An introduction to the clinical phenomenology of Tourette syndrome.

CHAPTER ONE

An Introduction to the Clinical Phenomenology of Tourette Syndrome Davide Martino*,†,{,1, Namrata Madhusudan}, Panagiotis Zis{, Andrea E. Cavanna},},||

*Queen Elizabeth Hospital, Woolwich, London, United Kingdom † Centre for Neuroscience and Trauma, Queen Mary University of London, London, United Kingdom { King’s College Hospital, London, United Kingdom } Department of Neuropsychiatry, University of Birmingham and BSMHFT, Birmingham, United Kingdom } School of Life and Health Sciences, Aston University, Birmingham, United Kingdom || Sobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology, UCL, London, United Kingdom 1 Corresponding author: e-mail address: [email protected]

Contents 1. Basic Nosography of Primary Tic Disorders 2. Phenomenology 2.1 Tics 2.2 Sensory phenomena: Urges, “just-right” phenomena and somatic hypersensitivity 2.3 Complex tic-like repetitive behaviors 2.4 Comorbidities: Obsessive–compulsive disorder 2.5 Comorbidities: Attention-deficit and hyperactivity disorder 2.6 Comorbidities: Affective disorders 2.7 Comorbidities: Impulse control disorders 2.8 Comorbidities: Autistic spectrum disorders 2.9 Comorbidities: Personality disorders 2.10 Natural history and multiple phenotypes 2.11 Final considerations References

2 3 3 6 9 11 13 15 17 18 20 21 22 25

Abstract Tourette syndrome (TS) is the primary tic disorder that reaches most commonly medical attention and monitoring, with an estimated prevalence close to 1% between 5 and 18 years of age. Motor and phonic tics are the core features of TS. In addition to their well-characterized phenomenology, tics display a peculiar variability over time, which is strongly influenced by a variety of contextual factors. The sensory phenomena of TS are increasingly recognized as another crucial symptom of TS and consist of premonitory urges and somatic hypersensitivity. A relevant proportion of patients with TS display International Review of Neurobiology, Volume 112 ISSN 0074-7742 http://dx.doi.org/10.1016/B978-0-12-411546-0.00001-9

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2013 Elsevier Inc. All rights reserved.

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Davide Martino et al.

complex, tic-like, repetitive behaviors that include echophenomena, coprophenomena, and nonobscene socially inappropriate behaviors (NOSIBs). The burden of behavioral comorbidities is very important in determining the degree of disability of TS patients. Only a small minority of TS patients presents exclusively with a tic disorder. Obsessive– compulsive symptoms and related disorder (OCD) are common in TS, and the clinical distinction between compulsions and complex tics may be difficult in some cases. Probably, the presence of comorbid attention deficit hyperactivity disorder (ADHD) is the main determinant of cognitive dysfunction in TS patients and influences heavily also the risk of developing disruptive behaviors. Affective disorders, impulse control disorders, autism spectrum disorders, and personality disorders complete the wide psychopathological spectrum of this condition, but have been less investigated than OCD and ADHD. The complexity of the Tourette spectrum has been confirmed by cluster and factor analytical approaches, and is likely to inform the study of the genetic basis of this disorder, as well as future reappraisal of its nosography, with the development of novel clinical subtypes.

1. BASIC NOSOGRAPHY OF PRIMARY TIC DISORDERS The term “tic disorder” indicates a medical condition in which a specific form of repetitive, stereotyped, involuntary movements, that is, tics, represent the prominent clinical manifestation. Although tics can be observed in a wide number of conditions in which they appear as prominent or accompanying features (see Kurlan, 2013 for a detailed review), primary tic disorders are the most common group of tic disorders. These may be defined as neurodevelopmental conditions typically starting in childhood, which may or may not persist as clinically relevant during adulthood, and in which tics cause distress or significant impairment in social or occupational functioning. Primary tic disorders are considered as multifactorial conditions, but their etiology remains elusive. The Diagnostic and Statistical Manual of Mental Disorders (5th ed.), published by the American Psychiatric Association in 2013, lists three main types of primary tic disorders. Tourette syndrome (TS) (or Tourette’s disorder, as labeled in the DSM-V) is the primary tic disorder that reaches most frequently medical attention and surveillance. The diagnosis of TS is formulated in the presence of multiple motor and vocal tics of onset in childhood or adolescence with duration of at least 1 year, during which a tic-free period cannot past longer than 3 consecutive months (American Psychiatric Association, 2013). A recent meta-analytic study estimated the prevalence of TS as being very close to 1% among children between 5 and 18 years of age (Robertson & Cavanna, 2009). Primary

Phenomenology of Tourette Syndrome

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tic disorders, moreover, are at least three times more common in males than in females. Tic disorders that past longer than 1 year but present exclusively with motor tics are diagnosed as chronic motor tic disorders, whereas those presenting exclusively with vocal tics as chronic vocal tic disorders. It is important to point out that this separation between motor and vocal tic disorders is unlikely to reflect relevant pathobiological and clinical differences between motor and vocal tics (apart from their different topography). Their separation has been rather justified by differences in natural history (vocal or phonic tics begin 1 or 2 years after the onset of motor tics) and, possibly, by different implications on the type of functional impairment caused by tics in the individual patient. Probably, the majority of youngsters who develop tics during their childhood grow out of them spontaneously within less than 1 year. In these cases, if tics have been severe enough to cause any form of impairment, the diagnostic label of provisional tic disorder may be used according to the DSM-V. The observation of transient tics, however, suggests that tics may represent a possible “variant” of the normal behavioral repertoire of a child or adolescent during the developmental period, reflecting specific phases of synaptogenesis in the complex circuitry connecting the frontal cortex to the basal ganglia and modulating executive control.

