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 REVIEW ARTICLE

Gilles de la Tourette syndrome

Gilbert Gravino, BSc Hons

Medical Imaging Department, Mater Dei Hospital, Msida MSD2080, Malta

BACKGROUND: Tourette’s syndrome is a developmental neuropsychiatric disorder characterized by multiple motor, stereotypical but non-rhythmic movements and vocalizations/phonics called tics. It is one of several disorders that have tics as their cardinal feature. These tics manifest themselves in various ways, ranging from simple eye blinking to coprolalia (involuntary swearing).

METHOD: We conducted a thorough search for the literature using Medline and ScienceDirect. A literature review was then carried out to identify relevant information and improve the profession's understanding of the syndrome, including its pathophysiology.

RESULTS: This disorder is much more common than once believed, and may interfere with patients’ social relationships and occupational functions. The development of new treatments is important to achieve more effective management with fewer side effects. Animal models of Tourette’s syndrome would help foster understanding the pathophysiology and pharmacological treatment of tic symptoms.

CONCLUSIONS: Although significant advances have been made, research in the field is crucial to clarify further the physiological aspects of the syndrome.

KEYWORDS: Tourette’s syndrome, pathophysiology, neurology

ANNALS OF CLINICAL PSYCHIATRY 2013;25(4):297-306

  INTRODUCTION

Tourette’s syndrome (TS) generally is defined as a developmental neuropsychiatric disorder characterized by multiple motor, stereotypical but non-rhythmic movements and vocalizations/phonics called tics.1,2 Several disorders present with tics as their cardinal feature, and TS simply represents 1 entity of this spectrum. DSM-53 presents and categorizes different forms of tic disorders under the subheading of motor disorders in the neurodevelopmental disorders chapter, as follows:

  • developmental coordination disorder

  • stereotypic movement disorder

  • Tourette’s disorder

  • persistent (chronic) motor or vocal tic disorder

  • provisional tic disorder

  • other specified tic disorder

  • unspecified tic disorder.

Research by The Tourette Syndrome Classification Study Group4 also has led to the development of formal diagnostic criteria that differ only slightly from those of the DSM-5. TABLE 1 shows the criteria common to both diagnostic schemas.


TABLE 1

Criteria for diagnosis of Tourette’s syndrome

  1. Age of onset before age 21 (The TS Classification Group); before age 18 (DSM-5)

  2. Multiple motor tics

  3. At least 1 vocal tic

  4. Evolving waxing and waning course of symptoms

  5. Duration >1 year

  6. Not due to direct physiological effects of medication or a general medical condition

Differences include the time of onset of symptoms as shown in TABLE 1 (age 18 or 21); the Study Group also includes the fairly obvious requirement that the tics must be witnessed by the medical professional.

A noticeable feature from the above mentioned criteria is that the diagnosis is based solely on patients’ historical features and clinical examination. In fact there are no laboratory, imaging, genetic, or electrographic tests that can confirm the diagnosis of TS,5,6 making TS a clinical diagnosis. Patients manifest tics in a variety of forms with different degrees of severity and duration. Common motor tics include eye blinking, nose twitching, jaw, neck, and shoulder or limb movements, whereas common vocal tics include sniffing, grunting, chirping, and throat clearing.7 In more severe cases, more complex tics may include grimacing with head twisting, gyrating, and kicking, whereas more complex phonetic tics may include coprolalia, echolalia, copropraxia, palilalia, and palipraxia.1,8 Old explanations of TS, like the 1 included in Stedman’s Medical Dictionary in 1930, defined the disorder as being characterized by coprolalia9; however, we now know that only about 10% of patients with the disorder experience this symptom.5 Unfortunately, many medical professionals still believe patients must have coprolalia to receive the diagnosis.10

Patients with TS have no cognitive deficits but often have other comorbidities, particularly attention-deficit/hyperactivity disorder (ADHD) and obsessive-compulsive disorder (OCD).11 TS patients typically have overlapping coexisting disorders. The Tourette International Consortium (TIC) database12 showed that only 12% of evaluated patients experience tics without other comorbidities.

