Kennedy Krieger Researchers Identify Potential Pathway to Improve Treatment For Newborns With Drug-Resistant Seizures

Researchers at the Kennedy Krieger Institute, with colleagues from Johns Hopkins University, have identified an important molecular mechanism that offers significant promise for understanding and developing novel treatment for drug-resistant seizures in newborns. Newborns with drug-resistant seizures often develop childhood epilepsy and cognitive disabilities. The findings were published online this week in the journal Science Signaling. The study was led by Shilpa Kadam, Ph.D., a research scientist at Kennedy Krieger’s Hugo W. Moser Research Institute, who is also director of the mouse in-vivo electrophysiology laboratory at Kennedy Krieger.

In the paper, Targeting ischemia-induced KCC2 hypofunction rescues refractory neonatal seizures and mitigates epileptogenesis in a mouse model, Dr. Kadam and colleagues from Kennedy Krieger and Johns Hopkins University School of Medicine showed that increasing the activity of an ion transporter in nerve cells, namely KCC2, by CLP290, a novel KCC2-selective activator, reduced seizures in mice.

According to the study authors, their findings are the first to validate the strategy of using KCC2 as a potential drug target for treatment-resistant seizures.  The findings provide important insights for future drug development. However, more work is needed to determine how best to translate these preclinical findings into human populations.

“We hope that a simple add-on intervention could effectively change the trajectory of a child’s life and may prevent the onset of lifelong epilepsy. We will be continuing to study these results and their potential application to improve child health,” Kadam said.

Seizure Control After Epilepsy Surgery in Early Childhood: A Systematic Review and Meta-Analysis

Abstract of study to be published in Epilepsy Behavior 

Objective: This meta-analysis aimed to determine the main factors influencing surgical outcomes in children <3 years old with refractory epilepsy.

Methods: The PubMed and Cochrane database were systematically searched for epilepsy surgery outcomes from December 1, 1991, to March 30, 2021, using the following search terms: “Epilepsy surgery OR Seizure operation” AND “under three years” OR “first three years” OR “early childhood” OR “infancy OR infants.” Seizure onset, duration of epilepsy, magnetic resonance imaging findings, age at the time of surgery, surgical methods, resection extent, and pathological findings were considered potential moderators of differences in seizure outcomes. The fixed-effects models, combined effect sizes, and 95% confidence intervals (CI) were used to calculate the influence of potential factors on seizure outcomes.

Results: Thirty two studies (559 cases) were included in the meta-analysis. The significant factors that correlated with a lower seizure control rate were frontal lobectomy (odds ratio [OR]: 0.33, 95% CI: 0.12-0.91; p = 0.03) and malformation of cortical development (MCD) (OR, 0.38; 95% CI: 0.24-0.62; p < 0.01). A higher seizure control rate was observed in children with tumors (92.86%) and Sturge-Weber syndrome (SWS, 91.43%). Frontal lobe epilepsy induced by MCD was related to the worst postoperative efficacy (OR, 0.26; 95% CI: 0.13-0.53; p < 0.01).

Significance: The results of our meta-analyses revealed that pathology and surgical location play critical roles in the outcome of epilepsy surgery in children <3 years old. Clarification of the etiology of epilepsy before surgery is critical for better postoperative outcomes.

Disordered Brain Activity in Rolandic Epilepsy can be Influenced by Brief Sounds During Sleep

Article published in, originally published in Universitaet Tübingen

Rolandic epilepsy is a common form of epilepsy in children which occurs primarily during sleep. Short sounds played during sleep can partially suppress the neuronal discharges characteristic of epilepsy. That’s according to a research team from the University of Tübingen and Tübingen University Hospitals. The team is headed by Dr. Hong-Viet Ngo and Professor Jan Born from the Institute of Medical Psychology and Behavioral Neurobiology. Their findings could form the basis for future research into treatment of this form of epilepsy.

