14 Deep Brain Stimulation in Tourette Syndrome

14.1 Introduction

Gilles de la Tourette syndrome (TS) is a complex neuropsychiatric and neurodevelopmental disorder whose treatment has been a challenge since Dr. Gilles de la Tourette first described it in 1885.1,2,3,4 Its evolving epidemiology, elusive etiology, and heterogeneous character are driving changes in its diagnosis and treatment. Deep brain stimulation (DBS) is emerging as a promising treatment for patients with severe, refractory TS, and research into its application and safety continues to unfold.

14.2 Epidemiology of Tourette Syndrome

Once considered a rare disorder, TS has now been shown to be prevalent in all cultures5,6,7 with wide range of reported incidence worldwide. Prevalence rates between 0.03 and 5.26%^5,7,8 have been reported in various population prevalence studies, but an international TS prevalence of 1% is safe to assume.^6,8 For the United States, at least, a more reliable estimate is that of The Diagnostic and Statistical Manual of Mental Disorders-5 (DSM-5), which gives prevalence ranges of 3 to 8 per 1,000 school-aged children and 3 per 1,000 in the U.S. population, with the male to female ratio ranging from 2:1 to 4:1, with a lower frequency in the African American and Hispanic populations.⁹ Such wide variations in prevalence reflect the wide differences in study methodologies, diagnostic criteria, and variations in cultural awareness of TS. However, as more studied factors gain in precision, the need for and impact of novel treatments like DBS will be better quantified.

14.3 Characteristics of Tourette Syndrome

The initial description of TS included, among other symptoms, motor tics and vocal tics of varying complexity, intensity, duration, and frequency.2,4 Tics are defined as sudden, rapid, recurrent, stereotyped, and nonrhythmic motor movements or vocalizations of varying intensity, frequency, and duration.⁹ The criteria for diagnosing TS according to the DSM-5 is that an individual should have multiple motor and one or more vocal tics not due to a substance or a medical condition, starting before age of 18 years, and lasting for at least 1 year.⁹ The presence of both motor and vocal tics is important in distinguishing TS from other tic disorders that are characterized by either motor or vocal tics. There are other diagnostic criteria for TS, as in the ICD-10 Classification of Mental and Behavioral Disorders, and the Chinese Classification of Mental Disorders-3 (CCMD-3), both of which are comparable to the DSM-5, although there’s a higher prevalence of TS with CCMD-3.^10,11

Tics usually begin between the ages of 4 and 6 years, peak in frequency around 10 years, and decrease during the adolescent and adult years. Most individuals never achieve complete remission.⁷ According to DSM-5 description, tics may be either simple or complex, with a waxing and waning frequency.⁹ Simple motor tics include eye blinking, shoulder shrugging, extremity extension, or head turning.⁹ Simple vocal tics range from throat clearing to grunting or sniffing. Complex tics involve a combination of motor and/or vocal tics and include copropraxia (an obscene or sexual movement), echopraxia (an imitation of someone’s movements), palilalia (repetition of sounds), echolalia (repeating the last heard word or phrase), or coprolalia (an obscene, ethnic, religious, or socially unacceptable utterance).⁹ Coprolalia is an uncommon vocal tic with 10 to 15% prevalence in TS patients and usually occurs at a later age.⁵ Among other features of tics are their suppressibility— individuals can voluntarily suppress a tic, although the tic usually rebounds with a greater intensity. Tics are also characterized by premonitory urges that are somatic sensations preceding the tic and can be suppressed. Because many tics occur in response to pathological urges where some degree of suppressibility is possible, the term “unvoluntary” has been applied to emphasize their location on a spectrum between voluntary and involuntary behavior.¹²

