One of the most important aspects of management is proper education and correction of misconceptions regarding Tourette syndrome and its behavioral complications. Parents should be informed that their child has a limited capacity to control the tics, which will be most prominent when the child feels his or her tics are unobserved or unlikely to provoke a negative social response, such as at home. Parents should tell the child's teachers of the diagnosis and prescribed medication, if any. Patients and families should know of the Tourette Syndrome Association as a valuable resource for informative literature.
Different forms of nonpharmacological therapeutic interventions, such as behavioral modification and transcranial magnetic stimulation, have been recommended since the disorder was first described, but few studies of such treatments have been subjected to rigorous scientific scrutiny (221; 164; 89; 90; 18; 92).
Comprehensive behavioral intervention for tics (CBIT) is primarily based on habit reversal therapy, which employs competing-response training; CBIT is different from deliberate tic suppression in that it teaches the patient to initiate a voluntary behavior to manage the premonitory urge. CBIT also includes relaxation training and a functional intervention. In a multicenter study designed to test the efficacy of CBIT, 126 children ages 9 to 17 with moderate to severe Tourette syndrome were randomly assigned to receive either CBIT or supportive counseling and education about Tourette syndrome (182). About one third of the children in the study were on a stable dose of anti-tic medication. Behavioral intervention led to a significantly greater decrease on the Yale Global Tic Severity Scale (24.7 vs. 17.1) from baseline to endpoint, compared with very minimal change in the control treatment group (24.6 vs. 21.1), with the overall effect size of 0.68. Furthermore, 52.5% of children receiving CBIT were rated as significantly improved, compared to 18.5% of those in the control group. The decrease of 7.6 points (31% from baseline) on the Total Tic score of the Yale Global Tic Severity Scale in the CBIT group is less than the decrease reported in clinical trials of antipsychotic medications or topiramate (94). Although in 1 review “half the subjects in the CBIT trials did not show a positive response,” some have suggested “CBIT can be considered a first-line treatment for persons with tic disorders” (195).
The decision to intervene in a tic disorder is based on a relative evaluation of the severity of the tics versus the consequences of potential side effects on schooling or work. Most patients with mild tics who have made a good adaptation in their lives can avoid the use of medications (128; 239). Educating patients, family members, peers, and school personnel regarding the nature of Tourette syndrome, restructuring the school or work environment, and providing supportive counseling are measures that may be sufficient to avoid medications (208). Drug therapy is considered if the symptoms of Tourette syndrome are functionally disabling and not remediable by nonpharmacological interventions (72; 88; 207). Medications are chosen on the basis of specific target symptoms and potential side effects. For many Tourette syndrome patients, the principal morbidity comes not from tics, but from the associated features of obsessive-compulsive symptoms, attention deficit hyperactivity disorder, and other behavioral disturbances. If practical, observing a patient for a period of time before using medication allows for a better appreciation of the baseline disorder and the difficulties encountered at home, at school, at work, and with peers.
Tics can rarely be eradicated entirely, so the goal of medication is to achieve maximum control with minimal side effects. All medications are initiated at the lowest possible dose and gradually increased until sufficient benefit is obtained or until intolerable side effects supervene. Those patients who receive medication should be re-evaluated approximately every 3 months and more frequently after dosage or medication changes. Clonazepam (0.5 to 5 mg/day) may be taken as a once-a-day medication at bedtime. It may relax patients just enough to give them control of mild to moderate tics, and may also help coexistent emotional and behavioral disorders. Clonidine (0.05 to 0.5 mg/day) appears to have tic-suppressing effects and may be particularly useful for children with associated attention deficit hyperactivity disorder. Clonidine is available as a weekly patch, but this formulation often causes hypersensitivity reactions. Guanfacine has also been recommended as first-line therapy for tics (224), but in has caused syncope in Tourette children (112). Despite “strong recommendation” made by some investigators for the use of clonidine and guanfacine in children with Tourette syndrome (221), we find the drug less effective than the antidopaminergic drugs in the treatment of tics in children and adults.
