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Aim: To study different developmental profiles and auditory perception in a representative group of children with language impairment (LI).Methods: A multidisciplinary investigation was carried out in a group of 25 children attending units specifically for language-impaired children. An assessment of the cognitive level, motor performance, behaviour and auditory perception was performed and the results were compared with those for age-matched groups of children.Results: Among those with moderate or severe language impairment (LI), around 90% had additional developmental disorders. In three tests of auditory perception, children with LI had problems with working memory and speech discrimination. No problems were found with the children's temporal resolution in auditory perception. Another conclusion from the auditory perceptual tests was that the children's cognitive abilities were important for their success in these tests.Conclusion: Neurodevelopmental deviations are very common in LI children. The optimal route for the assessment and treatment of these children would be a multidisciplinary approach. [ABSTRACT FROM AUTHOR]

Abstract Background The catecholaminergic and serotonergic neurotransmitter systems are implicated in the pathophysiology of attention-deficit/hyperactivity disorder (ADHD). The amino acid tyrosine is the precursor for synthesis of the catecholamines dopamine and norepinephrine, while tryptophan is the precursor of serotonin. A disturbed transport of tyrosine, as well as other amino acids, has been found in a number of other psychiatric disorders, such as schizophrenia, bipolar disorder and autism, when using the fibroblast cell model. Hence, the aim of this study was to explore whether children with ADHD may have disturbed amino acid transport. Methods Fibroblast cells were cultured from skin biopsies obtained from 14 boys diagnosed with ADHD and from 13 matching boys without a diagnosis of a developmental disorder. Transport of the amino acids tyrosine, tryptophan and alanine across the cell membrane was measured by the cluster tray method. The kinetic parameters, maximal transport capacity (Vmax) and affinity constant (Km) were determined. Any difference between the two groups was analyzed by Student's unpaired t-test or the Mann Whitney U test. Results The ADHD group had significantly decreased Vmax (p = 0.039) and Km (increased affinity) (p = 0.010) of tryptophan transport in comparison to controls. They also had a significantly higher Vmaxof alanine transport (p = 0.031), but the Km of alanine transport did not differ significantly. There were no significant differences in any of the kinetic parameters regarding tyrosine transport in fibroblasts for the ADHD group. Conclusions Tryptophan uses the same transport systems in both fibroblasts and at the blood brain barrier (BBB). Hence, a decreased transport capacity of tryptophan implies that less tryptophan is being transported across the BBB in the ADHD group. This could lead to deficient serotonin access in the brain that might cause disturbances in both the serotonergic and the catecholaminergic neurotransmitter systems, since these systems are highly interconnected. The physiological importance of an elevated transport capacity of alanine to the brain is not known to date.

Abstract Background Limited data from positron emission tomography (PET) studies of subjects with attention-deficit/hyperactivity disorder (ADHD) indicate alterations in brain dopamine neurotransmission. However, these studies have used conventional univariate approaches that are less sensitive to detect complex interactions that may exist between different brain dopamine pathways and individual symptoms of ADHD. We aimed to investigate these potential interactions in adolescents with ADHD. Methods We used a 3D PET scan to measure utilization of native L-[11C]-DOPA to map dopamine presynaptic function in various cortical, striatal and midbrain regions in a group of 8 male adolescents with ADHD and 6 age matched controls. To evaluate the interactions between the studied brain regions, multivariate statistical methods were used. Results Abnormal dopaminergic function was found in multiple brain regions of patients with ADHD. A main finding was lower L-[11C]-DOPA utilization in adolescent with ADHD as compared to control subjects, especially in subcortical regions. This pattern of dopaminergic activity was correlated specifically with symptoms of inattention. Conclusion Dopamine signalling in the brain plays an important modulatory role in a variety of motor and cognitive functions. We have identified region-specific functional abnormalities in dopaminergic function, which may help better account for the symptoms of ADHD.

