Movement Disorders

Vol. 15, No. 6, 2000, pp. 1051–1063

© 2000 Movement Disorder Society

Review

Current Issues in Tourette Syndrome

Harvey S. Singer, MD

Departments of Neurology and Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland, U.S.A.

In the late 19th century Georges Gilles de la Tourette dyskinesias,” which was briefly suppressible.3 Sign lan-
described nine patients with chronic tic disorders char- guage tics have occurred in a woman with TS who
acterized by the presence of involuntary motor and learned to sign in adulthood4 and in a prelingually deaf
phonic tics.1 He also noted that these individuals had a individual who replaced vocal tics with equivalent sign
variety of comorbid neurobehavioral problems, including language tics.5 On the basis of the latter case, it has been
obsessive-compulsive behaviors (OCB), anxieties, and suggested that semantics are more important than pho-
phobias. Since the initial description of this disorder, nology in the generation of tics.
Tourette syndrome (TS) has been considered to be a Several articles have re-emphasized the presence of
model neuropsychiatric condition with a complex inter- common, but misdiagnosed, symptoms in TS, such as a
action of biologic and psychologic factors. The goal of chronic persistent cough, eye blinking, ocular tics, tics
this article is to review newer developments in Tourette mimicking asthma, or atopic symptoms and dermatolog-
syndrome by focusing on recent information published ic manifestations.6–10 In nine patients with TS, the blink
within the past 2 to 3 years (notated in Medline). Areas rate was approximately two- to threefold higher at rest
to be covered include the phenomenology of tics, newer than the blink rate of control subjects. Task-specific
tic scales, epidemiology, genetics, neuroimmunology, events were shown to affect eye blinks and ocular tics;
neurobiology, and treatment. Although advances have eye blinks were increased by watching videos but not by
been made in each of these areas, it will become clear to conversation, whereas ocular tics were generally in-
the reader that many questions persist and much work creased while watching amusing videos but decreased
remains to be done. during active involvement in conversation.7 The poten-
PHENOMENOLOGY tial for tics in patients with developmental stuttering has
also been emphasized in the literature. An array of non-
Tics, the essential component of TS, are readily ob-
speech motor behaviors (eye blinking or deviation, head
served but broadly defined (involuntary, sudden, rapid,
jerks, limb and trunk movements) have often been noted
repetitive, nonrhythmic, stereotyped) movements or vo-
in individuals who stutter, but generally these move-
calizations. They are manifested in a variety of forms,
ments have not been considered to be tics. In a study of
have different degrees of severity and duration, and no
22 children and adults with developmental stuttering,
two patients have the same symptoms. Despite these
Abwender and colleagues11 suggested that one half had
wide guidelines, recent reports continue to document
unique presentations. Vomiting and retching have been undiagnosed TS symptoms. Lastly, in a study of tic char-
diagnosed as tics in 10 patients with TS, but it is possible acteristics, Peterson and Leckman12 measured intervals
that these symptoms represent a side effect of pharma- between temporarily adjacent tics and showed that tics
cotherapy or a coexisting psychiatric disorder.2 One occur in a “burst-like” fashion with a nonrandom pattern
teenager with numerous typical tics developed anterior– of recurrence. The authors suggest the presence of a
posterior displacement of the external ear, labeled “ear “fractal, deterministic, and possibly chaotic process” de-
termining tic activity, that is, regardless of the time in-
terval (minutes, hours, days), a similar bursting intermit-
Received April 3, 2000; revision received May 15, 2000. Accepted tency is present.
May 15, 2000. Overlapping clinical and pathologic features have
Address correspondence and reprint requests to Harvey S. Singer,
MD, Department of Neurology, Johns Hopkins Hospital, Harvey 811, been suggested to exist between individuals with TS and
600 N. Wolfe Street, Baltimore, MD 21287-8811, U.S.A. the restless legs syndrome (RLS). RLS is characterized

1051
1052 H. SINGER

by a desire to move the limbs in association with un- problem is not new, but has been emphasized in several
comfortable paresthesias or dysesthesias and is typically recent studies focusing on tic status during stimulant
worse in the evening and while at rest.13 The syndrome treatment.23,24 In particular, investigators questioned a
may appear in childhood, family history is often positive, clinician’s ability to rank changes in tic severity by
movements are performed to alleviate preceding sensory counting the number of tics observed during a 2-minute
symptoms, sleep disturbances are common, a dopamine interval. One recent effort to improve an existing proto-
mechanism has been proposed, and treatment includes col includes modification of the scoring for the Rush
the use of dopaminergic agonists. To further investigate Video-Based Tic Rating Scale.25 This 10-minute film
similarities between RLS and TS, seven medication-free protocol includes near and far body views obtained under
adults with TS were evaluated for the presence of peri- two conditions, patient relaxed with and without the ex-
odic limb movements in sleep (PLMS), a frequent find- aminer in the room. The new scoring system provides a
ing in RLS.14 Polysomnograms with electromyograms 0-4 comparison in five domains (number of body areas,
showed that five of seven subjects with TS had periodic frequency of motor and phonic tics, and severity of mo-
leg movements and four of seven had periodic arm tor and phonic tics) plus a total score of overall tic dis-
movements during sleep. Further comparison studies are ability. A video-based rating scale is advantageous for
expected. several reasons, including the collection of data with the
In addition to reports on new and old tic symptoms, patient in a relaxed setting without direct scrutiny, and
several articles have emphasized that there may be a the ability for the video to be replayed and validated. To
spectrum of movements in patients with TS that are not date, a long-awaited standardized Unified Tic Rating
tics.15,16 For example, it is always possible that these are Scale is still being field-tested.
drug-induced movements (akathisia, dystonia, chorea, In addition to challenges in the measurement of tic
parkinsonism) or those associated with comorbid condi- severity, until recently there has been no existing instru-
tions such as obsessive-compulsive disorder (OCD), at- ment to measure the lifetime likelihood of a person hav-
tention deficit hyperactivity disorder (ADHD), or anti- ing or ever having had TS, which is important informa-
social behavior. Tic symptoms have been reported as an tion for accurate pedigree linkage analysis. To correct
early expression of Lyme infection17 and after treatment this deficiency, a collaborative group of experts devel-
with lamotrigine18 or clomipramine.19 Several factors oped the Diagnostic Confidence Index: a questionnaire
may assist the clinician in differentiating between tics independent of current severity that provides a graded
and other conditions, including subjective perceptions, score of 0 to 100.26 Several of the more highly weighted
factors that suppress or exacerbate, suppressibility, vari- diagnostic confidence factors include a history of copro-
ability, presence during sleep, and associated distur- lalia, complex motor or vocal tics, a waxing and waning
bances (hyperactivity or compulsions).15,20 Clearly, the course, echophenomena, premonitory sensations, an or-
misinterpretation of symptoms can lead to ineffective chestrated sequence, and age of onset.
and inappropriate management.
Although TS was originally proposed to be a lifelong EPIDEMIOLOGY
disorder, its course may be variable, and some patients The estimated prevalence of TS has varied from 1 to
may have a spontaneous remission or marked improve- 10 per 10,000 individuals, in part as a result of selection
ment independent of the use of tic-suppressing medica- and attribution bias. To eliminate some of these meth-
tions. Leckman and colleagues,21 using a mathematical odologic problems, Mason and colleagues27 investigated
model to assess the time course of tic severity over the the prevalence in 13- to 14-year-old students attending a
first two decades, have suggested that maximum tic se- mainstream secondary school in the United Kingdom.
verity occurs between the ages of 8 and 12 years and is Five of 166 pupils were identified as having TS, resulting
then followed by a steady decline in symptoms. Similar in a prevalence estimate of 299 per 10,000. Because this
to other reports,22 early tic severity was not found to be study had a small sample size and the identified cases
a good predictor of later tic severity. The role of puberty were not reassessed or formally diagnosed by an expert,
in altering tics remains speculative, because the authors these results must be interpreted with caution. The study
did not assess pubertal changes by physical examination. does, however, emphasize that there may be many mild
cases with minimal psychopathology. For comparison,
TIC RATING SCALES Hanna and coworkers28 in Houston, Texas, found a
Because of their wide variability, spontaneous waxing prevalence rate of definite TS or TS by history in 0.7%
and waning, and ability to be partially volitionally sup- of 1142 students in second-, fifth-, and eighth-grade
pressed, tics are difficult to rate with reliability. This classrooms.

