Veinte años de neurodesarrollo / Twenty years of neurodevelopment

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Una agenda para la medicina del neurodesarrollo en el siglo XXI: lecciones aportadas por el autismo / An agenda for 21st century neurodevelopmental medicine: lessons from autism

El futuro de la medicina de los trastornos del neurodesarrollo posee el potencial de situar a la neurología infantil en la vanguardia de un amplio esfuerzo de la sanidad pública con miras a optimizar los resultados del proceso de neurodesarrollo en los niños nacidos con diversas cargas genéticas, pre y perinatales y ambientales, de prevalencia elevada, que ponen en riesgo el desarrollo temprano de su cerebro y acaban provocando incapacidad durante toda la vida. Construida sobre los avances de la neurociencia del desarrollo social y de la ciencia traslacional, esa transformación ya está teniendo lugar en el ámbito de un trastorno del neurodesarrollo emblemático como es el autismo. Aprovechando la neuroplasticidad temprana y la cuantificación de las trayectorias del desarrollo comunicativo y social, están viendo la luz nuevas tecnologías de diagnóstico con alta capacidad, rentables y viables para administrar potentes tratamientos en el ámbito comunitario, en perfecta integración entre redes de atención sanitaria que en el pasado estaban fragmentadas. Estas soluciones son susceptibles de utilizarse para atender a otros colectivos de recién nacidos y niños con un riesgo acusado de autismo y retraso de la comunicación, como los prematuros extremos o los niños con cardiopatías congénitas. La idea motriz de este futuro ambicioso es que la sanidad pública se concentre en la promoción de las condiciones óptimas para el desarrollo inicial del cerebro, de modo similar a las actuales campañas de fomento de la atención prenatal, la nutrición o la vacunación (AU)

The future of neurodevelopmental medicine has the potential of situating child neurology at the forefront of a broad-based public health effort to optimize neurodevelopmental outcomes of children born with high-prevalence and diverse genetic, pre- and peri-natal, and environmental burdens compromising early brain development and leading to lifetime disabilities. Building on advancements in developmental social neuroscience and in implementation science, this shift is already occurring in the case of emblematic neurodevelopmental disorders such as autism. Capitalizing on early neuroplasticity and on quantification of trajectories of social-communicative development, new technologies are emerging for high-throughput and cost-effective diagnosis and for community-viable delivery of powerful treatments, in seamless integration across previously fragmented systems of healthcare delivery. These solutions could be deployed in the case of other groups of children at greater risk for autism and communication delays, such as those born extremely premature or with congenital heart disease. The galvanizing concept in this aspirational future is a public health focus on promoting optimal conditions for early brain development, not unlike current campaigns promoting pre-natal care, nutrition or vaccination (AU)

Neurodevelopmental Disorders (ASD and ADHD): DSM-5, ICD-10, and ICD-11.

Neurodevelopmental disorders, specifically autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) have undergone considerable diagnostic evolution in the past decade. In the United States, the current system in place is the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), whereas worldwide, the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) serves as a general medical system. This review will examine the differences in neurodevelopmental disorders between these two systems. First, we will review the important revisions made from the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) to the DSM-5, with respect to ASD and ADHD. Next, we will cover the similarities and differences between ASD and ADHD classification in the DSM-5 and the ICD-10, and how these differences may have an effect on neurodevelopmental disorder diagnostics and classification. By examining the changes made for the DSM-5 in 2013, and critiquing the current ICD-10 system, we can help to anticipate and advise on the upcoming ICD-11, due to come online in 2017. Overall, this review serves to highlight the importance of progress towards complementary diagnostic classification systems, keeping in mind the difference in tradition and purpose of the DSM and the ICD, and that these systems are dynamic and changing as more is learned about neurodevelopmental disorders and their underlying etiology. Finally this review will discuss alternative diagnostic approaches, such as the Research Domain Criteria (RDoC) initiative, which links symptom domains to underlying biological and neurological mechanisms. The incorporation of new diagnostic directions could have a great effect on treatment development and insurance coverage for neurodevelopmental disorders worldwide.

Using the PDD Behavior Inventory as a Level 2 Screener: A Classification and Regression Trees Analysis.

