What are the main causes of peripheral neuropathy?

1. Why diabetes looms largest — the epidemic that explains most cases

Diabetes remains the single most frequent and reliably measured cause of peripheral neuropathy, accounting for large proportions of clinical series and population studies; estimates range from affecting about half of people with neuropathy in U.S.-focused reviews to comprising the majority of diagnosed cases in cohort analyses ^{[4] [2]}. The biological mechanism centers on hyperglycemia-driven metabolic injury, including glycation and microvascular ischemia, which preferentially damages long peripheral nerves and produces the typical distal symmetric sensory loss. Contemporary sources emphasize that glycemic control and metabolic risk management reduce incidence and progression, which frames prevention strategies in public health and primary care ^{[1] [4]}. This central role of diabetes explains why demographic shifts in obesity and diabetes prevalence directly elevate neuropathy burden in many countries ^[5].

2. Cancer treatments and infections: frequent iatrogenic and infectious culprits

Chemotherapy-induced peripheral neuropathy is a major, sometimes underappreciated contributor, affecting roughly one-third of cancer patients exposed to neurotoxic agents, while infectious diseases such as HIV and Lyme disease produce characteristic neuropathies in substantial patient subsets ^{[2] [6]}. These neuropathies often differ in course from diabetic neuropathy: chemotherapy neuropathy can be dose-dependent and partially reversible, whereas infection-associated neuropathies may respond to targeted antimicrobial or immune therapies when diagnosed early. Public health and oncology stakeholders emphasize surveillance and dose-modification strategies to balance curative cancer treatment against lasting neurologic harm, a tradeoff documented in recent analyses ^{[2] [6]}.

3. Alcohol, toxins, vitamins and the classic preventable causes

Excessive alcohol use, long-term exposure to industrial or prescription toxins, and nutritional deficiencies — particularly B-vitamin deficits — remain classic, largely preventable causes of peripheral nerve damage cited across clinical reviews ^{[6] [7]}. These etiologies share a common public-health implication: lifestyle modification, workplace protections, and nutritional screening can avert or improve many cases. Health systems that prioritize screening for alcohol misuse, occupational exposures, and vitamin status in at-risk populations can reduce the proportion of neuropathies categorized as progressive or idiopathic ^{[6] [7]}. The sources also highlight that these causes often coexist with metabolic disease, complicating attribution unless clinicians take a comprehensive exposure history ^[8].

4. Autoimmune, inflammatory and vascular mechanisms — treatable but complex

Autoimmune and inflammatory conditions (for example, Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, rheumatoid conditions, and vasculitides) produce neuropathies that are mechanistically distinct and often amenable to immunomodulatory therapies when recognized ^{[9] [4]}. Vascular disease and ischemia also contribute, particularly in patients with peripheral artery disease or other microvascular disorders, compounding nerve injury in metabolic disease. The literature stresses that identifying inflammatory markers or characteristic electrophysiologic patterns changes management from symptomatic care to disease-modifying treatment, which makes accurate diagnostic workups and referral to neurology essential ^{[9] [4]}.

5. Genetics and idiopathic cases — a sizable minority that challenges clinicians

Hereditary neuropathies such as Charcot–Marie–Tooth disease and Friedreich ataxia account for a meaningful subset of neuropathy presentations, especially in younger patients or those with family histories; meanwhile, idiopathic neuropathy remains common, with some series reporting roughly a quarter of cases unexplained after routine evaluation ^{[6] [2]}. The presence of idiopathic cases signals limitations in current diagnostic testing and varying access to genetic evaluation, and recent commentaries call for broader use of genetic panels and more comprehensive metabolic screening to reduce the unexplained fraction ^{[2] [8]}. Policy and payer incentives around diagnostic sequencing will influence how rapidly these idiopathic proportions decline.

6. The big picture: multiple overlapping causes require systematic evaluation

Contemporary syntheses and cohort studies converge on a practical conclusion: peripheral neuropathy is rarely traceable to a single cause in isolation; multiple overlapping factors — metabolic, toxic, infectious, autoimmune, genetic — commonly coexist, requiring stepwise, protocol-driven evaluation ^{[1] [3] [5]}. Public-health emphasis on diabetes prevention, safer chemotherapy protocols, occupational safeguards, nutritional screening, and improved access to electrophysiology and genetic testing will change the distribution of causes over time. Clinicians should prioritize reversible and high-prevalence causes first, while policymakers should fund prevention and diagnostic capacity to lower the overall burden ^{[1] [2] [3]}.