Posts tagged epilepsy
Articles and news from the latest research reports.
Epilepsy in a dish: Stem cell research reveals clues to disease’s origins and possible treatment
A new stem cell-based approach to studying epilepsy has yielded a surprising discovery about what causes one form of the disease, and may help in the search for better medicines to treat all kinds of seizure disorders.
The findings, reported by a team of scientists from the University of Michigan Medical School and colleagues, use a technique that could be called “epilepsy in a dish”.
By turning skin cells of epilepsy patients into stem cells, and then turning those stem cells into neurons, or brain nerve cells, the team created a miniature testing ground for epilepsy. They could even measure the signals that the cells were sending to one another, through tiny portals called sodium channels.
In neurons derived from the cells of children who have a severe, rare genetic form of epilepsy called Dravet syndrome, the researchers report abnormally high levels of sodium current activity. They saw spontaneous bursts of communication and “hyperexcitability” that could potentially set off seizures. Neurons made from the skin cells of people without epilepsy showed none of this abnormal activity.
They report their results online in the Annals of Neurology, and have further work in progress to create induced pluripotent stem cell lines from the cells of patients with other genetic forms of epilepsy. The work is funded by the National Institutes of Health, the American Epilepsy Society, the Epilepsy Foundation and U-M.
The new findings differs from what other scientists have seen in mice — demonstrating the importance of studying cells made from human epilepsy patients. Because the cells came from patients, they contained the hallmark seen in most patients with Dravet syndrome: a new mutation in SCN1A, the gene that encodes the crucial sodium channel protein called Nav1.1. That mutation reduces the number of channels to half the normal number in patients’ brains.
"With this technique, we can study cells that closely resemble the patient’s own brain cells, without doing a brain biopsy," says senior author and team leader Jack M. Parent, M.D., professor of neurology at U-M and a researcher at the VA Ann Arbor Healthcare System. "It appears that the cells are overcompensating for the loss of channels due to the mutation. These patient-specific induced neurons hold great promise for modeling seizure disorders, and potentially screening medications."
With the new paper, Parent, postdoctoral fellow Yu Liu, Ph.D. and their collaborators Lori Isom, Ph.D., professor of Pharmacology and of Molecular and Integrative Physiology at U-M, and Miriam Meisler, Ph.D., Distinguished University Professor of Human Genetics at U-M, report striking discoveries about what is happening at the cell level in the neurons of Dravet syndrome patients with a mutated SCN1A gene.
They also demonstrated that the effect is rooted in something that happens after function of the gene is reduced due to the mutation, though they don’t yet know how or why the nerve cells overcompensate for partial loss of this channel.
And, they found that the neurons didn’t show the telltale signs of hyperexcitability in the first few weeks after they were made — consistent with the fact that children with Dravet syndrome often don’t suffer their first seizures until they are several months old.
"In addition, reproduction of the hyperactivity of epileptic neurons in these cell cultures demonstrates that there is an intrinsic change in the neurons that does not depend on input from circuits in the brain," says co-author Meisler.
A platform for testing medications
Many Dravet patients don’t respond to current epilepsy medications, making the search for new options urgent. Their lives are constantly under threat by the risk of SUDEP, sudden unexplained death in epilepsy – and they never outgrow their condition, which delays their development and often requires round-the-clock care.
"Working with patient families, and translating our sodium channel research to a pediatric disease, has made our basic science work much more immediate and critical," says Isom, who serves on the scientific advisory board of the Dravet Syndrome Foundation along with Meisler. Parent, who co-directs U-M’s Comprehensive Epilepsy Program, was recently honored by the foundation.
The team is now working toward screening specific compounds for seizure-calming potential in Dravet syndrome, by testing their impact on the cells in the “epilepsy in a dish” model. The National Institutes of Health has made a library of drugs that have been approved by the U.S. Food and Drug Administration available for researchers to use — potentially allowing older drugs to have a second life treating an entirely different disease from what they were initially intended.
Parent and his colleagues hope to identify drugs that affect certain aspects of sodium channels, to see if they can dampen the sodium currents and calm hyperexcitability. The team is exploring new techniques that can make this process faster, using microelectrodes and calcium-sensitive dyes. They also hope to use the model to study potential drugs for non-genetic forms of epilepsy.
