Morvan syndrome and related disorders associated with CASPR2 antibodies
Jan. 18, 2022
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Tourette syndrome is a chronic neurodevelopmental disorder consisting of motor and phonic tics. The onset is in childhood, and as many as 2% of children are affected, but epidemiological studies have shown that 20% to 30% of children exhibit tics at some time during childhood. Its peak severity usually occurs just prior to adolescence. Although the majority of patients have at least a partial remission in their tics after the age of 18, for most patients, Tourette syndrome is a lifelong condition, often associated with numerous behavioral comorbidities, including obsessive-compulsive disorder and attention deficit hyperactivity disorder. In this article, the author provides a succinct but thorough review of the current knowledge regarding the phenomenology, pathogenesis, and treatment of Tourette syndrome.
• Tourette syndrome is a neurobehavioral disorder chiefly manifested by motor and phonic tics.
• Most patients with Tourette syndrome have a variety of behavioral comorbidities, including obsessive-compulsive behavior, attention deficit disorder with or without hyperactivity, and impulse control disorder.
• Although no consistently present gene mutation has been identified, Tourette syndrome is considered a genetic disorder, often inherited bi-lineally (from both parents).
• Treatment of Tourette syndrome must be individualized and tailored to the needs of each patient.
Georges Gilles de la Tourette was a French neurologist, a trainee of Charcot at the Salpetriere Hospital in Paris (117). In 1885 he described 9 patients with motor and phonic tics, some of whom had echo phenomena, repeating other people’s words and phrases (echolalia) and repeating other people’s gestures (echopraxia). In addition, 5 of the 9 individuals were uttering or shouting obscenities and profanities (coprolalia). He considered the condition to be closely related to a group of startle disorders that included "the jumping Frenchmen of Maine,” described by Beard in 1880. For many years, the etiology of Tourette syndrome was ascribed to psychogenic causes. Observations were made in the 1960s that neuroleptic drugs that act by blocking dopamine receptors were effective in treating Tourette syndrome, and this refocused attention from a psychological etiology to an organic central nervous system etiology. Although Gilles de la Tourette himself believed this condition was hereditary, it was not until the late 1970s that a familial, genetic etiology for Tourette syndrome was fully recognized (97; 192). Once considered a rare psychiatric curiosity, Tourette syndrome is now recognized as a relatively common neurobehavioral disorder. There has been speculation that many notable historical figures, including Dr. Samuel Johnson and possibly Wolfgang Amadeus Mozart (11), were afflicted with Tourette syndrome.
Tics are brief, sudden, irregularly occurring, repetitive movements or sounds.
Tics generally have a more coordinated appearance than other dyskinesias and, although performed at inappropriate times, often resemble purposeful movements.
The 2 major categories of tics are motor and phonic (also known as vocal tics), but this division is artificial as phonic are essential motor ticks involving the nose, mouth, throat, and larynx. Each category is further subdivided into simple and complex types according to the perceived intricacy of the movement or sound. Motor tics characteristically first appear in the face, manifested by frequent blinking and facial grimacing, but multiple body regions can be involved. Rhythmical clonic tics may rarely resemble tremor or rhythmical myoclonus, such as palatal myoclonus (03). Although typical tics are clonic (jerk-like) many patients with Tourette syndrome also exhibit dystonic tics, produced by more prolonged muscle contractions resulting in briefly sustained abnormal posture or a squeezing movement such as blepharospasm. Some patients with Tourette syndrome have also been reported to manifest dystonia, including dopa-responsive dystonia (246). The third type of motor tic, referred to as tonic tic, is associated with an isometric muscle contraction without observable movement (87).
Simple phonic tics are usually inarticulate noises, such as sniffing, grunting, barking, and throat clearing, whereas complex phonic tics generally involve words and phrases. Gilles de la Tourette stressed the importance of coprolalia, but this affects only a minority of patients. In a study of 597 individuals with Tourette syndrome from 7 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 (66). Over time, individual tics tend to come and go. Talking about individual types of tics may “suggest” their performance to patients, even tics the patients have not expressed for a long time. Suggestibility, suppressibility, and exacerbation during stress are among the reasons why the disorder has been wrongly thought to be primarily psychological in origin. Although emotional stress may exacerbate tics, onset of Tourette syndrome is not necessarily related to stressful life events (82).
Common tics include the following:
(1) Simple motor tics: blinking, eye rolling, grimacing, mouth opening, head tossing, shoulder shrugging, fist clenching, and toe curling.
(2) Complex motor tics: jumping, touching, smelling, rubbing, shaking, echopraxia, and copropraxia.
(3) Simple phonic tics: throat clearing, grunting, sniffing, snorting, growling, barking, clicking, and moaning.
(4) Complex phonic tics: singing, whistling, humming, coprolalia, echolalia, and palilalia.
According to the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) (08), the following are criteria for the diagnosis of Tourette syndrome:
A. Both multiple motor and 1 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 of age.
D. The disturbance is not attributable to the physiological effects of a substance (eg, cocaine) or a general medical condition (eg, Huntington disease, postviral encephalitis).
According to DSM-5, if a 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 (21). The point prevalence of provisional tic disorder varies with age, but it has been estimated that about 20% of children age 5 to 10 years have provisional tic disorder, although the lifetime prevalence is much higher. The majority of children whose tics started within the previous year will continue to have tics, and only about 32% remain completely tic-free over the next 5 to 10 years.
A core element of the diagnosis of tics is the presence of premonitory urge. Many patients are able to state that their tics are a response to an involuntary urge (often described in sensory terms such as tingling, aching, or itching) to perform a certain movement or make a certain sound (15; 125; 244), rather than a completely involuntary movement arising without their conscious knowledge. In 1 study, Bereitschaftspotential were identified prior to tics in 6/14 (43%) of Tourette patients (233). Although the investigators could not correlate the presence of Bereitschaftspotential with the premonitory sensation, the physiology of the premovement phenomenon requires further studies. Some investigators have suggested that premonitory urges result from a “sensorimotor gating” dysfunction and is an example of sensory aspect of movement disorders (188; 171). Using magnetoencephalography in 12 patients with Tourette syndrome, the investigators showed a biphasic modulation of cortical beta activity during the second before tic onset with transient decrease in beta power, resembling the typical pattern noted during the preparatory phase of voluntary movements (160). However, only the initial phase of the biphasic modulation, manifested by increase in beta power, positively correlated with the intensity of motor urges preceding tics. This is consistent with the findings of another study that utilized centromedian and cortical recordings and increase in low-frequency power (3-10 Hz) in the thalamus that was time-locked to the tic but not present during voluntary movement and a decrease in beta power in primary cortex that was present during tics and voluntary movements (32). Thus, the premonitory phenomenon may represent a failure of compensatory motor inhibitory mechanisms.