2. PHENOMENOLOGY 2.1. Tics Motor and phonic tics represent the clinical hallmark of TS (Jankovic, 1997). A tic is defined as a sudden, rapid, recurrent, nonrhythmic motor movement or vocalization (American Psychiatric Association, 2013). Tics may be differentiated from other nonvoluntary movements (e.g., chorea, dystonia, dyskinesias, and myoclonus) based on their association with preceding sensory phenomena (premonitory urges, PUs), described in detail below, and by their partial voluntary suppressibility (Cohen, Leckman, & Bloch, 2013). In addition, the repertoire, frequency, and intensity of tics in an individual patient typically fluctuates over time; this characteristic helps distinguishing tics from stereotypies, which are highly patterned motor routines that appear much more stable over time in quality, frequency, and interference with voluntary motor behavior. Conventionally, tics are defined as motor if they manifest as detectable movements of body segments in space, whereas are labeled as phonic if manifesting with the emission of audible sounds, as a result of contraction of muscles in the nasal, oral, pharyngeal, laryngeal,

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and diaphragmatic regions. Tics are also categorized as simple and complex, reflecting a possible difference in pathogenic mechanisms underlying these two categories: simple tics involve a single muscle group and usually consist of very brief movements or sounds, whereas complex tics are coordinated muscle contractions that involve different muscle groups, either simultaneously or in rapid succession. Examples of common simple tics are eye blinking, grimacing, lip movements, head flicks, shoulder shrugs, rapid arm or leg movements, sniffing, or throat clearing. Examples of complex tics include sequences of movements that vary enormously across individuals, or isolated motor routines involving different muscle groups, such as bending or twisting the torso or limbs, abdominal muscle tensing, complex head movements, or pronouncing syllables, words, or phrases. Despite some tics appear in a larger percentage of patients than others, virtually all body areas may be affected by tics. In most instances, tics correspond to fragments of learned automatic motor routines, which may vary across individuals also based on their baseline repertoire of voluntary motor routines: for example, tics corresponding to fragments of the sign language have been described in subjects with prelinguistic deafness (Lang, Consky, & Sandor, 1993), and monolingual verbal tics have been observed in bilingual subjects. Cluster and factor analyses have attempted to define tic symptom dimensions within large clinical cohorts. The most consistent finding of these studies is a separation of tics along two main dimensions (or subtypes): (i) predominantly simple tics and (ii) concurrence of multiple complex tics. Mathews et al. (2007) showed that the presence of multiple complex tics was associated with higher tic severity, higher overall impairment, and family history of tics in two independent cohorts from the Ashkenazi Jewish population in the United States and from the Central Valley of Costa Rica. Kircanski, Woods, Chang, Ricketts, and Piacentini (2010) confirmed the separation between simple and complex tics, identifying four different clusters of tic symptoms within a cohort of 99 youngsters with a chronic tic disorder: (a) predominantly complex tics; (b) simple head/face tics; (c) simple body tics; (d) simple vocal/facial tics. Interestingly, predominantly complex tics cluster scores were positively correlated with the number of comorbid diagnoses and with disease duration. Overall, these phenomenological studies support the heterogeneity of the clinical spectrum of tic disorders and suggest pathophysiological differences between simple and complex tics. Suppressibility by volitional control is one of the cardinal features of tics (Cohen et al., 2013). The extent of the ability to suppress tics may be age related and vary across individuals. Active suppression of tics may distract


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the subject’s attention from other mental attention-demanding tasks and negatively impact on learning processes and academic achievements in young patients (Packer, 1997). During the active suppression of tics, patients may experience an increase in the intensity and discomfort generated by PUs (Leckman, Walker, & Cohen, 1993). Recent evidence suggests, however, that the intensity or the type of the PUs do not correlate with the ability of subjects to suppress their own tics (Ganos, Kahl, et al., 2012). Not surprisingly, when tics are more severe the ability to suppress them is diminished, and this may also depend on contextual factors modulating the severity of tics, for example, baseline anxiety or stress levels (Conelea & Woods, 2008). High levels of stress and anxiety may reduce one’s ability to suppress tics voluntarily. Changes in frequency and intensity of tics may also depend upon the environmental context. Clinical research suggests that exposure to psychosocial stressors may worsen tic severity in the short term (Lin et al., 2007). An impact of biological stressors influencing immune activation, such as infections, has also been hypothesized and is currently the object of research (Lin et al., 2010). Other contextual factors, directly or indirectly related to stress, may also worsen tics, including anxiety and fatigue, but also exciting events, such as visits to amusement parks, watching an exciting film, etc. (Conelea & Woods, 2008). On the other hand, tics may improve when subjects are engaged in attention-demanding activities (e.g., playing videogames, practicing complex physical activities, etc.) or when they practice general physical exercise or relaxation. Tics also disappear during deep sleep. Some tics are suggestible, whereas others may respond to specific environmental sensory cues, that is, reflexive tics (Leckman, 2013). For example, old tics may reappear when these are mentioned during a clinical consultation. Also, specific tics, such as emitting a loud vocal noise, may be performed when a patient is explicitly asked to refrain from producing potentially disturbing noises, for example, in a theater, in a library, or during school classes. In some cases, these reflexive tics may involve potentially selfharming (e.g., breaching specific caution warnings like that of not touching a high voltage apparatus) or socially inappropriate actions (e.g., contextually inappropriate laughter triggered by hearing certain words). Regardless of contextual factors, tics wax and wane in repertoire and severity over time. Using complex mathematical models to analyze tic frequency distribution, Peterson & Leckman (1998) have suggested that the temporal occurrence of tics follows a fractal character, that is, individual tics are clustered in bouts of tics, which may cluster in bouts-of-bouts-of-tics;

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the latter may also occur in bouts-of-bouts-of-bouts-of-tics, and so forth, reproducing the same pattern across different time scales. Whether this pattern reflects specific temporal firing patterns of neural cells along the corticostriato-thalamo-cortical circuits needs to be addressed by future research, and the development of automatic devices for counting tics will contribute to this goal (Bernabei et al., 2010). Tics have a rather well-defined natural history. The onset of tics occurs between age 5 and 8 in the majority of patients (Khalifa & von Knorring, 2003). In most instances, the first tics are simple, whereas complex tics appear later during the course of the illness. In addition, the anatomical distribution is striking for its cranio-caudal spread over time, with the first tics usually involving the cranial and cervical musculature (blinking, ocular movements, nasal and facial movements, head and shoulder movements), with involvement of truncal and limb muscles later on (Leckman, King, & Cohen, 1998; Leckman, Zhang, et al., 1998). Cohort studies also suggest that phonic tics commence at a later age than motor tics (Leckman, 2013). In the majority of patients, the severity of tics peaks between age 10 and 13, after which it gradually diminishes over time, with a substantial reduction in severity at the passage to adulthood (Leckman, King, et al., 1998; Leckman, Zhang, et al., 1998). Longitudinal clinical studies have suggested that clinically significant tics are more likely to persist in adulthood in patients with higher tic severity, lower caudate volumes, and poor performance on tasks involving visuomotor skills during childhood (Bloch, Leckman, Zhu, & Peterson, 2005; Bloch, Peterson, et al., 2006; Bloch, Sukhodolsky, Leckman, & Schultz, 2006).

