Diagnosis and Prevalence

Tourette syndrome (TS) is a chronic neuropsychiatric disorder with an unknown etiology characterized by motor and vocal tics. The onset of tics occurs most commonly in early childhood around the age of 5–7 years, and the disorder follows a typical waxing and waning pattern over the years ( ). The severity and frequency of tics increase during the prepubescent years and decline most commonly by early adulthood ( ). The majority of TS patients will experience either a stabilization or remission of tics by adulthood ( ). TS is considered an inherited disorder, although the exact genetic abnormality remains unknown. The fact that the beginning of symptoms is present during the course of maturation suggests that it is a developmental disorder ( ). TS is considered a relatively common disorder affecting an estimated 1% of the population and occurring four or five times more commonly in males than in females ( ). Diagnosis is performed during childhood after the documentation of persistent involuntary motor and phonic tics over a period of at least 1 year without a symptom-free period of three consecutive months ( ). Tics in TS are sudden, rapid, repetitive, stereotyped, and preceded by a premonitory urge, which consists of muscle contractions (motor tics) or outbursts of sound by moving air through the mouth, nose, and throat (vocal tics) ( ). The presence of this premonitory sensation enables the individual to suppress tics, a typical characteristic of TS that usually does not occur in other psychiatric disorders ( ). Tics can be classified as simple when they involve an individual muscle or a small group with discrete tonic or clonic contractions, such as eye blinking, coughing, sniffing, throat clearing, grunting, or nose twitching. Complex tics involve the coordination of several muscle groups to produce movements that often appear purposeful, such as gesturing, scratching, head or extremity jerking, jumping, making animal sounds, or uttering short phrases ( ). The vociferation of short phrases or words (echolalia and palilalia) is more characteristic of TS than the more widely known association of uttering obscene words (coprolalia), which occurs only in a very few TS patients ( ). Normally, cognition is not directly affected by TS, but these abilities may be limited in many patients due to a functional social impairment ( ). In addition to the presence of tics, patients with TS are at risk for comorbidities, including attention deficit hyperactivity disorder (ADHD), obsessive–compulsive disorder (OCD), anxiety, depression, and affective disorders ( ). These comorbid disorders make the therapeutic strategy for TS difficult since they add another layer of complexity to the treatment of tics. Pathologic involvement of cortico–striatal–thalamo–cortical (CSTC) pathways is supported by neurophysiological, brain-imaging, and postmortem studies ( ). However, the exact primary site responsible for the pathophysiology remains controversial. Although several neurotransmitters are involved in the signaling of the CSTC circuitry, dopamine is considered a key candidate responsible for the dysfunction ( ). The dysregulation of dopamine is supported by multiple clinical and preclinical studies. For instance, suppression of tics has been observed after the administration of drugs that block dopaminergic D2 receptors, or after the administration of dopamine uptake inhibitors ( ). Furthermore, exacerbation of tics has been observed after withdrawal of neuroleptics or administration of drugs that increase central dopaminergic activity like l -Dopa ( ).

Treatment of Tourette Syndrome

There is currently no cure for tics in TS, but since in most of the mild cases all symptoms will disappear by early adulthood, not all patients will require long-term treatment. Behavioral therapy can be sufficient treatment for the majority of these patients. Since no side-effects are observed with behavioral therapy, it can be implemented simultaneously with other treatments. Pharmacological treatment may be required in moderate to severe cases when symptoms interfere with the social, academic, or professional performance of the individual. The most common group of drugs is the classic dopamine antagonists (D2 receptor antagonists), such as haloperidol or pimozide. Risperidone, clozapine, quetiapine, and other second-generation neuroleptics are also widely used and very effective on tics ( ). The use of a third group may be considered in case of severe side-effects, mainly extrapyramidal symptoms. These drugs include noradrenergic agents like clonidine, and others such as benzodiazepines. In case of comorbidity the use of psychostimulants such as methylphenidate or selective serotonin reuptake inhibitors might be an option for the treatment of ADHD and OCD, respectively ( ). However, these drugs may not be helpful for the treatment of tics.

