NEWS IN EARLY INTERVENTION IN AUTISM

Background: Autism Spectrum Disorder (ASD) is a complex neurodevelopmental trouble which prevents the child from sociocommunicative interaction, and learning from his environment. Non-medical early intervention attempts to improve prognosis. We will review the main current hypothesis, intervention models and scientific supports about early intervention. Methods: We conducted a search of the literature published on Medline between 2010 and 2015 related to intervention models provided to children with ASD aged less than 3 years. Data were extracted from systematic reviews and recent randomized controlled trials with moderate to high GRADE quality of evidence. Results: Early intervention refers to brain plasticity theory. With the epidemiological studies of infant “at risk” there is an attempt to intervene earlier before full syndrome is present. Interventions tend to follow more on a developmental hierarchy of sociocommunicative skills and to focus on the dyadic relation between the child and the caregivers to improve the core autistic symptoms. Over the last 6 years, there’s been news and fine-tuned ways about early intervention, and more and more systematic evaluation. Conclusion: However, there are only few interventions which were evaluated in trial with a strong GRADE recommendation and all of them have methodological concerns. It is important to be cautious in recommendations for mental health politic, even if it is important to improve access to services for all children and their families, hence finance and design rigorous project in research

THE CHILD “AFTER”: BETWEEN MATERNAL DEPRESSION AND TRANSMISSION OF THE TRAUMATISM

Born a little time after the death of his sister, our patient, Antoine, 13 years old, was suffering from severe obsessional compulsive disorders, which needed care in the hospital and adapted treatment. We tried to know if what we were led to observe by this adolescent could be explained by works and thoughts around the notion of substitute child. Building our thought on various theoretical approaches, including neurosciences, we tried to think the psychopathological signs of this patient by two ways. One is about the birth and the growth in the presence of depressed parents, and this since the pregnancy. The other one is about the necessity to deal with the traumatic story of the family, met by the parents, who are still facing it, that leads to the question of the transmission of the traumatism from the mother to the baby. Using the notion of maternal primary care, we proposed the term ‘the child after’, which appeared to us more able to represent the dynamic and the place really given to these children. This term could mean the question of an undone grief, a traumatism without temporality, and a relation between the mother and the child which seems to be uncertain because of the investment of the child as an impossible reparation of an unscarred loss

THE CHILD “AFTER”: BETWEEN MATERNAL DEPRESSION AND TRANSMISSION OF THE TRAUMATISM

Born a little time after the death of his sister, our patient, Antoine, 13 years old, was suffering from severe obsessional compulsive disorders, which needed care in the hospital and adapted treatment. We tried to know if what we were led to observe by this adolescent could be explained by works and thoughts around the notion of substitute child. Building our thought on various theoretical approaches, including neurosciences, we tried to think the psychopathological signs of this patient by two ways. One is about the birth and the growth in the presence of depressed parents, and this since the pregnancy. The other one is about the necessity to deal with the traumatic story of the family, met by the parents, who are still facing it, that leads to the question of the transmission of the traumatism from the mother to the baby. Using the notion of maternal primary care, we proposed the term ‘the child after’, which appeared to us more able to represent the dynamic and the place really given to these children. This term could mean the question of an undone grief, a traumatism without temporality, and a relation between the mother and the child which seems to be uncertain because of the investment of the child as an impossible reparation of an unscarred loss

Clinical predictors of psychotropic medication prescription in children with ASD of the ELENA cohort

Psychotropic drugs are often used to treat behavior problems in ASD with some evidence supporting efficacity (e.g.: risperidone and irritability) but also significant side effects at the short and longer-term. It is then essential to know better the factors associated with the prescription of these medications and potentially implement early behavioral and psychosocial intervention or cognitive remediation before to use medication. We designed a case–control study based on the population of the ELENA cohort to assess the factors associated with early psychotropic drugs use in children with ASD. Externalized behavior symptoms (measured by the Child Behavior Checklist) is the leading risk factor during the first years of follow-up (aOR = 2.8; CI [1.04; 7.67]; p = 0.04). Age, gender, autism severity, adaptive behaviors, or internalized behaviors were not associated with psychotropic medication prescription. Low IQ and parents who had received training tended to increase the risk of psychotropic medication prescription during follow-up but were not statistically significant. These findings underscore the need for early identification of symptoms of externalizing behaviour, early appropriate information for parents about treatment with and without medication, early analysis of externalising behaviour and targeted treatments

