INTRODUCTION — Tourette syndrome (TS) is a neurological disorder manifested by motor and phonic tics with onset during childhood. Although TS is the most common cause of tics, there are many potential etiologies in the differential diagnosis, including neuroacanthocytosis, certain drugs such as dopamine receptor blocking drugs and cocaine, pervasive developmental disorder and others.

PATHOGENESIS — TS was thought to be inherited in an autosomal dominant pattern, but the mode of inheritance may be more complex. In most cases a bilineal transmission (inheritance from both parents) is clearly evident. Although the genetic basis remains elusive, several loci have been identified as candidate susceptibility regions. The disorder likely results from a disturbance in the striatal-thalamic-cortical (mesolimbic) spinal system, which leads to disinhibition of the motor and limbic system.

The discovery of a mutation in the Slit and Trk-like 1 (SLITRK1) gene on chromosome 13q31.1 was a major advance in the search for the elusive TS gene or genes. The SLITRK1 gene is expressed in brain regions previously implicated in TS (cortex, hippocampus, thalamic, subthalamic and globus pallidus nuclei, striatum, and cerebellum) and it appears to play a role in dendritic growth. However, it is not clear how the altered gene product leads to the complex neurobehavioral disorder. This mutation appears to be a rare cause of TS as it has not been found in hundreds of TS patients tested.

Neuropathologic examinations have detected no consistent brain abnormalities in patients with TS, but a number of neuroimaging studies have found evidence of structural changes in the brain. As an example, a study using volumetric magnetic resonance imaging (MRI) found that gray matter volumes in the left frontal lobes were smaller in patients with TS than in controls, supporting the loss of the normal left > right asymmetry in this condition.

Although it has been proposed that antibodies to basal ganglia neurons from Group A streptococcal infection may contribute to pathogenesis of TS in some patients, there is little or no evidence that pediatric autoimmune neuropsychiatric disorder associated with streptococcal infection (PANDAS) plays a role in the development of TS. This issue is discussed separately.

CLINICAL FEATURES — Tics are the clinical hallmark of TS. The onset typically is between two and 15 years, although the diagnosis may be delayed until 21 years in some cases. The disorder is manifested by 11 years of age in 96 percent of patients. In a large international registry of 3500 patients with TS, tics began at an average of 6.4 years. More males than females were affected (4.3:1). TS was the sole diagnosis in only 12 percent of cases.

Tics resolve by age 18 in about half of patients with TS. Although tics may persist into adulthood, their severity usually diminishes gradually over time. Nonetheless, the most common cause of "adult-onset" tics is TS that remits after puberty and re-emerges as tics later in life. Other causes of tics seen in adults are less common.

Tics — Tics are sudden, brief, intermittent movements (motor tics) or utterances (vocal or phonic tics). Tics have been considered involuntary, but tics can temporarily be voluntarily suppressed. The tics in TS can be categorized as either simple or complex. Simple tics include blinking, facial grimacing, shoulder shrugging, and head jerking. Many patients have complex sequences of coordinated movements, including bizarre gait, kicking, jumping, body gyrations, scratching, and seductive or obscene gestures. Certain characteristics of the tics, including the waxing and waning nature, the irresistible urge before and relief after a tic, the temporary suppressibility, and occurrence during sleep, may result in the mistaken diagnosis of a psychogenic disorder. One of the most characteristic features of tics is the presence of premonitory feelings or sensations, which are relieved by the execution of the tic.

Involuntary vocalizations, ranging from simple noises to coprolalia (obscene words), echolalia (repetition of words), and palilalia (repetition of a phrase or word with increasing rapidity), frequently occur. Coprolalia occurs in approximately 40 percent of cases. Many patients also experience copropraxia (obscene gestures), echopraxia (mimicking of gestures), bizarre thoughts and ideas, thought fixation, compulsive ruminations, and perverse sexual fantasies. Approximately one-half of our patients have sleep complaints, including restlessness, insomnia, enuresis, somnambulism, nightmares, and bruxism. Motor tics were recorded during sleep by polysomnography in approximately two-thirds.

Comorbidity — Comorbidity in TS is frequent. In a large international registry of 3500 patients with TS, comorbid conditions included attention deficit hyperactivity disorder (ADHD) (60 percent), obsessive compulsive disorder (OCD, 27 percent), obsessive compulsive behavior (32 percent), learning disorder (23 percent), and conduct disorder/oppositional defiant disorder (15 percent). Patients with more comorbidities were more likely to have behavioral problems such as sleep difficulties, coprolalia, self-injurious behavior, and anger control problems. Motor and vocal manifestations were more frequent in boys, whereas girls were more likely to have behavioral problems such as OCD.

