Harvey's Garden

Polyneuropathy

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aliasesCharcot-Marie-Tooth disease, Mononeuritis multiplex

6 min read

Epidemiology

Etiology

  • Metabolic/Endocrine:
  • Toxic / Medication-Induced:
    • Alcohol abuse (direct neurotoxicity + nutritional deficiency).
    • Chemotherapy: Cisplatin, Oxaliplatin, Paclitaxel, Vincristine.
    • Other drugs: Isoniazid (INH), Metronidazole, Amiodarone, Nitrofurantoin, Phenytoin.
    • Heavy metals: Lead, Arsenic, Thallium.
  • Nutritional Deficiencies:
    • Vit B12 (Cobalamin) deficiency: Pernicious anemia, veganism, gastric bypass, ileal resection.
    • Vit B1 (Thiamine) deficiency: Dry beriberi, Wernicke-Korsakoff syndrome.
    • Vit B6 (Pyridoxine) deficiency (e.g., INH therapy without B6 co-administration) or toxicity.
    • Vit E deficiency (mimics Friedreich ataxia).
  • Inflammatory / Autoimmune / Paraproteinemic:
    • Chronic Inflammatory Demyelinating Polyneuropathy (CIDP), Guillain-Barré Syndrome (AIDP).
    • Monoclonal Gammopathy of Undetermined Significance (MGUS), Multiple Myeloma (MM), AL Amyloidosis.
    • Vasculitides (PAN, SLE, RA, EGPA, Sjögren syndrome).
  • Infectious:
    • HIV, Hepatitis C (cryoglobulinemia), Lyme disease, Leprosy (Hansen disease).
  • Hereditary:
    • Charcot-Marie-Tooth (CMT) disease (most commonly PMP22 duplication / CMT1A).

Tip

Diabetes mellitus and alcohol use disorder account for most cases in developed countries.

Pathophysiology

Clinical features

  • Symmetrical distal sensory loss (glove and stocking pattern)
    • Vibratory perception is often lost first, followed by loss of pin-prick, temperature, and light touch perception.
  • May be accompanied by neuropathic pain, paresthesias, and motor weakness
    • Burning-foot syndrome: burning pain, tingling, pins-and-needles sensation, or formication , hyperhidrosis
  • Atrophy of muscles: e.g., stork legs in the case of Charcot-Marie-Tooth disease
  • Sensory ataxia: caused by loss of sensation, particularly proprioception, that affects the afferent limb of postural reflexes (e.g., due to vitamin B12 deficiency).
  • ↓ Deep tendon reflexes

Subtypes and variants

Hereditary motor sensory neuropathy (HMSN)

Also known as Charcot-Marie-Tooth disease

  • Pathophysiology
    • Primarily demyelinating neuropathy
    • Various mutations cause impaired growth or function of the axons or Schwann cells (e.g., defects in axon or myelin sheath proteins).
  • Clinical features: onset before the age of 20 years with distal symmetrical sensorimotor polyneuropathy
    • Foot drop, pes cavus deformity, hammer toe
    • Atrophy of the calf muscles (stork leg appearance)
      • vs Myotonic syndromes, which has pseudohypertrophy (rather than atrophy) of the calf muscles.
    • Weak intrinsic hand muscles
    • Sensory loss

Chronic inflammatory demyelinating polyneuropathy

  • Overview:
    • Autoimmune demyelination of peripheral nerves and nerve roots.
    • Chronic course lasting > 8 weeks (distinguishes from GBS/AIDP).
    • Associated with MGUS, DM, HIV, and autoimmune disorders.
  • Clinical Presentation:
    • Motor: Symmetric, progressive proximal AND distal muscle weakness (difficulty climbing stairs and gripping objects).
    • Sensory: “Stocking-glove” sensory loss; loss of vibration & proprioception > pinprick/temperature; sensory ataxia ((+) Romberg).
    • Reflexes: Generalized areflexia or hyporeflexia.
  • Diagnosis:
    • Initial & Best Test: NCS/EMG showing primary demyelination (↓ conduction velocity, conduction blocks, prolonged distal latencies).
    • LP: Albuminocytologic dissociation (↑ CSF protein with normal CSF WBC count).
    • Imaging: Spine MRI shows gadolinium enhancement and hypertrophy of cauda equina/nerve roots.
    • Biopsy (rare): Sural nerve biopsy showing “onion-bulb” formations.
  • Differential Diagnosis:
    • GBS (AIDP): Acute onset (< 4 weeks to nadir), autonomic instability, steroids are ineffective.
    • Diabetic Neuropathy: Distal only (no proximal weakness), axonal pattern on NCS, normal CSF protein.
    • Charcot-Marie-Tooth (CMT): Autosomal dominant, childhood onset, pes cavus, hammer toes.
  • Management:
    • First-Line: Corticosteroids (steroid-responsive, unlike GBS), IVIG, or Plasma Exchange (PLEX) (all equally effective).
    • Maintenance: Periodic IVIG/SCIG or slow steroid taper + steroid-sparing agents (Azathioprine, Mycophenolate).
    • Refractory: Rituximab.
    • Symptomatic: Gabapentin/Pregabalin for neuropathic pain; PT/OT and AFOs for gait instability.

