Polyneuropathy

Polyneuropathy is a disorder that involves damage to multiple peripheral nerve fibers. Causes include diabetes mellitus, alcohol use disorder, hereditary diseases, toxins, infection, or other inflammatory conditions. The classic presentation is a symmetrical distal burning sensation or loss of sensation. Further clinical features depend on whether an axonal or demyelinating nerve injury has occurred. Diagnosis is usually clinical, supported by laboratory studies to rule out common causes such as diabetes. Further diagnostic tests such as electrodiagnostic studies are reserved for patients with 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).

• 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., chemotherapy-induced peripheral neuropathy)
    • Malnutrition/intestinal malabsorption
• Inflammatory
  • Vasculitis
  • Connective tissue disorders
  • Granulomatous diseases
  • Radiation exposure
  • Guillain-Barré syndrome
  • Chronic inflammatory demyelinating polyneuropathy
  • 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

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

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

General

• Symmetrical 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 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

Axonal vs. demyelinating

References:^{[8][9][10][11]}

Diabetic neuropathies

Diabetic neuropathies are the development of progressive nerve injury (e.g., peripheral, autonomic) due to chronic hyperglycemia.

Distal symmetric polyneuropathy in diabetes ^[12][13][14]

• Clinical features: distal symmetrical sensory loss and/or motor weakness
  • Sensory symptoms, e.g.:
    • Numbness, tingling
    • Burning feet syndrome with worsening of symptoms at night
    • Less common: allodynia, hyperesthesia
  • Motor symptoms, e.g., ataxia, balance issues
  • On neurological examination, loss of or reduction in:
    • Ankle reflex
    • Vibration sense
    • Tactile sense: sharp/dull discrimination (e.g., pinprick sensation), light touch (e.g., monofilament test)
    • Proprioception
    • Temperature sensation
• Diagnostics ^[12]
  • Usually clinical
  • Patients with atypical presentations : Order electrodiagnostic studies (see “Diagnostics of polyneuropathy”).
• Treatment ^[12]
  • Control of blood glucose (see “Treatment of diabetes”)
  • Foot care : to reduce the risk of foot ulcerations
  • Pain management (see “Treatment of polyneuropathy”).
• Complications
  • Diabetic foot ulcers
  • Diabetic neuropathic arthropathy (Charcot foot)

Patients with diabetic peripheral neuropathy are often asymptomatic. Regular examinations are recommended to identify sensory deficits early and initiate measures to prevent injury. ^[12]

Other forms of diabetic neuropathy ^[12]

• Autonomic neuropathy
  • Genitourinary: erectile dysfunction, neurogenic bladder
  • Gastrointestinal: gastroparesis, diarrhea
  • Cardiovascular: tachycardia at rest, orthostatic hypotension
  • Optic: Impaired pupillary tone
  • Skin changes; : anhidrosis
• Mononeuropathy: focal neuropathies that affect single nerves
• Diabetic amyotrophy: often manifests as thigh pain and proximal muscle weakness

Alcoholic polyneuropathy ^[15][16][17]

• Definition: progressive peripheral nerve injury due to a chronic alcohol use disorder
• Pathophysiology
  • Likely multifactorial
  • Mechanisms include malnutrition (e.g., thiamine deficiency) and the toxic effects of alcohol on the nervous system
• Clinical features: Symptoms usually begin in the distal lower extremities and progress slowly over months to years. ^[17]
  • Sensory deficits: usually symmetrical ^[6]
    • Numbness, paresthesias, impaired vibration sense
    • Decreased proprioception
    • Burning feet syndrome
  • Weakness of distal muscles
  • Reduced or absent reflexes
  • Rare: red, atrophic skin; muscle cramps
• Diagnostics
  • Usually diagnosed clinically
  • Laboratory studies help identify other conditions associated with alcohol use disorder.
  • Consider electrodiagnostic studies if there is diagnostic uncertainty (see “Diagnostics of polyneuropathy”).
• Treatment
  • Cessation of alcohol use (see “Treatment of alcohol use disorder”)
  • Vitamin supplementation (e.g., thiamine)
  • For symptom management, see “Treatment of polyneuropathy.”

Hereditary motor sensory neuropathy (HMSN) ^[18][19][20]

Overview ^[20]

• One of the most common inherited neurological diseases
• Also known as Charcot-Marie-Tooth disease
• Inheritance is usually autosomal dominant, but may be autosomal recessive or X-linked.
• Various mutations cause impaired growth or function of the axons or Schwann cells (e.g., defects in axon or myelin sheath proteins).
• Common clinical features include:
  • Distal muscle weakness and atrophy
  • Reduced or absent reflexes
  • Sensory deficits (e.g., decreased vibration, proprioception)
  • Associated with scoliosis and foot deformities; (e.g., high arches; , hammer toes)

