Pediatr Neonatol 2010;51(5):255−264

R EVIEW ART IC L E

Tourette Syndrome in Children: An Updated

Review
Jung-Chieh Du1*, Ting-Fang Chiu1, Kun-Mei Lee1, Hsin-Lin Wu1,
Ya-Chi Yang1, Shu-Yeh Hsu1, Chung-Shu Sun1, Betau Hwang1,2,
James F. Leckman3,4,5
1
Department of Pediatrics, Taipei City Hospital, Zhongxiao Branch, Taipei, Taiwan
2
National Yang-Ming University, Taipei, Taiwan
3
Yale Child Study Center, New Haven, CT, USA
4
Department of Pediatrics, School of Medicine, Yale University, New Haven, CT, USA
5
Department of Psychology, School of Medicine, Yale University, New Haven, CT, USA

Received: Mar 2, 2010
Revised: Apr 1, 2010
Accepted: Apr 21, 2010
KEY WORDS:
basal ganglia;
habit reversal therapy;
tics;
Tourette syndrome
Tourette syndrome (TS) is a common neuropsychiatric disorder in children character-
ized by multiple motor and vocal tics that fluctuate in severity and lasting for at least
1 year. Boys are more commonly affected than girls. Symptoms usually begin with
simple motor or vocal tics which then evolve into more complex motor and vocal
tics over time. Premonitory sensory urges are common in children over the age of
8 years, and these urges help distinguish tics from symptoms of other movement
disorders. Common comorbidities of TS include attention deficit hyperactivity dis-
order, obsessive-compulsive disorder and learning difficulties. Several genes have been
assessed as candidate genes for TS; environmental factors such as stress and strepto-
coccal infections might also contribute to its etiology. The pathophysiology of TS
mainly involves dysfunction of basal ganglia-related circuits and hyperactive dopami-
nergic innervations. A thorough history assessment and neurological examination are
important for the correct diagnosis and differentiation from other movement disor-
ders. Treatment for TS should focus on improving the patient’s social functioning, mini-
mizing the impairment from cormobid disorders, and controlling tics, if they are
severe. Commonly used medications for TS include α2-adrenergic agonists and atyp-
ical neuroleptics. Habit reversal therapy is an effective option for TS, and repetitive
transcranial magnetic stimulation may be a promising approach for severe cases.

1. Introduction occurs during early childhood, and the disorder af-

Tourette syndrome (TS) is a developmental neuropsy-
chiatric disorder characterized by multiple brief,
stereotypical but nonrhythmic movements and by
vocalizations called tics, with a duration of at least
1 year.1 The onset of tic symptoms in TS typically
fects 1−3% of Western2 and 0.56% of Taiwanese3
school-aged children. Boys are more commonly af-
fected than girls with a ratio of 9:2 in TS children
in Taiwan.3 Transient tic disorder, manifested by
tics that are present for less than 1 year, affects ap-
proximately 6−20% of children in lifetime prevalence.

*Corresponding author. Department of Pediatrics, Taipei City Hospital, Zhongxiao Branch, No. 87, Tong-De Road, Nangang
District, Taipei 115, Taiwan.
E-mail: DAL82@tpech.gov.tw; greened@ms77.hinet.net