Many individuals with Tourette syndrome, however, are unaware of their tics (168). Most people who are cognizant of their tics can suppress them for periods of a few minutes to more than half-an-hour (15). Patients may describe a gradually increasing inner tension as tic suppression is maintained, and a rebound effect of a flurry of tics occurs when the tics are finally expressed. However, formal objective studies of tic frequency during and after voluntary suppression have failed to detect a rebound increase (78; 151). Patients may report having to repeat a tic until they perform it “just right” (130). As is true of other dyskinesias, stress typically worsens tics; but tics are often more prominent when they are released after a period of suppressibility in social situations. For these and other unknown reasons, tic severity and frequency may wax and wane and vary from one moment or sound to another, hour to hour, day to day, week to week, and month to month. In a 3-month-interval study, patients with a later onset and shorter duration of their tic disorders, and better school performance, enjoyed more complete remissions (68).
Majority of all patients with Tourette syndrome also have obsessive-compulsive behaviors, some of which qualify for a DSM-5 diagnosis of obsessive-compulsive disorder (43).
As a result, many Tourette patients admit to repetitive checking, excessive orderliness, or ritualistic behavior (100). In fact, there is a clear parallel between tics and compulsions in the performance of intentional repetitive behaviors in response to psychic impulses. Many patients, most of them male, with Tourette syndrome have attention deficit hyperactivity disorder characterized by a shortened attention span, distractibility, impulsivity, and motoric hyperactivity (189; 192). Some of these problems are indirectly attributable to interference from tics, but for some children, the attention deficit hyperactivity disorder precedes the development of tics. Depression is common in Tourette syndrome and correlates with the severity of tics, obsessive-compulsive symptoms, and attention deficit hyperactivity disorder (79; 192). In a cross-sectional structured diagnostic interview conducted in 1374 patients with Tourette syndrome and in 1142 unaffected Tourette syndrome family members, the lifetime prevalence of any psychiatric comorbidity among individuals with Tourette syndrome was 85.7%; 57.7% of the population had 2 or more psychiatric disorders, and 72.1% of the individuals met the criteria for obsessive-compulsive disorder or attention deficit disorder/hyperactivity disorder (79). Other associated problems include learning disabilities such as dyslexia (30), mania, anxiety disorders, phobias, and self-injurious behavior (148), antisocial behavior, oppositional defiant behavior, sleep disorders, and personality disorders (119). In school, half of patients experience moderate to severe academic and peer problems (165). Approximately one third of children with Tourette syndrome have school difficulties severe enough to warrant extra measures such as tutoring or special education, and Tourette syndrome may account for one quarter of students in special education classes (122). In 1 large study in Sweden, individuals with Tourette syndrome were less likely to finish upper secondary education, start a university degree, or finish a university degree and experienced substantial academic underachievement (176).
Although Tourette syndrome is a childhood-onset disorder, many patients face challenges into adulthood, and their symptoms impair social interactions as well as employment opportunities and performance. Forty-three adults with Tourette syndrome who were referred to the Movement Disorders Clinic at Baylor College of Medicine over the past 5 years were compared to 100 Tourette syndrome patients aged 18 years old or younger (94). The adult Tourette patients had significantly more facial and truncal tics, as well as a greater prevalence of substance abuse and mood disorders; however, they had fewer phonic tics and lower rates of attention deficit/hyperactivity disorder and oppositional behavior than children with Tourette syndrome. Furthermore, adult Tourette syndrome largely represented a re-emergence or exacerbation of childhood-onset Tourette syndrome. During the course of Tourette syndrome, phonic and complex motor tics, self-injurious behaviors, and attention deficit/hyperactivity disorder tend to improve, but facial, neck, and trunk tics dominate the adult Tourette syndrome phenotype.
A phenomenon of paroxysmal outbursts of extreme anger, known as “episodic rages” or “explosive outbursts,” may affect as many as 30% of Tourette syndrome patients. These are more likely to occur in patients with comorbid attention deficit hyperactive disorder or obsessive-compulsive disorder (29). Other comorbidities include migraine headaches (126), restless legs syndrome (135), and other sleep disorders (193). In a study of 109 Tourette syndrome patients, Ghosh and colleagues found either migraine headaches or tension-type headaches in 55% of the patients; the rate of migraine headache within the Tourette syndrome group was found to be 4 times greater than that of the general pediatric population (69). Unfortunately, the interpretation of these data is difficult because the investigators did not administer the same questionnaire to a control, age-matched population without Tourette syndrome. This limitation, coupled, with the selected population of patients from a tertiary referral center, may make the findings not generalizable. Several studies have identified a variety of sleep abnormalities in patients with Tourette syndrome, including insomnia, excessive daytime sleepiness, disorders of arousal (sleepwalking, sleeptalking, sleep terrors, and enuresis), persistence of tics during sleep, and presence of periodic limb movements during sleep, especially in those with comorbid attention deficit hyperactivity disorder (102).
In some cases the tics and behavioral comorbidities may be so severe and disabling that they may be life threatening, hence the term “malignant” Tourette syndrome for this small subgroup of patients. Of 332 Tourette syndrome patients evaluated at Baylor College of Medicine Movement Disorders Clinic during a 3-year period, 17 (5.1%) met criteria for malignant Tourette syndrome, defined as 2 or more emergency room visits or 1 or more hospitalizations for Tourette syndrome symptoms or its associated behavioral comorbidities (38). The patients exhibited tic-related injuries, self-injurious behavior, uncontrollable violence and temper, and suicidal ideation/attempts. Compared to patients with nonmalignant Tourette syndrome, those with malignant Tourette syndrome were significantly more likely to have a personal history of obsessive-compulsive behavior/disorder, complex phonic tics, coprolalia, copropraxia, self-injurious behavior, mood disorder, suicidal ideation, and poor response to medications. Self-injurious behavior is 1 of the most serious manifestations of Tourette syndrome but may be encountered in many other neurobehavioral disorders (63).
