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Tourette Syndrome
Article Last Updated: Jun 23, 2008
AUTHOR AND EDITOR INFORMATION
Section 1 of 11
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Author: Jason S Hawley, MD, Chief of Neurology, Carl R Darnall Army Medical Center
Jason S Hawley is a member of the following medical societies:
American Academy of Neurology
Coauthor(s):
Sharette K Gray, MD, Chief of Outpatient Psychiatry, Carl R Darnall Army Medical Center
Editors:
Jennifer S Morse, MD, Assistant Clinical Professor, Department of Psychiatry, University of California at San Diego;
Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine;
Eduardo Dunayevich, MD, Adjunct Assistant Professor, Department of Psychiatry, University of Cincinnati; Clinical Research Physician, Neuroscience, Lilly Research Laboratories;
Harold H Harsch, MD, Program Director of Geropsychiatry, Department of Geriatrics/Gerontology, Associate Professor, Department of Psychiatry and Department of Medicine, Froedtert Hospital, Medical College of Wisconsin;
Stephen Soreff, MD, President of Education Initiatives, Nottingham, NH; Faculty, Metropolitan College of Boston University, Boston, MA
Author and Editor Disclosure
Synonyms and related keywords: Tourette syndrome, tic, motor tic, phonic tic, vocal tic, Tourette, obsessive-compulsive disorder, OCD, attention deficit hyperactivity disorder, ADHD, TS psychopathology, large dorsolateral prefrontal region, increased cortical white matter in the right frontal lobe, dopamine supersensitivity
Background
Tourette syndrome (TS) is a childhood neuropsychiatric disorder characterized by motor and phonic (vocal) tics. It is often associated with behavior disorders, particularly obsessive-compulsive disorder (OCD) and attention deficit hyperactivity disorder (ADHD). These behavior disorders often accompany the tics and may dominate the clinical picture in some patients. TS is a genetic condition that runs in families. However, the precise genetic abnormality responsible for the phenotype has not yet been elucidated.
In this article, the incidence, genetics, clinical picture, and management of TS are reviewed.
For more information, see Tourette Syndrome and Other Tic Disorders.
Historical perspective
In 1885, Gilles de la Tourette, the French neurologist and student of Charcot presented 9 children with childhood onset tics. These children also had associated coexisting behavior problems, as well as unusual vocalizations that we now recognize as phonic tics. Although Gilles de la Tourette correctly considered this a genetic disorder, the etiology was ascribed to psychogenic causes for nearly a century afterwards.
In the 1960s, with the emergence of neuroleptic medications, the tics of TS would respond favorably to these new medications. The fundamental perception of TS changed from a psychiatric disorder to a primary neurologic disorder where there was believed to be focal dysfunction within the brain. Since that time, extensive research has been performed to understand the underlying neurobiology behind TS. What was once viewed as a rare psychiatric disorder, TS is now viewed as a relatively common and diverse childhood onset genetic condition.
Pathophysiology
The precise pathophysiologic mechanisms of TS are yet to be determined. Most studies support that TS is an inherited developmental disorder of synaptic neurotransmission.1 The basal ganglia, particularly the caudate nucleus and the inferior prefrontal cortex, are implicated in the pathogenesis. Recently, cortical structures have been implicated in the pathogenesis of TS as volumetric MRI studies have shown that children with TS have larger dorsolateral prefrontal regions as well as increased cortical white matter in the right frontal lobe. The neurobiology of TS is currently accepted to involve the likely disinhibition in cortico-striatal-thalamic-cortical loops, with an overly active caudate nucleus. Similar models have been ascribed to ADHD and OCD. Dysfunction within these circuits results in an inability to suppress unwanted movements, behaviors, or impulses.
Functional neuroimaging studies, performed while patients are actively having tics, also demonstrate multifocal activation within the brain. This includes medial and lateral premotor cortices, anterior cingulated cortex, dorsolateral-rostral prefrontal cortex, inferior parietal cortex, putamen, caudate, primary motor cortex, Broca area, superior temporal gyrus, insula, and claustrum. The activity in these regions was synchronous with tic occurrences. This widespread, abnormal activity of interrelated circuits shows extensive involvement of the sensorimotor, language, and paralimbic regions.2, 3
While multiple neurotransmitters are likely involved, significant interest is shown in the role of dopamine, given the effectiveness of agents that act on dopamine receptors in controlling the symptoms of TS. Functional neuroimaging studies implicate abnormalities within dopaminergic systems within the striatum and prefrontal cortex. Patients with TS have increased density of the presynaptic dopamine transporter and an increased density of postsynaptic D2 dopamine receptors, suggesting increased uptake and release of dopamine. The increased density of the dopamine receptors have led some investigators to propose a supersensitivity to dopamine within the striatum, prefrontal cortex, and motor region, leading to the phenotype of tics and other behaviors associated with TS. The dopamine supersensitivity hypothesis may explain why tics are so responsive to the dopamine receptor blockers (neuroleptics).
The gene or genes responsible for TS have not been determined. Evidence supports an autosomal dominance inheritance pattern. TS is likely a polygenetic condition with variable penetrance. Twin studies indicate a greater than 90% concordance.4
Recent evidence challenges the conventional hypothesis for the etiology of TS as some have speculated that there may be an immune-mediated pathogenesis similar to pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS). In this model, antecedent infection with A beta-hemolytic streptococcus leads to the formation of antineuronal antibodies that cause neuronal dysfunction. Recent investigations comparing antineuronal antibody profiles in TS, PANDAS, and age-matched controls did not, however, demonstrate any differences. Treatments aimed at this pathophysiologic mechanism, such as plasmapheresis, intravenous immunoglobulin, or antibiotics, are not currently recommended.5
Data mitigate the impact of psychogenic etiologies. Although some tics may be partly voluntary, physiologic studies indicate that tics are not mediated via the same motor pathways of willed movements. Electrophysiologic data demonstrate the absence of premotor potentials in simple motor tics, suggesting that tics truly are involuntary or occur in response to an external cue. Sleep studies provide additional evidence that tics are involuntary. Polysomnography of 34 patients with TS demonstrated motor tics in various sleep stages in 23, and vocal tics in 4. Further studies are needed to elucidate the physiologic and cellular mechanisms underlying tics and TS.2
Frequency
United States
The precise prevalence of TS has been difficult to ascertain, and what once was thought to be a rare condition is now felt to be much more common. Most children with TS have non-disabling symptoms, their tics improve and resolve with age, and they never seek medical attention. As the clinical criteria for the condition has evolved, most investigators believe that the estimated prevalence is 0.7-4.2% based on observation studies in public schools. When the school-based studies were done on students in special education programs, 26% of those students had identified tics compared to 6% of students in mainstream classrooms.6, 7
International
TS occurs worldwide. Cases meeting current diagnostic criteria have been reported in the United States, Europe, New Zealand, Brazil, Japan, China, and the Middle East. The clinical phenomenology appears similar, regardless of ethnicity or culture, suggesting a common genetic basis.
