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
Front Cover 1
Diabetes and the Nervous System 4
Copyright 5
Handbook of Clinical Neurology 3rd Series 6
Foreword 8
Preface 10
Contributors 12
Contents 16
Section 1: Clinical Impact of Diabetes on the Nervous System 20
Chapter 1: Epidemiology of Polyneuropathy in Diabetes and Prediabetes 22
Introduction 22
Clinical Impact of Diabetic Distal Symmetric Sensorimotor Polyneuropathy 22
Testing for Peripheral Neuropathy 23
Painful Neuropathy 24
Population Selection 24
Prevalence in Diabetes 26
Prevalence in Prediabetes 27
Impaired Fasting Glucose or Impaired Glucose Tolerance to Diagnose Prediabetes? 27
Neuropathy in People With Prediabetes 28
Incidence and Natural History of diabetic Polyneuropathy 31
Etiologic Factors Related to diabetic Neuropathy 32
Hyperglycemia 32
Role of Intensive Diabetes Therapy in Prevention and Progression of Diabetic Neuropathy 33
Diabetes Duration 34
Age 34
Height 34
Hypoinsulinemia 35
Cardiovascular Risk Factors 35
Hypertension 35
Lipids 35
Obesity 35
Smoking 36
Alcohol Consumption 36
Depression 36
Genetic Factors 36
Conclusions 36
Chapter 2: Clinical Features of Diabetic Polyneuropathy 42
Early Studies of the Clinical Features of Diabetic Polyneuropathy 42
Symptoms of Diabetic Polyneuropathy 43
Clinical Signs of Diabetic Polyneuropathy 45
Abbreviated Forms of Assessment 47
Subtypes of Diabetic Polyneuropathy 47
Distinguishing Diabetic Polyneuropathy From Other Polyneuropathies 48
Conclusions 49
References 49
Chapter 3: Focal and Entrapment Neuropathies 50
Introduction 50
Cranial Mononeuropathies 50
Oculomotor, Trochlear, and Abducens Neuropathies 50
Anatomy and Pathophysiology 50
Literature and Epidemiology 51
Clinical Presentation 51
Laboratory/radiology Findings 52
Differential Diagnosis 52
Management and Prognosis 52
Facial Neuropathy 52
Anatomy and Pathophysiology 52
Literature and Epidemiology 53
Clinical Presentation 53
Laboratory/radiology Findings 53
Differential Diagnosis 53
Management and Prognosis 53
Malignant Cranial Nerve Syndromes 54
Rhinocerebral Mucormycosis 54
Malignant Otitis Externa 54
Other Cranial Nerve Syndromes 55
Upper Limb Mononeuropathies 55
Median Neuropathies: Carpal Tunnel Syndrome 55
Anatomy and Pathophysiology 55
Literature and Epidemiology 55
Clinical Presentation/differential Diagnosis 56
Laboratory/radiology Findings 56
Management 56
Ulnar Neuropathies: Ulnar Neuropathy At the elbow 56
Other Upper Limb Mononeuropathies 57
Truncal Mononeuropathies 57
Thoracic Monoradiculopathy 57
Phrenic Mononeuropathy 58
Lower Limb Mononeuropathies 58
Lateral Femoral Cutaneous Neuropathy 58
Fibular (peroneal) Mononeuropathy 58
Other Lower Limb Mononeuropathies 59
Conclusion 59
References 59
Chapter 4: Diabetic Radiculoplexus Neuropathies 64
Introduction 64
Clinical Features of the Diabetic Radiculoplexus Neuropathies 64
Epidemiology 67
Etiology and Pathogenesis 67
Treatment 68
Conclusion 70
References 70
Chapter 5: Painful Diabetic Neuropathy: Clinical Aspects 72
Introduction 72
Epidemiology of Painful Diabetic neuropathy 72
Pathogenesis of Neuropathic pain 73
Early Diagnosis and Intervention in Painful Neuropathy 74
Symptoms and Signs of Painful Diabetic Neuropathy 75
Acute Painful Neuropathies 76
Acute Painful Neuropathy of Poor Glycemic control 76
Acute Painful Neuropathy of Rapid Glycemic control 77
Natural History of Painful Diabetic Neuropathy 77
Neuropathic Pain Assessment 77
Differential Diagnosis of painful neuropathy 78
Diabetic Painful Neuropathy And autonomic Dysfunction 78
Conclusions 78
Acknowledgments 78
References 78
Chapter 6: Diabetic Autonomic Neuropathy 82
Introduction 82
Generalized Autonomic Neuropathy 82
Prevalence 82
Cardiovascular Autonomic Neuropathy 82
Gastrointestinal Autonomic Neuropathy 83
Urogenital 84
Bladder 84
Sexual Function 85
Sudomotor 85
Autonomic Neuropathy and Prediabetes 86
Background 86
Clinical Phenotype 86
Treatment-induced Neuropathy 87
Background 87
Clinical Features 87
Concomitant Features 88
Mechanisms 89
Pathology 89
Related Conditions 89
