Systematic approach to peripheral neuropathy workup: axonal vs demyelinating, and key treatable causes

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### Stepwise Approach to Axonal Polyneuropathy **1. Initial Clinical and Electrophysiologic Categorization** * **EMG/NCS:** The first step is to distinguish between axonal (low amplitudes, preserved velocities) and demyelinating (slowed velocities, prolonged latencies, conduction block) patterns. * **Clinical Context:** While diabetes is the most common cause of axonal neuropathy, a symmetric "stocking-glove" pattern warrants a screening for other reversible/treatable etiologies, especially if symptoms are rapidly progressive or severe. **2. Stepwise Biochemical Workup (Treatable Causes)** * **Tier 1 (Universal Screening):** * HbA1c (even in known diabetics, for glycemic control status). * Serum B12 level (with methylmalonic acid/homocysteine if borderline). * Serum Protein Electrophoresis (SPEP) with Immunofixation (IFE) to screen for monoclonal gammopathy (MGUS/Multiple Myeloma). * TSH (hypothyroidism). * Renal and hepatic function tests. * **Tier 2 (Directed by Clinical Clues):** * **Vasculitis Panel:** ANA, ANCA, ESR/CRP (if asymmetric/mononeuritis multiplex is suspected). * **Paraneoplastic Panel:** ANNA-1 (anti-Hu), etc. (if subacute onset or weight loss). * **Anti-MAG antibodies:** Typically seen in distal symmetric demyelinating neuropathy with IgM monoclonal protein. * **Infectious:** HIV, RPR, Hepatitis C. **3. Red Flags: Diabetic Neuropathy vs. CIDP** Chronic Inflammatory Demyelinating Polyradiculoneuropathy (CIDP) is a critical "don't miss" diagnosis because it is treatable with IVIG/steroids. * **CIDP Red Flags:** * Proximal weakness (difficulty climbing stairs or rising from a chair). * Global areflexia (diabetic neuropathy usually involves only distal ankle reflex loss early on). * Rapid progression (<8 weeks). * Demyelinating features on NCS. * **Diabetic Neuropathy:** Typically progresses over years, starts distally, and sensory symptoms predominate over motor. **4. Role of Nerve Biopsy** The utility of nerve biopsy has decreased due to improved serological and electrophysiological testing. * **Indications:** Suspected vasculitic neuropathy (mononeuritis multiplex), amyloid neuropathy, or when atypical neuropathy remains undiagnosed despite extensive workup. * **Target:** Usually the sural nerve (pure sensory) to minimize motor deficit. **References:** 1. Watson JC, Dyck PJ. Peripheral Neuropathy: A Practical Approach to Diagnosis and Symptom Management. *Mayo Clin Proc*. 2015. 2. Joint Task Force of the EFNS and the PNS. Guideline on management of chronic inflammatory demyelinating polyradiculoneuropathy. *J Peripher Nerv Syst*. 2021. 3. Callaghan BC, et al. Distal symmetric polyneuropathy: a review. *JAMA*. 2015.