a generalized syndrome, lies in diseases like polyarteritis nodosa (PAN), rheumatoid arthritis, Sjogren’s syndrome, and systemic lupus erythematosus (SLE) in main. 7. Despite vasculitic involvement, symmetric presentation of neuropathic abnormalities occurs in less than one in five subjects. Generally it is sequential, or random involvement of the major nerves, looking like mononeuritis multiplex with burning pain. 8. Fatigue, fever, and weight loss may be considered a clue to look for these disorders. Motor deficits may also occur. The investigation will consist of neuropathy and for the other maladies mentioned here.

3.11.3 Autoimmunity with Reference to T1DM Neuropathies 1. The role of autoimmunity has also been implicated in T1 diabetes. Autoantibodies against sympathetic ganglia, vagus nerve, and adrenal medulla were found in T1D patients. These antibodies were a class apart from islet autoimmunity. But its role in predicting future development of DAN and CAN is conflicting. 2. One pathophysiological mechanism that is specific to Cardiac Autonomic Neuropathy in general is autoimmunity. Antibodies to the nicotinic/acetylcholine receptor of autonomic ganglia cause widespread changes in these ganglia all over the body. It will then result in not only cardiac but also gastrointestinal, urinary, and other autonomic dysfunctions. These changes are also supposed to affect the cognitive functions of such patients [63, 64]. 3. Autoantibodies are directed against sympathetic ganglia, vagal afferents, and the adrenal medulla in T1DM patients with symptoms of autonomic neuropathy [65].

3.11.4 Autoimmunity from the Neuropathic Point of View Atypical chronic inflammatory distal polyneuropathy (CIDP) with distal sensory motor neuropathy, tremor, ataxia, and Guillain Barre Syndrome are the major autoimmune syndromes. Aquaporin channel 4 antibodies are responsible for demyelinating diseases. These antibodies are used nowadays as the biomarker for the diagnosis of patients with neuromyelitis optica spectrum disorders (NMOSD) also. Uni- or bilateral optic neuritis, transverse myelitis, and longitudinally extensive transverse myelitis are associated with anti-MOG antibodies. Many autoimmune neurological or demyelinating syndromes are negative for antibody as markers. Only high titers of GAD65 antibodies, >2000 U/mL, are likely to be associated with stiff person syndrome, ataxia, epilepsy, limbic encephalitis. These antibodies are found in 80% of type 1 patients of diabetes.

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3  Pathogenesis of Diabetic Neuropathies

3.12 C  hronic Inflammatory Demyelinating Polyradiculoneuropathy in Diabetes Mellitus To differentially diagnose CIDP v/s other forms of commoner diabetic polyneuropathy is a challenge because of many shared features between the two. It makes the application of the CIDP diagnostic criteria less stringent. Some diabetics present with progressive, painless, symmetrical, and both proximal and distal weakness of not just the lower but also of the upper limbs. The symptoms develop over many weeks to months and are severe enough to lead to areflexia or hyporeflexia. Physical examination also shows glove and stocking sensory impairment. This is also the classic symptom complex of diabetic polyneuropathy. American Academy of Neurology Research criteria of CIDP on electrophysiological diagnosis of CIDP are similar to DPN, but some axonal features are found only in diabetic polyneuropathy. CSF protein is frequently elevated in CIDP, but not in DPN [66]. The response to therapy is quite satisfactory in idiopathic-CIDP than in CIDP. These two CIDPs have more resemblance with each other than these have with DPN. A total number of 32 (16.9%) in 189 diabetics with various neuropathic/muscular disorders studied in electrodiagnostic facilities met the American Academy of Neurology criteria for CIDP. On the other hand, in patients without diabetes studied by electrophysiological diagnosis, only 1.8% had idiopathic CIDP [67]. The difference is marked indicating some mechanism that makes diabetics prone to CIDP.

3.12.1 American Academy of Neurology Research Criteria for the Diagnosis of CIDP 1. Progressive or relapsing motor and sensory dysfunction of more than one limb developing over 2 months, 2. Diffuse hypo- or areflexia, 3. CSF cells count less than 10/cm if negative for HIV and VDRL 4. Unequivocal evidence of demyelination and remyelination in nerve biopsy, 5. Three out of four electrodiagnostic criteria found in at least two nerves: (a) Decreased nerve conduction velocity less than 80% if amplitude is more than 80% of normal (b) Partial conduction block with more than 20% drop, (c) Prolonged distal latencies greater than 125% if amplitude is greater than 80% of normal (d) Prolonged F-wave greater than 120% if amplitude is greater than 80% of normal.

3.12.2 Conclusions About CIDP in Diabetes Mellitus 1. Demyelinating features are common in diabetic polyneuropathy both neurophysiologically and pathologically

3.13  Autoimmunity of the Optic Nerve and Retinal Diseases

41

2 . Elevated CSF protein is frequent. 3. Some patients with diabetic polyneuropathy meet the AAN criteria for CIDP. The features more consistent with CIDP than diabetic polyneuropathy: 1 . Proximal and symmetric weakness 2. Progressive course 3. Diffuse areflexia 4. Conduction block at sites not prone for compression 5. CSF protein elevation more than 100 mg/mL A therapeutic trial with steroids, intravenous immunoglobulin, or plasmapheresis may be necessary to distinguish between the two in diagnostically more challenging cases. In clinical practice of diabetes or without diabetes, such diagnosis is rarely considered under critical clinical reasoning. That leaves the clinical practice wanting in proper diagnosis of neuropathies, much more so in diabetes. In diabetes the inflammation and an element of autoimmunity are important additions to think of such differential diagnosis to be able to tell the patient with much more exactitude what is happening and what can and cannot be done for him or her.

3.13 Autoimmunity of the Optic Nerve and Retinal Diseases In diabetes the most prevalent is retinopathy. At times this routine assumption in visual disorders may be erroneous if there is no typical retinopathy or there is absence of glaucoma. This may get more intriguing with field defects, other neuropathic changes, or atypical cerebral syndromes (discussed later). The search for autoimmune pathology would turn out to be useful in such cases. Autoimmunity can affect either the optic nerve or the retina or both. Some antibodies to glycolytic energy producing enzymes (as seen above) are common to both retina and optic nerves. Some are specific for either retina or the optic nerve. Antibodies against astrocytes, neuronal fibers, and oligodendrocytes are found in optic nerves but not in retina. Anti-AQP4-antibodies found in demyelinating diseases have become the biomarker for neuromyelitis optica spectrum disorders (NMOSD.) It has an anti-endothelial cell antibody against the endoplasmic reticulum. This as a general effect may alter the blood–brain barrier. Anti-MOG antibodies (myelin oligodendrocyte glycoprotein) found in patients with acute disseminated encephalomyelitis (ADEM), transverse myelitis, and longitudinally extensive transverse myelitis are also found in uni- or bilateral optic neuritis and neuromyelitis optica. Clinically there is painless and progressive acute or subacute loss of visual acuity and/or visual field defects, optic nerve head changes, such as disc pallor, cupping of the optic nerve head, and/or frank optic nerve atrophy. Defects in color vision, decreased retinal function on electro-retinography (ERG), delayed visual evoked potentials (VEPs) or dropout of the retinal nerve fiber

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3  Pathogenesis of Diabetic Neuropathies

layer (RNFL) detected by optic coherence tomography (OCT) imaging, and thinning of the retina are the major changes at tissue level. The tissue loss occurs in photoreceptors and/or retinal ganglion cells (RGCs) and their axons [68]. Autoantibodies specific to glycolytic enzymes in neural tissues involved in energy production are found in both retinal autoimmunity and aquaporin 4 of the optic nerve as well. High frequency of various autoantibodies in neuro-retinopathy indicates that many clones of the B cells and humoral immune system response are activated. GADPH, a cytosolic protein, is involved in apoptosis, oxidative stress, and activation of transcription, membrane fusion, and vesicle transport. It can translocate to the nucleus in apoptotic processes which starts with the presence of free high calcium intracellularly. GADPH is also present in large quantities in retinal rods. Wherever autoimmune reactions involve glycolytic pathways for energy production, cell death will occur. GADPH possibly is also responsible in human age-related neurodegenerative diseases, including Alzheimer’s disease. The reason extended is that GADPH as an antigen evokes strong stimulus to produce its autoantibody, especially during infections. Such an antigen can be a target for stopping the autoimmune reaction to save further consequences of neural tissues [68].

3.13.1 The Cerebral Cortex and Autoimmunity Autoimmune diseases of the cerebral cortex affect different tissues like neurons, glial cells, or components of the blood–brain barrier. The autoimmune reactions occur mainly due to activity of T or B cells that recognize cerebral antigens. The major discovery of autoimmune responses was autoantibodies to synaptic or extra-­ synaptic membrane antigens. Patients with surface autoimmunity show substantial response to immunotherapy, probably because these autoimmune reactions are B-cell-mediated. IgG autoantibody react with glial fibrillary acidic protein (GFAP) in patients with relapsing steroid-responsive meningoencephalitis with or without myelitis. The intracellular antigens and autoimmune reactions are primarily and most frequently seen in malignancies in ovaries, breast, small cell lung carcinomas, testicular neoplasms, Hodgkin’s, adenocarcinoma of lungs, teratoma, carcinoid, salivary pleomorphic adenoma, prostate carcinoma, and melanoma. The presentation is like a paraneoplastic (PNS) or idiopathic neurological syndromes. Neuronal antibodies are good biomarkers for specific tumor with PNS. The cell-mediated immune attack is by the T cells which causes relentless neuronal destruction. Intracellular antibodies against key intracellular molecules—anti-protein-kinase C gamma (PKC gamma), anti-carbonic anhydrase-related protein VIII (CARP VIII), or anti-rhoGTPase-activating protein are found in patients with or even when a tumor is not present. The autoantibodies bind these molecules, highly expressed in Purkinje cells’ autoantibodies in patients with subacute autoimmune cerebellar ataxia.

References

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Anti-neuronal surface antibodies are sensitive and specific biomarkers for autoimmune encephalitis (AIE). The afflictions of the central nervous system commonly seen and can be loosely grouped together are as follows: 1. Anti-neuronal autoimmune encephalitis (AIE), encephalomyelitis, brain stem encephalitis, basal ganglia encephalitis, CNS demyelination, long transverse myelitis, 2. Sydenham’s chorea, movement disorders, myoclonus, tremor, facio-brachial dystonic seizures, oro-facial dyskinesias, cerebellar ataxia, opsoclonus-myoclonus, 3. Status epilepticus, seizures, 4. Psychological conditions like Hallucinations, agitation, psychosis, and limbic dysfunction 5. Functional alterations like hyponatremia, diarrhea, and non-REM and REM-­ sleep disorder, 6. Morvan syndrome—peripheral nerve hyper-excitability, autonomic instability, and encephalopathy with autoantibodies to voltage-gated potassium channel complexes (VGKCs); these are often associated with teratoma, prostate adenoma, and carcinoma in situ of the colon.

References 1. Tesfaye S, Boulton AJ, Dyck PJ, Freeman R, Horowitz M, Kempler P, Lauria G, Malik RA, Spallone V, Vinik A, Bernardi L, Valensi P. Diabetic neuropathies: update on definitions, diagnostic criteria, estimation of severity, and treatments. Diabetes Care. 2010;33:2285–93. https:// doi.org/10.2337/dc10-1303. PMID 20876709. 2. Basit A, Hydrie MZ, Hakeem R, Ahmedani MY, Masood Q. Frequency of chronic complications of type II diabetes. J Coll Physicians Surg Pak. 2004;14(2):79–83. 3. Booya F, Bandarian F, Larijani B, Pajouhi M, Nooraei M, Lotfi J. Potential risk factors for diabetic neuropathy: a case control study. BMC Neurol. 2005;5:24. 4. Aaberg ML, Burch DM, Hud ZR, Zacharias MP. Gender differences in the onset of diabetic neuropathy. J Diabetes Complicat. 2008;22(2):83–7. 5. Kiziltan ME, Benbir G.  Clinical and electrophysiological differences in male and female patients with diabetic foot. Diabetes Res Clin Pract. 2008;79(1):e17–8. 6. Kiziltan ME, Gunduz A, Kiziltan G, Akalin MA, Uzun N. Peripheral neuropathy in patients with diabetic foot ulcers: clinical and nerve conduction study. J Neurol Sci. 2007;258(1–2):75–9. 7. Albers JW, Brown MB, Sima AA, Greene DA. Nerve conduction measures in mild diabetic neuropathy in the Early Diabetes Intervention Trial: the effects of age, sex, type of diabetes, disease duration, and anthropometric factors. Tolrestat Study Group for the Early Diabetes Intervention Trial. Neurology. 1996;46(1):85–91. 8. Brandt U, Trumpower B. The proton motive Q cycle in mitochondria and bacteria. Crit Rev Biochem Mol Biol. 2008;29(3):165–97. 9. Shah MS, Brownlee M.  Molecular and cellular mechanisms of cardiovascular disorders in diabetes. Circ Res. 2016;118(11):1808–29. 10. Juranek J, Ray R, Banach M, Rai V. Receptor for advanced glycation end-products in neurodegenerative diseases. Rev Neurosci. 2015;26(6):691–8.

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11. Fernyhough P. Mitochondrial dysfunction in diabetic neuropathy: a series of unfortunate metabolic events. Curr Diabetes Rep. 2015;15(11):89. 12. Fernyhough P, Roy Chowdhury SK, Schmidt RE. Mitochondrial stress and the pathogenesis of diabetic neuropathy. Expert Rev Endocrinol Metab. 2010;5(1):39–49. 13. Cashman CR, Hoke A. Mechanisms of distal axonal degeneration in peripheral neuropathies. Neurosci Lett. 2015;596:33–50. 14. Edwards JL, Vincent AM, Cheng HT, Feldman EL. Diabetic neuropathy: mechanisms to management. Pharmacol Ther. 2008;120(1):1–34. 15. Soriano FG, Virág L, Szabó C. Diabetic endothelial dysfunction: role of reactive oxygen and nitrogen species production and activation. J Mol Med. 2001;79(8):437–48. 16. Dimitropoulos G, Tahrani AA, Stevens MJ.  Cardiac autonomic neuropathy in patients with diabetes mellitus. World J Diabetes. 2014;5(1):17–39. 17. Østergaard L, Finnerup NB, Terkelsen AJ, Olesen RA, Drasbek KR, Knudsen L, Jespersen SN, Frystyk J, Charles M, Thomsen RW, Christiansen JS, Beck-Nielsen H, Jensen TS, Andersen H.  The effects of capillary dysfunction on oxygen and glucose extraction in diabetic neuropathy. Diabetologia. 2015;58:666–77. https://doi.org/10.1007/s00125-014-3461-z. PMID: 25512003. 18. Ekberg K, Johansson BL. Effect of C-peptide on diabetic neuropathy in patients with type 1 diabetes. Exp Diabetes Res. 2008;2008:457912. https://doi.org/10.1155/2008/457912. PMID: 18350117. 19. Vinik AI, Park TS, Stansberry KB, Pittenger GL.  Diabetic neuropathies. Diabetologia. 2000;43:957–73. https://doi.org/10.1007/s001250051477. PMID: 10990072. 20. Vinik AI, Erbas T, Casellini CM. Diabetic cardiac autonomic neuropathy, inflammation and cardiovascular disease. J Diabetes Investig. 2013;4(1):4–18. 21. Zhu T, Meng Q, Ji J, Lou X, Zhang L. Toll-like receptor 4 and tumor necrosis factor-alpha as diagnostic biomarkers for diabetic peripheral neuropathy. Neurosci Lett. 2015;585:28–32. https://doi.org/10.1016/j.neulet.2014.11.020. PMID: 25445373. 22. Spallone V.  Update on the impact, diagnosis and management of cardiovascular autonomic neuropathy in diabetes: what is defined, what is new, and what is unmet. Diabetes Metab J. 2019;43:3–30. http://e-dmj.org. 23. Wahren J, Ekberg K, Johansson J, Henriksson M, Pramanik A, Johansson BL, Rigler R, Jörnvall H. Role of C-peptide in human physiology. Am J Physiol Endocrinol Metab. 2000;278:E759– 68. PMID: 10780930. 24. Krishnan AV, Kiernan MC. Altered nerve excitability properties in established diabetic neuropathy. Brain. 2005;128:1178–87. https://doi.org/10.1093/brain/awh476. PMID: 15758031. 25. Cameron NE, Cotter MA, Jack AM, Basso MD, Hohman TC.  Protein kinase C effects on nerve function, perfusion, Na(+), K(+) ATPase activity and glutathione content in diabetic rats. Diabetologia. 1999;42:1120–30. https://doi.org/10.1007/s001250051280. PMID: 10447525. 26. Koya D, King GL. Protein kinase C activation and the development of diabetic complications. Diabetes. 1998;47:859–66. https://doi.org/10.2337/diabetes.47.6.859. PMID: 9604860. 27. Møller HJ. Soluble CD163. Scand J Clin Lab Invest. 2012;72:1–13. https://doi.org/10.3109/0 0365513.2011.626868. PMID: 22060747. 28. Etzerodt A, Moestrup SK. CD163 and inflammation: biological, diagnostic, and therapeutic aspects. Antioxid Redox Signal. 2013;18:2352–63. https://doi.org/10.1089/ars.2012.4834. PMID: 22900885. 29. Llauradó G, González-Clemente JM, Maymó-Masip E, Subías D, Vendrell J, Chacón MR.  Serum levels of TWEAK and scavenger receptor CD163  in type 1 diabetes mellitus: relationship with cardiovascular risk factors: a case-control study. PLoS One. 2012;7:e43919. https://doi.org/10.1371/journal.pone.0043919. PMID: 22937125. 30. Osztovits J, Horváth T, Littvay L, et al. Effects of genetic vs. environmental factors on cardiovascular autonomic function: a twin study. Diabet Med. 2011;28(10):1241–8. 31. Dogrul A, Gul H, Yesilyurt O, Ulas UH, Yildiz O. Systemic and spinal administration of etanercept, a tumor necrosis factor alpha inhibitor, blocks tactile allodynia in diabetic mice. Acta Diabetol. 2011;48:135–42. https://doi.org/10.1007/s00592-0100237-x. PMID: 21104419.

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32. Husebye ES, Winqvist O, Sundkvist G, Kämpe O, Karlsson FA.  Autoantibodies against adrenal medulla in type 1 and type 2 diabetes mellitus: no evidence for an association with autonomic neuropathy. J Intern Med. 1996;239:139–46. https://doi.org/10.1046/j.13652796.1996.423766000.x. PMID: 8568481. 33. Tanaka Y, Niwa S, Dong M, Farkhondeh A, Wang L, Zhou R, Hirokawa N. The molecular motor KIF1A transports the TrkA neurotrophin receptor. Neuron. 2016;90(6):1215–29. 34. Solomon Tesfaye MD, Nish Chaturvedi MD, Simon EM, Eaton DM, John D, Ward MD, Christos Manes MD, Ionescu-Tirgoviste C, Witte DR, Fuller JH.  Vascular risk factors and diabetic neuropathy. N Engl J Med. 2005;352(4):341–50. www.nejm.org. 35. Ciccacci C, Morganti R, Di Fusco D, et  al. Common polymorphisms in MIR146a, and MIR27a genes contribute to neuropathy susceptibility in type 2 diabetes. Acta Diabetol. 2014;51(4):663–71. 36. Politi C, Ciccacci C, D’Amato C, Novelli G, Borgiani P, Spallone V.  Recent advances in exploring the genetic susceptibility to diabetic neuropathy. Diabetes Res Clin Pract. 2016;120:198–208. 37. Doria A. Genetics of diabetes complications. Curr Diabetes Rep. 2010;10(6):467–75. 38. Donaghue KC, Margan SH, Chan AK, Holloway B, Silink M, Rangel T, Bennetts B.  The association of aldose reductase gene (AKR1B1) polymorphisms with diabetic neuropathy in adolescents. Diabet Med. 2005;22(10):1315–20. 39. Themistocleous AC, Ramirez JD, Serra J, Bennett DL. The clinical approach to small fibre neuropathy and painful channelopathy. Pract Neurol. 2014;14(6):368–79. 40. Nilsen KB, Nicholas AK, Woods CG, Mellgren SI, Nebuchennykh M, Aasly J.  Two novel SCN9A mutations causing insensitivity to pain. Pain. 2009;143(1–2):155158. 41. Ji ZY, Li HF, Lei Y, Rao YW, Tan ZX, Liu HJ, Yao GD, Hou B, Sun ML. Association of adiponectin gene polymorphisms with an elevated risk of diabetic peripheral neuropathy in type 2 diabetes patients. J Diabetes Complicat. 2015;29:887–92. 42. Gosselin S, Kyle RA, Dyck PJ.  Neuropathy associated with monoclonal gammopathies of undetermined significance. Ann Neurol. 1991;30(1):54–61. https://doi.org/10.1002/ ana.410300111. 43. Kyle RA, Therneau TM, Rajkumar SV, Larson DR, Plevak MF, Offord JR, et al. Prevalence of monoclonal gammopathy of undetermined significance. N Engl J Med. 2006;354(13):1362–9. https://doi.org/10.1056/NEJMoa054494. 44. International Myeloma Working Group. Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders: a report of the International Myeloma Working Group. Br J Haematol. 2003;121(5):749–57. 45. Rison RA, Beydoun SR.  Paraproteinemic neuropathy: a practical review. BMC Neurol. 2016;16:13. https://doi.org/10.1186/s12883-016-0532-4. 46. Gorson KC.  An update on the management of chronic inflammatory demyelin ating polyneuropathy. Ther Adv Neurol Disord. 2012;5(6):359–73. https://doi. org/10.1177/1756285612457215. 47. Martyn CN, Hughes RA.  Epidemiology of peripheral neuropathy. J Neurol Neurosurg Psychiatry. 1997;62(4):310–8. 48. Rison RA, Beydoun SR.  Amyotrophic lateral sclerosis-motor neuron disease, monoclonal gammopathy, hyperparathyroidism, and B12 deficiency: case report and review of the literature. J Med Case Rep. 2010;4:298. https://doi.org/10.1186/1752-1947-4-298. 49. Hadden RD, Nobile-Orazio E, Sommer C.  European Federation of Neurological Societies/ Peripheral Nerve Society Guideline on Management of Paraproteinaemic demyelinating neuropathies. Report of a joint task force of the European Federation of Neurological Societies and the Peripheral Nerve Society. J Periph Nerv. 2010;15:185–95. 50. Kelly JJ Jr, Kyle RA, O’Brien PC, Dyck PJ. Prevalence of monoclonal protein in peripheral neuropathy. Neurology. 1981;31(11):1480–3. 51. Ferri C, La Civita L, Cirafisi C, Siciliano G, Longombardo G, Bombardieri S, et al. Peripheral neuropathy in mixed cryoglobulinemia: clinical and electrophysiologic investigations. J Rheumatol. 1992;19(6):889–95.

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52. Delmont E, Jeandel PY, Hubert AM, Marcq L, Boucraut J, Desnuelle C. Successful treatment with rituximab of one patient with CANOMAD neuropathy. J Neurol. 2010;257(4):655–7. https://doi.org/10.1007/s00415-009-5412-z. 53. Yeung KB, Thomas PK, King RH, Waddy H, Will RG, Hughes RA, et al. The clinical spectrum of peripheral neuropathies associated with benign monoclonal IgM, IgG and IgA paraproteinaemia. Comparative clinical, immunological and nerve biopsy findings. J Neurol. 1991;238(7):383–91. 54. Soubrier MJ, Dubost JJ, Sauvezie BJ. POEMS syndrome: a study of 25 cases and a review of the literature. French Study Group on POEMS Syndrome. Am J Med. 1994;97(6):543–53. 55. Kelly JJ, Karcher DS. Lymphoma and peripheral neuropathy: a clinical review. Muscle Nerve. 2005;31(3):301–13. https://doi.org/10.1002/mus.20163. 56. D’Souza A, Hayman SR, Buadi F, Mauermann M, Lacy MQ, Gertz MA, et  al. The utility of plasma vascular endothelial growth factor levels in the diagnosis and follow-up of patients with POEMS syndrome. Blood. 2011;118(17):4663–5. https://doi.org/10.1182/ blood-2011-06-362392. 57. Vinik AI, Casellini C, Parson HK, Colberg SR, Nevoret M-L. Cardiac autonomic neuropathy in diabetes: a predictor of cardiometabolic events. Front Neurosci. 2018;12:591. https://doi. org/10.3389/fnins.2018.00591. 58. Antonelli Incalzi R, Fuso L, Pitocco D, Basso S, Trové A, Longobardi A, et al. Decline of neuroadrenergic bronchial innervation and respiratory function in type 1 diabetes mellitus: a longitudinal study. Diabetes Metab Res Rev. 2007;23:311–6. https://doi.org/10.1002/dmrr.688. 59. Tantucci C, Scionti L, Bottini P, Dottorini ML, Puxeddu E, Casucci G, et  al. Influence of autonomic neuropathy of different severities on the hypercapnea drive to breathing in diabetic patients. Chest. 1997;112:145–53. https://doi.org/10.1378/chest.112.1.145. 60. Maser RE, Lenhard MJ. Cardiovascular autonomic neuropathy due to diabetes mellitus: clinical manifestations, consequences, and treatment. J Clin Endocrinol Metab. 2005;90(10):5896–903. 61. Koneczny I. A new classification system for IgG4 autoantibodies. Front Immunol. 9:97. www. frontiersin.org/articles/10.3389/fimmu.2018.00097/full. 62. Asati A, Kachurina O, Kachurin A. Simultaneous measurements of auto-immune and infectious disease specific antibodies using a high throughput multiplexing tool. PLoS One. 2012;7(8):e42681. www.plosone.org. 63. Ejskjaer N, Arif S, Dodds W, et al. Prevalence of autoantibodies to autonomic nervous tissue structures in type 1 diabetes mellitus. Diabet Med. 1999;16(7):544–9. 64. Zanone MM, Raviolo A, Coppo E, et al. Association of autoimmunity to autonomic nervous structures with nerve function in patients with type 1 diabetes: a 16-year prospective study. Diabetes Care. 2014;37(4):1108–15. 65. Zanone MM, Peakman M, Purewal T, Watkins PJ, Vergani D. Autoantibodies to nervous tissue structures are associated with autonomic neuropathy in type 1 (insulin-dependent) diabetes mellitus. Diabetologia. 1993;36:564–9. https://doi.org/10.1007/BF02743275. PMID:8335180. 66. Research criteria for diagnosis of chronic inflammatory demyelinating polyneuropathy (CIDP). Report from an Ad Hoc Subcommittee of the American Academy of Neurology AIDS Task Force. Neurology. 1991;41(5):617–8. 67. Sharma KR, Cross J, Farronay O, Ayyar DR, Shebert RT, Bradley WG. Demyelinating neuropathy in diabetes mellitus. Arch Neurol. 2002;59:758–65. PMID 12020257. 68. Adamus G, Brown L, Schiffman J, Iannaccone A.  Diversity in autoimmunity against retinal, neuronal, and axonal antigens in acquired neuro-retinopathy. J Ophthal Inflamm Infect. 2011;1:111–21. https://doi.org/10.1007/s12348-011-0028-8.

Part II Autonomic Neuropathies in Diabetes

4

Cardiovascular and Cerebral Dysfunction

4.1

Introduction

Nearly 80% of deaths in diabetes are caused by the cardiovascular events. It may be ironically said that if a person with diabetes does not suffer from death, the other complications like nephropathy and other will develop making the life miserable for her. Diabetes before menopause generally takes away the natural protection women have from developing cardiovascular disease. Women, it is long known, have greater morbidities and suffer more than men due to diabetes. Routine management of cardiovascular diseases in diabetes will not suffice. Unless the significance of various abnormalities of cardiovascular disorders is understood, proper treatment will leave many lacunae in care with suboptimal results. This chapter attempts to bring in that understanding, not to scare but to lead to rational understanding. Cerebral vascular or other cerebral disorders have received much less attention in general. Peripheral neuropathy has garnered it. That is why the understanding of it has remained somewhat elementary even among neurologists who have to deal with diabetes in addition to cerebral diseases. This chapter takes a wider view of these disorders, some of which may look unconnected. It is done to alert the clinicians about the odd elements which may surface at times and deal with it systematically. After all the clinical acumen should be directed more to such elements while the routine care, guidelines, and protocols are set.

4.2

 pidemiology of Cardiac Autonomic Neuropathy/ E Dysfunction in Diabetes

Cardiac autonomic neuropathy (CAN) affects at least 20% of unselected patients, and up to 65% of those with increasing age and diabetes duration. Prevalence of autonomic neuropathy in prediabetes and at diagnosis of type 2 diabetes is 11.4% under limitations of observations. It increases with diabetes duration by 4.6–6% [1]. © Springer Nature Singapore Pte Ltd. 2020 S. Kelkar, Diabetic Neuropathy and Clinical Practice, https://doi.org/10.1007/978-981-15-2417-2_4

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The populations studied will have inherent differences in their genetic makeup, environmental conditions, level of care and risk factors, duration of diabetes and common or unusual and specific aspects like consanguinity. The definition of CAN itself may vary in the patients studied. The patients are further divided into type 1 and 2 diabetes. Wide variations are therefore expected. It is found in 17–66% in type 1 diabetes and 31–73% in type 2 diabetes [2]. Prevalence rates of 60% and higher were reported in cohorts of patients with long-standing T2DM [3].

4.3

Clinical Profile: Symptoms

Cardiac autonomic neuropathy is a common enough condition in diabetes, but it remains undiagnosed for long. The signs of this condition are present in some distinct forms like resting tachycardia or significant bradycardia. The symptoms are often vague. These two findings are not put together and a diagnosis is not properly made early enough, late, or never. The laboratory methods are not easily available to all, but the clinical diagnosis or suspicion to go for laboratory methods is not a routine. Thus the prognostic significances of it remain unclear to the doctor and consequently the patient is left uninformed. That leads to a many unfortunate disastrous consequences. These are often seen in acute, high-risk situations like acute coronary syndromes or myocardial infarction [2]. Clinical diagnosis is easy and to say that there was no indication that a disaster will take place is an excuse which will not stand within the clinical condition of a patient with diabetes or otherwise also. Signs are always there in most of the patients. Sudden death is the most unfortunate. To explain it to the patient’s relatives asking for an explanation as to why it happened will be hard on the doctor if a clinical diagnosis and the possibility of such a disaster have not come up in the patient visits. Explaining it as a hind sight does not help. A situation that nothing was done for it with clear understanding leaves the doctor in embarrassing position. Cardiac autonomic neuropathy also masks the classic easily diagnosable symptom of acute myocardial infarction—pain. It presents as uneasiness, nausea, or right hypochondriac pain for which an abdominal pathology is first considered losing precious time for a clear diagnosis; at times such a diagnosis may not be made at all. Right hypochondriac pain would actually be the phenomenon of caudal radiation to a diseased gall bladder with chest pain absent. In addition it is associated with increased mortality, cardiovascular diseases like cardiomyopathy, chronic kidney disease in patients with DM.

4.3.1 Clinical Signs of Cardiac Autonomic Neuropathy Resting tachycardia need not always be defined only if the pulse rate is 100 per minute or beyond. Putting the finger on pulse and its character will easily tell if it exists or not. The unfortunate practice today is not to examine the patient in any way, certainly not in detail which is at the root of missing many a diagnosis. The absence of thorough history and examination listing out every abnormality is the

4.4 Physiology of Cardiac Innervation

51

single most important factor to make a complete clinical diagnosis. The practice of discussing what exactly is wrong with the patient’s condition is no longer there. The question of investigations thus remains without a discussion, is most often ill-­ founded on reason and therefore does not yield information relevant to the problem since it has not been defined clearly. The logical and just way of treating a patient is the explanation of reasons about why the investigation (or even a cross reference) is being ordered is a right of patients no one bothers about. Since the fingers do not rest on the pulse, missing unusual bradycardia is almost a given. There is a slow ponderous pulse progression in bradycardia just as there is restlessness in resting tachycardia. EKG or cardiac monitor does not give this vital information. The use of beta blockers in the practice of diabetes has increased, but it still has a concern about glycemic deterioration and masking of hypoglycemia. Its use or otherwise will make the interpretation of relative bradycardia more elusive. These aspects will be discussed later also. Significant or symptomatic postural dizziness may get noted, but the simplest of the examination of taking blood pressure in supine and then standing is another routine that is absent. As a result, the clarity about the pathophysiological basis of these (or any other symptoms for that matter) remains fuzzy in the clinician’s mind.

4.4

Physiology of Cardiac Innervation

In resting condition, there is a balance between the sympathetic and parasympathetic cardiac innervation which controls the heart rate. Under any stress, the sympathetic system goes in an overdrive, increases the heart rate, force of cardiac contractility, and cardiac output, will raise the blood pressure, and maintains the postural reflexes through carotid baroreceptor arc. Parasympathetic tone adjusts itself to these changes, and once the stress is over, it helps in the normalization of heart rate by its increased tone. It also lowers the heart rate, reduces the force of contraction (reduced chronotropic and inotropic actions). Sympathetic nerves supply all parts of the body. Sympathetic arborization is more diffuse. The parasympathetic nerves supply only special parts. These two divisions are partially antagonistic to the actions of each other by using two neurotransmitters, noradrenalin and acetylcholine [4]. As a general feature of arrangement, the sympathetic ganglia are distant to the organs they supply, whereas the parasympathetic ganglia with its final effecter motor nerves will be close to the organs they supply. The actions of these two are a complementary feedback with which the fine-­tuning and smooth response of the cardiovascular parameters. Reflex adjustments of vatious functions in any organ supplied by both nerve types can occur the same way [5].

4.4.1 Pathophysiological Basis of Three Events The imbalance of the two divisions of autonomic nervous system in the pathophysiology of heart failure, infarction, and the effects thereof is crucially important and are linked with each other. The effects are far more frequently adverse than in those

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who have normally functioning cardiac autonomic system. CAN is the basic cause of difference on the outcomes as well [4]. The all-important vascular innervation is supplied through an aortic plexus and more distal plexuses along the vascular tree.

4.4.2 Clinical Effects of Autonomous Imbalance 1. Sympathetic hyperactivity is found more commonly in diabetes. It is due to parasympathetic degeneration which occurs earlier, leaving unbridled activity of sympathetic fibers. 2. The denervation of both the autonomic and peripheral nervous systems occurs in an ascending manner, which is distant to proximal. Longer the length of a nerve, greater is the chance of its deterioration. It is also dependent on the length of the nerve fiber. The vagus is the longest of all cranial nerves and is first affected producing its cardiovascular effects. That is why sympathetic overtone is initially limited to reduction in the baroreceptor reflexes. It later affects the intrinsic ability of heart rate variability HRV and resting tachycardia [6–8]. 3. The vagus probably plays a part in reducing injury arising out of other pathological mechanisms, shown elsewhere in this chapter.

4.4.3 Degeneration of Sympathetics 1. Sympathetic degeneration with an intact or less damaged vagus will reverse the effects of sympathetic stimulation. Principally it will cause bradycardia. 2. There is also an inability to raise heart rate, force of contractility, and cardiac output in this situation due to sympathetic degeneration. This failure will not meet the oxygen demands of activity the body is subjected to every now and then in daily life. 3. This will then give rise to reduced exercise tolerance and cause postural hypotension. Degeneration of sympathetic nerves will also mask the angina or infarction pain [6].

4.5

The Normal Blood Pressure Regulation

1. As a person stands up, there is peripheral vasodilation and decreased venous return due to venous pooling due to gravity. Together, these two mechanisms reduce the blood volume the right ventricle receives. It reduces the normal stretch response1 to the ventricles and results in less forceful contractility of cardiac muscle. 1  Cardiac output is directly dependent on the length of the cardiac muscle fiber. The stretch is caused by the volume it receives, augmented by the atrial kick toward the end of diastolic filling of the left ventricle. The more stretched the muscle fiber is at the end of diastolic filling, the greater is the contractility of it. This is called as the Starling’s law. There is of course a limit of the fiber

4.6 Clinical Correlates of Cardiac Autonomic Neuropathy

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2. This in turn reduces the stretching of the baroreceptor mechanism of carotid sinus. The baroreceptors react extremely fast to increase the sympathetic tone to cause vasoconstriction and reflex rise in heart rate. 3. When sympathetics get affected or have degenerated, the baroreceptor mechanism also does not work fully and will not be able to compensate for the reflex rise of blood pressure on standing.

4.5.1 Baroreflex Sensitivity 1. An increase in blood pressure for any reason is immediately normally detected by baroreceptors. 2. There is then induced a reflex increase in vagal activity and reduction in sympathetic activity. 3. This results in a reduction in cardiac output, as well as peripheral vasodilation to control the increase in blood pressure. 4. The opposite occurs when there is a reduction in BP and thus baroreflex sensitivity (BRS) can assess both sympathetic and parasympathetic activities [6]. 5. An intact sympathetic innervation, once the vagal effects are adequately established, then causes reflex constriction in the peripheral arterial tree and also stimulates heart rate. 6. The cardiac output is a product of volume received by the left ventricle and the heart rate. Since the volume of left ventricle is reduced, it is compensated by the heart rate increase finally to keep the volume supplied to the brain with adequate perfusion pressure (and the whole body as well). 7. There is a cerebral autoregulation mechanism also to maintain its blood volume and pressure which kicks in. These reflexes are extremely fast. 8. In sympathetic degeneration this response is low. It leads to postural hypotension, fainting, dizziness, syncope, or light-headedness. The patients describe these symptoms in different ways [9].

4.6

Clinical Correlates of Cardiac Autonomic Neuropathy

1. It is an independent predictor of chronic kidney disease both in type 1 and 2 diabetes [10]. 2. Anemia in diabetes has many reasons. Its association with cardiac autonomic neuropathy is a surprising finding. No mechanism has been established for it. Chronic kidney disease, CKD, is associated with cardiac autonomic neuropathy. length till the Law is operative. If for any or many reasons the cardiac muscle fiber is stretched beyond that limit, the contractility will decrease. This is most easily seen in dilated cardiomyopathy or any condition which causes excessive end diastolic volume stretching the ventricle like in severe aortic or mitral regurgitation. The other factor which decides the force of contraction is the diameter of the cardiac muscle fiber and the total cardiac muscle mass available, within limits.

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It is a diabetes-specific cause.2 Cardiac autonomic neuropathy itself is associated with sex, age, smoking, body mass index, elevation of liver enzymes, hyperlipidemia, hypertension, duration of diabetes, HbA1c, retinopathy, and nephropathy [11]. 3. Hypothermic cardiac surgery increases the risk of mortality three times in the presence of cardiac autonomic neuropathy [12]. 4. Exercise is an important factor in the management of diabetes. The set criteria like target heart rate should not be applied to patients who have cardiac autonomic neuropathy. Setting up targets in such situations without doubt would require great deal of experience. The common sense advice would be to use much easier study protocols, pay close attention to the EKG changes and the severity or otherwise of the bodily symptoms which the patient is likely to develop. These can develop early. 5. Mechanical target settings will not be useful but even dangerous in this setting. A simple way is also to tell the patient that he should be able to talk comfortably while exercising. 6. This pathology must be established or ruled out before any new type of exercise is under consideration, particularly in patients who have long-standing diabetes. The common sense advice should be to limit any exercise before any discomfort is likely to start, something the patient must decide. Fatigue, reeling, exhaustion, and breathing difficulties are the guides [13].

4.6.1 O  bstructive Sleep Apnea (OSA) and Cardiac Autonomic Neuropathy 1. Obstructive sleep apnea (OSA) is more prevalent in type 1 diabetes even when these patients are likely to be younger. 2. These patients will also have higher frequencies of cardiac autonomic neuropathy. 3. Those adhering to treatment show improvement in many cardiac autonomic neuropathy parameters in type 2 diabetes [2]. Patients who used continuous positive airway pressure for OSA improve on several autonomic indicators [14]. 4. Among the undiagnosed patients or those not adhering to positive pressure treatment, the incidence and progression of cardiac autonomic neuropathy will increase. The intermittent hypoxia is thought to produce excessive quanta of reactive oxygen species and microvascular dysfunction like CAN. 5. That in turn may be the reason for higher cardiac autonomic neuropathy in OSA. 6. OSA and weaker sympathetic and parasympathetic tone were associated in patients with T2DM. 2  Anemia in diabetes with end-stage renal failure is due to lack of production of erythropoietin. However, it should be administered after assessing that the iron storage in the body is adequate and other deficiencies like B12, particularly in strict vegans corrected, to have full effect. Incidentally, folic acid supplementation also should be instituted when B12 is administered. Otherwise it will result in incomplete hemopoiesis.

4.6 Clinical Correlates of Cardiac Autonomic Neuropathy

55

4.6.2 H  ypoglycemia Unawareness and Cardiac Autonomic Neuropathy Hypoglycemia unawareness is the failure of the adrenergic symptoms to appear as hypoglycemia develops, due to sympathetic denervation. It thus fails to produce cardinal symptoms of hypoglycemia—palpitation, sweating, tremors, and hunger. Absence of these two will be strongly indicative of cardiac sympathetic denervation as well as Sudomotor dysfunction.3

4.6.3 I mpaired Glucose Tolerance (IGT) and Cardiac Autonomic Neuropathy 1. In an early stage, abnormal glucose metabolism like IGT, and autonomic dysfunction have a reciprocal role. 2. The reduced Heart Rate Variability (HRV) observed in patients with impaired glucose tolerance and/or impaired fasting glucose indicates lower parasympathetic activity and sympathetic overactivity. 3. In prediabetes and metabolic syndrome, many factors can contribute to the presence of an autonomic dysfunction, which might appear as either parasympathetic depression or predominance. 4. Sympathetic overactivity is also found in insulin-resistant condition, endogenous hyperinsulinism, driven through peripheral and central mechanisms as well as chemoreflex upregulation. It exacerbates metabolic derangements at different levels. 5. The independent correlates of autonomic indices in prediabetes are age and body mass index (BMI), waist circumference, other components of metabolic syndrome, hypertension and antihypertensive drugs, fasting and glucose estimation 2-h after glucose load, and also postprandial hyperglycemia. 6. Weight loss is likely to have favorable impact on cardiac autonomic neuropathy [15]. The multiple favorable effects of losing weight are well known and need not be repeated here. 7. There is an association of cardiac autonomic neuropathy with low vitamin B12 and vitamin D levels in T2DM as well as in T1DM. In type 2 diabetes, weight loss attempted through the use of high dose metformin leads to 30% of patients to develop B12 deficiency.

4.6.4 Diabetic Retinopathy Diabetic retinopathy follow-up over 7 years also predicted the cardiac autonomic neuropathy in more than 1000 patients [16]. Same study also showed prevention of progression of cardiac autonomic neuropathy but not that of peripheral sensory neuropathy. 3  There was a raging controversy at the time of introduction of human insulin which blamed hypogycemic unawareness on these insulins. That is no longer so. Hypoglycemia-associated autonomic failure is little different. It is the failure of adrenergic symptoms to appear although there is no autonomic neuropathy.

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4.6.5 Orthostatic Hypotension 1. Orthostatic hypotension is defined as a reduction of more than 20  mm Hg in systolic blood pressure and more than 10 mm Hg in diastolic blood pressure on standing up. Orthostatic hypotension develops much later in cardiac autonomic neuropathy syndrome [5]. The efferent sympathetic vasomotor fibers get denervated affecting the reflex arc, and an inadequate heart rate results. The peripheral arteries also under the same mechanism fail to constrict when a supine patient stands up. Peripheral vasodilation takes place [13]. 2. Symptoms include faintness, dizziness, and light-headedness, and in severe cases syncopal episodes are commonly experienced [17].

4.6.6 Other Factors Lower BMI and no exposure to selective serotonin reuptake inhibitors (SSRI) were the sole predictors of cardiac autonomic neuropathy over 2 years in a group of type 1 diabetes patients. No other clear predictive factor for the onset of cardiac autonomic neuropathy was identified [18].

4.6.7 D  CCT and Epidemiology of Diabetes Interventions and Complications (EDIC) Studies EDIC followed through the original two DCCT groups giving a mean 27 years of total follow-up. All the relevant data was obtained from 1429 (99.2%) of the original participants. The main outcomes were total and all-cause mortality. Treatment of diabetes and its comorbidities have vastly improved since DCCT days. Despite this, the benefits showed were not hugely but only marginally significant in cardiovascular mortality [19].

4.6.8 Risk Factors Within the Clinical Spectrum 1. Central obesity as a risk factor is an independent significant correlation found in much higher frequency in type 2 diabetes. This was found to be common across many different populations in Europe and USA [20]. 2. As would be expected, duration of diabetes, central obesity, age, postprandial glycemia, and diastolic blood pressure (DBP) are associations found with cardiac autonomic neuropathy in diabetes [21].

4.7 Cardiac Autonomic Neuropathy in the Pre, Intra, and Postoperative Course

57

3. Retinopathy, higher levels of microalbuminuria and albuminuria and duration of diabetes are other risk factors likely to give rise to cardiac autonomic neuropathy [22]. 4. Cardiac autonomic neuropathy in patients with type 1 diabetes is a predictor of cardiovascular morbidity and mortality. It also provides possible prognostic information for death and/or cardiac events. This prognostication is over and above the perfusion defects and indicates incremental risk. 5. Cardiac autonomic neuropathy was also associated with left ventricular systolic and particularly with diastolic dysfunction in the absence of cardiac (coronary artery) disease [23].

4.7

 ardiac Autonomic Neuropathy in the Pre, Intra, C and Postoperative Course

4.7.1 Intraoperative Mortality Patients with cardiac autonomic neuropathy have a greater risk of anesthetic-related complications in the form of varied hemodynamic response, hemodynamic instability to induction, and tracheal intubation. This may lead to intraoperative hypotension. Hypotension is considered to be the inability to respond to the use of vasodilatory anesthetic agents by developing a proper vasoconstrictor response [12].

4.7.2 Perioperative Mortality Patients with cardiac autonomic neuropathy have a two- to threefold increase in perioperative morbidity and mortality as a result of severe intraoperative hypothermia [24]. Hence all patients with diabetes should have a thorough preoperative assessment which includes some ascertainment of significant autonomic involvement. It will help reduce the occurrence of sudden unexplained deaths under anesthesia, and the patient and the relatives could be prewarned that in a particular case this is likely to happen intra- and perioperatively.

4.7.3 Mortality due to Cardiac Autonomic Neuropathy In presence of significant cardiac autonomic neuropathy, there is increased risk of hemodynamic lability, particularly with change in patient position under anesthesia, initiation of positive pressure ventilation, and institution of sympathetic blockade as in neuraxial blocks. A close monitoring is required along with meticulous maintenance of intravascular volume. Respiratory arrest is also seen in patients with autonomic neuropathy.

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4.8

4  Cardiovascular and Cerebral Dysfunction

 aboratory Diagnosis of Cardiac Autonomic L Neuropathy

4.8.1 Clinical Signs and Symptoms Cardiovascular signs are the resting tachycardia, bradycardia, exercise intolerance, orthostatic hypotension, and silent myocardial ischemia/infarction. Assessment of autonomic neuropathy, even a quick one is extremely important since it has the maximum potential to lead to the most serious complications. The probability of such untoward happening should be gauged and shared with the patients. The overt signs and symptoms of autonomic disease are as follows.

4.8.2 Laboratory Tests and Their Interpretation Tests results for Cardiovascular autonomic neuropathy (CAN) are valid if end organ failure, concomitant illness, and drugs such as antidepressants, antihistamines, diuretics, vasodilators, sympathetic blockers, and vagolytics are ruled out. Most measurable are the tests on the cardiovascular system.

4.8.3 Tests for Parasympathetic Autonomic Neuropathy In early stages abnormality of heart rate response during deep breathing alone may be manifested. In intermediate stage abnormality of Valsalva response may be seen and in late stages the presence of postural hypotension. More specific is the heart rate variability (HRV) in response to deep breathing and on standing. HRV testing methods are age-dependent but independent of the intrinsic heart rate. They are the standard screening methods for autonomic dysfunction. Valsalva maneuver is influenced by both parasympathetic and sympathetic activity.

4.8.4 Tests for Sympathetic Autonomic Neuropathy Control These consist of blood pressure response to standing or passive tilting, or during the sustained handgrip and the response to the Valsalva maneuver. In the standard Valsalva maneuver, the supine patient, connected to an ECG monitor and the blood pressure apparatus, forcibly exhales for 15 s against a fixed resistance (40  mm Hg) with an open glottis. This results in a sudden transient increase in intrathoracic and intraabdominal pressure, with a characteristic hemodynamic response which can be described as phases. In Phase I, there is a transient rise in blood pressure and a fall in heart rate due to compression of the aorta and propulsion of blood into the peripheral circulation. These hemodynamic changes are due to mechanical factors. In Phase II, there is an initial fall in blood pressure followed by the recovery of blood pressure later in the phase. The blood pressure changes are accompanied by

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an increase in heart rate. There is a fall in cardiac output due to decreased venous return which causes reflex tachycardia and increased peripheral resistance. In Phase III, there is a drop in blood pressure and rise in heart rate when expiration is stopped. In Phase IV, there is an overshoot of blood pressure above the baseline value due to residual vasoconstriction in a setting of a normal venous return and cardiac output. There is a reflex bradycardia. The Valsalva ratio is calculated from the ECG waveform by dividing the longest R–R interval after the maneuver (in Phase IV) to the shortest R–R interval during the maneuver. A Valsalva ratio less than 1.2 is abnormal.

4.8.5 Heart Rate Variability (HRV) HRV is the difference between the maximum and minimum heart rate during the respiratory cycle. Respiratory sinus arrhythmia (RSA) is normal and physiological due to vagal input to sinus node during expiration causing reduction in heart rate. Autonomic neuropathy decreases the HRV.  Specialized monitors are available to accurately determine the HRV.  A clinical but less accurate method is to ask the patient to breathe quietly and deeply at a rate of six breaths per minute. At this rate, there is maximum variation in heart rate. Normal variability is more than 15  beats/min; abnormal result is less than 10 beats/min. Aging is associated with decreased RSA due to decreased vagal tone and decreased beta receptor responsiveness and the criteria may not apply to patients above 60 years of age.

4.8.6 Response to Standing Up (30:15 ratio) There is a rapid increase in heart rate in response to standing that is maximal at approximately the 15th beat after standing. This is followed by a relative bradycardia that is maximal at approximately the 30th beat after standing. The heart rate should increase by 10%. 30:15 ratios are measured as the longest R–R interval during beats 20–40, divided by the shortest R–R interval during beats 5–25. In patients with cardiac autonomic neuropathy, there is only a gradual increase in heart rate. A 30:15 ratio more than 1.04 is normal, 1.01–1.03 is borderline, and less than 1.01 is abnormal.

4.8.7 Orthostatic Hypotension It is defined as a fall of more than 20/30 mm Hg in for systolic blood pressure (SBP) or more than 10 mm Hg for diastolic blood pressure in response to postural change, from supine to standing. Normally, blood pressure is rapidly corrected by baroreflex-­ mediated peripheral vasoconstriction and tachycardia. The fall in SBP is less than

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10 mm Hg in normal state. A drop by 11–29 mm Hg is border line and a drop of more than 30 mm Hg is significant. Response to tilting is a more precise stimulus and may be used instead of standing. The response is similar.

