Spain-Based Study: Epidyolex Safely Helps Prevent Seizures

Article published by Dravet Syndrome News

The efficacy and safety of Epidiolex, an oral cannabidiol, in children and adults with Dravet syndrome and Lennox-Gastaut syndrome (LGS) were supported in a real-world setting, with benefits similar to those seen in previous clinical trials and expanded access programs (EAPs), a Spanish EAP study reported.

EAPs are designed to make promising therapies available to eligible patients in the real-world setting before their regulatory approval.

The study, “Outcomes from a Spanish Expanded Access Program on cannabidiol treatment in pediatric and adult patients with epilepsy,” was published in the journal Epilepsy & Behavior.

Long-Term Efficacy and Safety of Cannabidiol (Epidiolex®) in Patients with Treatment-Resistant Epilepsies: 4-Year Results from the Expanded Access Program

Abstract found on PubMed

Objective: Cannabidiol (CBD) expanded access program (EAP), initiated in 2014, provided add-on CBD to patients with treatment-resistant epilepsy (TRE) at 35 US epilepsy centers. Prior publications reported results through December 2016; herein, we present efficacy and safety results through January 2019.

Methods: Patients received plant-derived highly purified CBD (Epidiolex®; 100 mg/mL oral solution), increasing from 2-10 mg/kg/d to tolerance or maximum 25-50 mg/kg/d dose, depending on the study site. Efficacy endpoints included percentage change from baseline in median monthly convulsive and total seizure frequency and ?50%, ?75%, and 100% responder rates across 12-week visit windows for up to 192 weeks. Adverse events (AEs) were documented at each visit.

Results: Of 892 patients in the safety analysis set, 322 (36%) withdrew; lack of efficacy (19%) and AEs (7%) were the most commonly reported primary reasons for withdrawal. Median (range) age was 11.8 years (0-74.5), and patients were taking a median (range) 3 (0-10) antiseizure medications (ASMs) at baseline; most common ASMs were clobazam (47%), levetiracetam (34%), and valproate (28%). Median top CBD dose was 25 mg/kg/d; median exposure duration was 694 days. Median percentage reduction from baseline ranged from 50%-67% for convulsive seizures and 46%-66% for total seizures. Convulsive seizure responder rates (?50%, ?75%, and 100% reduction) ranged from 51%-59%, 33%-42%, and 11%-17% of patients across visit windows, respectively. AEs were reported in 88% of patients and serious AEs in 41%; 8% withdrew because of an AE. There were 20 deaths during the study deemed unrelated to treatment by the investigator. Most common AEs (?20% of patients) were diarrhea (33%), seizure (24%), and somnolence (23%).

Significance: Add-on CBD was associated with sustained seizure reduction up to 192 weeks with an acceptable safety profile and can be used for long-term treatment of treatment-resistant epilepsies.

Epilepsy Research News: December 2022

This issue of Epilepsy Research News includes summaries of articles on:

 

Increased Seizures After COVID Compared to the Flu

Researchers have found that the risk of seizures or epilepsy following a COVID infection is significantly higher than after being infected with the flu. The team looked at the health records of people who had been infected with COVID and matched them (so that they were similar in characteristics such as age, sex, and medical conditions) with a group of people who had been infected with the flu. The team then compared the incidence of epilepsy and seizures between the two groups over a six-month period following the initial infection. The rate of new cases of epilepsy or seizures was 0.94% in the people who had COVID, compared with 0.6% in those who had the flu. The team indicated that while the overall risk of seizures was very low, people who had COVID were 55% more likely to develop epilepsy or seizures over the next six months than people who had the flu.

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New Statistical Tool to Understand Seizures

A new study seeks to understand how some people’s seizures change over time in what is known as a seizure ‘cycle’ and understand how certain triggers might increase or decrease seizure risk, perhaps giving people with epilepsy a better idea of how and why their seizures happen, and to better recognize the early warning signs. The study found that aging itself, as well as common triggers, may be contributing factors to how the medical condition affects those prone to seizures. The researchers studied the seizure diaries of more than 1,000 patients ages 2 months to 80 years and developed a new statistical model to explicitly capture the effect of factors that may drive transitions in seizure risk, looking at factors like antiseizure medications, illness, and menstrual cycles. In examining the way seizure cycles vary in people with epilepsy, the researchers found that individuals in older age groups had shorter “calm” stretches between seizures, while younger age groups had longer stretches. This work paves the way for future studies to further examine seizure cycles.