Mortality/Morbidity
TS, as described by the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) criteria, is associated with distress or social or functional impairment. The condition does not reduce lifespan. However, symptoms from TS can lead to significant limitations in otherwise normal activities.
Individuals with TS who have severe motor tics frequently avoid situations with high social visibility. Stress and anxiety in those situation frequently worsen or accentuate the tics themselves. Phonic or vocal tics (sounds or words) can cause significant social embarrassment. Coprolalia (verbalization of inappropriate words or phrases) and copropraxia (making obscene gestures) can cause significant social embarrassment and lead to isolating patients with TS. Moreover, in school-aged children, these tics can frequently be misinterpreted as rude behavior, leading to disciplinary action. The associated behavior disorders of ADHD, OCD, and other disorders, such as impulse control disorders, often cause more morbidity that the tics themselves. In children, the behavior complications frequently lead to poor academic performance, social isolation, and emotional problems. Disorders of attention and concentration may not be just secondary to ADHD, as patients with TS frequently have uncontrollable intrusions of thoughts or an obsessive fixation on irrelevant objects. Moreover, as described below, the associated tics of TS can be somewhat volitionally suppressed, and the mental and emotional effort used to suppress tics may also interfere with attention and concentration in school and work.
Race
Tourette syndrome occurs in all social classes and races.
Sex
Male to female ratio varies from 2-10:1. However, if OCD is included as a variant of TS, then the male to female ratio is equal.
Age
Children are much more likely to meet the diagnostic criteria for TS than adults. TS is a childhood-onset condition, and adults who display of symptoms of TS are likely to have had the symptoms since childhood.
Symptoms of TS can be seen in infancy, however, most children display readily identifiable symptoms around age 7 years. Most children with TS have their symptoms resolve by adulthood. Whether this resolution represents a compensatory process or resolution of the underlying pathology is unclear.
For more information, see Medscape's CME activity, Tics and Tourette Syndrome: A Clinical Review.
History
The hallmark clinical features of Tourette syndrome (TS) are tics with coexisting behavior disorders such as ADD, OCD, or impulse control behaviors. The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) has also established criteria for the clinical diagnosis of TS.
Diagnostic criteria from DSM-IV-TR for Tourette syndrome (307.23)
Both multiple motor and 1 or more vocal tics must be present at some time during the illness, although not necessarily concurrently. The tics occur many times a day (usually in bouts) nearly every day or intermittently over more than 1 year, during which time there must not have been a tic-free period of more than 3 consecutive months. The age at onset is younger than 18 years. The disturbance is not due to the direct physiological effects of a substance (eg, stimulants) or a general medical condition (eg, Huntington disease or postviral encephalitis).
This criteria was modified in the DSM-IV-TR compared to the earlier criteria in the DSM-IV. A fifth criteria that "The disturbance causes marked distress or significant impairment in social, occupational, or other important areas of functioning" was deleted in the DSM-IV-TR. The rationale behind removing this element of the diagnosis was that many patients with mild TS do not have symptoms that interfere with their daily function and job. Furthermore, this criteria may lead to a stigmatization of patients with TS that they have a condition that causes significant impairments in daily function. The authors felt that this could lead to job discrimination and other forms of labeling. The deletion of this criteria is a recognition that many patients with TS do not have significant problems related to their condition.
The clinical characteristics of tics
Tics are the hallmark feature of TS. Tics are abnormal movements or vocalizations that are diverse in presentation. Tics can be simple movements or vocalizations such as eye blinking, coughing, or grunting. They also can be highly complex movements such as running, jumping, or vocalizing phrases or repetitive words. This diversity of presentation can be challenging for the examiner to characterize these abnormal and somewhat bizarre movements.
However, distinctive characteristics can help distinguish tics from other abnormal movements, such as tremor, chorea, myoclonus, or dystonia. Tics are considered semivoluntary, meaning that the patient can often volitionally suppress the movement for a period a time, suppressing the emotional urge or uncomfortable feeling that often arises to perform the tic. Furthermore, an emotional release often occurs after the tic or repetitive tics are completed.
Tics are often suggestible, and can be worsened by stress, boredom, and fatigue. After a period of stress, patients with TS often release their tics when they are alone and relaxed. One frequent clinical observation is that children with TS often spend their time at school suppressing tics, only to come home to a more relaxed and secluded environment where they will release their tics. Between tics, no other abnormal movements occur. Thus, the suppression ability, the emotional urge and relief associated with the movement, and the suggestibility of the movement, are all clinical features that help differentiate tics from other hyperkinetic movement disorders.
Classifications of tics
Tics are diverse and sometimes bizarre. They are typically divided into motor or vocal/phonic tics. Tics can also be categorized as simple or complex tics based on the complexity of the movement or vocalization.