In order to improve discrimination accuracy between Autism Spectrum Disorder (ASD) and similar neurodevelopmental disorders, a data mining procedure, Classification and Regression Trees (CART), was used on a large multi-site sample of PDD Behavior Inventory (PDDBI) forms on children with and without ASD. Discrimination accuracy exceeded 80 %, generalized to an independent validation set, and generalized across age groups and sites, and agreed well with ADOS classifications. Parent PDDBIs yielded better results than teacher PDDBIs but, when CART predictions agreed across informants, sensitivity increased. Results also revealed three subtypes of ASD: minimally verbal, verbal, and atypical; and two, relatively common subtypes of non-ASD children: social pragmatic problems and good social skills. These subgroups corresponded to differences in behavior profiles and associated bio-medical findings.

Autism Spectrum Disorder in the DSM-5: Diagnostic Sensitivity and Specificity in Early Childhood.

Changes to the DSM-5 Autism Spectrum Disorder (ASD) criteria raised concerns among parents and practitioners that the criteria may exclude some children with Pervasive Developmental Disorder (PDD). Few studies have examined DSM-5 sensitivity and specificity in children less than 5 years of age. This study evaluated 185 children aged 20-55 months with DSM-IV PDD or developmental delay. Autism Diagnostic Interview-Revised (ADI-R) and Autism Diagnostic Observation Schedule (ADOS) data was assigned to DSM-5 subdomains. Children displaying the required symptomatology were classified with DSM-5 ASD. DSM-IV clinical diagnoses were compared to DSM-5 classifications. Using combined ADI-R/ADOS information, sensitivity was .84 and specificity was .54. Comorbid behaviour and emotional problems were significantly lower in children with PDD that did not meet DSM-5 criteria.

[Autism Spectrum Disorder and DSM-5: Spectrum or Cluster?]. / Autistische Störungen nach DSM-5: Spektrum oder Cluster?

Within the new DSM-5, the currently differentiated subgroups of "Autistic Disorder" (299.0), "Asperger's Disorder" (299.80) and "Pervasive Developmental Disorder" (299.80) are replaced by the more general "Autism Spectrum Disorder". With regard to a patient-oriented and expedient advising therapy planning, however, the issue of an empirically reproducible and clinically feasible differentiation into subgroups must still be raised. Based on two Autism-rating-scales (ASDS and FSK), an exploratory two-step cluster analysis was conducted with N=103 children (age: 5-18) seen in our social-pediatric health care centre to examine potentially autistic symptoms. In the two-cluster solution of both rating scales, mainly the problems in social communication grouped the children into a cluster "with communication problems" (51 % and 41 %), and a cluster "without communication problems". Within the three-cluster solution of the ASDS, sensory hypersensitivity, cleaving to routines and social-communicative problems generated an "autistic" subgroup (22%). The children of the second cluster ("communication problems", 35%) were only described by social-communicative problems, and the third group did not show any problems (38%). In the three-cluster solution of the FSK, the "autistic cluster" of the two-cluster solution differentiated in a subgroup with mainly social-communicative problems (cluster 1) and a second subgroup described by restrictive, repetitive behavior. The different cluster solutions will be discussed with a view to the new DSM-5 diagnostic criteria, for following studies a further specification of some of the ASDS and FSK items could be helpful.

Developmental trajectories of symptom severity and adaptive functioning in an inception cohort of preschool children with autism spectrum disorder.

IMPORTANCE: Symptom severity and adaptive functioning are fundamental domains of the autism spectrum disorder (ASD) phenotype. To date, the longitudinal association between these 2 domains has not been examined. OBJECTIVE: To describe the developmental trajectories of autistic symptom severity and adaptive functioning in a large inception cohort of preschool children with ASD. DESIGN, SETTING, AND PARTICIPANTS: The sample consisted of 421 newly diagnosed preschool children with ASD 2 to 4 years old (355 boys; mean age at study enrollment, 39.87 months) participating in a large Canadian multisite longitudinal study (Pathways in ASD Study). Prospective data collected at 4 points from time of diagnosis to age 6 years were used to track the developmental trajectories of children. MAIN OUTCOMES AND MEASURES: Autistic symptom severity was indexed using the Autism Diagnostic Observation Schedule. Adaptive functioning was indexed using the Vineland Adaptive Behavior Scales, Second Edition. RESULTS: Two distinct trajectory groups provided the best fit to the autistic symptom severity data. Group 1 (11.4% of the sample) had less severe symptoms and an improving trajectory (P < .05), whereas group 2 (88.6% of the sample) had more severe symptoms and a stable trajectory. Three distinct trajectory groups provided the best fit to the adaptive functioning data. Group 1 (29.2% of the sample) showed lower functioning and a worsening trajectory, group 2 (49.9% of the sample) had moderate functioning and a stable trajectory, and group 3 (20.9% of the sample) had higher functioning and an improving trajectory (P < .05). Cross-trajectory overlap between the autistic symptom severity and adaptive functioning groups was low (φ = 0.13, P < .05). Sex was a significant predictor of autistic symptom severity group membership and age at diagnosis, and language and cognitive scores at baseline predicted membership in adaptive functioning trajectories. Trajectories of both symptom severity and adaptive functioning predicted several different outcomes at age 6 years. CONCLUSIONS AND RELEVANCE: Findings confirm the heterogeneous nature of developmental trajectories in ASD. Change in adaptive functioning suggests that improvement is possible in roughly 20% of the sample. Autistic symptom severity appears to be more stable, with roughly 11% of the sample showing a marked decrease in symptom severity. During the preschool years, there appears to be only a small amount of "yoking" of developmental trajectories in autistic symptom severity and adaptive functioning. It is imperative that a flexible suite of interventions that target both autistic symptom severity and adaptive functioning should be implemented and tailored to each child's strengths and difficulties.

