September 12, 2018: LivaNova PLC announced the first implanted patient and official launch of a global registry to evaluate the use of LivaNova’s Vagus Nerve Stimulation Therapy® (VNS Therapy) System for patients with drug-resistant epilepsy (DRE), which affects nearly one in three people with epilepsy.1 The Comprehensive Outcomes Registry in Subjects with Epilepsy Treated with VNS Therapy (CORE-VNS) study will enroll up to 2,000 patients with five-year follow-up data, yielding one of the largest data sets in the world for DRE patients treated with various generations of VNS Therapy. Data from CORE-VNS will contribute to the body of research related to this disease state and advance the science behind VNS Therapy by evaluating the safety, effectiveness and clinical outcomes for patients.
“By following these patients for five years, we will gain a significant amount of high-quality, real-world clinical data on VNS Therapy as an adjunctive treatment for drug-resistant epilepsy”
The registry will include up to 80 sites globally, collecting outcomes in real-world settings by following participating patients for up to five years after treatment begins. Documented clinical outcomes will include seizure frequency, seizure severity, quality of life, quality of sleep, antiepileptic drug use, and seizure-related emergency visits and hospitalizations.
“Many patients with drug-resistant epilepsy have tried numerous treatment options with limited results. The CORE-VNS study will give us a greater understanding of the drug-resistant epilepsy patient population around the world and the role VNS Therapy can play in the overall management of this disease,” said Bryan Olin, LivaNova’s Senior Vice President of Clinical, Quality Assurance and Regulatory Affairs. “Additionally, this study will allow us to evaluate the latest advancements in VNS Therapy, including the capability to track and use real-time patient data to inform treatment.”
Dr. Kore Liow, FACP, FAAN, from the Comprehensive Epilepsy Center at Hawaii Pacific Neuroscience and Clinical Professor at the University of Hawaii John Burns School of Medicine, has enrolled the most patients to date in the CORE-VNS registry in preparation for VNS Therapy implants. “By following these patients for five years, we will gain a significant amount of high-quality, real-world clinical data on VNS Therapy as an adjunctive treatment for drug-resistant epilepsy,” said Liow.
VNS Therapy received CE Mark in 1994 and U.S. Food and Drug Administration approval in 1997 as an adjunctive treatment for drug-resistant epilepsy. The system consists of two implantable components: a programmable electronic pulse generator that is connected to a bipolar electrical lead, which sends mild pulses to stimulate the vagus nerve at regular intervals throughout the day.
To learn more about the study and locations go HERE.
About VNS Therapy for Epilepsy
VNS Therapy is clinically proven safe and effective for the treatment of drug-resistant epilepsy for adults and children. VNS Therapy is designed to prevent seizures before they occur and stop them if they do. It is a unique treatment approach developed for people with drug-resistant epilepsy—a condition that affects one in three people with epilepsy. For more information, visit www.VNSTherapy.com or www.VNSTherapy.co.uk.
The witness on the stand says he saw the accused at the scene of the crime. Is he sure? How sure? The jury’s verdict could hinge on that level of certainty.
Many decisions we make every day are influenced by our memories and the confidence we have in them. But very little is known about how we decide whether we can trust a memory or not.
A new Cedars-Sinai study provides some of the answers. Researchers have identified a unique set of neurons in the medial temporal lobe, an area of the brain where memories and memory-based decisions are processed. They show that the activity of these neurons is indicative of the confidence by which a memory will be retrieved. Findings are published in the June 8 online issue of Nature Neuroscience.
“The mechanisms that help us make confidence judgments about a memory-based decision are poorly understood, but we know they are impaired by many different diseases and disorders,” said Ueli Rutishauser, PhD, assistant professor of neurosurgery and director of human neurophysiology research at Cedars-Sinai, the article’s lead author. (more…)
Fycompa has not been approved by the FDA as an add-on therapy for seizures because additional benefit has yet to be proven.
The drug perampanel (trade name Fycompa) has been approved since July 2012 as adjunctive (“add-on”) therapy for adults and children aged 12 years and older with epileptic fits (seizures). In a new early benefit assessment according to the Act on the Reform of the Market for Medicinal Products (AMNOG), the German Institute for Quality and Efficiency in Health Care (IQWiG) examined whether perampanel offers an added benefit over the appropriate comparator therapy. However, such an added benefit cannot be derived from the new dossier either, as the drug manufacturer did not submit any relevant data for this comparison.
