How do I differentiate peripheral neuropathy from other causes of sensory, motor, or autonomic impairment?

Distinguishing Peripheral Neuropathy from Other Entities

Peripheral neuropathy is primarily a clinical diagnosis based on characteristic distal, symmetric sensory symptoms in a stocking-and-glove distribution, confirmed by clinical examination showing reduced vibration, proprioception, or pain/temperature sensation, with electrodiagnostic studies reserved for atypical presentations. 1, 2

Clinical Pattern Recognition

The hallmark features that distinguish peripheral neuropathy from other causes include:

• Distal symmetric distribution: Symptoms begin in the toes and progress proximally over time due to length-dependent axonal involvement, distinguishing it from radiculopathy, plexopathy, or central lesions 2, 3
• Sensory predominance: Most peripheral neuropathies affect sensory fibers more than motor fibers, with numbness, tingling, burning, and paresthesias as primary complaints 1, 2
• Bilateral symmetry: Asymmetric symptoms should raise suspicion for alternative diagnoses such as mononeuropathy multiplex (vasculitis, leprosy), radiculopathy, or focal nerve entrapment 1, 4

Fiber Type Differentiation

Large Fiber Neuropathy

• Clinical features: Loss of vibration sense (tuning fork test), proprioception impairment, sensory ataxia, and reduced/absent deep tendon reflexes 1, 4
• Common causes: Diabetes, vitamin B12 deficiency, hereditary neuropathies 5, 2

Small Fiber Neuropathy

• Clinical features: Burning feet, lancinating pain, reduced pain and temperature sensation, with preserved reflexes and proprioception 1
• Autonomic involvement: Orthostatic hypotension, constipation, bladder dysfunction, erectile dysfunction 1
• Key distinction: Standard nerve conduction studies may be completely normal; skin biopsy showing reduced intraepidermal nerve fiber density is the gold standard 1

Temporal Profile as Diagnostic Clue

• Acute onset (days to weeks): Consider Guillain-Barré syndrome, vasculitis, or toxic exposure rather than typical metabolic neuropathy 6, 7
• Subacute (weeks to months): Suggests inflammatory, infectious (HCV-related), or paraneoplastic causes 1
• Chronic progressive (months to years): Typical of diabetic neuropathy, hereditary neuropathies, or idiopathic axonal polyneuropathy 2, 3, 7

When to Suspect Alternative Diagnoses

Red Flags Against Peripheral Neuropathy

• Asymmetric presentation: Suggests mononeuropathy multiplex from vasculitis, entrapment syndromes, or radiculopathy 1, 4
• Proximal > distal weakness: Consider myopathy, motor neuron disease, or polyradiculopathy rather than typical peripheral neuropathy 6
• Upper motor neuron signs: Hyperreflexia, spasticity, or Babinski sign indicate central nervous system pathology, not peripheral neuropathy 4
• Sudden onset with severe motor involvement: Consider acute inflammatory demyelinating polyneuropathy or mononeuritis multiplex 1, 7

Specific Mimics to Exclude

• Spinal stenosis: Causes bilateral leg symptoms but with neurogenic claudication (worse with walking/standing, relieved by sitting/flexion) rather than constant symptoms 1
• Peripheral vascular disease: Check pedal pulses; absent pulses suggest arterial insufficiency rather than neuropathy 5
• Radiculopathy: Dermatomal rather than stocking-glove distribution, often with back pain 4, 6
• Myelopathy: Gait instability with upper motor neuron signs, bladder dysfunction, sensory level 4

Role of Electrodiagnostic Testing

Nerve conduction studies and EMG are NOT required for typical presentations but should be obtained when: 1

• Asymmetric symptoms or signs despite clinical suspicion of neuropathy 1
• Normal clinical examination despite patient complaints 1
• Rapid progression requiring differentiation of demyelinating from axonal pathology 4, 6
• Consideration of immune-mediated neuropathy where demyelinating features (prolonged distal latencies, slowed conduction velocity, conduction block) guide immunotherapy 4

Critical caveat: Electrodiagnostic studies will be normal in pure small fiber neuropathy; skin biopsy is required for diagnosis in this setting 1

Essential Laboratory Evaluation

Initial testing to identify treatable causes: 2, 3

• Fasting glucose or HbA1c (diabetes accounts for >50% of neuropathy) 2
• Vitamin B12 with methylmalonic acid ± homocysteine (especially in metformin users) 5, 2
• Serum protein electrophoresis with immunofixation (monoclonal gammopathy) 2, 3
• Thyroid-stimulating hormone 3
• Complete blood count and comprehensive metabolic panel 3

Second-tier testing only if initial workup negative and clinical suspicion warrants: 3

• Specific antibody assays for immune-mediated neuropathies
• Genetic testing for hereditary neuropathies if family history present
• Nerve biopsy only in highly selected cases with diagnostic uncertainty 4, 6

Drug-Induced and Toxic Neuropathies

Chemotherapy-induced peripheral neuropathy (CIPN) has distinct features: 1

• Temporal relationship: Symptoms develop during or shortly after neurotoxic chemotherapy (platinum agents, taxanes, vinca alkaloids, bortezomib) 1
• Coasting phenomenon: Oxaliplatin neuropathy paradoxically worsens for 2-3 months after stopping therapy before improving 1
• Upper extremity predominance: Oxaliplatin affects hands more than feet during treatment (opposite of typical neuropathy) 1
• Diagnosis is clinical: EMG/nerve conduction studies are not necessary when temporal relationship is clear 1

Common Pitfalls to Avoid

• Do not attribute all neuropathy to diabetes: Even in diabetic patients, exclude B12 deficiency (especially with metformin use), hypothyroidism, and other treatable causes 5, 3
• Do not order extensive testing for typical presentations: A 65-year-old with diabetes and symmetric distal sensory loss does not require EMG or nerve biopsy 1, 2
• Do not miss small fiber neuropathy: Patients with burning pain and normal reflexes/vibration sense need skin biopsy, not repeated nerve conduction studies 1
• Do not overlook autonomic features: Orthostatic hypotension, erectile dysfunction, and gastroparesis indicate small fiber/autonomic involvement and may guide etiology 1