Prospective randomized double-blind trial of bilateral thalamic deep brain stimulation in adults with Tourette syndrome

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Object

The severity of Tourette syndrome (TS) typically peaks just before adolescence and diminishes afterward. In some patients, however, TS progresses into adulthood, and proves to be medically refractory. The authors conducted a prospective double-blind crossover trial of bilateral thalamic deep brain stimulation (DBS) in five adults with TS.

Methods

Bilateral thalamic electrodes were implanted. An independent programmer established optimal stimulator settings in a single session. Subjective and objective results were assessed in a double-blind randomized manner for 4 weeks, with each week spent in one of four states of unilateral or bilateral stimulation. Results were similarly assessed 3 months after unblinded bilateral stimulator activation while repeated open programming sessions were permitted.

Results

In the randomized phase of the trial, a statistically significant (p < 0.03, Friedman exact test) reduction in the modified Rush Video-Based Rating Scale score (primary outcome measure) was identified in the bilateral on state. Improvement was noted in motor and sonic tic counts as well as on the Yale Global Tic Severity Scale and TS Symptom List scores (secondary outcome measures). Benefit was persistent after 3 months of open stimulator programming. Quality of life indices were also improved. Three of five patients had marked improvement according to all primary and secondary outcome measures.

Conclusions

Bilateral thalamic DBS appears to reduce tic frequency and severity in some patients with TS who have exhausted other available means of treatment.

Abbreviations used in this paper:BDI-2 = Beck Depression Inventory; DBS = deep brain stimulation; FDA = Food and Drug Administration; GPI = globus pallidus internus; HAM-A = Hamilton Rating Scale for Anxiety; HAM-D = Hamilton Rating Scale for Depression; MR = magnetic resonance; mRVRS = modified Rush Video-Based Rating Scale; SD = standard deviation; SF-36 = 36-Item Short Form Health Survey; TS = Tourette syndrome; TSSL = TS Symptom List; VAS = visual analog scale; Y-BOCS = Yale-Brown Obsessive Compulsive Scale; YGTSS = Yale Global Tic Severity Scale.

Tourette syndrome is a chronic movement disorder in which individuals repeatedly and randomly produce stereotyped behaviors (tics), commonly associated with premonitory urges and subsequent relief. The severity of symptoms typically peaks just before adolescence and diminishes during the teen years.4,30 However, the syndrome in adults is not insubstantial. Ninety percent of children with TS in a 14-year longitudinal study still demonstrated tics when videotaped as adults, although many were unaware of these behaviors.34 More than one quarter of this adult cohort was considered to be disabled by the tic disorder. Authors of other studies have rated the severity of tics as moderate or severe in 22 to 24% of adults with TS.4,15 Prevalence estimates for chronic tic disorders generally hover in the 0.4 to 2% range;23,26,27,35 therefore, it appears that a sizeable number of adults with TS remain severely affected.

The dysfunction in TS is believed to involve the corticostriatopallidothalamocortical loop but is incompletely understood.32 Conventional pharmacological treatment is aimed at the inhibition of dopamine or central α2 adrenergic transmission;28 however, such therapy can be ineffective. For medically refractory cases, neurosurgical lesioning procedures at a variety of brain targets have been attempted.40 Visser-Vandewalle and colleagues42 used DBS in an unblinded fashion in three adult patients with TS. The thalamic target was chosen to closely match that of Cooper,6,7 and Hassler20 and Dieckmann.21 In those studies, tic frequency was reduced by 70 to 90% during the stimulator-on compared with the stimulator-off state. We targeted the same thalamic region bilaterally in one patient and attained a rapid and significant reduction in tics, as measured using a video scoring procedure.31 Authors of subsequent case reports have documented similar benefits1,10,24,37 in targeting the thalamus or GPI.

Data in these reports have suggested a significant role for DBS in medically refractory TS. We conducted a prospective pilot surgical trial in five patients with TS. Using a double-blind crossover randomization design, we tested the hypothesis that bilateral thalamic DBS reduces the frequency and severity of motor and sonic tics. Given that unilateral stimulation to date has not been systematically studied in TS, we tested a second hypothesis that unilateral stimulation is more effective than no stimulation but less effective than bilateral stimulation, as well as the possibility that unilateral stimulation produces primarily contralateral effects. In addition, we wished to determine the effects of bilateral thalamic DBS on the quality of life and select neuropsychological measures. Finally, we sought to identify adverse events potentially related to this treatment of TS.

Clinical Material and Methods

Screening and Preoperative Evaluation

Prospective patients were selected from our movement disorders practice, referrals from other physicians, and self-referrals. For patients not already known to us, telephone interviews and record reviews were conducted to identify individuals with severe TS. After obtaining written informed consent, potential candidates were examined by a neurologist, psychiatrist, neurosurgeon, and neuropsychologist.

Inclusion criteria were a diagnosis of TS as defined in Diagnostic and Statistical Manual of Mental Disorders, 4th edition,2 a tic frequency of at least one per minute during the screening visit, an age of 18 years or older, an inadequate response to at least two dopamine blockers or catecholamine depletors, and a negative effect on the quality of life. Exclusion criteria were a significant structural brain lesion on imaging studies, significant dementia, a history of severe head trauma preceding the onset of tics, the use of dopamine receptor blockers before the recognition of tics, a previously implanted electrical device, electroconvulsion therapy in the past 24 months, a suicide attempt in the past 12 months, a significant sociopathic personality, and current or planned pregnancy.

