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Forecasting Cycles of Seizure Likelihood

Objective: Seizure unpredictability is rated as one of the most challenging aspects of living with epilepsy. Seizure likelihood can be influenced by a range of environmental and physiological factors that are difficult to measure and quantify. However, some generalizable patterns have been demonstrated in seizure onset. A majority of people with epilepsy exhibit circadian rhythms in their seizure times, and many also show slower, multiday patterns. Seizure cycles can be measured using a range of recording modalities, including self-reported electronic seizure diaries. This study aimed to develop personalized forecasts from a mobile seizure diary app.

Methods: Forecasts based on circadian and multiday seizure cycles were tested pseudoprospectively using data from 50 app users (mean of 109 seizures per subject). Individuals’ strongest cycles were estimated from their reported seizure times and used to derive the likelihood of future seizures. The forecasting approach was validated using self-reported events and electrographic seizures from the Neurovista dataset, an existing database of long-term electroencephalography that has been widely used to develop forecasting algorithms.

Results: The validation dataset showed that forecasts of seizure likelihood based on self-reported cycles were predictive of electrographic seizures for approximately half the cohort. Forecasts using only mobile app diaries allowed users to spend an average of 67.1% of their time in a low-risk state, with 14.8% of their time in a high-risk warning state. On average, 69.1% of seizures occurred during high-risk states and 10.5% of seizures occurred in low-risk states.

Significance: Seizure diary apps can provide personalized forecasts of seizure likelihood that are accurate and clinically relevant for electrographic seizures. These results have immediate potential for translation to a prospective seizure forecasting trial using a mobile diary app. It is our hope that seizure forecasting apps will one day give people with epilepsy greater confidence in managing their daily activities.

Study Finds More Mental Health Visits Decreases Risk of Suicide Among Youths

A multistate study of Medicaid enrollees led by researchers at The Ohio State University Wexner Medical Center found that suicide risk was highest among youth with epilepsy, depression, schizophrenia, substance use and bipolar disorder. In addition, the odds of suicide decreased among those who had more mental health visits within the 30 days before the date of suicide.

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Researchers compared the clinical profiles and mental health service patterns of children and adolescents who had died by suicide to see how they differed from the general population. The findings published in JAMA Pediatrics.

“To the best of our knowledge, no studies have examined the clinical profiles and health and mental health service utilization patterns prior to suicide for children and adolescents within the Medicaid population,” said lead researcher Cynthia Fontanella, an associate professor in the department of psychiatry and behavioral health at Ohio State Wexner Medical Center. “Understanding how health care utilization patterns of suicidal decedents differ from the general population is critical to target suicide prevention efforts.”

The Effect of an Emotional Intelligence Component Program on Happiness in Patients with Epilepsy

Emotional intelligence is a psychological component that may affect happiness level in patients with epilepsy. Given the high prevalence of depression in patients with epilepsy, as well as the limitations of studies in this regard in Iran, the aim of this study was to investigate the effect of an emotional intelligence component program on happiness in patients with epilepsy.

METHODS: This randomized clinical trial study conducted on 70 patients with epilepsy who were randomly divided into two experimental and control groups of 35 patients. Emotional Intelligence Training Based on Bar-On Combined Model was provided in eight 90-minute sessions for eight weeks. Data were collected using a two-part questionnaire: demographic data and the Oxford Happiness Questionnaire (OHQ).

RESULTS: The mean age of the subjects was 33.3 ± 10.4 years in the intervention group and 34.4 ± 9.3 years in the control group. The independent t-test results showed no significant difference between the two groups before the intervention (p = 0.195). The Mann-Whitney test results showed a significant difference between the two groups after emotional intelligence training (p < 0.001).

CONCLUSION: Overall, the findings of this study showed that emotional intelligence training led to improvement of happiness in patients with epilepsy. According to the results of the study, it is suggested that training based on emotional intelligence components be used as an approach to improve happiness level in patients with epilepsy.

Statistical Model Developed to Study the Placebo Response in Randomized Controlled Epilepsy Trials

BACKGROUND: Changes in patient-reported seizure frequencies are the gold standard used to test efficacy of new treatments in randomized controlled trials (RCTs). Recent analyses of patient seizure diary data suggest that the placebo response may be attributable to natural fluctuations in seizure frequency, though the evidence is incomplete. This study aims to develop a data-driven statistical model and assess the impact of the model on interpretation of placebo response.

