Epidemiology and prevalence

Tourette syndrome occurs worldwide and in different cultures. Boys and men are more commonly affected, with the male-to-female ratio between three and four to one. Clinical characteristics are similar irrespective of the country of origin. It is often reported that within families, the affected males have predominant tic symptoms, whereas the females have obsessive–compulsive behaviours (OCBs).^10,11

Tourette syndrome was once considered to be very uncommon, but the worldwide prevalence in children and young people is now estimated to be around 1%. Good-quality epidemiological studies (involving direct assessment of the subjects) show remarkably consistent findings and suggest a prevalence of between 0.4% and 3.8% for young people between the ages of 5 and 18 years (studies undertaken in the UK, Europe, USA, South America, the Middle East, Oceana, Asia, North Africa).^10–12 The prevalence of TS is higher in those with learning difficulties, emotional and behavioural disorders or autism spectrum disorder (ASD).^10–12

Comorbidities and coexisting psychopathologies

Robertson⁹ suggested a differentiation between comorbid disorders and coexisting psychopathology. This was based on emerging clinical, epidemiological and aetiological data suggesting that some disorders have more in common with TS than others, particularly from a genetic perspective. Thus, Robertson⁹ suggested that OCB and obsessive–compulsive disorder (OCD), attention deficit hyperactivity disorder (ADHD) and ASD are comorbid with TS. It is important to distinguish OCB (also known as ‘compulsive tics’ that are common in TS), such as ‘evening-up behaviours’, compulsive touching and counting rituals, from symptoms more typical of OCD such as checking, washing and cleaning rituals. In TS, the performance of OCBs results in a relief from a premonitory ‘urge’ (similar to other tics), while in OCD performance of rituals results in temporary relief from anxiety linked to specific fears (e.g. contamination). For this reason, OCB associated with a premoniraty urge are regarded as a complex tic rather than a symptom of a separate disorder (OCD). Some refer to mild OCB as obsessive–compulsive symptoms (OCSs).¹³

Prevalence of the comorbid disorders differ in clinical and community TS populations. In clinical TS samples, ADHD is present in about 60% of patients,⁷ while OCD occurs in just under 40%^7,13 and OCBs/OCSs may occur in up to 90% of patients.¹³ The prevalence of ASD in clinic patients with TS has not been widely studied, but in one large international multicentre study encompassing 7288 TS patients, the point prevalence of ASD was 4.6% (much higher than in the general population).¹⁴

In community studies, around 90% of TS individuals have other comorbid diagnoses^15–17 and in one community study, 36% of the individuals had three or more diagnoses.^15,16 In TS individuals, ADHD is the most common comorbid diagnosis occurring in 17.8% to 68%, then OCD in 10.9% to 20.5%, and “disruptive behaviours” in 10.9% to 16%.¹⁸ TS occurs in between 6% and 11% of youngsters with ASD in community studies.^7,9

The common neurodevelopmental comorbidities (ADHD, OCB/OCD and ASD) not only occur much more than by chance,¹⁹ but the research data also suggest that they share a common genetic aetiology.^19,20 In contrast, while depression and depressive symptomatology are common in TS, the two disorders are not genetically related.²¹ Thus, the coexistent psychopathologies (e.g. depression, social anxiety, substance misuse) may well be a consequence of having TS, rather than being an integral part of TS.

Thus, both in clinical populations as well as in the community, approximately only 10% of people with TS have solely tics or, another way of putting it is that 90% of individuals with TS, be they in the clinic or in the community, have other comorbid diagnoses or psychopathology.

Early research suggested that individuals with TS were at increased risk for depression, anxiety and hostility.²² Thereafter, in several controlled studies in adults with TS, the patients were shown to have more depressive, anxious, obsessional symptomatology and hostility symptoms than age- and sex-matched healthy control subjects, and the subjects with TS were also shown to have significantly more personality disorders.^21,23–26 In further controlled studies, young people with TS have been shown to have more depressive and obsessional symptomatology than control subjects.^27,28