©2010 Taiwan Pediatric Association

256
Chronic tic disorders, which are characterized by
either motor or vocal tics, but not both, occur in
5% of school-aged children.4−6 The main features
of TS are motor and vocal tics that wax and wane
in severity. Motor and vocal tics occur in bouts pe-
riodically over the course of a day, and change in
severity over weeks and months. Common comorbid-
ities include attention-deficit hyperactivity disor-
der (ADHD), obsessive−compulsive disorder (OCD),
learning disabilities, disruptive behavior disorders,
self-injurious behavior and sleep disturbances.2,3,7
The severity of tics in TS children usually declines
over the course of adolescence, but the comorbid-
ities may persist and often cause more functional
impairment.8 In this article, we review the updated
information about TS in children.
2. Tic Symptoms and Natural History
Common motor tics include eye blinking, facial
grimacing, nose twitching, jaw, neck, and shoulder
or limb movements, while common vocal tics consist
of sniffing, grunting and chirping, as well as throat
clearing.9 Motor tics usually appear between the
ages of 4 and 6 years, several years before the onset
of vocal tics, which usually begin between 8 and
12 years.10 With increasing age, motor tics may evolve
into more elaborate movements (e.g., purposeful-
like movements or lewd gestures), and vocal tics
often develop into repeating words (echolalia), or
phrases (palilalia), or obscene words (coprolalia).11
Motor and vocal tics often occur in discrete bouts
over the course of a day, and change in severity
over weeks and months.12 These bouts are charac-
terized by brief periods of stable inter-tic intervals
of short duration, typically 0.5−1.0 seconds, and
inter-bout intervals that last from minutes to
hours.10,12 Speculation has focused on the “frac-
tal” occurrence of tics in time, such that the wax-
ing and waning course of tics over weeks to months
might be the result of the same basic neurobiologi-
cal processes that underlie the occurrence of tics
in bouts in the shorter time scale of seconds and
minutes.11 In most patients, the course of worst tic
severity falls between 7 and 15 years of age, after
which the severity usually declines until early
adulthood.10,13 By late adolescence or young adult-
hood, over one third of TS patients are virtually
tic-free, less than half have minimal to mild tics,
and less than a quarter have persistently moderate
to severe tics.13 Slightly less than 5% of individuals
may report experiencing worse tics during young
adulthood than they did in childhood.
Many TS patients experience premonitory urges;
a premonitory urge is a sensory phenomenon that
occurs immediately prior to a tic, similar to the need
J.C. Du et al
to scratch or sneeze.14 Premonitory sensory urges
often prompt the tics, and a momentary sense of
relief frequently follows the successful perfor-
mance of a tic.15 Children under the age of 8−10 years
are usually totally unaware of these sensory urges,
and awareness increases with age. By 3 years after
the onset of tics, these urges are present in as many
as 90% of adolescents with TS.16 The shoulder girdle,
throat, hands, midline of the stomach, front of the
thighs and feet are “hot spots” for experiencing these
premonitory sensory urges,14 which can sometimes
prove more troublesome than the tics themselves,
particularly in patients who are able to suppress the
tics, but unable to resist the distracting urges.11 Ir-
respective of the use of medications or other treat-
ment, these urges typically subside as the tics
improve.17
TS patients can suppress tics volitionally, or merge
them into purposeful behaviors or utterances,
though often at the expense of a build-up of inner
tension leading to mental exhaustion.18 The ability
to suppress tics usually increases as TS children grow
up. The frequency and intensity of tics typically
worsen during periods of stress, anxiety, excite-
ment and fatigue.19 Several studies of TS children
have indicated that daily life stressors may play more
important roles in future tic outcome than major
life events.20 Elevated core body temperature is also
associated with increased tic frequency in some
patients.21 In contrast, tics are often alleviated dur-
ing periods that require attention and fine-motor
movements, such as playing a musical instrument,
dancing, or playing sports.19
Tics can also occur during sleep, which distinguish
them from many other movement disorders; how-
ever tics are much diminished compared with those
during awake periods. Polysomnographic studies
have demonstrated that TS children displayed lower
sleep efficiency and elevated arousal levels, and
that those TS children with comorbid ADHD were
additionally characterized by an increase in rapid
eye movement sleep.22,23 Associated comorbidities,
especially ADHD, are likely to contribute to these
sleeping disturbances.24
3. Comorbidity
Most TS children have other comorbidities, which
often cause more impairment than the tic symptoms
themselves. An epidemiological study in Taiwan re-
vealed that common comorbidities in elementary-
school-aged children with TS (aged 6−12 years) were
ADHD (36%), mild self-injurious behaviors (27%),
OCD (18%) and learning difficulties (9%).3 The prev-
alence of comorbid ADHD in all TS children may
reach as high as 60−70%.25 The onset of hyperactive
Tourette syndrome in children
symptoms of ADHD may precede the appearance of
tics by around 2 years. The simultaneous occurrence
of TS and ADHD symptoms has been associated with
disruptive behaviors, academic difficulties, peer re-
jection and family conflict.26,27 Comorbid ADHD
symptoms in childhood even correlate with a reduced
quality of life and global functioning in early adult-
hood in patients with TS.28 However, studies investi-
gating the clinical course of ADHD in individuals with
comorbid tic symptoms are still lacking.
Approximately 30−50% of TS children will expe-
rience comorbid OCD.13 Obsessive compulsive (OC)
symptoms associated with tics generally have a pre-
pubertal age at onset and can predate the onset of
tics.11 However, the period of worst OC symptoms
usually occurs on average 2 years after the period
of worst tics.13 When present, these symptoms are
usually practiced in secret and are most disabling
in the home environment.29 OC symptoms can lead to
periods of depression and impairment in adaptive,
as well as emotional functioning.30 Analysis of ver-
tical transmission patterns in families has revealed
that OCD and TS may share some underlying genetic
vulnerabilities.31 Adulthood outcome studies have
also indicated that childhood-onset OCD patients
with comorbid tics may achieve remission of OC
symptoms by adulthood.32 These data suggest that
OC symptoms in children with OCD and comorbid tics
may follow a similar developmental trajectory to
the tics themselves.33
Learning difficulties are not uncommon in TS
children. Indeed, a database of 5450 subjects with
TS showed that the prevalence of comorbid learn-
ing difficulties was about 22.7%.34 Individuals with
TS can show profound difficulties in fine motor con-
trol, motor inhibition and visual motor integration.35
TS children have also been reported to display def-
icits in procedural memory and habit learning rela-
tive to normal controls.36,37 Comorbid ADHD symptoms
in TS children are also the main cause of learning
difficulties.
Children with TS experience comorbid depres-
sion and anxiety disorders in adolescence and early
adulthood more frequently than the general popu-
lation does.28 Roughly 40% of TS children will expe-
rience depression or a non-OCD anxiety disorder.13
Children with TS and their parents should therefore
be educated to recognize the signs and symptoms
of these conditions.33
4. Etiology
4.1. Genetic factors
Genetic studies in twins and families provide com-
pelling evidence that genetic factors, particularly
257
polygenic hereditary patterns, are involved in the
vertical transmission of TS.31 Linkage analyses have
suggested the importance of several chromosomal re-
