CDKL5 deficiency disorder and other infantile-onset genetic epilepsies.

AIM: To differentiate phenotypic features of individuals with CDKL5 deficiency disorder (CDD) from those of individuals with other infantile-onset epilepsies. METHOD: We performed a retrospective cohort study and ascertained individuals with CDD and comparison individuals with infantile-onset epilepsy who had epilepsy gene panel testing. We reviewed records, updated variant classifications, and compared phenotypic features. Wilcoxon rank-sum tests and χ2 or Fisher's exact tests were performed for between-cohort comparisons. RESULTS: We identified 137 individuals with CDD (110 females, 80.3%; median age at last follow-up 3 year 11 months) and 313 individuals with infantile-onset epilepsies (156 females, 49.8%; median age at last follow-up 5 years 2 months; 35% with genetic diagnosis). Features reported significantly more frequently in the CDD group than in the comparison cohort included developmental and epileptic encephalopathy (81% vs 66%), treatment-resistant epilepsy (95% vs 71%), sequential seizures (46% vs 6%), epileptic spasms (66% vs 42%, with hypsarrhythmia in 30% vs 48%), regression (52% vs 29%), evolution to Lennox-Gastaut syndrome (23% vs 5%), diffuse hypotonia (72% vs 36%), stereotypies (69% vs 11%), paroxysmal movement disorders (29% vs 17%), cerebral visual impairment (94% vs 28%), and failure to thrive (38% vs 22%). INTERPRETATION: CDD, compared with other suspected or confirmed genetic epilepsies presenting in the first year of life, is more often characterized by a combination of treatment-resistant epilepsy, developmental and epileptic encephalopathy, sequential seizures, spasms without hypsarrhythmia, diffuse hypotonia, paroxysmal movement disorders, cerebral visual impairment, and failure to thrive. Defining core phenotypic characteristics will improve precision diagnosis and treatment.

Epileptic spasms in CDKL5 deficiency disorder: Delayed treatment and poor response to first-line therapies.

OBJECTIVE: We aimed to assess the treatment response of infantile-onset epileptic spasms (ES) in CDKL5 deficiency disorder (CDD) vs other etiologies. METHODS: We evaluated patients with ES from the CDKL5 Centers of Excellence and the National Infantile Spasms Consortium (NISC), with onset from 2 months to 2 years, treated with adrenocorticotropic hormone (ACTH), oral corticosteroids, vigabatrin, and/or the ketogenic diet. We excluded children with tuberous sclerosis complex, trisomy 21, or unknown etiology with normal development because of known differential treatment responses. We compared the two cohorts for time to treatment and ES remission at 14 days and 3 months. RESULTS: We evaluated 59 individuals with CDD (79% female, median ES onset 6 months) and 232 individuals from the NISC database (46% female, median onset 7 months). In the CDD cohort, seizures prior to ES were common (88%), and hypsarrhythmia and its variants were present at ES onset in 34%. Initial treatment with ACTH, oral corticosteroids, or vigabatrin started within 1 month of ES onset in 27 of 59 (46%) of the CDD cohort and 182 of 232 (78%) of the NISC cohort (p < .0001). Fourteen-day clinical remission of ES was lower for the CDD group (26%, 7/27) than for the NISC cohort (58%, 106/182, p = .0002). Sustained ES remission at 3 months occurred in 1 of 27 (4%) of CDD patients vs 96 of 182 (53%) of the NISC cohort (p < .0001). Comparable results were observed with longer lead time (≥1 month) or prior treatment. Ketogenic diet, used within 3 months of ES onset, resulted in ES remission at 1 month, sustained at 3 months, in at least 2 of 13 (15%) individuals with CDD. SIGNIFICANCE: Compared to the broad group of infants with ES, children with ES in the setting of CDD often experience longer lead time to treatment and respond poorly to standard treatments. Development of alternative treatments for ES in CDD is needed.

Genetic Diagnosis Impacts Medical Management for Pediatric Epilepsies.