Detection of Morphological Abnormalities in Schizophrenia: An Important Step to Identify Associated Genetic Disorders or Etiologic Subtypes

From MDPI via Jisc Publications RouterHistory: accepted 2021-08-06, pub-electronic 2021-08-31Publication status: PublishedCurrent research suggests that alterations in neurodevelopmental processes, involving gene X environment interactions during key stages of brain development (prenatal period and adolescence), are a major risk for schizophrenia. First, epidemiological studies supporting a genetic contribution to schizophrenia are presented in this article, including family, twin, and adoption studies. Then, an extensive literature review on genetic disorders associated with schizophrenia is reviewed. These epidemiological findings and clinical observations led researchers to conduct studies on genetic associations in schizophrenia, and more specifically on genomics (CNV: copy-number variant, and SNP: single nucleotide polymorphism). The main structural (CNV) and sequence (SNP) variants found in individuals with schizophrenia are reported here. Evidence of genetic contributions to schizophrenia and current knowledge on genetic syndromes associated with this psychiatric disorder highlight the importance of a clinical genetic examination to detect minor physical anomalies in individuals with ultra-high risk of schizophrenia. Several dysmorphic features have been described in schizophrenia, especially in early onset schizophrenia, and can be viewed as neurodevelopmental markers of vulnerability. Early detection of individuals with neurodevelopmental abnormalities is a fundamental issue to develop prevention and diagnostic strategies, therapeutic intervention and follow-up, and to ascertain better the underlying mechanisms involved in the pathophysiology of schizophrenia

USING ESDM 12 HOURS PER WEEK IN CHILDREN WITH AUTISM SPECTRUM DISORDER: FEASIBILITY AND RESULTS OF AN OBSERVATIONAL STUDY

Background: Early intervention for Autism Spectrum Disorder (ASD) in France is heterogeneous and poorly evaluated to date. Early Start Denver Model (ESDM) is a developmental and behavioral model ofintervention for toddlers with ASD which has already shown very interesting outcomes on the development of children with ASD in various studies with different settings. However, it is not possible with the current research to agree on the best setting. Thus, we implemented an ESDM program according to our context where children are often pre-schooling early from 30 months old. This therapy was applied by a multidisciplinary team working in close collaboration with parents and other partners. Subjects and methods: A prospective observational study including 19 toddlers with ASD was conducted. We evaluated improvement on the cognitive level of toddlers with ASD receiving therapist-delivered ESDM intervention for 12 hours per week. Results: Significant improvements in verbal and nonverbal cognitive skills at the Mullen Scale of Early Learning were obtained after 10 months of intervention in our sample. The largest improvement was in receptive language development quotient with a mean improvement of 19.6 points. We also observed promising outcomes in daily adaptive behavior, with a slight improvement in communication at the Vineland Adaptive Behavioral Scale. These outcomes, when compared to the conclusions of previous studies, are leading us to the need for a therapy duration beyond 10 months. Conclusions: Our outcomes were very encouraging even with lowcognitive and nonverbal children. These outcomes may be confirmed in a multicenter randomized controlled trial that is ongoing

