What are the recommended diagnostic tests and treatment options for an adult patient with suspected peripheral neuropathy, possibly related to diabetes or other metabolic disorders?

Diagnostic Testing for Peripheral Neuropathy

For an adult with suspected peripheral neuropathy, begin with a focused clinical examination using 10-g monofilament testing plus one additional sensory test (pinprick, temperature, or 128-Hz tuning fork vibration), followed by targeted laboratory testing including fasting glucose/HbA1c, vitamin B12 with metabolites, and serum protein electrophoresis with immunofixation. 1, 2, 3

Initial Clinical Assessment

Timing of screening matters: Screen at diagnosis for type 2 diabetes and after 5 years for type 1 diabetes, then annually thereafter, as up to 50% of diabetic peripheral neuropathy cases are asymptomatic. 1, 4

Bedside Neurological Examination

The clinical diagnosis of loss of protective sensation (LOPS) requires:

• 10-g monofilament testing at multiple plantar sites on both feet—inability to perceive the monofilament at any site confirms LOPS 1, 4
• Plus at least one additional test: 1
  • 128-Hz tuning fork for vibration (large fiber function) 1, 4
  • Pinprick sensation (small fiber function) 1
  • Temperature sensation (small fiber function) 1
  • Ankle reflexes 1

Interpretation: One or more abnormal tests suggests LOPS, while at least two normal tests (with no abnormal test) rules out LOPS. 1

Symptom Assessment

Document the temporal pattern and fiber type involvement:

• Small fiber symptoms: burning pain, tingling, dysesthesias, temperature sensitivity 5, 3
• Large fiber symptoms: numbness, loss of balance, loss of protective sensation 5
• Autonomic symptoms: orthostatic dizziness, syncope, erectile dysfunction, gastroparesis, bladder dysfunction 1, 5
• Temporal pattern: Chronic progressive symptoms over months to years suggest diabetic, hereditary, or chronic inflammatory causes 5

Comprehensive Foot Examination

Perform annually at minimum, or at every visit if prior ulceration or sensory loss exists: 1

• Skin inspection: integrity, calluses, pre-ulcerative signs, existing ulceration 4
• Structural assessment: hammertoes, prominent metatarsal heads, bunions, Charcot deformities 1
• Vascular assessment: palpate dorsalis pedis and posterior tibial pulses bilaterally, assess capillary refill 4
• Risk factor history: prior ulceration, amputation, Charcot foot, smoking, retinopathy, nephropathy 1

Essential Laboratory Workup

Order these tests on all patients with suspected peripheral neuropathy: 2, 3, 6, 7

First-Tier Testing (Order Immediately)

• Fasting blood glucose or HbA1c—diabetes is the single most common cause, affecting approximately 206 million people worldwide 2, 3, 7
• Vitamin B12 level with metabolites (methylmalonic acid ± homocysteine)—one of the most common treatable causes 2, 3, 6
• Serum protein electrophoresis with immunofixation—screens for monoclonal gammopathies and multiple myeloma 2, 3, 7
• Complete blood count 6, 7
• Comprehensive metabolic profile (includes renal function for uremic neuropathy) 2, 6, 7
• Thyroid-stimulating hormone—hypothyroidism is a treatable metabolic cause 6, 7
• Erythrocyte sedimentation rate 6

Critical Pitfall to Avoid

Do not assume diabetic neuropathy in a patient with diabetes without excluding other causes—nondiabetic neuropathies may be present and treatable, and diabetic peripheral neuropathy remains a diagnosis of exclusion. 2, 5

Electrodiagnostic Studies

Order nerve conduction studies and electromyography when: 2, 5, 6

• Clinical features are atypical for length-dependent symmetric polyneuropathy
• Diagnosis remains unclear after initial evaluation
• Need to differentiate axonal from demyelinating patterns (critical for identifying chronic inflammatory demyelinating polyneuropathy, a treatable cause) 2, 5, 6

Limitation: Conventional electrophysiology may miss early small fiber-predominant disease—if symptoms suggest small fiber involvement but nerve conduction studies are normal, consider skin biopsy for intraepidermal nerve fiber density. 2, 5

Additional Testing Based on Clinical Context

When Autoimmune or Inflammatory Causes Suspected

• Lumbar puncture with CSF analysis for chronic inflammatory demyelinating polyneuropathy or Guillain-Barré syndrome 2, 6
• Serum antiganglioside antibody tests for Guillain-Barré syndrome subtypes 2

When Hereditary Causes Suspected

• Genetic testing for Charcot-Marie-Tooth disease and other inherited neuropathies 2

When Peripheral Arterial Disease Suspected

• Ankle-brachial index in patients ≥50 years or those <50 years with PAD risk factors (smoking, hypertension, dyslipidemia, diabetes duration >10 years) 1
• Refer for further vascular assessment if claudication symptoms or decreased/absent pedal pulses 1

When Small Fiber Neuropathy Suspected with Normal Nerve Conduction Studies

• Skin biopsy for intraepidermal nerve fiber density assessment 2

When Structural Lesions or Nerve Root Pathology Suspected

• MRI of spine with and without contrast to rule out compressive lesions and evaluate for nerve root enhancement/thickening 2

Medication History Review

Carefully assess for neurotoxic medications—among the most common iatrogenic causes: 2

• Chemotherapy agents (cisplatin, paclitaxel, vincristine) 3
• Antimicrobials (HIV nucleotide reverse transcriptase inhibitors like stavudine, zalcitabine) 3
• Amiodarone 3
• Anti-TNF agents 5

Treatment Considerations for Neuropathic Pain

Once diagnosis is established, first-line pharmacologic treatments include: 1, 3

• Pregabalin: Start 50 mg three times daily (150 mg/day), may increase to 100 mg three times daily (300 mg/day) within 1 week based on efficacy and tolerability 8
• Duloxetine 1
• Gabapentin: 38% of patients with painful diabetic peripheral neuropathy achieved ≥50% pain reduction with 1200 mg daily 3

Common adverse effects of pregabalin: dizziness (21% at 300 mg/day), somnolence (12% at 300 mg/day), peripheral edema (9% at 300 mg/day), weight gain (4% at 300 mg/day), blurred vision (4% at 300 mg/day). 8

Alternative options: Tricyclic antidepressants (amitriptyline, nortriptyline), venlafaxine, carbamazepine, topical capsaicin, tramadol, or tapentadol. 1

Realistic expectations: Pain often persists despite medical management, and combination drug therapies may provide added benefit. 3

Preventive Foot Care for High-Risk Patients

High-risk patients (history of ulceration/amputation, severe neuropathy, foot deformities, peripheral arterial disease, dialysis, poor glycemic control, visual impairment, smoking) require: 1

• Foot inspection at every visit 1
• Referral to foot care specialists for ongoing preventive care and lifelong surveillance 1
• Specialized therapeutic footwear for those with severe neuropathy, deformities, ulcers, calluses, or poor circulation 1
• Multidisciplinary approach for foot ulcers and Charcot foot 1