Neurostimulation Poised to Take On Tough Seizures
SAN ANTONIO – It’s still too soon to know whether
neurostimulation will be the therapeutic advance that treatment-refractory
epilepsy patients have been waiting for, but the possibility that it might be
has the epilepsy community buzzing.
For approximately 30% of epilepsy patients, seizures cannot
be controlled with antiepileptic drugs or surgery. New long-term safety and
efficacy data for vagus nerve simulation (VNS) and the results of recent
pivotal trials of two approaches to direct brain stimulation offer beacons of
hope to these patients, Dr. Gregory K. Bergey said in a plenary session on
neurostimulation at the annual meeting of the American Epilepsy Society.
"One of the frustrating things for those of us treating
patients with epilepsy has been the fact that, although a number of new
antiepileptic drugs have been developed over the past 10-15 years and most are
better tolerated and have better pharmacokinetic profiles than earlier drugs,
the number of patients with seizures that don’t respond to medical therapy has
not been significantly reduced," said Dr. Bergey, director of the Johns
Hopkins Epilepsy Center, Baltimore.
"So we’re stepping back and saying, ‘Is there some other
way we can treat these patients?’ That has been the impetus for looking at
neurostimulation, which has been around for well over a decade, and what we’re
seeing is exciting."
Although the 40%-50% response rates observed in direct brain
stimulation trials do not appear to be overwhelming, "this is just the
beginning," Dr. Bergey stressed in an interview. "As opposed to a
drug trial, where you go up to a certain dose and it either works or it doesn’t
work, in the case of neurostimulation we don’t know the optimal stimulus parameters,
and I think that’s what you’re going to begin to see over the next several
years," he said.
"There’s going to be a lot of investigation into
neurostimulation of the brain structures to try to figure out who are the best
candidates and what the best stimulus parameters are. It’s easy to say we’re
stimulating the brain, but do we stimulate 100 times per second, 50 times per
second, 25 times per second, and what should the stimulus intensities be?"
Vagus Nerve Stimulation. Currently, Cyberonics’ VNS
Therapy System is the only Food and Drug Administration–approved form of
neurostimulation for the treatment of epilepsy. The technology was approved in
1997 for the treatment of medically refractory partial-onset seizures in
patients 12 years or older. It consists of a stimulator that sends electric
impulses to the left vagus nerve in the neck via a lead wire that is implanted
under the skin. Studies since 1997 have indicated efficacy in generalized
seizure disorders and children as well, according to Dr. Elinor Ben-Menachem,
professor of neurology and epilepsy at the Institute for Clinical Neurosciences
and Physiology, Göteborg (Sweden) University.
To date, more than 60,000 patients worldwide have been
treated with VNS, and studies suggest that approximately 50% of patients who
undergo the procedure experience a long-term decrease in mean seizure frequency
of 50% or more. But fewer than 10% become seizure-free, Dr. Ben-Menachem said
during the neurostimulation plenary presentation.
"[VNS] has a long history now, and what we know is that
it does not cure or affect seizures immediately. We actually don’t notice a
change in seizure activity until about 18 months or 2 years after
For example, a recent long-term follow-up study of VNS
patients in the Czech Republic showed that at 1 year post implantation, 44.4%
of patients achieved more than 50% seizure reduction. The percentage of
patients who reached that level of seizure reduction then increased from 58.7%
at 2 years after implant to 64.4% at 5 years. At the 5-year mark, 15.5% of the
patients had achieved a minimum 90% seizure reduction, and 5.5% were seizure
The mechanism of action of VNS remains uncertain, but a
number of possibilities have been suggested, including arousal of the reticular
formation; stimulation of locus coeruleus and noradrenaline pathways; changes
in a neurotransmitter, amino acid, or neuropeptide; or indirect thalamus stimulation,
according to Dr. Ben-Menachem. "It’s also possible that there is long-term
learning through synaptic structural changes," she said. "The more I
work with this, the more I think it is a learning paradigm. It’s like learning
to play the piano. You can’t just sit down and play, you have to redo and redo
until the brain is trained."
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
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 four deep brain electrodes that are implanted bilaterally
into the target structure with a pulse generator placed below the clavicle. It
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
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
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
Responsive Neurostimulation. Another direct brain
neurostimulating technology under FDA review is the Responsive Neurostimulator System
(RNS) by NeuroPace. "The system detects and aborts [functional mapping]
induced afterdischarges in the brain to prevent seizures," explained Dr.
Lawrence J. Hirsch of Columbia University in New York. "It is designed to
respond within seconds to abnormal activity in the brain by delivering a series
of up to five stimuli to terminate the abnormal discharge."
The RNS device is implanted in a recess of the skull, and is
connected to up to two four-contact electrodes that are placed within the brain
or on the brain surface, depending on where the seizures begin. The device
collects and stores seizure information, which the patient subsequently
downloads to a laptop using a wand. Physicians can access the stored
electrocorticograms via a secure Web page through which they can adjust
detection and stimulation parameters specific to the individual patient, Dr.
Hirsch said during the neurostimulation plenary session.
In the pivotal clinical trial of the RNS system, 191 patients
with medically intractable, partial-onset seizures localized to one or two foci
received the cranial implant. During a blinded period, patients received active
or sham stimulation, followed by an open-label phase in which all the patients
received active stimulation. During the entire blinded evaluation period,
active stimulation was associated with a mean 37.9% reduction in seizure
frequency, compared with a mean 17% reduction during the sham activation, Dr.
"In the final month of the blinded period – month 4 to 5
– the respective reduction in seizure frequency was 42% and 9%." During
the last 3 months of the open-label period, "47% of the patients had a
greater than 50% seizure reduction," he said. "And at 4 years post
implant, more than 50% of the patients had at least a 50% reduction in seizure
A subset analysis showed that neither prior surgery nor the
number of seizure foci had an effect on treatment response, Dr. Hirsch noted.
"It also showed that [RNS] is possibly more effective with medial temporal
With respect to adverse events, implant site infections were
reported in 5% of the patients, and led to explantation in 2%. The combined
rate of status epilepticus reported in all trials of the device (256 patients)
was 3.5%, and included episodes occurring between 5 months and 5 years post
implant. Intracranial hemorrhage was reported in 4% of the patients, and
included only one patient with neurological sequelae, which was chronic
headache, he said.
The chronic, intracranial EEG recordings provided by the RNS
technology have other potentially valuable uses, including seizure
prediction/warning; seizure awareness and counting as a way to assess treatment
efficacy; identification of circadian, catamenial, and other ictal and
interictal patterns; and the lateralization of bitemporal seizures, Dr. Hirsch
Dr. Bergey disclosed financial relationships with Pfizer,
UCB, and Eli Lilly. Dr. Ben-Menachem disclosed financial relationships with
UCB, Eisai, Janssen, Cilag, Cyberonics, Lundbeck, and Sunovion. Dr. Wennberg
disclosed a financial relationship with Medtronic. Dr. Hirsch reported having
no financial disclosures.
Medtronic's DBS system (top left) stimulates the anterior
nucleus of the thalamus, whereas NeuroPace's RNS device (bottom left) responds
to abnormal activity in targeted areas and Cyberonics' VNS Therapy System
(right) periodically stimulates the left vagus nerve. (Photo Credit: top left:
(c) Medtronic Inc., bottom left: (c) NeuroPace Inc., right: (c) Cyberonics
article misstated the action of the Responsive Neurostimulator System (RNS) by
NeuroPace. The system detects and aborts abnormal discharges in the brain. Also,
the programmed deep brain stimulation device manufactured by Medtronic contains
one deep brain electrode on each side, not four. This version has been