Already in the first dossier assessment in December 2012, there was no proof of an added benefit of perampanel because the manufacturer dossier provided no suitable data. The new assessment was conducted upon application of the manufacturer to the Federal Joint Committee (G-BA), which specifies the appropriate comparator therapy.
Appropriate comparator therapy expanded
Fits that affect only a small part of the brain are called “focal” or “partial seizures”. In this type of fit, the muscle twitches and spasms remain limited to isolated parts of the body. However, such seizures may spread across the whole body and are then referred to as “secondary generalization”. Perampanel is approved as add-on therapy for the treatment of partial seizures with or without secondary generalization in people aged 12 years and older.
The G-BA approved the manufacturer’s application for reassessment of the drug according to AMNOG because the appropriate comparator therapy had to be expanded following the change in the AMNOG Regulation for Early Benefit Assessment of New Pharmaceuticals (in §6 (1), Sentence 2, AM-NutzenV): Originally the more economical comparator therapy had to be chosen if several options were available, preferably a treatment with a fixed price. This regulation was dispensed with in 2013. If the G-BA specifies several options as appropriate comparator therapies, the manufacturer is now free to choose a therapy irrespective of the costs.
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New light-sensitive protein enables simpler, more powerful optogenetics
Optogenetics, a technology that allows scientists to control brain activity by shining light on neurons, relies on light-sensitive proteins that can suppress or stimulate electrical signals within cells. This technique requires a light source to be implanted in the brain, where it can reach the cells to be controlled.
MIT engineers have now developed the first light-sensitive molecule that enables neurons to be silenced noninvasively, using a light source outside the skull. This makes it possible to do long-term studies without an implanted light source. The protein, known as Jaws, also allows a larger volume of tissue to be influenced at once.
This noninvasive approach could pave the way to using optogenetics in human patients to treat epilepsy and other neurological disorders, the researchers say, although much more testing and development is needed. Led by Ed Boyden, an associate professor of biological engineering and brain and cognitive sciences at MIT, the researchers described the protein in the June 29 issue of Nature Neuroscience.
Optogenetics, a technique developed over the past 15 years, has become a common laboratory tool for shutting off or stimulating specific types of neurons in the brain, allowing neuroscientists to learn much more about their functions.
The neurons to be studied must be genetically engineered to produce light-sensitive proteins known as opsins, which are channels or pumps that influence electrical activity by controlling the flow of ions in or out of cells. Researchers then insert a light source, such as an optical fiber, into the brain to control the selected neurons.
Such implants can be difficult to insert, however, and can be incompatible with many kinds of experiments, such as studies of development, during which the brain changes size, or of neurodegenerative disorders, during which the implant can interact with brain physiology. In addition, it is difficult to perform long-term studies of chronic diseases with these implants.
Mining nature’s diversity
To find a better alternative, Boyden, graduate student Amy Chuong, and colleagues turned to the natural world. Many microbes and other organisms use opsins to detect light and react to their environment. Most of the natural opsins now used for optogenetics respond best to blue or green light.
Boyden’s team had previously identified two light-sensitive chloride ion pumps that respond to red light, which can penetrate deeper into living tissue. However, these molecules, found in the bacteria Haloarcula marismortui and Haloarcula vallismortis, did not induce a strong enough photocurrent – an electric current in response to light – to be useful in controlling neuron activity.
Chuong set out to improve the photocurrent by looking for relatives of these proteins and testing their electrical activity. She then engineered one of these relatives by making many different mutants. The result of this screen, Jaws, retained its red-light sensitivity but had a much stronger photocurrent – enough to shut down neural activity.
“This exemplifies how the genomic diversity of the natural world can yield powerful reagents that can be of use in biology and neuroscience,” says Boyden, who is a member of MIT’s Media Lab and the McGovern Institute for Brain Research.
Using this opsin, the researchers were able to shut down neuronal activity in the mouse brain with a light source outside the animal’s head. The suppression occurred as deep as 3 millimeters in the brain, and was just as effective as that of existing silencers that rely on other colors of light delivered via conventional invasive illumination.
Working with researchers at the Friedrich Miescher Institute for Biomedical Research in Switzerland, the MIT team also tested Jaws’s ability to restore the light sensitivity of retinal cells called cones. In people with a disease called retinitis pigmentosa, cones slowly atrophy, eventually causing blindness.