gions, including 11q23, 4q34−35, 5q35 and 17q25.38,39
Several identity-by-descent studies of TS popula-
tions have implicated regions near the centromere
of chromosome 2, and on 6p, 8q, 11q, 14q, 20q and
21q, as well as on the X chromosome.40−42 Some can-
didate genes have been assessed, including those
for various dopamine receptors (DRD1, DRD2, DRD4,
and DRD5), dopamine transporter, various noradren-
ergic genes (ADRA2a, ADRA2C, DBH, and MAO-A),
and a few serotonergic genes (5HTT).43,44 A study
in Taiwan demonstrated that the dopamine receptor
D2 gene with Taq I DRD2 and DRD2 (H313H) poly-
morphisms was associated with TS in children.45
More recently, the Slit and Trk-like family member
1 gene (SLITRK1) and the L-histidine decarboxylase
gene (HDC) have also been identified as possible vul-
nerability genes for TS.46,47 However, one genetic
analysis of 160 Taiwanese children with TS failed to
detect any mutation in the whole SLITRK1 gene se-
quence, including the promoter, the 3⬘-untranslated
region and the 5⬘-untranslated region.48
4.2. Epigenetic factors
Many epigenetic factors have been implicated in
the pathogenesis of TS, including perinatal insults,
exposure to androgens and psychologic stress, as
well as post-infectious autoimmune mechanisms.9
Perinatal hypoxic/ischemic events and prenatal ma-
ternal smoking have been reported as risk factors
for developing TS.49,50 Male sex is also recognized
as a risk factor for TS, based on clinical observations
of male dominance in the prevalence of TS. However,
frequent male-to-male transmission within fami-
lies seems to rule out the possibility of an X-linked
inheritance pattern. This observation has led to
the hypothesis that androgen exposure during criti-
cal periods in fetal brain development is a risk factor
for the development of TS.51
Patients with TS usually suffer increased psy-
chosocial stress, and some prospective longitudinal
studies also indicated that antecedent stress could
increase future tic and OC symptom severity.52 The
hypothalamic-pituitary-adrenal axis in TS patients
seems to be more responsive to stress than in nor-
mal subjects, resulting in a significant elevation of
cerebrospinal fluid corticotropin-releasing factor and
a greater circadian change in saliva cortisol levels.53,54
However, further investigations are needed to elu-
cidate the neurobiological mechanisms by which
stress contributes to the pathobiology of TS.
A postinfectious etiology for TS has been stud-
ied for years, and group A β-hemolytic streptococ-
cal (GABHS) infection is the most likely candidate
258
involving the onset of TS.55 GABHS are known to
trigger several immune-mediated diseases, such as
Sydenham’s chorea and pediatric autoimmune neu-
ropsychiatric disorder associated with streptococcal
infection (PANDAS), both of which share symptoms
similar to those seen in TS and OCD. One possible
mechanism is that antibodies directed against GABHS
could attack brain cells due to molecular mimicry.56
A case-control study of 144 children with diagnoses
of TS, OCD, or tic disorders revealed that these pa-
tients were more likely than controls to have had a
streptococcal infection in the 3 months prior to
the onset date. Having multiple GABHS infections
within a 12-month period was associated with a
13-fold increased risk for developing TS.55 Increased
proinflammatory cytokines (tumor necrosis factor-α,
interleukin-12), elevated synthesis of antineuronal
antibodies, and decreased number of regulatory
T-cells have also been reported to correlate with
disease severity in TS patients.57
Interestingly, a study of 72 Taiwanese children
with TS demonstrated a higher risk of having allergic
diseases (e.g., allergic rhinitis, asthma, atopic der-
matitis) than controls.58 However, the association
between the waxing-and-waning course of TS and
the seasonal variation in allergic diseases requires
further investigation.
5. Hypotheses for Pathophysiology of TS
The pathological processes of tics remain unclear, but
several hypotheses have been proposed. Dysfunction
of the basal ganglia has long been suggested to be
the major cause of tic symptoms. The basal ganglia
form a network of interconnected subcortical struc-
tures, including the striatum, globus pallidus, sub-
stantia nigra and subthalamic nucleus. The striatum
receives input from the cerebral cortex, thalamus,
hippocampus, midbrain and other structures. It
then relays processed information to the globus pal-
lidus and substantia nigra, which in turn project to
the thalamus and then back to the cortex (Figure 129).
The cortico-striato-thalamo-cortical circuits play a
critical role in coordinating motor and cognitive
processes, as well as in habit formation.59 Malfunction
of these circuits may contribute to the fragmentary
semi-autonomous behaviors that manifest as tics.60
Several volumetric magnetic resonance imaging
studies have reported that TS children had smaller
caudate volumes than age-matched controls.61,62
Caudate volumes of TS patients during childhood, as
demonstrated by magnetic resonance imaging, were
not correlated with tic severity in childhood, but
were strongly predictive of the severity of tic and
OC symptoms in early adulthood, with an inverse
association.63 The correlation between reduced
J.C. Du et al
Cerebral cortex
Striatum Striosome
Indirect pathway
Direct
pathway GPe
SNr GPi
Subthalamic nucleus
Basal ganglia
output system
GABA
Thalamus
Glutamate
Figure 1 Schematic diagram of the major connections
of the basal ganglia (adapted from Leckman, 200229).
GPe = globus pallidus, pars externa; GPi = globus pallidus,
pars interna; SNr = substantia nigra, pars reticulata.
caudate volume and tic severity in adulthood, but
not in childhood, supports the concept of a role
for developmental basal ganglia abnormalities in
TS. Functional neuroimaging studies in TS patients
have implicated the basal ganglia, thalamus and
prefrontal cortical regions as being associated
with abnormal cerebral activity during conscious
suppression of tics.64,65 These studies also revealed
that activation of the caudate nucleus was inversely
correlated with tic severity, suggesting that a re-
duced ability of the basal ganglia to suppress corti-
cal activity may be linked to increased tic severity.
The majority of cells in the striatum (around 80%
in humans) are medium spiny neurons (MSNs), which
receive excitatory glutamatergic signals from the cor-
tex and project GABAergic inhibitory signals out of
the striatum to the globus pallidus and the substantia
nigra (Figure 266).67 Several other less abundant stri-
atal neurons play critical roles in modulating the
firing of most MSNs, including cholinergic tonically
active neurons (TANs) and GABAergic parvalbumin-
positive fast-spiking interneurons (FSNs).68,69 A recent
postmortem analysis of the brains of five individuals
severely affected with TS demonstrated a 50−60%
reduction in both FSNs and TANs in the caudate and
putamen.70 A decreased inhibitory influence of TANs
and FSNs over MSNs could allow cortical sensori-
motor inputs to activate MSNs more easily, eliciting
premonitory sensory urges and tics in sequence.
These alterations may indicate a developmental de-
fect in the migration of GABAergic neurons from
their birthplace in the primordial striatum (the lat-
eral and medial ganglionic eminences), but further
studies are needed to confirm this hypothesis.9
Tourette syndrome in children
Prefrontal cortex Motor cortex
Mesiofrontal cortex Striatum
SS
Limbic cortex
SS
Hippocampus
SNc
Glutamatergic projections
GABAergic projections
GABAergic projections from FSN
Figure 2 Schematic diagram of the major connections of the basal ganglia associated with Tourette syndrome (adapted
from Leckman, 200666). MS = matrisomal medium spiny neurons; SS = striosomial medium spiny neurons; TAN = tonically
active neurons; FSN = fast-spiking interneurons; GPe = globus pallidus, pars externa; GPi = globus pallidus, pars interna;
SNr = substantia nigra, pars reticulata; SNc = substantia nigra, pars compacta; STN = subthalamic nucleus.
Dopaminergic pathways have been implicated
