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INVITED REVIEW
Tourette syndrome, associated conditions and the
complexities of treatment
Mary M. Robertson
Department of Psychiatry and Behavioural Sciences,
University College and The National Hospital for
Neurology and Neurosurgery, London, UK
Summary
Tourette syndrome (TS) is characterized by multiple
motor tics plus one or more vocal (phonic) tics, which
characteristically wax and wane. It can no longer be
considered the rare and bizarre syndrome that it was
once thought to be. The concepts surrounding TS, and
our understanding of it, are also becoming increasingly
complex and, in some individuals, TS is now recognized
to be associated with a wide variety of associated
behaviours and psychopathologies. It is suggested that TS
is heterogeneous from a variety of standpoints including
Introduction
Tourette syndrome (TS) used to be considered rare (see
Robertson 1989, 1994), with, for many years, case reports
being the only documentations in the medical literature.
Recently, the literature on TS has mushroomed, with
substantial cohorts of TS patients and scientifically rigorous
investigations being commonly described. It used to be
thought that the clinical phenomenology of TS was fairly
simple and standard, e.g. as defined by the Diagnostic and
Statistical Manuals (DSMs) criteria (American Psychiatric
Association, 1980, 1987, 1994), but it is now recognized that
TS is far from simple. There is no doubt that TS is genetic,
but the precise inheritance pattern is as yet unclear. Comorbid
conditions, associated behaviours and psychopathologies are
Oxford University Press 2000
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M. M. Robertson
ADHD
ADHD is probably one of the most common psychiatric
disorders affecting children, with prevalence estimates
ranging from 2 to 15%; the aetiology of ADHD is not fully
understood. As ADHD begins in early childhood, parents are
often the first to note clumsiness, excessive activity, low
frustration tolerance and accident proneness (Towbin and
Riddle, 1993). For a careful review of stand-alone
hyperkinetic disorder (which includes ADHD), influences on
pathogenesis, prevalence, diagnosis, comorbidity, differential
diagnosis, work-up and treatment guidelines, readers are
referred to the review by Taylor and colleagues (Taylor et al.,
1998). The present author suggests that as ADHD and TS
are so intimately related, it is valuable to familiarize oneself
with this ADHD literature.
As early as 1973, it was generally accepted that many
children who progress to TS first manifest various behavioural
disturbances often labelled as minimal brain dysfunction,
hyperactivity or attention deficit disorder (Shapiro et al.,
1973a, b). Although diagnostic criteria have changed over
time, in this review, for the sake of convenience, all these
types of symptom, unless otherwise specified, will be referred
to as ADHD. Components of this are a short attention span
and impulsivity; hyperactivity may or may not be present
(American Psychiatric Association, 1987). For a detailed
history of ADHD through the DSM variants, the reader is
referred to Towbin and Riddle (Towbin and Riddle, 1993).
It has been pointed out that of all the comorbid conditions
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SIB
In his original paper in 1885, Georges Gilles de la Tourette
described that two out of nine patients injured themselves
Anxiety
Anxiety is also common in TS patients and has been examined
frequently. Zausmer studied 96 children with tics. Anxiety
symptoms in the group were of four types including: sleep
difficulties; tension habits; motor unrest; phobias, worries,
poor concentration; they were recorded in over 80% of
patients (Zausmer, 1964). Corbett and colleagues investigated
children and adults with tics by means of chart reviews. In
52%, tics were the initial complaint; anxiety was documented
as the most frequent symptom (Corbett et al., 1969). Erenberg
and colleagues reported 45% of 58 TS individuals to have
extreme anxiety (Erenberg et al., 1987). Coffey and
colleagues investigated 84 TS patients, of whom 11 (13%)
had TS with OCD and 16 (19%) had TS with non-OCD
anxiety disorder (Coffey et al., 1992). Chee and Sachdev
reported on 50 TS adult patients using a structured schedule;
30% were found to have GAD (Chee and Sachdev, 1994).
431
Depression
Depression is a common disorder with a lifetime risk of
~10%, with rates almost doubled in women. It may be a
mild disorder, but if severe the lifetime suicide risk is ~15%.
