Functional Tic-Like Behaviors: A Common Comorbidity in Patients with Tourette Syndrome.

BACKGROUND: Comorbid functional tic-like behaviors (FTB) have been described only rarely in patients with Tourette syndrome (TS). OBJECTIVES: We present the first large sample of patients suffering from TS and FTB to raise awareness of this clinical presentation and to guide how to differentiate one from the other. METHODS: We analyzed clinical data of 71 patients (n = 27 [38.0%] female, mean age: 21.5, range: 11-55) with TS + FTB. RESULTS: In the majority of patients, FTB started abruptly on average 15 years after tic onset with "treatment-resistant" complex movements and ("coprophenomena-like") vocalizations preceded by timely related psychological stressors. Psychological evaluation revealed evidence for internal conflicts (79%), emotional dysregulation (56%), and maintaining factors (70%). About one third of patients had a positive history for further medically unexplained symptoms. Compared to a large TS sample (n = 1032), patients with TS + FTB were more likely to be female, and presented significantly more common with "coprophenomena-like" symptoms, atypical influential factors, atypical descriptions of premonitory sensations, and higher rates of comorbid obsessive-compulsive disorder and "self-injurious" behavior. CONCLUSIONS: Based on our data it can be assumed that FTB is a common comorbidity in TS, similar to functional overlay in other movement disorders and epilepsy. Before classifying a patient as suffering from treatment-resistant TS, FTB should be ruled out.

The Effect of Nabiximols on Driving Ability in Adults with Chronic Tic Disorders: Results of a Substudy Analysis of the Double-Blind, Randomized, Placebo-Controlled CANNA-TICS Trial.

Background: The multicenter, randomized, double-blind, parallel-group, phase IIIb CANNA-TICS (CANNAbinoids in the treatment of TICS) trial showed clear trends for improvement of tics, depression, and quality of life with nabiximols versus placebo in adult patients with Gilles de la Tourette syndrome and other chronic tic disorders. Although in general nabiximols was well tolerated, it is unclear whether treatment using this cannabis extract influences driving skills in patients with chronic tic disorders. Methods: Here we report results of the "Fitness to Drive" substudy of the CANNA-TICS trial. The key endpoint was fitness to drive as a binary criterion with a computerized assessment at baseline and after 9 weeks of stable treatment (week 13) with nabiximols or placebo. A patient was considered unfit to drive according to the German Federal Highway Research Institute guidelines. Results: In the substudy, a total of 64 patients (76.6% men, mean±standard deviation of age: 36.8±13.9) were recruited at two study sites. The number of patients who were fit to drive increased from 24 (55.8%) at baseline to 28 (71.8%) at week 13 among 43 patients treated with nabiximols, and decreased from 14 (66.7%) to 10 (52.6%) among 21 patients who received placebo. The risk difference (nabiximols - placebo) was 0.17 (95% confidence interval=-0.08 to 0.43) in favor of nabiximols. Specifically, only 2 of 24 (8.3%) patients in the nabiximols, but 4 of 14 (28.6%) patients in the placebo group changed for the worse from fit (at baseline) to unfit (at week 13) to drive, whereas 8 of 19 (42.1%) patients in the nabiximols, and only 2 of 7 (28.6%) patients in the placebo group improved from unfit to fit. Conclusion: Treatment with nabiximols does not impair skills relevant to driving in those patients with tic disorders who were fit to drive at baseline and even improved fitness to drive in a subset of patients who were unfit to drive before start of treatment. EudraCT number: 2016-000564-42.

What distinguishes patients with mass social media-induced illness presenting with Tourette-like behavior from those with Tourette syndrome? Results of a prospective cohort study.

