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Rajna Knez,1– 3 Dejan Stevanovic,1 Elisabeth Fernell,1 Christopher Gillberg1 1Gillberg Neuropsychiatry Centre, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; 2Department of Pediatrics, Skaraborg Hospital, Skövde, Sweden; 3School of Health Sciences, University of Skövde, Skövde, SwedenCorrespondence: Rajna Knez, Gillberg Neuropsychiatry Centre, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Kungsgatan 12, vån 2, Göteborg, 41119, Sweden, Email rajna.knez@gu.seAbstract: Early Symptomatic Syndromes Eliciting Neurodevelopmental Clinical Examinations (ESSENCE) is an umbrella term covering a wide range of neurodevelopmental difficulties and disorders. Thus, ESSENCE includes attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and other neurodevelopmental disorders (NDDs) and difficulties, with a variety of symptoms in cognitive, motor, sensory, social, arousal, regulatory, emotional, and behavioral developmental domains, frequently co-occurring and likely having partly common neurobiological substrates. The ESSENCE concept is a clinical paradigm that promotes organizing NDDs in everyday clinical practice according to their coexistence, symptom dimensions overlapping, and treatment possibilities. Despite increased knowledge regarding NDDs, the neurobiological mechanisms that underlie them and other ESSENCE-related problems, are not well understood. With its wide range of neural circuits and interactions with numerous neurotransmitters, the orexin/hypocretin system (Orx-S) is possibly associated with a variety of neurocognitive, psychobiological, neuroendocrine, and physiological functions and behaviors. Dysfunction of Orx-S has been implicated in various psychiatric and neurological disorders. This article provides an overview of Orx-S dysfunctions’ possible involvement in the development, presentation, and maintenance of ESSENCE. We provide a focused review of current research evidence linking orexin neuropeptides with specific clinical NDDs symptoms, mostly in ADHD and ASD, within the Research Domain Criteria (RDoC) framework. We propose that Orx-S dysfunction might have an important role in some of these neurodevelopmental symptom domains, such as arousal, wakefulness, sleep, motor and sensory processing, mood and emotional regulation, fear processing, reward, feeding, attention, executive functions, and sociability. Our perspective is presented from a clinical point of view. Further, more thorough systematic reviews are needed as well as planning of extensive new research into the Orx-S’s role in ESSENCE, especially considering RDoC elements.Keywords: attention-deficit/hyperactivity disorder, autism spectrum disorder, developmental coordination disorder, neurodevelopmental disorders, research domain criteria, orexin, hypocretin

Valdemar Landgren,1,2 Zohar Raanan Soltis,1 Emma Svensson,3 Michail Theodosiou,2,4 Magnus Landgren,2 Rajna Knez2,5 1Department of Psychiatry, Skaraborg Hospital, Skövde, Sweden; 2Gillberg Neuropsychiatry Centre, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; 3Department of Child Psychiatry, Skaraborg Hospital, Skövde, Sweden; 4School Health Services, City of Gothenburg, Gothenburg, Sweden; 5Department of Pediatrics, Skaraborg Hospital, Skövde, SwedenCorrespondence: Valdemar Landgren, Department of Psychiatry, Skaraborg Hospital Skövde, Lövängsvägen, Skövde, 541 45, Sweden, Tel +46702960450, Email valdemar.landgren@gu.sePurpose: Determine the prevalence of symptoms of neurodevelopmental problems (NDPs) with a semi-structured review of fourth grade students’ medical records, its interrater agreement and validity as compared with clinical assessment.Methods: A school-based sample of 11-year-old children provided child health care (CHC) records and school health care (SHC) records. A pediatric neurologist, child psychiatrist and an adult psychiatrist scored the records, with the “Early Symptomatic Syndromes Eliciting Neurodevelopmental Clinical Examinations-Questionnaire” (ESSENCE-Q, 12 items scored 0– 2, summary score range 0– 24). Agreement was measured with model-based kappa and intraclass correlation coefficient (ICC). Ratings were validated against a multidisciplinary assessment involving a physician, psychologist, teacher- and parental behavioral rating scales rendering a clinical global impression severity rating (CGI-S, range 1– 7) of NDPs.Results: Out of 223 participants, medical charts were available from 201, of whom 169 were rated by all three raters. Kappa agreement was moderate/strong (~0.8) for 7 of the 12 questionnaire items. Measured with the ICC, concordance in the summary score was good for agreement (~0.8) and excellent (~0.9) for consistency. Test–retest reliability was excellent (ICC = ~0.9). Area under the curve for the ESSENCE-Q in predicting clinical-level problems (CGI ≥ 4) was ~80% for all three raters, albeit with differing optimal cutoffs.Conclusion: Using the ESSENCE-Q as a template, NDPs appear to be common in medical records, are identified reliably, and predict clinical-level concern. Medical records screening may facilitate a structured review of medical records in work-ups or be applied in conjunction with other screening measures for neurodevelopmental disorders. However, differences in calibration currently preclude defining a universal cutoff for using the ESSENCE-Q for medical records screening.Keywords: neurodevelopmental disorders, medical records, abnormal development, child health, ESSENCE

Valdemar Landgren,1,2 Leif Svensson,3 Rajna Knez,1,3 Michail Theodosiou,1 Christopher Gillberg,1 Elisabeth Fernell,1 Magnus Landgren,1 Mats Johnson1 1Gillberg Neuropsychiatry Centre, Sahlgrenska Academy, Gothenburg University, Gothenburg, Sweden; 2Department of Psychiatry, Skaraborg Hospital, Skövde, Region Västra Götaland, Sweden; 3Department of Pediatrics, Skaraborg Hospital, Mariestad, Region Västra Götaland, SwedenCorrespondence: Valdemar Landgren, Department of Psychiatry, Skaraborg Hospital, Lövängsvägen, Skövde, Region Västra Götaland, 541 42, Sweden, Tel +46702960450, Email valdemar.landgren@gu.sePurpose: To determine the prevalence of parent-rated developmental concern using the ESSENCE-Q (Early Symptomatic Syndromes Eliciting Neurodevelopmental Clinical Examinations-Questionnaire, 12-items, score range 0– 24) and to ascertain the predictive validity and optimal cutoff level of the instrument in a school-based sample of 11-year-old children.Methods: In a cross-sectional, school-based study, participants underwent a clinical assessment by a physician and a psychologist, teachers and parents completed the SDQ (Strength and Difficulties Questionnaire), medical health records and national tests were reviewed, and parents independently completed the ESSENCE-Q. In a case-conference outcomes were defined as a) the need for further clinical work-up due to suspected neurodevelopmental problems (NDPs) and b) degree of investigator-rated symptoms/impairment from NDPs on the CGI-S (Clinical Global Impression-Severity instrument, range 1– 7, 4– 7 defined as clinically symptomatic). Classification and optimal cutoffs of the ESSENCE-Q were determined using ROC (Receiver Operating Characteristic) analysis.Results: Out of 343 eligible children, 223 enrolled, of whom 173 (50% of all eligible) had a parent-rated ESSENCE-Q. At least one of the 12 possible concerns was reported by parents of 36% of participants. Overall, in 101 (57%) participants a work-up was warranted, and 64 (37%) were clinically symptomatic from NDPs. The AUC of the ESSENCE-Q in detecting need for work-up was 0.70 (95% confidence interval [CI] 0.63– 0.77), and the AUC in detecting clinically symptomatic participants was 0.82 (95% CI 0.76– 0.88). ESSENCE-Q ratings correlated positively with CGI-S scores (r=0.48, p< 0.05). A cutoff of ≥ 3 had the highest accuracy (78%) with a negative predictive value of 82%. Ratings > 6 conferred few false positives cases with positive likelihood ratios > 10 and positive predictive values of 86% or more.Significance: This study of the ESSENCE-Q in 11-year-old children suggests it might be an acceptable instrument for screening of NDPs in children in middle school, optimally in conjunction with other methods.Keywords: screening, neurodevelopment, school, ESSENCE-Q