Hypoglycemia-associated Transient Autonomic Dysfunction 89
Background 89
Hypoglycemia and Glucose Counterregulation 90
Hypoglycemia-associated Autonomic Failure 90
Hypoglycemia and Cardiovascular Autonomic Function 90
Hypoglycemia and the Qt Interval 91
References 92
Chapter 7: Motor Neuropathy 100
Introduction 100
Motor Nerve Dysfunction 101
Electroneuronography 101
Electromyography 101
Muscle Strength 101
Evaluation of Muscle Strength 101
Muscle Strength in Healthy Subjects 102
Muscle Strength in Diabetes 104
Training 105
Muscular Atrophy 106
Muscle Energy Properties 109
Muscle Strength, Balance, Gait, and falls 109
Conclusions 111
References 111
Chapter 8: Diabetic Neuropathy and Foot Complications 116
Introduction 116
Historical Aspects of Diabetic Neuropathy and Foot Complications 116
Background: the Diabetic foot 117
Epidemiology and Health Economics of Diabetic Foot Problems 117
Neuropathy and Foot Ulceration 118
Chronic Sensorimotor Diabetic Peripheral Neuropathy 118
Clinical Presentation of Chronic Sensorimotor neuropathy 119
Assessment of Diabetic Peripheral Neuropathy 119
Symptoms 119
Signs 119
Simple Devices for Clinical Screening 119
Does the Presence of Diabetic Peripheral Neuropathy Increase the Risk of Ulceration? 120
Peripheral Sympathetic Autonomic Neuropathy 120
Other Risk Factors for Diabetic Foot Ulceration 121
The Pathway to Foot Ulceration in Diabetes 122
The Patient With Sensory loss 122
Principles of Management of Neuropathic Foot Ulcers 123
Charcot Neuroarthropathy (Cn) 124
Conclusions 124
References 125
Chapter 9: Glucose Intolerance, Metabolic Syndrome, and Neuropathy 128
Introduction 128
Hypotheses and Pathophysiology 128
Hyperglycemia-induced Nerve Injury 128
Pathophysiology Involved in Metabolic Syndrome 129
Definition and Prevalence of metabolic Syndrome 130
Impaired Glucose Tolerance and Impaired Fasting Glucose 130
Epidemiology 130
Association of Impaired Glucose Tolerance With Neuropathy 131
Obesity and Dyslipidemia 131
Clinical Presentation of Impaired Glucose Tolerance and Metabolic syndrome-associated Neuropathy 132
Laboratory Testing for Glucose Dysmetabolism 132
Overview of Ancillary Testing 133
Outcomes and Prognosis 134
Management and Treatment 134
Glucose Control 134
Lifestyle Interventions 134
Evidence-based Recommendations 136
Future Directions 136
More Robust Epidemiology 136
Focus on Earlier Diagnosis 137
Measuring Nerve Regeneration 137
Basic Mechanisms and Targeted Therapy 138
References 138
Chapter 10: Diabetic Neuropathy in Children 142
Background 142
Definition 142
Prevalence of Diabetic Neuropathy in Children 143
Pathogenesis of Diabetic Neuropathy 143
Diagnosis of Pediatric Diabetic Neuropathy 143
Clinical Assessment 143
Staging of Diabetic Neuropathy 151
Nerve Conduction study 151
Quantitative Sensory Testing 152
Autonomic Function test 153
Risk Factors for Pediatric Diabetic Neuropathy 154
Nonmodifiable Risk Factors 154
Modifiable Risk Factors 154
Treatment of Symptomatic Pediatric Diabetic Neuropathy 155
Effects of Cointervention 155
Screening for Other Diabetic Complications 156
Psychosocial Issues Related to pediatric Diabetes 156
Conclusion 156
References 157
Chapter 11: Cognitive disorders in diabetic patients 164
Introduction 164
Evaluation of cognitive functioning 164
History taking 164
Cognitive domains and neuropsychological tests 164
Screening for cognitive impairment 165
Quantification and interpretation of test results 165
Stages of cognitive dysfunction 166
Cognitive functioning in type 1 diabetes 166
Cross-sectional studies 166
Longitudinal studies 166
Cognitive functioning in type 2 diabetes 167
Modest cognitive decrements 167
Cross-sectional studies 167
Longitudinal studies 167
Dementia 167
Cognitive trajectories in type 2 diabetes 171
Cognitive functioning in prediabetic stages 171
Consequences of cognitive dysfunction in diabetes 171
Mood disorders in diabetes 172
Brain MRI studies 172
Structural abnormalities associated with cognitive functioning 172
Quantification of abnormalities 172
New MRI techniques 173
Type 1 diabetes 173