Since 2019, a global increase in patients presenting with functional Tourette-like behaviors (FTB) has been observed. This has been related to the exposure of tic-related content in social media, although other factors seem to further fuel this phenomenon. Recently, we, therefore, proposed the term mass social media-induced illness (MSMI) as, in our opinion, this phenomenon constitutes a new type of mass sociogenic illness (MSI) that is in contrast to all recent outbreaks spread solely via social media. In accordance with this hypothesis, we were able to identify the host of the German YouTube channel "Gewitter im Kopf" ("Thunderstorm in the brain") as the initial virtual index case. The purpose of this paper is to present clinical characteristics of a sample of 32 patients diagnosed with MSMI-FTB compared to a large sample of patients with Tourette syndrome (TS) and other chronic tic disorders (CTD) (n = 1032) from the same center in Germany indicating clinical factors helpful to distinguish between tics in TS/CTD and MSMI-FTB. Our main findings were: in patients with MSMI-FTB compared to those with TS/CTD we found (i) a significantly higher age at onset, (ii) a significantly higher rate of females, (iii) a significantly higher rate of obscene and socially inappropriate symptoms, (iv) a significantly lower rate of comorbid ADHD, and (v) a significantly lower rate of OCD/OCB. In contrast, rates of comorbid anxiety and depression as well as reported frequencies of premonitory urges/sensations and suppressibility of symptoms did not differ between groups.

Non-just-right experiences are more closely related to OCD than tics in Tourette patients.

Complex tics and obsessive or compulsive behaviour can be difficult to differentiate diagnostically. The majority of adult patients with Tourette syndrome report experiencing premonitory urges before tics. Some of these experiences have been linked to non-just-right experiences (NJRE), which are frequently reported by patients with obsessive-compulsive disorder or behaviours (OCD/OCB). We aimed to assess whether NJRE are more closely related to tics and tic-associated premonitory urges or whether they are more closely associated with OCD. A total of N = 111 patients (mean age = 34.77 + /-12.93; N = 37 female) with a confirmed diagnosis of Tourette syndrome completed the premonitory urges for tic disorders scale (PUTS), the revised non-just-right experiences scale (NJRE-QR), and questionnaires regarding their tic severity, and comorbid OCD/OCB. A multi-trait-multi-methods matrix was calculated to examine associations amongst scales measuring tic-related and OCB-related phenomena. The PUTS correlated overall higher with tic questionnaires than with OCD/OCB questionnaires. The NJRE correlated higher with OCD symptoms than with tic severity. The results indicate that non-just-right experiences are more closely associated with comorbid OCB than with tics in patients with Tourette syndrome.

CANNA-TICS: Efficacy and safety of oral treatment with nabiximols in adults with chronic tic disorders - Results of a prospective, multicenter, randomized, double-blind, placebo controlled, phase IIIb superiority study.

Preliminary data suggest that cannabis-based medicines might be a promising new treatment for patients with Tourette syndrome (TS)/chronic tic disorders (CTD) resulting in an improvement of tics, comorbidities, and quality of life. This randomized, multicenter, placebo-controlled, phase IIIb study aimed to examine efficacy and safety of the cannabis extract nabiximols in adults with TS/CTD (n = 97, randomized 2:1 to nabiximols:placebo). The primary efficacy endpoint was defined as a tic reduction of ≥ 25% according to the Total Tic Score of the Yale Global Tic Severity Scale after 13 weeks of treatment. Although a much larger number of patients in the nabiximols compared to the placebo group (14/64 (21·9%) vs. 3/33 (9·1%)) met the responder criterion, superiority of nabiximols could formally not be demonstrated. In secondary analyses, substantial trends for improvements of tics, depression, and quality of life were observed. Additionally exploratory subgroup analyses revealed an improvement of tics in particular in males, patients with more severe tics, and patients with comorbid attention deficit/hyperactivity disorder suggesting that these subgroups may benefit better from treatment with cannabis-based medication. There were no relevant safety issues. Our data further support the role of cannabinoids in the treatment of patients with chronic tic disorders.

The spectrum of functional tic-like behaviours: Data from an international registry.

