Research by Cardiff University has uncovered the brain activity that underlies absence epilepsy, offering new hope for the development of innovative therapies for this disabling disease.
Absence epilepsy – the most common form of epilepsy in children and teenagers – causes episodes of lack of awareness which are often mistaken for daydreaming. The brain activity that causes this form of epilepsy has remained poorly understood, until recent research has observed this activity for the first time.
An international team of researchers led by Professor Vincenzo Crunelli, from Cardiff University’s School of Biosciences, investigated the types of electrical activity that occurred in the brains of mice during an absence seizure.
Professor Crunelli said: “Although the origin of absence epilepsy remains poorly understood, we do know that if we monitor the electrical activity in the brain during a seizure, we see peaks in the activity called spike and wave discharges.
“We also know that synchronous activity in a part of the brain called the thalamocortical network, which is organised in a feedback loop, underlies the appearance of these spike-wave discharges.
“But the relationship between the brain cell activities in this loop, and how these relationships lead to the brain activity in absence seizures, is strongly debated.”
The group of researchers from Cardiff University, University of Malta, Centre National de la Recherche Scientifique and the University of Szeged in Hungary, simultaneously recorded brain activity between several different brain areas during absence seizures for the first time. This allowed them to observe the relationships between the different regions of the brain during an absence seizure, and they found that it played a role in the presence of the spike and wave discharges.
Professor Crunelli added: “We discovered that the activity of the thalamocortical brain cells were synchronised by other parts of the brain, increasing activity when receiving instruction from the cortex and decreasing activity when instructed by a part of the brain called the thalamic reticular nucleus.
“We also uncovered that, contrary to what was previously thought, the properties of the cells in the thalamocortical loop aren’t really involved in the development of the spike and wave discharges.
“This new research is fundamental for the development of innovative therapies for this disabling childhood and juvenile disease.”
Childhood absence epilepsy (CAE), a syndrome that occurs in 1 out of 1000 children, is one of the most common types of early childhood (first decade) seizures. A classic CAE scenario may be that of a little girl who has just started kindergarten and has periods of “blanking out” every day. Her teacher calls out her name, but she does not respond. She sometimes blinks her eyes a few times and is back to “normal” in about 20 seconds. The teacher alerts the parents, who then make an appointment to see the pediatrician. Typically, the parents report never noticing these episodes at home. (more…)
Consider two children who have childhood absence epilepsy (CAE), the most common form of pediatric epilepsy. They both take the same drug—one child sees an improvement in their seizures, but the other does not. A new study in the Annals of Neurology identified the genes that may underlie this difference in treatment outcomes, suggesting there may be potential for using a precision medicine approach to help predict which drugs will be most effective to help children with CAE. The study was funded by the National Institute of Neurological Disorders and Stroke (NINDS) and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), both part of the National Institutes of Health.
“A better understanding of genetic factors underlying a disease and the way that people respond to treatments may help healthcare providers select the best therapies for children with CAE,” said Vicky Whittemore, Ph.D., program director at NINDS.
A team led by Tracy A. Glauser, M.D., director of the Comprehensive Epilepsy Center at Cincinnati Children’s Hospital Medical Center and professor of pediatrics in the University of Cincinnati College of Medicine, investigated whether there may be a genetic basis for different responses to three drugs used for CAE (ethosuximide, valproic acid, and lamotrigine). The experiments focused on three genes that code for T-type calcium channels that are involved in CAE and one gene that codes for a transporter that shuttles the drugs out of the brain. T-type calcium channels help control the firing rate of brain cells.
The current study is part of a 32-center, randomized, controlled clinical trial that compared the effects of the three most commonly used drugs in 446 children who were recently diagnosed with CAE.
These results suggest knowledge of specific gene variants in children with CAE may help predict what drugs would work best for them. For example, two specific forms of the calcium channel genes appeared more often in children for whom ethosuximide did not work. Two other variants of the calcium channel genes were found in children for whom lamotrigine did work, but one form of the drug transporter gene was associated with a continuation of seizures.
Dr. Glauser and his colleagues conducted additional experiments using the form of calcium channel gene that was associated with ethosuximide failure in patients. When cells in a dish containing this calcium channel variant were treated with ethosuximide, the drug had less effect on inhibiting the channel, suggesting that the genetic form of calcium channel may determine patients’ response to the drug.
“We identified a potential link between genes and the children’s’ responses to certain treatments. We were also able to clearly show that one variant caused a change in how a key calcium channel responded to ethosuximide, confirming what was found in the clinical trial,” said Dr. Glauser.
CAE is characterized by absence seizures, in which children stare into space, unaware of their surroundings. The seizures are brief, often lasting less than 20 seconds, although children may have up to 100 of them per day. The disease usually begins in children who are between 4 and 8 years old. About one third of children with CAE also have problems with attention. Many children will stop experiencing absence seizures by the time they reach adolescence, although others go on to develop more severe seizures.
More research is needed to learn about the specific genes involved in CAE and the ways that they influence the effect of anti-epileptic drugs. In addition, researchers need to determine which factors, other than genetics, may play a role in treatment response.
Source: Medical Xpress
In November 2008, when he was just 6, William Moller had his first epileptic seizure, during a reading class at school. For about 20 seconds, he simply froze in place, as if someone had pressed a pause button. He could not respond to his teacher.
This is known as an absence seizure, and over the next year William, now 10, who lives with his family in Brooklyn, went from having one or two a day to suffering constant seizures. Not all were absence seizures; others were frightening tonic-clonics, also known as grand mals, during which he lost consciousness and convulsed.
The seizures often came while he was eating. As his body went rigid, William dropped his food and his eyes rolled back into their sockets. If he seized while standing, he suddenly crashed to the ground — in a corridor, in the driveway, on the stairs.
“It’s the scariest thing for any mother to hear that thump, and each time he would hit his head, so it only made things worse and worse,” said his mother, Elisa Moller, a pediatric nurse.
William is among the one-third of epilepsy sufferers who do not respond, or respond only poorly, to anti-epileptic medications. Now he and others with refractory epilepsy are benefiting from treatment that targets inflammation, the result of new research into how epilepsy damages the brain.
“Many of us theorize that the two are tied — inflammation causes seizures, and seizures cause inflammation,” said Orrin Devinsky, director of the Comprehensive Epilepsy Center at the New York University Langone Medical Center and William’s doctor. “Over time, both of them may feed off each other.” (more…)
Research could prove groundbreaking for treating epilepsy in children
It can look as if a child is simply in a daze, awake but daydreaming. Yet inside their brain, a flurry of high-frequency signals is firing from neurons resulting in a so-called absence seizure. Photograph by: Submitted photo, Fotolia.com
It can look as if a child is simply in a daze, awake but daydreaming. Yet inside their brain, a flurry of high-frequency signals is firing from neurons resulting in a so-called absence seizure.
A Canadian-led research team has developed a new drug that completely suppresses absence seizures in rats, and could have groundbreaking effects on the treatment of epilepsy in children.
The findings were published Wednesday in the peer-reviewed science journal Science Translational Medicine.
The team began testing the drug on humans in December and expects to finish the first phase of clinical trials later this year, said neuroscientist Terry Snutch, the senior author of the study.