Effectiveness of speech therapy in treating vocal blocking tics in children with Tourette syndrome: Two case reports.

Tourette syndrome is characterized by at least two motor tics and one vocal tic, which persist for over a year. Infrequently, tics can manifest as blocking tics in speech when they prevent a person from starting to speak or interrupt their speech flow. Vocal blocking tics (VBTs) resemble stuttering, and they can be difficult to differentiate from each other. A previous report described two patients with severe VBTs who did not benefit from stuttering-therapy-based speech therapy and were treated effectively with cannabis-based medicine. Here, we present the cases of two patients, seven- and nine-year-old boys, who benefited from speech therapy in which stuttering therapy techniques were used. Detailed descriptions of the interventions are included. Further research is needed to test the effectiveness of speech therapy in treating VBTs in a larger group of children with Tourette syndrome.

From urges to tics in children with Tourette syndrome: associations with supplementary motor area GABA and right motor cortex physiology.

Tourette syndrome (TS) is a childhood-onset disorder in which tics are often preceded by premonitory sensory urges. More severe urges correlate with worse tics and can render behavioral therapies less effective. The supplementary motor area (SMA) is a prefrontal region believed to influence tic performance. To determine whether cortical physiological properties correlate with urges and tics, we evaluated, in 8-12-year-old right-handed TS children (n = 17), correlations of urge and tic severity scores and compared both to cortical excitability (CE) and short- and long-interval cortical inhibition (SICI and LICI) in both left and right M1. We also modeled these M1 transcranial magnetic stimulation measures with SMA gamma-amino butyric acid (GABA) levels in TS and typically developing control children (n = 16). Urge intensity correlated strongly with tic scores. More severe urges correlated with lower CE and less LICI in both right and left M1. Unexpectedly, in right M1, lower CE and less LICI correlated with less severe tics. We found that SMA GABA modulation of right, but not left, M1 CE and LICI differed in TS. We conclude that in young children with TS, lower right M1 CE and LICI, modulated by SMA GABA, may reflect compensatory mechanisms to diminish tics in response to premonitory urges.

Use of Nutritional Supplements Based on L-Theanine and Vitamin B6 in Children with Tourette Syndrome, with Anxiety Disorders: A Pilot Study.

BACKGROUND: Tourette syndrome (TS) is a neurodevelopmental disorder characterized by tics and co-occurring disorders. It has been suggested that anxiety occurs in 2-45% patients affected by Tourette syndrome. Despite dietary and nutritional factors have been found to affect a range of neurological conditions, no more studies have investigated the relationship between nutritional supplements and tics. OBJECTIVE: To evaluate the effectiveness of supplementation of both L-Theanine and Vitamin B6 in reducing tics and co-occurring disorders in a sample of youth with chronic tic disorder (CTD) or Tourette syndrome with anxiety symptoms. DESIGN: A open-label trial. Patients affected by Tourette syndrome were randomized to receive nutritional supplements based on L-Theanine and vitamin B6, or psychoeducation (PE). PARTICIPANTS: 34 children (30 boys and 4 girls) aged between 4 and 17 years affected by Tourette syndrome or chronic tic disorder, associated with anxiety symptoms. RESULTS: Patients in both groups showed a reduction in the severity of tic and anxiety symptoms. Supplementation with L-Theanine and vitamin B6 was significantly more effective than psychoeducation in reducing tics and co-occurring disorders, as measured by neuropsychological findings. CONCLUSIONS: Supplementation of both L-Theanine and Vitamin B6 may help in the treatment of tic disorders associated with anxious symptoms. Between-group differences in clinician-rated severity did reach statistical significance only for tics. Despite this finding, further placebo-controlled trials are needed.

Frequency and Intensity of Premonitory Urges-to-Tic in Tourette Syndrome Is Associated With Supplementary Motor Area GABA+ Levels.

