Tourette syndrome (TS) is a chronic neurobehavioral disorder characterized by waxing and waning motor and phonic tics that persist for at least 12 months [1]. It is also a multifactorial neurodevelopmental disorder that affects up to 1 % of children as well as many adults worldwide. The first clear description of this condition, published by Georges Albert Édouard Brutus Gilles de la Tourette in 1885 [2], noted childhood onset of stereotyped, abnormal movements and vocalizations (called tics), heritability, coprolalia (the utterance of obscene or socially offensive words), echolalia (repeating other people’s words), and waxing and waning of symptoms; this description remains accurate and relevant today.

Tics generally occur in episodes and are preceded by premonitory sensations in the majority of patients. As many as 90 % of patients with TS have comorbid psychiatric conditions, such as obsessive compulsive behavior (OCB), attention deficit hyperactivity disorder (ADHD), or exhibit self-injurious behavior (SIB), depression and anxiety [3]; of these, OCB and ADHD are the most common, each occurring in up to 50 % of patients [4].

Once thought to be relatively rare, the prevalence of TS may in fact be as high as 50/10,000 in the general population [5]. The condition is approximately 10-fold more common in children than in adults, with a prevalence of up to 299/10,000 in 13- to 14-year-old children. In addition, TS is approximately 3 times more common in males than females. The onset of tics occurs at a mean age of 5–7 years, and severity appears to peak around age 10 years [5]. Symptoms may improve or even remit over time without treatment, and this tends to occur in the 3rd decade. However, no patient or clinical characteristics predictive of spontaneous resolution have been found [4].

Instruments used to diagnose TS include the Diagnostic and Statistical Manual, 4th edition (DSM-IV) [6], the World Health Organization International Classification of Disease and Related Health Problems, 10th edition (ICD-10) [7] and the Tourette’s Syndrome Classification Study Group (TSCSG) criteria [8]. According to the TSCSG, a diagnosis of definite Tourette’s syndrome requires motor and/or phonic tics to be witnessed by a reliable examiner or to be captured in a video recording [8]. A patient may be considered to have Tourette’s syndrome by history if a family member or close friend witnesses the tics and is able to provide a description to a reliable examiner that is accepted as indicative of TS. A diagnosis of TS is made when multiple motor tics and at least one vocal tic are present (not necessarily concurrently), develop before the age of 18 years, and last for more than 1 year from their onset, although the intensity and frequency of tics may wax and wane during this period. Other potential causes of tics, including direct physiological effects of drugs (such as cocaine), or medical conditions (such as stroke, Huntington disease, or postviral encephalitis), should also be excluded. Moreover, tics can sometimes resemble choreic, myoclonic movements and stereotypies, but the presence of premonitory urges and the ability to temporarily suppress tics can help to distinguish TS from other movement disorders, where ADHD, OCB, SIB, or non-obscene socially inappropriate behaviors are also present.

The natural history of TS is fairly well understood. Tics usually emerge in childhood between the ages of 4 and 6 years and then increase in severity, peaking between the ages of 10 and 12 years. Motor tics generally precede the development of vocal tics, and onset of simple tics often predates that of complex tics. Tics tend to decline in severity during adolescence and, by early adulthood, most individuals experience markedly reduced numbers of tics or are free of tics. Tics that appear during adulthood are often attributable either to reemergence of childhood tics or to other factors, such as drugs, trauma, and stroke or brain infection. Onset of psychiatric conditions, especially ADHD, can precede the development of tics, present concurrently, or emerge after the appearance of tics. These comorbidities sometimes follow a similar clinical course to the tics, but in other cases they differ greatly. Some features of psychiatric conditions, such as mood disorders and SIB, often persist or worsen during adulthood, irrespective of tic severity. Certain factors and events, such as stress, anxiety, and fatigue, can increase the occurrence of tics, whereas others, such as tasks requiring concentration and motor skills, including musical and athletic performances and/or physical exercise, can reduce or even temporarily halt tics. In addition, some individuals can voluntarily delay or suppress their tics for a short time; however, tics often reemerge with increased intensity and/or frequency.

The severity of tics and psychiatric disorders in patients with TS ranges from mild to severe. In some individuals, severe tics (for example, of the neck) can lead to self-inflicted pain, injury, and disability. However, for many patients with TS, the psychiatric comorbid disorders are more problematic than the tics, and can have a profoundly negative effect on quality of life . These individuals often live with various degrees of impairment in their academic and professional development, as well as reduced psychosocial wellbeing. Nonetheless, many individuals with TS lead successful lives, and can be unusually gifted and highly creative.

