The Severe Epilepsy Syndromes of Infancy: A Population-Based Study

Abstract, originally published in Epilepsia

Objective: To study the epilepsy syndromes among the severe epilepsies of infancy and assess their incidence, etiologies, and outcomes.

Methods: A population-based cohort study was undertaken of severe epilepsies with onset before age 18 months in Victoria, Australia. Two epileptologists reviewed clinical features, seizure videos, and electroencephalograms to diagnose International League Against Epilepsy epilepsy syndromes. Incidence, etiologies, and outcomes at age 2 years were determined.

Results: Seventy-three of 114 (64%) infants fulfilled diagnostic criteria for epilepsy syndromes at presentation, and 16 (14%) had “variants” of epilepsy syndromes in which there was one missing or different feature, or where all classical features had not yet emerged. West syndrome (WS) and “WS-like” epilepsy (infantile spasms without hypsarrhythmia or modified hypsarrhythmia) were the most common syndromes, with a combined incidence of 32.7/100 000 live births/year. The incidence of epilepsy of infancy with migrating focal seizures (EIMFS) was 4.5/100 000 and of early infantile epileptic encephalopathy (EIEE) was 3.6/100 000. Structural etiologies were common in “WS-like” epilepsy (100%), unifocal epilepsy (83%), and WS (39%), whereas single gene disorders predominated in EIMFS, EIEE, and Dravet syndrome. Eighteen (16%) infants died before age 2 years. Development was delayed or borderline in 85 of 96 (89%) survivors, being severe–profound in 40 of 96 (42%). All infants with EIEE or EIMFS had severe–profound delay or were deceased, but only 19 of 64 (30%) infants with WS, “WS-like,” or “unifocal epilepsy” had severe–profound delay, and only two of 64 (3%) were deceased.

Significance: Three quarters of severe epilepsies of infancy could be assigned an epilepsy syndrome or “variant syndrome” at presentation. In this era of genomic testing and advanced brain imaging, diagnosing epilepsy syndromes at presentation remains clinically useful for guiding etiologic investigation, initial treatment, and prognostication.

Mechanism Connects Epilepsy and Enzyme Deficiency

Summary, originally published in JCI Insight

Researchers from Kyushu University’s Medical Institute of Bioregulation in collaboration with Nihon University, Yasuda Woman’s University, and Nagoya University now report a better understanding of a mechanism causing epilepsy in infants as the result of a deficiency of an enzyme known as inosine triphosphatase, or ITPA.

The new study could also give insight into possible risks for the 2% of the Japanese population in which both copies of the gene for ITPA produce versions with reduced activity.

Using mice that were genetically engineered such that ITPA production is disrupted only in the nervous system, the researchers found that ITPA deficiency led to a reduction in the negative charge inside the neurons when signals are not being sent, a phenomenon known as depolarization. This depolarization in turn results in frequent excitation of neurons and epileptic seizures in the mice.

The new results indicate that Early Infantile Epileptic Encephalopathy 35 (EIEE35), a neurological disorder characterized by epileptic seizures and associated with deficiency of ITPA, may involve cell membranes becoming more excitable because of depolarization caused by ITPA deficiency.

Epilepsy Research News: January 2021

This month’s research news includes announcements about CURE Epilepsy’s Frontiers in Research seminar series, and an announcement from the CDC about an incidence and etiology funding opportunity.

We also share that the NINDS Clinical Trials Methodology Course is accepting applications, and that the deadline to apply to the National Science Foundation Enabling Discovery Through Genomics (EDGE) Program is March 16.

These news items are summarized below.

Research Highlights

CURE Epilepsy’s Frontiers in Research Seminar Series has gone virtual!

As part of our on-going commitment to supporting the research community through these difficult times, we are conducting our research seminar series virtually with the topics below. Mark your calendars!

The virtual Frontiers in Research Seminar Series is sponsored by the Nussenbaum-Vogelstein Family.

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CDC Epilepsy Incidence and Etiology Funding Opportunity Announcement
Projects are intended to inform incidence and social determinants of epilepsy including risk factors and protective factors that affect epilepsy incidence. Information about epilepsy incidence will provide invaluable information to help better guide interventions or services for preventing epilepsy, treating and rehabilitating people with epilepsy, and minimizing their health disparities and adverse outcomes.