The aetiology of depression is often multifactorial and
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Personality disorder
There is only one investigation of personality disorder in TS,
but as it is an important clinical issue, the results will be
discussed in detail. Robertson and colleagues examined 39
adult TS patients of whom 31 (79%) were male, with 34
age- and sex-matched controls. The TS patients were of
moderate severity (YGTSS; mean 26.2, range 1155). TS
patients and controls were examined using the Structured
Clinical Interview for DSM-III-R Personality Disorders II
(Spitzer et al., 1987; Nussbaum and Rogers, 1992) to
systematically determine personality axis II personality
disorders. Subjects also completed a self-rated scale for
personality disorders (Dowson, 1992). Results showed that,
using the Structured Clinical Interview for DSM-III-R
Personality Disorders II, 25 out of 34 (64%) TS cases had
one or more DSM-III-R personality disorders, compared with
only two of 34 (16%) control subjects (2 22.7,
P 0.0001). TS cases were also more likely to have multiple
personality disorders. Using the STCPD scale, 27 (71%) of
the 38 TS cases completing the scale were identified as
having one or more personality disorders compared with five
(15%) of the control group (Robertson et al., 1997). The
cause of this increase in personality disorder may well be
the result of the long-term outcome of childhood ADHD,
referred to earlier. Thus, it does appear that at least some
clinic TS populations have personality disorders which have
both treatment and prognosis implications.
Conclusions
The above conditions are no doubt found in many TS cases,
but the precise relationships between them and TS are as yet
unclear. Further studies will have to be undertaken on mild
TS individuals in non-clinic settings to see whether or
not they are more depressed and anxious, and have more
personality disorders than control subjects. Further genetic
studies are also called for. The clinic population, as said,
may well reflect referral bias (Berkson, 1946). Only when
the putative gene(s) are identified can one be absolutely sure
of the TS phenotype and which associated behaviours, if any,
form part of the phenotype.
Aetiological aspects
Genetics
It is now generally agreed that TS is genetically determined.
The assertion was made as there are large families documented
(Kurlan et al., 1986; Robertson and Gourdie, 1990; McMahon
et al., 1992) which, at least at face value, suggested autosomal
dominant inheritance and on their own should have been
large enough to enable detection of linkage. Indeed, TS was
shown to be autosomal dominant by complex segregation
analysis techniques (e.g. Curtis et al., 1992). To date, however,
no linkage studies have been replicated and much of the
genome has been excluded (over 80% by 1993; Heutink
et al., 1993). The question then is why has this proven so
difficult? This may be so for several reasons, including the
fact that the model for inheritance is wrong, the phenotype
cannot be accurately determined or there are other nongenetic factors at play. These are some of the reasons why
so many different models for inheritance have been proposed
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Perinatal factors
Based on observations that stressors at various times of the
life cycle could influence TS symptoms, Leckman and
colleagues suggested a stress-diathesis model for the
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Management of TS
Management can range from education to supportive
reassurance to intricate pharmacological interventions, and
ideally management should be multidisciplinary. At the outset
it must be pointed out that education is mandatory and
psychobehavioural methods and reassurance may well be
sufficient for many patients, especially those with mild
symptomatology.
Psychological techniques
A variety of psychological techniques have been used in the
treatment of TS. The first technique used was massed
negative practice (over-rehearsal of the target tic by the
patient, which would eventually disappear by a mechanism
called reactive inhibition). Subsequent literature has, however,
shown inconsistent results using this method (for review, see
Evers and van de Wetering, 1994). Other psychological
treatments which have proved useful in TS have included
assertiveness training (Mansdorf, 1986), self-monitoring
(Billings, 1978) and cognitive therapy (OConnor et al.,
1993). Relaxation therapy (Bergin et al., 1998), on the other
hand, has not proved useful in the treatment of tics. Evers
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Pharmacological management
The neurobiology of TS has been thoroughly reviewed
(Messiha, 1988; Baker et al., 1995; Singer, 1997; Robertson
and Stern, 1998) and many circuits (e.g. frontalsubcortical;
basal gangliathalamocortical, nucleus accumbenslimbic
system) and neurotransmitter and/or neuromodulator systems
have been implicated in the aetiopathogenesis. These
neurotransmitter systems include catecholamines (dopamine
and noradrenaline); tryptophan and its metabolites (serotonin,
kynurenine, tryptamine), acetylcholine, the GABA amino
acids (glutamate, phenylalanine, p-tyrosine), trace amines
(e.g. tyramine), opioid peptides (e.g. dynorphin), the second
messenger (cyclic AMP), and androgenic hormones.
