Liselotte Skov

European clinical guidelines for Tourette syndrome and other tic disorders. Part II: pharmacological treatment

To develop a European guideline on pharmacologic treatment of Tourette syndrome (TS) the available literature was thoroughly screened and extensively discussed by a working group of the European Society for the Study of Tourette syndrome (ESSTS). Although there are many more studies on pharmacotherapy of TS than on behavioral treatment options, only a limited number of studies meets rigorous quality criteria. Therefore, we have devised a two-stage approach. First, we present the highest level of evidence by reporting the findings of existing Cochrane reviews in this field. Subsequently, we provide the first comprehensive overview of all reports on pharmacological treatment options for TS through a MEDLINE, PubMed, and EMBASE search for all studies that document the effect of pharmacological treatment of TS and other tic disorders between 1970 and November 2010. We present a summary of the current consensus on pharmacological treatment options for TS in Europe to guide the clinician in daily practice. This summary is, however, rather a status quo of a clinically helpful but merely low evidence guideline, mainly driven by expert experience and opinion, since rigorous experimental studies are scarce.

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.

The Presence of Attention-Deficit Hyperactivity Disorder (ADHD) and Obsessive-Compulsive Disorder Worsen Psychosocial and Educational Problems in Tourette Syndrome

We assessed the psychosocial and educational consequences of Tourette syndrome using a structured interview and child behavior checklist in 314 children with Tourette syndrome and 81 healthy controls. Of the children with Tourette syndrome, 59.0% needed some kind of educational support, 44.7% had been teased, and 61.8% withheld themselves from taking part in social activities because of Tourette syndrome-related problems. There were significantly more psychosocial and educational problems in children with Tourette syndrome compared with healthy controls. A higher rate of these problems was also seen if the comorbidities attention-deficit hyperactivity disorder (ADHD) and/or obsessive compulsive disorder were present. It is very important for the physicians, teachers, and other professionals to be aware of the high prevalence of these social and educational problems to be able to deal with them and to teach the families to cope with them.

Intragenic deletions affecting two alternative transcripts of the IMMP2L gene in patients with Tourette syndrome

Tourette syndrome is a neurodevelopmental disorder characterized by multiple motor and vocal tics, and the disorder is often accompanied by comorbidities such as attention-deficit hyperactivity-disorder and obsessive compulsive disorder. Tourette syndrome has a complex etiology, but the underlying environmental and genetic factors are largely unknown. IMMP2L (inner mitochondrial membrane peptidase, subunit 2) located on chromosome 7q31 is one of the genes suggested as a susceptibility factor in disease pathogenesis. Through screening of a Danish cohort comprising 188 unrelated Tourette syndrome patients for copy number variations, we identified seven patients with intragenic IMMP2L deletions (3.7%), and this frequency was significantly higher (P=0.0447) compared with a Danish control cohort (0.9%). Four of the seven deletions identified did not include any known exons of IMMP2L, but were within intron 3. These deletions were found to affect a shorter IMMP2L mRNA species with two alternative 5′-exons (one including the ATG start codon). We showed that both transcripts (long and short) were expressed in several brain regions, with a particularly high expression in cerebellum and hippocampus. The current findings give further evidence for the role of IMMP2L as a susceptibility factor in Tourette syndrome and suggest that intronic changes in disease susceptibility genes should be investigated further for presence of alternatively spliced exons.

Limited Knowledge of Tourette Syndrome Causes Delay in Diagnosis

OBJECTIVE Tourette syndrome (TS) is characterized by the presence of tics and is often accompanied by other symptoms, like attention deficit hyperactive disorder (ADHD), obsessive-compulsive disorder. The presenting symptoms are supposed to be tics. Onset is usually around school age. Early diagnosis of TS is important in order to provide patients with the necessary support as early as possible. METHODS We examined the diagnostic process via a systematic interview in 314 children with TS. RESULTS Median age at onset of symptoms was 3.0 years. In 40.1%, tics were the presenting clinically meaningful symptoms; in the other cases it was an associated symptom, like ADHD symptoms, obsessive-compulsive behavior, or behavioral problems. Median age of tic onset was 5.5 years. If TS presented with an accompanying symptom, the median age of onset was earlier (0-3.5 years). The mean age at the time of diagnosis was 8.9 years. The median delay from onset of the presenting symptoms until diagnosis was 5.3 years and the delay from onset of tics until diagnosis 2.8 years. CONCLUSION There is a lack of knowledge about the normal course of TS among professionals and the public. Consequently, diagnosis is delayed and so accordingly is the initiation of the necessary support.

