First-Ever Attempt to Treat Naturally Occurring Epilepsy in an Animal Using Transplanted Cells

Abstract, originally published by University of California San Francisco

A cellular therapy for epilepsy developed at UC San Francisco has been employed for the first time in a sea lion with intractable seizures caused by ingesting toxins from algal blooms. The procedure is the first-ever attempt to treat naturally occurring epilepsy in any animal using transplanted cells.

Since 2009, the lab of former CURE Epilepsy Grantee Dr. Scott Baraban has been developing a way to replace these damaged interneurons by transplanting embryonic MGE (medial ganglionic eminence) progenitor cells into the hippocampus. As discovered two decades ago by Baraban’s UCSF colleagues Arturo Álvarez-Buylla, PhD, and John Rubenstein, PhD, MGE cells normally migrate into hippocampus during brain development and integrate themselves into the local circuitry as inhibitory neurons.

Baraban’s group has shown that it’s possible to transplant embryonic MGE cells into the brains of adult rodents with temporal lobe epilepsy, where they quickly spread through the hippocampus and repair its damaged circuitry. The procedure reliably reduces seizures in these animals by 90 percent, along with other side effects of epilepsy, such as anxiety and memory problems.

First Evidence of Altered Microbiota and Intestinal Damage and Their Link to Absence Epilepsy in a Genetic Animal Model, the WAG/Rij Rat

Abstract, originally published in Epilepsia

Objective: A large number of studies have highlighted the important role of the gut microbiota in the pathophysiology of neurological disorders, suggesting that its manipulation might serve as a treatment strategy. We hypothesized that the gut microbiota participates in absence seizure development and maintenance in the WAG/Rij rat model and tested this hypothesis by evaluating potential gut microbiota and intestinal alterations in the model, as well as measuring the impact of microbiota manipulation using fecal microbiota transplantation (FMT).

Methods: Initially, gut microbiota composition and intestinal histology of WAG/Rij rats (a well-recognized genetic model of absence epilepsy) were studied at 1, 4, and 8 months of age in comparison to nonepileptic Wistar rats. Subsequently, in a second set of experiments, at 6 months of age, untreated Wistar or WAG/Rij rats treated with ethosuximide (ETH) were used as gut microbiota donors for FMT in WAG/Rij rats, and electroencephalographic (EEG) recordings were obtained over 4 weeks. At the end of FMT, stool and gut samples were collected, absence seizures were measured on EEG recordings, and microbiota analysis and histopathological examinations were performed.

Results: Gut microbiota analysis showed differences in beta diversity and specific phylotypes at all ages considered and significant variances in the Bacteroidetes/Firmicutes ratio between Wistar and WAG/Rij rats. FMT, from both Wistar and ETH-treated WAG/Rij donors to WAG/Rij rats, significantly decreased the number and duration of seizures. Histological results indicated that WAG/Rij rats were characterized by intestinal villi disruption and inflammatory infiltrates already at 1 month of age, before seizure occurrence; FMT partially restored intestinal morphology while also significantly modifying gut microbiota and concomitantly reducing absence seizures.

Significance: Our results demonstrate for the first time that the gut microbiota is modified and contributes to seizure occurrence in a genetic animal model of absence epilepsy and that its manipulation may be a suitable therapeutic target for absence seizure management.

Researchers Identify a New Link Between Seizures and Connexin 36 Deficiency

Abstract, originally published in Frontiers in Molecular Neuroscience

For the brain to learn, retain memories, process sensory information, and coordinate body movements, its groups of nerve cells must generate coordinated electrical signals. Disorder in synchronous firing can impair these processes and, in extreme cases, lead to seizures and epilepsy.

Synchrony between neighboring neurons depends on the protein connexin 36, an essential element of certain types of synaptic connections that, unlike classical chemical synapses, pass signals between neurons through direct electrical connections. For more than 15 years, scientists have debated the tie between connexin 36 and epilepsy.

Now, a team of Virginia Tech scientists led by Yuchin Albert Pan, an associate professor at the Fralin Biomedical Research Institute at VTC, have identified a new link between seizures and connexin 36 deficiency. The discovery, published in Frontiers in Molecular Neuroscience, found that this interaction may make the brain more prone to having seizures.

