Psychometric properties of QI-Disability in CDKL5 Deficiency Disorder: Establishing readiness for clinical trials.

CDKL5 Deficiency Disorder (CDD) is a rare genetic disorder with symptoms of epilepsy, developmental impairments, and other comorbidities. Currently, there are no outcome measures for CDD with comprehensive evidence of validation. This study aimed to evaluate the psychometric properties of the Quality of Life Inventory-Disability (QI-Disability) in CDD. Quality of Life Inventory-Disability was administered to 152 parent caregivers registered with the International CDKL5 Disorder Database (ICDD). Confirmatory factor analysis was conducted and the goodness of fit of the factor structure was assessed. Fixed-effects linear regression models examined the responsiveness of QI-Disability to reported changes in child health. A subset of parent caregivers (n = 56) completed QI-Disability, as well as additional health-related questions, on two occasions separated by four weeks to evaluate test-retest reliability. Test-retest reliability was assessed using intra-class correlations (ICCs) calculated from QI-Disability scores. Based upon adjustments for changes in child health, ICCs were recalculated to estimate responsiveness to change. Confirmatory factor analysis, internal consistency, and divergent validity were mostly satisfactory, except divergent validity was not satisfactory for the Social Interactions and Independence domains. The Physical Health, Social Interactions, Leisure, and Total scores responded to changes in the child's Physical health, and the Negative Emotions and Leisure domains responded to changes in the child's behavior. Unadjusted and adjusted ICC values were above 0.8 for the Positive Emotions, Negative Emotions, Social Interactions, Leisure, Independence domains and Total score, and above 0.6 for the Physical Health domain. Findings suggest that QI-Disability is suitable to assess the quality of life of children and adults with CDD and could be of value for upcoming clinical trials.

A systematic review of the biological, social, and environmental determinants of intellectual disability in children and adolescents.

Aim: This systematic review aimed to identify the most important social, environmental, biological, and/or genetic risk factors for intellectual disability (ID). Methods: Eligible were published prospective or retrospective comparative studies investigating risk factors for ID in children 4-18 years. Exclusions were single group studies with no comparator without ID and a sample size <100. Electronic databases (Medline, Cochrane Library, EMBASE, PsycInfo, Campbell Collaboration, and CINAHL) were searched for eligible publications from 1980 to 2020. Joanna Briggs Institute critical appraisal instruments, appropriate for study type, were used to assess study quality and risk of bias. Descriptive characteristics and individual study results were presented followed by the synthesis for individual risk factors, also assessed using GRADE. Results: Fifty-eight individual eligible studies were grouped into six exposure topics: sociodemographic; antenatal and perinatal; maternal physical health; maternal mental health; environmental; genetic or biological studies. There were few eligible genetic studies. For half the topics, the certainty of evidence (GRADE) was moderate or high. Conclusion: Multiple studies have examined individual potential determinants of ID, but few have investigated holistically to identify those populations most at risk. Our review would indicate that there are vulnerable groups where risk factors we identified, such as low socioeconomic status, minority ethnicity, teenage motherhood, maternal mental illness, and alcohol abuse, may cluster, highlighting a target for preventive strategies. At-risk populations need to be identified and monitored so that interventions can be implemented when appropriate, at preconception, during pregnancy, or after birth. This could reduce the likelihood of ID and provide optimal opportunities for vulnerable infants. Systematic review registration: [https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=120032], identifier [CRD42019120032].

Oral health education and promotion in special needs children: Systematic review and meta-analysis.

OBJECTIVE: To review the effectiveness of oral health education and oral health promotion interventions for children and adolescents with intellectual and developmental disabilities (IDD), in ensuring optimal gingival health, caries experience and oral health-related quality of life, compared to no interventions or alternative interventions. METHODS: A systematic review was conducted to identify published studies from four databases (Medline, PsycINFO, CINAHL and ERIC). Randomised or quasi-randomised controlled trials were included. Two independent reviewers performed risk of bias and qualitative analysis. Meta-analysis was performed as appropriate. RESULTS: Eight treatment comparisons were identified. There was low certainty evidence that fluoride interventions provided long-term reductions in caries in those with IDD; and there was some evidence that chlorhexidine albeit with low certainty provided short-term and long-term reductions in plaque and gingivitis. There was moderate certainty evidence for short-term reductions in dental plaque from the use of modified toothbrushes, but not compelling evidence for powered toothbrushes. CONCLUSIONS: Most studies provided a low quality of evidence, and so any adaptations made to oral health practices of individuals with IDD need to consider their individual needs. PROSPERO registration: CRD42019145784.

