Tics and Tourette syndrome

Motor symptoms

TS, the most common cause of tics, is manifested by a broad spectrum of motor and behavioral disturbances ( Fig. 15.1 ). This clinical heterogeneity often causes diagnostic difficulties and presents a major challenge in genetic linkage studies. To aid in the diagnosis of TS, formulated the following criteria for definite TS: (1) Both multiple motor and one or more phonic tics have to be present at some time during the illness, although not necessarily concurrently. (2) Tics must occur many times a day, nearly every day, or intermittently throughout a period of more than 1 year. (3) The anatomic location, number, frequency, type, complexity, or severity of tics must change over time. (4) Onset must be before age 21. (5) Involuntary movements and noises cannot be explained by other medical conditions. (6) Motor and/or phonic tics must be directly witnessed by a reliable examiner at some point during the illness or must be recorded by videotape or cinematography. Probable TS type 1 meets all the criteria except for number 3 and/or number 4, and probable TS type 2 meets all the criteria except for number 1; it includes either a single motor tic with phonic tics or multiple motor tics with possible phonic tics. According to DSM-5 ( ) the following are criteria required for the diagnosis of definite TS:

• A.

  Both multiple motor and one or more vocal tics are present at some time during the illness, although not necessarily concurrently.

• B.

  The tics may wax or wane in frequency but have persisted for more than 1 year since first tic onset.

• C.

  Onset is before age 18 years.

• D.

  The disturbance is not attributable to the physiologic effects of a substance (e.g., cocaine) or a general medical condition (e.g., Huntington disease [HD], postviral encephalitis).

According to DSM-5, if child has tics of less than 1-year duration, the most appropriate diagnosis is provisional tic disorder (PTD), which replaced the term transient tic disorder ( ). The point prevalence of PTD varies with age, but it has been estimated that about 20% of children aged 5 to 10 years have PTD, although the lifetime prevalence is much higher. The majority of children whose tics started within the past year will continue to have tics, and only about 32% remain completely tic-free over the next 5 to 10 years.

The TSA International Genetic Collaboration developed the Diagnostic Confidence Index, which consists of 26 confidence factors, with weightings given to each of them and a total maximum score of 100. The most highly weighted diagnostic confidence factors include history of coprolalia, complex motor or vocal tics, a waxing and waning course, echo phenomenon, premonitory sensations, an orchestrated sequence, and age at onset. The Diagnostic Confidence Index was found to be a useful instrument in assessing the lifetime likelihood of TS ( ). Several instruments, some based on ratings of videotapes and others on monitoring wearable devices ( ), have been developed to measure and quantitate tics, but they all have some limitations ( ; ). The most widely used instrument to assess tics is the Yale Global Tic Severity Scale (YGTSS), which consists of two broad domains: Total Tic Severity (TTS) (with five dimensions: number, frequency, intensity, complexity, and interference, each rated on 0–5 scale), with two subdomains: Motor and Phonic Tics and Impairment. The TTS ranges from 0 to 50 (the usual range in most studies is 15–30) and the Total YGTSS is the sum of TTS and Impairment (0–50). A health-related quality of life (HRQOL) scale has been developed and validated for internal consistency, test–retest reliability, and against other clinical scales ( ). Use of the HRQOL scale showed that comorbidities such as ADHD and OCD rather than tic severity are more predictive of the long-term outcome. The Movement Disorders Society (MDS) subcommittee commissioned to rate psychometric quality of severity and screening instruments for tics and related sensory phenomena associated with TS, issued their recommendations ( ). Of the severity scales, the authors “recommended” five: (1) YGTSS, (2) Tourette Syndrome Clinical Global Impression, (3) Tourette’s Disorder Scale, (4) Shapiro TS Severity Scale, and (5) Premonitory Urges for Tics Scale, and “suggested” six scales: (1) Rush Video-Based Tic Rating Scale; (2) Motor Tic, Obsessions and Compulsions, Vocal Tic Evaluation Survey (MOVES); (3) Tourette Syndrome Global Scale; (4) Global Tic Rating Scale; (5) Parent Tic Questionnaire; and (6). Tourette Syndrome Symptom List. They also “recommended” two diagnostic screening instruments: (1) MOVES and (2) Autism-Tics, ADHD, and other comorbidities inventory. They concluded that there was no need to develop new tic severity or screening instruments.

