Long Term Outcomes After New-Onset Refractory Status Epilepticus (NORSE): Treatment with Vagus Nerve Stimulation

Abstract found on Wiley Online Library

New-onset refractory status epilepticus (NORSE) is associated with high mortality, therapy resistant epilepsy (TRE) and poor cognitive and functional outcomes. Some patients develop multifocal TRE, for whom surgery with a curative intention, is not an option. In these patients, Vagus Nerve Stimulation (VNS) is performed as a palliative treatment. We report the long-term outcomes regarding seizure frequency, functional and cognitive outcome, and effectiveness of VNS in two patients with TRE as a consequence of NORSE. In the first patient with cryptogenic new-onset refractory status epilepticus, vagus nerve stimulation implantation occurred during the acute stage, probably contributing to the cessation of her status epilepticus. However, in the long-term follow-up, the patient persisted with daily multifocal seizures. In the second patient, VNS implantation was delayed to manage his epilepsy when the NORSE, ultimately due to autoimmune encephalitis, had resolved. During long-term follow-up, no reduction in seizure frequency was achieved. The current evidence supporting the use of vagus nerve stimulation in patients with therapy resistant epilepsy after new-onset refractory status epilepticus warrants further investigation.

Successful Treatment of Adult Dravet Syndrome Patients with Cenobamate (XCOPRI ®)

Abstract found on Wiley Online Library

Dravet syndrome (DS) is a rare drug resistant severe developmental and epileptic encephalopathy caused by pathogenic variants in the ? subunit of the voltage-gated sodium channel gene SCN1A. Hyperexcitability in DS results from loss of function in inhibitory interneurons. Thus, sodium channel blockers are usually contraindicated in DS patients as they may lead to disease aggravation. Cenobamate (CNB) is a novel anti-seizure-medication (ASM) with promising rates of seizure freedom in patients with focal-onset drug resistant epilepsy. CNB blocks persistent sodium currents by promoting the inactive states of sodium channels. In a multi-center study, we analyzed retrospectively the effect of an add-on therapy of CNB in adult patients with DS. We report four adult patients with DS in whom the use of CNB resulted in a significant seizure reduction of more than 80%, with a follow-up of up to 542?days. CNB was the first drug in these patients that resulted in a long-lasting and significant seizure reduction. No severe adverse events occurred. We highlight cenobamate as an antiseizure medication that may lead to a clinically meaningful reduction of seizure frequency in adult patients with Dravet syndrome. It is, however, unclear if all patients with DS benefit, requiring further investigation and functional experiments.

Bone Development in Offspring of Pregnant Rats Treated with Carbamazepine: (Tegretol ®) Evaluation by Three Different Methods

Abstract found on Wiley Online Library

Objective: This study was carried out to determine the effect of intrauterine carbamazepine (Tegretol ®) exposure on fetal bone development during pregnancy.

Methods: In the study, 24 female pregnancy rats were used: Wistar. Rats were 20?weeks old. They have an average body weight of 150-200 grams. Pregnancy rats were randomly selected and divided (n=6) into control group, low dose CBZ (10 mg/kg/day) group, medium dose CBZ (25 mg/kg/day) group and high dose CBZ (50 mg/kg/day) group. The ossification length (mm) and ossification area (mm2) of the long bones of the fetuses in the experimental and control groups were calculated. The densities of alkaline phosphatase (AP) and tartrate resistant acid phosphatase (TRAP) were analyzed. The ossification regions of the femurs of the fetuses were examined under a light microscope. Microstructural images of the femurs were evaluated with scanning electron microscope photographs. The densities of minerals involved in the ossification process were analyzed.

Results: According to the results of the study, all three doses of CBZ caused loss of ossification areas and it was observed that this bone loss also increased statistically significantly depending on the dose increase (p<0.05). Calcium concentration decreased in the CBZ groups. When the electron microscope images were examined, it was determined that the cartilage matrix of the CBZ groups was thinned. In the histological evaluation of the groups, narrowing of the primary bone collar and smaller bone spicules in the ossification region compared to the control group were noted due to the increase in dose in the CBZ groups. In immunohistochemical staining; ?t was observed that the TRAP and AP expression values ??of the femurs were the lowest in the CBZ groups. These decreases were also statistically significant when compared with the control group.

Significance: As a result, it was revealed with both microscopic and macroscopic findings that exposure to intrauterine CBZ negatively affected ossification and bone growth.