in the performance of tics based on the clinical ob-
servation that tics can be suppressed by dopamine
antagonists and exacerbated by dopamine ago-
nists.71 Several studies using single photon emission
computed tomography or positron emission tomog-
raphy revealed higher densities of presynaptic do-
pamine transporters and postsynaptic dopamine
D2 receptors (D2Rs) in the basal ganglia of TS pa-
tients.44,72,73 A hypothesis of decreased tonic (basal)
and increased phasic (spike-dependent) release of
presynaptic dopamine in the striatum of TS patients
might explain the compensatory increase in postsyn-
aptic D2R densities, resulting in higher dopaminergic
activity and subsequent tic symptoms.74 Postmortem
brain immunohistochemistry analysis of TS subjects
also demonstrated elevated amounts of dopamine
transporters and D2Rs in the frontal cortex.75−77 This
evidence provides strong support to the idea that
increased dopaminergic innervations in the brain
play a critical role in the pathophysiology of TS.
6. Assessment and Diagnosis
Clinical evaluation of child or adolescent with TS
should properly consider the “whole person,” and
not just focus on the abnormal motor symptoms.
A complete assessment should include detailed
perinatal, developmental, familial, medical and
259
Sensorimotor cortex
Dorsal lateral
MS
FSN
MS
TAN
MS
FSN GPe
Ventromedial
SNr GPi STN
Nonspecific n.
Thalamus Cerebellum
Specific n.
Acetylcholinergic projections from TAN
Dopaminergic projections from SNc
psychosocial histories, along with screening for
ADHD, OCD and learning difficulties.
The clinician’s responsibility is to clarify the
degree of impairment that tics and/or other co-
morbidities cause in the child’s emotional, social,
familial and school experiences. The diagnosis of
TS is currently based on the criteria proposed by the
Diagnostic and Statistical Manual of Mental Disorders,
4th edition, Text Revision (DSM-IV-TR; Table 1).78
The proposed revisions of these criteria for DSM-V
are now available online (www.dsm5.org). Somewhat
different criteria are offered by the International
Classification of Disease and Related Health Problems,
10th Revision (ICD-10).79
Once a diagnosis of TS has been established,
continuous monitoring of tic symptoms over a pe-
riod of time is necessary to assess their severity,
fluctuations, and impact on the patient’s life. Long
term follow-up is aided by the use of a standard
rating instrument for tic severity evaluation, such
as the Yale Global Tic Severity Scale.80 Tics can
mimic the symptoms of other involuntary move-
ment disorders and are sometimes misdiagnosed
as dystonia, chorea, myoclonus, tardive dyskinesia
or other hyperkinetic movement disorders.81 Being
suppressible and often preceded by sensory urges
are the key features differentiating tics from other
movement disorders.81 A thorough neurological ex-
amination is important to rule out other abnormal-
ities but is often normal apart from the tics. Some
260
Table 1 Diagnostic criteria for Tourette syndrome
(Diagnostic and Statistical Manual of Mental
Disorders, 4th edition, Text Revision)78
1. Both multiple motor and one or more vocal tics
have been present at some time during the
illness, although not necessarily concurrently
2. The tics occur many times (usually in bouts)
nearly every day or intermittently throughout a
period of more than a year; during this period
there was never a tic-free period of more than
3 consecutive months
3. Onset before the age of 18 years
4. The disturbance is not due to the direct
physiological effects of a substance (e.g.,
stimulants) or a general medical condition (e.g.,
Huntington’s chorea or postviral encephalitis)
severely affected TS patients may have “soft signs”
on neuromaturational examination, suggesting dis-
turbances in motor control, which may have prog-
nostic significance.82 Electroencephalography and
neuroimaging studies are not indicated unless co-
existing seizures or changes in mental status are
suspected. No laboratory test for positive diagno-
sis of TS is currently available.29
7. Treatment
The treatment goal for TS children should focus on
maximizing their potential in school settings and so-
cial functioning, rather than attempting to eliminate
their tics. Education for TS children and their fam-
ilies about the natural course of TS and the potential
impact of stress on tics is warranted to promote bet-
ter tolerance, and may have a positive influence on
the course of the illness. Participation in physical ex-
ercise activities, learning special talents (e.g., play-
ing musical instruments), and maintaining good sleep
hygiene are often encouraged.29 No specific diet has
proven beneficial for relieving tics, but it is advisable
to avoid caffeine, which may exacerbate tics in some
children.83 The decision to start treating tics should
depend on their severity, and the interference in
daily life caused by the tic symptoms themselves.84
When patients present with other comorbidities,
such as ADHD or OCD, it is usually preferable to treat
these comorbid disorders first, since their successful
treatment often diminishes tic severity.
7.1. Anti-tic medications
Two classes of drugs are widely used to control tics
in TS: α2-adrenergic agonists and neuroleptics
(Table 285). The efficacy of α2-adrenergic agonists,
J.C. Du et al
including clonidine and guanfacine, is supported
by results of randomized, placebo-controlled clinical
trials.86,87 Clonidine reduces central noradrenergic
activity by stimulation of presynaptic α2-adrenergic
autoreceptors, while guanfacine acts on postsynap-
tic α2-adrenergic receptors. Clonidine is usually the
first choice in previously untreated TS patients.
A large randomized controlled trial also demon-
strated that clonidine was effective in reducing
ADHD and tic severity in TS children with comorbid
ADHD.88 The main side effects of clonidine are se-
dation and hypotension. Dose reduction is required
for these side effects, and periodic blood pressure
monitoring is advised because of possible rebound
hypertension associated with abrupt discontinua-
tion. Guanfacine acts longer than clonidine, and
hypotension is less commonly encountered.
Neuroleptics (or antipsychotics) are the most
effective drugs for treating tics; they act primarily
by blocking dopamine receptors and thereby decreas-
ing dopaminergic input to basal ganglia. Typical
neuroleptics such as haloperidol and pimozide have
been used successfully in the treatment of TS since
the 1960s. However, all these typical neuroleptics are
associated with significant side effects, e.g., ex-
trapyramidal syndrome and drug-induced parkin-
sonism. Thus atypical neuroleptics, which act by
partially blocking both dopamine and serotonin re-
ceptors, are usually better choices than typical neu-
roleptics because they show reduced incidence of
side effects. Risperidone has been demonstrated
to be superior to placebo and clonidine in several
double-blind trials in children with TS.89,90 The most
common adverse effects of risperidone were weight
gain, sedation, sleep disturbance and abnormal lipid
metabolism. Ziprasidone was also shown to be bet-
ter than placebo in a small, double-blind study in TS
children.90,91 Ziprasidone has a lower risk of weight
gain, but concern about its potential to alter car-
diac conduction, especially QTc prolongation, still
remains. Aripiprazole is a novel neuroleptic that has
been demonstrated to be effective in treating TS
children in several open-label studies,92,93 but ran-
domized controlled, double-blind trials have not
been reported.
7.2. Habit reversal therapy
Habit reversal therapy (HRT) is the first behavior
therapy that has shown promising results in reducing
tic severity in TS children.94 The major components
of HRT consist of awareness training and compet-
ing response practice. Awareness training is designed
to increase patients’ ability to detect the situation
in which tics occur and the earliest signs of tic onset.
Once patients are able to identify the premonitory
urges, they are taught to use a competing response
Tourette syndrome in children 261

