Download Tourette`s syndrome

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Seminar
Tourette’s syndrome
James F Leckman
As our knowledge of Gilles de la Tourette’s syndrome increases, so does our appreciation for the pathogenic
complexity of this disorder and the challenges associated with its treatment. Advances in the neurosciences have led
to new models of pathogenesis, whereas clinical studies have reinvigorated early hypotheses. The interdependent
roles of genes and environment in disease formation have yet to be fully elucidated. Results of epidemiological studies
have prompted debate on how best to characterise and diagnose this disorder. Absence of ideal anti-tic drugs,
combined with knowledge that uncomplicated cases of childhood Tourette’s syndrome frequently have a favourable
outcome, has led to striking changes in care and treatment of patients. This seminar focuses on these changing views
and offers a new perspective on our understanding of the pathogenesis of Tourette’s syndrome and on principles for
treatment of patients with this disorder.
Tic disorders have been the subject of speculation for at
least the past 300 years. Despite the overt nature of tics and
decades of scientific scrutiny, our ignorance remains great.
Notions of cause have ranged from “hereditary
degeneration” to the “irritation of the motor neural systems
by toxic substances, of a self-poisoning bacteriological
origin” to “a constitutional inferiority of the subcortical
structures . . . [that] renders the individual defenseless
against overwhelming emotional and dynamic forces”.1
Predictably, each of these aetiological explanations has
prompted new treatments and new ways of relating to
families.
Symptoms and natural history
The cardinal features of Tourette’s syndrome are motor
and phonic tics that wax and wane in severity.2 Motor tics
usually begin between the ages of 3 and 8 years, with
transient periods of intense eye blinking or some other facial
tic. Phonic tics, such as repetitive bouts of sniffing or throat
clearing, can begin as early as 3 years of age, but typically
they follow the onset of motor tics by several years.3 In
uncomplicated cases, severity of motor and phonic tics
peaks early in the second decade of life, with many patients
showing a striking reduction in tic severity by age 19 or
20 years.4 However, the most severe cases of Tourette’s
syndrome arise in adulthood. Extreme forms of this
disorder involve forceful bouts of self-injurious motor tics,
such as hitting or biting, and socially unacceptable
coprolalic utterances—eg, shouting obscenities, racial
slurs—and gestures.
Motor and phonic tics arise in bouts over the course of a
day, and change in severity over weeks and months.5 These
episodes are characterised by stable intra-tic intervals—ie,
time between successive tics—of short duration, typically
0·5–1·0 s. Less well known is the so-called self-similarity of
these patterns across different times.6 Over minutes to
hours, bouts of tics happen in groups. Over the course of
weeks to months, many episodes of tics arise (figure 1).
Lancet 2002; 360: 1577–86
Child Study Center and Departments of Paediatrics, Psychiatry,
and Psychology, Yale University, New Haven, CT 06520-7900, USA
(Prof J F Leckman MD)
(e-mail: [email protected])
THE LANCET • Vol 360 • November 16, 2002 • www.thelancet.com
This periodic higher-order combination of tic bouts could
be the basis of the well-known waxing and waning course of
Tourette’s syndrome.
Knowledge of the temporal patterning of tics is
important for the doctor, because it informs decisions about
when to initiate anti-tic drugs, when to change drugs, and
when to be patient and simply provide close monitoring
and support to the family. Stated simply, if a clinician
begins or changes a treatment at the end of a waxing period,
the patient’s condition will improve irrespective of the
efficacy of the intervention. Furthermore, a deeper
understanding of the multiplicative processes that govern
these timing patterns might clarify neural events arising
every few milliseconds and the natural history of tic
disorders over the first two decades of life.
Many patients with tic disorders report associated
sensory symptoms, including premonitory urges that
incessantly prompt tics and feelings of momentary relief
that follow performance of a tic.7 Many patients describe
being besieged by these bodily sensations that are generally
localised to discrete anatomical regions—eg, like an urge to
stretch one’s shoulder or a need to clear one’s throat. These
urges, and the internal struggle to control them, can be as
debilitating as the tics themselves. Other antecedent
sensory happenings include a generalised inner tension that
can be relieved only by performance of a tic. A large range
of auditory or visual cues can also prompt tics, but the
nature of these cues is usually highly selective for individual
patients—a cough, a particular word, an alignment of
angles or specific shapes.
Search strategy and selection criteria
A computerised and manual search on PubMed of published
work was done to identify studies about the pathogenesis of
Tourette’s syndrome and its treatment, with particular focus
on original reports published over the past 5 years. Selection
criteria included a judgment about novelty and importance of
studies and their relevance to the well-informed general
medical doctor. In the case of treatment studies, only those
interventions whose efficacy has been supported by at
least one randomised, double-blind, clinical trial are cited.
Keywords used included: “Tourette”, “tic”, “obsessivecompulsive”, “attention deficit hyperactivity disorder”, and
“PANDAS”, among others.
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in
individuals
with
Tourette’s
syndrome. Normal obsessive-compulsive-like symptoms are present in
many young children, peaking at 2·5
years of age. This disorder when
associated with tics generally has a
prepubertal age of onset. When
present, obsessive-compulsive symptoms are usually done in secret, and are
most disabling in the home environment. They can lead to periods of
depression.8–11
Individual tics
Seconds
Bouts of tics
Hours
Bouts-of-bouts of tics
Epidemiology and genetics
Days
Bouts-of-bouts-of-bouts of tics
Weeks
Bouts-of-bouts-of-bouts-of-bouts of tics
Months
Time
Figure 1: Fractal character of temporal occurrence of tics
Progressively longer time scales (seconds to months) are depicted.