The most effective agents against tics are neuroleptic (antidopaminergic) drugs. There are only 3 drugs approved by the United States Food and Drug Administration for the treatment of Tourette syndrome: haloperidol, pimozide, and aripiprazole. These medications, however, have a variety of potentially serious side effects, including tardive dyskinesia; therefore, these drugs are not considered first line of treatment (89).The most commonly used typical neuroleptics include haloperidol (0.25 to 15 mg/day), pimozide (1 to 10 mg/day), and fluphenazine (1 to 15 mg/day) (242). Pimozide and fluphenazine tend to produce less sedation than haloperidol, but pimozide therapy has led to prolongation of the Q-T interval and other changes on the ECG. The full spectrum of drug-induced movement disorders, from acute dystonic reactions to tardive syndromes, may complicate the use of these agents. Furthermore, some patients become refractory to medications. In 1 survey, 45 of the 68 (69%) patients were judged refractory due to lack of efficacy at the highest tolerated dose (138). The medications to which selected patients were judged as refractory were aripiprazole, clonidine, risperidone, haloperidol, pimozide, tiapride, and sulpiride. In addition to tardive dyskinesia, the typical and atypical antipsychotics (neuroleptics) can be associated with weight gain and metabolic syndrome, although Tourette patients may be at a higher-than-expected risk for metabolic and cardiovascular disorders irrespective of their exposure to these drugs (26; 62).
Presynaptic dopamine depletors, such as tetrabenazine, which act by inhibiting the central inhibitor of vesicular monoamine transporter type 2 (VMAT2), are emerging as the most effective and safest medications in the treatment of troublesome tics (90; 18; 92). Tetrabenazine (12.5 to 100 mg 3 times daily) is effective in a majority of patients with Tourette syndrome and is considered the first-line treatment in patients with troublesome motor and phonic tics (110; 109; 89). Generally well tolerated, tetrabenazine may cause drowsiness, parkinsonism, depression, insomnia, akathisia, and other less frequent, dose-related side effects. The drug’s advantage over conventional neuroleptics is that it does not cause tardive dyskinesias. Tardive disorders appear to be relatively rare in the Tourette syndrome population, but tardive dystonia may be more common than currently believed (218; 115). Besides little or no risk for tardive dyskinesia, tetrabenazine appears to be associated with less weight gain than the typical neuroleptics (163). Besides the potential side effects noted above, there are other limitations of tetrabenazine, including its relatively short half-life, necessitating at least 3 times per day administration. This is 1 reason why other dopamine depleters with longer duration of action are currently being investigated; these include deutetrabenazine and valbenazine, which are administered 2 times or once per day, respectively (90). In a pilot study involving 23 children with Tourette syndrome, the mean (SD [standard deviation]) baseline YGTSS Total Tic Severity Score (TTS) of 31.6 (7.9) decreased by 11.6 (8.2) points at week 8, a 37.6% reduction in tic severity (p< 0.0001) (90). Other measures of Tourette syndrome also improved in this open-label 8-week study, suggesting that deutetrabenazine may be a safe and effective treatment of tics associated with Tourette syndrome. The improvement observed in the open-label studies, however, could not be replicated in 2 randomized double-blind, placebo-controlled trials: 30046 ARTISTS 1 (flexible-dose titration) and 30060 ARTISTS 2 (fixed dose) (18). This, unfortunately, parallels the results of similar studies with valbenazine in pediatric and adult Tourette syndrome populations. Although the full reports have not yet been published, there are many possible explanations for the unexpected results, including difficulties in assessing a highly variable disorder and subtherapeutic dosing. The latter explanation is supported by the observation of very low frequency of adverse effects. Although the VMAT2 inhibitors are considered the treatment of choice in patients with tic disorders, they are often difficult to access because of cost and denials by third-party payers (161).
The development of atypical neuroleptics such as olanzapine (232), quetiapine, aripiprazole (166), and ziprasidone may make it possible to avoid these side effects in the future. In a phase 3, randomized, double-blind, placebo-controlled trial of aripiprazole involving 133 patients with Tourette syndrome, significant improvement in YGTSS and other measures were noted (194). The most common adverse events were sedation and fatigue. Although no tardive dyskinesia was reported in this trial other studies have found that aripiprazole can cause this adverse effect (175). Unfortunately, experience gathered with most of these agents over the years indicates that only clozapine can be considered a truly “atypical” agent in terms of reducing the risk of tardive complications (60). Patients with Tourette syndrome need to be educated regarding possible neuroleptic side effects (116). Although D2 receptor blockers can cause tardive dyskinesia, it is possible that D1 receptor blocking agents will have lower risk of this potentially disabling side effect. In this regard, a D1 receptor antagonist, ecopipam, has been reported to have potential benefits in patients with Tourette syndrome (73).