[A late debut of childhood disintegrative disorder]. / Disintegrativ udviklingsforstyrrelse med sen debut hos et barn

Actualized by the ongoing discussion of whether childhood disintegrative disorder is a diagnostic entity, we describe a case which in every aspect fulfils the ICD-10 criteria. A girl with a previous normal development who, from the age of 60 months, experienced a regression during 2-3 months with significant co-morbid psychiatric symptoms, leaving her in a state of mental retardation and autism. A thorough somatic assessment was normal. The importance of recognition of the condition and an integrated child psychiatric and paediatric assessment is emphasized.

Determination of psychosis-related clinical profiles in children with autism spectrum disorders using latent class analysis.

In children with autism spectrum disorders (ASD), high rates of idiosyncratic fears and anxiety reactions and thought disorder are thought to increase the risk of psychosis. The critical next step is to identify whether combinations of these symptoms can be used to categorise individual patients into ASD subclasses, and to test their relevance to psychosis. All patients with ASD (n = 84) admitted to a specialist national inpatient unit from 2003 to 2012 were rated for the presence or absence of impairment in affective regulation and anxiety (peculiar phobias, panic episodes, explosive reactions to anxiety), social deficits (social disinterest, avoidance or withdrawal and abnormal attachment) and thought disorder (disorganised or illogical thinking, bizarre fantasies, overvalued or delusional ideas). Latent class analysis of individual symptoms was conducted to identify ASD classes. External validation of these classes was performed using as a criterion the presence of hallucinations. Latent class analysis identified two distinct classes. Bizarre fears and anxiety reactions and thought disorder symptoms differentiated ASD patients into those with psychotic features (ASD-P: 51 %) and those without (ASD-NonP: 49 %). Hallucinations were present in 26 % of the ASD-P class but only 2.4 % of the ASD-NonP. Both the ASD-P and the ASD-NonP class benefited from inpatient treatment although inpatient stay was prolonged in the ASD-P class. This study provides the first empirically derived classification of ASD in relation to psychosis based on three underlying symptom dimensions, anxiety, social deficits and thought disorder. These results can be further developed by testing the reproducibility and prognostic value of the identified classes.

Repetitive behavior in 12-month-olds later classified with autism spectrum disorder.

OBJECTIVE: As compared to the utility of early emerging social communicative risk markers for predicting a later diagnosis of autism spectrum disorder (ASD), less is known about the relevance of early patterns of restricted and repetitive behaviors. We examined patterns of stereotyped motor mannerisms and repetitive manipulation of objects in 12-month-olds at high and low risk for developing ASD, all of whom were assessed for ASD at 24 months. METHOD: Observational coding of repetitive object manipulation and stereotyped motor behaviors in digital recordings of the Communication and Symbolic Behavior Scales was conducted using the Repetitive and Stereotyped Movement Scales for 3 groups of 12-month-olds: low-risk infants (LR, n = 53); high-familial-risk infants who did not meet diagnostic criteria for ASD at 24 months (HR-negative, n = 75); and high-familial-risk infants who met diagnostic criteria for ASD at 24 months (HR-ASD, n = 30). RESULTS: The HR-ASD group showed significantly more stereotyped motor mannerisms than both the HR-negative group (p = .025) and the LR group (p = .001). The HR-ASD and HR-negative groups demonstrated statistically equivalent repetitive object manipulation scores (p = .431), and both groups showed significantly more repetitive object manipulation than the LR group (p < .040). Combining the motor and object stereotypy scores into a Repetitive and Stereotyped Movement Scales (RSMS) composite yielded a disorder-continuum effect such that each group was significantly different from one another (LR < HR-negative < HR-ASD). CONCLUSION: These results suggest that targeted assessment of repetitive behavior during infancy may augment early ASD identification efforts.