Movement Disorders, Vol. 15, No. 6, 2000

 CURRENT ISSUES IN TOURETTE SYNDROME 1053

Other prevalence studies have sought to document the accurate diagnostic assessment, improper ascertainment
co-occurrence of autism and TS. In an extended study of methods, and problems with genetic modeling and data
447 pupils in special schools for autism, a rate of 6.5%, analysis.40,41
similar to results in smaller studies, exceeds that ex- Since gene mapping with large kindreds has failed to
pected by chance.29 TS was found to be equally common identify a specific consistent abnormality, efforts have
in children with autism, Asperger syndrome, and autistic begun to evaluate genetically isolated populations. For
spectrum disease, implying that TS is unrelated to the example, recent reports describe a genome scan in which
severity of autism. This report is in keeping with previ- DNA samples from patients with TS and unaffected con-
ous investigations that have shown children in special trol subjects in a South African Afrikaner population
school populations have an increased prevalence of TS.30 were examined.42 An additional approach has been to
Tourette syndrome occurs worldwide, with increasing search for a linkage to candidate genes, often those as-
evidence of common features in all cultures and races. A sociated with specific synaptic markers. Recent linkage
previous report suggested that the incidence of coprolalia studies, however, have yielded no positive results to do-
was lower in Japan than in the West.31 Kano and co- pamine D1–5 receptors43–46; glycine alpha 1 subunit
workers,32 however, in a combined in- and outpatient (GLRA1), GABA A receptor alpha-1, alpha-6, and
psychiatric cohort of 64 Japanese patients with TS, iden- gamma-2 subunits (GABRA1, GABRA6, GABRG2),
tified an incidence of coprolalia of 50%. This discrep- GABA A receptor beta-1 and alpha-2 subunits
ancy between studies within the same country empha- (GABARB1, GABARA2), glutamate receptor GLUR1,
sizes that ascertainment bias should always be consid- the alpha adrenergic receptor ADRA1, the beta adrener-
ered in reviewing clinical characteristics. gic receptor ADRB2, and the glucocorticoid receptor
GRL47; norepinephrine transporter gene48; and catechol-
GENETICS o-methyltransferase.49 Investigators have also sought to
Although Georges Gilles la Tourette suggested an in- identify associations between TS and other movement
herited nature for TS, the precise pattern of transmission disorders. Expanding on suggestions of a relationship
and the identification of the gene remains elusive. Strong between TS and dystonia,50 a three-generation family
support for a genetic disorder is provided by studies of in which the two cosegregates (5 with dystonia, 3 with
monozygotic twins that show an 86% concordance rate TS/facial tics) have been described.51 The authors hy-
with TS compared with 20% in dizygotic twins.33,34 Ear- pothesize that all are carrying a “susceptibility gene,”
lier proposals suggesting a sex-influenced autosomal- but larger pedigrees will be required to confirm these
dominant role of inheritance with variable expressivity assertions.
as TS, chronic tic disorder, or OCD35 have been seri- Most segregation analyses for TS consistently suggest
ously questioned. Other investigators have proposed hy- that the risk for TS is transmitted in a Mendelian fashion
potheses of a single major locus in combination with a with contributing genes of major effect. In contrast, a
multifactorial background, that is, either additional genes recent genetic study, with use of a data modeling com-
or environmental factors.36 puter program, REGTLhunt (modified from S.A.G.E.
The search for a genetic site is being actively pursued [Statistical Analysis for Genetic Epidemiology], avail-
but, despite several studies, to date no reproducible locus able from the Dept. of Epidemiology and Biostatistics,
has been identified. In a systematic genome scan of 76 Case Western Reserve University, Cleveland, OH,
affected sib-pair families with a total of 110 sib-pairs, the USA), to evaluate 108 extended families, each obtained
multipoint maximum likelihood scores for two regions through a TS proband, suggests that transmission of TS
(4q and 8p) showed a trend but did not reach acceptable is not consistent with Mendelian inheritance.52 This in-
statistical significance.37 Fine point mapping studies are vestigation also reported that the association between
currently in progress and additional families are being frequency of TS diagnosis and OCB/OCS was lower
collected. One region, chromosome 19p, suggested from than that previously reported. Hence, prior suggestions
a genome scan of multigeneration families,38 was also that TS is not genetic but rather represents a common
positive in the sib-pair study. Nevertheless, in the study disorder in the general population53 have received some
by Barr and colleagues,38 no logarithm of the odds scientific validation.
(LOD) score was greater than 2 for any marker. Tourette Further complicating our understanding of TS genetics
syndrome has also been diagnosed in three of five pa- is the issue of the influence of family history on clinical
tients with a fragile site at 16q22-23.39 Several variables expression. For example, the sex of the transmitting par-
have been proposed to explain the unsuccessful genome ent (genomic imprinting) may affect the clinical pheno-
search, including problems defining the phenotype, in- type. Lichter and coworkers54 suggested that paternal

Movement Disorders, Vol. 15, No. 6, 2000

1054 H. SINGER

transmission was associated with increased vocal tics clinical settings will be necessary before its significance
and ADHD, whereas maternal transmission led to greater can be truly assessed.
motor tic complexity and obsessive-compulsive symp-
toms. This concept is controversial, however, because NEUROIMMUNOLOGY
some investigators found no phenotypic effect associated A hypothesized role for environmental factors, espe-
with paternal transmission and no difference in age of cially infections, in the presentation or exacerbation of
onset.55,56 Eapen and colleagues56 did show that mater- neuropsychiatric diseases, such as tics and OCD, is not a
nally transmitted offspring had a significantly earlier age new phenomenon.62–64 More recently, Swedo and col-
of onset, possibly suggestive of a meiotic event or intra- leagues65 proposed that central nervous system manifes-
uterine influence. To date, the role of genomic imprint- tations of group A ␤-hemolytic streptococcal infection
ing remains controversial and conflicting reports need to (GABHS) account for a cohort of children with neuro-
be resolved. behavioral symptoms that include tic disorders, OCD,
A second issue is that of bilineal transmission, genetic and ADHD (that is, PANDAS; postinfectious autoim-
contribution from both sides of the family. In general, a mune neuropsychiatric disorders associated with strepto-
unilineal-inherited pattern implies dominant inheritance, coccal infection). Their diagnostic criteria, established in
whereas bilineality implies recessive or polygenic trans- 50 cases recruited from a nationwide search include: the
mission patterns. One issue that remains undetermined is presence of OCD and/or tic disorder; prepubertal age at
what behavior should be considered when assessing for onset; sudden, “explosive” onset of symptoms and/or a
bilineal transmission. For example, studies have reported course of sudden exacerbations and remissions; a tem-
that the likelihood of both parents of a TS proband hav- poral relationship between symptoms and GABHS; and
the presence of neurologic abnormalities, including hy-
ing tics is in the range of 6% to 15%, but when other
peractivity and choreiform movements. Volumetric mag-
factors (OCB, ADHD, panic attacks, drug or alcohol
netic resonance imaging (MRI) analysis in 34 children
abuse) are included, the incidence rises to 34% to
with PANDAS showed that the average size of the cau-
41%.57–59 Several recent studies have provided addi-
date, putamen, and globus pallidus, but not the thalamus
tional data on the incidence and effect of bilineal trans-
or total cerebrum, was significantly greater in the af-
mission. Hanna et al.28 found that 26% of patients with
fected group than in 82 healthy children.66 Based on a
TS had evidence of bilineality (tics, OCB, or ADHD),
proposed association between tics/OCD and GABHS, a
more fathers than mothers had tics, and more mothers
double-blind, cross-over trial with 250 mg oral penicillin
had OCB. A similar assessment in normal control fami-
V was undertaken to attempt to prevent recurrences of
lies showed that features of the TS spectrum were un- PANDAS.67 No significant change in either obsessive-
common. Lichter and coworkers60 showed that patient compulsive or tic symptom severity occurred between
age, sex, tic severity, and the presence of ADHD were the active and placebo phases but, because an acceptable
similar in patients with either sporadic or familial TS, level of streptococcal prophylaxis was not achieved, no
both bilineal and unilineal. Patients with familial trans- firm conclusions were possible.
mission did have more prominent obsessive-compulsive Pathophysiologically, based on a Sydenham’s chorea
behaviors and bilineal patients were more likely to ex- (SC) model, an immune-mediated mechanism involving
hibit self-injurious behaviors. These studies emphasize molecular mimicry has been proposed for PANDAS
that factors other than genetic dose effects, such as ge- (that is, antibodies produced against GABHS cross-react
netic heterogeneity, epigenetic factors, and gene– with neuronal tissue in specific brain regions). Indirect
environment interactions, may play an important role in support for this hypothesis is derived from a study ex-
determining tic severity in TS. amining the response of patients to two forms of immu-
In pursuit of assessing the importance of epigenetic notherapy, intravenous immunoglobulin (IVIG) and
risk factors, such as low proband birth weight, nonspe- plasmapheresis (PEX).68 Twenty-nine children with
cific maternal emotional stress, and severity of mother’s PANDAS, obtained from a nationwide search, were
nausea and vomiting during the pregnancy, Burd and randomized in a partially double-blind fashion (no
colleagues61 performed a univariate analysis of 92 Tou- sham apheresis) to an IVIG, IVIG placebo (saline), and
rette cases and 466 year- and month-of-birth-matched PEX group. One month after treatment, the severity of
control subjects. Several risk factors were identified, in- obsessive-compulsive symptoms (OCS) were improved
cluding the month and trimester that perinatal care be- by 58% and 45% in the PEX and IVIG groups, respec-
gan, number of prenatal visits, and the Apgar score at 5 tively, compared with only 3% in the IVIG control. In
minutes. Further replication of this study from other contrast, tic scores were only improved after PEX treat-