2.2. Sensory phenomena: Urges, “just-right” phenomena and somatic hypersensitivity Patients with TS and other tic disorders report also a complex constellation of sensory phenomena, which may be highly related to tics (Leckman et al., 1993), and which have generated the concept that tics might be associated with abnormalities of sensorimotor gating (Biermann-Ruben et al., 2012; Braff, Geyer, & Swerdlow, 2001; Kane, 1994). The most relevant and better characterized of these sensory phenomena are PUs, which can be defined as unpleasant somatic sensations typically building up immediately before tics and that can be momentarily relieved by the release of tics. PUs are reported by 80–90% of patients in the first two decades, with more than half stating that PUs enhance their ability to suppress tics (Leckman et al., 1993). The frequency of self-reported PU may be higher than 90% in adult patients with


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TS, in whom they may correlate with perceived tic severity and compulsivity (Crossley, Seri, Stern, Robertson, & Cavanna, 2013). Some patients may report that tics are initially a conscious, intentional, and self-directed movement that the subject performs in order to alleviate these aversive stimuli, becoming subsequently automatic motor routines. In particular, it has been suggested that the positive reinforcement deriving from the temporary relief of PU after tic release contributes to maintain the production of tics as automatic routines over time (Leckman, 2013). Indeed, Cohen and Leckman (1992) have reported that 57% of patients report their urges as being substantially more bothersome than the tics themselves. Self-awareness of this “urge-tic” complex increases with age during child development: Banaschewski, Woerner, and Rothenberger (2003) have reported that PUs are referred by only 24% of patients between age 8 and 10, 34% of those aged 11–14, and by 57% of patients aged 15–19. It remains unclear whether this relationship to age is the result of a developmental progression of the urge phenomenon itself or rather of the progressive increase in the ability of children to verbalize the nature of their urges. As highlighted earlier, Ganos, Kahl, et al. (2012) and Ganos, Ogrzal, Schnitzler, and Mu¨nchau (2012) did not detect any correlation between severity of PU (measured using the premonitory urge for tics scale (PUTS); Woods, Piacentini, Himle, & Chang, 2005) and pure motor tic inhibition potency, whereas PUTS scores correlated with subscores of the Yale Global Tic Severity Scale measuring interference of tics with voluntary actions. Examples of PU include bodily sensations like an itch or the sensation that triggers a sneeze; others have mixed “somatic” and “psychic” quality, experiencing restlessness, a build-up of inner tension, or a pressure over a body part. In many cases, patients report a striking topographical overlap between PU and tics; phenomenological studies of PU have documented that the predominant body sites of these phenomena include palms, throat, shoulders, and midline abdomen (Leckman et al., 1993). “Just-right” phenomena are another form of sensory phenomena described in TS patients, defined by the need of patients to compulsively reiterate sensory experiences of physical objects until these feel “just right” (Leckman, Walker, Goodman, Pauls, & Cohen, 1994; Prado, do Rosa´rio, Shavitt, & Miguel, 2007; Robertson, 2000). As much as PUs represent sensations experienced as negative and which patients try to escape releasing tics, “just-right” phenomena consist of repetitive actions aiming at obtaining satisfactory (hence, pleasant) sensory experiences. Despite the use of the term “just-right,” the repetition of the motor actions associated with this

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phenomenon is fostered by the perception that a certain sensory stimulus is initially perceived as “not right”; such negatively polarized perception is then gradually reversed into a fulfilling and pleasant experience through the self-induced repeated exposure to the same stimulus, until the latter is perceived as being “just right” (Coles, Frost, Heimberg, & Rhe´aume, 2003; Neal & Cavanna, 2013). Hence, these phenomena have a mental connotation, which is different from the prominently sensory connotation of PU. Leckman et al. (1994) documented “just-right” phenomena (particularly in respect to visual and tactile stimuli) in 44% of 130 patients with tic disorders in an age range of 9–71 years, whereas Worbe et al. (2010) indicated that 30% of their patients experienced these phenomena. Importantly, “just-right” phenomena are more common in patients with tic disorders with comorbid OCD compared to patients who do not fulfill diagnostic criteria for OCD (Leckman et al., 1994) and are comprised within the set of sensory phenomena observed in patients with OCD (Miguel, do Rosa´rio-Campos, Shavitt, Hounie, & Mercadante, 2001; Prado et al., 2007). Patients with tic disorders may also manifest somatic hypersensitivity, described by Kane (1994) as a state of keen bodily awareness, or a continual consciousness of muscle, joint, and skin sensations. This state may result from inadequate filter of sensory inputs on the basis of their salience. Hence, patients’ attention may be focused on a variety of poorly salient external stimuli coming from specific sites of the outer environment (a phenomenon called site sensitization), such as tags in new clothing, or from bodily cues, which may be perceived incessantly as increased awareness of muscles, joints, and skin. Using dedicated clinical questionnaires, Belluscio, Jin, Watters, Lee, and Hallett (2011) have recently compared somatic sensitivity between 19 TS patients and 19 healthy volunteers of the same age. Eighty percent of the TS patients experienced higher sensitivity to external stimuli in at least one sensory modality, although all sensory modalities could be involved. Statistically significant differences were observed in respect to olfactory, tactile, visual, and auditory stimuli in decreasing order of frequency of increased sensitivity within the TS group. Importantly, there was no difference between patients and control subjects in their baseline sensory functioning in any of the modalities explored, confirming that somatic hypersensitivity resulted from a dysfunction in orienting the focus of attention toward endogenous and exogenous sensory cues, rather than from mere sensory deficits. Somatic hypersensitivity is even more marked when stimuli are faint, repetitive, and of low salience.


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2.3. Complex tic-like repetitive behaviors Patients with TS may display a diverse variety of complex repetitive behaviors that present the core features of complex tics (association with PUs, partial voluntary suppressibility) but are characterized by a very specific phenomenology. These include (Robertson, 2000) echophenomena, paliphenomena, coprophenomena, and NOSIBs. Echophenomena (echopraxia, echolalia) consist of the involuntary repetition or imitation of another person’s gestures or words. These have been recognized as an important feature of TS since its first clinical description and have been recognized in several neuropsychiatric disorders for nearly two centuries (Fisher, 1988; Ford, 1989; Pick, 1924; Roberts, 1989). The repetition of another person’s activities is, to some extent, part of normal human behavior (Ganos, Ogrzal, et al., 2012). Below the age of three, these imitative behaviors are an essential component of the learning process of normal motor repertoire and social conduct. However, their persistence or reappearance may be symptomatic of an underlying disease process. In TS, current pathophysiological views suggest similarities between the defective action control/release mechanisms underlying tics and the erroneous imitation control/release mechanisms underlying echophenomena, thus indicating that echopraxia and echolalia are tics specifically subdued by an abnormal development of imitative behavior (Finis et al., 2012). Echophenomena have been associated with a higher tic severity and longer disease duration (Robertson, Trimble, & Lees, 1988). Earlier observational studies of clinic-based cohorts of TS patients suggested that 30% of patients reported the presence of one or more of echolalia or palilalia tics (Shapiro, Shapiro, Young, & Feinberg, 1988). Cohort studies applying factor and principal component analyses showed that echophenomena are a characteristic feature of TS, but not of its most common comorbid disorders (obsessive–compulsive and attention deficit hyperactivity disorders, ADHD). In a factor analysis by Mu¨ller et al. (1997), echolalia discriminated between obsessive–compulsive disorder and TS, together with coprolalia, self-injurious behavior (SIB), forced touching, and increased sense of symmetry. Cavanna et al. (2011) highlighted that echophenomena and paliphenomena were the prominent feature, together with motor tics, of one of the three main factors identified in a principal components analysis on 639 TS patients. Paliphenomena (palilalia and palipraxia) are very similar phenomena to echophenomena, involving, however, the repetition of the patient’s own words and actions (Robertson, 2000). Unlike other causes of