Historical Perspective

Neurosurgical treatment of the small group of patients with severe TS refractory to behavioral therapy and medication may be considered after careful clinical selection. In the past these patients were treated with neurosurgical ablative procedures ( ). Several different brain regions have been targets for this purpose, including the thalamus, the frontal lobes (e.g., frontal leucotomies and prefrontal lobotomies), the limbic system (e.g., anterior cingulotomy and limbic leucotomy), and the cerebellum. Most of the reports had a nonstandardized selection of patients and the clinical outcome was not objectively quantified. These reports showed variable clinical outcomes, often with unsatisfactory results, and the procedures resulted in a large amount of postsurgical complications and severe adverse effects.

Deep Brain Stimulation

Deep brain stimulation (DBS) was introduced for the first time in the field of neuropsychiatry in 1999, and is used in a number of target areas ( Fig. 77.1 ; Table 77.1 ). Vandewalle et al. reported on the chronic bilateral high-frequency stimulation of the medial part of the thalamus in a patient with intractable TS ( ). The electrode contacts were implanted at the medial part of the thalamus at the crossing point of the centromedian nucleus (CM), the subtantia periventricularis (Spv), and the nucleus ventro–oralis internus (Voi). The rationale for targeting the medial part of the thalamus was based on the beneficial effects obtained through thalamotomies performed in the 1970s by Hassler ( ). This hypothesis was supported by the fact that these nuclei project ipsilaterally into the cortex and contralaterally into the contralateral striatum, and therefore decrease the hyperactivity produced by the thalamus. The CM–Spv–Voi complex is an interesting target option, since the CM projects back into the dorsal or motor striatum, the Spv projects back into the ventral or limbic striatum, and the Voi projects directly into the premotor cortex. Thus the stimulation of this thalamic region could have an impact on both motor and limbic components of the disorder. Since then, several other targets have been tried by many centers with positive results: the globus pallidus internus (GPi) ( ), the globus pallidus externus (GPe) ( ), the internal capsule and nucleus accumbens (IC/Nac) ( ), and the subthalamic nucleus (STN). Furthermore, some variations within these targets have also been reported. Servello et al. reported on the beneficial effects obtained after thalamic DBS at the centromedian nucleus–parafascicular and ventrooralis nuclei (CM–Pf/Vo), 2 mm more anterior to the target described by Vandewalle ( ). In these reports the average tic reduction documented in 31 patients after chronic stimulation was of 47%, with a follow-up of 3 months to 4 years.

Target areas for DBS in Tourette syndrome. Anatomical visualization of target areas that have been used for DBS in TS. View on left hemisphere from frontal right. GPe , external globus pallidus; GPi , internal globus pallidus; NAC , nucleus accumbens; STN , subthalamic nucleus; THAL , thalamus. Segmentation based on adapting MRI atlas by Yelnik and Bardinet, using the Suretune Expert Tuning Tool software package. The help of Maxim Ryzhkov (Medtronic Eindhoven Design Center) is gratefully acknowledged.

In the case of the GPi, the rationale to target this nucleus is based on the differentiation and distance between its motor (posterior) and limbic (anterior) portions. This was based on previous reports from Parkinson’s disease (PD) patients that showed a beneficial effect on hyperkinetic motors symptoms induced by levodopa, such as dyskinesias. Van der Linden et al. described the first case of pallidal stimulation (posteroventral or motor part of the GPi) in one patient ( ). This report showed a tic reduction of 95% after a 6-month follow-up. In Houeto et al. reported on the effects of bilateral anteromedial pallidal stimulation (limbic part of the GPi) in a single patient. After 11 months there was a 65% reduction in tics. This patient was also implanted for bilateral stimulation of the thalamus (CM–Pf), which showed a similar effect to that obtained by GPi stimulation. Interestingly, simultaneous stimulation of both targets showed a decreased effect when compared to any of the targets individually. More recently Kefalopoulou et al. described the effects of bilateral stimulation of the anteromedial part of the GPi in 13 patients ( ). So far, this is the largest double-blind randomized controlled trial performed in TS patients. This analysis showed a tic reduction between 15% (blinded phase, off vs. on stimulation period) and 40% (baseline vs. open-label stimulation phase) after a mean follow-up of 8 and 36 months, respectively.

