Deep Brain Stimulation in Tourette Syndrome: A Description of 3 Patients With Excellent Outcome

Abstract

Tourette syndrome (TS) is a complex neuropsychiatric disorder often starting in childhood and characterized by the presence of multiple motor and vocal tics and psychiatric comorbidities. Patients with TS usually respond to medical treatment, and the condition often improves during adolescence; however, surgery has been considered a possible approach for the subset of patients with ongoing medically refractory disease. Ablative procedures have been associated with unsatisfactory results and major adverse effects, prompting trials of deep brain stimulation (DBS) as an alternative therapy. It remains unclear which of the various nuclear targets is most effective in TS. We describe 3 patients with TS who underwent DBS targeting the bilateral thalamic centromedian/parafascicular complex (CM/Pf) with an excellent clinical outcome. At 1-year follow-up, the mean reduction in the total Yale Global Tic Severity Scale score in the 3 patients was 70% (range, 60%-80%).Our study further supports the role of the CM/Pf DBS target in medically intractable TS.

Tourette syndrome (TS) is a complex neuropsychiatric disorder that usually begins in childhood¹ and is characterized by the presence of multiple motor and vocal tics.² Although TS is considered a rare disease, differences in diagnostic criteria complicate incidence and prevalence estimates.³ Patients with TS usually respond to medical treatment, and the condition often improves during adolescence; however, surgery has been considered a possible approach for the subset of patients with ongoing medically refractory disease. Ablative procedures have been associated with unsatisfactory results and major adverse effects,⁴ prompting trials of deep brain stimulation (DBS) as an alternative therapy.⁵ It remains unclear which of the various nuclear targets is most effective in TS; however, the globus pallidus internus and centromedian/parafascicular complex (CM/Pf) are emerging as the favored targets.⁶ Investigators reporting on CM/Pf stimulation generally have targeted the most anterior region of the complex, near its confluence with the nucleus ventralis oralis internus and the substantia periventricularis. We report the clinical outcome and the 1-year follow-up results in 3 patients with TS who underwent DBS targeting the center of the CM/Pf, 4 mm posterior to the previously reported target.

Patients and Methods

All 3 patients who underwent DBS for treatment of TS at our medical center to date were included. Preoperatively, each of these patients had been evaluated by movement disorders neurologists and psychiatrists with TS expertise, was found to fulfill Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) criteria for TS,⁷ and was unanimously approved for the DBS procedure by the Mayo Clinic Neuromodulation Committee. The study was approved by the Mayo Clinic Institutional Review Board. Preoperatively, and again after optimization of DBS parameters, each patient was tested with the Yale Global Tic Severity Scale (YGTSS),⁸ a semistructured, multidimensional test that has been developed to assess the severity of tic disorders. Fifty percent of the score is based on the tics themselves, whereas the other half reflects the level of tic-related impairment as assessed by the patient. The YGTSS score ranges from a possible score of 0 (no tics) to a maximum score of 100 (extreme severity). According to the current guidelines,⁹ a YGTSS score of 35 or higher for 1 year is a marker of disease severity sufficient to warrant consideration for DBS.

Two weeks after implantation, we performed a monopolar review probing the favorable and adverse effects of stimulation at each contact. Stimulation was generally well tolerated, and some degree of efficacy against tics was noted immediately. Stimulation voltage was regularly increased over time until optimal parameters were reached, generally at 3 to 6 months after implantation.

Surgical Procedure

Stimulating electrodes were implanted in the anesthetized patients using a stereotactic head frame and targeting the center of the thalamic CM/Pf, 5 mm lateral and 8 mm posterior to the mid-commissural point (MCP) along the superior-inferior plane of the anterior commissure-posterior commissure line (Figure).

FIGURE.

Line drawings depicting the thalamic centromedian (CM) and parafascicular (Pf) nuclei in blue at 5 mm (left) and 8 mm (right) lateral to the midline. The targeted coordinates in the anteroposterior and sagittal planes are shown for our patients (blue arrowhead) and for the previously published series (orange arrowhead). The trajectories to target (arrow shafts) were not published and are estimated here. v.o.m. = ventralis oralis, pars medialis.