A variety of other medications – including calcium channel blockers (verapamil, nifedipine), ondansetron, carbamazepine, baclofen, naltrexone, buspirone, nicotine (in smoke, gum, and transdermal patches), and cannabinoids – may suppress tics in certain Tourette syndrome patients (191; 156). In general, however, the response to these medications is less predictable than with the aforementioned neuroleptic drugs. An open-label trial of levetiracetam recorded benefit for tic severity in all 60 participants, and in behavior and school performance for the majority (12). Topiramate has been found to be effective in some open-label studies as well as in a multicenter, placebo-controlled trial (95). A seemingly paradoxical treatment for tics is dopamine agonists, probably on the basis of presynaptic inhibition at low doses (70; 09). Selected patients, particularly those with painful dystonic tics, may respond to local intramuscular injections of botulinum toxin (123; 144; 04; 91; 93). A variety of behavioral techniques, including massed (negative) practice, operant conditioning, anxiety management, habit-reversal training (33; 48), and hypnosis have been employed in the treatment of tics (181). Electroconvulsive therapy has been used successfully in a Tourette patient with psychosis and self-injurious behavior (107). The use of “alternative” medications among Tourette patients is common, and warrants systematic study in the future (143).
A number of antidepressant medications are effective for obsessive-compulsive symptoms, most notably serotonin-specific reuptake inhibitors (55). Fluoxetine (20 to 60 mg/day), sertraline (50 to 200 mg/day), paroxetine (20 to 60 mg/day), fluvoxamine (50 mg/day and up), and citalopram (20 to 40 mg/day) may all improve obsessive-compulsive symptoms without affecting tic severity. Serotonin-specific reuptake inhibitors may be less effective for obsessive-compulsive symptoms in the presence of tics (137), and doses higher than standard antidepressant doses are often required. Clomipramine (initiated at 25 mg/day) is equally effective but less well tolerated due to anticholinergic, cardiotoxic, and seizure-potentiating effects. Other pharmacologic agents for obsessive-compulsive symptoms include tryptophan, monoamine oxidase inhibitors, mianserin (a selective serotonin antagonist), and benzodiazepines. Because of its serotoninergic action, pimavanserin has been tried in Tourette syndrome with modest benefits on tics and obsessive-compulsive behavior (19).
Clonidine is often used as a first line drug for children with Tourette syndrome who have impaired school performance due to attention deficit hyperactivity disorder, because this medication may also be useful in suppressing tics. Another alpha 2-receptor agonist, guanfacine, may be used in a similar fashion. The selective norepinephrine reuptake inhibitor atomoxetine is effective for both attention deficit hyperactivity disorder and tics in Tourette syndrome (07). When these drugs are ineffective, the use of stimulants should be considered. Treatment of Tourette syndrome with stimulants is somewhat controversial because these drugs have been thought to exacerbate and even precipitate tics in some patients. Studies indicate that stimulants are safe and effective for attention deficit hyperactivity disorder in patients with Tourette syndrome (167). Methylphenidate (0.1 to 0.3 mg/kg twice daily) is the stimulant of choice in this situation, and its use may actually reduce tic severity (118). A sustained-release preparation of methylphenidate is available. For patients experiencing an unacceptable worsening of tics during stimulant therapy, a neuroleptic can be added. Tricyclic antidepressants such as imipramine (10 to 25 mg/day) and desipramine (25 to 100 mg/day) have also been effective treatments for attention deficit hyperactivity disorder in children with Tourette syndrome. Due to potential cardiotoxicity, ECG monitoring is recommended before and during treatment with desipramine. Selegiline may be beneficial for children with attention deficit hyperactivity disorder and tics (61). Paroxetine may be particularly useful for the unprovoked attacks of anger known as "episodic rages" (28). Pramipexole, a D3 and D2 receptor agonist, has not been found to be effective in a double-blind, placebo-controlled trial (120).
Psychological counseling may help with general difficulties in coping with Tourette syndrome, a chronic illness with specific behavioral features.
