Tourette Syndrome Deep Brain Stimulation: a Review and Updated Recommendations

REVIEW

Tourette Syndrome Deep Brain Stimulation: A Review and Updated Recommendations

Lauren E. Schrock, MD,1 Jonathan W. Mink, MD, PhD,2 Douglas W. Woods, PhD,3 Mauro Porta, MD,4 Dominico Servello, MD,5 Veerle Visser-Vandewalle, MD, PhD,6 Peter A. Silburn, MD,7 Thomas Foltynie, MRCP, PhD,8 Harrison C. Walker, MD,9 Joohi Shahed-Jimenez, MD,10 Rodolfo Savica, MD,1 Bryan T. Klassen, MD,11 Andre G. Machado, MD,12 Kelly D. Foote, MD,13 Jian-Guo Zhang, MD, PhD,14 Wei Hu, MD, PhD,11,14 Linda Ackermans, MD, PhD,15 Yasin Temel, MD, PhD,15 Zoltan Mari, MD,16 Barbara K. Changizi, MD,17 Andres Lozano, MD,18 M. Auyeung, MD,19 Takanobu Kaido, MD, PhD,20 Yves Agid, MD, PhD,21 Marie L. Welter, MD, PhD,22 Suketu M. Khandhar, MD,23 Alon G. Mogilner, MD, PhD,24 Michael H. Pourfar, MD,24 Benjamin L. Walter, MD,25 Jorge L. Juncos, MD,26 Robert E. Gross, MD,27 Jens Kuhn, MD,28 James F. Leckman, MD,29 Joseph A Neimat, MD,30 Michael S. Okun, MD,13* on behalf of the and Tourette Syndrome Association International Deep Brain Stimulation (DBS) Database and Registry Study Group

1Department of Neurology, University of Utah, Salt Lake City, Utah, USA 2Department of Neurology, University of Rochester Medical Center, Rochester, New York, USA 3Department of Psychology, Texas A&M University, College Station, Texas, USA 4Tourette Centre, IRCCS Galeazzi Hospital, Milan, Italy 5Functional Neurosurgical Unit, IRCCS Galeazzi Milano, Milan, Italy 6Department of Stereotactic and Functional Neurosurgery, University of Cologne, Cologne, Germany 7Royal Brisbane and Women’s Hospital, School of Medicine, University of Queensland, Brisbane, Queensland, Australia 8University College London Institute of Neurology, London, United Kingdom 9Department of Neurology, University of Alabama Birmingham, Birmingham, Alabama, USA 10Department of Neurology, Baylor College of Medicine, Houston, Texas, USA 11Department of Neurology, Mayo Clinic, Rochester, Minnesota, USA 12Center for Neurological Restoration, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA 13Departments of Neurology, Neurosurgery, and Psychiatry, University of Florida Center for Movement Disorders and Neurorestoration, Gainesville, Florida, USA 14Department of Neurosurgery, Beijing Tiantan Hospital, Capital University of Medical Sciences, Beijing, China 15Department of Neurosurgery, Maastricht University Medical Center, The Netherlands 16Department of Neurology, Johns Hopkins University, Baltimore, Maryland, USA 17Departments of Neurology and Psychiatry, The Ohio State University Wexner Medical Center, Ohio, USA 18Division of Neurosurgery, University of Toronto, Toronto, Ontario, Canada 19Department of Medicine, Pamela Youde Nethersole Eastern Hospital, Hong Kong, SAR China 20Department of Neurosurgery, National Center Hospital, National Center of Neurology and Psychiatry (NCNP), Tokyo, Japan 21Institut du Cerveau et de la Moelle Epinie` re (ICM), CHU Pitie-Salp etrie^ ` re, Paris, France 22Centre de Recherche de l’Institut du Cerveau et de la Moelle epinie ` re (CRICM), Universite Pierre et Marie Curie-Paris 6, Paris, France 23Northern California Kaiser Permanente, Surgical Movement Disorders Program, Sacramento, California, USA 24Departments of Neurosurgery and Neurology, New York University, Langone Medical Center, New York, New York, United States of America 25Movement Disorders Center, Neurological Institute, University Hospitals and Case Western Reserve University School of Medicine, South Euclid, Ohio, USA 26Department of Neurology, Emory University School of Medicine, Atlanta, Georgia, USA 27Department of Neurosurgery, Emory University School of Medicine, Atlanta, Georgia, USA 28Department of Psychiatry and Psychotherapy, University of Cologne, Cologne, Germany 29Child Study Center and the Yale Center for Clinical Investigation, Yale University School of Medicine, New Haven, Connecticut, USA 30Department of Neurological Surgery, Vanderbilt University Medical Center, Nashville, Tennessee, USA

------*Correspondence to: Michael S. Okun, MD, 3450 Hull Road, Department of Neurology, Center for Movement Disorders and Neurorestoration, Gaines- ville, FL 32607, E-mail: [email protected]fl.edu Funding agencies: Relevant conflicts of interest/financial disclosures: Nothing to report. Author roles may be found in the online version of this article. Received: 4 April 2014; Revised: 6 October 2014; Accepted: 8 October 2014

Published online 00 Month 2014 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/mds.26094

Movement Disorders, Vol. 00, No. 00, 2014 1 SCHROCK ET AL

ABSTRACT: Deep brain stimulation (DBS) may nized and addressed. We have removed the previously improve disabling tics in severely affected medication suggested 25-year-old age limit, with the speciﬁcation and behaviorally resistant Tourette syndrome (TS). Here that a multidisciplinary team approach for screening is we review all reported cases of TS DBS and provide employed. A local ethics committee or institutional updated recommendations for selection, assessment, review board should be consulted for consideration of and management of potential TS DBS cases based on cases involving persons younger than 18 years of age, the literature and implantation experience. Candidates as well as in cases with urgent indications. Tourette should have a Diagnostic and Statistical Manual of Men- syndrome patients represent a unique and complex tal Disorders, Fifth Edition (DSM V) diagnosis of TS with population, and studies reveal a higher risk for post- severe motor and vocal tics, which despite exhaustive DBS complications. Successes and failures have been medical and behavioral treatment trials result in signiﬁ- reported for multiple brain targets; however, the optimal cant impairment. Deep brain stimulation should be surgical approach remains unknown. Tourette syndrome offered to patients only by experienced DBS centers DBS, though still evolving, is a promising approach for after evaluation by a multidisciplinary team. Rigorous a subset of medication refractory and severely affected preoperative and postoperative outcome measures of patients. VC 2014 International Parkinson and Movement tics and associated comorbidities should be used. Tics Disorder Society and comorbid neuropsychiatric conditions should be optimally treated per current expert standards, and tics Key Words: Tourette syndrome; DBS; guidelines; should be the major cause of disability. Psychogenic deep brain stimulation tics, embellishment, and malingering should be recog-

Tourette syndrome (TS) is a chronic neurodevelop- with TS DBS provided suggested updates (Table 2) mental disorder characterized by motor and phonic and a consensus opinion on the TSA recommendations tics that by definition occur with a childhood onset.1 put in place in 2006.7 The syndrome is commonly associated with other neuropsychiatric comorbidities (eg, attention deficit hyperactivity disorder [ADHD], obsessive compulsive Literature Review features [OCD], and other behavioral manifestations). Deep brain stimulation is an established treatment In most TS cases, the motor manifestations can be for Parkinson’s disease (PD),8-12 essential tremor,13,14 managed using TS education, comprehensive behav- dystonia,15-17 and obsessive-compulsive disorder,18,19 ioral intervention for tics (CBIT), or a variety of medi- and has been granted either full Food and Drug Admin- cations.2-4 The natural history of TS is that most istration (FDA) approval (PD, essential tremor), or a patients will experience improvement of tics in late humanitarian device exemption (FDA; dystonia, OCD) adolescence or early adulthood.5,6 However, a subset for each of these indications (in the United States). of patients will continue to experience disabling tics Many studies and position papers detail careful and despite optimal medication and behavioral manage- meticulous techniques for screening patients for ment. For severely affected patients, deep brain stimu- DBS,13,16,20-22 including a few reports for TS lation (DBS) has the potential to improve refractory patients.23,24 General guidelines for selecting individual and disabling symptoms. TS patients for DBS therapy and for managing them preoperatively and postoperatively will have the poten- Methods tial to improve risk–benefit ratios. The importance of rigorous preoperative assessment, patient selection, DBS An experienced group of physicians participating in team expertise and experience, as well as postoperative the Tourette Syndrome Association (TSA) Interna- management has been demonstrated previously, espe- tional DBS Database/Registry, and also actively cially when groups have studied cohorts of patients involved in managing TS DBS patients, reviewed the who have failed DBS therapy.25,26 Because TS is a 2006 TSA guidelines7 and examined all reported cases childhood-onset disorder, often with complex clinical of TS DBS. The TSA Database/Registry group features, a waxing and waning course, and frequent accepted complete information sets on outcomes from neuropsychiatric comorbidities, the evaluation of TS DBS (database entry), as well as registration of patients has a greater level of complexity than many of cases performed with or without outcome information the other current DBS indications. (registry entry). The group summarized the literature In 2005, the TSA hosted a meeting of physicians (Table 1) and based on their collective experience with experience and expertise in TS and DBS to