Case 1

A 17-year-old boy with a 12-year history of TS and a strong family history of tic disorders presented for management of multiple severe vocal and motor tics that precluded smooth communication and included jaw-clenching/teeth-grinding tics forceful enough to have caused dental fractures on multiple occasions. Treatment for tics over the years included behavioral interventions, guanfacine, clonazepam, risperidone, quetiapine, and aripiprazole, none of which adequately controlled the tics. The patient's YGTSS score on presentation was 93 with an impairment subscore of 50. On psychiatric evaluation, his comorbid depression and obsessive-compulsive disorder (OCD) were judged to be stable, and he was approved for bilateral CM/Pf stimulation. The patient had modest early improvement in tics, and it took 6 months before optimal stimulating parameters were found (configuration of 1+3-/5+7-; bilateral amplitude, 3.7 V; pulse width, 120 μs; rate, 117 Hz). At 1-year follow-up, the YGTSS score was 29 with an impairment subscore of 10.

Case 2

A 35-year-old woman presented to our center with a history of TS dating back to age 10 years, when she developed simple vocal and focal motor tics. The verbal tics in particular increased in severity to the point that she began having severe impairment in verbal communication. After she was diagnosed with TS at age 16 years, she was given multiple medications including clonidine, guanfacine, clonazepam, haloperidol, pimozide, quetiapine, and olanzapine. Neither medications nor behavioral interventions were sufficiently helpful, and she continued to have socially disabling tics. We initiated tetrabenazine therapy, which was initially helpful but lost efficacy within a few months. Because her comorbid OCD and attention-deficit/hyperactivity disorder (ADHD) symptoms were judged to be stable, she was referred to our DBS program, where her preoperative YGTSS score was determined to be 80 with an impairment subscore of 40. Bilateral CM/Pf stimulators were placed. Within hours of the stimulators being activated, the patient and her family noted marked improvement in tics, which they estimated to represent a 75% reduction. Her YGTSS score was 53 (impairment subscore, 30) at 6-month follow-up and decreased to 32 (impairment subscore, 10) by 1 year. Stimulator parameters at optimization were symmetric and included bipolar configurations (0+3- and 4+7-), voltage of 4.1, pulse width of 120 μs, and rate of 107 Hz.

Case 3

A 17-year-old boy with a 9-year history of TS and comorbid OCD and ADHD symptoms presented to our center for evaluation. He had initially developed simple vocal tics at age 8 and soon thereafter experienced simple motor tics involving the face and arms; the tic repertoire later expanded to include complex vocalizations and patterned movements throughout all body segments. By 3 years before presentation, the patient developed forceful head-jerking tics that were painful enough to require narcotic analgesia and vigorous enough to raise concern for possible cervical spine injury. He had been hospitalized on multiple occasions for sedation to treat severe tic exacerbations. Trials of medication included clonidine, guanfacine, clomiprimine, pimozide, haloperidol, risperidone, aripiprazole, quetiapine, clonazepam, diazepam, valproate sodium, and botulinum toxin injections; however, the tics were improved only at medication doses sufficient to cause disabling sedation. Behavioral therapies for his tics and psychiatric symptoms were unsuccessful. Annual attempts at school enrollment were interrupted by tic exacerbations, and thus he had been homeschooled. On initial evaluation at our center, his YGTSS score was 70 with an impairment subscore of 50 (video segment 1, available at http://www.mayoclinicproceedings.org). Bilateral CM/Pf stimulators were implanted. Even before the stimulators were activated, the patient experienced nearly complete relief of his tics (video segment 2, available at http://www.mayoclinicproceedings.org). Monopolar stimulation (contacts 2 and 6 as cathodes) was begun and at optimization included bilateral amplitudes of 2.5 V, pulse width of 90 μs, and rate of 130 Hz. The patient tolerated stimulation quite well and experienced excellent control of tics, which were self-rated at 99% improvement. By last follow-up, his total YGTSS score was 14 with an impairment subscore of 10 (video segment 3, available at http://www.mayoclinicproceedings.org). He was better able to engage in behavioral therapies and noted considerable improvement in OCD and ADHD symptoms. He was able to successfully enroll in high school and eventually began serving as a tutor for younger students.

