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.

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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.

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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

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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.

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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.

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Epilepsy Research News: December 2020

In this month’s news, we spotlight a publication describing CURE Epilepsy’s Infantile Spasms (IS) Initiativea collaborative research program that brought a team science approach to understanding the causes and potential treatments for IS. Running from 2013-2016, this program led to numerous advances in understanding the pathways in the brain involved in IS. 

Also, this month we feature news from the EPISTOP study showing that preventative treatment with the drug vigabatrin decreased the number of days with seizures as well as the severity of epilepsy in infants with tuberous sclerosis complexWe also highlight recent work from CURE Epilepsy Grantee Dr. Jeffrey Loeb, whose team identified a protein found in healthy brain tissue that may work to prevent the spread of seizures. 

These studies and more are summarized below. 

Research Highlights

Infantile Spasms
This recent publication highlights CURE Epilepsy’s Infantile Spasms (IS) Initiative, established in 2013 to support collaborative, team science-based and milestone-driven effort to advance the understanding of causes of and potential treatments for IS. The combined efforts of the research team led to numerous advances in understanding the causes of IS. It also brought together a diverse group of investigators–who otherwise would not have collaborated–to study therapies for IS.

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Preventing the Spread of Seizures
New research may explain what prevents seizures in certain areas of the brain from spreading to other areas of the brain. In a study funded by the National Institutes of Health/American Epilepsy Society, CURE Epilepsy Grantee Dr. Jeffrey Loeb and his colleagues found that a protein called DUSP4 was increased in healthy brain tissue directly next to epileptic brain tissue. The research suggests that DUSP4 may work to prevent the spread of epilepsy in the brain and that boosting levels of DUSP4 could be a novel way of preventing or treating epilepsy.

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Tuberous Sclerosis Complex Treatment
Preventive treatment with vigabatrin effectively decreased the risk and severity of epilepsy in infants with tuberous sclerosis complex who were enrolled in the EPISTOP multi-center study. Vigabatrin resulted in a significantly longer time to first clinical seizure compared with conventional treatment as well as a lower proportion of days with seizures until age 2, according to the study findings. The EPISTOP study has shown that it may be possible to change the natural history of severe infantile epilepsy through early intervention with antiepileptic therapy,” the researchers wrote.

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Epilepsy and Dementia
Late-onset epilepsy has been linked to a substantially increased risk of subsequent dementia. Results of a retrospective analysis show that patients who develop epilepsy at age 67 or older have a threefold increased risk of subsequent dementia versus their counterparts without epilepsy. “We are finding that just as the risk of seizures is increased in neurodegenerative diseases, the risk of dementia is increased after late-onset epilepsy and seizures,” study investigator Emily L. Johnson, MD, assistant professor of neurology at Johns Hopkins University, Baltimore, said in an interview. “Several other on-going studies are finding similar results,” she added.

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Epilepsy Treatment Expansion Approval
The FDA expanded its approval of lacosamide, marketed as Vimpat, to include add-on therapy for primary generalized tonic-clonic seizures as well as an IV formulation for patients aged 4 years and older.

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Free App Helps With Optimal Choice of Antiseizure Medication

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 antiseizure medication that accounts for relevant clinical features. It is freely available at: https://epipick.org.

Would people living with epilepsy benefit from palliative care?

Abstract, originally published in Epilepsy & Behavior

Palliative care (PC) is an approach to the care of persons living with serious illness and their families that focuses on improving quality of life and reducing suffering by addressing complex medical symptoms, psychosocial needs, spiritual well-being, and advance care planning. While PC has traditionally been associated with hospice care for persons with cancer, there is now recognition that PC is relevant to many noncancer diagnoses, including neurologic illness, and at multiple points along the illness journey, not just end of life.

Despite the recent growth of the field of neuropalliative care there has been scant attention paid to the relevance of PC principles in epilepsy or the potential for PC approaches to improve outcomes for persons living with epilepsy and their families. We believe this has been a significant oversight and that PC may provide a useful framework for addressing the many sources of suffering facing persons living with epilepsy, for engaging patients and families in challenging conversations, and to focus efforts to improve models of care for this population.

