Neuroscience

Articles and news from the latest research reports.

Posts tagged epilepsy

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Molecular imbalance linked to brain tumour seizures
Researchers in France may have discovered why some patients with a type of brain tumour have epileptic seizures.
“This small study is interesting and shows that glioma-linked epilepsy may be connected to certain channels found in the membranes of nerve cells” - Dr Robin Grant, Edinburgh Cancer Research UK Centre
Their study, published in Science Translational Medicine, suggests that seizures in patients with glioma may be linked to an imbalance of chloride – which is involved in nerve activity – in certain brain cells.
Whether a patient has seizures is linked to how aggressive their tumour is – with less aggressive cases being more prone to epilepsy as tumour cells slowly progress and alter brain tissue.
It is hoped that further research could explore treatments for glioma-linked epilepsy by controlling chloride levels in the brain.
Glioma develops from specialised brain cells known as ‘glial cells’ that usually help to keep brain nerve cells in place, providing support and protection to ensure correct brain function.
In the latest study, scientists from Sorbonne University studied brain tissue samples from 47 glioma patients and found that nerve tissue infiltrated by glioma cells behaves in similar ways to other forms of epilepsy.
Looking at the patient samples, the team found that a particular type of nerve cell – called a pyramidal cell – released excessive amounts of chloride from inside the cells when exposed to a molecule called GABA, which is also involved in transmitting nerve signals.
GABA was released by other neighbouring nerve cells called ‘interneurons’. And the researchers believe that the release of chloride through specialised molecular channels in the membrane of nerve cells, may be responsible for the seizures experienced in some glioma patients.
Dr Robin Grant, an expert in epilepsy and glioma from the Edinburgh Cancer Research UK Centre, who was not involved in the research, said that the channels may make good drug targets for further investigation, but a finer understanding of the involvement of other processes is still needed.
“This small study is interesting and shows that glioma-linked epilepsy, as with other types of epilepsy, may be connected to certain channels found in the membranes of nerve cells.
“More research will be needed to understand the finer details of this process in glioma and whether these channels, along with other similar channels found in nerve cells, could be good targets for drugs to help control the condition.”

Molecular imbalance linked to brain tumour seizures

Researchers in France may have discovered why some patients with a type of brain tumour have epileptic seizures.

“This small study is interesting and shows that glioma-linked epilepsy may be connected to certain channels found in the membranes of nerve cells” - Dr Robin Grant, Edinburgh Cancer Research UK Centre

Their study, published in Science Translational Medicine, suggests that seizures in patients with glioma may be linked to an imbalance of chloride – which is involved in nerve activity – in certain brain cells.

Whether a patient has seizures is linked to how aggressive their tumour is – with less aggressive cases being more prone to epilepsy as tumour cells slowly progress and alter brain tissue.

It is hoped that further research could explore treatments for glioma-linked epilepsy by controlling chloride levels in the brain.

Glioma develops from specialised brain cells known as ‘glial cells’ that usually help to keep brain nerve cells in place, providing support and protection to ensure correct brain function.

In the latest study, scientists from Sorbonne University studied brain tissue samples from 47 glioma patients and found that nerve tissue infiltrated by glioma cells behaves in similar ways to other forms of epilepsy.

Looking at the patient samples, the team found that a particular type of nerve cell – called a pyramidal cell – released excessive amounts of chloride from inside the cells when exposed to a molecule called GABA, which is also involved in transmitting nerve signals.

GABA was released by other neighbouring nerve cells called ‘interneurons’. And the researchers believe that the release of chloride through specialised molecular channels in the membrane of nerve cells, may be responsible for the seizures experienced in some glioma patients.

Dr Robin Grant, an expert in epilepsy and glioma from the Edinburgh Cancer Research UK Centre, who was not involved in the research, said that the channels may make good drug targets for further investigation, but a finer understanding of the involvement of other processes is still needed.

“This small study is interesting and shows that glioma-linked epilepsy, as with other types of epilepsy, may be connected to certain channels found in the membranes of nerve cells.

“More research will be needed to understand the finer details of this process in glioma and whether these channels, along with other similar channels found in nerve cells, could be good targets for drugs to help control the condition.”

