W Zochodne MD / Malik Diabetes and the Nervous System

1. Auflage 2014
ISBN: 978-0-444-63541-9
Verlag: Elsevier Science & Techn.
Format: EPUB
Kopierschutz: 6 - ePub Watermark

E-Book, Englisch, 640 Seiten

Reihe: Handbook of Clinical Neurology

This is a unique compilation, by experts worldwide, addressing how diabetes impacts the nervous system. For example, diabetic polyneuropathy, a disorder more common than MS, Parkinson's disease, and ALS combined, is a major source of disability to diabetic persons worldwide. This book addresses diabetic polyneuropathy and how diabetes alters other parts of the nervous system. - Offers a unique emphasis on the neurological manifestations of diabetes - Provides thorough coverage of the clinical, experimental, mechanistic, therapeutic, peripheral, and central aspects of diabetic neuropathy - Edited work with chapters authored by leaders in the field around the globe - the broadest, most expert coverage available

Autoren/Hrsg.

W Zochodne MD, Frcpc

Malik, Rayaz A.

Inhaltsverzeichnis

1;Front Cover;1
2;Diabetes and the Nervous System;4
3;Copyright;5
4;Handbook of Clinical Neurology 3rd Series;6
5;Foreword;8
6;Preface;10
7;Contributors;12
8;Contents;16
9;Section 1: Clinical Impact of Diabetes on the Nervous System;20
9.1;Chapter 1: Epidemiology of Polyneuropathy in Diabetes and Prediabetes;22
9.1.1;Introduction;22
9.1.1.1;Clinical Impact of Diabetic Distal Symmetric Sensorimotor Polyneuropathy;22
9.1.2;Testing for Peripheral Neuropathy;23
9.1.3;Painful Neuropathy;24
9.1.4;Population Selection;24
9.1.5;Prevalence in Diabetes;26
9.1.6;Prevalence in Prediabetes;27
9.1.6.1;Impaired Fasting Glucose or Impaired Glucose Tolerance to Diagnose Prediabetes?;27
9.1.6.2;Neuropathy in People With Prediabetes;28
9.1.7;Incidence and Natural History of diabetic Polyneuropathy;31
9.1.8;Etiologic Factors Related to diabetic Neuropathy;32
9.1.8.1;Hyperglycemia;32
9.1.8.1.1;Role of Intensive Diabetes Therapy in Prevention and Progression of Diabetic Neuropathy;33
9.1.8.2;Diabetes Duration;34
9.1.8.3;Age;34
9.1.8.4;Height;34
9.1.8.5;Hypoinsulinemia;35
9.1.8.6;Cardiovascular Risk Factors;35
9.1.8.6.1;Hypertension;35
9.1.8.6.2;Lipids;35
9.1.8.6.3;Obesity;35
9.1.8.6.4;Smoking;36
9.1.8.7;Alcohol Consumption;36
9.1.8.8;Depression;36
9.1.8.9;Genetic Factors;36
9.1.9;Conclusions;36
9.2;Chapter 2: Clinical Features of Diabetic Polyneuropathy;42
9.2.1;Early Studies of the Clinical Features of Diabetic Polyneuropathy;42
9.2.2;Symptoms of Diabetic Polyneuropathy;43
9.2.3;Clinical Signs of Diabetic Polyneuropathy;45
9.2.3.1;Abbreviated Forms of Assessment;47
9.2.4;Subtypes of Diabetic Polyneuropathy;47
9.2.5;Distinguishing Diabetic Polyneuropathy From Other Polyneuropathies;48
9.2.6;Conclusions;49
9.2.7;References;49
9.3;Chapter 3: Focal and Entrapment Neuropathies;50
9.3.1;Introduction;50
9.3.2;Cranial Mononeuropathies;50
9.3.2.1;Oculomotor, Trochlear, and Abducens Neuropathies;50
9.3.2.1.1;Anatomy and Pathophysiology;50
9.3.2.1.2;Literature and Epidemiology;51
9.3.2.1.3;Clinical Presentation;51
9.3.2.1.4;Laboratory/radiology Findings;52
9.3.2.1.5;Differential Diagnosis;52
9.3.2.1.6;Management and Prognosis;52
9.3.2.2;Facial Neuropathy;52
9.3.2.2.1;Anatomy and Pathophysiology;52
9.3.2.2.2;Literature and Epidemiology;53
9.3.2.2.3;Clinical Presentation;53
9.3.2.2.4;Laboratory/radiology Findings;53
9.3.2.2.5;Differential Diagnosis;53
9.3.2.2.6;Management and Prognosis;53
9.3.2.3;Malignant Cranial Nerve Syndromes;54
9.3.2.3.1;Rhinocerebral Mucormycosis;54
9.3.2.3.2;Malignant Otitis Externa;54
9.3.2.4;Other Cranial Nerve Syndromes;55
9.3.3;Upper Limb Mononeuropathies;55
9.3.3.1;Median Neuropathies: Carpal Tunnel Syndrome;55
9.3.3.1.1;Anatomy and Pathophysiology;55
9.3.3.1.2;Literature and Epidemiology;55
9.3.3.1.3;Clinical Presentation/differential Diagnosis;56
9.3.3.1.4;Laboratory/radiology Findings;56
9.3.3.1.5;Management;56
9.3.3.2;Ulnar Neuropathies: Ulnar Neuropathy At the elbow;56
9.3.3.3;Other Upper Limb Mononeuropathies;57
9.3.4;Truncal Mononeuropathies;57
9.3.4.1;Thoracic Monoradiculopathy;57
9.3.4.2;Phrenic Mononeuropathy;58
9.3.5;Lower Limb Mononeuropathies;58
9.3.5.1;Lateral Femoral Cutaneous Neuropathy;58
9.3.5.2;Fibular (peroneal) Mononeuropathy;58
9.3.5.3;Other Lower Limb Mononeuropathies;59
9.3.6;Conclusion;59
9.3.7;References;59
9.4;Chapter 4: Diabetic Radiculoplexus Neuropathies;64
9.4.1;Introduction;64
9.4.2;Clinical Features of the Diabetic Radiculoplexus Neuropathies;64
9.4.3;Epidemiology;67
9.4.4;Etiology and Pathogenesis;67
9.4.5;Treatment;68
9.4.6;Conclusion;70
9.4.7;References;70
9.5;Chapter 5: Painful Diabetic Neuropathy: Clinical Aspects;72
9.5.1;Introduction;72
9.5.2;Epidemiology of Painful Diabetic neuropathy;72
9.5.3;Pathogenesis of Neuropathic pain;73
9.5.4;Early Diagnosis and Intervention in Painful Neuropathy;74
9.5.5;Symptoms and Signs of Painful Diabetic Neuropathy;75
9.5.6;Acute Painful Neuropathies;76
9.5.6.1;Acute Painful Neuropathy of Poor Glycemic control;76
9.5.6.2;Acute Painful Neuropathy of Rapid Glycemic control;77
9.5.7;Natural History of Painful Diabetic Neuropathy;77
9.5.8;Neuropathic Pain Assessment;77
9.5.9;Differential Diagnosis of painful neuropathy;78
9.5.10;Diabetic Painful Neuropathy And autonomic Dysfunction;78
9.5.11;Conclusions;78
9.5.12;Acknowledgments;78
9.5.13;References;78
9.6;Chapter 6: Diabetic Autonomic Neuropathy;82
9.6.1;Introduction;82
9.6.2;Generalized Autonomic Neuropathy;82
9.6.2.1;Prevalence;82
9.6.2.2;Cardiovascular Autonomic Neuropathy;82
9.6.2.3;Gastrointestinal Autonomic Neuropathy;83
9.6.2.4;Urogenital;84
9.6.2.4.1;Bladder;84
9.6.2.4.2;Sexual Function;85
9.6.2.5;Sudomotor;85
