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.

CDKL5 Deficiency Disorder: Some Lessons Learned 20 Years After the First Description.

Loss of function variants in the Cyclin-dependent kinase-like 5 gene (CDKL5) causes CDKL5 deficiency disorder (CDD). Most cases of CDD are due to a de novo missense or truncating variants. The CDKL5 gene was discovered in 1998 as part of the genomic mapping of the chromosome Xp22 region that led to the discovery of the serine-threonine kinases STK9. Since then, there have been significant advancements in the description of the disease in humans, the understanding of the pathophysiology, and the management of the disease. There have been many lessons learned since the initial description of the condition in humans in 2003. In this article, we will focus on pathophysiology, clinical manifestations, with particular focus on seizures because of its relevance to the medical practitioners and researchers and guidelines for management. We finalize the manuscript with the voice of the parents and caregivers, as discussed with the 2019 meeting with the Food and Drug Administration.

International Consensus Recommendations for the Assessment and Management of Individuals With CDKL5 Deficiency Disorder.

CDKL5 Deficiency Disorder (CDD) is a rare, X-linked dominant condition that causes a developmental and epileptic encephalopathy (DEE). The incidence is between ~ 1:40,000 and 1:60,000 live births. Pathogenic variants in CDKL5 lead to seizures from infancy and severe neurodevelopmental delay. During infancy and childhood, individuals with CDD suffer impairments affecting cognitive, motor, visual, sleep, gastrointestinal and other functions. Here we present the recommendations of international healthcare professionals, experienced in CDD management, to address the multisystem and holistic needs of these individuals. Using a Delphi method, an anonymous survey was administered electronically to an international and multidisciplinary panel of expert clinicians and researchers. To provide summary recommendations, consensus was set, a priori, as >70% agreement for responses. In the absence of large, population-based studies to provide definitive evidence for treatment, we propose recommendations for clinical management, influenced by this proposed threshold for consensus. We believe these recommendations will help standardize, guide and improve the medical care received by individuals with CDD.

Historical Overview of Hypsarrhythmia and Its Association to Epileptic Spasms: A Review of the Medical Literature From 1952 to 1982.

SUMMARY: The initial description of infantile spasms and its association to developmental abnormalities was attributed to Dr. Williams J. West in 1841 but the clinical scenario at the time had also been seen by other physicians. French physician Henry Gastaut proposed the eponym of West syndrome in the 9th Colloquium de Marseille in 1960. The description of hypsarrhythmia in 1952 by Gibbs and Gibbs added the EEG component to the triad of infantile spasms. The hypsarrhythmia discovery led to a sudden interest in understanding the etiology and developing treatments for this devastating disease affecting infants and young children. It was in the 1950s when cases of infantile spasms with absence of hypsarrhythmia were initially observed. Also, the treatment with adrenocorticotrophic hormone was initially reported as efficacious for treating infantile spasms and hypsarrhythmia in the late 1950s. Adrenocorticotrophic hormone remains the best treatment option for these epilepsy types. This article will provide a historical review of knowledge developments about hypsarrhythmia and infantile spasms, emphasizing the period 1952 to 1982. The goal of the article was to highlight clinical elements that were discovered then and remain clinically relevant today.

The Efficacy and Use of a Pocket Card Algorithm in Status Epilepticus Treatment.

OBJECTIVE: To determine whether a pocket card treatment algorithm improves the early treatment of status epilepticus and to assess its utilization and retention in clinical practice. METHODS: Multidisciplinary care teams participated in video-recorded status epilepticus simulation sessions from 2015 to 2019. In this longitudinal cohort study, we examined the sessions recorded before and after introducing an internally developed, guideline-derived pocket card to determine differences in the adequacy or timeliness of rescue benzodiazepine. Simulation participants were queried 9 months later for submission of a differentiating identification number on each card to assess ongoing availability and utilization. RESULTS: Forty-four teams were included (22 before and 22 after the introduction of the pocket card). The time to rescue therapy was shorter for teams with the pocket card available (84 seconds [64-132]) compared with teams before introduction (144 seconds [100-162]) (U = 94; median difference = -46.9, 95% confidence interval [CI]: -75.9 to -21.9). The adequate dosing did not differ with card availability (odds ratio 1.48, 95% CI: 0.43-5.1). At the 9-month follow-up, 32 participants (65%) completed the survey, with 26 (81%) self-reporting having the pocket card available and 11 (34%) confirming ready access with the identification number. All identification numbers submitted corresponded to the hard copy laminated pocket card, and none to the electronic version. CONCLUSIONS: A pocket card is a feasible, effective, and worthwhile educational tool to improve the implementation of updated guidelines for the treatment of status epilepticus.