BACKGROUND AND PURPOSE: Between 2019 and 2022, there was a marked rise in adolescents/young adults seeking urgent help for functional tic-like behaviours (FTLBs). Given the global scale of this phenomenon, we aimed to pool cases from different institutions in an international registry to better characterize this spectrum and facilitate future longitudinal observation. METHODS: An international collaborative group from 10 tertiary referral centres for tic disorders collected retrospective data on FTLB patients who sought specialists' attention between the last quarter of 2019 and June 2022. An audit procedure was used for collection of data, which comprised demographics, course of presentation and duration, precipitating and predisposing factors, phenomenology, comorbidities, and pharmacological treatment outcome. RESULTS: During the study period, we collected data on 294 patients with FTLBs, 97% of whom were adolescents and young adults and 87% of whom were female. FTLBs were found to have a peak of severity within 1 month in 70% of patients, with spontaneous remissions in 20%, and a very high frequency of complex movements (85%) and vocalizations (81%). Less than one-fifth of patients had pre-existing primary tic disorder, 66% had comorbid anxiety disorders, 28% comorbid depressive disorders, 24% autism spectrum disorder and 23% attention deficit/hyperactivity disorder. Almost 60% explicitly reported exposure to tic-related social media content. The vast majority of pharmacologically treated patients did not report benefit with tic-suppressing medications. CONCLUSIONS: Our data from the largest multicentre registry of FTLBs to date confirm substantial clinical differences from primary tic disorders. Social modelling was the most relevant contributing factor during the pandemic. Future longitudinal analyses from this database may help understand treatment approaches and responsiveness.

Mass social media-induced illness presenting with Tourette-like behavior.

Currently, we are facing a new manifestation of functional neurological disorder presenting with functional Tourette-like behavior (FTB). This study aimed to show characteristics of this phenotype presenting as an outbreak of "mass social media-induced illness" (MSMI) and to explore predisposing factors. Between 5-9/2021, we prospectively investigated 32 patients (mean/median age: 20.1/18 years, range: 11-53 years, n = 16 females) with MSMI-FTB using a neuro-psychiatric examination, a comprehensive semi-structured interview and aspects of the Operationalized Psychodynamic Diagnostic System. In contrast to tics, numbers of complex movements and vocalizations were nine times greater than of "simple" symptoms, and of vocalizations one and a half times greater than of movements. In line with our hypothesis of MSMI, symptoms largely overlapped with those presented by German YouTuber Jan Zimmermann justifying his role as "virtual" index case in current outbreak. Typically, symptoms started abruptly at a mean age of 19 years and deteriorated gradually with no differences between males and females. In all patients, we identified timely-related psychological stressors, unconscious intrapsychic conflicts, and/or structural deficits. Nearly all patients (94%) suffered from further psychiatric symptoms including abnormalities in social behavior (81%), obsessive-compulsive behavior (OCB) (47%), Tourette syndrome (TS) (47%), anxiety (41%), and depression (31%), about half (47%) had experienced bullying, and 75% suffered from coexisting somatic diseases. Our data suggest that pre-existing abnormalities in social behavior and psychiatric symptoms (OCB, anxiety, and depression), but also TS in combination with timely-related psychological stressors, unconscious intrapsychic conflicts, and structural deficits predispose to contagion with MSMI-FTB.

Implications for blinding in clinical trials with THC-containing cannabinoids based on the CANNA-TICS trial.

