Diabetic Neuropathy and Clinical Practice

Preface
Acknowledgments
Contents
About the Author
Part I: Anatomy and Pathophysiology of Diabetic Nerves
	1: Introduction
	2: Functional Anatomy of the Cranial, Peripheral, and Autonomic Nerves
		2.1	 Introduction
		2.2	 Cranial Nerves
			2.2.1	 General Features
			2.2.2	 Afflictions of Optic Tract
			2.2.3	 Oculomotor Nerves III, IV, and VI in Diabetes
			2.2.4	 Pupillary Abnormalities
			2.2.5	 Facial Neuropathy
			2.2.6	 Treatment and Prognosis of Facial Neuropathy
			2.2.7	 Tenth Cranial Nerve Vagus
		2.3	 Diabetic Peripheral and Autonomic Neuropathies
			2.3.1	 Diabetic Sensory Neuropathies
			2.3.2	 Diabetic Somatic Motor Neuropathies
			2.3.3	 Diabetic Autonomic Neuropathies
		2.4	 Functional Anatomy of Diabetic Somatic Peripheral Neuropathy
			2.4.1	 Diabetic Somatic Sensory Peripheral Neuropathy
			2.4.2	 Classification, Anatomy, and Functions of Sensory Receptors
		2.5	 Classification of Nerve Fibers: General
			2.5.1	 Alternative Classification Used by Neurophysiologists
		2.6	 General Principles and Sensory Physiology
			2.6.1	 Adaptation, Accommodation, and Inactivation of the Stimulus and Impulse
			2.6.2	 Nerve Fibers, Transmission of Different Signals, and Their Physiologic Significance
		2.7	 Sensory Perception of Touch, Pressure, and Vibration and the Nerve Ending Distribution
			2.7.1	 Meissner’s Corpuscle
			2.7.2	 Merkel’s Discs
			2.7.3	 Hair End Organ
			2.7.4	 Ruffini’s End-Organs
			2.7.5	 The Pacinian Corpuscles
		2.8	 Transmission of Tactile Signals in Peripheral Nerve Fibers
			2.8.1	 Anatomy and the Transmission of the Dorsal Column–Medial Lemniscal System
			2.8.2	 Signals and Functions Carried in the Dorsal Column–Medial Lemniscal System
			2.8.3	 Pressure and Vibratory Sensation Through the Dorsal Columns
			2.8.4	 Anatomy and Transmission in the Anterolateral Pathway
			2.8.5	 Signals and Functions Carried in the Antero-Lateral System
		2.9	 Functional Anatomy of Autonomic Nerves
			2.9.1	 Segmental Distribution of the Sympathetic Nerve Fibers
		2.10	 Functional Anatomy of Central Autonomic Nervous System
			2.10.1	 Sympathetic Nerve Fibers in the Skeletal Nerves
			2.10.2	 Functional Anatomy of the Parasympathetic Nervous System
			2.10.3	 Preganglionic and Postganglionic Parasympathetic Neurons
			2.10.4	 Sympathetic and Parasympathetic “Tone”
			2.10.5	 Tone Caused by Basal Secretion of Epinephrine and Norepinephrine by the Adrenal Medullae
		2.11	 Effect of Loss of Sympathetic or Parasympathetic Tone After Denervation
			2.11.1	 Denervation Super-Sensitivity of Sympathetic and Parasympathetic Organs
			2.11.2	 Sympathetic Stimulation and Skeletal Stimulation
			2.11.3	 Muscarinic and Nicotinic Receptors
	3: Pathogenesis of Diabetic Neuropathies
		3.1	 Pathological Hallmarks of Diabetic Neuropathy
		3.2	 Epidemiological Features of Diabetic Peripheral Neuropathy
			3.2.1	 Few Main Clinical Features of Diabetic Sensorimotor Polyneuropathy
			3.2.2	 Confirmatory Evidence of Peripheral Neuropathy
		3.3	 Pathogenetic Mechanisms in Development of Diabetic Neuropathy
			3.3.1	 Hyperglycemia
			3.3.2	 Generation of Superoxide Radicals and Its Subsequent Effects
			3.3.3	 Reactive Oxygen and Nitrogen Species— (ROS and RONS)—Mechanisms of Damage
			3.3.4	 RONS and Autonomic Ganglia
			3.3.5	 ROS and Synaptic Transmission
			3.3.6	 Oxidation and Chromosomal Damage, Vascular Factors, Hypoxia
		3.4	 Hypoxia in Neuropathies in Diabetes
			3.4.1	 Endoneurial and Epineurial Hypoxia
			3.4.2	 Some Other Factors of Pathogenic Importance
