RxPG News : Epilepsy

High frequency oscillation analysis on EEGs offers a new surgical approach to improve seizure control

Sat, 30 Jul 2011 19:27:47 PST

( from http://www.rxpgnews.com ) New research focusing on high-frequency oscillations, termed ripples and fast ripples, recorded by intracranial electroencephalography (EEG), may provide an important marker for the localization of the brain region responsible for seizure activity. According to the study now available in Epilepsia, a journal of the International League Against Epilepsy (ILAE), the resection of brain regions containing fast ripples, along with the visually-identified seizure-onset zone, may achieve a good seizure outcome in pediatric epilepsy.

High-frequency oscillations at 80-200 Hz are known as ripples and those above 200 Hz are considered fast ripples. Medical evidence suggests that fast ripples are a specific surrogate marker of the seizure generation zone. Studies in adults have suggested that resection of the brain region containing fast ripples was associated with good seizure outcome. However, these studies used a small number of electrode (EEG) contacts, with limited brain coverage, which may not be optimal for pediatric patients who often exhibit a more generalized epileptic network than adults.

Hiroshi Otsubo, MD, with The Hospital for Sick Children in Toronto, Canada and lead researcher of the current study explains, "In pediatric patients, extensive surgical resection are often used, but may overestimate the link between high-frequency oscillations and seizure outcome. Good surgical success may also be achieved by more limited surgeries that include both the brain region with high-frequency oscillations and the brain region that appears to initiate seizures, even when they are independent." To further explore this hypothesis, the research team evaluated the relationship of resection of brain regions containing high-frequency oscillations and the area of seizure onset in pediatric epilepsy patients.

Researchers retrospectively analyzed 28 pediatric patients with epilepsy who underwent intracranial EEG monitoring prior to focal resection surgery. Brain regions containing a high occurrence of high-frequency oscillations were determined, and spatial relationships between regions with fast ripples and seizure-onset zones were investigated. The team compared seizure outcome with the size of these regions, the surgical resection, and amount of the regions with fast ripples and areas of seizure onset within the resection area.

Results show that 2 years after surgery, 10 patients were completely seizure free and 18 continued to have some seizure activity. Complete resection of the brain regions exhibiting fast ripples was significantly associated with better seizure outcome. Improved seizure outcome was also observed with complete resection of brain regions with ripples; surprisingly, however, resection of the area of seizure onset did not correlate with seizure outcome. The size of surgical resection was not linked to seizure outcome.

Furthermore, the authors, Drs. Akiyama and Otsubo et al., noted that the visually- determined seizure onset zone partially overlapped with regions containing high-rate fast ripples. "The entire epileptic network, containing fast ripples, ripples and seizure onset zones, must be thoroughly analyzed to ensure complete resection of the area causing seizures with the smallest resection possible," advised Drs. Akiyama and Otsubo et al. "While our results are preliminary and further validation is necessary, the analysis of high frequency oscillations offers clinicians a new surgical approach that could potentially improve seizure outcome in children with epilepsy."

Anti-epileptic drugs increase risk of fractures in patients above the age of fifty years

Mon, 10 Jan 2011 21:18:44 PST

( from http://www.rxpgnews.com ) Most anti-epileptic drugs are associated with an increased risk of non-traumatic fracture in individuals 50 years of age and older, according to a report in the January issue of Archives of Neurology, one of the JAMA/Archives journals.

Anti-epileptic drugs are considered a secondary risk factor for osteoporosis, according to background information in the article, because epilepsy is highly prevalent in older adults, a population already at risk for osteoporosis. Additionally, anti-epileptic drugs are associated with greater bone density reduction in post-menopausal women with epilepsy.

While there have been studies that examined the link between anti-epileptic drugs and bone density loss in adults older than 65, little evidence exists for the association of individual anti-epileptic drugs with bone loss. Nathalie Jetté, M.D., M.Sc., of the University of Calgary, Foothills Hospital, Alberta, Canada, and colleagues studied medical records of 15,792 individuals who experienced non-traumatic fractures between April 1996 and March 2004. Each person was matched with up to three controls, persons without a history of fracture, for a total of 47,289 controls.

The individual anti-epileptic drugs studied included carbamazepine, clonazepam, ethosuximide, gabapentin, phenobarbital, phenytoin and valproic acid. Additional anti-epileptic drugs with fewer numbers of users were included together under "other anti-epileptic drugs."

The likelihood of fractures was highest for persons taking phenytoin followed by carbamazepine, other, phenobarbital, gabapentin and clonazepam. The only anti-epileptic drug not associated with an increased likelihood of fracture was valproic acid.

Similar results were found when testing for the use of anti-epileptic drugs in monotherapy (individuals taking only one anti-epileptic drug) and in polytherapy (individuals taking more than one anti-epileptic drug). All anti-epileptic drugs used in monotherapy were associated with a significantly increased risk of fracture except for valproic acid, phenobarbital and "other anti-epileptic drugs." The greatest risk of fracture was found in individuals in the polytherapy subgroups.

"In conclusion, our study showed that most anti-epileptic drugs except for valproic acid are associated with an increased likelihood of non-traumatic fracture in individuals aged 50 years or older," the authors write. "Future prospective studies of anti-epileptic drugs in newly treated drug-naïve patients are needed to better examine the individual effects of anti-epileptic drugs on bone health."

More research and attention needed for epilepsy

Tue, 28 Dec 2010 09:38:39 PST

( from http://www.rxpgnews.com ) Epilepsy, a common and serious neurologic disorder that affects millions of people, is not getting the public attention and funding for research it deserves, according to an editorial on a study published in the January 4, 2011, print issue of Neurology®, the medical journal of the American Academy of Neurology.

"We have almost nonexistent epilepsy surveillance, or ongoing collection of data on newly diagnosed epilepsy, in the United States," said Edwin Trevathan, MD, MPH, Dean of the St. Louis University School of Public Health in St. Louis and a member of the Neurology® Editorial Board. "As a result, we do not have good data to inform decisions made by our health leaders, and some of our best researchers are analyzing data that are 30 to 50 years old."

Trevathan points to narrowly focused funding lines from Congress to the Centers for Disease Control and Prevention (CDC) as one cause of inadequate epilepsy data. For example, these narrow funding lines result in funding for public awareness campaigns instead of essential public health infrastructure, such as public health surveillance for epilepsy. Major federal agencies such as the CDC also have other priorities that receive the limited, optional funding.

"Epilepsy has a major impact on public health. A national approach to monitoring epilepsy trends is desperately needed in order to monitor the impact of improvements in epilepsy care, to identify problems with epilepsy care that need to be corrected, and to provide up-to-date data for researchers," said Trevathan.

In the corresponding study, scientists aimed to discover the lifetime risk of developing epilepsy. They analyzed data on 412 people from Rochester, Minn., diagnosed with epilepsy between 1960 and 1979. The study found that at least one in 26 people will develop epilepsy in their lifetime. The risk was higher in the elderly, with a risk of 1.6 percent in people under age 50 and a 3.0 percent risk for people up to age 80.

"Our results highlight the need for more research using epilepsy surveillance data, especially given the aging population in the United States. Such surveillance will also provide useful information for health care planners as they address the service needs of people with epilepsy," said study author Dale C. Hesdorffer, PhD, associate professor of clinical epidemiology in the Sergievsky Center at Columbia University Medical Center.

Recent - onset seizures affect white matter development

Wed, 19 May 2010 14:19:59 PST

( from http://www.rxpgnews.com ) A newly published study reported that children with new/recent onset epilepsy have significantly slowed expansion of white matter volume compared to healthy children over a two year interval. The reduced white matter volume may affect brain connectivity and influence cognition. Results of this study conducted by researchers from the University of Wisconsin School of Medicine and Public Health are now available online and will appear in the July issue of Epilepsia, a journal published by Wiley-Blackwell on behalf of the International League Against Epilepsy.

Epilepsy, a common nervous system disorder, frequently develops in early childhood and causes recurrent seizures. Seizures can range from mild staring spells to major convulsions. According to the Epilepsy Foundation there are 326,000 children under the age of 15 with epilepsy in the U.S. More than 45,000 new cases of epilepsy are diagnosed in children each year.

