Key points

Introduction

Gilles de la Tourette syndrome (TS) is a movement disorder characterized by repetitive motor and phonic/vocal tics first described in 1885 by George Edouard Albert Brutus Gilles de la Tourette. The onset of the disease is typically during adolescence, with a natural history that consists of the waxing and waning of tics until the second decade of life, when many patients experience almost complete resolution of symptoms. As such, the prevalence of the disease is higher in children, with nearly 1% of the pediatric population being affected, whereas only 0.05% of adults carry the diagnosis. Although the severity and frequency of tics diminishes considerably in adulthood, most patients still have identifiable tics, albeit they are mild and infrequent enough to not require treatment.

In addition to the motor features, TS commonly has multiple neuropsychiatric comorbidities including obsessive-compulsive disorder (OCD), attention-deficit/hyperactivity disorder (ADHD), autistic spectrum disorder, and many others, with almost 90% of patients showing some concomitant disorder. As such, in addition to neuroleptic medications used to control tics, other medications including antidepressants are used to treat these psychiatric comorbidities as well.

Despite advancements in behavioral and pharmacologic therapies, there remains a subset of patients with TS who are resistant to these management modalities. As a result, there have been attempts to alter the underlying pathologic neural circuitry to alleviate, if not eliminate, tics by manipulating subcortical circuits. The first report of such methods was in 1970 by Hassler and colleagues, who showed partial relief of tics through the ablative lesioning of thalamic nuclei including the median and rostral intralaminar nuclei and the internal ventral oral nucleus. Subsequent studies reproduced varying degrees of symptomatic relief, but at the cost of considerable, and frequent, postoperative morbidity including dysarthria, dystonia, and hemiparesis.

In 1999, Vandewalle and colleagues reported on the first deep brain stimulation (DBS) of a patient with medically refractory TS. The stereotactic target was the centromedian-parafascicular (CM-Pf) nucleus and the ventro-oral internus (Voi) of the thalamus based on the work by Hassler and colleagues. The patient experienced a complete resolution of tics and tolerated the procedure well with only minimal neurologic sequelae from stimulation (excessive eye blinking). They and numerous other investigators have subsequently examined the effects of DBS at various targets within the corticostriatothalamocortical (CSTC) network thought to be implicated in the pathophysiology of TS, including the CM-Pf/Voi, the globus pallidus internus (GPi), globus pallidus externus (GPe), the anterior limb of the internal capsule (ALIC), the nucleus accumbens (NA), and the subthalamic nucleus (STN).

It is thought that through an aberrancy of the CSTC circuitry, the normal gating mechanisms of the basal ganglia in facilitating and inhibiting competing motor, limbic, and cognitive processes are disturbed, resulting in stereotyped behaviors or tics. Although the various hubs within this network allow for a diverse selection of targets for neuromodulation, it has resulted in a collection of nearly 40 studies describing more than 100 patients with varying targets, stimulation parameters, and follow-up time. This article consolidates and summarizes the DBS experience for TS to date.

Introduction

Gilles de la Tourette syndrome (TS) is a movement disorder characterized by repetitive motor and phonic/vocal tics first described in 1885 by George Edouard Albert Brutus Gilles de la Tourette. The onset of the disease is typically during adolescence, with a natural history that consists of the waxing and waning of tics until the second decade of life, when many patients experience almost complete resolution of symptoms. As such, the prevalence of the disease is higher in children, with nearly 1% of the pediatric population being affected, whereas only 0.05% of adults carry the diagnosis. Although the severity and frequency of tics diminishes considerably in adulthood, most patients still have identifiable tics, albeit they are mild and infrequent enough to not require treatment.

In addition to the motor features, TS commonly has multiple neuropsychiatric comorbidities including obsessive-compulsive disorder (OCD), attention-deficit/hyperactivity disorder (ADHD), autistic spectrum disorder, and many others, with almost 90% of patients showing some concomitant disorder. As such, in addition to neuroleptic medications used to control tics, other medications including antidepressants are used to treat these psychiatric comorbidities as well.

