Metformin remains a first-line therapy for type 2 diabetes mellitus. However, its use in patients with end-stage renal disease (ESRD), particularly those on dialysis, carries risks such as lactic acidosis and encephalopathy. Metformin-induced extrapyramidal syndrome accompanied by encephalopathy is rare. We report a 60-year-old man on peritoneal dialysis (PD), for glomerulonephritis who developed metformin-induced encephalopathy shortly after initiating the drug for new-onset diabetes. In addition to extrapyramidal symptoms, such as tremor in the right upper limb, the patient exhibited significant higher cortical dysfunction—manifested as markedly slowed responsiveness, lethargy, apparent apathy, psychomotor slowing, cognitive impairment, drooling, and failure to recognize familiar faces. These features reflect a severe neuropsychiatric phenotype that has rarely been emphasized in previous reports of metformin-associated encephalopathy. Brain magnetic resonance imaging showed symmetric basal ganglia hyperintensities with the "lentiform fork sign." Neurological symptoms persisted despite metformin discontinuation and only improved after transitioning to hemodialysis. A mild resting tremor remained at 24-month follow-up. This case illustrates metformin-induced extrapyramidal syndrome with encephalopathy in a patient with ESRD on dialysis. Proposed mechanisms include metformin-induced mitochondrial complex I inhibition, lactic acidosis exacerbating the accumulation of uremic toxins, and potential thiamine deficiency. This case highlights that metformin can precipitate severe encephalopathy even when initiated in patients with ESRD on PD. It is imperative to rigorously reevaluate metformin safety thresholds in ESRD patients and maintain a high vigilance for neurological symptoms in dialysis patients treated with metformin. Early recognition and prompt initiation of hemodialysis are essential for achieving optimal outcomes.
Ma et al. (2026) studied this question.