Parental experiences and perspectives on the value of seizure detection while caring for a child with epilepsy: A qualitative study

INTRODUCTION: Caring for a child with epilepsy has a significant impact on parental quality of life. Seizure unpredictability and complications, including sudden unexpected death in epilepsy (SUDEP), may cause high parental stress and increased anxiety. Nocturnal supervision with seizure detection devices may lower SUDEP risk and decrease parental burden of seizure monitoring, but little is known about their added value in family homes. METHODS: We conducted semi-structured in-depth interviews with parents of children with refractory epilepsy participating in the PROMISE trial (NCT03909984) to explore the value of seizure detection in the daily care of their child. Children were aged 4-16 years, treated at a tertiary epilepsy center, had at least one nocturnal major motor seizure per week, and used a wearable seizure detection device (NightWatch) for two months at home. Data were analyzed using inductive thematic analysis. RESULTS: Twenty three parents of nineteen children with refractory epilepsy were interviewed. All parents expressed their fear of missing a large seizure and the possible consequences of not intervening in time. Some parents felt the threat of child loss during every seizure, while others thought about it from time to time. The fear could fluctuate over time, mainly associated with fluctuations of seizure frequency. Most parents described how they developed a protective behavior, driven by this fear. The way parents handled the care of their child and experienced the burden of care influenced their perceptions on the added value of NightWatch. The experienced value of NightWatch depended on the amount of assurance it could offer to reduce their fear and the associated protective behavior as well as their resilience to handle the potential extra burden of care, due to false alarms or technical problems. CONCLUSION: Healthcare professionals and device companies should be aware of parental protective behavior and the high parental burden of care and develop tailored strategies to optimize seizure detection device care

Prevalence and onset of comorbidities in the CDKL5 disorder differ from Rett syndrome

Background: Initially described as an early onset seizure variant of Rett syndrome, the CDKL5 disorder is now considered as an independent entity. However, little is currently known about the full spectrum of comorbidities that affect these patients and available literature is limited to small case series. This study aimed to use a large international sample to examine the prevalence in this disorder of comorbidities of epilepsy, gastrointestinal problems including feeding difficulties, sleep and respiratory problems and scoliosis and their relationships with age and genotype. Prevalence and onset were also compared with those occurring in Rett syndrome. Methods: Data for the CDKL5 disorder and Rett syndrome were sourced from the International CDKL5 Disorder Database (ICDD), InterRett and the Australian Rett syndrome Database (ARSD). Logistic regression (multivariate and univariate) was used to analyse the relationships between age group, mutation type and the prevalence of various comorbidities. Binary longitudinal data from the ARSD and the equivalent cross-sectional data from ICDD were examined using generalized linear models with generalized estimating equations. The Kaplan-Meier method was used to estimate the failure function for the two disorders and the log-rank test was used to compare the two functions. Results: The likelihood of experiencing epilepsy, GI problems, respiratory problems, and scoliosis in the CDKL5 disorder increased with age and males were more vulnerable to respiratory and sleep problems than females. We did not identify any statistically significant relationships between mutation group and prevalence of comorbidities. Epilepsy, GI problems and sleep abnormalities were more common in the CDKL5 disorder than in Rett syndrome whilst scoliosis and respiratory problems were less prevalent. Conclusion: This study captured a much clearer picture of the CDKL5 disorder than previously possible using the largest sample available to date. There were differences in the presentation of clinical features occurring in the CDKL5 disorder and in Rett syndrome, reinforcing the concept that CDKL5 is an independent disorder with its own distinctive characteristics

Therapeutic Efficacy of a Potent Anti-venezuelan Equine Encephalitis Virus Antibody Is Contingent on FC Effector functionslc6a1 Variant Pathogenicity, Molecular Function and Phenotype: A Genetic and Clinical Analysis

