Abstract, published in Epilepsia Open

We report new genetic diagnoses of Dravet syndrome in a group of adults with complex epilepsy of unknown cause, under follow up at a tertiary epilepsy center. Individuals with epilepsy and other features of unknown cause from our unit underwent whole genome sequencing through the 100,000 Genomes Project. Virtual gene panels were applied to frequency-filtered variants based on phenotype summary. Of 1078 individuals recruited, 8 (0.74%) were identified to have a pathogenic or likely pathogenic variant in SCN1A. Variant types were: nonsense (stop gain) in five (62.5%) and missense in three (37.5%). Detailed review of childhood history confirmed a phenotype compatible with Dravet syndrome. Median age at genetic diagnosis was 44.5 years (range 28-52 years). Tonic-clonic seizures were ongoing in all despite polytherapy including valproate. All had a history of fever sensitivity and myoclonic seizures, which were ongoing in two (25%) and three (37.5%) individuals, respectively. Salient features of Dravet syndrome may be less apparent in adulthood, making clinical diagnosis difficult. Regardless of age, benefits of a genetic diagnosis include access to syndrome-specific treatment options, avoidance of harmful drugs, and monitoring for common complications.

Abstract, published in Epilepsy & Behavior

Background: Dravet syndrome (DS) is a severe developmental and epileptic encephalopathy, with predictable negative consequences for informal caregivers’ mental health. This systematic review aimed to evaluate the representativeness of depression, anxiety, and burden in these caregivers and assess their quality of life.

Methods: The PRISMA recommendations were followed, and a comprehensive search was conducted on PubMed/MEDLINE, WoS and Scopus databases, without date or language limits. Only observational quantitative studies on adult informal caregivers of patients with DS were considered.

Results: Of 876 records found, 21 full-text articles were assessed and only 6 met the inclusion criteria. The latter have mostly a cross-sectional design and include samples composed by 19 to 742 caregivers, mainly mothers/females. Most of the study participants had a Bachelor’s degree/higher educational level and were married. An important incidence of depression and anxiety on DS caregivers was reported, with significantly higher levels compared with population norms and with carers of other patients with epilepsy. Depression/anxiety were shown to be significantly associated with caregivers’ fatigue and compromised sleep quality. Other important aspects of burden have been identified; however, comparisons between studies were not possible as different scales were used. Caregivers’ health-related quality of life is also affected, with mothers reporting a worse perception on this domain.

Conclusions: Mental health and quality of life of DS caregivers are compromised, with mothers bearing an apparently greater burden. Studies using validated instruments for this population to assess the previously considered outcomes are needed, in order to inform the development of preventive strategies and problem-oriented interventions.

Abstract, published in Epilepsia

Objective: Alterations in metabolic homeostasis can contribute to neuronal hyperexcitability and seizure susceptibility. Although the pivotal role of impaired bioenergetics is obvious in metabolic epilepsies, there is a gap of knowledge regarding secondary changes in metabolite patterns as a result of genetic Scn1a deficiency and ketogenic diet in the Dravet syndrome.

Methods: A comprehensive untargeted metabolomics analysis, along with assessment of epileptiform activity and behavioral tests, was completed in a Dravet mouse model. Data sets were compared between animals on a control and a ketogenic diet, and metabolic alterations associated with Dravet mice phenotype and ketogenic diet were identified.

Results: Hippocampal metabolomic data revealed complex alterations in energy metabolism with an effect of the genotype on concentrations of glucose and several glycolysis and tricarboxylic acid (TCA) cycle intermediates. Although low glucose, lactate, malate, and citrate concentrations became evident, the increase of several intermediates suggested a genotype-associated activation of catabolic processes with enhanced glycogenolysis and glycolysis. Moreover, we observed an impact on the glutamate/?-aminobutyric acid (GABA)-glutamine cycle with reduced levels of all components along with a shift toward an increased GABA-to-glutamate ratio. Further alterations comprised a reduction in hippocampal levels of noradrenaline, corticosterone, and of two bile acids.

Significance: Considering that energy depletion can predominantly compromise the function of GABAergic interneurons, the changes in energy metabolism may contribute to seizure susceptibility and ictogenesis. They may also explain the therapeutic potential of the ketogenic diet, which aims to shift energy metabolism toward a more fat-based energy supply. Conversely, the increased GABA-to-glutamate ratio might serve as an endogenous compensatory mechanism, which can be further supported by GABAergic drugs, representing the mainstay of therapeutic management of Dravet syndrome. In view of a possible neuroprotective function of bile acids, it might be of interest to explore a possible therapeutic potential of bile acid-mediated therapies, already in discussion for neurodegenerative disorders.

Abstract, published in Epilepsia

Objective: Dravet syndrome (DS) is a rare but catastrophic genetic epilepsy, with 80% of patients carrying a mutation in the SCN1A gene. Currently, no Anti-seizure drug (ASD) exists that adequately controls seizures. In the clinic, individuals with DS often present first with a febrile seizure and, subsequently, generalized tonic-clonic seizures that can continue throughout life. To facilitate the development of ASDs for DS, the contract site of the National Institute of Neurological Disorders and Stroke (NINDS) Epilepsy Therapy Screening Program (ETSP) has evaluated a mouse model of DS using the conditional knock-in Scn1aA1783V/WT mouse.

Methods: Survival rates and temperature thresholds for Scn1aA1783V/WT were determined. Prototype ASDs were administered via intraperitoneal injections at the time-to-peak effect, which was previously determined, prior to the induction of hyperthermia-induced seizures. ASDs were considered effective if they significantly increased the temperature at which Scn1aA1783V/WT mice had seizures.

Results: Approximately 50% of Scn1aA1783V/WT survive to adulthood and all have hyperthermia-induced seizures. The results suggest that hyperthermia-induced seizures in this model of DS are highly refractory to a battery of ASDs. Exceptions were clobazam, tiagabine, levetiracetam, and the combination of clobazam and valproic acid with add-on stiripentol, which elevated seizure thresholds.

Significance: Overall, the data demonstrate that the proposed model for Dravet syndrome is suitable for screening novel compounds for the ability to block hyperthermia-induced seizures and that heterozygous mice can be evaluated repeatedly over the course of several weeks, allowing for higher throughput screening.

Summary, originally published in Dravet Syndrome News

The first participant has been enrolled in Envision, a natural history study that will follow children with Dravet syndrome for more than two years as it seeks to shed light on how this severe type of epilepsy affects motor and neurological development, seizures, and behavior.

Envision also will assess Dravet’s impact on parents and caregivers, in addition to examining health care resource use among patients.

“Natural history studies are incredibly important to understanding and developing treatments for disease,” the Dravet Syndrome Foundation notes on its website in an informational page about Envision.

“The information collected from a natural history study can then be used as a reference to inform health care decisions, including preventative interventions,” the website said.

Envision, conducted by Encoded Therapeutics, is recruiting about 50 children, ages 6 months to 5 years (60 months) for the two-year study. To be eligible, children must have a clinical diagnosis of Dravet and a confirmed mutation in the SCN1A gene — the most common underlying cause of the syndrome, which leads to overactivation of the nervous system and the development of seizures. For more information on locations and contacts, go here.