Transition in epilepsy - A pilot study with patients in and outside of academic centers.

RATIONALE: Epilepsy is a complex condition and seizures are only one part of this disease. The move from pediatric to adult healthcare system proves difficult for many adolescents with epilepsy and their families. The challenges increase when patients have epilepsies associated with intellectual and/or developmental disabilities, autism spectrum disorder, and motor disorders. Knowledge and system gaps may exist between the two systems, adding to the challenges. The main goal of this study is to understand the perception of patients with epilepsy and their families who were preparing to move from pediatric to adult healthcare system or had already moved. METHODS: A survey was distributed to patients/caregivers of patients with epilepsy through patient support groups in North America and in-person through the 2019 Epilepsy Awareness Day at Disneyland. Patients were required to be 12 years or older at the time of the survey and were divided into two groups: those between 12 and 17 years and those 18 years or older. Caregivers answered on behalf of patients who were unable to respond (e.g., intellectual disability). Major components of the survey included demographics, epilepsy details, quality and access to care received in pediatric and adult years, and questions regarding transition and readiness. RESULTS: Responses were received from 58 patients/caregivers of patients with epilepsy from Canada and the United States. In group A (patients between 12 and 17 years), none of the 17-year-old patients were spoken to about transition. Patients (caregivers) with epilepsy and intellectual and/or developmental disabilities (IDD) had less time to discuss important things during the transition/transfer phase than patients with normal intelligence. Finally, there was a statistically significant difference observed in access to specialty care reported in the adult years, compared to the years in the pediatric system. In the group B (patients 18 years and older) a) 35 % still visit their family doctor for epilepsy related treatment despite the majority being on 2 or more antiseizure medications (ASMs); b) 27 % of patients in this group were still being followed by their pediatric neurologist; c) one patient received care only through visits to the emergency department; d) only 4 % felt that they received clear instructions during transfer of care such as knowing the name of the adult healthcare practitioner and/or the name of the care institution they were being transferred to. CONCLUSIONS: This study highlights the lack of appropriate transition to adult healthcare system (AHCS) amongst an unselected group of patients with epilepsy in Canada and United States. An overwhelming majority of patients followed in the community and in academy centers were simply "transferred" to an adult health practitioner, or they remained under the care of pediatricians. Finally, most patients lack access to significant social and medical support after moving to the AHCS.

Adult Phenotype of SYNGAP1-DEE.

Background and Objectives: SYNGAP1 variants are associated with rare developmental and epileptic encephalopathies (DEEs). Although SYNGAP1-related childhood phenotypes are well characterized, the adult phenotype remains ill-defined. We sought to investigate phenotypes and outcomes in adults with SYNGAP1 variants and epilepsy. Methods: Patients 18 years or older with DEE carrying likely pathogenic and pathogenic (LP/P) SYNGAP1 variants were recruited through physicians' practices and patient organization groups. We used standardized questionnaires to evaluate current seizures, medication use, sleep, gastrointestinal symptoms, pain response, gait, social communication disorder and adaptive skills of patients. We also assessed caregiver burden. Results: Fourteen unrelated adult patients (median: 21 years, range: 18-65 years) with SYNGAP1-DEE were identified, 11 with novel and 3 with known LP/P SYNGAP1 de novo variants. One patient with a partial exon 3 deletion had greater daily living skills and social skills than others with single-nucleotide variants. Ten of 14 (71%) patients had drug-resistant seizures, treated with a median of 2 antiseizure medications. All patients (100%) had abnormal pain processing. Sleep disturbances, social communication disorders, and aggressive/self-injurious behaviors were each reported in 86% of patients. Only half of adults could walk with minimal or no assistance. Toileting was normal in 29%, and 71% had constipation. No adult patients could read or understand verbal material at a sixth-grade level or higher. Aggressive/self-injurious behaviors were leading cause of caregiver burden. The oldest patient was aged 65 years; although nonambulant, she had walked independently when younger. Discussion: Seventy-one percent of patients with SYNGAP1-DEEs continue to have seizures when adults. Nonseizure comorbidities, especially aggression and self-injurious behaviors, are major management challenges in adults with SYNGAP1-DEE. Only 50% of adults can ambulate with minimal or no assistance. Almost all adult patients depend on caregivers for many activities of daily living. Prompt diagnostic genetic testing of adults with DEE can inform clinical care and guide outcomes of precision therapies.

