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Marco Lamberti,1,2 Domenico Italiano,2 Laura Guerriero,1 Gessica D’Amico,3 Rosamaria Siracusano,1,4 Massimo Ingrassia,5 Eva Germanò,1 Maria Pia Calabrò,3 Edoardo Spina,2 Antonella Gagliano1 1Division of Child Neurology and Psychiatry, Department of Pediatrics, 2Department of Clinical and Experimental Medicine, 3Division of Pediatric Cardiology, Department of Pediatrics, University of Messina, Messina, Italy; 4Institution of Clinical Physiology, CNR, Pisa, 5Division of Psychology, Department of Humanities and Social Sciences, University of Messina, Messina, Italy Abstract: Attention-deficit hyperactivity disorder is a frequent condition in children and often extends into adulthood. Use of immediate-release methylphenidate (MPH) has raised concerns about potential cardiovascular adverse effects within a few hours after administration. This study was carried out to investigate acute effects of MPH on electrocardiogram (ECG) in a pediatric population. A total of 54 consecutive patients with attention-deficit hyperactivity disorder (51 males and 3 females; mean age =12.14±2.6 years, range 6–19 years), receiving a new prescription of MPH, underwent a standard ECG 2 hours before and after the administration of MPH 10 mg per os. Basal and posttreatment ECG parameters, including mean QT (QT interval when corrected for heart rate [QTc]), QTc dispersion (QTd) interval duration, T-peak to T-end (TpTe) intervals, and TpTe/QT ratio were compared. Significant modifications of both QTc and QTd values were not found after drug administration. QTd fluctuated slightly from 25.7±9.3 milliseconds to 25.1±8.4 milliseconds; QTc varied from 407.6±12.4 milliseconds to 409.8±12.7 milliseconds. A significant variation in blood pressure (systolic blood pressure 105.4±10.3 vs 109.6±11.5; P

Autism spectrum disorder is a neurodevelopmental disorder with a rising prevalence disorder. This high-cost/high-burden condition needs evidence-based behavioral treatments that are able to reduce the impact of symptoms on children’s functioning. This retrospective chart review study compared the impact of different types of early interventions on toddlers diagnosed with an autism spectrum disorder developmental profile. Analyses were conducted on 90 subjects (mean = 27.76 months, range 18−44 months; M:F = 4.29:1), of which 36 children underwent the usual treatment, 13 children underwent an intervention based on early intensive behavioral intervention (EIBI) and 41 children received the Early Start Denver Model, for one year, with the same weekly frequency of about 6 h a week. A significant decrease in the severity of autism symptoms was observed for all children when looking at the Ados-2 severity score (average difference = 3.05, SD = 0.71, p = < 0.001) and the Ados-2 social subscale (average difference = 2.87, SD = 0.59, p < 0.001). Otherwise, for most of the Griffiths subscales, we found a significant improvement only for those children who underwent the Early Start Denver Model intervention (General Quotient average difference = 14.47, SD = 3.22, corrected p < 0.001). Analyzing the influence of age on the investigated scores, we found a significant association with the Eye−hand Coordination Quotient (p = 0.003), Performance Quotient (p = 0.042) and General Quotient (p = 0.006). In all these domains, a mild negative correlation with age was observed, as measured by the Pearson’s correlation coefficient (r = −0.32, p = 0.002; r = −0.21, p = 0.044; r = −0.25, p = 0.019, respectively), suggesting less severe developmental skills at the start of treatment for older children. Our results are consistent with the literature that underlines the importance of early intervention, since prompt diagnosis can reduce the severity of autism symptoms; nevertheless, in toddlers, our study demonstrated that an intervention model based on naturalistic developmental behavioral principles such as the Early Start Denver Model is more effective on children’s developmental profile. Further studies are required to assess the extent of effectiveness of different early intervention models in community settings.