Gene × Environment interactions in autism spectrum disorders: role of epigenetic mechanisms.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Files. This article is open access.Several studies support currently the hypothesis that autism etiology is based on a polygenic and epistatic model. However, despite advances in epidemiological, molecular and clinical genetics, the genetic risk factors remain difficult to identify, with the exception of a few chromosomal disorders and several single gene disorders associated with an increased risk for autism. Furthermore, several studies suggest a role of environmental factors in autism spectrum disorders (ASD). First, arguments for a genetic contribution to autism, based on updated family and twin studies, are examined. Second, a review of possible prenatal, perinatal, and postnatal environmental risk factors for ASD are presented. Then, the hypotheses are discussed concerning the underlying mechanisms related to a role of environmental factors in the development of ASD in association with genetic factors. In particular, epigenetics as a candidate biological mechanism for gene × environment interactions is considered and the possible role of epigenetic mechanisms reported in genetic disorders associated with ASD is discussed. Furthermore, the example of in utero exposure to valproate provides a good illustration of epigenetic mechanisms involved in ASD and innovative therapeutic strategies. Epigenetic remodeling by environmental factors opens new perspectives for a better understanding, prevention, and early therapeutic intervention of ASD

Measuring effectiveness of early intervention in children with autism spectrum disorder (ASD) : internal and external validity of the results

