Neurodevelopmental Disorders and Suicide: A Narrative Review.

Specific risk factors for self-harm and suicide in children and adolescents with neurodevelopmental disorders (NDD) may differ from those in the general population within this age range. In the present review paper, we conducted a narrative analysis of the literature, aiming to establish a connection between suicide and affective disorders in children and adolescents with NDD. Emotion dysregulation (ED) as an individual factor and adverse childhood experiences (ACE) as environmental factors are discussed as risk factors for suicidality in all individuals with NDD. We propose a theoretical model in which ED and ACE can directly lead to self-harm or suicide, directly or indirectly by interacting with depressive spectrum disorders. Additionally, we suggest that specific risk factors are more frequently associated with each of the neurodevelopmental disorders listed in the DSM-V. This review underlines the key points useful to improve the knowledge of the trajectory leading to suicide risk in NDDs with the purpose to facilitate the early identification of the suicide risk.

The Impact of Methylphenidate on Pubertal Maturation and Bone Age in ADHD Children and Adolescents: Results from the ADHD Drugs Use Chronic Effects (ADDUCE) Project.

OBJECTIVE: The short-term safety of methylphenidate (MPH) has been widely demonstrated; however the long-term safety is less clear. The aim of this study was to investigate the safety of MPH in relation to pubertal maturation and to explore the monitoring of bone age. METHOD: Participants from ADDUCE, a two-year observational longitudinal study with three parallel cohorts (MPH group, no-MPH group, and a non-ADHD control group), were compared with respect to Tanner staging. An Italian subsample of medicated-ADHD was further assessed by the monitoring of bone age. RESULTS: The medicated and unmedicated ADHD groups did not differ in Tanner stages indicating no higher risk of sexual maturational delay in the MPH-treated patients. The medicated subsample monitored for bone age showed a slight acceleration of the bone maturation after 24 months, however their predicted adult height remained stable. CONCLUSION: Our results do not suggest safety concerns on long-term treatment with MPH in relation to pubertal maturation and growth.

Diet-Related Attitudes, Beliefs, and Well-Being in Adolescents with a Vegetarian Lifestyle.

Vegetarianism can meet healthy, ethical, or ecological values (such as equality and protection of animals or the environment). At the same time, it can represent a response to the need for self-determination in adolescence. Furthermore, some studies show vegetarians have greater depressive risk and a lower sense of body satisfaction. Considering the spread of non-meat diets in the Western world, researchers have investigated the benefits and risks to physical and psychological health. Despite this, few studies have been conducted on factors influencing adolescent's vegetarian diet-related attitudes. Through self-administered loosely structured interviews, this research investigated factors potentially associated with vegetarian choices in adolescence. It checked (a) gender differences in vegetarian choices; (b) religious, familial, ethical, or health factors implied in vegetarian choices; and (c) indicators of well-being among young vegetarians. The findings suggest that for our sample, non-vegetarians have lower scores on health-related questions than others, while for vegetarian adolescents, the benefits of vegetarianism mainly depend on their ethical stances, beliefs, and values. Conversely, it is unrelated to factors such as the desire to lose weight, dissatisfaction about one's body shape, or depressive feelings.

Postinfectious Inflammation, Autoimmunity, and Obsessive-Compulsive Disorder: Sydenham Chorea, Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcal Infection, and Pediatric Acute-Onset Neuropsychiatric Disorder.

Postinfectious neuroinflammation has been implicated in multiple models of acute-onset obsessive-compulsive disorder including Sydenham chorea (SC), pediatric acute-onset neuropsychiatric syndrome (PANS), and pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS). These conditions are associated with a range of autoantibodies which are thought to be triggered by infections, most notably group A streptococci (GAS). Based on animal models using huma sera, these autoantibodies are thought to cross-react with neural antigens in the basal ganglia and modulate neuronal activity and behavior. As is true for many childhood neuroinflammatory diseases and rheumatological diseases, SC, PANS, and PANDAS lack clinically available, rigorous diagnostic biomarkers and randomized clinical trials. In this review article, we outline the accumulating evidence supporting the role neuroinflammation plays in these disorders. We describe work with animal models including patient-derived anti-neuronal autoantibodies, and we outline imaging studies that show alterations in the basal ganglia. In addition, we present research on metabolites, which are helpful in deciphering functional phenotypes, and on the implication of sleep in these disorders. Finally, we encourage future researchers to collaborate across medical specialties (e.g., pediatrics, psychiatry, rheumatology, immunology, and infectious disease) in order to further research on clinical syndromes presenting with neuropsychiatric manifestations.

