Epilepsy in children continues to be a large-scale medical issue, affecting approximately 4 in 1,000 children in each year. Epilepsy is defined as having two unprovoked, nonfebrile seizures. Of children diagnosed with epilepsy, up to 30% will become resistant to medications, a state we call “treatment resistant” or “medically refractory” epilepsy. These are children who have a less than 5% chance of being free from their seizures with medication alone.
We define medically refractory epilepsy as failure of two appropriately dosed and tolerated medications. Once the child is diagnosed with medically refractory epilepsy, standard of care is to refer them to a comprehensive pediatric surgery center such as the Neurosurgery program at Phoenix Children’s.
Epilepsy Evaluations
At referral, a series of tests are performed to evaluate the child’s candidacy for epilepsy surgery. These tests include a high-resolution structural MRI, video EEG, expert epileptologist clinical evaluation, neuropsychology evaluation, functional MRI, PET scans and sometimes magnetoencephalography (MEG). Following these tests, a team of neurologists, neurosurgeons, neuropsychologists and other professionals meet to review the results and decide what surgical options can be offered. These could include stereo EEG, surgery to disconnect or remove brain regions, or implanted neuromodulation devices such as vagus nerve stimulation (VNS), responsive neurostimulation (RNS) or deep brain stimulation (DBS).
Cortical Dysplasia
By far the most common entity encountered in pediatric epilepsy surgery is cortical dysplasia. Cortical dysplasia, in lay terms, is a developmental anomaly in which neurons do not mature and migrate the way they should in the cortex. This results in neurons that are misoriented, stuck in the wrong cortical layers or even white matter, and are in developmentally immature states. All these together can result in catastrophic epilepsy. Sometimes, these lesions can be seen on MRI and can be safely disconnected then removed. Sometimes they are very subtle on MRI or are not visible at all. In these cases, they are diagnosed through a biopsy under the microscope. All in all, surgery to cure epilepsy in children with cortical dysplasia can have success rates ranging from 50-80% depending on the location of the lesions, visibility on MRI and proximity to critically important brain structures.
One question that remains is what happens to children with cortical dysplasia who do not have complete resolution of their epilepsy following surgery. That is where genetics comes in. Over the course of the last few years, work both nationally and abroad has highlighted the importance of certain molecular pathways in the development of cortical dysplasia and the result on epilepsy. One critical pathway is termed the PI3K-AKT-mTOR pathway. This pathway, appreciated much earlier in children with tuberous sclerosis, is a hot area of scientific investigation. There is still more to learn about how disruptions in this pathway lead to cortical dysplasia and the phenotype of epilepsy.
New Developments
An exciting development has been the use of mammalian target of rapamycin (mTOR) inhibitors in children with cortical dysplasia and catastrophic epilepsy. Early results suggest that these medications can be safe and potentially effective when surgery is not enough. We recently wrapped up a phase 1 clinical trial and open-label extension, with publications forthcoming, using mTOR inhibitors in this patient population. This research opened the door to the use of prior molecular targeted therapy – approved by the Food and Drug Administration – in children with pathway disruptions and epilepsy.
My hope is that in my lifetime we have solid medical options for children who fail epilepsy surgery. Perhaps also in my lifetime, these medical options could supplant epilepsy surgery altogether. The future is bright.