Epilepsy is present in 4% of the population, and is among the most common brain disorders in children. Modern medicine can prevent most seizure recurrences, but approximately 20% of patients do not respond to treatment. In these cases, the reason may originate in patches of damaged or abnormal brain tissue known as “malformations of cortical development” (MCD), which results in a diverse group of neurodevelopment disorders.
Surgical resection or removal of the patch can cure the seizures, and epilepsy surgery to improve neurological outcomes is now a key part of the modern medical armamentarium, but what causes the patches has largely remained a mystery.
Writing in the January 12, 2023 issue of Nature Genetics, researchers at University of California San Diego School of Medicine and Rady Children’s Institute for Genomic Medicine, collaborating with an international consortium of more than 20 children’s hospitals worldwide, report a significant breakthrough in understanding the genetic causes of MCD.
The team conducted intensive genomic discovery using state-of-art somatic mosaic algorithms developed by the National Institutes of Health-sponsored Brain Somatic Mosaicism Network, of which UC San Diego is a member.
“We tried our best to detect mutations in as little as 1 percent of cells,” said co-first author Xiaoxu Yang, PhD, a postdoctoral scholar in Gleeson’s lab. “Initially we failed. To solve these problems, we needed to develop novel artificial intelligence methods to overcome barriers in sensitivity and specificity.”
The team ultimately identified 69 different genes carrying somatic brain mutations, the majority of which have never previously reported in MCD.
Georgia Cook, PhD, Department of Psychology, Health and Professional Development, Centre for Psychological Re search, Faculty of Health and Life Sciences, Oxford Brookes University, and investigators aimed to understand the experience of parents with children who live with epilepsy. These children often face issues with sleep, but there’s very little insight on how parents and caretakers are affected, or how they manage the sleep disturbances of their children.
The neurological condition is characterized by recurrent seizures, with 0.32%–0.55% of children under the age of 18 having a diagnosis. In addition to problems with sleep, it’s also common for these children to have behavioral, cognitive, attention, academic, and psychosocial deficits, which has been shown to reduce their quality of life when compared with those who don’t have epilepsy.
According to this study, sleep and epilepsy have a complex and bidirectional relationship and have been described as ‘unfortunate bedfellows’. Epilepsy exacerbates the struggle to initiate sleep (settling and falling asleep), maintenance of sleep (experiencing night or early morning wakings), duration of sleep, daytime sleepiness and sleep anxiety.
The qualitative investigation included interviews of 9 mothers from 2018. The focus was to capture parental perceptions and experiences related to their child’s sleep habits, their management, the impact of sleep difficulties on the child and their family, and available support.
“Mothers were aware of the links between sleep and seizures, yet felt that they lacked guidance about how to address or improve their child’s sleep, including from their healthcare teams,” they wrote. “This appeared to heighten maternal anxieties and feelings of ‘helplessness’. This finding emphasizes the need to ensure adequate help and support is available to help support healthy sleep in children with epilepsy, as identified in previous work.”
Adolescents with epilepsy (AWE) commonly experience emotional and behavioral problems, which vary depending on demographic, clinical, and parental factors, according to a study published in Epilepsy & Behavior from the Korean Quality of Life in Epilepsy Study Group. The parental factors included how they perceived others treated their child.
Due to these findings, the study authors emphasized it is crucial to identify and properly manage these problems early to decrease comorbid psychopathology in AWE.
The cross-sectional multicenter study included 289 adolescents—180 boys and 109 girls—aged between 11 and 18 years, with a mean (SD) age of 15.4 (1.9) years.
The authors explained that psychopathology among this group was evaluated using the Youth Self-Report scale, consisting of 8 narrowband and 3 broadband syndrome scales, and the raw score and T-score of each syndrome scale was analyzed.
The study found 18.3% of AWE had at least 1 emotional or behavioral problem in the clinical range.
Social problems were most common (10.0%), followed by attention problems (6.9%) and aggressive behaviors (4.2%), and externalizing problems (11.8%) were twice as common as internalizing problems (6.2%).