Movement Disorders, Vol. 15, No. 6, 2000

 CURRENT ISSUES IN TOURETTE SYNDROME 1055

ment, that is, reductions of 49% (PEX), 19% (IVIG), and immune-mediated hypothesis for PANDAS also remains
12% (IVIG placebo). Improvements in both tics and mostly circumstantial. For example, the often-cited evi-
OCS were sustained for 1 year. Explanations for a lack of dence documenting an antineuronal hypothesis in SC75
therapeutic response in proportion to the rate of antibody relies on data obtained by use of a potentially inaccurate
removal, how peripheral changes affect events across the immunofluorescent antibody methodology. Additionally,
blood–brain barrier, and the mechanism by which the despite reported higher antineuronal antibody values in
immune therapy produces its beneficial response remain children with neurobehavioral problems and/or move-
elusive. Active immunomodulatory therapy, although ment disorders including tics,69,76,77 the sensitivity and
potentially promising for the highly selected patient, in specificity of these studies remain a major issue and
my opinion remains in the experimental phase, and all confirmatory longitudinal studies are needed.
treatments should be part of controlled double-blind
NEUROBIOLOGY
protocols.
The documentation of antineuronal antibodies in pa- The exact neuroanatomic localization of Tourette syn-
tients with TS or OCD has provided additional support drome remains unknown. Significant data, however, sup-
for a potential immune abnormality.69,70 In one study, port the concept that TS is a neurologic disorder associ-
Singer et al.69 showed that compared with control sub- ated with frontal–subcortical pathways.78 In the past,
jects (n ⳱ 39), children with TS (n ⳱ 41) had a signifi- routine noninvasive neuroradiographic studies (com-
cant increase in the mean and median optical density puted tomography and MRI) have identified only iso-
levels of serum antibodies (measured by ELISA) against lated defects that are considered to be incidental nonspe-
the putamen, but not the caudate or globus pallidus. cific findings unrelated to the basic pathology. In two
Western blot analyses indicated that specific antibodies recent publications, localized lesions have been associ-
ated with clinical symptoms. One was a 17-year-old boy
to caudate/putamen occurred more frequently in TS sub-
with TS and comorbid OCD, ADHD, stuttering, and gait
jects at 83, 67, and 60 kDa. Trifiletti et al. have con-
disturbance whose scan showed bilateral symmetric glo-
firmed the presence of a specific brain protein at an
bus pallidus lesions79 and a second was an 11-year-old
apparent molecular weight of 83 kDa that is recognized
boy with TS who had multicystic changes predominantly
by antibodies in the serum of 80% to 90% of patients
in the gyrus rectus of the left frontal lobe.80 On the basis
with TS or OCD.70 The importance of using human tis-
of a reduced cortical silent period after suprathreshold
sue as the antigenic substrate is emphasized by failure to
stimuli and diminished inhibition of a motor-evoked po-
confirm similar antibody changes with neuroblastoma
tential after pain stimuli, transcranial magnetic stimula-
cells.71 Development of dyskinesias (paw- and floor- tion studies have suggested decreased inhibition of the
licking, head- and paw-shaking) and phonic utterances motor cortex.81
has been reported in rodents after the microinfusion of
dilute IgG from TS subjects into their striatum.72 Morphology
The existence of PANDAS, however, is not free of Direct evidence for pathophysiological involvement of
controversy.73 For example, no prospective epidemio- frontal–subcortical circuits in TS is, in part, derived from
logic study has confirmed that an antecedent GABHS volumetric MRI studies. Several structural studies have
infection is specifically associated with either the onset reported that either the caudate or the lenticular nuclei
or exacerbation of tic disorders or OCD. Diagnostic cri- are abnormal in volume or asymmetry compared with
teria established for PANDAS are also potentially con- control subjects.82–84 Because TS is more common in
founded by the phenotypic variability commonly associ- boys than in girls by a ratio of at least 3:1, most research
ated with tic disorders: a normal fluctuation in the fre- has focused on male subjects, thereby limiting our
quency and severity of symptoms; exacerbation of tics knowledge of TS in girls. Using methodologies that pre-
by stress, anxiety, fatigue, and illness; the occurrence of viously identified structural abnormalities in young male
“sudden, abrupt” onset and/or recurrence of tics in non- TS patients, Zimmerman et al.85 showed that basal gan-
PANDAS subjects74; a variable response to pharmaco- glia volume and asymmetry differences did not distin-
therapy; and the lack of a precise definition for chorei- guish girls with TS from matched control subjects. Simi-
form movements. Additionally, longitudinal laboratory larly, the corpus callosum has been previously shown in
data, rather than studies that use only a throat culture or MRI studies to be abnormal in individuals with TS, pre-
only a single antistreptolysin O (ASO) or antideoxyribo- dominantly males.83,86,87 Once again, a study designed to
nuclease B titer, are necessary to confirm the presence of examine whether abnormalities in corpus callosum mor-
a previous GABHS infection. Evidence to support an phology were also present in girls with TS failed to show

Movement Disorders, Vol. 15, No. 6, 2000

1056 H. SINGER

a significant difference.88 The aforementioned studies do and control membranes.92 Overall, studies of D2 dopa-
not imply that the findings in males with TS were inva- mine receptors by PET and SPECT techniques have not
lid, but rather point out that there are gender differences consistently shown significant differences between pa-
in the neurobiologic manifestations of TS. tients with TS and control subjects. Nevertheless, several
studies have supported the hypothesis that the dopamine
fMRI receptor is involved in the neurobiology of TS. In five
Preliminary functional MRI studies have suggested sets of identical twins, increased binding of [123I]iodo-
that the pathogenesis of tics involves neuronal activity benzamide (123I-IBZM) was observed in the head of the
within subcortical neuronal circuits. Peterson et al.89 caudate nucleus in association with increased tic sever-
compared images acquired during periods of voluntary ity.93 Although no significant 123I-IBZM binding differ-
tic suppression with those acquired when subjects were ences were found between unmedicated patients with TS
allowed spontaneous expression of their tics. Significant and control subjects, patients with TS with advanced
changes in signal intensity were seen in the basal ganglia stages of the disorder did have reduced relative binding
and thalamus as well as in connected cortical regions. in the striatum compared with subjects in earlier stages.94
The magnitude of regional signal change in the basal Lastly, a PET study with a spiperone derivative, 3-N
ganglia and thalamus correlated inversely with tic sever- [11C] methylspiperone, and a two PET scan technique to
ity. To determine whether an abnormal organization of measure receptor density (BMAX), demonstrated levels
motor functions could be detected in patients with TS, beyond the 95th percentile prediction limit (normal re-
Biswal et al.90 studied activation of the sensorimotor gressed against age) in four of 20 subjects.95 In this same
cortex during a standard motor task paradigm. Functional group of 20 patients, multiple linear regression analyses
MRI imaging of five patients with TS during finger tap- revealed a trend between the severity of vocal tics and
ping showed an increased area of cerebral activation in BMAX values.
both sensorimotor cortex and supplementary motor area Dopamine Hyperinnervation. Attempts to provide
compared with healthy subjects. Their data support the support for a postulated dopamine hyperinnervation hy-
suggestion that frontal–subcortical pathways contribute pothesis by PET or SPECT binding have resulted in con-
to the pathogenesis of TS. Additional studies designed to tradictory reports. For example, several small studies
use fMRI to understand the mechanism of TS by direct with [123I]␤-CIT SPECT have shown striatal dopamine
imaging are currently in progress. transporter binding to be higher in affected subjects than
in control subjects.96 In contrast, other investigators us-
Neurotransmitter Abnormalities ing similar techniques in 10 adult patients with TS have
The distribution of classic neurotransmitters within the shown no difference in the mean ␤-CIT binding com-
frontal–subcortical circuits raises the possibility that a pared with control subjects.97 Studies evaluating dorsal
variety of transmitters may be involved in the pathobi- striatal dopaminergic innervation by use of in vivo mea-
ology of TS. Thus, dopaminergic and serotoninergic sys- sures of vesicular monoamine transporter type 2
tems have been studied extensively. Dopaminergic hy- (VMAT2) binding with the ligand (+)-alpha-[11C] dihy-
potheses have included abnormalities of both pre- and drotetrabenazine showed no differences between eight
postsynaptic function. For example, it has been proposed subjects with TS and 22 age-compatible normal con-
that TS is the result of supersensitive postsynaptic dopa- trol subjects.98 These results do not support the concept
mine receptors (that is, increased number or affinity), of increased striatal innervation, but do not exclude an
dopamine hyperinnervation, abnormal presynaptic func- abnormality in the regulation of dopamine release or
tion, or an excessive phasic release of dopamine. Despite reuptake.
the aforementioned hypotheses, some investigators have Presynaptic DA Abnormality. A third broad proposal
emphasized that abnormalities of dopamine fail to ex- implicates a presynaptic dopamine abnormality involv-
plain many clinical and laboratory observations, includ- ing dopa decarboxylase activity. In a PET study, 11 ado-
ing the description of unchanged tics in four adults who lescents with TS accumulated [18F] fluorodopa at a level
developed parkinsonism and received treatment with 25% higher in the left caudate nucleus and 53% higher in
91
L-dopa. the right midbrain compared with levels in control sub-
jects.99 The authors suggest that an up-regulation of dopa
Dopamine decarboxylase activity could explain these alterations
Postsynaptic Dopamine Receptors. Limited studies of and that the process reflects deficits in a variety of func-
D1 and D2 receptor binding in postmortem striatal tissue tional elements of the dopamine system. Nevertheless, a
show trends but no significant differences between TS previous study of imaging with [18F] fluorodopa showed