The most widely used instrument to assess tics is the Yale Global Tic Severity Scale, which consists of 2 broad domains: total tic severity (with 2 sub-domains: motor and phonic tics) and impairment. Within each category there are 5 dimensions, scored 0 to 5: number of tics, frequency, intensity, complexity, and interference. The total tic score ranges from 0 to 50, and the usual ranges in most studies are from 15 to 30. A health-related quality of life scale has been developed and validated for internal consistency and test-retest reliability and against other clinical scales (34). Utilization of the health-related quality of life scale showed that attention deficit hyperactivity disorder and obsessive-compulsive disorder, rather than tic severity, are more predictive of the long-term outcome.
After onset in early childhood, the severity of Tourette syndrome tends to peak just before adolescence (210). In a study designed to address the long-term prognosis of Tourette syndrome, 46 children with Tourette syndrome underwent a structured interview at a mean age of 11.4 years, and again at 19.0 years (23). The mean worst-ever tic severity occurred at a mean age of 10.6 years. This first prospective longitudinal study also showed that only 22% continued to experience tic symptoms at follow-up, whereas nearly one third were in complete remission of tic symptoms at follow-up. Although some patients do not demonstrate any improvement of their tics in adulthood, the general long-term prognosis for Tourette syndrome is favorable. A 15-year follow-up study of initially school-aged patients found that tic severity declined on average by 59% and that 44% of patients were free or virtually free of symptoms (168). In another longitudinal study involving 314 patients with Tourette syndrome with an age range from 5 to 19 years followed for up to 6 years (n = 227), there was a 0.8 point decline on the Yale Global Tic Severity Scale; 17.7% of patients had no tics after age 16 but 59.5% had minimal or mild tics and 22.8% had moderate or severe tics (75). At follow-up, only 37.0% had pure Tourette syndrome; the remainder had a variety of comorbidities. Only 13% to 22% of adult Tourette patients still take medication for tics (31; 168). However, many adults with childhood-onset Tourette syndrome who believe they have become free of tics do still have them (168), and 22% to 24% of adult Tourette patients have moderate or severe tics (74; 23). When 40 children and 31 adults with Tourette syndrome 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 (45).
The natural history of the associated behavioral disorders is less well-defined than that of the tic disorder. It has been reported that, for many children with Tourette syndrome, symptoms of attention deficit hyperactivity disorder antedate the appearance of tics by an average of 2.5 years (42). Park and colleagues found it unusual for attention deficit hyperactivity disorder or obsessive-compulsive disorder to be absent at the time of initial diagnosis of Tourette syndrome and then to appear later on; only 4% to 6% of patients followed this course (169). On the other hand, disruptive behaviors (20%) and school problems (13%) appeared more frequently over time. As children with Tourette syndrome mature and start driving, because of their tics, such as blinking and blepharospasm or dystonic neck and trunk tics and a variety of other complex tics, coupled with comorbid attention deficit, they should be screened for such troublesome tics that could possibly put them or others in danger while driving (141; 235). Furthermore, impulsive behavior, coprophenomenon, and alcohol and substance abuse may eventually lead to involvement with the law enforcement and legal system and criminal convictions (98; 235).
There is no single etiologic factor responsible for all cases of Tourette syndrome. This disorder may arise from a variety of genetic and environmental mechanisms (22; 76; 192). It appears that most cases of Tourette syndrome have some hereditary basis, and offspring of affected parents are at increased risk of developing Tourette syndrome, obsessive-compulsive disorder, and attention deficit hyperactivity disorder (150). However, the genetic basis of Tourette syndrome is complex (172) and may be different in different families. For males, penetrance is nearly complete when strictly tic disorders (Tourette syndrome or chronic multiple tic disorder) are included, whereas penetrance is only 56% in females. However, when obsessive-compulsive disorder is considered an alternative expression of the Tourette syndrome trait, penetrance estimates rise to 70% for females. The observation that bilineal transmission is common in Tourette syndrome families, and that it appears to influence symptom severity (77; 136), suggests that genetic homozygosity or polygenic factors (such as the inheritance of susceptibility loci) may be important.
Finding a genetic marker, and ultimately a gene, has been the highest priority in Tourette syndrome research for more than 2 decades (49; 198). That goal was finally achieved in 2005, when Abelson and colleagues identified an individual with a chromosome inversion at 13q31.1-31.3 (01). Subsequent screening of a regional candidate gene in a cohort of 174 patients yielded 1 with a frameshift mutation due to a single-base deletion in SLITRK1. One of 4 family members had the same mutation and had exhibited trichotillomania but not tics. Two unrelated patients from the cohort were found to have a noncoding variant in a RNA binding site of SLITRK1 (01). Although clearly of importance for only a small minority of Tourette patients (50; 59), the discovery of the etiologic role of SLITRK1 has established the pathogenic plausibility of single-gene disruption. Another genetic abnormality implicated in Tourette syndrome is the L-histidine decarboxylase gene (HDC) mutation W317X, located on 15q21.1-15q21.3, inherited in an autosomal dominant fashion in a 2-generation family (57).
There are many other genes that have been linked to Tourette syndrome, but none have been replicated in large populations of Tourette syndrome (223; 85; 243). Genome scans and studies of chromosomal abnormalities have identified numerous candidate susceptibility loci (10; 250; 44; 234; 46; 47; 52; 170; 131). However, no overall consistencies have emerged from these studies. Polymorphisms in the DRD4 and MOA-A genes have been associated with Tourette syndrome in family-based association studies (53). Based on GWAS meta-analysis, genetic enrichment analyses, and other genetic studies in 4,819 patients with Tourette syndrome and 9,488 control subjects, genetic variants spanning evolutionarily conserved regions significantly explained 92.4% of Tourette syndrome heritability (249).
Although the concept of a hereditary foundation for Tourette syndrome is widely accepted, genetics do not explain the entire clinical picture, and environmental (including intrauterine) factors appear to influence the clinical expression of the disorder (129). In some cases, Tourette syndrome may have an autoimmune basis, but at present there is insufficient evidence to justify routine immune-based therapy (81). Walker and colleagues have reported that 6 of 42 patients with rheumatic, or Sydenham, chorea later developed PANDAS (pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection, discussed under Differential Diagnosis), and 5 Tourette syndrome (238). Some Tourette syndrome patients have detectable antineuronal or antinuclear antibodies. When sera from these patients are infused in rats they have been found to increase oral stereotypies in the animals (228). Comorbid attention deficit hyperactivity disorder may be due to a single nucleotide polymorphism in the tyrosine phosphatase (ACP1) gene (25). Potential immune mechanisms of Tourette syndrome have been reviewed in reports (84).
