Abstracts

Rationale: Hemimegalencephaly (HME) is a hamartomatous malformation involving one cerebral hemisphere, often resulting in treatment resistant seizures, intellectual disability, and autistic features. Hemispherectomy is the definitive treatment, but there is risk of high morbidity and mortality, especially when done in early infancy. Various preclinical studies have shown that dysregulation of the mTOR pathway has an integral role in the development of various epilepsy syndromes, including tuberous sclerosis complex (TSC), focal cortical dysplasia and HME. Recently, mTOR inhibitors were proven to effective in treating seizures in TSC.  Methods: We present a case of hemimegancephaly and treatment resistant epilepsy, was treated with Rapamycin (Sirolimus). The seizure frequency was obtained based on bedside nurse and or parents observation. The total seizure burden was calculated as the total amount of time occupied by electrographic seizures during the video-EEG monitoring.  Results: Baby girl was born at term with normal prenatal care and delivery. Seizures started at day 6 of life and refractory to 9 antiseizure medications and ketogenic diet since 3 weeks old. Her seizure initially was characterized by eye deviation to one side, stiffening of the limbs, with or without clonic movements of the right arm and leg, with or without increase in heart rate and reparatory rate. In the first 3 weeks,   she was given phenobarital, phenytoin , levetiractam and then on a continuous midazolam infusion for 2 weeks. The amplitude integrated electroencephalography (aEEG) showed about 50 seizures per day, with clusters of 5-10 seizure per hour. At 30 days old, a 4h EEG showed 26 seizures arising from right posterior quadrant region and the seizure burden was 27 %.  At 6 weeks of age, she was transferred to ward. At that time, she had frequent seizure, up to 68 clinical seizures a day.  She was having clusters of 5-10 seizures, lasting 1-5 hours. At 3 months of age, she developed new type of seizure characterized by facial flushing, increased heart rate and reparatory rate, and oxygen desaturation to 70’s. The duration of each seizure was prolonged to about 3-15 minutes. She has epilepticus status lasting more than 1 hour in most of days and requiring seizure rescue medications. She had no gains developmentally. The neurosurgery team met with the family and a tentative date for surgery at 3.5 months of age when  the risk of complications can be reduced. In anticipation for surgery, and to obtain seizure control, the patient’s primary neurologist has discussion with the family about an mTOR inhibitor. The family was in agreement, and Rapamycin (Sirolimus) started at age 3 months old. It was initiated at 0.3mg daily (0.06mg/kg) and increased to 0.35mg (0.07mg/kg) 10 days later. The highest level was 4.4. No side effects were noted. After 1 week of the initiation, she had more than 50% reduction in seizure frequency and total seizure burden and the duration of seizures decreased.   At two weeks, the parents felt that for the first time, she was making developmental gains. She also appeared brighter and more interactive. Due to her response to treatment, her hemispherectomy was deferred to when she was older with an increased weight. She had a functional hemispherectomy without any complications and is now seizure free. Histopathology shows focal cortical dysplasia type 2A. The brain tissue was sent out for genetic test and shows somatic  mTOR pathway mutation.  Conclusions: This case exemplifies how mTOR inhibitors should be considered as a treatment option for patients with HME and refractory epilepsy. Funding: none