Healthcare utilization and clinical characteristics of genetic epilepsy in electronic health records.

Understanding the clinical characteristics and medical treatment of individuals affected by genetic epilepsies is instrumental in guiding selection for genetic testing, defining the phenotype range of these rare disorders, optimizing patient care pathways and pinpointing unaddressed medical need by quantifying healthcare resource utilization. To date, a matched longitudinal cohort study encompassing the entire spectrum of clinical characteristics and medical treatment from childhood through adolescence has not been performed. We identified individuals with genetic and non-genetic epilepsies and onset at ages 0-5 years by linkage across the Cleveland Clinic Health System. We used natural language processing to extract medical terms and procedures from longitudinal electronic health records and tested for cross-sectional and temporal associations with genetic epilepsy. We implemented a two-stage design: in the discovery cohort, individuals were stratified as being 'likely genetic' or 'non-genetic' by a natural language processing algorithm, and controls did not receive genetic testing. The validation cohort consisted of cases with genetic epilepsy confirmed by manual chart review and an independent set of controls who received negative genetic testing. The discovery and validation cohorts consisted of 503 and 344 individuals with genetic epilepsy and matched controls, respectively. The median age at the first encounter was 0.1 years and 7.9 years at the last encounter, and the mean duration of follow-up was 8.2 years. We extracted 188,295 Unified Medical Language System annotations for statistical analysis across 9659 encounters. Individuals with genetic epilepsy received an earlier epilepsy diagnosis and had more frequent and complex encounters with the healthcare system. Notably, the highest enrichment of encounters compared with the non-genetic groups was found during the transition from paediatric to adult care. Our computational approach could validate established comorbidities of genetic epilepsies, such as behavioural abnormality and intellectual disability. We also revealed novel associations for genitourinary abnormalities (odds ratio 1.91, 95% confidence interval: 1.66-2.20, P = 6.16 × 10-19) linked to a spectrum of underrecognized epilepsy-associated genetic disorders. This case-control study leveraged real-world data to identify novel features associated with the likelihood of a genetic aetiology and quantified the healthcare utilization of genetic epilepsies compared with matched controls. Our results strongly recommend early genetic testing to stratify individuals into specialized care paths, thus improving the clinical management of people with genetic epilepsies.

Epilepsy with eyelid myoclonia in the setting of de novo pathogenic variant in ATP1A3.

Mutations in the ATP1A3 gene have been associated with several syndromes, including rapid-onset dystonia-parkinsonism, alternating hemiplegia of childhood, and cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss. In this clinical commentary, we report a 2-year-old female patient with de novo pathogenic variant in the ATP1A3 gene associated with an early-onset form of epilepsy with eyelid myoclonia. The patient had frequent eyelid myoclonia occurring 20-30 times per day, without loss of awareness or other motor manifestations. EEG showed generalized polyspikes and spike-and-wave complexes maximal in the bifrontal regions, with prominent eye closure sensitivity. A sequencing-based epilepsy gene panel revealed a de novo pathogenic heterozygous variant in ATP1A3. The patient showed some response to flunarizine and clonazepam. This case highlights the importance of considering ATP1A3 mutations in the differential diagnosis of early-onset epilepsy with eyelid myoclonia and the potential benefit of flunarizine in improving language and coordination development in patients with ATP1A3-related disorders.

Data-driven historical characterization of epilepsy-associated genes.

Many epilepsy-associated genes have been identified over the last three decades, revealing a remarkable molecular heterogeneity with the shared outcome of recurrent seizures. Information about the genetic landscape of epilepsies is scattered throughout the literature and answering the simple question of how many genes are associated with epilepsy is not straightforward. Here, we present a computationally driven analytical review of epilepsy-associated genes using the complete scientific literature in PubMed. Based on our search criteria, we identified a total of 738 epilepsy-associated genes. We further classified these genes into two Tiers. A broad gene list of 738 epilepsy-associated genes (Tier 2) and a narrow gene list composed of 143 epilepsy-associated genes (Tier 1). Our search criteria do not reflect the degree of association. The average yearly number of identified epilepsy-associated genes between 1992 and 2021 was 4.8. However, most of these genes were only identified in the last decade (2010-2019). Ion channels represent the largest class of epilepsy-associated genes. For many of these, both gain- and loss-of-function effects have been associated with epilepsy in recent years. We identify 28 genes frequently reported with heterogenous variant effects which should be considered for variant interpretation. Overall, our study provides an updated and manually curated list of epilepsy-related genes together with additional annotations and classifications reflecting the current genetic landscape of epilepsy.

Meta-analysis of associations of genetic polymorphisms with cerebral vasospasm and delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage.