Click here for details. Search opportunity number by RFA-DP-21-004 and SIP 21-007.

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NINDS Clinical Trials Methodology Course-Application Deadline February 28
The NINDS Clinical Trials Methodology Course (CTMC) is accepting applications for the 2021 cohort. The overarching goal of the CTMC is to help investigators develop scientifically rigorous, yet practical clinical trial protocols. The focus is on investigators who have not previously designed their own prospective, interventional clinical trials.

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National Science Foundation Enabling Discovery Through Genomics (EDGE) Program-Application Deadline March 16
The goal of the EDGE program is to provide support for genomic research and associated theory, approaches, tools, and infrastructure development to address the mechanistic basis of complex traits in diverse organisms within the context (environmental, developmental, social, and/or genomic) in which they function.

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Cerebral Palsy and Epilepsy in Children: Clinical Perspectives on a Common Comorbidity

Abstract, originally published in Children

Cerebral palsy (CP) is a frequent cause of childhood disability often associated with a complex group of disorders, including epilepsy, which is reported to impact approximately 40% of affected individuals. This retrospective study involved a group of children affected by CP, some of whom also had comorbid epilepsy. The aim of this study was to report our experience of analyzing, in particular, (a) some of the clinical aspects of the different type of CP, and (b) the relationship between the clinical data of children affected by CP plus epilepsy and each type of CP.

Methods: This retrospective single-center study was performed with 93 children admitted to the Pediatric Department of the University of Catania, Italy, affected by CP and distinguished according to the type of motor clinical presentation, with 46 showing epileptic seizures, compared to a control group of 136 children affected by epilepsy without other neurologic disorders.

Results: Among the 93 CP children, 25 (27%) had spastic quadriplegia (plus one patient with dystonic quadriplegia), 39 (42%) had spastic hemiplegia, 11 (12%) had spastic diplegia (plus two with ataxia and one with dyskinetic CP), and 14 (15%) did not have a well-defined type of CP. The frequency of epilepsy was higher in affected CP children who showed major motor dysfunction (GMFCS IV-V types). As regards the 46 children with CP plus epilepsy, compared to the group of the control, the age of epilepsy onset was found to be statistically significant: 21 ± 35.1 months vs. 67 ± 39.7.

Conclusions: Epilepsy represents one of the most frequent comorbidities of cerebral palsy. In children with CP, particular attention should be paid to the early identification and treatment of comorbid epilepsy.

Design and Implementation of Electronic Health Record Common Data Elements for Pediatric Epilepsy: Foundations for a Learning Health Care System

Abstract, originally published in Epilepsia

Objective: Common data elements (CDEs) are standardized questions and answer choices that allow aggregation, analysis, and comparison of observations from multiple sources. Clinical CDEs are foundational for learning health care systems, a data-driven approach to health care focused on continuous improvement of outcomes. We aimed to create clinical CDEs for pediatric epilepsy.

Methods: A multiple stakeholder group (clinicians, researchers, parents, caregivers, advocates, and electronic health record [EHR] vendors) developed clinical CDEs for routine care of children with epilepsy. Initial drafts drew from clinical epilepsy note templates, CDEs created for clinical research, items in existing registries, consensus documents and guidelines, quality metrics, and outcomes needed for demonstration projects. The CDEs were refined through discussion and field testing. We describe the development process, rationale for CDE selection, findings from piloting, and the CDEs themselves. We also describe early implementation, including experience with EHR systems and compatibility with the International League Against Epilepsy classification of seizure types.

Results: Common data elements were drafted in August 2017 and finalized in January 2020. Prioritized outcomes included seizure control, seizure freedom, American Academy of Neurology quality measures, presence of common comorbidities, and quality of life. The CDEs were piloted at 224 visits at 10 centers. The final CDEs included 36 questions in nine sections (number of questions): diagnosis (1), seizure frequency (9), quality of life (2), epilepsy history (6), etiology (8), comorbidities (2), treatment (2), process measures (5), and longitudinal history notes (1). Seizures are categorized as generalized tonic-clonic (regardless of onset), motor, nonmotor, and epileptic spasms. Focality is collected as epilepsy type rather than seizure type. Seizure frequency is measured in nine levels (all used during piloting). The CDEs were implemented in three vendor systems. Early clinical adoption included 1294 encounters at one center.

