Screening for autism in older and younger toddlers with the Modified Checklist for Autism in Toddlers.

The Modified Checklist for Autism in Toddlers (M-CHAT) was used to screen younger (16-23 months) versus older (24-30 months) high- and low-risk toddlers. Refusal rates for follow-up interview showed no group differences, but parents of younger/low-risk children were more likely to refuse evaluation than parents of high-risk children. PPP for an ASD diagnosis was: younger/high-risk 0.79, older/high-risk 0.74, younger/low-risk 0.28, and older/low-risk 0.61, with PPP differing by age within the low-risk group. Most of the children in all groups, however, were diagnosed with a developmental disorder. Symptom severity generally did not differ among groups. Cognitive and adaptive measures showed minimal group differences. Therefore, older and younger toddlers had similar symptomatology and developmental delays; PPP for ASD is better at 24 than 18 months for low-risk children; however, these children are still highly likely to show a developmental disorder. Clinical decision making should balance early identification against the lower specificity of M-CHAT screening for the younger/low-risk group.

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

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.

TITLE: Una agenda para la medicina del neurodesarrollo en el siglo XXI: lecciones aportadas por el autismo.El futuro de la medicina de los trastornos del neurodesarrollo posee el potencial de situar a la neurologia infantil en la vanguardia de un amplio esfuerzo de la sanidad publica con miras a optimizar los resultados del proceso de neurodesarrollo en los niños nacidos con diversas cargas geneticas, 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 transformacion ya esta teniendo lugar en el ambito de un trastorno del neurodesarrollo emblematico como es el autismo. Aprovechando la neuroplasticidad temprana y la cuantificacion de las trayectorias del desarrollo comunicativo y social, estan viendo la luz nuevas tecnologias de diagnostico con alta capacidad, rentables y viables para administrar potentes tratamientos en el ambito comunitario, en perfecta integracion entre redes de atencion sanitaria que en el pasado estaban fragmentadas. Estas soluciones son susceptibles de utilizarse para atender a otros colectivos de recien nacidos y niños con un riesgo acusado de autismo y retraso de la comunicacion, como los prematuros extremos o los niños con cardiopatias congenitas. La idea motriz de este futuro ambicioso es que la sanidad publica se concentre en la promocion de las condiciones optimas para el desarrollo inicial del cerebro, de modo similar a las actuales campañas de fomento de la atencion prenatal, la nutricion o la vacunacion.

Unique profile for erythrocyte membrane acetylcholinesterase in hereditary spherocytosis.

Acetylcholinesterase of human erythrocytes from healthy donors and from patients with hematological disorders was analysed in a search for differential membrane parameters. Two substrates were used to estimate the exposure of acetylcholinesterase active site in the membrane: phenylacetate, a hydrophobic substrate, to determine total enzyme activity, and acetylcholine, an ionic substrate, to measure the externally reactive enzyme. The sensitivity of acetylcholinesterase to added stearic acid was also analysed. Three categories of the disorders studied were discerned: (a) The erythrocyte acetylcholinesterase profile was indistinguishable from normal control in beta-thalassemia minor and groups of patients with autoimmune hemolytic anemia or congenital dyserythropoietic anemia type II. (b) A marked decline in acetylcholinesterase with both substrates and reduced sensitivity to stearic acid were exhibited by the erythrocytes of paroxysmal nocturnal hemoglobinuria, beta-thalassemia major and other autoimmune hemolytic anemia and congenital dyserythropoietic anemia type II patients. Normal erythrocytes, either aged or pretreated to 50 degrees C, also showed similar characteristics. (c) Hereditary spherocytosis was singly differentiated by an elevated acetylcholinesterase activity with acetylthiocholine and by a vastly diminished sensitivity to stearic acid, while activity with phenylacetate was equal to control. This distinct profile may reflect the unique organization of the erythrocyte membrane in hereditary spherocytosis.

Abnormal ventral temporal cortical activity during face discrimination among individuals with autism and Asperger syndrome.