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verbal dysfluency like stuttering, palilalia may present with the typical core characteristics of complex tics (variability over time, association with PUs, partial suppressibility). Coprophenomena consist of the uncontrollable expression of socially unacceptable words or gestures often having a vulgar (obscene), religious (profane), racially or ethnically insulting content, not expressed out of immediate anger or frustration, or solely for purposes of emphasis. The most recent prevalence estimates of coprolalia and copropraxia in TS patients treated in specialty clinics range between 15% and 20% (Freeman et al., 2009). The frequency of coprophenomena may, however, vary on the basis of ethnicity and cultural background of the individual (Eapen & Robertson, 2008). Cavanna et al. (2011) showed that coprolalia and complex vocal tics are the prominent features of one of the three factors identified in their principal component analysis on 639 patients, suggesting that these phenomena are typical features of TS. Moreover, coprolalia was indicated by consensus of the group of experts who developed the Diagnostic Confidence Index for TS as the clinical feature most representative of pathognomonic symptoms of this condition (Robertson et al., 1999). A recent analysis from a large international database showed that coprolalia may be up to three times as frequent as copropraxia, with a mean onset age at approximately 11 years. Freeman et al. (2009) also observed that coprophenomena were associated with the number of nontic repetitive behaviors, spitting, and inappropriate sexual behavior. An earlier onset of coprophenomena was not predictive of longer persistence throughout the course of the illness; nevertheless, there is evidence showing that coprolalia may be more common in TS patients with persisting symptoms during adulthood. The complex phenomenology of TS encompasses also repetitive behaviors that, like coprophenomena, are considered socially inappropriate but lack an obscene content. These have been termed “NOSIBs” and generally consist of inappropriate personal comments, such as commenting on someone’s appearance, height, weight, etc., often in an insulting manner (Kurlan et al., 1996). Usually family members or individuals close to the family setting are the preferred targets of NOSIBs, and this may lead to important relational difficulties. Similar to echo-, pali-, and coprophenomena, patients describe having an urge to release these behaviors in 20–30% of cases, as well the ability to actively suppress them. NOSIBs have also been found to be associated with behavioral comorbidities such as conduct disorder, ADHD, and impulse control disorders (ICDs) (see below).

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2.4. Comorbidities: Obsessive–compulsive disorder Tics and compulsions share a number of clinical characteristics. They can have similar aggravating (e.g., stress, anxiety, excitement) and alleviating (e.g., concentration) factors; they are both characterized by a degree of suppressibility, which is usually for a shorter time (seconds to minutes) in the case of tics. The common coexistence of these symptoms has led to a closer inspection (Cath et al., 2011; Worbe et al., 2010). On a basic level, patients feel compelled to act upon tics, compulsions and obsessions; however, these urges can be resisted at the expense of internal tension. By acting on the urges, there is a risk that the symptom might be reinforced through operant conditioning (Cavanna & Rickards, 2013). In an attempt to distinguish tics from obsessions and compulsions (Table 1.1), research has found that obsessive–compulsive phenomena are usually accompanied by autonomic anxiety and complex thinking processes, which may begin long before the execution of the act. Tics, on the other hand, are usually preceded by short-lived sensory symptoms and are not associated with autonomic arousal. While patients with obsessions and compulsions may feel that “by not washing my hands, I might contaminate my children,” those with tics do not have the thought that they “have to tic.” It should be noted, however, that exceptions have been reported (Robertson & Cavanna, 2007a), and in fact repetitive behaviors may lie along a “tic-compulsion” spectrum (Prado et al., 2008). When considering the rates of concomitant GTS and OCD, a wide prevalence has been described, ranging from 11% to 80% (Cavanna, Servo, Monaco, & Robertson, 2009; Robertson, 2000). Research has shown a significantly higher rate of OCD tics in first-degree relatives of GTS patients, in both GTS þ OCD and GTS–OCD groups. This was also Table 1.1 Main differentiating features between tics and compulsions Feature Tics Compulsions

Onset

5–7 years

8–10 years

Course

Waxing and waning

Stable

Subjective perception

Ego-syntonic

Ego-dystonic

Sensory experiences

Premonitory urges

Anxiety-generating thoughts

Will for action

Involuntary

Voluntary

Duration

Short (e.g., jerks)

Prolonged (e.g., rituals)

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the case when compared to adoptive relatives and control samples (Cavanna, Servo, et al., 2009; Pauls, Towbin, Leckman, Zahner, & Cohen, 1986). There is therefore evidence to suggest that a common pathogenic mechanism underpins both conditions. Compulsions are often related to counting, maintaining symmetry, and thoughts and actions that feel “just right” (Neal & Cavanna, 2013). Examples of this include having to cross a door threshold in a certain manner and counting all the floor tiles in a room. In the context of GTS, patients with comorbid compulsions feel they must perform a tic in a particular way (which can lead to repetitive tics). While obsessive–compulsive symptoms in pure OCD tend to be associated with fear of contamination or harm coming to another person, inappropriate sexual or aggressive thoughts are relatively more common in people with GTS (Frankel et al., 1986; George, Trimble, Ring, Sallee, & Robertson, 1993; Worbe et al., 2010). It has been reported by Frankel et al. (1986) that patients with GTS have significantly higher obsessional scores compared to controls, when measured on a specially designed inventory. Cluster analysis of the inventory responses showed that patients with GTS preferentially endorsed seven questions related to blurting obscenities and counting compulsions and impulsions to hurt oneself. When compared to OCD patients, results showed that 11 questions related to ordering, arranging, routines, rituals, touching one’s body, and obsessions about people hurting each other yielded higher results. Younger patients also reported obsessional tendencies related to impulse control; in contrast, older patients endorsed items concerned with arranging, checking, and a fear of contamination. While patients with GTS and OCD have been shown to exhibit significantly more sexual, violent, and symmetrical obsessions, patients with OCD only have more obsessions related to dirt and germs, with a resultant compulsion to clean (George et al., 1993). It has been theorized that there are common neurobiological mechanisms at play in both GTS and OCD, but specific obsessive and compulsive symptoms are likely to be intrinsically linked to GTS (Cavanna, Servo, et al., 2009; Lombroso & Scahill, 2008; Robertson, 2000). The presence of comorbid conditions such as OCD has an impact on both conservative and medical management strategies in GTS. Habit reversal therapy has been shown to be the most widely studied and used form of behavioral therapy for patients with GTS, however other therapies include supportive psychotherapy and biofeedback training (Frank & Cavanna, 2013). The first line therapy for OCD is cognitive behavioral therapy (Verdellen, van de Griendt, Hartmann, Murphy, & ESSTS Guidelines