An Overview of the Electroencephalographic (EEG) Features of Epilepsy with Eyelid Myoclonia (Jeavons Syndrome).

Epilepsy with eyelid myoclonia or Jeavons Syndrome is a unique idiopathic generalized epilepsy with onset in childhood. It is characterized by eyelid myoclonia which may be associated with absence seizures, eyelid closure-induced epileptiform discharges and/or seizures and photosensitivity. It is frequently underrecognized and misdiagnosed because it may be mistaken for some other type of generalized epilepsy or facial tic disorder. The intent of this narrative review is to focus on existing literature and highlight the distinct electroencephalographic features including characteristic eye movements, associated waveforms, interictal and ictal findings that are suggestive and characteristic of Jeavons Syndrome to aid in timely recognition of this syndrome.

Severity Assessment in CDKL5 Deficiency Disorder.

BACKGROUND: Pathologic mutations in cyclin-dependent kinase-like 5 cause CDKL5 deficiency disorder, a genetic syndrome associated with severe epilepsy and cognitive, motor, visual, and autonomic disturbances. This disorder is a relatively common genetic cause of early-life epilepsy. A specific severity assessment is lacking, required to monitor the clinical course and needed to define the natural history and for clinical trial readiness. METHODS: A severity assessment was developed based on clinical and research experience from the International Foundation for CDKL5 Research Centers of Excellence consortium and the National Institutes of Health Rett and Rett-Related Disorders Natural History Study consortium. An initial draft severity assessment was presented and reviewed at the annual CDKL5 Forum meeting (Boston, 2017). Subsequently it was iterated through four cycles of a modified Delphi process by a group of clinicians, researchers, industry, patient advisory groups, and parents familiar with this disorder until consensus was achieved. The revised version of the severity assessment was presented for review, comment, and piloting to families at the International Foundation for CDKL5 Research-sponsored family meeting (Colorado, 2018). Final revisions were based on this additional input. RESULTS: The final severity assessment comprised 51 items that comprehensively describe domains of epilepsy; motor; cognition, behavior, vision, and speech; and autonomic functions. Parental ratings of therapy effectiveness and child and family functioning are also included. CONCLUSIONS: A severity assessment was rapidly developed with input from multiple stakeholders. Refinement through ongoing validation is required for future clinical trials. The consensus methods employed for the development of severity assessment may be applicable to similar rare disorders.

Cyclin-Dependent Kinase-Like 5 Deficiency Disorder: Clinical Review.

Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) is a developmental encephalopathy caused by pathogenic variants in the gene CDKL5. This unique disorder includes early infantile onset refractory epilepsy, hypotonia, developmental intellectual and motor disabilities, and cortical visual impairment. We review the clinical presentations and genetic variations in CDD based on a systematic literature review and experience in the CDKL5 Centers of Excellence. We propose minimum diagnostic criteria. Pathogenic variants include deletions, truncations, splice variants, and missense variants. Pathogenic missense variants occur exclusively within the kinase domain or affect splice sites. The CDKL5 protein is widely expressed in the brain, predominantly in neurons, with roles in cell proliferation, neuronal migration, axonal outgrowth, dendritic morphogenesis, and synapse development. The molecular biology of CDD is revealing opportunities in precision therapy, with phase 2 and 3 clinical trials underway or planned to assess disease specific and disease modifying treatments.

Variation of the prevalence of pediatric polypharmacy: A scoping review.

