Efficacy of Low-Dose Buspirone for Restricted and Repetitive Behavior in Young Children with Autism Spectrum Disorder: A Randomized Trial.

OBJECTIVES: To determine safety and efficacy of the 5HT1A serotonin partial agonist buspirone on core autism and associated features in children with autism spectrum disorder (ASD). STUDY DESIGN: Children 2-6 years of age with ASD (N = 166) were randomized to receive placebo or 2.5 or 5.0 mg of buspirone twice daily. The primary objective was to evaluate the effects of 24 weeks of buspirone on the Autism Diagnostic Observation Schedule (ADOS) Composite Total Score. Secondary objectives included evaluating the effects of buspirone on social competence, repetitive behaviors, language, sensory dysfunction, and anxiety and to assess side effects. Positron emission tomography measures of tryptophan metabolism and blood serotonin concentrations were assessed as predictors of buspirone efficacy. RESULTS: There was no difference in the ADOS Composite Total Score between baseline and 24 weeks among the 3 treatment groups (P = .400); however, the ADOS Restricted and Repetitive Behavior score showed a time-by-treatment effect (P = .006); the 2.5-mg buspirone group showed significant improvement (P = .003), whereas placebo and 5.0-mg buspirone groups showed no change. Children in the 2.5-mg buspirone group were more likely to improve if they had fewer foci of increased brain tryptophan metabolism on positron emission tomography (P = .018) or if they showed normal levels of blood serotonin (P = .044). Adverse events did not differ significantly among treatment groups. CONCLUSIONS: Treatment with 2.5 mg of buspirone in young children with ASD might be a useful adjunct therapy to target restrictive and repetitive behaviors in conjunction with behavioral interventions. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00873509.

Face and location processing in children with early unilateral brain injury.

Human visuospatial functions are commonly divided into those dependent on the ventral visual stream (ventral occipitotemporal regions), which allows for processing the 'what' of an object, and the dorsal visual stream (dorsal occipitoparietal regions), which allows for processing 'where' an object is in space. Information about the development of each of the two streams has been accumulating, but very little is known about the effects of injury, particularly very early injury, on this developmental process. Using a set of computerized dorsal and ventral stream tasks matched for stimuli, required response, and difficulty (for typically-developing individuals), we sought to compare the differential effects of injury to the two systems by examining performance in individuals with perinatal brain injury (PBI), who present with selective deficits in visuospatial processing from a young age. Thirty participants (mean=15.1 years) with early unilateral brain injury (15 right hemisphere PBI, 15 left hemisphere PBI) and 16 matched controls participated. On our tasks children with PBI performed more poorly than controls (lower accuracy and longer response times), and this was particularly prominent for the ventral stream task. Lateralization of PBI was also a factor, as the dorsal stream task did not seem to be associated with lateralized deficits, with both PBI groups showing only subtle decrements in performance, while the ventral stream task elicited deficits from RPBI children that do not appear to improve with age. Our findings suggest that early injury results in lesion-specific visuospatial deficits that persist into adolescence. Further, as the stimuli used in our ventral stream task were faces, our findings are consistent with what is known about the neural systems for face processing, namely, that they are established relatively early, follow a comparatively rapid developmental trajectory (conferring a vulnerability to early insult), and are biased toward the right hemisphere.

Pediatric neuroenhancement: ethical, legal, social, and neurodevelopmental implications.

The use of prescription medication to augment cognitive or affective function in healthy persons-or neuroenhancement-is increasing in adult and pediatric populations. In children and adolescents, neuroenhancement appears to be increasing in parallel to the rising rates of attention-deficit disorder diagnoses and stimulant medication prescriptions, and the opportunities for medication diversion. Pediatric neuroenhancement remains a particularly unsettled and value-laden practice, often without appropriate goals or justification. Pediatric neuroenhancement presents its own ethical, social, legal, and developmental issues, including the fiduciary responsibility of physicians caring for children, the special integrity of the doctor-child-parent relationship, the vulnerability of children to various forms of coercion, distributive justice in school settings, and the moral obligation of physicians to prevent misuse of medication. Neurodevelopmental issues include the importance of evolving personal authenticity during childhood and adolescence, the emergence of individual decision-making capacities, and the process of developing autonomy. This Ethics, Law, and Humanities Committee position paper, endorsed by the American Academy of Neurology, Child Neurology Society, and American Neurological Association, focuses on various implications of pediatric neuroenhancement and outlines discussion points in responding to neuroenhancement requests from parents or adolescents. Based on currently available data and the balance of ethics issues reviewed in this position paper, neuroenhancement in legally and developmentally nonautonomous children and adolescents without a diagnosis of a neurologic disorder is not justifiable. In nearly autonomous adolescents, the fiduciary obligation of the physician may be weaker, but the prescription of neuroenhancements is inadvisable because of numerous social, developmental, and professional integrity issues.