Randomized double-blind placebo-controlled trials (RCTs) are regarded as the gold standard for clinical trials. While there are established standards to avoid unblinding, in RCTs using tetrahydrocannabinol (THC) containing cannabinoids, however, accidental unblinding and intentional self-unbinding must be considered as a particular issue, since THC tests are widely available. To investigate unblinding rates in an RCT using a THC-containing cannabinoid, we re-contacted 54 out of 97 participants of the CANNA-TICS trial who had participated in our study center in Hannover. Of the 54 participants, 53 could be reached. Of these, one participant (2%) stated that she had unblinded herself intentionally during the treatment phase, and another three patients (6%) reported intentional unblinding after the end of the treatment. Noteworthy, two patients provided discrepant information and denied self-unblinding during the interview, although during study/clinic visits they had reported having done so. Thus, based on all available information, three participants (6%) unblinded themselves intentionally during the treatment phase and another three (6%) after the end of the treatment. Accidental unblinding during the treatment phase was reported by 4/54 participants (7%) (during study visits). Since one participant reported both intentional self-unblinding (during the interview) and accidental unblinding (during a study visit), the total unblinding rate was 17% (n = 9). Of these, seven participants (13%) reported unblinding during the treatment phase. When asked in the interview whether they knew that self-unblinding would have been possible, only 34% (n = 18/53) of participants stated that they had been aware of this possibility. Thus, altogether 33% (n = 6/18) of those being informed about the possibility of self-unblinding did so and half of them (3/18, 17 %) during the treatment phase. It can be expected that in parallel to increasing knowledge of medicinal and recreational use of cannabinoids, more and more people will also be informed about the availability of THC tests. Hence, in future RCTs using THC-containing cannabinoids, researchers have to take the possibility of accidental and intentional unblinding into consideration, when designing the study.

ONLINE-TICS: Internet-Delivered Behavioral Treatment for Patients with Chronic Tic Disorders.

Comprehensive Behavioral Intervention for Tics (CBIT) is considered a first-line therapy for tics. However, availability of CBIT is extremely limited due to a lack of qualified therapists. This study is a multicenter (n = 5), randomized, controlled, observer-blind trial including 161 adult patients with chronic tic disorders (CTD) to provide data on efficacy and safety of an internet-delivered, completely therapist-independent CBIT intervention (iCBIT Minddistrict®) in the treatment of tics compared to placebo and face-to-face (f2f) CBIT. Using a linear mixed model with the change to baseline of Yale Global Tic Severity Scale-Total Tic Score (YGTSS-TTS) as a dependent variable, we found a clear trend towards significance for superiority of iCBIT (n = 67) over placebo (n = 70) (-1.28 (-2.58; 0.01); p = 0.053). In addition, the difference in tic reduction between iCBIT and placebo increased, resulting in a significant difference 3 (-2.25 (-3.75; -0.75), p = 0.003) and 6 months (-2.71 (-4.27; -1.16), p < 0.001) after the end of treatment. Key secondary analysis indicated non-inferiority of iCBIT in comparison to f2f CBIT (n = 24). No safety signals were detected. Although the primary endpoint was narrowly missed, it is strongly suggested that iCBIT is superior compared to placebo. Remarkably, treatment effects of iCBIT even increased over time.

Endocannabinoid Modulation Using Monoacylglycerol Lipase Inhibition in Tourette Syndrome: A Phase 1 Randomized, Placebo-Controlled Study.

INTRODUCTION: Tourette syndrome (TS) is a complex neurodevelopmental disorder characterized by chronic motor and vocal tics. While consistently effective treatment is lacking, evidence indicates that the modulation of endocannabinoid system is potentially beneficial. Lu AG06466 (previously ABX-1431) is a highly selective inhibitor of monoacylglycerol lipase, the primary enzyme responsible for the degradation of the endocannabinoid ligand 2-arachidonoylglycerol. This exploratory study aimed to determine the effect of Lu AG06466 versus placebo on tics and other symptoms in patients with TS. METHODS: In this phase 1b cross-over study, 20 adult patients with TS on standard-of-care medications were randomized to a single fasted dose of Lu AG06466 (40 mg) or placebo in period 1, followed by the other treatment in period 2. The effects on tics, premonitory urges, and psychiatric comorbidities were evaluated using a variety of scaled approaches at different time points before and after treatment. RESULTS: All scales showed an overall trend of tic reduction, with two out of three tic scales (including the Total Tic Score of the Yale Global Tic Severity Score) showing a significant effect of a single dose of Lu AG06466 versus placebo at various timepoints. Treatment with Lu AG06466 resulted in a significant reduction in premonitory urges versus placebo. Single doses of Lu AG06466 were generally well-tolerated, and the most common adverse events were headache, somnolence, and fatigue. CONCLUSION: In this exploratory trial, a single dose of Lu AG06466 showed statistically significant positive effects on key measures of TS symptoms.

