SEMINAR

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 This periodic higher-order combination of tic bouts could
least the past 300 years. Despite the overt nature of tics and be the basis of the well-known waxing and waning course of
decades of scientific scrutiny, our ignorance remains great. Tourette’s syndrome.
Notions of cause have ranged from “hereditary Knowledge of the temporal patterning of tics is
degeneration” to the “irritation of the motor neural systems important for the doctor, because it informs decisions about
by toxic substances, of a self-poisoning bacteriological when to initiate anti-tic drugs, when to change drugs, and
origin” to “a constitutional inferiority of the subcortical when to be patient and simply provide close monitoring
structures . . . [that] renders the individual defenseless and support to the family. Stated simply, if a clinician
against overwhelming emotional and dynamic forces”.1 begins or changes a treatment at the end of a waxing period,
Predictably, each of these aetiological explanations has the patient’s condition will improve irrespective of the
prompted new treatments and new ways of relating to efficacy of the intervention. Furthermore, a deeper
families. understanding of the multiplicative processes that govern
these timing patterns might clarify neural events arising
Symptoms and natural history every few milliseconds and the natural history of tic
The cardinal features of Tourette’s syndrome are motor disorders over the first two decades of life.
and phonic tics that wax and wane in severity.2 Motor tics Many patients with tic disorders report associated
usually begin between the ages of 3 and 8 years, with sensory symptoms, including premonitory urges that
transient periods of intense eye blinking or some other facial incessantly prompt tics and feelings of momentary relief
tic. Phonic tics, such as repetitive bouts of sniffing or throat that follow performance of a tic.7 Many patients describe
clearing, can begin as early as 3 years of age, but typically being besieged by these bodily sensations that are generally
they follow the onset of motor tics by several years.3 In localised to discrete anatomical regions—eg, like an urge to
uncomplicated cases, severity of motor and phonic tics stretch one’s shoulder or a need to clear one’s throat. These
peaks early in the second decade of life, with many patients urges, and the internal struggle to control them, can be as
showing a striking reduction in tic severity by age 19 or debilitating as the tics themselves. Other antecedent
20 years.4 However, the most severe cases of Tourette’s sensory happenings include a generalised inner tension that
syndrome arise in adulthood. Extreme forms of this can be relieved only by performance of a tic. A large range
disorder involve forceful bouts of self-injurious motor tics, of auditory or visual cues can also prompt tics, but the
such as hitting or biting, and socially unacceptable nature of these cues is usually highly selective for individual
coprolalic utterances—eg, shouting obscenities, racial patients—a cough, a particular word, an alignment of
slurs—and gestures. angles or specific shapes.
Motor and phonic tics arise in bouts over the course of a
day, and change in severity over weeks and months.5 These Search strategy and selection criteria
episodes are characterised by stable intra-tic intervals—ie, A computerised and manual search on PubMed of published
time between successive tics—of short duration, typically work was done to identify studies about the pathogenesis of
0·5–1·0 s. Less well known is the so-called self-similarity of Tourette’s syndrome and its treatment, with particular focus
these patterns across different times.6 Over minutes to on original reports published over the past 5 years. Selection
hours, bouts of tics happen in groups. Over the course of criteria included a judgment about novelty and importance of
weeks to months, many episodes of tics arise (figure 1). studies and their relevance to the well-informed general
medical doctor. In the case of treatment studies, only those
Lancet 2002; 360: 1577–86 interventions whose efficacy has been supported by at
least one randomised, double-blind, clinical trial are cited.
Child Study Center and Departments of Paediatrics, Psychiatry, Keywords used included: “Tourette”, “tic”, “obsessive-
and Psychology, Yale University, New Haven, CT 06520-7900, USA compulsive”, “attention deficit hyperactivity disorder”, and
(Prof J F Leckman MD) “PANDAS”, among others.
(e-mail: James.Leckman@yale.edu)

