What are the causes of neuropathy?

Causes of Neuropathy

Neuropathy is most commonly caused by diabetes, but numerous other important causes must be considered including toxins, medications, vitamin deficiencies, and systemic diseases, as diabetic neuropathy is a diagnosis of exclusion. 1

Primary Causes of Neuropathy

Metabolic and Endocrine Causes

• Diabetes mellitus - Most common identifiable cause of neuropathy 1

  • Up to 50% of diabetic peripheral neuropathy may be asymptomatic
  • Usually presents as length-dependent sensorimotor polyneuropathy
  • Risk increases with duration of diabetes and poor glycemic control

• Vitamin deficiencies 2, 3

  • Vitamin B12 deficiency - Associated with elevated methylmalonic acid and homocysteine
  • Vitamin B1 (thiamine) deficiency - Can cause painful neuropathy
  • Other B vitamin deficiencies

• Hypothyroidism - Can cause sensorimotor neuropathy 1

Toxic Causes

• Alcohol - Common toxin causing neuropathy 1, 4
• Chemotherapy agents - Particularly platinum compounds, taxanes, vinca alkaloids 1, 5
• Heavy metals - Lead, mercury, arsenic 5
• Industrial toxins - Organic solvents, insecticides 5

Medication-Induced Neuropathy 5, 3

• Antibiotics - Especially fluoroquinolones, metronidazole, nitrofurantoin
• Anticonvulsants - Phenytoin
• Cardiovascular drugs - Amiodarone, statins
• Antimycobacterials - Isoniazid, ethambutol
• Immunosuppressants - Tacrolimus, leflunomide

Systemic Diseases

• Renal disease - Uremic neuropathy 1

• Malignancies 1

  • Multiple myeloma
  • Bronchogenic carcinoma
  • Paraneoplastic syndromes

• Infections 1, 6

  • HIV
  • Hepatitis C
  • Lyme disease

Immune-Mediated Causes 6

• Chronic inflammatory demyelinating polyneuropathy (CIDP) - 8% of chronic neuropathies
• Multifocal motor neuropathy (MMN) - 3% of chronic neuropathies
• Paraproteinemic neuropathies - 8% of chronic neuropathies
• Vasculitis - Can cause mononeuritis multiplex
• Celiac disease-associated neuropathy - 6% of chronic neuropathies
• Systemic autoimmune diseases - Lupus, rheumatoid arthritis, Sjögren's syndrome

Hereditary Neuropathies

• Charcot-Marie-Tooth disease and other inherited neuropathies 1

Idiopathic Neuropathy

• Despite thorough evaluation, approximately 19% of chronic neuropathies remain idiopathic 6

Clinical Approach to Neuropathy Diagnosis

1. Determine pattern of involvement:

   • Length-dependent sensorimotor (most common)
   • Non-length dependent
   • Mononeuropathy vs. polyneuropathy
   • Small fiber vs. large fiber involvement

2. Key diagnostic tests:

   • Small-fiber function: Pinprick and temperature sensation
   • Large-fiber function: Vibration perception and 10-g monofilament
   • Protective sensation: 10-g monofilament

3. Laboratory evaluation:

   • Glucose/HbA1c
   • Vitamin B12, methylmalonic acid, homocysteine
   • Thyroid function tests
   • Renal function
   • Serum protein electrophoresis
   • HIV testing
   • Autoimmune markers when indicated

Important Clinical Pitfalls

• Diabetic neuropathy is a diagnosis of exclusion - Even in patients with diabetes, other causes of neuropathy must be considered 1
• Medication history is critical - Many commonly prescribed medications can cause or exacerbate neuropathy 5, 3
• Vitamin B12 deficiency may occur despite normal B12 levels - Check methylmalonic acid and homocysteine when suspicion is high 2
• Treatable causes can be missed - Dysimmune neuropathies and vitamin deficiencies are potentially reversible 6
• Multiple causes may coexist - Especially in elderly patients or those with multiple comorbidities

Early recognition and management of the underlying cause of neuropathy is essential to prevent progression and improve outcomes. In patients with diabetic neuropathy, optimizing glucose control can prevent or delay development in type 1 diabetes and slow progression in type 2 diabetes, but it does not reverse neuronal loss 1.