4.8.8 Sustained Hand Grip Sustained muscle contraction causes a rise in systolic and diastolic blood pressure and heart rate. Exercising muscles stimulate a reflex arc resulting in increased cardiac output and heart rate. As the peripheral vascular resistance is maintained, the diastolic pressure rises by more than 16 mm Hg. A response of less than 10 mm Hg is considered abnormal.

4.8.9 T  he differential diagnosis of cardiac autonomic neuropathy (CAN) It should try to establish which of the conditions listed below could be partly or fully responsible for the test results of cardiac autonomic neuropathy. 1 . Pure autonomic failure (idiopathic orthostatic hypotension) 2. Multiple system atrophy with autonomic failure (Shy-Drager syndrome) 3. Addison’s disease, hypothyroidism, and hypopituitarism 4. Pheochromocytoma, hyperthyroidism 5. Hypovolemia 6. Medications with anticholinergic or sympatholytic effects (vasodilators, sympathetic blockers) 7. Peripheral autonomic neuropathies (e.g., amyloid neuropathy and idiopathic autonomic neuropathy)

4.8.10 Electrocardiogram in Cardiac Autonomic Neuropathy: QT Prolongation An electrocardiogram is a routine examination in diabetes. Attention should be provided in particular to see if there is QT prolongation. There are many causes for QT prolongation outside diabetes. But it is associated with cardiac arrhythmias and sudden death in diabetes. The mechanism leading to the prolongation and death is the disequilibrium in cardiac sympathetic innervation and left ventricular hypertrophy. The latter is also easily visible in an electrocardiogram [9]. The perceived mechanisms include, in addition to left ventricular hypertrophy, increased oxidative stress, altered substrate utilization, and mitochondrial dysfunction as responsible for QT prolongation in diabetes [25]. The combination of

4.9 Autoregulation of Cerebral Blood Flow

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sympathetic predominance (that is resting tachycardia) and autonomic myocardial denervation leads to reduced coronary blood flow. It leads to diastolic and eventually systolic dysfunction [26, 27].

4.9

Autoregulation of Cerebral Blood Flow

People with diabetes and many other disorders coming with concussive injury is not a rarity in practice. These patients are already likely to have autonomic nervous system abnormalities. These may get aggravated in concussion and remain operative long after it. In emergency department, the prevalence of persisting symptoms at 6  months or more ranges from about 30 to 50%. Autonomic nervous system works in concert with the hypothalamic–pituitary–adrenal axis and has intricate feedback loops with other body systems such as the immune system, which may be already compromised in diabetes [28]. Cerebral autoregulation could be of importance in such cases as also in diabetes.

4.9.1 Maintenance of Normal Cerebral Perfusion Pressure The carotid baroreceptor reflexes provide input regarding carotid blood pressure to the nucleus of the solitary tract in the brain stem, nucleus ambiguus, the dorsal motor nucleus, and the caudal and rostral, ventro-lateral medulla oblongata. When pressure in the carotid arteries changes, signals from the brain are sent through parasympathetic and sympathetic autonomic nervous system pathways to the sinoatrial node in the right atrium. In response, the vasculature changes the appropriate blood pressure to increased or lowered levels for restoration, which is achieved by varying the vascular resistance, heart rate, and contractility in the appropriate direction. Sympathetic overtone increases the vascular resistance by vasoconstriction, and parasympathetic overtone will cause vasodilation. It affects the rest of the body and the cerebral circulation as well [28].

4.9.2 C  hanges in the Regulation of Cerebral Circulation and Blood Pressure Cerebral circulation is not uniform. More active networks get higher blood supply as the oxygen demand increases; the level of localized circulating carbon dioxide increases and changes in neural capillary diameter are brought about by the pericytes. The main surface cerebral cortical arteries have an extrinsic autonomic supply to respond to. The arterioles embedded in the cerebral cortex have their own intrinsic autonomous nerve supply. This can respond in tandem with the response of the surface arteries or can vary it depending upon the activity level within the local circulation. In case of higher activity in a local neuronal network, the intrinsic arterioles will dilate to supply more blood

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wherein the relatively inactive neural networks will contract and deliver less blood volume. The cerebral arteries embedding in the brain parenchyma have the intrinsic innervation which supplies locus ceruleans, raphe nucleus, basal forebrain, and thalamus. These are the core CNS networks which control the autonomic nervous system maintaining appropriate blood pressure and perfusion [28]. The normal mechanisms get affected and result in dysregulation of the autonomic nervous system control. Chronic pain, stress, depression, chronic fatigue syndrome, fibromyalgia, cervical strain/whiplash-associated disorders, headaches, memory dysfunction, attention span, brain fog, anxiety, insomnia, and nausea are conditions in which cerebral perfusion and baroreceptor reflex efficiency and cerebral blood flow are likely to get affected. Autonomic anomalies are more apparent during exercise after concussive injuries. The common anomaly is reduced parasympathetic nervous system involvement in concussed groups. In dealing with postconcussional injuries, the distinction between the psychic overlay and physical injuries is not easy to make. Presence of disorders like diabetes may have caused depression and other states which must be teased out and therapy made more accurate. The modification of drug regimes which already interfere with autonomic nervous system must be kept in mind.

4.10 P  rofiling Clinical Autonomic Symptom Profile: Questionable Questionnaires Autonomic neuropathy in diabetes has a large spectrum which can be divided into orthostatic intolerance, vasomotor, secretomotor, gastrointestinal, bladder, and pupillomotor autonomic neuropathy. Not all cases will need each and every question to be answered to make more definitive diagnosis. Covering all domains initially led to tabulation of 169 questions with redundancy, and excessive time was consumed to get the answers. A standardized way which withstands the rigor of statistical analysis shows fair diagnostic accuracy for small fiber polyneuropathy, and excellent internal validity was obviously desirable. The next questionnaire of 89 questions was also put aside and a COMPASS 31 was designed which withstands all criteria mentioned above. It is reliable to study small fiber neuropathy with it [29]. Basically it is a research tool and has been used in conditions like multiple sclerosis also. Nerve growth factor (NGF) is now characterized. The sympathetic nervous system is dependent on the presence and adequacy of NGF for its maintenance. NGF is vitally important for maintenance of dendrites, the short neural fibers which connect neuronal networks in hundreds and thousands in extremely small areas of the clusters. NGF is also important for this arborization. Synaptic connections between preganglionic and postganglionic sympathetic neurons also depend on NGF. If NGF is blocked chemically, there is a reduction in preganglionic transmission and synaptic function. In conclusion, detection and as best management as can be offered to patients with cardiac autonomic neuropathy is what the doctors can give to protect her from catastrophic events.

References

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References 1. Spallone V.  Update on the impact, diagnosis and management of cardiovascular autonomic neuropathy in diabetes: what is defined, what is new, and what is unmet. Diabetes Metab J. 2019;43:3–30. http://e-dmj.org. 2. Fisher VL, Tahrani AA. Cardiac autonomic neuropathy in patients with diabetes mellitus: current perspectives. Diabetes Metab Syndr Obes. 2017;10:419–34. 3. Kempler P, Tesfaye S, Chaturvedi N, Stevens LK, Webb DJ, Eaton S, Kerenyi Z, Tamas G, Ward JD, Fuller JH. Autonomic neuropathy is associated with increased cardiovascular risk factors: the EURODIAB IDDM Complications Study. Diabet Med. 2002;19:900–9. PubMed: 12421426. 4. Ernsberger U, Rohrer H. Sympathetic tales: sub divisions of the autonomic nervous system and the impact of developmental studies. Neural Dev. 2018;13:20. https://doi.org/10.1186/ s13064-018-0117-6. 5. Vinik AI, Freeman R, Erbas T.  Diabetic autonomic neuropathy. Semin Neurol. 2003;23(4):365–72. 6. Dimitropoulos G, Tahrani AA, Stevens MJ.  Cardiac autonomic neuropathy in patients with diabetes mellitus. World J Diabetes. 2014;5(1):17–39. 7. Chung T, Prasad K, Lloyd TE. Peripheral neuropathy: clinical and electrophysiological considerations. Neuroimaging Clin N Am. 2014;24(1):49–65. 8. Albers JW, Pop-Busui R. Diabetic neuropathy: mechanisms, emerging treatments, and subtypes. Curr Neurol Neurosci Rep. 2014;14(8):473. 9. Ninkovic VM, Ninkovic SM, Miloradovic V, et al. Prevalence and risk factors for prolonged QT interval and QT dispersion in patients with type 2 diabetes. Acta Diabetol. 2016;53(5):737–44. 10. Tahrani AA, Dubb K, Raymond NT, et al. Cardiac autonomic neuropathy predicts renal function decline in patients with type 2 diabetes: a cohort study. Diabetologia. 2014;57(6):1249–56. 11. Chung JO, Park SY, Cho DH, Chung DJ, Chung MY. Anemia, bilirubin, and cardiovascular autonomic neuropathy in patients with type 2 diabetes. Medicine (Baltimore). 2017;96(15):e6586. 12. Oakley I, Emond L.  Diabetic cardiac autonomic neuropathy and anesthetic management: review of the literature. AANA J. 2011;79(6):473–9. 13. Vinik AI, Ziegler D.  Diabetic cardiovascular autonomic neuropathy. Circulation. 2007;115(3):387–97. 14. Stevens M, Ali A, Dubb K, Begum S, Piya M, Tahrani A.  Obstructive sleep apnea is associated with cardiac autonomic abnormalities in patients with type 2 diabetes. Diabet Med. 2014;31:37. https://insights.ovid.com/diabetic-medicine/diame/2014/03/001/obstructivesleep-apnea-associated-cardiac/110/00003135. Accessed 21 Sept 2017. 15. Maser RE, Lenhard MJ.  Cardiovascular autonomic neuropathy due to diabetes mellitus: clinical manifestations, consequences, and treatment. J Clin Endocrinol Metab. 2005;90(10): 5896–903. 16. Gæde P, Oellgaard J, Carstensen B, et al. Years of life gained by multifactorial intervention in patients with type 2 diabetes mellitus and microalbuminuria: 21 years follow-up on the Steno-2 randomized trial. Diabetologia. 2016;59(11):2298–307. 17. Pop-Busui R. What do we know and we do not know about cardiovascular autonomic neuropathy in diabetes. J Cardiovasc Transl Res. 2012;5(4):463–78. 18. Matta M, Pavy-Le Traon A, Perez-Lloret S, Laporte C, Berdugo I, Nasr N, Hanaire H, Senard JM.  Predictors of cardiovascular autonomic neuropathy onset and progression in a cohort of type 1 diabetic patients. J Diabetes Res. 2018;2018:5601351. https://doi. org/10.1155/2018/5601351. 19. Wright EE Jr. Results of the epidemiology of diabetes interventions and complications trial. Clin Diabetes. 2015;33(3):144–5. PMCID: PMC4503938 PMID: 26203207. 20. Dimova R, Tankova T, Guergueltcheva V, et  al. Risk factors for autonomic and somatic nerve dysfunction in different stages of glucose tolerance. J Diabetes Complicat. 2017;31(3): 537–43.

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21. Valensi P, Pariès J, Attali JR.  Cardiac autonomic neuropathy in diabetic patients: influence of diabetes duration, obesity, and microangiopathic complications—the French multicenter study. Metabolism. 2003;52(7):815–20. 22. Ko SH, Park SA, Cho JH, et  al. Progression of cardiovascular autonomic dysfunction in patients with type 2 diabetes: a 7-year follow-up study. Diabetes Care. 2008;31(9):1832–6. 23. Spallone V, Ziegler D, Freeman R, Bernardi L, Frontoni S, Pop-Busui R, Stevens M, Kempler P, Hilsted J, Tesfay S, Low P, Valensi P.  Cardiovascular autonomic neuropathy in diabetes: clinical impact, assessment, diagnosis, and management. Diabetes Metab Res Rev. 2011;27:639–53. 24. Latson TW, Ashmore TH, Reinhart DJ, Klein KW, Giesecke AH. Autonomic reflex dysfunction in patients presenting for elective surgery is associated with hypotension after anesthesia induction. Anesthesiology. 1994;80(2):326–37. 25. Boudina S, Abel ED. Diabetic cardiomyopathy, causes and effects. Rev Endocr Metab Disord. 2010;11(1):31–9. 26. Balcıoğlu AS, Müderrisoğlu H.  Diabetes and cardiac autonomic neuropathy: clinical manifestations, cardiovascular consequences, diagnosis and treatment. World J Diabetes. 2015;6(1):80–91. 27. Vinik AI, Erbas T. Diabetic autonomic neuropathy. Handb Clin Neurol. 2013;117:279–94. 28. Pertaba JL, Merkleyb TL, Cramondc AJ, Cramondc K, Paxtone H, Wue T. Concussion and the autonomic nervous system: an introduction to the field and the results of a systematic review. NeuroRehabilitation. 2018;42:397–427. https://doi.org/10.3233/NRE-172298IOSPress. 29. Greco C, Di Gennaro F, D’Amato C, Morganti R, Corradini D, Sun A, Longo S, Lauro D, Pierangeli G, Cortelli P, Spallone V. Validation of the composite autonomic symptom score 31 (COMPASS 31) for the assessment of symptoms of autonomic neuropathy in people with diabetes. Diabet Med. 2017;34:834–8. https://doi.org/10.1111/dme.13310.

5

Gastrointestinal and Urinary Dysfunction

5.1

Introduction

Gastrointestinal (GI) autonomic neuropathy like other autonomic neuropathies by common consensus is also grossly underdiagnosed in diabetes. Nonspecific symptomatology and delayed clinical appreciation of the same are the most important factors among other likely ones. The diagnostics available is sparse, costly, and not always without some variation in its undertaking. As a result, no satisfactory explanation of symptoms is given by the physicians. That is likely to result in unfocused haphazard investigation and drug treatment which resolves neither the issue nor the diagnostic dilemma. The symptoms arising from diabetes are troublesome and disrupt the quality of life of a patient.

5.1.1 Correlations of Autonomic Neuropathy The survival rate among those who develop autonomic neuropathies is believed to be as low as 47% in 5 years [1]. Diabetes management has improved vastly since 1980 or 1990, but increasing life expectancy even within diabetes and gross effects of life style changes will counterbalance each other, and the net effect today also may not be significantly different. Autonomic neuropathy generally coexists with peripheral neuropathy [2]. Charcot’s osteoarthropathy is a classic example of this coexistence. Unapparent autonomic neuropathy may develop within 1 year in type 2 and 2 years in type 1 diabetes [3].

5.1.2 Prevalence of Diabetic Autonomic GI Neuropathies The prevalence of various kinds of organ affliction will vary a great deal from population to population. The overall imprecision of symptomatic and diagnostic correlations of laboratory findings, widely differing glycemic control issues, food habits, © Springer Nature Singapore Pte Ltd. 2020 S. Kelkar, Diabetic Neuropathy and Clinical Practice, https://doi.org/10.1007/978-981-15-2417-2_5

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and life styles of people with GI neuropathies, will make epidemiological details more an academic exercise and part of discipline when such a topic is discussed in detail. However, diabetes is not the only reason for this. Hence a small description of it is given below to widen the scope of diagnosis even in the absence of diabetes but with suggestive symptoms which are always central to any management of an autonomic syndrome. About one-third of patients with gastroparesis will have diabetes [4]. In USA, an estimated five million patients suffer from some form of gastroparesis; the female:male ratio is 4:1 [5, 6]. While gastroparesis has multiple etiologies, in a large single-center study of 146 gastroparesis patients, 29% were found to have diabetes, 13% developed symptoms after gastric surgery, and 36% were idiopathic [7]. Even then little is known about the epidemiology of diabetic gastroparesis, in part because the weak association between symptoms and objective studies of gastric emptying confounds diagnosis.

5.2

 rganization and Function of the Enteric Nervous O System (ENS)

5.2.1 Autonomic Innervation of the Digestive Tract GI tract receives both sympathetic and parasympathetic innervation with a considerable control from the cerebral cortex as well. All sympathetic neurons are divided as norepinephrine 1 to 5 and act upon different tissues and organs. The cervical and thoracic sympathetic system acts upon the duodenum and jejunum. The effecter fibers run through the vagus nerve. Neurons from the celiac ganglia and the splanchnic nerves act upon the upper intestines. Lumbar sympathetic nervous system through the mesenteric ganglia acts upon the colon via postganglionic neurons in colonic nerves. Autonomic neurons from the sacral spinal cord also innervate the more distal parts of the colon. The preganglionic axons form a bundle and segregate from the ventral spinal roots as a white branch and innervate the paravertebral sympathetic chain and synapse on postganglionic neurons. The postganglionic sympathetic neurons innervating abdominal viscera are located in the paravertebral chain of ganglia and the superior hypogastric plexus, and in the pelvic ganglions. The pelvic ganglion or plexus has a dual composition with both the presence of large numbers of cholinergic, which are parasympathetic nerves, and in addition noradrenergic neurons, the sympathetic nerves.

5.2.2 A  utonomic Innervation and Reflexes of Gastrointestinal Tract The uppermost part of the gastrointestinal tract and the rectum are controlled principally by autonomic reflexes. For instance, the smell of appetizing food or the presence of food in the mouth initiates signals from the nose and mouth to the vagal,

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glossopharyngeal, and salivatory nuclei of the brain stem. These in turn transmit signals through the parasympathetic nerves to the secretory glands of the mouth and stomach, causing secretion of digestive juices sometimes even before food enters the mouth. When fecal matter distends the rectum, sensory impulses initiated by stretching are sent to the sacral portion of the spinal cord, and a reflex signal is transmitted back through the sacral parasympathetics to the distal parts of the colon; these result in strong peristaltic contractions that cause defecation. Sympathetic system controls and constricts the various sphincters of the gastrointestinal tract and decreases the peristaltic action and relaxes the lumen. Parasympathetics increase the tone of the walls of the lumen, the anterograde peristalsis, propulsion of food, and the secretory function of various gastrointestinal glands and may reduce the sphincteric tone.

5.2.3 Non-spinal Reflex Pathways Many of the sympathetic reflexes that control gastrointestinal functions operate by way of nerve pathways that do not even enter the spinal cord, merely passing from the gut mainly to the paravertebral ganglia, and then back to the gut through sympathetic nerves to control motor or secretory activity.

5.3

I ntramural Nerve Plexuses of the Gastrointestinal System

The autonomic nervous system in GI tract consists of the enteric nervous system and both the sympathetic (SNS) and parasympathetic nervous systems (PNS). Normal function of the gastrointestinal tract is not greatly dependent on external sympathetic nerve stimulation. The gastrointestinal system has its own intrinsic set of nerves known as the intramural plexus or the intestinal enteric nervous system, located in the walls of the gut. Both parasympathetic and sympathetic stimulation originating in the brain can affect gastrointestinal activity mainly by increasing or decreasing specific actions in the gastrointestinal intramural plexus. The enteric nervous system (ENS) under the diabetic state could undergo remodeling. There could be a loss in the excitatory and inhibitory neurons of the enteric nerves or an imbalance therein in diabetes. Neuropeptides that serve the sensory function may get reduced [8]. ENS is a complex network of neurons and enteric glial cells (EGCs). It is embedded in the wall of the GI tract. The myenteric plexus is situated between the circular and longitudinal muscle layers and influences GI motility. The sub-mucosal plexus is in close proximity to the muscularis mucosa, intrinsic vasculature, and the mucosa [9]. It regulates the secretion of hormones and neurotransmitters. The two systems are connected by interneurons. In addition, local sensory neurons called intrinsic primary afferent neurons (IPANs) also regulate motility and maintain homeostasis. The ENS also receives signals from the efferents of the central nervous system via sympathetic and

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parasympathetic autonomic pathways which also contribute and supplement regulations and coordination of GI function. But the dependence of ENS or IPAN systems on these is limited [10]. The interstitial cells of Cajal (ICCs) are not neuronal. These cells generate and convey electrical impulses to smooth muscle cells facilitating the slow wave peristaltic movement of the stomach and intestines. These are referred to as “pacemaker” cells of the GI tract [11]. The ENS thus comprises of three pan-enteric adjacent networks—neurons, EGCs, and ICCs. The detailed role of EGCs is discussed below. Both enteric neurons and EGCs are particularly vulnerable to hyperglycemia. Although the majority of enteric afferent axons are confined to the gut wall, a large amount of sensory neurons from the CNS following either vagal or spinal routes have wide distribution in different layers of the GI wall and monitor GI homeostasis [12]. Approximately 80–85% of the nerve fibers in the vagus nerve are afferent and project from the viscera to the vagus nucleus [13].

5.4

Diabetic Enteropathy: Pathogenesis

The pathogenesis of diabetic neuropathy overall is discussed separately in extensor in this volume. The section below concerns itself with some specific issues of pathogenesis related to the GI tract autonomic neuropathy. Diabetes changes the tissue-level environment in the ENS quite considerably. Hyperglycemia, oxidative stress, neuro-inflammation, reduced levels of nerve growth factors, and structural vascular changes are caused by diabetes [14–16].

5.4.1 Hyperglycemia and Intracellular Biochemical Changes Hyperglycemia in diabetes causes up to fourfold increase in glucose levels. Persistent or repetitive hyperglycemia changes the intracellular glucose metabolism causing neuronal damage, the “glucose neurotoxicity” in the peripheral and central nervous systems [17]. The same mechanisms are present in the enteric nervous system. Enteric neurons like other neurons need high glucose supply at all times. It comes from the extracellular glucose concentration and facilitated diffusion, mediated primarily by glucose transporter 3 (GLUT3).

5.4.2 D  iabetes-Induced Marked Structural Remodeling of GI Tract Wall Different populations of neurons have different susceptibility levels to oxidative stress. That result in different neurological responses. The extrinsic sympathetic supply, via celiac and superior mesenteric ganglia to the ENS, is more sensitive [18]. All processes described in the pathogenesis of neuropathy in the earlier

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chapter also affect the ENS the same way. There is a reduction in the quantity of colonic ENS, assessed by total ganglion content in patients with diabetes and healthy controls [19]. Diabetes also affects large fiber neurons in the dorsal root ganglion and inhibitory neurons in the gut wall preferentially. Selective loss of nitric oxide synthase and loss of inhibitory neurons that express neuropeptide Y have been found in diabetic colon. ICCs are the pacemakers of the gastrointestinal tract motility. These generate the slow peristaltic wave in the gut. The frequency of spontaneous muscular contractions is reduced [19]. IPANs are also vulnerable to chronic hyperglycemia. Degeneration and/or loss of ICCs throughout the GI tract are found in diabetes patients [20, 21]. Finally, smooth muscle myopathy and loss of ICCs also result [22]. Angiopathy is considered a contributing factor in the development of diabetic enteropathy. All these changes alter the overall motility, coordination, and GI homeostasis function of the GI tract [15].

5.4.3 Role of Entero Glial Cells (EGCs) EGCs provide neurotrophic support to ENS, mediate interactions between enteric neurons and other cell types. EGCs communicate with immune cells, entero-­ endocrine cells, epithelial cells, and blood vessels. This specialized circuit controls and integrates signals to and from neurons to other cells [23]. EGCs has immunosuppressive and anti-inflammatory effects that protect the ENS against intraluminal foreign antigens. In diabetes, the loss of EGCs throughout the GI tract influences GI functions directly. The neuro-supportive factors secreted by the EGCs also decline. The differentiation and migration of enteric neurons, their survival, and protection against hyperglycemia are mediated by neurotrophic factor. The loss of EGCs leads to neuronal neglect and apoptosis in the diabetic ENS. Innate autoimmunity in gastric parietal cells has been speculated to occur in patients with type 1 diabetics with diabetic gastroparesis [24]. Clock genes have been implicated in certain GI motility disorders, including gastroparesis, due to variations in circadian rhythm [25].

5.5

 utonomic Nervous System Disturbances A in Gastrointestinal Tract

5.5.1 Parasympathetic Nervous System and the Gut Parasympathetic stimulation, in general, increases peristalsis and relaxes the sphincters of the gastrointestinal tract facilitating rapid propulsion of contents along the tract. With propulsion, there is a simultaneous increase in secretion by many of the gastrointestinal glands. The background “tone” of the parasympathetics in the gastrointestinal tract is normally more important for the gut.

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Surgical removal of the parasympathetic supply to most of the gut by cutting the vagus nerves can cause serious and prolonged gastric and intestinal atony, with resulting considerable decrease in the normal gastrointestinal propulsion. It consequently leads to serious constipation. This tone can be decreased by the brain, thereby inhibiting gastrointestinal motility, or it can be increased, thereby promoting increased gastrointestinal activity. The motor nerves of gastrointestinal tract come mainly from vagus. Parasympathetic degeneration leads to gastroparesis which is suspected if there is complaint of postprandial fullness or bloating. However presence of gastroparesis weakly correlates with upper GI autonomic symptoms (nausea, vomiting, early satiety, postprandial fullness, bloating, and abdominal pain), which are very common in T1DM and T2DM patients. Hence clinical suspicion is the only way to detect it early. Changes in gastric emptying lead to unpredictable delivery of nutrition, glucose, as well as oral drugs in the small bowel. Thus, both chronic gastroparesis and unstable control affect each other in a vicious cycle.

5.5.2 C  linical Features and Effects of Accelerated/Rapid Gastric Emptying Rapid gastric emptying of solids and/or liquids with features of dumping syndrome and diarrhea is fairly frequent in diabetes. These must be recognized due to the hemodynamic and glycemic instabilities caused by it. Other causes for rapid or accelerated gastric emptying are after the surgery of fundal plication, gastric post-­ bariatric surgeries, functional diarrhea, functional dyspepsia, autonomic dysfunction, and even short duration of type 2 diabetes [26]. Such patients will have poor glycemic stability. Initially the rapid emptying will cause increased absorption of the gastric content raising the glucose levels, and later the rate of absorption will suddenly reduce causing hypoglycemia, at least hypoglycemia like symptoms. The postprandial symptoms like abdominal discomfort and nausea with or without vomiting are also found in gastroparesis. However, weight loss is more common in gastroparetic patients [27]. Severe and prolonged diabetic gastroparesis and undernutrition go hand in hand leading to micronutrients, minerals, possibly vitamin B12 deficiency, vitamin D deficiency, and low bone mass; the endocrine consequences of malnutrition are hypogonadism and amenorrhea [28].

5.5.3 C  linical Effects of Disturbances in Sympathetic Innervation on Gut Strong sympathetic stimulation inhibits peristalsis and increases the tone of the sphincters slowing the progression of food through the intestines. Sometimes even the secretion of the intestinal glands decreases. It leads to constipation and sometimes even to obstipation—constipation with stoppage of even the gas escape.

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Nausea and vomiting in sympathetic degeneration of the GI tract are also common symptoms of coronary artery disease with cardiac sympathetic denervation. These two pathologies can well coexist. Hence oversimplification for making a hasty diagnosis of acid peptic disease or reflux esophagitis or unduly over suspicious interpretation and diagnosis of cardiac vascular disease and unstable/acute coronary syndrome are better avoided. The overall clinical setting, short therapeutic trial of one after the other would be a judicious approach. The devastating effects of sympathetic overdrive due to parasympathetic degeneration are described under cardiac autonomic neuropathy elsewhere. Such an overdrive should be treated with care as is described in the treatment of cardiovascular autonomic neuropathy elsewhere.

5.5.4 Main GI Effects 5.5.4.1 Gastroparesis Impairment of nitrergic-mediated gastric accommodation due to vagal dysfunction in diabetes mellitus predisposes to higher gastric pressures and rapid gastric emptying of liquids. Parasympathetic autonomic neuropathy alters the tone of the stomach, increases tone of the pyloric sphincter and causes gastroparesis. If the gastroesophageal sphincter tone gets reduced due to sympathetic degeneration and if food remains in the stomach even after 8 h of fasting due to gastroparesis it raises the risk of aspiration due to regurgitation, especially if general anesthesia is given. Hence gastroparesis wherever possible should either be confirmed or ruled out preoperatively; it is highly advisable to prevent aspiration. To make a diagnosis of gastroparesis two criteria are used. The food must remain in the stomach for after 8–12 h fast, and the pyloric sphincter should not be obstructing the propulsion of the food. Routine 8 h fasting thus may not be sufficient prior to anesthesia in patients with gastroparesis. The irregular and often delayed emptying of the stomach could lead to hypoglycemia, and/or uneven levels of blood glucose. Conversely the uneven glucose control in its turn may also lead to short-time disturbances in GI functions [29]. 5.5.4.2 Swallowing Reflex The ability to coordinate swallowing is also decreased since that mechanism is largely controlled by the extrinsic autonomic nerve supply. Sympathetic autonomic neuropathy alters the tone of the gastroesophageal sphincter. This is likely to cause esophageal reflux disease more often since diabetes is a signal cause of autonomic neuropathy and is widely prevalent. 5.5.4.3 Diarrhea If sympathetics degenerate, leading to parasympathetic overtone, it will cause diarrhea and fecal incontinence. Diarrhea will be often nocturnal, explosive, and watery with no signs of infection causing it. This sequence of diarrhea and (after) constipation is a common indicator sign of GI malignancies also. In GI malignancies, the fecal output is likely to be putrid as it follows a certain obstructed time which is not the case of diabetic diarrhea. This should be kept in mind.

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5.5.4.4 Constipation and Obstipation Sympathetic innervation also maintains a sufficient tone in the anal sphincter to prevent fecal incontinence. In general in diabetes, parasympathetic degeneration precedes the sympathetic degeneration. As a result, the food propulsion is affected much more. The anal sphincter remains constricted due to unaffected and now unopposed sympathetic “tone” leading to constipation and delayed transit times. Constipation and at times obstipation could resemble subacute intestinal obstruction. 5.5.4.5 Gall Bladder Atony Gall bladder atony will lead to delayed gallbladder emptying disturbing the normal digestive processes. The autonomic innervation of pancreas is facilitatory to pancreatic secretions. The loss of autonomic control as in pancreatic transplant will affect it and disturb the normal digestive processes.

5.6

Laboratory Diagnosis of GI Autonomous Disorders

5.6.1 Preconditions Acute changes in glycemic fluxes in its turn can produce transient changes in the GI autonomic nervous system. Therefore, it is routinely advised to get as stable control of glycemia as possible. Any drugs that may influence gastric motility should be withdrawn for 48–72 h for obvious erroneous results that may emanate. Nicotine use during the test period which can be as long as 72 h (see below) is also prohibited for similar reasons.

5.6.2 D  iagnosis of Gastroparesis, Intestinal, and Colonic Abnormalities The simplest and widely available test for gastroparesis is a standing X-ray of the abdomen. But no one thinks of that. The profession is intimately familiar with different standard forms of stomach in such an X-ray to at least raise a strong enough evidence in support of diagnosis.1 Instead, expensive tests that are not available routinely, located far away, may be advised if at all a suspicion is there. 1  Even otherwise, standing abdomen X-ray is a test vanishing from clinical practice in India like many other simple investigations. Aside of perforation in stomach or gastroparesis, subacute or acute obstruction is so easily diagnosable. Subacute variety can be seen in diabetes and making a sound diagnosis taking a total clinical situation in account. It can save a lot of inconvenience, money, make a quick, correct diagnosis and achieve ease of treatment.

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5.6.3 S  cintigraphy in Gastroparesis, Intestinal, and Colonic Transit Time The gold standard here is the gastric emptying time measured 2 or 4 h after feeding a standardized meal of 99mTc­sulfur colloid containing eggs by a gamma camera. Gastroparesis is diagnosed if more than 60% of the isotope activity remains in the stomach at 2 h after the standard meal is taken. If at least 10% of the initial activity is still detected 4  h after the standard meal, gastroparesis is then confirmed [30, 31]. Scintigraphic small bowel and colonic motility measures the transit time as an extension to gastric emptying. If less than 40% of the total isotope accumulates at the ileo-cecal junction in 6 h, the intestinal transit time is considered delayed. To assess colonic transit, gamma camera takes colonic images at 24, 48, and 72 h after the radiolabeled meal. Colonic transit time is considered delayed if the activity is not detected adequately after 72 h.

5.6.4 Disadvantages of Scintigraphy It is relatively expensive and is also associated with radiation exposure and still not standardized across centers. Since the scintigraphic burden is considerable, it should not be performed in children and women in childbearing age.

5.6.5 Radiopaque Markers for GI Motility Alternatively a nondigestible radiopaque markers (ROM) can be swallowed with a nonradioactive standardized meal with fixed fat and protein content. Hourly X-ray or fluoroscopic imaging may be done applying similar criteria as the scintigraphy for 6 h or till the ROM is emptied. It is quite specific but less sensitive. ROM is a useful and reasonable “screening test” for delayed gastric emptying. Even then normal ROM test does not necessarily exclude delayed gastric emptying. If the clinical suspicion of gastroparesis continues even after a normal ROM transit, scintigraphy should be undertaken. ROM is not useful for colonic transit time due to considerable lack of standardization. It is inexpensive and is available in western societies [32].

5.6.6 Gastric Emptying Breath Testing Nonradioactive Carbon13 as octanoic acid is mixed with a safe ingestible food or with liquid products. As the meal gets absorbed, the 13-octanoic acid is metabolized in intestine and C13O2 is formed, absorbed, and expired in breath. The

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rate-limiting factor here is the gastric emptying time. If an adequate quantity of C13O2 is not detected in breath at a standard interval, it indicates delayed gastric emptying time. Several advantages this test has are as follows: 1. It correlates well with radioactive substance using scintigraphy, the gold standard test. 2. It saves the exposure to ionizing radiation hence can be given to anyone. 3. It is inexpensive, with little equipment needed and easy to perform. 4. It can be conducted as an office test. 5. It is noninvasive [33].

5.6.7 Wireless Motility Capsule for GI Motility Studies It is an indigestible, wireless, single-use capsule transmitting signals. After an overnight fast, a standardized meal of known fat and calorific content is given to the patient. It stimulates the gut motility just like a usual meal will and the capsule is swallowed immediately after. The patient is given a wearable receiver with analysis software for the duration of the test before leaving. The software detects the transmissions from the capsule [34]. The capsule records the pH, pressure, and temperature as it passes through the GI tract. An abrupt pH change is detectable as it goes from the acidic environment of the stomach (pH 4.5) to the alkaline medium of the duodenum (pH 8.3.) The time taken for it after the time of swallowing the capsule and time noted at the pH change is the time for gastric emptying. As the capsule comes in to the ileocecal region, pH being recorded decreases by 1 pH unit. The time taken after entering duodenum to reaching ileocecal junction is the intestinal transit time. From this point till the capsule is excreted is the colonic transit time. The total gut transit time is considered delayed if the capsule remains in the body for more than 73 h [35]. The test is a little cumbersome because the patient has to carry the recorder. But it is a standardized office procedure. The test uses a physiologic meal, but if food taken by the patients and the time period to swallow the capsule is variable gastric emptying time may vary. The pressures recorded are moveable single point measurements all along the GI tract [36, 37].

5.6.8 Transit Time Detection and Diagnosis In one study in patients with GI symptoms, 65% had prolonged gastric emptying, 24% had prolonged small intestinal transit time, and 58% had prolonged colon transit time [38]. In adults with diabetes and sensorimotor neuropathy, 44% had abnormal transit in one or more GI segments. These findings did not correspond to the symptomatology [39].

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It is well known that many factors vary the transit times in stomach, small intestine, and the colon. Not only that but there is not necessarily any correspondence with each other. Gastroparesis thus could be a standalone abnormality. However, it need not be so and could have intestinal and/or colonic transit time delays also [40, 41]. The lowering of pH across the ileocecal junction may be a surrogate marker indicating cecal fermentation process, which in its turn may also influence colonic transit times [39]. Increased fermentation levels in the cecum increase the quantity of short chain fatty acids, increasing the acid level in cecum. This may become a target for treatment in future.

5.6.9 M  anometric Measurements of GI Tract: Esophageal Evaluation Three esophageal abnormalities commonly met are its dysmotility, transit time, and the decrease in the tightness of gastroesophageal sphincter [42]. Conventional manometry catheters do not record continuous pressure through the entire esophageal passage. High-resolution newer esophageal manometers however record gastric emptying and esophageal motility much less frequently which is quite contrary to the expected results. The extent of gastrointestinal disorders previously reported may have now come down. It is proposed that it may be indicative of better care and better glycemic control [43]. It may not necessarily be due to the advent of more sophisticated devices. These new manometers can be used to study gastrocolonic response and not just the transit time. Gastrocolonic response is due to the extrinsic gut innervation and not the intrinsic enteral neural networks. It may be useful in the study of constipation. An absent response will then indicate the dysfunction in the extrinsic gut neuronal system [44, 45]. Trans-abdominal ultrasonography is a much simpler non­invasive test. Despite observer dependency, it highly correlates with scintigraphy for gastric emptying. Magnetic resonance imaging and its protocols are limited to research laboratories. Although noninvasive, the costs would be an issue with other factors. It can however measure the segmental motility quite well.

5.7

Treatment of Diabetic Neuropathy of GI Tract

No cure is known for diabetic entero-neuropathy. The key to preventing or delaying GI autonomic neuropathy is optimal diabetes control. The goals of treatment therefore are to 1 . Slow the progression of it, 2. Relieve the symptoms arising from it, 3. Manage the complications as they develop, 4. Restore function as much as possible.

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5.7.1 The Variables of Planning and Monitoring Therapy 1. Age, symptom severity, disease duration, 2. Improvement in the overall health improving the symptoms, 3. Dietary management and lifestyle improvement for better control (see below also), 4. Individualized insulin regimen to intake and frequency of meals with better control, 5. Using multiple subcutaneous insulin injections for ease of dose variability, 6. Preprandial insulins to be given after food in gastroparesis, if there is no vomiting after food, 7. Use of insulin pumps in brittle diabetes improving glycemic excursions in type 1 diabetes, which is known to cause gut neural dysfunction, 8. Continuous glucose monitoring and continuous intravenous insulin treatment to control glycemic variability, for the same reason as above, 9. Age and activity level to be factored in—[46–49], 10. Such intensive measures may avoid further damage and protect the delicate autonomic nerves.

5.8

 astrointestinal Organ-Specific Management G in Diabetic Autonomic Neuropathy

5.8.1 General Remarks Significant (upper) GI symptoms would be associated with peripheral as well as autonomic neuropathy with many symptoms arising out of gut described through the volume. Patients who have severe symptoms are likely to have normal sensory perceptions and those with milder symptoms are likely to have considerably depressed sensory levels [50]. This clearly indicates that intact sensory system is able to register symptoms in their severity but those with considerable damage can sense only fewer symptoms due to which the dysfunction looks mild even with much greater damage.

5.9

Esophageal Disorders in Diabetes

It appears to have a high prevalence, as much as 63%. Gastroesophageal reflux disease is its common secondary complication and is associated with retinopathy [51]. Esophageal dysfunction manifests as reduced amplitude of contractions, and develops fewer peristaltic waves, with decreased force. These two together reduce the speed of food propulsions downwards. The pressure at the lower esophageal sphincter decreases, giving rise to an abnormal gastroesophageal reflux [52–54].

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5.9.1 Investigation of Esophageal Disorders A device called wireless Bravo capsule and a new pH meter to differentiate between acid and nonacid reflux are now available. The high-resolution manometry records pressures at closer distances which gives a composite picture of time and place of esophageal pressures and contraction. Upper GI endoscopy should be performed first to rule out achalasia, esophageal candidiasis common in diabetes, and malignancy in dysphagia. Chest pain should not be routinely ascribed to esophageal disorder unless the cardiac involvement is ruled out.

5.10 Gastroesophageal Reflux Disease Gastroesophageal reflux disease (GERD) is caused by the abnormal reflux of gastric contents into the esophagus [55]. Heartburn, acid regurgitation, and non­cardiac chest pain are common symptoms. Age, gender, body mass index (BMI), body weight, alcohol consumption, and smoking increase the frequency [56–59].

5.10.1 Esophageal Complications of GERD Serious esophageal complications of GERD are erosive esophagitis and stricture, Barrett’s esophagus (in which the normal tissue lining the esophagus changes to tissue that resembles the lining of the intestine) and esophageal adenocarcinoma. Predisposing conditions for GERD to develop and produce complications are decreased tone of the lower esophageal sphincter, increased gastric acid production, and increased intragastric pressure commonly present in obese patients [60–62].

5.10.2 Prevalence of GERD and Diabetes GERD is highly prevalent in Western and Asian societies. It influences the quality of life with considerable costs. Patients with diabetes and GERD have a fairly strong association which increases with age [63, 64]. But it may be little more prevalent in patients with diabetes below 50  years with a more pronounced association in the Asians. Patients with diabetes frequently have neuropathy without any gastrointestinal symptoms, which is attributed to simultaneous efferent and afferent nerve damage [65].

5.10.3 Treatment of GERD The information available on esophageal dysfunction and GERD in diabetes and its treatment is limited. Sodium Alginate offers a wide coverage to extensively prevent esophagus from getting exposed to the gastric acid reflux. It is more efficient than

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omeprazole within the first hour and is comparable with efficacy of ranitidine. For an immediate reduction in gastroesophageal reflux, sodium alginate was significantly better than control, ranitidine, and omeprazole. It is available as powder, liquid, or as a polymer [66]. The other drugs used are the protein pump inhibitors. Once started these are used over years. Food to which the patient is intolerant is avoided. In severe cases, the cephalic elevation of bed is also used.

5.11 D  iabetic Gastroparesis: Clinical Profile and Management Issues The absence of mechanical gastric outlet obstruction is a precondition to diagnose gastroparesis. Five percent of adults with type 1 diabetes and 1% of adults with type 2 diabetes develop gastroparesis 10 years after the diagnosis of diabetes [5]. The principle symptoms of gastroparesis are early satiety, fullness even when only a portion of food is consumed. Bloating, nausea, pain, and vomiting are prominent. In severe cases there will be weight loss [67]. The presentation of symptoms is varied in its intensity and frequency and are quite different between patients. Severity of symptoms is a function of duration of diabetes as well as state of control of hyperglycemia [67, 68]. The symptoms are troublesome and the health expenditure rises with admissions and longer stays [69]. Acute hyperglycemia reduces the rate of gastric emptying and increases the sense of fullness during gastric distension directly [70, 71]. The correlation between visceral neuropathy and GI symptoms remains incompletely understood [72].

5.11.1 Systematic Record of Upper GI Symptomatology: An Extension to History Taking A few clinical instruments are mentioned here for anyone who may be interested in this exercise in his practice. The corresponding reference will be helpful in locating full information. Gastroparesis Cardinal Symptom Index (GCSI) is used when gastroparesis is suspected. Nausea/vomiting, postprandial fullness/early satiety, and bloating are recorded with a 15-day recall [73]. To note—the symptoms generally do not correlate with laboratory findings. It is a validated instrument developed to evaluate the response to treatment over a long duration. Few other instruments will be mentioned later.

5.11.2 Management and Treatment of Gastroparesis Best possible achievement to control of blood glucose level with as few swings as possible is fundamental in managing any diabetic comorbidities. Diabetic GI autonomic neuropathies are no exception. The glucose control methods will not be discussed. Only those pertaining to each abnormal conglomeration of individual states will be discussed here.

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5.11.3 Non-Pharmacological Management 1. Low soluble fibers, low fat, and small meals with vitamin, mineral, and protein supplementation will help initially. This will need substantial modifications in the standard dietary practices and may change diabetic control regimes. 2. Small particle-sized, small liquid nutritious diet is helpful. Blendarized or homogenized diets will help. 3. In extreme cases jejunal feeding tubes may be the only alternative. To test the tolerability of it, it is advised to pass a nasogastric tube first, do the suction, and attempt feeding the patient. If this is not tolerated, then jejuna feeding will have to be undertaken. 4. Parenteral nutrition may have to be called for when even the above alternative is of little help.2

5.11.4 Pharmacologic Management of Gastroparesis Prokinetics widely used for gastroparesis and lower bowel sluggishness are of some help over long or shorter duration [74]. The transit times may improve, but the symptom improvement may not be reported [75]. Most prokinetic drugs can be used for short duration also because of the development of the tardive dyskinesias in sensitive individuals in whom it will start in the very first or the first few doses. It is reversible only after stopping the drugs. Details of individual drugs, site, and mechanism of action and other untoward effects if any are given below.

5.11.5 Metoclopramide Metoclopramide, 5-HT4 receptor agonist, D2-receptor antagonist, tablet 10 mg is used three times a day or with less frequency. There are black box warnings for long-term use of metoclopramide: FDA has limited its use to less than 3 months, and European Medicines Agency (EMA) has limited it to less than or equal to 5 days. It has anticholinergic, antiemetic, and prokinetic effects while relaxing the pylorus. The central nervous effects it has are, in addition, anxiety, restlessness, dizziness, and drowsiness in 20% of individuals [50]. It may be useful to remember that it can produce hyperprolactinemia, breast enlargement, and tenderness in males, menstrual irregularities in females. For these reasons, Cisapride replaced metacloprimide as the first-line prokinetic. Cisapride was withdrawn from the market following reports of adverse cardiac events published by the FDA. 2  Total Parenteral Nutrition used extensively in critical medicine is much less used in indoor care. This topic is extensively discussed to help clinicians undertake this modality in the author’s volume on “Towards Optimal Management of Diabetes in Surgery,” also published by Springer in August 2019. The discussion will be found in the chapter on commonly asked questions.

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5.11.6 Domperidone Domperidone is a peripheral D2-receptor antagonist, with action on chemoreceptor trigger zone outside the blood–brain barrier, similar to metoclopramide, in 10 mg tablet. It also comes as a 30 mg twice a day as suppository or can be used intravenously. The frequency of neurologic effects is less than metoclopramide [50, 76]. It should be avoided in the presence of prolonged QT interval.

5.11.7 Erythromycin Erythromycin is a macrolide antibiotic and also a motilin receptor agonist, cholinergic receptor agonist, and activates L type of calcium channels, comes in 250 or 500 mg tablets, and is given in 50–500 mg four times if needed. Motilin is secreted by the upper duodenum during fasting. It serves only one function of increasing gastrointestinal motility. Motilin is released cyclically and stimulates waves of gastrointestinal motility called inter-digestive myoelectric complexes. Under fasting conditions, a wave is initiated in the stomach which goes through the small intestine every 90 min. Motilin secretion is inhibited after ingestion. The motilin receptors are downregulated with longer use of erythromycin. Clinical efficacy often diminishes after 2–4  weeks due to tachyphylaxia. Prokinetic action of erythromycin is likely to be a drug class effect. Other macrolides like azithromycin and clarithromycin with less toxicity may be used, but there is no evidence for them per se. The contractions start in the stomach fundus and in the pyloric canal. One disadvantage of Erythromycin is to deposit undigested material not ready for pancreatic digestion. This may happen due to contractions at pyloric region. Intravenous erythromycin is more effective than oral doses. The common side effects, especially in higher and prolonged doses, are abdominal cramping, nausea, diarrhea, and ototoxicity if used in renal failure. Pseudomembranous colitis is a serious side effect [77].

5.11.8 Other (Experimental) Drugs Used in Gastroparesis 1. Prucalopride, a 5-HT4 receptor agonist, 2 mg (tablet), currently under investigation for diabetic gastroparesis in phase III trials. May be used off-label in selected cases. 2. Granisetron, a 5-HT3 receptor agonist, 3.1 mg per 24 h (patch) for which evidence from controlled trials is lacking in diabetic gastroparesis. 3. Relamorelin is a synthetic ghrelin analog which may hold some promise. It increases growth hormone levels and accelerates gastric emptying. It has proven itself to be better than placebo for symptom relief in phase IIA studies. It does not reduce the frequency of vomiting, in data so far available. It is well tolerated and is safe without cardiac or neurologic adverse effects. It awaits approval by the Food and Drug Administration.

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4. Tricyclic antidepressants are given in low dose. Nortriptyline, amitriptyline, and desipramine have shown improvement in symptoms like chronic vomiting. These effects have led to the inclusion of these drugs in gastroparesis treatment protocols. 5. Botulinum: Exclusion of anatomical obstruction to gastric emptying at the level of pylorus is a precondition to diagnosis of gastroparesis, as mentioned above. Functional obstruction however may be assumed to be present in the form of pyloric spasm. To relieve that intra-pyloric injection of botulinum was tried. It shows improved gastric emptying only transitorily. 6. Transpyloric stenting and endoscopic myomectomy of pylorus were attempted based on similar assumption. There is neither data nor evidence to undertake these methods. 7. Gastric electrical stimulation (GES) was approved by the FDA as a Humanitarian Device Exemption for those patients with refractory symptoms, particularly nausea and vomiting. The reported response rates up to 60% come from trials not well controlled. After implantation of the stimulation device, it however did work for a long time. 8. Total or subtotal gastrectomy would be a mutilating procedure and decision about it should be taken after consultation with multiple clinical disciplines and patient-related stakeholders. It is or should be a last resort when nothing else seems to work, and the clinical situation continues to worsen. The outcome analysis comes from uncontrolled studies with short-term follow-up which is a deterrent to undertake it casually. 9. Ghrelin is a peptide produced mainly by the predominantly by the enteric endocrine cells in the gastric mucosa. It is sometimes called a hunger hormone since it stimulates appetite. Its secretion and plasma concentration increase with continued fasting. It also stimulates the secretion of adrenocorticotropic hormone, ACTH, growth hormone, and prolactin and inhibits insulin secretion. The ghrelin analog TZP-101 after IV administration in doses of 80, 160, 320, or 600 μg/ kg, administered intravenously, accelerated the gastric emptying. Its efficiency is low and is not used anymore. 10. Bethanecol is a muscarinic receptor agonist, usually given in a dose of 25 mg four times a day. Its reported side effects include headache, tachycardia, flushing, hypotension, and urinary urgency [78].

5.11.9 Acute Diabetic Gastroparesis In case of severe symptoms, the following measures have to be undertaken: 1 . Hospitalization, with nil by mouth order, 2. Repetitive gastric suction, 3. IV fluids to correct dehydration, electrolyte imbalance, azotemia, and correction of hypo- or hyperglycemia. 4. Upper GI endoscopy to rule out any other pathology.

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5. Physical breaking up of bezoars. Bezoar is a solid mass of indigestible material that accumulates in stomach in gastroparesis, diabetes, end-stage kidney disease, and gastric surgery that reduces the stomach capacity. [https://www. mayoclinic.org/diseases-conditions/gastroparesis/expert-answers/bezoars/ faq-20058050]. 6. Intravenous erythromycin, 3 mg/kg 8 hourly for a maximum of 5–7 days, which has largely made bezoar breaking unnecessary [50]. 7. This may be followed up by erythromycin 250–500 mg four times a day for a few more days to clear the bezoar residues. 8. Slow introduction of oral food intake.

5.12 Abnormal Bowel Function: Diarrhea and Constipation 5.12.1 Pathophysiology of Diarrhea Adrenergic nerves stimulate the absorption of fluids from the GI tract aided also by its simultaneous effect of reducing peristalsis which increases contact time for the absorption. Hypofunction of adrenergic nerves will allow large volumes of unabsorbed fluids in the gut lumen. The parasympathetic nerves predominate and peristalsis will be rapid leading to the watery diarrhea of diabetes. Diabetic diarrhea is a diagnosis of exclusion. It is often nightly, explosive, and watery without any pain.

5.12.2 The Differential Diagnosis 1 . Infectious and inflammatory bowel diseases, 2. Celiac disease, 3. Exocrine pancreatic insufficiency which will lead to steatorrhea, 4. And small bowel intestinal overgrowth, which is common [79].

