INTRODUCTION	Section 2 of 10
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Bibliography

Background: Tourette syndrome (TS) is characterized by motor and phonic (vocal) tics. Comorbid conditions, particularly obsessive-compulsive disorder (OCD) and attention deficit disorder (ADD), often accompany the tics and may dominate the clinical picture in some patients.

In this article, the incidence, genetics, clinical picture, and management of TS are reviewed.

Historical perspective

One of the earliest reports of TS dates to 1825, when Itard described a French noblewoman with body tics, barking sounds, and uncontrollable utterances of obscenities. Sixty years later, Georges de la Tourette, the French neurologist and student of Charcot, reviewed Itard's original case and added 8 more patients. Gilles de la Tourette noted that all 9 patients shared one common feature; they all exhibited brief involuntary movements or tics. An additional 6 patients made noises, 5 shouted obscenities (coprolalia), 5 repeated the words of others (echolalia), and 2 mimicked others' gestures (echopraxia). Although Gilles de la Tourette considered the disorder that he described to be hereditary, the etiology was ascribed to psychogenic causes for nearly a century following the original report.

In the 1960s, the perception of TS began to change when the beneficial effects of neuroleptic drugs on the symptoms experienced by patients with TS began to be recognized. This observation helped to refocus attention from psychogenic causes to primarily organic etiologies involving a dysfunction of the central nervous system (CNS). A reexamination of biographic material has led to the recognition that many notable historical figures, including Samuel Johnson, MD, and possibly Wolfgang Amadeus Mozart, were afflicted with TS.

The view of TS as a life-long disorder, once held as a certainty, has changed considerably in the past 2 decades. In most cases, tics are known to ebb in severity and are not problematic by the adult years; however, this discovery has been accompanied by the realization that TS is a far more complex disorder than originally was conceptualized. The association of tics with OCD and ADD symptomatology and with several other impulse control disorders has caused TS to be investigated as a model neuropsychiatric disorder and has raised more questions than it has answered.

Pathophysiology: Although the pathophysiologic mechanisms of TS still are unknown, the weight of evidence supports an organic rather than a psychogenic origin. Despite the observation that some tics may be partly voluntary, physiologic studies suggest that tics are not mediated through normal motor pathways used for willed movements. The common absence of premotor potentials in simple motor tics suggests that tics truly are involuntary or that they occur in response to some external cue.

Sleep studies have provided additional evidence regarding the idea that tics truly are involuntary. In polysomnographic studies of 34 patients with TS, motor tics occurred in various stages of sleep in 23 of the patients and vocal tics occurred in 4 of the patients. Further studies are needed to elucidate the physiologic and cellular mechanisms underlying tics and TS. Positron emission tomography (PET) scanning of patients with TS has shown a decreased signal in the caudate nuclei, similar to that found in patients with Huntington disease.

Frequency:

• In the US: TS carries an annual incidence of 0.46 cases per 100,000 persons or approximately 1000 new cases annually in the entire US population. The generally accepted prevalence of TS is 0.5 cases per 1000 persons (ie, 5 in 10,000). Incidence is higher in special groups (eg, children with special education). One study showed that 12% of children in special education programs had TS and that 28% of these children fell in the larger tic diagnostic criteria.

• Internationally: 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 of the syndrome appears similar regardless of ethnicity or culture, suggesting a common genetic basis. Ethnic or regional differences in the prevalence of TS might help to identify the gene(s) involved; however, because of the difficulty of diagnosis and case ascertainment, the high level of background noise precludes any direct comparison of national or regional prevalences. Further international research using population-based methodology is suggested.

Mortality/Morbidity: Tourette syndrome, as described by the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria, is associated with distress or social or functional impairment.

• Patients with TS usually avoid social encounters because stress and different environmental stresses can provoke tics. Children with TS, therefore, often do not do well in school irrespective of their intelligence quotient.

• Very rarely, especially when associated with OCD or obsessive-compulsive symptoms (OCSs), TS can lead to death due to suicide.