METHODS: A synthetic seizure diary generator matching statistical properties seen across multiple epilepsy diary datasets was constructed. The model was used to simulate the placebo arm of 5000 RCTs. A meta-analysis of 23 historical RCTs was compared to the simulations.

RESULTS: The placebo 50%-responder rate (RR50) was 27.3 ± 3.6% (simulated) and 21.1 ± 10.0% (historical). The placebo median percent change (MPC) was 22.0 ± 6.0% (simulated) and 16.7 ± 10.3% (historical).

CONCLUSIONS: A statistical model of daily seizure count generation which incorporates quantities related to the natural fluctuations of seizure count data produces a placebo response comparable to those seen in historical randomized controlled trials. This model may be useful in better understanding the seizure count fluctuations seen in patients in other clinical settings.

Epilepsy Research Findings: March 2020

This month’s research highlights feature promising work by former CURE Grantees and CURE partners.

Former CURE Grantee Dr. Kristina Simeone’s recent research has uncovered a potential predictive biomarker for Sudden Unexpected Death in Epilepsy (SUDEP). Dr. Simeone’s work was supported by the Benninghoven family in memory of Cameron Benninghoven.

We also feature research by another former CURE Grantee, Dr. Angelique Bordey, who along with her research team published exciting findings showing that targeting a particular protein in the brain can reduce or prevent seizures in mouse models of difficult-to-treat epilepsy.

We are also highlighting research by Dr. Daniel Correa and his work through the EpiBioS4Rx Public Engagement Core, a project in which CURE participates. Dr. Correa’s research indicates that greater efforts should be made to ensure online epilepsy health education materials are more easily understandable to the general population to increase epilepsy literacy.

These findings, as well as others, can be found below:

Research Discoveries & News

  • SUDEP: Research featuring the work of former CURE Grantee Dr. Kristina Simeone found a potential time-based biomarker of impending SUDEP. Dr. Simeone found cardiac and respiratory dysfunction that changed over time in mice at risk for SUDEP and may serve as a biomarker to indicate who is at risk for SUDEP. She also found that this dysfunction could be lessened by blocking a particular type of receptor in the brain, the orexin receptorLearn More

    This research was supported by the Benninghoven family in memory of Cameron Benninghoven.

  • Uncontrolled Epilepsy Treatment: Former CURE Grantee Dr. Angelique Bordey and her research team utilized an experimental drug to reduce seizures in mouse models of tuberous sclerosis complex (a rare genetic epilepsy) and a subset of focal cortical dysplasia type II (a brain malformation causing epilepsy). The team found that seizures can be prevented or reduced by targeting a protein called actin-cross linking protein filament A which is often elevated in the brains of humans with these epilepsies. Learn More
  • Online Epilepsy Education: Researcher Dr. Daniel Correa found that the majority of online health education materials related to traumatic brain injury (TBI), epilepsy, and post-traumatic epilepsy (PTE) do not meet the sixth-grade reading level recommendation from most health organizations. This study was published as part of the CURE-supported EpiBioS4Rx Public Engagement Core, an NINDS initiative focused on ensuring successful future clinical trials to prevent the development of PTE following TBI. This study suggests that improving the readability of health education materials may increase epilepsy-related health literacy, leading to more effective recruitment efforts for future clinical trials, as well as better patient-centered results. Learn More
  • New Treatment: Valtoco (diazepam), a nasal spray intended to treat seizure emergencies in patients 6 years of age and older, is now commercially available in the US. Learn More
  • Clinical Trial: Engage Therapeutics announced that its Phase 2b StATES study of Staccato® alprazolam, an orally inhaled therapy designed to terminate an active epileptic seizure, met its primary endpoint. This endpoint was a proportion of responders achieving cessation of seizure activity within two minutes of treatment administration and no recurrence within two hours. Learn More
  • Post-Traumatic Epilepsy: Research suggests that rats treated with certain drugs within a few days of a traumatic brain injury have a dramatically reduced risk of developing epilepsy later in life. Researchers found that suppressing an immune system receptor called Toll-like receptor 4 shortly after brain injury reduces seizure susceptibility and neuronal excitability in an important part of the brain called the hippocampus. Learn More
  • SCN8A Encephalopathy: A therapy that enables researchers to control gene expression in the brain, called antisense oligonucleotides (ASOs), has been utilized to stop seizures in a mouse model of SCN8A encephalopathy, a rare childhood epilepsy. By using ASOs, researchers delayed seizure activity and increased the lifespan of these mice. Learn More

