Temporal association between adjunctive repetitive transcranial magnetic stimulation and seizure reduction in a pediatric patient with DNM1L-associated EMPF1: a case report

Background Encephalopathy, lethal, due to defective mitochondrial and peroxisomal fission 1 (EMPF1) is a rare, severe mitochondrial disorder characterized by acute-onset refractory seizures that rapidly progress to status epilepticus and are associated with a poor prognosis. Conventional therapies, including antiepileptic drugs and the ketogenic diet, exhibit limited efficacy. Although repetitive transcranial magnetic stimulation (rTMS) has shown promise in other forms of drug-resistant epilepsy, its potential role in managing EMPF1 remains unexplored. Case presentation A 7-year-old boy, previously healthy with normal development, presented with right-hand clonic movements and impaired consciousness, which progressed to status epilepticus. Brain MRI revealed diffuse cytotoxic edema involving the bilateral frontal, parietal, and temporal cortices, basal ganglia, and thalami. EEG recording showed generalized periodic spike-wave discharges with background slowing. Genetic testing identified a novel de novo DNM1L mutation (c.1949T > C, p.Leu650Pro), which was classified as likely pathogenic according to ACMG/AMP guidelines and provided strong support for the diagnosis of EMPF1. In addition to a regimen of antiepileptic drugs and a metabolic “cocktail,” 1-Hz rTMS (90% of the resting motor threshold, 40 trains daily) was applied over the left primary motor cortex on Day 16. Following initiation of this combined therapy, seizure frequency was temporally associated with a marked reduction, decreasing from ∼20 to 5–6 episodes/day after one day, 2–3 by Day 27 (12 days after rTMS initiation), and 0–1 by Day 36 (21 days after rTMS initiation). Despite this reduction in clinical seizure burden, the patient developed progressive pneumonia leading to sepsis and acute heart failure, and died on Day 65 (hospital day 65). Conclusions In this case, adjunctive rTMS applied alongside standard antiepileptic and metabolic “cocktail” therapy was temporally associated with a pronounced reduction in seizure frequency in a patient with DNM1L-associated EMPF1. This temporal association is hypothesis-generating and does not permit attribution of the observed seizure reduction to rTMS; further investigation in larger cohorts is warranted.