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Identification of a Possible Molecule to Treat Temporal Lobe Epilepsy (TLE)

Researchers have recently identified and developed a small molecule called D4 with the potential to treat TLE by suppressing neuroinflammation. The findings suggest that D4 strongly suppresses TLE-induced neuroinflammation, curbs TLE seizures, and increases survival rate in an animal model of TLE. D4 works by blocking “hemichannels” in the brain, which are channels that act as pathways for neuroinflammatory molecules. The researchers note that their findings bring forward a possible new pathway for drug development for epilepsy and also highlight the involvement of neuroinflammation in epilepsy.

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Pinpointing Brain Areas Involved in GLUT1 Deficiency Syndrome Seizures

A small group of brain cells linked to a circuit in the brain is responsible for setting off whole-brain seizures in a rare form of epilepsy affected by blood sugar levels, a new study suggests. This rare genetic disorder is known as GLUT1 deficiency syndrome. Researchers used a combination of electroencephalography (EEG) as well as brain imaging in humans to show that the seizures started from brain areas called the thalamus and somatosensory cortex. When blood sugar levels dipped, abnormal electrical activity in the circuit formed by these areas spread throughout the brain. The researchers also used an animal model of GLUT1 deficiency syndrome to further investigate this circuit and pinpoint the cell types important in causing an imbalance in inhibitory brain activity compared to excitatory brain activity (which can lead to seizures). The researchers suggested these results could point to a mechanism for seizures in GLUT1 deficiency syndrome that might be targeted as a potential treatment for seizures related to GLUT1 Deficiency syndrome.

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A Randomized, Open-Label, Two-Treatment Crossover Study to Evaluate the Effect of Food on the Pharmacokinetics of Diazepam Nasal Spray (Valtoco ®) in Healthy Adult Subjects

Abstract found on Wiley Online Library

Objective: The pharmacokinetics of oral diazepam are affected by food, but food effect studies have not been conducted for diazepam nasal spray because it is believed that most absorption occurs via the nasal mucosa. However, gastrointestinal side effects reported with nasal diazepam suggest that at least a portion of the drug may be absorbed enterally and thus subject to food effects. The objective of this study was to evaluate the possible effects of food on the pharmacokinetics of diazepam nasal spray in healthy adults.

Methods: This randomized, open-label crossover study compared equal doses of diazepam nasal spray after an overnight fast and after a standardized high-fat, high-calorie breakfast. Each subject served as their own control, and there was a washout period of at least 21?days between treatments.

Results: Twenty-four healthy adults enrolled in this study. Two subjects withdrew consent, and two subjects had pre-dose diazepam concentrations that exceeded the protocol-defined minimum after the washout period and were excluded from the final analysis population of 20 subjects. Under fed conditions, the mean maximum plasma diazepam concentration was decreased by 48% (P <0.0001) and the overall diazepam exposure during the first four hours was reduced by 57% (P <0.0001) compared with fasted conditions. The time to maximum plasma concentration was 4.0 hours in the fed state compared with 2.0 hours in the fasted state (P <0.0001). At two hours post-dose, diazepam concentrations were ?150 ng/mL for 100% of subjects when fasted and 30% when fed. Significantly more subjects experienced adverse events when fasted (83.3%) than when fed (54.5%; P =?0.0340).

Significance: This study in healthy volunteers demonstrated that food significantly decreases and delays the absorption of diazepam dosed via nasal spray. Patients using diazepam nasal spray after eating may obtain diazepam concentrations that are below those needed for seizure control.

CURE Epilepsy Grantee Announcement Fall 2022

CURE Epilepsy is honored to announce our newest CURE Epilepsy grantees. Our research grants are awarded for cutting-edge, novel research projects that seek to accelerate treatments, improve outcomes, and get us to cures so that we can live in a world free of seizures. This year’s grantees’ research will focus on a wide range of epilepsies – sudden unexpected death in epilepsy (SUDEP), sleep and epilepsy, genetic causes of epilepsy, Lafora disease, post-traumatic epilepsy, pediatric epilepsy, and focal epilepsy.

TAKING FLIGHT AWARD GRANTEES – $100,000 for one year 

This award seeks to promote the careers of early-career epilepsy investigators to allow them to develop a research focus independent of their mentor(s).

Jeffrey Calhoun, PhD
Northwestern University – Chicago, Illinois

With this grant, funded by the Joseph Gomoll Foundation, Dr. Calhoun’s research will work to develop a new method to assess the functionality of variants of the SCN1A gene.
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William Tobin, PhD
The University of Vermont and State Agriculture  – Burlington, Vermont

With a grant co-funded by the KCNT1 Epilepsy Foundation, Dr. Tobin will test strategies to optimize cutting-edge gene therapy methods for the gene KCNT1.
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Gerben van Hameren, PhD
Dalhousie University– Nova Scotia, Canada

Dr. van Hameren will study a possible way to prevent the development of post-traumatic epilepsy.
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CURE EPILEPSY AWARD GRANTEES – $250,000 over two years  

This award reflects CURE Epilepsy’s continued focus on scientific advances that have the potential to truly transform the lives of those affected by epilepsy, with prevention and disease modification as critical goals.