Historical background

Several references predate Gilles de la Tourette’s description of tic disorders, including the description by Sprenger and Kraemer in 1489 of a priest with vocal and motor tics in the Malleus Maleficarum (Witches’ Hammer).13 In 1825, the French physician Itard provided the first full medical description of tic disorders.10 Then in 1885, Georges Gilles de la Tourette described 9 patients (who exhibited a combination of motor and phonic tics, spectacular and vulgar outbursts, echolalia, obsessive thoughts, and repetitive behaviors) in Maladie des Tics, which earned him eponymous fame.9,14 Today’s definition of TS incorporates many of the original diagnostic criteria proposed by Gilles de la Tourette: childhood onset, motor and vocal tics, natural waxing and waning, and chronicity (the proposed definition also included lifelong duration).13

Famous people with whom the disorder of TS has been associated and questioned include Samuel Johnson, the British lexicographer, and Wolfgang Amadeus Mozart. These associations have been made through clinical descriptions that have been retrieved from written documents predating Gilles de la Tourette’s original publication.15

Etiology and pathogenesis

Originally, in 1885, Gilles de la Tourette made no reference to the involvement of any anatomical or biological causes, but rather suggested a psychiatric cause.16 However, recent studies suggest a neurophysiological and neurobiological etiology.

Neuropathological, neuroanatomical, and neuroradiological studies have implicated consistently the basal ganglia together with related thalamic and cortical structures in the pathobiology of TS. The interconnected relationships between movement disorders and associated behaviors may be understood by a series of parallel cortico-striatal-thalamocortical (CSTC) circuits.17-20 Investigators have described 5 distinct parallel circuits that subserve different functions; these are presented in TABLE 2. We present different lines of evidence reflecting the involvement of these circuits in TS and discuss other possible etiologies throughout this article.


TABLE 2

Cortico-striatal-thalamocortical circuits

Circuit Route
1. Motor Originates primarily from supplementary motor cortex and projects to the putamen in a somatotopic distribution
2. Oculomotor Originates principally in frontal eye fields and connects to the central region of the caudate
3. Dorsolateral prefrontal Links Brodmann areas 9 and 10 with the dorsolateral head of the caudate and appears to be involved with “executive function” and motor planning
4. Lateral orbitofrontal Originates in the inferolateral prefrontal cortex and projects to ventromedial caudate; its injury is associated with personality changes, mania, disinhibition, irritability, and OCD
5. Anterior cingulate Originates in the anterior cingulate gyrus and projects to the ventral striatum that receives input from the amygdala, hippocampus, and entorhinal and peripheral cortex
OCD: obsessive compulsive disorder.
Source: Adapted from references 16 and 25.

Incidental and direct evidence support the involvement of dysfunctional CSTC circuits. These include the induction or ablation of stereotypic behaviors after micro-injection of dopaminergic agents into rodent striatum,21 pathological studies in individuals with tics secondary to encephalitis,22 suppression of tics following surgical treatment that disrupts the CSTC circuitry,23 evidence through volumetric MRI studies, and examination of ocular movements.21 The pathogenesis at a molecular and cellular level remains unidentified; however, structural and functional neuroimaging studies indicate the involvement of the basal ganglia and relate the CSTC as the neuroanatomical site for TS. In addition, TS has a strong genetic component, and considerable progress has been made in understanding the mode of transmission and in identifying potential genomic loci.

Electrophysiological studies

Physiological evaluation of TS started with EEG studies, which attempted a clearer understanding of the disorder.26 Studies have been mainly of 2 forms; 1 aims to investigate areas of dysfunction in the cerebral cortex, while the other form aims to demonstrate neuronal mechanisms of tics and relevant symptoms by analyzing neuronal functions and neuronal pathways. A variety of electrophysiological studies have been performed to shed light on the mechanisms involved.