Alcoholic polyneuropathy

  • Pathophysiology & Risk Factors:
    • Direct neurotoxicity from chronic heavy ethanol/acetaldehyde exposure.
    • Concurrent nutritional deficiency, predominantly thiamine (vitamin B1), folate, and B12.
    • Associated with chronic, severe alcohol use disorder (AUD).
  • Clinical Features:
    • Sensory (early/prominent): Symmetric, distal-to-proximal “stocking-glove” loss; burning pain, paresthesias, allodynia, loss of vibration/proprioception.
    • Motor (late): Distal muscle weakness, intrinsic foot/hand atrophy, bilateral foot drop (steppage gait). c
    • Reflexes: ↓ or absent deep tendon reflexes (DTRs); loss of ankle jerks (Achilles reflex) is the earliest sign.
    • Gait/Coordination: Sensory ataxia with (+) Romberg sign.
    • Autonomic (severe): Orthostatic hypotension, erectile dysfunction, impaired sweating, GI dysmotility.
  • Diagnosis:
    • Clinical: History of heavy AUD + symmetric length-dependent sensorimotor polyneuropathy.
    • EMG & Nerve Conduction Studies (NCS): Symmetric, length-dependent sensorimotor axonal degeneration (marked ↓ in SNAP and CMAP amplitudes; normal/mildly reduced conduction velocity).
    • Exclusionary Labs: Whole blood thiamine, vitamin B12 & MMA, HbA1c/fasting glucose, TSH, folate, CBC (↑ MCV), LFTs (AST:ALT > 2:1).
  • Key Differentials:
    • Diabetic Peripheral Neuropathy: Identical distribution; differentiated by elevated HbA1c and absence of severe AUD.
    • B12 Deficiency (Subacute Combined Degeneration): Differentiated by UMN signs (hyperreflexia, spasticity, (+) Babinski) + elevated MMA.
    • Guillain-Barré Syndrome (AIDP): Acute ascending motor paralysis, demyelinating pattern on NCS, and albuminocytological dissociation on LP.
  • Management:
    • Etiology-directed (First-line):
      • Strict alcohol cessation/abstinence (mandatory to halt progression).
      • Nutritional repletion: High-dose Thiamine (vitamin B1) + comprehensive B-complex and multivitamin.
    • Neuropathic Pain:
      • 1st-line: Gabapentin, Pregabalin, Duloxetine, or TCAs (e.g., Amitriptyline).
      • Topical/Adjunct: Capsaicin cream or Lidocaine 5% patch.
    • Supportive & Rehabilitative:
      • Physical/Occupational therapy for fall prevention and gait retraining.
      • Ankle-foot orthosis (AFO) for foot drop.
      • Routine daily foot inspections to prevent unperceived trauma/ulcers.
  • Complications:
    • Recurrent falls, gait instability, and traumatic fractures.
    • Neurotrophic skin breakdown, painless neuropathic ulcers, and secondary osteomyelitis.
    • Permanent lower-extremity paresis and wheelchair dependence.

Diagnostics

Differential diagnostics

Mononeuritis multiplex

  • Definition & Pathophysiology:
    • Infarction of the vasa nervorum causing ischemic axonal injury.
    • Presents as painful, asymmetric, asynchronous sensorimotor deficits in ≥2 discrete peripheral nerves.
  • High-Yield Etiologies:
  • Clinical Presentation:
    • Sudden, patchy nerve deficits: e.g., Foot drop (common peroneal n.) + Wrist drop (radial n.) occurring days/weeks apart. c
    • Neuropathic symptoms: Severe burning pain, paresthesias, localized sensory loss, and asymmetric weakness/areflexia.
    • Systemic vasculitic signs: Fever, weight loss, palpable purpura, livedo reticularis, renal involvement (hematuria/proteinuria).
  • Diagnosis:
    • Initial / Best Neuro Test: EMG / NCS shows multifocal, asymmetric axonal neuropathy (decreased CMAP/SNAP amplitudes).
    • Etiology Labs: ↑ ESR/CRP, ANCA (c-ANCA/p-ANCA), HBV/HCV serologies, cryoglobulins, ANA, RF, complement (↓ C3/C4).
    • Confirmatory / Gold Standard: Nerve & muscle biopsy (typically sural nerve) shows necrotizing transmural vasculitis and axonal degeneration.
  • Key Differentials:
    • Diabetic Polyneuropathy: Symmetric, length-dependent (“stocking-glove”) pattern (not patchy/asymmetric).
    • Guillain-Barré (AIDP): Symmetric, ascending weakness; CSF shows albuminocytologic dissociation.
    • Multifocal Motor Neuropathy (MMN): Pure motor (no sensory loss), asymmetric, (+) anti-GM1 Ab, conduction block on NCS.
  • Management:
    • 1st-Line (Systemic Vasculitis): High-dose corticosteroids (IV Methylprednisolone oral Prednisone) + Cyclophosphamide or Rituximab (for severe/organ-threatening disease).
    • Viral-Associated:
      • HBV: Short-course steroids + Plasma exchange (PLEX) + Antivirals (Entecavir/Tenofovir).
      • HCV: Direct-acting antivirals (DAAs) ± Rituximab.
    • Symptomatic / Supportive:
      • Neuropathic pain: Gabapentin, Pregabalin, or Duloxetine.
      • Functional support: Ankle-foot orthosis (AFO) for foot drop; PT/OT.

Treatment

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