Posts tagged seizures
Posts tagged seizures
New research by clinical psychologists from Arizona State University and the United Kingdom has revealed seizures that could be mistaken for epilepsy are linked to feelings of anxiety.
The team of researchers devised a new set of tests to determine whether there was a link between how people interpret and respond to anxiety, and incidences of psychogenic nonepileptic seizures (PNES).
Nicole Roberts, an associate professor in ASU’s New College of Interdisciplinary Arts and Sciences, collaborated with colleagues from the University of Lincoln, University of Nottingham and University of Sheffield in the United Kingdom. The team’s findings were published in the journal Epilepsy and Behavior.
The researchers used a series of questionnaires and computer tests to determine if a patient regularly avoids situations which might bring on anxiety.
These tests correctly predicted whether a patient had epilepsy or PNES – seizures that can be brought on by threatening situations, sensations, emotions, thoughts or memories – in 83 percent of study participants. Such seizures appear on the surface to be similar to epileptic fits, which are caused by abnormal brain activity.
“This research underscores the fact that PNES is a ‘real’ and disabling disorder with a potentially identifiable pathophysiology,” said Roberts, who directs New College’s Emotion, Culture, and Psychophysiology Laboratory, located on ASU’s West campus. “We need to continue to search for answers, not just in epilepsy clinics, but also in the realm of affective science and complex brain-behavior relationships.”
“PNES can be a very disabling condition, and it is important that we understand the triggers so that we provide the correct care and treatment,” said Lian Dimaro, a clinical psychologist based at Nottinghamshire Healthcare NHS Trust, who served as lead researcher for the study.
“This study was one of the first to bring modern psychological tools of investigation to this problem,” Dimaro said. “The findings support the idea that increasing a person’s tolerance of unpleasant emotions and reducing avoidant behavior may help with treatment, suggesting that patients could benefit from a range of therapies, including acceptance and commitment therapy to help reduce the frequency of seizures, although more research is needed in this area.”
Participants completed questionnaires to determine the level to which they suffered from anxiety, their awareness of their experiences and if they would avoid situations which would make them feel anxious.
They then completed a computer task which required rapid responses to true or false statements. This test was designed to gather data on immediate, or implicit, beliefs about anxiety. Participants also answered questions about common physical complaints that may have no medical explanation, also called somatic symptoms. These can include things like gastrointestinal problems, tiredness and back pain.
Results showed that those with PNES reported significantly more somatic symptoms than others in the study, as well as avoidance of situations which might make them anxious. The group with PNES also scored significantly higher on a measure of how aware they were of their anxiety compared with the control group.
The test subjects were 30 adults with PNES, 25 with epilepsy and 31 with no reported history of seizures who served as a nonclinical control group.
The researchers suggest that including tests to determine levels of anxiety and avoidance behavior may enable health professionals to make earlier diagnosis, and develop more effective intervention plans.
“Epileptic seizures are caused by abnormal electrical activity in the brain, while most PNES are thought to be a consequence of complex psychological processes that manifest in physical attacks,” said David Dawson, a research clinical psychologist from the University of Lincoln.
“It is believed that people suffering with PNES may have difficulty actively engaging with anxiety – a coping style known as experiential avoidance,” Dawson said. “We wanted to examine whether it was possible to make a clear link between seizure frequency and how people experience and manage anxiety. Our study is another step in understanding PNES, which could ultimately lead to better treatment and, therefore, patient outcomes in the future.”
Roberts, who received her doctorate in clinical psychology from the University of California, Berkeley, focuses her research on the study of emotion and on the cultural and biological forces that shape emotional responses. Examples include investigating how ethnicity and culture influence emotional displays and experiences; how the daily hassles of life, such as job stress and sleep deprivation, impact emotion regulation among individuals and couples; and how the emotion system breaks down in patients with psychopathology (such as PNES and post-traumatic stress disorder) or neurological dysfunction (such as epilepsy).