Erik Kindgren,1,2 Antonia Quiñones Perez,1 Rajna Knez1,3 1Department of Pediatrics, Skaraborg Hospital, Skövde, Sweden; 2Division of Pediatrics, Department of Biomedical and Clinical Sciences (BKV), Medical Faculty, Linköping University, Linköping, Sweden; 3Sahlgrenska Academy, Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, SwedenCorrespondence: Erik KindgrenDepartment of Pediatrics, Skaraborg Hospital, Lövängsvägen, Skövde, 541 42, SwedenTel +46104739222Fax +46500478356Email erik@kindgren.orgIntroduction: Hypermobility spectrum disorders (HSD) and hypermobile Ehlers-Danlos syndrome (hEDS) are both characterized by generalized hypermobility, in combination with pain, affected proprioception, and pronounced fatigue. Clinical observation indicates that behavioral problems, hyperactivity, and autistic traits are overrepresented in children with those conditions. The purpose of this retrospective study was to establish the prevalence of attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) among children with HSD and hEDS treated in our clinic since 2012.Subjects and Methods: Since Ehlers-Danlos syndrome (EDS) diagnostic criteria and international classification were changed in 2017, we equate the older diagnosis EDS hypermobility type with the newer hEDS and the older hypermobility syndrome with HSD. A registry search from the computerized medical record system found 201 children (88 boys, 113 girls) aged 6– 18 years who were treated at our pediatrics department with the diagnoses HSD or EDS. All medical records (113 with HSD, 88 with EDS) were reviewed, and key symptoms such as fatigue and pain, as well as diagnosis of ADHD/ASD, were recorded.Results: All EDS cases could be classified as hEDS. Of the entire study cohort, 16% had a verified ADHD diagnosis and a further 7% were undergoing ADHD diagnostic investigation. Significantly more children with hEDS had ADHD compared to children with HSD (p=0.02). In the age group 15– 16 years, 35% of those with hEDS had ADHD and, among those aged 17– 18 years, ADHD was present in 46%. Children with coexisting ADHD showed a significantly higher proportion of associated symptoms such as fatigue, sleep-problems, and urinary tract problems. ASD had been verified in 6% of the children. Of those with ASD, 92% had sleep problems.Conclusion: This study shows a strong association between HSD or hEDS and ADHD or ASD. Therefore, children with HSD or hEDS may need to be routinely screened for neuropsychiatric symptoms.Keywords: ADHD, autism spectrum disorder, children, hypermobility spectrum disorder, Ehlers-Danlos syndrome

Rajna Knez,1 Dejan Stevanovic,2 Salmir Nasic,3 Ana Doric,4 Elisabet Wentz5 1Department of Pediatrics, Skaraborgs Hospital, Skövde, Sweden; Sahlgrenska Academy, Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden; 2Psychiatry Department, Clinic for Neurology and Psychiatry for Children and Youth, Belgrade, Serbia; 3Research & Development Centre, Skaraborgs Hospital, Skövde, Sweden; 4Department of Psychology, Faculty of Humanity and Social Sciences, University of Rijeka, Rijeka, Croatia; 5Sahlgrenska Academy, Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, SwedenCorrespondence: Dejan StevanovicPsychiatry Department, Clinic for Neurology and Psychiatry for Children and Youth, Dr Subotic 6a, Belgrade 11 000, SerbiaTel +381 69 241 2006Fax +381 11 265 8355Email stevanovic.dejan79@gmail.comIntroduction: The Quantified behavior Test (QbTest), which combines a continuous performance task (CPT) and motion tracking, provides data for the core signs of attention-deficit/hyperactivity disorder (ADHD): attention, hyperactivity, and impulsivity. This study aimed to evaluate the performance of children and adolescents with ADHD on the QbTest before and after a single methylphenidate (MPH) dose.Subjects and Methods: This retrospective chart review study included data from 149 children and 215 adolescents who completed the QbTest. A summary index of the CPT and motion capture data on the QbTest is provided by three cardinal parameters: QbActivity, QbImpulsivity, and QbInattention. The test was performed twice on the same day, before and up to three hours after MPH intake. A