What is the workup for small fiber polyneuropathy?

Workup for Small Fiber Polyneuropathy

For symptomatic patients with suspected small fiber polyneuropathy, skin biopsy with intraepidermal nerve fiber (IENF) density assessment should be considered as the primary diagnostic test, combined with autonomic function testing to document small fiber dysfunction. 1, 2

Clinical Diagnosis

History and Physical Examination

• Look specifically for: burning pain in the feet, tingling, paresthesias, and numbness in a distal distribution, typically starting in the toes 3, 4
• Assess for autonomic symptoms: orthostatic hypotension (drop in systolic BP >20 mmHg or diastolic >10 mmHg upon standing), alternating diarrhea and constipation, urinary retention, erectile dysfunction, and abnormal sweating patterns 1, 3, 4
• Physical exam findings: assess temperature sensation (small-fiber function) and pinprick sensation, which are often abnormal, while vibration sense and reflexes may be preserved early in the disease 1
• Key distinguishing feature: conventional nerve conduction studies are typically normal in isolated small fiber neuropathy, as these tests only assess large fiber function 3, 2

Objective Diagnostic Testing

Skin Biopsy (Primary Test)

• Technique: 3 mm punch biopsy from the distal leg, immunostained with anti-PGP 9.5 antibodies to quantify IENF density 1
• Diagnostic accuracy: sensitivity 77.2-88% and specificity 79.6-88.8% for detecting small fiber pathology 2
• Interpretation: reduced IENF density importantly raises the likelihood of polyneuropathy, though normal density does not completely rule it out (sensitivity ranges 45-90% across studies) 1
• Advantage: provides direct objective measure of somatic unmyelinated C fibers, which are predominantly affected in small fiber neuropathy 1

Autonomic Function Testing (Complementary)

• Quantitative sudomotor axon reflex test (QSART): documents small fiber (sudomotor axon) loss with high sensitivity 1, 2
• Additional tests: heart rate variability with deep breathing, thermoregulatory sweat testing 2, 4
• Recommendation: use a battery of validated autonomic tests rather than a single test to achieve highest diagnostic accuracy 3
• Clinical utility: particularly valuable when skin biopsy is unavailable or to document autonomic nervous system dysfunction 1

Quantitative Sensory Testing (QST)

• Purpose: assess thermal thresholds to complement skin biopsy findings 2
• Note: less specific than skin biopsy but can provide supportive evidence 2

Etiologic Workup

Initial Laboratory Screening

• Metabolic causes: fasting glucose, HbA1c (diabetes is the most common cause), thyroid function (TSH) 3, 5
• Nutritional deficiencies: vitamin B12, folate 3
• Infectious causes: HIV testing 3
• Paraproteinemia: serum protein electrophoresis with immunofixation 3

Additional Testing Based on Clinical Context

• Autoimmune screening: particularly important in young patients and otherwise healthy individuals, where autoimmune causes account for up to 50% of cases 6, 7
• Genetic testing: consider for familial cases, childhood onset, or when initial workup is negative—includes Fabry disease, transthyretin amyloidosis, hereditary sensory autonomic neuropathy-1, and ion-channel mutations 6
• Cerebrospinal fluid analysis: when inflammatory or infectious causes are suspected 8

When to Avoid Nerve Conduction Studies

• Do not order EMG/NCS for typical small fiber neuropathy with burning pain, normal strength, and preserved reflexes, as these tests assess only large fiber function and will be normal 3, 2
• EMG/NCS is indicated only when there is clinical suspicion of large fiber involvement (weakness, areflexia) or when the diagnosis is atypical 1, 5

Common Pitfalls

• Relying solely on nerve conduction studies will miss small fiber neuropathy, as these tests only assess large myelinated fibers 2
• Avoid dismissing patients as having non-organic symptoms when EMG is normal—this often represents undiagnosed small fiber neuropathy that requires skin biopsy or autonomic testing for confirmation 7
• Do not delay diagnosis in young patients, as early identification and treatment of reversible causes (autoimmune, metabolic) can permit nerve fiber regrowth and prevent permanent damage 6, 7
• Caution patients against excessive cooling of extremities for pain relief, as this may worsen tissue damage and lead to ulcerations 2

Clinical Significance

The distinction between small fiber and large fiber neuropathy is crucial because small fiber damage often precedes large fiber damage (particularly in diabetic neuropathy), and early diagnosis allows for intervention before irreversible progression occurs 2, 4. Small fibers can regenerate throughout life if the underlying cause is addressed, making prompt diagnosis particularly important for improving quality of life and potentially achieving disease resolution 6.