Robertson and Orth²⁹ reviewed the literature of depressive symptoms and illness in people with TS in detail, showing that, in 16 uncontrolled studies in specialist centres that examined mood changes among 5409 TS patients, depressive symptomatology, dysthymia, mood swings and/or major depressive disorder (MDD) or depressive illness were found in between 13% and 76% of the patients . The main diagnosis was that of MDD. In addition, 13 controlled investigations found both young people and adults with TS (n = 741) to be significantly more depressed than age- and sex-matched healthy control subjects.²⁹

Since 2000, some research groups have separated TS individuals on the basis of clinical symptoms into subgroups, specifically separating those with and without ADHD, demonstrating significant differences. Thus, they have examined cohorts of children including children with TS only, and are comparing them with other groups such as TS plus ADHD, ADHD only and unaffected healthy controls.^27,30,31 These studies generally indicated that youngsters (aged 7–18 years) with TS only did not differ from unaffected controls on many ratings, including aggression, delinquency or conduct difficulties. In contrast, children with TS plus ADHD scored significantly above the unaffected controls and, similarly to those with ADHD only, on the indices of disruptive behaviours. Studies further showed that youngsters with TS plus ADHD showed more internalising behaviour problems and poorer social adaptation than children with TS only or controls. Of importance is that youngsters with TS only were not significantly different from unaffected controls on most measures of externalising behaviours and social adaptation, but did have more internalising symptoms. Similarly, in an adult TS population, those patients with TS only were not disadvantaged, whereas those with TS plus ADHD showed signs of social difficulties including drug and alcohol abuse and more aggression and more instances of breaking the law.³² In summary, those individuals with TS only appear to be no different from healthy control subjects (apart from having more internalising problems) and have significantly fewer externalising problems and social adjustment difficulties than those with TS plus ADHD. This clearly has major management and prognostic implications.

After an initial publication on the reduced quality of life (QoL) in adult patients with TS,³³ there have been over a dozen or so studies investigating QoL in young people with TS (review and references)⁷ and, more recently, a study by Cavanna et al.³⁴ The conclusions that can be drawn from these are that patients with TS have a reduced QoL when compared with healthy controls, but have a better QoL than patients with epilepsy or other psychiatric illnesses. The reduced QoL is generally associated with unemployment, underachievement, increased tic severity, the presence of OCB, ADHD, anxiety and depression.⁷ It has also been shown that the OCD and ADHD have differential effects on the QoL.³⁵

The psychosocial aspects and adaptive functioning of people with TS have been addressed by both Robertson³⁶ and Sukhodolsky et al.³⁷ There are numerous triggers which increase the tics and patients’ distress. In addition, patients with TS suffer as a consequence of their tics and associated comorbid conditions and coexistent psychopathologies. Sukhodolsky et al.³⁷ cited cases from their TS clinic (Yale Child Study Centre, CT, USA) and also reviewed studies not included/mentioned above as their brief was different. In essence, in their clinic, youngsters (aged 7–18 years) with TS had been teased because of their tics. In one controlled study, TS youngsters were rated by their peers as more withdrawn and less likeable than their peers. The severity of tics was not related with ratings of popularity, but was associated with ADHD. In a second controlled study,³⁸ peer victimisation was compared between youngsters with chronic tic disorder (CTD) and type 1 diabetes mellitus and matched healthy controls: the youngsters with tics were classified as reporting clinically significant greater peer victimisation (27%) than for 9% of both youngsters with diabetes mellitus and healthy controls.³⁷

Lee et al.³⁹ showed that more ‘stress’ (e.g. parental burden, psychopathology) was reported in the parents of youngsters with TS, with one of the main stressors being child care difficulties. In addition, a correlation was found between parenting stress and child sex, age, school situation, disease severity, parent age and family income. Disease severity and family income were the variables with the greatest predictive power for parenting stress, accounting for 42% of the variance.³⁹ Cooper et al.⁴⁰ compared ‘caregiver burden’ (CGB) in parents of youngsters with TS with the parents of youngsters with asthma using standardised assessment schedules including the Child and Adolescent Impact Assessment. The TS parents were significantly more psychiatrically disturbed and had greater CGB than the parents of children with asthma.⁴⁰ Overall, studies have shown considerable parenting stress, CGB and psychopathology in the parents of youngsters with TS.

In summary, QoL in patients with TS is reduced, with children and young people with TS rated as less likeable by their peers and also suffering significant ‘peer-victimisation’; the adverse effects on parents of a child with TS are substantial.

