Peripheral Neuropathy

Background

• Peripheral neuropathy encompasses a broad range of disorders characterized by damage to nerves after they exit the central nervous system with clinical manifestations including weakness, pain, numbness, tingling, imbalance, and/or autonomic dysfunction depending on the type of peripheral nerve involved.
• Length-dependent distal symmetric polyneuropathy is the most common type. Other types include mononeuropathies, multiple mononeuropathies, small fiber neuropathy, polyradiculoneuropathies, sensory neuronopathy, motor neuropathy, cranial neuropathies, polyradiculopathy, radiculoplexopathy, and plexopathy.
• Neuropathies can also be classified by the functions that are predominantly impaired - sensory, motor, or autonomic. The most common form is sensory-dominant sensorimotor neuropathy (distal symmetric polyneuropathy)
• Neuropathy may result from damage to axons, myelin sheath, nerve cell body, connective tissue, blood vessels, or a combination of these factors.
• Peripheral neuropathy has many potential causes (most commonly diabetes and heavy alcohol use), but is often idiopathic, especially in older patients.
• Symptoms depend in part on the type of nerve fiber that is damaged.
  • Small-diameter thinly myelinated or unmyelinated sensory fibers - burning, tingling, "pins-and-needles" sensations, "electric shock" sensation, hyperalgesia, or allodynia.
  • Medium and large myelinated sensory fibers - numbness, imbalance, and gait abnormalities.
  • Large myelinated motor fibers - weakness, fatigue, muscle atrophy, cramps, twitching, and myokymia.
  • Small-diameter thinly myelinated or unmyelinated autonomic fibers - orthostatic hypotension, heart rate changes, gastrointestinal dysfunction (including constipation, nausea, diarrhea, early satiety, and bloating), urogenital (neurogenic bladder, urinary incontinence, difficultly urinating, or erectile dysfunction), sweating abnormalities, and cold extremities.

Evaluation

• Suspect peripheral neuropathy in patients presenting with impaired sensations, limb weakness, light-headedness, or any combination of sensory, autonomic, and/or motor disturbances. Possible patterns of involvement are broad and can include:
  • sensory symptoms - pain, hyperalgesia, allodynia, burning, tingling, "pins-and-needles" sensations, "electric shock" sensation, numbness (absent or reduced sensation), imbalance, and gait abnormalities
  • motor symptoms - muscle weakness (typically felt in limbs), fatigue, muscle atrophy, cramps, twitching, and myokymia
  • autonomic symptoms - orthostatic hypotension, heart rate changes, gastrointestinal dysfunction (including constipation, nausea, diarrhea, early satiety, and bloating), urogenital dysfunction (neurogenic bladder, urinary incontinence, difficultly urinating, or erectile dysfunction), sweating abnormalities, and cold extremities
• Conduct thorough history and physical to help determine type of neuropathy and, if possible, underlying cause.
  • Ask if there is sensory impairment and weakness in both feet, with symptoms starting in toes and slowly progressing upward. This is consistent with distal symmetric polyneuropathy, the most common type of peripheral neuropathy.
  • Ask when symptoms started, if they progressed gradually, and if they are intermittent.
  • Ask if symptoms are symmetric, if they are in areas other than hands or feet, if the main symptoms are muscle weakness, and if they occur in "patches" in different parts of the body.
  • Thoroughly review medications and past medical history (particularly diabetes), alcohol use, other substance use, sexual history, occupation, and family history of medical conditions.
  • Conduct a general physical exam, and a neurological exam, checking cranial nerve, motor, sensory, reflex, and autonomic functions.
• Consider screening laboratory tests as part of initial evaluation of suspected distal symmetric polyneuropathy (Weak recommendation).
  • Screening tests with the highest yield include blood glucose, serum B12 with metabolites (methylmalonic acid with or without homocysteine), and serum protein electrophoresis with immunofixation.
  • Consider additional tests for prediabetes such as glucose tolerance testing if routine blood glucose testing is not clearly abnormal in patients with distal symmetric sensory polyneuropathy (especially when accompanied by pain) (Weak recommendation).
• Consider additional blood tests for specific causes of neuropathy as directed by the clinical history and presentation or if the diagnosis remains unclear after the initial investigations.
• Consider electrodiagnostic studies, especially in patients with atypical features (acute onset, asymmetry, proximal involvement, motor predominance, or unexpected severity) to define neuroanatomic localization and underlying physiology.
• Other diagnostic investigations that may be useful depending on suspected underlying cause include:
  • additional studies (in addition to serum protein electrophoresis with immunofixation) such as urine protein electrophoresis, urine immunofixation electrophoresis, and serum / urine free light chain quantification if suspected paraproteinemic neuropathy
  • imaging - usually not needed but can be considered for some patients such as magnetic resonance imaging (MRI) or ultrasound for suspected focal mononeuropathies, polyradiculopathy, plexopathy, or radiculoplexus neuropathies
  • cerebrospinal fluid analysis if infection, immune-mediated polyradiculoneuropathy, or neoplastic cause suspected, or if symptoms are rapidly progressive
  • skin biopsy, nerve biopsy (with combined muscle biopsy for certain suspected disorders), or biopsy of other tissues - rarely required but may be considered in some patients such as select patients with suspected vasculitis or amyloidosis
  • genetic testing if hereditary neuropathy suspected

Management

• Treating underlying disease can halt or slow progression and may improve symptoms.
• For management of neuropathic pain:
  • First-line agents (unless contraindications) include:
    • Antidepressants including:
      • Duloxetine 60-120 mg orally once daily or in 2 divided doses
      • Venlafaxine extended release 75-225 mg orally once daily or in 2-3 divided doses
      • Amitriptyline 25-150 mg orally once daily at bedtime
    • Gabapentinoids including:
      • Pregabalin 150-600 mg/day orally in 3 divided doses
      • Gabapentin 300-3,600 mg/day orally in 3-4 divided doses
  • If particular first-line agent is ineffective or not tolerated, offer any of the other remaining untried first-line agents before trying other treatments.
  • Other options include topical capsaicin and topical lidocaine.
  • Opioids may reduce pain but should generally be avoided for management of chronic neuropathic pain due to serious safety concerns and weak evidence for long-term efficacy.
  • Use a numeric rating scale (NRS) or visual analog scale (VAS) to assess effects of treatment on neuropathic pain intensity (Strong recommendation).
  • See Small Fiber Neuropathy for a complete discussion of options and recommendations from professional organizations.
• Other management depends on the specific symptoms and/or the specific type of neuropathy.
  • Diabetic peripheral neuropathy - optimize glucose levels in addition to offering agents for management of neuropathic pain. See Diabetic Peripheral Neuropathy for details.
  • Mononeuropathies - conservative management including rest and activity modification, simple analgesics, local corticosteroid options, other nonoperative strategies, and, if necessary, surgery.
  • HIV-related neuropathic pain - offer agents for management of neuropathic pain.
  • For management of other specific types of peripheral neuropathy, see
    • Neuropathy-specific Management section
    • Individual topics in Related Topics section