However, there have been relatively few post-mortem TS
brains studied pathologically. Many parts of the brain have
been invoked as abnormal in TS. Studies of eye movements
have implicated basal ganglia dysfunction. MRI studies
have implicated corpus callosum size and loss of normal
asymmetrical predominance of the caudate. Much of the
imaging and neurochemical data has been potentially
conflicting. In fact, it has been pointed out that the efficacy
of neuroleptics in treating tics (see below) was the main
factor behind the prevailing theory of dysfunctional
dopaminergic basal ganglia circuitry (Robertson and Stern,
1998).
Chemotherapy is, at present, the mainstay of treatment of
the motor and vocal symptoms of TS, as well as some of
the associated behaviours. Thus, this communication will
concentrate on pharmacological manoeuvres in the treatment
of TS. Many studies and case reports will be reviewed, not
only to demonstrate drug efficacy, but also to indicate the
most favoured drugs and reasons for this.
The pharmacological treatment of TS can be complex and
may be difficult in many cases. It can be hampered by
the fact that there have been relatively few double-blind
medication studies and the controlled trials that there are
have been conducted on relatively small numbers of patients.
Combination strategies are often required according to which
symptoms are being primarily targeted, and relatively few
studies of these exist; augmentation strategies are also used
for certain symptom groups. Some patients, however, with
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Dopamine-modulating drugs
Typical neuroleptics (dopamine antagonists). The
neuroleptics are most often used as antipsychotic agents and
are also misleadingly referred to as major tranquilizers.
They are considered to act primarily by interfering with
dopaminergic transmission in the brain by blocking dopamine
receptors. They also affect cholinergic, -adrenergic,
histaminergic and serotinergic receptors (British National
Formulary, 1998).
Haloperidol (Dozic, Haldol, Halperon, Peridol, Serenace).
Haloperidol, a butyrophenone derivative, is primarily a
dopamine D2 receptor blocker (Messiha, 1988). It is one of
the most widely used agents used in treating in TS in the
USA, Canada, UK, Europe, Australasia and the Far East.
Seignot first documented its use in the treatment of TS
(Seignot, 1961), but it has recently been shown that the
patient previously had a frontal lobotomy (Rickards et al.,
1997). Since then, however, it has been the most tried and
tested medication, with many case reports of its successful
use (Caprini and Melotti, 1961; Challas and Brauer, 1963;
Chapel et al., 1964; Stevens and Blachly, 1966; Fernando,
1967; Lucas et al., 1967; Boris, 1968; Shapiro and Shapiro,
1968; Stanciu et al., 1972; Shapiro et al., 1973c; Perera,
1975; Feinberg and Carroll, 1979; Singer et al., 1986; Wright
and Peet, 1989). Shapiro and colleagues reviewed 41 reports
of its use over a 14-year period and found its efficacy to be
between 78 and 91% (Shapiro et al., 1988). It has also,
however, withstood the rigours of DBTs (Connell et al.,
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Dopamine agonists
Pergolide (Celance, Parkotil, Permax). Pergolide is a
dopamine agonist with its agonist properties both at D2 and,
to a lesser extent, at D1 receptors, and is used mainly in
Parkinsons disease (Reynolds, 1996). Lipinski and colleagues
used pergolide in 32 TS patients aged 1719 years in a 6week open-label fixed-flexible dosing schedule. Overall 75%
of patients (24 out of 32) had a drop of 50% in all aspects
of tic severity with a mean treatment dose of 177 61 g/
day. Of interest is that the presence of restless legs syndrome
comorbidity (59%) was highly associated with a positive
response (Lipinski et al., 1997).
Side-effects pertinent to TS include dyskinesia and NMS
(British National Formulary, 1998). Abrupt withdrawal of
pergolide may precipitate hallucinations and confusion
(Reynolds, 1996).
Amantadine
(Mantadix,
Symadine,
Symmetral).