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 SEMINAR

in individuals with Tourette’s

syndrome. Normal obsessive-com-
Individual tics pulsive-like symptoms are present in
many young children, peaking at 2·5
years of age. This disorder when
associated with tics generally has a
Seconds prepubertal age of onset. When
Bouts of tics present, obsessive-compulsive symp-
toms are usually done in secret, and are
most disabling in the home environ-
Hours ment. They can lead to periods of
depression.8–11
Bouts-of-bouts of tics
Epidemiology and genetics
Once thought to be a rare disorder,12
Days the prevalence of Tourette’s syndrome
Bouts-of-bouts-of-bouts of tics 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
Weeks
sample, and method of assessment. For
Bouts-of-bouts-of-bouts-of-bouts of tics example, studies on direct classroom
observation and that use multiple
informants consistently yield substan-
tially higher prevalence estimates than
Months
Time do other assessment methods. Many
patients identified with these
Figure 1: Fractal character of temporal occurrence of tics techniques have mild characteristics
Progressively longer time scales (seconds to months) are depicted. and do not need long-term intervention
apart from educational and other
In addition to tics, many patients with Tourette’s support. However, behavioural problems, in particular
syndrome have symptoms of hyperkinetic disorder hyperkinetic disorder, are frequently associated with
(known as attention-deficit hyperactivity disorder in the Tourette’s syndrome. Once diagnosed, these problems
USA), obsessive-compulsive disorder, or both. These usually need prompt intervention to prevent or keep to a
coexisting disorders can add greatly to morbidity minimum adverse long-term results. In part, because of
associated with Tourette’s syndrome and detract from this association, children in special-education settings are
the patient’s overall quality of life8–11 (figure 2). Tics more likely to be diagnosed with a tic disorder than
typically have the greatest effect on a patient’s self-esteem children in community-based samples.14
and peer and family relationships from age 7–12 years,
especially during periods of waxing forceful motor tics Genes
and loud phonic tics that can go on for hours virtually Genetic studies in twins and families provide compelling
nonstop. Hyperkinetic disorder takes a heavy toll from evidence that genetic factors are implicated in vertical
onset, with a negative effect on peer acceptance, school transmission in families with a vulnerability to Tourette’s
performance, and self-esteem. Increased irritability and syndrome and related disorders. At present, the nature of
rage attacks, and an increased vulnerability for drug vulnerability genes that predispose individuals to develop
abuse, depression, and antisocial behaviour are also not the disorder are unknown. Many genes probably have a
uncommon among patients with Tourette’s syndrome role. Clarity about the nature and normal expression of
and hyperkinetic disorder.8–11 Lesser variants are typical 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
Tics characteristic, biologically established, endophenotypes
that are closely associated with specific vulnerability
genes. Endophenotypes are measurable aspects of human
Hyperkinetic psychiatric disorders that can either be used in linkage
disorder
analyses as quantitative traits, be modelled in animals with
the disease, or both. Promising endophenotypes include
Obsessive-
compulsive neurophysiological and neuroanatomical measures and
disorder 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
0 5 10 15 20 analyses accord with models of autosomal
Age (years) transmission.15,16 Historically, efforts to identify suscep-
tibility genes within these high-density families with
Figure 2: Age at which tics and coexisting disorders affect traditional linkage strategies have met with limited
patients success. However, investigators studying a large French-
Width of bars shows schematically the amount the disorder affects a Canadian family have reported evidence for linkage at
patient at a particular age. 11q23.17

