Accessible subtle epilepsy of Epilepsy

People regularly feel panicked when they hear that their tyke had epilepsy. In any case, anticonvulsant medications can keep the event of seizures in 75 percent of epileptic youngsters.

Previously, those diagnosed with epilepsy were thought to need deep rooted medication treatment to keep their seizures. Get some information about any new alternatives accessible for treatment. Presently how about we examine in subtle element what is epilepsy sickness? It's regularly a staggering knowledge when we get the opportunity to see an individual having hit by an epileptic seizure.

A neurological issue

Epilepsy is a neurological issue described by seizures. Roughly 33% of individuals with cerebral paralysis likewise have some level of epilepsy. It is acknowledged that in individuals with both conditions, the etiology is connected; that is, the same cerebrum harm in charge of the cerebral paralysis is in all probability the reason for the epilepsy.

While youth epilepsy happens in numerous structures, the most well-known is unlucky deficiency epilepsy. Epilepsy is a condition which influences the correspondence between the nerve cells of the sensory system when there is a sudden overactive electrical release in the mind.

Alternative obligation that maters a lot

We as www.newspsychology.com have done a lot of work on this regard and we found out that the alternate obliges that when the child sticks to a high fat eating routine that limits carbs for a long time. Following two years, the kid can start to steadily include sugars once again into his or her eating regimen without the event of seizures.

While neither of these methodologies is new, they speak to substantial choices when others come up short. Epilepsy is an endless issue happening most regularly in teenagers and the elderly. It can likewise happen in patients that have as of late had or recouped from mind surgery. The medications utilized regularly had unfavourable symptoms that blocked them from taking part in ordinary social exercises. Then again, new medicines and treatment conventions are accessible today. 

Seriousness of epilepsy seizures: things that is crucial

Epilepsy can be viewed as an emotional sickness. This is likewise not genuine. Epilepsy is a physical condition with real physical appearances. It influences engine capacities amid the seizure.

It doesn't weaken a singular's brain science. Once diagnosed, epilepsies can be grouped in an assortment of ways and this likewise constitutes one of the more essential pushes when drug looks to characterize epilepsy. The most widely recognized method for characterization investigates the birthplace of the seizures in light of which a piece of the mind the unusual movement is originating from. In middle age, a portion of the reasons for epilepsy are strokes, tumours and different sores.

Particular sizes of epilepsy seizures

Epilepsy is infectious! This is an enormous confusion that causes individuals to modest far from individuals with epilepsy. This is in no way, shape or form genuine. This method makes ready for prominent treatment choices and pharmaceutical that can help minimize or lessen the recurrence and seriousness of epilepsy seizures. Anticonvulsants are exceptionally prevalent in such manner in light of the fact that there is presently a high level of connection between particular seizure disorder sorts and the anticonvulsants that work best with those conditions.

Strategies that are meaningful

Our studies conducted by www.newspsychology.com show The more reasonable and general techniques for the treatment of epilepsy are a hostile to epileptic treatment and surgeries. It is apropos to specify that these two strategies are not corrective. Epileptic patients ought to take the recommended medicine routinely. They help control seizures. The patient ought to experience standard checkups. At the point when the solution does not help, surgery is the following choice.

Then again, give careful consideration to your way of life to enhance and keep up psychological well-being in great condition. Children may have a deformity in his mind at birth. They may have endured a head damage or infection. In teenagers, extreme head injury is the most widely recognized known reason for epilepsy. 

Steps and treatment for the ailment of Epilepsy

In epilepsy this request is disturbed by some neurone releasing flags improperly. Epilepsy is not a solitary circumstance, but rather a gathering of conditions with complementary reasons for medicines and anticipations or at times depression.

There may be a sort of brief electrical tempest emerging from neurones that are naturally flimsy in view of a hereditary desert as in the different sorts of acquired epilepsy, or from neurones made precarious by metabolic irregularities, for example, low blood glucose, or liquor. Then again, the unusual release may originate from a limited zone of the cerebrum. This is the circumstance in patients with epilepsy brought about by head harm, or mind tumour.

Controlling the best ailment to happen

Epilepsy can strike anybody whenever, yet it is not an ailment. It influences the cerebrum; however it is not a mental or psychiatric mishap and also issue. It might not bring here things are going to be from place to place, however it is not infectious.