The clinical criteria are designed to assist in accurate diagnosis, in genetic linkage studies, and in differentiating TS from other tic disorders ( ) (see Table 15.1 ). A body of evidence supports the notion that many, if not all, patients with other forms of idiopathic tic disorders represent one end of the spectrum in a continuum of TS ( ). The most common and mildest of the idiopathic tic disorders is the transient tic disorder (TTD) of childhood. This disorder is essentially identical to TS except the symptoms last less than 1 year, and therefore the diagnosis can be made only in retrospect. TTD has been estimated to occur in up to 24% of schoolchildren ( ). Chronic multiple tic disorder is also similar to TS, but the patients have either only motor or, less commonly, only phonic tics lasting at least 1 year. Chronic single tic disorder is the same as chronic multiple tic disorder, but the patients have only a single motor or phonic tic. This separation into transient tic disorder, chronic multiple tic disorder, and chronic single tic disorder seems artificial because all can occur in the same family and probably represent a variable expression of the same genetic defect ( ).

Although the diagnostic criteria require that the onset is present before the age of 21, in 96% of patients the disorder is manifested by age 11 (Robertson, 1989). In 36% to 48% of patients, the initial symptom is eye blinking, followed by tics involving the face and head. Blink rate in TS is about double of that of normal, age-matched controls ( ). During the course of the disease, nearly all patients exhibit tics involving the face or head, two-thirds have tics in the arms, and half have tics involving the trunk or legs. According to one study, the average age at onset of tics is 5.6 years, and the tics usually become most severe at age 10; by 18 years of age, half of the patients are tic-free ( ). In a study of 58 adults who had been diagnosed with TS during childhood, Goetz and colleagues (1992) found that tics persisted in all patients but were moderate or severe in only 24%, although 60% had moderate or severe tics during the course of the disease. Tic severity during childhood had no predictive value for the future course, but patients with mild tics during the preadult period had mild tics during adulthood. In a longitudinal study that involved structured interviews of 976 children, aged 1 to 10 years, 776 of whom were reassessed 8, 10, and 15 years later, tics and ADHD symptoms were associated with OCD symptoms in late adolescence and early adulthood ( ). Furthermore, ADHD was associated with lower IQ and lower social status, whereas OCD was associated with higher IQ. These findings are similar to those of another study designed to address the long-term prognosis of children with TS as they reach adulthood ( ). In this study, 46 children with TS underwent a structured interview at a mean age of 11.4 years and again at 19.0 years. The mean worst-ever tic severity score was 31.6 out of a possible 50 on the YGTSS and occurred at a mean age of 10.6 years. By the time of the second interview, mean YGTSS score decreased to 10. This first prospective longitudinal study also showed that 22% continue and nearly one-third were in complete remission of tic symptoms at follow-up. In contrast to the study by Goetz and associates (1992), the severity of childhood tics was predictive of increased tic severity at follow-up. The peak OCD severity occurred 2 years after peak tic severity. Interestingly, a 10-point increase in baseline IQ increased the risk for OCD symptoms at follow-up by 2.8 fold. The authors point out that the later average onset of OCD symptoms indicates the importance of counseling parents about the possibility of OCD development in children recently diagnosed with tics. Although the long-term prognosis for TS is generally favorable for most patients, a minority of cases may have persistent, severe tic symptoms, which may be resistant to medications ( ). In a large prospective study in which the clinical cohort was recruited at the Danish National Tourette Clinic, with data collected at baseline (n = 314, age range 5–19 years) and at follow-up 6 years later (n = 227), tic severity declined yearly (0.8 points on the YGTSS during adolescence ( ). Of all the participants older than 16 years, 17.7% had no tics, 59.5% had minimal or mild tics, and 22.8% had moderate or severe tics. However, the authors found that 63.0% of participants had comorbidities or coexistent psychopathologic conditions at last follow-up. In another study, the investigators reviewed videotapes of 31 patients, with an average age of 24.2 ± 3.5 years, approximately 12 years after their initial video and found that 90% of the adults still had tics, even though they often considered themselves tic-free ( ). There was, however, a significant improvement in tic disability and tic severity. When 40 children and 31 adults with TS were compared no difference in tic phenomenology or severity was found, but children were more frequently managed without medications, and sedation was more common in adults but weight gain was more common in children ( ). We reviewed 43 adults with TS referred to our Movement Disorders Clinic over the past 5 years and compared them with 100 TS patients 18 years of age or younger ( ). We found that adult TS patients had significantly more facial and truncal tics, as well as a greater prevalence of substance abuse and mood disorders, but fewer phonic tics and lower rates of ADHD and oppositional behavior than children with TS. Furthermore, adult TS largely represented a re-emergence or exacerbation of childhood-onset TS. During the course of TS, phonic and complex motor tics, self-injurious behaviors (SIBs), and ADHD tend to improve, but facial, neck, and trunk tics dominate the adult TS phenotype.

