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. |