5.12.3 Treatment of Diabetic Diarrhea 1. Dietary fiber supplementation may help in some cases, but it may worsen symptoms of gastroparesis. 2. Diabetic diarrhea is a clearly unbalanced state of parasympathetic dominance and sympathetic obliteration. That is why the simple drug loperamide that binds the mu opioid receptors (but has no abuse potential) tightens the rectal tone anal sphincter, also has some antisecretory effects, and is effective [80]. 3. Codeine in doses from 120 to 60 mg is an opioid which is effective. It is discussed in detail in the chapter on Treatment of Painful Neuropathy. 4. Diphenoxylate, 1–2.5 mg, less potent than codeine and is useful.

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5.13 Diabetic Constipation Constipation is a huge psychosomatic problem in India.3 Assessment of Constipation Symptoms and Patient Assessment of Constipation-Quality of Life (PAC-QoL), if used in India, would reveal the psychic or functional side, the physical disabilities, and the Quality of Life issues with particular reference to constipation. A modified version (M-PAC-SYM) excluding item 7 (rectal bleeding/tearing) may be more relevant for the evaluation of functional constipation in diabetes. PAC-QoL that includes assessing worries and concerns, physical discomfort, psychosocial discomfort, and satisfaction is comprehensive. This is a licensed product and can be obtained by payment.

5.13.1 Treatment of Refractory Constipation The steps could consist of the following: 1. Proctoscopy to rule out local pathologies, such as fissures and tight sphincters including rectal cancer. 2. Removal of hard fecolith impaction and subsequent clearing of bowel by enema. 3. Colonoscopy. 4. Conventional laxatives are fairly efficient and safe in the treatment of GI neuropathic constipation [81]. 5. Colonic/intestinal transit time if facilities are available. 6. In markedly slow transit times, osmotic laxatives are better than fiber supplementation and bulk forming substances as the former stimulates intestinal absorption of fluids from the body. 7. Prucalopride may be helpful. It improves gastroparesis also. 8. If diabetic constipation and irritable bowel syndromes are present together, linaclotide may be particularly helpful.

5.13.2 Treatment of Abdominal Pain in Diabetic Autonomic Neuropathy of GI Tract The pain could be secondary to bacterial overgrowth, constipation, or food transit problems for which appropriate therapy may be used. Psychiatric evaluation for depression and severe anxiety syndromes must be diagnosed and treated. A patient on opioids for some other indication is also likely to develop significant constipation [82].

 The huge response that an Indian motion picture entirely based on the constipation neurosis, “PICU,” received is an indicator of how dear the issue is to Indian patient. 3

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5.14 Autonomic Dysfunction of the Urinary Tract 5.14.1 Functional Anatomy of Autonomic Innervation Urinary bladder has a criss-cross muscle arrangement which on contracting exerts its full force on bladder neck. The detrusor is supplied by parasympathetic nerves arising from pelvic nerve S3-4 spinal segment. The trigone is the base of the bladder, and the bladder neck receives sympathetic supply from T11-12, thoracic segments. Voiding of urine thus needs both the detrusor contraction and sphincter relaxation. The sensation of fullness is carried by the afferents of detrusor, and motor action for voiding impulse is cerebrally controlled for evacuation.

5.14.2 Diabetic Cystopathy In main it is the inability to void because of lack of sensation of bladder fullness. As a result, there is no cerebral signal generated to void. There is no pain or discomfort either. The continued rise in the bladder capacity without incontinence suggests that the sphincters have retained the tone and are not allowing incontinence. Incontinence can or does occur when the detrusor is completely denervated, the bladder becomes excessively full, the intra-vesicular pressure increases beyond the pressure the sphincters can resist and leads to urinary incontinence. Typically these older men and women will not be voiding urine most of the time in a day. This functional loss occurs in 10% which is to say that most people with voiding dysfunction will have a detrusor sensation loss most of the time with large collection of urine. Contrasting this with prostatic symptoms is easy. Those with diabetic cystopathy will void urine much less frequently; will usually not suffer from any hesitancy, precipitancy, and nocturia typical of prostatic involvement. The loss of force may be a common feature. There are other causes of urinary incontinence in women. Grand multi-paras, uterine prolapsed grade three, poorly estrogenized mucosa of vagina, the atrophic vaginitis, vaginal candidiasis, weakness of pelvic muscles, massive urinary tract infections are also seen to give rise to incontinence in women. Type 1 diabetes is also not exempt from developing diabetic cystopathy.

5.14.3 Laboratory Investigation of Diabetic Cystopathy In the presence of symptoms, ultrasonography is more likely to give an indication of large residual post void urine volume. In the presence of diabetes and if the prostatic measurements do not show it to be a likely cause of retention, then uroflowmetry is quite useful. It is a device that measures the flow rate of urine. It is widely available now in India. The patient voids in a well with a device that gives a weight of the column of urine in instantaneous fashion which measures the urine flow. Urine flow in this condition is supposed to give a “straining” pattern.

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Ultrasonography showing a large prostate does not always mean that the retention is due to it. If there is a prostatic overgrowth impinging upon the urethra, even in a much smaller prostatic enlargement it is more likely to cause retention in the presence of symptoms, than a large prostate withot urethral impingement. Cystometry is more sophisticated and can detect the (residual) functional ability of the detrusor. The bladder is filled with known volumes of fluid or carbon dioxide via a urethral catheter in this procedure. In normal persons 200 mils will evoke a sensation for urination which the person is easily able to suppress on command. In early cystopathy, the volumes of fluid need to be increased, before a detrusor reflex is obtained and can still be suppressed voluntarily. The suppression will cause an immediate and drastic fall in the intra-vesicular pressure. In later stages, volumes even up to 900 mils will not cause a detrusor contraction reflex. Invariably there will be an increasing gradation of weaker flows, and the contractions may not be constant or will wane off. A patient may even hold his breath, exhale against resistance, and increase abdominal pressure to be able to void more effectively.

5.14.4 Detrusor Hyperreflexia It is the inability to suppress the detrusor contraction reflex. It is seen in patients with diabetes as well. This is an indication of disruption of the spinal or the cortical control (much like a hyperreflexia of pyramidal lesion) over the detrusor nerves. This can also occur with weak detrusor action and diminished flow. By filling the bladder with a radiopaque dye and asking the patient to void under fluoroscopic imaging can detect bladder outlet patency, or can detect a stricture. Use of fluid in these procedures is more useful than gas as it can be used for uroflowmetry as well.

5.14.5 Electromyography Testing Either by a needle insertion or by surface electrodes, the activity of the external urethral sphincter can be detected. It can detect the decoupling of the detrusor sphincter action—the dys-synergism between the two or uninhibited relaxation of the sphincter. EMG cannot be used for detrusor contraction measurements. By some adaptation of the electrodes, the sphincter can be stimulated. The impulses are carried in the pelvic nerve with a sensory fiber for detrusor muscles as well to the Cz area of sensory cortex where the evoked potential can be measured with a normal latency of 44–80 ms. In patients with diabetes, it is more likely to be absent [50]. In urinary retention, it detects these abnormalities five times more in males than in females, due to an absent reflex. It could be because of the injury to the pudendal nerve from prior childbirth or pelvic surgery. The positive response is expected in patients with urinary retention from common disorders like prostate hypertrophy. In spinal cord injury above the S2 to S4 level (i.e., lesion of upper motor neurons innervating the S2 to S4 segment), the bulbocavernosus reflex also disappears, temporarily for a period of 1–6 weeks.

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62. Iwakiri K, Sugiura T, Hayashi Y, Kotoyori M, Kawakami A, Makino H, Nomura T, Miyashita M, Takubo K, Sakamoto C. Esophageal motility in Japanese patients with Barrett’s esophagus. J Gastroenterol. 2003;38:1036–41. https://doi.org/10.1007/s00535-003-1193-9. PMID: 14673719. 63. Johnson DA, Fennerty MB.  Heartburn severity underestimates erosive esophagitis severity in elderly patients with gastroesophageal reflux disease. Gastroenterology. 2004;126:660–4. PMID: 14988819. 64. Mohammed I, Cherkas LF, Riley SA, Spector TD, Trudgill NJ. Genetic influences in gastro-­ oesophageal reflux disease: a twin study. Gut. 2003;52:1085–9. PMID: 12865263. 65. Frøkjaer JB, Andersen SD, Ejskaer N, Funch-Jensen P, Arendt Nielsen L, Gregersen H, Drewes AM. Gut sensations in diabetic autonomic neuropathy. Pain. 2007;131:320–9. https:// doi.org/10.1016/j.pain.2007.04.009. PMID: 17521809. 66. Dettmar PW, Sykes J, Little SL, Bryan J.  Rapid onset of effect of sodium alginate on gastro-oesophageal reflux compared with ranitidine and omeprazole, and relationship between symptoms and reflux episodes. Int J Clin Pract. 2006;60:275–83. https://doi. org/10.1111/j.1368-5031.2006.00800.x. 67. Bytzer P, Talley NJ, Leemon M, Young LJ, Jones MP, Horowitz M. Prevalence of gastrointestinal symptoms associated with diabetes mellitus: a population-based survey of 15,000 adults. Arch Intern Med. 2001;161(16):1989–96. 68. Ko GTC, Chan WB, Chan JCN, Tsang LWW, Cockram CS.  Gastrointestinal symptoms in Chinese patients with type 2 diabetes mellitus. Diabet Med. 1999;16(8):670–4. 69. Wang YR, Fisher RS, Parkman HP. Gastroparesis related hospitalizations in the United States: trends, characteristics, and outcomes, 1995–2004. Am J Gastroenterol. 2008;103(2):313–22. 70. Horowitz M, Harding PE, Maddox AF, et al. Gastric and esophageal emptying in patients with type 2 (non-insulin dependent) diabetes mellitus. Diabetologia. 1989;32(3):151–9. 71. Rayner CK, Verhagen MAMT, Hebbard GS, DiMatteo AC, Doran SM, Horowitz M. Proximal gastric compliance and perception of distension in type 1 diabetes mellitus: effects of hyperglycemia. Am J Gastroenterol. 2000;95(5):1175–83. 72. Enck P, Rathmann W, Spiekermann M, et al. Prevalence of gastrointestinal symptoms in diabetic patients and nondiabetic subjects. Z Gastroenterol. 1994;32(11):637–41. 73. Revicki DA, Rentz AM, Dubois D, et al. Development and validation of a patient-assessed gastroparesis symptom severity measure: the Gastroparesis Cardinal Symptom Index. Aliment Pharmacol Ther. 2003;18(1):141–50. 74. Camilleri M. Novel diet, drugs, and gastric interventions for gastroparesis. Clin Gastroenterol Hepatol. 2016;14(8):1072–80. 75. Janssen P, Scott Harris M, Jones M, et al. The relation between symptom improvement and gastric emptying in the treatment of diabetic and idiopathic gastroparesis. Am J Gastroenterol. 2013;108(9):1382–91. 76. Patterson D, Abell T, Rothstein R, Koch K, Barnett J. A double-blind multicenter comparison of domperidone and metoclopramide in the treatment of diabetic patients with symptoms of gastroparesis. Am J Gastroenterol. 1999;94(5):1230–4. 77. Janssens J, Peeters TL, Vantrappen G, et al. Improvement of gastric emptying in diabetic gastroparesis by erythromycin. N Engl J Med. 1990;322(15):1028–31. 78. Hasler WL.  Emerging drugs for the treatment of gastroparesis. Expert Opin Emerg Drugs. 2014;19:261–79. 79. Törnblom H.  Treatment of gastrointestinal autonomic neuropathy. Diabetologia. 2016;59(3):409–13. 80. Lavö B, Stenstam M, Nielsen AL. Loperamide in treatment of irritable bowel syndrome—a double-blind placebo controlled study. Scand J Gastroenterol. 1987;130:77–80. 81. Ford AC, Suares NC. Effect of laxatives and pharmacological therapies in chronic idiopathic constipation: systematic review and meta-analysis. Gut. 2011;60(2):209–18. 82. Drewes AM, Munkholm P, Simrén M, et al. Definition, diagnosis and treatment strategies for opioid-induced bowel dysfunction-recommendations of the Nordic Working Group. Scand J Pain. 2016;11(1):111–22.

6

Dysfunction of Sexual and Accessory Sex Organs

6.1

Introduction

The issue of sexual dysfunction in diabetes is not limited to purveying prescriptions for drugs that are of help in this situation. Sex is one of the deepest drives of human existence and has many layers and concerns which need a much deeper understanding of this issue, much of which is beyond prescription. The understanding of nondrug issues is also essential to deal with those not infrequent unsatisfactory results after drug treatment. The need for a humanistic, emphatic, and supportive understanding to develop in dealing with female sexuality is profound and deeply rooted in the psyche developed over millions of generations. To cause a change is necessary in today’s times which incidentally will lead to an equally profound change in the treating physicians themselves. His chapter may be read from this perspective.

6.2

Neurophysiology of Penile Erection

Neuronal stimulus for performance of the male sexual act arises from the sensory nerve signals in the glans penis, which has an especially sensitive sensory end organ system. The signals are transmitted through the pudendal nerve, the sacral plexus of the spinal cord to the central nervous system to undefined areas of the brain. Impulses may also enter the spinal cord from areas adjacent to the penis to aid in stimulating the sexual act. For instance, stimulation of the anal epithelium, the scrotum, and perineal structures in general can send signals into the cord that add to the sexual sensation. Sexual sensations can even originate in internal structures, such as areas of the urethra, bladder, prostate, seminal vesicles, testes, and vas deferens. One of the causes of “sexual drive” is filling up of the sexual organs with secretions. Mild infection and inflammation of these sexual organs sometimes cause almost continual sexual desire, and some “aphrodisiac” drugs, such as cantharidin, increase sexual desire by irritating the bladder and urethral mucosa, inducing inflammation

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and vascular congestion [1]. The male sexual act also results from mechanisms initiated by either psychic stimulation from the brain or actual sexual stimulation from the sex organs, but usually it is a combination of both.

6.2.1 Penile Erection: Role of the Parasympathetic Nerves Penile erection is the first effect of male sexual stimulation, and the degree of erection is proportional to the degree of stimulation, whether psychic or physical. Erection is caused by parasympathetic impulses that pass from the sacral portion of the spinal cord through the pelvic nerves to the penis. These parasympathetic nerve fibers in contrast to most other parasympathetic fibers are believed to release nitric oxide and/or vasoactive intestinal peptide in addition to acetylcholine. The nitric oxide especially relaxes the arteries of the penis as well as relaxes the trabecular meshwork of smooth muscle fibers in the erectile tissue of the corpora cavernosa and corpus spongiosum in the shaft of the penis. This erectile tissue consists of large cavernous sinusoids, which are normally relatively empty of blood but become dilated tremendously when arterial blood flows rapidly into them under pressure. The venous outflow is partially occluded at the same time. Also, the erectile bodies, especially the two corpora cavernosa, are surrounded by strong fibrous coats; therefore, high pressure within the sinusoids causes ballooning of the erectile tissue to such an extent that the penis becomes hard and elongated. This is the phenomenon of erection [2].

6.2.2 Lubrication, a Parasympathetic Function During sexual stimulation, the parasympathetic impulses, in addition to promoting erection, cause urethral and bulbo-urethral glands to secrete mucus, which flow through the urethra during intercourse to aid lubrication during coitus. However, most of the lubrication of coitus is provided by the female sexual organs rather than by the male. Without satisfactory lubrication, the male sexual act is seldom successful because intercourse without lubrication causes grating, painful sensations that inhibit rather than excite sexual sensations and the act.

6.2.3 E  mission and Ejaculation: Function of the Sympathetic Nerves Emission and ejaculation are the culmination of the male sexual act. When the sexual stimulus becomes extremely intense, the reflex centers of the spinal cord begin to emit sympathetic impulses that leave the cord at T-12 to L-2 and pass to the genital organs through the hypogastric and pelvic sympathetic nerve plexuses to initiate emission, the forerunner of ejaculation. Emission begins with contraction of the vas deferens and the ampulla to cause expulsion of sperm into the internal urethra.

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Then, contractions of the muscular coat of the prostate gland followed by contraction of the seminal vesicles expel prostatic and seminal fluids also into the urethra, forcing the sperm forward. All these fluids mix in the internal urethra with mucus already secreted by the bulbo-urethral glands to form the semen. The process to this point is emission. The filling of the internal urethra with semen elicits sensory signals that are transmitted through the pudendal nerves to the sacral regions of the cord, giving the feeling of sudden fullness in the internal genital organs. Also, these sensory signals further excite rhythmical contraction of the internal genital organs and cause contraction of the ischiocavernosus and bulbocavernosus muscles that compress the bases of the penile erectile tissue. These effects together cause rhythmical, wavelike increases in pressure in both the erectile tissue of the penis and the genital ducts and urethra, which “ejaculate” the semen from the urethra to the exterior. At the same time, rhythmical contractions of the pelvic muscles and even of some of the muscles of the body trunk cause thrusting movements of the pelvis and penis, which also help propel the semen into the deepest recesses of the vagina and perhaps even slightly into the cervix of the uterus. This entire period of emission and ejaculation is called the male orgasm. At its termination, the male sexual excitement disappears almost entirely within 1–2 min and erection ceases, a process called resolution [2].

6.3

 linical Factors Leading to Erectile Dysfunction (ED)in C Diabetes

1. Conglomerate of diabetes, hypertension, metabolic syndrome, cigarette smoking, atherogenic dyslipidemia, central obesity and overweight, depression, sedentary lifestyle, physical inactivity, and increased caloric consumption, advanced age, and longer duration of diabetes [3–6]. 2. β-blockers, thiazide diuretics and spironolactone, psychotropic antidepressant drugs, and certain fibrates also lead to erectile dysfunction [7, 8]. 3. A diagnosis of ED indicates coronary artery work up in asymptomatic diabetic patients just as it is in the case of a diagnosed peripheral arterial disease [9]. 4. ED is the connection suggested between the coronary artery disease (CAD) [10]. 5. Psychological issues involving relationship tensions, selective ED vis a vis the desired partner. 6. However, organic factors are more important than psychological factors. The former should not be made a generalized first diagnosis, blaming it on age or other ideational factors unless laboratory and therapeutic testing and trial rule out organic causes of ED. 7. ED is associated with early mortality as well, hence the importance of the advice above. 8. A moderate consumption of alcohol may have a protective effect on ED in men with or without diabetes. The set limits are “total calories from alcohol should not exceed 5% of total daily calories” [11, 12].

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6.3.1 Factors Responsible at Organ Level 1. Macroangiopathy leading to atherosclerotic changes in the penile artery limiting blood supply is the chief requirement of erection. Cardiovascular risk factors associated with diabetes contribute to the genesis of penile arterial insufficiency also [4, 5, 13]. 2. Microangiopathy and endothelial dysfunction are the basic common factors leading to vascular ED. Autonomic neuropathy, so widely prevalent in any diabetic patient, will affect penile neural supply or its function leading to ED. Visceral adiposity causes hormonal imbalance and hypogonadism. 3. There is an increase in endothelial microparticles circulating at a higher level compared to men without diabetes. This is a new marker for endothelial dysfunction [14]. 4. Microvascular disease causes ischemic damage in the distal circulation. 5. Somatic neuropathies impair sensory impulses from the penis to the reflexogenic erectile center. 6. For relaxation of the smooth muscle of the corpus cavernosum, parasympathetic activity is necessary. It has been repeatedly pointed out in this volume that parasympathetics are the usually the first to degenerate in diabetes. Together the neuropathies will contribute to the development of ED [15]. 7. Penile fibrosis and tethering will be seen occasionally if the physician cares to examine. 8. Insulin resistance putative to type 2 diabetes.

6.3.2 Molecular Mechanisms Involved in ED Endothelial dysfunction, the result of long-standing hyperglycemia, has the greatest possible role in penile erection; in no other organ the need for maximum dilation of blood vessels in macroscopic quantities is required as in penile erection. Nitric oxide (NO) secreted by the endothelium relaxes the vascular smooth muscle of the corpora cavernosa to be filled maximally for erection. The reduction in the availability of NO for the engorgement of penis is caused by the following: 1 . Accumulation of advanced glycation end products; 2. increased levels of oxygen-free radicals that reduce the bioavailability of NO; 3. impaired endothelial and neuronal NO synthesis, expression, and activity; 4. Insulin resistance and visceral adiposity of type 2 diabetes are a pro-­inflammatory state, which reduces availability and activity of NO, especially in overweight and obese diabetic men [16]. 5. An imbalance between the vasoconstrictive and vasorelaxant intracellular pathways favoring increased vasoconstriction will lead to failure of tumescence and rigidity [17, 18].

6.4 Hormonal Changes

6.4

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Hormonal Changes

6.4.1 Testosterone Testosterone regulates all components of erectile function: 1 . From pelvic ganglions to smooth muscle, 2. The endothelial cells of the corpora cavernosa, 3. Modulation of timing of the erectile process, 4. Which occurs as a function of sexual desire, directly related to testosterone, 5. Coordinates penile erection with sexual activity. Subnormal testosterone concentrations have been found in 25% of men with type 2 diabetes in association with inappropriately low concentrations of luteinizing hormone (LH) and follicle stimulating hormone (FSH) [19, 20].

6.4.2 Causes of Testosterone Deficiency in Diabetes 1 . Low levels of the sex hormone-binding globulin due to insulin resistance, 2. Increased aromatase activity in visceral adipose tissue, 3. Leading to an augmented conversion of testosterone in estradiol, 4. Leptin resistance causing reduced secretion of LH and testosterone, 5. Increased levels of inflammatory mediators, 6. Which may suppress the secretion of gonadotropin-releasing hormone and LH [21]. 7. Presence of anti-pituitary antibodies at much high titers than age-matched controls is an autoimmune mechanism leading to hypogonadotropic hypogonadism in type 2 diabetes [22].

6.4.3 Testosterone and ED: Newer Evidence 1. There is a continuing belief that exogenous testosterone may have adverse health effects. More recent evidence suggests otherwise. Supplemental testosterone, maintained within the normal physiological range, does not contribute to the development of CVD [23–25]. 2. Testosterone has been attributed the function of improving vascular function by being a vasodilator. It also participates in producing helpful changes in vascular remodeling/reducing arterial stiffness, and reducing or inhibiting inflammation, oxidative stress, and atherosclerosis. 3. Testosterone stimulates NO production by nNOS and ultimately activates BKCa and KV channels through cGMP-stimulated protein kinase G [26, 27].

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4. Physiologic concentrations of testosterone activate Ca2+ influx to stimulate NO production by increasing eNOS expression and phosphorylation through the cSrc/PI3K/Akt pathway [28–32]. 5. Low testosterone has been related to increased oxidative stress in men [33], and testosterone replacement in symptomatic hypogonadal men reduced circulating levels of inflammatory cytokines [34]. 6. Low testosterone levels may also lead to development of metabolic disease and T2DM [35–39]. Thus, testosterone influences body fat content, steroid hormone and adipokine levels, insulin sensitivity, and glucose metabolism. 7. Low levels of testosterone set in the multiple and self-perpetuating metabolic dysregulation. These mechanisms are also common with cardiovascular pathology to a considerable extent [40, 41]. 8. Testosterone can affect the initiation of erection. It also changes factors related to the release of central neurotransmitters like dopamine, oxytocin, or NO. These are released from the medial preoptic area of hypothalamus under the testosterone influence [42, 43]. 9. Endothelial morphology changes, decrease in the trabecular smooth muscle content, increased extracellular matrix deposition, and a loss of elastic fibers in the tunica albuginea occur in castrated men with low testosterone [44–47]. 10. Both testosterone and dihydrotestosterone can directly relax penile arteries and cavernous tissue [48–50]. 11. Combining testosterone and PDE 5 (phophodiesterase 5) inhibitors stands to logic. It has been shown to be beneficial in improving erectile function in men with hypogonadism. However, this hypothesis has been challenged [51–53].

6.4.4 Testosterone and Cardiovascular Risks/Benefits 1. There is evidence in favor, doubtful and at times biased (as in large industry funded trials) which indicates doubtful benefits or clinically significant benefits with respect to cardiovascular benefits using testosterone. Hence its use in these conditions is not a full-throated approval [54–56]. 2. Further, in a prospective evaluation of elderly men enrolled in the Framingham heart study did not find any connection between the sex steroid and gonadotropin levels and nor was there clinical incident cardiovascular disease, nor an increase in all-cause mortality over 10 years [57]. Therefore, a shortcut approach to injecting testosterone without regard to the entire therapeutic correction and other measures including the full examination of what kind of pathologies exist will be totally unacceptable. In hypogonadism, however, this single correction will be needed. 3. The role of testosterone where hypogonadism is present is clearer than its use in erectile dysfunction. Clinically, the standard rule would be to keep the testosterone levels in normal limits. The purpose of the detailed discussion above is to underline the importance and a possible substantial role it may play in this condition and thinking about ED should not be limited to PDE 5 inhibitors. 4. If administration of testosterone fails or the responses are inadequate and unsatisfactory, where the clinician has to alert about alternate pathologies like penile

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fibrosis or penile arterial insufficiency and additional therapeutics may then be brought in. Similarly it should be understood that multiple mechanisms are operating influencing the outcomes whether in ED or CVD and multipronged strategy to control or mitigate the severity of complications is needed. 5. The most prevalent form of ED is corporal veno-occlusive dysfunction and the corporal smooth muscle inability to relax arteries and compress the veins against the rigid tunica albuginea. The detailed discussion also aims at today’s practice where patients are vocal and need much detailed explanations about their disease or complications, for which this detailed perspective must be available to/internalized by the treating clinicians.

6.4.5 Other Incidental Factors 1. Triglycerides do not seem to have any significant role in causing erectile dysfunction. This is a little surprising because in the pathogenesis of diabetic neuropathy, hypertriglyceridimia has been implicated as a signal factor. 2. High levels of uric acid contribute to cellular oxidative stress, increase arginase activity, and directly scavenge NO [58]. Uric acid is considered a potential marker for erectile dysfunction among other hyperglycemia-related complications like cardiovascular disease [59]. 3. This also underlines a physiological fact that the types of cells in different organs may be the similar, but the susceptibility to risk factors or development of another disease will not be the same for all.

6.5

Erectile Dysfunction and Cardiovascular Disease

1. Symptoms suggestive of ED can precede by as many as 20 years among other comorbidities and risk factors in the setting for cardiovascular disease, hypertension, dyslipidemia, and diabetes as metabolic diseases [60]. 2. 95,038 men without previous CVD were compared for those with or without severe ED. The risk ratios for CV diseases were calculated. For those with ED, these were 1.60 for ischemic heart disease, 8.00 for heart failure, 1.92 for peripheral vascular disease, 1.26 for other CVD, 1.35 for all CVD combined, and 1.93 for all-cause mortality compared to those without ED [61]. 3. ED precedes CVD. The cause is probably the small diameter of cavernosal and helicine arteries having less than 1–2  mm [62]. When the diameter becomes smaller, the penile arteries cannot sustain the blood flow and maintain erection even with minimal narrowing of the lumen. This is not likely to happen in coronary arteries that easily since the diameters of these are much larger. That supposedly makes it vulnerable to early endothelial dysfunction and atherosclerosis. 4. Human cavernosal endothelial cells have a high mRNA activity forming collagen types I, III, IV, and VI. These types are considered responsible for the distension achieved in the sinusoidal spaces with the penile cavernous spaces. These collagen types may also be responsible for the required occlusion of the veins necessary for maintaining erection [63].

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5. At the gene and protein level components of endothelial cell junction complexes also differ between cavernosal endothelial cells and endothelial cells from other vascular beds. A variety of cellular processes, including adhesion, para-cellular transport, growth, apoptosis, and signaling events, are controlled by these junctional complexes [21]. The tissue specificity of these components indicates that they may provide selective cell–cell recognition and/or specific functional properties. Wessells et  al. [63] found greater expression levels of cadherin 2 (a cell–cell adhesion molecule of adherens junction) and claudin-11 (a tight junction protein) in cavernosal endothelial cells compared with that of coronary artery or umbilical vein endothelial cells and suggested they reflect a requirement for junctional and barrier integrity associated with high intracavernosal pressure during erection.

6.5.1 Smooth Muscle Abnormalities in Penile Cavernosa There is reduction in the abundance of SM and the SM cell/collagen ratio as well. There is increased apoptosis in the media of the penile dorsal artery,

6.6

Symptomatology and Physical Examination

• Loss of erectile rigidity, inability to maintain erection, and decrease in genital sensations, • At times complaint of diminution of libido, • Failure of ejaculation or its diminished force (this is discussed in much greater detail elsewhere), • Development of the symptoms is almost always slow and progresses over years, • Symptoms of various autonomic neuropathy like bladder or gut dysfunction, • Symptoms and signs of peripheral neuropathy and neuropathic ulcers, • Inquiry should consist of previous surgery on genitalia or any pelvic surgery, • Peripheral arterial disease as history of claudication or angina, • Psychological factors like depression, full medication history, spouse-specific erectile dysfunction, and extramarital partnerships must be investigated in history-­taking even if there is presence of organic disease and certainly in those who have normal penile circulation.

6.6.1 Physical Examination • General and systemic examination, including peripheral arteries and lower limb neuropathies. • Penile examination for structural abnormalities, testicular descent and normalcy of position. • Loss of secondary sexual characters. • Genial and perineal sensations in the saddle area.

6.8 Treatment of Erectile Dysfunction

6.7

99

Laboratory Diagnosis

6.7.1 Penile Tumescence Test It is tested by a portable device which records the tumescence as well as the rigidity. In normal sleep pattern tumescence occurs four to five times. Inadequacy or decreased frequency and degree of tumescence and rigidity indicate the organ. But a normal test will mean that the erectile dysfunction is due to psychogenic factors.

6.7.2 Bulbocavernous Reflex It tests the conus medullaris (distal end of the spinal cord) and the S2–S4 pelvic nerves. It is elicited by electrical stimulation of the dorsal penile nerve with recording of the subsequent motor response in the bulbocavernosus muscle. Both the afferent and efferent responses of this reflex travel via the pudendal nerve. In patients with sacral cord (S2–S4) lesions or pudendal nerve lesions, latency of this reflex may be prolonged, or the reflex may be absent altogether. However, the sensitivity of this test is less than optimal, and its value in evaluating erectile dysfunction has been questioned. The reflexes are studied better if the penis is made tumescent by pharmacotherapy as the dorsal nerve of penis shows more activity than that in flaccid penis [64].

6.7.3 Vascular Evaluation Vascular evaluation is conducted by using duplex sonography and color Doppler and imaging the dorsal artery of penis. It can also demonstrate abnormal arteriovenous communication which will cause a runoff instead of causing rigidity, whereas little or no venous filling is seen in normal persons.

6.7.4 Hormonal Testing Hormonal testing is undertaken in the presence of loss of libido (which is not an accompaniment of erectile dysfunction) and the cause of all frustration lies therein. Clinical examination suggestive of hypogonadism will mandate testing for testosterone, follicle stimulating hormone (FSH), and luteinizing hormone (LH). It could indicate the rhythmicity of FSH and LH and a comparable testosterone level. Prolactin, usually present as a micro-adenoma or a macro-adenoma, could also interfere with testosterone and libido [65].

6.8

Treatment of Erectile Dysfunction

The treatment of ED in diabetic men should be multipronged. Prevention is desirable but difficult to achieve. The most important, oft neglected is the control of hyperglycemia before structural changes occur and even after. There is no

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curative treatment for ED today. Uncontrolled diabetes will exacerbate the pathophysiological changes, and ED will deteriorate and an otherwise effective treatment will fail.

6.8.1 Lifestyle Changes Lifestyle changes are important even in ED and its treatment. Increased physical activity and weight loss make a difference [66]. Mediterranean diet advocated is not a useful alternative in India but is shown to improve ED by improving endothelial function [67]. Mediterranean diet is more effective than a usual diet in ameliorating or restoring ED in obese people with or without metabolic syndrome [68].

6.8.2 Hormonal Changes Hormonal changes should be treated (see above). If not, effectiveness of treatment is much significantly reduced in obesity. Diuretics like thiazide or spironolactone in men should be replaced with calcium channel blockers or angiotensin receptor antagonists since the former two interfere with normal sexual functions. These drugs may even enhance sexual function not only due to endothelium-dependent vasodilatation but also due to reduction in oxidative stress and reactions involving monocyte attraction and adhesion [69]. With beta blocker withdrawal, it is important to see that the patient does not go into a sympathetic overdrive and burdens the heart on a second to second basis with disastrous consequences.

6.8.3 Antidepressants Antidepressants also cause erectile dysfunction. In diabetes, depression is nearly always of exogenous variety due to poor quality of life style, due to failure to cope with the burden of disease as well as its complications. Unless there is immense support and positivity, understanding, empathy encouragement, and appreciation, no antidepressants will ever work. With such a support, the antidepressants may not be needed at all. In the treatment of ED, the patient and partners must be encouraged to participate in the discussion process [70]. Proper treatment of CVD and cardiac autonomic neuropathy and its evaluation in a patient with ED if not already done should be undertaken (see the chapter on Treatment of Cardiac Autonomic Neuropathy also for a more detailed discussion on Beta Blockers).

6.9

Phosphodiesterase Type 5 Inhibitors PDE5i

The type of ED most prevalent is treated by the class of drugs called phosphodiesterase type 5 inhibitors PDE5i, as the first line of treatment. Their efficacy and safety profile are quite good with few drug interactions and side effects, even the dropout

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rates. Sildenafil is available as 25, 50, and 100 mg tablets, tadalafil, 10 and 20 mg, 2.5 and 5 mg for daily dosing, vardenafil, 5, 10, and 20 mg, with a mouth dissolving form of 10  mg, and avanafil, 50, 100, and 200  mg, available since 2014. Several other PDE5i like lodenafil, mirodenafil and udenafil are available only in some countries.

6.9.1 Sildenafil The efficacy, measured as erections lasting long enough for successful intercourse, is about 60–70% in the general ED population. It is much lower in men with diabetes. Sildenafil improved erections in 66.6% of type 1 diabetic men. The efficacy of sildenafil was evident even in men with poor glycemic control and chronic complications. In those type 1 diabetic patients treated with placebo, only 28.6% achieved adequate erection. Those in either group who could complete intercourse successfully were similar in number [71]. Three more randomized, placebo-controlled studies have confirmed these results [72–74]. Results of other trials are similar, underlining the fact that all people with diabetes do not respond adequately to sildenafil.

6.9.2 Tadalafil International Index of Erectile Function (IIEF) erectile function domain score in men with diabetes receiving tadalafil 20 mg had a score of 7.4 against 0.9 in the placebo group. Fifty-three percent of tadalafil as against 22% of placebo group reported successful intercourse. Twelve placebo-controlled trials against tadalafil analyzed retrospectively indicated similar figures [75]. All differences were highly significant.

6.9.3 Verdenafil Verdenafil, in similar patient situations, gave mean IIEF erectile function domain score improvement of 17.1 and 19.0 for the 10 and 20 mg fixed dose, respectively. The placebo group reported only a 12.6 score [76]. In another measure called sexual encounter profile (SEP) 2 and 3 used in treatment with verdanafil 20 mg, success was met within 64% and 36% in SEP2 and 54% and 23% in SEP3, respectively, between the active drug use and placebo. Success rates were affected by neither the severity of ED nor the level of glycemia at the time of study. There was no difference between patients with type 1 or type 2 diabetes. Similar results have been reported with flexible dose vardenafil in men with type 1 diabetes with respect to successful intercourse as well as IIEF scores [77]. At the end of this study, vardenafil 20 mg was found to be suitable for 87.7% of patients.

6.9.4 Avanafil Avanafil 100 and 200 mg and placebo were compared using the IIEF-EF values as well as using SEP2. SEP2 at baseline and after treatment have not shown much improvement.

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6.9.5 Mirodenafil and Udenafil Mirodenafil and udenafil were developed in Korea and are among the two new PDE5i. These are available only in some countries. The trials are placebo-controlled and randomized using IIEF and SEP2 and SEP3 scores. An improvement in the IIEF-EF score of nearly seven times was observed in those treated with mirodenafil [78]. Differences between the SEP2, SEP3, and IIEF-EF scores were significantly greater with udenafil treatment [79]. The most frequently reported adverse events for all PDE5i were headache, flushing, rhinitis, and dyspepsia. However, these were generally mild to moderate and tend to decrease during long-term treatment. Serious adverse events and dropout rates were infrequent, reported by 25  V is considered abnormal and the risk of ulceration is increased ­fourfold. The risk of ulceration then gradually increases. Once VPT exceeds 42 V, it is over 20 times [28, 33].

8.10.5 Interpretation of Second-Time Reading It is not the first value on a patient that is the most important observation. It is the direction in which the second value appears is important and the quantum change. It may be obtained in the next 1 year or 6 months by repeat testing. If the second or the third values are progressively higher, then it is clear that there is a progressive deterioration in the neuropathic status of the individual. If the values do not vary much and cluster around the first value, the position regarding the status of neuropathy is more or less stable. If the change is unidirectional (or monotone), then higher the value or the quantum of the change, the greater will it indicate the deterioration to be.

8.10.6 Vibration Threshold Detection and its Correlations Quantitative sensory testing of VDT is a particularly sensitive and specific measure of large fiber function because it can be done quickly and is noninvasive, simple, painless, and highly reproducible. VDT reflects the activation of mechanoreceptors and conduction in large fiber nerves that are important for proprioception, position, balance, gait, and muscle strength. Highly sensitive and validated instrument for VDT are available in India since the beginning of 2001. It has faced a long opposition in the initial years as being unnecessary and that the monofilament was adequate to detect the diabetic foot at risk. It was then (justifiably) used as mass VDT detection of abnormalities. This instrument is available with literally thousands of doctors. The immense value of it however has not been fully appreciated since it is used as a simplistic instrument. The value lies in the correlations that this modality has about so many other modalities in either directions. If VPT/VDT worsens, the other modalities detected in the earlier testing would also travel in the same direction. More importantly it has high correlation value with EMG NCV studies which are available only at few places, are far more expensive and cumbersome with some inter-examiner variability. Hence VDT is an excellent marker for progression or deterioration of neuropathy in place of electrophysiology, and on the other hand it is far better than SW monofilament in quantifying the risk for ulceration in diabetic foot. A few important collaborations are described below so that the use of VDT in clinical practice will be much more and with a greater understanding.

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1. Neurologic examination, quantitative sensory testing, and electrophysiologic nerve conduction testing are accepted as objective measures for assessing the presence and severity of DPN. 2. Vibration detection threshold (VDT) is a sensitive measure of nerve function [34]. 3. Patients with less severe DPN and those who have positive sural nerve action potential have significantly lower VDT.  These patients will also have faster nerve conduction velocity of the peroneal and tibial motor nerves, higher amplitudes of the peroneal and tibial motor and ulnar sensory nerves. Ulnar sensory nerve as being an essential component of electrophysiological investigation of lower limb nerves is discussed elsewhere. 4. One of the rather invariable finding is the high latencies. Patients with detectable sural nerve potentials have shorter latencies in the peroneal motor nerve, whereas patients without detectable sural nerve potentials have longer latencies in the peroneal nerve [35]. It then correlates well with VDT which may have lower thresholds in the former and higher ones in the latter situation. 5. VDT, a quantitative neurologic examination, also correlates well with the Diabetic Peripheral Nerve Impairment score which is semiquantitative and has subjective elements. Both travel in the same direction. If one worsens, the other also will show worsening [11]. 6. Increased VDT also strongly correlates with areflexia in the lower extremities, both in patients with diabetes and without diabetes [36]. 7. VDT also correlated well with peroneal motor nerve conduction velocity in 21 patients with diabetes and peripheral somatic polyneuropathy [37]. 8. The onset latency or F wave directly and closely relates to VDT. In most diabetic patients, both VDT and F-wave latencies were found above the 99th percentile. The conduction velocity or amplitude in such cases was below the first percentile which could match with and for age, sex, and anthropometric measures of height and weight [11]. 9. A somewhat unusual looking correlation was found between VDT and microvascular abnormalities like basement membrane area and cellular debris, as well as myelinated fiber density, in a study of 104 patients [38]. 10. In a smaller study of 11 patients, VDT showed a strong correlation with myelinated fiber density [37]. 11. Loss of vibration perception is associated with ataxia and loss of balance in individuals with diabetes. It impairs the daily activities and quality of life for patients with diabetes. The risk of such patients falling and getting fractured is much higher [39, 40]. 12. Persons with diabetes and peripheral neuropathy have a 15-fold greater likelihood of falling down, The risk is increased due to the weakness of dorsiflexion of foot in such patients. They are also susceptible to tripping and falling. Such patients also have loss of vibration perception. A simple routine measurement of VDT can alert both the clinician and the patient with his/her relatives.

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13. The weakness of the intrinsic small muscles of the feet, common in diabetes, which leads to deformities like hammer toe described elsewhere in detail also suffer from loss of VDT [41, 42]. 14. Changes in VDT have been correlated with clinically meaningful changes in nerve fiber content [43]. Some more abnormalities:

important

interrelations

of

thresholds

and

neuropathic

1. The vibration perception thresholds (VPTs) are higher in lower limbs in persons with diabetes compared to normal people. 2. The VPT for great toe is higher and is positively associated with longer duration of diabetes. 3. VPT values correlate positively with the observed sensory loss and areflexia, correlate with increasingly severe stages of person with diabetes neuropathy. 4. One abnormality of quantitative sensory testing correlates well with some other form of quantitative testing. For example, vibration and cooling thresholds were strongly associated with clinical deficits. 5. The vibration and cooling threshold help establish minimum criteria to diagnose polyneuropathy.

References 1. Korean Diabetes Association. Treatment guideline for diabetes. J Korean Diabetes. 2015;12:S109–12. 2. Kim SS, Won JC, Kwon HS, Kim CH, Lee JH, Park TS, et al. Prevalence and clinical implications of painful diabetic peripheral neuropathy in type 2 diabetes: results from a nationwide hospital-­based study of diabetic neuropathy in Korea. Diabetes Res Clin Pract. 2014;103:522–9. 3. Won JC, Kwon HS, Kim CH, Lee JH, Park TS, Ko KS, et al. Prevalence and clinical characteristics of diabetic peripheral neuropathy in hospital patients with type 2 diabetes in Korea. Diabet Med. 2012;29:e290–6. 4. Chawla A, Bhasin G, Chawla R. Validation of neuropathy symptoms score (NSS) and neuropathy disability score (NDS) in the clinical diagnosis of peripheral neuropathy in middle aged people with diabetes. Int J Fam Pract. 2013;12(1):1–4. 5. Asad A, Hameed MA, Khan UA, Butt MU, Ahmed N, Nadeem A. Comparison of nerve conduction studies with diabetic neuropathy symptom score and diabetic neuropathy examination score in type-2 diabetics for detection of sensorimotor polyneuropathy. J Pak Med Assoc. 2009;59(9):594–8. 6. Afifi L, Abdelalim AM, Ashour AS, Al-Athwari A. Correlation between clinical neuropathy scores and nerve conduction studies in patients with diabetic peripheral neuropathy. Egypt J Neurol Psychiatry Neurosurg. 2016;53(4):248. 7. Kamel SR, Hamdy M, Omar HA, Kamal A, Ali LH, Elkarim AH. Clinical diagnosis of distal diabetic polyneuropathy using neurological examination scores: correlation with nerve conduction studies. Egypt Rheumatol Rehabil. 2015;42(3):128. 8. Young MJ, Boulton AJ, MacLeod AF, Williams DR, Sonksen PH. A multicentre study of the prevalence of diabetic peripheral neuropathy in the United Kingdom hospital clinic population. Diabetologia. 1993;36(2):150–4.

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9. Abbott CA, Carrington AL, Ashe H, Bath S, Every LC, Griffiths J, Hann AW, Hussein A, Jackson N, Johnson KE, et al. The north-west diabetes foot care study: incidence of, and risk factors for, new diabetic foot ulceration in a community-based patient cohort. Diabet Med. 2002;19(5):377–84. 10. Papanas N, Papatheodorou K, Papazoglou D, Kotsiou S, Maltezos E. A prospective study on the use of the indicator test Neuropad(R) for the early diagnosis of peripheral neuropathy in type 2 diabetes. Exp Clin Endocrinol Diabetes. 2011;119(2):122–5. 11. Dyck PJ, Bushek W, Spring EM, Karnes JL, Litchy WJ, O’Brien PC, Service FJ. Vibratory and cooling detection thresholds compared with other tests in diagnosing and staging diabetic neuropathy. Diabetes Care. 1987;10(4):432–40. 12. Dyck PJ.  Detection, characterization, and staging of polyneuropathy: assessed in diabetics. Muscle Nerve. 1988;11(1):21–32. 13. Perkins BA, Bril V.  Diabetic neuropathy: a review emphasizing diagnostic methods. Clin Neurophysiol. 2003;114(7):1167–75. 14. Meijer JW, Smit AJ, Sonderen EV, Groothoff JW, Eisma WH, Links TP. Symptom scoring systems to diagnose distal polyneuropathy in diabetes: the diabetic neuropathy symptom score. Diabet Med. 2002;19(11):962–5. 15. Dyck PJ, Davies JL, Litchy WJ, O’Brien PC. Longitudinal assessment of diabetic polyneuropathy using a composite score in the Rochester diabetic neuropathy study cohort. Neurology. 1997;49(1):229–39. 16. van Hecke O, Austin SK, Khan RA, Smith BH, Torrance N. Neuropathic pain in the general population: a systematic review of epidemiological studies. Pain. 2014;155:654–62. 17. Bennett M. The LANSS pain scale: the Leeds assessment of neuropathic symptoms and signs. Pain. 2001;92:147–57. [PubMed: 11323136] 18. Bouhassira D, Lanteri-Minet M, Attal N, Laurent B, Touboul C. Prevalence of chronic pain with neuropathic characteristics in the general population. Pain. 2008;136:380–7. [PubMed: 17888574] 19. Venkataramana AB, Skolasky RL, Creighton JA, et  al. Diagnostic utility of the subjective peripheral neuropathy screen in HIV-infected persons with peripheral sensory polyneuropathy. AIDS Read. 2005;15:341–4. 20. Spallone V, Morganti R, D’Amato C, et al. Validation of DN4 as a screening tool for neuropathic pain in painful diabetic polyneuropathy. Diabet Med. 2012;29:578–85. 21. Bouhassira D, Attal N, Fermanian J, et al. Development and validation of the neuropathic pain symptom inventory. Pain. 2004;108:248–57. 22. Sheehan DV, Harnett-Sheehan K, Raj BA.  The measurement of disability. Int Clin Psychopharmacol. 1996;11:89–95. 23. Singleton JR, Bixby B, Russell JW, Feldman EL, Peltier A, Goldstein J, Howard J, Smith AG. The Utah early neuropathy scale: a sensitive clinical scale for early sensory predominant neuropathy. J Peripher Nerv Syst. 2008;13:218–27. PubMed: 18844788. 24. Sharma S, Kerry C, Atkins H, Rayman G. The Ipswich touch test: a simple and novel method to screen patients with diabetes at home for increased risk of foot ulceration. Diabet Med. 2014;31(9):1100–3. 25. Saltzman CL, Rashid R, Hayes A, Fellner C, Fitzpatrick D, Klapach A, Frantz R, Hillis SL. 4.5-gram monofilament sensation beneath both first metatarsal heads indicates protective foot sensation in diabetic patients. J Bone Joint Surg Am. 2004;86:717–23. 26. Miranda-Palma B, Sosenko JM, Bowker JH, Mizel MS, Boulton AJM. A comparison of the monofilament with other testing modalities for foot ulcer susceptibility. Diabetes Res Clin Pract. 2005;70:8–12. 27. Bril V, Perkins BA.  Comparison of vibration perception thresholds obtained with the Neurothesiometer and the CASE IV and relationship to nerve conduction studies. Diabet Med. 2002;19(8):661–6. 28. Young MJ, Breddy JL, Veves A, Boulton AJ.  The prediction of diabetic neuropathic foot ulceration using vibration perception thresholds. A prospective study. Diabetes Care. 1994;17(6):557–60.

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29. Willits I, Cole H, Jones R, Dimmock P, Arber M, Craig J, Sims A. VibraTip for testing vibration perception to detect diabetic peripheral neuropathy: a NICE medical technology guidance. Appl Health Econ Health Policy. 2015;13:315. 30. Bowling FL, Abbott CA, Harris WE, Atanasov S, Malik RA, Boulton AJ. A pocket-sized disposable device for testing the integrity of sensation in the outpatient setting. Diabet Med. 2012;29(12):1550–2. 31. Ponirakis G, Odriozola MN, Odriozola S, et  al. NerveCheck: an inexpensive quantita tive sensory testing device for patients with diabetic neuropathy. Diabetes Res Clin Pract. 2016;113:101–7. 32. Haanpaa M, Attal N, Backonja M, et al. NeuPSIG guidelines on neuropathic pain assessment. Pain. 2011;152:14–27. 33. Armstrong DG, Lavery LA, Vela SA, Quebedeaux TL, Fleischli JG.  Choosing a practical screening instrument to identify patients at risk for diabetic foot ulceration. Arch Intern Med. 1998;158(3):289–92. 34. Vinik AI, Suwanwalaikorn S, Stansberry KB, et al. Quantitative measurement of cutaneous perception in diabetic neuropathy. Muscle Nerve. 1995;18:574–84. 35. Bril V, Vinik AI, Litchy WJ, for the MBBQ Study Group, et al. Detectable sural nerve action potential (SNAP) identifies patients with early diabetic peripheral neuropathy (DPN). Diabetes. 2002;51(Suppl 2):A197. 36. Steiness I. Vibratory perception in normal subjects: a biothesiometric study. Acta Med Scand. 1957;158:315–25. 37. Malik RA, Newrick PG, Sharma AK, et al. Microangiopathy in human diabetic neuropathy: relationship between capillary abnormalities and the severity of neuropathy. Diabetologia. 1989;32:92–102. 38. Giannini C, Dyck PJ. Basement membrane reduplication and pericyte degeneration precede development of diabetic polyneuropathy and are associated with its severity. Ann Neurol. 1995;3995(37):498–504. 39. Resnick HE, Vinik AI, Schwartz AV, et al. Independent effects of peripheral nerve dysfunction on lower- extremity physical function in old age: the Women's health and aging study. Diabetes Care. 2000;23:1642–7. 40. Menz HB, Lord SR, St George R, Fitzpatrick RC. Walking stability and sensorimotor function in older people with diabetic peripheral neuropathy. Arch Phys Med Rehabil. 2004;85:245–52. 41. Boulton AJ, Malik RA, Arezzo JC, Sosenko JM.  Diabetic somatic neuropathies. Diabetes Care. 2004;27:1458–86. 42. Coppini DV, Young PJ, Weng C, et  al. Outcome on diabetic foot complications in relation to clinical examination and quantitative sensory testing: a case-control study. Diabet Med. 1998;15:765–71. 43. Russell JW, Karnes JL, Dyck PJ.  Sural nerve myelinated fiber density differences associated with meaningful changes in clinical and electrophysiologic measurements. J Neurol Sci. 1996;135:114–7.