Having a U-M team that includes experts in induced pluripotent stem cell biology, sodium channel physiology and epilepsy genetics expertise helps the research progress, Parent notes. “Epilepsy is a complicated brain network disease,” he says. “It takes team-based science to address it.”
Patients as part of the research team
The U-M team’s research wouldn’t be possible without the participation of patients with Dravet syndrome and other genetic forms of epilepsy, and their parents.
More than 100 of them have joined the International Ion Channel Epilepsy Patient Registry, which is based at U-M and Miami Children’s Hospital and co-funded by the Dravet Syndrome Foundation and the ICE Epilepsy Alliance. The researchers hope to be able to conduct clinical trials of potential drugs with participation by these patients and others.
Meanwhile, patients with other genetically based neurological diseases can also help U-M scientists discover more about their conditions, by taking part in other efforts to create induced neurons from skin cells. Parent and his team have worked with several other U-M faculty to create stem cell lines from skin cells provided by patients with other diseases including forms of ataxia and lysosmal storage disease.
Nerve Cells Can Work in Different Ways with Same Result
Epilepsy, irregular heartbeats and other conditions caused by malfunctions in the body’s nerve cells, also known as neurons, can be difficult to treat. The problem is that one medicine may help some patients but not others. Doctors’ ability to predict which drugs will work with individual patients may be influenced by recent University of Missouri research that found seemingly identical neurons can behave the same even though they are built differently under the surface.
“To paraphrase Leo Tolstoy, ‘every unhappy nervous system is unhappy in its own way,’ especially for individuals with epilepsy and other diseases,” said David Schulz, associate professor of biological sciences in MU’s College of Arts and Science. “Our study suggests that each patient’s neurons may be altered in different ways, although the resulting disease is the same. This could be a major reason why doctors have difficulty predicting which medicines will be effective with specific individuals. The same problem could affect treatment of heart arrhythmia, depression and many other neurological conditions.”
It turns out, even happy neurons may be happy in their own way. Neurons have a natural electric activity that they are biologically programmed to maintain. If a neuron isn’t in that preferred state, the cell tries to restore it. However, contrary to some previous beliefs about neuron functioning, Schulz’s research found that two essentially identical neurons can reach the same preferred electrical activity in different ways.
In Schulz’s study, individual neurons used different combinations of cellular pores, known as ion channels, to achieve the same end goal of their preferred electrical and chemical balances. Schulz compared the situation to five people in separate rooms being given sets of blocks and told to construct a tower. Each person could devise a different method for constructing the same structure.
Schulz’s finding could inform doctor’s treatment of epilepsy. In epileptics, the neurons of the brain frequently receive too little stimulation from other neurons. Those under-stimulated epileptic neurons may overcompensate and become too sensitive. Then, when any impulses actually do reach them from other neurons, those hyper-sensitive epileptic neurons may over-react and cause a seizure.
Schulz worked with Satish Nair, professor of electrical and computer engineering in MU’s College of Engineering. The collaboration allowed their team to model nerve cell behavior in computer simulations in addition to his physical experiments using crab nervous systems.
The study, “Neurons with the same network independently achieve conserved output by differentially balancing variable conductance magnitudes,” was published in the Journal of Neuroscience. Joseph L. Ransdell, an MU doctoral student was the lead researcher of the study.
Animal study shows promising path to prevent epilepsy
Duke Medicine researchers have identified a receptor in the nervous system that may be key to preventing epilepsy following a prolonged period of seizures.
Their findings from studies in mice, published online in the journal Neuron on June 20, 2013, provide a molecular target for developing drugs to prevent the onset of epilepsy, not just manage the disease’s symptoms.
"Unfortunately, there are no preventive therapies for any common disorder of the human nervous system – Alzheimer’s, Parkinson’s, schizophrenia, epilepsy – with the exception of blood pressure-lowering drugs to reduce the likelihood of stroke," said study author James O. McNamara, M.D., professor of neurobiology at Duke Medicine.
Epilepsy is a serious neurological disorder marked by recurring seizures. Temporal lobe epilepsy – where seizures occur in the region of the brain where memories are stored and language, emotions and senses are processed – is the most common form, and can be devastating. Because afflicted individuals have seizures that impair their awareness and may have associated behavioral problems, they may have difficulty with everyday activities, including holding a job or obtaining a driver’s license.