Comorbid conditions such as obsessive–compulsive disorder or attention-deficit/hyperactivity disorder were allowed as long as tics were the major source of disability according to the clinical evaluation. Medical comorbidity was allowed, as is typical in all DBS procedures. Any medication for the treatment of tics was permitted, as long as the regimen did not change within 21 days of the surgery and until after the 3-month follow-up visit. Patients were required to travel to University Hospitals Case Medical Center leveland for required follow-up visits and to have an adequate social support system for the anticipated postoperative period.

We reached a consensus about each patient subject to inclusion and exclusion criteria following his or her clinical evaluation. An independent committee consisting of a neurosurgeon, neurologist, and psychiatrist then reviewed screening data for each patient and certified his or her suitability for participation in the trial.

Additional preoperative (baseline) evaluations included a neuropsychological test battery, two quality-of-life instruments (SF-3643 and VAS41), the YGTSS,29 a tic diary incorporating the TSSL,13 and a video recording session.

Trial Design Overview

Patients underwent bilateral implantation of DBS electrodes in one session, followed by connection of the pulse generators 4 to 7 days later (Fig. 1). In a single session conducted between 17 and 21 days after implantation, each electrode contact was systematically tested, and an optimum set of stimulation parameters was chosen for each side. On that date, a 28-day randomized period began. Stimulators were independently enabled (on) or disabled (off) on the right and left sides in four combinations (off-off, off-on, on-off, and on-on) for 7 days each. The order of these stimulator states was randomized, with the patient and study investigators blinded to the status of the stimulators. Assessment instruments were applied on Days 7, 14, 21, and 28, as described in a later section. At the conclusion of the 4 weeks, both stimulators were activated and an open-label clinical observation phase began. Formal assessment was repeated 3 months after the start of the open-label clinical observation phase (4 months after the start of the randomized phase). A final formal assessment, similar to that at 3 months, is planned 1 year after the start of the open-label clinical observation phase.

Fig. 1.
Fig. 1.

Timeline representing steps in the pilot study. Video camera icons designate video recording sessions. Assessment of secondary outcome measures are indicated by N (neuropsychological battery), Q (quality of life), T (TSSL), and Y (YGTSS). Combins = combinations; f/u = follow-up.

During the randomized period, no adjustment of stimulator parameters was allowed (except to turn the stimulators on or off as predefined). During the open-label period, patients could return as needed for stimulator adjustments. From 21 days before intracranial implantation through the end of the 3-month follow-up period, all TS-related medications were to be held constant.

All procedures followed in this trial were approved by the University Hospitals Case Medical Center Institutional Review Board. An investigational device exemption was approved by the FDA for a pilot study limited to five patients.

Surgical Procedures

The thalamic target used to anchor the surgical trajectory was 4 mm posterior, 5 mm lateral, and 0 mm inferior to the midcommissural point, as reported by Visser-Vandewalle et al.42 This target appears to correspond to the anterior extent of the centromedian-parafascicular complex (Hassler nomenclature) in the Schaltenbrand and Wahren atlas. Customary stereotactic targeting and procedures were performed. Trajectories were defined using a computed tomography–compatible Cosman-Roberts-Wells stereotactic frame and the BrainLab @Target functional software (BrainLAB AG; Fig. 2). Microelectrode recording was accomplished using FHC, Inc., microelectrodes and LeadPoint computer system. Intraoperative test stimulation was performed after the stimulating electrode (model 3387, Medtronic) was implanted at the target. Lead location was confirmed on postoperative MR imaging. At a second setting, neurostimulators (Soletra, Medtronic) were implanted bilaterally and were attached to lead extensions.

Fig. 2.
Fig. 2.

Coronal and axial T1-weighted MR images featuring the target point in all five surgically treated patients. A, D, and E: Responders (Cases 1, 4, and 5). B and C: Nonresponders (Cases 2 and 3). The image labeled “Plan” (lower right) is in the oblique plane, along electrodes, of the planned thalamic target and electrode trajectory using the BrainLab software.

Establishing Initial Stimulator Settings

To determine the best initial stimulator setting on each side, each electrode contact (0, 1, 2, and 3) was first tested in the unipolar mode (with case positive) beginning with Electrode 0. The pulse width and rate were held constant at 60 μsec and 130 Hz, respectively, while the amplitude was gradually increased from 0 V in 0.1- to 0.2-V increments. The threshold for tic reduction was recorded for each electrode, if present. Thresholds for transient (< 60 seconds) or persistent (≥ 60 seconds) adverse effects were also recorded for each electrode, if present. If persistent adverse effects developed, voltage was raised no further at that particular electrode contact.

Based on these observations, the electrode(s) that produced the most obvious immediate beneficial effect was (were) selected. For example, if Electrode 1 resulted in a reduction in leg tics but Electrode 2 was effective for arm tics, both electrodes were activated. The selected electrode combination was then tested in a manner similar to that described earlier.

If a satisfactory benefit was not achieved at 3.6 V (above which the Soletra pulse generators [Medtronic] consume more power), then voltage was reset to 0, and testing was continued as previously described at an increased pulse width or rate. Based on the best available responses, the final settings for each side included one or more active electrodes, and the system was in either unipolar or bipolar mode. Settings were not necessarily identical bilaterally. Once optimum settings had been identified, both stimulators were set to 0 V and output off.