Filed under brain tumours epileptic seizures epilepsy glioma glial cells nerve cells neuroscience science

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GABA actions and ionic plasticity in epilepsy
Concepts of epilepsy, based on a simple change in neuronal excitation/inhibition balance, have subsided in face of recent insights into the large diversity and context-dependence of signaling mechanisms at the molecular, cellular and neuronal network level. GABAergic transmission exerts both seizure-suppressing and seizure-promoting actions. These two roles are prone to short-term and long-term alterations, evident both during epileptogenesis and during individual epileptiform events. The driving force of GABAergic currents is controlled by ion-regulatory molecules such as the neuronal K-Cl cotransporter KCC2 and cytosolic carbonic anhydrases. Accumulating evidence suggests that neuronal ion regulation is highly plastic, thereby contributing to the multiple roles ascribed to GABAergic signaling during epileptogenesis and epilepsy.
Full Article

GABA actions and ionic plasticity in epilepsy

Concepts of epilepsy, based on a simple change in neuronal excitation/inhibition balance, have subsided in face of recent insights into the large diversity and context-dependence of signaling mechanisms at the molecular, cellular and neuronal network level. GABAergic transmission exerts both seizure-suppressing and seizure-promoting actions. These two roles are prone to short-term and long-term alterations, evident both during epileptogenesis and during individual epileptiform events. The driving force of GABAergic currents is controlled by ion-regulatory molecules such as the neuronal K-Cl cotransporter KCC2 and cytosolic carbonic anhydrases. Accumulating evidence suggests that neuronal ion regulation is highly plastic, thereby contributing to the multiple roles ascribed to GABAergic signaling during epileptogenesis and epilepsy.

Full Article

Filed under epilepsy GABA ionic plasticity epileptic seizures neuroscience science

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International study yields important clues to the genetics of epilepsy

An international team of researchers has discovered a significant genetic component of Idiopathic Generalized Epilepsy (IGE), the most common form of epilepsy. Epilepsy is a neurological disorder characterized by sudden, uncontrolled electrical discharges in the brain expressed as a seizure. The new research, published in this week’s issue of EMBO Reports, implicates a mutation in the gene for a protein, known as cotransporter KCC2.

KCC2 maintains the correct levels of chloride ions in neurons, playing a major part in regulating excitation and inhibition of neurons. The results indicate that a genetic mutation of KCC2 might be a risk factor for developing IGE.

“We found a clear statistical association between two variants of KCC2 and severe IGE in a large French-Canadian patient sample,” said Dr. Guy Rouleau, Director of the Montreal Neurological Institute and Hospital (The Neuro) at McGill University and the McGill University Health Centre, and senior author of the study. “Our data not only corroborate recent findings by other groups but vastly extend them from genetic, physiological and biochemical standpoints.” The first authors on the paper are Dr. Kristopher Kahle, chief neurosurgery resident at Massachusetts General Hospital and post-doctoral fellow at Harvard University, and Dr. Nancy Merner, a former post-doctoral fellow in Dr. Rouleau’s laboratory and now a professor at Auburn University.

The study examined 380 French Canadians with IGE living in Montreal and Quebec City. Results were compared to data from a control group of more than 1,200 people. “KCC2 is a hot topic in neuroscience given its important role in neuronal signaling and in its potential role in neurological diseases such as epilepsy, neuropathic pain, and other diseases,” said Dr. Rouleau.

Each day in Canada, an average of 42 people learn that they have epilepsy. In 50 – 60% of cases, the cause of epilepsy is unknown. The major form of treatment is long-term drug therapy. Drugs are not a cure and can have numerous, sometimes severe, side effects. Brain surgery is recommended only when medication fails and when the seizures are confined to one area of the brain where brain tissue can be safely removed without damaging personality or function.

(Source: publications.mcgill.ca)

Filed under epilepsy KCC2 GABA genetics neuroscience science

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Breakthrough Study Sheds New Light on Best Medication for Children with Seizures

A recently published clinical study in the Journal of the American Medical Association has answered an urgent question that long puzzled ER pediatricians: Is the drug lorazepam really safer and more effective than diazepam – 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 study, “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.

(Source: media.wayne.edu)

Filed under epilepsy epileptic seizures lorazepam diazepam medicine science

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Biologists pave the way for improved epilepsy treatments

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.

“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.

(Source: media.utoronto.ca)

Filed under epilepsy hippocampal neurons schizophrenia neurons neuroscience science

