CHOP Researchers Develop First-Of-Its-Kind Prediction Model for Newborn Seizures

Article published by NewsWise

Researchers from the Neuroscience Center at Children’s Hospital of Philadelphia (CHOP) have developed a prediction model that determines which newborn babies are likely to experience seizures in the Neonatal Intensive Care Unit (NICU). This model could be incorporated into routine care to help the clinical team decide which babies will need electroencephalograms (EEGs) and which babies can be safely managed in the Neonatal Care Unit without monitoring through EEGs. This would allow families and providers to care for babies without intrusive and unnecessary procedures. The findings were published by The Lancet Digital Health.

Neonatal seizures are a common neurological issue in newborn babies. In particular, approximately 30% of newborn babies with temporary lack of oxygen to the brain (known as hypoxic-ischemic encephalopathy, or HIE) will have seizures. Most of these seizures can only be detected through EEG monitoring and not simply through clinical observation, an important lesson that has shaped the management of babies with seizures in the last two decades. Newborns with HIE are at an increased risk for neurobehavioral problems and epilepsy later in life, and detecting and treating seizures is important to reduce seizure-induced injury, thereby improving outcomes for newborns with early seizures.

Current guidelines suggest that newborns with HIE undergo four to five days of EEG monitoring to detect seizures. However, this approach is not always feasible, as many of these babies receive care in NICUs that do not have access to continuous EEG (CEEG). Even NICUs in large healthcare networks often only have limited EEG resources, especially as the interpretation of EEG readings is time intensive for the entire care team, including physicians and technologists.

Predicting which newborns will experience seizures is complex, and prior attempts to predict future seizures using clinical and EEG data have not yielded highly accurate results. To help address these issues, researchers at CHOP used data from a recently developed EEG reporting form that is used for all EEGs to build prediction models using machine learning methods.

“In this study, we used data from the EEGs of more than 1,000 newborns to build models to predict neonatal seizures,” first study author Jillian McKee, MD, PhD, a pediatric epilepsy fellow in the Division of Neurology and the Pediatric Epilepsy Program at CHOP. “This data helped us optimize which newborns should receive EEG monitoring in the NICU.”

Outcomes of the Second Withdrawal of Anti-Seizure Medication in Patients with Pediatric Onset-Epilepsy

Abstract found on PubMed

Withdrawal of anti-seizure medication (ASM) is challenging, especially in patients with recurrent seizures. Only limited evidence exists regarding the success or recurrence rate and risk factors for seizure recurrence after withdrawal of ASM for a second time in patients with pediatric-onset epilepsy. In this observational study, we evaluated 104 patients with recurrent pediatric-onset epilepsy who had ASM withdrawn for a second time. The success rate was 41.3% after the second withdrawal of ASM. The absence of self-limiting epilepsy syndrome, shorter seizure-free intervals before the second withdrawal of ASM, and relapse during tapering after the initial withdrawal of ASM were factors significantly associated with the success of ASM withdrawal for a second time. Even after a second seizure recurrence, all patients eventually became seizure-free after restarting their previous ASM (78.7%) or readjusting the ASM (21.3%). Our findings that 40% of patients with recurrent pediatric-onset epilepsy could achieve long-term seizure freedom and that all patients with a second seizure recurrence remained seizure free suggest that ASM may be withdrawn for a second time after carefully stratifying clinical risk.

Epilepsy Research News: March 2023

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


Epilepsy-Causing Neural “Hubs” in Children

A new method of determining which brain cells lead to seizures in children has been developed. The team used noninvasive techniques and advanced computational methods to measure the electric and magnetic signals generated by neural cells to identify brain “hubs” responsible for the generation of seizures in children with epilepsy. This team retrospectively analyzed electroencephalography (EEG) and magnetoencephalography data recorded from 37 children and young adults with drug-resistant epilepsy who had neurosurgery. They then created a virtual model of the brain and virtually implanted sensors at locations where invasive EEG contacts had been placed during neurosurgery. The researchers found that the virtual sensors could non-invasively identify highly connected hubs in patients with drug-resistant epilepsy. The authors stated that the discovery could help to identify areas of the brain that generate epileptic activity in children with drug-resistant epilepsy in a non-invasive way.