It is not typically treatable, but rather in up to 80 every penny of cases it can be controlled successfully by drugs. Even though epilepsy can begin anytime amid in life of many, most of the epilepsy is diagnosed in the youth, and irrespective of all in the first year of life – around 140 out of every infant not less than 100,000 infants who are not less than at least one year old are diagnosed with epilepsy every year.

Things that drop the best dominant idea

This drops to 40 adults every 100,000. The dominant part of individuals with epilepsy takes against epileptic pharmaceutical to stop or lessen the quantity of ceases they have. It is ordinary to talk about somebody having epilepsy; however it may be better especially in connection to advancing better medication treatment if we somehow happened to think as far as one of the epilepsies. Epilepsy is an extremely individual condition and individuals can have altogether different encounters.. 

Scientists show biological mechanism can trigger epileptic seizures

Scientists have discovered the first direct evidence that a biological mechanism long suspected in epilepsy is capable of triggering the brain seizures — opening the door for studies to seek improved treatments or even preventative therapies.

Researchers at Cincinnati Children's Hospital Medical Center report Sept. 19 in Neuron that molecular disruptions in small neurons called granule cells — located in the dentate gyrus region of the brain — caused brain seizures in mice similar to those seen in human temporal lobe epilepsy. The dentate gyrus is in the hippocampus of the temporal lobe, and temporal lobe epilepsy is one of the most common forms of the disorder.

"Epilepsy is one of those rare disorders where we have no real preventative therapies, and current treatments after diagnosis can have significant side effects," said Steven Danzer, PhD, principal investigator on the study and a neuroscientist in the Department of Anesthesia at Cincinnati Children's. "Establishing which cells and mechanisms are responsible for the seizures allows us to begin working on ways to control or eliminate the problem therapeutically, and in a more precise manner."

Epilepsy can develop from a wide range of causes, including birth defects in children that disrupt normal brain development. It can also surface in children and adults who suffer serious brain injuries. These individuals can have high risk of developing some form of epilepsy, depending on the location and severity of their injury, Danzer said.

Technical advances in genetically altering laboratory mice to mimic human disease made it possible for the scientists to generate animals with a specific molecular disruption in dentate gyrus granule cells (DGCs). DGCs are one of only two populations of neural cells that continue to form in significant numbers in the mature brain — the other being olfactory neurons. This is beneficial considering the hippocampus is responsible for learning and memory, and the dentate gyrus acts as a gate for excitatory signals in the brain that can lead to seizures if not properly regulated.

The presence of abnormal DGCs in epilepsy has been observed for decades, although evidence linking them to seizures was lacking until the current study. Danzer and his colleagues were able to delete a gene called PTEN from mouse DGCs that formed after birth. This caused hyper-activation of a molecular pathway called mTOR (mammalian target of rapamycin), which regulates cell growth and is also linked to tumor formation and cancer when hyper-activated under certain circumstances.

In tests by Danzer and his colleagues, hyper-activation of mTOR caused mice to develop abnormal neural connections among their DGCs — similar to that observed in human temporal lobe epilepsy — and the animals experienced seizures. Abnormal neural connections and seizures occurred even in mice that had the PTEN gene deleted in less than 10 percent of their total DGC population, strengthening the link between biological disruption of DGCs and seizures.

When researchers treated epileptic mice with a drug that blocks the mTOR pathway — rapamycin — the seizures stopped, solidifying the link to the PTEN-mTOR pathway. Rapamycin has been tested successfully at Cincinnati Children's in the treatment of a disease called tuberous sclerosis, in which benign but still dangerous tumors can form around critical organs. Interestingly, people with tuberous sclerosis are also at risk for developing epilepsy, Danzer said. Newer mTOR inhibitors are also being tested at Cincinnati Children's for the treatment of epilepsy.

Danzer is following up the current study by trying to eliminate abnormal DGCs from the brains of mice that already have epilepsy and to see if this will stop the seizures. Researchers are attempting this by treating mice systemically with diphtheria toxin.

Although diphtheria toxin is not normally toxic to mouse cells, in their experiments the researchers will add a molecule to abnormal mouse DGCs that binds with the toxin. In theory, this should allow the toxin to kill off abnormal DGCs. If treatment stops the seizures, it would further verify the connection between abnormal DGCs and the onset of epilepsy, Danzer said. This would also allow researchers to begin laboratory testing of prospective therapeutic strategies for treatment and prevention.

