Curr Neurol Neurosci Rep (2014) 14:458 DOI 10.1007/s11910-014-0458-4

MOVEMENT DISORDERS (M OKUN, SECTION EDITOR)

Updates in Medical and Surgical Therapies for Tourette Syndrome Irene A. Malaty & Umer Akbar

# Springer Science+Business Media New York 2014

Abstract Tourette syndrome is a complex neurobehavioral disorder defined by multiple motor and at least 1 vocal tic, persisting over 1 year, waxing and waning in severity, and not explained by another condition. The condition may range from mild nuisance to debilitating and disabling in severity. Management includes counseling and reassurance, behavioral interventions, pharmacologic, and rarely, surgical interventions. Traditionally, alpha-2 agonists and dopamine receptor antagonists have been utilized. In addition, a number of different pharmacotherapies have been implemented in the search for improved management of tics with better tolerability. In rare, severely disabling cases, neuromodulation with deep brain stimulation may be indicated. Optimal brain targets and candidate selection are still in evolution. This article will review the evidence for current medical and surgical therapies with a focus on recent updates. Keywords Tourette . Tic . Treatment . Neuroleptic . Antipsychotic . Alpha-2 receptor agonist . Deep brain stimulation . Movement disorders

Introduction Tourette syndrome (TS) is a complex neuropsychiatric disorder characterized by multiple motors and phonic tics and often complicated by comorbid conditions which can be more disabling than the tics. A tic is a sudden, rapid, recurrent, nonrhythmic motor movement or vocalization. Motor tics This article is part of the Topical Collection on Movement Disorders I. A. Malaty (*) : U. Akbar Department of Neurology, University of Florida, UF Center for Movement Disorders and Neurorestoration, P.O. Box 100236, Gainesville, FL 32610, USA e-mail: [email protected]

can be simple, such as blinking, transient eye deviations, head nods or shrugs, or more complex sequences of patterned motor programs. Phonic or vocal tics are those which produce sound, most commonly sniffing or throat clearing, but potentially squeaks, hums, words, or phrases. These behaviors may initially mask as “normal” movements, allergies, or even seizures. Tics are distinguished in many cases by a premonitory urge or sensory phenomenon that provokes the action, and a sense of relief with completion of the motoric act. Some individuals describe palpable sensory experiences such as a muscle tension needing to be stretched, while others have a nondescript discomfort that is satisfied temporarily by performing the tic. There is typically a component of temporary suppressibility, but often at the cost of eventual rebound of the tics. Tics may be diminished during focused, directed attention and may be exacerbated by stress in some individuals, but tics characteristically wax and wane despite any impact of external factors. Coprophenomena (socially unacceptable vocalizations or gestures—coprolalia and copropraxia), though commonly considered defining of TS by the lay population, are actually rare and occur in a minority of individuals. A large international database of 3500 patients observed that 14 % had coprolalia [1]. “Malignant TS” is rare, and has been defined as TS requiring ≥2 emergency room visits or at least 1 hospitalization. Self-injurious tic behavior, injuries from tics, aggressive, or suicidal behaviors contribute. At 1 specialty referral center, only 5 % of patients met “malignant” criteria [2]. The TS eponym was coined by Charcot after his resident Georges Albert Édouard Brutus Gilles de la Tourette described 9 cases of individuals with typical symptoms in 1885 [3]. The Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV criteria require onset in childhood (1 year) did not detect a single case [41]. Akathisia and neuroleptic malignant syndrome are additional risks. Appropriate counseling regarding risks, alternatives, and potential benefit is critical. Haloperidol Haloperidol is a butyrophenone [35]. It is the neuroleptic with the longest experience in TS, and 1 of the 2 FDA approved for TS in adults and children in the U.S. Haloperidol has been studied against pimozide and against pimozide and placebo (twice) in RCTs, as well as against clonidine, fluphenazine, and other agents. It consistently demonstrates efficacy in reducing tics in adults and children, but with fatigue, sedation, and extrapyramidal side effects [30••, 32••]. Haloperidol has demonstrated slight superiority to pimozide in efficacy but with lower tolerability and more serious side events in a double-blind placebo-controlled trial. Of note, dose ranges considered in that trial were wide (2–20 mg/day haloperidol, 2–48 mg/day pimozide), and not necessarily typical for those

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used in routine practice [32••]. Dosing more typically starts 0.25–0.5 mg daily and therapeutic range is 0.75–5 mg daily or divided bid [35••, 36]. Keeping dose to minimum necessary is advisable to reduce risk of adverse events.

gynecomastia has received media attention, although that risk is not unique to risperidone.

