LRPN is an immune mediated neuropathy characterized by unilateral or asymmetrical lower limb weakness, pain, prickling, and sensory loss. Initially, it was thought to occur only in people with diabetes mellitus (DLRPN.), but the disorder can also affect people without diabetes, known as nondiabetic LPRP. (NDLRPN). The pathophysiology of LRPN is not been fully elucidated. Several pathologic studies have shown evidence of ischemic injury and micro vasculitis of nerve and up regulation of inflammatory mediators and nerves for patient with LRPN, which makes LRPN and a nonsystemic vasculitic neuropathy. Diabetes mellitus is a definite risk factor, but how diabetes triggers an autoimmune attack to roots, plexus, and nerves are still largely unknown. In addition, the influence of anthropomorphic variables or other comorbidities on LRPN such as HTN, stroke, hyperlipidemia, dementia, obesity, and other autoimmune disorders are associated. Many of these variables are part of the metabolic syndrome.

DM (chronic hyperglycemia) may induce neuronal damage by several mechanisms, including formation of advanced glycation end-products, increased oxidative stress, mitochondrial dysfunction, and activation of the polyol and hexosamine pathways. Rapid glycemic changes may led to neuronal apoptosis due to glucose deprivation and microvascular neuronal damage due to recurrent hypoglycemia.

Hyperlipidemia induces excessive fatty acid oxidation, which generates reactive species of oxygen and systemic and local inflammation by macrophage activation, with subsequent cytokine and chemokine production; this may injure the peripheral nervous system, especially the Schwann cells.

Metabolic syndrome and diabetes mellitus are associated with accumulation of neurotoxic deoxysphingolipids that may induce neuronal apoptosis. Although none of these mechanisms seem to directly cause LRPN it is postulated that metabolic mediated peripheral nerve injury may trigger an inflammatory response against the roots, plexus, and nerves, manifesting as LRPN. This may relate to rapid glycemic change as can occur in DLRPN and has been shown to occur in treatment induced diabetic neuropathy.

Comorbid autoimmune disorders that are commonly encountered are autoimmune thyroiditis, inflammatory bowel disease, and type 1 diabetes mellitus. It is unclear whether type 1 diabetes mellitus is a risk factor because of the diabetic state or because of its autoimmune pathogenesis. Genetic predisposition is likely to play a role in the autoimmunity, which may explain autoimmune disorders "occurring with an individual and family. HLA is the most reported genetic factor associated with several autoimmune diseases, being the most associated with type 1 diabetes mellitus, rheumatoid arthritis, celiac disease, ankylosing spondylitis, and multiple sclerosis. History of stroke and obesity (increased BMI) are also risk factors for elevated LRPN. Patient with LRPN have a particular genetic predisposition for developing this neuropathy when challenged by these metabolic factors.