In addition to tics, many patients with Tourette’s
syndrome have symptoms of hyperkinetic disorder
(known as attention-deficit hyperactivity disorder in the
USA), obsessive-compulsive disorder, or both. These
coexisting disorders can add greatly to morbidity
associated with Tourette’s syndrome and detract from
the patient’s overall quality of life8–11 (figure 2). Tics
typically have the greatest effect on a patient’s self-esteem
and peer and family relationships from age 7–12 years,
especially during periods of waxing forceful motor tics
and loud phonic tics that can go on for hours virtually
nonstop. Hyperkinetic disorder takes a heavy toll from
onset, with a negative effect on peer acceptance, school
performance, and self-esteem. Increased irritability and
rage attacks, and an increased vulnerability for drug
abuse, depression, and antisocial behaviour are also not
uncommon among patients with Tourette’s syndrome
and hyperkinetic disorder.8–11 Lesser variants are typical
Tics
Hyperkinetic
disorder
Obsessivecompulsive
disorder
0
5
10
15
Age (years)
Figure 2: Age at which tics and coexisting disorders affect
patients
Width of bars shows schematically the amount the disorder affects a
patient at a particular age.
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20
Once thought to be a rare disorder,12
the prevalence of Tourette’s syndrome
is presently estimated to be between 31
and 157 cases per 1000 in children
aged 13–14-years.13 Frequency of the
disorder varies by age, sex, source of
sample, and method of assessment. For
example, studies on direct classroom
observation and that use multiple
informants consistently yield substantially higher prevalence estimates than
do other assessment methods. Many
patients
identified
with
these
techniques have mild characteristics
and do not need long-term intervention
apart from educational and other
support. However, behavioural problems, in particular
hyperkinetic disorder, are frequently associated with
Tourette’s syndrome. Once diagnosed, these problems
usually need prompt intervention to prevent or keep to a
minimum adverse long-term results. In part, because of
this association, children in special-education settings are
more likely to be diagnosed with a tic disorder than
children in community-based samples.14
Genes
Genetic studies in twins and families provide compelling
evidence that genetic factors are implicated in vertical
transmission in families with a vulnerability to Tourette’s
syndrome and related disorders. At present, the nature of
vulnerability genes that predispose individuals to develop
the disorder are unknown. Many genes probably have a
role. Clarity about the nature and normal expression of
even a few of the susceptibility genes in Tourette’s
syndrome is likely to provide a major step forward in
understanding the pathogenesis of this disorder. Future
progress could also depend on identification of
characteristic, biologically established, endophenotypes
that are closely associated with specific vulnerability
genes. Endophenotypes are measurable aspects of human
psychiatric disorders that can either be used in linkage
analyses as quantitative traits, be modelled in animals with
the disease, or both. Promising endophenotypes include
neurophysiological and neuroanatomical measures and
patterns of treatment response (see section on neural
substrates).
The pattern of vertical transmission in family members
suggests major gene effects, and results of segregation
analyses
accord
with
models
of
autosomal
transmission.15,16 Historically, efforts to identify susceptibility genes within these high-density families with
traditional linkage strategies have met with limited
success. However, investigators studying a large FrenchCanadian family have reported evidence for linkage at
11q23.17
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Non-parametric approaches with families in which two
or more siblings are affected with Tourette’s syndrome
have also been undertaken.18 This sib-pair approach is
suitable for diseases with an unclear mode of inheritance,
and has been used successfully in studies of other
complex disorders, such as type 1 diabetes mellitus and
essential hypertension. In one sib-pair study of Tourette’s
syndrome, two areas were suggestive of linkage, one on
chromosome 4q and another on chromosome 8p.18 A
genome scan of hoarding symptoms (a component of
obsessive-compulsive disorder that can be seen in some
patients with Tourette’s syndrome) as a quantitative
phenotype was done with the same affected sib-pair data
obtained by the Tourette’s Syndrome Association
International Consortium for Genetics.19 Significant allele
sharing was noted for hoarding phenotypes for markers at
4q34–35, 5q35, and 17q25. 4q is in close proximity to the
region linked to Tourette’s syndrome.18
Identity-by-descent approaches have been used in
populations in South Africa and Costa Rica. These
techniques assume that a few so-called founder
individuals contributed the vulnerability genes that are
now distributed within a much larger population. The
South African study implicated regions near the
centromere of chromosome 2, and on 6p, 8q, 11q, 14q,
20q, and 21q.20,21 The marker in the French-Canadian
family17 that was associated with the highest LOD score
was the same marker for which significant linkage
disequilibrium with Tourette’s syndrome was detected in
the South African population. However, none of the
chromosomal regions in which cytogenetic abnormalities
have been found to co-segregate with phenotypes of
Tourette’s syndrome has shown any convincing evidence
for linkage in the high-density families, the sib-pair study,
or the identity-by-descent studies.
Several candidate genes have been assessed in people
with Tourette’s syndrome, including various dopamine
receptors (DRD1, DRD2, DRD4, and DRD5), the
dopamine transporter, various noradrenergic genes
(ADRA2a, ADRA2C, and DBH), and a few serotonergic
genes (5HTT).22 Genetic variation at any one of these loci
is unlikely to be a major source of vulnerability to the
disorder, but in concert, these alleles could have an
important cumulative effect.