Anatomical and neurochemical changes that underlie the clinical manifestations of TS are unclear [9]. However, several studies provide evidence that both functional and structural alterations in the basal ganglia and other neuronal systems have a role in the complex symptomatology of the disorder. These changes could lead to alterations in filtering or sensorimotor gating mechanisms, resulting in urges to perform motor and vocal activities that are inappropriate, poorly timed, excessive, and/or very frequent [9].

Neuropathological studies in patients with TS demonstrate a reduction of up to 60 % in the number of fast-spiking γ-aminobutyric acid-releasing (GABAergic) and cholinergic interneurons in the caudate nucleus and putamen. Such individuals also demonstrate a decreased number of parvalbumin-positive GABAergic neurons in the globus pallidus externa (GPe), whereas the number of these neurons is markedly increased in the globus pallidus interna (GPi). These findings need to be confirmed in future studies, but they raise the possibility that defects in neuronal migration occurring during CNS development lead to altered basal ganglia circuitry and function [10, 11].

Brain imaging studies in patients with TS have produced inconsistent and sometimes conflicting results. Magnetic resonance imaging (MRI) , for example, reveals considerable alterations in the volumes of certain neuroanatomical structures, including a notable reduction in the volume of the caudate nucleus and an increase in the volume of the hippocampus, amygdala, and thalamus. Similar studies have also reported thinning of sensory and motor cortical areas in individuals with this disorder. Functional MRI studies of patients with TS who were performing tasks to control their tics demonstrated alterations in the activity of various cortical, limbic, and basal ganglia areas. These observations might reflect either how the brain is affected by TS or how it seeks to compensate for the illness.

Overall, patients with TS seem to exhibit hypoactivity in the basal ganglia and hyperactivity in motor and/or premotor areas, consistent with the structural neuroimaging findings. Exactly how the above-mentioned neuroanatomical changes are related to TS is not clear, although an increasing body of evidence suggests that alterations in basal ganglia function, specifically within the corticostriatal–thalamocortical circuitry and perhaps also the dopaminergic nigrostriatal pathway, play a role in the pathophysiology of this disorder. Ablation or electrical stimulation of the globus pallidus internal segment or thalamic nuclei has been reported to reduce the severity of tics. Similarly, dopamine D₂ receptor antagonists, such as haloperidol and pimozide, and dopamine-depleting agents, such as tetrabenazine, are effective in alleviating the motor symptoms of TS. By contrast, drugs that increase dopamine levels and/or activity in the brain, such as levodopa, also increase the frequency of tics. Notably, other neuronal pathways, including noradrenergic, serotoninergic, histaminergic, glutaminergic, GABAergic, and cholinergic systems, have been implicated in TS, perhaps because drugs that target these systems can improve some symptoms of the disorder.

The early attempts to treat individuals with TS are considered, by today’s standards, bizarre, inventive, and largely ineffective. These approaches included application of leeches to the skin, cooling of the body, static electricity, hydrotherapy, spinal elongation, and the use of various chemical agents, such as herbs. To date, no cure exists for TS, but several rational approaches are now available for management of the disorder, although they are not universally effective. Importantly, the complex presentation of motor dysfunction, psychiatric features, and psychosocial impairments in individuals with TS clearly require a multifactorial approach to management of the disorder.

After a diagnosis is obtained, educating the patient, their parents, and other interested parties (for example, a child’s teachers) about TS can help to define appropriate expectations for these individuals, as well as to optimize the patient’s treatment strategy. Indeed, for most children with TS, addressing the many popular misconceptions about the disorder among their peers often leads to informed and improved relationships and can substantially reduce the burdens associated with this condition. Medication is not necessary for many individuals with TS, especially those with only mild tics. However, for those with moderate to severe tics or psychiatric comorbidities , which are often more problematic than the tics, several pharmacological agents are available, although such treatments frequently produce ineffective results, whereby the risks associated with treatments outweigh the benefits. Some patients with TS find that professional counseling, guidance, and psychotherapy sessions are invaluable, whereas others, such as children with learning impairments, might benefit from access to specialist educational and disability services. Behavioral and surgical approaches to TS are also currently being investigated and are expected to become accessible treatment options in the future for some people with this disorder. Treatment for TS is, therefore, highly personalized, and optimization requires effort from both the care provider and the patient.

During the 1960s and 1970s, researchers showed that the dopamine D₂ receptor blocker haloperidol could reduce tic severity in patients with TS. These findings led to the investigation of many other potential drug treatments for the disorder. Notably, none had been specifically developed to treat TS; instead, these agents were all in use for other indications, both neurological (such as schizophrenia) and non-neurological (such as hypertension), before they were found to be effective in the treatment of TS. Haloperidol and pimozide are currently the only FDA-approved medications for this syndrome. These two drugs and other medications can be used to reduce tic severity, as well as some of the psychiatric comorbidities associated with TS.