9

Small Fiber and Painful Neuropathy

9.1

Introduction

Pain being highly subjective in nature it is difficult to assess its severity in fully objective manner. Various neuropathy disability or symptom or impairment scores are not easy to administer in day-to-day clinical practice at the beginning and later to see the effects of therapy. Hence objective evidence becomes necessary. Except for nerve conduction studies the other “objective” tests also have subjective variables. Hence producing objective evidence that parameters are improving does not fully satisfy the patients if the subjective pain components have not disappeared fully or adequately enough to improve the quality of life. Treatment of Painful Neuropathy is also an extremely difficult task achieved only partially in practice.

9.2

Small Fiber Neuropathies

9.2.1 Symptoms of Small Fiber Neuropathy Symptoms of small fiber neuropathy can vary widely in severity. Many individuals report the gradual onset of distal symptoms that include vague disturbances of sensation in the feet. These symptoms may include the feeling of a wrinkle in a sock that cannot be removed or of small pebbles or sand in the shoe. Others may report a cold-like pain, tingling, or a pins and needles sensation. More severe symptoms of small fiber neuropathy may include burning pain that often is persistent, although it may vary in intensity through the day. Many patients also report transient electric shock-like pain, usually lasting only seconds, but quite severe and potentially multiple times per day. Many symptoms worsen during periods of rest and at night. In addition to spontaneous pain, many individuals report allodynia and hyperesthesia. Patients with small fiber neuropathy frequently complain that even a contact with the bed sheets is exquisitely painful, and therefore wear socks or use “foot tents” to keep the sheets from making physical contact with the feet. Cardiac Sympathetic © Springer Nature Singapore Pte Ltd. 2020 S. Kelkar, Diabetic Neuropathy and Clinical Practice, https://doi.org/10.1007/978-981-15-2417-2_9

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Fibers also come under small fibers which initiate the pain during Infarctions which will be masked if these are degenerated. Here mainly the peripheral small fiber paiful neuropathy is discussed.

9.2.2 Small Fiber Neuropathies and Autonomic Dysfunction Small nerve fiber neuropathies also may result in autonomic and enteric dysfunction. Patients often do not identify the relationship of autonomic symptoms to their compliant list. However, if they are asked about it directly, dry eyes, dry mouth, postural light headedness, and presence of other autonomic symptoms would be common answers. Syncope, abnormal sweating, erectile dysfunction, nausea, vomiting, diarrhea, constipation, early satiety, difficulty with urinary frequency, nocturia, and/or voiding may be among the commoner complaints [1, 2]. The autonomic neuropathies affecting different organs and organ systems are already described in great detail. Here these are listed for a more comprehensive picture of small fiber neuropathies.

9.2.3 Causes of Small Fiber Neuropathy 1. Diabetes and prediabetes frequently are associated with pure small fiber neuropathy; however, concomitant large fiber involvement is also seen quite often. Nearly half of all subjects with idiopathic small fiber neuropathy have abnormal 2-h glucose tolerance tests or abnormal fasting glucose levels. The abnormal glucose testing may be seen despite normal glycosylated hemoglobin. Several studies have also established a link between pain in small fiber neuropathy and abnormal glucose metabolism [3, 4]. 2. There also is a large overlap between the two conditions of prediabetes and metabolic syndrome which have many aspects in common, the full expression of which is achieved in metabolic syndrome. The metabolic syndrome comprises hyperlipidemia, hypertension, and obesity in addition to abnormal glucose metabolism with insulin resistance. Each of these separate factors appears to add to an increased possibility of developing a small fiber neuropathy [5]. 3. Individuals with diabetes and metabolic syndrome appear to have twice the risk of developing a small fiber neuropathy compared to those with diabetes alone [6]. 4. Recent reports now are suggesting an unusual and also the single largest factor contributing to neuropathy development. It is hyperlipidemia [7]. Another important paper reviews the data relating to hyperlipidemia and the development of diabetic neuropathy [8]. This chapter also highlights the sudden shift in our understanding of the pathophysiology of diabetic neuropathy. 5. Some patients with diabetes also may experience an acute painful small fiber neuropathy associated with rapid glycemic control, also referred to as insulin neuritis or treatment-induced neuropathy [9]. This chapter describes the effects of rapid glycemic control, previously referred to as insulin neuritis, on the devel-

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opment of a severe small fiber neuropathy manifesting with both pain and autonomic dysfunction. More detailed discussion will be found about this in the chapter on Insulin and Diabetic Nerve Pathologies. 6. Other conditions associated with acquired small fiber neuropathy include HIV, inflammatory neuropathies, such as Guillain-Barre syndrome and chronic inflammatory demyelinating polyneuropathy, celiac disease, hepatitis C, restless legs syndrome, and complex regional pain syndrome type I which are not discussed but are listed out since these are somewhat common situations in clinical practice. Paraproteinemic conditions are discussed separately earlier. Neurotoxic drug use, Isoniazid, Vacor, systemic lupus erythematosus, Sjogren’s syndrome, abnormal thyroid function, amyloidosis, is not a comprehensive list. There are many case reports describing small fiber neuropathies in other diseases. In addition, there are inherited conditions which cause small fiber neuropathies, such as Fabry’s disease and the hereditary sensory and autonomic neuropathies.

9.3

Generation and Flows of Painful Neural Impulses

1. Noxious stimuli get transduced into electrical activity at peripheral terminals of unmyelinated C fibers carried by these fibers. 2. Primary afferent neurons which lie in the dorsal horn of the spinal cord, outside the spinal canal receive these activated neural electrical impulses. 3. These are then transmitted to the dorsal horn of the spinal cord. 4. The second-order neurons lying in the dorsal horn receive them and 5. Project these impulses through the anterolateral, also known as the spinothalamic tract to supra-spinal structures in the brain. 6. At the level of the dorsal horn within the spinal cord, pain transmission is modulated. This site is targeted for pain relief as discussed in the Treatment of Painful Neuropathies in a separate chapter. 7. Just as the sensations go up, there are descending bulbo-spinal pathways which interlace with the intrinsic spinal inter-neurons. 8. Antero-lateral system in the spinal cord carries these pain, thermal sensations, including both warmth and cold sensations, crude touch and pressure sensations capable only of crude localizing ability on the surface of the body, tickle and itch sensations, 9. The fast-sharp pain signals are elicited by mechanical or thermal pain stimuli; they are transmitted in the peripheral nerves to the spinal cord by small type A delta fibers at velocities between 6 and 30 m/s. They terminate mainly in lamina I (lamina marginalis) of the dorsal horns. 10. The axons of these second-order neurons give rise to long fibers that cross immediately to the opposite side of the cord through the anterior commissure and then turn upward, passing to the brain in the anterolateral columns constituting a neospinothalamic tract. 11. A few fibers of the neospinothalamic tract terminate in the reticular areas of the brain stem, but most pass all the way to the thalamus without interruption, terminating in the ventro-basal complex.

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12. A few fibers also terminate in the posterior nuclear group of the thalamus. From these thalamic areas, the signals are transmitted to other basal areas of the brain as well as to the somatosensory cortex [10].

9.3.1 Generation of Pain—At the Nerve Fiber and Cellular Levels 1 . Neuropathic pain arises following injury or dysfunction of the nervous system. 2. After nerve damage, there is an increase in transcription and axonal trafficking of sodium channels to the site of injury. 3. Simultaneous to that is reduction in potassium channels. 4. The altered ion-channel expression and consequent imbalance of these two ions, changes the normal neuronal excitability into a neuronal hyper-excitability. 5. Such hyperactivity can and does generate abnormal or ectopic activity. 6. This is considered to be the cause of instantaneous or sudden, spontaneous pain. 7. It can also generate the suddenly appearing severe pains which may remain only for a short time. This is called as the paroxysmal pain. 8. The injury also activates many different kinases and proteins. 9. It also enhances the activity of the NMDA receptor activity. Blocking NMDA receptor site thus is a therapeutic option.

9.3.2 Pain Generation at the Cell Body 1. This is the cell body that lies at the end of the primary afferents, neurons located within the dorsal root ganglia. 2. Sympathetic neuronal sprouting may account for sympathetically maintained pain. 3. Nerve injury also elicits hypertrophy and activation of microglia and other glial cells which are situated in the gray matter of the spinal cord. 4. Microglia express purinergic receptors. 5. These are activated by ATP. 6. Following activation, microglia release various cytokines—IL-1, TNF-α, neurotrophins, and brain-derived neurotrophic factor, all of which are pain producing. 7. The activation greatly increases pain transmission, sensitization, and maintenance of neuropathic pain. 8. Several peripheral mechanisms like sodium, potassium, and calcium channels and vanilloid receptors and central glutamate and substance P receptor mechanisms have been well shown to participate in pain generation. 9. Glutamate is believed to be the probable neurotransmitter of the type A delta fast pain fibers, secreted in the spinal cord at the type A delta pain nerve fiber endings. This is one of the most widely used excitatory transmitters in the central nervous system, usually having duration of action lasting for only a few milliseconds.

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10. Some of the chemicals that excite the chemical type of pain are bradykinin, serotonin, histamine, potassium ions, acids, acetylcholine, and proteolytic enzymes. 11. Special importance of chemical pain stimuli during tissue damage is seen when extracts from damaged tissue cause intense pain when injected beneath the normal skin. Most of the chemicals listed above and a few more mentioned below that excite the chemical pain receptors can be found in these extracts. Bradykinin elicits greater pain than others. 12. Most other chemicals responsible for causing pain do so following tissue damage. 13. The chemical substances are especially important in stimulating the slow, suffering type of pain that occurs after tissue injury. 14. Also, the intensity of the pain felt correlates with the local increase in potassium ion concentration or the increase in proteolytic enzymes that directly attack the nerve endings and excite pain by making the nerve membranes more permeable to ions. 15. Prostaglandins and substance P enhance the sensitivity of pain endings but do not directly excite the pain fibers [10].

9.3.3 Perception of Pain Each single nerve fiber arborizes into hundreds of minute free nerve endings that serve as pain receptors. The entire cluster of these endings from one pain fiber frequently covers an area of skin as large as 5 cm in diameter. This area is called the receptor field of that fiber. The number of endings is large in the center of the field but diminishes towards the periphery. Number of individual nerve fibers with their arborizing fibrils overlaps areas of the other adjacent pain fibers. Therefore, a pinprick of the skin usually stimulates endings from many different pain fibers simultaneously. When the pinprick is in the center of the receptive field of a particular pain fiber, the degree of stimulation of that fiber is far greater than when it is in the periphery of the field, because the number of free nerve endings in the middle of the field is much greater than at the periphery. Three Types of Stimuli excite Pain Receptors—Mechanical, Thermal, and Chemical. Fast pain is elicited by the mechanical and thermal types of stimuli, whereas slow pain can be elicited by all three types [10].

9.3.4 Nonadaptive Nature of Pain Receptors In contrast to most other sensory receptors of the body, pain receptors adapt very little and sometimes not at all. In fact, under some conditions, excitation of pain fibers becomes progressively greater, especially so for slow-aching nauseous pain, as the pain stimulus continues. This increase in sensitivity of the pain receptors is called hyperalgesia. One can readily understand the importance of this failure of pain receptors to adapt, because it allows the pain to keep the person apprised of a tissue-­ damaging stimulus as long as it persists so that preventive action could be taken [10].

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9.3.5 Rate of Tissue Damage as a Stimulus for Pain The average person begins to perceive pain when the skin is heated above 45 °C at which the tissues begin to be damaged by heat; the tissues are eventually destroyed if the temperature remains above this level for a long time. Therefore, pain from heat is closely correlated with the rate at which damage to the tissues is occurring and not with the total damage that has already occurred. The intensity of pain is also closely correlated with the rate of tissue damage from other causes like bacterial infection, tissue ischemia, tissue contusion, and so forth.

9.3.6 Tissue Ischemia as a Cause of Pain When blood flow to a tissue is blocked, the tissue often becomes very painful within a few minutes. The greater the rate of metabolism of the tissue, the more rapidly the pain appears. When a blood pressure cuff obliterates the arterial supply and the arm is exercised, it can cause muscle pain within 15–20  s. Accumulation of large amounts of lactic acid in the tissues, formed as a consequence of anaerobic metabolism, is suggested to be the cause of pain. In addition, bradykinin and proteolytic enzymes, formed in damaged cells and tissues, add to pain. Muscle spasm is a common cause of pain and the basis of many clinical pain syndromes. It probably results from the direct effect stimulating mechano-sensitive pain receptors and compression of the blood vessels, causing ischemia and increasing metabolic rate of the tissue under spasm by the release of chemical pain-­inducing substances.

9.3.7 Localization of Fast Pain in the Body The fast-sharp type of pain can be localized much more exactly in the different parts of the body than can slow-chronic pain. However, when only pain receptors are stimulated, without the simultaneous stimulation of tactile receptors, even fast pain may be poorly localized, often only within 10  cm or so of the stimulated area. Yet, when tactile receptors that excite the dorsal column–medial lemniscal system are simultaneously stimulated, the localization can be nearly exact [10].

9.3.8 The Slow-Chronic Pain The slow-chronic pain is elicited mostly by chemical pain stimuli and sometimes by persisting mechanical or thermal stimuli. This slow-chronic pain is transmitted to the spinal cord by type C fibers at velocities between 0.5 and 2 m/s.

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9.3.9 P  aleospinothalamic Pathway for Transmitting Slow-­ Chronic Pain The paleospinothalamic pathway evolutionarily is a much older system and transmits pain mainly from the peripheral slow-chronic type C pain fibers. It however transmits some signals from type A delta fibers as well. In this pathway, the peripheral fibers terminate in the spinal cord almost entirely in laminae II and III of the dorsal horns, which together are called the substantia gelatinosa. Most of the signals then pass through one or more additional short fiber neurons within the dorsal horns themselves before entering mainly lamina V, also in the dorsal horn. Here the last neurons in the series give rise to long axons passing first through the anterior commissure to the opposite side of the cord, then upward to the brain in the anterolateral pathway.

9.3.10 Substance P, the Probable Slow-Chronic Neurotransmitter of Type C Nerve Endings Type C pain fiber terminals entering the spinal cord secrete both glutamate transmitter and substance P transmitter. The glutamate transmitter acts instantaneously and lasts for only a few milliseconds. Substance P is released much more slowly, building up in concentration over a period of seconds or even minutes. The “double” pain sensation one feels after a pinprick might result partly from glutamate immediately and substance P transmitter giving a more lingering pain sensation.

9.3.11 Chronic Pain Signals into the Brain Stem and Thalamus The slow-chronic paleospinothalamic pathway terminates widely in the brain stem on the reticular nuclei of the medulla, pons, and mesencephalon (the mid brain), the tectal area of the mesencephalon deep to the superior and inferior colliculi and/or the periaqueductal gray region surrounding the aqueduct of Sylvius. These lower regions of the brain appear to be important for the suffering from pain. Pain receptors are nonadapting type, and in terminating in the reticular system it is supposed to serve the alertness function. That is why when significant pain exists, sleep is generally not possible. From the reticular nuclei the pain fibers are then relayed to the intralaminar nuclei of the thalamus for further processing. Only a small fraction of the pain signals project directly to the ventro-basal complex of the thalamus. The nervous system has poor capacity to localize chronic pain transmitted by the slow-chronic pathway through the paleospinothalamic pathway. For instance, slow-­ chronic pain can usually be localized only to a major part of the body, such as to one arm or leg but not to a specific point on the arm or leg. This is in keeping with the multisynaptic and diffuse connectivity of this pathway. It explains why patients often have serious difficulty in localizing the source of some chronic types of pain [10].

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9.3.12 Physiologic Mitigation of Pain Periventricular nuclei and nuclei from the periaqueductal gray area secrete enkephalin at their endings. The endings of many fibers in the raphe magnus nucleus also release enkephalin when stimulated. Fibers originating in this area send signals to the dorsal horns of the spinal cord to secrete serotonin at their endings. The serotonin causes local cord neurons to secrete enkephalin as well. The enkephalin is believed to cause both presynaptic and postsynaptic inhibition of incoming type C and type A delta pain fibers where they synapse in the dorsal horns. Thus, the analgesia system can block pain signals at the initial entry point to the spinal cord. In fact, it can also block many local cord reflexes that result from pain signals, especially withdrawal reflexes. Nearly 10–12 such opiate-like substances have now been found at different points of the nervous system. All of these are breakdown products of three large protein molecules: proopiomelanocortin, proenkephalin, and prodynorphin. Among the more important of these opiate-like substances are b-endorphin, met-­enkephalin, leuenkephalin, and dynorphin. The two enkephalins are found in the brain stem and spinal cord and b-endorphin is present in both the hypothalamus and the pituitary gland. Dynorphin is found mainly in the same areas as the enkephalins, but in much lower quantities.

9.3.13 Some Clinical Abnormalities of Pain and Other Somatic Sensations Hyperalgesia is excessive sensory stimulation when the eliciting stimulus is not a noxious type. If the excessive stimulation results in a pain sensation, it is called as allodynia, for example, a light cloth drawn across the feet. Paresthesia is a sensation that is not expected of from a particular stimulus, like paraosmia. These sensations may result from the sensitization of the pain sensitive nerves (primary hyperalgesia), or because the transmission of the impulses is facilitated, called the secondary hyperalgesia. The other causes are in cases where the axonal degeneration is going on with a fast tempo, or the A delta and C fibers are damaged, or pain the regenerating axons sometimes cause, with some other causes and mechanisms described earlier. Disconnection of the sensory fibers with the dorsal root ganglia or after an axonal death is taking place centripetally, pain may occur by the spontaneous generation of ectopic impulses in the dorsal root ganglion. Analgesia is the absence of any pain sensation on stimulation. Possible causes of hyperalgesia are (1) excessive sensitivity of the pain receptors themselves—the primary hyperalgesia, and (2) facilitation of sensory transmission, which is called secondary hyperalgesia. An example of primary hyperalgesia is the extreme sensitivity of sunburned skin, causing sensitization of the skin pain endings by local tissue products from the burn. The implicated products are—perhaps histamine, perhaps prostaglandins, perhaps others. Secondary hyperalgesia frequently

9.4  Clinical and Laboratory Correlates of Small Fiber Neuropathy Diabetes (SFN…

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results from lesions in the spinal cord or the thalamus. Any disequilibrium between the normal afferent inputs on the dorsal horn and the substantia gelatinosa in complex ways may give rise to pain.

9.3.14 Surgical Interruption of Pain Pathways When a person has severe and intractable pain (sometimes resulting from rapidly spreading cancer), it is necessary to relieve the pain. To do this, the pain nervous pathways can be cut at any one of several points. If the pain is in the lower part of the body, a cordotomy in the thoracic region of the spinal cord often relieves the pain for a few weeks to a few months. To do this, the spinal cord on the side opposite to the pain is partially cut in its anterolateral quadrant to interrupt the anterolateral sensory pathways which are crossing from the opposite side of the body (see above). A cordotomy, however, is not always successful in relieving pain, for two reasons. First, many pain fibers from the upper part of the body do not cross to the opposite side of the spinal cord until they have reached the brain, so that the cordotomy does not transect these fibers. Second, pain frequently returns several months later, partly as a result of sensitization of other pathways that normally are too weak to be effectual (e.g., sparse pathways in the dorsolateral cord). Another experimental operative procedure to relieve pain has been to cauterize specific pain areas in the intralaminar nuclei in the thalamus, which often relieves suffering types of pain while leaving intact one’s appreciation of “acute” pain, an important protective mechanism.

9.4

 linical and Laboratory Correlates of Small Fiber C Neuropathy Diabetes (SFN) and Diabetes

The section discusses some features uncovered so far. The importance of it lies in the relationship both with testing the functions in laboratory and in some cases with the therapeutics of painful neuropathy. 1. SFN has been beautifully and allegorically described as the microalbuminuric equivalent of DPN. 2. It can be present without any particular disturbance in the pain sensing mechanisms. This will be more likely in type 1 diabetes. 3. Small fibers are the first to be affected in diabetes before the other somatosensory large thick fibers are affected. The small unmyelinated C fibers are the pain, heat, cold, heat pain and cold pains and thermal sensation carrying fibers. 4. These are protective sensations. Hence detecting them as early as possible is a necessity. This should be recognized and tested in a newly detected diabetic in particular once the initial controls are started. In established cases the likelihood is that even the large fibers will have dysfunction and some symptoms.

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5. The autonomic nerve fibers do not carry these sensations although small in diameter. These however could also be affected similarly early since these are also small fibers. The issues related with the autonomic fibers are discussed in many chapters of this volume. 6. The proportion of any of the Quantitative Sensory Testing (QST) abnormalities is higher in painful DSPN and could be beyond the 2 standard deviations, compared with DSPN without pain [11]. 7. The “loss of function” is generally more prevalent. The nerve fibers are affected in degrees. An “irritable nociceptor” may have preserved small fiber function of cold, warm, and pinprick sensitivity, and has hyperalgesia. The patients showing irritable nociceptors pattern are much less frequent. 8. Whereas the “deafferentation” is more easily detected by the thermal or mechanical sensory loss. Deafferentation is much more prevalent, over half getting affected. 9. A third type of pain sensation is also characterized, over 30% which do not fall in either category. Paradoxical heat sensations (PHS) during the procedure of alternating warm and cold stimuli, technically described as thermal sensory limen (TSL). 10. There appears to be an exclusive relationship between higher thermal sensory thresholds and hyperinsulinemia, as well as reduced insulin sensitivity. This indicates why the involvement of the small nerve fibers precedes others as the earliest detectable sign of neuropathy in glycemic abnormalities starting from IGT (see above) [12]. 11. Cold and cold-pain detection are transmitted through lightly myelinated Aδ fibers which are also early to degenerate. Thus, lowering of cold pain or higher heat pain thresholds are more important to detect early since these are the real protective sensations in a hot country like India with barefoot walking. Thermal thresholds are the most useful and specific for detection and evaluation of a small fiber neuropathy. 12. In the presence of altered pain sensations, nerve conduction tests are often normal indicating earlier development of small fiber neuropathy. NCS detects the axonal degeneration or demyelination of large, thick, and myelinated fibers which are likely to take longer time to degenerate than small fibers to produce symptoms specific to them. 13. As discussed above and elsewhere classification of diabetic neuropathy is a losing battle. So is the case with SFN. Hence, under the perspective of diabetic neuropathy and clinical practice, it is better to identify and adequately quantify as well as measure the progression or regression of SFN, correlating the sensory abnormality with the affected fibers. There is little doubt that SFN worsens over time, the primary factor being the nonoptimal control of glycemia, taking care of the inflammation in diabetes at tissue level, and control of risk factors and so on. 14. Diabetes affects rhythmic vasomotion of small arterioles due to sympathetic damage early in disease. Loss of warm thermal threshold also occurs early with C fiber damage and correlates significantly to reduced vasomotion. Exact cause and effect or association between vasomotion and C fiber damage as a time relationship is not established. Since these deficits may occur as a part of sensory neuropathy, a patient is not likely to be aware if his feet come in contact with a hot object. This causes necrosis of the skin leading to ulcers.

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15. Skin biopsies in persons with diabetes show uniform depletion of substance P, calcitonin gene-related peptide (CGRP), and the cytoplasmic proteins, for small fiber specificity. Glabrous skin of the foot is far more affected by diabetes than that of hand.

9.5

Laboratory Assessment of Pain

1. One of the most comprehensive laboratory evaluations is the quantitative sensory testing [13]. There are other QST protocols like in USA or Czech protocols. 2. Cold detection thresholds (CDT); warm detection thresholds (WDT); paradoxical heat sensations (PHS) during the procedure of alternating warm and cold stimuli, (the thermal sensory limen); cold pain thresholds (CPT); and heat pain thresholds (HPT) specifically test the small fibers. These parameters relate to thermal sensations. There are other parameters as well. 3. A long prevalent method of testing mechanical pain sensitivity was qualitative using pinpricks or the Neuropen® from Owen Mumford, Oxford, UK [14]. 4. In addition, mechanical pain thresholds (MPT) for pinprick and pressure pain thresholds (PPT), pinprick sensitivity, and pain summation are tested by 5 or 10 repetitive pinprick stimuli, to test small fibers. The last method is called the wind-up ratio. (WUR.) WUR sums up the numerical ratings of each of the five a single pinprick stimulus, followed by 10 repetitive pinprick stimuli. Both the 5 and 10 prick stimulus rating are summed up separately. The sum of 10 is divided by the sum of 5 pricks giving a WUR ratio. 5. Using a set of seven custom-made weighted pinprick stimulators with a flat contact area of 0.2  mm diameter that exert forces between 8 and 512 mNewtons [15–17]. The final threshold is the geometric mean of five series of ascending and descending stimulus intensities. 6. The dorsum of the foot is the area tested. Pain prick test (PPT) is done on the sole of the foot. 7. Mechanical pain sensitivity (MPS) for pinprick stimuli and dynamic mechanical allodynia assess A delta-mediated sensitivity to sharp stimuli (pinprick).

9.5.1 The SET Device 1. The SET device contrasts with Neuropen by a semiquantitative assessment by increasing the gradation of pain perception thresholds. For this reason it is considered to be a better parameter to assess the progression/regression of diabetic neuropathy [18]. 2. SET, a prototype developed by Dr. W.  Henniges, Zülpich, Germany, is a new handheld device to quantify mechanical pain sensitivity by pressing a plastic tip to the skin of defined anatomical sites. So far, mechanical pain sensitivity was examined qualitatively using pinpricks or the Neuropen® (Owen Mumford,

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Oxford, UK). In contrast to the Neuropen, the SET device allows a semiquantitative assessment by providing a gradation of pain perception thresholds between 0 and 20. Therefore the new SET device might serve as a parameter for judgment of the clinical course of diabetic neuropathy. It can be used at any location of the human body. 3. The device looks like a pen and consists of an interchangeable pin prick at one side and a calibration scale (meter) at the opposite side. The gradation of the calibration scale with an enclosed spring device records and increases the pressure very slowly until the patient recognized a pain sensation, and the corresponding value at the calibration scale was recorded to a defined area of the attached tip. Consequently the pressure for producing pain is calculable as power per area. The calibration scale is in a range of 0–20. The areas suggested are two plantar skin areas—first metatarsal head and heel. Two dorsal areas are first metatarsal head and the base of metatarsal. 4. Dorsal SET measurements show much higher pain thresholds in the neuropathic group than in non-neuropathic patients. Plantar SET measurements show only a trend towards higher SET measurements in the neuropathic group only. SET measurements from both feet are closely related. 5. Mechanical pain sensitivity using the SET device has the highest sensitivity for the detection of impaired sensations in feet of diabetic patients. The specificity is relatively lower but still acceptable. The 10-gauge monofilament contrarily gives a poor sensitivity but excellent specificity.

9.5.2 Quantitative Sensory Testing by NerveCheck 1. This testing modality needs different apparatuses. NerveCheck is a new device costing around $500, is portable, and measures the vibration perception threshold (VPT), cold perception threshold (CPT), warm perception threshold (WPT), and the heat pain threshold (HPT) of the patient. It uses different levels of stimulation of a particular type. The range of intensity of the stimulus is quite broad. Naturally it gives a clear response, the degree of which can decide the severity or otherwise of neuropathy. It has been shown to have good reproducibility. Its diagnostic accuracy is comparable to other established QST equipment. It is also claimed to accurately identify sensory deficits of patients with painful diabetic neuropathy [19]. 2. The diagnostic utility of NerveCheck to detect large fibers is claimed validated by comparing it with nerve conduction studies in the same patients. Similarly small fiber neuropathy has been compared with CCM and IENFD [20]. Objective tests of small fiber neuropathy include structural loss of small nerve fibers detected by corneal confocal microscopy (CCM) in the eye and intraepidermal nerve fiber density (IENFD) in skin biopsies taken from the foot discussed in the chapter on Sudomotor Dysfunction and Histology in Diabetic Neuropathy

9.6  Details for Laboratory Measurement of Thermal Sensations

181

9.5.3 Q  uantitative Sensory Testing—Some More Aspects 1. It extends the traditional questionnaires, clinical bedside and neurological examination of somatosensory function [21]. 2. To remind, standard electrodiagnostic studies do not asses pain. 3. Laser evoked potentials (LEP) and functional neuroimaging (fMRI and PET) are some other highly sophisticated examination modalities discussed in the chapter of Electrophysiology in Diabetic Neuropathy [22]. 4. Pressure pain thresholds assess the cutaneous as well as the deep pain sensitivity [13, 23–25]. It uses a pressure gauge with a flat probe with diameter of 1.1 cm. The pressure is gradually increased to 20 kg/cm2/increased by 0.50 kg/s to determine the pressure pain threshold [13, 26, 27]. 5. In particular, small fiber neuropathy cannot be identified at all by standard electrophysiology.

9.6

 etails for Laboratory Measurement D of Thermal Sensations

In a hot country like India where barefoot walking is not uncommon injuries due to excessive heat causing ulcers in diabetic foot is a reality. It is compounded by the concomitant presence of sensory neuropathy and loss of pain which does not sense the excessive heat damaging the foot leading to big ulcers. Barefoot walking is a religious norm in temple visits, holy places, and pilgrimages which add to the damage. Other examples of thermal injuries in India cited by Indian workers are the contact of feet on the hot exhausts of motorbikes or the cover of the engine in the driver’s cabin in public transport system, where people tend to rest their feet after removing whatever foot wear they have. A person with diabetic foot may not sense temperatures as high as engine casing of a running vehicle which may result into burn injuries. Another common cause of thermal injury is that Indian fondness for hot fomentations or immersing the feet in hot water. As seen above, the thermal sensory fibers are the earliest to lose their function. On this background it is relevant to test for thermal thresholds, make patients aware that this needs to be addressed properly. Of the two pain sensations thermal threshold technique is more objective and more convincing to the patient to take precautions. It is discussed in this chapter in greater detail as it is an important small fiber neuropathy.

9.6.1 The Thermal Receptors Human being can perceive different gradations of cold and heat, from freezing cold to cold to cool to indifferent to either cool or warm, to warm, hot to burning hot. Thermal gradations are discriminated by at least three types of sensory

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receptors: cold receptors, warmth receptors, and pain receptors. The pain receptors are stimulated only by extreme degrees of heat or cold and, therefore, are responsible, along with the cold and warmth receptors, for “freezing cold” and “burning hot” sensations. The cold and warmth receptors are located immediately under the skin at discrete separated spots. In most areas of the body, there are 3–10 times as many cold spots as warmth spots. This could be more damaging in a hot country like India. The number in different areas of the body varies from 15 to 25 cold spots per square centimeter in the lips to 3–5 cold spots per square centimeter in the finger to less than 1 cold spot per square centimeter in some broad surface areas of the trunk. A definitive cold receptor has been identified. It is a special, small type A delta myelinated nerve ending that branches a number of times, the tips of which protrude into the bottom surfaces of basal epidermal cells. Signals are transmitted from these receptors via type A delta nerve fibers at velocities of about 20 m/s. Some cold sensations are believed to be transmitted in type C nerve fibers as well, which suggests that some free nerve endings also might function as cold receptors. Although the existence of distinctive warmth nerve endings is quite certain, based on psychological tests, they have not been identified histologically. They are presumed to be free nerve endings, because warmth signals are transmitted mainly over type C nerve fibers at transmission velocities of only 0.4–2  m/s [10]. There are five types of responses that occur when thermal stimulation is applied—Cold, Cool, Indifferent (also called a neutral zone), Warm, and Hot. These fibers respond differently at different levels of temperature. In the very cold region, only the cold-pain fibers are stimulated. If the skin becomes even colder, so that it nearly freezes or actually does freeze, these cold fibers cannot be stimulated. That is how probably the Frost Bite occurs. The cold pain is manifest when the skin temperature drops below 15°. As the temperature lowers to 10° and further below the cold-pain impulses cease, but the cool receptors begin to be stimulated, if the temperature starts rising from that level. It reaches peak stimulation at about 24 °C and fading out slightly above 40 °C. Above at about 30  °C, the warmth receptors begin to be stimulated, but these also fade out at about 49 °C. Finally, at around 45 °C, the heat-pain fibers begin to be stimulated by heat and, paradoxically, some of the cold fibers begin to be stimulated again, possibly because of damage to the cold endings caused by the excessive heat. There are four types of nerve fibers: (1) a pain fiber stimulated by cold, (2) a cool fiber, (3) a warmth fiber, and (4) a pain fiber stimulated by heat. The response from each has a zone of its own but also spreads over to the next temperature range. However the response then declines on entering the next zone of cold or heat stimulation [10]. A person determines the different gradations of thermal sensations by the relative degrees of stimulation of the different types of endings. One can also understand why extreme degrees of both cold and heat can be painful and why both these sensations, when intense enough, may give almost the same quality of sensation—that is, freezing cold and burning hot sensations feel almost alike.

9.6  Details for Laboratory Measurement of Thermal Sensations

183

9.6.2 S  timulatory Effects of Rising and Falling Temperature—Adaptation of Thermal Receptors When a cold receptor is suddenly subjected to an abrupt fall in temperature, it becomes strongly stimulated at first, but this stimulation fades rapidly during the first few seconds and progressively more slowly during the next 30 min or more. In other words, the receptor “adapts” to a great extent, but never 100%. Thus, it is evident that the thermal senses respond to marked rapid changes in temperature, in addition to being able to respond to steady states of temperature. This means that when the temperature of the skin is actively falling, a person feels much colder than when the temperature remains cold at some level. Conversely, if the temperature is actively rising, the person feels much warmer than he or she would at the same temperature if it were constant. The response to changes in temperature explains the extreme degree of heat one feels on first entering a tub of hot water and the extreme degree of cold felt on going from a heated room to the out-of-doors on a cold day.

9.6.3 Mechanism of Stimulation of Thermal Receptors It is believed that the cold and warmth receptors are stimulated by changes in their metabolic rates, and that these changes result from the fact that temperature alters the rate of intracellular chemical reactions more than twofold for each 10 °C change. In other words, thermal detection probably results not from direct physical effects of heat or cold on the nerve endings but from chemical stimulation of the endings as modified by temperature.

9.6.4 Rate of Change of Temperature and its Physiology The thermal sensations are carried by C fibers. Small fibers detect five sensations as described above—warm, heat pain, cold and cold pain, with an addition of a neutral zone. The rate of conduction for these sensations is slower, have a period of latency of about 500 milliseconds before the impulse gets initiated and 2 s more for it to reach the spinal cord if initiated from the great toe. The other characteristics of the conduction of the impulses and its distribution are also described in the anatomy of peripheral sensory nerves. Consequently there is a compounded delay in the sensation reaching the cortical areas, its registration of the sensation, and response to it. The rate of rise or fall of temperature in degrees as well as time is also a determinant of cognition of these sensations. All these physiological variables have been taken into account in designing the instruments to detect various cold and heat thresholds. Lastly there is a correlation between the thresholds of various sensations and how it translates to deficits. Deficits can be quantified now through various means described so far. What is important is—these thresholds and deficits can now be linked to predicting the likelihood of a foot at risk for ulceration. In general, it may be stated that greater (for heat pain) or lower (for cold pain) the threshold, higher is the deficit. For example, a vibration perception deficit recorded as 25 volts increases the risk of ulceration. The same reaching 42 volts will result in a much higher risk

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than one at 25 volts. Hence this relation should also be borne in mind when normal thresholds are not detected in testing thermal sensations.

9.6.5 P  hysiological Ranges of Thermal Sensations in Normal Individuals Any thermal stimulus applied to the plantar surface for long enough (explained later) and heats up the skin (or cools it down) have been used to determine the normal ranges. The temperatures between 32 and 34 °C produce neither the sensation of heat nor cool sensation, hence is called a neutral zone. Temperature just below 32 °C and up to 27 °C is the cool threshold range. Both the heat and cold temperature ranges are age dependent. The heat sensation level increases to a higher degree with age since there are fewer nociceptors/thermal nerve fibers in a square skin area. The cool sensation also increases in the negative direction whereby greater fall is required for the cool sensation to appear. The concept of heat pain and cold pain should be understood; these thresholds are higher and lower than warm and cool sensations, respectively. Cool pain is sensation of coolness with an additional component of discomfort something similar to standing near the AC. Heat pain is warmth plus pricking sensation. As a consequence, the heat pain threshold increases to a higher level and cold pain threshold drops to a lower ­temperature range if there fibers are dmamged or decrease in numbers with age. The patient needs to be told that it is the slight discomfort to be detected for these pain thresholds and should be reported immediately. It is not his ability to bear chill or heat that is being tested but the sensitivity. Similarly, cold pain thresholds drop further down before cold pain, which is also equally damaging, is sensed. The sensation of cool pain appears within the range of 27–25 °C. The interval for the sensation of warmth is 36–38  °C.  The normal heat pain zone is from 42 to 45 °C. The above ranges are true for clinical practice in an ambient t­emperature of 27–37 °C which does not affect the skin temperature significantly.

9.6.6 Tissue Damage under Thermal Stimuli Although the normal heat pain threshold range is 42 to 45 °C, erythema of the skin takes place after an hour at 45 °C. But at 50 °C it needs 10 s to a minute for tissue damage, and just 1 s at 55 °C when the skin proteins coagulate.

9.7

 hermal Threshold Measuring Instrument T and the Process

India has achieved one more distinction in this area of measuring the thermal thresholds. The widely available heat and cold perception sensitometer developed by the Dhansai Laboratories in collaboration with the Diabetic Foot Society of India, a unique body of its own kind, now recognized worldwide for the work it has done

9.8  Components of Heat and Cold Perception Sensitometer

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since 2002 from its inception and for a couple of years earlier to that with Novo Nordisk Education Foundation Bengaluru. At this point suffice it to say that it is much more compact and far easier to use compared to similar instruments used in the Western World. There are other instruments which will also be described later but the Indian instrument can be considered really sophisticated.

9.8

Components of Heat and Cold Perception Sensitometer

9.8.1 Methods of Generating the Heat Quanta It uses an electrical heat pump by using P and N junctions of transistors as a thermopile which transmits heat from one side to the other. The gold tipped probe also has a sensor to measure the heat transmission.

9.8.2 Issues about the Probe Tip Parabolic tips are best for equal pressure and total skin contact. Rounded tips produce uneven pressure or higher pressures near center and less at the edges, hence not recommended. The best material to coat the tip is gold which distributes the heat generated or removes it uniformly within itself. It would give the near exact accuracy. The weight of the handheld probe also provides stability and uniformity of contact.

9.8.3 Accuracy and Traceability In the best instruments it should be ten times higher than the resolution that is 0.01 °C. Traceability to National Physical Laboratory, New Delhi, is required. If an integrated circuit is used, system calibration is a must. Radiation ratio measurement can be used to measure the uniformity of the surface temperature only.

9.8.4 Method of Testing for Temperature Perception The method most applicable to clinical settings in India is described below. It will be discussed in some details in this section. There are four keys with which to raise or lower the temperatures, one for resetting the temperature to a neutral zone. 1 . Set the rate of change to 4 s per °C, explained again below, as the most ideal. 2. Apply the gold tipped probe to the same sites as monofilament testing. 3. Warm and cold sensations should be tested separately. 4. First test heat perception/pain, then test the cold and cold pain. 5. The tip contact should be withdrawn as soon as the patient responds to either heat or heat pain in a zone above the heat pain, i.e., up to 42 °C.

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6. The same phenomenon can occur while testing for the cold and cold pain sensation. 7. The test can be repeated at the same site after about 2 min if required. This lag is necessary for the skin temperature to return to normal. The heat and cold perceptions are quite likely to be lost in feet in diabetic patients. The patient can appreciate the loss better when the same temperatures during testing are applied to his hands. Hence it should be done prior to testing the lower limbs.

9.8.5 Interpretation If the subject does not sense the warmth of tip at the abovementioned cold and heat range, loss of protective sensations is contemplated. Also, the loss of cold and/or heat pain beyond the normal threshold is indicative of an at-risk foot for Frost Bite.

9.9

 etails about Heat and Cold Perception (HCP) D Sensitometer

The instrument is shown in the figure alongside. It has nine user-friendly programs to raise and lower the temperature once the probe is applied to the skin. It has no fluids, liquids, or filtering. It is a stand-alone operation which can be interfaced with computer and is fully controllable through computer. The additional features are that of real-time graph on the monitor, data storage on Personal Computer (PC), computerized report generation in both tabular and graphical format which can be seen and the report can thus be printable. The Four Keys for Operation: 1. The cool key is used for starting the cool and cold pain threshold testing. It is also used as a reduce key in other settings. 2. The warm key is used for starting the warm and heat pain threshold testing. It is also used as an increase key in other settings. 3. Set key is used to set desired temperature. It also starts the communication to the computer. In combination with cool/warm keys the settings can be decreased or increased. 4. Program key is used to set the program or change it with cool/warm keys. It also aborts the ongoing test process and computer communication.

9.9.1 The Programs Program 0 to 2 – In these three programs the probe is in contact with skin at the location to be tested. The program starts with the base temperature. If the cool

9.10  Steps for Cool Testing as a General Example

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Fig. 9.1  Heat and Cold Perception Sensitometer with a parabolic gold tipped probe (Courtesy DHANSAI Laboratories)

side is to be tested, the temperature should be set at 34 °C. This is also the default setting, whereas 30 °C is preferred for warm side testing. In both settings it helps to detect the gradual transition from a higher to a lower or a lower to higher temperature. The operation process irrespective of the program one may set is the same (Fig. 9.1).

9.10 Steps for Cool Testing as a General Example 9.10.1 First Part of Operation • • • • • •

Press the cool key. Let the temperature reach the cool base, i.e., 34 degrees. Put the probe in skin contact firmly and uniformly. Keep the cool button pressed. Let the temperature start dropping. Ask the patient to say yes when he feels cold. Note the temperature. On receiving “YES” response the key is released and then warm key is kept pressed to increase the temperature. • The probe even now remains in contact.

9.10.2 Second Part of Operation Now ask the patient to say NO when he loses the cool sensation. Note the temperature again. On receiving the “NO” response to the stimuli change the direction to cool again till a YES response is obtained again. The average of these temperatures is the cool threshold (Fig. 9.2).

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Fig. 9.2  Parabolic gold tipped probe for the most uniform contact with the skin and for uniform distribution or removal of heat (Courtesy DHANSAI Laboratories)

If the operator desires a finer testing, the test can be repeated as many as five times. That will give five pairs of YES and NO. The average of all is the absolute cool detection threshold.

9.10.3 The Nine Programs The nine programs differ in only one respect—the rate of change of temperature in either direction, cool or hot. In program zero the rate of change of temperature is fixed to 1 °C per second. It is a simple program which is fast, hence suitable for initial screening (Fig. 9.3).

9.10.4 Program 1 The rate of change of temperature can be set from 1 °C per 1–8 s. With these rates of change in temperature one can get more accurate thresholds but it is a slow program.

9.10  Steps for Cool Testing as a General Example

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Fig. 9.3  Ambient Skin Temperature Detector as used with Heat and Cold Perception Sensitometer Courtesy DHANSAI Laboratories

9.10.5 Program 2 It is a combination of previous programs. Here the rate of change of temperature reduces by half every time there is a change in direction. One can thus reach near the threshold quicker and then detect it accurately with slower rates of change. This allows for adaptation to the effect of long latency and slow transmission velocities of the C fibers to carry sensations.

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9.10.6 Program 3 From program three onwards the method of testing changes. The desired temperature is preset. On reaching that temperature one big LED lights up. The probe is then touched to the skin at appropriate location. Two beeps are heard after 5 s as the skin reaches the desired temperature. After these beeps the response from the person should be elicited. The next temperature setting has to be decided. The desired temperature can be set by pressing the “Set” key and “Cool” or “Warm” key together to decrease or increase the set temperature. The merits of this program is its suitability for most of the test methods like method of limits, method of constant stimuli, adjustment, and any other method to be implemented through computer.

9.10.7 Program 4 It is same as 3 with an addition of step temperature. On pressing both “Set” and “Prg” keys simultaneously the step is displayed. It can be increased or decreased by pressing “Warm” or “Cool” key additionally. To start the test—Press the “Cool” key for cool side testing as before and release. The set temperature will reduce by one step, that is, if the step is 1 °C and set temperature is 34 °C, then the temperature will become 33 °C. It will reduce by 1° every time the “Cool” key is pressed. Pressing “Warm” key the temperatures will raise in the same manner. This program is most suitable for method of limits and method of adjustments.

9.10.8 Programs 5 and 6 These programs are designed for the most popular and trusted method—the successive approximation or 4,2,1 method. Program 5 is for cool or warm thresholds. Therefore in program 5 the starting step is 2 °C. Program 6 is for cold or heat pain. Here the step is 8 °C in program 6. On pressing the “Cool” key, the temperature drops by 8 °C. If the response is YES for cool, press “Cool” key. The temperature will rise by 4 °C If the response now is warm, then on pressing the cool key again it will decrease further by 2°. For every reversal the step will reduce by half and zero on the threshold.

9.10.9 Program 7 and 8 The skin temperature is displayed when the skin probe is attached to the connector in the front and then touched to the appropriate skin area.

References

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9.10.10  Base Temperatures One can change the cool base and heat base temperature in program 7 and 8, respectively. It is done in the same way as one change the set temperature in earlier programs. A rate of 1° per second is generally recommended by some investigators. But for the correct comprehension and reporting for heat and cold thresholds, the rate of rise or fall of temperature seems best at 1 °C over 4 s since C fibers carry sensations at a much slower speed as shown above. These factors determine the rate of rise or fall of temperature that the patient needs to sense and respond to. This makes testing a little longer but gives precise thresholds, reduces the need for many readings, averaging, etc.

9.10.11  The Report • When the computer is connected, the report can be generated through it. • When the tab is in appropriate location even by double clicking on the temp the data is transferred. • By clicking “report” one can see the tabular report. • By clicking “show graph” one can see the graphical format. • Any of the reports can be printed by clicking on print button. • The total and average is automatically done. • But for individual point if you need to take the averages one needs to do it manually [28].

References 1. Singer W, Spies JM, McArthur J, Low J, Griffin JW, Nickander KK, Gordon V, Low PA. Prospective evaluation of somatic and autonomic small fibers in selected autonomic neuropathies. Neurology. 2004;62:612–8. PubMed: 14981179. 2. Dabby R, Vaknine H, Gilad R, Djaldetti R, Sadeh M.  Evaluation of cutaneous autonomic innervation in idiopathic sensory small-fiber neuropathy. J Peripher Nerv Syst. 2007;12:98– 101. [PubMed: 17565534]. 3. Russell JW, Sullivan KA, Windebank AJ, Herrmann DN, Feldman EL. Neurons undergo apoptosis in animal and cell culture models of diabetes. Neurobiol Dis. 1999;6:347–63. [PubMed: 10527803]. 4. Singleton JR, Smith AG, Bromberg MB. Increased prevalence of impaired glucose tolerance in patients with painful sensory neuropathy. Diabetes Care. 2001;24:1448–53. [PubMed: 11473085]. 5. Tesfaye S, Chaturvedi N, Eaton SE, Ward JD, Manes C, Ionescu-Tirgoviste C, Witte DR, Fuller JH.  Vascular risk factors and diabetic neuropathy. N Engl J Med. 2005;352:341–50. [PubMed: 15673800]. 6. Costa LA, Canani LH, Lisboa HR, Tres GS, Gross JL. Aggregation of features of the metabolic syndrome is associated with increased prevalence of chronic complications in type 2 diabetes. Diabet Med. 2004;21:252–5. [PubMed: 15008835]. 7. Vincent AM, Hinder LM, Pop-Busui R, Feldman EL. Hyperlipidemia: a new therapeutic target for diabetic neuropathy. J Peripher Nerv Syst. 2009;14:257–67. [PubMed: 20021567].

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8. Wiggin TD, Sullivan KA, Pop-Busui R, Amato A, Sima AA, Feldman EL. Elevated triglycerides correlate with progression of diabetic neuropathy. Diabetes. 2009;58:1634–40. PubMed: 19411614. 9. Gibbons CH, Freeman R. Treatment-induced diabetic neuropathy: a reversible painful autonomic neuropathy. Ann Neurol. 2010;67:534–41. [PubMed: 20437589]. 10. Guyton & Hall. Pennsylvania, USA. In: Textbook of Medical Physiology. 11th ed: Elsevier Inc.; 2006. International Edition ISBN 0-8089-2317-X. 11. Raputova J, Srotova I, Vlckova E, Sommer C, Üçeyler N, Birklein F, Rittner HL, Rebhorn C, Adamova B, Kovalova I, Kralickova Nekvapilova E, Forer L, Belobradkova J, Olsovsky J, Weber P, Dusek L, Jarkovsky J, Bednarik J. Sensory phenotype and risk factors for painful diabetic neuropathy: a cross-sectional observational study. Pain. 2017;158(12):2340–53. 12. Sumner CJ, Sheth S, Griffin JW, Cornblath DR, Polydefkis M. The spectrum of neuropathy in diabetes and impaired glucose tolerance. Neurology. 2003;60:108–11. 13. Rolke R, Baron R, Maier C, Tolle TR, Treede RD, Beyer A, Binder A, Birbaumer N, Birklein F, Botefur IC, Braune S, Flor H, Huge V, Klug R, Landwehrmeyer GB, Magerl W, Maihofner C, Rolko C, Schaub C, Scherens A, Sprenger T, Valet M, Wasserka B. Quantitative sensory testing in the German research network on neuropathic pain (DFNS): standardized protocol and reference values. Pain. 2006;123:231–43. 14. Paisley AN, Abbott CA, van Schie CH, Boulton AJ. A comparison of the Neuropen against standard quantitative sensory-threshold measures for assessing peripheral nerve function. Diabet Med. 2002;19:400–5. 15. Baumgartner U, Magerl W, Klein T, Hopf HC, Treede R-D. Neurogenic hyperalgesia versus painful hypoalgesia: two distinct mechanisms of neuropathic pain. Pain. 2002;96:141–51. 16. Chan AW, MacFarlane IA, Bowsher D, Campbell JA. Weighted needle pinprick sensory thresholds: a simple test of sensory function in diabetic peripheral neuropathy. J Neurol Neurosurg Psychiatry. 1992;55:56–9. 17. Magerl W, Wilk SH, Treede R-D. Secondary hyperalgesia and perceptual wind-up following intradermal injection of capsaicin in humans. Pain. 1998;74:257–68. 18. Nguyen M, Henniges W, Lobisch M, Reifert S, Larbig M, Pfützner A, and Forst T, Evaluation of SET–A New Device for the Measurement of Pain Perception in Comparison to Standard Measures of Diabetic Neuropathy. Diabetes Technol Ther. 2004;6(5):601–606. Published Online:12 October 2004. 19. Ponirakis G, Odriozola MN, Odriozola S, et  al. NerveCheck: an inexpensive quantita tive sensory testing device for patients with diabetic neuropathy. Diabetes Res Clin Pract. 2016;113:101–7. 20. Haanpaa M, Attal N, Backonja M, et al. NeuPSIG guidelines on neuropathic pain assessment. Pain. 2011;152:14–27. 21. Greenspan JD.  Quantitative assessment of neuropathic pain. Curr Pain Headache Rep. 2001;5:107–13. 22. Dworkin RH, Backonja M, Rowbotham MC, Allen RR, Argoff CR, Bennett GJ, et al. Advances in neuropathic pain: diagnosis, mechanisms, and treatment recommendations. Arch Neurol. 2003;60:1524–34. 23. Bendtsen L, Jensen R, Olesen J. Qualitatively altered nociception in chronic myofascial pain. Pain. 1996;65:259–64. 24. Brennum J, Kjeldsen M, Jensen K, Jensen TS. Measurements of human pressure–pain thresholds on fingers and toes. Pain. 1989;38:211–7. 25. Treede R-D, Rolke R, Andrews K, Magerl W. Pain elicited by blunt pressure: neurobiological basis and clinical relevance. Pain. 2002;98:235–40. 26. Fischer AA. Pressure algometry over normal muscles. Standard values, validity, and reproducibility of pressure thresholds. Pain. 1987;30:115–26. 27. Kosek E, Ekholm J, Hansson P. Pressure pain thresholds in different tissues in one body region. The influence of skin sensitivity in pressure algometry. Scand J Rehabil Med. 1999;31:89–93. 28. Dhansai Laboratory, Mumbai, India (2019) Manual Of Operation for Heat and Cold Sensitometer.