		3.5	 Advanced Glycation End Products (AGEs)
		3.6	 The Polyol Pathways
			3.6.1	 Mechanism in Detail
		3.7	 Role of Inflammation
			3.7.1	 Role of TNF Alpha in Inflammation
			3.7.2	 Role of CD 163 in Inflammation
			3.7.3	 Role of Adipose Tissues in Inflammation
			3.7.4	 Other Pathogenic Mechanisms of Inflammation
			3.7.5	 Clinical Risk Factors for Neuropathy
		3.8	 Genetic Susceptibility
			3.8.1	 More Recent Genetic Studies in DPN and Other Microvascular Complications
			3.8.2	 Counterargument for Genetic Susceptibilities
		3.9	 Paraproteinemic Neuropathy (PPN)
			3.9.1	 Clinical Features of PPN
			3.9.2	 Associations of PPN with Neuropathy
			3.9.3	 Prevalence of PPN
		3.10	 Key Mechanisms Leading to Neuropathy in Diabetes
		3.11	 Autoimmune Etiopathogenesis of Diabetic Neuropathies
			3.11.1	 Molecular Mechanisms Involved in Autoimmune Reactions
			3.11.2	 Autoimmunity and Axonal Neuropathic Damage
			3.11.3	 Autoimmunity with Reference to T1DM Neuropathies
			3.11.4	 Autoimmunity from the Neuropathic Point of View
		3.12	 Chronic Inflammatory Demyelinating Polyradiculoneuropathy in Diabetes Mellitus
			3.12.1	 American Academy of Neurology Research Criteria for the Diagnosis of CIDP
			3.12.2	 Conclusions About CIDP in Diabetes Mellitus
		3.13	 Autoimmunity of the Optic Nerve and Retinal Diseases
			3.13.1	 The Cerebral Cortex and Autoimmunity
		References
Part II: Autonomic Neuropathies in Diabetes
	4: Cardiovascular and Cerebral Dysfunction
		4.1	 Introduction
		4.2	 Epidemiology of Cardiac Autonomic Neuropathy/Dysfunction in Diabetes
		4.3	 Clinical Profile: Symptoms
			4.3.1	 Clinical Signs of Cardiac Autonomic Neuropathy
		4.4	 Physiology of Cardiac Innervation
			4.4.1	 Pathophysiological Basis of Three Events
			4.4.2	 Clinical Effects of Autonomous Imbalance
			4.4.3	 Degeneration of Sympathetics
		4.5	 The Normal Blood Pressure Regulation
			4.5.1	 Baroreflex Sensitivity
		4.6	 Clinical Correlates of Cardiac Autonomic Neuropathy
			4.6.1	 Obstructive Sleep Apnea (OSA) and Cardiac Autonomic Neuropathy
			4.6.2	 Hypoglycemia Unawareness and Cardiac Autonomic Neuropathy
			4.6.3	 Impaired Glucose Tolerance (IGT) and Cardiac Autonomic Neuropathy
			4.6.4	 Diabetic Retinopathy
			4.6.5	 Orthostatic Hypotension
			4.6.6	 Other Factors
			4.6.7	 DCCT and Epidemiology of Diabetes Interventions and Complications (EDIC) Studies
			4.6.8	 Risk Factors Within the Clinical Spectrum
		4.7	 Cardiac Autonomic Neuropathy in the Pre, Intra, and Postoperative Course
			4.7.1	 Intraoperative Mortality
			4.7.2	 Perioperative Mortality
			4.7.3	 Mortality due to Cardiac Autonomic Neuropathy
		4.8	 Laboratory Diagnosis of Cardiac Autonomic Neuropathy
			4.8.1	 Clinical Signs and Symptoms
			4.8.2	 Laboratory Tests and Their Interpretation
			4.8.3	 Tests for Parasympathetic Autonomic Neuropathy
			4.8.4	 Tests for Sympathetic Autonomic Neuropathy Control
			4.8.5	 Heart Rate Variability (HRV)
			4.8.6	 Response to Standing Up (30:15 ratio)
			4.8.7	 Orthostatic Hypotension
			4.8.8	 Sustained Hand Grip
			4.8.9	 The differential diagnosis of cardiac autonomic neuropathy (CAN)
			4.8.10	 Electrocardiogram in Cardiac Autonomic Neuropathy: QT Prolongation
		4.9	 Autoregulation of Cerebral Blood Flow
			4.9.1	 Maintenance of Normal Cerebral Perfusion Pressure
			4.9.2	 Changes in the Regulation of Cerebral Circulation and Blood Pressure
		4.10	 Profiling Clinical Autonomic Symptom Profile: Questionable Questionnaires
		References
	5: Gastrointestinal and Urinary Dysfunction
		5.1	 Introduction
