Spain-Based Study: Epidyolex Safely Helps Prevent Seizures

Article published by Dravet Syndrome News

The efficacy and safety of Epidiolex, an oral cannabidiol, in children and adults with Dravet syndrome and Lennox-Gastaut syndrome (LGS) were supported in a real-world setting, with benefits similar to those seen in previous clinical trials and expanded access programs (EAPs), a Spanish EAP study reported.

EAPs are designed to make promising therapies available to eligible patients in the real-world setting before their regulatory approval.

The study, “Outcomes from a Spanish Expanded Access Program on cannabidiol treatment in pediatric and adult patients with epilepsy,” was published in the journal Epilepsy & Behavior.

Gene Therapy Offers Hope for Severe Epilepsy

Article published by Macquarie University

A study published this month in Science Advances by a team of researchers at Macquarie University’s Dementia Research Centre showed their treatment could prevent seizures in mice by clearing build ups of a protein in the brain.

Epilepsy is the most common neurological disorder worldwide, affecting about 70 million people. Two-thirds of those with severe epilepsy can be treated with traditional medications, but about a third of patients do not benefit from any of the available treatments. In some cases, the seizures worsen when treated with standard drugs.

Dravet syndrome, which is caused by a genetic mutation and begins in infancy, is one such form of severe epilepsy. It can result in as many as 40 seizures an hour, and is associated with serious developmental delays and a high mortality rate.

Professor Lars Ittner and his team have been studying the causes of neurological diseases for many years, including extensive investigations into the role played by the build-up of tau proteins.

One of their recent studies found hyperexcitation of the neurons caused by tau protein build-up is a key driver of the progression of Alzheimer’s disease.

Hyperexcited neurons fire continuously instead of only when stimulated, and can result in seizures, neural network dysfunction, and cognitive decline.

Walking Difficulties With Dravet May Signal Limited Mobility

Article published by Dravet Syndrome News

Children and adolescents with Dravet syndrome with walking difficulties commonly experience impairments in functional mobility and greater restrictions in daily life activities, a study suggests.

Its researchers recommend that physiotherapy be given patients to improve their gait, potentially allowing for better mobility in daily life.

The study, “The relation between gait abnormalities and daily functional mobility in developmental epileptic encephalopathies: The case of Dravet syndrome,” was published in the journal Gait & Posture.

Dravet syndrome, a rare and severe type of epilepsy that usually appears during the first year of life, is characterized by impaired cognitive and motor development. Patients often show walking problems which, according to caregivers, affect their and their family’s quality of life.

Researchers in Belgium investigated whether walking difficulties in Dravet children correlate with limitations in functional mobility — the ability to move freely — in daily life.

They analyzed data from 40 children and teenagers (19 girls and 21 boys; mean age, 12.3 years) with Dravet. The children’s walking ability was evaluated annually using instrumented 3D gait analysis. The gait profile score (GPS) was used to assess their overall walking ability and how much it deviated from normal.

The analysis revealed that patients — particularly children younger than age 8 years, and those older than 18 years — showed mobility limitations, especially for longer distances (500 meters).

Successful Treatment of Adult Dravet Syndrome Patients with Cenobamate (XCOPRI ®)

Abstract found on Wiley Online Library

Dravet syndrome (DS) is a rare drug resistant severe developmental and epileptic encephalopathy caused by pathogenic variants in the ? subunit of the voltage-gated sodium channel gene SCN1A. Hyperexcitability in DS results from loss of function in inhibitory interneurons. Thus, sodium channel blockers are usually contraindicated in DS patients as they may lead to disease aggravation. Cenobamate (CNB) is a novel anti-seizure-medication (ASM) with promising rates of seizure freedom in patients with focal-onset drug resistant epilepsy. CNB blocks persistent sodium currents by promoting the inactive states of sodium channels. In a multi-center study, we analyzed retrospectively the effect of an add-on therapy of CNB in adult patients with DS. We report four adult patients with DS in whom the use of CNB resulted in a significant seizure reduction of more than 80%, with a follow-up of up to 542?days. CNB was the first drug in these patients that resulted in a long-lasting and significant seizure reduction. No severe adverse events occurred. We highlight cenobamate as an antiseizure medication that may lead to a clinically meaningful reduction of seizure frequency in adult patients with Dravet syndrome. It is, however, unclear if all patients with DS benefit, requiring further investigation and functional experiments.

