Toxic & Metabolic Neuropathies
Toxic and metabolic neuropathies encompass a broad group of peripheral nerve disorders caused by exogenous toxins (medications, heavy metals, industrial agents) and metabolic derangements (nutritional deficiencies, paraproteinemia). Although most neuropathies encountered in clinical practice are diabetic or idiopathic, recognizing toxic and metabolic etiologies is critical because many are reversible or arrestable with timely intervention. This topic synthesizes drug-induced, nutritional, environmental, and paraproteinemic neuropathies into a unified clinical framework for the neuromuscular specialist.
Bottom Line
- Chemotherapy-induced peripheral neuropathy (CIPN): The most common dose-limiting side effect of neurotoxic chemotherapy, affecting 40–60% of exposed patients; duloxetine is the best-evidenced treatment for CIPN-related pain
- Immune checkpoint inhibitor (ICI) neuropathy: A growing cause of toxic neuropathy as 40% of cancer patients become eligible for ICIs; presents with diverse phenotypes including GBS-like syndromes that, unlike classic GBS, respond to corticosteroids
- Vitamin B12 deficiency: Classic cause of subacute combined degeneration; neurologic manifestations may occur without hematologic abnormalities; elevated methylmalonic acid is more specific than low serum B12 alone
- Pyridoxine (B6) toxicity: Excess supplementation (≥100 mg/d) causes a sensory ganglionopathy — a critical consideration in patients taking B6 for nausea or empirically
- Copper deficiency: Produces a myeloneuropathy indistinguishable from B12 deficiency; most commonly seen after bariatric surgery or with zinc excess from denture creams or supplements
- Paraproteinemic neuropathies: Found in ~10% of otherwise idiopathic neuropathies; IgM anti-MAG neuropathy, POEMS syndrome, and AL amyloidosis are the three major entities with distinct clinical and electrodiagnostic profiles
- Heavy metals: Lead causes motor-predominant neuropathy with wrist drop; arsenic causes painful sensory axonal neuropathy with Mees lines; thallium causes rapid painful neuropathy with alopecia
Drug-Induced Neuropathies
Chemotherapy-Induced Peripheral Neuropathy (CIPN)
CIPN is a common, length-dependent toxic neuropathy occurring in 40–60% of patients treated with neurotoxic chemotherapy agents. It is the most frequent cause of chemotherapy dose reduction or cessation and is associated with impaired physical and psychological function, increased fall risk, and decreased quality of life. Healthcare costs for patients with CIPN exceed those of matched cancer survivors without CIPN by approximately $20,000 per year.
CIPN generally presents as a subacute, symmetric, length-dependent, sensory greater than motor axonal neuropathy. Risk factors include older age, African American race, diabetes, higher BMI, preexisting neuropathy, and specific pharmacogenomic variants. Charcot-Marie-Tooth type 1A (PMP22 duplication) is considered a contraindication to vinca alkaloid therapy.
| Agent Class | Examples | Mechanism | Pattern | Distinguishing Features |
|---|---|---|---|---|
| Taxanes | Paclitaxel, docetaxel | Microtubule disruption → impaired axonal transport | Sensory > motor; hands and feet | Paclitaxel-associated acute pain syndrome (myalgias/arthralgias 1–7 days post-infusion) |
| Platins | Cisplatin, oxaliplatin, carboplatin | DRG toxicity via DNA cross-linking | Sensory neuronopathy; hands and feet simultaneously | "Coasting" (worsening ≤3–6 months after cessation); oxaliplatin → cold-induced dysesthesias |
| Vinca alkaloids | Vincristine, vinblastine | Microtubule destabilization | Sensorimotor, painful; up to 10% with weakness | Prominent autonomic involvement (constipation in ~33%); rare GBS-like fulminant presentations |
| Proteasome inhibitors | Bortezomib, carfilzomib, ixazomib | DRG toxicity; small fiber predilection | Painful, length-dependent, minimal weakness | Difficult to distinguish from myeloma-related neuropathy; threshold ~25 mg/m² |
| Thalidomide | Thalidomide, lenalidomide | TNF-alpha inhibition | Sensorimotor axonal; significant autonomic involvement | Lenalidomide has lower neurotoxicity; constipation and erectile dysfunction common |
CIPN Management Principles
- No proven preventive agents: ASCO recommends against any supplements or medications for CIPN prevention; exercise and cryotherapy are under investigation
- First-line pain treatment: Duloxetine (30–60 mg/d) has the best supporting evidence; alternatives include gabapentinoids, TCAs, and SNRIs
- Rehabilitation: Referral to physical therapy/occupational therapy for fall-risk reduction, gait aids, and ADL modifications is essential
- Prognosis: Recovery occurs in a proximal-to-distal gradient over ~2 years; many survivors have persistent symptoms
Immune Checkpoint Inhibitor (ICI) Neuropathy
With the expanding use of ICIs (PD-1 inhibitors, PD-L1 inhibitors, CTLA-4 inhibitors) in oncology, ICI-related neuropathy is becoming increasingly common. Neurologic immune-related adverse events occur in 1–12% of ICI-treated patients, with 75% affecting the peripheral nervous system. ICI-related neuropathy typically presents 8–12 weeks after ICI initiation and comprises 29% of neurologic immune-related adverse events.
