Abstract
We present here a work in progress, summarizing research from 2018 relevant to Tourette syndrome. This working draft aims towards a preprint that we plan to submit for publication around the end of 2018. The authors briefly summarize a few reports they consider most important or interesting. We welcome article suggestions and thoughtful feedback from readers, who can comment using the balloon icons that appear if you hover the mouse pointer over the upper right edge of the text on this page.
Introduction
This article is meant to disseminate recent scientific progress on Gilles de la Tourette Syndrome (TS). Through the end of the year, it will be a work in progress, maintained as a web page on the
Authorea online authoring platform. Around the end of the year, we plan to submit it for publication as the annual update for
the Tics collection on F1000Research.
Methods
We searched PubMed from time to time during 2018 using the search strategy “("Tic Disorders"[MeSH] OR Tourette NOT Tourette[AU]) AND 2018[PDAT] NOT 1950:2017[PDAT]”. On 03 February 2019 this search
returned 178 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.
Results
Phenomenology and natural history
The EMTICS ONSET and COURSE studies: a plan for important research on development and course of tic disorders \citep{29982875}.
Review of heterogeneity in tic disorders \citep{Eapen_2018}.
Epidemiology
Lowe and colleagues performed a very long interval follow-up study TS, assessing tic severity, quality of life, and psychosocial function \cite{Lowe2019}. Of 150 surveys mailed to patients seen 25-32 years ago, 45 were returned (30%). 79% reported still having at least some tics, 40% reported some level of social impairment, and 20% were either unemployed, disabled or financially supported by family. However, the great majority of patients had improved in terms of tics and were doing well in other areas of their lives. Tics are 4-6 times more common in children with ADHD than in those without, and tics add to clinical problems and reduced quality of life \citep{29317441}.
Transient environmental effects on tic severity
Tic suppression
Sensory phenomena and premonitory urges
A new instrument, the Individualized Premonitory Urge for Tics Scale (I-PUTS) was developed to measure premonitory phenomena in children \citep{McGuire_2017}. The clinician-administered questionnaire assesses multiple dimensions of the premonitory urge, including urge frequency, urge intensity, and urge location experienced in the past. I-PUTS was administered to 75 children and adolescents diagnosed with TS or a tic disorder. The measure had strong inter-rater reliability, good convergent validity of individual dimensions with total I-PUTS score, small-to-moderate positive correlation with tic severity, and no significant correlations with any comorbid psychopathology. I-PUTS results revealed that 79% of subjects reported premonitory urges, which were most frequently experienced in the head/face (35%), neck/throat (22%), and arms (19%). Urges experienced in the whole body/other region were reported less frequently, but with the greatest intensity score; urges in the neck/throat had the second-greatest intensity score. Subjects reported an average of three premonitory urges of mild-to-moderate intensity, experienced during more than 50% of instances of tic expression.
Interoception is interesting as it shares features with sensory phenomena in TS \citep{29884281}. A derived measure of interoception predicts tic severity and premonitory sensations in TS; the authors suggest their results suggest "a heightened higher-order sensitivity to bodily sensations in TS, relative to a noisier perceptual representation of afferent bodily signals." \citep{30544073}.
Impaired olfactory function, but normal peripheral detection of olfactory stimuli, was demonstrated in TS. Subjects with TS (n = 28) did not differ in odor detection threshold, but did present with impairments in both odor discrimination and odor identification. There was no significant difference in tobacco usage between the groups. 25% percent of subjects with TS met criteria for functional anosmia, compared to 7% of controls. This suggests that alterations in olfactory phenomena likely occur during higher-order processing, rather than during peripheral detection, in people with TS \cite{Kronenbuerger2018}. This observation is consistent with previous similar conclusions about tactile sensory function in TS.