Physicians typically follow a sequential approach to treating tics in people with TS. α-Adrenergic agonists, such as guanfacine and clonidine, are the usual first-line treatment. These two drugs are recommended for individuals with mild tics, since these medications are associated with fewer adverse effects than are other classes of drugs. Second-line treatment (used owing to lack of efficacy of α-adrenergic agonists) consists of antipsychotic agents, which are the most effective drugs for treating TS. However, these agents are associated with serious adverse effects. Antipsychotic drugs are classified as either typical or atypical; the typical agents are dopamine D₂ receptor antagonists (such as haloperidol, pimozide and fluphenazine), whereas the atypical antipsychotic drugs are dopaminergic and serotonergic receptor antagonists (such as risperidone and aripiprazole). Atypical antipsychotic drugs are preferred over typical ones as the atypical agents carry a lower risk of extrapyramidal and other adverse effects (such as tardive dyskinesias). In addition, atypical antipsychotic drugs improve behavioral comorbidities, as well as tics, in patients with TS.

Other medications beneficial for treating TS include benzodiazepines, such as clonazepam, topiramate, and injections of botulinum toxin into the muscle groups associated with bothersome or disabling tics (for example, those of the eyelids, neck, or larynx). Some case reports suggest that tetrabenazine, a dopamine -depleting agent, can reduce tic severity in patients with TS, but double-blind studies are required to define its efficacy [3, 5, 12].

As previously mentioned, psychiatric comorbidities often pose a greater problem than tics for people with TS. The stimulant drug methylphenidate, the α-adrenergic agonists guanfacine and clonidine, and the selective norepinephrine reuptake blocker atomoxetine, can improve ADHD in patients with TS. Initial concerns that stimulant drugs could worsen tics and other features of TS have been refuted by the results of further studies. Cognitive behavioral therapy, selective serotonin reuptake inhibitors such as fluoxetine, and both typical and atypical antipsychotic drugs have all been used to treat OCB in patients with TS.

Behavioral therapies for patients with TS aim to teach the individual how to modify the environmental factors that influence their tic severity, as well as offer skills that can be used by the individual to optimize their management of the symptoms of the disorder. The therapeutic potential of these approaches, such as habit reversal training and exposure with response prevention, has long been known, but these approaches have not been investigated as extensively as pharmacological interventions for TS. In recent years, however, major advances have been made in behavioral therapies for TS. A randomized controlled trial in children and adolescents with TS or chronic tic disorders showed that comprehensive behavioral intervention for tics (CBIT), an enhancement of the widely used habit reversal training method for treating behavioral disorders, significantly reduced tic severity in almost 50 % of patients. CBIT is a promising therapy that should be further developed and tested in future studies, and will probably become accessible to many people with TS.

Although it is frequently self-limited, some patients remain symptomatic and require chronic treatment. The standard treatment is pharmacologic involving mainly neuroleptics, 2-adrenergic agonists, and sometimes benzodiazepines. In some cases, behavioral treatment may provide temporary control of symptoms but certain patients prove medically untreatable or experience unbearable side effects from the medication. It is these patients who are potential candidates for neurosurgical interventions. During the past few decades, many ablative procedures have been performed in an attempt to treat intractable TS. In total, 65 patients underwent ablative surgery varying from “tailored” stereotactic operations to more rigorous prefrontal lobotomies, which were lobotomy, limbic leucotomy , leucotomy, cingulotomy , campotomy, thalamotomy , dentatotomy, coagulation, ablative surgery, and stereotactic surgery .