The perceived effects of cannabis products in the management of seizures in CDKL5 Deficiency Disorder.

INTRODUCTION: CDKL5 Deficiency Disorder (CDD) is a severe treatment-resistant form of early-onset epilepsy. Current treatment options are often ineffective and associated with adverse effects, forcing families to seek alternative therapies for their children including products derived from cannabis. Reportsof miraculous cures and a public preferencefor 'natural' therapies have resulted in considerable public interest, and so this study aimed to characterize the use of cannabis in these individuals, as well as compare caregiver perceptions of efficacy and safety to objective evidence of seizure control and number of antiepileptic drugs used. METHODS: Families from the International CDKL5 Disorder Database were invited to complete questionnaires which included data relating to their child's current and past treatments, including use of any cannabis-derived preparations. Perceived effects on seizure control, as well as additional benefits and adverse effects were reported. Seizure frequency and number of antiepileptic drugs were compared between those actively using cannabis products and those who were not. Longitudinal analysis was performed on a subset of the study population to compare these same variables at pre-treatment and post-treatment time points. RESULTS: Three hundred and twelve caregivers answered questions regarding their child's use of antiepileptic medications. Of these, 82 (26%) described use of cannabis preparations either at present, or in the past, with the most common being cannabidiol. Of 70 caregivers that described their perceived effect on seizure control, more than two thirds reported an improvement in seizure control, either temporary (16%) or lasting (54%). Additional benefits included improvements in attention, cognition, and sleep. The majority of responses (78%) described adverse effects as 'none', though some reported an increase in sedation and gastrointestinal upset. There was no reduction in the median seizure frequency nor the number of different antiepileptic drugs, for those who were actively using cannabis products compared to those who were not. Similarly, individuals who were not using cannabis products at an initial time point had no differences in seizure frequency nor number of antiepileptic drugs at a second timepoint when they had started using this treatment. CONCLUSIONS: Although this is an observational study, limited by potential participation bias and the unreliable nature of unblinded self-assessment, it suggests that caregivers perceive cannabis products, especially cannabidiol, to have a tolerable adverse effect profile and adequate efficacy. Despite this, cannabis was not associated with a reduction in seizure frequency nor number of antiepileptic drugs when compared to non-users or when compared to pre-treatment. Randomized controlled trials are urgently needed to more reliably assess this treatment's safety and efficacy.

Exploring quality of life in individuals with a severe developmental and epileptic encephalopathy, CDKL5 Deficiency Disorder.

BACKGROUND: CDKL5 Deficiency Disorder (CDD) is a rare genetic disorder caused by a mutation in the cyclin-dependent kinase-like 5 (CDKL5) gene. It is now considered to be a developmental and epileptic encephalopathy because of the early onset of seizures in association with severe global delay. Other features include cortical visual impairment, sleep and gastro-intestinal problems. Progress in clinical understanding, especially regarding the spectrum of functional ability, seizure patterns, and other comorbidities was initially slow but accelerated in 2012 with the establishment of the International CDKL5 Database (ICDD). Our aim was to use this data source to investigate quality of life (QOL) and associated factors in this disorder. METHOD: A follow-up questionnaire was administered in 2018 to parents of children registered with the ICDD who had a pathogenic CDKL5 variant. QOL was assessed using QI Disability, an instrument, specifically developed to measure total and specific domains of QOL (physical health, positive emotions, negative emotions, social interaction, leisure and the outdoors (leisure) and independence) in children with intellectual disability. Associations with functional abilities, physical health, mental health and family factors were investigated, initially using univariate analyses followed by multivariate analyses for each of these groups with a final composite model which included the important variables identified from previous models. RESULTS: Questionnaires were returned by 129/160 families with a child aged >3 years. Functional impairment, including lack of ability to sit, use hands and communicate had the greatest adverse impact on QOL. There were also some relationships with major genotype groupings. Individuals using three or more anti-epileptic medications had poorer QOL than those on one or no medication, particularly in the physical health domain. There was also variation by geographical region with those living in North America typically having the best QOL and those living in middle or lower income countries poorer QOL. CONCLUSION: Although lower functional abilities were associated with poorer quality of life further research is needed to understand how environmental supports might mitigate this deficit. Comprehensive care and support for both the child and family have important roles to play in helping families to thrive despite the severity of CDD.

