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DIABETES: NEUROPATHIES & NEUROMUSCULAR DISORDERS

Neuropathy   General   Symmetric     Chronic       Distal sensory/autonomic       Autonomic       Sensory-motor     Acute       Painful       Reversible   Asymmetric     Lumbosacral plexopathy     Mononeuropathies     Mononeuritis multiplex     HIEM   Immune PN: Predisposition     CIDP     Diabetic amyotrophy     HIEM     Perineuritis Muscle   Infarction

Overview: Diabetes   Classification     Type 1: IDDM     Type 2: NIDDM     Other   Mitochondrial disorders   Neuromuscular disorders   Screening   Metabolic syndrome Banting & Best

• Type 1: Insulin-Dependent Diabetes Mellitus (T1D; IDDM)
  • Epidemiology
    • 5% of diabetes
    • Ages: Typically Children & Young adults
  • Clinical
    • Onset
      • Usual: 1st 2 decades
      • Most <: 45 years
      • Abrupt
    • Body weight: Usually lean
    • Insulin deficiency: Absolute
    • Genetics
      • 15-fold risk
      • 6% of 1st degree relatives affected
      • 0.4% of unrelated individuals affected
    • Immune
      • Immune-mediated destruction of pancreatic beta cells
      • Increased incidence of associated autoimmune phenomena
    • Metabolism
      • Ketosis prone
      • Lethal if not treated
    • Treatment: Insulin
    • Polyneuropathy
      • Clinical type: Sensory, Axon loss
      • Risk Associations ²¹
        • Diabetes duration: Longer
        • Alcohol consumption: Higher
        • Total cholesterol: Higher
        • LDL: Higher
        • eGFR: Lower
        • ACR: Higher
  • Pathology
    • β cell destruction
    • Usually leads to
      • Reduced pandreatic insulin production
      • Absolute insulin deficiency
  • Etiologies
    • Immune-mediated: Associated with antibodies to
      • Insulin: 50% to 90%; Higher titers in young children
      • Glutamate decarboxylase₆₅ : 80%; Adult onset type IA
      • Tyrosine phosphatase-like molecules
        • PTPRN (IA2) : 74%
        • PTPRN2 (IA2-β; Phogrin) : 61%
      • Glycolipids: GT3 ganglioside; ? Sulfatide; ? GM2-I
      • Cytoplasmic islet cell antigens (ICA)
      • Carboxypeptidase H: 10%
    • Genetic
      • HLA Class II DR-DQ Linkage Patterns and IDDM Susceptibility in Whites
        • Main susceptibility haplotypes in Caucasians (95%)
          • HLA-DR2: With 0102, 0502 and 1601
          • HLA-DR3: Also associated with Xp11 locus
          • HLA-DR4: With 0301, 0302 and 0401 or 0402
        • Protective haplotype
          • HLA-DR2: With 0102,0602,1501
      • T1D# (IDDM): Genetic predisposition chromosome loci
        

        1: 6p21.3 2: INS; 11p15.5 3: 15q26 4: 11q13 5: SUMO4; 6q25 6: 18q21 7: 2q31 8: 6q25-q27 9: 3q21-q25 10: IL2RA; 10p15.1   11: 14q24.3-q31 12: CTLA4; 2q33 13: 2q34 15: 6q21 17: 10q25 18: 5q31.1-q33.1 19: IFIH1; 2q24.3 20: HNF1A; 12q24.2 21: 6q25 22: CCR5; 3p21 23: 4q27 24: 10q23.31 IPEX: FOXP3 Xp11 PSMB8: 6p21

    
    
  
  
• Type 2: Non Insulin-Dependent Diabetes Mellitus (T2D; NIDDM)
  
  • Epidemiology
    • 95% of diabetes
  • General metabolic features
    • Pancreatic insulin production: High
    • Insulin resistance: Muscle, Fat & Liver cells poorly responsive to insulin
    • Subtype spectrum
      • Predominantly insulin resistant with relative deficiency
        
      • Predominant insulin secretory defect with insulin resistance
  • Clinical
    • Onset: Usually > 30 years
    • Genetics: > 20% of 1st degree relatives affected
    • Immune: No increase in associated autoimmune phenomena
    • Body weight: Usually obese
    • Metabolism
      • Ketosis resistant
      • Primary metabolic disorder
    • Treatment: Weight loss ± Oral agent or Insulin
    • Polyneuropathy: Sensory
      • Not strongly related to glycemic control
      • Other possible associations: Obesity, Hypertension, Dyslipidemia, Inflammation, Insulin resistance
  • Predisposing factors: General
    • Age > 45 years
    • Positive family history
    • Race: Native American; Hispanic; Asian, African American
      
    • Personal features
      • Obesity
      • Hypertension
      • Dyslipidemia
      • h/o Gestational diabetes
    • Genetic
      • TCF7L2 gene
        • Genetic marker: Microsatellite in intron 3
        • Risk: Homozygote (2.4x) > Heterozygote (1.5x) > Control
        • Gene function: Transcription factor
      • Calpain 10 cysteine protease
        • Polymorphisms in intron 3
      • Peroxisome proliferator-activated receptor γ (PPARG)
        • Transcriptional partner of PGC-1α : Regulator of mitochondrial biogenesis
        • Pro115Gln mutation: Severe obesity
        • Pro12Ala mutation: 15% decreased risk of type 2 diabetes
        • Other mutations: Familial partial lipodystrophy, type 3
      • Adiponectin (APM1; ACDC)
      • WNT5B
        • Mechanism: ? Regulation of adipocyte function
        • Population: Japanese
      • Monozygotic twins: Concordance 3.5x higher than dizygotic
      • Icelandic population: Locus on 5q
  • Specific genetic subtypes: 5% of NIDDM
    • Maturity-onset diabetes of the young (MODY) 1
      ● Hepatocyte nuclear factor-4-α ; Chromosome 20q12-q13.1; Dominant
      