The phenotypic diversity of ICI-related neuropathy is striking. A 2021 systematic review identified the following distribution: acute/subacute demyelinating neuropathy (25%), cranial neuropathies (25%), acute axonal motor or sensorimotor neuropathies (13%), sensory neuropathy/neuronopathy (8%), CIDP (6%), and Miller Fisher syndrome (3%). The incidence increases with combination PD-L1 + CTLA-4 therapy.
Critical Differences from Classic GBS
- ICI-related AIDP often shows CSF pleocytosis (atypical for classic GBS, where albuminocytologic dissociation is expected)
- ICI-related GBS-like neuropathy responds to corticosteroids — unlike classic GBS
- Overlap syndromes are very common — facial neuropathy + myositis + hepatitis can coexist
- Screen for paraneoplastic antibodies (anti-Hu/ANNA-1, CRMP-5/anti-CV2) in severe sensory neuronopathy, especially with neuroendocrine tumors
- Monitor for concurrent myositis and myocarditis — associated with poor prognosis
Management follows the ASCO-recommended grading system (grades 1–5). Grade 1 (mild sensory symptoms) requires neurology consultation. Grade 2 (any weakness) warrants holding ICIs and considering oral prednisone (0.5–1 mg/kg). Grades 3–4 (impaired ambulation or respiratory compromise) require permanent ICI discontinuation and IV methylprednisolone (2–4 mg/kg/d), with IVIg or plasma exchange for refractory cases. Approximately 70–80% of patients partially or fully improve, but ~10% of GBS-like presentations are fatal.
Antimicrobial-Associated Neuropathies
| Agent | Pattern | Key Features | Management |
|---|---|---|---|
| Metronidazole | Sensory axonal, length-dependent | Risk increases with ≥42 g total or ≥4 weeks; seen with H. pylori treatment and Crohn disease | Cessation; good prognosis for recovery |
| Isoniazid | Sensory large fiber axonal | Mechanism: B6 depletion; slow acetylators at higher risk | Pyridoxine prophylaxis (avoid oversupplementation); cessation if neuropathy develops |
| Linezolid | Sensory axonal; optic neuropathy | Prolonged courses (>28 days); mitochondrial toxicity | Cessation; improvement variable |
| Dapsone | Motor-predominant axonal | May mimic motor neuron disease | Cessation; monitor for methemoglobinemia |
| Nucleoside analogues (older ARVs) | Sensory > motor axonal | Stavudine, didanosine, zalcitabine; look for systemic toxicity signs (lipodystrophy, elevated lactate) | Switch to newer ARVs (lower neurotoxicity) |
| Fluoroquinolones | Length-dependent symmetric | Predilection for men >60 years; tendinopathy may coexist | Cessation; screen for tendon rupture |
Cardiovascular Drug Neuropathies
Amiodarone: High doses (>400 mg/d) for >1 year can cause a chronic length-dependent sensorimotor axonal neuropathy, often accompanied by tremors, cognitive impairment, and optic neuropathy. Statins: A 2022 meta-analysis found no increased risk of peripheral neuropathy with statin use in diabetic or nondiabetic populations, suggesting statin-induced neuropathy is far rarer than previously believed and should be a diagnosis of exclusion. Hydralazine: Causes neuropathy through vitamin B6 depletion, presenting as a sensory-predominant axonal polyneuropathy.
