Posts tagged seizures
Posts tagged 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.
The smooth operation of the brain requires a certain robustness to fluctuations in its home within the body. At the same time, its extraordinary power derives from an activity structure poised at criticality. In other words, it is highly responsive to many low-threshold events. When forced beyond its comfort zone in parameter space—its operating temperature, electrolytes, sugars, blood gas or even sensory input— the direct result is seizure, coma, or both. It would appear that anything rendered too hot or cold, too concentrated or scarce, precipitates seizure. In those genetically predisposed, or compromised by head trauma, the seizing tends toward full-blown epilepsy. A group in Hamburg, led by Michael Frotscher has been chipping away at the causes of common form a epilepsy, temporal lobe epilepsy (TLE). Their latest research published in the journal, Cerebral Cortex, takes a closer at differentiated neurons in the dentate gyrus of mouse hippocampus. Once thought to be completely immobilized by virtue of their broadly integrated dendritic trees, these neurons are now shown to become migratory once again in direct response to seizure activity.
Genetic predisposition to seizure can come in the form of ongoing chemical or metabolic imbalance due to defects in enzymes, ion channels or receptors. Alternatively it manifests through direct structural defect as a result of a developmental flaw. In slice preparations, Frotscher looked at a particular form of TLE, where the granule cell layer (GCL) in the dentate gyrus is disrupted. The cells there have either failed to migrate along glial scaffolds into a compact layer with clearly defined margins, or aberrant clumps of cells congregate in the wrong places. Seizures secondary to fever have been known to cause this aberrant migration of granule cells, as has a particular kind of mouse mutant known as the reeler mouse.
The catalog of mouse mutants is expansive; it is a veritable library of hopeless monsters. The reeler mutant, known since 1951, has a unique set of issues wherein cells fail to migrate to the right spots in the cerebellum, cortex, and hippocampus. The protein, reelin was later discovered as one of the causes of this particular phenotype. Reelin is an extracellular matrix protein which initially provides scaffolding for neuron migration, and later a fence to fix neurons in place. In mice with mutated reelin protein, cells in all parts of the hippocampus, not just the dentate gyrus are spread out into a broad and diffuse layer.
By injecting kainate (KA), an excitotoxin that predictably results in seizures, into the dentate gyrus, Frotscher biased the granule cells into entering a phase of bursting activity. With their glutamate receptors fully activated by KA, the granule cells fire rapid volleys of spikes followed by deep depolarization periods. Cells that had been fluorescently labeled with GFP and observed with real time video microscopy were also seen to become motile and dispersed. The normal band of granule cells doubled, or tripled, in thickness. Next, Frostcher looked for a link between this response to KA and the reelin protein. Both reelin mRNA and reelin immunoreactivity were found to be reduced in the dentate granule cells that had been dispersed by KA.
Against this tableau of complex responses to KA, is the fact that adult neurogenesis of dentate granule cells occurs within many mammalian species. A narrowly-defined rostral migratory stream normally delivers fresh cells to both the dentate gyrus and olfactory bulb. Application of BrdU, a marker of newly born cells, labeled microglial and astrocytes near the site of injection, but only a few of the granule cells. As an excitotoxin, KA may be expected to kill at least some cells outright, and cause significant dendritic degeneration in many more. An interesting question to ask, is how does KA induce granule cell dispersion despite the dense interconnections with their neighbors?
During KA induced motility, the nucleus was typically observed to translocate within the cell into one of the dendrites, pulling the soma along with it. This process is believed to involve a myosin-dependant forward flow of actin structural protein within the cell. Outside the cell, changes to the reelin matrix appear to be involved as well. One potential mechanism that has emerged is that reelin induces serine phosporylation of cofilin, an actin-associated protein involved in depolymerization. The authors conclude reelin-induced cofilin phosphorylation controls neuronal migration during development, and prevents abnormal motility in the mature brain.
Undoubtedly many mechanisms are involved in the KA-induced seizure and reelin story. Other cell types in the dentate gyrus need to be looked at in closer detail. For example, how reelin expression is regulated, and which cells manufacture it are current areas of study. It is important as well to differentiate between the causes of seizure, and its consequences. On paper they can be neatly packaged concepts but in the real tissue, and in intact animals, they can be anything but.
Electroencephalogram (EEG), which measures and records electrical activity in the brain, is a quick and efficient way of determining whether seizures are the cause of altered mental status (AMS) and spells, according to a study by scientists at the UC San Francisco.
The research, which focused on patients who had been given an EEG after being admitted to the hospital for symptoms such as AMS and spells, appears on March 27 in Mayo Clinic Proceedings.
“We have demonstrated a surprisingly high frequency of seizures – more than 7 percent – in a general inpatient population,” said senior investigator John Betjemann, MD, a UCSF assistant professor of neurology. “This tells us that EEG is an underutilized diagnostic tool, and that seizures may be an underappreciated cause of spells and AMS.”
The results are important, he said, because EEG can identify treatable causes of AMS or spells, and because “it can prompt the physician to look for an underlying reason for seizures in persons who did previously have them.”
Seizures are treatable with a number of FDA-approved anticonvulsants, he said, “so patients who are quickly diagnosed can be treated more rapidly and effectively. This may translate to shorter lengths of stay and improved patient outcomes.”
In one of the first studies of its kind, Betjemann and his team analyzed the medical records of 1,048 adults who were admitted to a regular inpatient unit of a tertiary care hospital and who underwent an EEG. They found that 7.4 percent of the patients had a seizure of some kind while being monitored.
“As I tell my patients, seizures come in all different flavors, from a dramatic convulsion to a subtle twitching of the face or hand or finger,” said Betjemann. “There might be no outward manifestation at all, other than that the person seems a little spacey. It’s easily missed by family members and physicians alike, but can be picked up by EEG.”
Another 13.4 percent of patients had epileptiform discharges, which are abnormal patterns that indicate patients are at an increased risk of seizures.
Almost 65 percent of patients had their first seizure within one hour of EEG recording, and 89 percent within six hours.
“This is good news for smaller hospitals that don’t have 24 hour EEG coverage, but that do have a technician on duty during the day,” Betjemann said.
He speculated that lack of 24-hour coverage is a major reason that EEG is not used as an inpatient diagnostic tool as often as it might be. “This paper shows that, fortunately, it’s not necessary. Almost two thirds of patients with seizures can be identified in the first hour, and almost 90 percent in the course of a shift.”
EEGs are easy to obtain, painless and noninvasive, said Betjemann. “The technician applies some paste and electrodes and hooks up the machine. All the patient has to do is rest in bed.”
Betjemann said that the next logical research step would be a prospective study. “We have to start at the beginning, see if patients are altered when they are admitted, and do an EEG in a formal standardized setting. Then we’d want to see how often EEG is changing the management of patients – either starting or stopping medications,” he said. “A patient may be having spells, and an EEG might tell you this is not a seizure, and that it’s important not to treat it with anti-epileptic medications.”
(Image: Rex Features)