Aim: To study academic, social and psychiatric outcomes among adults in the general population in southwestern Sweden. Groups of individuals born in 1998 and ineligible, eligible but not completed, and eligible and completed upper secondary school were followed in 2020., Methods: Data were retrieved from Statistics Sweden, the Swedish National Agency for Education, the Longitudinal Integrated Database for Health Insurance and Labour Market Studies, the Swedish National Crime Register and the National Patient Register. The four adverse outcomes neither engaging in post-secondary studies nor having a regular salary, needing social benefits, having any criminal conviction, and having a psychiatric disorder at age ≥16 were examined., Results: Of the final sample of 2706 individuals who had attended 9th grade of compulsory school in 2014, 273 (10%) were ineligible for upper secondary school. Of eligible individuals, 82 (3%) never started, 282 (10%) did not complete and 2065 (77%) completed upper secondary school. Compared with completers, the odds ratios for adverse outcomes were markedly increased for all other groups up to 22 years old., Conclusion: Inability to start or complete upper secondary school strongly predicted unemployment and psychosocial and psychiatric adversities. School authorities should consider offering vocational programmes post compulsory school without grade restrictions., (© 2024 The Authors. Acta Paediatrica published by John Wiley & Sons Ltd on behalf of Foundation Acta Paediatrica.)

Aim: To assess the validity of the Early Symptomatic Syndromes Eliciting Neurodevelopmental Clinical Examinations-Questionnaire (ESSENCE-Q), a simple screening tool for neurodevelopmental problems, in Japan., Method: Parents/caregivers completed the 11-item ESSENCE-Q for 77 612 children aged 2 years 6 months included in a national birth cohort study. Information about neurodevelopmental disorders (NDDs: autism spectrum disorder; intellectual disability and/or developmental language disorder; motor delay/motor disorder) was collected at age 3 years. Each ESSENCE-Q item was scored on a binary (0,1) scale, with a total score range of 0 to 11. Total scores and individual items were compared across children with and without NDDs., Results: NDDs were recorded in 854 children (1.1%). With a total ESSENCE-Q score cut-off of ≥3, receiver operating characteristic curve analysis showed an area under the curve of 0.91, with sensitivity 84.9%, specificity 84.8%, positive predictive value 5.9%, and negative predictive value 99.8%. The proportion of parental concerns at 2 years 6 months differed significantly by NDD status for communication (89.5% vs 14.2%) and general development (80.2% vs 7.4%). ESSENCE-Q total scores were moderately negatively correlated (-0.36, p < 0.001) with Japanese Ages and Stages Questionnaire scores., Interpretation: The parent/caregiver-completed ESSENCE-Q is useful as a tool for screening out children with neurotypical development at this early age. Further research into longer-term predictive validity will be possible as more NDD diagnoses are given as the children grow up., (© 2024 The Author(s). Developmental Medicine & Child Neurology published by John Wiley & Sons Ltd on behalf of Mac Keith Press.)

Aim: While associations between vitamin D deficiency and neurodevelopmental disorders have been found, large studies on child vitamin D, neurodevelopment, and sex differences among the general population are lacking. This study aimed to investigate the association between child serum 25-hydroxyvitamin D (25(OH)D)) levels and neurodevelopmental problems (NDPs)., Methods: Serum 25(OH)D and NDPs were measured at age two among the subcohort study of the Japan Environment and Children's Study. NDPs were assessed with the Kyoto Scale of Psychological Development 2001 (Kyoto scale). Adjusted odds ratios (aORs) for the Kyoto-scale developmental quotient scores <70 were calculated, for postural-motor, cognitive-adaptive, and language-social domains and overall scores, adjusted for test month, latitude, small for gestational age, maternal age, and daycare attendance., Results: Among 2363 boys and 2290 girls, boys had higher 25(OH)D levels, but scored lower in the Kyoto scale. For boys in the vitamin D deficiency (<20 ng/mL) group, aORs of scoring the Kyoto-scale DQs <70 were 2.33 (p = 0.006) for overall DQs, 1.91 (p = 0.037) for cognitive-adaptive, and 1.69 (p = 0.024) for language-social domains. For girls, results were inconclusive., Conclusion: Only boys showed a clear and cross-modal association between vitamin D deficiency and NDPs., (© 2023 The Authors. Acta Paediatrica published by John Wiley & Sons Ltd on behalf of Foundation Acta Paediatrica.)

