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).

• 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 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

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

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 and paresis of muscles: e.g., “stork legs” in the case of HMSN type I
• Sensory ataxia: e.g., sensory ataxia due to vitamin B₁₂ deficiency
• ↓ Deep tendon reflexes

Axonal vs. demyelinating

	Axonal		Demyelinating
	Chronic	Acute	Chronic	Acute
Progression	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
Associated conditions	Chronic idiopathic axonal polyneuropathy (CIAP) Diabetes Alcohol use disorder Hereditary motor sensory neuropathies Leprosy HIV Borreliosis Hypothyroidism Toxic polyneuropathy (e.g. due to cisplatin, doxorubicin)	Axonal Guillain-Barré syndrome	Chronic inflammatory demyelinating neuropathy (CIDP) Hereditary motor sensory neuropathies (Charcot-Marie-Tooth disease) Uremic polyneuropathy Toxic polyneuropathy (e.g. due to diphtheria toxin, suramin, amiodarone)	Guillain-Barré syndrome

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
  • 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

• 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)
• Important types
  • HMSN type I (Charcot-Marie-Tooth disease): demyelinating 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 → phytanic acid is not metabolized 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
    • 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
• Treatment: See “Treatment” 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 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)
• 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: : a group of disorders characterized by ≥ 2 isolated mononeuropathies; e.g., concurrent sciatic neuropathy and radial neuropathy
  • Etiology: axonal damage caused by systemic conditions; e.g., diabetes mellitus, rheumatoid arthritis, vasculitides, SLE, Lyme disease, amyloidosis, HIV
  • Clinical features: painful, asymmetrical sensory and motor symptoms
  • Diagnostics: confirm with electrodiagnostic testing and test for possible etiology.
  • Treatment: analgesia and treatment of underlying condition
• 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

Differential diagnosis of impaired sensation and sensory ataxia

	Polyneuropathy	Multiple sclerosis	Subacute combined degeneration	Tabes dorsalis	Compressive myelopathy
Pathogenesis	Acute or chronic demyelination and/or axonal degeneration due to: Toxins: e.g., in diabetes mellitus or alcohol use Trauma Inflammation or infection	Immune-mediated chronic demyelination of white matter in the brain and spinal cord	Chronic demyelination of dorsal columns, lateral corticospinal tracts, and spinocerebellar tracts due to vitamin B12 deficiency	Demyelination of the dorsal columns and the dorsal root ganglia due to Treponema pallidum infection(tertiary syphilis)	Spinal cord demyelination and ischemia that is caused by compression due to: Disc herniation Osteophytes Tumors and metastases
Impairment of sensation	Symmetrical distal loss of all the types of sensation (stocking-and-glove distribution)	Loss of all the types of sensation is possible (distribution depends on the lesion).	Loss of position and vibration sense below the level of the lesion	Loss of position and vibration sense below the level of the lesion	Loss of pain and temperature sensation below the level of compression is most common.
Motor neuron signs	Lower motor neuron signs: distal flaccid paresis	Upper motor neuron signs	Upper motor neuron signs: spastic paresis	None	Lower motor neuron signs at the level of the lesion Upper motor neuron signs below the level of cord compression
Other features	Burning-foot syndrome and neuropathic pain are common.	Internuclear ophthalmoplegia (INO) Lhermitte sign Charcot neurologic triad Exacerbations followed by periods of remission	Megaloblastic anemia Neuropsychiatric symptoms	Argyll Robertson pupils Sharp, shooting pain in the legs and the abdomen Gumma, aortitis	Back pain

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 (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 can be an acceptable treatment goal!

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