What is the approach to diagnosing and treating peripheral neuropathy?

Approach to Peripheral Neuropathy: Clinical Examination and Differential Diagnosis

Initial Clinical Assessment

The diagnosis of peripheral neuropathy is primarily clinical, based on detailed history and focused neurological examination, with nerve conduction studies reserved for asymmetric patterns, uncertain diagnosis, or when distinguishing axonal from demyelinating pathology is critical for management. 1

Key Historical Elements to Obtain

• Symptom characterization: Assess for numbness, tingling, burning sensations, lancinating pain, dysesthesia, allodynia, or hyperalgesia in hands and/or feet 1, 2
• Distribution pattern: Determine if symptoms follow a "stocking-glove" distribution starting distally in fingers and toes, potentially progressing proximally 3, 1
• Temporal course: Distinguish acute versus chronic onset, as acute presentations may suggest Guillain-Barré syndrome while chronic suggests metabolic or toxic etiologies 4, 5
• Diabetes history: This is the most common treatable cause and must be specifically evaluated 1, 4
• Medication exposure: Specifically inquire about chemotherapy (bortezomib, thalidomide, paclitaxel, oxaliplatin), as these have distinct neuropathy patterns 3
• Alcohol use and toxin exposure: These represent common reversible causes 4, 6
• Family history: Hereditary neuropathies show uniform demyelinating features on electrodiagnostic studies 7
• Occupational exposures: May reveal toxic causes requiring specific testing 4, 7

Focused Neurological Examination

Large fiber neuropathy assessment:

• Test vibration sense using a 128-Hz tuning fork at the great toe 1
• Assess proprioception by testing joint position sense 1
• Evaluate for sensory ataxia and gait abnormalities 7
• Check deep tendon reflexes, which are typically reduced or absent distally 1
• Examine for distal muscle atrophy in feet and distal weakness 1

Small fiber neuropathy assessment:

• Test pain sensation using pinprick 1
• Assess temperature discrimination 7
• Note that standard nerve conduction studies are often completely normal in small fiber neuropathy 1

Autonomic involvement assessment:

• Check orthostatic blood pressure for postural hypotension 1, 2
• Inquire about constipation, bladder dysfunction, delayed gastric emptying, or reduced heart rate variability 1

Pattern Recognition for Differential Diagnosis

Distribution Patterns

Symmetric distal polyneuropathy (most common):

• Suggests metabolic (diabetes, hypothyroidism), toxic (alcohol, chemotherapy), or nutritional causes 4, 6
• Diabetes mellitus is the leading cause in this pattern 1, 4

Asymmetric or mononeuropathy multiplex:

• Suggests vasculitis, leprosy, or nerve compression/entrapment 7, 5
• Requires nerve conduction studies to localize lesions 1

Acute ascending paralysis with areflexia:

• Suggests Guillain-Barré syndrome requiring lumbar puncture and CSF analysis 4, 7

Chemotherapy-Specific Patterns

Paclitaxel-induced neuropathy:

• Primarily sensory with symptoms more prominent in lower extremities during treatment 3
• Tends to improve over several months after completion of chemotherapy 3
• Symptoms include numbness, tingling, and pain in a stocking-glove distribution 3

Oxaliplatin-induced neuropathy:

• Acute symptoms worsen with cold exposure 3
• Chronic symptoms more severe in upper extremities during treatment 3
• Exhibits "coasting phenomenon" where neuropathy worsens for 2-3 months after cessation, then improves 3
• Hand symptoms improve faster than feet, resulting in worse foot neuropathy months after completion 3

Laboratory Evaluation

Initial Baseline Testing (Order for All Patients)

The American College of Physicians recommends ordering baseline laboratory tests to identify treatable causes: 1

• Fasting blood glucose and hemoglobin A1c (to assess for diabetes) 1, 2
• Complete blood count 4, 6
• Comprehensive metabolic profile 4, 6
• Vitamin B12 level 2, 4, 6
• Thyroid-stimulating hormone 2, 4, 6
• Erythrocyte sedimentation rate 4
• Serum protein electrophoresis with immunofixation 6

Additional Testing Based on Clinical Suspicion

• Hepatitis B, C, and HIV testing if risk factors present 2
• Anti-ganglioside antibodies if Guillain-Barré syndrome suspected 2
• Anti-MAG antibodies if demyelinating neuropathy suspected 2
• Lumbar puncture and CSF analysis for suspected Guillain-Barré syndrome or chronic inflammatory demyelinating polyneuropathy 4, 7

Neurophysiological Testing

Indications for Nerve Conduction Studies

The American Academy of Neurology suggests considering neurophysiology in specific scenarios: 1

• Asymmetric pattern of symptoms 1
• Normal clinical examination despite patient complaints 1
• Need to distinguish axonal from demyelinating neuropathy, as this dramatically narrows the differential diagnosis 1, 5

Interpretation of Electrodiagnostic Studies

Axonal degeneration pattern:

• Progressive reduction of sensory nerve action potential amplitude 1
• Followed by impaired nerve conduction velocity 1
• Marginal slowing with small compound muscle or sensory action potentials 7

Demyelinating pattern:

• Prolonged terminal latency 7
• Marked slowing of nerve conduction velocity 7
• Temporal dispersion and conduction block 7
• Uniform demyelinating features suggest hereditary causes, while variability between nerves suggests acquired demyelination 7

Small Fiber Neuropathy Diagnosis

Skin biopsy is the gold standard for diagnosing small fiber neuropathy, demonstrating degeneration of small C and Aδ fibers. 1, 5

Screening Recommendations

The American Diabetes Association recommends:

• Screen all patients with type 2 diabetes at diagnosis for diabetic neuropathy 1, 2
• Screen patients with type 1 diabetes starting 5 years after diagnosis 1, 2
• Continue annual screening thereafter 1, 2
• Monitor for foot ulcer development in patients with diabetic neuropathy 2

Common Pitfalls and Caveats

Avoid over-testing in typical presentations:

• If a patient on neurotoxic chemotherapy develops new numbness, tingling, or pain in hands/feet with no other explanation, the diagnosis is clinical and extensive testing is unnecessary 3
• Nerve conduction studies in asymptomatic patients receiving neurotoxic chemotherapy can predict CIPN development but are not routinely used 3

Recognize idiopathic neuropathy:

• Peripheral neuropathy remains idiopathic in 25% to 46% of cases despite thorough workup 6
• Approximately 20% of patients remain undiagnosed, but prognosis is not necessarily poor in this group 7

Chemotherapy dose modifications:

• For bortezomib: Grade 1 with pain or Grade 2 requires dose reduction to 1.0 mg/m²; Grade 2 with pain or Grade 3 requires suspension until toxicity disappears, then reinitiate at 0.7 mg/m² once weekly; Grade 4 requires discontinuation 3
• For thalidomide: Grade 1 with pain or Grade 2 requires 50% dose reduction; Grade 2 with pain or Grade 3 requires suspension until toxicity disappears; Grade 4 requires discontinuation 3
• Early diagnosis is essential as 45% of patients discontinuing bortezomib due to grade ≥2 neuropathy do so within the first three cycles 3

Vitamin supplementation caution:

• High doses of pyridoxine (vitamin B6) may induce sensory neuron lesions, especially with renal insufficiency 3
• High doses of vitamin C may interfere with bortezomib metabolism and reduce efficacy 3