Tourette Syndrome ?>

Tourette Syndrome

Tourette Syndrome


Introduction
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.
Clinical

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

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