Browsing by Author "De Vries, Petrus J"

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    Open Access
    Identification of natural TSC-Associated Neuropsychiatric Disorders (TAND) clusters
    (2017) Leclezio, Loren; De Vries, Petrus J
    Tuberous Sclerosis Complex (TSC) is associated with many learning, behavioural, neurodevelopmental and psychiatric difficulties. Over 90% of individuals with TSC will have some of these concerns yet no more than 20% receive support and treatment, even though these issues may cause the greatest burden of disease in TSC. The Neuropsychiatry Panel at the 2012 TSC Consensus Conference coined the term TAND (TSC-Associated Neuropsychiatric Disorders) to capture the multidimensional concerns seen in TSC, and recommended that each person with TSC should be screened for TAND every year. To facilitate the process, a TAND Checklist was designed. Many professionals and families feel overwhelmed by the complexity of TAND and say that they do not know where to start and how to access relevant information, tips or 'next step' approaches. This may in part be due to the multi-dimensionality of TAND, and in part due to lack of access to clear, useful and evidence-based resources for TAND. This project aimed to address the complexity of TAND. The hypothesis was that, even though each individual will typically have their own unique TAND profile, there will be key natural TAND Clusters - combinations of behaviours across multi-dimensional levels - that will simplify further evaluations and treatment. The study was performed over 36 months, in two phases using a mixed-methods approach. Phase I was a pilot phase. TAND Checklist data were collected from 56 individuals with TSC in South Africa (n=20) and in Australia (n= 36). Using R, these data were explored with various multivariate data analysis techniques to identify suitable analysis methods for the identification of potential natural TAND clusters. WARD's cluster analysis method rendered six TAND clusters with good face validity, and convergence with a six-factor exploratory factor analysis solution. Pilot results suggested that a combination of cluster analysis and exploratory factor analysis methods may be able to identify clinically-meaningful natural TAND clusters. Phase II set out to replicate and expand on pilot results. TAND checklist data were collected from n=453 across six international TSC sites, and the multivariate analysis techniques identified in phase I were applied. WARD's method rendered seven natural TAND clusters with good clinical face validity. This data-driven strategy identified a 'Scholastic' cluster of TAND manifestations, a 'Neuropsychological' cluster, a 'Mood/Anxiety' cluster, an 'ASD-like' cluster, a 'Behaviours that Challenge' cluster, a 'Hyperactive/Impulsive' cluster, and an 'Eating/Sleeping' cluster. Results showed significant convergence with an exploratory factor analysis solution. The larger-scale study findings were remarkably consistent with pilot findings, supporting the robustness of these naturally occurring clusters. We propose that the seven natural TAND clusters identified can in future be used to generate clinical toolkits for use in real-life setting. In addition, findings suggest that the aetiology and molecular treatments of TAND may also show differential clustering across human and animal models, pointing towards novel hypotheses regarding neuropsychiatric phenomena in TSC to be explored in future studies.
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    Long-term use of Everolimus in patients with Tuberous Sclerosis Complex: final results from the EXIST-1 study
    (Public Library of Science, 2016) Franz, David N; Belousova, Elena; Sparagana, Steven; Bebin, E Martina; Frost, Michael D; Kuperman, Rachel; Witt, Olaf; Kohrman, Michael H; Flamini, J Robert; Wu, Joyce Y; Curatolo, Paolo; De Vries, Petrus J; Berkowitz, Noah; Niolat, Julie; Jóźwiak, Sergiusz
    BACKGROUND: Everolimus, a mammalian target of rapamycin (mTOR) inhibitor, has demonstrated efficacy in treating subependymal giant cell astrocytomas (SEGAs) and other manifestations of tuberous sclerosis complex (TSC). However, long-term use of mTOR inhibitors might be necessary. This analysis explored long-term efficacy and safety of everolimus from the conclusion of the EXIST-1 study (NCT00789828). Methods and FINDINGS: EXIST-1 was an international, prospective, double-blind, placebo-controlled phase 3 trial examining everolimus in patients with new or growing TSC-related SEGA. After a double-blind core phase, all remaining patients could receive everolimus in a long-term, open-label extension. Everolimus was initiated at a dose (4.5 mg/m 2 /day) titrated to a target blood trough of 5-15 ng/mL. SEGA response rate (primary end point) was defined as the proportion of patients achieving confirmed ≥50% reduction in the sum volume of target SEGA lesions from baseline in