What initial laboratory tests are recommended for a patient presenting with axonal neuropathy?

Initial Laboratory Workup for Axonal Neuropathy

For patients with confirmed axonal neuropathy on electrodiagnostic studies, obtain screening labs including blood glucose, serum B12 with metabolites (methylmalonic acid with or without homocysteine), and serum protein immunofixation electrophoresis, as these provide the highest diagnostic yield. 1

Core Screening Panel

The following tests should be performed for all patients with axonal polyneuropathy:

First-Tier Essential Tests

• Blood glucose (fasting) and hemoglobin A1c to detect diabetes mellitus, the most common cause of axonal neuropathy 1, 2, 3
• Serum vitamin B12 with metabolites (methylmalonic acid with or without homocysteine) - critical because serum B12 in the low-normal range may still indicate deficiency 1, 2
• Serum protein immunofixation electrophoresis to screen for paraproteinemia and monoclonal gammopathies 1, 2
• Complete blood count to detect cytopenias or hematologic abnormalities 2, 4, 3
• Comprehensive metabolic panel including creatinine, electrolytes, and liver function to assess for renal disease and metabolic derangements 2, 4, 3
• Erythrocyte sedimentation rate as a nonspecific inflammatory marker 2, 4
• Thyroid-stimulating hormone to exclude hypothyroidism 2, 4, 3

Important Nuance on Glucose Testing

If routine fasting blood glucose is normal but clinical suspicion remains high for metabolic neuropathy, obtain oral glucose tolerance testing to identify impaired glucose tolerance, which is frequently missed with standard fasting glucose alone 1, 2

Additional Testing Based on Clinical Context

When Specific Etiologies Are Suspected

• Hepatitis B, C, and HIV serologies if risk factors present or clinical features suggest infectious etiology 5
• Serum and urine protein electrophoresis with immunofixation if not already obtained in initial screening 3
• Lipid profile as dyslipidemia can be associated with certain neuropathies 2

For Atypical or Severe Presentations

Consider additional workup when features are atypical, rapidly progressive, or severe:

• Heavy metal screening (lead, arsenic, mercury) if occupational or environmental exposure suspected 1
• Alcohol use assessment as alcohol is a common toxic cause 4, 3
• Medication review for neurotoxic agents including chemotherapy 5, 4

Critical Pitfalls to Avoid

• Do not rely on serum B12 alone - always order metabolites (methylmalonic acid) as B12 levels in the low-normal range can still represent functional deficiency 2, 6
• Do not skip glucose tolerance testing in patients with normal fasting glucose who have distal symmetric sensory neuropathy, as impaired glucose tolerance is frequently the culprit 1, 2
• Do not order extensive autoimmune panels without specific clinical indicators, as the yield is extremely low in typical axonal polyneuropathy 1
• Do not perform genetic testing unless the patient exhibits a hereditary neuropathy phenotype (early onset, family history, specific patterns on exam) 1, 2

Tests with Low Yield in Typical Axonal Neuropathy

The following have limited utility in routine axonal neuropathy evaluation:

• Cerebrospinal fluid analysis - reserve for suspected demyelinating polyneuropathies (Guillain-Barré, CIDP), not typical axonal patterns 2, 4
• Nerve biopsy - only indicated when vasculitis or specific inflammatory conditions are suspected based on clinical features 2
• Routine genetic testing - insufficient evidence for cryptogenic cases without hereditary phenotype 1

Diagnostic Yield Considerations

Laboratory testing alone has only a 37% diagnostic yield without proper clinical correlation, emphasizing the importance of targeted testing based on clinical presentation rather than shotgun approaches 2. The three highest-yield tests remain glucose assessment, B12 with metabolites, and serum protein immunofixation 1.