diabetic peripheral neuropathy

**Definition:** Length-dependent, symmetric distal sensorimotor polyneuropathy attributable to diabetes after excluding other causes. It is the most common form of diabetic neuropathy (others: autonomic, mononeuropathies, radiculoplexopathy/amyotrophy).

**Pathophysiology:** - Chronic hyperglycemia drives the **polyol pathway**: aldose reductase converts glucose to sorbitol, which accumulates (osmotic injury). NADPH depletion reduces glutathione regeneration, causing oxidative stress. Sorbitol is further converted to fructose by sorbitol dehydrogenase. - **Advanced glycation end-products (AGEs)** damage nerve proteins and vessels. - **Microvascular disease:** thickening of the basement membrane and endothelial dysfunction of the vasa nervorum cause nerve ischemia. - Other contributors: protein kinase C activation, mitochondrial dysfunction, inflammation, and dyslipidemia/obesity (also a factor in prediabetes and type 2 DM). - Pathology: axonal degeneration (small and large fibers) with segmental demyelination. Small unmyelinated C and thin Aδ fibers are affected early.

**Clinical features:** - Onset is insidious, with a **symmetric "stocking-glove"** distribution beginning in the toes/feet and progressing proximally. Hands are involved once symptoms reach the mid-calf/knee. - **Small-fiber involvement:** burning, stabbing, or electric pain, allodynia, and loss of pain and temperature sensation. Pain is often worse at night. - **Large-fiber involvement:** loss of vibration and proprioception, absent ankle reflexes, sensory ataxia, and a positive Romberg sign. - Motor involvement is late: distal weakness and intrinsic foot muscle atrophy, causing hammer toes and claw toes. - **Complications:** painless foot ulcers (from repetitive trauma and loss of protective sensation), infection/osteomyelitis, **Charcot neuroarthropathy** (painless destruction of the midfoot joints), and lower-extremity amputation. DPN is the leading cause of non-traumatic amputation, together with PAD. - Related autonomic neuropathy: gastroparesis, orthostatic hypotension, erectile dysfunction, neurogenic bladder, resting tachycardia, and hypoglycemia unawareness.

**Diagnosis (clinical):** - Screen at diagnosis in type 2 DM and 5 years after diagnosis in type 1 DM, then annually. - Bedside tests: **10-g monofilament** (loss of protective sensation), 128-Hz tuning fork (vibration), pinprick, temperature, and ankle reflexes. - Exclude other causes: B12 deficiency (especially with metformin use), hypothyroidism, alcohol, uremia, medications (e.g., chemotherapy, isoniazid), paraproteinemia, and CIDP. Check B12, TSH, CBC, CMP, and SPEP as indicated. - Nerve conduction studies/EMG are generally not required for typical presentations; they are used for atypical or rapidly progressive cases. They show decreased amplitudes (axonal) with mildly slowed velocities.

**Management:** - **Prevention/slowing:** tight glycemic control (most effective in type 1 DM; modest benefit in type 2 DM), along with BP and lipid control. - **Neuropathic pain, first line:** duloxetine (SNRI), pregabalin or gabapentin (α2δ calcium channel ligands), TCAs (amitriptyline), and sodium channel blockers. Topical capsaicin or lidocaine patches are adjuncts. Opioids (including tramadol/tapentadol) are not recommended. - **Foot care:** daily foot inspection, proper footwear, podiatry referral, and prompt ulcer treatment. - Rapid, intensive glycemic improvement can cause **treatment-induced neuropathy** (insulin neuritis), an acute painful small-fiber and autonomic neuropathy.

**High-yield associations/differentials:** - Stocking-glove sensory loss in a diabetic is DPN until proven otherwise. - **Diabetic mononeuropathy:** CN III palsy with a **pupil-sparing** pattern (ischemic injury to the central fibers), plus CN VI and carpal tunnel syndrome. - **Diabetic amyotrophy (lumbosacral radiculoplexus neuropathy):** asymmetric thigh pain, weakness, and atrophy. - **Thoracic radiculopathy:** truncal pain. - **Step 1 pearl:** Schwann cells and pericytes contain aldose reductase. Tissues with aldose reductase and little sorbitol dehydrogenase (lens, retina, kidney, Schwann cells) accumulate sorbitol, which explains cataracts, retinopathy, nephropathy, and neuropathy. - **Step 2 pearl:** The next step for a diabetic with new foot numbness is a monofilament exam and B12 check (especially on metformin). Tight glycemic control is the main preventive measure.