Epilepsy Research News: May 2023

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

 

Epilepsy with Eyelid Myoclonia (EEM)

A newly published article, written by a steering committee convened by CURE Epilepsy, provides a comprehensive review of the characteristics of EEM, also known as Jeavons syndrome. EEM is a type of epilepsy?that occurs in childhood, with seizures often continuing into adulthood. It is more common in females and its hallmark traits consist of eyelid myoclonia (brief jerks of the eyelids) with or without absence seizures, eye closure-induced seizures, and photosensitivity. Individuals with EEM are often misdiagnosed and anti-seizure medication resistance is common, highlighting the need for further studies to understand more about this epilepsy and possible interventions to treat it.  

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A Computer Model of Epilepsy Brain Used in Clinical Trial for Epilepsy Surgery

Scientists in France are looking at how a computer model of the brain can improve the localization of the seizure zone before epilepsy surgery. The models are created using the Virtual Epileptic Patient (VEP), which employs brain scans and brainwave-recording data from individuals with epilepsy to build a personalized model to improve the understanding of where their seizures originate. The study authors said that VEP showed a 60% precision in identifying the epileptogenic zones in 53 patients with drug-resistant focal epilepsy. VEP is being evaluated in an ongoing clinical trial called EPINOV. If the trial results are promising, this computer model may become a new, personalized tool used in epilepsy surgical evaluations to improve surgical outcomes.  

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Worsened Perinatal Outcomes in Women with Epilepsy

Recently published findings showed that women with epilepsy have worse perinatal outcomes compared with women without epilepsy, including a 5-fold increase in the odds of maternal death. Combining the results of 76 already-published papers, investigators found that relative to women without epilepsy, those with epilepsy had increased odds of gestational hypertension, preeclampsia, intrauterine growth restriction, miscarriage, preterm birth, induced labor, stillbirth, cesarean delivery, and maternal death. “When counseling pregnant women with epilepsy and those of childbearing age, clinicians should consider these findings,” a lead investigator concluded. “In addition, clinicians and women with epilepsy should bear in mind the increased odds of negative adverse maternal and neonatal outcomes.”  

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Early-Life Meningitis Associated with Risk of Developing Epilepsy in Later Childhood

Infants exposed to invasive Group B Streptococcus (iGBS) meningitis during their first three months of life could have a greater risk of developing epilepsy in later childhood compared to infants who were not exposed, according to a recent study. Investigators evaluated the cumulative risk (CR) of an infant diagnosed with iGBS sepsis or meningitis during the first three months of age developing epilepsy. Examining a group of 1,432 children with iGBS and 14,211 without iGBS, the team found that the overall CR of developing epilepsy into later childhood was 3.6% among children with iGBS disease, whereas the CR of later-adulthood epilepsy was 2.3% in the group without iGBS. The study authors noted that the data have implications for affected individuals and underline the need for better long-term follow-up and care. 

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A Comprehensive Narrative Review of Epilepsy with Eyelid Myoclonia

Article published by Epilepsy Research

Epilepsy with eyelid myoclonia (EEM) is a generalized epilepsy syndrome with childhood-onset and 2:1 female predominance that consists of: 1. eyelid myoclonia with or without absence seizures, 2. eye closure induced seizures or EEG paroxysms, 3. clinical or EEG photosensitivity. While eyelid myoclonia is the disease hallmark, other seizure types, including absence seizures and generalized tonic-clonic seizures, may be present. It is thought to have a genetic etiology, and around one-third of patients may have a positive family history of epilepsy. Recently, specific genetic mutations have been recognized in a minority patients, including in SYNGAP1, NEXMIF, RORB, and CHD2 genes. There are no randomized controlled trials in EEM, and the management literature is largely restricted to small retrospective studies. Broad-spectrum antiseizure medications such as valproate, levetiracetam, lamotrigine, and benzodiazepines are typically used. Seizures typically persist into adulthood, and drug-resistant epilepsy is reported in over 50%.

Early-Life Meningitis Associated with Risk of Developing Epilepsy in Later Childhood

Article published by Pharmacy Times

Infants exposed to invasive Group B Streptococcus (iGBS) meningitis during their first 3 months of life could have a greater risk of developing epilepsy in later childhood compared to infants who were not exposed, according to a 20-year study conducted from Denmark that was recently published in JAMA Network Open. iGBS is a leading cause of neonatal/young infant mortality. It is also associated with maternal death, stillbirth, and neurodevelopmental impairment (NDI) in the surviving neonates. NDIs include stroke, encephalopathy, cerebral palsy, intellectual and/or motor, vision, hearing impairment, sepsis, and meningitis. Among the limited and small studies that analyze NDI outcomes, most focus on meningitis.

Meningitis may cause epilepsy following neonatal iGBS disease. However, more research is needed to understand iGBS disease on the risk of long-term epilepsy, and the risk among patients with neonatal iGBS sepsis. Investigators evaluated the cumulative risk (CR) of an infant diagnosed with iGBS sepsis or meningitis during the first 3 months of age developing epilepsy. The team accounted for sex, prematurity, and maternal socioeconomic position (SEP) as effect modification factors.