In the study, the research team non-invasively recorded the electrical brain activity of seven children suffering from Rolandic epilepsy and seven healthy control subjects of the same age, in electroencephalograms (EEG) during sleep. “Our work confirms earlier findings that there are differences in the child patients’ brain activity during sleep compared to healthy children,” says the first author of the study, Dr. Jens Klinzing of Born’s research group. “This particularly affects what is known as “sleep spindles,” a pattern of activity important for processing memories during sleep.” In children with the disease, the epileptic discharges—each recorded as a spike in the curve on the EEG—were also measured during sleep and during quiet periods of wakefulness. The rate and strength of these discharges are thought to determine how pronounced the abnormalities in the cognitive domains are.

The spikes likely originate at the connections between the diencephalon and the cerebral cortex; this gave the researchers the idea to conduct experiments with sound during sleep. “The connections between the diencephalon and cerebral cortex are involved in the origin of both spikes and sleep spindles,” Klinzing says. “It was known from previous studies that sleep spindles can be stimulated by sounds.” The researchers therefore suspected that the epileptic discharges could also be influenced in this way. In fact, it turned out that the softly played sounds reduced both the spike frequency and the intensity of the following spikes in the children suffering from Rolandic epilepsy.

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Early Childhood Epilepsies: Epidemiology, Classification, Aetiology, and Socio-Economic Determinants Abstract

Abstract originally published in Brain

Epilepsies of early childhood are frequently resistant to therapy and often associated with cognitive and behavioural comorbidity. Aetiology focused precision medicine, notably gene-based therapies, may prevent seizures and comorbidities. Epidemiological data utilizing modern diagnostic techniques including whole genome sequencing and neuroimaging can inform diagnostic strategies and therapeutic trials.

We present a 3-year, multicentre prospective cohort study, involving all children under 3 years of age in Scotland presenting with epilepsies. We used two independent sources for case identification: clinical reporting and EEG record review.

Three hundred and ninety children were recruited over 3 years. The adjusted incidence of epilepsies presenting in the first 3 years of life was 239 per 100?000 live births [95% confidence interval (CI) 216–263]. There was a socio-economic gradient to incidence, with a significantly higher incidence in the most deprived quintile (301 per 100?000 live births, 95% CI 251–357) compared with the least deprived quintile (182 per 100?000 live births, 95% CI 139–233), ?2 odds ratio = 1.7 (95% CI 1.3–2.2). The relationship between deprivation and incidence was only observed in the group without identified aetiology, suggesting that populations living in higher deprivation areas have greater multifactorial risk for epilepsy. Aetiology was determined in 54% of children, and epilepsy syndrome was classified in 54%. Thirty-one per cent had an identified genetic cause for their epilepsy. We present novel data on the aetiological spectrum of the most commonly presenting epilepsies of early childhood. Twenty-four months after presentation, 36% of children had drug-resistant epilepsy (DRE), and 49% had global developmental delay (GDD). Identification of an aetiology was the strongest determinant of both DRE and GDD. Aetiology was determined in 82% of those with DRE, and 75% of those with GDD.

In young children with epilepsy, genetic testing should be prioritized as it has the highest yield of any investigation and is most likely to inform precision therapy and prognosis. Epilepsies in early childhood are 30% more common than previously reported. Epilepsies of undetermined aetiology present more frequently in deprived communities. This likely reflects increased multifactorial risk within these populations.

Dravet Syndrome: A Quick Transition Guide for the Adult Neurologist

Abstract, originally published in Epilepsy Research

Introduction: Dravet syndrome (DS) is still seen as a “pediatric disease”, where patients receive excellent care in pediatric centers, but care is less than optimal in adult health care systems (HCS). This creates a barrier when young adults need to leave the family-centered pediatric system and enter the adult, patient-centered HCS. Here we create a guide to help with the transition from pediatric to adult for patients with DS.

Methods: Experts in Dravet syndrome flagged the main barriers in caring for adults with DS and created a 2-page transition summary guide based on their expertise and a literature review.

Results: The 2-page guide addresses: DS diagnosis in children and adults; clinical manifestations, including the differences in seizures types and frequencies between children and adults with DS; the natural history of intellectual disability, behavior, gait, motor disorders and dysautonomia; a review of optimal treatments (including medications not commonly used in adult epilepsy settings such as stiripentol and fenfluramine), as well as emergency seizure management; avoidance of triggers, preventive measures, and vaccine administration in adults with DS.