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Potential Cause of Infantile and Epileptic Spasms Syndrome

New research featuring the work of a former CURE Epilepsy grantee, Dr. Chris Dulla, and colleagues suggests that the timing of the death of a subset of neurons in the brain shortly after birth may be partly to blame for infantile and epileptic spasms syndrome (a form of which is also called infantile spasms (IS) or West syndrome), a childhood epilepsy with poor outcomes. These neurons are responsible for providing inhibitory input to the brain; the lack of these neurons may lead to too much excitation and epileptic spasms. The research suggests that it may be the timing of inhibitory neuron cell death which is important, not just the fact that it occurs. This research may suggest a potential target for the future development of treatments for infantile and epileptic spasms.

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Underreported Symptoms in Patients with Genetic Epilepsy

A new study increases our understanding of symptoms associated with changes in the STXBP1 gene, one of the most common genetic causes of childhood epilepsies and neurodevelopmental disorders. By systematically mapping symptoms and assessing their impacts on patients and their caregivers, the researchers identified previously underreported symptoms beyond just neurological symptoms. To understand these symptoms, the researchers performed more than 24 hours of interviews among 19 caregivers of 16 individuals with STXBP1-related disorders and seven healthcare professionals. In doing so, the researchers created a so-called “disease concept model,” which is meant to determine which outcomes are relevant in everyday clinical practice. These results may serve as an important foundation for future trials assessing the effectiveness of therapeutic interventions for all related symptoms.

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How Cannabidiol Counters Epileptic Seizures

A study reveals a previously unknown way in which cannabidiol (CBD), a substance found in cannabis, reduces seizures in many treatment-resistant forms of pediatric epilepsy. The new study found that CBD blocked signals carried by a molecule called lysophosphatidylinositol (LPI). Found in brain cells called neurons, LPI is thought to amplify nerve signals as part of normal function but can also be hijacked by disease to promote seizures. The work confirmed a previous finding that CBD blocks the ability of LPI to amplify nerve signals in a brain region called the hippocampus. The current findings suggest for the first time that LPI also weakens signals that counter seizures, further explaining the value of CBD treatment. “Our results deepen the field’s understanding of a central seizure-inducing mechanism, with many implications for the pursuit of new treatment approaches,” stated a study author. “The study also clarified, not just how CBD counters seizures, but more broadly how neural circuits are balanced in the brain.”

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How the Brain’s Immune System Response Worsens Epilepsy

In a new study using a fruit fly model of epilepsy, researchers describe a chain of events that link the brain’s immune system response to worsening seizures. The researchers used flies with a mutation in a gene known as the prickle gene, similar to the mutation in the PRICKLE gene found in humans with progressive myoclonus epilepsy with ataxia, and found that this particular mutation can lead to increases in a condition called oxidative stress. The researchers found that oxidative stress can activate the brain’s resident immune cells (called glia), which in turn triggers more severe seizures. “We have provided genetic proof that both oxidative stress and activation of the brain immune system make epilepsy worse,” stated a study author. “This is hugely significant because our data suggest that we can now repurpose exceedingly well-tolerated anti-inflammatory compounds as well as perhaps antioxidants to help control epilepsy progression.”

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Seizures, Altered Brain Structures Linked in Angelman Children: Study

Article published by Angelman Syndrome News

Certain structures within the brains of children with Angelman syndrome were altered compared with unaffected children of the same age, an MRI study concluded.

Imaging found a thinner and more folded outer cortex layer and reduced gray matter volume within the inner subcortex region in Angelman children.

More serious abnormal brain patterns appeared to be linked to the occurrence of seizures, the researchers noted in the MRI study, “Cortical and subcortical morphological alteration in Angelman syndrome,” which was published in the Journal of Neurodevelopmental Disorders.

Angelman syndrome is a neurodevelopmental disorder marked by poor muscle control (ataxia), intellectual disability, speech impairment, seizures, and hyperactivity.

Emerging evidence from MRI imaging studies indicates changes in several structures within the brains of Angelman patients, which may affect brain function and cause symptoms.

Researchers in China applied a set of high-resolution brain MRI measurements to detail the Angelman brain and determine whether any detected abnormalities are associated with seizures.

“To the best of our knowledge, this is the first study conducted on a Chinese population with [Angelman syndrome],” they wrote.