The choice of the GPe as a target for DBS was based on the hypothesis of the pathophysiological changes that show hyperactivity of this nucleus in Vilela-Filho et al. These authors reported on the beneficial effects of bilateral GPe stimulation in seven patients on a double-blinded prospective study ( ). The authors documented a significant effect, with tic reduction of 74%. Another report from this group showed a tic reduction of 71% by GPe stimulation in one patient after 6 months ( ).

The rationale of targeting the IC/Nac lies in the fact that TS and OCD share many clinical similarities and show a very high rate of comorbidity. This brain region became a potential target after several studies showed the beneficial effects obtained in controlling obsessions and compulsions by Nac DBS after the first report from Nuttin et al. ( ). In Flaherty et al. described the effects of bilateral DBS of the anterior portion of the IC for the first time in a TS patient. The authors reported a reduction in tics of 25% after a follow-up of 18 months. However, the patient suffered from depression and mild apathy after stimulation of the most ventral contacts (Nac), whereas hypomania was documented when the most dorsal contacts were activated (IC). Kuhn et al. reported on the beneficial effects of IC/Nac stimulation in one patient with tics and associated OCD behavior with a follow-up of 30 months ( ). The authors reported a tic reduction of 41% and a decrease in obsessions and compulsions of 64%. Servello et al. published the biggest series of IC/Nac stimulation, with four cases ( ). In these report, three of these patients received a rescue therapy since they had already undergone thalamic stimulation before this procedure. Only one patient received DBS for TS for the first time. After 19–44 months tics were reduced by a maximum of 41%, although one patient showed a reduction of 81% after both thalamus and IC/Nac were simultaneously stimulated.

The rationale to stimulate the STN in TS was based on observations obtained by Martinez-Torres et al. in a PD patient who suffered from tics and benefited from STN DBS ( ).

Although DBS is nowadays an accepted treatment for TS, supported by several reports including over 190 patients worldwide, only five double-blind randomized controlled trials have been performed to date (for a total of 32 patients). The first three of these trials showed a significant average tic reduction of 66% (ranging from 30% to 96%) after 4–60 months of stimulation ( ). The targets included were the CM–Spv–Voi (n = 5 patients), the CM–Pf and anteromedial GPi (n = 3 patients), and the CM–Voi (n = 6 patients). The most recent two trials, including the biggest study to date, showed a modest tic reduction ranging from 5% to 40% after 6–36 months of stimulation ( ). The targets included for these reports were the CM–Voi (n = 5 patients) and the anteromedial GPi (n = 13 patients).

Inclusion Criteria

• 1.
  

  The TS diagnosis should be established by an expert clinician based on the Diagnostic and Statistical Manual of Mental Disorders , 5th edition (DSM-V).

  
  
• 2.
  

  Patients of all ages can be considered for surgery. If the patient is under the age of 18, an ethics committee should deliberate if the candidate can undergo the procedure.

  
  
• 3.
  

  Tics should be chronic, severe, and considered as the main source of disability. The severity of the tics should be documented on the Yale Global Tic Severity Scale (YGTSS) and show a score over 35/50 points.

  
  
• 4.
  

  Symptoms should be refractory to behavioral and pharmacological therapies. At least three different classes of drugs should be applied.

  
  
• 5.
  

  In cases of comorbidity, the psychiatric or neurological condition should be treated and considered as stable for a period of at least 6 months.

  
  
• 6.
  

  The patient should demonstrate the capacity to endure the surgical procedure and the demands of the perioperative care, and to understand the recommended therapies. In addition, the candidate will be required to display a stable psychosocial state.

Exclusion Criteria

• 1.
  

  TS patients cannot be considered as candidates if they present an active suicidal or homicidal ideation in a period of 6 months or less before the procedure.

  
  
• 2.
  

  Persistent depressive episodes and active or recent substance abuse would make a candidate unsuitable for DBS.

  
  
• 3.
  

  Patients are excluded if they show contraindications for surgical treatment for DBS, such as structural brain lesions documented on a magnetic resonance imaging (MRI) scan.

  
  
• 4.
  

  Patients are excluded if they have severe medical conditions that increase the risk of complications and can result in a failed procedure or inappropriate postoperative care of the patient.

  
  
• 5.
  

  Psychogenic tics or the presence of a factitious disorder should be ruled out.