COVID-19 vaccine in patients with Dravet syndrome: Observations and real-world experiences.

OBJECTIVE: Vaccination against the 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 vaccine 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 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 older than 12 years (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 younger than 12 years, 60 of whom indicated they would not seek COVID-19 vaccination when their child with DS became 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 occurred in only 13% of vaccinated individuals, and none had status epilepticus. This study provides critical and reassuring insights for caregivers and health care providers making decisions about the safety of COVID-19 vaccinations for individuals with DS.

Progressive Worsening of Gait and Motor Abnormalities in Older Adults With Dravet Syndrome.

BACKGROUND AND OBJECTIVES: Relative to the pediatric population, there is limited information about Dravet syndrome (DS) in adults. In addition to some of the gait abnormalities reported in children with DS (such as crouch gait and ataxia), adults with this condition have other gait and motor disturbances. Our primary objective was to examine gait and motor manifestations in adults with DS. METHODS: This study includes a prospective arm where 6 patients (mean age, 32 years) were examined through a modified version of the Unified Parkinson's Disease Rating Scale (mUPDRS) in 2014 and again in 2019. mUPDRS scores were assigned to gait, resting tremors, facial expression, arising from a chair, posture, and body bradykinesia. The cross-sectional arm includes mUPDRS testing in patients who were not evaluated in 2014 and an instrumental gait analysis (IGA). These cross-sectional tests were done in the 2019-2020 period. The IGA was performed using ProtoKinetics software with a gait mat built with sensors and 2 cameras capturing the sagittal and coronal planes. The IGA was performed in a group of 17 patients with DS (mean age, 31 years); the control group consisted of 81 healthy individuals, whose mean age was 62 years. Regression analyses were performed for the IGA and mUPDRS data. RESULTS: Five out of 6 participants evaluated prospectively over 5 years experienced worsening of their parkinsonian manifestations, including gait. Two patients (47 and 51 years of age) who were initially ambulatory could no longer walk 5 years later. The cross-sectional analysis of mUPDRS in a larger group of adults showed that worse scores for arising from a chair (p = 0.04), body bradykinesia (p = 0.01), and gait (p = 0.0003) were positively associated with age. The IGA cross-sectional arm revealed that all 17 adults with DS had abnormal gait measures in all domains tested. This group of patients performed worse than the healthy and older control group. DISCUSSION: Although seizures may decrease in older adults with DS, this prospective and cross-sectional study showed that their motor symptoms and gait become progressively worse as they age.

Genome sequencing identifies rare tandem repeat expansions and copy number variants in Lennox-Gastaut syndrome.

Epilepsies are a group of common neurological disorders with a substantial genetic basis. Despite this, the molecular diagnosis of epilepsies remains challenging due to its heterogeneity. Studies utilizing whole-genome sequencing may provide additional insights into genetic causes of epilepsies of unknown aetiology. Whole-genome sequencing was used to evaluate a cohort of adults with unexplained developmental and epileptic encephalopathies (n = 30), for whom prior genetic tests, including whole-exome sequencing in some cases, were negative or inconclusive. Rare single nucleotide variants, insertions/deletions, copy number variants and tandem repeat expansions were analysed. Seven pathogenic or likely pathogenic single nucleotide variants, and two pathogenic deleterious copy number variants were identified in nine patients (32.1% of the cohort). One of the copy number variants, identified in a patient with Lennox-Gastaut syndrome, was too small to be detected by chromosomal microarray techniques. We also identified two tandem repeat expansions with clinical implications in two other patients with Lennox-Gastaut syndrome: a CGG repeat expansion in the 5'untranslated region of DIP2B, and a CTG expansion in ATXN8OS (previously implicated in spinocerebellar ataxia type 8). Three patients had KCNA2 pathogenic variants. One of them died of sudden unexpected death in epilepsy. The other two patients had, in addition to a KCNA2 variant, a second de novo variant impacting potential epilepsy-relevant genes (KCNIP4 and UBR5). Overall, whole-genome sequencing provided a genetic explanation in 32.1% of the total cohort. This is also the first report of coding and non-coding tandem repeat expansions identified in patients with Lennox-Gastaut syndrome. This study demonstrates that using whole-genome sequencing, the examination of multiple types of rare genetic variation, including those found in the non-coding region of the genome, can help resolve unexplained epilepsies.

