European clinical guidelines for Tourette syndrome and other tic disorders-version 2.0. Part III: pharmacological treatment.

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.

Pharmacological treatment for Tourette syndrome in children and adults: What is the quality of the evidence? A systematic review.

BACKGROUND: Tourette syndrome (TS) is a neurodevelopmental disorder characterised by involuntary muscle movements manifesting as motor and vocal tics. In the majority, tics are manageable without medication. Where tics cause discomfort or impair function, behavioural or pharmaceutical treatments may be considered. AIMS: To provide a meticulous examination of the quality of evidence for the current pharmacological treatments for TS. METHODS: PubMed and Google Scholar were searched to identify randomised, placebo-controlled trials (RCTs) of aripiprazole, risperidone, clonidine, guanfacine, haloperidol, pimozide, tiapride and sulpiride for the treatment of tics in children and adults with TS. Quality of reporting and risk of bias were assessed against the CONSORT checklist and Cochrane risk of bias criteria, respectively. RESULTS: Seventeen RCTs were identified. Response rates reached 88.6% for aripiprazole, 68.9% for clonidine, 62.5% for risperidone and 19% for guanfacine. Statistically significant improvements were reported for all medications compared to placebo in at least one study and for at least one measure of tic severity. Most studies predated the CONSORT and Cochrane criteria and did not score highly when assessed on these measures. CONCLUSIONS: There are relatively few placebo-controlled trials of commonly prescribed medications. Studies are often of poor quality and short duration. There is evidence for the efficacy of each medication, but no drug is clearly superior. Clonidine and guanfacine are better tolerated than antipsychotics, but less effective. There is too little evidence to determine whether adults respond differently from children.

Driving with Tic Disorders: An International Survey of Lived Experiences.

BACKGROUND: Little is known about the lived experiences of individuals with tic disorders when driving vehicles or trying to obtain a driving license. OBJECTIVE: To survey the driving-related experiences of adults with tic disorders. METHODS: A global survey was disseminated via social media, international patient organizations, and experts between April 27, 2020 and July 20, 2020. RESULTS: Participants were 228 adult individuals self-reporting a confirmed diagnosis of Tourette syndrome or chronic tic disorder. Of these, 183 (87.7%) had a driver's license. A minority (9%) reported that they had found it hard to pass the driving test. Tics only interfered with driving "a bit" (58.5%) or "not at all" (33%). A majority of participants reported being able to suppress their tics (39.5%) or that their tics are unchanged (28.5%) while driving. Nearly half of the participants (46.5%) had been involved in accidents, but only a negligible percentage (3.2%) considered that these were linked to the tics. Participants without a driver's license (n = 28, 12.3%) reported significantly more severe tics, compared to those with a license. The majority of these (60.7%) identified their tics as the main reason for not having a license and 64.3% said that they would like to receive support to obtain one. CONCLUSIONS: The majority of surveyed participants with chronic tic disorders reported minimal difficulties with driving. However, a non-negligible minority of more severe cases struggle with driving or refrain from driving altogether and would benefit from additional support. The results have implications for clinicians and vehicle licensing agencies.

Gilles de la Tourette Syndrome: advice in the times of COVID-19.

The novel coronavirus disease (COVID-19) was identified as the cause of an outbreak of respiratory disease in China at the end of 2019. It then spread with enormous rapidity and by mid-March 2020 was declared a world pandemic. Gilles de la Tourette Syndrome (GTS) is a childhood-onset neurodevelopmental disorder with a worldwide prevalence of about 1% of the population. The clinical symptoms include multiple motor and one or more phonic (vocal) tics. Germane to this communication is that 85% of patients with GTS have associated psychiatric co-morbidities, many of which are being exacerbated in the current global health crisis. In addition, several symptoms of GTS may mimic COVID-19, such as a dry cough and sniffing (phonic tics), while other symptoms such as spitting, inappropriate touching of others and "non-obscene socially inappropriate symptoms" can potentially get patients with GTS into trouble with the law. We suggest that a clear explanation of the COVID-19 illness and GTS is important to enable colleagues of various specialities who tend to patients with GTS. It is important to acknowledge at the outset that the information available on the COVID-19 pandemic changes daily, including cases infected, deaths reported, and how various national health systems are planning and or coping or not. It is fair to say that having read the current medical and lay press we conclude that it is not easy to reassure our patients with absolute certainty. However, notwithstanding that, we hope our documentation is of some assistance.

Tourette's syndrome and its borderland.

