Epilepsynews

Biologists pave the way for improved epilepsy treatments

Date:

June 6, 2014

Source:

University of Toronto

Summary:

 Biologists leading an investigation into the cells that regulate proper brain function, have identified and located the key players whose actions contribute to afflictions such as epilepsy and schizophrenia. The discovery is a major step toward developing improved treatments for these and other neurological disorders.

University of Toronto biologists leading an investigation into the cells that regulate proper brain function, have identified and located the key players whose actions contribute to afflictions such as epilepsy and schizophrenia. The discovery is a major step toward developing improved treatments for these and other neurological disorders.

“Neurons in the brain communicate with other neurons through synapses, communication that can either excite or inhibit other neurons,” said Professor Melanie Woodin in the Department of Cell and Systems Biology at the University of Toronto (U of T), lead investigator of a study published today in Cell Reports. “An imbalance among the levels of excitation and inhibition – a tip towards excitation, for example – causes improper brain function and can produce seizures. We identified a key complex of proteins that can regulate excitation-inhibition balance at the cellular level.”
This complex brings together three key proteins – KCC2, Neto2 and GluK2 – required for inhibitory and excitatory synaptic communication. KCC2 is required for inhibitory impulses, GluK2 is a receptor for the main excitatory transmitter glutamate, and Neto2 is an auxiliary protein that interacts with both KCC2 and GluK2. The discovery of the complex of three proteins is pathbreaking as it was previously believed that KCC2 and GluK2 were in separate compartments of the cell and acted independently of each other.
“Finding that they are all directly interacting and can co-regulate each other’s function reveals for the first time a system that can mediate excitation-inhibition balance among neurons themselves,” said Vivek Mahadevan, a PhD candidate in Woodin’s group and lead author of the study.
Mahadevan and fellow researchers made the discovery via biochemistry, fluorescence imaging and electrophysiology experiments on mice brains. The most fruitful technique was the application of an advanced sensitive gel system to determine native protein complexes in neurons, called Blue Native PAGE. The process provided the biochemical conditions necessary to preserve the protein complexes that normally exist in neurons. Blue Native PAGE is advantageous over standard gel electrophoresis, where proteins are separated from their normal protein complexes based on their molecular weights.

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“The results reveal the proteins that can be targeted by drug manufacturers in order to reset imbalances that occur in neurological disorders such as epilepsy, autism spectrum disorder, schizophrenia and neuropathic pain,” said Woodin. “There is no cure for epilepsy; the best available treatments only control its effects, such as convulsions and seizures. We can now imagine preventing them from occurring in the first place.”
“It was the cellular mechanisms that determine the excitation-inhibition balance that needed to be identified. Now that we know the key role played by KCC2 in moderating excitatory activity, further research can be done into its occasional dysfunction and how it can also be regulated by excitatory impulses,” said Mahadevan.

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Story Source:
The above story is based on materials provided by University of Toronto. Note: Materials may be edited for content and length.

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Journal Reference:

1. Vivek Mahadevan, Jessica C. Pressey, Brooke A. Acton, Pavel Uvarov, Michelle Y. Huang, Jonah Chevrier, Andrew Puchalski, Caiwei M. Li, Evgueni A. Ivakine, Matti S. Airaksinen, Eric Delpire, Roderick R. McInnes, Melanie A. Woodin. Kainate Receptors Coexist in a Functional Complex with KCC2 and Regulate Chloride Homeostasis in Hippocampal Neurons. Cell Reports, 2014; DOI:  