Surgical Procedure and Perioperative Management

DBS for TS can be performed under either general anesthesia or local anesthesia with a combination of sedatives. The decision of which anesthetics to use should be carried out on an individual basis. Intraoperative testing could contribute evidence of undesired stimulation side-effects, so it may be preferable for the patient to be awake during the procedure. If the patient is a good candidate for local anesthesia and sedation, this could be performed with a combination of lormetazepam and clonidine or a propofol-controlled infusion ( ). The technique of the DBS procedure in TS is similar to that used in stereotactic procedures for other classical indications like PD. The imaging used for stereotactic trajectory planning depends on the preference and experience of each center, and can include MRI scans only or images obtained from fused computed tomography (CT) and MRI scans. However, certain targets in TS, like the medial thalamus, are not directly visible on MRI scans. Preoperative CT scans with the use of medium contrast can help avoid blood vessels during the stereotactic planning. Postoperatively, it is crucial to determine the exact location of the electrodes using CT or MRI scans. Clinical outcome should be correlated with the exact position of the active contacts. A meticulous description of the programming and all positive and negative effects should be recorded and properly documented. This can be performed using a record of the patient on video during both on and off stimulation periods. After this, two investigators blinded to the stimulation status can evaluate the video independently. The most common scale for tic rating in TS is the YGTSS.

Stimulation Parameters

DBS parameters reported for the most frequent targets used in TS (medial portion of the thalamus, IC/Nac, and GPi) are within the range of 110–180 Hz ( ). However, in the case of stimulation of the medial portion of the thalamus significant tic reduction has been observed with a frequency as low as 70 Hz ( ). Moreover, this reduced frequency has shown a greater positive effect on the arousal levels reported by TS patients. These findings suggest that the frequency parameters may affect the energy of the patient as an undesired side-effect during thalamic DBS. In regard to the pulse width, the parameters range between 60 and 270 μs ( ). In the case of the amplitude, the voltage can be set at 0.5 or 1 V after implantation and progressively increased until the best clinical effect without side-effects has been obtained. Stimulation parameters with amplitudes between 2 and 5 V have been reported to reduce tics in TS significantly ( ).

Diagnosis and Prevalence

Tourette syndrome (TS) is a chronic neuropsychiatric disorder with an unknown etiology characterized by motor and vocal tics. The onset of tics occurs most commonly in early childhood around the age of 5–7 years, and the disorder follows a typical waxing and waning pattern over the years ( ). The severity and frequency of tics increase during the prepubescent years and decline most commonly by early adulthood ( ). The majority of TS patients will experience either a stabilization or remission of tics by adulthood ( ). TS is considered an inherited disorder, although the exact genetic abnormality remains unknown. The fact that the beginning of symptoms is present during the course of maturation suggests that it is a developmental disorder ( ). TS is considered a relatively common disorder affecting an estimated 1% of the population and occurring four or five times more commonly in males than in females ( ). Diagnosis is performed during childhood after the documentation of persistent involuntary motor and phonic tics over a period of at least 1 year without a symptom-free period of three consecutive months ( ). Tics in TS are sudden, rapid, repetitive, stereotyped, and preceded by a premonitory urge, which consists of muscle contractions (motor tics) or outbursts of sound by moving air through the mouth, nose, and throat (vocal tics) ( ). The presence of this premonitory sensation enables the individual to suppress tics, a typical characteristic of TS that usually does not occur in other psychiatric disorders ( ). Tics can be classified as simple when they involve an individual muscle or a small group with discrete tonic or clonic contractions, such as eye blinking, coughing, sniffing, throat clearing, grunting, or nose twitching. Complex tics involve the coordination of several muscle groups to produce movements that often appear purposeful, such as gesturing, scratching, head or extremity jerking, jumping, making animal sounds, or uttering short phrases ( ). The vociferation of short phrases or words (echolalia and palilalia) is more characteristic of TS than the more widely known association of uttering obscene words (coprolalia), which occurs only in a very few TS patients ( ). Normally, cognition is not directly affected by TS, but these abilities may be limited in many patients due to a functional social impairment ( ). In addition to the presence of tics, patients with TS are at risk for comorbidities, including attention deficit hyperactivity disorder (ADHD), obsessive–compulsive disorder (OCD), anxiety, depression, and affective disorders ( ). These comorbid disorders make the therapeutic strategy for TS difficult since they add another layer of complexity to the treatment of tics. Pathologic involvement of cortico–striatal–thalamo–cortical (CSTC) pathways is supported by neurophysiological, brain-imaging, and postmortem studies ( ). However, the exact primary site responsible for the pathophysiology remains controversial. Although several neurotransmitters are involved in the signaling of the CSTC circuitry, dopamine is considered a key candidate responsible for the dysfunction ( ). The dysregulation of dopamine is supported by multiple clinical and preclinical studies. For instance, suppression of tics has been observed after the administration of drugs that block dopaminergic D2 receptors, or after the administration of dopamine uptake inhibitors ( ). Furthermore, exacerbation of tics has been observed after withdrawal of neuroleptics or administration of drugs that increase central dopaminergic activity like l -Dopa ( ).