Race:

• Currently, no epidemiologic studies show a racial predilection. TS occurs in all social classes.

Sex:

• Males are associated consistently with an increased risk of TS, regardless of study methodology.

• The male-to-female ratio varies from 1.6-10:1, with all studies finding higher disease prevalence in males than in females.

• The risk of comorbid symptomatology also appears to vary by sex, with males more likely to have attentional problems and females more likely to have obsessive-compulsive behaviors (OCBs). These sexual differences may be mediated partially by the effect of sex hormones on early CNS organization.

Age:

• Children are much more likely to meet the diagnostic criteria for TS than adults.

• TS has been described as early as infancy, but symptoms most commonly begin around age 7 years.

• In most children with TS, the frequency and severity of symptoms improve significantly by adulthood. Whether this symptomatic improvement represents a resolution of the underlying disease pathology or improved compensatory mechanisms is not known.

	CLINICAL	Section 3 of 10
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Bibliography

History:

• Onset of TS

• TS is recognized as a disorder with childhood onset. The upper age limit for symptom development is somewhat controversial and has been reflected by several revisions of diagnostic criteria in the past 2 decades; for example, the reported upper age limit is 14 years in the Diagnostic and Statistical Manual of Mental Disorders, Third Edition (DSM-III); 21 years in the Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition (DSM-III-R); and 18 years in the DSM-IV.

• Tics may present suddenly; however, they usually become noticeable gradually or have intervening spontaneous remissions. Although symptoms can begin during infancy or in late adolescence, the usual age of onset of tics has been found to occur in patients aged 2-15 years, with a mean age range of 6-7 years. Approximately 75% of patients with TS have symptoms by age 11 years.

• In most patients, simple tics (eg, blinking, nose twitching) are the presenting symptoms. A review of several large studies, composed of approximately 2400 patients, indicates that 50-70% of patients with TS reported facial tics as their initial symptom.

• Other simple tics, involving mostly neck or shoulder movements, are the next most common presenting symptoms, followed by involuntary movements of the upper extremities.

• Tics of the lower extremities and trunk are the least common.

• Vocal tics occur as initial symptoms in only 12-37% of patients with TS. Although vocal tics may be the precipitant for consultation with a physician, a careful history often reveals examples or prior motor tics that were overlooked or forgotten. Presenting vocal tics generally are noises rather than words. In many patients, vocalizations simply may consist of motor tics that affect the vocal apparatus. In most patients, the utterance of actual words is virtually pathognomonic of TS but is very rare as a presenting symptom.

• Progression of TS

• Tics typically wax and wane in intensity and frequency and change in character over time. Initial symptoms may disappear, although new ones take their place. The variety of tics increases as new tics are added and older ones recur. Most patients have 1-2 tics that become enduring characteristics, either returning persistently or remaining stubbornly unchanged.

• Over the next decade (or more), several types of tics may coexist at the same time, and complex tics (eg, skipping, squatting, touching, twirling) become more common. Vocal tics may change from meaningless sounds to words or phrases. Coprolalia, the most complex type of vocal tic, usually does not appear until 4-7 years after the onset of the disorder; however, coprolalia only occurs in less than one third of patients with TS. These more complex tics may contribute to the bizarre clinical presentation of TS that, in the past, has been erroneously attributed to attention-seeking behaviors or severe psychopathology.

• Although never experiencing coprolalia, some patients describe intrusive coprolalic thoughts (eg, mental coprolalia) or may even exhibit coprographia.

• Other symptoms may appear as the syndrome develops to its fullest severity, to include the following:
  • Slower more sustained movements (eg, dystonic tics)

  • Self-injurious tics

  • Sensory tics

  • Copropraxia

  • Echolalia

  • Palilalia

  • Irregular speech intonations

  • Talking with different accents

• Symptoms wax and wane over time, and sometimes, this occurs for no identifiable reason; however, this may occur in response to identifiable physical or emotional stresses, as follows:
  • Exogenous agents (eg, caffeine, certain medications) may cause symptom exacerbation; however, this response varies from patient to patient.