Other Drug-Induced Neuropathies
Colchicine: Causes a rare sensorimotor axonal neuropathy primarily in patients with end-stage renal disease; neuromyopathy pattern on EMG. Chloroquine/hydroxychloroquine: Chronic use causes neuromyopathy with vacuolar myopathy and mixed demyelinating-axonal neuropathy; risk increases at doses >5 mg/kg and duration >5 years. Tacrolimus: Up to 40% of transplant recipients develop a chronic multifocal demyelinating neuropathy; risk factors include peak drug levels and liver failure. Phenytoin: Long-term high doses cause a length-dependent sensory axonal neuropathy.
Nutritional Neuropathies
Nutritional neuropathies are generally axonal, and the presence of a predominantly demyelinating pattern should prompt a search for alternative etiologies. Multiple deficiencies often coexist, particularly in patients with alcohol use disorder, bariatric surgery, or malabsorption syndromes. Both the central and peripheral nervous systems can be involved simultaneously.
Vitamin B12 (Cobalamin) Deficiency
Vitamin B12 deficiency is the most clinically significant nutritional cause of myeloneuropathy. The classic neurologic manifestation is subacute combined degeneration of the spinal cord, characterized by dorsal column and corticospinal tract involvement. Peripheral neuropathy may coexist or be independently present as a sensory-predominant axonal neuropathy.
B12 Deficiency: Key Clinical Points
- Causes: Pernicious anemia, atrophic gastritis, gastrectomy/bariatric surgery, ileal resection, vegan diet, prolonged PPI use, nitrous oxide abuse ("whippets")
- Clinical clues: Simultaneous hand and foot paresthesias, disproportionate dorsal column dysfunction, brisk knee jerks with reduced ankle reflexes, Lhermitte sign
- Important caveat: Neurologic manifestations frequently occur without hematologic abnormalities (macrocytosis, megaloblastic anemia)
- Diagnosis: Serum B12 lacks sensitivity/specificity; elevated methylmalonic acid (more specific) and homocysteine (less specific) confirm metabolic significance; holotranscobalamin is useful in equivocal cases
- Nitrous oxide: Oxidizes the cobalt core → functionally inactive B12 despite low-normal levels; produces a classic B12 deficiency syndrome
- Treatment: 1000 μg IM daily × 5 days, then weekly × 4 weeks, then monthly; neurologic recovery is slower and less predictable than hematologic recovery
- Timeline: Typically 4–5 years of malabsorption needed to deplete hepatic stores
Thiamine (Vitamin B1) Deficiency
Thiamine deficiency should be considered in any critically ill patient with unexplained neurologic symptoms. Unlike B12, the body stores only limited amounts, and clinically significant depletion can occur in just 2–3 weeks of a thiamine-deficient diet.
The most characteristic neurologic manifestations are Wernicke encephalopathy (mental status changes, ophthalmoparesis, ataxia — classic triad rarely seen in full), Korsakoff psychosis (amnestic-confabulatory state), and beriberi. Dry beriberi refers to a distal sensorimotor axonal neuropathy, while wet beriberi adds high-output cardiac failure. A GBS-mimicking rapidly progressive ascending neuropathy is well described with thiamine deficiency but lacks the prominent autonomic dysfunction and respiratory failure typical of GBS.
Thiamine Deficiency: Red Flags
- At-risk patients must receive parenteral thiamine before glucose administration — glucose consumption depletes marginal thiamine stores and can precipitate Wernicke encephalopathy
- Serum/plasma thiamine levels normalize rapidly with any oral intake — draw blood before treatment; erythrocyte thiamine diphosphate is the preferred test
- Wernicke encephalopathy/alcohol use disorder/severe malnutrition: use 500 mg thiamine IV 3 times daily for 2–3 days, then 250 mg IV/IM for 3–5 days
- High-risk populations: alcohol use disorder, bariatric surgery patients, refeeding syndrome, patients on dialysis, pregnant/lactating patients, critically ill
Pyridoxine (Vitamin B6): Deficiency and Toxicity
Deficiency: Seen with malnutrition, alcohol use disorder, and drugs (isoniazid, hydralazine, phenytoin). Even with low levels, symptomatic neuropathy from B6 deficiency alone is rare. Replacement: 50–100 mg/d orally.
Toxicity: The clinically more important scenario. Excess B6 supplementation, typically ≥100–200 mg/d for prolonged periods, causes a sensory ganglionopathy characterized by sensory ataxia, areflexia, impaired cutaneous and deep sensation, and positive Romberg sign. This is particularly relevant in cancer patients taking B6 for nausea. Gradual improvement occurs with timely cessation.