Simple motor tics involve a single muscle or group of muscles. The tic may be a brief jerking movement (clonic tic), a slowed sustain movement or posture (dystonic tic) or a tensing of individual muscle groups (tonic tic). Examples of simple motor tics include eye blinking, nose sniffing, coughing, neck twitching or jerking, eye rolling, and jerking or postured movements of the extremities. Simple motor tics typically consist of simple, nonpurposeful movements. Complex motor tics involve movements that often involve multiple muscle groups and may appear as semipurposful movements or behaviors. Examples of complex motor tics include touching oneself or others, hitting, jumping, shaking, or performing a simulated motor task. Also included in the spectrum of complex motor tics is copropraxia and echopraxia (imitating movements of others). Simple phonic tics are simple vocalizations or sounds. Examples include grunting, coughing, throat clearing, swallowing, blowing, or sucking sounds. Complex phonic tics are vocalizations of words and/or complex phrases. These verbalizations can be complex and sometimes socially inappropriate. Coprolalia is a complex phonic tic characterized by the shouting of socially inappropriate language (obscenities and profanities). Patients with TS may have complex phonic tics characterized by the repetition of someone else's words (echolalia) or the repetition of one's own words (palilalia). Coprolalia occurs in fewer than half of patients with TS, although it can be one of the most distressing symptoms of the condition.
Premonitory symptoms of tics
Premonitory feelings or sensations precede motor and vocal tics in more than 80% of patients. These premonitory phenomena may be localizable sensations or discomforts, including the following:
Burning feeling in the eye before an eye blink Tension or a crick in the neck that is relieved by stretching of the neck or jerking of the head Feeling of tightness or constriction relieved by arm or leg extension Nasal stuffiness before a sniff Dry or sore throat before throat clearing or grunting Itching before a rotatory movement of the scapula
Rarely, these premonitory feelings, termed in one report as extracorporeal phantom tics, involve sensations in other people and objects and are temporarily relieved by touching or scratching them.
Behavioral symptoms associated with TS
Behavior symptoms are common in TS. The 2 most common disorders are obsessive-compulsive disorder (OCD) and attention deficit hyperactive disorder (ADHD). Questionnaire studies for patients with TS have also demonstrated high rates of mood disorders, and anxiety disorders, including panic disorder and simple phobias. Compared with the general population, patients with TS have a higher rate of bipolar disorder.
OCD is the most frequent behavior symptom associated with TS. The rates of OCD in patients with TS range from 20-60%. Obsessive-compulsive symptoms have an increased prevalence in first-degree relatives with tics. Obsessions are defined by the DSM-IV-TR criteria as recurrent and persistent thoughts, impulses, or images experienced at some time during the disturbance as intrusive and inappropriate and cause marked anxiety and distress. The thoughts, impulses, or images are not simply worries about real-life problems.
Compulsions are repetitive behaviors (eg, hand washing, ordering, checking) or mental acts (eg, praying, counting, repeating words silently) in response to an obsession or according to rules that must be applied rigidly. The behaviors or mental acts are aimed at preventing or reducing distress or preventing some dreaded event or situation; however, these behaviors or mental acts either are not connected in a realistic way with what they are meant to neutralize or prevent or they are clearly excessive.
Increasing evidence shows a genetic link between tic disorders and OCD. While the neurobiology for both symptoms is not yet known, they may share a common neuroanatomic localization. Mounting evidence shows the involvement of the caudate nucleus in both tics and OCD.
The symptoms of OCD (as well as ADHD) may be the dominating and debilitating feature of TS in certain patients. The rates of ADHD in TS have ranged from 40-70%. Individuals with ADHD have difficulty focusing their attention, with either difficulty inhibiting their attention to nonrelevant stimuli or difficulty focusing and concentrating on relevant tasks for prolonged periods of time (such as schoolwork) without becoming distracted. Unlike OCD, a genetic link between ADHD and tics is not as clear. Studies have not shown an increased incidence of ADHD in first-degree relatives of individuals with TS. The symptoms of ADHD are often recognized before the tics. Typically, ADHD is commonly treated with stimulants, which can worsen tics. Stimulants do not cause TS, but are more likely to bring out the underlying and often unrecognized tics. Like OCD, the symptoms from ADHD may be more limiting than the tics. While OCD and ADHD are the 2 most common neurobehavioral symptoms of TS, other disorders pertaining to poor impulse control are frequently seen in individuals with TS. Irritability, rage attacks, inappropriate sexual aggressiveness, and antisocial behavior have all been reported. A rare but very challenging behavior associated with TS is self-mutilating behavior. This behavior has components of both obsession and compulsions and can cause significant morbidity. Individuals often damage their own body by scratching, biting, cutting, or hitting themselves. Often an irresistible urge arises to perform these behaviors. Specific learning disabilities and subtle neurologic signs are more frequent in patients with TS, further complicating management. Children, although intelligent, may have poor academic achievement, and slight motor coordination difficulties may preclude them from doing well in athletic endeavors. Anxiety and mood disorders are common in TS. Mood disorders are well recognized as being more prevalent in individuals with TS than the general population. The genetic association between these mood disorders and tics/TS is not clear.
For more information, see Medscape's ADHD and Anxiety Disorders Resource Centers.
Physical
Aside from the presence of tics, children with TS will have a normal neurologic examination. Similarly, the mental status examination has no particularly abnormal findings with the exception of the presence of tics, which should be commented on in the behavior, speech, and/or psychomotor sections of the mental status examination, as appropriate. Occasionally, although not consistently, some decreased attention may be noted, if the patient is distracted by their tics. TS is often comorbid with other psychiatric conditions; therefore, features of comorbid conditions may be noted on the examination. For example, depressed or anxious affect may be noted if the patient has a comorbid mood or anxiety disorder, or difficulty focusing, distractibility, or increased psychomotor behaviors may be noted if the patient has comorbid ADHD.
Because of the increased risks of psychiatric comorbidities such as depression, OCD, and anxiety, individuals with TS are suspected to have a slightly increased risk of self-injurious behavior and suicide. Although data remain unclear, in a recent examination on life-threatening behavior in patients with TS, sub groups within the TS population warranted close attention. A retrospective study showed that individuals with malignant TS, defined as having at least 2 emergency department visits or at least 1 hospitalization for TS symptoms, account for approximately 5% of patients referred for subspecialty evaluation. In this group, mood disorders, self-injurious behavior, suicidal ideation, and poor response to therapy significantly increased. This group is at risk, and a more detailed examination for suicide risk is recommended for individuals with a history suggesting malignant TS.8
It is not unusual for children with TS to suppress their tics during medical evaluation, only to release them when they are out of the physician's office. As with any hyperkinetic movement disorder, direct visualization of the abnormal movement aids significantly in making the diagnosis. Parents should be encouraged to videotape their children at home when they are having frequent tics.