Despite advancements in behavioral and pharmacologic therapies, there remains a subset of patients with TS who are resistant to these management modalities. As a result, there have been attempts to alter the underlying pathologic neural circuitry to alleviate, if not eliminate, tics by manipulating subcortical circuits. The first report of such methods was in 1970 by Hassler and colleagues, who showed partial relief of tics through the ablative lesioning of thalamic nuclei including the median and rostral intralaminar nuclei and the internal ventral oral nucleus. Subsequent studies reproduced varying degrees of symptomatic relief, but at the cost of considerable, and frequent, postoperative morbidity including dysarthria, dystonia, and hemiparesis.

In 1999, Vandewalle and colleagues reported on the first deep brain stimulation (DBS) of a patient with medically refractory TS. The stereotactic target was the centromedian-parafascicular (CM-Pf) nucleus and the ventro-oral internus (Voi) of the thalamus based on the work by Hassler and colleagues. The patient experienced a complete resolution of tics and tolerated the procedure well with only minimal neurologic sequelae from stimulation (excessive eye blinking). They and numerous other investigators have subsequently examined the effects of DBS at various targets within the corticostriatothalamocortical (CSTC) network thought to be implicated in the pathophysiology of TS, including the CM-Pf/Voi, the globus pallidus internus (GPi), globus pallidus externus (GPe), the anterior limb of the internal capsule (ALIC), the nucleus accumbens (NA), and the subthalamic nucleus (STN).

It is thought that through an aberrancy of the CSTC circuitry, the normal gating mechanisms of the basal ganglia in facilitating and inhibiting competing motor, limbic, and cognitive processes are disturbed, resulting in stereotyped behaviors or tics. Although the various hubs within this network allow for a diverse selection of targets for neuromodulation, it has resulted in a collection of nearly 40 studies describing more than 100 patients with varying targets, stimulation parameters, and follow-up time. This article consolidates and summarizes the DBS experience for TS to date.

Targets for TS neuromodulation

CM-Pf Nucleus and the Voi Nucleus of the Thalamus

The initial target for DBS for TS was based on thalamic lesioning studies performed by Hassler and colleagues in the late twentieth century. This target, namely the centromedian-parafascicular (CM-Pf) nucleus of the thalamus, along with the Voi, is thought to be situated in a unique position within the action-gating pathways of the basal ganglia. Diffusion tensor imaging (DTI) studies in humans show structural connectivity between the CM-Pf nucleus and the putamen, pallidum, NA, amygdala, and hippocampus. These findings corroborate primate studies that reveal sensorimotor projections from the ventrolateral GPi (motor pallidum) to the CM thalamus, and limbic projections from the ventral striatum/NA to the anteromedial GPi (limbic pallidum), which in turn projects to the rostral Pf thalamus and then back to the ventral striatum/NA region ( Fig. 1 ). Through modulating the excitatory feedback loops between the CM-Pf/Voi and the motor and limbic striatum, it is thought that the observed benefits of DBS for TS are achieved.

The putative connectivity of the CSTC circuit in relation to TS DBS targets. The rostromedial (limbic) GPi has limbic projections to the Pf nucleus of the thalamus, which in turn projects to the NA/ventral striatum, which then projects back to the rostromedial GPi ( gray arrows ). The sensorimotor connectivity consists of projections from the ventrolateral (motor) GPi to the CM nucleus of the thalamus, which then projects to the putamen, which then projects back to the ventrolateral GPi ( red arrows ). The cognitive connectivity of the CSTC circuit consists of 2 loops. One consists of projections from the caudate to the dorsal GPi, which in turn projects to the Pf nucleus of the thalamus, which then projects to the putamen ( black arrows ). The other also arises from the caudate, but projects instead to the SNr, and then to the Pf nucleus of the thalamus ( black arrows ). Diagram based on primate studies performed by Sidibe and colleagues (2002). dGPi, dorsal GPi; rmGPi, rostromedial GPi; SNr, substantia nigra pars reticulata; vlGPi, ventrolateral GPi.

