Brain, Vol. 123, No. 3, 425-462,
March 2000
© 2000 Oxford University Press
Invited review |
Tourette syndrome, associated conditions and the complexities of treatment
Department of Psychiatry and Behavioural Sciences, University College and The National Hospital for Neurology and Neurosurgery, London, UK
Correspondence to:
Professor Mary M. Robertson, Department of Psychiatry and Behavioural Sciences, University College London, 2nd Floor, Wolfson Building, 48 Riding House Street, London W1N 8AA, UK E-mail: rejummr{at}ucl.ac.uk
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Abstract |
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 Top Abstract IntroductionHistory, prevalence and...Clinical characteristics and...Aetiological aspectsCourse and prognosisManagement of TSConclusionsReferences |
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Tourette syndrome (TS) is characterized by multiple motor tics plus one or more vocal (phonic) tics, which characteristically wax and wane. It can no longer be considered the rare and bizarre syndrome that it was once thought to be. The concepts surrounding TS, and our understanding of it, are also becoming increasingly complex and, in some individuals, TS is now recognized to be associated with a wide variety of associated behaviours and psychopathologies. It is suggested that TS is heterogeneous from a variety of standpoints including clinical presentation and psychopathology, and thus neuropharmacological responses and possibly even aetiological and genetic mechanisms. In this paper, mention is made of recent findings in epidemiology and genetics, highlighting the complexities of the disorder; these have been chosen because findings in both areas have clinical and management implications. The literature on the clinical manifestations, associated behaviours, psychopathology (and/or comorbid conditions) and management, in particular, is reviewed in detail.
Tourette syndrome; clinical phenomenology; psychopathology; treatment
ADHD = attention deficit hyperactivity disorder; BNF = British National Formulary; CCEI = Crown Crisp Experimental Index; DBT = double-blind trial; DSMs = Diagnostic and Statistical Manuals; EPSE = extrapyramidal side-effect; GAD = generalized anxiety disorder; 5-HT = 5-hydroxytryptamine; MDD = major depressive disorder; NMS = neuroleptic malignant syndrome; NOSI = non-obscene complex socially inappropriate behaviours; OCB = obsessive–compulsive behaviour; OCD = obsessive–compulsive disorder; OCS = obsessive–compulsive symptoms; PANDAS = paediatric autoimmune neuropsychiatric disorders associated with group A ß-haemolytic streptococcal infections; SIB = self-injurious behaviour; SSRI = selective serotonin reuptake inhibitor; TCA = tricyclic antidepressant; TD = tardive dyskinesia; TS = Tourette syndrome; YGTSS = Yale Global Tic Severity Scale
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Introduction |
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TopAbstractIntroductionHistory, prevalence and...Clinical characteristics and...Aetiological aspectsCourse and prognosisManagement of TSConclusionsReferences |
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Tourette syndrome (TS) used to be considered rare (see Robertson 1989, 1994), with, for many years, case reports being the only documentations in the medical literature. Recently, the literature on TS has mushroomed, with substantial cohorts of TS patients and scientifically rigorous investigations being commonly described. It used to be thought that the clinical phenomenology of TS was fairly simple and standard, e.g. as defined by the Diagnostic and Statistical Manuals (DSMs) criteria (American Psychiatric Association, 1980
, 1987, 1994), but it is now recognized that TS is far from simple. There is no doubt that TS is genetic, but the precise inheritance pattern is as yet unclear. Comorbid conditions, associated behaviours and psychopathologies are increasingly being described, but it is unclear whether or not they all represent the `genetic' expression of the TS gene(s). Recent epidemiological studies also indicate that TS is no longer rare; but is the mild phenotype being described in family and population studies merely a forme fruste of that seen in TS clinics? In addition, apart from the inherited genetic vulnerability to TS, it has also been suggested that perinatal insults (e.g. birth injuries) and more recently (and somewhat speculatively) infections with streptococci or viruses may affect the expression of TS; clearly this has both aetiological and treatment implications. A MEDLINE search performed in August 1998, covering the period since January 1997, using `Tourette' as the title keyword, identified 108 articles; as many as 31, however, were reviews of the literature. With this in mind it was decided that this review should be very specific and the review will therefore concentrate on the clinical presentation, comorbid clinical conditions and psychopathology, and then focus, in particular, on the complexities of treatment of TS.
The clinical presentation of TS will be dealt with in detail and the effects of stress on TS will also be discussed. The more common comorbid conditions such as attention deficit hyperactivity disorder (ADHD), obsessive–compulsive behaviours (OCB), self-injurious behaviours (SIBs), anxiety, depression and personality disorder will be examined. Comments will be made on the less common, but also important, aspects, such as oppositional defiant disorder, conduct disorder, aggression, learning difficulties, rage and autism. The main focus of the paper will then be on the complexities of management which have evolved alongside the recognition of the clinical complexities.
For recent reviews about other aspects the readers are referred to the following articles: genetics (Patel, 1996; Alsobrook and Pauls, 1997); epidemiology (Staley et al., 1997; Tanner and Goldman, 1997); phenomenology and classification of tics (Jankovic, 1997); neurobiology (Baker et al., 1995; Singer, 1997); social and educational resources (Packer, 1997); reviews of instruments used to measure aspects of TS (Kompoliti and Goetz, 1997); neuropsychology (Como, 1997); autism and pervasive developmental disorders (Stern and Robertson, 1997); secondary tic disorders (Kumar and Lang, 1997); structural (Robertson, 1998) and functional (Buitelaar et al., 1998) neuroimaging; and recent articles highlighting mainly current findings (Robertson and Stern, 1997, 1998).
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History, prevalence and epidemiology |
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TopAbstractIntroductionHistory, prevalence and...Clinical characteristics and...Aetiological aspectsCourse and prognosisManagement of TSConclusionsReferences |
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The first case of TS, the Marquise de Dampierre, was documented by Itard (Itard, 1825
) and later by Georges Gilles de la Tourette (Gilles de la Tourette, 1885). There have been translations of some of these early case reports (e.g. Goetz and Klawans, 1982; Robertson and Reinstein, 1991) and ideas (Kushner et al., 1999), but the recent and scholarly exposition of the history of TS (Kushner, 1999) is recommended for anyone interested in either TS or indeed the history of neuropsychiatry.
