Epilepsy Research News: September 2023

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

 

 

The Cerebellum as a Source of Generalized Convulsive Seizures

A recent study provides new insights into how convulsive seizures happen, implicating a “circuit” in the brain, specifically a connection of neurons between the cerebellum and thalamus, in driving convulsive seizures. To investigate the importance of this circuit in causing seizures, the team utilized a technique called optogenetic imaging to record the activity of neurons in the brain before, during, and after convulsive seizures. The team found that a group of neurons in a specific area of the thalamus called the ventral posteromedial nucleus were initiating convulsive seizures. The team then found that neurons in the cerebellum that connect to this area of the thalamus not only significantly contribute to the seizures, but that blocking activity from the cerebellum to the thalamus blocked seizures from occurring. The team noted that the findings not only deepen the understanding of how seizures originate but also create the possibility of targeting this cerebellum-thalamus circuit to treat convulsive seizures.

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Examining the Benefit of Rapid Genome Sequencing for Infantile Epilepsy

A recent study shows that rapid genome sequencing (a process that looks for changes across the entire genome) can provide a rapid diagnosis of genetic mutations and influence clinical care of infants with new-onset epilepsy. As part of this study, researchers sequenced the genomes of 100 infants with unexplained seizures along with their parents to better understand the potential diagnostic value of this approach for infantile epilepsy. The researchers found that across all children enrolled in the study, 43% received a diagnosis within weeks, and that diagnosis impacted the medical outcomes in nearly 90% of those cases, guiding treatment options for over half. This study provides an initial framework for further investigation of the long-term benefits of early genetic diagnosis in infants, and the potential use of targeted “precision” treatments that are specific to an infant’s genetic diagnosis.

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Large Genetic Study Provides Insights on Why Epilepsy Develops and Potential Treatments

The largest genetic study of its kind has discovered specific changes in our DNA that increase the risk of developing epilepsy. The research advances our knowledge of why epilepsy develops and may inform the development of new treatments for the condition. The researchers identified 26 distinct areas in our DNA that appear to be involved in epilepsy. This included 19 which are specific to a particular form of epilepsy called genetic generalized epilepsy. They were also able to identify 29 genes within these DNA regions that probably contribute to epilepsy. The researchers also showed that many of the current medications for epilepsy work by targeting the same epilepsy risk genes that were highlighted in the study. Furthermore, based on their data, the researchers were able to propose some potentially effective alternative drugs. The researchers noted that these discoveries, only achieved through international collaboration, help us to better understand the genetics of this type of epilepsy and potential treatments.

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Preventive Epilepsy Treatment with Vigabatrin Does Not Improve Neurocognitive Development in Infants with Tuberous Sclerosis Complex (TSC)

In new study results, researchers found that administering the preventive epilepsy treatment vigabatrin (Sabril ®) prior to seizure onset did not improve neurocognitive outcomes in TSC infants at two years of age. In the original results, this study (known as the PREVeNT trial) showed that preventative treatment delayed the start and lowered the number of infantile spasms in infants with TSC. This study enrolled 84 infants with TSC between 2016 and 2020, who had been diagnosed with TSC either through prenatal testing, physical examination, or genetic testing, but had yet to have any seizures. Infants who developed a specific EEG biomarker that indicates a risk of developing seizures were then placed in two groups, one receiving preventative vigabatrin treatment and one receiving a placebo. In this new study, the researchers found that infants who received vigabatrin still had drug-resistant epilepsy at 24 months, that focal seizures remained prominent in the infants, and there was no benefit in cognitive outcomes. The researchers state that these findings indicate the need to develop more effective therapies to treat cognitive and behavioral dysfunction in TSC.