   04-06-2014 | New epilepsy treatment may prevent seizures with a pill

   There may be a new way for those with epilepsy to suppress seizures. Researchers may have created a new treatment for drug-resistant epilepsy that allows someone to take a pill in order to keep a seizure at bay.
   The treatment combines genetic and chemical approaches to suppress seizures without disrupting normal brain function. The technique was demonstrated in rodents, but could potentially be used in humans with the use of a simple pill.
   "First, we inject a modified virus into the area of the brain where seizures arise," said Dimitri Kullmann, one of the researchers, "This virus instructs the brain cells to make a protein that is activated by CNO (clozapine-N-oxide), a compound that can be taken as a pill. The activated protein then suppresses the over-excitable brain cells that trigger seizures, but only in the presence of CNO."
   In fact, CNO could be given as a pill in the event that patients could predict when seizures were likely to occur. For example, many people with treatment-resistant epilepsy experience a cluster of seizures; severe seizures are preceded by smaller ones. In theory, a person could take a pill as a preventative measure.
   CNO has a half-life of only about a few hours. It also only impacts the pre-treated epileptic parts of the brain.
   "After the one-off injections into affected areas of the brain, our new technique would require nothing beyond CNO, administered as an injection or a pill, to suppress seizures when required," said Kullmann "This makes it more attractive than alternative forms of targeted therapy such as surgery to remove the brain region where seizures arise, or gene therapy that permanently alters the excitability of brain cells."
   The findings could be huge for those suffering from epilepsy. That said, more research will have to be conducted before scientists begin to conduct human trials.
   
   The findings are published in the journal Nature Communications.
   

   13-05-2014 | New cause of epilepsy revealed

   A team of researchers from Sanford-Burnham Medical Research Institute (Sanford-Burnham) and SUNY Downstate Medical Centre (SUNY Downstate) has found that deficiencies in hyaluronan, also known as hyaluronic acid or HA, can lead to spontaneous epileptic seizures.
   The multicentre study used mice to provide the first evidence of a physiological role for HA in the maintenance of brain ECS volume. It also suggests a potential role in human epilepsy for HA and genes that are involved in hyaluraonan synthesis and degradation.
   Although epilepsy treatment is available and effective for about 70 percent of cases, a substantial number of patients could benefit from a new therapeutic approach.
   "Hyaluronan is widely known as a key structural component of cartilage and important for maintaining healthy cartilage. Curiously, it has been recognized that the adult brain also contains a lot of hyaluronan, but little is known about what hyaluronan does in the brain," said Yu Yamaguchi, M.D., Ph.D., professor in the Human Genetics Program at Sanford-Burnham.
   "This is the first study that demonstrates the important role of this unique molecule for normal functioning of the brain, and that its deficiency may be a cause of epileptic disorders. A better understanding of how hyaluronan regulates brain function could lead to new treatment approaches for epilepsy," Yamaguchi added.
   "We believe that this study not only addresses one of the longstanding questions concerning the in-vivo role of matrix molecules in the brain, but also has broad appeal to epilepsy research in general," said Katherine Perkins, Ph.D., associate professor in the Department of Physiology and Pharmacology at SUNY Downstate.
   "More specifically, it should stimulate researchers in the epilepsy field because our study reveals a novel, non-synaptic mechanism of epileptogenesis. The fact that our research can lead to new anti-epileptic therapies based on the preservation of hyaluronan adds further significance for the broader biomedical community and the public," the authors added.
   For more see Science Daily.com
   
   
   

   New Light on Best Medication for Children With Seizures

   The debate over which is better, drug Lorazepam and diazepam, has long puzzled ER pediatricians, but has been answered in a recently published clinical study in the Journal of the American Medical Association. The drug diazepam has been the U.S. Food and Drug Administration-approved medication as first line therapy most often used by emergency room doctors to control major epileptic seizures in children?

   

   The answer to that question - based on a double-blind, randomized clinical trial that compared outcomes in 273 seizure patients, about half of whom were given lorazepam - is a clear-cut "no," said Prashant V. Mahajan, M.D., M.P.H., M.B.A, one of the authors of the study.
   

   
   "The results of our clinical trial were very convincing, and they showed clearly that the two medications are just about equally effective and equally safe when it comes to treating status epilepticus [major epileptic brain seizures in children]," Dr. Mahajan said. "This is an important step forward for all of us who frequently treat kids in the ER for [epilepsy-related] seizures, since it answers the question about the best medication to use in ending the convulsions and getting these patients back to normal brain functioning."
   