			5.1.1	 Correlations of Autonomic Neuropathy
			5.1.2	 Prevalence of Diabetic Autonomic GI Neuropathies
		5.2	 Organization and Function of the Enteric Nervous System (ENS)
			5.2.1	 Autonomic Innervation of the Digestive Tract
			5.2.2	 Autonomic Innervation and Reflexes of Gastrointestinal Tract
			5.2.3	 Non-spinal Reflex Pathways
		5.3	 Intramural Nerve Plexuses of the Gastrointestinal System
		5.4	 Diabetic Enteropathy: Pathogenesis
			5.4.1	 Hyperglycemia and Intracellular Biochemical Changes
			5.4.2	 Diabetes-Induced Marked Structural Remodeling of GI Tract Wall
			5.4.3	 Role of Entero Glial Cells (EGCs)
		5.5	 Autonomic Nervous System Disturbances in Gastrointestinal Tract
			5.5.1	 Parasympathetic Nervous System and the Gut
			5.5.2	 Clinical Features and Effects of Accelerated/Rapid Gastric Emptying
			5.5.3	 Clinical Effects of Disturbances in Sympathetic Innervation on Gut
			5.5.4	 Main GI Effects
				5.5.4.1	 Gastroparesis
				5.5.4.2	 Swallowing Reflex
				5.5.4.3	 Diarrhea
				5.5.4.4	 Constipation and Obstipation
				5.5.4.5	 Gall Bladder Atony
		5.6	 Laboratory Diagnosis of GI Autonomous Disorders
			5.6.1	 Preconditions
			5.6.2	 Diagnosis of Gastroparesis, Intestinal, and Colonic Abnormalities
			5.6.3	 Scintigraphy in Gastroparesis, Intestinal, and Colonic Transit Time
			5.6.4	 Disadvantages of Scintigraphy
			5.6.5	 Radiopaque Markers for GI Motility
			5.6.6	 Gastric Emptying Breath Testing
			5.6.7	 Wireless Motility Capsule for GI Motility Studies
			5.6.8	 Transit Time Detection and Diagnosis
			5.6.9	 Manometric Measurements of GI Tract: Esophageal Evaluation
		5.7	 Treatment of Diabetic Neuropathy of GI Tract
			5.7.1	 The Variables of Planning and Monitoring Therapy
		5.8	 Gastrointestinal Organ-Specific Management in Diabetic Autonomic Neuropathy
			5.8.1	 General Remarks
		5.9	 Esophageal Disorders in Diabetes
			5.9.1	 Investigation of Esophageal Disorders
		5.10	 Gastroesophageal Reflux Disease
			5.10.1	 Esophageal Complications of GERD
			5.10.2	 Prevalence of GERD and Diabetes
			5.10.3	 Treatment of GERD
		5.11	 Diabetic Gastroparesis: Clinical Profile and Management Issues
			5.11.1	 Systematic Record of Upper GI Symptomatology: An Extension to History Taking
			5.11.2	 Management and Treatment of Gastroparesis
			5.11.3	 Non-Pharmacological Management
			5.11.4	 Pharmacologic Management of Gastroparesis
			5.11.5	 Metoclopramide
			5.11.6	 Domperidone
			5.11.7	 Erythromycin
			5.11.8	 Other (Experimental) Drugs Used in Gastroparesis
			5.11.9	 Acute Diabetic Gastroparesis
		5.12	 Abnormal Bowel Function: Diarrhea and Constipation
			5.12.1	 Pathophysiology of Diarrhea
			5.12.2	 The Differential Diagnosis
			5.12.3	 Treatment of Diabetic Diarrhea
		5.13	 Diabetic Constipation
			5.13.1	 Treatment of Refractory Constipation
			5.13.2	 Treatment of Abdominal Pain in Diabetic Autonomic Neuropathy of GI Tract
		5.14	 Autonomic Dysfunction of the Urinary Tract
			5.14.1	 Functional Anatomy of Autonomic Innervation
			5.14.2	 Diabetic Cystopathy
			5.14.3	 Laboratory Investigation of Diabetic Cystopathy
			5.14.4	 Detrusor Hyperreflexia
			5.14.5	 Electromyography Testing
		References
	6: Dysfunction of Sexual and Accessory Sex Organs
		6.1	 Introduction
		6.2	 Neurophysiology of Penile Erection
			6.2.1	 Penile Erection: Role of the Parasympathetic Nerves
			6.2.2	 Lubrication, a Parasympathetic Function
			6.2.3	 Emission and Ejaculation: Function of the Sympathetic Nerves
		6.3	 Clinical Factors Leading to Erectile Dysfunction (ED)in Diabetes