Table 2 Medications for Tourette syndrome (adapted from Bloch, 200885)

CEBM evidence
grade* Starting dose Typical dose
Side effects
(mg/d) (mg/d)
Adults Children

α2-agonists
Clonidine Low High 0.025−0.05 0.1−0.3 Sedation, hypotension
Guanfacine Low High 0.5 1.5−3 Sedation, lightheadedness

Typical neuroleptics
Haloperidol High High 0.25−0.5 1−4 EPS, sedation, weight gain
Pimozide High High 0.5−1 2−8 QTc prolongation, sedation
Fluphenazine Low Low 0.5−1 1.5−10 Better tolerated than haloperidol

Atypical neuroleptics
Risperidone High High 0.25−0.5 1−3 Sedation, weight gain, abnormal
lipid metabolism
Ziprasidone Low High 20 20−80 QTc prolongation, sedation,
weight gain
Aripiprazole Low Low 2.5−5 10−20 Sedation, weight gain
Olanzapine Low Low 2.5−5 10−20 Sedation, weight gain
Quetiapine Low Low 25−50 75−250 Sedation, weight gain

*High CEBM evidence grade indicates efficacy in randomized, double-blind trials, where as low grade indicates probable efficacy
in an observational study. CEBM = Center for Evidence-based Medicine; EPS = extrapyramidal syndrome.

in a movement or vocalization that is incompatible
with the movements or sound production required
to perform the tic. Indeed, HRT seems to be a prom-
ising option for treating TS patients with prominent
premonitory urges.
therapy, DBS is currently only advisable for se-
verely affected, treatment-refractory TS adults.
8. Future Perspectives

