Posts tagged epilepsy

May 23, 2012 by R. Alan Leo

For decades, neurologists have known that a diet high in fat and extremely low in carbohydrates can reduce epileptic seizures that resist drug therapy. But how the diet worked, and why, was a mystery—so much so that in 2010, The New York Times Magazine called it “Epilepsy’s Big, Fat Miracle.”

Now, researchers at Dana-Farber Cancer Institute and Harvard Medical School have proposed an answer, linking resistance to seizures to a protein that modifies cellular metabolism in the brain. The research, to be published in the May 24th issue of the journal Neuron, may lead to the development of new treatments for epilepsy.

The research was led jointly by Nika Danial, HMS assistant professor of cell biology at Dana-Farber Cancer Institute, and Gary Yellen, professor of neurobiology at Harvard Medical School. The first author was Alfredo Giménez-Cassina, a research fellow in Danial’s lab.

Epilepsy is a neurological disorder characterized by repeated seizures, an electrical storm in the brain that can manifest as convulsions, loss of motor control, or loss of consciousness. Some cases of epilepsy can be improved by a diet that drastically reduces sugar intake, triggering neurons to switch from their customary fuel of glucose to fat byproducts called ketone bodies. The so-called ketogenic diet, which mimics effects of starvation, was described more than 80 years ago and received renewed interest in the 1990s. Recent studies corroborate that it works, but shed little light on how.

"The connection between metabolism and epilepsy has been such a puzzle," said Yellen, who was introduced to the ketogenic diet through his wife, Elizabeth Thiele, HMS professor of neurology, who directs the Pediatric Epilepsy Program at MassGeneral Hospital for Children, but was not directly involved in the study. "I’ve met a lot of kids whose lives are completely changed by this diet," Yellen said. "It’s amazingly effective, and it works for many kids for whom drugs don’t work."

"We knew we needed to come at this link between metabolism and epilepsy from a new angle," said Danial, who had previously discovered a surprising double duty for a protein known for its role in apoptosis: The protein, BCL-2-associated Agonist of Cell Death, or BAD, also regulated glucose metabolism.

Giménez-Cassina further discovered that certain modifications in BAD switched metabolism in brain cells from glucose to ketone bodies. “It was then that we realized we had come upon a metabolic switch to do what the ketogenic diet does to the brain without any actual dietary therapy,” said Gimenez-Cassina, who went on to show that these same BAD modifications protect against seizures in experimental models of epilepsy. Still, it wasn’t clear exactly how.

Yellen suspected the solution involved potassium ion channels. While sodium and calcium ion channels tend to excite cells, including neurons, potassium channels tend to suppress cell electrical activity. His lab had previously linked ketone bodies to the activation of ATP-sensitive potassium (KATP) channels in neurons. Yellen had hypothesized that the ketogenic diet worked because ketone bodies provide neurons enough fuel for normal function, but when the electrical and energy storm of an epileptic seizure threatens, the activated KATP channels can shut the storm down. But the effects of diets are broad and complex, so it was impossible to say for sure.

The effects that Danial’s lab had discovered—BAD’s ability to alter metabolism and seizures—offered a new avenue for studying the therapeutic effects of altered metabolism. Together, the researchers decided to investigate whether Danial’s switch governed Yellen’s pathway, and whether they could reverse engineer the seizure protection of a ketogenic diet.

They could. Working in genetically altered mice, the researchers modified the BAD protein to reduce glucose metabolism and increase ketone body metabolism in the brain. Seizures decreased, but the benefit was erased when they knocked out the KATP channel—strong evidence that a BAD-KATP pathway conferred resistance to epileptic seizures. Further experiments suggested that it was indeed BAD’s role in metabolism, not cell death that mattered. The findings make the BAD protein a promising target for new epilepsy drugs.

"Diet sounds like this wholesome way to treat seizures, but it’s very hard. I mean, diets in general are hard, and this diet is really hard," said Yellen, whose wife’s Center for Dietary Therapy in Epilepsy hosts a candy-free Halloween party for its many patients on the ketogenic diet. “So finding a pharmacological substitute for this would make lots of people really happy.”