Sense of Control, Selective Attention, Cognitive Inhibition, and Psychosocial Outcomes after Retraining and Control Therapy (ReACT) in Pediatric Functional Seizures

Abstract found on PubMed

Background: Differences in sense of control, cognitive inhibition, and selective attention in pediatric functional seizures (FS) versus matched controls implicate these as potential novel treatment targets. Retraining and Control Therapy (ReACT), which targets these factors, has been shown in a randomized controlled trial to be effective in improving pediatric FS with 82% of patients having complete symptom remission at 60 days following treatment. However, post-intervention data on sense of control, cognitive inhibition, and selective attention are not yet available. In this study, we assess changes in these and other psychosocial factors after ReACT.

Methods: Children with FS (N = 14, Mage = 15.00, 64.3% female, 64.3% White) completed 8 weeks of ReACT and reported FS frequency at pre and post-1 (7 days before and after ReACT). At pre, post-1, and post-2 (60 days after ReACT), all 14 children completed the Pediatric Quality of Life Inventory Generic Core Scales, Behavior Assessment System (BASC2), and Children’s Somatic Symptoms Inventory-24 (CSSI-24), and 8 children completed a modified Stroop task with seizure symptoms condition in which participants are presented with a word and respond to the ink color (e.g., “unconscious” in red) to assess selective attention and cognitive inhibition.

Results: Awareness that control was manipulated in the turbulence condition of the MAT increased at post-1 vs. pre- (p = 0.02, ?2 = 0.57). This change correlated with a reduction in FS frequency after ReACT (r = 0.84, p < 0.01). Reaction time significantly improved for the seizure symptoms Stroop condition at post-2 compared to pre- (p = 0.02, ?2 = 0.50), while the congruent and incongruent conditions were not different across time points. Quality of life was significantly improved at post-2, but the improvement was not significant when controlling for change in FS. Somatic symptom measures were significantly lower at post-2 vs. pre (BASC2: t(12) = 2.25, p = 0.04; CSSI-24: t(11) = 4.17, p < 0.01). No differences were observed regarding mood.

Conclusion: Sense of control improved after retraining and control therapy (ReACT), and this improvement was proportional to a decrease in functional seizures (FS), suggesting this as a possible mechanism by which ReACT treats pediatric FS. Selective attention and cognitive inhibition were significantly increased 60 days after ReACT. The lack of improvement in QOL after controlling for change in FS suggests QOL changes may be mediated by decreases in FS. ReACT also improved general somatic symptoms independent of FS changes.

The Impact of Parent Treatment Preference and Other Factors on Recruitment: Lessons Learned from a Paediatric Epilepsy Randomised Controlled Trial

Abstract found on Trails Journal

Background: In paediatric epilepsy, the evidence of effectiveness of antiseizure treatment is inconclusive for some types of epilepsy. As with other paediatric clinical trials, researchers undertaking paediatric epilepsy clinical trials face a range of challenges that may compromise external validity.

Main body: In this paper, we critically reflect upon the factors which impacted recruitment to the pilot phase of a phase IV unblinded, randomised controlled 3×2 factorial trial examining the effectiveness of two antiseizure medications (ASMs) and a sleep behaviour intervention in children with Rolandic epilepsy. We consider the processes established to support recruitment, public and patient involvement and engagement (PPIE), site induction, our oversight of recruitment targets and figures, and the actions we took to help us understand why we failed to recruit sufficient children to continue to the substantive trial phase.

The key lessons learned were about parent preference, children’s involvement and collaboration in decision-making, potential and alternative trial designs, and elicitation of stated preferences pre-trial design.

Despite pre-funding PPIE during the trial design phase, we failed to anticipate the scale of parental treatment preference for or against antiseizure medication (ASMs) and consequent unwillingness to be randomised. Future studies should ensure more detailed and in-depth consultation to ascertain parent and/or patient preferences. More intense engagement with parents and children exploring their ideas about treatment preferences could, perhaps, have helped predict some recruitment issues. Infrequent seizures or screening children close to natural remission were possible explanations for non-consent. It is possible some clinicians were unintentionally unable to convey clinical equipoise influencing parental decision against participation. We wanted children to be involved in decisions about trial participation. However, despite having tailored written and video information to explain the trial to children we do not know whether these materials were viewed in each consent conversation or how much input children had towards parents’ decisions to participate. Novel methods such as parent/patient preference trials and/or discrete choice experiments may be the way forward.

Conclusion: The importance of diligent consultation, the consideration of novel methods such as parent/patient preference trials and/or discrete choice experiments in studies examining the effectiveness of ASMs versus no-ASMs cannot be overemphasised even in the presence of widespread clinician equipoise.