Gordon Buchanan, MD, PhD
University of Iowa Medicine – Iowa City, Iowa

For this grant, generously funded by The Joanna Sophia Foundation, Dr. Buchanan’s group will examine whether a signaling molecule called serotonin drives a time-of-day vulnerability to SUDEP (Sudden Unexpected Death in Epilepsy).
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Annaelle Devergnas, PhD
Emory University – Atlanta, Georgia

The hypothesis for Dr. Devergnas’ project is that frontal seizures disrupt the normal function of the brain structure called the pedunculopontine nucleus (PPN), leading to changes in sleep, and that manipulating PPN activity might restore normal sleep activity.
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Juliet Knowles, MD, PhD
Stanford School of Medicine – Palo Alto, California

For this project, Dr. Knowles and her team will study the therapeutic potential for targeting myelin plasticity in Lennox-Gastaut syndrome.
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CATALYST AWARD GRANTEES – $250,000 over two years 

The CURE Epilepsy Catalyst Award stimulates and accelerates the development of new, transformative therapies for epilepsy, moving promising preclinical and/or clinical research closer to clinical application.

James Pauly, PhD, Greg Gerhardt, PhD, and Matthew Gentry, PhD
University of Kentucky – Lexington, Kentucky

In collaboration with Enable Therapeutics, Drs. PaulyGerhardt, and Gentry developed a potential drug called VAL-1221 that can penetrate brain cells and degrade the aberrant sugar aggregates therein that cause LaFora disease. Having obtained promising initial results, this project will test the safety and brain distribution of this novel therapy.
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John Gledhill, PhD
Cognizance Biomarkers, LLC  – Philadelphia, Pennsylvania

Dr. Gledhill and the team at Cognizance will build upon their preliminary research showing that people with treatment-resistant epilepsy have differences in inflammation-associated proteins in the blood compared with those who do respond to treatment. For this project, the team proposes to extend their observations by assessing additional blood samples from treatment-resistant and treatment-responsive people with epilepsy and developing an algorithm to predict response to initial anti-seizure medications.
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Neuroscientists Discover a New Drug Candidate for Treating Epilepsy

Article published by Medical Xpress


Temporal lobe epilepsy (TLE) is one of the most common types of epilepsy worldwide. Although symptomatic medications are available, one-third of TLE patients remain unresponsive to current treatment, so new drug targets are critically needed. A research team co-led by a City University of Hong Kong (CityU) neuroscientist has recently identified and developed a new drug candidate with the potential for effectively treating TLE by suppressing neuroinflammation.

A research team co-led by Dr. Geoffrey Lau Chun-yue, Assistant Professor in the CityU Department of Neuroscience, identified a new, small organic molecule called D4, whose effects the team investigated in treating TLE using a mouse model. The findings suggest that D4 strongly suppresses TLE-induced neuroinflammation, curbs TLE seizures, and increases the animal’s survival rate.

“These are very exciting and encouraging results for translational research in epilepsy,” said Dr. Lau. “We have found a very promising new drug candidate for treating epilepsy that works through a new mechanism—blocking connexin hemichannels. Our findings also highlight the important involvement of neuroinflammation in neurological disorders such as epilepsy.”

First-Line Levetiracetam (Keppra ®) Versus Enzyme-Inducing Antiseizure Medication in Glioma Patients with Epilepsy

Abstract found on Wiley Online Library

Objective: This study aimed to directly compare the effectiveness of first-line monotherapy levetiracetam (LEV) versus enzyme-inducing antiseizure medications (EIASMs) in glioma patients.

Methods: In this nationwide retrospective observational cohort study grade 2-4 glioma patients were included, with a maximum duration of follow-up of 36 months. Primary outcome was ASM treatment failure for any reason and secondary outcomes were treatment failure due to uncontrolled seizures and due to adverse effects. For estimation of the association between ASM treatment and ASM treatment failure, multivariable cause-specific cox proportional hazard models were estimated, adjusting for potential confounders.

Results: In the original cohort a total of 808 brain tumour patients with epilepsy were included, of which 109 glioma patients were prescribed first-line LEV and 183 glioma patients first-line EIASMs. The EIASMs group had a significantly higher risk of treatment failure for any reason compared to LEV (adjusted hazard ratio [aHR]=1.82 [95%CI=1.20-2.75], p=0.005). Treatment failure due to uncontrolled seizures did not differ significantly between EIASMs and LEV (aHR=1.32 [95%CI=0.78-2.25], p=0.300), but treatment failure due to adverse effects differed significantly (aHR=4.87 [95%CI=1.89-12.55], p=0.001).

