What investigations should be done for small fiber neuropathy?

Diagnostic Workup for Small Fiber Neuropathy

Skin biopsy with intraepidermal nerve fiber density (IENFD) assessment using PGP 9.5 immunohistochemistry is the gold standard diagnostic test for small fiber neuropathy and should be performed when clinical suspicion exists, particularly when standard nerve conduction studies are normal. 1, 2

Primary Diagnostic Tests

Skin Biopsy (First-Line)

• IENFD assessment is a validated, reproducible marker with sensitivity of 77.2-88% and specificity of 79.6-88.8% 2, 3
• A cutoff of ≤8.8 fibers/mm at the ankle demonstrates good diagnostic accuracy 3
• This test changed management or diagnosis in 52% of patients evaluated for possible SFN 4
• Consider repeat biopsy in select cases to monitor disease progression or treatment response 2, 3

Quantitative Sensory Testing (QST)

• Thermal threshold testing (heat and cold detection) complements skin biopsy findings 2, 3
• Heat-pain testing has higher sensitivity than cooling detection 5
• When combined with QSART, laboratory testing diagnosed 88% of patients 5

Autonomic Function Testing

• Quantitative sudomotor axon reflex test (QSART) documents small fiber dysfunction with high sensitivity 1, 2
• Thermoregulatory sweat testing provides additional autonomic assessment 2
• Heart rate variability testing shows low correlation and is less reliable 5

Proposed Diagnostic Algorithm

Based on clinical presentation and test results 5:

• Definite SFN: Abnormal neurological examination + both QSART and QST abnormal
• Probable SFN: Abnormal neurological examination + either QSART or QST abnormal
• Possible SFN: Abnormal neurological examination, QSART, or QST alone

Etiological Workup

Once SFN is confirmed, investigate underlying causes 6:

• Metabolic screening: Fasting glucose, HbA1c, oral glucose tolerance test (diabetes and glucose intolerance are leading causes)
• Autoimmune markers: Anti-Sjögren antibodies (SSA/SSB), serum protein electrophoresis with immunofixation for monoclonal gammopathy
• Genetic testing: Consider transthyretin gene mutation (familial amyloidosis), alpha-galactosidase A activity (Fabry disease), sodium channel gene testing if family history suggests hereditary SFN
• Additional serologies: Vitamin B12, thyroid function, hepatitis B/C, HIV 1

Critical Pitfalls to Avoid

• Never rely solely on nerve conduction studies—these only assess large fiber function and will miss SFN entirely 2, 3
• Standard electrophysiological investigations are normal in SFN by definition 1, 6
• Small fiber damage often precedes large fiber damage in diabetic neuropathy, so normal NCS does not exclude neuropathy 2, 3
• Neurological consultation with specialized evaluation including electromyography/nerve conduction studies should be considered to rule out large fiber involvement, but these tests cannot diagnose SFN 1

Additional Considerations

• Nerve biopsy is generally not indicated for SFN evaluation 1
• In patients with neuropathy and systemic disease (e.g., Waldenström's macroglobulinemia), test for anti-MAG antibodies if demyelinating features present, or anti-GM1 antibodies if motor neuropathy predominates 1
• Laser-evoked potentials and electrochemical skin conductance are additional specialized tests that may be informative 6