Autism and Seizures May Share Roots in Development

Early behavioral signs predict seizures in autistic children, according to a new study.

Previous work has shown that 5 to 46 percent of people with autism experience seizures. And autistic adults with epilepsy have, on average, less cognitive ability and weaker daily living skills than their autistic peers who do not have seizures.

The new study shows that people with autism who begin having seizures during childhood show small but significant behavioral differences before they ever experience a seizure, compared with those who do not develop epilepsy. They score lower than their peers on measures of quality of life and adaptive behaviors, which include communication, daily living skills, socialization and motor skills. They score higher on a measure of hyperactivity.

The results suggest that seizures and certain behavioral issues in autism could have common origins, says co-lead investigator Jamie Capal, associate professor of pediatrics and neurology at the University of North Carolina at Chapel Hill.

“I think it really does show us that in individuals with autism who eventually have epilepsy, there is some shared mechanism early on that we just haven’t been able to identify,” Capal says.

A blond woman cradles her infant in her arms, trying to soothe them.

Levetiracetam (Keppra®) Versus Phenobarbital (Solfoton®) for Seizures in Newborn Children: A Randomized Controlled Trial

Abstract, published in Pediatrics

BACKGROUND AND OBJECTIVES: There are no US Food and Drug Administration–approved therapies for neonatal seizures, which are seizures that occur in newborn children. Phenobarbital and phenytoin frequently fail to control seizures. There are concerns about the safety of seizure medications in the developing brain. Levetiracetam has proven efficacy and an excellent safety profile in older patients; therefore, there is great interest in its use in newborn children. However, randomized studies have not been performed. Our objectives were to study the efficacy and safety of levetiracetam compared with phenobarbital as a first-line treatment of neonatal seizures.

METHODS: The study was a multicenter, randomized, blinded, controlled, phase IIb trial investigating the efficacy and safety of levetiracetam compared with phenobarbital as a first-line treatment for neonatal seizures of any cause. The primary outcome measure was complete seizure freedom for 24 hours, assessed by independent review of the pattern of brain waves by 2 neurophysiologists.

RESULTS: Eighty percent of patients (24 of 30) randomly assigned to phenobarbital remained seizure free for 24 hours, compared with 28% of patients (15 of 53) randomly assigned to levetiracetam. A 7.5% improvement in efficacy was achieved with a dose escalation of levetiracetam from 40 to 60 mg/kg. Although more adverse effects were seen in subjects randomly assigned to phenobarbital, they were not statistically significant.

CONCLUSIONS: In this phase IIb study, phenobarbital was more effective than levetiracetam for the treatment of neonatal seizures. Higher rates of adverse effects were seen with phenobarbital treatment. Higher-dose studies of levetiracetam are warranted, and definitive studies with long-term outcome measures are needed.

A mother sits beside he son, consoling him after school.

Study Shows that Mothers, Not Fathers, Bear More of the Impact of Caring for a Child with Dravet Syndrome

Abstract, published in Epilepsy & Behavior

Background: The aim of this study was to understand the impact of Dravet syndrome (DS) on patients with Dravet syndrome and their families, with a focus on the social and economic impact on both mothers and fathers.

Results: Survey responses were available for 91 patients (median age 7.6 years). Total seizure frequency varied from less than 1 to greater than 8 seizures per month, with tonic–clonic and myoclonic being the most frequent seizure types. DS adversely affected concentration, school learning, appetite, sleep, and overall behavior.

Compared with the general population, more parents were married and had higher educational achievement, while monthly net income was similar. Preparation of medication was generally done by the mother and father or the mother only. Most caregivers reported very low or no difficulty with treatment preparation and low or no risk of error. Parents typically spent < 30 min per day on treatment preparation and administration and around 4 hours per week for attending therapy appointments. Although most patients and parents were perceived to have good general health, mothers had a worse perception of their own general health than fathers. Compared with fathers, mothers reported a greater impact of caring for a child with DS on their social life, relationships with family and friends, time and energy, and professional life.

Conclusion: Families caring for a child with Dravet syndrome experience considerable social and economic impact, with an apparent greater burden of care on the mother than the father.