      • Clinical
        • Frequency: 1 American family of Prussian descent
          
        • Mechanism: Insulin secretory defect; 2^o insulin resistance
          
        • DM type: MODY
        • Clinical
          • Severe diabetes
          • Onset: Post pubertal
          • Complications: Frequent
      
      
    • MODY 2
      ● Glucokinase ; Chromosome 7p15-p13; Dominant
      
      • Clinical
        • Frequency: Common; Worldwide
        • Mechanisms
          • Pancreas: Impaired insulin secretion
            
          • Liver: Reduced processing of glucose to glycogen
        • DM types: MODY; NIDDM; Gestational
        • Clinical
          • Mild diabetes
          • Onset: Childhood
          • Complications: Rare
      
      
    • NIDDM II & MODY3
      ● Hepatic transcription factor 1 (TCF1) ; Chromosome 12q24.2; Dominant
      • Clinical
        • Frequency: Common; U.S., Europe, Japan
        • Mechanism: Insulin secretory defect; No insulin resistance
        • Clinical
          • Severe diabetes
          • Onset: Post-pubertal
          • Complications: Frequent
      
      
    • MODY4
      ● Insulin promoter factor (IPF1); Chromosome 13q12.1; Dominant
      • Homozygosity: Pancreatic agenesis & Neonatal diabetes mellitus
      
      
    • MODY5
      ● Hepatic transcription factor-2 (TCF2; HNF1B) Chromosome 17q12; Dominant
      • Clinical
        • Mild diabetes
        • Renal disease: Non-diabetic
        • Mullerian aplasia (50%): Vaginal aplasia; Rudimentary uterus
        • Gitelman-like syndrome
      
      
    • MODY 6
      ● Neurogenic differentiation 1 (NEUROD1) ; Chromosome 2q32; Dominant
      • Onset: 30 to 59 years
      
      
    • MODY 7
      ● Kruppel-like factor 11 (KLF11) ; Chromosome 2p25; Dominant
      • Diabetes & Glucose intolerance
      
      
    • MODY 8
      ● Carboxyl-ester lipase (CEL) ; Chromosome 9q34.3; Dominant
      • Diabetes & Primary pancreatic beta-cell dysfunction
      
      
    • MODY 9
      ● Paired box gene 4 (PAX4) ; Chromosome 7q32; Dominant
      • Mutations also in: Diabetes, type 2 & Susceptibility to Diabetes mellitus, ketosis-prone
      
      
    • MODY 10
      ● Insulin (INS) ; Chromosome 11p15.5; Dominant
      • Mutations also in: Hyperproinsulinemia & Permanent neonatal diabetes mellitus
      
      
    • MODY 11
      ● Tyrosine kinase, B-lymphocyte specific (BLK) ; Chromosome 8p23-p22; Dominant
      
      
    • MODY 13
      ● KCNJ11 (Kir6.2) ; Chromosome 11p15.1; Dominant
      • Allelic disorders
        • Diabetes mellitus, permanent neonatal, with neurologic features (PNDM)
        • Diabetes mellitus, transient neonatal 3
        • Diabetes, permanent neonatal or relapsing
        • Hyperinsulinemic hypoglycemia, familial 2 (HHF2)
        • Diabetes mellitus, type 2, susceptibility to
      
      
      
    • Noninsulin dependent diabetes mellitus (NIDDM)
      ● Mitogen-activated protein kinase 8-interacting protein 1 (MAPK8IP1) ; Chromosome 11p12-p11.2; Dominant
      
      
    • Noninsulin dependent diabetes mellitus (NIDDM) I: Predisposition factors in ethnic groups
      • Mexican Americans from Starr County, Texas: Chromosomes 2q37 (Calpain 10 ); 15q21.1; 10q26
      • Pima Indians: Chromosomes 1q21-1q23; 11q23-q25 (DM & Obesity)
      • Whites: Chromosomes 1q21-1q23; 12q24
      • French whites: 1q21-1q24; 3q27-qter (Early onset < 45 years)
      
      
    • Insulin receptor substrate (IRS) 1
      ● Chromosome 2q36
      
      • IRS protein
        • Mediates insulin action
        • Prominent role in skeletal muscle
      • Single patient identified
      • Clinical DM type: NIDDM
      
      
    • Solute carrier family 2, member 2 (SLC2A2): Glucose transporter 2 (GLUT2)
      ● Chromosome 3q26.1-q26.3
      
      • Genetics
        • Mutation: Val197Ile
        • Other mutations produce: Fanconi-Bickel syndrome
          • Hepatorenal glycogenosis
          • Renal Fanconi syndrome
          • Galactose intolerance
          • Malabsorption
          • Psychomotor retardation
      • GLUT2 Protein
        • Function: Low-affinity glucose transporter present in the plasma membrane
        • Location
          • Insulin-producing β cells of pancreatic islets: Highest in microvilli facing adjacent endocrine cells
          • Not in other islet endocrine cells
      
      
    • Noninsulin dependent diabetes mellitus (NIDDM)
      ● Solute carrier family 2, member 4 (SLC2A4) ; Chromosome 17p13; Dominant
      • Mutation: Val383Ile
      • 1 patient identified
      