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MRI-Guided Laser Procedure Provides Alternative to Epilepsy Surgery
For patients with mesial temporal lobe epilepsy (MTLE) that can’t be controlled by medications, a minimally invasive laser procedure performed under MRI guidance provides a safe and effective alternative to surgery, suggests a study in the June issue of Neurosurgery, official journal of the Congress of Neurological Surgeons. The journal is published by Lippincott Williams & Wilkins, a part of Wolters Kluwer Health. "Real-time magnetic resonance-guided stereotactic laser amygdalohippocampotomy (SLAH) is a technically novel, safe and effective alternative to open surgery," according to the new research by Dr. Robert E. Gross of Emory University School of Medicine, Atlanta, and colleagues.
MRI Guides Precise Laser Destruction of Area Causing Epilepsy…The researchers report their experience with MRI-guided SLAH in 13 adult patients with epilepsy mapped to a part of the brain called the mesial temporal lobe. The patients, median age 24 years, had “intractable” seizures despite treatment with antiepileptic drugs.
In the SLAH procedure, a saline-cooled fiberoptic laser probe was precisely targeted to the area of the brain—the “amygdalohippocampal complex”—responsible for the procedures. Using real-time MRI guidance, the neurosurgeon was able to pinpoint the area of the brain responsible for seizure activity and destroy (ablate) by computer-controlled laser energy, without harming neighboring brain tissue.
The technical aspects of the procedure were successfully carried out in all patients. Using thermal imaging and MRI guidance, the surgeons were able to see the area of laser ablation as treatment proceeded. The average laser exposure time was just under ten minutes.
On average, 60 percent of the amygdalohippocampal complex was destroyed in the SLAH procedure; the average length of the ablated area was 2.5 centimeters. Median time spent in the hospital was just one day—compared to a typical two to five-day stay after conventional temporal lobe surgery, and SLAH patients did not have to be admitted to the intensive care unit.
…With Good Control of Seizures at Follow-UpMost important, the procedure was effective in reducing or eliminating seizures in patients with MTLE. At a median of 14 months after SLAH, ten out of thirteen patients achieved meaningful seizure reductions, while seven were free of “disabling seizures.” This included six out of nine patients whose epilepsy was caused by an abnormality called mesial temporal sclerosis.
Although some complications occurred, none were directly caused by laser application. Two patients had an additional SLAH procedure to control seizures, and another patient underwent standard open surgery.Open brain surgery is the standard treatment for patients with intractable MTLE. Surgery has a high success rate, but carries a significant risk of neurological and cognitive (intellectual) impairment. Minimally invasive approaches like the new MRI-guided laser ablation technique might produce similar seizure control with lower risks than surgery.
The new study shows “technical feasibility and encouraging results” with the minimally invasive MRI-guided SLAH technique for patients with MTLE. Effectiveness in relieving or eliminating seizures approaches that of surgery—perhaps especially among patients whose seizures are caused by mesial temporal sclerosis. “These are promising results considering that this reflects our initial experience, and results may improve with greater experience with this novel technique,” notes Dr. Gross.
"Such minimally invasive techniques may be more desirable to patients and result in increased use of epilepsy surgery among the large number of medically intractable epilepsy patients," Dr. Gross and colleagues conclude. They note that a larger, longer-term study of SLAH is underway, including assessment of the effects on cognitive function as well as seizures.

MRI-Guided Laser Procedure Provides Alternative to Epilepsy Surgery

For patients with mesial temporal lobe epilepsy (MTLE) that can’t be controlled by medications, a minimally invasive laser procedure performed under MRI guidance provides a safe and effective alternative to surgery, suggests a study in the June issue of Neurosurgery, official journal of the Congress of Neurological Surgeons. The journal is published by Lippincott Williams & Wilkins, a part of Wolters Kluwer Health.
"Real-time magnetic resonance-guided stereotactic laser amygdalohippocampotomy (SLAH) is a technically novel, safe and effective alternative to open surgery," according to the new research by Dr. Robert E. Gross of Emory University School of Medicine, Atlanta, and colleagues.

MRI Guides Precise Laser Destruction of Area Causing Epilepsy…
The researchers report their experience with MRI-guided SLAH in 13 adult patients with epilepsy mapped to a part of the brain called the mesial temporal lobe. The patients, median age 24 years, had “intractable” seizures despite treatment with antiepileptic drugs.

In the SLAH procedure, a saline-cooled fiberoptic laser probe was precisely targeted to the area of the brain—the “amygdalohippocampal complex”—responsible for the procedures. Using real-time MRI guidance, the neurosurgeon was able to pinpoint the area of the brain responsible for seizure activity and destroy (ablate) by computer-controlled laser energy, without harming neighboring brain tissue.

The technical aspects of the procedure were successfully carried out in all patients. Using thermal imaging and MRI guidance, the surgeons were able to see the area of laser ablation as treatment proceeded. The average laser exposure time was just under ten minutes.

On average, 60 percent of the amygdalohippocampal complex was destroyed in the SLAH procedure; the average length of the ablated area was 2.5 centimeters. Median time spent in the hospital was just one day—compared to a typical two to five-day stay after conventional temporal lobe surgery, and SLAH patients did not have to be admitted to the intensive care unit.

…With Good Control of Seizures at Follow-Up
Most important, the procedure was effective in reducing or eliminating seizures in patients with MTLE. At a median of 14 months after SLAH, ten out of thirteen patients achieved meaningful seizure reductions, while seven were free of “disabling seizures.” This included six out of nine patients whose epilepsy was caused by an abnormality called mesial temporal sclerosis.