  • Endogenous processes (eg, menstrual cycles, other hormonal changes) also may alter the severity of symptoms.

  • Excitement, positive or negative in nature, causes a worsening of tics.

  • Currently, 4 patients are known to have had symptoms that became precipitously and dramatically worse after a traumatic event (eg, automobile accident), and the symptoms were so severe that the patients had to be taken to the emergency department. In the emergency department, patients initially were considered to have status epilepticus; but eventually, this condition was ruled out in all of the patients.

• Relaxation usually lessens tics; however, if tics are suppressed voluntarily for a time, relaxation may result in a period of more intense tic expression, as if the tics were reserved and then released all at once.

• Exacerbations of tics

• Recently, certain bacterial and viral infections have been associated with an autoimmune response that may cause or exacerbate tics and OCSs. Other stresses that may influence the severity of tics include pain, allergies, and temperature changes (patients often cite heat as an exacerbating factor). Although the scientific basis of some of these factors may be in doubt, they cannot be dismissed until further knowledge of the pathogenesis of TS is obtained.

• In a study of 60 patients with tic disorders, 41 (68%) of the patients thought that all their tics were produced intentionally and 15 (25%) additional patients had both voluntary and involuntary movements; therefore, 93% of the tics were perceived to be irresistibly but purposefully executed. The intentional component of the movement may be a useful feature in differentiating tics from other hyperkinetic movement disorders.

• Characteristics of tics

• Complex motor tics may be difficult to differentiate from compulsions, which frequently accompany tics, particularly in patients with TS. A complex repetitive movement or noise may be considered a compulsive tic when preceded by or associated with a feeling of anxiety, tension, or other discomfort, which is relieved, at least temporarily, by the performance of the activity. Another clue that helps to differentiate a motor tic from a compulsive tic is that the latter usually is preceded by an irresistible urge to perform the movement or sound or a fear that something bad will happen if the movement or sound is not promptly or properly executed.

• Self-injurious behavior (eg, scratching, picking) is an example of the borderline between a compulsion and a complex motor tic. The distinction between complex motor tics and compulsions is not always possible, particularly when the patient is unable to verbalize such feelings.

• In contrast to other hyperkinetic movement disorders, tics usually are intermittent but may be repetitive and stereotypic. Fluctuation or waxing and waning in frequency, intensity, and distribution is a typical feature of tics. Typically, tics can be suppressed volitionally, although this may require intense mental effort. Suppressibility is not unique or specific for patients with tics, and it has been well documented in patients with other hyperkinetic movement disorders. Besides temporary suppressibility, tics also are characterized by suggestibility and exacerbation with stress, excitement, boredom, fatigue, and heat exposure.

• Tics also may increase during relaxation after a period of stress. In contrast to other hyperkinetic movement disorders that usually are suppressed completely during sleep, motor and phonic tics may persist during all stages of sleep.

• Many patients note a reduction in their tics when distracted by concentrating on mental or physical tasks (eg, playing a video game, during an orgasm). Others have increased frequency and intensity of their tics when distracted, especially when they no longer have the need to suppress the tics. Tics also typically are exacerbated by dopaminergic drugs and CNS stimulants, including methylphenidate and cocaine.

• Premonitory symptoms

• 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 temporarily are relieved by touching or scratching them.

• Course of associated symptoms or conditions

• Obsessive-compulsive disorder
  • Several closely related neuropsychiatric disorders are associated with TS. Some evidence suggests that OCD or OCSs have a genetic link with TS or may be an alternative expression of TS. Although estimates of the incidence of OCD in patients with TS varies considerably, most studies rate it as higher than 30%.