The relationships between the comorbidities and psychopathology and psychosocial aspects and TS are complex and have been discussed fully elsewhere,^7,9,36,41 and are summarised as follows: (1) OCB/OCD is generally accepted as an integral part of and genetically related to TS; (2) ADHD is common in TS and now recognised to be genetically related in some cases (a subgroup); and (3) ASD is common, sharing some genetic/neurodevelopmental underpinnings with TS.

In summary, the comorbidities of TS change with age as do some of the psychopathologies (e.g. depression worsens with age). This highlights the importance to address the TS phenotype and why the separation of the other disorders in TS is crucial. This also clearly has treatment implications.

Lifespan prognosis

It was initially thought that TS was lifelong with continuing severity, but then Erenberg et al.⁴⁷ first indicated that TS symptoms reduced with age. Leckman et al.⁴⁸ subsequently highlighted the natural course of the disorder, suggesting that the prognosis was better than previously thought, with the onset of TS at 5.6 years, the worst severity being at 10 years and the majority of symptoms disappearing/reducing in half of the patients by the age of 18 years. Coffey et al.⁴⁹ assessed youngsters (aged 6–17 years) with TS having a mean age of onset of 5.1 years. At baseline, 88% of subjects met threshold criteria for at least mild symptoms, but only 30% met criteria for impairment. At a 2-year follow-up, 82% of the subjects met criteria for tic persistence (no significant difference from baseline), but only 14% met criteria for TS-associated impairment, which was significant. Bloch et al.⁵⁰ more recently studied 46 TS children at follow-up after 7.6 years and reported 85% had a reduction in tics during adolescence, only increased tic severity in childhood was associated with increased tic severity at follow-up. The average age at worst tic severity was 10.6 years; however, worst ever OCD symptoms occurred approximately 2 years later than worst tic severity, and increased childhood intelligence quotient (IQ) was associated with increased OCD severity at follow-up. Thus, although the prognosis of TS is better than originally thought with regards to tic symptomatology, the course of associated psychopathology, such as OCD, may show greater persistence later on in the individual’s life. Finally, a follow-up study, using a rigorous design, reviewed TS patients’ (aged 8–14 years) assessments.⁵¹ Patients (n = 56) were filmed for 5 minutes originally between 1978 and 1991 according to a strict protocol. Thirty-six of these patients aged > 20 years were contacted again and 31 were included into the follow-up video study. A blinded video-rater assessed the 62 tapes and rated five tic domains; the two videotapes were compared for each tic domain as well as a composite tic disability score. Results showed that 90% of the adults still had tics and many adults who had suggested that they were tic free were incorrect, as no fewer than 50% had objective evidence (on video) of tics. The mean tic disability score reduced significantly with age. All tic domains improved with age and there were significant improvements (p = 0.008) for motor tics. The improvements in tic disability were not related to medication, as only 13% of adults received medication for tics, compared with 81% of children. The authors concluded that although tics improve with time, most adults have persistent, but mild, tics.⁵¹ Finally, in a recent study examining the effects of psychosocial stress predicting future symptoms in children with TS and/or OCD, advancing chronological age was robustly associated with reductions in tic severity.⁵²

The presence of comorbidities in a person with TS is associated with a worse prognosis. Rizzo et al.⁵³ investigated 100 TS patients who were assessed at onset and at then again at follow-up 10 years later to evaluate the severity of the tics, the presence of comorbidities and coexistent psychopathologies. In brief, they demonstrated that the comorbid conditions altered with increasing age and that those with the ‘Pure TS’ phenotype (38% at the original assessment) had the best long-term outcome. In contrast, those patients who presented at their original assessments with comorbidities (TS plus OCD, TS plus ADHD, TS plus ADHD plus OCD) had a poorer prognosis.

What is also important to understand is that in a person with TS who also has multiple comorbidities, the ASD typically begins first, then the ADHD, then the motor tics, then the vocal/phonic tics and then the OCB (which is usually present by the time of diagnosis), while the OCD usually develops later. The depression, anxiety, substance misuse and other coexistent psychopathologies usually emerge later and may well be a consequence as much of the comorbid disorders as of TS itself.

