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Progress in Pharmacological and Surgical Management of Tourette Syndrome and Other Chronic Tic Disorders

Pandey, Sanjay MD, DM*; Dash, Deepa MD, DM

doi: 10.1097/NRL.0000000000000218
Review Article

Background: Tourette syndrome (TS) and other chronic tic disorders are clinically heterogenous and cause physical discomfort, social difficulties, and emotional distress. In addition to tics, TS patients have a variety of behavioral comorbidities, including obsessive-compulsive disorders and attention-deficit hyperactivity disorders. TS treatment is multidisciplinary, involving behavioral therapy, oral medications, and botulinum toxin injections.

Methods: Relevant studies on pharmacological and surgical treatment options for TS and other chronic tic disorders, their limitations and current recommendations were reviewed using the PubMed search till April 2, 2018. Besides, the reference lists of the retrieved publications were manually searched to explore other relevant studies. This review aims to discuss the progress in pharmacological and surgical treatment options for TS and other chronic tic disorders.

Results and Conclusions: Both typical and atypical antipsychotic agents are mainstays of pharmacological treatment of TS and other chronic tic disorder patients; however, their use is limited by serious side effects considering their potential of dopamine blockade. Because of the phenotypic variability, no medication has proven effective for all persons with TS and other chronic tic disorders. Botulinum toxin has emerged as a good therapeutic option, especially for focal and dystonic tics. But, their uses are limited by lack of sufficient evidence and high cost. Surgical treatment is considered in medically refractory and severely disabled tics patients. Deep brain stimulation has replaced lesional surgeries; however, there is uncertainty regarding the selection of patients and target of stimulation.

*Department of Neurology, Govind Ballabh Pant Postgraduate Institute of Medical Education and Research

Department of Neurology, All India Institute of Medical Sciences, New Delhi, India

The authors declare no conflict of interest.

Correspondence to: Sanjay Pandey, MD, DM, Department of Neurology, Govind Ballabh Pant Postgraduate Institute of Medical Education and Research, Academic Block, Room No. 507, New Delhi 110002, India. E-mail:

Gilles de la Tourette syndrome, which is more commonly known as Tourette syndrome (TS), is diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) criteria as the presence of both motor and vocal (phonic) tics for >12 months, which manifest before the age of 18 years, in the absence of secondary causes.1,2 TS is often accompanied by attention-deficit hyperactivity disorder (ADHD), obsessive-compulsive disorder (OCD), poor impulse control, and other comorbid behavioral problems.3 TS affects between 0.3% and 1% of the population, depending on the age of the study group.4 The mean age at onset is around 5 years and there is a male to female (3:1 to 4.3:1) preponderance.3,4 According to the European clinical guidelines for TS and other tic disorders, the course of tics is relatively favorable over time and studies indicate that up to 80% of persons who presented with tic disorder before the age of 10 years experience a significant decrease in tics during adolescence, and by age 18 years will no longer experience any impairment from tics.4 The remaining 20% of patients do not experience a decrease in tics and some of these patients may develop more severe forms of tics.

The most widely used assessment tools for tic characteristics and severity include the diagnostic confidence index (DCI), Yale Global Tic Severity Scale (YGTSS), and the Gilles de la Tourette syndrome quality of life scale (GTS-QOL) scale.3,4 A considerable difficulty in assessing and quantifying tics is caused by large variability in an individual over a period of time. One of the main problems in establishing a treatment model for tic syndromes is the phenotypic variability. Other difficulties in treatment are the presence of co-morbidities, which are usually associated with TS and the fluctuations in their severity. Another challenge is variability in response to treatment, the reasons for which are largely unknown, but very important in managing patients as this limits the usefulness of all the evidence. The quality of the available evidence is limited by the fact that trials are usually short, over weeks, and real life responses if seen are not always sustained. The current treatment options for TS and tics include behavioral, pharmacological and surgical interventions, with the latter reserved for the severe and debilitating patients.5 Nonpharmacological approaches like comprehensive behavioral intervention for tics have clear evidence suggesting improvements in tics which is clinically meaningful and should be considered as one of the first therapeutic options for patients with TS, but because it is beyond the scope of this article we have not gone into the details of the same.

