Zeroing in on a New Treatment for Autism and Epilepsy

Article published by Gladstone Institutes

Children with Dravet syndrome, a severe form of epilepsy that begins in infancy, experience seizures, usually for their entire life. They are at high risk of sudden unexpected death in epilepsy (SUDEP) and can also develop intellectual disability and autism. Available treatments typically fail to improve these symptoms.

Now, a group of scientists at Gladstone Institutes led by Lennart Mucke, MD, reports new findings in the journal Science Translational Medicine that could guide the development of better therapeutic strategies for Dravet syndrome and related conditions.

The researchers previously discovered, in a mouse model of Dravet syndrome, that genetically removing the protein tau from the entire body during embryonic development reduces epilepsy, SUDEP, and autism-like behaviors. In the new study, they pinpoint the key cell type in the brain in which tau levels must be reduced to avoid these problems. They also show that lowering tau is still effective in mice when the intervention is delayed until after their birth.

“Our findings provide new insights into the cellular mechanisms by which tau reduction prevents abnormal overexcitation in the brain,” says Mucke, director of the Gladstone Institute of Neurological Disease. “They are also encouraging from a therapeutic perspective, since in humans, initiating treatment after birth is still more feasible than treating embryos in the womb.”

COVID-19 Vaccine in Patients with Dravet Syndrome: Observations and Real-World Experiences

Abstract found on Wiley Online Library

Objectives: Vaccination against SARS-CoV-2 virus is a primary tool to combat the COVID-19 pandemic. However, vaccination is a common seizure trigger in individuals with Dravet syndrome (DS). Information surrounding COVID-19 vaccines side-effects in patients with DS would aid caregivers and providers in decisions for and management of COVID-19 vaccination.

Methods: A survey was emailed to the Dravet Syndrome Foundation’s (DSF) Family Network and posted to the Dravet Parent & Caregiver Support Group on Facebook between May and August 2021. Deidentified information obtained included demographics and vaccination status for individuals with DS. Vaccine type, side effects, preventative measures, and changes in seizure activity following COVID-19 vaccination were recorded. For unvaccinated individuals, caregivers were asked about intent to vaccinate and reasons for their decision.

Results: Of 278 survey responses, 120 represented vaccinated individuals with DS (median age 19.5 years) with 50% reporting no side effects from COVID-19 vaccination. Increased seizures following COVID-19 vaccination were reported in 16 individuals, but none had status epilepticus. Of the 158 individuals who had not received a COVID-19 vaccination, 37 were over the age of 12 (i.e., eligible at time of study) and only six of these caregivers indicated intent to seek vaccination. The remaining 121 responses were caregivers to children under the age of 12, 60 of whom indicated they would not seek COVID-19 vaccination when their child with DS is eligible. Reasons for vaccine-hesitancy were fear of increased seizure activity and concerns about vaccine safety.

Significance: These results indicate COVID-19 vaccination is well-tolerated by individuals with DS. One main reason for vaccine hesitancy was fear of increased seizure activity, which only occurred in 13% of vaccinated individuals and none had status epilepticus. This study provides critical and reassuring insights for caregivers and healthcare providers making decisions about safety of COVID-19 vaccinations for individuals with DS.

CHOP Researchers Redefine the Mechanisms of Dravet Syndrome

Article published by CHOP News

Researchers from Children’s Hospital of Philadelphia (CHOP) have found that dysfunction in an important cell subtype in the brain’s neuronal network contribute to chronic symptoms in the neurodevelopmental disorder Dravet syndrome. The findings were published today in the journal Cell Reports.

Dravet syndrome is a form of genetic epilepsy that is characterized by seizures that begin in the first year of life, along with differences in childhood development and features of autism spectrum disorder. Children with Dravet syndrome are also at an increased chance of early death, making proper diagnosis and treatment of the disorder critical. More than 90% of children with Dravet syndrome have a pathogenic, or disease-causing, variant in the SCN1A gene, which makes the protein Nav1.1, a sodium channel that is important for the activity of seizure-suppressing cells called interneurons and, in particular, a subtype of interneuron called the parvalbumin interneuron.

“Dravet syndrome affects 1 in 14,000 children in the world and has a profound impact on children and their families,” said Ethan Goldberg, MD, PhD, a pediatric neurologist and Director of the Epilepsy Neurogenetics Initiative (ENGIN) at CHOP and lead author of the study. “We can model Dravet syndrome in the laboratory to understand precisely how the loss of SCN1A produces the clinical features characteristic of the disease to drive development of novel therapies, and, one day, a cure.”