      
    • Mitochondrial
      • Clinical DM type: NIDDM & Deafness
        
        
    • Hyperproinsulinemia
      ● Chromosome 11p15.1-p15.5; Dominant
      
      • Clinical DM type: NIDDM; MODY
• Other types of DM
  
  
  • Genetic defects
    • β cell function
      
    • Insulin action
    • Insulin receptor
      • Diabetes mellitus: Insulin resistant or NIDDM
      • Other associations: ± Acanthosis Nigricans ; Leprechaunism ; Rabson-Mendenhall syndrome
    • Peroxisome proliferator-activated receptor γ (PPARG)
      • Diabetes mellitus, insulin-resistant
      • Acanthosis nigricans
      • Hypertension
    • Diabetes, transient neonatal
      ● Chromosome 6q24; Recessive
    • Diabetes, permanent neonatal
      ● Glucokinase ; Chromosome 7p15-p13; Recessive
    • Immunodeficiency, Polyendocrinopathy & Enteropathy, X-linked (IPEX)
      ● Forkhead Box P3 (FOXP3) ; Chromosome Xp11.23-q21.1; Recessive
      • Diabetes mellitus: Insulin-dependent
      • GI: Enteropathy; Peritonitis
      • Hypothyroidism
      • Anemia; Thrombocytopenia
      • Skin: Dermatitis; Eczema
    • Other genetic syndromes associated with diabetes
  • Pancreas: Exocrine disease
    • Pancreatic agenesis: Insulin promoter factor 1
      
  • Endocrinopathy
  • Mitochondrial
  • Toxic: Drug or chemical induced
  • Infection related
  • Immune-related DM: Autoantibodies
    • Glutamic acid decarboxylase (GAD): 65 kD
      
      • Occur in: 25% of presymptomatic DM patients; Adult onset DM type IA
      • Also associated with: Stiffman syndrome
      • Sensitivity: Occur in 69% of IDDM sibs who develop DM
      • Specificity: 42% of positives developed DM over 7.7 years
    • Islet cells (ICA)
      • Sensitivity: Occur in 81% of IDDM sibs who develop DM
      • Specificity: 43% of positives developed DM over 7.7 years
    • Tyrosine phosphatase-like molecules
      • ICA512 (IA-2)
        • Sensitivity: Occur in 69% of IDDM sibs who develop DM
        • Specificity: 55% of positives developed DM over 7.7 years
      • IA2-β : 61% sensitivity
    • Insulin
      • Sensitivity: Occur in 29% of IDDM sibs who develop DM
      • Specificity: 25% of positives developed DM over 7.7 years
      • Higher titers in young children
    • Glycolipids: GT3 ganglioside; ? Sulfatide; ? GM2-I
    • Antibodies: Clinical correlations ⁴
      • Multiple antibodies: Higher risk for developing diabetes; Lower C-peptide
      • ICA + GAD65 antibodies: Less neuropathy, nephropathy or hypertension in adult type I DM
      • Single antibody positivity & low Ab titers: Phenotype similar to NIDDM (type 2 DM) patients
      • Antibody negative patients: More DM complications in adult type I DM
• Gestational DM

• Diabetes mellitus: Prevalence
  • US population: 6%
  • Increasing worldwide: 4.5% in 1980; 8.5% in 2014
• Neuropathy in Diabetes mellitus: Prevalence
  • Disease onset: 7.5%
  • 25 years after onset: 50%
  • Overall: 30%
  • Similar or slightly higher in NIDDM (Type 2) vs. IDDM (Type 1)
• Risk factors for developing diabetic neuropathy ⁹
  • Glycemic control: Higher glycosylated hemoglobin
  • Cardiovascular risk factors: Metabolic syndrome
    • Hypertension
    • Smoking
    • Obesity
    • Triglyceride levels: High
  • Presence of cardiovascular disease
  • Type 2 diabetes: α2B adrenoceptor gene (ADRA2B) ¹³
    • Gene has Insertion (I)/Deletion(D) polymorphism: I/D of 3 glutamic acid residues
    • 2x greater frequency of D allele in Type 2 patients with peripheral neuropathy
    • More severe neuropathy in patients with D allele
    • Polymorphism also associated with
      • Obesity
      • Impaired insulin secretion
      • Earlier onset of diabetes
      • Increased risk of acute coronary ischaemia
      • Autonomic dysfunction: Increased sympathetic nervous system activity
  • Type 2 diabetes
    • Uric acid levels 50% higher with neuropathy than without
  • Susceptibility to microvascular complications of diabetes
    • MVCD1 (6p12) : VEGF
    • MVCD2 (7q21) : EPO
    • MVCD3 (17q23) : ACE
    • MVCD4 (2q14.2) : IL1RN
    • MVCD5 (7q21.3) : PON1
    • MVCD6 (6p25.3) : SOD2
    • MVCD7 (6p21.3) : HFE
• Screening test for diabetes mellitus: Fasting plasma glucose
  • After 8 hour fast
  • Level: > 126
  • Repeated on 2 separate occasions
  • Glycosylated hemoglobin may be used but is less standardized
• Neuromuscular & other disorders with associated Diabetes
  • Genetic
    • Ataxia telangectasia
    • Friedreich's ataxia
    • Myotonic dystrophy
    • Amyloid
    • IPEX
    • Lipodystrophies
    • Acute Intermittent Porphyria
    • Refsum's syndrome
    • Glycogen storage disease
    • Cystinosis
  • Other
    • Mitochondrial
    • Stiffman syndrome
    • Vacor toxicity
• Pathological mechanisms & morphology in DM
  • Hyperglycemia results in ⁵
    • Protein glycation
      • Example is Hemoglobin A1C
      • Associated with increased permeability of proteins across blood-nerve barrier: Accumulation in nerve
    • Advanced glycosylation endproducts (AGEs)
      • Supply free radicals: Autoxidative glycation, or Glycoxidation
      • AGE receptors: Trigger cellular oxidant stress by inducing cytokines
    • Oxidative stress
  • Nerve pathology ¹⁸
    • Axon loss
    • Endoneurium
      • Collagen VI: Increased in diabetes immediately surrounding groups of Schwann cells
      • Collagen I & III: Increased in diabetes & other disorders
    • Perineurium
      • Increased types IV & V collagen: Especially in innermost lamellae
    • Endoneurial microvessels
      • Collagen around microvessels: Increased types IV, V and VI
      • C_5b-9 deposition
• Sequellae
  • Pain
  • Falls
  • Charcot Neuro-Arthropathy
  • Ulcers & Amputation: Foot
    • Mortality: 23% at 2 years; 71% at 10 years
• CNS: Spinal cord atrophy reported with diabetes

