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Headache is one of the most common and disruptive pain manifestations in children and adolescents. This review examines the current evidence for the impact of primary headaches on well-being and quality of life in children with headaches. Several studies support that headaches cause a significant reduction in quality of life, which can be related to the headaches themselves and lead to limitations in family, social, and school activities. There is a need for more studies on well-being among children with headaches as well as a greater focus on other primary headache forms than migraine., (Published under Open Access CC-BY-NC-BD 4.0. https://creativecommons.org/licenses/by-nc-nd/4.0/.)

Objective: This study aimed to examine the reliability and validity of a newly developed questionnaire for Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infections (PANDAS) and Pediatric Acute-onset Neuropsychiatric Syndrome (PANS). The aim was to contribute to future standardisation of screening methods for symptoms and comorbidity, as well as the measurement of symptom severity, daily life impairment, and treatment effectiveness in individuals diagnosed with PANDAS/PANS., Methods: 27 items from the PANDAS/PANS questionnaire concerning symptoms and comorbidities associated with PANDAS/PANS were divided into ten domains. To assess the external validity, 119 PANDAS/PANS questionnaires from a cohort of 65 children with PANDAS/PANS were correlated with three well-known validated questionnaires: the Children's Yale-Brown Obsessive-Compulsive Scale (CY-BOCS), Attention Deficit Hyperactivity Disorder Rating Scale (ADHD-RS), and the Strengths and Difficulties Questionnaire (SDQ). The internal validity of the PANDAS/PANS questionnaire was assessed by correlating the PANDAS/PANS items with the domains., Results: Internal consistency of the PANDAS/PANS questionnaire was high, measuring moderate to very strong correlations. The external correlations for the PANDAS/PANS questionnaire showed a higher correlation with the ADHD-RS and CY-BOCS (r s  ≥ 0.60) than with the SDQ (r s  < 0.40)., Conclusion: The validity and clinical feasibility of the PANDAS/PANS questionnaire were confirmed as an effective tool for screening symptoms, assessing symptom severity, and evaluating comorbidity and daily life impairment in individuals with PANDAS/PANS. These findings can potentially enhance the management of PANDAS/PANS patients in both clinical and research settings., Competing Interests: Declaration of competing interest None of the authors have stated any conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Cognitive dysfunction is a well-known consequence of epilepsy in children. This review summarizes cognitive difficulties presenting in different types of childhood epilepsy. The possibility of screening and monitoring cognitive dysfunction is desirable to provide optimal support and treatment. The clinical test tool EpiTrack Junior is introduced. It was developed for screening and continuous monitoring of cognitive function in children with epilepsy., (Published under Open Access CC-BY-NC-BD 4.0. https://creativecommons.org/licenses/by-nc-nd/4.0/.)

Background: The Danish National Cerebral Palsy Follow-up Program (CPOP) is a nationwide program offering standardized treatment to all children with cerebral palsy (CP) since 2004. We aimed to establish if its implementation had a positive impact on the diagnostic age of CP., Methods: Children with validated CP diagnoses were identified from the Danish Cerebral Palsy Registry and the CPOP. We then compared the age at diagnosis and the clinical features of children with CP born in 2000 to 2003 with those born in 2010 to 2013. Differences in time to diagnosis were compared using log-rank test., Results: The age at diagnosis was not different in the two periods (P = 0.23), with identical overall median diagnostic ages at 13.0 months. The number of children with severe motor disability decreased markedly from 47.5% in 2000 to 2003 to 32.0% in 2010 to 2013 (P < 0.001). There was increased usage of cerebral magnetic resonance imaging; however, this was not associated with lower diagnostic age., Conclusions: The diagnostic age of CP did not change after the implementation of a nationwide follow-up program, offering standardized and early assessments. However, central clinical aspects also changed significantly between the periods compared, which possibly affected the diagnostic age., Competing Interests: Declaration of competing interest None., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Early diagnosis of cerebral palsy (CP) is important to enable intervention at a time when neuroplasticity is at its highest. Current mean age at diagnosis is 13 months in Denmark. Recent research has documented that an early-diagnosis set-up can lower diagnostic age in high-risk infants. The aim of the current study is to lower diagnostic age of CP regardless of neonatal risk factors. Additionally, we want to investigate if an early intervention program added to standard care is superior to standard care alone., Methods: The current multicentre study CP-EDIT (Early Diagnosis and Intervention Trial) with the GO-PLAY intervention included (Goal Oriented ParentaL supported home ActivitY program), aims at testing the feasibility of an early diagnosis set-up and the GO-PLAY early intervention. CP-EDIT is a prospective cohort study, consecutively assessing approximately 500 infants at risk of CP. We will systematically collect data at inclusion (age 3-11 months) and follow a subset of participants (n = 300) with CP or at high risk of CP until the age of two years. The GO-PLAY early intervention will be tested in 80 infants with CP or high risk of CP. Focus is on eight areas related to implementation and perspectives of the families: early cerebral magnetic resonance imaging (MRI), early genetic testing, implementation of the General Movements Assessment method, analysis of the GO-PLAY early intervention, parental perspective of early intervention and early diagnosis, early prediction of CP, and comparative analysis of the Hand Assessment for Infants, Hammersmith Infant Neurological Examination, MRI, and the General Movements method., Discussion: Early screening for CP is increasingly possible and an interim diagnosis of "high risk of CP" is recommended but not currently used in clinical care in Denmark. Additionally, there is a need to accelerate identification in mild or ambiguous cases to facilitate appropriate therapy early. Most studies on early diagnosis focus on identifying CP in infants below five months corrected age. Little is known about early diagnosis in the 50% of all CP cases that are discernible later in infancy. The current study aims at improving care of patients with CP even before they have an established diagnosis., Trial Registration: ClinicalTrials.gov ID 22013292 (reg. date 31/MAR/2023) for the CP-EDIT cohort and ID 22041835 (reg. date 31/MAR/2023) for the GO-PLAY trial., (© 2023. The Author(s).)