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Group, 2011; Steeves et al., 2012). Since different behavioral strategies are used to manage tics and obsessive–compulsive symptoms, a clinical distinction between these two phenomena is important. The most effective medical management for tics is through the use of antidopaminergic agents, such as neuroleptics and atypical antipsychotics (Pringsheim et al., 2012; Roessner et al., 2011; Waldon, Hill, Termine, Balottin, & Cavanna, 2012). In contrast to this, antidepressants including selective serotonin reuptake inhibitors are commonplace in the treatment of depression. When used at higher doses, they are useful in managing OCD (Miguel, Shavitt, Ferrao, Brotto, & Diniz, 2003). For treatmentrefractory OCD in the context of GTS, small doses of antidopaminergic agents have been shown to be effective (Cavanna & Rickards, 2013). For patients whose GTS is severe and treatment refractory, deep brain stimulation has yielded positive results. This has been the case with and without comorbid OCD (Hariz & Robertson, 2010; Muller-Vahl et al., 2011; Piedad, Rickards, & Cavanna, 2012). Porta et al. (2009) reported that 15 out of 18 with severe and refractory GTS who underwent DBS experienced a significant reduction in tic severity and a significant improvement in obsessive–compulsive symptoms, anxiety and depressive symptoms, and subjective quality of life measures. Although existing data are preliminary and partly conflicting, there is therefore some evidence that thalamic DBS in GTS might improve obsessive–compulsive symptoms alongside tics.

2.5. Comorbidities: Attention-deficit and hyperactivity disorder The most frequently diagnosed comorbidity in GTS is ADHD, with as many as 60–80% of GTS patients fulfilling diagnostic criteria for GTS and ADHD (Cavanna, Servo, et al., 2009; Robertson, 2000), therefore demonstrating an overlap in the clinical spectrum of these two disorders. It is yet unclear as to whether the presence of both GTS and ADHD should result in a clinically distinct diagnosis rather than two coexisting disorders (Gillberg et al., 2004), and this is a controversial topic of discussion. There has been increasing interest in the mechanisms responsible for the development of GTS and ADHD, and seven genes have been implicated in the pathogenesis of both conditions, suggesting a common pathogenic mechanism. These include DRD2, HRH3, MAOB, BDNF, SNAP25, SLC6A4, and SLC22A3 (Gunther et al., 2012). The presence of comorbid ADHD has been suggested as the main impacting factor on executive functioning in neuropsychological

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performance in children with GTS (Rizzo, Gulisano, Cali, & Curatolo, 2013). ADHD may also be one of the major contributing factors in poor school performance and behavioral disturbances (Eddy, Rizzo, & Cavanna, 2009; Robertson & Cavanna, 2009). Impulse control problems and difficulties with attention have often been found to precede the presence of tics (Cavanna, Servo, et al., 2009; Jankovic, 2001; Leckman, 2002; Simpson, Jung, & Murphy, 2011). However, young patients may appear to have poor concentration and focus, in an attempt to suppress their tics (Cavanna, Servo, et al., 2009); thorough assessment is required to differentiate between GTS and ADHD-related symptoms (Table 1.2). This can be difficult however, as there is a recognized overlap in symptomatology. In recent years, there has been an increase in the comparison of behavior of children with GTS only with GTS and ADHD, ADHD only, and unaffected controls (Carter et al., 2000; Sukhodolsky et al., 2003). Interestingly, patients with GTS and ADHD reported levels of disruptive behavior, which were not only significantly higher than controls, but were similar to levels displayed by patients with ADHD alone. Patients with GTS alone were reported to have similar levels of aggression, delinquency, and conduct difficulties to unaffected controls. It is difficult to know, however, whether these behaviors are related to GTS-specific anger symptoms or comorbid ADHD (Cavanna, Cavanna, & Monaco, 2008; Rizzo et al., 2007). The presence of ADHD is common in people with GTS, and ADHDrelated symptoms are often present in patients with mild GTS. There are major management and prognostic implications to having a dual diagnosis; Robertson (2006a) reviewed the treatment of both conditions and suggested Table 1.2 Main differentiating features between tics and hyperactivity Feature Tics Hyperactivity

Localization of motor phenomena

Focal

Generalized

Temporal pattern

Sudden and intermittent

Slowly increasing

Repetition

Uniform bouts

Irregular

Motor patterns

Dynamic repertoire

Random

Sensory experiences

Premonitory urges

Restlessness

Strongest precipitants

Stress, anxiety, excitement, tiredness

Waiting situation


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that the most problematic symptoms should be addressed and treated first (Rizzo et al., 2013; Robertson, 2006a). In order to achieve the most effective management strategies for children, it is important that the assessment incorporates feedback from teachers, parents, or other relatives, whenever possible (Termine et al., 2011; Cavanna, Luoni, et al., 2012). While pharmacological therapies such as the two alpha-2 agonists clonidine and guanfacine have proven effective for both tics and ADHD symptoms (Eddy, Rickards, & Cavanna, 2011; Robertson, 2006a), the use of central nervous stimulants first line for ADHD can precipitate tics. Evidence from pharmacological studies conducted over the past decade supports the use of stimulants, prioritizing the treatment of debilitating ADHD symptoms over tics (Bloch, Panza, Landeros-Weisenberger, & Leckman, 2009; Erenberg, 2005; Robertson, 2006a). However, the management of ADHD symptoms in the context of GTS is therefore particularly challenging and requires cautious and judicious use of central nervous system stimulants.