Provided by Harvard Medical School

Source: medicalxpress.com

May 11, 2012

A brain study in infant rats demonstrates that the anti-epilepsy drug phenobarbital stunts neuronal growth, which could prompt new questions about using the first-line drug to treat epilepsy in human newborns.

In Annals of Neurology EarlyView posted online May 11, researchers at Georgetown University Medical Center (GUMC) report that the anti-epilepsy drug phenobarbital given to rat pups about a week old changed the way the animals’ brains were wired, causing cognitive abnormalities later in life.

The researchers say it has been known that some of the drugs used to treat epilepsy increase the amount of neurons that die shortly after birth in the rat brain, but, until this study, no one had shown whether this action had any adverse impact on subsequent brain development.

"Our study is the first to show that the exposure to these drugs — and just a single exposure — can prevent brain circuits from developing their normal connectivity, meaning they may not be wired correctly, which can have long-lasting effects on brain function,” says the study’s senior investigator, Karen Gale, Ph.D., a professor of pharmacology at GUMC. “These findings suggest that in the growing brain, these drugs are not as benign as one would like to believe.”

For their study, the Georgetown researchers studied four agents including phenobarbital.

"The good news is not all anti-epilepsy drugs have this disruptive effect in the animal studies," Gale says.

The researchers found that the anti-epilepsy drug levetiracetam did not stunt synaptic growth. Animals treated with a third drug, lamotrigine, showed neural maturation, but it was delayed. An additional finding involved melatonin. When added to phenobarbital, it appeared to prevent the persistent adverse neural effects in the rat pups. Melatonin has been used clinically to protect cells from injury in humans.

"Many clinicians have been advocating for a reexamination of the use of these drugs in infants, and our findings provide experimental data to support that need," says the study’s co-lead investigator, Patrick A. Forcelli, Ph.D., a postdoctoral fellow in the department of pharmacology and physiology at GUMC. "Phenobarbital has been used to treat seizures for over 100 years — well before a Food and Drug Administration approval process was established— and for more than 50 years, it has been the first drug of choice in the treatment of seizures in neonates."

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April 3, 2012

Epilepsy affects 50 million people worldwide, but in a third of these cases, medication cannot keep seizures from occurring. One solution is to shoot a short pulse of electricity to the brain to stamp out the seizure just as it begins to erupt. But brain implants designed to do this have run into a stubborn problem: too many false alarms, triggering unneeded treatment. To solve this, Johns Hopkins biomedical engineers have devised new seizure detection software that, in early testing, significantly cuts the number of unneeded pulses of current that an epilepsy patient would receive.

Sridevi Sarma’s research focuses on a system with three components: electrodes implanted in the brain, which are connected by wires to a neurostimulator or battery pack, and a sensing device, also located in the brain implant, which detects when a seizure is starting and activates the current to stop it. Credit: Greg Stanley/JHU

Sridevi V. Sarma, an assistant professor of biomedical engineering, is leading this effort to improve anti-seizure technology that sends small amounts of current into the brain to control seizures.

"These devices use algorithms — a series of mathematical steps —to figure out when to administer the treatment," Sarma said. "They’re very good at detecting when a seizure is about to happen, but they also produce lots of false positives, sometimes hundreds in one day. If you introduce electric current to the brain too often, we don’t know what the health impacts might be. Also, too many false alarms can shorten the life of the battery that powers the device, which must be replaced surgically."

Her new software was tested on real-time brain activity recordings collected from four patients with drug-resistant epilepsy who experienced seizures while being monitored. In a study published recently in the journal Epilepsy & Behavior, Sarma’s team reported that its system yielded superior results, including flawless detection of actual seizures and up to 80 percent fewer alarms when a seizure was not occurring. Although the testing was not conducted on patients in a clinical setting, the results were promising.

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April 2, 2012

New research confirms that childhood onset temporal lobe epilepsy has a significant impact on brain aging. Study findings published in Epilepsia, a peer-reviewed journal of the International League Against Epilepsy (ILAE), show age-accelerated ventricular expansion outside the normal range in this patient population.