Although some complications occurred, none were directly caused by laser application. Two patients had an additional SLAH procedure to control seizures, and another patient underwent standard open surgery.

Open brain surgery is the standard treatment for patients with intractable MTLE. Surgery has a high success rate, but carries a significant risk of neurological and cognitive (intellectual) impairment. Minimally invasive approaches like the new MRI-guided laser ablation technique might produce similar seizure control with lower risks than surgery.

The new study shows “technical feasibility and encouraging results” with the minimally invasive MRI-guided SLAH technique for patients with MTLE. Effectiveness in relieving or eliminating seizures approaches that of surgery—perhaps especially among patients whose seizures are caused by mesial temporal sclerosis. “These are promising results considering that this reflects our initial experience, and results may improve with greater experience with this novel technique,” notes Dr. Gross.

"Such minimally invasive techniques may be more desirable to patients and result in increased use of epilepsy surgery among the large number of medically intractable epilepsy patients," Dr. Gross and colleagues conclude. They note that a larger, longer-term study of SLAH is underway, including assessment of the effects on cognitive function as well as seizures.

Filed under epilepsy amygdalohippocampal complex mesial temporal lobe seizures mesial temporal sclerosis neuroscience science

101 notes

Neural Transplant Reduces Absence Epilepsy Seizures in Mice
New research from North Carolina State University pinpoints the areas of the cerebral cortex that are affected in mice with absence epilepsy and shows that transplanting embryonic neural cells into these areas can alleviate symptoms of the disease by reducing seizure activity. The work may help identify the areas of the human brain affected in absence epilepsy and lead to new therapies for sufferers.

Absence epilepsy primarily affects children. These seizures differ from “clonic-tonic” seizures in that they don’t cause muscle spasms; rather, patients “zone out” or stare into space for a period of time, with no memory of the episode afterward. Around one-third of patients with absence epilepsy fail to respond to medication, demonstrating the complexity of the disease.

NC State neurobiology professor Troy Ghashghaei and colleagues looked at a genetic mouse model for absence epilepsy to determine what was happening in their brains during these seizures. They found that the seizures were accompanied by hyperactivity in the areas of the brain associated with vision and touch – areas referred to as primary visual and primary somatosensory cortices in the occipital and parietal lobes, respectively.

“There are neurons that excite brain activity, and neurons that inhibit activity,” Ghashghaei says. “The inhibitory neurons work by secreting an inhibitory neurotransmitter called gamma-aminobutyric acid, or GABA. The ‘GABAergic’ interneurons were recently shown by others to be defective in the mice with absence seizures, and we surmised that these malfunctioning neurons might be part of the problem, especially in the visual and somatosensory cortical areas.”

Ghashghaei’s team took embryonic neural stem cells from a part of the developing brain that generates GABAergic interneurons for the cerebral cortex. They harvested these cells from normal mouse embryos and transplanted them into the occipital cortex of the genetic mice with absence seizures. Absence seizure activity in treated animals decreased dramatically, and the mice gained more weight and survived longer than untreated mice.

“This is a profound and remarkably effective first result, and adds to the recent body of evidence that these transplantation treatments can work in mouse models of epilepsy. But we still don’t understand the mechanisms behind what the normal inhibitory cells are doing in areas of the visual cortex of absence epileptic mice,” Ghashghaei says. “We know that you can get positive results even when a small number of transplanted neurons actually integrate into the cortex of affected mice, which is very interesting.  But we don’t know how the transplanted cells are connecting with other cells in the cortex and how they alleviate the absence seizures in the mouse model we employed.

“Our next steps will be to explore these questions. In addition, we are very interested in methods being devised by multiple labs around the world to ‘reprogram’ cells from transplantation patients to generate normal GABAergic and other types of neurons. Once established, this would eliminate the need for embryonic stem cells for this type of treatment. The ultimate goal is to develop new therapies for humans suffering from various forms of epilepsies, especially those for whom drugs do not work.”

Neural Transplant Reduces Absence Epilepsy Seizures in Mice

New research from North Carolina State University pinpoints the areas of the cerebral cortex that are affected in mice with absence epilepsy and shows that transplanting embryonic neural cells into these areas can alleviate symptoms of the disease by reducing seizure activity. The work may help identify the areas of the human brain affected in absence epilepsy and lead to new therapies for sufferers.

Absence epilepsy primarily affects children. These seizures differ from “clonic-tonic” seizures in that they don’t cause muscle spasms; rather, patients “zone out” or stare into space for a period of time, with no memory of the episode afterward. Around one-third of patients with absence epilepsy fail to respond to medication, demonstrating the complexity of the disease.