Attention Deficit Hyperactivity Disorder (ADHD) and Autism Spectrum Disorders (ASD) are two of the most represented neurodevelopmental conditions in childhood. The diagnostic shift introduced by the DSM-5, allowing a combined diagnosis of ADHD and ASD, poses different clinical challenges related to diagnostic overshadowing, accuracy of clinical judgment and potential delay in an ASD diagnosis in children presenting with ADHD. Here we tried to disentangle the clinical phenotype and specificity of the two co-occurring conditions in relation to autism traits and empathy, by comparing children with ASD with and without comorbid ADHD with children presenting ADHD only and children with typical development. The child versions of the Autism Quotient (C-AQ) and Empathy Quotient (C-EQ) were administered to a total sample of 198 male children between 6 and 14 years old with age appropriate language skills and normal intelligence. Univariate analysis demonstrated no significant differences in the C-AQ total and subscale scores as well as the C-EQ between children with ASD and children with ASD + ADHD, while children with ADHD alone presented an intermediate phenotype between ASD and TD. Furthermore, a receiver operating characteristic (ROC) analysis was applied to discriminate among the different phenotypes. We found that the C-AQ and C-EQ were accurate at distinguishing with satisfactory reliability between: (a) ASD vs. non- ASD (N-ASD) groups comprising both ADHD and TD children (Area Under the Curve AUC 88% for C-AQ and 81% for C-EQ); (b) ASD and TD (AUC 92% for C-AQ and 95% for C-EQ); (c) ASD and ADHD (AUC 80% for C-AQ and 68% for C-EQ). Our data confirm the reliability of the C-AQ and C-EQ as behavioral markers to differentiate ASD (regardless of comorbid ADHD) from an ADHD condition and TD. Interestingly, in our sample an ADHD condition does not increase the severity of the clinical phenotype in terms of autism traits distribution and empathy, suggesting that the psychological measures detected by the two quantitative instruments are independent of ADHD traits. This evidence will contribute to the translational efforts in developing better tailored treatments and preventive strategies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Aiello, Vagni, Cerasa, Leonardi, Carrozza, Famà, Campisi, Marino, Siracusano, Alquino, Mainiero, Germano, Tartarisco, Pioggia, Gagliano and Ruta.)

Some studies show that the diagnosis of Autism Spectrum Disorder could be considered reliable and stable in children aged 18 to 24 months. Nevertheless, the diagnostic stability of early ASD diagnosis has not yet been fully demonstrated. This observational study examines the one-year diagnostic stability of autism spectrum disorder diagnosis in a clinical sample of 147 children diagnosed between 18 and 48 months of age. The ADOS-2 scores were used in order to stratify children in three levels of symptom severity: Autism (AD; comparison score 5-7), Autism Spectrum Disorder (ASD; comparison score 3-4), and Sub-Threshold Symptoms; (STS; comparison score 1-2). Results: Overall, the largest part of children and toddlers diagnosed with autism spectrum disorder between 18 and 48 months continued to show autistic symptoms at one-year follow-up evaluation. Nevertheless, a significant percentage of children with higher ADOS severity scores exhibited a reduction of symptom severity and, therefore, moved towards a milder severity class one year later. Conversely, the number of subjects of the STS group meaningfully increased. Therefore, at one-year follow-up a statistically significant (χ 2 (2) = 181.46, p < 0.0001) percentage of subjects (25.2% of the total) who had received a categorical diagnosis of Autistic Disorder or Autism Spectrum Disorder in baseline no longer met the criteria for a categorical diagnosis. Furthermore, children who no longer met the criteria for autism spectrum disorder continue to show delays in one or more neurodevelopmental areas, possibly related to the emergence of other neurodevelopmental/neuropsychiatric disorders. Overall, the comprehensive results of the study account for a high sensibility but a moderate stability of ASD early diagnosis.