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Advances in Cannabidiol (CBD) for Epilepsy Treatment and Prevention

A series of recently published articles details new breakthroughs in the field of medical cannabinoids for epilepsy and seizure disorders. Two publications review the effectiveness of CBD, a compound found in cannabis, in treating epilepsy and seizures. Another publication in the series describes the results of a meta-analysis (a type of study that reviews and combines the results of multiple other studies) to determine the overall effectiveness and safety of CBD treatment in children with genetic epilepsies such as Dravet syndrome, Lennox-Gastaut syndrome, and Tuberous Sclerosis Complex. This analysis revealed that CBD was effective in managing these genetic epilepsies, albeit with an increase in adverse events such as diarrhea, somnolence, sedation, and potential drug interactions. A separate publication showed potential effects of CBD as a prevention against seizures that are similar to those associated with temporal lobe epilepsy. Together, these publications provide information on the use of CBD in the treatment of epilepsy and open up the possibility of utilizing CBD in individuals at risk for developing epilepsy.

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CDKL5-Mediated Developmental Tuning of Neuronal Excitability and Concomitant Regulation of Transcriptome

Abstract found on PubMed

Cyclin-dependent kinase-like 5 (CDKL5) is a serine-threonine kinase enriched in the forebrain to regulate neuronal development and function. Patients with CDKL5 deficiency disorder (CDD), a severe neurodevelopmental condition caused by mutations of CDKL5 gene, present early-onset epilepsy as the most prominent feature. However, spontaneous seizures have not been reported in mouse models of CDD, raising vital questions on the human-mouse differences and the roles of CDKL5 in early postnatal brains. Here, we firstly measured electroencephalographic (EEG) activities via a wireless telemetry system coupled with video-recording in neonatal mice. We found that mice lacking CDKL5 exhibited spontaneous epileptic EEG discharges, accompanied with increased burst activities and ictal behaviors, specifically at postnatal day 12 (P12). Intriguingly, those epileptic spikes disappeared after P14. We next performed an unbiased transcriptome profiling in the dorsal hippocampus and motor cortex of Cdkl5 null mice at different developmental timepoints, uncovering a set of age-dependent and brain region-specific alterations of gene expression in parallel with the transient display of epileptic activities. Finally, we validated multiple differentially expressed genes (DEGs), such as glycine receptor subunit 2 and cholecystokinin, at the transcript and/or protein levels, supporting the relevance of these genes to CDKL5-regulated excitability. Our findings reveal early-onset neuronal hyperexcitability in mouse model of CDD, providing new insights into CDD etiology and potential molecular targets to ameliorate intractable neonatal epilepsy.

CURE Epilepsy Update September 2023

Greetings Epilepsy Community,

There is no other way to start this Update than with a thank you. CURE Epilepsy has been busy these past few weeks with everything from our webinar on Jeavons syndrome to our first-ever Epilepsy Awareness Night with the Chicago White Sox to our virtual event UNITE to CURE Epilepsy, which culminated with a Day of Giving on the anniversary of our founding 25 years ago. So many of you participated in UNITE to CURE Epilepsy (and if you were unable to attend live, you can still watch the recordings here), families joined the CURE Epilepsy community at the Chicago White Sox game to raise epilepsy awareness and have a night of fun, and 177 donors from 38 states helped us raise money to find a cure during our Day of Giving. If you look at the map below and see your state has not yet given, make a donation to help us color it in so that we have all 50 states represented!

Thank you to our entire community. Whether you attended any of our recent events, made a donation, or helped spread awareness, you made a difference in the lives of those living with epilepsy and have helped drive us closer to finding a cure.

With a commitment to inspire hope and deliver impact.


In this CURE Epilepsy Update, please find information on:


Thank You for Helping Us Reach Over $80K During Our Day of Giving

Thanks to the generous support of our donors, individuals from 38 states have helped bring us closer to finding a cure for epilepsy. There is still time to make a gift and through our generous donor match, your gift will go three-times as far! Donate $25 and we will get $75. Donate $100 and we will get $300!

 

 

Make a Gift

 


ReSearching to CURE Epilepsy Report

Read our latest ReSearching to CURE Epilepsy report to see the impact CURE Epilepsy has had on the epilepsy community over the past 25 years and the research we are funding to help us find a cure.

 

 

 

See CURE Epilepsy’s Impact

 


My Shot at Epilepsy Hamilton Raffle – Coming Soon!