Originally, TS was thought to be very rare. The generally accepted prevalence figure for TS has for some time been 0.5 per 1000 (5 per 10 000) (Bruun, 1984). A careful population-based epidemiological study that systematically screened for the presence of TS among Israeli armed forces personnel reported an overall prevalence estimate of 4.28 per 10 000 (Apter et al., 1992, 1993). Another recent, substantial, multistage epidemiological study reported TS in 0.1% of 4500 randomly selected children (aged 9, 11 and 13 years) in south-eastern USA (Costello et al., 1996). A more recent study was undertaken by Mason and colleagues (Mason et al., 1998) who examined all year 9 pupils (aged 13 and 14 years) in a randomly selected regular mainstream secondary school in West Essex, UK, in a two-stage procedure. Standardized questionnaires were completed by parents, teachers and pupils. Classroom observations were also employed to identify tics. Those pupils identified as having tics underwent a semi-structured interview, using a shortened version of the National Hospital Interview Schedule (Robertson and Eapen, 1996), by a research psychologist. Five out of 166 pupils (2.9%) satisfied DSM-III-R criteria for TS (three definite, two probable). Of importance is that only one showed no evidence at all of any hyperactivity, depression, emotional disorder or conduct disorder; four of the five were hyperactive (one satisfied DSM-IV criteria for ADHD). The Yale Global Tic Severity Scale (YGTSS) (Leckman et al., 1989) scores did, however, indicate mild TS in all subjects. Tic-possible children (30 out of 166, 18%) in the same study were also evaluated. The prevalence of psychopathology such as depression, OCB and ADHD were no different in tic possibles when compared with the total school population; teachers, however, did rate them as having more emotional and conduct disorders (Mason et al., 1998). The study, resulting in such a high prevalence, was criticized (Traverse, 1998), but was well defended and justified by the original authors (Banerjee et al., 1998). Interestingly, however, Traverse did suggest that in his own personal experience there has been an increase in the prevalence of TS over the last 12 years (Traverse, 1998). Banerjee and colleagues pointed out in particular that the lower figures documented before (e.g. Lucas et al., 1982) had relied on TS cases admitted to hospital (the Mayo clinic) (Banerjee et al., 1998). In the author's experience in community research settings, the number of TS cases seen by a doctor are very few (eight out of 50; Robertson and Gourdie, 1990).
In studies in children with special educational needs in particular, the prevalence of TS has been demonstrated to be very high. Thus, Comings and colleagues working in a southern Californian school district, screened 3034 pupils referred for psycho-educational assessment from three schools over a 2-year period; they estimated that 12% of all children in special education classes had TS and that 28% fell within a broader tic diagnostic category (Comings et al., 1990). Kurlan and colleagues directly examined 35 children from special education classes and 35 regular classroom children in Monroe County, New York, for the presence of tics (Kurlan et al., 1994a). Of the special education students, nine (26%) had definite or probable tics, while two (6%) of the regular school children had tics; about one-third of those with tics met diagnostic criteria for TS. Eapen and colleagues directly examined children from schools in West Essex, UK. They studied 20 children from a residential school for emotional and behavioural difficulties, 27 from a residential school for children with learning difficulties, 17 `problem' children and 19 normal children from a mainstream school. Of the students with emotional and behavioural difficulties, 65% were judged to have tics, compared with 24% of students with learning difficulties (P < 0.05), 6% of problem children (P < 0.003) and none of the normal children (P < 0.006); most of the affected students met diagnostic criteria for TS (Eapen et al., 1997a).
To complement these recent findings, a retrospective study examining other factors in 138 children with TS found that 64 (46%) experienced a school-related problem. Regression analysis of subjects without a diagnosis of learning disability revealed that the presence of ADHD served as a significant predictor of school problems (Abwender et al., 1996).
Thus, it seems that TS is more common than was previously estimated; it is more common in children, especially in those with special educational needs; and in mainstream children TS is generally mild, but may well even then be associated with hyperactivity or, in some cases, ADHD.
TS is found in all cultures, countries and racial groups and is three to four times more common in males (Robertson, 1989, 1994; Staley et al., 1997; Tanner and Goldman, 1997; Robertson and Baron-Cohen, 1998). TS is found in all social classes, although some studies suggest that TS patients may well underachieve socially (Robertson et al., 1988; Sandor et al., 1990).
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Clinical characteristics and complexities |
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TopAbstractIntroductionHistory, prevalence and...Clinical characteristics and...Aetiological aspectsCourse and prognosisManagement of TSConclusionsReferences |
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It has been pointed out that TS is difficult to investigate as the syndrome has no definitive `gold standard'. There is no hallmark imaging abnormality, no neuropathological lesion at post-mortem and no genetic test yet to aid symptom based clinical diagnosis (e.g. Tanner and Goldman, 1997).
TS is characterized by both multiple motor and one or more phonic tics which occur many times a day in bouts; the number, frequency and complexity of the tics change over time and they are present for at least 1 year (World Health Organization, 1992; American Psychiatric Association, 1994). The DSM-IV criteria have, however, been criticized (Comings, 1995; Freeman et al., 1995; Erenberg and Fahn, 1996; Kurlan, 1997b) as, in brief, DSM-IV criteria stipulate, amongst other things, the presence of significant impairment and personal distress, which is clearly not evident in non-clinic studies (e.g. epidemiological and school populations and/or family members in genetic studies).
The main characteristics of TS appear to be independent of culture and, by and large, symptoms are similar worldwide (Robertson, 1994; Staley et al., 1997; Tanner and Goldman, 1997). Motor and phonic tics are the hallmark of TS; Jankovic makes the point that the term phonic tic is preferred to vocal tic, as not all abnormal sounds and noises in TS are produced by the vocal cords (Jankovic, 1997). It is important to note that symptoms fluctuate in severity and change character within the same person; this variability of expression may contribute to diagnostic confusion and misdiagnosis (Jankovic, 1997). Jankovic elegantly describes the intimate phenomenology of tics showing how most tics encountered in TS are semi-voluntary (unvoluntary) or involuntary (suppressible). Jankovic also suggests that the characteristics of tics are such that premonitory feelings or sensations precede the tic, they are temporarily suppressible, they are suggestible, they increase with stress but also increase with the relaxation after stress, they decrease with distraction and concentration, they wax and wane with transient remissions and they persist during sleep (Jankovic, 1997).