  • Obsessive thoughts and compulsive rituals reportedly occur 3-6 years after the onset of tics, reaching a peak in late adolescence or early adulthood (the same time that tics may be remitting or waning). If tics still are problematic at the time that OCSs appear, the tics may be entwined with ritual behaviors. For example, a child may have to perform a certain tic over and over until it feels right to stop. The tics involved usually are complex in nature, and distinguishing between tics and compulsions may be virtually impossible. In late adolescent and adult years, this type of association is less common, but OCD usually is more enduring than tics and continues, with exacerbations and ameliorations or remissions, throughout adulthood.

  • Many patients with TS have more difficulty with OCSs than with the tics, and a growing tendency may exist for physicians to consider a diagnosis of TS when a child presents with difficult OCSs, even if the tics are minimal.

• Attention deficit hyperactivity disorder
  • ADD, usually with attention deficit hyperactivity disorder (ADHD), commonly is associated with TS. Typically, symptoms of hyperactivity, distractibility, inattentiveness, low frustration tolerance, and impulsivity are first noted in children aged 3-5 years, before the tics become prominent. Because of this, many patients are treated with stimulant medications prior to the development of TS. Although evidence suggests that stimulants may cause or exacerbate tics, this occurs only in some patients who are more vulnerable, and no hard evidence proves that TS may be caused by stimulants.

  • Symptoms of ADHD, like those of OCD, can be far more debilitating than the tics and can cause a significant number of patients with TS to desire treatment. Although ADD is estimated to last into the adult years in at least 50% of patients, the symptoms often level off or become more manageable with maturity.

• Specific learning disabilities and soft neurologic signs are found to have a higher incidence in patients with TS. These difficulties often add further complications to an already difficult school experience. Children, although intelligent, may have poor academic achievement, and slight motor coordination difficulties may preclude these children from doing well in athletic endeavors.

• Depression and anxiety disorders, impulse disorders, and antisocial behaviors have been demonstrated to have an increased incidence in association with TS. Generally, these conditions occur somewhat later than OCD and ADHD. Whether these are biologically engendered or result from living with a chronic, often embarrassing, and socially isolating debilitating disorder remains to be better defined.

• Self-abusive behaviors, specifically self-abusive tics (eg, hitting or biting oneself, even to the point of breaking ribs) are a problem for a small percentage of patients with TS. Such symptoms often are misunderstood as being intentionally self-mutilative. The natural course of such symptoms is poorly defined.

• Sudden explosive episodes of uncontrollable rage have been reported in several patients with TS. The rages can occur in the absence of an obvious precipitant and can lead to severe impairment of social and family functioning.

• Clinical classification of tics

• Simple motor tics: These are isolated, involving only one group of muscles, and may be single or repetitive.
  • Clonic - Brief (usually <100 m/s), jerklike (eg, blinking, nose twitching, head jerking)

  • Dystonic - Sustained (usually >300 m/s), twisting, or squeezing movement or posture (eg, blepharospasm, oculogyric movements, bruxism, mouth opening, torticollis, shoulder rotation)

  • Tonic - Sustained (usually >500 m/s), isometric contraction (eg, abdominal or limb tensing)

• Complex motor tics: These are coordinated, sequential movements that may resemble normal motor acts or gestures but are inappropriately intense and timed and may be repetitive (stereotypic).
  • Seemingly nonpurposeful (eg, head shaking, trunk bending)

  • Seemingly purposeful - May be difficult to differentiate from compulsions (eg, touching, throwing, hitting, jumping, kicking), copropraxia (obscene gestures), echopraxia (imitating the gestures of others)

• Simple phonic tics: These tics are single meaningless sounds and noises (eg, throat clearing, grunting, sniffing, squeaking, coughing, barking, screaming, whistling, blowing, sucking).

• Complex phonic tics: These tics are linguistically meaningful utterances and verbalizations (eg, coprolalia, echolalia, palilalia (involuntary repetition of words or phrases).

• Compulsive tics: These tics are movements or sounds that occur in response to an inner urge or feeling.

