European clinical guidelines for Tourette syndrome and other tic disorders-version 2.0. Part I: assessment.

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.

EWAS of Monozygotic Twins Implicate a Role of mTOR Pathway in Pathogenesis of Tic Spectrum Disorder.

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.

Elevated Expression of SLC6A4 Encoding the Serotonin Transporter (SERT) in Gilles de la Tourette Syndrome.

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 LAC/LAC 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.

Predictors of the Clinical Course of Tourette Syndrome: A Longitudinal Study.

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.

Co-morbid disorders in Tourette syndrome.

Tourette syndrome (TS) is often accompanied by other symptoms and syndromes. The two best-known co-morbidities are Attention Deficit Hyperactivity Disorder (ADHD) and Obsessive Compulsive Disorder (OCD), but also other conditions like rage-attacks, depression, and sleeping disturbances are frequent in persons with TS. Both in clinical cohorts and in population-based cohorts the prevalence of co-morbidities is high. The presence of co-morbid ADHD and/or OCD has an impact on psychosocial, educational, and neuropsychological consequences of TS and it is associated with higher rates of other co-morbid disorders, like rage, anxiety, and conduct disorders. The symptoms of a co-morbid disorder might appear prior to the time that tics reach clinical attention. The TS phenotype probably changes during the course of the disease. The exact aetiology of the co-occurrence of co-morbid disorders and TS is not known, but they probably all are neurotransmitter disorders. European guidelines recommend first-choice pharmacological treatment, but randomised double-blinded trials are needed. Professionals need to be aware of the close relationship between TS and co-morbidities in order to give the patients the right treatment and support.

A functional magnetic resonance imaging study of a large clinical cohort of children with Tourette syndrome.

There is evidence that cortico-striato-thalamo-cortical pathways are involved in the pathophysiology of Tourette syndrome. During the performance of neuropsychological tests in subjects with Tourette syndrome there are suggestions for increased activity in the sensimotor cortex, supplementary motor areas, and frontal cortex. To replicate findings, the authors examined 22 medication-naive children with Tourette syndrome only, 17 medication-naive children with Tourette syndrome and comorbidity, and 39 healthy controls with functional magnetic resonance imaging (MRI). There were no differences in activation in brain regions between the children with Tourette syndrome (divided according to the presence of comorbidity) and healthy controls after correction for the confounders age, sex, and intelligence. Activation in the cingulated gyrus, temporal gyrus, and medial frontal gyrus was correlated significantly with obsessive-compulsive disorder score. The authors did not find significant correlations between activation patterns and age, sex, duration of disease, intelligence, severity of tics, and attention-deficit hyperactivity disorder (ADHD) score.

Performance on Wechsler intelligence scales in children with Tourette syndrome.

BACKGROUND: There is some evidence that Tourette syndrome is associated with cognitive disabilities. AIMS: To examine the cognitive performance of a clinical cohort of children with Tourette syndrome. METHODS: 266 children with Tourette syndrome have been examined with Wechsler Intelligence Scales. The presence of the co-morbidities attention deficit hyperactivity disorder (ADHD) and obsessive-compulsive disorder (OCD) was assessed using validated diagnostic instruments. Eighty healthy controls matched a part of the TS cohort. RESULTS: The children with Tourette syndrome had a mean verbal IQ (VIQ) of 92.9, performance IQ (PIQ) of 87.1, and full-scale IQ (FSIQ) of 88.8. We found statistically significant higher PIQ and FSIQ in the control group compared with a matched TS cohort and a trend towards a higher VIQ among the healthy controls. There was a statistically significant influence of age at onset of tics on PIQ. The children with co-morbid OCD scored higher on FSIQ compared with the other groups. The children with co-morbid ADHD and OCD showed problems in motor tasks and speed tasks and the children with co-morbid ADHD showed attention deficits. CONCLUSIONS: Children with Tourette syndrome have lower IQ scores than the general population (but less than one standard deviation below) and our control group. Early onset of tics and the presence of co-morbidities might cause specific deficits on cognitive performance.

Predictive factors for familiality in a Danish clinical cohort of children with Tourette syndrome.