For patients with mesial temporal lobe epilepsy (MTLE) that can’t be controlled by medications, a minimally invasive laser procedure performed under MRI guidance provides a safe and effective alternative to surgery, suggests a study in the June issue of Neurosurgery, official journal of the Congress of Neurological Surgeons. The journal is published by Lippincott Williams & Wilkins, a part of Wolters Kluwer Health.
"Real-time magnetic resonance-guided stereotactic laser amygdalohippocampotomy (SLAH) is a technically novel, safe and effective alternative to open surgery," according to the new research by Dr. Robert E. Gross of Emory University School of Medicine, Atlanta, and colleagues.
MRI Guides Precise Laser Destruction of Area Causing Epilepsy…
The researchers report their experience with MRI-guided SLAH in 13 adult patients with epilepsy mapped to a part of the brain called the mesial temporal lobe. The patients, median age 24 years, had “intractable” seizures despite treatment with antiepileptic drugs.
In the SLAH procedure, a saline-cooled fiberoptic laser probe was precisely targeted to the area of the brain—the “amygdalohippocampal complex”—responsible for the procedures. Using real-time MRI guidance, the neurosurgeon was able to pinpoint the area of the brain responsible for seizure activity and destroy (ablate) by computer-controlled laser energy, without harming neighboring brain tissue.
The technical aspects of the procedure were successfully carried out in all patients. Using thermal imaging and MRI guidance, the surgeons were able to see the area of laser ablation as treatment proceeded. The average laser exposure time was just under ten minutes.
On average, 60 percent of the amygdalohippocampal complex was destroyed in the SLAH procedure; the average length of the ablated area was 2.5 centimeters. Median time spent in the hospital was just one day—compared to a typical two to five-day stay after conventional temporal lobe surgery, and SLAH patients did not have to be admitted to the intensive care unit.
…With Good Control of Seizures at Follow-Up
Most important, the procedure was effective in reducing or eliminating seizures in patients with MTLE. At a median of 14 months after SLAH, ten out of thirteen patients achieved meaningful seizure reductions, while seven were free of “disabling seizures.” This included six out of nine patients whose epilepsy was caused by an abnormality called mesial temporal sclerosis.
Although some complications occurred, none were directly caused by laser application. Two patients had an additional SLAH procedure to control seizures, and another patient underwent standard open surgery.
Open brain surgery is the standard treatment for patients with intractable MTLE. Surgery has a high success rate, but carries a significant risk of neurological and cognitive (intellectual) impairment. Minimally invasive approaches like the new MRI-guided laser ablation technique might produce similar seizure control with lower risks than surgery.
The new study shows “technical feasibility and encouraging results” with the minimally invasive MRI-guided SLAH technique for patients with MTLE. Effectiveness in relieving or eliminating seizures approaches that of surgery—perhaps especially among patients whose seizures are caused by mesial temporal sclerosis. “These are promising results considering that this reflects our initial experience, and results may improve with greater experience with this novel technique,” notes Dr. Gross.
"Such minimally invasive techniques may be more desirable to patients and result in increased use of epilepsy surgery among the large number of medically intractable epilepsy patients," Dr. Gross and colleagues conclude. They note that a larger, longer-term study of SLAH is underway, including assessment of the effects on cognitive function as well as seizures.
A study out today in the journal Nature Medicine suggests a potential new treatment for the seizures that often plague children with genetic metabolic disorders and individuals undergoing liver failure. The discovery hinges on a new understanding of the complex molecular chain reaction that occurs when the brain is exposed to too much ammonia.
The study shows that elevated levels of ammonia in the blood overwhelm the brain’s defenses, ultimately causing nerve cells to become overexcited. The researchers have also discovered that bumetanide – a diuretic drug used to treat high blood pressure – can restore normal electrical activity in the brains of mice with the condition and prevent seizures.