Obeso et al27 evaluated tic movements using surface electromyography (EMG), and showed that simple motor tics involve muscle activities of <200 ms that may be confined to a single muscle or occasionally involve simultaneous contraction of both agonistic and antagonistic muscles. The study also showed the contrasting characteristics of complex motor tics, which involve a burst of muscle activities of multiple muscle groups for a prolonged duration. In 1996, Stevens et al28 used EEG studies showing an abnormal increase of activity in the fields with a right-frontal/left-posterior configuration and suggested that the abnormal EEG patterns seen in TS patients are not similar to those elicited by simple or complex movements. Also, Hyde et al29 observed significantly more abnormal EEG readings with excessive frontocentral theta activity in twins with a more severe clinical course. These studies revealed asymmetric involvement of the cortex and impairment of various cortical areas.26

Obeso et al27 also evaluated Bereitschaft potentials (premovement potentials) to find that they were missing before onset of tic-dependent EMG activities, but present as arising from the opposite sensorimotor cortex in individuals examined in relation to voluntary movements mimicking tics. The experiment also suggested that simple motor tics originate in the deep structures of the brain because abrupt negative potentials occurred 100 ms before onset of the tic movement. The absence of Bereitschaft potentials before involuntary tics demonstrates that these movements are not generated by typical pathways. However, the evaluation of TS has become more complicated since Papa et al30 revealed that not all voluntary movements are preceded by Bereitschaft potentials.

Castellanos et al31 performed studies of prepulse inhibition using supraorbital nerve electrical stimulation and suggested the presence of a deficient pallidal inhibition leading to disinhibition of thalamic centers. This mechanism also was supported and reinforced through investigation of contingent negative variation (CNV) by Weate et al.32 CNV represents the sensorimotor integration process in voluntary movement and a significant role in the generation of late CNV is attributed to the CSTC circuit.33 TS patients showed higher CNV amplitudes and more frequent postimperative negative variations than controls. The outcomes of this study led Weate et al32 to propose the possibility of excess dopamine activity in TS patients, because CNV is altered in a number of different dopaminergic abnormalities. Striatal CNVs may inhibit the ascending pathway from the pallidum by hindering the striatal direct or indirect pathways, thereby disinhibiting the thalamocortical projections and causing a disturbance in the function of target areas in the cortex.

Neurochemistry and neurotransmitter abnormalities

The involvement of dopaminergic, glutamatergic, GABAergic, serotoninergic, cholinergic, noradrenergic, and opioid systems in the CSTC circuitry indicates a high probability that various specific neurotransmitter abnormalities are responsible for the pathophysiology of TS. The dopaminergic system seems to play a dominant role, but the rest may have other important implications. The neurochemistry of TS has been studied mainly through medicinal responses, evaluation of cerebrospinal fluid (CSF), blood, and urine, neurochemical assays on post-mortem brain tissues, and positron emission tomography (PET) studies.19

Some researchers also considered the possibility of abnormal second messenger systems and therefore the correlation of TS with cyclic adenosine monophosphate (cAMP) levels. D1 (dopamine receptor subtype 1) and α-adrenergic receptors normally stimulate adenylate cyclase, whereas D2 (dopamine receptor subtype 2), serotonergic, muscarinic, α2-adrenergic, and opiate receptors normally inhibit adenylate cyclase.34 Abnormalities in the vesicle docking proteins known as soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNARE) also were investigated but no consistent changes were found in their expression.35

Dopamine. Usually dopamine antagonists have an ameliorating effect on tics, whereas dopaminergic system-enhancing drugs tend to exacerbate the symptoms36,37; this partly explains why researchers continue to focus attention on dopamine implications. Dopamine input from the substantia nigra pars compacta (part of the CSTC) may exert both excitatory and inhibitory effects, depending on its interaction with different receptors. Activation of D1 receptors, primarily located on the medium sized spiny neurons (MSSN) of the direct pathway, stimulates the activation of adenylate cyclase and ultimately causes movement-release, whereas activation of D2 receptors, located on MSSN of the indirect pathway, blocks adenylate cyclase activity and ultimately inhibits movement.19 Therefore, this means that both scenarios lead to disinhibition of thalamic excitatory neurons that may cause hyperexcitability or disinhibition of cortical motor areas with resultant tics as a presenting symptom. Some have suggested that over the long term, dopamine may modulate cortico-striatal transmission,38,39 and others have hypothesized that this could cause the characteristic tic to wax and wane.40 The aberrant form of a dopaminergic system may have abnormalities primarily at 4 levels:

  1. Supersensitive postsynaptic dopamine receptors: The initial understanding of this abnormality was revealed by the finding of low basal levels of homovanillic acid (a dopamine metabolite) in CSF.41,42 Few studies also have indicated differential trends in D1 and D2 receptor binding between TS patients and controls.43

  2. Dopamine hyperinnervation: The 2 modalities that have been used to evaluate this hypothesis are PET or single photon emission computed tomography (SPECT)44-46 and in vivo measurements of (+)-α-[11C]dihydrotetrabenazine binding to vesicular monoamine transporter type 2 (VMAT2).47,48 However, results from different studies generated inconsistent results.

  3. Presynaptic dopamine abnormality: The probable cause involves upregulation of dopa decarboxylase with insufficiency of various functional elements constituting the dopaminergic system.49

  4. Elevated intrasynaptic dopamine release: A study by Singer et al50 using PET provided evidence to suggest that intrasynpatic dopamine levels at the putamen are higher in TS patients when compared with controls after administration of amphetamine (a psychostimulant drug that increases dopamine release and blocks its reuptake).51 Various possible mechanisms have been postulated to explain this phenomena; these include an increase in dopamine release from presynaptic terminal due to a localized defect in the release mechanism, deficient presynaptic inhibition, enhanced firing of presynaptic neurons, functional defect in dopamine reuptake from synaptic cleft, or abnormalities in the basal levels of dopamine (“tonic-phasic” model of dopamine release).19,52 The latter refers to extracellular dopamine present in low concentrations that determines long-term mechanisms. Singer et al50 propose that the pathophysiological mechanism underlying TS could be an overactive dopamine transporter system that causes a decrease in tonic dopamine levels.

Glutamate. Approximately 60% of brain neurons use glutamate as the primary excitatory neurotransmitter, and therefore the amino acid also is involved in the CSTC circuitry.53,54 The glutaminergic system also is involved in extensive interaction with the dopaminergic neurotransmitter system.55,56 Abnormalities in the glutaminergic system have been implicated in the etiology of TS. A study by Anderson et al54 showed reduced glutamate levels in postmortem TS brains, specifically in the globus pallidus interna (GPi), globus pallidus externa (GPe), and substantia nigra pars reticulate (SNpr). The study hypothesized that abnormally low levels of glutamate in the subthalamic nucleus may cause insufficient excitation of the inhibitory GPi/SNpr, which in turn results in excessive thalamocortical excitation.

γ-aminobutyric acid (GABA). The major form of neurons projecting from the striatum to the direct and indirect pathways is indeed the GABAergic type. The involvement of GABA in the pathophysiology of TS lacks support by research data. However, proposed mechanisms include a lower than normal striatal GABAergic projections with insufficient inhibition of excitatory thalamocortical neurons, and reduced activity of GABAergic inhibitory interneurons that causes impairment of cortical inhibition of thalamocortical afferent signals.19

Serotonin. The role of a serotoninergic system in TS also has been evaluated. Evidence shows that serum serotonin and tryptophan levels are decreased,57 and that the major metabolite of serotonin, 5-hydroxyindoleacetic acid (5-HIAA), is decreased in the CSF of some TS patients.58 Also, studies reported a negative correlation between the tic severity and serotoninergic binding to serotonin transporter (SERT) in the midbrain and serotoninergic or noradrenergic binding in the thalamus.46,59 Generally, it is suggested that the serotoninergic system is not a causal factor, but rather a modulatory factor in the pathogenesis of TS.