A research team, led by Bruce Hermann, Ph.D., investigated the neurodevelopmental changes in brain structure in children with new or recent-onset epilepsy. Thirty-four healthy children (control group) and 38 with new/recent onset epilepsy were enrolled in the study. The epilepsy group contained 21 children with localization-related epilepsy and 17 with idiopathic generalized epilepsy. Children in both groups had a mean age of 12.9 years and underwent magnetic resonance imaging (MRI) at baseline and 2 years later.

At the 2 year follow-up, seizure frequency was evaluated. During the prior year, 53% of children with epilepsy were seizure free; 34% reported only one seizure. In the remaining children with epilepsy, 5% reported monthly, 5% weekly, and 3% daily seizures.

"Our study determined that children with new or recent-onset epilepsy exhibited an altered brain development pattern characterized by delayed age-appropriate increase in white matter volume," said Dr. Hermann. The research team found that total cerebral white matter volume increased significantly in the healthy control group over the 2-year period. However, the epilepsy group did not show significant change in white matter volume in the total cerebrum and across all lobes—the difference from normal controls being most pronounced in the frontal lobes.

Researchers suspect that the delayed white matter volume increase in children with epilepsy may affect cognitive development by reducing brain connectivity. With altered brain development, children with epilepsy may also experience impaired executive function—mental tasks such as organizing, planning, and paying attention which are commonly reported in people with epilepsy.

"Research into the symmetry between patterns of cognitive change and age-appropriate brain development remains to be addressed in childhood epilepsy," concluded Dr. Hermann. "Further exploration of how subtle neurodevelopmental alterations in brain development affect cognition is needed. Longer term follow-up is also needed to determine whether this finding represents a temporary delay in brain development versus a fixed difference."

Ethosuximide - most effective treatment for childhood absence epilepsy

Sun, 14 Mar 2010 02:08:39 PST

( from http://www.rxpgnews.com ) One of the oldest available anti-seizure medications, ethosuximide, is the most effective treatment for childhood absence epilepsy, according to initial outcomes published in this week's New England Journal of Medicine.

OHSU Doernbecher Children's Hospital is one of 32 comprehensive pediatric epilepsy centers nationwide selected to participate in this landmark clinical trial as part of the NIH Childhood Absence Epilepsy Study Group.

The study group compared three medications typically used to treat the most common childhood epilepsy syndrome, childhood absence epilepsy, which is characterized by frequent non-convulsive seizures that cause the child to stop what he or she is doing and stare for up to 30 seconds at time.

Prior to this study, there was no definitive evidence on which drug worked best.

"Much of our scientific understanding of childhood epilepsy care today comes from historical experience or studies involving adult patients with related, but not identical, conditions," explained Colin Roberts, M.D., OHSU Doernbecher's principal investigator for the study, assistant professor of pediatrics and neurology, and director of OHSU Doernbecher's Pediatric Epilepsy Program,

"This study is an important milestone in our understanding of childhood absence epilepsy. Never before have we been able to document in such a comprehensive, scientific fashion the best options to treat children with this condition."

The study group enrolled 453 children newly diagnosed with childhood absence epilepsy from July 2004 to October 2007. Study participants were randomly assigned to ethosuximide, valproic acid or lamotrigine. Drug doses were incrementally increased until the child was seizure-free. After 16 weeks of therapy, the researchers found ethosuximide and valproic acid were significantly more effective than lamotrigine in controlling seizures, with no intolerable side effects. They also determined ethosuximide was associated with significantly fewer negative effects on attention.

Nick and Michelle Skimas, of Vancouver, Wash., enrolled their daughter Julia in the study in April 2007. Julia stopped having seizures after starting medication.

Before diagnosis and treatment, Julia, now 8, would stop abruptly while reading aloud, pause for 10 to 15 seconds, then resume where she left off, not aware that anything had occurred. Michelle assumed Julia was just taking breaks to look at the pictures.

This went on for two to three weeks, and Michelle didn't think anything of it. Then, while on a family vacation, Julia suddenly stopped in the midst of pitching a baseball and began slowly turning in a circle. Julia was unaware of what was happening and had no recollection of what had occurred.

"That did it," said Michelle. "We took Julia to be evaluated as soon as we got back." After an EEG, and an MRI to rule out a brain tumor, Julia was diagnosed with childhood absence epilepsy. Her primary care physician recommended she enroll in a new drug trial at OHSU Doernbecher. Nick and Michelle were leery of giving their daughter medication, but Roberts and his team explained that without treatment Julia's seizures would have a serious impact on her learning and development.

"They said to think of Julia's brain as a classroom in which one child is continuously disruptive. The rest of the class can't function. It was a hard decision, but we are glad we participated. We feel blessed that she has been seizure-free for more than 2 ½ years."

The national study group recommended long-term follow up for the study participants and recently received a five-year extension from the NIH.

Julia, who stopped taking the medication several months after she became seizure-free because it increased her BMI, or body mass index, continues to participate in the newly extended trial, representing one of three study groups: participants who took medication, became seizure-free and stopped taking the medication. The other groups comprise children who are taking the medication but still having seizures, and children taking the medication who are not experiencing seizures, respectively.

"We told Julia all along that what she was doing could very well help other kids in her position, and now she knows it did. That will make a big difference in her life," said Michelle.

"The initial outcomes from this study describe one of many aspects of childhood absence epilepsy evaluated by the study group. Collaborative studies like this lay the groundwork for many critically important studies to follow that will define the proper care of children with seizures," said Roberts.

Studies focusing on early diagnosis and treatment of epilepsy with minimal side-effects

Sun, 07 Dec 2008 14:20:28 PST

( from http://www.rxpgnews.com ) Early diagnosis and treatment that quickly achieves seizure freedom with nominal side effects is the key goal to epilepsy management. Three studies highlighted at the AES annual meeting address this goal from different vantage points:
The course to seizure freedom? Identifying factors that may change the landscape of epilepsy treatment to improve patients' quality of life.
New EEG technology that may facilitate accurate seizure screening by non-specialists in urgent care settings.
Task force report on disparity in standards for Epilepsy Monitoring Units amidst rise in number of epilepsy treatment centers.

"Each clue we uncover in understanding epilepsy and how to suppress the disruptions it causes for those affected takes us closer to the goal of successfully treating this chronic condition. Data from this year's meeting lead us towards answers about characteristics we can focus on to more effectively diagnose and treat epilepsy," said Dennis D. Spencer, M.D., AES President, Harvey and Kate Cushing Professor and Chair of Neurosurgery, Yale University School of Medicine. "This is especially critical because we know that an estimated one-third of seizures are not controlled with existing therapies."

Epilepsy Patients Achieving Seizure Freedom More Quickly, According to New Analysis

An analysis of epilepsy patients demonstrated that the time to seizure freedom significantly decreased by 10% every year from 1995 to 2005, according to data presented by Jukka Peltola, MD, PhD, Department of Neurology, Tampere University Hospital, Tampere, Finland.

Dr. Peltola and his colleagues studied records of 571 epilepsy patients aged nine to 78 years, who were diagnosed and treated in Tampere University Hospital from 1995 to 2005. Using various methods of analysis, they identified the amount of time for 70% of patients to achieve seizure freedom:

Patients diagnosed in 1995-1998: 10 years.
Patients diagnosed in 1999-2001: 6 to 7 years.
Patients diagnosed in 2002-2005: 4 years.

"The first-line treatment protocol has not changed over the duration of this study in Finland, but several other changes in the landscape may have contributed to this positive trend. These include new second- and third-line agents, earlier and more aggressive intervention, and greater access to advanced MRI and EEG technology," explained Dr. Peltola. "We are actively analyzing this data further to ascertain the reasons for the decrease in time to seizure freedom. If identified, this could make an important clinical difference."

New EEG Technology—a Seizure Vector Algorithm—Facilitates Seizure Screening in Urgent Care Settings

A group of researchers from Infinite Biomedical Technologies (IBT) and The Johns Hopkins University School of Medicine presented findings demonstrating the accuracy of investigational screening technology designed to assess if a patient's symptoms should be classified as a seizure or another condition.