Although the vast majority of tics in adults represent recurrences of childhood-onset tics, rare patients may have their first tic occurrence during adulthood ( ). In adults with new-onset tics, it is important to search for secondary causes, such as infection, trauma, stroke ( ; ), multiple sclerosis (Silvers and Menkes, 2009), cocaine use, neuroleptic exposure, and peripheral injury ( Video 15.14 ) ( ; ; ). One study of eight patients with adult-onset tics (three of whom had childhood-onset OCD and three of whom had a family history of tics and OCD) found that in comparison to the patients with more typical childhood-onset tics, the former group had more severe symptoms, greater social morbidity, and less favorable response to medications ( ). Poor motor control, which can lead to poor penmanship and, at times, almost illegible handwriting, can contribute to the academic difficulties faced by many patients with TS.

Video 15.14 Peripherally induced tics.

Tics, although rarely disabling, can be quite troublesome for TS patients because they cause embarrassment, interfere with social interactions, and at times can be quite painful or uncomfortable. Rarely, cervical tics may be so forceful and violent, the so-called “whiplash tics,” that they may cause secondary neurologic deficits, such as cervical artery dissection and noncompressive ( ; ) or compressive cervical myelopathy ( ; ) ( Video 15.2 ). The truncal bending tics, which resemble intermittent, repetitive camptocormia, may cause secondary degenerative changes in the thoracic spine ( ) ( Video 15.5 ). These disabling tics and other severe symptoms of TS draw attention to the subset of patients with TS so severe that they may be life-threatening, hence labeled as “malignant” TS. Of 332 TS patients evaluated at Baylor College of Medicine Movement Disorders Clinic during a 3-year period, 17 (5.1%) met criteria for malignant TS, defined as two or more emergency department (ED) visits or one or more hospitalizations for TS symptoms or its associated behavioral comorbidities ( ). The patients exhibited tic-related injuries, SIB, uncontrollable violence and temper, and suicidal ideation/attempts. Compared with patients with nonmalignant TS, those with malignant TS were significantly more likely to have a personal history of obsessive compulsive behavior/disorder (OCB/OCD), complex phonic tics, coprolalia, copropraxia, SIB, mood disorder, suicidal ideation, and poor response to medications. Severe or malignant TS, associated with SIB and other disabling features, also has been reported in families, including consanguine kindreds ( ). In a study of 75 patients diagnosed with “tic disorder,” ages 6 to 18 years, 61% expressed at least some suicidal ideation and 8% expressed clinically significant symptoms ( ). Suicidal ideation correlated with higher anxiety, depression and externalizing symptoms, affective lability, lower distress tolerance, and overall function; tic severity was not associated with suicidal ideation.

Vocalizations have been reported as the initial symptom in 12% to 37% of patients, throat clearing being the most common (Robertson, 1989). Phonic tics can be quite troublesome for patients and those around them. In addition to involuntary noises, some patients have speech dysfluencies that resemble developmental stuttering and up to half of all patients with developmental stuttering have been thought to have undiagnosed TS ( ). Coprolalia, perhaps the most recognizable and certainly one of the most distressing symptoms of TS, is actually present in only half of patients ( Video 15.8, Video 15.15 ). When describing the distress caused by his severe coprolalia, one of our patients remarked that immediately after shouting an obscenity, he reaches out with his hand in an attempt to “catch the word and bring it back before others can hear it.” Coprolalia appears to be markedly influenced by cultural background. Although in one retrospective analysis of 112 children with TS, only 8% exhibited coprolalia ( ), the true prevalence of coprolalia in TS children and adults is about 50% in the U.S. population, when mental coprolalia (without actual utterance) is included. In a study of 597 individuals with TS from seven countries, coprolalia occurred at some point in the course of the disease in 19.3% of males and 14.6% of females, and copropraxia in 5.9% of males and 4.9% of females ( ). Coprolalia has been reported to occur in 26% of Danish patients and 4% of Japanese patients (Robertson, 1989). Copropraxia has been found in about 20% of patients, echolalia in 30%, echopraxia in 25%, and palilalia in 15%. Although coprolalia is a characteristic feature of TS and, based on fMRI studies, attributed to abnormal activation particularly in the left middle frontal gyrus and right precentral gyrus, and possibly the caudate nucleus, cingulate gyrus, cuneus, left angular gyrus, left inferior parietal gyrus, and occipital gyri ( ), this language abnormality is not universally present or specific for TS.

Video 15.15 Coprolalia.

Except tics, the neurologic examination in patients with TS is usually normal. In one case-control study, TS patients were found to have a shorter duration of saccades, but the saccades were performed with a greater mean velocity than in normal controls, and the TS patients had fewer correct antisaccade responses, suggesting a mild oculomotor disturbance in TS ( ). Although the ability to inhibit reflexive saccades is normal, TS patients make more timing errors, indicating an inability to appropriately inhibit or delay planned motor programs ( ).

