PHILADELPHIA—Neurostimulation may modify the course of epilepsy, but the data are not robust enough to prove the conclusion definitively, according to an overview of recent literature presented at the 69th Annual Meeting of the American Epilepsy Society. Studies of animals with epilepsy and of patients with epileptic encephalopathies also suggest the potential for disease modification, but these data are not conclusive, either.
Disease modification may be understood as modification of the expression of the disease, modification of the course of the disease, or modification of the comorbidities associated with the disease. One methodologic difficulty of research into disease modification is that it occurs over long periods of time, and not simply after a few doses of treatment. Furthermore, the methods of measurement and the statistical approach that investigators choose strongly influence the magnitude of the treatment effect. “Disease modification stands to be a great challenge for a long time to come,” said Andrew J. Cole, MD, Professor of Neurology at Harvard Medical School and Director of the Epilepsy Service at Massachusetts General Hospital in Boston.
Encouraging Data on Neurostimulation
Despite the challenges, research indicates that neurostimulation may have the potential to modify epilepsy. In the SANTE trial, Fisher et al studied the Medtronic DBS System, which provides bilateral stimulation of the anterior nuclei of the thalamus, in a double-blind, randomized trial of adults with medically refractory partial seizures. At the end of the three-month blinded phase of the trial, reduction in seizures was 29% greater among patients who received stimulation, compared with controls. At three months after surgery, median seizure frequency decreased by 40.4% for active patients and by 14.5% for controls. All patients subsequently received unblinded stimulation for at least two years. At two years, median percent reduction in seizure frequency was 56%, 54% of patients had a seizure reduction of at least 50%, and 14 patients were seizure-free for at least six months.
The investigators continued to follow study participants in an open-label fashion for three more years and published their results in 2015. The population’s median percent seizure reduction from baseline was 69% at five years, compared with 41% at one year. At five years, 68% of patients had a reduction in seizure frequency of at least 50%, compared with 43% of patients at one year. In addition, 16% of participants were seizure-free for at least six months during the five years of follow-up.
“What we see here is potential, reasonable evidence for the occurrence of disease modification,” said Dr. Cole. “These are patients who had … bad epilepsy with 30 to 40 seizures a month, who, over many years of a particular form of treatment, seem to be getting better and better, as if the nature of their disease is changing.”
In another study, Cukiert et al examined nine adults who had received three years of deep brain stimulation for refractory epilepsy. For most patients, seizure frequency decreased significantly during active stimulation. The investigators followed participants for six months after their devices’ batteries were depleted. Seizure frequency did not change for two participants after battery depletion. Seizure frequency increased for five patients, but remained lower than it had been at baseline. Two patients returned to their baseline level of seizure frequency after battery depletion.“If you still have a reduction in seizure frequency after the device is no longer active, it’s stronger evidence that the biology has been modified,” said Dr. Cole. “There appears to be a trend for persistence of reduced seizure frequency even after the battery runs out, suggesting that indeed, long-term stimulation treatment may modify the biology of the disease.”
Investigators found similar results for the responsive neurostimulation system (RNS). In a study by Heck et al, 191 patients with medically intractable partial onset seizures were implanted with an RNS and randomized to five months of active or sham stimulation. All participants then received open-label stimulation for a total of two years of post-implant follow-up. At the end of the blinded period, the active group had a 37.9% reduction in seizures, compared with a 17.3% reduction among controls. During the open-label phase, the median percent reduction in seizures was 44% at one year and 53% at two years. “This is an example of a plasticity response, not purely a straightforward symptomatic response,” said Dr. Cole.
Persistent Seizure Reduction in Mice
A study of rodents provides a “robust example of a demonstration of disease modification,” said Dr. Cole. Blumenfeld et al examined WAG/Rij mice, which have a form of childhood absence epilepsy. When the mice were 21 days old, which is considered the end of their juvenile phase, they were randomized to receive water or water mixed with ethosuximide. Animals treated with water had frequent bursts of spike and wave over 20-minute periods.