What are the causes of peripheral neuropathy in older adults?

Causes of Peripheral Neuropathy in Older Adults

Diabetes mellitus is the single most common cause of peripheral neuropathy in older adults, accounting for over 50% of cases in Western populations and affecting approximately 206 million people worldwide. 1, 2, 3

Metabolic and Endocrine Causes

• Diabetes mellitus presents as distal symmetric polyneuropathy affecting both sensory and motor fibers, with up to 50% of cases being asymptomatic yet still at high risk for complications including foot ulceration. 1, 2, 3
• Impaired glucose tolerance (prediabetes) can cause small fiber damage even before overt diabetes develops, making screening for prediabetic states essential. 1
• Hypothyroidism is a treatable metabolic cause that should be evaluated with thyroid-stimulating hormone levels in all patients. 4
• Uremic neuropathy from chronic kidney disease and dialysis-related complications contributes significantly to neuropathy development in older adults. 1, 2

Nutritional Deficiencies

• Vitamin B12 deficiency is one of the most common treatable causes and must be checked in all patients, causing both symptomatic and asymptomatic small fiber loss with reduced intraepidermal nerve fiber density. 1, 2, 4, 5
• Vitamin E, thiamine, nicotinamide, and red-cell folate deficiencies should be excluded, particularly in patients with malabsorption or inflammatory bowel disease. 1
• Copper deficiency can cause peripheral neuropathy and should be considered in the differential diagnosis. 1

Drug-Induced Neuropathy

Drug-induced neuropathy is among the most common iatrogenic causes in older adults, particularly those receiving cancer treatment or chronic medications. 2

• Chemotherapy agents: Bortezomib causes predominantly sensory neuropathy with motor impairment in ~10% of cases; thalidomide is a major cause in multiple myeloma patients; vincristine causes motor neuropathy in ~10% of patients; taxanes (paclitaxel) and platinum compounds (oxaliplatin, cisplatin) primarily affect sensory fibers. 6, 1, 3
• Antimicrobials: Metronidazole is a common cause requiring temporal association assessment and discontinuation when suspected. 1
• Cardiovascular medications: Amiodarone can cause toxic neuropathy. 3
• HIV medications: Nucleotide reverse transcriptase inhibitors (stavudine, zalcitabine) are known neurotoxic agents. 3
• Anti-TNF agents can cause peripheral neuropathy and may worsen central demyelinating diseases. 1

Toxic Causes

• Alcohol is a major neurotoxin causing peripheral neuropathy and must be assessed in all patients with a history of excessive consumption. 1, 2, 3, 4

Infectious Causes

• HIV infection should be screened in at-risk populations as it is a known cause of peripheral neuropathy. 1, 2
• Hepatitis C infection (particularly with cryoglobulins) can cause peripheral neuropathy. 1

Autoimmune and Inflammatory Causes

• Chronic inflammatory demyelinating polyneuropathy (CIDP) is a treatable cause that must not be missed and should be screened for in all patients with peripheral neuropathy. 2, 4
• Guillain-Barré syndrome requires lumbar puncture with CSF analysis and serum antiganglioside antibody testing for diagnosis. 2, 4
• Autoimmune mechanisms can cause neuropathy, including in the context of inflammatory bowel disease. 1

Monoclonal Gammopathies and Plasma Cell Disorders

• Monoclonal gammopathies should be screened with serum protein electrophoresis with immunofixation in all patients. 2, 3, 5
• Multiple myeloma can cause neuropathy through direct nerve compression, light chain deposits (amyloidosis), or associated conditions like POEMS syndrome. 6, 1, 2
• Cryoglobulinemia should be evaluated as a potential cause. 1

Hereditary Causes

• Charcot-Marie-Tooth disease (particularly type 1A) should be ruled out in cases with predominant motor involvement and distinct deformities (hollow foot, stork legs), especially in patients with family or personal history of hereditary peripheral neuropathy. 1, 2
• Genetic testing should be considered in patients with suspected hereditary causes, particularly those with early onset or family history. 2

Mechanical and Structural Causes

• Direct nerve compression (radicular or medullary) from cervical and lumbar disease (nerve root compression, spinal stenosis, cervical and lumbar degeneration) must be excluded. 6, 1
• Cerebral infarction should be ruled out as it can mimic peripheral neuropathy. 6

Idiopathic Neuropathy

• Idiopathic peripheral neuropathy accounts for 25-46% of cases after comprehensive evaluation, representing a diagnosis of exclusion. 1, 3, 5, 7
• Nearly half (41-48%) of small fiber neuropathy cases remain idiopathic despite thorough workup. 1

Critical Risk Factors in Older Adults

Patient factors that increase susceptibility to neuropathy development include: pre-existing diabetes mellitus, prior history of peripheral neuropathy, smoking, retinopathy and nephropathy (particularly dialysis or post-transplant patients), foot deformities, and prior ulceration or amputation. 1, 2

Important Clinical Pitfall

Do not assume diabetic neuropathy in a patient with diabetes without excluding other causes, as nondiabetic neuropathies may be present and treatable—this is particularly critical in older adults who often have multiple comorbidities and medication exposures. 2