"Access to an EEG reading, the gold standard for identifying and classifying seizures, is limited in most urgent care settings. Often the EEG machine and/or technologists are not readily available to the Emergency Department (ED), and eventual diagnosis by a specialist may be delayed for hours, or in some cases days," said study author Peter W. Kaplan, MB, FRCP, Professor of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD.

To address this problem, the collaborative team, with grant support from the National Institutes of Health, designed the Seizure Vector (SV) algorithm to express EEG readings as a numeric seizure score. Based on the score, ED staff could quickly classify and triage patients. Potential classifications include:

Epileptic seizures: refer to a neurologist for further evaluation.
Non-epileptic events: refer for neurological, medical or psychiatric evaluation.

The team's hope is that this technology, when used in the ED setting, will enable first-response personnel to screen for seizures in patients and make rapid triage decisions, such as timely referral to a specialist for evaluation, diagnosis and treatment.

To validate the algorithm, researchers collected EEGs from 40 adults with a variety of seizure types, and a blinded epileptologist classified them into "normal" or "seizure" categories. A total of 2,035 episodes of seizures and 3,867 episodes of normal data were recorded. When the SV algorithm was applied to the same recordings, it differentiated between "seizure" and "normal" episodes with 95.0% sensitivity and 95.2% specificity.

Surveys Reveal Lack of Consensus on Patient Care, Safety Measures in Epilepsy Monitoring Units

A new AES survey of physicians and nurses provided the basis for a working group discussion at this week's meeting regarding a need for the creation of standards in patient care and safety measures in epilepsy monitoring units (EMUs) across the United States.

Patients are admitted to EMUs to determine if they are having seizures, to consider if surgery is an option, for medication changes, or other diagnostic procedures. Some of the monitoring procedures require sleep deprivation and/or taking patients off medications to provoke seizures for simultaneous recording of symptoms and related brain wave activity.

The surveys evaluated EMU practices related to these monitoring procedures, as well as patient supervision. Results revealed discrepancies across EMUs in these areas, with relatively few physicians and nurses reporting that their facilities had protocols in place for seizure monitoring or patient supervision.

"In the continuum of patient care, EMUs are critically important and can significantly drive outcomes," said EMU Study Group member Gregory L. Barkley, MD, Clinical Vice Chair, Department of Neurology, Henry Ford Hospital. "This is why the AES has made it a priority to examine EMUs and formulate best practices and guidelines that will establish a standard, increase efficiency and, most importantly, improve patient outcomes."

Sudden Unexpected Death In Epilepsy

Mon, 17 Nov 2008 12:11:21 PST

( from http://www.rxpgnews.com ) A new study by researchers at UC Davis Medical Center suggests that the sudden unexplained deaths of some epilepsy patients may be a result of their brains not telling their bodies to breathe during seizures.

"Significant drops in blood oxygen levels are more common than we thought in patients with partial seizures," said study senior author Masud Seyal, a professor of neurology at UC Davis Medical Center and director of the UC Davis Comprehensive Epilepsy Program.

The study, published online in the Oct. 24 issue of the journal Brain, studied Sudden Unexpected Death in Epilepsy, what doctors call SUDEP for short, to examine deaths of epileptics not explained by repeated convulsive seizures, accidents or other mishaps.

"What we've known for a long time is that SUDEP appears to be the most important cause of increased mortality in epilepsy patients. What we haven't known is what causes it," Seyal said.

The findings suggest that some cases of SUDEP may result from the brain not signaling the patient to continue breathing during seizures, though more conclusive evidence is needed, he said.

"It may have to do with an abnormal heart rhythm or it just may be that the brain stops sending the proper signals to maintain normal breathing," Seyal said.

In the retrospective study, Seyal and his colleagues examined records of 300 seizures in 57 epilepsy patients with chronic, recurrent, unprovoked seizures. They compared patients with severe convulsive seizures to those with milder symptoms like transient confusion, lip smacking and head turning.

One-third of all seizures were associated with drops in blood-oxygen levels below 90 percent. Seyal said he was surprised to find that 12 percent of these patients' blood oxygen levels actually dropped below 70 percent during their seizures.

They also discovered that seizures in the temporal lobe of the brain are more often associated with significant drops in blood-oxygen levels and that males are more likely than females to experience dangerously low levels of oxygen during seizures.

The findings support the idea that some cases of SUDEP may be caused by a lack of brain signaling that makes the patient keep breathing, though scientists need to do more research before they know for sure, Seyal said.

The study is important, Seyal said, because it suggests that hospitals that monitor inpatients for seizures should use both continuous blood-oxygen monitoring that sets off alarms when blood levels are too low and around-the-clock monitoring by staff or relatives.

In a hospital setting, blood-oxygen levels below 85 percent require intervention, such as giving supplemental oxygen, turning the patient on his side or suctioning the patient's airway, to help the patient breathe.

Patients hospitalized for seizure monitoring in the UC Davis Comprehensive Epilepsy Program must have a relative or friend with them around the clock who can recognize their seizures and summon assistance when they occur, in addition to constant blood-oxygen monitoring.

Some medical centers also use video monitors that are continuously monitored by hospital staff. But many do not employ this kind of close monitoring.

"Our data show that it's important that respiratory parameters be closely monitored in the hospital," Seyal said.

The best strategy to reduce the likelihood of SUDEP is to promptly and effectively control patients' seizures, Seyal said.

Most seizures can be stopped with medication. Patients with seizures poorly controlled with medication often are candidates for surgery, which can have a high success rate. To perform the surgery, however, patients must be observed in the hospital, their medication must be reduced and seizures allowed to take place.

"This is the only way we can pinpoint the region of the brain responsible for the seizures and know where to operate," he said.

Seyal and his colleagues are working to determine the best ways to deal with patients who have severe drops in oxygen levels with seizures.

"The important thing here is to see how we can intervene to deal with the hypoxemia when it happens," he said.

Topiramate may increase the risk of birth defects

Tue, 22 Jul 2008 10:41:23 PST

( from http://www.rxpgnews.com ) Taking the epilepsy drug topiramate alone or along with other epilepsy drugs during pregnancy may increase the risk of birth defects, according to a study published in the July 22, 2008, issue of Neurology®, the medical journal of the American Academy of Neurology.

Research has shown that many epilepsy drugs increase the risk of birth defects, but little research has been done on topiramate. Studies have shown that topiramate increases the risk of birth defects in animals. Maintaining effective epilepsy treatment during pregnancy is crucial because seizures may cause harm to the fetus.

For the study, researchers examined women who became pregnant while taking topiramate either on its own or along with other epilepsy drugs. Of 178 babies born, 16 had major birth defects. Three of these were in infants whose mothers were taking only topiramate, and 13 were in those whose mothers were taking topiramate and other epilepsy drugs.

Four of the babies had cleft palates or cleft lips, a rate 11 times higher than that expected if these women were not taking epilepsy drugs. Four male babies had genital birth defects, with two of those classified as major defects, which is 14 times higher than the normal rate for this defect.

"More research needs to be done to confirm these results, especially since it was a small study," said John Craig, MRCP, of the Royal Group of Hospitals in Belfast, Northern Ireland. "But these results should also get the attention of women with migraine and their doctors, since topiramate is also used for preventing migraine, which is an even more common condition that also occurs frequently in women of childbearing age."

Craig said the risk of birth defects may be different for women taking the drug for migraine, but that the pregnancies of women exposed to topiramate should be monitored.

This study found that more birth defects occurred in women taking topiramate along with the drug valproate, or valproic acid, than in women taking topiramate and another epilepsy drug. Research has shown that valproate is associated with a high risk of birth defects.