To date there have been 20 published reports detailing approximately 68 distinct patients who have received DBS at the CM-Pf and Voi thalamus ( Table 1 ). The initial report of the clinical success of CM-Pf/Voi DBS for TS was promising, with complete resolution of tics at 12 months. However, on long-term follow-up (10 years), the patient had sustained only 78% tic reduction. Despite the decline in symptom improvement in this patient, another patient was found by the same group to have 93% tic reduction at 6 years, supporting the longevity of tic suppression with stimulation. Other studies have reported similarly promising results using a well-regarded clinical measure for TS, the Yale Global Tic Severity Scale (YGTSS), which details patient severity by tics, functional impairment, and overall score. At the last assessment (range 2–120 months), the reduction in the mean global YGTSS score for each study ranged from 19% to 78%, although some individual patients had as little as 5% improvement. Notable exceptions include 2 patients reported by Maciunas and colleagues who did not experience any significant relief of their tics at 3 months’ follow-up. In addition, Duits and colleagues detailed their experience with 1 patient who experienced an increase in tics during double-blinded stimulation. This patient was thought to have severe concomitant psychiatric comorbidity that led to her refusal to eat and eventually to her death.

Table 1

Comprehensive summary of clinical studies involving TS DBS to date

Investigators	Patient Sex, Age (y)	Follow-up (mo)	Targets	Stimulation Parameters	Outcomes (Reduction in YGTSS/MRVRS)	Complications	Comments
						Sequelae of Stimulation (Number of Patients)
Vandewalle et al, 1999 a	1 M (42)	12	CM-Pf, Voi	4 V, 130 Hz, 450 μs (at 1 y, 1.5 V was sufficient to abolish all tics)	Complete resolution of tics	Excessive eye blinking	—
Visser-Vandewalle et al, 2003 a	3 M (28, 42, 45)	8, 12, 60	CM-Pf, Voi	2.2–3 V, 65–100 Hz, 210 μs	82% mean reduction in number of tics	Decreased energy. Increased libido (1), decreased libido (1)	One pt is from Vandewalle et al, 1999 study
Ackermans et al, 2010 a	2 M (42, 45)	72 and 120	CM-Pf, Voi	1–8 V, 100–130 Hz, 90–210 μs	85% mean reduction in number of tics	Reduction in energy	Long-term follow-up of Visser-Vandewalle et al, 2003. Mild decrease in verbal fluency; transient worsening on Stroop task
Houeto et al, 2005 b	1 F (36)	24	CM-Pf and amGPi	1.5 V, 130 Hz, 60 μs	CM-Pf, 65% (global YGTSS)/77% (MRVRS); GPi, 65% (global YGTSS)/67% (MRVRS); CM-Pf + GPi stimulation, 60% (global YGTSS)/77% (MRVRS)	CM-Pf: weight loss. GPi: nausea, hypotonia and anxiety with increasing voltage	Implanted with both thalamic and GPi leads. Was not cumulative stimulation because they had different stimulation stages; prospective double-blinded study (with sham control)
Welter et al, 2008 b	2 F, 1 M (36, 30; 30)	60, 27, 20	CM-Pf and amGPi	CM-Pf, 1.5–1.7 V. 130 Hz, 60 μs. GPi, 1.5–3.5 V, 130 Hz, 60 μs	Mean reductions during blinded stimulation periods: GPi, 78% (global YGTSS); CM-Pf, 45% (global YGTSS). CM-Pf + GPi, 60% (global YGTSS)	Transient cheiro-oral or arm paresthesias (few minutes) or lethargy (3–4 d); nausea (2), vertigo (2), anxiety (1), decreased libido (1)	Implanted with both thalamic and GPi leads. Prospective, randomized, crossover trial using double-blind assessments comparing thalamic and GPi stimulation. Best improvement seen with GPi stimulation. Two of 3 were able to reintegrate socially