The age of onset of TS symptoms ranges from 2 to 21 years, with a mean of 7 years being commonly reported, and symptoms usually begin with motor tics. The onset of phonic tics is later, with a mean age of onset of 11 years. Patients also often demonstrate a variety of complicated movements including touching, licking, spitting, jumping, smelling, squatting, abnormalities of gait and forced touching (Robertson, 1994; Staley et al., 1997). Premonitory feelings or `sensory' experiences, which are distinct from the actual motor or phonic tics and precede the tics, occur in over 80% of TS patients (Cohen and Leckman, 1992; Leckman et al., 1993). Tics may be abrupt in onset, fast and brief (clonic tics) or may be slow and sustained (dystonic or tonic tics) (Jankovic, 1997). Dystonic tics are more likely to be associated with premonitory sensations (Jankovic, 1997).
Coprolalia (inappropriate involuntary uttering of obscenities) occurs in less than one-third of clinic TS patients, but in few children or mild cases (Robertson, 1994), and it usually manifests itself by 15 years of age. There is some suggestion that it may be culturally determined as only 4% have true coprolalia in Japan (Nomura and Segawa, 1982) and some countries show higher figures than in USA or Europe (Staley et al., 1997). Copropraxia (involuntary inappropriate obscene gestures), echolalia (imitation of sounds or words of others), echopraxia (imitation of actions of others) and palilalia (repetition of the last word, phrase or last syllable of a word uttered by the patient) occur in a substantial proportion of TS clinic patients. Whilst these clinical features are not essential to make the diagnosis, their presence would strengthen the clinician's diagnostic confidence (Robertson, 1994).
Non-obscene complex socially inappropriate behaviours (NOSI) (Kurlan et al., 1996) and `disinhibition behaviours' (Cohen and Leckman, 1992) have also been described in TS. Kurlan and colleagues surveyed 87 adolescent and adult TS patients (mean age 28 years) and reported NOSI such as insulting others (22%, e.g. aspersions on weight, height, intelligence, general appearance, breath or body odour, parts of the anatomy, racial or ethnic slurs), other socially inappropriate comments (5%) and socially inappropriate actions (14%). More often subjects described having an urge to carry out the NOSI (insulting others, 30%; other socially inappropriate comments, 26%; socially inappropriate actions, 22%), which they attempted to suppress. NOSI were usually directed at a family member (31%) or familiar person (36%), at home or in a familiar setting such as work or school; less commonly NOSI were directed at a stranger (17%) in public settings (20%). Social difficulties such as verbal arguments, school problems, fist-fights, job problems, removal from a public place and legal trouble or arrest commonly resulted. NOSI were more common in young boys and were closely related with ADHD (P < 0.005) and conduct disorder (P < 0.005), but not OCB, and it was suggested that they may well represent part of a more general dysfunction of impulse control in TS (Kurlan et al., 1996).
The course of TS is important to examine, as not only do symptoms wax and wane in the short term, but symptom patterns may well change over the individual's lifetime. By late adolescence or early adulthood, follow-up studies have consistently demonstrated an improvement in tic frequency or severity in the majority of TS patients (Bruun et al., 1976; Erenberg et al., 1987); this may be especially so in treated patients, as it has been shown that untreated TS patients demonstrate virtually no sustained change in their tics over time (Sandor et al., 1990). A recent study (Leckman et al., 1998) has demonstrated that in a single birth cohort of 36 TS patients, the mean tic onset was earlier than previously reported, being at 5.6 years (SD = 2.3), which was followed by a progressive pattern of tic worsening. The average age of the most severe tics was 10 years (SD = 2.4). In eight patients (22%) the tics were so severe during the `worst ever' period that school functioning was significantly impaired. In most cases the severe period was followed by a decline in tic severity. By 18 years nearly half of the cohort was virtually tic free (Leckman et al., 1998).
Of importance is that some investigators document a reduction of the tic-related phenomena with time, but a persistence or increase in the behavioural disorders (Erenberg et al., 1987; Singer and Rosenberg, 1989; de Groot et al., 1994) which will be described below.
It has been suggested (Robertson and Baron-Cohen, 1998) that it may be useful to clinically subdivide TS into: (i) `pure TS', consisting primarily and almost solely of motor and phonic tics; (ii) `full blown TS' which includes coprophenomena, echophenomena and paliphenomena; (iii) `TS-plus' (originally coined by Packer, 1997), in which an individual also has ADHD, significant OCB or obsessive-compulsive disorder (OCD) and SIB. Others with severe psychopathology (e.g. depression, anxiety, personality disorders and other difficult and antisocial behaviours) may also be included in this group.
In summary, it can be seen that although the basic clinical picture of TS, i.e. the motor and phonic tics, is remarkably consistent irrespective of country of origin, an in-depth analysis of symptomatology reveals marked heterogeneity.
Psychopathology and associated behaviours
Many types of behaviours and psychopathologies have been reported to occur frequently in TS individuals. It is important to acknowledge once again (see Robertson, 1989) that in the author's opinion, some types of behaviour such as OCB and SIB are strongly linked to TS (see below) and are probably an integral part of the syndrome; this may now also be true for at least some types of ADHD. The other behavioural disturbances (see below) occur in a substantial proportion of TS patients and are often the reason for referral to a physician.
It is important to question whether these antisocial (in the broadest sense) behaviours are truly increased in TS or not. There are those who argue that they are increased and are therefore integral to TS (e.g. Comings and Comings, 1987; Comings, 1990). However, in the author's own experience in clinical (e.g. Robertson et al., 1988, 1989, 1993, 1997), family-pedigree (Robertson and Gourdie, 1990) and school settings (Mason et al., 1998), and in epidemiological (Caine et al., 1988) and family-pedigree (Kurlan et al., 1986, 1987; McMahon et al., 1992) studies of others, the TS cases are often of mild severity, unknown to medical professionals, and are not associated with major behavioural disturbances. They may well have emotional problems, but these are probably not of the severity necessitating referral. Clinic populations of TS, on the other hand, may include severe, full blown and often TS-plus individuals, which may be reflective of referral bias (Berkson, 1946). Until the putative gene(s) is identified, however, the precise phenotype (and whether or not it includes the associated behaviours and psychopathologies) will remain unclear.
Let us now examine the individual associated behaviours and psychopathologies encountered in TS patients. The reason for considering this in detail is that recently there have been controlled studies which employ standardized rating scales and are thus more probing into the exact nature of the pathologies and their relationship to TS.