This paper offers a comprehensive review of the available evidence to recommend different pharmacological and surgical options for the management of TS and other chronic tic disorders.

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Relevant studies on pharmacological and surgical treatment of tics and TS were reviewed using the PubMed search till April 2, 2018.

A total of 2116 articles on “Treatment of tics,” 2666 articles on “Treatment of Tourette’s syndrome,” 1024 articles on “Pharmacological treatment of tics,” 1442 articles on “Pharmacological treatment of Tourette’s syndrome,” 96 articles on “Botulinum toxin for tics,” 54 articles on “Botulinum toxin for Tourette’s syndrome,” 336 articles on “Surgery for tics,” 315 articles on “Surgery for Tourette’s syndrome,” 155 articles on “Deep brain stimulation for tics,” and 329 articles on “Deep brain stimulation for Tourette’s syndrome” were found. The majority of the articles searched using the term “Surgery for tics/Tourette’s syndrome” was related to deep brain stimulation (DBS). No articles were found using the search term “Magnetic resonance imaging–guided focused ultrasound ablation for tics or Tourette’s syndrome.” The final reference list was based on the relevance to the topic of review.

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Antipsychotic Medications

Antipsychotic medications have been used effectively in the management of TS, but their uses have been limited by serious side effects including drug-induced movement disorders and metabolic disorders (Table 1). Haloperidol and pimozide have been approved by the food and drug administration (FDA) for the treatment of TS. Other antipsychotic agents used in the treatment of TS and chronic tic disorder are risperidone, aripiprazole, and fluphenazine (Table 1). Sallee and colleagues reported a placebo-controlled double cross-over study for 24 weeks showing the efficacy and safety of equivalent dose formulations of haloperidol and pimozide in the treatment of children and adolescents with TS.6 Pimozide proved significantly different from placebo in affecting the primary outcome variable (Tourette Syndrome Global Scale). In the same dosages haloperidol failed to have any effect and exhibited 3-fold higher frequency of serious side effects. In a Cochrane review, Pringsheim and Marras7 reported 6 randomized trials including 162 patients (age range: 7 to 53 y). Pimozide was compared with placebo and haloperidol in 2 trials, with placebo in 1 trial, with haloperidol in 1 trial, and with risperidone in 2 trials. Pimozide was superior to placebo in 3 studies, and inferior to haloperidol in 1 study. The other 2 studies showed no significant difference between the drugs. There were no significant differences between pimozide and risperidone.



In a retrospective chart review of 268 patients with a mean age of 15.8±10.7 years (range: 4.1 to 70.2 y), fluphenazine appeared to be safe and effective in the treatment of TS. There were no cases of tardive dystonia in this cohort treated up to 16.80 years.8

Aripiprazole is a partial agonist of dopaminergic (D2, D3, and D4 receptor) and serotonergic (5-HT1A and 5-HT2C) receptors. In a 10-week multicenter, double-blind, randomized, placebo-controlled trial aripiprazole was efficacious in comparison with placebo, generally well tolerated and safe in the short-term treatment of children and adolescents with TS.9 Risperidone is a 5-HT2 receptor antagonist at low doses and functions as a D2 antagonist at high doses. The efficacy of risperidone has been demonstrated in 5 randomized controlled trials (RCTs), but its uses have been limited due to long-term side effects including hyperprolactinemia, which is secondary to tubero-infundibular D2 antagonism.10–14 Risperidone may also be useful in treating the co-morbid conditions such as aggression and OCDs. Olanzapine is another atypical antipsychotic used in the management of tics, due to its high-affinity antagonism of D1, D2, D3, D4, 5-HT2A, 5-HT2C, H1, and muscarinic receptors. The use of olanzapine in TS is supported by 3 open-label studies, 2 nonrandomized studies, and 1 single blind study reporting a decrease in tic severity.15–19 Further, there is lower incidence of medication induced dyskinesia and hyperprolactinemia with olanzapine due to its greater antagonism to 5HT2C than D2.20 However, the metabolic side effects including weight gain may limit its use.

