Robertson 2017

PRIMER
Gilles de la Tourette syndrome

Mary M. Robertson1,2, Valsamma Eapen3,4, Harvey S. Singer5, Davide Martino6,
Jeremiah M. Scharf7–9, Peristera Paschou10,11, Veit Roessner12, Douglas W. Woods13,
Marwan Hariz14,15, Carol A. Mathews16, Rudi Črnčec3,4 and James F. Leckman17
Abstract | Gilles de la Tourette syndrome (GTS) is a childhood-onset neurodevelopmental disorder that
is characterized by several motor and phonic tics. Tics usually develop before 10 years of age, exhibit
a waxing and waning course and typically improve with increasing age. A prevalence of approximately
1% is estimated in children and adolescents. The condition can result in considerable social stigma and
poor quality of life, especially when tics are severe (for example, with coprolalia (swearing tics) and
self-injurious behaviours) or when GTS is accompanied by attention-deficit/hyperactivity disorder,
obsessive–compulsive disorder or another neuropsychiatric disorder. The aetiology is complex and
multifactorial. GTS is considered to be polygenic, involving multiple common risk variants combined
with rare, inherited or de novo mutations. These as well as non-genetic factors (such as perinatal events
and immunological factors) are likely to contribute to the heterogeneity of the clinical phenotype,
the structural and functional brain anomalies and the neural circuitry involvement. Management
usually includes psychoeducation and reassurance, behavioural methods, pharmacotherapy and,
rarely, functional neurosurgery. Future research that integrates clinical and neurobiological data,
including neuroimaging and genetics, is expected to reveal the pathogenesis of GTS at the neural
circuit level, which may lead to targeted interventions.
Gilles de la Tourette syndrome (GTS), also known as time and refer to GTS as a syndrome. Tics were first
Tourette disorder or Tourette syndrome, is a childhood- mentioned in the American Diagnostic and Statistical
onset disorder with a long, tortuous and somewhat con- Manual of Mental Disorders (DSM) diagnostic criteria
troversial history (FIG. 1). The core diagnostic features in 1952, but GTS was only included in DSM-III in 1980,
are several motor and one or more phonic tics lasting resulting in a tranche of publications on the topic. In the
>1 year. Pathognomonic features that are less c ommon DSM system, which is currently in its 5th edition2, GTS
but are consistently described from early reports include is referred to as a disorder, as opposed to a syndrome.
coprolalia and echophenomena (BOX 1), as well as many Aspects of the DSM criteria for GTS have changed over
Correspondence to
M.M.R. and V.E.
comorbidities (which co‑occur and have a shared the years, including the specific age of onset, presence
1
Department of or overlapping aetiology, for example, obsessive– or absence of impairment, level of distress, and ability
Neuropsychiatry, compulsive disorder (OCD), obsessive–compulsive or inability to suppress tics. Impairment in this context
UCL Division of Psychiatry, behaviour (OCB), attention-deficit/hyperactivity dis implies that the tics hinder normal functioning, for
6th Floor, Maple House,
order (ADHD) and possibly autism spectrum disorder). example, not being able to sit still because of leg tics or
149 Tottenham Court Road,
London W1T 7NF, UK. Coexistent psychopathologies (which co‑occur but with- being unable to participate in conversations because of
4
Academic Unit of Child out an evident shared aetiology) include depression, tics involving the head, or repetitive and loud coprolalia
Psychiatry, South Western anxiety, oppositional defiant disorder, conduct disorder interfering with conversations or speech. Other diag-
Sydney Local Health District
and/or personality disorders1. Although these features nostic systems exist, such as the Chinese diagnostic
and Ingham Institute,
Liverpool Hospital,
are characteristic for GTS, they are not essential for a criteria3,4 (stipulating impairment and distress), but
Mental Health Centre, diagnosis (BOX 2). the majority of clinicians, and researchers in particu-
Locked Bag 7103, Liverpool, Several diagnostic criteria for GTS exist, the estab- lar, opt for the DSM criteria as comparison of data
1871, New South Wales, lishment of which (and resulting research worldwide) is important 5.
Australia.
has led the scientific community to view GTS as a Although several motor and at least one phonic tic
[email protected];
[email protected] common disorder. The WHO criteria (the 10th revi- are the cardinal features of GTS, there is a spectrum
sion of the International Statistical Classification of of tic disorders6, including provisional tic disorder,
Article number: 16097
doi:10.1038/nrdp.2016.97 Diseases and Related Health Problems (ICD‑10; 1993); chronic (persistent) motor tic disorder, chronic (persis-
Published online 2 Feb 2017 code F95.2) have remained reasonably constant over tent) vocal tic disorder (together, chronic tic disorder)
NATURE REVIEWS | DISEASE PRIMERS VOLUME 3 | 2017 | 1

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PRIMER
Author addresses diagnosis and management of GTS in detail. We have

chosen to review both historically important papers as
1
Department of Neuropsychiatry, UCL Division of Psychiatry, 6th Floor, Maple House, well as the newest and exciting papers, which we hope
149 Tottenham Court Road, London W1T 7NF, UK. will give the reader a broad and accurate understand-
2
Department of Psychiatry, Groote Schuur Hospital, University of Cape Town, Cape Town, ing of GTS, its manifestations and therapies to help its
South Africa.
myriad of symptoms.
3
Infant, Child and Adolescent Psychiatry, School of Psychiatry, University of New South
Wales, Sydney, New South Wales, Australia.
4
Academic Unit of Child Psychiatry, South Western Sydney Local Health District and Epidemiology
Ingham Institute, Liverpool Hospital, Mental Health Centre, Locked Bag 7103, Liverpool, GTS was thought to be a rare condition for many years,
1871, New South Wales, Australia. until Comings et al.13 somewhat controversially sug-
5
Department of Neurology and Pediatrics, Johns Hopkins University School of Medicine, gested in 1990 that GTS occurred in 0.66% of school
Baltimore, Maryland, USA. children. If only boys were included, the prevalence
6
Department of Clinical Neurosciences, University of Calgary, Calgary, Canada. was even estimated to be 1%, which is consistent with
7
Departments of Neurology and Psychiatry, Center for Human Genetics Research, the finding that GTS is more common in boys than in
Massachusetts General Hospital, Boston, Massachusetts, USA. girls with a male‑to‑female ratio of 3–4/1 (REFS 1,14,15).
8
Division of Cognitive and Behavioral Neurology, Brigham & Women’s Hospital, Boston,
Importantly, tics typically have their onset at 4–6 years
Massachusetts, USA.
9
Department of Neurology, Harvard Medical School, Boston, Massachusetts, USA. of age, reach their most severe level at 10–12 years of
10
Department of Biological Sciences, Purdue University, West Lafayette, Indiana, USA. age and then decline in severity throughout adolescence
11
Department of Molecular Biology and Genetics, Democritus University of Thrace, (FIG. 2). Tics can persist into adulthood and many of the
Alexandroupoli, Greece. most severe and debilitating cases occur in adulthood.
12
Department of Child and Adolescent Psychiatry, Faculty of Medicine, TU Dresden, This explains why epidemiological studies are mainly
Dresden, Germany. conducted in children and why the age range has such
13
Department of Psychology, Marquette University, Milwaukee, Wisconsin, USA. an important affect when interpreting results.
14
Unit of Functional Neurosurgery, UCL Institute of Neurology, London, UK. Some controversy has prevailed since the early
15
Department of Clinical Neuroscience, Umeå University, Umeå, Sweden. Comings paper 13, with a wide prevalence range being
16
Department of Psychiatry and Genetics Institute, University of Florida, Gainesville,
reported in many subsequent studies1. Studies on the
Florida, USA.
17
Department of Psychiatry, Pediatrics, and Psychology, Child Study Center, Yale basis of clinically diagnosed GTS (for example, those
University, New Haven, Connecticut, USA. conducted by the US Centers for Disease Control and
Prevention16) have reported rates ranging from 0.3% to
0.76%, whereas studies that have assessed GTS prev-
and GTS (BOX 2). Furthermore, most research suggests alence in the general population have reported rates
that GTS and chronic tic disorder are part of the same ranging from 0.5% to 1%1,17. A meta-analysis of stud-
condition7; however, GTS is more commonly associated ies in children reported a prevalence rate of 0.77%,
with the aforementioned comorbidities and coexistent but the prevalence rose to 1.06% when only boys were
psychopathologies. accounted for 18. Another meta-analysis reported a child-
Supportive therapy (including psychoeducation and hood prevalence of 0.52% when both boys and girls
reassurance) is often sufficient for most patients. If tics were included19.
are severe or debilitating, behavioural therapy is the An explanation for this variation is that studies
first-line option, followed by psychopharmacological have varied enormously in methodology. For example,
treatment. Neuroleptics (also known as antipsychotics), some studies included individuals who had been hos-
such as haloperidol and pimozide, interfere with dopa- pitalized for their GTS (that is, not measuring the ‘true’
mine signalling pathways and are still used8,9 despite the prevalence), whereas in other studies, patients were not
fact that these older drugs are associated with numerous directly interviewed or assessed by the investigators (that
adverse effects, including drowsiness, movement dis is, cases were not directly confirmed) (4 out of 21 of the
orders and hyperprolactinaemia10. Indeed, haloperidol available studies)16. In addition, other investigations were
remains the only anti-tic medication that is prescribed conducted by telephone and included a wide age range of
on licence in many parts of the world. α2‑Adrenergic participants (4–17 years), different cohorts (birth cohort
agonists11 and second-generation ‘atypical’ neuroleptics, versus school pupils), assessment methods (1–3 stages)
such as risperidone and aripiprazole, are currently gain- and/or assessment schedules, which further increases
ing popularity, owing to improved adverse-effect pro- the heterogeneity between studies.
files. Newer treatments that are under investigation Although some studies point to geographical and
include, among others, tetrabenazine10,12, cannabinoids ethnic differences in prevalence, the data are inconclu-
and deep brain stimulation (DBS) for refractory cases. sive. Global prevalence data are reported to be some-
GTS is a complex neuropsychiatric disorder, with what higher than those of many studies from the United
multiple phenotypic manifestations and limited, but States. Such differences in rates may partially reflect a
evolving, treatment options. This disorder affects chil- sampling bias. For example, the low rates in an Israeli
dren, adolescents and adults worldwide, and, together study could be because of the older ages of individuals
with the disorders that are frequently comorbid with examined (16–17 years versus <15 years in most other
it, GTS has profound effects on quality of life (QOL) studies) and because participants were military recruits,
throughout the lifespan of the individual. In this who might have hidden their symptoms20. Studies con-
Primer, we describe the epidemiology, pathophysiology, ducted in schools in Colombia, Denmark, Iran, Israel,
2 | 2017 | VOLUME 3 www.nature.com/nrdp