Glutamate- involved in blocking response to anti-epileptic medication

Mon, 14 Apr 2008 13:41:38 PST

( from http://www.rxpgnews.com ) Using a rodent model of epilepsy, researchers found one of the body’s own neurotransmitters released during seizures, glutamate, turns on a signaling pathway in the brain that increases production of a protein that could reduce medication entry into the brain. Researchers say this may explain why approximately 30 percent of patients with epilepsy do not respond to antiepileptic medications. The study, conducted by researchers at the National Institute of Environmental Health Sciences (NIEHS), part of the National Institutes of Health, and the University of Minnesota College of Pharmacy and Medical School, in collaboration with Heidrun Potschka’s laboratory at Ludwig-Maximilians-University in Munich, Germany, is available online and will appear in the May 2008, issue of Molecular Pharmacology.

“Our work identifies the mechanism by which seizures increase production of a drug transport protein in the blood brain barrier, known as P-glycoprotein, and suggests new therapeutic targets that could reduce resistance,” said David Miller, Ph.D., a principal investigator in the NIEHS Laboratory of Pharmacology and co-author on the paper.

The blood-brain barrier (BBB), which resides in brain capillaries, is a limiting factor in treatment of many central nervous system disorders. It is altered in epilepsy so that it no longer permits free passage of administered antiepileptic drugs into the brain. Miller explained that P-glycoprotein forms a functional barrier in the BBB that protects the brain by limiting access of foreign chemicals.

“The problem is that the protein does not distinguish well between neurotoxicants and therapeutic drugs, so it can often be an obstacle to the treatment of a number of diseases, including brain cancer,” Miller said. Increased levels of P-glycoprotein in the BBB has been suggested as one probable cause of drug resistance in epilepsy.

Using isolated brain capillaries from mice and rats and an animal model of epilepsy, the researchers found that glutamate, a neurotransmitter released when neurons fire during seizures, turns on a signaling pathway that activates cyclooxygenase-2 (COX-2), causing increased synthesis of P-glycoprotein in these experiments. Increased transporter expression was abolished in COX-2 knockout mice or by COX-2 inhibitors. It has yet to be shown in animals or patients that targeting COX-2 will reduce seizure frequency or increase the effectiveness of anti-epileptic drugs.

"These findings provide insight into one mechanism that underlies drug resistance in epilepsy and possibly other central nervous system disorders," said Bjoern Bauer, Ph.D., lead author on the publication. "Targeting blood-brain barrier signals that increase P-glycoprotein expression rather than the transporter itself suggests a promising way to improve the effectiveness of drugs that are used to treat epilepsy, though more research is needed before new therapies can be developed.”

Responsive Neurostimulator System: An implantable device to treat epilepsy

Thu, 14 Sep 2006 16:54:00 PST

( from http://www.rxpgnews.com )

Responsive Neurostimulator System

About 2.5 million Americans of all ages have epilepsy. Think of it as a tiny electrical storm in the brain. Many people suffer from seizures affecting their quality of life or have side effects from epilepsy medications. However, patients with some types of the disease don't respond to surgery or may be at high risk for complications. That's why new devices surgically implanted in the brain itself offer hope for an effective epilepsy treatment.

Neurologists at the University of Virginia Health System are now testing two separate devices to treat epilepsy. Participants are being enrolled in a national, clinical trial of an implantable device called the RNS or Responsive Neurostimulator System, manufactured by Neuropace, Inc., of Sunnyvale, Calif.

The RNS is a flat device about the size of a half-dollar. It is implanted just under the scalp and connected to insulated wires with small electrodes at the end. These leads are implanted in the patient's brain or on the brain surface near where seizures are believed to start. When a seizure is detected by the RNS, a brief, mild electrical shock is delivered to suppress it.

"Until now, drugs have been the mainstay of therapy for people with epilepsy," said Dr. Nathan Fountain, a UVa neurologist and director of the F. E. Dreifuss Comprehensive Epilepsy Program. "The idea that we can implant a Star Trek-type device that will detect seizures and interrupt them without causing injury is entirely new. Many people with epilepsy have seizures that begin at one focal point in the brain, but they aren't appropriate for epilepsy surgery. If we show that responsive neurostimulation is safe and effective, then it has the potential to help many patients with epilepsy lead more normal lives."

Usually, the activity in brain waves is intentionally uncoordinated. But during an epileptic seizure, brain waves from thousands of the brain's neurons start firing together. It's the opposite of what happens in a heart attack when the heart muscle beats wildly. "The idea behind the RNS is that a small electrical discharge, less than that of a battery across your thumb, will be enough to stop a seizure," Fountain said.

UVa neurologists are also participating in a clinical trial of a deep brain stimulation (DBS) device manufactured by Medtronic, Inc. to treat epilepsy. DBS is currently being used to treat people with Parkinson's Disease. In DBS, surgeons implant a wire in a deep part of the brain that sends signals to the part of the brain-the thalmus-- that produces most epileptic seizures. "We are confident that DBS is safe for people with epilepsy since it is now being used on older people with Parkinson's. They do well with a low complication rate," Fountain said.

These two devices-RNS and DBS- could offer new, potential treatment for patents with epilepsy without a lot of other treatment options, especially those whose seizures aren't controlled by drugs and who aren't good surgical candidates. Patients who have epileptic seizures after using one drug tend to continue to have them on another, Fountain said.

As for what causes one person to get epilepsy and another not? Fountain and other neurologists say a specific cause remains a mystery. But they do know that people who have had brain tumors, brain trauma, a neurological infection or a genetic predisposition to epilepsy are more likely to be diagnosed with the condition.

Defibrillator to prevent epileptic seizures?

Wed, 13 Sep 2006 20:10:00 PST

( from http://www.rxpgnews.com ) Researchers at MIT are developing a device that could detect and prevent epileptic seizures before they become debilitating.

Epilepsy affects about 50 million people worldwide, and while anticonvulsant medications can reduce the frequency of seizures, the drugs are ineffective for as many as one in three patients.

The new treatment builds on an existing treatment for epilepsy, the Cyberonics Inc. vagus nerve stimulator (VNS), which is often used in patients who do not respond to drugs. A defibrillator typically implanted under the patient's collar bone stimulates the left vagus nerve about every five minutes, which has been shown to help reduce the frequency and severity of seizures in many patients.

The MIT researchers and colleagues at Beth Israel Deaconess Medical Center (BIDMC) seek to improve the treatment by combining it with a detector that measures brain activity to predict when a seizure is about to occur. The new device would sense the oncoming seizure and then activate the VNS, in principle halting the seizure before it becomes manifest.

"Our contribution is the software that decides when to turn the stimulator on," said John Guttag, MIT's Dugald C. Jackson Professor in the Department of Electrical Engineering and Computer Science. Guttag developed the system along with Ali Shoeb, a graduate student in the Harvard-MIT Division of Health Sciences and Technology.

"Our colleague Dr. Steven Schachter, professor of neurology at Harvard Medical School and epileptologist at BIDMC, suggested hooking our detector up to the VNS," he said. MIT and BIDMC researchers plan to test the new device in epilepsy patients this fall. If it seems effective, more comprehensive trials will be launched.

A look at brain patterns

The detector works by measuring brain activity with electrodes placed on the patient's scalp. In its current form, the patient wears something resembling a bathing cap, in which electrodes are embedded. In order to adapt the detector to work with the VNS, researchers connected wires from the cap to a laptop computer or microprocessor that activates the implanted defibrillator.

Guttag said he believes the technology could be refined so the electrodes could be worn inside of a headband or baseball cap, making the device less obvious to observers.

Each epilepsy patient has different brain activity patterns, so the detector is programmed to measure an individual's patterns to determine what the precursors to a seizure look like for each patient.

"It's quite tricky to try to detect very early signs of seizures because there are abnormal electrical signals that don't evolve into seizures," Guttag said. "If we can learn what the right profile is for an individual, we can build a seizure onset detector that works really well for that person."

Ideally, when the device senses an impending seizure, it sends a magnetic signal to the implanted stimulator, which in turn activates the left vagus nerve. The vagus nerve sends electrical signals up to the brain as well as down toward the viscera, controlling heart rate, gastrointestinal peristalsis, sweating and keeping the larynx open for breathing. The mechanism by which VNS prevents seizures is not known, but the technique has been FDA approved to treat epilepsy for about 10 years.

