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What tests and diagnostics confirm peripheral neuropathy and its underlying cause?
Executive summary
Diagnostic confirmation of peripheral neuropathy rests first on history and focused neurological exam, then is commonly supported by electrodiagnostic testing — nerve conduction studies (NCS) and electromyography (EMG) — plus targeted laboratory screening for common causes such as diabetes, B12 deficiency, and monoclonal protein (eg, HbA1c, vitamin B12, serum protein electrophoresis) [1] [2] [3]. For small‑fiber or autonomic neuropathies, skin biopsy for intraepidermal nerve‑fiber density, quantitative sensory testing, autonomic reflex screens and specialized sweat testing are used because NCS/EMG predominantly test large myelinated fibers [3] [4].
1. Begin with history and a focused neurological exam — the diagnostic lynchpin
A careful history and physical exam identify neuropathic symptom patterns (length‑dependent distal sensory loss, symmetric vs focal, pain vs motor predominance) and guide testing choices; exam maneuvers such as vibration with a 128‑Hz tuning fork and 10‑g monofilament increase diagnostic utility in diabetic populations [1] [5]. Multiple centers emphasize that exam + history will often suggest whether to pursue basic blood testing or refer directly for electrodiagnostic studies [6] [7].
2. Electrodiagnostic testing: when and what it proves
Nerve conduction studies and EMG are the most widely used confirmatory tests for peripheral neuropathy of large fibers; abnormal NCS/EMG findings confirm neuropathy and help categorize axonal versus demyelinating processes, localize mononeuropathies, and exclude mimics such as radiculopathy [1] [8]. Limitations: NCS/EMG predominantly evaluate large, myelinated fibers and can be normal in pure small‑fiber neuropathy, so a normal study does not exclude all neuropathies [3] [1].
3. Laboratory screening to find common, treatable causes
High‑yield blood tests recommended across guidelines include glucose / HbA1c (for diabetes/prediabetes), vitamin B12 (with methylmalonic acid where indicated), complete blood count, thyroid, renal and liver function tests, and serum protein studies including immunofixation / electrophoresis to detect monoclonal gammopathy [2] [3] [1]. Additional blood tests (hepatitis C, HIV, autoimmune panels, cryoglobulins, paraneoplastic panels) are pursued based on history, exposures, or atypical phenotypes [9] [10].
4. Tests for small‑fiber and autonomic neuropathies
When symptoms suggest small‑fiber involvement (prominent pain, burning, dysautonomia, preserved strength and normal NCS), specialized testing is required: epidermal skin biopsy for intraepidermal nerve‑fiber density, quantitative sensory testing, autonomic reflex screening and sweat function tests—some of which are not widely available but are the preferred methods to confirm small‑fiber neuropathy [3] [4].
5. Spinal fluid, imaging, nerve biopsy and genetic testing — targeted, not routine
Cerebrospinal fluid (CSF) analysis via lumbar puncture can support diagnoses of inflammatory neuropathies (eg, Guillain–Barré syndrome or chronic inflammatory demyelinating polyneuropathy) when elevated protein or inflammatory changes are expected [11] [10]. Nerve biopsy is occasionally used to detect vasculitis or other pathologies when noninvasive tests fail, and genetic testing is indicated when hereditary neuropathy is suspected based on phenotype or family history [11] [4] [10]. MRI or CT imaging are not routinely needed for typical peripheral neuropathy but can localize plexopathies, radiculopathies, or atypical presentations [1] [5].
6. A tiered, pragmatic approach increases diagnostic yield and cost‑effectiveness
Contemporary reviews and practice guidelines recommend a two‑tiered approach: use history/exam to define phenotype, perform high‑yield, low‑cost screens (glucose/HbA1c, B12, SPEP/immunofixation) first, then proceed to electrodiagnostics and targeted advanced tests guided by those results [3] [4]. Studies show clinicians underuse these high‑yield screens, which can miss treatable causes [3].
7. Limitations, disagreements and practical takeaways
Sources agree on core tests (history/exam, NCS/EMG, basic labs) but differ on scope: some emphasize early referral for electrodiagnostics while others prioritize stepwise lab screening before specialty testing [1] [6]. Important caveat: normal NCS/EMG does not rule out small‑fiber neuropathy and additional tests (skin biopsy, autonomic testing) may be necessary [3]. Available sources do not mention specific test availability and wait times in local health systems — that practical constraint should guide local care decisions (not found in current reporting).
Bottom line: confirm peripheral neuropathy with history, exam and electrodiagnostic testing for large‑fiber disease; concurrently run targeted blood tests for diabetes, B12 deficiency, monoclonal proteins and other common causes; employ skin biopsy and autonomic testing when small‑fiber disease is suspected; reserve CSF, nerve biopsy, imaging, and genetic testing for specific, atypical, or unexplained cases [1] [2] [3] [4].