• Distal: Sensory ± Autonomic
  • Epidemiology: Risk factors & associations
    • Most common type of diabetic neuropathy
    • Temporal risk of neuropathy after onset of DM
      • Symptomatic evidence
        • 5 years: 4% to 10%
        • 25 years: Mean 30%; Range 13% to 50%
        • Mean time after DM onset: 8 years
        • Increased Frequency: Women; Increased Age
      • Objective evidence (Clinical or electrophysiologic): 65% to 80% of all diabetics
    • Clinical features
      • General: Increased
        • Age
        • Body weight (Waist circumference)
        • Height
        • Disease duration
      • Diabetes
        • Duration: Longer
        • Hemoglobin A1C: High: ? More with T2D & A1C > 6.5-7.1 ²³
        • Triglycerides high: More progressive axon loss ¹⁴
        • Type 1 diabetes ¹⁶
          • Poor glycemic control
        • Type 2 diabetes ¹⁵
          • Arterial stiffening & thickness
          • Metformin treatment: Associated with low B₁₂ & More severe neuropathy
        • Adolescents & Young adults
          • Neuropathy prevalence: More with type 2 (26%) than type 1 (8%) diabetes
          • No difference between types 1 & 2 after adjusting for age, sex, waist size & other diabetes risk factors
      • Systemic disorders
        • Hypertension (Diastolic)
        • Retinopathy
        • Metabolic syndrome
        • Dyslipidemia
        • Renal disease (Microalbuminuria)
      • Smoking
    • Laboratory features
      • Lipids: Increased risk
        • HDL-cholesterol: Reduced
        • Triglycerides: Increased
          • Progressive axonal loss: Somewhat more
      • Vitamin D (25-hydroxyvitamin D(25(OH)D)) deficiency (<20 ng/mL)
      • Albuminuria
      • Methylglyoxal ¹⁷
        • Higher serum levels in painful neuropathies
        • Activates Na_v1.8 channel
      • Hyperglycemia: Degree, Duration & Variability
        • ? Related to polyol pathway
          • Aldose reductase & sorbitol dehydrogenase convert glucose to fructose
          • Poorly controlled diabetes → More Sorbitol & Fructose in cell
          • More Sorbitol → Hypoxia & ischemia
          • ? Myoinositol: Reduced → Slowing of nerve conduction velocity
          • Mice transgenic for Aldose reductase → Galactosemic neuropathy
        • Protein glycosylation
        • Intensive insulin therapy
          • Reduce mean glycated hemoglobin (HbA1C) from 9.1% to 7.2%
          • Reduces risk of developing neuropathy by 60%
      • Aldose reductase 2 gene polymorphism
        • Dinucleotide repeat 2.1 kb upstream (5' end) of transcription start site
          • Near osmoregulatory element for aldose reductase gene transcription
        • Z+2 allele: 14% risk of DM neuropathy after 20 years
        • Other alleles: 38% risk
      • T-cell Receptor β chain
        • Associated with susceptibility to microvascular complications in IDDM
      • Other possible pathogenic factors
        • Metabolic compromise
        • Ischemia
        • Oxidative stress
        • Neurotrophic support: Reduced
  • Neuropathy: Clinical features ²⁰
    • Early: Often asymptomatic
    • Sensory loss
      • Usual: Pansensory (Small & Large fiber modalities)
      • Occasional: Selective involvement of fiber types
        • Small fiber
          • Thermal thresholds: Reduced
          • Pain
          • Often involved early
        • Large fiber
          • Vibration sense: Reduced
          • Paresthesias
          • Ankle reflexes: Absent
          • Gait disorder
      • Distribution
        • Legs > Arms
        • "Stocking-Glove"
      • Associated with foot ulcers in chronic DM
        • 7x increase
        • Age: Middle-aged & elderly
        • Location: Soles of feet
        • Neuropathic osteoarthropathy: Frequency increased
    • Discomfort
      • Risk factors
        • Similar to Diabetic PN in general
        • More sensory loss
      • Types
        • Pain
        • Burning
        • Fatigue
      • Distribution
        • Distal: Usual
        • Orofacial: Occasional; Burning mouth; Fatigue
      • Onset
        • Spontaneous
        • Evoked: Allodynia; Hyperalgesia
    • Weakness
      • Severity: Mild or Absent
      • Distribution: Legs; Distal
      • Associations
        • Chronic DM
        • Disorders other than DM
    • Autonomic involvement: Some patients
      • Sympathetic denervation: Increased peripheral blood flow
      • Cardiac denervation
    • Charcot joints (Neurogenic osteoarthropathy)
      • Onset
        • Age: 50 to 65 years
        • Course: Usually gradual, Ocasionally acute
        • Location: Navicular bone
      • Locations: Foot 60%; Ankle 10%
      • Associations
        • Poorly controlled insulin-dependent diabetes
        • Osteopenia (100%)
        • Calcification: Vascular smooth muscle cells (78% to 90%)
        • ? Regional increased blood flow (Hyperemia)
        • ? Related to disorders of OPG/RANK-L pathway
      • X-rays: Bone & Joint destruction; Calcific deposits around joint
    • Progression
      • Neuropathy may be asymptomatic for long periods
      • Longer latency: After onset of Type I, than Type II, diabetes
      • Slow over 5 to 20 years
      • Effects of glycemic control ¹¹
        • Progression of neuropathy occurs despite good efforts at control
        • Least progression: Aggressive blood sugar control
        • Control benefits other associated features: Triglyceride & high-density lipoprotein cholesterol levels
  • Neuropathy: Laboratory features
    • Electrodiagnostic testing
      • SNAP amplitudes: Reduced
      • Conduction velocities: Normal or Mildly reduced
      • Refractory periods
        • Shorter in diabetic nerves: ? Related to reduced nodal Na⁺ currents
    • Pathology
      • Axon loss
        • Size: Large & Small axons
        • Younger patients with IDDM: Loss is unform among fascicles
        • Older patients with NIDDM: May have multifocal axonal loss
      • Axon regeneration
      • Capillary walls
        • Thickened
        • Hyalinization (Reduplication of basement membranes)
      • Axonal swellings: In distal axons
      • Collagen: Increased around vessels ¹
        • Collagen I & III increase: Common change in many neuropathies
        • Collagen IV, V, VI increase
          • Around endoneurial vessels
          • Collagen, Type VI increase relatively specific for diabetes
      • Basal lamina: Tubes often persist after axonal degeneration
  