About 32,000 epilepsy patients already have VNS implants, according to Guttag. Some of them are able to use a handheld magnet to activate the VNS on demand, but many cannot. If the new detection device is successful, it would allow many more patients to use the VNS on demand.

The device could also be adapted to provide warnings for patients who don't need or want VNS implants. Once the device alerts the patient that a seizure is imminent, that person could take steps to minimize injury, such as sitting down or moving away from potentially dangerous objects, such as a hot stove.

"If you could just give someone a little bit of warning they're about to have a seizure, it could be hugely valuable," Guttag said. "The seizures themselves aren't usually damaging to the brain in the long term. It's mostly about the collateral damage."

Although the seizure detector could have a huge impact on epilepsy patients, there are plenty of other potential applications for technology that analyzes electrical activity in individual brains, Guttag said. Depression, schizophrenia and attention deficit disorder are just a few of the conditions that could be studied.

"My hope is that we'll be able to use some of the technology to get insight into a lot of those mysterious neurological conditions," he said.

Septum sets the tempo of brain's electrical activity

Tue, 20 Jun 2006 19:06:00 PST

( from http://www.rxpgnews.com ) The brain's septum helps prevent epileptic seizures by inducing rhythmical electrical activity in the circuits of another area of the brain known as the hippocampus, according to a new study in the Journal of Neurophysiology. The researchers found that, by imposing a normal "theta" rhythm on chronically epileptic rats, they could reduce epileptic seizures by 86-97 percent.

The study "Septo-hippocampal networks in chronically epileptic rats: Potential antiepileptic effects of theta rhythm generation," by Luis V. Colom, Antonio García-Hernández, Maria T. Castañeda, Miriam G. Perez-Cordova and Emilio R. Garrido-Sanabria, The University of Texas at Brownsville/Texas Southmost College, appears in the June issue of the Journal of Neurophysiology, published by The American Physiological Society.

The septum acts as the conductor, orchestrating brain impulses as they pass from the brain stem through the septum and on to the hippocampus, said the study's lead researcher, Luis V. Colom, of the University of Texas at Brownsville/Texas Southmost College. The hippocampus is a part of the brain that plays a role in memory, spatial navigation and sensory motor integration, among other functions.

Normally, the hippocampus oscillates at a frequency of 3-12 Hz, a frequency that is called the theta rhythm, Colom explained. Oscillations at theta frequency are important in processing and storing relevant sensory information and appears important to certain memory processes.

"My hypothesis is that the septum keeps the electrical activity of neurons within certain areas of the brain working within normal ranges," Colom said. "By keeping the neurons firing normally, the septum inhibits neuronal hyperexcitability, such as epilepsy, and hypoexcitablity, such as Alzheimer's disease." In addition, septal impulses may help to maintain the anatomical integrity of other brain structures.

The brain's neurons are constantly chatting with each other through electrical impulses but it's a chatter that has to be kept in check, or it can snowball into an electrical storm that marks an epileptic seizure, Colom explained. Epilepsy affects an estimated 4 million Americans, he said.

There are a variety of ways to induce neurons to fire rhythmically, including, interestingly, engaging in stimulating cognitive activities.

Scientists and medical providers know that brain lesions, skull fractures, and high fever are among the factors that can produce epilepsy. But in most cases, there is no obvious cause, Colom said.

Colom's lifelong interest in how the brain works has led him to study epilepsy and Alzheimer's disease. People who suffer Alzheimer's, a degenerative disorder that affects various brain regions including the septum, have a higher risk of epileptic seizures, in the 10-22 percent range, he noted.

Previous studies have suggested that the septum plays an antiepileptic role. But in this study, Colom et al. showed what happens among the septum's neurons during epilepsy, knowledge that is important to understanding the mechanism underlying seizure generation. This line of inquiry could one day lead to the development of anti-epileptic drugs, said Colom.

In this study, the researchers induced epilepsy by injecting anesthetized rats with pilocarpine, a drug that excites the brain's neurons and activates the synapses between the neurons to produce status epilepticus, in which sustained seizures occur. The rats received diazepam three hours later to interrupt the seizures, but became chronically epileptic, experiencing 3-5 seizures weekly.

The researchers then used electrodes to record individual neurons within the septum of the anesthetized rats to see what happened within the nerve pathways. They found that the epileptic rats suffered significantly more epileptic episodes when the brain did not have the proper theta rhythm.

The researchers also found that when the theta rhythm was induced in the rats, it reduced epileptic discharges 86-97 percent. (The researchers induced theta in one of three ways by regulating the rats' anesthesia, by stimulating the septum directly with an injection of carbachol, or by using the sensory stimulation method of pinching the tail.)

The amplitude and frequency of the theta rhythm of the epileptic rats was significantly altered compared to the control group. In effect, the theta rhythm became faster and more jittery. Also, the septal neurons of epileptic rats doubled their firing rates in relation to the controls, from about 14 spikes per second to about 29 spikes per second.

Colom and his fellow researchers at the University of Texas at Brownsville/Texas Southmost College are looking at two different approaches to stopping epilepsy. One group is taking the approach of making the neurons less excitable (this effort is led by Emilio Garrido-Sanabria and Masoud Zarei). Colom's group is looking for a new treatment that will focus on inducing theta.

"The understanding of the theta rhythm's anti-epileptic effect at the cellular and molecular levels may result in novel therapeutic approaches dedicated to protect the brain against abnormal excitability states," the authors wrote.

Although this research gives more insight into how epilepsy occurs, a cure is still years away. "But I would say there is hope," Colom said. "We want to offer people with epilepsy new options," he said, but progress will depend upon funding, he added.

The researchers will repeat the study using animals that are awake and mobile, though it is more difficult to record the brain's discharges in freely moving animals. Then the research can move to humans.

Multiple-stage surgery brings hope for Tuberous Sclerosis with intractable seizures

Sat, 06 May 2006 18:50:00 PST

( from http://www.rxpgnews.com ) Sadly, none of the treatments for epilepsyanti-seizure medications, a procedure called vagus nerve stimulation, a special diet could quell the electrical storms in the young boys brain. Caused by a rare genetic disease called tuberous sclerosis, the seizures began when he was only 2 months old. By the time he was 5, he was having more than 10 a day. The seizures left him with the developmental capabilities of a 1-year-old child.

Today the boy rarely experiences seizures and his development has improved dramatically thanks to a bold three-stage brain operation being performed at NYU Medical Center by pediatric neurosurgeon Howard Weiner, M.D., Associate Professor of Neurosurgery and Pediatrics at New York University School of Medicine.

This childs case study is part of a report in the May issue of the journal Pediatrics that describes 25 children with tuberous sclerosis who have been operated on by Dr. Weiner over the last six years. It is the largest report of epilepsy surgery in young children with the disease by a single surgeon in the medical literature.

The youngest child was 7 months old, and the oldest 17. They initially were evaluated extensively by a team of physicians that included Dr. Weiner and Orrin Devinsky, M.D., Professor of Neurology, Neurosurgery, and Psychiatry and Director of NYUs Comprehensive Epilepsy Center. The evaluation included an overnight stay in a special inpatient pediatric epilepsy unit at NYUs Tisch Hospital, equipped with 24-hour electroencephalography (EEG) and video monitoring to correlate the childrens behavior with unusual brain activity.

After the evaluation revealed that seizures were affecting many areas of their brains, the team determined that the multi-stage operation would be necessary. Nearly all of the children underwent three separate brain operations over a 2-1/2 week period. Some of the operations lasted as long as nine hours. During the entire period the children remained in Tisch Hospital, where their parents could sleep next to them.

Two or more years after the operations, 17 of the 25 children were free of seizures or had only mild non-disabling attacks. Six children still experienced more severe non-disabling seizures but the number of such seizures was reduced by more than 90 percent. In two children the number was reduced by 50 percent to 90 percent. Despite the risks of brain surgery, Dr. Weiner and his colleagues report that the multiple surgeries did not cause serious infections or permanent damage to the brain.

At some centers multiple-stage surgery would be considered aggressive, but we have established that this type of surgery is safe, says Dr. Weiner. Certainly this type of surgery should only be reserved for the toughest caseschildren with tuberous sclerosis who are having uncontrolled seizures in association with developmental delay or even regression.