2.6. Comorbidities: Affective disorders The term depression encompasses many disorders, such as major depressive disorder (MDD), unipolar and bipolar depression, and dysthymia. It can therefore be considered as a spectrum disorder, and the distinction between unipolar and bipolar, or severe and mild forms, is often favored (Robertson, 2006b). Depression carries a lifetime suicide risk of 15% and is therefore of great clinical importance (Robertson, 2006b). When considered in the context of GTS, it is a well-recognized comorbidity (Montgomery, Clayton, & Friedhoff, 1982). The lifetime risk of developing an affective disorder in GTS in both controlled and uncontrolled studies as found by Robertson (2006b) is 10%, with a prevalence of 1.8–8.9%. There is interplay between genetic and environmental factors, with twin studies showing that lifetime major depression is moderately heritable, particularly in women (42%) over men (29%) (Kendler, Gatz, Gardner, & Pedersen, 2006). Environmental factors also play an important role in the etiology of depression, with adverse life events, childhood events, and physical illness precipitating the onset of depressive periods (Cavanna, Servo, et al., 2009). In patients with GTS seen at specialist clinics, depression and depressive symptomatology were found to occur in between 13% and 76% of cases, respectively (Robertson, 2006b). While depression has been shown to have a genetic predisposition, GTS itself can be a distressing condition, especially

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in its moderate to severe forms. Factors such as tic severity and duration, premonitory sensations, complex tics, OCD, sleep disturbances, aggression, childhood conduct disorder, and in some cases ADHD (Robertson, 2006b) have been associated with depression in GTS. The clinical characteristics, including the fact that GTS predominantly presents in childhood, can also play a part in the development of depression; children are often subject to bullying, consequently resulting in reactive depression. It has been suggested, however, that the presence of depression or depressive symptoms is integral to GTS rather than secondary to the development of tics (Comings & Comings, 1987). Snijders, Robertson, and Orth (2006) suggested the use of the Beck Depression Inventory to screen for MDD in patients with GTS. It has been suggested that the high prevalence of comorbidities such as OCD and ADHD might be the underlying cause of depressive symptoms in a large number of patients with GTS (Robertson, 2000, 2006b). The development of depression may also be as a result of learning difficulties (LDs) or disabilities in some patients with GTS (Cavanna & Rickards, 2013). Eddy, Rizzo, et al. (2011) found that patients with no comorbidities, that is, “pure GTS,” experienced more depressive symptoms than healthy controls and patients with epilepsy. They also reported a lower quality of life than controls. It is therefore important to consider that the presence of depression and depressive symptoms is not limited to GTS with comorbidities. Patients who receive antidopaminergic agents to aid in tic management must be monitored for depression, as chronic therapy with antidopaminergic agents has been shown to result in depressive symptoms. Examples of drugs include haloperidol, tetrabenazine, clonidine, sulpiride, tiapride, and risperidone (Eddy, Rickards, et al., 2011; Robertson, 2000). When considering depression in the context of GTS, it is important to fully understand the possible cause for depressive symptoms, as alleviating tic severity and frequency and modifying treatment regimens may a have a consequent impact on depressive symptoms. Further research is required to better characterize the etiology and phenomenology of depression in GTS, as well as to aid in its recognition and treatment. Bipolar affective disorder (BAD) has also been reported in patients with GTS, although to a lesser degree. While the etiology of BAD in GTS is not fully understood, common neurophysiological features such as abnormal noradrenergic, dopaminergic, and serotonergic neurotransmission suggest a common pathophysiology. This is further supported by the fact that the use of stimulants in patients with both GTS–ADHD and GTS þ ADHD


17

has been shown to precipitate BAD (Robertson, 2006b). Burd and Kerbeshian (1984) reported that there was a positive correlation between the presence of motor and vocal tic frequency and severity, with an inverse correlation with depressive symptoms. The impact of psychosocial factors such as disruptive life events may not be limited to depressive symptoms, but may play a part in the development of manic symptoms also (Robertson, 2006b). It is difficult to know the true etiology and epidemiology of comorbid BAD and GTS. Epidemiological studies are often underpowered, do not always reach statistical significance, and rely heavily on case reports. BAD was shown by Spencer, Biederman, Harding, Wilens, and Faraone (1995) to be present in 4 out of 32 children with GTS, and in 11 of 39 children with tics, and in only one control subject. In a consecutive series of 90 adult patients with GTS, 30 were found to have concomitant BAD and GTS. Comings and Comings (1987) also reported that patients with 19.1% of GTS reported a mania score 4, compared to none of the controls, as measured by the National Institute of Mental Health Diagnostic Interview Schedule. These data suggest that there is a link between BAD and GTS, however new epidemiological and etiological studies are required to gain further understanding.

2.7. Comorbidities: Impulse control disorders ICDs are also reported to occur concomitantly with GTS. While the true prevalence of ICDs in GTS has not been investigated, in a study of 23 patients with GTS, Frank, Piedad, Rickards, and Cavanna (2011) reported that 74.2% of patients had at least one ICD, with intermittent explosive disorder (IED) the most prevalent (51.6%). ICDs are categorized as a group of clinical conditions characterized by difficulties in impulse control and reward-seeking behavior. These occur in spite of their negative consequences (Frank et al., 2011). Other examples include kleptomania, pyromania, trichotillomania, and pathological gambling, to name a few. Research has shown that approximately 23–40% of patients with clinically referred GTS experience episodes of aggressive impulses that are disproportionate to the severity of a precipitating stressor or IED (Budman, Bruun, Park, & Olson, 1998; Wright, Rickards, & Cavanna, 2012). When asked about precipitating factors, Kano, Ohta, Nagai, Spector, and Budman (2008) reported that 94.7% of a group of 29 adolescent patients experienced attacks when someone told them they were mistaken or wrong about a topic, 78.9% when patients’ own wishes were deviated from, and 73.7%

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when there was an alteration in their schedule. There was an increase in symptomatology in patients who experienced comorbid GTS and ADHD (56.7%), and a further increase with comorbid GTS, ADHD, and OCD (70.6%) (Mol Debes, Hjalgrim, & Skov, 2008). In an international study looking at 6805 patients with GTS, 14.8% reported SIB such as head banging, body slapping, head or face slapping, banging into hard objects with their bodies, and poking their bodies with sharp objects. The prevalence of SIB was found to increase when patients experienced comorbid ADHD when compared to GTS without comorbidities. By considering tics as part of a “tic-compulsion” spectrum, this may aid in offering an explanation for the presence of comorbid ICDs and GTS. Underlying both ICDs and GTS is a need to execute repetitive behaviors and an inability to inhibit these desires. However, the driving factors behind each condition differ; while patients with ICDs have impulses which result in gratification, patients with GTS have compulsions and tics, the execution of which reduces anxiety and internal distress. However, the increasing prevalence of ICDs in patients with GTS and comorbid OCD and ADHD also suggests that there is a degree of overlap between compulsions and impulses, and over time it might be difficult to ascertain where the need to obtain gratification stops and the urge to relieve dysphoria starts.