  
• Autonomic neuropathy, Diabetic ⁷
  • Also see: Acute treatment-related diabetic neuropathy
  • General
    • Most common cause of autonomic neuropathy in developed contries
    • Clinical symptoms: General
      • Multiple autonomic systems involved: Sympathetic & Parasympathetic
      • Usually only occur long after onset of diabetes
      • Often associated with: Distal sensory-motor neuropathy
    • Subclinical autonomic dysfunction can occur within
      • One year of diagnosis in type 2 diabetes
      • Two years of diagnosis in type 1 diabetes
    • Patterns of involvement
      • Sympathetic & Parasympathetic involvement: Common in type 1 & type 2 diabetes
      • Type 1 diabetes: Sympathetic & Parasympathetic functions correlate
      • Type 2 diabetes: Parasympathetic function more affected
    • Increased risk with
      • Duration of diabetes
        • Subclinical manifestations: 30% after 10 to 15 years
          
        • Clinical symptoms: 1% to 5%
      • Severity of hypoglycemia
      • Hemoglobin A1C: High
      • Age: Increased
      • Body weight: High
      • Systemic disorders: Albuminuria; Retinopathy
      • Presence of associated polyneuropathy
      • Insulin-dependent diabetes
      • Hypertriglyceridemia
    • Long term
      • Overall mortality & Sudden death: Increased
      • Mortality rates with cardiovascular autonomic neuropathy: 27% to 56% over 5–10 years
  • Genito-urinary
    • Erectile dysfunction
      • Frequency
        • Most common symptom of diabetic autonomic neuropathy
        • 30–75% of diabetic men
        • May be earliest sign of diabetic autonomic neuropathy
      • Clinical syndromes
        • Ejaculatory failure: Sympathetic nervous system dysfunction
        • Erectile dysfunction with preserved ejaculation & orgasm
          • Impaired nitric-oxide mediated relaxation of smooth muscle in corpus cavernosum
          • Locations: Autonomic nerves; Endothelium
      • Course
        • Initially partial
        • Progression to complete over 1 to 2 years
        • Usually irreversible
      • Increased frequency with
        • Age
        • Duration of diabetes
        • Vascular disease
      • Pathogenic factors
        • Autonomic neuropathy
        • Atherosclerotic involvement of the internal pudendal artery
        • Impaired endothelium-dependent relaxation of penile smooth muscle
        • Metabolic control impaired
        • Somatic sensory impairment
    • Retrograde ejaculation: Uncommon; Occurs in diabetics with selective sympathetic failure
    • Voiding dysfunction: Dysfuncton of bladder emptying
      • Frequency: Symptomatic in up to 50% of patients with diabetes, and there is
      • Physiological evidence of bladder dysfunction: 43–87% of insulin-dependent diabetes
      • Earliest manifestation of autonomic bladder dysfunction
        • Impaired sensation
        • Increases the threshold for initiating micturition reflex
      • Intermediate features: Reduced detrusor activity causes
        • Incomplete bladder emptying
        • Increased postvoid residual
        • Reduced peak urinary flow rate
        • Bladder overdistension
      • Late features
        • Urinary retention
        • Overflow incontinence
    • Females: Reduced vaginal lubrication
  • Cardiovascular
    • Dysfunction present in 20% of asymptomatic diabetics
      • Longitudinal testing: R-R variation; Valsalva maneuver; Postural blood pressure testing
      • Vagal denervation: High resting heart rate
      • Cardiovascular reflexes: Impaired
    • Postural hypotension
      • Pathophysiology: Efferent sympathetic vasomotor denervation; Reduced vasoconstriction
      • Subclinical changes: 17% to 43%
      • Symptomatic involvement
        • Symptoms: Lightheadedness, Weakness, Cognitive impairment, Blurred vision
        • Cognitive impairment without lightheadedness: Common in patients > 60 years
        • Less than 1% of diabetic neuropathy
        • Symptoms may be reduced with more chronic involvement
      • Prominent involvement associated with: Multisystem autonomic failure
      • Exacerbation: Postprandial; Early morning; Increased ambient temperature
    • Cardiac disorders
      • Sympathetic denervation