BACKGROUND: Evidence of the impact of genetic diagnosis on medical management in individuals with previously unexplained epilepsy is lacking in the literature. Our goal was to determine the impact of genetic diagnosis on medical management in a cohort of individuals with early-onset epilepsy. METHODS: We performed detailed phenotyping of individuals with epilepsy who underwent clinical genetic testing with an epilepsy panel and/or exome sequencing at Boston Children's Hospital between 2012 and 2019. We assessed the impact of genetic diagnosis on medical management. RESULTS: We identified a genetic etiology in 152 of 602 (25%) individuals with infantile- or childhood-onset epilepsy who underwent next-generation sequencing. Diagnosis impacted medical management in at least one category for 72% of patients (110 of 152) and in more than one category in 34%. Treatment was impacted in 45% of individuals, including 36% with impact on antiseizure medication choice, 7% on use of disease-specific vitamin or metabolic treatments, 3% on pathway-driven off-label use of medications, and 10% on discussion of gene-specific clinical trials. Care coordination was impacted in 48% of individuals. Counseling on a change in prognosis was reported in 28% of individuals, and 1% of individuals had a correction of diagnosis. Impact was documented in 13 of 13 individuals with neurotypical development and in 55% of those with epilepsy onset after age two years. CONCLUSION: We demonstrated meaningful impact of genetic diagnosis on medical care and prognosis in over 70% of individuals, including those with neurotypical development and age of epilepsy onset after age two years.

Current neurologic treatment and emerging therapies in CDKL5 deficiency disorder.

BACKGROUND: CDKL5 deficiency disorder (CDD) is associated with refractory infantile onset epilepsy, global developmental delay, and variable features that include sleep, behavioral disturbances, and movement disorders. Current treatment is primarily symptom-based and informed by experience in caring for this population. METHODS: We describe medication and non-medication approaches to treatment of epilepsy and additional key neurologic symptoms (sleep disturbances, behavioral issues, movement disorders, and swallowing dysfunction) in a cohort of 177 individuals meeting criteria for CDD, 154 evaluated at 4 CDKL5 Centers of Excellence in the USA and 40 identified through the NIH Natural History Study of Rett and Related Disorders. RESULTS: The four most frequently prescribed anti-seizure medications were broad spectrum, prescribed in over 50% of individuals. While the goal was not to ascertain efficacy, we obtained data from 86 individuals regarding response to treatment, with 2-week response achieved in 14-48% and sustained 3-month response in 5-36%, of those with known response. Additional treatments for seizures included cannabis derivatives, tried in over one-third of individuals, and clinical trial medications. In combination with pharmacological treatment, 50% of individuals were treated with ketogenic diet for attempted seizure control. Surgical approaches included vagus nerve stimulators, functional hemispherectomy, and corpus callosotomy, but numbers were too limited to assess response. Nearly one-third of individuals received pharmacologic treatment for sleep disturbances, 13% for behavioral dysregulation and movement disorders, and 43% had gastrostomy tubes. CONCLUSIONS: Treatment for neurologic features of CDD is currently symptom-based and empiric rather than CDD-specific, though clinical trials for CDD are emerging. Epilepsy in this population is highly refractory, and no specific anti-seizure medication was associated with improved seizure control. Ketogenic diet is commonly used in patients with CDD. While behavioral interventions are commonly instituted, information on the use of medications for sleep, behavioral management, and movement disorders is sparse and would benefit from further characterization and optimization of treatment approaches. The heterogeneity in treatment approaches highlights the need for systematic review and guidelines for CDD. Additional disease-specific and disease-modifying treatments are in development.

Integration of thought and action continued: Scale errors and categorization in toddlers.

