SEATTLE—Deep brain stimulation (DBS) can safely and effectively reduce the frequency of seizures in patients with medically refractory epilepsy, according to findings presented at the 62nd Annual Meeting of the American Epilepsy Society. Individuals who received DBS had a greater median improvement in seizure frequency than those in the control arm, and the degree of improvement appeared to be sustained over time. The findings from the first large randomized trial of DBS for epilepsy suggest that the procedure can be used selectively by clinicians to expand treatment options for patients who are refractory to antiepileptic drugs (AEDs), reported Robert S. Fisher, MD, PhD, Professor of Neurology and Director of the Comprehensive Epilepsy Center at Stanford University in Palo Alto, California.
The Stimulation of the Anterior Nucleus of the Thalamus in Epilepsy (SANTE) study was divided into four phases: three months of baseline; a double-blind phase of three months; an open-label phase of nine months; and long-term follow-up. At the end of the blinded phase, the stimulation group had a 37% median improvement in seizure frequency—compared with a 14.5% improvement for the control group—meeting the primary end point at a statistically significant P value of .038. By the end of the open-label period, a 40% median seizure reduction had been achieved, and during the last three months of long-term follow-up, there was a 64% median reduction of seizures. Approximately one in five participants in the trial had a greater than 90% improvement in their seizure frequency.
In addition, the investigators found that by the end of the open-label phase, both quality of life and seizure severity had improved. Of the five deaths that occurred during the study—one at baseline and four during the open-label period—none was attributed to electrical stimulation or to the implantation procedure. There were no clinically significant hemorrhages. In general, the stimulation was found to be well tolerated, although outcomes in several patients—particularly those with preexisting conditions—raised questions about depression, memory impairment, and anxiety that require further study.
Dr. Fisher expressed a cautious optimism that the findings represent a real breakthrough for the treatment of patients with epilepsy. “This study was indeed positive,” he said. “Stimulation was superior. The trial had a positive outcome of the controlled phase …, and by the end of the long-term follow-up, the seizure rate was reduced a little bit over one-third from baseline.”
The Significance of Stimulation Over Time
The primary objective of the study was to demonstrate that subjects in the DBS group would have a greater reduction in seizure frequency than those in the control group, particularly throughout the entire three-month double-blind phase. “However, pilot work and experience with other stimulation therapies suggest that stimulation might build up over time,” Dr. Fisher said. “Built into the analysis was the capacity to capture the significance of the stimulation building up by use over time.”
Among the 17 study sites, all in the United States, a total of 110 patients were implanted. Patients were ages 18 to 65, experienced more than six partial or secondarily generalized seizures per month, and had seizures that were refractory to more than three AEDs. Ineligible were those who were candidates for conventional epilepsy surgery.
During the three months of baseline, patients kept a daily diary of their seizures, and medications remained constant. All patients were then implanted with wires in the left and right anterior nucleus of the thalamus, leading to a dual- channel stimulator. Following implantation, patients were allowed to recover with the stimulator off for the first month, and at the start of the blinded phase, the stimulator was either turned on (at 5 volts, given in intervals of one minute on, five minutes off) or kept at 0 volts. Neither group could sense whether the stimulator was on.
After the three-month blinded phase, the open-label phase lasted for an additional nine months, during which the researchers kept medications constant but allowed limited changes of stimulation parameters. During long-term follow-up, the investigators could set stimulation to any safe parameter.
Regarding the one-to-one randomization schedule, Dr. Fisher emphasized two key points. “One is that this is a pretty severely affected group, with almost half having had vagus nerve stimulation and a quarter having had prior epilepsy surgery,” he said. “Despite being fairly young [mean age, 30], they had epilepsy for a majority of their life, for a lot of years. They were on a lot of antiepileptic medications. The second point is that the randomization worked.… [T]he control and stimulated groups are similar in their demographic features.”