Other
Weingarden et al. report that self-esteem is decreased in adults with TS and CTD (n=122) \cite{Weingarden_2018}. This, however, is less related to tics / tic severity but rather related to psychiatric comorbidities. When treating these patients, self-esteem was improved more by comprehensive Behavioral Intervention for Tics (CBIT) than by Psychoeducation and Supportive Therapy (PST), which seems plausible. It would be interesting to replicate the same study in children and adolescents. A review also examines the concept of self-esteem in TS and CTD, drawing a similar conclusion, i.e. that poor self-esteem appears more strongly related to psychiatric comorbidities than to tic severity, and, unsurprisingly, affects quality of life \cite{Silvestri2018}.
TS phenotypes were investigated in 174 children and adolescents in French University Clinic \cite{Cravedi2018}. Three clusters were identified. One of them corresponded to a tic-only phenotype ('pure' TS) whereas another cluster included learning and intellectual disabilities, ASD, and ADHD. The third cluster corresponded to an ADHD profile with rather high intelligence and handwriting problems due to tics. Therapeutic implications are discussed.
A survey of almost 700 parents, about half with tics, found that children with current or past tics slept an average of 1.5 hours less per night than did control children \citep{Ricketts_2017}. This result supports clinical experience and underlines both the impact of tic disorders on quality of life and a potential avenue for treatment.
Religious symptoms were not associated with various clinical variables including outcome in children and adolescents with OCD \citep{Wu_2018}. This result suggests that scrupulosity and similar symptoms in children with TS can be expected to improve just as much as other OCD symptoms with appropriate treatment.
Severe neck tics led to a vertebral artery dissection \citep{Aydin_2018}, a reminder that tics are not always benign. Another case report describes closed head trauma due to head banging in a 15 year old, with important sequelae \cite{Fasano2018}. These reports underline the need for rapid and aggressive tic management in some patients.
\citet*{29636375} discusses cases on the borders of TS, such as tic disorder beginning in adulthood and the question of functional (conversion) tics.
Etiology
Genetics
Tying genetics of TS to genetics of brain volumes \citep{Mufford_2018}
Polygenic risk scores from a GWAS validated in the Avon Longitudinal Study \citep{30424865}
Genetic overlap of OCD and ADHD subtypes with Tourette syndrome \citep{28651666}
Epigenetics
Environmental risk factors
A large, full-population study from Sweden studied all singleton births in Sweden over a 30-year period, using siblings as controls \citep{28348386}. It found that "impaired fetal growth, preterm birth, breech presentation and cesarean section were associated with a higher risk of" TS or chronic tic disorder. The risks were dose-dependent, with hazard ratios rising from 1.41 for one adverse perinatal event to 2.42 for 5 or more such events. This report is important for its careful design, sample size and implications. It confirms previous indications that not all of the risk for TS is inherited, and points specifically to intrauterine and birth insults as contributing to that risk.
Pathophysiology
Animal models
\citep{Nespoli2018} found that dopaminergic imbalance in the dorsal striatum induced a Tourette's-like phenotype in a rodent model. Administration of quinpirole, a selective D2/D3 receptor agonist, in juvenile rats with lesions to striatal projection neurons produced both simple and complex tics in the neck, limbs, and mouth. A modified YGTSS was created to comprehensively score tic-like movements based on frequency, complexity, and severity of impairment. Immunohistochemical analyses revealed significantly decreased D1 receptor RNA expression at the lesion site, consistent with the decreased striatal D1 receptor expression seen in a human post-mortem study of Tourette's \citep{Lennington2016}. The dopaminergic imbalance induced by decreased striatal D1 receptor activity, coupled with increased D2 receptor activity, may also be relevant to the pathophysiology of Tourette's syndrome.
Pathological studies
Electrophysiology
Eight awake TS patients undergoing DBS electrode implantation had recordings of individual cells of the external and internal globus pallidus (GP) \citep{28556479}. Some cells in each division of the GP showed transient changes in firing rates associated with tics.