Treatment of Tourette Syndrome

There is currently no cure for tics in TS, but since in most of the mild cases all symptoms will disappear by early adulthood, not all patients will require long-term treatment. Behavioral therapy can be sufficient treatment for the majority of these patients. Since no side-effects are observed with behavioral therapy, it can be implemented simultaneously with other treatments. Pharmacological treatment may be required in moderate to severe cases when symptoms interfere with the social, academic, or professional performance of the individual. The most common group of drugs is the classic dopamine antagonists (D2 receptor antagonists), such as haloperidol or pimozide. Risperidone, clozapine, quetiapine, and other second-generation neuroleptics are also widely used and very effective on tics ( ). The use of a third group may be considered in case of severe side-effects, mainly extrapyramidal symptoms. These drugs include noradrenergic agents like clonidine, and others such as benzodiazepines. In case of comorbidity the use of psychostimulants such as methylphenidate or selective serotonin reuptake inhibitors might be an option for the treatment of ADHD and OCD, respectively ( ). However, these drugs may not be helpful for the treatment of tics.

Historical Perspective

Neurosurgical treatment of the small group of patients with severe TS refractory to behavioral therapy and medication may be considered after careful clinical selection. In the past these patients were treated with neurosurgical ablative procedures ( ). Several different brain regions have been targets for this purpose, including the thalamus, the frontal lobes (e.g., frontal leucotomies and prefrontal lobotomies), the limbic system (e.g., anterior cingulotomy and limbic leucotomy), and the cerebellum. Most of the reports had a nonstandardized selection of patients and the clinical outcome was not objectively quantified. These reports showed variable clinical outcomes, often with unsatisfactory results, and the procedures resulted in a large amount of postsurgical complications and severe adverse effects.

Deep Brain Stimulation

Deep brain stimulation (DBS) was introduced for the first time in the field of neuropsychiatry in 1999, and is used in a number of target areas ( Fig. 77.1 ; Table 77.1 ). Vandewalle et al. reported on the chronic bilateral high-frequency stimulation of the medial part of the thalamus in a patient with intractable TS ( ). The electrode contacts were implanted at the medial part of the thalamus at the crossing point of the centromedian nucleus (CM), the subtantia periventricularis (Spv), and the nucleus ventro–oralis internus (Voi). The rationale for targeting the medial part of the thalamus was based on the beneficial effects obtained through thalamotomies performed in the 1970s by Hassler ( ). This hypothesis was supported by the fact that these nuclei project ipsilaterally into the cortex and contralaterally into the contralateral striatum, and therefore decrease the hyperactivity produced by the thalamus. The CM–Spv–Voi complex is an interesting target option, since the CM projects back into the dorsal or motor striatum, the Spv projects back into the ventral or limbic striatum, and the Voi projects directly into the premotor cortex. Thus the stimulation of this thalamic region could have an impact on both motor and limbic components of the disorder. Since then, several other targets have been tried by many centers with positive results: the globus pallidus internus (GPi) ( ), the globus pallidus externus (GPe) ( ), the internal capsule and nucleus accumbens (IC/Nac) ( ), and the subthalamic nucleus (STN). Furthermore, some variations within these targets have also been reported. Servello et al. reported on the beneficial effects obtained after thalamic DBS at the centromedian nucleus–parafascicular and ventrooralis nuclei (CM–Pf/Vo), 2 mm more anterior to the target described by Vandewalle ( ). In these reports the average tic reduction documented in 31 patients after chronic stimulation was of 47%, with a follow-up of 3 months to 4 years.