Stop that! It's not Tourette's but a new type of mass sociogenic illness.

We report the first outbreak of a new type of mass sociogenic illness that in contrast to all previously reported episodes is spread solely via social media. Accordingly, we suggest the more specific term 'mass social media-induced illness'. In Germany, the current outbreak of mass social media-induced illness is initiated by a 'virtual' index case, who is the second most successful YouTube creator in Germany and enjoys enormous popularity among young people. Affected teenagers present with similar or identical functional 'Tourette-like' behaviours, which can be clearly differentiated from tics in Tourette syndrome. Functional 'Tourette-like' symptoms can be regarded as the 'modern' form of the well-known motor variant of mass sociogenic illness. Moreover, they can be viewed as the 21st century expression of a culture-bound stress reaction of our post-modern society emphasizing the uniqueness of individuals and valuing their alleged exceptionality, thus promoting attention-seeking behaviours and aggravating the permanent identity crisis of modern man. We wish to raise awareness of the current global Tourette-like mass social media-induced illness outbreak. A large number of young people across different countries are affected, with considerable impact on health care systems and society as a whole, since spread via social media is no longer restricted to specific locations such as local communities or school environments spread via social media is no longer restricted to specific locations such as schools or towns.

Cannabis Improves Stuttering: Case Report and Interview with the Patient.

Introduction: Speech dysfluency, often referred to as stuttering, is a frequent speech disorder encountered in about 5% of children. Although in the majority of people affected, symptoms improve in adulthood, in some patients, stuttering persists and significantly impairs everyday functioning and quality of life. Treatment for stuttering includes speech therapy, cognitive behavioral therapy, and relaxation techniques. However, a substantial number of patients do not benefit sufficiently from these treatment strategies or are even treatment resistant. Methods: We present the case of a 20-year-old male with treatment-resistant stuttering, who markedly improved after treatment with medicinal cannabis. Results: Besides improved speech fluency as assessed by several phoniatric tests, we observed remission of (social) anxiety, improved mood, and reduced stress, resulting in an overall improvement of quality of life after cannabis therapy. The patient, in addition, reported improved attention, concentration, and sleep, increased self-confidence, and better social life. No side effects occurred. Over a time period of more than a year, treatment was equally effective. In an interview, the patient describes his personal view and the influence of cannabis-based treatment on his life. Conclusions: Medicinal cannabis could be effective in treatment of refractory stuttering, but these preliminary data have to be confirmed in controlled studies.

Monoacylglycerol Lipase Inhibition in Tourette Syndrome: A 12-Week, Randomized, Controlled Study.

BACKGROUND: Modulation of the endocannabinoid system via monoacylglycerol lipase inhibition with Lu AG06466 (formerly known as ABX-1431) has previously been shown to reduce tics in patients with Tourette syndrome. OBJECTIVE: The aim of this study was to evaluate the efficacy and safety of Lu AG06466 in reducing tics, premonitory urges, and comorbidities in patients with Tourette syndrome. METHODS: This was a 12-week, multicenter, randomized, placebo-controlled, double-blind clinical trial of Lu AG06466 given at two dose levels in 49 adults with Tourette syndrome. RESULTS: Both treatment groups showed improvement on the Total Tic Score of the Yale Global Tic Severity Scale; the mean (95% CI) treatment difference at week 8 of 3.0 (0.1, 5.9) (P = 0.043) favored placebo. No significant differences were seen for other endpoints assessing changes in tic severity, premonitory urges, quality of life, and common psychiatric comorbidities. Treatment with Lu-AG06466 was generally safe. CONCLUSIONS: There was no evidence that Lu AG06466 has efficacy in suppressing tics. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Yale Global Tic Severity Scale (YGTSS): Psychometric Quality of the Gold Standard for Tic Assessment Based on the Large-Scale EMTICS Study.

