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Abstract
Background Recent studies using quantitative methods, such as principal component factor analysis, hierarchical cluster analysis and latent class analysis have suggested that Gilles de la Tourette syndrome (GTS) should no longer be considered a unitary condition as in current classification systems.
Objective To identify quantitative components of GTS symptomatology using a large, well characterised cohort of singleton individuals with GTS in order to inform future genetic studies with more homogeneous phenotypes.
Methods Principal component factor analysis with oblique rotation was used to analyse symptom data from a sample of 639 patients recruited at two tertiary referral centres using identical schedules during the period 1980–2008.
Results Three Factors were identified: (1) complex motor tics and echo-paliphenomena; (2) attention deficit and hyperactivity symptoms plus aggressive behaviours; and (3) complex vocal tics and coprophenomena. Obsessive compulsive behaviours loaded significantly on the first two factors. The three factors accounted for 48.5% of the total symptomatic variance.
Conclusions GTS is a phenotypically heterogeneous condition encompassing simple tics, specific complex tics and associated behavioural problems. The results, coupled with previous findings, identified a clinical continuum of complex tics, hyperactivity/impulsivity symptoms and semantically relevant utterances and gestures. A better characterisation of the GTS phenotypes will help to identify susceptibility genes.
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Introduction
Gilles de la Tourette syndrome (GTS) is a neurodevelopmental disorder characterised by the presence of multiple motor tics and one or more vocal/phonic tics.1 Studies conducted both in the community and in clinical settings have consistently shown that up to 90% of patients with GTS present with associated behavioural problems, which can have a significant impact on the health related quality of life of sufferers.2 3 Specific complex tics which are commonly reported include coprolalia (inappropriate swearing), copropraxia (inappropriate making of obscene gestures), echophenomena (the imitation of other people's words or actions), palilalia (the repetition of the same words), self-injurious behaviours (SIB) and other socially inappropriate behaviours. Moreover, a substantial proportion of patients fulfil diagnostic criteria for comorbid psychiatric disorders, including attention deficit hyperactivity disorder (ADHD), obsessive–compulsive disorder (OCD), depression, oppositional defiant disorder, conduct disorder and impulse dyscontrol.1
The complexity of the clinical picture of GTS has prompted a new conceptualisation of GTS encompassing its behavioural spectrum.2 The co-occurrence of both tics and specific complex tics has been referred to as ‘full blown GTS’ whereas the term ‘GTS plus’ was coined to describe patients presenting with comorbid psychiatric disorders.1 Moreover, aetiological heterogeneity has been advocated for GTS, including genetic influences, post-infection autoimmune processes and pre/perinatal difficulties.1 2 While the mode of inheritance is not simple, GTS has a significant genetic basis and different phenotypes could manifest variant expressions of the same genetic susceptibility factors.2
In this study we set out to examine the validity of the multilayered model of the GTS spectrum using principal component factor analysis on a large cohort of patients diagnosed with GTS.
Methods
Two of the authors (AEC and MBY) reviewed the clinical files of 654 patients attending two specialist Tourette Clinics located in London (National Hospital for Neurology and Neurosurgery (n=516) and St George's Hospital (n=138)) over a 28 year period (1980–2008). All adult patients gave written informed consent and parents gave consent for their children prior to enrolment in the study, for which ethics approval was granted by the local committee, via the Central Office for Research Ethics Committees protocol or its predecessors, at both sites.
Each subject underwent a comprehensive clinical assessment using the National Hospital Interview Schedule (NHIS)4 for GTS or its preliminary versions. The NHIS is a detailed semi-structured interview schedule which covers personal and family histories and demographic details. For the diagnosis of various GTS associated psychiatric disorders, such as OCD and ADHD, the NHIS was originally developed by incorporating the relevant questions and items from the Diagnostic Interview Schedule and WHO criteria to yield a diagnosis as per DSM-III-R and ICD-10, and was subsequently updated based on the DSM-IV-TR criteria.
As other schedules were devised and published, these were added to the assessment schedule. Thus the Diagnostic Confidence Index5 was used to rate the clinician's confidence in diagnosing GTS, according to the clinical characteristics of the tics (eg, waxing and waning course, presence of premonitory urges and tic suppressibility) and the presence of specific complex tics, including coprolalia, echopraxia, echolalia and palilalia. In addition, the severity of tic symptoms was assessed using the Yale Global Tic Severity Scale.6
For the current study, a principal component factor analytic technique was then applied to detect structure in the relationship among GTS symptoms.7 After factor analysis, an oblique rotation method was used to obtain a clear pattern of loadings.8 Finally, an absolute value of 0.400 was used as a threshold for the interpretation of factor loadings, as required by our group size.
All the instruments used were clinician rated and we deliberately chose to include in the factor analysis only the variables which were collected in a standardised fashion and for which there were no missing data. Data analyses were carried out using the Statistical Package for Social Sciences (V.16.0 for Windows, SPSS Inc) and Microsoft Excel 2003.
Results
Of the 654 subjects, three were not enrolled because informed consent was not explicit within the patient notes and related paperwork and 12 were excluded from the analysis because they fulfilled diagnostic criteria for tic disorders other than GTS. The resulting clinical sample consisted of 639 patients (mean age 26.1±13.2 years; 70.1% male) with a clinical diagnosis of GTS (Diagnostic Confidence Index score 62.2±18.4). Mean age at tic onset was 7.2±4.0 years while disease duration was 18.7±12.5 years. Tic severity ratings were consistent with moderate to severe symptoms (Yale Global Tic Severity Scale score 46.1±22.3) and 75.7% of patients had a positive family history for tics.