Type 2 diabetes 174
Determinants and mechanisms 174
Type 1 diabetes 174
Demographic and lifestyle factors 174
Diabetes-specific factors 174
Vascular risk factors 175
Diabetic complications 175
Genetic factors 175
Type 2 diabetes 175
Demographic and lifestyle factors 175
Hypo- and hyperglycemia 175
Vascular risk factors 176
Diabetic complications 176
Genetic factors 176
Underlying mechanisms 176
Treatment of cognitive dysfunction 177
Lifestyle factors: diet and physical activity 177
Glycemic control 177
Vascular risk factors 178
Practical implications 178
References 179
Chapter 12: Stroke and Diabetes Mellitus 186
Introductory Concepts 186
Clinical Features 186
Causes: Stroke Mechanism 187
Ischemic Stroke 187
Subarachnoid Hemorrhage 189
Intracerebral Hemorrhage 189
Epidemiology and Risk Factors 189
Acute Stroke: Special Considerations in Diabetic Patients 189
Stroke Prevention: Special Considerations in Diabetic Patients 190
Conclusions 192
References 192
Chapter 13: Neurologic Infections in Diabetes Mellitus 194
Introduction 194
Viruses 195
Herpes zoster 195
West Nile Neuroinvasive Disease 196
Bacteria 197
Hyperglycemia and Hypoglycorrhachia In bacterial Meningitis 197
Neurolisteriosis 197
Malignant External Otitis 198
Pyogenic Spine Infections: Epidural Abscess and Vertebral Osteomyelitis 199
Pyomyositis 201
Diabetic Foot Infections and Charcot Neuroarthropathy 202
Fungi 203
Molds: Mucormycosis, Aspergillosis, Scedosporiosis 203
Dimorphic Fungi: Blastomycosis 205
Yeasts: Candidiasis and Cryptococcosis 207
Parasitic Infections in the Pathogenesis of Diabetes Mellitus 207
Protozoans 207
Helminths 207
Summary 208
References 208
Chapter 14: Recognition and Management of Psychosocial Issues in Diabetic Neuropathy 214
Introduction 214
The Burden of Painful Diabetic Neuropathy 214
Emotional Side of the Diabetic Neuropathy Experience 215
The Role of Diabetic Neuropathy and Its Symptoms in Generating Depression 215
Differential Effects of Diabetic Neuropathy Symptoms on Anxiety Versus Depression 216
The Role of Psychological Factors in Shaping Pain Experience 217
Psychosocial Interventions for Diabetic Neuropathy Symptom Management 218
Painful Diabetic Neuropathy 218
Postural Instability 219
The Case for an Integrated Biopsychosocial Approach to Diabetic Neuropathy Symptom Management 219
Measuring Quality of Life in Diabetic Neuropathy: Generic, Specific, or Combined Approach? 220
Limitations of the Generic Quality of Life Instruments 220
The Shift From Generic to Diabetic neuropathy-specific Quality of Life Assessment 221
The Role of Psychosocial and Behavioral Factors in Diabetic Foot Ulcer Prevention 221
Depression Versus Diabetic Foot ulceration-specific Emotional Distress and Foot self-care 222
Patient Cognitive and Emotional Representations of Diabetic Foot Ulcer Risk And foot self-care 222
The Role of Psychosocial and Behavioral Factors in Diabetic Foot Ulcer Healing 223
Concluding Remarks 224
Acknowledgments 225
References 225
Chapter 15: General Aspects of Diabetes Mellitus 230
Diagnosis of Diabetes 230
Classification of Diabetes 231
Diabetes types 232
Screening for Diabetes 233
The Diabetic History 233
The Diabetic Physical Examination 233
Glycemic goals 233
Diabetes Pharmacotherapy 233
Management Outline in Newly Diagnosed Type 2 Diabetes Mellitus: an Algorithm 233
Oral Hypoglycemic Agents and Insulin In type 2 Diabetes Mellitus 233
Insulin in Type 2 Diabetes Mellitus 234
Insulin in Type 1 Diabetes Mellitus 235
Insulin Pumps (continuous Subcutaneous Insulin Infusion) 237
Corticosteroids and Diabetes Management 237
Diabetes Control of Inpatients 238
Critically Ill Patients 239
Noncritically Ill Patients 239
Cerebral Infarction and Glycemic Control 239
Enteral and Parenteral Nutrition and Glycemic Control 239
Acknowledgments 240
References 240
Chapter 16: Sexual Dysfunction in Diabetes 242
Introduction 242
Sexual Dysfunction In diabetic women 242
Sexual Dysfunction In diabetic men 242
Erectile Dysfunction 243
Definition 243
Prevalence of Erectile Dysfunction in Diabetes 243