Microduplication of 15q13.3 and Xq21.31 in a family with tourette syndrome and comorbidities

Tourette syndrome (TS) is a childhood onset neurodevelopmental disorder. Although it is widely accepted that genetic factors play a significant role in TS pathogenesis the etiology of this disorder is largely unknown. Identification of rare copy number variations (CNVs) as susceptibility factors in several neuropsychiatric disorders such as attention deficit‐hyperactivity disorder (ADHD), autism and schizophrenia, suggests involvement of these rare structural changes also in TS etiology. In a male patient with TS, ADHD, and OCD (obsessive compulsive disorder) we identified two microduplications (at 15q13.3 and Xq21.31) inherited from a mother with subclinical ADHD. The 15q duplication included the CHRNA7 gene; while two genes, PABPC5 and PCDH11X, were within the Xq duplication. The Xq21.31 duplication was present in three brothers with TS including the proband, but not in an unaffected brother, whereas the 15q duplication was present only in the proband and his mother. The structural variations observed in this family may contribute to the observed symptoms, but further studies are necessary to investigate the possible involvement of the described variations in the TS etiology.

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.

Association of AADAC Deletion and Gilles de la Tourette Syndrome in a Large European Cohort

BACKGROUND Gilles de la Tourette syndrome (GTS) is a complex neuropsychiatric disorder with a strong genetic influence where copy number variations are suggested to play a role in disease pathogenesis. In a previous small-scale copy number variation study of a GTS cohort (n = 111), recurrent exon-affecting microdeletions of four genes, including the gene encoding arylacetamide deacetylase (AADAC), were observed and merited further investigations. METHODS We screened a Danish cohort of 243 GTS patients and 1571 control subjects for submicroscopic deletions and duplications of these four genes. The most promising candidate gene, AADAC, identified in this Danish discovery sample was further investigated in cohorts from Iceland, the Netherlands, Hungary, Germany, and Italy, and a final meta-analysis, including a total of 1181 GTS patients and 118,730 control subjects from these six European countries, was performed. Subsequently, expression of the candidate gene in the central nervous system was investigated using human and mouse brain tissues. RESULTS In the Danish cohort, we identified eight patients with overlapping deletions of AADAC. Investigation of the additional five countries showed a significant association between the AADAC deletion and GTS, and a final meta-analysis confirmed the significant association (p = 4.4 × 10(-4); odds ratio = 1.9; 95% confidence interval = 1.33-2.71). Furthermore, RNA in situ hybridization and reverse transcription-polymerase chain reaction studies revealed that AADAC is expressed in several brain regions previously implicated in GTS pathology. CONCLUSIONS AADAC is a candidate susceptibility factor for GTS and the present findings warrant further genomic and functional studies to investigate the role of this gene in the pathogenesis of GTS.

Headache in children: effectiveness of multidisciplinary treatment in a tertiary paediatric headache clinic.

Aim The aim of this article is to evaluate the effectiveness of a specific multidisciplinary treatment programme for children with headache and to describe the concept and settings of the Children’s Headache Clinic in Denmark. Method All new patients were included and evaluations were conducted after six and 12 months. Pharmacological and non-pharmacological treatments were offered by a team of specialists (physicians, headache nurses, a physiotherapist and a psychologist). Patients The subjects comprised 169 children (mean age 11.7 (range 4–17), 91 females, 78 males), 39% of whom suffered from chronic headache (≥15 days/month). All children were diagnosed according to the International Classification of Headache Disorders, second edition; 20% had migraine, 34% tension-type headache, 27% mixed headache, 4% medication-overuse headache, and 15% were diagnosed with other types of headaches. Results Fifty per cent of the children had an improvement in headache frequency above 50% at six months. By the use of repeated measurement analysis, we found a significant decrease in headache frequency in all of the six headache groups, whereas the increase in quality of life (PedsQL™ 4.0) was significant for the group as a whole. Conclusion Though preliminary, the results show a good outcome for multidisciplinary treatment programmes for children who suffer from frequent or chronic headache.

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.