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BRAIN STIMULATION OFFERS HOPE FOR SOME PATIENTS WITH EPILEPSY
CLEVELAND—Two methods of cerebral stimulation seem to be expanding their therapeutic utility. While the majority of clinical experience with deep brain stimulation (DBS) has been in patients with Parkinson’s disease and essential tremor, speakers at the Cleveland Clinic Foundation’s Neuromodulation Symposium told of extending its use to other groups of patients, including those with epilepsy who are refractory to medications and are not surgical candidates. Likewise, transcranial magnetic stimulation (TMS), which is currently used to treat conditions ranging from depression to cerebral ischemia, offers a more problematic but potentially promising method of reducing epileptic seizure frequency.
DEEP IMPACT
Alim-Louis Benabid, MD, of the University Joseph Fournier, Grenoble, France, said that patients with epilepsy selected for DBS include those who are medically resistant and those who cannot be operated on because seizure foci are too close to vital structures. Dr. Benabid said DBS has caused “dramatic improvement” in some of these cases and lesser improvements in others.
Likewise, Hans Lüders, MD, PhD, of the Cleveland Clinic Foundation, listed the hippocampus, mammillary bodies, and cingulate gyrus as some of the successful targets for DBS seizure inhibition, but he allowed that stimulation of the caudate in these patients has had “mixed reviews.”
More wholly positive results were garnered by Andres Lozano, MD, PhD, of the University of Toronto. Dr. Lozano reported that five patients with generalized or complex partial seizures who received anterior thalamic stimulation had a 93% reduction in their seizures. “The mechanism of action of DBS in epilepsy patients is unclear,” he said, “but it may be that the stimulation is of cell bodies or axons.” The fact that some patients lost their seizures altogether for several months after the stimulator was turned off without their knowledge also suggests that the DBS affects brain plasticity.
CENTROMEDIAN THALAMIC NUCLEI—SEIZURE CENTERS?
During the past 15 years, Francisco Velasco, MD, and colleagues at the General Hospital of Mexico and the Technological Institute of Mexico have been treating patients with hard-to-control seizures who are not candidates for conventional ablative procedures. Dr. Velasco defines such patients as those with “mainly generalized seizures without evidence of focal onset, such as cases of Lennox-Gastaut syndrome, as well as cases with a multifocal onset of seizures, particularly those with bitemporal or bifrontal independent foci.”
These patients are treated with bilateral implanted electrodes in both centromedian thalamic nuclei, using intermittent, alternating, bilateral stimulation because of evidence that the intralaminar and midline thalamic nuclei “participate in both the genesis and propagation of seizure activity.” Dr. Velasco added that the centromedian area was chosen because it is “a large nucleus, placed immediately above and in front of easily recognized stereotactic landmarks such as the anterior commissure/posterior commissure line and the vertical line touching the anterior border of the posterior commissure.”
Electrode placement was done under general anesthesia, using ventriculography control. Correct placement of the electrodes was verified “by simple electrophysiological techniques.” Inappropriate placement of electrodes, with a lateral or posterior deviation from the trajectory of the electrodes, may also be determined by the fact that they can cause paresthesia or pain.
“Once the corroboration has been made, the electrodes are connected to internalized pulse generators placed in subcutaneous pockets in each subclavicular region,” Dr. Velasco said. A sub-acute trial conducted during a two- to four-week period will decrease seizures and paroxysmal discharge and in most cases yield a long-term favorable result. Overall, the best results were obtained from patients with Lennox-Gastaut, who demonstrated a highly significant decrease in tonic-clonic and atypical absence seizures. “Simultaneously,” Dr. Velasco added, “generalized spikes, spike wave complexes, and bilateral synchronous discharges are significantly decreased.” Focal temporal spikes, however, are not decreased, and DBS had little efficacy on complex partial seizure patients.
In another study, Dr. Velasco reported that continuous stimulation of the epileptic focus was given to 10 patients scheduled for temporal lobectomy. Treatment lasted for 10 to 15 days, while the patients were off drugs. Quantification of the number of seizures and interictal spikes at the epileptic focus indicated that low-intensity, high-frequency stimulation of temporal lobe foci did result in a significant decrease in clinical seizures and in interictal spikes.
After the trial an en bloc resection of the hippocampus and parahippocampal and fusiform cortices was done in order to compare receptor binding density of those who underwent brain stimulation with those of patients who underwent lobectomy but did not have preoperative stimulation, and also with autopsy cases of patients with no history of neurologic disorders. Benzodiazepine receptor binding density was found to be significantly lower in the temporal lobe of seizure patients than in non-epileptic specimens, although DBS partially restored receptor binding in the parahippocampal cortex, “which may be the mechanism to control epileptic activity,” Dr. Velasco noted.
TRANSMAGNETIC STIMULATION—THE WAVE OF THE FUTURE?
Yet another approach to the treatment of epilepsy is transcranial magnetic stimulation over the epileptic foci. Mark Hallett, MD, of the National Institute of Neurological Disorders and Stroke, said there have been some promising animal studies, and now some human studies in a small number of patients, although he described the use of TMS for various neurologic disorders as being “not yet ready for prime time.”
TMS produces a brief, high-current pulse in a circular wire, which is called the magnetic coil. The mechanism of action, Dr. Hallett said, is the production of a magnetic field with lines of flux passing perpendicularly to the coil. Perpendicular to the magnetic field, an electric field is induced. The magnetic coils may be produced in different shapes. Round coils are relatively powerful, Dr. Hallett explained, but figure-eight coils, on the other hand, are “more focal, producing maximum current at the intersection of the two round components.”
Two main types of TMS are being considered for treatment purposes. Single pulse TMS, used mainly in research, has been shown to be very safe. Repetitive (from more than 1 to 30 Hz) TMS, or rTMS, can produce seizures even in normal individuals, although there are published safety guidelines which should prevent this, Dr. Hallett said. There appears to be no lasting effect for single pulses of TMS, although rTMS can have a lasting effect.
In 1999, a pilot study cohort of nine patients with frequent partial or tonic-clonic seizures had rTMS applied on five consecutive days, using two trains of 500 pulses applied through a 9-cm diameter round coil placed over the vertex of the skull. Eight of the nine described an improvement in the number or severity of seizures, or both. The number of seizures per week declined to 5.8 from 10.3.
Unfortunately, current implementation of TMS is limited because it “affects only the superficial cortex, and the physics dictates that it will never be possible to stimulate more than superficially.” Dr. Hallett remains hopeful, however, that “it may be possible to develop coils that stimulate at greater depth.”
NR
—Jean McCann
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