Mutations involving PTEN and the mTOR pathway have also been identified in other neurological conditions, such as autism and schizophrenia. Danzer said findings in the current study will likely attract the interest of researchers studying these diseases and others involving abnormal granule neurons generated after birth.

"The profound impact of disrupting this pathway in just a small number of granule cells suggests the dentate may be a critical target for mTOR pathway mutations in other neurological diseases," Danzer said. "We believe neuroscientists will be surprised by the huge neurological impact of granule cell disruption and interested in the demonstration of a potentially novel disease mechanism."

First author on the current study was Raymond Y.K. Pun, PhD, a researcher in the Department of Anesthesia at Cincinnati Children's. Funding for the research came from the Cincinnati Children's Research Foundation and the National Institute of Neurological Disorders and Stroke (R01NS065020 and R01NS062806).

 

Journal Reference:

  1. Raymund Y.K. Pun, Isaiah J. Rolle, Candi L. LaSarge, Bethany E. Hosford, Jules M. Rosen, Juli D. Uhl, Sarah N. Schmeltzer, Christian Faulkner, Stefanie L. Bronson, Brian L. Murphy, David A. Richards, Katherine D. Holland, Steve C. Danzer. Excessive Activation of mTOR in Postnatally Generated Granule Cells Is Sufficient to Cause Epilepsy. Neuron, 2012; 75 (6): 1022 DOI: 10.1016/j.neuron.2012.08.002

Engineered flies spill secret of seizures

Scientists have observed the neurological mechanism behind temperature-dependent — febrile — seizures by genetically engineering fruit flies to harbor a mutation analogous to one that causes epileptic seizures in people. In addition to contributing the insight on epilepsy, their new study also highlights the first use of genetic engineering to swap a human genetic disease mutation into a directly analogous gene in a fly.

In a newly reported set of experiments that show the value of a particularly precise but difficult genetic engineering technique, researchers at Brown University and the University of California-Irvine have created a Drosophila fruit fly model of epilepsy to discern the mechanism by which temperature-dependent seizures happen.

The researchers used a technique called homologous recombination — a more precise and sophisticated technique than transgenic gene engineering — to give flies a disease-causing mutation that is a direct analogue of the mutation that leads to febrile epileptic seizures in humans. They observed the temperature-dependent seizures in whole flies and also observed the process in their brains. What they discovered is that the mutation leads to a breakdown in the ability of certain cells that normally inhibit brain overactivity to properly regulate their electrochemical behavior.

In addition to providing insight into the neurology of febrile seizures, said Robert Reenan, professor of biology at Brown and a co-corresponding author of the paper in the Journal of Neuroscience, the study establishes

"This is the first time anyone has introduced a human disease-causing mutation overtly into the same gene that flies possess," Reenan said.

Engineering seizures

Homologous recombination (HR) starts with the transgenic technique of harnessing a transposable element (jumping gene) to insert a specially mutated gene just anywhere into the fly's DNA, but then goes beyond that to ultimately place the mutated gene into exactly the same position as the natural gene on the X chromosome. HR does this by outfitting the gene to be handled by the cell's own DNA repair mechanisms, essentially tricking the cell into putting the mutant copy into exactly the right place. Reenan's success with the technique allowed him to win a special grant from the National Institutes of Health last year.

The new paper is a result of that grant and Reenan's collaboration with neurobiologist Diane O'Dowd at UC-Irvine. Reenan and undergraduate Jeff Gilligan used HR to insert a mutated version of the para gene in fruit flies that is a direct parallel of the mutation in the human gene SCN1A that causes febrile seizures in people.

When the researchers placed flies in tubes and bathed the tubes in 104-degree F water, the mutant fruit flies had seizures after 20 seconds in which their legs would begin twitching followed by wing flapping, abdominal curling, and an inability to remain standing. After that, they remained motionless for as long as half an hour before recovering. Unaltered flies, meanwhile, exhibited no temperature-dependent seizures.

The researchers also found that seizure susceptibility was dose-dependent. Female flies with mutant strains of both copies of the para gene (females have two copies of the X chromosome) were the most susceptible to seizures. Those in whom only one copy of the gene was a mutant were less likely than those with two to seize, but more likely than the controls.

