What are the causes of non-diabetic neuropathy?

Causes of Non-Diabetic Neuropathy

Non-diabetic neuropathy has numerous identifiable causes that must be systematically excluded, including toxins (especially alcohol), neurotoxic medications (particularly chemotherapy agents), vitamin B12 deficiency, hypothyroidism, renal disease, malignancies, infections, chronic inflammatory demyelinating neuropathy, inherited neuropathies, and vasculitis. 1

Most Common Etiologies

Toxic Causes

• Alcohol is a leading toxic cause of peripheral neuropathy and should be assessed through detailed history 1, 2
• Neurotoxic medications include chemotherapy agents (cisplatin, paclitaxel, vincristine), amiodarone, and HIV nucleotide reverse transcriptase inhibitors (stavudine, zalcitabine) 2, 3
• Metformin can cause vitamin B12 deficiency after chronic use (occurs in 30% of patients), which may present as peripheral neuropathy rather than diabetic neuropathy 4

Metabolic and Nutritional Deficiencies

• Vitamin B12 deficiency is a critical reversible cause that must be screened with serum B12 levels plus metabolites (methylmalonic acid with or without homocysteine) 2, 3
• Hypothyroidism should be evaluated as part of the initial workup 1
• Vitamin B12 deficiency can present without anemia and is often misdiagnosed as diabetic neuropathy, though clinical findings differ 4

Hematologic and Oncologic Causes

• Monoclonal gammopathies require screening with serum protein electrophoresis with immunofixation 2
• Malignancies including multiple myeloma and bronchogenic carcinoma can cause paraneoplastic neuropathy 1

Infectious Causes

• HIV infection should be considered, particularly in at-risk populations 1

Autoimmune and Inflammatory Causes

• Chronic inflammatory demyelinating neuropathy (CIDP) presents with progressive weakness and sensory loss, often requiring electrophysiological testing for diagnosis 1
• Vasculitis can cause mononeuritis multiplex or asymmetric neuropathy patterns 1

Hereditary Causes

• Inherited neuropathies such as Charcot-Marie-Tooth disease should be considered, especially with family history or atypical presentations 1, 2

Renal Disease

• Uremic neuropathy from chronic kidney disease is an important metabolic cause 1

Diagnostic Approach

Initial Screening Tests

The recommended initial workup includes:

• Blood glucose testing (to exclude diabetes) 2
• Serum B12 with metabolites (methylmalonic acid ± homocysteine) 2
• Serum protein electrophoresis with immunofixation 2
• Thyroid function tests 1
• Renal function assessment 1

Clinical Assessment

• Evaluate small-fiber function with pinprick and temperature sensation tests 1, 5
• Assess large-fiber function with vibration perception using 128-Hz tuning fork and 10-g monofilament testing 1, 5
• Electrophysiological testing or neurology referral is indicated when clinical features are atypical or diagnosis remains unclear 1

Critical Pitfalls to Avoid

Misdiagnosis Risk

• Metformin-induced B12 deficiency is frequently misdiagnosed as diabetic neuropathy in patients with diabetes, but the clinical findings typically differ 4
• Failure to diagnose B12 deficiency will result in progression of neuronal damage that can be arrested but not reversed with replacement therapy 4
• Vitamin B12 stores typically become exhausted after 12-15 years of absolute deficiency, coinciding with the duration metformin has been available 4

Idiopathic Neuropathy

• Up to 27% of adults with neuropathy have no identifiable etiology after comprehensive diagnostic testing 2
• This diagnosis should only be made after systematic exclusion of treatable causes 1

Treatment Implications

• Many non-diabetic neuropathies are treatable or reversible if identified early (particularly B12 deficiency, hypothyroidism, and CIDP) 1
• First-line pain management remains similar across etiologies: pregabalin, gabapentin, duloxetine, or tricyclic antidepressants 2, 6
• However, addressing the underlying cause is essential to prevent progression 1, 3