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Anticonvulsant Agents

Topiramate is a broad-spectrum anticonvulsant agent and it has also shown some efficacy in the management of tics patients. The effect of the drug is GABAergic, but it also blocks AMPA (a-amino-3-hydroxy-5-methylisoxazole-4-propionic acid)/kainate receptors. There is only one randomized, double-blind placebo-controlled trial of topiramate (25 to 200 mg/d) in TS patients (n=29), which reported a significant reduction in YGTSS total tic score.21

Clonazepam, a benzodiazepam has also been used in the treatment of TS, but no placebo-controlled trial has been done. Poor quality evidence in the form of 2 single blind comparative trials of clonazepam have demonstrated efficacy of clonazepam over clonidine for tic suppression and over haloperidol in subjects who have higher red blood cell to plasma choline ratio.22,23 The usual side effects of benzodiazepines include tolerance, sedation, ataxia, and paradoxical disinhibition.

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Antispasticity Agent

Baclofen is a GABAB receptor agonist and commonly used in the management of spasticity. Using the GABAergic properties of baclofen, an open label study was published in 1999, where 264 children (6 to 18 y) with TS were treated with a starting dose of 10 mg/d, which was escalated (10 mg/wk), till tics completely suppressed or side effects developed.24 Statistically significant reduction was seen in YGTSS with a mean dose of 30 mg/d (range: 10 to 80 mg/d). Side effects including sedation and drowsiness were reported in 6 patients. In a low-quality RCT of 10 children, treated for 4 weeks with baclofen or placebo reported a decrease in YGTSS that was statistically not significant.25 Constipation, nausea, anxiety, and headache were common adverse effects reported.

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Tetrabenazine inhibits VMAT-2 and prevents translocation of neurotransmitter monoamines from the cytoplasm into synaptic vesicles.20 In a long-term open label study tetrabenazine was used in 9 patients.26 Marked and lasting improvement occurred in 4 patients. Mild and transient improvement occurred in 3 patients and 2 patients had minimal or no response. Side effects included drowsiness, nervousness, parkinsonism, and oculogyric crises, but all cleared with maintenance or reduction of the dosage.

Deutetrabenazine is another VMAT-2 inhibitor, which has been recently approved for treatment in Huntington disease and tardive dyskinesia patients. This medication has been studied in a 6-week open label trial of TS patients and there was a reduction in the mean YGTSS score on doses of 18 to 36 mg a day, and the reported side effects were headache, fatigue, and irritability.27

Valbenazine is a new VMAT-2 inhibitor, which has been recently approved for the treatment of tardive dystonia and presently 3 phase II trials are underway in the United States for TS.20 Sedation, anticholinergic effects, and balance disorders are common side effects.

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Clonidine is an alpha-2 adrenergic receptor agonist and it has been used in the treatment of tics for many years.5 Clonidine is available as an oral and transdermal preparation. Most common side effects seen with clonidine are sedation, dry mouth, orthostatic hypotension, and bradycardia. A starting dose of 0.05 mg/d is recommended, which should be titrated up slowly with a close monitoring of heart rate and blood pressure. Initial case reports and open-label trials were contradictory regarding its efficacy in TS patients.20 Later, a TS study group conducted a multicenter, randomized, double-blind clinical trial and recruited 136 children with ADHD and chronic tic disorder.28 Tic severity improved the most in the clonidine and methylphenidate group followed by the clonidine alone group. Least improvement was seen in the methylphenidate alone group followed by the placebo group. Many clinicians feel that clonidine is not usually an effective drug in adults, especially those without ADHD.29 Delayed maturation of prefrontal cortex has been observed in children with ADHD. It has been proposed that alpha-2 agonist medications enhance prefrontal function explaining a mechanism why they may be more effective in treating tic symptoms in children with comorbid ADHD.