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 SEMINAR

Non-parametric approaches with families in which two

or more siblings are affected with Tourette’s syndrome
Panel 1: Possible risk factors
have also been undertaken.18 This sib-pair approach is Genetic vulnerability
suitable for diseases with an unclear mode of inheritance,
Gestational and perinatal risk factors
and has been used successfully in studies of other
● Severe nausea and vomiting during the first trimester
complex disorders, such as type 1 diabetes mellitus and
● Severe psychosocial stress of the mother during pregnancy
essential hypertension. In one sib-pair study of Tourette’s
● Maternal use during pregnancy of coffee (more than 2 cups
syndrome, two areas were suggestive of linkage, one on
a day), cigarettes (more than ten a day), or alcohol (fewer
chromosome 4q and another on chromosome 8p.18 A
than two drinks a day)
genome scan of hoarding symptoms (a component of
● Identical twin with a lower birthweight
obsessive-compulsive disorder that can be seen in some
● Low-birthweight children with evidence of parenchymal
patients with Tourette’s syndrome) as a quantitative
lesions, ventricular enlargement, or both
phenotype was done with the same affected sib-pair data
● Transient hypoxia or ischaemia during birth (labour >24 h),
obtained by the Tourette’s Syndrome Association
use of forceps, nuchal cord, evidence of fetal distress
International Consortium for Genetics.19 Significant allele
● Low Apgar scores
sharing was noted for hoarding phenotypes for markers at
4q34–35, 5q35, and 17q25. 4q is in close proximity to the Severe psychosocial trauma, recurrent daily stresses
region linked to Tourette’s syndrome.18 (eg, teasing by peers), or extreme emotional excitement
Identity-by-descent approaches have been used in Recurrent streptococcal infections with post-infectious
populations in South Africa and Costa Rica. These autoimmune response
techniques assume that a few so-called founder
individuals contributed the vulnerability genes that are Drug abuse
now distributed within a much larger population. The ● Exposure to androgenic drugs
South African study implicated regions near the ● Chronic intermittent use of cocaine and other
centromere of chromosome 2, and on 6p, 8q, 11q, 14q, psychostimulants
20q, and 21q.20,21 The marker in the French-Canadian Co-existing medical or psychiatric disorders
family17 that was associated with the highest LOD score ● Hyperkinetic disorders
was the same marker for which significant linkage ● Learning disabilities
disequilibrium with Tourette’s syndrome was detected in ● Depression
the South African population. However, none of the ● Manic depression
chromosomal regions in which cytogenetic abnormalities
have been found to co-segregate with phenotypes of
Tourette’s syndrome has shown any convincing evidence related neurotransmitters and hormones have also been
for linkage in the high-density families, the sib-pair study, implicated in Tourette’s syndrome. For example,
or the identity-by-descent studies. compared with healthy controls, patients with the
Several candidate genes have been assessed in people disorder have been reported to excrete substantially more
with Tourette’s syndrome, including various dopamine norepinephrine in the 20 h preceding a lumbar puncture,
receptors (DRD1, DRD2, DRD4, and DRD5), the to have raised concentrations of adrenocorticotropin
dopamine transporter, various noradrenergic genes hormone after this procedure,28 and to have high
(ADRA2a, ADRA2C, and DBH), and a few serotonergic concentrations of norepinephrine and corticotropin-
genes (5HTT).22 Genetic variation at any one of these loci releasing factor in their cerebrospinal fluid.29,30 Taken
is unlikely to be a major source of vulnerability to the together, these findings suggest that a subset of patients
disorder, but in concert, these alleles could have an with Tourette’s syndrome could be characterised by
important cumulative effect. heightened reactivity of the hypothalamic-pituitary-
adrenal axis and related noradrenergic sympathetic
Environment systems.
Many epigenetic factors have been implicated in the The past decade has seen the re-emergence of the
pathogenesis of Tourette’s syndrome (panel 1). For hypothesis that post-infectious autoimmune mechanisms
example, children with a low birthweight with ischaemic contribute to the pathogenesis of some cases of Tourette’s
parenchymal brain lesions are more likely to have tics and syndrome. Speculation about a post-infectious (or at least
hyperkinetic symptoms by age 6 years than controls.23 a post-rheumatic fever) cause for symptoms of tic
Low Apgar scores recorded 5 min after birth have also disorder dates from the late 1800s.1 Group A ␤
been associated with an increased risk for tic symptoms.24 haemolytic streptococci (GABHS) are known to be a
Males are more often affected with Tourette’s possible trigger of immune-mediated disease in
syndrome than females. Although this association could genetically predisposed individuals. Acute rheumatic
be attributable to genetic mechanisms, frequent male-to- fever is a delayed sequela of these bacteria, arising about
male transmissions within families seem to rule out the 3 weeks after an inadequately treated infection of the
presence of an X-linked vulnerability gene. This upper respiratory tract. Rheumatic fever is characterised
observation has led to the hypothesis that androgenic by inflammatory lesions of the joints, heart, or central
steroids during critical periods in fetal development could nervous system (Sydenham’s chorea). This disorder and
have a role in later development of the syndrome.25 It has Tourette’s syndrome probably affect common anatomic
also led investigators to test the efficacy of antiandrogenic areas—the basal ganglia of the brain and related cortical
drugs in treatment of refractory tics.26 and thalamic sites. Some patients with Sydenham’s
Tic disorders have long been identified as stress- chorea have motor and phonic tics and symptoms of
sensitive problems. Typically, symptom exacerbations obsessive-compulsive and attention-deficit hyperactivity
follow in the wake of stressful life-events. These events disorder, suggesting that, at least in some instances, these
need not be adverse in character, as long as there is a high disorders share a common cause. As in Sydenham’s
level of emotional excitement—eg, the start of school, chorea, antineural antibodies have been reported to be
impending holidays or birthdays, vacation trips.27 Stress- raised in the sera of some patients with Tourette’s

