Epilepsy Research News: August 2022

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

Impact of the COVID-19 Pandemic on People with Epilepsy: Findings From the US Arm of the COV-E Study

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.
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Ketamine: An Effective Treatment for Neonatal, Pediatric Epilepsy

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.”
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Seizures in Young Stroke Survivors Doubles Dementia Risk

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.”
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Age at Epilepsy Diagnosis and EEG can Help Predict Returning Seizures After Stopping Antiseizure Medication

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.
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A New Technique to Understand Temporal Lobe Epilepsy

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.
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Impact of Development and Recent-Onset Epilepsy on Language Dominance

Abstract found on Wiley Online Library

Objective: Reorganization of the language network from typically left-lateralized frontotemporal regions to bilaterally distributed or right-lateralized networks occurs in anywhere from 25-30% of patients with focal epilepsy. In patients recently diagnosed with epilepsy, an important question remains as to whether it is the presence of seizures or the underlying epilepsy etiology that lead to atypical language representations. This question becomes even more interesting in pediatric samples, where the typical developmental processes of the language network may confer more variability and plasticity in the language network. We assessed a carefully selected cohort of children with recent-onset epilepsy to examine whether it is the effects of seizures or their underlying cause that leads to atypical language lateralization.

Methods: We used functional magnetic resonance imaging (fMRI) to compare language laterality in children with recently diagnosed focal unaware epilepsy and age-matched controls. Age of epilepsy onset (age 4 to 6?years vs age 7 to 12?years) was also examined to determine if age of onset influenced laterality.

Results: The majority of recent-onset patients and controls exhibited left-lateralized language. There was a significant interaction such that the relationship between epilepsy duration and laterality differed by age of onset. In children with onset after age 6, a longer duration of epilepsy was associated with less left-lateralized language dominance. In contrast, children with onset between 4-6, a longer duration of epilepsy was not associated with less left language dominance.

Significance: Our results demonstrate that while language remained largely left-lateralized in children recently diagnosed with epilepsy, the impact of seizure duration depended on age of onset indicating that timing of developmental and disease factors are important in determining language dominance.

Quantifying and Reporting Outcomes in Pediatric Epilepsy Surgery: A Systematic Review

Abstract found on Wiley Online Library

Objective: Several instruments and outcomes measures have been reported in pediatric patients undergoing epilepsy surgery. The objective of this systematic review is to summarize, evaluate, and quantify outcome metrics for the surgical treatment of pediatric epilepsy that address seizure frequency, neuropsychological, and health-related quality of life (HRQL).

Methods: We performed a systematic review according to PRISMA guidelines to identify publications between 2010 and June 2021 from PubMed, Embase, and the Cochrane Database of Systematic Reviews that report clinical outcomes in pediatric epilepsy surgery.

Results: Eighty-one papers were included for review. Overall, rates of post-operative seizure frequency were the most common metric reported (n=?78 studies, 96%). Among the seizure frequency metrics, the Engel Epilepsy Surgery Outcome Scale (n=?48 studies, 59%) was most commonly reported. Neuropsychological outcomes, performed in 32 studies (40%) were assessed using 36 different named metrics. Health-Related Quality of Life (HRQL) outcomes were performed in 16 studies (20%) using 13 different metrics. Forty-six studies (57%) reported postoperative changes in anti-epileptic drug (AED) regimen and time-to-event analysis was performed in 15 (19%) studies. Only 13 outcomes metrics (1/5 seizure frequency, 6/13 HRQL, 6/36 neuropsychological) have been validated for use in pediatric patients with epilepsy and only 13 have been assessed through reliability studies (4/5 seizure frequency, 6/13 HRQL, and 3/36 neuropsychological). Of the 81 included studies, 17 (21%) used at least one validated metric.