Cannabis for refractory epilepsy in children: A review focusing on CDKL5 Deficiency Disorder.

Severe paediatric epilepsies such as CDKL5 Deficiency Disorder (CDD) are extremely debilitating, largely due to the early-onset and refractory nature of the seizures. Existing treatment options are often ineffective and associated with a host of adverse effects, causing those that are affected to seek alternative treatments. Cannabis based products have attracted significant attention over recent years, primarily driven by reports of miraculous cures and a renewed public preference for 'natural' therapies, thus placing intense pressure on health professionals and the government for regulatory change. This study provides a comprehensive overview of the potential role for cannabis in the treatment of CDD. Key areas discussed include the history, mechanism of action, efficacy and safety of cannabis based preparations as well as the burden related to CDD. The evidence supports the use of cannabinoids, especially cannabidiol, in similar forms of refractory epilepsy including Dravet and Lennox-Gastaut syndromes. Evidence for cannabinoids specifically in CDD is limited but growing, with multiple anecdotal reports and an open-label trial showing cannabidiol to be associated with a significant reduction in seizure activity. This review provides the first comprehensive overview of the potential role for cannabis based preparations in the treatment of CDD and provides justification for further clinical and observational research.

Psychometric properties of the Quality of Life Inventory-Disability (QI-Disability) measure.

PURPOSE: Children with intellectual disability encounter daily challenges beyond those captured in current quality of life measures. This study evaluated a new parent-report measure for children with intellectual disability, the Quality of Life Inventory-Disability (QI-Disability). METHODS: QI-Disability was administered to 253 primary caregivers of children (aged 5-18 years) with intellectual disability across four diagnostic groups: Rett syndrome, Down syndrome, cerebral palsy or autism spectrum disorder. Exploratory and confirmatory factor analyses were conducted and goodness of fit of the factor structure assessed. Associations between QI-Disability scores, and diagnostic and age groups were examined with linear regression. RESULTS: Six domains were identified: physical health, positive emotions, negative emotions, social interaction, leisure and the outdoors, and independence. Goodness-of-fit statistics were satisfactory and similar for the whole sample and when the sample was split by ability to walk or talk. On 100 point scales and compared to Rett syndrome, children with Down syndrome had higher leisure and the outdoors (coefficient 10.6, 95% CI 3.4,17.8) and independence (coefficient 29.7, 95% CI 22.9, 36.5) scores, whereas children with autism spectrum disorder had lower social interaction scores (coefficient - 12.8, 95% CI - 19.3, - 6.4). Scores for positive emotions (coefficient - 6.1, 95% CI - 10.7, - 1.6) and leisure and the outdoors (coefficient 5.4, 95% CI - 10.6, - 0.1) were lower for adolescents compared with children. CONCLUSIONS: Initial evaluation suggests that QI-Disability is a reliable and valid measure of quality of life across the spectrum of intellectual disability. It has the potential to allow clearer identification of support needs and measure responsiveness to interventions.

Clinical Guidelines for Management of Bone Health in Rett Syndrome Based on Expert Consensus and Available Evidence.

OBJECTIVES: We developed clinical guidelines for the management of bone health in Rett syndrome through evidence review and the consensus of an expert panel of clinicians. METHODS: An initial guidelines draft was created which included statements based upon literature review and 11 open-ended questions where literature was lacking. The international expert panel reviewed the draft online using a 2-stage Delphi process to reach consensus agreement. Items describe the clinical assessment of bone health, bone mineral density assessment and technique, and pharmacological and non-pharmacological interventions. RESULTS: Agreement was reached on 39 statements which were formulated from 41 statements and 11 questions. When assessing bone health in Rett syndrome a comprehensive assessment of fracture history, mutation type, prescribed medication, pubertal development, mobility level, dietary intake and biochemical bone markers is recommended. A baseline densitometry assessment should be performed with accommodations made for size, with the frequency of surveillance determined according to individual risk. Lateral spine x-rays are also suggested. Increasing physical activity and initiating calcium and vitamin D supplementation when low are the first approaches to optimizing bone health in Rett syndrome. If individuals with Rett syndrome meet the ISCD criterion for osteoporosis in children, the use of bisphosphonates is recommended. CONCLUSION: A clinically significant history of fracture in combination with low bone densitometry findings is necessary for a diagnosis of osteoporosis. These evidence and consensus-based guidelines have the potential to improve bone health in those with Rett syndrome, reduce the frequency of fractures, and stimulate further research that aims to ameliorate the impacts of this serious comorbidity.

