Polyneuropathy

Polyneuropathy is a systemic disease which involves damage to multiple peripheral nerve fibers. The condition can be caused by diabetes mellitus, alcoholism, hereditary diseases, toxins, infectious or other inflammatory conditions. The classic presentation is a symmetric distal sensory loss or burning sensation associated with motor weakness. Further clinical features depend on whether an axonal or demyelinating nerve injury has occurred. Diagnostic tests, usually beginning electrodiagnostic testing, are indicated in patients with atypical clinical features, unknown etiology, and/or severe or rapidly progressive symptoms. Therapy includes treatment of the underlying disorder and symptomatic therapy (e.g., control of neuropathic pain).

• Diabetes mellitus and alcohol use disorder account for most cases in developed countries
• Idiopathic
• Hereditary
  • Charcot-Marie-Tooth disease
  • Krabbe disease
  • Adrenoleukodystrophy
  • Metachromatic leukodystrophy
• Toxins
  • Endogenous
    • Metabolic/endocrine causes: diabetes mellitus, acromegaly, pregnancy
    • Hereditary causes: hereditary motor and sensory neuropathy (HMSN), hereditary sensory neuropathy (HSN), amyloidosis, porphyria
  • Exogenous
    • Alcohol
    • Heavy metal poisoning (lead, arsenic, thallium)
    • Solvents (e.g., trichloroethylene)
    • Medication (e.g., chemotherapeutic agents)
    • Malnutrition/intestinal malabsorption
• Inflammatory
  • Vasculitis
  • Connective tissue disorders
  • Granulomatous diseases
  • Radiation exposure
  • Guillain-Barre syndrome
  • Critical illness polyneuropathy
• Infectious
  • Bacterial: borreliosis; , diphtheria, leprosy
  • Viral: AIDS, CMV, VZV, Herpes zoster, measles, mumps, rubella, influenza
• Environmental
  • Prolonged exposure to cold
  • Hypoxemia
  • Vibration-induced damage

References:^{[1][2][3][4][5][6][7][8][9]}

General

• Symmetric distal sensory loss or burning and motor weakness (most common presentation)
  • Burning-foot syndrome: ↓ fine touch, vibration: , pain, tingling, pins-and-needles sensation or formication . Distribution most often in a distal and symmetric pattern (glove and stocking pattern)
  • Atrophy and paresis of muscles (e.g., “stork-legs” in the case of HMSN type I)
  • Ataxia (e.g., sensory ataxia due to vitamin B₁₂ deficiency)
  • ↓ Deep tendon reflexes

Axonal vs Demyelinating

	Axonal		Demyelinating
	Chronic	Acute	Chronic	Acute
Natural history	Slow decline over years	Months to years of slow, yet incomplete recovery	Variable (periods of recovery, stabilization, exacerbations, or slow decline)	Variable
Characteristics	Affects longer axons first (begins in lower extremities → sternum (intercostal nerves) → head) Early disease: sensory symptoms > motor symptoms	Similar, but symptoms more severe Significant pain	Early disease: motor symptoms = sensory symptoms	Early disease: motor symptoms > sensory symptoms
	Distal muscle wasting: feet, lower legs, hands (severe cases) Distal sensory loss (pain, temperature, proprioception, vibration) Reduced or absent distal reflexes (usually begins in the ankles)		Generalized muscle weakness: distal > proximal Distal sensory loss (abnormal vibration and proprioception > pain or temperature) Diffusely reduced or absent reflexes

References:^{[10][11][12][9]}

Diabetic polyneuropathy

• Definition: progressive peripheral nerve injury due to chronic hyperglycemia
• Clinical features
  • Sensory deficits
    • Distal symmetric sensory loss and/or motor weakness (common); less commonly, random involvement of multiple peripheral nerves (mononeuritis multiplex)
    • Burning feet syndrome with worsening of symptoms at night
  • Cranial nerve involvement is very common (especially of the oculomotor and abducens nerve)
  • Trophic skin changes; (due to autonomic neuropathy): anhidrosis; , edema, ulcers
  • Autonomic features: erectile dysfunction, gastric atony; , postprandial diarrhea, tachycardia at rest, impaired pupillary tone
  • Diabetic amyotrophy: initially painful proximal muscle weakness; distal sensory loss may occur
• Treatment: control of blood glucose and foot care

Alcoholic polyneuropathy

• Definition: progressive peripheral nerve injury as a result of thiamine deficiency due to a chronic alcohol use disorder
• Clinical features
  • Sensory deficits
    • Symmetrically decreased distal perception (especially joint position sense)
    • Burning feet syndrome
  • Atrophy and paresis of distal muscles; a hypoactive ankle jerk reflex
  • Hyperpigmented, anhidrotic, and atrophic skin
  • Calf cramps
• Treatment: thiamine and cessation of alcohol use (see alcohol use disorder)