Movement Disorders, Vol. 15, No. 6, 2000

 CURRENT ISSUES IN TOURETTE SYNDROME 1057

no abnormality in presynaptic dopamine function in 10 between therapy groups were apparent. Thus, on the ba-
patients with TS compared with normal subjects.100 sis of this pilot study, relaxation therapy appears to have
An additional presynaptic hypothesis suggests an ab- a limited role in the treatment of tics in TS.
normal phasic dopamine release from the presynaptic Traditional Chinese medicine, acupuncture, has been
terminal.101 suggested for tic suppression,105 although it has not re-
ceived much attention in the scientific literature. Elec-
Serotonin
troconvulsive therapy has been reported in a single
A ␤-CIT SPECT binding study has reported a negative case.106 Lastly, thalamic deep brain stimulation, a mod-
correlation between overall tic severity and binding in ern stereotactic treatment proposed for use in other
the midbrain (serotoninergic) and thalamus (serotonin or movement disorders, has been suggested as a potential
noradrenergic).97 There was no overall reduction in se- therapy for the control of tics.107 While this technique
rotonin transporter density in patients with TS. The au- has several advantages over other neurosurgical ap-
thors suggest that serotoninergic transmission is a modi- proaches (for example, lack of permanent complications
fying, but not causal, factor in the pathogenesis of tics. often associated with lesioning procedures, access to less
In summary, available data have not confirmed a defi- surgically “accessible” brain regions, and simultaneous
nite, consistent abnormality of synaptic neurotransmis- bilateral stimulation), pending determination of patient
sion. Although this author continues to think the dopa- selection criteria and the outcome of carefully controlled
minergic system has an important role, it is likely that clinical trials, a cautious approach is recommended.
other systems may also be involved, possibly through a
common membrane or channel abnormality. Pharmacotherapy
TREATMENT Neuroleptics that block D2 dopamine receptors such
The decision to treat an individual patient should be as pimozide and haloperidol are generally considered the
based on an initial comprehensive evaluation, including most effective tic-suppressing agents. A double-blind,
analysis of tics, documentation of comorbid conditions, 24-week, placebo-controlled cross-over study of 22 chil-
assessment of problem severity, and determination of dren and adolescents compared the efficacy and safety of
resulting impairment. It is essential that an individual pimozide and haloperidol.108 The authors suggest that at
with TS be carefully examined for comorbid features and equivalent doses pimozide was a more effective tic sup-
the treatment of various symptoms should be prioritized. pressor and had fewer serious side effects (depression
Treatment must be individualized with respect to func- and separation anxiety) and extrapyramidal symptoms.
tional impairments of tics and/or comorbid illnesses, Alternative selective D2 antagonists not available in the
sources of support, capacities for coping, and challenges United States but used in Europe include sulpiride and
associated with various stages of development.102 It has tiapride. The appropriate duration of neuroleptic treat-
been emphasized that behavioral problems are often as- ment has been partially addressed in a prospective, ran-
sociated with comorbid ADHD or OCD rather than with domized pilot of patients with TS who had achieved a
tic severity.103 medication-induced stable level of tic control.109 Long-
term treatment with pimozide was more effective in con-
Tics trolling the course of tics than pimozide used solely to
Drug therapy for tics is reserved for patients with tics treat an exacerbation. A regional cerebral perfusion study
that are functionally disabling, because none of the avail- with technetium-99m HMPAO has shown that neurolep-
able pharmacotherapies for tics is curative and all are tics increase perfusion to orbital and anterior medial re-
associated with potential side effects. A variety of non- gions of frontal lobes and the left medial temporal cor-
pharmacologic behavioral treatments (conditioning, tex.110 The authors propose that treatment decreases do-
techniques, relaxation training, biofeedback, hypnosis) paminergic hyperactivity, leading to improvement of
have been proposed as alternative therapeutic ap- clinical symptoms and reperfusion of some previously
proaches, but few have been adequately evaluated. Ber- hypoperfused regions.
gin and colleagues104 reported a study of 16 patients who Smaller studies or case reports have been published on
were randomized and stratified according to initial tic the use of several atypical neuroleptic agents for tic sup-
severity into either a relaxation therapy or minimal pression. These newer antipsychotics (risperidone, olan-
therapy (control) group. At the end of a 6-week training zapine, ziprasidone, clozapine) are all characterized by
period, tics showed greater improvement in the relax- having a relatively greater affinity for 5-HT2 receptors
ation treatment group, but values failed to reach statisti- than for D2 receptors. Risperidone has been evaluated in
cal significance. At a 3-month evaluation, no differences several preliminary studies111,112 and in a larger cohort

Movement Disorders, Vol. 15, No. 6, 2000

1058 H. SINGER

of 38 patients with TS.113 The results of the latter open- prior use of marijuana; 14 of 17 reported a reduction of
label, 1-month clinical trial showed that 58% improved, tics.125 A single uncontrolled, open clinical trial supports
18% had no change, 3% had documented worsening of a beneficial response of TS to delta-9-tetrahydro-
tics, and 21% did not complete the study because of side cannabinol, the major psychoactive ingredient of mari-
effects. Other investigators have suggested that risperi- juana.126 Prospective, controlled trials, which would pre-
done may be most beneficial in patients having a comor- sumably be heavily subscribed, are clearly indicated.
bid obsessive-compulsive disorder.114,115 Olanzapine has Evidence suggesting a hormonal influence in TS (for
also been shown to produce partial control of tic symp- example, a strong sex specificity with males > females
toms. For example, four boys, aged 9 to 16 years, with and knowledge that sex steroids affect gene expression
refractory tics improved after treatment with this medi- and neuronal functioning) has led to trials of antiandro-
cation.116,117 A similar positive response with olanzapine gens in the treatment of this disorder. In a double-blind,
was reported in an open-label study of 12 patients with placebo-controlled, cross-over trial with flutamide, a
severe tics.118 Side effects included weight gain and mild nonsteroidal androgen receptor antagonist, there was a
sedation. Treatment with ziprasidone was significantly modest, short-lived reduction in motor (not vocal) tics in
more effective than placebo in suppressing tic symptoms 13 adult subjects with TS (10 men and three women).127
in 28 patients with TS, ages 7 to 17, randomly assigned The limited tic improvement and the potential serious
to treatment groups.119 Although ziprasidone was well- side effect of hepatic necrosis suggest that flutamide
tolerated, additional studies are indicated for a fuller should probably not be used in the treatment of TS.
evaluation of safety and efficacy. The combination of Nicotine has a variety of potential mechanisms of ac-
5-HT2 and D2 receptor antagonists is not always suc- tion in the central nervous system, including a direct
cessful, because the responsiveness of tics to treatment action on cholinergic receptors or an indirect action
with clozapine has been inconsistent.120,121
through interaction with dopaminergic, serotoninergic,
Pergolide, a mixed D1/D2/D3 dopamine receptor ago-
or noradenergic systems.128 Reports have suggested im-
nist, is typically used in the treatment of Parkinson’s
proved tic control when nicotine gum or a skin patch is
disease. Despite concerns that a postsynaptic agonist
used in conjunction with a neuroleptic drug.129–131 De-
might exacerbate tics, several studies have suggested that
spite these open-labeled reports, side effects of nausea
tics are actually improved. In an initial open-label clini-
and the addictive potential of nicotine makes any puta-
cal trial, pergolide at dosages of 0.1 to 0.3 mg per day
tive benefit from this compound socially undesirable.
decreased tics in 24 of 32 children by more than 50%
Mecamylamine, a nicotinic acetylcholine receptor an-
from baseline.122 The presence of restless legs syndrome
was highly associated with a positive response. In a tagonist, has also been reported to reduce tics in 11 of 13
double-blind, placebo-controlled, 6-week treatment patients with TS.132 A multisite, double-blind control
cross-over study in 24 children, pergolide treatment was study has been initiated.
associated with significantly lower tic severity scores.123 Two children treated with donepezil, a noncompetitive
The treatment dose of pergolide, 0.15 to 0.3 mg per day, inhibitor of acetylcholinesterase, showed tic improve-
is approximately one tenth the typical dose for treating ment.133 A 20-year-old with TS and neuroleptic-induced
Parkinson’s disease. Side effects were mild and electro- tardive dystonia had improvement of dystonic move-
cardiograms showed no difference from control. The ments, motor tics, and coprolalia after treatment with
mechanism of action of low-dose pergolide is unknown, reserpine.134 Baclofen, which contains both GABA and
but it is speculated to involve presynaptic rather then phenylethylamine moieties, is postulated to act by alter-
postsynaptic striatal or cortical dopamine receptors. Ap- ing inhibitory neurotransmission. In an open-label study
parently not all DA agonists produce similar therapeutic of this medication containing 264 patients, 95% reported
effects, because talipexole treatment of adults with TS a significant decrease in the severity of motor and vocal
failed to improve tics.124 tics.135 The most common side effects were sedation and
A variety of nondopaminergic therapies have been drowsiness. These outstanding results are surprising and
proposed for the treatment of tic disorders but few have need to be confirmed, because only small amounts of
been adequately evaluated. Because cannabinoid recep- baclofen cross the blood–brain barrier. Lastly, botulinum
tors are densely located within the basal ganglia (globus toxin has been successfully used in treating both motor
pallidus and substantia nigra pars reticulata), a possible and vocal tics.135,136
role in the control of movement disorders has been hy- In view of proposed serotoninergic hypotheses for TS
pothesized. Suggestive benefit in TS is based on the re- (presence of OCD and abnormalities in SPECT studies),
sults of interviews of 17 patients with TS who described several investigators have evaluated the effect of medi-