ADHD
ADHD is probably one of the most common psychiatric disorders affecting children, with prevalence estimates ranging from 2 to 15%; the aetiology of ADHD is not fully understood. As ADHD begins in early childhood, parents are often the first to note clumsiness, excessive activity, low frustration tolerance and `accident proneness' (Towbin and Riddle, 1993). For a careful review of stand-alone hyperkinetic disorder (which includes ADHD), influences on pathogenesis, prevalence, diagnosis, comorbidity, differential diagnosis, work-up and treatment guidelines, readers are referred to the review by Taylor and colleagues (Taylor et al., 1998). The present author suggests that as ADHD and TS are so intimately related, it is valuable to familiarize oneself with this ADHD literature.
As early as 1973, it was generally accepted that many children who progress to TS first manifest various behavioural disturbances often labelled as minimal brain dysfunction, hyperactivity or attention deficit disorder (Shapiro et al., 1973a, b). Although diagnostic criteria have changed over time, in this review, for the sake of convenience, all these types of symptom, unless otherwise specified, will be referred to as ADHD. Components of this are a short attention span and impulsivity; hyperactivity may or may not be present (American Psychiatric Association, 1987). For a detailed history of ADHD through the DSM variants, the reader is referred to Towbin and Riddle (Towbin and Riddle, 1993).
It has been pointed out that of all the comorbid conditions ADHD is probably the most commonly encountered in TS, as evidenced by a vast literature on the subject (Towbin and Riddle, 1993; Freeman, 1997). Although early studies found ADHD in as few as 13% of TS patients (Mak et al., 1982), it is now evident that ADHD occurs in a substantial proportion of TS patients, ranging from 21 to 90% of clinic populations (Robertson and Eapen, 1992), clearly far in excess of the 2–15% (Towbin and Riddle, 1993) or 4–19% (Taylor et al., 1998) in the general population. Two epidemiological studies have, however, also examined ADHD in TS. Apter and colleagues examined all those recruited into the Israeli Defence Force during 1 year and reported the rate of ADHD in people with TS to be 8.3% compared with a population point prevalence of 3.9% in individuals without TS (Apter et al., 1993). Recently, Mason and colleagues undertook a school epidemiological study examining TS and tics. Of the 30 out of 167 (18%) tic possibles, there was no increase in ADHD in tic possibles compared with the other children, as rated by the short Connors scale; there was also no increase in hyperactivity as assessed by both the General Health and Behaviour Questionnaire, and Strength and Difficulty Questionnaire of Goodman (1994, 1997). Four out of five (80%) of the identified TS individuals (definite and probable) were, however, reported as hyperactive by their teachers, parents or both; one satisfied DSM-IV criteria for ADHD (Mason et al., 1998).
It has also been pointed out that it is the symptoms of ADHD which often contribute to the behavioural disturbances, poor school performance and impaired executive functioning testing in children with TS (Singer et al., 1995a).
Attentional problems and difficulties with hyperactivity and impulse control frequently precede the emergence of the actual tics (Jagger et al., 1982; Singer et al., 1995a). In fact, for the DSM-IV diagnosis to be made, symptoms of ADHD must be present in two or more settings before the age of 7 years; the TS tic symptoms, however, often begin later (Robertson, 1989, 1994).
Only one study to date has examined the phenomenology of `pure' (primary) ADHD and compared it with that of TS plus ADHD (Spencer et al., 1998). It was demonstrated that in TS there were increased rates of both OCD and ADHD. In contrast to the comorbidity with OCD, it was found that the other comorbidities (such as disruptive behaviours, mood disorder, anxiety disorder) were indistinguishable in the comparison between children with TS plus ADHD and children with ADHD alone. This suggests that some psychopathology (e.g. mood and anxiety) could be secondary to the comorbidity with ADHD, rather than the TS per se. In addition it was shown that children with TS plus ADHD had lower psychosocial functioning than children with ADHD alone (Spencer et al., 1998). A more recent paper (Spencer et al., 1999) compared 128 male children and adolescents with 110 controls, at baseline and 4 years later; when compared with controls, ADHD youngsters had more tic disorders initially and more new onsets at follow-up. Of interest is that tic disorders and ADHD had independent courses, with ADHD showing markedly less remission.
Three fairly recent studies (Weiss et al., 1985; Mannuzza et al., 1993, 1998) in non-TS youngsters, have all demonstrated that childhood ADHD was predictive of antisocial personality disorder in adulthood. As so many TS children have ADHD symptoms, this may well account for the apparent increase in at least some of the adulthood psychopathologies in TS (e.g. personality disorder) (see below).
The precise relationship between ADHD and TS is thus complex and has stimulated debate for a long time; there appear currently to be four possibilities as to the nature of the relationship. First, there have been suggestions that the two disorders are genetically related (e.g. Comings and Comings, 1984, 1987; Knell and Commings, 1993), although this has been disputed (Pauls et al., 1986a, 1988; Eapen and Robertson, 1996). The data from another study, however, have suggested a second possibility—that there may be two types of individuals with TS plus ADHD, one in whom ADHD is independent of TS and others in whom ADHD is secondary to TS (Pauls et al., 1993). A third possibility is that pure ADHD and TS plus ADHD are different phenomenologically, but the exact relationship is unclear. A fourth possibility as to the cause of the apparent relationship has been put forward by Towbin and Riddle, who suggested that TS individuals may have reduced capacities for concentration, attention and impulse control, but at a level subthreshold for a DSM diagnosis of ADHD; the frequency of comorbidity therefore depends on where the cut-off point for ADHD is set (Towbin and Riddle, 1993). The three latter possibilities may well be related in some way and more research needs to be undertaken.
In the author's opinion, ADHD or similar symptoms are common in people with TS and it appears that they may occur in even mild TS cases who are identified in epidemiological studies. It is unlikely therefore to be wholly due to referral bias. Whether or not the symptoms are sufficient to warrant an actual ADHD diagnosis is as yet unknown, and whether or not the symptoms in TS plus ADHD are identical to those seen in pure ADHD has to be investigated further.
Obsessive–compulsive behaviours, symptoms and disorder
Obsessive-compulsive disorder (OCD) is characterized by persistent obsessions [recurrent, intrusive, senseless thoughts, which are egodystonic (internally uncomfortable)] or compulsions (repetitive and seemingly purposeful behaviours which are performed according to certain rules or in a stereotyped fashion); they are a significant source of distress to the individual or interfere with social or role functioning (American Psychiatric Association, 1987, 1994). Early studies reported a prevalence rate in the general population of 0.05%, but recent research suggests a lifetime prevalence rate of between 1.9 and 3.2% (Dinan, 1995). It has been suggested that there are essentially three types of OCD: (i) familial type related to tic disorders; (ii) familial type unrelated to tics; (iii) non-familial type (Pauls et al., 1995).