Significance: Outcome variable metrics in pediatric epilepsy surgery are highly variable. While nearly all studies report seizure frequency, there is considerable variation in reporting. Health-related quality of life and neuropsychological outcomes are less frequently and much more heterogeneously reported. Reliable and validated outcomes metrics should be used to increase standardization and accuracy of reporting outcomes in pediatric patients undergoing epilepsy surgery.

Ketamine Effective Treatment for Neonatal, Pediatric Epilepsy

Article published by Healio

Treatment with ketamine significantly improved seizure occurrence related to refractory status epilepticus in both neonates and children, according to results of a study published in Neurology.

“Many children with status epilepticus have persistent seizures despite administration of at least two appropriately dosed antiseizure medications,” Marin Jacobwitz, CRNP, of the department of pediatrics, Children’s Hospital of Philadelphia, and colleagues wrote. “Ketamine, a noncompetitive N-methyl-D-aspartate glutamate receptor antagonist, may be a beneficial alternative anesthetic.”

Researchers sought to determine the safety and efficacy of ketamine as a therapeutic for refractory status epilepticus (RSE) in children and neonates.

Results showed that ketamine infusion was followed by seizure termination in 32 patients, seizure reduction in 19 patients and no change in 18 patients. Data also revealed 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.

Antiseizure Medication Use and Medical Resource Utilization After Resective Epilepsy Surgery in Children in the United States: A Contemporary Nationwide Cross-Sectional Cohort Analysis

Abstract published in Wiley Online Library

Objective: Antiseizure drug (ASD) therapy can significantly impact quality of life for pediatric patients whose epilepsy remains refractory to medications and who experience neuropsychological side effects manifested by impaired cognitive and social development. Contemporary patterns of ASD reduction after pediatric epilepsy surgery across practice settings in the United States are sparsely reported outside of small series. We assessed timing and durability of ASD reduction after pediatric epilepsy surgery and associated effects on health care utilization.

Methods: We performed a retrospective analysis of 376 pediatric patients who underwent resective epilepsy surgery between 2007 and 2016 in the United States using the Truven MarketScan database. Filled ASD prescriptions during the pre- and postoperative periods were compared. Univariate and multivariate analyses identified factors associated with achieving a stable discontinuation of or reduction in number of ASDs. Health care utilization and costs were systematically compared.

Results: One hundred seventy-one patients (45.5%) achieved a >90-day ASD-free period after surgery, and 84 (22.3%) additional patients achieved a stable reduction in number of ASDs. Achieving ASD freedom was more common in patients undergoing total hemispherectomy (n = 21, p = .002), and less common in patients with tuberous sclerosis (p = .003). A higher number of preoperative ASDs was associated with a greater likelihood of achieving ASD reduction postoperatively (hazard ratio [HR]: 1.85, 95% confidence interval [CI]: 1.50–2.28), but was not associated with a significant difference in the likelihood of achieving ASD freedom (0.83, 95% CI: 0.49–1.39). Achieving an ASD-free period was associated with fewer hospital readmissions within the first year after surgery.

Significance: Patterns of antiseizure drug use and discontinuation after pediatric epilepsy surgery provide an unbiased surgical outcome endpoint extractable from administrative databases, where changes in seizure frequency are not captured. This quantitative measure can augment traditional surgical outcome scales, incorporating a significant clinical parameter associated with improved quality of life.

Effectiveness of Zonisamide (Zonegran®) in Childhood Refractory Epilepsy

Abstract appeared in PubMed

Introduction: Zonisamide (ZNS) is a new generation antiepileptic drug (AED) used in refractory epilepsy. This study assessed the effectiveness and reliability of ZNS in childhood refractory epilepsy.

Method: Sixty-eight epilepsy patients who were followed up in the paediatric neurology clinic, between 2013 and 2019, and in whom add-on therapy ZNS had been added as their seizures had continued despite multiple drugs being used, were included in this retrospective study. Their demographic findings, seizure aetiology, pre-treatment and post-treatment electroencephalography findings, treatment responses and any side effects of the drugs given were assessed in these patients.

