# Approach to Peripheral Neuropathy: Evaluation and Classification

## Overview

Peripheral neuropathy affects approximately 2-8% of the general population, with prevalence increasing with age. The etiologies are numerous, and a systematic approach based on pattern recognition is essential for efficient diagnosis. The classification framework considers fiber type (motor, sensory, autonomic), distribution pattern, temporal course, pathophysiology (axonal versus demyelinating), and electrodiagnostic findings. Despite thorough evaluation, 20-30% of neuropathies remain idiopathic, with most being distal sensory neuropathies likely related to metabolic syndrome or cryptogenic causes.

## Classification Framework

### By Fiber Type

Motor predominant neuropathies include GBS, CIDP, multifocal motor neuropathy, hereditary motor neuropathies, and the lower motor neuron component of ALS. Sensory predominant neuropathies include diabetic polyneuropathy, B12 deficiency, chemotherapy-induced neuropathy, and small fiber neuropathy. Sensorimotor neuropathies are the most common pattern and include CMT, CIDP, vasculitic neuropathy, and many metabolic and toxic neuropathies. Autonomic predominant neuropathies include diabetic autonomic neuropathy, amyloidosis, autoimmune autonomic ganglionopathy, and hereditary sensory and autonomic neuropathies.

### By Distribution Pattern

Length-dependent (dying-back) neuropathy begins distally in the longest nerves, affecting the feet first and then the hands in a "stocking-glove" pattern. This is the most common pattern and suggests a metabolic, toxic, or hereditary cause. Non-length-dependent patterns with proximal or patchy involvement suggest inflammatory, vasculitic, or sensory neuronopathy (ganglionopathy). Mononeuropathy involves a single nerve (carpal tunnel syndrome, ulnar neuropathy at the elbow, peroneal neuropathy). Mononeuropathy multiplex involves multiple individual nerves in an asymmetric pattern and suggests vasculitis, diabetes, sarcoidosis, leprosy, or hereditary neuropathy with liability to pressure palsies. Polyradiculoneuropathy involves both proximal and distal segments and is seen in GBS, CIDP, and diabetic amyotrophy.

### By Temporal Course

| Temporal Course | Time Frame | Examples |
|---|---|---|
| Acute | Days to 4 weeks | GBS, toxic (thallium, arsenic), porphyria, critical illness |
| Subacute | 4–8 weeks | Vasculitic, paraneoplastic, nutritional deficiency |
| Chronic | Months to years | Diabetic, CIDP, CMT, amyloid, idiopathic |
| Relapsing-remitting | Variable | CIDP, HNPP |

Acute neuropathies (days to 4 weeks) include GBS, toxic exposures (thallium, arsenic), porphyria, and critical illness neuropathy. Subacute neuropathies (4-8 weeks) include vasculitic, paraneoplastic, and nutritional deficiency neuropathies. Chronic neuropathies (months to years) include diabetic, CIDP, hereditary (CMT), amyloid, and idiopathic neuropathies. Relapsing-remitting patterns are seen in CIDP and HNPP.

### By Pathophysiology

| Feature | Axonal | Demyelinating |
|---|---|---|
| Amplitudes (CMAP/SNAP) | Reduced | May be preserved early |
| Conduction velocity | Normal or mildly reduced | Significantly slowed (<70% LLN) |
| Distal latency | Normal | Prolonged (>130% ULN) |
| Conduction block | Absent | Present (acquired) |
| Temporal dispersion | Absent | Present |
| EMG | Fibrillations, reinnervation | Less prominent denervation |
| Examples | Diabetic, toxic, metabolic, most hereditary | CIDP, GBS (AIDP), CMT1, anti-MAG |

Axonal neuropathies show reduced CMAP and SNAP amplitudes with relatively preserved conduction velocities and denervation on EMG. Most toxic, metabolic, and hereditary neuropathies are axonal. Demyelinating neuropathies show slowed conduction velocities, prolonged distal latencies, conduction block, and temporal dispersion. They include CIDP, GBS (AIDP subtype), CMT1, and anti-MAG neuropathy. Mixed patterns with features of both are common in chronic disease.