Many Kids with Epilepsy Don’t Respond to Drugs. Cook Children’s Research Could Help Them 

Article published by Fort Worth Star-Telegram

Researchers at Cook Children’s Health Network published new research in February demonstrating noninvasive ways to measure electric signals in the brain, a tool that could be used to treat children with epilepsy. Of the roughly 50 million people worldwide who suffer from epilepsy, researchers estimate that existing drugs don’t work to stop seizures for at least 20% of people. For these patients, brain surgery is often the best option for treatment, as repeated, untreated seizures over time can cause lasting damage. For these complex surgeries, doctors must identify the areas of the brain where seizures originate.

The research, led by a neuroscientist at Cook Children’s, offers new information on these brain surgeries, and has identified a potential way to identify the areas where seizures originate. The peer-reviewed research was published in “Brain,” a neurology journal. TOP VIDEOS “This novel method has the potential to improve the outcome of children with epilepsy, particularly those who were previously ineligible for neurosurgery due to the absence of abnormal activity in their electrophysiological conventional diagnostic tests,” Papadelis, the director of neuroscience research at Cook Children’s, said in a statement.

Researchers retrospectively reviewed the cases of 37 children and young adults with drug-resistant epilepsy who had undergone brain surgery at Boston Children’s Hospital. Their work concluded that noninvasive techniques to prepare for surgery could work better than existing, invasive methods.

Ketamine as Advanced Second Line Treatment in Benzodiazepine-Refractory Convulsive Status Epilepticus in Children

Abstract found on PubMed

Status epilepticus (SE) is one of the most common neurological emergencies in children. To date, there is no definitive evidence to guide treatment of SE refractory to benzodiazepines. The main objectives of treatment protocols are to expedite therapeutic decisions and to use fast and short-acting medications without significant adverse effects. Protocols differ among institutions and most frequently valproate, phenytoin, and levetiracetam are used as second line treatment. After failure of first- and second-line medications, admission to the intensive care unit and continuous infusion of anesthetics are usually indicated. Ketamine is a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist that has been safely used for the treatment of refractory SE in adults and children. In animal models of SE ketamine demonstrated antiepileptic and neuroprotective properties and synergistic effects with other antiseizure medications. We reviewed the literature to demonstrate the potential role of ketamine as advanced second line agent in the treatment of SE. Pharmacological targets, pathophysiology of SE and the receptor trafficking hypothesis are reviewed and presented. The pharmacology of ketamine is outlined with related properties, advantages and side effects. We summarized the most recent and relevant publications on experimental and clinical studies on ketamine in SE. Key-experts’ opinion is also reported. Considering the current knowledge on SE pathophysiology, early sequential polytherapy should include ketamine for its wide range of positive assets. Future research and clinical trials on SE pharmacotherapy should focus on the role of ketamine as second line medication.

WWOX Developmental and Epileptic Encephalopathy (WWOX-DEE): Understanding the Epileptology and the Mortality Risk

Abstract found on PubMed

Objective: WWOX is an autosomal recessive cause of early infantile developmental and epileptic encephalopathy (WWOX-DEE), also known as WOREE (WWOX-related epileptic encephalopathy). We analysed the epileptology and imaging features of WWOX-DEE, and investigated genotype-phenotype correlations, particularly with regards to survival.

Methods: We studied thirteen patients from twelve families with WWOX-DEE. Information regarding seizure semiology, comorbidities, facial dysmorphisms and disease outcome were collected. EEG and brain MRI data were analysed. Pathogenic WWOX variants from our cohort and the literature were coded as either null or missense allowing individuals to be classified into one of three genotype classes: 1) null/null 2) null/missense, 3) missense/missense. Differences in survival outcome were estimated using the Kaplan-Meier method.

Results: All patients experienced multiple seizure types (median onset 5 weeks, range: 1 day – 10 months); the most frequent being focal (85%), epileptic spasms (77%) and tonic seizures (69%). Ictal EEG recordings in 6/13 patients showed tonic (n=5), myoclonic (n=2), epileptic spasms (n=2), focal (n=1) and migrating focal (n=1) seizures. Interictal EEGs demonstrated slow background activity with multifocal discharges, predominantly over frontal or temporo-occipital regions. 11/13 patients had a movement disorder, most frequently dystonia. Brain MRIs revealed severe frontotemporal, hippocampal, and optic atrophy, thin corpus callosum, and white matter signal abnormalities. Pathogenic variants were located throughout WWOX and comprised both missense and null changes including five copy number variants (4 deletions; 1 duplication). Survival analyses showed that patients with two null variants are at higher mortality risk (p-value = 0.0085, log-rank test).

