SANTE Trial of Deep Brain Stimulation in Epilepsy Published; FDA Panel Recommends Approval in Close Vote

Pauline Anderson

March 19, 2010

March 19, 2010 — A multicenter randomized trial has shown that bilateral stimulation of the anterior nuclei of the thalamus (ANT) is initially superior to placebo and then to baseline in reducing seizure frequency in patients with refractory epilepsy.

After completion of an initial 3-month placebo phase, there was a 40.4% reduction in seizures in patients receiving deep brain stimulation (DBS) compared with 14.5% in a control group who had a stimulator device implanted but did not receive any stimulation.

Two years after implantation of the DBS device, seizures were reduced by a median 56% compared with baseline, and 14 patients (12.7%) became seizure free for at least 6 months.

These results indicate that DBS is an important new option for treating disabling seizures, said lead author Robert S. Fisher, MD, PhD, professor of neurology and director of Stanford Epilepsy Center in California.

The study was published online March 17 in Epilepsia, the journal of the International League Against Epilepsy.

Advisory Panel Recommendation

On March 12, the Neurological Devices Panel of the Food and Drug Administration (FDA) Medical Devices Advisory Committee recommended approval of DBS in the ANT as adjunctive therapy for patients with severe and refractory partial-onset seizures with or without secondary generalization. It was a majority vote but not a unanimous one at 7 to 5. Medtronic's application was based on results of the Stimulation of the ANT for Epilepsy (SANTE) study, and it was Dr. Fisher who presented the data to the advisory panel.

The panel's recommendation for approval came with conditions though, including, for example, that proper warnings be included on the label and follow-up monitoring studies be performed, said Dr. Fisher. "I'm almost sure that the FDA will ask for warnings that stimulation might produce or increase a feeling of depression and it might produce or increase a feeling of memory problems," he added.

Patients eligible for the SANTE study were aged 18 to 65 years and were diagnosed as having epilepsy characterized by partial-onset seizures, with or without secondary generalization. They had to have at least 6 partial seizures per month but no more than 10 per day. Before baseline, their seizures were not adequately controlled with a trial of at least 3 antiepileptic drugs (AEDs).

The mean age of the 110 final study participants was 36.1 years and about half were women. They had a median of 19.5 baseline seizure counts per month.

All patients underwent the DBS implantation. The procedure involves the insertion of electrodes in the ANT bilaterally. A small programmable stimulator containing a battery that lasts 3 to 5 years is inserted under the clavicle in the chest wall. A wire is inserted under the skin, up 1 side of the neck, behind the ear, and to the top of the head, where, guided by computer magnetic resonance imaging, it is positioned through 2 small drill holes to the thalamus.

Gateway to Cortex

"The thalamus is the gateway to the cortex," explained Dr. Fisher. "The cortex is your thinking brain and also part of the brain that seizes. Nothing gets from the sensory world — from your eyes to your touch to your hearing — to the cortex without going through the thalamus, except for smell. So you can influence a lot of cortex by electrically stimulating the thalamus."

One month after implantation, study subjects were randomized to no stimulation or 0 volts (55 control patients) or stimulation at 5 volts (54 patients), using 90-microsecond pulses, 145 pulses per second, "ON" for 1 minute, then "OFF" for 5 minutes.

At the end of the blinded phase, at 4 months from baseline, the unadjusted median decreases in seizure frequency were 14.5% in the control group and 40.4% in the stimulated group. After adjustment and exclusion of 1 outlier who had a seizure every 6 minutes with the stimulation, although these stimulation-provoked seizures immediately decreased when the voltage was turned down to 4 volts, the stimulated group had a 29% greater reduction in seizures compared with the control group (P = .0022).

Dr. Fisher noted that there was some debate during the FDA panel meeting about this outlier included in the study.

After the initial blinded phase of the trial, all participants received stimulation from month 4 to month 13 in an unblinded phase. "At that point, everyone was put on stimulation because we didn't think it ethical to implant the wires in people's brains and never actually give them the stimulation," said Dr. Fisher.

At 13 months, 41% of patients showed a reduction in seizures, but this increased to 56% at 25 months. The 50% responder rate (the percentage of patients whose seizures were at least cut in half) was 43% at 13 months, 54% at 25 months, and 67% at 37 months.

"That means that at this point, the seizures had been cut down to about a third of their level from baseline," said Dr. Fisher.

Two participants were seizure free from months 4 to 13, and 14 (12.7%) were seizure free for at least 6 months.

Death, infection, and hemorrhage rates were not higher than expected, they note.

There were 5 deaths, but none were judged to be related to lead implantation or stimulation. None occurred during the operative month or in the 3-month double-blind phase. In each of the unblinded and long-term follow-up phases, 1 person died of sudden unexplained death in epilepsy, for a rate of 6.2 per 1000 years. There were no symptomatic or clinically significant hemorrhages, but 5 hemorrhages (4.5% of participants) were detected incidentally by neuroimaging.

During the entire study period, 14 subjects (12.7%) developed implant site infections, which is similar to that seen in prospective studies of DBS for Parkinson's disease.

Five patients experienced status epilepticus. Two patients had stimulus-linked seizures on stimulus initiation, but this resolved with lower voltage.

Depression and Memory

The 2 groups were about the same with respect to cognition and mood, although participants in the stimulated group were more likely to report depression (8 vs 1) or memory problems (7 vs 1). However, 7 of the 8 reporting depression had a prior history of depression, and half of the depression events resolved during an average of 76 days. All blinded phase reports of memory impairment also resolved.

There was 1 suicide in the stimulation group that occurred at about 3 years out, but it was not believed to be related to the stimulation, said Dr. Fisher.

When used for movement disorders, DBS invokes a mixture of excitatory and inhibitory effects, resulting in disruption of neuronal networks, but the mechanism of action of DBS in epilepsy remains unknown. The most plausible theory is that it disrupts the "electrical storm" involving brain cells and the resonance that occurs during a seizure, said Dr. Fisher.

In this study, subjects whose seizures originated in the temporal region achieved relatively greater benefit of stimulation during the blinded phase compared with those with seizures from other lobes or seizures multifocal in origin, the study authors pointed out.

Safe Track Record

Dr. Fisher pointed out that the DBS device has a long and safe track record and that 75,000 people all over the world have already had the device implanted for movement disorders. The same device, manufactured by Medtronic, is implanted in the subthalamus in patients with Parkinson's disease, and the surgical technique used to implant the device in epilepsy is the same. "So there are lots of surgeons quite experienced in this," he said.

Now that the device appears to be reaching FDA approval, Dr. Fisher said a "natural next step" would be to test the device in children. "It hasn’t been tested on children, and I think it's quite reasonable that it could and at some point should be."

According to the World Health Organization, epilepsy affects 50 million people worldwide.  An estimated one-third of those with epilepsy do not respond adequately to AEDs. 

The SANTE trial was funded by Medtronic and a grant from the National Institutes of Health to Dr. Fisher to assist in planning the study. Dr Fisher receives no funding and has no equity holdings from Medtronic. He has stock options from NeuroVista (seizure prediction) and IntelliVision (seizure notification). He has done paid consulting for Sony (videogame-induced seizures) and Jazz Pharmaceuticals (intranasal midazolam). For conflict of interest information on the other study authors, please refer to the original article.

Epilepsia. Published online March 18, 2010.