This is the ninth yearly article in the Tourette Syndrome Research Highlights series, summarizing selected research reports from 2022 relevant to Tourette syndrome. The authors briefly summarize reports they consider most important or interesting., Competing Interests: Competing interests: AH is a consultant for Noema Pharma. PA has received royalties from the Tourette OCD Alberta Network. CD is a consultant for Medtronic. KJB participated in a clinical trial sponsored by Emalex Biosciences and was an unpaid consultant for Noema Pharma AG. NMD has no conflicts of interest. VC has no conflict of interest. KU participated in a clinical trial sponsored by Emalex Biosciences. Kirsten Müller-Vahl has received financial or material research support from EU (FP7-HEALTH-2011 No. 278367, FP7-PEOPLE-2012-ITN No. 316978), DFG: GZ MU 1527/3-1 and GZ MU 1527/3-2, BMBF: 01KG1421, National Institute of Mental Health (NIMH), Tourette Gesellschaft Deutschland e.V., Else-Kröner-Fresenius-Stiftung, GW pharmaceuticals, Almirall, Abide Therapeutics, Emalex Biosciences, Inc., Noema Pharma, CannaXan, and Therapix Biosiences. She has received consultant’s and other honoraria from Abide Therapeutics, adjupharm, Alexion, AMP Alternative Medical Products GmbH, Ingelheim International GmbH, Bionorica Ethics GmbH, CannaMedical Pharma GmbH, Canopy Grouth, Columbia Care, CTC Communications Corp., Demecan, Enua pharma, Ethypharm GmbH, Eurox Group, Global Praxis Group Limited, Hormosan Pharma GmbH, Lundbeck, MCI Germany, Neuraxpharm, Noema Pharma, Sanity Group, Stadapharm GmbH, Synendos Therapeutics AG, Syqe, Tilray, and Zambon. She is an advisory/scientific board member for Alexion, Branchenverband Cannabiswirtschaft e.V. (BvCW), CannaMedical Pharma GmbH, Bionorica Ethics GmbH, CannaXan GmbH, Canopy Growth, Columbia Care, Ethypharm GmbH, Hormosan Pharma GmbH, IMC Germany, Leafly Deutschland GmbH, Neuraxpharm, Sanity Group, Stadapharm GmbH, Synendos Therapeutics AG, Syqe Medical Ltd., Therapix Biosciences Ltd., and Tilray. She has received speaker’s fees from Agaplesion Frankfurter Diakonie Kliniken gemeinnützige GmbH, Almirall, Aphria Deutschland GmbH, Arbeitsgemeinschaft Cannabis als Medizin (ACM), Bedrocan, Branchenverband Cannabiswirtschaft e.V. (BvCW), Camurus, CEREBRO SPAIN BIDCO S.L, Cogitando GmbH, Deutsche Gesellschaft für Psychiatrie und Psychotherapie, Psychosomatik und Nervenheilkunde (DGPPN), Diplomado Internacional de Endocannabinología (Programa Universitario de Investigación en Salud - PUIS, UNAM), Dresden International University (DIU), Emalex, Eurox Deutschland GmbH, Ever pharma GmbH, Georgia Medical Cannabis Project (GMCP), GROW, Hessische Landesstelle für Suchtfragen e.V. (HLS), LIO Pharmaceuticals GmbH, Medizinischer Dienst Westfalen Lippe, Meinhardt Congress GmbH, PR Berater, Spectrum Therapeutics GmbH, Swiss Alpinopharm, targoEvent GmbH, Takeda GmbH, Tilray, von Mende Marketing GmbH, and Wayland Group. She has received royalties from Deutsches Ärzteblatt, Der Neurologie und Psychiater, Elsevier, Medizinisch Wissenschaftliche Verlagsgesellschaft Berlin, and Kohlhammer. She served as a guest editor for Frontiers in Neurology on the research topic “The neurobiology and genetics of Gilles de la Tourette syndrome: new avenues through large-scale collaborative projects”, is an associate editor for “Cannabis and Cannabinoid Research” and an Editorial Board Member of “Medical Cannabis and Cannabinoids” und “MDPI-Reports” and a Scientific board member for “Zeitschrift für Allgemeinmedizin”. NSZ participated in clinical trial supported by Emalex and Nuvelution. NSZ received scientific grants from the Polish Neurological Society, European Stroke Organisation, Polish Ministry of Health, Polish Foundation of Science, Tourette Association of America, American Academy of Neurology and American Brain Foundation. She received speaker honoraria from Biogen. PP has no conflict of interest. PP was supported by EMTICS (Grant No. 278367), TS-EUROTRAIN (Grant No. 316978), the National Institute of Neurological Disorders and Stroke (Grant No. R01NS105746), U.S. National Science Foundation (Grant Nos. 2006929 and 1715202), and the National Institute of Mental Health (Grant No. R01MH126213). AT has no conflict of interest. CAC has no conflict of interest., (Copyright: © 2023 Hartmann A et al.)