Blinded Activation of Stimulators

Each patient was advised that zero, one, or both stimulators were to be activated, and that all four possible combinations would be tested in random order. One investigator (C.M.W.) performed the initial stimulator testing and all subsequent adjustments. Neither the order of stimulator states nor the present state was revealed to the patient or any other investigator.

At each randomized state-change visit, the investigator applied the programming device to each side. Active contact configuration, pulse width, and rate remained constant; only the voltage and output enable/disable settings were adjusted. The voltage of disabled stimulators was set to 0 to avoid inadvertent environmental activation of a stimulator during the subsequent week. The programming investigator appeared to perform the same actions for each stimulator on each side at each visit, even if no change to the stimulator state was scheduled.

Assessment of Tics by Video

The primary outcome measure was the score on the mRVRS14,16 at seven defined time points. Recordings were conducted preoperatively, Day 0 of the randomized phase (prior to initial activation), at the end of each of the four weekly randomized settings, and at the follow-up visit 3 months after the end of the randomized phase (Fig. 1). In each recording session, patients were dressed in surgical scrub suits with caps to obscure visual clues such as hair length and wound sites. Session conditions conformed to those described by Goetz et al.;16 5 minutes of recordings were obtained for actual scoring with the investigator out of the room. Each of the seven 5-minute epochs was divided into ten 30-second segments and intermixed by an independent technician into a random sequence for presentation and scoring.

Video scoring was independently performed after all study data were collected by the two movement-disorders specialists (B.N.M. and D.E.R.), one of whom had been the study neurologist for a given patient. The shuffled video and uniform recording conditions obscured the preoperative or postoperative status, the stimulation state, and even the session during which any particular video clip had been recorded. Each rater viewed the scoring videos in the same sequence.

The complexity and frequency of behaviors in all of the patients required a multipass approach to counting tics. In separate playbacks of the video, the rater counted tics involving each limb, the axial muscle groups, and cranial musculature, regardless of simultaneous activity in other body regions. The raw motor tic count was therefore a sum of components by body region. The reported data are averages of the scores obtained by the two raters.

Secondary Outcome Assessments

The YGTSS was administered by a neurologist (B.N.M. or D.E.R.) at the same time points as the video recordings. Patients were provided tic diaries incorporating the TSSL to complete at home for 7 consecutive days following the screening visit, for each of the 4 weeks during the randomized phase, and for the week prior to the 3-month follow-up. For YGTSS and TSSL, lower scores represent fewer tics and less impact on the quality of life.

Quality-of-life scales SF-36 and VAS were administered at the preoperative and 3-month follow-up visits. The raw data for the SF-36 scores were transformed into normalized scores from 0 to 100 in which 50 corresponded to the age-adjusted US population mean and the SD was 10.43 The VAS comprised a 100-mm bar; the distance from the left edge to the crossing of the patient's mark is reported. For these quality-of-life scales, higher scores are better.

The neuropsychological profile was performed at the preoperative evaluation and again at the 3-month follow-up. The quantitative battery was designed to evaluate attention and vigilance, memory, language, cognitive and motor speed, and other functional aspects. Subjective behavioral measures were assessed, including the BDI-2,3 HAM-D,19 HAM-A,18 and Y-BOCS.17 The Minnesota Multiphasic Personality Inventory-222 was applied at the screening evaluation only. The instruments used were based on prior research of TS indicating sensitivity to hypothesized deficits5,12,33,38,39 as well as inclusion of an instrument designed to be sensitive to attention problems exhibited by patients with diagnosed attention-deficit/hyperactivity disorder.8

Statistical Analysis

For pairwise comparisons (for example, at the 3-month follow-up compared with preoperatively), exact Wilcoxon signed-rank tests were used. The Friedman test was used to assess any effect of the four states in the randomized phase on the measured outcome variable; this test is an exact rank-based randomization that makes use of the randomized ordering of the four states to produce a null reference distribution and, subsequently, a probability value defined as the number of random orderings that would give a more extreme result than the one observed. Analyses were performed using the SAS system (version 8, SAS Institute), SPSS (version 12.0, SPSS, Inc.), and StatXact (version 4.0, Cytel Software Corp.).

Results

Patient Profiles

After preliminary phone interview and record review revealed an appropriate diagnosis and disease severity, 10 patients (nine men and one woman) with TS according to stated criteria underwent screening and preoperative evaluation. The FDA limited approval of the surgical procedure to five patients. Of 10 patients screened, two were excluded because psychiatric comorbidity outweighed tic severity. Screening began with the expectation that a larger cohort would undergo the trial. When FDA approval was limited to five patients, surgery was offered to the five patients with the highest YGTSS scores. Three declined after reconsideration. Surgery was then offered to the three remaining eligible candidates, all of whom elected to proceed with DBS. Table 1 provides the profiles of the 10 screened candidates and outlines the final selection of five patients. The operations were conducted between June 3 and July 1, 2005.