Pimozide

Quetiapine antagonizes D2 receptors but also 5HT1a and 5HT2, histamine H1, and alpha 1 and 2 adrenergic receptors. Small open label and retrospective pediatric studies have shown tic improvement using doses ranging approximately 50–300 mg [35••, 46, 47]. Olanzapine binds D1 and D2 receptors, 5HT 2a and 2c, D2, D4, and alpha1 adrenergic receptors [35••]. Tic reduction over placebo has been shown in open label pediatric studies and a double-blind cross over 52 week adult study vs low dose (2– 4 mg/day) pimozide [35••, 48]. More recently, an open label 6 week study of 12 youth demonstrated significant tic reduction and also improved ADHD symptoms, but in this short study mean weight gain was about 4 kg. Starting dose is 2.5 mg, with target range 5–10 mg total per day [30••, 35••].

Pimozide is a diphenylbutylpiperidine derivative that antagonizes D2 receptors [35••]. It has demonstrated efficacy for tic reduction against placebo and has been studied against haloperidol in multiple studies demonstrating equivalency, slight inferiority, or superiority in different studies. It has also been studied against risperidone with equivalent benefit and risk profile [30••, 31••, 32••]. Typical starting dose is 0.5–1 mg and therapeutic range is 2–4 mg (up to 10 mg) [35••, 36]. Prolonged QT interval is a particular risk, especially if paired with other medications that contribute further risk. It is advisable to obtain a baseline and postinduction EKG as risk of sudden cardiac death is reported [35••]. A Cochrane review for pimozide in TS has been published , including 162 patients in 6 trials (age 7–53), concluding it is an effective option but longer trials are needed [42]. Fluphenazine Fluphenazine antagonizes D1 and D2 dopamine receptors. In addition to smaller open label studies reporting efficacy with improved tolerability over haloperidol [43], a retrospective study of 268 patients with TS (ages 4–70) demonstrated marked to moderate improvement in 80.5 % of the patients, at an average optimal dose of roughly 3 mg daily (range 0.5– 12 mg). Drowsiness and fatigue were the most common side effects, with no reports of tardive dyskinesia (average 2.6 year duration; .01–16.8 years) [44•]. Starting dose range is 0.5– 1 mg, with therapeutic range 2–5 mg daily [35••]. QT prolongation is a risk with this medication as well, and narrow angle glaucoma is a contraindication. Atypical Neuroleptics Risperidone Risperidone is the most well-studied atypical neuroleptic for TS. It works at D2 receptors but also 5HT2, histamine H1, alpha 1 adrenergic, D3, and D4 receptors [35••]. It has demonstrated tic reduction against placebo and efficacy at least equal to pimozide in head to head trials. In the U.S. it has an additional indication for irritability associated with autism spectrum disorder. In 2012 a meta-analysis was published concluding efficacy similar to traditional agents [45•]. Starting dose is 0.25–0.5 mg with target range typically 2– 4 mg daily total [35••]. QT prolongation is a concern, as well as the other typical risks of neuroleptics. Recently

Quetiapine

Aripiprazole Aripiprazole is a D2 receptor antagonist as well as a partial agonist of D2 receptors and a 5-HT1-A and 5-HT2-A antagonist [36]. It has recently gained favor as an atypical neuroleptic that may be better tolerated but adequately potent to treat TS, and evidence is mounting to support its use. An open label study of 28 consecutive TS patients with comorbid ADHD found that motor and vocal tics improved by 42.5 % and 47.9 %, respectively, using YGTSS. In that study, attention (ADHD-Rating Scale IV) also improved by 22.5 % [49]. A retrospective review of 100 cases at 1 specialty center reported that patients (27 +/–11.5 years) had been treated with doses (5–45 mg daily). Eighty-two had significant benefit in tic severity and 48 patients followed to 1 year had lasting benefit, although 31 % discontinued for side effects or lack of efficacy [50]. Enduring benefit was demonstrated in another study of 20 adult patients treated with a mean dose of 11.8 mg daily for up to 56 months [51]. Most recently, a 10-week multicenter RCT with 61 patients (6–18 y old) demonstrated improvement in total tic score on YGTSS and TS CGIS. Aripiprazole was well-tolerated. Mean weight gain was 1.6 kg compared with 0.2 kg on placebo [52•]. In a multicenter controlled trial of 195 children with TS in China, aripiprazole led to tic reduction of 29 points on YGTSS, equivalent to the comparator, the D2 and D3 receptor blocker tiapride [53]. Ziprasidone Ziprasidone is a D2 receptor antagonist that also binds 5HT2, alpha 1 adrenergic, and H1 histamine receptors. A pilot study involving 28 pediatric patients demonstrated efficacy over