Flaherty et al, 2005	1 M (27)	18	ALIC	4.1 V, 185 Hz, 210 μs	20% (global YGTSS), 17% (tic YGTSS), 25% (impairment YGTSS)	Hypomania when dorsal in body of capsule vs apathy/depression in NA	—
Diederich et al, 2005	1 M (27)	14	pvlGPi	2 V, 185 Hz, 120–150 μs	47% (global YGTSS); 44% (tic YGTSS)	Small ICH in right pallidum; bradykinesia of left hand	—
						Transient fatigue for a few months
Ackermans et al, 2006 Ackermans et al, 2007	2 M (27, 45)	12	CM-Pf, Voi (1); pvlGPi (1)	CM-Pf, 6.4 V, 130 Hz, 120 μs; GPi, 3.1 V, 170 Hz, 210 μs	CM-Pf, 85% reduction in number of tics/min; GPi, 93% reduction in number of tics/min	Small ICH in midbrain; vertical gaze palsy	—
						Decreased energy, decreased libido (1); vertical gaze palsy (1)
Shahed et al, 2006	1 M (16)	6	pvlGPi	5 V, 145–160 Hz, 90 μs	76% (global YGTSS), 72% (tics YGTSS)/21% (RVBTS)	—	First adolescent patient; YBOCS improved 69% (mostly obsessions). Neurocognitive testing indicated improvement in verbal reasoning, psychomotor speed, mental flexibility, and visual perception, with poorer memory
Gallagher et al, (2006)	1 M (26)	Several months	pvlGPi	NA	Disappearance of vocal tics, improvement of motor tics	Infection requiring hardware removal (1)	—
Kuhn et al, 2007	1 M (26)	30	NA	7 V, 130 Hz, 90 μs	41% (global YGTSS)/50% (MRVRS)	—	52% decrease in YBOCS
Bajwa et al, 2007	1 M (48)	24	CM-Pf, Voi	2 V, 130 Hz, 90 μs	66% (tic YGTSS)	Occasional oozy feeling	Required numerous programing sessions; YBOCS improved 75%
Maciunas et al, 2007	5 M (18–34)	3	CM-Pf, Voi	3.5–3.6 V, 130–185 Hz, 90–210 μs	44% (global YGTSS), 24% (tic YGTSS)	Acute psychosis	Prospective randomized crossover trial with On-Off stimulation periods; assessments done in double-blind fashion; 3 of 5 patients improved >50% (2 did not have any meaningful improvement)
Dehning et al, 2008 c	1 F (44)	12	pvlGPi	4.2 V, 145 Hz, 210 μs	88% (global YGTSS)	Depressive moods, vertigo, stomach aches	—
Dehning et al, 2011 c	1 M (38), 3 F (25, 28, 44)	5–48	pvlGPi	3.5–4.2 V, 130–145 Hz, 150–210 μs	Responders (2), 76% (global YGTSS). Other 2 patients had minimal response and discontinued stimulation	None	One patient from Dehning et al (2008). Thought that responders had SIB and vocal tics as predominant symptoms and had some response to ECT
Shields et al, 2008	1 F (40)	ALIC, 18; CM-Pf/Voi, 3	ALIC, then CM-Pf, Voi	ALIC, 4.1 V, 185 Hz, 210 μs; CM-Pf/Voi, 7 V, 185 Hz, 90 μs	ALIC (18 mo), 23% (global YGTSS), 21% (tic YGTSS); CM-Pf/Voi, 46% (global YGTSS), 41% (tic YGTSS)	Electrode connector fractures necessitating replacement of leads	Moderate benefit with ALIC stimulation, did not completely suppress tics so thalamic stimulators placed when hardware was revised
						Hypomania when dorsal in body of capsule vs apathy/depression in NA
Zabek et al, 2008	1 M (31)	28	Right NA	3 V, 130 Hz, 210 μs	Reduction of vocal (88%) and motor tics (75%) during on stimulation at 28 mo	—	Unilateral DBS; kept stimulator on, but then evaluated in On-Off conditions separated by 12 h