7.3. Other developing therapies
Repetitive transcranial magnetic stimulation (rTMS)
involves the repetitive generation of a brief, pow-
erful magnetic field by a small coil positioned over
the skull, inducing an electric current in the brain.
This noninvasive brain stimulation may change the
abnormal cortical excitability in TS patients.95 A
recent study using low-frequency rTMS over the bi-
lateral supplementary motor area significantly im-
proved tic severity in five TS patients.96 However,
this study was unblinded and uncontrolled; further
randomized, sham-controlled trials of rTMS are
needed to confirm its efficacy.
Deep brain stimulation (DBS) is a stereotactic,
neurosurgical technique that places electrodes in
certain brain regions (e.g., globus pallidus, thala-
mus) to suppress abnormal oscillatory activity. DBS
has been used successfully to treat Parkinson’s dis-
ease, dystonia and other movement disorders.
Several case series using DBS for treatment of pa-
tients with refractory TS have reported significant
improvement of tic severity after the proce-
dure.97,98 Infection, stroke, nausea and blurred vi-
sion are uncommon side effects. As an invasive
Developing proper animal models of TS, though
difficult, will be important for studying the patho-
physiology and pharmacologic treatment of tic
symptoms. If current candidate genes such as
SLITRK1 and HDC are confirmed to have major ef-
fects, then valid animal models of TS should be
forthcoming. Based on the evidence of relatively
reduced amounts of cholinergic TANs and GABAergic
parvalbumin-positive FSNs in the striatum of TS
patients, it is possible to develop animal models of
TS by specifically destroying these neurons or in-
terneurons with immunotoxic antineuronal anti-
bodies or genetically engineered viral vectors. On
the other hand, at least one randomized sham-
controlled study using rTMS for the treatment of
TS is being conducted at present. If this study con-
firms its efficacy, rTMS will become a promising
treatment for TS.
TS is considered to be a model disorder for
studying the interactions among genetic vulnera-
bilities, environmental effects, and neurobiologi-
cal systems active during early brain development.
The results of research on TS will enhance our un-
derstanding not only of TS itself, but also that of
many other neurological and behavioral disorders.
262
References
1. Leckman JF, Peterson BS, Pauls DL, Cohen DJ. Tic disor-
ders. Psychiatr Clin North Am 1997;20:839−61.
2. Robertson MM. Diagnosing Tourette syndrome: is it a com-
mon disorder? J Psychosom Res 2003;55:3−6.
3. Wang HS, Kuo MF. Tourette’s syndrome in Taiwan: an epide-
miological study of tic disorders in an elementary school at
Taipei County. Brain Dev 2003;25(Suppl 1):S29−31.
4. Scahill L, Sukhodolsky DG, Williams SK, Leckman JF. Public
health significance of tic disorders in children and adoles-
cents. Adv Neurol 2005;96:240−8.
5. Robertson MM. The prevalence and epidemiology of Gilles
de la Tourette syndrome. Part 2: tentative explanations for
differing prevalence figures in GTS, including the possible
effects of psychopathology, aetiology, cultural differences,
and differing phenotypes. J Psychosom Res 2008;65:473−86.
6. Robertson MM. The prevalence and epidemiology of Gilles
de la Tourette syndrome. Part 1: the epidemiological and
prevalence studies. J Psychosom Res 2008;65:461−72.
7. Kurlan R, Whitmore D, Irvine C, McDermott MP, Como PG.
Tourette’s syndrome in a special education population:
a pilot study involving a single school district. Neurology
1994;44:699−702.
8. Bernard BA, Stebbins GT, Siegel S, et al. Determinants of
quality of life in children with Gilles de la Tourette syndrome.
Mov Disord 2009;24:1070−3.
9. Swain JE, Scahill L, Lombroso PJ, King RA, Leckman JF.
Tourette syndrome and tic disorders: a decade of progress.
J Am Acad Child Adolesc Psychiatry 2007;46:947−68.
10. Leckman JF, Zhang H, Vitale A, et al. Course of tic severity in
Tourette syndrome: the first two decades. Pediatrics 1998;
102:14−9.
11. Leckman JF, Bloch MH, Scahill L, King RA. Tourette syn-
drome: the self under siege. J Child Neurol 2006;21:642−9.
12. Peterson BS, Leckman JF. The temporal dynamics of tics in
Gilles de la Tourette syndrome. Biol Psychiatry 1998;44:
1337−48.
13. Bloch MH, Peterson BS, Scahill L, et al. Adulthood outcome of
tic and obsessive-compulsive symptom severity in children
with Tourette syndrome. Arch Pediatr Adolesc Med 2006;
160:65−9.
14. Leckman JF, Walker DE, Cohen DJ. Premonitory urges in
Tourette’s syndrome. Am J Psychiatry 1993;150:98−102.
15. Kwak C, Dat Vuong K, Jankovic J. Premonitory sensory phe-
nomenon in Tourette’s syndrome. Mov Disord 2003;18:1530−3.
16. Woods DW, Piacentini J, Himle MB, Chang S. Premonitory
Urge for Tics Scale (PUTS): initial psychometric results and
examination of the premonitory urge phenomenon in youths
with Tic disorders. J Dev Behav Pediatr 2005;26:397−403.
17. Banaschewski T, Woerner W, Rothenberger A. Premonitory
sensory phenomena and suppressibility of tics in Tourette
syndrome: developmental aspects in children and adoles-
cents. Dev Med Child Neurol 2003;45:700−3.
18. Himle MB, Woods DW, Conelea CA, Bauer CC, Rice KA.
Investigating the effects of tic suppression on premonitory
urge ratings in children and adolescents with Tourette’s syn-
drome. Behav Res Ther 2007;45:2964−76.
19. Conelea CA, Woods DW. The influence of contextual factors
on tic expression in Tourette’s syndrome: a review. J Psychosom
Res 2008;65:487−96.
20. Hoekstra PJ, Steenhuis MP, Kallenberg CG, Minderaa RB.
Association of small life events with self reports of tic sever-
ity in pediatric and adult tic disorder patients: a prospec-
tive longitudinal study. J Clin Psychiatry 2004;65:426−31.
21. Scahill L, Lombroso PJ, Mack G, et al. Thermal sensitivity
in Tourette syndrome: preliminary report. Percept Mot Skills
2001;92:419−32.
J.C. Du et al
22. Kostanecka-Endress T, Banaschewski T, Kinkelbur J, et al.
Disturbed sleep in children with Tourette syndrome: a
polysomnographic study. J Psychosom Res 2003;55:23−9.
23. Kirov R, Kinkelbur J, Banaschewski T, Rothenberger A. Sleep
patterns in children with attention-deficit/hyperactivity
disorder, tic disorder, and comorbidity. J Child Psychol
Psychiatry 2007;48:561−70.