			6.3.1	 Factors Responsible at Organ Level
			6.3.2	 Molecular Mechanisms Involved in ED
		6.4	 Hormonal Changes
			6.4.1	 Testosterone
			6.4.2	 Causes of Testosterone Deficiency in Diabetes
			6.4.3	 Testosterone and ED: Newer Evidence
			6.4.4	 Testosterone and Cardiovascular Risks/Benefits
			6.4.5	 Other Incidental Factors
		6.5	 Erectile Dysfunction and Cardiovascular Disease
			6.5.1	 Smooth Muscle Abnormalities in Penile Cavernosa
		6.6	 Symptomatology and Physical Examination
			6.6.1	 Physical Examination
		6.7	 Laboratory Diagnosis
			6.7.1	 Penile Tumescence Test
			6.7.2	 Bulbocavernous Reflex
			6.7.3	 Vascular Evaluation
			6.7.4	 Hormonal Testing
		6.8	 Treatment of Erectile Dysfunction
			6.8.1	 Lifestyle Changes
			6.8.2	 Hormonal Changes
			6.8.3	 Antidepressants
		6.9	 Phosphodiesterase Type 5 Inhibitors PDE5i
			6.9.1	 Sildenafil
			6.9.2	 Tadalafil
			6.9.3	 Verdenafil
			6.9.4	 Avanafil
			6.9.5	 Mirodenafil and Udenafil
			6.9.6	 Pharmacokinetics and Efficacy of All Phosphodiesterase 5 Inhibitors
			6.9.7	 Cardiovascular Assessment and PDE 5i Use
			6.9.8	 Other Pharmacological Agents
			6.9.9	 Alprostadil
			6.9.10	 Papaverine and Phentolamine
			6.9.11	 Vacuum Erection Devices
			6.9.12	 Penile Prosthesis
			6.9.13	 Low-Intensity Shock Wave Therapy
		6.10	 Female Sexual Dysfunction (FSD)
			6.10.1	 Salient Features Affecting FSD
			6.10.2	 Patterns of FSD
			6.10.3	 Factors Affecting Female Sexual Dysfunction in Diabetes
			6.10.4	 Molecular Basis of FSD in Diabetes
			6.10.5	 Drugs Affecting Various Components of FSD
			6.10.6	 Treatment of Female Sexual Dysfunction
			6.10.7	 Therapeutic Options
			6.10.8	 Choosing Between the Two
			6.10.9	 A Word About Hormone Therapy
		6.11	 Diabetic Autonomic Neuropathy, Seminal Vesiculitis, and Infertility
			6.11.1	 USG Diagnosis of Individual Organs
			6.11.2	 Ultrasonography (USG) in MAGI
			6.11.3	 Abnormalities of the Semen Examination
			6.11.4	 Innervation of Prostate, Seminal Vesicles, and Epididymis with Disease Association
		References
	7: Sudomotor Dysfunction and Histopathology in Diabetic Neuropathy
		7.1	 Sudomotor Dysfunction
			7.1.1	 Introduction
			7.1.2	 Physiology of Sudomotor Function
			7.1.3	 Thermoregulation
			7.1.4	 Neural Architecture of Sudomotor Function of the Sweat Glands
			7.1.5	 Causes for Sudomotor Dysfunction
			7.1.6	 Sweating and the Plantar Skin in Diabetes
		7.2	 Laboratory Tests for Sudomotor Function
			7.2.1	 Thermoregulatory Sweat Testing (TST)
			7.2.2	 Quantitative Sudomotor Axon Reflex Sweat Test (QSART) for Postganglionic Sudomotor Function
			7.2.3	 Electrochemical Skin Conductance (ESC)
			7.2.4	 Normal Values of ESC
			7.2.5	 Correlations for Electrochemical Skin Conductance
			7.2.6	 Correlations, Sensitivities: QSART, ESC, TST
		7.3	 Histology in Diabetic Neuropathy
		7.4	 Skin Biopsy
			7.4.1	 General Remarks
			7.4.2	 Demonstrable Skin Biopsy Findings
			7.4.3	 Skin Biopsy Findings in Diabetes and Impaired Glucose Tolerance (IGT)
			7.4.4	 Some Other Concerns
			7.4.5	 IENFD, Thermal Thresholds, and Nerve Conduction Studies (NCS)
		7.5	 Other Histopathology Study Methods
			7.5.1	 Pathological Assessment of Teased Longitudinal Fibers
			7.5.2	 Histopathological Changes in Diabetic Peripheral Nerves: Detailed Description
		7.6	 Corneal Confocal Microscopy
			7.6.1	 The Place of CCM in Investigating Diabetic Neuropathy
			7.6.2	 Human Corneal Innervation
			7.6.3	 Capture and Storage of CCM Image
			7.6.4	 CCM Image Quantification
			7.6.5	 CCM in Diabetic Peripheral Neuropathy