Target areas for DBS in Tourette syndrome. Anatomical visualization of target areas that have been used for DBS in TS. View on left hemisphere from frontal right. GPe , external globus pallidus; GPi , internal globus pallidus; NAC , nucleus accumbens; STN , subthalamic nucleus; THAL , thalamus. Segmentation based on adapting MRI atlas by Yelnik and Bardinet, using the Suretune Expert Tuning Tool software package. The help of Maxim Ryzhkov (Medtronic Eindhoven Design Center) is gratefully acknowledged.

In the case of the GPi, the rationale to target this nucleus is based on the differentiation and distance between its motor (posterior) and limbic (anterior) portions. This was based on previous reports from Parkinson’s disease (PD) patients that showed a beneficial effect on hyperkinetic motors symptoms induced by levodopa, such as dyskinesias. Van der Linden et al. described the first case of pallidal stimulation (posteroventral or motor part of the GPi) in one patient ( ). This report showed a tic reduction of 95% after a 6-month follow-up. In Houeto et al. reported on the effects of bilateral anteromedial pallidal stimulation (limbic part of the GPi) in a single patient. After 11 months there was a 65% reduction in tics. This patient was also implanted for bilateral stimulation of the thalamus (CM–Pf), which showed a similar effect to that obtained by GPi stimulation. Interestingly, simultaneous stimulation of both targets showed a decreased effect when compared to any of the targets individually. More recently Kefalopoulou et al. described the effects of bilateral stimulation of the anteromedial part of the GPi in 13 patients ( ). So far, this is the largest double-blind randomized controlled trial performed in TS patients. This analysis showed a tic reduction between 15% (blinded phase, off vs. on stimulation period) and 40% (baseline vs. open-label stimulation phase) after a mean follow-up of 8 and 36 months, respectively.

The choice of the GPe as a target for DBS was based on the hypothesis of the pathophysiological changes that show hyperactivity of this nucleus in Vilela-Filho et al. These authors reported on the beneficial effects of bilateral GPe stimulation in seven patients on a double-blinded prospective study ( ). The authors documented a significant effect, with tic reduction of 74%. Another report from this group showed a tic reduction of 71% by GPe stimulation in one patient after 6 months ( ).

The rationale of targeting the IC/Nac lies in the fact that TS and OCD share many clinical similarities and show a very high rate of comorbidity. This brain region became a potential target after several studies showed the beneficial effects obtained in controlling obsessions and compulsions by Nac DBS after the first report from Nuttin et al. ( ). In Flaherty et al. described the effects of bilateral DBS of the anterior portion of the IC for the first time in a TS patient. The authors reported a reduction in tics of 25% after a follow-up of 18 months. However, the patient suffered from depression and mild apathy after stimulation of the most ventral contacts (Nac), whereas hypomania was documented when the most dorsal contacts were activated (IC). Kuhn et al. reported on the beneficial effects of IC/Nac stimulation in one patient with tics and associated OCD behavior with a follow-up of 30 months ( ). The authors reported a tic reduction of 41% and a decrease in obsessions and compulsions of 64%. Servello et al. published the biggest series of IC/Nac stimulation, with four cases ( ). In these report, three of these patients received a rescue therapy since they had already undergone thalamic stimulation before this procedure. Only one patient received DBS for TS for the first time. After 19–44 months tics were reduced by a maximum of 41%, although one patient showed a reduction of 81% after both thalamus and IC/Nac were simultaneously stimulated.

The rationale to stimulate the STN in TS was based on observations obtained by Martinez-Torres et al. in a PD patient who suffered from tics and benefited from STN DBS ( ).