In summary, following onset of TS, tic symptomatology may get worse until early teens with subsequent improvement and although some tic symptoms usually remain into adult life, they usually do not impair the individual. Those with ‘TS-only’ (‘pure-tics’) have the best prognosis. The comorbidities (ASD, ADHD, OCD) and associated psychopathologies (e.g. depression) change with age and their impact many may well increase during adolescence.

Aetiological theories

The main aetiological candidates for TS include genetic influences, infections and perinatal difficulties. Originally, the aetiology of TS was considered to be psychological^54,55 but, in the 1980s and 1990s, large pedigrees with multiple affected family members were documented with tics or obsessive–compulsive symptomatology, suggesting a familial pattern and possible genetic origin. Subsequent investigations employing complex segregation analysis indicated that TS was inherited, consistent with a single major gene and autosomal dominant transmission, but with incomplete penetrance. However, much of the genome was subsequently excluded.^7,9 The Tourette Syndrome Association International Consortium for Genetics⁵⁶ using sib-pair analysis, undertook one of the first genome scans in TS, as well as the first Genome Wide Association Study (GWAS).⁵⁷ The genetic susceptibility in TS has been recently reviewed by Fernandez and State.²⁰ There are five essential findings/conclusions: (1) that the GWAS identified the COL27A1 gene as a possible contributing gene in a multiethnic cohort,⁵⁸ but the finding requires replication, (2) some rare variant studies have identified a mutation to the SLITRK1 gene,⁵⁹ but subsequent studies have been conflicting,⁶⁰ (3) linkage analysis of an individual outlier TS family identified a deleterious mutation in the histidine decarboxylase gene suggesting that histaminergic neurotransmission may be involved in the pathophysiology of TS,⁶¹ (4) pathway analysis of rare copy number variants has proven useful,²⁰ and (5) there seems to be a significant overlap of genes mapping within rare copy number variants in TS and those identified in ASD.^19,20

Neuroimmunological theories possibly operating via the process of molecular mimicry have become of interest in the aetiology of TS. Swedo et al.⁶² described a group of 50 children with OCD and tic disorders, designated as Paediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infection (PANDAS). The diagnostic criteria included presence of OCD and/or a tic disorder, pre-pubertal symptom onset (usually acute, dramatic), association with group A beta-haemolytic streptococcus (GABHS) infections, episodic course of symptom severity and association with neurological abnormalities. The relapsing, remitting course was associated with significant psychopathology including emotional liability, separation anxiety, night-time fears, bedtime rituals, cognitive deficits, oppositional behaviours and hyperactivity.

Other centres have found laboratory evidence of GABHS infections in some patients with TS, and/or documenting that some TS patients have increased antibasal ganglia antibodies in cohort studies⁶³ and controlled studies.^63–69 As most researchers have findings that supported a role of GABHS and basal ganglia autoimmunity in a subgroup of TS patients, it was suggested that further research was needed to clarify the phenomenology associated with antibasal ganglia antibodies.⁷⁰ The majority of studies have indicated a role of GABHS infections in TS, but there is a dissenting view predominantly from one laboratory.⁷¹ Clearly, streptococcus does not cause TS, but it may well be that individuals inherit a susceptibility to TS and to the way they react to some infections, including GABHS infections. The above theory has now expanded into broadly two theories: (1) a lowered immunity and (2) autoimmunity.⁹

Murphy⁷² reviewed the literature on the role of infections in the aetiopathogenesis of tic disorders including TS and notes that many infectious agents have been suggested including not only GABHS but also Mycoplasma pneumoniae, other respiratory infections and, indeed, the common cold, have been linked to the exacerbation of both OCD and tic symptomatology. Lyme disease, a complex multisystemic illness, is the most common vector-borne disease in the USA and is caused by bacterial spirochete Borrelia.⁷³ Lyme disease has been reported as presenting as TS;⁷⁴ in the UK,⁷⁵ it is spread to humans by infected ticks and named after the city of Lyme in Connecticut. If the tick bites an infected animal, the tick becomes infected and can pass the disease to humans; most bites occur in late spring and early summer and it is estimated that there are 3000 new cases in UK per year.⁷⁶ Thus, there are more than one infectious agent thought to be involved in the aetiopathology of TS, none of which cause TS, but may trigger tics in an already vulnerable individual via mechanisms of lowered immunity or autoimmunity.

