Definition and Overview
Small fiber neuropathy (SFN) is a neuropathy characterized by selective damage to thinly myelinated A-delta fibers (diameter 1–6 μm) and unmyelinated C fibers (diameter < 1 μm), which transmit pain and temperature sensation among peripheral nerves. Because large fibers (which mediate touch, vibration sense, and deep tendon reflexes) are preserved, standard electromyography and nerve conduction studies show no abnormalities, often leading to delayed diagnosis [2].
The prevalence is estimated at approximately 53 per 100,000 population, with the highest incidence in those aged 40–60 years [2]. Small fiber neuropathy affects not only peripheral pain fibers (sensory small fibers) but also autonomic small fibers, giving rise to a variety of autonomic symptoms.
Causes and Classification
Classification by Cause
- Metabolic: diabetic neuropathy, prediabetes (impaired fasting glucose or impaired glucose tolerance), hypothyroidism [4]
- Immune/autoinflammatory: Sjögren's syndrome, lupus, rheumatoid arthritis, sarcoidosis, celiac disease
- Hereditary: mutations in voltage-gated sodium channel genes SCN9A (Nav1.7), SCN10A (Nav1.8), SCN11A (Nav1.9)
- Post-infectious: HIV, hepatitis B and C, post-COVID-19 sequelae (Long COVID)
- Chemotherapy-related: oxaliplatin, paclitaxel, etc.
- Idiopathic (unknown cause): accounts for approximately 50% of cases
Symptoms
Sensory Symptoms
Symptoms of small fiber neuropathy typically begin bilaterally in the feet and progress proximally in a glove-stocking distribution.
- Burning pain: persistent pain described as a burning sensation in the feet
- Stabbing pain, electric shock sensations
- Allodynia: pain triggered by light touch (socks, bedding)
- Tingling, numbness, and abnormal cold/warm sensations
Symptoms tend to worsen at night and may be exacerbated by warmth (hot showers) or heat.
Autonomic Symptoms
Since small fibers include autonomic nerve fibers, damage to autonomic small fibers produces the following symptoms.
- Sweating abnormalities (anhidrosis or hyperhidrosis)
- Orthostatic hypotension
- Tachycardia
- Gastrointestinal dysmotility (constipation, nausea)
- Bladder dysfunction
Diagnosis
Skin Small Fiber Biopsy (Punch Biopsy)
Measurement of intraepidermal nerve fiber density (IENFD) is the gold standard for diagnosing small fiber neuropathy [1]. Small skin samples are obtained from 10 cm above the ankle and the upper thigh, stained with PGP9.5 antibody, and nerve fiber counts are measured. A diagnosis is supported when IENFD falls below the 5th percentile of age- and sex-matched normative values.
Quantitative Sensory Testing (QST)
Quantitative measurement of cold/warm sensation and pain thresholds is used to evaluate small fiber sensory abnormalities [2].
Autonomic Function Testing
Heart rate variability (HRV) and QSART (quantitative sudomotor axon reflex test) are used to assess autonomic small fiber function.
Blood Tests and Genetic Testing
Fasting glucose, glycated hemoglobin (HbA1c), 75 g oral glucose tolerance test (OGTT), autoantibodies (ANA, anti-SSA/SSB), thyroid function, and SCN9A/SCN10A genetic analysis are used to identify the underlying cause.
Treatment
Cause-Directed Treatment
When prediabetes is the underlying cause, lifestyle modifications (exercise, weight loss) and glycemic control may help restore nerve fiber density. In immune-mediated small fiber neuropathy, intravenous immunoglobulin (IVIG) and corticosteroid therapy may be effective.
Pharmacotherapy for Neuropathic Pain
First-line medications [5]:
- Tricyclic antidepressants (amitriptyline): useful for nocturnal pain control
- SNRIs (duloxetine, venlafaxine): management of pain and autonomic symptoms
- Gabapentin, pregabalin: neuropathic pain control
Topical treatments:
- Lidocaine 5% patch or gel
- Capsaicin 8% patch: high-concentration capsaicin desensitizes C fibers
Management of Autonomic Symptoms
For orthostatic hypotension and sweating abnormalities caused by autonomic small fiber involvement, cause-specific autonomic function treatments are administered concurrently.