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Dopamine Depletor

have compared topiramate with haloperidol (12) or tiapride (2) with similar benefit [30••, 60•]. Duration was variable (days to 1 year) as have been the doses utilized (1–9 mg/kg/ day for children, 50–200 day for adults) and outcome measures, but benefit did occur. A retrospective study of 41 patients treated at a single center found that average efficacy was “moderate improvement” using a global impression of response (none/worse, mild, moderate, or marked) [61]. A RCT of 29 patients (children and adults) demonstrated improved total tic score on YGTSS of 14.3 vs 5.0 on placebo with mean daily dose 118 mg [62]. Drowsiness, loss of appetite and weight, and cognitive side effects occurred. Paresthesias, slight increase in risk of kidney stones and glaucoma need to be discussed when prescribing. This agent may be a consideration for patients who have experienced excessive weight gain on neuroleptics, or those with comorbid migraine or seizure disorders.

Tetrabenazine

GABAergic Agents

Tetrabenazine works by reversibly inhibiting human vesicular monoamine transporter type 2 (VMAT) and decreasing presynaptic monoamine uptake into vesicles, depleting monoamine stores. It also has mild postsynaptic dopamine receptor antagonism [35••]. Evidence for tic reduction comes from several open label and retrospective studies. Retrospective reviews have suggested that 77 %–80 % of patients had improvement in tics [35••, 56, 57]. Starting dose is 12.5 mg daily, with slow titration to efficacy (50–150 mg/day). Poor CYP2D6 metabolizers may encounter benefit or side effects at lower doses, and CYP2D6 genotyping may be considered particularly when titrating above 50 mg/day. A recent study, however, determined that extensive vs intermediate metabolizers had similar benefit and risk of adverse events, but faster metabolizers take longer to titrate to efficacy [58]. Induction or worsening of depression needs to be monitored, as well as risk of somnolence, hypotension, gastrointestinal upset, and emergence of parkinsonism, or other extrapyramidal syndromes. Weight gain is much less than with neuroleptics; In 1 pediatric study, 0.8 lb/mo were gained vs 1.7 lb/mo over approximately a 2-year study [59].

Clonazepam

placebo and tolerability at mean dose of 28.2 mg (5–40 mg) [54]. QT prolongation is an important risk. Ecopipam Ecopipam is a promising agent with a novel mechanism of selective D1 receptor antagonism. It is proposed that this mechanism might impact the excitatory direct pathway in the basal ganglia, whereas D2 modulation theoretically targets faulty inhibition of inhibitory pathways. In an open label 8-week study of 18 adults, YGTSS total tic scores, motor and vocal tics, and impairment were reduced with no serious adverse events and no impact on weight. Sedation, fatigue, insomnia, and somnolence were the most common side effects [55•].

Other Agents Topiramate Topiramate is an anticonvulsant that inhibits voltage gated sodium channels and has GABAergic as well as glutamate antagonistic effects [35••]. A recent meta-analysis (2013) concluded that quality of evidence was insufficient to support topiramate as a tic-suppression agent [60•]. However, 14 trials