BACKGROUND: Individuals with Tourette syndrome (TS) often report that they express tics as a means of alleviating the experience of unpleasant sensations. These sensations are perceived as an urge to act and are referred to as premonitory urges. Premonitory urges have been the focus of recent efforts to develop interventions to reduce tic expression in those with TS. OBJECTIVE: The aim of this study was to examine the contribution of brain γ-aminobutyric acid (GABA) and glutamate levels of the right primary sensorimotor cortex (SM1), supplementary motor area (SMA), and insular cortex (insula) to tic and urge severity in children with TS. METHODS: Edited magnetic resonance spectroscopy was used to assess GABA+ (GABA + macromolecules) and Glx (glutamate + glutamine) of the right SM1, SMA, and insula in 68 children with TS (MAge = 10.59, SDAge = 1.33) and 41 typically developing control subjects (MAge = 10.26, SDAge = 2.21). We first compared GABA+ and Glx levels of these brain regions between groups. We then explored the association between regional GABA+ and Glx levels with urge and tic severity. RESULTS: GABA+ and Glx of the right SM1, SMA, and insula were comparable between the children with TS and typically developing control subjects. In children with TS, lower levels of SMA GABA+ were associated with more severe and more frequent premonitory urges. Neither GABA+ nor Glx levels were associated with tic severity. CONCLUSIONS: These results broadly support the role of GABAergic neurotransmission within the SMA in the experience of premonitory urges in children with TS. © 2021 International Parkinson and Movement Disorder Society.

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.

Morning light therapy in adults with Tourette's disorder.

BACKGROUND: Sleep disturbance is common among individuals with Tourette's Disorder (TD). Given that sleep is influenced by the circadian system, this study examined circadian rhythms and sleep in adults with TD, and explored the possible benefit of short-wavelength wearable morning light therapy. METHODS: Participants were 34 adults with TD (n = 14) and age- and sex-matched healthy controls (HC; n = 20). Participants were screened using clinician-rated diagnostic and tic severity interviews, and procedures lasted 3 consecutive weeks. Participants completed a baseline week of actigraphy. Adults with TD completed 2 weeks of Re-Timer™ morning light therapy and continued actigraphy monitoring. Dim light melatonin-onset (DLMO) phase assessment, tic severity interview, and measures of chronotype, sleep disturbance, daytime sleepiness, disability, depression, anxiety, and stress were completed at baseline and post-intervention. RESULTS: Adults with TD reported significantly greater eveningness and sleep disturbance relative to controls. Per wrist actigraphy, adults with TD exhibited significantly longer sleep-onset latency, lower sleep efficiency, and greater sleep fragmentation than HC. Following morning light therapy, there was a significant advance in DLMO phase, but not self-report or actigraphy sleep variables. There were small, statistically significant decreases in tic severity and impairment. There were also significant reductions in daytime sleepiness, and self-reported anxiety, but not depression, stress, or disability. Participants reported minimal side effects and rated light therapy as acceptable and comfortable. CONCLUSIONS: Findings showed some benefits following brief light therapy in TD; further exploration of the impact of spectral tuning the photic environment as part of treatment for TD subjects is warranted.

Speechlessness in Gilles de la Tourette Syndrome: Cannabis-Based Medicines Improve Severe Vocal Blocking Tics in Two Patients.

We report the cases of two young German male patients with treatment-resistant Tourette syndrome (TS), who suffer from incapacitating stuttering-like speech disfluencies caused by vocal blocking tics and palilalia. Case 1: a 19-year old patient received medical cannabis at a dose of 1 × 0.1 g cannabis daily. Case 2: a 16-year old patient initially received dronabinol at a maximum dose of 22.4-33.6 mg daily. Both treatments provided significant symptom improvement of vocal blocking tics as well as of comorbid conditions and were well tolerated. Thus, cannabis-based medicine appears to be effective in treatment-resistant TS patients with vocal blocking tics.

Relationship of serum ferritin level and tic severity in children with Tourette syndrome.

PURPOSE: Tics can be considered hyperkinetic movements akin to restless leg syndrome (RLS). Drawing the analogy of iron deficiency as an etiology of RLS, it is conceivable that iron deficiency may underlie or worsen tics in Tourette syndrome (TS). The purpose of this study was to evaluate the relationship between serum ferritin levels and tic severity, as well as consequent impact on life, in children with TS. METHODS: Children <18 years, diagnosed with TS during 2009-2015, were reviewed. Only those with serum ferritin testing were included. The following data were collected: tic severity, impact on life, medication, comorbidities, blood count, and serum ferritin at diagnosis and follow-up. RESULTS: In fifty-seven patients, M:F = 2:1, serum ferritin was 48.0 ± 33.28 ng/mL, tic severity score 2.3 ± 0.80, impact on life score 2.2 ± 0.93, and composite score 4.57 ± 1.6. Serum ferritin was not influenced by comorbid obsessive compulsive disorder (OCD), attention deficit hyperactive disorder (ADHD), or anxiety (P > 0.16). Thirty-eight percent with low serum ferritin (≤50 ng/mL) (n = 37) had severe tics (>5 composite score), compared with 25% in normal ferritin group (n = 20). Over 6-12 months, tic severity score improved in both iron treated groups, deficient (2.70 to 1.90) and sufficient (2.40 to 1.95), whereas tics worsened or remained the same when not treated with iron. CONCLUSIONS: Our data suggest iron deficiency may be associated with more severe tics with higher impact on TS children, independent of the presence of OCD, ADHD, or anxiety. Iron supplementation showed a trend towards improvement of tic severity upon follow-up. We suggest a double-blind, placebo-controlled prospective study to reach a definite conclusion.