Conventional therapies to treat epilepsy address the disease’s symptoms by trying to reduce the likelihood of having a seizure. However, many people with temporal lobe epilepsy still have seizures despite taking these drugs.
"This study opens a promising new avenue of research into treatments that may prevent the development of epilepsy," said Vicky Whittemore, PhD, a program director at the National Institute of Neurological Disorders and Stroke, who oversees the grants that funded this study.
Retrospective studies of people with severe temporal lobe epilepsy reveal that many of them initially have an episode of prolonged seizures, known as status epilepticus. Status epilepticus is often followed by a period of seizure-free recovery before people start to experience recurring temporal lobe seizures.
In animal studies, inducing status epilepticus in an otherwise healthy animal can cause them to become epileptic. The prolonged seizures in status epilepticus are therefore thought to cause or importantly contribute to the development of epilepsy in humans.
"An important goal of this field has been to identify the molecular mechanism by which status epilepticus transforms a brain from normal to epileptic," said McNamara. "Understanding that mechanism in molecular terms would provide a target with which one could intervene pharmacologically, perhaps to prevent an individual from becoming epileptic."
Earlier research in epilepsy flagged a receptor in the nervous system called TrkB as a key player in transforming the brain from normal to epileptic. In the current study, McNamara and his colleagues sought to confirm if TrkB was important for status epilepticus-induced epilepsy.
Using an approach combining chemistry and genetic analyses, the researchers studied normal and genetically altered mice. The genetically altered mice were unique in that a drug, 1NMPP1, inhibited TrkB in their brains. If the drug stopped the genetically altered mice from becoming epileptic, this genetic approach would prove that inhibiting TrkB prevents the onset of epilepsy.
When the researchers caused status epilepticus in the animals, both the normal and genetically modified mice developed epilepsy. However, treatment with 1NMPP1 after the prolonged period of seizures prevented epilepsy in the genetically altered but not the normal mice.
"This demonstrated that it is possible to intervene following status epilepticus and prevent the animal from becoming epileptic," McNamara said.
Importantly, the researchers only administered treatment with 1NMPP1 for two weeks, which was sufficient to prevent epilepsy from developing in the mice when tested many weeks later. The results suggest that a preventive therapy may only need to be given for a limited period of time following the initial bout of prolonged seizures, not an individual’s entire life, which could prevent unnecessary side effects that come with long-term use of drugs.
In future studies, the researchers hope to determine the exact time window in which TrkB signaling needs to be repressed to prevent the onset of epilepsy. Long term, this research provides a molecular target for developing the first drugs to prevent epilepsy.
"This study provides a strong rationale for the development of selective inhibitors of TrkB signaling," said McNamara.
Pendulum Swings Back on 350-Year-Old Mathematical Mystery
A 350-year-old mathematical mystery could lead toward a better understanding of medical conditions like epilepsy or even the behavior of predator-prey systems in the wild, University of Pittsburgh researchers report.
The mystery dates back to 1665, when Dutch mathematician, astronomer, and physicist Christiaan Huygens, inventor of the pendulum clock, first observed that two pendulum clocks mounted together could swing in opposite directions. The cause was tiny vibrations in the beam caused by both clocks, affecting their motions.
The effect, now referred to by scientists as “indirect coupling,” was not mathematically analyzed until nearly 350 years later, and deriving a formula that explains it remains a challenge to mathematicians still. Now, Pitt professors apply this principle to measure the interaction of “units”—such as neurons, for example—that turn “off” and “on” repeatedly. Their findings are highlighted in the latest issue of Physical Review Letters.
“We have developed a mathematical approach to better understanding the ‘ingredients’ in a system that affect synchrony in a number of medical and ecological conditions,” said Jonathan E. Rubin, coauthor of the study and professor in Pitt’s Department of Mathematics within the Kenneth P. Dietrich School of Arts and Sciences. “Researchers can use our ideas to generate predictions that can be tested through experiments.”
More specifically, the researchers believe the formula could lead toward a better understanding of conditions like epilepsy, in which neurons become overly active and fail to turn off, ultimately leading to seizures. Likewise, it could have applications in other areas of biology, such as understanding how bacteria use external cues to synchronize growth.
