What are the common causes of neuropathy and what laboratory tests should be ordered to evaluate it?

Common Causes of Neuropathy and Laboratory Evaluation

The most common causes of neuropathy include diabetes mellitus, vitamin B12 deficiency, toxins (including alcohol), medications, hypothyroidism, and renal disease, and all patients should undergo a comprehensive laboratory evaluation to identify treatable underlying causes before accepting a diagnosis of idiopathic neuropathy. 1, 2, 3

Common Causes of Peripheral Neuropathy

Metabolic/Endocrine Causes

• Diabetes mellitus - most common identifiable cause 1
• Prediabetes/impaired glucose metabolism - accounts for 25.3% of previously labeled "idiopathic" neuropathies 4
• Hypothyroidism 1, 2
• Renal disease 1

Toxic/Nutritional Causes

• Alcohol abuse 1, 3
• Vitamin deficiencies:
  • Vitamin B12 deficiency 1, 2
  • Vitamin B1 (thiamine) deficiency 4
  • Vitamin B6 deficiency 4
  • Folate deficiency 2
• Medications/chemotherapy - especially neurotoxic chemotherapeutic agents 1
• Heavy metal poisoning 1

Immune-Mediated Causes

• Chronic inflammatory demyelinating polyneuropathy (CIDP) - accounts for 20% of previously labeled "idiopathic" neuropathies 4
• Monoclonal gammopathy - accounts for 7% of previously labeled "idiopathic" neuropathies 4
• Vasculitis 1, 4
• Sjögren's disease 4
• Celiac disease 4
• Other immune-mediated diseases 4

Infectious Causes

• HIV 1
• Lyme disease 4

Other Causes

• Inherited neuropathies 1
• Amyloidosis 4
• Malignancies (e.g., multiple myeloma, bronchogenic carcinoma) 1

Laboratory Tests for Neuropathy Evaluation

Initial Laboratory Evaluation

1. Complete blood count (CBC) 2, 5, 3
2. Comprehensive metabolic profile 2, 5, 3
3. Fasting blood glucose and HbA1c 2, 5, 3
4. Vitamin B12 level 2, 5, 3
5. Thyroid-stimulating hormone (TSH) 2, 5, 3
6. Serum protein electrophoresis with immunofixation 2, 3
7. Erythrocyte sedimentation rate (ESR) 5

Additional Testing Based on Clinical Suspicion

• Autoimmune markers if inflammatory neuropathy suspected:
  • Antinuclear antibody (ANA) 1
  • ESR and C-reactive protein (CRP) 1
  • Anti-neutrophil cytoplasmic antibody (ANCA) 1
• Specific antibody assays for suspected immune-mediated neuropathies 2, 3
• Vitamin B1 and B6 levels if nutritional deficiency suspected 4
• Lyme disease testing if exposure history suggests 4
• Anti-sulfatide antibody for suspected immune neuropathy 4
• Celiac disease screening if symptoms suggest 4

Specialized Testing When Initial Evaluation Is Inconclusive

• Electrodiagnostic studies (nerve conduction studies and electromyography) to differentiate axonal vs. demyelinating neuropathy 2, 5, 3
• Lumbar puncture and CSF analysis for suspected Guillain-Barré syndrome or CIDP 2, 5
• Nerve biopsy in select cases where diagnosis remains unclear 2, 3

Clinical Approach to Neuropathy Evaluation

1. Determine pattern of involvement:

   • Length-dependent (stocking-glove distribution) suggests metabolic causes
   • Asymmetric/multifocal pattern suggests inflammatory or compression causes
   • Proximal weakness suggests inflammatory demyelinating neuropathy

2. Assess fiber type involvement:

   • Small-fiber (pain, temperature sensation, autonomic function)
   • Large-fiber (vibration, proprioception, reflexes)
   • Mixed involvement

3. Evaluate for diabetic neuropathy in all patients with diabetes:

   • Screen at diagnosis of type 2 diabetes and 5 years after diagnosis of type 1 diabetes 1
   • Assess small-fiber function (pinprick and temperature sensation) 1
   • Assess large-fiber function (vibration perception using 128-Hz tuning fork, 10-g monofilament) 1
   • Assess protective sensation (10-g monofilament) 1

Important Pitfalls to Avoid

• Attributing neuropathy to diabetes without excluding other causes - up to 10% of diabetic patients with neuropathy have another etiology 2
• Overlooking prediabetes as a cause of neuropathy 4
• Missing treatable inflammatory neuropathies like CIDP 4
• Failing to recognize monoclonal gammopathy as a potential cause 4
• Accepting "idiopathic" diagnosis prematurely - thorough evaluation can identify causes in approximately 70% of cases 4

By systematically evaluating patients with neuropathy and performing appropriate laboratory testing, clinicians can identify treatable causes and improve patient outcomes through targeted interventions.