14.3.1 Comorbidities

The diagnostic challenge and complexity of TS lies not only in the varied character of tics that can present in a patient, but also in the various psychiatric, mood, and personality disorders that are usually comorbid with the tics. The most common are DSM-5 autism spectrum disorder (ASD), obsessive-compulsive disorder (OCD) or behavior (OCB), attention deficit hyperactive disorder (ADHD), oppositional defiant disorder (ODD), conduct disorder (CD), anxiety and depression. Migraines are also common in TS patients and are reported to occur in 25% cases.13,14 Comorbid self-injurious behaviors (SIB), although rare, can be life-threatening and warrant intervention.^15,16 In one cross-sectional study,¹⁷ diagnostic interviews of TS participants and their family members were conducted to find out the lifetime prevalence, heritability, ages of maximal risk, age at onset, and associations with symptom severity of comorbid disorders with TS. It was found that 85.7% of TS patients have one or more comorbid psychiatric disorder, with 57.7% patients having at least two.¹⁷ A majority of their study population (72.1%) met the criteria for OCD or ADHD, and other mood disorders such as anxiety and disruptive behavior, each can be diagnosed in 30% of their interviewees.¹⁷ The greatest risk for onset of these comorbidities was between 4 and 10 years, with ADHD and disruptive behaviors preceding tic onset and OCD, and anxiety beginning within a year before or after tic onset.¹⁷ Furthermore, it was found, through genetic factors, that OCD further predisposes TS individuals to mood disorders and ADHD to disruptive behaviors. OCD was more common in females, adults and adolescents, and ADHD was more prevalent in males and children.¹⁷ However, the study did not specifically isolate the prevalence of SIB which is one of the comorbidities that has a significant impact in selecting TS patients for DBS.^17,18,19

14.3.2 Tic Measurement Scales

Various measurement and screening tools have been developed to aid in the diagnosis and management of TS and other tic disorders. One of the most widely used scale is the Yale Global Tic Severity Scale (YGTSS), which is a 15- to 20-minute clinician-rated scale covering multiple aspects of the patient’s tics, including number, frequency, intensity, complexity, interference, and overall impairment.2,20 The advantage of the YGTSS lies in its internal consistency, interrater reliability, and convergent and divergent validity.²⁰ In addition, the total tic severity subscore of the YGTSS can identify clinically significant changes of tics,²⁰ which is useful in evaluating responses to treatment in the clinical or research setting. However, the training requirement and the length of time to administer YGTSS can limit its use, especially in a fast-paced outpatient setting. Other measurement scales such as the Premonitory Urges for Tics Scale (PUTS) and the Rush Video-Based Tic Rating Scale (RVBTRS) are different in the dimensions they address and the methodology of tic evaluation, respectively, and are recommended as complements to the YGTSS.²¹ The PUTS is the only scale that evaluates premonitory urges that are a defining characteristic of tics.²⁰ An important drawback of this scale is that its metric has a low yield in patients less than 10 years of age.²⁰ Similar to the YGTSS, the RVBTRS assesses tics along a list of dimensions, albeit a less exhaustive list.²⁰ It is, however, the only validated scale that uses video recordings to allow clinicians to get an objective measure of tics and also measure the ability of the patient to actively inhibit tics.²⁰ Specific scales, such as Tourette Disorder Scale, Motor tic, Obsessions and compulsions, Vocal tic Evaluation Survey (MOVES), and Autism-Tics, AD/HD and Other Comorbidities Inventory (A-TAC) are also available to assess for tics and their comorbid conditions.

14.4 Pathophysiology of Tourette Syndrome

The etiology of TS is still unknown, but several studies have suggested a strong genetic influence.22,23 Twins studies have reported concordance as high as 86% in monozygotic twins, and family studies have shown that first-degree relatives of TS individuals are at greater risk of developing TS.^2,24 Further, genetic studies of TS argue for a multigenetic etiology, which might explain the co-occurrence of some psychiatric disorders with tics. Genome-wide association studies (GWAS) have identified several genes that might be related to TS, but only one gene on chromosome 2p, NRXN1 (Neurexin 1) has reached genome-wide significance.^25,26 Many of the genes that have been implicated in TS are connected to neurotransmitters like dopamine and serotonin which have been shown to play key roles in various movement disorders.^21,23,25 For example, dopamine receptor D2 (DRD2), monoamine oxidase-A (MAO-A), and dopamine transporter-1 (DAT1) have all been suspects that are supported clinically by the efficacy of dopamine antagonists in suppressing tics.^24,25,27