HMSN type I

• Epidemiology: most common subtype
• Pathophysiology
  • Primarily demyelinating neuropathy
  • Usually caused by duplication of the PMP22 gene on chromosome 17
• Clinical features: onset before the age of 20 years with distal symmetrical sensorimotor polyneuropathy
  • Foot drop, pes cavus deformity, hammer toe ^[21]
  • Atrophy of the calf muscles (stork leg appearance)
  • Weak intrinsic hand muscles
  • Sensory loss
  • Nociceptive pain
  • May be associated with sleep apnea
• Diagnostics
  • Nerve conduction studies: ↓ impulse conduction velocity in both sensory and motor nerves
  • Sural nerve biopsy: hypertrophic neuropathy (onion bulb appearance from repeated demyelination and remyelination in large nerve fibers) ^[22]
• Management: primarily symptomatic; see “Treatment of polyneuropathy.”
  • Consider surgery for foot deformities.
  • Avoidance of neurotoxic medications (e.g., vincristine)
  • Genetic counseling

Other types of HMSN ^[20][23][24]

• HMSN type II: primarily axonal neuropathy
• HMSN type III (Dejerine-Sottas disease): severe symptoms with an early onset
• HMSN type IV
  • Previously synonymous with Refsum disease ^[25]
  • Now used to describe autosomal recessive demyelinating neuropathy
• HMSN type V: associated with spastic paraplegia
• HMSN type VI: manifests with neuropathy and optic atrophy
• HMSN type VII: manifests with neuropathy and retinitis pigmentosa

HMSN is a heterogeneous group of diseases with variable symptom onset and severity. Generally, progression of symptoms is slow and life expectancy is unaffected. ^[18]

Refsum disease ^[26][27]

• Pathophysiology: 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
  • Muscle weakness and atrophy
  • Ataxia
  • Sensorineural hearing loss
  • Anosmia
  • Ichthyosis
  • Cataracts and nyctalopia caused by retinitis pigmentosa
  • Shortened third and fourth toe
  • Epiphyseal dysplasia
  • Cardiac abnormalities: cardiomyopathy, aberrant conduction
• Diagnosis: detection of phytanic acid in plasma
• Treatment: The goal is to reduce plasma phytanic acid levels.
  • Diet: elimination of foods that contain phytanic acid, e.g., dairy products, beef, lamb, and fish
  • Plasmapheresis in severe cases

Chronic inflammatory demyelinating polyneuropathy (CIDP) ^[28]

• Definition: A chronic immune-mediated polyneuropathy primarily affecting peripheral nerves ^[29]
• Epidemiology
  • More common in men ^[30]
  • Peak incidence is 40–60 years old. ^[28]
• Etiology
  • Macrophage-associated demyelination ^[31]
  • Likely autoimmune, autoantibodies (e.g., anti‑GM1 antibodies anti-contactin 1, anti-neurofascin 155) have been detected ^[28]
  • CIDP has not been linked to a particular pathogen. ^[32]
• Predisposing factors
  • Diabetes mellitus
  • HIV infection
  • Monoclonal gammopathies (e.g., MGUS)
  • Malignancies (e.g., hepatocellular carcinoma)
• Pathophysiology
  • Macrophages phagocyte myelin sheath → demyelination of peripheral nerves → remyelination by Schwann cells → onion bulb formation
  • Autoantibodies against nodal and paranodal proteins → detachment of myelin sheath around the nodes of Ranvier → abnormal nerve conduction
• Clinical features: progress or relapse/remit over > 8 weeks^[28]
  • Symmetric weakness of both proximal and distal muscles ^[31]
  • ↓ Deep tendon reflexes in both upper and lower extremities
  • Sensory involvement (e.g., paresthesias)
  • Autonomic dysfunction and cranial nerve involvement are rare.
  • CIDP variants can manifest with asymmetric symptoms and/or purely sensory or motor symptoms.
• Diagnostics: See also “Diagnostics of polyneuropathy.” ^[28]
  • Perform nerve conduction; diagnosis is confirmed if in ≥ 2 nerves either of the following are present:
    • Signs of motor nerve demyelination (e.g., reduced conduction velocity)
    • Impaired sensory nerve conduction
  • Assess for monoclonal gammopathy with serum protein electrophoresis and serum and urine immunofixation.
  • If nerve conduction studies are not diagnostic, consider additional testing.
    • Lumbar puncture: elevated proteins (albuminocytologic dissociation) and normal WBC count ^[31]
    • Imaging: Ultrasound or MRI may show nerve enlargement.
    • Nerve biopsy: shows reduced nerve myelination
    • Antibody testing (e.g., anti-NF155, anti-CNTN1, anti-Caspr1)
  • Further studies may be recommended by a specialist depending on the subtype.
• Treatment ^[28]
  • First-line therapies: corticosteroids or intravenous immunoglobulin
  • Alternative therapies
    • Plasmapheresis
    • Immunomodulatory drugs (e.g., azathioprine, cyclophosphamide): reserved for treatment failure
  • Provide symptomatic treatment for pain (see “Treatment of polyneuropathy”).
  • Tailor long-term treatment plans to the patient's clinical response.