2 Movement Disorders, Vol. 00, No. 00, 2014 TABLE 1. Review of reported TS DBS cases

Target: Thalamic Postoperative SIB With Immedi- Lead Location Sample size Age at DBS Subjects < 25 Study Level of Tic Outcome Comorbidity ate Risk of Bodily Reported (AC-PC Adverse Events Study Target (n) (years) yrs (ages) Follow-up Design Evidence Measures Outcome Measures Harm (Yes/No) Coordinates) Reported

Servello et al., CM-Pfc, Voa 18 (15M, 3F) 17–47 8 (2 3–18 mo Case series IV 1.YGTSS None reported Yes (9 with SIB; 3 No 1. Transient stim-induced 200861 18 yrs) 64.7% mean cervical myelop- vertigo & visual AE improvement athy, 1 disc 2. Poor scalp incision herniation, 2 healing due to repetitive unable to eat) touching; body shield required (n 5 1) 3. Abdominal hematoma (n 5 1) 4. Frequent programming required in many Porta et al., CM-Pfc, Voa 15 (12M, 3F); 17–46 7 (218 yrs) 24 mo Case series IV 1. YGTSS 1. Y-BOCS Yes No 1. 3 pts from previous 200958 *all previ- 52% mean 31% mean improvement cohort (n 5 18) were ously improvement 2. STAI excluded: 62 reported 33% mean improvement 2 pts requested removal 3. BDI of IPG and DBS was 26% mean improvement stopped 4.VAS subjective social 1 pt did poorly and impairment required subsequent GPi 31% mean improvement DBS Ackermans CM-Spv-Voi 8 (2F, 6M); 21–48 1 (21) 12 mo Double-blind III 1. YGTSS 1. Y-BOCS—no change Yes (1 life- Yes 1. Decreased energy lev- et al., *2F lost to randomized 49% improvement 2. CAARS—no change threatening, lost els, subjective gaze dis- 201130 follow-up cross-over trial 2. mRVTRS 3. BDI (Dutch)—no to follow-up) turbance, negative impact 3 6 mo, then 35% improvement change on daily living in all pts 6 mo open- 4. BAI—no change 2. 1 small hemorrhage at label 5. VAS for SIB—no lead tip—gaze palsy 3 6 change mo, persistent nystagmus 3.1 IPG Infection 4. Severe complications, psychogenic symptoms, & eventual death in 1 pt lost to follow-up (see details below40) Duits et al., CM-Spv-Voi 1 (F)* enrolled 21 1 (21) 23 mo Case report IV 1. YGTSS—worse 1. Y-BOCS: Yes (life- No 1. Severe postoperative 39 2012 but didn’t with DBS ON: Preop—20 threatening) complications with psy- complete Pre-op—42 Stim OFF—8 chogenic paroxysmal previously Stim OFF—12 Stim ON—7 hypertonia, disturbances reported Stim ON—39 2. CAARS: of consciousness, and 31 trial Pre-op—58 mutism Stim OFF—42 2. No change with DBS Stim ON—45 OFF (Continued) TABLE 1. Continued

3. BDI-II: 3. Somatoform disorder Pre-op—12 identiﬁed retrospectively Stim OFF—20 4. Pt died of dehydration, Stim ON—15 refusal to eat/drink @3 4. BAI yrs postoperatively Pre-op—32 Stim OFF—41 Stim ON—44 5. SIB (VAS) Pre-op—5.7 Stim OFF—0 Stim ON—8.9 Ackermans CM-Spv-Voi 1 (M) *previ- 39 0 6 mo case report IV NA None reported Yes (head- No 1. Hemorrhage at distal 200728 ously banging) electrode tip --> verti- reported31 cal gaze palsy: subjective worsening with DBS ON Ackermans CM-Spv-Voi 1 (M) *prev 45 0 1 yr Case report IV 1. Videotaped tic fre- 1. Padua Inventory— No No 1. Decreased energy level et al., reported70 quency (tics/min) by 2 Revised (obsession-com- 2. Sexual dysfunction 200627 blinded raters pulsion rating) 85% reduction 62% better ON than OFF stim Vandewalle CM-Spv-Voi 1 (M) 42 0 4 mo Case report IV 1. Videotaped tic None reported No No Not reported et al., frequency 199968 —Nearly 100% reduction (“except for some excessive eye blinking”) Visser-Vande- CM-Spv-Voi 3 (3M); *1M 28,42,45 0 8 mo—5 Case series IV 1. Videotaped tic fre- None reported No (burning eye- No 1. Reduced energy levels walle et al., previously yrs quency (tics/10min) lashes with cig- in all 3 70 27 2003 reported —72%—90% arettes, break- 2. Sexual dysfunction in 2 reduction ing glass in pts hands) 3. 2 pts each required 3 revisions of IPG and extension wires due to traction pain 4.1 pt had lower scores on timed tasks on neuropsychological testing (Continued) TABLE 1. Continued

Ackermans CM-Spv-Voi 2 (2M); *previ- 42, 45 0 6–10 yrs Case reports IV 1. Videotaped tic fre- None reported No (breaking glassNo 1. Reduced energy levels et al., ously quency (tics/10min) in hands) in both pts 201029 reported27,28 by 3 blinded raters 2. Both with hardware- 78%-92.6% reduction related complications (traction of lead in neck) requiring multiple surgical revisions and local injec- tions (previously described63) 3. Mild visual side effects (vertigo, blurry vison) in both 4. Sexual dysfunction in both 5. Increased aggression, social adaptation in 1 pt. Maciunas CM-Pf 5 (4M, 1F) 18–34 1 4 mo Prospective III 1. mRVTRS 1. SF-36 (19% mean Not reported Yes (only mean 1. 1 pt had acute psycho- et al., double-blind 40%-67% improvement) coordinates sis on day 28 of 49 2007 crossover trial; mean motor tic 2. VAS (53% provided) randomized phase— four 7-d reduction mean improvement) thought to be related to randomized 21%-70% 3. BDI-2* (60% acute life stressors DBS conditions mean vocal tic mean improvement) R/L, ON/OFF, reduction 4. HAM-D* (29% and open-label 2. YGTSS mean improvement) 4-mo follow-up 43.6% mean 5. HAM-A* (51% improvement mean improvement) 2 nonresponders 6. Y-BOCS* (44% with 4.3–260.9% tic mean improvement) exacerbation 3. TSSL *Trend toward 43% mean reduction improvement at 4 mo Bajwa et al., CM-Spv-Voi 1 (M) 48 0 2 yrs Case report IV 1.YGTSS 1. Y-BOCS Yes (head-snap- No 1. Although tics dramati- 200731 63.6% improvement 72.4% improvement ping tics caus- cally reduced, the 2. CGI ing cervical head-snapping tics had “very much improved” myelopathy) only mild reduction in forcefulness and he had continued neurological deterioration due to myelopathy (Continued) TABLE 1. Continued

