The EEG helps scientists to predict seizures a few minutes in advance

DALLAS – February 20, 2019 – Elizabeth Delacruz can not crawl or walk like most kids who are nearing their second birthday.

A rare metabolic disorder that has decimated its mobility has also resulted in cortical blindness – its brain is unable to process images received from a set of brown, otherwise healthy eyes. And several times a day, Elizabeth suffers from seizures that continually reduce her brain function. She can only offer an occasional smile or make soft, sparkling sounds to communicate her mood.

"But a few months ago, I heard her say" Mom "and I started crying," said Carmen Mejia, a flickering voice in her voice as she remembered the joy of hearing his daughter. "It's the first time she's been saying something."

Ms. Mejia realizes that this could also be the last one, unless doctors find a way to detect and prevent epileptic seizures resulting from a terminal illness called pyruvate dehydrogenase deficiency (PDHD). , which occurs when the mitochondria do not provide enough energy to the cells. .

A study by UT Southwestern gives parents like Ms. Mejia renewed hope for their children: by monitoring the brain activity of a specific cell type responsible for seizures, scientists can predict seizures at least four minutes in advance, both in humans and in the mouse. Research also shows that an edible acid called acetate can effectively prevent seizures when it is detected sufficiently in advance.

Although the forecasting strategy can not yet be used clinically (it would be necessary to develop a mobile technology to measure brain activity), it represents a potential advance in a field that could have predicted seizures only a few times. seconds in advance.

"Many families I meet are not only embarrbaded by seizures, the problem is unpredictability, not knowing when and where a seizure may occur," said Dr. Juan Pascual, pediatric neurologist at O Donnell Brain, UT Southwestern. Institute that led the study published in Translational medicine science. "We have found a new approach that could someday solve this problem and, hopefully, help other scientists find the source of epileptic seizures for many types of epilepsy."

The theory denied

The crucial difference between the study and previous efforts has been to refute researchers' long-held belief that most cells in epilepsy patients have mitochondrial dysfunction.
In fact, Dr. Pascual's team spent a decade or so developing a murine PDHD model that allowed them to discover the major metabolic defect in the brain and then determine only one type neuron was responsible for the seizures resulting from the metabolic defect. They studied the electrical activity of these neurons with an electroencephalogram (EEG) to detect readings of brain waves signaling an impending crisis.

"It's much harder to predict seizures if you do not know the cell type and its activity on the EEG," Dr. Pascual said. "Up to this result, we thought it was an overall cell deficiency and we did not even know that we needed to look for a specific type."

Predict crises

The study shows how a PDHD mouse model helped scientists trace the attacks of inhibitory neurons located near the cortex, which normally control the electrical activity of the brain.

The scientists then tested a method for calculating when seizures would occur in mice and humans by examining EEG files and looking for a decrease in activity in energy deficit neurons. Their calculations allowed them to predict 98% of convulsions at least four minutes in advance.

Dr. Pascual hopes that his lab will be able to refine the EEG badyzes to extend the warning window by several minutes. Even in this case, live clinical predictions will only be feasible if scientists develop a technology to automatically interpret brain activity and calculate when a crisis is imminent.

Nevertheless, he said, the discovery that only one type of cell can be used to predict seizures is a paradigm-shifting discovery that can be applied to all mitochondrial diseases and epilepsies badociated.

Potential therapy

Dr. Pascual's ongoing efforts to extend the prediction time may be a crucial step to use the other intriguing discovery of the study: the use of acetate to prevent seizures.

The study showed that the administration of acetate in the bloodstream of mice with PDHD gave their neurons enough energy to normalize their activity and reduce seizures as long as the ## EQU1 ## Acetate was in the brain.
However, Dr. Pascual said that acetate would probably need more time – maybe 10 minutes or so – to produce effects in humans if it was taken by mouth.

Acetate, naturally present in some foods, has been used in patients for decades, including in infants requiring intravenous nutrition or in patients whose metabolism is stopped. But it had not yet been established as an effective treatment against mitochondrial diseases at the origin of epilepsy.

According to Dr. Pascual, among other reasons, the laboratories fought to create an animal model of these diseases in order to study the effects; his own lab has spent about a decade doing it. Another example is the widespread acceptance of the ketogenic diet to reduce the frequency of seizures.

But in the face of growing concern about the potentially unhealthy side effects of ketogenic diets, Dr. Pascual has been researching alternatives that could safely supply the brain and improve cognition.

Frequent crises

Elizabeth, among a handful of patients whose EEG data was used in the new study, has been seen prescribing a ketogenic diet and certain vitamins to control convulsions.
His family has seen little improvement. Elizabeth often has more than a dozen seizures a day and her muscles and cognition continue to decline. She can not keep her head up and her mother wonders how many more fits her brain can handle.

Elizabeth was only a few months old when she was diagnosed with PDHD, which occurs when certain cells lack certain enzymes to effectively convert food into energy. Patients with such early signs often do not survive beyond a few years.

Ms. Mejia is doing what she can to comfort her daughter, in the hope that Dr. Pascual's work may one day change the prognosis for Parkinson's disease. Ms. Mejia sings, talks and offers stuffed toys and other toys to her daughter. Although her granddaughter can not see, the objects offer some degree of mental stimulation, she said.

"It's so hard to see her go through that," Ms. Mejia said. "Whenever she's having a seizure, her brain is deteriorating, I always hope that one day she will be able to receive a treatment that could stop all that and improve her life."

& # 39; Big Questions & # 39;

Dr. Pascual is already pursuing his research on acetate treatments, with the goal of launching a clinical trial for patients like Elizabeth in the years to come.

His lab is also studying other epilepsy conditions – such as glucose transporter deficiency type I (Glut1) – to determine whether inhibitory neurons located in other parts of the brain are responsible. crises. If so, the results could provide strong evidence to determine where scientists should turn to the brain to detect and prevent neurons with misfires.

"It's an exciting time, but there is still a lot to be done to make this research helpful to patients," said Dr. Pascual. "How to find an automated way to detect the activity of neurons when patients are not in the lab? What are the best ways to intervene when we know that a crisis is occurring?" are big questions that the field has yet to answer. "

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About the study

The study was funded by the National Institutes of Health, the Once Upon a Time Foundation and patient donations.

Among the collaborators who helped Dr. Pascual develop the PDHD mouse model, Drs. Vikram Jakkamsetti, Isaac Marin-Valencia and Qian Ma.

Dr. Pascual is Professor of Neurology and Neurotherapy, Pediatrics and Physiology at the Peter O Donnell Jr. Brain Institute and the Eugene McDermott Center for Human Growth and Development. He holds the Once Upon a Time Chair in Pediatric Neurological Diseases and the Ed and Sue Rose Chair in Neurology.

About UT Southwestern Medical Center

UT Southwestern, one of the country's leading academic medical centers, combines pioneering biomedical research with exceptional clinical care and education. The faculty of the institution has received six Nobel Prizes and includes 22 members from the National Academy of Sciences, 17 members of the National Academy of Medicine and 15 researchers from the Howard Hughes Medical Institute. The full-time faculty of more than 2,500 people is responsible for breakthrough medical breakthroughs and is committed to rapidly translating scientific research into new clinical treatments. Southwestern UT physicians provide care in approximately 80 specialties to more than 105,000 inpatients, nearly 370,000 emergency cases and oversee approximately 3 million outpatient visits per year.