decrease by ≥ 0.5 in a cardinal parameter score was considered an improvement, whereas an increase by ≥ 0.5 a deterioration.Results: QbActivity improvement after MPH intake was present in 71.7% and 76.2% of the children and adolescents, respectively. QbImpulsivity improvement was observed in 50.4% of the children and 44.7% of the adolescents, and QbInattention improvement in 85.1% and 91.1% of the children and adolescents, respectively. All three parameters improved simultaneously in 27.7% of the children and 28.7% of the adolescents. The likelihood that one parameter deteriorated after MPH use was greater if that parameter was within the normal range before medication. This was most pronounced for QbImpulsivity. Among male adolescents, QbInattention improvement was often accompanied by QbImpulsivity deterioration.Conclusion: The QbTest inattention and motor activity parameters improved markedly after a single MPH dose in children and adolescents with ADHD, while less so for impulsivity. Improvement of one parameter is not necessarily associated with improvement of the other two, and deterioration, especially regarding impulsivity, may occur. If confirmed, these results highlight the need for optimization and individualization of MPH treatment, while monitoring all aspects of the ADHD symptomatology based on the QbTest performance.Keywords: continuous performance task, inattention, impulsivity, motor activity, stimulants

Rajna Knez1,2 1Gillberg Neuropsychiatry Centre, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; 2Department of Pediatrics, Skaraborgs Hospital, Skövde, SwedenCorrespondence: Rajna KnezGillberg Neuropsychiatry Centre, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Kungsgatan 12, Vanning 2, Gothenburg, 411 19, SwedenTel +46317860000Email rajna.knez@gu.se View the original paper by Prof. Dr. Gagliano and colleagues

Dejan Stevanovic,1 Rajna Knez,2,3 Tatjana Zorcec,4 Marija Anderluh,5 Jana Kodrič,5 Petar Petrov,6 Feriha Hadžagić Ćatibušić,7 Azra Deljković,8 Slavica Brkic Cvetkovic,1 Nikolina Vrljičak Davidovic,9 Radenka Kuzmanić Šamija,10 Ana Ðorić,11 Christopher Gillberg12 1Psychiatry Department, Clinic for Neurology and Psychiatry for Children and Youth, Belgrade, Serbia; 2Department of Child and Adolescent Psychiatry, Skaraborgs Hospital, Skövde, Sweden; 3Department of Psychiatry and Psychological Medicine, Faculty of Medicine, University of Rijeka, Rijeka, Croatia; 4Developmental Department, University Children’s Hospital, Skopje, Macedonia; 5Department of Child Psychiatry, University Children’s Hospital, University Medical Center Ljubljana, Ljubljana, Slovenia; 6Department of Child and Adolescent Psychiatry, University Hospital St Marina, Varna, Bulgaria; 7Pediatric Clinic, Clinical Center Sarajevo, Bosnia and Herzegovina; 8Psychiatry Department, Mental Health Center Pljevlja, Pljevlja, Montenegro; 9Department of Child and Adolescent Psychiatry, Clinical Hospital Center, Split, Croatia; 10Clinic for Children’s Disorders, Clinical Hospital Center, Split, Croatia; 11Center of Applied Psychology, Faculty of Humanity and Social Sciences, University of Rijeka, Rijeka, Croatia; 12Gillberg Neuropsychiatry Center, University of Gothenburg, Gothenburg, Sweden Purpose: The Early Symptomatic Syndromes Eliciting Neurodevelopmental Clinical Examinations – Questionnaire (ESSENCE-Q) was developed as a brief screener to identify children with developmental concerns who might have neurodevelopmental disorders (NDDs). This study aimed to translate the ESSENCE-Q into south Slavic languages, namely, Bosnian, Bulgarian, Croatian, Macedonian, Montenegrin, Serbian, and Slovenian, and to evaluate its psychometric properties for screening purposes in clinical settings. Patients and methods: In the study, the ESSENCE-Q was completed for 251 “typically developing” children and 200 children with 1 or more diagnosed NDDs, all aged 1–6 years. Internal consistency and construct validity were tested first, followed by generating receiver operating characteristic curves and the area under the curve. Optimal cutoff values were then explored. Results: The Cronbach’s α coefficients were 0.91, 0.88, and 0.86 for