9.6.3;Autonomic Neuropathy and Prediabetes;86
9.6.3.1;Background;86
9.6.3.2;Clinical Phenotype;86
9.6.4;Treatment-induced Neuropathy;87
9.6.4.1;Background;87
9.6.4.2;Clinical Features;87
9.6.4.3;Concomitant Features;88
9.6.4.4;Mechanisms;89
9.6.4.5;Pathology;89
9.6.4.6;Related Conditions;89
9.6.5;Hypoglycemia-associated Transient Autonomic Dysfunction;89
9.6.5.1;Background;89
9.6.5.2;Hypoglycemia and Glucose Counterregulation;90
9.6.5.3;Hypoglycemia-associated Autonomic Failure;90
9.6.5.4;Hypoglycemia and Cardiovascular Autonomic Function;90
9.6.5.5;Hypoglycemia and the Qt Interval;91
9.6.5.6;References;92
9.7;Chapter 7: Motor Neuropathy;100
9.7.1;Introduction;100
9.7.2;Motor Nerve Dysfunction;101
9.7.2.1;Electroneuronography;101
9.7.2.2;Electromyography;101
9.7.3;Muscle Strength;101
9.7.3.1;Evaluation of Muscle Strength;101
9.7.3.2;Muscle Strength in Healthy Subjects;102
9.7.4;Muscle Strength in Diabetes;104
9.7.4.1;Training;105
9.7.5;Muscular Atrophy;106
9.7.5.1;Muscle Energy Properties;109
9.7.6;Muscle Strength, Balance, Gait, and falls;109
9.7.7;Conclusions;111
9.7.8;References;111
9.8;Chapter 8: Diabetic Neuropathy and Foot Complications;116
9.8.1;Introduction;116
9.8.2;Historical Aspects of Diabetic Neuropathy and Foot Complications;116
9.8.3;Background: the Diabetic foot;117
9.8.4;Epidemiology and Health Economics of Diabetic Foot Problems;117
9.8.5;Neuropathy and Foot Ulceration;118
9.8.5.1;Chronic Sensorimotor Diabetic Peripheral Neuropathy;118
9.8.5.1.1;Clinical Presentation of Chronic Sensorimotor neuropathy;119
9.8.5.1.2;Assessment of Diabetic Peripheral Neuropathy;119
9.8.5.1.2.1;Symptoms;119
9.8.5.1.2.2;Signs;119
9.8.5.1.3;Simple Devices for Clinical Screening;119
9.8.5.2;Does the Presence of Diabetic Peripheral Neuropathy Increase the Risk of Ulceration?;120
9.8.5.3;Peripheral Sympathetic Autonomic Neuropathy;120
9.8.6;Other Risk Factors for Diabetic Foot Ulceration;121
9.8.6.1;The Pathway to Foot Ulceration in Diabetes;122
9.8.6.2;The Patient With Sensory loss;122
9.8.6.3;Principles of Management of Neuropathic Foot Ulcers;123
9.8.6.4;Charcot Neuroarthropathy (Cn);124
9.8.7;Conclusions;124
9.8.8;References;125
9.9;Chapter 9: Glucose Intolerance, Metabolic Syndrome, and Neuropathy;128
9.9.1;Introduction;128
9.9.2;Hypotheses and Pathophysiology;128
9.9.2.1;Hyperglycemia-induced Nerve Injury;128
9.9.2.2;Pathophysiology Involved in Metabolic Syndrome;129
9.9.3;Definition and Prevalence of metabolic Syndrome;130
9.9.4;Impaired Glucose Tolerance and Impaired Fasting Glucose;130
9.9.4.1;Epidemiology;130
9.9.4.2;Association of Impaired Glucose Tolerance With Neuropathy;131
9.9.5;Obesity and Dyslipidemia;131
9.9.6;Clinical Presentation of Impaired Glucose Tolerance and Metabolic syndrome-associated Neuropathy;132
9.9.7;Laboratory Testing for Glucose Dysmetabolism;132
9.9.8;Overview of Ancillary Testing;133
9.9.9;Outcomes and Prognosis;134
9.9.10;Management and Treatment;134
9.9.10.1;Glucose Control;134
9.9.10.2;Lifestyle Interventions;134
9.9.10.3;Evidence-based Recommendations;136
9.9.11;Future Directions;136
9.9.11.1;More Robust Epidemiology;136
9.9.11.2;Focus on Earlier Diagnosis;137
9.9.11.3;Measuring Nerve Regeneration;137
9.9.11.4;Basic Mechanisms and Targeted Therapy;138
9.9.11.5;References;138
9.10;Chapter 10: Diabetic Neuropathy in Children;142
9.10.1;Background;142
9.10.2;Definition;142
9.10.3;Prevalence of Diabetic Neuropathy in Children;143
9.10.4;Pathogenesis of Diabetic Neuropathy;143
9.10.5;Diagnosis of Pediatric Diabetic Neuropathy;143
9.10.5.1;Clinical Assessment;143
9.10.5.2;Staging of Diabetic Neuropathy;151
9.10.5.3;Nerve Conduction study;151
9.10.5.4;Quantitative Sensory Testing;152
9.10.5.5;Autonomic Function test;153
9.10.6;Risk Factors for Pediatric Diabetic Neuropathy;154
9.10.6.1;Nonmodifiable Risk Factors;154
9.10.6.2;Modifiable Risk Factors;154
9.10.7;Treatment of Symptomatic Pediatric Diabetic Neuropathy;155
9.10.8;Effects of Cointervention;155
9.10.9;Screening for Other Diabetic Complications;156
9.10.10;Psychosocial Issues Related to pediatric Diabetes;156
9.10.11;Conclusion;156
9.10.12;References;157
9.11;Chapter 11: Cognitive disorders in diabetic patients;164
9.11.1;Introduction;164
9.11.2;Evaluation of cognitive functioning;164
9.11.2.1;History taking;164
9.11.2.2;Cognitive domains and neuropsychological tests;164
9.11.2.3;Screening for cognitive impairment;165
9.11.2.4;Quantification and interpretation of test results;165
9.11.2.5;Stages of cognitive dysfunction;166
9.11.3;Cognitive functioning in type 1 diabetes;166
9.11.3.1;Cross-sectional studies;166
9.11.3.2;Longitudinal studies;166
9.11.4;Cognitive functioning in type 2 diabetes;167
9.11.4.1;Modest cognitive decrements;167
9.11.4.1.1;Cross-sectional studies;167
9.11.4.1.2;Longitudinal studies;167
9.11.4.2;Dementia;167
9.11.4.3;Cognitive trajectories in type 2 diabetes;171
9.11.5;Cognitive functioning in prediabetic stages;171
9.11.6;Consequences of cognitive dysfunction in diabetes;171
9.11.7;Mood disorders in diabetes;172
9.11.8;Brain MRI studies;172
9.11.8.1;Structural abnormalities associated with cognitive functioning;172
9.11.8.2;Quantification of abnormalities;172
9.11.8.3;New MRI techniques;173
9.11.8.4;Type 1 diabetes;173
9.11.8.5;Type 2 diabetes;174
9.11.9;Determinants and mechanisms;174
9.11.9.1;Type 1 diabetes;174
9.11.9.1.1;Demographic and lifestyle factors;174
9.11.9.1.2;Diabetes-specific factors;174
9.11.9.1.3;Vascular risk factors;175
9.11.9.1.4;Diabetic complications;175
9.11.9.1.5;Genetic factors;175
9.11.9.2;Type 2 diabetes;175
9.11.9.2.1;Demographic and lifestyle factors;175
9.11.9.2.2;Hypo- and hyperglycemia;175
9.11.9.2.3;Vascular risk factors;176
