What is the approach to diagnosing and treating peripheral neuropathy?

Diagnosing Peripheral Neuropathy

The diagnosis of peripheral neuropathy is primarily clinical, based on a detailed history and focused neurological examination, with nerve conduction studies reserved for cases with asymmetric patterns, uncertain diagnosis, or when distinguishing axonal from demyelinating pathology is critical for management. 1

Clinical Assessment

History and Symptom Characterization

Obtain a detailed pain assessment using a simple pain scale and characterize the distribution and quality of symptoms. 2

Key symptom patterns to identify:

• Large fiber involvement: Numbness, loss of vibration sense, impaired proprioception, and "glove and stocking" distribution of sensory loss 1
• Small fiber neuropathy: Burning feet/hands, lancinating pain, dysesthesia, allodynia, and hyperalgesia—note that standard neurophysiology may be completely normal in these cases 1
• Motor involvement (less common): Distal weakness, muscle atrophy in feet, reduced/absent deep tendon reflexes, tremor, or cramps 1
• Autonomic symptoms: Constipation, postural hypotension, bladder dysfunction, delayed gastric emptying, or reduced heart rate variability 1

Physical Examination

Perform focused bedside testing to assess both small and large fiber function: 1

• Small fiber function: Pinprick and temperature sensation testing 1
• Large fiber function: Vibration perception using a 128-Hz tuning fork 1
• Protective sensation: 10-g monofilament testing (critical for identifying feet at risk for ulceration) 1
• Deep tendon reflexes: Document presence, reduction, or absence 1

Laboratory Evaluation

Initial Screening Tests

Order the following baseline laboratory tests to identify treatable causes: 2, 3, 4

• Fasting blood glucose and hemoglobin A1c (diabetes is the most common cause) 2, 3
• Complete blood count 3, 4
• Comprehensive metabolic profile 3, 4
• Vitamin B12 level 2, 3, 4
• Thyroid-stimulating hormone 2, 3, 4
• Erythrocyte sedimentation rate 3
• Serum protein electrophoresis with immunofixation 4

Additional Testing When Clinically Indicated

• Hepatitis B, C, and HIV testing if risk factors present 2
• Anti-ganglioside antibodies if Guillain-Barré syndrome suspected 2
• Anti-MAG antibodies if demyelinating neuropathy suspected 2

Note: No biomarker is currently recommended for routine diagnosis or monitoring of peripheral neuropathy, though serum neurofilament light (NfL) shows promise for future use. 1

Neurophysiological Testing

When to Order Nerve Conduction Studies/EMG

Consider neurophysiology in the following specific scenarios: 1

• Asymmetric pattern of symptoms 1
• Normal clinical examination despite patient complaints 1
• Need to distinguish axonal from demyelinating neuropathy (critical for narrowing differential diagnosis) 1, 5
• Suspected pre-existing or subclinical neuropathy 1

Key Findings and Limitations

• Axonal degeneration: Progressive reduction of sensory nerve action potential (NAP) amplitude, followed by impaired nerve conduction velocity 1
• Motor involvement: Reduced compound muscle action potential (CMAP) correlating with axonal damage on EMG 1

Critical caveat: Conventional nerve conduction studies are often normal in small fiber neuropathy and do not reliably mirror symptom severity or functional recovery. 1

Specialized Testing for Small Fiber Neuropathy

If small fiber neuropathy is suspected (burning pain, normal standard neurophysiology), skin biopsy examined by an experienced pathologist is the gold standard, demonstrating degeneration of small C (heat) and Aδ (cold) fibers. 1

Autonomic Testing

If autonomic neuropathy is suspected, conduct neurophysiology including sympathetic skin response and heart rate variability. 1

Screening Recommendations for Diabetic Neuropathy

Screen all patients with type 2 diabetes at diagnosis and patients with type 1 diabetes starting 5 years after diagnosis, then annually thereafter. 1, 2

Annual screening should include:

• Careful history for numbness, tingling, pain, or burning in extremities 2
• Assessment of temperature or pinprick sensation (small-fiber function) 1
• Vibration sensation using 128-Hz tuning fork (large-fiber function) 1
• 10-g monofilament testing to identify feet at risk for ulceration and amputation 1

Common Pitfalls to Avoid

• Do not rely solely on nerve conduction studies—they may be normal in small fiber neuropathy despite significant symptoms 1
• Do not overlook baseline assessment—early detection before neuropathy becomes irreversible is critical 1
• Do not skip neurologist consultation when uncertainty exists in pretreatment assessment 1
• Healthcare professionals tend to underestimate symptoms—patient-reported outcomes differ significantly from clinician assessments 1

Treatment Approach

Disease-Modifying Management

Optimize glucose control to prevent or delay neuropathy development in type 1 diabetes and slow progression in type 2 diabetes. 1, 2

First-Line Pharmacological Treatment for Neuropathic Pain

Pregabalin, duloxetine, or gabapentin are recommended as initial pharmacologic treatments for neuropathic pain. 1, 2

• Duloxetine: 60 mg once daily, may increase to 120 mg daily if needed 2, 6, 7
• Pregabalin: 300-600 mg/day 6, 8
• Gabapentin: 300-2,400 mg/day 6

Non-Pharmacological Interventions

Consider regular physical activity, acupuncture, and cognitive behavioral therapy as adjunctive non-pharmacological interventions. 2