Pediatric Tourette Syndrome

Tourette syndrome (TS) is a complex childhood-onset neurodevelopmental 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 can greatly impact one's quality of life due to the disorder itself and more so in presence of other behavioral disorders. TS is a genetic condition that runs in families (see Pathophysiology and Etiology). 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 cases of childhood-onset tics. These children also had associated coexisting behavior problems, as well as unusual vocalizations that we now recognize as phonic tics. Although 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 were found to respond favorably to these new medications. The fundamental perception of TS changed from that of a psychiatric disorder to a primary neurologic disorder believed to involve focal dysfunction within the brain. Since that time, extensive research has been performed to understand the underlying neurobiology behind TS. Once viewed as a rare psychiatric disorder, TS is now understood to be a relatively common and diverse childhood-onset genetic condition.

The precise pathophysiologic mechanisms of TS are yet to be determined. Most studies support the hypothesis that TS is an inherited developmental disorder of synaptic neurotransmission. ^[1] Further studies are needed to elucidate the physiologic and cellular mechanisms underlying tics and TS. ^[2]

The basal ganglia, particularly the caudate nucleus and the inferior prefrontal cortex, are implicated in the pathogenesis of TS. Volumetric magnetic resonance imaging 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. ^[3]  Close association of basal ganglia with ventral striatal-limbiic complex is implicated in co-occurrence of TS with behavioral disorders including 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, involving the following areas:

• Medial and lateral premotor cortices

• Anterior cingulated cortex

• Dorsolateral-rostral prefrontal cortex

• Inferior parietal cortex

• Putamen

• Caudate nucleus

• Primary motor cortex

• Broca area

• Superior temporal gyrus

• Insula

• Claustrum

The activity in these regions was found to be synchronous with tic occurrences. This widespread, abnormal activity of interrelated circuits shows extensive involvement of the sensorimotor, language, and paralimbic regions. ^{[2, 4]}

While multiple neurotransmitters are likely involved, dopamine has gained particular interest, 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.

Upregulation of the dopamine receptors has led some investigators to propose another hypothesis about increased sensitivity 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).

Genetic aspects

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. ^[5] In addition, increasing evidence shows a genetic link between tic disorders and OCD. Environmental components are also predicted to influence expression of TS including prenatal factors like fetal hypoxia, infections, smoking by pregnant femailes, maternal stress during pregnancy or early chidlhood adverse events. ^[6]

Immune-mediated pathogenesis

Some researchers have proposed that TS may have an immune-mediated pathogenesis similar to pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS). In this model, antecedent infection with group A beta-hemolytic Streptococcus leads to the formation of antineuronal antibodies that cause neuronal dysfunction.

Investigations comparing antineuronal antibody profiles in TS, PANDAS, and age-matched controls did not demonstrate any differences, however. Treatments aimed at this pathophysiologic mechanism, such as plasmapheresis, intravenous immunoglobulin, or antibiotics, are not currently recommended. ^[7]

Volition

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.

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.

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. ^[4]

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 a possible genetic locus. Data also support possible loci on chromosomes 5 and 11. ^[8]

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

Autoimmune theory

The autoimmune theory of TS posits that antibodies directed against an antecedent infection (eg, 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 found in patients 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. ^[7]

In summary, although 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, treatment of TS with antibiotics or therapy such as immunosuppressants, IVIG, or plasmapheresis is not recommended.

Risk factors

Risk factors for the TS include the following:

• Male sex

• Young age

• Family history of TS

TS occurs worldwide, in all social classes and races. 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.

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 nondisabling 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. In school-based studies, tics were identified in 26% of students in special education programs, compared with 6% of students in mainstream classrooms. ^{[9, 10]}

Sex- and age-related demographics

The 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 1:1.

Children are much more likely to meet the diagnostic criteria for TS than adults. TS is a childhood-onset condition, and adults who display symptoms of TS are likely to have had the symptoms since childhood.

Symptoms of TS can be seen in infancy, but most children with TS display readily identifiable symptoms at around age 7 years. Symptoms resolve by adulthood in most children with TS. Whether this resolution represents a compensatory process or resolution of the underlying pathology is unclear.

In most cases of TS, symptoms reach their fullest expression some time during adolescence, roughly a decade after onset. At some point, 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. Lifelong remissions are rare, however. 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 regarding what percentage of patients become worse, what percentage remain much the same, and what percentage 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 rare.

One of the most important aspects of treating TS is educating the patient and family members about tic disorders and associated behavioral disturbances. The Tourette Syndrome Association is an excellent tool for patient education. 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.