According to the Centers for Disease Control and Prevention (CDC), epilepsy affects nearly 2 million Americans. Temporal lobe epilepsy is the most common form of partial epilepsy, with 60% of all patients having this form of the disease. Previous evidence suggests that patients with childhood onset epilepsy have significant cognitive and developmental deficiencies, which continue into adulthood, particularly in those resistant to antiepileptic drugs.

Prior imaging studies of patients with temporal lobe epilepsy have shown abnormalities in brain structure in hippocampus, in thalamus and other subcortical structures, and also in cortical and white matter volume. However, there is limited knowledge of the effects of aging on these structural changes.

To characterize differences in brain structure and patterns of age-related change, Dr. Bruce Hermann and colleagues from the University of Wisconsin-Madison recruited 55 patients with chronic temporal lobe epilepsy and 53 healthy controls for their study. Participants were between the ages of 14 and 60, with patients having mean age of onset of epilepsy in childhood/adolescence. Magnetic resonance imaging (MRI) was used to measure cortical thickness, area and volume in the brains of all subjects.

In participants with epilepsy, there were extensive abnormalities in brain structure, involving subcortical regions, cerebellum and cortical gray matter thickness and volume in the temporal and extratemporal lobes. Furthermore, researchers found that increasing chronological age was associated with progressive changes in cortical, subcortical and cerebellar regions for both epilepsy subjects and healthy controls. The pattern of change was similar for both groups, but epilepsy patients always showed more extensive abnormalities. In particular, epilepsy patients displayed age-accelerated expansion of the lateral and third ventricles. “The anatomic abnormalities in patients with epilepsy indicate a significant neurodevelopmental impact,” said Dr. Hermann.

"Patients with epilepsy are burdened with significant neurodevelopmental challenges due to these cumulative brain abnormalities," concludes Dr. Hermann. "The consequences of these anatomical changes for epilepsy patients as they progress into elder years remain unknown and further study of the adverse effects in those of older chronological age is needed."

Provided by Wiley

Source: medicalxpress.com

March 30, 2012

An estimated 2.2 million people in the United States live with epilepsy, a complex brain disorder characterized by sudden and often unpredictable seizures. The highest rate of onset occurs in children and older adults, and it affects people of all ethnicities and socio-economic backgrounds, yet this common disorder is widely misunderstood. Epilepsy refers to a spectrum of disorders with seizures that vary in type, cause, severity, and frequency. Many people do not know the causes of epilepsy or what measures to take if they witness a seizure. A new report from the Institute of Medicine highlights numerous gaps in the knowledge and management of epilepsy and recommends actions for improving the lives of those with epilepsy and their families and promoting better understanding of the disorder.

Effective treatments for epilepsy are available but access to treatment and timely referrals to specialized care are often lacking, the report’s expert committee found. Reaching rural and underserved populations, as well as providing state-of-the art care for people with persistent seizures, is particularly crucial. The report’s recommendations for expanding access to patient-centered health care include early identification and treatment of epilepsy and associated health conditions, implementing measures that assess quality of care, and establishing accreditation criteria and processes for specialized epilepsy centers. In addition, the wide variety of health professionals who care for those with epilepsy need improved knowledge and skills to provide the highest quality health care.

Some causes of epilepsy, such as traumatic brain injury, infection, and stroke, are preventable. Prevention efforts should continue for these established risk factors, as well as for recurring seizures in people with epilepsy and depression, and for epilepsy-related causes of death, the report says.

People with epilepsy need additional education and skills to optimally manage their disorder. Consistent delivery of accurate, clearly communicated health information from sources that include health care professionals and epilepsy organizations can better prepare those with epilepsy and their families to cope with the disorder and its consequences, the report says. Accurate, current data on the extent and consequences of epilepsy and its associated health conditions are especially needed to inform policymakers and identify opportunities for reducing the burden of epilepsy.

Living with epilepsy can affect employment, driving ability, and many other aspects of quality of life. The report stresses the importance of improved access to a range of community services, including vocational, educational, transportation, transitional care, and independent living assistance as well as support groups. The committee urged collaboration among federal agencies, state health departments, and relevant epilepsy organizations to improve and integrate these services and programs, particularly at state and local levels.