Friedrich Miescher Institute scientists Botond Roska and Volker Busskamp have previously shown that some vision can be restored in mice by engineering those cone cells to express light-sensitive proteins. In the new paper, Roska and Busskamp tested the Jaws protein in the mouse retina and found that it more closely resembled the eye’s natural opsins and offered a greater range of light sensitivity, making it potentially more useful for treating retinitis pigmentosa.
This type of noninvasive approach to optogenetics could also represent a step toward developing optogenetic treatments for diseases such as epilepsy, which could be controlled by shutting off misfiring neurons that cause seizures, Boyden says. “Since these molecules come from species other than humans, many studies must be done to evaluate their safety and efficacy in the context of treatment,” he says.
Boyden’s lab is working with many other research groups to further test the Jaws opsin for other applications. The team is also seeking new light-sensitive proteins and is working on high-throughput screening approaches that could speed up the development of such proteins.
Kevin Ramsey, an epilepsy sufferer who has a stimulator in his skull, used a wandlike device to download data on his brain activity.
For most of his life, Kevin Ramsey has lived with epileptic seizures that drugs cannot control.
At least once a month, he would collapse, unconscious and shaking violently, sometimes injuring himself. Nighttime seizures left him exhausted at dawn, his tongue a bloody mess. After episodes at work, he struggled to stay employed. Driving became too risky. At 28, he sold his truck and moved into his mother’s spare bedroom.
Cases of intractable epilepsy rarely have happy endings, but today Mr. Ramsey is seizure-free. A novel battery-powered device implanted in his skull, its wires threaded into his brain, tracks its electrical activity and quells impending seizures. At night, he holds a sort of wand to his head and downloads brain data from the device to a laptop for his doctors to review.
“I’m still having seizures on the inside, but my stimulator is stopping all of them,” said Mr. Ramsey, 36, whose hands shake because of one of the three anti-seizure drugs he still must take. “I can do things on my own I couldn’t do before. I can go to the store on my own, and get my groceries. Before, I wouldn’t have been able to drive.”
Just approved by the Food and Drug Administration, the long-awaited device, called the RNS System, aims to reduce seizures and to improve the lives of an estimated 400,000 Americans whose epilepsy cannot be treated with drugs or brain surgery. “This is the first in what I believe is a new generation of therapy for epilepsy,” said Dr. Dileep R. Nair, head of adult epilepsy at the Cleveland Clinic and an investigator in the pivotal trial for NeuroPace’s RNS. “It’s delivering local therapy. It’s not taking tissue out; the brain is left intact. And it’s unlike a drug, which is a shotgun approach.”
Already, Dr. Nair’s center has 70 people on a waiting list for the device. Roughly 110 epilepsy centers with sophisticated diagnostic testing have filed paperwork to be able to offer it, said Dr. Martha J. Morrell, the chief medical officer at NeuroPace, based in Mountain View, Calif. That represents most of the estimated 130 Level 4 centers that treat adults with epilepsy.
Unfortunately, many patients are not referred to these centers by their doctors until they have spent years, even decades, grappling with their condition.
“We want this yesterday,” said Dr. Orrin Devinsky, director of theComprehensive Epilepsy Center at NYU Langone Medical Center. Next month, pending insurance approval, the center plans to implant the device in its first patient.
An estimated 2.3 million adults nationwide have epilepsy, and in a third of them, seizures are not controlled by drugs. Brain surgery can relieve seizures completely, but many patients aren’t candidates because their seizures start in parts of the brain that can’t be removed, such as those needed for language or memory.
Without treatment options, people with intractable epilepsy often find it difficult to hold jobs or to find spouses. They can suffer repeated injuries from falls and burns; their mortality rate is two to three times higher than that of the general population. “There are people out there who are just desperate for the next treatment,” said Janice Buelow, the vice president of research for the Epilepsy Foundation.
With his neurostimulator, Mr. Ramsey, who is partial to ice fishing and wisecracks, is living on his own in a patched-up trailer heated by an indoor wood stove. Inside is the mounted head of a deer he shot. He drives his purple Ford Ranger to appointments at Dartmouth-Hitchcock Medical Center.