The Gilles de la Tourette syndrome (or Tourette's syndrome) has a prevalence of 1% of children with a wide range of severity and associated comorbidities. The last 20 years have seen advances in the understanding of the syndrome's complex genetics and underlying neurobiology. Investigation with imaging and neurophysiology techniques indicate it is a neurodevelopmental condition with dysfunction of basal ganglia-cortical interactions, which are now also being studied in animal models. There is also increasing evidence for treatments although it often remains difficult to manage. First-line options include neuroleptics, other drugs and specialised behavioural treatments. Deep brain stimulation is an evolving field, not yet fully established. This review focuses on the phenomenology of tics, how to assess and manage the syndrome, and uses examples of atypical cases to explore the characteristics and limits of its clinical spectrum.

Comprehension of direct and indirect sarcastic remarks in children and adolescents with Tourette's syndrome.

Previous research has reported that aspects of social cognition such as nonliteral language comprehension are impaired in adults with Tourette's syndrome (TS), but little is known about social cognition in children and adolescents with TS. The present study aims to evaluate a measure of sarcasm comprehension suitable for use with children and adolescents (Experiment 1), and to examine sarcasm comprehension in children and adolescents with TS-alone or TS and attention deficit hyperactivity disorder (ADHD; Experiment 2). In Experiment 1, the measure of sarcasm comprehension was found to be sensitive to differences in nonliteral language comprehension for typically-developing children aged 10 to 11 years old compared to children aged 8 to 9 years old; the older group performed significantly better on the comprehension of scenarios ending with either direct or indirect sarcastic remarks, whereas the two age groups did not differ on the comprehension of scenarios ending with sincere remarks. In Experiment 2, both the TS-alone and TS+ADHD groups performed below the level of the control participants on the comprehension of indirect sarcasm items but not on the comprehension of direct sarcasm items and sincere items. Those with TS+ADHD also performed below the level of the control participants on measures of interference control and fluency. The findings are discussed with reference to the possible contribution of executive functioning and mentalizing to the patterns of performance.

The First World Congress on Tourette Syndrome and Tic Disorders: Controversies and Hot Topics in Etiology and Treatment.

The first World Congress on Tourette Syndrome and Tic Disorders was held in London, June 2016 by the Tourette Association of America, Tourettes Action (UK), and the European Society for the Study of Tourette Syndrome. Presentations arising from large-scale collaborative projects were an important component of the scientific programme. This article focuses on areas raised in the hot topics session and two moderated debates, which covered emerging research in etiology and treatment. The hot topics ranged across genetics, arguably including the first confirmed Tourette Syndrome (TS) susceptibility gene NRXN1, neurocognition, and neurophysiology, including the possibility of a neurocognitive endophenotype for TS and the use of depth and cortical surface electrodes to investigate the neurophysiology of tics on the background of the evolving field of deep brain stimulation (DBS), to novel treatment approaches such as dental orthotics and an online behavioral intervention. The debates aired controversies in treatment; pharmacotherapy vs. behavioral treatment and the place of medical cannabinoids. These sessions demonstrate the vibrancy of a field that has considerably expanded in the last decade, the significant progress that has been made, and the direction that some of the most fruitful next phases of research will take.

Serial pharmacological prescribing practices for tic management in Tourette syndrome.

Pharmacological treatments for Tourette syndrome (TS) vary in efficacy between different patients. The evidence base is limited as even high quality controlled studies tend to be of relatively short duration which may lose relevance in clinical usage. Patients are frequently treated with serial agents in the search for efficacy and tolerability. The success of this strategy has not been previously documented. We examined 400 consecutive TS patients seen over a 10-year period, some with a longer prior history in other clinics; 255/400 (64%) were prescribed medication. We present this heterogeneous cohort in terms of the number of drugs they had tried, and as a proxy measure of some benefit of the last drug used, whether it had been prescribed under our supervision for ≥ 5 months. The most commonly prescribed medications were aripiprazole (64%), clonidine (40%), risperidone (30%) and sulpiride (29%) with changes in prescribing practises over the period examined. The number of different drugs tried were one (n = 155), two (n = 69), three (n = 36), four (n = 14), five (n = 15), six (n = 5), seven (n = 2) and eight (n = 1). The data illustrate the difficulty in drug treatment of tics and suggest that even after trials of several agents there is potential benefit in trying further options.

Premonitory urges for tics in adult patients with Tourette syndrome.

OBJECTIVE: Patients with Tourette syndrome (TS) often report characteristic sensory experiences, also called premonitory urges (PUs), which precede tic expression and have high diagnostic relevance. This study investigated the usefulness of a scale developed and validated in children and adolescents-the Premonitory Urge for Tics Scale (PUTS, Woods et al., 2005 [13])-for the assessment of PUs in adult patients with TS. METHOD: Standard statistical methods were applied to test the psychometric properties of the PUTS in 102 adult TS outpatients recruited from two specialist clinics in the United Kingdom. RESULTS: The PUTS showed good acceptability and endorsement rates, with evenly distributed scores and low floor and ceiling effects. Item-total correlations were moderate to strong; PUTS total scores were significantly correlated with quantitative measures of TS severity. The PUTS showed excellent internal consistency reliability (Cronbach's alpha=0.85) and Spearman's correlations demonstrated satisfactory convergent and discriminant validity. CONCLUSIONS: Although originally devised to assess urges to tic in young patients with TS, the PUTS demonstrated good psychometric properties in a large sample of adults recruited at specialist TS clinics. This instrument is therefore recommended for use across the life span as a valid and reliable self-report measure of sensory experiences accompanying tic expression.