The Yale Global Tic Severity Scale (YGTSS) is a clinician-rated instrument considered as the gold standard for assessing tics in patients with Tourette's Syndrome and other tic disorders. Previous psychometric investigations of the YGTSS exhibit different limitations such as small sample sizes and insufficient methods. To overcome these shortcomings, we used a subsample of the large-scale "European Multicentre Tics in Children Study" (EMTICS) including 706 children and adolescents with a chronic tic disorder and investigated convergent, discriminant and factorial validity, as well as internal consistency of the YGTSS. Our results confirm acceptable convergent and good to very good discriminant validity, respectively, indicated by a sufficiently high correlation of the YGTSS total tic score with the Clinical Global Impression Scale for tics (r s = 0.65) and only low to medium correlations with clinical severity ratings of attention deficit/hyperactivity symptoms (r s = 0.24), obsessive-compulsive symptoms (r s = 27) as well as internalizing symptoms (r s = 0.27). Internal consistency was found to be acceptable (Ω = 0.58 for YGTSS total tic score). A confirmatory factor analysis supports the concept of the two factors "motor tics" and "phonic tics," but still demonstrated just a marginal model fit (root mean square error of approximation = 0.09 [0.08; 0.10], comparative fit index = 0.90, and Tucker Lewis index = 0.87). A subsequent analysis of local misspecifications revealed correlated measurement errors, suggesting opportunities for improvement regarding the item wording. In conclusion, our results indicate acceptable psychometric quality of the YGTSS. However, taking the wide use and importance of the YGTSS into account, our results suggest the need for further investigations and improvements of the YGTSS. In addition, our results show limitations of the global severity score as a sum score indicating that the separate use of the total tic score and the impairment rating is more beneficial.

The CANNA-TICS Study Protocol: A Randomized Multi-Center Double-Blind Placebo Controlled Trial to Demonstrate the Efficacy and Safety of Nabiximols in the Treatment of Adults With Chronic Tic Disorders.

Background: Gilles de la Tourette syndrome (TS) is a chronic neuropsychiatric disorder characterized by motor and vocal tics. First-line treatments for tics are antipsychotics and tic-specific behavioral therapies. However, due to a lack of trained therapists and adverse events of antipsychotic medication many patients seek alternative treatment options including cannabis. Based on the favorable results obtained from case studies on different cannabis-based medicines as well as two small randomized controlled trials using delta-9-tetrahydrocannabinol (THC), we hypothesize that the cannabis extract nabiximols can be regarded as a promising new and safe treatment strategy in TS. Objective: To test in a double blind randomized clinical trial, whether treatment with the cannabis extract nabiximols is superior to placebo in patients with chronic tic disorders. Patients and Methods: This is a multicenter, randomized, double-blind, placebo controlled, parallel-group, phase IIIb trial, which aims to enroll 96 adult patients with chronic tic disorders (TS or chronic motor tic disorder) across 6 centers throughout Germany. Patients will be randomized with a 2:1 ratio into a nabiximols and a placebo arm. The primary efficacy endpoint is defined as tic reduction of at least 30% (compared to baseline) according to the Total Tic Score of the Yale Global Tic Severity Scale (YGTSS-TTS) after 13 weeks of treatment. In addition, several secondary endpoints will be assessed including changes in different psychiatric comorbidities, quality of life, driving ability, and safety assessments. Discussion: This will be the first large, controlled study investigating efficacy and safety of a cannabis-based medicine in patients with TS. Based on available data using different cannabis-based medicines, we expect not only a reduction of tics, but also an improvement of psychiatric comorbidities. If the cannabis extract nabiximols is proven to be safe and effective, it will be a valuable alternative treatment option. The results of this study will be of high health-economic relevance, because a substantial number of patients uses cannabis (illegally) as self-medication. Conclusion: The CANNA-TICS trial will clarify whether nabiximols is efficacious and safe in the treatment of patients with chronic tic disorders. Clinical Trial Registration: This trial is registered at clinicaltrialsregister.eu (Eudra-CT 2016-000564-42) and clinicaltrials.gov (NCT03087201).