Movement Disorders, Vol. 15, No. 6, 2000

 CURRENT ISSUES IN TOURETTE SYNDROME 1059

cations directed at serotonin mechanisms, including pearance of clinically significant tics was not more fre-
meta-chlorophenylpiperazine (m-CPP) and ondansetron. quent, either as an initial appearance (20% vs 16%) or an
In 12 medication-free patients with TS, a single dose exacerbation of preexisting tics (33% vs 33%), in the
treatment of m-CPP, a selective 5-HT2c agonist, had no MPH-treated compared with the placebo cohort. Forty
effect on tics.137 In contrast, in an open-label trial, six of percent of the tics appeared after 4 or more months of
seven children who received ketanserin, a 5-HT2 antago- MPH treatment and 3% developed Tourette-like symp-
nist and ␣-adrenergic agonist, showed improvement of toms. The study was limited by its sample size and re-
tics within a few days.138 Ondansetron, a selective sults do not address populations using higher dosages.
5-HT3 antagonist, was used in six patients resistant to Gadow and coworkers24 evaluated 34 prepubertal chil-
haloperidol in a 3-week open-label trial; two improved, dren with ADHD plus a chronic multiple tic disorder
two had a probable response, and two did not im- who were receiving treatment with MPH over a 2-year
prove.139 Therapeutic trials with several selective sero- period. Expressed as grouped data, most ratings of tic
tonin reuptake inhibitors (SSRIs) have produced variable severity were unchanged, except for a significantly in-
results. A double-blind, placebo-controlled cross-over creased 2-minute physician motor tic count. Data plots
trial of fluoxetine monotherapy did not result in improve- for individual children did show considerable fluctua-
ment of tics after 8 weeks of treatment in 14 subjects tions in the frequency and severity of tics. The authors
with TS.140 In small, open-label 8-week trials with cita- think individual tic variations occur naturally and sug-
lopram and fluvoxamine (three subjects in each group), gest that such variations explain some of the reported tic
only the former produced a significant improvement in exacerbations in children with preexisting tics. Lastly,
motor and vocal tic symptomatology over time.141 the temporary withdrawal of long-term stimulant medi-
In summary, despite the plethora of agents used to cation from 19 subjects with ADHD and tics (switched to
treat TS, substantive conclusions cannot be made be- placebo under double-blind conditions for 2 weeks) did
cause most studies have included few patients. not appear to affect group data of tic frequency or se-
verity.23 These latter results do, however, differ from a
ADHD study of five prepubertal boys who had a meaningful
Although psychostimulant medications are generally reduction in tic status after the withdrawal of long-term
regarded as the treatment of choice for ADHD, their use MPH treatment.150
in children with TS has been controversial. Because of In summary, there is strong evidence that stimulants
early reports suggesting that stimulant medications were are beneficial for ADHD symptoms in children who also
associated with a potential to provoke or intensify tics have a tic disorder. For most children receiving low–
and that tics might persist even when the medication was moderate doses of MPH (less information is available for
withdrawn,142–144 some clinicians discourage the use of other stimulant medications), there appears to be no
stimulant medications in patients with tics or even a fam- clinically significant effect on tics, that is, tics may fluc-
ily history of tic disorders.145 In contrast, other investi- tuate but not require pharmacologic adjustments; lastly,
gators have countered that patients receiving stimulants because stimulant medications are not tolerated by all
did not have a clinically significant worsening of tics or individuals with tics and the possibility exists for tic
that exacerbations occurred only with lower (starting)146 exacerbation in individual cases, prudent follow up is
or higher doses of medication.143 Investigators also sug- appropriate.
gested that methylphenidate (MPH) was better tolerated Alternative medications suggested for the treatment of
than dextroamphetamine (DEX); MPH exacerbations di- ADHD symptoms in children with TS include clonidine,
minished with time even with continued administration, guanfacine,151 desipramine,152 deprenyl,153 and nortrip-
whereas fewer DEX exacerbations diminished over the tyline. A meta-analysis of clonidine for symptoms of
long term.143 ADHD in children and adolescents (based on 11 reports)
Several new reports have provided additional informa- showed a moderate effect size.154 The results of a large
tion pertaining to the ongoing question of the role of multicenter, double-blind treatment study comparing the
stimulants in worsening tic disorders. To assess the issue effects of clonidine, MPH, clonidine plus MPH, and pla-
of inconsistent prevalence estimates, which range from cebo are expected in the near future.
1.6% to 60%,147,148 Law and Schacher149 performed a
1-year prospective study in 90 children with ADHD CONCLUSIONS
with/without mild–moderate tics (not severe tics or TS). Despite its long history, the phenomenology of Tou-
Seventy-two subjects received MPH (average dose of 0.5 rette syndrome continues to evolve with the addition of
mg/kg twice a day) and 18 received a placebo. The ap- new symptoms, clarification of tic diagnoses, and a bet-

Movement Disorders, Vol. 15, No. 6, 2000

1060 H. SINGER

ter understanding of the longitudinal course of this dis- Kurlan R . Features resembling Tourette’s syndrome in develop-
mental stutterers. Brain Lang 1998;62:455–464.
order. Tic rating scales are becoming more precise, but 12. Peterson BS, Leckman JF. The temporal dynamics of tics in
the intrinsic variability of motor and vocal tics continues Gilles de la Tourette syndrome. Biol Psychiatry 1998;44:1337–
to make it difficult to rate these symptoms with reliabil- 1348.
13. Walters AS and the International Restless Legs Syndrome Study
ity. Once considered to be a rare disorder, newer studies Group. Toward a better definition of the restless legs syndrome.
show a higher prevalence in both normal and autistic- Mov Disord 1995;10:634–642.
spectrum populations. The search for a specific gene has 14. Voderholzer U, Muller N, Haag C, Riemann D, Straube A. Pe-
intensified, but to date a major breakthrough has re- riodic limb movements during sleep are a frequent finding in
Gilles de la Tourette’s syndrome. J Neurol 1997;244:521–526.
mained elusive. Genetic heterogeneity and issues such as 15. Kompoliti K, Goetz CG. Hyperkinetic movement disorders mis-
genomic imprinting and bilineal transmission are further diagnosed as tics in Gilles de la Tourette syndrome. Mov Disord
complicating factors. The potential role of environmental 1998;13:477–480.
16. Mennesson M, Klink BA, Fortin AH. Case study: worsening
influences, especially infection, and autoimmune contri- Tourette’s disorder or withdrawal dystonia? J Am Acad Child
butions to the etiology of tics has gained widespread Adolesc Psychiatry 1993;37:785–788.
interest. Brain imaging has provided new information on 17. Riedel M, Straube A, Schwarz MJ, Wilske B, Muller N. Lyme
disease presenting as Tourette’s syndrome. Lancet 1998;351:
neuroanatomic abnormalities, areas of enhanced cerebral 418–419.
activation, and potential neurotransmitter abnormalities. 18. Lombroso CT. Lamotrigine-induced tourettism. Neurology 1999;
Nevertheless, there remains no compelling neurobiologic 52:1191–1194.
19. Moshe K, Iulian I, Seth K, Eli L, Joseph Z. Clomipramine-
hypothesis. Therapeutically, traditional neuroleptics rep- induced tourettism in obsessive-compulsive disorder: clinical and
resent standard treatment but there is expanding interest theoretical implications. Clin Neuropharmacol 1994;17:338–343.
in both atypical neuroleptics and nonneuroleptic medi- 20. Lang A. Patient perception of tics and other movement disorders.
cations. Although multiple pharmaceutical agents are Neurology 1991;41:223–228.
21. Leckman JF, Zhang H, Vitale A, et al. Course of tic severity in
discussed, most have not been adequately evaluated in Tourette syndrome: the first two decades. Pediatrics 1998;102:
randomized, controlled trials. Lastly, there is accumulat- 14–19.
ing evidence supporting the routine use of stimulants for 22. Goetz CG, Tanner CM, Stebbins GT, Leipsig G, Carr WC. Adult
tics in Gilles de la Tourette syndrome. Neurology 1992;42:784–
the treatment of ADHD symptoms in individuals with tic 788.
disorders. This author remains optimistic that discoveries 23. Nolan EE, Gadow KD, Sprafkin J. Stimulant medication with-
in the near future will dramatically increase our under- drawn during long-term therapy in children with comorbid
attention-deficit hyperactivity disorder and chronic multiple tic
standing of this unique and intriguing disorder. disorder. Pediatrics 1999;103:730–737.
24. Gadow KD, Sverd J, Sprafkin J, Nolan EE, Grossman S. Long-
REFERENCES term methylphenidate therapy in children with comorbid
attention-deficit hyperactivity disorder and chronic multiple tic
1. Gilles de la Tourette G. Etude sur une affection nerveuse carac- disorder. Arch Gen Psychiatry 1999;56:330–336.
terisee par de l’incoordination motrice accompagnee d’echolalie 25. Goetz CG, Pappert EJ, Louis ED, Raman R, Leurgans S. Advan-
et de copralalie. Arch Neurol 1885;9:19–42,158–200. tages of a modified scoring method for the Rush Video-Based Tic
2. Rickards H, Robertson MM. Vomiting and retching in Gilles de Rating Scale. Mov Disord 1999;14:502–506.
la Tourette syndrome: a report of ten cases and a review of the 26. Robertson MM, Banerjee S, Kurlan R, et al. The Tourette syn-
literature. Mov Disord 1997;12:531–535. drome diagnostic confidence index: development and clinical as-
3. Cardoso F, Faleiro R. Tourette syndrome: another cause of move- sociations. Neurology 1999;53:2108–2112.
ment disorder of the ear. Mov Disord 1999;14:888–889. 27. Mason A, Banerjee S, Eapen V, Zeitlin H, Robertson MM. The
4. Lang AE, Consky E, Sandor P. ‘Signing tics’—insights into the prevalence of Tourette syndrome in a mainstream school popu-
pathophysiology of symptoms in Tourette’s syndrome. Ann Neu- lation. Dev Med Child Neurol 1998;40:292–296.
rol 1993;33:212–215. 28. Hanna PA, Janjua FN, Contant CF, Jankovic J. Bilineal transmis-
5. Morris HR, Thacker AJ, Newman PK, Lees AJ. Sign language sion in Tourette syndrome. Neurology 1999;53:813–818.
tics in a prelingually deaf man. Mov Disord 2000;15:318–320. 29. Baron-Cohen S, Scahill VL, Izaguirre J, Hornsey H, Robertson
6. Plaza V. Chronic persistent cough due to Gilles de la Tourette’s MM. The prevalence of Gilles de la Tourette syndrome in chil-
syndrome. Respiration 1999;66:380. dren and adolescents with autism: a large scale study. Psychol
7. Tulen JH, Azzolini M, de Vries JA, Groeneveld WH, Passchier J, Med 1999;29:1151–1159.
van De Wetering BJ. Quantitative study of spontaneous eye 30. Eapen V, Robertson MM, Zeitlin H, Kurlan R. Gilles de la To-
blinks and eye tics in Gilles de la Tourette’s syndrome. J Neurol urette’s syndrome in special education schools: a United King-
Neurosurg Psychiatry 1999;67:800–802. dom study. J Neurol 1997;244:378–382.
8. Kim H, Moote W, Mazza J. Tourette’s syndrome in patients 31. Nomura Y, Segawa M. Tourette syndrome in Oriental children:
referred for allergy evaluation. Ann Allergy Asthma Immunol clinical and pathophysiological consideration. In: Friedhoff AJ,
1997;79:347–349. Chase TN, eds. Advances in Neurology, vol 35. 1982:277–280.
9. Hogan MB, Wilson NW. Tourette’s syndrome mimicking 32. Kano Y, Ohta M, Nagai Y. Clinical characteristics of Tourette
asthma. J Asthma 1999;36:253–256. syndrome. Psychiatry Clin Neurosci 1998;52:51–57.
10. Jankovic J, Sekula S. Dermatological manifestations of Tourette 33. Price RA, Kidd KK, Cohen DJ, Pauls DL, Leckman JF. A twin
syndrome and obsessive-compulsive disorder. Arch Dermatol study of Tourette syndrome. Arch Gen Psychiatry 1985;42:815–
1998;134:113–114. 820.
11. Abwender DA, Trinidad KS, Jones KR, Como PG, Hymes E, 34. Hyde TM, Aaronson BA, Randolph C, Rickler KC, Weinberger