Intervenir précocement pour diminuer la sévérité du Trouble du Spectre de l’Autisme (TSA) est à ce jour une évidence. En revanche, le type d’intervention précoce à appliquer ne fait pas consensus . Certaines interventions montrent une efficacité d’intensité faible à modérée dans des essais randomisés contrôlés. Mais ces derniers comportent de nombreux biais méthodologiques qui remettent en question la validité du résultat. Nous avons fait l’hypothèse qu’une intervention précoce avec le modèle de Denver (Early Start Denver Model-ESDM) permettrait de diminuer la sévérité de la symptomatologie d’enfants avec TSA âgés de moins de 3 ans. Dans l’étude pilote, l’objectif était d’évaluer l’effet d’une intervention ESDM 12 heures par semaine pendant 1 an dans une population de 19 enfants avec TSA. Le résultat montrait une amélioration significative du développement global avant après intervention. La taille d’effet en langage réceptif était la plus importante avec un d de Cohen à 0.72. Ces résultats étaient comparables avec ceux d’études publiées précédemment. La majorité des professionnels et des parents étaient satisfaits de cette intervention. L’adhérence au traitement en termes de dose était de 8.3±1.2 heures au lieu de 12 heures par semaine dans cette étude pilote. Cette diminution de dose était majoritairement due à l’absence des professionnels. Nous discutons, ici, le choix de notre critère de jugement principal pour mesurer l’efficacité clinique réelle de l’intervention. Ce choix était difficile du fait du manque d’outils qui mesurent avec précision le changement dans la symptomatologie ou le handicap dans le TSA . Pour confirmer ou infirmer notre hypothèse, un essai randomisé contrôlé multicentrique comparant 2 bras en parallèle a été mis en place. Le groupe expérimental recevait une intervention ESDM, conduite majoritairement par une équipe pluridisciplinaire, 12 heures par semaine, pendant 2 ans. Le groupe contrôle recevait les interventions habituellement proposées dans la communauté. L’essai a été conçu pour avoir une puissance élevée et être à haut niveau de preuve selon les recommandations Cochrane . Nous avons pour cela mesuré le nombre nécessaire de sujet de notre population à partir d’une différence de 15 points à l’échelle de Mullen entre nos deux groupes, un risque alpha de 0,5 et un risque bêta à 90%. Étant limités par le nombre de places disponibles en intervention ESDM, nous avons mis en place une randomisation 1:2. La phase d’inclusion s’est terminée en mars 2019. 61 enfants ont été inclus dans le groupe ESDM et 119 enfants dans le groupe contrôle. Nous discutons la validité interne et externe ainsi que la pertinence clinique selon les différents résultats possibles. Si nous montrons une efficacité, une étude coût-conséquence permettra une mesure de l’efficience de ce traitement. Une étude de suivi a par ailleurs débuté et mesurera l’effet à 5 ans, d’une intervention ESDM précocement reçue, sur la symptomatologie TSA et le niveau scolaire des enfants. Il est bien évidemment essentiel de mesurer l’efficacité clinique et l’efficience à long terme des interventions mais la recherche interventionnelle implique également d’autres mesures et observations. Ainsi, la connaissance des facteurs médiateurs de l’effet de l’intervention, comme celle des facteurs modérateurs permettra d’aller vers des interventions personnalisées, qui agissent précisément sur les processus physiopathologiques impliqués dans le TSA. Une meilleure connaissance de ces facteurs mais aussi de tous les potentiels obstacles ou facilitateurs au transfert dans d’autres contextes de l’intervention permettra de plus de développer des interventions transférables et durables. Nous concluons sur l’importance de prévoir des temps de phase pilote suffisants pour estimer les différents facteurs impliqués et modifier l’intervention initialement prévue si nécessaire, avant de réaliser des essais d’efficacité ou d’efficience coûteuxEarly intervention in order to decrease the severity of Autism Spectrum Disorder has come to be self-evident . However, there is no consensus on the type of early intervention, as we have previously shown in a literature review . Some interventions have shown weak to moderate effects in randomized controlled trials. But many methodological biases call into question the validity of those results. We have chosen to implement and evaluate the Early Start Denver Model (ESDM) at our intervention center. Our hypothesis was that ESDM intervention will diminish the severity of ASD symptoms in children under 3 years old. In our pilot study, we evaluated the effect of a 12 hours per week ESDM intervention, during one year, in a population of 19 children with ASD. The primary measure was the global development, measured by the Mullen Scales of Early Learning. Our results show a significant improvement in global development pre/post intervention. Effect size in receptive language was the most important with a Cohen’s d of 0.72. These results are comparable to those of previous published studies. This trial enabled also to data collection on the feasibility of implementing this intervention in our context. Most parents and professionals were satisfied of the intervention. Treatment adherence was of 8.3±1.2 hours per week instead of 12 hours per week during the pilot study. This reduction of intervention dose was largely due to absences (holidays, training) of the professionals delivering the intervention. We discuss here the choice of criteria for the measure of effectiveness of the intervention. This choice was difficult due to the lack of tools measuring precisely the change in ASD symptomatology. To test our hypothesis, a two-parallel, multi-center randomized controlled trial was set up. The experimental group received ESDM intervention, delivered by a multidisciplinary team, 12 hours per week, during the 2 years. The control group received treatment as usual. The protocol has been published. The trial was design to have high power and high-level evidences as defined by the Cochrane recommendations. In order to achieve this, we estimated the simple size for our population from a 15 points difference between the groups on the Mullen scale, an alpha risk of 0.5 and a beta risk at 90%. As we were limited by the number of availabilities for ESDM intervention, we used 1:2 randomization. The inclusion phase ended in March 2019. 61 children were included to the ESDM group and 119 children to the control group. We discuss the internal and external validity, as well as the clinical relevance according to the possible outcomes. If outcomes show effectiveness of the intervention, a cost-consequence study will allow us to measure the efficiency of this treatment. A follow-up study has also started and will measure the effectiveness of ESDM intervention on ASD symptomatology and academic achievements five year after initial inclusion. It is evidently essential to measure the long-term effectiveness and efficiency of early interventions; however, intervention research must also collect other measures and observations. Thus, determine mediators and moderators of the intervention will make it possible to move towards personalized interventions, aiming specifically the physiological processes involved in ASD. Better understanding of these factors, and of all potential barriers or facilitators to the transfer in other contexts, will allow us to develop transferable and sustainable interventions. We will conclude on the importance of pilot studies to estimate the different factors involved. This may allow for modification of the initial intervention if necessary, prior to conducting costly effectiveness or efficiency trial. We also stress the importance of involving clinicians in research. Their practical experience of evaluation and intervention allow the formulation of hypotheses and bring complementary data to that of researcher

Le modèle de Denver à début précoce pour jeunes enfants avec autisme : description, origines, efficience