A general neurologic examination is important to exclude other conditions that can present with tics. Moreover, the abnormal movement needs to be correctly characterized as a tic to differentiate it from myoclonus, chorea, tremor, and dystonia.
A developmental history, including developmental milestones and growth curves, is important to exclude genetic disorders such as Down syndrome, autistic spectrum disorders, and other developmental and chromosomal disorders. Tics, ADHD, and OCD can be seen in these conditions. While TS is the most common cause of inherited tics, other more progressive neurodegenerative conditions can present with tics. These disorders include Huntington disease, neuroacanthocytosis, Wilson disease, Hallervorden-Spatz disease, and primary dystonia. A thorough neurologic examination should examine for features suggestive of these conditions.
The presence of Kayser Fleisher rings in the eye is diagnostic of Wilson disease, and should be assessed for in any young patient with a hyperkinetic movement disorder. Tics have been described in Huntington disease, and the presence of chorea, motor impersistence, abnormal saccades, and gait difficulties is suggestive of this neurodegenerative disorder. In children, Huntington disease often presents with rigidity and bradykinesia (the Westphal variant). A thorough gait and motor examination should be performed to assess tone and strength. Examination of the skin should be performed. Neurocutaneous syndromes such as tuberous sclerosis and neurofibromatosis have been rarely reported to be associated with the presence of tics.
Causes
The precise cause of TS is unknown, but the preponderance of evidence suggests that TS is an inherited developmental condition. Recently, an alternative autoimmune-mediated theory for the etiology of TS has become of interest. The 2 proposed mechanisms are as follows:
Genetic theory
Analysis of families with TS suggests an autosomal dominant pattern of inheritance. The concordance rate among monozygotic twins is 53% compared with 8% for dizygotic twins.3 Significant efforts have been made over the past 15 years to determine the precise gene or genes responsible for TS. Genetic studies performed through the Tourette Syndrome Association as well as studies of 91 families in South Africa have implicated chromosome 8 as possible genetic loci. Data also support a possible loci on chromosomes 5 and 11.9
Autoimmune theory
The autoimmune theory as the cause of TS poses that antibodies directed against an antecedent infection (such as streptococcal infection) cross react with neuronal structures in the central nervous system. This is the presumed mechanism of action for Sydenham chorea and pediatric autoimmune neuropsychiatric disorder associated with streptococcal infection (PANDAS).
Selected individuals with TS have elevated titers of antistreptococcal antibodies and antineuronal antibodies similar to those individuals diagnosed with PANDAS. However, no correlation exists between the presence or absence of antineuronal antibodies and the severity of the tics, the onset of TS symptoms, or the presence of neuropsychiatric symptoms. Examination of serum antibodies in patients with PANDAS and TS compared with age-matched controls failed to differentiate the 2 disorders from age matched controls.5 Streptococcal infection may trigger the onset of symptoms associated with TS in a small group of patients. Further studies are needed to further examine the validity of an autoimmune/postinfectious cause of TS. Currently individuals with TS are not recommended to be treated with antibiotics or therapy such as immunosuppressives, IVIG, or plasmapheresis.
In the future, major advances in our understanding of the neurobiology of TS will likely depend on progress in elucidating genetic mechanisms.
Risk factors
Male sex Young age Family history of TS
Anxiety Disorders
Attention Deficit Hyperactivity Disorder
Autistic Spectrum Disorders
Huntington Disease Dementia
Obsessive-Compulsive Disorder
Stimulants
Systemic Lupus Erythematosus
Toxicity, Cocaine
Wilson Disease
Other Problems to be Considered
Tuberous sclerosis
Neuroacanthocytosis
Dystonia
Hallervorden-Spatz disease
Neurofibromatosis type 1
Chromosomal disorders
Sydenham chorea
Motor restlessness
Akathisia
Excessive startle
Transient tic disorder of childhood: This syndrome is similar to TS, but it lasts for less than a year.
Chronic multiple tic disorder: This has a great similarity to TS but remains present in adulthood.
Chronic single tic disorder: This is a motor or vocal tic in adulthood. Since patients with TS can have multiple behavioral disorders, other DSM-IV-TR diagnoses to consider are depression, OCD, and personality disorders.
Lab Studies
Tourette syndrome (TS) is a clinical diagnosis; therefore, no specific laboratory or genetic tests exist to help establish the diagnosis. The keys to diagnosis are recognition and an index of suspicion.
Imaging Studies
Routine community based neuroimaging (CT and MRI) studies are normal in patients with TS. Neuroimaging studies performed on a research basis have yielded subtle abnormalities that may give clues to understanding the pathophysiology of TS.
Children and adults with TS have reduced caudate volumes compared with controls. Moreover, recent studies have suggested that the degree of volume reduction within the caudate nucleus correlates with the severity of tics and OCD. Event-related functional MRI studies of patients with tics have indicated that paralimbic and sensory association areas are critically implicated in tic generation, similar to movements triggered internally by unpleasant sensations, as has been shown for pain or itching. Positron-emission tomography (PET) studies have also shown increased activity in sensomotor, paralimbic, language, and frontal subcortical regions that were event-related to motor and phonic tics, as well as the compulsions to perform these behaviors.
Medical Care
The management of Tourette syndrome (TS) is a multifaceted approach primarily aimed at medical management of frequent or disabling tics, treatment of coexisting behavior symptoms, and patient and family education.
Patient and family education: Ideally, patients with mild tics who have made a good adaptation in their lives can avoid the use of medications. Educating patients, family members, peers, and school personnel regarding the nature of TS; restructuring the school environment; and providing supportive counseling are measures that may be sufficient to avoid pharmacotherapy. See Patient Education.
Medical therapy for the treatment of tics is considered when tics interfere with social interactions, school performance, or activities of daily living. The goal of medical therapy for tics is not complete elimination of the tic, but rather control of tics to alleviate the social embarrassment or discomfort due to the tic, therefore improving social functioning.
Various therapeutic agents are now available to treat patients with tics, and each medication should be chosen on the basis of expected efficacy and potential adverse effects. Dosages should be titrated slowly to achieve the lowest satisfactory dosage that is sufficient to attain a tolerable level of symptoms. See Medication.