Epilepsy Research Findings: May 2020

In this month’s epilepsy research news, we highlight an unexpected health benefit of epilepsy neurostimulators and report on a potential explanation for the effectiveness of fenfluramine in Dravet syndrome. We also present a study suggesting that people who have achieved long-term seizure freedom should speak with their doctors more often about the possibility of weaning off medications to reduce unnecessary drug burdens.

In addition, given the impact that the COVID-19 pandemic is having on all our lives, we feature two COVID-19 related articles: one examines the psychological well-being of people with epilepsy and the other highlights recommendations for patients, caregivers, and clinicians from a group of well-known neurologists.

Finally, we encourage you to participate in ongoing research about COVID-19’s impact on the rare disease community. Patients and caregivers who take this survey will help the rare disease research community shed light on their needs during the COVID-19 pandemic and future health crises.

Summaries of these articles are presented below:

Research News

  • Neurostimulators and Psychiatric Disorders: Brain wave recordings from responsive neurostimulator systems allow physicians to differentiate seizure-induced neurobehavioral symptoms from those caused by comorbid psychiatric disorders such as anxiety, depression, and psychosis. This additional information can help guide medication or therapy changes to target the psychiatric illness itself instead of similar symptoms brought on by the seizures themselves. Learn More
  • Fenfluramine and Dravet Syndrome: Researchers may have discovered how fenfluramine, which is currently being investigated as an add-on therapy to reduce seizures in people with Dravet syndrome, also seems to promote long-term improvements in cognition, behavior and emotional control. The beneficial effects of seizure reduction and cognitive enhancement may result from the drug’s synergistic effect on two different proteins found on the surface of nerve cells. Learn More
  • Antiseizure Drug (ASD) Withdrawal: A Norwegian survey found that people who have achieved long-term seizure-freedom are not talking to their doctors often enough about a plan for discontinuing drug treatment. This suggests that many patients may be living with an unnecessary drug burden. Learn More
  • COVID-19 and Psychological Distress: A study conducted at the epilepsy center of West China Hospital showed that people with epilepsy suffered from significantly more psychological distress compared to controls. The research found that independent predictors of this distress are time spent paying attention to COVID-19 and a diagnosis of drug-resistant epilepsy. Learn More
  • COVID-19, Epilepsy Management, and Safety: Leading neurologists published two key suggestions on caring for people with epilepsy during the COVID-19 pandemic. First, as much care as possible should be administered at home, including the strategic use of rescue therapies, to keep people out of health care facilities, where they are more likely to encounter COVID-19. Second, to minimize the risk of increased seizure severity or frequency, physicians should ensure that their patients adhere to treatment plans and have a regular supply of medication. Learn More
  • Rare Disease Community and COVID-19, a Survey: A new online survey created by the National Institute of Health aims to find out how the COVID-19 pandemic is impacting individuals with rare diseases, their families, and their caregivers. We encourage you to check it out! Learn More

In case you missed it! Our COVID-19 and Epilepsy Resource Hub is now live with resources to help families understand the potential impacts of COVID-19 on epilepsy care. This resource hub includes a guide to preparing for telehealth visits, recorded Q&A sessions, frequently asked questions, and more. Visit Now

Heart Abnormalities Unlikely behind Sudden Unexpected Deaths in Dravet

Heart abnormalities are unlikely to be the reason behind the high rate of Sudden Unexpected Death in Epilepsy (SUDEP) in people with Dravet syndrome, a new study suggests, though further research is needed. The underlying cause of SUDEP in people with Dravet is unclear, but multiple interconnecting factors are likely at play. Better understanding these factors could aid in the development of strategies to help prevent SUDEP.

Studies in mice have suggested that SUDEP might be related to heart rhythm abnormalities, but it is unclear whether these findings might also translate to human disease.

The new study reports findings from a clinical trial (NCT02415686) in which people with Dravet wore electrocardiogram (ECG or EKG) devices to monitor their heartbeats. The devices were worn daily and continuously recorded data. For each Dravet patient, researchers identified two people who were similar in age and sex to serve as controls.