Behavioral symptoms

Patients with TS generally have normal intelligence and may even perform better and faster than age-matched controls on certain tasks that require grammar skills that depend on procedural, rather than declarative memory ( ). Although TS patients have no cognitive deficits, they often exhibit a variety of behavioral symptoms, particularly ADHD and OCD ( ). In the Tourette International Consortium (TIC) database, which includes information on 3500 patients with TS evaluated by neurologists or psychiatrists, 12% had tics only, without other comorbidities ( ). Kurlan and colleagues (2002) interviewed 1596 children, ages 9 to 17, in schools in Rochester and Monroe Counties, New York, and identified tics in 339 children (21%) after 60 to 150 minutes of observation. They found the following behavioral problems more frequently ( P < 0.05) in children with tics than in those without tics: OCD, ADHD, separation anxiety, overanxious disorder, simple phobia, social phobia, agoraphobia, mania, major depression, and oppositional defiant behavior. In addition, children with tics were younger (mean age: 12.5 versus 13.3 years) and were more likely to require special education services (27% versus 19.8%). In cross-sectional structured diagnostic interviews conducted in 1374 patients with TS and in 1142 TS-unaffected family members, the lifetime prevalence of any psychiatric comorbidity among individuals with TS was 85.7%; 57.7% of the population had two or more psychiatric disorders, and 72.1% of the individuals met the criteria for OCD or ADHD ( ). Other disorders, including mood, anxiety, and disruptive behavior, each occurred in approximately 30% of the participants. The age of greatest risk for the onset of most comorbid psychiatric disorders was between 4 and 10 years, with the exception of eating and substance use disorders, which began in adolescence (interquartile range, 15–19 years for both).

A thorough discussion of the pathogenesis of comorbid disorders and their relationship to TS is beyond the scope of this review, and the reader is referred to some reviews on these topics ( ; ; ). The diagnosis of ADHD and OCD is based on clinical history; there are no laboratory or other tests that reliably diagnose these neurobehavioral disorders ( ; ; ; Grant, 20014; ) ( Table 15.2 ). The biologic basis of frequent coexistence of ADHD and OCD is not well understood, but certain genetic variants are present in both disorders and similar deficits in executive functions are shared by the two disorders and may be responsible for the compulsive symptoms in OCD and disinhibited and impulsive symptoms in ADHD ( ). These comorbid behavioral conditions often interfere with learning and with academic and work performance ( ). In contrast to tics, ADHD and obsessional symptom severity are significantly associated with impaired social and emotional adjustment ( ). The clinician should be skilled not only in the recognition and treatment of ADHD but also in documenting the ADHD-related deficits ( ). One study provided compelling evidence that patients with TS experience substantial academic underachievement across all educational levels compared with children without the diagnosis of TS ( ). Such documentation is essential for the parents and educators to provide the optimal educational setting for the affected individual.

Because nearly all studies on the frequency of associated features have been based on a population of TS patients who have been referred to physicians, usually specialists, there is a certain selection bias; therefore, accurate figures on the prevalence of these behavioral disorders in TS patients are not available. It has been estimated, however, that 3% to 6% of the school-aged population suffers from ADHD ( ) and probably a majority of patients with TS have had symptoms of ADHD, OCD, or both at some time during the course of their illness ( ). In a review of 1500 patients with TS, 48% were diagnosed as having ADHD, a figure that is consistent with the results of other studies ( ). The symptoms of ADHD may be the initial manifestations of TS and may precede the onset of motor and phonic tics by about 3 years. During this time, therapy with stimulant drugs may trigger the onset of tics and may precipitate the emergence of other TS symptoms ( ).

There are three types of ADHD: predominantly inattentive, predominantly hyperactive-impulsive, and combined ( ) (see Table 15.2 ). ADHD is one of the most common neurobehavioral disorders, affecting 3% to 10% of children and 4% of adults ( ; ). Adults with ADHD often have childhood histories of educational and discipline problems; and during adulthood they usually have lower socioeconomic status, lower rates of professional employment, and higher rates of marital problems, driving violations, and other life failures. In a genome scan of 106 families, including 128 affected sib-pairs with estimated heritability of 60% to 80%, multipoint multilevel selection values greater than 1 were evidence of a gene locus on chromosomes 4, 9, 10, 11, 12, 16, and 17 ( ). Further research is needed to improve our understanding of the genetics and neurobiology of ADHD ( ; ).