Surgical Care
Surgical approaches for TS have been attempted in patients who are severely disabled and have inadequate responses to other therapies. Deep brain stimulation (DBS) has been suggested as a potential therapy for severe and disabling tics. At this time, only isolated cases report the effectiveness of DBS. Patient selection and criteria formation for controlled trials is currently underway.
Consultations
Treatment of patients with TS should be a collaborative effort among the neurologist, psychiatrist, psychologist, family members, and school professionals.
Alpha2-adrenergic agonists and D2 dopamine receptor blocking medications are used primarily for tic suppression. The alpha2-adrenergic agonists may be effective at treating underlying ADHD symptoms, although CNS stimulants and atypical neuroleptics can be used concurrently as mentioned above. SSRIs are predominantly used to treat OCD symptoms in TS.
Treatment of tics
The alpha2-adrenergic drugs clonidine and guanfacine are first-line agents in treating mild to moderate tics. Clonidine decreases plasma norepinephrine levels and can also reduce the symptoms of ADHD. Guanfacine, with a similar mechanism of action as clonidine, has a longer half-life and may treat ADHD symptoms not responsive to clonidine. The daily dosage range for clonidine is 0.10-0.30 mg in divided doses. For guanfacine, the daily dosage range is 0.5-3.0 mg in divided doses. Clonazepam and baclofen can be considered first-line alternatives as well. The D2 dopamine receptor—blocking medications (neuroleptics) are the most effective medications for treating tics; however, the side effect profile to include extrapyramidal symptoms/tardive dyskinesia is often a limitation to using them as first-line therapy, although many experts use the neuroleptics as the initial agent of choice due to effectiveness. Haloperidol and pimozide, the 2 most studied neuroleptics, have been FDA approved for the treatment of tics in TS. Well-controlled clinical trials indicate that haloperidol has a response rate approaching 80% for tic suppression. More recently, the atypical neuroleptics that interact with both serotonin and dopamine receptors and have less extrapyramidal effects have been shown to be effective in suppressing tics. Out of this group, risperidone has been the most studied, showing equal efficacy when compared with clonidine. Olanzapine, ziprasidone, and quetiapine have shown promise in small studies. Tetrabenazine, a drug that blocks dopamine and depletes catecholamines at presynaptic terminals may be a potent drug in suppressing tics. Low doses of the dopamine agonist pergolide (withdrawn from US market March 29, 2007) and ropinirole have been shown to improve tics in small studies. Botulinum toxin-A has been effective in treating motor and vocal tics in select patients.
Treatment of ADHD:
The most effective medications for the treatment of ADHD are the central nervous system stimulants. Methylphenidate and dextroamphetamine are first-line agents for the treatment of ADHD. Unfortunately, these medications may increase the frequency and intensity of tics. However, with prolonged use, the initial worsening of tics may stabilize. The dopamine-blocking agents can be used concurrently with the CNS stimulants for tic suppression. Alpha2-adrenergic blockers may be helpful in controlling tics and treating symptoms of ADHD. Both clonidine and guanfacine can control the symptoms of ADHD and impulse control. Other medications that can be effective in treating ADHD symptoms without worsening tics include Wellbutrin and the tricyclic antidepressants.
Treatment of OCD in Tourette syndrome:
The selective serotonin reuptake inhibitors (SSRIs) are the most effective treatment of OCD symptoms in TS. This includes fluoxetine, fluvoxamine, paroxetine, sertraline, escitalopram, and citalopram. Clomipramine is also effective due to its serotonin reuptake action. Augmentation of SSRIs with atypical antipsychotics may be beneficial in patients with TS and OCD that are poorly responsive to treatment with SSRIs. Various psychotherapeutic techniques, including assertiveness training, cognitive therapy, and self-monitoring, have been tried in the treatment of patients with TS.
Drug Category: Neuroleptic drugs
Dopamine-receptor antagonists are the most predictably effective tic-suppressing agents.
Drug Name Haloperidol (Haldol)
Description Haloperidol and droperidol are of the butyrophenone class and are noted for high potency and low potential for causing orthostasis. High potential for EPS/dystonia exists.
Adult Dose 1-2 mg PO qhs, titrate prn and as tolerated by 1-3 mg/d
Typical doses range from <5 mg/d up to 15 mg/d
Pediatric Dose 0.25 mg PO qhs, increase slowly by 0.5-1 mg/d prn and as tolerated
Contraindications Documented hypersensitivity; narrow-angle glaucoma; bone marrow suppression; severe cardiac or liver disease; severe hypotension; subcortical brain damage
Interactions May increase tricyclic antidepressant serum concentrations and hypotensive action of antihypertensive agents; phenobarbital or carbamazepine may decrease effects; coadministration with anticholinergics may increase intraocular pressure; encephalopathylike syndrome associated with concurrent administration with lithium
Pregnancy C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions Severe neurotoxicity manifesting as rigidity or inability to walk or talk may occur in patients with thyrotoxicosis also receiving antipsychotics; if IV/IM, watch for hypotension; caution in patients diagnosed with CNS depression or cardiac disease; if history of seizures, benefits must outweigh risks; significant increase in body temperature may indicate intolerance to antipsychotics (discontinue if occurs)
Drug Name Pimozide (Orap)
Description Dopamine-receptor antagonist that alters effects of dopamine in the CNS. Possesses anticholinergic and alpha-adrenergic blocking activity. Because of its long half-life (55 h), a single daily dose may be feasible.
Adult Dose 0.5-1 mg PO qd, titrate up prn and as tolerated by 0.5 mg q5-7d; not to exceed 20 mg/d
Pediatric Dose 1 mg PO qhs, gradually titrate up prn and as tolerated (average <10 mg/d); not to exceed 0.2 mg/kg/d
Contraindications Documented hypersensitivity; history of cardiac arrhythmias or long QT syndrome; presently receiving macrolide antibiotics
Interactions Increases toxicity of MAOIs, alfentanil, CNS depressants, and guanabenz
Pregnancy C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions ECG recommended at initiation of therapy and at regular intervals thereafter; careful observation for appearance of extrapyramidal symptoms, especially necessary in elderly patients
Drug Name Fluphenazine (Prolixin)
Description Blocks postsynaptic mesolimbic dopaminergic D1 and D2 receptors in the brain. Exhibits strong alpha-adrenergic and anticholinergic effects and may depress the reticular activating system.
