diabetic polyneuropathy

**Definition/Epidemiology**: Diabetic peripheral neuropathy (DPN) is the most common form of diabetic neuropathy, affecting ~50% of long-standing diabetics. The typical form is chronic, length-dependent, distal symmetric sensorimotor polyneuropathy. It occurs in both type 1 and type 2 DM, and may be present at diagnosis in type 2 because of prior undetected hyperglycemia.

**Pathophysiology**: - Chronic hyperglycemia drives the polyol pathway: aldose reductase converts glucose to sorbitol, which accumulates (sorbitol is poorly diffusible). This causes osmotic injury and depletes NADPH, which lowers glutathione and increases oxidative stress. Schwann cells and nerves are affected, as are the lens (cataracts) and the retinal pericytes. - Advanced glycation end-products (AGEs) damage proteins and vessels. - Microvascular disease of the vasa nervorum causes endoneurial ischemia (basement membrane thickening). - Other contributors are oxidative stress, mitochondrial dysfunction, inflammation, and dyslipidemia/obesity (important in type 2). - Pathology shows axonal degeneration, with segmental demyelination. Small and large fibers are both involved.

**Clinical Features**: - Onset is distal and symmetric, starting in the toes and feet and progressing proximally. Once symptoms reach the knees, the hands become involved, producing the "stocking-glove" distribution. - Small fiber involvement (Aδ and C fibers) causes loss of pain and temperature sensation, plus burning, stabbing, or electric pain and allodynia, often worse at night. - Large fiber involvement causes loss of vibration, proprioception, and ankle reflexes. It leads to sensory ataxia (positive Romberg) and a risk of falls. - Motor involvement is late. It causes intrinsic foot muscle atrophy, hammer toes, and pes cavus. - Complications: painless foot ulcers (neuropathic ulcers on pressure points, such as the plantar metatarsal heads), Charcot neuroarthropathy (a neuropathic joint with a "rocker-bottom" foot), osteomyelitis, and amputation. - Autonomic involvement (a distinct but frequently coexisting form) includes gastroparesis, orthostatic hypotension, resting tachycardia, erectile dysfunction, neurogenic bladder, and hypoglycemia unawareness.

**Other diabetic neuropathies (differential on boards)**: - Mononeuropathy/mononeuritis multiplex: acute, due to microvascular infarct. Examples are CN III palsy that is "pupil-sparing" (ptosis and "down and out" eye with a normal pupil), CN VI palsy, and carpal tunnel syndrome. - Diabetic amyotrophy (lumbosacral radiculoplexus neuropathy): asymmetric thigh pain, weakness, and wasting. - Truncal radiculopathy: pain in a thoracoabdominal dermatomal pattern.

**Diagnosis**: This is mainly clinical. Use a 10-g monofilament test plus one other test (128-Hz tuning fork for vibration, pinprick, temperature, or ankle reflexes), done annually in type 2 DM and starting 5 years after diagnosis in type 1 DM. Nerve conduction studies/EMG are reserved for atypical presentations (asymmetric, rapid, or predominantly motor). Exclude other causes: B12 deficiency (especially with metformin use), hypothyroidism, alcohol, uremia, CIDP, and paraproteinemia/monoclonal gammopathy, medications (e.g., chemotherapy, isoniazid), and HIV.

**Management**: - Prevention/slowing progression: tight glycemic control (strongest effect in type 1 DM; modest in type 2 DM). Avoid very rapid HbA1c drops, which can cause treatment-induced neuropathy. - Painful neuropathy, first line: gabapentinoids (pregabalin, gabapentin), SNRIs (duloxetine, venlafaxine), TCAs (amitriptyline), and sodium channel blockers (e.g., carbamazepine, a commonly tested option). Topical capsaicin or lidocaine is an alternative. Pregabalin and duloxetine are FDA-approved for DPN pain. Tapentadol is also approved, but opioids are generally avoided. - Foot care: daily foot inspection, proper footwear, podiatry referral for high-risk feet, and prompt treatment of ulcers. - Note that glycemic control does not reverse established neuropathy, and none of the symptomatic therapies are disease-modifying.

**High-yield pearls**: - It is the most common cause of neuropathic foot ulcers and non-traumatic lower extremity amputation. - The polyol pathway (aldose reductase/sorbitol) is a classic Step 1 mechanism. Aldose reductase inhibitors (e.g., epalrestat, available only in some countries) have been studied. - Painless ulcer + diabetes → neuropathy. Charcot foot is another classic association. - Always check B12 in a metformin-treated patient with neuropathy.