Neuroimmunology: Infections and autoimmune disorders

Several researchers have questioned an autoimmune etiology for TS. This is because some observed that pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS) occur secondary to pharyngitis caused by Group A β-hemolytic Streptococci (GABHS), and present as an acute onset of tic disorders and obsessive-compulsive behaviors.60,61 However, the PANDAS hypothesis remains controversial because of several inconsistent findings, such as failure to identify GABHS infections as an ongoing contribution to tics, OCD, or behavioral symptoms.62 Another discordancy points at whether GABHS is a distinct etiology for tics or just another environmental exacerbating factor.63,64

The potential role of antineuronal antibodies also has been explored by assessing its serum levels. Logically, if PANDAS is an autoimmune disease, then serum antineuronal antibodies should be detected in TS patients. However, no conclusion has been drawn, despite the different techniques, such as enzyme-linked immunosorbent assay (ELISA) and Western immunoblotting, used to detect the antibodies.65,66 Archelos and Hartung67 strongly argue that there is no solid basis to confirm autoimmunity as an etiological component. This is because certain criteria have not been fulfilled: consistent identification of autoantibodies, the presence of immunoglobulins at the pathologic site, a positive response to immunomodulatory therapy, the induction of symptoms with autoantigens, and the ability to transfer passively the disorder to animal models with the induction of behavioral symptoms.

Genetics and epigenetics

As has been previously explained, initially the etiology of TS was thought to be psychological, despite Gilles de la Tourette’s suggestion in the 1800s that the syndrome has an inherited nature.6 Contribution to changes in this belief includes documentation in the 1980s and 1990s of a familial pattern of TS.10 The greatest supportive evidence is provided by a high concordance rate of TS in monozygotic twins but not in dizygotic twins.68,69

Linkage analyses allowed the identification of several chromosomal regions that may be involved; these include 11q23, 4q34-35, 5q35, and 17q25.70,71 Other implicated regions through identity-by-descent studies include regions near the centromere of chromosomes 2, 6p, 8q, 11q, 14q, 20q, 21q, and the X chromosome.72-74 Genes encoding various dopamine receptors, dopamine transporters, noradrenergic components, serotonergic components and recently even Slit and Trk-like family member gene 1 (SLITRK1), also have been assessed.75 Current understandings are directed mostly to sex-influenced autosomal dominant mode of inheritance with almost complete penetrance in males and 56% penetrance in females. Contrarily, Coming and Coming76 suggest that TS is a semidominant, semirecessive disorder.

The understanding of TS genetics is complicated by possible effects of genomic imprinting, bilineal transmission, genetic heterogeneity, epigenetic factors and gene-environment interactions.6,77 An epigenetic trait refers to “a stably inherited phenotype resulting from changes in a chromosome without alterations in the DNA sequence.”78 Several epigenetic factors have been proposed for the pathogenesis of TS. These include:

  • hypoxic events during pregnancy and prenatal smoking79,80

  • exposure to androgens during a critical period in fetal brain development, with male sex being recognized as a risk factor81

  • psychological stress could increase future tic and obsessive-compulsive symptoms, with hypersensitivity of the hypothalamic-pituitary-adrenal axis to stress in TS patients82

  • post-infectious immune mechanisms as the ones described in an earlier section on neuroimmunology; antibodies directed towards GABHS instead may attack brain cells.83

Neuroimaging studies

Specialized neuroimaging techniques have allowed researchers to evaluate TS from a different perspective and led to findings with strong implications for its pathophysiology.

MRI. Some volumetric MRI studies have revealed that TS patients are abnormal in that they lack the usual normal asymmetry of the basal ganglia seen with normal individuals. It is normal anatomy to have a larger volume of the left anterior brain, caudate, and pallidum, but according to specific studies this asymmetry is reduced or reversed in TS patients.84,85 Another study supporting these findings provided evidence that TS patients have smaller grey matter volumes.86 Bloch et al87 reported that caudate volumes correlate significantly and inversely with the severity of tic and OCD in early adulthood.