Adult Dose 0.5-1 mg PO, not to exceed 4 mg, divided tid/qid
Pediatric Dose Not recommended
Contraindications Documented hypersensitivity; narrow-angle glaucoma
Interactions May potentiate effects of narcotics, including respiratory depression; CNS effects increase when coadministered with lithium; barbiturates may decrease effects
Pregnancy C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions Besides extrapyramidal symptoms as described for haloperidol, mild leukocytosis, leukopenia, and eosinophilia may occasionally occur; dermatologic reactions are common; monitor patient for urinary retention, blurred vision, dry mouth, and constipation caused by anticholinergic effects
Drug Name Trifluoperazine (Stelazine)
Description Piperazine phenothiazine. Blocks postsynaptic mesolimbic dopaminergic D1 and D2 receptors in the brain. Increases dopamine turnover by blockade of the D2 somatodendritic autoreceptor. Antipsychotic and extrapyramidal effects correlate with decreased dopamine neurotransmission.
Adult Dose 1-2 mg PO bid, titrate up prn and as tolerated; not to exceed 40 mg/d
Pediatric Dose 2-15 mg/d PO divided doses
Contraindications Documented hypersensitivity; coma; circulatory collapse; prior blood dyscrasias
Interactions Additive anticholinergic effects may be seen with drugs possessing anticholinergic properties (ie, atropine, glycopyrrolate, scopolamine, other phenothiazines, some tricyclic antidepressants) and drugs with antimuscarinic properties (ie, amantadine, benztropine, clozapine, cyclobenzaprine, dicyclomine, diphenoxylate, disopyramide, hyoscyamine, maprotiline, meclizine, molindone, orphenadrine, oxybutynin, propantheline, tolterodine, trihexyphenidyl)
Enhances CNS depressant action of alcohol, anxiolytics, benzodiazepines, general anesthetics, hypnotics, opiate agonists (ie, butorphanol, nalbuphine, pentazocine), sedatives, skeletal muscle relaxants, and hypnotics
Diminishes antiparkinsonian effects of levodopa, pergolide, pramipexole, and ropinirole
Propranolol and phenothiazines appear to inhibit hepatic metabolism of each other, increasing serum levels and effects
Increased risk of adverse CNS effects with droperidol, haloperidol, metoclopramide, metyrosine, and risperidone
Pregnancy C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions Monitor for extrapyramidal symptoms (eg, dystonic reaction, akathisia, pseudoparkinsonism); neuroleptic malignant syndrome (hyperthermia, severe extrapyramidal dysfunction, alterations in consciousness or mental status, autonomic instability); tardive dyskinesia (involuntary movements of the perioral region); other adverse effects (eg, leukocytosis, leukopenia, eosinophilia, dermatologic, urinary retention, blurred vision, dry mouth, constipation)
Drug Category: Atypical neuroleptic drugs
Selective dopamine receptor D2 and 5-HT2 antagonists.
Drug Name Risperidone (Risperdal)
Description Selective monoaminergic antagonist with high affinity for serotonergic 5-HT2 and dopaminergic D2 receptors. Postulated to antagonize dopamine receptors in limbic system only. Exhibits selective serotonin blockade in mesocortical tract. Dopamine levels and transmission increase.
Adult Dose 0.5-4 mg/d PO single or divided doses
Start at 0.5-1 mg PO qd and titrate slowly prn and as tolerated
Common dose range 2-6 mg/d
Contraindications Documented hypersensitivity
Interactions May increase effects of antihypertensives; may antagonize effects of levodopa; carbamazepine decreases serum concentration and effects; clozapine increases levels and effects
Pregnancy C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions Associated with GI distress; adverse CNS effects (eg, drowsiness, agitation, anxiety, insomnia, headache); extrapyramidal symptoms (ie, akathisia, dystonic reaction, pseudoparkinsonism); other adverse reactions include blurred vision, fatigue, rhinitis, libido increase, impotence, ejaculation dysfunction, and priapism
Drug Name Olanzapine (Zyprexa)
Description Considered a second-line agent for tic suppression. Small studies have shown clinical effectiveness. Of the atypical neuroleptics, risperidone has been more thoroughly studied than olanzapine.
Adult Dose 2.5-20 mg PO qhs
Pediatric Dose Not established; 2.5-5 mg PO qhs
Contraindications Documented hypersensitivity
Interactions Fluvoxamine may increase effects of olanzapine; antihypertensives may increase risk of hypotension and orthostatic hypotension; levodopa, pergolide, bromocriptine, charcoal, carbamazepine, omeprazole, rifampin, and cigarette smoking may decrease the effects of olanzapine
Pregnancy C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions Caution in narrow-angle glaucoma, cardiovascular disease, cerebrovascular disease, prostatic hypertrophy, seizure disorders, hypovolemia, and dehydration; hyperglycemia may occur (some cases extreme), resulting in ketoacidosis, hyperosmolar coma, or death; administration of more than one IM injection is associated with substantial orthostatic hypotension (33%), maintain patient in recumbent position and monitor blood pressure before repeating IM doses
Drug Name Ziprasidone (Geodon)
Description Atypical antipsychotic approved by FDA in 2001. In recent head-to-head study, caused less weight gain than olanzapine in schizophrenia.
Adult Dose Not established; 10-40 mg PO qhs
Pediatric Dose 5-40 mg PO qhs (mean final daily dose in one study = 28.2 mg)
Contraindications Documented hypersensitivity; history of prolonged QT
Interactions CYP450-3A4 inhibitors (eg, erythromycin, ketoconazole) may increase serum levels; CYP450-3A4 inducers (eg, carbamazepine, rifampin) may decrease serum levels; coadministration with drugs that increase QT/QTc interval (eg, amiodarone, fluoroquinolones) increases risk of life-threatening arrhythmias; amphetamines may decrease efficacy of ziprasidone; ziprasidone may decrease efficacy of levodopa
Pregnancy C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions Prolongs QT/QTc; caution in patients with known risk factors (eg, hypomagnesemia, hypokalemia); caution in seizure disorders; may cause hypotension, extrapyramidal symptoms, and somnolence; hyperglycemia may occur (some cases extreme), resulting in ketoacidosis, hyperosmolar coma, or death
Drug Category: Alpha2-adrenergic agonists
First agents for pharmacotherapy for tics
Drug Name Clonidine (Catapres)
Description Stimulates alpha2-adrenoreceptors in brain stem, activating an inhibitory neuron, which, in turn, results in reduced sympathetic outflow. These effects result in a decrease in vasomotor tone and heart rate. Clonidine is a first-line agent for tic suppression and treatment of ADHD in TS.