BACKGROUND: Recognition of individual faces is an integral part of both interpersonal interactions and successful functioning within a social group. Therefore, it is of considerable interest that individuals with autism and related conditions have selective deficits in face recognition (sparing nonface object recognition). METHOD: We used functional magnetic resonance imaging (fMRI) to study face and subordinate-level object perception in 14 high-functioning individuals with autism or Asperger syndrome (the autism group), in comparison with 2 groups of matched normal controls (normal control group ] [NC1] and normal control group 2 [NC2]) (n = 14 for each). Regions of interest (ROIs) were defined in NC1 and then applied in comparisons between NC2 and the autism group. Regions of interest were also defined in NC2 and then applied to comparisons between NC1 and the autism group as a replication study. RESULTS: In the first set of comparisons, we found significant task x group interactions for the size of activation in the right fusiform gyrus (FG) and right inferior temporal gyri (ITG). Post hoc analyses showed that during face (but not object) discrimination, the autism group had significantly greater activation than controls in the right ITG and less activation of the right FG. The replication study showed again that the autism group used the ITG significantly more for processing faces than the control groups, but for these analyses, the effect was now on the left side. Greater ITG activation was the pattern found in both control groups during object processing. CONCLUSIONS: Individuals with autism spectrum disorders demonstrate a pattern of brain activity during face discrimination that is consistent with feature-based strategies that are more typical of nonface object perception.

Field trial for autistic disorder in DSM-IV.

OBJECTIVE: This project focused on the development of the definition of autism for DSM-IV. METHOD: Multiple sites were involved in obtaining information regarding 977 patients with the following clinician-assigned diagnoses: autism (N = 454), other pervasive developmental disorders (N = 240), and other disorders (N = 283). A standard coding system was used, and the raters (N = 125) had a range of experience in the diagnosis of autism. Patterns of agreement among existing diagnostic systems were examined, as was the rationale for inclusion of other disorders within the class of pervasive developmental disorders. RESULTS: The DSM-III-R definition of autism was found to be overly broad. The proposed ICD-10 definition most closely approximated the clinicians' diagnoses. Inclusion of other disorders within pervasive developmental disorders appeared justified. Partly on the basis of these data, modifications in the ICD-10 definition were made; this and the DSM-IV definition are conceptually identical. CONCLUSIONS: The resulting convergence of the DSM-IV and ICD-10 systems should facilitate both research and clinical service.

Elective mutism and mental retardation.

The association of elective mutism and mental retardation is noted. Two cases of elective mutism associated with mental retardation are presented. Both individuals had long-standing patterns of inhibition, shyness, and anxiety manifested by general refusal to talk outside the home, particularly at school. The importance of assessment of intellectual functioning and linguistic skills for the establishment of intervention priorities and clinical management is discussed. The possibility of the presence of mental retardation in individuals with elective mutism should be considered.

Higher-functioning pervasive developmental disorders: rates and patterns of psychotropic drug use.

OBJECTIVE: To explore the frequency, characteristics, and associated target symptoms of psychotropic drug use among subjects with higher-functioning pervasive developmental disorders (HFPDDs). METHOD: A total of 109 children, adolescents, and adults (mean age = 13.9 years, SD = 6.9) consecutively seeking enrollment into the Yale Child Study Center's Project on Social Learning Disabilities were included in the study. Individuals in whom Asperger's disorder, autism, or pervasive developmental disorder-not otherwise specified had been previously diagnosed and who had a documented Full Scale IQ > or = 70 completed surveys on demographic, clinical, and medication history information. To naturalistically evaluate medication use patterns in this population, each drug class was analyzed with respect to demographic and clinical variables. RESULTS: In all, 55% of subjects were taking psychotropics, with 29.3% taking 2 or more medications simultaneously. Antidepressants were the most commonly used agents (32.1%), followed by stimulants (20.2%) and neuroleptics (16.5%). The clinical presentation of subjects taking psychotropic agents was heterogeneous, and most consistently included anxiety-related target symptoms (in 65% of medicated individuals). CONCLUSIONS: Psychotropic medication use appears to be common among subjects with HFPDDs, yet not generally based on the results of empirical research. Clinical heterogeneity among treated subjects suggests that psychiatric comorbidity may be overlooked in this population.