24. Ivanenko A, Crabtree VM, Gozal D. Sleep in children with psy-
chiatric disorders. Pediatr Clin North Am 2004;51:51−68.
25. Eapen V, Fox-Hiley P, Banerjee S, Robertson M. Clinical fea-
tures and associated psychopathology in a Tourette syn-
drome cohort. Acta Neurol Scand 2004;109:255−60.
26. Carter AS, O’Donnell DA, Schultz RT, Scahill L, Leckman JF,
Pauls DL. Social and emotional adjustment in children affected
with Gilles de la Tourette’s syndrome: associations with
ADHD and family functioning. Attention deficit hyperactivity
disorder. J Child Psychol Psychiatry 2000;41:215−23.
27. Sukhodolsky DG, Scahill L, Zhang H, et al. Disruptive behav-
ior in children with Tourette’s syndrome: association with
ADHD comorbidity, tic severity, and functional impairment.
J Am Acad Child Adolesc Psychiatry 2003;42:98−105.
28. Gorman DA TN, Plessem KJ, Robertson MM, Leckman JF,
Peterson BS. A controlled study of psychosocial outcome
and psychiatric comorbidity in children with Tourette syn-
drome followed up in late adolescence. Am J Psychiatry
[Submitted]
29. Leckman JF. Tourette’s syndrome. Lancet 2002;360:1577−86.
30. Peterson BS, Pine DS, Cohen P, Brook JS. Prospective, longi-
tudinal study of tic, obsessive-compulsive, and attention-
deficit/hyperactivity disorders in an epidemiological sample.
J Am Acad Child Adolesc Psychiatry 2001;40:685−95.
31. Pauls DL. An update on the genetics of Gilles de la Tourette
syndrome. J Psychosom Res 2003;55:7−12.
32. Bloch MH, Craiglow BG, Landeros-Weisenberger A, et al.
Predictors of early adult outcomes in pediatric-onset obsessive-
compulsive disorder. Pediatrics 2009;124:1085−93.
33. Bloch MH, Leckman JF. Clinical course of Tourette syn-
drome. J Psychosom Res 2009;67:497−501.
34. Burd L, Freeman RD, Klug MG, Kerbeshian J. Tourette
Syndrome and learning disabilities. BMC Pediatr 2005;5:34.
35. Schultz RT, Carter AS, Gladstone M, et al. Visual-motor
integration functioning in children with Tourette syn-
drome. Neuropsychology 1998;12:134−45.
36. Keri S, Szlobodnyik C, Benedek G, Janka Z, Gadoros J.
Probabilistic classification learning in Tourette syndrome.
Neuropsychologia 2002;40:1356−62.
37. Marsh R, Alexander GM, Packard MG, et al. Habit learning in
Tourette syndrome: a translational neuroscience approach
to a developmental psychopathology. Arch Gen Psychiatry
2004;61:1259−68.
38. Merette C, Brassard A, Potvin A, et al. Significant linkage for
Tourette syndrome in a large French Canadian family. Am J
Hum Genet 2000;67:1008−13.
39. The Tourette Syndrome Association International Consortium
for Genetics. A complete genome screen in sib pairs affected
by Gilles de la Tourette syndrome. Am J Hum Genet 1999;
65:1428−36.
40. Simonic I, Gericke GS, Ott J, Weber JL. Identification of
genetic markers associated with Gilles de la Tourette syn-
drome in an Afrikaner population. Am J Hum Genet 1998;
63:839−46.
41. Mathews CA, Reus VI, Bejarano J, et al. Genetic studies of
neuropsychiatric disorders in Costa Rica: a model for the use
of isolated populations. Psychiatr Genet 2004;14:13−23.
42. Diaz-Anzaldua A, Joober R, Riviere JB, et al. Tourette syn-
drome and dopaminergic genes: a family-based association
study in the French Canadian founder population. Mol
Psychiatry 2004;9:272−7.
Tourette syndrome in children
43. Comings DE. Clinical and molecular genetics of ADHD and
Tourette syndrome. Two related polygenic disorders. Ann N Y
Acad Sci 2001;931:50−83.
44. Cheon KA, Ryu YH, Namkoong K, Kim CH, Kim JJ, Lee JD.
Dopamine transporter density of the basal ganglia assessed
with [123I]IPT SPECT in drug-naive children with Tourette’s
disorder. Psychiatry Res 2004;130:85−95.
45. Lee CC, Chou IC, Tsai CH, Wang TR, Li TC, Tsai FJ. Dopamine
receptor D2 gene polymorphisms are associated in Taiwanese
children with Tourette syndrome. Pediatr Neurol 2005;33:
272−6.
46. Abelson JF, Kwan KY, O’Roak BJ, et al. Sequence variants in
SLITRK1 are associated with Tourette’s syndrome. Science
2005;310:317−20.
47. Ercan-Sencicek AG, Stillman AA, Ghosh AK, et al. L-histidine
decarboxylase and Tourette’s syndrome. New Eng J Med
2010;362:1901−8.
48. Chou IC, Wan L, Liu SC, Tsai CH, Tsai FJ. Association of the
Slit and Trk-like 1 gene in Taiwanese patients with Tourette
syndrome. Pediatr Neurol 2007;37:404−6.
49. Khalifa N, von Knorring AL. Tourette syndrome and other tic
disorders in a total population of children: clinical assess-
ment and background. Acta Paediatr 2005;94:1608−14.
50. Mathews CA, Bimson B, Lowe TL, et al. Association between
maternal smoking and increased symptom severity in
Tourette’s syndrome. Am J Psychiatry 2006;163:1066−73.
51. Peterson BS, Zhang H, Anderson GM, Leckman JF. A double-
blind, placebo-controlled, crossover trial of an antiandro-
gen in the treatment of Tourette’s syndrome. J Clin
Psychopharmacol 1998;18:324−31.
52. Lin H, Katsovich L, Ghebremichael M, et al. Psychosocial stress
predicts future symptom severities in children and adoles-
cents with Tourette syndrome and/or obsessive-compulsive
disorder. J Child Psychol Psychiatry 2006;48:157−66.
53. Chappell P, Leckman J, Goodman W, et al. Elevated cere-
brospinal fluid corticotropin-releasing factor in Tourette’s
syndrome: comparison to obsessive compulsive disorder and
normal controls. Biol Psychiatry 1996;39:776−83.
54. Corbett BA, Mendoza SP, Baym CL, Bunge SA, Levine S.
Examining cortisol rhythmicity and responsivity to stress in
children with Tourette syndrome. Psychoneuroendocrinology
2008;33:810−20.
55. Mell LK, Davis RL, Owens D. Association between strepto-
coccal infection and obsessive-compulsive disorder, Tourette’s
syndrome, and tic disorder. Pediatrics 2005;116:56−60.
56. Snider LA, Swedo SE. PANDAS: current status and directions
for research. Mol Psychiatry 2004;9:900−7.
57. Martino D, Dale RC, Gilbert DL, Giovannoni G, Leckman JF.
Immunopathogenic mechanisms in Tourette syndrome: a
critical review. Mov Disord 2009;24:1267−79.
58. Ho CS, Shen EY, Shyur SD, Chiu NC. Association of allergy
with Tourette’s syndrome. J Formos Med Assoc 1999;98:
492−5.
59. Yin HH, Knowlton BJ. The role of the basal ganglia in habit
formation. Nat Rev Neurosci 2006;7:464−76.
60. Leckman JF, Riddle MA. Tourette’s syndrome: when habit-
forming systems form habits of their own? Neuron 2000;
28:349−54.
61. Hyde TM, Stacey ME, Coppola R, Handel SF, Rickler KC,