The anatomic localization and the biochemical nature of Tourette syndrome are unknown. It is generally accepted that dysfunction of cortico-striato-thalamo-cortical pathways is involved (215; 80). Several lines of evidence support the notion that dopaminergic striatal and prefrontal dysfunction contributes to tic disorders (209; 06). Foremost are the clinical observations that dopamine receptor antagonists suppress tics, whereas dopaminergic agents such as amphetamines may exacerbate them. The phenomenon of tardive tics following chronic dopamine receptor antagonist therapy suggests that dopamine receptor supersensitivity can cause a syndrome similar to Tourette syndrome. Fluorodopa accumulation on PET studies is elevated in the regions of substantia nigra and caudate nucleus (58). Striatal dopamine transporter binding, as assessed by SPECT ligands, is increased in Tourette patients (37; 203). Amphetamine induces excessive release of dopamine in the putamen in patients compared to controls (216). A postmortem study of Tourette syndrome brains demonstrated an increased density of presynaptic dopamine nerve terminals, which was attributed to dopamine hyperinnervation of the striatum (212). Some have hypothesized that there is early termination of nigrostriatal neuron maturation in Tourette syndrome (201). A postmortem study of 3 patients found elevated concentrations of D2 receptor protein in prefrontal cortex (153), lending weight to the notion that dysfunction of a cortico-striato-thalamo-cortical circuit rather than a single structure underlies the pathogenesis of Tourette syndrome. An autopsy study of 3 Tourette brains found consistent increases in dopamine transporter and D2 receptor as well as D1 and alpha-2A density, suggesting that dopaminergic hyperfunction in the frontal lobe may play a role in the pathophysiology of Tourette syndrome (247). In support of the “tryptophan hypothesis” is a study that used alpha-[(11)C]methyl-L-tryptophan PET to assess global and focal brain abnormalities of tryptophan metabolism in 26 children with Tourette syndrome and 9 controls. The findings indicate that tryptophan uptake is significantly decreased in the dorsolateral prefrontal cortex and increased in the thalamus of Tourette syndrome patients (16).
Numerous other neurochemical systems have been investigated, and it is possible that multiple presynaptic and postsynaptic mechanisms play roles in producing this disorder (217). In addition to dopaminergic system the GABAergic and glutamatergic pathways have been also implicated in Tourette syndrome. Using PET scan and [11C]flumazenil as a GABAergic ligand, Lerner and colleagues found decreased binding of [11C]flumazenil in bilateral ventral striatum, bilateral thalamus right insula, and bilateral amygdala and increased binding in bilateral substantia nigra, eft periaqueductal grey, right posterior cingulate cortex, and bilateral cerebellum and dentate nuclei (134). This study suggests widespread abnormality in the GABAergic system in patients with Tourette syndrome. In another study neurochemical profile was assessed in 37 well-characterized, drug-free adult patients with Tourette syndrome and 36 age/gender-matched healthy control subjects via 3 Tesla magnetic resonance spectroscopy (106). The study found significant reductions in striatal and thalamic concentrations of glutamate and glutamine. It has also been hypothesized that a disturbance of sex hormone influences in normal brain development may contribute to the appearance of Tourette syndrome (179). The observed benefit in patients with obsessive-compulsive symptoms from drugs that are inhibitors of serotonin reuptake implicates this neurotransmitter system in the development of this associated disorder. SPECT with 123I beta-CIT has shown a significant reduction in serotonin transporter binding in Tourette patients (157). The serotonergic system may also underlie the beneficial effect of stimulants for attention deficit hyperactivity disorder (67).
Although there are no animal models that express all the typical features of Tourette syndrome, studies of stereotypies in animals may provide insight into the pathogenesis of habits, rituals, tic-like and impulsive behaviors in humans. However, several animal models of tics have been developed (Bronfeld and Bar-Gad; 245). The mechanism of self-injurious behavior associated with Tourette syndrome is not well understood, but an animal model may shed some light on this very important behavior that is occasionally associated with Tourette syndrome. A mouse with genetic deletion of Sapap3, a gene that codes for postsynaptic scaffolding protein at excitatory striatal synapses, is characterized by excessive compulsive grooming resulting in self-injurious behavior, such as facial hair loss and skin lesions. The similarity of this phenotype to obsessive-compulsive disorder is further supported by the observation that the mice markedly improved after treatment with a selective serotonin reuptake inhibitor (240).
Several animal models of tics have been developed, including microinjections of bicuculline into the sensorimotor putamen and primary motor cortex of a monkey (27; 149), injections of axonal tracers into the primate striatum (245), and numerous other primate and rodent models (27).
Volumetric magnetic resonance imaging studies have revealed reduced volumes of the caudate nuclei (180) and of the left lenticular nucleus (178), and enlargement of the left thalamus (132), in patients with Tourette syndrome compared to controls. Despite reports of some abnormalities on imaging studies in patients, these findings could not be confirmed in a cohort of children with medication-free Tourette syndrome (101). Nevertheless, abnormal development in Tourette syndrome is supported by other imaging studies that have found abnormal structural pattern of cortical sulci, which correlates with severity of clinical symptoms (155). Using 3 Tesla structural neuroimaging, the investigators compared sulcal depth, opening, length, and thickness of sulcal gray matter in 52 adult patients with Tourette syndrome and 52 matched controls. Patients with Tourette syndrome had lower depth and reduced thickness of gray matter in the pre- and postcentral as well as superior, inferior, and internal frontal sulci.
Diffusion-tensor MRI used to investigate the structural integrity of basal ganglia and thalamus in 23 children with Tourette syndrome found increased mean water diffusivity bilaterally in the putamen and decreased anisotropy in the right thalamus, indicating impairment of white matter integrity in the fronto-striatal-thalamic circuit at a microstructural level (142). Additional imaging studies have identified frontal and parietal cortical thinning, most prominent in ventral portions of the sensory and motor homunculi in patients with Tourette syndrome (220). Using resting-state functional connectivity MRI in 33 adolescents with Tourette syndrome, Church and colleagues found anomalous connections primarily in the fronto-parietal network, suggesting widespread immature functional connectivity, particularly in regions related to adaptive online control (41). When resting-state functional MRI was performed in 13 adults with Tourette syndrome and 13 matched controls, the right dorsal anterior insula demonstrated higher connectivity, especially with the frontostriatal nodes of the urge-tic network and bilateral supplementary motor area, even though the patients did not exhibit any overt tics (231).These findings suggest that the right dorsal anterior insula is part of the urge-tic network and could influence the urge- and tic-related cortico-striato-thalamic regions in Tourette syndrome. The dorsal anterior part of the insula has been found to integrate sensory and emotional information with cognitive valuation. The right dorsal anterior insula also participates in urge suppression in healthy subjects (86; 113).