Pathophysiology of Erectile Dysfunction In diabetes 243
Diagnosis of Erectile Dysfunction 244
Treatment of Erectile Dysfunction in Diabetic Patients 244
First-line Therapy 245
Pde-5 Inhibitors 246
Second-line Therapy 248
Third-line Therapy 248
References 249
Section 2: Diagnostic and Therapeutic Approaches to diabetic neurological Complications 252
Chapter 17: Electrophysiologic Testing in Diabetic Neuropathy 254
Electrophysiologic Studies: Background 254
Introduction to Electrophysiology 254
Methodology 254
Nerves Tested for Polyneuropathy 254
Electromyography 256
Results of Nerve Conduction Studies 257
Advantages of Nerve Conduction Studies 258
Limitations of Nerve Conduction Studies In diabetes 259
Large Fiber Measure 259
Accuracy 259
Small Nerve Fiber Measures 260
Rationale for Electrophysiologic Studies 261
Diagnosis of Axonal Versus Demyelinating Polyneuropathy 261
Follow Response to Therapy or Disease Progression 261
Changes in Electrophysiologic Studies in Diabetes 261
Impaired Glucose Tolerance 261
Diabetes 262
What is the Role of electrophysiologic Studies In diabetes? 262
Diagnosis 262
Staging 263
Monitoring 263
Prognosis 263
Summary 264
References 264
Chapter 18: Pathology of Human Diabetic Neuropathy 268
Introduction 268
Nerve Biopsy 268
Myelinated Fibers 268
Density 268
Axonal Atrophy 270
Axoglial Dysjunction 271
Unmyelinated Fibers 272
Microvessels 273
Extracellular Matrix 273
Neuropathology in Variants of Diabetic Neuropathy 274
Skin Biopsy 275
Sudomotor Innervation 275
Motor Abnormalities 275
References 276
Chapter 19: Epidermal Innervation in Diabetes 280
Introduction 280
An Overview of Skin Innervation 280
Skin Biopsy Technique and Methodology 282
Selection of Biopsy Site and Processing Technique 282
Skin Blister Technique 283
Cutaneous Nerve Injury Models 283
Chemical Axotomy 283
Tissue Processing for Immunohistochemistry and Immunofluorescence 283
Quantitation of Epidermal Fibers 285
Normative Epidermal Nerve Fiber data 285
Skin Biopsy as a Diagnostic Test in Small Fiber Sensory Neuropathies 285
Evaluation of Epidermal Fibers In diabetic Neuropathy 285
Skin Biopsy as a Marker for Early Diabetic Neuropathy 286
Skin Biopsy as a Biomarker of neuropathic pain 287
Morphologic Features of epidermal Nerve Fibers 287
Epidermal Innervation in Clinical Trials 288
Cutaneous Autonomic Nerve Fiber Innervation in Diabetes 288
Regeneration of Epidermal Nerve Fibers in Diabetic Neuropathy 289
References 290
Chapter 20: Clinical and Diagnostic Features of Small Fiber Damage in Diabetic Polyneuropathy 294
Introduction 294
Clinical Features 294
Diagnostic Criteria 295
Differential Diagnosis 296
Diagnostic tests 297
Quantitative Sensory Testing 297
Pain-related Evoked Potentials 298
Nerve Axon Reflex/flare Response 298
Nerve Biopsy 298
Skin Biopsy 299
Diagnostic Yield of Intraepidermal Nerve Fiber Quantification 299
Diabetic Neuropathy 300
Corneal Confocal Microscopy 302
Sudomotor Dysfunction 303
Sympathetic Skin Response 303
QSART 303
Thermoregulatory Sweat test 303
Neuropad 303
Sudomotor Innervation 304
Conclusion 304
References 304
Chapter 21: Central Nervous System Imaging in Diabetic Cerebrovascular Diseases and White Matter Hyperintensities 310
Introduction 310
Stroke in Patients With Diabetes Mellitus 310
Neuroimaging of the Acute Stroke Syndrome in Diabetes 311
Acute Ischemic Stroke Pathophysiology Pertaining to Imaging 311
Goals of Imaging in Acute Diabetic Cerebrovascular Disease 312
Computed tomography-based Neuroimaging in Acute Stroke 312
Noncontrast Computed Tomography 312
Ct Angiography 312
Ct Perfusion Imaging 314
Multimodal Magnetic Resonance Imaging In acute Stroke 314
Diffusion-weighted Imaging and Apparent Diffusion Coefficient 315
T2-weighted and fluid-attenuated Inversion Recovery Imaging 315
Magnetic Resonance Perfusion Imaging 315
Perfusion Imaging/diffusion-weighted Imaging Mismatch Concept 316
Magnetic Resonance Angiography 316
Use of Transcranial Doppler in Acute Stroke 317
Imaging Techniques in Patients With Diabetes mellitus-related Chronic Cerebrovascular Disorders 317