There has been a long line of surgical procedures for tics (229), and experience has expanded. Zhang and colleagues have performed unilateral pallidotomies on 22 patients and obtained significant reduction of tic frequencies (251). Sun and colleagues reported that bilateral anterior capsulotomy resulted in greater than 80% tic reduction in 5 patients in whom the posterior third of the anterior limbs of the internal capsules was targeted (222). In the same study, lesser, but still greater than 50%, benefit was obtained in 7 patients in whom the anterior one third of the anterior limbs was lesioned. The technology of deep brain stimulation has been applied to Tourette syndrome. Deep brain stimulation of the thalamus has shown marked success in ameliorating tics in a small number of patients (236). Comparable benefit has been achieved targeting the internal globus pallidus (54; 02; 237). More modest improvement was reported in 1 patient with deep brain stimulation and electrode implantation in the anterior internal capsule (64). Globus pallidus interna (Gpi) has been increasingly used as the target in patients with disabling tics (205; 237). Stimulation of various targets involved in the limbic striatopallidal-thalamocortical system could be beneficial in the treatment of various aspects of Tourette syndrome (14). Based on a double-blind assessment of 5 patients with Tourette syndrome undergoing bilateral thalamic deep brain stimulation, there was a significant improvement in several measures of tic and behavioral severity (139). In the largest reported series, 18 Tourette syndrome patients underwent bilateral deep brain stimulation of the centromedian parafascicular and ventralis oralis complex of the thalamus (204). Followed up to 18 months, most patients apparently showed improvement in tics as well as obsessive-compulsive disorder, self-injurious behavior, and other comorbidities. In a prospective 24-month follow-up of 15 of the original 18 patients, there continued to be marked improvement in tics, obsessive-compulsive disorder, anxiety, and depression with subjective perception of improved social functioning and quality of life (183). It would be helpful to know what happened to the 3 patients not included in this open-label, observational study. Also, a blinded review of videos before and after treatment would provide more objective measure of efficacy (20). Finally, the observation that vagal nerve stimulation also favorably modifies the frequency and intensity of facial tics suggests that the brainstem plays a role in generation of modulation of tics (51). One of the largest controlled trials of GPi deep brain stimulation in Tourette syndrome involved 15 patients (11 men, 4 women; mean age 34.7 years [SD 10.0]), 14 patients of whom were randomly assigned and 13 completed assessments (108). The mean YGTSS total score in these 13 patients was 80.7 (SD 12·0) for the off-stimulation period and 68.3 (SD 18·6) for the on-stimulation period, with a mean improvement of 12.4 points (95% CI 0.1-24.7, p=0.048), equivalent to a difference of 15.3%. The authors concluded that GPi stimulation led to a significant improvement in tic severity, with an overall acceptable safety profile. In another study involving 16 patients with Tourette syndrome randomly assigned to deep brain stimulation of the anterior globus pallidus internum or sham stimulation, no significant difference in the Yale Global Tourette Syndrome Scale was noted between the beginning and the end of the 3-month double-blind period (241). One interpretation of this negative result is that 3 months of stimulation may not be sufficient to decrease tic severity. This is supported by a 1-year follow-up of 185 patients with Tourette syndrome treated with deep brain stimulation included in a public registry (145). This showed that the Yale Global Tourette Syndrome Scale mean total score improved from 75.0 at baseline to 41.2 at 1 year after implantation (p < .001) and the motor and phonic tic subscores also improved significantly (both p < .001). The overall adverse event rate was 35.4%, with intracranial hemorrhage occurring in 1.2% of patients, infection in 2.5%, and lead explantation in 1%; the most common stimulation-induced side effects were dysarthria (6.3%) and paresthesia (8.2%). In a retrospective analysis of clinical data and imaging from 13 international sites in 110 patients with Tourette syndrome who were implanted in the centromedial thalamus (n = 51), globus pallidus internus (n = 47), nucleus accumbens/anterior limb of the internal capsule (n = 4), or a combination (n = 8), tics and obsessive-compulsive behavior significantly improved over time (p < 0.01) (105). The median time was 13 months to reach a 40% improvement in tics. There were no significant differences across targets (p = 0.84). A randomized, double-blind, sham-controlled trial of deep brain stimulation in 10 patients with Tourette syndrome suggested that the initial effect targeting globus pallidus internus was superior to thalamic target; long-term benefits seemed greater with the latter target (158). Deep brain stimulation continues to be evaluated in patients with Tourette syndrome and future advances should lead to better selection of patients and better long-term outcomes (147).
The American Academy of Neurology issued practice guidelines based on a systematic review of the literature on the treatment of Tourette syndrome (186; 187). They concluded that there was high confidence that the Comprehensive Behavioral Intervention for Tics was more likely than psychoeducation and supportive therapy to reduce tics. There was moderate confidence that haloperidol, risperidone, aripiprazole, tiapride, clonidine, onabotulinum toxin A injections, 5-ling granule, and Ningdong granule were probably more likely than placebo to reduce tics. There was low confidence that pimozide, ziprasidone, metoclopramide, guanfacine, topiramate, tetrahydrocannabinol, and deep brain stimulation of the globus pallidus were possibly more likely than placebo to reduce tics.