Servello et al, 2008 d	15 M (18–47), 3 F (20–31)	3–17	CM-Pf, Voi	2.5–4 V, 120–130 Hz, 60–120 μs	65% (global YGTSS), 63% (tic YGTSS)	Wound healing problems requiring plastics repair (1), abdominal hematoma requiring evacuation (1)	9 of the patients underwent an On-Off blinded evaluation (8 of 9 deteriorated during Off state)
						Transient vertigo, blurring of vision (4), abdominal discomfort (2), and upward ocular deviation (1)
Porta et al, 2009 d	12 M, 3 F (17–46)	24	CM-Pf, Voi	—	52% (global YGTSS)	—	31% reduction in YBOCS; improvement of comorbid symptoms of depression, anxiety, and OCD behavior in 14 of 15 subjects
Servello et al, 2009 d	3 M (25, 37, 47), 1 F (31)	10–44	CM-Pf and ALIC/NA (3); ALIC/NA (1)	4–4.5 V, 130–160 Hz, 150–180 μs	Simultaneous CM-Pf and ALIC-NA (n = 1): 83% (global YGTSS), 60% (YBOCS). ALIC-NA alone (n = 1): 68% (global YGTSS), 54% (YBOCS). Rescue ALIC-NA (n = 2), 34% and 27% (global YGTSS) after CM-Pf DBS, failed to improve significantly in YBOCS following ALIC-NA DBS (9% and 21%); 49% and 62% (global YGTSS from baseline) following addition of ALIC-NA DBS	—	Two repeat patients from 2008 study; rescue therapy to help reduce OCD symptoms to improve quality of life that remained poor despite improvement in tics from thalamic DBS
Servello et al, 2010 d	28 M (17–57), 8 F (20–47) (only 30 included in analysis)	3 mo minimum (22 pts >2 y)	CM-Pf, Voi alone (30); unilateral CM-Pf, Voi (1); CM-Pf, Voi + rescue ALIC/NA (3); pvlGPi-ALIC/NA (1); ALIC/NA alone (1)		47% (YGTSS); 52% at 2 y for 19 pts who had long-term follow-up	3.2% needed leads repositioned; 19.3% rate of need for hardware replacement/wound revision because of infection	VAS, BDI, STAI, and YBOCS significantly decreased as well
Porta et al, 2012 d	15 M (17–47), 3 F (20–31)	60–72	CM-Pf, Voi	—	59% (YGTSS)	Wound healing problems and multiple infections (1); abdominal pouch hematoma (1)	Mean reductions of 22.9% (YBOCS), 25.6% (STAI), 27% (BDI). Not all individual patients had reductions in scores
						Blurring vision with >4 V stimulation (2)
Martinez-Torres et al, (2009)	1 M (38)	12	STN	3–3.2 V, 130 Hz, 60 μs	Tic frequency reduced 89% at 6 mo and 97% at 1 y	—	Patient with Parkinson disease with concomitant untreated tics
Neuner et al, 2009	1 M (38)	36	NA	6 V, 145 Hz, 90 μs	44% (global YGTSS); 58% (MRVRS); 56% (YBOCS)	—	—
Dueck et al, 2009	1 M (16)	12	Ventral GPi	4 V, 130 Hz, 120 μs	No significant improvement (modified YGTSS)	Visual disturbances with ventral lead, nausea/dizziness when voltage increased	Negative report; comorbid mental retardation
Vernaleken et al, 2009	1 M (22)	6	DM thalamus	4.4 V, 130 Hz, 180 μs	36% (global YGTSS), 33% (tic YGTSS)	—	Failed GPi DBS before thalamic DBS. Postoperative PET shows decreased thalamic dopamine release with stimulation
Idris et al, 2010	1 M (24)	2	CM-Pf, Voi	3.5 V, 130 Hz, 120 ms	Improved	Bilateral ICH	Factor XIIIa deficiency, suggesting that patients with TS may be prone to factor XIIIa deficiency
Burdick et al, 2010	1 M (33)	30	ALIC/NA	6.5 V, 135 Hz, 90 μs	No improvement objectively (subjective improvement stated by patient)	—	Negative report
Kaido et al, 2011	1 M (20), 2 F (19, 21)	12	CM-Pf, Voi	2.1–3.2 V, 180–210 Hz, 80–130 μs	39% (global YGTSS), 35% (tic YGTSS)	Some visual disturbances with high voltage	Denied any YBOCS or wechsler adult intelligence scale changes. Cognition mildly improved
Lee et al, 2011	1 M (31)	18	CM-Pf, Voi	3.5 V, 180 Hz, 180 ms	58% (global YGTSS)/39% (MRVRS)	—	Some improvement in neuropsychiatric testing caused by tic control