CBD Epidiolex Fails to Improve Life Quality in Dravet Children in Study

Article published by Dravet Syndrom News

Management of Functional Seizures and Functi Six months of treatment with the oral cannabidiol (CBD) solution Epidiolex among children and adolescents with Dravet syndrome or Lennox-Gastaut syndrome (LGS) was not associated with improvements in caregiver-reported quality of life or adaptive behaviors.

That’s according to a small Korean study — though researchers noted that the ability to identify such improvements may have been hampered by the clinical severity of the included patients. These children had treatment-resistant seizures, significant developmental delays, and intellectual disability.

“The relationship between CBD and [quality of life] needs to be investigated in larger patient populations,” the researchers wrote.

“CBD has been found to be an efficacious antiseizure drug for patients with Lennox-Gastaut syndrome and Dravet syndrome, but it did not improve [quality of life] in pediatric patients with treatment-resistant epilepsy in our study,” the team wrote.

The study, “Effects of Cannabidiol on Adaptive behavior and Quality of Life in Pediatric Patients With Treatment-Resistant Epilepsy,” was published in the Journal of Clinical Neurology.

Cannabidiol, also called CBD, is the major non-psychoactive component of the cannabis plant, and has received considerable recent attention for its therapeutic properties.

Expert Consensus Opinions Published in Neurology and Therapy Discuss Adjustment of Anti-Seizure Medication Dosing for Optimal Care

Published by SK Life Science

Featuring the work of CURE Epilepsy grantee Dr. Pavel Klein

Consensus opinions report that lowering the doses of certain anti-seizure medications (ASMs) when beginning treatment with XCOPRI® (cenobamate tablets) CV may help manage possible side effects. SK Life Science, Inc. announced the publication in the journal Neurology and Therapy.

“When a new medication is added to a patient’s antiseizure medication (ASM) regimen, it is important to consider the overall drug load that may increase the possibility for adverse reactions,” said Pavel Klein, M.D., epileptologist and neurologist, Mid-Atlantic Epilepsy and Sleep Center, Bethesda, MD. “To help manage those potential adverse events, when adding the new medication, you may consider reducing the dose of existing ASMs” 

Why Does Fasting Reduce Seizures?

Article found on MedicalXpress

Calorie restriction has long been associated with reduced seizures in epilepsy. New research from Boston Children’s Hospital helps explain how fasting affects neurons in the brain and could lead the way to new approaches that would avoid the need for fasting or restrictive diets. The findings were published August 30 in the journal Cell Reports.

“This study is the first step in understanding how dietary therapies for epilepsy work,” says first author Christopher J. Yuskaitis, MD, Ph.D., a neurologist with the Epilepsy Center and Epilepsy Genetics Program at Boston Children’s Hospital. “The mechanisms have until now been completely unknown.”


DEPDC5, mTOR, and fasting

To connect the dots between diet and seizures, the researchers began with existing knowledge. They knew that the well-known mTOR cellular pathway is involved in many neurological disorders and had shown previously that over-activation of this pathway in neurons increases susceptibility to seizures. Studies by others had shown that mTORC activity is inhibited by acute fasting, though these studies didn’t look at the brain.

In the new study, they showed in a mouse seizure model that mTOR signaling was reduced in the brain after fasting. Additional studies of cultured rat neurons in a dish suggest that this fasting effect is primarily driven by the lack of three amino acids (leucine, arginine, and glutamine).

Going further, the team demonstrated that the presence of these nutrients is sensed by the DEPDC5 protein. When they knocked out DEPDC5 in the brain, mTOR activity was not reduced and fasting no longer protected the mice against seizures.

Irritability and Its Relationship with Psychosocial Symptoms and Quality of Life in Adolescents with Epilepsy Receiving Levetiracetam Therapy: A Case-Control Study

Abstract found on PubMed 

Background: Levetiracetam, a widely used anticonvulsant drug in children and adolescents, has been associated with irritability, psychosocial symptoms, and low quality of life, which are also influenced by other epilepsy variables.

Purpose: The objective of this study was to investigate the level of treatment-related irritability in adolescents receiving levetiracetam, and to evaluate the relationship between irritability levels and psychosocial symptoms, and quality of life.

Methods: A cross-sectional, case-control study was conducted. Consecutive adolescent patients with epilepsy aged 11-17 years with partial or generalized seizures, treated with either levetiracetam or valproic acid for at least 6 months, and healthy controls were recruited. The Affective Reactivity Index parent report and self-report, Strengths and Difficulties Questionnaire, and Pediatric Quality of Life Inventory-Psychosocial subscale were utilized to assess irritability, psychosocial symptoms, and functioning.