Clonazepam is a benzodiazepine and GABA-A receptor agonist, as well as alpha-2 adrenergic agonist with case reports and small open label trials demonstrating benefit against placebo and clonidine, at doses up to 6 mg daily [35••, 63–65]. Anxiolysis may be a secondary benefit, and this agent may be a choice for anxious patients with tics. Starting dose is 0.25–0.5 mg daily and target 0.5–4 mg/day divided bid or tid [35••]. Sedation, cognitive clouding, hypotension, ataxia, paradoxical agitation, and risk for addiction/dependence must be considered. Baclofen Baclofen is a GABA-B receptor agonist and was studied in a small (n=10) 4-week pediatric (8–14years) double-blind placebo-controlled crossover trial at 60 mg/day. YGTSS total score had nonsignificant improvement relative to placebo (14.7 points) and significant improvement in Clinical Global impression Severity score [66]. In an open label study of 264 children (6–18years), there were significant decreases in motor and vocal tics in 250 patients at 30 mg/day [67]. Somnolence, constipation, and nausea were among common side effects reported. Withdrawal seizures or psychosis can occur with abrupt cessation. Dose ranges typically employed are 10–60 mg daily starting 5–10 mg tid and titrating as needed [30••, 35••]. Dopamine Agonists The selective nonergot ropinirole 0.25–0.5 mg bid had shown tic reduction in a small open-label trial of 15 children [68], and pergolide has been shown to improve tic severity in 2 trials [69,

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70], but the latter was withdrawn from the market in the U.S. due to valvular heart disease risk. Subsequently, a multicenter randomized placebo-controlled trial involving 63 children and adolescents found no benefit of pramipexole for tics, but some potential impact on ADHD based on DuPaul scores [71].

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Levetiracetam Levetiracetam has been compared with clonidine in a double-blind, crossover study [83] and had no positive impact on tics (YGTSS total tic score, total score, or CGIS behavioral measures) [84].

Cannabinoids Other Agents A Cochrane review exists for Delta-9-tetrahyrdrocannabinol (Delta 9-THC) including 28 participants and 2 studies (1 double-blind crossover study and 1 double-blind parallel group study), doses of 5–10 mg/day. There were small improvements reported in some of the outcome measures used. Demonstrable benefit did not balance risk [72–74]. Nicotinic Agents Nicotine Nicotine, an agonist of nicotinic acetylcholine receptors, has been shown to potentiate the benefit of neuroleptics in reducing tics in open-label studies and in controlled trials of both nicotine gum and patches [75, 76]. Although initially there was suggestion that benefit could last up to weeks [77], double-blind placebo controlled trial of a single transdermal dose of nicotine failed to reach significant improvement in primary outcomes of tics. Commonly, nausea, vomiting, or headache were side effects [32••, 77]. Mecamylamine Mecamylamine is a nonselective antagonist of nicotinic acetylcholine receptors that failed to show efficacy over placebo in a randomized double-blind trial of 61 pediatric patients (only 38 completed the study) [78]. Botulinum Toxin Botulinum Toxin inhibits acetylcholine release at the neuromuscular junction injection by being internalized at the presynaptic membrane, cleaving a SNARE protein called SNAP 25, and preventing docking of acetylcholine vesicles. Botulinum toxin injection leads to temporary relaxation of muscles and has been studied as a means to reduce motor and vocal tics in open label studies [79–81]. One RCT demonstrated reduced number of tics/minute and reduced urge to tic [82]. Potential side effects are dependent on injection site, but include ptosis, dysphagia, weakness, hypophonia, and evolution of tics into other manifestations. The role is likely limited to focal and particularly bothersome tics, but may be 1 more tool in the treatment arsenal [82].

Other agents have been explored, including case reports of tic remission with clozaril (including 1 patient with comorbid schizophreniform disorder) [85–87]. Risk of agranulocytosis and minimal data make this less appealing. Atomoxetine was shown to improve both attention and tics (total YGTSS score) over placebo and reached statistical significance at the endpoint (though not at interval time points where placebo improved as well) [88]. Metoclopramide showed 55 % total tic reduction in an open label study of 10 patients, and 39 % reduction (vs 13 % on placebo) in an 8-week RCT of 27 young patients with chronic tic or TS [89, 90]. Longer term studies with close safety monitoring were recommended.

Deep Brain Stimulation Brief Historical Perspective Given the shortcomings in efficacy and risks of chronic therapy with current pharmacologic options, there has been a hunger for more aggressive and innovative therapies to treat severe TS. The similarity of tics to other extrapyramidal hyperkinetic movements led to investigation of surgical approaches. In 1970, Hassler and Dieckman [91] reported 70 %–100 % improvement in tics of 3 patients with ablation of thalamic targets. Ablative procedures over the next 2 decades were retrospectively studied and intolerable adverse effects were reported in a majority of patients [92], leading to a halt of further expansion of this approach. With the success of DBS in modulating other basal ganglia disorders, the appeal of a modifiable treatment intervention was recognized. In 1999, Vandewalle et al [93] introduced an alternative surgical method using stimulation, rather than ablation, at the junction of the centromedial parafascicular complex (CM-Pf), ventro-oralis nucleus (Vo) and substantia periventricularis (Spv) on the basis of Hassler and Dieckman’s success in lesioning the same focus. This represented the dawn of a new era in the surgical management of medication-refractory TS in the late 1990s. Subsequently interest blossomed in alternative targets including other foci in the thalamus, globus pallidus and ventral striatum.