Background and Aims: Autism Spectrum Disorder (ASD) is characterized by the impairment of communication and social interaction and by repetitive, restricted and stereotyped interests. ASD is often accompanied by comorbidities; eating disorders are frequent and imply important nutritional deficits (i.e. deficiencies of vitamins, minerals and fatty acids). Vitamin D has a critical role in neurodevelopment and serum levels in ASD are reported inadequate. A useful reference for setting up a correct diet in childhood is the food pyramid, which is inspired by the Mediterranean Diet (MD). The MD guarantees an intake of nutrients, considered optimal to maintain an adequate nutritional status. The aim of this study is to explore serum levels of Vitamin D and food habits (through MD adherence) in a sample of children with ASD and evaluate a possible correlation between these factors., Methods: study participants include 91 children 47 presenting ASD and 44 healthy typically-developing (TD) subjects, as control group. We evaluated serum level of Vitamin D in both group; anthropometric parameters (weight, height, body mass index-BMI-and growth percentile) and MD adherence have been explored, in order to investigate the correlation among those data and level of Vitamin D in children with ASD. Lastly, the association between Vitamin D levels and severity of ASD symptoms has been analysed., Results and Conclusion: 74% of ASD group presented blood levels of Vitamin D under 30 ng/ml (normal range 30-100 ng/ml). The analysis performed showed that the two groups were significant different regards Vitamin D levels (t = 2.24, p < 0.05), according to literature. 31.9% of children with ASD presented a condition of overweight and 12.6% a condition of obesity. Adherence to the MD was low in 25.5% of cases. No significant statistical correlation has been found between Vitamin D serum levels, anthropometric parameters and the adherence to MD in the ASD group., Competing Interests: Conflict of interest: All authors declare no conflicts of interest in this paper., (© 2020 the Author(s), licensee AIMS Press.)

Identifying effective, community-based specialized interventions for young children with autism spectrum disorder is an international clinical and research priority. We evaluated the effectiveness of the Early Start Denver Model intervention in a group of young children with autism spectrum disorder living in an Italian community compared to a group of Italian children who received treatment as usual. A total of 22 young children diagnosed with autism spectrum disorder received the Early Start Denver Model in a center-based context for 6 h per week over 6 months. The Early Start Denver Model group was compared to a group of 70 young children diagnosed with autism spectrum disorder who received treatment as usual for an average of 5.2 h over 6 months. Children in both groups improved in cognitive, adaptive, and social skills after 3 months and 6 months of treatment. Children in the Early Start Denver Model group made larger gains in cognitive and social skills after 3 and 6 months of treatment. The Early Start Denver Model group made larger gains in adaptive skills after 3 months of treatment. Our results are discussed in terms of implications for intervention research and clinical practice. Our study supports the positive impact of the Early Start Denver Model in a non-English-speaking community.

Background: Autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) are frequently overlapping neurodevelopmental disorders. Individuals in whom the disorders are comorbid show more severe impairment because of deficits in the processing of social situations, adaptive functioning, and executive control than individuals with either disorder alone., Objective: This open-label pilot study aimed to evaluate and compare the efficacy and tolerability of risperidone and aripiprazole for treating ADHD symptoms in patients with both ASD and ADHD over the course of 24 weeks of treatment., Methods: Patients (n = 44) were randomly assigned to start treatment with risperidone (22 patients) or aripiprazole (22 patients). Children were evaluated before starting treatment (T0), and after 12 weeks (T1) and 24 weeks (T2) of treatment. At each visit, specific psychiatric clinical scales were administered to assess the efficacy of the two drugs., Results: The mean age was 8.4 ± 2.9 years in the aripiprazole group and 7.8 ± 2.3 years in the risperidone group. A total of 37 children (29 boys and 8 girls) completed the study (18 in the aripiprazole group and 19 in the risperidone group). Aripiprazole and risperidone appeared to have similar benefits in terms of efficacy and tolerability, although there were slight differences between the two drugs. Both groups showed a significant improvement in ADHD symptoms after 24 weeks of treatment (ADHD Rating Scale, Conners Parent Rating Scale-Hyperactivity, and Clinical Global Improvement-Severity Scale). No significant difference between the two drugs on any parameters at 24 weeks were found. Prolactin levels were decreased in the aripiprazole group. Both drugs were well tolerated, with no serious adverse events detected., Conclusions: Our study confirms the efficacy of both aripiprazole and risperidone in ameliorating ADHD symptoms of children also presenting with ASD.

Attention-deficit/hyperactivity disorder (ADHD) is frequently associated with negative psychological outcomes. This study explores the relationship between self-esteem, ADHD symptoms and parental stress. It compares children with ADHD, children with epilepsy (E) and typical developmental controls (TD). Participants included 65 children (aged 9-12 yrs) and their parents. The assessment was conducted by Multidimensional Self-Concept Scale (MSCS), Parent Stress Index (PSI) and Conners' Parent Rating Scales-Revised. Significant differences were found in Social, Competence and Academic areas of self-esteem between children with ADHD, with E and TD. Moreover, parents of children with ADHD showed a higher overall stress than both other groups. In conclusion, it seems important to evaluate the psychological aspects of ADHD con-dition, both in children and in parents, in order to suggest an individual multimodal treatment.