Background: This study explores the longitudinal impact of severity of Tourette Syndrome (TS), diagnosis and severity of Attention-Deficit/Hyperactivity Disorder (ADHD) and Obsessive-Compulsive Disorder (OCD), and guardian socioeconomic status on the level of substance use of pediatric patients with TS., Methods: A total of 314 pediatric patients with TS participated at time 1 (T1). During these visits, the severity of the patients' TS, ADHD, and OCD symptoms were assessed, along with their guardians' socioeconomic status. At time 2 (T2), between four and eight years later (median 5.6 years), 227 patients returned for a follow-up. Here, the patients answered questions about their intake of alcohol, cigarettes, and illegal substances. The relationship between the patients' diagnoses, symptom severity, and socioeconomic status at T1 and reported substance use at T2 was then analyzed using binary logistic regression., Results: Increased severity of ADHD and lower guardian socioeconomic status at T1 significantly increased the odds of later high cigarette consumption. Furthermore, both presence and increased severity of ADHD at T1 increased the odds of illegal substance consumption at T2. Conversely, increased severity of OCD at T1 significantly decreased cigarette and illegal substance consumption at T2, whereas both presence and increased severity of OCD decreased alcohol consumption., Conclusions: Pediatric patients with TS with increased ADHD severity have increased risk of consuming illegal substances and high amounts of cigarettes as adolescents, whereas increased OCD severity may act as a protective factor. Having preventative conversations about substance consumption with patients with TS with high ADHD severity is important., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Currently, melatonin is used to treat children and adolescents with insomnia without knowing the full extent of the short-term and long-term consequences. Our aim was to provide clinicians and guideline panels with a systematic assessment of serious-and non-serious adverse events seen in continuation of melatonin treatment and the impact on pubertal development and bone health following long-term administration in children and adolescents with chronic insomnia., Methods: We searched PubMed, Embase, Cinahl and PsycINFO via Ovid, up to March 17, 2023, for studies on melatonin treatment among children and adolescents (aged 5-20 years) with chronic insomnia. The language was restricted to English, Danish, Norwegian, and Swedish. Outcomes were non-serious adverse events and serious adverse events assessed 2-4 weeks after initiating treatment and pubertal development and bone health, with no restriction on definition or time of measurement. Observational studies were included for the assessment of long-term outcomes, and serious and non-serious adverse events were assessed via randomised studies. The certainty of the evidence was assessed using Grades of Recommendation, Assessment, Development and Evaluation (GRADE). The protocol is registered with the Danish Health Authority., Findings: We identified 22 randomised studies with 1350 patients reporting on serious-and non-serious adverse events and four observational studies with a total of 105 patients reporting on pubertal development. Melatonin was not associated with serious adverse events, yet the number of patients experiencing non-serious adverse events was increased (Relative risk 1.56, 95% CI 1.01-2.43, 17 studies, I 2  = 47%). Three studies reported little or no influence on pubertal development following 2-4 years of treatment, whereas one study registered a potential delay following longer treatment durations (>7 years). These findings need further evaluation due to several methodological limitations., Interpretation: Children who use melatonin are likely to experience non-serious adverse events, yet the actual extent to which melatonin leads to non-serious adverse events and the long-term consequences remain uncertain. This major gap of knowledge on safety calls for caution against complacent use of melatonin in children and adolescents with chronic insomnia and for more research to inform clinicians and guideline panels on this key issue., Funding: The Danish Health Authority. The Parker Institute, Bispebjerg and Frederiksberg Hospital, supported by the Oak Foundation., Competing Interests: LB is a member of the Danish medication reimbursement committee. AV has previously received honoraria for lectures at AGB pharma, Takeda & Medice, and holds stocks at Novo Nordisk. All other authors declare no competing interests. Statements of conflicts of interests can be found for all members of the guideline panel, the external reviewer of the national clinical guideline, the reference–and project group at the Danish Health Authority website (www.sst.dk)., (© 2023 The Authors.)

Background: Melatonin prescriptions for children and adolescents have increased substantially during the last decade. Existing clinical recommendations focus on melatonin as a treatment for insomnia related to neurodevelopmental disorders. To help guide clinical decision-making, we aimed to construct a recommendation on the use of melatonin in children and adolescents aged 5-20 years with idiopathic chronic insomnia., Methods: A systematic search for guidelines, systematic reviews and randomised controlled trials (RCT) were performed in Medline, Embase, Cochrane Library, PsycInfo, Cinahl, Guidelines International Network, Trip Database, Canadian Agency for Drugs and Technologies in Health, American Academy of Sleep Medicine, European Sleep Research Society and Scandinavian Health Authorities databases. A search for adverse events in otherwise healthy children and adolescents was also performed. The latest search for guidelines, systematic reviews, and adverse events was performed on March 18, 2023. The latest search for RCTs was performed on to February 6, 2023. The language was restricted to English, Danish, Norwegian, and Swedish. Eligible participants were children and adolescents (5-20 years of age) with idiopathic chronic insomnia, in whom sleep hygiene practices have been inadequate and melatonin was tested. There were no restrictions on dosage, duration of treatment, time of consumption, or release formula. Primary outcomes were quality of sleep, daytime functioning and serious adverse events. Secondary outcomes included total sleep time, sleep latency, awakenings, drowsiness, quality of life, all-cause dropouts, and non-serious adverse events. Outcomes were assessed at different time points to assess short-term and long-term effects. Meta-analysis was performed using inverse variance random-effects model and risk of bias was assessed using Cochrane risk of bias tool. If possible, funnel plots would be constructed to investigate publication bias. Heterogeneity was calculated via I 2 statistics. A multidisciplinary guideline panel formulated the recommendation according to Grading of Recommendations Assessment, Development and Evaluation (GRADE). The certainty of evidence was considered either high, moderate, low or very low depending on the extent of risk of bias, inconsistency, imprecision, indirectness, or publication bias. The evidence-to-decision framework was subsequently used to discuss the feasibility and acceptance of the constructed recommendation alongside the impact on resources and equity. The protocol is registered with the Danish Health Authority., Findings: We included eight RCTs with 419 children and adolescents with idiopathic chronic insomnia. Melatonin led to a moderate increase in total sleep time by 30.33 min (95% confidence interval (CI) 18.96-41.70, 4 studies, I 2  = 0%) and a moderate reduction in sleep latency by 18.03 min (95% CI -26.61 to -9.44, 3 studies, I 2  = 0%), both as assessed by sleep diary. No other beneficial effects were found. None of the studies provided information on serious adverse events, yet the number of participants experiencing non-serious adverse events was increased (Relative risk 3.44, 95% CI 1.25-9.42, 4 studies, I 2  = 0%). Funnel plots were not constructed due to the low number of studies. The certainty of evidence was very low on the quality of sleep and low for daytime functioning., Interpretation: Evidence of very low certainty shows that benefits are limited and unwanted events are likely when melatonin is used to treat otherwise healthy children and adolescents with chronic insomnia. Melatonin should never be the first choice of treatment for this particular population, yet carefully monitored short-term use may be considered if sleep hygiene practices and non-pharmacological interventions have proven inadequate, and only if daytime function is compromised., Funding: The Danish Health Authority and the Parker Institute, Bispebjerg and Frederiksberg Hospital supported by the Oak Foundation., Competing Interests: LB is a member of the Danish medication reimbursement committee. AV has previously received honoraria for lectures at AGB pharma, Takeda & Medice and holds stocks at Novo Nordisk. All other authors declare no competing interests. Statements of conflicts of interests can be found for all members of the guideline panel, the external reviewer of the national clinical guideline, the reference–and project group at the Danish Health Authority website (www.sst.dk)., (© 2023 The Authors.)