Imaging Large Artery Abnormalities In patients With Diabetes Mellitus 317
Utility of Carotid Doppler 317
Magnetic Resonance Imaging of Vulnerable Carotid Plaques in Diabetes Mellitus 319
Imaging Small Vessel Abnormalities In diabetes Mellitus 319
Use of Transcranial Doppler in Diabetic Patients With Chronic Cerebrovascular Disease 319
Imaging Diabetes Mellitus Patients With Cognition, Gait, and Mood Disorders 320
Diabetes as Risk Factor and Pathophysiology of lacunar Infarctions 320
Imaging Lacunar Infarction 320
Imaging Cerebral Atrophy Associated With diabetes Mellitus 321
Use of Magnetic Resonance Imaging to measure Cerebral Atrophy 321
Measuring Localized or Focal Brain Volumes 321
Measuring Total Brain Volumes 321
Use of Imaging in Diabetes Mellitus to Assess Brain Metabolism 322
Magnetic Resonance Spectroscopy 322
White Matter Hyperintensities in Patients With Diabetes Mellitus 322
Magnetic Resonance Imaging of White Matter Hyperintensities 324
Quantitative and Qualitative Analysis of White Matter Hyperintensities 324
Emerging Neuroimaging Techniques That could Be Applied to Diabetes Mellitus to measure White Matter Integrity 325
Magnetization Transfer ratio 325
Diffuse Tensor Imaging 326
Conclusions 327
References 328
Chapter 22: Therapy for Diabetic Neuropathy: an Overview 336
Introduction 336
Treatment Strategies for Preventing Neuropathy 336
Glycemic Control 336
Symptomatic Treatment Strategies 336
Diabetic Polyneuropathy 336
Neuropathic pain 336
Diagnosis of Diabetic Painful Neuropathy 337
Pharmacotherapies for Painful Diabetic Neuropathies 337
Antidepressants 337
Antiepileptics 339
Opiods 340
Tramadol 341
Nonsteroidal Antiinflammatory drugs 341
N-methyl-d-aspartate Antagonists (Nmda Antagonists) 341
Topical Agents 341
Botulinum toxin 342
Electrical Nerve Stimulation and Acupuncture 342
Foot care 342
Overview of Adverse Effects, Drug Interactions, and Recommendations for Patients With Impaired Renal and Hepatic Function... 343
Serotonin Syndrome 343
Risk of Gastrointestinal Bleeding 343
Cardiovascular Considerations 343
Renal Impairment 343
Hepatic Impairment 343
Diabetic Autonomic Neuropathy 344
New Treatment Strategies 345
Polyol Pathway: Aldose Reductase Inhibitors 345
Sorbinil 345
Epalrestat, Ranirestat, and Fidarestat 346
Hexosamine Pathway 346
Benfotiamine 346
Receptor for Advanced Glycation End Products (Rage) Pathway 346
Poly (Adp-ribose) Polymerase Inhibitors 347
Antioxidants 347
Angiotensin-converting Enzyme Inhibitors and Angiotensin Ii Receptor Antagonists 347
Mapk-inhibitors 348
Summary 348
References 349
Chapter 23: Methodology for Conduct of Epidemiologic Surveys and Randomized Controlled Trials of Diabetic Polyneuropathy 354
Reasons Why Epidemiologic Surveys and Randomized Controlled Clinical Trials of diabetic Polyneuropathy Are difficult... 354
Choice of Neuropathy End Points 355
Single Versus Composite Outcome Measurements in Epidemiologic Surveys or Randomized Controlled Trials 355
Reference Values of Neurophysiologic End Points 356
Proficiency and Neurophysiologic Test and Clinical Assessment 356
References 356
Section 3: Fundamental Studies of Diabetic Neuroscience 358
Chapter 24: Neuroscience of Glucose Homeostasis 360
Introduction 360
Daily Rhythm in Plasma Glucose Concentrations 360
The Role of the Hypothalamic Output to the Autonomic Nervous System in the 24 hour Rhythm in Plasma Glucose Concentrations... 363
Brain Areas and Neuropeptides Important for Glucose Metabolism 364
Arcuate Nucleus 364
Lateral Hypothalamus 365
Ventromedial Hypothalamus 365
Central Nervous System Control of Hormones Influencing Glucose Metabolism 366
References 368
Chapter 25: Mechanisms of Disease: Mitochondrial Dysfunction in Sensory Neuropathy and Other Complications in Diabetes 372
Overview of Diabetic Neuropathy 372
Epidemiology and Clinical Signature of diabetic Neuropathy 372
Pathophysiologic Appearance of Diabetic Neuropathy 372
Role of Oxidative Stress in Neurodegeneration in Diabetes 373
Oxidative Stress as an Etiologic Factor In diabetic Neuropathy 373
Aberrant Mitochondrial Function and Generation of Oxidative Stress in Diabetes 373
