Dr. Jensen is researching not only treatment of seizures but also prevention of the long-term effects of seizures. She noted that seizures early in life predict cognitive impairment, epilepsy, and other neurologic deficits. “We’re hoping to pick up biomarkers to know which babies are going to develop epilepsy later in life and which aren’t, and what might be the therapeutic targets,” she said. Research has uncovered numerous biochemical effects of early seizures, including posttranslational changes of receptors, transcriptional events, neuronal death, and inflammatory reactions. Other physiologic events include mossy fiber sprouting, gliosis, and even neurogenesis. Animal studies have observed that after a single seizure, the brain is permanently hyperexcitable, and a second seizure leads to hippocampal cell death. “You can approach this by saying that by treating the seizures, we expect to prevent these abnormalities,” Dr. Jensen said. “But what we and others have started to do is think about treating after the seizures, thinking about what we might use that can prevent the long-term consequences.”
Finally, looking again at the long term, Dr. Jensen warned of overaggressively targeting mechanisms that are valuable for brain development, and she raised concerns over the long-term effects of antiepileptic drugs. “Many antiepileptic drugs induce apoptosis during early development in animal models,” she said, “though this has never been shown in humans, and we’re not sure what it means. [Bittigau et al] showed that a single dose of valproate, phenytoin, or phenobarbital caused massive up-regulation of apoptosis. Interestingly, topiramate doesn’t cause this, nor do any of the AMPA receptor antagonists, nor levetiracetam or bumetanide.” She added, “This stage of development, where there’s a lot of excitation and a little bit of inhibition, is there for a reason. This is the critical window for plasticity and synaptogenesis. The trick is how to think about therapeutics without interfering with normal development, which is a huge challenge.”
—Rose Fox