References

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Further Reading American Association of Electrodiagnostic Medicine Review: Quantitative Sensory Testing Equipment and Reproducibility Studies; A literature review of QST can be found in Muscle & Nerve, in the May 2004 issue, volume 29, pages 734–747 or on the Muscle & Nerve website at: http://www3.interscience.wiley.com/cgibin/fulltext/108066505/HTMLSTART. Rolke R, Magerl W, Campbell KA, Schalber C, Caspari S, Birklein F, Treede RD. Quantitative sensory testing: a comprehensive protocol for clinical trials. Eur J Pain. 2006;10:77–88.

Motor Neuropathy and Diabetic Hand Syndrome

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10.1 Introduction The sequence of diabetic sensory neuropathy, ulcer, infection, gangrene, and amputation generally captures more attention in practice as well as in literature. However there has to be a component of motor neuropathy without which the ulcers and its consequences to gangrene occur in substantial number than neuropathy alone. It is also now accepted that the motor neuropathy can even precede diabetic sensory neuropathy. It means that motor neuropathic abnormalities also would be high in prevalence by which time the sensory neuropathic disturbances catch up known to be frequent. The first issue therefore is to recognize the concurrence of these two and its consequences. Secondly, the motor neuropathy in diabetes is not restricted to foot alone. Like sensory neuropathy as has been repeatedly mentioned in the preceding chapter, the motor neuropathy affects other muscle groups in the upper limbs as well and some substantial muscle groups in the lower limb which will also be discussed. Some of these manifestations will be described briefly, in addition to what has been showed till now. The affliction of motor component neuropathy of the hands in diabetes is least understood. Its detailed review with lower limb motor neuropathies will enhance its understanding of the clinicians.

10.2 The Basic Pathophysiological Mechanisms 1. In normal conditions the foot shape is maintained. A normal foot shape distributes half of the weight of a person on each foot. This weight is distributed on six points—the five metatarsal heads and heel. 2. Ligaments of the foot are many. The basic function served by these ligaments is to hold the foot as one functional unit during locomotion and to prevent the unnecessary movement within the bones which could be destructive. 3. The shape is maintained also by the small muscles of the foot by a few layers of muscles in the foot which act in synergy to maintain the shape. © Springer Nature Singapore Pte Ltd. 2020 S. Kelkar, Diabetic Neuropathy and Clinical Practice, https://doi.org/10.1007/978-981-15-2417-2_10

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4. The numerous ligaments bind different bones and maintain the rigid structure of the foot. This results in addition to maintaining the shape in the formation or two arches in each foot—namely the lateral plantar arch and the medial plantar arch. 5. The lateral arch is constructed by the calcaneum, cuboid, and the last two metatarsals. Although slenderer of the two it is in full contact with the floor on standing and carries out function of an additional weight-bearing area resulting in addition to the weight/pressure borne by the six points described above. 6. The medial arch is the result of the strong plantar fascia which exerts a pull on the bones by its anterior and posterior attachments. It is formed by the calcaneum, talus, and the first three metatarsals. This is much higher in its curvature and forms a compartment like space in which all the main vessels that reach the foot as well as the nerves are present. This obviously does not bear much weight, but the strength of the fascia gives protection to these structures before these are further divided and supply all the structures of the foot proper. 7. The powerful and thick plantar fascia or the plantar aponeurosis works like a spring and absorbs the shock of walking or jumping, recoils, and goes back to the normal shape. As the spring recoils, it also helps in pushing the foot forward. 8. These two arches are considered complete arches since these meet the ground at the two ends. However, there is a third arch of which each foot bears one half. The lateral ends of these two arches are in ground contact, and the curvilinear rise ends in the middle of the medial arch. The arch becomes complete when the 2 feet are brought together and aligned with each other. 9. The challenge to maintaining the foot shape arises while walking, running, jumping, and so on where under the force of weight there are some changes for a brief interval in which the pressure increases sharply and then declines within a few milliseconds. 10. There has to be therefore a mechanism for this to happen. The primary mechanism arises from the tensile strength of the ligaments which, after the stretch in activity, recoil and form their original length thereby getting the foot back in shape. This incidentally also reforms the arches. 11. The most important is the plantar fascia which is one of the strong structures to be able to take the load and reform. 12. The sole of the foot is a specialized structure and has the ability to spread the weight from the small area of bones to the large area of the skin. 13. Weakness of the small muscles of the foot causes intrinsic destabilization of foot, its anatomical position, and leads to deformity.

10.2.1 The Pathophysiology of Diabetic Foot—The Ligaments 1. The structures described above undergo changes under the diabetic environment, uncontrolled state in particular. Therefore, all the mechanisms described in the pathogenesis of diabetic peripheral and autonomic neuropathy apply to these structures also described in the chapteron Pathogenesis of Diabetic Neuropathies.

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2. Certain changes are brought about by glycation in the ligamental structure under which these ligaments can become rigid or lax. 3. If rigid, these will cause a high arch foot called pes cavus. 4. If lax, the ligaments, particularly the plantar fascia, will not be able to hold the medial arch in its form and the arch will collapse. This is a classic early abnormality of Charcot’s Neuro-osteo-arthropathy, a disastrous consequence of diabetic foot. A detailed description is out of the scope of this volume but can be seen in National Guidelines of Diabetic Foot Manangement published by Diabetic Foot Society of India in November 2017 edited by the author. 5. Rigidity of the ligaments under glycation loses the spring action of the plantar fascia in particular. 6. The ligaments also serve an important function in weight distribution. 7. When these ligaments lose their elasticity, the mobility of the joints increases leading to the destabilization of the foot.

10.2.2 The Pathophysiology of Diabetic Foot—The Muscles 1. All effects on the muscles of the diabetic foot arise mainly due to motor neuropathy. As seen before, the axonal degeneration and loss would be the primary reason for the muscle atrophy, fibrillary potentials, and tone. 2. The motor nerves supply different muscle groups, and there will be variability of the number of axons that degenerate in each of the muscle groups. This in turn will give rise to differential muscle tones in different groups of these muscles; those with higher number of axons intact will have a more normal tone, but the other groups may have much greater axonal loss. 3. These muscle groups will show weakening of the basic muscle tone, may become hypotonic, atrophic, and will lose force of action. With axonal loss, there will be degeneration of the motor end plate which will further reduce the muscle tone and power. 4. The other effect of degenerating axons and its effect on motor end plate is fibrillation in the muscle fibers. Fasciculation and fibrillations are different. The first is seen as the larger muscle bundles having a wormlike contraction in clinical examination commonly seen in calcium inadequacy. Fibrillation can be picked up only on electromyography studies. 5. The interosseous muscles of the foot (see later) are small muscles in between the metatarsal bones. Motor neuropathy leads to the loss of ability of the small or the intrinsic muscles to hold the foot in normal shape and place it in the correct position. This differential tone also leads to the deformity of foot. 6. With motor neuropathy comes the atrophy which is well detectable by ultrasonography or MRI studies (see later). 7. The moment the foot is deformed either by muscle pathology or by ligamental changes described above, the entire foot-pressure dynamic changes. From the evenly distributed pressures along the six points and the lateral arch, some points will lose contact with the ground due to deformity and some points will remain in contact bearing weight for the other points as well.

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8. Obviously, the pressure on these points will be excessive and unphysiological. Such a foot then becomes maladapted to the shoes one wear, and the abnormal point of contact becomes a high-pressure area. 9. The repetitive pressure leads to keratosis and callus formation. The keratosis is said to develop more inappropriately in the presence of sensory neuropathy that is almost always present. 10. The pressure at the callus is nearly 20 times higher than the surrounding skin. Allowing the patient to walk with callus is akin to patient walking with pebble in his shoes. 11. Development of a callous is a good indicator of severity of neuropathy. The high pressure at the callus results in the damage to the tissues of the foot and can start the formation of ulcer below the callus that later on breaks through.

10.3 Anatomy of the Foot 10.3.1 Anatomy of the Ligaments This will be better understood now with the physio-pathological explanations given above. 1 . Each foot consists of 29 joints, 26 bones, and 42 muscles. 2. The plantar fascia arises from the tuberosity of calcaneum. It splits in the medial plantar aponeurosis (a more appropriate nomenclature) attaches to the lateral side of the first metatarsal. The middle, thick fibrous aponeurotic band proceeds distally, splits in five slips, and attaches itself to the bases of all five metatarsals. 3. The posterior tibial artery and the posterior tibial nerves which wind around the medial malleolus split at the base of the middle plantar aponeurosis into medial and lateral plantar artery and nerve.

10.3.2 Anatomy of the Muscles of the Foot Muscles of the foot are in four layers described as starting from the plantar side up.

10.3.2.1  The First Layer 1. Flexor digitorum brevis which digitates and its tendons attach themselves to the four metatarsal heads from 2 to 5. 2. The abductor hallucis attaches to the first metatarsal. 3. The abductor digiti minimi attaches to the fifth metatarsal.

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10.3.2.2  The Second Layer of Muscles in the Foot 1. The flexor digitorum longus tendon attaches to the lateral four metatarsals. 2. The flexor hallucis longus tendon is attached to the first metatarsal base.1 3. Quadratus plantae is a square muscle which also attached to the lateral four metatarsal bases, by splitting into four lumbricals. 10.3.2.3  The Third Layer 1. Flexor hallucis brevis connects with the base first metatarsal. 2. The adductor hallucis with its oblique and a transverse head also connects to the base first metatarsal. 3. Flexor digiti minimi brevis is attached to the last metatarsal head. 10.3.2.4  The Fourth Layer 1. Seven interossei of which three are designated as plantar and four are designated as dorsal. 2. The bigger muscles having their origin in the calf control the grosser and more powerful movements, but it is the interossei by their synergistic and antagonistic actions keep the mid foot in proper shape. 3. There are two tendons present in this layer: tibialis posterior and peroneal longus. 4. The last of the pathological change will be the insensate feet2 resulting in repetitive unrecognized trauma and abnormal distribution of pressure on feet due to simultaneous motor neuropathy. 5. Excessive mechanical pressure or friction with loss of protective sensation finally leads to the diabetic foot complications. 6. In motor neuropathy, it is the deformities that lead to these complications.

10.4 Examination of Motor Neuropathy Deformities are virtually pathognomonic of motor neuropathy of small muscles of feet and cause changes of importance. These can be easily noted on inspection.  From surgical anatomy point of view, the flexor hallucis longus tendon is in close proximity of first metatarsal head where most ulcers in diabetic foot occur and the infection spreads along the flexor hallucis longus tendon all the way up in the calf. Hence the entire flexor hallucis longus tendon has to be traced back in such cases and excised till one comes across a viable tendon portion. 2  Once the sensory neuropathy appears with, before or after the motor neuropathy, the feet become insensate and the person keeps walking even when an ulcer is formed since there is no pain. The ulcer then widens and deepens, serves as an entry point for infection and the subsequent complications. Most neuropathies in India and other less developed countries in South East Asia are sensory which thus adds to the burden of diabetic foot infections. Most ulcers begin small and should be taken care of, then the amputation rates will drastically come down (see the additional reading for all other details mentioned in other chapters). 1

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10.4.1 Deformities of the Toes The crowded tows tend to get above or below the adjacent toes or come to lie in an oblique direction, while in the same plain. These tows may then hurt the adjacent toes with their nails. Crowding of toes in the presence of sensory loss and poor foot hygiene can cause extensive web space fungal infection that leads to gangrene. Teaching the patient to separate the toes with cotton wool, foam pads, or commercially available separators of the toes can avert this. Cock up toes: The toes, especially the great toe, could cock up and is not level with the other toes of the foot. This makes them susceptible to trauma if shoes are habitually worn. The cock-up toes come in repetitive traumatic contact with the upper of the shoes and develops ulceration. In these cases, the fibro-fatty pad of the metatarsal head moves forward and exposes metatarsal head to direct pressure and trauma.

10.4.2 Deformities of Hallux and the Toes Hallus Valgus is the deformity of, the great toe is which is not in alignment with the next and causes deformity.

10.4.2.1  Hallux Rigidus Here the big toe does not move with the movement of the foot, does not bend or extend, hence becomes the site for repetitive injury and ulcer. 10.4.2.2  Clawing of Toes Due to an imbalance in the muscle tone of the intrinsic muscles of the foot, the toes bend down. This brings the tips of the toes in contact with the surface and bear pressure. The tips do not have the fatty insulation the toes in normal position have. There is little between the skin and the bone, and the pressure thus tends to ulcerate the tips of the toes. 10.4.2.3  The Hammer Toe The last of the phalangeal joint bends downward and takes the shape of a hammer. This causes the tip of the hallux to bear the pressure as the toe remains flexed. The bone is directly in contact with the ground with no cushion of fat in between. This leads to ulceration. 10.4.2.4  Foot Drop It occurs due to the weakness of dorsal flexors or the various proximal motor neuropathies that result in group wasting of muscles. Feet lying asymmetrically will indicate unequal muscle power. Wide, cautious, unstable gait, with patient looking down while walking, indicates posterior column involvement.

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10.4.3 Assessment of Motor Function The information obtained by testing following items is also mentioned along with the tested sign to indicate the pathophysiological basis of its development. Asymmetric nature of the findings, correlating the muscle abnormality with its corresponding nerve supply, hyperreflexia, hyporeflexia, or areflexia, Babinsky’s sign, tone, and power are the elements tested. 1. The muscle girth measured by flexible tape at the thigh and leg level by selecting same level from a bony point on both the sides. Asymmetrical girths indicate unilateral disease with involvement of major nerve trunks. 2. Testing for foot drop by asking the patient to lift his foot dorsally first without resistance but only antigravity. If he/she can do that, the patient should be asked to dorsiflex against minimal and gradually increase resistance. Similarly, the strength of plantar flexion could be tested against resistance. It should be then graded and entered in the recording sheet. The record should indicate which nerve is involved and the muscle group affected. 3. The flexion and extension at knees and hips should be carried out after that. The tone of the muscles should be tested. Gastrocnemius and soleus are flexors of the ankle joint and their tightness will reduce the ankle flexion, which is important for walking. 4. Motor stretch reflexes at the ankle and knee. Deep tendon reflexes of upper and lower extremity are part of normal neurological evaluation. 5. The strength of the muscles should be tested for both upper and lower extremities and graded as per the 0–5 Rankin’s Scale. 6. Plantar, the Babinskie’s reflex if present will detect pyramidal involvement and permanent hypertonic plantar flexion. This could become liable to pressure points as described above. 7. It is always advisable to check for at least the flexion and extension particularly at hips suspecting of having proximal femoral neuropathy or diabetic amyotrophy, a severe but self-limiting condition found among people with diabetes. It is necessary to reassure patients on that. It is described later.

10.4.4 Foot Pressure Studies in Diabetic Motor Neuropathy Abnormally high-pressure areas do develop on the plantar surface. High foot pressures predict ulcers. Such high foot pressures are associated with the first and recurrent plantar neuropathic ulcers. Foot pressure abnormalities may precede the appearance of sensory neuropathy. Plantar callus is associated with high pressure and predicts ulcer formation. These effects are an outcome of motor neuropathy mainly associated with diabetic foot. It does not have a direct bearing on diabetic motor neuropathy and its understanding. Hence it is not discussed here in any further details. The reader is referred to “National Guidelines of Management of Diabetic Foot,” a volume published by Diabetic Foot Society of India in 2017.

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Motor neuropathy involves large muscle groups as well. The most significant of this abnormality is discussed as follows.

10.5 Proximal Motor Neuropathy The various names given to this condition are diabetic amyotrophy, diabetic cachexia, Bruns-Garland syndrome, diabetic lumbosacral radiculoplexus neuropathy, diabetic mononeuritis multiplex, diabetic polyradiculopathy, and proximal diabetic neuropathy. Since the inception of the term, its nomenclature has been controversial because of its variable presentations.

10.5.1 General Features The clinical presentation is characterized by the following: 1. It is an important cause of walking disability due to motor and not sensory afflictions in type 2 diabetes in middle or later age. 2. Diabetes is usually of shorter duration, and glycemic excursions are not severe. 3. It would start as a sudden, sharp pain in one hip and thigh, later involving the other side within weeks to months. It could be painless as well. 4. As the pain improves, weakness becomes the major symptom. 5. Weakness and unilateral foot drop is first manifest in one-third of cases, becoming bilateral. 6. It affects both proximal and distal leg muscles. 7. Respiratory weakness may also be the initial manifestation of diabetic proximal neuropathy. 8. Prominent bulbar symptoms have also been noted in this condition. 9. In 25–35% diagnosis of diabetic amyotrophy leads to the diagnosis of diabetes. 10. Long-term diabetic complications of retinopathy and nephropathy are often absent. It is quite different from other diabetic neuropathies because it causes gross atrophy of the proximal muscles of the lower extremities and muscle weakness. 11. There is diffuse pain and loss of tendon reflexes. 12. A significant weight loss is observed, which alarms both the patient and the clinician as it could well point to an as yet asymptomatic malignancy. 13. That is why it is important to diagnose it at once to prevent money- and time-­ consuming unnecessary work up to rule out the malignancy, which the patient is going to be subjected to. 14. It is more commonly found in older male patients of type 2 diabetes. Its pathogenesis is obscure. 15. Muscle Involvement of severe degree is the most striking part. 16. The muscles supplied by femoral nerves are affected more than others.

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17. It usually presents acutely as unilateral thigh pain followed by weakness and later wasting in the anterior thigh muscles. It usually becomes bilateral over time. 18. Other muscles supplied by the lumbosacral nerve plexuses are also affected. 19. When severe and progressive, chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) mentioned at places in this volume should be considered. 20. There is generally the presence of diffuse bilateral mild to moderate polyneuropathy. 21. Diabetic amyotrophy can occur in nondiabetic people also and has very similar changes when compared to diabetic amyotrophy. That has led to the proposition that diabetes is a risk factor and not the cause of diabetic amyotrophy [1, 2]. 22. In this condition, a number of single nerves, nerves with multiple segment origin radiculopathy, and probably some spinal cord lesions are involved. 23. In its fully developed form, it is bilateral with severe atrophy of the muscles supplied by the femoral nerve, and also involves ileopsoas muscles bilaterally. It is accompanied by significant weight loss which becomes a matter of worry. It is a pure motor neuropathy but may be accompanied by sensory symptoms. The latter is a part of the generalized affliction of neuropathy in diabetes and not an integral part of diabetic amyotrophy. There are many elements which make its early diagnosis difficult which are listed in the following. The involvement of proximal large muscles against the distal muscle involvement in diabetes would be confusing. Slow evolution presents initially as asymmetric versus symmetric involvement. Sometimes instead of a slow evolution, the onset is abrupt against an insidious onset. There could be some differences in different electrophysiological and biopsy findings. There is often either an early or late onset of pain which could be severe, a feature that does not fit in the picture of pure motor neuropathy. There is also a spontaneous improvement in about 12 to 18 months. Diabetes control per se does not help in any way. It does not cause any end organ damage by itself [2]. Earlier it was considered that starting insulin to control diabetes or injecting insulin in the atrophying muscles might help. But no such evidence is available.

10.5.2 Differential Diagnosis 1. Systemic vasculitis: polyarteritis nodosa and other rheumatologic, vasculitic, and collagen vascular disorders. 2. Isolated peripheral nerve vasculitis: the second most common cause of vasculitic neuropathy after the above three. 3. Chronic inflammatory demyelinating polyradiculoneuropathy. 4. Compressive lumbosacral plexus lesions (tumors, trauma, hematoma, etc.) 5. Quadriceps myopathies (inclusion-body myositis, dystrophinopathies, etc.).

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10.5.3 Pathological Changes Two kinds of changes have been noticed in the histopathological examination of motor neuropathic changes in diabetic amyotrophy. Some point to the etiology as diabetic–ischemic, and some indicate autoimmune mechanisms and inflammation.

10.5.4 Diabetic Ischemic Changes 1. No pathological indication of vasculitis; it thereby de-emphasizes an immune basis [3]. 2. Comparison between diabetic and nondiabetic lumbosacral radiculoplexus neuropathy reveals striking similarities, suggesting that diabetes mellitus is merely an additional risk factor rather than a cause [2]. 3. Multifocal axonal neuropathy with multiple areas of nerve ischemia within the lumbosacral plexus have been detected in postmortem study [3]. 4. These studies suggested that the mechanism of injury was ischemic vasculopathy. 5. Hemosiderin-laden macrophages indicate previous bleeding [4]. 6. Endoneurial red blood cells, endoneurial hemorrhage, and ferric deposits (a sign of previous bleeding) [5].

10.5.5 (Auto)Immune-Mediated Changes 1. Majority of nerves showed staining for tumor necrosis factor, interleukin-6, and interleukin-1-beta. 2. Necrotizing vasculitis of perineurial and endoneurial blood vessels supporting the mechanism of ischemic injury from microvasculitis. 3. Perivascular inflammation in most patients of diabetic amyotrophy. 4. An immune-mediated epineurial microvasculitis has been demonstrated in nerve biopsies. 5. In a third of a small group of patients, sural nerve biopsies showed a mononuclear cell infiltrate and a perivascular infiltrate of activated T cells. 6. T cells expressed interleukin-2 as well as the major histocompatibility complex class II antigens in six patients [6]. 7. However, there was no evidence of B cells or polymorphonuclear cells. 8. Furthermore, C3d and C5b-9 complement proteins were found within the endoneurial and epineurial blood vessel walls in all patients [6]. 9. In a biopsy study, small-vessel neutrophilic vasculitis with polymorphonuclear infiltration in postcapillary venules along with IgM deposition and ­complement deposition in endoneurium and in affected vessel walls was ­demonstrated [7].

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10.5.6 Other Changes 1. In diabetic amyotrophy, cerebrospinal fluid protein is frequently elevated (44–214 mg/dl), suggesting extension of the disease process to the nerve roots.

10.5.7 Detecting Other Abnormalities Muscle pains and “cramps” are common in neuropathy, in a third of patients. The cause is the hyperexcitability of peripheral nerve. Repetitive slow nerve stimulation, mimicking the hyperexcitability to assess cramp, is a neurophysiological technique to detect this. It has a sensitivity of 79% and a specificity of 88% [8, 9].

10.6 Electrophysiological Changes in Diabetic Amyotrophy 1. Prominent fibrillation potentials in proximal muscles innervated by the L2 to L4 lumbar spinal nerves. 2. Muscles supplied by the quadriceps femoris and with it ilio-psoas, adductor, and gracillis muscles also record abnormal fibrillary potentials. 3. Paraspinal muscles show extensive fibrillary potentials bilaterally up to lower thoracic levels and lumbar levels. 4. Thoracic and abdominal muscles also have fibrillation potentials. This is a distinguishing point for amyotrophy against lumbar disc involvement. 5. Mild to moderate reduction in motor unit recruitment. 6. Arms also show mild slowing of conduction velocities. 7. Fibrillation potentials improve with the recovery which is usual but may be a little incomplete [10, 11]. 8. In the affected nerves, there is an asymmetric marked reduction in amplitudes of compound muscle action potential of affected motor nerves. 9. Sensory nerve action potentials show low amplitude or, more frequently, absent responses in the affected regions [4]. 10. Nerve conduction velocities slow down to a mild degree [12]. 11. These neurophysiologic findings indicate multifocal axonal degeneration rather than demyelination. 12. Long duration and high amplitude motor unit potentials in muscles supplied by multiple nerve roots or different peripheral nerves support the axonal pathology and not demyelination as the mechanism for the development of amyotrophy [13]. 13. Simultaneous presence of background diabetic sensory polyneuropathy shows an absent sural sensory nerve action potentials. 14. The peroneal and tibial compound motor action potential amplitudes are reduced.

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15. Nerve conduction studies usually reveal marked reduction in compound muscle action potential amplitudes of affected motor nerves but in a very asymmetrical fashion. 16. Sensory nerve action potentials show low amplitude or, more frequently, absent responses in the affected regions [6]. Mild slowing of nerve conduction velocities is also seen [12]. 17. Needle examination shows spontaneous activity, reduced recruitment of motor unit potentials, and long duration and high amplitude motor unit potentials in muscles supplied by multiple nerve roots and/or different peripheral nerves, further supporting the occurrence of axonal pathology [13]. 18. The EMG abnormalities tend to be much more prevalent and widespread than those the clinical picture suggest. Muscle biopsy in amyotrophy may reveal atrophic and hypertrophic fibers, typically seen in of denervation. There is no destruction of muscle fiber. This explains the reason behind recovery as the muscles for whatever reason regain their girth. Type 2a muscle fibers are increased in proportion. This may possibly indicate re-innervation.

10.6.1 Imaging Muscles Ultrasonography can measure the cross-sectional areas of foot muscles. It shows a direct relationship with the amplitude of the Compound Muscle Action Potentials (CMAP) and NCV of the peroneal and tibial nerves. Using the converse, it has been said that in diabetic patients motor nerve conduction studies can reliably determine the size of small foot muscles.

10.7 Treatment of Diabetic Amyotrophy 10.7.1 Pain in Amyotrophy Pain is treated as discussed in detail in the section of painful neuropathies elsewhere. One of the drugs not mentioned there is mexiletine, an anti-arrhythmic, which has been used effectively in treating neuropathic pain in several clinical trials. It is not considered safe and does not find a place in standard protocols due to its actions on ionic channels and higher percentage of arrhythmia.

10.7.2 Other Pain Treatments Other pain treatments not mentioned in that section are hypnosis, relaxation training, and biofeedback. Elastic stockings may help leg pain. Only one trial has shown improvement in acupuncture. Good glycemic control is of paramount importance. Oral hypoglycemic agents may need to be changed to insulin therapy for that purpose.

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10.7.3 Exercise Exercise aimed at affected muscles like walking regularly and range-of-motion exercises, not just general exercise may help. Neurologic recovery is slow. Exercise is helpful to maintain and improve function and avoid contractures.

10.7.4 Methylprednisolone Methylprednisolone IV 1  g for over 8–12  weeks has given remarkable results in nondiabetic patients, and it is argued that the response will be similar in diabetes with amyotrophy [2]. The factor difficult to control during/after therapy for some time would be blood glucose [14]. Because the treatment outcome is not clearly better, and because of the side effects of steroids and intravenous immunoglobulin, these treatments may only be considered in severe and progressive cases.

10.8 Diabetic Hand Neuropathy and Other Changes 10.8.1 Introduction As has been repeatedly pointed out especially in connection with electrophysiological studies, hands also get affected because of the neuropathy of median and ulnar nerves in diabetes. The hypotheses that longer the nerve fiber more it is likely to develop neuropathy does not negate similar development in upper extremity with a concession that it may be milder or delayed, neither of which is completely true. Following is a brief summary to keep the practitioner informed with all the necessary information and supportive reading in case such a problem has to be attended.

10.8.2 Stiff Hand Syndrome It is an uncommon condition causing restriction of the hand movement and function more commonly found in patients with diabetes duration of over 20 years. Circulatory failure is suggested as the cause. Diabetic cheiroarthropathy is a cutaneous condition in which the skin is thickened and the joint mobility gets restricted. It is observed in roughly 30% of diabetic patients with longstanding disease [15]. The cause for this is the nonenzymatic glycosylation of proteins and abnormal cross-­linking of collagen in joints and other tissues. It assumes significance in patients who need general anesthesia since the atlantoaxial joint along with the hand joints (see below) gets stiffened resulting in limited neck extension and laryngeal intubation. Two tests can preempt the diagnosis of this difficulty prior to anesthesia induction. The “Prayer” sign is the inability to oppose the palms and fingers as in a Namaste position. Diabetic patients with stiff joints are unable to do this. That leaves the ulnar side of the fingers not opposing with each other snugly.

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Palm print test demonstrates the stiffness of the fourth and fifth interphalangeal joints which causes alteration in palm print. The palm and fingers of the dominant hand of the patient is painted with ink. Then the hand is firmly pressed on a white sheet of paper on a hard surface. The severity is judged by the following observations. Grade 0 is when all phalangeal areas are visible. Grade 1 is the deficient print areas in the interphalangeal areas of fourth and/or fifth digit. Grade 2 is the deficient print area in the interphalangeal areas of second to fifth digit and in Grade 3 only the tips of digits seen. The skin is hard in the palmer but soft in the dorsal region, affecting all fingers at the same time. The symptoms progressively increase, vessel calcification occurs, which can be easily seen on X rays. Pricking and burning sensation are frequent, pain is rare. Cheiroarthropathy and reflex sympathetic dystrophy would be the main differential diagnosis. In reflex sympathetic dystrophy, history of trauma, arm fracture, stroke, herpes zoster, and myocardial infarction with pain constitute the main features distinguishing it from diabetic stiff hand syndrome. Immobilization would be detrimental to the hand, but physiotherapy helps preserve the hand functions [16].

10.8.3 Carpal Tunnel Syndrome (CTS, Entrapment Neuropathy) Carpal tunnel syndrome is described in detail in the chapter on Electrophysiological Studies in this volume. A few details are added here. It is six times more common in women. Diabetes is the most common metabolic disease that causes CTS [17]. Paresthesia in the thumb, index, and middle fingers of the hands worsens toward evening and can wake the patient up. Pain in the wrist and hand can make hand movements clumsy. Clinical examination may be normal in early stages but atrophy of the thenar muscles, sensory deficits in the median nerve supply area, and weakness in the abduction of the thumb are observed in chronic cases, with denervation of the median nerve. Definitive diagnosis is by nerve conduction tests [18]. In addition to the thickening and fibrosis of the flexor tendon sheaths in the carpal tunnel leading to nerve compression, increased endoneural ischemia due to diabetic neuropathic factors and microvascular disease may also play a role in the CTS development in diabetes. Histopathology commonly shows noninflammatory tenosynovial fibrosis. Increased transforming growth factor, fibroblast proliferation induced by TGF-­ beta-­RI and basic fibroblast growth factor, and increased type III collagen are also observed. The severity of the disease depends on duration no doubt, but it is even more associated with compromised microvascular insufficiency. Conservative treatment is advised only in milder cases with a wrist splint to keep the wrist in neutral position. This helps to prevent nightly paresthesia and relieves mild symptoms. Steroid local injections also provide relaxation and significant but temporary relief and are more effective than nonsteroidal anti-inflammatory agents. Sonic local therapy is effective, but the results of lasers are inconsistent. Exercises

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do not help [19]. Surgical intervention in nonrespondent or severe cases gives excellent results in both diabetic and nondiabetic CTS [20].

10.8.4 Dexterity of Hands in Diabetic Hand Neuropathies Several tests and assessments have shown compromise of the hand movements, skilled actions as well as sensations. Diabetic patients have been shown to lack finer movements or handling smaller objects. Some of them are described below with references to find additional information. An ingenious study was the pinch-­ holding-­up activity (PHUA), static and moving two-point discrimination (S2PD and M2PD), maximal pinch strength, and precision pinch performance tests to evaluate sensation, motor, and sensorimotor status. The importance of the test was its administration to asymptomatic diabetic patients. In spite of this, these tests showed clear differences between diabetic patients progressively deteriorating with mono and polyneuropathy, and had good sensitivity and specificity. The test included both the dominant and nondominant hands for testing [21]. Detection of the hand function abnormalities early is a given benefit to prevent further complications. Electrophysiological studies have their own difficulties. SW monofilament tests are at best crude. A few simpler assessment tools have been tested aside of the pinch test to explore sensorimotor control in diabetic hands.

10.8.5 Quality of Life Study This study also showed that even in the absence of symptoms, the functional hand performance and quality of life of diabetes patients gets affected even with only slight neuropathic deficits of the hands [22].

10.8.6 Purdue Pegboard Test It is a standard and common hand function test used to assess manual dexterity. It consists of four subtests, for the right, left, both hands. A higher score on the Purdue pegboard test indicates better hand dexterity. It is reliable in the setting of retests also [23].

10.8.7 Michigan Hand Outcomes Questionnaire The Michigan Hand Outcomes Questionnaire (MHQ) is a self-administered questionnaire to assess patient satisfaction with regard to own hand function and the performances for both hands. The six dimensions within it cover all hand functions, activities of daily living, work performance, pain, sensations, and

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patient satisfaction in 37 questions. Lower scores in all dimensions, except pain, indicate worse hand functional performance. The reliability of this test is quite high [24].

10.8.8 Diabetes-39 This is also a disease-specific self-reported assessment with 39 questions in five subdimensions. It includes diabetes control, sexual function, social pressures, anxiety, energy, and mobility, for assessing the quality of life. Higher scores in each dimension indicate a worsening quality of life. The reliability of the Chinese version of it is quite satisfactory and discrimination [25, 26].

References 1. Dyck PJ, Engelstad JN, Norell J, Dyck PJ. Microvasculitis in nondiabetic lumbosacral radiculoplexus neuropathy (LSRPN): similarity to the diabetic variety (DLSRPN). J Neuropathol Exp Neurol. 2000;59:525–38. PMID 10850865. 2. Dyck PJ, Norell JE, Dyck PJ. Methylprednisolone may improve lumbosacral radiculoplexus neuropathy. Can J Neurol Sci. 2001a;28(3):224–7. PMID 11513340. 3. Raff MC, Sangalang V, Asbury AK. Ischemic mononeuropathy multiplex associated with diabetes mellitus. Arch Neurol. 1968;18:487–99. PMID 5647941. 4. Dyck PJ, Norell JE, Dyck PJ. Microvasculitis and ischemia in diabetic lumbosacral radiculoplexus neuropathy. Neurology. 1999;53:2113–21. PMID 10599791. 5. Said G, Goulon-Goeau C, Lacroix C, Moulonguet A. Nerve biopsy findings in different patterns of proximal diabetic neuropathy. Ann Neurol. 1994;35:559–69. PMID 8179302. 6. Krendel DA, Castigan DA, Hopkins LC. Successful treatment of neuropathies in patients with diabetes mellitus. Arch Neurol. 1995;52:1053–61. PMID 7487556. 7. Kelkar P, Masood M, Parry GJ. Distinctive pathological finding in proximal diabetic neuropathy. Neurology. 2000;55:83–8. PMID 10891910. 8. Benatar M, Chapman KM, Rutkove SB.  Repetitive nerve stimulation for the evaluation of peripheral nerve hyperexcitability. J Neurol Sci. 2004;221(1):47–52. 9. Harrison TB, Benatar M. Accuracy of repetitive nerve stimulation for diagnosis of the cramp– fasciculation syndrome. Muscle Nerve. 2007;35(6):776–80. 10. Smith LL, Burnet SP, McNeil JD. Musculoskeletal manifestations of diabetes mellitus. Br J Sports Med. 2003;37:30. -5. 41. 11. Sander HW, Chokroverty S.  Diabetic amyotrophy: current concepts. Semin Neurol. 1996;16:173–8. 12. Subramony SH, Wilbourn AJ. Diabetic proximal neuropathy: clinical and electromyographic studies. J Neurol Sci. 1982;53:293–304. PMID 7057213. 13. Said G, Elgrably F, Lacroix C, et al. Painful proximal diabetic neuropathy: inflammatory nerve lesions and spontaneous favorable outcome. Ann Neurol. 1997;41:762–70. PMID 9189037. 14. Dyck PJ, Norell JE, Dyck PJ. Non-diabetic lumbosacral radiculoplexus neuropathy. Natural history, outcome and comparison with the diabetic variety. Brain. 2001b;124:1197–207. PMID 11353735. 15. https://www.diabetes.co.uk/diabetes-complications/stiff-hand-syndrome.html. 16. Arkkila PE, Gautier JF. Musculoskeletal disorders in diabetes mellitus: an update. Best Pract Res Clin Rheumatol. 2003;17:945–70.

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17. Cagliero E, Apruzzese W, Perlmutter GS, Nathan DM. Musculoskeletal disorders of the hand and shoulder in patients with diabetes mellitus. Am J Med. 2002;112:487–90. 18. Bland JD. Carpal tunnel syndrome. BMJ. 2007;335:343–6. 19. Piazzini DB, Aprile I, Ferrara PE, Bertolini C, Tonali P, Maggi L, et al. A systematic review of conservative treatment of carpal tunnel syndrome. Clin Rehabil. 2007;21:299–314. 20. Makepeace A, Davis WA, Bruce DG, Davis TM. Incidence and determinants of carpal tunnel decompression surgery in type 2 diabetes: the Fremantle diabetes study. Diabetes Care. 2008;31:498–500. 21. Chiu H-Y, Hsu H-Y, Kuo L-C, Su F-C, Yu H-I, et al. How the impact of median neuropathy on sensorimotor control capability of hands for diabetes: an achievable assessment from functional perspectives. PLoS One. 2014;9(4):e94452. https://doi.org/10.1371/journal.pone.0094452. 22. Cederlunda RI, Thomsenb N, Thrainsdottirc S, et al. Hand disorders, hand function, and activities of daily living in elderly men with type 2 diabetes. J Diabetes Complicat. 2009;23:32–9. 23. Tiffin J, Asher EJ. The Purdue pegboard: norms and studies of reliability and validity. J Appl Psychol. 1948;32:234. 24. Horng YS, Lin MC, Feng CT, et al. Responsiveness of the Michigan hand outcomes questionnaire and the disabilities of the arm, shoulder, and hand questionnaire in patients with hand injury. J Hand Surg. 2010;35:430–6.22. 25. Boyer J, Earp J. The development of an instrument for assessing the quality of life of people with diabetes: diabetes-39. Med Care. 1997;35:440–53. 26. Huang IC, Hwang CC, Wu MY, et al. Diabetes-specific or generic measures for health-related quality of life? Evidence from psychometric validation of the D-39 and SF-36. Value Health. 2008;11:450–61.

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11.1 Introduction Electrophysiological studies (EPS) are used for any kind of neuropathy. In diabetes like other neuropathies it provides a diagnosis of many nerve abnormalities. The spectrum of diabetic neuropathy is so wide, with different types of fibers giving different clinical picture, could be symmetric, asymmetric, could involve just one nerve or many different nerves, the evolution of neuropathy being generally slow and affects differently the nerves likely to be involved in full picture (like distal sensorimotor symmetrical neuropathy, the commonest type), and two types of neuropathies existing in one patient, for example, symmetrical polyneuropathy with a carpal tunnel or a radiculopathy, and thus make EPS a specialized examination. Many nerve abnormalities, both functional and structural, can occur in a single nerve or many nerves. These are often asymmetric for both the upper and the lower limb nerves and other peripheral nerves. This must be remembered before referring the patient for EPS studies (see below).

11.1.1 Terminology The terms the reader will come across must be explained. Nerve conduction studies (NCS) are done on both motor and sensory nerves. Any reference in the text below as NCS will indicate both the nerves. Motor nerve conduction velocities (MNCV), sensory nerve conduction velocities (SNCV), and electromyography (study of electrophysiological muscle properties or EMG) will be frequently encountered and must be understood as covering both nerves. NCS is a sensitive, specific, reproducible, and validated measure and a reliable and objective diagnostic method to evaluate the DPN treatment response [1]. It is totally objective in the sense that the patient’s response is not involved anywhere.

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11.1.2 Diagnosis of an Abnormality Diagnosis of an abnormality in diabetic sensory motor neuropathies, collectively referred hereafter as DPN or DSPN, in electrophysiological studies has been clearly defined. The basic criteria before the abnormality is diagnosed must show it to be present in two separate nerves, one of which must be the sural nerve. The Nerve Conduction Criteria Study indicated subclinical distal symmetric polyneuropathy to be clinically acceptable for clinical practce if “≥1 among abnormal attributes in ≥2 separate nerves” are present [2]. It was also defined as “an abnormality (≥99th or ≤first percentile) of any nerve conduction attribute. Demyelination of nerve fibers is an early change in diabetes even when the symptoms of polyneuropathy may not manifest. Axonal loss is a delayed phenomenon in established long duration diabetes and could be responsible for the symptoms. The old argument of Dyck that axonal loss precedes demyelination may not hold for another reason. The autoimmune mechanisms have many sites of the myelin structural components which could act independently without reference to axonal change. (See the discussion on autoimmunity in pathogenesis of diabetic neuropathy).

11.1.3 Electrophysiological Testing in Clinical Practice The NCS/EMG studies are exhaustive, time consuming, not easily available, and costly. To simplify the situation the AAN, American Academy of Neurology by a consensus in 2005 suggested that sural sensory and peroneal motor NCS were the most sensitive ones. Hence, in EPS these two were considered as the must-betested nerves, as the first-line testing on any one limb. If these two tests on the limb tested were normal, no further testing was declared unnecessary. If any abnormalities were detected, inclusion of ulnar and median sensory NCS and median motor values were to be undertaken on the other limb also.1 FDA laid another caveat of including motor conduction velocity as a surrogate endpoint. This was applicable to both epidemiological and in those clinical studies related to drug development [3]2.

11.1.4 What Is and What Is Not Tested by EPS? It tests only the large, thickly myelinated peripheral nerve fibers, A alpha, A beta, and A gamma, which mediate touch, vibration, and proprioception, motor nerves, 1  This minimalistic testing can be made to yield much more information if the EPS reference indicates which limb has a symptom complex more pronounced. (See below.) 2  As will be seen later the emphasis of literature has, despite this condition, been on the studies of the sensory aspects of diabetic nerves. Even the great Peter J Dyck of Mayo Clinic Rochester has complained about this as incorrect.

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neuromuscular end plate abnormalities, and different types of myopathies (which are outside the scope of this volume). Specifically it does not test the smaller unmyelinated C fibers and the thin sympathetic/parasympathetic nerve fibers. A bit of paradox that has occurred here is drug evaluation for painful neuropathies, one of the most significant issues in the practice of diabetes that is not in any way helped by the EPS. Yet it is included as a must (See also the chapter on treatment of painful neuropathy for further clarification).

11.1.5 Referring for EPS In view of the variety of symptoms and their asymmetric distribution, the variations in their appearance temporally, temporal variability of asymmetric progression and the resulting mixed pictures there from, likely presence of a focal pathology complicated by more diffuse, extensive bilateral nerve pathologies makes a rigorous clinical examination as well as recording the findings a must before sending a patient for EPS. In the absence of such clinically derived detailed information some routine testing may be done which will not provide further clarification, explanation, or definition of any other unexpected findings which do come up in EPS studies. It will lead to huge loss of resources with futile outcomes. The EPS therefore must be an individualized investigation for maximum benefit of both the clinician and the patient in information terms. A fairly strong, detailed, and localized diagnosis/diagnoses of abnormalities can be made by rigorous clinical examination. For more precise characterization, electrodiagnostic studies of nerve conduction parameters remain the benchmark for the diagnosis of DSPN and atypical neuropathies.

11.1.6 The Detectable Abnormalities in DPN Demyelination, which can be extensive or focal, remyelination, axonal loss, or axonal regeneration, in both sensory and motor nerves, is what is most detectable in EPS. Explanations about the meaning of each and the effects arising out of it in clinical and EPS terms are given below. Initially, based on the observation it was considered that segmental demyelination along with axon loss were the hallmarks of diabetic neuropathy [4, 5]. However, Dyck et al. after careful observations, clinical and EPS, have now concluded that segmental demyelination was secondary to axonal degeneration [6, 7]. This was a major etio-pathological sequence established. However the subnormal conduction velocity in distal sural nerve in impaired glucose tolerance subjects without clinical neuropathy also indicates demyelination as the earliest detectable change in dysglycemic states. Thus the unequivocal position of axonal loss may not be an absolute change [8].

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11.1.7 Frequencies of Various Abnormalities Detected by NCS and EMG One of the refrains of this volume about both epidemiology and classification of DPN is the enormous variability of factors described earlier with a somewhat helpless view that indulging in its dissection does not serve great purpose in the overall understanding of DPN. However to give some basic idea about what could be expected in terms of frequencies of various abnormalities a few remarks are included here. 1. The most distal sensory nerves like sural nerve generally provide the first electrodiagnostic abnormalities pointing to DSPN. 2. Progressive changes continue to development in the distal sensory and motor nerves not only in the lower but also in the upper limbs. 3. The Rochester Diabetic Neuropathy Study has the distinction of not only being a pioneer study but had a well-defined population. The frequencies of various abnormalities found therein can be considered as base line. 4. The most frequent abnormalities were reduced peroneal motor nerve conduction velocity (26.3%) and reduced sural sensory nerve action potential (25.4%); tibial MNCV (24.8%) and ulnar MNCV (21.3%) were also reduced. The fibular F wave latency (16.9%) and ulnar F latency (16.0%) increased [2].

11.2 Electrophysiology of Nerves—General Features The information below will come handy for a much deeper understanding of EPS in diabetes, without having to go into intricacies of the performance of EPS. 1. Nerve conduction studies (NCS) and electromyography (EMG) is a combined unit particularly when it comes to diabetes. However NCS gets more space in electrophysiological (EPS) studies probably because amplitude is somewhat less specific than conduction impulse measurement. NCS is and should be used for both the motor and sensory nerves. Compound muscle action potential (CMAP) is a muscle-specific modality which “must” be tested. 2. Electromyography and nerve conduction velocity is a modality that has become available more routinely in only last few years with the subspecialty of neurology in India. The situation is not likely to be different in most countries in the world. For primary physicians and Diabetologists, its routine use is still expensive and not easily available outside metros and capital cities. That makes the repeat testing for assessing the efficacy of interventional strategies not only costly but also difficult. 3. No doubt electromyography and nerve conduction velocity are the only truly objective tests in evaluation of neuropathy since it has no contribution of response from the patients.3 3  The tests for sudomotor nerves are the only ones where the patient’s sensate response is not needed.

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4. The only variability likely to be quite prevalent would be the operator dependent or inter-operator dependent which can be corrected by well-trained operators using it. Attention paid to exact electrode placement and maintaining the temperature of the limbs are two important precautions. 5. EPS can localize a lesion in a nerve; it demonstrates the kind of lesion it is or its degree of affliction. 6. It is common in EPS where unexpected findings surface which were not obvious on clinical examination. For example, fibrillation potentials on needle insertion in small foot muscles which are not detectable clinically. 8. As important as that is its use in identifying the level at which the lesion has occurred in the spinal cord and even in brain stem. The latter becomes important since the brain stem is particularly susceptible to vascular injury and death in diabetes. 9. The only other tests which are equally objective are of sudomotor (sweating and related) dys/function. Biopsies of skin have the innate variability of nerve fiber densities that vary with many cofactors operating in diabetes; yet without doubt the data is objective if a really well trained person is making an assessment. 10. In brain stem-evoked potentials there is a pontine arc which may be seen interrupted due to ischemic focal strokes in diabetes. 11. To detect the impulse travel in the spinal cord, EPS uses potentials evoked by stimuli which transmit to the brain stem and the rest of neocortex and thalamus in particular. If the impulse fails to reach beyond a level, the spinal cord pathology can be localized. 12. Similarly there are visual and auditory brain stem-evoked potentials. The lesion can be localized to the point on its pathway. These can come handy in testing nerves in or without diabetes. 13. NCS and EMG like no other test can, differentiate or identify together both axonal losses and abnormalities of myelination in such clear terms. 14. EMG studies again like no other can give etiological diagnosis of many muscle pathologies which are of considerable help in diabetes. 15. Muscle weakness in diabetes is particularly related to small muscles of the foot most frequently. EPS can detect early fibrillations at times even before atrophy of the small muscles has set in or diabetes is yet to be detected.4 16. Diabetic amyotrophy has many other titles. Many of its abnormalities will need EMG for its understanding if the clinical features do not give an unequivocal answer. Muscle weakness is the direct result of considerable motor neuron axonal losses. (This particular abnormality of diabetes is described under the chapter of Motor Neuropathy.) See below also. 17. The two most important attributes studied by EPS are amplitude and velocity of both sensory and motor nerve conduction. The amplitude in both cases is the summation of all the impulses that actually travel through the number of axons in sensory as well as motor nerves. Histological presence of axon and presence of a conducting axon are two different things. Amplitude is related to only con It is akin to detecting gross retinopathy and then test for diabetes, undiagnosed so far.

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ducting axons. Axons that may be degenerating due to nerve injury or other metabolic injury will not conduct impulses in either nerve. Hence substantial or significant decrease in amplitude unequivocally indicates axonal loss. 18. Amplitude is considered as more important. Many believe that all other changes—demyelination and other—are secondary to axonal degeneration and death. 19. A differential slowing of the amplitude (or conduction velocity at certain point) can directly point the level of lesion, as is found strikingly in carpal tunnel syndrome which is more common in diabetes. To make the diagnosis it is mandatory to test the same nerve amplitude or velocity on the other side or some unrelated nerve of the other limb, both of which should be greater than the suspected nerve. 20. The velocity of the nerve conduction is also studied electrically. The velocity directly depends upon the state of myelination of the nerves, the fiber size, and the averaging distance between two nodes on a nerve fiber. In different situation of afflictions the axon has certain resistance to the traveling impulse which also is responsible for the final velocity measured. 21. The term latency is often used instead of velocity. It is measured in milliseconds it takes to travel a short distance on the limb at each end of which an electrode is placed to produce an impulse and to record it at the other point and the time it takes. 22. Latency or an abrupt slowing of conduction can decide the focal point of lesion as close as 1 cm along the course of nerve which is therapeutically important especially if surgical intervention is needed. 23. Nerves with thicker myelination will have the fastest conducting velocities and those with thinnest one will have correspondingly decreased velocities (See in the section of Anatomy of Nerves which describes the progressively decreasing myelination of different nerves with which the velocity function these serve also changes). 24. Either amplitude or velocity can be grossly different—for example, velocity can be near normal and amplitude grossly deranged. When large number of axons die without affecting the myelination, this is likely to be seen to happen. 25. The axonal sheaths will remain intact and different EPS observations will be seen as the axons regenerate (See below also). 26. Unmyelinated fibers of two types—C fibers and those of sympathetic nerves are unmyelinated and have the slowest velocities and are not testable by EPS. 27. Nerve conduction velocity is an electrical impulse which jumps from one node of Ranvier to the next, all along the length of a nerve fiber. That is why the velocities are so high.5 Nodes of Ranvier are histologically seen constrictions which impinge closely on the axon at regular intervals where the smooth myelination dips.  The fastest velocity observed is 120 meters/second. This distance is larger than a football field.

