What is the appropriate diagnostic workup and treatment for an adult presenting with burning feet syndrome?

Burning Feet Syndrome: Diagnostic Workup and Treatment

Begin with a focused clinical examination to distinguish small-fiber neuropathy (the most common cause of burning feet) from large-fiber or mixed neuropathy, then proceed with a targeted three-test laboratory panel before considering electrodiagnostic studies or skin biopsy.

Initial Clinical Assessment

Characterize the pain pattern and associated symptoms to guide your diagnostic approach:

• Burning pain quality: Pure burning sensation in the feet suggests small-fiber neuropathy, which affects unmyelinated C-fibers involved in pain and temperature perception 1, 2
• Distribution pattern: Symmetric "stocking" distribution beginning in the toes indicates length-dependent polyneuropathy, while asymmetric or patchy involvement suggests vasculitic neuropathy or mononeuritis multiplex 1, 2
• Associated sensory symptoms: Tingling, lancinating pain, and allodynia are "plus" features of small-fiber involvement 1
• Motor symptoms: Weakness, atrophy, or gait instability suggests large-fiber or mixed neuropathy requiring different evaluation 1, 3
• Autonomic features: Orthostatic hypotension (≥20 mmHg systolic or ≥10 mmHg diastolic drop), constipation, bladder dysfunction, or erectile dysfunction indicate autonomic fiber involvement 1, 2

Focused Physical Examination

Perform specific bedside tests to determine fiber-type involvement:

Small-Fiber Function Assessment

• Pinprick testing: Decreased pain perception in areas of burning pain is characteristic of small-fiber neuropathy 1
• Temperature sensation: Use cold tuning fork or temperature discrimination testing 1, 3
• Note: Conventional reflexes and vibration sense remain normal in pure small-fiber neuropathy 1, 2

Large-Fiber Function Assessment

• Vibration testing: Use 128-Hz tuning fork at the great toe—most sensitive bedside test for large-fiber dysfunction 3, 2
• Proprioception: Test joint position sense at the great toe 3
• Ankle reflexes: Reduced or absent reflexes suggest large-fiber involvement 1, 3
• 10-g monofilament: Test multiple plantar sites to detect loss of protective sensation 1, 3

Red Flags Requiring Urgent Evaluation

• Asymmetric distribution: Suggests vasculitis, mononeuritis multiplex, or radiculopathy 1, 2
• Rapid progression: Over weeks to months warrants urgent workup 2
• Motor weakness or atrophy: Indicates need for electrodiagnostic studies 3, 2
• Gait instability: Wide-based, unsteady gait suggests proprioceptive loss from large-fiber involvement 1, 2

High-Yield Laboratory Screening Panel (Order for All Patients)

These three tests provide the highest diagnostic yield and should be obtained first:

1. Fasting glucose/HbA1c 3, 2

   • If normal but clinical suspicion remains high (especially with prominent pain), order 2-hour oral glucose tolerance test 4
   • Impaired glucose tolerance (pre-diabetes) is highly prevalent in patients with burning feet 3

2. Serum vitamin B12 with metabolites (methylmalonic acid ± homocysteine) 3, 2

   • Metabolite testing increases sensitivity for true B12 deficiency that may be missed by standard B12 levels alone 3
   • Critical in patients on metformin (≥2g daily increases risk) 4

3. Serum protein immunofixation electrophoresis 3, 2

   • Preferred over standard SPEP for detecting monoclonal gammopathies 3
   • Identifies paraproteinemic neuropathies that require specific treatment 2

Additional Targeted Laboratory Tests (Based on Clinical Context)

Order selectively based on history and examination findings:

• TSH: Screen for hypothyroidism as a reversible cause 2, 4
• Comprehensive metabolic panel: Assess for chronic kidney disease and uremic neuropathy 2, 4
• HIV serology: Distal symmetric sensory neuropathy occurs in approximately 57% of HIV-infected individuals 2
• Hepatitis B/C serology: Up to 50% of HCV-infected patients develop peripheral neuropathy 4
• ESR/CRP: If vasculitis is suspected based on asymmetric distribution 4

When to Order Electrodiagnostic Studies

Nerve conduction studies are NOT required for typical burning feet syndrome with symmetric distribution and normal strength. 3, 2

Order electrodiagnostic studies only when:

• Symptoms are asymmetric or multifocal 3, 2
• Disease progresses rapidly over weeks to months 2
• Predominant motor weakness or distal muscle atrophy is present 3, 2
• Diagnostic uncertainty persists after clinical and laboratory evaluation 2

Common pitfall: Ordering EMG/NCS for typical diabetic neuropathy with classic stocking-glove distribution adds cost without changing management 3

When to Order Skin Biopsy

Skin biopsy with intraepidermal nerve fiber (IENF) density measurement is the gold standard for diagnosing small-fiber neuropathy when conventional nerve conduction studies are normal. 3, 2, 5