Conclusion: Several young adults with Dravet syndrome (DS) are still followed by their child neurologist. This 2-page transition guide should help facilitate the transition of patients with DS to the adult healthcare system and should be given to families as well as adult health care providers that may not be familiar with DS.

Surgical Candidates for Pediatric Epileptic Spasms Can Be Selected Without Invasive Monitoring

Abstract, originally published in Epilepsy Research

Selecting children with epileptic spasms for surgery based on the location and extent of lesions detected on brain MRI, nearby eloquent regions and preexisting deficits yields seizure-free results comparable to a strategy that includes intracranial monitoring. This MRI-based approach not only reduces risk by avoiding an invasive procedure but allows surgery to be conducted more promptly. So concludes a study — recently published in Epilepsy Research — of a large series of children who underwent surgery for epileptic spasms without invasive monitoring.

“In prior surgical series of children with epileptic spasms, invasive intracranial EEG monitoring has been used in 20% to 65% of patients,” says the study’s corresponding author, Ahsan N.V. Moosa, MD, a Cleveland Clinic pediatric epileptologist. “At Cleveland Clinic, almost all children who have epileptic spasms with an epileptogenic lesion on MRI undergo surgery without invasive intracranial EEG monitoring. This series confirms that this approach is sound.”

Altered Cytokine Levels in Cerebrospinal Fluid Following Ketogenic Diet of Children with Refractory Epilepsy

Abstract, originally published in Epilepsy Research

Ketogenic diet is an effective treatment which has the potential to achieve a significant seizure reduction in drug-resistant epilepsy. The mechanism behind this effect is unclear, but one hypothesis is that the mechanism is anti-inflammatory. In this prospective study on pediatric patients we compared levels of cytokines and chemokines in the cerebrospinal fluid before and after three months on treatment to evaluate a possible anti-inflammatory effect.

We analyzed 34 cytokines and chemokines in the cerebrospinal fluid of pediatric patients (n = 21) with refractory epilepsy by a multiplex assay. Beta-hydroxybutyric acid was measured in blood and cerebrospinal fluid. Seizure frequency in relation to diet treatment was assessed. For 9 different cytokines (CCL 7, CCL 21, CCL 22, CCL 25, CCL 27, IL-2, IL-10, CX3CL1 and MIF), a significant decrease ranging from 7 to 27% was seen after three months as compared to levels before the diet. In contrast, no cytokine displayed a significant increase during diet. A seizure reduction ? 50 % was seen in 15/21 patients (71 %) but no significant differences in cytokine decreases were found between responders and non-responders during treatment. A non-significant trend towards higher initial pre-treatment levels of cytokines was seen in responders, which were reduced following treatment. The levels of betahydroxybutyric acid were not related to seizure response.

We conclude that while it is not possible to state a primary anti-inflammatory effect by dietary treatment from these data, an unequivocal immunological effect is seen and may be a part of the mechanism of ketogenic dietary treatment.

Parental Experience and Decision-Making for Epilepsy Surgery: A Systematic Review of Qualitative and Quantitative Studies

Abstract, originally published in Epilepsy & Behavior

Objective: In selected children with drug-resistant epilepsy (DRE), epilepsy surgery is the most effective treatment option, but unfortunately remains highly underutilized. One of the critical obstacles to pursuing surgical therapy is parents/caregivers’ decision against surgery or to delay the surgery until no other treatment option exists. Understanding caregiver decision-making around epilepsy surgery can improve patient/caregiver experience and satisfaction while facilitating appropriate decision-making that optimizes clinical outcomes. The current review systematically explores the existing evidence on caregiver experience and the decision-making process toward epilepsy surgery.

Methods: The study was conducted as per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines for systematic literature review. Databases (PubMed Ovid, PubMed Medline, Web of Science, CINHAL, PsycInfo) were systematically searched in February 2021 using a defined search strategy and inclusion/exclusion criteria. Total 1304 articles were screened for titles and abstracts, and 54 full-text articles were retrieved for further assessment. We included 14 articles with critical quality assessment using two different tools for qualitative and questionnaire-based studies. A qualitative content analysis was performed to characterize caregiver experience, perception, and decision-making toward favorable or unfavorable opinions of epilepsy surgery.