A systematic review of adults with Dravet syndrome.

Dravet Syndrome (DS) is a rare and severe infantile-onset epileptic encephalopathy. DS research focuses mainly on children. We did a systematic review, completed on January 18th, 2021, examining the number of clinical DS studies. We show that there are 208 studies on children exclusively, 28 studies on adults exclusively, and 116 studies involving adults and children combined. This 7:1 ratio of children to adult studies exclusively shows the dearth of research that addresses long-term natural history of DS into adulthood. Through this systematic review, we examine the most up-to-date information in DS adults as it pertains to seizures, electroencephalogram, imaging, treatment, motor abnormalities, cognitive and social behavior outcomes, cardiac abnormalities, sleep disturbances, diagnosis in adults, and mortality. Overall, the frequency of seizures increases in the first decade of life and then myoclonic, atypical absences and focal seizures with impaired awareness tend to decrease in frequency or even disappear in adulthood. Adults tend to have a notable reduction in status epilepticus, especially after 30 years of age. Parkinsonian features were seen in patients as young as 19 years old and are more severe in older patients, suggesting a progression of the parkinsonian symptoms. In adulthood, patients continue to present with behavior problems, associated with a lower health-related quality of life. The leading reported cause of death in DS adults is Sudden Unexpected Death in Epilepsy (SUDEP). Further studies in older adults are needed to understand the long-term outcomes of patients with DS.

Starting stiripentol in adults with Dravet syndrome? Watch for ammonia and carnitine.

OBJECTIVE: Dravet syndrome (DS) is a rare cause of severe and pharmacoresistant epileptic encephalopathy. Stiripentol (STP) has a significant therapeutic benefit in the pediatric DS population. However, STP effects on adult patients have not been well studied. In our adult STP-naive DS patient population, STP initiation was associated with encephalopathy, despite decreases in valproate and clobazam dosage. Here we explored the cause and treatment of encephalopathic manifestations associated with STP in adults. METHODS: Twenty-eight patients with a confirmed clinical and genetic diagnosis of DS who attended the Adult Epilepsy Genetics Clinic were identified retrospectively. Patients who declined or discontinued STP after fewer than 3 months of use, patients who were deceased before starting STP or seizure-free when the genetic diagnosis was confirmed, and those who started STP before leaving the pediatric system (<18 years) were excluded. Levels of ammonia, carnitine, and other anti-epileptic drugs (AEDs) were observed for patients receiving STP. Patients with high ammonia levels who received carnitine supplementation were reevaluated. They were also offered an increased dosage of stiripentol if treatment with carnitine improved the encephalopathy. RESULTS: We observed hyperammonemic encephalopathy in 77% of patients treated with STP. In seven of nine patients, we observed a rate of improvement in ammonia levels of 35% (95% confidence interval [CI] 21%-49%) at a mean carnitine dose of 991 ± 286 mg/d (range 660-1320 mg/d). Five patients whose ammonia levels normalized were also offered an increase in STP dose and they were able to tolerate higher doses with improvement in side effects. Despite such adjustments, the mean maximum stiripentol dose reached was 14.89 ± 8.72 mg/kg/d, which is lower than what is typically recommended in children (50 mg/kg/d). SIGNIFICANCE: We report hyperammonemia in adult STP-naive patients who were on valproate and clobazam, despite dose reduction of the latter drugs. We also report that treatment with carnitine improved hyperammonemia, allowing the continuation of STP.