Causes of Peripheral Neuropathy
The most common causes of peripheral neuropathy include diabetes, vitamin deficiencies, toxins (including alcohol and medications), hypothyroidism, renal disease, malignancies, infections, inflammatory conditions, and inherited neuropathies 1, 2.
Classification of Peripheral Neuropathy Causes
Metabolic/Endocrine Causes
- Diabetes mellitus: The leading cause of peripheral neuropathy worldwide, accounting for approximately 50% of all cases 3, 4
- Prediabetes and metabolic syndrome: Increasingly recognized as risk factors for neuropathy even before diabetes develops 3
- Hypothyroidism: Common treatable cause of neuropathy 2
- Renal disease: Uremic neuropathy from metabolic toxins 1
Nutritional/Deficiency Causes
- Vitamin B12 deficiency: Critical for nerve health and function 1, 2
- Thiamine (B1) deficiency: Often associated with alcoholism 1
- Vitamin E deficiency: Can cause neuropathy, especially with fat malabsorption 1
- Copper deficiency: Less common but important to consider 1
- Folate deficiency: Can contribute to neuropathy 1
Toxic/Drug-Induced Causes
- Alcohol: Direct neurotoxic effect and indirect effect through nutritional deficiencies 1
- Medications:
Inflammatory/Immune-Mediated Causes
- Guillain-Barré syndrome: Acute inflammatory demyelinating polyneuropathy 4, 2
- Chronic inflammatory demyelinating polyneuropathy (CIDP) 4, 2
- Vasculitis: Can cause mononeuritis multiplex 4
- Inflammatory bowel disease-associated neuropathy: Rare complication 1
Infectious Causes
- HIV: Direct viral effect and medication-related 1, 5
- Hepatitis C: Often associated with cryoglobulinemia 1, 2
- Tuberculosis: Both from the disease and anti-TB medications 5
Malignancy-Associated Causes
- Multiple myeloma: Through direct infiltration or paraneoplastic effects 1
- Bronchogenic carcinoma: Often paraneoplastic 1
- Other paraneoplastic syndromes 2
Hereditary/Genetic Causes
- Charcot-Marie-Tooth disease: Most common inherited neuropathy 4
- Hereditary sensory and autonomic neuropathies 4
- Familial amyloid polyneuropathy 4
Mechanical/Trauma Causes
- Entrapment neuropathies: Carpal tunnel syndrome (most common), cubital tunnel syndrome 4
- Compression from prolonged positioning 4
Idiopathic
- Cryptogenic sensory peripheral neuropathy: In approximately 20-25% of chronic polyneuropathies, no direct cause can be found despite thorough evaluation 4
Clinical Approach to Diagnosis
Comprehensive history: Focus on onset (acute vs. chronic), progression, distribution (symmetric vs. asymmetric), type of symptoms (sensory, motor, autonomic), and associated conditions 2
Targeted examination: Assess for:
Initial laboratory testing:
- Complete blood count
- Comprehensive metabolic profile
- Fasting blood glucose
- Hemoglobin A1c
- Vitamin B12 levels
- Thyroid-stimulating hormone
- Erythrocyte sedimentation rate
- Serum protein electrophoresis (if monoclonal gammopathy suspected) 2
Additional testing based on clinical suspicion:
- Nerve conduction studies and electromyography to differentiate axonal vs. demyelinating neuropathy
- Specialized antibody testing for autoimmune neuropathies
- Cerebrospinal fluid analysis for inflammatory neuropathies
- Genetic testing for hereditary neuropathies 2
Important Clinical Pearls
- Diabetic neuropathy is a diagnosis of exclusion; always consider other potential causes of neuropathy in diabetic patients 1
- Acute onset neuropathy with rapid progression warrants urgent evaluation for Guillain-Barré syndrome 4
- Asymmetric or multifocal neuropathy should raise suspicion for vasculitis, infection, or compression 4
- Peripheral neuropathy can occur in prediabetes and metabolic syndrome, not just established diabetes 3
- Sudden improvement in glycemic control can paradoxically trigger acute painful neuropathy ("insulin neuritis") 1
By systematically evaluating patients with peripheral neuropathy and identifying the underlying cause, appropriate treatment can be initiated to prevent progression and manage symptoms effectively.