        • Abnormal vasoconstriction
        • Impaired myocardial coronary blood flow & myocardial contractility
      • Parasympathetic denervation
        • Reduced R-R interval variation
        • Vagus involvement: Increased heart rate
        • Increased cardiovascular mortality after myocardial infarction
      • Sympathetic + Parasympathetic
        • Heart rate fixed
        • Inadequate capacity to increase rate with physiological demands
      • Cardiovascular autonomic function: Reduced
        • Associated with increased risk of silent myocardial ischemia & mortality
  • Gastrointestinal
    • May involve all parts of GI tract
    • Esophagus
      • Features
        • Reflux
        • Regurgitation
        • Dysphagia
      • Barrett esophagus: Increased frequency
    • Gastroparesis
      • Gastric motor disorders are relatively common: Occur in up to 50% of brittle diabetics
      • Symptoms
        • Discomfort: Nausea, Vomiting, Early satiety, Postprandial bloating, Diffuse epigastric pain
        • Early satiety
        • Weight loss: Variable; May be profound
        • Some patients asymptomatic
        • Laboratory: Food residue retained in stomach
      • Other associations
        • Poor correlation between symptoms and laboratory-demonstrated gastroparesis
        • Reversible component: Asociated with hyperglycemia
      • Physiology
        • Gastric emptying: Impaired
        • Gastric accommodation: Impaired
        • Visceral hypersensitivity
        • Gastric dysrhythmia
    • Constipation
      • Most common lower-GI symptom: Up to 60%
      • Can alternate with episodes of diarrhea
    • Nocturnal diarrhea
      • Profuse watery diarrhea
        • May persist for hours to several days
        • Can be accompanied by fecal incontinence
      • Associated with somatic & autonomic neuropathy
      • More common: Type 1 diabetes
      • May be associated with: Small intestinal bacterial overgrowth
      • Rule out drug toxicity: Metformin
    • Fecal incontinence
      • Due to: Incompetence of anal sphincter or Reduced rectal sensation
      • Exacerbated by diarrhea
  • Sudomotor syndromes
    • Hypohidrosis
      • Loss of thermoregulatory sweating
      • Initially distal: Glove-stocking distribution
      • May become diffuse: With more severe autonomic neuropathies
    • Hyperhidrosis: Feet associated with coldness
    • Gustatory sweating
      • Excessive facial sweating in response to food, especially spicy
      • Associated with cervical sympathetic denervation
  • Skin: May be among earliest manifestations of autonomic neuropathy
    • Mechanisms: Changes in microvascular skin blood flow & sudomotor function
    • Clinical features
      • Hypohidrosis & Dry
      • Ulcers, fissures & cracks
  • Other
    • "Brittle diabetes"
    • Hypoglycemic autonomic failure
  • Differential diagnosis: Autonomic neuropathy
  • Laboratory evaluation
    • Cardiovascular heart rate tests: Heart rate response to deep breathing, Valsalva maneuver & standing
    • Sudomotor: QSART to evaluate distal postganglionic axons
    • Adrenergic function: Cardiovascular responses to stimuli
  • Prognosis: Moderately increased mortality over 10 years with autonomic neuropathy
  
  
• Sensory-Motor
  • Clinical
    • Wekness: Distal weakness
    • Sensory loss: Pan-modal
    • Progressive over 1 to 20 years
    • May be due to
      • Immune multifocal vasculopathic neuropathy
      • HIEM
  • Nerve biopsy
    • Blood vessels: Complement deposition & Cellular infiltrates
    • Axon loss: May be variable within nerve & fascicles
  
  
• Gustatory ²⁴
  • Type I Diabetes
    • Salt taste: Reduced sensitivity
    • Sweet taste: Increased sensitivity
  • Gustatory sweating
  
  
• Chronic immune demyelinating polyneuropathy (CIDP)
  • Possible increased incidence in diabetes

• Acute painful
  • Pain
    • Burning & hypersensitivity: Feet
    • May be severe
    • Often worse at night
  • Signs: Often only mild changes
    • Mild sensory loss: Distal; Symmetric
    • Tendon reflexes: Normal or Reduced
  • Associations
    • Poorly controlled diabetes
    • Recent onset of insulin therapy
    • Rapid weight loss
  • Improvement: After control of diabetes & weight gain
  