Shields et al., CM* (ALIC 1 (F) 40 0 3 mo Case report IV 1. YGTSS None reported Yes (head-snap- No 1. High stimulation set- 200867 leads previ- 46% improvement ping tics, limb tings required causing ously fractures, IPG depletion q1–2 yrs removed) retinal detachment) Savica et al., CM-Pf 3 (2M, 1F) 17–35 2 (17,17) 1 yr Case series IV 1. YGTSS None reported Yes (jaw- No 1. Mild stimulation-related 201260 70% mean clenching caus- adverse effects amena- improvement ing dental frac- ble to programming tures; head- changes. snapping tics) Idris et al., CM-Pf, Voa 1 (M) 24 1 2 mo Case report IV No scales reported None reported No No 1. Postoperative bilateral 201043 (tics noted to subcortical hematomas improve) attributed to low factor XIIIA Marceglia CM-Pf, Voa 7 (6M, 1F) 24–52 1 (24) 6 mo-2 yr Case series IV 1. YGTSS 1. Y-BOCS (3% mean Not reported No Not reported et al., *many/all 33% mean improve- improvement; 24% 201050 reported ment (10%-49%) improvement to 47% elsewhere worsening) (62) 2. BDI (7% mean improvement) 3. STAI (20% mean improvement) 4. 10-pt VAS of social integration (14% mean improvement Servello et al., CM-Pfc, Voa 31 (25M, 6F,); 17–57 11 3 mo-4 yr Case series (36 pt IV 1. YGTSS 1. Y-BOCS Yes (2 with cervi- No 1. Infection of IPG/exten- 201063 (1 unilateral, *18 previ- cohort; 6 47% mean improve- 17.3% improvement at cal myelopathy, sions requiring system excluded ously excluded from ment at last f/u last f/u (p 5 .017) 1 with col- removal (n 5 1) from reported(62) analysis due to (p < 0.001) 2.BDI lapsed trachea, 2. Infection of IPG site analysis) (4 additional <3 mo f/u or 32.4% improvement at from tics) requiring revision (n 5 2) pts received non-thalamic last f/u (p < 0.001) 3. Wound revision along leads in target) 3. STAI lead extensions due to multiple tar- 31.7% improvement at picking behavior (n 5 2) gets & 1 in last f/u (p < 0.002) 4. Lead revision 3 2in ALIC/NA 4.10-pt VAS of social 1 patient only) integration 5. Rupture of lead exten- 30.7% improvement at sion (n 5 1) last f/u (p < 0.001) 6. IPG removed @ 27 mo at pt request due to unsat- isfactory results 1 aes- thetic concerns (n 5 1) (Continued) TABLE 1. Continued

7. DBS turned off at patient request (n 5 2; after 2 mo [excluded from analysis] and 2 yr) Porta et al., CM-Pfc, Voa 18 (3F, 15M); 17–47 8 5–6 yrs Case series IV 1. YGTSS 1. Y-BOCS Yes No 1. Poor wound healing 201259 *previously 73% mean improve- 42% mean improvement due to patient picking (n reported(62) ments (p < 0.001) (p 5 0.003) (4 pts 5 1) 2. GCI—ratings worsened) 2. Abdominal wall varied between pro- 2. STAI hematoma viders and between 46% mean improvements 3. 2 pts requested DBS provider and patients (p < 0.001) turned off @ 3–4 yrs for 3. BDI personal reasons 55% mean improvement 4. 1 pt told to have DBS (p < 0.001) removed due to repeated infections despite improvement of tics 5. Issues with noncompli- ance in some patients Kuhn et al., Vop-Voa-Voi 2 27 (F); 39 (M) 0 12 mo Case series IV 1. YGTSS 1. BDI-2—No negative No No 1. Reduced verbal fluency 201146 (Unilateral) 75%-100% impact @ 1 yr in both pts improvement 2. GAF—Both had contin- (25% worsening) 2. MRVRS uous improvement (52%- 77%-100% 73%) during 12 mo improvement Lee et al., CM-Pf 1 31 (M) 0 18 mo Case report IV 1. YGTSS None reported Yes No 1. None reported; pro- 48 2011 62% improvement @ gramming was 6 mo (sustained at 18 reported to be difficult mo) 2. MRVRS 38% improvement 3. VAS 70% improvement Okun et al., CM (scheduled 5 (3F, 2M) 28–39 0 6 mo NIH-sponsored III 1. YGTSS 1. Y-BOCS Yes (3 of 5 pts) Yes 1. No major adverse 201255 stimulation) clinical trials 19% mean 2. HDRS events planning study improvement (p 5 3. YMRS (Young Mania of safety and 0.01; 5%-30%) Rating Scale preliminary effi- 2. mRVTRS 4. SF-36 cacy; delayed 36% mean improve- 5. QOLAS start activation ment (p 5 0.01) *None of these measures (30d) improved, although a trend toward improved physical functioning in both QOL measures (Continued) TABLE 1. Continued

Kuhn et al., Thalamus, pal-3 (2M, 1F);*2 22–27 2 (22,22) NA Case series IV 1. YGTSS None reported Not reported Yes None reported 201247 lidal, & nig- previously 36%-83% ral input reported47,69 improvement areas (unilateral in 1) Vernaleken Pf-DM-LM 1 (M) 22 1 NA Case report IV 1. YGTSS None reported Not reported Yes 1. Patient had previously et al., 36% improvement undergone bilateral GPi 200969 DBS without improvement Servello et al., NA 39;*most pre- NA NA Retrospective IV Not reported Not reported Not reported Not reported 1. Lead fracture due to 201164 viously review head-snapping tics reported(64) 2. 18% incidence of infectious complications (7 patients), requiring surgical revision 3. All 7 patients with infections had recurrent infection 4. Infections thought related to compulsive touching of surgical scars Kaido et al., CM-Pfc 3 (1M, 2F) 19–21 3 (20,21,19) 12 mo Case series IV 1. YGTSS—39.1% 1. Y-BOCS—slight Yes (2 of 3 pts) Not reported 1. Temporary blurred 201144 mean decrease in 2 pts, vision with increased improvement increase in 1 pt stimulation amplitude 2. BDI-II—varied between patients 3. IQ—no significant mean change Motlagh et al., Midline 4M 16–44 2 (16,17) 6–95 mo Case series IV 1. YGTSS—dramatic 1. Y-BOCS—100% Yes (2 of 4 pts) Yes 1. 44-yo M had compul- 201353 thalamic improvement improvement in 1 pt; sive picking at chest and in the 2 young pts minimal change or wor- cranial incisions; DBS (67%-85%); sening in the others system removed because limited improve- 2. HDRS and HARS—no of infection ment in the older significant change 2. 42-yo M had DBS sys- pts (7%-20%) tem removed because of lack of therapeutic benefit (Continued) TABLE 1. Continued

Target: Pallidal Diederich pvGPi 1 27 (M) 0 14 mo Case report IV 1. Videotaped tic 1. BDI (75% No No 1. Permanent left-sided et al., frequency (tic/min) improvement) bradykinesia (grade 2–3 36 2005 85% reduction 2. STAI (30% on UPDRS)—tolerated by (66% tic increase improvement) pt; reduced mildly with with DBS OFF) 3. SRSI-90-R stimulation OFF 3 48 hr 2. YGTSS (31%-61% 2. Small non–mass- 47.0% improvement improvement) occupying hematoma @ tip of R electrode on post-op MRI 3. Transient mild fatigue for several months Shahed et al., pvGPi 1 (M) *also 16 1 6 mo Case report IV 1. YGTSS 1. Children’s Y-BOCS No No 1. Patient compulsively 200765 reported 84% improvement (69% improvement) pushed on IPGs, requir- (66) 2. TSSR 2. SF-36 v2 ing body shield for 4 88% improvement (65% improvement) wks 3. mRVTRS 3. BASC-2 21% improvement (improvements in several domains, including hyperactivity, aggression, anxiety, depression, somatization) Shahed et al., pvGPi 3 3M (16–35) 2 (16,16) 3–12 mo Case series IV 1. YGTSS 1. Y-BOCS (22%-69% Not reported No 1. No surgical adverse 66 2007 35%-76% improvement) events. improvement 2. 1 patient compulsively 2. TSSR pushed on the IPG site. 16%-90% improvement 3. RVTRS 17%-50% improvement 4.Tic frequency (tics/min) 37%-69% reduction (Continued) TABLE 1. Continued