Despite these remarkable findings, Moriarty et al88 performed studies with inconsistent results: No absolute differences were found in caudate nucleus volumes between TS patients and controls. The same study, along with studies by Baumgardner et al89 and Peterson et al,90 showed that TS patients, predominantly males, have an abnormal corpus callosum. This suggests disruption in communication between the 2 frontal lobes and therefore possibly leads to alterations in the functionality of the cerebral hemispheres.19

Functional MRI also has been used to study the syndrome. Peterson et al91 compared images obtained during periods of voluntary tic suppression with periods of spontaneous tic expression. This showed considerable changes in signal intensity in the basal ganglia and the thalamus, with the magnitude correlating inversely with tic severity. Therefore, researchers have suggested that suppression of voluntary tics involves activation of the prefrontal cortex and caudate with simultaneous bilateral inhibition of the putamen and globus pallidus. Other data support CTSC involvement in the pathophysiology of TS. Functional MRI on a finger tapping exercise revealed increased activity in both the sensorimotor cortex and the supplementary motor area in TS patients, unlike normal patients.92 This may imply that the motor functional organization of TS patients has a different organization than that of normal individuals.

Positron emission tomography and single photon emission computed tomography. PET and single photon emission computed tomography (SPECT) of TS patients, compared with those of normal persons, suggest increased density of presynaptic dopamine transporters and postsynaptic D2 transporters, together with greater dopamine release in the putamen.77 This points to a role for dopamine in TS.

PET has been used to assess cortico-striatal glucose metabolism. Stoetter et al93 and Baxter et al94 revealed that after administration of [18F]2-fluoro-2-deoxyglucose there was decreased activity in the frontal, cingulated, and insular cortices, plus bilateral increase or decrease in a symmetrical fashion of glucose utilization within the basal ganglia. TS patients also differed from normal individuals in connectivity of the ventral striatum when assessing the functional coupling of regional cerebral metabolic rates for glucose.95

SPECT has been used to study cerebral blood flow. Using this technique, Hall et al96 identified decreased perfusion of the basal ganglia, and Riddle et al97 discovered decreased flow to the left lenticular region. Diler et al98 used an agent called 99mTc-ECD (Technetium-99m Ethyl Cysteinate Dimer) on TS patients to find that the left caudate, cingulum, right cerebellum, and right and left dorsolateral prefrontal regions have low regional blood flow.

Treatment

Because there is no actual cure for the syndrome, pharmacotherapy in TS patients only addresses symptoms. Emphasis has been made to reserve therapy only for cases of functional disability and those in which non-drug therapy does not work.6 The ultimate aim is to reduce symptoms and decrease their impact on the physical and psychosocial wellbeing of the patient.99 In this paper, which concentrates on underlying physiological concepts of TS, we will focus on pharmacological treatment. The therapeutic plan for patients with tic disorders is outlined in TABLE 3 and is carried out in the sequence listed.


TABLE 3

Sequential approach for treatment of tic disorders

  1. Education

  2. Behavioral approach

  3. Pharmacotherapy

    • First tier

    • Second tier

    • Other

  4. Deep brain stimulation

Source: Adapted from reference 6.
Pharmacotherapy

As noted in TABLE 3, a tiered approach has been developed for medicinal use in the treatment of tics. Often, the available literature categorizes the drugs used into first (non-neuroleptic) and second tiers (neuroleptic/antipsychotic drugs that may be further subdivided into typical and atypical).6,77,100-102 Collins et al5 also present a categorization consisting of tiers 1, 2, and 3, but for this review we shall describe the 2-tier system that has been more widely used.