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 SEMINAR

differ by their cortical inputs, with the striosomal medium

spiny projection neurons mainly receiving convergent
Cerebral cortex
limbic and prelimbic inputs, and neurons in the matrix
mainly receiving convergent input from ipsilateral primary
motor and sensory motor cortices and contralateral
Striatum Striosome
primary motor cortices. The response of particular
Indirect pathway medium spiny projection neurons in the striatum is partly
Direct dependent on perceptual cues that are judged salient, so
pathway GPe rewarding and aversive stimuli can both serve as cues.44
Several other less abundant striatal cell types probably
SNr GPi
have a key role in this form of habit learning, including
Subthalamic nucleus cholinergic tonically active neurons and fast spiking
Basal ganglia interneurons. Tonically active neurons are very sensitive
output system
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
GABA dopaminergic inputs from the substantia nigra, and these
Thalamus
Glutamate signals probably participate in calculation of the perceived
salience (reward value) of perceptual cues along with
Figure 3: Schematic diagram of the major connections of the excitatory inputs from midline thalamic nuclei.40,45 The
basal ganglia fast spiking spiny interneurons of the striatum are
GPe=globus pallidus, pars externa; GPi=globus pallidus, pars interna; electrically coupled via gap junctions that connect
SNr=substantia nigra, pars reticulata. adjacent dendrites. Once activated, these fast spiking
neurons can inhibit many striatal projection neurons
syndrome.31–34 Paediatric autoimmune neuropsychiatric synchronously.46 The characteristic electrophysiological
disorder associated with streptococcal infection properties of the striatal fast spiking neurons—eg,
(PANDAS) has been suggested to represent a distinct irregular bursting with stable intra burst frequencies—are
clinical entity and include cases of Tourette’s syndrome reminiscent of temporal patterning of tics.5 These fast
and obsessive-compulsive disorder, in which a GABHS spiking interneurons are also very sensitive to cholinergic
infection is likely to have preceded symptom onset.35 drugs, suggesting that they are functionally related to
Although the importance of antibodies against neurons in tonically active neurons.47
relation to cause, and the association with previous Under normal circumstances, peak metabolic activity
GABHS infections, remains a topic of great debate,36 happens in the matrix compartment (matrix>striosome),
treatments based on this mechanism show some as shown in figure 5.42 However, when this balance is
promise.37 Furthermore, if specific immunological reversed (striosome>matrix), tics and stereotypies are
alterations are associated with onset or acute clinical likely to arise.48
exacerbations, then the nature of these alterations should Although alterations in the structure of the basal
provide insight into the genetic, neuroanatomical, and ganglia, including loss of right-left asymmetry in the
immunological mechanisms implicated. This knowledge volumes of the lenticular nuclei, in patients with
could provide a basis for rational design of therapeutic or Tourette’s syndrome have been reported,49 present data
preventative interventions. from in-vivo neuroimaging and neurophysiological studies
suggest that broadly distributed cortical systems (or their
Neural substrates of habit formation and tics thalamic inputs) might be even more important
Habits are assembled routines that link
sensory cues with motor action. Ideas at GABA Striosomal medium Fast spiking aspiny
present have suggested neural S
spiny neuron
FS
Glutamate neuron
substrates of habit formation are crucial Acetylcholine Medium spiny neuron
for a better understanding of Tourette’s Dopamine M Tan Tonically active neuron
in the matrix
syndrome38–42 (figures 3, 4, and 5).
Neuroscientists who are interested in
Inputs to Midline thalamic nuclei Cortical inputs
learning and habit formation have striosomes to the matrix
focused on the motor, sensorimotor,
association, inhibitory, and limbic Hippocampus
(motivational and threat detection) Striosome Prefrontal cortex
M
neural circuits that course through the
Anterior cingulate S FS
basal ganglia.39–42 These circuits direct
cortex
information from the cerebral cortex to M Motor and premotor
Tan
the subcortex, and then back to specific cortex
Orbital frontal
regions of the cortex, thereby forming S FS
cortex
multiple cortical-subcortical loops M Sensorimotor
(figure 3). cortex
Cortical neurons projecting to the Amygdala Matrix
striatum outnumber striatal neurons by
about a factor of ten.43 These cortical Substantia nigra, pars
projection neurons to the striatum compacta
segregate into two structurally similar,
but neurochemically distinct, compart-
ments: striosomes and matrix Figure 4: Schematic diagram of the major inputs into the medium spiny GABAergic
(figure 4). These two compartments projection neurons of the striatum

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 SEMINAR

alterations in dopamine pathways, such as an increase in

Balance of activity Striosomes Matrix dopamine transporter capacity, are possible, but not
necessary, features of pathophysiology.57
M

