What are the causes of peripheral neuropathy?

Causes of Peripheral Neuropathy

Peripheral neuropathy has multiple etiologies, with the most common treatable causes being diabetes mellitus, hypothyroidism, and nutritional deficiencies, while drug-induced neuropathy—particularly from chemotherapeutic agents—has emerged as a leading iatrogenic cause. 1

Metabolic and Endocrine Causes

• Diabetes mellitus is the most common metabolic cause, presenting as distal symmetric polyneuropathy affecting both sensory and motor fibers, though motor involvement is typically less prominent 2, 3
• Up to 50% of diabetic peripheral neuropathy may be asymptomatic but still increases risk for complications 3
• Hypothyroidism represents another common treatable endocrine cause that should be screened in all patients with new-onset neuropathy 1

Drug-Induced Peripheral Neuropathy

Chemotherapeutic Agents

Drug-induced neurotoxicity has become the leading cause of peripheral neuropathy in oncology and hematology patients 4:

• Bortezomib (proteasome inhibitor) causes predominantly sensory neuropathy, but motor impairment occurs in approximately 10% of cases with mild to severe distal weakness 2
• Thalidomide is a major cause of treatment-related neuropathy in multiple myeloma patients 4
• Vincristine causes motor neuropathy in approximately 10% of patients, ranging from grade 1-3 distal weakness to rare life-threatening grade 4 motor neurotoxicity 2
• Taxanes (paclitaxel) and platinum compounds (oxaliplatin) primarily affect sensory fibers but can have motor components 4, 2

Other Medications

• Metronidazole is a common antimicrobial cause that requires temporal association assessment and discontinuation when suspected 4
• Anti-TNF agents can cause peripheral neuropathy and may worsen central demyelinating diseases 4
• Statins and other cardiovascular drugs are frequently prescribed and can cause neuropathy 5
• Anticonvulsants and psychotropic medications are implicated in drug-induced peripheral neuropathy 5

Nutritional Deficiencies

• Vitamin B12 deficiency is a critical treatable cause that should be measured in initial screening 1
• Vitamin E, thiamine, nicotinamide, and red-cell folate deficiencies should be excluded, particularly in patients with malabsorption or inflammatory bowel disease 4
• Copper deficiency can cause peripheral neuropathy and should be considered in the differential 4

Disease-Related Causes

Hematologic and Oncologic

• Plasma cell dyscrasias (particularly POEMS syndrome) cause neuropathy through direct effects 4
• Light chain deposits (amyloidosis) lead to neuropathy through nerve infiltration 4
• Cryoglobulinemia and monoclonal gammopathies should be screened 4

Autoimmune and Inflammatory

• Autoimmune mechanisms can cause neuropathy, including in the context of inflammatory bowel disease 4
• Chronic inflammatory demyelinating polyneuropathy (CIDP) is a rare but important immune-mediated cause 6
• Guillain-Barré syndrome represents an acute immune-mediated neuropathy 1, 6

Infectious

• Hepatitis C infection (with cryoglobulins) can cause peripheral neuropathy 4

Hereditary Causes

• Charcot-Marie-Tooth type 1A should be ruled out in cases of severe motor neurotoxicity, particularly with vincristine exposure, as these patients present with predominant motor involvement and distinct deformities (hollow foot, stork legs) 2
• Family or personal history of hereditary peripheral neuropathy predisposes patients to chemotherapy-induced neuropathy and should be assessed before treatment 4

Mechanical and Structural Causes

• Direct nerve compression (radicular or medullary) can cause neuropathy in multiple myeloma patients 4
• Carpal tunnel syndrome (median nerve compression) is the most common mononeuropathy, with a prevalence of 5% and incidence of 1-2 per 1000 person-years 6

Risk Factors That Increase Susceptibility

Patient factors that predispose to neuropathy development include 4:

• Pre-existing diabetes mellitus
• Prior history of peripheral neuropathy
• Smoking
• Retinopathy and nephropathy (particularly dialysis or post-transplant patients)
• Foot deformities
• Prior ulceration or amputation

Clinical Approach

Initial screening blood tests should include 1:

• Complete blood count
• Comprehensive metabolic profile
• Erythrocyte sedimentation rate
• Fasting blood glucose
• Vitamin B12 level
• Thyroid-stimulating hormone

The mechanisms involved depend on the specific agent used, patient's medical history (particularly diabetes), and duration of exposure and/or treatment doses 4. In approximately 20-25% of chronic polyneuropathies, no direct cause can be identified despite thorough evaluation 6.