A Machine Learning Approach to the Diagnosis of Autism Spectrum Disorder and Multi-Systemic Developmental Disorder Based on Retrospective Data and ADOS-2 Score.

Early and accurate diagnosis of autism spectrum disorders (ASD) and tailored therapeutic interventions can improve prognosis. ADOS-2 is a standardized test for ASD diagnosis. However, owing to ASD heterogeneity, the presence of false positives remains a challenge for clinicians. In this study, retrospective data from patients with ASD and multi-systemic developmental disorder (MSDD), a term used to describe children under the age of 3 with impaired communication but with strong emotional attachments, were tested by machine learning (ML) models to assess the best predictors of disease development as well as the items that best describe these two autism spectrum disorder presentations. Maternal and infant data as well as ADOS-2 score were included in different ML testing models. Depending on the outcome to be estimated, a best-performing model was selected. RIDGE regression model showed that the best predictors for ADOS social affect score were gut disturbances, EEG retrievals, and sleep problems. Linear Regression Model showed that term pregnancy, psychomotor development status, and gut disturbances were predicting at best for the ADOS Repetitive and Restricted Behavior score. The LASSO regression model showed that EEG retrievals, sleep disturbances, age at diagnosis, term pregnancy, weight at birth, gut disturbances, and neurological findings were the best predictors for the overall ADOS score. The CART classification and regression model showed that age at diagnosis and weight at birth best discriminate between ASD and MSDD.

Effectiveness of an Educational Filmmaking Project in Promoting the Psychological Well-Being of Adolescents with Emotive/Behavioural Problems.

Evidence suggests that adolescents respond positively to simple, early interventions, including psychosocial support and educational interventions, even when offered in non-clinical settings. Cinematherapy can help manage life challenges, develop new skills, increase awareness, and offer new ways of thinking about specific problems. This pilot trial was conducted in Italy, aiming to investigate the effects of a six-week filmmaking course on the psychological well-being of adolescents (N = 52) with emotional/behavioural problems and neurodevelopmental disorders. At the end of the project, most participants showed improvements mostly in social skills, such as social cognition (p = 0.049), communication (p = 0.009), and motivation (p = 0.03), detected using the SRS Social Responsiveness Scale. In addition, social awareness (p = 0.001) increased in all patients. Statistically significant differences resulted in four sub-scales of Youth Self-Report Scale: withdrawn/depressed (p = 0.007), social problems (p = 0.003), thought problems (p < 0.001), and rule-breaking behaviour (p = 0.03); these results showed a decrease in emotional and behavioural problems. This study is an innovative therapeutic and educational approach based on the filmmaking art. This research can offer an empirical basis for the effectiveness of alternative therapeutic tools in child and adolescent psychiatric disorders. At the same time, it can be replicated in broader contexts (e.g., school and communities) to promote children's psychological well-being.

Pediatric Acute-Onset Neuropsychiatric Syndrome: Current Perspectives.