Scheduled, intermittent stimulation of the thalamus reduces tics in Tourette syndrome.

INTRODUCTION: Personalized, scheduled deep brain stimulation in Tourette syndrome (TS) may permit clinically meaningful tic reduction while reducing side effects and increasing battery life. Here, we evaluate scheduled DBS applied to TS at two-year follow-up. METHODS: Five patients underwent bilateral centromedian thalamic (CM) region DBS. A cranially contained constant-current device delivering stimulation on a scheduled duty cycle, as opposed to the standard continuous DBS paradigm was utilized. Baseline vs. 24-month outcomes were collected and analyzed, and a responder analysis was performed. A 40% improvement in the Modified Rush Tic Rating Scale (MRTRS) total score or Yale Global Tic Severity Scale (YGTSS) total score defined a full responder. RESULTS: Three of the 4 patients followed to 24 months reached full responder criteria and had a mean stimulation time of 1.85 h per day. One patient lost to follow-up evaluated at the last time point (month 18) was a non-responder. Patients exhibited improvements in MRTRS score beyond the improvements previously reported for the 6 month endpoint; on average, MRTRS total score was 15.6% better at 24 months than at 6 months and YGTSS total score was 14.8% better. Combining the patients into a single cohort revealed significant improvements in the MRTRS total score (-7.6 [5.64]; p = 0.02). CONCLUSION: Electrical stimulation of the centromedian thalamic region in a scheduled paradigm was effective in suppressing tics, particularly phonic tics. Full responders were able to achieve the positive DBS effect with a mean of 2.3 ± 0.9 (SEM) hours of DBS per day.

Electrophysiological correlates of reinforcement learning in young people with Tourette syndrome with and without co-occurring ADHD symptoms.

Altered reinforcement learning is implicated in the causes of Tourette syndrome (TS) and attention-deficit/hyperactivity disorder (ADHD). TS and ADHD frequently co-occur but how this affects reinforcement learning has not been investigated. We examined the ability of young people with TS (n=18), TS+ADHD (N=17), ADHD (n=13) and typically developing controls (n=20) to learn and reverse stimulus-response (S-R) associations based on positive and negative reinforcement feedback. We used a 2 (TS-yes, TS-no)×2 (ADHD-yes, ADHD-no) factorial design to assess the effects of TS, ADHD, and their interaction on behavioural (accuracy, RT) and event-related potential (stimulus-locked P3, feedback-locked P2, feedback-related negativity, FRN) indices of learning and reversing the S-R associations. TS was associated with intact learning and reversal performance and largely typical ERP amplitudes. ADHD was associated with lower accuracy during S-R learning and impaired reversal learning (significantly reduced accuracy and a trend for smaller P3 amplitude). The results indicate that co-occurring ADHD symptoms impair reversal learning in TS+ADHD. The implications of these findings for behavioural tic therapies are discussed.

Five-months-postoperative neuropsychological outcome from a pilot prospective randomized clinical trial of thalamic deep brain stimulation for Tourette syndrome.