Asperger's syndrome.

This Grand Rounds is concerned with the classification of Asperger's syndrome and its continuity/discontinuity with autism. Information on a 15-year-old with the condition is presented as are data on other family members. The proband exhibited a longstanding pattern of marked deficits in social interaction, motor awkwardness, and unusual, circumscribed interest consistent with a diagnosis of Asperger's syndrome. Both the proband and his father exhibited unusual discrepancies between verbal and performance (nonverbal) cognitive abilities favoring the former. Deficits were observed in the social use of language. Father and son had similar abnormalities on magnetic resonance imaging examination. Potential differences between higher-functioning autism and Asperger's syndrome are important areas for future research.

Auditory brainstem responses in autism: brainstem dysfunction or peripheral hearing loss?

The advent of electrophysiological techniques for audiologic and neurologic assessment in the late 60s has generated at least 11 auditory brainstem response (ABR) studies in autism designed to test the integrity of the auditory brainstem pathways. The results reported are contradictory, involving prolongation, shortening, and no abnormalities in central transmission latencies. When sample and methodological factors influencing the ABR are taken into consideration in the interpretation of results, the ABR data available at present can be seen as only suggestive, rather than supportive, of brainstem involvement in autism. Paradoxically, these studies revealed the presence of peripheral hearing impairment in a non-negligible number of autistic individuals. Additional evidence of auditory abnormalities as well as the implications for the clinician are considered.

Young autistic children's listening preferences in regard to speech: a possible characterization of the symptom of social withdrawal.

Autism is a childhood disorder diagnosed primarily in the presence of severe social unresponsiveness in the first 3 years of life (Volkmar, 1987). Since speech exerts a prepotent attraction on the attention of normally developing infants, hence facilitating social engagement, we designed a technique to examine whether this inborn reaction could be at fault in young autistic children. They were given a choice between their mothers' speech and the noise of superimposed voices (a sound effect obtained in a busy canteen). Data were obtained utilizing a specially designed automated and computerized device which recorded the children's responses in their own homes. In contrast to comparison groups of mentally retarded and normally developing children who showed the expected strong preference for their mothers' speech, the autistic children actively preferred the alternative sound or showed a lack of preference for either audio segment. These results suggest that such abnormal reactions to speech are a feature of these children's overall disregard to people.

Nosological and genetic aspects of Asperger syndrome.

The validity of Asperger syndrome (i.e., apart from high-functioning autism) continues to be the topic of considerable debate. Consistent with Asperger's original description of the condition there appear to be some important potential differences from autism if both conditions are strictly defined. Although the importance of genetic factors in the transmission of autism is increasingly clear it also appears that genetic factors may play an even more important role in Asperger syndrome (AS). The nosological validity of this condition and its relation to the various PDD spectrum disorder remains an important topic for future research. Well-designed and carefully controlled studies are needed in which patterns of comorbidity and associated problems in family members can be carefully assessed. Such studies will contribute to our understanding of the relationship of AS and autism and may clarify important genetic mechanisms of relevance to autism.

Exploring the boundaries of pervasive developmental disorder not otherwise specified: analyses of data from the DSM-IV Autistic Disorder Field Trial.