9.11.9.2.4;Diabetic complications;176
9.11.9.2.5;Genetic factors;176
9.11.9.3;Underlying mechanisms;176
9.11.10;Treatment of cognitive dysfunction;177
9.11.10.1;Lifestyle factors: diet and physical activity;177
9.11.10.2;Glycemic control;177
9.11.10.3;Vascular risk factors;178
9.11.11;Practical implications;178
9.11.12;References;179
9.12;Chapter 12: Stroke and Diabetes Mellitus;186
9.12.1;Introductory Concepts;186
9.12.2;Clinical Features;186
9.12.3;Causes: Stroke Mechanism;187
9.12.3.1;Ischemic Stroke;187
9.12.3.2;Subarachnoid Hemorrhage;189
9.12.3.3;Intracerebral Hemorrhage;189
9.12.4;Epidemiology and Risk Factors;189
9.12.5;Acute Stroke: Special Considerations in Diabetic Patients;189
9.12.6;Stroke Prevention: Special Considerations in Diabetic Patients;190
9.12.7;Conclusions;192
9.12.8;References;192
9.13;Chapter 13: Neurologic Infections in Diabetes Mellitus;194
9.13.1;Introduction;194
9.13.2;Viruses;195
9.13.2.1;Herpes zoster;195
9.13.2.2;West Nile Neuroinvasive Disease;196
9.13.3;Bacteria;197
9.13.3.1;Hyperglycemia and Hypoglycorrhachia In bacterial Meningitis;197
9.13.3.2;Neurolisteriosis;197
9.13.3.3;Malignant External Otitis;198
9.13.3.4;Pyogenic Spine Infections: Epidural Abscess and Vertebral Osteomyelitis;199
9.13.3.5;Pyomyositis;201
9.13.3.6;Diabetic Foot Infections and Charcot Neuroarthropathy;202
9.13.4;Fungi;203
9.13.4.1;Molds: Mucormycosis, Aspergillosis, Scedosporiosis;203
9.13.4.2;Dimorphic Fungi: Blastomycosis;205
9.13.4.3;Yeasts: Candidiasis and Cryptococcosis;207
9.13.5;Parasitic Infections in the Pathogenesis of Diabetes Mellitus;207
9.13.5.1;Protozoans;207
9.13.5.2;Helminths;207
9.13.6;Summary;208
9.13.7;References;208
9.14;Chapter 14: Recognition and Management of Psychosocial Issues in Diabetic Neuropathy;214
9.14.1;Introduction;214
9.14.2;The Burden of Painful Diabetic Neuropathy;214
9.14.3;Emotional Side of the Diabetic Neuropathy Experience;215
9.14.3.1;The Role of Diabetic Neuropathy and Its Symptoms in Generating Depression;215
9.14.3.2;Differential Effects of Diabetic Neuropathy Symptoms on Anxiety Versus Depression;216
9.14.4;The Role of Psychological Factors in Shaping Pain Experience;217
9.14.5;Psychosocial Interventions for Diabetic Neuropathy Symptom Management;218
9.14.5.1;Painful Diabetic Neuropathy;218
9.14.5.2;Postural Instability;219
9.14.6;The Case for an Integrated Biopsychosocial Approach to Diabetic Neuropathy Symptom Management;219
9.14.7;Measuring Quality of Life in Diabetic Neuropathy: Generic, Specific, or Combined Approach?;220
9.14.7.1;Limitations of the Generic Quality of Life Instruments;220
9.14.7.2;The Shift From Generic to Diabetic neuropathy-specific Quality of Life Assessment;221
9.14.8;The Role of Psychosocial and Behavioral Factors in Diabetic Foot Ulcer Prevention;221
9.14.8.1;Depression Versus Diabetic Foot ulceration-specific Emotional Distress and Foot self-care;222
9.14.8.2;Patient Cognitive and Emotional Representations of Diabetic Foot Ulcer Risk And foot self-care;222
9.14.8.3;The Role of Psychosocial and Behavioral Factors in Diabetic Foot Ulcer Healing;223
9.14.9;Concluding Remarks;224
9.14.10;Acknowledgments;225
9.14.11;References;225
9.15;Chapter 15: General Aspects of Diabetes Mellitus;230
9.15.1;Diagnosis of Diabetes;230
9.15.2;Classification of Diabetes;231
9.15.3;Diabetes types;232
9.15.4;Screening for Diabetes;233
9.15.5;The Diabetic History;233
9.15.6;The Diabetic Physical Examination;233
9.15.7;Glycemic goals;233
9.15.8;Diabetes Pharmacotherapy;233
9.15.9;Management Outline in Newly Diagnosed Type 2 Diabetes Mellitus: an Algorithm;233
9.15.9.1;Oral Hypoglycemic Agents and Insulin In type 2 Diabetes Mellitus;233
9.15.9.2;Insulin in Type 2 Diabetes Mellitus;234
9.15.9.3;Insulin in Type 1 Diabetes Mellitus;235
9.15.9.4;Insulin Pumps (continuous Subcutaneous Insulin Infusion);237
9.15.9.5;Corticosteroids and Diabetes Management;237
9.15.10;Diabetes Control of Inpatients;238
9.15.10.1;Critically Ill Patients;239
9.15.10.2;Noncritically Ill Patients;239
9.15.11;Cerebral Infarction and Glycemic Control;239
9.15.12;Enteral and Parenteral Nutrition and Glycemic Control;239
9.15.13;Acknowledgments;240
9.15.14;References;240
9.16;Chapter 16: Sexual Dysfunction in Diabetes;242
9.16.1;Introduction;242
9.16.2;Sexual Dysfunction In diabetic women;242
9.16.3;Sexual Dysfunction In diabetic men;242
9.16.4;Erectile Dysfunction;243
9.16.4.1;Definition;243
9.16.4.2;Prevalence of Erectile Dysfunction in Diabetes;243
9.16.4.3;Pathophysiology of Erectile Dysfunction In diabetes;243
9.16.4.4;Diagnosis of Erectile Dysfunction;244
9.16.5;Treatment of Erectile Dysfunction in Diabetic Patients;244
9.16.5.1;First-line Therapy;245
9.16.5.1.1;Pde-5 Inhibitors;246
9.16.5.2;Second-line Therapy;248
9.16.5.3;Third-line Therapy;248
9.16.6;References;249
10;Section 2: Diagnostic and Therapeutic Approaches to diabetic neurological Complications;252
10.1;Chapter 17: Electrophysiologic Testing in Diabetic Neuropathy;254
10.1.1;Electrophysiologic Studies: Background;254
10.1.1.1;Introduction to Electrophysiology;254
10.1.1.2;Methodology;254
10.1.1.2.1;Nerves Tested for Polyneuropathy;254
10.1.1.2.2;Electromyography;256
10.1.1.2.3;Results of Nerve Conduction Studies;257
10.1.1.2.4;Advantages of Nerve Conduction Studies;258
10.1.1.2.5;Limitations of Nerve Conduction Studies In diabetes;259
10.1.1.2.5.1;Large Fiber Measure;259
10.1.1.2.5.2;Accuracy;259
10.1.1.2.5.3;Small Nerve Fiber Measures;260
10.1.2;Rationale for Electrophysiologic Studies;261
10.1.2.1;Diagnosis of Axonal Versus Demyelinating Polyneuropathy;261
10.1.2.2;Follow Response to Therapy or Disease Progression;261