Tuberous sclerosis produces tubers on many organs in the body, including the skin, kidneys, lungs, and eyes. In the brain, the hard calcified growths cause seizures. Mental retardation, autism, and other developmental problems can occur in as many as two-thirds of individuals with the disease, according to the National Institute of Neurological Disorders and Stroke. Children with tuberous sclerosis typically have more than two tubers but some may have up to 20 in their brain, says Dr. Weiner.

Many children with the disease arent usually considered candidates for brain surgery because it is difficult to identify which tubers are causing seizures using electroencephalography (EEG), which records electrical activity in the brain through electrodes placed on the scalp. The seizures in these children are spreading so quickly that by the time the electrodes pick up the abnormal nerve firings, it is no longer possible to determine where they originated. Other noninvasive imaging techniques cannot accurately pinpoint where seizures begin.

To overcome this problem, neurosurgeons place electrodes directly on the brain itself, which requires removing a portion of the bony cranium and cutting through the dura mater, the tough fibrous tissue covering the brain. The implanted grid of electrodes, attached to an EEG machine, is used to continuously monitor seizure activity over several days, providing a map for the surgeon to the location where the seizures arise. In the second operation, the surgeon removes the seizure-causing tissue in the brain.

Dr. Weiner takes the operation one step further. He places another set of electrodes in the brain after the second operation in order to locate any other areas that may be causing seizures. So children are again monitored with a grid of electrodes over a period of days, and then undergo a third operation to remove any tissue that still may be causing seizures.

Despite the promising results so far, Dr. Weiner says that it hasnt yet been demonstrated that there is a direct correlation between freedom from seizures and developmental normalcy. However, he adds, it is important to treat children as early as possible because persistent seizures are associated with a host of serious learning and developmental problems.

Flexible Drug Dosing in Epilepsy Reduces Side Effects

Fri, 30 Dec 2005 15:49:00 PST

( from http://www.rxpgnews.com ) For the first time, researchers compared dosing regimens of an antiepileptic drug (AED) used for treatment of partial epilepsy in adults, in conjunction with other AEDs. They looked at dosing used in clinical everyday life (flexible dosing) and that used in classical clinical trials (fixed dose) and discovered that the flexible dosing method was superior. The study is published in Epilepsia, the official journal of the International League Against Epilepsy.

Researchers observed how patients responded to these two methods of dosing therapy over a 12-week period. According to the researchers, while clinical trials have traditionally used fixed doses throughout a treatment period, clinical practice allows for the gradual adjustment of medication dose to enhance patient tolerability and enable optimum effective dosing, based on individual patient response.

Results showed that both regimens were highly effective in reducing seizure frequency in patients who were refractory to treatment. However, "the ability to adjust the dose also permitted the patients to remain on this particular AED (pregabalin) longer since they experienced fewer side-effects and did not drop out of the study (76% for flexible dose versus 58% for fixed dose completed the study)," states lead researcher, Christian Elger. "It also shows that studies copying the clinical picture of epilepsy treatment give more realistic data on the balance between efficacy and tolerability of an antiepileptic drug."

The study demonstrates a significant clinical advantage in treating patients with epilepsy when their dose is adjusted according to the individual patient.

Depression and anxiety improve after epilepsy surgery

Tue, 13 Dec 2005 21:45:00 PST

( from http://www.rxpgnews.com ) Depression and anxiety are common problems for people whose epilepsy cannot be controlled by medication. A new study found that depression and anxiety improve significantly after epilepsy surgery.

The study, which is published in the December 13, 2005, issue of Neurology, the scientific journal of the American Academy of Neurology, found that the rate of depression and anxiety disorders decreased by more than 50 percent up to two years after the surgery. People who no longer experienced any seizures after surgery were even more likely to be free of depression and anxiety.

"These results are important because depression and anxiety can significantly affect the quality of life," said study author Orrin Devinsky, MD, a Fellow of the American Academy of Neurology with the New York University School of Medicine. "For people with refractory epilepsy, studies show that depression is more likely to affect their quality of life than how often they have seizures or how many drugs they have to take."

The study involved 360 people in seven U.S. epilepsy centers who were undergoing epilepsy surgery to remove the area of the brain producing the seizures. Epilepsy surgery is generally reserved for those whose seizures cannot be adequately controlled by medication. The majority of participants had surgery on the brain's temporal lobe. The participants' mental health and any symptoms of depression and anxiety were evaluated before surgery and at three months, one year, and two years after surgery.

Prior to the surgery, 22 percent of the participants met the criteria for a diagnosis of depression, compared to 9 percent two years after the surgery. For anxiety disorders, 18 percent met the criteria for a diagnosis before the surgery, compared to 10 percent two years after the surgery.

Of those who had no seizures following surgery, 8 percent met the criteria for depression, compared to 18 percent of those who still had some seizures after surgery. For anxiety, 8 percent of those who were seizure free had depression, compared to 15 percent of those with ongoing seizures.

Researchers aren't sure why depression and anxiety improve after epilepsy surgery. "Removing dysfunctional areas of the brain may be critical," Devinsky said. "Whether the benefit comes from reducing or eliminating seizures or other effects is not clear. People may also be benefiting from an improved sense of self-control, less fear of seizures, higher activity levels and a lessened burden from medications."

Ketogenic diet prevents seizures

Sun, 13 Nov 2005 19:55:00 PST

( from http://www.rxpgnews.com ) Although the high-fat, calorie-restricted ketogenic diet (KD) has long been used to prevent childhood epileptic seizures that are unresponsive to drugs, physicians have not really understood exactly why the diet works. New studies by a research team at Emory University School of Medicine show that the diet alters genes involved in energy metabolism in the brain, which in turn helps stabilize the function of neurons exposed to the challenges of epileptic seizures. This knowledge could help scientists identify specific molecular or genetic targets and lead to more effective drug treatments for epilepsy and brain damage.

"These findings support our hypothesis that a dietary regimen can dramatically affect the expression of genes and the function of neurons within the brain, which enhances the ability of these neurons to withstand the metabolic challenges of epileptic seizures," Dr. Dingledine said.

The ketogenic diet causes molecules called ketone bodies to be produced as fat is broken down. Scientists have understood that these molecules somehow cause a change in metabolism leading to a potent anticonvulsant effect. According to some animal studies they also may limit the progression of epilepsy.

The Emory research team studied the link between diet and epileptic seizures on the behavioral, cellular and genetic level. They found, as had others, that in rats fed the KD the resistance to seizures develops slowly, over one to two weeks, in contrast to rats treated with conventional anticonvulsant drugs. On the cellular level, they found that the anticonvulsant effect of the ketogenic diet did not correlate with a rise in plasma ketone levels or with a decrease in plasma glucose. Because longer treatment with the KD was necessary to increase the resistance to seizures, they concluded that changes in gene expression might hold the key to the diet's anticonvulsant effects.

To identify which genes might be involved, the researchers used microarray "gene chips" to examine changes in gene expression for more than 7,000 rat genes simultaneously. They focused on the hippocampus, a region of the brain known to play an important role in many kinds of epilepsies. More than 500 of the genes they examined were correlated with treatment with the KD. The most striking finding was the coordinated up-regulation of genes involved in energy metabolism.

To explain this genetic effect, the scientists first eliminated the possibility that the KD diet might cause enhanced production of GABA, a chemical messenger in the brain that helps limit seizure activity. They found that GABA levels in the hippocampus were unchanged with the KD.

To test whether energy reserves in hippocampal neurons were enhanced with the KD, they counted the number of energy "factories," or mitochondria, within cells using electron microscopy. They found that KD treatment significantly increased the number of mitochondria per unit area in the hippocampus. This finding, along with the concerted increase in the expression of genes encoding energy metabolic enzymes, led them to conclude that KD treatment enhances energy production in the hippocampus and may lead to improved neuronal stability.

Finally, the researchers tested whether brain tissue affected by the KD would be more resistant to low levels of glucose (an effect of seizures) because of their enhanced energy reserves. They found that synaptic communication in KD-fed rats was more resistant to low glucose levels than in control animals fed a regular diet.