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Brief Review of the Evidence After the initial report of successful tic improvement postDBS of the thalamus, the body of evidence has edged forward by trickles of case series (primarily single-case reports) and small clinical trials, culminating in approximately 100 reported cases thus far. Tic improvement of varying degrees has been reported after DBS and several cases have also reported improvement in the associated comorbidities. Since these outcomes varied by target, we briefly discuss the results achieved with each target. Tic Outcomes Thalamic targets are most commonly chosen and have yielded tic improvement (as measured by YGTSS) ranging from 24 % to 90 % [93, 94••, 95–100]. Tics in the first 3 reported TS patients improved by 72 %–90 % after DBS [93, 100]. In a prospective, double-blind, cross-over trial of 5 patients, Maciunas et al [98] reported a 53 % and 70 % improvement in motor and vocal tics during the randomized phase, respectively, but the benefit decreased to 40 % improvement in motor tics and 21 % worsening in vocal tics during the open label, 3-month follow-up. A single case by Bajwa et al [96]. improved by 66 %. Ackermans et al [94••] reported a 49 % reduction in tics of 6 patients in a doubleblind RCT. A case-series of 18 patients [101] with DBS implantation 2 mm anterior to the traditional thalamic target demonstrated 24 %–79 % tic improvement. Fifteen of the same 18 patients maintained 52 % tic reduction after 2 years [102]. Vernaleken et al [103] targeted the dorsomedial (DM) thalamus which resulted in a 36 % improvement in a single-patient. Mean tic reduction of 70 % was observed at 1-year post-DBS in 3 patients implanted more posteriorly, in the center of the CM-Pf complex [104•]. Most recently, Okun et al [105•] compared the classic continuous stimulation paradigm with scheduled intermittent stimulation in 5 patients and found mean reduction in tics of 19 %. Although the 50 % reduction endpoint criterion was not met, scheduled stimulation was found to be safe and feasible. With the exception of an unsuccessful outcome in a mentally retarded patient [106], DBS of the posteroventral (PV) or anteromedial (AM) globus pallidus internus (GPi) has resulted in 37 %–96 % improvement [106–117]. Martinez-Fernandez et al [114] reported 2 patients implanted in each of these distinct targets of the GPi, and 1 in both targets. The anteromedial target yielded a greater improvement than posteroventral GPi (54 % vs 37 %). Massano et al [117] reported a 60 % tic reduction in a 14-year-old boy and

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Shahed et al [111] demonstrated 84 % tic improvement in a 16-year-old boy. Welter et al [115] studied patients who were implanted bilaterally in the CM-Pf and GPi (4 leads) and stimulated each nucleus independently, as well as simultaneously, and found improvement of 78 % with GPi stimulation, 45 % with CM-Pf stimulation and 60 % with simultaneous stimulation of both targets. In response to urgent DBS implantation for cervical cord compression caused by morbid TS, tic reduction of 55 % was observed at 1-year follow-up in a recent case-report [116]. Improvement of 61 %–96 % was seen with stimulation of the globus pallidus externa (GPe) in a caseseries of 7 patients [118]. One patient reported worsening of tics by 17 % with the ALIC/NA target [119], while other cases demonstrated an improvement of 25 %–82 % [120–125]. A parkinsonian patient implanted DBS in the STN reported 97 % coincident improvement of co-existing tics [126]. In summary, the majority of the DBS cases reported to date have documented significant tic reduction. The European Society for the Study of Tourette Syndrome (TSSTS) published guidelines in 2011 after review of 69 cases, 59 (93.7 %) of which reported significant improvement in tics [127••]. However, it must be remembered that reported literature has a bias for successful results, while unsuccessful outcomes may not be eagerly reported. Our search has yielded at least 3 cases [98, 106, 119] in which tics (motor, vocal, or both) were unchanged or worsened after DBS. Additionally, adapting and reintegrating even after tic improvement can be difficult for patients with longstanding social and psychological strain. A suicide attempt could not be avoided in a 42-year-old male who experienced a major depressive episode 4 years after successful DBS therapy [122].