Significance: Biallelic WWOX pathogenic variants cause an early-infantile developmental and epileptic encephalopathy syndrome. The most common seizure types are focal seizures and epileptic spasms. Mortality risk is associated with mutation type; patients with biallelic null WWOX pathogenic variants have significantly lower survival probability compared to those carrying at least one presumed hypomorphic missense pathogenic variant.

Epilepsy Research News: February 2023

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


Combining Diet with Drugs to Reduce Seizures

Following a modified Atkins diet that is high in fat and low in carbohydrates in addition to taking antiseizure medication(s) may reduce seizures in people with tough-to-treat epilepsy, according to a recently published study. The study involved 160 adults and adolescents who had epilepsy for more than 10 years on average and had at least 27 seizures per month, despite trying an average of four antiseizure medications at the maximum tolerated dose. After six months, researchers found that 26% of people who used drug therapy and followed the modified Atkins diet had more than a 50% reduction in seizures, compared to only 3% of the people who had drug therapy alone. Four people in the diet group were seizure free by the end of the study, while no one in the medication-only group was seizure free. A limitation of the study is that seizures were self-reported or reported by caregivers, so some seizures may not have been reported. Despite this important consideration, “for people with drug-resistant epilepsy, or those who have been unable to find effective treatment to reduce seizures, it’s encouraging to see that there are lifestyle changes that can be combined with standard drug therapy to reduce the number of seizures,” stated a study author.

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Parents Need Guidance Managing Sleep Issues in Children with Epilepsy

According to a new qualitative study that included interviews with nine mothers, sleep and epilepsy have a complex and bidirectional relationship. The aim of the study was to capture parental perceptions and experiences related to their child’s sleep habits and management, the impact of sleep difficulties on the child and their family, and available support. According to the study, epilepsy exacerbated 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. Study authors noted that 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. The authors also stated that the finding emphasizes the need to ensure adequate help is available to support healthy sleep in children with epilepsy.

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New Understanding of the Cause of Post-Traumatic Epilepsy (PTE)

A research team has uncovered information about changes that occur in the brain following a traumatic brain injury (TBI) that could help advance future preventative treatments for PTE, a type of epilepsy caused by a TBI. The findings show that activation of a subset of neurons within an area of the brain called the hippocampus plays a key role in the changes that occur during the development of PTE. For this study, the team looked at neurons called dentate granule cells, which continuously regenerate in areas of the brain that are crucial for learning and memory and are also commonly impacted by epilepsy. The team found that when the dentate granule cells were activated, the activity of other brain cells involved in epilepsy was inhibited. They also found that the cells that were formed just prior to a were much more likely to activate this circuit than those generated at other points in time. The team noted that being able to get to a point of understanding the changes that occur in the development of epilepsy may lead to the ability to prevent or reverse epilepsy.

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Links Between Parental Factors, Emotional, and Behavioral Issues Found in Pediatric Epilepsy

Adolescents with epilepsy commonly experience emotional and behavioral problems, which vary depending on demographic, clinical, and parental factors, according to a new study. The parental factors included how parents perceived that others treated their child. The study included 289 adolescents aged between 11 and 18 years. The study found 18.3% of adolescents with epilepsy had at least one emotional or behavioral problem in the clinical range. Additionally, consistent with findings of prior studies, this study showed one in four parents of adolescents with epilepsy perceived that other people felt uncomfortable with their child, treated their child as inferior, or preferred to avoid their child because of their epilepsy. Due to these findings, the study’s authors emphasized it is crucial to identify and properly manage these problems early to decrease comorbid psychopathology in adolescents with epilepsy.

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Use of Newer Antiseizure Medications for Epilepsy Differs by Race, Ethnicity

Racial and ethnic minority groups are less likely to be taking newer-generation antiseizure medications for their epilepsy, an analysis of Medicaid data showed. Compared with white patients, Black, Hispanic, and Native Hawaiian/Pacific Islander patients had lower odds of being on newer antiseizure medications, the study found. Of note, taking a second-generation antiseizure medication was associated with better treatment adherence, and those seeing a neurologist had higher odds of being on newer antiseizure medications. The study authors stated that being on a newer, second and third-generation antiseizure medication may represent an important marker of quality of care for people with epilepsy and that differences appear to reflect racial and ethnic inequities in epilepsy care.

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