INTRODUCTION: Cerebral vasospasm (CV) and delayed cerebral ischemia (DCI) are among the most hazardous complications of aneurysmal subarachnoid hemorrhage (aSAH). Genetic factors are thought to play a significant role in the development of both complications. AIM: To perform a comprehensive meta-analysis of studies that study the association between different genetic polymorphisms and development of DCI and/or CV. METHODS: We searched MEDLINE and Science Direct databases on May 29, 2021, using iterations of the keywords "subarachnoid hemorrhage", "vasospasm", "delayed cerebral ischemia", and "gene". After duplicates were removed, the two reviewers screened the titles of the articles and abstracts independently. A random-effect model was used to calculate the relative risk with 95% CI; a fixed-effect model was additionally explored. RESULTS: We pooled data from 16 articles that reported an association between eNOS, apolipoprotein E4 (ApoE4), haptoglobin (Hp), or ryanodine-1 (RYR-1) and CV, DCI, or both. Presence of Hp 2-2 was associated both with CV (RR 2.10, 95% CI 1.33-3.31, p = 0.0014) and DCI (RR 1.57, 95%CI 1.06-2.34, p = 0.026). ApoE4 allele had a borderline association with CV (RR 1.48, 95%CI 0.99-2.21, p = 0.054). CONCLUSION: Our meta-analysis supports the association between the presence of the Hp2-2 allele and the occurrence of CV and DCI after aSAH. Further studies investigating this association are needed to reinforce this finding.

The impairment of the functional system and fatigue at the onset of the disease predict reaching disability milestones in relapsing-remitting multiple sclerosis differently in female and male patients.

Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system with variable types of disability progression (DP). Previous studies, defining different disability milestones (DMs), have reported symptoms at MS onset to be the predictors of DP and sex as a risk factor. Meanwhile, accounting for sex differences in MS, predictors in female and male patients might differ. To investigate whether the symptoms at MS onset predict reaching DMs in patients with relapsing-remitting (RR) MS and whether the predictors vary between different DMs and female and male patients. Data from 128 RR MS patients (84 females, 44 males) was retrospectively studied. EDSS scores 4 and 6 (associated with impaired ambulation) were taken as DMs. Association between symptoms at MS onset and time to reach DMs was assessed with Cox multiple regression model. Pyramidal symptoms and fatigue at MS onset predicted the progression to EDSS 4 in the whole study population (HR 1.84, 95% CI 1.07-3.2, p = 0.028 and HR 2.01, 95% CI 1.12-3.4, p = 0.011, correspondingly). The same symptoms predicted reaching DM in female, but not male patients. Bowel/bladder symptoms predicted reaching EDSS 6 in the whole study population (HR 4.31, 95% CI 1.47-12.6, p = 0.008) and female patients only (HR 3.93, 95% CI 1.04-14.8, p = 0.043). In female patients, fatigue was also the predictor of reaching EDSS 6 (HR 3.54, 95% CI 1.16-10.8, p = 0.026). Impairment of functional symptoms at MS onset can predict reaching DMs in patients with RR-MS, but the predictors for EDSS 4 and EDSS 6 differ in female and male patients.

Is Initial Misdiagnosis Associated with Reaching Disability Milestones in Patients with Multiple Sclerosis?

Background and objectives: multiple sclerosis (MS) is a chronic demyelinating disorder of the CNS with a variable course and disability progression. The latter may be prevented with disease-modifying therapy (DMT). Initial misdiagnosis may postpone the use of DMT. There are no studies to explore whether initial misdiagnosis is indeed associated with a higher rate of reaching disability in MS patients. We aimed to investigate the association between initial misdiagnosis and reaching disability milestones in relapsing-remitting MS (RR-MS) patients. Materials and methods: Data from 128 RR-MS patients were retrospectively reviewed. EDSS 4 and EDSS 6 were chosen as disability milestones as those associated with a significant decrease in ambulation. Survival analysis was used, and Kaplan-Meier curves were generated to investigate how initial misdiagnosis affects reaching the defined milestones. Results: 53 patients (41.4%, 31 females, 22 males) were initially misdiagnosed. Initially misdiagnosed patients had a lesser risk of reaching EDSS 4 up to 11 years and EDSS 6 up to 22 years from the onset than non-misdiagnosed patients (p = 0.22 and p = 0.25 correspondingly). Median time to reaching EDSS 4 and 6 was eight years (95% CI 0.0-17.6) and 10 years (95% CI 4.25-20.75) in misdiagnosed and three years (95% CI 0.0-20.0 years) and five years (95% CI 0.0-13.73 years) in non-misdiagnosed patients correspondingly. Conclusions: Initially misdiagnosed RR-MS patients tended to reach disability milestones later than non-misdiagnosed ones, which might reflect an intrinsically milder disease. Individuals presenting with mild or non-specific symptoms suspicious of MS, must be deliberately managed.