Adult Sensory Neurons Exhibit Alternative Responses to High Glucose Compared With Endothelial Cells and Embryonic Neurons... 373
Calcium Dysfunction in Diabetic Neuropathy 374
Aberrant Ca2+ Homeostasis and Mitochondrial Dysfunction 374
Mitochondrial Bioenergetics and Ros Generation: Role of [Ca2+]m 375
Impaired Mitochondrial Function in Pathogenesis of Type 2 Diabetes and Other Complications 376
Mitochondrial Dysfunction as a Determinant of Type 2 Diabetes in Humans 376
Mitochondrial Function and Insulin Resistance in Humans 376
Experimental Evidence Linking Mitochondrial Dysfunction and Insulin Resistance 377
Mechanisms Explaining Insulin Resistance Following Mitochondrial Dysfunction 377
Exercise as a Therapeutic Strategy to Improve Mitochondrial Function and Restore Insulin Sensitivity in Type 2 Diabetes... 379
Mitochondria and Cardiac Dysfunction In diabetes 379
Overview of Mitochondrial Dysfunction In insulin Insensitivity and Diabetic Cardiomyopathy 381
Aberrant Mitochondrial Bioenergetics in Diabetic Neuropathy 382
Recent Evidence for Impaired Mitochondrial Physiology in Neuropathy 382
In vitro Imaging Studies of Mitochondrial Inner Membrane Polarization in Axons of Sensory Neurons 382
Axons of Diabetic Neurons Exhibit Reduced Superoxide Generation From the Respiratory chain 385
Impaired Mitochondrial Function is Linked to nutrient Excess and Downregulation of Amp-activated Protein Kinase Activity... 385
Ultrastructural Phenotype of Mitochondria in Neurons and Schwann Cells in Diabetes 386
Conclusions 388
Acknowledgments 389
References 389
Chapter 26: Mechanisms of Diabetic Neuron Damage: Molecular Pathways 398
Introduction 398
How are Neurons Targeted By Diabetic Polyneuropathy? 398
What Mechanisms Target Neurons? 400
Classic Pathways 400
Neuronal Molecules and Novel Pathways 401
Structural Proteins 401
Plasticity Proteins 402
Caspase-3 and apoptosis-related Molecules 403
Repair Molecules 404
Survival Proteins 406
Neurotrophic Molecules of the NGF Family 406
Age-rage 407
Peptides 407
Ion Channels 407
Nitric Oxide Synthase 408
Other Proteins 409
Abnormal Insulin Signaling 409
Rationale for Examining Insulin 410
Direct Neuronal Actions of Insulin 410
Insulin Signaling Pathways 410
Conclusions: Linking Diverse Pathways of Neuropathy Development 411
Acknowledgments 411
References 413
Chapter 27: Mechanisms of Diabetic Neuropathy: Schwann Cells 420
Introduction 420
Schwann Cell Development 420
Schwann Cell Structure 422
Myelinated Fibers 422
Unmyelinated Fibers 424
Schwann Cell Function 425
Uninjured nerve 425
Injured nerve 426
Diabetic Neuropathy 426
Myelinated Fibers 426
Unmyelinated Fibers 431
Blood-nerve Interface 432
Endoneurial Connective Tissue 433
Schwann Cells and Pathogenic Mechanisms 434
Polyol Pathway 434
Oxidative Stress 436
Advanced Glycosylation End Products 437
Deficient Neurotrophic Support 437
Conclusions 438
References 438
Chapter 28: Mechanisms of Diabetic Neuropathy: Axon Dysfunction 448
Introduction 448
Structural Changes 448
Underlying Metabolic Mechanisms 450
Insulin and Insulin Signaling 452
Hyperglycemia 454
Polyol Pathway and Associated Metabolic Derangements 454
Nonenzymatic Glycation 455
Oxidative Stress 455
Therapies Related to Axonal Degeneration In diabetic Polyneuropathy 456
Concluding Remarks 457
References 457
Chapter 29: Mechanisms of Disease: Role of Neurotrophins in Diabetes And diabetic Neuropathy 462
Introduction 462
Neurotrophins: Complexities to consider 462
Neurotrophins and Metabolism: A special Role for brain-derived Neurotrophic factor 464
Neurotrophin Impact on Neuroendocrine Regulation of Metabolism: Signals of Satiety and Obesity 464
Impact of Diabetes, Obesity, and Insulin Resistance on brain-derived Neurotrophic Factor Abundance 464
Hyperglycemia and Neuronal Metabolic demand 465
Pancreatic Function: a Neurotrophin/neurogenic Basis for Diabetes? 465
Adipose Tissue as a Source of Neurotrophins: Rationale for Neurogenic Regulation in Diabetes 466
Neurotrophin Therapy: Impact on Metabolic Processes Associated With Diabetic Neuropathy 466