Although DBS is nowadays an accepted treatment for TS, supported by several reports including over 190 patients worldwide, only five double-blind randomized controlled trials have been performed to date (for a total of 32 patients). The first three of these trials showed a significant average tic reduction of 66% (ranging from 30% to 96%) after 4–60 months of stimulation ( ). The targets included were the CM–Spv–Voi (n = 5 patients), the CM–Pf and anteromedial GPi (n = 3 patients), and the CM–Voi (n = 6 patients). The most recent two trials, including the biggest study to date, showed a modest tic reduction ranging from 5% to 40% after 6–36 months of stimulation ( ). The targets included for these reports were the CM–Voi (n = 5 patients) and the anteromedial GPi (n = 13 patients).

Inclusion Criteria

• 1.
  

  The TS diagnosis should be established by an expert clinician based on the Diagnostic and Statistical Manual of Mental Disorders , 5th edition (DSM-V).

  
  
• 2.
  

  Patients of all ages can be considered for surgery. If the patient is under the age of 18, an ethics committee should deliberate if the candidate can undergo the procedure.

  
  
• 3.
  

  Tics should be chronic, severe, and considered as the main source of disability. The severity of the tics should be documented on the Yale Global Tic Severity Scale (YGTSS) and show a score over 35/50 points.

  
  
• 4.
  

  Symptoms should be refractory to behavioral and pharmacological therapies. At least three different classes of drugs should be applied.

  
  
• 5.
  

  In cases of comorbidity, the psychiatric or neurological condition should be treated and considered as stable for a period of at least 6 months.

  
  
• 6.
  

  The patient should demonstrate the capacity to endure the surgical procedure and the demands of the perioperative care, and to understand the recommended therapies. In addition, the candidate will be required to display a stable psychosocial state.

Exclusion Criteria

• 1.
  

  TS patients cannot be considered as candidates if they present an active suicidal or homicidal ideation in a period of 6 months or less before the procedure.

  
  
• 2.
  

  Persistent depressive episodes and active or recent substance abuse would make a candidate unsuitable for DBS.

  
  
• 3.
  

  Patients are excluded if they show contraindications for surgical treatment for DBS, such as structural brain lesions documented on a magnetic resonance imaging (MRI) scan.

  
  
• 4.
  

  Patients are excluded if they have severe medical conditions that increase the risk of complications and can result in a failed procedure or inappropriate postoperative care of the patient.

  
  
• 5.
  

  Psychogenic tics or the presence of a factitious disorder should be ruled out.

Surgical Procedure and Perioperative Management

DBS for TS can be performed under either general anesthesia or local anesthesia with a combination of sedatives. The decision of which anesthetics to use should be carried out on an individual basis. Intraoperative testing could contribute evidence of undesired stimulation side-effects, so it may be preferable for the patient to be awake during the procedure. If the patient is a good candidate for local anesthesia and sedation, this could be performed with a combination of lormetazepam and clonidine or a propofol-controlled infusion ( ). The technique of the DBS procedure in TS is similar to that used in stereotactic procedures for other classical indications like PD. The imaging used for stereotactic trajectory planning depends on the preference and experience of each center, and can include MRI scans only or images obtained from fused computed tomography (CT) and MRI scans. However, certain targets in TS, like the medial thalamus, are not directly visible on MRI scans. Preoperative CT scans with the use of medium contrast can help avoid blood vessels during the stereotactic planning. Postoperatively, it is crucial to determine the exact location of the electrodes using CT or MRI scans. Clinical outcome should be correlated with the exact position of the active contacts. A meticulous description of the programming and all positive and negative effects should be recorded and properly documented. This can be performed using a record of the patient on video during both on and off stimulation periods. After this, two investigators blinded to the stimulation status can evaluate the video independently. The most common scale for tic rating in TS is the YGTSS.

Stimulation Parameters

DBS parameters reported for the most frequent targets used in TS (medial portion of the thalamus, IC/Nac, and GPi) are within the range of 110–180 Hz ( ). However, in the case of stimulation of the medial portion of the thalamus significant tic reduction has been observed with a frequency as low as 70 Hz ( ). Moreover, this reduced frequency has shown a greater positive effect on the arousal levels reported by TS patients. These findings suggest that the frequency parameters may affect the energy of the patient as an undesired side-effect during thalamic DBS. In regard to the pulse width, the parameters range between 60 and 270 μs ( ). In the case of the amplitude, the voltage can be set at 0.5 or 1 V after implantation and progressively increased until the best clinical effect without side-effects has been obtained. Stimulation parameters with amplitudes between 2 and 5 V have been reported to reduce tics in TS significantly ( ).

