Tag: seizures

Categories : NeurologyTags :

An Arthritis Drug Might Unlock Lasting Relief from Epilepsy and Seizures

On By ModernMedia
Source: Pixabay

A drug typically prescribed for arthritis halts brain-damaging seizures in mice that have a condition like epilepsy, according to researchers at the University of Wisconsin–Madison. The drug, called tofacitinib, also restores short-term and working memory lost to epilepsy in the mice and reduces inflammation in the brain caused by the disease.

If the drug proves viable for human patients, it would be the first to provide lasting relief from seizures even after they stopped taking it.

“It ticks all the boxes of everything we’ve been looking for,” says Avtar Roopra, a neuroscience professor in the UW–Madison School of Medicine and Public Health and senior author of the study, which appears in Science Translational Medicine.

Epilepsy is one of the most common neurological diseases, afflicting more than 50 million people around the world. While there are many known causes, the disease often appears after an injury to the brain, like a physical impact or a stroke.

Some days, months or even years after the injury, the brain loses the ability to calm its own activity. Normally balanced electrical activity through the brain goes haywire.

“The system revs up until all the neurons are firing all the time, synchronously,” says Roopra. “That’s a seizure that can cause massive cell death.”

And the seizures repeat, often at random intervals, forever. Some drugs have been useful in addressing seizure symptoms, protecting patients from some of the rampant inflammation and memory loss, but one-third of epilepsy patients do not respond to any known drugs, according to Olivia Hoffman, lead author of the study and a postdoctoral researcher in Roopra’s lab. The only way to stop the most damaging seizures has been to remove a piece of the brain where disruptive activity starts.

On their way to identifying tofacitinib’s potential in epilepsy, Hoffman and co-authors used relatively new data science methods to sift through the way thousands of genes were expressed in millions of cells in the brains of mice with and without epilepsy. They found a protein called STAT3, key to a cell signaling pathway called JAK, at the centre of activity in the seizure-affected mouse brains.

“When we did a similar analysis of data from brain tissue removed from humans with epilepsy, we found that was also driven by STAT3,” Hoffman says.

Meanwhile, Hoffman had unearthed a study of tens of thousands of arthritis patients in Taiwan aimed at describing other diseases associated with arthritis. It turns out, epilepsy was much more common among those arthritis patients than people without arthritis — but surprisingly less common than normal for the arthritis patients who had been taking anti-inflammatory drugs for more than five-and-a-half years.

“If you’ve had rheumatoid arthritis for that long, your doctor has probably put you on what’s called a JAK-inhibitor, a drug that’s targeting this signaling pathway we’re thinking is really important in epilepsy,” Hoffman says.

The UW researchers ran a trial with their mice, dosing them with the JAK-inhibitor tofacitinib following the administration of a brain-damaging drug that puts them on the road to repeated seizures. Nothing happened. The mice still developed epilepsy like human patients.

Remember, though, that epilepsy doesn’t often present right after a brain-damaging event. It can take years. In the lab mice, there’s usually a lull of weeks of relatively normal time between the brain damage and what the researchers call “reignition” of seizures. If it’s not really epilepsy until reignition, what if they tried the drug then? They devised a 10-day course of tofacitinib to start when the mouse brains fell out of their lull and back into the chaos of seizures.

“Honestly, I didn’t think it was going to work,” Hoffman says. “But we believe that initial event sort of primes this pathway in the brain for trouble. And when we stepped in at that reignition point, the animals responded.”

The drug worked better than they could have imagined. After treatment, the mice stayed seizure-free for two months, according to the paper. Collaborators at Tufts University and Emory University tried the drug with their own mouse models of slightly different versions of epilepsy and got the same, seizure-free results.

Roopra’s lab has since followed mice that were seizure-free for four and five months. And their working memory returned.

“These animals are having many seizures a day. They cannot navigate mazes. Behaviourally, they are bereft. They can’t behave like normal mice, just like humans who have chronic epilepsy have deficits in learning and memory and problems with everyday tasks,” Roopra says. “We gave them that drug, and the seizures disappear. But their cognition also comes back online, which is astounding. The drug appears to be working on multiple brain systems simultaneously to bring everything under control, as compared to other drugs, which only try to force one component back into control.”

Because tofacitinib is already FDA-approved as safe for human use for arthritis, the path from animal studies to human trials may be shorter than it would be for a brand-new drug. The next steps toward human patients largely await NIH review of new studies, which have been paused indefinitely amid changes at the agency.