Pediatric acute-onset neuropsychiatric syndrome (PANS) features a heterogeneous constellation of acute obsessive-compulsive disorder (OCD), eating restriction, cognitive, behavioral and/or affective symptoms, often followed by a chronic course with cognitive deterioration. An immune-mediated etiology is advocated in which the CNS is hit by different pathogen-driven (auto)immune responses. This narrative review focused on recent clinical (ie, diagnostic criteria, pre-existing neurodevelopmental disorders, neuroimaging) and pathophysiological (ie, CSF, serum, genetic and autoimmune findings) aspects of PANS. We also summarized recent points to facilitate practitioners with the disease management. Relevant literature was obtained from PubMed database which included only English-written, full-text clinical studies, case reports, and reviews. Among a total of 1005 articles, 205 were pertinent to study inclusion. Expert opinions are converging on PANS as the effect of post-infectious events or stressors leading to "brain inflammation", as it is well-established for anti-neuronal psychosis. Interestingly, differentiating PANS from either autoimmune encephalitides and Sydenham's chorea or from alleged "pure" psychiatric disorders (OCD, tics, Tourette's syndrome), reveals several overlaps and more analogies than differences. Our review highlights the need for a comprehensive algorithm to help both patients during their acute distressing phase and physicians during their treatment decision. A full agreement on the hierarchy of each therapeutical intervention is missing owing to the limited number of randomized controlled trials. The current approach to PANS treatment emphasizes immunomodulation/anti-inflammatory treatments in association with both psychotropic and cognitive-behavioral therapies, while antibiotics are suggested when an active bacterial infection is established. A dimensional view, taking into account the multifactorial origin of psychiatric disorders, should suggest neuro-inflammation as a possible shared substrate of different psychiatric phenotypes. Hence, PANS and PANS-related disorders should be considered as a conceptual framework describing the etiological and phenotypical complexity of many psychiatric disorders.

Corrigendum: Steroid treatment response to post SARS-CoV-2 PANS symptoms: Case series.

[This corrects the article DOI: 10.3389/fneur.2023.1085948.].

Metabolomic Changes in Patients Affected by Multiple Sclerosis and Treated with Fingolimod.

Current treatment for Multiple Sclerosis (MS) consists of a multidisciplinary approach including disease-modifying therapies. The response to treatment is heterogeneous, representing a crucial challenge in the classification of patients. Metabolomics is an innovative tool that can identifies biomarkers/predictors of treatment response. We aimed to evaluate plasma metabolic changes in a group of naïve Relapsing-Remitting MS patients starting Fingolimod treatment, to find specific metabolomic features that predict the therapeutic response as well as the possible side effects. The study included 42 Relapsing-Remitting MS blood samples, of which 30 were classified as responders after two years of FINGO treatment, whereas 12 patients were Not-Responders. For fifteen patients, samples were collected at four time points: before starting the therapy; at six months after the initiation; at twelve months after; and at twenty-four months after initiation. The serum was analysed through Nuclear Magnetic Resonance and multivariate and univariate statistical analysis. Considering the single comparison between each time point, it was possible to identify a set of metabolites changing their concentrations based on the drug intake. FINGO influences aminoacidic and energy metabolisms and reduces oxidative stress and the activity of the immune system, both typical features of MS.

Steroid treatment response to post SARS-CoV-2 PANS symptoms: Case series.

Background: Pediatric acute-onset neuropsychiatric syndrome (PANS) is characterized by a wide spectrum of symptoms, including the onset of obsessive-compulsive disorder and/or severely restricted food intake, associated with emotional symptoms, behavioral symptoms, developmental regression, and somatic symptoms. Among the possible triggering agents, infectious agents have been extensively explored. More recently, sporadic case reports describe a possible association between PANS and SARS-CoV-2 infection but data on clinical presentation and treatment are still scarce. Methods: We describe a case series (10 children) with acute onset or relapse of PANS symptoms after SARS-CoV-2 infection. Standardized measures (CBCL, CPRS, C-GAS, CGI-S, Y-BOCS, PANSS, and YGTSS) were used to describe the clinical picture. The efficacy of a pulse treatment with steroids for three consecutive months was assessed. Results: Our data suggest that the clinical presentation of the COVID-19-triggered PANS is largely similar to that reported in typical PANS, including acute onset, with OCD and/or eating disorders, and associated symptoms. Our data suggest that treatment with corticosteroids may be beneficial for both global clinical severity and global functioning. No serious adverse effects were observed. Both OCD symptoms and tics consistently improved. Among psychiatric symptoms, affective and oppositional symptoms appeared more sensitive to the steroid treatment than the other symptoms. Conclusion: Our study confirms that COVID-19 infection in children and adolescents could trigger acute-onset neuropsychiatric symptoms. Thus, in children and adolescents with COVID-19, a specific neuropsychiatric follow-up should be routinely included. Even if a small sample size and a follow-up with only two points (baseline and endpoint, after 8 weeks) limit the conclusions, it seems that steroid treatment in the acute phase may be beneficial and well tolerated.