Amantadine, another dopamine agonist which also has
antiviral properties, has modest effects when used in
Parkinsons disease, but not drug induced extrapyramidal
symptoms (Reynolds, 1996; British National Formulary,
1998). Trials with amantadine are under way in the USA in
the treatment of TS. To the best of the authors knowledge
there is only one publication of its use in TS in which it was
found not to be useful (Walsh et al., 1986).
Selegiline (Deprenyl, Eldepryl, Movergan). Selegiline is a
dose-dependent selective irreversible inhibitor of monoamine
oxidase, type B, which is another dopamine agonist
(Reynolds, 1996). The main use of this agent is in the
treatment of Parkinsons disease (Reynolds, 1996; British
National Formulary, 1998).
Jankovic first reported the successful use of selegiline
(8 mg/day) in 26 out of 29 (i.e. 90%) youngsters with TS
and ADHD, in an open trial (Jankovic, 1993).
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Other medications
Nicotine. It has been suggested that the pathophysiology of
TS may be linked to a relative imbalance between cholinergic
and dopaminergic activity within the striatum and that nicotine
may alter this imbalance (Dursun and Reveley, 1996).
Animal experiments in the late 1980s and early 1990s
demonstrated that nicotine potentiated haloperidol-induced
catalepsy and reduced locomotor activity (Manderscheid
et al., 1988; Sanberg et al., 1989; Emerich et al., 1991). At
around the same time, there was a case report that chewing
nicotine gum reduces tics (Brill, 1988). Devor and Isenberg
reported a male TS patient whose symptoms reduced
markedly when he smoked cigarettes (Devor and Isenberg,
1989).
In open studies involving small numbers of TS patients
who were being treated with haloperidol, the frequency of
tics was reduced significantly during a 30-min nicotine
gum (Nicorette) chewing period and the hour afterwards,
suggesting once again that nicotine appears to potentiate the
effects of haloperidol (Sanberg et al., 1988, 1989; McConville
et al., 1991); the methods involved, however, have been
criticized (Arevalo et al., 1992; Rickards, 1992). In addition,
many discontinued the gum because of side-effects, especially
nausea and a bitter taste in the mouth (Sanberg et al., 1989;
McConville et al., 1991). Subsequent DBTs suggested that
nicotine markedly potentiated haloperidol effects in treating
TS and showed lesser effects on symptoms when used alone;
placebo gum had no effect (McConville et al., 1992). Mainly
because of the unacceptable side-effects of gum, transdermal
nicotine patches (TNP) were subsequently used (Silver and
Sanberg, 1993; Dursun et al., 1994; Reveley et al., 1994);
at a dose of 710 mg/24 h, although there was a broad range
in individual response, TS patients improved significantly
for up to 14 weeks, but not as long as 16 weeks, and sideeffects were transient (Silver et al., 1996; Dursun and Reveley,
1997). Other side-effects of TNPs include headache, lightheadedness, sweating, tremor and sleep disturbances (Davila
et al., 1994).
A recent study, on the other hand, evaluated the effect of
nicotine smoking in 47 TS patients; of the 28 smoking
patients only two (7%) reported a tic reduction when smoking
cigarettes (Muller-Vahl et al., 1997).
Nicotine is also available as a nasal spray and an inhaler
is under development (Benowitz, 1996); to the best of the
authors knowledge, neither of these applications has been
used in TS.
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M. M. Robertson
Conclusions
TS is probably a heterogeneous condition, from an
aetiopathological, genetic, clinical phenomenological and
psychopathological point of view.
To summarize, and in the authors opinion (taking into
account the literature and personal experience), there is no
doubt that ADHD is very common in TS, even in mild cases.
It is thought that, in time, it will be clear that there is a
specific type of ADHD which is peculiar to TS, which is
phenomenologically different from that in pure ADHD, but it
is unclear as to whether or not this has treatment implications.
There is no doubt at all, as evidenced by the literature, that
OCS/OCB are integral to TS; they are common in TS and
genetically related, but are different from pure OCD and
different clinically from the egodystonicity point of view;
this does have treatment implications (neuroleptics are used
in addition to SSRIs). SIB is also common in TS, and in the
authors opinion may well prove to be integral to TS; it can
occur in mild TS individuals, is related to OCS/OCB and is
often difficult to treat. In the authors opinion, the depression
in TS is highly likely to be multifactorial in aetiology,
highlighting the importance of a full psychiatric history
449
Acknowledgements
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