Together with G. Bard Ermentrout, University Professor of Computational Biology and professor in Pitt’s Department of Mathematics, and Jonathan J. Rubin, an undergraduate mathematics major, Jonathan E. Rubin examined these forms of indirect communication that are not typically included in most mathematical studies owing to their complicated elements. In addition to studying neurons, the Pitt researchers applied their methods to a model of artificial gene networks in bacteria, which are used by experimentalists to better understand how genes function.
“In the model we studied, the genes turn off and on rhythmically. While on, they lead to production of proteins and a substance called an autoinducer, which promotes the genes turning on,” said Jonathan E. Rubin. “Past research claimed that this rhythm would occur simultaneously in all the cells. But we show that, depending on the speed of communication, the cells will either go together or become completely out of synch with each another.”
To apply their formula to an epilepsy model, the team assumed that neurons oscillate, or turn off and on in a regular fashion. Ermentrout compares this to Southeast Asian fireflies that flash rhythmically, encouraging synchronization.
“For neurons, we have shown that the slow nature of these interactions encouraged ‘asynchrony,’ or firing at different parts of the cycle,” Ermentrout said. “In these seizure-like states, the slow dynamics that couple the neurons together are such that they encourage the neurons to fire all out of phase with each other.”
The Pitt researchers believe this approach may extend beyond medical applications into ecology—for example, a situation in which two independent animal groups in a common environment communicate indirectly. Jonathan E. Rubin illustrates the idea by using a predator-prey system, such as rabbits and foxes.
“With an increase in rabbits will come an increase in foxes, as they’ll have plenty of prey,” said Jonathan E. Rubin. “More rabbits will get eaten, but eventually the foxes won’t have enough to eat and will die off, allowing the rabbit numbers to surge again. Voila, it’s an oscillation. So, if we have a fox-rabbit oscillation and a wolf-sheep oscillation in the same field, the two oscillations could affect each other indirectly because now rabbits and sheep are both competing for the same grass to eat.”
(Source: news.pitt.edu)
New tasks become as simple as waving a hand with brain-computer interfaces
Small electrodes placed on or inside the brain allow patients to interact with computers or control robotic limbs simply by thinking about how to execute those actions. This technology could improve communication and daily life for a person who is paralyzed or has lost the ability to speak from a stroke or neurodegenerative disease.
Now, University of Washington researchers have demonstrated that when humans use this technology – called a brain-computer interface – the brain behaves much like it does when completing simple motor skills such as kicking a ball, typing or waving a hand. Learning to control a robotic arm or a prosthetic limb could become second nature for people who are paralyzed.
“What we’re seeing is that practice makes perfect with these tasks,” said Rajesh Rao, a UW professor of computer science and engineering and a senior researcher involved in the study. “There’s a lot of engagement of the brain’s cognitive resources at the very beginning, but as you get better at the task, those resources aren’t needed anymore and the brain is freed up.”
Rao and UW collaborators Jeffrey Ojemann, a professor of neurological surgery, and Jeremiah Wander, a doctoral student in bioengineering, published their results online June 10 in the Proceedings of the National Academy of Sciences.
In this study, seven people with severe epilepsy were hospitalized for a monitoring procedure that tries to identify where in the brain seizures originate. Physicians cut through the scalp, drilled into the skull and placed a thin sheet of electrodes directly on top of the brain. While they were watching for seizure signals, the researchers also conducted this study.
The patients were asked to move a mouse cursor on a computer screen by using only their thoughts to control the cursor’s movement. Electrodes on their brains picked up the signals directing the cursor to move, sending them to an amplifier and then a laptop to be analyzed. Within 40 milliseconds, the computer calculated the intentions transmitted through the signal and updated the movement of the cursor on the screen.
Researchers found that when patients started the task, a lot of brain activity was centered in the prefrontal cortex, an area associated with learning a new skill. But after often as little as 10 minutes, frontal brain activity lessened, and the brain signals transitioned to patterns similar to those seen during more automatic actions.
“Now we have a brain marker that shows a patient has actually learned a task,” Ojemann said. “Once the signal has turned off, you can assume the person has learned it.”
While researchers have demonstrated success in using brain-computer interfaces in monkeys and humans, this is the first study that clearly maps the neurological signals throughout the brain. The researchers were surprised at how many parts of the brain were involved.
“We now have a larger-scale view of what’s happening in the brain of a subject as he or she is learning a task,” Rao said. “The surprising result is that even though only a very localized population of cells is used in the brain-computer interface, the brain recruits many other areas that aren’t directly involved to get the job done.”