Consistent with findings of prior studies, this study showed 1 in 4 parents of AWE said they perceived that other people felt uncomfortable with their child, treated their child as inferior, or preferred to avoid their child because of their epilepsy.
“Adolescents whose parents perceived stigma had higher levels of all types of emotional and behavioral problems, except for withdrawal and anxiety/depression than those whose parents perceived no stigma,” the authors explained further. “Specifically, these adolescents were more likely to have externalizing problems and social problems.”
CURE Epilepsy is honored to announce our newest CURE Epilepsy grantees. Our research grants are awarded for cutting-edge, novel research projects that seek to accelerate treatments, improve outcomes, and get us to cures so that we can live in a world free of seizures. This year’s grantees’ research will focus on a wide range of epilepsies – sudden unexpected death in epilepsy (SUDEP), sleep and epilepsy, genetic causes of epilepsy, Lafora disease, post-traumatic epilepsy, pediatric epilepsy, and focal epilepsy.
TAKING FLIGHT AWARD GRANTEES – $100,000 for one year
This award seeks to promote the careers of early-career epilepsy investigators to allow them to develop a research focus independent of their mentor(s).
Jeffrey Calhoun, PhD Northwestern University – Chicago, Illinois
With this grant, funded by the Joseph Gomoll Foundation, Dr. Calhoun’s research will work to develop a new method to assess the functionality of variants of the SCN1A gene. Learn More
William Tobin, PhD The University of Vermont and State Agriculture – Burlington, Vermont
With a grant co-funded by the KCNT1 Epilepsy Foundation, Dr. Tobin will test strategies to optimize cutting-edge gene therapy methods for the gene KCNT1. Learn More
Gerben van Hameren, PhD
Dalhousie University– Nova Scotia, Canada
Dr. van Hameren will study a possible way to prevent the development of post-traumatic epilepsy. Learn More
CURE EPILEPSY AWARD GRANTEES – $250,000 over two years
This award reflects CURE Epilepsy’s continued focus on scientific advances that have the potential to truly transform the lives of those affected by epilepsy, with prevention and disease modification as critical goals.
Gordon Buchanan, MD, PhD University of Iowa Medicine – Iowa City, Iowa
For this grant, generously funded by The Joanna Sophia Foundation, Dr. Buchanan’s group will examine whether a signaling molecule called serotonin drives a time-of-day vulnerability to SUDEP (Sudden Unexpected Death in Epilepsy). Learn More
Annaelle Devergnas, PhD Emory University – Atlanta, Georgia
The hypothesis for Dr. Devergnas’ project is that frontal seizures disrupt the normal function of the brain structure called the pedunculopontine nucleus (PPN), leading to changes in sleep, and that manipulating PPN activity might restore normal sleep activity. Learn More
Juliet Knowles, MD, PhD Stanford School of Medicine – Palo Alto, California
For this project, Dr. Knowles and her team will study the therapeutic potential for targeting myelin plasticity in Lennox-Gastaut syndrome. Learn More
CATALYST AWARD GRANTEES – $250,000 over two years
The CURE Epilepsy Catalyst Award stimulates and accelerates the development of new, transformative therapies for epilepsy, moving promising preclinical and/or clinical research closer to clinical application.
James Pauly, PhD, Greg Gerhardt, PhD, and Matthew Gentry, PhD University of Kentucky – Lexington, Kentucky
In collaboration with Enable Therapeutics, Drs. Pauly, Gerhardt, and Gentry developed a potential drug called VAL-1221 that can penetrate brain cells and degrade the aberrant sugar aggregates therein that cause LaFora disease. Having obtained promising initial results, this project will test the safety and brain distribution of this novel therapy. Learn More
John Gledhill, PhD Cognizance Biomarkers, LLC – Philadelphia, Pennsylvania
Dr. Gledhill and the team at Cognizance will build upon their preliminary research showing that people with treatment-resistant epilepsy have differences in inflammation-associated proteins in the blood compared with those who do respond to treatment. For this project, the team proposes to extend their observations by assessing additional blood samples from treatment-resistant and treatment-responsive people with epilepsy and developing an algorithm to predict response to initial anti-seizure medications. Learn More
Purpose: To ascertain the rates of 30-day readmissions and emergency department presentations among pediatric patients with an index admission for functional seizures.