Surgery to manage TS symptoms lies in the theory that disruptions in the cortico-striato-thalamo-cortical network (CSTC) underlie the pathophysiology of TS.^2,27 The CSTC pathway includes circuits connecting the frontal cortex with deep sub-cortical structures such as the thalamus and the basal ganglia (BG), where parallel circuits are segregated based on cortical regions and functions. Notably, the BG is a crucial modulatory station for the CSTC loop circuitry, disinhibiting and inhibiting thalamus via the direct (striatum → GPi and SNr → thalamus) and indirect (STN → GPi and SNr → thalamus) pathway, respectively ( Fig. 14.1).^2,27 The striatum is thought to participate in the formation of complex preservative behaviors and facial movements, and stereotyped behaviors that are characteristics of TS and OCD.²⁷ Neuropathological and neuroanatomical evidence suggest that TS is the result of an aberrant focus of striatal neurons inhibiting globus pallidus pars interna (GPi) and substantia nigra pars reticulata (SNr) neurons, resulting in disinhibition of competing motor patterns and execution of adventitious behaviors (tics) ( Fig. 14.1).²⁷

14.5 Treatment for Tourette Syndrome

As the frequency of tics waxes and wanes, some individuals with TS can tolerate their tics with moderate discomfort. However, for those in whom tics become a psychosocial impairment, create functional problems, or cause physical discomfort, treatment is indicated.24,28 In many instances, the treatment approach also has to be targeted at comorbidities that are often more debilitating than the tics and may confound treatment results.^24,29,30 Behavioral modification methods and pharmacological treatment are first line and can be used exclusively or in combination.^24,28

Fig. 14.1 The basal ganglia in a (a) normal patient versus (b) TS patient. In the normal circuitry, striatal inhibition of the globus pallidus interna (GPi) and substantia nigra pars reticulata (SNr) is less and subthalamic nucleus predominantly excites inhibitory GPi and SNr neurons, which inhibits thalamocortical targets and prevents involuntary movements (i.e., a tic). However, in the TS circuitry, an aberrant focus of striatal inhibitory neurons causes striatal inhibition of the GPi to predominate causing disinhibition of the thalamocortical target, allowing involuntary movements (tics) to occur. (Used with permission from Albin RL, Mink JW. Recent advances in Tourette syndrome research. Trends in Neurosciences. Elsevier; 2006.)

Behavioral modification methods include various refinements of cognitive behavioral therapy (CBT), which have been shown to be effective for tic reduction, with and without medication.24 Examples of CBT include contingency management, relaxation training, habit reversal training (HRT), and comprehensive behavioral interventions (CBIT). Contingency management aims to control tics through the contingencies surrounding the tics (praise, rewords, and punishment).²⁴ Relaxation training reduces factors that exacerbate tics, such as stress and anxiety, and has been shown to be effective, although its effects are short-lived.²⁴ CBIT combines various aspects of other behavioral methods with the primary component being HRT. There have also been reports of possible benefits with acupuncture and alternative dieting therapies.²⁴

The pharmacological management of TS involves several medications that alter neurotransmitters such as dopamine, norepinephrine, serotonin, and gamma-aminobutyric acid (GABA). These medications allow 30 to 65% improvement in tics, although the evidence for their effectiveness has been minimal to fair.^24,28 It must be noted that prior to starting any pharmacological treatment, it is important to identify the primary driver of disability as comorbid conditions such as OCD or ADHD respond well to specific medications.

A two-tiered approach to medication selection is recommended.²⁴ The first-tier medications are usually for mild TS symptoms and include the non-neuroleptics, like clonidine, guanfacine, topiramate, baclofen, and the benzodiazepines ( Table 14.1).²⁴ These drugs act primarily by decreasing noradrenergic or GABAergic neurotransmission. Their tic suppression effect is less than the neuroleptics, but these drugs are especially useful in TS patients with concomitant ADHD (clonidine, guanfacine) or anxiety (benzodiazepines).^24,28,29 Sedation is a common side effect with clonidine, guanfacine, and the benzodiazepines.²⁹ Blood pressure variability is especially a concern with clonidine and guanfacine may cause mania in patients with a high risk for bipolar disorder.²⁹