Several types of brain-computer interfaces are being developed and tested. The least invasive is a device placed on a person’s head that can detect weak electrical signatures of brain activity. Basic commercial gaming products are on the market, but this technology isn’t very reliable yet because signals from eye blinking and other muscle movements interfere too much.
A more invasive alternative is to surgically place electrodes inside the brain tissue itself to record the activity of individual neurons. Researchers at Brown University and the University of Pittsburgh have demonstrated this in humans as patients, unable to move their arms or legs, have learned to control robotic arms using the signal directly from their brain.
The UW team tested electrodes on the surface of the brain, underneath the skull. This allows researchers to record brain signals at higher frequencies and with less interference than measurements from the scalp. A future wireless device could be built to remain inside a person’s head for a longer time to be able to control computer cursors or robotic limbs at home.
“This is one push as to how we can improve the devices and make them more useful to people,” Wander said. “If we have an understanding of how someone learns to use these devices, we can build them to respond accordingly.”
The research team, along with the National Science Foundation’s Engineering Research Center for Sensorimotor Neural Engineering headquartered at the UW, will continue developing these technologies.
Freiburg Researchers Use Signals from Natural Movements to Identify Brain Regions
Whether we run to catch a bus or reach for a pen: Activities that involve the use of muscles are related to very specific areas in the brain. Traditionally, their exact location has only been determined through electrical stimulation or unnatural, experimental tasks. A team of scientists in Freiburg has now succeeded for the first time in mapping the brain’s surface using measurements of everyday movements.
Attributing abilities to specific brain regions and identifying pathological areas is especially important in the treatment of epilepsy patients, as severe cases require removal of neural tissue. Until now, such “mapping” involved stimulating individual regions of the brain’s surface with electric currents and observing the reaction or sensation. Alternatively, patients were asked to perform the same movements again and again until the physicians isolated the corresponding patterns in brain activity. However, these methods required for the patient to cooperate and to provide detailed answers to the physicians’ questions. This is a prerequisite that small children or patients with impaired mental abilities can hardly meet, and hence there is a need for other strategies.
Scientists from the group of Dr. Tonio Ball at the Cluster of Excellence “BrainLinks-BrainTools” and the Bernstein Center Freiburg report in the current issue of NeuroImage that the brain’s natural activity during everyday movements can also be used to reliably identify the regions responsible for arm and leg movements.
The researchers examined data from epilepsy patients who had electrodes implanted under their skull prior to surgery. Using video recordings, the team captured the spontaneous movements of their patients, searching for concurrent signals of a certain frequency in the data gathered on the surface of the brain. They succeeded in creating a map of the brain’s surface for arm and leg movements that is as accurate as those created through established experimental methods.
A big hope for the team of researchers is also to gain new insights into the control of movements in the brain, as their method allows them to explore all manner of behaviors and is no longer limited to experimental conditions. Last but not least, the scientists explain that this new method of analyzing signals from the brain will contribute to the development of brain-machine interfaces that are suitable for daily use.
Research discovers link between epilepsy and autism
Our researchers have found a previously undiscovered link between epileptic seizures and the signs of autism in adults.
Dr SallyAnn Wakeford from the Department of Psychology revealed that adults with epilepsy were more likely to have higher traits of autism and Asperger syndrome.
Characteristics of autism, which include impairment in social interaction and communication as well as restricted and repetitive interests, can be severe and go unnoticed for many years, having tremendous impact on the lives of those who have them.
The research found that epileptic seizures disrupt the neurological function that affects social functioning in the brain resulting in the same traits seen in autism.
Dr Wakeford said: “The social difficulties in epilepsy have been so far under-diagnosed and research has not uncovered any underlying theory to explain them. This new research links social difficulties to a deficit in somatic markers in the brain, explaining these characteristics in adults with epilepsy.”
Dr Wakeford and her colleagues discovered that having increased autistic traits was common to all epilepsy types, however, this was more pronounced for adults with Temporal Lobe Epilepsy (TLE).
The researchers suggest that one explanation may be because anti-epileptic drugs are often less effective for TLE. The reason why they suspect these drugs are implicated is because they were strongly related to the severity of autistic characteristics.