Tourette syndrome (TS) is a chronic, neurobiological disease, characterized by the presence of motor and vocal tics and it is often accompanied by associated symptoms. The two best-known co-morbidities are Obsessive-Compulsive Disorder (OCD) and Attention Deficit Hyperactivity Disorder (ADHD). The fact that TS aggregates strongly in families suggests that family members share either genetic and/or environmental risk factors contributing to TS. Numerous studies have been performed to examine the familiality in TS, but clear-cut factors to predict hereditability in TS have not been found yet. We have examined a large Danish clinical cohort of children with TS (N=307). Validated diagnostic instruments were used to assess the presence of co-morbidities in the children with TS. A three-generation pedigree was drawn for all the probands and through reports from the family, a family history and the frequency of affected relatives was noted. The rates of tics, symptoms of OCD, and ADHD among relatives are similar to the rates found in other countries and are higher than in the general population. Although the role of sex in determining the phenotype has to be examined more thoroughly, we found that male relatives were more likely to have tics and female relatives were more likely to have symptoms of OCD. When comparing the relatives to male patients with relatives to female patients, there were no differences in the rates of symptoms, apart from symptoms of ADHD that were more frequent in second-degree relatives to female patients. The severity of tics and the presence of co-morbidity did not seem to predict the familiality of TS and its associated symptoms.

The presence of comorbidity in Tourette syndrome increases the need for pharmacological treatment.

Tourette syndrome is often accompanied by other syndromes, like attention-deficit hyperactivity disorder (ADHD) and obsessive-compulsive disorder, and its treatment is symptomatic. Because there are no European guidelines for pharmacological treatment in Tourette syndrome, we wanted to contribute to a better insight into the common practice in Scandinavia. Furthermore, we wanted to elaborate the influence of the presence of comorbidities and of the severity of tics on pharmacological treatment. We have examined the frequency, art, and reason for pharmacological treatment in a Danish clinical cohort of 314 children with Tourette syndrome. In total, 60.5% of the children once had received pharmacological treatment. Mostly, the treatment was started because of tics or ADHD. If ADHD or obsessive-compulsive disorder were present, more children received pharmacological treatment and more different agents were tried. The children who received pharmacological treatment had more severe tics than those without medication.

Validation of the presence of comorbidities in a Danish clinical cohort of children with Tourette syndrome.

Tourette syndrome (TS) is characterized by the presence of motor and vocal tics and is often accompanied by comorbid symptoms. We assessed the frequency of the comorbid symptoms obsessive-compulsive disorder obsessive-compulsive disorder, attention-deficit hyperactivity disorder (ADHD), rage attacks, sleeping disturbances, and depressive symptoms in a Danish clinical cohort of 314 children with TS using validated diagnostic instruments. For the assessment of symptoms of seasonal affective disorder and stuttering, we used a nonvalidated systematic interview. In total, only 10.2% of the children did not have any comorbid symptoms at all. If ADHD and/or obsessive-compulsive disorder were present, the rates of the comorbidities rage, symptoms of seasonal affective disorder, sleep disturbances, and depressive symptoms were significantly higher than if ADHD and/or obsessive-compulsive disorder were absent. The most severe tics were found in the group for which both ADHD and obsessive-compulsive disorder were present. Furthermore, there was a tendency toward more severe tics if other comorbid symptoms were present.

[Tourette syndrome. Genetics, neuroanatomy and neurotransmitters]. / Tourettes syndrom. Genetik, neuroanatomi og neurotransmittere.

The etiology and pathophysiology of Tourette syndrome (TS) have not yet been clarified. Despite inconsistencies in the literature, some conclusions can be drawn on genetics, neuroanatomy and neurotransmitters. The inheritance of TS is unknown; the etiology seems to be polygenic. The basal ganglia are probably smaller in patients with TS. A dysfunction in the dopaminergic pathway causes tics. ADHD results from a decreased concentration of dopamine and an increased concentration of noradrenaline. OCD is caused by a dysfunction in serotonin and probably dopamine.

[Clinical aspects of Tourette syndrome]. / Kliniske aspekter ved Tourettes syndrom.

Tourette syndrome (TS) is a hereditary, chronic, neurobiological disease, characterized by the presence of motor and vocal tics. The disease is often accompanied by other symptoms: Attention Deficit Hyperactive Disorder (ADHD), Obsessive Compulsive Disorder (OCD), sleeping disorders, learning disabilities, speech disfluencies, outbursts of extreme anger and behavioural problems. Treatment must be multidisciplinary. The most disabling symptom should be treated medically and the drug of first choice depends on the pathophysiology of this symptom.

[Omphalitis with fatal outcome in new-born baby boy]. / Omfalitis med fatal udgang hos en nyfødt dreng.

Omphalitis is a serious condition with important morbidity and mortality, especially in developing countries. The most commonly involved micro-organisms are Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa. We describe a Danish patient with cellulitis, severe septicaemia, and portal vein thrombosis as fatal complications of omphalitis. In spite of early recognition and prompt treatment in this case, it was not possible to save the child.