Early occurrence of cerebral white matter abnormality detected in a neonate with salt-wasting congenital adrenal hyperplasia.

The development of white matter signal abnormalities on magnetic resonance brain imaging (MRI) in children and young adults with congenital adrenal hyperplasia has been well documented. Existing theories regarding the development of these findings include effects of electrolyte imbalances, effects of disease-related hormone abnormalities, and non-physiologic long-term administration of corticosteroids. Many of the patients previously described were normal neurologically. We describe the case of white matter signal abnormalities in a neonate with salt-wasting congenital adrenal hyperplasia who presented with seizures during the first week of life, possibly due to a transient blood calcium disturbance. This case suggests that white matter changes are not simply the result of chronic insults and that they may not always be subclinical.

Perinatal risk factors and later social, thought, and attention problems after perinatal stroke.

Objective. Survivors of perinatal stroke may be at risk for behavioral problems. Perinatal risk factors that might increase the likelihood of later behavior problems have not been identified. The goal of this study was to explore whether perinatal factors might contribute to behavior problems after perinatal stroke. Methods. 79 children with unilateral perinatal stroke were studied. Perinatal factors included gender, gestational age, neonatal seizures, instrumented delivery, fetal distress, acute birth problems, birth weight, and time of diagnosis. Subjects with evidence of hypoxic ischemic encephalopathy were excluded. Parents completed the Achenbach Child Behavior Checklist (CBCL) (Achenbach 1985). The CBCL yields T-scores in several symptom scales. We focused on Social, Thought, and Attention Problems scates. Results. Gestational age and the presence of uteroplacental insufficiency were associated with significant differences on the Thought Problems scale; Attention Problems scores approached significance for these variables. Fetal distress, neonatal seizures, or neonatal diagnosis was associated with 25-30% incidence of clinically significant T-scores on Social, Thought, and Attention Problems scales. Conclusions. Several perinatal factors were associated with a high incidence of social, thought, and behavior problems in children with perinatal stroke. These findings may be useful in anticipatory guidance to parents and physicians caring for these children.

The clinical utility of the Social Responsiveness Scale and Social Communication Questionnaire in tuberous sclerosis complex.

Tuberous sclerosis complex (TSC) is often associated with epilepsy, mental retardation, and autism spectrum disorders (ASDs). Thus, screening for ASDs is important when evaluating these individuals. We examined the utility of the Social Responsiveness Scale (SRS) and Social Communication Questionnaire (SCQ), two measures for screening for ASDs, in a TSC population. Twenty-one children were evaluated, with 52.4% classified as having ASDs on the SRS and 42.9% classified as such on the SCQ. Number of antiepileptic drugs significantly correlated with SRS Total score, as did level of intellectual functioning. Evidence for convergent validity was obtained between the SRS and SCQ Total scores (r=0.605). Moreover, all SRS subscales correlated with SCQ Total score (r>0.400). All SCQ subscales except for Communication correlated with SRS total. Overall, the results demonstrate that these questionnaires appear to be effective screens for ASDs in a TSC population and are measuring similar constructs.

Effects of early focal brain injury on memory for visuospatial patterns: selective deficits of global-local processing.

Selective deficits in visuospatial processing are present early in development among children with perinatal focal brain lesions (PL). Children with right hemisphere PL (RPL) are impaired in configural processing, while children with left hemisphere PL (LPL) are impaired in featural processing. Deficits associated with LPL are less pervasive than those observed with RPL, but this difference may reflect the structure of the tasks used for assessment. Many of the tasks used to date may place greater demands on configural processing, thus highlighting this deficit in the RPL group. This study employed a task designed to place comparable demands on configural and featural processing, providing the opportunity to obtain within-task evidence of differential deficit. Sixty-two 5- to 14-year-old children (19 RPL, 19 LPL, and 24 matched controls) reproduced from memory a series of hierarchical forms (large forms composed of small forms). Global- and local-level reproduction accuracy was scored. Controls were equally accurate on global- and local-level reproduction. Children with RPL were selectively impaired on global accuracy, and children with LPL on local accuracy, thus documenting a double dissociation in global-local processing.

