Small Fiber Neuropathy

Background

• Small fiber neuropathy is due to damage to the small diameter unmyelinated C-fibers and the thinly myelinated A-delta fibers, which mediate pain (most common symptom), thermal sensation, and autonomic function.
• Length-dependent small fiber neuropathy symptoms are usually symmetric and typically start in the feet, with a gradual rise into the legs and hands ("stocking-glove" distribution); nonlength dependent small fiber neuropathy is much less common and typically presents with asymmetric, patchy, intermittent, and migratory symptoms involving the face, proximal limbs, or trunk.
• Many conditions can cause small fiber neuropathy (with diabetes and immunological conditions being the most common identifiable causes), but > 50% of cases are idiopathic.
• The reported overall prevalence is 53 cases per 100,000 persons, and it is more common in older persons.
• Small fiber neuropathy is typically slowly progressive with a clinical plateau lasting for years, and large fiber neuropathy may develop in 13%-35% of patients.

Evaluation

• Suspect small fiber neuropathy in patients with altered pain and temperature sensations, especially if there are no signs of large fiber involvement (such as impaired proprioception, vibratory sensation, reflexes).
  • Pain (usually in feet or hands) may be described as burning, prickling, shooting, and/or aching.
  • Patients may also report impaired sensations or autonomic symptoms such as dizziness when standing, palpitations, abnormal sweating, dry mouth, eyes, or skin, gastrointestinal dysfunction (cramping, diarrhea, or constipation), urinary dysfunction, and/or sexual dysfunction.
• Ask about:
  • location of sensory symptoms, how they have progressed over time, when they occur, and if they're generally consistent or change in location and type, as these characteristics may help distinguish between length-dependent and nonlength dependent neuropathies
  • past medical history of conditions or medications that may cause small fiber neuropathy including diabetes, immune-mediated conditions, infections, nutritional deficits, alcohol use, and use of neurotoxic medications such as metronidazole
  • family history of neuropathies or hereditary diseases known to cause small fiber neuropathy such as Fabry disease, sodium channelopathies, or transthyretin familial amyloidosis
• Perform a physical examination, looking for:
  • altered pain and temperature sensations and responses to tactile stimuli
  • signs of large fiber involvement (such as impaired proprioception, vibratory sensation, reflexes), as the lack of signs further increases suspicion of small fiber neuropathy
• Also consider assessing for vagal and sympathetic autonomic dysfunction with autonomic testing. A combination of autonomic screening tests (such as with composite autonomic scoring scale) should be considered to increase diagnostic accuracy.
• No universally accepted criteria for diagnosis of small fiber neuropathy exist, but proposed criteria include the 2008 Besta criteria, 2010 NEURODIAB criteria, 2011 Toronto criteria, and 2017 Blackmore and Siddiqi criteria, all of which incorporate all or most of the following for making a diagnosis:
  • clinical signs of small fiber impairment
  • reduced intraepidermal nerve fiber density (IENFP) on skin biopsy (preferred test) (Strong Recommendation)
  • abnormal quantitative sensory testing (QST)
  • abnormal autonomic testing
  • normal nerve conduction studies
• Tests to help identify the underlying cause of small fiber neuropathy based on clinical suspicion include:
  • blood tests
  • urine tests
  • chest X-ray if suspected sarcoidosis
  • biopsy of lip and salivary gland, small bowel, nerve, or abdominal fat and rectal mucosa depending on suspected etiology

Management

• For managing neuropathic pain
  • Offer one of the following first-line agents (unless contraindications) (Strong Recommendation):
    • 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 a particular first-line agent is ineffective or is not tolerated, offer any of the other remaining untried first-line agents before trying other treatments.
  • Consider the following agents as second-line or third-line options; evidence demonstrating efficacy for neuropathic pain is limited:
    • topical capsaicin, options include:
      • 0.075% cream
      • 8% patches (particularly for patients with HIV-associated polyneuropathy) (Weak Recommendation)
    • lidocaine patches (5% lidocaine plaster), particularly when there are concerns about the safety and side effects of first-line options (for example in frail and older patients) (Weak Recommendation)
    • botulinum toxin type A 50-200 units subcutaneously once every 3 months (Weak Recommendation)
  • Opioids may reduce pain but should generally be avoided.
    • The use of opioids for management of chronic neuropathic pain is generally discouraged due to serious safety concerns and weak evidence for long-term efficacy.
    • Consider tramadol 100-400 mg/day in up to 4 doses (alone or with acetaminophen) for acute pain exacerbations, but it should probably not be considered for long-term management of neuropathic pain due to risks of serious adverse effects including addiction (Weak Recommendation).
• Nonpharmacologic treatments include physical activity and cognitive behavioral therapy, but evidence is limited.
• Consider symptomatic management of autonomic symptoms of small fiber neuropathy (see Autonomic Neuropathy for additional information).
• Consider disease-specific management strategies for small fiber neuropathy if underlying cause is known; examples include:
  • glycemic therapies, lipid-lowering therapies, exercise, and diet for diabetes
  • parenteral vitamin B12 supplementation for vitamin B12 deficiency
  • intravenous immunoglobulin (IVIG), corticosteroids, and other immunosuppressants for Sjogren syndrome
  • ARA 290 (Cibinetide), IVIG, or infliximab for sarcoidosis
  • sodium channel blockers (particularly lacosamide) for sodium channelopathies
  • inotersen, patisiran, or vutrisiran for transthyretin familial amyloidosis polyneuropathy
• Follow-up the management of pain using the Neuropathic Pain Scale (NPS) or the Neuropathic Pain Symptom Inventory (NPSI) to evaluate the effects of treatment on neuropathic pain symptoms (Strong Recommendation).