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28. In all situations where the myelin sheath is disrupted, degenerated, or attacked by inflammation or immune reactions or direct damage to a nerve, the velocities go down. Myelin sheaths are damaged at multiple sites or the impulses could be slowed at specific points (like in entrapment neuropathy) for which a full section is written below. 29. At various places in this volume the changes that myelin sheaths undergo is described. 30. Both the abnormalities can be present in a single nerve or many nerves and in different individuals. 31. Additionally, EPS has great value in differentiating between the purely nerve fiber pathology, vis-à-vis, the possible disconnections of reflex arc at the spinal level. 32. Its usefulness for assessment of the posterior columns of spinal cord is valuable to those who deal with spinal cord and vertebral column problems, though not always for the assessments for Diabetologists. 33. EPS can also identify the exact nerve which is dysfunctional and the others which are normal. 34. EPS can also detect the leftover effects of a superimposed disease on a more general spread of nervous involvement. For example, it can detect degenerating or regenerating axons from a radiculopathy of a single nerve in a diffuse widespread bilateral neuropathy. 35. EPS has the ability to differentiate distal axonal and sensory changes of DSPN from proximal motor demyelination or its causes [9]. 36. Increased F wave latency may serve as a sensitive indicator of DSPN [10, 11]. However, its role in diagnosis and characterization of DSPN remains unclear, and both the AAN consensus and Toronto consensus do not provide specific recommendations on its use. 37. Demyelination leads to significant reduction in motor nerve conduction velocity and prolonged distal motor latency. It is a result of segmental demyelination. 38. Amplitude typically gets reduced if there is a substantial axonal death. It may be associated with DSPN in some patients. This makes it difficult to differentiate DSPN from the immunologically mediated chronic inflammatory demyelinating polyneuropathy [12]. The differences between the two for diagnostic/ therapeutic purposes are discussed in an earlier chapter. 39. Electromyography (EMG) supplements the NCS. It is more likely to be of help to detect in addition to DSPN, radiculopathy, inflammatory myopathy, or atypical motor neuropathy. 40. Reliability of measurements is dependent upon the proper technique ­mentioned earlier. In given situation reproducibility of results is a difficult proposition. For example, the conduction and distal latency have a variation of 4–10%. The amplitude is least reproducible with 10–15% variation and F waves are best reproducible—there is only a 2–3% variation [13] (See below also).

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11.3 D  escription of some Common Terms and their Meaning As Used in EPS 11.3.1 F Waves An orthodromic impulse in an axon travels in the physiological direction from anterior horn cells to the motor end plate. An antidromic impulse in an axon is conducted opposite of the normal direction. Thus, it is an impulse conducted along the axon but away from the axon terminals. F waves are low amplitude responses produced by electrical antidromic activation of motoneurons. F waves are the most sensitive and reliable nerve conduction study for assessing the focal proximal nerve dysfunction, which is their best use. F waves are certainly as or more sensitive as needle electromyography for defining lumbosacral radiculopathies. In radiculopathies there is a marked increase in the fibrillations in the paraspinal muscles which is not found in any diabetic polyneuropathy without radicular compression. This is the specific use which Dyck has pointed out (see below) as well as its great value in detecting focal neuropathies like carpal tunnel syndrome. F waves can be useful in detecting polyneuropathies as well and could provide an insight in disorders of central nervous system. F waves may not appear after each stimulus. These are also by their nature variable in latency, amplitude, and configuration. Their proper interpretation and careful analysis of the numbers, wave forms, the muscles from which these are recorded, and using certain dexterity and deeper understanding of their physiology [14] are possible only if well-trained electrophysiologists do the studies. It assumes importance because F waves are most frequently studied in clinical neurophysiology and give valuable information about proximal nerve lesions needed to differentiate radicular and peripheral nerve involvements, since 11% of all diabetic polyneuropathies will have nondiabetic etiological factors [13].

11.3.2 H Reflexes H reflexes are a sensitive test for polyneuropathies. Even in early, milder neuropathies these could be abnormal. H reflexes are detectable in proximal as well as distal nerve fibers. Thus, the utility of H reflexes is that they can identify proximal nerve injury, that is to say as the nerves leave the spinal canal. Even if the distal conduction functions are normal but the proximal ones are abnormal, H reflexes can detect the abnormality. Absent H reflexes are characteristic of acute inflammatory demyelinating polyneuropathy (Guillain–Barré syndrome.) The H reflexes are absent from early to later progressive dysfunction. It may be the only finding in early stages and patients studied for several days after the onset of the disorder [15].

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11.3.3 Fasciculations These are seen in lower motor neuron lesions and are visible as spontaneous contractions of muscle fiber bundles.

11.3.4 Fibrillations Fibrillation are the fine, rapid twitching of “individual” muscle fibers; unlike the fasciculations which are visible, fibrillations are not visible. Even when these are present, there is no muscle fiber movement like fasciculations. When a motor neuron or its axon is destroyed, the muscle fibers it innervates undergo denervation atrophy. This leads to hypersensitivity of individual muscle fibers to acetyl choline, which results in spontaneous isolated activity of individual muscle fibers. It is generally recorded as short-duration spike in EMG.

11.3.5 Recruitment It occurs when a nerve is repeatedly and rapidly stimulated, typically in a motor nerve, because of which more and more neuromuscular junctions are activated resulting in greater contractile strength of muscle.

11.4 EPS in Diabetes EPS findings in all diabetic neuropathies characteristically are related to the duration and the severity of diabetes. The greater the severity (or longer uncontrolled states) and greater the duration of diabetes, the more abnormal the EPS becomes. The spectrum of diabetic neuropathy is wide; that makes EPS a specialized examination. If the EPS has to be ordered, the neurophysiologist must be given a complete picture of symptoms, which nerves are suspected as affected, the symptom duration, and other information like age, diabetes duration or glycosylation levels, lipids, kidney status, any other factors like alcohol or smoking or vitamin B 12 deficiency to make the EPS a valuable source of information on the disease status, signs of recovery, localization of lesions, and so on. If it is not done, the neurophysiologist will examine a standard set of nerves from the four limbs and it will make little sense. Age usually lowers the values of EPS in any patient. The duration of diabetes added, there will be greater reduction. Whether to accept the values as normal or abnormal in patients over the spectrum of decades needs a standard way. The values reported are compared with the normal age ranges and are considered to be normal between three standard deviations on either side.

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Some of the typical findings of EPS in diabetes are given below. The constant reminder will be that there would be overlaps of different types and etiologies. All values should be considered as below or above the mean normal values [13].

11.4.1 Asymptomatic Patients 1. Mildly reduced conduction velocities to the tune of 30%. 2. Amplitude reduces more than the conduction velocity reduction. 3. Sensory conduction values are reduced much more. 4. The changes as expected, are more pronounced distally. 5. Larger, thicker among the myelinated fibers are affected more. 6. The corresponding nerves may have values which are quite different—a sign that the involvement is occurring asymmetrically. 7. Many values in a single patient may be outside the ranges. This is considered to have happened due to the methods of creating normative data which is discussed in some detail. 8. Upper limb nerves are not spared. EPS abnormalities are detectable there also. This is contrary to the widespread belief that DPN is only a lower limb phenomenon since it is connected with the length of fiber. 9. Ulnar is the most susceptible nerve for insult and has lower values. 10. Hence it is measured with lower limb EPS. 11. Electromyography changes may actually precede the conduction changes in diabetes. 12. One such early change is fibrillation potentials in small muscles of the foot. 13. Somatosensory-evoked potentials are abnormal despite having no symptoms.

11.4.2 Moderately Symptomatic Symmetric Peripheral Neuropathy Patients 1. Very considerable reduction in the sensory nerve action potential particularly in the lower limbs. 2. Sometimes there are no detectable potentials. 3. This fact has been utilized by the researchers to differentiate early and late neuropathy. Detection meant early and milder neuropathies and absence as long-­ standing or more severe neuropathies. 4. If a response is detectable, the latencies are mildly prolonged and conduction velocities are near normal. 5. The arms are also affected but to a lesser degree. 6. Many other study elements will vary without a consistent pattern. 7. Motor nerve conduction abnormalities are mostly mild. 8. But the F wave latencies are longer and H reflex latencies also increase. 9. Electrophysiological studies for different purposes do not report EMG findings as pointed out earlier. It is an incomplete way of doing EPS.

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1 0. The EMG studies are also important to add to the diagnostic accuracy. 11. The motor nerve axonal degeneration being the earliest the recruitment is affected with even the hand muscles showing impairment. 12. Fibrillation potentials seen in up to 25% of patients especially in legs or foot.

11.4.3 Mixed Motor and Sensory Neuropathies 1. As in moderately symptomatic neuropathies the findings are similar but defects are enhanced. 2. Sensory conductions are more often absent in legs. 3. Sensory potentials in arms are also abnormally low in 30–40% of these patients. 4. Sensory conduction velocities are reduced to 40 or 50 m/s. 5. When these are further reduced, it is due to fiber loss. 6. Distal sensory latencies are prolonged by up to 30%. 7. Naturally it affects the somatosensory-evoked potential (SSEP) in three-fourths of the patients which either get prolonged or become unrecordable. 8. Compared to sensory predominant neuropathies this condition is characterized by –– Much more marked reduction in the motor parameters of EPS. –– Compound motor action potentials are reduced in legs by 50% or more, often becoming unrecordable. –– Motor conduction velocities could be as low as 20 m/s which is one-sixth of normal. –– Needle insertion will almost always record fibrillation potential in distal muscle especially in legs but also in arms. –– Notably, such fibrillation potentials are found even in paraspinal muscles. –– F waves prolongation is proportionate to the degree of reduction of the conduction values. 9. Localized slowing or conduction blocks are also found in this group where the neuropathic changes are extensive along most nerves and generalized.

11.4.4 Differential Diagnosis of Motor Neuropathy from CTS 1 . It mimics the carpal tunnel syndrome and would create diagnostic difficulties. 2. If the slowing occurs in regions normally known to manifest as entrapment neuropathies, the effort to fix the diagnosis either of CTS or simple motor neuropathy should be more energetic. 3. An incorrect diagnosis of CTS will unnecessarily lead to surgical intervention and there will be no benefit which normally is high. 4. If within these regions asymmetric involvement of one but not the corresponding nerve on the other limb is noticed, the more likely the entrapment will have occurred. 5. In the latencies exceed 1  m/s, then the suspicion of CTS should be much stronger.

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11.4.5 Painful Neuropathies in Diabetes and EPS First of all it must be remembered that pain carrying C fibers are not testable by EMG nerve conduction studies. Hence any EPS findings will relate to other diffuse or distal or symmetric/asymmetric mixed motor sensory or dominantly sensory losses described by symptoms and clinical examination and will be in accordance with the changes described above in different clinical syndromic situations.

11.4.6 EPS in Autonomic Neuropathy Like C fibers autonomic fibers cannot be studied electrophysiologically. The only association mentioned is high frequency of combined urodynamic and EPS abnormalities in patients who do not have clinical neuropathy. It is also found that EPS changes (in somatic nerves) are greater in sympathetic autonomic neuropathy. Other detectable changes will fall in various neuropathic patterns described so far [13].

11.4.7 Limitations of Electrodiagnostic Studies 1. Although a NCS is regarded as the gold standard in clinical research, it is not that useful in clinical practice. It requires special devices and trained examiners. The inconveniences include the need for referral to a neurophysiology lab, the long testing time, and patient discomfort [13]. 2. NCS may not have significant intra-observer differences, but has significant inter-observer differences even within a single facility where many operators may be working [16]. 3. Methodically well-derived normative values will help to differentially and specifically diagnose DPN with greater accuracy. Age, gender, type of diabetes, and anthropometric measures have a significant effect on NCS outcomes. Yet, it is not as easy a matter as it may look [17, 18]. 4. The primacy of NCS as the preferred endpoints is challenged by the earlier involvement of SFN (see elsewhere) and their ability to regenerate for short periods, which could serve as better indicators. 5. Thus, it has no general consensus regarding its criteria, even after multiple investigations. In addition, a NCS is sensitive enough to detect abnormalities in large nerve fibers but is not sensitive enough to detect to small nerve neuropathy, which is the earliest detectable sign of DPN [19]. 6. For the significant decrements of either velocities or amplitudes, a larger number of axonal fibers need to be either demyelinated or dead to get a consistent picture of neural pathology. The other sensory modalities like vibration or heat and cold could be detectable earlier than that. 7. Specifically EMG and NCV do not detect the small C fiber functions which are easily detectable by excellent heat and cold perception threshold measuring

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instruments now available in India. Nerve conduction studies and electromyography are not a part of routine examination of patients with diabetes or diabetic foot.

11.4.8 Correlations If there is detectable abnormality in say vibration perception, there will be some abnormality in the EMG/NCV testing also. Thus, suffice it to say that the simpler tools like vibration threshold measuring instruments we have sought to elaborate upon in this volume, should be placed in the hands of physician and Diabetologists to prevent foot problems. These instruments are like surrogate markers for the EMG/NCV abnormality. Often therapeutic intervention will cause some of the parameters of EMG and NCV to improve but that does not always mean a reversal of neural pathologies as a whole, or often the Neuropathic Symptoms Scores, may not improve, as shown by several reviews on whether the neuropathy is reversible or not in diabetes in this monograph.

11.4.9 Differentiation from Nondiabetic Neuropathies The other significant causes of neuropathy in a patient with diabetes are as high as 11% [13]. EMG and NCV should be used to identify such causes like posterior column pathologies, if suspected on clinical examination. This will be important especially in surgical intervention which may relieve some of the symptoms. The purely diabetic neuropathic symptoms may prevail. Such a situation can lead to acrimonious arguments of surgical failure. Hence what the surgery will and will not achieve should be clearly told and recorded. The difficulties in postoperative period, in controlling the diabetic neuropathic symptoms, should also be clearly explained. The way of differentiating the two pathologies will be found in the discussion on F waves above.

11.5 Focal or Entrapment Neuropathies (EN) 11.5.1 Entrapment in the Upper and Lower Extremities Median nerve entrapment neuropathy at the wrist (MNW) is the prototype of entrapment neuropathies (EN). It is caused by the compression and traction of the median nerve within the carpal tunnel. Carpal tunnel is an osteofibrous outlet located between the transverse carpal ligament and the carpal bones on the volar surface of the arm. The carpal bones are slightly concave ventrally and the ligament serves to keep the tendons strapped down which increases mechanical efficiency. If these were to stand out, the resultant force would be split in two directions causing inefficiency. The other nerves which frequently get affected are ulnar, peroneal, tibial, and sural nerves.

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11.5.2 Pathological Changes in Nerves Leading to Entrapment All the metabolic changes described so far in this volume lead to functional impairment and mainly swelling in the nerves and structural changes which can lead to entrapment as it passes the various “tunnels” which are rather inflexible. This could affect the flow in the axonal plasma. There is frequent association between diabetes and carpal tunnel syndrome (CTS) [20].

11.5.3 Pathogenic Involvement of Median Nerves in Entrapment The pressure in the carpal tunnel rises 8 to 10 fold in the flexion/extension movements of the wrist. In addition, there is traction on the nerves which may reduce the intraneural microcirculation and damage the myelin sheath and the connective tissues. With the nerve swelling, due to edema and hypoxia, it sets up a vicious cycle (See below also) [21]. Small myelinated and C fibers are now known to be involved earlier than the larger fibers, mostly in diabetes but also without diabetes. It is possible that these may get involved early in entrapment as well. Demyelination or marked thinning of myelin is also seen as the first human nerve response under chronic compression [22, 23]. Myelinated neurons may be particularly susceptible to mechanical stress, a key factor in entrapment. It occurs due to Schwann cell proliferation and increased apoptosis [24]. In addition, in diabetes the endoneurial ischemia would have already set in and alters axonal excitability, which makes these nerves more susceptible to compression. All of this put together induce demyelination and cause further local vascular impairment with axonal damage in anatomically rigid tunnels superimposed [25]. These changes then get set in a vicious circle, worsening the damage relentlessly, unless surgically treated. Once entrapment has occurred in MNW/CTS, movements may increase the already existing metabolic and ischemic nerve damage, leading to axonal degeneration, conduction failure even in people without diabetes, and worsening of symptoms. Hence surgery is the only answer. These changes recur with each movement. The compressive forces probably alter energy-dependent processes during movements [26]. In patients with diabetes with and without metabolic syndrome, the severity was greater in those with metabolic syndrome in electrophysiologically confirmed CTS. It suggests the presence of other disease modifying factors of the metabolic syndrome [27].

11.5.4 Symptomatic Profile of Entrapment Neuropathies Like diabetic neuropathies, entrapment neuropathies, mainly median and ulnar nerve entrapment (MNE, UNE), are often found to be subclinically affected,

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detected only due to neurophysiological alterations [28–31]. The electromyography studies in addition can detect a superimposed radiculopathy, presence of which is common [32].

11.5.5 Imaging in Diagnosis of Entrapment—Ultrasonography This appears to be particularly useful in the diagnosis of entrapment. It consistently detects nerve enlargement, just proximal to the site of entrapment [33]. This enlargement is found to be consistently fusiform and not discretely focal. It is measured as the cross-sectional area of the involved nerve. The enlargement is due to the obstruction to the axoplasmic flow within the nerve. The changes noted are hypoechoic nerve echo-texture, nerve flattening and pinching at the entrapment site, enlargement of single or multiple fascicles, and/or increased vascularity within the nerve. Ultrasonography is cost-effective and time-efficient, and can assess long nerve segments including some dynamic maneuvers. There are no contraindications; it is portable and noninvasive.

11.5.6 Magnetic Resonance Imaging (MRI) It is useful to exclude the presence of another lesion which may cause EN.  It is particularly useful in cases of focal or regionally distributed multifocal neuropathy, when clinical and electrodiagnostic findings are inconclusive. MRI neurography can diagnose extra-neural affections that may mimic neuropathic symptoms, such as Charcot arthropathy, osteomyelitis, or plantar fasciitis [34].

11.5.7 Prevalence of Entrapment Neuropathies 1. Prevalence of carpal tunnel syndrome (CTS) of 2.3–4.3% has been reported in two large cohorts of France [35]. 2. CTS has been detected in 14% of diabetic subjects without polyneuropathy and in 30% of subjects with polyneuropathy [25]. 3. Prevalence of both median nerve at wrist (MNW) and CTS seems to be many times higher in diabetes compared to general population. It further increases in diabetic polyneuropathy with or without long duration of diabetes. 4. Moreover, an MNW was found in 28% of newly diagnosed diabetes patients, compared to 62.5% of patients with an average diabetes duration of 14.5 years [28, 29, 36]. 5. In another study of 146 patients with diabetes, CTS was diagnosed in 28% of males and 46% of females [37]. 6. The risk of hand syndromes, including CTS, stenosing flexor tenosynovitis, and Dupuytren’s disease, was studied in 606,152 diabetic patients and 609,970 matched for age and gender, where the hazard ratio for CTS was much higher, 1.3 in diabetes [38].

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7. The lifetime risk of CTS in type 1 DM patients could be up to 85% after 54 years of having diabetes [39]. 8. The dominant hand in females is most commonly affected with a higher prevalence, possibly because the tunnel is smaller. It is also higher in obese diabetic individuals [37, 40].

11.5.8 Diagnosis of CTS/MNW and Ulnar Nerve In median nerve the symptoms of pain and numbness will be confined to the second to fourth fingers and the medial half of the little finger. There could be weakness in the flexion of the distal phalanx. Tinel’s sign, elicited by tapping the middle of the flexor retinaculum, will cause electric shock-like symptoms and is clinically indicative of MNW. The ulnar nerve symptoms are confined to the remaining little finger. Diagnostic of MNW/CTS are the nerve conduction studies that measure median nerve sensory and motor conduction parameters, and also test the severity. These can also detect focal abnormalities within the carpal tunnel. The sensory response is particularly useful to diagnose CTS. The sensory fibers have more large myelinated fibers and higher energy requirement. Hence these are more susceptible to ischemic and metabolic damage described above [41]. Although quantitative sensory testing for the different modalities (temperature, pain, vibration perception threshold, perception testing) may be more sensitive than standard clinical tests, it has considerable subjective components making it unreliable for diagnosis in entrapment neuropathies [42, 43]. Comparison of sensory nerve latencies of the median with ulnar or radial latency gives a clearer indication of median nerve involvement when compared to the value of median nerve alone. This would be of greater help in CTS with diabetes and a polyneuropathy already existing. In such a situation the values from the general population is used for adjustment to arrive at more precise diagnosis [44]. By measuring the distal to proximal velocities in median nerve, the segmental/ focal abnormalities also can be detected. This technique has a high 90% sensitivity in patients with diabetes and polyneuropathy.

11.5.9 Treatment of Carpal Tunnel Syndrome In mild to moderate CTS, oral steroids, splinting, ultrasound, yoga, and carpal bone mobilization have significant short-term benefits, but there is no evidence for long-­ term benefits [45].

11.5.10  Surgery in CTS Surgery is the preferred modality to decompress the carpal tunnel by sectioning the carpal tunnel ligament. It can be done by an open or an endoscopic method. The

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latter procedure is believed to give better grip strength. In view of the many additional complicating factors present in diabetes, surgical relief of CTS is slower and lesser as compared to CTS in those without diabetes [46]. The long-term relief in sensory-motor function and cold intolerance is comparable to that of nondiabetic controls. Improvement in cold intolerance means that C fibers have potential for regeneration over long time [47]. The neurophysiologic recovery over a period in patients with diabetes with or without polyneuropathy with significant slowing of conduction did not differ between these groups and also when compared with nondiabetic patients after surgery. Peripheral neuropathy thus appears not to be a factor in the recovery [48]. The impairment of quality of life in CTS patients with or without diabetes was not different [49].

11.5.11  U  NE and Ulnar Entrapment Neuropathy at the Wrist (UNW) Ulnar nerve entrapment due to its passing in the retro-epicondylar groove is the second most frequent entrapment neuropathy. In one estimate it was claimed to be 20.9% 100,000 person-years [50]. The entrapment in the retro-epicondylar groove is far higher, 76%, and was mainly of the demyelinating variety. At the humero-­ ulnar aponeurotic arcade it was just 17%, and was mostly axonal [51]. The symptoms of ulnar neuropathy are painful paresthesia of the fourth and fifth finger with weakness of thenar muscles or its wasting. The ulnar entrapment at both elbow and wrist in diabetes with or without polyneuropathy can be nearly 50% and is as vulnerable as the median nerve to entrapment [29]. Like MNW the ulnar neuropathy is subclinical in a third of patients. The possible mechanism extended for this asymptomatic state is the sensory thresholds which may get altered [28]. Both MNW and ulnar entrapment are assumed to coexist and should be actively investigated. Whether idiopathic, post-traumatic, or diabetic the electrophysiological characteristics are the same. However, in presence of diabetes the sensory amplitudes may be lower due to underlying axonal polyneuropathy.

11.5.12  Peroneal Nerve Entrapment The prevalence of peroneal entrapment at the fibular head and of the tarsal tunnel syndrome is much less than the median nerves in diabetes. The peroneal motor response amplitude is reduced at multiple sites and weakness of dorsiflexion of foot is quite high when it is present, 66% in people with diabetic neuropathy who are over the age of 65 [42, 52]. Conduction block or reduced motor conduction velocity across the fibular head are the diagnostic signs of peroneal entrapment and must be looked for. Otherwise other superimposed conditions like diabetic neuropathy, L 5 lumbar radiculopathy, and lumbar spinal canal stenosis will make a differential diagnosis of peroneal entrapment difficult.

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11.5.13  Entrapment of the Tibialis Nerve The tibialis nerve curves behind the medial malleolus under the flexor retinaculum. It can be entrapped wholly in a tarsal tunnel syndrome or selectively entrap the medial or lateral plantar nerves, the two main terminal branches of tibial nerve. Diagnosing it or the selectivity of any one or two needs more complex electrodiagnostic protocol. Such an algorithm analyzes the motor conduction velocities in a segmental manner in the distal tibial nerve [53]. Attention to these differential elements is not found in many a studies on lower limb nerve evaluations. This may or could also be a reason why the prevalence of lower limb entrapment is reported much less than the upper extremities in the general and even more so in diabetic population. In the imaging studies the lower limb nerves also are seen to have an increased area in cross sections. It therefore can be assumed that the rest of the changes described in detail above and the discussion on these are applicable to peroneal/ tibial entrapment situations. The nerve cross-sectional area is increased at the ankle in the diabetic group. The movement along the length of tibialis nerve was reduced at the ankle and knee. The reduction was proportional to the severity of neuropathy.

11.5.14  Surgery on Entrapped Nerves and its after Effects Surgery invariably helps in entrapment due to diabetes or idiopathic causes. Neurolysis was carried at multiple sites in lower limbs on 158 consecutive patients, 96 with diabetes and 62 with idiopathic entrapment. In this retrospective review all were found to have significant improvement in sensation and reduction in pain at a minimum follow-up of 1 year. Assessment of balance also seemed to improve. There was no statistically significant difference in both groups [54, 55].

11.6 C  ritical Review of Surgical Treatment of Entrapment Neuropathy There is a vacuum in the area of treatment for diabetic polyneuropathy since effective drugs addressing the causes of it are not available. Surgical decompression of multiple lower or upper limb nerves is being advocated as the treatment for symptomatic and generalized DPN.  This fundamental contradiction is based on many faulty assumptions. 1. The signs and symptoms of (generalized) diabetic neuropathy are due to multiple nerve entrapments—peroneal nerve at both the fibular head and the anterior tarsal tunnel, the tibial nerve in the tarsal tunnel, and the sural nerve in the distal posterior calf.

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2. In the upper hand numbness—entrapment of the ulnar nerve at both wrist and elbow, the radial nerve in the radial tunnel, and the median nerve at the wrist. 3. A trained examiner can diagnose entrapments by Tinel’s sign. 4. Surgical “release” of these nerves will correct DPN by decompression. 5. Special surgical training is needed to be able to identify these patients and operate on them. This series of hypotheses has spawned an entire industry. Despite this, patients have undergone these operations with neuropathy above the level of the foot and hand. There is much that is wrong with this thinking. 1. First, the distal neuropathy is due to progressive distal axonal loss. 2. The proposed pathophysiological mechanism of entrapment cannot explain sensory or motor symptoms or signs above the anatomic levels of the “entrapped” nerves. 3. The actual frequency of peripheral nerve entrapment in diabetic individuals is small. 4. Some patients can have a superimposed nerve entrapment syndrome with DPN at well-known sites of classic entrapments mentioned above. 5. The other postulated sites have been considered rare or even nonexistent which directly destabilize basis of the epidemic of decompressions carried out in numerous centers in the USA. 6. The Tinel’s sign was originally described in the setting of nerve regeneration and not in entrapment. It is poorly standardized and lacks sensitivity and specificity. 7. The proponents of the subjective Tinel’s sign ignore the proven value of electrodiagnostic studies, an objective test for localizing entrapment and nerve function. 8. Third, the American Academy of Neurology (AAN) used an evidence-based criteria review for decompression surgery for generalized DPN. Using standard procedures to assess evidence, there was only one prospective trial which cannot be sufficient. 9. The utility of surgical decompression received a grade IV rating; evidence from uncontrolled studies, case reports, or expert opinion. 10. It was assigned a U grading—“data inadequate or conflicting given current knowledge, treatment is unproven.” 11. Given that conclusion, AAN said “we believe that the treatment cannot be recommended at this point in time. A report on this topic by the Cochrane Collaboration will shortly follow”.

11.6.1 Claims for the Success of Decompression 1. Pain relief as assessed by the operating surgeon occurred in 80–92% of patients, some even on the operating table while recovering from the anesthetic. 2. Patients reporting bilateral improvement from unilateral procedures.

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3 . Patients claiming relief beyond the anatomic distribution of the released nerves. 4. Results may not have been any better than other noninvasive procedures for symptom relief (15–18), all of which claim short-term improvement. 5. Fourth, numerous centers have sprung up around the USA and the world, touting the benefits of procedures. 6. The most important are the placebo effects and the natural history of the disorder that explains it among many other explanations. 7. Unfortunately, medicine has seen these epidemics for surgical procedures over 50 years, for all sorts of diseases, finally proven wrong.

11.6.2 The Answer 1. Only well-controlled, randomized, double-masked, sham procedure, controlled clinical trials will allow us to know whether these surgeries are safe and effective for this indication—the same standard that any drug for DPN would have to meet. 2. Academy of Neurology’s evidence-based review is a strong evidence that such procedures are not a definitive cure and should be subjected to rigorous research until proven beneficial. 3. The ADA strongly support trials; pilot trials should be conducted to see whether there is reason to mount large phase 3 studies. 4. ADA support further research into the causes and treatment of DPN, an unmet medical need. Until the supporting evidence is stronger, surgical decompression should not be recommended for patients with diabetic sensorimotor polyneuropathy [56]

11.7 Other Electrophysiological Diagnostic Modalities 11.7.1 Laser-Evoked Potentials (LEPs), Nociceptive Functions Not Tested by Standard EPS 1. Neurophysiological technique of laser-evoked potentials (LEPs) is widely considered the most reliable tool to assess nociceptive functions [57, 58]. 2. For example, standard neurophysiological techniques in nerve conduction studies of the Aβ fiber-mediated trigeminal reflexes and somatosensory-evoked potentials do not provide information on nociceptive pathways. But they are still quite useful to detect damage along the somatosensory pathways and are widely used for assessing peripheral and CNS diseases that cause neuropathic pain [59] 3. Laser stimulations selectively activate Aδ and C nociceptors in the superficial layers of the skin [60]. LEPs related to Aδ fiber activation have been standardized for clinical application. The responses to stimulation are recorded from the scalp and consist of waveforms with different latencies.

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4. In diseases associated with damage to the nociceptive pathway, LEPs can be absent, reduced in amplitude, or delayed in latency [61–63]. 5. Among nociceptive-evoked potentials, contact heat-evoked potentials are also widely used in assessing neuropathic pain [64] (See below as well). 6. Concentric electrodes have also been introduced to measure pain-related evoked potentials and the small fiber involvement in neuropathic pain [65]. 7. Nevertheless, some studies suggest that concentric electrodes also activate non-­ nociceptive Aβ fibers; hence, pain-related evoked potential recording is not suitable for assessing nociceptive systems.

11.7.2 Contact Heat-Evoked Potential Stimulator (CHEPS) The contact heat-evoked potential stimulator (CHEPS) (Medoc Advanced Medical Systems LTD, Minneapolis, MN) device is for evaluating human pain reception and transmission of sensory pathways as well together. CHEPS rapidly delivers heat pulses with adjusted peak temperatures to assess warm/heat pain thresholds. Other thermal devices by Medoc include the GSA Genito, and TSA-2001 Sensory Analyzer (FDA, 2005). Atherton et al. (2007) conducted a study, including 41 patients with small fiber sensory neuropathy. Clinical assessment, contact heat-evoked potentials using CHEPS, skin flare response to histamine, skin biopsies, and QST, including vibratory and thermal perception, were performed on all patients. Nine healthy patients were used as controls. Warm and cold perception thresholds at the calf indicated a change of 8.2 ± 0.8 degrees Celsius (°C) and 3.6 ± 0.6 °C, respectively. Warm and thermal perception thresholds were within normal limits in 20 and 21 patients, respectively, in the same study. Seven patients demonstrated nerve conduction study abnormalities in sural nerve sensory action potentials, and all motor studies were normal. Compared to controls, results of CHEPS recorded reduced A delta amplitudes in legs, arms, and face, all of which values were highly significant. There were no recorded evoked stimulations of the leg, arm (n = 13), or face (n  =  4) in 24 patients. Responses were recorded in all testing areas in control subjects. Sixteen patients with normal thermal perception thresholds demonstrated reduced A delta responses. Latency responses for face, arm, and leg stimulation were similar in subjects and controls. The authors reported a significant positive correlation between skin flare areas and leg-evoked potential A delta amplitude [66].

11.7.3 Neurometer and Contact Heat-Evoked Potentials (CHEPS) Current perception thresholds (Neurometer®) and contact heat-evoked potentials (CHEPS) are new emerging tools with data on reproducibility and its relationship to more established reference parameters [67]. The recently developed normative values for CHEPS may allow for its wider adoption in research studies.

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In conclusion the EPS has important uses in diabetic neuropathies with certain limitations. Newer methods will need to find wider application in this field of study.

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39. Singh R, Gamble G, Cundy T.  Lifetime risk of symptomatic carpal tunnel syndrome in type 1 diabetes. Diabet Med. 2005;22:625–30,. PMID: 15842519. https://doi. org/10.1111/j.1464-5491.2005.01487.x. 40. Becker J, Nora DB, Gomes I, Stringari FF, Seitensus R, Panosso JS, Ehlers JC.  An evaluation of gender, obesity, age and diabetes mellitus as risk factors for carpal tunnel syndrome. Clin Neurophysiol. 2002;113:1429–34. PMID: 12169324. https://doi.org/10.1016/ S1388-2457(02)00201-8. 41. Werner RA, Andary M.  Electrodiagnostic evaluation of carpal tunnel syndrome. Muscle Nerve. 2011;44:597–607. [PMID: 21922474]. https://doi.org/10.1002/mus.22208. 42. Vinik A, Mehrabyan A, Colen L, Boulton A.  Focal entrapment neuropathies in dia betes. Diabetes Care. 2004;27:1783–8. [PMID: 15220266]. https://doi.org/10.2337/ diacare.27.7.1783. 43. Werner RA, Andary M. Carpal tunnel syndrome: pathophysiology and clinical neurophysiology. Clin Neurophysiol. 2002;113:1373–81. [PMID: 12169318]. 44. Gazioglu S, Boz C, Cakmak VA. Electrodiagnosis of carpal tunnel syndrome in patients with diabetic polyneuropathy. Clin Neurophysiol. 2011;122:1463–9. [PMID: 21330198]. https:// doi.org/10.1016/j.clinph.2010.11.021. 45. O’Connor D, Marshall S, Massy-Westropp N. Non-surgical treatment (other than steroid injection) for carpal tunnel syndrome. Cochrane Database Syst Rev. 2003;(1.): CD003219 [PMID: 12535461]) https://doi.org/10.1002/14651858.CD003219. 46. Ozkul Y, Sabuncu T, Kocabey Y, Nazligul Y. Outcomes of carpal tunnel release in diabetic and non-diabetic patients. Acta Neurol Scand. 2002;106:168–72. [PMID: 12174177]. 47. Thomsen NO, Cederlund RI, Andersson GS, Rosén I, Björk J, Dahlin LB.  Carpal tunnel release in patients with diabetes: a 5-year follow-up with matched controls. J Hand Surg Am. 2014;39:713–20. [PMID: 24582843]. https://doi.org/10.1016/j.jhsa.2014.01.012. 48. Thomsen NO, Rosén I, Dahlin LB.  Neurophysiologic recovery after carpal tunnel release in diabetic patients. Clin Neurophysiol. 2010;121:1569–73. [PMID: 20413347]. https://doi. org/10.1016/j.clinph.2010.03.014. 49. Thomsen NO, Cederlund R, Björk J, Dahlin LB.  Health-related quality of life in diabetic patients with carpal tunnel syndrome. Diabet Med. 2010;27:466–72. [PMID: 20536520]. https://doi.org/10.1111/j.1464-5491.2010.02970.x. 50. Mondelli M, Giannini F, Ballerini M, Ginanneschi F, Martorelli E.  Incidence of ulnar neuropathy at the elbow in the province of Siena (Italy). J Neurol Sci. 2005;234:5–10. [PMID: 15993135]. https://doi.org/10.1016/j.jns.2005.02.010. 51. Omejec G, Podnar S. Precise localization of ulnar neuropathy at the elbow. Clin Neurophysiol. 2015;126:2390–6. [PMID: 25743266]. https://doi.org/10.1016/j.clinph.2015.01.023. 52. Resnick HE, Stansberry KB, Harris TB, Tirivedi M, Smith K, Morgan P, Vinik AI. Diabetes, peripheral neuropathy, and old age disability. Muscle Nerve. 2002;25:43–50. [PMID: 11754184]. 53. Troni W, Parino E, Pisani PC, Pisani G. Segmental analysis of motor conduction velocity in distal tracts of tibial nerve: a coaxial needle electrode study. Clin Neurophysiol. 2010;121:221–7. [PMID: 19948425]. https://doi.org/10.1016/j.clinph.2009.10.005. 54. Valdivia JM, Weinand M, Maloney CT, Blount AL, Dellon AL. Surgical treatment of superimposed, lower extremity, peripheral nerve entrapments with diabetic and idiopathic neuropathy. Ann Plast Surg. 2013;70:675–9. [PMID: 23673565]. https://doi.org/10.1097/ SAP.0b013e3182764fb0. 55. Rota E, Morelli N.  Entrapment neuropathies in diabetes mellitus. World J Diabetes. 2016;7(17):342–53. https://doi.org/10.4239/wjd.v7.i17.342. http://www.wjgnet.com/esps/ helpdesk.aspx, ISSN 1948-9358 (online). 56. American Diabetes Association, Diabetes Care. Surgical decompression for diabetic sensorimotor polyneuropathy – Position Statement by American Diabetes Association, Diabetes Care, Volume 30, Number 2, February 2007, quoted verbatim]. 57. Cruccu G, et al. EFNS guidelines on neuropathic pain assessment: revised 2009. Eur J Neurol. 2010;17:1010–8. [PubMed: 20298428].

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Part IV Therapeutics of Diabetic Neuropathies

Treatment of Painful Diabetic Neuropathy

12

12.1 Introduction Despite having a detailed understanding of pathophysiology of diabetic neuropathy and considerable work on its painful part, it still remains a difficult if not impossible task to control pain in painful neuropathies in diabetes. Relief comes, often partial and almost never complete, with a heavy burden of drugs and lingering side effects. Strangely the drugs that are generally effective have little to do with the pathogenesis of the neuropathy or pain. Severe neuropathic pain often leads to depression and the drugs which are often effective in it are useful for alleviating diabetic neuropathy pain also as will be shown below. There are other drugs which may have to do something with pathogenesis, remain experimental or extremely difficult to administer, like C-peptide, or have been proved to be of no use at all like the aldose reductase inhibitors despite the pathophysiological connection to their actions. According to a position statement from the American Diabetes Association, the only compounds approved for DPN are meant to relieve pain, and none are approved to treat the underlying disease [1]. It is commonly supposed that DPN is not reversible. Actually it is in certain instances described in the chapter on insulin and diabetic nerves. In addition, the reader is also referred to the chapter on treatment of cardiovascular autonomic dysfunction which follows. These three chapters will give the complete picture of therapeutics of diabetic neuropathies. In interventional studies of small fiber neuropathy where putative agents to treat diabetic neuropathy are used, the tests can indicate quantified improvement. Combined with IENFD and NCS studies it could be a better indicator of such improvement. Since the information about the various modalities is quite lengthy, the author has purposely divided them in different chapters indicated above. This gives space to discuss other aspects which could not be otherwise discussed.

© Springer Nature Singapore Pte Ltd. 2020 S. Kelkar, Diabetic Neuropathy and Clinical Practice, https://doi.org/10.1007/978-981-15-2417-2_12

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12.2 The Ad Hoc Panel on Endpoints for Diabetic Neuropathy In discussing individual drugs, in most places objective experiences recorded in well-designed double blind randomized control studies are analyzed with the author’s impressions about the same. Not much scope is left for the “experiential” side of therapy of diabetic painful polyneuropathy. The trial work underlines many other aspects. Clearly not all drugs are equally effective and many will suffer in addition to the adverse elements of dropouts and troublesome side effects. Hence the overall efficacy is judged here by the following criteria suggested by authorities to be impartial in evaluation of individual drugs. 1. The agent should reduce neuropathy sensory symptoms to a statistically significant degree (see Note 1 below). 2. Improvements should not be related to objective parameters of testing showing worsening of neuropathy. 3. The agent should result in clinically meaningful improvements in neuropathy sensory symptoms [2]. Note 1: Many trials used 30% reduction equal to 2-point reduction in visual analog pain scale whereas greater than or equal to a 50% reduction has been accepted as a level of effectiveness in other trials. Author has preferred the latter option as being adequately effective. Note 2: Some information is provided judged by similar criteria for nondrug procedures also.

12.2.1 The Burden of Disappointment and Psychological Support The overall efficacy of the drugs and modalities to treat painful diabetic neuropathy is not high, cure of even symptoms is almost never complete, and the neuropathic changes once initiated are difficult to halt in most cases if not all. These factors together impose on the clinicians certain extra burden to psychologically support the patients through the many unhappy stages of treatment of painful neuropathies.

12.2.2 The Sequence of Discussion Followed Here the information related to the trials to find a solution to the pain will first be discussed for the treating physician to get a prior idea about its likely effectiveness and percentages of persons that would be helped. The discussion will also include the drug-related information of its administration, side effects and clinical value as well as efficacy. Full knowledge of this is essential since questions will keep coming up when the results are either not satisfactory or there is a burden of side effects. All of these will be discussed together.

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The evidence of trials will have information about the symptom scores on one side and more objective evidence like quantitative sensory testing and electrophysiological evidence on the other. It will be followed by a brief summary of what seems to succeed in practice in treating diabetic painful neuropathy. These details are and will be found to be of immense value in communicating the patient about the expected results and prepare the patients for partial to substantial recovery and free her from unrealistic expectations and save oneself from blames to follow. The pathogenesis of diabetic peripheral as well as autonomic neuropathies has also been described earlier. Some drug-specific information about the molecular action and/or the anatomical site of action is provided under a few individual drugs or as class of drugs for greater understanding of the clinicians. Unless specifically mentioned all trials chosen will be randomized double blind but placebo controlled trials either single or multicenter. These trials will almost always include the vibration, heat cold thresholds, neuropathic scores of different varieties, pain assessment, and many a times the autonomic tests for cardiovascular autonomic neuropathies giving a complete picture of the neuropathic spectrum. In most trials the numbers investigated are not large and the improvement criteria not fully acceptable (see above). This issue is further complicated by evidence suggesting that some diseases causing neuropathic pain respond differently to the same medications. Neither HIV nor chemotherapy-related neuropathic pain responds to treatments that are effective for other forms of neuropathic pain. It is unclear if these discrepancies are methodological or due to differences in the underlying disease state. In addition, head-to-­ head trials of medications and long-term outcome data for small fiber neuropathies are lacking. When possible, disease-specific treatment guidelines should be selected for management of pain in small fiber neuropathy (for example, diabetes, HIV, or chemotherapy). The anatomy of the sensory nerves including the small fibers which finally carry pain sensation has been described earlier. The various methods of testing diabetic nerves have been discussed in various places, all of which will form the backdrop of what is being discussed hereafter. Causes of nondiabetic painful neuropathies are discussed in the chapter of Small Fiber Neuropathies.

12.3 Treatment of Painful Polyneuropathy in Diabetes 12.3.1 Tricyclic Antidepressants (TCAs) Selective serotonin synaptic reuptake inhibitors (SSSRI) like tricyclic antidepressants, amitriptyline, imipramine, and desipramine inhibit only serotonin. Their anticholinergic actions could be inconvenient at least initially. Patients generally adapt to it as the doses are increased gradually over weeks. Tricyclic antidepressants (TCAs) consistently are recommended as first-tier drugs across all guidelines [3–8] Moulin’s (ref 5) and Bohlega’s S (ref 7) are comprehensive reviews of different

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agents used to treat neuropathic pain and are recommended for additional reading. The latter highlights the strength and weakness of pharmacologic agents across a spectrum of diseases and calculating the number needed to treat. The number needed to treat (NNT) is understood as the patients required to be treated before the first patient gets a relief of 50%. The NNT was 2.1–2.5 based on the type of TCA.  TCAs consistently were selected as first-line choices based on their efficacy and other factors such as cost and availability. TCAs have anticholinergic effects that can cause significant side effects for some patients, and specifically should be avoided in elderly adults. They are contraindicated in patients with a significant cardiac history, glaucoma, or recent monoamine oxidase inhibitor (MAOI) use and advanced age. Guidelines (vide above) note that safety and tolerability factors may limit the use of TCAs.

12.3.2 Amitriptyline As a typical and probably the most used in this class is available as 10, 25, and 50 mg tablets. The target dose could be as high as 150 mg/day. To avoid and to be able to tolerate its anticholinergic side effects like dryness of the mouth, slowing down of urination, constipation, and drowsiness in the initial period, it is best to build the drug dose up. Over weeks as the dosage gradually reaches 75  mg, the effects could be expected to be substantial, and further increase should be considered if the possibility of further reduction in pain is likely and/or the side effects are not causing any difficulties in the routine of these patients. In clinical practice in India this or higher level dosing is seldom achieved.

12.3.3 Important Clinical Considerations Amitriptyline can be combined with anticonvulsants like oxcarbazepine or carbamazepine. The evidence for this kind of combination in trials is not present since most are single drug, placebo controlled trials. It may be wise to remember that one of the particularly disturbing varieties of lancinating pain was considered as the equivalent of epileptic discharge and carbamazepine has been used. This is a useful combination again in gradually increasing doses. Diabetic painful neuropathy is such a debilitating and depressing condition that it is not at all irrational to use drugs from the bygone era. The reasons are many. No great evidence has been produced for newly tested drugs and the trials do not show much improvement. The idea is to find that drug or drugs which will relieve the patient. In today’s evidence “burdened” statistical medicine, the approach described above is abandoned. Using an independent clinical judgment, recognizing that older drugs also had beneficial effects and whose safety profile is well known to the professionals is not taken into consideration. That in times gone by, these were the only drugs available. Clinical judgment has been surrendered to the protocolized evidence burdened practice today. It does not help the patient in any way. Secondly,

12.4 Pregabalin

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there has been a critique on clinical trials using inappropriate criteria as end points to decide the efficacy of a drug. It may be recalled that this is allegedly one of the reasons why FDA approval for many drugs has not come through. In line with the argument above it must also be stated that the declaration of conflict of interest in reporting trials is a comparatively newer element. In earlier days influences of the sponsor are well recognized. An extensive discussion on this issue can be found in many chapters of the author’s volume of “India’s Private health Care Delivery; Critique and Remedies,” to be published by Palgrave Macmillan shortly.

12.4 Pregabalin 12.4.1 Mechanism of Action—Animal Studies These studies show pregabalin selectively binding to the 2-delta subunit protein of voltage-gated calcium channels in various regions of brain. It also binds in the ­superficial dorsal horn of the spinal cord. In vitro, pregabalin acts as a presynaptic inhibitor of the release of excitatory neurotransmitters in stimulated neurons [9–12]. Pregabalin’s mechanism of action also is believed to be through presynaptic inhibitor of the release of glutamate, substance P, and calcitonin gene-related peptide (CGRP). Noradrenergic and serotonergic neurons modulate nociceptive transmission at two levels—in the brain and in the spinal cord [13]. It reduces influx of calcium into isolated synaptic endings, thereby reducing release of synaptic vesicles by exocytosis [13]. This has been measured in  vitro for several excitatory neurotransmitters, mentioned above. These are especially relevant for analgesic action [14]. Pregabalin effect of inhibiting neurotransmitter release is enhanced by prolonged depolarization or prior inflammation [13, 15]. Pregabalin has no activity at GABAA, GABA B, or benzodiazepine receptors.

12.4.2 Pharmacodynamics and Pharmacokinetics Pregabalin is structurally related to gabapentin. But pregabalin exhibits linear pharmacokinetics across its therapeutic dose range, with low variations in different subjects unlike gabapentin [16]. Gabapentin in increasing doses does not show that [17].

12.4.3 Efficacy of Pregabalin Pregabalin has fewer troublesome side effects than tricyclic antidepressants and hardly any noticeable interaction with other drugs. The effectivity of pregabalin is dose dependent. The 75-mg/day dose appears to be ineffective, but 300- and 600-mg/day doses are more effective compared with

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placebo. The best benefit may lie between 150 and 300 mg/day. If the studies are conducted with 150 mg/day once or twice one may come cross a sufficient but lesser dose. In India it is available as 75  mg used to start treatment, reduction of side effects and then use 150 mg. Another study however indicated that the patients receiving 150 mg did not differ from placebo but those receiving 600 mg/day orally have had far better response. For India it would probably mean that the pregabalin strengths presently ­available—75 and 150  mg even in multiple dose regimes may not be adequate. There are in addition a few extended release pregabalin brands for which it is difficult to understand the logic/evidence used to get the DCGI approval to market them.

12.4.4 Clinical Efficacy—Pregabalin Patients in the 300- and 600-mg/day pregabalin groups show more improvements in various mean pain scores in studies and practice when compared with placebo. Improvements in pain level are seen in each week of administration of the drug, as does the improvement in sleep and overall change. Improvements in pain and sleep are also seen as early as week 1 and are then sustained. Pregabalin is well tolerated after the initial phase of dizziness and drowsiness reduces. The discontinuation rates are not high. Nearly half of patients in 300 mg/day achieved more than 50% pain reduction. In the 600-mg/day pregabalin group patients pain reduction was 48% compared with placebo (17/97, 18%). Patients in the 600-mg/day group who achieved much higher pain relief described it as “much improved” and “very much improved,” to the tune 60 to 80%, which exceeded in numbers compared to 300  mg [18]. Pregabalin treatment also showed improvement in social function, bodily pain, and energy levels. Dizziness, somnolence, and peripheral edema were the most common adverse events reported. Weight gain however could be a concern since many gained nearly 7% of the pre-pregabalin weight. Mostly it is water retention and edema [18]. Pregabalin has also come to be the first-line treatment of diabetic and postherpetic neuropathic pain like gabapentin. The NNT for pregabalin was 4.2 [5]. It should be used with caution in patients with congestive heart failure. Angioedema rarely has been described as a side effect.

12.4.5 Gabapentin Gabapentin, the first drug before pregabalin, has come to be used as first-line treatment of diabetic and postherpetic neuropathic pain. The NNT for it is 3.9–4 [5]. It is well tolerated and not known to cause significant drug–drug interactions. In rare circumstances, it has been associated with Stevens-Johnson syndrome. It acts through the voltage-gated α2δ calcium channel, by modifying the release of excitatory neurotransmitters. The dose range is from 600 to 1800. Initially the dose is

12.5 Duloxetine and Others

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slowly built up to 900 mg. Further increase in doses will depend upon continuous improvement showed with increasing doses and tolerability of its side effects. Combination of gabapentin and morphine compared to each drug administered singly was found to be much better in a group, predominantly diabetic with neuropathic pain. This study however has a handicap of just about 50 patients included in the study as in many other studies as will be seen in this chapter [18]. This study mode has not been repeated either.

12.5 Duloxetine and Others 12.5.1 Background This and many other drugs discussed below belong to serotonin and/or noradrenaline uptake inhibitors. Many of them are antidepressants as well. These will have similar mechanisms of actions. These actions will also be dose dependent and there will be a few intrinsic variations in their actions, side effect profile, and efficacy.

12.5.2 Analysis of some Major Studies One systematic review has opined that tricyclic antidepressants, traditional anticonvulsants, and opioids have better efficacy than newer generation anticonvulsants like gabapentin or the selective serotonin reuptake inhibitor, and a serotonin noradrenalin reuptake inhibitor for relieving the pain of diabetic neuropathy [19]. In light of these long-standing preferences the newer drugs are described below.