Weinberger DR. Cerebral morphometric abnormalities in
Tourette’s syndrome: a quantitative MRI study of monozy-
gotic twins. Neurology 1995;45:1176−82.
62. Peterson BS, Thomas P, Kane MJ, et al. Basal ganglia volumes
in patients with Gilles de la Tourette syndrome. Arch Gen
Psychiatry 2003;60:415−24.
63. Bloch MH, Leckman JF, Zhu H, Peterson BS. Caudate volumes
in childhood predict symptom severity in adults with Tourette
syndrome. Neurology 2005;65:1253−8.
263
64. Peterson BS, Skudlarski P, Anderson AW, et al. A functional
magnetic resonance imaging study of tic suppression in
Tourette syndrome. Arch Gen Psychiatry 1998;55:326−33.
65. Gerard E, Peterson BS. Developmental processes and brain
imaging studies in Tourette syndrome. J Psychosom Res
2003;55:13−22.
66. Leckman JF, Vaccarino FM, Kalanithi PS, Rothenberger A.
Annotation: Tourette syndrome: a relentless drumbeat−driven
by misguided brain oscillations. J Chil Psychol Psychiatr
2006;47:537−50.
67. Holt DJ, Graybiel AM, Saper CB. Neurochemical architec-
ture of the human striatum. J Comp Neurol 1997;384:1−25.
68. Berke JD, Okatan M, Skurski J, Eichenbaum HB. Oscillatory
entrainment of striatal neurons in freely moving rats.
Neuron 2004;43:883−96.
69. Gonzalez-Burgos G, Krimer LS, Povysheva NV, Barrionuevo G,
Lewis DA. Functional properties of fast spiking interneurons
and their synaptic connections with pyramidal cells in pri-
mate dorsolateral prefrontal cortex. J Neurophysiol 2005;
93:942−53.
70. Kataoka Y KP, Grantz H, Schwartz ML, Saper CB, Leckman JF,
Vaccarino FM. Decreased number of parvalbumin and cholin-
ergic interneurons in the striatum of individuals with Tourette
syndrome. J Comparat Neurol 2010;518:277−91.
71. Scahill L, Erenberg G, Berlin CM Jr, et al. Contemporary
assessment and pharmacotherapy of Tourette syndrome.
NeuroRx 2006;3:192−206.
72. Wong DF, Singer HS, Brandt J, et al. D2-like dopamine recep-
tor density in Tourette syndrome measured by PET. J Nucl
Med 1997;38:1243−7.
73. Serra-Mestres J, Ring HA, Costa DC, et al. Dopamine trans-
porter binding in Gilles de la Tourette syndrome: a [123I]
FP-CIT/SPECT study. Acta Psychiatr Scand 2004;109:140−6.
74. Harris K, Singer HS. Tic disorders: neural circuits, neurochem-
istry, and neuroimmunology. J Child Neurol 2006;21:678−89.
75. Yoon DY, Gause CD, Leckman JF, Singer HS. Frontal dopami-
nergic abnormality in Tourette syndrome: a postmortem
analysis. J Neurol Sci 2007;255:50−6.
76. Minzer K, Lee O, Hong JJ, Singer HS. Increased prefrontal D2
protein in Tourette syndrome: a postmortem analysis of fron-
tal cortex and striatum. J Neurol Sci 2004;219:55−61.
77. Singer HS, Hahn IH, Moran TH. Abnormal dopamine uptake
sites in postmortem striatum from patients with Tourette’s
syndrome. Ann Neurol 1991;30:558−62.
78. American Psychiatric Association. Diagnostic and Statistical
Manual of Mental Disorders, 4th edition. Washington, DC:
American Psychiatric Association, 2000.
79. World Health Organization. Multiaxial Classification of
Child and Adolescent Psychiatric Disorder-International
Classification of Disease and Related Health Problems, 10th
Revision (ICD-10). Cambridge: Cambridge University Press,
1998.
80. Leckman JF, Riddle MA, Hardin MT, et al. The Yale Global
Tic Severity Scale: initial testing of a clinician-rated scale
of tic severity. J Am Acad Child Adolesc Psychiatry 1989;28:
566−73.
81. Dooley JM. Tic disorders in childhood. Semin Pediatr Neurol
2006;13:231−42.
82. Bloch MH, Sukhodolsky DG, Leckman JF, Schultz RT. Fine-
motor skill deficits in childhood predict adulthood tic sever-
ity and global psychosocial functioning in Tourette’s syndrome.
J Child Psychol Psychiatry 2006;47:551−9.
83. Davis RE, Osorio I. Childhood caffeine tic syndrome.
Pediatrics 1998;101:E4.
84. Swain JE, Leckman JF. Tourette’s Syndrome in Children. Curr
Treat Options Neurol 2003;5:299−308.
85. Bloch MH. Emerging treatments for Tourette’s disorder.
Curr Psychiatry Rep 2008;10:323−30.
264
86. Leckman JF, Hardin MT, Riddle MA, Stevenson J, Ort SI,
Cohen DJ. Clonidine treatment of Gilles de la Tourette’s
syndrome. Arch Gen Psychiatry 1991;48:324−28.
87. Scahill L, Chappell PB, Kim YS, et al. A placebo-controlled
study of guanfacine in the treatment of children with tic
disorders and attention deficit hyperactivity disorder. Am J
Psychiatry 2001;158:1067−74.
88. Treatment of ADHD in children with tics: a randomized
controlled trial. Neurology 2002;58:527−36.
89. Scahill L, Leckman JF, Schultz RT, Katsovich L, Peterson BS.
A placebo-controlled trial of risperidone in Tourette syn-
drome. Neurology 2003;60:1130−5.
90. Gaffney GR, Perry PJ, Lund BC, Bever-Stille KA, Arndt S,
Kuperman S. Risperidone versus clonidine in the treatment
of children and adolescents with Tourette’s syndrome. J Am
Acad Child Adolesc Psychiatry 2002;41:330−6.
91. Sallee FR, Kurlan R, Goetz CG, et al. Ziprasidone treatment
of children and adolescents with Tourette’s syndrome: a pilot
study. J Am Acad Child Adolesc Psychiatry 2000;39:292−9.
92. Seo WS, Sung HM, Sea HS, Bai DS. Aripiprazole treatment of
children and adolescents with Tourette disorder or chronic tic
disorder. J Child Adolesc Psychopharmacol 2008;18:197−205.
J.C. Du et al
93. Yoo HK, Kim JY, Kim CY. A pilot study of aripiprazole in chil-
dren and adolescents with Tourette’s disorder. J Child
Adolesc Psychopharmacol 2006;16:505−6.
94. Himle MB, Woods DW, Piacentini JC, Walkup JT. Brief review
of habit reversal training for Tourette syndrome. J Child
Neurol 2006;21:719−25.
95. George MS, Sallee FR, Nahas Z, Oliver NC, Wassermann EM.
Transcranial magnetic stimulation (TMS) as a research tool in
Tourette syndrome and related disorders. Adv Neurol 2001;
85:225−35.
96. Mantovani A, Lisanby SH, Pieraccini F, Ulivelli M,
Castrogiovanni P, Rossi S. Repetitive transcranial magnetic
stimulation (rTMS) in the treatment of obsessive-compulsive
disorder (OCD) and Tourette’s syndrome (TS). Int J Neuro-
psychopharmacol 2006;9:95−100.
97. Porta M, Brambilla A, Cavanna AE, et al. Thalamic deep
brain stimulation for treatment-refractory Tourette syn-
drome: two-year outcome. Neurology 2009;73:1375−80.
98. Maciunas RJ, Maddux BN, Riley DE, et al. Prospective ran-
domized double-blind trial of bilateral thalamic deep brain
stimulation in adults with Tourette syndrome. J Neurosurg
2007;107:1004−14.