It is becoming increasingly evident that there is a clear and strong association between TS and OCD, both in TS patients and in their family members, with evidence for the association being obtained from phenomenological, genetic and epidemiological investigations (Robertson and Yakeley, 1993; Robertson, 1995).
At the outset the author wishes to make the point that the obsessive-compulsive symptoms (OCS) and obsessive-compulsive behaviour (OCB) encountered in TS may well be describing one and the same phenomenon, but that they are clinically and significantly different from the OCS encountered in pure OCD.
Twelve studies undertaken between 1969 and 1985 reported TS patients with obsessive–compulsive traits or illnesses, varying from single case reports to significant percentages of TS populations ranging from 11% to as high as 80% (Robertson, 1989). Substantial studies in the late 1980s also indicated that OCS/OCB were common in TS, occurring in 37% (Robertson et al., 1988), 47% (van de Wetering et al., 1988) and 49% (Caine et al., 1988) of TS patients. One controlled study in children also suggested significant OCS/OCB in 28% of the TS group (Grad et al., 1987). Clearly, all these figures are far in excess of the 1.9–3.2% for OCD in the general population (Dinan, 1995); even though the OCS/OCB in TS are different from those in OCD (see below), the high rates in TS individuals are remarkable.
Three studies have suggested that OCS/OCB in TS change with age or duration of TS. Montgomery and colleagues and Nee and colleagues both suggested that OCS/OCB increased in frequency with the duration of TS (Montgomery et al., 1982; Nee et al., 1982). Frankel and colleagues suggested that younger TS patients exhibited OCS/OCB related to impulse control, while older patients were more concerned with checking and arranging (Frankel et al., 1986).
Robertson and colleagues reported that coprolalia and echophenomena were significantly related to OCS/OCB (Robertson et al., 1988). The only study to control for depression showed that TS patients are disproportionately obsessional, which is not accounted for by depression (Robertson et al., 1993).
Several elegant investigations have demonstrated significant phenomenologic differences between `pure' (primary) OCD and the OCS/OCB encountered in TS (Frankel et al., 1986; Pitman et al., 1987; George et al., 1993a; Holzer et al., 1994; Leckman et al., 1994–5; Eapen et al., 1997b; Miguel et al., 1997; Müller et al., 1997; Zohar et al., 1997; Petter et al., 1998). In essence, the obsessions seen in TS have to do with sexual, violent, religious, aggressive and symmetrical themes; the compulsions are to do with checking, ordering, counting, repeating, forced touching, symmetry (`evening up'), getting things `just right' and self-damage or SIB. In contrast, the obsessions seen in pure OCD are to do predominantly with contamination, dirt, germs, being neat and clean, fear of something going wrong or bad happening and the fear of becoming ill; compulsions in pure OCD are mainly to do with cleaning and washing. In addition, the compulsions in OCD are preceded by cognitions and autonomic anxiety and have fewer prior sensory phenomena. Certainly, at a clinical level, the OCS/OCB in TS appear to be egosyntonic (personally comfortable), rather than the egodystonic (subjectively uncomfortable) symptoms which characterize OCD.
Other investigations have also highlighted the special phenomenology of the OCS/OCB seen in TS. Leckman and colleagues have described the `just right' phenomenon in TS. For example, an individual would have to arrange, re-arrange and even re-arrange things further in a particular order and in certain positions or patterns until they looked `just right' to the individual; the subtle differences in this re-arranging would probably not be discernible to other people watching (Leckman et al., 1994). In another study of TS subjects with OCS/OCB, the most common obsessions concerned the fear that one might harm oneself or others, intrusive nonsense sounds, words or music, and thoughts that something terrible such as fire, death or illness might happen; common compulsions included checking, excessive washing and toothbrushing, rituals of cleaning household or inanimate objects, and counting, hoarding or collecting rituals (Hebebrand et al., 1997).
In one study (George et al., 1993a) the TS group reported that their compulsions arose de novo or spontaneously, while the pure OCD group reported that their compulsions were frequently preceded by stimuli such as guilt or worry. In another study (Eapen et al., 1997b), those probands who shared a similar symptom profile to TS subjects all had a positive family history of OCD; all other OCD probands were isolated cases.
There is general agreement now that at least some forms of OCS/OCB are genetically related to TS and may well be a phenotype of the putative TS gene(s) (Pauls and Leckman, 1986; Pauls et al., 1986a, b, 1991; Eapen et al., 1993a). Other studies have also showed that there were elevated rates of OCB/OCD in family members of TS probands (Walkup et al., 1996). In contrast, one study found no increase of OCB/OCD in family members of TS probands (Hebebrand et al., 1997).
In summary, and in the author's opinion, it does appear that there are specific OCS/OCB in the majority of TS patients, but that they are significantly different to the obsessions and compulsions seen in pure OCD. In addition, the OCS/OCB in TS seem clinically less egodystonic than in pure OCD. Finally, there may well be a genetic relationship between some types of OCS/OCB/OCD and TS.
SIB
In his original paper in 1885, Georges Gilles de la Tourette described that two out of nine patients injured themselves (Gilles de la Tourette, 1885). From 1916 to 1989 there were over a dozen case reports of SIB in TS patients (Robertson et al., 1989). Investigations have reported SIB to occur in 33% (Robertson et al., 1989), 34% (Stefl, 1984), 43% (Van Woert et al., 1976), 48% (Nee et al., 1980) and 53% (Moldofsky et al., 1974) of TS patients.
In the most detailed investigation into SIB to date, Robertson and colleagues (Robertson et al., 1989) reported that over one-third of clinic TS patients carried out SIB. Twenty-three types of SIB were described; 14 patients showed more than one type of SIB. The types of SIB seemed to be non-specific and were similar to that found in learning disabled/mentally retarded populations; they included head banging (47%, the most common), body punching/slapping, head or face punching/slapping, banging or poking sharp objects into the body, scratching parts of the body and, curiously, inflicting severe eye injuries. SIB was related to the severity of TS, a past psychiatric history and to psychopathology, particularly hostility and obsessionality, as measured on standardized psychiatric rating scales (Robertson et al., 1989). This association between SIB and obsessionality has also been described by others both in general (e.g. McKerracher et al., 1968; Gardner and Gardner, 1975) and OCD (Stinnet and Hollender, 1970; Gardner and Gardner, 1975; Primeau and Fontaine, 1987) populations. Of note is that in severe TS patients who also have OCS/OCB characterized by SIB, psychosurgery has been life-saving (e.g. Kurlan et al., 1990; Robertson et al., 1990a).