[Autism spectrum disorders - epidemiology, symptoms, comorbidity and diagnosis]. / Zaburzenia ze spektrum autyzmu - epidemiologia, objawy, wspólzachorowalnosc i rozpoznawanie.

In the new classification of American Psychiatric Association - DSM-5 - a category of autistic spectrum disorders (ASD) was introduced, which replaced autistic disorder, Asperger syndrome, childhood disintegrative disorder and pervasive developmental disorder not otherwise specified. ASD are defined by two basic psychopathological dimensions: communication disturbances and stereotyped behaviors, and the diagnosis is complemented with the assessment of language development and intellectual level. In successive epidemiological studies conducted in 21 century the prevalence of ASD has been rising, and currently is estimated at 1% in general population. The lifetime psychiatric comorbidity is observed in majority of patients. The most common coexisting diagnoses comprise disorders ofanxiety-affective spectrum, and in about 1/3 of patients attention deficit/ hyperactivity disorders could be diagnosed. Prodromal symptoms of ASD may emerge before 12 months of life, however reliability of diagnosis at such an early age is poor. Several screening instruments, based on the parental and/or healthcare professional assessments may be helpful in ASD detection. However, structured interviews and observation schedules remain the gold standard of diagnosis.

[Autism spectrum syndrome replaces Asperger syndrome and autism]. / Autismspektrumsyndrom ersätter Aspergers syndrom och autism.

Autism spectrum disorder describes a behaviourally defined impairment in social interaction and communication, along with the presence of restricted interests and repetitive behaviours. Although the etiology is mostly unknown, it is evident that biological factors affect the brain and result in the autistic clinical presentation. Assessment for diagnosing autism spectrum disorder should be comprehensive in order to cover all sorts of problems related to the disorder. Knowledge and experience from working with neurological and psychiatric disorders are a prerequisite for quality in the examination. Up to now, there is no cure for autism spectrum disorder, but support and adaptations in education are nevertheless important for obtaining sufficient life quality for the patients and the family.

[ESSENCE gathers the diagnoses into a whole]. / ESSENCE samlar diagnoserna till en helhet.

Co-existence of attention-deficit/hyperactivity disorder, oppositional defiant disorder, tic disorders, developmental coordination disorder, language disorder, learning problems, and autism spectrum disorder and sharing of symptoms across disorders, contribute to the typical clinical presentation in child psychiatry as well as in developmental medicine. The acronym ESSENCE refers to Early Symptomatic Syndromes Eliciting Neurodevelopmental Clinical Examinations. Affected children are brought for clinical assessment because of impairing symptoms that raise concern before the age of about 5 years in general development, communication and language, social inter-relatedness, motor coordination, attention, activity, behaviour, mood, and/or sleep. Such children are usually in need of a range of expert assessments, but a holistic approach is rarely taken from the start. Major problems in at least one ESSENCE domain before 5 years of age predict poor mental health later in life. Expert ESSENCE centres for assessment, habilitation and treatment of these children are needed.

Testing the accuracy of an observation-based classifier for rapid detection of autism risk.

Current approaches for diagnosing autism have high diagnostic validity but are time consuming and can contribute to delays in arriving at an official diagnosis. In a pilot study, we used machine learning to derive a classifier that represented a 72% reduction in length from the gold-standard Autism Diagnostic Observation Schedule-Generic (ADOS-G), while retaining >97% statistical accuracy. The pilot study focused on a relatively small sample of children with and without autism. The present study sought to further test the accuracy of the classifier (termed the observation-based classifier (OBC)) on an independent sample of 2616 children scored using ADOS from five data repositories and including both spectrum (n=2333) and non-spectrum (n=283) individuals. We tested OBC outcomes against the outcomes provided by the original and current ADOS algorithms, the best estimate clinical diagnosis, and the comparison score severity metric associated with ADOS-2. The OBC was significantly correlated with the ADOS-G (r=-0.814) and ADOS-2 (r=-0.779) and exhibited >97% sensitivity and >77% specificity in comparison to both ADOS algorithm scores. The correspondence to the best estimate clinical diagnosis was also high (accuracy=96.8%), with sensitivity of 97.1% and specificity of 83.3%. The correlation between the OBC score and the comparison score was significant (r=-0.628), suggesting that the OBC provides both a classification as well as a measure of severity of the phenotype. These results further demonstrate the accuracy of the OBC and suggest that reductions in the process of detecting and monitoring autism are possible.