Although attention deficit is certainly one of the most common and disabling symptoms of TS, in many patients the inability to pay attention is due to not only a coexistent ADHD but also uncontrollable intrusions of thoughts. Some patients are unable to pay attention because of a compulsive fixation of gaze. For example, while they are sitting in a classroom or a theater or during a conversation, their gaze becomes fixated on a particular object, and despite concentrated effort, they are unable to break the fixation. As a result, they miss the teacher’s lesson or a particular action in a play. Another reason for impaired attention in some TS patients is mental concentration exerted in an effort to suppress tics. Yet another cause for inattention is the sedative effect of anti-TS medications. It is therefore important to determine which mechanism or mechanisms are most likely to be responsible for the patient’s attention deficit. This is particularly important in selecting the best therapeutic approach. Despite growing publicity about ADHD, there is little evidence of widespread overdiagnosis or overtreatment of ADHD ( ). One study showed that children and adolescents with ADHD compared with those without ADHD are more likely to have major injuries and asthma, and their 9-year medical costs are double ( ). The mechanism of ADHD with or without TS is not well understood, and there are no specific pathologic abnormalities identified. However, by using high-resolution MRI, abnormal morphology was observed in the frontal cortices, reduction in the anterior temporal cortices, and increased gray matter in the posterior and inferior parietal cortices in children and adolescents with ADHD ( ). Children with ADHD have been found to have great theta/beta power on electroencephalogram (EEG). The U.S. Food and Drug Administration (FDA) approved the Neuropsychiatric EEG-Based ADHD Assessment Aid to be used by a clinician as confirmatory support or to pursue further testing after an evaluation for ADHD, in a child aged 6 to 17, but subsequent reviews suggested more research was needed before it could be recommended as a routine test for ADHD ( ).

OCD as a part of the spectrum of neurobehavioral manifestations in TS is well accepted ( ; ; ; ; ; ). OCD, with an estimated lifetime prevalence of 2% to 3% ( ; ) and an incidence of 0.55 per 1000 person years ( ) is one of the most frequent causes of disability ( ). It may occur alone without other features of TS (Micallef and Blin, 2001). The instrument used most frequently to measure the severity of OCD is the Yale-Brown Obsessive Compulsive Scale ( ). A distinction should be made between obsessive-compulsive symptoms or traits, obsessive-compulsive personality disorder, and OCD. Obsessions are characterized by intense, intrusive thoughts, such as concerns about bodily wastes and secretions; unfounded fears; need for exactness, symmetry, evenness, and neatness; excessive religious concerns; perverse sexual thoughts; and intrusions of words, phrases, or music. Compulsions consist of subjective urges to perform meaningless and irrational rituals, such as checking, counting, cleaning, washing, touching, smelling, hoarding, and rearranging. Leckman and colleagues (1994) have drawn attention to the frequent occurrence of the “just right” perception in patients with OCD and TS. Although obsessional slowness accounts for some of the school problems experienced by TS patients, cognitive slowing (bradyphrenia) is also a contributing factor ( ). Patients with OCD can usually be divided into those with a predominantly cognitive form (in which an idea is followed by a ritual) and those with a sensorimotor type (in which a physical sensation is followed by a movement). In contrast to primary OCD, in which the symptoms relate chiefly to hygiene and cleanliness, the obsessive symptoms associated with TS usually involve concerns with symmetry, violent aggressive thoughts, forced touching, fear of harming self or others, and need for saying or doing things “just right” ( ). A principal-components factor analysis of 13 categories that are used to group types of obsessions and compulsions in the Yale-Brown Obsessive Compulsive Scale symptom checklist identified the obsessions and checking and the symmetry and ordering factors as particularly common in patients with tic disorders ( ). Miguel and colleagues (2000) showed that patients who have OCD associated with TS tend to have more bodily sensations occurring either before or during the patient’s performance of the repetitive behaviors and mental sensations, including urge only, energy release (mental energy that builds up and needs to be discharged), and “just right” perceptions. Cognitive inflexibility manifested by impaired task-switch ability in patients with OCD has been suggested to be due to “imbalance in brain activation between dorsal and ventral striatal circuits” ( ). Studies have found that OCD patients exhibited excessive habits that were associated with hyperactivation of the caudate nucleus ( ).

In addition to an idiopathic sporadic or familial disorder and TS, OCD has been reported to occur as a result of a variety of lesions in the frontal-limbic-subcortical circuits ( ; ; ). Although both ADHD and OCD are regarded as integral findings of the syndrome, only OCD has been shown to be genetically linked to TS ( ). A pathogenic link between TS and OCD is also suggested by the finding in one study that 59% of 54 patients with OCD had a lifetime history of tics, and 14% fulfilled the criteria for TS during the 2- to 7-year follow-up ( ). Alsobrook and Pauls (2002) identified four significant factors: (1) aggressive phenomena (e.g., kicking, temper fits, argumentativeness), (2) purely motor and phonic tic symptoms, (3) compulsive phenomena (e.g., touching of others or objects, repetitive speech, throat clearing), and (4) tapping and absence of grunting, which accounted for 61% of the phenotypic symptom variance in TS probands and their first-degree relatives.