OBJECTIVE: Tourette syndrome (TS) is a neuropsychiatric disorder presenting with motor and/or sonic tics associated with frontostriatal dysfunction. This study provided pilot data of the neuropsychological safety of bilateral thalamic deep brain stimulation (DBS) to treat medication-refractory TS in adults. METHOD: This study used a repeated-measures design with pretest and 3-month follow-up from start of continuous bilateral DBS. Five male patients underwent DBS surgery for medically refractory TS. Repeated-measures ANOVA was used to evaluate for any change in neuropsychological test scores, employing a false discovery rate. Outcome measures included 14 neuropsychological tests assessing psychomotor speed, attention, memory, language, visuoconstructional, and executive functions, as well as subjective mood ratings of depression and anxiety. RESULTS: Average age was 28.2 years (SD = 7.5) with 12-17 years of education. Participants were disabled by tics, with a tic frequency of 50-80 per minute before surgery. At baseline, subjects' cognitive function was generally average, although mild deficits in sequencing and verbal fluency were present, as were clinically mild obsessive-compulsive symptoms. At 3 months of continuous DBS (5 months after implantation), 3 of 5 participants had clinical reductions in motor and sonic tics. Cognitive scores generally remained stable, but declines of moderate to large effect size (Cohen's d > 0.6) in verbal fluency, visual immediate memory, and reaction time were observed. Fewer symptoms of depression and anxiety, as well as fewer obsessions and compulsions, were reported after 3 months of continuous high-frequency DBS. CONCLUSIONS: Bilateral centromedian-parafascicular thalamic DBS for medically refractory TS shows promise for treatment of medically refractory TS without marked neuropsychological morbidity. Symptoms of depression and anxiety improved.

Effects of Chinese herbal medicine Ningdong granule on regulating dopamine (DA)/serotonin (5-TH) and gamma-amino butyric acid (GABA) in patients with Tourette syndrome.

Many studies have indicated that a variety of neurotransmitters are implicated in the pathophysiology of Tourette syndrome (TS), including dopamine (DA), serotonin (5-TH), homovanillic acid (HVA), and gamma-amino butyric acid (GABA). Our previous studies found that Ningdong granule (NDG) is effective on a rat model with TS. NDG can regulate the metabolic disturbance of DA, 5-TH and HVA in the rat brain. However, the mechanisms of NDG in patients with TS are still not clear. To further evaluate the efficiency, safety, and possible mechanisms of NDG, a randomized and double-blind study was carried out. One hundred and twenty patients with TS were enrolled in this study, that were randomly divided into 4 groups (NDG group, Haloperidol (Hal) group, NDG + Hal group and Control group). First, the efficiency of NDG was assessed using the Yale Global Tic Severity Score (YGTSS). Second, the concentration of DA, HVA, 5-TH, 5-hydroxyindoleacetic acid (5-HIAA) and GABA in sera were tested by ELISA. In addition, the influence of NDG on liver and renal function was recorded. We found that NDG could ameliorate tics significantly according the YGTSS score. The concentration of HVA and GABA were increased after treatment with NDG. Furthermore, we found that there was no liver or renal damage in children treated with NDG. We also found that the NDG + Hal group was more effective and safe compared with other groups. In conclusion, the current study indicates that NDG might be effective on patients with TS by regulating dopamine (DA)/serotonin (5-TH) and gamma-amino butyric acid (GABA).

Double-blind clinical trial of thalamic stimulation in patients with Tourette syndrome.

Deep brain stimulation of the thalamus has been proposed as a therapeutic option in patients with Tourette syndrome who are refractory to pharmacological and psychotherapeutic treatment. Patients with intractable Tourette syndrome were invited to take part in a double-blind randomized cross-over trial assessing the efficacy and safety of stimulation of the centromedian nucleus-substantia periventricularis-nucleus ventro-oralis internus crosspoint in the thalamus. After surgery, the patients were randomly assigned to 3 months stimulation followed by 3 months OFF stimulation (Group A) or vice versa (Group B). The cross-over period was followed by 6 months ON stimulation. Assessments were performed prior to surgery and at 3, 6 months and 1 year after surgery. The primary outcome was a change in tic severity as measured by the Yale Global Tic Severity Scale and the secondary outcome was a change in associated behavioural disorders and mood. Possible cognitive side effects were studied during stimulation ON at 1 year postoperatively. Interim analysis was performed on a sample of six male patients with only one patient randomized to Group B. Tic severity during ON stimulation was significantly lower than during OFF stimulation, with substantial improvement (37%) on the Yale Global Tic Severity Scale (mean 41.1 ± 5.4 versus 25.6 ± 12.8, P = 0.046). The effect of stimulation 1 year after surgery was sustained with significant improvement (49%) on the Yale Global Tic Severity Scale (mean 42.2 ± 3.1 versus 21.5 ± 11.1, P = 0.028) when compared with preoperative assessments. Secondary outcome measures did not show any effect at a group level, either between ON and OFF stimulation or between preoperative assessment and that at 1 year postoperatively. Cognitive re-assessment at 1 year after surgery showed that patients needed more time to complete the Stroop Colour Word Card test. This test measures selective attention and response inhibition. Serious adverse events included one small haemorrhage ventral to the tip of the electrode, one infection of the pulse generator, subjective gaze disturbances and reduction of energy levels in all patients. The present preliminary findings suggest that stimulation of the centromedian nucleus-substantia periventricularis-nucleus ventro-oralis internus crosspoint may reduce tic severity in refractory Tourette syndrome, but there is the risk of adverse effects related to oculomotor function and energy levels. Further randomized controlled trials on other targets are urgently needed since the search for the optimal one is still ongoing.