Environment
Many epigenetic factors have been implicated in the
pathogenesis of Tourette’s syndrome (panel 1). For
example, children with a low birthweight with ischaemic
parenchymal brain lesions are more likely to have tics and
hyperkinetic symptoms by age 6 years than controls.23
Low Apgar scores recorded 5 min after birth have also
been associated with an increased risk for tic symptoms.24
Males are more often affected with Tourette’s
syndrome than females. Although this association could
be attributable to genetic mechanisms, frequent male-tomale transmissions within families seem to rule out the
presence of an X-linked vulnerability gene. This
observation has led to the hypothesis that androgenic
steroids during critical periods in fetal development could
have a role in later development of the syndrome.25 It has
also led investigators to test the efficacy of antiandrogenic
drugs in treatment of refractory tics.26
Tic disorders have long been identified as stresssensitive problems. Typically, symptom exacerbations
follow in the wake of stressful life-events. These events
need not be adverse in character, as long as there is a high
level of emotional excitement—eg, the start of school,
impending holidays or birthdays, vacation trips.27 Stress-
THE LANCET • Vol 360 • November 16, 2002 • www.thelancet.com
Panel 1: Possible risk factors
Genetic vulnerability
Gestational and perinatal risk factors
● Severe nausea and vomiting during the first trimester
● Severe psychosocial stress of the mother during pregnancy
● Maternal use during pregnancy of coffee (more than 2 cups
a day), cigarettes (more than ten a day), or alcohol (fewer
than two drinks a day)
● Identical twin with a lower birthweight
● Low-birthweight children with evidence of parenchymal
lesions, ventricular enlargement, or both
● Transient hypoxia or ischaemia during birth (labour >24 h),
use of forceps, nuchal cord, evidence of fetal distress
● Low Apgar scores
Severe psychosocial trauma, recurrent daily stresses
(eg, teasing by peers), or extreme emotional excitement
Recurrent streptococcal infections with post-infectious
autoimmune response
Drug abuse
● Exposure to androgenic drugs
● Chronic intermittent use of cocaine and other
psychostimulants
Co-existing medical or psychiatric disorders
● Hyperkinetic disorders
● Learning disabilities
● Depression
● Manic depression
related neurotransmitters and hormones have also been
implicated in Tourette’s syndrome. For example,
compared with healthy controls, patients with the
disorder have been reported to excrete substantially more
norepinephrine in the 20 h preceding a lumbar puncture,
to have raised concentrations of adrenocorticotropin
hormone after this procedure,28 and to have high
concentrations of norepinephrine and corticotropinreleasing factor in their cerebrospinal fluid.29,30 Taken
together, these findings suggest that a subset of patients
with Tourette’s syndrome could be characterised by
heightened reactivity of the hypothalamic-pituitaryadrenal axis and related noradrenergic sympathetic
systems.
The past decade has seen the re-emergence of the
hypothesis that post-infectious autoimmune mechanisms
contribute to the pathogenesis of some cases of Tourette’s
syndrome. Speculation about a post-infectious (or at least
a post-rheumatic fever) cause for symptoms of tic
disorder dates from the late 1800s.1 Group A ␤
haemolytic streptococci (GABHS) are known to be a
possible trigger of immune-mediated disease in
genetically predisposed individuals. Acute rheumatic
fever is a delayed sequela of these bacteria, arising about
3 weeks after an inadequately treated infection of the
upper respiratory tract. Rheumatic fever is characterised
by inflammatory lesions of the joints, heart, or central
nervous system (Sydenham’s chorea). This disorder and
Tourette’s syndrome probably affect common anatomic
areas—the basal ganglia of the brain and related cortical
and thalamic sites. Some patients with Sydenham’s
chorea have motor and phonic tics and symptoms of
obsessive-compulsive and attention-deficit hyperactivity
disorder, suggesting that, at least in some instances, these
disorders share a common cause. As in Sydenham’s
chorea, antineural antibodies have been reported to be
raised in the sera of some patients with Tourette’s
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Cerebral cortex
Striatum
Striosome
Indirect pathway
Direct
pathway
GPe
SNr
GPi
Basal ganglia
output system
Thalamus
Subthalamic nucleus
GABA
Glutamate
Figure 3: Schematic diagram of the major connections of the
basal ganglia
GPe=globus pallidus, pars externa; GPi=globus pallidus, pars interna;
SNr=substantia nigra, pars reticulata.
syndrome.31–34 Paediatric autoimmune neuropsychiatric
disorder associated with streptococcal infection
(PANDAS) has been suggested to represent a distinct
clinical entity and include cases of Tourette’s syndrome
and obsessive-compulsive disorder, in which a GABHS
infection is likely to have preceded symptom onset.35
Although the importance of antibodies against neurons in
relation to cause, and the association with previous
GABHS infections, remains a topic of great debate,36
treatments based on this mechanism show some
promise.37 Furthermore, if specific immunological
alterations are associated with onset or acute clinical
exacerbations, then the nature of these alterations should
provide insight into the genetic, neuroanatomical, and
immunological mechanisms implicated. This knowledge
could provide a basis for rational design of therapeutic or
preventative interventions.