The 22q11.2 deletion syndrome (22q11.2DS), affects physical as well as cognitive and emotional functioning with increased risk for psychiatric and behavioral problems. This longitudinal study of 79 individuals (18-50 years) with 22q11.2DS investigated neurodevelopmental (NDD) and psychiatric disorders in adulthood, evaluated the stability of childhood diagnoses over time, and examined associations between clinical characteristics in childhood/adolescence and diagnostic outcome in adult age. Examination using validated instruments for cognitive, psychiatric, and global functional problems in the context of an in-depth clinical evaluation found adult age stability of NDD diagnoses made in childhood, however, rates increased at follow-up. Rates of anxiety, mood, and psychotic disorders were high, with a majority meeting diagnostic criteria for one or more psychiatric disorder. The rate of psychotic disorders was much lower compared to many other studies. Variability in functioning at follow-up was primarily associated with intellectual ability at T1. The findings obtained highlight the increased risk of NDD and psychiatric problems and of cognitive impairment and reduced levels of global functioning over time. Results emphasize the importance of clinical follow-up to enable appropriate support for the promotion of optimal health along with a need for future research on effective interventions and treatment strategies., (© 2023 The Authors. American Journal of Medical Genetics Part C: Seminars in Medical Genetics published by Wiley Periodicals LLC.)

Neuropsychiatric and neurodevelopmental disorders are often associated with coordination problems. Pediatric Acute-onset Neuropsychiatric Syndrome (PANS) constitutes a specific example of acute and complex symptomatology that includes difficulties with motor control. The present proof-of-concept study aimed at testing a new, bespoke tablet-based motor coordination test named SpaceSwipe, providing fine-grained measures that could be used to follow-up on symptoms evolution in PANS. This test enables computationally precise and objective metrics of motor coordination, taking into account both directional and spatial features continuously. We used SpaceSwipe to assess motor coordination in a group of children with PANS (n = 12, assessed on in total of 40 occasions) and compared it against the motor coordination subtest from the Beery-Buktenica Developmental Test of Visual-Motor Integration (Beery VMI) 6th edition, traditionally used to follow-up symptomatology. Using a bivariate linear regression, we found that 33 s of the directional offset from tracking a moving target in SpaceSwipe could predict the Beery VMI motor coordination (VMI MC) raw scores (mean absolute error: 1.75 points). Positive correlations between the predicted scores and the VMI MC scores were found for initial testing (r adj  = 0.87) and for repeated testing (r adj  = 0.79). With its short administration time and its close prediction to Beery VMI scores, this proof-of-concept study demonstrates the potential for SpaceSwipe as a patient-friendly tool for precise, objective assessment of motor coordination in children with neurodevelopmental or neuropsychiatric disorders., (© 2023. The Author(s).)

This brief article gives a short overview of "comorbidity" in autism. The most common co-occurring disorders will be presented and discussed within the context of ESSENCE (Early Symptomatic Syndromes Eliciting Neurodevelopmental Clinical Examinations), a concept that provides a holistic perspective for neurodevelopmental disorders. The ESSENCE concept also considers the heterogeneous and changing clinical panorama of developmental disorders over time, and also the multifactorial etiologies, including so called behavioral phenotype syndromes. Aspects on behavioral interventions in autism are presented-interventions that need to be adapted and take into account all non-autism associated ESSENCE, including intellectual disability and Attention-Deficit/Hyperactivity Disorder (ADHD). The article also focuses on current research on pharmacological intervention based on the hypothesis of imbalance in excitatory/inhibitory transmitter systems in autism and some other ESSENCE., 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 © 2023 Fernell and Gillberg.)