Background: Melatonin has become a widely used sleeping aid for young individuals currently not included in existing guidelines. The aim was to develop a recommendation on the use of melatonin in children and adolescents aged 2-20 years, with chronic insomnia due to disorders beyond indication., Methods: We performed a systematic search for guidelines, systematic reviews, and randomised trials (RCTs) in Medline, Embase, Cochrane Library, PsycInfo, Cinahl, Guidelines International Network, Trip Database, Canadian Agency for Drugs and Technologies in Health, American Academy of Sleep Medicine, European Sleep Research Society and Scandinavian Health Authorities databases. A separate search for adverse events was also performed. The latest search for guidelines, systematic reviews, and adverse events was performed on March 17, 2023. The latest search for RCTs was performed on to February 6, 2023. The language was restricted to English, Danish, Norwegian, and Swedish. Eligible participants were children and adolescents (2-20 years of age) with chronic insomnia due to underlying disorders, in whom sleep hygiene practices have been inadequate and melatonin was tested. Studies exclusively on autism spectrum disorders or attention deficit hyperactive disorder were excluded. There were no restrictions on dosage, duration of treatment, time of consumption or release formula. Primary outcomes were quality of sleep, daytime functioning and serious adverse events, assessed at 2-4 weeks post-treatment. Secondary outcomes included total sleep time, sleep latency, awakenings, drowsiness, quality of life, non-serious adverse events, and all-cause dropouts (assessed at 2-4 weeks post-treatment), plus quality of sleep and daytime functioning (assessed at 3-6 months post-treatment). Pooled estimates were calculated using inverse variance random effects model. Statistical heterogeneity was calculated using I 2 statistics. Risk of bias was assessed using Cochrane risk of bias tool. Publication bias was assessed using funnel plots. A multidisciplinary guideline panel constructed the recommendation using Grades of Recommendation, Assessment, Development and Evaluation (GRADE). The certainty of evidence was considered either high, moderate, low or very low depending on the extent of risk of bias, inconsistency, imprecision, indirectness, or publication bias. The evidence-to-decision framework was used to discuss the feasibility and acceptance of the constructed recommendation and its impact on resources and equity. The protocol is registered with the Danish Health Authority., Findings: We identified 13 RCTs, including 403 patients with a wide range of conditions. Melatonin reduced sleep latency by 14.88 min (95% CI 23.42-6.34, 9 studies, I 2  = 60%) and increased total sleep time by 18.97 min (95% CI 0.37-37.57, 10 studies, I 2  = 57%). The funnel plot for total sleep time showed no apparent indication of publication bias. No other clinical benefits were found. The number of patients experiencing adverse events was not statistically increased however, safety data was scarce. Certainty of evidence was low., Interpretation: Low certainty evidence supports a moderate effect of melatonin in treating sleep continuity parameters in children and adolescents with chronic insomnia due to primarily medical disorders beyond indication. The off-label use of melatonin for these patients should never be the first choice of treatment, but may be considered by medical specialists with knowledge of the underlying disorder and if non-pharmacological interventions are inadequate. If treatment with melatonin is initiated, adequate follow-up to evaluate treatment effect and adverse events is essential., Funding: The Danish Health Authority. The Parker Institute, Bispebjerg and Frederiksberg Hospital, supported by the Oak Foundation., Competing Interests: LB is a member of the Danish medication Reimbursement Committee. AV has previously received honoraria for lectures at AGB pharma, Takeda & Medice and holds stocks at Novo Nordisk. All other authors declare no competing interests. Statements of conflicts of interests can be found for all members of the guideline panel, the external reviewer of the national clinical guideline, the reference–and project group at the Danish Health Authority website (www.sst.dk)., (© 2023 The Authors.)

Self-limited epilepsy with centrotemporal spikes (SeLECTS) is one of the most frequent epilepsies in childhood, characterised by typical clinical presentation with characteristic EEG findings. This review investigates the existing knowledge regarding cognitive function, the potential effect of anti-seizure medicines on cognitive development as well as prognosis of SeLECTS based on recent studies. There is evidence supporting that SeLECTS may not be as benign as previously assumed due to the possible neurocognitive comorbidities.

Children and adolescents with psychiatric or neurologic disorders often suffer from sleep problems. Disrupted sleep might lead to different comorbidities in the child/adolescent. These symptoms often mimic other psychiatric symptoms, which makes the diagnostic process challenging. Sleep problems can lead to aggravation of existing symptoms, exacerbation into psychiatric problems, or arise as a response to pharmacological treatment. In order to provide an efficient and well-qualified treatment, it is important to understand the pathogenesis of sleep problems to be able to distinguish between the cause and consequence, as argued in this review.

Due to the global increase in the number of patients with Functional Tic-Like Behaviors (FTLB), it has become increasingly important to find reliable differences between this patient group and patients with organic tics (OTs), which can be used in differential diagnosis. The purpose of this retrospective study was to critically examine both established and suggested differences between the patient groups. A total of 53 FTLB patients and 200 OT patients were included. Several findings from the current literature were replicated in this study: Compared to patients with OTs, patients with FTLB had significantly more complex tics, were older at symptom onset, were more likely to be female, and were less likely to have family members with tics. Furthermore, the study also revealed new differences between the groups: Patients with FTLB had significantly more family members with a psychiatric disorder, were more likely to have experienced an adverse psychosocial event immediately before symptom onset, and had significantly fewer simple tics. Finally, this study was unable to replicate the previously found differences in comorbidities between patients with OTs and FTLB. These findings could contribute significantly to the understanding of FTLB's etiology and to improve diagnosis, as including the presence of simple tics and comorbidities in the diagnostic criteria might be discussed in future studies.

