Metformin remains a cornerstone first-line therapy for type 2 diabetes mellitus due to its efficacy, low cost, and favorable safety profile in patients with preserved renal function. However, its use is contraindicated in severe renal impairment (eGFR <30 mL/min/1.73 m²) owing to the risk of accumulation and metformin-associated lactic acidosis (MALA), with encephalopathy representing a rarer neurological manifestation. This report details a 44-year-old woman with type 2 diabetes, hypothyroidism, insomnia, hypertension, and end-stage diabetic nephropathy requiring maintenance hemodialysis three times weekly. One month after initiating immediate-release metformin 1000 mg/day at a primary care clinic, she presented to the emergency department with two days of dysarthria and generalized weakness. She was slightly somnolent but communicative, exhibited difficulty maintaining posture, gait instability, and no focal motor or sensory deficits.
Laboratory evaluation revealed severe metabolic acidosis (pH 7.197, bicarbonate 11.7 mmol/L, base excess -15.7 mmol/L), marked hyperlactatemia (12.4 mmol/L), hyperkalemia (6.2 mEq/L), and advanced renal dysfunction (creatinine 7.4 mg/dL, eGFR 5.4 mL/min/1.73 m²). Brain CT showed hypodensity in bilateral basal ganglia, while MRI demonstrated T2/FLAIR hyperintensities consistent with the “Lentiform fork sign,” a characteristic finding in some metabolic encephalopathies.
Metformin was immediately discontinued, and emergent hemodialysis was initiated, followed by resumption of maintenance sessions. Clinical improvement was rapid: dysarthria resolved by hospital day 5, gait disturbance partially improved (residual unsteadiness allowing slow ambulation), and follow-up MRI on day 14 confirmed resolution of basal ganglia abnormalities. She was transferred to a rehabilitation facility on day 35 for ongoing mobility support.
The authors attribute the encephalopathy to metformin’s inhibition of mitochondrial complex I, promoting anaerobic metabolism, lactate accumulation, and selective vulnerability of basal ganglia mitochondria. Despite MALA incidence of ~10 per 100,000 patient-years, encephalopathy remains underrecognized. This case underscores the importance of medication reconciliation in renal impairment, awareness of clinical (neurological symptoms with acidosis/hyperlactatemia) and imaging features, and prompt intervention with hemodialysis for favorable outcomes in this rare, potentially serious adverse effect.