Results: There were 46 (67.6%) patients in the refractory generalized epilepsy (RGE) group using multiple AEDs and 22 (32.35%) patients in the refractory focal epilepsy (RFE) group. Of these patients, 12 (17.65%) were being followed up for idiopathic epilepsy and 8 (11.76%) were being followed up for epilepsy of unknown aetiology. Twenty-two (32.36%) patients were followed up for structural abnormality, 8 patients (11.77%) were followed up for genetic disease, 4 patients (5.88%) were followed up for infectious sequel, 14 patients (20.59%) were followed up for metabolic reasons. In the RGE group, a more than 50% reduction was found in the seizures of 26 (56.5%) patients, while the seizures of 7 (15.2%) patients were found to have terminated completely. In the RFE group, a more than 50% reduction was found in the seizures of 19 (86.4%) patients, while the seizures of 2 (9.1%) patients were found to have terminated completely. The termination or a more than 50% reduction in seizures in 4 of the 6 patients followed up for a diagnosis of tuberous sclerosis complex (TSC) was significant.

Conclusion: ZNS is an effective and reliable option as an add-on therapy in paediatric refractory epilepsy, especially in focal epilepsy. It can also be considered for treatment in TSC patients.

Discovery of Genetic Variants Linked to Febrile Seizures

Article published in Statens Serum Institut News, original research published in Brain

A large-scale case-control study implicates genes critical for fever response and genes for communication between nerve cells.

It is usually an unexpected and frightening experience for parents when their child has a febrile seizure. Occurring in 3-5% of infants febrile seizures are the most common type of abnormal brain activity during childhood. While most febrile seizures are benign and self-limiting with no recurrence, about 7% of children with febrile seizures will later develop epilepsy.

Now, a new international genetic study led by researchers from Statens Serum Institut (SSI) in Copenhagen and conducted in collaboration with other research groups in Denmark and Australia have identified seven novel regions of the genome linked to febrile seizures in the largest case-control study reported for this common childhood disorder.

The research has just been published in the leading international neurological journal Brain.

Genes related to fever response

The researchers analyzed variants in the DNA of 7,635 children from Denmark and Australia, who had experienced one or more episodes of febrile seizures. They also analyzed a control group of 83,966 children without febrile seizures.

Almost 7 million genetic variants were interrogated and the study identified seven new gene regions robustly linked to increased risk of developing febrile seizures. The study also confirmed four previously known genetic associations for febrile seizures established by the same team in 2014.

Two of the new regions contained genes of major importance in the development of fevers in mammals. For one gene, called PTGER3, the mechanism has been elucidated in mouse experiments. When this gene was silenced in a specific brain region called the median preoptic nucleus, the mice were unable to develop fevers. Another gene called IL10 encodes a signaling molecule that normally functions to suppress fevers.

Dr. Bjarke Feenstra, a senior researcher and group leader at Statens Serum Institut in Denmark, who was the lead author of the study, said: “The connections to fever response are intriguing. We hypothesize that genetic changes that affect the way the PTGER3 and IL10 genes function may lead to a more pronounced fever response, which in turn could increase the susceptibility of children to febrile seizures”.

Racial Disparities in Medication Adherence Barriers: Pediatric Epilepsy as an Exemplar

Abstract, originally published in the Journal of pediatric psychology

Objective: To evaluate how racial disparities in medication adherence barriers relate to key clinical outcomes (i.e., seizure control and adherence) in pediatric epilepsy and to identify the most critical barriers in determining health outcomes in Black youth and White youth.

Methods: This observational study included a sample of youth aged 2-17 years with epilepsy obtained by combining data from four different studies. A total of 226 caregivers and 43 adolescents reported on adherence barriers. An electronic monitor was used to measure adherence to the primary antiepileptic drug. Racial disparities in individual barriers were examined. The relative importance of different types of barriers in determining clinical outcomes was evaluated in both Black and White youth.