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PRIMER
Italy, Poland, Spain, Sweden, the United States and the The var321 mutation altered a binding site for the
United Kingdom showed a somewhat higher prevalence microRNA hsa-miR‑189 and impaired neurite out-
than studies conducted in schools in the Far East. This growth in vitro34. Subsequent sequencing and association
potential difference may well be due to the different ages studies have produced mixed results35–38, supporting the
of individuals in the studies and the use of different notion that, if SLITRK1 is involved in GTS aetiology, it
diagnostic criteria1, such as the Chinese classification might only account for a small fraction of cases, cur-
system3,4,21. It should be noted that the figures from two rently on the order of 1 per 1,000 patients if only exonic
studies from China, reporting rates of 0.43–0.55%22,23, variants are considered.
are not that dissimilar to some western data16. It has The discovery of a deleterious premature termin
been suggested that GTS does not occur in sub-Saharan ation codon (p.W317*, c.951G>A) mutation in the gene
black African populations, potentially owing to genetic encoding l‑histidine decarboxylase (HDC), which is the
factors17. However, this hypothesis requires further rate-limiting enzyme in histamine biosynthesis, in a GTS
assessment, both epidemiological and genetically, to be family with an affected father and eight affected children
confirmed or refuted. GTS has indeed been shown to (out of eight) has raised the intriguing hypothesis of
occur in individuals of African descent in the United the involvement of neuronal histaminergic pathways
States and Europe, but less frequently than in those of in GTS pathophysiology 39. Subsequently, a genome-
Caucasian European ancestry 16,17. Finally, studies from wide analysis of de novo GTS copy number variation
Denmark24 and Finland25, based on national GTS regis (CNV) found enrichment in genes encoding proteins
ters, suggest that the incidence of GTS may be rising, in the histaminergic pathway in patients with GTS
although this finding might reflect increased awareness compared with the general population40. In addition,
by patients wanting to be diagnosed and by physicians a targeted study of 520 families with GTS found a sig-
recognizing the disorder. nificant association between HDC tagging variants and
GTS41. However, the largest GTS genome-wide associ
Mechanisms/pathophysiology ation study to date did not confirm this association42.
Genetics This genome-wide association study, which included
Several twin and family studies have demonstrated that 1,285 cases and 4,964 ancestry-matched controls, found
GTS is one of the most heritable, non-Mendelian neuro no genetic variants that achieved genome-wide signifi-
psychiatric disorders. The population-based heritability cance, although the strongest signal was located within
estimate was found to be 0.77 (95% CI: 0.70–0.85), with an intron of COL27A1, the gene encoding collagen‑α1
a value of 1 suggesting 100% heritability; the risk of chain42. A subsequent targeted study of 42 of the top loci
GTS in combination with chronic tic disorder (some- in 609 independent cases and 610 ancestry-matched
times analysed together, as part of a broader tic spec- controls revealed the most significant GTS association
trum) was increased by 15‑fold in siblings of patients to date: a single-nucleotide polymorphism (SNP) close to
with GTS compared with the general population26–28. NTN4, which encodes an axon guidance molecule that
However, no definitive GTS-associated risk gene of is expressed in the developing striatum43.
major effect has been identified29,30. Instead, GTS seems Genome-wide investigations of CNVs in r elation to
to be highly polygenic, with a large proportion of disease GTS aetiopathogenesis have revealed multiple de novo
heritability attributable to common risk variants that are or recurrent, rare and exon-affecting CNVs in several
distributed across the genome31. Inter-individual vari genes. The largest reported GTS CNV study to date
ation in polygenic burden, combined with rare, inherited (2,435 patients with GTS and 4,100 controls) identified
or de novo mutations in a subset of patients, as well as two genome-wide significant loci: deletions in NRXN1
environmental factors might account for the substan- (odds ratio (OR) = 20.3; P = 6 × 10−6), which encodes
tial heterogeneity of the phenotype and complex aetio neurexin 1, and duplications of CNTN6 (OR = 10.2;
logy of GTS (FIG. 3). This genetic basis parallels that of P = 5.1 × 10−5), which encodes contactin 6 (REF. 44). The
other developmental neuropsychiatric disorders, such implication of NRXN1 deletions confirmed two earlier
as schizophrenia and ADHD32,33. studies involving 111 and 210 individuals with GTS,
respectively 45,46. In addition, one of these studies also
Candidate gene, genome-wide association and copy identified recurrent exon-affecting microdeletions
number variation studies. Although no individual in the gene encoding arylacetamide deacetylase
genes have yet met statistical criteria as definitive GTS (AADAC)45, which was confirmed in a large meta-
risk factors, several potential susceptibility genes, which analysis that included a total of 1,181 patients with
might provide clues to the neurobiology of the disorder, GTS and 118,730 controls from six European countries
have been identified. The implication of a member (P = 4.4 × 10−4)47.
of the SLIT and NTRK family of proteins (SLITRK1)
in GTS aetiology has spurred intense debate. The first Shared genetic basis with other neuropsychiatric and
mutation involving SLITRK1 was a de novo chromo- neurological disorders. The high rates of comorbid
some 13 inversion with one of the breakpoints approx- and/or coexisting psychiatric disorders in patients
imately 350 kb from SLITRK1; subsequently, two rare, with GTS lend support to the hypothesis of shared or
functional SLITRK1 mutations were identified: a trun- overlapping neural circuitry alterations and genetic
cating, frameshift mutation (varCDfs) and a missense susceptibility 48–51. Some of the rare CNVs identified in
variant (var321) in the 3ʹ untranslated region (3ʹ UTR). GTS were previously identified in other developmental

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PRIMER
Description of GTS in the context of witchcraft Guinon, Gilles de la Tourette, Grasset, Janet, and Meige First book describing
and lesser known historical individuals (for example, and Feindel highlight the associated psychopathology GTS published221
Mary Hall of Gadsden reported by William Drage) (especially obsessions and phobias) in people with tics
Early scientific descriptions of GTS by Itard, Psychoanalysis continued to reign

Trousseau and Hughlings-Jackson (Ferenczi, Mahler, Rangel, Luke and Fenichel)
1489–1670 1850 1825–1884 1885 1886 1907 1899 1921–1945 1952 1961 1972 1978
Georges Gilles de la Tourette describes nine cases of GTS Psychoanalytic Haloperidol Psychoanalytic
and earned eponymous fame for describing the syndrome perspective, introduced first used to perspective
in detail in a cohort of patients by Freud, describes tics manage GTS on GTS
as a functional illness questioned
Several well-known historical figures (for example, King William III of England,
Napoleon Bonaparte, Peter the Great of Russia, Samuel Johnson and US Tourette Syndrome
Leo Tolstoy) are described to have symptoms that are compatible with GTS Tics are included in the first edition of DSM Association established
Figure 1 | Key events in the history of Gilles de la Tourette syndrome. Timeline depicting the key events in the history
of Gilles de la Tourette syndrome (GTS), including events in the early description era, psychoanalytic era, early diagnostic
era, and advanced diagnostic and research era. DSM, Diagnostic and Statistical Manual of Mental Disorders; PANDAS,
Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infections; QOL, quality of life;
YGTSS, Yale Global Tic Severity Scale.
neuropsychiatric disorders (such as autism spectrum A large-scale cross-disorder study using genome-
disorder, schizophrenia and epilepsy), including dele- wide association study data from 23 different neuro-
tions in 1q21, NRXN1 and 16p13.11, as well as 22q11 logical and psychiatric disorders demonstrated that a
duplications45,52. Another study independently identified significant proportion of GTS polygenic heritability is
an overall enrichment of CNVs in genes associated with shared with OCD, ADHD and migraine56. Although
autism spectrum disorder in GTS40. In addition, the top OCD and ADHD have long been known to share
loci in the first reported epigenome-wide association heritability with GTS48, the shared genetic relationship
study for GTS, although limited in size, were signifi- between migraine and GTS is new. GTS and migraine
cantly enriched in genes that were previously found to have been observed to co‑occur more frequently than
be associated with other neuropsychiatric and neuro- control rates57. Interestingly, a cross-disorder meta-
logical disorders53. Finally, genes encoding cell adhesion analysis of top loci from genome-wide association
molecules, such as neurexins and neuroligins, were not studies of GTS and ADHD58 reported TBC1D7 (which
only found to be associated with GTS but also with other encodes a protein involved in the tuberous sclerosis
neurodevelopmental phenotypes54. protein complex) as the top signal; TBC1D7 was also
Two studies analysed genome-wide association study identified to be associated with migraine59.
data to examine the unique and shared components
of heritability for GTS and OCD, which is the neuro Immune and environmental factors
psychiatric disorder most strongly aetiologically associ Increasing evidence links the crosstalk between neural
ated with GTS31,55. Davis et al.31 observed a significant and immune pathways to the pathogenesis of GTS,
proportion of shared heritability between the two dis- which is consistent with observations in other neuro
orders (r = 0.41; SE = 0.15), although the overall genetic developmental disorders. Recapitulating a model pre-
architecture (for example, the specific proportion of viously proposed for psychosis60, prenatal and perinatal
heritability attributed to each chromosome and the rela- factors (for example, infections, maternal stress during
tive contribution of common and rare variants) differed. pregnancy and gestational smoking)61 could, on a back-
Yu et al.55 used polygenic risk scores to identify distinct ground of increased genetic susceptibility, trigger the
differences between polygenic risk burden of OCD with priming of microglia (which are glial cells belonging to
or without co‑occurring GTS and chronic tic disorder; the monocytic/macrophagic lineage that are involved
while OCD polygenic risk scores predicted OCD case in synapse formation and elimination). Subsequent hits
status when examined in cases without co‑occurring (for example, psychosocial stressors or infections) could,
GTS or chronic tic disorder, these risk scores were less at a central level, activate microglia, thereby influencing
strongly associated with case status among individuals synaptic plasticity close to symptom onset, and enhance
with OCD plus co‑occurring tic disorders. Similarly, in peripheral immune or inflammatory responses62,63.
one study involving 222 patients with pure GTS (that Initial evidence suggests that these secondary hits might
is, GTS with only tics and without comorbidities, such contribute to the waxing and waning course of tics in
as OCD), no family history of OCD was found, which an interactive manner. For example, the predictive
suggests that additional genes or environmental factors effect of psychosocial stressors on tic and obsessive–
may be at play when GTS is associated with OCD and compulsive severity becomes three-times stronger
perhaps also with other comorbidities5. when an infection (such as a group A streptococcal

