🧬 27% of neuropathy cases: no cause after testing

A JAMA review highlights the missing link in neuropathy workups: up to 27% of adults with peripheral neuropathy have no identifiable etiology even after diagnostic testing. Diabetes mellitus (DM) remains the leading cause in Western populations (accounting for >50%), but a substantial minority stay “idiopathic” despite evaluation.

Why It Matters To Your Practice

▪ Peripheral neuropathy affects ~1% of adults worldwide and can progress from mild distal numbness to disabling pain, weakness, and autonomic symptoms.

▪ A notable share of patients will have persistent symptoms without a clear cause, which can drive repeated testing, delays in symptom control, and patient frustration.

▪ DM is common but not the only culpritmedications/toxins, vitamin deficiencies, monoclonal gammopathies, alcohol use, and hereditary neuropathies remain key differentials.

Clinical Benefits

▪ Use a focused initial lab set to efficiently identify treatable causes: blood glucose (for diabetes), serum B12 with metabolites (methylmalonic acid  homocysteine), and serum protein electrophoresis with immunofixation.

▪ Start evidence-based neuropathic pain treatment when indicated: gabapentin/pregabalin, SNRIs (duloxetine/venlafaxine), or TCAs (amitriptyline/nortriptyline).

▪ Set expectations: even with treatment, complete reversal of nerve damage is uncommon; symptom control and function are often the main goals.

Managing Risks

▪ Screen for red flags that warrant urgent referral (e.g., rapid progression, marked asymmetry, prominent motor weakness, systemic symptoms, or significant autonomic dysfunction such as syncope/orthostatic hypotension).

▪ Medication safety: titrate slowly and monitor for sedation, dizziness, falls, anticholinergic effects (TCAs), and drug interactions; reassess benefit vs adverse effects regularly.

▪ Avoid “test creep” when initial evaluation is unrevealingdocument whats been ruled out, revisit exposure/med lists (chemo agents, amiodarone, HIV NRTIs), and consider neurology referral for atypical presentations.

The Bottom Line

▪ Even with appropriate testing, up to 27% of neuropathy remains unexplainedplan for symptom management and longitudinal reassessment.

▪ Prioritize high-yield screening (glucose, B12 with metabolites, SPEP with immunofixation) and initiate first-line neuropathic pain therapies early when clinically appropriate.

▪ DM is the most common cause in Western settings, but a broad differential and clear patient counseling are essential.