Guanfacine is another alpha-2 adrenergic receptor agonist used in treatment of tics based on evidence from 3 RCTs and 2 open label studies. The first RCT included 34 children with TS and ADHD, where patients on guanfacine had a significant reduction in YGTSS and patients in the placebo group had no change.30 The second RCT failed to show any difference in guanfacine and placebo group.31 In the third RCT, extended release guanfacine was compared with placebo, but there was no significant benefit.32 The starting recommended dose is 0.5 mg/d, which may be titrated up to 4 mg/d. Fatigue, insomnia, stomachache, and light-headedness are important side effects seen with guanfacine.

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Delta-9-tetrahydrocannabinol (THC) acts as an agonist of the cannabinoid receptor and it has been used in different types of neurological disorders including tics. There are 2 placebo-controlled trials showing statistically significant reductions in both tics and OCD; however, a Cochrane review concluded that currently there is not significant data to show its efficacy.33–35

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Ecopipam (A Novel D1 Receptor Antagonist)

Ecopimam is a selective D1/D5 antagonist and currently being studied in the management of TS.20 In a multicenter, nonrandomized, open label study in adults with TS, tics were reduced after 8 weeks of treatment with ecopipam. The most commonly reported side effects were sedation, fatigue, insomnia, somnolence, anxiety, headache, and muscle twitching.36,37

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Evidence for efficacy of many pharmacological agents considered in the treatment of TS and other tic disorders is often based upon open studies or randomized, double-blind, placebo-controlled studies with quite small sample sizes. Haloperidol is the only drug approved for TS in Europe. However, because of its frequent side effects it is usually a drug of third line in clinical practice. European recommendation based on a survey of European Society for the Study of Tourette syndrome (ESSTS) members for the treatment of tics for children and adolescents considered risperidone as a first choice agent followed by clonidine, aripiprazole, and pimozide.38 They also recommended that coexisting OCD can be managed effectively by risperidone and coexisting ADHD can be managed with stimulants, atomoxetine or clonidine. In a very well conducted systematic review of the various modalities of treatment for TS, Hollis et al39 concluded that antipsychotics, and noradrenergic agents, are effective in reducing tics in children and young people. The risk benefit ratio favors use of drugs like risperidone, clonidine, and aripiprazole, which have good effect on tics and minimal adverse effects.

All existing Cochrane reviews on the pharmacological treatment of tics in TS patients concluded that the evidence for efficacy and safety of the studied drugs does not allow firm recommendations.7,35,40

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Oral pharmacological agents are associated with a number of adverse effects and on many occasions they fail to treat all tics, so additional treatment options are required (Fig. 1). Botulinum toxin injections are reported to be an effective treatment for motor and phonic tics in TS patients. However, the current evidence is based on only one randomized, cross-over study.41 Marras and colleagues recruited 20 participants over 3 years, 18 of whom completed the study. Fourteen participants had a diagnosis of TS, with relatively mild and nondisabling tics (21 treated tics), and 8 participants were taking oral medication. A statistically significant reduction in tic frequency was seen in 15 of 18 patients; however, phonic tics were not measured. Subjective nondisabling weakness, were reported by 9 participants. There were other studies (Table 2) also reporting effect of botulinum toxin in tics patients, which included 4 open label studies (3 motor tics42–44 and 1 phonic tics45), 5 case reports (2 motor tics46–47 and 3 phonic tics48–50) and 1 case series (phonic tics51).