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PRIMER
First twin study Description of a tic disorder after group A streptococcal infection (PANDAS) Development Early description era
hinting to hypothesis, which eventually gave rise to the immune hypothesis for GTS of manualized
a genetic behavioural Psychoanalytic era
component treatment Early diagnostic era
Obsessive–compulsive behaviour Neuroimaging showing basal Advanced diagnostic
as an alternative phenotypic ganglia volume reduction in GTS and research era
expression of GTS
1980 1985 1988 1989 1990 1993 1998 1999 2001 2002 2003 2008 2010 2015 2016
First behavioural Development Largest GTS treatment

treatments for GTS First QOL of GTS-specific randomized controlled
First use of deep brain study in QOL measures trial conducted
Development of the YGTSS stimulation in GTS GTS
First meta-analysis Meta-analyses across a range of
DSM-III First epidemiological, large of epidemiological areas including epidemiology,
includes GTS family and genetic studies Unitary nature of GTS challenged data genetics, treatment and QOL
Nature Reviews | Disease Primers

pharyngitis) co‑occurs with raised psychosocial stress controls70. Interestingly, some of these transcripts also
levels64. Exploring the effect of in utero versus post encode proteins that are involved in cholinergic and
natal environmental influences in the context of valid noradrenergic signalling (which is relevant for patho-
animal models of tic generation would add to our gen recognition), as well as γ-aminobutyric acid (GABA)
understanding of their complex aetiology 65. signalling (which is relevant for its immunosuppressant
The genetic basis of the dysregulation of immune- properties at both a central and a peripheral level)71,72.
mediated mechanisms in GTS is poorly understood. In addition, clinical studies have reported several periph-
A study using a Danish health care population registry eral immunological changes (for example, dysgamma
has shown that a maternal history of autoimmune dis- globulina emia, a decreased number of regulatory
orders is associated with a 29% higher risk of GTS in the T cells and an increased antibody response to patho
male offspring but not in female offspring 66. However, gens) in patients with GTS, which point to chronically
this finding does not clarify whether this association hyperactive innate and a daptive mechanisms63,73.
depends on inherited genetic factors, whether it involves
transplacental transfer of antibodies or other immune CSTC circuits and neurotransmitters
effector molecules or whether it is merely epiphenom- Parallel, interacting cortico–striato–thalamo–cortical
enal. Likewise, the interesting observed association (CSTC) circuits, which link specific regions in the fron-
between tics in the context of ADHD and common tal cortex to subcortical structures (including the
allergies is still unexplained67. basal ganglia and thalamus), provide the framework
Direct evidence of altered function of immune cells for understanding GTS (FIG. 4a). Three CSTC circuits
located in the central nervous system in GTS is limited, are potentially involved in GTS: the habitual behav-
but intriguing. The post-mortem analysis of the striatal ioural circuit (the premotor cortex–putamen circuit),
transcriptome of nine adult patients with GTS and nine the goal-directed circuit (the ventral medial prefrontal
closely matched control individuals showed a wide- cortex–c audate nucleus circuit) and the emotion-
spread upregulation of inflammatory response tran- related limbic circuit (inputs from the hippocampus,
scripts related to the activity of microglia68. Some of these amygdala, prefrontal cortex and anterior cingulate
transcripts reflect the expression of ‘hub’ genes (genes gyrus to the ventral striatum)74–77. Which neurotrans-
that are present in the highly connected hub nodes mitter, or combination of neurotransmitters, located
according to pathway analysis) that are crucial in the within these pathways is relevant in GTS pathogenesis
regulation of both innate and adaptive immune mecha- remains to be determined. Likely neurotransmitter
nisms. In addition, preliminary in vivo evidence shows candidate abnormalities in GTS, which are probably the
activated microglia in the caudate nucleus of c hildren end result of more-proximal developmental abnormal
with GTS69. These findings support the hypothesis that ities related to the organization or maintenance of
immune-competent neural cells play an important part CSTC circuits, include dopamine, glutamate, serotonin
in the pathophysiology of GTS across different age and acetylcholine.
periods, which is sustained by functional interactions
with cortico–basal ganglia circuits ranging from early Dopamine. The strongest neurochemical evidence
influences on synaptogenesis and circuit formation to continues to favour a major role for dopamine in GTS
post-developmental influences on circuit activity. (FIG. 4b). Dopaminergic inputs from the ventral tegmen-
The analysis of peripheral lymphoid and myeloid tal area innervate the frontal cortex and ventral stria-
immune cells of children and adolescents with GTS tum. In addition, in the striatum, dopaminergic outputs
also indicates upregulation of genes encoding proteins from the substantia nigra pars compacta synapse pre-
that are involved in pathogen recognition and cell- synaptically on glutamatergic cortical projections and
mediated innate and adaptive response, compared with on direct and indirect GABAergic striatal projections.

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PRIMER
The direct projections contain excitatory dopamine D1 have been identified in post-mortem globus pallidus
receptors, whereas the indirect pathway expresses inhib- interna, globus pallidus externa and substantia nigra
itory dopamine D2 receptors. Hypotheses involving pars reticulata in patients with GTS compared with
dopamine abnormalities in GTS have included pre controls78. By contrast, glutamate levels measured by 7T
synaptic, intrasynaptic and postsynaptic dysfunctions78. magnetic resonance spectroscopy in children with GTS
Presynaptic alterations include a developmental hypo- were higher within the striatum and premotor cortex
function of dopaminergic neurons, hyperinnervation than for controls79. Animal models support a role for
and an increased number of dopamine transporters. cortico–striatal glutamatergic afferents in the gener
Postsynaptic changes include variable increases in ation of tic-like movements80. However, therapeutically,
the number of striatal and cortical dopamine recep- tic suppression did not exceed that of a placebo control
tors. Furthermore, a proposed intrasynaptic hypoth- group following treatment with either a glutamate ago-
esis involves the phasic (stimulus-induced) release of nist (d‑serine) or a glutamate antagonist (riluzole) in a
dopamine. This suggestion is based on observations small study 78.
such as an increased release of dopamine following
amphetamine stimulation78, tic exacerbation by environ GABA. GABA is the primary neurotransmitter of
mental stimuli and tic suppression with very low doses striatal synaptic projection neurons and interneurons
of dopamine agonists. The positive therapeutic effect of located in both the striatum and the cortex (FIG. 4b).
dopamine antagonists in GTS and the multiple inter- Alterations of GABAergic function in GTS are sup-
actions between the dopaminergic system and both ported by post-mortem, PET and magnetic resonance
glutamatergic and GABAergic systems within CSTC spectroscopy studies78. In the striatum, post-mortem
pathways further support the role of dopamine as the studies have identified a reduction in the number of
primary neurotransmitter abnormality 78. GABAergic parvalbumin-containing interneurons.
By contrast, measurements of striatal GABA in children
Glutamate. Glutamate, which is an excitatory agent, 5–12 years of age with GTS showed increased concen-
is the neurotransmitter of cortical and thalamic pro- trations of GABA within the striatum79. The increased
jection neurons and the subthalamic nucleus (FIG. 4b). quantities probably represent tonic extrasynaptic levels
Arguments in favour of a role of the glutamatergic of GABA and greater inhibitory tone. PET imaging of
system in GTS include its essential role in CSTC path- GABA receptors showed decreased binding bilater-
ways, extensive interaction between the glutamatergic ally in the ventral striatum, globus pallidus, thalamus,
and dopaminergic systems and a possible beneficial amygdala and right insula78. In the cortex, a deficiency
therapeutic effect of glutamate-altering medications of inhibitory interneurons is suggested based on a reduc-
on OCD symptoms78. Reduced levels of glutamate tion of short-interval intracortical inhibition measured
by transcranial magnetic stimulation81 and a reduction
in the levels of GABA in the primary sensorimotor cor-
Box 1 | Definitions tex 82. By contrast, increased concentrations of GABA
• Bereitschaftspotential: a measure of activity in the motor cortex and supplementary were observed within the supplementary motor area83.
motor area of the brain, leading up to voluntary muscle movement In rodent and primate models, disruption of striatal and
• Blepharospasm: abnormal twitching of the eye lid, which results in the eyes being cortical GABAergic connectivity by local injections of
shut tight or closed for a sustained period of time GABA type A receptor antagonists has produced tic-like
• Coprolalia: a type of complex phonic tic that involves the uttering of obscene words behaviours80,83,84. Other supporting evidence for GABA
or phrases involvement includes the beneficial therapeutic effect of
• Coprophenomena: complex motor and phonic tics with obscene connotations benzodiazepines (which enhance the effects of GABA)
• Copropraxia: movements or gestures of an obscene nature and an association between mutations in GABA-related
• Echolalia: copying someone else’s words or phrases genes and tic severity 78.
• Echophenomena: copying behaviours or sounds made by others
Acetylcholine. Large aspiny cholinergic striatal inter
• Echopraxia: the need to mimic a movement made by someone else in the
immediate environment
neurons influence striatal projection neurons and local
interneurons. Results of pharmacological studies in GTS
• Non-obscene socially inappropriate behaviours: behaviours that are non-obscene
but are very inappropriate (for example, shouting out ‘bomb’ in an airport), which can
using agents that affect cortical nicotinic and muscar
have serious social consequences, and are related to impulsivity and disinhibition inic receptors (for example, transdermal nicotine,
• Palilalia: repetition of one’s own utterances
mecamylamine and donepezil) have been variable. Post-
mortem studies have shown a decrease in the number
• Palipraxia: repetition of one’s own movements (for example, repetitive buttoning
of choline acetyltransferase-containing interneurons in
and unbuttoning of coat buttons)
the striatum, supporting reports of an anatomical reduc-
• Psychogenic tics: tics that are psychological, rather than neurological, in origin
tion of cholinergic interneurons in the region78. In mice,
(also known as functional tics)
ablation of 50% of cholinergic interneurons in the dorso
• Self-injurious behaviours: behaviours that, when milder, are associated with
medial striatum caused no effect, whereas ablation in the
obsessive–compulsive behaviour or obsessive–compulsive disorder, and when more
severe are associated with impulsivity dorsolateral striatum plus a stressful stimuli or ampheta-
mine challenge caused tic-like stereotypical behaviours85.
• Suicidality: thoughts or behaviours that involve deliberate self-harm
Striatal cholinergic interneurons may co‑opt dopamine
• Torticollis: abnormal sustained twisting of the neck
terminals and drive GABA release86.