“Ammonia is a ubiquitous waste product of regular protein metabolism, but it can accumulate in toxic levels in individuals with metabolic disorders,” said Maiken Nedergaard, M.D., D.M.Sc., co-director of the University of Rochester Medical Center (URMC) Center for Translational Neuromedicine and lead author of the article. “It appears that the key to preventing the debilitating neurological effects of ammonia toxicity is to correct a molecular malfunction which causes nerve cells in the brain to become chemically unbalanced.”
In healthy people, ammonia is processed in the liver, converted to urea, and expelled from the body in urine. Because it is a gas, ammonia can slip through the blood-brain-barrier and make its way into brain tissue. Under normal circumstances, the brain’s housekeeping cells – called astrocytes – sweep up this unwanted ammonia and convert it into a compound called glutamine which can be more easily expelled from the brain.
However, individuals with certain genetic metabolic disorders and people with impaired liver function because of chronic hepatitis, alcoholism, acetaminophen overdose, and other toxic liver conditions cannot remove ammonia from their bodies quickly enough. The result is a larger than normal concentration of ammonia in the blood, a condition called hyperammonemia.
When too much ammonia makes its way into the central nervous system, it can lead to tremors, seizures and, in extreme cases, can cause comas and even lead to death. In children with metabolic disorders the frequent seizures can lead to long-term neurological impairment.
While ammonia has long been assumed to be the culprit behind the neurological problems associated with inherited metabolic disorders and liver failure, the precise mechanisms by which it triggers seizures and comas have not been fully understood. The new study reveals that ammonia causes a chain of events that alters the chemistry and electrical activity of the brain’s nerve cells, causing them to fire in uncontrolled bursts.
One of the keys to unraveling the effects of ammonia on the brain has been new imagining technologies such as two-photon microscopy which allow researchers to watch this phenomenon in real time in the living brains of mice. As suspected, they observed that when high levels of ammonia enter the brain, astrocytes become quickly overwhelmed and cannot remove it fast enough.
The abundant ammonia in the brain mimics the function of potassium, an important player in neurotransmission, and tricks neurons into becoming depolarized. This makes it more likely that electrical activity in the brain will exceed the threshold necessary to trigger seizures.
Furthermore, the researchers observed that one of the neuron’s key molecular gatekeepers – a transporter known as NKCC1 – was also fooled into thinking that the ammonia was potassium. As a result, it went into overdrive, loading neurons with too much chloride. This in turn prevents the cells from stabilizing itself after spikes in activity, keeping the cells in a heightened level of electrical “excitability.”
The team found that the drug bumetanide, a known NKCC1 inhibitor, blocked this process and prevented the cells from overloading with chloride. By knocking down this “secondary” cellular effect of ammonia, the researchers were able to control the seizures in the mice and prolong their survival.
“The neurologic impact of hyperammonemia is a tremendous clinical problem without an effective medical solution,” said Nedergaard. “The fact that bumetanide is already approved for use gives us a tremendous head start in terms of developing a potential treatment for this condition. This study provides a framework to further explore the therapeutic potential of this and other NKCC1 inhibitors.”
50 years after valproate was first discovered, research published today in the journal Neurobiology of Disease, reports how the drug works to block seizure progression.
Valproate (variously labelled worldwide as Epilim, Depacon, Depakene, Depakote, Orlept, Episenta, Orfiril, and Convulex) is one of the world’s most highly prescribed treatments for epilepsy. It was first discovered to be an effective treatment for epilepsy, by accident, in 1963 by a group of French scientists. In thousands of subsequent experiments, animals have been used to investigate how valproate blocks seizures, without success. Scientists from Royal Holloway and University College London have now identified how valproate blocks seizures in the brain, by using a simple amoeba.
“The discovery of how valproate blocks seizures, initially using the social amoeba Dictyostelium, and then replicated using accepted seizure models, highlights the successful use of non-animal testing in biomedical research,” said Professor Robin Williams from the School of Biological Sciences at Royal Holloway.