Miguel Cervantes will wrap up his incredible run as Broadway’s Hamilton early next year, so don’t throw away your shot to see him perform One Last Time! You’ll be able to enter for your chance to win tickets to see the Tony Award-winning musical in New York City and meet Miguel after the show. Raffle tickets will be available for purchase soon, so stay tuned for details!

 

 

Learn More

 


Epilepsy Discovery: CURE Epilepsy’s Efforts Lead to an Increased Understanding of Epilepsy with Eyelid Myoclonia (EEM), Formerly Known as Jeavons Syndrome

To better understand the clinical symptoms and treatment of Epilepsy with eyelid myoclonia (EEM), formerly known as Jeavons syndrome, CURE Epilepsy convened a panel of expert neurologists and individuals with lived experience to summarize existing knowledge, develop consensus about the diagnostic approach and clinical management, and identify areas where further study is needed.

 

Read Discovery

 


Limited Tickets Available for Hamilton Unplugged in New York

Get your tickets now for Hamilton Unplugged on October 23 in NYC. Join Broadway star Miguel Cervantes, the longest-running lead of Hamilton starring in both Chicago and New York City, for a special, interactive evening of conversation and song. This intimate gathering of only 200 guests will feature an exclusive performance by Miguel and some of his friends with proceeds going to CURE Epilepsy.

 

Learn More

 


Miss UNITE to CURE Epilepsy 2023? Check Out the Recordings!

Did you miss our annual virtual event UNITE to CURE Epilepsy? Check out the recordings of the live events, resources, and more here!

 

 

 

Event Site

 


 

What’s New from the Seizing Life® Podcast

A Young Woman’s Journey with Jeavons Syndrome

 

Recent college graduate and CURE Epilepsy’s Marketing and Communications summer intern, Kiley Flowers, joins us to talk about Jeavons syndrome and share her personal journey with this rare form of generalized epilepsy.

Watch or Listen

 

 

Pursuing Effective Epilepsy Treatment and Running for Research

 

Clare Phelps shares the difficult diagnosis and frustrating treatment journey of her young daughter Sophie, whose epilepsy has so far been treatment resistant.

 

Watch or Listen

 

 

 

Watch these and all of our upcoming Seizing Life episodes here.


The CURE Epilepsy Store

 

Check out the CURE Epilepsy Store to get apparel or accessories to raise epilepsy awareness!

 

 

 

 

Shop Now


Please mark your calendar for the following key dates in the epilepsy community:

  • January 1 – December 31, 2023 – CURE Epilepsy’s 25th Anniversary
  • October 18 – SUDEP Action Day
  • October 31- November 1 – Epilepsy Awareness Day at Disneyland
  • November – Epilepsy Awareness Month
  • November 13 – Jeavons Syndrome Awareness Day
  • December 1-7 – Infantile Spasms Awareness Week

 

1 in 26 individuals will be impacted by epilepsy in their lifetime.
Each person has their own story.

Read Kiley’s Story

 

CURE Epilepsy Discovery: CURE Epilepsy’s Efforts Lead to an Increased Understanding of Epilepsy with Eyelid Myoclonia (EEM)

Key Points

  • Epilepsy with eyelid myoclonia (EEM) is a type of absence epilepsy that was formerly known as Jeavons syndrome; its main characteristic is eyelid myoclonia (a brief jerking of the eyelids that may manifest with or without absence seizures).
  • The symptoms of EEM may be confused with ocular tics and many characteristics overlap with other epilepsy syndromes, so this form of epilepsy is routinely misdiagnosed.
  • To better understand the clinical manifestations and treatment of EEM, CURE Epilepsy convened a panel of EEM expert neurologists and individuals with EEM lived experience to summarize existing knowledge, develop consensus about the diagnostic approach and clinical management of EEM and identify areas where further study is needed.
  • Several areas of consensus were identified, e.g., the use of electroencephalogram (EEG) to diagnose EEM, the recommendation for genetic testing if an individual has a family history of epilepsy, and the use of valproic acid as a first-line therapy (except in women of childbearing age) to manage EEM.