Movement Disorders, Vol. 15, No. 6, 2000

 CURRENT ISSUES IN TOURETTE SYNDROME 1061

DR. Relationship of birth weight to the phenotypic expression of genetic imprinting in Gilles de la Tourette syndrome. Am J Med
Gilles de la Tourette’s syndrome. Neurology 1992;42:652–658. Genet 1994;51:51–54.
35. Pauls DL, Leckman JF. The inheritance of Gilles de la Tourette 56. Eapen V, O’Neill J, Gurling H, Robertson MM. Sex of parent
syndrome and associated behaviors: evidence for autosomal dom- transmission effect in Tourette’s syndrome: evidence for earlier
inant transmission. N Engl J Med 1986;315:993–997. age at onset in maternally transmitted cases suggests a genomic
36. Walkup JT, LaBuda MC, Singer HS, Brown J, Riddle MA, Hurko imprinting effect. Neurology 1997;48:934–937.
O. Family study and segregation analysis of Tourette syndrome: 57. Comings DE, Comings BG, Knell E. Hypothesis: homozygosity
evidence for a mixed model of inheritance. Am J Hum Genet in Tourette syndrome. Am J Med Genet 1989;34:413–421.
1996;59:684–693. 58. Kurlan R, Eapen V, Stern J, McDermott MP, Roberson MM.
37. The Tourette Syndrome Association International Consortium for Bilineal transmission in Tourette’s syndrome families. Neurology
Genetics. A complete genome screen in sib pairs affected by 1994;44:2336–2342.
Gilles de la Tourette syndrome. Am J Hum Genet 1999;65:1428– 59. McMahon WM, van de Wetering BJM, Filloux F, Betit K, Coon
1436. H, Leppert M. Bilineal transmission and phenotypic variation of
38. Barr CL, Wigg KG, Pakstis AJ, et al. Genome scan for linkage to Tourette’s disorder in a large pedigree. J Am Acad Child Adolesc
Gilles de la Tourette syndrome. Am J Med Genet 1999;88:437– Psychiatry 1996;35:672–680.
445. 60. Lichter DG, Dmochowski J, Jackson LA, Trinidad KS. Influence
39. Kerbeshian J, Severud R, Burd L, Larson L. Peek-a-boo fragile of family history on clinical expression of Tourette’s syndrome.
site at 16d associated with Tourette syndrome, bipolar disorder, Neurology 1999;52:308–316.
autistic disorder, and mental retardation. Am J Med Genet 2000; 61. Burd L, Severud R, Klug MG, Kerbeshian J. Prenatal and peri-
96:69–73. natal risk factors for Tourette disorder. J Perinat Med 1999;27:
40. Heutink P, van de Wetering BJM, Pakstis AJ, et al. Linkage 295–302.
studies on Gilles de la Tourette syndrome: what is the strategy of 62. Selling L. The role of infection in the etiology of tics. Arch
choice? Am J Hum Genet 1995;57:465–473. Neurol Psychiatry 1929;22:1163–71.
41. Sadovnick D, Kurlan R. The increasingly complex genetics of 63. Matarazzo EB. Tourette’s syndrome treated with ACTH and
Tourette’s syndrome. Neurology 1997;48:801–802. prednisone: report of two cases. Journal of Child and Adolescent
42. Simonic I, Gericke GS, Ott J, Weber JL. Identification of genetic Psychopharmacology 1992;2:215–226.
markers associated with Gilles de la Tourette syndrome in an 64. Kiessling LS. Tic disorders associated with evidence of invasive
Afrikaner population. Am J Hum Genet 1998;63:839–846. group A beta hemolytic streptococcal disease [Abstract]. Devel
43. Hebebrand JH, Nothen MM, Ziegler A, et al. Nonreplication of Med Child Neurol 1989;31(suppl 59):48.
linkage disequilibrium between the dopamine D4 receptor locus 65. Swedo SE, Leonard HL, Garvey M, et al. Pediatric autoimmune
and Tourette syndrome. Am J Hum Genet 1997;61:238–239. neuropsychiatric disorders associated with streptococcal infec-
44. Barr CL, Wigg KG, Zovko E, Sandor P, Tsui LC. Linkage analy- tions PANDAS. A clinical description of the first fifty cases. Am
sis of the dopamine D5 receptor gene and Gilles de la Tourette J Psychiatry 1998;155:264–271.
syndrome. Am J Med Genet 1997;74:58–61. 66. Giedd JN, Rapoport JL, Garvey MA, Perlmutter S, Swedo SE.
45. Thompson M, Comings DE, Feder L, George SR, O’Dowd BF. MRI assessment of children with obsessive-compulsive disorder
Mutation screening of the dopamine D1 receptor gene in To- or tics associated with streptococcal infection. Am J Psychiatry
urette’s syndrome and alcohol dependent patients. Am J Med 2000;157:281–283.
Genet 1998;81:241–244. 67. Garvey MA, Perlmutter SJ, Allen AJ, et al. A pilot study of
46. Devor EJ, Dill-Devor RM, Magee HJ. The Bal I and Msp I penicillin prophylaxis for neuropsychiatric exacerbations trig-
polymorphisms in the dopamine D3 receptor gene display, link- gered by streptococcal infections. Biol Psychiatry 1999;45:1564–
age disequilibrium with each other but no association with To- 1571.
urette syndrome. Psychiatr Genet 1998;8:49–52. 68. Perlmutter SJ, Leitman SF, Garvey MA, et al. Therapeutic plasma
47. Brett PM, Curtis D, Robertson MM, Gurling HM. Neuroreceptor exchange and intravenous immunoglobulin for obsessive-
subunit genes and the genetic susceptibility to Gilles de la To- compulsive disorder and tic disorders in childhood. Lancet 1999;
urette syndrome. Biol Psychiatry 1997;42:941–947. 354:1153–1158.
48. Stober G, Hebebrand J, Cichon S, et al. Tourette syndrome and 69. Singer HS, Giuliano JD, Hansen BH, et al. Antibodies against
the norepinephrine transporter gene: results of a systematic mu- human putamen in children with Tourette syndrome. Neurology
tation screening. Am J Med Genet 1999;88:158–163. 1998;50:1618–1624.
49. Barr CL, Wigg KG, Sandor P. Catechol-O-methyltransferase and 70. Trifiletti RR, Packard AM. Immune mechanisms in pediatric neu-
Gilles de la Tourette syndrome. Molecular Psychiatry 1999;4: ropsychiatric disorders. Tourette’s syndrome, OCD, and
492–495. PANDAS. Child and Adolescent Psychiatric Clinics of North
50. Tolosa ES. Clinical features of Meige’s disease (idiopathic oro- America 1999;8:767–775.
facial dystonia): a report of 17 cases. Arch Neurol 1981;38:147– 71. Singer HS, Giuliano JD, Hansen BH, et al. Antibodies against a
151. neuron-like (HTB-10 neuroblastoma) cell in children with To-
51. Németh AH, Mills KR, Elston JS, Williams A, Dunne E, Hyman urette syndrome. Biol Psychiatry 1999;46:775–780.
NM. Do the same genes predispose to Gilles de la Tourette syn- 72. Hallett JJ, Harling-Berg CJ, Agrawal JR, et al. Tic-like phonation
drome and dystonia? Report of a new family and review of the and dyskinesia in rats after intracaudate microinfusion of sera
literature. Mov Disord 1999;14:826–831. from children with Tourette syndrome [Abstract]. FASEB 1996;
52. Seuchter SA, Hebebrand J, Klug B, et al. Complex segregation 10:A1357.
analysis of families ascertained through Gilles de la Tourette 73. Kurlan R. Tourette’s syndrome and ‘PANDAS’; will the relation
syndrome. Genet Epidemiol 2000;18:33–47. bear out? Neurology 1998;50:1530–1534.
53. Kurlan R. Hypothesis II: Tourette’s syndrome is part of a clinical 74. Singer HS, Giuliano JD, Zimmerman A, Walkup JT. Infection as
spectrum that includes normal brain development. Arch Neurol an environmental stimuli in children with tic disorders. Pediatr
1994;51:1145–1150. Neurol. In press.
54. Lichter DG, Jackson LA, Schachter M. Clinical evidence of ge- 75. Husby G, van de Rijn I, Zabriskie JB, Abdin ZH, Williams RC.
nomic imprinting in Tourette’s syndrome. Neurology 1995;45: Antibodies reacting with cytoplasm of subthalamic and caudate
924–928. nuclei neurons in chorea and acute rheumatic fever. J Exp Med
55. Furtado S, Suchowersky O. Investigation of the potential role of 1976;144:1094–1110.