Neuropsychological and Behavioral Profile in Sleep-Related Hypermotor Epilepsy (SHE) and Disorders of Arousal (DOA): A Multimodal Analysis.

STUDY OBJECTIVES: Disorder of arousal (DOA) and sleep-related hypermotor epilepsy (SHE) are complex, often bizarre, involuntary sleep behaviors, whose differential diagnosis may be challenging because they share some clinical features, such as sleep fragmentation. Mounting evidence highlights the critical role of sleep in cognitive functions. Controversial findings are raised about the cognitive profile in SHE; however, no studies have investigated the cognitive profile in DOA. This study aimed to assess whether sleep instability affects cognitive functions in patients with SHE or DOA. METHODS: This study analyzed 11 patients with DOA, 11 patients with SHE, and 22 healthy controls (HC). They underwent full-night video polysomnography (vPSG) and comprehensive neuropsychological and behavioral evaluation. Differences in the variables of interest among the SHE group, DOA group, and their respective control groups were evaluated. The auto-contractive map (auto-CM) system was used to evaluate the strength of association across the collected data. RESULTS: The SHE group had reduced sleep efficiency and increased wake after sleep onset (WASO); both the SHE and DOA groups showed increased % of N2 and REM sleep compared to the HC group. Neuropsychological and behavioral evaluations showed a different cognitive profile in the SHE group with respect to the HC group. The auto-CM showed that Pittsburgh Sleep Quality Index (PSQI), Beck depression inventory (BDI), MWCST_PE, Epworth sleepiness scale (ESS), WASO, N1, and % REM were strictly correlated with SHE, whereas the SE and arousal index (AI) were strictly related to DOA. CONCLUSIONS: Patients with SHE and DOA present different cognitive and psychiatric profiles, with subtle and selective cognitive impairments only in those with SHE, supporting the discriminative power of cognitive and psychiatric assessment in these two conditions.

Clinical characteristics, neuroimaging findings, and neuropsychological functioning in attention-deficit hyperactivity disorder: Sex differences.

Recent clinical studies, in both children/adolescents and adults, have shown the extreme neuropsychological heterogeneity of attention-deficit hyperactivity disorder (ADHD): specific neuropsychological deficits have been found only in a minority of individuals, with no direct correlation between discrete cognitive performances and the trajectory of clinical symptoms. Deficits in specific neuropsychological functions may be common in ADHD, but nevertheless no cognitive or neuropsychological profile may fully explain the disorder. Sex differences in the ADHD presentation, both at a neuropsychological and clinical level, also contribute to this clinical and neuropsychological heterogeneity. At a neuropsychological level, females with ADHD may show greater working memory problems, poorer vocabulary skills and worse visual spatial reasoning. Structural and functional imaging study also show discrete differences across sex; however, the great majority of clinical studies mainly or exclusively include male participants with insufficient data to draw firm conclusions on sex differences within the disorder. Here, we report the recent literature data, discussing still open research questions about the clinical presentation, neuroimaging findings, and neuropsychological functioning in ADHD with a focus on the impact of sex differences-a deeper insight in these unresolved issues may have relevant clinical and therapeutic implications for tailored, effective, and long-lasting interventions.

1H-NMR-Based Metabolomics in Autism Spectrum Disorder and Pediatric Acute-Onset Neuropsychiatric Syndrome.