 

Deep Dive  

Epilepsy with eyelid myoclonia (EEM), formerly called Jeavons syndrome, is a generalized epilepsy syndrome (meaning that all areas of the brain are impacted by abnormal electrical activity). Onset of EEM is in childhood and affects girls more than boys. There are three main characteristics of EEM; the first and hallmark symptom of EEM is eyelid myoclonia – a brief but intense and repeated jerking of the eyelids followed by the eyeballs rolling up that may be present with or without absence seizures. The second characteristic is eye closure-induced or bright and/or flickering light-induced seizures or EEG paroxysms which are abnormal EEG patterns, and the third is photosensitivity.[1] While seizures in EEM may be as short as six seconds, they typically occur many times a day. Around one-third of people with EEM have a positive family history of epilepsy, and recently, mutations in specific genes have also been found.[1]

Although EEM was first documented in 1977,[2] the condition still is frequently underrecognized and there are delays in diagnosis.[1] EEM is a rare condition and its prevalence (the proportion of people who have EEM at a given time) in people with epilepsy is unclear but past estimates suggest it accounts for up to 2.7% of people seen at epilepsy centers.[3-5] Currently, EEM is diagnosed using routine EEG, and people with EEM have a unique EEG pattern that is characteristic of this syndrome.[6, 7] The average age of onset of EEM is 6-8 years of age [8, 9]; however, the exact time of seizure onset is difficult to establish, as eyelid jerks are routinely discounted as behavioral mannerisms.8 Indeed, the average length of time to diagnosis of EEM is reported to be delayed by as much as 9.6 years,[10] and more than 70% of patients were diagnosed with another epilepsy syndrome [10] or tics.[11] The potential for intellectual disability associated with EEM has been reported. Furthermore, issues such as irritability, anxiety, and psychosis may be seen, but knowledge about intellectual ability and psychiatric comorbidities in patients with EEM is limited.[12]

Current treatment strategies for EEM are informed by small studies; the first line of treatment consists of broad-spectrum anti-seizure medications (ASMs).[13] However, resistance to ASMs is common.[14] While for many individuals EEM persists into adulthood, it is not known whether the clinical characteristics remain the same, change, or worsen with age. 

Recently, the International League Against Epilepsy (ILAE) updated the classification of epilepsy syndromes to include EEM as a generalized epilepsy syndrome of childhood with a genetic cause.[3] This, combined with the recent advances in epilepsy genetics made it an opportune time to revisit the understanding of the syndrome and develop consensus on the approach to clinical diagnosis and treatment of EEM.[13] CURE Epilepsy convened an international steering committee of EEM experts and used a modified Delphi process to survey experts around the world to develop a better understanding of the clinical presentation of EEM and establish best practices for its management.

The committee reviewed current literature and brought together a panel of 25 physicians and five individuals with lived experiences of EEM (patients and caregivers) to participate in the modified Delphi process, which consisted of three rounds of consensus-building surveys. The Delphi method is used in the medical field as a way to gather knowledge in a field, develop consensus or solve a complex problem.[15] This initiative led to three separate publications: a literature review, a summary of the clinical presentation and approach to diagnosis EEM,[13] and consensus on the treatment and management of EEM.[16]

Clinical presentation of EEM:

There was strong consensus among experts that EEM affects predominantly females and that it is a generalized epilepsy syndrome with an onset at three to 12 years of age. There was strong agreement that eyelid myoclonia must be present to make a diagnosis of EEM. The experts reiterated that eyelid myoclonia may go unnoticed for many years before a diagnosis of epilepsy is made. Absence seizures or generalized tonic-clonic seizures are seen with EEM, and EEG is critical for diagnosis. Experts recommend genetic testing when one or more of these factors is present: 1. a family history of epilepsy, 2. intellectual disability, and 3. seizures that do not respond to ASMs (drug-resistant epilepsy).[13]