Of importance, however, is that even individuals with mild TS, encountered in epidemiological (Caine et al., 1988) and pedigree (Robertson and Gourdie, 1990) settings, have also exhibited such SIBs.
In summary, and in the author's opinion, SIB is an important part of TS which may well be integral and not merely reflective of severity or referral bias. SIB in TS is particularly related to OCS/OCB and this clearly has treatment implications.
Anxiety
Anxiety is also common in TS patients and has been examined frequently. Zausmer studied 96 children with tics. Anxiety symptoms in the group were of four types including: sleep difficulties; tension habits; motor unrest; phobias, worries, poor concentration; they were recorded in over 80% of patients (Zausmer, 1964). Corbett and colleagues investigated children and adults with tics by means of chart reviews. In 52%, tics were the initial complaint; anxiety was documented as the most frequent symptom (Corbett et al., 1969). Erenberg and colleagues reported 45% of 58 TS individuals to have extreme anxiety (Erenberg et al., 1987). Coffey and colleagues investigated 84 TS patients, of whom 11 (13%) had TS with OCD and 16 (19%) had TS with non-OCD anxiety disorder (Coffey et al., 1992). Chee and Sachdev reported on 50 TS adult patients using a structured schedule; 30% were found to have GAD (Chee and Sachdev, 1994). Thibert and colleagues examined 98 responses to a mailed questionnaire and showed that the group of TS patients with high OCS/OCB scored higher on social anxiety than the general population (Thibert et al., 1995).
Pitman and colleagues examined 16 TS patients, 16 OCD patients and 16 controls; results indicated that TS subjects had significantly more generalized anxiety disorder (GAD) than controls (Pitman et al., 1987). Comings and Comings studied anxiety disorders in 246 patients with TS and 47 controls. Sixteen per cent of the TS patients and none of the controls experienced more than three panic attacks per week. Nineteen per cent of TS patients and none of the controls had phobias which interfered with their life; 26% of TS subjects had more than three phobias in contrast with 8.5% of controls. Fourteen per cent of TS patients and 4.2% of controls had both panic attacks and phobias (Comings and Comings, 1987).
Robertson and colleagues have examined four different TS cohorts for the presence of anxiety. First, Robertson and colleagues examined 90 clinic patients with TS using the Crown Crisp Experimental Index (CCEI, previously known as the Middlesex Hospital Questionnaire) and the Mood Adjective Checklist, both of which include anxiety subscales, as well as the Spielberger State Trait Anxiety Inventory; TS patients scored much higher on anxiety than the normative data on all three scales (Robertson et al., 1988). Using the Spielberger State Trait Anxiety Inventory in two separate controlled studies, adult TS patients had significantly more state and trait anxiety than the control subjects (Robertson et al., 1993, 1997). In contrast, in a group of mild TS cases (relatives of a TS proband in the family study previously referred to), the scores of the TS cases on the three anxiety subscales of the CCEI were no different from the scores of non-TS cases (Robertson and Gourdie, 1990).
In a careful genetic study, Pauls and colleagues interviewed 338 biological first degree relatives of 85 TS probands, 92 biological first degree relatives of 27 unaffected control probands and 21 non-biological first degree relatives of six adopted TS probands. The relatives of the unaffected probands and adopted TS probands served as a control sample for the whole data set. The rates of GAD were not significantly higher in the TS probands than controls; also, the rates of GAD were not significantly different between relatives of TS probands and controls, suggesting that GAD and TS are not genetically related (Pauls et al., 1994).
Once again, in the author's opinion, it seems that anxiety is common in clinic TS patients, but its exact relationship to TS is as yet unclear; it may well be secondary to having moderate or severe TS.
Depression
Depression is a common disorder with a lifetime risk of ~10%, with rates almost doubled in women. It may be a mild disorder, but if severe the lifetime suicide risk is ~15%. The aetiology of depression is often multifactorial and includes genetic factors as well as psychosocial variables such as recent adverse life events, adverse childhood circumstances (e.g. parental loss, stress or abuse), adverse current social circumstances and physical illness (Katona and Robertson, 1995).
Several studies have found both children (Ferrari et al., 1984; Wodrich et al., 1997) and adult TS patients to be depressed, and this may be more so in older individuals with a longer duration of illness (Robertson et al., 1988). Robertson and colleagues examined 90 adult TS patients using standardized psychiatric rating scales including the Beck Depression Inventory, the Mood Adjective Checklist and the CCEI, both with depression subscales; on all three measures the TS patients' scores were substantially higher than normative data (Robertson et al., 1988). TS patients have, in addition, also been found to be significantly more depressed than control groups (Comings and Comings, 1987; Robertson et al., 1993, 1997); in the two studies by Robertson and colleagues, once again the Beck Depression Inventory was employed (Robertson et al., 1993, 1997).
In the genetic study referred to previously, Pauls and colleagues studied TS probands and controls, examining for rates of major depressive disorder (MDD), which were significantly higher for TS probands than control subjects. MDD was also significantly increased among relatives of TS probands. When this association was examined further, however, the rate of MDD in relatives of TS plus MDD probands was higher than controls, but the rate of MDD in relatives of TS probands without MDD was no higher than controls (Pauls et al., 1994). This is compatible with MDD being genetic in its own right, but not with the notion that TS and MDD are genetically related. These results are in contrast to the findings of Comings who has always considered TS and depression to be genetically related (Comings, 1990).
In a recent clinic study, bipolar affective disorder was found to occur commonly in 30% of TS patients (Berthier et al., 1998). A previous epidemiological study, however, had shown only a trend towards such an association (Kerbeshian et al., 1995).
In a group of mild TS cases (relatives of a TS proband in a family study by Robertson and Gourdie, referred to earlier), the scores of the TS cases on the depression subscale of the CCEI were no different from the scores of non-TS cases (Robertson and Gourdie, 1990).
This depression in TS clinic patients and probands could be explained, at least in part, by the fact that sufferers have a chronic, socially disabling and stigmatizing disease (Robertson, 1994). This depression in clinic TS patients may also be due to the side-effects of neuroleptics (depression, dysphoria; see below). In addition, it has been shown that children who have been bullied (as have many TS children encountered in clinic) may become anxious and depressed (Salmon et al., 1998). Finally, it may reflect the fact that clinic attenders often have more than one problem/disorder. One must not forget, however, that depression is a common illness and for this reason a certain proportion of TS patients could be depressed in any event, i.e. it may be a chance association.