While the researchers at Brown compared the seizure susceptibility of whole flies, O'Dowd, lead author Lei Sun, and colleagues at Irvine studied individual fly neurons implicated in seizure activity to see how they behaved as the brains were heated. What their measurements revealed in the mutant flies were flaws in how "GABAergic" neurons take in sodium through channels in the cell membrane. Under normal circumstances, the neurons inhibit brain overactivity. But the mutants' mishandling of sodium led them to fail electrically.

"When [O'Dowd's team] isolates those currents due to the sodium channel, which is what's mutated in this case, and she compares the normal animals to the disease-model animals, what happens is the mutant channels pass too much current," Reenan said. "The channels open too easily and they take more effort to close. They open too soon and they close too late. That effect is magnified at higher temperature. Then the neuron can't send any [inhibitory] signals."

Searching for therapies

With a useful genetic model of epilepsy in fruit flies, Reenan said he is optimistic that researchers can now look for potential treatments for the disease. The next step, he said, is to use the practice of "forward genetics" to look for further mutations that might counter febrile seizures.

Given thousands of flies with model of the disease, scientists can purposely subject them to different DNA-altering conditions and then look to see if any flies lose their propensity for seizures. Among those that do, the researchers can then identify the specific genetic alteration responsible and determine whether that could ever be clinically applied. For example, if it turns out that a mutation proves therapeutic because it causes a certain protein to be overexpressed, then perhaps that protein could be refined into some kind of biologic pharmaceutical.

Reenan said he'd expect to see researchers follow a similar roadmap for other diseases as well.

"Knock-in of specific disease-causing mutations into the fly genome has the potential to provide a rapid and low-cost platform for studying the cellular mechanisms of heritable human diseases," the authors wrote. "In addition, knock-in flies can be used in combination with forward genetic screens to identify suppressor and/or enhancer mutations, a strategy that is challenging in humans and rodent models but well established in Drosophila."

In addition to Reenan, Gilligan, O'Dowd and Sun, other authors are Cynthia Staber of Brown and Ryan Schutte and Vivian Nguyen of UC Irvine.

In addition to the National Institutes of Health, the Howard Hughes Medical Institue and the Ellison Medical Foundation funded the research.

 

Journal Reference:

  1. L. Sun, J. Gilligan, C. Staber, R. J. Schutte, V. Nguyen, D. K. O'Dowd, R. Reenan. A Knock-In Model of Human Epilepsy in Drosophila Reveals a Novel Cellular Mechanism Associated with Heat-Induced Seizure. Journal of Neuroscience, 2012; 32 (41): 14145 DOI: 10.1523/JNEUROSCI.2932-12.2012

Mathematics or memory? Study charts collision course in brain

The area in red is the posterior medial cortex, the portion of the brain that is most active when people recall details of their own pasts. (Credit: Courtesy of Josef Parvizi)

You already know it's hard to balance your checkbook while simultaneously reflecting on your past. Now, investigators at the Stanford University School of Medicine — having done the equivalent of wire-tapping a hard-to-reach region of the brain — can tell us how this impasse arises.

The researchers showed that groups of nerve cells in a structure called the posterior medial cortex, or PMC, are strongly activated during a recall task such as trying to remember whether you had coffee yesterday, but just as strongly suppressed when you're engaged in solving a math problem.

The PMC, situated roughly where the brain's two hemispheres meet, is of great interest to neuroscientists because of its central role in introspective activities.

"This brain region is famously well-connected with many other regions that are important for higher cognitive functions," said Josef Parvizi, MD, PhD, associate professor of neurology and neurological sciences and director of Stanford's Human Intracranial Cognitive Electrophysiology Program. "But it's very hard to reach. It's so deep in the brain that the most commonly used electrophysiological methods can't access it."

In a study published online Sept. 3 in Proceedings of the National Academy of Sciences, Parvizi and his Stanford colleagues found a way to directly and sensitively record the output from this ordinarily anatomically inaccessible site in human subjects. By doing so, the researchers learned that particular clusters of nerve cells in the PMC that are most active when you are recalling details of your own past are strongly suppressed when you are performing mathematical calculations. Parvizi is the study's senior author. The first and second authors, respectively, are postdoctoral scholars Brett Foster, PhD, and Mohammed Dastjerdi, PhD.