Neural substrates of habit formation and tics
Habits are assembled routines that link
sensory cues with motor action. Ideas at
present
have
suggested
neural
substrates of habit formation are crucial
for a better understanding of Tourette’s
syndrome38–42 (figures 3, 4, and 5).
Neuroscientists who are interested in
learning and habit formation have
focused on the motor, sensorimotor,
association, inhibitory, and limbic
(motivational and threat detection)
neural circuits that course through the
basal ganglia.39–42 These circuits direct
information from the cerebral cortex to
the subcortex, and then back to specific
regions of the cortex, thereby forming
multiple
cortical-subcortical
loops
(figure 3).
Cortical neurons projecting to the
striatum outnumber striatal neurons by
about a factor of ten.43 These cortical
projection neurons to the striatum
segregate into two structurally similar,
but neurochemically distinct, compartments:
striosomes
and
matrix
(figure 4). These two compartments
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differ by their cortical inputs, with the striosomal medium
spiny projection neurons mainly receiving convergent
limbic and prelimbic inputs, and neurons in the matrix
mainly receiving convergent input from ipsilateral primary
motor and sensory motor cortices and contralateral
primary motor cortices. The response of particular
medium spiny projection neurons in the striatum is partly
dependent on perceptual cues that are judged salient, so
rewarding and aversive stimuli can both serve as cues.44
Several other less abundant striatal cell types probably
have a key role in this form of habit learning, including
cholinergic tonically active neurons and fast spiking
interneurons. Tonically active neurons are very sensitive
to salient perceptual cues because they signal the networks
within the cortico-basal ganglia learning circuits when
these cues arise44 (figure 4). They are responsive to
dopaminergic inputs from the substantia nigra, and these
signals probably participate in calculation of the perceived
salience (reward value) of perceptual cues along with
excitatory inputs from midline thalamic nuclei.40,45 The
fast spiking spiny interneurons of the striatum are
electrically coupled via gap junctions that connect
adjacent dendrites. Once activated, these fast spiking
neurons can inhibit many striatal projection neurons
synchronously.46 The characteristic electrophysiological
properties of the striatal fast spiking neurons—eg,
irregular bursting with stable intra burst frequencies—are
reminiscent of temporal patterning of tics.5 These fast
spiking interneurons are also very sensitive to cholinergic
drugs, suggesting that they are functionally related to
tonically active neurons.47
Under normal circumstances, peak metabolic activity
happens in the matrix compartment (matrix>striosome),
as shown in figure 5.42 However, when this balance is
reversed (striosome>matrix), tics and stereotypies are
likely to arise.48
Although alterations in the structure of the basal
ganglia, including loss of right-left asymmetry in the
volumes of the lenticular nuclei, in patients with
Tourette’s syndrome have been reported,49 present data
from in-vivo neuroimaging and neurophysiological studies
suggest that broadly distributed cortical systems (or their
thalamic inputs) might be even more important
GABA
Glutamate
Acetylcholine
Dopamine
Inputs to
striosomes
S
Striosomal medium
spiny neuron
FS
M
Medium spiny neuron
in the matrix
Tan Tonically active neuron
Cortical inputs
to the matrix
Midline thalamic nuclei
Hippocampus
Prefrontal cortex
Striosome
Anterior cingulate
cortex
M
FS
S
M
Tan
Orbital frontal
cortex
S
Motor and premotor
cortex
FS
M
Amygdala
Fast spiking aspiny
neuron
Sensorimotor
cortex
Matrix
Substantia nigra, pars
compacta
Figure 4: Schematic diagram of the major inputs into the medium spiny GABAergic
projection neurons of the striatum
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Balance of activity
Striosomes
Matrix
M
alterations in dopamine pathways, such as an increase in
dopamine transporter capacity, are possible, but not
necessary, features of pathophysiology.57
Developmental models
S
Under normal conditions
S
M
Stereotypies and tics?
Figure 5: Effect of an imbalance between medium spiny
neurons in the two striatal compartments
determinants of tic and hyperkinetic behaviours.50,51 These
cross-sectional data also emphasise the need to gain a
better understanding of developmental processes, sexual
dimorphisms, and compensatory responses through
prospective longitudinal studies.
Early results of functional in-vivo neuroimaging studies
have shown that voluntary tic suppression involves
activation of regions of the prefrontal cortex and caudate
nucleus and bilateral deactivation of the putamen and
globus pallidus.52 If confirmed, these findings accord with
the well-known finding that chemical or electrical
stimulation of inputs into the putamen can provoke motor
and phonic responses that resemble tics. They also
reinforce the view that prefrontal cortical regions have a
crucial role in expression of tic symptoms. In addition to
behavioural inhibition paradigms, neurophysiological
studies—eg, transcranial magnetic stimulation and
prepulse inhibition of startle responses—have shown that
the cortical silent period is shortened and intracortical
inhibition is defective in patients with Tourette’s
syndrome.53,54 This finding provides a possible explanation
for the reduced motor inhibition and intrusive sensory
occurrence in Tourette’s syndrome and obsessivecompulsive disorder. These in-vivo neuroimaging and
neurophysiological findings might also be useful
endophenotypes that could be proven to have value in
prediction of treatment response to specific drugs or in
clarification of the role of specific vulnerability genes.