An important link between motor and behavioral manifestations of TS is the loss of impulse control. Many TS patients suffer from poor impulse control, disinhibition of aggression and emotions, and obsessive thoughts that may dictate their actions. Indeed, many behavioral symptoms of TS, including some complex tics, coprolalia, copropraxia, and many behavioral problems, can be explained by loss of normal inhibitory mechanisms (disinhibition) manifested by poor impulse control. It is as though the TS patients have lost their ability to suppress vestiges of primitive behavior. Poor impulse control might also explain the inability to control anger, as a result of which many patients have frequent and sometimes violent temper outbursts and rages. Rarely, TS patients exhibit inappropriate sexual aggressiveness and antisocial, oppositional, and even violent, unlawful, or criminal behavior. TS, indeed, serves as a model medical disorder that can predispose one to engage in uncontrollable and offensive behaviors that are misunderstood by the law-abiding community and the legal justice system ( ). The social and legal aspects of TS patients have yet to be investigated, but there is growing concern regarding media misrepresentation that attributes violent criminal behavior in certain individuals to TS. Although TS should not be used as an excuse to justify unlawful or criminal behaviors, studies are needed to determine whether TS-related symptoms and neurobehavioral comorbidities predispose TS patients to engage in such behaviors. Often, the avolitional nature of behaviors in response to involuntary internal thought and emotional patterns is supported by the subsequent remorse and lack of secondary gain. This suggests that the preponderance of unlawful acts committed by TS patients are not premeditated but may result from a variety of TS-related mechanisms such as poor impulse control, OCD associated with addictive behavior (e.g., drugs, alcohol, gambling), attention deficit disorder (ADD), distractibility (e.g., motor vehicle accidents), and coprolalia. Furthermore, there is no evidence that anti-TS medications increase risk for criminal behavior and, in fact, anti-ADHD medications have been found to reduce the risk for criminality ( ). A previous study ( ) compared conduct in 246 TS patients to that of controls for behaviors such as lying, stealing, fighting or inability to stop fighting, violence against animals, physically attacking peers or parents, vandalism, running away from home, starting fires, poor temper control, alcohol and drug abuse, and other misdemeanors. A group of 35% of TS patients had a conduct score higher than 13, significantly greater than the 2.1% of controls with high scores ( P < 0.0005). All behaviors with the exception of running away from home and trouble with the law occurred at a significantly greater rate in TS patients. Although no difference was found for the law variable, TS patients were significantly more likely to vandalize ( P < 0.0005), fight ( P < 0.0005), abuse drugs or alcohol ( P < 0.003), and steal ( P < 0.015). An interesting finding in this study was that certain behaviors, such as starting fires, shouting, and physically attacking, were significantly greater only in TS patients with comorbid ADD, supporting the well-established association of ADD in conduct disorder ( ). It was estimated from this study that 10% to 30% of conduct disorder cases in non–economically disadvantaged children may be attributed to a possible TS gene. In a more recent study, however, TS accounted for 2% of all cases that were referred for forensic psychiatric investigation in Stockholm, Sweden, between 1990 and 1995; 15% of the subjects had ADHD, 15% had PDD, and 3% had Asperger syndrome ( ). Scandinavian investigators also failed to find increased criminal behavior among schizophrenics or patients with bipolar disorder and general population ( ). There is no evidence that TS patients carry mutations in genes that have been implicated in violent behavior, such as monoamine oxidase A low-activity genotype or the CDH13 gene (coding for neuronal membrane adhesion protein) (Tiihonen et al., 2014).

Focal frontal lobe dysfunction, demonstrated in TS by various functional and imaging studies, has been associated with impulsive subtype of aggressive behavior ( ). It has been postulated that impulse disorders stem from exaggerated reward-, pleasure-, or arousal-seeking brain centers, resulting in failure of inhibition. Animal studies of rats with lesions of the nucleus accumbens core, the brain region that is noted for reward and reinforcement, showed that the lesioned rats preferred small, immediate rewards over larger, delayed rewards ( ). In addition to the ventromedial prefrontal cortices, lesions in the amygdala have also been known to result in altered decision-making processes and a disregard for future consequences ( ).

One of the most distressing symptoms of TS is an SIB, which has been reported in up to 53% of all patients (Robertson, 1989; ). A common form of SIB is damage of skin by biting, scratching, cutting, engraving, or hitting, particularly in the eye and throat (compulsions), often accompanied by an irresistible urge (obsession) ( ) ( Video 15.16, Video 15.17 ). In some patients, SIB can be life-threatening, hence the term “malignant” TS ( ). The mechanism of SIB is not well understood, but animal model may shed some light on this very important behavioral disorder that may accompany TS. A mouse with genetic deletion of Sapap3, a gene that codes for postsynaptic scaffolding protein at excitatory striatal synapses, has been proposed as a possible model of OCD because its phenotype is characterized by excessive compulsive grooming resulting in SIB, such as facial hair loss and skin lesions ( ). The similarity of this behavior to OCD is further supported by the observation that the mice markedly improved after treatment with a selective serotonin reuptake inhibitor (SSRI). Thus, SIB appears to be related to OCD, which has treatment implications. Besides OCD, SIB also correlates with impulsivity ( ). Conduct disorders and problems with discipline at home and in school are recurrent themes during discussions of behavioral problems with TS families. The inability to suppress or “edit” intentions because of a “dysfunctional intention editor” has been proposed as one of the chief reasons for poor impulse control in patients with TS ( ).