Le trouble du spectre autistique est un trouble neurobiologique dont le principal traitement est actuellement une intervention précoce non médicamenteuse psycho-éducative. Certains modèles d’intervention ont montré dans des essais randomisés une efficacité modérée le plus souvent à court terme selon les revues systématiques internationales. Parmi ceux-ci, le modèle d’intervention précoce de Denver (ESDM) a été recommandé chez l’enfant de moins de 4 ans avec un TSA. Nous avons choisi de présenter ce modèle parce qu’il est de notre point de vue un précieux guide pour les équipes d’intervention et les parents d’enfant avec un TSA. La mise en place de routines d’activités conjointes et ludiques est au coeur de ce modèle. L’ESDM favorise les expériences partagées, la communication dyadique, les initiatives et la diversification du jeu et des centres d’intérêts de l’enfant. Il utilise un ensemble de techniques partagées avec d’autres modèles actuels d’interventions comportementales et développementales implémentées en milieu naturel. Il prévoit un ajustement des techniques selon les progrès et les besoins de chaque enfant. Il a par ailleurs fait l’objet d’au moins un essai randomisé contrôlé (évaluant ce modèle délivrée 20 h par semaine par des professionnels en thérapie individuelle à domicile pendant 2 ans) et d’une étude de suivi à moyen-long terme. Les pouvoirs publics doivent toutefois résister à un engouement trop rapide devant des résultats prometteurs et soutenir la poursuite de l’évaluation rigoureuse de ce type de modèle sur un plus grand nombre d’enfant avec TSA à différents stades du développement

Mesure de l’efficacité clinique d’une intervention précoce dans une population d’enfants avec un Trouble du Spectre de l’Autisme : validité interne et externe du résultat