Dehning et al., pvGPi 1 44 (F) 0 12 mo Case report IV 1. YGTSS None reported No (self-biting, Yes 1. Frequent visits in 1st 34 2008 88% improvement; beating) few months for depres- no remaining tics sion, vertigo, stomach aches; difﬁculty adjust- ing to new situation without tics. Dehning et al., pvGPi 4; *1 previ- 3F (25–44); 0 5–13 mo Case series IV 1. YGTSS None reported Yes (burning of No 1. Stimulation stopped 201135 ously 1M (38) 6% worsening to skin with iron) due to lack of response reported(35) 88% improvement (n 5 2) 2. CGI 2. Lead revision to a 67% mean improve- more posterior location ment (including 2 with was done in 1 nonres- no change) ponder, without 3. TSGS improvement 12% worsening to 80% improvement (mean 37%) Dong et al., pvGPi (unilat- 2 2 M (22, 41) 1 (22) 1 year Case report IV 1. YGTSS None reported No No 1. No severe adverse 201237 eral R) 53%-59%22 reduction effects Dueck 200938 pvGPi 1 16 (M) 1 (16) 1 year Case report IV 1.YGTSS (adapted for Reported no associated No Yes Not reported children; in Ger- psychiatric symptoms man)—no signiﬁ- cant improvement Gallagher pvGPi 1 26 (M) 0 NA Case report IV “Disappearance of NA None reported No Not reported 200641 vocal tics and marked improvements in neck movements” Martinez-Fer- pvGPi (3); 5 4M(21–60); 1F1 (21) 3–24 mo Case series IV 1. YGTSS 1. Y-BOCS (26% mean Yes (2 with No 1. Two infections in 1 nandez amGPi (3) (35) 29% mean reduction) cervical patient (requiring system 52 2011 improvement 2. GTS-QOL (55% mean myelopathy removal 3 1, IPG/exten- 2. mRVTRS improvement; available in from head- sions removal 3 1) 45% mean 3 pts) snapping tics) 2. Lethargy, agitation, improvement 3. GTS-QOL VAS—40 anxiety; unhappy with Impression: amGPi is points mean improvement results despite reduced superior to pvGPi (total 100) tics (n 5 1) (YGTSS 38% vs. 20% 3. Low threshold capsu- improvement; lar side effects; lead revi- mRVTRS 54% vs. sion to anteromedial 37%) target, then anxiety with >100 Hz stimulation (Continued) TABLE 1. Continued

4. Acute deterioration in tics with transient stim OFF—only 70% of previous control after back ON 5. Weight gain (n 5 1) Cannon et al., amGPi 11 8M (22–50);3F2 (18,22) 4–30 mo Case series IV 1. YGTSS 1. Y-BOCS (59% mean Yes (requiring 24- No 1. One pt did not tolerate 201233 (18–34) 50% mean improvement) hr monitoring to DBS and turned OFF after reduction @ 3 mo 2. HDRS (74% prevent head 3 mo because of somatic mean improvement) injury) complaints 3. GTS-QLS—significant 2. Hardware malfunction improvement (102% (lead fracture) in 3 pts mean improvement) (because of: SIB tic, MVA, unknown) 4. GAF (57% mean improvement) 3. Lead infection requiring bilateral lead replacement (n 5 1) 4. Increased anxiety in 2 pts (1 transient, 1 persistent, & fluctuating) Filho et al., GPe 1 NA NA 23 mo Case report IV 1. YGTSS—81 % 1. Y-BOCS—84% Not reported No Not reported 200756 (abstract only) reduction reduction Piedimonte GPe 1 47 (M) 0 2 yrs Case report IV 1. YGTSS 1. Y-BOCS (no OCD No No Not reported et al., 71% improvement @ pre- or post-op) 57 2013 6mo 2. HDRS (82% significant worsening improvement @ 6 mo) @ 2 yr when IPG bat- 3. HARS (75% tery died improvement @ 6 mo) 4. GAF—(36% improvement @ 6mo) Motlagh et al., pvGPi 2 2M (24, 42) 1(24) 8–51 mo Case series IV 1. YGTSS—20%-44% 1. Y-BOCS—no Yes (2 of 2; Yes 1. Lead extender revision 201353 improvement significant change punching self, due to post-auricular dis- 2. HDRS—no change to neck-snapping comfort, possible IPG mild improvement tics 1 cervical malfunction with revision 3. HARS—slight spine injury) to abdominal placement improvement 2. Stimulation-induced side effects: hyperkinetic left arm movement, right foot cramping, flashing in eyes, restlessness; Left lead quite medial (Continued) TABLE 1. Continued

Target: Multiple Targets Servello et al., CM-Pfc, Voa 3; *Also 25–37 (2M, 0 19–44 mo Case series IV 1. YGTSS 1. BDI Yes (1 cut self No 1. None reported 62 62 2009 1 ALIC/NA reported 1F) (part of 4 pt 2 pts had 2. STAI with knife, 1 2. ALIC/NA rescue leads (n 5 1); cohort) modest reduction in 3. YBOCS punched self in were not very effective CM-Pfc, Voa tics (23%-34%) 4. VAS of social head) 1 ALIC/NA after initial CM- integration add-on (n Pfc,Voa DBS but 2 pts with “rescue” 5 2) depression/OCD ALIC/NA leads had only remained disabling mild improvement on 83% reduction in pt these measures with simultaneous pt with simultaneous CM- CM-Pfc, Voa 1 Pfc, Voa 1 ALIC/NA did ALIC/NA have signiﬁcant improvement (45%, 39%, 61%, 35%, respectively) Servello et al., pGPi 1 ALIC/ 1 42 (F) 0 pGPi: 23 Case series IV 1. YGTSS 1. Y-BOCS (26% Not reported No 1. Required “rescue” 201063 NA add-on mo; GPi (part of 14% improvement reduction with GPi; for this case ALIC/NA leads because 1 ALIC/ 36 pt cohort) @ 23 mo with pGPi 16% further after of social impairment NA 41% further ALIC/NA) and poor QOL despite improvement after 2. STAI (23% improve- reduction in tics with ALIC/NA (49% total) ment with GPI; 12% fur- GPi DBS ther after ALIC/NA) 3. BDI (5% improvement with GPi; 30% further after ALIC/NA) 4. VAS of social integration (15% improvement with GPi; 12% further after ALIC/NA) Ackermans pvGPi 1 CM- 1 27 (M) 0 1 yr Case report IV 1. Videotaped exam 1. PI-R for compulsive No No 1. Reduced energy level et al., Spv-Voi (part of with tic frequency symptoms—noted to 2. Brief dystonic jerk each 200627 (*only GPi 2 pt series) (tics/min) by 2 have “total resolution” time turned ON activated) blinded raters ; 93% reduction Welter et al., CM-Pf 1 GPi 3; *1 previ- 2F (36, 30); 0 20–60 Controlled, III 1. YGTSS None reported Yes (eye No 1. Thalamic—decreased 200871 (limbic) ously 1M (30) mo double-blind, (cross-over period) mutilation, libido in 1 pt reported(43) randomized a) GPi): burning of 2. GPi—lethargy (3–4 d); crossover 65%-96% skin) nausea & vertigo at study 1 open improvement higher settings (n 5 2); long-term f/u b) CM-Pf anxiety (n 5 1) (Continued) TABLE 1. Continued

30%-64% improvement c) GPi 1 CM-Pf 43%-76% improvement 2. YGTSS (long-term f/u) CM-Pf/GPi ON (n 5 2; 74%-82% improvement) GPi ON (n 5 1; mild improvement) 3. RVTRS Houeto CM-Pf 1 GPi 1 36 (F) 0 11 mo Prospective III 1. YGTSS 1. MADRS Yes (eye mutila- No 1. Weight loss (18 kg et al., (limbic) double-blind CM-Pf: 64% 2. BAS (anxiety) tion, burning of with CM-Pf, continued 42 2005 randomized N reduction 3. BIS (impulsivity) skin) with GPi)—may have 5 1 crossover GPi: 65% reduction SUMMARY: been related to with- trial “Sham” STIM: worse drawal of neuroleptics CM-Pf: mood & than baseline 2. During SHAM stim: impulsivity improved: SIB CM-Pf 1 GPi: 34 SIB, excoriations at cables resolved (60% reduction) GPi: mood & impulsivity 2. RVTRS worse than CM-Pf; SIB CM-Pf: 77% resolved reduction SHAM: little change of GPi: 54% reduction depression/anxiety “Sham” STIM: 15% CM-Pf 1 GPi: SIB reduction resolved CM-Pf 1 GPi: 77% reduction Shields ALIC/NA (*later 1 40 (F) 0 18 mo Case report IV 1. YGTSS None reported Yes (head-snap- No 1. Lead extension fracture et al., revised to 23% improvement ping tics, limb due to residual head- 200867 CM DBS) fractures, retinal snapping tics after ALIC/ detachment) NA DBS 2. Stimulation-induced altered mood and impulse control problems 2 48, 19 (2M) 1 (19) Case series IV 1. YGTSS Yes 1. 48yoM: (Continued) TABLE 1. Continued