Dr Wakeford carried out a comprehensive range of studies with volunteers with epilepsy and discovered that all of the adults with epilepsy showed autism traits.
She said: “It is unknown whether these adults had a typical developmental period during childhood or whether they were predisposed to having autistic traits before the onset of their epilepsy. However what is known is that the social components of autistic characteristics in adults with epilepsy may be explained by social cognitive differences, which have largely been unrecognised until now.”
Dr Wakeford said the findings could lead to improved treatment for people with epilepsy and autism. She said: “Epilepsy has a history of cultural stigma, however the more we understand about the psychological consequences of epilepsy the more we can remove the stigma and mystique of this condition.
“These findings could mean that adults with epilepsy get access to better services, as there is a wider range of treatments available for those with autism condition.”
Margaret Rawnsley, research administration officer at Epilepsy Action welcomed the findings.
She said: “We welcome any research that could further our understanding of epilepsy and ultimately improve the lives of those with the condition. This research has the potential to tell us more about the links between epilepsy and other conditions, such as autism spectrum disorders.”
(Source: bath.ac.uk)
Geneticists Find Causes for Severe Childhood Epilepsies
Researchers at the University of Arizona have successfully determined the genetic mutations causing severe epilepsies in seven out of 10 children for whom the cause of the disorder could not be determined clinically or by conventional genetic testing.
Instead of sequencing each gene one at a time, the team used a technique called whole-exome sequencing: Rather than combing through all of the roughly 3 billion base pairs of an individual’s entire genome, whole-exome-sequencing deciphers only actual genes, and nearly all of them simultaneously.
"My initial hope was that we would find something in one out of the 10 children in our study. But a 70 percent success rate is beyond anyone’s imagination," said study leader Michael Hammer, who is a research scientist in the UA’s Arizona Research Labs Division of Biotechnology and a member of the UA BIO5 Institute.
For Hammer, the research hit very close to home. Just last year, his lab tracked down the mutation that had caused the severe – and ultimately fatal – epilepsy in his teenage daughter.
"I figured, if we could do this for one child, we could do it for others." Hammer explained. "These are children who have had every test imaginable and tried every possible drug combination, and nobody has figured out where their seizures come from and how to stop them."
The children who participated in the study, published online in the journal Epilepsia, all suffered from severe seizure disorders, and most of them started having seizures within the first year or two after birth.
Unlike individuals afflicted with epilepsy later in life, many of whom can live normal lives with the right medical oversight and medications, early-onset epilepsy can be devastating. Children often develop other severe complications such as intellectual disability, autism and loss of muscle tone or coordination. Early death is not uncommon.
"Because their seizures are not well controlled, and that firestorm of electrical activity in the brain is bad for brain development, the damage can be extensive," added Linda Restifo, a professor in the UA department of neurology and a BIO5 member who co-authored the study. "The earlier the seizures start and the more severe and frequent they are, the more likely they are to leave the child with permanent developmental disability."
"The sooner we can catch problems in children and understand what is causing them, the better the chance we have to try and correct them," Hammer added.
To identify changes in the DNA that are the most likely cause of the disorders, the team focused on a class of mutations called de novo mutations: “typos” in the DNA sequence that are present only in the child. In order to find such mutations, the study included both parents and their child.
Overall, the team found 15 mutations in nine children, seven of which are known or likely to cause epilepsy. No mutations could be found in one of the children.
"In four of the patients. we found mutations that were already known to be associated with epilepsy," said Krishna Veeramah, a postdoctoral fellow in Hammer’s group and the study’s first author. "However, three patients had mutations in genes that were not previously associated with epilepsy in humans but presented plausible explanations for the disorder."
"The fact that we found three genes – in a study involving only 10 subjects – that had never been implicated in epilepsy before suggests that many more genetic defects related to developmental brain disorders remain to be discovered," Veeramah said.
One of the participants in the study was Ashley Wilhelm, a 14-year-old girl from Phoenix, Ariz., whose seizures started when she was only 5 months old. Her first seizures appeared to be triggered by fever, leading doctors to believe they were just that – a side effect of the fever.
"But she soon began to have more and more seizures, and they would last half an hour or longer," said her mother, Ann. "We had all sorts of tests done, but the doctors kept saying her brain was normal, and that they didn’t see any reason she’d have those seizures."