Method: A retrospective chart review of pediatric patients with an index discharge from the pediatric epilepsy monitoring unit (EMU) or general neurology service for functional seizures. Data collected included demographics, comorbidities, risk factors, and treatment during the index admission.
Results: A total of one hundred and two patients were included, of which nearly one in five had a 30-day readmission or emergency department presentation. Index admission to the general neurology service was independently associated with more re-presentations to the hospital (t = 3.26, p < 0.0015). The univariate analysis indicated that cognitive impairment and autism were associated with a lower likelihood of readmission, while a neurology referral and being started on an anti-seizure medication were associated with a greater likelihood of readmission.
Conclusion: A substantial proportion of pediatric patients with functional seizures return to the hospital within 30 days of discharge. Our data suggest that patients admitted to the epilepsy monitoring unit (Emu) service have a lower likelihood of readmission. We speculate that this may be due to differences in patient clinical characteristics as well as the comprehensiveness of the diagnostic evaluation and management in the EMU compared to the general neurology service.
Objective: Many seizing neonates fail to respond to first-line anticonvulsant medications. Phenobarbital, an allosteric modulator of GABAA receptors, has low efficacy in treating neonatal seizures and causes neuronal apoptosis [cell death]. Yet, it is one of the most used anticonvulsants in this age group. In neonatal mice, phenobarbital’s poor effectiveness is due in part to high intraneuronal chloride concentration, which causes GABA to exert depolarizing actions. Therefore, another approach to treat neonatal seizures could be to use anticonvulsants that do not rely on GABAergic modulation. We evaluated if lacosamide decreases seizures in neonatal mice and if it increases apoptosis in vitro and in vivo.
Methods: In vitro, we measured the effect of different lacosamide concentrations on seizure-like activity induced by the pro-convulsant drug 4-aminopyridine in neocortical brain slices (layer IV/V) from neonatal (postnatal day P8-11) and adult (1-1.6-months-old) C57BL/6J mice. In vivo, we recorded the effect of different lacosamide concentrations on neonatal behavioral seizures induced by kainic acid. We studied neocortical apoptosis in vitro and in vivo, measuring TUNEL signal and cleaved-caspase 3.
Results: Lacosamide reduced epileptiform activity in neocortical brain slices of neonates and adults in a concentration-dependent manner. In vivo, lacosamide reduced the duration and number of behavioral seizures. Lacosamide did not increase total or neuronal apoptosis in the neocortex in vitro or in vivo.
Significance: Lacosamide reduces neocortical seizure-like activity in neonatal mice in vitro and in vivo without an acute increase in apoptosis. Our results support the use of lacosamide to treat neonatal seizures, with the advantage of not increasing apoptosis acutely.
Posttraumatic epilepsy (PTE) is a well-known chronic complication following traumatic brain injury (TBI). Despite some evidence that age at the time of injury may influence the likelihood of PTE, the incidence of PTE in pediatric populations remains unclear. We, therefore, conducted a systematic review to determine the overall reported incidence of PTE, and explore potential risk factors associated with PTE after pediatric TBI. A comprehensive literature search of the PubMed, Embase, and Web of Science databases was conducted, including randomized controlled trials and cohort studies assessing the incidence of PTE in TBI pediatric patients. We excluded studies with a sample size of <10 patients and those in which a pediatric cohort was not clearly discernable. The review was conducted in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. We found that the overall incidence of PTE following pediatric TBI was 10% (95% confidence interval [CI] = 5.9%–15%). Subgroup analysis of a small number of studies demonstrated that the occurrence of early seizures (cumulative incidence ratio [CIR] = 7.28, 95% CI = 1.09–48.4, p =?.040), severe TBI (CIR = 1.81, 95% CI = 1.23–2.67, p <?.001), and intracranial hemorrhage (CIR = 1.60, 95% CI = 1.06–2.40, p =?.024) increased the risk of PTE in this population. Other factors, including male sex and neurosurgical intervention, were nonsignificantly associated with a higher incidence of PTE. In conclusion, PTE is a significant chronic complication following childhood TBI, similar to in the adult population. Further standardized investigation into clinical risk factors and management guidelines is warranted.
