Small Fibre Neuropathy

Small fibre neuropathy is a disorder of the thinly myelinated Adelta and unmyelinated C fibres, causing burning pain, abnormal sensation and autonomic symptoms with normal strength, reflexes and nerve conduction studies. It is a common cause of chronic neuropathic pain.

The prevalence is about 50 to 53 in every 100,000 people, and the incidence about 12 in every 100,000 each year, with the true figure likely higher. It occurs at any age, with a mean onset around 50 years.

Causes. Diabetes and impaired glucose tolerance (commonest), vitamin B12 deficiency, alcohol, thyroid disease, coeliac disease, HIV, hepatitis C, Sjögren syndrome, sarcoidosis, amyloidosis, Fabry disease, sodium channel variants (SCN9A, SCN10A, SCN11A), chemotherapy and other drugs. About one third have no cause found.

Course. Slowly progressive in a length dependent pattern, or non-length-dependent. Large fibre involvement can develop in some.

Pathophysiology.

Injury to small nerve fibres from metabolic stress, inflammation, toxins or channelopathy causes spontaneous firing of nociceptors and degeneration of the distal terminals.

Autonomic C fibre damage explains sweat, vascular and visceral symptoms.

• Burning, stabbing or electric pain and tingling, usually in the feet, spreading proximally, worse at night and with rest.
• Allodynia, hyperalgesia and cold or heat sensitivity.
• Autonomic features: dry eyes and mouth, abnormal sweating, orthostatic dizziness, gastrointestinal dysmotility, urinary symptoms and erectile dysfunction.
• Normal power, normal reflexes and normal vibration and joint position sense; reduced pinprick and temperature sensation.
• Erythromelalgia like redness and burning in some.

Red flags.

• Weakness, absent reflexes or large fibre signs (consider other neuropathies).
• Rapid progression, severe autonomic failure or weight loss (amyloidosis, paraneoplastic or inflammatory disease).
• Features of systemic illness: dry eyes and mouth, rash, lymphadenopathy or fever.

• Clinical history and examination; normal nerve conduction studies exclude large fibre involvement.
• Skin biopsy at the distal leg with intraepidermal nerve fibre density measurement is the reference test; quantitative sudomotor axon reflex testing and corneal confocal microscopy are alternatives.
• Quantitative sensory testing and autonomic function testing (heart rate variability, tilt table).
• Blood tests: glucose and HbA1c with oral glucose tolerance test, B12, folate, thyroid function, ESR, antinuclear antibodies, extractable nuclear antigens, coeliac serology, HIV and hepatitis serology, serum protein electrophoresis, alpha galactosidase A in men and women, and ferritin.
• Genetic testing for sodium channel variants and transthyretin amyloidosis when no cause is found.

Differential diagnosis. Large fibre peripheral neuropathy, diabetic neuropathy, fibromyalgia, erythromelalgia, complex regional pain syndrome, radiculopathy, amyloid neuropathy with large fibre loss and functional pain.

• Treat the cause: glycaemic control and lifestyle change for diabetes and prediabetes, B12 replacement, stop alcohol, treat coeliac disease, thyroid disease and infection.
• Duloxetine: 30 mg orally once daily for 1 week, then 60 mg once daily. Maximum 120 mg daily. Review at 4 to 6 weeks. Monitor blood pressure, sodium, mood and suicidal thoughts, and liver function. Avoid with monoamine oxidase inhibitors, hepatic impairment, severe renal impairment (creatinine clearance under 30 mL/min), uncontrolled hypertension and angle closure glaucoma; avoid in pregnancy unless benefit outweighs risk.
• Pregabalin: 75 mg orally twice daily, increased after 1 week to 150 mg twice daily, then to a maximum of 300 mg twice daily (600 mg daily). Monitor sedation, weight gain, oedema, mood and misuse. Adjust for renal function: creatinine clearance 30 to 59 mL/min, 75 to 300 mg daily; 15 to 29 mL/min, 25 to 150 mg daily; under 15 mL/min, 25 to 75 mg daily. Avoid in pregnancy unless benefit outweighs risk.
• Amitriptyline: 10 mg orally at night, increased by 10 mg every 1 to 2 weeks to 30 to 50 mg. Maximum 75 mg at night (50 mg in older adults). Monitor sedation, anticholinergic effects, postural hypotension and mood; baseline ECG over age 40 or with cardiac risk. Avoid after recent myocardial infarction, with arrhythmia, in angle closure glaucoma or urinary retention; reduce dose in hepatic impairment.
• Immunotherapy (intravenous immunoglobulin 2 g/kg in total over 2 to 5 days, repeated every 4 to 8 weeks if effective) for immune mediated disease, by a specialist.
• Enzyme replacement for Fabry disease and amyloid specific treatment through metabolic or specialist centres.
• Topical lidocaine for focal pain, foot care, and avoidance of triggers (heat, tight footwear).
• Cognitive behavioural therapy, sleep and graded activity; treat autonomic symptoms individually.

Monitoring. Review at 4 to 6 weeks, then every 3 to 6 months; assess pain scores, sleep, mood and autonomic symptoms; repeat tests when new features arise.

Referral and escalation. Neurology or pain service for refractory pain; endocrinology, rheumatology or genetics as directed by the cause.

Special groups. Older adults: lower starting doses and slower titration. Diabetes: tight glucose control without hypoglycaemia.