Hereditary motor sensory neuropathies

• Definition: progressive hereditary peripheral nerve disorders due to impaired Schwann cell growth and function
• Etiology
  • Usually autosomal dominant
  • Associated with scoliosis and foot deformities; (flat feet, high arches; , hammer toes)
• Characteristic feature: Ascending flaccid paralysis; and atrophy, which begins distally; sensory deficits may occur later (type I, III, and IV cause hypertrophic neuropathy)
• Types
  • HMSN type I (Charcot-Marie-Tooth disease)
    • Distal symmetric sensorimotor polyneuropathy with atrophy of the calf muscles (“stork-legs”) and pes cavus deformity (sensory loss occurs late)
    • Intrinsic hand musculature may become involved after several years.
    • Associated sleep apnea possible
    • Nerve biopsy: repeated demyelination and remyelination evident in large nerve fibers (onion peel appearance)
    • Nerve conduction studies: ↓ impulse conduction velocity
  • HMSN type II
    • Axonal disease (no demyelination and remyelination) → no nerve hypertrophy, no onion peel appearance
    • Asymmetric patterns of nerve involvement have been reported
    • Normal nerve conduction velocity
  • HMSN type III (Dejerine-Sottas disease)
    • Palpably thickened nerves
    • Severely ↓ nerve conduction velocity
  • HMSN type IV (Refsum's disease)
    • Etiology: autosomal recessive defect affecting alpha-oxidation in peroxisomes → phytanic acid is not metabolized to pristanic acid → accumulation of phytanic acid
    • Clinical features
      • Neurological deficits
        • Symmetrical, ascending polyneuropathy
        • Ataxia
        • Sensorineural hearing loss
      • Ichthyosis
      • Cataracts, nyctalopia
      • Retinitis pigmentosa
  • HMSN type V
    • Associated with hereditary spastic paraplegia
    • Combination of spastic spinal paralysis, type VI and VII HSMN, and ocular symptoms
    • Nerve conduction studies: normal or mildly ↓
  • HMSN type VI: presents with optic atrophy
  • HMSN type VII: presents with retinitis pigmentosa
• Treatment: see treatment section below

References:^{[13][12][14][15][16][17][18][19][20][21][22][23][24][25][26]}

Further tests are usually indicated in patients with atypical clinical features, an unknown etiology, and/or severe or rapidly progressive symptoms.

• Electrodiagnostic testing
  • Nerve conduction studies on the sural nerve: to determine the type of neuropathy and with it the possible cause
    • Primary demyelination = ↓ impulse conduction velocity, normal amplitude
    • Axonal degeneration = normal impulse conduction velocity, ↓ amplitude
  • Electromyography (EMG): e.g., spontaneous electrical activity at rest (denervation potentials) in the case of axonal degeneration
• Laboratory tests (selection depends on the suspected underlying disorder)
  • Abnormal CBC, ESR and other markers of inflammation
  • ↑ Fasting and postprandial serum glucose
  • Abnormal thyroid function tests
  • Positive rapid plasma reagin
  • Serum electrophoresis and urine electrophoresis
  • Hepatitis screen
  • Lumbar puncture to exclude infections
  • Vitamin B₁₂ and folic acid levels
  • Serum levels of toxins (such as lead, thallium, and arsenic)
  • Delta aminolevulinic acid levels (porphyria, lead intoxication)
  • Borrelia antibodies (Lyme disease)
• If necessary: nerve-muscle biopsies (useful to identify a small fiber sensory neuropathy or infiltrative disorders), skin biopsy (useful to identify small fiber sensory neuropathies), molecular genetic tests for suspected hereditary disorders

References:^{[27][9][28][29]}

• Mononeuritis multiplex (multiple mononeuropathy)
  • Definition: Group of disorders characterized by ≥ 2 isolated mononeuropathies (usually unrelated, e.g., concurrent sciatic neuropathy and radial neuropathy)
  • Etiology: axonal damage caused by systemic conditions (e.g., diabetes mellitus, rheumatoid arthritis)
  • Clinical features: painful, asymmetrical sensory and motor features
  • Diagnostics: confirm with electrodiagnostic testing and test for possible etiology
  • Treatment: treat underlying condition and analgesia
• Radicular neuropathy (associated with acute onset of severe back pain that radiates to the legs and arms)
• Amyotrophic lateral sclerosis (asymmetric limb weakness with fasciculations and muscle stiffness)
• Peripheral vascular disease (trophic skin changes and pain exacerbated by walking)
• Subacute combined degeneration (demyelinated spinal cord tracts that also present with features of anemia and neuropsychiatric symptoms)
• Tabes dorsalis (myelopathy associated with a broad based ataxia and peripheral sensory deficits; perform serological tests for syphilis)

References:^[30][31]

The differential diagnoses listed here are not exhaustive.

• Definitive therapy: treat the underlying disease!
• Symptomatic therapy
  • Pain management
    • Antidepressants (amitriptyline; , duloxetine), anticonvulsants (carbamazepine; , pregabalin)
    • Analgesics: opioids
    • Topical therapy (lidocaine patches; , capsaicin patches/ointment)
  • Physical therapy and foot care

Treatment efficacy can only be assessed after 2–4 weeks of therapy! Since complete pain relief is often not possible, a tolerable level of pain can be an acceptable treatment goal!

The patient can be weaned off medications slowly after one year or once the underlying cause has been effectively treated (e.g., optimal control of serum glucose levels in cases of diabetic neuropathy)!

References:^{[9][32][33][34]}