NC State neurobiology professor Troy Ghashghaei and colleagues looked at a genetic mouse model for absence epilepsy to determine what was happening in their brains during these seizures. They found that the seizures were accompanied by hyperactivity in the areas of the brain associated with vision and touch – areas referred to as primary visual and primary somatosensory cortices in the occipital and parietal lobes, respectively.

“There are neurons that excite brain activity, and neurons that inhibit activity,” Ghashghaei says. “The inhibitory neurons work by secreting an inhibitory neurotransmitter called gamma-aminobutyric acid, or GABA. The ‘GABAergic’ interneurons were recently shown by others to be defective in the mice with absence seizures, and we surmised that these malfunctioning neurons might be part of the problem, especially in the visual and somatosensory cortical areas.”

Ghashghaei’s team took embryonic neural stem cells from a part of the developing brain that generates GABAergic interneurons for the cerebral cortex. They harvested these cells from normal mouse embryos and transplanted them into the occipital cortex of the genetic mice with absence seizures. Absence seizure activity in treated animals decreased dramatically, and the mice gained more weight and survived longer than untreated mice.

“This is a profound and remarkably effective first result, and adds to the recent body of evidence that these transplantation treatments can work in mouse models of epilepsy. But we still don’t understand the mechanisms behind what the normal inhibitory cells are doing in areas of the visual cortex of absence epileptic mice,” Ghashghaei says. “We know that you can get positive results even when a small number of transplanted neurons actually integrate into the cortex of affected mice, which is very interesting.  But we don’t know how the transplanted cells are connecting with other cells in the cortex and how they alleviate the absence seizures in the mouse model we employed.

“Our next steps will be to explore these questions. In addition, we are very interested in methods being devised by multiple labs around the world to ‘reprogram’ cells from transplantation patients to generate normal GABAergic and other types of neurons. Once established, this would eliminate the need for embryonic stem cells for this type of treatment. The ultimate goal is to develop new therapies for humans suffering from various forms of epilepsies, especially those for whom drugs do not work.”

Filed under epilepsy cerebral cortex visual cortex interneurons epileptic seizures somatosensory cortex neuroscience science

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New epilepsy treatment offers ‘on demand’ seizure suppression

A new treatment for drug-resistant epilepsy with the potential to suppress seizures ‘on demand’ with a pill, similar to how you might take painkillers when you feel a headache coming on, has been developed by UCL researchers funded by the Wellcome Trust.

image

The treatment, described in Nature Communications, combines genetic and chemical approaches to suppress seizures without disrupting normal brain function. The technique was demonstrated in rodents but in future we could see people controlling seizures on-demand with a simple pill.

Epilepsy affects around 50 million people worldwide including 600,000 in the UK and around a quarter of cases are resistant to conventional treatments. Many of these cases could be addressed by the new treatment method, which relies on genetic modification of brain cells to make them sensitive to a normally inactive compound.

“First, we inject a modified virus into the area of the brain where seizures arise,” explains Professor Dimitri Kullmann of the UCL Institute of Neurology, senior author of the research. “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.

“At the moment, severe seizures are treated with drugs that suppress the excitability of all brain cells, and patients therefore experience side effects. Sometimes the dose required to stop seizures is so high that patients need to be sedated and taken to intensive care. If we can take our new method into the clinic, which we hope to do within the next decade, we could treat patients who are susceptible to severe seizures with a one-off injection of the modified virus, and then use CNO only when needed.

“CNO would 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 clusters of seizures, where severe seizures are preceded by smaller ones. Seizure risk is also high when people are ill, sleep deprived, or at certain times of the menstrual cycle, so these would all be good times to take the pill as a preventative measure. In urgent situations, the compound could be given as an injection. We could even consider a fully automatic delivery system, where CNO was given by a pump, as is done for insulin in some people with diabetes.”

As CNO has a half-life of about a few hours and only affects the pre-treated epileptic parts of the brain, the new method avoids the need to permanently alter the brain or treat the whole brain with seizure-suppressing drugs. It builds on similar work by Professor Kullmann’s group using gene therapy to ‘calm down’ brain cells, or using light pulses to activate seizure-suppressing receptors in the brain. The new technique works in a similar way but is reversible and avoids the need for invasive devices to deliver light to the brain.

“After the one-off injection 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,” says Professor 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.

“Although there is currently no evidence that permanently suppressing excitability in a small area affects brain function, we cannot be sure that it would have no impact long-term. Our new method is completely reversible, so if there were any side-effects then people could simply stop taking the CNO pill.”