Zebrafish serve as a powerful animal model, allowing researchers to evaluate the effects of connexin 36 on the whole brain in an intact living system during neural hyperactivity.

As an essential component of electrically coupled synapses between neurons, connexin 36 plays an important role in rapid and synchronous activation of interconnected neworks of neurons within the brain, which is necessary for normal brain processes.

Identifying Seizure Risk Factors: A Comparison of Sleep, Weather, and Temporal Features Using a Bayesian Forecast

Abstract, originally published in Epilepsia

Objective: Most seizure forecasting algorithms have relied on features specific to electroencephalographic recordings. Environmental and physiological factors, such as weather and sleep, have long been suspected to affect brain activity and seizure occurrence but have not been fully explored as prior information for seizure forecasts in a patient-specific analysis. The study aimed to quantify whether sleep, weather, and temporal factors (time of day, day of week, and lunar phase) can provide predictive prior probabilities that may be used to improve seizure forecasts.

Methods: This study performed post hoc analysis on data from eight patients with a total of 12.2 years of continuous intracranial electroencephalographic recordings (average = 1.5 years, range = 1.0-2.1 years), originally collected in a prospective trial. Patients also had sleep scoring and location-specific weather data. Histograms of future seizure likelihood were generated for each feature. The predictive utility of individual features was measured using a Bayesian approach to combine different features into an overall forecast of seizure likelihood. Performance of different feature combinations was compared using the area under the receiver operating curve. Performance evaluation was pseudoprospective.

Results: For the eight patients studied, seizures could be predicted above chance accuracy using sleep (five patients), weather (two patients), and temporal features (six patients). Forecasts using combined features performed significantly better than chance in six patients. For four of these patients, combined forecasts outperformed any individual feature.

Significance: Environmental and physiological data, including sleep, weather, and temporal features, provide significant predictive information on upcoming seizures. Although forecasts did not perform as well as algorithms that use invasive intracranial electroencephalography, the results were significantly above chance. Complementary signal features derived from an individual’s historic seizure records may provide useful prior information to augment traditional seizure detection or forecasting algorithms. Importantly, many predictive features used in this study can be measured noninvasively.

Optimal Choice of Antiseizure Medication: Agreement Among Experts and Validation of a Web-Based Decision Support Application

Abstract, originally published in Epilepsia

Objective: Optimal choice of antiseizure medication (ASM) depends on seizure type, syndrome, age, gender, comorbidities and co-medications. There are no fixed rules on how to weigh these factors; choices are subjective and experience-driven. We investigated agreement among experts in selecting ASM as monotherapy and used their prevailing choices to validate a web-based decision-support application.

Methods: Twenty-four international experts, blinded to the app, selected the optimal ASM for 25 individual patient-cases covering a wide variation of seizure types and other factors influencing ASM selection. The app ranked ASMs in order of likely appropriateness for each case. In a second step, experts rated anonymously the choices of the app.

Results: Of the 25 patient-cases (age 13-74 years), 13 were female, 18 (72%) had comorbidities, six (24%) were on contraceptives, and 13 (52%) had other co-medications. The median number of experts who selected the same ASM for a given case was 15 (62.5%) and interquartile range (IQR) 13-18 (54%-75%). Gwet’s agreement coefficient among experts was 0.38 (95% confidence interval [CI] 0.32-0.44), corresponding to a “fair” agreement. Agreement between the app and the prevailing expert choice for each case was 0.48 (95% CI 0.29-0.67), corresponding to a “moderate” beyond chance agreement. The percent agreement between the highest ranked selections of the app and the expert selections was 73% (95% CI 64%-82%). Ninety-five percent of the experts considered that no incorrect or potentially harmful ASMs were ranked highest by the app, and most experts strongly agreed with the app’s selections.

Significance: This app, now validated by experts, provides an objective, reproducible method for selecting ASM that accounts for relevant clinical features. It is freely available at: https://epipick.org.

Pregnancy Does Not Increase Seizures in Women With Epilepsy

Abstract, originally published in The New England Journal of Medicine

Women with epilepsy do not have an increased seizure rate during pregnancy as long as they have their medication levels carefully monitored, a new study suggests.