Movement Disorders, Vol. 15, No. 6, 2000

1062 H. SINGER

76. Kiessling LS, Marcotte AC, Culpepper L. Anti-neuronal antibod- monoaminergic vesicles are not increased in Tourette’s syn-
ies in movement disorders. Pediatrics 1993;92:39–43. drome. Neurology 1999;53:371–374.
77. Laurino JP, Hallett J, Kiessling L, Benson M, Pelletier T, Kuhn C. 99. Ernst M, Zametkin AJ, Jons PH, Matochik JA, Pascualvaca D,
An immunoassay for antineuronal antibodies associated with in- Cohen RM. High presynaptic dopaminergic activity in children
voluntary repetitive movement disorders. Ann Clin Lab Sci 1997; with Tourette’s disorder. J Am Acad Child Adolesc Psychiatry
3:230–235. 1999;38:86–94.
78. Singer HS. Neurobiology of Tourette syndrome. Neurol Clin N 100. Turjanski N, Sawle GV, Playford ED, et al. PET studies of the
Am 1997;15:357–379. presynaptic and postsynaptic dopaminergic system in Tourette’s
79. Demirkol A, Erdem H, Inan L, Yigit A, Guney M. Bilateral syndrome. J Neurol Neurosurg Psychiatry 1994;47:688–692.
globus pallidus lesions in a patient with Tourette syndrome and 101. Singer HS, Szmanski S, Giuliano J, et al. Increased intrasynaptic
related disorders. Biol Psychiatry 1999;46:863–867. dopamine release in Tourette’s syndrome [Abstract]. Ann Neurol
80. McAbee GN, Wark JE, Manning A. Tourette syndrome associ- 1997;42:528.
ated with unilateral cystic changes in the gyrus rectus. Pediatr 102. Peterson BS, Cohen DJ. The treatment of Tourette’s syndrome:
Neurol 1999;20:322–324. multimodal, developmental intervention. J Clin Psychiatry 1998;
81. Ziemann U, Paulus W, Rothenberger A. Decreased motor inhi- 59(suppl 1):62–72.
bition in Tourette’s disorder: evidence from transcranial magnetic 103. Stephen RJ, Sandor P. Aggressive behavior in children with To-
stimulation. Am J Psychiatry 1997;154:1277–1284. urette syndrome and comorbid attention-deficit hyperactivity dis-
82. Singer HS, Reiss AL, Brown JE, et al. Volumetric MRI changes order and obsessive-compulsive disorder. Can J Psychiatry 1999;
in basal ganglia of children with Tourette’s syndrome. Neurology 44:1036–1042.
1993:43:950–956. 104. Bergin A, Waranch HR, Brown J, Carson K, Singer HS. Relax-
83. Moriarty J, Varma A, Stevens J, Fish M, Trimble M, Robertson ation therapy in Tourette syndrome: a pilot study. Pediatr Neurol
M. A volumetric MRI study of Gilles de la Tourette’s syndrome. 1998;18:136–142.
Neurology 1997;49:410–415. 105. Wu L, Li H, Kang L. 156 cases of Gilles de la Tourette’s syn-
84. Peterson B, Riddle MA, Cohen DJ, et al. Reduced basal ganglia drome treated by acupuncture. J Tradit Chin Med 1996;16:211–
volumes in Tourette’s syndrome using three-dimensional recon- 213.
struction techniques from magnetic resonance images. Neurology 106. Rapoport M, Feder V, Sandor P. Response of major depression
1993;43:941–949. and Tourette’s syndrome to ECT: a case report. Psychosom Med
85. Zimmerman AM, Abrams MT, Giuliano JD, Denckla MB, Singer 1998;60:528–529.
HS. Subcortical volumes in female children with Tourette syn- 107. Vandewalle V, van de Linden C, Groenewegen HJ, Caemaert J.
drome: support for a gender effect. Neurology. In press. Stereotactic treatment of Gilles de la Tourette syndrome by high
86. Peterson B, Leckman J, Duncan J, et al. Corpus callosum mor- frequency stimulation of thalamus. Lancet 1999;353:724.
phology from magnetic resonance images in Tourette’s syn- 108. Sallee FR, Nesbitt L, Jackson C, Sine L, Sethuraman G. Relative
drome. Psychiatry Res 1994;55:85–99. efficacy of haloperidol and pimozide in children with adolescents
87. Baumgardner T, Singer HS, Denckla MB, et al. Morphology of with Tourette disorder. Am J Psychiatry 1997;8:1057–1062.
the corpus callosum in children with Tourette syndrome and at- 109. Tourette Syndrome Study Group. Short-term versus longer term
tention deficit hyperactivity disorder. Neurology 1996;47:477– pimozide therapy in Tourette’s syndrome: a preliminary study.
482. Neurology 1999;52:874–877.
88. Mostofsky SH, Wendlandt J, Cutting L, Denckla MB, Singer HS. 110. Lampreave JL, Molina V, Mardomingo MJ, et al. Technetium-
Corpus callosum measurements in girls with Tourette syndrome. 99m-HMPAO in Tourette’s syndrome on neuroleptic therapy and
Neurology 1999;53:1345–1347. after withdrawal. J Nucl Med 1998;39:624–628.
89. Peterson BS, Skudlarski P, Anderson AW, et al. A functional 111. Lombroso PJ, Scahill L, King RA, et al. Risperidone treatment of
magnetic resonance imaging study of tic suppression in Tourette children and adolescents with chronic tic disorders: a preliminary
syndrome. Arch Gen Psychiatry 1998;55:326–333. report. J Am Acad Child Adolesc Psychiatry 1995;34:1147–1152.
90. Biswal B, Ulmer JL, Krippendorf RL, et al. Abnormal cerebral 112. Van der Linden C, Bruggeman R, Van Woerkom T. Serotonin-
activation associated with a motor task in Tourette syndrome. Am dopamine antagonist and Gilles de la Tourette’s syndrome: an
J Neuroradiol 1998;19:1509–1512. open pilot dose-titration study with risperidone [Letter]. Mov Dis-
91. Kumar R, Lang AE. Coexistence of tics and parkinsonism: evi- ord 1994;9:687–688.
dence for non-dopaminergic mechanisms in tic pathogenesis. 113. Bruun RD, Budman CL. Risperidone as a treatment for Tourette’s
Neurology 1997;49:1699–1701. syndrome. J Clin Psychiatry 1996;57:29–31.
92. Singer HS, Hahn I-M, Moran TH. Abnormal dopamine uptake 114. Robertson MM, Scull DA, Eapen V, Trimble MR. Risperidone in
sites in postmortem striatum from patients with Tourette syn- the treatment of Tourette syndrome: a retrospective case note
drome. Ann Neurol 1991;30:558–562. study. J Psychopharmacol 1996;10:317–320.
93. Wolf SS, Jones DW, Knable MB, et al. Tourette syndrome: pre- 115. Stein DJ, Bouwer C, Hawkridge S, Emsley RA. Risperidone aug-
diction of phenotypic variation in monozygotic twins by caudate mentation of serotonin reuptake inhibitors in obsessive-
nucleus D2 receptor binding. Science 1996;273:1225–1227. compulsive and related disorders. J Clin Psychiatry 1997;58:119–
94. Muller-Vahl KR, Berding G, Kolbe H, et al. Dopamine D2 re- 122.
ceptor imaging in Gilles de la Tourette syndrome. Acta Neurol 116. Benji Semerci Z. Olanzapine in Tourette’s disorder. J Am Acad
Scand 2000;101:165–171. Child Adolesc Psychiatry 2000;39:140.
95. Wong DF, Singer HS, Brandt J, et al. D2-like dopamine receptor 117. Karam-Hage M, Ghaziuddin N. Olanzapine in Tourette’s disor-
density in Tourette syndrome measured by PET. J Nucl Med der. J Am Acad Child Adolesc Psychiatry 2000;39:139.
1997;38:1243–1247. 118. Stamenkovic M, Schnidler SD, Aschauer HN, et al. Effective
96. Malison RT, McDougle CJ, van Dycke, et al. [123I] Beta-CIT open-label treatment of Tourette’s disorder with olanzapine. Int
SPECT imaging demonstrates increased striatal dopamine bind- Clin Psychopharmacol 2000;15:23–28.
ing in Tourette’s syndrome. Am J Psychiatry 1995;152:1359– 119. Sallee FR, Kurlan R, Goetz CG, et al. Ziprasidone treatment of
1361. children and adolescents with Tourette’s syndrome: a pilot study.
97. Heinz A, Knable MB, Wolf SS, et al. Tourette’s syndrome: J Am Acad Child Adolesc Psychiatry 2000;39:292–299.
[I-123]beta-CIT SPECT correlates of vocal tic severity. Neurol- 120. Schmider J, Hoff P. Clozapine in Tourette’s syndrome. J Clin
ogy 1998;51:1069–1074. Psychopharmacol 1998;18:88–89.
98. Meyer P, Bohnen NI, Minoshima S, et al. Striatal presynaptic 121. Caine ED, Polinsky RJ, Kartzinel R, Ebert MH. The trial use of