Neurodevelopmental disorders (NDDs) in children are associated with a complex combination of genetic and/or environmental factors. Pre-/perinatal events are major known environmental suboptimal factors, and their individual and combined contributions vary. This study investigated the association between pre-/perinatal reduced optimality and child development observed by parents at 1 month, as well as NDDs at 3 years of age (i.e., motor delay, intellectual disability, developmental language disorder, and autism spectrum disorder), in the context of the Japan Environment and Children's Study. The study also assessed whether child development at 1 month predicted NDDs at 3 years of age. Associations between 25 pre-/perinatal factors and (a) developmental concerns at 1 month of age and (b) NDDs at 3 years were analyzed (n = 71,682). Binomial regression models were used to investigate risk ratios of the developmental outcome at each time point for total pre-/perinatal reduced optimality scale scores, as well as for individual pre-/perinatal factors of the reduced optimality scale. Finally, we assessed the ability of parental observations of offspring development at 1 month to predict NDDs at 3 years. Total reduced optimality scores were positively associated with 1-month developmental concerns and 3-year NDDs, with higher scores (i.e., a reduction in optimality) associated with an increased risk of both NDDs and earlier parental concerns. Neonatal transportation, epidural analgesia, advanced maternal age, cesarean section delivery, Apgar score ≤8, and hyperbilirubinemia were identified as individual risk factors for 3-year NDDs, overlapping with 14 risk factors for 1-month developmental concerns except Apgar score ≤8. Among six developmental items assessed at 1 month of age, concerns about gross motor function and difficulty holding/trouble calming down had the strongest associations with later-diagnosed motor delay and autism spectrum disorder, respectively. Five perinatal factors and advanced maternal age were associated with NDD at 3 years of age, as were early parental developmental concerns regarding their offspring's overall development, indicating the importance of careful follow-up of offspring born with pre-/perinatal reduced optimality. The results also implicated early parental concerns, as early as 1 month, may also be a useful indicator of later NDD status., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Yasumitsu-Lovell et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The need for effective intervention programs for youth with neurodevelopmental problems (ESSENCE) and challenging behaviour is great. This study examines Problem Resolution in ESSENCE (PR-ESSENCE), a newly developed model in which children and parents develop mutual problem resolution strategies. Ten-week randomized controlled trial of PR-ESSENCE for children and adolescents aged 5-18 years, compared to treatment as usual. Outcomes were assessed at baseline and randomized period endpoint. Primary outcome was the Clinical Global Impression-Improvement scale (CGI-I) rated by blinded assessors. Secondary outcomes were rated by parents-SNAP-IV, Eyberg Child Behavior Inventory (ECBI), Relationship Problems Questionnaire, Family Burden of Illness Module, and children-Beck Youth Inventories (BYI). ClinicalTrials.gov identifier: NCT03780413. The study enrolled 108 participants (active n = 72; controls n = 36, randomized 2:1), of whom 95 completed the randomized period. No clinically significant group differences were found in baseline characteristics. More than half had autism and 80% had ADD or ADHD. Large treatment effects were seen on CGI-I (ITT analysis, Effect Size 1.48). Treatment responders, much/very much improved on CGI-I, were 51.4% in active group and 5.6% of controls. Effect sizes were medium to large in parent ratings on SNAP-IV (ODD and ADHD symptoms), ECBI (behaviour problems), and in BYI child self-ratings of disruptive behaviour. PR-ESSENCE treatment improved global symptoms and functioning (CGI-I), behaviour problems, ADHD and ODD symptoms, and disruptive behaviour. Treatment effects were at least equivalent to those in previous studies of well-established Parent Management Training and Collaborative Problem Solving programs., (© 2021. The Author(s).)