Motlagh 1. Midline tha- 37–107 19yo with 3 1. Y-BOCS – 48yo had Yes (2 of 2; slam- 2nd target added due to et al., lamic 1 pvGPi mo targets had no signiﬁcant improvement ming forearm continued head-snapping 53 2013 2. amGPi 1 improvement (29-->8); 19yo had no against head, tics midline tha- 48yo had 72% OCB head-snapping GPi lead extender mal- lamic 1 GPi- improvement 2. HDRS – both had wor- tics 1 cervical function due to head- pv sening of depression injury; poking snapping tics 3. HARS – no change left eye, left thalamic and GPi leads cheek biting) now OFF 2. 19yoM: ICU hospitalization with sedation for worsening tics 2mo after amGPi placement to prevent eye injury 3 separate DBS surgeries for 3 total bilateral targets due to refractory tics; currently has only R pvGPi lead on and no improvement Other Targets: ALIC/NA, STN Kuhn et al., ALIC/NA 1 26 (M) 0 30 mo Case report IV 1. YGTSS 1. Y-BOCS (52% Yes No 1. High stim requirements 200745 41% improvement improvement) (2 IPG replacements in 30 2. mRVTRS 2. GAF—signiﬁcantly mo) 50% improvement improved (7->41) 2. Temporary deterioration in symptoms with battery depletion 3 2 Flaherty ALIC/NA 1 37 (F) 0 18 mo Case report IV 1. YGTSS None reported Yes (head-snap- No 1. Stim-induced dysarth- et al., 25% improvement\ ping tics, limb ria, rhythmic jaw 40 2005 2. Patient tic logs fracture, retinal clenching 45% decrease in detachments) 2. High-voltage stim in frequency and ventral contacts (near severity NA)—mild apathy and depression; dorsal contacts in body of capsule—agitated hypomania (hrs to days onset for mood effects) (Continued) TABLE 1. Continued

3. IPG accidentally turned off several times—symptom worsening 4. Fractured lead extension requiring replacement—due to tics Zabek ALIC/NA (uni- 1 31 (M) 0 28 mo Case report IV 1. 15-min videotaped None reported Yes (retinal No 1. IPG malfunction at 9 et al., lateral R) exams with tic counts detachment, months due to RUE 200872 80% improvement blindness) motor tics ! sx deterioration ! improvement after IPG replaced Neuner ALIC/NA 1 38 (M) 0 36 mo Case report IV 1. YGTSS 1. Y-BOCS (56% Yes (self-mutila- No 1. Rapid IPG depletion—2 et al., 44% improvement reduction) tion; breaking IPG replacements in 36 200954 2. mRVTRS glass in hands) months 58% improvements Burdick ALIC/NA 1 33 (M) 0 30 mo Case report IV 1. YGTSS 1. Y-BOCS (no significant No Yes Not reported et al., 15% worse in 1st 6 improvement) 201032 mo 2. mRVTRS Tics 20% worse @ 30 mo (5->6) Martinez- STN 1 38 (M) 0 1 yr Case report IV 1. RVTRS 1. UPDRS (pt had PD; No No Not reported Torres 97% improvement 57% improvement) et al., 200951 Servello ALIC/NA 1;*Previously 47 (M) 0 10 mo Case series (part IV 1. YGTSS 1. Y-BOCS (54% No No None reported et al., reported(64) of 4 pt cohort) 79% improvement improvement) 62 2009 2. BDI (9% improvement; not significant) 3. STAI (19% improvement; not significant) 4. 10-pt VAS of social integration (no change)

BAS, Brief Anxiety Scale; BIS, Barratt’s Impulsivity Scale; CM-Pfc, Voa, centromedian nucleus-parafascicular, and ventro-oralis complex; CM-Spv-Voi, centromedian nucleus-substantia periventricularis-nucleus ventro-oralis internus complex; CM-Pf, centromedian nucleus–parafascicular complex; Vop-Voa-Voi 5 nucleus ventro-oralis posterior, ventro-oralis anterior, and ventro-oralis internus complex; Pf-DM-LM, parafascicular, dorsomedial nucleus, and lamella medialis; CM, centromedian nucleus region; GPi, globus pallidus internus; pvGPi, posteroventral globus pallidus internus; amGPi, anteromedial globus pallidus internus; YGTSS, Yale Global Tic Severity Rating Scale; Y-BOCS, Yale- Brown Obsessive Compulsive Scale; BDI, Beck Depression Inventory; BDI-2, Beck Depression Inventory, 2nd Ed.; HARS, Hamilton Anxiety Rating Scale; HDRS, Hamilton Depression Rating Scale; STAI, State-Trait Anxiety Inventory; AC-PC, anterior commissure–posterior commissure; mRVTRS, modiﬁed Rush Video-based Tic Rating Scale; RVTRS, Rush Video-based Tic Rating Scale; CAARS, Conners Adult ADHD Rating Scale; PDD-SQ, Pervasive Develop- mental Disorder-Self Questionnaire; TSSL, Tourette Syndrome Symptom List; YMRS, Young Mania Rating Scale; QOLAS 5 Quality of Life Assessment Schedule; SRSI-90-R, Self-report symptom inventory 90 Items—revised; TSSR 5 Tic Symptom Self Report; BASC-2, Behavior Assessment System for Children—2nd Ed; TSGS, Tourette Syndrome Global Scale; PI-R, 5 Padua Inventory of obsessive compulsive disorder symptoms—Revised. SCHROCK ET AL

TABLE 2. Updates to 2006 TS DBS Guidelines

2006 Guidelines Revised Guidelines

Diagnosis DSM-IV diagnosis of TS by expert clinician DSM-V diagnosis of TS by expert clinician Agea 25 yrs 1. Age is not a strict criterion 2. Local ethics committee involvement for cases < 18 years old Tic severity 1.Severe tic disorder with functional impairment 1. Severe tic disorder with functional impairment 2. YGTSS > 35/50 2. YGTSS > 35/50 3. Document with standardized video assessment 3. Document with standardized video assessment Neuropsychiatric comorbidities 1. Tics should be the major symptom causing 1. Tics should be the major symptom causing (ie, ADHD, OCB, depression, anxiety, etc.) disability disability 2. Comorbid conditions should be stably treated 2. Comorbid conditions should be stably treated 3. Comorbid conditions should be assessed using 3. Comorbid conditions should be assessed using valid rating scales when available valid rating scales when available Failed conventional therapya 1. Failed treatment trials from 3 pharmacological 1. Failed treatment trials from 3 pharmacological classes: a) alpha-adrenergic agonist, b) 2 dopamine classes: a) alpha-adrenergic agonist, b) 2 dopamine agonists (typical & atypical), c) benzodiazepine agonists (typical & atypical), c) a drug from at least 2. Evaluated for suitability of behavioral interventions one additional class (eg, clonazepam, tetrabenazine) for tics 2. A trial of CBIT should be offered Comorbid medical disorders Stable for 6 months before DBS Stable for 6 months before DBS Psychosocial factors a 1. Adequate social support without acute or suba- 1. Adequate social support without acute or subacute psychosocial stressors cute psychosocial stressors 2. Active involvement with psychological interven- 2. Active involvement with psychological interventions when necessary tions when necessary 3. Caregiver available to accompany patient for frequent follow-up 4. Psychogenic tics, embellishment, factitious symptoms, personality disorders, and malingering must be recognized and addressed Suicidal/homicidal ideation (SI/HI) a Not speciﬁcally addressed Documentation of no active SI/HI for 6 months aRecommendations have changed since 2006. TS, Tourette syndrome; DBS, deep brain stimulation; DSM, Diagnostic and Statistical Manual of Mental Disorders; YGTSS, Yale Global Tic Severity Scale; ADHD, attention deﬁcit hyperactivity disorder; OCB, obsessive compulsive behaviors; CBIT, cognitive behavioral intervention therapy.

develop recommendations, and these were published tral GPi targets (n 5 16). One case report of globus in 2006.7 Subsequently, a collaborative international pallidus externa (GPe) DBS has also been published. network of investigators was established, and in 2010 The anterior limb of the internal capsule/nucleus to 2011 the TSA commissioned an International Data- accumbens target in isolation has been used in six case base/Registry of DBS outcomes and cases performed reports, and one case of STN DBS has been reported in patients with a diagnosis of TS. The purpose of this in a patient who had both tics and Parkinson’s paper is to critically review the literature of all pub- disease. lished cases of TS DBS and to provide updated opin- Eleven reported cases have employed more than one ions and recommendations for patient selection and brain target (2 targets in 10 cases, and 1 case with 3 assessment since 2006.7 Additionally, we aimed to brain targets). In most of these cases, however, the encourage all clinicians and investigators who care for additional target leads were added as “rescue” leads TS DBS patients to participate in the TSA DBS Data- because of inadequate response to the initial TS DBS base/Registry to collect more data and to enhance the leads. Three cases reported were part of a prospective, understanding of surgical approaches and outcomes. double-blind, randomized crossover study comparing Since 1999, 48 TS DBS studies have been published, the CM-Pf and the anteromedial GPi targets.42,71 including approximately 120 patients from 23 centers Although nearly all studies reported a beneﬁcial in 13 countries. At least seven separate brain targets effect on tics, most of these reports were uncontrolled have been employed27-72 (Table 1). The most com- cases (n 5 100), and the results revealed wide varia- monly used targets have been the medial thalamic tions in study methods and outcomes, thus limiting region targets (eg, centromedian nucleus–parafascicu- meaningful interpretation. Approximately one ﬁfth of lar complex [CM-Pf]), with 70 reported cases. Thirty- the papers did not report using a validated outcome one cases of pallidal TS DBS have been reported and or videotape analysis. Rating scales to capture TS have included both anteromedial globus pallidus inter- comorbidities (eg, obsessive-compulsive behavior, anx- nus (GPi; “limbic”) targets (n 5 14) and posteroven- iety) were used in fewer than one third of reported