Recent neurosurgical procedures reinforce the
functional importance of thalamic regions that are part of
these cortical-subcortical loops.55 Results of one case
study showed that high frequency stimulation of the
median and rostral intralaminar thalamic nuclei produced
an important reduction of tics. This effect could be caused
by the effect of these midline thalamic nuclei on the
tonically active neurons (figure 4), or on broadly
distributed cortical systems and their corticostriatal
projections. As in other movement disorders, a deeper
understanding of the circuitry involved in Tourette’s
syndrome could lead to specific circuit-based therapies,
with deep-brain stimulation to treat refractory cases.
As with habits and stereotypies, ascending
dopaminergic pathways probably have a key role in
consolidation and performance of tics. First, dopamine
D2 receptor-blocking drugs are the mainstay of traditional
pharmacological approaches to treatment of tics. Second,
studies of monozygotic twins suggest that developmental
shifts in the balance of tonic-phasic dopaminergic tone
arise as a result of epigenetic differences, and density of
dopamine D2 receptors might affect severity of Tourette’s
syndrome.56 Third, further evidence shows that a range of
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Future progress in elucidation of the pathogenesis and
treatment of Tourette’s syndrome could be greatly
accelerated with development of animal models. Thus far,
the use of psychomotor stimulants, direct dopamine
receptor agonists, behavioural stress sensitisation
conditioning paradigms, and immune-based challenges to
induce different levels of stereotypy in rats and other
species seem to offer the greatest promise in modelling key
components of the disorder’s phenotype.48,58–60
If tics, like stereotypies, vary in accordance with the
balance of activity of medium spiny projection neurons in
the striosome and matrix compartments of the striatum,
then it should be possible to investigate the clinical effect
of genetics, developmental insults, or both, that affect the
number and sensitivity of medium spiny projection
neurons in the two striatal compartments. For example,
perinatal ischaemic and hypoxic insults involving
parenchymal lesions strikingly increase risk of tic
disorders.24
Furthermore, this model could provide a meaningful
integration of knowledge about tics drawn from several
perspectives. These include the stress responsiveness of
tics (limbic activation), the presence of premonitory
sensory urges (as sensory motor and primary motor
cortical inputs converge on the fewer medium spiny
projection neurons in the matrix), the reduction of tics
when an individual is engaged in acts that need selective
attention, and guided motor action (heightened activity
within the matrix compartment).
Results of two studies have shown an increase in oral
stereotypies in rats after infusion of sera from patients
with Tourette’s syndrome with high concentrations of
antibodies against neurons compared with controls.59,60
One plausible hypothesis is that these antibodies could
alter synaptic transmission and alter the balance between
the striosomal and matrix compartments of the striatum.
From a developmental perspective, many GABAergic
interneurons of the cerebral cortex clearly migrate
tangentially from the same embryonic regions in the
ganglionic eminence that also give rise to the GABAergic
medium spiny projection neurons of the striatum.61 Could
adverse events arising at a specific point in development—
eg, the differential loss of medium spiny projection
neurons in the matrix compartment—account for the
striatal imbalance and intracortical deficits in inhibition
seen in some patients with Tourette’s syndrome?53
Assessment and diagnosis
Clinical examination of a child with tics should include an
assessment of the child or adolescent as a whole not
merely as someone with tics.62,63 During the examination,
the full range of difficulties and competencies should be
charted: the clinician, family, and child must collaborate
to reconstruct the child’s history, tic symptoms (onset,
progression, waxing and waning, and factors that have
worsened or ameliorated tic status), and present
functioning. An important question is the extent to which
tics are interfering with the child’s emotional, social,
familial, and school experiences. To establish this fact, it
is useful to monitor symptoms over a few months to assess
their severity and fluctuation, effect on the family, and
adaptation of the child and family to them. This
monitoring can be helped if the family keeps records or uses
standard forms.3
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A central task of assessment is to explicate, clarify, and
address family issues. Diagnostic assessment is closely
connected with the first steps of treatment. During the
process of clinical inquiry, the doctor can approach
sensitive issues through clarification, education, and an
opening therapeutic discussion with the child and family.
As with other children with school-performance
problems, the child with Tourette’s syndrome needs careful
assessment of cognitive functioning and school
achievement. Children with this disorder tend to have
difficulties in attentional deployment, perseverance, and
ability to keep themselves and their work organised. Many
have poor penmanship. Schoolwork can be impaired by
compulsions, such as the need to scratch out words or
return to the beginning of a sentence.
Neurological examination of a child with Tourette’s
syndrome can be of great value. Tics are sudden habitual
movements or utterances that typically mimic some
fragment of normal behaviour and that use discrete muscle
groups. As such, they can be confused with normal
coordinated movements or vocalisations. Tics can also be
mistaken for akathisia, tardive dyskinesia, or other
hyperkinetic movement disorders.64 Once established, any
given tic tends to persist for a time. Tics are often
exacerbated by stress and fatigue. By contrast with other
movement disorders, tics can arise during sleep, but are
usually much attenuated. Some severely affected patients
have immaturities or atypicalities on the neuromaturational
examination (so-called soft signs). These signs might
suggest disturbances in the body schema and in integration
of motor control, but their relevance is not really clear.
Findings on electroencephalography and structural MRI
are generally normal and are not yet of proven clinical use
(apart from patients in whom other neurological suspicions
are present). Similarly, laboratory studies can establish a
child’s general health profile and assist in differential
diagnosis of other movement disorders, but there are no
laboratory tests for positive diagnosis of Tourette’s
syndrome or other tic disorders.