<image>Diagram showing the clinical patterns of peripheral neuropathy: length-dependent stocking-glove, mononeuropathy multiplex, polyradiculoneuropathy, and sensory neuronopathy/ganglionopathy distributions</image>

## Electrodiagnostic Principles (NCS/EMG)

### Nerve Conduction Studies (NCS)

Motor NCS measure CMAP amplitude (reflecting axon number), distal latency, conduction velocity, and F-wave latency. Sensory NCS measure SNAP amplitude and conduction velocity. Demyelinating criteria include conduction velocity below 70% of the lower limit of normal, distal latency above 130% of the upper limit of normal, temporal dispersion, and conduction block (defined as more than 50% CMAP amplitude drop between proximal and distal stimulation). Conduction block is the hallmark of acquired demyelinating neuropathies (CIDP, GBS, MMN) and is rare in hereditary demyelinating neuropathies, which show uniform slowing without block (as in CMT1).

### Electromyography (EMG)

Acute denervation produces fibrillation potentials and positive sharp waves, which appear 2-3 weeks after axonal injury. Chronic denervation with reinnervation produces large-amplitude, long-duration, polyphasic motor unit potentials with reduced recruitment. A myopathic pattern shows small-amplitude, short-duration, polyphasic motor unit potentials with early recruitment, distinguishing it from a neuropathic process.

### Key EDx Patterns

Uniform demyelination characterizes CMT1 (hereditary). Non-uniform demyelination with conduction block characterizes CIDP and GBS (acquired). Axonal sensorimotor patterns are seen in diabetic, toxic, and most metabolic neuropathies. Axonal motor predominant patterns are seen in ALS (with upper motor neuron signs), MMN (with conduction block), and hereditary motor neuropathy. Pure sensory loss with absent SNAPs but normal motor studies suggests sensory neuronopathy (ganglionopathy).

## Laboratory Workup

### First-Tier (All Patients with Unexplained Neuropathy)

The initial workup includes complete blood count, comprehensive metabolic panel (glucose, renal function, liver function), hemoglobin A1c and fasting glucose (or 2-hour oral glucose tolerance test if suspicion is high), vitamin B12 and methylmalonic acid, thyroid function tests, serum protein electrophoresis with immunofixation (SPEP/IFE), and ESR with CRP.

### Second-Tier (Based on Clinical Suspicion)

For inflammatory or autoimmune suspicion: ANA, ANCA, rheumatoid factor, complement levels, cryoglobulins, anti-ganglioside antibodies (GM1 for MMN, GQ1b for Miller Fisher), and anti-MAG antibodies. For infectious causes: HIV, hepatitis B/C, Lyme serology, and RPR/VDRL. For nutritional deficiencies: folate, thiamine, pyridoxine (noting that excess B6 causes neuropathy), copper, and vitamin E. For toxic causes: heavy metals (arsenic, lead, thallium) and medication review. For metabolic conditions: 24-hour urine for porphyrins and very long chain fatty acids. For paraneoplastic causes: anti-Hu (ANNA-1), anti-CV2/CRMP5, and amphiphysin antibodies. For hereditary causes: genetic testing panels for CMT, TTR amyloidosis, and HNPP.

### Specialized Testing

CSF analysis showing elevated protein with normal cells (albuminocytologic dissociation) supports GBS and CIDP. Nerve biopsy (sural or superficial peroneal) is reserved for suspected vasculitic neuropathy, amyloidosis, sarcoidosis, leprosy, or atypical CIDP. Skin biopsy for intraepidermal nerve fiber density (IENFD) is the gold standard for diagnosing small fiber neuropathy. Autonomic testing (QSART, tilt table, thermoregulatory sweat test) evaluates autonomic neuropathy.