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In a pilot study, Jankovic42 recruited 10 TS patients (all male) of 13 to 53 years of age with disabling focal tics. Five patients had involvement of eyes in the form of frequent eye blinking and blepharospasm and 5 patients had dystonic tics of neck. All patients had moderate to marked improvement in the intensity and frequency of tics and premonitory symptoms were completely abolished or markedly relieved. None of the patients had serious complications. The author concluded that botulinum toxin is effective in controlling motor tics as well as premonitory sensory urge.

In 2000, Kwak and colleagues described the results of a longitudinal follow-up study, which included 35 (30 male and 5 female) TS patients with a mean age of 23.3±15.5 years.43 All patients received intramuscular botulinum toxin injection and there were total 115 treatment sessions. Twenty-nine patients experienced improvement in tics following injection and 23 patients had marked relief in premonitory discomfort. No severe complications were reported with the exception of neck weakness in 4 patients, ptosis in 2 patients, generalized weakness in 1 patient, nondisabling dysphagia in 2 patients, fatigue in 1 patient and nausea/vomiting in 1 patient. Although this was an open label evaluation and, as such, subject to biases, the findings of this study supports the use of botulinum toxin as a safe and effective treatment for tics.

In 2010, Rath and colleagues evaluated the short-term and long-term treatment effects of botulinum toxin type A in 15 consecutive patients (18 tics) with simple motor tics.44 Short-term efficacy was reported in 89% patients (16/18 tics), and long-term efficacy was reported in 66.66% patients (12/18 tics). Premonitory urge decreased following treatment in all patients and disappeared in 2 patients. None of the patients had serious adverse effects. The authors concluded that botulinum toxin type A appears a safe and effective treatment for simple motor tics and retains its efficacy over long-term.

In 2008 Aguirregomozcorta and colleagues reported complete resolution of cervical dystonic tics in a 42 year male with TS, 2 months following 300 units of botulinum toxin type A injected bilaterally to the sternocleidomastoid muscle (50 U) and to the splenium capitis (100 U).46 Srirompotong and colleagues in 2007 reported complete disappearance of ear wiggling tics 9 days following 40 units of botulinum toxin type A injection in the pinna muscle (ie, the auricularis anterior and superior).47

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In 2004, Porta and colleagues assessed the effect of type A botulinum toxin injection (2.5 U in both vocal cords) on phonic tics in 30 patients with TS.45 Following treatment vocal tics improved in 93% of patients, with 50% being tic free. The only side effect was hypophonia present in 80% patients. The authors concluded that type A botulinum toxin is an effective and safe treatment for phonic tics in TS patients.

In 1996, Salloway and colleagues reported efficacy of botulinum toxin type A in a 28-year-old male patient with TS having simple and complex phonic tics including coprolalia.48 In 1996 Scott and colleagues also reported a 13-year-old boy with TS injected with 30 units of botulinum toxin in left vocal cord under electromyography guidance and 5 weeks later he had sustained reduction in coprolalia without associated hoarseness.49 In 1998 Trimble and colleagues reported a 34-year-old person with TS having copropraxia, showing significant reduction in loudness of coprolalia after receiving 3.75 units of botulinum toxin type A (Dysport) in his bilateral thyroarytenoid muscles under electromyography guidance.50

In a case series published in 2008, Vincent demonstrated the utility of botulinum toxin type A in 2 patients (48 y female and 14-y male) with laryngeal tics.51

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Although botulinum toxin did appear to improve focal tics, the treatment should only be considered in select cases. In a Cochrane review Pandey and colleagues concluded that they were uncertain about botulinum toxin effects in the treatment of focal motor and phonic tics, as the quality of the evidence was very low.52 In an evidence-based review, Hallett and colleagues classified the current evidence for botulinum toxin in the management of tics as class II and level U recommendation (data inadequate).53

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In a significant number of patients tics are severe and available pharmacological treatments are ineffective or cause significant adverse effects.54 In most of these patients depression, self-injurious behavior, ADHD, OCD, and anxiety exist. Once these patients are considered refractory to pharmacological treatments surgical options may have to be considered.