Indications for skin biopsy:

• Burning pain with normal nerve conduction studies (small-fiber neuropathy cannot be detected by conventional NCS) 1, 3, 2
• Clinical suspicion for small-fiber neuropathy with negative initial workup 5, 6
• Skin biopsy is more sensitive than quantitative sudomotor axon testing (QSART) or quantitative sensory testing (QST) 5

Technical note: Punch biopsy from distal leg (10 cm above lateral malleolus) is standard 5, 7

Specific Diagnostic Considerations

Erythromelalgia

If burning pain is accompanied by visible erythema, warmth, and swelling triggered by heat or exercise:

• This represents erythromelalgia, not typical small-fiber neuropathy 1
• Episodes are characteristically relieved by cooling 1
• Approximately 5% have familial (SCN9A gene mutation) form 1
• Requires different management approach focused on trigger avoidance and specific pharmacotherapy 1

Chemotherapy-Induced Peripheral Neuropathy (CIPN)

If patient has recent chemotherapy exposure (platinum compounds, taxanes, vinca alkaloids, bortezomib, thalidomide):

• Small-fiber neuropathy with burning feet is characteristic of taxanes, vinca alkaloids, thalidomide, and bortezomib 1
• Symptoms typically occur within first 2 months of treatment 1
• "Coasting phenomenon" (worsening after treatment cessation) can occur with platinum drugs and paclitaxel 1
• Conventional nerve conduction studies may be normal in small-fiber predominant CIPN 1

Hand-Foot Syndrome (Palmar-Plantar Erythrodysesthesia)

If patient is on specific chemotherapy agents (5-FU, capecitabine, doxorubicin) or BRAF/MEK inhibitors:

• This is a distinct dermatologic toxicity, not peripheral neuropathy 1
• Presents with dysesthesia, burning pain, swelling, and erythema progressing to hyperkeratosis 1
• Requires dose modification and topical management (high-potency steroids, lidocaine) 1

Treatment Algorithm

Step 1: Address Underlying Cause (Disease-Modifying Therapy)

Diabetes mellitus:

• Tight glycemic control prevents or delays neuropathy in type 1 diabetes (Level A evidence) 1, 2, 4
• In type 2 diabetes, improved control modestly slows progression but does not reverse established neuropathy (Level B evidence) 1, 2

Vitamin B12 deficiency:

• Supplement with 2500 mcg daily, especially in metformin-induced neuropathy 4

Hypothyroidism:

• Thyroid hormone replacement 2

Uremic neuropathy:

• Optimize renal replacement therapy 2

Step 2: First-Line Pharmacologic Treatment for Neuropathic Pain

Choose one of these three agents (all have Level A evidence): 1, 3, 2

1. Pregabalin: Start 75 mg twice daily, titrate to 150-300 mg twice daily based on response 1
2. Duloxetine: Start 30 mg daily for one week, then increase to 60 mg daily 1, 4
3. Gabapentin: Start 300 mg at bedtime, titrate to 300-1200 mg three times daily 1

Selection considerations:

• Duloxetine preferred if comorbid depression or anxiety 4
• Pregabalin/gabapentin preferred if renal function is normal and sedation is tolerable 1
• Start low and titrate based on efficacy and tolerability 2

Step 3: Second-Line Agents (If First-Line Fails or Not Tolerated)

• Tricyclic antidepressants (amitriptyline, nortriptyline): Start 10-25 mg at bedtime 1, 2
• Venlafaxine: Alternative SNRI if duloxetine not tolerated 4
• Tramadol: Consider for breakthrough pain 2

Common pitfall: Avoid polypharmacy—optimize one agent before adding another 2

Step 4: Non-Pharmacologic Interventions

• Physical activity: Shown to improve neuropathy symptoms 4
• Foot care education: Daily foot inspections to prevent ulceration in patients with loss of protective sensation 1, 3
• Avoid exacerbating factors: Alcohol, tight footwear, prolonged standing 8

When to Refer to Neurology

Refer promptly when:

• Atypical features present (asymmetric distribution, rapid progression, predominant motor weakness) 3, 2
• Diagnostic uncertainty persists after initial workup 3, 2
• Suspected vasculitis requiring nerve biopsy 2
• Suspected hereditary neuropathy requiring genetic testing 3
• Refractory pain despite optimized first- and second-line therapy 2

Follow-Up and Monitoring

• Serial neurologic examinations every 6 months to assess disease progression 2
• Annual 10-g monofilament testing if loss of protective sensation is documented 1, 3
• Routine repeat EMG/NCS is NOT recommended for stable neuropathy—clinical examination is sufficient 3, 2
• Monitor for medication side effects and adjust treatment accordingly 2