Tier 2 medications are the typical neuroleptics such as haloperidol and pimozide and the atypical neuroleptics such as risperidone and olanzapine. These medications are classic D2 antagonists that decrease dopaminergic input to the BG. They have been shown to be 70 to 80% successful in suppressing tics.²⁴ However, it must be noted that tier 2 medications are usually used only after failure of tier 1 medications or for severe tics. The typical neuroleptics, especially haloperidol, have been shown to be very effective at suppressing severe tics, however, their side effects, including sedation, weight gain, metabolic derangements, and extrapyramidal symptoms like parkinsonism and tardive dyskinesia, limit their use.^24,28,29 Consequently, the atypical neuroleptics are supplanting the typical neuroleptics for treatment of severe tics, and some of these like risperidone have been shown to be equally effective.^31,32 Unlike typical neuroleptics, such as haloperidol, with a predominantly D2 antagonistic activity, the atypical neuroleptics, such as risperidone, are antagonists at D2, 5-HT2-A, and 5-HT2-C receptors.²⁸ However, metabolic derangements, especially weight gain, are a major concern and patients should have regular liver function tests, lipids, prolactin, and glucose labs while on atypical neuroleptics.^28,29

Table 14.1 Treatment approaches for Tourette Syndrome

Abbreviations: CBIT, comprehensive behavioral intervention for tics; DBS, deep brain stimulation; HRT, habit reversal training; TMS, transcranial magnetic stimulation.
Source: Adapted from Singer24.

More recently, valbenazine vesicular monoamine transporter-2 (VMAT2) inhibitor has been considered in clinical trials and has shown promising results with significant improvement in symptoms as measured by the Clinical Global Impression scale.³³ However clinical trials for other VMAT2 inhibitors such as tetrabenazine and deutetrabenazine, have not been convincing.^34,35 Other trial data for therapies like cannabinoids for TS, specifically delta 9-tetrahydrocannabinol (Δ-9-THC), remain inconclusive with positive, yet small improvements in tic frequency and severity.^36,37,38

Most TS patients have tics that are benign and do not cause any functional impairment;¹⁶ however, about 5% of TS patients develop malignant TS, which is defined in one study as requiring two or more emergency room visits, or one or more hospitalizations due to TS symptoms or its comorbidities.^15,16 In some cases, TS individuals can have violent motor tics that result in severe neurological injuries like cervical myelopathy, stroke, spinal cord injury (especially with violent head jerking), and arterial dissection.^3,16 For these patients, neurosurgery may be a strong consideration. ( Table 14.1)

14.5.1 History of Lesioning

Neurosurgery to treat TS started with various ablative interventions at locations ranging from the frontal lobe to various sub-cortical structures to the cerebellum.39,40 Many of these surgeries were reported to decrease tic frequency with minimal side effects, but some were ineffective, lacked accurate tic measurement scales and follow-up, and resulted in major complications such as quadriplegia.³⁹ Hassler and Dieckmann’s thalamotomies, performed in the 1970s, were notable for their location, i.e., the intralaminar and medial thalamic nuclei, and ventro-oralis internus (Voi).^1,39 They reported 70 to 100% tic reduction when these sites were lesioned in each of the three patients.³⁹ Later thalamic DBS studies would report electrode placement at the centromedian nucleus–substantia periventricularis–Voi (CM–Spv–Voi) complex, stimulation of which would encompass the nuclei lesioned by Hassler and Dieckmann.³⁹

14.5.2 Deep Brain Stimulation for Tourette Syndrome

The transition from lesioning to DBS began with Vandewalle’s 1999 report in which they performed high-frequency DBS on a 42-year-old man with intractable TS, placing the electrodes at the CM–Spv–Voi complex to target the thalamic nuclei lesioned by Hassler.39,41 They followed this case with two more similar ones and reported 70 to 90% tic reduction in all three patients.^39,41,42 Vandewalle and colleagues chose DBS because of its safety, reversibility, and adjustability, and since then the number of DBS cases and targets have been steadily rising.^39,43 In their review of DBS for TS, Schrock et al identified at least seven different targets among the 120 cases reported, including: thalamus, GPi (postrema and anteromedial), GPe, the ventral anterior internal capsule, nucleus accumbens, and the substantia nigra.19 Among these, the CM–Spv–Voi complex of the thalamus and the GPi are the most frequently targeted.