Pediatric acute-onset neuropsychiatric syndrome (PANS) is an abrupt-onset neuropsychiatric disorder. PANS patients have an increased prevalence of comorbid autoimmune illness, most commonly arthritis. In addition, an estimated one-third of PANS patients present with low serum C4 protein, suggesting decreased production or increased consumption of C4 protein. To test the possibility that copy number (CN) variation contributes to risk of PANS illness, we compared mean total C4A and total C4B CN in ethnically matched subjects from PANS DNA samples and controls (192 cases and 182 controls). Longitudinal data from the Stanford PANS cohort (n = 121) were used to assess whether the time to juvenile idiopathic arthritis (JIA) or autoimmune disease (AI) onset was a function of total C4A or C4B CN. Lastly, we performed several hypothesis-generating analyses to explore the correlation between individual C4 gene variants, sex, specific genotypes, and age of PANS onset. Although the mean total C4A or C4B CN did not differ in PANS compared to controls, PANS patients with low C4B CN were at increased risk for subsequent JIA diagnosis (hazard ratio = 2.7, p value = 0.004). We also observed a possible increase in risk for AI in PANS patients and a possible correlation between lower C4B and PANS age of onset. An association between rheumatoid arthritis and low C4B CN has been reported previously. However, patients with PANS develop different types of JIA: enthesitis-related arthritis, spondyloarthritis, and psoriatic arthritis. This suggests that C4B plays a role that spans these arthritis types., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

In their latest survey from 2017/18, the Public Health Agency in Sweden reported an increase in multiple mental health complaints among children and adolescents. The study is part of a collaborative WHO project that started in 1985/86 and collects data every four years. With this background, a working group was commissioned by the Swedish Medical Association to identify areas for improvement within the school system and to work out proposals for effective interventions. In this report, we summarize research data on evidence-based knowledge within five areas. How to promote daily physical activity at school to enhance wellbeing and cognitive abilities; how to balance time on the internet; what is known about school-based intervention programs to promote mental health; the need to adapt knowledge requirements in the national curriculum to children's development and cognitive abilities, and to describe specific risk groups for impaired mental health. Finally, we describe competence-enhancing initiatives and emphasize the need for collaboration between school health, child and adolescent mental health services, pediatrics and the social services.

Aim: Some school age children with autism spectrum disorder (ASD) struggle with literacy development, yet, the individual differences are major and not well understood. Moreover, literacy attainment is multi-faceted and literacy skills and difficulties manifest in more than one way. The aim of this study was to describe this variability and to identify language/cognitive predictors of different literacy skills., Methods: We assessed different literacy skills (word reading accuracy, reading fluency, reading comprehension, and spelling), along with a set of language/cognitive predictor skills (listening comprehension, rapid automatized naming, phonological awareness and nonverbal cognitive ability), in 12-year-old children with ASD without intellectual disability recruited from a longitudinal study in Sweden., Results: There was great heterogeneity (from floor to ceiling levels) in literacy skills, with a statistically increased prevalence of poor reading comprehension and reading fluency compared with population norms. In regression analyses, it was shown that concurrent language/cognitive predictor skills (e.g. phonological awareness) were differentially associated with literacy subskills. Moreover, a longitudinal analysis showed that preschool language problems were associated with poor word reading accuracy and spelling in middle school., Conclusions: The results confirm previous findings as well as provide new knowledge regarding profiles of literacy (difficulties) in children with ASD; interestingly, the identified predictors of literacy skills in ASD resembled those identified as important in general reading (and dyslexia) research, which might indicate that similar kinds of support and training would be beneficial.