12.5.3 Mechanism of Action Selective serotonin synaptic reuptake inhibitors (SSSRI) like tricyclic antidepressants, amitriptyline, imipramine, and desipramine inhibit only serotonin uptake. Their anticholinergic actions could be inconvenient at least initially. Patients generally adapt to it as the doses are increased gradually over weeks. See below also. Duloxetine is a “balanced inhibitor” (dual uptake inhibitor) of both serotonin and norepinephrine. Its initial use in depression has proved its clinical safety. It modulates the pain or the nociceptive transmission especially in the anterolateral spinal tract synapses and the brain [13, 20]. The endogenous pain pathways are thus modulated. The central pathways and the hyperexcitability of the spinal and supraspinal pain transmitting p­ athways are supposed to have become unbalanced. By its inhibitory actions at two levels the imbalance is corrected. Such imbalances can manifest as persistent pain which is akin to that of diabetic painful polyneuropathy [21]. Four varieties of ­hyperalgesia—of the skin, referred pain, neuropathic pain, and postoperative pain indicate that central sensitization as well as continuous sensory signals inputs

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from damaged peripheral tissue both take part in pain production. The reactivity in dorsal horn neurons thus persists. Therefore treatment should be directed towards peripheral as well as central sources of pain.

12.5.4 Trials and Tribulations of Duloxetine There are as many reviews as original articles on duloxetine. The many trials seem to struggle with establishing efficacy of duloxetine on 30% reduction in pain. This translates into a reduction of 2 points on 11-point scale. The statistical significances are also worked out on that basis. Another confounding factor found in some trials is the substantial improvement in placebo treated patients as well. The last limitation common to all drugs used in painful neuropathy is the absence of active comparator crossover double blinded RCTs. Then there is a considerable dropout and persistent and somewhat unsettling side effects among those who continued the Duloxetine trial. The liver function tests get affected to some extent. It is reported to reduce more severe pain more effectively. The most effective dose seems to be 60 mg twice a day if side effects are mild. Lower dose trials at 10 and 20 mg did not give significant effects. All in all, a drug that should be superior on its basis of action like many other drugs used for painful peripheral neuropathy does not seem to occupy a prime position. Duloxetine is considered effective in painful diabetic neuropathy with 5.2 as its NNT [5]. As it has not been studied for other forms of neuropathic pain, it is mostly recommended as second- or third-line treatment. It has a rapid onset of action and is well tolerated. It should be avoided in patients with uncontrolled narrow-angle glaucoma or those on Mon-amine-oxidase-inhibitors, MAOIs. Abnormal bleeding is rarely reported.

12.5.5 Venlafaxine Hydrochloride Treatment with the 5-HT and NE reuptake inhibitor venlafaxine at high doses results in lower pain intensity and greater pain relief. However, at low doses, it is predominantly serotonergic, whereas higher doses add substantial noradrenergic effects [22–25]. Various other studies have shown that venlafaxine may be useful in treating pain associated with diabetic neuropathy. Venlafaxine is another but a second-line agent SSSRI. It is effective for mixed neuropathy also and has an NNT of 4.6 and is well tolerated [5]. It may occasionally increase blood pressure and cause ECG changes. Rarely there may be bleeding, hyperlipidemia, development of interstitial lung disease, and eosinophilic pneumonia. In a rare active comparator study in these classes of drugs imipramine was found to be more effective than venlafaxine. It should not be coadministered with MAOIs. Due to lower NNT, TCAs are recommended over newer SSSRIs. But venlafaxine is preferred over TCAs in elderly patients and others with higher risk for adverse events.

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12.6 Mexiletine Anti-arrhythmic drugs like Mexiletine have been used to treat neuropathic pain. This class no longer features in the list of drugs for this indication because of excessive number of potential side effects [5]. When prescribed it used to be considered as a good drug.

12.7 Opioids in Painful Neuropathy Opioids in painful neuropathy could be a matter of contention in situations other than its use in pain in malignancies. The side effects of opioids would be welcome in malignancies especially of the terminal settings and addiction would not matter. Both these factors could be interfering with the life quality and productivity of people with diabetes. This was not fully borne out in a well-designed study using controlled release Oxycodon in painful diabetic neuropathy. It could reduce the pain intensity to mild in just about 6 days with milder pain continuing than effected by placebo. This population however had various side effects related to opioid drugs [26]. The number needed to treat to obtain one patient with at least 50% pain relief was as low as 2.6 with Oxycodon. Around 50% of the patients did not need any other analgesic. Effects of CR oxycodone could last as long as 12 months of administration. No withdrawal effects were found after the blinded trial of fewer weeks was completed and the quality of life improved.

12.7.1 Opioids and Tramadol Both these drugs are often recommended as second- or third-line medications in all guidelines, in which the constant concern is drug dependence as well as overdosing is voiced. Different types of pain, not just diabetic painful neuropathy, are reviewed by these guidelines with different opioids like oxycodone, morphine, methadone, and levorphanol. These reviews found the Numbers Needed to Treat (NNT) for the opioids as 2.5–2.7 [3–5]. Oxycodone is also suggested for severe breakthrough pain when other analgesics are being used, opioids having their own side effects, notwithstanding.

12.7.2 Tramadol It is a mixed opioid with two different mechanisms of action. Tramadol and its active metabolite bind to central μ-opiate receptors and inhibit ascending pain pathways. It also causes serotonin and norepinephrine reuptake inhibition. In India it is probably one of the most frequently used opioids for short-term severe pains as in surgery. It is advisable to use it in diabetic painful neuropathy as a second or third

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line of drug since these neuropathic pains are chronic and dependence and overdosing may develop. The NNT for different types of pain with tramadol is 3.4–4.8 [5]. Dyspnea, respiratory depression, and a rare association with myocardial infarction, pancreatitis, convulsions, and serotonin syndrome are some of the side effects. It should be avoided in patients using alcohol, hypnotics, other opioids, or psychotropic drugs. Tramadol interacts with most antidepressants causing potential synergism enhancing inhibition of serotonin and norepinephrine reuptake. 10% of Caucasians do not metabolize tramadol efficiently (on which the action actually depends) due to poor cytochrome P450 2D6 activity. It results in ineffective action [27]. Tramadol, an opioid agonist and serotonin-noradrenaline reuptake inhibitor, has also been shown to be effective, mainly in peripheral neuropathic pain; its efficacy is less clearly established in central neuropathic pain. Animal studies have shown that there are kappa-opioid receptors in neural tissues also and not just centrally. Agents like peripherally acting kappa-opioid agonist, asimadoline have shown pain relief confirming this presence [28].

12.8 Miscellaneous Drugs 12.8.1 Strong Opioids and Botulinum Toxin A Strong opioids and botulinum toxin A (the latter administered by specialists) have weak recommendations for use as third-line treatments in painful diabetic neuropathy [29].

12.8.2 Oromucosal Cannabinoids Oromucosal cannabinoids have been found to be variably effective in pain associated with multiple sclerosis and in peripheral neuropathic pain with allodynia, but several unpublished trials were negative on the primary outcome.

12.8.2.1  Combination of Pregabalin or Gabapentin with a Tricyclic Antidepressant or Opioid Combination of pregabalin or gabapentin with a tricyclic antidepressant or opioid at lower doses has resulted in beneficial effects as compared to monotherapy in peripheral neuropathic pain [29, 30]. This systematic review [30] updates the recommendations for the pharmacological management of neuropathic pain, emphasizing that modest efficacy, considerable placebo responses, heterogeneous diagnostic criteria, and poor phenotypic profiling account for moderate trial outcomes and the unmet needs of the patients persist. The efficacy and adverse effects of high-dose monotherapy were similar to those of moderate-dose combination therapy in patients with diabetic neuropathic pain who did not respond to monotherapy at moderate doses [31].

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12.8.3 Topical Lidocaine Topical Lidocaine frequently is recommended as a first- or second-line treatment of focal neuropathic pain. These recommendations are typically for the lidocaine patch, although there is also evidence available for lidocaine gel. The guidelines included three or four studies (primarily for postherpetic neuralgia) and the NNT is 4.4 [3–5]. It is generally most effective for patients with focal regions of pain and offers the advantage of less systemic side effects and drug interactions. It also may be used for breakthrough pain. It is believed to act by decreasing neuronal membrane permeability to sodium ions. Topical lidocaine is more expensive than some of the other treatments, but is generally well tolerated. It should be avoided in regions of skin breakdown. Rare allergic or anaphylactic reactions can occur.

12.8.4 Capsaicin Patches High-concentration capsaicin (the active component of chili peppers) patche has weak evidence in support of its use and is recommended as second-line treatments for peripheral neuropathic pain only [29]. Capsaicin initially and additionally activates Transient Receptor Potential Cation Channel Subfamily V member 1 (TRPV1) ligand-gated channels on nociceptive fibers, leading to TRPV1 desensitization and makes it defunct. The sustained efficacy of a single application of a high-concentration capsaicin patch (8%) has been reported in postherpetic neuralgia, as well as painful diabetic neuropathy [32]. In this trial in patients with painful DPN, capsaicin 8% patch repeat treatment plus standard care was well tolerated over 52 weeks. It did not throw up any negative functional or neurological effects when compared with standard care alone.

12.8.5 Interventional Treatments Interventional treatments, such as nerve blocks or surgical procedures that deliver drugs to targeted areas, for modulation of specific neural structures, provide ­alternative treatment strategies in selected patients with refractory neuropathic pain [33, 34].

12.8.6 Oral Treatment with Alpha-Lipoic Acid In the Sydney 2 trial following observations were made by the trialists. Excess oxidative stress and diminished cellular antioxidant response in a hyperglycemic, stressful and pro-inflammatory milieu have been described numerously in diabetes literature. The role of Omega 3 fatty acids in restoring the pro-inflammatory milieu versus that of saturated fatty acids has also been numerously quoted.

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That is why agents like alpha lipoic acid (ALA) have been considered as effective in restoring many of these changes. Like other drugs used in painful neuropathy it also has a sound and strong basis.1 Alpha lipoic acid is a thiol-replenishing and redox-modulating agent. Its antioxidant actions consist of metal chelating activity, scavenging of reactive oxygen species (ROS), regenerating endogenous antioxidants like glutathione, vit C and E, and repair of proteins, DNA, and lipids. It stimulates skeletal muscle glucose uptake and changes NADH/NAD+ and GSH/GSSG ratios [35]. ALA was used in the SYDNEY 2 study as an oral agent with 4 arms—placebo, ALA 600, 1200, and 1800 mg daily for 5 weeks [35] the scores recorded were as follow. 1. Among the 181 patients randomly assigned, a total of 15 (8%) subjects discontinued during the treatment period, and 166 patients completed the trial. 2. The patients (12/15) discontinued because of adverse events: 1 in the placebo group, 0 in the ALA 600 group, 5 in ALA 1200, and 6 in ALA 1800 mg group. 3. One patient in the ALA 1800 group did not complete the trial because of lack of efficacy; one patient each in the ALA1200 and ALA1800 group discontinued for other reasons. 4. The response rates in Total Symptom Scores (TSS) of more than 50% reduction after 5 weeks were 62, 50, and 56% in ALA 600, 1200, and 1800 mg and 26% in placebo. 5. The mean levels of the Neuropathic Symptoms and Change (NSC) scores, Neuropathic Impairment Scores (NIS), and Neuropathic Impairment Scores Lower limbs, NIS[LL], at screening and their changes after 5 weeks of treatment were not significantly different within the groups. 6. These however improved significantly when compared to the placebo group in 600 and 1200 mg dose range but the NSC in ALA 1800 was less significant. The nerve conduction studies showed no significant differences among the groups. 7. In NIS, a significant improvement was noted in ALA 1200 and a borderline improvement in ALA 1800 versus placebo. 8. In NIS [LL] a trend for borderline significance was found in the ALA 600 group. NIS-[LL] sensory function showed a significant difference between ALA 600 and placebo and borderline improvement in ALA 1200 with placebo. 9. The percentages for the global estimate of efficacy of patients as very good/ good, satisfactory, and insufficient, respectively, were as shown below. 10. In ALA 600 group 29, 40, and 32%, in placebo group, as against 62, 27, and 11% as very good, good, and satisfactory for the ALA 600 group, 1  This agent has been in use extensively in India for over decade now, but the exact contributions and efficacy have not been registered in the minds of clinicians adequately clearly. Since it is a popular agent it is described under trial evidence in a little more detailed fashion to bring out clarity in this area.

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1 1. For the ALA 1200 group – 56, 31, and 13%, 12. For theALA1800 group – 71, 21, and 9%. 13. Treatment-related adverse events were—9  in placebo group, 12  in ALA 600 group, 20 in the ALA 1200 group, and 25 in the ALA 1800 group. 14. The rates of treatment-related adverse events increased with increasing doses for all ALA groups—nausea, 6, 10, and 22; vomiting, 1, 2, and 12; vertigo 2, 2, and 5, respectively. Another independent Grecian study has also produced similar results [36]. The overall conclusion is that the effective and best tolerated dose of alpha lipoic acid is 600  mg per day. This trial was a follow-up of the meta-analysis using IV ALA 600 mg daily. 1258 diabetic patients with symptomatic diabetic neuropathy from four randomized trials after meta-analysis suggested that 600 mg of IV ALA daily as infusion for 3 weeks reduced pain, paresthesia, and numbness and neuropathic deficits to a meaningful level clinically. This led to considering this agent as a potential drug favorably influencing the pathology.

12.9 Experimental Drugs 12.9.1 Ruboxistaurin Mesylate PKC beta as the Final Arbiter of DPN and its actions can be described as a series in a sequence. 1. Impairment of microvascular function has been associated with the nerve damage in DM [37, 38] 2. Hyperglycemia induces synthesis of di-acyl-glycerol (DAG). 3. It then activates protein kinase C (PKC), a family of 13 enzymes, which plays an important role in the development of diabetes-related complications in the nerves and other end organs [39] 4. The beta-isoform of the PKC is closely linked to the diabetic microvascular ­complications including diabetic painful neuropathy. DM-induced activation of PKC beta appears to mediate changes in nerve structure and microvasculature [40].

12.9.2 Rationale of Using RBX in Diabetic Neuropathy Ruboxistaurin (RBX) Mesylate is a specific inhibitor of PKC beta. Hence the interventional study was undertaken to see the effects of treatment after 1 year [41]. The hypotheses was—this is a type of patients who had detectable sural nerve potentials and a high value of vibration threshold indicating early DPN may possibly respond to treatment [42].

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12.9.3 Efficacy and Related Issues for Ruboxistaurin Mesylate (RBX) 1. RBX appeared to be more effective in patients who have significant symptoms but diabetic neuropathy is milder as decided by various laboratory parameters. This was seen as a reduction in the NTSS-6 total score with RBX 64 mg/d. All the patients enrolled had a score well above 6. But none of the three groups had adequate statistical significance. 2. Objectively speaking, similar significant improvement was seen in the vibration detection thresholds in both RBX 32 and 64 mg/day against placebo. 3. In 83 of these patients the overall reduction in pain after a year’s trial therapy RBX 64  mg/day achieved statistical significance but not the RBX 32  mg/day compared with placebo. 4. In these patients, there was statistically significant improvement in VDT for both RBX 32 mg/day and RBX 64 mg/day compared with placebo. 5. Neuropathy Impairment Score however did not change in placebo, 32  mg, or 64 mg patient groups. 6. RBX 32 mg/day group did not seem to perform much better than the placebo in the number improved, or worsened, so was the case with the combination of 32 + 64 mg RBX group. 7. Number of patients who worsened was smaller in RBX 32 mg/day group compared with placebo [37].

12.9.4 Adverse Reactions 1. Out of 205, 161 patients experienced more than 1 adverse event (AE) in one year and had no intergroup differences. 2. 32 patients discontinued treatment for various reasons but 5 in treatment groups discontinued because of adverse reactions. 3. Mild or moderate, self-limiting diarrhea was significantly more often in the RBX 64 mg/day group than in the placebo group. Only 1 was possibly drug related. 4. The serious AEs included vomiting, pneumonia, dehydration, and diabetic ketoacidosis that occurred more than one time in the combined RBX-treated groups. 5. Within the severe neuropathy patients—sural nerve conduction absent, there was no change in VDT in any group [37].

12.9.5 Remarks In spite of identification of a specific and likely mechanism causing diabetic painful polyneuropathy and a specific agent to block the adverse effects another drug has failed to become a drug better than the conventional SSSRI or the anticonvulsants. The action of RBX is not central or analgesic but it acts on the peripheral nerves.

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12.10 Vitamins Minerals and Diabetic Polyneuropathy In a volume of Diabetic Neuropathy it will be useful to find information which can guide the clinical choices of these vitamins more rationally. The greatest difficulty in finding dependable information is the quality of trials available. Most studies suffer in quality because these have not taken in to consideration many fundamental attributes when a study is designed. The single ingredient studies have small number of patients with short treatment intervals as mentioned many a times earlier. With these limitations what best conclusions that can be put forward is briefly given below. The antioxidant properties possessed by vitamin C and E. Vitamin E are used by some clinicians. Vitamin C is comparatively much less used for any indication including its antioxidant properties in diabetes. Practical experience of using vit E in painful lower extremity pains, calf pains may be found to be quite useful in some or not at all. Hence given its mode of action vit E be used in an otherwise recalcitrant condition of diabetic painful neuropathy for variable periods. The main functions of vitamin C are more or less forgotten—collagen synthesis, prevention of scurvy, and a precursor to steroid synthesis. It has dedicated antioxidant properties and should be tried for its at least theoretical multifunction utility. Information about these two is given below, together.

12.10.1  Vitamin C and E Theoretically the major role vit C and E are to play is in mounting an antioxidant response to the oxidative stress, one of the most important pathogenetic factor in diabetes and its neuropathy. If these causes have to be controlled, actual use of antioxidants after adequately controlling diabetes should be useful and theoretically sound strategy. Any one of the two or both can be used, if subjective, clinical, and laboratory improvements would conclusively indicate the use of such antioxidants as a complementary therapy. Analysis of information of 1248 patients from the systematic review thus recommends: 1. Vitamin E was related to significant reduction of blood glucose as well as glycated hemoglobin compared to placebo 2. Both vitamins C and E were mainly associated with reducing the formation of malondialdehyde (MDA) and thiobarbituric acid reactive substances, TBARS. Reduction of glutathione peroxidase (GPx) and reduction in the enzyme Superoxide Dysmutase which combat oxidative stress are the hallmarks of unmitigated oxidative stress and tissue damage. 3. There was an elevation in glutathione peroxidase (GPx) and enhancement in superoxide dismutase (SOD) and total antioxidant capacity (TAC) using these vitamins compared to placebo 4. Addition of vitamin E seems to be valuable for diabetes control and its complications as well as to increase the antioxidant capacity

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5. The effects of other micronutrients should be further investigated in larger and well-designed trials to properly place these complementary therapies in clinical practice 6. Vitamins C or D had no demonstrable differences with placebo 7. But for mean change in blood glucose (Mg/dL) and reduction of HbA1c the effects of vitamin E were significantly better than the control [43]

12.10.2  Vitamin D Since 2015 there has been a massive outbreak of data on extremely high vit D deficiencies in Indian and populations. It has dramatically increased the administration of vitamin D3 albeit orally with calcium. A variety of claims have been made about improvements caused in diabetes by using these two ingredients. Generating intracellular free calcium of adequate level is where all the changes in membrane potentials and fluxes of ions finally lead. Adequacy of calcium in the cells for any action in its full force like insulin exocytosis or muscle contraction requires full complement of calcium and to continue to work to the full capacity. Inadequacy would probably result in fewer cells acting. Replacement of vitamin D and calcium will increase the numbers of cells working, leading to a better milieu by restoring adequate calcium lvels intracellualrly. To claim that it improves diabetes would be contestable since all this replacement will do is to get the full complement to work and does not address the abnormalities that lead to development of diabetes, merely correcting the physiological inadequacy. The same will apply to the organs which respond to insulin in better calcium level milieu but will not change the properties of the organs of response to insulin. The reader can draw her own conclusions about the research in this area.2

12.10.3  Vitamin E in Diabetic Neuropathy All evidence about use of vit E suffers from the limited number as well as short duration of trials. However, the results seem to be valuable. Vitamins so far (end 2018) have been studied in just about 30 trials of which only a dozen were found analyzable. All were RCTs with placebo. Eleven patients were put on vitamin E 900 mg per day and 10 on placebo with nearly equal dietary vit E for 6 months. In main electrophysiological tests and HbA1 were studied at starting and after 6 months. HbA1c did not change in either group. The electrophysiological improvement was seen in 2 of the 12 parameters. Vit E 2  In vit D correction regimens it appears to the author desirable that some study about which is more effective in correcting vit D deficiency—oral weekly doses of vit D3 against massive doses of injectable vit D2 is worthwhile. Oral vit D 3 may have to be considered as a drug reserved for those with end-stage renal disease where conversion of injected vit D 2 is not possible. But in vast majority of calcium/vit D deficiency it appears to be a legitimate question which one corrects the deficiency better and quicker. Added to that is the high cost of vit D3.

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group improved in median motor nerve fibers and tibial motor nerve distal latency quite considerably, achieving statistical significance, which was much higher for median motor nerve than tibial which could be a fiber length-related deterioration with reduced potential for improvement [44]. Random experience in painful diabetic neuropathy and use of vit E suggests that if it works it works well or it does not work at all. More work on this useful agent will be helpful. Given that it is a normal ingredient of food, a trial of this agent in otherwise non-responding pain could be worthwhile. It is also a useful agent to treat nonalcoholic fatty infiltration of liver, a finding common in clinical practice due to widespread use of ultrasonography of the abdomen.

12.10.4  Vitamin B 12 With metformin topping the list for diabetic drug regimens over two decades now it would be helpful to remember that long-term use of metformin leads to vit B12 deficiency in about 30% of all users. It would also be equally useful to remember that the typical microscopic picture on peripheral blood smear with macrocytosis of RBCs may not be seen or may get overlooked. In automated hemograms the RDW, random width distribution indicative of turnover of RBCs, is routinely given and could be normal or again could be overlooked missing the vit B 12 deficiency. Vegetarianism, initially contested whether it causes vit B 12 deficiency, seems to have resolved in its favor. Combined with metformin the chances of deficiency would rise. An acid environment in the stomach is a normal condition. The use of proton pump inhibitors in clinical practice has touched almost universal presence of these agents at least in India, whether or not indicated, mostly the latter. The author believes that it has high addictive potential. Alcohol is another cause for vitamin B 12 deficiency, which can act in concert with other factors. Clinical experience suggests that subnormal hemopoiesis is not the only manifestation of vit B 12 to develop typical dimorphic anemia. In fact with better nutritional conditions it is likely to be preserved first at the cost of B 12 deficiency of other organs. One of the most typical manifestation of it will be subacute combined degeneration clinically detectable as weakness in both legs and up going plantar reflexes and hyperreflexia with high vibration perception threshold indicating an upper motor neuron lesion and posterior column/sensory nerve dysfunction in spinal cord, leading to an altogether different line of investigations. In today’s practice, younger generation of physicians would have taken the last ankle reflex when they passed the graduate or postgraduate examinations if they had to present a neurology case. These are harsh words but these are true. In clinical practice a normal touch sensation, sketal muscle reflexes and vibration perception threshold, if these are tested at all, will help localize abnormalities. If the vibration sense is absent or the VDT threshold goes beyond highest range, if the plantars are going up and hyperreflexia is present the simplest diagnosis of subacute combined degeneration is made without any further aid and effectively treated. It affects the posterior spinal cord columns carrying the vibration sensations and the pyramidal damage to the fibers descending through and arborizing on the anterior motor horn cells.

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In the long experience of the author vit B 12 deficiency has been encountered with a symptom complex with profound effects on cognitive intellectual functions, myalgias, fatigue, etc. without the presence of any of the factors described above. This is an extremely intriguing situation, not rare as may be considered, if not a day-­to-­day occurrence. If it gets diagnosed in routine testing it is worthwhile to remember that injectable vit B 12 may produce dramatic effects on improvement (see below). The conditions described above in diabetic patients will complicate the picture further on all counts and particularly if clinical neuropathic assessment is not undertaken.

12.10.5  Replacement of B 12 in Deficiency Only 1% of all the dietary/supplemental vit B 12 is absorbed. Assuming that it could prevent deficiency the likelihood that one could replace it adequately orally in an actual deficiency state would be debatable. In today’s proton pump inhibitor (PPIs) universally treated patient population the normal acid stomach environment is gone. Hypochlorhydria prevails. Factor 1 with which oral B 12 combines and is carried to the ileocecal junction for absorption may also be absent. There is no information on atrophic changes in the stomach on people who have been on PPIs without or with indication for administering the same. In such a scenario parenteral replacement of B 12 will have to be considered in practice.3

12.11 Experimental Electrical Studies to Reduce Painful DPN Evidence supporting conservative non-pharmacological treatments, physiotherapy, transcutaneous electric nerve stimulation, and many others is limited and the rigorous evidence still indicates primacy of pharmacological therapy [45]. However drug therapies are often unsuccessful in painful diabetic neuropathy. This prompts nondrug symptomatic treatments like acupuncture, near-infrared phototherapy low-intensity laser therapy, static and pulsed magnetic field therapies, transcutaneous electrical nerve stimulation (TENS), percutaneous electrical nerve stimulation, and spinal cord electro-stimulation. Electrical nerve stimulation used in other painful conditions has been controversial while some benefits are also reported. These have been cognized here since the attraction to such modalities is high in India and elsewhere. An honest appraisal is needed. Severe limitations of studies in almost all modalities tested do not make a case for its use. 3  The author has seen something similar happening in areas with high content of arsenic and such other metals as in West Bengal. Oral iron replacement over months, which patients any way do not adhere to, does not change the anemia profile in any way. This frustrating experience has led the author to routinely replace iron by intravenous route. In the tribals in Tripura a peculiar microcytic anemia without much iron deficiency is seen. This is also not correctable beyond 9 g/dl, which however is an acceptable level for full functioning. Use of vit B 12 should routinely be combined with Folic acid for full hemtologic/neurological recovery.

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12.11.1  High-Frequency External Muscle Stimulation (HF) High-frequency external muscle stimulation (HF) and transcutaneous electrical nerve stimulations, TENS, were compared in two groups of patients with diabetic sensory neuropathy. The rate of response was much higher in the HF group, than in the TENS group, in relief symptoms of non-painful neuropathy and painful neuropathy [46]. As a limitation, this study is too small with little follow-up over any duration but may be investigated more experimentally than claiming a therapeutic status.

12.11.2  Frequency-Modulated Electromagnetic Neural Stimulation Frequency-modulated electromagnetic neural stimulation (FREMS) is a new electrotherapy. It is different from TENS and other known electrotherapy systems. It uses electrical stimuli varying automatically in pulse frequency, duration, and voltage amplitude. The basis of action argued is—sum of many subthreshold electrical stimuli may induce composite motor action potentials in excitable tissues in a noninvasive system. The single impulse of low intensity and short duration, in conventional electrotherapies, is not sufficient to reach and excite the subcutaneous nerves or muscular tissue. In FREMS, variable weak impulses with rapid increase and decrease in pulse frequency and duration results in the gradual increases in membrane potentials in the stimulated tissues [47, 48]. The applied voltage varies from 0 to 225 V, pulse frequencies from 0 to 50 Mhz, and pulse duration from 10 to 40 μs. The results reported were as follows: 1. Decrease in daytime (p = 0.0025) and nighttime pain score (p = 0.0107). 2. Decrease in the number of points insensitive to the Semmes–Weinstein monofilament (p = 0.0077). 3. Decrease in the vibration perception threshold (making it more sensitive). 4. MNCV increased by almost 5 m/s. 5. Nonsignificant trends towards improvements in quality of life. 6. No carryover effect within the crossover analysis. 7. Four-month follow-up showed persistence of all statistically significant changes. 8. In addition, bodily pain, social functioning, physical functioning, and general mental health improved. 9. A nonsignificant trend towards improvement of sural NCV. 10. General health perception, emotional problems, or vitality did not change. 11. It was safe without any systemic adverse effects. Limitations of this modality are obvious, despite such positive results. The numbers investigated were too small. The end point was pain reduction of 29 and 25% for day and night, vibration threshold drop of 2 volts from the baseline above 25 V,

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the number of foot points insensitive to the Semmes–Weinstein monofilament decreasing by 1.2 V do not really show a worthwhile utility. All in all it is at present a mere experimental modality at best and cannot be considered a valid therapeutic tool.

12.11.3  Monochromatic Infrared Energy (MIRE) Thirty minutes of active monochromatic infrared energy (MIRE) applied 3 days/ week for 4 weeks was no more effective than placebo MIRE in increasing sensation in subjects with diabetic peripheral neuropathy. Clinicians should be aware that MIRE is not an effective modality for improving sensory impairments in patients with diabetic neuropathy [49]. The long-term safety of repeated applications seems favorable based on open studies, but there are no long-term data on the effects on epidermal nerve fibers in patients with neuropathic pain.

12.11.4  Botulinum Toxin A Botulinum toxin A is a potent neurotoxin commonly used for the treatment of focal muscle hyperactivity and has shown efficacy of repeated administrations over 6 months, with enhanced effects of the second injection. The toxin has a role in the treatment of peripheral neuropathic pain, for example, diabetic neuropathic pain, postherpetic neuralgia, and trigeminal neuralgia. But the results are not greatly encouraging [50]. This trial indicates that botulinum toxin A reduces pain intensity over 24 weeks compared with a placebo treatment. Another trial in postherpetic neuralgia [51] did not show much encouraging results. Meta-analysis of just two trials in painful DPN [52] concluded merely reporting no clinical improvement with “minimum change in pain” recommending further large-scale controlled trials. In conclusion treatment of diabetic neuropathy remains symptomatic and responses to any drug are patient specific. This will require patience, use of combinations with slow dose increases, clear communication of the difficulties, and psychological support for the relief of patients which may never be complete.

References 1. Boulton AJ, Vinik AI, Arezzo JC, et al. For the American Diabetes Association. Diabetic neuropathies: a statement by the American Diabetes Association. Diabetes Care. 2005;28:956–62. 2. Apfel SC, Asbury AK, Bril V, for the Ad Hoc Panel on Endpoints for Diabetic Neuropathy Trials, et al. Positive neuropathic sensory symptoms as endpoints in diabetic neuropathy trials. J Neurol Sci. 2001;189:3–5. 3. Attal N, Cruccu G, Baron R, Haanpaa M, Hansson P, Jensen TS, Nurmikko T. EFNS guidelines on the pharmacological treatment of neuropathic pain: 2009 revision. Eur J Neurol. 2010;17:1113. –1e88. [PubMed: 20402746].

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4. Dworkin RH, O'Connor AB, Audette J, Baron R, Gourlay GK, Haanpaa ML, Kent JL, Krane EJ, Lebel AA, Levy RM, Mackey SC, Mayer J, Miaskowski C, Raja SN, Rice AS, Schmader KE, Stacey B, Stanos S, Treede RD, Turk DC, Walco GA, Wells CD. Recommendations for the pharmacological management of neuropathic pain: an overview and literature update. Mayo Clin Proc. 2010;85:S3–S14. [PubMed: 20194146]. 5. Moulin DE, Clark AJ, Gilron I, Ware MA, Watson CP, Sessle BJ, Coderre T, Morley-Forster PK, Stinson J, Boulanger A, Peng P, Finley GA, Taenzer P, Squire P, Dion D, Cholkan A, Gilani A, Gordon A, Henry J, Jovey R, Lynch M, Mailis-Gagnon A, Panju A, Rollman GB, Velly A.  Pharmacological management of chronic neuropathic pain  - consensus statement and guidelines from the Canadian Pain Society. Pain Res Manag. 2007;12:13–21. [PubMed: 17372630]. 6. Acevedo JC, Amaya A, Casasola OL, Chinchilla N, De GM, Florez S, Genis MA, Gomez-­ Barrios JV, Hernandez JJ, Ibarra E, Moreno C, Orrillo E, Pasternak D, Romero S, Vallejo M, Velasco M, Villalobos A.  Guidelines for the diagnosis and management of neuropathic pain: consensus of a group of Latin American experts. J Pain Palliat Care Pharmacother. 2009;23:261–81. [PubMed: 19670022]. 7. Bohlega S, Alsaadi T, Amir A, Hosny H, Karawagh AM, Moulin D, Riachi N, Salti A, Shelbaya S. Guidelines for the pharmacological treatment of peripheral neuropathic pain: expert panel recommendations for the middle east region. J Int Med Res. 2010;38:295–317. [PubMed: 20515552]. 8. Attal N, Cruccu G, Haanpaa M, Hansson P, Jensen TS, Nurmikko T, Sampaio C, Sindrup S, Wiffen P. EFNS guidelines on pharmacological treatment of neuropathic pain. Eur J Neurol. 2006;13:1153–69. [PubMed: 17038030]. 9. Dooley DJ, Mieske CA, Borosky SA. Inhibition of K(+)-evoked glutamate release from rat neocortical and hippocampal slices by gabapentin. Neurosci Lett. 2000;280:107–10. 10. Maneuf YP, McKnight AT. Block by gabapentin of the facilitation of glutamate release from rat trigeminal nucleus following activation of protein kinase C or adenylyl cyclase. Br J Pharmacol. 2001;134:237–40. 11. Dooley DJ, Donovan CM, Pugsley TA. Stimulus-dependent modulation of [3H]-norepinephrine release from rat neocortical slices by gabapentin and pregabalin. J Pharmacol Exp Ther. 2000;295:1086–93. 12. Field MJ, Oles RJ, Singh L. Pregabalin may represent a novel class of anxiolytic agents with a broad spectrum of activity. Br J Pharmacol. 2001;132:1–4. 13. Basbaum AI, Fields HL.  Endogenous pain control systems: brainstem spinal pathways and endorphin circuitry. Annu Rev Neurosci. 1984;7:309–38. 14. Fehrenbacher JC, Taylor CP, Vasko MR.  Pregabalin and gabapentin reduce release of substance P and CGRP from rat spinal tissues only after inflammation or activation of protein kinase C. Pain. 2003;105:133–41. 15. Dooley DJ, Donovan CM, Meder WP, et al. Preferential action of gabapentin and pregabalin at P/Q-type voltage-sensitive calcium channels: inhibition of K-evoked [3H]-norepinephrine release from rat neocortical slices. Synapse. 2002;45:171–90. 16. Busch J, Strand JA, Posvar EL, et  al. Pregabalin single-dose pharmacokinetics and safety/ tolerance in healthy subjects after oral administration of pregabalin solution or capsule doses. Epilepsia. 1998;39(suppl 6):58. Abstract. 17. Jones DL, Sorkin LS.  Systemic gabapentin and S(+)-3-isobutyl-gammaaminobutyric acid block secondary hyperalgesia. Brain Res. 1998;81:93–9. 18. Gilron I, Bailey JM, Tu D, Holden RR, Weaver DF, Houlden RL. Morphine, gabapentin, or their combination for neuropathic pain. N Engl J Med. 2005;352:1324–34. 19. Wong M-c, Chung JWY, Wong TKS. Effects of treatments for symptoms of painful diabetic neuropathy: systematic review. BMJ. 2007;335:87.; originally published online 11 Jun 2007. https://doi.org/10.1136/bmj.39213.565972.AE. 20. Clark FM, Proudfit HK. The projections of noradrenergic neurons in the A5 catecholamine cell group to the spinal cord in the rat: anatomical evidence that A5 neurons modulate nociception. Brain Res. 1993;616:200–10.

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21. Coderre TJ, Katz J. Peripheral and central hyperexcitability: differential signs and symptoms in persistent pain. Behav Brain Sci. 1997;20:404–19. 22. Rowbotham MC, Goli V, Kunz NR, et al. Venlafaxine extended release in the treatment of painful diabetic neuropathy: a double-blind, placebo-controlled study. Pain. 2004;110:697–706. 23. Davis JL, Smith RL.  Painful peripheral diabetic neuropathy treated with venlafaxine HCL extended release capsules. Diabetes Care. 1999;22:1909–10. 24. Lithner F. Venlafaxine in treatment of severe painful peripheral diabetic neuropathy. Diabetes Care. 2000;23:1710–1. 25. Bymaster FP, Dreshfield-Ahmad LJ, Threlkeld PG, et al. Comparative affinity of duloxetine and venlafaxine for serotonin and norepinephrine transporters in  vitro and in  vivo, human serotonin receptor subtypes, and other neuronal receptors. Neuropsychopharmacology. 2001;25:871–80. 26. Gimbel JS, Richards P, Portenoy RK. Controlled release oxycodone for pain in diabetic neuropathy, A randomized controlled trial. Neurology. 2003;60:927. 27. Kroemer HK, Eichelbaum M. “It's the genes, stupid”. Molecular bases and clinical consequences of genetic cytochrome P450 2D6 polymorphism. Life Sci. 1995;56:2285–98. [PubMed: 7791516]. 28. Binder W, Walker JS. Effect of the peripherally selective kappa-opioid agonist, asimadoline, on adjuvant arthritis. Br J Pharmacol. 1998;124:647–54. 29. Finnerup NB, Attal N. Pharmacotherapy of neuropathic pain: time to rewrite the rulebook? Pain Manag. 2016;6:1–3. [PubMed: 26678278]. 30. Finnerup NB, et al. Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis. Lancet Neurol. 2015;14:162–73. [PubMed: 25575710]. 31. Tesfaye S, et  al. Duloxetine and pregabalin: high-dose monotherapy or their combination? The “COMBO-DN study” — a multinational, randomized, double-blind, parallel-group study in patients with diabetic peripheral neuropathic pain. Pain. 2013;154:2616–25. [PubMed: 23732189]. 32. Vinik AI, et al. Capsaicin 8% patch repeat treatment plus standard of care (SOC) versus SOC alone in painful diabetic peripheral neuropathy: a randomised, 52-week, open-label, safety study. BMC Neurol. 2016;16:251. [PubMed: 27919222]. 33. Cruccu G, et  al. EFNS guidelines on neurostimulation therapy for neuropathic pain. Eur J Neurol. 2007;14:952–70. [PubMed: 17718686]. 34. Dworkin RH, et al. Interventional management of neuropathic pain: NeuPSIG recommendations. Pain. 2013;154:2249–61. [PubMed: 23748119]. 35. Ziegler D, Ametov A, Barinov A, Dyck PJ, Gurieva I, Low PA, Munzel U, Yakhno N, Raz T, Novosadova M, Maus J, Samigullin R. Oral treatment with alpha-lipoic acid improves symptomatic diabetic polyneuropathy TheSYDNEY2 trial. Diabetes Care. 2006;29:2365–70. 36. Agathos E, Tentolouris A, Eleftheriadou I, Katsaouni P, Nemtzas I, Petrou A, Papanikolaou C, Tentolouris N. Effect of a-lipoic acid on symptoms and quality of life in patients with painful diabetic neuropath. J Int Med Res. 2018;46(5):1779–90. 37. Vinik AI, Bril V, Kempler P, Litchy WJ, Tesfaye S, Price KL, Bastyr EJ III. Treatment of symptomatic diabetic peripheral neuropathy with the protein kinase C beta-inhibitor ruboxistaurin mesylate during 1year, randomized, placebo-controlled, Double-Blind Clinical Trial. Clin Ther., Express Track online publication. 2005; https://doi.org/10.1016/j.clinthera.2005.08.001. 38. Cameron NE, Cotter MA. Metabolic and vascular factors in the patho-genesis of diabetic neuropathy. Diabetes. 1997;46(Suppl 2):S31–7. 39. Ways DK, Sheetz MJ. The rote of protein kinase C in the development of the complications of diabetes. Vitam Horm. 2000;60:149–93. 40. Ozaki H, Yasuda K, Kim YS, et  al. Possible role of the protein kinase C/CPI-17 pathway in the augmented contraction of human myometrium after gestation. Br J Pharmacol. 2003;140:1303–12. 41. Vinik A, Tesfaye S, Zhang D, Bastyr E, for the MBBQ Study Group. LY333531 treatment improves diabetic peripheral neuropathy (DPN) with symptoms. Diabetes. 2002;51 (Suppl 2):A79.

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42. Bril V, Vinik AI, Litchy WJ, for the MBBQ Study Group, et al. Detectable sural nerve action potential (SNAP) identifies patients with early diabetic peripheral neuropathy (DPN). Diabetes. 2002;51(Suppl 2):A197. 43. Balbi ME, Tonin FS, Mendes AM, Borba HH, Wiens A. Antioxidant effects of vitamins in type 2 diabetes: a meta-analysis of randomized controlled trials. Diabetol Metab Syndr. 2018;10:18. Published online 2018 Mar 14. https://doi.org/10.1186/s13098-018-0318-5. 44. Tutuncu NB, Bayraktar M, Varli K. Reversal of defective nerve conduction with vitamin E supplementation in type 2 diabetes – a preliminary study. Diabetes Care. 1998;21:1915–8. 45. Finnerup NB, Otto M, Mcquay HJ, Jensen TS, Sindrup SH. Algorithm for neuropathic pain treatment: an evidence based proposal. Pain. 2005;118:289–305. 46. Reichstein L, Labrenz S, Ziegler D, Martin S.  Effective treatment of symptomatic diabetic polyneuropathy by high-frequency external muscle stimulation. Diabetologia. 2005;48:824–8. https://doi.org/10.1007/s00125-005-1728-0. 47. Bevilacqua M, Barrella M, Toscano R et  al (2004) Disturbances of vasomotion in diabetic (type 2) neuropathy: increase of vascular endothelial growth factor, elicitation of sympathetic efflux and synchronization of vascular flow (vasomotion)during frequency modulated neural stimulation (FREMS). 86th Annual Meeting of the Endocrine Society, p 321, P 2–61 (abstract). 48. Bosi E, Conti M, Vermigli C, Cazzetta G, Peretti E, Cordoni MC, Galimberti G, Scionti L.  Effectiveness of frequency-modulated electromagnetic neural stimulation in the treatment of painful diabetic neuropathy. Diabetologia. 2005;48:817–23. https://doi.org/10.1007/ s00125-005-1734-2. 49. Clifft JK, Kasser RJ, Newton TS, Bush AJ. The effect of monochromatic infrared energy on sensation in patients with diabetic peripheral neuropathy a double-blind, placebo-controlled study. Diabetes Care. 2005;28:2896–900. 50. Attal N, et al. Safety and efficacy of repeated injections of botulinum toxin a in peripheral neuropathic pain (BOTNEP): a randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2016;15:555–65. 51. Shackleton T, et al. The efficacy of botulinum toxin for the treatment of trigeminal and postherpetic neuralgia: a systematic review with meta-analyses. Oral Surg Oral Med Oral Pathol Oral Radiol. 2016;122:61–71. [PubMed: 27260275]. 52. Lakhan SE, Velasco DN, Tepper D. Botulinum toxin-a for painful diabetic neuropathy: a metaanalysis. Pain Med. 2015;16:1773–80. [PubMed: 25800040].

Insulin and Diabetic Peripheral Nerve Pathologies

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13.1 Introduction Sensory nerve damage in prediabetes and type 1 and type 2 diabetes is widely prevalent. Both insulin deficiency and/or hyperinsulinemia (as in prediabetes) should logically be contributing to the neuropathic changes. In addition and importantly peripheral sensory neurons respond to insulin like other insulin-sensitive tissues. Presently it is accepted that insulin signaling pathways are active contributors to sensory nerve modulation. New insight into insulin’s role in peripheral and central nervous system diseases is now emerging [1].

13.2 New Evidences about Insulin Effects on Nervous Tissues 13.2.1 Animal Evidence There is considerable animal evidence for insulin and central nervous system, which may not be relevant to the volume but will improve understanding about importance of insulin. It is presented below as observations without going in the complexities of the experiments. 1. Insulin may also be involved in regulation of synapse number, hippocampal plasticity, and spatial learning of rats [2] 2. Intraventricular insulin injections may control liver gluconeogenesis, obesity, central hepatic regulation, and insulin resistance in rats [3] 3. Insulin receptors are expressed in dorsal and ventral spinal cord neurons [4] 4. Insulin may have a role for signaling in the spinal cord. 5. Insulin receptor signaling in the CNS may be regulating neuronal development [5] 6. In 18-month-old GK rats classic DPN changes developed in low insulin euglycemic state [6] © Springer Nature Singapore Pte Ltd. 2020 S. Kelkar, Diabetic Neuropathy and Clinical Practice, https://doi.org/10.1007/978-981-15-2417-2_13

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7. Impaired glucose tolerance and insulinopenia in the GK rat causes peripheral neuropathy. The authors suggest these changes to be related more to decrease in neuronal insulin support. 8. Low-dose insulin without decreasing the hyperglycemic level can have ­beneficial effects on the signs and symptoms of DN.  Intrathecal delivery of insulin or equimolar IGF1 daily for 4 weeks could restore both motor and sensory nerve conduction deficits, but could also prevent axonal atrophy in type 1 diabetic rats [7] 9. Both intrathecal insulin and IGF1 were able to reverse the loss of epidermal nerve fiber density and length in diabetic rats [8]. 10. Intra-plantar delivery of insulin without lowering glucose much reversed the loss of intra-epidermal nerve fiber density, epidermal axons, increased epidermal innervation, and reduced a little some symptoms like mechanical allodynia but not thermal sensation in several mouse models [9]. GAP43/B50, a growth-­ associated protein, also increased with insulin treatment. These results also corroborate the neuronal growth promoting qualities of insulin. 11. Insulin prevents depolarization of the mitochondrial inner membrane in sensory neurons, helps normalize the mitochondrial protein expression of type 1 diabetic rats in the presence of sustained hyperglycemia, and protects against late-stage motor neuropathy in diabetes [10]. 12. Overall, these observations suggest that although neurons do not take up glucose in an insulin-dependent manner, many neuronal populations do seem to be insulin responsive and insulin may be important to maintaining proper neuronal function.

13.2.2 Insulin in Humans 1. Insulin is a member of a super family that includes insulin, IGF1, and IGF2. IGF1 is a well-known neurotrophic factor; positive effects of insulin on neurons have been recognized in the past 15–20 years. Insulin is a potent neurotrophic factor essential to promote proper neuronal function. Insulin receptors are expressed both on the DRG neuron soma and in the peripheral nerve [11–13]. 2. Insulin receptors are predominantly expressed in small nociceptive neurons. Roughly, 40% of DRG neurons express the insulin receptors. A few other peptide are also expressed in varying proportions on insulin receptor dorsal horn cells. 75% of these neurons have peripherin [14], 25% of all DRG neurons with insulin receptors co-express TRPV1. 68% of TRPV1-positive neurons express the insulin receptor [14]. 3. Calcium gene related peptide (CGRP) (peptidergic) related to recovery of thermal sensitivity or IB4 (nonpeptidergic) are expressed on insulin receptor neural cells [14] 4. Insulin sensitizes and potentiates TRPV1 signaling by lowering the threshold for activation and increasing membrane translocation [15–17]. TRPV1 could also be related to thermal sensitivity [18]

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5. Neurofilament-H, a marker of large myelinated neurons, strongly co-labels with insulin receptors [9, 19]. 6. In primary culture models of embryonic sympathetic and sensory neurons, insulin supplementation has been shown to have many positive effects on cell growth, neurite formation [20–23]. 7. Insulin stimulation increases neurite length and area of both sympathetic and sensory neurons in a dose-dependent manner with insulin in cultures [22]. 8. Insulin and insulin-like growth factor (IGF) II catalyze nerve growth factor binding and the neurite formation response in cultured human neuroblastoma cells [23]. This insulin effect could be like a developmental neurotrophic factor. Insulin however is not as potent as nerve growth factor itself. (Interestingly, this effect appears to be additive with NGF supplementation [22, 24]. 9. In adult DRG neurons, insulin increased the rate of neurite regeneration in rat DRG cultures 3.5-fold compared to control cultures without insulin supplementation [25]. 10. An increase in neurite outgrowth possibly is through stabilization of tubulin microtubule mRNA, an essential component for neurite formation [25]. 11. There is an increase noted in neuronal survival with insulin supplementation in cultured adult sympathetic neurons, sensory neurons [22, 26] 12. Insulin is one of the few essential molecules required for cultured primary peripheral neurons [27] 13. Stimulation of peripheral nervous system (PNS) with insulin strongly activates a pathway directly related to axonal growth and neuronal survival, which in turn shuts down apoptosis [28, 29] 14. Insulin may play an important role in Schwann cell physiology and its dysfunction found in diabetic neuropathy [30]. Schwann cells express the insulin receptor at different locations [31] 15. Insulin receptor expression in Schwann cells during development parallels myelin glycoprotein P zero (P0) expression and growth of the myelin sheath [13]. 16. Schwann cells proliferation with insulin is also reported [13] 17. Insulin and the insulin-like growth factors I and II are mitogenic to cultured rat sciatic nerve segments and its differentiation [32] and myelination [33]. 18. Insulin modifies myelin protein expression in diabetic neuropathy [34]. 19. Recovery from the changes in nerve injury models is accelerated by insulin supplementation, increasing the rate of motor endplate reinnervation [35]. 20. Intrathecal and near nerve insulin injections have a much more dramatic effect on injured nerve cells preventing the retrograde degeneration of axons proximal to the nerve injury and accelerating regeneration of axons distal to the crush site [36]. 21. The complex insulin signaling cascade, finally results in increased transcription, translation, and translocation of the proteins necessary to carry out insulin’s actions in humans [37]. 22. Neurons have expressive insulin receptors [38]; the neurons also express the glut 1 and glut 3 glucose transporters and take up glucose, across a concentration gradient receptor [39].

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23. Olfactory bulb, hippocampus, and hypothalamus express glut 4 transporters in humans [40]. 24. Insulin crosses the blood-brain barrier (BBB) through endothelial cells of the blood brain barrier, a saturable receptor transport leading to transcytosis of insulin [41]. 25. This is currently one of the most targeted systems in drug development to transport chemicals across the BBB [42]. 26. Diabetes appears to be a strong risk factor for Alzheimer’s and Parkinson’s disease [43–48]. 27. These findings have aroused interest in insulin vis-à-vis the nervous system, with marked similarities in brains of these diseases and diabetes like increased beta amyloid and tau phosphorylation [49]. 28. Brains of Alzheimer’s patients show signs of insulin resistance [50] 29. Insulin sensitizing drugs, thiazolidinediones, have been shown to improve memory [51]. 30. Recently, in phase 1 clinical trials, Alzheimer’s patients receiving intranasal insulin showed improved memory and daily activities [52].

