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.

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.

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.

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.

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.

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.

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.

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.