Neurostimulation Poised to Take On Tough Seizures

Neurostimulation Poised to Take On Tough Seizures

By: DIANA MAHONEY,
Internal Medicine News Digital Network

12/15/10 

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
starting."

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
free (Seizure
2009;18: 269-74).

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
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 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
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).

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.
Hirsch said.

"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
frequency."

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
onset."

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
said.

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
Inc.)

* CORRECTION, 12/16/2010: The original version of this
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
updated.

http://www.internalmedicinenews.com/news/neurology/single-article/neurostimulation-poised-to-take-on-tough-seizures/17d1537114.html

Med Hypotheses. 2010 Dec 6. [Epub ahead of print]

Vagus nerve stimulation as a strategy to prevent and manage metabolic syndrome.

Das UN.

School of Biotechnology, Jawaharlal Nehru Technological University, Kakinada 533 003, India; UND Life Sciences, 13800 Fairhill Road, #321, Shaker Heights, OH 44120, USA.

Abstract

An increase in pro-inflammatory cytokines, decrease in endothelial nitric oxide (eNO) and adiponectin levels and an alteration in hypothalamic peptides and gastrointestinal hormones such as incretins and cholecystokinin that regulate satiety, hunger, and food intake occur in metabolic syndrome. Thus, metabolic syndrome is a low-grade systemic inflammatory condition and could be due to inappropriate cross-talk between the peripheral tissues and the hypothalamic centers implying that methods designed to restore these two abnormalities to normal could be of significant benefit in metabolic syndrome. Vagus nerve stimulation has been shown to suppress inflammation and acetylcholine, the principal vagal neurotransmitter, modulates the actions of several hypothalamic peptides and incretins and cholecystokinin. Based on these evidences, it is proposed that vagus nerve stimulation could be of significant benefit in the management of the metabolic syndrome.

PMID: 21144670 [PubMed - as supplied by publisher]

http://www.ncbi.nlm.nih.gov/pubmed/21144670

Epilepsy Behav. 2010 Dec 6. [Epub ahead of print]

Vagus nerve stimulation in 436 consecutive patients with treatment-resistant epilepsy: Long-term outcomes and predictors of response.

Elliott RE, Morsi A, Kalhorn SP, Marcus J, Sellin J, Kang M, Silverberg A, Rivera E, Geller E, Carlson C, Devinsky O, Doyle WK.

Department of Neurosurgery, New York University Langone Medical Center, New York, NY, USA.

Abstract

OBJECTIVE: The goal of this study was to assess the efficacy and safety of vagus nerve stimulation in a consecutive series of adults and children with treatment-resistant epilepsy (TRE).

METHODS: In this retrospective review of a prospectively created database of 436 consecutive patients who underwent vagus nerve stimulator implantation for TRE between November 1997 and April 2008, there were 220 (50.5%) females and 216 (49.5%) males ranging in age from 1 to 76years at the time of implantation (mean: 29.0±16.5). Thirty-three patients (7.6%) in the primary implantation group had inadequate follow-up (<3months from implantation) and three patients had early device removal because of infection and were excluded from seizure control outcome analyses.

RESULTS: Duration of vagus nerve stimulation treatment varied from 10days to 11years (mean: 4.94years). Mean seizure frequency significantly improved following implantation (mean reduction: 55.8%, P<0.0001). Seizure control ≥90% was achieved in 90 patients (22.5%), ≥75% seizure control in 162 patients (40.5%), ≥50% improvement in 255 patients (63.75%), and <50% improvement in 145 patients (36.25%). Permanent injury to the vagus nerve occurred in 2.8% of patients.

CONCLUSION: Vagus nerve stimulation is a safe and effective palliative treatment option for focal and generalized TRE in adults and children. When used in conjunction with a multidisciplinary and multimodality treatment regimen including aggressive antiepileptic drug regimens and epilepsy surgery when appropriate, more than 60% of patients with TRE experienced at least a 50% reduction in seizure burden. Good results were seen in patients with non-U.S. Food and Drug Administration-approved indications. Prospective, randomized trials are needed for patients with generalized epilepsies and for younger children to potentially expand the number of patients who may benefit from this palliative treatment.

http://www.ncbi.nlm.nih.gov/pubmed/21144802

Research Nerve Stimulation Therapy May Improve Outcomes and Reduce Healthcare Costs...