A brief history of the European Society for the Study of Tourette Syndrome.

The European Society for the Study of Tourette syndrome (ESSTS) was established in Denmark in 2000 by Mary Robertson and Anne Korsgaard. The aims of the organisation are to foster research activity and raise awareness of Tourette syndrome throughout Europe. The organisation went into abeyance in 2002 but was resurrected in 2007 in Bari, Italy. Since that time ESSTS has grown and prospered. We have established elected officers and a constitution. We have successfully applied for three large scale European research grants and have members throughout the European Union. We have held yearly meetings across Europe including two training schools and we have developed successful alliances with patient support groups. ESSTS has developed and published the first European guidelines on assessment, diagnosis and treatment of Tourette syndrome.

Emotional processing and executive functioning in children and adults with Tourette's syndrome.

Tourette's syndrome (TS) is predominantly a childhood disorder, with many of those who meet diagnostic criteria in childhood experiencing a remission of symptoms in adulthood. This indicates that the influence of TS on cognitive and emotional processing can best be understood by examining performance in both adults and children with TS. The present study examined emotional processing using a battery of face and prosody tasks with increasing levels of difficulty (same-different emotion discrimination, emotion naming, and emotion naming with conflict for prosody only). Experiment 1 compared the performance of children with TS-alone (n = 16) or TS+ADHD (n = 15) to healthy matched control children (n = 27). Compared to healthy control children, no significant group differences were found for those with TS-alone. Children with TS+ADHD showed subtle impairments on the more difficult emotion processing tasks relative to healthy control children, and differences were more pronounced for anger items (voice emotion naming, p < .05; voice emotion naming with conflict, p < .01). Experiment 2 compared the performance of adults with TS-alone (n = 23) to healthy matched controls (n = 21). No significant group differences were found, other than evidence of subtle impairment in the adults with TS-alone on the most complex task, again particularly for anger items (p < .05). Separate measurement of executive skills detected no evidence of impairment in children or adults with TS and little in the way of correlational evidence linking emotion recognition and executive skills. Implications of the findings for our understanding of emotion processing in TS are discussed.

Possible role of repetitive practice of activities requiring reflexive responses in the treatment of Tourette's disorder.

We report 2 boys, 11 and 7 years old, whose Tourette's disorder improved significantly after a period of repeated, sustained practice of activities requiring reflexive responses One boy engaged in physical exercise including hand-eye co-ordination (table tennis for 6 hours every weekday) and the other learned foreign languages (5 languages within 3 years). Tics may be thought of as a kind of overflow of energy, and excessive energy consumption with physical or mental exercise may improve the motor disorder and associated comorbidities. However, the exercise may require a quick, reflexive response to visual or verbal stimuli.

Dissecting the Gilles de la Tourette spectrum: a factor analytic study on 639 patients.

BACKGROUND: Recent studies using quantitative methods, such as principal component factor analysis, hierarchical cluster analysis and latent class analysis have suggested that Gilles de la Tourette syndrome (GTS) should no longer be considered a unitary condition as in current classification systems. OBJECTIVE: To identify quantitative components of GTS symptomatology using a large, well characterised cohort of singleton individuals with GTS in order to inform future genetic studies with more homogeneous phenotypes. METHODS: Principal component factor analysis with oblique rotation was used to analyse symptom data from a sample of 639 patients recruited at two tertiary referral centres using identical schedules during the period 1980-2008. RESULTS: Three Factors were identified: (1) complex motor tics and echo-paliphenomena; (2) attention deficit and hyperactivity symptoms plus aggressive behaviours; and (3) complex vocal tics and coprophenomena. Obsessive compulsive behaviours loaded significantly on the first two factors. The three factors accounted for 48.5% of the total symptomatic variance. CONCLUSIONS: GTS is a phenotypically heterogeneous condition encompassing simple tics, specific complex tics and associated behavioural problems. The results, coupled with previous findings, identified a clinical continuum of complex tics, hyperactivity/impulsivity symptoms and semantically relevant utterances and gestures. A better characterisation of the GTS phenotypes will help to identify susceptibility genes.