For now, the researchers are focused on trying to identify which types of brain cells are shifted back to healthy behavior by tofacitinib and on animal studies of even more of the many types of epilepsy. Hoffman and Roopra have also filed for a patent on the use of the drug in epilepsy.

Source: University of Wisconsin-Madison

Categories : Neurology PaediatricsTags :

Seizures Identified as Potential Cause of Sudden Unexplained Death in Children

On By ModernMedia
Photo by Caleb Woods on Unsplash

In a study designed to better understand sudden, unexpected deaths in young children, which usually occur during sleep, researchers have identified brief seizures, accompanied by muscle convulsions, as a potential cause.

Experts estimate in excess of 3000 families each year in the US lose a baby or young child unexpectedly and without explanation. Most are infants in what is referred to as sudden infant death syndrome, or SIDS, but 400 or more cases involve children aged 1 and older, and in what is called sudden unexplained death in children (SUDC). Over half of these children are toddlers.

The study, published in the journal Neurology, used a registry of more than 300 SUDC cases, set up a decade ago by researchers at NYU Grossman School of Medicine. Researchers used extensive medical record analysis and video evidence donated by families to document the inexplicable deaths of seven toddlers between the ages of 1 and 3 that were potentially attributable to seizures. These seizures lasted less than 60 seconds and occurred within 30 minutes immediately prior to each child’s death, say the study authors.

For decades, researchers have sought an explanation to sudden death events in children, noticing a link between those with a history of febrile seizures (seizures accompanied by fever). Earlier research had reported that children who died suddenly and unexpectedly were 10 times more likely to have had febrile seizures than children who did not die suddenly and unexpectedly. Febrile seizures are also noted in one-third of SUDC cases registered at NYU Langone Health.

The new study involved an analysis by a team of eight physicians of the rare SUDC cases for which there were also home video recordings, from either security systems or commercial crib cameras, made while each child was sleeping on the night or afternoon of their death.

Five of seven recordings were running nonstop at the time and showed direct sound and visible motion indicative of a seizure happening. The remaining two recordings were triggered by sound or motion, but only one suggested that a muscle convulsion, a sign of seizure, had occurred. As well, only one toddler had a documented previous history of febrile seizures. All children in the study had previously undergone an autopsy that revealed no definitive cause of death.

“Our study, although small, offers the first direct evidence that seizures may be responsible for some sudden deaths in children, which are usually unwitnessed during sleep,” said study lead investigator Laura Gould, a research assistant professor at NYU Langone. Gould lost her daughter, Maria, to SUDC at the age of 15 months in 1997, a tragedy that prompted her successful lobby for establishment of the NYU SUDC Registry and Research Collaborative. Gould points out that if not for the video evidence, the death investigations would not have implicated a seizure.

“These study findings show that seizures are much more common than patients’ medical histories suggest, and that further research is needed to determine if seizures are frequent occurrences in sleep-related deaths in toddlers, and potentially in infants, older children, and adults,” said study senior investigator and neurologist Orrin Devinsky, MD.

Devinsky, a professor in the Departments of Neurology, Neurosurgery, and Psychiatry at NYU Langone, as well as chief of its epilepsy service, adds that “convulsive seizures may be the ‘smoking gun’ that medical science has been looking for to understand why these children die.

“Studying this phenomenon may also provide critical insight into many other deaths, including those from SIDS and epilepsy,” said Devinsky, who cofounded the SUDC Registry and Research Collaborative at NYU Langone with Gould.

Further research, Devinsky notes, is also needed to determine precisely how seizures with or without fever may induce sudden death. Previous research in epilepsy patients, he says, points to difficulty breathing that is known to occur immediately after a seizure and that can lead to death. This has been found to happen more frequently in epilepsy patients, as it does in the children involved in the study, while they are sleeping face down on the stomach and without anyone witnessing the death.

Continuous monitoring of child deaths and improvements in health records to track how often these convulsive seizures precede death, he explains, will be needed for this to be confirmed. Seizure-related deaths are underreported in people with and without epilepsy.

For the study, experts in forensic pathology, neurology, and sleep medicine analysed each recording for video quality, sound, and motion. From this, they were able to determine which toddlers showed signs of muscle convulsions as a sign of seizures prior to their death and when. Access to the videos was and remains strictly limited to the researchers involved in the study.

Source: NYU Langone Health / NYU Grossman School of Medicine