From HealthNewsDigest.com

 

Research Nerve Stimulation Therapy May Improve Outcomes and Reduce Healthcare Costs for Epilepsy

By

Dec 6, 2010 - 3:37:16 PM

(HealthNewsDigest.com) - ATLANTA – The use of nerve stimulation therapy
in patients with refractory epilepsy is associated with a lower occurrence of
epilepsy-related health problems and a lower use of healthcare resources,
according to a new study from the Emory University School of Medicine.
Refractory epilepsy is the occurrence of seizures that are not controlled with
medication alone.

Findings of the study were presented Dec. 5 at the American Epilepsy Society
Meeting in San Antonio, Texas. Sandra L. Helmers, MD, MPH, the R. Edward
Faught, MD, professor of neurology at Emory School of Medicine, conducted the
retrospective study of 1,655 patients treated with vagus nerve stimulation
(VNS) therapy from 1997 to 2009.

Using data from five Medicaid state claims databases, including Florida, Iowa,
Kansas, Missouri and New Jersey, the study is the first to review the long-term
medical and economic impact of VNS therapy for treatment of refractory epilepsy
in a clinical setting.

VNS therapy is an adjunctive therapy to antiepileptic drugs in patients 12
years or older and the only FDA-approved implantable medical device for the
treatment of refractory epilepsy. An implanted stimulator sends electric
impulses to the left vagus nerve in the neck via a lead wire implanted under
the skin.

“Poorly controlled seizures are an important risk factor for mortality in
people with epilepsy and put patients at higher risk of physical injuries such
as fractures or head injuries, as well as morbidities including depression and
anxiety,” says Helmers.

“The results of this study demonstrate that with VNS therapy for patients with
refractory epilepsy there may be improved clinical outcomes for patients that
subsequently result in significant savings for the healthcare system.”

The study evaluated epilepsy-related health problems such as frequency of
fractures and head trauma related to seizures. It also reviewed patient data
for healthcare utilization including seizure-related and non-seizure-related
emergency room visits, outpatient services, neurology services, and factors
such as length of hospital stay and prescription drug claims.

Study results confirmed that use of VNS therapy in patients with refractory
epilepsy is associated with:

A lower occurrence of epilepsy-related co-morbidities. Patients experienced
fewer injuries and other health issues after being implanted with VNS therapy,
compared to the period before VNS implantation.

A lower utilization of healthcare. All-cause hospitalizations and emergency
room visits significantly decreased over time after implantation with VNS
therapy compared to the six months prior to implantation.

Significant longer term cost savings. With a reduction in healthcare
utilization and co-morbidities as a result of VNS therapy, there is a
significant net total healthcare cost savings beginning at 1.5 years after
implantation. The study found that average quarterly total healthcare costs
were reduced approximately 28 percent, from an average of $19,945 pre-VNS
implantation to $14,316 at 1.5 years after implantation.

“While there are initial costs to VNS therapy including the surgical procedure
and the cost of the device, our study finds that the cost savings of VNS are
usually seen in about 18 months,” says Helmers. “By reducing overall healthcare
utilization such as emergency room visits, VNS therapy becomes a reasonable
option for patients with medically refractory epilepsy.”

http://www.healthnewsdigest.com/news/Research_270/Nerve_Stimulation_Therapy_May_Improve_Outcomes_and_Reduce_Healthcare_Costs_for_Epilepsy.shtml

 

Epilepsy Res. 2010 Dec 1. [Epub ahead of print]

Magnetoencephalography in epilepsy patients carrying a vagus nerve stimulator.

Carrette E, De Tiège X, De Beeck MO, De Herdt V, Meurs A, Legros B, Raedt R, Deblaere K, Van Roost D, Bourguignon M, Goldman S, Boon P, Van Bogaert P, Vonck K.

Reference Center for Refractory Epilepsy, Department of Neurology, Ghent University Hospital, De Pintelaan 185, 9000 Gent, Belgium.