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Lesional Surgery

Ablative surgery in TS was performed for the first time in 1955.55 Subsequently, Baker in 1962, reported the first leucotomy for TS in a 22-year old and reported decrease in refractory tics and OCD at 1-year follow-up.56 However, the patient had brain abscess as a complication following the surgery.

In 1964, Stevens reported the outcomes of prefrontal lobotomy done on a 37-year-old man who had extreme disability because of his motor and vocal tics.57 After 2 years follow-up patient demonstrated improvement in his symptoms, which persisted for 6 years. But, due to confounding use of neuroleptics the effect of surgery in symptoms was not fully evident.

Alternative targets like cingulotomy were reported to decrease tics by Kurlan et al,58 and Korzen et al,59 ranging from 25% to 30% to disappearance of symptoms. Sawle et al,60 suggested that cingulotomy normalizes abnormal basal ganglia-thalamo-cortical circuit by demonstrating the normalization of hypermetabolsim of caudate and thalamus. Contrary to these reports of good outcome, Beckers recommended against use of cingulotomy due to its cognitive side effects like apathy, intellectual impairment and difficulties with concentration.61 Baer et al62 also reported to have no improvement after cingulotomy and reported worsening of tics in his report of one patient.

Targeting the corticostriatal hyperactivity by thalamotomy has also been tried in patients with TS. Hassler and Dieckmann63 reported 70% to 100% subjective improvement in tics in 3 patients who underwent bilateral thalmotomy targeting rostral intralaminar and medial nuclei. Contrary to Hassler, Cappabianca et al64 reported only temporary and slight reduction in tics and compulsions. Nonreversible disabling complications were reported by Leckman et al65 in a patient who underwent bilateral cingulotomies and infrathalamic lesionectomy. The patient developed dysarthria, dysphagia, gait and hand-writing difficulties, mild hemiparesis, abnormal extraocular movements, axial rigidity, and bradykinesia post operatively.

In a retrospective study Babel et al,66 reported use of unilateral and bilateral coagulation of zona incerta and or thalamotomy in 17 patients and demonstrated tic score reduction ranging from 45% to 52%. Unilateral zona incerta lesioning and thalamus lesioning selected by asymmetry of symptoms provide an effective control of tic severity. Transient complications occurred in 68% of patients like dysarthria, hemiparesis, and dystonia.

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Lesional surgery resulted in improvement in symptoms for some patients, but was associated with a number of permanent and disabling side effects. Most of these reports do not mention details regarding impedance measurements, depth recordings, or postoperative imaging thus raising concerns about the real target localization. With the advent of alternative functional surgical options like DBS, lesional surgery is gradually becoming obsolete.

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In 1999, Vandewalle et al,67 reported the use of DBS in medically refractory TS in a 42-year-old male patient with the targets being the thalamic nuclei and found 90% reduction in his tics at 1 year follow-up. Since then, there are many published case reports, case series, and original peer reviewed articles regarding DBS in TS and tic disorder patients, which have been summarized in Table 3.67–140







The age of patients undergoing DBS has ranged from 12 to 60 years. There was a clear male dominance with most case series and reports having more male subjects with TS undergoing DBS.

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DBS Targets for TS and Chronic Tic Disorders

  • Thalamus: centromedian parafascicular complex, the cross point of the centromedian nucleus-substantia periventricularis/nucleus ventralis oralis intermedius (Voi) (CM-Spv-Voi), nucleus ventro-oralis posterior-ventro oralis anterior-Voi complex (Vop-Voa-Voi).
  • Globus pallidus internus (GPi): postero-ventrolateral and anteromedial part.
  • Globus pallidus externus.
  • Nucleus accumbens.
  • Anterior limb of the internal capsule (ALIC).
  • Subthalamic nucleus.
  • Field H1 of forel.

