Laboratory and Diagnostic Testing for Foot Neuropathy
For a patient presenting with neuropathy in the feet, obtain blood glucose (or HbA1c), serum vitamin B12 with metabolites (methylmalonic acid ± homocysteine), and serum protein electrophoresis with immunofixation as initial screening labs. 1
Initial Laboratory Workup
The three essential screening tests identify the most common treatable causes of peripheral neuropathy:
Blood glucose or HbA1c: Diabetes accounts for >50% of peripheral neuropathy cases in Western populations and affects approximately 206 million people worldwide 1. The American Diabetes Association recommends measuring HbA1c to diagnose diabetes in patients with neuropathy 2.
Vitamin B12 with metabolites: Measure serum B12 along with methylmalonic acid (with or without homocysteine) to detect B12 deficiency, which is a reversible cause of neuropathy 1. This combination improves diagnostic accuracy over B12 alone.
Serum protein electrophoresis with immunofixation: Screens for monoclonal gammopathies, which are an important cause of peripheral neuropathy 1.
Additional Laboratory Tests Based on Clinical Context
Renal function: Measure serum creatinine and estimated glomerular filtration rate (eGFR), particularly in diabetic patients, as renal insufficiency is associated with increased risk of neuropathy and foot complications 2.
Thyroid function, complete blood count, comprehensive metabolic panel: Consider when initial screening is unrevealing 3.
Toxin/medication screen: Evaluate for alcohol use and neurotoxic medications (chemotherapies like cisplatin, paclitaxel, vincristine; amiodarone; HIV medications) 1.
Clinical Examination Components
The neurological examination should focus on identifying loss of protective sensation (LOPS):
- 10-g monofilament test (Semmes-Weinstein) is the most useful screening tool 4
- Plus at least one additional test: pinprick, temperature, vibration (128-Hz tuning fork), or ankle reflexes 4
- Absent monofilament sensation suggests LOPS; at least two normal tests rule out LOPS 4
Vascular Assessment
- Initial screening: Assess lower-extremity pulses, capillary refill time, rubor on dependency, pallor on elevation, and venous filling time 4
- Ankle-brachial index (ABI): Obtain in patients with symptoms of claudication, leg fatigue, or decreased/absent pedal pulses 4, 2
- Toe-brachial index (TBI): Measure in diabetic patients or those with renal insufficiency who have ABI >1.40 (falsely elevated due to arterial calcification) 2
When to Consider Advanced Testing
- Nerve conduction studies: Reserve for atypical presentations (asymmetric, rapid progression, predominant motor involvement, or upper extremity involvement) 4, 3
- Genetic testing: Consider in younger patients or those with family history suggesting hereditary neuropathy (Charcot-Marie-Tooth disease) 1, 3
- Specialized small-fiber testing: Epidermal nerve fiber density, quantitative sensory testing, or sudomotor testing may be useful when standard nerve conduction studies are normal but small-fiber neuropathy is suspected 5
Common Pitfalls
Up to 27% of patients with neuropathy have no identifiable cause after diagnostic testing 1. However, this should only be concluded after completing the initial three-test screening panel plus appropriate additional testing based on clinical features. The key is recognizing that diabetes is by far the most common cause, making glucose/HbA1c testing absolutely essential in every case 1.