(Source: ucl.ac.uk)

Filed under epilepsy seizure suppression brain cells gene therapy optogenetics neuroscience science

202 notes

First Non-Study Site to Implant Device for Stopping Uncontrolled Seizures
NYU Langone Medical Center last month became the first hospital outside of a clinical trial site to implant a pacemaker-like device in the brain that may be a game-changer for patients with epilepsy.
The device, called the RNS System, was implanted April 17, 2014 in a patient with seizures that previously could not be controlled with medication, or intractable epilepsy, by Werner Doyle, MD, an associate professor in the Department of Neurosurgery at NYU Langone. The patient has recovered completely from the surgery.
The first-of-its-kind device is similar to an implantable cardioverter-defibrillator (ICD), which delivers electrical pulses to the heart to prompt it to beat a normal rhythm and provides a new alternative treatment to vagus nerve stimulation and surgical removal of the focus site – parts in the brain where the seizures originate — for people with intractable epilepsy.
Prior to last month’s surgery, the only implants of the seizure-reducing medical device took place at U.S. medical centers that had previously researched the device’s effectiveness and safety, making NYU Langone the first non-study hospital in the U.S. and New York metropolitan area to offer the RNS System to patients.
"Medically intractable epilepsy is often a debilitating disorder that puts sufferers at risk from sudden loss of consciousness and uncontrolled movements. It stigmatizes patients and restricts their independence," said Dr. Doyle. "Epilepsy surgery is an important therapeutic option for patients, which can significantly or completely control their seizures and return their lives to normal. The RNS device improves our ability to control seizures with surgery and now offers patients who may not have been surgical candidates in the past a surgical option."
According to the Centers for Disease Control and Prevention, about 2.3 million Americans suffer from epilepsy, with about one in 26 people expected to be diagnosed in their lifetimes. Approximately one-third of patients do not respond to medications and face major challenges with daily living. Uncontrolled seizures may interfere with normal activities such as working, going to school and driving. Patients also face increased risk for anxiety, depression, injury, brain damage, and in rare cases, death.
The RNS System, manufactured by NeuroPace Inc. of Mountain View, Calif., is a responsive stimulation device that’s implanted in the skull along with brain electrodes to detect abnormal electrical activity in the brain associated with seizures. After two or more weeks of recording the activity, doctors program the device to specifically respond to these abnormal signals by delivering imperceptible electrical pulses to the brain that normalize the activity. The device essentially “reboots” the portion of the brain where the seizure is originating, thereby effectively interrupting the abnormal electrical activity before it spreads or causes its unwanted effects.
The RNS System received pre-market approval from the Food and Drug Administration in November 2013 to treat patients’ seizures that have not been controlled by two or more antiepileptic medications.
In clinical trials performed at medical centers across the U.S., including at Saint Barnabas Medical Center in New Jersey by Dr. Doyle and Orrin Devinsky, MD, director of the Comprehensive Epilepsy Center at NYU Langone, 55 percent of patients experienced a 50 percent or greater reduction in seizures two years post implantation.
"The RNS System represents one of the most important and innovative therapies to treat people with epilepsy," says Dr. Devinsky. "This new surgical therapy uses information to target and shut down points in the brain where seizures start without removing tissue, providing a novel option for patients with uncontrolled seizures."
For more information:Neurology, Morrell et al, 2011.
Epilepsia, Heck et al, 2014.
NeuroPace

First Non-Study Site to Implant Device for Stopping Uncontrolled Seizures

NYU Langone Medical Center last month became the first hospital outside of a clinical trial site to implant a pacemaker-like device in the brain that may be a game-changer for patients with epilepsy.

The device, called the RNS System, was implanted April 17, 2014 in a patient with seizures that previously could not be controlled with medication, or intractable epilepsy, by Werner Doyle, MD, an associate professor in the Department of Neurosurgery at NYU Langone. The patient has recovered completely from the surgery.

The first-of-its-kind device is similar to an implantable cardioverter-defibrillator (ICD), which delivers electrical pulses to the heart to prompt it to beat a normal rhythm and provides a new alternative treatment to vagus nerve stimulation and surgical removal of the focus site – parts in the brain where the seizures originate — for people with intractable epilepsy.

Prior to last month’s surgery, the only implants of the seizure-reducing medical device took place at U.S. medical centers that had previously researched the device’s effectiveness and safety, making NYU Langone the first non-study hospital in the U.S. and New York metropolitan area to offer the RNS System to patients.

"Medically intractable epilepsy is often a debilitating disorder that puts sufferers at risk from sudden loss of consciousness and uncontrolled movements. It stigmatizes patients and restricts their independence," said Dr. Doyle. "Epilepsy surgery is an important therapeutic option for patients, which can significantly or completely control their seizures and return their lives to normal. The RNS device improves our ability to control seizures with surgery and now offers patients who may not have been surgical candidates in the past a surgical option."

