Tourette syndrome and other neurodevelopmental disorders: a comprehensive review

According to the DSM-5 classification, Gilles de la Tourette syndrome (TS) is a developmental neuropsychiatric disorder characterised by multiple motor and one or more phonic tics, lasting at least 1 year, with onset during childhood or adolescence [1]. A tic is a brief, sudden movement or sound that occurs in an inappropriate context and frequency. The distinguishing characteristics of tic include variability in severity with a waxing and waning course and suppressibility and presence of an anticipatory uncomfortable sensory sensation called a premonitory urge.

Although initially considered to be rare, TS is more common than previously expected, with a suggested overall prevalence of 1/200 in children. TS is reported worldwide in all cultures and is more common in males than females (M/F ratio ranging from 1.6:1 to 9:1) [2, 3]. The aetiopathogenesis of TS is still unclear and more complex than previously perceived, and it involves environmental (infections, perinatal problems, and autoimmunity) and genetic factors that result in a dysfunction of cortico-striato-thalamo-cortical-circuits [4‐8].

Comorbidities and coexistent pathologies in TS are also common. Hirschtritt et al. in a large clinical based study, analysed 1374 TS patients and found a lifetime prevalence of any psychiatric comorbidity among 85.7% and that 57.7% of the patients involved at least 2 psychiatric disorders [9]. Moreover, recent factor analysis studies have suggested that TS is not a unitary condition but can be subdivided into more homogeneous components that, similar in phenotype, are suitably share the same genetic background [10, 11]. Because TS comorbidities provide a better understanding of the syndrome not only in terms of classification and aetiopathogenesis but also in terms of outcome, comorbidities are one of the main factors contributing to the psychological and psychosocial impairment observed in TS, often more than the severity of tics [12].

In the DSM-5, TS belongs to the “neurodevelopmental disorders” group, together with intellectual disabilities, communication disorder, autism spectrum disorder, attention deficit hyperactivity disorder, and specific learning disorder. This group includes conditions that co-occur frequently, typically in the early stages of development, and produce deficits in social, personal, academic and occupational functioning [1]. As evidenced by recent literature, TS shares a similar genetic background and risk factors with other neurodevelopmental disorders, that eventually produce similar neuropathological alterations [13, 14]. In particular, recent studies have found similar connectivity alterations among ASD, ADHD and TS patients [6, 15]. Considering all of these findings, the purpose of this article was to provide an extensive review on comorbidity in TS and other neuro-developmental disorders.

A Medline (PubMed version) search was performed using the following keywords: Tourette and attention deficit hyperactivity disorder (ADHD) or autism or pervasive developmental disorder or Asperger syndrome or learning disorder or Dyslexia or Dysgraphia or Dysorthographia or Dyscalculia or communication disorders or developmental coordination disorder. We included studies and reviews published in English between 1965 and February 2017. We screened all identified studies or reviews by reading the titles and the abstracts. The inclusion criteria for articles were as follows: the analysis of comorbidity between TS and ADHD/autism (ASD)/learning disorders (LD), in term of prevalence, clinical characteristics and prognosis, resulting from cohorts of TS clinical ascertained samples and population-based studies. Duplicate studies were excluded. To identify any potential study missed by our literature research, we applied, as our second step, a cross-referencing search within retained articles. The initial search sorted out 1633 references. After excluding duplicates, the number was reduced to 1009 reports. Comorbidities between TS and communication disorders or developmental coordination disorder were not analysed due to the lack of detailed literature. In total, 36 papers that fulfilled the study criteria were retained. A PRISMA diagram flow-chart, presented in Fig. 1, summarises the literature selection process and details the primary cause of exclusion. For ease of presentation, we distinguish general population studies (N = 5) and comorbidities in TS clinical-based studies (N = 27) with a specific focus on TS and ASD co-occurrence (N = 6).