2.8. Comorbidities: Autistic spectrum disorders In recent years, there has been an increasing interest in the etiology of GTS. While no unified theory yet exists, there has been a particular focus on its genetic and molecular etiologies. Through this research, it has also brought to light a pathogenic link with autism spectrum disorders (ASDs) (State, 2010). As the name suggests, ASD encompasses a spectrum of developmental syndromes of a deficit in social communication, language development, and stereotyped behaviors. Autism in its classical form requires deficits in all three domains, while the presence of one or two domains results in disorders along the disease spectrum (State, 2010). As with many other GTS comorbidities, there is inconsistency in the rates of concomitant ASD and GTS, with values ranging from 6.5% to 50%. However, this may be due to variable study populations, with differing clinical characteristics, disease severity, cognitive abilities, and the presence or absence of brain damage (Baron-Cohen, O’Riordan, Stone, Jones, & Plaisted, 1999; Burd, Kerbeshian, Wikenheiser, & Fisher, 1986; Simonoff et al., 2008). Fernandez et al. (2012) recently carried out an analysis of gene copy number

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variants in GTS and found significant overlap and enrichment of genes implicated in ASD in patients with GTS when compared to controls, suggesting a common pathogenetic mechanism. GTS and ASD share common clinical features; of particular interest is the presence of involuntary movements, which take the form of tics in GTS and stereotypies in ASD (Clarke, Lee, & Eapen, 2012). Stereotypies are repetitive movements or postures that are ritualistic in nature (Clarke et al., 2012). They can be suppressed more easily than tics (Singer, 2010). Examples include head nodding, rocking, and hand flapping (Singer, 2010) and can be misdiagnosed as complex motor tics. There are specific differences between stereotypies and tics (Table 1.3), which should be recognized to ensure that concomitant GTS and ASD are both identified. Stereotypies are also a feature of patients with LDs, which are characterized by cognitive, adaptive, and social skill deficits (Matson & Shoemaker, 2009), and have been found to be most common in patients with comorbid LD and ASD (Smith & Matson, 2010). Burd, Freeman, Klug, and Kerbeshian (2005) used the Tourette Syndrome International Consortium database to further study the relationship between GTS and LD. Of 5450 patients with GTS across an international scale, 1235 patients were found to have comorbid LD, with a diagnosis of either specific LD or learning disorders not otherwise specified in the DSM-IV. Logistic regression analysis was used to produce a five-variable model, which predicted the presence of LD in 65.2% of patients with GTS. These included male gender, younger age at diagnosis, complications during labor and delivery, fewer family members affected, and increased comorbid disease. Interestingly, in an Table 1.3 Main differentiating features between tics and stereotypies Feature Tics Stereotypies

Onset

5–7 years

1–4 years

Sensory experiences

Premonitory urges

Nil

Motor patterns

Dynamic repertoire

Fixed repertoire

Most common localization

Face, neck

Arms, hands

Temporal pattern

Sudden and intermittent, nonrhythmic

Repeated and prolonged, rhythmic

Strongest alleviating factors

Concentration

External distraction

Response to antidopaminergic treatment

Good

Poor

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association study looking at the relationship between tic disorders and poor academic performance in 1867 school-aged children, Cubo et al. (2013) found that the rate of LD and the need for academic support were similar in children with and without tics. Regardless, it is important to identify patients with concomitant LD and GTS and provide them with the academic support they require.

2.9. Comorbidities: Personality disorders The term “personality disorders” encompasses a wide range of clinical disorders whereby patients exhibit behaviors and cognitive processes that deviate from cultural expectations. These differences can be in five major personality disorders, including extraversion, neuroticism, agreeableness, conscientiousness, and openness (Eddy, Rickards, Critchley, & Cavanna, 2013). Research has shown that patients with GTS are more likely to exhibit personality disorders. In a study carried out by Robertson, Banerjee, FoxHiley, and Tannock (1997), 25/39 patients with GTS were found to have at least one personality disorder, compared to 2/34 controls. Patients experienced a wide range of personality disorders, the most common of which was borderline (n ¼ 11), followed by depressive (n ¼ 9), obsessive– compulsive (n ¼ 9), paranoid (n ¼ 9), passive aggressive (n ¼ 9), avoidant (n ¼ 8), antisocial (n ¼ 4), narcissistic (n ¼ 4), hysterical (n ¼ 3), schizoid (n ¼ 3), schizotypal (n ¼ 2), and self-defeating (n ¼ 2). These results are a reflection of the seminal study carried out by Shapiro, Shapiro, Bruun, and Sweet (1978), who were the first to report personality disorders in 27 of 36 patients with GTS. More recently, Eddy et al. (2013) found that in 25 patients with GTS there were overarching differences, when compared to controls, in four out of five personality domains, including conscientiousness, openness, extraversion, and emotional stability. Interestingly, these results were obtained despite there being no differences between patients and controls, in the context of depressive scores or personal experience of positive and negative emotions. The differences in personality traits also tended to be more pronounced in the presence of comorbid conditions such as OCD and ADHD. There was hence a suggestion that the differences in personality were independent of affect and emotion in patients with GTS. The relationship between schizotypy, tic-related symptoms, and other comorbid psychopathologies was further explored by Cavanna, Robertson, and Critchley (2007), in addition to quantifying the prevalence of schizotypal personality traits in GTS. Through using a combination of the


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Schizotypal Personality Questionnaire, standardized neurological and psychiatric rating scales, 15/102 patients were diagnosed with a schizotypal personality disorder, as defined by the DSM-IV criteria. In patients with multiple psychiatric comorbidities, there was a positive correlation with schizotypy scores; due to the high prevalence of comorbidities in GTS, schizotypy and schizotypal personality disorder should not be ignored. The presence of high anxiety ratings and obsessionality were the strongest predictors of schizotypy and reflect the possibility of a common psychopathology with anxiety spectrum disorders such as OCD (Cavanna, Martino, et al., 2009; Cavanna et al., 2007). There is currently limited research and understanding of the possible causal relationship between tics and personality traits or disorders, and there is a wide scope for further research in this area. It is likely that personality disorders in the context of GTS are both underinvestigated and underdiagnosed, and should be acknowledged as a clinically relevant issue.