We recently described a unique plasma metabolite profile in subjects with pediatric acute-onset neuropsychiatric syndrome (PANS), suggesting pathogenic models involving specific patterns of neurotransmission, neuroinflammation, and oxidative stress. Here, we extend the analysis to a group of patients with autism spectrum disorder (ASD), as a consensus has recently emerged around its immune-mediated pathophysiology with a widespread involvement of brain networks. This observational case-control study enrolled patients referred for PANS and ASD from June 2019 to May 2020, as well as neurotypical age and gender-matched control subjects. Thirty-four PANS outpatients, fifteen ASD outpatients, and twenty-five neurotypical subjects underwent physical and neuropsychiatric evaluations, alongside serum metabolomic analysis with 1H-NMR. In supervised models, the metabolomic profile of ASD was significantly different from controls (p = 0.0001), with skewed concentrations of asparagine, aspartate, betaine, glycine, lactate, glucose, and pyruvate. Metabolomic separation was also observed between PANS and ASD subjects (p = 0.02), with differences in the concentrations of arginine, aspartate, betaine, choline, creatine phosphate, glycine, pyruvate, and tryptophan. We confirmed a unique serum metabolomic profile of PANS compared with both ASD and neurotypical subjects, distinguishing PANS as a pathophysiological entity per se. Tryptophan and glycine appear as neuroinflammatory fingerprints of PANS and ASD, respectively. In particular, a reduction in glycine would primarily affect NMDA-R excitatory tone, overall impairing downstream glutamatergic, dopaminergic, and GABAergic transmissions. Nonetheless, we found metabolomic similarities between PANS and ASD that suggest a putative role of N-methyl-D-aspartate receptor (NMDA-R) dysfunction in both disorders. Metabolomics-based approaches could contribute to the identification of novel ASD and PANS biomarkers.

Impact of Three Kinds of Early Interventions on Developmental Profile in Toddlers with Autism Spectrum Disorder.

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.

Omega-3/6 supplementation for mild to moderate inattentive ADHD: a randomised, double-blind, placebo-controlled efficacy study in Italian children.

Recently there has been a growing interest in non-pharmacological treatments for ADHD. We evaluated the efficacy of a specific Omega-3/6 dietary supplement (two capsules containing 279 mg eicosapentaenoic acid [EPA], 87 mg Docosahexaenoic Acid [DHA], 30 mg gamma linolenic acid [GLA] each) in ameliorating inattentive symptoms in inattentive-ADHD children (6-12 years) with a baseline ADHD-RS-Inattention score ≥ 12. Secondary objectives included changes in global functioning, severity of illness, depression, and anxiety symptoms, learning disorders and in the fatty acids blood levels. The study was a randomised, double-blind, placebo-controlled efficacy and safety trial with a 6-month double-blind evaluation of Omega-3/6 vs placebo (Phase-I) and a further 6-month-open-label treatment with Omega-3/6 on all patients (Phase-II). In total 160 subjects were enrolled. No superiority of Omega-3/6 supplement to placebo was observed on the primary outcome (ADHD-RS-inattention score) after the first 6-months, with 46.3% of responders in the Omega-3/6 group and 45.6% in the placebo group; a slight (not statistically significant) reduction in Omega-6/3 ratio blood levels was measured in the active treatment group. Twelve months after enrolment, percentages of responders were similar between groups. A mild statistical, although not clinically significant, improvement was observed on the ADHD-RS-total score in the Omega-3/6 group but not on the ADHD-RS-Inattention score; a slight (not-statistically significant) reduction in Omega-6/3 ratio was observed in the group taking active treatment only during Phase II. In conclusion, no clinical beneficial effects of Omega-3/6 were detected on inattentive symptoms, suggesting a limited role of Omega-3/6 dietary products in children with mild ADHD-I.Trial registration: At the time of the Ethical submission, according to the clinical trial Italian law, registration was not mandatory for food additive as Omega 3/6 were then classified. The trial was approved by the Ethical Committee of the Cagliari University Hospital (resolution n. 662; September 22nd, 2011).

Autistic Traits and Empathy in Children With Attention Deficit Hyperactivity Disorder, Autism Spectrum Disorder and Co-occurring Attention Deficit Hyperactivity Disorder/Autism Spectrum Disorder.

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.