CBD Epidiolex Fails to Improve Life Quality in Dravet Children in Study

Article published by Dravet Syndrom News

Management of Functional Seizures and Functi Six months of treatment with the oral cannabidiol (CBD) solution Epidiolex among children and adolescents with Dravet syndrome or Lennox-Gastaut syndrome (LGS) was not associated with improvements in caregiver-reported quality of life or adaptive behaviors.

That’s according to a small Korean study — though researchers noted that the ability to identify such improvements may have been hampered by the clinical severity of the included patients. These children had treatment-resistant seizures, significant developmental delays, and intellectual disability.

“The relationship between CBD and [quality of life] needs to be investigated in larger patient populations,” the researchers wrote.

“CBD has been found to be an efficacious antiseizure drug for patients with Lennox-Gastaut syndrome and Dravet syndrome, but it did not improve [quality of life] in pediatric patients with treatment-resistant epilepsy in our study,” the team wrote.

The study, “Effects of Cannabidiol on Adaptive behavior and Quality of Life in Pediatric Patients With Treatment-Resistant Epilepsy,” was published in the Journal of Clinical Neurology.

Cannabidiol, also called CBD, is the major non-psychoactive component of the cannabis plant, and has received considerable recent attention for its therapeutic properties.

The SCN1A Philadelphia Variant – a Gain-of-Function Mutation Causing an Early-Onset Epileptic Encephalopathy

Abstract found in BioRxiv

 Objective: Loss-of-function variants in SCN1A cause Dravet Syndrome, the most common genetic developmental and epileptic encephalopathy (DEE). However, emerging evidence suggests separate entities of SCN1A-related disorders due to gain-of-function variants. Here, we aim to refine the clinical, genetic, and functional electrophysiological features of a recurrent p.R1636Q gain-of-function variant, identified in four individuals at a single center.

Methods: Individuals carrying the recurrent SCN1A p.R1636Q variant were identified through diagnostic testing. Whole-cell voltage-clamp electrophysiological recording in HEK-293T cells was performed to compare the properties of sodium channels containing wild-type Nav1.1 or Nav1.1-R1636Q along with both Nav?1 and Nav?2 subunits, including response to oxcarbazepine. To delineate differences to other SCN1A-related epilepsies, we analyzed electronic medical records.

Results: All four individuals had an early-onset DEE characterized by focal tonic seizures and additional seizure types starting in the first few weeks of life. Electrophysiological analysis showed a mixed gain-of-function effect with normal current density, a leftward (hyperpolarized) shift of steady-state inactivation, and slower inactivation kinetics leading to a prominent late sodium current (INa). The observed functional changes closely paralleled effects of pathogenic variants in SCN3A and SCN8A at corresponding positions. Both wildtype and variant exhibited sensitivity to block by oxcarbazepine, partially correcting electrophysiological abnormalities of the SCN1A p.R1636Q variant. Clinically, a single individual responded to treatment with oxcarbazepine. Across 51 individuals with SCN1A-related epilepsies, those with the recurrent p.R1636Q variants had the earliest ages of onset.

Interpretation: The recurrent SCN1A p.R1636Q variant causes a clinical entity with a wider clinical spectrum than previously reported, characterized by ultra early-onset epilepsy and absence of prominent movement disorder. Functional consequences of this variant lead to mixed loss- and gain-of-function that is partially corrected by oxcarbazepine. The recurrent p.R1636Q variant represents one of the most common causes of early-onset SCN1A-related epilepsies with separate treatment and prognosis implications.

Walking Ability Found to Worsen With Age in Adults With Dravet

Article published by Dravet Syndrome News

Adults with Dravet syndrome commonly experience walking difficulties that tend to worsen with age, a small study reports.

“In this study, it was observed that gait parameters and parkinsonian symptoms were abnormal across all ages, but clearly worse in older patients, suggesting a progressive gait disorder,” researchers wrote.

By the end of the five-year study period, one-third of the patients who were ambulatory at its start were no longer able to walk, the team noted.

The study, “Progressive Worsening of Gait and Motor Abnormalities in Older Adults With Dravet Syndrome,” was published in Neurology.

The team of scientists in the U.S. and Canada conducted a small study to assess how walking ability changes in adults with Dravet over time. The scientists were inspired to do the research by anecdotal reports from caregivers that described adults with Dravet syndrome who had been able to walk but then lost that ability.