TABLE 1

Summary of characteristics in 10 patients with TS*

ParameterSurgeryNo Surgery
age in yrs
 at screening28.2 (18–34)27.4 (18–39)
 at onset7.6 (3–12)7.0 (3–9)
 at diagnosis10.4 (6–13)9.8 (6–12)
yrs of education13.8 (12–17)13.6 (12–16)
no. of patients
 total55
 male54
 rt-handed55
 employed at screening11
 w/ADHD33
 w/OCD42
 w/depression52
 w/coprolalia02
YGTSS score
 tics only37.2 (26–49)40.7 (36–45)
 complete scale79.2 (56–99)81.7 (56–90)
SF-36 score
 physical40.7 (20.2–53.6)44.1 (33.6–55.8)
 mental41.2 (29.4–50.2)44.8 (34.2–57.3)
VAS score42.6 (18–70)55.8 (18–82)
BDI-2 score10.6 (4–23)7.6 (0–23)
HAM-D score13.6 (12–16)13.8 (4–31)
HAM-A score16.4 (10–21)17.8 (10–27)
Y-BOCS score12.6 (0–29)10.8 (0–25)

* Numbers are expressed as the mean values (ranges), unless indicated otherwise. Abbreviations: ADHD = attention-deficit/hyperactivity disorder; OCD = obsessive–compulsive disorder.

Target Location

With respect to the midcommissural point, electrode tips were positioned as follows (mean ± SD): lateral 4.3 ± 0.7 mm, posterior 4.5 ± 0.5 mm, and inferior 0.1 ± 0.1 mm. Trajectory angles were 33.6 ± 3.1° lateral and 25.9 ± 2.9° anterior. Postoperative MR images demonstrated satisfactory targeting in all cases (Fig. 2).

Randomization and Stimulation Parameters

The order of stimulator states in the randomized phase for each patient was determined prior to the first postoperative stimulator activation. Stimulation parameters derived at the initial stimulator activation remained constant during the entire 28-day randomization phase. These parameters are listed in Table 2. Blinding was maintained throughout the 4-week period.

TABLE 2

Randomized phase: stimulator parameters and order of stimulator states*

Lt SideRt SideOrder of Stimulator States
Case No.0123CPAPWPR0123CPAPWPRLt Off/Rt OffLt Off/Rt OnLt On/Rt OffLt On/Rt On
1+3.690160+3.5901303rd4th2nd1st
2+3.6210185+3.62101852nd4th3rd1st
3+3.6120130+3.61201303rd4th1st2nd
4+3.6120170+3.61201854th2nd3rd1st
5+3.5120130+3.6901301st4th2nd3rd

* Electrode contacts are designated as 0 (tip) to 3 (proximal) and C (case, that is, implantable pulse generator case polarity when used as an electrode). Blank spaces indicate that the electrode was inactive. Abbreviations: PA = pulse amplitude in volts; PR = pulse rate in Hz; PW = pulse width in microseconds; − = negative; + = positive.

Video Assessment

The primary outcome variable was the mRVRS score, and Table 3 features the scoring data. Compared with those in the preoperative state, the mean mRVRS scores were reduced by 4.2 points in the randomized on-on state, by 5.4 points at the start of the open-label phase, and by 2.6 points 3 months after the start of the open-label phase.

TABLE 3

Primary outcome measure: mRVRS scores in five patients with TS*

Case No.PreopPrestimLt Off/Rt OffLt Off/Rt OnLt On/Rt OffLt On/Rt OnStart of Open Programming3-Mo FU
1202020202014.56.510
21815.51818.5151717.518
31312.51314.5121214.514
4181617.51815.51513.511
516188.589.55.5619
mean ± SD17.0 ± 2.616.4 ± 2.815.4 ± 4.615.8 ± 4.814.4 ± 4.012.8 ± 4.511.6 ± 5.114.4 ± 4.0

* In a comparison of the four randomized stimulator states (p = 0.026, Friedman test). Abbreviation: FU = follow-up; Prestim = pre-stimulation.

† Refers to the time 17 to 21 days after electrode implantation, immediately before initial activation.

In Table 4 and Fig. 3, the preoperative raw tic counts for each patient were normalized to 1, and all subsequent counts were referenced to that baseline. The mean reduction in motor tics was 53% in the randomized on-on state, 67% at the start of the open-label phase, and 40% at the 3-month follow-up. Sonic tics were reduced by 70% in the randomized on-on state and by 31% at the start of the open-label phase but were increased by 21% at the 3-month follow-up.