Copper Deficiency
Acquired copper deficiency produces a myeloneuropathy that is clinically and radiologically indistinguishable from B12 deficiency (dorsal column T2 hyperintensity, sensory ataxia, spastic gait). It should be considered in any patient with myeloneuropathy, especially after bariatric surgery or with a history of excess zinc ingestion (supplements, denture creams).
Copper Deficiency: Diagnostic and Treatment Pearls
- Common causes: Gastric/bariatric surgery, zinc excess (denture creams, supplements, coin ingestion), celiac disease (even without GI symptoms), TPN
- Hematologic clues: Anemia, neutropenia, pancytopenia — may be misdiagnosed as myelodysplastic syndrome
- Lab workup: Serum copper, ceruloplasmin, 24-hour urine copper and zinc, serum zinc
- Timing: Neurologic symptoms typically delayed by years after inciting event (large body stores)
- Treatment: Oral elemental copper: 8 mg/d week 1 → 6 mg/d week 2 → 4 mg/d week 3 → 2 mg/d maintenance; parenteral if severe malabsorption
- Response: Hematologic improvement is prompt; neurologic recovery is variable and often incomplete
- Caution: Oral iron interferes with copper absorption
Vitamin E Deficiency
Vitamin E deficiency causes a spinocerebellar syndrome with variable dorsal column and peripheral nerve involvement, phenotypically resembling Friedreich ataxia. Ptosis, pigmentary retinopathy, and ophthalmoparesis may be seen. Many years of fat malabsorption are required to deplete stores. True dietary insufficiency is rare. Causes include pancreatic insufficiency, chronic cholestasis, and inherited conditions (ataxia with vitamin E deficiency, abetalipoproteinemia). Treatment involves high-dose IM or oral alpha-tocopherol, depending on the degree of malabsorption.
At-Risk Populations
Bariatric surgery: In a Mayo Clinic study, 16% of 435 bariatric surgery patients developed peripheral neuropathy. Thiamine deficiency causes early neurologic complications; B12 and copper deficiency cause later manifestations. A meta-analysis found thiamine deficiency in 27% of post-bariatric patients. Alcohol use disorder: Alcoholic neuropathy is a slowly progressive, painful, predominantly sensory neuropathy with small-fiber predilection, distinct from thiamine-deficiency neuropathy (which progresses more rapidly with large-fiber dysfunction). Always rule out coexisting nutritional deficiencies. Malabsorption syndromes: Celiac disease, inflammatory bowel disease, and gastric surgery all predispose to multiple concurrent deficiencies.
Paraproteinemic Neuropathies
Approximately 10% of patients with otherwise idiopathic neuropathy have an associated paraproteinemia. Because both neuropathy and monoclonal gammopathy are common, concurrence does not always imply causation. However, the IgM subtype has the strongest causal association (50–75% of paraproteinemic neuropathies). Serum immunofixation electrophoresis is far more sensitive than routine SPEP and should always be obtained when evaluating idiopathic neuropathies.
Anti-MAG Neuropathy
Anti-MAG (myelin-associated glycoprotein) neuropathy is the most well-characterized IgM paraproteinemic neuropathy. It presents as a distal acquired demyelinating symmetric (DADS) neuropathy in older males, with progressive sensory ataxia, tremor, and mild distal weakness.
Anti-MAG Neuropathy: Key Features
- Antibody: IgM anti-MAG, usually kappa light chain; present in 50–65% of IgM DADS patients
- Electrodiagnostic hallmark: Uniformly slow conduction velocities with disproportionately prolonged distal motor latencies and short terminal latency index (distal > proximal demyelination); no conduction block or temporal dispersion
- Pathology: Widening of myelin lamellae from IgM/complement deposition in the interperiodic space
- Prognosis: Generally benign; disability rates: 16% at 5 years, 24% at 10 years, 50% at 15 years
- Treatment: Mild/stable → supportive care; progressive → rituximab (first-line); helps 30–50% of patients; immunochemotherapy may be considered for rapidly progressive cases
POEMS Syndrome
POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder, skin changes) syndrome is a rare paraneoplastic disorder associated with plasma cell dyscrasia. It is frequently misdiagnosed as CIDP, often with prolonged diagnostic delays.