Early intervention in order to decrease the severity of Autism Spectrum Disorder has come to be self-evident . However, there is no consensus on the type of early intervention, as we have previously shown in a literature review . Some interventions have shown weak to moderate effects in randomized controlled trials. But many methodological biases call into question the validity of those results. We have chosen to implement and evaluate the Early Start Denver Model (ESDM) at our intervention center. Our hypothesis was that ESDM intervention will diminish the severity of ASD symptoms in children under 3 years old. In our pilot study, we evaluated the effect of a 12 hours per week ESDM intervention, during one year, in a population of 19 children with ASD. The primary measure was the global development, measured by the Mullen Scales of Early Learning. Our results show a significant improvement in global development pre/post intervention. Effect size in receptive language was the most important with a Cohen’s d of 0.72. These results are comparable to those of previous published studies. This trial enabled also to data collection on the feasibility of implementing this intervention in our context. Most parents and professionals were satisfied of the intervention. Treatment adherence was of 8.3±1.2 hours per week instead of 12 hours per week during the pilot study. This reduction of intervention dose was largely due to absences (holidays, training) of the professionals delivering the intervention. We discuss here the choice of criteria for the measure of effectiveness of the intervention. This choice was difficult due to the lack of tools measuring precisely the change in ASD symptomatology. To test our hypothesis, a two-parallel, multi-center randomized controlled trial was set up. The experimental group received ESDM intervention, delivered by a multidisciplinary team, 12 hours per week, during the 2 years. The control group received treatment as usual. The protocol has been published. The trial was design to have high power and high-level evidences as defined by the Cochrane recommendations. In order to achieve this, we estimated the simple size for our population from a 15 points difference between the groups on the Mullen scale, an alpha risk of 0.5 and a beta risk at 90%. As we were limited by the number of availabilities for ESDM intervention, we used 1:2 randomization. The inclusion phase ended in March 2019. 61 children were included to the ESDM group and 119 children to the control group. We discuss the internal and external validity, as well as the clinical relevance according to the possible outcomes. If outcomes show effectiveness of the intervention, a cost-consequence study will allow us to measure the efficiency of this treatment. A follow-up study has also started and will measure the effectiveness of ESDM intervention on ASD symptomatology and academic achievements five year after initial inclusion. It is evidently essential to measure the long-term effectiveness and efficiency of early interventions; however, intervention research must also collect other measures and observations. Thus, determine mediators and moderators of the intervention will make it possible to move towards personalized interventions, aiming specifically the physiological processes involved in ASD. Better understanding of these factors, and of all potential barriers or facilitators to the transfer in other contexts, will allow us to develop transferable and sustainable interventions. We will conclude on the importance of pilot studies to estimate the different factors involved. This may allow for modification of the initial intervention if necessary, prior to conducting costly effectiveness or efficiency trial. We also stress the importance of involving clinicians in research. Their practical experience of evaluation and intervention allow the formulation of hypotheses and bring complementary data to that of researchersIntervenir précocement pour diminuer la sévérité du Trouble du Spectre de l’Autisme (TSA) est à ce jour une évidence. En revanche, le type d’intervention précoce à appliquer ne fait pas consensus . Certaines interventions montrent une efficacité d’intensité faible à modérée dans des essais randomisés contrôlés. Mais ces derniers comportent de nombreux biais méthodologiques qui remettent en question la validité du résultat. Nous avons fait l’hypothèse qu’une intervention précoce avec le modèle de Denver (Early Start Denver Model-ESDM) permettrait de diminuer la sévérité de la symptomatologie d’enfants avec TSA âgés de moins de 3 ans. Dans l’étude pilote, l’objectif était d’évaluer l’effet d’une intervention ESDM 12 heures par semaine pendant 1 an dans une population de 19 enfants avec TSA. Le résultat montrait une amélioration significative du développement global avant après intervention. La taille d’effet en langage réceptif était la plus importante avec un d de Cohen à 0.72. Ces résultats étaient comparables avec ceux d’études publiées précédemment. La majorité des professionnels et des parents étaient satisfaits de cette intervention. L’adhérence au traitement en termes de dose était de 8.3±1.2 heures au lieu de 12 heures par semaine dans cette étude pilote. Cette diminution de dose était majoritairement due à l’absence des professionnels. Nous discutons, ici, le choix de notre critère de jugement principal pour mesurer l’efficacité clinique réelle de l’intervention. Ce choix était difficile du fait du manque d’outils qui mesurent avec précision le changement dans la symptomatologie ou le handicap dans le TSA . Pour confirmer ou infirmer notre hypothèse, un essai randomisé contrôlé multicentrique comparant 2 bras en parallèle a été mis en place. Le groupe expérimental recevait une intervention ESDM, conduite majoritairement par une équipe pluridisciplinaire, 12 heures par semaine, pendant 2 ans. Le groupe contrôle recevait les interventions habituellement proposées dans la communauté. L’essai a été conçu pour avoir une puissance élevée et être à haut niveau de preuve selon les recommandations Cochrane . Nous avons pour cela mesuré le nombre nécessaire de sujet de notre population à partir d’une différence de 15 points à l’échelle de Mullen entre nos deux groupes, un risque alpha de 0,5 et un risque bêta à 90%. Étant limités par le nombre de places disponibles en intervention ESDM, nous avons mis en place une randomisation 1:2. La phase d’inclusion s’est terminée en mars 2019. 61 enfants ont été inclus dans le groupe ESDM et 119 enfants dans le groupe contrôle. Nous discutons la validité interne et externe ainsi que la pertinence clinique selon les différents résultats possibles. Si nous montrons une efficacité, une étude coût-conséquence permettra une mesure de l’efficience de ce traitement. Une étude de suivi a par ailleurs débuté et mesurera l’effet à 5 ans, d’une intervention ESDM précocement reçue, sur la symptomatologie TSA et le niveau scolaire des enfants. Il est bien évidemment essentiel de mesurer l’efficacité clinique et l’efficience à long terme des interventions mais la recherche interventionnelle implique également d’autres mesures et observations. Ainsi, la connaissance des facteurs médiateurs de l’effet de l’intervention, comme celle des facteurs modérateurs permettra d’aller vers des interventions personnalisées, qui agissent précisément sur les processus physiopathologiques impliqués dans le TSA. Une meilleure connaissance de ces facteurs mais aussi de tous les potentiels obstacles ou facilitateurs au transfert dans d’autres contextes de l’intervention permettra de plus de développer des interventions transférables et durables. Nous concluons sur l’importance de prévoir des temps de phase pilote suffisants pour estimer les différents facteurs impliqués et modifier l’intervention initialement prévue si nécessaire, avant de réaliser des essais d’efficacité ou d’efficience coûteu