PET and SPECT studies have shown deficiencies in the basal ganglia, most often the left ventral striatum (178). Using [18F]fluorodeoxyglucose, 2 patterns of abnormalities have been identified in patients with Tourette syndrome. Pattern 1 is reportedly associated with tics, and pattern 2 correlates with the overall severity of Tourette syndrome. In a follow-up study involving 12 adult Tourette patients (untreated for more than 2 years) and 12 controls, the investigators found a Tourette syndrome-related metabolic pattern that was characterized by increased premotor cortex and cerebellum activity and reduced resting activity of the striatum and orbitofrontal cortex (184). With voxel-by-voxel analysis, the investigators found increased [11C]dihydrotetrabenazine binding in the ventral striatum (right greater than left) in patients with Tourette syndrome as compared to age-matched controls. However, in a subsequent PET study involving 33 adults with Tourette syndrome and utilizing not only [11C]dihydrotetrabenazine but also [11C]methylphenidate, a ligand for dopamine transporter binding, Albin and colleagues found no differences between subjects with Tourette syndrome and controls (05). Infantile sonographic lenticulostriate vasculopathy may represent an early radiologic marker (206).
Structures other than the basal ganglia have been implicated in the pathogenesis of tics. Electrophysiological studies indicate that hyperexcitable brainstem neurons are found in Tourette patients, whereas magnetic stimulation discloses increased excitability of the motor cortex (17). PET studies of regional cerebral metabolic rates show positive functional coupling between motor and lateral orbitofrontal circuits, a reversal of the normal interrelationship, implicating impaired limbic-motor interactions (99). Impaired frontal cortical inhibition has been documented by recording event-related brain potentials (104). One case report documented the conversion of a simple motor tic disorder into full-blown Tourette syndrome with obsessive-compulsive disorder following temporal lobectomy for intractable epilepsy (36).
Tourette syndrome is among the most common movement disorders. Various epidemiological studies have shown that 20% to 30% of children exhibit tics sometime during childhood and 2% to 3% of children develop some features of Tourette syndrome, although the worldwide prevalence of Tourette syndrome in children has been reported to range from 0.3% to 0.8% (35). Correctly ascertaining its prevalence is fraught with difficulty (227), though, and an accurate lifetime prevalence rate for Tourette syndrome has not been established. It is clear that systematic searches for Tourette syndrome turn up much higher prevalence rates than those obtained through conventional means. Examination of affected kindreds indicates many cases are mild and do not come to medical attention. Prevalence estimates for chronic tic disorders generally hover in the 0.4% to 2% range (83; 191; 103; 111). The prevalence is considerably higher in special education classes (121; 191). Various epidemiological studies have shown that 20% to 30% of children exhibit tics sometime during childhood and 2% to 3% of children develop some features of Tourette syndrome, although the worldwide prevalence of Tourette syndrome in children has been reported to range from 0.3% to 0.8% (35). There is no known geographic predilection. Males consistently outnumber females in large studies by a ratio around 4:1 (65; 239; 127). In 1 survey of nearly 10,000 children in China, the ratio of affected males to females was greater than 10:1 (103). Rarely, a disorder identical to Tourette syndrome will arise de novo in adults (39), and this may carry a poorer prognosis (56). The new onset of tics in an adult should prompt consideration of a secondary cause. Meta-analysis of 13 studies of children yielded a prevalence of Tourette syndrome of 0.77% (95% confidence interval, 0.39-1.51%); the boys:girls ratio was 1.06%: 0.25% and meta-analysis of 2 studies assessing adults with Tourette syndrome revealed a prevalence of 0.05% (95% confidence interval, 0.03-0.08%) (114). The prevalence of tic disorders was higher in all studies performed in the special education population. Similar findings were reported based on a prospective cohort study following 6768 children in Avon, United Kingdom, where 0.3% of 13-year-old children met criteria for clinically definite Tourette syndrome and 0.7% with clinically probably Tourette syndrome (197). It is not known why tics disappear in a majority of children and further studies are needed to understand mechanisms of conversion from pre-Tourette syndrome state to Tourette syndrome. Among the 21 population-based prevalence studies, the pooled Tourette syndrome population prevalence estimate was 0.52% (95% confidence interval: 0.32 to 0.85), 0.3% to 0.9% in children, but the true prevalence was thought to be much higher (196).
Genetic counseling regarding family planning may influence a couple's decision to have a child at risk for Tourette syndrome. There is no biological marker to detect an affected fetus during pregnancy. There is no known way to modulate the onset of tics in children at risk.
Tourette syndrome is a member of a group of primary tic disorders. Transient tic disorder, which occurs in up to 2% of children, differs from Tourette syndrome by its duration of less than 1 year, leaving no residual manifestations. Patients with chronic sinmple tic disorder (motor or vocal) experience only 1 type of tic. Chronic multiple tic disorder (motor or vocal) differs from Tourette syndrome in that either motor or vocal tics, but not both, are present. Tourette syndrome, chronic multiple tic disorder, transient tic disorder, and possibly chronic simple tic disorder are generally viewed as clinical variants of the same genetic defect.
Tourette syndrome accounts for the vast majority of chronic tics, but secondary causes of tics are increasingly recognized. These include infections, toxins, trauma (140), stroke (124), degenerative diseases (174), metabolic disorders (200), chromosomal disorders, and others (152). In these conditions, tics are usually ancillary features to obvious neurologic manifestations that are not part of the Tourette syndrome spectrum. Dopamine receptor blockers can cause a tardive syndrome resembling Tourette syndrome (190). Stimulant drugs have long been blamed for causing or aggravating tics (in a reversible fashion), but longitudinal studies indicate that the severity of tics does not increase with long-term methylphenidate therapy (167). Psychogenic tics are difficult to diagnose and are rarely documented (226; 13).