The genetic basis of many epilepsies is increasingly understood. This gives rise to the possibility of precision treatments that can be tailored to a person’s specific genetic epilepsy. CURE Epilepsy Taking Flight grantee Juliet Knowles, MD, PhD, led a collection of prominent stakeholders within the epilepsy community, including CURE Epilepsy’s Dr. Laura Lubbers, in authoring a critical review that describes recent progress, new or persistent challenges, and future directions of precision medicine for genetic epilepsies, among other things. The article states that though current medical therapy for most epilepsies remains imprecise, the epilepsy community is ready to make big steps forward in precision therapy tailored to a person’s specific genetic epilepsy because of increased access to genetic testing and counseling and advances in the ability to diagnose genetic epilepsies. The authors conclude that the future of precision medicine for genetic epilepsy looks bright if progress in this area continues in a strategic and coordinated manner. Learn More
According to data from an observational cohort study, US veterans with drug-resistant epilepsy have higher rates of mortality than the general population, suggesting a critical need for appropriate management of epilepsy in this population. The findings showed that lower mortality was associated with increased utilization of medical care, especially when utilizing a Veterans Affairs Epilepsy Center of Excellence compared to a neurology clinic alone. The study authors noted that the higher mortality risk might be lowered by appropriate referrals for comprehensive evaluation, adequate diagnostic testing, and optimal medication management and that adequate resources should be allocated to care for this patient group. Learn More
A recent study found an increased risk among adults for epilepsy or seizures two years after COVID-19 infection. Researchers used data collected as part of a two-year retrospective cohort study to investigate the neurological and psychiatric impact of SARS-CoV-2 infections. The researchers discovered that participants who had been infected with the Delta COVID-19 variant had an increased risk for epilepsy or seizures (amongst other risks) when compared to participants who had been infected with the Alpha variant. They also found that while the death rate decreased after the emergence of the Omicron variant, the virus still carried about the same risks for psychiatric or neurological problems, including epilepsy or seizures, compared to the Delta variant. The authors note that these findings emphasize there is a need for further research into the long-term impact of COVID-19. Learn More
Epilepsy can have a variety of causes, including genetic variants in a family of proteins that regulate potassium ions in the brain. A research team is examining the mechanisms behind the function and dysfunction of two of these proteins, the potassium ion channels KCNQ2 and KCNQ3, as well as their interactions with an antiseizure medication, to develop a new strategy to treat epilepsy. The team identified a set of mutations in these ion channels associated with early infantile epileptic encephalopathy, a severe form of childhood epilepsy, that specifically disrupts the function of these channels. The researchers took advantage of the antiseizure drug retigabine, given its mechanism of action on neuronal KCNQ channels, and demonstrated that the function of these mutated KCNQ channels can be restored. Their studies suggest that targeting the function of KCNQ channels may be an effective strategy for developing more effective therapies for epilepsy. Learn More
An artificial intelligence (AI) algorithm to detect subtle brain abnormalities that cause epileptic seizures has been developed. The abnormalities, known as focal cortical dysplasias (FCDs), can often be treated with surgery but are difficult to visualize on an MRI. The new algorithm is expected to give physicians greater confidence in identifying FCDs in patients with epilepsy. To develop the algorithm, the team quantified features of the brain cortex—such as thickness and folding—in more than 1,000 patient MRI scans from 22 epilepsy centers around the world. They then trained the algorithm on examples labeled by expert radiologists as either being healthy or having FCD. The study’s authors state that the algorithm automatically learns to detect lesions from thousands of MRI scans of patients and can reliably detect lesions of different types, shapes, and sizes. The algorithm can even detect many of those lesions that were previously missed by radiologists. Ultimately, the team would like this AI algorithm to help doctors confidently identify FCDs, and then use surgery to remove them, in hopes of providing a cure for epilepsy. Learn More
Objective: Parents of children with epilepsy need support when managing epileptic seizures outside medical-care-center-settings. Previously developed training programs only provide information-based support. Therefore, within the scope of the Virtual Reality-based Seizure Management Education Program for Parents (VR-ESMEPP), a conceptual framework was developed in this study with the aim of developing parents’ skills and motivation as well as providing them information regarding seizure management.