Significance: We created, piloted, refined, finalized, and implemented a novel set of clinical CDEs for pediatric epilepsy.

Are You Tuned In? The Challenges of Seizure Identification in Children with Intellectual Disability: A Potential for Video-Based Care-Pathway

Abstract, originally published in Epilepsy & Behavior

This qualitative study explores the challenges parents/carers face in seizure identification in children with coexisting epilepsy and intellectual disability (ID).

Semi-structured interviews with parents/carers provided ten hours of data, transcribed verbatim for data analysis. Themes and subthemes were identified and grouped to reflect the findings. The importance of knowing the child’s usual behavior and recognizing changes to this was a consistent theme. All participants reported that being ‘in tune’ with their child helped in seizure recognition. Participants felt that the healthcare professionals (HCP) were poor at recognizing seizures in their children at times. They had mixed thoughts on the difficulty the presence of an ID contributes to seizure recognition. The severity of ID and the seizure type were the two main variables discussed.

The study concludes that knowing the child well and understanding the usual behavior of the child is crucial to seizure recognition. A video-based care pathway with videos of both usual behavior and seizure activity available to the HCP to classify the events correctly may be potentially beneficial to improve patient care.

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.

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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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Educational Interventions Improving Knowledge About Epilepsy in Preschool Children

Abstract, originally published in Epilepsy & Behavior

Objective: Sufficient public knowledge about epilepsy is a starting point for reducing epilepsy-related stigma and improving quality of life of people with this condition. Thus, interventions aimed at improving such knowledge are greatly needed. However, there is a significant lack of such interventions and none have been applied to preschool children. We aimed to develop effective interventions using the educational board game Action Zone! and a technique known as educational story, and by focusing on the acquisition of knowledge about epilepsy in children aged 5-6 years with no previous knowledge of epilepsy.

Methods: Knowledge about epilepsy was measured using a 20-item test consisting of questions selected from educational game and an 11-item test used successfully in our previous intervention study focused on children aged 9-11 years. Both measures exhibited acceptable internal consistency with Cronbach’s alpha of 0.72 and 0.67. In total, 296 children participated in three intervention studies (educational game, educational story, and a revised version of educational story). Level of knowledge was assessed immediately after each intervention and again one month later.

Results: We found that all interventions were effective (p = 0.001) in comparison of retest results with baseline of zero level of knowledge based on the statements of children before intervention. Intervention based on educational game resulted in a higher percentage of correct responses in comparison with educational story (p = 0.020). However, the revised version of educational story developed using participatory action research was superior in comparison with the original version (p < 0.001) and fully comparable with educational game (p = 0.864).

Conclusions: The results showed the aforesaid interventions were significant and effective ways to establish basic knowledge about epilepsy in the given age group.

Usefulness, Limitations, and Parental Opinion about Teleconsultation for Rare Pediatric Epilepsies

Abstract, originally published in Epilepsy & Behavior

Aim: Evaluation of the usefulness and the parental opinion about teleconsultation (TC) for rare pediatric epilepsies.

Method: One-month prospective survey of consecutive TCs. All clinics on site have been turned into TC in the context of COVID-19 pandemic. The physicians quoted all TCs while the parents expressed their opinion though an invitation for an online questionnaire.

Results: We included 151 TCs (145 patients) among the 259 epilepsy TCs done during the study period. The parental questionnaire has been answered 105 times. The physicians felt confident to organize a TC for the next visit of 74.8% of the children, but some limits were identified such as the absence of physical examination, weight, and psychomotor development evaluation. The physicians felt more confident for a new TC in older patients (9.5 ± 5.5 years versus 5.3 ± 4.3 years) and in stable patients (73.8% confident for instable, 82.8% for stable). Parents were satisfied with TC feeling that it answered health issues in a better manner than a clinic pinpointing the gain of time and the absence of travel. However, half of them would prefer a clinic for the next appointment.

Interpretation: Teleconsultation seems useful answering the patients’ needs according to both physicians and families. Despite some limitations, it is most likely that TCs become a new part of the clinical activities in rare pediatric epilepsy centers.

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.

Learn more

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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