Workup for Progressive Peripheral Neuropathy
A comprehensive diagnostic workup for progressive peripheral neuropathy should begin with screening for reversible causes including diabetes, vitamin deficiencies, thyroid dysfunction, and autoimmune conditions, followed by specialized testing based on clinical presentation. 1
Initial Diagnostic Evaluation
Basic Laboratory Testing
- Complete blood count
- Comprehensive metabolic profile
- Fasting blood glucose/HbA1c
- Vitamin B12, folate, vitamin B6
- Thyroid-stimulating hormone (TSH)
- Serum protein electrophoresis and immunofixation
- Erythrocyte sedimentation rate (ESR)/C-reactive protein (CRP)
Additional Testing Based on Clinical Suspicion
- HIV testing
- Hepatitis B and C screening
- Lyme disease serology
- ANA, ANCA, anti-smooth muscle antibodies
- SSA/SSB, RNP, anti-dsDNA antibodies
- Ganglioside antibodies
- Anti-MAG antibodies
- Anti-Hu (ANNA-1) antibodies
- Paraneoplastic panel
Neurologic Consultation and Advanced Testing
Imaging Studies
- MRI of spine with and without contrast (to rule out compressive lesions and evaluate for nerve root enhancement)
- MRI of brain if cranial nerve involvement is present
- MRI of plexus if plexopathy is suspected
Electrodiagnostic Studies
- Nerve conduction studies (NCS)
- Electromyography (EMG)
- These studies help differentiate between:
- Axonal neuropathy
- Demyelinating neuropathy
- Mixed neuropathy
Cerebrospinal Fluid Analysis (if indicated)
- Cell count and differential
- Protein and glucose levels
- Cytology for malignant cells
- Viral/bacterial cultures
- Consider when Guillain-Barré syndrome or chronic inflammatory demyelinating polyneuropathy is suspected
Nerve Biopsy (in select cases)
- Reserved for cases where diagnosis remains unclear after above testing
- Particularly useful for suspected vasculitis, amyloidosis, or certain hereditary neuropathies
Management Approach Based on Severity
Grade 1 (Mild) Neuropathy
- Low threshold to hold immune checkpoint inhibitors if that's the cause
- Monitor symptoms closely
- Consider gabapentin, pregabalin, or duloxetine for neuropathic pain 2
Grade 2 (Moderate) Neuropathy
- Hold causative medications if identified
- Consider prednisone 0.5-1 mg/kg/day if progressing from mild
- Pregabalin starting at 50mg three times daily for diabetic neuropathy, titrating up to 100mg three times daily as needed 2
- For postherpetic neuralgia, pregabalin 75-150mg twice daily or 50-100mg three times daily 2
Grade 3-4 (Severe) Neuropathy
- Permanently discontinue causative agents
- Consider hospital admission for rapidly progressive cases
- Neurology consultation is mandatory
- For suspected immune-mediated neuropathy:
- IV methylprednisolone 2-4 mg/kg/day
- Consider IVIG (0.4 g/kg/day for 5 days) or plasmapheresis
- Frequent neurological checks and pulmonary function monitoring
Special Considerations
Guillain-Barré-like Presentation
- Requires immediate hospitalization with capability for ICU transfer
- Start IVIG or plasmapheresis promptly
- Monitor for respiratory compromise and autonomic dysfunction
- Corticosteroids may be beneficial in immune checkpoint inhibitor-related cases 1
Autonomic Neuropathy
- Screen for orthostatic hypotension
- Evaluate for gastrointestinal manifestations (gastroparesis, constipation, diarrhea)
- Consider specialized autonomic testing
- Treat symptomatically based on affected systems
Diabetic Peripheral Neuropathy
- Tight glycemic control is the only strategy convincingly shown to prevent or delay progression 1
- Screen annually starting at diagnosis of type 2 diabetes or 5 years after diagnosis of type 1 diabetes
- Use 10-g monofilament testing for screening
- Pregabalin starting at 50mg three times daily, may increase to 100mg three times daily (maximum 300mg/day) 2
Common Pitfalls to Avoid
- Failing to screen for reversible causes before attributing to idiopathic neuropathy
- Not considering medication-induced neuropathy (especially chemotherapeutics)
- Missing rapidly progressive forms that may lead to respiratory compromise
- Overlooking non-length-dependent presentations that may indicate inflammatory or infiltrative processes
- Treating symptoms without addressing the underlying cause when identifiable
- Using opioids as first-line treatment for neuropathic pain instead of gabapentinoids or antidepressants
Remember that peripheral neuropathy has a variety of systemic, metabolic, and toxic causes, and a systematic approach to diagnosis will lead to identification of potentially treatable conditions in many cases 3, 4.