Causes of Neuropathy Beyond B12 and Folate Deficiency
When a patient presents with neuropathy and normal B12/folate levels, you must systematically evaluate metabolic disorders (especially diabetes and prediabetes), neurotoxic medications, other nutritional deficiencies, autoimmune conditions, and hereditary causes before concluding the neuropathy is idiopathic.
Metabolic and Endocrine Causes
Diabetes mellitus is the single most common cause of peripheral neuropathy, presenting as distal symmetric polyneuropathy with sensory symptoms (burning, tingling, numbness) starting in the toes and progressing proximally 1, 2.
Up to 50% of diabetic neuropathy cases are asymptomatic, yet these patients remain at high risk for foot ulceration and other complications—absence of symptoms does not exclude the diagnosis 2, 3.
Impaired glucose tolerance (prediabetes) causes small fiber neuropathy even before overt diabetes develops—standard fasting glucose may be normal, so glucose tolerance testing should be performed in idiopathic neuropathy cases 1, 2.
Hypothyroidism is a reversible endocrine cause that must be screened with thyroid function tests 1.
Neurotoxic Medications
Chemotherapy agents are major causes: taxanes (paclitaxel), platinum compounds (oxaliplatin), vincristine, bortezomib, and thalidomide all cause dose-dependent neuropathy, predominantly sensory but with motor involvement in 10% of cases 2.
Metronidazole is a common antimicrobial cause requiring temporal association assessment and immediate discontinuation when suspected 2.
Anti-TNF agents can cause or worsen peripheral neuropathy and demyelinating diseases 2.
Amitriptyline itself can cause peripheral neuropathy as an adverse effect, creating a paradoxical situation when used to treat neuropathic pain 4.
Other Nutritional Deficiencies
Vitamin B12 deficiency can occur despite normal serum B12 levels—methylmalonic acid and homocysteine should be measured, as 44% of B12-deficient neuropathy patients have normal B12 levels but elevated metabolites 1, 5, 6, 7.
Vitamin E, thiamine, nicotinamide, and copper deficiencies should be excluded, particularly in patients with malabsorption, inflammatory bowel disease, or bariatric surgery 8, 2.
Folate deficiency alone can cause reversible neuropathy and dementia, even when B12 levels are normal 9.
Toxic Exposures
Alcohol abuse is a common neurotoxin that must be assessed in all neuropathy patients through careful history 1, 2.
Heavy metal poisoning (lead, mercury, arsenic) should be considered based on occupational or environmental exposure history 1.
Autoimmune and Inflammatory Causes
Chronic inflammatory demyelinating neuropathy (CIDP) presents with progressive weakness and sensory loss, often with elevated CSF protein 1.
Vasculitis can cause mononeuritis multiplex or asymmetric polyneuropathy 1.
Autoimmune mechanisms related to inflammatory bowel disease or other systemic conditions 2.
Hematologic and Oncologic Causes
Monoclonal gammopathies (MGUS, multiple myeloma, Waldenstrom's) are more common in neuropathy patients than the general population—serum protein immunofixation electrophoresis has a 9% diagnostic yield 1, 2.
POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, M-protein, skin changes) causes severe progressive neuropathy 2.
Amyloidosis from light chain deposits causes rapidly progressive small fiber neuropathy (15-20 times faster than diabetic neuropathy) with early autonomic involvement 2, 3.
Cryoglobulinemia (often associated with hepatitis C) should be screened 2.
Infectious Causes
HIV infection should be screened in at-risk populations, as it causes distal symmetric polyneuropathy 1, 2.
Hepatitis C (particularly with cryoglobulins) can cause peripheral neuropathy 2.
Hereditary Causes
Charcot-Marie-Tooth disease type 1A should be ruled out, especially in patients with family history, early onset, or distinctive features (hollow foot, stork legs, severe motor involvement) 2.
Inherited neuropathies may be unmasked or worsened by chemotherapy exposure 1, 2.
Renal Disease
- Chronic kidney disease and dialysis-related complications cause uremic neuropathy, which is length-dependent and predominantly sensory 1, 2.
Malignancies
Paraneoplastic neuropathy from bronchogenic carcinoma, lymphoma, or other malignancies can precede cancer diagnosis 1.
Direct nerve compression from tumors (particularly in multiple myeloma with vertebral involvement) 2.
Idiopathic Cases
- 41-48% of small fiber neuropathy cases remain idiopathic despite comprehensive evaluation—this is a diagnosis of exclusion only after thorough workup 2.
Diagnostic Algorithm
Initial screening laboratory tests should include: complete blood count, comprehensive metabolic panel (glucose, renal function, liver function), erythrocyte sedimentation rate, thyroid function tests, serum B12 with methylmalonic acid and homocysteine, and serum protein immunofixation electrophoresis 1.
For patients with normal B12 levels but high clinical suspicion, measure methylmalonic acid and homocysteine—these metabolites are elevated in 5-10% of patients with low-normal B12 (200-500 pg/dL) and identify an additional 44% of B12-deficient cases 1, 5, 6.
Glucose tolerance testing should be performed in idiopathic cases, as 25-36% of patients with unexplained neuropathy have impaired glucose tolerance versus 15% of controls 1.
Small fiber testing (pinprick and temperature sensation) detects early neuropathy before conventional nerve conduction studies show abnormalities, since small fibers constitute 70-90% of peripheral nerves and are damaged earliest 2, 3.
Common Pitfalls
Relying solely on serum B12 levels misses 44% of B12-deficient neuropathy cases—always measure metabolites in unexplained neuropathy 1, 5, 6, 7.
Assuming normal fasting glucose excludes diabetes—glucose tolerance testing identifies an additional 25-36% of cases with impaired glucose tolerance causing neuropathy 1, 2.
Using only nerve conduction studies misses small fiber neuropathy, which represents the earliest and most common pattern in metabolic and toxic neuropathies 2, 3.
Failing to obtain medication history overlooks neurotoxic drugs as reversible causes 1, 2.
Not screening for monoclonal proteins misses a 9% diagnostic yield from a simple blood test 1.