16 Movement Disorders, Vol. 00, No. 00, 2014 TOURETTE SYNDROME DBS GUIDELINES studies, and postoperative DBS lead locations were at increased risk for hardware malfunction. Six cases reported in only 10 of 50 studies. of lead or lead extension fractures, or alternatively Based on the levels of evidence classification scheme IPG malfunction, have been reported,33,40,53,67,72 four that has been used by the American Academy of Neu- of which were attributed to residual head-snapping rology,73 only four of these 48 studies30,49,55,71 met tics. These findings highlight the unique and poten- criteria for class III level of evidence (n 5 19), tially severe issues in the TS population. Whereas tics whereas the others were class IV. Given the small that are life threatening or carry significant risk of number of patients and the use of multiple brain tar- immediate bodily harm are observed in only 5.1% of gets within the class III studies, these data would all TS patients, nearly 50 TS DBS cases with signifi- likely receive the lowest evidence rating (level U), indi- cant SIB have been reported in the literature, with cating that the therapy remains unproven because of more than half of these cases involving a severe behav- inadequate or conflicting data. ior or risk of severe bodily harm (eg, cervical myelop- Since the last TSA guidelines were published in athy from head-snapping tics, bone fractures, retinal 2006,7 the field has gained important insight about detachment). safety and the potential for specific adverse effects of Although few data are available to guide postopera- TS DBS. Thirty-three patients had TS DBS before the tive management of TS DBS patients, Servello et al. age of 25 years, including nine patients younger than have the greatest experience with TS DBS to date. 18. The risk of surgical complications and adverse These authors have reported that TS DBS patients events did not appear to be higher in these age groups require more frequent visits for DBS adjustments (ie, when compared with patients older than 25 years. in excess of monthly visits stipulated in their protocol) However, Servello et al.,61 in their series of 18 than for other DBS indications, and also TS DBS patients who underwent bilateral CM-Pf DBS, cau- patients require substantial personal and family sup- tioned that three of the four cases who were implanted port. For this reason, a thorough evaluation of the before the age of 20 years had less than satisfactory patient’s adherence to recommendations, a clear results after 3 to 6 months of follow-up (significant assessment of the patient’s psychosocial situation spontaneous waxing and waning of symptoms requir- inclusive of family dynamics, and the need for realistic patient and family expectations should be ing frequent DBS programming). 58,61,63 30 emphasized. Ackermans et al. reported substantial improve- Given the dearth of double-blind controlled studies ment in six patients on the Yale Global Tic Severity of TS DBS, the lack of consistent outcome measures Scale (YGTSS) between the ON and OFF stimulation related to TS comorbidities, and the lack of rigorous conditions (37%), and also improvement after 6 studies comparing brain targets, few data are available months of open-label therapy (49%) in a double-blind to guide target choice either in general or in specific randomized cross-over trial of centromedian nucleus– patients. substantia periventricularis–nucleus ventro-oralis inter- Chronic continuous stimulation has been widely nus (CM-Spv-Vo) DBS. Significant adverse effects assumed to be the only effective approach to TS DBS. were reported, including decreased energy levels as Recently, however, this notion has been challenged by well as subjective gaze disturbances. One patient with 55 Okun et al., who demonstrated the potential of non- comorbid depression, pervasive developmental disor- continuous DBS paradigms in TS in a class III clinical der, compulsions, and severe self-injurious behavior trial planning study (n 5 5) of safety and preliminary (SIB) had surgery under the condition of clinical effectiveness.55 Additionally, these authors have sug- urgency and had to be withdrawn from the trial gested that responsive approaches may be possible, because of severe postoperative complications with especially by using oscillations (eg, the gamma band) psychogenic paroxysmal hypertonia, disturbances of and other brain network oscillations associated with consciousness, and mutism. Somatoform disorder in DBS efficacy.74 this patient was only recognized retrospectively, and the patient eventually died of dehydration after refus- ing intravenous fluids.39 Special Considerations Relevant to Servello et al.64 has reported the most robust experi- TS DBS and Guideline Updates ence with TS DBS, and also published an important paper analyzing the rates of infectious and hardware- The official DSM V diagnostic criteria require the related complications for different DBS indications presence of tics for more than a year, with onset (eg, PD, TS, tremor, and dystonia). Servello’s group before the age of 18 years, and occurrence of both reported an increased risk of infectious complications multiple motor and at least one phonic tic for a defini- in TS DBS (7 of 39 [18%] patients) compared with an tive diagnosis of TS.1 The variability (variability of tic overall infection rate for all DBS indications of 3.7% types, as well as the waxing and waning of tic sever- (10 of 272 patients). The TS DBS patients also may be ity) in TS provides an extra level of complexity when

Movement Disorders, Vol. 00, No. 00, 2014 17 SCHROCK ET AL considering TS candidates for DBS therapy. Tics can compelling arguments have been made for considera- be influenced by both environmental and psychologi- tion of surgical intervention at younger ages in cer- cal factors. Many TS patients can suppress tics par- tain cases of severe TS.86,87 The risk–benefit data for tially or even completely for short periods, such as TS and for other DBS indications have shown that when being examined or when in public, but then the actual DBS procedure is safe and well tolerated in release tics when returning to a more comfortable set- children, particularly as demonstrated in those with ting. The recognition of embellishment, psychogenic dystonia.88 Because of increased evidence of a favor- tics, factitious symptoms, personality disorders, and able risk–benefit ratio for DBS in children with dysto- malingering all need to be considered in the preopera- nia and TS, the age guideline has been adjusted by tive workup,39,75-77 similar to the experience in epi- most experts to recommend a multidisciplinary evalu- lepsy surgery with nonepileptic events.78 ation and discussion, without setting a firm age limit. A clinician with expertise and experience with TS Delaying surgery in younger incapacitated TS patients should confirm the diagnosis by strict criteria1 patients could potentially result in irreparable harm and address all psychological comorbidities and non- to social, psychological, and intellectual development, motor features before consideration of DBS. Patient- even if the symptoms eventually subside with age. or family-expressed psychological “urgency” should Similarly, in rare cases of “malignant tics” that occur not heavily influence the clinician’s decision to proceed in younger individuals, the tics themselves (eg, whip- to an operation.79,80 All psychological and non-motor lash tics) may carry greater risk for bodily harm, features should be stabilized before consideration for paralysis, or even death. surgery. The evaluating team should be aware that the A feature of TS with implications for determining usual onset of TS occurs before the age of 10 years the efficacy of DBS is its frequent association with dis- and has an average onset of 5.6 years. Tics typically abling psychiatric and behavioral comorbidities. The follow a waxing and waning course, and they peak in most common of these are ADHD and OCD. Comor- severity in early adolescence. This peak is followed in bidities have a significant negative impact on the qual- most cases by a gradual reduction in tic severity in late ity of life in TS and can be a larger source of 89,90 adolescence and early adulthood.6,81 Longitudinal impairment when compared with motor tics. Iden- studies have reported either complete remission or tification of comorbid psychiatric symptoms is critical alternatively mild tics in early adulthood for more than for a DBS workup, because when left untreated, these two thirds of TS patients.5,6 Clinicians selecting DBS symptoms may be the best predictors of a worse qual- 91 candidates would likely benefit from a list of predictive ity of life, with or without DBS therapy. Comorbid factors that would facilitate identification of patients symptoms should be adequately treated before sur- who will remain severely affected into adulthood. This gery, and patients should be informed that individuals information is not currently known. Recent research who are deemed to be good candidates for DBS may suggests that tic severity, premonitory urges, and a experience a 30% to 50% or greater improvement in family history of TS may be childhood predictors of a motor tics. However, based on all available published worse health-related quality of life in adulthood.82 cases, how DBS will impact TS comorbidities remains Although TS rarely causes severe disability, and gen- unclear. Notably, comorbid OCD, ADHD, and mood erally has a favorable prognosis, in a small subset of issues have improved after DBS in some but not all 31,33,36,45,52,54,57,58,63,65,66 patients the symptoms cause severe disruption of inter- cases. personal relationships, as well as impairments of Deep brain stimulation should be offered to TS social, psychological, and intellectual development. In patients only after evaluation by a multidisciplinary or extreme cases, TS may even become life threatening interdisciplinary team. This team should include (eg, whiplash tics causing vertebral artery dissection83 experts in TS and associated comorbidities (ie, neurol- or myelopathy84). This severe form of the syndrome is ogist, neurosurgeon, psychiatrist, neuropsychologist, associated with a higher rate of behavioral comorbid- DBS programmer [nurse or physician]). Centers per- ities (particularly OCD) and is more likely to be forming DBS should have a high level of expertise refractory to conservative medical management. with DBS therapy, especially given the complexities of Although malignant TS may affect only 5.1% of all the TS patient. Potential therapy candidates should be TS patients, these cases will frequently come to the independently evaluated by each member of the team, attention of TS DBS teams.85 and discussion of candidacy, risks, benefits, operative The appropriate age to perform TS DBS is approach, and postoperative care should be pursued unknown and has been widely debated. In 2006, the before a decision on candidacy is reached. first TSA guidelines7 proposed a minimum age crite- The ideal DBS candidate will have a DSM V diagno- rion of 25 years to ensure that individuals who might sis of TS and severe motor and vocal tics, which experience spontaneous tic remission would not be despite exhaustive medical and behavioral treatment implanted with a surgical device. Since that time, trials result in significant impairment of self-esteem,