Results: Four concepts generated from the analysis may act as enablers or barriers to decision-making around epilepsy surgery: 1. Access to knowledge and information, 2. Communication and coordination issues, 3. Caregiver’s emotional state, and 4. Socioeconomic effects. Subsequently, we provided a narrative synthesis of practice recommendations and a conceptual framework to adopt multi-pronged interventions to overcome identified diverse barriers to effective caregiver decision-making.

Conclusion: Multiple influences impact how caregivers decide about epilepsy surgery for their children, with no single factor identified as the primary driver for or against surgery. However, limited research has explored these influences. Future studies should focus on quantitatively examining factors to identify significant variables most likely to influence caregiver decision-making, ultimately overcoming barriers that limit utilization of epilepsy surgery as a treatment tool.

ADHD and Epilepsy-Related QoL in Youth with Epilepsy

Abstract, originally published in Epilepsy & Behavior

Objective: Pediatric epilepsy and attention-deficit/hyperactivity disorder (ADHD) present a cumulative vulnerability to youth, particularly in the domains of executive function (EF) and quality of life (QoL). The aim of this study was to explore the relationships between EF and epilepsy-specific QoL in youth with epilepsy (YWE) who also have ADHD.

Methods: Youth with epilepsy aged 5-18 years and caregivers participated in a large multi-site national validation of the PedsQL™ Epilepsy Modules. YWE and their caregivers were asked to complete measures of epilepsy-specific QoL, ADHD symptoms, and EF. Previous ADHD diagnosis was reported by caregivers as well as abstracted from the medical record.

Results: Caregiver and YWE reports of current ADHD symptoms significantly predicted all epilepsy-specific QoL domains. Suboptimal QoL was reported for those YWE whose ADHD symptoms were above the clinical threshold compared to YWE whose ADHD symptoms were within the average range. Results were similar for YWE with a documented ADHD vs no ADHD diagnosis. In addition, poorer metacognition and behavioral regulation EF was associated with lower epilepsy-specific QoL for both YWE with ADHD and without ADHD diagnosis. However, in YWE with ADHD, effect sizes were consistently larger for behavioral regulation compared to metacognition across epilepsy-specific QoL domains, with behavioral regulation accounting for 50% of the variance in each of the EF and mood QoL domains.

Significance: Addressing ADHD symptoms, epilepsy-specific, quality of life, and executive function as part of routine epilepsy care may promote optimal outcomes for YWE with ADHD as well as relieve burden on the healthcare system.

‘To Reveal or to Conceal’- Disclosure Strategies in Parents of Children With Epilepsy in India

Abstract, originally published in Seizure

Purpose: Disclosure of epilepsy is a relevant but under-researched topic in epilepsy research. This study was done to assess the disclosure strategies in parents of children with epilepsy in a developing country with conservative culture. The study also assessed the influence of demographic factors and seizure characteristics on the choice of disclosure. Enablers and barriers behind disclosure and the consequences after disclosure were evaluated.

Methods: A cross-sectional analytical, self-report survey was done in 284 parents of CWE with the help of a semi-structured questionnaire over a 7-month period in the paediatric epilepsy clinic. Disclosure was considered present if epilepsy was revealed to two or more of the five target groups (extended family, school, friends, neighbours, and peers of children). Separate set of questions was given for reasons behind their choice and consequences after disclosure. For continuous variables, unpaired T test or Mann – Whitney U test between group and for categorized variables, Pearson’s Chi square test or Fisher’s exact test was used.

Results: 92.96 % of 284 subjects disclosed their child’s epilepsy while 7.04% concealed. Demographic factors and seizure characteristics did not influence the disclosure choice. Most parents revealed to the extended family followed by teachers. Type of seizure was the commonest information revealed. The main reason behind disclosure was better acceptance of the child followed by safety while main barrier was considering epilepsy as private grief. 92.8% felt their children were better accepted after disclosure.

Conclusion: Disclosure practices have improved in parents of children with epilepsy in India and well-being and safety of the child has overridden the fear of stigma and discrimination. This could be the first major step to bring epilepsy out of the shadows at national and global levels.