Cannabis Improves Obsessive-Compulsive Disorder-Case Report and Review of the Literature.

Although several lines of evidence support the hypothesis of a dysregulation of serotoninergic neurotransmission in the pathophysiology of obsessive-compulsive disorder (OCD), there is also evidence for an involvement of other pathways such as the GABAergic, glutamatergic, and dopaminergic systems. Only recently, data obtained from a small number of animal studies alternatively suggested an involvement of the endocannabinoid system in the pathophysiology of OCD reporting beneficial effects in OCD-like behavior after use of substances that stimulate the endocannabinoid system. In humans, until today, only two case reports are available reporting successful treatment with dronabinol (tetrahydrocannabinol, THC), an agonist at central cannabinoid CB1 receptors, in patients with otherwise treatment refractory OCD. In addition, data obtained from a small open uncontrolled trial using the THC analogue nabilone suggest that the combination of nabilone plus exposure-based psychotherapy is more effective than each treatment alone. These reports are in line with data from a limited number of case studies and small controlled trials in patients with Tourette syndrome (TS), a chronic motor and vocal tic disorder often associated with comorbid obsessive compulsive behavior (OCB), reporting not only an improvement of tics, but also of comorbid OCB after use of different kinds of cannabis-based medicines including THC, cannabis extracts, and flowers. Here we present the case of a 22-year-old male patient, who suffered from severe OCD since childhood and significantly improved after treatment with medicinal cannabis with markedly reduced OCD and depression resulting in a considerable improvement of quality of life. In addition, we give a review of current literature on the effects of cannabinoids in animal models and patients with OCD and suggest a cannabinoid hypothesis of OCD.

Intravenous Immunoglobulin Treatment Did Not Improve Tics in a Patient With Gilles de la Tourette Syndrome and Intrathecal Antibody Synthesis.

Gilles de la Tourette syndrome (GTS) is a neuropsychiatric disorder characterized by motor and vocal tics. There are several hypotheses as to the cause of the disease. One of which suggests that the immune system is involved in the pathophysiology of GTS. Here, we present a 40-year-old female patient with a typical history and clinical presentation of GTS with tics and psychiatric comorbidities, in whom positive oligoclonal bands (OCBs) type 2 in cerebral spinal fluid (CSF) were detected in an earlier study. At that time point, all other investigations were unremarkable (including neurological examination and cMRI), but 2 years later, she presented with further neurological symptoms including tetraparesis mostly affecting the left limbs, distal hypesthesia and paresthesia, and dyspnea. Since further examinations (including EMG, MRI, CSF, virological, and bacteriological tests, as well as autoimmune-encephalitis antibodies) revealed normal results, based on clinical presentation, the diagnosis of Guillain-Barré-like immune-mediated neuropathy was made and treatment with intravenous immunoglobulins (IVIg) (30 g/day for 5 days) was initiated resulting in complete remission of immune-mediated neuropathy. Based on the "immune hypothesis" of GTS, we were interested in whether in this patient positive CSF OCBs might serve as a biomarker for treatment response of tics and additional GTS-related psychiatric symptoms to IVIg, and therefore assessed tics, premonitory urges, and psychiatric comorbidities before and several times after the IVIg treatment. However, even though immune-mediated neuropathy resolved after treatment, tics, premonitory urges, and comorbidities remained unchanged. Thus, this case study suggests that treatment with IVIg is not effective in the treatment of GTS-even in a patient with intrathecal antibody synthesis as expressed by CSF isolated OCBs.