| Feature | Details |
|---|---|
| Mandatory criteria | Polyneuropathy (typically demyelinating) + monoclonal plasma cell disorder (almost always lambda light chain) |
| Major criteria (1 required) | Castleman disease, sclerotic bone lesions, or VEGF elevation |
| Minor criteria (1 required) | Organomegaly, edema/effusions, endocrinopathy, skin changes, papilledema, thrombocytosis/polycythemia |
| Key distinguishing lab | Plasma VEGF >200 pg/mL (68% sensitive, 95% specific); thrombocytosis is a characteristic finding |
| EDx vs. CIDP | More uniform conduction slowing; conduction block uncommon; lower limb CMAPs disproportionately affected; more axonal loss |
| Treatment | 1–3 bone lesions without marrow involvement → radiation therapy; widespread disease → autologous HSCT or systemic therapy (lenalidomide, bortezomib, daratumumab) |
POEMS: Diagnostic Pitfalls
- Consider POEMS in all cases of refractory CIDP that fail IVIg and plasma exchange
- SPEP may be normal — immunofixation is essential (IgA or IgG lambda)
- Neuropathic pain at onset is common in POEMS but uncommon in typical CIDP
- Look for systemic clues: skin hyperpigmentation, edema, thrombocytosis, hypogonadism
- Neurologic response after treatment may be delayed 6–36 months
Light Chain (AL) Amyloidosis
AL amyloidosis, the most common systemic amyloidosis in the United States (prevalence ~2.5 per 100,000), is caused by misfolded light chain immunoglobulins deposited as amyloid fibrils in multiple organs. Peripheral neuropathy occurs in 17–36% of patients, typically presenting as a rapidly progressive, painful, length-dependent sensory neuropathy with early small fiber and autonomic involvement (orthostatic hypotension, gastroparesis, erectile dysfunction, sweating abnormalities).
AL Amyloidosis Neuropathy: Red Flags
- Rapidly progressive painful neuropathy with prominent autonomic dysfunction
- Carpal tunnel syndrome (present in up to 21%) — may precede systemic diagnosis
- Periorbital purpura, macroglossia, hepatomegaly (minority of patients)
- Heart failure with preserved ejection fraction, nephrotic-range proteinuria
- Lambda light chain predominance; nerve conduction studies show axonal > demyelinating pattern
- Diagnosis: Abdominal fat aspirate preferred over nerve biopsy; Congo red stain with apple-green birefringence; mass spectrometry for amyloid subtyping (to exclude hereditary TTR amyloidosis)
- Treatment: Address underlying plasma cell dyscrasia; high-dose chemotherapy + stem cell transplant in eligible patients; avoid bortezomib in patients with neuropathy
Cryoglobulinemia
Cryoglobulins are immunoglobulins that precipitate below body temperature. Type I cryoglobulinemia (monoclonal) develops in the setting of MGUS (40%) or B-cell malignancies (60%, including Waldenstrom macroglobulinemia and myeloma). Type II (mixed, polyclonal) is usually associated with hepatitis C. Peripheral neuropathy occurs in ~30% of cases, typically as a painful sensory neuropathy affecting small fibers or as mononeuritis multiplex (vasculitic neuropathy). Treatment targets the underlying hematologic or infectious condition.
Environmental Toxins: Heavy Metals
Heavy metal neuropathies are uncommon but important to identify because of their reversibility and the forensic/occupational implications. A thorough social, occupational, and exposure history is essential when heavy metal toxicity is suspected.
| Metal | Sources | Neuropathy Pattern | Systemic Clues | Diagnostic Test |
|---|---|---|---|---|
| Lead | Paint, contaminated water, smelting, herbal medicines, distilled alcohol | Acute: motor-predominant, radial nerve predilection (wrist drop); Chronic: distal sensorimotor axonal | Lead lines on gums, basophilic stippling, cognitive dysfunction, abdominal pain, hypertension | Serum lead level |
| Arsenic | Intentional poisoning, mining, alternative medicines, contaminated water | Distal large fiber axonal, painful | Mees lines (horizontal nail lines), skin hyperkeratosis, GI symptoms, renal impairment | Acute: 24-hour urine; Chronic: hair analysis |
| Mercury | Thermometer/fluorescent light manufacturing, mining, dental amalgams | Acute: motor axonal; Chronic: sensory > motor, length-dependent | Encephalopathy, psychosis, ataxia, acrodynia (pink peeling skin), renal impairment | Serum or 24-hour urine levels |
| Thallium | Rodenticides, industrial exposure, intentional poisoning | Rapidly progressive, painful sensory neuropathy | Alopecia (hallmark), GI symptoms, tachycardia, confusion | 24-hour urine thallium |
| Zinc excess | Supplements, denture creams, coins | Myeloneuropathy (via copper depletion) | Anemia, neutropenia, gait ataxia from dorsal column degeneration | Serum zinc, serum copper, ceruloplasmin |
Management of heavy metal neuropathies centers on identification and elimination of the exposure source. Chelation therapy (succimer for lead, dimercaprol for arsenic, DMPS for mercury) is reserved for significantly elevated levels with systemic toxicity. Improvement is generally expected with exposure cessation, though recovery may be prolonged and incomplete.