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

A working group of the European Society for the Study of Tourette Syndrome (ESSTS) has developed the first European assessment guidelines of Tourette Syndrome (TS). The available literature including national guidelines was thoroughly screened and extensively discussed in the expert group of ESSTS members. Detailed clinical assessment guidelines of tic disorders and their comorbidities in both children and adults are presented. Screening methods that might be helpful and necessary for specialists' differential diagnosis process are suggested in order to further analyse cognitive abilities, emotional functions and motor skills. Besides clinical interviews and physical examination, additional specific tools (questionnaires, checklists and neuropsychological tests) are recommended.

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.

The role of cellular oxidative stress in regulating glycolysis energy metabolism in hepatoma cells.

BACKGROUND: The Warburg effect has been found in a wide spectrum of human cancers, however the underlying mechanisms are still unclear. This study aims to explore the role of cellular oxidative stress in relation to glycolysis and the Warburg effect in hepatoma cells. METHODS: Various cell lines combining environmental hypoxia was used as an in vitro model to mimic tumor microenvironment in vivo. Superoxide dismutases (SOD) and xanthine oxidase (XO) gene transfection were used to produce various cellular redox levels. 2',7'-dichlorofluorescin (DCF) fluorescence and ESR spectrum were used to detect cellular reactive oxygen species (ROS). RESULTS: We found that endogenous or exogenous interference with the cellular oxidative stress can sensitively regulate glycolysis and the Warburg effect in hepatoma cells. Hepatoma cells displayed a high level of free radicals compared to immortalized normal hepatocyte cells. Increasing the level of ROS stress in hepatoma cells can directly upregulate HIF-1 and activate glycolysis without requirement of a hypoxic condition. This explains the mechanism whereby aerobic glycolysis, i.e. the Warburg effect arises. Either endogenously upregulating SOD or exogenously administration with antioxidant can, through downregulating ROS level, effectively regulate energy pathways in hepatoma cells and can inhibit the growth of tumor cells and xenograft tumors. CONCLUSION: This study suggests that the Warburg effect was related to an inherently high level of cellular ROS and HIF-1. Hepatoma cells adaptation to hypoxia for survival and rapid growth exploits oxidative stress ectopically activated glycolysis to compensate the energy supply. This specific mechanism in which tumor cells through cellular oxidative stress activate glycolysis to meet their energy metabolism requirement could be exploited to selectively kill tumor cells.

Coprophenomena in Tourette syndrome.

The aims of this descriptive study were to examine the prevalence and associations of coprophenomena (involuntary expression of socially unacceptable words or gestures) in individuals with Tourette syndrome. Participant data were obtained from the Tourette Syndrome International Database Consortium. A specialized data collection form was completed for each of a subset of 597 consecutive new patients with Tourette syndrome from 15 sites in seven countries. Coprolalia occurred at some point in the lifetime of 19.3% of males and 14.6% of females, and copropraxia in 5.9% of males and 4.9% of females. Coprolalia was three times as frequent as copropraxia, with a mean onset of each at about 11 years, 5 years after the onset of tics. In 11% of those with coprolalia and 12% of those with copropraxia these coprophenomena were one of the initial symptoms of Tourette syndrome. The onsets of tics, coprophenomena, smelling of non-food objects, and spitting were strongly intercorrelated. Early onset of coprophenomena was not associated with its longer persistence. The most robust associations of coprophenomena were with the number of non-tic repetitive behaviors, spitting, and inappropriate sexual behavior. Although coprophenomena are a frequently feared possibility in the course of Tourette syndrome, their emergence occurs in only about one in five referred patients. Because the course and actual impact of coprophenomena are variable, additional prospective research is needed to provide better counseling and prognostic information.

Stroke during induction of labour in a patient with carotid aneurysm and prior multiple venous thromboses.

A case of stroke during induction of labour in a pregnant patient at term anticoagulated for prior venous thrombosis is reported. The cause was a middle cerebral artery embolism, originating from a false dissecting aneurysm of the internal carotid artery. Investigations and causes of stroke in a pregnant patient are briefly outlined.

Alpha-lipoic acid induces apoptosis in hepatoma cells via the PTEN/Akt pathway.

We report here that alpha-lipoic acid (alpha-LA), a naturally-occurring antioxidant, scavenges reactive oxygen species (ROS) followed by an increase in apoptosis of human hepatoma cells. Apoptosis induced by alpha-LA was dependent upon the activation of the caspase cascade and the mitochondrial death pathway. alpha-LA induced increases in caspase-9 and caspase-3 but had no significant effect on caspase-8 activity. Apoptosis induced by alpha-LA was found to be mediated through the tensin homologue deleted on chromosome 10 (PTEN)/Akt pathway. Prior to cell apoptosis, PTEN was activated and its downstream target Akt was inhibited. Our findings indicate that increasing ROS scavenging could be a therapeutic strategy to treat cancer.