Diagnostic criteria presently in use include the
international classification of disease and related health
problems, 10th revision (ICD-10)65 and diagnostic and
statistical manual, 4th edition text revision (DSM-IVTR).66
Although clear differences exist between these classification
schemes, they are broadly congruent with each other. To
keep error to a minimum in case ascertainment and to
produce an instrument measuring the likelihood of having
Tourette’s syndrome, an international team of experts has
published a diagnostic confidence index.67 Scores on this
index are highly correlated with present tic severity, as
measured by a psychometrically sound, widely used,
clinician-rating scale, the Yale global tic severity scale.68
Once diagnosis of tic disorder has been established,
careful assessment will allow the clinician to learn about
fluctuation of symptoms. As the child becomes more
comfortable, he or she will show his or her symptoms with
less suppression or inhibition. Patients or family members
might recognise a symptom as a tic after they have been
educated about possible symptoms.
The history of patients with long-standing Tourette’s
syndrome is often confused by use of drugs. Often, drugs
have been stopped because they were thought to have been
useless or to have caused side-effects. The history of
treatments and what they have meant to the child and
family can be pieced together during the assessment. Also,
the clinician can learn why earlier treatment attempts were
not useful.
When a child or adolescent, and his or her parents, is
given enough time, over the course of several sessions, to
1582
Panel 2: Possible protective factors
Informed and supportive home and school or occupational
environment
● Maintenance of good sleep hygiene
● Regular physical exercise regimen
● Presence and use of special talents (eg, exceptional social
skills, athletic skills, musical abilities, academic gifts)
●
narrate their experiences, sadness, and disappointments,
they may feel that their full story has finally been heard,
perhaps for the first time, after having seen many doctors.
This process of rethinking the past and integrating disparate
threads of experience can be therapeutic in its own right,
and could help to ease the immediate crisis that led to the
consultation. The experience of being understood through
the diagnostic process is reassuring. Many patients and
families often feel supported, understood, and reassured by
hearing a more or less detailed account of our
understanding of the pathogenesis and natural history of
Tourette’s syndrome. Knowledge that their experience is
similar to that of other families, and that many of the most
puzzling features of the disorder are typical (such as waxing
and waning, symptom variation, ability to suppress tic for
brief periods, and premonitory urges), can be a great
reassurance to families.
Treatment
Multimodal treatment for Tourette’s syndrome is usually
indicated.69 As noted above, this approach includes
educational and supportive interventions appropriate for
any chronic disease. Panel 2 outlines possible protective
factors for the disorder. The various manifestations of the
disorder are best treated in the context of a long-term
relationship with a clinician who can help the patient,
family, and school deal with the changing manifestations of
the disorder through the years. Because acute and chronic
stress can exacerbate tics, psychotherapeutic attention to
difficulties of self-esteem, social coping, family issues, and
school adjustment could have non-specific ameliorative
effects on tic severity and on attendant anxiety and
depression. Local chapters of patients’ advocacy
organisations, such as the Tourette’s Syndrome
Association, can have a very supportive role, by putting
families of newly diagnosed children in contact with more
experienced families. Parents should be encouraged to
build on their child’s strengths.
Many cases of uncomplicated Tourette’s syndrome can
be successfully managed with just these interventions, and
do not need anti-tic drugs. When patients present with coexisting hyperkinetic disorder, obsessive-compulsive
disorder, depression, or two or three of these disorders, it is
usually better to treat these comorbid disorders first, since
successful treatment of them will often diminish tic severity.
Anti-tic treatments
Ideal anti-tic treatments are not presently available. None
of the drugs or techniques can be used effectively just when
tics are at their worst. Most of the available
pharmacological drugs need long-term treatment, and
many have potentially serious side-effects. Indeed, for some
drugs, it is much easier to begin their use than to stop them.
The natural waxing and waning pattern of tics often
confounds the results of drug trials. Even without
intervention, periods of severe tics will be followed by one
of spontaneous waning. Because tic-suppressant drugs
generally need several weeks to have their full effect, it is
often difficult to distinguish response to a drug from
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SEMINAR
spontaneous waning of symptoms. Thus, it is usually best
to avoid beginning or increasing drugs as soon as an
exacerbation begins.
Two classes of drug are most widely used to control tics
associated with Tourette’s syndrome: ␣2 adrenergic
agonists and neuroleptics.70 Guanfacine and clonidine are
two ␣2 adrenergic agents originally developed as antihypertensives for adults. In low doses, clonidine reduces
central noradrenergic activity by stimulation of presynaptic
␣2 adrenergic autoreceptors; guanfacine is believed to act
more selectively on postsynaptic ␣2 adrenergic receptors in
the prefrontal cortex. Use of these drugs is supported by
results of randomised, placebo-controlled, clinical trials.71–73
However, this support is not uniform.74,75 Although they are
generally not as potent as neuroleptics in suppression of
tics, guanfacine and clonidine are more benign than
neuroleptics in terms of potential short-term and long-term
side-effects and are frequently the first choice in previously
untreated individuals, especially those with mild-tomoderate symptoms.
Treatment with these drugs for children and adults is
usually started at a low dose and gradually increased.
Beginning with a morning dose of 0·025 mg or 0·05 mg of
clonidine, additional doses are added every 3–4 h. The size
of each dose can be gradually increased to a total dose of
0·2–0·3 mg daily. Although the effect of each individual
dose of clonidine wears off after about 3–5 h, the full ticsuppressant effects of the regimen could need 10–12 weeks
to be apparent. Guanfacine is longer acting than clonidine,
but is given in a similar way, in a range of 0·25–1·0 mg two
or three times a day.