A peculiar feature of TS, which is now classified among the DSM-5 neurodevelopmental disorders, is represented by the frequent association with different comorbidities occurring in the majority of patients. In this paper, we reviewed the literature on comorbidity between TS and other DSM-5 neurodevelopmental disorders, focussing on ADHD, autism spectrum disorders and learning disabilities. Communication disorders and developmental coordination disorders were not included in this review because the scientific literature on this topic is still lacking. The available evidence suggests that neurodevelopmental comorbidities in TS are the rule rather than the exception. The high rate of neurodevelopmental comorbidities is found in general population studies as well as in clinical sample studies (Tables 2, 3). Among these neurodevelopmental comorbidities, ADHD is by far the most frequent. Considering the literature analysed, ADHD is one of the main determinants in terms of quality of life, psychosocial and psychological outcome. We found only few studies in which the abovementioned association distinguished the various ADHD subtypes. These studies demonstrated high rates of association with the combined and prevalent inattentive subtypes. Although we are aware that searches on TS and ASD as well as TS and LD produced few publications, they confirm an association between these disorders and support the idea of a continuum between simple TS without neurodevelopmental comorbidities and more complexes phenotypes (TS + ADHD + LD and TS + ASD). Other limitations of this review are the small number of studies or samples regarding several neurodevelopmental comorbidities (e.g., ASD) and the frequent lack of adequate diagnostic instruments for assessing patients and defining comorbidities. In particular, a further bias caused by the different quality of the studies evaluated, could lie in the absence of specific assessments performed by clinicians expert in the field, thus resulting in a possible overestimation of the rates of comorbidities, such LD and ASD [46]. Moreover, we are aware that the variability of the age of the populations investigated is a factor affecting the prevalence rate. However, the current results favour the inclusion of TS among neurodevelopmental disorders as a DSM-5 group of conditions. The inclusion criteria were based on prevalence, clinical characteristics and prognosis. Interestingly, TS not only co-occurs often with other neurodevelopmental disorders, but it is also likely linked through common genetic background and common risk factors, as evidenced by the recent literature [11, 13, 14, 47, 48]. Figure 2 provides a graphical representation of this spectrum of neurodevelopmental comorbidities based on the data obtained in TS clinical samples and according to frequency and age of onset. In this sense, it appears advisable to explore clusters of neurodevelopmental problems rather than screen them separately. This is consistent with the concept of “ESSENCE” (early symptomatic syndromes eliciting neurodevelopmental clinical examinations), a term coined by Gillberg to refer to children with major difficulties in one or more of the following fields: general development, communication and language, social inter-relatedness, motor coordination, attention, activity, behaviour, mood, and sleep [49].

From an empirical research perspective, additional studies that specifically address the comorbidity between TS and other neurodevelopmental disorders, use appropriate assessment instruments and design and do not neglect certain areas are warranted. First, studies evaluating the co-occurrence of all neurodevelopmental disorders as classified in DSM-5 (thus also including developmental coordination disorder, communication disorders and intellectual disabilities) in the same TS patients’ sample and in a developmental perspective are needed. Second, additional studies should address ADHD for a better characterization of comorbid ADHD into different subtypes. Similarly, subtypes of LD should be determined, using objective neuropsychological assessment of both attention and executive functions or specific learning investigations, such as literacy or calculation assessments. Third, from the literature analysed, it appears that most patients with ASD found in TS samples correspond to patients previously classified in DSM-IV as PDD-NOS or to patients affected by MCDD (multiple complex developmental disorder), a term proposed by Cohen et al. in 1986 [50] to refer to a group of children with atypical development. In this sense, more detailed studies focussing on comorbid ASD using developmental and dimensional perspectives are recommended.

In conclusion, a prompt diagnosis of comorbidities in TS patients and a characterisation of them in a more comprehensive approach are important not only to understand the aetiological basis of neurodevelopmental disorders but also, as clinical relevance, for a prompt definition of rehabilitative and therapeutic approaches. These include pharmacotherapy [51, 52] and, equally importantly, cognitive-behavioural therapy and social interventions [53].