Patients with acute onset, or sudden exacerbations, of obsessive-compulsive disorder or tic disorder have shown a significant association with group A beta-hemolytic streptococcal antibody titers (159). These patients may represent a syndrome known as PANDAS (pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection) (219). Although diagnostic criteria for this syndrome include prepubertal symptom onset (133), a similar disorder may affect adults (24). The concept of PANDAS is not universally embraced (214; 71; 199). Strong supportive evidence has come from finding antibasal ganglia antibodies in more than 20% of Tourette patients (40), and in 64% of PANDAS patients versus 9% of those with uncomplicated active Group A streptococcal infection (173). However, even this finding has been disputed (209; 211; 146). A placebo-controlled trial of immunomodulatory treatment (plasma exchange or intravenous immunoglobulin) demonstrated dramatic benefit in acute postinfectious obsessive-compulsive and tic disorders (177). Patients treated in this fashion have shown benefit for up to 5 years (133). In an attempt to address the controversy surrounding PANDAS, a new entity termed “pediatric acute-onset neuropsychiatric syndrome” (PANS) has been proposed to acknowledge that there is a subgroup of children presenting with an abrupt onset of obsessive-compulsive disorder (OCD) and acute neuropsychiatric symptoms, accompanied by a variety of comparably severe and acute neuropsychiatric symptoms (225). In contrast to PANDAS, the diagnostic criteria for PANS no longer include tics.
Tics must be differentiated from other hyperkinetic movement disorders, including myoclonus, blepharospasm, stereotypies, and hyperekplexia (87). Because of the young onset, tics are often mistaken for rheumatic, or Sydenham, chorea. It may be difficult to differentiate complex motor tics and compulsions. In contrast to tics, compulsions are more closely associated with obsessions, performed in response to nonmotor obsessional thoughts, and may be performed according to certain rules (rituals), such as in a specified order or a specified number of times. Compulsive rituals, but not tics, may be performed with the thought of preventing discomfort or a dreaded event.
There is no diagnostic laboratory test for Tourette syndrome, so it remains a clinical diagnosis. Routine neuroimaging and other diagnostic studies are generally not required, and do not help identify most of the secondary causes of tics noted above. Detailed assessments, including psychiatric evaluations and testing with standardized neuropsychologic measures of attention and obsessive-compulsive behavior, may be helpful for defining associated behavioral disturbances.
One of the most important aspects of management is proper education and correction of misconceptions regarding Tourette syndrome and its behavioral complications. Parents should be informed that their child has a limited capacity to control the tics, which will be most prominent when the child feels his or her tics are unobserved or unlikely to provoke a negative social response, such as at home. Parents should tell the child's teachers of the diagnosis and prescribed medication, if any. Patients and families should know of the Tourette Syndrome Association as a valuable resource for informative literature.
Different forms of nonpharmacological therapeutic interventions, such as behavioral modification and transcranial magnetic stimulation, have been recommended since the disorder was first described, but few studies of such treatments have been subjected to rigorous scientific scrutiny (221; 164; 89; 90; 18; 92).
Comprehensive behavioral intervention for tics (CBIT) is primarily based on habit reversal therapy, which employs competing-response training; CBIT is different from deliberate tic suppression in that it teaches the patient to initiate a voluntary behavior to manage the premonitory urge. CBIT also includes relaxation training and a functional intervention. In a multicenter study designed to test the efficacy of CBIT, 126 children ages 9 to 17 with moderate to severe Tourette syndrome were randomly assigned to receive either CBIT or supportive counseling and education about Tourette syndrome (182). About one third of the children in the study were on a stable dose of anti-tic medication. Behavioral intervention led to a significantly greater decrease on the Yale Global Tic Severity Scale (24.7 vs. 17.1) from baseline to endpoint, compared with very minimal change in the control treatment group (24.6 vs. 21.1), with the overall effect size of 0.68. Furthermore, 52.5% of children receiving CBIT were rated as significantly improved, compared to 18.5% of those in the control group. The decrease of 7.6 points (31% from baseline) on the Total Tic score of the Yale Global Tic Severity Scale in the CBIT group is less than the decrease reported in clinical trials of antipsychotic medications or topiramate (94). Although in 1 review “half the subjects in the CBIT trials did not show a positive response,” some have suggested “CBIT can be considered a first-line treatment for persons with tic disorders” (195).
The decision to intervene in a tic disorder is based on a relative evaluation of the severity of the tics versus the consequences of potential side effects on schooling or work. Most patients with mild tics who have made a good adaptation in their lives can avoid the use of medications (128; 239). Educating patients, family members, peers, and school personnel regarding the nature of Tourette syndrome, restructuring the school or work environment, and providing supportive counseling are measures that may be sufficient to avoid medications (208). Drug therapy is considered if the symptoms of Tourette syndrome are functionally disabling and not remediable by nonpharmacological interventions (72; 88; 207). Medications are chosen on the basis of specific target symptoms and potential side effects. For many Tourette syndrome patients, the principal morbidity comes not from tics, but from the associated features of obsessive-compulsive symptoms, attention deficit hyperactivity disorder, and other behavioral disturbances. If practical, observing a patient for a period of time before using medication allows for a better appreciation of the baseline disorder and the difficulties encountered at home, at school, at work, and with peers.
Tics can rarely be eradicated entirely, so the goal of medication is to achieve maximum control with minimal side effects. All medications are initiated at the lowest possible dose and gradually increased until sufficient benefit is obtained or until intolerable side effects supervene. Those patients who receive medication should be re-evaluated approximately every 3 months and more frequently after dosage or medication changes. Clonazepam (0.5 to 5 mg/day) may be taken as a once-a-day medication at bedtime. It may relax patients just enough to give them control of mild to moderate tics, and may also help coexistent emotional and behavioral disorders. Clonidine (0.05 to 0.5 mg/day) appears to have tic-suppressing effects and may be particularly useful for children with associated attention deficit hyperactivity disorder. Clonidine is available as a weekly patch, but this formulation often causes hypersensitivity reactions. Guanfacine has also been recommended as first-line therapy for tics (224), but in has caused syncope in Tourette children (112). Despite “strong recommendation” made by some investigators for the use of clonidine and guanfacine in children with Tourette syndrome (221), we find the drug less effective than the antidopaminergic drugs in the treatment of tics in children and adults.