Ashley, whose development has severely suffered as a consequence of the repeated seizures, was enrolled in the study through her neurologist, Dinesh Talwar, who co-authored the paper.
Even though her treatment is unlikely to change with the new information, the family said the results brought “more relief than we can explain.”
"Since insurance wouldn’t pay for the testing, and we couldn’t afford it on our own, we were very grateful we were able to participate in the study," said Jeff Wilhelm, Ashley’s father. "If such a test could be done much earlier, it would ease the pain for everyone involved. What if our son had decided not to consider having children of his own out of concern they might have the disorder?"
"The results from this study have at last given us a breakthrough," said the mother of another participating teenager. "We had pursued every possible avenue to understand what might be responsible for his epilepsy – magnetic resonance imaging, CT scans, searches for gross chromosome abnormalities or markers associated with epilepsy – with no success."
"Although the discovery doesn’t yet give us a treatment, it gives us hope for finding one," she said. "As more research is done on this mutation, drugs to control our son’s seizures will be identified. If more children with epilepsy can be studied and families with children with similar mutations can organize and share resources, there will be more progress."
Hammer said the approach is applicable to other conditions in which conventional genetic testing has failed to reveal the cause.
"Our work bridges research and clinical practice," he added. "We can sequence all the genes in your genome in a matter of days and report it to the patient’s family and the physician. That may make a difference in the treatment and management of the disorder in question."
Centers with the capabilities to do this kind of analysis are few and far between.
"Other centers that do this kind of work will sequence your genome and tell you where and what the mutation is in the DNA sequence, but it’s not that simple," Hammer said. "In most cases, we find a mutation in a gene not previously known to cause disease, so we need to perform a follow-up study to find out what that mutation actually does."
To perform these follow-up studies, the UA team has established collaborations with leading scientists at the UA and at other institutions.
"Right now, the benefit to families is primarily to get answers," said Restifo. "The long-term goal is to collect this kind of information from more children, which will hopefully lead to new research into medications that improve brain development and function."
Hammer added: “In the meantime, a molecular diagnosis provides immediate relief to the unnecessary guilt parents might feel for their role in causing their child’s suffering. They want answers, not endless doctors visits and tests with negative results, or to have their hopes raised and dashed over and over.”
Encouraged by the success of their approach so far, Hammer and his colleagues already have bigger plans.
"We hope to involve other clinical areas such as cardiology, immunology, gastroenterology – anything that we can apply molecular diagnostics or clinical genomics to at the UA, we want to explore. We want to make the University the core for clinical diagnostics using new sequencing technologies for at least the entire Southwest."
UA pediatric geneticist Robert Erickson, another co-author and member of the UA Steele Children’s Research Center added, “these efforts will be very important in the diagnosis of newborns with unusual birth defects.”
Epilepsy Cured in Mice Using Brain Cells
Epilepsy that does not respond to drugs can be halted in adult mice by transplanting a specific type of cell into the brain, UC San Francisco researchers have discovered, raising hope that a similar treatment might work in severe forms of human epilepsy.
UCSF scientists controlled seizures in epileptic mice with a one-time transplantation of medial ganglionic eminence (MGE) cells, which inhibit signaling in overactive nerve circuits, into the hippocampus, a brain region associated with seizures, as well as with learning and memory. Other researchers had previously used different cell types in rodent cell transplantation experiments and failed to stop seizures.
Cell therapy has become an active focus of epilepsy research, in part because current medications, even when effective, only control symptoms and not underlying causes of the disease, according to Scott C. Baraban, PhD, who holds the William K. Bowes Jr. Endowed Chair in Neuroscience Research at UCSF and led the new study. In many types of epilepsy, he said, current drugs have no therapeutic value at all.
“Our results are an encouraging step toward using inhibitory neurons for cell transplantation in adults with severe forms of epilepsy,” Baraban said. “This procedure offers the possibility of controlling seizures and rescuing cognitive deficits in these patients.”
The findings, which are the first ever to report stopping seizures in mouse models of adult human epilepsy, will be published online May 5 in the journal Nature Neuroscience.
During epileptic seizures, extreme muscle contractions and, often, a loss of consciousness can cause seizure sufferers to lose control, fall and sometimes be seriously injured. The unseen malfunction behind these effects is the abnormal firing of many excitatory nerve cells in the brain at the same time.