Tourette syndrome and chronic tic disorders are characterized by the presence of tics. Different behavioral therapies have shown to be efficacious for treating tics in children and adolescents, but Exposure and Response Prevention (ERP) is a less researched method. However, ERP is a method often used in the clinical setting. Therefore, the present study evaluated the severity of tics over time from beginning of ERP to follow-up approximately 1 year after last training session.In total, 116 patients treated with ERP face to face or ERP via web-based videoconferencing were included. The primary outcome measure was tic severity measured with the Danish version of the Yale Global Tic Severity Scale.The results showed that tic severity decreased during ERP and lasted in the follow-up period, with a statistically higher decrease in the group with patients who completed ERP as planned and the group that stopped earlier than planned because of reduction in tics, compared with those who dropped out due to lack of motivation ( p  < 0.001).The study concludes that ERP seems to have an immediate and a long-term effect on severity of tics, especially in those who complete the program or those who discontinue earlier due to good results., Competing Interests: None declared., (Thieme. All rights reserved.)

Background: Previous studies have shown that Tourette syndrome (TS) has an impact on academic achievements. The aim of this study was to investigate the association between the severity of tics and comorbidities and educational outcomes., Methods: From 2005 to 2007, 395 participants were included in a large cohort (314 with TS and 81 controls) and the mean age was 12.60 ± 2.64 years. The cohort was re-examined after 4 to 8 years (median 5.6) where n  = 276 participants (223 with TS and 53 controls) were included with a mean age of 18.52 ± 2.73 years. At both time points, severity of tics and the presence and severity of psychiatric comorbidity were assessed. Educational achievements were assessed through structured interviews., Results: Children with TS had a lower passing rate at lower secondary and high school compared to healthy controls. More severe vocal tics were associated with fewer passing lower secondary school at a prospective level. At a cross-sectional level, more severe motor tics were associated with fewer passing high school. Tic severity only influenced children with TS without comorbidity. The severity of comorbidity was found to be associated with the educational level at a longitudinal view, but not cross-sectional., Conclusion: Overall, children with TS had a lower passing rate at lower secondary school and high school compared to healthy controls. We found that this difference was more likely driven by the severity of comorbidities than tic severity. It is important to be aware of academic achievement in children with TS in order to give them the right support and thereby optimize educational opportunities., Competing Interests: None declared., (Thieme. All rights reserved.)

Background and Purpose: In 2020, health professionals witnessed a dramatic increase in referrals of young people with rapid onset of severe tic-like behaviours. We assembled a working group to develop criteria for the clinical diagnosis of functional tic-like behaviours (FTLBs) to help neurologists, pediatricians, psychiatrists, and psychologists recognize and diagnose this condition., Methods: We used a formal consensus development process, using a multiround, web-based Delphi survey. The survey was based on an in-person discussion at the European Society for the Study of Tourette Syndrome (ESSTS) meeting in Lausanne in June 2022. Members of an invited group with extensive clinical experience working with patients with Tourette syndrome and FTLBs discussed potential clinical criteria for diagnosis of FTLBs. An initial set of criteria were developed based on common clinical experiences and review of the literature on FTLBs and revised through iterative discussions, resulting in the survey items for voting., Results: In total, 24 members of the working group were invited to participate in the Delphi process. We propose that there are three major criteria and two minor criteria to support the clinical diagnosis of FTLBs. A clinically definite diagnosis of FTLBs can be confirmed by the presence of all three major criteria. A clinically probable diagnosis of FTLBs can be confirmed by the presence of two major criteria and one minor criterion., Conclusions: Distinguishing FTLBs from primary tics is important due to the distinct treatment paths required for these two conditions. A limitation of the ESSTS 2022 criteria is that they lack prospective testing of their sensitivity and specificity., (© 2023 European Academy of Neurology.)

Chronic tic disorders, such as Tourette syndrome, are characterized by motor and vocal tics. Tics present a considerable burden for some patients, and therefore, effective treatment is important. One evidence-based treatment option is a behavioral therapy called exposure and response prevention (ERP). Despite its effectiveness, access to ERP remains limited due to a lack of treatment sites. Web-based videoconferences can connect patients at home with a therapist located in the hospital, allowing for treatment delivery over a wide geographic area. The primary aim of this study was to compare the development of tics during and 1 year after ERP delivery, respectively, via web-based videoconferences and traditional face-to-face methods in a naturalistic setting. In total, 116 patients treated using either the face-to-face method ( n  = 72) or web-based videoconferences ( n  = 44) were included. The primary outcome measure was tic severity. In both training modalities, tic severity decreased during ERP and the effect lasted in the follow-up period. No statistically significant differences in tic severity between the training modalities were found at baseline, last training session, or at follow-up. Our results suggest that ERP delivered via web-based videoconferences is a good alternative to the traditional face-to-face method., Competing Interests: None declared., (Thieme. All rights reserved.)

Cytokines are an important modulator of the immune system and have been found to be altered significantly in many neurological and psychiatric disorders, like obsessive compulsive disorder (OCD) and movement disorders. Also, in pediatric autoimmune neuropsychiatric disorders associated with group A streptococcal infections (PANDAS), which are characterized by abrupt debut of symptoms of OCD and /or movement disorder symptoms, alterations in the immune system have been suggested. The aim of this paper was to review the current literature on the cytokine profile of pediatric patients with symptoms of OCD and/or movement disorder symptoms. A search of PubMed and Medline was performed with specific keywords to review studies measuring cytokines in pediatric patients with symptoms of OCD and/or movement disorders. Nineteen studies were found, twelve of which included a healthy control group, while four studies had control groups of children with other disorders, primarily neurological or psychiatric. One study compared cytokines measurements to reference intervals, and two studies had a longitudinal design. Many cytokines were found to have significant changes in patients with symptoms of OCD and/or movement disorders compared to both healthy controls and other control groups. Furthermore, differences were found when comparing cytokines in periods of exacerbation with periods of remission of symptoms in study participants. The cytokines that most studies with healthy control groups found to be significantly altered were TNF-α, IL-1β and IL-17. Although the exact role of these cytokines in OCD and movement disorder symptoms remains unclear, the available literature suggests a proinflammatory cytokine profile. This offers interesting perspectives on the pathogenesis of OCD and/or movement disorder symptoms in children, and further research into the implications of cytokines in neuropsychiatric disorders is warranted., 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. The handling editor UL-T declared a shared parent affiliation with the author ND at the time of review., (Copyright © 2022 Fabricius, Sørensen, Skov and Debes.)