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PRIMER
Box 2 | Spectrum of tic disorders ganglia and plasma in patients with GTS, and the levels
of its metabolite, 3‑methoxy‑4‑hydroxyphenylethylene
According to the Diagnostic and Statistical Manual of Mental Disorders (DSM), tic glycol, are normal in plasma and cerebrospinal fluid, but
disorders are classified according to the type (motor or phonic) and duration of tics. variable in urine. α2-Adrengerigc receptor densities have
DSM‑5 classifies the spectrum of tic disorders as follows: been variable in post-mortem cortex studies, and either
Provisional tic disorder normal or increased in Brodmann area 10 and area 11
Replaces transient tic disorders in the DSM‑IV‑TR definition (ICD‑9 code 307.21; (REF. 78). Increased α2‑adrenergic receptor densities, if
ICD‑10 code F95.0). confirmed, could lead to a reduction in the basal release
• Single or multiple motor and/or vocal tics of dopamine, given that activation of α2-adrenergic recep-
• Tics have been present for <1 year since first tic onset tors has been shown to inhibit dopamine release in the
• Age of onset is before 18 years prefrontal cortex.
• The disturbance is not attributable to the physiological effects of a substance
(for example, cocaine) or another medical condition (for example, Huntington disease Histamine. G protein-coupled histamine H3 recep-
or post-viral encephalitis) tors are located postsynaptically on striatal projection
• Criteria have not been met for Gilles de la Tourette syndrome (GTS) or persistent neurons and modulate dopamine neurotransmission.
(chronic) motor or vocal tic disorder Results in several animal models, including an Hdc-
Chronic (persistent) tic disorder knockout mouse, and mutations in patients with GTS
Single or multiple motor or vocal tics have been present for >1 year during the illness, support a role for histamine deficiency in GTS39,40,88,89.
but not both motor and vocal tics (ICD‑9 code 307.22; ICD‑10 code F95.1).
GTS
Endogenous cannabinoid and opioids system. The two
A combination of both motor tics (more than one) and phonic tics (one or more) for most relevant cannabinoid receptors are CB1, which is
>1 year, with an age of onset before 18 years (ICD‑9 code 307.23; ICD‑10 code F95.2). primarily located in areas of the brain that are associated
In 90% of patients, GTS is accompanied by comorbid or coexisting conditions. GTS and with reward, appetite regulation and nociception, and
the other chronic (persistent) tic disorders have the same typical comorbid conditions, CB2, which was initially thought to be solely peripheral,
but they are more frequent in GTS. Comorbid conditions are conditions that co‑occur but has been identified in the striatum, ventral tegmental
and have a shared or overlapping aetiology. Examples are obsessive–compulsive disorder area, hippocampus and thalamus. The endocannabin
(OCD), obsessive–compulsive behaviour, attention-deficit/hyperactivity disorder and oid system interacts with the opioid system90,91. Several
there is some evidence for autism spectrum disorder. Migraine is significantly more reports and two small placebo-controlled studies have
common in GTS than in the general population and various control populations; there
suggested that cannabinoids (smoking marijuana or
has been one exciting documentation of a shared genetic aetiology59. Coexistent
conditions co‑occur without a shared aetiology. Examples are depression, non-OCD
using oral δ-9‑tetrahydrocannabinol (THC)) have a
anxiety, separation anxiety, impulsive anger outbursts, hair-pulling and skin-picking beneficial effect on tics in patients with GTS92.
disorders, substance abuse, conduct disorder, oppositional defiant disorder, personality
disorders and learning disorders. Neuroimaging studies
Neuroimaging studies in GTS have shown somewhat
diverse findings. Functionally, it has been shown that
Serotonin. Axons from serotonergic neurons within the patients with GTS have significantly increased cere-
median raphe nucleus project to the striatum, substan- bral blood flow and tic-related hyperperfusion to the
tia nigra pars compacta, ventral tegmental area, nucleus left caudate nucleus and anterior cingulate and hypo
accumbens and prefrontal cortex. Evidence support- perfusion to the left dorsolateral prefrontal cortex, which
ing serotonergic involvement in GTS includes reduced were related to mood. Hypoperfusion in striatal, frontal
serum and cerebrospinal fluid levels of serotonin and and temporal areas has also been observed; however,
tryptophan (the serotonin precursor) in patients with identification of an endophenotype has not been possible,
GTS compared with healthy controls, and PET i maging as there are no observed differences between individ
showing diminished serotonin transporter binding uals within families with different phenotypes, namely,
capacity in the midbrain and thalamus78. However, tics, GTS and/or OCB or OCD93,94. Structural imaging
these findings may be associated with the presence of studies have also shown cortical thinning in frontal and
comorbid OCD. PET imaging of tryptophan demon- sensorimotor areas, as well as diminished sulcal depth
strated decreased uptake in the dorsolateral prefrontal and reduced sulcal cortical thickness95. Furthermore,
cortical regions and increased uptake in the caudate smaller caudate nucleus volume in children with GTS is
nucleus and thalamus87. associated with more severe tic symptoms in adulthood96.
Overall, most neuroimaging studies have been limited
Noradrenaline. Evidence for the involvement of due to small sample size and motion artefacts; further
noradrenaline in GTS is limited and partly based on the studies are required to overcome these issues.
therapeutic tic-suppressing effect of α2‑adrenergic ago-
nists (such as clonidine and guanfacine)78. However, cloni- Diagnosis, screening and prevention
dine also decreases the release of glutamate and regulates Tics
spontaneous and glutamate-modulated firing activity in Tics are sudden, repetitive and disinhibited movements
medial frontal cortical pyramidal neurons, and its activity (motor tics) or noises (phonic tics) that typically mimic
can, therefore, not be solely attributed to the modulation some fragment of normal behaviour (for example, repeti
of the adrenergic pathway. Measurements of noradren- tive brief eye blinking)93,97. Diagnosis of GTS requires
aline are normal in post-mortem cerebral cortex, basal the occurrence of both multiple motor and one or more

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PRIMER
5 GTS who seek specialist treatment have coprolalia100–102.

In large pedigrees103,104 (for example, multiple affected
GTS families) or epidemiological studies105–108, coprola-
Relative tic severity (ARRTS)

4
lia almost never occurs. Thus, the Tourette Syndrome
Association of America has concluded that, overall,
3
only a small minority (<10%) of individuals with GTS
actually have coprolalia.
2 The severity and intensity of tics vary. They can
be unobtrusive and go almost unnoticed, or they can
1 be extremely frequent, forceful and intrusive. Many
Actual means patients report that their tics can be exacerbated by
Estimates from model
stress, tiredness and high temperatures109,110. In very
0
0 5 10 15 20
severe cases (4–5%), the tics can be self-injurious and
extremely serious14,111,112. Importantly, when individuals
Age (years)
with GTS engage in behaviours that require focused
Figure 2 | Course of tic severity in Gilles de la Tourette
attention and motor control, such as playing the piano,
syndrome. Plot of averageNature Reviews
tic severity Disease
in a |cohort ofPrimers
reciting a poem or participating in sport, their tics often
36 children 1–18 years of age with Gilles de la Tourette
syndrome (GTS). The Annual Rating of Relative Tic Severity completely disappear.
(ARRTS) is a scale that is rated by the parent, which uses a
six-point ordinal scale ranging from the absence of tics Premonitory urges and tic suppression. By 8–10 years
(0 points) to most severe tics (6 points). Similar data are also of age, the majority of individuals with tics are acutely
available from an independent cohort128. From REF. 129; aware of premonitory urges, such as feelings of tightness,
reproduced with permission from Pediatrics, Vol. 102, tension or itching that are accompanied by a mounting
Pages 14–19, Copyright © 1998 by the AAP. sense of discomfort or distress that can be relieved only
by the performance of a specific tic113,114. These premoni
phonic tics, whereas chronic (persistent) motor or vocal tory urges are similar to the sensation that precedes an
tic disorder requires only one or the other type of tic, but itch or a sneeze. The majority of patients also report a
not both (BOX 2). This distinction has been suggested to momentary and fleeting sense of relief after a tic or bout
be arbitrary, as phonic tics are actually motor tics that of tics has occurred.
involve oral, nasal, pharyngeal, laryngeal and respir Of note, most individuals are able to suppress their
atory musculature; in some cases, air passing through tics, but only for a limited period of time and only with
makes the sounds (for example, sniffing), whereas others mounting discomfort. Enhancing an individual’s aware-
(for example, palatal tics) do not require air movement14. ness of their premonitory urges followed by a competing
response (that is, the selection and subsequent imple-
Tic characteristics. A single tic typically lasts <1–2 sec- mentation of a physically incompatible behaviour to the
onds and typically occurs in bouts, whereby the same emerging tic) is at the core of behavioural treatments
tic occurs repetitively with short inter-tic intervals98. that have proven to be the most effective115. In the major-
Intriguingly, bouts of tics also recur throughout the day. ity of patients, there is rebound after suppression of a
Tics are classified as simple or complex. Simple motor tic1, although this might not always occur in adults116.
tics, such as blinking and head jerking, involve only one Although tics have historically been considered to
group of muscles causing brief jerk-like movements and be involuntary, this may not always be so, with some
are usually abrupt and rapid (clonic). Slow movements patients describing tics as semi-voluntary with some
are also possible, resulting in a briefly sustained abnor- degree of control and others describing tics as voluntary
mal posture (dystonic tics, such as blepharospasm and in response to the premonitory urges117–119.
torticollis; BOX 1) or an isometric contraction (tonic tics,
such as abdominal tensing). Complex motor tics consist Clinical rating scales. The severity of tics can vary
of coordinated sequenced movements resembling motor dramatically according to the setting and activity, and,
acts or gestures that are inappropriately timed and intense because many individuals with GTS can suppress their
(for example, repetitive touching, jumping and bend- symptoms for brief periods of time, objective measure
ing)14. These tics may involve the need for the individual is important. To this end, direct observational methods
to maintain a specific abnormal distorted posture for a are the most objective measure of tic severity; indeed,
few seconds to >1 minute99. Very rarely (<5%), associated a range of clinical rating scales have been developed
gestural echopraxia presents or complex motor tics of an (TABLE 1). The Yale Global Tic Severity Scale (YGTSS)
obscene nature (copropraxia) occur (BOX 1). is the most widely used assessment tool that records an
Simple phonic tics include sniffing, throat clearing, individual’s current repertoire of tics120,121. The Modified
coughing and belching. Complex phonic tics are of Rush Video-based Rating Scale (MRVS)122 is an excel-
longer duration than simple phonic tics and include lent method to objectively record tics; compared with
linguistically meaningful verbalizations and utter- the original version, only the scoring was changed
ances, such as words and phrases, as well as echolalia in the modified rating scale121,123. The Premonitory
and palilalia14 (BOX 1). Although coprolalia is commonly Urge for Tics Scale (PUTS) is a validated instrument to
associated with GTS, only 20–35% of adult patients with characterize and quantify the p
remonitory urges114.