The main side-effect of these two drugs in the
recommended dose range is sedation, sometimes
accompanied by irritability. This unwanted effect may need
dose reduction or a change of drug. Reversible cardiac
arrhythmias have been rarely reported with clonidine;
however, the need for electrocardiographic studies at
baseline and as soon as a stable dosage is reached remains
controversial. Hypotension has not been a typical drawback
in children taking these drugs. If a decision is made to
discontinue these drugs, gradual tapering over a week or
two is advisable to avoid tic flare-ups or rebound
hypertension.
Several typical and atypical neuroleptics are frequently
used for treatment of Tourette’s syndrome, especially
in patients with severe tics or whose tic symptoms
are unresponsive to ␣2 adrenergic agonists. Efficacy of
these drugs is associated with their potency in blockage
of postsynaptic dopamine-2 receptors. Pimozide,
haloperidol, sulpiride, and tiapride are the most frequently
used typical neuroleptics, whereas risperidone and
ziprasidone are two atypical neuroleptics with proven ticsuppressant efficacy.76–85
Sulpiride is a substituted benzamide and a selective
dopamine-2 antagonist, and has been widely used,
especially in Europe.86 In the only double-blind trial with
this drug, George and colleagues87 undertook a 14-week
placebo-controlled crossover study of fluvoxamine versus
sulpiride, followed by single-blind combined treatment in
11 patients with comorbid Tourette’s syndrome and
obsessive-compulsive disorder. Sulpiride monotherapy
greatly reduced tics and non-significantly improved
obsessive-compulsive symptoms. With neuroleptics, it is
best to start with a low daily dose and gradually increase the
dose. With sulpiride, the initial dose is 200 mg per day,
gradually increasing to 1 g per day.
However, use of high doses of these drugs rarely shows
additional improvement in tics, and very often produces
bothersome side-effects. Withdrawal from neuroleptics
THE LANCET • Vol 360 • November 16, 2002 • www.thelancet.com
can produce tic exacerbations and dyskinesias that can be
delayed in onset by several weeks. Although neuroleptics
are widely prescribed for patients with Tourette’s
syndrome, many patients do not adhere to treatment. The
most typical, dose-related side-effects of neuroleptics are
sedation or dysphoria. Weight gain is also a drawback with
most of these drugs, especially risperidone. Some children
taking neuroleptics develop de-novo separation anxiety
and school refusal.
Although atypical neuroleptics are believed to have a
low risk of tardive dyskinesia, acute extrapyramidal
reactions—eg, torticollis, oculogyric crisis, akathisia—do
arise, and they might need anticholinergic drugs. Because
of potential QT changes, baseline and follow-up
electrocardiography is recommended for risperidone,
ziprasidone, and pimozide. It is also essential for the
prescribing clinician to be familiar with potential
cytochrome P450-related drug reactions, because fatal
interactions have arisen with pimozide and erythromycinrelated antibiotics.
In accordance with the neuromodulatory role of
tonically active neurons in the striatum (figure 4),
nicotinic drugs, especially in combination with
neuroleptics, have shown some promise in clinical
trials.86,87 Other drugs with some promise include low
doses of pergolide, a mixed D1-D2-D3 dopamine
receptor agonist,88 and locally injected dilute botulinum
toxin.89 Some patients report a striking reduction in
premonitory sensory urges after local injections of
botulinum toxin.
Furthermore, investigators have used several specific
behavioural techniques, eg, habit reversal, hypnotherapy,
relaxation, and biofeedback techniques, and a growing use
of alternative treatments—eg, acupuncture and dietary
supplements—has been seen. The most promising of
these approaches is habit-reversal training. Azrin and
Nunn90 developed this procedure for treatment of tics and
other habits. As originally described, the intervention
consists of several inter-related components.
Four components focus on increasing patient’s awareness of their tic behaviour. The first component is
response description, in which the patient is trained to
describe tic occurrences in detail and to re-enact tic
movements while looking in a mirror. The second one is
response detection, in which the therapist points out each
tic as soon as it takes place. The third includes practices
aimed at helping the patient to identify the earliest signs of
tic occurrence. The fourth is functional analysis, to
identify situations in which tics are most likely to happen.
A fifth component comprises competing response
practice, which teaches individuals to produce
incompatible physical responses dependent upon the urge
to perform a tic. Individuals are instructed to isometrically
contract tic-opposing muscles for 1–3 min, or until the
urge to tic has passed. Other components include ones
used to increase and sustain motivation and adherence, as
well as one aimed at generalisation training. This
intervention may be useful for some individuals, but
systematic clinical trials have not been done.91
Treatment of hyperkinetic disorder in children with tics
Treatment of hyperkinetic disorder in patients with a
personal history of tics is common, complex, and
controversial. In addition to classroom interventions—eg,
small classes, close monitoring, assigned seat at the front
of the classroom, assignment of a teacher’s aide, and other
accommodations—and behavioural interventions at home
(eg, parents’ management training and behavioural
management are often very important, especially when the
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SEMINAR
child manifests disruptive behaviour), clinicians typically
find drugs to be helpful in treatment of this disorder.