Keratoconus caused by eye rubbing in patients with Tourette Syndrome.

OBJECTIVE: To report the association between keratoconus and Tourette Syndrome (TS) and to reinforce that eye rubbing may be a causative factor for keratoconus. DESIGN: Observational case series. PARTICIPANTS: Three patients with TS who presented with clinical and topographic findings suggestive of asymmetric or unilateral keratoconus. METHODS: Evaluation of patients in a single clinical practice. RESULTS: Patients' histories revealed asymmetric or unilateral rubbing of the affected eye as a result of a TS tic. Other organic causes associated with keratoconus were absent in these patients. CONCLUSIONS: A possible association between TS and keratoconus exists with chronic eye rubbing being the suggested mechanism. Eye rubbing seems to be an important causative factor for keratoconus.

Altered fronto-striato-thalamic connectivity in children with Tourette syndrome assessed with diffusion tensor MRI and probabilistic fiber tracking.

The aim of the study was to determine whether abnormal connectivity of the fronto-striato-thalamic circuit underlies the morphological changes in subcortical structures of patients with Tourette syndrome and to correlate these changes with neurobehavioral measures. A total of 18 children with Tourette syndrome and 12 age-matched healthy controls underwent diffusion tensor magnetic resonance imaging. Tractography of the fronto-striato-thalamic circuit was achieved using probability distribution function of individual voxels. The Tourette syndrome group had significantly lower probability of connection between caudate nucleus and anterior-dorsolateral-frontal cortex on the left (P = .038). Obsessive-compulsive behavior was negatively associated with connectivity score of the left caudate and anterior dorsolateral frontal cortex (P = .01) and was positively associated with connectivity score for the subcallosal gyrus (P = .009) and for the lentiform nucleus (P = .008). The abnormal connectivity among components of the fronto-striato-thalamic circuit bilaterally (ie, seeds on the caudate and thalamus) in patients with Tourette syndrome provides direct evidence for the involvement of these circuits in the pathophysiology.

Neuroimaging of tic disorders with co-existing attention-deficit/hyperactivity disorder.

BACKGROUND: Tourette syndrome (TS) and Attention-Deficit/Hyperactivity Disorder (ADHD) are common and debilitating neuropsychiatric illnesses that typically onset in the preschool years. Recently, both conditions have been subject to neuroimaging studies, with the aim of understanding their underlying neurobiological correlates. OBJECTIVE: The relation of TS and ADHD is discussed against the background of findings from previous Magnetic Resonance Imaging (MRI) studies. METHODS: We review the designs and major findings of previous studies that have examined TS with comorbid ADHD, and we briefly contrast these findings with those in ADHD without comorbid tic disorders. RESULTS: The frequent comorbidity of TS and ADHD may reflect a common underlying neurobiological substrate, and studies confirm the hypothesized involvement of fronto-striatal circuits in both TS and ADHD. However, poor inhibitory control and volumetric reductions in fronto-striatal circuits appear to be core features of ADHD, whereas reduced volumes of the caudate nucleus, together with activation and hypertrophy of prefrontal regions that likely help to suppress tics, seem to be core features of TS. CONCLUSION: The etiological relationship between TS and ADHD must be clarified further with cross-sectional and, if possible, longitudinal imaging studies that examine samples of substantial size, including subgroups with pure TS and ADHD, as well as with comorbid conditions.

Gilles de la Tourette syndrome and voluntary movement: a functional MRI study.

Tourette syndrome (TS) is hypothesised to be caused by an abnormal organization of movement control. The aim of this study was to use functional magnetic resonance imaging to study motor cortex activation in a TS patient. Usual and unusual self-paced voluntary movements were performed. The TS patient displayed supplementary motor area (SMA) activation during both tasks. This activation reflects a continuous use of the SMA to perform the voluntary motor movements required in both tasks. Moreover, the absence of tics during the execution of these voluntary motor tasks suggests that tic activity may be suppressed by additional mental effort.