Mental retardation and relation to seizure and tuber burden in tuberous sclerosis complex.

In patients with tuberous sclerosis complex (TSC), the high rates of mental retardation are associated with cortical tubers, seizure activity, and genetic factors. The goal of the study was to investigate the relationship between bilateral cortical tubers and seizure variables and mental retardation in individuals with TSC. The records of 27 patients with TSC (age 6 months to 33 years) undergoing neuropsychological assessment and the following clinical variables were examined: bilateral versus non-bilateral cortical tubers, the age of seizure onset, and presence of infantile spasms. Results were statistically analyzed. Bilateral cortical tubers (p=0.02) and early age of seizure onset (p=0.04) were significantly related to impaired cognitive functioning. Only one of the seven patients with normal cognitive functioning had bilateral tubers, whereas 13/21 patients with intellectual impairment had bilateral tubers. Patients with normal cognitive functioning experienced a mean age of seizure onset after 6 years. A trend was observed between infantile spasms and cognitive functioning (p=0.06); the lack of statistical significance likely reflects the small sample size. Neither age nor gender was related to cognitive status. Further investigation incorporating additional neuroimaging factors, antiepileptic treatment effects, and genetic variables, is needed.

Evaluation and assessment issues in the diagnosis of attention deficit hyperactivity disorder.

This article discusses the availability and appropriateness of various assessment techniques for diagnosing ADHD. In terms of the interview/history, the necessity and viability of using formal structured, semi structured, computerized and informal interviews for making an ADHD diagnosis are critiqued. The pros and cons of the various questionnaires frequently used to diagnose ADHD are addressed. The conundrum raised by multiple informants who often disagree is discussed, as are the effects of age and gender. The contributions of the medical and neurological examinations to the diagnosis of ADHD are considered. The utility of a neuropsychological assessment and of continuous performance testing to diagnosis is critiqued. Finally the lack of need for laboratory tests and the lack of necessity of neurological workup, specifically EEG and imaging, are argued.

Social and affective impairments are important recovery after acquired stroke in childhood.

Despite a congenital stroke, overall intelligence at school age is generally within the normal range. Language acquisition problems are more prominent when children are younger (<5 years of age) than when they are older. They are present after both right and left lesions, but appear to have different features. They are less apparent than in the child with a developmental language disorder. Acquired aphasia in childhood results in subtle and often persisting deficits. Children with congenital strokes are at risk for behavioral and psychiatric problems. Those with congenital right hemisphere strokes appear to be more difficult infants, but there is no clear side of lesion effect in older children. Children with congenital right hemisphere strokes have more prominent spatial difficulties than their left lesion counterparts. Evaluating both the process and the product highlights this. Increasing the difficulty of the task often brings out deficits in the right lesion group even when they seemingly recovered.

Effects of mothers' autoimmune disease during pregnancy on learning disabilities and hand preference in their children.

OBJECTIVES: To determine whether children (and particularly sons) of women with systemic lupus erythematosus (SLE) during pregnancy are more likely to have learning disabilities (LD) and be non-right-handed, and if maternal disease variables (ie, presence of maternal antibodies, disease activity level, and use of corticosteroids) predict the prevalence of LD in offspring. DESIGN: Case-controlled study with subjects matched by age and sex. PARTICIPANTS: We studied 58 children whose mothers had SLE during pregnancy and 58 children of healthy mothers. Measures Data collected included maternal disease variables in women with SLE during their pregnancies. All children took a standardized intelligence test (Wechsler Intelligence Scale for Children-III) and completed a modified version of the Edinburgh Hand Preference Questionnaire. They also took standardized tests of reading, arithmetic, and writing achievement. Learning disability was defined as having an academic achievement score of at least 1.5 SDs below the Full-Scale IQ. RESULTS: Sons of women with SLE were significantly more likely to have LD than daughters of women with SLE or children of either sex in the control group. Maternal SLE was not associated with non-right-handedness in sons or daughters. The presence of anti-Ro/La antibodies and disease activity (flare) in mothers during pregnancy were significantly related to higher prevalence of LD in offspring. CONCLUSIONS: Autoimmune disease in women during pregnancy is associated with an increased risk for LD in their sons. Maternal antibodies, particularly anti-Ro/La, likely affect the fetal brain of male offspring and result in later learning problems. These findings should promote greater awareness of the risk for LD in sons of women with autoimmune disease and the possible need for early educational intervention in those children.