The most commonly used targets have been the thalamic region followed by pallidal targets. In the thalamus, CM-Pf region is the most widely studied target. Servello et al,92 evaluated the effect of CM-Pf stimulation in 36 subjects and reported improvement in YGTSS by 47% over a follow-up period ranging from 3 to 48 months. In a recent study of 48 patients who underwent DBS for TS, authors reported that 27 of the 37 patients had 78% reduction in YGTSS score.122

The second most commonly employed target is the Gpi. Zhang et al116 reported a mean reduction of 52.1% in YGTSS in 13 subjects who underwent GPi DBS over a follow-up period 13 to 80 months. Kefalopoulou et al121 in a randomized double-blinded trial used pallidal DBS and demonstrated improvement in YGTSS by 15.3% when off and on stimulations were compared. More than one DBS targets have also been reported by many authors.70

Most of the studies published in literature reported beneficial effect of DBS in TS, but of these only 6 were randomized controlled studies. Houeto et al,70 conducted the first prospective double-blind study of one patient who underwent bilateral CM-Pf thalamic and bilateral anteromedial GPi lead implantation. The tic severity was assessed using the YGTSS and Rush Video-Based Tic Rating Scale (RVBTS) in various phases including sham stimulation. After 2 months of bilateral thalamic stimulation, a 65% reduction in the YGTSS and a 77% improvement on RVBTS was observed. When bilateral GPi stimulation was used, a 65% reduction in the YGTSS and a 67% improvement in the RVBTS were reported. When combined thalamic and GPi stimulations were tried, there was remission of self-injurious behavior and a 70% reduction in YGTSS, which persisted for 2 years. One month after the stimulation was stopped (during sham stimulation), the tics and panic attacks progressively returned.70 In another randomized, double-blinded trial of bilateral thalamic CM-Pf in 5 patients, Maciunas et al74 demonstrated 40% to 67% mean motor tic reduction and 21% to 70% mean vocal tic reduction using the modified Rush Video-based Tic Rating Scale (mRVTRS) in the stimulation state.

Welter and colleagues in a double-blind, randomized cross-over trial studied the effect of high frequency stimulation of the CM-Pf and/or the ventromedial GPi in 5 patients and recorded improvement in the YGTSS score from 65% to 96%with bilateral GPi stimulation. A less robust reduction of 30% to 64% was noted with CM-Pf stimulation. When combined GPi and thalamic stimulation was tried the improvement ranged from 43% to 76%.81

In 2011, Ackermans and colleagues in a randomized double-blind cross-over trial studied the effect of DBS stimulation in Cm-Spv-Voi of thalamus in 6 patients. When tic severity was compared between on and off state, a significant 37% improvement in YGTSS was reported.103

In a recent double-blind multicenter parallel-group trial evaluating efficacy of anteromedial GPi-DBS in 16 patients of TS, no significant reduction in tic severity was reported between the sham and active stimulation groups during the 3 month double-blind period. There was no reduction in depression, anxiety and other neuropsychological measures.131

The prospective international DBS database and registry is the largest registry of patients of medically refractory TS, who underwent DBS implantation at 31 institutions in 10 countries around the world. Over a period of 4 years the registry reported 185 patients of TS who underwent DBS. The mean total YGTSS improved from 75.01 to 41.19 at 1 year, which is almost an improvement of 45.1% after DBS.135

In a meta-analysis Baldermann and colleagues included 57 studies (156 cases) and concluded that overall, DBS resulted in a significant improvement of 52.68% in the YGTSS. Significant YGTSS reductions were seen after stimulation of the thalamus, the posteroventrolateral part and the anteromedial part of the GPi, the ALIC and nucleus accumbens; however, there was no significant difference between these targets.141

Most of the randomized double-blind trials of DBS have their own inherent fallacies. Data collected from multiple centers have several limitations including different surgical techniques and treatment approaches that can affect results. In RCTs where unblinded adjustment of parameters were done, patients may have known whether they were actually in ON or OFF stimulation phase of the trial and thus bringing in bias. Similarly in the sham arm, the duration of the stimulation effects from the previous stimulation phase could have led to a carryover effect and the possibility of a placebo effect must also be considered, particularly in a population known to be suggestible.