Ackermans et al, 2011	6 M (35–48)	12	CM-Pf, Voi	1–7.3 V, 70–130 Hz, 60–210 μs	On-Off stimulation period: YGTSS score was 37% lower at end of On period compared with Off assessed at 1 y. Unblinded assessment: 49% (YGTSS)/35% (RVBRS)	ICH (1), infection of generator (1)	Double-blind, randomized, crossover trial; after crossover period, 1 patient opted for intermittent stimulation. Secondary measures: no group differences in YBOCS, CAARS, BAI, BDI, SIB; but 1 pt had worse OCD and better depression and ADHD, but overall showed improvement at 1 year. Some mild decrease in Stroop task performance
						Subjective gaze disturbances, reduction of energy level
Duits et al, 2012	1 F (20)	36	CM-Pf, Voi	5 mV, 110 Hz, 60 μs	Off period, 71% (motor YGTSS); On period, 7% (motor YGTSS)	Disturbances in consciousness, mutism, and inability to tolerate food with refusal of intravenous hydration/alimentation resulting in death	From the same trial reported in Ackermans et al (2011); however, this patient’s data were not included in that report because of unexplained complications. Paradoxic increase in tics when stimulation was on.
						Hypertonia in extremities with or without stimulation
Martinez-Fernandez et al, 2011	4 M (21–6), 1 F (35)	9–24	amGPi (2) vs pvlGPi (2) (see comment)	2.5–4.2 V, 20–170 Hz, 60–210 μs	All patients: 29% (global YGTSS)/26% (MRVRS). amGPi: 38% (global YGTSS)/54% (MRVRS). pvGPi: 20% (global YGTSS)/37% (MRVRS). One pt first had pvGPi: motor GPi (42% motor, and 60% phonic) and then amGPi (75% motor and 74% phonic tic reduction). Improved YBOCS (26%). 3 pts with preoperative and postoperative GTS-QOL measures showed improvement of 54.5%	Two hardware infections (1)	amGPi (2), pvGPi (2), and pvGPi then amGPi (1). Comparison of amGPi and pvGPi stimulation
						Anxiety, agitation, constant tiredness (1); capsular effects when >2.8 V (1); weight gain with attempted smoking cessation (1)
Cannon et al, 2012	8 M (22–50), 3F (18–34)	4–30	amGPi	3–5 V, 100–160 Hz, 60–120 μs	49.6% (global YGTSS) at 3 mo. Reduction in YBOCS (59%) and HAM-D (74%)	Mechanical breakage necessitating lead repair/replacement (3); infection requiring bilateral lead replacement (1)	Open-label. Improvement in quality-of-life scale and global assessment of functioning as well
						Increased tics (1); anxiety/panic attack increased with changes in stimulation (2)
Savica et al, 2012	2 M (17, 17), 1 F (35)	12	CM-Pf, Voi	2.5–4.1 V, 107–130 Hz, 90–120 μs	70% (global YGTSS); 60% (motor YGTSS)	Light headedness, mild paresthesias	Two pediatric patients
Piedimonte et al, 2012	1 M (47)	6	GPe	3 V, 150 Hz, 300 μs	70.5% (global YGTSS)	—	Some improvement on HAM-A and HAM-D with stimulation
Dong et al, 2012	2 M (22, 41)	12	Ventral GPi (unilateral right)	2.8–3.5 V, 130–160 Hz, 90 μs	55.8% (tic YGTSS)	—	—
Okun et al, 2013	2 M (27, 35), 3 F (32–38)	6	CM region	0.5–4.5 mA, 125 Hz, 80–200 μs	19.4% (global YGTSS)/36% (MRTRS)	Paresthesias, dizziness, and subjective eye movements. Unable to tolerate stimulation requiring patient-controlled Off times (2)	Had assessments at different stimulation periods (continuous stimulation, off stimulation, schedule on stimulation) at 3 mo. No change in YBOCS or QOLAS scale

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