What lab tests are recommended for a patient presenting with neuropathy?

Laboratory Workup for Neuropathy

For patients presenting with neuropathy, three screening tests provide the highest diagnostic yield and should be ordered first: blood glucose (fasting glucose and/or HbA1c), serum B12 with metabolites (methylmalonic acid with or without homocysteine), and serum protein immunofixation electrophoresis. 1, 2, 3, 4

Initial High-Yield Screening Tests

The American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, and American Academy of Physical Medicine and Rehabilitation recommend these three tests as the foundation of neuropathy evaluation, as they identify the most common treatable causes 1:

Blood Glucose Testing

• Order both fasting blood glucose AND hemoglobin A1c to screen for diabetes mellitus, which accounts for over 50% of peripheral neuropathy cases in Western populations 2, 3, 4
• If routine glucose testing is not clearly abnormal, consider glucose tolerance testing (GTT) in patients with distal symmetric sensory polyneuropathy, especially if accompanied by pain 1, 3
• Diabetes affects approximately 206 million people worldwide and is the single most common identifiable cause of neuropathy 4

Vitamin B12 with Metabolites

• Order serum B12 PLUS methylmalonic acid (with or without homocysteine) rather than B12 alone 1, 2, 3
• This combination is critical because 5-10% of patients with low-normal B12 levels (200-500 pg/dL) still have true B12 deficiency detectable only by elevated metabolites 1, 5
• Methylmalonic acid is more specific than homocysteine for B12 deficiency (98.4% vs 95.9% sensitivity), as homocysteine can be elevated in folate deficiency and other conditions 1
• B12 deficiency accounts for 2.2-8% of polyneuropathy cases, and 44% of patients with B12-deficient neuropathy have deficiency based on abnormal metabolites alone 1, 5
• This is especially important in patients taking metformin, which commonly causes B12 deficiency 2, 3

Serum Protein Immunofixation Electrophoresis

• Order immunofixation electrophoresis (IFE), NOT standard serum protein electrophoresis (SPEP) 1, 2, 5
• IFE is significantly more sensitive, detecting 30% of small IgM monoclonal gammopathies that SPEP misses 1
• Monoclonal gammopathies occur in 10% of patients with otherwise unexplained polyneuropathy, substantially higher than in the general population 1

Additional Baseline Laboratory Tests

While the three tests above have the highest yield, a comprehensive metabolic panel and complete blood count are reasonable to obtain initially 1, 5:

• Complete blood count (CBC) to screen for anemia, infection, or hematologic disorders 5
• Comprehensive metabolic panel including renal function, liver function, and electrolytes 1, 5
• Thyroid-stimulating hormone (TSH) to evaluate for hypothyroidism 2
• Erythrocyte sedimentation rate (ESR) as part of initial screening 1

Electrodiagnostic Studies

• Nerve conduction studies (NCS) and electromyography (EMG) should be performed to differentiate axonal from demyelinating neuropathies and to confirm the diagnosis 2, 3, 6, 7, 8
• This is the primary diagnostic tool for large-fiber polyneuropathy and helps narrow the differential diagnosis dramatically 6, 7
• Uniform demyelinating features suggest hereditary causes, while variability between nerves suggests acquired demyelination 8

Additional Testing Based on Clinical Context

When Infectious Causes Are Suspected

• HIV testing when clinically indicated 2, 3, 5
• Hepatitis B and C screening when clinically indicated 2, 3
• Lyme disease and syphilis testing based on risk factors and geographic exposure 5

When Immune-Mediated Neuropathy Is Suspected

• Vasculitic/autoimmune panel including ESR, CRP, ANA, RF, and ANCA in appropriate clinical contexts 2, 5
• Lumbar puncture with CSF analysis for suspected inflammatory neuropathies (may show elevated protein with normal cell count in Guillain-Barré syndrome or CIDP) 2, 5

For Sensory-Predominant Neuropathies

• Anti-myelin-associated glycoprotein (anti-MAG) antibodies for patients with sensory peripheral neuropathies 2, 3
• Cryoglobulins and cold agglutinin titers when symptoms suggest these disorders 2, 3

For Motor-Predominant Neuropathies

• Anti-ganglioside antibodies for suspected Guillain-Barré syndrome or motor neuropathies 2
• Anti-ganglioside M1 antibodies for patients with motor neuropathy 2, 3

When Monoclonal Gammopathy Is Detected

• 24-hour urine for total protein, creatinine clearance, urine protein electrophoresis, and urine immunofixation electrophoresis 2

For Suspected Small-Fiber Neuropathy

• Skin biopsy to assess intraepidermal nerve fiber density if small-fiber neuropathy is suspected and standard NCS/EMG is normal 6

Genetic Testing Considerations

Genetic testing is established as useful (Level A evidence) for accurate diagnosis and classification of hereditary neuropathies 1, 3:

• Consider genetic testing in patients with cryptogenic polyneuropathy who exhibit a hereditary neuropathy phenotype (Level C recommendation) 1
• Initial genetic testing should focus on the most common abnormalities: CMT1A duplication/HNPP deletion, Cx32 (GJB1), and MFN2 mutation screening 1
• Testing should be guided by clinical phenotype, inheritance pattern (if available), and electrodiagnostic features (demyelinating versus axonal) 1
• There is insufficient evidence to support routine genetic testing in cryptogenic polyneuropathy patients without a classical hereditary phenotype 1

Critical Pitfalls to Avoid

• Never fail to screen for diabetes in ALL patients with peripheral neuropathy, as it is the most common cause and may be asymptomatic in up to 50% of cases 2, 3, 5, 4
• Do not overlook non-diabetic causes of neuropathy in patients with known diabetes—up to 27% of neuropathy cases have no identifiable etiology even after comprehensive testing 4
• Always test B12 with metabolites, not B12 alone, especially in patients taking metformin 2, 3, 5
• Order immunofixation electrophoresis, not standard protein electrophoresis, as SPEP misses 30% of small monoclonal proteins 1, 5
• Do not forget to evaluate for autonomic neuropathy symptoms (orthostatic hypotension, gastroparesis, bladder dysfunction), which significantly impact morbidity and mortality 5
• Recognize that laboratory abnormalities alone do not establish causation—only 9-37% of laboratory abnormalities in cryptogenic polyneuropathy are etiologically diagnostic 1

Special Clinical Scenarios

For Rapidly Progressive Neuropathy

• Paraneoplastic antibody panel when neuropathy is rapidly progressive or associated with constitutional symptoms suggesting malignancy 5
• Immediate hospitalization and specialized testing for suspected Guillain-Barré syndrome 2

For Occupational or Toxic Exposures

• Heavy metal screening (lead, arsenic) with occupational exposure or unexplained axonal neuropathy 5
• Medication review for neurotoxic drugs (chemotherapies like cisplatin, paclitaxel, vincristine; amiodarone; HIV nucleotide reverse transcriptase inhibitors) 4

For Pediatric Type 2 Diabetes

• Screen for neuropathy at diagnosis and annually with foot examination including inspection, foot pulses, pinprick and 10-g monofilament sensation, 128-Hz tuning fork vibration testing, and ankle reflexes 1