Comprehensive Summary Table
| Agent/Deficiency | Pattern | Key Features | Management |
|---|---|---|---|
| Platinum agents | Sensory neuronopathy | Coasting phenomenon; cold dysesthesias (oxaliplatin) | Dose reduction; duloxetine for pain |
| Taxanes | Sensory > motor, hands and feet | Acute pain syndrome; starts at high cumulative doses | Dose adjustment; rehabilitation |
| Vinca alkaloids | Painful sensorimotor | Motor involvement; autonomic (constipation); CMT1A contraindication | Dose reduction or cessation |
| ICI therapy | Diverse (GBS-like, cranial, axonal) | Onset 8–12 weeks; overlap syndromes; CSF pleocytosis | Hold/stop ICI; steroids ± IVIg/PLEX |
| Metronidazole | Sensory axonal | Dose-dependent (≥42 g total) | Cessation; good recovery expected |
| Isoniazid | Sensory axonal | B6 depletion mechanism | B6 prophylaxis; cessation |
| Amiodarone | Sensorimotor axonal | >400 mg/d, >1 year; optic neuropathy | Dose reduction or cessation |
| B12 deficiency | Sensory axonal ± myelopathy | Subacute combined degeneration; nitrous oxide link | IM B12 replacement |
| B1 (thiamine) deficiency | Sensorimotor axonal; GBS mimic | Wernicke-Korsakoff; dry/wet beriberi; rapid depletion | IV thiamine (high-dose if Wernicke) |
| B6 toxicity | Sensory ganglionopathy | ≥100 mg/d chronically; sensory ataxia, areflexia | Cessation of supplementation |
| Copper deficiency | Myeloneuropathy | Mimics B12 deficiency; post-bariatric, zinc excess | Oral/IV copper; eliminate zinc source |
| Vitamin E deficiency | Spinocerebellar ± neuropathy | Resembles Friedreich ataxia; fat malabsorption | High-dose alpha-tocopherol |
| Anti-MAG neuropathy | Distal demyelinating (DADS) | Prolonged distal latencies; short TLI; sensory ataxia | Rituximab for progressive disease |
| POEMS syndrome | Demyelinating with axonal loss | Lambda light chain; VEGF >200; thrombocytosis | Radiation or HSCT; lenalidomide |
| AL amyloidosis | Painful sensory, small fiber early | Autonomic dysfunction; lambda predominant; Congo red+ | Chemotherapy ± stem cell transplant |
| Lead | Motor > sensory (acute); sensorimotor (chronic) | Wrist drop; lead gum lines; basophilic stippling | Exposure elimination ± chelation |
| Arsenic | Sensory axonal, painful | Mees lines; GI/renal toxicity; intentional poisoning | Exposure elimination ± chelation |
Diagnostic Approach
Evaluation Framework for Suspected Toxic/Metabolic Neuropathy
- History: Detailed medication review (including supplements, OTC medications); occupational/environmental exposure history; dietary habits; alcohol use; surgical history (bariatric procedures); timeline of symptom onset relative to exposures
- Examination: Differentiate length-dependent (most toxic/metabolic) from non-length-dependent (ganglionopathy — B6 toxicity, platinum agents); assess for motor predominance (lead, vinca alkaloids, dapsone); evaluate for autonomic features (AL amyloidosis, vinca alkaloids, thalidomide)
- Laboratory workup: HbA1c, vitamin B12 + methylmalonic acid, serum protein electrophoresis with immunofixation, serum free light chains, thiamine (erythrocyte TDP), B6, copper/zinc, vitamin E; consider paraneoplastic panel if neuronopathy pattern
- Electrodiagnostic studies: Distinguish axonal from demyelinating patterns; identify neuronopathy (non-length-dependent sensory loss with low/absent SNAPs); assess for DADS pattern (anti-MAG) or CIDP-like pattern (POEMS)
- Additional tests based on suspicion: Heavy metal levels (serum, urine, hair); VEGF (POEMS); abdominal fat aspirate (amyloidosis); skin biopsy for intraepidermal nerve fiber density (small fiber neuropathy)
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