<image>Flowchart for the laboratory evaluation of peripheral neuropathy showing first-tier and second-tier testing based on clinical pattern and electrodiagnostic findings</image>

## Common Etiologies

### Diabetic Neuropathy

Diabetic neuropathy is the most common cause of peripheral neuropathy in developed countries. Distal symmetric polyneuropathy is length-dependent, sensory predominant over motor, and painful in approximately 50% of cases. Diabetic autonomic neuropathy produces GI dysmotility, orthostatic hypotension, and resting tachycardia. Diabetic amyotrophy (diabetic lumbosacral radiculoplexus neuropathy) presents with acute or subacute proximal leg pain and weakness, often asymmetric, with an immune-mediated component.

### Chemotherapy-Induced Peripheral Neuropathy (CIPN)

Platinum compounds (cisplatin, oxaliplatin) cause a sensory neuronopathy/ganglionopathy. Taxanes (paclitaxel, docetaxel) produce distal sensory greater than motor neuropathy. Vinca alkaloids (vincristine) cause motor greater than sensory neuropathy. Bortezomib and thalidomide produce painful sensory neuropathy. The "coasting" phenomenon refers to worsening for weeks after drug discontinuation.

### Alcoholic/Nutritional Neuropathy

This results from a combination of direct alcohol toxicity and nutritional deficiency (thiamine, folate, B12), producing a painful distal sensorimotor neuropathy treated with nutritional repletion and alcohol cessation.

### Paraproteinemic Neuropathy

MGUS-associated neuropathy is demyelinating when associated with IgM (often anti-MAG) and axonal when associated with IgA or IgG. Associated conditions include Waldenstrom macroglobulinemia, multiple myeloma, AL amyloidosis, and POEMS syndrome (Polyneuropathy, Organomegaly, Endocrinopathy, M-protein, Skin changes), which is associated with VEGF elevation and osteosclerotic myeloma.

### Small Fiber Neuropathy

Small fiber neuropathy involves isolated damage to small unmyelinated C fibers and thinly myelinated A-delta fibers. It presents with burning pain, allodynia, and temperature insensitivity. NCS and EMG are normal because these tests evaluate only large fibers; diagnosis requires skin biopsy showing reduced IENFD. Causes include diabetes and prediabetes, Sjogren syndrome, Fabry disease, sarcoidosis, celiac disease, and hereditary sodium channelopathies (SCN9A, SCN10A, SCN11A).

<image>Skin punch biopsy photomicrograph showing normal intraepidermal nerve fiber density compared with reduced density in small fiber neuropathy using PGP 9.5 immunostaining</image>

## When to Refer and Red Flags

Red flags warranting urgent referral include rapidly progressive neuropathy (suggesting GBS, vasculitis, or paraneoplastic disease), asymmetric or mononeuropathy multiplex pattern (vasculitis until proven otherwise), motor-predominant or non-length-dependent pattern, young age of onset (hereditary versus inflammatory), demyelinating features on NCS (CIDP, GBS variants), and neuropathy with systemic symptoms such as weight loss, rash, or organomegaly (suggesting vasculitis, sarcoidosis, amyloidosis, or POEMS).

## Clinical Pearls

A normal B12 level does not exclude B12 deficiency as a cause of neuropathy; methylmalonic acid should be checked (it is more sensitive) when clinical suspicion is high. Serum protein electrophoresis with immunofixation is essential in all unexplained neuropathies; missing a paraprotein can delay diagnosis of POEMS, amyloidosis, or myeloma. Vitamin B6 (pyridoxine) excess above 200 mg per day causes a sensory neuronopathy; supplement intake should always be checked. In mononeuropathy multiplex, the stepwise pattern of acute individual nerve involvement (rather than diffuse progression) is the clinical hallmark, and vasculitis should be considered first. The 2-hour oral glucose tolerance test is more sensitive than HbA1c for detecting prediabetes-associated neuropathy. Hereditary neuropathy with liability to pressure palsies (HNPP) should be considered in young patients with recurrent mononeuropathies or painless peroneal palsies. Sural nerve biopsy is being increasingly replaced by less invasive alternatives (skin biopsy, genetic testing) and should be reserved for suspected vasculitis, amyloidosis, or granulomatous disease.

## References
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