10.1.3;Changes in Electrophysiologic Studies in Diabetes;261
10.1.3.1;Impaired Glucose Tolerance;261
10.1.3.2;Diabetes;262
10.1.4;What is the Role of electrophysiologic Studies In diabetes?;262
10.1.4.1;Diagnosis;262
10.1.4.2;Staging;263
10.1.4.3;Monitoring;263
10.1.4.4;Prognosis;263
10.1.5;Summary;264
10.1.6;References;264
10.2;Chapter 18: Pathology of Human Diabetic Neuropathy;268
10.2.1;Introduction;268
10.2.2;Nerve Biopsy;268
10.2.3;Myelinated Fibers;268
10.2.3.1;Density;268
10.2.3.2;Axonal Atrophy;270
10.2.3.3;Axoglial Dysjunction;271
10.2.4;Unmyelinated Fibers;272
10.2.5;Microvessels;273
10.2.6;Extracellular Matrix;273
10.2.7;Neuropathology in Variants of Diabetic Neuropathy;274
10.2.8;Skin Biopsy;275
10.2.9;Sudomotor Innervation;275
10.2.10;Motor Abnormalities;275
10.2.11;References;276
10.3;Chapter 19: Epidermal Innervation in Diabetes;280
10.3.1;Introduction;280
10.3.2;An Overview of Skin Innervation;280
10.3.2.1;Skin Biopsy Technique and Methodology;282
10.3.2.2;Selection of Biopsy Site and Processing Technique;282
10.3.2.3;Skin Blister Technique;283
10.3.2.4;Cutaneous Nerve Injury Models;283
10.3.2.5;Chemical Axotomy;283
10.3.2.6;Tissue Processing for Immunohistochemistry and Immunofluorescence;283
10.3.3;Quantitation of Epidermal Fibers;285
10.3.3.1;Normative Epidermal Nerve Fiber data;285
10.3.4;Skin Biopsy as a Diagnostic Test in Small Fiber Sensory Neuropathies;285
10.3.5;Evaluation of Epidermal Fibers In diabetic Neuropathy;285
10.3.6;Skin Biopsy as a Marker for Early Diabetic Neuropathy;286
10.3.7;Skin Biopsy as a Biomarker of neuropathic pain;287
10.3.8;Morphologic Features of epidermal Nerve Fibers;287
10.3.9;Epidermal Innervation in Clinical Trials;288
10.3.10;Cutaneous Autonomic Nerve Fiber Innervation in Diabetes;288
10.3.11;Regeneration of Epidermal Nerve Fibers in Diabetic Neuropathy;289
10.3.12;References;290
10.4;Chapter 20: Clinical and Diagnostic Features of Small Fiber Damage in Diabetic Polyneuropathy;294
10.4.1;Introduction;294
10.4.2;Clinical Features;294
10.4.3;Diagnostic Criteria;295
10.4.4;Differential Diagnosis;296
10.4.5;Diagnostic tests;297
10.4.5.1;Quantitative Sensory Testing;297
10.4.5.2;Pain-related Evoked Potentials;298
10.4.5.3;Nerve Axon Reflex/flare Response;298
10.4.5.4;Nerve Biopsy;298
10.4.5.5;Skin Biopsy;299
10.4.5.6;Diagnostic Yield of Intraepidermal Nerve Fiber Quantification;299
10.4.5.6.1;Diabetic Neuropathy;300
10.4.5.6.2;Corneal Confocal Microscopy;302
10.4.5.7;Sudomotor Dysfunction;303
10.4.5.7.1;Sympathetic Skin Response;303
10.4.5.7.2;QSART;303
10.4.5.7.3;Thermoregulatory Sweat test;303
10.4.5.7.4;Neuropad;303
10.4.5.7.5;Sudomotor Innervation;304
10.4.6;Conclusion;304
10.4.7;References;304
10.5;Chapter 21: Central Nervous System Imaging in Diabetic Cerebrovascular Diseases and White Matter Hyperintensities;310
10.5.1;Introduction;310
10.5.2;Stroke in Patients With Diabetes Mellitus;310
10.5.2.1;Neuroimaging of the Acute Stroke Syndrome in Diabetes;311
10.5.2.1.1;Acute Ischemic Stroke Pathophysiology Pertaining to Imaging;311
10.5.2.1.2;Goals of Imaging in Acute Diabetic Cerebrovascular Disease;312
10.5.2.2;Computed tomography-based Neuroimaging in Acute Stroke;312
10.5.2.2.1;Noncontrast Computed Tomography;312
10.5.2.2.2;Ct Angiography;312
10.5.2.2.3;Ct Perfusion Imaging;314
10.5.2.3;Multimodal Magnetic Resonance Imaging In acute Stroke;314
10.5.2.3.1;Diffusion-weighted Imaging and Apparent Diffusion Coefficient;315
10.5.2.3.2;T2-weighted and fluid-attenuated Inversion Recovery Imaging;315
10.5.2.3.3;Magnetic Resonance Perfusion Imaging;315
10.5.2.3.4;Perfusion Imaging/diffusion-weighted Imaging Mismatch Concept;316
10.5.2.3.5;Magnetic Resonance Angiography;316
10.5.2.4;Use of Transcranial Doppler in Acute Stroke;317
10.5.3;Imaging Techniques in Patients With Diabetes mellitus-related Chronic Cerebrovascular Disorders;317
10.5.3.1;Imaging Large Artery Abnormalities In patients With Diabetes Mellitus;317
10.5.3.1.1;Utility of Carotid Doppler;317
10.5.3.1.2;Magnetic Resonance Imaging of Vulnerable Carotid Plaques in Diabetes Mellitus;319
10.5.3.2;Imaging Small Vessel Abnormalities In diabetes Mellitus;319
10.5.3.2.1;Use of Transcranial Doppler in Diabetic Patients With Chronic Cerebrovascular Disease;319
10.5.3.3;Imaging Diabetes Mellitus Patients With Cognition, Gait, and Mood Disorders;320
10.5.3.3.1;Diabetes as Risk Factor and Pathophysiology of lacunar Infarctions;320
10.5.3.4;Imaging Lacunar Infarction;320
10.5.3.5;Imaging Cerebral Atrophy Associated With diabetes Mellitus;321
10.5.3.6;Use of Magnetic Resonance Imaging to measure Cerebral Atrophy;321
10.5.3.6.1;Measuring Localized or Focal Brain Volumes;321
10.5.3.6.2;Measuring Total Brain Volumes;321
10.5.3.7;Use of Imaging in Diabetes Mellitus to Assess Brain Metabolism;322
10.5.3.7.1;Magnetic Resonance Spectroscopy;322
10.5.3.8;White Matter Hyperintensities in Patients With Diabetes Mellitus;322
10.5.3.8.1;Magnetic Resonance Imaging of White Matter Hyperintensities;324
10.5.3.8.2;Quantitative and Qualitative Analysis of White Matter Hyperintensities;324
10.5.3.9;Emerging Neuroimaging Techniques That could Be Applied to Diabetes Mellitus to measure White Matter Integrity;325
10.5.3.9.1;Magnetization Transfer ratio;325
10.5.3.9.2;Diffuse Tensor Imaging;326
10.5.4;Conclusions;327
10.5.5;References;328
10.6;Chapter 22: Therapy for Diabetic Neuropathy: an Overview;336
10.6.1;Introduction;336
10.6.2;Treatment Strategies for Preventing Neuropathy;336
10.6.2.1;Glycemic Control;336
10.6.3;Symptomatic Treatment Strategies;336
10.6.3.1;Diabetic Polyneuropathy;336
10.6.3.1.1;Neuropathic pain;336
10.6.3.1.2;Diagnosis of Diabetic Painful Neuropathy;337