• General characteristics of tics

• Premonitory feelings or sensations

• Temporary suppressibility

• Suggestibility

• Increase with stress

• Increase during relaxation after stress

• Decrease with distraction and concentration

• Waxing and waning, transient remissions

• Persist during sleep

• Etiologic classification of tics

• Physiologic tics (mannerisms)

• Pathologic tics (primary sporadic)
  • Transient motor or phonic tics (<1 y)

  • Chronic motor or phonic tics (>1 y)

  • Adult-onset (recurrent) tics

  • Tourette syndrome

• Pathologic tics (inherited)
  • Tourette syndrome

  • Huntington disease

  • Primary dystonia

  • Neuroacanthocytosis

• Pathologic tics (secondary [tourettism])
  • Infections - Encephalitis, Creutzfeldt-Jakob disease

  • Sydenham chorea

  • Drugs - Stimulants, levodopa, carbamazepine, phenytoin, phenobarbital, antipsychotics (tardive tics)

  • Toxins - Carbon monoxide

  • Developmental - Static encephalopathy, mental retardation syndromes, chromosomal abnormalities

  • Other - Head trauma, stroke, neurocutaneous syndromes, chromosomal abnormalities, schizophrenia, neuroacanthocytosis degenerative disorders

• Related disorders
  • Stereotypies

  • Self-injurious behaviors

  • Hyperactivity syndrome

  • Compulsions

  • Excessive startle

Physical: TS is difficult to study, primarily because of diagnostic uncertainty. TS has no definitive diagnosis. Diagnostic criteria, even if applied systematically, cannot be confirmed as constituting a distinct pathophysiologic (let alone etiologic) entity. No hallmark neuropathologic lesion at autopsy serves to confirm symptom-based diagnosis, and a TS gene has yet to aid with diagnosis. Diagnosis must be made by clinical examination and history and must meet an empirically derived constellation of symptoms.

• Diagnostic criteria for TS, as presented in the DSM-IV, include the following:

• Both multiple motor and one or more vocal tics have been 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 throughout a period of more than 1 year, and, during this period, a tic-free period of more than 3 consecutive months is not reported.

• The disturbance causes marked distress or significant impairment in social, occupational, or other important areas of functioning.

• The onset is before age 18 years.

• The disturbance is not due to the direct physiologic effects of a substance or a general medical condition.

• No one symptom is pathognomonic for TS, and symptom type and intensity show great variety and variability. Epidemiologic methods are especially vulnerable to errors because of the clinical characteristics of TS, including a large variance in symptom intensity and expression and the fact that the symptoms are situation-dependent and often are not recognizable by the patient or family.

• Because TS symptom intensity and frequency decrease with increasing age, studies with a greater proportion of young subjects have observed more easily the signs of disease and may overestimate population prevalence. Comparisons between populations with different age distributions can be made only after they have been adjusted for these age differences. Similarly, because TS is more apparent in male subjects, study populations with a higher proportion of male subjects would be expected to report a higher disease prevalence. Comparisons between 2 study populations can be made only after adjustment for differing sex proportions.

• Tics typically occur less frequently in social situations. If study diagnostic criteria require clinically observed signs, disease frequency may be underestimated, especially if based on a single examination. Although TS awareness in the medical community seems to be reducing the length of time to diagnosis, long delays in diagnosis still occur. In addition to the problem of misdiagnosis, studies based on clinic or physician records miss patients with less severe cases who have not sought medical care, and these studies could be biased by differential access to care in different populations.

• If diagnosis or screening is obtained by a questionnaire-based self-assessment, disease frequency may be underestimated, owing to underreporting of tic symptoms. Mildly affected patients and their family members commonly are unaware of their tics, and cultural factors may result in differences in symptom interpretation, further complicating population comparisons.

• Diagnosis is complicated further by the co-occurrence of TS and various other neuropsychiatric disorders.

• Transient tic syndrome: The most common and mildest of the idiopathic tic disorders is the transient tic disorder (TTD) of childhood. This disorder is essentially identical to TS, except the symptoms last less than 1 year, and, therefore, the diagnosis can be made only in retrospect. TTD is estimated to occur in as many as 24% of school children.