All patients and caregivers mentioned stress and sleep deprivation as triggers for their seizures; they also reported that the uncontrolled eyelid myoclonia seen in EEM affects them in social and psychological settings (e.g., bullying in school). Given this, there was a strong recommendation that physicians working with people who have EEM should inquire whether their patients are experiencing psychosocial impacts.[13] Since there is not a lot known about psychosocial issues in EEM, it was recommended as an area of further investigation and research.[13]

Medical management of EEM:

In this area, there was strong consensus that valproic acid be used as the first-line treatment and that levetiracetam or lamotrigine be used as alternatives for women of childbearing age. There was strong consensus to avoid sodium channel-blocking medications (except for lamotrigine).[16] It was recognized that seizures usually continue into adulthood and that remission occurs in less than half of patients. The panel also stated that some individuals have a milder course of EEM and that they may not require ASMs at all.[16] Two manifestations of EEM emerged: one group of individuals had seizures at an earlier age, exhibited intellectual disability, and had more frequent generalized tonic-clonic seizures and/or drug-resistant epilepsy. In contrast, individuals with seizures starting at a later age and who did not have intellectual disability were likely to respond to ASM therapy.[16] For issues such as driving there was no consensus among panelists about whether patients with uncontrolled eyelid myoclonia alone should be advised not to drive, but there was a strong consensus that EEG should be used when making determinations about driving candidacy as interictal epileptiform discharges on EEG have been shown to affect driving ability.

In conclusion, the international panel convened by CURE Epilepsy identified areas of consensus regarding the clinical presentation of EEM and ways to optimally manage seizures. Areas of minimal consensus were also revealed; these include the presence of psychosocial issues, matters related to driving, and potential dietary therapies that may be beneficial in EEM. It was also discussed that there may be variability in how EEM is diagnosed worldwide, given that features of EEM are seen in other epilepsy syndromes as well.[8] These topics of further research could inform clinical trials and the development of novel therapies. 

Click here to watch the recording or read the transcript for our webinar on EEM/Jeavons syndrome that took place on September 15, 2023.

 

Literature Cited:

  1. Smith KM, Wirrell EC, Andrade DM, Choi H, Trenité DK, Knupp KG, et al. A comprehensive narrative review of epilepsy with eyelid myoclonia Epilepsy Res. 2023 Jul;193:107147.
  2. Jeavons PM. Nosological problems of myoclonic epilepsies in childhood and adolescence Dev Med Child Neurol. 1977 Feb;19:3-8.
  3. Specchio N, Wirrell EC, Scheffer IE, Nabbout R, Riney K, Samia P, et al. International League Against Epilepsy classification and definition of epilepsy syndromes with onset in childhood: Position paper by the ILAE Task Force on Nosology and Definitions Epilepsia. 2022 Jun;63:1398-1442.
  4. Jonsson P, Eeg-Olofsson O. 10-year outcome of childhood epilepsy in well-functioning children and adolescents Eur J Paediatr Neurol. 2011 Jul;15:331-337.
  5. Asadi-Pooya AA, Homayoun M. Idiopathic (genetic) generalized epilepsies with absences: clinical and electrographic characteristics and seizure outcome Neurol Sci. 2020 Dec;41:3677-3682.
  6. Giannakodimos S, Panayiotopoulos CP. Eyelid myoclonia with absences in adults: a clinical and video-EEG study Epilepsia. 1996 Jan;37:36-44.
  7. Joshi CN, Patrick J. Eyelid myoclonia with absences: Routine EEG is sufficient to make a diagnosis Seizure. 2007 2007/04/01/;16:254-260.
  8. Striano S, Capovilla G, Sofia V, Romeo A, Rubboli G, Striano P, et al. Eyelid myoclonia with absences (Jeavons syndrome): a well-defined idiopathic generalized epilepsy syndrome or a spectrum of photosensitive conditions? Epilepsia. 2009 May;50 Suppl 5:15-19.
  9. Reyhani A, Özkara Ç. Pitfalls in the diagnosis of Jeavons syndrome: a study of 32 cases and review of the literature Epileptic Disord. 2020 Jun 1;22:281-290.
  10. Smith KM, Youssef PE, Wirrell EC, Nickels KC, Payne ET, Britton JW, et al. Jeavons Syndrome: Clinical Features and Response to Treatment Pediatr Neurol. 2018 Sep;86:46-51.
  11. Madaan P, Jauhari P, Chakrabarty B, Gulati S. Jeavons Syndrome: An Overlooked Epilepsy Syndrome Pediatric Neurology. 2019 2019/04/01/;93:63.
  12. Nilo A, Crespel A, Genton P, Macorig G, Gigli GL, Gelisse P. Epilepsy with eyelid myoclonias (Jeavons syndrome): An electro-clinical study of 40 patients from childhood to adulthood Seizure. 2021 Apr;87:30-38.
  13. Smith KM, Wirrell EC, Andrade DM, Choi H, Trenité DK, Jones H, et al. Clinical presentation and evaluation of epilepsy with eyelid myoclonia: Results of an international expert consensus panel Epilepsia. 2023 Jun 16.
  14. Zawar I, Toribio MGG, Xu X, Alnakhli RS, Benech D, Valappil AMN, et al. Epilepsy with Eyelid myoclonias ? A diagnosis concealed in other genetic generalized epilepsies with photoparoxysmal response Epilepsy Research. 2022 2022/03/01/;181:106886.
  15. Niederberger M, Spranger J. Delphi Technique in Health Sciences: A Map Front Public Health. 2020;8:457.
  16. Smith KM, Wirrell EC, Andrade DM, Choi H, Trenité DK, Jones H, et al. Management of epilepsy with eyelid myoclonia: Results of an international expert consensus panel Epilepsia. 2023 Jun