The most effective agents against tics are neuroleptic (antidopaminergic) drugs. There are only 3 drugs approved by the United States Food and Drug Administration for the treatment of Tourette syndrome: haloperidol, pimozide, and aripiprazole. These medications, however, have a variety of potentially serious side effects, including tardive dyskinesia; therefore, these drugs are not considered first line of treatment (89).The most commonly used typical neuroleptics include haloperidol (0.25 to 15 mg/day), pimozide (1 to 10 mg/day), and fluphenazine (1 to 15 mg/day) (242). Pimozide and fluphenazine tend to produce less sedation than haloperidol, but pimozide therapy has led to prolongation of the Q-T interval and other changes on the ECG. The full spectrum of drug-induced movement disorders, from acute dystonic reactions to tardive syndromes, may complicate the use of these agents. Furthermore, some patients become refractory to medications. In 1 survey, 45 of the 68 (69%) patients were judged refractory due to lack of efficacy at the highest tolerated dose (138). The medications to which selected patients were judged as refractory were aripiprazole, clonidine, risperidone, haloperidol, pimozide, tiapride, and sulpiride. In addition to tardive dyskinesia, the typical and atypical antipsychotics (neuroleptics) can be associated with weight gain and metabolic syndrome, although Tourette patients may be at a higher-than-expected risk for metabolic and cardiovascular disorders irrespective of their exposure to these drugs (26; 62).
Presynaptic dopamine depletors, such as tetrabenazine, which act by inhibiting the central inhibitor of vesicular monoamine transporter type 2 (VMAT2), are emerging as the most effective and safest medications in the treatment of troublesome tics (90; 18; 92). Tetrabenazine (12.5 to 100 mg 3 times daily) is effective in a majority of patients with Tourette syndrome and is considered the first-line treatment in patients with troublesome motor and phonic tics (110; 109; 89). Generally well tolerated, tetrabenazine may cause drowsiness, parkinsonism, depression, insomnia, akathisia, and other less frequent, dose-related side effects. The drug’s advantage over conventional neuroleptics is that it does not cause tardive dyskinesias. Tardive disorders appear to be relatively rare in the Tourette syndrome population, but tardive dystonia may be more common than currently believed (218; 115). Besides little or no risk for tardive dyskinesia, tetrabenazine appears to be associated with less weight gain than the typical neuroleptics (163). Besides the potential side effects noted above, there are other limitations of tetrabenazine, including its relatively short half-life, necessitating at least 3 times per day administration. This is 1 reason why other dopamine depleters with longer duration of action are currently being investigated; these include deutetrabenazine and valbenazine, which are administered 2 times or once per day, respectively (90). In a pilot study involving 23 children with Tourette syndrome, the mean (SD [standard deviation]) baseline YGTSS Total Tic Severity Score (TTS) of 31.6 (7.9) decreased by 11.6 (8.2) points at week 8, a 37.6% reduction in tic severity (p< 0.0001) (90). Other measures of Tourette syndrome also improved in this open-label 8-week study, suggesting that deutetrabenazine may be a safe and effective treatment of tics associated with Tourette syndrome. The improvement observed in the open-label studies, however, could not be replicated in 2 randomized double-blind, placebo-controlled trials: 30046 ARTISTS 1 (flexible-dose titration) and 30060 ARTISTS 2 (fixed dose) (18). This, unfortunately, parallels the results of similar studies with valbenazine in pediatric and adult Tourette syndrome populations. Although the full reports have not yet been published, there are many possible explanations for the unexpected results, including difficulties in assessing a highly variable disorder and subtherapeutic dosing. The latter explanation is supported by the observation of very low frequency of adverse effects. Although the VMAT2 inhibitors are considered the treatment of choice in patients with tic disorders, they are often difficult to access because of cost and denials by third-party payers (161).
The development of atypical neuroleptics such as olanzapine (232), quetiapine, aripiprazole (166), and ziprasidone may make it possible to avoid these side effects in the future. In a phase 3, randomized, double-blind, placebo-controlled trial of aripiprazole involving 133 patients with Tourette syndrome, significant improvement in YGTSS and other measures were noted (194). The most common adverse events were sedation and fatigue. Although no tardive dyskinesia was reported in this trial other studies have found that aripiprazole can cause this adverse effect (175). Unfortunately, experience gathered with most of these agents over the years indicates that only clozapine can be considered a truly “atypical” agent in terms of reducing the risk of tardive complications (60). Patients with Tourette syndrome need to be educated regarding possible neuroleptic side effects (116). Although D2 receptor blockers can cause tardive dyskinesia, it is possible that D1 receptor blocking agents will have lower risk of this potentially disabling side effect. In this regard, a D1 receptor antagonist, ecopipam, has been reported to have potential benefits in patients with Tourette syndrome (73).
A variety of other medications – including calcium channel blockers (verapamil, nifedipine), ondansetron, carbamazepine, baclofen, naltrexone, buspirone, nicotine (in smoke, gum, and transdermal patches), and cannabinoids – may suppress tics in certain Tourette syndrome patients (191; 156). In general, however, the response to these medications is less predictable than with the aforementioned neuroleptic drugs. An open-label trial of levetiracetam recorded benefit for tic severity in all 60 participants, and in behavior and school performance for the majority (12). Topiramate has been found to be effective in some open-label studies as well as in a multicenter, placebo-controlled trial (95). A seemingly paradoxical treatment for tics is dopamine agonists, probably on the basis of presynaptic inhibition at low doses (70; 09). Selected patients, particularly those with painful dystonic tics, may respond to local intramuscular injections of botulinum toxin (123; 144; 04; 91; 93). A variety of behavioral techniques, including massed (negative) practice, operant conditioning, anxiety management, habit-reversal training (33; 48), and hypnosis have been employed in the treatment of tics (181). Electroconvulsive therapy has been used successfully in a Tourette patient with psychosis and self-injurious behavior (107). The use of “alternative” medications among Tourette patients is common, and warrants systematic study in the future (143).
A number of antidepressant medications are effective for obsessive-compulsive symptoms, most notably serotonin-specific reuptake inhibitors (55). Fluoxetine (20 to 60 mg/day), sertraline (50 to 200 mg/day), paroxetine (20 to 60 mg/day), fluvoxamine (50 mg/day and up), and citalopram (20 to 40 mg/day) may all improve obsessive-compulsive symptoms without affecting tic severity. Serotonin-specific reuptake inhibitors may be less effective for obsessive-compulsive symptoms in the presence of tics (137), and doses higher than standard antidepressant doses are often required. Clomipramine (initiated at 25 mg/day) is equally effective but less well tolerated due to anticholinergic, cardiotoxic, and seizure-potentiating effects. Other pharmacologic agents for obsessive-compulsive symptoms include tryptophan, monoamine oxidase inhibitors, mianserin (a selective serotonin antagonist), and benzodiazepines. Because of its serotoninergic action, pimavanserin has been tried in Tourette syndrome with modest benefits on tics and obsessive-compulsive behavior (19).