TABLE 4

Tic counts obtained by video scoring in five patients with TS*

Case No.PreopPrestimLt Off/Rt OffLt Off/Rt OnLt On/Rt OffLt On/Rt OnStart of Open Programming3-Mo FU
motor tics
 1189.2 (1.00)136 (0.72)113.7 (0.60)262.3 (1.39)226.0 (1.20)18.1 (0.10)6.7 (0.04)15.1 (0.08)
 2135.9 (1.00)108.9 (0.80)92.4 (0.68)133.0 (0.98)145.4 (1.07)96.1 (0.71)89.5 (0.66)104.5 (0.77)
 336.6 (1.00)40.5 (1.11)33.1 (0.90)54.3 (1.48)33.7 (0.92)31.9 (0.87)28.4 (0.76)32.3 (0.88)
 4460.4 (1.00)423.3 (0.92)398.5 (0.87)333.9 (0.73)291.8 (0.63)257.6 (0.56)50.5 (0.11)28.8 (0.06)
 550.5 (1.00)67.2 (1.33)11.4 (0.23)12.0 (0.24)8.7 (0.17)6.6 (0.13)3.3 (0.07)60.5 (1.20)
 raw count174.5 ± 171.6155.2 ± 154.3129.8 ± 155.9159.1 ± 136.5141.1 ± 121.482.1 ± 104.135.7 ± 35.648.2 ± 35.5
 normalized count1.00 ± 00.975 ± 0.2710.655 ± 0.2710.962 ± 0.5080.798 ± 0.4070.472 ± 0.3460.329 ± 0.3580.598 ± 0.506
sonic tics§
 149.1 (1.00)33.7 (0.69)45.6 (0.93)34.6 (0.71)48.9 (1.00)5.2 (0.11)0 (0.00)3.9 (0.08)
 29.0 (1.00)3.2 (0.36)9.0 (1.00)10.2 (1.13)3.5 (0.39)4.7 (0.52)6.5 (0.72)10.9 (1.21)
 33.5 (1.00)3.0 (0.86)3.5 (1.00)6.1 (1.75)1.3 (0.37)1.9 (0.54)6.6 (1.89)4.0 (1.14)
 413.6 (1.00)6.7 (0.49)11.5 (0.85)9.9 (0.73)4.6 (0.34)4.4 (0.32)1.5 (0.11)0.1 (0.01)
 54.6 (1.00)9.9 (2.16)0.6 (0.13)0.4 (0.09)0.5 (0.11)0.1 (0.02)1.0 (0.22)16.6 (3.61)
 raw count16.0 ± 19.011.3 ± 12.814.0 ± 18.212.2 ± 13.111.8 ± 20.83.3 ± 2.23.1 ± 3.27.1 ± 6.6
 normalized count1.00 ± 00.910 ± 0.7260.781 ± 0.3690.880 ± 0.6120.441 ± 0.3300.303 ± 0.2370.587 ± 0.7761.21 ± 1.46

* Values represent the number of counts per minute (values in parentheses are normalized counts). Some values are presented as the means ± SDs.

† In a comparison of the four stimulator states (p = 0.020, Friedman test).

‡ To obtain normalized counts for each individual, raw counts were divided by the preoperative raw count.

§ In a comparison of the four stimulator states (p = 0.067, Friedman test).

Unilateral activation of the stimulators did not result in a reduction in tic number or severity (Tables 3 and 4). A possible exception is the case of sonic tics with unilateral left-sided stimulation (Fig. 3).

Fig. 3.
Fig. 3.

Plots depicting motor (A and C) and sonic (B and D) tic counts normalized so that the preoperative count equals 1. The cross-hairs indicate the 50th percentile; the upper and lower box limits, the 25th and 75th percentiles; and the vertical span, the 0 and 100th percentiles. L = left; pre-stim = prestimulation; R = right.

Using the Friedman test to compare the four stimulator states, a significant difference (p = 0.03) was identified in the primary outcome variable, that is, the mRVRS score. The reduction in the motor tic counts was significant as well (p = 0.02). Using the Wilcoxon signed-rank test to compare pairs of observations, no significant difference was found when comparing the bilateral on state with the start of the open-label phase or the 3-month follow-up.

Of the five patients, three were objectively improved when assessed using the primary outcome variable (mRVRS) or simple tic counts at three time points as follows: with both stimulators on during the randomized phase, immediately after unblinding, and 3 months after un-blinding.

The YGTSS and TSSL

The YGTSS data in Table 5 include only the two 25-point subscores reflecting motor and sonic tics (maximum score: 50). Compared with the preoperative state, the mean YGTSS scores were reduced by 2.4 points in the randomized on-on state and by 9.0 points at the 3-month follow-up. In Fig. 4 and Table 6, the complete-scale YGTSS preoperative score (maximum: 100, including the 50-point sub-score for global functioning) was compared with that at 3 months after the end of the randomized phase. The mean complete-scale YGTSS score was reduced 38.8 points (44%) at 3 months compared with the preoperative score. The mean TSSL scores (on a per day basis) were reduced by 30.1 points in the randomized on-on state and by 23.1 points at 3 months. As with the video scores, unilateral activation of the stimulators did not improve tic number or severity.

TABLE 5

Secondary outcome measures in five patients with TS

Case No.PreopPrestimLt Off/Rt OffLt Off/Rt OnLt On/Rt OffLt On/Rt On3-Mo FU
YGTSS score*
 149393742442818
 242444847494347
 326273536282926
 431414243423912
 538474136453538
 mean score37.2 ± 9.039.6 ± 7.740.6 ± 5.240.8 ± 4.841.6 ± 8.034.8 ± 6.428.2 ± 14.3
TSSL score
 172.635.645.779.059.612.913.7
 235.043.332.127.031.633.049.0
 332.621.618.322.012.614.130.3
 445.432.647.647.644.632.77.3
 582.264.752.328.052.025.052.0
 mean score53.6 ± 22.539.5 ± 16.139.2 ± 13.940.7 ± 23.540.1 ± 18.523.5 ± 9.730.5 ± 20.2

* Maximum score is 50. In a comparison of the four stimulator states (p = 0.060, Friedman test).

† Per day maximum score is 180 (p = 0.493, Friedman test).

Fig. 4.
Fig. 4.

Plots revealing secondary outcome measures at the preoperative and 3-month follow-up assessments. A: Complete-scale YGTSS scores. B: The VAS scores. C: The SF-36 scores. The cross-hairs indicate the 50th percentile; the upper and lower box limits, the 25th and 75th percentiles; and the vertical span, the 0 and 100th percentiles. QoL = quality of life.