In the author's opinion, depression is certainly associated with TS but the exact relationship is unclear. It may well be a secondary phenomenon, i.e. secondary to having moderate or severe TS, or bullying in children. In the authors' opinion, the depression in TS is highly likely to be multifactorial in origin, as is depression in non-TS populations.
Personality disorder
There is only one investigation of personality disorder in TS, but as it is an important clinical issue, the results will be discussed in detail. Robertson and colleagues examined 39 adult TS patients of whom 31 (79%) were male, with 34 age- and sex-matched controls. The TS patients were of moderate severity (YGTSS; mean 26.2, range 11–55). TS patients and controls were examined using the Structured Clinical Interview for DSM-III-R Personality Disorders II (Spitzer et al., 1987; Nussbaum and Rogers, 1992) to systematically determine personality axis II personality disorders. Subjects also completed a self-rated scale for personality disorders (Dowson, 1992). Results showed that, using the Structured Clinical Interview for DSM-III-R Personality Disorders II, 25 out of 34 (64%) TS cases had one or more DSM-III-R personality disorders, compared with only two of 34 (16%) control subjects (
2 = 22.7, P < 0.0001). TS cases were also more likely to have multiple personality disorders. Using the STCPD scale, 27 (71%) of the 38 TS cases completing the scale were identified as having one or more personality disorders compared with five (15%) of the control group (Robertson et al., 1997). The cause of this increase in personality disorder may well be the result of the long-term outcome of childhood ADHD, referred to earlier. Thus, it does appear that at least some clinic TS populations have personality disorders which have both treatment and prognosis implications.
Other associated behaviours
Other behaviours such as aggression (Moldofsky et al., 1974; Stefl, 1984; Robertson et al., 1988; van de Wetering et al., 1988; Palumbo et al., 1997), antisocial behaviours (Nee et al., 1980; Stefl, 1984), learning disabilities, oppositional defiant disorder, conduct disorder (Comings and Comings, 1987; Palumbo et al., 1997), severe temper outbursts (Erenberg et al., 1987), schizoid symptoms (Comings and Comings, 1987), inappropriate sexual behaviour (Moldofsky et al., 1974; Nee et al., 1980; Robertson et al., 1988) and rage (Bruun and Budman, 1997) are also seen in TS clinic patients. No studies to date, however, have examined these types of behaviour in either epidemiological settings, in mild TS patients or in a controlled setting.
A number of case reports (e.g. Realmuto and Main, 1982; Barabas and Matthews, 1983) and a systematic pilot study by our group (Baron-Cohen et al., 1999a), have suggested an association between TS and autism. In the latter study three of 37 (8.1%) pupils with autism were found to have TS; the presence of TS was not associated with superior intellectual, language or social development. In a more recent large scale study, 447 pupils from nine schools for youngsters with autism were examined in a six-stage investigation involving combined observational and family interview/history methods (Baron-Cohen et al., 1999b). Results showed that definite TS was confirmed in 19 children giving a prevalence rate of 4%; 10 more children were diagnosed as having probable TS (2.2%). Many others (34%) showed tics on observation (but not both motor and vocal tics) and thus the observed rate of 6.48% of TS in autism may well be an underestimate. Of interest is that family histories for tics or OCB were positive in 25 out of 32 youngsters (78%). TS was not related to the severity of autism in the youngsters (Baron-Cohen et al., 1999b). The presence of TS in people with autism may well have treatment implications and should therefore be examined for.
Conclusions
The above conditions are no doubt found in many TS cases, but the precise relationships between them and TS are as yet unclear. Further studies will have to be undertaken on mild TS individuals in non-clinic settings to see whether or not they are more depressed and anxious, and have more personality disorders than control subjects. Further genetic studies are also called for. The clinic population, as said, may well reflect referral bias (Berkson, 1946). Only when the putative gene(s) are identified can one be absolutely sure of the TS phenotype and which associated behaviours, if any, form part of the phenotype.
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Genetics
It is now generally agreed that TS is genetically determined. The assertion was made as there are large families documented (Kurlan et al., 1986
; Robertson and Gourdie, 1990; McMahon et al., 1992) which, at least at face value, suggested autosomal dominant inheritance and on their own should have been large enough to enable detection of linkage. Indeed, TS was shown to be autosomal dominant by complex segregation analysis techniques (e.g. Curtis et al., 1992). To date, however, no linkage studies have been replicated and much of the genome has been excluded (over 80% by 1993; Heutink et al., 1993). The question then is why has this proven so difficult? This may be so for several reasons, including the fact that the model for inheritance is wrong, the phenotype cannot be accurately determined or there are other non-genetic factors at play. These are some of the reasons why so many different models for inheritance have been proposed and why the definition of the phenotype has taken on such crucial importance.
Thus, more recently, a mixed model has been proposed (Hasstedt et al., 1995; Walkup et al., 1996) in which it is suggested that there is a genetic predisposition involving one copy of the gene which renders the individual vulnerable, and other factors (e.g. infections, perinatal factors) which determine the extent of the expression of the gene; the number of genes (one or two) may determine the severity of TS. Polygenic inheritance (involving many genes) (Comings et al., 1996), which is more controversial, and bilineality (Kurlan et al., 1994b) (both matrilineal and patrilineal inheritance) have also been suggested. Two studies have shown the effects of genomic imprinting (Lichter et al., 1995; Eapen et al., 1997c). Many authorities believe that an individual may inherit a vulnerability to a spectrum disorder including TS and OCB (Eapen et al., 1993a). Pauls and colleagues suggested that, although ADHD is not a variant expression of TS, the two conditions may be aetiologically related in some individuals, such that there may be two types of people with TS and ADHD; those in whom ADHD is independent of TS (with onset of ADHD before onset of TS) and others in whom ADHD is secondary to the occurrence of TS (concurrent or later onset of ADHD) (Pauls et al., 1993).
There may also be genetic heterogeneity, i.e. different genes may be responsible for TS in different families. Future research in the area will also concentrate on the precise definition of the phenotype. To date, as has been said before, it is not clear which manifestations of TS the putative gene(s) will be responsible for in the phenotype; e.g. will the gene for `pure TS' be the same as that for `full blown' or `TS-plus'?