The study showed very similar fluctuations in seizure rates in women with epilepsy during pregnancy and the peripartum period to that of a group of matched nonpregnant controls.

“Our results show that pregnancy in and of itself does not increase seizures in women with epilepsy in the setting of recognition of increased drug clearance and increased medication dosing as needed,” lead author Page Pennell, MD, professor of neurology at Harvard Medical School, and Brigham and Women’s Hospital, Boston, Massachusetts, told Medscape Medical News.

“This is very much a reassuring result,” Pennell added. “Women with epilepsy are generally scared about pregnancy. While many want to start a family, they don’t want to risk their seizures getting worse, which has been a concern. Our results show that they don’t have to worry about that — that their risk is no different to that of non-pregnant controls, as long as they have their medication levels monitored.”

Employment Status as a Major Determinant for Lower Physical Activity of Patients with Epilepsy: A Case-Control Study

Abstract, originally published in Epilepsy & Behavior

Background: People with epilepsy (PWE) may have a sedentary lifestyle and less physical activity (PA) as they are often advised against engaging in sports, despite a plethora of evidence suggesting seizure control, major health and psychosocial benefits associated with PA. We aimed to investigate PWE’s beliefs on PA and their level of PA compared to controls.

Methods: The Baecke questionnaire for measuring habitual PA in adults, comprising three domains (occupational PA, leisure, and locomotion), was applied in 97 consecutive PWE (96.9% with focal epilepsy, 39.2% well controlled with pharmacological treatment) and 45 healthy controls matched for gender, age, and socioeconomic characteristics.

Results: The total Baecke score was significantly lower in PWE than controls (7.6 ± 1.5 versus 8.2 ± 1.2; p < 0.01). PWE showed a significantly lower employment rate than controls (34.0% versus 73.3%; p < 0.01), and consequently lower occupational PA (p < 0.01). Physical exercise during sports time (p = 0.23) and leisure activities (p = 0.55) scores were similar between patients and controls. When PWE and controls’ sociodemographic characteristics were analyzed together by multiple linear regression, 21% of the Baecke total score variation was explained by diagnosis of epilepsy (B = -0.26; p = 0.05), years of education (B = -0.35; p = 0.03), and occupational status (B = -0.41; p < 0.01). However, diagnosis of epilepsy alone explained only 4% (B = -0.64; p = 0.01) of Baecke total score variation.

Conclusion: The level of physical activity in people with epilepsy is only slightly lower than in controls (8% lower score) and it may be explained by lower occupational physical activity, probably related to lower employment rate among people with epilepsy.

Epilepsy Research News: December 2020

This month’s research news includes announcements about the Curing the Epilepsies 2021 Conference, and a reminder about the Cure Epilepsy and Taking Flight grant letters of intent (LOIs).

We also share that the Health Disparities Research Institute will be accepting applications, and that the TESS Research Foundation is hiring.

These news items are summarized below.

Research Highlights

Curing the Epilepsies 2021 Conference–January 4-6, 2021

Please join the epilepsy community from around the world to discuss the progress made in understanding the biological mechanisms underlying the epilepsies, and the inroads being made towards potential cures.

The main outcome and priority of the meeting will be to identify transformative research priorities that will accelerate development of cures and improve outcomes for people with epilepsy. The meeting takes place from January 4-6, 2021. It will be open to the public and freely available via livestream.

Learn more

Understanding & Treating Temporal Lobe Epilepsy
A team of researchers has found that an amino acid produced by the brain could play a crucial role in preventing cell loss and seizures associated with temporal lobe epilepsy. Utilizing an animal model of temporal lobe epilepsy, the research team found that administration of the amino acid D-serine prevented cell loss characteristic of temporal lobe epilepsy and reduced the number and severity of seizures.

Learn More

CURE Epilepsy and Taking Flight Grant Timeline–Letter of Intent (LOI) due January 11, 2021 9 PM EST
Reminder, CURE Epilepsy is accepting LOIs for both the CURE Epilepsy and Taking Flight grant awards now through Monday, January 11, 2021 at 9 PM ET. Don’t miss your opportunity to be considered!