Researchers looked for seizure-associated heart abnormalities that were more common among the Dravet patients than the controls. Such abnormalities could explain the comparatively high rate of SUDEP in Dravet.

Although some of the findings may warrant further study, the researchers found that none of the seizure-associated heart abnormalities could account for the comparatively high SUDEP rate in Dravet Syndrome.

Study suggests that the dual mechanism of a new antiepileptic drug may explain its effectiveness in Dravet Syndrome

In addition to promoting the release of serotonin, a brain chemical typically associated with feelings of well-being and happiness, fenfluramine also seems to control the activity of sigma-1 receptors found on the surface of nerve cells, a study has found.

This dual mechanism of action is likely responsible for the deep and sustained effectiveness of the medication at reducing the frequency of seizures in children and young adults with Dravet syndrome, researchers noted.

Results of the study, “Fenfluramine acts as a positive modulator of sigma-1 receptors,” were published in the journal Epilepsy & Behavior.

Study Generates a Model to Study KCNQ2-Related Epileptic Encephalopathy in the Lab

Objective

Early onset epileptic encephalopathy with suppression-burst is one of the most severe epilepsy phenotypes in human patients. A significant proportion of cases have a genetic origin, and the most frequently mutated gene is KCNQ2, encoding Kv7.2, a voltage-dependent potassium channel subunit, leading to so-called KCNQ2-related epileptic encephalopathy (KCNQ2-REE). To study the pathophysiology of KCNQ2-REE in detail and to provide a relevant preclinical model, this research team generated and described a knock-in mouse model carrying the recurrent p.(Thr274Met) variant.

Methods

Researchers introduced the p.(Thr274Met) variant by homologous recombination in embryonic stem cells, injected into C57Bl/6N blastocysts and implanted in pseudopregnant mice. Mice were then bred with 129Sv Cre-deleter to generate heterozygous mice carrying the p.(Thr274Met), and animals were maintained on the 129Sv genetic background. The scientists studied the development of this new model and performed in vivo electroencephalographic (EEG) recordings, neuroanatomical studies at different time points, and multiple behavioral tests.

Results

The Kcnq2Thr274Met/+ mice are viable and display generalized spontaneous seizures first observed between postnatal day 20 (P20) and P30. In vivo EEG recordings show that the paroxysmal events observed macroscopically are epileptic seizures. The brain of the Kcnq2Thr274Met/+ animals does not display major structural defects, similar to humans, and their body weight is normal. Kcnq2Thr274Met/+ mice have a reduced life span, with a peak of unexpected death occurring for 25% of the animals by 3 months of age. Epileptic seizures were generally not observed when animals grew older. Behavioral characterization reveals important deficits in spatial learning and memory in adults but no gross abnormality during early neurosensory development.

Significance

Taken together, researchers state that their results indicate they have generated a relevant model to study the pathophysiology of KCNQ2-related epileptic encephalopathy and perform preclinical research for that devastating and currently intractable disease.

Ovid Therapeutics Announces Initial Data with Soticlestat in CDKL5 Deficiency Disorder and Dup15q Syndrome

Ovid Therapeutics Inc announced initial data from its ongoing exploratory Phase 2 open-label study of soticlestat (OV935/TAK935) in patients with CDKL5 deficiency disorder (CDD) and Dup15q syndrome (Dup15q). CDD and Dup15q are two rare, highly refractory developmental and epileptic encephalopathies (DEE) that have no approved treatment options. These early data demonstrate that soticlestat, a potent, highly selective, first-in-class inhibitor of the enzyme cholesterol 24-hydroxylase (CH24H), shows a reduction in seizure frequency compared to baseline levels in individual patients. CH24H plays a major role in clearing cholesterol in the brain, and by blocking this enzyme, soticlestat is thought to reduce activation of a neuronal signaling pathway associated with epilepsy, according to Ovid.