10.6.3.2;Pharmacotherapies for Painful Diabetic Neuropathies;337
10.6.3.2.1;Antidepressants;337
10.6.3.2.2;Antiepileptics;339
10.6.3.2.3;Opiods;340
10.6.3.2.3.1;Tramadol;341
10.6.3.2.4;Nonsteroidal Antiinflammatory drugs;341
10.6.3.2.5;N-methyl-d-aspartate Antagonists (Nmda Antagonists);341
10.6.3.3;Topical Agents;341
10.6.3.4;Botulinum toxin;342
10.6.3.5;Electrical Nerve Stimulation and Acupuncture;342
10.6.3.6;Foot care;342
10.6.3.7;Overview of Adverse Effects, Drug Interactions, and Recommendations for Patients With Impaired Renal and Hepatic Function...;343
10.6.3.7.1;Serotonin Syndrome;343
10.6.3.7.2;Risk of Gastrointestinal Bleeding;343
10.6.3.7.3;Cardiovascular Considerations;343
10.6.3.7.4;Renal Impairment;343
10.6.3.7.5;Hepatic Impairment;343
10.6.3.8;Diabetic Autonomic Neuropathy;344
10.6.4;New Treatment Strategies;345
10.6.4.1;Polyol Pathway: Aldose Reductase Inhibitors;345
10.6.4.2;Sorbinil;345
10.6.4.3;Epalrestat, Ranirestat, and Fidarestat;346
10.6.4.4;Hexosamine Pathway;346
10.6.4.4.1;Benfotiamine;346
10.6.4.5;Receptor for Advanced Glycation End Products (Rage) Pathway;346
10.6.4.6;Poly (Adp-ribose) Polymerase Inhibitors;347
10.6.4.7;Antioxidants;347
10.6.4.8;Angiotensin-converting Enzyme Inhibitors and Angiotensin Ii Receptor Antagonists;347
10.6.4.9;Mapk-inhibitors;348
10.6.5;Summary;348
10.6.6;References;349
10.7;Chapter 23: Methodology for Conduct of Epidemiologic Surveys and Randomized Controlled Trials of Diabetic Polyneuropathy;354
10.7.1;Reasons Why Epidemiologic Surveys and Randomized Controlled Clinical Trials of diabetic Polyneuropathy Are difficult...;354
10.7.2;Choice of Neuropathy End Points;355
10.7.3;Single Versus Composite Outcome Measurements in Epidemiologic Surveys or Randomized Controlled Trials;355
10.7.4;Reference Values of Neurophysiologic End Points;356
10.7.5;Proficiency and Neurophysiologic Test and Clinical Assessment;356
10.7.6;References;356
11;Section 3: Fundamental Studies of Diabetic Neuroscience;358
11.1;Chapter 24: Neuroscience of Glucose Homeostasis;360
11.1.1;Introduction;360
11.1.2;Daily Rhythm in Plasma Glucose Concentrations;360
11.1.3;The Role of the Hypothalamic Output to the Autonomic Nervous System in the 24 hour Rhythm in Plasma Glucose Concentrations...;363
11.1.4;Brain Areas and Neuropeptides Important for Glucose Metabolism;364
11.1.4.1;Arcuate Nucleus;364
11.1.4.2;Lateral Hypothalamus;365
11.1.4.3;Ventromedial Hypothalamus;365
11.1.5;Central Nervous System Control of Hormones Influencing Glucose Metabolism;366
11.1.6;References;368
11.2;Chapter 25: Mechanisms of Disease: Mitochondrial Dysfunction in Sensory Neuropathy and Other Complications in Diabetes;372
11.2.1;Overview of Diabetic Neuropathy;372
11.2.1.1;Epidemiology and Clinical Signature of diabetic Neuropathy;372
11.2.1.2;Pathophysiologic Appearance of Diabetic Neuropathy;372
11.2.2;Role of Oxidative Stress in Neurodegeneration in Diabetes;373
11.2.2.1;Oxidative Stress as an Etiologic Factor In diabetic Neuropathy;373
11.2.2.2;Aberrant Mitochondrial Function and Generation of Oxidative Stress in Diabetes;373
11.2.2.3;Adult Sensory Neurons Exhibit Alternative Responses to High Glucose Compared With Endothelial Cells and Embryonic Neurons...;373
11.2.3;Calcium Dysfunction in Diabetic Neuropathy;374
11.2.3.1;Aberrant Ca2+ Homeostasis and Mitochondrial Dysfunction;374
11.2.3.2;Mitochondrial Bioenergetics and Ros Generation: Role of [Ca2+]m;375
11.2.4;Impaired Mitochondrial Function in Pathogenesis of Type 2 Diabetes and Other Complications;376
11.2.4.1;Mitochondrial Dysfunction as a Determinant of Type 2 Diabetes in Humans;376
11.2.4.2;Mitochondrial Function and Insulin Resistance in Humans;376
11.2.4.3;Experimental Evidence Linking Mitochondrial Dysfunction and Insulin Resistance;377
11.2.4.4;Mechanisms Explaining Insulin Resistance Following Mitochondrial Dysfunction;377
11.2.4.5;Exercise as a Therapeutic Strategy to Improve Mitochondrial Function and Restore Insulin Sensitivity in Type 2 Diabetes...;379
11.2.4.6;Mitochondria and Cardiac Dysfunction In diabetes;379
11.2.4.7;Overview of Mitochondrial Dysfunction In insulin Insensitivity and Diabetic Cardiomyopathy;381
11.2.5;Aberrant Mitochondrial Bioenergetics in Diabetic Neuropathy;382
11.2.5.1;Recent Evidence for Impaired Mitochondrial Physiology in Neuropathy;382
11.2.5.2;In vitro Imaging Studies of Mitochondrial Inner Membrane Polarization in Axons of Sensory Neurons;382
11.2.5.3;Axons of Diabetic Neurons Exhibit Reduced Superoxide Generation From the Respiratory chain;385
11.2.5.4;Impaired Mitochondrial Function is Linked to nutrient Excess and Downregulation of Amp-activated Protein Kinase Activity...;385
11.2.5.5;Ultrastructural Phenotype of Mitochondria in Neurons and Schwann Cells in Diabetes;386
11.2.6;Conclusions;388
11.2.7;Acknowledgments;389
11.2.8;References;389
11.3;Chapter 26: Mechanisms of Diabetic Neuron Damage: Molecular Pathways;398
11.3.1;Introduction;398
11.3.2;How are Neurons Targeted By Diabetic Polyneuropathy?;398
11.3.3;What Mechanisms Target Neurons?;400
11.3.3.1;Classic Pathways;400
11.3.3.2;Neuronal Molecules and Novel Pathways;401
11.3.3.2.1;Structural Proteins;401
11.3.3.2.2;Plasticity Proteins;402
11.3.3.2.3;Caspase-3 and apoptosis-related Molecules;403
11.3.3.2.4;Repair Molecules;404
11.3.3.2.5;Survival Proteins;406
11.3.3.2.6;Neurotrophic Molecules of the NGF Family;406
11.3.3.2.7;Age-rage;407
11.3.3.2.8;Peptides;407
11.3.3.2.9;Ion Channels;407
11.3.3.2.10;Nitric Oxide Synthase;408
11.3.3.2.11;Other Proteins;409
11.3.3.3;Abnormal Insulin Signaling;409
11.3.3.3.1;Rationale for Examining Insulin;410
11.3.3.3.2;Direct Neuronal Actions of Insulin;410
11.3.3.3.3;Insulin Signaling Pathways;410