Much of our understanding of what roles different parts of the brain play has been obtained by techniques such as functional magnetic resonance imaging, which measures the amount of blood flowing through various brain regions as a proxy for activity in those regions. But changes in blood flow are relatively slow, making fMRI a poor medium for listening in on the high-frequency electrical bursts (approximately 200 times per second) that best reflect nerve-cell firing. Moreover, fMRI typically requires pooling images from several subjects into one composite image. Each person's brain physiognomy is somewhat different, so the blending blurs the observable anatomical coordinates of a region of interest.

Nonetheless, fMRI imaging has shown that the PMC is quite active in introspective processes such as autobiographical memory processing ("I ate breakfast this morning") or daydreaming, and less so in external sensory processing ("How far away is that pedestrian?"). "Whenever you pay attention to the outside world, its activity decreases," said Parvizi.

To learn what specific parts of this region are doing during, say, recall versus arithmetic requires more-individualized anatomical resolution than an fMRI provides. Otherwise, Parvizi said, "if some nerve-cell populations become less active and others more active, it all washes out, and you see no net change." So you miss what's really going on.

For this study, the Stanford scientists employed a highly sensitive technique to demonstrate that introspective and externally focused cognitive tasks directly interfere with one another, because they impose opposite requirements on the same brain circuitry.

The researchers took advantage of a procedure performed on patients who were being evaluated for brain surgery at the Stanford Epilepsy Monitoring Unit, associated with Stanford University Medical Center. These patients were unresponsive to drug therapy and, as a result, suffered continuing seizures. The procedure involves temporarily removing small sections of a patient's skull, placing a thin plastic film containing electrodes onto the surface of the brain near the suspected point of origin of that patient's seizure (the location is unique to each patient), and then monitoring electrical activity in that region for five to seven days — all of it spent in a hospital bed. Once the epilepsy team identifies the point of origin of any seizures that occurred during that time, surgeons can precisely excise a small piece of tissue at that position, effectively breaking the vicious cycle of brain-wave amplification that is a seizure.

Implanting these electrode packets doesn't mean piercing the brain or individual cells within it. "Each electrode picks up activity from about a half-million nerve cells," Parvizi said. "It's more like dotting the ceiling of a big room, filled with a lot of people talking, with multiple microphones. We're listening to the buzz in the room, not individual conversations. Each microphone picks up the buzz from a different bunch of partiers. Some groups are more excited and talking more loudly than others."

The experimenters found eight patients whose seizures were believed to be originating somewhere near the brain's midline and who, therefore, had had electrode packets placed in the crevasse dividing the hemispheres. (The brain's two hemispheres are spaced far enough apart to slip an electrode packet between them without incurring damage.)

The researchers got permission from these eight patients to bring in laptop computers and put the volunteers through a battery of simple tasks requiring modest intellectual effort. "It can be boring to lie in bed waiting seven days for a seizure to come," said Foster. "Our studies helped them pass the time." The sessions lasted about an hour.

On the laptop would appear a series of true/false statements falling into one of four categories. Three categories were self-referential, albeit with varying degrees of specificity. Most specific was so-called "autobiographical episodic memory," an example of which might be: "I drank coffee yesterday." The next category of statements was more generic: "I eat a lot of fruit." The most abstract category, "self-judgment," comprised sentences along the lines of: "I am honest."

A fourth category differed from the first three in that it consisted of arithmetical equations such as: 67 + 6 = 75. Evaluating such a statement's truth required no introspection but, instead, an outward, more sensory orientation.

For each item, patients were instructed to press "1" if a statement was true, "2" if it was false.

Significant portions of the PMC that were "tapped" by electrodes became activated during self-episodic memory processing, confirming the PMC's strong role in recall of one's past experiences. Interestingly, true/false statements involving less specifically narrative recall — such as, "I eat a lot of fruit" — induced relatively little activity. "Self-judgment" statements — such as, "I am attractive" — elicited none at all. Moreover, whether a volunteer judged a statement to be true or false made no difference with respect to the intensity, location or duration of electrical activity in activated PMC circuits.