The trajectories of sleep disturbances in Rett syndrome.

Rett syndrome is a rare neurodevelopmental disorder usually affecting females, and is associated with a mutation in the MECP2 gene. Sleep problems occur commonly and we investigated the trajectories and influences of age, mutation and treatments. Data were collected at six time points over 12 years from 320 families registered with the Australian Rett Syndrome Database. Regression analysis was used to investigate relationships between sleep disturbances, age, mutation type and use of treatment, and latent class growth analysis was performed to identify sleep problem phenotypes and model the effect of mutation type. The age range of subjects was 2.0-35.8 years. The study showed that sleep problems occurred in more than 80% of individuals and the prevalence decreased with age. Night laughing and night screaming occurred in 77 and 49%, respectively, when younger. Those with a large deletion had a higher prevalence of night laughing, which often occurred frequently. Treatment was associated with a 1.7% reduction in risk of further sleep problems. High and low baseline prevalence groups were identified. Approximately three-quarters of girls and women with sleep disturbances were in the high baseline group and problems persisted into adulthood. Conversely, 57% with night laughing and 42% with night screaming in the high baseline group exhibited mild improvement over time. Mutation type was not found to be a significant predictor of group membership. In conclusion, the evolution of sleep problems differed between subgroups of girls and women with Rett syndrome, in part explained by age and genotype. Treatment was not associated with improvement in sleep problems.

"It's not what you were expecting, but it's still a beautiful journey": the experience of mothers of children with Down syndrome.

AIM: The purpose of this study was to describe qualitatively the experience of parenting for mothers of a child with Down syndrome and to explore what if any was the role of spirituality and organized religion in this experience. METHOD: A homogenous sample of eight mothers of children between 7 and 12 years of age with Down syndrome was recruited through a population-based source of families of children with Down syndrome in Western Australia. In-depth interviews were used to explore the mother's experience of parenting and to examine the role of spirituality and organized religion in their personal experience of mothering. RESULTS: In this study, stressful life events recounted by the mothers included initial acceptance, developmental behaviour of the child, functionality of the child, health conditions and financial stress. Overall spirituality was described as a stronger and more dynamic source of support than organized religion in coping with stressors and life's challenges associated with raising a child with Down syndrome. CONCLUSION: Findings from this study revealed that being a mother to a child with Down syndrome can best be described as a mosaic of experiences, emotions and a journey of self growth. Both spirituality and organized religion to a greater or lesser extent were useful in mediating stress and supporting mothers particularly during challenging life events in the course of their journey with their child with Down syndrome.

Direct health care costs of children and adolescents with Down syndrome.

OBJECTIVE: To assess the direct annual health care costs for children and adolescents with Down syndrome in Western Australia and to explore the variation in health care use including respite, according to age and disease profile. STUDY DESIGN: Population-based data were derived from a cross-sectional questionnaire that was distributed to all families who had a child with Down syndrome as old as 25 years of age in Western Australia. RESULTS: Seventy-three percent of families (363/500) responded to the survey. Mean annual cost was $4209 Australian dollars ($4287 US dollars) for direct health care including hospital, medical, pharmaceutical, respite and therapy, with a median cost of $1701. Overall, costs decreased with age. The decline in costs was a result of decreasing use of hospital, medical, and therapy costs with age. Conversely, respite increased with age and also with dependency. Health care costs were greater in all age groups with increasing dependency and for an earlier or current diagnosis of congenital heart disease. Annual health care costs did not vary with parental income, including cost of respite. CONCLUSIONS: Direct health care costs for children with Down syndrome decrease with age to approximate population costs, although costs of respite show an increasing trend.