This study aimed to explore the boundaries between PDD and related disorders and to develop classificatory algorithms for what is currently called Pervasive Developmental Disorder Not Otherwise Specified (PDDNOS). Data collected by means of a standard coding system for the DSM-IV field trial for autistic disorder were used. Information on diagnostic criteria for autistic disorder as listed in ICD-10 and DSM-IV was compared between subjects functioning at least in the mildly retarded range and clinically classified as autistic disorder (n = 205), PDDNOS (n = 80) and other non-PDD disorders (n = 174). Only a limited number of items from the ICD-10 and DSM-IV systems for autistic disorder significantly discriminated the PDDNOS group from other disorders. A scoring rule based on a short set of 7 ICD-10/DSM-IV criteria with a cutoff of 3 items and 1 social interaction item set as mandatory had the best balance between high sensitivity and high specificity in discriminating PDDNOS from non-PDD disorders. These rules yielded a somewhat better prediction than most effective rules based on the full set of 12 criteria for autistic disorder with a cutoff of 4 items and 1 social item as mandatory. Generally accepted and well-validated criteria to identify individuals with PDDNOS should facilitate both research and clinical services.

Season of birth in autism: a fiction revisited.

Variations of season of birth among autistic individuals were studied. The replicability of previously reported increases in birth rates in the months of March and August were examined in groups of individuals with autism or mental retardation (the comparison group). The sample was obtained from the Yale Child Study Center Developmental Disabilities Clinic and from the DSM-IV Autism/PDD field trial. Data were analyzed by applying the Jonckheere test of ordinal trend and the chi-square test, with Yates correction factor. With respect to March and August births, and with calculations based on the beginning and middle of the month, no significant seasonal effect was observed. Samples were subcategorized into verbal and mute groups, and again results failed to support the seasonality hypothesis.

A normed study of face recognition in autism and related disorders.

Although the interpretation of studies of face recognition in older children, adolescents, and adults with autism is complicated by the fact that participating samples and adopted methodologies vary significantly, there is nevertheless strong evidence indicating processing peculiarities even when task performance is not deficient. Much less is known about face recognition abilities in younger children with autism. This study employed a well-normed task of face recognition to measure this ability in 102 young children with autism, pervasive developmental disorder not otherwise specified (PDDNOS), and non-PDD disorders (mental retardation and language disorders) matched on chronological age and nonverbal mental age, and in a subsample of 51 children divided equally in the same three groups matched on chronological age and verbal mental age. There were pronounced deficits of face recognition in the autistic group relative to the other nonverbally matched and verbally matched groups. Performance on two comparison tasks did not reveal significant differences when verbal ability was adequately controlled. We concluded that young children with autism have face recognition deficits that cannot be attributed to overall cognitive abilities or task demands. In contrast to controls, there was a lower correlation between performance on face recognition and nonverbal intelligence, suggesting that in autism face recognition is less correlated with general cognitive capacity. Contrary to our expectation, children with PDDNOS did not show face recognition deficits.

Assessment in multisite randomized clinical trials of patients with autistic disorder: the Autism RUPP Network. Research Units on Pediatric Psychopharmacology.

Assessment of autistic disorder (autism) symptoms, primary and secondary, poses more challenging problems than ordinarily found in multisite randomized clinical trial (RCT) assessments. For example, subjects may be uncommunicative and extremely heterogeneous in problem presentation, and current pharmacological treatments are not likely to alter most core features of autism. The Autism Research Units on Pediatric Psychopharmacology (RUPP Autism Network) resolved some of these problems during the design of a risperidone RCT in children/adolescents. The inappropriateness of the usual anchors for a Clinical Global Impression of Severity (CGI-S) was resolved by defining uncomplicated autism without secondary symptoms as a CGI-S of 3, mildly ill. The communication problems, compromising use of the patient as an informant, were addressed by several strategies, including careful questioning of care providers, rating scales, laboratory tests, and physical exams. The broad subject heterogeneity requires outcome measures sensitive to individual change over a wide spectrum of treatment response and side effects. The problems of neuropsychologically testing nonverbal, lower functioning, sometimes noncompliant subjects requires careful instrument selection/adaptation and flexible administration techniques. The problems of assessing low-end IQs, neglected by most standardized test developers, was resolved by an algorithm of test hierarchy. Scarcity of other autism-adapted cognitive and neuropsychological tests and lack of standardization required development of a new, specially adapted battery. Reliability on the Autism Diagnostic Interview (currently the most valid diagnostic instrument) and other clinician instruments required extensive cross-site training (in-person, videotape, and teleconference sessions). Definition of a treatment responder required focus on individually relevant target symptoms, synthesis of possible modest improvements in many domains, and acceptance of attainable though imperfect goals. The assessment strategy developed is implemented in a RCT of risperidone (McDougle et al., 2000) for which the design and other methodological challenges are described elsewhere (Scahill et al., 2000). Some of these problems and solutions are partially shared with RCTs of other treatments and other disorders.