Developmental models
S Future progress in elucidation of the pathogenesis and
Under normal conditions treatment of Tourette’s syndrome could be greatly
accelerated with development of animal models. Thus far,
the use of psychomotor stimulants, direct dopamine
S
receptor agonists, behavioural stress sensitisation
conditioning paradigms, and immune-based challenges to
M induce different levels of stereotypy in rats and other
Stereotypies and tics? 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
Figure 5: Effect of an imbalance between medium spiny balance of activity of medium spiny projection neurons in
neurons in the two striatal compartments the striosome and matrix compartments of the striatum,
then it should be possible to investigate the clinical effect
determinants of tic and hyperkinetic behaviours.50,51 These of genetics, developmental insults, or both, that affect the
cross-sectional data also emphasise the need to gain a number and sensitivity of medium spiny projection
better understanding of developmental processes, sexual neurons in the two striatal compartments. For example,
dimorphisms, and compensatory responses through perinatal ischaemic and hypoxic insults involving
prospective longitudinal studies. parenchymal lesions strikingly increase risk of tic
Early results of functional in-vivo neuroimaging studies disorders.24
have shown that voluntary tic suppression involves Furthermore, this model could provide a meaningful
activation of regions of the prefrontal cortex and caudate integration of knowledge about tics drawn from several
nucleus and bilateral deactivation of the putamen and perspectives. These include the stress responsiveness of
globus pallidus.52 If confirmed, these findings accord with tics (limbic activation), the presence of premonitory
the well-known finding that chemical or electrical sensory urges (as sensory motor and primary motor
stimulation of inputs into the putamen can provoke motor cortical inputs converge on the fewer medium spiny
and phonic responses that resemble tics. They also projection neurons in the matrix), the reduction of tics
reinforce the view that prefrontal cortical regions have a when an individual is engaged in acts that need selective
crucial role in expression of tic symptoms. In addition to attention, and guided motor action (heightened activity
behavioural inhibition paradigms, neurophysiological within the matrix compartment).
studies—eg, transcranial magnetic stimulation and Results of two studies have shown an increase in oral
prepulse inhibition of startle responses—have shown that stereotypies in rats after infusion of sera from patients
the cortical silent period is shortened and intracortical with Tourette’s syndrome with high concentrations of
inhibition is defective in patients with Tourette’s antibodies against neurons compared with controls.59,60
syndrome.53,54 This finding provides a possible explanation One plausible hypothesis is that these antibodies could
for the reduced motor inhibition and intrusive sensory alter synaptic transmission and alter the balance between
occurrence in Tourette’s syndrome and obsessive- the striosomal and matrix compartments of the striatum.
compulsive disorder. These in-vivo neuroimaging and From a developmental perspective, many GABAergic
neurophysiological findings might also be useful interneurons of the cerebral cortex clearly migrate
endophenotypes that could be proven to have value in tangentially from the same embryonic regions in the
prediction of treatment response to specific drugs or in ganglionic eminence that also give rise to the GABAergic
clarification of the role of specific vulnerability genes. medium spiny projection neurons of the striatum.61 Could
Recent neurosurgical procedures reinforce the adverse events arising at a specific point in development—
functional importance of thalamic regions that are part of eg, the differential loss of medium spiny projection
these cortical-subcortical loops.55 Results of one case neurons in the matrix compartment—account for the
study showed that high frequency stimulation of the striatal imbalance and intracortical deficits in inhibition
median and rostral intralaminar thalamic nuclei produced seen in some patients with Tourette’s syndrome?53
an important reduction of tics. This effect could be caused
by the effect of these midline thalamic nuclei on the Assessment and diagnosis
tonically active neurons (figure 4), or on broadly Clinical examination of a child with tics should include an
distributed cortical systems and their corticostriatal assessment of the child or adolescent as a whole not
projections. As in other movement disorders, a deeper merely as someone with tics.62,63 During the examination,
understanding of the circuitry involved in Tourette’s the full range of difficulties and competencies should be
syndrome could lead to specific circuit-based therapies, charted: the clinician, family, and child must collaborate
with deep-brain stimulation to treat refractory cases. to reconstruct the child’s history, tic symptoms (onset,
As with habits and stereotypies, ascending progression, waxing and waning, and factors that have
dopaminergic pathways probably have a key role in worsened or ameliorated tic status), and present
consolidation and performance of tics. First, dopamine functioning. An important question is the extent to which
D2 receptor-blocking drugs are the mainstay of traditional tics are interfering with the child’s emotional, social,
pharmacological approaches to treatment of tics. Second, familial, and school experiences. To establish this fact, it
studies of monozygotic twins suggest that developmental is useful to monitor symptoms over a few months to assess
shifts in the balance of tonic-phasic dopaminergic tone their severity and fluctuation, effect on the family, and
arise as a result of epigenetic differences, and density of adaptation of the child and family to them. This
dopamine D2 receptors might affect severity of Tourette’s monitoring can be helped if the family keeps records or uses
syndrome.56 Third, further evidence shows that a range of standard forms.3