Significance: In this study it was demonstrated that levetiracetam (LEV) had a significantly better effectiveness (i.e. less often ASM treatment failure for any reason or due to adverse effects) compared to enzyme-inducing anti-seizure medications (EIASMs), supporting the current neuro-oncology guideline recommendations to avoid EIASMs in glioma patients.

Parents’ Opinions About Epilepsy Surgery in Children with Epilepsy

Abstract found on  PubMed

Objective: This survey aimed to investigate the opinions of the parents of children with epilepsy with regard to the application of epilepsy surgery for their children.

Methods: We surveyed all the parents of children with epilepsy referred to our neurology clinic (Shiraz University of Medical Sciences) in April-July 2022. We collected their opinions about epilepsy surgery based on a predesigned questionnaire. The inclusion criteria included parents of all children with epilepsy (1 to 16 years of age, with at least one-year history of epilepsy, and with at least one drug used in the past 12 months).

Results: In total, 472 people participated in the study; 277 participants (58.7%) were willing to have epilepsy surgery for their child; the most common reason was to be able to discontinue the drugs. Sex (male), age (younger), and education (college) of the parents had significant associations with the parental willingness to have surgery for their children. The patient’s drug regimen (polytherapy) and history of ictal injury (in the child) also had significant associations with the parental willingness to have surgery for the children.

Conclusion: Most parents of children with epilepsy are willing to have epilepsy surgery for their children if their physician presents epilepsy surgery to them as an established, safe, and effective treatment option. Patient and parental-related factors should be considered when designing educational materials and programs for preoperative counseling for the parents of children with drug-resistant seizures.

Epilepsy Research News: November 2022

This issue of Epilepsy Research News includes summaries of articles on:

 

Development of Seizures in an Animal Model of West Syndrome

A new publication that features the work of former CURE Epilepsy grantee Dr. John Swann describes the development of an animal model of West syndrome. West syndrome is characterized by infantile spasms (a type of seizure that begins in infancy) and is often accompanied by developmental delay, and hypsarrhythmia or an irregular pattern of brain waves seen on an electroencephalographic (EEG) recording. The study’s authors state that this work is the first to show the progressive development of infantile spasms on EEG, providing an animal model that might allow for an in-depth study of the role of spasm development on decreasing cognitive abilities. The authors also state that this model may be helpful in understanding why early treatment is essential for improved neurodevelopmental outcomes in children with West syndrome.

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Psychogenic Nonepileptic Seizures (PNES) Show Structural Abnormalities in Brain Scans

PNES, also known as functional seizures, have long been thought to be caused by psychological factors such as anxiety and post-traumatic stress disorder. However, a new study finds that PNES is associated with structural changes in the brain that can be seen using MRI. A team of researchers analyzed more than 650 clinical-grade MRIs, comparing images from patients with PNES to those who did not experience seizures and could have other mental health conditions, such as depression and anxiety. The results of the study revealed that patients with PNES had thinning in an area of the brain called the superior temporal cortex, which affects a person’s cognitive awareness and control of one’s actions, and thickness in an area of the brain called the left occipital cortex, responsible for the processing of visual and other sensory information. These changes were not present in people who had depression, anxiety, or obsessive-compulsive disorder. The researchers hope that by understanding changes in the brain associated with PNES, therapies can be developed to counter these changes and treat PNES.

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Creation of Data Standardization Tools for Preclinical Epilepsy Research

The International League Against Epilepsy/American Epilepsy Society Joint Translational Task Force has published a set of “tools” to improve data standardization and transparency in preclinical epilepsy research. These “tools” are known as common data elements (CDEs) which describe the important variables to be considered in the collection and reporting of epilepsy research, and case report forms (CRFs) which contain these CDEs. This work is published in a two-part series that focuses on tools to improve the standardization of omics research. Contributors to the work include numerous CURE Epilepsy advisors, grantees, and staff.

Part 1

Part 2

Epilepsy: Gene Therapy Technique Targeting Overactive Brain Cells Shows Promise in Treating Drug-Resistant Form of the Condition

Article published by The Conversation

Since epileptic seizures are caused by excessive activity of brain cells (neurons) in specific parts of the brain, being able to target these neurons and turn them off could very well prevent seizures from happening.

Using an innovative new gene therapy approach the authors developed, the authors report that they were able to show in cell and animal models that it is possible to specifically target the neurons that cause epileptic seizures. This subsequently prevented them from becoming overactive and causing seizures in the future.

This discovery not only has major implications for treating drug-resistant epilepsy, but there’s a chance it may also be used to treat other neurological conditions caused by overactive neurons, including Parkinson’s disease and migraines.

This research is published in Science.