			7.6.6	 Correlations Between CNFD and IENFD
			7.6.7	 Other Correlations
			7.6.8	 Prognostic Significance of CCM
			7.6.9	 CCM Beyond Diabetic Neuropathy
			7.6.10	 The Downside of Sophisticated Investigations
		References
Part III: Diabetic Peripheral Neuropathies
	8: Clinical and Laboratory Measurements in Diabetic Neuropathies
		8.1	 Introduction
		8.2	 Difficulties in the Diagnosis of Diabetic Peripheral Neuropathies (DPN)
			8.2.1	 Early Diagnosis
			8.2.2	 A Diagnosis of Exclusion
			8.2.3	 Prevalence of DPN
		8.3	 Classification of Diabetic Peripheral Neuropathies
		8.4	 Assessment of Peripheral Sensory Neuropathy
			8.4.1	 History
			8.4.2	 Neuropathic Sensations
			8.4.3	 Symptomatic Progression
			8.4.4	 Pruritis or Itching
			8.4.5	 History of any Kind of Foot Care
			8.4.6	 Injurious Practices
			8.4.7	 End of the Day Edema
			8.4.8	 Sensation of Pain in Particular
			8.4.9	 Weakness or Malfunctions in Hands, Pelvic and Leg Muscles
			8.4.10	 Skin Changes of Sensory Neuropathy
			8.4.11	 Inspection and Palpation of Limbs
		8.5	 Instrumentation in Clinical Practice of Diabetic Neuropathy
			8.5.1	 Preamble
			8.5.2	 The Purpose
			8.5.3	 Facilitating Communication
			8.5.4	 An Important Clarification
		8.6	 Neuropathy Scores—An Extension to Clinical Examination
			8.6.1	 Challenges of Systematic Study of Symptoms in DPN
			8.6.2	 Neuropathy Scores in Practice
			8.6.3	 Validated Neuropathy Scores
			8.6.4	 NSS and NDS
			8.6.5	 Neuropathy Deficit (or Disability) Score (NDS) of Boulton
			8.6.6	 Neuropathy Impairment Score (NIS)
			8.6.7	 Neuropathy Symptom Score Lower Limb (NIS-LL) and NIS (LL) +7
			8.6.8	 Nis-LL +7
			8.6.9	 Neuropathy Symptom and Change Score—NSC
			8.6.10	 Neuropathic Pain Questionnaire
			8.6.11	 painDETECT
			8.6.12	 ID Pain
			8.6.13	 Neuropathic Pain Symptom Inventory
			8.6.14	 Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) Pain Scale
			8.6.15	 Subjective Peripheral Neuropathy Screen Questionnaire (SPNSQ)
			8.6.16	 Douleur Neuropathique (DN) 4 Questionnaire
			8.6.17	 Neuropathic Pain Symptom Inventory (NPSI)
			8.6.18	 Sheehan Disability Scale (SDS)
			8.6.19	 Patient Global Impression-Improvement (PGI-I)
			8.6.20	 Utah Early Neuropathic Pain
		8.7	 Basic to Sophisticated Methods of Clinical Testing
			8.7.1	 Introduction
			8.7.2	 The Well-Trained Paramedics: A Must for Laboratory Testing
			8.7.3	 Standard Practices in Testing
			8.7.4	 Meaning and Significance of the Thresholds and Deficits
		8.8	 Qualitative and Quantitative Sensations
			8.8.1	 The Monofilament (MF) Testing
			8.8.2	 Number of Sites to Be Tested
			8.8.3	 The Method of Using Monofilament
			8.8.4	 Inquiry
			8.8.5	 “Don’ts” for Monofilament Testing
			8.8.6	 Reusability
			8.8.7	 The Inference of a Negative Monofilament Test
		8.9	 Tests for Vibration Detection/Perception Thresholds—VDT or VPT
			8.9.1	 Neurothesiometer
			8.9.2	 The VibraTip™
			8.9.3	 NerveCheck
		8.10	 Indian Vibration Perception Threshold Sensitometer (VPT)
			8.10.1	 Calibration and Qualities of Sensitometer
			8.10.2	 The Probe and the Motor
			8.10.3	 Testing Vibration Perception
			8.10.4	 Interpretation of the First-Time Reading
			8.10.5	 Interpretation of Second-Time Reading
			8.10.6	 Vibration Threshold Detection and its Correlations
		References
	9: Small Fiber and Painful Neuropathy
		9.1	 Introduction
		9.2	 Small Fiber Neuropathies
			9.2.1	 Symptoms of Small Fiber Neuropathy
			9.2.2	 Small Fiber Neuropathies and Autonomic Dysfunction
			9.2.3	 Causes of Small Fiber Neuropathy