We summarize selected research reports from 2021 relevant to Tourette syndrome that the authors consider most important or interesting. The authors welcome article suggestions and thoughtful feedback from readers., Competing Interests: Competing interests: KJB participated in a clinical trial sponsored by Emalex Biosciences and served on an advisory board for SK Life Science, Inc. AH is a consultant for Noema Pharma and SciSparc., (Copyright: © 2022 Hartmann A et al.)

Although migraine in adult and pediatric patients are overall very similar to each other, differences in prevalence, presentation, and treatment efficacy may reflect slight differences in the pathophysiological processes underlying migraine in these patient groups, perhaps because of ongoing development of the nervous system during childhood and adolescence. Although major gains have been made in understanding the pathophysiology of migraine in adults in recent years, equivalent research on migraine in pediatric patients continues to lag behind. In this review, we will describe the current state of migraine research in pediatric patients with regard to presentation and frequency of prodromal and postdromal symptoms, ictal and interictal calcitonin gene-related peptide elevation, and evidence for cortical spreading depression, thus covering all phases of migraine, and discuss how the findings seen here may relate to possible underlying pathophysiological mechanisms of migraine. We aim to elucidate possible differences between migraine in children and adults, and the need for further research specific to pediatric patients with migraine in order to improve treatment in this patient group.

Part II of the European clinical guidelines for Tourette syndrome and other tic disorders (ECAP journal, 2011) provides updated information and recommendations for psychological interventions for individuals with tic disorders, created by a working group of the European Society for the Study of Tourette Syndrome (ESSTS). A systematic literature search was conducted to obtain original studies of psychological interventions for tic disorders, published since the initial European clinical guidelines were issued. Relevant studies were identified using computerized searches of the MEDLINE and PsycINFO databases for the years 2011-2019 and a manual search for the years 2019-2021. Based on clinical consensus, psychoeducation is recommended as an initial intervention regardless of symptom severity. According to a systematic literature search, most evidence was found for Habit Reversal Training (HRT), primarily the expanded package Comprehensive Behavioral Intervention for Tics (CBIT). Evidence was also found for Exposure and Response Prevention (ERP), but to a lesser degree of certainty than HRT/CBIT due to fewer studies. Currently, cognitive interventions and third-wave interventions are not recommended as stand-alone treatments for tic disorders. Several novel treatment delivery formats are currently being evaluated, of which videoconference delivery of HRT/CBIT has the most evidence to date. To summarize, when psychoeducation alone is insufficient, both HRT/CBIT and ERP are recommended as first-line interventions for tic disorders. As part of the development of the clinical guidelines, a survey is reported from ESSTS members and other tic disorder experts on preference, use and availability of psychological interventions for tic disorders., (© 2021. The Author(s).)

In 2011, the European Society for the Study of Tourette Syndrome (ESSTS) published the first European guidelines for Tourette Syndrome (TS). We now present an update of the part on pharmacological treatment, based on a review of new literature with special attention to other evidence-based guidelines, meta-analyses, and randomized double-blinded studies. Moreover, our revision took into consideration results of a recent survey on treatment preferences conducted among ESSTS experts. The first preference should be given to psychoeducation and to behavioral approaches, as it strengthens the patients' self-regulatory control and thus his/her autonomy. Because behavioral approaches are not effective, available, or feasible in all patients, in a substantial number of patients pharmacological treatment is indicated, alone or in combination with behavioral therapy. The largest amount of evidence supports the use of dopamine blocking agents, preferably aripiprazole because of a more favorable profile of adverse events than first- and second-generation antipsychotics. Other agents that can be considered include tiapride, risperidone, and especially in case of co-existing attention deficit hyperactivity disorder (ADHD), clonidine and guanfacine. This view is supported by the results of our survey on medication preference among members of ESSTS, in which aripiprazole was indicated as the drug of first choice both in children and adults. In treatment resistant cases, treatment with agents with either a limited evidence base or risk of extrapyramidal adverse effects might be considered, including pimozide, haloperidol, topiramate, cannabis-based agents, and botulinum toxin injections. Overall, treatment of TS should be individualized, and decisions based on the patient's needs and preferences, presence of co-existing conditions, latest scientific findings as well as on the physician's preferences, experience, and local regulatory requirements., (© 2021. The Author(s).)

In 2011 a working group of the European Society for the Study of Tourette Syndrome (ESSTS) has developed the first European assessment guidelines for Tourette syndrome (TS). Now, we present an updated version 2.0 of these European clinical guidelines for Tourette syndrome and other tic disorders, part I: assessment. Therefore, the available literature has been thoroughly screened, supplemented with national guidelines across countries and discussions among ESSTS experts. Diagnostic changes between DSM-IV and DSM-5 classifications were taken into account and new information has been added regarding differential diagnoses, with an emphasis on functional movement disorders in both children and adults. Further, recommendations regarding rating scales to evaluate tics, comorbidities, and neuropsychological status are provided. Finally, results from a recently performed survey among ESSTS members on assessment in TS are described. We acknowledge that the Yale Global Tic Severity Scale (YGTSS) is still the gold standard for assessing tics. Recommendations are provided for scales for the assessment of tics and psychiatric comorbidities in patients with TS not only in routine clinical practice, but also in the context of clinical research. Furthermore, assessments supporting the differential diagnosis process are given as well as tests to analyse cognitive abilities, emotional functions and motor skills., (© 2021. The Author(s).)