New GABA-Targeting Therapies for the Treatment of Seizures and Epilepsy: II. Treatments in Clinical Development

Abstract found on PubMed

The inhibitory neurotransmitter ?-aminobutyric acid (GABA) plays an important role in the modulation of neuronal excitability, and a disruption of GABAergic transmission contributes to the pathogenesis of some seizure disorders. Although many currently available antiseizure medications do act at least in part by potentiating GABAergic transmission, there is an opportunity for further research aimed at developing more innovative GABA-targeting therapies. The present article summarizes available evidence on a number of such treatments in clinical development. These can be broadly divided into three groups. The first group consists of positive allosteric modulators of GABAA receptors and includes Staccato® alprazolam (an already marketed benzodiazepine being repurposed in epilepsy as a potential rescue inhalation treatment for prolonged and repetitive seizures), the ?2/3/5 subtype-selective agents darigabat and ENX-101, and the orally active neurosteroids ETX155 and LPCN 2101. A second group comprises two drugs already marketed for non-neurological indications, which could be repurposed as treatments for seizure disorders. These include bumetanide, a diuretic agent that has undergone clinical trials in phenobarbital-resistant neonatal seizures and for which the rationale for further development in this indication is under debate, and ivermectin, an antiparasitic drug currently investigated in a randomized double-blind trial in focal epilepsy. The last group comprises a series of highly innovative therapies, namely GABAergic interneurons (NRTX-001) delivered via stereotactic cerebral implantation as a treatment for mesial temporal lobe epilepsy, an antisense oligonucleotide (STK-001) aimed at upregulating NaV1.1 currents and restoring the function of GABAergic interneurons, currently tested in a trial in patients with Dravet syndrome, and an adenoviral vector-based gene therapy (ETX-101) scheduled for investigation in Dravet syndrome. Another agent, a subcutaneously administered neuroactive peptide (NRP2945) that reportedly upregulates the expression of GABAA receptor ? and ? subunits is being investigated, with Lennox-Gastaut syndrome and other epilepsies as proposed indications. The diversity of the current pipeline underscores a strong interest in the GABA system as a target for new treatment development in epilepsy. To date, limited clinical data are available for these investigational treatments and further studies are required to assess their potential value in addressing unmet needs in epilepsy management.