The CURE Epilepsy Research Mobile App delivers research news to the palm of your hand! With frequent updates, you’ll always be in-the-know about the latest in epilepsy science. Download today. iOS | Android

Scientists Pinpoint a Brain Region that Stops Breathing in Pediatric Epilepsy

University of Iowa neuroscientists have identified a specific area of the brain involved in the loss of breathing that occurs during a seizure. The findings, published in JCI Insight on March 12, could have important implications for predicting, or even treating and preventing sudden unexpected death due to epilepsy (SUDEP).

Although it has been known for more than a century that seizures can cause people to stop breathing, for much of that time this transient effect has not been taken very seriously. More recently, evidence has been building, though studies done at the UI and elsewhere, suggesting that seizure-induced loss of breathing plays a critical role in SUDEP, which is the leading cause of death in people who have uncontrolled epilepsy.

In the new study, the UI team led by neurosurgeon Brian Dlouhy, MD, studied eight pediatric patients with epilepsy, ranging in age from 3 to 17, who were undergoing seizure mapping with implanted, intracranial electrodes. Previous studies in adults from UI and elsewhere have shown that the amygdala is important for seizure-induced loss of breathing (apnea), but no one has looked at the role of the amygdala and loss of breathing in children with epilepsy.

Using brain recordings from the implanted electrodes and continuous monitoring of breathing, the researchers showed that a specific (medial) subregion of the amygdala was the critical site in the children’s brains. In two patients they observed loss of breathing when the seizure reached the amygdala; and electrically stimulating the amygdala, but not other parts of the brain, produced apnea in all eight patients. These effects did not depend on the age of the child or type of epilepsy affecting the children.

Remarkably, none of the children were aware that they had stopped breathing during the stimulation trials, and none of them had any of the normal feelings of stress or discomfort that usually happen if a person stops breathing.

Magnolia Bark Compound Could Someday Help Treat Drug-Resistant Epilepsy

In patients with epilepsy, normal neurological activity becomes disrupted, causing debilitating seizures. Now, researchers report in ACS Chemical Neuroscience that they have found a potential new treatment for this disorder by turning to traditional Chinese medicine. Tests of extracts from plants used in these ancient remedies led the team to one compound, derived from a magnolia tree, that could quell drug-resistant seizures in both fish and mice.

To look for new drug leads that could help even those patients who don’t respond to conventional anti-seizure medications, Peter de Witte and colleagues set their sights on plants used in traditional Chinese medicine.

The team collected 14 plants used in traditional Chinese medicine anti-seizure remedies. They then tested the plants’ extracts in two types of zebrafish with epileptic-like seizures, one of which could respond to conventional anti-seizure medications, whereas the other type could not. Only extracts from the bark of Magnolia officinalis, a tree native to China, reduced seizure-like behavior in both types of fish.

Keep Safe: The When, Why and How of Epilepsy Risk Communication

PURPOSE: Risk communication between clinicians and people with epilepsy (PWE) and their families is under researched. There is limited guidance about when and how to have these discussions. This paper explores the current evidence on quality of risk related conversations in epilepsy and suggests a concept of an evidence-based guideline for person centered structured risk communication.

METHODS: A literature search of four electronic database, Ovid Medline, Ovid Embase, PUBMED, and CINAHL, was conducted by two independent reviewers using relevant search terms following the principals of the PRISMA guidance. No limits were applied. Supplementary searches included using backwards and forwards citation searching. A predesigned inclusion and exclusion criteria was administered to the identified results.

RESULTS: From 376 results identified, 17 studies met the final criteria of which ten were quantitative, five qualitative and two mixed methods. Perspectives of PWE and clinicians were represented. Extracted data was clustered into three domains: communication initiation (e.g. timing, individual tailoring); communication methods (preference for face to face with neurologists); and communication content (acknowledging the anxiety produced by risk communication, the benefits of being self-aware, normalizing risk etc.). No papers focused on conversation structure (e.g. helpful phrases), or the best locations to hold conversations.