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 SEMINAR

A central task of assessment is to explicate, clarify, and Panel 2: Possible protective factors
address family issues. Diagnostic assessment is closely
connected with the first steps of treatment. During the ● Informed and supportive home and school or occupational
process of clinical inquiry, the doctor can approach environment
sensitive issues through clarification, education, and an ● Maintenance of good sleep hygiene
opening therapeutic discussion with the child and family. ● Regular physical exercise regimen
As with other children with school-performance ● Presence and use of special talents (eg, exceptional social
problems, the child with Tourette’s syndrome needs careful skills, athletic skills, musical abilities, academic gifts)
assessment of cognitive functioning and school
achievement. Children with this disorder tend to have
difficulties in attentional deployment, perseverance, and narrate their experiences, sadness, and disappointments,
ability to keep themselves and their work organised. Many they may feel that their full story has finally been heard,
have poor penmanship. Schoolwork can be impaired by perhaps for the first time, after having seen many doctors.
compulsions, such as the need to scratch out words or This process of rethinking the past and integrating disparate
return to the beginning of a sentence. threads of experience can be therapeutic in its own right,
Neurological examination of a child with Tourette’s and could help to ease the immediate crisis that led to the
syndrome can be of great value. Tics are sudden habitual consultation. The experience of being understood through
movements or utterances that typically mimic some the diagnostic process is reassuring. Many patients and
fragment of normal behaviour and that use discrete muscle families often feel supported, understood, and reassured by
groups. As such, they can be confused with normal hearing a more or less detailed account of our
coordinated movements or vocalisations. Tics can also be understanding of the pathogenesis and natural history of
mistaken for akathisia, tardive dyskinesia, or other Tourette’s syndrome. Knowledge that their experience is
hyperkinetic movement disorders.64 Once established, any similar to that of other families, and that many of the most
given tic tends to persist for a time. Tics are often puzzling features of the disorder are typical (such as waxing
exacerbated by stress and fatigue. By contrast with other and waning, symptom variation, ability to suppress tic for
movement disorders, tics can arise during sleep, but are brief periods, and premonitory urges), can be a great
usually much attenuated. Some severely affected patients reassurance to families.
have immaturities or atypicalities on the neuromaturational
examination (so-called soft signs). These signs might Treatment
suggest disturbances in the body schema and in integration Multimodal treatment for Tourette’s syndrome is usually
of motor control, but their relevance is not really clear. indicated.69 As noted above, this approach includes
Findings on electroencephalography and structural MRI educational and supportive interventions appropriate for
are generally normal and are not yet of proven clinical use any chronic disease. Panel 2 outlines possible protective
(apart from patients in whom other neurological suspicions factors for the disorder. The various manifestations of the
are present). Similarly, laboratory studies can establish a disorder are best treated in the context of a long-term
child’s general health profile and assist in differential relationship with a clinician who can help the patient,
diagnosis of other movement disorders, but there are no family, and school deal with the changing manifestations of
laboratory tests for positive diagnosis of Tourette’s the disorder through the years. Because acute and chronic
syndrome or other tic disorders. stress can exacerbate tics, psychotherapeutic attention to
Diagnostic criteria presently in use include the difficulties of self-esteem, social coping, family issues, and
international classification of disease and related health school adjustment could have non-specific ameliorative
problems, 10th revision (ICD-10)65 and diagnostic and effects on tic severity and on attendant anxiety and
statistical manual, 4th edition text revision (DSM-IVTR).66 depression. Local chapters of patients’ advocacy
Although clear differences exist between these classification organisations, such as the Tourette’s Syndrome
schemes, they are broadly congruent with each other. To Association, can have a very supportive role, by putting
keep error to a minimum in case ascertainment and to families of newly diagnosed children in contact with more
produce an instrument measuring the likelihood of having experienced families. Parents should be encouraged to
Tourette’s syndrome, an international team of experts has build on their child’s strengths.
published a diagnostic confidence index.67 Scores on this Many cases of uncomplicated Tourette’s syndrome can
index are highly correlated with present tic severity, as be successfully managed with just these interventions, and
measured by a psychometrically sound, widely used, do not need anti-tic drugs. When patients present with co-
clinician-rating scale, the Yale global tic severity scale.68 existing hyperkinetic disorder, obsessive-compulsive
Once diagnosis of tic disorder has been established, disorder, depression, or two or three of these disorders, it is
careful assessment will allow the clinician to learn about usually better to treat these comorbid disorders first, since
fluctuation of symptoms. As the child becomes more successful treatment of them will often diminish tic severity.
comfortable, he or she will show his or her symptoms with
less suppression or inhibition. Patients or family members Anti-tic treatments
might recognise a symptom as a tic after they have been Ideal anti-tic treatments are not presently available. None
educated about possible symptoms. of the drugs or techniques can be used effectively just when
The history of patients with long-standing Tourette’s tics are at their worst. Most of the available
syndrome is often confused by use of drugs. Often, drugs pharmacological drugs need long-term treatment, and
have been stopped because they were thought to have been many have potentially serious side-effects. Indeed, for some
useless or to have caused side-effects. The history of drugs, it is much easier to begin their use than to stop them.
treatments and what they have meant to the child and The natural waxing and waning pattern of tics often
family can be pieced together during the assessment. Also, confounds the results of drug trials. Even without
the clinician can learn why earlier treatment attempts were intervention, periods of severe tics will be followed by one
not useful. of spontaneous waning. Because tic-suppressant drugs
When a child or adolescent, and his or her parents, is generally need several weeks to have their full effect, it is
given enough time, over the course of several sessions, to often difficult to distinguish response to a drug from