Diagnosis and Prevalence

Tourette syndrome (TS) is a chronic neuropsychiatric disorder with an unknown etiology characterized by motor and vocal tics. The onset of tics occurs most commonly in early childhood around the age of 5–7 years, and the disorder follows a typical waxing and waning pattern over the years ( ). The severity and frequency of tics increase during the prepubescent years and decline most commonly by early adulthood ( ). The majority of TS patients will experience either a stabilization or remission of tics by adulthood ( ). TS is considered an inherited disorder, although the exact genetic abnormality remains unknown. The fact that the beginning of symptoms is present during the course of maturation suggests that it is a developmental disorder ( ). TS is considered a relatively common disorder affecting an estimated 1% of the population and occurring four or five times more commonly in males than in females ( ). Diagnosis is performed during childhood after the documentation of persistent involuntary motor and phonic tics over a period of at least 1 year without a symptom-free period of three consecutive months ( ). Tics in TS are sudden, rapid, repetitive, stereotyped, and preceded by a premonitory urge, which consists of muscle contractions (motor tics) or outbursts of sound by moving air through the mouth, nose, and throat (vocal tics) ( ). The presence of this premonitory sensation enables the individual to suppress tics, a typical characteristic of TS that usually does not occur in other psychiatric disorders ( ). Tics can be classified as simple when they involve an individual muscle or a small group with discrete tonic or clonic contractions, such as eye blinking, coughing, sniffing, throat clearing, grunting, or nose twitching. Complex tics involve the coordination of several muscle groups to produce movements that often appear purposeful, such as gesturing, scratching, head or extremity jerking, jumping, making animal sounds, or uttering short phrases ( ). The vociferation of short phrases or words (echolalia and palilalia) is more characteristic of TS than the more widely known association of uttering obscene words (coprolalia), which occurs only in a very few TS patients ( ). Normally, cognition is not directly affected by TS, but these abilities may be limited in many patients due to a functional social impairment ( ). In addition to the presence of tics, patients with TS are at risk for comorbidities, including attention deficit hyperactivity disorder (ADHD), obsessive–compulsive disorder (OCD), anxiety, depression, and affective disorders ( ). These comorbid disorders make the therapeutic strategy for TS difficult since they add another layer of complexity to the treatment of tics. Pathologic involvement of cortico–striatal–thalamo–cortical (CSTC) pathways is supported by neurophysiological, brain-imaging, and postmortem studies ( ). However, the exact primary site responsible for the pathophysiology remains controversial. Although several neurotransmitters are involved in the signaling of the CSTC circuitry, dopamine is considered a key candidate responsible for the dysfunction ( ). The dysregulation of dopamine is supported by multiple clinical and preclinical studies. For instance, suppression of tics has been observed after the administration of drugs that block dopaminergic D2 receptors, or after the administration of dopamine uptake inhibitors ( ). Furthermore, exacerbation of tics has been observed after withdrawal of neuroleptics or administration of drugs that increase central dopaminergic activity like l -Dopa ( ).

Treatment of Tourette Syndrome

There is currently no cure for tics in TS, but since in most of the mild cases all symptoms will disappear by early adulthood, not all patients will require long-term treatment. Behavioral therapy can be sufficient treatment for the majority of these patients. Since no side-effects are observed with behavioral therapy, it can be implemented simultaneously with other treatments. Pharmacological treatment may be required in moderate to severe cases when symptoms interfere with the social, academic, or professional performance of the individual. The most common group of drugs is the classic dopamine antagonists (D2 receptor antagonists), such as haloperidol or pimozide. Risperidone, clozapine, quetiapine, and other second-generation neuroleptics are also widely used and very effective on tics ( ). The use of a third group may be considered in case of severe side-effects, mainly extrapyramidal symptoms. These drugs include noradrenergic agents like clonidine, and others such as benzodiazepines. In case of comorbidity the use of psychostimulants such as methylphenidate or selective serotonin reuptake inhibitors might be an option for the treatment of ADHD and OCD, respectively ( ). However, these drugs may not be helpful for the treatment of tics.