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PRIMER
Psychogenic tics. Psychogenic tics or functional tic dis- remain part of an individual’s tic repertoire for weeks to
orders (BOX 1) are rare (5% of patients with psychogenic months, but an individual’s tic repertoire typically evolves
movement disorders have tics124, as opposed to the 95% over time. Some tics persist, others disappear and new
of patients who have tremor, weakness and sensory loss, tics emerge. Most patients experience peak tic severity
among others), but it can be difficult to distinguish from at 10–12 years of age, following which there is a gradual
tics that are associated with GTS. Clues for functional decline in severity 128,129 (FIG. 2).
tics include acute onset, precipitation by a physical event, A complete remission of both motor and phonic
incongruous symptoms, inconsistent phenomenology, symptoms can occur by adulthood, but estimates vary
distractibility, entrainment of symptoms, no premoni- considerably 15,97,128, with some studies reporting rates of
tory sensations, not being able to suppress the tic, the remission of 30–50%128,129. If tics resolve by adulthood,
presence of a Bereitschaftspotential (BOX 1) preceding the legacy of GTS in adult life is most closely associated
the movement and also a lack of response to otherwise with the affect the disorder has had during childhood.
effective pharmacological therapies used in GTS124. It is For example, a patient who was misunderstood and
also important to emphasize that functional tics do not punished will fare worse than a child whose immedi-
follow the typical neurological patterns and, notably, they ate interpersonal environment was more understand-
can also be seen as an overlay in the presence of a true ing and supportive130. Intriguingly, in a study in which
tic disorder (such as GTS). Although psychogenic tics patients were videoed when they were young and then at
can arise in children, it is more commonly encountered >20 years of age at follow-up131, adult patients said they
in adults (average age of onset: 34–50 years)125,126 and in were tic free, but on video, 90% of the adults still had tics.
female patients124,125,127. However, the tics no longer caused distress and the need
for medication was much less131.
Clinical course However, in a minority of patients, adulthood is the
Tics usually have their onset in the first decade of life, period when the most severe and debilitating forms of
with a median onset of simple motor tics at 5–7 years tic disorder are encountered, possibly following on from
of age1,97. The first symptoms usually occur in the head childhood severity or a re‑emergence of tics later in life.
and neck area and might progress to include muscles of In approximately 4–5% of patients, severe, self-injurious
the trunk and extremities. Motor tics generally precede tics14,112 (referred to by some as ‘malignant’ tics111) can
the development of phonic tics and simple tics often persist or re‑emerge with considerable intensity. These
precede complex tics. Once present, individual tics can treatment-refractory, severe tics can lead to permanent
disability and injury, for example, severe and forceful
head-snapping tics that lead to permanent injury to the
Provisional tic cervical spinal cord, hitting one-self or persistent eye-
disorder poking tics that lead to blindness111,112, and head bang-
20–25% ing with resultant ventricular enlargement and cavum
Common genetic septum pellucidum cavities detected by neuroimaging
Chronic tic
variants distributed disorder (which is similar to the pathology seen in boxers) or
continuously in the even death resulting from a subdural haematoma112.
general population 1–2%
Compared with patients with ‘non-malignant’ GTS,
GTS with those with ‘malignant’ GTS are considerably more likely
simple tics
to have greater severity of motor symptoms, comorbid
1% OCD, complex phonic tics, coprolalia, copropraxia,
Persistent or self-injurious behaviours, mood disorders, suicidal
severe GTS ideation and poor response to medications111,112 (BOX 1).
0.1% A study reported differences between those whose
tics had started before 18 years of age and those after
19 years of age; the latter group had fewer phonic tics
and lower rates of ADHD and oppositional behaviour
–3 –2 –1 0 +1 +2 +3 than the former group. From an aetiological perspective,
Standard deviation older-onset patients with GTS might largely represent
Figure 3 | Genetic architecture of Gilles de la TouretteNature
syndrome and| related
Reviews Disease Primers re‑emergence or exacerbation of childhood-onset GTS;
developmental tic disorders. In the polygenic risk model, in which genetic risk arises the adult phenotype is dominated by facial, neck and
from a cumulative burden of hundreds of small effect size risk variants, every individual truncal tics, and a greater prevalence of substance abuse
in the general population has some degree of genetic risk, but only develops symptoms and mood disorders132.
when a threshold of risk is surpassed. Under this hypothesis, the same genetic risk factors
might contribute to each of the developmental tic disorders, with a higher burden of Comorbidity and coexistent conditions
disease causing more severe or persistent disease. Gilles de la Tourette syndrome (GTS)
The majority of patients (90%) with GTS do not have
disease severity and/or comorbidity could arise from high levels of polygenic risk, low
polygenic risk in combination with a detrimental, large effect size variant (that is, copy ‘pure GTS’ (that is, tics only), but have additional
number variation, gene-disrupting coding mutations or deleterious chromosomal comorbid and/or coexistent disorders that contribute to
rearrangement), low‑to‑moderate polygenic risk in combination with non-genetic, the GTS phenotype: this pattern is seen in both com-
environmental risk factors or all of the above. Standard deviation represents the munity and clinical settings1. Comorbid conditions are
theoretical normal distribution of underlying disease risk. those that are not only more common in patients with

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PRIMER
GTS than in the general population but also have clin- be multifactorial141, but not involving genetic factors142,
ical similarities and definite or purported genetic links and may be related to the OCD48. Other behavioural or
with GTS133. Comorbid disorders that meet these cri- emotional problems, such as aggression, difficulties with
teria are OCD (40–60% of patients), OCB (60–90% of anger control, sleep disturbances, self-injurious behav-
patients)7,26,31,34,55,133 and ADHD (about 60% of patients)134. iours and non-obscene socially inappropriate behaviours
There have also been early possible hints for autism spec- (NOSIs) occur at higher rates than expected in people
trum disorder 135,136 but was not substantiated in later with GTS than in people with tic disorders who also
studies56,137 (BOX 2). Migraine has been documented to have ADHD or OCD. High rates of mood disorders
occur in 25–26% of cohorts of patients with GTS57,138 associated with GTS may be accounted for by OCD,
and the percentages are significantly higher than in the whereas mood, anxiety and disruptive behaviours may
control populations (8–13%); it is thus exciting that a be accounted for by ADHD48.
recent report indicates a shared genetic vulnerability to NOSIs are seen in about 30–60% of patients with GTS,
GTS and migraine139. which often reduces the QOL, are often socially disabling
By contrast, coexistent conditions co‑occur in and can have serious consequences143,144; NOSIs occur at
patients with GTS, but a genetic or other aetiological higher rates in people with tic disorders who also have
overlap has not (yet) been identified31,55. Coexistent ADHD or OCD. NOSIs are also related to ADHD and
conditions include depression, non-OCD anxiety, separ conduct disorder independent of tic severity, suggest-
ation anxiety, substance abuse, conduct disorder, per- ing the possibility that it is fundamentally a problem of
sonality disorders and learning disorders1,101,140 (BOX 2). impulse control144. This is particularly important in the
Depression affects 13–76% of all patients with GTS141, light of recent genetic findings that social disinhibition is
which is more than observed in the general population141. a heritable sub-phenotype of tics in GTS145,146.
Echophenomena and coprophenomena, premonitory
sensations, sleep disturbances, self-injurious behaviours, Phenotype
childhood conduct disorder, OCD, OCB and ADHD When discussing phenotype of GTS, we first acknow
are all correlated with depression. The aetiology of the ledge that there are many tic phenotypes (as described
depression in the context of GTS has been suggested to above), but it is to be noted that in all somewhat similar
a b Cortex Ventral tegmental area
Striatum
Direct pathway Indirect pathway

(D1 receptors) (D2 receptors) GPe
Cortex
Caudate
nucleus
Putamen
STN Thalamus SNpc
GPi
SNpr STN
SNpr
GPe GPi SNpc Basal
ganglia
Glutamate
Thalamus
Dopamine
GABA
Figure 4 | CSTC circuit. a | The cortico–striato–thalamo–cortical (CSTC) externa (GPe) to the subthalamic nucleus Nature Reviews
(STN). Direct| Disease
pathway Primers
MSNs
circuit is a complex interconnection between the cortex, basal ganglia and express dopamine D1 receptors, muscarinic M1 and M4 acetylcholine
thalamus, which regulates complex behaviours and involves many receptors and the neuropeptide substance P. Indirect pathway MSNs
neurotransmitters (including dopamine, glutamate and γ-aminobutyric acid express dopamine D2 receptors, muscarinic M1 receptors, adenosine A2A
(GABA)). An imbalance in one or more of these neurotransmitters might receptors and enkephalin. Each pathway has an opposing effect on
explain some of the characteristics of Gilles de la Tourette syndrome (GTS). GABAergic GPi and SNpr output neurons: the direct pathway inhibits and
b | A simplified CSTC circuit includes projections from excitatory the indirect pathway stimulates. Consequently, these pathways have a
glutamatergic pyramidal neurons located in the frontal cortex to reverse effect on excitatory projections from thalamic neurons to the frontal
GABAergic medium spiny neurons (MSNs) in the striatum. Striatal output cortex and striatum, and, in turn, the facilitation of motor activity.
pathways include a direct pathway that transmits striatal information Specifically, activation of the direct pathway facilitates motor activity,
monosynaptically to the globus pallidus interna (GPi) and substantia nigra whereas activation of the indirect pathway reduces motor activity. The
pars reticulata (SNpr) and an indirect pathway that conveys information to dopaminergic pathway, which is likely to be involved in GTS, is also
these same regions via a disynaptic relay from the globus pallidus indicated. SNpc, substantia nigra pars compacta.

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PRIMER
eight investigations to date — despite using differing EMTICS study), examining onset, course, peaks and
methods (for example, using cluster analysis, latent class simultaneous measures of prenatal and postnatal insults,
analysis, hierarchical cluster analysis and principal com- immune status and other factors in both patients with
ponent factor analysis) — have reported several classes GTS and those at risk for GTS.
(phenotypes) based on tics. The resulting phenotypes
have included variously OCD or OCB, ADHD, depres- Management
sion, phobias and panic attacks147. However, the only The optimal treatment strategy for individuals with
phenotype that has been consistently replicated in all GTS must take the severity of tics and their effect on
studies that examined for it is pure GTS. Interestingly, daily functioning and QOL into consideration, in addi-
coprolalia does not seem to be class specific, other than tion to determining which symptoms are the most
not arising in pure GTS5. It is also noteworthy that prominent, disabling and causing the patient the most
less-severe tic phenotypes (for example, persistent motor difficulty (FIG. 5). Indeed, comorbidities and coexisting
or vocal tic disorder) have lower rates of comorbidity conditions (BOX 2) may be more problematic than the
than does GTS148. Clearly, with regard to psychopatho motor and phonic tics per se11. For most individuals with
logy, more research is required. A recent similar study GTS whose tics are mild to moderate and do not impair
was performed across multiple symptom dimensions. social functioning, the provision of psychoeducation
The exploratory factor analysis revealed a five factor to parents, teachers and peers and the exploration of
structure: tic/aggression/symmetry symptoms; obses- associated coping strategies are typically sufficient.
sive–compulsive symptoms associated with compulsive If motor and phonic tics are severe enough to warrant
tics and a preoccupation with numbers and patterns; treatment, where resources permit, behavioural inter-
ADHD symptoms; autism symptoms; and hoarding/ ventions are currently considered the first-line treat-
inattention symptoms49. Another study showed that the ment for tics154–157. However, the limited number of
mean number of lifetime comorbid diagnoses in patients trained therapists, inconveniences (for example, travel
with GTS was 2.1; if OCD and ADHD were excluded, the distance) and willingness to engage can serve as barriers.
mean number was 0.9 (REF. 48). GTS was also associated Pharmacological interventions are typical second-line
with an increased risk of anxiety and a decreased risk options, whereas experimental approaches include DBS
of substance abuse disorders. High rates of mood dis- (for severe and treatment-refractory cases). Although
orders may be accounted for by OCD, whereas mood, combining tic-reducing medication and behavioural
anxiety and disruptive behaviours may be accounted for therapy may theoretically seem to have a synergistic
by ADHD48. However, another study showed no associ effect, the data are currently conflicting and addi-
ations of specific symptom clusters to either the presence tional research into this topic is needed to provide
of coexisting psychiatric conditions or to treatment out- supporting data.
comes149. A further study reported that social disinhib
ition is a heritable sub-phenotype146. These examples Behavioural treatments
illustrate that the GTS phenotype is more complex than Habit reversal therapy (HRT) was the first behavioural
was initially thought, and, importantly, all challenge the treatment for tics with a significant evidence base158
unitary nature suggested by the main diagnostic criteria (BOX 3). HRT involves three primary components: aware-
(both ICD and DSM). ness training, competing response training and social
Finally, suicidality (ideation and attempts) (BOX 1) support. Awareness training is aimed at noticing the
shows a higher prevalence in GTS (9.7%) than in healthy premonitory urge or tic onset. In competing response
controls (3%)150. Associated factors include tic-related training, the patient learns to do an action that is incom-
factors (such as severity, coprophenomena, complex patible with the target tic. Social support is important
phonic tics and self-injurious behaviours), poor response to praise the proper use of the competing response and to
to medication and the presence of comorbidities and remind the patients. In HRT, tics are treated one at a time,
coexistent psychopathologies111,151–153. at a rate of one per week. Function-based treatment ele-
The comorbid and coexisting conditions might ments have been added to traditional HRT procedures.
complicate the diagnosis of GTS, especially to the non- These therapeutic strategies are aimed at reducing tic
expert. Many of these disorders are more common in frequency and/or severity and are based on the assess-
patients with GTS than in the general population, and ment of contextual factors that reliably increase tics and
contribute substantially to the functional impairment of reactions to tics that may inadvertently reinforce tics.
GTS and reduction of QOL, occur early in childhood, Comprehensive behavioural intervention for tics
and should be assessed for at first interview and subse- (CBIT), a combination of HRT, function-based inter-
quently screened for on a regular and recurring basis. ventions, relaxation training, psychoeducation about
Future collaborative research, using uniform methods, GTS and a reward procedure to enhance treatment
will be used to ascertain the longitudinal course and compliance159, has been recommended as a first-line
predictors of long-term outcome, including a focus treatment for those with GTS in multiple practice guide-
on individual variability in tic symptoms, which are lines154,155,160. Two large randomized controlled trials115,161
important considerations along with risk and resilience compared CBIT (eight structured 60–90 minute sessions
factors for successful long-term outcomes. Ideally, the over 10 weeks) with a control group receiving support-
clinical research could be conducted with basic science ive therapy (comprising broad psychoeducation about
(as is being undertaken, for example, in Europe, in the GTS and nonspecific therapy and emotional support