Terminological debate over language impairment in children: forward movement and sticking points.

BACKGROUND: There is no agreed terminology for describing childhood language problems. In this special issue Reilly et al. and Bishop review the history of the most widely used label, 'specific language impairment' (SLI), and discuss the pros and cons of various terms. Commentators from a range of backgrounds, in terms of both discipline and geographical background, were then invited to respond to each lead article. AIMS: To summarize the main points made by the commentators and identify (1) points of consensus and disagreement, (2) issues for debate including the drivers for change and diagnostic criteria, and (3) the way forward. CONCLUSIONS & IMPLICATIONS: There was some common ground, namely that the current situation is not tenable because it impedes clinical and research progress and impacts on access to services. There were also wide-ranging disagreements about which term should be adopted. However, before debating the broad diagnostic label it is essential to consider the diagnostic criteria and the systems used to classify childhood language problems. This is critical in order to facilitate communication between and among clinicians and researchers, across sectors (in particular health and education), with the media and policy-makers and with families and individuals who have language problems. We suggest four criteria be taken into account when establishing diagnostic criteria, including: (1) the features of language, (2) the impact on functioning and participation, (3) the presence/absence of other impairments, and (4) the language trajectory or pathway and age of onset. In future, these criteria may expand to include the genetic and neural markers for language problems. Finally, there was overarching agreement about the need for an international and multidisciplinary forum to move this debate forward. The purpose would be to develop consensus regarding the diagnostic criteria and diagnostic label for children with language problems. This process should include canvassing the views of families and people with language problems as well as the views of policy-makers.

Comparing the results of DAADD and ABC of children included in autism spectrum disorders.

PURPOSE: To verify if there are characteristic behaviors of the different diagnosis included in the autism spectrum according to the Differential Assessment of Autism and Other Developmental Disorders (DAADD) and to the Autism Behavior Checklist (ABC). METHOD: Participants were 45 individuals and their respective speech-language therapists. All therapists are graduate students working with the children for at least 1 year. This time was considered sufficient to the therapists to have the information required by the DAADD questionnaire. It is comprised by 3 protocols specifically designed to children with 2 to 4 years, 4 to 6 years and 6 to 8 years, the same criteria used to separate the research groups, G1, G2 and G3, respectively. Data referring to the ABC were retrieved from the subject's files at the Laboratório de Investigação Fonoaudiológica nos Distúrbios do Espectro do Autismo (Research Laboratory on Language Disorders in the Autism Spectrum) of the School of Medicine, Universidade de São Paulo, where it is routinely applied during the annual assessment. RESULTS: Answers to the different areas of DAADD are similar to the different areas of ABC. These data show data the diagnosis by DAADD is easier in older children. Although there is no significant difference, the large occurrence of Rett's syndrome diagnosis according to the DAADD was associated to higher risk for autism according to the ABC in G1. With increasing age this tendency decreases and either in G2 and G3 Autism is the most frequent diagnosis. CONCLUSION: Although the results of both questionnaires tend to agree more with increasing age, the DAADD is more sensitive in the different ages while the ABC if more specific only to older children.

Disruptive CHD8 mutations define a subtype of autism early in development.

Autism spectrum disorder (ASD) is a heterogeneous disease in which efforts to define subtypes behaviorally have met with limited success. Hypothesizing that genetically based subtype identification may prove more productive, we resequenced the ASD-associated gene CHD8 in 3,730 children with developmental delay or ASD. We identified a total of 15 independent mutations; no truncating events were identified in 8,792 controls, including 2,289 unaffected siblings. In addition to a high likelihood of an ASD diagnosis among patients bearing CHD8 mutations, characteristics enriched in this group included macrocephaly, distinct faces, and gastrointestinal complaints. chd8 disruption in zebrafish recapitulates features of the human phenotype, including increased head size as a result of expansion of the forebrain/midbrain and impairment of gastrointestinal motility due to a reduction in postmitotic enteric neurons. Our findings indicate that CHD8 disruptions define a distinct ASD subtype and reveal unexpected comorbidities between brain development and enteric innervation.