The association of behavior disorders with tics in a community-based study was similar to clinic-based reports. In a study of school children aged 9 to 17 years, OCD, ADHD, anxiety disorders, and mood disorders were significantly more common in children with than without tics and with than without TS.

Examination — The neurologic examination in patients with TS is often normal except for the presence of tics. However, some patients have increased rates of normal blinking, subtle oculomotor disturbances related to saccadic eye movements, or other evidence of mild impairment of motor control.

Neuroimaging — Standard anatomical neuroimaging studies such as routine head CT and brain MRI are unremarkable in patients with Tourette's syndrome. However, volumetric magnetic resonance imaging studies have found evidence of structural changes in the brain. In addition, accumulating evidence suggests that caudate nucleus volume loss may be a disease marker of TS. A study using high resolution MRI found that the average volume of caudate nucleus was reduced in patients with TS by five to eight percent compared with healthy controls. Furthermore, a prospective longitudinal study of 43 children with TS found that childhood caudate volume on MRI was inversely associated with the severity of both tics and obsessive-compulsive symptoms in late adolescence and early adulthood.

DIAGNOSIS — The diagnosis of TS is based on the clinical features of the disease, particularly the presence of multiple motor and vocal tics, with onset before age 21. The presence of vocal tics such as grunting is required for the diagnosis. The diagnosis is often supported by the presence of coexisting behavioral disorders including attention deficit hyperactivity disorder (ADHD) and obsessive compulsive disorder (OCD). A family history of similar symptoms also supports the diagnosis of TS.

The main entity in the differential diagnosis is that of transient tics of childhood, which occur in approximately 25 percent of normal children. The ability to temporarily suppress tics is a feature of TS that helps to differentiate tics from other hyperkinetic movement disorders such as chorea, dystonia, athetosis, myoclonus, and paroxysmal dyskinesias.

As noted above, the mistaken diagnosis of a psychogenic disorder may occur because of certain characteristics of the tics in patients with TS, including the waxing and waning nature, the irresistible urge before and relief after a tic, exacerbation during periods of stress and reduction during mental concentration, and the temporary suppressibility.

Diagnostic criteria — There is no confirmatory laboratory test; the diagnosis is based on a set of clinical diagnostic criteria. The Tourette Syndrome Classification Study Group criteria for a definite diagnosis of TS are as follows: Both multiple motor tics and one or more phonic tics must be present at some time during the illness, although not necessarily concurrently. Tics must occur many times a day, nearly every day, or intermittently throughout a period of more than one year. Anatomical location, number, frequency, type, complexity, or severity of tics must change over time. Onset of tics before the age of 21 years. Involuntary movements and noises must not be explained by another medical condition. Motor tics, phonic tics, or both must be witnessed by a reliable examiner at some point during the illness or be recorded by videotape or cinematography.

MANAGEMENT — Education about TS is important for the patient, family, teachers, employers, and all who interact with the patient. This should be the first step in management of TS. Information and resources are available online from the Tourette Syndrome Association at www.tsa-usa.org.

Pharmacotherapy is indicated when symptoms of TS are interfering with social interactions, school or job performance, or activities of daily living. Specific treatment of TS is guided by the need to treat the most troublesome symptoms.

Dopamine agonists/antagonists — We treat tics with drugs that block dopamine receptors, such as fluphenazine, pimozide, and tetrabenazine, which depletes neuronal dopamine. These drugs appear to have a similar response rate, reducing the frequency and intensity of tics by approximately 60 to 80 percent. In our experience, these drugs are more effective and better tolerated than haloperidol. Tetrabenazine, which depletes dopamine by inhibiting vesicular monoamine transporter type 2 (VMAT2), is particularly useful because it is as effective as the typical neuroleptics, but it does not cause tardive dyskinesias.

The use of pergolide, a mixed D1/D2/D3 dopamine receptor agonist, has been suggested to treat chronic tic disorders and TS. In one trial, 57 children, ages 7 to 17 years, with severe tics (Yale Global Tic Severity Scale >30) were randomly assigned to pergolide (0.15 to 0.45 mg per day) or placebo in a two to one ratio. Pergolide resulted in significantly lower scores of tic severity and attention deficit hyperactivity disorder symptoms than placebo. The drug was well tolerated and no serious adverse events were observed. Similar results were found in an earlier smaller trial.