Background: Treatment with intravenous immunoglobulin (IVIG) in children with Paediatric Acute-onset Neuropsychiatric Syndrome (PANS) has for many years been used on clinical indications, but the research evidence for its efficacy is insufficient., Methods: Open-label prospective in-depth trial including ten children (median age 10.3 years) with PANS, who received IVIG treatment 2 g/kg monthly for three months. Primary outcomes were changes in symptom severity and impairment from baseline to first and second follow-up visits one month after first and one month after third treatment, using three investigator-rated scales: Paediatric Acute Neuropsychiatric Symptom (PANS) scale, Clinical Global Impression - Severity and Improvement (CGI-S and CGI-I) scales. Secondary outcomes reported here were changes in Children's Yale-Brown Obsessive Compulsive Scale (CY-BOCS) scores, and side effects., Results: All ten children received three treatments at one-month intervals according to study plan. From baseline to second follow-up marked reductions were seen in mean total PANS scale scores (p = .005), and CGI-S scores (p = .004). CGI-I ratings showed much to very much global improvement (mean CGI-I 1.8). Nine children had clinical response defined as > 30% reduction in PANS Scale scores. Improvements were also noted for CY-BOCS scores (p = .005), and in school attendance. Three children suffered moderate to severe temporary side effects after the first treatment, and the remaining seven had mild to moderate side effects. Side effects were much less severe after second and third treatments., Conclusions: Considerable and pervasive improvements in symptoms and clinical impairments were seen in these ten children after three monthly IVIG treatments. Moderate to severe transient side effects occurred in three cases., Trial Registration: EudraCT no. 2019-004758-27, Clinicaltrials.gov no. NCT04609761, 05/10/2020., (© 2022. The Author(s).)

The recent development of assays that accurately quantify neurofilament light, a neuronal cytoskeleton protein, in plasma has generated a vast literature supporting that it is a sensitive, dynamic, and robust biomarker of neuroaxonal damage. As a result, efforts are now made to introduce plasma neurofilament light into clinical routine practice, making it an easily accessible complement to its cerebrospinal fluid counterpart. An increasing literature supports the use of plasma neurofilament light in differentiating neurodegenerative diseases from their non-neurodegenerative mimics and suggests it is a valuable biomarker for the evaluation of the effect of putative disease-modifying treatments (e.g. in multiple sclerosis). More contexts of use will likely emerge over the coming years. However, to assist clinical interpretation of laboratory test values, it is crucial to establish normal reference intervals. In this study, we sought to derive reliable cut-offs by pooling quantified plasma neurofilament light in neurologically healthy participants (5-90 years) from eight cohorts. A strong relationship between age and plasma neurofilament light prompted us to define the following age-partitioned reference limits (upper 95 th percentile in each age category): 5-17 years = 7 pg/mL; 18-50 years = 10 pg/mL; 51-60 years = 15 pg/mL; 61-70 years = 20 pg/mL; 70 + years = 35 pg/mL. The established reference limits across the lifespan will aid the introduction of plasma neurofilament light into clinical routine, and thereby contribute to diagnostics and disease-monitoring in neurological practice., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Aim: Paediatric acute-onset neuropsychiatric syndrome (PANS) is defined by an acute onset of obsessive-compulsive disorder and/or eating restrictions and at least two other severe neuropsychiatric symptoms. The condition is suspected to have an immune-mediated pathophysiology, but reliable biomarkers have not been identified., Methods: We hypothesised that PANS, like narcolepsy, might have a human leucocyte antigen (HLA) association, as found in 95% of children developing narcolepsy after H1N1 immunisation. Low resolution genotyping of the MHC class II antigens HLA-DRB1 and HLA-DQB1 was performed using two different PCR-based methods. In addition, parents were interviewed regarding a detailed family history of autoimmune diseases in first-degree relatives. A total of 18 children, aged 5-14 (mean 8.2) years at onset of PANS met symptom criteria., Results: No evident association between PANS and the specific HLA alleles examined was observed. In first-degree relatives of 10 of the 18 children, an autoimmune disease had been diagnosed, and three of the 18 children themselves had an autoimmune disease., Conclusion: No HLA allele association such as seen in children with narcolepsy after H1N1 immunisation could be confirmed in this group of children with PANS. However, more than half the group had a first-degree relative with a diagnosed autoimmune disease., (©2021 The Authors. Acta Paediatrica published by John Wiley & Sons Ltd on behalf of Foundation Acta Paediatrica.)