CONCLUSION: More research is needed to develop structured communication of risk. An attempt has been made to put current evidence into this format. Clearer guidance will enhance clinicians’ confidence in communicating person centered epilepsy risk with people with epilepsy and their families thus improving outcomes.

Study Shows Inflammation, Neuronal Damage and Transitory Disruption of the Blood Brain Barrier Following Single Generalized Convulsive Seizures

PURPOSE: Neuroinflammation and disruption of blood brain barrier (BBB) are important players in epileptogenesis, ictogenesis and pharmacoresistance. In this context, we investigated blood levels of HMGB1 and other inflammatory and BBB markers after generalized and focal to bilateral tonic-clonic seizures in serum, summarized under the term generalized convulsive seizures (GCS).

METHODS: The research team included consenting adults who were admitted to the epilepsy monitoring unit. Blood samples were drawn at baseline and immediately after a GCS as well as after 2, 6 and 24 h. The team measured leukocytes, c-reactive protein (CRP), the danger-associated molecular patterns (DAMPs) high mobility group box 1 (HMGB1) and S100, receptor of advanced glycation end products (RAGE) alongside the BBB markers intercellular adhesion molecule-1 (ICAM1) and matrix metalloproteinase 9 (MMP9). Noradrenaline and lactate measurements were available from a previous study. P-levels < 0.05 were regarded as significant.

RESULTS: Twenty-eight patients with 28 GCS were included. Leukocytosis occurred immediately after GCS and normalized within two hours (p < 0.001). S100 and HMGB1 both increased by ?80 % (p < 0.001). MMP9 peaked after six hours with levels at 48.6 % above baseline. RAGE decreased by 17.6 % with a nadir at 24 h. CRP increased by 118 % with a peak at 24 h. ICAM1 remained stable (p = 0.068). Postictal HMGB1 correlated with postictal leukocytosis (r = 0.42; p = 0.025) and with MMP9 levels six hours later (r = 0.374; p = 0.05). Postictal lactate levels correlated with MMP9 at 6 h (r = 0.48; p = 0.01) and CRP at 24 h (r = 0.39; p = 0.04). Postictal noradrenaline correlated with lactate (r = 0.57; p = 0.02) and leukocytes (r = 0.39; p = 0.047).

DISCUSSION: The serum level of the DAMPs HMGB1 and S100 increase immediately after GCS. The hypothetical mechanism includes central nervous processes, such as glutamate toxicity and ROS release from seizing neurons but also muscular tissues. BBB breakdown is marked by the release of MMP9. Further research is needed to understand the complex interactions between electrical and metabolic stress, neuroinflammation and BBB mechanics in seizures and epilepsy.

CONCLUSION: According to the researchers, this study reveals signs of inflammation, neuronal damage and transitory disruption of blood brain barrier following single generalized convulsive seizures, underscoring the widespread and possibly detrimental effects of recurrent seizures on brain properties. The long term impact on the disease course, however, is unclear.

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Marinus Pharmaceuticals Completes Targeted Enrollment in Pivotal Phase 3 Study for CDKL5 Deficiency Disorder

Marinus Pharmaceuticals, Inc., announced it has reached the 100 patient enrollment target for the Marigold Study.  The Marigold Study is a pivotal Phase 3 study evaluating oral ganaxolone in children and young adults with CDKL5 Deficiency Disorder (CDD), a rare refractory form of pediatric epilepsy with no currently approved treatments.  The Company will continue enrollment through the end of the month to capture the remaining few patients in the screening phase.

“Enrolling 100 patients in our registrational, pivotal Phase 3 trial evaluating ganaxolone in children with CDD is a significant milestone for both Marinus and the CDD community,” said Joe Hulihan, M.D., Chief Medical Officer of Marinus. “Our ability to identify and rapidly enroll qualified patients into this study is indicative of the significant need for a new therapy to reduce seizure burden and improve patient outcomes. The study has been well conducted and we are encouraged by the limited adverse events, low dropout rates and the vast majority of patients entering the open-label extension. We are appreciative of the patients and broader CDD community for their participation in the Marigold study and we remain committed to addressing the unmet need of these patients who currently have no approved treatment options.”