Multiplex developmental disorders. The role of communication in the construction of a self.

This article discusses the integration of various aspects of the child's development, particularly the development of language and communication and the way in which these developments interact to enable the child to construct a coherent sense of self. Multiplex developmental disorder is presented as an example of a disorder that affects several of these crucial strands of development. Recent research and controversies regarding the diagnostic descriptions of multiplex and other pervasive developmental disorders are presented. This discussion is used to illustrate the ways in which such disorders affect not only the individual aspects of development, but the child's ability to form a cohesive sense of self. The implications of these difficulties in self-definition for treating children with disorders that affect a variety of aspects of development are also discussed.

Speech and prosody characteristics of adolescents and adults with high-functioning autism and Asperger syndrome.

Speech and prosody-voice profiles for 15 male speakers with High-Functioning Autism (HFA) and 15 male speakers with Asperger syndrome (AS) were compared to one another and to profiles for 53 typically developing male speakers in the same 10- to 50-years age range. Compared to the typically developing speakers, significantly more participants in both the HFA and AS groups had residual articulation distortion errors, uncodable utterances due to discourse constraints, and utterances coded as inappropriate in the domains of phrasing, stress, and resonance. Speakers with AS were significantly more voluble than speakers with HFA, but otherwise there were few statistically significant differences between the two groups of speakers with pervasive developmental disorders. Discussion focuses on perceptual-motor and social sources of differences in the prosody-voice findings for individuals with Pervasive Developmental Disorders as compared with findings for typical speakers, including comment on the grammatical, pragmatic, and affective aspects of prosody.

Integrating biological and behavioral perspectives in the study and care of autistic individuals: the future.

The core clinical feature of autism is a profound disturbance in the emergence of social relations, apparent as early as the very first months of life and almost always by age three years. Many different theories have been proposed to explain this dramatic developmental dysfunction, including cognitive, linguistic, arousal and, most recently, "theory of mind" hypotheses. There is great heterogeneity among autistic individuals and no single explanation captures all the clinical phenomena. Because of the divergent theories and their associated treatment approaches, parents are often burdened by conflicting advice. Field trials and other studies have provided excellent diagnostic criteria for autism for DSM-IV and ICD-10, with high sensitivity and specificity. Careful definition of the clinical phenotype is essential for neurobiological, genetic and behavioral research. While many lines of evidence point to underlying disturbances in brain maturation, no specific CNS dysfunction or biological correlate has been discovered. Rigorous research is not only essential for improving the understanding and treatment of autism; such studies may also help elucidate the normal preconditions for socialization and the pathways that allow a child to enter into the world of human relationships.

[Theoretical perspectives on autism]. / Perspectives théoriques sur l'autisme.

The French and American views of autism have often been seen as irreconcilable, the theoretical and inferential aspects of one conflicting with the empiricism and positivism of the other. Nevertheless, multiple lines of convergence tie together these two traditions, from the commitment to phenomenology embodied in the early work of Jean Itard and his American disciples, to the emphasis on developmental issues represented in French psychoanalytic approach and Kanner's reliance on Gesell's work. Several important differences remain, with an oftentimes sharp contrast between the predominantly psychogenic views in France and the predominantly neurobehavioral views in the United States. This divergence has important implications to research and services affecting individuals with autism. However, recent developments are bringing together these two viewpoints, with mutual benefits. There is a renewed commitment to cross cultural discussions, resulting in constructive reappraisal of concepts and research in both countries, and leading to the attention to important phenomena. The stimulation engendered by this dialogue is leading to new research.

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)