A 2016 systematic review and meta-analysis of DBS showed a significant symptom reduction in 80% of patients with an absolute YGTSS score reduction of 43.5 points.⁴⁴ Furthermore, their analysis of randomized, double-blinded controlled studies showed that DBS was effective in treating both vocal and motor tics in GTS, with a significantly greater reduction of vocal tics than motor tics.⁴⁴

Thalamus

The thalamus is a major DBS target for TS treatment. Many studies target the motor thalamus, but despite the use of a common nomenclature to report targeted territories, the specific area that was stimulated varies across studies. Two widely used nomenclatures for the human motor thalamus are that of Hassler and Hirai and Jones.⁴⁵ In Hassler’s classification, the motor thalamus is divided into lateral-polar (lateropolaris, Lpo), oral (ventral-oralis anterior, Voa; ventral-oralis posterior, Vop; and ventral-oralis intermediate, Voi), intermediate (ventrointermedius, Vim), and caudal (ventrocaudalis, Vc) segments.⁴⁵ In contrast, Hirai and Jones divided the motor thalamus into ventral anterior (VA), ventral medial (VM), ventral lateral (VL), and ventral posterior (lateral, VPL).⁴⁵ However, there is some level of overlap between the two systems. Hassler’s Lpo, Voa, and Vop correspond to Jones’s VA and VL (anterior) which receive pallidal afferents and project to the premotor cortex. Jones’s VL (posterior) corresponds to Hassler’s Vim and Voi, which receive deep cerebellar afferents and projects to the motor cortex.⁴⁵ The caudal segment of Hassler system corresponds to the posterior segment of Jones, receives medial lemniscus afferents, and sends efferents to the somatosensory cortex ( Fig. 14.2 and Table 14.2).

The intralaminar nuclei (the CM, and the parafasicular nucleus, Pf) and the Spv are also frequently used in DBS for TS. These nuclei form connections that are believed to regulate cortical, limbic, and striatal circuits whose dysfunction is implicated in the pathophysiology of TS.^43,47,48,49 The Spv has connections with the prefrontal cortex, nucleus accumbens, and amygdala, and it participates in awareness of vicerosensory stimuli and response to stress.⁴⁷ The CM–Pf complex is notable for its prevalent connections to the motor and limbic areas of the BG and is implicated in sensorimotor learning.^47,49 Despite their distinct projections, these nuclear regions are essentially similar in their morphology, electrophysiology, and connections to the cerebral cortex, striatum, and specific limbic nuclei.^43,47,49 They contain matrix cells, which are different from the typical thalamic relay cells in their diffuse projections to layer I of the cerebral cortex, and they receive major input from the reticular activating system, which might explain resulting side effects in arousal and energy levels when these nuclei are stimulated.^{19,41,42,47,49}

Studies that report stimulation of only thalamic nuclei demonstrate 19 to 100% improvement on the YGTSS score.¹⁹ For example, DBS of the Vop–Voa–Voi complex in two patients resulted in 75 to 100% improvement of the YGTSS score.¹⁹ However, this is one of the few studies that target the Vop–Voa–Voi complex. Many thalamic DBS studies target the Voi, the midline periventricular nuclei, and the intralaminar CM–Pf complex. In their initial 1993 and 2003 publications, Visser-Vandewalle and colleague reported stimulation of the CM–Spv–Voi complex and achieving almost complete elimination of tics as measured by the RVBTRS.^19,41,42 Side effects from DBS of these targets included reduced energy levels and sexual dysfunction. The first randomized control trial (RCT) targeting the CM–Pf complex in five patients reported a 43.6% mean improvement in tics by the YGTSS.⁵⁰ Two patients, however, had a 4.3 to 260.9% increase in tic exacerbation, and one patient had an adverse effect of acute psychosis.

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