TABLE 6

Mean scores for secondary outcome measures in five patients with TS

ScalePreop3-Mo FU
YGTSS (complete scale)*89.0 ± 9.050.2 ± 32.5
VAS42.6 ± 22.065.0 ± 21.4
SF-36
 physical40.7 ± 14.148.5 ± 7.7
 mental41.2 ± 8.949.0 ± 7.6
BDI-2§10.6 ± 7.64.2 ± 5.4
HAM-D§**13.6 ± 1.59.6 ± 6.5
HAM-A§††16.4 ± 4.28.0 ± 7.0
Y-BOCS§‡‡12.6 ± 10.77.0 ± 4.2

* Scale includes 50-point disability subscale; total maximum score is 100.

† Maximum score is 100; higher values indicate a better quality of life.

‡ Values represent the Z scores. The US mean score is 50. Higher scores indicate a better quality of life.

§ Lower scores indicate fewer symptoms.

‖ Score range is 0 to 63.

** Score range is 0 to 54.

†† Score range is 0 to 56.

‡‡ Score range is 0 to 40.

Neither the Friedman test comparing the four randomized stimulator states nor the Wilcoxon signed-rank test comparing pairs of observations revealed a significant difference in either the YGTSS or TSSL scores.

Of the five patients, three were objectively improved when assessed using the secondary outcome measures, YGTSS and TSSL. These three patients were the same persons in whom improvement was documented by video assessment.

Quality-of-Life Measures

Table 6 presents the mean scores of the VAS and SF-36 at the preoperative and 3-month follow-up assessments. Both instruments revealed a mean improved quality of life. Results are illustrated graphically in Fig. 4.

Neuropsychological Measures

Measures of 29 variables revealed a nonsignificant trend for decreased verbal fluency, memory, and sustained attention and reaction time at the 3-month follow-up compared with levels at the preoperative assessment. The BDI-2, HAM-D, HAM-A, and Y-BOCS showed a trend toward improved mood, reduced anxiety, and fewer obsessions and compulsions (Table 6).

Adverse Events

No morbidity or death was associated with the surgical procedure.

One patient (Case 1) experienced acute psychosis on Day 28 of the randomized phase, when the right stimulator was on and the left was off. Acute life stressors were identified and considered to be the precipitant in this individual with prior personal and family histories of psychiatric illness. Unblinded bilateral stimulator activation was accomplished on Day 28 as scheduled, with an immediate significant reduction in tic frequency. The patient was hospitalized and treated with antipsychotics, and his psychosis resolved within 2 weeks without any interruption in bilateral stimulation. His psychosis has not recurred, and medications have been steadily tapered.

Two patients (Cases 1 and 5) experienced spontaneous recurrence of tics during the open-programming phase. In each case, one stimulator was found to be off (presumably due to environmental factors), and symptom improvement was rapidly regained on reactivation of the stimulator.

In one patient (Case 5), initially excellent symptom control substantially waned by the 3-month follow-up evaluation. Assessment procedures, including a video session, were recorded per our protocol. Stimulator parameters were then adjusted with prompt and sustained improvement, although this result was not reflected in the 3-month scores.

One patient (Case 3) sustained soft tissue injuries in a motor vehicle collision during the open-programming phase. He had reported subjective improvement in symptoms until that point but then lost benefit. Ongoing pain was reflected in his quality-of-life assessment at 3 months.

Discussion

Data from previous publications suggest that DBS can be an efficacious treatment for medically refractory TS.1,10,24,31,37,40,42 To date, all of these reports have been case reports or retrospective series. The present trial was designed to address inherent limitations in such reports by incorporating a randomized double-blinded design and video scoring to limit rater bias. We measured the efficacy of thalamic DBS in reducing tic frequency and severity, compared unilateral with bilateral stimulation, and assessed the durability of the effect.

Patient Outcomes

A statistically significant difference in the primary outcome variable (mRVRS) was detected when comparing the randomized stimulator states. The mRVRS score cannot be used as a direct measure of tic frequency, because it reflects a combination of tic frequency and severity. A simple measure of tic counts, a secondary outcome variable, also revealed a statistically significant improvement. Although the results of the secondary outcome variables YGTSS and TSSL were not statistically significant, the trend corroborated the video analysis results for each patient. Quality-of-life measures were improved after 3 months. Measures of anxiety, depression, and obsessive–compulsive behaviors showed a trend toward improvement.

Of the five patients, three were clearly improved on clinical inspection and study measures, whereas two were not (at 3 months). Factors that might predict a beneficial or absent response were not evident. Postoperative imaging results demonstrated satisfactory targeting in all cases. No interpretable differences in baseline characteristics were identified.

The latency to response appeared to be short. At least some measurable reduction in tics or urge was clinically apparent in all responders within the time frame required to perform the initial programming. In responders (Cases 1, 4, and 5), tic count immediately following (unblinded) bilateral activation was reduced, compared with the recording made 1 hour or so earlier documenting the final week of the randomized phase. In nonresponders (Cases 2 and 3), a reduction in tics did not emerge during the 3-month open-programming observation period.

A beneficial response appears to be reproducible and durable. All whose tics were reduced in the on-on state during the randomized phase also responded when the open-label phase began. In two patients who reported a recurrence in tics, benefit was restored on discovering an inactive stimulator and its subsequent reactivation. The beneficial effect was readily restored in the patient in Case 5 (by clinical assessment), who had relapsed by the 3-month follow-up. The scores in two of the three responders improved at 3 months compared with the first unblinded assessment.