This suggests, both Parvizi and Foster said, that the PMC is not the brain's "center of self-consciousness" as some have proposed, but is more specifically engaged in constructing autobiographical narrative scenes, as occurs in recall or imagination.

Foster, Dastjerdi and Parvizi also found that the PMC circuitry activated by a recall task took close to a half-second to fire up, ruling out the possibility that this circuitry's true role was in reading or making sense of the sentence on the screen. (These two activities are typically completed within the first one-fifth of a second or so.) Once activated, these circuits remained active for a full second.

Yet all the electrodes that lit up during the self-episodic condition were conspicuously deactivated during arithmetic calculation. In fact, the circuits being monitored by these electrodes were not merely passively silent, but actively suppressed, said Parvizi. "The more a circuit is activated during autobiographical recall, the more it is suppressed during math. It's essentially impossible to do both at once."

The study was funded by the National Institutes of Health, with partial sponsorship from the Stanford Institute for NeuroInnovation and Translational Neuroscience.

New non-invasive method for diagnosing epilepsy

Brain scans of test patients using new technology and methods show that the frontal lobe of the brain is most involved in severe seizures. (Credit: Image courtesy of University of Minnesota)

NewsPsychology (Aug. 24, 2012) — A team of University of Minnesota biomedical engineers and researchers from Mayo Clinic just published a groundbreaking study that outlines how a new type of non-invasive brain scan taken immediately after a seizure gives additional insight into possible causes and treatments for epilepsy patients. The new findings could specifically benefit millions of people who are unable to control their epilepsy with medication.

The study’s findings include:

  • Important data about brain function can be gathered through non-invasive methods, not only during a seizure, but immediately after a seizure.
  • The frontal lobe of the brain is most involved in severe seizures.
  • Seizures in the temporal lobe are most common among adults. The new technique used in the study will help determine the side of the brain where the seizures originate.

“This is the first-ever study where new non-invasive methods were used to study patients after a seizure instead of during a seizure,” said Bin He, a biomedical engineering professor in the University of Minnesota’s College of Science and Engineering and senior author of the study. “It’s really a paradigm shift for research in epilepsy.”

Epilepsy affects nearly 3 million Americans and 50 million people worldwide. While medications and other treatments help many people of all ages who live with epilepsy, about 1 million people in the U.S. and 17 million people worldwide continue to have seizures that can severely limit their lives.

The biggest challenge for medical researchers is to locate the part of the brain responsible for the seizures to determine possible treatments. In the past, most research has focused on studying patients while they were having a seizure, or what is technically known as the “ictal” phase of a seizure. Some of these studies involved invasive methods such as surgery to collect data.

In the new study, researchers from the University of Minnesota and Mayo Clinic used a novel approach by studying the brains of 28 patients immediately after seizures, or what is technically know as the “postictal” phase of a seizure. They used a specialized type of non-invasive EEG with 76 electrodes attached to the scalp for gathering data in contrast to most previous research that used 32 electrodes. The researchers used specialized imaging technology to gather data about the patient. The findings may lead to innovative means of locating the brain regions responsible for seizures in individual patients using non-invasive strategies.

“The imaging technology that we developed here at the University of Minnesota allowed us to tackle this research and gather several thousand data points that helped us determine our findings,” He said. “The technical innovation was a big part of what helped us make this discovery.”

He, who was recently appointed the director of the University of Minnesota’s Institute for Engineering in Medicine, said this study was also a good example of a true partnership between engineering and medicine to further medical research.

“The innovations in engineering combined with collaborations with clinicians at Mayo Clinic made this research a reality,” He said.

In addition to He, members of the research team included University of Minnesota biomedical engineering Ph.D. student Lin Yang; Gregory A. Worrell, Mayo Clinic, Neurology and Division of Epilepsy; Cindy Nelson, Mayo Clinic, Neurology; and Benjamin Brinkmann, Mayo Clinic, Neurology. The research was funded by the National Institutes of Health.


Story Source:

The above story is reprinted from materials provided by University of Minnesota.

Note: Materials may be edited for content and length. For further information, please contact the source cited above.


Journal Reference:

  1. Lin Yang, Gregory A. Worrell, Cindy Nelson, Benjamin Brinkmann, and Bin He. Spectral and spatial shifts of post-ictal slow waves in temporal lobe seizures. Brain, 2012 DOI: 10.1093/brain/aws221

Predicting treatment response in central nervous system diseases: Simple way of avoiding dangerous side effects?