The researchers believe their new knowledge could lead to the development of more effective drug treatments for epilepsy and brain damage.

And because the diet enhances the brain's ability to withstand metabolic challenges, they also believe the ketogenic diet should be studied as a possible treatment for other neurodegenerative disorders such as Alzheimer's or Parkinson's diseases.

Blood Test Can Help Determine Type of Seizure

Wed, 14 Sep 2005 01:54:00 PST

( from http://www.rxpgnews.com ) Using a blood test to measure the level of the hormone prolactin can help determine, in certain clinical settings, whether an epileptic seizure has occurred, according to a guideline developed by the American Academy of Neurology and published in the September 13, 2005 issue of Neurology. The guideline authors reviewed all of the scientific evidence available on use of the prolactin blood test to diagnose seizures and developed evidence-based recommendations.

The blood test, which must be used within 10 to 20 minutes after a seizure, can identify the types of seizures called generalized tonic-clonic seizures and complex partial seizures in both adults and older children. The level of prolactin in the blood increases after these types of seizures occur.

The release of prolactin from the pituitary gland is controlled by the area of the brain called the hypothalamus. Researchers have hypothesized that epileptic seizures may affect the hypothalamus, altering the release of prolactin.

The test cannot distinguish epileptic seizures from a fainting condition called syncope, because prolactin levels may also increase after syncope, according to guideline authors David K. Chen, MD, Yuen T. So, MD, PhD, and Robert S. Fisher MD, PhD, of Stanford University in Palo Alto, Calif.

The guidelines found that a prolactin test can be useful in differentiating epileptic seizures versus psychogenic seizures, or seizures caused by mental problems.

There was not enough evidence to determine whether the prolactin test is useful in evaluating cases of status epilepticus, repetitive seizures, or neonatal seizures.

The guidelines state that the test is useful as an adjunct test, especially in cases where video EEG (electroencephalography) monitoring is not readily available. Future research needs to be done to determine whether the test is valid for younger children.

Propofol is effective in pediatric refractory status epilepticus

Thu, 01 Sep 2005 08:03:00 PST

( from http://www.rxpgnews.com ) Propofol is a safe and effective drug to treat children with refractory status epilepticus, and it is recommended before thiopental, according to a study in the August 23, 2005 issue of Neurology, the scientific journal of the American Academy of Neurology. Propofol and thiopental are widely used intravenous anesthetics which are also known to help control seizures.

Researchers in the Netherlands examined the effects of propofol and thiopental in 33 children (34 episodes total) with refractory status epilepticus. Refractory status epilepticus is a state in which seizures occur in rapid succession without recovery of consciousness between them. These seizures are resistant to treatment and persist for more than 60 minutes.

Propofol effectively controlled seizures in 14 out of 22 patients. Side effects from propofol were infrequent and minor. Propofol was given at rates lower than 5 mg/kg/h, due to previous reports about potentially fatal side effects when the delivery rate was greater than 5 mg/kg/h. Two patients successfully treated with propofol died, but their deaths were attributed to severe neurological damage after bacterial meningitis.

Twenty patients were treated with thiopental, including the eight in whom propofol was used first without success. Eleven were effectively treated and had seizure control. There were serious side effects during thiopental treatment. Most patients required higher ventilator settings and supplemental oxygen due to suspected pneumonia. The respiratory problems with thiopental treatment were greater than expected, according to the researchers. Eight of the 20 patients died. Two deaths could be attributed to thiopental, but the others were related to the underlying diseases that had caused the refractory seizures.

The average duration of propofol treatment was about 2.4 days, compared to 8.6 days for thiopental treatment.

We suggest the use of propofol before thiopental in children with refractory status epilepticus, said study author J. P. J. van Gestel, MD, of the University Medical Center Utrecht, Wilhelmina Childrens Hospital, in the Netherlands. Propofol is a fast-acting drug, and little time is lost if it fails to control seizures.

A related editorial in the same issue of Neurology says this study underscores the need for a systematic, prospective study in children and adolescents with this disorder.

The study by van Gestel et al is retrospective, sequential, and historical in design which prevents definitive conclusions regarding effectiveness, said editorial authors Nina F. Schor, MD, PhD, a pediatric neurologist at Childrens Hospital of Pittsburgh and James J. Riviello, Jr., MD, of Childrens Hospital, Boston. Given the devastating nature of refractory status epilepticus, the search for newer and better treatments to control this condition safely and quickly is critically important.

Astrocytes appear to play a key role in development of epilepsy

Mon, 15 Aug 2005 17:50:00 PST

( from http://www.rxpgnews.com ) Star-shaped brain cells that are often overlooked by doctors and scientists as mere support cells appear to play a key role in the development of epilepsy, researchers say in a study published on-line August 14 in Nature Medicine. It's one of the first times scientists have produced firm evidence implicating the cells, known as astrocytes, in a common human disease.

Scientists found that astrocytes can serve as ground zero in the brain, setting off a harmful cascade of electrical activity in the brain by sending out a brain chemical that triggers other brain cells to fire out of control.

While it's impossible to tell at this early stage what effect the finding will have on treatment, the investigators at the University of Rochester Medical Center are hopeful the results will give doctors and pharmaceutical firms a new target in efforts to treat and prevent the disease.

"This opens up a new vista in efforts to treat epilepsy. It might be possible to treat epilepsy not by depressing or slowing brain function, as many of the current medications do, but by targeting brain cells that have been completely overlooked," says Maiken Nedergaard, M.D., Ph.D., professor in the Department of Neurosurgery and a researcher in the Center for Aging and Developmental Biology, who led the research. "We are hopeful that someday, this will be very beneficial to patients,"

When most people and many scientists think of brain cells, they think of neurons, the nerve cells that send electrical signals and are at the heart of what is considered to be brain activity. In diseases like Alzheimer's, Parkinson's and Huntington's diseases, it's the neurons that become sick and die, and so they are the focus of intense study.

But neurons represent just a small proportion of brain cells. Astrocytes are present in vastly greater numbers there are approximately 10 times as many astrocytes as neurons in the human brain. Nedergaard is part of a growing group of scientists who are focusing on the pivotal role that astrocytes may play in several human diseases.

"The main function of astrocytes is to maintain a healthy environment for neurons," says Nedergaard, whose study was funded by the National Institute of Neurological Disorders and Stroke. "The electrical signaling in the brain is so sophisticated that it's crucial that the environment be optimal. There's not much room for error. When the astrocytes start acting abnormally, it's easy to see how serious disease might result."

Last year she showed that astrocytes magnify the damage to neurons after spinal cord injury. And currently she's looking at their role in Alzheimer's disease.

Nedergaard notes that in epilepsy, scientists have long known that an early sign of the disease in the brain are abnormal cells called reactive astrocytes over-sized, bloated, star-shaped cells that no longer function properly. "People have thought that reactive astrocytes were caused by epilepsy, not that they could be the cause."

In the study, Nedergaard and colleagues showed that astrocytes actually generate seizure activity, and the team linked astrocytes to a brain chemical long known to be a key player in the development of epilepsy. They showed that glutamate, which hypes up neurons and can make them fire uncontrollably, is released by astrocytes and can trigger seizure-like activity in the brain.

Then the team tested medications currently used to treat the disease. Epilepsy describes a condition in the brain where neurons start firing wildly and uncontrollably, sometimes resulting in seizures, and most medications aim to reduce such firing. The team showed that agents like gabapentin and valproate reduced the type of chemical signaling that causes astrocytes to release glutamate.

According to Nedergaard, many scientists have thought that epilepsy occurs when neurons that normally inhibit or slow down other neurons lose their power, as if the brakes on a speeding car were faulty. Current medications are aimed at making those molecular "brakes" more powerful and reining signals back in. But such drugs have side effects like drowsiness. Her work opens up a new avenue to understand the disease.

"The potential role of astrocytes in the generation of epilepsy has been largely ignored," says Michel Berg, M.D., medical director of the Strong Epilepsy Center. "Epilepsy involves a re-organization of the brain's pathways, in a way that is not completely understood, that results in recurrent seizures. Currently we have drugs to treat seizures, but not to prevent the whole process. Perhaps someday there will be ways to intervene before the circuitry is re-written, to prevent epilepsy completely."