It is possible that simple insertion of the DBS electrode without activation might have led to a reduction in tic frequency and severity. This “microlesion effect” has been reported for other conditions and target sites.9 Houeto and colleagues24 implanted thalamic and GPI site electrodes simultaneously, and the microlesion effect lasted 1 month. No report of a similar effect was mentioned by Diederich et al.10 or Visser-Vandewalle et al.42 In our trial, the average scores on the mRVRS and tic counts (both motor and sonic) at the prestimulation point (17–21 days postoperatively) were within 10% of those obtained preoperatively (Tables 3 and 4).

Tourette syndrome symptoms are known to fluctuate over time.28 Therefore, the baseline characteristics, against which the effect of treatment is measured, might have been sampled at unrepresentative times, or the fluctuation may have coincided with an apparent response. In the present study, individual mRVRS scores preoperatively, prestimulation, and in the off-off state were comparable in four of five patients.

The possibility of a placebo effect must be considered, particularly in a population known to be suggestible.25 However, medical treatment had failed in all of the patients, whereas 60% of them experienced benefit with DBS. Typically, the magnitude of the placebo effect is expected to be approximately 30%.

For all patients, unilateral stimulation did not appear as efficacious as bilateral stimulation. Unilateral right-sided stimulation appears to be either completely ineffective for motor and sonic tics or possibly detrimental.

Target Nucleus

We selected as our target point the coordinates 4 mm posterior, 5 mm lateral, and 0 mm inferior to the midcommissural point. Because it was our intention to access the anatomical location of the lesions documented by Cooper6,7 and Hassler and Dieckmann,20,21 we took care to angle our trajectory 26° anteriorly and 34° laterally. Postoperatively, the observation that Electrode 0 (target) was never the most effective contact (see Table 2) demonstrates that our true surgical target was closer to that described by Cooper and Hassler and Dieckmann than Visser-Vandewalle and colleagues.42

Favorable results of DBS in the thalamus24,31,42 and GPI1,10,24,37 have been reported, although the stimulation of the anterior limb of the internal capsule11 appears to be less successful. Current concepts of TS implicate dysfunction along the corticostriatopallidothalamocortical loop,32 but our understanding is incomplete. The mechanism by which DBS causes improvement in any movement disorder remains unclear. Insufficient data are available to determine whether the thalamus or GPI is the optimum site or whether an as yet untried site might be better.

Trial Design Considerations

The use of DBS for TS is still an emerging area of study. No guidelines have yet been established for appropriate patient selection, choice of stimulator site, or measures for successful therapy. Our trial was limited to adults older than 18 years to minimize the confounding effect of an evolving natural history. Recognizing that many people with TS are burdened with neuropsychiatric comorbidity,36 the primary focus of the present trial was the movement disorder. Thus, the entry criteria were designed to include patients in whom the primary effect of TS was tics. Although preoperative evaluation included formal neuropsychological testing and validated instruments such as the YGTSS, insufficient information was available to select threshold values for trial inclusion. Thus, in our study design, selection criteria were assessed by clinical evaluation. Future clinical trial investigators may use formal rating scale data in the selection of potential participants.

The primary outcome measure (mRVRS) was selected for its capacity to objectively reflect tic frequency, severity, and body distribution in a single setting as captured on video recording. Advantages of video recording have been documented, and the mRVRS has been validated.16

The secondary assessment tools (YGTSS and TSSL) were selected to identify objective and subjective tic symptoms in the prior week. The YGTSS is a widely used, validated instrument that combines rater observations with the patient's own subjective reports.29 The TSSL is entirely based on the patient's own report (tic diary).13

The FDA investigational device exemption approval was limited to five patients in a pilot trial. Despite the limitation imposed by the small sample size, the four-way crossover randomization was a strength of the trial design; it provided sufficient power to detect statistical significance. Conversely, the small sample size would not be expected to reveal statistical significance in any pairwise comparison between stimulator states.

In the design of this trial, we anticipated the possibility that patients might not be fully unaware of the state of the stimulators. In our clinical experience with DBS, patients can experience sensations associated with the activity of the stimulator system, as well as more externally obvious alleviation of symptoms. We considered formally assessing the blind by recording the guesses of patients and neurologists at the time of recording or scoring of each stimulator state but decided against that approach because it might sensitize the patients and otherwise introduce bias.

The scoring of randomly shuffled unidentified video segments with uniform recording conditions (including patient clothing and head covering) was intended to reduce rater bias. A single investigator (who did not perform any evaluations during the randomized phase) maintained the states of the stimulators. The scoring video, prepared by a non-investigator, thus had two levels of blinding: raters were unaware of not only the state of the stimulator but also the session in which the recording was made. Only after both raters had completed scoring of the video was information released to unscramble and identify stimulator states for any given patient.

Some consideration was given to the duration of each of the four combinations of left and right stimulator states in the randomized phase. A 7-day period was chosen for practicality. Our previous experience in a patient with thalamic DBS for TS suggested that the effect of stimulation occurred within minutes of activation or a change in stimulus parameters.31 These results are similar to the effects seen in thalamic stimulation for essential tremor, in contrast to those commonly experienced in patients with dystonia undergoing GPI stimulation. The available information from reported cases thus far10,24,42 is variable and incomplete but not incompatible with our observation.