ESSENCE-Q parent-completed form, and the telephone and direct interview forms administered by trained nurse or specialist, respectively. The 3 versions produced area under the curve values (95% confidence interval): 0.96 (0.93–0.99), 0.91 (0.86–0.95), and 0.91 (0.86–0.97), respectively. An optimal cutoff for ESSENCE-Q parent-completed form was found to be ≥3 points, while for the telephone and direct interviews, it was ≥5 points. Conclusion: We found adequate measurement properties of the south Slavic languages versions of the ESSENCE-Q as a screener for NDDs in clinical settings. This study provided additional data supporting sound psychometric properties of the ESSENCE-Q. Keywords: early screening, questionnaire, autism, intellectual disability

The present study evaluated the psychometric properties of a self-report scale for assessing Internet Gaming Disorder (IGD) symptoms according to the DSM–5 and ICD–11 among 3270 college/university students (2095 [64.1%] females; age mean 21.6 [3.1] years) from different countries worldwide. Croatian, English, Polish, Portuguese, Serbian, Turkish, and Vietnamese versions of the scale were tested. The study showed that symptoms of IGD could be measured as a single underlying factor among college/university students. A nine item symptom scale following DSM–5, and a short four-item scale representing the main ICD–11 symptoms, had sound internal consistency and construct validity. Three symptom-items were found non-invariant across the language samples (i.e., preoccupation with on-line gaming, loss of interests in previous hobbies and entertainment, and the use of gaming to relieve negative moods). This study provides initial evidence for assessing IGD symptoms among college/university students and will hopefully foster further research into gaming addiction in this population worldwide especially with taking into account language/cultural differences. [Project of the Serbian Ministry of Education, Science and Technological Development, Grant no. 179002]

Accessible summary Study reveals that alcohol and substance use and abuse is common among adolescents sampled from developing countries, and that it may be as high as have been reported in the developed nations. The risk factors also appear similar., To this extent, current strategies to combat adolescent alcohol and substance abuse in developed countries can be adopted in developing countries as well. There is, however, a need to adapt some of these well-established intervention programmes into the reality of the developing countries. Peculiar challenge in these countries includes lack of human resource capacity in child and adolescent psychiatry. Therefore, such programmes will necessarily have to be simplified and implementable by allied professionals like teachers, social workers, school counsellors, nurses and spiritual advisers. Family cohesion - which is a potential strength of developing countries - also needs to be strengthened as a bulwark against adolescent involvement in social vices like alcohol and substance abuse., Abstract Most studies examining adolescent alcohol and substance use or abuse hardly include samples from developing countries. To bridge some gap, the prevalence and associated social correlates of alcohol and substance use and abuse was examined among a cohort of school-going adolescents sampled from seven developing countries. Alcohol and substance abuse was measured using the CRAFFT instrument, independent socio-demographic correlates were determined using regression models. A total of 2454 adolescents completed the study, among which 40.9% reported using either alcohol or at least one other substance during the previous 12 months. This was mostly alcohol (37.8%), followed by marijuana/hashish (8.6%) and other substances (8.1%). Among the adolescents who reported using at least one substance, 45% (18.3% of total sample) had CRAFFT scores indicative of problematic or hazardous substance use. Several personal and family factors were independently associated with use/abuse, and the modifiable nature of these factors calls for appropriate intervention strategies. [ABSTRACT FROM AUTHOR]