Tantalizing hints support the possibility that disease modification of epilepsy is possible, but while the best evidence available today for disease modification may be “very encouraging and strongly suggestive,” it also remains low-level evidence drawn from modest numbers of patients, Dr. Andrew J. Cole said during the annual meeting of the American Epilepsy Society.
The upshot is that proving disease modification is feasible for some epilepsy types “stands to be a great challenge for a long time to come,” said Dr. Cole, professor of neurology at Harvard Medical School and director of the epilepsy service at Massachusetts General Hospital, both in Boston.
|Mitchel L. Zoler/Frontline Medical News
Dr. Andrew J. Cole
Dr. Cole started by defining disease modification: A treatment that modifies a disease’s expression, course, severity or duration, or modifies comorbidities integral to the disease. These effects need not be mutually exclusive, he added. Another issue about disease modification is that it presumably takes a long time to happen, which makes it harder to recognize. “Disease modification likely happens over the long term, which produces a severe methodological challenge,” Dr. Cole said.
Perhaps the best example of what appears to be disease modification of epilepsy are the long-term outcomes of patients with severe disease – 30 or more seizures a month – who receive long-term treatment with deep brain stimulation (DBS). These patients “seem to get better and better over several years [of treatment], as if their disease was changing,” he said.
For example, both the short- and long-term follow-up of patients enrolled in the Stimulation of the Anterior Nucleus of the Thalamus for Epilepsy (SANTE) trial, which enrolled 157 patients, showed that over time continued DBS linked with a steady decrease in seizure numbers. Recently published long-term follow-up results showed that seizure reduction grew from an average drop of 41% from baseline numbers after 1 year of DBS to an average reduction from baseline of 69% after 5 years (Neurology. 2015 Mar 10;84:1017-25).
A similar pattern of this DBS effect came in 2-year follow-up results from the 191-patient pivotal trial for the responsive neurostimulation system, which showed a 44% reduction, compared with baseline in seizure incidence after 1 year and a 53% reduction after 2 years (Epilepsia. 2014 March;55:432-41). Once again, the findings suggest “a plasticity response and not a purely symptomatic response,” Dr. Cole said.
He also cited findings from two additional, much smaller series of patients who stopped prolonged treatment with DBS and continued to have low seizure rates, compared with the incidence before DBS began. In short, observations from several series of patients who underwent DBS make a “reasonable case for disease modification by suggesting disease modification can occur,” Dr. Cole said.
He cited two additional lines of evidence: a rat model of early treatment for spike-wave epilepsy (Epilepsia. 2008 Mar;49:400-9), and studies of patients with epileptic encephalopathy that have shown associations between early treatment and better cognitive outcomes regardless of the type of treatment patients received (Epilepsia. 2015 Oct;56:1482-5). One limitation of the epileptic encephalopathy examples is the difficulty, if not impossibility. of conducting randomized trials to truly test the hypothesis that treatment can be disease modifying. “The big problem is distinguishing an anticonvulsant effect of treatment from a disease-modifying antiepileptogenic effect,” Dr. Cole said.
He proposed a clinical setting where it’s possible to envision a randomized clinical trial that could test whether a disease-modifying effect occurs: Prophylactic treatment of people who have experienced brain insults known to potentially trigger epilepsy, such as head trauma or stroke. So far, this approach has not been used to test possible disease-modifying treatments. Although such studies are plausible they would also be limited by the number of patients required to produce statistically meaningful results.
Dr. Cole estimated that based on assumptions of epilepsy incidence following various types of brain insults and the possible efficacy of a disease-modifying intervention, such trials could require anywhere from several hundred to several thousand patients, with price tags ranging from more than $10 million to more than $100 million per study. Plus, “even if we had success, [the treatment] would be relevant to a relatively small fraction of patients with epilepsy,” he said.
Dr. Cole said that he has been a consultant to Precisis, NeuroPace, and Nestec.