Vaporized Cannabis Is Effective and Well-Tolerated in an Adolescent with Tourette Syndrome.

We present the case of a 12-year-old boy diagnosed with Tourette syndrome, who was successfully treated with a combination of vaporized medicinal cannabis and oral pure tetrahydrocannabinol (THC). Due to severe motor tics resulting in insomnia, the parents - both of whom were medical doctors - decided to initiate treatment with 0.02 g vaporized cannabis (Bedrocan with a THC content of 22% and a cannabidiol content of 1%; corresponding to a dose equivalent to 4.4 mg THC) without prior consultation of a Tourette expert. This treatment resulted - according to the parents' report - in an immediate and nearly complete remission of the tics. Due to a further increase in tics, the parents therefore decided to implement a regular treatment with a combination of vaporized medicinal cannabis (up to 0.1 g cannabis per day, varieties Bedrocan and Amnesia Haze, corresponding to 22 mg THC/day) plus orally administered oil-based THC drops (maximum daily dose = 12.5 mg THC) resulting in a marked tic reduction. During a visit in our clinic, we were able to observe the reported beneficial effects 30 min after vaporization of 0.15 g cannabis (Amnesia Haze, equivalent to 33 mg THC; in addition, 7 mg oral THC were taken at home 6 h before the visit): tics, premonitory urges, and overall impairment significantly improved according to self-ratings, parent and clinician questionnaires. Importantly, no adverse events were reported. From this single case study, it is suggested that cannabis-based medicines and their combination (such as oral THC plus vaporized medicinal cannabis) are effective and safe in the treatment of severe tics in minors with TS. However, long-term follow-up is needed to confirm the beneficial treatment effects. We want to emphasize that in this boy treatment with cannabis was initiated by the parents before a consultation in our clinic has taken place. In our opinion, treatment with cannabis-based medicine in children should be regarded as a last-line treatment, when well-established treatments have failed to improve tics.

Investigation of previously implicated genetic variants in chronic tic disorders: a transmission disequilibrium test approach.

Genetic studies in Tourette syndrome (TS) are characterized by scattered and poorly replicated findings. We aimed to replicate findings from candidate gene and genome-wide association studies (GWAS). Our cohort included 465 probands with chronic tic disorder (93% TS) and both parents from 412 families (some probands were siblings). We assessed 75 single nucleotide polymorphisms (SNPs) in 465 parent-child trios; 117 additional SNPs in 211 trios; and 4 additional SNPs in 254 trios. We performed SNP and gene-based transmission disequilibrium tests and compared nominally significant SNP results with those from a large independent case-control cohort. After quality control 71 SNPs were available in 371 trios; 112 SNPs in 179 trios; and 3 SNPs in 192 trios. 17 were candidate SNPs implicated in TS and 2 were implicated in obsessive-compulsive disorder (OCD) or autism spectrum disorder (ASD); 142 were tagging SNPs from eight monoamine neurotransmitter-related genes (including dopamine and serotonin); 10 were top SNPs from TS GWAS; and 13 top SNPs from attention-deficit/hyperactivity disorder, OCD, or ASD GWAS. None of the SNPs or genes reached significance after adjustment for multiple testing. We observed nominal significance for the candidate SNPs rs3744161 (TBCD) and rs4565946 (TPH2) and for five tagging SNPs; none of these showed significance in the independent cohort. Also, SLC1A1 in our gene-based analysis and two TS GWAS SNPs showed nominal significance, rs11603305 (intergenic) and rs621942 (PICALM). We found no convincing support for previously implicated genetic polymorphisms. Targeted re-sequencing should fully appreciate the relevance of candidate genes.