  
• Rapidly reversible diabetic neuropathies
  • Hyperglycemic
    • Time: Newly diagnosed, untreated diabetes
    • Clinical: Asymptomatic
    • Laboratory: Reduction of nerve conduction velocities
  • Glycemic-control, Diabetes Treatment induced ⁸
    • Nosology: "Insulin neuritis"
    • Diabetes relations
      • Diabetes type: I or II
      • Treatment
        • Drugs: Hypoglycemic initiation, especially insulin
    • Clinical
      • Onset
        • Time
          • 1st 4 weeks (< 8 weeks) after onset of hypoglycemic treatment
          • Months to years after onset of diabetes
        • Age: May occur in children or adults
        • Association: Large improvement in glycemic control
          • HbA1c reduced by ≥ 2% over 3 months: 20% Risk of acute neuropathy
          • HbA1c reduced by ≥ 4% over 3 months: 80% Risk of acute neuropathy
      • Discomfort
        • Paresthesias
        • Burning
        • Leg tenderness
        • Hyperalgesia & Allodynia (57%)
        • Distribution: Hands & Feet; Occasionally diffuse
        • Often severe
        • More pain with greater reduction in HbA1c
      • Sensory loss
        • Pan-modal: Especially Pain & Temperature
        • Distribution
          • Common: Distal; Lower limbs; Symmetric
          • More severe involvement: May be non-length dependent
      • Autonomic
        • More common & severe in type I diabetes
        • Cardiovascular
          • Orthostatic symptoms: Lightheaded & Dizzy; Presyncope
          • Parasympathetic abnormalities: Heart rate response to deep breathing; Expiratory to inspiratory ratio; Valsalva ratio
          • Sympathetic: Orthostatic hypotension
        • Gastrointestinal: Nausea; Diarrhea; Appetite change
        • Genitourinary: Frequency; Anuria; Erectile dysfunction
        • Sudomotor: Anhidrosis
        • Also see: Chronic diabetic autonomic neuropathy
      • Weight loss
      • Course
        • Monophasic
        • Symptoms disappear or abate with continued control of blood sugar
        • 50% improvement in pain in 12 to 28 months
          • More improvement with type I than type II diabetes
      • Associated with
        • Retinopathy progression
        • Weight loss: Recent or Remote
      • Treatments
        • Continue glycemic control
          • Neuropathy association: Reduced Hemoglobin A1C
            • 3% reduction: Neuropathy frequency 60%
            • 6% reduction: Neuropathy frequency 100%
        • Pain control
    • Laboratory
      • Nerve conduction: Abnormalities may persist after resolution of symptoms
      • Skin biopsy
        • Small axons
          • Reduced numbers of intraepidermal axons (80%) by 4 weeks
          • Return toward normal after ~ 8 months
        • Large axons: Swellings
      • Microalbuminuria
    • Also see: Acute Diabetic neuropathies

Diabetic Neuropathies: Asymmetric

General Amyotrophy Lumbosacral plexopathy Mononeuropathy Mononeuritis multiplex Multifocal

Diabetic neuropathy, Ongoing: Wallerian degeneration Auche MB; Arch Med Exp Anat Pathol 1890;2:635–676

• General features
  • Onset: Often Acute or Stepwise
  • Nosology: Bruns Garland Syndrome
  
  
• Lumbosacral plexopathy
  • Nosology: Similar syndromes
    • Proximal diabetic neuropathy
    • Diabetic amyotrophy
    • Multifocal diabetic neuropathy
    • Also see
      • Non-diabetic Lumbosacral plexopathy
      • Diabetic cervical polyradiculopathy
  • Epidemiology
    • Overall prevalence: 0.08% of diabetics
    • More frequent with type II (1.1%) than type I (0.3%) diabetes
  • Clinical features
    • Weakness
      • Asymmetric
      • Proximal weakness: Quadriceps; Thigh adductors; Psoas
      • Distal weakness: Ankles & Toes
      • Localized to lumbosacral plexus or lumbar roots
    • Pain
      • Localized to: Hip, buttock, or thigh
      • May be severe
      • Usuallly lasts months after disease onset
    • Sensory loss: Distal
  • Associated factors
    • Poor diabetic control
    • Weight loss
    • Non-insulin dependent diabetes
  • Differential diagnosis
    • Lumbosacral plexopathy
    • Cauda equina lesion
  • Electrodiagnostic
    • EMG: Multifocal denervation in paraspinous & leg muscles
    • NCV: Axonal loss; Small CMAPS & SNAPs
  • Pathology: Inflammatory or Humoral vasculopathy ³
    • Inflammation
      • Location
        • Epineurial
        • Perivascular: Near smaller vessels
      • Type: Mononuclear ± PMN (Early in disease course)
    • Endoneurial capillaries
      • Pipestem: Thick walls
      • C5b-9 complement deposition
      • RBC extravasation or hemosiderin: Near vessels
    • IgM deposition: Endoneurium & Subperineurial space
    • Axon loss
      • Myelinated & Unmyelinated axons
      • Differential fascicular
  • Treatment
    • Pain control
    • Diabetic control
    • Corticosteroids
      • Treatment: Solumedrol, iv, pulse
      • Reduce pain
      • Often associated with improved strength
    • ? IVIg: Hastens recovery; dose 2g/kg q month x3
  • Prognosis
    • Slow recovery over 6 to 24 months after diabetic control
    • Partial or complete
  • Variant syndrome: Diabetic amyotrophy
    • Nosology: Proximal diabetic neuropathy
    • Frequency: Rare
    • Onset: Sub-acute
    • Associations: Diabetes, poorly controlled; Weight loss, prominent
    • Clinical features
      • Pain: Severe; Unilateral
      • Weakness: Proximal, especially quadriceps & psoas; Unilateral
      • Sensory loss: Not prominent
      • Disease course: Monophasic; Recovery over months, even without treatment
  • Variant syndrome: Multifocal diabetic neuropathy ⁶
    • Frequency: Occasional
    • Onset: Sub-acute
    • Clinical
      • Pain
      • Weakness
        • Asymmetric
        • Predominant pattern: Distal; Legs
        • Other: Proximal legs; Thoracic (Radiculopathy); Arms (Ulnar, Radial)
      • Sensory loss
      • Impotence in males
    • Laboratory
      • Electrophysiology: Asymmetric axonal loss
      • CSF: Protein often high
    • Pathology
      • Inflammation: Perivascular inflammation & hemorrhage; Vasculitis in some
      • Axonal degeneration & loss
  • Variant syndrome: Diabetic Cervical Radiculoplexopathy ¹⁹
    • Nosology: May be same as Brachial neuritis in diabetic patients
    • Clinical
      • Onset age: Mean 62 years; Range 32 to 85 years
      • Distribution
        • Asymmetric, Often unilateral
        • Arms: Upper, Middle & Lower Brachial plexus segments
        • Other body parts (60%)
          • Opposite arm
          • Lumbosacral
          • Thoracic
      • Weakness (98%)
      • Pain (80%)
      • Numbness (70%)
      • Course
        • Often monophasic
        • Relapse in 25%
    • Laboratory
      • NCV: Axon loss
      • EMG: Denervation in arms & some paraspinals (30%)
      • MRI: Brachial plexus involvement
      • Nerve biopsy
        • Differential axon loss
        • Perineurial thickening
        • Inflammation: Epineurial; Perivascular
  