According to the Centers for Disease Control and Prevention, about 2.3 million Americans suffer from epilepsy, with about one in 26 people expected to be diagnosed in their lifetimes. Approximately one-third of patients do not respond to medications and face major challenges with daily living. Uncontrolled seizures may interfere with normal activities such as working, going to school and driving. Patients also face increased risk for anxiety, depression, injury, brain damage, and in rare cases, death.

The RNS System, manufactured by NeuroPace Inc. of Mountain View, Calif., is a responsive stimulation device that’s implanted in the skull along with brain electrodes to detect abnormal electrical activity in the brain associated with seizures. After two or more weeks of recording the activity, doctors program the device to specifically respond to these abnormal signals by delivering imperceptible electrical pulses to the brain that normalize the activity. The device essentially “reboots” the portion of the brain where the seizure is originating, thereby effectively interrupting the abnormal electrical activity before it spreads or causes its unwanted effects.

The RNS System received pre-market approval from the Food and Drug Administration in November 2013 to treat patients’ seizures that have not been controlled by two or more antiepileptic medications.

In clinical trials performed at medical centers across the U.S., including at Saint Barnabas Medical Center in New Jersey by Dr. Doyle and Orrin Devinsky, MD, director of the Comprehensive Epilepsy Center at NYU Langone, 55 percent of patients experienced a 50 percent or greater reduction in seizures two years post implantation.

"The RNS System represents one of the most important and innovative therapies to treat people with epilepsy," says Dr. Devinsky. "This new surgical therapy uses information to target and shut down points in the brain where seizures start without removing tissue, providing a novel option for patients with uncontrolled seizures."

For more information:

Neurology, Morrell et al, 2011.

Epilepsia, Heck et al, 2014.

NeuroPace

Filed under epilepsy epileptic seizures NeuroPace RNS system brain activity neuroscience science

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Widely Used Drug No More Effective Than FDA Approved Medication in Treating Epileptic Seizures in Children
A National Institutes of Health-sponsored study published in the Journal of the American Medical Association (JAMA) showed that lorazepam - a widely used but not yet Food and Drug Administration (FDA) approved drug for children - is no more effective than an approved benzodiazepine, diazepam, for treating pediatric status epilepticus.
Status epilepticus is a state in which the brain is in a persistent state of seizure. By the age of 15, 4 to 8 percent of children experience a seizure episode, which can be life threatening if they aren’t stopped immediately. Status epilepticus is a continuous, unremitting seizure lasting longer than five minutes or recurrent seizures without regaining consciousness between seizures for more than five minutes.
Before this current study, published April 23, there was no evidence indicating which of the two treatments might prove more effective. Although it is not yet approved by the FDA, James M. Chamberlain, MD, Division Chief of Emergency Medicine at Children’s National Health System, the study’s principal investigator, estimates that lorazepam is used as first-line therapy in most emergency departments.
“The study results provide reassurance to emergency medicine personnel who must act within minutes,” said Chamberlain. The study was conducted at 11 hospitals in the United States using the infrastructure of the Pediatric Emergency Care Applied Research Network (PECARN), under a contract from the National Institutes of Health’s (NIH) Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD).
Both lorazepam and diazepam are used to treat status epilepticus. Diazepam, also known as Valium, is the only one of the two drugs to have been approved by the FDA for use in adults and children.
Lorazepam, marketed under the trade name Ativan, has been approved by the FDA only for use in adults. Once the FDA has approved a drug for use in adults, physicians may then prescribe it for other uses and in pediatric patients if, in their best judgment, they believe their patients will benefit.
“Sometimes physicians are forced to rely on their best judgment alone,” said George Giacoia, MD, of the NICHD’s Obstetric and Pediatric Pharmacology and Therapeutics Branch. “However, it’s always better to make treatment decisions on the evidence that comes only from conducting large comparison studies. We now know that lorezapam offers no advantage over diazepam in treating pediatric seizure disorder, and that diazepam is more suited to use by emergency teams.”
In 2007, the National Institutes of Health’s Pediatric Seizure study sought to determine which of two drugs—diazepam or lorazepam—was more effective in treating the life-threatening condition, status epilepticus. This condition can occur without warning. For reasons not fully understood, a child may be gripped by continuous seizures, which, if not stopped within minutes, may lead to brain damage or even death.
Because of the random nature of seizures and their significantly life altering affects, lorezapam is commonly prescribed to treat status epilepticus in children, even though it hasn’t been specifically approved for that use. The results of the Pediatric Seizure study do not support the use of lorezapam instead of diazepam for treating status epilepticus, Dr. Chamberlain said.  Also, because lorezapam needs to be refrigerated and diazepam does not, diazepam is more suited for use by ambulance crews.
A few previous studies indicated that lorazepam might be more effective at ending a seizure and might be less likely than diazepam to depress breathing—a side effect of benzodiazapines, the category of medications that includes both drugs.
In their study, Chamberlain and colleague wrote, “There is no conclusive evidence to support lorazepam as a superior treatment and there is little consensus as to which is the preferred agent.”
The current study was the largest, most comprehensive comparison study of the two treatments for pediatric seizure disorder. Dr. Chamberlain and his colleagues enrolled 310 children at the 11 institutions, between 2008 and 2012. The researchers found that both medications successfully halted seizures in 70 percent of cases, and each had rates of severe respiratory depression of less than 20 percent.
It’s important that “we get the most important scientific information about such medications so there are government approvals for pediatric use,” Chamberlain said. “Pediatric patients are not just small adults.”
(Image: Alamy)