Lately, he’s started to look for part-time work. But he’s cautious. “Because of my epilepsy, a lot of people don’t want to take the risk,” he said.
His treatment has been more successful than most. In a randomized clinical trial of 191 people at 32 sites, patients received stimulators but did not know whether they were activated or not. Those with stimulators activated reported a 38 percent reduction in seizures over three months, compared to a 17 percent decrease among those whose stimulators were not, according to the results published in Neurology. Over two years, 90 subjects with the devices turned on experienced a 50 percent or greater reduction in seizures.
Until he received a stimulator in 2008, Andrew Stocksdale, 32, of Mansfield, Ohio, experienced up to 20 seizures a day. By contrast, in the past month, he’s had three. He is now married, holds a full-time job, and has a newborn son.
“My life fell together like a jigsaw puzzle,” Mr. Stocksdale said. “I was afraid to have a son before. I couldn’t do things. I was afraid of falling. I couldn’t hold him.”
Implantation surgery requires two days in the hospital, but extensive evaluation is necessary beforehand, including days of monitoring without anti-seizure drugs.
The device, which requires a battery change every two to three years, works only for people whose seizures start in one or two places in their brain. Electrical stimulation delivered through thin wires placed precisely at those places helps prevent an incipient seizure from spreading.
By contrast, another treatment, a vagus nerve device — which is a stimulator implanted in the chest to prevent seizures — fires “on a preprogrammed basis with no relationship to what’s happening in the brain,” said Dr. Devinsky of the NYU Langone epilepsy center.
Before the RNS is turned on, a patient’s unique seizure patterns must be detected, a process that takes months and multiple clinic visits. Then comes a period of trial and error, when the intensity of stimulation is increased or decreased, or the number of pulses altered, to see if the patient experiences fewer seizures.
“I like to call it a smart device,” said Dr. Christianne Heck, an investigator in the RNS study who is the medical director of the comprehensive epilepsy program at the University of Southern California. “We actually teach the device to detect specific patterns that represent a seizure for each particular patient.”
Soon after Mr. Ramsey’s stimulator was turned on, his major convulsive seizures stopped, said Dr. Barbara C. Jobst, the director of the epilepsy program at Dartmouth-Hitchcock, who was also an investigator in the study. But it took three years of tweaking to stop another kind of seizure that resulted in his simply staring.
Mr. Ramsey’s case was in some ways exceptional, she warned: “It’s not always as clear where the seizures are coming from as it is in him.”
The size of the area where seizures start also affects how well the neurostimulator works, said Dr. David W. Roberts, a neurosurgeon at Dartmouth-Hitchcock. “If a patient’s seizures are confined to thehippocampus, you have a good chance of helping him,” he said, noting that the hippocampus is small.
But if seizures originate over the whole frontal lobe, Dr. Roberts said, the same number of electrical leads are “much less likely to have the same effect.”
Even for patients who are good candidates, access to the new device may be difficult if patients aren’t referred to Level 4 epilepsy centers. Such centers tend to be near universities or larger cities. New York City has eight, while no Level 4 centers exist in Montana, Arkansas or the Dakotas.
Dr. David M. Labiner, the president of the National Association of Epilepsy Centers, said the “lag time” between diagnosis and referral to a comprehensive center “is still up to 20 years.”
Another hurdle is cost. The RNS, with the equipment required to download data, is up to $40,000. That figure doesn’t include $10,000 to $20,000 for the surgery, or diagnostic testing. Thus far, insurers have paid most of the expenses for five or so cases since F.D.A. approval, including one covered by Medicare.
In the long run, seizure reduction is cost-effective, some experts argued.
“Even if seizures are only cut in half, insurers’ costs are cut in half,” said Dr. Labiner, who also heads the epilepsy program at the University of Arizona.
RNS may reduce seizure frequency, but it won’t cure memory loss or repair a difficult marriage. “Psychosocial problems aren’t necessarily better if your seizures are well controlled,” said Dr. Gregory L. Barkley, co-founder of the epilepsy program at Henry Ford Hospital in Detroit.
Mr. Ramsey still has cognitive issues. “I forget people’s names all the time,” he said. At a restaurant in January, he kept forgetting he had decided to order the seafood pie moments before.
As much as his neurostimulator has changed his life, he’s hoping for another sea change: “Finding a really nice girl,” he said. “I would like to have a baby so I can raise a family.”