PURPOSE: To examine the range of prevalence of pediatric polypharmacy in literature through a scoping review, focusing on factors that contribute to its heterogeneity in order to improve the design and reporting of quality improvement, pharmacovigilance, and research studies. METHODS: We searched Ovid Medline, PubMed, EMBASE, CINAHL, Ovid PsycINFO, Cochrane CENTRAL, and Web of Science Core Collection databases for studies with concepts of children and polypharmacy, along with a hand search of the bibliographies of six reviews and 30 included studies. We extracted information regarding study design, disease conditions, and prevalence of polypharmacy. RESULTS: Two hundred eighty-four studies reported prevalence of polypharmacy. They were more likely to be conducted in North America (37.7%), published after 2010 (44.4%), cross-sectional (67.3%), in outpatient settings (59.5%). Prevalence ranged from 0.9% to 98.4%, median 39.7% (interquartile range [IQR] 22.0%-54.0%). Studies from Asia reported the highest median prevalence of 45.4% (IQR 27.3%-61.0%) while studies from North America reported the lowest median prevalence of 30.4% (IQR 14.7%-50.2%). Prevalence decreased over time: median 45.6% before 2001, 38.1% during 2001 to 2010, and 34% during 2011 to 2017. Studies involving children under 12 years had a higher median prevalence (46.9%) than adolescent studies (33.7%). Inpatient setting studies had a higher median prevalence (50.3%) than studies in outpatient settings (38.8%). Community level samples, higher number and duration of medications defining polypharmacy, and psychotropic medications were associated with lower prevalence. CONCLUSIONS: The prevalence of pediatric polypharmacy is high and variable. Studies reporting pediatric polypharmacy should account for context, design, polypharmacy definition, and medications evaluated.

Defining pediatric polypharmacy: A scoping review.

OBJECTIVES: Lack of consensus regarding the semantics and definitions of pediatric polypharmacy challenges researchers and clinicians alike. We conducted a scoping review to describe definitions and terminology of pediatric polypharmacy. METHODS: Medline, PubMed, EMBASE, CINAHL, PsycINFO, Cochrane CENTRAL, and the Web of Science Core Collection databases were searched for English language articles with the concepts of "polypharmacy" and "children". Data were extracted about study characteristics, polypharmacy terms and definitions from qualifying studies, and were synthesized by disease conditions. RESULTS: Out of 4,398 titles, we included 363 studies: 324 (89%) provided numeric definitions, 131 (36%) specified duration of polypharmacy, and 162 (45%) explicitly defined it. Over 81% (n = 295) of the studies defined polypharmacy as two or more medications or therapeutic classes. The most common comprehensive definitions of pediatric polypharmacy included: two or more concurrent medications for ≥1 day (n = 41), two or more concurrent medications for ≥31 days (n = 15), and two or more sequential medications over one year (n = 12). Commonly used terms included polypharmacy, polytherapy, combination pharmacotherapy, average number, and concomitant medications. The term polypharmacy was more common in psychiatry literature while epilepsy literature favored the term polytherapy. CONCLUSIONS: Two or more concurrent medications, without duration, for ≥1 day, ≥31 days, or sequentially for one year were the most common definitions of pediatric polypharmacy. We recommend that pediatric polypharmacy studies specify the number of medications or therapeutic classes, if they are concurrent or sequential, and the duration of medications. We propose defining pediatric polypharmacy as "the prescription or consumption of two or more distinct medications for at least one day". The term "polypharmacy" should be included among key words and definitions in manuscripts.

Pre-operative evaluation in pediatric patients with cortical dysplasia.

INTRODUCTION: Focal cortical dysplasia (FCD) is an important cause of refractory seizures and catastrophic epilepsy in infants and children who had epilepsy surgery. AIMS OF THE REVIEW: This manuscript will discuss age-related unique clinical characteristics in evaluation of infants and young children because the understanding of these age-related features is critical in selecting children who can benefit from epilepsy surgery. In addition, we will review the non-invasive tools available for the presurgical evaluation of children with FCD and their individual contribution to the formulation of the presurgical hypothesis.

Increasing utilization of pediatric epilepsy surgery in the United States between 1997 and 2009.

OBJECTIVE: To examine national trends of pediatric epilepsy surgery usage in the United States between 1997 and 2009. METHODS: We performed a serial cross-sectional study of pediatric epilepsy surgery using triennial data from the Kids' Inpatient Database from 1997 to 2009. The rates of epilepsy surgery for lobectomies, partial lobectomies, and hemispherectomies in each study year were calculated based on the number of prevalent epilepsy cases in the corresponding year. The age-race-sex adjusted rates of surgeries were also estimated. Mann-Kendall trend test was used to test for changes in the rates of surgeries over time. Multivariable regression analysis was also performed to estimate the effect of time, age, race, and sex on the annual incidence of epilepsy surgery. RESULTS: The rates of pediatric epilepsy surgery increased significantly from 0.85 epilepsy surgeries per 1,000 children with epilepsy in 1997 to 1.44 epilepsy surgeries per 1,000 children with epilepsy in 2009. An increment in the rates of epilepsy surgeries was noted across all age groups, in boys and girls, all races, and all payer types. The rate of increase was lowest in blacks and in children with public insurance. The overall number of surgical cases for each study year was lower than 35% of children who were expected to have surgery, based on the estimates from the Connecticut Study of Epilepsy. SIGNIFICANCE: In contrast to adults, pediatric epilepsy surgery numbers have increased significantly in the past decade. However, epilepsy surgery remains an underutilized treatment for children with epilepsy. In addition, black children and those with public insurance continue to face disparities in the receipt of epilepsy surgery.

