Empagliflozin in Lafora disease: A first-in-human 6-month pilot study with electroclinical and FDG-PET findings

OBJECTIVE: Lafora disease (LD) is a rare, fatal neurodegenerative epilepsy with no approved treatments. Empagliflozin, a sodium-glucose cotransporter-2 (SGLT2) inhibitor, has shown neuroprotective actions in preclinical models through modulation of glycogen metabolism, induction of a pseudo-ketogenic state, improved mitochondrial efficiency, and reduction of excitatory neurotransmission. Based on this rationale, we conducted a first-in-human pilot study of empagliflozin in two genetically confirmed LD patients. METHODS: Two patients with genetically confirmed LD received empagliflozin 10 mg/day for 6 months. Serial assessments included safety and tolerability, seizure frequency, myoclonus severity, electroencephalographic findings, neuropsychological and motor evaluations, brain MRI, and quantitative FDG-PET with regional Z-score analysis. RESULTS: Empagliflozin was safe and well tolerated, with no serious adverse events. Seizure frequency, myoclonus, and overall clinical status remained largely stable over 6 months, although some neuropsychological and motor measures showed variable changes between patients. EEG background activity and spike index were largely unchanged. Brain MRI showed stable mild cortical atrophy in both patients. In contrast, FDG-PET revealed progressive and spatially expanding cerebral hypometabolism in both patients, with worsening regional Z-scores, particularly in the parietal and precuneus regions. SIGNIFICANCE: In this first-in-human, 6-month pilot study, empagliflozin showed acceptable short-term safety and feasibility in LD, but no definitive conclusions on efficacy can be drawn. The dissociation between relative electroclinical stability and progressive metabolic impairment suggests that quantitative FDG-PET may represent a sensitive biomarker for monitoring disease trajectory in this ultra-rare epilepsy.