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Table 1 | Clinical rating systems used in Gilles de la Tourette syndrome

Symptoms Measurements Comments
Tics and characteristic features of GTS
Yale Global Tic Severity Rating Tic severity (50 points out of 100) and impairment (50 points out of Gold standard for tic severity and the most
Scale (YGTSS) 100) in the preceding week widely used scale. Estimates tic severity
based on the number, frequency, intensity,
complexity and interference associated
with their motor and phonic tics viewed
in separate aggregates. Total score from
0–100 points rated by the clinician
Hopkins Motor and Vocal Tic Tic presence, type and severity using visual analogue scales Simple, accurate and comprehensive rating
Scale (HMVTS) (0–10 score) system that is accessible and can be used
by a clinician or parent
Parent Tic Questionnaire (PTQ) Devised for use in children and adolescents. Parents are asked to Rating system for the parents to assess
assess the number of tics from a list of 14 common tics, each of them tics in young children. Mainly used in the
rated for tic presence in the past week. Frequency and intensity United States
are rated on a four‑point scale and these are added for each tic to
produce scores ranging from 0 (tic not present) to 8 (constant and
intense tics)
National Hospital Interview Data on tics, OCB, OCD, ADHD, family history, physical and Too long and detailed for regular use
Schedule (NHIS) psychological health and substance abuse in clinics; requires a trained medical
professional. Developed at the National
Hospital for Neurology and Neurosurgery
and University College London, UK
Motor tic, Obsessions and Motor and vocal tics, obsessions and compulsions. Self-reporting Good correlation with YGTSS and
compulsions, Vocal tic based on 16 statements, which generate five subscales (scored 0–3) suggested to be used in epidemiological
Evaluation Scale (MOVES) studies
Diagnostic Confidence Index Scoring system from 0–100 based on the presence of positive Performed by the clinician. Developed
symptoms (for example, coprolalia, echophenomena, complex tics, at the National Hospital for Neurology
waxing and waning course, suppressibility, suggestibility, rebound, and Neurosurgery and University College
premonitory sensations and relief after tic) and also negative London
symptoms (for example, the absence of medical problems that might
cause tics, such as stimulants or a history of encephalitis)
Modified Rush Video-based The original scale and video protocol were retained but a new (and Tic ratings of values 0–4 on five categories
Rating Scale better) scoring system was added are the new (modified) form, with tic
disability currently scored from 0 to 20
Premonitory urges*
Premonitory Urge for Tics Scale Premonitory urges. The scale is quite brief, containing 10 Self-reporting in young and adult patients;
descriptions of somatic sensations. The severity of the urges is translated in Hebrew and Italian
rated on a four-point scale ranging from 1 (not at all true) to 4
(very much true)
University of São Paulo Sensory Sensory phenomena. The externally triggered sensory experiences Rated by the clinician; good correlation
Phenomena Scale (tactile, auditory and visual) and the inner ‘just right’ perceptions with the Premonitory Urge for Tics Scale
are measured. Severity is rated on a six‑point scale, which indicates
the frequency, distress and interference of the phenomena
(with a maximum severity score of 15)
Comorbidities and symptomatology
Y‑BOCS (Yale-Brown Past or present OCBs Performed by the clinician
Obsessive–Compulsive
Scale) or C Y‑BOCS
(Children’s Yale Brown
Obsessive–Compulsive Scale)
Leyton Obsessional Inventory Obsessive–compulsive symptomatology Self-reporting
(LOI) short questionnaire form
Maudsley Obsessive Obsessive–compulsive symptomatology Self-rating of 30 items in four subgroups
Compulsive Inventory (MOCI)
The Obsessive–Compulsive OCBs (the short version (the OCI‑R) consists of 18 items) The original OCI is a self-report scale
Inventory (OCI) consisting of 42 items, for which patients
are asked to rate the presence of their
symptoms during the previous month on a
five‑point scale
Swanson, Noland and ADHD symptoms and oppositional defiant disorder Self-reporting or performed by the parent
Pelham‑IV (MTA SNAP-IV) Scale or teacher

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Table 1 (cont.) | Clinical rating systems used in Gilles de la Tourette syndrome

Symptoms Measurements Comments
Comorbidities and symptomatology
Conners ADHD Rating Scales ADHD symptoms in young people and adults Self-reporting or performed by the parent
or teacher
The assessment and psychometric properties of some of the instruments used in patients with Gilles de la Tourette syndrome (GTS) and their associated
comorbidities and psychopathology (modified, adapted and updated from REFS 93,121,222–224). ADHD, attention-deficit/hyperactivity disorder;
OCB, obsessive–compulsive behaviour; OCD, obsessive–compulsive disorder. *Premonitory urges are the sensory phenomena associated with tics in GTS (they are
sometimes called sensory tics). They are usually difficult to describe: most patients will frequently refer to them as unpleasant somatic phenomena that build up
prior to the tic (or upon attempts to resist the tic) and are momentarily alleviated by performance of the tic; they are bodily sensations113. Another type of sensory
phenomena frequently encountered in patients with GTS involves a need for things to feel, look or sound ‘just right’ (REF. 225), and most patients can readily
distinguish these from premonitory urges or sensations. The ‘just right’ phenomenon is often more of a ‘mental phenomenon’ rather than a bodily sensation; the
‘just right’ awareness is usually visual or tactile and the patients with GTS with these often have comorbid OCD225. There may also be inner ‘just right’ perceptions224.
for the difficulties experienced when living with tics). For those who do not respond to a particular agent,
Children with GTS who received CBIT showed signifi a switch to another agent or group of agents as well as
cant improvements in tics and tic-related impairment, combining two agents will generally lead to the desired
defined as clinical response, at the end of acute-phase benefits. Refractory disease only occurs in a minority of
treatment compared with the control group (53% of patients169. With respect to managing the key comorbid-
the CBIT group versus 19% of the control group). ities, prescribing practices that are used when GTS is not
Furthermore, 6‑month follow‑up data of treatment present generally apply.
responders showed that gains were maintained and The aim of psychopharmacological treatment of
associated with significant decreases in anxiety and dis- GTS is to ameliorate tics and to improve psychosocial
ruptive behaviours relative to baseline (before treatment) functioning as soon as possible with as few adverse
compared with non-responders115. Similar findings effects as possible. On average, anti-tic medication can
were observed in adults161. No adverse events associ- reduce tics by 25–70% depending on the dose within
ated with CBIT were observed. CBIT delivered via tele 2–4 weeks. Over-medication, driven by the belief that
conferencing devices162, Skype163 and through nurses164 higher dosages will necessarily be more effective, can
has also been shown to be effective. The mechanisms cause considerable adverse reactions, particularly seda-
by which CBIT is effective are unclear, but improved tion, apathy, extrapyramidal effects, weight gain and
motoric inhibition and habituation to the aversive metabolic abnormalities.
premonitory urge are suggested to be involved165,166. Historically, pharmacological management of tics
Finally, exposure and response prevention (ERP)167, involved dopamine receptor blockers (also called neuro
a technique that encourages the patient to fully experi leptics) and α2-adrenergic agonists, although they can
ence urges to tic while actively suppressing tics during result in adverse effects that can limit tolerability 12,170–173.
therapeutic sessions, seems promising in pilot tests. Haloperidol and pimozide were among the earliest
Unlike CBIT, ERP focuses on all tics at the same time, neuroleptics that were shown to lead to improvements
whereas CBIT addresses tics sequentially. It is possible of motor and behavioural symptoms in GTS8,9, but are
that ERP and CBIT share a similar mechanism of action. not often used in many countries owing to problem-
atic adverse effects. Indeed, little difference in efficacy
Psychopharmacological treatments among the different dopamine receptor blockers exists.
In situations where behavioural therapies are ineffec However, the adverse-effect profile is very different 10,
tive, not available, not age-appropriate or not the and the tolerability profile and the treatment require-
patient’s or the family’s preference, then pharmacologi- ments of the comorbid conditions would also merit
cal treatments should be considered (BOX 3). Indeed, the consideration170,171. Substituted benzamides, particu-
European, Canadian and American guidelines suggest larly sulpiride and tiapride, have been recommended as
that tic-specific psychopharmacotherapy should be first-line treatment for GTS in Europe because of their
considered when tics are causing pain or injury, social favourable benefit-to‑risk ratio10,172. However, these
and emotional problems, and/or functional interference agents are not available in the United States, Canada and
(for example, impairing academic achievement)11,154,168. other parts of the world. In the United States, Canada
If tics are not severe or disabling, the use of a medica- and the United Kingdom, atypical neuroleptics, such as
tion may not be warranted. Although these guidelines risperidone and aripiprazole, have become the preferred
are in place, the choice of psychopharmacological treat- choice over the older neuroleptics described above
ment of tics is still often based on personal experience. because of their improved tolerability.
Additional impediments to the development of a con- In the United States, Canada and Australia,
sensus psychopharmacological treatment algorithm are α 2‑adrenergic agonists (clonidine and guanfacine)
the waxing and waning course of GTS and the presence are considered first-line pharmacotherapy, particu-
of comorbid and coexistent disorders that can influence larly in children, primarily because of their preferable
tic severity. The required doses, response time and effi- adverse-effect profiles compared with the typical anti
cacy are highly variable, which makes decisions on when psychotics. In a recent meta-analysis, superiority for
and how to treat tics difficult and not well standardized. both α2‑adrenergic agonists to placebo was confirmed,