Results: Adherence barriers, including running out of medications, access to pharmacies, competing demands, and difficulty swallowing, disproportionally affected Black children with epilepsy compared to White children. System- and community-level barriers emerged as the most important in determining seizure outcomes among Black youth. Both system- and individual-level barriers, on the other hand, were important for adherence outcomes.

Conclusions: System- and community-level barriers, as opposed to individual-level barriers, are more highly endorsed by Black families compared to White families. These barriers are also the most critical in driving seizure outcomes among Black youth. There is a critical need to shift from a primary focus on individual-level barriers to an approach that deliberately targets larger systemic barriers to reduce the existing adherence and health disparities that affect Black children with pediatric conditions.

Pediatric Epilepsy Learning Healthcare System Quality of Life (PELHS-QOL-2): A Novel Health-Related Quality of Life Prompt for Children with Epilepsy

Abstract, originally published in Epilepsia

Objective: Pediatric epilepsy is often associated with diminished health-related quality of life (HRQOL). Our aim was to establish the validity of the Pediatric Epilepsy Learning Healthcare System Quality of Life (PELHS-QOL-2) questions, a novel two-item HRQOL prompt for children with epilepsy, primarily for use in clinical care.

Methods: We performed a multicenter cross-sectional study to validate the PELHS-QOL-2. Construct validity was established through bivariate comparisons with four comparator measures and known drivers of quality of life in children with epilepsy, as well as by creating an a priori multivariable model to predict the Quality of Life in Childhood Epilepsy Questionnaire (QOLCE-55). Validity generalization was established through bivariate comparisons with demographic and clinical information. Content validity and clinical utility were established by assessing how well the PELHS-QOL-2 met eight design criteria for an HRQOL prompt established by a multistakeholder group of experts.

Results: The final participant sample included 154 English-speaking caregivers of children with epilepsy (mean age = 9.7 years, range = .5-18, 49% female, 70% White). The PELHS-QOL-2 correlated with the four comparator instruments (? = .44-.56), was significantly associated with several known drivers of quality of life in children with epilepsy (p < .05), and predicted QOLCE-55 scores in the multivariate model (adjusted R2 = .54). The PELHS-QOL-2 item was not associated with the age, sex, and ethnicity of the children nor with the setting and location of data collection, although PELHS-QOL-Medications was significantly associated with race (worse for White race). Following both quantitative and qualitative analysis, the PELHS-QOL-2 met seven of eight design criteria.

Significance: The PELHS-QOL-2 questionnaire is a valid health-related quality of life prompt and is well suited for use in clinical care as a mechanism to routinely initiate conversations with caregivers about quality of life in children with epilepsy. The association of PELHS-QOL-Medications with race merits further study.

Genetic Diagnosis May Aid Management of Pediatric Epilepsy

Article, originally published in Medical Press

For individuals with unexplained infantile or childhood-onset epilepsy, genetic testing to establish a genetic diagnosis may impact medical care and prognosis, according to a study presented at the annual meeting of the American Epilepsy Society, held from Dec. 3 to 7 in Chicago. Isabel Haviland, M.D., from Boston Children’s Hospital, and colleagues assessed the individualized medical impact of a genetic diagnosis in a cohort of patients with infantile or childhood-onset epilepsy. The analysis included 152 individuals (46 percent female; median age of onset, 6 months) with a clinical diagnosis of genetic epilepsy, who underwent next-generation sequencing between 2012 and 2019.

The researchers found that a genetic diagnosis had a direct impact on medical management in at least one category for 72 percent of patients and in more than one category for 34 percent. In just under half of individuals (45 percent), treatment was impacted, including an impact on antiseizure medication choice (36 percent), use of disease-specific vitamin or metabolic treatments (7 percent), off-label use of medications (3 percent), and discussion of gene-specific clinical trials (10 percent). Additionally, care coordination was impacted in nearly half of individuals (48 percent), including surveillance for disease-associated features, disease-specific diagnostic testing, and referrals to specialists or disease-specific multidisciplinary clinics.