18 Movement Disorders, Vol. 00, No. 00, 2014 TOURETTE SYNDROME DBS GUIDELINES

TABLE 3. Pre- and post-operative outcome measures rec- Regular postoperative evaluations to include standardized rating scales ommended by the TSA* of TS and co-morbidities YGTSS Preoperative Information: Patient Assessment and Selection Blinded video-based rating Age, sex, ethnicity Y-BOCS Age of TS onset Premonitory Urge for Tics Scale (PUTS) 132 Age at diagnosis of TS Conner’s ADHD Scale Age at time of surgery Depression: BDI-2, HDRS or MADRS Psychiatric comorbidities (OCB, ADHD, depression, anxiety, SIB, other) Anxiety: HARS, STAI TS medications tried and stopped bfore DBS (medication name, dose, Mania: YMRS, K-SADS, MRS and duration of trial) CGI TS medications at the time of DBS (including dose) Suicide Assessment Scale (eg, Columbia Suicide Severity Rating Documentation of CBIT being offered or of the trial and outcome Scale) Standardized evaluation of tic type and severity (pre- and postoperatively) a The exact measures are less important than the adherence to measure- Yale Global Tic Severity Score (YGTSS) ment of pre/post outcomes in each of the major domains (motor, non- Blinded video-based rating (e.g., Rush video scale rating of body motor, mood, quality of life). regions involved, tic severity and frequency) TSA, Tourette Syndrome Association; TS, Tourette syndrome; OCB, obses- 132 sive compulsive behaviors; ADHD, attention deﬁcit hyperactivity disorder; Premonitory Urge for Tics Scale SIB, self-injurious behavior; DBS, deep brain stimulation; CBIT, cognitive Clinical Global Impression (CGI for TS) behavioral intervention therapy; K-SADS, kiddie schedule for affective dis- Standardized evaluation of comorbid symptoms with valid and reliable orders and schizophrenia; OCD, obsessive-compulsive disorder; SF-36, instruments when available (pre- and post-operatively) short form health surgery 36; CM-Pfc-Voa, centromedian nucleus-parafascicular complex; Gpi, globus pallipus internus; ALIC/NA, anterior limb of Yale-Brown Obsessive Compulsive Scale (Y-BOCS) the internal capsule/nucleus accumbens; IPG, implantable—pulse genera- Conners’ Adult ADHD Rating Scale (CAARS) tor; MRI, magnetic resonance imaging; CT, computed tomography; DVT, Depression: Beck Depression Inventory, 2nd Ed. (BDI-2), Hamilton deep venus thrombosis. Depression Rating Scale (HDRS), Montgomery-Asberg Depression Rating Scale (MADRS) Anxiety: Hamilton Anxiety Rating Scale (HARS), State-Trait Anxiety social acceptance, family life, school or job functioning, Inventory (STAI) or physical well-being. Psychosocial, medical, neurolog- Mania: Young Mania Rating Scale (YMRS), K-SADS Mania Rating ical, or psychiatric conditions that increase the risk of Scale (MRS) the procedure, preclude full participation in the opera- CGI (for ADHD and OCD) Suicide Assessment Scale (e.g., Columbia Suicide Severity Rating tion or post-DBS care, or that will potentially compro- Scale) mise the accurate assessment of outcomes should all be Quality of Life Measurement (eg, Gilles-de-la-Tourette-Syndrome Qual- addressed by the DBS multidisciplinary team before ity-of-Life scale [GTS-QOL], Global Assessment of Functioning scale surgery. Tics and comorbid conditions should be opti- [GAF], SF-36) mally treated medically and behaviorally per current Surgical information: targeting and lead location 3,9 Brain target (eg, CM-Pfc-Voa thalamus, Gpi, ALIC/NA, other) expert standards. Deep brain stimulation should not Procedure (unilateral, bilateral, simultaneous, staged) be performed during periods of severe psychosocial Lead models and IPG models used (eg, Medtronic 3387/3389, ANS, instability, which is likely to interfere with the close Neuropace, primary cell, rechargeable, other) monitoring and follow-up required. Psychosocial stress Lead location veriﬁcation with postoperative MRI or CT (x-y-z coordi- also may increase the risk of suicide after surgery.92,93 nates of each contact in relation to the midcommissural point) Postoperative information: programming, outcome data and adverse events In general, DBS surgery should be avoided if a patient 80 Stimulation parameters (active contacts, amplitude or current, fre- is judged to be at imminent risk of suicide. quency, pulse width, 6 impedence) at each follow-up visit and time duration at that setting Frequency of programming adjustments (# to optimization, # per year) Inclusion and Exclusion Criteria Stimulation-induced and general adverse effects Psychiatric/cognitive (exacerbation of tics, mania, hypomania, cogni- A DSM V diagnosis of TS should be made by an tive decline, anxiety, OCB, depression, smile or laughter induction, expert clinician who has experience in the evaluation impulsivity, psychosis, suicidal ideation/attempt, completed suicide, other) and management of tic disorders (updated from DSM General (paresthesias, muscle contractions, dyskinesias, bradykinesia, IV). Age should no longer be a strict criterion. Deep dystonia, dysarthria, stuttering, nausea or vertigo, lethargy, gait disorder, brain stimulation should be considered only when all sexual side effects, weight loss/gain >10 pounds, death, other) standard medical and behavioral therapies have failed Intraoperative or early surgical (1st post-op week) adverse events regardless of the patient’s age. Tourette syndrome (symptomatic/asymptomatic hemorrhage, ischemic stroke, seizure, post- op confusion, infection, air embolism, DVT, death, other) DBS should rarely be an urgent indication, with the Delayed surgical adverse events (infection of intracranial lead, extracra- possible exception of impending paralysis from head- nial lead/lead extender infection, infection of IPG, lead dislodgment, lead snapping tics or profound SIB. A local ethics commit- fracture, lead revision, suboptimally positioned lead, lead removal, IPG tee or institutional review board should be consulted removal, other) for consideration of cases involving persons younger Timing of IPG replacement or need for recharging than 18 years of age, as well as in cases with urgent (Continued) indications, particularly those with lower YGTSS scores or with shorter durations of symptoms.