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 SEMINAR

spontaneous waning of symptoms. Thus, it is usually best can produce tic exacerbations and dyskinesias that can be
to avoid beginning or increasing drugs as soon as an delayed in onset by several weeks. Although neuroleptics
exacerbation begins. are widely prescribed for patients with Tourette’s
Two classes of drug are most widely used to control tics syndrome, many patients do not adhere to treatment. The
associated with Tourette’s syndrome: ␣2 adrenergic most typical, dose-related side-effects of neuroleptics are
agonists and neuroleptics.70 Guanfacine and clonidine are sedation or dysphoria. Weight gain is also a drawback with
two ␣2 adrenergic agents originally developed as anti- most of these drugs, especially risperidone. Some children
hypertensives for adults. In low doses, clonidine reduces taking neuroleptics develop de-novo separation anxiety
central noradrenergic activity by stimulation of presynaptic and school refusal.
␣2 adrenergic autoreceptors; guanfacine is believed to act Although atypical neuroleptics are believed to have a
more selectively on postsynaptic ␣2 adrenergic receptors in low risk of tardive dyskinesia, acute extrapyramidal
the prefrontal cortex. Use of these drugs is supported by reactions—eg, torticollis, oculogyric crisis, akathisia—do
results of randomised, placebo-controlled, clinical trials.71–73 arise, and they might need anticholinergic drugs. Because
However, this support is not uniform.74,75 Although they are of potential QT changes, baseline and follow-up
generally not as potent as neuroleptics in suppression of electrocardiography is recommended for risperidone,
tics, guanfacine and clonidine are more benign than ziprasidone, and pimozide. It is also essential for the
neuroleptics in terms of potential short-term and long-term prescribing clinician to be familiar with potential
side-effects and are frequently the first choice in previously cytochrome P450-related drug reactions, because fatal
untreated individuals, especially those with mild-to- interactions have arisen with pimozide and erythromycin-
moderate symptoms. related antibiotics.
Treatment with these drugs for children and adults is In accordance with the neuromodulatory role of
usually started at a low dose and gradually increased. tonically active neurons in the striatum (figure 4),
Beginning with a morning dose of 0·025 mg or 0·05 mg of nicotinic drugs, especially in combination with
clonidine, additional doses are added every 3–4 h. The size neuroleptics, have shown some promise in clinical
of each dose can be gradually increased to a total dose of trials.86,87 Other drugs with some promise include low
0·2–0·3 mg daily. Although the effect of each individual doses of pergolide, a mixed D1-D2-D3 dopamine
dose of clonidine wears off after about 3–5 h, the full tic- receptor agonist,88 and locally injected dilute botulinum
suppressant effects of the regimen could need 10–12 weeks toxin.89 Some patients report a striking reduction in
to be apparent. Guanfacine is longer acting than clonidine, premonitory sensory urges after local injections of
but is given in a similar way, in a range of 0·25–1·0 mg two botulinum toxin.
or three times a day. Furthermore, investigators have used several specific
The main side-effect of these two drugs in the behavioural techniques, eg, habit reversal, hypnotherapy,
recommended dose range is sedation, sometimes relaxation, and biofeedback techniques, and a growing use
accompanied by irritability. This unwanted effect may need of alternative treatments—eg, acupuncture and dietary
dose reduction or a change of drug. Reversible cardiac supplements—has been seen. The most promising of
arrhythmias have been rarely reported with clonidine; these approaches is habit-reversal training. Azrin and
however, the need for electrocardiographic studies at Nunn90 developed this procedure for treatment of tics and
baseline and as soon as a stable dosage is reached remains other habits. As originally described, the intervention
controversial. Hypotension has not been a typical drawback consists of several inter-related components.
in children taking these drugs. If a decision is made to Four components focus on increasing patient’s aware-
discontinue these drugs, gradual tapering over a week or ness of their tic behaviour. The first component is
two is advisable to avoid tic flare-ups or rebound response description, in which the patient is trained to
hypertension. describe tic occurrences in detail and to re-enact tic
Several typical and atypical neuroleptics are frequently movements while looking in a mirror. The second one is
used for treatment of Tourette’s syndrome, especially response detection, in which the therapist points out each
in patients with severe tics or whose tic symptoms tic as soon as it takes place. The third includes practices
are unresponsive to ␣2 adrenergic agonists. Efficacy of aimed at helping the patient to identify the earliest signs of
these drugs is associated with their potency in blockage tic occurrence. The fourth is functional analysis, to
of postsynaptic dopamine-2 receptors. Pimozide, identify situations in which tics are most likely to happen.
haloperidol, sulpiride, and tiapride are the most frequently A fifth component comprises competing response
used typical neuroleptics, whereas risperidone and practice, which teaches individuals to produce
ziprasidone are two atypical neuroleptics with proven tic- incompatible physical responses dependent upon the urge
suppressant efficacy.76–85 to perform a tic. Individuals are instructed to isometrically
Sulpiride is a substituted benzamide and a selective contract tic-opposing muscles for 1–3 min, or until the
dopamine-2 antagonist, and has been widely used, urge to tic has passed. Other components include ones
especially in Europe.86 In the only double-blind trial with used to increase and sustain motivation and adherence, as
this drug, George and colleagues87 undertook a 14-week well as one aimed at generalisation training. This
placebo-controlled crossover study of fluvoxamine versus intervention may be useful for some individuals, but
sulpiride, followed by single-blind combined treatment in systematic clinical trials have not been done.91
11 patients with comorbid Tourette’s syndrome and
obsessive-compulsive disorder. Sulpiride monotherapy Treatment of hyperkinetic disorder in children with tics
greatly reduced tics and non-significantly improved Treatment of hyperkinetic disorder in patients with a
obsessive-compulsive symptoms. With neuroleptics, it is personal history of tics is common, complex, and
best to start with a low daily dose and gradually increase the controversial. In addition to classroom interventions—eg,
dose. With sulpiride, the initial dose is 200 mg per day, small classes, close monitoring, assigned seat at the front
gradually increasing to 1 g per day. of the classroom, assignment of a teacher’s aide, and other
However, use of high doses of these drugs rarely shows accommodations—and behavioural interventions at home
additional improvement in tics, and very often produces (eg, parents’ management training and behavioural
bothersome side-effects. Withdrawal from neuroleptics management are often very important, especially when the