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Tic disorder
Finally, it is noteworthy that interest remains in alter-
Symptoms or indications
native agents, particularly in cases that are refractory to
Treatment
classical agents12. Local injections of botulinum toxin
Psychoeducation
can be an effective treatment for focal, cervical spine
and phonic tics, which does not have systemic adverse
Presence of tics, but no Yes
effects176. There is some promising evidence regarding
indication for treatment Monitoring cannabinoids and Chinese herbal medicines177,178. In addi-
No tion, numerous other agents have been tried for the treat-
ment of tics, although none of these agents have support
Presence of tics, but
comorbid disorder(s) have Yes Treatment of from adequately powered controlled trials168,179. Several
treatment priority comorbid disorder(s) new agents are currently either in early development or
No in the midst of ongoing clinical trials180 (BOX 3).
Indication for treatment
of tics, with preference DBS
for (and availablilty of) Yes Behavioural therapy Although DBS (that is, the modulation of pathological
behavioural treatment (HRT, CBIT and ERP) neuronal activity in specific brain networks using
high-frequency electrical current delivered by implanted
tiny electrodes connected to a neuropacemaker) might
Combination of
pharmacotherapy and be an option for some patients with GTS181, the paucity of
No
Tics still with indication behavioural therapy evidence-based publications, the heterogeneity of results
for treatment Yes Combined
and the lack of consensus on the optimal brain target all
pharmacotherapy with point to the fact that DBS for GTS is not yet established.
different agents Some of the issues surrounding studies on DBS in GTS
Indication for treatment are related to the small number of patients who would
Yes
of tics, with preference for Pharmacotherapy require surgery, the young age of most patients, the wax-
pharmacological treatment ing and waning disease course, the variability in GTS
Yes
phenotypes and comorbidities, and the improvement of
symptoms with age for many individuals. Furthermore,
Alternative therapies in specialized which of the hitherto nine brain targets182,183 within
Tics still with indication Yes centres (DBS, cannabinoids and
for treatment botulinum toxin, among others ) the CTCS circuitries is the best target for DBS remains
unclear. Well-designed trials that collect data on the out-
Figure 5 | Decision tree for the management of GillesNaturede la Tourette come (tics or comorbidities) to define patient selection
Reviewssyndrome.
| Disease Primers criteria are needed. Noteworthy, the rate of infection
If Gilles de la Tourette syndrome (GTS) is suspected, diagnosis needs to be confirmed by
considering other tic disorders and carrying out the indicated investigations. seems high in patients with GTS184,185, which might be
If symptoms are not distressing and/or causing dysfunction, supportive therapy owing to tic-related behaviours (for example, scratch-
(for example, psychoeducation) is recommended. If symptoms are distressing, ing or picking at the surgical wound) and comorbidities,
pharmacological or non-pharmacological interventions should be given. However, or indeed distinct immunological profiles: this remains
if comorbid conditions are present and more impairing than GTS, they should have unclear 185 and further research is needed. The relatively
treatment priority. When treatment is successful, monitoring remains essential. recent initiative of the Tourette Association of America
Solid arrows indicate the next level of evaluation or treatment; dashed arrows indicate to launch an international GTS DBS registry and data-
alternation between two treatments. CBIT, comprehensive behavioural intervention
base to share data, determine best practices, improve
for tics; DBS, deep brain stimulation; ERP, exposure and response prevention; HRT, habit
reversal therapy. Adapted with permission from REF. 11, Springer. outcomes and to provide information to regulatory
agencies, is a step in the right direction186.
but this benefit was significant only for children or Quality of life
adolesc ents with GTS and comorbid ADHD, and Since the pioneering study by Elstner et al.187, patients
minimal in those with GTS without ADHD173. with GTS have consistently been shown to have a
A meta-analysis examined the adverse effects associ lower QOL than the general population. Several GTS-
ated with several of the widely used neuroleptics174. specific tools have been developed that will facilitate
Although olanzapine, risperidone and, to a lesser extent, the incorporation of QOL into research studies and
aripiprazole were all associated with weight gain, this clinical practice188,189.
was greatest for olanzapine and the least for aripipra- Consistent with the idea that GTS is more than
zole. Other adverse effects vary depending on the study, having motor and phonic tics, subsequent studies have
but risperidone and aripiprazole have been found to be highlighted the compounding effect of numerous factors
associated with increased prolactin levels and olanza associated with GTS in reducing QOL190 (FIG. 6). In addi-
pine with increased glucose, total cholesterol and pro tion to tic severity and the presence of coprophenomena,
lactin levels. Clinician surveys have found that the most these factors include associated comorbidities and coex-
common neuroleptic medications used to treat tics are isting psychopathologies (BOX 2). Patients with pure
risperidone and aripiprazole11,175. Although aripipra- GTS have a higher QOL than patients who have GTS
zole has one of the best benefit-to-risk ratios10, it is not and comorbidities191. Meta-analyses have suggested
available in many countries. that, although OCD is a common factor affecting QOL

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throughout a patient’s lifetime, other factors may vary impaired emotional and school functioning as well as
across the lifespan, with tic severity and ADHD being impaired social functioning and peer relationships
particularly associated with lower QOL in children, in children and adolescents with GTS. Patients may
whereas in adults, anxiety and depression become develop coping strategies over time to manage difficul-
increasingly relevant190,192. Another study 193 found strong ties that are prominent in childhood, which may also
associations between parent-reported comorbidity and moderate with age, only to then be confronted with new
decreased QOL, increased emotional symptomatology, challenges in adulthood.
Numerous QOL domains are affected in people
with GTS, including psychological, obsessional, social,
Box 3 | Treatment options for Gilles de la Tourette syndrome* physical, school-based or work-based and cognitive194
(FIG. 6). As a consequence of these, psychological dis-
Behavioural therapy‡ tress, frustration and depression are commonly experi-
• Comprehensive behavioural intervention for tics (CBIT) enced by patients with GTS195,196. Depressed mood and
• Exposure and response prevention (ERP) low QOL may be outcomes of the heavy psychosocial
Psychopharmacological treatments§ burden that can be experienced by patients with GTS
• Neuroleptics (also known as antipsychotics): over time197. OCD, OCB, obsessionality and perfection-
-- Typical neuroleptics: haloperidol and pimozide ism also contribute to this psychosocial burden, which
-- Atypical neuroleptics: aripiprazole, risperidone, ziprasidone, olanzapine in turn makes the process of adapting to life with tics
and quetiapine difficult. Difficulties with social skills and poor peer
-- Substituted benzamides: sulpiride and tiapride relationships are common in GTS130,144,198,199, as are the
-- Other typical neuroleptics less frequently used: fluphenazine, trifluoperazine, additional difficulties of dealing with stigma and bully-
penfluridol and thioproperazine ing. Severe tics can result in physical pain and injuries200
• Other dopamine antagonists (dopamine depletors): tetrabenazine, piquindone as well as in difficulties with activities of daily living 201.
and inosine Tics with comorbid ADHD often result in school-based
• Dopamine agonists: pergolide, amantadine, selegiline and pramipexole problems due to reduced concentration associated with
• α2-Adrenergic agonists (in cases of coexisting attention-deficit/hyperactivity ADHD that is further compounded by difficulties in task
disorder): clonidine and guanfacine completion due to the time and mental energy spent on
• Botulinum toxin injections (in cases of stable, single tics or isolated group of muscles, performing the tics or trying to suppress the tics, which
for example, blepharospasm and vocal cords) underscore the importance of the teachers’ knowledge,
• Antiepileptics: topiramate, carbamazepine, clonazepam and levetiracetam understanding and flexibility 202.
• Others: Reciprocal effects on QOL of parents and family
-- Cannabinoids members of patients with GTS are likely, although these
-- Agent with γ-aminobutyric acid (GABA) type B receptor and phenylmethylamine are presently less well understood203. Caregiver burden
actions: baclofen (children only) was shown to be significantly higher in parents of patients
-- Agents acting on endogenous opioid system: naloxone and naltrexone with GTS than in parents of age-matched young people
-- Calcium channel blockers: verapamil, nifedipine and flunarizine with asthma204. The correlates of increased caregiver
-- Androgen receptor antagonist: flutamide
burden and greater parental psychopathology included
-- Benzamide: metoclopramide (children only), usually used as antiemetic and is not
antipsychotic in normal doses
a GTS diagnosis and behavioural difficulties in the index
-- Selective serotonin 5‑HT3 antagonist: ondansetron children204.
-- β‑Blocker: propranolol
-- Alternative therapies: omega‑3 fatty acids and Chinese traditional medicine, such as Outlook
Ningdong granule and the 5‑Ling Granule Epidemiology and clinical course
Deep brain stimulation|| From a clinical and epidemiological perspective, there
Reserved for individuals with severe, treatment-resistant ‘malignant’ Gilles de la is wide variation in GTS prevalence rates in the litera-
Tourette syndrome (GTS). ture ranging from 0.25% to 5.7%1, which is attributed to
• Thalamus varying sample size, methodology, changing diagnostic
• Globus pallidus criteria over the years and the use of different assessment
methods and measures in different studies. However,
• Nucleus accumbens (some evidence)
consensus is emerging, aided by two meta-analyses
Emerging therapies¶ and one meta-regression of GTS prevalence rates, sug-
• Dopamine D1 receptor antagonist: ecopipam gesting the rate to be between 0.6% and 0.8% (95% CI:
• Vesicular monoamine transporter type 2 (VMAT2) inhibitors: deutetrabenazine or 0.3–1%)18,19. Future research using uniform methodology
valbenazine to inform longitudinal course and predictors of long-term
• Histamine H3 receptor antagonist: AZD5213 outcome, including focus on individual variability in tic
• New deep brain stimulation targets: subthalamic nucleus and globus pallidus interna symptoms, are important considerations along with risk
versus globus pallidus externa and resilience factors for successful long-term outcomes.
*The references cited with regard to each treatment domain include the recommendations
from the currently available European, Canadian and American guidelines, as well as recent Genetics and epigenetics
scientific reviews and advances concerning the treatment of GTS. ‡See REFS 12,154,155, The field of GTS genetics is poised for an upsurge in
157,160,220. §See REFS 11,12,154,157,168,172,177,178,220. ||See REFS 12,154,157, the discovery of definitive GTS susceptibility genes.
160,220. ¶See REFS 12,154,157,178,220.
Current sample sizes are approaching those for which