In 1962, Baker [13] described TS as an “involuntary paroxysmal hyperkinesis involving the entire skeletal musculature” and reported the first leucotomy for TS. The procedure was complicated by a frontal lobe abscess, which was aspirated. In the same year, Cooper [14] published the case of a 16-year-old girl, and a right chemothalamectomy was performed, followed by a left chemothalamectomy 1 year later. Cooper reported that after the surgery, the patient experienced substantial tic reduction and was fully functional. Two years later, Stevens [15] published long-term follow-up results of a 37-year-old man who had undergone the first prefrontal lobotomy, carried out by James Watts in 1955. In 1970, Hassler and Dieckmann [16] reported the results of bilateral thalamotomies in 3 patients with intractable TS. They performed more than 10 coagulations of the intralaminar and medial thalamic nuclei, and, in case of facial tics, in the ventro-oralis internus (Voi). Only the effects with respect to tics were reported, which improved after surgery by 100 % in Patient 1, 90 % in Patient 2, and 70 % in Patient 3. No details regarding the tic-rating method were provided. Nadvornik and associates [17] described a case of stereotactic dentatotomy and bilateral frontal leucotomy. Beckers [18] published the outcome of neurosurgical treatment in 3 TS patients. Two stereotactic operations (target unclear) were performed on Patient 1 (female) with a interval of 1 year between surgeries. Patient 2 (male) underwent a bilateral campotomy and prefrontal leucotomy in two surgical sessions. A bilateral leucotomy was performed on the third patient (female). The author observed that these stereotactic interventions resulted in partial tic reduction. Nevertheless, surgery was not advocated as a good treatment option for intractable TS because of the side effects, which were not specified. In 1978, Wassmann and associates [19] briefly mentioned a female patient who had undergone a prefrontal lobotomy but they did not provide any information regarding the outcome. Asam and colleagues [20] provided a brief (and incomplete) review of the literature on surgical interventions for TS and reported their experience with two TS patients. The patients were male, 14 and 15 years old, with a disease duration of 5 and 11 years, respectively. Their first patient underwent stereotactic surgery (target unclear) with temporary relief of tics. Postoperatively, this patient developed a spastic hemiplegia. Coagulation of the left zona incerta (ZI) was performed in the second patient, who also experienced a postoperative hemiplegia. The same patient was operated on 15 months later, for unclear reasons, in the contralateral ZI. Postoperatively, this patient developed hemiplegia of the left side and became quadriplegic. According to the authors, temporary relief of symptoms was achieved in this patient. Later, tics reoccurred in combination with complex dystonic movements. They concluded that surgical intervention in TS may produce temporary improvement of tics but that surgery can be accompanied by severe side effects. In 1982, Hassler [21] updated the material on stereotaxic surgery for psychiatric disturbances in Schaltenbrand’s textbook and briefly mentioned his experience with thalamic surgery in 15 patients suffering from intractable TS. No details were provided about the outcome.

In 1987, Cappabianca and coworkers [22] published the long-term results of 3 patients described initially by de Divitiis and associates [23], and of 1 new patient. In addition, they provided a review of (all) operated patients. Their operation was based on stereotactic coordinates proposed by Hassler and Dieckmann. The intralaminar and dorsomedian nuclei of the thalamus were coagulated bilaterally in 1 patient and unilaterally in 3 patients. The authors reported temporary tic improvement in 2 patients lasting a few months, a slight reduction in compulsive symptoms in 1 patient, and almost complete tic regression in the fourth. Follow-up examinations of these patients were several years earlier than one would expect when considering the publication year. Robertson and associates [24] reported on a 19-year-old man with disease onset at the age of 5.5 years, presenting with a variety of verbal and motor tics. The tics were treated successfully with the D₂ receptor antagonist, sulpiride; however, compulsions could not be treated. Stereotactic limbic leucotomy was performed involving bilateral lesions in the lower medial quadrants of the frontal lobes and separate lesions in the anterior cingulum (limbic leucotomy ). Postoperatively, compulsions disappeared within 6 weeks. Side effects consisted of apathy, general intellectual impairment, organizational problems, and difficulties in concentration. After 2 years, the patient was socially independent and free from SIB. Robertson and colleagues concluded that limbic leucotomy should be considered an effective treatment in TS patients with severe self-injurious behavior, but emphasized that long-term effects on tics required further assessment. Again, the authors did not mention the method of tic evaluation, the impact or the time course of side effects, or criteria for the diagnosis of TS. In 1993, Sawle and colleagues reported on the results of bilateral limbic leucotomy in a 45-year-old man suffering from TS. The symptoms consisted of severe SIB, obsessions and compulsions [25], and vocal and motor tics. Long-term trials of pharmacologic and behavioral therapy had failed. During limbic leucotomy , bilateral coagulations were performed on the anterior hypothalamus and cingulate gyrus. In a personal communication to Rauch and coworkers [26], Sawle remarked that the actual targets were those of conventional limbic leucotomy (cingulotomy plus thermocoagulation of the frontothalamic fibers). According to the authors, the surgery had no direct effect on tics whereas the compulsions were reduced. Nineteen months after surgery, however, there were no longer any signs of tics and the patient reported excellent improvement with regard to his obsessions . Leckman and associates [27] in 1993 reported on a 40-year-old man suffering from TS and OCB who underwent surgery. Disease onset was at the age of 3 years with motor tics. Vocal tics appeared later, and checking and cleaning compulsions were present, as was SIB. Symptoms failed to respond to medication trials. The patient underwent bilateral stereotactic infrathalamic lesioning and anterior cingulotomy . Postoperatively, the obsessions and compulsions improved, but the patient continued to experience severe motor and vocal tics. Three weeks later, the left infrathalamic and cingulated lesions were repeated. During this second surgical session, the infrathalamic lesion was extended more inferiorly within the borders of the red nucleus and a subsequent coagulation was performed in the H fields of Forel. The patient experienced severe neurological deficits postoperatively including dysarthria, dysphagia, handwriting and gait problems, mild hemiparesis, abnormal extraocular movements, axial rigidity, and bradykinesia. The authors suggested that these side effects were due to extension of the infrathalamic lesion. Long-term, tics and OCB returned. The authors concluded that brain lesioning not only influences pathological symptoms, but also damages physiological functioning.