In this manuscript we review areas of significant unmet needs where a PC approach may improve patient and family-centered outcomes, including complex symptom management, goals of care, advance care planning, psychosocial support for patient and family and spiritual well-being. When relevant we highlight areas where epilepsy patients may have unique PC needs compared to other patient populations and conclude with suggestions for future research, clinical, and educational efforts.

Affordability, availability and tolerability of anti-seizure medications are better predictors of adherence than beliefs: Changing paradigms from a low resource setting

Abstract, originally published in Seizure

Objectives: Anti-seizure medication (ASM) non-adherence contributes to treatment gap and increases mortality and morbidity associated with epilepsy. Beliefs about medications are considered better predictors of ASM non-adherence than clinico-demographic factors. We aimed to look into ASM non-adherence rates among adults with epilepsy (AWE), identify the contributing barriers and determine whether medication beliefs were more powerful predictors than clinico-demographic factors.

Methods: This was a cross-sectional study of AWE receiving ASMs. Participants (n = 304) were assessed by validated questionnaires, for non-adherence (8-item Morisky Medication Adherence Scale) and perceptions of ASMs (Beliefs about Medicines Questionnaire) along with clinico-demographic details.

Results: Our group with high literacy and low-income had a high non-adherence rate (55 %) despite having positive beliefs (Mean necessity-concern differential [NCD] = 2.86). Among the beliefs, ASM non-adherence was significantly associated with ASM-concern (t = 4.23, p < 0.001) and NCD (t = -4.11, p < 0.001). Stepwise multiple linear regression analysis showed that non-adherence was significantly associated with per-capita income (? -0.215, p < 0.001), ASM side effects (? 0.177, p = 0.001), high seizure frequency (? 0.167, p = 0.002), ASM availability (? -0.151, p = 0.004), ASM costs (? -0.134, p = 0.013 and NCD (? -0.184, p = 0.001). NCD accounted for 2.9 % of the variance in non-adherence whereas the other clinico-demographic variables together accounted for 14.6 %.

Conclusion: We describe a paradigm shift in adults with epilepsy with high non-adherence to anti-seizure medications, wherein clinico-demographic variables emerge as better predictors of non-adherence than beliefs. High literacy facilitates the perception of need for anti-seizure medications whereas costs and side effects hamper adherence.

Effects of valproate (Depakote), lamotrigine (Lamictal), and levetiracetam (Keppra) monotherapy on bone health in newly diagnosed adult patients with epilepsy

Abstract, originally published in Epilepsy & Behavior

Purpose: The aim of this study was to evaluate the effects of valproate (VPA), lamotrigine (LTG), and levetiracetam (LEV) on bone turnover and bone mineral density (BMD) in newly diagnosed adult patients with epilepsy.

Methods: Eligible adult patients who were newly diagnosed with epilepsy were treated with VPA, LTG, and LEV. The chemical indicators of bone metabolism and BMD were measured before treatment and 2 years after treatment with different antiseizure medication (ASM) monotherapies. Then, the differences in these parameters before and after treatment were analyzed.

Results: One hundred twenty-four patients completed the 2 years follow-up; 43 received monotherapy with VPA, 32 received LTG, and 49 received LEV. Serum parathyroid hormone (PTH), bone alkaline phosphatase (B-ALP), and ?-cross-linked C-telopeptide of type I collagen (?-CTX) levels were elevated in adult patients after 2 years of VPA administration; the serum procollagen I intact N-terminal peptide (PINP) level was noticeably higher in patients after LEV treatment than before treatment. Meanwhile, the BMD of the lumbar spine and femoral neck did not change in patients treated with VPA, LTG, and LEV.

Conclusions: Valproate altered bone turnover in adult patients with epilepsy, while lamotrigine and levetiracetam did not exert harmful effects on bone health in adult patients.