Objective: Investigate predictors of adverse outcome in children with and without attention-deficit/hyperactivity disorder (ADHD) combined with developmental coordination disorder (DCD) at 6 years of age., Design: Prospective population-based cohort study., Setting: Western Sweden., Participants: From a screening-based population cohort of 589 individuals, 62 (11 female) diagnosed with ADHD+DCD at mean age 6.6 years, and a comparison group of 51 population-matched (10 female) children were followed prospectively., Outcome Measures: Drawn from a clinical reassessment at age 9 years of 110 of the 113 individuals, neuropsychiatric symptoms, continuous performance test results and measures of motor function were used as predictors of outcome in linear regression models. Participants were followed in national registers up to 30-31 years of age for outcomes in adulthood. Predictors were regressed onto an adverse outcome score (range 0-7) comprising seven binary endpoints, and when applicable onto each continuous outcome separately (low educational attainment, low occupation level, psychiatric disorder, psychotropic medication prescription, sick pension, high dependence on social benefits and criminal conviction)., Results: Of the 110 individuals, 3 had died. In univariable regression onto the adverse outcome score, the strongest predictors at age 9 years were symptoms of conduct disorder, oppositional defiant disorder, ADHD and motor dysfunction, with an R 2 around 25%, followed by autistic traits (R 2 =15%) and depressive symptoms (R 2 =8%). Combining these six strongest predictors in a multivariable model yielded an adjusted R 2 =38%. Subgroup analyses were similar, except for a strong association of autistic traits with the adverse outcome score in females (n=20, R 2 =50%)., Conclusion: Several neurodevelopmental symptoms, including ADHD severity at age 9 years, accounted for a considerable amount of the variance in terms of adulthood adverse outcome. Broad neurodevelopmental profiling irrespective of diagnostic thresholds should inform research and clinical practice. The study highlights the importance of considering associated comorbidities and problems in ADHD., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Aim: To estimate the accumulated prevalence of neurodevelopmental problems from preschool to school age in children with a history of febrile seizures (FS)., Methods: In a community-based cohort of children with previous FS, 25/73 clinically assessed children met diagnostic criteria for neurodevelopmental disorders or had major indications of such problems at the age of 4-5 years. Parents of 54 of the 73 children accepted to take part in an interview according to the Autism-Tics, ADHD and other Comorbidities (A-TAC) inventory, when the children were 9-10 years., Results: There was a trend for ADHD symptom scores to be higher in the FS group. Non-participants at age 9-10 years had had much higher rates of neurodevelopmental problems at 4-5 years, and the total number of such problems at either 4-5 or age 9-10 was 41% (30/73)., Conclusion: High rates of neurodevelopmental problems (41%) were found at either age 4-5 or 9-10 years or both in this group of 73 children with FS. Non-participants at 9-10 years had had much higher rates of neurodevelopmental problems at 4-5 years. Further follow-up of this cohort is needed before definite conclusions can be drawn about whether FS should be considered a marker for more complex neurodevelopmental problems., (© 2021 The Authors. Acta Paediatrica published by John Wiley & Sons Ltd on behalf of Foundation Acta Paediatrica.)

Objective: Paediatric Acute-onset Neuropsychiatric Syndrome (PANS) is characterised by an acute onset of obsessive compulsive disorder, combined with at least two other neuropsychiatric symptoms with acute onset. Diagnostic criteria also require that no specific medical aetiology is identified. Although there are no verified aetiological biomarkers, PANS is assumed to be a neuroinflammatory disorder with a possible autoimmune aetiology. Neurochemical markers such as neurofilament light (NfL, a neuronal injury marker) and glial fibrillary acidic protein (GFAP, an astrocytic activation marker) have not been published for this patient group. Method: Blood samples from 17 children meeting diagnostic criteria for PANS, after assessment at a child neuropsychiatry clinic were analysed for serum concentrations of NfL and GFAP. Ten age-matched children without any neurological or psychiatric disorder served as a comparison group. Results: No difference was found in mean NfL and mean GFAP serum concentrations between children with PANS and controls. Conclusion: Neuronal injury and astrocyte activation do not seem to be a major event in PANS. The study group was small, and even if findings may be reassuring for parents and patients, they should be interpreted with caution and verified in larger cohorts and possibly with other markers in both serum and CSF.