More than 2 million Americans have epilepsy. Current medications stop seizures in about two-thirds of patients, but others often struggle for years or even a lifetime to cope with symptoms including seizures. Surgery to remove a small amount of troublesome brain tissue is often successful in such cases. The disease can come about as a result of a brain injury or because of genetic abnormalities in the way the brain develops.

Novel treatment targets for absence seizures - Study

Mon, 04 Jul 2005 13:52:00 PST

( from http://www.rxpgnews.com ) New research suggests novel treatment targets for the most common form of childhood epilepsy with the potential to have fewer side effects than traditional therapy. The findings from Wake Forest University School of Medicine are reported today in the July issue of the Journal of Neurophysiology.

Through studies in animals, the researchers learned more about the possible brain pathways involved in absence, or petit mal, seizures and tested a drug that revealed a potential new target for blocking seizures before they spread.

"Many current therapies act on the entire nervous system and can have such side effects as sleep disruptions, dizziness and increased risk of developmental side effects," said Georgia Alexander, who with Dwayne Godwin, Ph.D., co-authored the new study. "Because this treatment blocks the pathway that may cause the spread of seizures, it could be more effective and have fewer side effects."

Absence seizures, which are most common in children between 6 and 12, get their name because during the seizure the child seems to be temporarily unconscious of his or her surroundings. Although they last only a few seconds, the seizures can occur hundreds of times a day and can dramatically impact learning and development.

Doctors don't know exactly what causes the seizures, but a prevalent theory is that an abnormal electrical discharge originates in the cerebral cortex, the part of the brain that controls thinking and feeling, and travels to the thalamus, a part of the brain that controls consciousness and certain brain rhythms. The abnormal rhythmic discharges that result may then spread to other parts of the brain. Other types of seizures may also spread this way, including Lennox-Gastaut seizures, a severe form of childhood epilepsy that is often resistant to treatment.

"We know that the cortex communicates with the thalamus continuously, and current theories suggest that when the 'conversation' gets too loud, seizures can occur," said Alexander. "We wanted to see if there was a way to calm the dialog."

In studying this possible pathway of seizures, Alexander made an important finding about its organization. It was already known that cells in the thalamus communicate with cells in the cortex by releasing the neurotransmitter glutamate. The glutamate travels across the gap -- creating a pathway for cell-to-cell communication.

Alexander and Godwin were the first to show that in addition to releasing glutamate, thalamus cells also have a special type of glutamate receptor that acts almost as a braking system slowing the release of glutamate when there is high-intensity brain activity associated with a seizure.

"It's like the gas and brake pedals of your car, "said Godwin, associate professor of neurobiology and anatomy and the senior researcher on the project. "Glutamate is important for normal communication in the brain, but sometimes it's necessary to put on the brakes in order to preserve normal function. This receptor appears to slow down the rate at which glutamate is released across the synaptic gap, and may protect the cells from becoming overexcited."

Alexander hypothesizes that in epilepsy patients, the protective receptors may not function well or that glutamate production may be abnormal. A treatment that targets these protective glutamate receptors has the potential to block the pathway involved in seizures, with the added benefit of allowing normal communication to continue.

"If this research leads to drugs that can target these newly discovered receptors, it would be an important advance in therapy," said William L. Bell, M.D., a specialist in epilepsy at Wake Forest University Baptist Medical Center.

Godwin explained that design of improved drugs to target the receptors wouldn't be a cure, but would short-circuit the type of abnormal activity that results in seizures.

In this research, the scientists studied the pathway by simulating seizure-related activity within brain circuits. They will continue the research by studying animals that are genetically predisposed to epilepsy.

Noninvasive evaluation of epilepsy patients prior to surgery- Funtional MRI

Tue, 28 Jun 2005 23:35:00 PST

( from http://www.rxpgnews.com ) OAK BROOK, Ill.--Functional magnetic resonance imaging (fMRI) of the brain reduces the need for invasive testing of seizure disorder patients being considered for surgical treatment, according to a study published in the July issue of the journal Radiology.
"fMRI gives the surgical team an important roadmap of the brain function without contrast injections or invasive tests," said the study's lead author, L. Santiago Medina, M.D., M.P.H., co-director of neuroradiology and director of the Health Outcomes, Policy and Economics Center at Miami Children's Hospital. "This imaging technology is a powerful tool that improves surgical decision making in patients being considered for seizure surgery."

Dr. Medina's study evaluated the effect of fMRI results on the diagnostic work-up and treatment planning of 60 consecutive seizure disorder patients, including 33 male and 27 female patients. The fMRI findings helped five patients avoid additional surgery and altered the extent of surgery in four others.

A seizure is an outward sign of a malfunction in the electrical activity of the brain. Seizures that occur more than once without special cause are called seizure disorder or epilepsy. According to the Epilepsy Foundation of America, 2.5 million Americans have been diagnosed with epilepsy.

Brain surgery has proven to be an effective treatment for patients with seizure disorders who do not respond to medication. The surgical treatment involves resecting, or cutting away, brain tissue that contains a seizure focus--the location in the brain where the seizures originate. Before resection surgery is performed, the treatment team uses diagnostic tests to help determine the proximity of a seizure focus to vital areas of brain function and to provide a map of the area.

Until recently, the Wada test and electrical cortical mapping--both invasive, costly tests that require large medical teams--were the only methods for identifying these critical areas. fMRI, which uses radio waves and a strong magnetic field, is a non-invasive test capable of identifying the location of critical brain functions that could be affected by the location of the seizure focus.

Based on fMRI results, five patients in Dr. Medina's study avoided a two-stage surgery with extra-operative direct electrical stimulation mapping and instead received a one-stage resection surgery. The extent of surgical resection was altered in another four patients, because fMRI images identified critical areas of the brain close to the seizure focus.

Other changes in patient care based on fMRI results included:

The team altered patient and family counseling in 58 percent of patients;
Intraoperative mapping was altered in 52 percent of patients;
Overall surgical plans were altered in 42 percent of patients;
63 percent of patients were able to avoid further studies, including the Wada test.
"When the medical team reviewed functional MR images of the brain, they significantly changed the patient's diagnostic and treatment plans," said neurologist Byron Bernal, M.D., co-author of the study. "With fMRI, the physician, patient and family have more information about important critical areas of brain function, helping them make more informed decisions."

Of the study's 60 patients, 32 were not candidates for surgery or refused surgical treatment. Of the 28 patients who proceeded with surgery, 17 were seizure-free following the resection, and eight had a 50 percent to 90 percent reduction in seizures. Three of the surgical patients experienced less than a 50 percent reduction in seizures at six-month follow-up.

Epilepsy surgery shows good results even after 30 years

Tue, 14 Jun 2005 03:23:00 PST

( from http://www.rxpgnews.com ) A new study shows that the prognosis is good for people who have epilepsy surgery, even 30 years after the surgery. The study is published in the June 14 issue of Neurology, the scientific journal of the American Academy of Neurology.

"Few studies have looked at the long-term prognosis for epilepsy surgery," said neurologist and study author William H. Theodore, MD, of the National Institute of Neurological Disorders and Stroke in Bethesda, Md. "We found that 50 percent of the patients were free of seizures 30 years after the surgery."

In epilepsy, surgery is generally considered for those whose seizures do not respond to medication. The study involved people who had a temporal lobectomy, which is the surgical removal of the portion of the brain where seizures most often occur.

The study examined 48 people who had a temporal lobectomy at the National Institutes of Health in Bethesda an average of nearly 30 years previously. The patients or their families were questioned about whether they had experienced seizures at one year after the surgery, and at five, 10, and 30 years after the surgery.

At 30 years, 14 people were free of seizures and taking no epilepsy drugs; 10 people were free of seizures while taking epilepsy medication. Those who had seizures within the first year after surgery were least likely to be free of seizures in the future.

"These results suggest a good prognosis for long-term seizure control after temporal lobectomy," Theodore said.