Associated Comorbidity Outcomes Follow-up assessment of associated comorbid disorders, like OCD (measured by YBOCS), ADHD, and selfinjurious behavior (SIB), was reported in some, but not all, of the studies. Using thalamic targets, Maciucna et al [98] reported a trend for improvement in mood, anxiety, and OCD symptoms. Bajwa et al [96] demonstrated a 76 % improvement in OCD in their case-report. The double-blind RCT of 6 patients reported no significant change in comorbidities [94••]. In the long-term follow-up of the first 3 TS patients [93, 100] and a large-case series [101], a subjective improvement in associated comorbidities, including compulsions and mood was noted. The 5 patients reported by Okun et al

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[105•] had no improvement in depression, mania, OCD, or QOL measures. In the GPi targets, Houeto et al [113] reported cessation of SIB and Shahed et al [111] reported improvement of 69 % in OCD symptoms and 65 % in QOL. A 14-year-old boy experienced significant improvement in OCD, mood, and QOL 2years after DBS of anteromedial GPi [117]. Cases reported of ALIC/NA DBS demonstrated 8 %–64 % improvement in associated comorbidities, including OCD improvement of 64 % and SIB reduction in one [121], 50 % OCD improvement and complete cessation of SIB up to 36 months postimplantation in another [123] and subjective improvement in OCD and SIB in a third [125]. Complications DBS for TS has proven to be relatively safe. Of the 3 major complications reported, 2 resulted from hematomas at tips of the electrodes: 1 patient [109] experienced a permanent but mild reduction in rapidity of alternating hand movements, and the other [128] suffered vertical gaze palsy which improved over the following 6 months. Bilateral subcortical hematomas were observed post-DBS in a patient with coagulopathy [97]. In studying their DBS implantations, Servello et al [129•] noticed a higher rate of postoperative infections of extracranial cables and generator pockets in TS patients compared with other movement disorders (18 % vs 3.7 %). Stimulationrelation adverse effects are as varied as the targets used and respective outcomes. Fatigue, apathy, and lethargy have been reported occasionally with several targets [94••, 95, 99, 100, 109, 112, 120]. Transient visual disturbances [94••, 101], and less commonly, sexual problems [95, 100, 115] have also been reported. Presurgical Assessment The assessment for DBS candidacy in TS should be a team approach, as with other movement disorders. After confirming a diagnosis, a comprehensive assessment by an experienced multidisciplinary team including a neurologist, psychiatrist, neuropsychologist, and a functional neurosurgeon is essential to a successful outcome. A thorough assessment of the tics and associated behavioral comorbidities should be performed with direct observation and video-recording. The impairment of QOL should be primarily by tics [95, 127••], since comorbidities may not respond. Recommendations for presurgical assessment have been detailed in several published guidelines including the Tourette Syndrome Association (American) [130], a Dutch-Flemish group [95], an Italian group [131], and most recently by the European Society for the Study of Tourette Syndrome (ESSTS) [127••] and the UK group [132]. The

