Small fiber neuropathy: diagnosis and causes

Burning feet with reduced pinprick and thermal sense but normal reflexes, vibration and nerve conduction suggest small fiber neuropathy; confirm with distal leg skin biopsy for intraepidermal nerve fiber density against age-matched norms.

1. Small fibers are A-delta and C fibers. Small fiber neuropathy affects thinly myelinated A-delta and unmyelinated C fibers; neuropathic pain dominates, with positive symptoms such as burning and allodynia and negative signs such as thermal and pinprick loss, often with autonomic symptoms ¹.
2. Nerve conduction studies are typically normal. Diagnosis combines compatible symptoms and signs with evidence of small fiber involvement from skin biopsy and/or quantitative sensory testing ¹.
3. Skin biopsy is the Level A test. Distal leg biopsy quantifying intraepidermal nerve fiber density is reliable and efficient, and must be compared with age-matched normative values ².
4. Patterns vary. Typical disease begins in the feet and is length-dependent, but patchy, asymmetric, multifocal, diffuse or predominantly autonomic patterns occur ¹.
5. Look widely for a cause. Causes include diabetes, immune-mediated disease, infection, toxins and drugs, and gain-of-function Nav1.7, Nav1.8 and Nav1.9 variants; a significant proportion remain idiopathic despite extensive screening, and autoantibodies are a growing focus ¹.
6. HIV sensory neuropathy is distal and symmetric. Incidence has fallen with earlier combination antiretroviral therapy and less neurotoxic regimens, and low CD4 count and high viral load no longer predict it ³.

A normal nerve conduction study does not exclude neuropathy when burning pain and pinprick or thermal loss are length-dependent; proceed to skin biopsy or quantitative sensory testing rather than stopping the work-up ¹².

• Reduced intraepidermal fiber density is linked to risk of neuropathic pain but does not correlate with pain intensity ².
• Serial skin biopsies may track degeneration and regeneration and predict progression (Level C) ².
• Corneal confocal microscopy is a validated noninvasive structural marker of small fiber damage, especially in diabetes ¹.
• Drug and toxin causes include metronidazole, nitrofurantoin, linezolid, statins, bortezomib, alcohol and hypervitaminosis B6 ¹.
• Hereditary causes include sodium channelopathies (SCN9A, SCN10A, SCN11A), Fabry disease and familial amyloidosis ¹.
• Small fiber pathology is also described in fibromyalgia, typically non-length-dependent, and in Parkinson's disease and ALS ¹.
• Case series suggest IVIg may help antibody-associated forms, but the only double-blind placebo-controlled trial found no benefit on pain or fiber density at 6 months ¹.
• Even mild neuropathic pain in HIV sensory neuropathy meaningfully impairs quality of life and function ³.

• Ruling out neuropathy because nerve conduction studies are normal ¹.
• Interpreting fiber density without age-matched norms ².
• Assuming low CD4 counts still predict HIV sensory neuropathy ³.
• Using fiber density to grade pain severity; density does not correlate with pain intensity ².