Widely Used Drug No More Effective Than FDA Approved Medication in Treating Epileptic Seizures in Children

A National Institutes of Health-sponsored study published in the Journal of the American Medical Association (JAMA) showed that lorazepam - a widely used but not yet Food and Drug Administration (FDA) approved drug for children - is no more effective than an approved benzodiazepine, diazepam, for treating pediatric status epilepticus.

Status epilepticus is a state in which the brain is in a persistent state of seizure. By the age of 15, 4 to 8 percent of children experience a seizure episode, which can be life threatening if they aren’t stopped immediately. Status epilepticus is a continuous, unremitting seizure lasting longer than five minutes or recurrent seizures without regaining consciousness between seizures for more than five minutes.

Before this current study, published April 23, there was no evidence indicating which of the two treatments might prove more effective. Although it is not yet approved by the FDA, James M. Chamberlain, MD, Division Chief of Emergency Medicine at Children’s National Health System, the study’s principal investigator, estimates that lorazepam is used as first-line therapy in most emergency departments.

“The study results provide reassurance to emergency medicine personnel who must act within minutes,” said Chamberlain. The study was conducted at 11 hospitals in the United States using the infrastructure of the Pediatric Emergency Care Applied Research Network (PECARN), under a contract from the National Institutes of Health’s (NIH) Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD).

Both lorazepam and diazepam are used to treat status epilepticus. Diazepam, also known as Valium, is the only one of the two drugs to have been approved by the FDA for use in adults and children.

Lorazepam, marketed under the trade name Ativan, has been approved by the FDA only for use in adults. Once the FDA has approved a drug for use in adults, physicians may then prescribe it for other uses and in pediatric patients if, in their best judgment, they believe their patients will benefit.

“Sometimes physicians are forced to rely on their best judgment alone,” said George Giacoia, MD, of the NICHD’s Obstetric and Pediatric Pharmacology and Therapeutics Branch. “However, it’s always better to make treatment decisions on the evidence that comes only from conducting large comparison studies. We now know that lorezapam offers no advantage over diazepam in treating pediatric seizure disorder, and that diazepam is more suited to use by emergency teams.”

In 2007, the National Institutes of Health’s Pediatric Seizure study sought to determine which of two drugs—diazepam or lorazepam—was more effective in treating the life-threatening condition, status epilepticus. This condition can occur without warning. For reasons not fully understood, a child may be gripped by continuous seizures, which, if not stopped within minutes, may lead to brain damage or even death.

Because of the random nature of seizures and their significantly life altering affects, lorezapam is commonly prescribed to treat status epilepticus in children, even though it hasn’t been specifically approved for that use. The results of the Pediatric Seizure study do not support the use of lorezapam instead of diazepam for treating status epilepticus, Dr. Chamberlain said.  Also, because lorezapam needs to be refrigerated and diazepam does not, diazepam is more suited for use by ambulance crews.

A few previous studies indicated that lorazepam might be more effective at ending a seizure and might be less likely than diazepam to depress breathing—a side effect of benzodiazapines, the category of medications that includes both drugs.

In their study, Chamberlain and colleague wrote, “There is no conclusive evidence to support lorazepam as a superior treatment and there is little consensus as to which is the preferred agent.”

The current study was the largest, most comprehensive comparison study of the two treatments for pediatric seizure disorder. Dr. Chamberlain and his colleagues enrolled 310 children at the 11 institutions, between 2008 and 2012. The researchers found that both medications successfully halted seizures in 70 percent of cases, and each had rates of severe respiratory depression of less than 20 percent.

It’s important that “we get the most important scientific information about such medications so there are government approvals for pediatric use,” Chamberlain said. “Pediatric patients are not just small adults.”

(Image: Alamy)

Filed under lorazepam diazepam epilepsy benzodiazepines status epilepticus epileptic seizures neuroscience science

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