Diabetic Neuropathy in the Brain: Synaptic Dysfunction Associated With Dementia 467
Cardiac Neuropathy and Neurotrophin Influences 467
Neurotrophins and Diabetic Polyneuropathy: a Focus on Humans 468
Skin 468
Muscle 469
Soluble P75Ntr: Potential Marker of Dn 470
Failure of Human Trials 470
Therapeutic Strategies to Improve Neurotrophin Support 471
Acknowledgments 473
References 473
Chapter 30: Experimental Motor Neuropathy in Diabetes 480
Introduction 480
Motor Nerve Conduction Velocity in Experimental Models of Diabetic Neuropathy 481
Pathologic Changes in Motor Neurons in Experimental Models 482
Diabetes-induced Effects On skeletal Muscle cells 483
Sensory Dysfunction in Feedback From Muscle 483
Considerations for Improved Models to Study Motor Dysfunction in Diabetes 484
Conclusions 484
Chapter 31: Ischemia and Diabetic Neuropathy 488
Introduction 488
Experimental Ischemic Neuropathy 488
Nerve Blood Supply: Special Anatomy and Physiology of Nerve Microvasculature 488
Experimental Ischemic Neuropathy 489
Reperfusion Nerve Injury 490
Ischemia and Diabetic nerve 492
Resistance to Ischemic Conduction Failure 492
Morphologic Susceptibility to Nerve Ischemia 492
Physiologic and Morphologic Vulnerability to reperfusion Nerve Injury 494
Ischemia and Endoneurial Hypoxia in Diabetic Polyneuropathy 497
Historical Evolution 497
Evidence From Diabetic Animals 498
Evidence From Humans With Diabetes 499
Microangiopathy 499
Functional Changes of Microvessels 499
Structural Changes of Microvessels 500
Macroangiopathy 500
Ischemia in Other Diabetic Neuropathies 501
Mononeuropathy: Third Nerve palsy 501
Proximal Neuropathy 501
Other Neuropathies in Diabetes 502
References 502
Chapter 32: Diabetes and Neurodegeneration in The brain 508
Introduction 508
Links Between Alzheimer Disease and Diabetes 509
Alzheimer Disease Pathology And pathophysiology 509
Pathologic Manifestations of Alzheimer Disease And relationships to Diabetic Encephalopathy 509
Diabetic Encephalopathy Pathology and Pathophysiology 509
Clinical Manifestations In diabetic Subjects 513
Memory 513
Processing speed 515
Language 515
Visuospatial Construction 515
Perception 515
Attention and Executive Function 515
Summary of Cognitive Findings 515
Issues With Studies of Cognition 515
When Do Cognitive Findings Develop? 515
Risk Factors for Impaired Cognition and Dementia in Diabetes 516
Demographic Factors 516
Vascular Risk Factors 516
Severity of Type 2 Diabetes 516
Genetic Factors 517
Other Factors 517
Risk of Dementia With Diabetes 517
Cerebrovascular Disease and Development of Diabetic Encephalopathy 518
The Role of Animal Models In understanding Diabetic Encephalopathy 518
The Role of Brain Imaging In diabetic Encephalopathy 520
Potential Pharmacologic Targets in Diabetic Encephalopathy 521
Summary and Future Directions 522
References 523
Chapter 33: Neurologic Damage in Hypoglycemia 532
Introduction 532
Definition and Symptoms of Hypoglycemia 533
On Hypoglycemia and Central Nervous System Damage 533
Observations in Humans 533
Psychological, Neurophysiologic, and Imaging Observations 533
Neuropathologic Observations 534
Observations in Animals 535
Observations In vitro 536
On Hypoglycemia and Peripheral Nervous System Damage 537
Observations in Humans 537
Neurophysiologic Observations 537
Neuropathologic Observations 537
Observations in Animals 538
Observations In vitro 540
Possible Cellular Mechanisms of Neurologic Damage in Hypoglycemia 541
Conclusions 543
References 544
Chapter 34: Painful Neuropathy: Mechanisms 552
Painful Diabetic Neuropathy 552
Animal Models of Painful Diabetic Neuropathy 552
Responses to Mechanical Stimulation 553
Responses to Thermal Stimulation 554
Responses to Chemical Stimulation 554
Summary 555
Mechanisms of Painful Diabetic Neuropathy 555
Peripheral drive 555
Neuronal Degeneration/regeneration 556
Nociceptor Activation 556
Nociceptor Activity 556
Spinal Sensitization 557
Postsynaptic Receptors 558
Disinhibition 558
Inflammation 559
Glial Cell Activation 560
Higher Processing 560
