Michele Michelin Becker

Translation and validation of Autism Diagnostic Interview-Revised (ADI-R) for autism diagnosis in Brazil

OBJECTIVE To translate into Brazilian Portuguese the Autism Diagnostic Interview-Revised (ADI-R), an extremely useful diagnostic tool in autism. METHODS A case-control study was done to validate the ADI-R. After being translated, the interview was applied in a sample of 20 patients with autism and 20 patients with intellectual disability without autism, in order to obtain the initial psychometric properties. RESULTS The internal consistency was high, with a of Crombach of 0.967. The validity of criterion had sensitivity and specificity of 100%, having as a gold standard the DSM-IV diagnostic criteria. The interview had high discriminant validity, with higher scores in the group of patients with autism, as well as high interobserver consistency, with median kappa of 0.824. CONCLUSION The final version of ADI-R had satisfactory psychometric characteristics, indicating good preliminary validation properties. The instrument needs to be applied in bigger samples in other areas of the country.

The role of β3 integrin gene variants in Autism Spectrum Disorders--diagnosis and symptomatology.

Autism Spectrum Disorders (ASDs) represent a group of very complex early-onset neurodevelopmental diseases. In this study, we analyzed 5 SNPs (rs2317385, rs5918, rs15908, rs12603582, rs3809865) at the β3 integrin locus (ITGB3), which has been suggested as a possible susceptibility gene, both as single markers and as part of haplotypes in 209 ASD children and their biological parents. We tested for association with the following: a) DSM-IV ASD diagnosis; b) clinical symptoms common in ASD patients (repetitive behaviors, echolalia, seizures and epilepsy, mood instability, aggression, psychomotor agitation, sleep disorders); and c) dimensional scores obtained with the Autism Screening Questionnaire and the Childhood Autism Rating Scale. These hypotheses were investigated using family-based tests, logistic regression models and analysis of covariance. The family-based tests showed an association with the H5 haplotype (composed by GTCGA alleles, the order of SNPs as above), which was transmitted less often than expected by chance (P=0.006; Pcorr=0.036). The analyses of the clinical symptoms showed a trend for an association with rs12603582 (P=0.008; Pcorr=0.064) and positive results for the haplotype composed of rs15908 and rs12603582 (Pglcorr=0.048; Pindcorr=0.015), both in symptoms of echolalia. Other nominal associations with different variants were found and involved epilepsy/seizures, aggression symptoms and higher ASQ scores. Although our positive results are not definitive, they suggest small effect associations of the ITGB3 gene with both ASD diagnosis and symptoms of echolalia. Other studies are nonetheless needed to fully understand the involvement of this locus on the etiology of ASDs and its different clinical aspects.

Treatment of refractory neonatal seizures with topiramate.

OBJECTIVE The objective of this study is to describe the usefulness of topiramate in refractory neonatal seizures. RESULTS We reported the clinical off-label use of topiramate in three cases of refractory neonatal seizures of unclear origin with no response to conventional antiepileptic drugs. In all cases, the seizures were completely controlled with adding topiramate. All patients became seizure free during hospitalization and were followed by approximately 1 year after hospital discharge, with monotherapy with topiramate. COMMENTS The clinical off-label use of topiramate in neonatal seizures is still incipient. When searching publications in this matter, only one report was identified. Because of its efficacy for both seizures and neuroprotection, topiramate could be a useful choice in refractory neonatal seizures.

Post‐H1N1 vaccine acute disseminated encephalomyelitis

Acute disseminated encephalomyelitis (ADEM) is a rare autoimmune demyelinating disorder of the central nervous system (CNS) that affects mainly children. Typically it happens after an infection and rarely after vaccination, with compromise of the white matter of the brain and/or spinal cord, characterized by a rapid development of encephalopathy in combination with multifocal and extremely varied neurological deficits. Brain and spinal cord magnetic resonance imaging (MRI) show disseminated demyelization in the CNS. Cerebrospinal fluid (CSF) examination can demonstrate unspecific alterations. We report the case of a previously healthy 8-year-old boy, who had fever, headache and somnolence 12 days after the first dose of vaccine against influenza H1N1. There was no previous history of infection or other vaccines in the previous 30 days, as well as no evidence of ongoing influenza H1N1 infection. The CSF was a crystalline fluid with 45 leukocytes/μL with 100% monocytes, glucose 62 mg/dL, and proteins 27 mg/dL. No infectious pathogens were identified in the blood or in the CSF. The patient had clinical seizures controlled with i.v. diazepam, became aphasic, and developed left hemiparesis. Electroencephalogram indicated slowing background activity with multifocal spikes and one electrographic seizure, after which i.v. phenytoin was initiated. He was transferred to the intensive care unit (ICU) due to coma and necessity of mechanical ventilation and did not have metabolic abnormalities. He was discharged from ICU with residual neurologic deficits, such as aphasia, paresis of extrinsic ocular muscles and ataxia. Brain MRI was compatible with ADEM (Fig. 1). Spine MRI showed no lesion. I.v. methylprednisolone pulse therapy (30 mg/kg per day) was given for 5 days, followed by 4 weeks of oral prednisone (2 mg/kg per day). The patient was discharged from hospital after 30 days. During follow up, a complete remission of symptoms occurred. According to the World Health Organization, in 2009 approximately 40 countries started national campaigns of vaccination against influenza A. Nearly 80 million doses of H1N1 vaccine were distributed and 65 million people were vaccinated. In this sense, rigorous surveillance of side-effects is necessary to establish the vaccine safety. ADEM usually occurs after unspecific viral upper respiratory airway infection. Only 5% are post-vaccine cases, more frequently after vaccination against measles, rubella and mumps. Only two case reports of ADEM after vaccine against H1N1 have been identified on publication database search. Obviously, vaccines are considered safe and provide one of the most cost-effective treatments. Vaccination campaigns have prevented thousands of deaths and disabling consequences, allowing the eradication of some diseases. In contrast, the worrying side-effects, although rare, must be promptly described in order to prevent undesirable events. Even recognizing that this is a description of a single case as well as that the causal association between this vaccine and the neurological alterations could not be totally proved, to our knowledge this paper represents the third description of a case of ADEM identified after H1N1 influenza vaccine. In the present case, early identification and treatment of ADEM were sufficient to ensure complete neurological recovery.