One year later, Baer and coworkers [28] reported on the effects of cingulotomy in a patient with TS and OCB. The patient was a 35-year-old man with OCB and associated TS with onset at age 5 years. He failed to respond to either behavioral therapy or medication. The patient underwent two cingulotomies with an interval of 18 months between procedures. After the first and second operation, there was no clear effect on his tics. This procedure, however, resulted in an improvement in OCB. The authors concluded that cingulotomy alone was not an effective treatment for TS. In 1995, Rauch and colleagues [28] published a comprehensive review of neurosurgical treatments for TS. They provided detailed information regarding the different neurosurgical approaches by summarizing the available literature. In their report, emphasis was placed on the rationale for the different targets. Mention was made, however, regarding 3 patients who underwent bilateral anterior cingulotomies and infrathalamic lesioning, which had not been published previously. The first patient was a 34-year-old woman with severe TS, OCB, and bipolar disorder. The patient underwent an anterior cingulotomy plus infrathalamic lesioning. Tic counting using videotapes, performed by Rauch and co-workers, revealed a decrease in the number of tics from 18 to 2 tics/min. The second patient was a 40-year-old man suffering from self-injurious motor tics, coprolalia, and OCB. The third patient was not described in detail. The latter 2 patients underwent the same procedure as the first, with a poor outcome. Furthermore, the second patient experienced dysarthria and swallowing, handwriting, and gait problems, postoperatively. Only a moderate improvement in tics and OCB was observed. The third patient experienced no improvement in symptoms at all. In addition, Rauch and associates noted a case published in the Russian literature by Korzenin in 1991. This involved a 19-year-old man with TS and associated OCB who underwent bilateral cryothalamotomy (ventrolateral nuclei) with good results observed at a 1-year follow-up. Several years later, Korzenev and colleagues [29] published results of their surgical treatment of 4 intractable TS patients. They concluded that stereotactic surgery was an effective method of treatment for severe incurable TS. However, in their article no description of the TS patients was provided with respect to patient characteristics, tics, surgical target, or method of evaluation.

Many different lesioning procedures have been performed in TS throughout the history of surgical treatment of this disorder. Frontal lobe operations included prefrontal lobotomies and bimedial frontal leucotomies. The limbic system was targeted during limbic leucotomy and anterior cingulotomy . Thalamic operations included lesioning of the medial, intralaminar, and ventrolateral thalamic nuclei. Infrathalamic lesions were performed at the level of Forel’s fields (campotomies) and the zona incerta, and cerebellar surgeries included dentatotomies. In an attempt to achieve total control of symptoms, more complex operations have been performed, such as combined anterior cingulotomies and infrathalamic lesioning.

Deep brain stimulation (DBS) is a reversible and adjustable neurosurgical technique involving the implantation of stimulating electrodes that send continuous electrical impulses to specific target areas in the brain. Following implantation of the electrodes, the stimulator settings are adjusted at follow-up endpoints to achieve optimal results with minimal adverse effects.

In 1999, the first DBS was performed for intractable TS, with the target for thalamic stimulation based on the thalamotomies described by Hassler [30]. Since then, different targets have been used. While DBS is a well-established treatment option for different neurological disorders, including Parkinson’s disease, dystonia, and tremor, its use in TS is still experimental.

Although DBS has shown potential in the treatment of refractory TS, there are numerous issues still to be resolved: (1) The proper indications for DBS and the definition of ‘refractoriness’ to conventional treatments, (2) the choice of target area on the basis of the clinical picture, (3) the suitability of general anesthesia during DBS, (4) postoperative issues, such as follow-up evaluation techniques, and (5) optimization of pulse generator settings.