In the UCSF study, the transplanted inhibitory cells quenched this synchronous, nerve-signaling firestorm, eliminating seizures in half of the treated mice and dramatically reducing the number of spontaneous seizures in the rest. Robert Hunt, PhD, a postdoctoral fellow in the Baraban lab, guided many of the key experiments.
In another encouraging step, UCSF researchers reported May 2 that they found a way to reliably generate human MGE-like cells in the laboratory, and that, when transplanted into healthy mice,the cells similarly spun off functional inhibitory nerve cells. That research can be found online in the journal Cell Stem Cell.
In many forms of epilepsy, loss or malfunction of inhibitory nerve cells within the hippocampus plays a critical role. MGE cells are progenitor cells that form early within the embryo and are capable of generating mature inhibitory nerve cells called interneurons. In the Baraban-led UCSF study, the transplanted MGE cells from mouse embryos migrated and generated interneurons, in effect replacing the cells that fail in epilepsy. The new cells integrated into existing neural circuits in the mice, the researchers found.
“These cells migrate widely and integrate into the adult brain as new inhibitory neurons,” Baraban said. “This is the first report in a mouse model of adult epilepsy in which mice that already were having seizures stopped having seizures after treatment.”
The mouse model of disease that Baraban’s lab team worked with is meant to resemble a severe and typically drug-resistant form of human epilepsy called mesial temporal lobe epilepsy, in which seizures are thought to arise in the hippocampus. In contrast to transplants into the hippocampus, transplants into the amygdala, a brain region involved in memory and emotion, failed to halt seizure activity in this same mouse model, the researcher found.
Temporal lobe epilepsy often develops in adolescence, in some cases long after a seizure episode triggered during early childhood by a high fever. A similar condition in mice can be induced with a chemical exposure, and in addition to seizures, this mouse model shares other pathological features with the human condition, such as loss of cells in the hippocampus, behavioral alterations and impaired problem solving.
In the Nature Neuroscience study, in addition to having fewer seizures, treated mice became less abnormally agitated, less hyperactive, and performed better in water-maze tests.
(Source: newswise.com)
Implanted device predicts oncoming seizures in those with epilepsy
A new device may offer hope to people with epilepsy as the technology could predict the onset of seizures in adults who have the condition and can’t be treated with medication, according to Australian scientists.
The small device is implanted in the brain. Researchers at the University of Melbourne said their proof-of-concept study found that it can successfully detect brain activity that would lead to episodes of seizures.
“Knowing when a seizure might happen could dramatically improve the quality of life and independence of people with epilepsy and potentially allow them to avoid dangerous situations, such as driving or swimming, or to take drugs to stop the seizures before they start,” Dr. Mark Cook said.
“The first thing of this was to give people back some independence. If they know when a seizure is going to happen, they can arrange their lives to be better, make themselves safer, go about work and so on in a much more comfortable and relaxed way.”
His complete findings were published Thursday night in the prestigious journal, Lancet Neurology.
Epilepsy is a physical condition marked by sudden, brief changes in the brain’s functioning.
The unusual activity in the brain causes patients to have recurring, unprovoked seizures.
There is a wide spectrum when identifying a seizure, from convulsions on one end to tuning out for just a few seconds before returning to regular activities.
Device monitors abnormal brain activity in patients
In the study, 15 people with focal epilepsy between the ages of 20 and 62 had the device implanted between the skull and brain surface.
The study participants typically experienced between two and 12 seizures per month. Although most cases of epilepsy can be treated with medication, theirs was not responsive to at least two drug therapies.
The device, developed by Seattle-based company NeuroVista, monitors electrical activity in the brain.
Once abnormal electrical activity is flagged, the device sends a message to a second device implanted under the skin of the chest similar to a pacemaker.
The information then makes its way to a wireless, hand-held device that calculates the likelihood of a seizure.
Three coloured lights – red, white or blue – warn users of the probability of encountering a seizure.
The researchers found that the system was right about “high warning” of seizures more than 65 per cent of the time and in about 11 of the 15 subjects.
Eight of the patients kept the device activated for about four months – the accuracy ranged from 56 to 100 per cent.
However, three patients had serious side effects, with two needing the device to be removed.
Cook said the findings are promising. If they’re replicated in larger, longer studies, the technology could even offer insight into how to prevent seizures using fast-acting drugs or brain stimulation to stifle a seizure.