Objective: To assess effects of treatment against a hypothesized neuroinflammation in children with symptoms corresponding to the research condition Pediatric Acute-onset Neuropsychiatric Syndrome (PANS) which is not included in current diagnostic systems., Methods: Systematic literature searches were performed (1998 to June 2020) in PubMed, Embase, the Cochrane Library, CINAHL, PsycInfo, and HTA databases. Inclusion criteria: patients (P) were children (<18 years) with PANS; intervention (I)/comparison (C) was use of, versus no use of, anti-inflammatory, antibacterial or immunomodulating treatments; outcomes (O) were health-related quality of life (HRQL), level of functioning, symptom change, and complications., Results: Four randomised controlled trials (RCTs) and three non-RCTs, including 23 to 98 patients, fulfilled the PICO. HRQL was not investigated in any study. Regarding level of functioning, two RCTs investigated antibiotics (penicillin V, azithromycin) and one RCT investigated immunomodulating treatments (intravenous immunoglobulins (IVIG), plasma exchange). Regarding symptoms, two non-RCTs investigated anti-inflammatory treatment (cyclooxygenase (COX) inhibitors, corticosteroids), two RCTs and one non-RCT investigated antibiotics (penicillin V, azithromycin), and two RCTs investigated immunomodulating treatments (IVIG, plasma exchange). Complications, reported in five studies, were consistent with those listed in the summary of products characteristics (SPC). All studies were assessed to have some or major problems regarding directness, the absence of an established diagnosis contributing to clinical diversity in the studied populations. All studies were assessed to have major risk of bias, including selection and detection biases. Due to clinical and methodological diversity, meta-analyses were not performed., Conclusion: This systematic review reveals very low certainty of evidence of beneficial effects, and moderate certainty of evidence of adverse effects, of anti-inflammatory, antibacterial or immunomodulating treatments in patients with symptoms corresponding to the research condition PANS. Available evidence neither supports nor excludes potential beneficial effects, but supports that such treatment can result in adverse effects., Registration: PROSPERO (CRD42020155714)., Competing Interests: M.J. and E.F. work at the Child Neuropsychiatry Centre and the Gillberg Neuropsychiatry Centre, to which referrals of patients occur, for assessments and treatment, when the research condition PANS/PANDAS is suspected. M. J. has received research grants from Shire and has been engaged as a speaker or consultant by Eli Lilly, Shire, Ginsana, PCM Scientific, Evolan, and New Nordic, all unrelated to the present work. S.E., P.H., C.W., and S.M.W. declare no competing interests. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

The association between birth month and neurodevelopmental or psychiatric disorders has been investigated in a number of previous studies; however, the results have been inconsistent. This study investigated the association between birth month and child gross motor development at 6 and 12 months of age in a large cohort of infants (n = 72,203) participating in the Japan Environment and Children's Study (JECS). Gross motor development was assessed using the Ages and Stages Questionnaire (ASQ-3). At 6 months and 12 months, 20.7% and 14.2%, respectively, had ASQ-3 indications of gross motor problems. Birth month was strongly associated with gross motor development at both time points, particularly at 6 months. Summer-born infants had the worst outcomes at both 6 months and 12 months of age. This outcome applied to the ASQ-3 score itself and to the adjusted Relative Risk (aRR), with the highest aRRs (relative to January-born) among August-born (aRR 2.51; 95%CI 2.27-2.78 at 6 months), and June-born (aRR 1.84; 95%CI 1.63-2.09 at 12 months). Boys had better scores than girls both at 6 and 12 months of age. We speculate that seasonal factors-such as maternal vitamin D deficiency and influenza infection-affecting the fetus in early pregnancy might account for the findings., Competing Interests: The authors have declared that no competing interests exist.