Adult Dose 0.1 mg PO bid, titrate up prn and as tolerated; usual dose 0.2-1.2 mg/d PO divided bid/tid
Pediatric Dose 0.05 mg PO qd, gradually increased to achieve the lowest effective dosage
Contraindications Documented hypersensitivity
Interactions Tricyclic antidepressants inhibit hypotensive effects; coadministration with beta-blockers may potentiate bradycardia; tricyclic antidepressants may enhance hypertensive response associated with abrupt clonidine withdrawal; hypotensive effects are enhanced by narcotic analgesics
Pregnancy C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions Caution in cerebrovascular disease, coronary insufficiency, sinus node dysfunction, and renal impairment
Drug Name Guanfacine (Tenex)
Description Proven in randomized controlled trial to benefit both ADHD and, to lesser extent, tic severity in children with chronic tics and ADHD. Considered a first-line agent. Has a longer half-life than clonidine, and can be less sedating.
Adult Dose 0.5-2 mg PO tid
Pediatric Dose 0.5-1 mg PO tid
Contraindications Documented hypersensitivity
Interactions Increases effect of other hypotensive agents; tricyclic antidepressants may decrease hypotensive effects of guanfacine
Pregnancy C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions Caution in hepatic impairment, severe coronary insufficiency, recent myocardial infarction
Drug Category: Benzodiazepines
Inhibit calcium ions from entering slow channels, select voltage-sensitive areas, or smooth muscle.
Drug Name Clonazepam (Klonopin)
Description Suppresses muscle contractions by facilitating inhibitory GABA neurotransmission and other inhibitory transmitters.
Adult Dose 0.25-0.5 mg PO tid, titrate up prn and as tolerated by 0.5-1 mg q3d
Common dose range 0.5-2 mg tid; bid or qhs doses also are used often
Pediatric Dose <10 years or 30 kg: 0.01-0.03 mg/kg/d PO divided bid/tid; not to exceed 0.2 mg/kg/d
>10 years or >30 kg: Administer as in adults
Contraindications Documented hypersensitivity; severe liver disease; acute narrow-angle glaucoma
Interactions Phenytoin and barbiturates may reduce effects; coadministration of CNS depressants increases toxicity
Pregnancy B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions Caution in chronic respiratory disease or impaired renal function; withdrawal symptoms can result from abrupt discontinuation of medication
Drug Category: Dopamine agonists
Hypothesized to reduce dopamine receptor supersensitivity, which is one proposed theory to the underlying pathophysiology of TS. While evidence for the effectiveness of dopamine agonists in TS is encouraging, the studies have been small. More research needs to be done for this class of medications in TS.
Pergolide, a dopamine agonist, was withdrawn from the US market March 29, 2007, because of heart valve damage resulting in cardiac valve regurgitation. Pergolide should not be stopped abruptly. Health care professionals should assess patients’ need for dopamine agonist (DA) therapy and consider alternative treatment. If continued treatment with a DA is needed, another DA should be substituted for pergolide. For more information, see FDA MedWatch Product Safety Alert and Medscape Alerts: Pergolide Withdrawn From US Market.
Drug Name Ropininirole (Requip)
Description Considered a third-line agent for treatment of TS. Lower doses have been shown to be effective (lower than the doses used in Parkinson disease)
Nonergot dopamine agonist that has high relative in vitro specificity and full intrinsic activity at D2 subfamily of dopamine receptors, binding with higher affinity to D3 than to D2 or D4 receptor subtypes. Has moderate affinity for opioid receptors. Metabolites have negligible affinity for dopamine D1, 5HT-1, 5HT-2, benzodiazepine, GABA, muscarinic, alpha1-, alpha2- and beta-adrenoreceptors.
Precise mechanism of action as treatment for Parkinson disease is unknown. However, possibly related to the stimulation of dopamine receptors in striatum.
Discontinue ropinirole gradually over a 7-day period. Decrease frequency of administration from tid to bid for 4 days. For the remaining 3 days, decrease frequency to once daily prior to complete withdrawal of ropinirole.
Adult Dose Studies in individuals with TS have used 0.25 mg at bedtime for the first 2 weeks, 0.25 mg bid during week 3–4, followed by 0.75 mg during week 5 - 6, and then a final dose of 0.5 mg bid
Pediatric Dose Not established
Contraindications Documented hypersensitivity
Interactions Estrogens may reduce ropinirole clearance by 36%; dose adjustment may be required if estrogen therapy stopped or started during treatment with ropinirole; potential exists for substrates or inhibitors of CYP1A2 to alter ropinirole's clearance; if therapy with a potent CYP1A2 inhibitor stopped or started during ropinirole treatment, dose adjustments may be necessary; dopamine antagonists such as phenothiazines, butyrophenones, thioxanthenes, and metoclopramide may diminish effectiveness; coadministration with sedatives and other CNS depressants may cause additive sedation
Pregnancy X - Contraindicated; benefit does not outweigh risk
Precautions Monitor for signs and symptoms of orthostatic hypotension; dopamine receptor agonists may potentiate dopaminergic side effects of levodopa and may cause or exacerbate pre-existing dyskinesia (decreasing the dose of levodopa may ameliorate this side effect); cases of retroperitoneal fibrosis, pulmonary infiltrates, pleural effusion, and pleural thickening have occurred in some patients treated with ergot-derived dopaminergic agents; complete resolution of these complications does not always occur when drug is discontinued; may cause patients to fall asleep or feel very sleepy while doing normal activities, such as driving; may cause orthostatic hypotension; common adverse effects while treating restless leg syndrome include nausea, somnolence, vomiting, dizziness, and fatigue
Drug Name Pergolide (Permax)
Description Pergolide withdrawn from US market. Mixed ergot derivative dopamine agonist. Proven effective for tic suppression
Adult Dose Not established; 0.05-1 mg PO qhs to tid
Pediatric Dose 0.05 mg PO qhs to 0.1 mg PO tid
Contraindications Documented hypersensitivity
Interactions Dopamine antagonists such as the neuroleptics phenothiazines, butyrophenones, thioxanthenes, or metoclopramide may diminish effectiveness of pergolide, a dopamine agonist; because pergolide mesylate is more than 90% bound to plasma proteins, exercise caution if pergolide is coadministered with other drugs known to affect protein binding
Pregnancy C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions Caution in cardiac dysrhythmias; may cause or exacerbate preexisting states of confusion and hallucinations or dyskinesia
Drug Category: Neuromuscular blocker agents
Inhibit muscle contractions.