Movement Disorders, Vol. 15, No. 6, 2000

 CURRENT ISSUES IN TOURETTE SYNDROME 1063

clozapine for abnormal involuntary movement disorders. Am J 140. Scahill L, Riddle MA, King RA, et al. Fluoxetine has no marked
Psychiatry 1979;136:317–320. effect on tic symptoms in patients with Tourette’s syndrome: a
122. Lipinski JF, Sallee FR, Jackson C, Sethuraman G. Dopamine double-blind placebo-controlled study. J Child Adolesc Psycho-
agonist treatment of Tourette disorder in children: results of an pharmacol 1997;7:75–85.
open-label trial of pergolide. Mov Disord 1997;12:402–407. 141. Bajo S, Battaglia M, Pegna C, Bellodi L. Citalopram and fluvox-
123. Gilbert DL, Sethuraman G, Sine L, Peters S, Sallee FR. Tourette amine in Tourette’s disorder. J Am Acad Child Adolesc Psychia-
syndrome improvement with pergolide in a randomized, double- try 1999;38:230–231.
blind crossover trial. Neurology 2000;54:1310–1315.
142. Pollack MA, Cohen NL, Friedhoff AJ. Gilles de la Tourette’s
124. Goetz CG, Stebbins GT, Thelen JA. Talipexole and adult Gilles
syndrome: familial occurrence and precipitation by methylpheni-
de la Tourette’s syndrome: double-blind, placebo-controlled
clinical trial. Mov Disord 1994;9:315–317. date therapy. Arch Neurol 1977;34:630–632.
125. Muller-Vahl KR, Kolbe H, Schneider U, Emrich HM. Cannabi- 143. Castellanos FX, Giedd JN, Elia J, et al. Controlled stimulant
noids: possible role in pathophysiology and therapy of Gilles de treatment of ADHD and comorbid Tourette’s syndrome: effects
la Tourette syndrome. Acta Psychiatr Scand 1998;98:502–506. of stimulant and dose. J Am Acad Child Adolesc Psychiatry 1997;
126. Muller-Vahl KR, Schneider U, Kolbe H, Emrich HM. Treatment 35:589–596.
of Tourette’s syndrome with delta-9-tetrahydrocannabinol. Am J 144. Golden GS. The effect of central nervous system stimulants on
Psychiatry 1999;156:495. Tourette syndrome. Ann Neurol 1977;2:69–70.
127. Peterson BS, Zhang H, Anderson GM, Leckman JF. A double- 145. Lowe TL, Cohen DJ, Detlor J, Kremenitzer MW, Shaywitz BA.
blind, placebo-controlled, crossover trial of an antiandrogen in the Stimulant medications precipitate Tourette’s syndrome. JAMA
treatment of Tourette’s syndrome. J Clin Psychopharmacol 1998; 1982;247:1729–1731.
18:324–331.
146. Gadow KD, Nolan E, Sprafkin J, Sverd J. School observations of
128. Dursun SM, Kutcher S. Smoking, nicotine and psychiatric disor-
children with attention-deficit hyperactivity disorder and comor-
ders: evidence for therapeutic role, controversies and implications
for future research. Med Hypothesis 1999;52:101–109. bid tic disorder: effects of methylphenidate treatment. Develop-
129. Dursun SM, Reveley MA. Differential effects of transdermal mental and Behavioral Pediatrics 1995;16:167–176.
nicotine on microstructured analyses of tics in Tourette’s syn- 147. Denckla MB, Bemporad JR, MacKay MC. Tics following meth-
drome: an open study. Psychol Med 1997;27:483–487. ylphenidate administration: a report of 20 cases. JAMA 1976;235:
130. Sanberg PR, McConville BJ, Fogelson HM, et al. Nicotine po- 1349–1351.
tentiates the effects of haloperidol in animals and in patients with 148. Borcherding BG, Keysor CS, Rapoport JL, Elia J, Amass J. Mo-
Tourette syndrome. Biomed Pharmacother 1989;43:19–23. tor/vocal tics and compulsive behaviors on stimulant drugs: is
131. Sanberg PR, Silver AA, Shytle RD, et al. Nicotine for the treat- there a common vulnerability. Psychiatry Res 1990;33:83–94.
ment of Tourette’s syndrome. Pharmacol Ther 1997;74:21–25. 149. Law SF, Schachar RJ. Do typical clinical doses of methylpheni-
132. Sanberg PR, Shytle RD, Silver AA. Treatment of Tourette’s syn- date cause tics in children treated for attention-deficit hyperac-
drome with mecamylamine. Lancet 1998;352:705–706. tivity disorder? J Am Acad Child Adolesc Psychiatry 1999;38:
133. Hoopes SP. Donepezil for Tourette’s disorder and ADHD. J Clin 944–951.
Psychopharmacol 1999;19:381–382. 150. Riddle MA, Lynch KA, Scahill L, et al. Methylphenidate discon-
134. Rojas VM, Davies RK. Reserpine treatment of comorbid To- tinuation and reinitiation during long-term treatment of children
urette’s disorder and tardive dystonia. J Clin Psychiatry 1999;60: with Tourette’s disorder and attention-deficit hyperactivity disor-
709–710. der: a pilot study. J Child Adolesc Psychopharmacol 1995;5:205–
135. Awaad Y. Tics in Tourette syndrome: new treatment options. J 214.
Child Neurol 1999;14:316–319.
151. Cohn LM, Caliendo GC. Guanfacine use in children with atten-
136. Trimble MR, Whurr R, Brookes G, Robertson MM, Traverse L.
tion deficit hyperactivity disorder. Ann Pharmacother 1997;31:
Vocal tics in Gilles de la Tourette syndrome treated with botuli-
918–919.
num toxin injections. Mov Disord 1998;13:617–619.
137. Cath DC, Gijsman HJ, Schoemaker RC, et al. The effect of 152. Singer HS, Brown J, Quaskey S, Rosenberg LA, Mellits ED,
m-CPP on tics and obsessive-compulsive phenomena in Gilles de Denckla MB. The treatment of attention-deficit hyperactivity dis-
la Tourette syndrome. Psychopharmacology (Berl) 1999;144: order in Tourette’s syndrome: a double-blind placebo-controlled
137–143. study with clonidine and desipramine. Pediatrics 1995;95:74–81.
138. Bonnier C, Nassogne MC, Evrard P. Ketanserin treatment of 153. Feigin A, Kurlan R, McDermott MP, et al. A controlled trial of
Tourette’s syndrome in children. Am J Psychiatry 1999;156: deprenyl in children with Tourette’s syndrome and attention defi-
1122–1123. cit hyperactivity disorder. Neurology 1996;46:965–968.
139. Toren P, Laor N, Cohen DJ, Wolmer L, Weizman A. Ondanse- 154. Connor DF, Fletcher KE, Swanson JM. A meta-analysis of clo-
tron treatment in patients with Tourette’s syndrome. Int Clin Psy- nidine for symptoms of attention-deficit hyperactivity disorder. J
chopharmacol 1999;14:373–376. Am Acad Child Adolesc Psychiatry 1999;38:1551–1559.

Movement Disorders, Vol. 15, No. 6, 2000