• Such symptoms are estimated to occur in 4-24% of school children. The true prevalence of transient tics is unknown because these symptoms often are fleeting and rarely are documented. Because these symptoms, by definition, do not persist for prolonged periods, the course of TTD is assumed to be both brief and benign.

• Tics originally diagnosed as transient sometimes persist for several years before remitting and, then, might remain in remission for as long as 10 years.

• Children presenting initially with both motor and vocal tics or vocal tics alone are at higher risk for subsequent development of TS.

• Classification of TS

• Pure TS - Consists only of motor and vocal tics

• Full-blown TS - Also includes coprophenomena, echophenomena, and paliphenomena

• TS plus syndromes - When a patient also has ADHD, OCBs, or OCD

• Emotional and behavioral impact

• The psychodynamic consequences of TS vary widely.

• As a group, affected children tend to be more withdrawn and less popular than their peers. Interference from any of the comorbid conditions additionally threatens positive social adaptation.

• Feelings of guilt, shame, and embarrassment may be present and are compounded when the child suffers ridicule from classmates or siblings and impatience or admonitions from uninformed parents or teachers.

• Even informed parents may react with quick-tempered responses to annoying noises or activity levels, or, they may feel guilty for periodic desires to not spend time with the child. Blends of isolation, school failure, depression, social anxiety, aggressive behaviors, and family dysfunction may ensue.

Causes:

• Genetic theory

• TS was shown to be autosomal dominant by complex segregation analysis techniques. Current scientific thinking is that almost all cases of primary TS are determined genetically. Studies investigating the mode of inheritance in families have indicated major gene involvement, with the most widely held notion of the hereditary transmission pattern being autosomal dominant.

• However, recent information suggests that the pattern of inheritance may be more complicated than previously was thought. For example, bilinear transmission, involving both the maternal and paternal sides, is common in families with TS and may be related to the severity of symptoms. Therefore, polygenic influences possibly are important, with clinical expression being determined by the number of susceptibility loci that are inherited from either the mother or father.

• The best approaches to clarify the hereditary pattern of TS may come from recent advances in the field of quantitative genetics.

• Postinfectious theory

• Some recent work suggests that brain involvement may be occurring only indirectly. Keissling and others have observed an association between TS and recent streptococcal infection. The authors have speculated that an immunologic response to the pathogen occurs, resulting in the formation of brain-directed antineuronal antibodies that cause the tic disorder (analogous to the pathogenesis of Sydenham chorea). Therefore, the inherited dysfunction in patients with TS could be an abnormal susceptibility or reaction to streptococcal infection.

• TS also may be associated with pediatric autoimmune neuropsychiatric disorders associated with Streptococcus (PANDAS).

• In an analogous situation, an inherited susceptibility to middle-ear infections in the first 6 months of life might lead to altered sensory input, with resulting disturbances in brain neuronal connectivity, explaining the development of language problems observed in persons with dyslexia.

• An important future direction in TS research is to better define the interrelationships between genetic and environmental factors in the pathogenesis of the disorder. Postinfectious immune-mediated mechanisms may not be involved in primary TS, but a secondary tic disorder with this etiology is evident. Some recent work suggests that antistreptococcal antibodies may not be significantly different in persons with TS, but B cell–mediated immune mechanisms still may be important.

• Future theories

• In the future, major advances in our understanding of the neurobiology of TS likely depend on progress in elucidating genetic mechanisms.

• An interesting lead is the consistent finding from various neuroimaging techniques (eg, MRI, single-photon emission computed tomography [SPECT], PET) that an abnormality exists in structural and functional relationships between the left and right sides of the brain, particularly in the region of the basal ganglia.

• Another promising line of investigation regarding the pathogenesis of TS involves the role of sex hormones in brain developmental processes. Recent findings raise the possibility that sex hormones may mediate the abnormal development of specific brain regions, particularly the basal ganglia and limbic system, resulting in TS.

• Risk factors

• Male sex

• Young age

• Family history of TS

• Prior use of cocaine (correlation shown by some studies)