Of note, only 10.6% of the subjects who were interviewed presented with GTS only. With regards to specific complex tics (‘full blown GTS’), 30.4% of patients had coprolalia, 21.1% copropraxia, 43.0% echolalia, 36.9% echopraxia and 31.7% palilalia, while SIB of different severity were reported by 46.1% of patients. With regards to associated psychiatric conditions (‘GTS plus’), 36.4% of patients were diagnosed with comorbid OCD, 66.6% with comorbid ADHD and 36.1% fulfilled diagnostic criteria for affective disorders.
Three significant factors resulted from the principal component factor analysis, accounting for 48.5% of the symptomatic variance (see table 1).
Oblique three factor solution for 12 GTS symptoms in 639 patients
Factor 1 (‘complex motor tics and echo-paliphenomena’) consisted predominantly of complex movements (tics involving more than one muscular group, including whole body movements such as jumping, squatting and twisting) plus specific complex tics involving mimicking and repeating. Factor 2 (‘ADHD symptoms and aggressive behaviours’) was characterised primarily by attention deficit and hyperactivity/impulsivity symptoms, plus aggressive behaviours (temper dyscontrol resulting in destruction of property, verbal and/or physical abuse) towards others and self (SIB). Of note, OCD symptoms (predominantly checking, touching, arithmomania and concerns for symmetry) loaded significantly on both factors 1 (0.452) and 2 (0.482). Finally, the third factor (‘complex vocal tics and coprophenomena’) was characterised by the production of words or partial words, including talking to oneself and barely audible muttering, plus inappropriate swearing and making rude gestures, sharing a semantic component.
Discussion
Over the past few years, studies using different statistical techniques8–14 have consistently suggested that GTS is not a unitary condition as it has been thought since its first description by Georges Gilles de la Tourette in 1884 (table 2).
Studies on symptom factors/clusters in GTS
We tested this hypothesis using principal component factor analysis in a clinical sample of 639 subjects with GTS spanning three decades. Since the aim of this study was the investigation of the GTS spectrum, we focused on the relationship between GTS and GTS associated behavioural symptoms, rather than on the phenomenology of the specific motor and phonic tics. The characteristics of our sample were in accord with published data from studies conducted in clinical settings, including the high prevalence of specific complex tics and behavioural problems.1 2 In particular, we have confirmed that GTS without comorbidities occurs in only 10% of individuals and GTS is not a unitary condition.
In addition, our results confirmed previous findings suggesting intrinsic symptom associations or shared genetic vulnerability within the GTS spectrum. Our results support the hypothesis that GTS should be considered a phenotypically heterogeneous entity, with a predominantly motor component ranging from complex motor tics to echo/paliphenomena (factor 1), a separate hyperactivity/impulsivity/aggressiveness cluster (factor 2) and a continuum of semantically relevant symptoms, including complex vocal tics and coprophenomena (factor 3). Specifically, this study provides empirical support for the heretofore primarily historical requirement that GTS patients with complex vocal tics (factor 3) accompanying their motor tics have a different condition than those without. Another nosologically important finding is that ADHD and aggressive symptoms can be separated from the defining features of GTS. Interestingly, factor 2 partially overlaps with the ‘ADHD aggressive behaviours’ factor obtained in a large GTS pedigree study.8 Finally, it appears that although OCD is not the same as GTS, it cannot be easily removed from core features of GTS. The associations of OCD symptoms with both complex motor tics12 and SIB8 have been replicated in our analysis but future studies are needed to investigate repetitive behaviours and OCD symptoms in the context of GTS.15 Likewise, specific complex tics such as echolalia and copropraxia load on different factors to other complex vocal tics and complex motor tics, respectively, thus prompting further investigation for the nosografic dissection of these symptoms.
One of the main limitation of previous studies was the statistical power: our factor analysis was conducted on a large heterogeneous GTS cohort, allowing a subject:variable ratio of 53. Moreover, in most studies the percentage of variance explained by the statistical model was inferior to the present value of 48.5%, which suggests that about half of the phenotypic variance could be attributable to environmental factors.8 10 14 However, the present study also has limitations. Firstly, referral bias needs to be taken into account as the patient cohorts were recruited at tertiary referral centres and may therefore not be representative of the community population of people with GTS. For instance, in a large community based study of 4479 children, the mean age at onset of GTS was 4.6 years (SD 2.9 years), and comorbid ADHD/learning disability was present in 56% of GTS cases, OCD/anxiety disorder in 32% and depressive disorders in 24%.16 Likewise, our cohort is not representative of all tic disorders but only of the GTS cases seen in specialist clinics: this is in line with the aim of the present study which was to investigate the relationship between the different symptoms of the behavioural spectrum of GTS. Secondly, different clinicians assessed the patients across three decades, thus possibly introducing inter-rater reliability issues, although they were all experts in GTS, were all supervised by the senior author of the present paper (MMR) and used the same clinician rated instruments. A further limitation of this study is intrinsic to its retrospective approach.
Data from a recent neuroimaging study support the hypothesis that different symptom dimensions in GTS are associated with dysfunction of distinct cortical areas and have clear implications for the current neuroanatomical model of this syndrome.17 We believe that our results should inform future genetic studies aiming at a better characterisation of phenotype/genotype correlations within the GTS spectrum. Novel findings like the recent identification of a large kindred with monogenic Tourette syndrome highlight the relevance of phenotype analytical studies.18 Future studies should focus on characterising clinical phenotypes of patients with and without complex tics, and patients whose clinical course features predominantly complex tics.
Acknowledgments
The authors thank all participants for their time and effort.
References
Footnotes
Funding Gratitude is expressed to Tourettes Action-UK for their financial support with a grant awarded to MMR specifically to undertake the study.
Competing interests None.
Ethics approval This study was conducted with the approval of COREC.
Provenance and peer review Not commissioned; externally peer reviewed.