Different paradigms of DBS stimulation have been studied and their safety and efficacy have been evaluated. Okun and colleagues tested the efficacy of scheduled, rather than the classic continuous, DBS paradigm with target of 50% improvement in the YGTSS total score to prove its efficacy. Six-month data revealed that reductions in the YGTSS total score did not achieve the prestudy criterion of a 50% improvement on scheduled stimulation settings.109 One of the most promising paradigms is that of adaptive DBS, which will be a closed-loop system designed to measure and analyze local field potentials recorded by DBS electrodes reflecting the patient’s clinical condition and give feedback so as to modify online stimulation settings.142

The adverse effects may be categorized as related to surgery, hardware and stimulation effects. The adverse effects related to surgery and hardware include hematoma at tip of electrodes, intracranial haemorrhage, lead breakage, poor wound healing, infections in the battery pouch, and abdominal hematoma.76,89,95,99 In the International Deep Brain Stimulation Database and Registry, the overall adverse event rate was 35.4% with intracranial hemorrhage occurring in 1.3%, and infection in 3.2%.135 The most common stimulation-induced adverse effects were dysarthria (10 [6.3%]) and paresthesia (13 [8.2%]). Servello and colleagues evaluated the rates of hardware and infection related complications during DBS for different disorders.99 A much higher rate of DBS related infection in TS is reported compared with DBS in other disorders, which may be because of the associated compulsive behaviors.95 Some specific adverse effects like lead fracture due to head-snapping tics was reported because of the comorbidity associated with the disease, which may add further challenges.80

The adverse effects related to stimulation are weight loss, mood changes, changes in sexual behavior, psychiatric symptoms including psychosis, depression, hypomania, and decreased energy levels.76,80,99 The side effects related to stimulation varied according to the target of DBS. Gaze and visual disturbances were associated with CM-Spv-Voi of the thalamus.68

When the Ventral Anterior and Ventrolateral Motor part of the thalamus was stimulated the eye disturbances became less, but there were mood deterioration and stimulation-dependent dysarthria.135 Pallidal stimulation-have been linked with memory and behavioural disturbances.135,128 Stimulation of the ALIC/Nac region has been associated with side effects related to mood and affect of patients.70

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Although there is lack of large randomized controlled studies assessing efficacy of DBS in TS, the evidence from current literature suggest that DBS may be considered as one of the therapeutic options in patients with medically refractory TS. European clinical guidelines for DBS in TS and other tic disorders patients classified the recommendations as undisputed for treatment resistant severe tics with no major depression.54 They have also highlighted debatable issues where no equivocal recommendations can be given, like minimum age, duration of severe tics, definition of treatment resistance, and which target should be selected. New advances in stimulation paradigm can make this procedure safer and produce better clinical outcomes. A large multicentric randomized double-blind trial with large number of patients will further test its efficacy and also the side effect profile of this procedure. There are still questions like the best target for stimulation, which needs to addressed in trials with high-quality design with minimal bias. The prohibitive cost and the limited availability of centers with this facility are also important concerns which lead to less use of this therapeutic modality.

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Tic disorders represent a wide range of tics and coexisting symptoms. Comprehensive assessment strategies are crucial to a correct management approach. In patients requiring pharmacological treatment antipsychotics and alpha agonists remain first line options. Injection botulinum toxin may be considered for the management of focal and dystonic tics. DBS has emerged as a potential option for medically refractory and severely disabled tics patients; however, there is uncertainity regarding age and target selection requiring further research.

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tics; antipsychotics; botulinum toxin; deep brain stimulation

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