Summary 561
Mechanism-targeted Therapies 561
Prophylaxis 562
Targeting Gain of Function 562
Targeting Enhancement of Function 562
Targeting Normal Function 562
Summary 567
Conclusions and Speculation 567
Acknowledgments 567
References 567
Chapter 35: Insights Into the Pathogenesis and Treatment of Painful Diabetic neuropathy 578
Introduction 578
Painful Diabetic Neuropathy 578
Painful Diabetic Peripheral Neuropathy 578
Definition, Epidemiology, and Natural History 578
Painful Diabetic Peripheral Neuropathy: Risk factors 579
Diagnosis of Painful Diabetic Peripheral Neuropathy 579
Complications 580
Treatment of Painful Diabetic Peripheral Neuropathy 581
Pathogenesis of Painful Diabetic Peripheral Neuropathy 582
Peripheral Nerve Histology in Painful Diabetic Peripheral Neuropathy 582
Theories of Neuropathic Pain Generation 582
Peripheral Sensitization 582
Receptor Activation 583
Sodium and Calcium Channel Expression In neuropathy Leading to Ectopic Excitability 584
Neurotrophins 584
Intraepidermal Nerve Fiber Density 585
Central Mechanisms 585
Central Sensitization 585
Spinal Mechanisms of Central Sensitization In painful Diabetic Peripheral Neuropathy 585
Pronociceptive Facilitation At the Dorsal horn 585
Loss of Antinociceptive Descending Inhibition 586
Magnetic Resonance Imaging of the Central Nervous System In painful Diabetic Peripheral neuropathy 587
Magnetic Resonance Perfusion Imaging 587
Supporting Evidence for Increased Cerebral Blood Volume in the Thalamus in Painful Diabetic peripheral Neuropathy... 588
Blood Oxygen level-dependent (Bold) Functional Magnetic Resonance Imaging 588
Magnetic Resonance Spectroscopy in Painful Diabetic Peripheral Neuropathy 589
Proton Magnetic Resonance Spectroscopy 589
Proton Magnetic Resonance Spectroscopy In painful Diabetic Neuropathy 589
Diffusion Tensor Imaging of the Brain In diabetic Painful Neuropathy 590
Anatomical Magnetic Resonance Imaging Scans and Volumetric Analysis 590
Future Role of Neuroimaging in Painful Diabetic Peripheral Neuropathy 591
Conclusion 591
References 591
Chapter 36: Autonomic neuropathy in experimental models of diabetes mellitus 598
Experimental diabetic autonomic neuropathy 598
Central nervous system 598
Sympathetic ganglia 598
Sympathetic ganglionic heterogeneity in diabetes 600
Parasympathetic ganglia 600
Peripheral nerves and end organ innervation 601
Alimentary tract 601
Diabetes-induced alimentary dysfunction 601
Enteric neurons 601
Interstitial cells of Cajal 601
Sympathetic (SNS) innervation 601
Parasympathetic (PaNS) innervation 604
Sensory (DRG-derived) innervation 604
Other 605
Genitourinary tract 605
Cardiovascular system 605
Skin 605
Miscellaneous 605
Pathology overview 608
Proposed pathogenetic mechanisms of diabetic autonomic neuropathy 608
Oxidative/nitrosative stress 608
The polyol pathway 609
Abnormal axonal transport 609
Neurotrophic substances 610
Neurotrophins (NGF and NT-3) 610
Insulin-like growth factors 610
Glial cell line-derived neurotrophic factor family 610
Erythropoietin 611
Glycation and advanced glycosylation end products 611
Mitochondriopathy 611
Abnormalities of regeneration and synaptic dysplasia 611
Autoimmune mechanisms 611
Ischemia 611
Synaptic degradation of organelles 612
Apoptosis 612
Summary 612
References 612
Index 622
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: dan.ziegler@ddz.uni-duesseldorf.de
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...
| Erscheint lt. Verlag | 5.11.2014 |
|---|---|
| Sprache | englisch |
| Themenwelt | Medizinische Fachgebiete ► Innere Medizin ► Diabetologie |
| Medizinische Fachgebiete ► Innere Medizin ► Endokrinologie | |
| Medizin / Pharmazie ► Medizinische Fachgebiete ► Neurologie | |
| Studium ► 1. Studienabschnitt (Vorklinik) ► Biochemie / Molekularbiologie | |
| Naturwissenschaften ► Biologie ► Humanbiologie | |
| Naturwissenschaften ► Biologie ► Zoologie | |
| ISBN-10 | 0-444-63541-6 / 0444635416 |
| ISBN-13 | 978-0-444-63541-9 / 9780444635419 |
| Haben Sie eine Frage zum Produkt? |
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