The commonly-used epilepsy drug, valproic acid (VPA), can have a highly beneficial effect on some babies born with spinal muscular atrophy (SMA), the number one genetic killer during early infancy. But in about two-thirds of such cases it is either damaging or simply has no effect. Now, for the first time, researchers have found a way to identify which patients are likely to respond well to VPA prior to starting treatment. Their results have major implications, not just for SMA patients, but for other conditions treated with the drug such as migraine and epilepsy, and may even provide the conditions for turning VPA non-responders into responders, the researchers say.

Dr. Lutz Garbes, from the Institute of Human Genetics, University of Cologne, Germany, will tell the annual conference of the European Society of Human Genetics on June 24 that he and his colleagues had analysed blood RNA samples from a small group of SMA patients who had been treated with VPA. They found, as expected, that only about one third of patients responded well. In an attempt to discover whether blood sampling was the most appropriate test method to use, they also looked at VPA response in another tissue — fibroblasts (a type of skin cell). They found that the response in blood and in skin was the same in 60% of cases.

The researchers then generated pluripotent stem cells from fibroblasts of both a VPA responder and a non-responder, and differentiated them into GABAergic neurons (neurons that produce the amino acid GABA, the chief neurotransmitter in the mammalian nervous system). These neurons, when treated with VPA, exhibited a similar response to that previously found in blood and fibroblasts.

"This indicates for the first time that response to VPA is the same among blood and skin and suggests that monitoring blood for VPA therapy is indeed feasible in central nervous system diseases," says Dr. Garbes. "But, even more importantly, by using the SMA patients' fibroblasts we were able to identify a decisive factor in the suppression of the positive response to VPA treatment. Utilising transcriptome-wide microarray profiling*, we found that high levels of the fatty acid transporter protein CD36 are associated with the lack of positive response to treatment.

"The implications of this discovery are far-reaching. First, we have been able to prove that monitoring blood is a reliable method for doctors to determine response to VPA treatment in many central nervous system diseases, since our findings are not specific to SMA. Second, the identification of CD36 as the crucial factor in suppressing response to treatment provides a simple way of appraising whether a patient will respond to therapy before treatment starts. And third, in the long run we may find a way to target CD36 in order to be able to change a non-VPA responder into a responder."

Knowing that CD36 is a crucial factor here means that the current, potentially dangerous, 'trial and error' approach to VPA treatment is now obsolete, the researchers say. Screening of patients for CD36 prior to treatment would mean that only those who would respond positively to VPA would be given it. This is important because, in some cases, VPA can cause life-threatening side-effects such as impairment of liver, blood cell and pancreatic function, especially in those just starting the treatment. "But we still do not understand how CD36 suppresses response to VPA, only that it does so," says Dr. Garbes. "A greater understanding of its effects could also lead to the detection of even better targets to overcome the problem. "

In the case of SMA, VPA works by inhibiting enzymes called histone deacetylase (HDACs) which are involved in regulating the packaging of DNA. HDACs lead to a denser DNA packaging whereby protein production from genes is reduced. Other enzymes called histone acetyltransferases (HATs) lead to a more relaxed DNA structure, producing more protein. By inhibiting HDACs with VPA, the DNA packaging balance shifts towards the more relaxed structure and thus genes get activated and proteins produced. In SMA, the crucial gene is SMN2, a copy gene of the disease-determining gene SMN1. In healthy individuals, SMN1 is the major source of SMN protein, but SMN2 cannot fully compensate for the loss of SMN1 in SMA patients. By increasing SMN2 activity, it will produce more SMN protein and ameliorate the condition.

"Avoiding needless VPA treatment of non-responders would have a major effect on healthcare costs and improve quality of life for patients," Dr. Garbes will say. "Half of the babies born with SMA will die within two years, but the other half can live to twenty or even longer, so this is an important finding for them. Our findings may also help identify patients who are candidates for VPA treatment in many other diseases of the central nervous system, some of them very common.

"In the EU, approximately 550 SMA babies are born each year, and there are about 311,000 new cases of epilepsy per year. It is estimated that, in Europe, migraine affects up to 28% of people at some time in their lives. We are happy that we may have been able to contribute to the development of personalised medicine for so many people," he will conclude.