Epilepsy Research News: April 2023

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

 

Predicting Seizures in Temporal Lobe Epilepsy

Seizures can be predicted more than 30 minutes before they occur in patients with temporal lobe epilepsy, possibly opening the door to preventing seizures from happening, according to a new study. Researchers used electroencephalography (EEG), which measures electrical activity in the brain, to examine periods of potentially heightened risk for seizures known as “pro-ictal states.” The researchers were able to detect pro-ictal states in patients with temporal lobe epilepsy approximately 30 minutes or more before seizure onset. This information could lead to the development of electrical stimulation or drug therapies aimed at preventing seizures in people with this type of epilepsy. “The ability to predict seizures before they occur is a major step forward in the field of epilepsy research,” a study author stated.

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Altered Brain Signaling in People with Epilepsy Detected Through Non-Invasive Approach

New research has found that large-scale changes in the activation of neurons can be detected in the brains of people with temporal lobe epilepsy during a resting state (a state in which the brain is not stimulated by tasks or input), even when no seizure is occurring. The non-invasive approach uses EEG to detect changes in brain activity and could lead to a new method to aid in the diagnosis of epilepsy. While the brain is at rest, spontaneous waves of neuronal activation are constantly generated in a phenomenon called a “neuronal avalanche.” The researchers demonstrated that even during the resting state it is possible to detect a change in the neuronal avalanches in the brains of people with epilepsy. The researchers suggested that this method might be used as a preliminary diagnostic method, especially for difficult cases where standard scalp EEG fails to detect seizures, but additional investigations are necessary.

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Simple Blood Test Shows Potential Biomarker to Distinguish Epileptic from Non-Epileptic Psychogenic Seizures

Researchers have discovered higher levels of immune proteins in the blood before and after an epileptic seizure. In this study, researchers discovered that levels of five inflammation markers, or proteins, were elevated in people with temporal or frontal lobe epilepsy who had experienced a seizure. Among patients with psychogenic non-epileptic seizures (PNES), however, there was no change in the protein levels. These proteins, therefore, have the potential to be future biomarkers for a diagnosis of epilepsy. Diagnosing epilepsy from a simple blood draw would provide a significant advantage over the current diagnostic standards which may include admittance to a hospital for several days with constant video and EEG surveillance.

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Study Investigates Therapy for Treatment-Resistant Epilepsy

In a new study, researchers report that sodium selenate could be the first curative drug therapy for epilepsy. The study, conducted in an animal model of drug-resistant epilepsy, revealed sodium selenate to have a long-lasting effect (after months of stopping the medication) in reducing the frequency of seizures and in 30% of cases stopping them altogether. Sodium selenate also improved other aspects of epilepsy such as memory, learning, and sensor-motor functioning. The researchers will next begin a clinical trial of sodium selenate as a curative treatment in patients with drug-resistant epilepsy. “Despite the cost of the disease and the enormous amount of research into it, there has not been a single therapy developed to prevent the development of epilepsy,” stated a study author. “This Phase 2 clinical trial, if effective, has the potential to tackle a disease that is an enormous global burden as well as being truly transformative for people who are impacted by often daily seizures, with no respite.”

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Insights into the Drivers of Glioma-Related Epilepsy

Researchers at Baylor College of Medicine, including former CURE Epilepsy grantee Dr. Jeff Noebels, report that glioma tumors in the brain can interfere with the ability of surrounding neurons to handle potassium, an important ion in neuronal communication. The disruption of this normal neural function drives seizures and favors the progression of epilepsy. The team found that patients who have seizures have increased expression of genes involved in the formation of neuronal connections or synapses. In both humans with glioma and animal models, the researchers identified one of the genes, IGSF3, as the driver that mediated seizures in glioma-related epilepsy. The team found that IGSF3 suppresses the ability of these cells to take up potassium, which leads to its accumulation of this ion and then seizures. “Our studies reveal that tumor progression and seizures are triggered by disruption of potassium handling. The findings support further studies into novel strategies to control seizures and tumor growth,” stated one of the study’s authors.

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Researchers Identify Cause of Mysterious Cases of Childhood Epilepsy

Article published by  SciTechDaily

International research teams have uncovered a new cause for pediatric seizures: mosaicism, a condition in which cells within the same individual have different genetic compositions.

Approximately 4% of the population is affected by epilepsy, making it one of the most prevalent brain disorders among children. While modern medicine is effective in preventing seizures in the majority of patients, unfortunately, 20% of those with epilepsy do not respond to treatment.

In some cases, the cause of epilepsy may stem from patches of damaged or abnormal brain tissue known as “malformations of cortical development” (MCD). These MCDs result in a variety 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.

In a recent paper published in Nature Genetics, researchers at the 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.

Members of the Focal Cortical Dysplasia Neurogenetics Consortium investigated 283 brain resections from children across a range of MCD types, with parental consent, looking for potential genetic causes. Because most brain tissue in these children is normal, the scientists focused on mutations present in a small subset of brain cells, a phenomenon termed genetic somatic mosaicism.

“This was a decade-long journey, bringing specialists together from around the world, to recruit patients for this study,” said senior study author Joseph Gleeson, MD, Rady Professor of Neuroscience at UC San Diego School of Medicine and director of neuroscience research at the Rady Children’s Institute for Genomic Medicine. “Until recently, most hospitals did not study resected brain tissue for genetic causes. The consortium organized a biobank to store tissue for high-throughput mosaicism analysis.”

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.