What is the stepwise workup for peripheral neuropathy?

Peripheral Neuropathy Workup

Begin with a structured clinical examination including 10-g monofilament testing plus at least one additional neurological test (pinprick, temperature, vibration with 128-Hz tuning fork, or ankle reflexes), followed by a focused laboratory panel to exclude treatable causes. 1, 2

Step 1: Clinical History and Symptom Assessment

Document the following specific elements:

• Symptom characteristics: numbness, tingling, burning sensations, or sharp shooting pain in a distal symmetric "stocking and glove" distribution 1, 3
• Temporal pattern: acute (days to weeks) versus chronic (months to years) onset, and whether symptoms worsen at night 1, 4
• Distribution: symmetric versus asymmetric presentation (asymmetric symptoms suggest alternative etiologies, not typical peripheral neuropathy) 1, 5
• Pain severity: quantify using 0-10 numeric rating scale 1
• Autonomic symptoms: orthostatic dizziness, syncope, constipation, diarrhea, urinary retention, erectile dysfunction, abnormal sweating, or hypoglycemia unawareness 1, 2
• Risk factors: diabetes duration and control, alcohol use, chemotherapy exposure, HIV risk, family history of neuropathy, occupational toxin exposures 1, 6, 4

Step 2: Physical Examination

Perform a comprehensive neurological examination assessing both small-fiber and large-fiber function:

• 10-g monofilament testing: test multiple sites on each foot—this is the single most sensitive test for identifying ulceration risk and must not be skipped 1, 2
• Pinprick sensation: assesses small-fiber function 1, 2
• Temperature perception: cold/warm discrimination for small-fiber assessment 1, 2
• Vibration sense: using 128-Hz tuning fork at bony prominences for large-fiber function 1, 2
• Ankle reflexes: assess deep tendon reflexes bilaterally 1, 2
• Motor examination: document weakness, muscle wasting, gait abnormalities, and balance deficits 3, 4
• Skin integrity: inspect feet for ulcers, calluses, deformities, and vascular changes 2

Loss of protective sensation (LOPS) is confirmed when 10-g monofilament sensation is absent PLUS one other abnormal neurological test. 1, 2

Step 3: Initial Laboratory Testing

Order the following panel for all patients with suspected peripheral neuropathy:

• Fasting blood glucose and hemoglobin A1c 1, 6
• Complete blood count 1, 6
• Comprehensive metabolic profile (includes renal and hepatic function) 6, 5
• Vitamin B12 level 1, 6
• Thyroid-stimulating hormone (TSH) and free T4 1, 6
• Erythrocyte sedimentation rate 6

Step 4: Additional Testing Based on Clinical Context

Consider these specialized tests when clinically indicated:

• Hepatitis B, C, and HIV testing: if risk factors present 1
• Serum protein electrophoresis with immunofixation: if suspecting paraproteinemia or multiple myeloma 6, 5
• Anti-ganglioside antibodies and anti-MAG antibodies: for suspected immune-mediated neuropathy 1, 5
• Genetic testing: if family history suggests hereditary neuropathy 4, 5
• Lumbar puncture and CSF analysis: for suspected Guillain-Barré syndrome or chronic inflammatory demyelinating polyneuropathy (look for albuminocytologic dissociation) 6, 5

Step 5: Electrodiagnostic Studies (When Indicated)

Nerve conduction studies (NCS) and electromyography (EMG) are rarely needed for typical diabetic neuropathy but should be ordered when clinical features are atypical, the diagnosis is unclear, or asymmetric symptoms are present. 1

These studies help differentiate:

• Axonal versus demyelinating neuropathy: uniform demyelinating features suggest hereditary causes, while variable demyelination suggests acquired causes 6, 7
• Entrapment syndromes from generalized neuropathy 1
• Severity and distribution of nerve involvement 1, 4

Step 6: Specialized Testing (Select Cases Only)

• Skin biopsy: to assess intraepidermal nerve fiber density if small-fiber neuropathy is suspected and standard testing is normal 4, 5
• Nerve biopsy: reserved for cases where diagnosis remains unclear after comprehensive workup, particularly when vasculitis or infiltrative processes are suspected 6, 4
• MRI of spine or plexus: if focal or radicular symptoms suggest structural lesions 4, 5

Critical Pitfalls to Avoid

• Do not rely on symptoms alone: up to 50% of diabetic peripheral neuropathy is asymptomatic, making annual screening with objective testing mandatory 1, 2
• Peripheral neuropathy is a diagnosis of exclusion: always evaluate for other treatable causes before attributing symptoms to diabetes or idiopathic neuropathy 1, 6
• Asymmetric presentation demands alternative evaluation: this pattern should prompt investigation for vasculitis, mononeuropathy multiplex, radiculopathy, or focal nerve lesions rather than typical polyneuropathy 1, 5
• Never skip the 10-g monofilament test: it identifies feet at highest risk for ulceration and amputation, which are preventable complications 1, 2
• Recognize urgent presentations: rapidly progressive weakness, respiratory muscle involvement, or severe autonomic dysfunction require immediate hospitalization and consideration of Guillain-Barré syndrome or other acute inflammatory neuropathies 8, 6