2.10. Natural history and multiple phenotypes As GTS is a syndrome with onset in childhood, there is great interest in the natural history and prognosis of children with GTS as they progress into adulthood. Through prognostic studies, it has come to light that the majority of patients display a consistent course of disease (Leckman, King, et al., 1998; Leckman, Zhang, et al., 1998), reaching a peak in disease severity at approximately 10 years of age. In the majority of cases, this is followed by a gradual decline in tic severity during the second decade of life (Hassan and Cavanna, 2012; Leckman, King, et al., 1998; Leckman, Zhang, et al., 1998). There is therefore a positive prognosis for these patients, with 10–44% of patients being reported as achieving almost or total remission by early adulthood (Burd et al., 2001; Pappert, Goetz, Louis, Blasucci, & Leurgans, 2003). Looking at both historical and recent data, there has been a reported decline of tic severity over time, as experienced by between 59% and 85% of patients (Bloch, Peterson, et al., 2006; Burd et al., 2001; Erenberg, Cruse, & Rothner, 1986; Zausmer, 1954). While this positive prognosis is the case for the majority of patients, it is important to note that in a prospective study, approximately 10% of patients experienced greater tic severity (Burd et al., 2001). As highlighted earlier on in this chapter, factors that may influence this negative prognosis may include greater tic severity during childhood (Bloch, Peterson, et al., 2006), and neurobiological features such as caudate nucleus volume, which has been found to be inversely proportional to the

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severity of tics and OCD symptoms in early adulthood (Bloch, 2005). Rizzo, Gulisano, Cali, and Curatolo (2012) examined the long-term course of patients with GTS and found that patients with GTS and concomitant ADHD and OCD were more likely to experience a variable clinical picture at 10 years after follow-up and achieved worse symptom control than patients with pure GTS. Understanding the natural history of disease is of particular importance when interacting with children and their parents; often patients’ families are concerned about their prognosis as they develop through childhood and adolescence. Prognostic studies may be important in allaying their fears and concerns.

2.11. Final considerations Since its first description by Georges Gilles de la Tourette in 1885, our understanding of GTS has evolved and increased. While this is the case, every answer brings with it more questions (Mariam & Cavanna, 2012). At its most fundamental level, GTS bridges the gap between neurology and psychiatry. The presence of behavioral problems, motor and vocal tics, and other commonly occurring psychiatric comorbidities means that it may be more accurate to consider GTS as a spectrum of disease, rather than a single syndrome. This also has important implications in the diagnosis and subsequent management of patients. Although the World Health Organization (1992) and the American Psychiatric Association DSM-5 criteria consider GTS as a single condition, there is increasing evidence to suggest that there may not be one single GTS phenotype. This has been shown using principal component factor analysis (Alsobrook & Pauls, 2002; Eapen, Fox-Hiley, Banerjee, & Robertson, 2004; Robertson & Cavanna, 2007b, 2008; Storch et al., 2004), hierarchical cluster analysis (Mathews et al., 2007; Robertson & Cavanna, 2008), and latent class analysis (Grados, Mathews, & The Tourette Syndrome Association International Consortium for Genetics, 2008) (Table 1.4). This expansion in the spectrum and phenotypic variation in GTS presents clinicians with challenges in developing treatment strategies aimed at improving patients’ health-related quality of life (Cavanna, David, Robertson, & Orth, 2012; Cavanna et al., 2013; Cavanna, Schrag, et al., 2008; Eddy, Cavanna, et al., 2011; Eddy et al., 2012; Eddy, Rizzo, et al., 2011). Patients are diagnosed with GTS in early childhood. However, despite the fact that most symptoms diminish in severity as patients enter adulthood, Tourette syndrome is considered to be a lifelong neuropsychiatric disorder.

Table 1.4 Studies on the clinical phenotypes of Gilles de la Tourette syndrome Genetically Study Sample (n) related Clinical variables

Method(s)

Factors/clusters

Alsobrook and Pauls (2002) 85

No

Tics

HCA þ PCFA Aggression Tics Compulsions Tapping þ absence of grunting

Eapen et al. (2004)

91

No

Behavioral symptoms

PCFA

Obsessionality Anxiety/depression

Storch et al. (2004)

76

No

Tics þ behavioral symptoms

PCFA

Aggression ADHD OCD Tics

Mathews et al. (2007)

254

No

Tics

HCA

Simple tics Complex tics þ OCS

Robertson and Cavanna (2007a, 2007b)

69 from 1 large pedigree

Yes


HCA þ PCFA Tics ADHD þ aggression Anxiety/depression/ obsessionality þ SIB

Grados et al. (2008)

952 subjects from 222 families

Yes


LCA

GTS þ OCS GTS þ OCD GTS þ OCD þ ADHD Minimally affected class CMT þ OCD Continued

Table 1.4 Studies on the clinical phenotypes of Gilles de la Tourette syndrome—cont'd Genetically Study Sample (n) related Clinical variables Method(s)

Factors/clusters

Robertson and Cavanna (2008)

410

No

Tics

HCA þ PCFA NOSIB þ CVT CMT Simple tics Compulsions Self-touching

Cavanna et al. (2011)

639

No


PCFA

Complex motor tics þ echo/paliphenomena ADHD symptoms þ aggressive behaviors Complex vocal tics þ coprophenomena

GTS, Gilles de la Tourette syndrome; PCFA, principal-component factor analysis; HCA, hierarchical cluster analysis; LCA, latent class analysis; ADHD, attention deficit hyperactivity disorder; OCD, obsessive compulsive disorder; SIB, self-injurious behaviors; NOSIB, nonobscene socially inappropriate behaviors; CVT, complex vocal tics; CMT, complex motor tics; OCS, obsessive compulsive symptoms.


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The presence of comorbidities is common and occurs in approximately 90% of patients. Although ADHD and OCD are most common, patients also experience affective and personality disorders (Cavanna, Servo, et al., 2009; Robertson, 2000), LDs, and ASD. By considering GTS as a spectrum of disease, it is also possible to think of a “behavioral spectrum” of GTS. This has been reflected in similar findings in specialist services and clinics (Cavanna et al., 2011; Freeman et al., 2000) and in the community (Khalifa & von Knorring, 2005). Despite the fact that TS since its first description was considered a unitary condition, converging data from recent studies suggest that the TS phenotype is heterogeneous. More specifically, it has been suggested (Robertson, 2000) that dividing TS into three subcategories would be clinically useful: (i) pure TS, consisting primarily and almost solely of motor and phonic tics; (ii) full blown TS, including coprophenomena, echophenomena, and paliphenomena; and (iii) TS-plus, a category coined by Packer (1997), where TS coexists with ADHD, significant obsessive compulsive behavior or obsessive compulsive disorder and SIB. Patients with severe psychopathology (such as symptoms of depression, anxiety, antisocial behavior, etc.) can be included in the latter category. In summary, it is becoming increasingly evident that this quintessentially neuropsychiatric condition affects all aspects of patients’ lives. In particular, the social implications of a diagnosis of GTS are considerable, insomuch as the general public’s perceptions of normality dictate the stigma associated with GTS. Through transgressing social “norms,” patients are subject to exclusion and prejudice. Through conducting further cohort studies and identifying specific biomarkers for subtypes of the disorder (Albin & Mink, 2006; Felling & Singer, 2011; Singer, 2005), it might be possible to tailor treatments to patients’ comorbidities and behavioral problems.

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