*A transcriptome-wide microarray profile provides a way of identifying all the genes that are differentially expressed in distinct cell populations or subtypes, allowing the effects of treatment to be monitored.

 

Response to first drug treatment may signal likelihood of future seizures in people with epilepsy

How well people with newly diagnosed epilepsy respond to their first drug treatment may signal the likelihood that they will continue to have more seizures, according to a study published in the May 9, 2012, online issue of Neurology®, the medical journal of the American Academy of Neurology.

"Our research shows a pattern based on how a person responds to initial treatment and specifically, to their first two courses of drug treatment," said study author Patrick Kwan, MD, PhD, with the University of Melbourne in Australia.

For the study, 1,098 people from Scotland between the ages of nine and 93 with newly diagnosed epilepsy were followed for as long as 26 years after being given their first drug therapy. Participants were considered seizure-free if they had no seizures for at least a year without changes in their treatment. If they had further seizures, a second drug was chosen to be given alone or to be added to the first. If seizures continued, a third drug regimen was selected, and the process continued for up to nine drug regimens.

The study found that 50 percent of the people were seizure-free after the first drug tried, 13 percent were seizure-free after the second drug regimen tried and 4 percent were seizure-free after the third drug regimen tried. Less than two percent of the participants stopped having seizures on additional drug treatment courses up to the seventh one tried, and none became seizure-free after that.

The research also found that 37 percent of people in the study became seizure-free within six months of treatment. Another 22 percent became seizure-free after more than six months of starting treatment. Both groups continued to be seizure-free. However, 16 percent had fluctuating periods of seizure freedom and relapses, and 25 percent were never seizure-free for one year.

At the end of the study, 749 people (68 percent) were seizure-free and 678 people (62 percent) were on only one drug. The results were independent of the age when the person had the first seizure or the type of epilepsy.

"A person who doesn't respond well to two courses of epilepsy drug treatment should be further evaluated to verify an epilepsy diagnosis and to identify whether surgery is the best next step," said Patricia E. Penovich, MD, with the Minnesota Epilepsy Group PA and the University of Minnesota School of Medicine in St. Paul, Minn., and a Fellow with the American Academy of Neurology, who wrote an accompanying editorial on the study.

 

Molecule movements that make us think: Ion channel’s voltage sensor can change its form

Every thought, every movement, every heartbeat is controlled by lightning-quick electrical impulses in the brain, the muscles, and the heart. But too much electrical excitability in the membranes of the cells can cause things like epilepsy and cardiac arrhythmia. A research group at Linköping University has now published new discoveries that can lead to new medicines for these diseases.

The key molecules behind the electrical impulses are voltage-activated ion channels – pores in cell membranes, the opening and closing of which are controlled by the electrical potential between the inside and outside of the cell.

Research over the past few years has revealed the ion channels’ molecular structure, and how the pores change form when they open and close. On the other hand, the mechanism explaining how the electric potential is detected on the molecular level remains unclear.

LiU researchers have now shown how an ion channel’s voltage sensor can change its form. This change of form leads to the pore in the channel opening up.

Ulrike Henrion, Jakob Renhorn, Sara Börjesson, and Erin Nelson, all in Professor Fredrik Elinder’s research group, have succeeded through comprehensive experimental work in identifying 20 different molecular interactions that occur in the voltage sensor’s different states.

In collaboration with Professor Erik Lindahl’s group at the KTH Royal Institute of Technology, and associate professor Björn Wallner at the Department of Physics, Chemistry and Biology at LiU, the group has built five different molecular models of the voltage sensor, which together can explain all the experimental data. The five models were then linked together to a film that shows how a central part of the voltage detector moves between the outer walls of the voltage sensor.

The published work is an important piece of the puzzle in the research group’s quest to develop substances with raised electrical excitability, which hopefully can lead to new medicines for epilepsy and cardiac arrhythmia.


Journal Reference:

  1. U. Henrion, J. Renhorn, S. I. Börjesson, E. M. Nelson, C. S. Schwaiger, P. Bjelkmar, B. Wallner, E. Lindahl and F. Elinder. Tracking a complete voltage-sensor cycle with metal-ion bridges. Proceedings of the National Academy of Sciences, April 2012 (in press)