Video 15.16 Self-injurious behavior.

Video 15.17 Self-injurious behavior.

The TS gene(s) may, in addition to tics, ADHD, and OCD, express itself in a variety of behavioral manifestations, including learning and conduct disorders, schizoid and affective disorders, antisocial behaviors, oppositional defiant disorder, anxiety, depression, conduct disorder, severe temper outbursts, rage attacks, impulse control problems, inappropriate sexual behavior, and other psychiatric problems ( ; ). Personality disorder and depression have been reported in 64% of patients with TS ( ). Whether these behavioral problems indeed occur with higher frequency in TS patients and whether they are pathogenically linked to TS are debatable ( ; ).

Besides comorbid behavioral conditions, TS has been reported to be frequently associated with migraine headaches. In one study, 26.6% of TS patients, with a mean age of 11.9 years, exhibited migraine headaches ( ). We found migraine headaches in 25 carefully screened TS patients at a significantly greater rate than the estimated 11% to 13% in the general adult population ( P < 0.0001) and the general pediatric population ( P < 0.04) ( ). This compares to 4.0% to 7.4% in the general population of school-aged children. In a study of 109 TS patients, Ghosh and associates (2012) found either migraine headaches or tension-type headaches in 55% of the patients; the rate of migraine headache within the TS group was found to be four times greater than that of the general pediatric population. Unfortunately, the interpretation of the data is difficult because the investigators did not administer the same questionnaire to a control, age-matched population without TS. This limitation, coupled with the selected population of patients from a tertiary referral center, may not make the findings generalizable.

The Tourette International Consortium Database ( ), which included information on 3500 patients with TS collected from 64 centers from around the world, showed that 12% of patients with TS had no other disorders; ADHD was seen in 60%, symptoms of OCD in 59%, anger control problems in 37%, sleep disorder in 25%, learning disability in 23%, mood disorders in 20%, anxiety disorders in 18%, and SIB in 14%.

Neurophysiology

Although the pathogenic mechanisms of TS are still unknown, the weight of evidence supports an organic rather than psychogenic origin, probably involving the basal ganglia circuitry ( ; ; ; ; ; ; ; ) ( Fig. 15.2 ). Despite the observation that some tics may be voluntary, at least in part, physiologic studies suggest that tics are not mediated through normal motor pathways used for willed movements ( ). Using back-averaging techniques, Obeso and colleagues (1982) observed normal Bereitschaftspotential in six subjects who voluntarily simulated tic-like movements, but no such premovement potential was noted in association with an actual tic. The common absence of premotor potentials in simple motor tics suggests that tics are truly involuntary or that they occur in response to some external cue ( ). Karp and colleagues (1996), however, documented premotor negativity in 2 of 5 patients with simple motor tics. In another study Bereitschaftspotential was identified before tics in 6 in 14 (43%) of TS patients ( ). Although the investigators could not correlate the presence of Bereitschaftspotential with the premonitory sensation, the physiology of the premovement phenomenon requires further studies. Human physiologic recordings have revealed low frequency (1–10 Hz), the centro-median parafascicular (CM-PF) activity during tics, and modulations in beta rhythms over the motor cortex (Shute et al., 2016).

Transmagnetic stimulation used to study cortical excitability in 11 TS patients found evidence of motorcortical disinhibition at rest ( ). Using optogenetics in mice repeated stimulation of orbitofrontal cortex (OFC)-ventromedial striatum (VMS) (5 minutes per day for 5 days) generated a progressive increase in grooming, a behavior considered analogous to human OCD ( ). This behavior was reversed by chronic treatment with fluoxetine. Thus, increased activity at OFC-VMS may lead to dysregulation of cortico-striato-thalamo-cortical circuit and “multiple downstream events including (i) plasticity in downstream structures such as thalamus and prefrontal cortex and increased motivational saliency mediated by the ventral tegmental area.” This is consistent with the findings from clinical studies showing “efficacy of ventral capsule–ventral striatum deep brain stimulation (DBS) in OCD, which is thought to act via inhibition of OFC hyperactivity.” Further studies are needed to elucidate the pathophysiologic mechanisms of OCD and OCD subtypes ( ).

Conventional neurophysiologic investigations have found that TS patients have defective inhibitory mechanisms, as is suggested by the increased duration of the late response of the blink reflex and reduced inhibition at paired pulse testing ( ; ). TS patients also have exaggerated audiogenic startle response ( ). About 20% of patients with TS have exaggerated startle responses, which may fail to habituate with repetition ( ).