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variations in these guidelines highlight the lack of uniformity in the practice of DBS in TS. Experts agree that the diagnosis of TS should rely on the DSM IV criteria or assessment by an experienced clinician. Two groups [95, 132] suggest the additional use of the Diagnostic Confidence Index. A total score of ≥35/50 on the YGTSS meets the symptom severity criteria for all groups [127••, 130–132] except 1 [95], which uses the cutoff of >20. Most groups specify that severity criteria should be met for at least 12 months [127••, 130, 132] and that tics should be the primary symptom affecting QOL (not comorbidities) [95, 127••]. Presence of significant functional and social impairment is unanimously a criterion. The criteria for treatmentrefractoriness vary. Partial or no response, or intolerance to 3 medications is generally considered refractory [95, 127••, 130, 132]. Whether the 3 medications must be from different classes is debated. A thorough assessment and optimal treatment of comorbid conditions is essential to establish DBS candidacy. Implementation of behavioral therapy, or at least evaluation for its suitability, is emphasized. Comprehensive evaluation of tics and comorbid symptoms should include validated measures for tic severity, such as the YGTSS, an OCD scale (YaleBrown Obsessive-Compulsive Scale), an anxiety scale (such as State-Trait Anxiety Inventory), and depression index (Beck Depression Inventory). Other associated symptoms, including ADHD, anger control, and conduct disorders, can be detected by a detailed interview and the use of DSM-IV criteria checklist. The TS-quality of life scale (TS-QOL) [133] is a disease-specific measure incorporating 4 domains of QOL: psychological, physical (ADLs), OCD, and cognitive. Since spontaneous regression of symptoms in TS is common and predicting which patients will improve is difficult, determining an optimal age for intervention is challenging. DBS surgery at a young age might expose a patient to unnecessary risks, particularly when remission may have been the natural course, while delaying surgery for an otherwise qualified candidate might cause unnecessary strain on QOL and patient’s psychology, hindering learning, social integration, emotional growth, and productivity [134, 135]. Groups with earlier guidelines [95, 130] suggested age for DBS >25 years but more recent publications have suggested lower cutoffs (>18 years [127••, 131], >20 years [132]). Increasing experience demonstrating safety and feasibility of DBS in TS has likely contributed to the expansion of the criteria to younger patients. Rare cases have been reported in even younger patients: a 14-year-old [117], 2 16-year-old [106, 111], and 2 17-year-old [104•] boys. Since DBS in TS is still considered experimental, surgery for pediatric patients should be considered on a case-by-case basis with involvement of the young patient and perhaps a member of the ethics board.

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Fig. 1 Potential therapeutic targets of DBS for TS. Figure is not drawn to scale. ALIC anterior limb internal capsule

Target Selection Until now, 9 targets have been used, individually or in combination, for the treatment of TS: 4 within the thalamus (CM-Pf complex [93, 94••, 96–98, 100, 105•], 2 mm anterior [101] or 4 mm posterior [104•], DM nucleus [103]), 2 within the GPi (posteroventral [106–111, 114] and anteromedial [112–117]), GPe [118], NA/ALIC [99, 119–121, 123–125], and STN [126] (Fig. 1). Targets within the thalamus have been used most frequently, followed by GPi, NA/ALIC, GPe and STN in decreasing frequency. Judging the superiority of any 1 target over another is challenging since the inclusionary criteria and outcomes vary throughout the literature. However, it appears that although improvement in tics has been reported with all targets, improvement in associated comorbidities is more frequently reported with thalamic targets. As more data becomes

Table 1 Factors to consider before DBS in Tourette Syndrome • Diagnosis confirmation • Tic severity and associated disability • Medication refractoriness • Adequateness of therapeutic trials- duration of therapies and titration or intolerance • Age • Reasonable expectations Red flags • Secondary tics • Severe psychiatric comorbidities • Anticipated poor compliance • Poor access to follow-up care for programming and battery surveillance • Significant brain imaging abnormalities • Compulsive picking- risk for hardware infection • General surgical contraindications-cardiovascular, pulmonary, or hematologic disorders

available potential approach comes in

about the efficacy of each target as well as distinct side effect profiles, a more tailored can be recommended to achieve better outindividual patients.

Other Considerations As with DBS in other movement disorders, the risks, benefits and alternative therapies must be discussed with each candidate. The potential of failed DBS surgery and possibility of encountering adverse effects or worsening symptoms must be effectively communicated. Presurgical counseling and setting appropriate expectations is critical to achieving an optimal surgical outcome. Patient or caregiver noncompliance can result in a failed surgery, and thus, should be considered a contraindication for DBS. Other potential contraindications include abnormalities on brain MRI, poor general medical condition, and uncontrolled severe psychiatric disorder (Table 1). Compulsive picking in particular has to be carefully considered as a potential risk for infection. In some cases, chronic social isolation and environmental aspects remain destructive even after improvement of tics. In these scenarios, a case-bycase approach with the help of a multidisciplinary team should be utilized.

Conclusions Tourette syndrome is a complex and fascinating neuropsychiatric disorder. Medical and surgical therapies, when indicated, may improve quality of life but with risks of side effects that must be weighed against impact of tics on well-being. Research is desperately needed to continue to advance the care of individuals with TS.

458, Page 10 of 13 Compliance with Ethics Guidelines Conflict of Interest Umer Akbar declares no conflict of interest. Irene A. Malaty has received speaker honoraria and paid travel expenses from the Tourette Syndrome Association for participation in TSA International Consortium for Genetics study. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.

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