In this study, the researchers developed a method to assess parvalbumin interneuron function at two different points in time. Early disease severity is caused by abnormalities in parvalbumin interneuron electrical activity, which allows neurons to send a message to neighboring neurons. However, chronic dysfunction was due instead to impaired synaptic transmission; while parvalbumin interneurons recovered the ability to generate electrical activity, this activity did not spread down the nerve or “axon” to the synapse to inhibit of other neurons, which is required for seizure suppression.

While more work is needed to translate this research into direct human applications, the researchers note that SCN1A may be a viable therapeutic target for Dravet syndrome patients, particularly if there are ways to increase its expression in the axon to overcome impaired signaling and synaptic transmission.

Little Impact on Children’s Height, Weight With Long-term Fintepla

Article appeared in Dravet Syndrome News; the original article appeared in Epilepsy & Behavior

Treatment for one year or longer with the antiseizure therapy Fintepla (fenfluramine) was shown to have a minimal impact on height and weight in children with Dravet syndrome, according to data from an open-label extension study.

Despite Fintepla’s active ingredient being fenfluramine — a medicine initially developed to suppress appetite — the data showed that children on long-term treatment had growth comparable to that of same-aged patients not on the therapy.

Moreover, the findings “suggest that most patients who initially lose appetite or weight eventually stabilize over time,” the researchers wrote.

However, the team suggested that body measurements should nonetheless be monitored during routine care for children on Fintepla treatment.

The study, “Treatment with fenfluramine in patients with Dravet syndrome has no long-term effects on weight and growth,” was published in the journal Epilepsy & Behavior.

To find out, data were collected from eligible patients, ages 2 to 18, who completed clinical trials evaluating Fintepla and entered a three-year open-label extension (OLE) study. All OLE participants started at a dose of 0.2 mg/kg/day and adjustments were made for efficacy from 0.2 to 0.7 mg/kg/day.

Epilepsy Research Boosts Case for New Gene Therapy

Research from the UVA School of Medicine suggests how a newly developed gene therapy can treat Dravet syndrome, a severe form of epilepsy, and potentially prolong survival for people with the condition.

The gene therapy, developed by Stoke Therapeutics, is now in clinical trials. Because most Dravet syndrome cases are caused by a mutation in the SCN1A gene, resulting in a reduction in SCN1A protein production, the novel approach is designed to boost production of SCN1A to normal levels. If successful, the approach, called Targeted Augmentation of Nuclear Gene Output, or TANGO, would be the first treatment for the fundamental cause of the disease, a lack of this particular protein in specialized brain cells.

The new research – from UVA’s Manoj K. Patel, PhD, and Eric R. Wengert, PhD, and their collaborators – demonstrates how the experimental therapy restores the cells’ proper function and reduces seizures in lab mice.

“Our results show that a single treatment with the TANGO approach into infant mice completely prevented seizures and the premature death typically seen in our mouse model of Dravet syndrome,” said Patel, of UVA’s Department of Anesthesiology. “Further, our study provides the first evidence that TANGO treatment actually targets and rescues the physiological impairment of one group of brain cells known to cause seizures in Dravet syndrome.”

A European Pilot Study in Dravet Syndrome to Delineate What Really Matters for the Patients and Families

Abstract originally published in Epilepsia Open

We aimed to identify caregivers’ opinions on the outcome measures that matter in clinical trials in individuals with Dravet syndrome (DS). We conducted a prospective European multicenter study based on a 11-closed questions’ survey developed by the French reference center for rare epilepsies and DS patients’ advocacy groups. Items included questions on seizures and daily life outcomes that a clinical trial on a therapy for individuals with DS should target. Statistical analyses were performed to evaluate the impact of the country of residence and of the patients’ age.

The survey was answered by 153 caregivers (68%: France, 28%: Germany and 24%: Italy) for individuals with DS. Individuals with DS included 86 males (mean age of 11.4 [interquartile:7-20.4] years). Families ranked as important almost all the items proposed. However, items related to daily life had the highest rank in all 3 countries compared to items about seizures (p=0.02). Increase of individuals’ age was associated with a higher age at diagnosis (? =0.26, p=0.02) and a less important impact of seizure duration (? =-0.25, p=0.005) and of the need of hospital referral (? =-0.26, p=0.005). These data can help tailor patient-centered outcome measures in future clinical and real-life trials for DS.

Protective Effects of Medium Chain Triglyceride Diet in a Mouse Model of Dravet Syndrome

Abstract originally published in Epilepsia

Objective: Dravet syndrome (DS) is a severe developmental and epileptic encephalopathy with early childhood onset. Patients with DS do not respond well to antiepileptic drugs and have only a few treatment options available. Here, we evaluated the effect of medium-chain triglyceride (MCT) diet therapy in a mouse model of DS.