Results: A total of 120 participants were analyzed; 33 patients in the LEV group, 45 patients in the VPA group, and 42 healthy controls. Both self and parent report irritability levels of the LEV group were found to be significantly higher than those of healthy controls. The irritability levels of the LEV and VPA groups were not statistically different, but still the LEV group had higher irritability levels on both scales. In the LEV group, irritability was positively correlated with behavioral, emotional, and attention/hyperactivity problems, and also negatively correlated with psychosocial quality of life.

Conclusion: Adolescents with epilepsy using LEV have a high level of irritability and this is associated with some psychosocial symptoms and poor quality of life.

AI Model May Help Epilepsy Patients Become Seizure-Free

Article published by Medical Xpress

A study led by Monash University and believed to be a world first has demonstrated that an Artificial Intelligence (AI) model can potentially predict the best personalized, anti-seizure medication for patients with newly diagnosed epilepsy.

The predictive model, once fully developed, would spare these patients the uncertainty of not knowing when their lives would be returned to normal by taking anti-seizure medications, and possibly the harmful side-effects associated with some drugs.

Professor Patrick Kwan, a neurologist and researcher from the Monash Central Clinical School’s Department of Neuroscience is leading an international collaboration that is “training” the deep-learning prediction model (deep learning is a type of machine learning).

Their study is published in the influential JAMA Neurology.

“If the patient doesn’t respond to the first treatment, quite a few will respond to the second or third one, meaning that they might have become seizure-free sooner if the ‘right’ drug was chosen at the outset,” he said. “But if they get the wrong medication they still have seizures and may also get side-effects from it—they’re not getting the benefit and are getting harm from the drug.”

CURE Epilepsy Discovery: Developing Precision Medicine Treatments for Genetic Epilepsies: Present Challenges, Recent Scientific Advances, and Future Prospects

Key Points:

  • Epilepsy is a serious neurological disorder with many possible causes, and those directly linked to genetic abnormalities have undergone significant scientific breakthroughs in recent years.
  • Precision medicine is “an emerging approach for disease treatment and prevention that takes into account individual variability in genes, environment, and lifestyle for each person”. This concept is being applied to genetic epilepsies, but significant challenges have limited the rate at which basic science has translated into new treatments.
  • New strategies and scientific techniques may hasten the process. A recent publication in Epilepsia highlights some of them, along with the basic science that has fostered the hope for the eventual realization of precision medicine [1]. The authors suggest that greater coordination of efforts by scientists, physicians, patient advocates, and the federal government will accelerate effective, ethical, and equitable precision medicine for genetic epilepsy.
  • This publication stems from discussions at the Epilepsy Precision Medicine conference, funded in part by CURE Epilepsy and held in Washington, DC in 2019. This conference brought together the many stakeholders involved in developing precision therapies for epilepsy including researchers, physicians, funding agencies, and people with lived experience to share their experiences of epilepsy. The publication’s writing team was led by recent CURE Epilepsy Taking Flight grantee Juliet Knowles, MD, PhD.


Deep Dive:

Epilepsy is a debilitating but surprisingly common neurological disorder, with 1 in 26 people in the United States developing it over the course of their lives [2]. Despite the availability of numerous antiseizure medications (ASMs), one-third of people with epilepsy have seizures that remain treatment-resistant [3]. There are many possible causes of epilepsy, ranging from traumatic brain injuries to specific genetic mutations. Regardless of the cause, treatment remains primarily empirical or based on observation, with patients and their epileptologists often trying different and multiple ASMs in an attempt to eliminate the seizures while managing unwanted side effects. Ideally, treatments for epilepsy would precisely target the underlying biological mechanism, control seizures, and reduce the occurrence of negative side effects.

Optimism for this approach of “precision medicine” for epilepsy grew following the complete sequencing of the human genome and fueled the hope that individual genetic information could be used to develop more specific ways to treat epilepsy. Precision medicine, also known as personalized medicine, is the “tailoring of medical treatment to the individual characteristics of each patient. It does not literally mean the creation of drugs or medical devices that are unique to a patient, but rather the ability to classify individuals into subpopulations that differ in their susceptibility to a particular disease or their response to a specific treatment.” Unfortunately, for most types of genetic epilepsy, the individual genetic makeup of a patient has not yet translated to clinical application of precision medicines for epilepsy. This has been due, in part, to the complexity of the underlying biological mechanisms as well as limitations in the technologies needed to advance genetic discovery to appropriate treatments.