   Describing the brain convulsions that were targeted by the study, its authors pointed out that status epilepticus occurs when an epilepsy-related seizure lasts more than 30 minutes. Such seizures - which occur in more than 10,000 U.S. pediatric epilepsy patients every year - can cause permanent brain damage or even death, if allowed to persist.
   
   Published in JAMA, the jama.jamanetwork.com, "Lorazepam vs Diazepam for Pediatric Status Epilepticus: A Randomized Clinical Trial," was designed to test earlier assertions by many clinicians that lorazepam was more effective at controlling pediatric seizures. The study-authors wrote, "Potential advantages proposed in some studies of lorazepam include improved effectiveness in terminating convulsions, longer duration of action compared with diazepam, and lower incidence of respiratory depression. Specific pediatric data comparing diazepam with lorazepam suggest that lorazepam might be superior, but they are limited to reports from single institutions or retrospective studies with small sample sizes, thus limiting generalizability."
   
   Based on data collected over four years at 11 different U.S. pediatric emergency departments, the new study found that "treatment with lorazepam [among pediatric patients with convulsive status epilepticus] did not result in improved efficacy or safety, compared with diazepam."
   
   That determination led the study authors to conclude: "These findings do not support the preferential use of lorazepam for this condition."
   
   Dr. Mahajan, a nationally recognized researcher in pediatric emergency medicine and a Wayne State University School of Medicine pediatrics professor recently appointed chair of the American Academy of Pediatrics Executive Committee of the Section on Emergency Medicine, said the JAMA study provides "a compelling example of how effective research in pediatric medicine, based on treatment of patients right in the clinical setting, can play a major role in improving outcomes."
   
   Children's Hospital of Michigan Chief of Pediatrics Steven E. Lipshultz, M.D., said this recent breakthrough will "undoubtedly result in better care for pediatric patients who present in the emergency room with seizures related to epilepsy.
   
   "There's no doubt that combining excellent research with excellent treatment is the key to achieving the highest-quality outcomes for patients - and Dr. Mahajan's cutting-edge study is a terrific example of how kids are benefiting from the research that goes on here at Children's every single day," said Dr. Lipshultz.

   Cellular mechanisms involved in causing epilepsy discovered

   Scientists from the University of Toronto have identified a number of cellular mechanisms that play a potentially important role in causing epilepsy, opening the door for the development of new therapy approaches.
   The Canadian researchers have been looking at how neurons in the brain excite or inhibit each other through synapses, as well as how imbalances in levels of excitation and inhibition can cause improper brain function, leading to seizures.
   They were able to identify a key complex of proteins that regulates this balance at the cellular level, bringing together three proteins – KCC2, Neto2 and GluK2 – required for inhibitory and excitatory synaptic communication.
   Previously, it was believed that KCC2 and GluK2 were in separate compartments of the cell and acted independently of each other, whereas in actual fact they directly interact and can co-regulate each other’s functions.
   Now that the team has been able to demonstrate the role played by KCC2 in moderating excitatory activity, further research can be carried out into its occasional dysfunction, looking at how it can also be regulated by excitatory impulses.
   Not only can this process be used as a means of developing epilepsy treatments, it could also lay the foundation for further research into a number of neurological conditions.
   Lead author Professor Melanie Woodin of the department of cell and systems biology at the University of Toronto, said: “The results reveal the proteins that can be targeted by drug manufacturers in order to reset imbalances that occur in neurological disorders such as epilepsy, autism spectrum disorder, schizophrenia and neuropathic pain.
   “There is no cure for epilepsy; the best available treatments only control its effects, such as convulsions and seizures. We can now imagine preventing them from occurring in the first place.”
   Currently, around 70 per cent of epilepsy cases are successfully controlled by antiepileptic drugs, but for the proportion of patients who do not benefit from this kind of treatment, additional therapy options are needed.

(CNN) -- An estimated 2.3 million adults in the United States have epilepsy, according to the Centers for Disease Control and Prevention. Actress Sky McCole Bartusiak, who passed away Saturday, was one of them.