As was noted before, fMRI showed decreased neuronal activity during periods of suppression in the ventral globus pallidus, putamen, and thalamus and increased activity in the right caudate nucleus, right frontal cortex, and other cortical areas that are normally involved in the inhibition of unwanted impulses (prefrontal, parietal, temporal, and cingulate cortices) ( ). In another study of three patients with TS, fMRI showed marked reduction or absence of activity in secondary motor areas while the patient attempted to maintain a stable grip-load force control ( ). The authors interpreted the findings as an ongoing activation of the secondary motor reflecting patients’ involuntary urges to move. In a study of children with ADHD, fMRI showed increased frontal activation and reduced striatal activation on various tasks and an enhancement of striatal function after treatment with methylphenidate ( ). fMRI studies show decreased neuronal activity during periods of suppression in the ventral GP, putamen, and thalamus and increased activity in the caudate, frontal cortex, and other cortical areas that are normally involved in the inhibition of unwanted impulses (prefrontal, parietal, temporal, and cingulated cortical areas) ( ). By using event-related fMRI in 10 patients with TS, a brain network of paralimbic areas such as anterior cingulate and insular cortex, SMA, and parietal operculum was identified that predominantly activated before tic onset, whereas at the beginning of tic action, significant fMRI activities were found in sensorimotor areas, including superior parietal lobule bilaterally and cerebellum ( ). Resting-state functional connectivity MRI (rs-fcMRI) in 33 adolescents with TS, Church and colleagues (2009) found anomalous connections primarily in the frontoparietal network, suggesting widespread immature functional connectivity, particularly in regions related to adaptive online control. Functional immaturity and global functional disorganization of cortico–basal ganglia networks was found in another study using fMRI ( ). Using microinjections of bicuculline into the sensorimotor putamen as model of tics (predominantly in the orofacial region) in primates, the investigators found that 64% of the recorded cerebellar cortex neurons exhibited increases in activity in relationship to the tics ( ). Furthermore, the occurrence of tic movement was most closely associated with local field potential spikes in the cerebellum and primary motor cortex, indicating cerebellar involvement in the pathophysiology of tics. It is, however, doubtful that the orofacial movements produced by the bicuculline injections represent a true example of motor tic.

Transcranial magnetic stimulation studies have demonstrated a shortened cortical silent period and defective intracortical inhibition (determined in a conditioning test paired-stimulus paradigm) in patients with TS ( , ) and OCD ( ), thus providing a possible explanation for intrusive phenomena. Subsequent studies using the same technique have demonstrated that patients with tic-related OCD have more abnormal motor cortex excitability than do OCD patients without tics ( ). Transcranial magnetic stimulation studies have also demonstrated that TS children have a shorter cortical silent period but that their intracortical inhibition was not different from that of controls, although intracortical inhibition is reduced in children with ADHD ( ). There is evidence of additive inhibitory deficits, as demonstrated by reduced intracortical inhibition and a shortened cortical silent period in children with TS and comorbid ADHD. In another study, ADHD more than tics were associated with short-interval intracortical inhibition ( ). Both short-interval intracortical inhibition and short-interval afferent inhibition, modulated by nicotinic receptors, were reduced in 8 patients with TS (aged 24–38 years) compared with 10 matched healthy controls ( ). Comprehensive discussion of the neuroscience of ADHD is beyond the scope of this chapter, but the reader is referred to some reviews of this topic ( ). In addition to repetitive transcranial magnetic stimulation, transcranial electric stimulation targeting supplementary motor area or the temporo-parietal junction is being investigated as a treatment option in TS ( ).

Sleep studies have provided additional evidence that some tics are truly involuntary ( ). Polysomnographic studies in 34 TS patients recorded motor tics in various stages of sleep in 23 patients and phonic tics in 4 patients ( ; ). Additional sleep studies have suggested that some patients with TS have alterations of arousal, decreased percentage (up to 30%) of stage 3/4 (slow wave) sleep, decreased percentage of REM sleep, paroxysmal events in stage 4 sleep with sudden intense arousal, disorientation and agitation, restless legs syndrome (RLS), and periodic leg movement in sleep ( ; ; ). RLS has been reported to be present in about 10% of patients with TS and in 23% of parents ( ). In this regard, it is of interest that in a study in which 14 single-nucleotide polymorphisms were typed spanning the 3 genomic loci associated with RLS in 298 TS trios, 322 TS cases (including 298 probands from the cohort of TS trios), and 290 control subjects, the same variant of the gene BTBD9 that increases the risk for RLS also increases the risk for TS without OCD or ADD (“pure” TS) ( ). Other sleep-related disorders that are associated with TS include sleep apnea, enuresis, sleepwalking and sleep talking, nightmares, myoclonus, bruxism, and other disturbances (Rothenberger et al., 2000; ).