The Impact of the COVID-19 Epidemic During the Lockdown on Children With the Pediatric Acute-Onset Neuropsychiatric Syndrome (PANDAS/PANS): The Importance of Environmental Factors on Clinical Conditions.

Introduction: In March 2020, SARS-CoV-2 declared a pandemic by the World Health Organization. Restrictive isolation measures have also brought psychological distress to the pediatric population. Building on the syndrome's characteristics, the present study explored the impact of lockdown on the clinical course of young people with PANDAS/PANS. The initial hypothesis considered both the reduced exposure to viral agents and the strategies of the parents and other containment actions as protective factors against the worsening of symptoms. Methods: One hundred and eight children, adolescents, and young adults were recruited according to the multicenter PANDAS/PANS research program. Parents participated in a web-based survey. Results: contrary to our hypothesis, the study results show an increase in symptoms during the block in 71% of the sample. Psychometric analyzes allowed us to exclude a relationship between the main symptoms of PANDAS and the increase in symptoms or the presence of symptoms before the block and their increase over time. The increase in symptoms is best explained by the presence of sleep disturbances and emotional lability. The exacerbation also appears to be linked to the onset of new symptoms in children and adolescents with depressed moods and eating problems. Furthermore, irritability and oppositionality are significant predictors of acute exacerbation. Equally statistically significant is the factor linked to the effects of pandemic stress, such as the fear of contracting the virus. No significant associations for symptom reduction have been identified between parental strategies or other parent-initiated actions, but the study demonstrates that caregiver perceived efficacy on the strategies used can reduce the risk of exacerbation. Conclusion: This preliminary study highlights the importance of studying the causes of increased symptoms in children with PANDAS/PANS. Life events can exacerbate the clinical condition or generate new symptoms in young patients. In particular, environmental, family, and social changes in the course of clinical symptoms in PANDAS/PANS patients should be investigated. It highlights the importance of emotional and behavioral management, which can be improved by enhancing coping strategies in young people with PANDAS/PANS and their caregivers through a combination treatment in which CBT and PMT are included, in line with guidelines. Limits: An experimental proxy-report questionnaire not yet standardized and validated on the PANS/PANDAS pediatric clinical sample was used for the exploratory study. There is also a small sample size (N = 108) and the absence of a control group (pre-lockdown or children without PANDAS/PANS). It would be interesting to evaluate the exact long-term dimensions to see the course of symptoms after covid and conduct a new study focusing on the impact of stressful events on the clinical course of the syndrome.

Artificial Neural Networks Analysis of polysomnographic and clinical features in Pediatric Acute-Onset Neuropsychiatric Syndrome (PANS): from sleep alteration to "Brain Fog".

STUDY OBJECTIVES: PANS (pediatric acute onset neuropsychiatric syndrome) is thought to be the result of several mechanisms and multiple etiologies, ranging from endocrine/metabolic causes to postinfectious autoimmune and neuroinflammatory disorders. Sleep disorders represent one of the most frequent manifestations of PANS, involving around 80% of patients. The present study describes the clinical and polysomnographic features in a group of PANS children identifying the relationships between sleep disorders and other PANS symptoms. METHODS: All participants underwent a clinical evaluation including comprehensive sleep history, polysomnography, cognitive assessment and blood chemistry examination. A data mining approach with fourth-generation artificial neural networks has been used in order to discover subtle trends and associations among variables. RESULTS: Polysomnography showed abnormality in 17 out of 23 recruited subjects (73.9%). In particular, 8/17 children (47%) had ineffective sleep, 10/17 (58.8%) fragmented sleep, 8/17 (47.1%) periodic limb movement disorder (PLMD) and 11/17 (64.7%) REM-sleep without atonia (RSWA). Most subjects presented more than one sleep disturbances. Notably, among the 19/23 patients diagnosed with Tic/Tourette disorder, 8/19 (42.1%) show PLMD and 10/19 (52.6%) RSWA. Artificial neural network methodology and the auto-contractive map exploited the links among the full spectrum of variables revealing the simultaneous connections among them, facing the complexity of PANS phenotype. CONCLUSION: Disordered sleep represents, for prevalence and impact on quality of life, a cardinal symptom in patients with PANS. Thus, considering the weight of sleep disturbances on diagnosis and prognosis of PANS, we could consider the possibility of including them among the major diagnostic criteria.