Psychostimulants, such as methylphenidate, dexamfetamine, and related drugs are the most effective agents for
uncomplicated hyperkinetic disorder. Although these drugs
could be used with impunity in some individuals with tics,
in a few cases, they can precipitate de-novo tics or
exacerbate pre-existing tics in some individuals with
Tourette’s syndrome. As a result, many clinicians will begin
with clonidine or guanfacine, which, although not as potent
as the stimulants, seem to be less prone to exacerbation of
tics.71–73 Researchers in one large-scale, double-blind,
clinical trial reported that the combination of clonidine and
methylphenidate was most efficacious in treatment of
children with both attention-deficit hyperactivity disorder
and chronic tics.73 This study showed that these two drugs
had differential effects, with clonidine being most helpful
for impulsivity and hyperactivity, and methylphenidate
being most helpful for symptoms of inattention.
Treatment of tic-related obsessive-compulsive disorder
Specific cognitive behavioural techniques (eg, exposure and
response prevention training) might be useful for selected
patients with Tourette’s syndrome who present with
obsessive-compulsive
disorder.
Serotonin
reuptake
inhibitors are usually useful in treatment of symptoms of
this disorder, but might not produce a complete therapeutic
response.92 Augmentation with a low dose of a neuroleptic
might increase the anti-obsessional efficacy of these
drugs.93,94 At higher dosages, the serotonin reuptake
inhibitors might occasionally precipitate or exacerbate tics.
PANDAS interventions
Although some cases of Tourette’s syndrome have been
proposed to be a sequela of GABHS infections, this
connection remains controversial, and is likely to be a
contributing mechanism in only a few people with the
syndrome.95
Antibiotic
prophylaxis
and
arduous
investigational interventions, such as plasma exchange or
intravenous immunoglobulins, have been successfully used
in a few patients with exacerbations after streptococcal
infection.37,96 Such measures should be considered only with
expert child psychiatric and paediatric consultation. At
present, the main mandate for the clinician is to be vigilant
in assessment of children with pharyngitis or those exposed
to Streptococcus spp, and vigorous treatment and follow-up
of those with positive throat culture results.
development. Research paradigms used in these studies,
and many of the empirical findings resulting from them,
will probably be relevant to other chronic disorders of
childhood onset and will also advance our understanding of
normal development.
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1
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Future prospects
Present ideas about Tourette’s syndrome have been shaped
by advances in the neurosciences and our emerging
understanding of the role of the basal ganglia in learning
and habit formation. Although evidence that the same
mechanisms have a role in habit formation and tics is
circumstantial, progress has set the stage for a major
advance in our understanding of this disorder. Continued
success in these areas will lead to molecular insights into
functioning of neural networks, complexities of information
transfer, and targeting of specific circuits for more intensive
study. Diagnostic, treatment, and prognostic advances can
also be anticipated.
The identification of susceptibility genes in Tourette’s
syndrome will doubtless point us in new therapeutic
directions, as will characterisation of possible autoimmune
mechanisms active in the PANDAS subgroup of patients.
In view of this potential, Tourette’s syndrome can be
deemed a model disorder in which to study the dynamic
interplay of genetic vulnerabilities, environmental events,
and neurobiological systems active during early brain
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Uses of error
Tackers on the diaphragm
K Thijssens, C Hoff, J Meyerink
An 84-year-old woman had suffered from heartburn,
nausea, vomiting, and postprandial abdominal pain. Her
history contained bilateral hip prosthesis and repeated
pulmonary embolism. A chest radiograph and endoscopy
showed a type IV diaphragmatic hernia with a tortuous
intrathoracic stomach and a grade II oesophagitis. A
laparoscopic hernia repair was performed. The stomach
was reduced into the abdominal cavity and the hernial sac
resected. The resulting defect in the diaphragm was
deemed too large for primary closure and a coated polyester
mesh was attached to the crura with 5 mm titanium helical
fasteners or tackers. After an uneventful recovery the
patient suddenly developed a cardiogenic shock on the 14th
postoperative day (central venous pressure 14 cm H2O,
arterial oxygen saturation 70%). Chest radiography
revealed no abnormality, including pneumothorax. With
the medical history in mind the primary diagnosis of
pulmonary embolism was made above the diagnosis of
cardiac tamponade. When maximum supportive care,
including intravenous fluids and high doses of inotropic
agents, respiratory support, and human recombinant tissue
plasminogen activator was ineffective, a cardiac ultrasound
was done, establishing cardiac tamponade. Pericardiocentesis yielded 300 mL of blood per hour. A left
thoracotomy was subsequently done. There was active
bleeding of the epicardium from a number of pointed
lesions, just opposite the tackers which had penetrated the
pericardium. The offending tackers were removed and the
defects in the epicardium sutured. The patient then went
on to recover without further complications and was
discharged 18 days after thoracotomy. One obvious point
to make is that in spite of a history of pulmonary embolism,
cardiac tamponade should have been considered from the
onset of obstructive shock. In fact the administration of
alteplase had a detrimental effect on the course of cardiac
tamponade, which was already present at that time.
Furthermore it is essential to consider the use of tackers in
this and possibly other areas of endoscopic surgery. These
5 mm titanium helical tackers are introduced under manual
pressure. Since the layers of tissue that are to be fastened
are compressed there is no possibility of accurately
controlling their depth of penetration.
Department of Surgery, Medisch Centrum Leeuworden, Henri Dunantweg 2, 8934 AD Leeuworden, Netherlands (K Thijssens MD, C Hoff MD,
J Meyerink MD)
1586
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