Andreas Hartmann

and 2 more

Copyright © 2019, the authors. AH: ORCiD 0000-0002-0335-984XYW: ORCiD 0000-0001-5903-9370AbstractThis is the sixth yearly article in the Tourette Syndrome Research Highlights series, summarizing research from 2019 relevant to Tourette syndrome and other tic disorders. The highlights from 2020 is being drafted on the Authorea online authoring platform; readers are encouraged to add references or give feedback on our selections comments feature on page. After the calendar year ends, article is submitted as the annual update for the Tics collection F1000Research.IntroductionThis article is meant to disseminate recent scientific progress on Gilles de la Tourette Syndrome (TS). MethodsWe searched PubMed from time to time during 2019 using the search strategy “("Tic Disorders"[MeSH] OR Tourette NOT Tourette[AU]) AND 2019[PDAT] NOT 1950:2018[PDAT]”. On 16January 2020 this search returned 211 citations. Colleagues also recommended articles, and we attended selected medical conferences. We selected material for this review subjectively, guided by our judgment of possible future impact on the field.ResultsPhenomenology and natural history\citet{30661132} present a stimulating argument based on data that demonstrate a severity continuum between chronic tics and TS using a database regrouping 1018 subjects. They thus conclude that TS and chronic tics do not represent distinct diagnostic categories. Accordingly, they suggest the introduction of the the term "tic spectrum disorders" (in analogy to autism spectrum disorders) which might present the added benefit of decreased social stigma related to TS.  Martino and Hedderly provide an excellent review on the differences between tics and stereotypies, and their clinical management \citep*{30773283} A useful resource is the video atlas of various vocalizations with includes tics and helps with differential diagnosis \citep{31651053}.EpidemiologySeveral good epidemiological studies and meta-analyses on the childhood prevalence of TS have been published over the past years, with most figures ranging between 0.5 to 0.8%. However, prevalence in adulthood remains unknown. Levine et al. analyzed three studies (published 1986, 2011 and 2016) involving 2,356,485 participants \citep{31220521}. Overall prevalence of TS in adulthood was estimated to be 118 cases of TS per million adults, that is  0.0118%. This appears very low, even factoring in remission in two thirds to three quarters of childhood cases during adulthood (which, in itself, is debatable). Clearly, more research is needed on this important topic, preferrably using current DSM-5 criteria. Tic suppression Tic suppression in children with recent-onset tics predicts one-year tic outcome \citep{31241402}Sensory phenomena and premonitory urgesA hypothesis about sensorimotor causation of tics \citep{30890965}OtherDavid Mataix-Cols’ group continue their epidemiological exploration of patients with Tourette syndrome (TS) and chronic tic disorders (CTD) using the Swedish National Patient Register. This time, they look for metabolic and cardiovascular disorders in these patients, and find that the risk is doubled compared to the general population, especially with regard to obesity, type 2 diabetes and circulatory system diseases. With regard to co-morbidities, the presence of attention-deficit / hyperactivity disorder significantly increases the risk (however, excluding ADHD does not normalize the risk, still 50% higher than in the general population). Most surprisingly, use of antipsychotic medication for more than one year was associated with a significantly decreased risk for metabolic and cardiovascular disorders in patients with TS or CTD. This counterintuitive finding, giving antipsychotics’ propensity to induce metabolic syndrome, requires further clarification. For now, the authors speculate that patients with TS or CTD receiving medication benefit from frequent follow ups and better monitoring of their general health. In any case, this a further demonstration, after papers on suicide and educational attainment in patients with TS or CTD, that these conditions are far from benign and require correct diagnosis, then regular care and follow up \citep{30640363}EtiologyGenetics2019 has seen the publication of a variety of studies using whole exome sequencing. Depienne et al. \citep{Depienne2019} investigated 120 TS patients and identified disrupting variants of OPRK1, encoding the opioid kappa receptor, in a significant subset of subjects compared to controls. This result points to a role, already discussed since the 1980s, of the opioid system as involved in the pathophysiology of TS and also as a potential therapeutic target. Further, after whole exome sequencing of 100 trios (TS patients and their parents), point mutations  ASH1 Like Histone Lysine Methyltransferase (ASH1L - causing defects in its enzymatic activity) were identified as a susceptibility gene for TS \citep{31673123}. A transgenic mouse line (Ash1l heterozygous mice) indeed displayed tic-like motor and compulsive behaviors; also dopaminergic hyperinnervation  was observed in the dorsal striatum, conferring this model good construct validity. Two more genes, chromodomain helicase DNA binding protein 8 (CHD8) and Signal Peptide, CUB Domain And EGF Like Domain Containing 1 (SCUBE1), were identified by whole exome sequencing in a cohort of 222 OCD parent-child trios, and it was further show these genes overlap with genes previously implicated in TS \citep{31771860}.Using the Swedish National Registry, it was shown that maternal polycystic ovary syndrome (PCOS), as a model for investigating the role of prenatal androgen exposure, is a risk for TS, ADHD and ASD \citep{30857571}. These results support a potential causal influence of prenatal androgen exposure on the development of male-predominant neuropsychiatric disorders in female offspring of women with PCOS.
Many (though not all) of my patients who have tried marijuana have felt that their tics improved after using it. Such self-treatment is not rare (poster P94 here), and other doctors report similar results (see for example poster P6 here). Pharmacological benefits from cannabis products are plausible, since cannabinoid receptors in the brain's basal ganglia are well positioned to affect movement . Of course, in addition to any real benefit from marijuana, there could be expectation effects, or one could simply care less about tics when high. Random allocation clinical trials with blind rating of benefit (RCTs) are essential to demonstrating whether marijuana has any true benefit for tics. Müller-Vahl and colleagues carried out two RCTs about 15 years ago in Tourette syndrome (TS) using THC (tetrahydrocannabinol), the main intoxicating ingredient in cannabis . Both trials showed benefit, but the trials were relatively small. Two to 3 years ago, the Tourette Association of America funded two pilot studies in this field, but results have not yet been reported. One trial, at Yale, was to study the FAAH (fatty acid amide hydrolase) inhibitor PF-04457845 in TS , but the trial was placed on clinical hold pending results from a different trial. Investigators at Toronto Western Hospital were funded for a trial in TS of medical cannabis products with varying concentrations of THC and cannabidiol . Cannabidiol is being studied in several brain disorders, including epilepsy, with hopes that it may provide benefit without the psychological side effects of THC. Not surprisingly, the paucity of data has led to different viewpoints. Müller-Vahl has argued that THC may be appropriate in some TS patients , whereas an American Academy of Neurology review and a Cochrane-style review in JAMA concluded that the evidence was insufficient to recommend THC for tic disorders . The clinical utility of cannabinoids in TS was one of two clinical controversies debated at the 2015 First World Congress on Tourette Syndrome and Tic Disorders .