Methods: Scn1aR1407X/+ DS mice were given diets supplemented with MCTs with varying ratios of decanoic (C10) and octanoic (C8) acid or a control diet for 4 weeks. Video monitoring was performed to evaluate spontaneous convulsive seizure frequency. Susceptibility to hyperthermia-induced seizures was also examined. Medium-chain fatty acids and mitochondrial and antioxidant markers were assessed in brain homogenate.

Results: Dietary intervention with MCTs significantly prolonged survival and reduced convulsive seizure frequency during the critical period of highest seizure occurrence in the Scn1aR1407X/+ DS mice. Moreover, MCT diet therapy showed protective effects against hyperthermia-induced seizures. We demonstrated that coadministration of C10/C8 was effective at reducing both seizures and mortality, whereas C10 alone only reduced mortality, suggesting that the ratio of C10 to C8 in the MCT is an important factor for efficacy. When C10 and C8 are supplemented at an 80:20 ratio in the diet, C10 accumulates in the brain in high enough concentrations to enhance brain energy metabolism by both stimulating mitochondrial enrichment and increasing its antioxidant status.

Significance: The results from this study indicate that medium-chain triglyceride diet therapy may provide therapeutic benefits in DS. Future clinical studies would elucidate whether these positive effects are mirrored in human patients.

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Fenfluramine Significantly Reduces Day-to-Day Seizure Burden by Increasing Number of Seizure-Free Days and Time Between Seizures in Patients with Dravet Syndrome: A Time-to-Event Analysis

Abstract, originally published in Epilepsia

Objective: The number, unpredictability, and severity of seizures experienced by patients with Dravet syndrome (DS) negatively impact quality of life (QOL) for patients, caregivers, and families. Metrics are needed to assess whether patients with residual seizures have moved meaningfully toward seizure freedom after treatment with new antiseizure medications.

Methods: We evaluated the time required postrandomization for each patient to experience the same number of seizures experienced during baseline (i.e., time-to-nth seizure), using a post hoc time-to-event (TTE) analysis of data from two Phase 3 placebo-controlled trials of adjunctive fenfluramine for DS (Study 1, N = 119; Study 2, N = 87). Patients aged 2–19 years were randomized to placebo or adjunctive fenfluramine (Study 1: .7 mg/kg/day or .2 mg/kg/day; Study 2: .4 mg/kg/day with stiripentol). Data were analyzed by Kaplan–Meier TTE curves and waterfall plots.

Results: The proportion of patients who never reached baseline seizure frequency was greater with fenfluramine than with placebo (Study 1: fenfluramine .7 mg/kg/day, 60%; fenfluramine .2 mg/kg/day, 31%; placebo, 13%; Study 2: fenfluramine .4 mg/kg/day, 58%; placebo, 2%). Median time-to-nth seizure was longer after fenfluramine than after placebo (Study 1: fenfluramine .7 mg/kg/day, 13 weeks; .2 mg/kg/day, 10 weeks; placebo, 7 weeks; Study 2: fenfluramine .4 mg/kg/day, 13 weeks; placebo, 5 weeks; p < .001). Longest duration of convulsive seizure-free days was increased in active groups versus the placebo group (Study 1: fenfluramine .7 and .2 mg/kg/day, 25.0 and 15.0 days; placebo, 9.5 days [p = .0001; p = .0352]; Study 2: fenfluramine .4 mg/kg/day, 22.0 days; placebo, 13.0 days [p = .004]). The most common adverse events included decreased appetite, pyrexia, upper respiratory tract infection, diarrhea, and fatigue.

Significance: These data demonstrate that fenfluramine can significantly reduce day-to-day seizure burden in patients with Dravet syndrome, providing prolonged periods of convulsive seizure-free days, which may help reduce the physical and emotional disease toll while improving health-related quality of life for patients and caregivers.

Dravet Syndrome: A Quick Transition Guide for the Adult Neurologist

Abstract, originally published in Epilepsy Research

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

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

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

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

Early-Onset Eyelid Stereotypies are a Frequent and Distinctive Feature in Dravet Syndrome

Abstract, originally published in Seizure.

Dravet syndrome (DS) is a severe infantile-onset epilepsy syndrome featuring drug resistant epilepsy, global developmental delay and intellectual disability. In addition to ataxia and progressive crouch gait, Parkinsonism has recently been reported as characteristic in young adults with DS. We describe 5 patients out of a series of 23 patients with DS who present between 12 and 24 months of age with repetitive episodes of eyelid closure, sometimes as fast as eye blinking or flickering. Consistent lack of any EEG correlate in serial video-EEG ruled out an epileptic origin. We propose that this movement disorder, namely ‘eyelid stereotypies’, might be an early motor trait of SCN1A-associated Dravet syndrome.