Noninvasive predictors of subdural grid seizure localization in children with nonlesional focal epilepsy.

PURPOSE: Subdural grid evaluation (SDE) in refractory focal epilepsy aims to precisely define the ictal onset zone and map eloquent cortex. In a small but significant proportion of children, SDE shows multifocal or diffuse, rather than focal, seizure onset. Resective epilepsy surgery is denied, or is unsuccessful, in the majority of such patients. The authors investigated whether the noninvasive data could be abstracted to predict subsequent SDE electrographic outcome (focal vs. multifocal/diffuse ictal onset). METHODS: The authors retrospectively reviewed charts of 66 children with refractory focal epilepsy undergoing SDE at Cleveland Clinic over a 7-year period, studied previously by Pestana Knight et al. A semiquantitative "score" summarizing the localizing value and concordance between selected noninvasive investigations (interictal and ictal EEG; positron emission tomography [PET], and/or single-photon emission computed tomography [SPECT]), as well as Bayesian predictors of individual investigations and their combinations, were adapted from the study of Kalamangalam et al to the subset of patients with nonlesional cranial MRI. RESULTS: Forty (60.6%) patients had a single MRI brain lesion, 7 (10.6%) had bilateral or diffuse MRI changes, and 19 (28.8%) were nonlesional. Subdural grid evaluation ictal onset was nonfocal in four patients in the first group (10%) and in two patients (28.5%) in the second group. One patient in the third (nonlesional) group was excluded because of incomplete data. In the remainder (n = 18), SDE ictal onset was multifocal or diffuse in 5 (27.8%) and focal in 13 (72.2%). Focality on SDE was positively correlated with higher noninvasive scores in the nonlesional patient group (χ test, P < 0.025). Bayesian predictors in this group were highest for concordance between the interictal and ictal scalp EEG (likelihood ratio = 3.85). Considered separately, interictal and ictal EEG were of equivalent predictive value (likelihood ratio = 2.3 and 2.1, respectively). Metabolic imaging was the least useful modality. CONCLUSIONS: (1) Diffuse or multifocal ictal onsets on SDE are almost three times as likely in nonlesional patients as in those with a single definite MRI brain lesion. (ii) The noninvasive data of children with nonlesional brain MRI may be summarized by a score that rewards localizing information and intermodality concordance: low-scoring patients are more likely to exhibit diffuse or multifocal ictal onset on subsequent SDE. (iii) Bayesian likelihood ratios predictive of ictal focality on SDE are highly favorable for concordant scalp interictal-ictal EEG combinations. (iv) Decision-theoretic methods of this type may find use in the selection of nonlesional pediatric presurgical candidates offered SDE.

Cerebral and systemic infarcts after bronchial artery embolization.

Bronchial artery embolization with microspheres constitutes an effective, safe procedure for controlling hemoptysis. A 17-year-old girl with cystic fibrosis developed hemoptysis and underwent bilateral bronchial artery embolization with 300-500 µm and 500-700 µm microsphere particles. Afterward, she was delirious and complained of headache. On initial examination, she manifested altered mental status and diffuse hyperreflexia. Her left fifth digit was painful and cyanotic. Neuroimaging demonstrated multiple embolic infarcts in the cerebellum, thalamus, and cerebral hemispheres. An echocardiogram produced normal results. An evaluation of her thrombophilia revealed heterozygosity for a prothrombin 20210A mutation. Her functional neurologic recovery was complete. To our knowledge, this is the first pediatric case of cerebral and systemic embolism after bronchial artery embolization. Although this complication is not predictable, it should be suspected in patients with underlying chronic lung disease who develop acute neurologic signs after bronchial artery embolization, because these patients are prone to anomalous arterial-arterial shunt formation.