What laboratory tests should be ordered for a patient presenting with peripheral neuropathy?

Laboratory Testing for Peripheral Neuropathy

First-Line Essential Blood Tests

Order a focused initial panel consisting of fasting blood glucose (or HbA1c), serum vitamin B12 with metabolites (methylmalonic acid ± homocysteine), comprehensive metabolic panel, complete blood count, thyroid-stimulating hormone, and serum protein electrophoresis with immunofixation. 1

Highest-Yield Tests

• Fasting blood glucose or HbA1c is the single most important test, as diabetes accounts for over 50% of peripheral neuropathy cases in Western populations and was elevated in approximately 11% of patients with distal symmetric polyneuropathy. 1, 2

• Serum B12 with metabolites (methylmalonic acid) is critical because standard B12 levels alone miss 44% of deficiency cases, and methylmalonic acid is more specific than homocysteine for detecting true B12 deficiency. 1

  • B12 deficiency was found in 2.2-8% of neuropathy patients, with metabolites detecting an additional 5-10% of cases when serum B12 was in the low-normal range. 1

• Serum protein electrophoresis with immunofixation detects monoclonal gammopathies, which were abnormal in approximately 9% of patients with distal symmetric polyneuropathy. 1, 2

Standard Screening Panel Components

• Complete blood count to assess for anemia and hematologic abnormalities. 1, 3

• Comprehensive metabolic panel to evaluate renal function, electrolytes, and liver function. 1, 3

  • Serum creatinine and eGFR are particularly important in diabetic patients, as renal insufficiency increases neuropathy risk and foot complication rates. 1, 4

• Thyroid-stimulating hormone to screen for hypothyroidism, one of the most common treatable causes. 1, 3

• Erythrocyte sedimentation rate may be included in the initial workup. 3

Second-Tier Testing Based on Clinical Context

When to Order Additional Tests

Order specialized testing only when atypical features are present or the initial panel is unrevealing:

• Hepatitis B, C, and HIV serology if risk factors are present or clinical suspicion exists. 1

• Heavy metal screening (lead, arsenic, mercury) if occupational or environmental exposure is suspected. 1

• Genetic testing for hereditary neuropathies (e.g., Charcot-Marie-Tooth disease) if family history is positive or clinical phenotype suggests hereditary cause. 1, 2

• Specialized antibody testing (anti-MAG, anti-GM1, anti-ganglioside) when immune-mediated neuropathy is suspected. 5, 1

• Cerebrospinal fluid analysis has low yield except in suspected demyelinating polyneuropathies (Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy), where elevated protein is expected. 1, 3

Tests with Low Diagnostic Yield to Avoid

• Glucose tolerance test is rarely obtained (only 1.0% of patients) despite being low-cost and high-yield, though HbA1c or fasting glucose are adequate alternatives. 6

• MRI of brain or spine was ordered in 23.2% of patients but represents high-cost, low-yield testing in typical peripheral neuropathy presentations. 6

Expected Diagnostic Yield

When combining clinical history, neurological examination, electrodiagnostic studies, and the recommended screening laboratory panel, an etiological diagnosis is established in 74-82% of peripheral neuropathy cases. 1 Up to 27% of adults with neuropathy have no identifiable etiology after diagnostic testing. 2

Critical Clinical Distinctions

Laboratory tests do not diagnose diabetic peripheral neuropathy—clinical examination with the 10-g monofilament and 128-Hz tuning fork establishes the diagnosis. 1, 4 Laboratory testing serves only to exclude alternative diagnoses in atypical cases. 1

Nerve conduction studies and electromyography are not routine laboratory tests but are indicated when clinical examination cannot confirm the diagnosis or when differentiating axonal from demyelinating neuropathy is necessary. 1, 3, 7