Preventive treatment positively alters ‘natural history of severe infantile epilepsy’

Article, originally published in Annals of Neurology

Preventive treatment with vigabatrin effectively altered the natural history of seizures among infants with tuberous sclerosis complex, decreasing the risk for and severity of epilepsy, according to results published in Annals of Neurology.

Katarzyna Kotulska, MD, PhD, of the department of neurology and epileptology at the Children’s Memorial Health Institute in Poland, and colleagues conducted the present study as part of the EPISTOP project, a long-term prospective study examining clinical and molecular biomarkers for epileptogenesis in a genetic model of epilepsy/TSC. The trial was conducted from March 2014 through October 2018 at nine sites in Europe and one site in Australia.

In both the RCT and OLT, no patients who received preventive treatment developed infantile spasms compared with four of 13 (31%) patients receiving conventional treatment in the RCT and six of 12 (50%) patients in the OLT, for a statistically significant difference in both the OLT and the pooled analysis (P = .015 and P < .001, respectively). No EPISTOP subject who completed the study developed a severe intellectual disability at the age of 2 years.

“… This EPISTOP study has shown that it may be possible to change the natural history of severe infantile epilepsy through early intervention with antiepileptic therapy,” the researchers wrote.

UCB’s VIMPAT® (Lacosamide) CV Now Approved by FDA for Primary Generalized Tonic-Clonic Seizures and Expanded Pediatric Use for People Living With Epilepsy

Press release, originally published on the UCB website

UCB, a global pharmaceutical company, today announced that the U.S. Food and Drug Administration (FDA) has approved VIMPAT® (lacosamide) CV as adjunctive therapy in the treatment of primary generalized tonic-clonic seizures (PGTCS) in patients four years of age and older and VIMPAT injection for intravenous use in children four years of age and older. PGTCS is a type of seizure that occurs all over the brain, affecting both sides of the brain from the start, causing muscles to stiffen and convulsions to occur for up to a few minutes.

“These approvals underscore UCB’s commitment to people living with epilepsy and our focus on finding solutions for specific unmet needs within the epilepsy community,” said Mike Davis, Head of U.S. Neurology at UCB. “We are pleased that VIMPAT is now available as a treatment option for people living with primary generalized tonic-clonic seizures on their journey to seizure control.”

The PGTCS approval is based, in part, on results of a Phase 3 study recently published in the Journal of Neurology, Neurosurgery & Psychiatry.  Adjunctive treatment with VIMPAT resulted in a significantly lower risk of developing a second PGTCS during the 24-week treatment period, with the corresponding risk reduction being 45% (p=0.001), and a significantly higher rate of freedom from PGTCS during the treatment period compared with placebo (31.3% vs 17.2%, p=0.011).

People living with generalized tonic-clonic seizures have an increased risk of injury and those who experienced three or more in one year had a fifteen-fold increased risk of sudden unexpected death in epilepsy.

“The treatment of primary generalized tonic-clonic (convulsive) seizures is challenging, with about one-third of patients still being refractory while on therapy,” said David Vossler, MD, FAAN FACNS FAES, Department of Neurology, University of Washington, Seattle, USA. “Bolstered by a wealth of data demonstrating the efficacy and safety of VIMPAT, this new indication gives people suffering from PGTCS a chance at freedom from these seizures, which many have never experienced.”

Results from the Phase 3 study showed that VIMPAT was generally tolerated in patients with Idiopathic Generalized Epilepsy (IGE) and PGTCS. The most common adverse reactions (?10%) reported in patients treated with VIMPAT were dizziness (23%), somnolence (17%), headache (14%), and nausea (10%) compared to 7%, 14%, 10%, and 6%, respectively, of patients who received placebo.

Regarding the expanded pediatric population, VIMPAT tablets and oral solution were already approved to treat partial-onset seizures in adults and children four years and older as monotherapy and adjunctive therapy. VIMPAT injection was previously approved for the treatment of partial-onset seizures only in adult patients (17 years of age and older).