Atypical antipsychotics (AP) are increasingly being used in children and adolescents for the treatment of psychiatric disorders. Atypical AP may cause QT prolongation on the electrocardiogram (ECG), which predisposes patients to an increased risk of developing threatening ventricular arrhythmias. Although this phenomenon has been exhaustively reported in adults, few studies investigated the safety of these drugs in pediatric patients. We performed an open-label, prospective study to assess the arrhythmic risk of aripiprazole and risperidone in a pediatric population. A total of 60 patients (55 M/5F, mean age 10.2+2.6 years, range 4-15 years), receiving a new prescription of aripiprazole or risperidone in monotherapy underwent a standard ECG before and after two months from the beginning of antipsychotic treatment. Basal and post-treatment ECG parameters, including mean QT (QTc) and QT dispersion (QTd), were compared within treatment groups. Twenty-nine patients were treated with aripiprazole (mean dosage 7.4+3.1mg/day) and 31 with risperidone (mean dosage 1.5+1mg/day). In our series, no patient exhibited pathological values of QTc or QTd before and after treatment for both drugs. However, treatment with risperidone was associated with a slight increase of both mean QTc and QTd values (407.4+11.9 ms vs 411.2+13.0 ms, p<0.05; and 40.0+4.4 ms vs 44.7+5.5 ms, p<0.001, respectively). Treatment with aripiprazole was associated with no changes of mean QTc, even if a small increase of QTd, (40.6+6.5 ms vs 46.3+7.2 ms, p<0.01) was observed. Although our data suggest a slight effect of aripiprazole and risperidone on ventricular repolarization, it is unlikely that such a change results in clinically relevant effects. The treatment with risperidone and aripiprazole in children with psychiatric disorders is not associated with clinically relevant modifications of QT interval. Caution in prescribing these drugs, however, is necessary in patients with family history of a genetic predisposition to arrhythmias in order to warrant a reliable assessment of drug-induced QT prolongation., (© 2013.)

Aim: The aim of this study was to evaluate adverse drug reactions (ADRs) of psychotropic medications in childhood., Methods: One hundred and two children and adolescents (M 82.4%, F 17.6%) followed-up at the Division of Child Neurology and Psychiatry at the University of Messina, and at the Scientific Institute Child Neurology and Psychiatry, IRCCS Stella Maris, Calambrone, Pisa, were recruited between January 2009 and December 2011. All participants met DSM-IV diagnostic criteria for psychiatric disorders. The data were collected using a recording sheet for ADRs. An electronic database was also used. The recording sheet was designed to note all relevant information about drug treatment and ADRs according to AIFA (Agenzia Italiana del Farmaco) suggestions., Results: The most prescribed drugs were: risperidone (19.6%), aripiprazole (18.4%) and valproic acid (14.8%). The ADRs more frequently recorded had been: weight gain (12.6%), sleepiness (8.4%), and irritability (6.7%). None of recorded ADRs were classified as "serious"., Conclusion: This study can provide a basic model to collect information on safety and tolerability of psychotropic drugs in childhood.