13.2.3 Insulin and Diabetic Neuropathy 1. Hyperglycemia and insulinopenia resulting in various pathogenetic changes in diabetic neuropathy and treatments have been discussed at length in this volume. Now, after so much evidence insulin supplementation and its likely healing effects on DPN with not just glycemic control but molecular and cellular level effects is where the focus is shifting [53, 54]. 2. Diabetes Control and Complications Trial (DCCT) provided strong evidence in intensive insulin therapy with a whopping 64% percent reduction in ­neuropathy over a 5-year period as compared to patients on conventional therapy [55]. 3. Steady deterioration nerve conduction velocity of patients on conventional therapy but not with intensive treatment group indicates a more balanced, steady, and physiological insulin exposure and restoration of the lost neuronal insulin signaling maintaining proper sensory function [56]. 4. Low insulin without hyperglycemia causes abnormalities in sensory function. Low-dose insulin treatment of animals with diabetic neuropathy can reverse many abnormal morphologic and behavioral changes without significantly altering glucose levels. Treatment of rats with STZ does not always result in diabetes but in a low insulin euglycemic state. These euglycemic-STZ rats displayed mechanical hyperalgesia due to a reduced threshold but no other sensory elements [57]. 5. The lowered threshold and low insulin levels correlated with each other and could be ameliorated with low-dose insulin treatment [58]. 6. This is indicative of loss of neuronal insulin support. Topical application of insulin to the cornea prevented the nerve depletion in the cornea [59]

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7. Low-dose insulin through subcutaneous insulin pellet can nearly normalize diabetes-induced tactile allodynia and mechanical hyperalgesia, despite persistent high level of hyperglycemia. The blood glucose in this experiment dropped from 600 mg/dl to 400 mg/dl 2 weeks after insulin pellet insertion [60] 8. Mitochondrial dysfunction is proposed as a central mediator of neurodegeneration in the central and peripheral nervous systems [61]. 9. In diabetic peripheral nerves mitochondria get swollen, its internal cristae disrupt in Schwann cells but rarely so in axons [62]. 10. Mitochondrial contribution to DPN under chronic hyperglycemia is discussed in the pathogenesis of DPN in this volume. Insulin and mitochondria are intimately connected through numerous metabolic pathways. Proper insulin signaling is absolutely necessary for Schwann cells, neurons, or dorsal root ganglia mitochondria to properly function. 11. Intranasal insulin (and subcutaneous insulin to a lesser extent) benefits motoneuron morphology and function and protects against electrophysiological decline, loss of neuromuscular junctions, and loss of motor function. These findings are indicative of neurotrophic effects of insulin [63]. 12. An unexpected experimental result demonstrated that the peripheral nervous system cells also can develop insulin resistance. This in clinical terms will decrease the neurotrophic effects like reducing the neurite outgrowth, described so far, and changes in mitochondrial-associated proteins [64, 65]. 13. Neurite outgrowth stimulated by insulin also appears to be sensitive to higher doses of insulin. This also could be indicative of insulin resistance [19]. It should also be added that insulin is the single purely anabolic hormone and has myriad effects over all body cells in its preservation in normal state, normal function, and growth, all of which affect the cells equally in the opposite direction in insulinopenia. A detailed discussion is out of scope for this volume. The reader is referred to the author’s volume on “Towards Optimal Management of Diabetes in Surgery” published by Springer in August 2019. The chapters on Physiology of Insulin and Commonly Asked Questions in particular will give a lot of insight about insulin which commonly available literature may not. The entire volume if read will certainly transform and improve diabetes management as a whole in every related situation. In addition, the volume published by Diabetic Foot Society of India in November 2017, “National Guidelines for Management of Diabetic Foot,” will also be a useful adjunct to the reader making a complete reference library for diabetes.

13.2.4 Diabetic Neuropathy and Insulin in Clinical Practice So far the evidence for insulin as a protector of nerves and neural cells has been presented. In an earlier chapter it was said that there are many situations in which the development of neuropathy can be either halted or even reversed. The discussion following will give some evidence about when it will be possible and what way could that happen.

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13.3 Chronic Intermittent Intravenous Insulin Therapy (CIIIT) This particular method of treatment has been shown to reverse sympathetic autonomic neuropathy and shows consistent improvement in patients with postural dizziness. It also accomplishes many other changes beneficial to the diabetic person. The procedure works on the principle of mimicking the small pulsatile insulin release in normal individuals @ 8–16 min which smoothens the glucose levels in the postabsorptive phase and works round the clock effectively. The improved performance is attributed to more efficient handling of hepatic glucose output, especially during the postabsorptive or fasting periods. Diabetic liver can put out as much as 10 g of glucose compared to 1 g in similar conditions by a nondiabetic individual in unit time. That is claimed to be the reason for many effects it produces listed below. CIIIT increases the portal vein insulin concentration or reduces sustained hyperglucagonemia.

13.3.1 Improvement in Autonomic Neuropathy Function CIIIT resulted in complete disappearance of syncopal episodes, within 3 months of CIIIT. The results suggest that it could be due to an improvement in the vasoconstrictor mechanisms in response to postural changes. This can result by way of improvement in diabetic autonomic neuropathy, which in turn will serve the function of adequate vasoconstriction on standing up. The normalization of the circadian blood pressure pattern and the improved cardiovascular reflex score have also been demonstrated with CIIIT. The nocturnal tone of blood pressure is not suppressible in diabetes. CIIIT seems to achieve this. The improvement in the autonomic neuropathy was likely secondary to the improved metabolic milieu during CIIIT as reflected by significantly decreased HbA1c levels also.

13.3.2 Other Benefits of CIIIT CIIIT is also shown to bring brittle diabetes including the frequent severe and milder hypoglycemic episodes reduced in a highly significant manner, nearly normalizing the HbA1c in weekly treatments. For this to be achieved the treatment could be long. The reported trial went on for over 41 months. That really is a limitation but it may be tried for lesser periods for which some indication in the trial could be found to see if such a result could be accomplished. The long trial also reported no hypoglycemic events contrary to all experience. For any treatment modality which reduces HbA1c, there is a rise in hypoglycemic episodes. The efforts to find an agent which does it least number of times and least severity have thrown up a few but rather costly alternatives. The experimental and treatment base of CIIIT is small but has produced astounding results. It appears that clinicians could use this simple tool as an experimental therapy if all treatments have failed in their patients or as a therapeutic trial for more

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experience [65] The weekly procedure on the background state of intensive subcutaneous insulin therapy has shown further significantly improved glycemic control, decreased incidence of hypoglycemic events (virtually none), improved hypertension control by improving the circadian rhythm of nocturnal rise in blood pressure and reversed severe intractable postural hypotension, and hypoglycemia unawareness; all of these are indicators of improved of diabetic autonomic neuropathy [66].

13.3.3 Method Used in CIIIT Chronic intermittent intravenous insulin therapy (CIIIT) delivers insulin in a pulsatile fashion @ 35  mU/kg body weight, q6  min in forearm vein, achieving peak venous free insulin of at least 200 mU/ml. Initial CIIIT consists of two consecutive treatment days, followed by weekly treatment days.

13.4 O  ther Situations of Improvement in Diabetic Polyneuropathy 13.4.1 Pancreatic Transplant with or without Kidney Transplant The CIIIT claims to improve the small peaks of insulin release from the pancreas increasing the endogenous portal insulin levels. As may be recalled, these peaks are the first to go when diabetic milieu is around. Even a fifth of the first-degree relatives of the index case have been known to lose these peaks even when there is no diabetes in them. Pancreatic as well as pancreatic and kidney transplant together will produce a normal milieu by restoring the capacity of secreting the normal quanta of insulin at appropriate times. It stops the further deterioration of all types of diabetic neuropathies and reverses the same to a substantial degree over a long follow-up of 115 transplants for 10 years. Even with insulin-treated patient the progression in these 10 years could not be slowed. The principle difference and probably the cause of success of one over the failure of others is the success of pancreatic transplant and is due to its secretion in the portal vein. Exogenous insulin does not achieve this. It must also be noted that the pancreatic–kidney transplants do not come with their additional neural equipment, yet achieve this feat. Such small but significant details help add to patient communication and give greater assurance [67].

13.4.2 Reduction of Polyneuropathy in Critically Ill Patients Intensive insulin therapy in critically ill patients reduced critical-illness polyneuropathy by 44 percent which the conventional insulin treatment, the other arm of the study, did not show. In fact it showed an odds ratio, 2.6 (from 1.6 to 4.2), in a multivariate analysis, as an independent predictor of critical illness polyneuropathy.

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This landmark paper should be read by all involved in diabetes management. Greet published several papers in years to come and a look at all of these will deepen our understanding greatly in this area. A comparative analysis of these papers will be found in “Towards Optimal Management of Diabetes in Surgery” mentioned above in the chapter on Commonly Asked Questions [68].

13.4.3 C-Peptide in Neuropathy The principle difference between type 1 and 2 diabetes is the total absence of C-peptide which connects the A and B chain of insulin molecule. C-peptide has been injected for variable periods in type 1 patients with remarkable improvements. It is fully discussed in the chapter on Treatment of Cardiovascular Autonomic Neuropathy next.

13.5 A  n Uncommon Cause of Painful Neuropathy—Insulin Neuritis Admittedly this is an uncommon cause but an adequate understanding of this is necessary in practice since it is in a way an iatrogenic complication induced by enthusiastic too rapid and tight control particularly with insulin. That appears to be the common background and the overriding cause in what little is reported in literature. In clinical practice the neuritic pain of oral medication is mild and self-­ limiting. Hence insulin neuritis as a name can be considered valid for almost all instances.

13.5.1 Symptom Profile and Temporal Progression 1. Symptoms begin in 2 weeks to 3 months after starting insulin. A severe excruciating generalized bilateral pain mainly distally in feet with burning sensation, hypersensitivity, and contact discomfort of the skin (allodynia) are the most common features [69]. 2. Acute painful neuropathy induced by rapid correction of serum glucose levels in diabetes patients [70, 71]. 3. Symptoms usually last up to 6  months and respond to the usual treatment of painful neuropathy that is usually needed up to 6 months [72]. 4. Diabetic neuropathic cachexia with insulin neuritis may occur, the cause of which is unknown. It generally recovers with weight gain in a year or 18 months. 5. It may cause truncal unilateral dermatome specific neuropathy with hypoesthesia, regional hyperalgesia, allodynia, and sometime focal weakness [73]. 6. Insulin neuritis may precipitate autonomic neuropathy, for example, gastroparesis, neurogenic bladder, dry feet, depressed cough reflex, postural hypotension, or high blood flow to foot [74].

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13.5.2 Mechanism of Genesis 1. Such rapid and tight blood glucose control in otherwise poorly controlled patients disturbs the osmotic equilibrium across the membrane between the neural (or retinal also) glucose content and the low levels of glucose in plasma. 2. It causes flux of blood glucose and metabolic shift, resulting in structural changes at nerve endings of endoneural blood vessels. It causes steal effect and hypoxia and generation of impulses in the nerves, indicating that it is the combination of structural and functional defects. Treatment management of neuropathic pain in insulin neuritis is symptomatic including first-line medication tricyclic antidepressants (Amitriptyline) or selective serotonin uptake inhibitor (Duloxetine). Second-line medications include antiepileptic medications (Gabapentin, Pregabalin, Carbamazepine, and Topiramate) and opioids. In conclusion, it can safely be claimed that adequate insulin use in diabetes has much more to do with the integrity of the nervous system than just preventing hyperglycemia-induced damages by lowering glucose to normal. As is well known, the fullest functionality of insulin is achievable with supraphysiological quantities with adequate substrate supply. For a detailed review of physiology of insulin the reader is referred to a volume “Towards Optimal Management of Diabetes in Surgery” by the same author published by Springer August 2019.

References 1. Grote CW, Wright DE. A role for insulin in diabetic neuropathy. Front Neurosci. 2016; https:// doi.org/10.3389/fnins.2016.00581. 2. Grillo CA, Piroli GG, Lawrence RC, Wrighten SA, Green AJ, Wilson SP, et al. Hippocampal insulin resistance impairs spatial learning and synaptic plasticity. Diabetes. 2015;64:3927–36. https://doi.org/10.2337/db15-0596. 3. Obici S, Feng Z, Karkanias G, Baskin DG, Rossetti L. Decreasing hypothalamic insulin receptors causes hyperphagia and insulin resistance in rats. Nat Neurosci. 2002a;5:566–72. https:// doi.org/10.1038/nn0602-861. 4. Sugimoto K, Murakawa Y, Sima AA.  Expression and localization of insulin receptor in rat dorsal root ganglion and spinal cord. J Peripher Nerv Syst. 2002;7:44–53. https://doi. org/10.1046/j.1529-8027.2002.02005.x. 5. Chiu SL, Cline HT. Insulin receptor signaling in the development of neuronal structure and function. Neural Dev. 2010;5:7. https://doi.org/10.1186/1749-8104-5-7. 6. Murakawa Y, Zhang W, Pierson CR, Brismar T, Ostenson CG, Efendic S, et al. Impaired glucose tolerance and insulinopenia in the GK-rat causes peripheral neuropathy. Diabetes Metab Res Rev. 2002;18:473–83. https://doi.org/10.1002/dmrr.326. 7. Brussee V, Cunningham FA, Zochodne DW. Direct insulin signaling of neurons reverses diabetic neuropathy. Diabetes. 2004;53:1824–30. https://doi.org/10.2337/diabetes.53.7.1824. 8. Toth C, Brussee V, Zochodne DW.  Remote neurotrophic support of epidermal nerve fibres in experimental diabetes. Diabetologia. 2006b;49:1081–8. https://doi.org/10.1007/ s00125-006-0169-8. 9. Guo G, Kan M, Martinez JA, Zochodne DW. Local insulin and the rapid regrowth of diabetic epidermal axons. Neurobiol Dis. 2011;43:414–21. https://doi.org/10.1016/j.nbd.2011.04.012.

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10. Francis GJ, Martinez JA, Liu WQ, Zochodne DW, Hanson LR, Frey WH II, et  al. Motor end plate innervation loss in diabetes and the role of insulin. J Neuropathol Exp Neurol. 2011;70:323–39. https://doi.org/10.1097/NEN.0b013e318215669a. 11. Sugimoto K, Murakawa Y, Zhang W, Xu G, Sima AA. Insulin receptor in rat peripheral nerve: its localization and alternatively spliced isoforms. Diabetes Metab Res Rev. 2000;16:354–63. https://doi.org/10.1002/1520-7560(200009/10)16:53.0.CO;2-H. 12. Sugimoto K, Murakawa Y, Sima AA.  Expression and localization of insulin receptor in rat dorsal root ganglion and spinal cord. J Peripher Nerv Syst. 2002;7:44–53. https://doi. org/10.1046/j.1529-8027.2002.02005.x. 13. Shettar A, Muttagi G. Developmental regulation of insulin receptor gene in sciatic nerves and role of insulin on glycoprotein P0 in the Schwann cells. Peptides. 2012;36:46–53. https://doi. org/10.1016/j.peptides.2012.04.012. 14. Baiou D, Santha P, Avelino A, Charrua A, Bacskai T, Matesz K, et al. Neurochemical characterization of insulin receptor-expressing primary sensory neurons in wild-type and vanilloid type 1 transient receptor potential receptor knockout mice. J Comp Neurol. 2007;503:334–47. https://doi.org/10.1002/cne.21389. 15. Sathianathan V, Avelino A, Charrua A, Santha P, Matesz K, Cruz F, et  al. Insulin induces cobalt uptake in a subpopulation of rat cultured primary sensory neurons. Eur J Neurosci. 2003;18:2477–86. https://doi.org/10.1046/j.1460-9568.2003.03004.x. 16. Van Buren JJ, Bhat S, Rotello R, Pauza ME, Premkumar LS. Sensitization and translocation of TRPV1 by insulin and IGF-I. Mol Pain. 2005;1:17. https://doi.org/10.1186/1744-8069-1-17. 17. Lilja J, Laulund F, Forsby A.  Insulin and insulin-like growth factor type-I up-regulate the vanilloid receptor-1 (TRPV1) in stably TRPV1-expressing SH-SY5Y neuroblastoma cells. J Neurosci Res. 2007;85:1413–9. https://doi.org/10.1002/jnr.21255. 18. Pabbidi RM, Yu SQ, Peng S, Khardori R, Pauza ME, Premkumar LS. Influence of TRPV1 on diabetes-induced alterations in thermal pain sensitivity. Mol Pain. 2008;4:9. https://doi. org/10.1186/1744-8069-4-9. 19. Singh B, Xu Y, McLaughlin T, Singh V, Martinez JA, Krishnan A, et al. Resistance to trophic neurite outgrowth of sensory neurons exposed to insulin. J Neurochem. 2012;121:263–76. https://doi.org/10.1111/j.1471-4159.2012.07681.x. 20. Snyder EY, Kim SU. Insulin: is it a nerve survival factor. Brain Res. 1980;196:565–71. https:// doi.org/10.1016/0006-8993(80)90426-6. 21. Bothwell M. Insulin and somatomedin MSA promote nerve growth factor independent neurite formation by cultured chick dorsal root ganglionic sensory neurons. J Neurosci Res. 1982;8:225–31. https://doi.org/10.1002/jnr.490080212. 22. Recio-Pinto E, Lang FF, Ishii DN. Insulin and insulin-like growth factor II permit nerve growth factor binding and the neurite formation response in cultured human neuroblastoma cells. Proc Natl Acad Sci U S A. 1984;81:2562–6. https://doi.org/10.1073/pnas.81.8.2562. 23. Recio-Pinto E, Rechler MM, Ishii DN. Effects of insulin, insulin like growth factor-II, and nerve growth factor on neurite formation and survival in cultured sympathetic and sensory neurons. J Neurosci. 1986;6:1211–9. 24. Jones DM, Tucker BA, Rahimtula M, Mearow KM. The synergistic effects of NGF and IGF-1 on neurite growth in adult sensory neurons: convergence on the PI 3-kinase signaling pathway. J Neurochem. 2003;86:1116–28. https://doi.org/10.1046/j.1471-4159.2003.01925.x. 25. Fernyhough P, Mill JF, Roberts JL, Ishii DN. Stabilization of tubulin mRNAs by insulin and insulin-like growth factor I during neurite formation. Brain Res Mol Brain Res. 1989;6:109– 20. https://doi.org/10.1016/0169-328X(89)90044-2. 26. Li ZG, Zhang W, Sima AA.  C-peptide enhances insulin-mediated cell growth and protection against high glucose-induced apoptosis in SH-SY5Y cells. Diabetes Metab Res Rev. 2003;19:375–85. https://doi.org/10.1002/dmrr.389. 27. Skaper SD, Selak I, Varon S.  Molecular requirements for survival of cultured avian and rodent dorsal root ganglionic neurons responding to different trophic factors. J Neurosci Res. 1982;8:251–61. https://doi.org/10.1002/jnr.490080215.

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28. Huang TJ, Verkhratsky A, Fernyhough P.  Insulin enhances mitochondrial inner membrane potential and increases ATP levels through phosphoinositide 3-kinase in adult sensory neurons. Mol Cell Neurosci. 2005;28:42–54. https://doi.org/10.1016/j.mcn.2004.08.009. 29. Datta SR, Dudek H, Tao X, Masters S, Fu H, Gotoh Y, et al. Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell. 1997;91:231–41. https:// doi.org/10.1016/s0092-8674(00)80405-5. 30. Eckersley L. Role of the Schwann cell in diabetic neuropathy. Int Rev Neurobiol. 2002;50:293– 321. https://doi.org/10.1016/S0074-7742(02)50081-7. 31. Shetter AR, Muttagi G, Sagar CB.  Expression and localization of insulin receptors in dissociated primary cultures of rat Schwann cells. Cell Biol Int. 2011;35:299–304. https://doi. org/10.1042/CBI20100523. 32. Ogata T, Iijima S, Hoshikawa S, Miura T, Yamamoto S, Oda H, et al. Opposing extracellular signal-regulated kinase and Akt pathways control Schwann cell myelination. J Neurosci. 2004;24:6724–32. https://doi.org/10.1523/jneurosci.5520-03.2004. 33. Liang G, Cline GW, Macica CM. IGF-1 stimulates de novo fatty acid biosynthesis by Schwann cells during myelination. Glia. 2007;55:632–41. https://doi.org/10.1002/glia.20496. 34. Rachana KS, Manu MS, Advirao GM.  Insulin influenced expression of myelin proteins in diabetic peripheral neuropathy. Neurosci Lett. 2016;629:110–5. https://doi.org/10.1016/j. neulet.2016.06.067. 35. Xu QG, Li XQ, Kotecha SA, Cheng C, Sun HS, Zochodne DW. Insulin as an in vivo growth factor. Exp Neurol. 2004;188:43–51. https://doi.org/10.1016/j.expneurol.2004.03.008. 36. Toth C, Brussee V, Martinez JA, McDonald D, Cunningham FA, Zochodne DW.  Rescue and regeneration of injured peripheral nerve axons by intrathecal insulin. Neuroscience. 2006a;139:429–49. https://doi.org/10.1016/j.neuroscience.2005.11.065. 37. White MF. IRS proteins and the common path to diabetes. Am J Physiol Endocrinol Metab. 2002;283:E413–22. https://doi.org/10.1152/ajpendo.00514.2001. 38. Plum L, Schubert M, Brüning JC. The role of insulin receptor signaling in the brain. Trends Endocrinol Metab. 2005;16:59–65. https://doi.org/10.1016/j.tem.2005.01.008. 39. Choeiri C, Staines W, Messier C. Immunohistochemical localization and quantification of glucose transporters in the mouse brain. Neuroscience. 2002;111:19–34. https://doi.org/10.1016/ S0306-4522(01)00619-4. 40. Leloup C, Arluison M, Kassis N, Lepetit N, Cartier N, Ferré P, et al. Discrete brain areas express the insulin-responsive glucose transporter GLUT4. Brain Res Mol Brain Res. 1996;38:45–53. https://doi.org/10.1016/0169-328X(95)00306-D. 41. Baura GD, Foster DM, Porte D Jr, Kahn SE, Bergman RN, Cobelli C, et al. Saturable transport of insulin from plasma into the central nervous system of dogs in vivo. A mechanism for regulated insulin delivery to the brain. J Clin Invest. 1993;92:1824–30. https://doi.org/10.1172/ JCI116773. 42. Wang YY, Lui PC, Li JY. Receptor-mediated therapeutic transport across the blood-brain barrier. Immunotherapy. 2009;1:983–93. https://doi.org/10.2217/imt.09.75. 43. Luchsinger JA, Tang MX, Stern Y, Shea S, Mayeux R. Diabetes mellitus and risk of Alzheimer’s disease and dementia with stroke in a multiethnic cohort. Am J Epidemiol. 2001;154:635–41. https://doi.org/10.1093/aje/154.7.635. 44. Hu G, Jousilahti P, Bidel S, Antikainen R, Tuomilehto J.  Type 2 diabetes and the risk of Parkinson's disease. Diabetes Care. 2007;30:842–7. https://doi.org/10.2337/dc06-2011. 45. Jolivalt CG, Lee CA, Beiswenger KK, Smith JL, Orlov M, Torrance MA, et  al. Defective insulin signaling pathway and increased glycogen synthase kinase-3 activity in the brain of diabetic mice: parallels with Alzheimer’s disease and correction by insulin. J Neurosci Res. 2008;86:3265–74. https://doi.org/10.1002/jnr.21787. 46. Jolivalt CG, Hurford R, Lee CA, Dumaop W, Rockenstein E, Masliah E. Type 1 diabetes exaggerates features of Alzheimer’s disease in APP transgenic mice. Exp Neurol. 2010;223:422– 31. https://doi.org/10.1016/j.expneurol.2009.11.005. 47. Jolivalt CG, Calcutt NA, Masliah E. Similar pattern of peripheral neuropathy in mouse models of type 1 diabetes and Alzheimer’s disease. Neuroscience. 2012;202:405–12. https://doi. org/10.1016/j.neuroscience.2011.11.032.

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48. Fadel JR, Jolivalt CG, Reagan LP. Food for thought: the role of appetitive peptides in age-­ related cognitive decline. Ageing Res Rev. 2013;12:764–76. https://doi.org/10.1016/j. arr.2013.01.009. 49. Akter K, Lanza EA, Martin SA, Myronyuk N, Rua M, Raffa RB.  Diabetes mellitus and Alzheimer's disease: shared pathology and treatment? Br J Clin Pharmacol. 2011;71:365–76. https://doi.org/10.1111/j.1365-2125.2010.03830.x. 50. Talbot K, Wang HY, Kazi H, Han LY, Bakshi KP, Stucky A, et al. Demonstrated brain insulin resistance in Alzheimer's disease patients is associated with IGF-1 resistance, IRS-1 dysregulation, and cognitive decline. J Clin Invest. 2012;122:1316–38. https://doi.org/10.1172/ JCI59903. 51. Sato T, Hanyu H, Hirao K, Kanetaka H, Sakurai H, Iwamoto T.  Efficacy of PPAR-gamma agonist pioglitazone in mild Alzheimer disease. Neurobiol Aging. 2011;32:1626–33. https:// doi.org/10.1016/j.neurobiolaging.2009.10.009. 52. Craft S, Baker LD, Montine TJ, Minoshima S, Watson GS, Claxton A, et al. Intranasal insulin therapy for Alzheimer disease and amnestic mild cognitive impairment: a pilot clinical trial. Arch Neurol. 2012;69:29–38. https://doi.org/10.1001/archneurol.2011.233. 53. Zochodne DW.  Mechanisms of diabetic neuron damage: molecular pathways. Handb Clin Neurol. 2014;126:379–99. https://doi.org/10.1016/B978-0-444-53480-4.00028-X. 54. Zochodne DW. Diabetes and the plasticity of sensory neurons. Neurosci Lett. 2015;596:60–5. https://doi.org/10.1016/j.neulet.2014.11.017. 55. Diabetes Control Complications Trial Research Group. The effect of intensive diabetes therapy on the development, and progression of neuropathy. Ann Intern Med. 1995a;122:561–8. https://doi.org/10.7326/0003-4819-122-8-199504150-00001. 56. Diabetes Control Complications Trial Research Group. Effect of intensive diabetes treatment on nerve conduction in the diabetes control and complications trial. Ann Neurol. 1995b;38:869–80. https://doi.org/10.1002/ana.410380607. 57. Romanovsky D, Wang J, Al-Chaer ED, Stimers JR, Dobretsov M. Comparison of metabolic and neuropathy profiles of rats with streptozotocin-induced overt and moderate insulinopenia. Neuroscience. 2010;170:337–47. https://doi.org/10.1016/j.neuroscience.2010.06.059. 58. Romanovsky D, Cruz NF, Dienel GA, Dobretsov M. Mechanical hyperalgesia correlates with insulin deficiency in normoglycemic streptozotocin-treated rats. Neurobiol Dis. 2006;24:384– 94. https://doi.org/10.1016/j.nbd.2006.07.009. 59. Chen DK, Frizzi KE, Guernsey LS, Ladt K, Mizisin AP, Calcutt NA. Repeated monitoring of corneal nerves by confocal microscopy as an index of peripheral neuropathy in type-1 diabetic rodents and the effects of topical insulin. J Peripher Nerv Syst. 2013;18:306–15. https://doi. org/10.1111/jns5.12044. 60. Hoybergs YM, Meert TF. The effect of low-dose insulin on mechanical sensitivity and allodynia in type I diabetes neuropathy. Neurosci Lett. 2007;417:149–54. https://doi.org/10.1016/j. neulet.2007.02.087. 61. Nicholls DG, Budd SL. Mitochondria and neuronal survival. Physiol Rev. 2000;80:315–60. 62. Kalichman MW, Powell HC, Mizisin AP. Reactive, degenerative, and proliferative Schwann cell responses in experimental galactose and human diabetic neuropathy. Acta Neuropathol. 1998;95:47–56. 63. Chowdhury SK, Zherebitskaya E, Smith DR, Akude E, Chattopadhyay S, Jolivalt CG, et al. Mitochondrial respiratory chain dysfunction in dorsal root ganglia of streptozotocin-induced diabetic rats and its correction by insulin treatment. Diabetes. 2010;59:1082–91. https://doi. org/10.2337/db09-1299. 64. Grote CW, Morris JK, Ryals JM, Geiger PC, Wright DE. Insulin receptor substrate 2 expression and involvement in neuronal insulin resistance in diabetic neuropathy. Exp Diabetes Res. 2011;2011:212571. https://doi.org/10.1155/2011/212571. 65. Kim B, McLean LL, Philip SS, Feldman EL.  Hyperinsulinemia induces insulin resistance in dorsal root ganglion neurons. Endocrinology. 2011;152:3638–47. https://doi.org/10.1210/ en.2011-0029.

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66. Aoki TT, Grecu EO, Arcangeli MA, Benbarka MM, Prescott P, Ahn JH.  Chronic intermittent intravenous insulin therapy: a new frontier in diabetes therapy. Diabetes Technol Ther. 2001;3(1). Mary Ann Liebert, Inc. 67. Navarro X, DER S, Kennedy WR. Long-term effects of pancreatic transplantation on diabetic neuropathy. Ann Neurol. 1997;42(5):727. 68. Van den Berghe G, Wouters P, Weekers F, Verwaest C, Bruyninckx F, Schetz M, Vlasselaers D, Ferdinande P, Lauwers P, Bouillon R. Intensive Insulin Therapy in Critically Ill Patients. N Engl J Med. 2001;345:1359–67. https://doi.org/10.1056/NEJMoa011300. 69. Dabbya R, Sadeha M, Lampla Y, Gilad R, Watemberg N. Acute painful neuropathy induced by rapid correction of serum glucose levels in diabetes patients. Biomed Pharmacother. 2009;63(10):707–9. 70. Archer A, Watkins PJ, Thomas PK. The natural history of acute painful neuropathy in diabetes mellitus. J Neurol Neurosurg Psychiatr. 1983;46(6):491–9. 71. Leow MKS, Wyckoff J. Under-recognised paradox of neuropathy from rapid glycemic control. Postgrad Med J. 2005;81(952):103–7. 72. Larsen PR, Kronenberg HM, et al. Williams Textbook of Endocrinology. 10th ed. Philadelphia; 2002. 73. Ibitoye R, Rajbhandari SM.  Neuropathic truncal pain  – a case series. Q J Med. 2012;105(10):1027–31. 74. Watkins. ABC of diabetes. 5th ed. London: BMJ Publishing Group; 2003. p. 32–7.

Further Reading He is also referred to the chapter on Physiology of Insulin in the author’s volume on – ‘Towards Optimal Management of Diabetes in Surgery,’ also published by SpringerNature. National Guidelines for Management of Diabetic Foot Diabetic Foot Society of India in November 2017. The reader is referred to this paper [66.Oki Thomas et al., see ref. below for an excellent expose of the physiology of insulin in normal and its changes after the development of diabetes. Towards ‘Optimal Management of Diabetes in Surgery’ published by Springer in August 2019. Van den Berghe G, Wouters P, Weekers F, Verwaest C, Bruyninckx F, Schetz M, Vlasselaers D, Ferdinande P, Lauwers P, Bouillon R.  Intensive Insulin Therapy in Critically Ill Patients. N Engl J Med. 2001;345:1359–67. https://doi.org/10.1056/NEJMoa011300.

Treatment of Cardiac Autonomic Neuropathy

14

14.1 Introduction The treatment of cardiac autonomic neuropathy can be divided in controlling the abnormalities at the molecular cellular level, or mitigating the extent of clinical aberrations induced by cardiac autonomic neuropathy by drugs and other measures. Controlling the pathophysiological/molecular abnormalities is necessary since these can, over a period of time, worsen and then accentuate the end organ damage leading to more complications, additional and expensive treatments, with disastrous economic effects or deterioration of quality of life, by no means less important. Prolonged high level glycemia is obviously at the root of all pathogenesis and treatment. Management of hyperglycemia per se will not be discussed. The discussion below assumes that best of glycemic control is established and other treatment options that are available. The utility and limitations of these options are also discussed. It is important to keep the information about the pathogenesis of diabetic autonomic and sensorimotor neuropathies in chap. 3 fresh in background. It will be helpful to understand the basis of the different treatments offered for cardiac autonomic neuropathy with a logical understanding of this serious abnormality. Lastly it must be noted that there is no causal cure of cardiac autonomic neuropathy, and in most situations, once developed it can be slowed down in progressing to a limited extent but cannot be reversed. As has been shown in the treatment of painful peripheral diabetic neuropathy, there is considerable understanding about the molecular changes at the cellular levels that lead to all kinds of neuropathies but attempting to interrupt these pathological changes by external agents like drugs, while completely logical, does not seem to work. Hence aside of good glycemic control most of the management is by drugs, some of which control the symptoms and some the other clinical consequences, say like resting tachycardia but nothing more than that. Some of the drug treatments listed below will be found in the chapter on treatment of painful peripheral diabetic neuropathy in greater detail. © Springer Nature Singapore Pte Ltd. 2020 S. Kelkar, Diabetic Neuropathy and Clinical Practice, https://doi.org/10.1007/978-981-15-2417-2_14

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14.2 Pharmacologic Treatment 14.2.1 Antioxidants Prolonged hyperglycemia leads to excessive production of reactive oxygen species, ROS. In diabetes the normal intrinsic mechanisms that quench the ROS, even after good glycemic control are likely to remain inadequate. That is why antioxidants have always been an attractive as well as a rationally based treatment option for the practitioners. The evidences in its effectivity however are not adequately compelling. That should be the deterrent to irrational practice of its wholesale prescriptions particularly for peripheral neuropathies. Some of the studies as shown earlier are small in size and duration. The drug therapy described below has used only hard evidence to enable the physicians to decide which therapies they would like to use. DEKAN is a small short duration study using α-lipoic acid in which the small benefits for cardiac autonomic neuropathies became apparent only after 4 months [1]. Prolonged use of vitamin E in pharmacologic doses has shown a beneficial effect on cardiac autonomic neuropathy [2]. Three antioxidants, allopurinol, α-lipoic acid, and nicotinamide, were used for 2 years in another trial. The expected result was improvement of perfusion or non-­ progression of the perfusion status of myocardial tissue at the beginning. Neither was achieved [3]. The α-lipoic acid and vitamin E used might have a favorable effect in cardiac autonomic neuropathy [4].

14.2.1.1 Vitamin E in Cardiac Autonomic Neuropathy Cardiovascular autonomic neuropathy in vit E administered patients was studied in 50 patients. 600 mg of vitamin E or placebo was given for 4 months. The parameters of pathophysiological significance measured were—glycated hemoglobin, plasma insulin, norepinephrine and epinephrine and a homeostatic assessment index, and improved indexes of oxidative stress. The vit E administered group results showed significantly greater normalization in all these parameters. Vitamin E treated group also showed increase in the R-R interval, the high-­ frequency component of heart rate variability and decreases in the low-frequency component, and the ratio of low to high frequency. It was found to be independent of homeostasis model assessment index and plasma catecholamines concentration changes [2]. Prolonged use of vitamin E in pharmacologic doses has shown a beneficial effect on cardiac autonomic neuropathy [2].

14.2.2 Aldose Reductase Inhibitors Polyol–sorbitol pathway abnormalities are one of the main and frequent mechanisms causing nerve damage. A drug that can bring the mechanism towards optimal should logically cause fair to good improvement. Aldose reductase inhibitors have been shown to improve autonomic functions only in early stages. The effects were seen in three or more of the standardized

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cardiac autonomic reflex tests (CART.) However it did not have any effect in patients with advanced stages of cardiac autonomic neuropathy [5]. Aldose reductase inhibitors in a much earlier study were found to merely stabilize the abnormalities of left ventricle associated with cardiac autonomic neuropathy [6]. On the whole, this class of drug has not been of much use.

14.2.3 The ACE Inhibitors The first ACE inhibitor enalapril was convincingly shown to reduce left ventricular hypertrophy as it controlled hypertension. Amlodipine failed to do that in a large trial which therefore was never published [7]. Quinapril has been shown to improve the imbalance between the parasympathetic and sympathetic activity as well as the circadian sympathetic and parasympathetic modulation [8, 9]. Reduced/impaired heart rate variations, integral to the heart response to increased demand on work, is a primary effect of cardiac autonomic neuropathy. ACE inhibitors combined with α-lipoic acid were tried to improve the same. These were considered useful [10]. It was a long duration four-year trial which increases the value of evidence, yet the treatment duration may not be sustainable. There was a question of whether combining angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers will have additive effects which are now answered and are practiced when one or the other needs supplementation for better blood pressure control [11]. ACE inhibitors beginning with low doses and increasing gradually have been shown to be effective in heart failure.

14.2.4 Beta Blockers Use of beta blockers in diabetes has always been an argument against or in favor in clinical practice. Those who do not use beta blockers have the following objections. These drugs will increase the glycemic levels. These will also mask particularly the adrenergic symptoms of hypoglycemia which appear first and easily caution the onset of hypoglycemia, further arguing that the masked symptoms will push the patient directly in neuroglycopenia leading to unconscious states. In addition, the peripheral arterial vasoconstrictive effects of beta blockers are additive to the damage it may cause particularly to the lower limbs in diabetes. There was also a likely bronchoconstriction effect which was an additional unnecessary complication that could be introduced in a patient with diabetes with compromised cardiac condition with or without cardiac autonomic neuropathy. This effect was most commonly seen in the first beta blocker propranolol. The newer and later more refined beta blockers are however mostly free of this effect. These objections did have some validity when the only nonselective beta blocker available was propranolol. Successive cardioselective beta blockers were developed with Atenolol coming up first followed by metoprolol and other similar ones which today are far more

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commonly and rightly used in clinical practice. In the use of these selective beta blockers none of the objections above are really valid, especially when compared with the beneficial effects it has on cardiac circulatory physiology discussed below.

14.2.4.1 Reduced Exercise Tolerance Parasympathetic denervation and sympathetic predominance are known to impair exercise tolerance. The quantum gap to increase the heart rate in response to activity/ exercise has already been reduced by the resting tachycardia and the simultaneously increased cardiac output, both of which cannot rise further [12]. Resting tachycardia is associated with an increased risk of death and CV complications as shown in a study involving 11,400 T2DM patients. The increased risk could also be only a marker of other factors responsible for poorer outcome [13]. In sympathetic predominance there is resting tachycardia. The vasoconstrictive effect of the same is also already prevailing. Thus there is little scope for further enhancement of cardiac response to activity leading to impaired exercise tolerance. This observation underlines the importance of reducing tachycardia. Lowering blood pressure has to be extremely judicious - this aspect however is beyond the scope of this volume. 14.2.4.2 Physiology of Cardiac Perfusion Coronary arteries are perfused only during the diastolic period of cardiac cycle. The sum of all diastolic time periods in a minute will increase if the heart rates are lower. In higher heart rates or more particularly in resting tachycardia as is commonly found in diabetes, the cardiac muscle requirement of oxygen and nutrients increases. But the diastolic filling period for heart in a minute-to-minute basis is drastically curtailed. This affects the cardiac muscle mechanism. Resting tachycardia caused due to parasympathetic degeneration is unwarranted in resting conditions. If it is not controlled, the disadvantageous balance between cardiac muscle requirement and its diminished supply due to reduced diastolic filling time continues over long periods relentlessly and is bound to cause deterioration of the heart. Added to that are two more factors—coronary vascular disease and diabetic cardiomyopathy which further compromises the ability to meet demands and will lead to heart failure. (Since these effects do not have much to do with cardiac autonomic neuropathy these are not discussed here.) 14.2.4.3 Reply to Objections to Using Beta Blockers Hypoglycemia in clinical practice is frequently seen in outpatient practice as well as in inpatient management. Not all of them are severe or dangerous either. More importantly, the transient, detectable episodes of hypoglycemia that are missed are far too common. However the fear of inducing hypoglycemia among the clinicians is pervasive and gripping. Objections to using beta blockers are yet another reason for undetectable hypoglycemia. World over the percentage of well-controlled diabetes is just about 30%. As it is, hypoglycemia as a whole is not a well-understood phenomenon by the physician community, primarily because of their inadequate knowledge of the pharmacodynamics and pharmacokinetics of hypoglycemic agents of all varieties. An extensive discussion of it will be found in the volume

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under the title of “Towards Optimal Management of Diabetes in Surgery” published by SpringerNature (2019). The worry about hypoglycemia developing is so gripping that most clinical management of diabetes does not even achieve good glycemic control in routine or critical or complex conditions. Beta blockers are but a probable cause among scores of others. To encounter hypoglycemia, near normal blood glucose control round the clock is a precondition. Therefore beta blockers masking early symptoms of hypoglycemia and its glycemic effects for not using it are unacceptable arguments against the enormous benefits it offers to the heart itself.

14.2.4.4 Utility of Beta Blockers The beta blockers are cardioselective. The potential for masking the other general symptoms like sweating are not likely to be blocked by its use. Cardioselective beta blockers when properly used will cause only a reasonable control of heart rate as it should. The rate can and will increase if the resting conditions are changed to activity and in stressful conditions. For the same reasons the effects on peripheral arterial vasoconstriction as well as bronchoconstriction are not an issue, something the physician community in its vast experience of using beta blockers has realized. Cardioselective β-blockers will have a positive effect on autonomic dysfunction as it cuts down the unnatural demand on the heart to work unnecessarily round the clock. Metoprolol improved autonomic function in patients with T1DM when used in combination with an ACE inhibitor [14]. This is a routine strategy today in type 2 diabetes as well where there is resting tachycardia. In the Beta-Blocker Heart Attack trial, propranolol was given to patients with diabetes after occurrence of myocardial infarction. It was shown to improve the parasympathetic tone. It also decreased the physiological morning sympathetic predominance, which is often not fully controlled in practice [15]. Cardioselective β-blockers can have a positive effect on autonomic dysfunction and are quite useful to treat heart failure if the dosages are increased gradually under hemodynamic monitoring. The effect enhances when these are used in combination with angiotensin receptor blocker or to angiotensin-converting enzyme inhibitor [11]. 14.2.4.5 N  octurnal Elevation of Blood Pressure and its Unwelcome Effects Sleep-time hypertension is much more common than suspected. It is also present in patients with sleep disorders, in elderly or with essential hypertension, or patients with type 2 diabetes, chronic kidney disease, and resistant hypertension. This abnormal circadian rhythm can be observed only under 24 h ambulatory blood pressure monitoring and not just the clinic-based blood pressure assessment. Reduction in the night blood pressure and the suppression of no dip or reverse dipping is well established to reduce the untoward effects of this night elevation. It reduces the cardiovascular (CVD) events by 61%, decreases CVD death, myocardial infarction, and ischemic and hemorrhagic stroke by 67%. The Spanish MAPEC (monitorización ambulatoria para predicción de eventos cardiovasculares (i.e., ambulatory

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blood pressure monitoring for prediction of cardiovascular events) was the first prospective randomized treatment-time investigation to assess these possible benefits. It ran over 5.6 median years of observations [16] Frankly speaking the morning elevation and the rise of blood pressure in later bedtime hours is a physiological phenomenon in the populations, just as steroid levels rise in the morning before awakening. Yet prevalent clinical practice insists that the blood pressure medication should be taken in the morning and not night, something which the author has found inexplicable. Morning medications also result in the routinely detected undue reductions which leave the patients uncomfortable. Blood pressure reduction during sleep is the most significant prognostic marker of CVD for this protection. Naturally night time reduction of hypertension is certainly preferred in conditions mentioned above. With each 5 mm Hg reduction in blood pressure, the cardiovascular events were found to be decreased by 12% [17].

14.2.5 Sodium Glucose Transporter 2 Inhibitors, SGLT2i Supplementing SGLT2i with nightly administration of one or all antihypertensives in diabetes have better effect on control of hypertension and on no dip or reverse dipping, compared to daytime administration of antihypertensives. This effect is separate from its action on heart failure which it improves as a class effect. Increased efferent sympathetic activity results in increased reabsorption of sodium from the renal proximal tubules. SGLT2i dapagliflozin inhibits the noradrenaline in kidneys and the heart. SGLT2i may thus be useful in cardiac autonomic neuropathy and other conditions which have sympathetic over activity. Acute administration of empagliflozin in 22 metformin-treated patients with T2DM for 4 days also did not increase sympathetic activity. Hence SGLT2i inhibitory to sympathetic tone in kidney as well as centrally may be another mechanism to treat cardiac autonomic neuropathy. It may briefly be mentioned that the most unexpected was the effects of SGLT2i on heart failure in diabetes. In the class of SGLT2i the renal tubular reabsorption of glucose is inhibited and glycosuria increases. This reduces the glucose availability to the body and a mild ketosis develops. The ketones are then utilized by the heart in diabetes which appears to be a more efficient fuel. Since it does not concern with cardiac autonomic neuropathy it will not be discussed further. There are many members of his group having selective or better action profile on one or the other comorbidities which is also out of scope for this volume [18].

14.2.6 C-Peptide Furthermore, C-peptide has shown beneficial effects on HRV in T1DM patients as it enhanced endoneurial blood flow, Na+/K+ pump activity, and neurotrophic factors release. C-peptide is also briefly discussed in treatment of diabetic neuropathy.

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14.2.7 Additional Treatment Methods for CAN 14.2.7.1  ACE Inhibitors, Digoxin and Verapamil Similarly, HRV may be treated with antihypertensive drugs like ACE inhibitors, angiotensin receptor blockers, cardioselective β-blockers, digoxin, and verapamil [18]. 14.2.7.2  Caffeine and Acarbose Postprandial hypotension may occur due to redistribution of blood flow into splanchnic vessels. Caffeine and acarbose are likely to be useful in treating this condition [19]. 14.2.7.3  Spironolactone Spironolactone, a potassium sparing mild diuretic, has beneficial effects with three other drugs frequently used in diabetes—enalapril, furosemide, and digoxin. It also has some remarkable effects in treatment of polycystic ovarian syndrome. 14.2.7.4  Enalapril Enalapril use has to be titrated to keep the supine as well as standing blood pressure within limit. However the ACE inhibitor class as such has little effect on postural drop of blood pressure, except an occasional one as a first dose hypotensive response for which reason it used to be given initially in the night. This probably is no longer relevant. 14.2.7.5  Furosemide Furosemide in larger does can produce electrolyte losses, both potassium and sodium. Using spironolactone or a similar congener with it is always helpful. For avoiding digoxin toxicity maintaining potassium levels is of utmost importance, a function well served by spironolactone. Such an addition has shown a beneficial effect on autonomic function. The effect was assessed by testing the heart rate variability indicating better balance in sympathetic and vagal effects on this function [20]. 14.2.7.6  GLP-1 and DPP4i The use of glucagon-like peptide 1 analogs or the dipeptidyl peptidase 4 inhibitors has been found to be protective to the heart as well as peripheral and autonomic neuropathy [21, 22].

14.3  Treatment of Orthostatic Hypotension Orthostatic hypotension in cardiac autonomic neuropathy is a complex, complicated, and difficult-to-treat condition. There are multiple non-pharmacological and pharmacological methods to treat it.

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14.3.1 Non-pharmacological Interventions 1. Drinking larger quantities of water, 500  ml, rapidly to maintain intravascular volume. 2. Slow speed of the change in the usual body postures—from lying down to sitting and then getting up, accompanied by short periods of inactivity in between. This allows time for the diminished reflexes to get activated. 3. Any activity that increases the intrathoracic or intra-abdominal pressure should be avoided as it reduces the venous return, inadequate filling of the right and then the left ventricle, reduced stretching of the heart muscle fibers leading to poorer inotropic action. 4. Using compression stockings on lower limbs is helpful to increase peripheral venous return and avoid pooling of blood. 5. Large meals increase the splanchnic circulatory volume reducing the overall circulating intravascular volume, hence smaller and more frequent meals are better to prevent such episodes [23].

14.3.2 Drugs Enhancing Orthostatic Hypotension Diuretics, vasodilators, tricyclic antidepressants and α-adrenoreceptor antagonists are among the medication routinely given to patients with diabetes. Adding these in the presence of orthostatic hypertension not diagnosed by clinicians will aggravate the symptoms and should thus be stopped [23]. If symptoms develop newly or are aggravated, progressive reduction in doses may be tried to avoid sudden stoppage of these drugs.

14.4 Pharmacotherapy of Orthostatic Hypotension Symptomatic orthostatic hypotension therapy has been extensively investigated. When life style, behavioral measures, and physical counter-maneuvers are no longer effective, pharmacological intervention should be considered. The aim of the treatment is to increase the standing systolic blood pressure. In doing so the supine systolic blood pressure may rise to an unacceptable high level. The challenge will consist of maintaining mainly the supine systolic blood pressure within a normal or an acceptable higher range as the drugs causing or aggravating orthostatic hypotension are being reduced [22]. Monitoring both supine and standing blood pressures frequently and adjusting the drugs to achieve a balance towards normalcy is necessary as the blood pressure medications are withdrawn or reduced over time. ACE inhibitors do not particularly affect standing blood pressure and may be gainfully used. Control of supine blood pressure with minimum drug would be desirable to avoid postural fall of blood pressure.

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14.4.1 Midodrine Midodrine is a peripheral selective α1-adrenergic agonist. It causes a selective peripheral vasoconstriction of arterioles and veins. It is the only drug the Food and Drug Administration has approved. That has led to its more common usage [22]. Although only midodrine, an α1-adrenergic agonist, has been approved by the Food and Drug Administration for the therapy of orthostatic hypotension, α-2 antagonists (clonidine) may be tried.

14.4.2 Fludrocortisone Fludrocortisone, predominantly a mineralocorticoid, with minimal ability to destabilize glycemia retains sodium and is helpful in some cases.

14.4.3 Somatostatin and its Analog Octreotide Octreotide causes splanchnic vasoconstriction by stopping the liberation of vasoactive peptides in the GI tract. It results in the rise of mean blood pressure, a useful index to treat orthostatic hypotension without necessarily increasing the systolic blood pressure to unacceptably high levels.

14.4.4 Erythropoietin Erythropoietin particularly useful in end-stage renal failure increases blood viscosity and intravascular volume. Pyridostigmine, a cholinesterase inhibitor, is also tried [24]. Nonselective β-blockers will cause generalized vasoconstriction and may be useful.

14.4.5 Desmopressin Acetate Desmopressin acetate has been found to ameliorate symptoms through different mechanisms, albeit with limited effectiveness.

14.4.6 Pyridostigmine Bromide Pyridostigmine bromide cholinesterase inhibitor, caffeine and acarbose also have some effect on orthostatic hypotension.

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14.4.7 Future Strategies Inhibitors of specific antioxidant pathways, especially NF-kB and Nfr-2, mitochondria targeted antioxidants as well as enhancers of mitochondrial functions have been suggested as future strategies against diabetic autonomic neuropathy (DAN). Finally, new possibilities have been opened by stem cells and gene therapy [18]. In India there is abhorrence among the hypertensive patients for increasing sodium intake if advised and is strongly resisted. The numbers suffering from hyponatremic states of various severities are large. As an observation, not rigorously studied is that in orthostatic hypotension the first instruction in India to increase salt intake may be helpful. There does not appear any a priori reason why some of the therapies should not be combined.

14.5 P  revention and Mitigation of Cardiac Autonomic Neuropathy High glucose levels found in routine care certainly worsen the cardiac autonomic neuropathy in both type 1 and 2 diabetes. Trials like DCCT and Steno 2, expensive and too rigorous for day-to-day care, have shown that some mitigation in cardiac autonomic neuropathy does occur. On the whole, as duration of diabetes prolongs, cardiac autonomic neuropathy is likely to be present almost always and will be probably progressive. Another variable found is in the practice of Continuous Glucose Monitoring Systems (CGMS.) High glucose variability is also a predictor of cardiac autonomic neuropathy now discovered in CGMS [17]. Minimizing these excursions would help.

14.5.1 Treatment of Cardiac Autonomic Neuropathy Insulin-like growth factor-1 (IGF-1) and neurotrophin-3 (NT-3) have been shown to reverse experimental diabetic neuropathy. However, all the clinical management, parameter control, and all other modalities for good control of diabetes will continue to remain the mainstay of treatment.

References 1. Ziegler D, Schatz H, Conrad F, Gries FA, Ulrich H, Reichel G.  Effects of treatment with the antioxidant on cardiac autonomic neuropathy in NIDDM patients: a 4-month randomized controlled multicenter trial, Deutsche Kardiale Autonome Neuropathie. Diabetes Care. 1997;20(3):369–73. [PMID: 9051389]. https://doi.org/10.2337/diacare.20.3.369. 2. Manzella D, Barbieri M, Ragno E, Paolisso G. Chronic administration of pharmacologic doses of vitamin E improves the cardiac autonomic nervous system in patients with type 2 diabetes. Am J Clin Nutr. 2001;73:1052–7.

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