		9.3	 Generation and Flows of Painful Neural Impulses
			9.3.1	 Generation of Pain—At the Nerve Fiber and Cellular Levels
			9.3.2	 Pain Generation at the Cell Body
			9.3.3	 Perception of Pain
			9.3.4	 Nonadaptive Nature of Pain Receptors
			9.3.5	 Rate of Tissue Damage as a Stimulus for Pain
			9.3.6	 Tissue Ischemia as a Cause of Pain
			9.3.7	 Localization of Fast Pain in the Body
			9.3.8	 The Slow-Chronic Pain
			9.3.9	 Paleospinothalamic Pathway for Transmitting Slow-Chronic Pain
			9.3.10	 Substance P, the Probable Slow-Chronic Neurotransmitter of Type C Nerve Endings
			9.3.11	 Chronic Pain Signals into the Brain Stem and Thalamus
			9.3.12	 Physiologic Mitigation of Pain
			9.3.13	 Some Clinical Abnormalities of Pain and Other Somatic Sensations
			9.3.14	 Surgical Interruption of Pain Pathways
		9.4	 Clinical and Laboratory Correlates of Small Fiber Neuropathy Diabetes (SFN) and Diabetes
		9.5	 Laboratory Assessment of Pain
			9.5.1	 The SET Device
			9.5.2	 Quantitative Sensory Testing by NerveCheck
			9.5.3	 Quantitative Sensory Testing—Some More Aspects
		9.6	 Details for Laboratory Measurement of Thermal Sensations
			9.6.1	 The Thermal Receptors
			9.6.2	 Stimulatory Effects of Rising and Falling Temperature—Adaptation of Thermal Receptors
			9.6.3	 Mechanism of Stimulation of Thermal Receptors
			9.6.4	 Rate of Change of Temperature and its Physiology
			9.6.5	 Physiological Ranges of Thermal Sensations in Normal Individuals
			9.6.6	 Tissue Damage under Thermal Stimuli
		9.7	 Thermal Threshold Measuring Instrument and the Process
		9.8	 Components of Heat and Cold Perception Sensitometer
			9.8.1	 Methods of Generating the Heat Quanta
			9.8.2	 Issues about the Probe Tip
			9.8.3	 Accuracy and Traceability
			9.8.4	 Method of Testing for Temperature Perception
			9.8.5	 Interpretation
		9.9	 Details about Heat and Cold Perception (HCP) Sensitometer
			9.9.1	 The Programs
		9.10	 Steps for Cool Testing as a General Example
			9.10.1	 First Part of Operation
			9.10.2	 Second Part of Operation
			9.10.3	 The Nine Programs
			9.10.4	 Program 1
			9.10.5	 Program 2
			9.10.6	 Program 3
			9.10.7	 Program 4
			9.10.8	 Programs 5 and 6
			9.10.9	 Program 7 and 8
			9.10.10 Base Temperatures
			9.10.11 The Report
		References
			Further Reading
	10: Motor Neuropathy and Diabetic Hand Syndrome
		10.1	 Introduction
		10.2	 The Basic Pathophysiological Mechanisms
			10.2.1	 The Pathophysiology of Diabetic Foot—The Ligaments
			10.2.2	 The Pathophysiology of Diabetic Foot—The Muscles
		10.3	 Anatomy of the Foot
			10.3.1	 Anatomy of the Ligaments
			10.3.2	 Anatomy of the Muscles of the Foot
				10.3.2.1 The First Layer
				10.3.2.2 The Second Layer of Muscles in the Foot
				10.3.2.3 The Third Layer
				10.3.2.4 The Fourth Layer
		10.4	 Examination of Motor Neuropathy
			10.4.1	 Deformities of the Toes
			10.4.2	 Deformities of Hallux and the Toes
				10.4.2.1 Hallux Rigidus
				10.4.2.2 Clawing of Toes
				10.4.2.3 The Hammer Toe
				10.4.2.4 Foot Drop
			10.4.3	 Assessment of Motor Function
			10.4.4	 Foot Pressure Studies in Diabetic Motor Neuropathy
		10.5	 Proximal Motor Neuropathy
			10.5.1	 General Features
			10.5.2	 Differential Diagnosis
			10.5.3	 Pathological Changes
			10.5.4	 Diabetic Ischemic Changes
			10.5.5	 (Auto)Immune-Mediated Changes
			10.5.6	 Other Changes
			10.5.7	 Detecting Other Abnormalities
		10.6	 Electrophysiological Changes in Diabetic Amyotrophy
			10.6.1	 Imaging Muscles
		10.7	 Treatment of Diabetic Amyotrophy
			10.7.1	 Pain in Amyotrophy
			10.7.2	 Other Pain Treatments