Purpose: The aim of the study was to perform a detailed assessment of cognitive abilities and behaviour in a series of epileptic patients with Dravet syndrome (DS) in order to establish a possible cerebellar-like pattern., Methods: Nine children with DS without major behavioural disturbances and with cognitive abilities compatible with the assessment of specific cognitive skills (IQ>45) were enrolled in the study, in parallel with another group of nine epileptic patients (cryptogenic or symptomatic with minor brain injuries) consecutively admitted into the hospital matched for chronological age and IQ. All cases underwent neurological examination, long term EEG monitoring, neuroimaging and genetic analysis as well as a neuropsychological assessment including specific cognitive skills., Results: On neurological examination 8 of the 9 DS patients had cerebellar signs, which were mild in six and more severe in the other two cases. DS patients had a constant discrepancy between verbal and performance items scales (verbal better than visual-spatial) that was not found in the control group. As to specific cognitive competence, the DS patients differ from the control group in the pattern of cognitive defects involving four main areas of cognitive abilities (a) expressive language with relatively spared comprehension, (b) visual-spatial organization, (c) executive function defects, (d) behavioural disorders., Cunclusions: The pattern of cognitive difficulties found in DS patients is consistent with what is reported in literature as cerebellar cognitive syndrome and may account for a possible cerebellar origin (at least as co-factor) of the cognitive decline observed in DS patients, as suggested by other clinical and experimental studies., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Objective: To outline specific sleep disturbances in different clinical subsets of Attention Deficit/Hyperactivity Disorder (ADHD) and to confirm, by means of nocturnal video-polysomnography (video-PSG), a variety of sleep disorders in ADHD besides the classically described periodic leg movement disorder (PLMD), restless legs syndrome (RLS) and sleep related breathing disorder (SRBD)., Methods: Fifty-five ADHD children (47 M, 8F; mean age=8.9 y) were included: 16 had Inattentive and 39 Hyperactive/Impulsive or Combined ADHD subtype. Behavior assessment by Conners and SNAP-IV Scales, a structured sleep interview and a nocturnal video-PSG were administered., Results: Most children/parents reported disturbed, fragmentary sleep at night; complaints were motor restlessness (50%), sleep walking (47.6%), night terrors (38%), confusional arousals (28.5%), snoring (21.4%), and leg discomfort at night associated with RLS (11.9%). There is a significant difference (p value <0.05 or <0.001) in almost all the studied sleep variables between ADHD children and controls. International RLS Rating Scale scoring, Periodic Limb Movements during Sleep (PLMS) and Wake (PLMW) indexes, hyperactivity and opposition scores and ADHD subtype appear related. Different sleep disorders seem to address specific ADHD phenotypes and correlate with severity of symptoms as in sleep related movement disorders occurring in Hyperactive/Impulsive and Combined ADHD subtypes. Besides, an abnormality of the arousal process in slow wave sleep with consequent abnormal prevalence of disorders of arousal possibly enhanced by SRBD has also been detected in 52% of our sample., Conclusions: This study underlines the opportunity to propose and promote the inclusion of sleep studies, possibly by video-PSG, as part of the diagnostic screening for ADHD. This strategy could address the diagnosis and treatment of different specific ADHD phenotypic expressions that might be relevant to children's symptoms and contribute to ADHD severity.

This study investigated prolactin levels in two groups of children and adolescents receiving risperidone (N=29) or olanzapine (N=13). It focused not only on significant differences but also on effect sizes; took into account dose effects and gender differences; used a longitudinal design (months 1, 3, 6 and 12) that helped control for individual differences; and took into account response differences due to the duration of antipsychotic treatment. Additionally, this study investigated tolerance development using statistical tests, and explored the effect of antipsychotic plasma concentrations at months 1 and 3. After adjusting for gender, treatment duration and individual effects, mean prolactin levels on risperidone were 4.9 ng/mL higher than on olanzapine (10.3 times higher after controlling for dosing potency). On risperidone treatment, the adjusted mean prolactin level at the 3rd month of treatment was significantly higher than at the 1st month; at the 12th month it was significantly lower than at the 1st month; the 1st and 6th months were not significantly different. On olanzapine treatment, adjusted mean prolactin levels at the 3rd and 6th months of treatment were significantly higher than at the 1st month; at the 12th month it was lower than at the 1st month, but the difference was not significant. In males, at the 3rd month, an increase of 1 ng/mL in plasma 9-hydroxyrisperidone concentrations raised prolactin levels significantly by 0.44 ng/mL. In females, independently of duration (1 or 3 months), an increase of 1 ng/mL in plasma olanzapine concentrations raised prolactin levels significantly by 2.1 ng/mL. After adjusting for dose and the greater potency of risperidone, the increase in prolactin levels during risperidone treatment appeared to be 10.3 times higher than that during olanzapine treatment. Our study showed a pattern consistent with the development of prolactin tolerance over time. Future prolactin studies in children and adolescents taking antipsychotics need to include larger samples with more frequent prolactin measures and long-term plasma concentrations.