In October 2020, The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) issued a positive opinion for VIMPAT as adjunctive therapy in the treatment of PGTCS in adults, adolescents and children from four years of age with idiopathic generalized epilepsy. Regulatory reviews for use of VIMPAT in the treatment of PGTCS are also underway in Japan and Australia.

Precision Medicine: Academic dreaming or clinical reality?

Abstract, originally published in Epilepsia

Precision medicine can be distilled into a concept of accounting for an individual’s unique collection of clinical, physiologic, genetic, and sociodemographic characteristics to provide patient?level predictions of disease course and response to therapy. Abundant evidence now allows us to determine how an average person with epilepsy will respond to specific medical and surgical treatments. This is useful, but not readily applicable to an individual patient. This has brought into sharp focus the desire for a more individualized approach through which we counsel people based on individual characteristics, as opposed to population?level data. We are now accruing data at unprecedented rates, allowing us to convert this ideal into reality. In addition, we have access to growing volumes of administrative and electronic health records data, biometric, imaging, genetics data, microbiome, and other “omics” data, thus paving the way toward phenome?wide association studies and “the epidemiology of one.” Despite this, there are many challenges ahead. The collating, integrating, and storing sensitive multimodal data for advanced analytics remains difficult as patient consent and data security issues increase in complexity. Agreement on many aspects of epilepsy remains imperfect, rendering models sensitive to misclassification due to a lack of “ground truth.” Even with existing data, advanced analytics models are prone to overfitting and often failure to generalize externally. Finally, uptake by clinicians is often hindered by opaque, “black box” algorithms. Systematic approaches to data collection and model generation, and an emphasis on education to promote uptake and knowledge translation, are required to propel epilepsy?based precision medicine from the realm of the theoretical into routine clinical practice.

Study Finds Diet Therapy to be Most Effective Therapy in Children with Myoclonic-Atonic Seizures (Doose Syndrome)

Abstract, originally published in Epilepsia

Objective: Epilepsy with myoclonic-atonic seizures (EMAS) is a rare childhood onset epileptic encephalopathy. There is no clear consensus for recommended treatments, and pharmacoresistance is common. To better assess the clinical phenotype, most effective treatment, and determinants of cognitive and seizure outcomes, three major pediatric epilepsy centers combined data, creating the largest cohort of patients with EMAS ever studied to date.

Methods: Authors performed a retrospective chart review of patients with EMAS who received care at the authors’ institutions.

Results: A total of 166 children were identified. Global developmental delay (>1 domain) was present in 2% of children at onset and 49% during the course of the disease. Afebrile seizures occurred after the age of 2 years in 88%, generalized tonic-clonic seizures in 60%, and drop attack or myoclonic seizures in 30%. At onset, electroencephalography (EEG) found 28% normal, background slowing in 20%, and epileptiform discharges or seizures in 69%. Subsequent EEG found slowing in 62% and discharges or seizures in 90%. Response (>50% seizure reduction) to the first three antiseizure drugs (ASDs) was 26% (levetiracetam, 17%; valproic acid, 31%; other ASDs combined, 26%). Diet therapy was used as a second or third therapy in 19% and ultimately used in 57%; response was 79%, significantly greater than the first three ASDs (P = .005, ?2). Seizure freedom occurred in 57% and was less likely in the case of persistent global developmental delays (P < .001), seizure recorded on subsequent EEGs (P = .027), and failure to respond to diet therapy (P = .005). Development was normal in 47%, and 12% had delays in one domain, which was less likely in the case of global developmental delay after epilepsy onset (P < .001) and failure to achieve seizure freedom (P < .001).

Significance: This large cohort of children with EMAS clarifies areas of variability in practice. Diet therapy is by far the most effective treatment; failure to respond was associated with failure to attain seizure freedom. This therapy should be used early in the treatment in EMAS. This study also identified a bidirectional link between cognitive and seizure outcomes.