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TABLE 4. TS DBS Inclusion and Exclusion Criteria rabenazine should be tried if accessible.97,98 In addi- tion, CBIT delivered by a trained CBIT therapist Inclusion Criteria Exclusion Criteria should be offered,2,4 and the patient must have dem- 1. DSM-V Diagnosis of TS by expert 1. Active suicidal or homicidal onstrated his or her ability to adhere to recommended clinician ideation within 6 months treatment plans before serious surgical consideration. 2. Age is not a strict criterion. Local 2. Active or recent substance Unfortunately, in many locations, including some cen- ethics committee involvement for abuse ters experienced with TS, substantial issues of access, cases involving persons < 18 years, 3. Structural lesions on brain and for cases considered “urgent” MRI wait times, and lack of insurance reimbursement make (eg, impending paralysis from head- 4. Medical, neurological, or therapies such as CBIT not always feasible, particu- snapping tics) psychiatric disorders that larly in cases of malignant TS. 3. Tic Severity: YGTSS >35/50 increase the risk of a failed The neuropsychological profile must indicate that the 4. Tics are primary cause of procedure or interference candidate will be well suited to tolerate the surgical proce- disability with postoperative management dure, rigorous postoperative follow-up, and the possibility 5. Tics are refractory to conservative 87 therapy (failed trials of medications 5. Malingering, factitious dis- of both a negative or positive outcome. The potential for from 3 classes, CBIT offered) order, or psychogenic tics progressive cognitive impairment should be absent on this 6. Co-morbid medical, neurological, profile, or a follow-up profile should be performed to con- and psychiatric disorders are treated firm findings and to also track progression. and stable 3 6 months Because of the substantial time commitment 7. Psychosocial environment is stable 8. Demonstrated ability to adhere to required for optimization of DBS therapy, as well as recommended treatments the significant impact that psychosocial factors can 9. Neuropsychological profile indi- have on the disorder, any candidate for TS DBS must cates candidate can tolerate have adequate social support, and there should not be demands of surgery, postoperative acute or subacute psychosocial stressors. A caregiver follow-up, and possibility of poor outcome must be available to accompany the patient for visits and for frequent programming.

TS, Tourette syndrome; DBS, deep brain stimulation; DSM-V, Diagnostic Similar to that proposed in the previous guidelines, and Statistical Manual of Mental Disorders; YGTSS, Yale Global Tic Sever- there should be documentation of no suicidal idea- ity Scale; CBIT, cognitive behavioral intervention therapy. tion and no psychiatric hospitalization for 6 months before surgery. Depression and mood disorders must The candidate should have a chronic and severe tic be stable and treated. Preferably suicidal tendency disorder with severe functional impairment. A standar- should be monitored preoperatively and postopera- dized videotape assessment (eg, Rush Video-Based Tic 94 tively with a scale such as the Columbia Suicide Rating Scale ) and a validated rating scale (eg, Yale Scale99 or another similar measure. Active or recent Global Tic Severity Scale [YGTSS]95) should be used dependence on drugs or alcohol are contraindications to document tic severity. In most cases the TS patient for surgery. No structural lesions should be seen on should have a total YGTSS score greater than 35/50 magnetic resonance imaging that are deemed to pres- documented over the course of a year. ent a signiﬁcant risk by the neurosurgeon, nor medi- Motor or vocal tics should be the primary symp- cal, neurological, or cognitive disorders that would tom causing disability for a patient. Although most signiﬁcantly increase the risk of a failed procedure, candidates are likely to have comorbid ADHD, surgical complications, or interfere with postopera- OCD, depression, anxiety, or other non-motor symptoms, these symptoms should be adequately treated tive management. A new criterion employed by most and stable for a minimum of 6 months and should centers involved with TS DBS since 2006 is that an not be the major source of functional impairment. In expert clinician should feel comfortable that malin- some patients, the commonly noted comorbidity of gering, factitious disorder, or psychogenic tics are not SIB, particularly severe SIB,96 may be inextricably present. intertwinedwithtics,andthusmaybeaprimary Teams implanting TS patients should record preop- contributor to disability. Patients with SIB or picking erative and postoperative outcome measures, including behavior should be warned preoperatively of an age, disease duration, tic subtypes, motor, mood, increased risk of infection or hardware-related behavior, quality of life, medications, postoperative complications.64 lead locations, stimulation settings, and suicidal ten- At a minimum, documentation of unsuccessful treat- dencies. Validated clinical rating scales of tics and TS ment trials is needed from three pharmacological comorbidities are critical. A full list of the measures classes: (1) an alpha-adrenergic agonist, (2) two dopa- recommended by the TSA and employed in in the mine antagonists (including one typical and one atypi- International TSA DBS Database/Registry is provided cal), and (3) a drug from at least one additional class in Table 3. The exact measures are less important (e.g., clonazepam, topiramate, or tetrabenazine). Tet- than the adherence to measurement of preoperative

20 Movement Disorders, Vol. 00, No. 00, 2014 TOURETTE SYNDROME DBS GUIDELINES

FIG. 1. Flow diagram of recommended DBS evaluation process for TS.

and postoperative outcomes in each of the major changes were based on the expanded experience in the domains (motor, non-motor, mood, quality of life). ﬁeld since the 2006 guidelines. The changes and particularly the inclusion criteria (Table 4) reﬂect the grow- ing experience with more than 120 cases reported Discussion worldwide. In particular, the relative safety of the procedure has been better established. Additionally, some The centers participating in the TSA International TS cases may be appropriate for DBS before the previ- Database/Registry have employed several important ously recommended age of 25 years. Most centers now practice pattern changes to the selection and assess- employ a multidisciplinary team approach for screening ment recommendations for the use of TS DBS. These rather than an age limit. For patients younger than age

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18, one should have additional institutional approval. 10. Kleiner-Fisman G, Herzog J, Fisman DN, et al. Subthalamic nucleus deep brain stimulation: summary and meta-analysis of out- Centers performing TS DBS should use preoperative comes. Mov Disord 2006;21(Suppl 14):S290-S304. and postoperative outcome measures, regardless of 11. Pahwa R, Factor SA, Lyons KE, et al. Practice parameter: treat- whether they adopt the TS DBS Database/Registry ment of Parkinson disease with motor fluctuations and dyskinesia (an evidence-based review): report of the Quality Standards Sub- guidelines. All patients undergoing TS DBS should be committee of the American Academy of Neurology. Neurology aware that there is a reasonable chance for motor and 2006;66:983-995. vocal tic improvement, but that other co-morbidities in 12. Weaver FM, Follett K, Stern M, et al. Bilateral deep brain stimulation vs best medical therapy for patients with advanced Parkinson general respond less consistently to therapy. Clinicians disease: a randomized controlled trial. JAMA 2009;301:63-73. should educate patients and families on the increased 13. Lyons KE, Pahwa R. Deep brain stimulation and tremor. Neuro- infection rate, and the potential for increased therapeutics 2008;5:331-338. hardware-related issues. Figure 1 provides a diagram of 14. Zesiewicz TA, Elble R, Louis ED, et al. Practice parameter: therapies for essential tremor: report of the Quality Standards Subcom- the recommended evaluation before TS DBS. mittee of the American Academy of Neurology. Neurology 2005; The most appropriate brain target for an individual 64:2008-2020. symptom profile remains unknown. The consensus of 15. Kupsch A, Benecke R, Muller J, et al. Pallidal deep-brain stimulation in primary generalized or segmental dystonia. N Engl J Med the centers implanting TS DBS includes the following: 2006;355:1978-1990. (1) all adverse events, whether major or minor, surgi- 16. Ostrem JL, Starr PA. Treatment of dystonia with deep brain stimu- cal or nonsurgical, related or unrelated to the therapy, lation. Neurotherapeutics 2008;5:320-330. should be recorded and reported; (2) detailed descrip- 17. Vidailhet M, Vercueil L, Houeto JL, et al. Bilateral deep-brain stimulation of the globus pallidus in primary generalized dystonia. tions of all surgical and programming procedures N Engl J Med 2005;352:459-467. should be recorded; and (3) preoperative and postop- 18. Greenberg BD, Malone DA, Friehs GM, et al. Three-year outcomes erative targeting should be reported, because where in deep brain stimulation for highly resistant obsessive-compulsive the optimal target regions are located, even within tar- disorder. Neuropsychopharmacology 2006;31:2384-2393. 19. Greenberg BD, Gabriels LA, Malone DAJ, et al. Deep brain stimu- gets, remains unclear. Psychological issues should be lation of the ventral internal capsule/ventral striatum for obsessive- screened preoperatively and monitored postopera- compulsive disorder: worldwide experience. Mol Psychiatry 2010; tively. Finally, rigorous reporting of DBS failures and 15:64-79. 100 20. Bronstein JM, Tagliati M, Alterman RL, et al. Deep brain stimula- adverse events is needed. Databases and registries tion for Parkinson disease: an expert consensus and review of key may be our best hope of advancing the field quickly, issues. Arch Neurol 2011;68:165. because most expert centers will do less than a hand- 21. Bronte-Stewart H, Taira T, Valldeoriola F, et al. Inclusion and exclusion criteria for DBS in dystonia. Mov Disord 2011;26(Suppl ful of TS surgeries. 1):S5-S16. After an extensive review of the literature and con- 22. Greenberg BD, Price LH, Rauch SL, et al. 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