Approach ^[6][33][34]

• All patients
  • Obtain initial laboratory workup to evaluate for common causes.
  • Consider further laboratory studies based on clinical features.
• Atypical clinical presentation or nondiagnostic initial workup: Refer to neurology for further studies.
  • First-line: electrodiagnostic studies
  • Persistent diagnostic uncertainty: imaging, genetic studies, or nerve or skin biopsies

In many cases of polyneuropathy, the underlying cause remains unknown despite thorough clinical evaluation, laboratory testing, and electrodiagnostic studies. ^[6]

Laboratory studies ^[6][35]

• Initial studies
  • CBC: to assess for anemia
  • CMP
    • To evaluate for kidney and liver disease
    • ↑ Fasting and postprandial serum glucose suggest possible diabetes
  • Vitamin B₁₂: ↓ levels can cause polyneuropathy ^[33]
  • Serum electrophoresis with immunofixation: to assess for monoclonal gammopathies
  • TSH: to assess for thyroid disease
• Additional laboratory studies: Perform based on clinical suspicion.
  • Infections
    • Bloodbourne viruses: hepatitis B serology, hepatitis C testing, HIV screening
    • Diagnostic studies for Lyme disease
    • Syphilis screening
  • Nutritional deficiencies: serum folic acid, phosphorus, thiamine
  • Heavy metal toxicity: urine or serum levels of toxins (such as lead; , thallium, and arsenic)
  • Sarcoidosis: ACE levels
  • Autoimmune or inflammatory disease: ESR, CRP ANA, c-ANCA, p-ANCA ^[36]
  • Alcohol use disorder: ethanol level
  • Malignancy: paraneoplastic panel
  • Defective heme synthesis (e.g., porphyria, lead intoxication; ): Consider specific tests (e.g., urine delta aminolevulinic acid levels). ^[37]

Electrodiagnostic studies ^[6]

• Indications
  • Acute onset or rapid progression of symptoms
  • Asymmetrical symptoms
  • Primarily motor or autonomic dysfunction
  • Diffuse reflex loss ^[38]
  • Nondiagnostic initial workup
• Modalities ^[38]
  • Nerve conduction studies
    • Demyelinating disease: ↓ impulse conduction velocity, normal amplitude of response ^[6]
    • Axonal disease: normal impulse conduction velocity, ↓ amplitude of response
  • Electromyography ^[39]
    • Can differentiate between neuropathy and myopathy
    • Polyneuropathy findings may include spontaneous electrical activity (fibrillation potentials) and reduced interference pattern.

Electrodiagnostic studies can help identify and localize nerve dysfunction, but often do not reveal the underlying cause of neuropathy. ^[38]

Additional testing ^[6][36]

• Imaging
  • Central nervous system imaging: only for patients with symptoms of CNS lesions or radiculopathies
    • MRI brain: patients with cranial nerve palsies, ataxia, or dysarthria
    • MRI spine: patients with suspected radiculopathy
  • Peripheral nerve imaging: advanced imaging, e.g., MR neurography, may be considered in atypical neuropathies. ^[40]
• Sural nerve biopsy: performed in diagnostic uncertainty or prior to starting aggressive treatments ^[6]
• Skin biopsy: may be performed in patients with a burning sensation or painful neuropathy
• Genetic testing: for suspected hereditary disorders
• Cerebrospinal fluid analysis: for suspected infections or CIDP

Only request imaging of the brain or spine if there are clinical features of CNS lesions or radiculopathy. ^[6]

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: asymmetrical 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.

Approach ^[6][33][41]

• Identify and treat the underlying disease (e.g., alcohol use disorder, diabetes mellitus).
• Educate patients on the expected course of their disease. ^[42][43]
• Consider referral to neurology. ^[6]
• Recommend nonpharmacological measures.
• For patients with pain:
  • Start pharmacological therapy.
  • Consider referral to a pain management specialist in severe or refractory cases.

Management of polyneuropathy is based on treating the underlying cause and providing symptom control.

Nonpharmacological methods ^[6]

• The aim is to prevent a worsening of symptoms through overuse or injury.
• Refer patients to:
  • Podiatry: for foot care (e.g., appropriate shoes, foot hygiene)
  • Physical therapy: for exercises (including balance and gait retraining)
  • Occupational therapy: for home hazard assessment and modification
• Consider the need for orthotics.
• Patients may additionally benefit from management of obesity. ^[44]

Pharmacological therapy ^[6][41]

• Initial therapy
  • First-line: tricyclic antidepressants (e.g., amitriptyline), SNRIs (e.g., duloextine), or gabapentinoids
  • Adjuvants: topical analgesics (e.g., lidocaine, capsaicin)
• If response to a 3–8 week trial of a first-line pharmacological agent is inadequate, consider:
  • Switching to another first-line agent
  • Adding a second first-line agent or an adjuvant
• Treatment failure: Consider tramadol. ^[6]
• For further information, see “Pain management.”

Avoid combining antidepressant classes or antidepressants with tramadol because of the risk of serotonin syndrome. ^[41]

Treatment efficacy can only be assessed after 3–8 weeks of therapy. Since complete pain relief is often not possible, a tolerable level of pain may be an acceptable treatment goal. ^[41]