Results

The mean reduction in the total YGTSS scores in the 3 patients was 70% (range, 60%-80%) (Table). The tic severity subscores improved by a mean of 60% (range, 45%-80%), whereas the impairment subscores improved by a mean of 78% (range, 75%-80%). No patient experienced a surgical complication, and the only stimulation-related adverse effects were mild parenthesia and light-headedness that were amenable to programming changes and no longer present at optimal settings. Comorbid psychiatric symptoms remained stable or slightly improved in all patients according to the consulting psychiatrists, and each of the patients attained a self-reported higher level of social functioning.

TABLE.

Yale Global Tic Severity Scale Scores in 3 Patients Who Underwent Deep Brain Stimulation (DBS) for Tourette Syndrome

Case	Pre-DBS			Post-DBS			Change, %
	Motor subscore	Impairment subscore	Total score	Motor subscore	Impairment subscore	Total score	Motor subscore	Impairment subscore	Total score
1	43	50	93	19	10	29	55.8	80.0	68.8
2	40	40	80	22	10	32	45.0	75.0	60.0
3	20	50	70	4	10	14	80.0	80.0	80.0

Post-DBS scores determined at last available follow-up.

Discussion

We report the cases of 3 patients with medically intractable TS who experienced excellent tic suppression following DBS targeting the thalamic CM/Pf. The average 70% improvement of the YGTSS score found in our patients compares favorably to previously reported results. The largest series to date reported a 65% improvement in YGTSS scores at a mean follow-up of 3 to 18 months¹⁰; 2-year outcomes in 15 of these original 18 patients were reported to include a 52% reduction of the YGTSS score.¹¹ Two double-blind trials including 5 to 6 patients each found improvements of 43% to 49%,^12,13 and smaller case reports and series have reported improvements ranging from 45%¹⁴ to 90%.⁵

The pathophysiology of TS is still unclear. Some have suggested that overactivity of thalamocortical drive, through an inhibition of the indirect pathway of the basal ganglia circuit, could generate tics and compulsions.¹⁵ Others believe that the loops from the CM/Pf to the motor striatum and the substantia periventricularis to the limbic striatum are implicated in TS and that it is possible that the effect of thalamic DBS is mediated through these latter circuits.¹⁶ In an attempt to modulate both of these regions, the previously published series^10-13 have targeted the anterior-most region of the CM/Pf, generally 4 mm posterior to the MCP. By contrast, in our patients the target was set near the center of the CM/Pf itself (8 mm posterior to the MCP) in an attempt to better modulate its circuit with motor striatum (Figure).

Because TS may spontaneously remit around adolescence, early recommendations for patient selection suggested that DBS be reserved for those at least 25 years of age.⁹ However, severe TS in late adolescence can be disruptive to development, often jeopardizing educational opportunities, and some tics are of such severity to raise concern for self-injury. For these reasons, some of the largest series do include patients as young as 17 or 18 years old,^10,13 and more recently published guidelines concede that there is not yet a consensus among experts.¹⁷ Although 2 of our patients were 17 years old at the time of DBS, both were exhibiting self-injurious tics that were clearly interfering with their transitions to adulthood, and therefore our Neuromodulation Committee felt justified in offering them surgery. Although we agree that it is preferable to delay DBS as long as possible to allow for possible spontaneous improvement, we also believe that tic severity must be a consideration when selecting candidates for the procedure.

Conclusion

Our study supports the role of the CM/Pf DBS target in medically intractable TS; however, given the variety of other reported surgical targets, multicenter randomized controlled studies comparing multiple targets and long-term motor, cognitive, and disability outcomes are needed.

Supplemental Online Material

Video 1

Author Interview Video