			10.7.3	 Exercise
			10.7.4	 Methylprednisolone
		10.8	 Diabetic Hand Neuropathy and Other Changes
			10.8.1	 Introduction
			10.8.2	 Stiff Hand Syndrome
			10.8.3	 Carpal Tunnel Syndrome (CTS, Entrapment Neuropathy)
			10.8.4	 Dexterity of Hands in Diabetic Hand Neuropathies
			10.8.5	 Quality of Life Study
			10.8.6	 Purdue Pegboard Test
			10.8.7	 Michigan Hand Outcomes Questionnaire
			10.8.8	 Diabetes-39
		References
	11: Electrophysiology in Diabetic Neuropathy
		11.1	 Introduction
			11.1.1	 Terminology
			11.1.2	 Diagnosis of an Abnormality
			11.1.3	 Electrophysiological Testing in Clinical Practice
			11.1.4	 What Is and What Is Not Tested by EPS?
			11.1.5	 Referring for EPS
			11.1.6	 The Detectable Abnormalities in DPN
			11.1.7	 Frequencies of Various Abnormalities Detected by NCS and EMG
		11.2	 Electrophysiology of Nerves—General Features
		11.3	 Description of some Common Terms and their Meaning As Used in EPS
			11.3.1	 F Waves
			11.3.2	 H Reflexes
			11.3.3	 Fasciculations
			11.3.4	 Fibrillations
			11.3.5	 Recruitment
		11.4	 EPS in Diabetes
			11.4.1	 Asymptomatic Patients
			11.4.2	 Moderately Symptomatic Symmetric Peripheral Neuropathy Patients
			11.4.3	 Mixed Motor and Sensory Neuropathies
			11.4.4	 Differential Diagnosis of Motor Neuropathy from CTS
			11.4.5	 Painful Neuropathies in Diabetes and EPS
			11.4.6	 EPS in Autonomic Neuropathy
			11.4.7	 Limitations of Electrodiagnostic Studies
			11.4.8	 Correlations
			11.4.9	 Differentiation from Nondiabetic Neuropathies
		11.5	 Focal or Entrapment Neuropathies (EN)
			11.5.1	 Entrapment in the Upper and Lower Extremities
			11.5.2	 Pathological Changes in Nerves Leading to Entrapment
			11.5.3	 Pathogenic Involvement of Median Nerves in Entrapment
			11.5.4	 Symptomatic Profile of Entrapment Neuropathies
			11.5.5	 Imaging in Diagnosis of Entrapment—Ultrasonography
			11.5.6	 Magnetic Resonance Imaging (MRI)
			11.5.7	 Prevalence of Entrapment Neuropathies
			11.5.8	 Diagnosis of CTS/MNW and Ulnar Nerve
			11.5.9	 Treatment of Carpal Tunnel Syndrome
			11.5.10 Surgery in CTS
			11.5.11 UNE and Ulnar Entrapment Neuropathy at the Wrist (UNW)
			11.5.12 Peroneal Nerve Entrapment
			11.5.13 Entrapment of the Tibialis Nerve
			11.5.14 Surgery on Entrapped Nerves and its after Effects
		11.6	 Critical Review of Surgical Treatment of Entrapment Neuropathy
			11.6.1	 Claims for the Success of Decompression
			11.6.2	 The Answer
		11.7	 Other Electrophysiological Diagnostic Modalities
			11.7.1	 Laser-Evoked Potentials (LEPs), Nociceptive Functions Not Tested by Standard EPS
			11.7.2	 Contact Heat-Evoked Potential Stimulator (CHEPS)
			11.7.3	 Neurometer and Contact Heat-Evoked Potentials (CHEPS)
		References
Part IV: Therapeutics of Diabetic Neuropathies
	12: Treatment of Painful Diabetic Neuropathy
		12.1	 Introduction
		12.2	 The Ad Hoc Panel on Endpoints for Diabetic Neuropathy
			12.2.1	 The Burden of Disappointment and Psychological Support
			12.2.2	 The Sequence of Discussion Followed
		12.3	 Treatment of Painful Polyneuropathy in Diabetes
			12.3.1	 Tricyclic Antidepressants (TCAs)
			12.3.2	 Amitriptyline
			12.3.3	 Important Clinical Considerations
		12.4	 Pregabalin
			12.4.1	 Mechanism of Action—Animal Studies
			12.4.2	 Pharmacodynamics and Pharmacokinetics
			12.4.3	 Efficacy of Pregabalin
			12.4.4	 Clinical Efficacy—Pregabalin
			12.4.5	 Gabapentin
		12.5	 Duloxetine and Others
			12.5.1	 Background
			12.5.2	 Analysis of some Major Studies
			12.5.3	 Mechanism of Action