“Sodium valproate is one of the most effective antiepileptic drugs in many people with epilepsy, but its use has been limited by side-effects, in particular its effect in pregnant women on the unborn child,” said Professor Matthew Walker from the Institute of Neurology at University College London. “Understanding valproate’s mechanism of action is a first step to developing even more effective drugs that lack many of valproate’s side-effects.
“Our study also found that the decrease of a specific chemical in the brain at the start of the seizure causes even more seizure activity. This holds important implications for identifying underlying causes,” added Professor Williams.
When Chris Chafe and Josef Parvizi began transforming recordings of brain activity into music, they did so with artistic aspirations. The professors soon realized, though, that the work could lead to a powerful biofeedback tool for identifying brain patterns associated with seizures.
Josef Parvizi was enjoying a performance by the Kronos Quartet when the idea struck. The musical troupe was midway through a piece in which the melodies were based on radio signals from outer space, and Parvizi, a neurologist at Stanford Medical Center, began wondering what the brain’s electrical activity might sound like set to music.
He didn’t have to look far for help. Chris Chafe, a professor of music research at Stanford, is one of the world’s foremost experts in “musification,” the process of converting natural signals into music. One of his previous works involved measuring the changing carbon dioxide levels near ripening tomatoes and converting those changing levels into electronic performances.
Parvizi, an associate professor, specializes in treating patients suffering from intractable seizures. To locate the source of a seizure, he places electrodes in patients’ brains to create electroencephalogram (EEG) recordings of both normal brain activity and a seizure state.
He shared a consenting patient’s EEG data with Chafe, who began setting the electrical spikes of the rapidly firing neurons to music. Chafe used a tone close to a human’s voice, in hopes of giving the listener an empathetic and intuitive understanding of the neural activity.
Upon a first listen, the duo realized they had done more than create an interesting piece of music. [Listen to the audio here]
"My initial interest was an artistic one at heart, but, surprisingly, we could instantly differentiate seizure activity from non-seizure states with just our ears," Chafe said. "It was like turning a radio dial from a static-filled station to a clear one."
If they could achieve the same result with real-time brain activity data, they might be able to develop a tool to allow caregivers for people with epilepsy to quickly listen to the patient’s brain waves to hear whether an undetected seizure might be occurring.
Parvizi and Chafe dubbed the device a “brain stethoscope.”
The sound of a seizure
The EEGs Parvizi conducts register brain activity from more than 100 electrodes placed inside the brain; Chafe selects certain electrode/neuron pairings and allows them to modulate notes sung by a female singer. As the electrode captures increased activity, it changes the pitch and inflection of the singer’s voice.
Before the seizure begins – during the so-called pre-ictal stage – the peeps and pops from each “singer” almost synchronize and fall into a clear rhythm, as if they’re following a conductor, Chafe said.
In the moments leading up to the seizure event, though, each of the singers begins to improvise. The notes become progressively louder and more scattered, as the full seizure event occurs (the ictal state). The way Chafe has orchestrated his singers, one can hear the electrical storm originate on one side of the brain and eventually cross over into the other hemisphere, creating a sort of sing-off between the two sides of the brain.
After about 30 seconds of full-on chaos, the singers begin to calm, trailing off into their post-ictal rhythm. Occasionally, one or two will pipe up erratically, but on the whole, the choir sounds extremely fatigued.
It’s the perfect representation of the three phases of a seizure event, Parvizi said.
Part art exhibit, part experiment
Caring for a person with seizures can be very difficult, as not all seizure activity manifests itself with behavioral cues. It’s often impossible to know whether a person with epilepsy is acting confused because they are having a seizure, or if they are experiencing the type of confusion that is a marker of the post-ictal seizure phase.
To that end, Parvizi and Chafe hope to apply their work to develop a device that listens for the telltale brain patterns of an ongoing seizure or a post-ictal fatigued brain state.
"Someone – perhaps a mother caring for a child – who hasn’t received training in interpreting visual EEGs can hear the seizure rhythms and easily appreciate that there is a pathological brain phenomenon taking place," Parvizi said.
The device can also offer biofeedback to non-epileptic patients who want to hear the music their own brain waves create.