Bartusiak's mother said her daughter had suffered from epileptic seizures since she was a baby. Epilepsy is a general term for several diagnoses that involve recurring seizures. The seizures are triggered by abnormal electrical activity in the brain that results in involuntary changes in body movement, behavior, sensation and, in some cases, loss of consciousness.

Here are seven things to know about epilepsy:

1. There is no identifiable cause in 50% of cases.

About half of diagnosed epilepsy cases have no known cause, according to the Mayo Clinic. For the cases that are identifiable, epilepsy is the result of:

-- Genetics. It's estimated that up to 500 genes could be associated with epilepsy, according to the National Institute of Neurological Disorders and Stroke, but genes are only part of the cause. Genes also make certain people more sensitive to environmental conditions that can trigger seizures.

-- Head trauma after a traumatic fall or car accident.

-- Brain conditions such a strokes, Alzheimer's disease and tumors. Strokes are the leading cause of epilepsy in adults over age 35.

-- Infectious diseases such as AIDS, viral encephalitis and meningitis.

-- Prenatal injury, such as poor nutrition or oxygen deficiencies. Developmental disorders such as autism or neurofibromatosis can also play a role.

2. Having a seizure does not mean that you have epilepsy.

In order to be considered an epileptic seizure, "the seizure has to be unprovoked and occur two or more times," according to Dr. Lawrence Seiden, a board certified neurologist and psychiatrist at the Peachtree Neurological Clinic.

While it may be difficult to identify between epileptic and nonepileptic seizures, nonepileptic seizures are provoked by a temporary medical condition such as a high fever or low blood sugar levels. In addition, epileptic seizures are caused by an electrical problem in the brain, unlike nonepileptic seizures.

3. Symptoms of epilepsy can vary.

Epilepsy symptoms vary from a blank stare during a seizure to repeated twitching of one's arms and legs, according to the Mayo Clinic. However, even mild seizures can be dangerous especially while driving, swimming or being at another unsafe location at the time of the seizure.

Epilepsy is also associated with other chronic health problems such as depression, obesity, bone loss and reproductive disorders.

4. Up to 18% of people with epilepsy die from SUDEP.

It's known as Sudden Unexplained Death in Epilepsy, according to the Mayo Clinic. The cause of SUDEP is unclear, but doctors have several theories.

Epileptic seizures can cause pauses in breathing, also known as apnea. When these pauses are long enough, oxygen levels in the blood can be reduced to dangerous levels. SUDEP may also be caused by an irregular heart rhythm or cardiac arrest.

5. Epileptic patients don't suffer from mental illness.

One of the common misconceptions about epilepsy, Seiden said, is the belief that epileptic patients are not normal and suffer from mental illness or mental retardation. While people with mental retardation may experience seizures, most epileptic patients have normal or above-average intelligence.

"The majority of people with epilepsy are completely normal except for the few seconds they are having seizures," said Seiden.

6. Medical marijuana may help.

The verdict is still out on medical marijuana among epilepsy experts. Some scientists believe the healing compound in marijuana called cannabidiol, or CBD, has medicinal properties that quiet the excessive electrical and chemical activity in the brain that causes seizures.

While much research is still needed, some children and adults who suffer from severe seizures have responded to medical marijuana when other medications did not work.

Anti-epileptic medications are effective in nearly 50% of the people who are newly diagnosed with epilepsy, according to the Mayo Clinic. When medications are not effective and the exact area of the brain where the seizure is generated is identified, surgery is recommended.

Doctors also recommend a high-fat, low-carb ketogenic diet for children who suffer from epilepsy.

7. People can thrive with epilepsy.

Some of the more famous sufferers (or rumored sufferers) of epilepsy include the philosopher Socrates, French military and political leader Napoleon Bonaparte, Nobel prize founder Alfred Nobel, Russian novelist Fyodor Dostoyevsky, and several Olympic medalists, according to the National Institute of Neurological Disorders and Stroke