Leckman⁷⁷ outlined the potential role of pre-natal and perinatal events in the pathogenesis of TS. The first study in the area was a controlled study⁷⁸ embracing a large sample size and the use of obstetric hospital records, which demonstrated that the mothers of children with tics were 1.5 times as likely to have experienced a complication during pregnancy than the mothers of children who did not have tics. Two studies showed that among monozygotic twins discordant for TS, the twins with TS always had lower birthweights than their unaffected twins. Leckman’s own group demonstrated that the severity of maternal life stress during pregnancy, severe nausea and/or vomiting during the first trimester are risk factors for developing tic disorders. A second controlled study⁷⁹ demonstrated that TS patients have had more pre-natal and perinatal difficulties than a control group. Several groups have now shown that maternal smoking of cigarettes during pregnancy can produce more severe TS in the child.⁸⁰ More recently, both smoking and psychosocial stressors during pregnancy have been implicated in altering the TS phenotype.⁵² In addition to the factors mentioned above, other perinatal risk factors for TS in the child include older paternal age, more and earlier prenatal care visits, delivery complications, premature low birthweight children as well as those with low Apgar scores at 5 minutes after birth.^77,81 Maternal smoking during pregnancy and low birthweight are risk factors for the presence of comorbid ADHD.⁸¹ Older paternal age, maternal use of caffeine, cigarettes or alcohol during pregnancy and forceps delivery are risk factors for the presence of comorbid OCD.⁸¹ These perinatal factors appear to also non-specifically increase the risk of a range of neurodevelopmental disorders including TS, ADHD and ASD.

In summary, the aetiopathology of TS is more complex than previously recognised, with genetic risk potentially interacting with some infections and pre-natal and perinatal difficulties to affect the susceptibility to tics and phenotype of TS.

Cognitive functioning in Tourette syndrome

The neuropsychological assessment and functioning in TS has been recently reviewed by Murphy and Eddy.⁸² The results of neuropsychological studies are, on the whole, inconsistent; more difficulties are demonstrated in child rather than adult populations; those with ‘Pure TS’ (tics only) show no evidence of global impairment of intellectual function and any difficulties (especially in adults) are mild and likely to consist of subtle decrements in attention or inhibitory processing; and patients with TS seem likely to have changes in social cognition. In addition, those with TS plus OCD may have a higher IQ, while those with TS plus ADHD have a lower IQ and many of the neuropsychological difficulties are associated with the presence of ADHD.⁸² This ‘ADHD effect’ is also seen with more behavioural difficulties in both youngsters (aged 7–18 years)³⁰ and adults³² and those with lower QoL, all of which have been mentioned above.^7,9,36

On the other hand, there may be some cognitive advantages in having TS. There has been some evidence that children with ‘pure TS’ (tics only) may have some enhanced aspects of executive function, possibly as a compensatory mechanism resulting from habitual tic suppression.⁸³ In addition, Jackson et al.⁸⁴ employed a manual switching task that created high levels of interhemispheric conflict in a study with those with ‘Pure TS’ and control subjects, and results indicated that the TS subjects showed faster reaction times than controls.

Neurobiology and neuroimaging

There have been many studies and reviews and these give evidence that those with TS may have the following abnormalities: (1) basal ganglia and corticostriatal thalamic circuitry dysfunction, (2) a reduction in caudate nucleus volume, with a negative correlation between caudate nucleus volume in childhood and tic severity in later in life, (3) thinning of the sensory–motor cortices in both children and adults with TS, with a negative correlation between thickness and orofacial tic severity, (4) adults with TS show cortical thinning and reduced grey matter in pre-frontal areas (suggesting a failure in neural compensation to control the tics into adulthood, (5) the supplementary motor area may be involved in the premonitory urges/premonitory symptoms as shown by functional magnetic resonance imaging, (6) white matter measurements have shown larger volumes and reduced fractional anisotropy in the corpus callosum in TS, (7) putative cognitive control networks in TS are functionally immature and anomalous, and (8) changes in the volume of the dorsolateral pre-frontal cortex. Apart from the suggestions given above, quite how the changes affect brain function are unclear.^85,86