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For personal use. Only reproduce with permission from The Lancet Publishing Group.
 SEMINAR

child manifests disruptive behaviour), clinicians typically development. Research paradigms used in these studies,
find drugs to be helpful in treatment of this disorder. and many of the empirical findings resulting from them,
Psychostimulants, such as methylphenidate, dexamfet- will probably be relevant to other chronic disorders of
amine, and related drugs are the most effective agents for childhood onset and will also advance our understanding of
uncomplicated hyperkinetic disorder. Although these drugs normal development.
could be used with impunity in some individuals with tics,
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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, plasminogen activator was ineffective, a cardiac ultrasound
nausea, vomiting, and postprandial abdominal pain. Her was done, establishing cardiac tamponade. Pericardio-
history contained bilateral hip prosthesis and repeated centesis yielded 300 mL of blood per hour. A left
pulmonary embolism. A chest radiograph and endoscopy thoracotomy was subsequently done. There was active
showed a type IV diaphragmatic hernia with a tortuous bleeding of the epicardium from a number of pointed
intrathoracic stomach and a grade II oesophagitis. A lesions, just opposite the tackers which had penetrated the
laparoscopic hernia repair was performed. The stomach pericardium. The offending tackers were removed and the
was reduced into the abdominal cavity and the hernial sac defects in the epicardium sutured. The patient then went
resected. The resulting defect in the diaphragm was on to recover without further complications and was
deemed too large for primary closure and a coated polyester discharged 18 days after thoracotomy. One obvious point
mesh was attached to the crura with 5 mm titanium helical to make is that in spite of a history of pulmonary embolism,
fasteners or tackers. After an uneventful recovery the cardiac tamponade should have been considered from the
patient suddenly developed a cardiogenic shock on the 14th onset of obstructive shock. In fact the administration of
postoperative day (central venous pressure 14 cm H2O, alteplase had a detrimental effect on the course of cardiac
arterial oxygen saturation 70%). Chest radiography tamponade, which was already present at that time.
revealed no abnormality, including pneumothorax. With Furthermore it is essential to consider the use of tackers in
the medical history in mind the primary diagnosis of this and possibly other areas of endoscopic surgery. These
pulmonary embolism was made above the diagnosis of 5 mm titanium helical tackers are introduced under manual
cardiac tamponade. When maximum supportive care, pressure. Since the layers of tissue that are to be fastened
including intravenous fluids and high doses of inotropic are compressed there is no possibility of accurately
agents, respiratory support, and human recombinant tissue 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 THE LANCET • Vol 360 • November 16, 2002 • www.thelancet.com

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