Metabolomic Characterization of Pediatric Acute-Onset Neuropsychiatric Syndrome (PANS).

INTRODUCTION: PANS is a controversial clinical entity, consisting of a complex constellation of psychiatric symptoms, adventitious changes, and expression of various serological alterations, likely sustained by an autoimmune/inflammatory disease. Detection of novel biomarkers of PANS is highly desirable for both diagnostic and therapeutic management of affected patients. Analysis of metabolites has proven useful in detecting biomarkers for other neuroimmune-psychiatric diseases. Here, we utilize the metabolomics approach to determine whether it is possible to define a specific metabolic pattern in patients affected by PANS compared to healthy subjects. DESIGN: This observational case-control study tested consecutive patients referred for PANS between June 2019 to May 2020. A PANS diagnosis was confirmed according to the PANS working criteria (National Institute of Mental Health [NIMH], 2010). Healthy age and sex-matched subjects were recruited as controls. METHODS: Thirty-four outpatients referred for PANS (mean age 9.5 years; SD 2.9, 71% male) and 25 neurotypical subjects matched for age and gender, were subjected to metabolite analysis. Serum samples were obtained from each participant and were analyzed using Nuclear Magnetic Resonance (NMR) spectroscopy. Subsequently, multivariate and univariate statistical analyses and Receiver Operator Curves (ROC) were performed. RESULTS: Separation of the samples, in line with the presence of PANS diagnosis, was observed by applying a supervised model (R2X = 0.44, R2Y = 0.54, Q2 = 0.44, p-value < 0.0001). The significantly altered variables were 2-Hydroxybutyrate, glycine, glutamine, histidine, tryptophan. Pathway analysis indicated that phenylalanine, tyrosine, and tryptophan metabolism, as well as glutamine and glutamate metabolism, exhibited the largest deviations from neurotypical controls. CONCLUSION: We found a unique plasma metabolic profile in PANS patients, significantly differing from that of healthy children, that suggests the involvement of specific patterns of neurotransmission (tryptophan, glycine, histamine/histidine) as well as a more general state of neuroinflammation and oxidative stress (glutamine, 2-Hydroxybutyrate, and tryptophan-kynurenine pathway) in the disorder. This metabolomics study offers new insights into biological mechanisms underpinning the disorder and supports research of other potential biomarkers implicated in PANS.

Use of Machine Learning to Investigate the Quantitative Checklist for Autism in Toddlers (Q-CHAT) towards Early Autism Screening.

In the past two decades, several screening instruments were developed to detect toddlers who may be autistic both in clinical and unselected samples. Among others, the Quantitative CHecklist for Autism in Toddlers (Q-CHAT) is a quantitative and normally distributed measure of autistic traits that demonstrates good psychometric properties in different settings and cultures. Recently, machine learning (ML) has been applied to behavioral science to improve the classification performance of autism screening and diagnostic tools, but mainly in children, adolescents, and adults. In this study, we used ML to investigate the accuracy and reliability of the Q-CHAT in discriminating young autistic children from those without. Five different ML algorithms (random forest (RF), naïve Bayes (NB), support vector machine (SVM), logistic regression (LR), and K-nearest neighbors (KNN)) were applied to investigate the complete set of Q-CHAT items. Our results showed that ML achieved an overall accuracy of 90%, and the SVM was the most effective, being able to classify autism with 95% accuracy. Furthermore, using the SVM-recursive feature elimination (RFE) approach, we selected a subset of 14 items ensuring 91% accuracy, while 83% accuracy was obtained from the 3 best discriminating items in common to ours and the previously reported Q-CHAT-10. This evidence confirms the high performance and cross-cultural validity of the Q-CHAT, and supports the application of ML to create shorter and faster versions of the instrument, maintaining high classification accuracy, to be used as a quick, easy, and high-performance tool in primary-care settings.