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specialty clinics210. In fact, the US National Institute of

Mental Health (NIMH) Strategic Plan identified GTS
as a priority disorder for expansion of DNA samples
Psychological
impacts that are available for study (Strategy 1.2, Priority A.4)211.
Once GTS susceptibility variants are identified, the
often-discussed challenge of transitioning from genes
to biology will benefit greatly from techn ological
advances in systems biology and international efforts
Obsessional Cognitive
impacts impacts to generate large-scale, publicly available gene expres-
Tics sion and epigenomic data sets from multiple mouse
and human brain regions across different neuro
Associated
clinical features developmental time points212,213. These spatiotemporal
maps of gene activity and gene regulation will be
Comorbidities instrumental in pinpointing the specific brain region
(for example, OCD (or regions) and critical periods where susceptibility
and ADHD)
genes influence GTS pathophysiology at the molecu-
Coexisting
lar level214,215. In parallel, collaborations in the field of
psychopathologies neuroimaging genetics (the largest example of which is
Physical
impacts
Social the ENIGMA Consortium; http://enigma.ini.usc.edu)
impacts will facilitate integration of GTS genetics with systems
neuroscience to uncover underlying GTS biology at the
neural circuit level216.
A third strategy already in progress is to leverage
School data from related neuropsychiatric disorders to iden-
and/or work
impacts tify gene variants in common across these disorders31,55.
QOL domains The Psychiatric Genomics Consortium (PGC; https://
Factors associated with GTS www.med.unc.edu/pgc) has led the field in this work32,33
and both GTS and OCD consortia have joined the latest
Figure 6 | Stylized depiction of quality-of-life domains affected
Nature in Gilles
Reviews de laPrimers
| Disease PGC cross-disorder analyses. Similarly, the emergence
Tourette syndrome. The quality of life (QOL) of patients with Gilles de la Tourette
syndrome (GTS) is affected in several domains, which are influenced by tics and other of robust, alternative symptom-based GTS phenotypes
conditions associated with GTS. ADHD, attention-deficit/hyperactivity disorder; that cut across traditional diagnostic boundaries may
OCD, obsessive–compulsive disorder. benefit GTS genetics, neuroimaging and treatment
studies by addressing phenotypic heterogeneity and
comorbidity 146. For example, two recent studies in
other polygenic disorders, such as schizophrenia, 3,500 patients with GTS and their relatives demon-
began to identify individual genes with certainty 205,206. strated that the subgroup of individuals with socially
A genome-wide association study ‘inflection point’ inappropriate tics (including coprophenomena) and
is suggested, which corresponds to the sample size at those with a combination of GTS, OCD and ADHD
which a study is adequately powered to identify any had the most heritable form of the disorder 145,146.
one of possibly hundreds of small effect, polygenic risk In addition, individuals with GTS and family members
variants (~10,000 cases for schizophrenia)205. Parallel who endorsed symmetry, ordering or arranging and
accelerations in disease gene discovery for CNVs and counting obsessions had higher mean GTS polygenic
de novo gene-disrupting coding mutations have also risk scores (but not higher OCD polygenic risk scores)
been observed, suggesting that large-scale, rare variant than those without these symptoms, despite the fact
discovery efforts will be equally successful207. As such, that this set of symptoms is traditionally considered to
the success of GTS genetics will require continued be OCD-related145.
expansion of international genetic collaborations and
concerted efforts to identify innovative approaches Pathophysiology
to large-scale sample collection. On the collaborative At this point, we have limited understanding of the
front, US and European GTS genetics consortia have pathophysiology, with unresolved questions on what
already harmonized phenotypic assessments and constitute GTS phenotypes and the modulators of
established pre-publication data sharing and joint phenotypic variability. Although genetic factors fur-
meta-analyses 30,43. For sample collection, multiple ther modified by sex and numerous non-genetic factors
strategies are being pursued, including leveraging or second hits (such as prematurity; perinatal trauma,
of data-rich electronic health records linked to bio- injury or hypoxia; oxidative stress; infections, inflam-
banks208, identifying cases among population registry mations or autoimmunity; and neural and psychosocial
studies with available DNA209 and the development of stressors) have all been implicated in the pathogenesis
validated, internet-based assessments combined with of GTS, these are not unique to GTS and are shared by
local biospecimen collection to bring sample collec- several neurodevelopmental disorders, including autism,
tion to the patients, rather than focusing on collections ADHD and OCD. Cross-disorder analysis examining
that are limited to academic medical centres with GTS genetic determinants to endophenotypic and clinical

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PRIMER
phenotypic characteristics in these neurodevelopmental DBS

disorders, for example, using neuroimaging, is expected The first DBS surgery for GTS was in 1999, and although
to ultimately clarify the overlaps and delineations in the this procedure is still considered to be an experimental
pathogenesis of GTS. treatment, since then, >150 individuals worldwide have
Although the precise pathophysiological basis of undergone this treatment218 and an international registry
GTS remains unresolved, converging evidence suggests has recently been developed in an effort to track cases
the involvement of the CSTC circuitry, which medi- using consistent metrics and outcome measures186. Early
ates the integration of movement, sensation, emotion case studies reported on several brain targets that were
and attention, and the dopamine system, which regu- used in these surgeries182,183,186; more recently, three brain
lates the motor circuitry. Although the dopamine model regions have emerged as the most commonly used: the
has gained much attention through clinical treatment thalamus, the posteroventrolateral sensorimotor part of
studies, recent research, including preclinical studies and the globus pallidus interna and the anteromedial ‘limbic’
post-mortem findings, has highlighted the role of care- part of the globus pallidus interna186,218. Of these, the
ful calibration of the excitatory–inhibitory balance135 evidence is strongest for the thalamus and the globus
through glutamate and GABA in conjunction with pallidus, although within those brain areas, there is still
other neurotransmitter systems, as described earlier 78. discussion about the precise targets (for example, antero-
Furthermore, animal studies could assist in informing medial versus posteroventrolateral globus pallidus). One
the effect of specific genetic and epigenetic influences recent meta-analysis of existing cases suggests that, when
on molecular pathways, cellular process or circuitry all targets are considered, approximately 80% of individ
formation along with opportunities for new treatment uals undergoing DBS show at least 25% reduction in
development. Thus, a deeper understanding of the symptoms and over half show >50% reduction in symp-
neurochemical systems in GTS will ultimately translate toms on stimulation compared with no stimulation218.
to empirically supported pharmacological interven- Mean improvement for motor tic severity is approx
tions (several such agents are currently under trial)180, imately 45%, with a 50% improvement in vocal tic sever-
whereas neurophysiological studies will unravel the ity, and an effect size of 0.96 overall for DBS compared
mechanism of action in brain stimulation techniques, with controls218. However, more modest improvements
such as transcranial magnetic stimulation217 and tran- were also seen in obsessive–compulsive symptoms and
scranial direct current stimulation (ANZCTR clinical depressive symptoms in one meta-analysis218.
trial ID: ACTRN12615000592549 and ClinicalTrials.gov These data indicate that DBS can be effective, at least
identifier: NCT02216474). in treatment-refractory cases. However, the number of
Animal models of tic generation and the affect of patients who have undergone this treatment is still small,
modulating factors, such as stress and infections, will and some issues remain. For example, although a few
help to elucidate the complex interplay between genetic, children <18 years of age have undergone this surgery, the
environmental (including prenatal and perinatal factors) waxing and waning disease course and the improvement
and neuroimmunological risk factors, which affect the of symptoms with age for many individuals suggest that
phenotype and outcome; however, considerable debate further work is needed to determine the best candidates
continues over the validity of most existing animal for DBS (including symptom type and whether the treat-
models of tics, given the inability to assess animals for ment should be limited to adults only, among others),
premonitory sensations and tic suppression, which given the inherent surgical risks. DBS may be suggested
are crucial for distinguishing tics from other repeti- for some patients, and well-designed prospective con-
tive movements, such as myoclonus, stereotypies and trolled trials that collect data on the outcome (tics or
psychogenic tics. Furthermore, gene‑by‑environment comorbidities) to define patient selection criteria are still
and epigenetic studies will provide valuable clues to the needed, as are more thorough investigations of potential
GTS pathophysiology. complications of DBS in individuals with GTS219.
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32, 1128–1134 (2010). 205. Levinson, D. F. et al. Genetic studies of major Foundation, the European Multicentre Tics in Children
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Tourette syndrome. Neurosurg. Clin. N. Am. 25, and what can we do about it? Biol. Psychiatry 76, Fondazione Child, and How I Decide. He has also received
117–135 (2014). 510–512 (2014). royalties from John Wiley and Sons, McGraw-Hill and Oxford
184. Servello, D., Zekaj, E., Saleh, C., Lange, N. & Porta, M. 206. Schizophrenia Psychiatric Genome-Wide Association University Press. M.M.R., V.E., H.S.S., D.M., P.P., V.R., C.A.M.
Deep brain stimulation in Gilles de la Tourette Study Consortium. Genome-wide association study and R.Č. declare no competing interests.

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PRIMER

Gilles de la Tourette syndrome

NATURE REVIEWS | DISEASE PRIMERS VOLUME 3 | 2017 | 1

Author addresses diagnosis and management of GTS in detail. We have

2 | 2017 | VOLUME 3 www.nature.com/nrdp

NATURE REVIEWS | DISEASE PRIMERS VOLUME 3 | 2017 | 3

Early scientiﬁc descriptions of GTS by Itard, Psychoanalysis continued to reign

4 | 2017 | VOLUME 3 www.nature.com/nrdp

First behavioural Development Largest GTS treatment

Nature Reviews | Disease Primers

NATURE REVIEWS | DISEASE PRIMERS VOLUME 3 | 2017 | 5

6 | 2017 | VOLUME 3 www.nature.com/nrdp

NATURE REVIEWS | DISEASE PRIMERS VOLUME 3 | 2017 | 7

5 GTS who seek specialist treatment have coprolalia100–102.

Relative tic severity (ARRTS)

8 | 2017 | VOLUME 3 www.nature.com/nrdp

NATURE REVIEWS | DISEASE PRIMERS VOLUME 3 | 2017 | 9

a b Cortex Ventral tegmental area

Direct pathway Indirect pathway

10 | 2017 | VOLUME 3 www.nature.com/nrdp

NATURE REVIEWS | DISEASE PRIMERS VOLUME 3 | 2017 | 11

Table 1 | Clinical rating systems used in Gilles de la Tourette syndrome

12 | 2017 | VOLUME 3 www.nature.com/nrdp

Table 1 (cont.) | Clinical rating systems used in Gilles de la Tourette syndrome

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specialty clinics210. In fact, the US National Institute of

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phenotypic characteristics in these neurodevelopmental DBS

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