Neuroimaging studies
\cite{Sigurdsson2018} WM microstructure, structural connectivity between M1 and insula \cite{Sigurdsson2018} include
7T spectroscopy, glutamate and GABA, increased glutamate in premotor area in TS \cite{Mahone2018} include
Tic suppression, blink suppression \citep{30268027} look into this one look into this one
Pharmacological studies
\citet{Maia_2018} elaborate on their theory of how dopamine may relate to tics in TS.
\citet{30072700} provide a meta-analysis of PET and SPECT studies in TS measuring the dopamine transporter (DAT) or D2-like dopamine receptors.
Clinical and neuropsychological studies
A research consortium in Germany has recently proposed that tics may correspond to altered perception-action binding \cite{Beste2018}. Here comes a first experimental demonstration in 35 adolescents with TS and 39 healthy controls using a Go/no-go task and subsequent EEG analysis, providing support for the idea that stimulus-action binding is stronger in patients with TS, and that "unbinding" may thus represent a useful therapeutic venue \cite{Petruo2018}.
On motor inhibition: \citep{30485912}
Autoimmune diseases in OCD and TS/CTD \cite{29133949}
Other
Inhibition in children with OCD and TS \cite{Mancini2018}
Executive control in TS and tic reduction \cite{Yaniv2018}
Treatment
Psychological interventions
Group-based psychotherapeutic interventions for tics bear the promise of reduced costs and easier access to appropriate care. One recent paper has investigated the long term effects of this approach on tic severity, quality of life and school attendance in 28 children with TS 12 months after completing HRT training or education (a follow up to the 2016 study, \cite{Yates2016}), both showing positive effects in the long run but apparently without significant differences between both groups \cite{Dabrowski2018}.
A Scandinavian study investigated a combined ERP / HRT protocol comparing group with individual sessions (n=27 per group, n=54 total). The efficacy on decreasing tic severity was similar in both treatment arms \citep{Nissen2018}.
Traditionally, ERP sessions (as compared to HRT / CBIT) were supposed to last for two hours, making them more difficult and expensive. In this study, session duration was shortened to one hour and shorter exposure was as effective, if not more, than the classic format \citep{van2018}.
Final publication of this clinical trial: Seragni G, Chiappedi M, Bettinardi B, Zibordi F, Colombo T, Reina C, Angelini L: Habit Reversal Training in children and adolescents with chronic tic disorders: an Italian randomized, single blind, pilot study. Minerva Pediatr 70(1):5-11, 2018.
Link to full text
Medication
Swedish treatment registries were searched to identify patterns of medication prescribing for almost 7000 patients with TS/CTD from 2005–2013 \citep{29870273}. Among other interesting findings, ADHD drugs, antidepressants, and hypnotics/sedatives were all prescribed more often than antipsychotics.
A first direct comparison of pharmacotherapy with behavioral therapy in children and adolescents with TS / CTD \cite{Rizzo2018}. Both approaches were effective in reducing tics and improving quality of life; however, only pharmacotherapy was effective in reducing OC symptoms.
The D1 receptor antagonist ecopipam was compared to placebo in a double-blind, crossover, randomized controlled trial (RCT) in children and adolescents with TS \citep{chipkin2017}\citep{chipkin2018}. YGTSS total tic score (TTS) declined significantly more with the active drug.
Neurosurgery
Efficacy and Safety of Deep Brain Stimulation in Tourette Syndrome: The International Tourette Syndrome Deep Brain Stimulation Public Database and Registry \citep{Martinez_Ramirez_2018}. This report summarizes information on 185 Tourette patients from 10 countries. Mean improvement in total YGTSS score was 40% at 6 months after vs. before surgery, and 45% at 12 months. The difference between stimulation sites (CM-Pf, anterior GPi, posterior GPi) was not statistically significant. About a third of patients had side effects, mostly related to stimulation not surgery.
\citet{Smeets2018} discuss ethical considerations regarding DBS in TS patients under the age of 18. \citet{Canaz2018} also offer their experience in two pediatric TS patients who underwent DBS.
Butson and colleagues, 3D analysis of DBS results (poster)