Gilles de la Tourette Syndrome (GTS) is a multifactorial neurodevelopmental disorder characterized by tics and multiple comorbidities. The pathophysiology is not yet fully understood, but both environmental and genetic risk factors seem to be involved. Twin studies provide important knowledge on genetic factors. We assessed the concordance of GTS and chronic tic disorders (CTD) in monozygotic (MZ) twins, and examined tic severity, symptoms of obsessive-compulsive disorder (OCD), attention deficit/hyperactivity disorder and autism spectrum disorder. Twin pairs, where at least one twin was diagnosed with any tic disorder, were identified through Danish Twin Registry, Psychiatric Central Registry, Danish National Patient Registry and National Tourette Clinic, Copenhagen University Hospital, Herlev. Zygosity was tested with single-nucleotide polymorphism (SNP) genotyping and clinical assessment was done with validated tools. 14 MZ twin pairs were included: five were discordant. Seven twin pairs were concordant for GTS, and for two pairs one twin had GTS and the other CTD. Among the twins with CTD or GTS, 50% had at least one comorbidity, which is higher than in background populations. The GTS + OCD-phenotype was significantly more frequent among GTS-concordant than among discordant twins. No statistically significant differences were found between the GTS-concordant and discordant twin pairs regarding tic severity or comorbidities. Thorough clinical assessment and SNP-based genotyping are important when conducting clinical twin studies. We found high concordance of GTS and CTD, which supports the notion that both disorders have common genetic risk factors. Further studies with larger cohorts including dizygotic twins are warranted for more conclusive results., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

During 2020, an increase of functional tics in children and adolescents has been observed. In this review, we present phenotypes, differential diagnosis and treatment for functional tics. We discuss potential contributing causes, like the COVID-19 pandemic and the focus on tics on social media. Functional tics are more complex than tics seen in Tourette syndrome and develop more suddenly in relation to stressors mainly in teenage girls. Psychosocial issues and comorbidities must be addressed and treated by a multidisciplinary team through psychoeducation and if necessary, cognitive-behavioural therapy.

Pediatric acute-onset neuropsychiatric syndrome is a clinical concept used to describe a subgroup of children with sudden onset of psychiatric and somatic symptoms. The diagnostic term and especially management of children differs depending on the clinical setting to which they present, and the diagnosis and management is controversial. The aim of this paper is to propose a clinical guidance including homogenous diagnostic work-up and management of paediatric acute onset neuropsychiatric syndrome within the Nordic countries. The guidance is authored by a Nordic-UK working group consisting of paediatric neurologist, child psychiatrists and psychologists from Denmark, Norway, Sweden and Great Britain, and is the result of broad consensus. CONCLUSION: Consensus was achieved in the collaboration on work-up and treatment of patients with paediatric acute-onset neuropsychiatric syndrome, which we hope will improve and homogenise patient care and enable future collaborative research in the field., (© 2021 The Authors. Acta Paediatrica published by John Wiley & Sons Ltd on behalf of Foundation Acta Paediatrica.)

Tic spectrum disorder (TSD) is an umbrella term which includes Gilles de la Tourette syndrome (GTS) and chronic tic disorder (CTD). They are considered highly heritable, yet the genetic components remain largely unknown. In this study we aimed to investigate disease-associated DNA methylation differences to identify genes and pathways which may be implicated in TSD aetiology. For this purpose, we performed an exploratory analysis of the genome-wide DNA methylation patterns in whole blood samples of 16 monozygotic twin pairs, of which eight were discordant and six concordant for TSD, while two pairs were asymptomatic. Although no sites reached genome-wide significance, we identified several sites and regions with a suggestive significance, which were located within or in the vicinity of genes with biological functions associated with neuropsychiatric disorders. The two top genes identified ( TSC1 and CRYZ / TYW3 ) and the enriched pathways and components (phosphoinosides and PTEN pathways, and insulin receptor substrate binding) are related to, or have been associated with, the PI3K/AKT/mTOR pathway. Genes in this pathway have previously been associated with GTS, and mTOR signalling has been implicated in a range of neuropsychiatric disorders. It is thus possible that altered mTOR signalling plays a role in the complex pathogenesis of TSD.

Introduction: For more than two decades several initiatives have emerged to increase recruitment of paediatric patients in drug trials. While trials of newly approved drugs have successfully included paediatric patients in their drug development plan, the collection of safety and efficacy data in paediatric patients treated with off-patent drugs poses a major challenge., Aim: This paper aims to draw attention to problems and solutions across countries in investigator-initiated trials with off-patent drugs and recommendations for improvement., Discussion: Off-patent drugs represent a particular challenge when they are included in a paediatric trial; these trials are frequently investigator-initiated and have limited resources, off-patent drugs are used in clinical settings and the trial protocol must accommodate e.g. flexible dosing and specimen sampling schedules, off-patent drugs typically exist in few formulations and concentrations which necessitates special or imported formulations. Paediatric trials are in some countries confined by e.g. consent from both parents, regardless of whether the Investigational Medicinal Product (IMP) is a well-known drug or a new experimental drug., Conclusion: Facilitation of research in off-patent drugs can improve evidence-based and safe treatment for the paediatric population. The following supportive initiatives are recommended: Harmonised regulatory change that improves the consent process in low risk trials to prevent inadequate recruitment. Pharmaceutical expertise should be prioritized to secure the best choice of IMP and supply. Constant focus on flexibility in design to accommodate a multifaceted paediatric population and ensure that trial protocols fit in well with routine clinical care and family life., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 The Authors.)

Gilles de la Tourette syndrome (GTS) is a complex neurodevelopmental disorder characterized by motor and vocal tics. Most of the GTS individuals have comorbid diagnoses, of which obsessive-compulsive disorder (OCD) and attention deficit-hyperactivity disorder (ADHD) are the most common. Several neurotransmitter systems have been implicated in disease pathogenesis, and amongst these, the dopaminergic and the serotonergic pathways are the most widely studied. In this study, we aimed to investigate whether the serotonin transporter (SERT) gene ( SLC6A4 ) was differentially expressed among GTS individuals compared to healthy controls, and whether DNA variants (the SERT-linked polymorphic region 5-HTTLPR, together with the associated rs25531 and rs25532 variants, and the rare Ile425Val variant) or promoter methylation of SLC6A4 were associated with gene expression levels or with the presence of OCD as comorbidity. We observed that SLC6A4 expression is upregulated in GTS individuals compared to controls. Although no specific genotype, allele or haplotype was overrepresented in GTS individuals compared to controls, we observed that the L AC /L AC genotype of the 5-HTTLPR/rs25531/rs25532 three-locus haplotype was associated with higher SLC6A4 mRNA expression levels in GTS individuals, but not in the control group.