  • CURE Epilepsy Award, $250,000 over two years: This award reflects CURE Epilepsy’s continued focus on scientific advances that have potential to truly transform the lives of those affected by epilepsy.
  • Taking Flight Award, $100,000 for one year: This award seeks to promote the careers of young epilepsy investigators, allowing them to develop a research focus independent of their mentors.
  • Research areas: Sudden unexpected death in epilepsy (SUDEP), acquired epilepsy, treatment-resistant epilepsy, pediatric epilepsy, and sleep and epilepsy

Learn More

2021 Health Disparities Research Institute–Accepting Applications February 1-March 8, 2021The next Health Disparities Research Institute–featuring lectures on minority health and health disparities research, mock grant review, seminars and more–will be held virtually August 9-13, 2021.

The program’s intent is to support early-career minority health/health disparities research scientists and stimulate research in the disciplines supported by health disparities science. Admission to this program is by application only. The application cycle is open February 1-March 8, 2021.

Learn More

Job Opportunity: Research Program Manager Position with TESS Research Foundation
Looking for an opportunity to make a difference in the area of rare epilepsies? The TESS Research Foundation is seeking a Research Program Manager to oversee all scientific research focused on SLC13A5 Epilepsy, including research coordination, grant program oversight, community outreach, and scientific communication and cultivation.

Learn More

Forecasts of Epilepsy Seizures Could Become a Reality

Summary, originally published in Scientific American

Seizures are like storms in the brain—sudden bursts of abnormal electrical activity that can cause disturbances in movement, behavior, feelings and awareness. For people with epilepsy, not knowing when their next seizure will hit can be psychologically debilitating. Clinicians have no way of telling people with epilepsy whether a seizure will likely happen five minutes from now, five weeks from now or five months from now, says Vikram Rao, a neurologist at the University of California, San Francisco. “That leaves people in a state of looming uncertainty.”

Despite the apparent unpredictability of seizures, they may not actually be random events. Hints of cyclical patterns associated with epilepsy date back to ancient times, when people believed seizures were tied to the waxing and waning of the moon. While this particular link has yet to be definitively proven, scientists have pinpointed patterns in seizure-associated brain activity. Studies have shown that seizures are more likely during specific periods in the day, indicating an association with sleep–wake cycles, or circadian rhythms.

In 2018, Rao and his colleagues reported the discovery of long-term seizure-associated brain rhythms—most commonly in the 20- to 30-day range—which they dubbed as “multidien” (multiday) rhythms. By examining these rhythms in brain activity, the group has now demonstrated that seizures can be forecast 24 hours in advance—and in some patients, up to three days prior. Their findings, published December 17 in Lancet Neurology, raise the possibility of eventually providing epilepsy patients with seizure forecasts that could predict the likelihood that a seizure will occur days in advance.

Seizure Detection at Home: Do Devices on the Market Match the Needs of People Living With Epilepsy and Their Caregivers?

Abstract, originally published in Epilepsia

In patients with epilepsy, the potential to prevent seizure-related injuries and to improve the unreliability of seizure self-report have fostered the development and marketing of numerous seizure detection devices for home use.

Understanding the requirements of users (patients and caregivers) is essential to improve adherence and mitigate barriers to the long-term use of such devices. Here we reviewed the evidence on the needs and preferences of users and provided an overview of currently marketed devices for seizure detection (medically approved or with published evidence for their performance). We then compared devices with known needs. Seizure-detection devices are expected to improve safety and clinical and self-management, and to provide reassurance to users.

Key factors affecting a device’s usability relate to its design (attractive appearance, low visibility, low intrusiveness), comfort of use, confidentiality of recorded data, and timely support from both technical and clinical ends. High detection sensitivity and low false alarm rates are paramount. Currently marketed devices are focused primarily on the recording of non–electroencephalography (EEG) signals associated with tonic-clonic seizures, whereas the detection of focal seizures without major motor features remains a clear evidence gap. Moreover, there is paucity of evidence coming from real-life settings.

A joint effort of clinical and nonclinical experts, patients, and caregivers is required to ensure an optimal level of acceptability and usability, which are key aspects for a successful continuous monitoring aimed at seizure detection at home.