11.3.4;Conclusions: Linking Diverse Pathways of Neuropathy Development;411
11.3.5;Acknowledgments;411
11.3.6;References;413
11.4;Chapter 27: Mechanisms of Diabetic Neuropathy: Schwann Cells;420
11.4.1;Introduction;420
11.4.2;Schwann Cell Development;420
11.4.3;Schwann Cell Structure;422
11.4.3.1;Myelinated Fibers;422
11.4.3.2;Unmyelinated Fibers;424
11.4.4;Schwann Cell Function;425
11.4.4.1;Uninjured nerve;425
11.4.4.2;Injured nerve;426
11.4.5;Diabetic Neuropathy;426
11.4.5.1;Myelinated Fibers;426
11.4.5.2;Unmyelinated Fibers;431
11.4.5.3;Blood-nerve Interface;432
11.4.5.4;Endoneurial Connective Tissue;433
11.4.6;Schwann Cells and Pathogenic Mechanisms;434
11.4.6.1;Polyol Pathway;434
11.4.6.2;Oxidative Stress;436
11.4.6.3;Advanced Glycosylation End Products;437
11.4.6.4;Deficient Neurotrophic Support;437
11.4.7;Conclusions;438
11.4.8;References;438
11.5;Chapter 28: Mechanisms of Diabetic Neuropathy: Axon Dysfunction;448
11.5.1;Introduction;448
11.5.2;Structural Changes;448
11.5.3;Underlying Metabolic Mechanisms;450
11.5.3.1;Insulin and Insulin Signaling;452
11.5.3.2;Hyperglycemia;454
11.5.3.2.1;Polyol Pathway and Associated Metabolic Derangements;454
11.5.3.2.2;Nonenzymatic Glycation;455
11.5.3.2.3;Oxidative Stress;455
11.5.3.3;Therapies Related to Axonal Degeneration In diabetic Polyneuropathy;456
11.5.4;Concluding Remarks;457
11.5.5;References;457
11.6;Chapter 29: Mechanisms of Disease: Role of Neurotrophins in Diabetes And diabetic Neuropathy;462
11.6.1;Introduction;462
11.6.2;Neurotrophins: Complexities to consider;462
11.6.3;Neurotrophins and Metabolism: A special Role for brain-derived Neurotrophic factor;464
11.6.3.1;Neurotrophin Impact on Neuroendocrine Regulation of Metabolism: Signals of Satiety and Obesity;464
11.6.3.2;Impact of Diabetes, Obesity, and Insulin Resistance on brain-derived Neurotrophic Factor Abundance;464
11.6.3.3;Hyperglycemia and Neuronal Metabolic demand;465
11.6.3.4;Pancreatic Function: a Neurotrophin/neurogenic Basis for Diabetes?;465
11.6.3.5;Adipose Tissue as a Source of Neurotrophins: Rationale for Neurogenic Regulation in Diabetes;466
11.6.3.6;Neurotrophin Therapy: Impact on Metabolic Processes Associated With Diabetic Neuropathy;466
11.6.3.7;Diabetic Neuropathy in the Brain: Synaptic Dysfunction Associated With Dementia;467
11.6.3.8;Cardiac Neuropathy and Neurotrophin Influences;467
11.6.3.9;Neurotrophins and Diabetic Polyneuropathy: a Focus on Humans;468
11.6.3.10;Skin;468
11.6.3.11;Muscle;469
11.6.3.12;Soluble P75Ntr: Potential Marker of Dn;470
11.6.4;Failure of Human Trials;470
11.6.5;Therapeutic Strategies to Improve Neurotrophin Support;471
11.6.6;Acknowledgments;473
11.6.7;References;473
11.7;Chapter 30: Experimental Motor Neuropathy in Diabetes;480
11.7.1;Introduction;480
11.7.2;Motor Nerve Conduction Velocity in Experimental Models of Diabetic Neuropathy;481
11.7.3;Pathologic Changes in Motor Neurons in Experimental Models;482
11.7.4;Diabetes-induced Effects On skeletal Muscle cells;483
11.7.5;Sensory Dysfunction in Feedback From Muscle;483
11.7.6;Considerations for Improved Models to Study Motor Dysfunction in Diabetes;484
11.7.7;Conclusions;484
11.8;Chapter 31: Ischemia and Diabetic Neuropathy;488
11.8.1;Introduction;488
11.8.2;Experimental Ischemic Neuropathy;488
11.8.2.1;Nerve Blood Supply: Special Anatomy and Physiology of Nerve Microvasculature;488
11.8.2.2;Experimental Ischemic Neuropathy;489
11.8.2.3;Reperfusion Nerve Injury;490
11.8.3;Ischemia and Diabetic nerve;492
11.8.3.1;Resistance to Ischemic Conduction Failure;492
11.8.3.2;Morphologic Susceptibility to Nerve Ischemia;492
11.8.3.3;Physiologic and Morphologic Vulnerability to reperfusion Nerve Injury;494
11.8.4;Ischemia and Endoneurial Hypoxia in Diabetic Polyneuropathy;497
11.8.4.1;Historical Evolution;497
11.8.4.2;Evidence From Diabetic Animals;498
11.8.4.3;Evidence From Humans With Diabetes;499
11.8.4.4;Microangiopathy;499
11.8.4.4.1;Functional Changes of Microvessels;499
11.8.4.4.2;Structural Changes of Microvessels;500
11.8.4.5;Macroangiopathy;500
11.8.5;Ischemia in Other Diabetic Neuropathies;501
11.8.5.1;Mononeuropathy: Third Nerve palsy;501
11.8.5.2;Proximal Neuropathy;501
11.8.5.3;Other Neuropathies in Diabetes;502
11.8.6;References;502
11.9;Chapter 32: Diabetes and Neurodegeneration in The brain;508
11.9.1;Introduction;508
11.9.2;Links Between Alzheimer Disease and Diabetes;509
11.9.3;Alzheimer Disease Pathology And pathophysiology;509
11.9.4;Pathologic Manifestations of Alzheimer Disease And relationships to Diabetic Encephalopathy;509
11.9.5;Diabetic Encephalopathy Pathology and Pathophysiology;509
11.9.6;Clinical Manifestations In diabetic Subjects;513
11.9.6.1;Memory;513
11.9.6.2;Processing speed;515
11.9.6.3;Language;515
11.9.6.4;Visuospatial Construction;515
11.9.6.5;Perception;515
11.9.6.6;Attention and Executive Function;515
11.9.6.7;Summary of Cognitive Findings;515
11.9.6.8;Issues With Studies of Cognition;515
11.9.6.9;When Do Cognitive Findings Develop?;515
11.9.7;Risk Factors for Impaired Cognition and Dementia in Diabetes;516
11.9.7.1;Demographic Factors;516
11.9.7.2;Vascular Risk Factors;516
11.9.7.3;Severity of Type 2 Diabetes;516
11.9.7.4;Genetic Factors;517
11.9.7.5;Other Factors;517
11.9.8;Risk of Dementia With Diabetes;517
11.9.9;Cerebrovascular Disease and Development of Diabetic Encephalopathy;518
11.9.10;The Role of Animal Models In understanding Diabetic Encephalopathy;518
11.9.11;The Role of Brain Imaging In diabetic Encephalopathy;520
11.9.12;Potential Pharmacologic Targets in Diabetic Encephalopathy;521
11.9.13;Summary and Future Directions;522
11.9.14;References;523
11.10;Chapter 33: Neurologic Damage in Hypoglycemia;532