Breath-holding spells are involuntary reflexive episodes in infants triggered by a provocation, which can result in seizures and loss of consciousness. The exact pathophysiology is yet unknown, but a dysregulation of the autonomic system seems to play a role. Several studies have examined the influence of iron, personality traits and oxidative stress, and treatment with iron has been shown to be effectful in some cases. Concentration problems and an increased risk of developing syncope later in life have been described. The level of evidence is low, and more future studies are needed, as argued in this review.

Objective: Tourette syndrome (TS) is a chronic childhood neurodevelopmental disorder characterized by motor and vocal tics and frequent comorbidities. The clinical presentation of Tourette syndrome is heterogeneous and the prognosis for each individual child is difficult to define. This large prospective longitudinal study explores predictors in childhood of the clinical course of tics and comorbidities in early adulthood., Methods: The cohort was recruited at the Danish National Tourette Clinic. Data were collected at baseline (N = 314; ages, 5-19 years) and follow-up 6 years later (n = 227; ages, 11-26 years) to examine changes in the expression of tics and comorbidities. Childhood clinical factors, represented by 4 binary clinical outcomes, were selected as possible predictors of the clinical course of tics and comorbidities in early adulthood; these were tic severity and diagnoses of obsessive compulsive disorder (OCD), attention-deficit hyperactivity disorder (ADHD), and emotional disorders., Results: The strongest predictors of high tic scores, OCD, or ADHD diagnoses in early adulthood were the corresponding tic (odds ratio [OR]: 1.09), OCD (OR: 1.08), and ADHD (OR: 1.13) severity scores (per scale point) in childhood. Being female (OR: 3.94) and childhood ADHD severity (OR: 1.11) predicted future emotional disorders. Special education, genetic factors, and psychosocial factors were also predictive for the clinical course of Tourette syndrome., Conclusion: We identified strong clinical predictors of Tourette syndrome-associated outcomes in early adulthood that are directly applicable to clinical Tourette syndrome populations and may help to guide new patients, plan early interventions, and implement preventive measures.

An old myth asserts, that the lunar phases influence epileptic seizures. This Christmas article examines the assertion by reviewing four articles about the correlation between the lunar phases and the frequency of seizures in patients with epilepsy and in patients with non-epileptic seizures. Hypotheses suggest, that sleep disturbances, melatonin level and nocturnal illumination may play a role in the relation between lunar phases and epileptic seizures. However, because of inconsistency in the literature, we cannot conclude any relation between the occurrence of epileptic seizures and the lunar phases.

Paediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) and paediatric acute-onset neuropsychiatric syndrome (PANS) have been suggested to be a result of a disordered immune response following an infection causing neuropsychiatric symptoms. Although the diagnosis PANDAS/PANS has been controversial, an increasing attention has been paid to the diagnosis, pathophysiology and treatment during the recent years. This review provides an update on knowledge of aetiology, recommended investigations and treatment in children with suspected PANDAS/PANS.

Tourette syndrome, obsessive-compulsive disorder, ticlike compulsions and motoric stereotypies are all movement disorders, which start in childhood and can be difficult to differentiate. In this article, we have outlined the most important focus points on how to differentiate the conditions in order to diagnose correctly and in order to refer to proper treatment.

Migraine is common and well-known in the adult population, but also frequent among children. In this review, the latest evidence on how to treat migraine in children is presented. The headache diary in which the episodes of headache are recorded, is an important tool in order to optimize the medical treatment and to avoid identified trigger factors. While the acute treatment of migraine is well-established, preventive medical treatment is not strongly evidence-based and should only be used in selected cases of severe or refractive migraine.

Headache is an increasingly common symptom among children and adolescents with a prevalence of 58.4%, and it may have profound impact on everyday life. A poorer prognosis is seen for children, who are not referred to specialist care, and long-term follow-up is shown to indicate a better outcome. A thorough headache history and a full neurological examination is vital to a correct diagnosis. The acute and prophylactic treatment is poorly studied, but acetaminophen and ibuprofen are first-line choices in acute treatment, and prophylactic treatment should be carried out by specialists.

Tourette syndrome (TS) is a neurodevelopmental disorder characterized by frequent comorbidities and a wide spectrum of phenotype presentations. This study aimed to describe the development of phenotypes in TS and tic-related impairment in a large longitudinal study of 226 children and adolescents followed up after 6 years. The participants were clinically examined to assess tic severity and impairment, obsessive compulsive disorder (OCD), and attention-deficit/hyperactivity disorder (ADHD). The development in phenotypes changed toward less comorbidity with 40% TS-only (no OCD or ADHD) (TS without OCD or ADHD) at baseline and 55% at follow-up.Tic-related impairment was expected to improve with an age-related tic decline, but surprisingly the impairment score did not reflect the tic decline. Sex, vocal and motor tics, and OCD and ADHD severity were highly significantly correlated to the impairment score. Knowledge of TS phenotype development is used in clinical settings to guide patients and for genetic, etiological, and clinical research purposes.

Chronic tic disorder and Tourette syndrome are both chronic and impairing neurobiological disorders starting in childhood with a prevalence between 0.4 and 1.6%. Traditionally, pharmacological therapies have been first-line treatment but are often associated with adverse effects. Recently behavioural therapy has shown to be effective in treating tics and today both habit reversal (HR) and exposure and response prevention (ERP) are recommended as first-line treatments. HR and ERP are now available for Danish patients. This article describes the evidence and recommendations for both therapies.