Drug Name Botulinum toxin (BOTOX®)
Description Neurotoxin produced from fermentation of Clostridium botulinum type A. Exerts neuromuscular blockade by binding to receptor sites on presynaptic motor nerve terminals and inhibiting calcium-dependent release of acetylcholine from vesicles situated within nerve endings. Partial chemical denervation of muscle results, which diminishes muscle activity in area of injection.
Adult Dose Not established
Pediatric Dose Not established
Contraindications Documented hypersensitivity; disease of neuromuscular transmission; coagulability (ie, anticoagulant therapy); injections into the central area of upper eye lid
Interactions Drugs that interfere with neuromuscular transmission (ie, aminoglycosides) may potentiate neurotoxic effects
Pregnancy C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions Do not exceed recommended dosage
Further Inpatient Care
Only rarely do patients with Tourette syndrome (TS) need hospitalization. Most of the patients who do require hospitalization have comorbid conditions and are a threat to themselves or to others. Patients with the complex tics of coprolalia or copropraxia might need a brief hospitalization if their families have difficulty controlling them.
Further Outpatient Care
Psychotherapeutic counseling and support
Other measures should be taken to nurture self-esteem and self-correction. Individual counseling, cognitive and behavioral therapies, and group therapy should be considered. Areas of strength should be emphasized, such as talents and skills, interests, any family or peer supports, and psychological resilience. Social skills training can help develop and reinforce more effective methods of confident and prosocial communication. Parents or other guardians may benefit from parent behavior management and discipline training, recognizing that the underlying purpose of discipline is to instill a sense of self-control and responsibility for one's behavior. Allowances must be made for the child's uncontrollable behaviors that result from processes of the disorder, but some behaviors, such as spitting at others or obscene gestures, have negative social connotations and require special guidance. Methods to help the child manage these behaviors include nonjudgmental acceptance of the child regardless of the nature of the behaviors and working with the child to adapt or substitute alternative, more appropriate behaviors that satisfy premonitory urges, such as spitting into a handkerchief instead of spitting openly. Parenting skills books, workshops, and trained specialists are widely available and emphasize practical methods in positive reinforcement of desirable behaviors through giving praise or rewards, modeling appropriate behaviors, and administering "time-outs" from rewards or attention for inappropriate or uncontrolled behaviors. Parents also may benefit from group support and education or other topical groups and from individual supportive counseling to cope with accompanying stress.
Information is available through school counselors, psychologists, representatives of local chapters of the Tourette Syndrome Association, Inc, or related topical organizations.
Prognosis
For most patients, symptoms reach their fullest expression some time during adolescence, roughly a decade after onset. At some time, symptoms become more unpredictable, sometimes changing markedly from day to day or week to week. Despite this, the later teenage years are often a time when the severity of tics levels off and remission begins. Several retrospective studies indicate that many patients, even those with severe tics during childhood, improve considerably during the late teenage to early adult years. Approximately one third of patients experience complete remissions of tics during this period, whereas another one third of patients improve to the point that their tics are relatively mild and do not cause impairment. Some evidence shows that adolescent tic severity may be of more prognostic value. Two thirds of children with TS can anticipate a significant amelioration of their tics or almost complete remission. Life-long remissions are rare. The continued presence of such tics is often denied or minimized by these parents but is reported by other family members. At times, tics do not occur in a physician's office, and assessment of these very mild, but persistent tic disorders is difficult. Approximately one third of patients with TS do not experience a significant amelioration of symptoms as adults. For these patients, little data are available on which percentages become worse, remain much the same, or improve to some degree. A fair number of patients present in their third, fourth, and fifth decades for treatment after self-diagnosis. Elderly patients who have never been diagnosed are far more rare but also do present for diagnosis.
Patient Education
The Tourette Syndrome Association is an excellent tool for patient education. One of the most important aspects of treating TS is educating the patient and family members about tic disorders and associated behavioral disturbances. In addition to lengthy discussions with the patient and family at the time of diagnosis, a packet of educational brochures prepared by the Tourette Syndrome Association is helpful. A local TS support group may be of great benefit to patients and family members. Individual, group, or family counseling may help in facilitating a healthy adaptation to the illness. Several relaxation or stress management treatment approaches reportedly improve the tics. For example, tics are known to worsen from stress and to improve during periods of relaxation. Whether such therapies have a direct effect on the tics or exert an indirect influence by allowing patients to deal more productively with life stresses is unclear.
Medical/Legal Pitfalls
Patients with Tourette syndrome (TS) may go undiagnosed. The excessive movements are implicated as twitchiness or anxiety and not necessarily considered a disease. Patients and families may not necessarily alert the practitioner regarding the symptoms. The practitioner could potentially diagnose tics as chorea or myoclonus, and initiate an unnecessary work up to evaluate these conditions. Improper diagnosis of phonic tics, such as throat clearing, sniffing or cough, as allergies or asthma.
I would like to acknowledge the help and support of Dr. Mark Landau, Staff Neurologist at Walter Reed Army Medical Center. His advise and review of this article and topic was greatly appreciated and necessary for the submission of the updated eMedicine review of Tourette Syndrome.
The authors and editors of eMedicine gratefully acknowledge the contributions of previous author, Emad Soliman, MD, to the development and writing of this article.
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