In a recent study of 144 patients who had undergone VNS implantation, 10 patients were seizure free for more than 1 year post implantation, 89 patients experienced seizure improvement, and no changes were observed in 45 patients. "Stepwise multivariate analysis showed that unilateral interictal epileptiform discharges [IEDs], cortical dysgenesis, and younger age at implantation were independent predictors of seizure freedom in the long-term follow-up," they wrote (Seizure 2010;19: 264-8).
Most of the adverse events associated with VNS therapy, such as hoarseness and cough, tend to be mild and are stimulation related, Dr. Ben-Menachem explained. "Typically, they occur only during stimulation and they generally diminish over time on their own, or they may be diminished or eliminated by adjustment of the parameter settings."
Programmed Deep Brain Stimulation. The programmed deep brain stimulation device manufactured by Medtronic, one of the two emerging neurostimulation treatments for intractable epilepsy that is under FDA review, demonstrated efficacy in a pivotal trial that involved stimulation in the anterior thalamus. This site has connections with the temporal lobe, which is a common site for the origin of partial seizures, Dr. Bergey explained.
The device, which is already approved for Parkinson's disease, comprises two leads* that are implanted bilaterally into the target structure with a pulse generator placed below the clavicle. Each lead contains four electrodes. The device delivers stimuli at scheduled intervals "to hopefully modulate and reduce the number of seizures the patient is having," he said.
In the Medtronic-funded Stimulation of the Anterior Nucleus of the Thalamus for Epilepsy (SANTE) study, 110 patients with medically refractory partial seizures were implanted with the device and randomized to intermittent bilateral stimulation (1 minute on/5 minutes off) or no-stimulation for a 3-month blinded stage, followed by unblinded stimulation for all of the patients (Epilepsia 2010;51:899-908). At the end of the blinded period, patients who received stimulation experienced a median seizure reduction of 40.4%, compared with 14.5% of patients with the stimulator off, reported study coauthor Dr. Vincenta Salanova of Indiana University, Indianapolis.
In the open-label follow-up, 56% of all the patients had greater than 50% seizure reduction at 2 years, and there was a median 68% reduction in seizures among the 42 patients for whom 3-year data were available. Over the course of the study, "14 [12.7%] of the patients were seizure free for at least 6 months," she reported in a press briefing at the meeting.
Although the mechanism of action is not fully understood, Dr. Salanova said that "the thalamus has connections between the limbic system and the frontal lobe, so it’s possible that high-frequency stimulation may prevent the propagation of seizures."
Five deaths occurred in the study population, but none were attributed to lead implantation or stimulation, Dr. Salanova stressed. There were no symptomatic or clinically significant hemorrhages associated with implantation, but 4.5% of patients experienced asymptomatic intracranial hemorrhages – detected via neuroimaging – that were not clinically significant. Additionally, two patients experienced seizures that were linked to the stimulus, which were resolved by lowering the voltage.
Direct stimulation of the hippocampus may also offer seizure relief in some patients, according to Dr. Richard Wennberg of the University of Toronto. "The hippocampus is clinically recognized as a region of high epileptogenicity, and animal studies have demonstrated antiepileptic properties of electrical fields applied to the region," he said in a presentation during the neurostimulation plenary session, noting that the goal of direct hippocampal stimulation is to prevent seizure generation and spread from the temporal limbic region.
To date, the experimental procedure has been evaluated in small series and has shown some efficacy, Dr. Wennberg said. For example, in a recent study designed to assess the effect of continuous electrical stimulation of the hippocampus bilaterally, two patients with seizures from both mesial temporal lobes who were not candidates for surgical resection were implanted bilaterally with two four-contact electrodes along the hippocampal axis. After randomization to either stimulation on or off conditions for 3-month intervals, seizure frequency decreased by 33% during stimulation, and stayed and remained lower by 25% for the 3 months after stimulation was turned off, after which the seizure frequency returned to baseline, the authors reported. Although seizure frequency was reduced both during and for a period after bilateral hippocampal stimulation, "the overall impact in this study is not as robust as has been previously reported," the authors stated (Epilepsia 2010;51:304-7).