  
• Mononeuropathies: May involve single nerves or roots
  • Cranial nerve
    • Especially in older diabetics
    • Third nerve most common
      • Onset: Late adulthood
      • Sudden onset
      • Retro-orbital pain
      • Sparing of pupil involvement
      • Recovery: No misregeneration; Within weeks to months
    • 7th nerve
      • Probably involved more often than general population
  • Limb
    • Vascular lesions: Major limb nerves can be affected
      • Onset: Abrupt & painful
      • Common location: Lumbosacral plexopathy
      • Recovery: Best with distal lesions, acute onset
    • Damage at common compression sites
      • Carpal tunnel syndrome: 25% asymptomatic; 8% symptomatic
      • Other: Ulnar; Posterior tibial (Tarsal tunnel)
  • Trunk
    • Sensory
      • Acute, unilateral pain
      • Distribution: 1 or multiple thoracic nerves
      • Pain is non-radicular & difficult to manage
      • Hypersensitive skin region
    • Motor: Weak abdominal wall muscles; May lead to heriation
    • Associations
      • Especially in patients > 50 years
      • Some patients with weight loss: r/o malignancy
    • Course: Spontaneous improvement over 1 to 2 years
  
  
• Mononeuritis multiplex
  • Multiple mononeuropathies with polyneuropathy
  • Coexisting focal compression neuropathies
    • Ulnar compression at elbow: More common in diabetes
    • Median at wrist: Often asymptomatic
  • See: Lumbar plexopathy; Diabetic amyoptrophy

Associated features Diabetes Chronic Insulin-dependent Poorly controlled (22%) Type I (80%) or II (20%) Duration: Long; Mean 16 years; Range 1 to 50 years Other microvascular complications: Common (97%) Renal (90%): Most with nephropathy; 25% failure Retinopathy (65%) Neuropathy (80%) Hypertension Female (61%) ≥ Male Clinical Onset Acute Pain & tenderness Swelling Age: Mean 40 years Location Thigh Anterior (65%) Gracilis; Rectus femoris; Vastus medialis Medial (21%) Posterior (14%) Other muscles Distal leg: Anterior or Posterior Arms (3%) Multiple (27%) Pain: At rest; Increased with movement Examination: Mass in thigh; Tenderness Course Self limited Resolution: Over weeks to months; Mean 2 months Recurrence common Frequency: 37% to 62% May recur several times May be Contralateral Median time: 2 months Long term High 5 year mortality with cardiovascular complications Laboratory Serum CK: High in 45%; Mean 2x Sedimentation rate: Often elevated > 100 mm/h X-ray: Vascular mineralization MRI: Best diagnostic modality Muscle: Enlargement & "Edema" Signal High & Asymmetric: T2 & Inversion-recovery images Gadolinium: Minimal enhancement T1: Isointense or hypointense Location of damage: Muscle; Perifascial space; Subcutaneous Tissue planes: Fluid Muscle biopsy Necrotic & regenerating muscle fibers Hyaline thickening of arterioles Perivascular inflammation Hemorrhage Edema Ultrasound Internal linear echogenic structures No internal motion under transducer pressure No predominantly anechoic areas Cause: ? Diabetic microangiopathy Thickening of small artery walls Vascular occlusion Treatment: Symptomatic Rest Analgesics Gradual mobilization

Swelling of left distal leg MRI: Diabetic myonecrosis of L leg MRI: Diabetic myonecrosis of L thigh (Quadriceps)

• Model of type I diabetes
• Mechanisms
  1. ? ADP-Ribosyltransferase (PARP) activation ®
  2. Reduced substrates NAD(+) & ATP ®
  3. Cellular death 2° energy depletion
• Effects: Destroys insulin-producing β islet cells of the pancreas

• Triglyceride level >300 mg/dl: Frequent asymptomatic sensory-motor axonal neuropathy
  • Sensory nerves: Prolonged distal latencies
  • Motor & Sensory nerves
    • Conduction velocities: Mildly slowed
    • Amplitudes: Normal
  • Anatomy: Legs more involved than arms
• Triglyceride level: High
  • Increased risk of neuropathy in diabetes
  • Higher levels in patients with idiopathic sensory neuropathy
• Triglyceride level: Very High
  • Epidemiology: 6 patients described
  • Clinical: Polyneuropathy
    • Painful
    • Distal: Feet
    • No weakness or autonomic changes
    • Tendon reflexes: Reduced at ankles (50%)
  • Treatment: Improvement in 1 patient with reduction of triglycerides
• Other disorders
  • Tangier disease
  • Triglyceride storage disease with impaired long-chain fatty acid oxidation
  • Neutral lipid storage disease with myopathy