“This initial data set from the open-label study includes the first 11 patients enrolled. This data cut was designed to confirm the safety profile of soticlestat in these patient populations and assess any signals of efficacy. These initial data suggest that soticlestat continues to be safe and well tolerated and appears to reduce seizure frequency in a majority of the individual patients,” said Amit Rakhit, M.D., MBA, President and Chief Medical Officer of Ovid Therapeutics. “These early results are encouraging and are supportive of continuation of the study. We are also encouraged that all ARCADE patients that have completed the study to date have opted to roll over into the ENDYMION open-label extension study. We will work closely to evaluate the full data from the ARCADE study, expected in the first quarter of 2021.”

Matthew During, M.D., D.Sc., Chairman of the Company’s Scientific Advisory Board and Visiting Professor of Translational Neuroscience, University of Oxford, commented, “While this initial data includes only a limited number of patients, these results of the open-label trial are encouraging and support the safety and tolerability of soticlestat in CDD and Dup15q. More data is needed to assess efficacy, but initial data support the potential of soticlestat to provide a clinical benefit for patients with these ultra-rare and treatment-refractory epilepsy disorders. These initial results support continued recruitment and enrollment into the study.”

The Features of Neonatal Seizures as Predictors of Drug-Resistant Epilepsy in Children

PURPOSE: The aim of this study was to evaluate the predictive value of the features of neonatal seizures for pharmacoresistant epilepsy in children.

METHOD: This is a retrospective study that involved all children diagnosed as having epilepsy who had neonatal seizures and who were hospitalized at the Neurology Department of the Mother and Child Healthcare Institute in Belgrade from January the 1st 2017 until December 31st 2017. The following parameters and their impact on the outcome were investigated: perinatal data, the characteristics of epileptic seizures in the neonatal period, and the response to anticonvulsant treatment. The presence of pharmacoresistance was observed as an outcome parameter. Univariate and multivariate logistic regression analyses were used to define predictors of drug-resistant epilepsy.

RESULTS: The study involved 55 children, 35 (63.6%) male and 20 (36.4%) female. The average age of the children at the end of the observation period was 5.17?years (min: 0.25, max: 17.75, iqr (interquartile range): 6.92). Pharmacoresistant epilepsy was found in 36 (65.5%) children. The most common type of epilepsy was focal, which affected 30 patients (54.5%), than generalized, which affected 15 patients (27.3%), and combined generalized and focal, which affected 8 patients (14.5%). At the end of the observation period, 28 patients (50.9%) had no seizures, while 14 (25.5%) had daily seizures. It was found that the pharmacoresistant neonatal seizures and metabolic-genetic disorders were predictive factors of the occurrence of pharmacoresistant epilepsy.

CONCLUSION: Patients prone to developing pharmacoresistant epilepsy might be identified as early as the neonatal and early infant period. High incidence of asphyxia co-occurring with established genetic-metabolic disease further emphasizes need for genetic testing in infants with neonatal seizures including in the presence of hypoxic-ischemic injury.

ELEKTRA Trial Completes Enrollment to Test Soticlestat in Children With Dravet and LGS

The ELEKTRA clinical trial assessing the investigational oral therapy soticlestat (OV935/TAK-935) in children with Dravet syndrome and Lennox-Gastaut syndrome (LGS) has completed patient enrollment, Ovid Therapeutics recently announced.

“We completed enrollment significantly ahead of schedule in our placebo-controlled Phase 2 ELEKTRA trial in children with Dravet syndrome and Lennox-Gastaut syndrome, and as a result, we now expect data to be available in the third quarter of 2020,” Amit Rakhit, MD, president and chief medical officer of Ovid, said in a press release.

Soticlestat was developed by Takeda Pharmaceuticals in collaboration with Ovid Therapeutics for the treatment of rare developmental and epileptic encephalopathies, including Dravet and LGS.

The investigational therapy is a potent, highly-selective, first-in-class inhibitor of the enzyme cholesterol 24-hydroxylase, which has a major role in clearing cholesterol in the brain. By blocking this enzyme, soticlestat is thought to reduce the activation of a neuronal signaling pathway — glutamatergic signaling via NMDA receptors — potentially reducing seizure susceptibility and improving seizure control in patients with Dravet, according to Ovid.