11.10.1;Introduction;532
11.10.1.1;Definition and Symptoms of Hypoglycemia;533
11.10.2;On Hypoglycemia and Central Nervous System Damage;533
11.10.2.1;Observations in Humans;533
11.10.2.1.1;Psychological, Neurophysiologic, and Imaging Observations;533
11.10.2.1.2;Neuropathologic Observations;534
11.10.2.2;Observations in Animals;535
11.10.2.3;Observations In vitro;536
11.10.3;On Hypoglycemia and Peripheral Nervous System Damage;537
11.10.3.1;Observations in Humans;537
11.10.3.1.1;Neurophysiologic Observations;537
11.10.3.1.2;Neuropathologic Observations;537
11.10.3.2;Observations in Animals;538
11.10.3.3;Observations In vitro;540
11.10.4;Possible Cellular Mechanisms of Neurologic Damage in Hypoglycemia;541
11.10.5;Conclusions;543
11.10.6;References;544
11.11;Chapter 34: Painful Neuropathy: Mechanisms;552
11.11.1;Painful Diabetic Neuropathy;552
11.11.2;Animal Models of Painful Diabetic Neuropathy;552
11.11.2.1;Responses to Mechanical Stimulation;553
11.11.2.2;Responses to Thermal Stimulation;554
11.11.2.3;Responses to Chemical Stimulation;554
11.11.2.4;Summary;555
11.11.3;Mechanisms of Painful Diabetic Neuropathy;555
11.11.3.1;Peripheral drive;555
11.11.3.1.1;Neuronal Degeneration/regeneration;556
11.11.3.1.2;Nociceptor Activation;556
11.11.3.1.3;Nociceptor Activity;556
11.11.3.2;Spinal Sensitization;557
11.11.3.2.1;Postsynaptic Receptors;558
11.11.3.2.2;Disinhibition;558
11.11.3.2.3;Inflammation;559
11.11.3.2.4;Glial Cell Activation;560
11.11.3.3;Higher Processing;560
11.11.3.4;Summary;561
11.11.4;Mechanism-targeted Therapies;561
11.11.4.1;Prophylaxis;562
11.11.4.2;Targeting Gain of Function;562
11.11.4.3;Targeting Enhancement of Function;562
11.11.4.4;Targeting Normal Function;562
11.11.4.5;Summary;567
11.11.5;Conclusions and Speculation;567
11.11.6;Acknowledgments;567
11.11.7;References;567
11.12;Chapter 35: Insights Into the Pathogenesis and Treatment of Painful Diabetic neuropathy;578
11.12.1;Introduction;578
11.12.1.1;Painful Diabetic Neuropathy;578
11.12.2;Painful Diabetic Peripheral Neuropathy;578
11.12.2.1;Definition, Epidemiology, and Natural History;578
11.12.2.2;Painful Diabetic Peripheral Neuropathy: Risk factors;579
11.12.2.3;Diagnosis of Painful Diabetic Peripheral Neuropathy;579
11.12.2.4;Complications;580
11.12.2.5;Treatment of Painful Diabetic Peripheral Neuropathy;581
11.12.3;Pathogenesis of Painful Diabetic Peripheral Neuropathy;582
11.12.3.1;Peripheral Nerve Histology in Painful Diabetic Peripheral Neuropathy;582
11.12.3.2;Theories of Neuropathic Pain Generation;582
11.12.3.3;Peripheral Sensitization;582
11.12.3.3.1;Receptor Activation;583
11.12.3.3.2;Sodium and Calcium Channel Expression In neuropathy Leading to Ectopic Excitability;584
11.12.3.3.3;Neurotrophins;584
11.12.3.3.4;Intraepidermal Nerve Fiber Density;585
11.12.3.4;Central Mechanisms;585
11.12.3.5;Central Sensitization;585
11.12.3.6;Spinal Mechanisms of Central Sensitization In painful Diabetic Peripheral Neuropathy;585
11.12.3.6.1;Pronociceptive Facilitation At the Dorsal horn;585
11.12.3.6.2;Loss of Antinociceptive Descending Inhibition;586
11.12.4;Magnetic Resonance Imaging of the Central Nervous System In painful Diabetic Peripheral neuropathy;587
11.12.4.1;Magnetic Resonance Perfusion Imaging;587
11.12.4.1.1;Supporting Evidence for Increased Cerebral Blood Volume in the Thalamus in Painful Diabetic peripheral Neuropathy...;588
11.12.4.2;Blood Oxygen level-dependent (Bold) Functional Magnetic Resonance Imaging;588
11.12.4.3;Magnetic Resonance Spectroscopy in Painful Diabetic Peripheral Neuropathy;589
11.12.4.3.1;Proton Magnetic Resonance Spectroscopy;589
11.12.4.3.2;Proton Magnetic Resonance Spectroscopy In painful Diabetic Neuropathy;589
11.12.4.4;Diffusion Tensor Imaging of the Brain In diabetic Painful Neuropathy;590
11.12.4.5;Anatomical Magnetic Resonance Imaging Scans and Volumetric Analysis;590
11.12.5;Future Role of Neuroimaging in Painful Diabetic Peripheral Neuropathy;591
11.12.6;Conclusion;591
11.12.7;References;591
11.13;Chapter 36: Autonomic neuropathy in experimental models of diabetes mellitus;598
11.13.1;Experimental diabetic autonomic neuropathy;598
11.13.1.1;Central nervous system;598
11.13.1.2;Sympathetic ganglia;598
11.13.1.3;Sympathetic ganglionic heterogeneity in diabetes;600
11.13.1.4;Parasympathetic ganglia;600
11.13.1.5;Peripheral nerves and end organ innervation;601
11.13.1.5.1;Alimentary tract;601
11.13.1.5.1.1;Diabetes-induced alimentary dysfunction;601
11.13.1.5.1.2;Enteric neurons;601
11.13.1.5.1.3;Interstitial cells of Cajal;601
11.13.1.5.1.4;Sympathetic (SNS) innervation;601
11.13.1.5.1.5;Parasympathetic (PaNS) innervation;604
11.13.1.5.1.6;Sensory (DRG-derived) innervation;604
11.13.1.5.1.7;Other;605
11.13.1.5.2;Genitourinary tract;605
11.13.1.5.3;Cardiovascular system;605
11.13.1.5.4;Skin;605
11.13.1.5.5;Miscellaneous;605
11.13.1.6;Pathology overview;608
11.13.2;Proposed pathogenetic mechanisms of diabetic autonomic neuropathy;608
11.13.2.1;Oxidative/nitrosative stress;608
11.13.2.2;The polyol pathway;609
11.13.2.3;Abnormal axonal transport;609
11.13.2.4;Neurotrophic substances;610
11.13.2.4.1;Neurotrophins (NGF and NT-3);610
11.13.2.4.2;Insulin-like growth factors;610
11.13.2.4.3;Glial cell line-derived neurotrophic factor family;610
11.13.2.4.4;Erythropoietin;611
11.13.2.5;Glycation and advanced glycosylation end products;611
11.13.2.6;Mitochondriopathy;611
11.13.2.7;Abnormalities of regeneration and synaptic dysplasia;611
11.13.2.8;Autoimmune mechanisms;611
11.13.2.9;Ischemia;611
11.13.2.10;Synaptic degradation of organelles;612
11.13.2.11;Apoptosis;612
11.13.3;Summary;612
11.13.4;References;612
12;Index;622