Clinical Approach in Autism: Management and Treatment

The terms Autism and ASD (Autism Spectrum Disorders) can be interchangeable in the clinical setting, and have been used to describe one of the most intriguing neurobehavioral syndromes, that include the so-called “triad of Wing”: problems in communication, social skills, and restrict repertoire of interests. However, it is somewhat difficult to precisely define autism, because of the imprecise boundaries between different kinds of ASD as well as the fact that there is no biological marker to date (Gottfried and Riesgo 2011).

Improvement in Symptoms of Autism Spectrum Disorder in Children With the Use of Gastrin-Releasing Peptide: An Open Trial.

ObjectivesThe aim of this study was to determine the efficacy and tolerability of gastrin-releasing peptide (GRP) for core symptoms of autism spectrum disorder. MethodsThis is a prospective, open-label study with 160 pmol/kg of GRP tested in 10 children with autism. Outcome measures used were the Clinical Global Impressions-Improvement Scale, Aberrant Behavior Checklist (ABC), Childhood Autism Rating Scale, and Autism Diagnostic Interview-Revised. Positive response was defined as a score of 1 (very much improved) or 2 (much improved) on the Clinical Global Impressions-Improvement Scale and an improvement of 25% or greater on at least 1 subscale of ABC. ResultsSix (60%) of the 10 subjects responded to GRP. Improvements were observed on the ABC irritability and hyperactivity subscales in 80% of patients, and 70% exhibited improvement on the social withdrawal subscale. On the Childhood Autism Rating Scale, there was a mean reduction of 4 points (4.3 ± 2.9). Analysis of the Autism Diagnostic Interview-Revised results detected significant improvements in the domain that assesses social interaction, with a mean reduction of 2.4 points (2.4 ± 2.83). Adverse effects occurred in 3 patients. ConclusionsGastrin-releasing peptide was safe and well tolerated by most subjects and may be effective for core symptoms of autism.

Evidence for Association Between OXTR Gene and ASD Clinical Phenotypes

Autism spectrum disorder (ASD) is an early-onset neurodevelopmental disorder characterized by impairments in social behaviors and communication. Oxytocin and its signaling pathway are related to a range of human behaviors, from facial expression recognition to aggressive behaviors, and have been suggested as involved in the etiology of ASD. Our aim was to evaluate the influence of two polymorphisms (rs1042778, rs53576) at the oxytocin receptor gene (OXTR) on ASD diagnosis and on specific ASD-related clinical symptoms (seizures, panic, and aggressive behaviors). We also assessed if these SNPs could be related to changes in OXTR availability and functionality using a bioinformatic approach. The sample was composed by 209 probands with ASD and their biological parents. Family-based approach and logistic regression models were used to investigated the outcomes. We observed that panic and aggressive behaviors were nominally associated with presence of rs1042778 T allele (P = 0.019/Pcorr = 0.114; P = 0.046/Pcorr = 0.276 respectively). Also, in the family-based analysis, a trend towards association with ASD susceptibility was observed for rs1042778 (G allele) (P = 0.066). In a bioinformatic approach, we demonstrated that rs1042778 G allele is determinant for the binding of the transcription factor MAZ, suggesting that when the T allele is present, the absence of MAZ binding might be associated with lower transcription levels of the OXTR gene. The overall findings suggest that the OXTR gene may play a role in ASD diagnosis and some of its clinical phenotypes, supported by previous animal and clinical studies. Further investigations are necessary to replicate our findings and fully understand the effects of the oxytocin pathway on ASD.

A Placebo-controlled Crossover Trial of Gastrin-releasing Peptide in Childhood Autism.

Objectives The aim of this study was to evaluate the efficacy, safety, and tolerability of gastrin-releasing peptide (GRP) compared with placebo in autism spectrum disorder symptoms. Methodology This is a randomized, double-blind, placebo-controlled crossover trial using GRP 160 pmol/kg for 4 consecutive days in 10 children with autism. Outcomes were measured by the Aberrant Behavior Checklist (ABC) scale. Results All participants were boys, aged between 4 and 9 years. There was a reduction in the scores of the ABC range and its subscales after use GRP and placebo. The reduction was more prominent with GRP, particularly in the subscale “hyperactivity and noncompliance,” but there was no statistical difference between the results (P = 0.334). After a week of infusion, 5 children showed improvement of 25% or greater in the total score of the ABC scale with GRP use and 2 with placebo use; however, there was no statistical difference (P = 0.375). There were no adverse effects, changes in vital signs, or laboratory abnormalities associated with the use of GRP. Conclusions The results of this study, despite the small sample size, reinforce previous data on the safety of the GRP in short-term use. There is a need for further research with other designs and a larger sample size to evaluate the efficacy and safety of GRP in children with autism.