Misperceptions about epilepsy persist and a focus on raising public awareness and knowledge is needed, the report adds. Educating community members such as teachers, employers, and others on how to manage seizures could help improve public understanding of epilepsy. The report suggests several strategies for stakeholders to improve public knowledge of the disorder, including forming partnerships with the media, establishing advisory councils, and engaging people with epilepsy and their families to serve as advocates and educators within their communities.

Provided by National Academy of Sciences

Source: medicalxpress.com

ScienceDaily (Mar. 7, 2012) — While the thought of any type of surgery can be disconcerting, the thought of brain surgery can be downright frightening. But for people with a particular form of epilepsy, surgical intervention can literally be life-restoring.

A PET scan of a brain from a patient with epiepsy, between seizures. The red indicates healthy tissue. On the right side of the image, there is less red in the mesial temporal area. This is hypometabolism, reflecting decreased brain function in the area where seizures begin. (Credit: Image courtesy of University of California - Los Angeles)

Yet among people who suffer from what’s known as medically intractable epilepsy, in which seizures are resistant to drugs, only a small fraction will seek surgery, seeing it only as a last resort. As a result, they continue to suffer seizures year after year. They can’t drive, they can’t work and they lose cognitive function as the years pass. Premature death is not uncommon.

But a multi-center study led by researchers at UCLA shows that for people suffering from intractable temporal lobe epilepsy, the most common form of intractable epilepsy, early surgical intervention followed by antiepileptic drugs stopped their seizures, improved their quality of life and helped them avoid decades of disability.

The report appears in the March 7 edition of the Journal of the American Medical Association.

"In short, they got their lives back," said Dr. Jerome Engel, the study’s principal investigator and director of the UCLA Seizure Disorder Center.

But the frustration of Engel and his colleagues is this: Few patients are referred to them for surgical evaluation, and those who are have had epilepsy for an average of 22 years.

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March 6, 2012

Patients with epilepsy who underwent brain surgery soon after failing to respond to drug treatment, but who also continued to receive drug therapy, had a lower risk of seizures during the 2nd year of follow-up compared to patients who received drug treatment alone, according to a study in the March 7 issue of JAMA.

"Epilepsy is a worldwide serious health concern, accounting for 1 percent of the global burden of disease, equivalent to lung cancer in men and breast cancer in women. The 20 percent to 40 percent of patients who have medically intractable epilepsy account for 80 percent of the cost of epilepsy. Temporal lobe epilepsy (TLE) is the most common cause of drug-resistant seizures, but it can be treated surgically," according to background information in the article. The American Academy of Neurology practice parameter recommends surgery as the treatment of choice for medically intractable TLE, but use of this treatment is delayed and underutilized. Patients who are referred for surgery have had epilepsy for an average of 22 years, more than 10 years after failure of 2 antiepileptic drugs (AEDs). Because earlier surgery could prevent significant illness and premature death, it has been recommended that a randomized controlled trial be conducted to evaluate its efficacy.

Jerome Engel Jr., M.D., Ph.D., of the University of California, Los Angeles, and colleagues conducted a study to compare outcomes of surgery for epilepsy with those of continued drug treatment. The clinical trial, performed at 16 U.S. epilepsy surgery centers, included 38 participants (18 men and 20 women; age 12 years or older) who had mesial temporal lobe (a section of the brain) epilepsy (MTLE) and disabling seizures for no more than 2 consecutive years following adequate trials of 2 brand-name AEDs. Planned enrollment was 200, but the trial was halted prematurely due to slow accrual. Eligibility for anteromesial temporal resection (AMTR; surgery/removal of tissue of a section of the brain) was based on a standardized presurgical evaluation protocol. Participants were randomized to continued AED treatment (n = 23) or a standardized AMTR plus AED treatment (n = 15). In the medical group, 7 participants underwent AMTR prior to the end of follow-up and 1 participant in the surgical group never received surgery. The primary outcome measure for the study was freedom from disabling seizures during year 2 of follow-up. Other outcomes included measures on health-related quality of life (QOL) and cognitive function. 

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