Despite the results of these studies, it is found that pergolide to be a powerful anti-tic drug. In addition, valvular heart disease has been reported in up to 33 percent of adult patients taking pergolide. Thus, pergolide should probably be used only for children with severe TS that is refractory to other therapies.

The selective nonergoline dopamine agonist ropinirole (0.25 to 0.5 mg twice a day) was beneficial for all features of TS in a small open-label study involving 15 children. This result requires further confirmation in a large controlled clinical trial.

Botulinum toxin injection — Focal motor and vocal tics may be treated with injections of botulinum toxin into the affected muscles. This treatment was safe and effective for the reduction of tic frequency in a single randomized controlled clinical trial.

Alpha adrenergic agonists and SSRIs — The alpha adrenergic agonists (ie, clonidine and guanfacine) and the selective serotonin uptake inhibitors (SSRIs) may be helpful in patients with predominant behavioral symptoms, particularly impulse control problems and rage attacks. The SSRIs also are effective in treating associated OCD.

Attention deficit disorder and tics — Attention deficit disorder with or without hyperactivity associated with TS usually is treated with central nervous system stimulants such as methylphenidate or dextroamphetamine.

While it has been recommended that CNS stimulants be used with caution because they may precipitate or exacerbate tics, a well-designed trial did not support the notion that methylphenidate worsens tics. In one study, 136 children with attention deficit hyperactivity disorder (ADHD) and a chronic tic disorder (>90 percent with TS) were randomly assigned to clonidine alone, methylphenidate alone, clonidine plus methylphenidate, or placebo. The results included Significant improvement of ADHD in all treatment groups compared to placebo Tic severity lessened in all treatment groups compared to placebo. A similar proportion of patients with worsening tics with methylphenidate, clonidine, and placebo (20, 26, 22 percent, respectively). The combination of clonidine and methylphenidate was most effective in improving ADHD and lessening tic severity. Drugs were well tolerated, although clonidine was associated with moderate to severe sedation in 28 percent of patients

Transcranial magnetic stimulation — A possible approach to improve symptoms is reduction of hyperexcitability in the motor and premotor cortex. In a small single-blinded, placebo-controlled, crossover trial in patients with TS, repetitive transcranial magnetic stimulation to reduce activity in these areas did not improve symptoms.

Deep brain stimulation — Patients with disabling tics that are refractory to optimal medical management may be candidates for deep brain stimulation of globus pallidus, thalamus or other subcortical targets.

SUMMARY AND RECOMMENDATIONS — Tourette syndrome (TS) is a common movement and neurobehavioral disorder in children characterized by multiple motor and vocal tics. The genetic basis of TS remains elusive, but several loci have been identified as candidate susceptibility regions. A mutation in the Slit and Trk-like 1 (SLITRK1) gene on chromosome 13q31.1 is of particular interest. The onset of TS is typically between age 2 and 15 years and occurs by 11 years of age in 96 percent of patients. However, the diagnosis may be delayed until 21 years in some cases. Common comorbid conditions in TS include attention deficit hyperactivity disorder (ADHD), obsessive compulsive disorder (OCD), disordered impulse control and other behavioral problems. The diagnosis of TS is based on the clinical features, particularly the presence of multiple motor and vocal tics, with onset before age 21. The diagnosis is often supported by the presence of coexisting behavioral disorders such as ADHD and/or OCD, and a family history of similar symptoms. Pharmacotherapy is indicated only when symptoms of TS are interfering with social interactions, school or job performance, or activities of daily living. For patients with TS and bothersome tics, we recommend drugs such as fluphenazine starting at 1 mg daily, pimozide starting at 2 mg daily, or tetrabenazine starting at 12.5 mg daily. For patients with TS who have only focal motor or vocal tics, we recommend treatment with botulinum toxin injections into the affected muscles. For patients who have TS and ADHD, we recommend stimulants such as methylphenidate starting at 5 mg daily or dextroamphetamine starting at 5 mg daily. For patients who have TS and predominant behavioral symptoms, particularly impulse control problems and rage attacks, we recommend clonidine starting at 0.1 mg daily or guanfacine starting at 1 mg daily. For patients who have TS and OCD, we recommend serotonergic drugs such as fluoxetine starting at 20 mg daily.