Abstract

Due to technical constraints, magnetoencephalography (MEG) is challenging in vagus nerve stimulation (VNS) patients. This study evaluates (1) the feasibility of MEG in VNS patients and (2) the added value of MEG in their presurgical evaluation (PE). Ten VNS patients were studied by MEG using the spatiotemporal signal space separation (tSSS) method. Equivalent current dipoles (ECD) were classified "clustered"/"scattered". It was evaluated whether MEG (1) confirmed localisation of the hypothesized epileptogenic zone (HEZ), (2) improved delineation of the HEZ, or (3) identified 1 out of multiple HEZs. Finally it was evaluated whether adding MEG to the PE improved patient management by changing or supporting the hypothesis. In 7/10 patients, tSSS allowed to obtain interpretable MEG data, with interictal epileptiform discharges in 6/7. ECD clustered within 1 lobe in 4/6; confirming the localisation of the HEZ in 2/4 and improving delineation of the HEZ in 2/4. When ECD clustered within 2 lobes (1/6) or were scattered (1/6), MEG could not identify 1 out of multiple HEZs. In 2 patients, MEG changed management to invasive video-EEG monitoring (IVEM) and resective surgery (RS). In 4 patients, MEG further supported the management; IVEM in 2/4 and unsuitability for RS in 2/4. So far IVEM, performed in 2, resulted into RS. This study demonstrates the feasibility of MEG in VNS patients. MEG changed management in 20% and further supported the proposed management in 40% illustrating the clinical value of MEG in the PE of VNS patients.

PMID: 21129918 [PubMed - as supplied by publisher]

http://www.ncbi.nlm.nih.gov/pubmed/21130042

Epilepsy Behav. 2010 Dec 1. [Epub ahead of print]

Vagus nerve stimulator treatment in adult-onset Rasmussen's encephalitis.

Grujic J, Bien CG, Pollo C, Rossetti AO.

Service de Neurologie, Département de Neurosciences Cliniques, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Switzerland.

Abstract

We describe a patient with adult-onset Rasmussen's encephalitis (RE) responsive to vagus nerve stimulation. This previously healthy woman developed RE in the right hemisphere at the age of 27. Despite antiepileptic drug polytherapy, she continued to experience subcontinuous, simple-partial left-sided motor seizures and slowly progressive cognitive impairment. Resective surgery was not considered owing to the preservation of left motor skills. She was implanted with a vagus nerve stimulator at the age of 41; after 6months she experienced a greater than 50% reduction in seizure frequency, which persisted over 2years together with improvement of her neurological and cognitive status.

PMID: 21130042 [PubMed - as supplied by publisher]

http://www.ncbi.nlm.nih.gov/pubmed/21130042

Heart Fail Rev. 2010 Dec 3. [Epub ahead of print]

Vagus nerve stimulation in experimental heart failure.

Sabbah HN, Ilsar I, Zaretsky A, Rastogi S, Wang M, Gupta RC.

Department of Medicine, Division of Cardiovascular Medicine, Henry Ford Heart and Vascular Institute, Henry Ford Hospital, 2799 West Grand Boulevard, Detroit, MI, 48202, USA, hsabbah1@hfhs.org.

Abstract

Chronic heart failure (HF) is associated with autonomic dysregulation characterized by a sustained increase in sympathetic drive and by withdrawal of parasympathetic activity. Sympathetic overdrive and increased heart rate are predictors of poor long-term outcome in patients with HF. Considerable evidence exists that supports the use of pharmacologic agents that partially inhibit sympathetic activity as effective long-term therapy for patients with HF; the classic example is the wide use of selective and non-selective beta-adrenergic receptor blockers. In contrast, modulation of parasympathetic activation as potential therapy for HF has received only limited attention over the years given its complex cardiovascular effects. In this article, we review the results of recent experimental animal studies that provide support for the possible use of electrical Vagus nerve stimulation (VNS) as a long-term therapy for the treatment of chronic HF. In addition to exploring the effects of chronic VNS on left ventricular (LV) function, the review will also address the effects of VNS on potential modifiers of the HF state that include cytokine production and nitric oxide elaboration. Finally, we will briefly review other nerve stimulation approaches which is also currently under investigation as potential therapeutic modalities for treating chronic HF.

PMID: 21128115 [PubMed - as supplied by publisher

http://www.ncbi.nlm.nih.gov/pubmed/21128115