			12.5.4	 Trials and Tribulations of Duloxetine
			12.5.5	 Venlafaxine Hydrochloride
		12.6	 Mexiletine
		12.7	 Opioids in Painful Neuropathy
			12.7.1	 Opioids and Tramadol
			12.7.2	 Tramadol
		12.8	 Miscellaneous Drugs
			12.8.1	 Strong Opioids and Botulinum Toxin A
			12.8.2	 Oromucosal Cannabinoids
				12.8.2.1 Combination of Pregabalin or Gabapentin with a Tricyclic Antidepressant or Opioid
			12.8.3	 Topical Lidocaine
			12.8.4	 Capsaicin Patches
			12.8.5	 Interventional Treatments
			12.8.6	 Oral Treatment with Alpha-Lipoic Acid
		12.9	 Experimental Drugs
			12.9.1	 Ruboxistaurin Mesylate
			12.9.2	 Rationale of Using RBX in Diabetic Neuropathy
			12.9.3	 Efficacy and Related Issues for Ruboxistaurin Mesylate (RBX)
			12.9.4	 Adverse Reactions
			12.9.5	 Remarks
		12.10	 Vitamins Minerals and Diabetic Polyneuropathy
			12.10.1 Vitamin C and E
			12.10.2 Vitamin D
			12.10.3 Vitamin E in Diabetic Neuropathy
			12.10.4 Vitamin B 12
			12.10.5 Replacement of B 12 in Deficiency
		12.11	 Experimental Electrical Studies to Reduce Painful DPN
			12.11.1 High-Frequency External Muscle Stimulation (HF)
			12.11.2 Frequency-Modulated Electromagnetic Neural Stimulation
			12.11.3 Monochromatic Infrared Energy (MIRE)
			12.11.4 Botulinum Toxin A
		References
	13: Insulin and Diabetic Peripheral Nerve Pathologies
		13.1	 Introduction
		13.2	 New Evidences about Insulin Effects on Nervous Tissues
			13.2.1	 Animal Evidence
			13.2.2	 Insulin in Humans
			13.2.3	 Insulin and Diabetic Neuropathy
			13.2.4	 Diabetic Neuropathy and Insulin in Clinical Practice
		13.3	 Chronic Intermittent Intravenous Insulin Therapy (CIIIT)
			13.3.1	 Improvement in Autonomic Neuropathy Function
			13.3.2	 Other Benefits of CIIIT
			13.3.3	 Method Used in CIIIT
		13.4	 Other Situations of Improvement in Diabetic Polyneuropathy
			13.4.1	 Pancreatic Transplant with or without Kidney Transplant
			13.4.2	 Reduction of Polyneuropathy in Critically Ill Patients
			13.4.3	 C-Peptide in Neuropathy
		13.5	 An Uncommon Cause of Painful Neuropathy—Insulin Neuritis
			13.5.1	 Symptom Profile and Temporal Progression
			13.5.2	 Mechanism of Genesis
		References
			Further Reading
	14: Treatment of Cardiac Autonomic Neuropathy
		14.1	 Introduction
		14.2	 Pharmacologic Treatment
			14.2.1	 Antioxidants
				14.2.1.1	 Vitamin E in Cardiac Autonomic Neuropathy
			14.2.2	 Aldose Reductase Inhibitors
			14.2.3	 The ACE Inhibitors
			14.2.4	 Beta Blockers
				14.2.4.1	 Reduced Exercise Tolerance
				14.2.4.2	 Physiology of Cardiac Perfusion
				14.2.4.3	 Reply to Objections to Using Beta Blockers
				14.2.4.4	 Utility of Beta Blockers
				14.2.4.5	 Nocturnal Elevation of Blood Pressure and its Unwelcome Effects
			14.2.5	 Sodium Glucose Transporter 2 Inhibitors, SGLT2i
			14.2.6	 C-Peptide
			14.2.7	 Additional Treatment Methods for CAN
				14.2.7.1 ACE Inhibitors, Digoxin and Verapamil
				14.2.7.2 Caffeine and Acarbose
				14.2.7.3 Spironolactone
				14.2.7.4 Enalapril
				14.2.7.5 Furosemide
				14.2.7.6 GLP-1 and DPP4i
		14.3 Treatment of Orthostatic Hypotension
			14.3.1	 Non-pharmacological Interventions
			14.3.2	 Drugs Enhancing Orthostatic Hypotension
		14.4	 Pharmacotherapy of Orthostatic Hypotension
			14.4.1	 Midodrine
			14.4.2	 Fludrocortisone
			14.4.3	 Somatostatin and its Analog Octreotide
			14.4.4	 Erythropoietin
			14.4.5	 Desmopressin Acetate
			14.4.6	 Pyridostigmine Bromide
			14.4.7	 Future Strategies
		14.5	 Prevention and Mitigation of Cardiac Autonomic Neuropathy
			14.5.1	 Treatment of Cardiac Autonomic Neuropathy
		References