Methods: The conceptual framework of the VR-ESMEPP was developed in four steps. In step 1, a scenario was developed wherein a pediatric patient with epilepsy is having a seizure. The selected seizure type was “Focal to bilateral tonic-clonic” seizure, which is the most common and most skill-intensive type of tonic-clonic-seizure. In step 2, data collection tools related to epileptic seizure management were developed for parents. These tools included Child and Parent Introductory Form, Parental Information Assessment Form for Epileptic Seizure Management, and Parental Skills Assessment Form for Epileptic Seizure Management. In step 3, the conceptual framework and data collection tools developed were confirmed by a group of 10 specialists consisting of physicians and pediatric nurses working in the field of pediatric neurology. In step 4, the epileptic-pediatric-patient-scenario and data collection tools confirmed by experts were programmed into an application by a software company and integrated into virtual reality headsets.
Results: The Virtual Reality-based Seizure Management Education Program for Parents with the conceptual framework described in the present study is a valid virtual reality-based program, which can be carried out under nurses’ supervision and used to provide epilepsy-related education to parents.
Significance: The Virtual Reality-based Seizure Management Education Program for Parents helped parents increase their knowledge and skills of epileptic seizure.
A recent survey of people with epilepsy and their caregivers showed that the COVID-19 pandemic has had negative effects on self-management and mental health for those with epilepsy. Some of the topics covered in the study include timeliness of taking medications, mental health, stress, and discussions with a healthcare provider about sleep, antiseizure medications, and potential side effects. The findings highlight the need for healthcare providers to be more aware of the increased emotional distress in people with epilepsy. Learn More
Treatment with a prescription medication called ketamine significantly reduced seizure occurrence related to refractory status epilepticus in neonates and children, according to results of a new study. In the study, researchers sought to determine the safety and efficacy of ketamine in young patients for this difficult to treat form of epilepsy. Results showed that after ketamine infusion, 32 patients experienced seizure cessation, 19 patients experienced seizure reduction, while there was no change in 18 patients. Three patients had adverse events requiring intervention during or within 12 hours of ketamine administration, including hypertension in two patients and delirium in one patient. “Many children with status epilepticus have persistent seizures despite administration of at least two appropriately dosed antiseizure medications,” stated the study authors. “Ketamine… may be a beneficial alternative.” Learn More
For young stroke survivors, the subsequent development of seizures more than doubles their risk of developing dementia, according to a recently published study. Researchers used the IBM Watson Health MarketScan Commercial Claims and Encounters database to identify 23,680 patients (aged 18 to 60 years) with ischemic strokes or hemorrhagic strokes from 2006 through 2009. The researchers found that young patients with stroke who developed seizures had a greater risk for dementia than those without seizures. The authors noted that “since strokes are occurring in younger people and survival rates are increasing, it is important to understand the long-term effects and determine who is at greatest risk for severe complications like dementia.” Learn More
Recent research has identified characteristics that can help predict the likelihood of seizures returning in children who have stopped taking antiseizure medication (ASM) after becoming seizure free. Among the characteristics studied, three were associated with a higher chance of having returning seizures after stopping ASM and included adolescent age at diagnosis, unusual EEG findings after the medication was stopped, and having a high number of seizures while taking medication. This information may be useful to doctors as they consider discontinuing antiseizure medication in their patients. Learn More
A team of researchers used a new technique to find a link between a specific protein in the brain and increased vulnerability to neurodegeneration for individuals with temporal lobe epilepsy. The technique used by the researchers made it possible to study small amounts of tissue from hard-to-reach regions within the brain. Using this new technique, the researchers identified changes in a protein called GluN3 that is associated with cellular damage. The technique allowed the researchers to narrow the focus to specific areas of the brain where neurons are dying. The study author has applied to patent the technique, known as ‘area-specific tissue analysis’. This advanced technique may lead to a new understanding of the causes of epilepsy and therapies to help patients, stated the study author. Learn More