A total of six adults with Dravet, with a mean age of 32, were involved in the study. They were assessed five years apart, once in 2014 and then again in 2019. A modified version of the Unified Parkinson’s Disease Rating Scale (mUPDRS) was used to measure gait abnormalities, as well as resting tremors, facial expression, standing up from a seated position, posture, and body bradykinesia, which is an abnormal slowness of movement.

Results showed that, over the five years between assessments, mUPDRS scores worsened for all but one of the six patients.

Epilepsy Research News: May 2022

This month Epilepsy Research News features findings by former CURE Epilepsy Grantee Dr. Juliet Knowles and her colleagues showing that the brains of rodents with seizures developed changes and in effect “learned” to have epilepsy. Next, we report on a study using a zebrafish model of epilepsy to investigate which type of cells in the brain contribute to seizures.

We also feature study findings that could guide the development of better therapeutic strategies for Dravet syndrome, a severe form of childhood epilepsy, by pinpointing a key cell type in the brain.

The final two studies featured below find that people with epilepsy live 10-12 years less than those who do not have the condition. They also highlight that people with epilepsy associated with head injuries, especially the type not well controlled by medication, are more likely to have other health conditions like depression that may result in a lower quality of life.

Summaries of these research discoveries can be found below.

The Brain “Learns” How to Have Seizures: A new study featuring the work of former CURE Epilepsy Grantee Dr. Juliet Knowles and colleagues have found that laboratory rodents that have seizures similar to those commonly seen in people with epilepsy developed changes in the brain circuitry that advanced their epilepsy. These changes in brain circuitry were driven by a process that also plays a role in learning, memory, and attention. The study is the first to report that a key feature of the brain’s ability to change and adapt, known as activity-dependent myelination, can contribute to seizures. Blocking this process reduced the number of seizures in the animals. Dr. Knowles is now investigating whether these findings hold true in people.
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Pinpointing Seizure Origin: New evidence from a zebrafish model of epilepsy may help shed light on the cells in the brain from which seizures originate and then spread to other areas. In the study, the researchers tracked the activity of cells throughout the brains of larval zebrafish during seizures. The researchers showed that the seizures originated from an excess of “excitatory” cell activity compared to “inhibitory” cell activity in relatively confined regions of the brain and only spread to other areas when they overcame strong inhibitory activity in the surrounding regions. The team plans to confirm their findings by looking across multiple brain regions in a mouse model.
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Investigating Treatment for Epilepsy and Autism: A group of researchers reports new findings focused on a protein called tau, that could guide therapeutic strategies for Dravet syndrome, a severe childhood epilepsy that is often associated with autism and higher rates of Sudden Unexpected Death in Epilepsy (SUDEP). The researchers pinpoint the key cell type in the brain in which tau levels must be reduced to decrease seizures, autism-like behaviors, and SUDEP. They also show that lowering tau is effective in mice when the intervention is delayed until after their birth. The researchers state that their findings provide new insights into the cellular mechanisms by which tau reduction prevents brain dysfunction associated with Dravet syndrome.
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Epilepsy and Mortality: On average, people with epilepsy live 10-12 years less than those who do not have the condition, according to a recent research study using the Danish healthcare register that follows almost six million individuals, including 130,000 people with epilepsy. The potential for a shorter lifespan is particularly pronounced among people who have epilepsy and a mental health disorder. Reduced life expectancy for people with epilepsy was related to a wide range of causes including cardiovascular diseases, psychiatric disorders, alcohol-related conditions, accidents, and suicide. The researchers state that the results provide important information to all healthcare professionals and could be used to develop measures to reduce the mortality gap currently seen in people with epilepsy.
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Epilepsy and Quality of Life: A new study suggests that people with epilepsy that is associated with head injury (a type of epilepsy called post-traumatic epilepsy or PTE), especially when seizures are not well controlled by medication, are more likely to have other health conditions like depression, post-traumatic stress disorder, and headache which may result in a lower quality of life. The study examined 529 military veterans with epilepsy and found that 45% of those with PTE had drug-resistant epilepsy, compared to 33% of those with epilepsy not associated with a head injury. Those with drug-resistant epilepsy reported the lowest quality of life. The study’s authors note that understanding drug-resistant epilepsy and finding more effective interventions may lead to ways to help people live longer, more satisfying lives.
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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.