Genetic variants in the SLC6A1 gene can cause a broad phenotypic disease spectrum by altering the protein function. Thus, systematically curated clinically relevant genotype-phenotype associations are needed to understand the disease mechanism and improve therapeutic decision-making. We aggregated genetic and clinical data from 172 individuals with likely pathogenic/pathogenic (lp/p) SLC6A1 variants and functional data for 184 variants (14.1% lp/p). Clinical and functional data were available for a subset of 126 individuals. We explored the potential associations of variant positions on the GAT1 3D structure with variant pathogenicity, altered molecular function and phenotype severity using bioinformatic approaches. The GAT1 transmembrane domains 1, 6 and extracellular loop 4 (EL4) were enriched for patient over population variants. Across functionally tested missense variants (n = 156), the spatial proximity from the ligand was associated with loss-of-function in the GAT1 transporter activity. For variants with complete loss of in vitro GABA uptake, we found a 4.6-fold enrichment in patients having severe disease versus non-severe disease (P = 2.9 × 10−3, 95% confidence interval: 1.5–15.3). In summary, we delineated associations between the 3D structure and variant pathogenicity, variant function and phenotype in SLC6A1-related disorders. This knowledge supports biology-informed variant interpretation and research on GAT1 function. All our data can be interactively explored in the SLC6A1 portal (https://slc6a1-portal.broadinstitute.org/)

Respiratory Disturbances in Rett Syndrome: Don't Forget to Evaluate Upper Airway Obstruction

Rett syndrome is characterized by loss of motor and social functions, development of stereotypic hand movements, seizures, and breathing disturbances. This study evaluates the presence of overnight respiratory disturbances. Polysomnography in combination with a questionnaire (the Sleep Disturbance Scale for Children) was performed in 12 Dutch patients with Rett. Respiratory disturbances were present in all, clinically relevant in 10 (apnea hypopnea per hour 1.0-14.5). In 8 children, central apneas were present during the day often with obstructive apneas at night. In 6, obstructive sleep apnea syndrome was diagnosed, in 3 severe, with frequent oxygen desaturations. Significant respiratory complaints were present in 3 patients, all had obstructive sleep apnea syndrome. Of the 12 patients with Rett, 8 (67%) snored, and in 5 obstructive sleep apnea syndrome was present. In children, hypertrophied tonsils and adenoids are a common cause of obstructive sleep apnea syndrome, which may benefit from therapeutic intervention. We recommend performing polysomnography in patients with Rett syndrome and respiratory complaint

Magnetic resonance imaging of the lumbosacral spine in children with chronic constipation or non-retentive fecal incontinence: a prospective study

OBJECTIVE: To determine the prevalence of lumbosacral spine (LSS) abnormalities in children with defecation disorders, intractable constipation, or non-retentive fecal incontinence (NRFI) and evaluate whether LSS abnormalities on magnetic resonance imaging (MRI) are clinically detected by neurologic examination. STUDY DESIGN: MRI of the LSS and complete neurologic examination by a pediatric neurologist blinded to the MRI results were performed in patients with intractable defecation disorders. RESULTS: Patients with intractable constipation (n = 130; 76 males; median age, 11 years; range, 6-18 years), and patients with NRFI (n = 28; 18 males; median age, 10 years; range, 7-15 years) participated. One occult spina bifida (OSB) and 3 terminal filum lipomas were found in patients with a normal neurologic examination. One patient had a terminal filum lipoma and neurologic complaints. Gluteal cleft deviation was found in 3 of 4 patients with LSS abnormalities. Neurosurgical treatment was not required in any patient during the 12-week follow-up. CONCLUSIONS: MRI showed LSS abnormalities in 3% of patients with defecation disorders and normal neurologic examination, all of whom reported symptom relief at the 12-week follow-up without neurosurgical intervention. Thus, whether or not LSS abnormalities play a role in defecation disorders remains unclear

A case of neonatal dural sinus malformation: clinical symptoms, imaging and neuropathological investigations

We report a case of neonatal dural sinus malformation already visible on antenatal ultrasound. This is a rare disease entity in infants and children. Clinical diagnosis was made by demonstrating a cranial murmur on auscultation; macrocrania and signs of progressive cardiac failure. Imaging studies as cerebral ultrasound, postnatal MRI scan and MR angiography demonstrated a large dural sinus malformation originating from the sagittal sinus with extensive arteriovenous fistulae. Due to the extent of the lesion, the existing ischemic brain damage and involvement of the torcular, no therapeutic options were available and the child died of irreversible cardiac failure. The diagnosis was confirmed with autopsy. We discuss the clinical presentation, imaging and neuropathological results and relate our findings to embryological data and the existing literatur