A possible new approach to solving the problems of identifying the genetic mechanisms involved may be sib-pair analysis. A large international investigation spearheaded by the Tourette Syndrome Association (USA) is now employing this technique. As this method is more robust to mis-specification of models of inheritance, it should eventually either find linkage to chromosomal loci or not.
In the first publication from the group and the first complete genome scan in TS, two areas are suggestive of linkage (Tourette Syndrome Association International Consortium for Genetics, 1999). These results are exciting and further research is under way.
Perinatal factors and infections
Recently there have been suggestions that a variety of other factors are involved in the aetiopathogenesis of TS, including pre- and perinatal stressors/insults, and, somewhat later, various bacterial and viral infections.
Perinatal factors
Based on observations that stressors at various times of the life cycle could influence TS symptoms, Leckman and colleagues suggested a stress-diathesis model for the pathogenesis of TS, according to which the clinical expression of TS is a product of the interaction of an inherited vulnerability (such as that discussed above) with environmental factors; these may include CNS stimulants or intermittent, uncontrollable stress during a critical period of brain development (Leckman et al., 1986). Thus, it has been proposed that prenatal events or exposures such as maternal life stress during pregnancy, severe nausea and vomiting during pregnancy, and antiemetic medication may lead to changes in the sensitivity of some dopaminergic receptors and this could partially determine the eventual severity of expression of the diathesis to TS (Leckman et al., 1987Leckman et al., 1990). Others have also reported a high incidence of birth complications in 25% of 53 TS patients (Lees et al., 1984), which included induced labour, umbilical cord round the neck, neonatal jaundice, caesarian section, forceps delivery, prolonged labour, prematurity and a twin sibling dying at birth. Unfortunately, none of these were controlled studies, so it is not possible to say whether or not these factors are found more with TS individuals than any other group or the general population.
Neuroimmunology and infections
Several groups have recently investigated the possible role of infections in the aetiopathology of TS and related disorders. These will all be discussed as they have important, though as yet novel, treatment implications (see below).
There have been recent suggestions that paediatric autoimmune neuropsychiatric disorders associated with group A ß-haemolytic streptococcal infections (PANDAS) (Swedo et al., 1998) may be of importance in the understanding of the aetiopathology of TS. Robertson and Stern suggest a possible clinical spectrum between TS and Sydenham's chorea, a variant of rheumatic fever with neurological involvement (Robertson and Stern, 1998); this theory is strengthened by the findings of both OCD symptoms (Swedo et al., 1989, 1993) and vocal tics (Mercadante et al., 1997) in Sydenham's chorea.
The PANDAS disorders, associated with either abrupt onset or exacerbations of tics or OCS/OCB symptoms, have been described in a series of reports (Allen et al., 1995; Swedo et al., 1997, 1998). Carrying on related research, studies have now also examined a trait marker of rheumatic fever susceptibility (a ß-lymphocyte antigen labelled D8/17) and have found it to be increased in patients with both TS and OCD (Murphy et al., 1997; Swedo et al., 1997).
The neuroimmune diathesis of TS has been of interest for some time (Hallett and Kiessling, 1997). Antineuronal antibodies were found to be increased in the sera of children with movement disorders including Sydenham's chorea and TS (Kiessling et al., 1993, 1994). The same group later developed a sensitive and specific assay for the determination of these human antineuronal antibodies in TS and related disorders (Laurino et al., 1997).
Although the idea of PANDAS is intriguing, it is still speculative and only a few cases have been described which support the hypothesis. The topic has been well reviewed by Kurlan who suggests that further research is required to establish more clearly the role of post-infectious and immune-mediated mechanisms in TS (Kurlan, 1998, 1999). He also suggests that with the present state of knowledge, testing and treating of patients should not form part of a routine clinical work-up and should only be used in the context of research protocols (Kurlan, 1998, 1999).
Moving on to other infections, Budman and colleagues reported an 11-year-old girl who had no family history of TS, but who, at the age of 5 years, began to have symptoms of TS including motor and vocal tics, ADHD and OCD. Gestation, birth and early development were normal. At 3 years she developed herpes simplex type 1 oral lesions; she continued to have these periodically. Over the years her response to traditional anti-TS medication was variable. Acyclovir was given twice for tic exacerbations and she improved markedly on both occasions (Budman et al., 1997).
Riedel and colleagues documented a boy who began blinking excessively at the age of 4 years; it resolved within a year without treatment. At the age of 9 years he developed multiple motor tics, a vocal tic and poor impulse control, and was hospitalized 11 months after the onset. The results of all special investigations suggested an infection with Borrelia burgdorferi (Lyme disease). He was treated with an intravenous antibiotic (ceftriaxone 2 g) daily for 14 days which resulted in both a decrease of symptoms and a decrease in Borrelia-specific antibody titres. The authors suggested that such an infection should be considered in all cases of TS in endemic areas (Riedel et al., 1998).
In summary, several recent investigations have identified some TS patients associated with streptococcal infections; others have reported TS symptoms to be associated with Lyme disease and a viral infection. All of these findings, although interesting, must be considered as speculative and almost anecdotal as yet, and although they have treatment implications, these also must be considered to be in their infancy. This, once again, highlights the heterogeneity of so many aspects of TS, including aetiology.
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Course and prognosis |
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TS has a life-long course. Characteristically, the course of TS is punctuated by the appearance of new tics and the disappearance of older ones; during adolesence the symptoms tend to be more unpredictable from day to day, but it is estimated that in 30–40% of cases the tic symptoms will remit completely by late adolescence (Robertson, 1994
).
A recent study by Leckman and colleagues demonstrated that there was a mean tic onset at age 5.6 years which was followed by a progressive pattern of tic worsening. The period of greatest tic severity occurred at 10 years. In eight of 36 cases (22%) the frequency and forcefulness of the tics during the worst period were so severe that functioning in school was impossible; in practically every case this period was followed by a steady decline in tic severity. By the age of 18 nearly half of the cohort was virtually tic free. The onset of puberty was not associated with either the timing or severity of tics (Leckman et al., 1998).
There is little doubt that stress is involved in the pathogenesis and worsening of TS, but the topic has received relatively little systematic attention in the literature. Stress has been implicated in the pathogenesis (e.g. Leckman et al., 1986, 1990) as well as the perpetuation or increase of TS symptoms.
Stress has been shown to increase the severity of tics. Case reports have documented an increase in TS symptoms following the death of a parent, personal illness, birth of a sibling (Eisenberg et al., 1959), beginning school (Eisenberg et al., 1959; Surwillo et al., 1978), parental separation (Stevens, 1964