Polyneuropathy

Polyneuropathy is a disorder that involves damage to multiple peripheral nerve fibers. The condition can be caused by diabetes mellitus, alcoholism, hereditary diseases, toxins, infection, or other inflammatory conditions. The classic presentation is a symmetric distal burning or loss of sensation. Further clinical features depend on whether an axonal or demyelinating nerve injury has occurred. Diagnostic tests such as electrodiagnostic studies are indicated in the case of atypical clinical features, unknown etiology, and/or severe or rapidly progressive symptoms. Management involves treatment of the underlying disorder and symptomatic therapy (e.g., control of neuropathic pain).

• Systemic disorders: Diabetes mellitus and alcohol use disorder account for most cases in developed countries.
• 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 metals (lead poisoning, arsenic, thallium)
    • Solvents (e.g., trichloroethylene)
    • Medication (e.g., chemotherapeutic agents)
    • Malnutrition/intestinal malabsorption
• Inflammatory
  • Vasculitis
  • Connective tissue disorders
  • Granulomatous diseases
  • Radiation exposure
  • Guillain-Barré 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
• Idiopathic

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

General

• Symmetric distal sensory loss (glove and stocking pattern)
• 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 HMSN type I
• 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

Axonal vs. demyelinating

References:^{[6][8][9][10]}

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
  • Foot care
  • Neuropathic pain management (e.g. with tricyclic antidepressants or gabapentin)
  • Alpha-lipoic acid (antioxidant)

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 (HMSN)

• Definition: progressive hereditary peripheral nerve disorders due to impaired axonal or Schwann cell growth and function
• Etiology
  • Usually autosomal dominant
  • Associated with scoliosis and foot deformities; (flat feet, high arches; , hammer toes)
  • Caused by defects in proteins of the axons or the myelin sheath
• Characteristic feature: ascending flaccid paralysis; and atrophy, which begins distally; sensory deficits may occur later (type I, III, and IV cause hypertrophic neuropathy)

HMSN type I (Charcot-Marie-Tooth disease)

• Etiology: most commonly caused by duplication of the gene PMP22 in chromosome 17
• Clinical features
  • Distal symmetric sensorimotor polyneuropathy
    • Foot drop
    • Atrophy of the calf muscles (“stork legs”)
    • Pes cavus deformity
    • Hammer toe
    • Intrinsic hand musculature may become involved after several years.
    • Sensory loss (occurs late)
  • May be associated with sleep apnea
• Diagnostics
  • Nerve biopsy: repeated demyelination and remyelination evident in large nerve fibers (onion peel appearance)
  • Nerve conduction studies: ↓ impulse conduction velocity

HMSN type IV (Refsum disease)

• Etiology: autosomal recessive defect affecting alpha-oxidation in peroxisomes → ↓ conversion of phytanic acid (a branched-chain fatty acid that can only be metabolized by alpha-oxidation in the peroxisome) to pristanic acid → accumulation of phytanic acid
• Clinical features
  • Symmetrical, ascending polyneuropathy
  • Ataxia
  • Sensorineural hearing loss
  • Anosmia
  • Ichthyosis
  • Cataracts and nyctalopia caused by retinitis pigmentosa
  • Shortened fourth toe
  • Epiphyseal dysplasia
• Diagnosis: detection of phytanic acid in plasma or urine
• Treatment: The goal is to reduce plasma phytanic acid levels.
  • Diet
  • Plasmapheresis in severe cases

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 ↓ nerve conduction

Other types of hereditary motor sensory neuropathies

• 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 decreased nerve conduction velocity
• HMSN type VI: manifests with neuropathy and optic atrophy
• HMSN type VII: manifests with neuropathy and retinitis pigmentosa

References:^{[10][11][12][13][14][15][16][17][18][19][20][21]}

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

• Electrodiagnostic studies
  • 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)
• Other tests
  • Nerve-muscle biopsy: useful in identifying small fiber sensory neuropathy or infiltrative disorders
  • Skin biopsy (useful to identify small fiber sensory neuropathies)
  • Genetic tests for suspected hereditary disorders

References:^{[6][22][23][24]}

Mononeuritis multiplex

• Definition: : a group of disorders characterized by ≥ 2 isolated mononeuropathies; e.g., concurrent sciatic neuropathy and radial neuropathy
• Etiology
  • Axonal injury caused by damage to vasa nervorum
  • Occurs in conditions characterized by the development of granulomas and/or microangiopathy (e.g., diabetes mellitus, rheumatoid arthritis, vasculitides, SLE, Lyme disease, amyloidosis, HIV, polyarteritis nodosa)
• Clinical features: painful, asymmetrical sensory and motor symptoms
• Diagnostics: Confirm with electrodiagnostic testing and test for possible etiology.
• Treatment: analgesia (see “Pain management”) and treatment of the underlying condition

Differential diagnosis of impaired sensation and sensory ataxia

Other considerations

• 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

The differential diagnoses listed here are not exhaustive.

• Definitive therapy: Treat the underlying disease.
• Symptomatic therapy
  • Pain management
    • Antidepressants (amitriptyline, duloxetine), anticonvulsants (gabapentin, 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 may be an acceptable treatment goal.

References:^{[6][25][26][27]}