The first-line drugs that are used to treat tics, generally referred to as tier 1 drugs, are non-neuroleptic drugs. Randomized, placebo-controlled clinical trials support the efficiency of α2-adrenergic agonists, including clonidine, which acts on presynaptic α2-adrenergic to reduce central noradrenergic activity, and guanfacine, which acts on postsynaptic α2-adrenergic receptors.103,104 Clinicians should try this category for patients with relatively mild symptoms, initially at low doses and gradually increased if necessary.102

Tier 2 antipsychotic drugs act mainly by blocking dopamine receptors, thereby decreasing dopaminergic input to the basal ganglia.101 The typical neuroleptics include haloperidol and pimozide, and have been associated with significant side effects, such as extrapyramidal syndrome and drug-induced parkinsonism.6,100,101 In addition, tardive dyskinesia is a long-term adverse effect of antipsychotic medication associated with a poor quality of life.105 The term “Tardive Tourette-like syndrome,” which was first reported by Klawans et al106 and given its name by Steven Stahl,107 also has been coined for this side-effect. Therefore, clinicians may choose to restrict their use and replace them with atypical neuroleptics as the preferred choice because they are less likely to cause side effects. These work by partially blocking both dopamine and serotonin receptors101 and have a relatively greater affinity for 5-HT2 receptors than for D2 receptors.6

Other medications that do not form part of this categorization system include low-dose dopamine agonists (eg, pergolide and ropinirole), which clinicians should avoid because of side effects from ergot content,108,109 delta-9-tetrahydrocannabinol, which has been effective but is illegal in most countries,110,111 and Botulinum toxin (Botox), which has been used to treat both motor and vocal tics successfully.112,113

Neurosurgical approach

As a last resort, practitioners may consider surgery in patients who do not improve with any other form of treatment. In the past, surgeons have attempted to treat these patients with neurosurgical ablative techniques,114 which included median thalamotomy for severe tics and pallidotomy for hyperkinesias.115,116 However, the results were often unsatisfactory, sometimes with major irreversible adverse effects such as hemiplegia or dystonia.117,118 While the overall experience of the latter type of surgery has been disappointing, the reversible neurosurgical procedure known as deep brain stimulation (DBS) has been reported to be very effective.114,119-125 DBS is a stereotactic technique that inserts electrodes into specific brain regions to suppress abnormal oscillatory activity.101 These specific brain regions have included the centromedian parafascicular complex of the thalamus, the globus pallidus interna and the anterior limb of the internal capsule.126

Adequate patient selection is one of the key elements for successful outcomes of DBS in TS.127 TS patients are considered only for DBS in severe cases after undergoing careful trials of standard therapies without benefit.118 Guidelines have been developed by the Dutch-Flemish Tourette Surgery Study Group to guide the use of DBS in TS:128

Inclusion criteria
  • The patient has definite TS, established by 2 independent clinicians

  • The patient has severe and incapacitating tics as his/her primary problem

  • The patient is treatment refractory

  • The patient has undergone a trial of at least 10 sessions of behavioral therapy for tics

  • The patient is age >25.

Exclusion criteria
  • The patient has a tic disorder other than TS

  • The patient has severe psychiatric comorbid conditions (other than associated behavioral disorders)

  • The patient has mental deficiency

  • Other contraindications included in these guidelines are severe cardiovascular, pulmonary or hematological disorders, structural MRI abnormalities, and active suicidal ideation.

  CONCLUSIONS

This review presents an updated collection of data from extensive resources that have been combined and evaluated to highlight the most important pathophysiological concepts underlying TS. TS is common and occurs in all races. The initial description by Gilles de la Tourette emphasized lifelong persistence; however, this has been minimized with occasional reports of tic resolution and clinical-based studies showing milder tics in adulthood than in childhood.13 Although significant advances have been made, research in the field is crucial to clarify further the physiological aspects of the syndrome. Symptom-targeted treatment is important as it may improve prognosis in terms of tics, psychopathology, and social functioning.10 The development of new treatments is important to achieve more effective management with fewer side effects. Animal models of TS would help improve our understanding of the pathophysiology and pharmacological treatment of tic symptoms.101

DISCLOSURE: The author reports no financial relationship with any company whose products are mentioned in this article, or with manufacturers of competing products.

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CORRESPONDENCE: Gilbert Gravino, BSc Hons Medical Imaging Department Mater Dei Hospital Msida MSD2080 Malta E-MAIL: gilbert.gravino@gmail.com