Causes of Peripheral Neuropathy

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 1, 2
Up to 50% of diabetic peripheral neuropathy may be asymptomatic but still increases risk for complications 2

Bortezomib (proteasome inhibitor) causes predominantly sensory neuropathy, but motor impairment occurs in approximately 10% of cases with mild to severe distal weakness 1
Thalidomide is a major cause of treatment-related neuropathy in multiple myeloma patients 3, 4, 5
Vincristine causes motor neuropathy in approximately 10% of patients, ranging from grade 1-3 distal weakness to rare life-threatening grade 4 motor neurotoxicity 1
Taxanes (paclitaxel) and platinum compounds (oxaliplatin) primarily affect sensory fibers but can have motor components 6, 1
Metronidazole is a common antimicrobial cause that requires temporal association assessment and discontinuation when suspected 7
Anti-TNF agents can cause peripheral neuropathy and may worsen central demyelinating diseases 7

Vitamin E, thiamine, nicotinamide, and red-cell folate deficiencies should be excluded, particularly in patients with malabsorption or inflammatory bowel disease 7
Copper deficiency can cause peripheral neuropathy and should be considered in the differential 7

Plasma cell dyscrasias (particularly POEMS syndrome) cause neuropathy through direct effects 3, 4, 5
Light chain deposits (amyloidosis) lead to neuropathy through nerve infiltration 3, 4, 5
Cryoglobulinemia and monoclonal gammopathies should be screened 7
Autoimmune mechanisms can cause neuropathy, including in the context of inflammatory bowel disease 3, 4, 5
Hepatitis C infection (with cryoglobulins) can cause peripheral neuropathy 7

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) 1
Family or personal history of hereditary peripheral neuropathy predisposes patients to chemotherapy-induced neuropathy and should be assessed before treatment 6

Direct nerve compression (radicular or medullary) can cause neuropathy in multiple myeloma patients 3, 4, 5

Patient factors that predispose to neuropathy development include pre-existing diabetes mellitus 8, prior history of peripheral neuropathy 3, smoking 8, retinopathy and nephropathy (particularly dialysis or post-transplant patients) 8, foot deformities 8, and prior ulceration or amputation 8
The American Diabetes Association recommends screening for diabetes mellitus in patients with peripheral neuropathy 8

Impaired glucose tolerance can cause small fiber damage even before overt diabetes develops, highlighting the importance of screening for prediabetic states 9

Vitamin B12 deficiency causes both symptomatic and asymptomatic small fiber loss similar to diabetes mellitus, with histopathological confirmation of reduced intraepidermal nerve fiber density 10
Alcohol is a common neurotoxin that must be assessed in all patients 10
HIV infection should be screened in at-risk populations 10
Chronic kidney disease and dialysis-related complications contribute to small fiber neuropathy development 10

Nearly half (41-48%) of small fiber neuropathy cases remain idiopathic despite comprehensive evaluation, representing a diagnosis of exclusion after thorough workup 11
The American Diabetes Association emphasizes that up to 50% of diabetic peripheral neuropathy may be asymptomatic, yet these patients remain at high risk for complications including foot ulceration 11
Small fibers constitute 70-90% of peripheral nerve fibers and are damaged earliest in diabetic neuropathy, often before conventional electrophysiology shows abnormalities—relying solely on nerve conduction studies will miss early small fiber-predominant disease 9