BALTIMORE—Since 2004, 13 separate animal studies have found that epilepsy can be prevented or modified before seizure onset, said Asla Pitkänen, MD, Professor of Neurobiology at the University of Eastern Finland in Kuopio.
“These are experiments where treatment has been started before epilepsy onset, and they have had some positive effect on epileptogenesis,” she said. “They have been done in status epilepticus models, in traumatic brain injury models, and in genetic models. When you look at their mechanisms of action, you see that there is no general pattern. This is good news, because we probably have a large number of targets that can help prevent epileptogenesis.”
Dr. Pitkänen described experimental research on disease-modifying treatments for epilepsy at the 65th Annual Meeting of the American Epilepsy Society. She also discussed the possibility of translating this research into clinical work.
Modifying Epilepsy
Disease-modifying treatments for epilepsy would differ from current antiepileptic treatments, which generally are aimed only at preventing seizures, Dr. Pitkänen explained. The new treatments would affect both the clinical outcomes and the underlying pathology of the condition and/or its comorbidities. In addition, they would have a finite duration and prevent signs and symptoms even after their withdrawal.
Research into disease-modifying treatments for epilepsy has focused on antiepileptogenesis—that is, countering epileptogenesis, the generation of tissues capable of generating spontaneous seizures. Epileptogenesis can include such changes as neurogenesis, neurodegeneration, inflammation, and mossy fiber sprouting. As epileptogenesis begins during the development of an epileptic condition but progresses even after the condition is established, antiepileptogenesis might begin either before or after seizure onset.
Antiepileptogenesis can have any of three goals: complete prevention of epilepsy, modification of the condition (halting its progression or causing seizures to become milder, less frequent, shorter, or less severe), or cure. “The ultimate goal should be cure, meaning that there’s a complete and permanent reversal of epilepsy such that no seizures occur even after treatment is withdrawn,” said Dr. Pitkänen.
She went on to describe a hypothetical example of epilepsy disease modification. “Let’s take a traumatic brain injury patient who has a temporal lobe contusion,” she said. “Let’s say that he or she is eventually going to develop an ictogenic network in the hippocampus. And maybe, because of the contusion, he or she is going to develop a comorbidity network in a laterally located temporal area. If we put this patient on disease-modifying treatment, we hope that this ictogenic network never develops. The treatment may or may not do anything to the comorbidity network.”
Antiepileptogenesis Success Stories
Of the various disease-modifying treatments for epilepsy that have shown success in animal models, two have had particularly impressive results—gene therapy and rapamycin.
Gene therapy prior to seizure onset has been used to supplement two nerve tissue growth factors: fibroblast growth factor-2 (FGF-2) and brain-derived neurotropic factor (BDNF), said Dr. Pitkänen. Researchers induced status epilepticus in animals and, days later, injected vectors expressing FGF-2 and BDNF into the hippocampi of some animals and empty vectors into the hippocampi of control animals. Eventually, the treated animals showed protection of inhibitory neurons and normalized neurogenesis, as well as reductions in inflammation, mossy fiber sprouting, and seizure frequency, compared with controls.
“Recently, antiepileptic drugs have shown surprising antiepileptogenic effects in some genetic models,” Dr. Pitkänen added. In multiple studies conducted over the past year, rats with genetic predispositions to epilepsy have benefited from long-term therapy with such drugs before seizure onset. Levetiracetam, ethosuximide, zonisamide, and vigabatrin all reduced absence seizures in such rats, and levetiracetam also reduced the rats’ tonic convulsions. However, “there is overwhelming evidence that antiepileptic drugs don’t really prevent epileptogenesis in acquired epilepsy models,” Dr. Pitkänen added. “Why they would work in genetic models is a new and exiting field of research.”
Rapamycin treatment before seizure onset has alleviated epilepsy by blocking the mammalian target of rapamycin pathway, Dr. Pitkänen noted. In many epilepsies, the activation of this pathway causes the proliferation, survival, and death of various cells. But rapamycin has blocked these changes in animal models, stabilizing seizure frequency, normalizing brain weight, and reversing pathology. The treatment was effective in rats and/or mice with epileptogenesis induced by tuberous sclerosis, cortical dysplasia, status epilepticus, and traumatic brain injury.
Other disease-modifying treatments used successfully before seizure onset include atipamezole, celecoxib, alpha 4 integrin–specific antibody, erythropoietin, parecobix, neuron restrictive silencer element–sequence decoy oligodeoxynucleotides, rimonabant, minozac, and hypothermia.
Although researchers have yet to find evidence that epilepsy can be cured, rapamycin has had beneficial effects following seizure onset, said Dr. Pitkänen. In animal models of both genetic and acquired epilepsy, late initiation of the drug reduced seizure occurrence and interictal spiking, although seizures returned following drug discontinuation. Researchers “could see the partial reversal of pathology—but not as complete as what they could see when the treatment was started before epilepsy onset,” Dr. Pitkänen said. Furthermore, three small-cohort studies have suggested that rapamycin can benefit humans following the onset of seizures caused by tuberous sclerosis.