The documented reduction in tic frequency and severity in the responders (Cases 1, 4, and 5) is evidence that 7 days is sufficient to allow an effect to appear, although we acknowledge that a longer-duration stimulator state might have revealed a more substantial effect. For example, the reduction in tics in the patient in Case 4 was less robust during the randomized phase than at the 3-month follow-up. The possibility of a carryover effect requiring a washout period after each stimulator state is also acknowledged. In this trial, by chance, the bilateral on state preceded at least one other state in all patients (Table 2). In the three responders, tic counts in the state following on-on were uniformly higher, suggesting that the residual effect of stimulation is not apparent 1 week later.

In the design of this trial, patients were not required to be off tic-suppressive medications, although an inadequate effect was an inclusion criterion. However, any medications relevant to the control of tics were held constant to isolate the effect of the stimulators. With one exception, medication adjustments were not allowed within 21 days prior to surgery and up to 3 months after the start of the clinical observation period. Treatment of psychosis in the patient in Case 1 (including ziprasidone and haloperidol) began after his evaluation at the start of the open-label period, following completion of the randomized phase. Therefore, only one data point (at 3 months) was potentially affected by the deviation from protocol. Notably, each of these agents had been used unsuccessfully in this patient in an attempt to suppress tics before the trial.

Safety of DBS

The safety of bilateral thalamic DBS for TS in this pilot study appears comparable with that of DBS surgery in other populations. No morbidity or death occurred as a result of the surgery itself. No adverse neuropsychological outcomes were detected at the 3-month evaluation. The most serious adverse event, a reversible psychotic episode, was successfully treated without requiring alteration of the stimulators.

Conclusions

By all criteria, as measured using primary and secondary outcome variables, three of five patients significantly improved with bilaterally active thalamic DBS. Unilateral stimulation was less effective or frankly ineffective. Despite the small sample size and the potential risk of inadequate statistical power, the video assessment instrument in fact demonstrated a statistically significant benefit of bilateral stimulation when compared with other stimulator states. In individuals who responded to DBS treatment, measures utilizing a patient's own report (diary) and a rater's structured interview correlated with the video assessments. Quality-of-life measures improved for all but one nonresponder. Although we noted a trend toward fewer obsessive–compulsive or other neuropsychiatric symptoms (such as depression and anxiety), the primary effect appears to have been exerted on the tics themselves, an observation compatible with findings in patients with other movement disorders. The safety of bilateral thalamic DBS appears comparable with DBS performed for other indications.

Our data suggest that DBS may play a role in the therapeutic management of medically refractory TS in adults, especially in those for whom the primary source of disability is motor and sonic tics. This result can be better defined through future clinical studies.

Disclosure

Financial support was provided in part by a physician-sponsored research agreement with Medtronic, Inc.

Acknowledgments

We are grateful to the following individuals: Arlene Brown, Lisa M. Brown, William Campbell, M.D., Philip Cola, Benedict Columbi, M.D., Barbara Dabb, M.D., Gina Dalton, Kyra Dawson, Nada El-Zohbi, Carol Fedor, Roberta Lilly-Trakas, Carter McAdams, Kathy Miller, Sherry Nehamkin, Sing Ng, Pamela Owen-Ragone, Wayne Ray, Ph.D., Fred Rothstein, M.D., Stephen Sagar, M.D., John Sanitato, M.D., James Sisler, R.N., Jose Suarez, M.D., Deborah Ware, and Edward Westbrook, M.D.

References

This work was supported by a Medtronic, Inc., physician-sponsored research agreement (R.J.M.).

Article Information

Address correspondence to: Robert J. Maciunas, M.D., M.P.H., Department of Neurosurgery, Neurological Institute, University Hospitals Case Medical Center, 11100 Euclid Avenue, Cleveland, Ohio 44106. email: robert.maciunas@uhhospitals.org.

© AANS, except where prohibited by US copyright law."

Headings

Figures

  • View in gallery

    Timeline representing steps in the pilot study. Video camera icons designate video recording sessions. Assessment of secondary outcome measures are indicated by N (neuropsychological battery), Q (quality of life), T (TSSL), and Y (YGTSS). Combins = combinations; f/u = follow-up.

  • View in gallery

    Coronal and axial T1-weighted MR images featuring the target point in all five surgically treated patients. A, D, and E: Responders (Cases 1, 4, and 5). B and C: Nonresponders (Cases 2 and 3). The image labeled “Plan” (lower right) is in the oblique plane, along electrodes, of the planned thalamic target and electrode trajectory using the BrainLab software.

  • View in gallery

    Plots depicting motor (A and C) and sonic (B and D) tic counts normalized so that the preoperative count equals 1. The cross-hairs indicate the 50th percentile; the upper and lower box limits, the 25th and 75th percentiles; and the vertical span, the 0 and 100th percentiles. L = left; pre-stim = prestimulation; R = right.

  • View in gallery

    Plots revealing secondary outcome measures at the preoperative and 3-month follow-up assessments. A: Complete-scale YGTSS scores. B: The VAS scores. C: The SF-36 scores. The cross-hairs indicate the 50th percentile; the upper and lower box limits, the 25th and 75th percentiles; and the vertical span, the 0 and 100th percentiles. QoL = quality of life.

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