However, the authors describe how epilepsy research is entering an exciting new phase that may enable new precision therapies for many more types of genetic epilepsy. Over the last decade, significant progress in advancing precision medicine approaches has been achieved for epilepsies caused by discrete mutation(s) in a single gene. This work has involved 1) acceleration and efficiency of gene sequencing technology and identification of epilepsy-causing, including the location and type of specific mutations in the DNA sequence of these genes, and 2) clarification of the neuronal function(s)/dysfunction of the corresponding protein and underlying biochemical pathways. In addition, the development of specific laboratory methods such as cell-based models that replicate aspects of the structure and function of the human brain and the use of zebrafish that are sensitive to ASMs have accelerated the testing of novel epilepsy treatments. Finally, new epilepsy gene-targeted technologies, for example, antisense oligonucleotides, are being tested in clinical trials, and there is active discussion about changes in clinical trial design that could enable smaller clinical trials needed for rare genetic epilepsies.

Despite these successes, multiple challenges remain for the future development and accessibility of precision therapies for epilepsy. First, genetic testing and counseling remain inaccessible to many groups, including the elderly and the poor, across the world. Second, nearly 70% of epilepsy cases involve more than one gene and thus require an improved understanding of disease risk in the context of multiple genetic mutations, overall genetic background, and environmental exposure. Third, although gene therapy is conceptually encouraging there are challenges related to large-scale development of safe, ethical, and equitable delivery of gene-based therapies to overcome. It will be critical for the research community to work together to overcome these challenges to ensure the delivery of new precision therapies for genetic epilepsies.

An important driver for the advancements that have been made toward the development of precision therapies are the many new stakeholders calling for action. Numerous patient advocacy groups, professional societies such as the American Epilepsy Society, government and non-profit funding agencies such as the National Institute of Neurological Disorders and Stroke and CURE Epilepsy, respectively, have collectively called for a coordinated and systematic approach to developing new epilepsy treatments. Progress stemming from this call to action could bring a new age of treatments for those with epilepsy, shifting from observational experience to data-driven and patient-centered precision therapy.


Literature Cited:

  1. Knowles JK, Helbig I, Metcalf CS, Lubbers LS, Isom LL, Demarest S, Goldberg EM, George AL, Lerche H, Weckhuysen S, Whittemore V, Berkovic SF, Lowenstein DH. Precision medicine for genetic epilepsy on the horizon: Recent advances, present challenges, and suggestions for continued progress. Epilepsia 2022
  2. Hesdorffer D, Logroscino G, Benn E, Katri N. Cascino G, Hauser W. Estimating risk for developing epilepsy. A population-based study in Rochester, Minnesota. Neurology 2011; 76:23–27
  3. Chen Z, Brodie MJ, Liew D, Kwan P. Treatment outcomes in patients with newly diagnosed epilepsy treated with established and new antiepileptic drugs. A 30-Year Longitudinal Cohort Study. JAMA Neurology 2018 75:279-286.

Precision Medicine for Genetic Epilepsy on the Horizon: Recent Advances, Present Challenges, and Suggestions for Continued Progress

Featuring the work of CURE Epilepsy Chief Scientific Officer Dr. Laura Lubbers, CURE Epilepsy Advisors Dr. Daniel Lowenstein and Dr. Vicky Whittemore, and CURE Epilepsy grantees Dr. Juliet Knowles, Dr. Lori Isom and Dr. Ethan Goldberg

Abstract found on PubMed

The genetic basis of many epilepsies is increasingly understood, giving rise to the possibility of precision treatments tailored to specific genetic etiologies. Despite this, current medical therapy for most epilepsies remains imprecise, aimed primarily at empirical seizure reduction rather than targeting specific disease processes. Intellectual and technological leaps in diagnosis over the past 10 years have not yet translated to routine changes in clinical practice. However, the epilepsy community is poised to make impressive gains in precision therapy, with continued innovation in gene discovery, diagnostic ability, and bioinformatics; increased access to genetic testing and counseling; fuller understanding of natural histories; agility and rigor in preclinical research, including strategic use of emerging model systems; and engagement of an evolving group of stakeholders (including patient advocates, governmental resources, and clinicians and scientists in academia and industry). In each of these areas, we highlight notable examples of recent progress, new or persistent challenges, and future directions. The future of precision medicine for genetic epilepsy looks bright if key opportunities on the horizon can be pursued with strategic and coordinated effort.