Diabetic Peripheral Neuropathy

Symptoms

• Insidious onset, stocking-then-glove progression
• Sensory: numbness, tingling, burning, prickling, allodynia (pain from non-painful stimuli), hyperalgesia, lancinating pain
• Symptoms often worse at night
• Loss of protective sensation predisposes to unnoticed foot injury, ulceration, and Charcot arthropathy
• Motor: weakness late (intrinsic foot, then distal lower-extremity), foot drop occasional
• Autonomic: orthostatic hypotension, resting tachycardia, gastroparesis, neurogenic bladder, erectile dysfunction, gustatory sweating, anhidrosis of feet (predisposes to dry, cracked skin)
• Atypical syndromes: diabetic amyotrophy (proximal asymmetric leg weakness with pain), cranial mononeuropathies (CN III with pupil sparing, CN VI), thoracic radiculoneuropathy, treatment-induced neuropathy after rapid glucose lowering

Signs / physical exam

• Stocking-distribution decreased pinprick, light touch, vibration (128-Hz tuning fork), and proprioception
• Diminished or absent ankle reflexes (knee reflexes usually preserved early)
• 10-g Semmes-Weinstein monofilament insensate at one or more sites — high sensitivity for risk of foot ulceration
• Intrinsic foot muscle wasting, hammer/claw toes, pes cavus deformity (late)
• Romberg may be positive (large-fiber involvement)
• Look for foot ulcers, fissures, calluses, Charcot deformity
• Autonomic: postural BP drop, resting tachycardia, abnormal heart rate variability

Classic findings

Symmetric stocking-distribution sensory loss with absent ankle reflexes in a patient with diabetes.

Diagnostic criteria

ADA/Toronto Consensus: typical DPN = patient with diabetes and distal symmetric polyneuropathy attributable to diabetes after exclusion of other causes; supported by characteristic signs/symptoms and confirmed by nerve conduction studies (in atypical or research settings).

Labs

• Confirm diabetes and assess control: fasting glucose, A1c
• Exclude common alternative or coexisting causes: CBC, BMP, TSH, vitamin B12 (with MMA if borderline), serum/urine protein electrophoresis with immunofixation (especially in older patients or atypical features), LFTs
• Consider HIV, hepatitis C, Lyme, heavy metals, paraneoplastic antibodies if clinical suspicion
• Lipid panel (cardiovascular risk and triglyceride-related neuropathy)

Imaging

• Electrodiagnostic studies (NCS/EMG): not routinely required for typical DPN, but indicated for atypical features (asymmetric, predominantly motor, rapidly progressive, proximal involvement, areflexia, family history) to distinguish from CIDP, hereditary, or compressive neuropathies
• Foot exam with monofilament and tuning fork at least annually in all patients with diabetes (ADA/IWGDF recommendation)
• Skin biopsy for intraepidermal nerve fiber density and corneal confocal microscopy — research/specialty tools for small-fiber neuropathy

First-line

• Glycemic control — strongest evidence for delaying progression in type 1 (DCCT/EDIC); more modest effect in type 2 (UKPDS, ACCORD). Avoid hypoglycemia in autonomic neuropathy.
• Cardiovascular risk factor management: BP control (<130/80), statin therapy, smoking cessation, weight loss
• Foot care education: daily inspection, well-fitting footwear, no barefoot walking, podiatry care; annual comprehensive foot exam by clinician; offload pressure points
• Symptomatic treatment of painful DPN — FDA-approved or first-line agents (ADA 2022, AAN):
• • Pregabalin 150-600 mg/day in divided doses (FDA-approved; sedation, edema, weight gain)
• • Duloxetine 60-120 mg/day (FDA-approved; nausea, dry mouth, somnolence, hepatic caution)
• • Gabapentin 900-3600 mg/day in divided doses (off-label but widely used; sedation, dizziness, edema)
• • Tricyclic antidepressant — amitriptyline, nortriptyline 25-100 mg qhs (anticholinergic side effects, QT prolongation, orthostasis — caution in elderly and cardiac disease)
• • Tapentadol ER (FDA-approved) — opioid; consider only after non-opioid options exhausted
• Topical agents: capsaicin 8% patch (FDA-approved), topical lidocaine 5%

Second-line / adjunct

• Combination therapy if monotherapy insufficient (e.g., gabapentinoid + duloxetine, gabapentinoid + TCA)
• Tramadol short-term; avoid chronic opioids if possible (limited efficacy, dependence/overdose risk)
• Spinal cord stimulation (10-kHz high-frequency) — refractory painful DPN; FDA-approved 2021
• Treat autonomic complications: orthostatic hypotension (compression stockings, midodrine, droxidopa, fludrocortisone), gastroparesis (small frequent meals, metoclopramide — limit duration; prokinetics; gastric pacing), neurogenic bladder (timed voiding, intermittent catheterization), erectile dysfunction (PDE5 inhibitors)
• Address vitamin B12 deficiency (oral 1000 mcg/day or parenteral); ADA recommends periodic B12 screening in patients on chronic metformin
• Aldose reductase inhibitors and alpha-lipoic acid — modest evidence; not FDA-approved in the US
• Multidisciplinary diabetes care including podiatry, vascular surgery, and wound care for at-risk feet
• Smoking cessation counseling, alcohol reduction