The effort to build this device is funded by Stanford’s Bio-X Interdisciplinary Initiatives Program (Bio-X IIP), which provides money for interdisciplinary projects that have potential to improve human health in innovative ways. Bio-X seed grants have funded 141 research collaborations connecting hundreds of faculty since 2000. The proof-of-concept projects have produced hundreds of publications, dozens of patents, and more than a tenfold return on research funds to Stanford.
From a clinical perspective, the work is still very experimental.
"We’ve really just stuck our finger in there," Chafe said. "We know that the music is fascinating and that we can hear important dynamics, but there are still wonderful revelations to be made."
Next year, Chafe and Parvizi plan to unveil a version of the system at Stanford’s Cantor Arts Center. Visitors will don a headset that will transmit an EEG of their brain activity to their handheld device, which will convert it into music in real time.
"This is what I like about Stanford," Parvizi said. "It nurtures collaboration between fields that are seemingly light-years apart – we’re neurology and music professors! – and our work together will hopefully make a positive impact on the world we live in."
People with epilepsy could be helped by new research into the way a key molecule controls brain activity during a seizure.
Researchers have identified the role played by of a protein – called BDNF – and say the discovery could lead to new drugs that calm the symptoms of epileptic seizures.
Scientists analysed the way cells communicate when the brain is most active – such as in epileptic seizures – when electrical signalling by the brain’s neurons is increased.
They found that the BDNF molecule – which is known to be released in the brain during seizures – blocks a specific process known as activity-dependent bulk endocytosis (ABDE).
By blocking this process during an epileptic seizure, BDNF increases the release of neurotransmitters and causes heightened electrical activity in the brain.
Since ADBE is only triggered during high brain activity, drugs designed to target this process could have fewer side effects for normal day to day brain function, researchers say.
Experts say that not all epilepsy patients respond to current drug treatments and the finding could lead to the development of new medicines.
The team, however, offered a word of caution. Since ABDE is also implicated in a range of brain functions, such as creating new memories, more research is needed to establish what the effects of manipulating this molecule might be on these key processes.
The study, led by the University of Edinburgh, is published in the journal Nature Communications. The research was funded by the Wellcome Trust and the Medical Research Council.
Dr Mike Cousin, of the University of Edinburgh’s Centre for Integrative Physiology, who led the research, said: “Around one third of people with epilepsy do not respond to the treatments we currently have available. By studying the way brain cells behave during seizures, we have been able to uncover an exciting new research avenue for research into anti-epileptic therapies.”
Researchers will now focus on identifying specific genes that control this brain process to determine whether they hold the key to new drug treatments.
Neuroscientists often use electroencephalography (EEG) as an inexpensive way to record electrical signals in the brain. Though it would be useful to run these recordings for long periods of time, that usually isn’t practical: EEG recording traditionally involves attaching many electrodes and cables to a patient’s scalp.
Now engineers at Imperial College in London have developed an EEG device that can be worn inside the ear, like a hearing aid. They say the device will allow scientists to record EEGs for several days at a time; this would allow doctors to monitor patients who have regularly recurring problems like seizures or microsleep.
“The ideal is to have a very stable recording system, and recordings which are repeatable,” explains co-creator Danilo Mandic. “It’s not interfering with your normal life, because there are acoustic vents so people can hear. After a while, they forget they’re having an EEG.”
By nestling the EEG inside the ear, the engineers avoid a lot of signal noise usually introduced by body movement. They can also ensure that the electrodes are always placed in exactly the same spot, which, they say, will make repeated readings more reliable.
Since the device attaches to just one area, it can record only from the temporal region. This limits its potential applications to events that involve local activity. Tzzy-Ping Jung, co-director of the University of California, San Diego’s Center for Advanced Neurological Engineering, says that this does not mean the device will not be valuable.
“Different modalities will have different applications. I would not rule out the usefulness of any modalities,” says Jung. “I think it’s a very good idea with very promising results.”
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 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.
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.