Leseproben

Chapter 1

Epidemiology of polyneuropathy in diabetes and prediabetes

Dan Ziegler1,*; Nikolaos Papanas2; Aaron I. Vinik3; Jonathan E. Shaw4    1 Institute for Clinical Diabetology, German Diabetes Center at Heinrich Heine University, Leibniz Center for Diabetes Research; Department of Endocrinology and Diabetology, University Hospital, Düsseldorf, Germany
2 Second Department of Internal Medicine, Democritus University of Thrace, Alexandroupolis, Greece
3 Diabetes Center for Endocrine and Metabolic Disorders and Neuroendocrine Unit, Eastern Virginia Medical School, Norfolk, VA, USA
4 Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia
* Correspondence to: Professor Dan Ziegler, MD, FRCPE, Institute for Clinical Diabetology, German Diabetes Center at Heinrich Heine University, Leibniz Center for Diabetes Research, Auf’m Hennekamp 65, 40225, Düsseldorf, Germany. Tel: + 49-211-33820, Fax: + 49-211-3382244. email address: [e-mail]

Abstract

Diabetic distal symmetric sensorimotor polyneuropathy (DSPN) represents a major health problem, associated with excruciating neuropathic pain, increased morbidity and impaired quality of life. The understanding of its epidemiology is difficult due to methodological issues. Inconsistency in the selection of diagnostic procedures renders comparison between studies problematic. Further problems arise from selection bias due to the inclusion of hospital-based populations. DSPN affects approximately 30% of hospital-based populations, 20% of community-based samples, and 10% of the diabetic population identified by screening. Chronic painful DSPN is present in 13–26% of diabetic patients. Between 25% and 62% of patients with idiopathic peripheral neuropathy have prediabetes. Among pre-diabetic subjects, 11–25% exhibit peripheral neuropathy and 13–26% neuropathic pain. Evidence from population-based studies indicates that there is a gradient in the prevalence of neuropathy. Indeed, the highest frequency is found in patients with manifest diabetes mellitus, followed by individuals with impaired glucose tolerance, then impaired fasting glucose and, finally, those with normoglycemia. The most important etiologic factors are poor glycemic control, age, diabetes duration, visceral obesity, height, hypertension, age, smoking, hypoinsulinemia, and dyslipidemia. Clinic-based data suggest that DSPN is associated with increased mortality in diabetes, but confirmatory prospective population-based studies are required.

Keywords

Complications

diabetes

peripheral neuropathy

prediabetes

Introduction

The epidemiology of a disease primarily describes the frequency with which it occurs, and determines the risk factors associated with it. The former informs the clinician about the likelihood that the patient in front of him or her has the condition, and the public health authorities about the potential overall burden relating to the condition. The latter sheds light on etiologic processes, although the associations described by epidemiologic studies cannot alone be taken as proof of causality.

In order to understand the epidemiology of a disease properly, it is crucial to have well validated diagnostic tests that can be used by a variety of investigators assessing different populations in a similar manner. Furthermore, it is important that the populations studied are representative of the total population being considered, and have not been subjected to significant selection biases. However, the study of the epidemiology of diabetic distal symmetric sensorimotor polyneuropathy has been beset by numerous problems relating both to diagnostic tests and to population selection.

Clinical impact of diabetic distal symmetric sensorimotor polyneuropathy

Diabetic distal symmetric sensorimotor polyneuropathy (DSPN) represents a major health problem as it may present with excruciating neuropathic pain and is responsible for substantial morbidity, resulting from foot ulceration, amputations and impaired quality of life, as well as being associated with increased mortality (Abbott et al., 1998; Forsblom et al., 1998; Galer et al., 2000). Neuropathic pain can cause considerable interference with sleep, daily activities, and enjoyment of life. The neurologic impairment caused by DSPN may lead to functional limitations of walking ability (Resnick et al., 2000). Older patients with DSPN perform worse on tests of walking speed, static and dynamic balance, and coordination than those without DSPN (Resnick et al., 2002; Strotmeyer et al., 2008; Strotmeyer et al., 2009). In women above 85 years, diabetes still contributes to large fiber peripheral nerve dysfunction which is markedly accelerated by age, but no synergistic effect of age and diabetes was observed (Resnick et al., 2001).

There is accumulating evidence suggesting that not only surrogate markers of microangiopathy such as albuminuria but also markers used for DSPN such as nerve conduction velocity (NCV) and vibration perception threshold (VPT) predict mortality in diabetic patients (Forsblom et al., 1998; Coppini et al., 2000). Elevated VPT also predicts the development of neuropathic foot ulceration, one of the most common causes for hospital admission and lower limb amputations among diabetic patients (Abbott et al., 1998). Two recent studies underline the major impact of DSPN on morbidity and mortality. In the DIAD study (Young et al., 2009), both sensory deficits and neuropathic pain were independent predictors of cardiac death or nonfatal myocardial infarction. Self-reported history of neuropathy was a significant predictor for increased mortality in type 2 diabetic subjects allocated to a very intensive diabetes therapy aimed at HbA1c < 6.0% in the ACCORD trial (Calles-Escandón et al., 2010).

Testing for peripheral neuropathy

DSPN is a symmetric, length-dependent sensorimotor polyneuropathy attributable to metabolic and microvessel alterations as a result of chronic hyperglycemia exposure and associated cardiovascular risk factors (Tesfaye et al., 2010). DSPN is a complex disorder, in which the disease process may affect different sets of nerve fibers to different degrees in different individuals. Thus, one individual may have an abnormality of large fiber sensory function, which could be detected by measuring the vibration perception threshold (VPT), while another may have a predominantly small fiber neuropathy that can only be detected by measuring the thermal perception threshold (TPT). This feature of neuropathy can be problematic in selecting a single test with which to screen a population. The issue of measurement of neurologic function is further complicated by the nature of the tests. Many are psychophysical tests, in which the subject is required to interpret the nature of an external stimulus (usually applied to the foot). This subjectivity can lead to relatively poor reproducibility of tests such as VPT, in which the subject has to differentiate light touch from vibratory sensation.

This lack of certainty over the value of individual tests for the assessment of diabetic neuropathy has led to recommendations that several different tests should be performed, and that diabetic neuropathy should only be diagnosed when more than one is abnormal (Consensus Statement, 1988). While this may make the diagnostic process more rigorous in any individual or in an individual study, it can make comparisons between studies more difficult. Such recommendations have been only patchily adopted, and where they have been put into practice, the selection of tests has not been uniform. Thus, we are faced with having to compare the prevalence when neuropathy is determined by a single test with a prevalence when neuropathy is diagnosed when any two out of perhaps three to five tests are abnormal. Increasing the number of tests that are performed will automatically increase the number of individuals in whom an abnormality is found, while requiring that more than one abnormality is present will then tend to decrease the prevalence. The overall effect is thus complex. The impact of varying the diagnostic testing procedure is exemplified by the Diabetes Control and Complications Trial (DCCT) data, where the prevalence of DSPN at baseline in the standard therapy cohort varied from 0.3% (abnormalities of reflexes, sensory examination and neuropathic symptoms) to 21.8% (abnormal nerve conduction in at least two nerves) (Diabetes Control and Complications Trial Group, 1995). Confirmed clinical neuropathy (abnormal history or examination, confirmed by abnormal nerve conduction or autonomic function) was the gold standard for the study, and was found in 2.1% of this cohort. This 73-fold difference in the prevalence of DSPN, between the two extremes, but within a single population, highlights the difficulties of comparing studies with differing diagnostic criteria.

The influence of test selection on the understanding of etiologic factors associated with neuropathy is likely to be considerably smaller than that on prevalence. As long as each diagnostic process is indeed measuring some aspect (or aspects) of neuropathy, it is likely that those who are rated as having neuropathy are genuinely more severely affected than those who are not so rated. Thus, associations with factors such as age...