To further explore the effect of weighted arms on toddler's performance in problem solving (Arterberry et al., 2018, Infancy, 23(2), 173), the present study explored scale errors and categorization, two instances where infants appear to show more advanced knowledge than toddlers. Experiment 1 (N = 67) used a novel task for inducing scale errors among 24- to 29-month-olds. Results replicated rates of scale errors found in previous research that used different tasks. Experiment 2 used sequential touching (N = 31) and sorting measures (N = 23) to test categorization in 24-month-old children. In both measures, children showed categorization at the basic level when there was high contrast between the exemplars, but not at a basic level with low contrast or a subordinate level. In Experiments 1 and 2, half the participants were tested while wearing weighted wristbands. Weighting the arms did not affect error rates, in contrast to previous research showing that weights improved performance in search tasks. The findings are discussed in light of children's difficulty in integrating perception, cognition, and action.

Telehomecare: a comparison of three Canadian models.

The delivery of health care is often segmented into sectors. In Canada, hospital care has traditionally been distinct from community care, and thus the transition of patients across sectors has been challenging. This paper focuses on the systematic development of an integrated model of care for children, for the purpose of smoothing the transition from hospital to home. The new service model uses emerging telecommunications technology to link hospital care providers to patients at home and is termed "telehomecare" (THC). Independent models of THC were developed for three sites across Canada through semistructured interviews and focus groups. Participants included health care providers and administrators from the hospital and community, and patient families. The resulting models were compared using content analysis to determine whether there was a core model of THC that was generalisable across Canada. A core model of THC was identified that includes the use of videoconferencing to enable the integration of hospital- and community-based care to support patients during the initial stages of the transition to home. Each site also articulated unique characteristics in their service model that were related to the nature of their health care delivery system and patient population. This paper describes the core model of transitional care, presents a synopsis of each of the three models, and compares the models. THC provides opportunities to address limitations in the current system and to improve upon equity of access to quality care for children making the transition from hospital to home.

Preference for pediatric telehome care support following hospitalization: a report on preference and satisfaction.

Infants and children hospitalized with complex conditions often face sudden and dramatic reduction in supervision and monitoring after discharge. A telehome care program was designed to improve the transition home for these children by integrating visiting home care services with outreach from pediatric nurses located in the hospital via videoconferencing. Children were recruited into a trial of telehome care for up to 6 weeks following discharge. Parental preference for this service was measured prior to and following participation. There were 10 enrollments in the pilot stage and 57 during the trial. These children had serious chronic conditions with comorbidity. The majority had a cardiac, respiratory, or otolaryngolic primary diagnosis. More than half of the respondents (59%) indicated strong preferences for telehome care prior to participation. The satisfaction for care delivered at home was no different from care in the hospital. There was no difference in satisfaction or preference observed by sociodemographic factors, diagnosis, or clinical circumstance. Parents with children who have significant health care needs have a strong preference for and satisfaction with telehome care. Additional evidence on costs and benefits may be important for promoting further development of this type of service.

Children in need of Pharmacare: medication funding requests at the Toronto Hospital for Sick Children.

OBJECTIVES: Although a national Pharmacare program ensuring access to and affordability of needed medications has repeatedly been cited as a priority to policymakers, 20% of families remain either uninsured or under-insured. The Hospital for Sick Children's Patient Amenities Fund (PAF) covers out-of-pocket medication expenses for inpatient and outpatient children. The research objectives were to 1) examine family demographics and socio-economic status (SES), the types of medications requested and government program process issues of PAF applicants in 1998 and 1999, and 2) describe trends in PAF requests from 1998 to 2000. METHODS: Data were extracted retrospectively from fund requests, charts and social work and discharge planning reports. Descriptive statistics were used to summarize the data and to examine time trends. RESULTS: Eighty-six applicants submitted 112 requests from 1998-1999. Most were for children with cancer, neurological disorders and transplant patients. Medication expenditures were 22,408 dollars in 1999, a 39% increase over 1998. Most requests came from two-parent nuclear families where one or both parents were employed. High deductibles, waiting time, application form complexity and request denials were cited as problems encountered with government drug plans. DISCUSSION: The findings suggest that for provinces that do not provide universal drug insurance programs, relying on a patchwork of government plans and community agencies may not be effective in ensuring easy and timely access to necessary medications for children.