the absence of worsening nontarget SEGA lesions, new target SEGA lesions, and new or worsening hydrocephalus. Of 111 patients (median age, 9.5 years) who received ≥1 dose of everolimus (median duration, 47.1 months), 57.7% (95% confidence interval [CI], 47.9-67.0) achieved SEGA response. Of 41 patients with target renal angiomyolipomas at baseline, 30 (73.2%) achieved renal angiomyolipoma response. In 105 patients with ≥1 skin lesion at baseline, skin lesion response rate was 58.1%. Incidence of adverse events (AEs) was comparable with that of previous reports, and occurrence of emergent AEs generally decreased over time. The most common AEs (≥30% incidence) suspected to be treatment-related were stomatitis (43.2%) and mouth ulceration (32.4%). CONCLUSIONS: Everolimus use led to sustained reduction in tumor volume, and new responses were observed for SEGA and renal angiomyolipoma from the blinded core phase of the study. These findings support the hypothesis that everolimus can safely reverse multisystem manifestations of TSC in a significant proportion of patients. Trial Registration ClinicalTrials.gov NCT00789828
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    Towards the quantification of intellectual disability in children and adolescents in Africa: an exploration of the psychometric properties of the Wessex Behaviour Schedule (WBS) in Khayelitsha, South Africa
    (2017) Abbo, Catherine; De Vries, Petrus J; London, Leslie; Adnams, Colleen
    Background: Intellectual Disability (ID) is important and has a major impact on life, quality of life, mental illness, economic and educational well-being. Little research has taken place in Africa about ID. One of the key challenges is to identify appropriate, useful, and free screening tools that might identify those at risk of ID both for clinical purposes and for prevalence studies. One tool that has been used to investigate the broad category of 'disability' (which includes ID) is the Ten Questions Questionnaire (TQQ). The TQQ has given some rates of 'disability' in lowand middle-income countries (LMICS) in the order of 10-25%. However, no further dissection of ID within the broader category of 'disability' has been performed given that the TQQ was not developed with ID in mind. The Wessex Behavioural Schedule (WBS) is a UK screening tool for functional ability for adults with ID, and therefore seemed an appropriate candidate instrument to evaluate for potential use in Africa. However no psychometric data for the tool were available and no clinical cut-off scores for ID had ever been developed. A broader project using the WBS in Khayelitsha, a township area in Cape Town, South Africa, generated a prevalence rate of 19% 'disability'. The purpose of this study was to explore the psychometric properties of WBS to determine its suitability for use in children and adolescents in a South African setting, and to generate clinical cut-offs to define ID. Methods: The study consisted of a secondary analysis of the data from the broader Khayelitsha prevalence study, which was a cluster randomized door-to-door household survey in Khayelitsha using the WBS. Firstly, data were used to evaluate the internal consistency and to perform factor analysis of the WBS. Secondly, the Minimal Difference Perceived 75% of time (MDP75) approach was used on a subset of 100 randomly selected participants to generate an intellectual disability cut-off score for the WBS. Results: Data were available on 452 children and adolescents aged 5-18 years. The mean age was 10.3 (SD 3.9), 54% were female, over 90% were in school, and 53% had a mother as primary carer. The WBS had good internal consistency (alpha = 0.80) and all items appeared to be worthy of retention. Exploratory factor analysis suggested the WBS to be a multidimensional scale composed of four subscales: conceptual abilities, practical skills, sensory abilities and continence. Even though four expert raters were used for the MDP75 calculation, inter-rater reliability was low-58% (Fleiss kappa = 0.08). It was therefore not deemed appropriate to proceed to further analysis to determine the MDP75 and cut-off values for the WBS. Possible reasons for low inter-rater reliability suggested by the raters included age-based expectations, inclusion of physical disabilities, limited information to make a diagnosis of ID contained in the WBS, and the need to take environmental factors into consideration. Conclusion: The good internal consistency and factor analysis structure of the WBS was encouraging, but the low inter-rater reliability brought into question the usefulness of the WBS in a child and adolescent age group. Whilst the WBS may remain useful in an adult age range, we recommend that a more developmentally-sensitive measure be sought or developed as a screening tool for ID. Keywords: Wessex Behavioural Schedule, children and adolescents, intellectual disability, Khayelitsha