Clonidine is often used as a first line drug for children with Tourette syndrome who have impaired school performance due to attention deficit hyperactivity disorder, because this medication may also be useful in suppressing tics. Another alpha 2-receptor agonist, guanfacine, may be used in a similar fashion. The selective norepinephrine reuptake inhibitor atomoxetine is effective for both attention deficit hyperactivity disorder and tics in Tourette syndrome (07). When these drugs are ineffective, the use of stimulants should be considered. Treatment of Tourette syndrome with stimulants is somewhat controversial because these drugs have been thought to exacerbate and even precipitate tics in some patients. Studies indicate that stimulants are safe and effective for attention deficit hyperactivity disorder in patients with Tourette syndrome (167). Methylphenidate (0.1 to 0.3 mg/kg twice daily) is the stimulant of choice in this situation, and its use may actually reduce tic severity (118). A sustained-release preparation of methylphenidate is available. For patients experiencing an unacceptable worsening of tics during stimulant therapy, a neuroleptic can be added. Tricyclic antidepressants such as imipramine (10 to 25 mg/day) and desipramine (25 to 100 mg/day) have also been effective treatments for attention deficit hyperactivity disorder in children with Tourette syndrome. Due to potential cardiotoxicity, ECG monitoring is recommended before and during treatment with desipramine. Selegiline may be beneficial for children with attention deficit hyperactivity disorder and tics (61). Paroxetine may be particularly useful for the unprovoked attacks of anger known as "episodic rages" (28). Pramipexole, a D3 and D2 receptor agonist, has not been found to be effective in a double-blind, placebo-controlled trial (120).
Psychological counseling may help with general difficulties in coping with Tourette syndrome, a chronic illness with specific behavioral features.
There has been a long line of surgical procedures for tics (229), and experience has expanded. Zhang and colleagues have performed unilateral pallidotomies on 22 patients and obtained significant reduction of tic frequencies (251). Sun and colleagues reported that bilateral anterior capsulotomy resulted in greater than 80% tic reduction in 5 patients in whom the posterior third of the anterior limbs of the internal capsules was targeted (222). In the same study, lesser, but still greater than 50%, benefit was obtained in 7 patients in whom the anterior one third of the anterior limbs was lesioned. The technology of deep brain stimulation has been applied to Tourette syndrome. Deep brain stimulation of the thalamus has shown marked success in ameliorating tics in a small number of patients (236). Comparable benefit has been achieved targeting the internal globus pallidus (54; 02; 237). More modest improvement was reported in 1 patient with deep brain stimulation and electrode implantation in the anterior internal capsule (64). Globus pallidus interna (Gpi) has been increasingly used as the target in patients with disabling tics (205; 237). Stimulation of various targets involved in the limbic striatopallidal-thalamocortical system could be beneficial in the treatment of various aspects of Tourette syndrome (14). Based on a double-blind assessment of 5 patients with Tourette syndrome undergoing bilateral thalamic deep brain stimulation, there was a significant improvement in several measures of tic and behavioral severity (139). In the largest reported series, 18 Tourette syndrome patients underwent bilateral deep brain stimulation of the centromedian parafascicular and ventralis oralis complex of the thalamus (204). Followed up to 18 months, most patients apparently showed improvement in tics as well as obsessive-compulsive disorder, self-injurious behavior, and other comorbidities. In a prospective 24-month follow-up of 15 of the original 18 patients, there continued to be marked improvement in tics, obsessive-compulsive disorder, anxiety, and depression with subjective perception of improved social functioning and quality of life (183). It would be helpful to know what happened to the 3 patients not included in this open-label, observational study. Also, a blinded review of videos before and after treatment would provide more objective measure of efficacy (20). Finally, the observation that vagal nerve stimulation also favorably modifies the frequency and intensity of facial tics suggests that the brainstem plays a role in generation of modulation of tics (51). One of the largest controlled trials of GPi deep brain stimulation in Tourette syndrome involved 15 patients (11 men, 4 women; mean age 34.7 years [SD 10.0]), 14 patients of whom were randomly assigned and 13 completed assessments (108). The mean YGTSS total score in these 13 patients was 80.7 (SD 12·0) for the off-stimulation period and 68.3 (SD 18·6) for the on-stimulation period, with a mean improvement of 12.4 points (95% CI 0.1-24.7, p=0.048), equivalent to a difference of 15.3%. The authors concluded that GPi stimulation led to a significant improvement in tic severity, with an overall acceptable safety profile. In another study involving 16 patients with Tourette syndrome randomly assigned to deep brain stimulation of the anterior globus pallidus internum or sham stimulation, no significant difference in the Yale Global Tourette Syndrome Scale was noted between the beginning and the end of the 3-month double-blind period (241). One interpretation of this negative result is that 3 months of stimulation may not be sufficient to decrease tic severity. This is supported by a 1-year follow-up of 185 patients with Tourette syndrome treated with deep brain stimulation included in a public registry (145). This showed that the Yale Global Tourette Syndrome Scale mean total score improved from 75.0 at baseline to 41.2 at 1 year after implantation (p < .001) and the motor and phonic tic subscores also improved significantly (both p < .001). The overall adverse event rate was 35.4%, with intracranial hemorrhage occurring in 1.2% of patients, infection in 2.5%, and lead explantation in 1%; the most common stimulation-induced side effects were dysarthria (6.3%) and paresthesia (8.2%). In a retrospective analysis of clinical data and imaging from 13 international sites in 110 patients with Tourette syndrome who were implanted in the centromedial thalamus (n = 51), globus pallidus internus (n = 47), nucleus accumbens/anterior limb of the internal capsule (n = 4), or a combination (n = 8), tics and obsessive-compulsive behavior significantly improved over time (p < 0.01) (105). The median time was 13 months to reach a 40% improvement in tics. There were no significant differences across targets (p = 0.84). A randomized, double-blind, sham-controlled trial of deep brain stimulation in 10 patients with Tourette syndrome suggested that the initial effect targeting globus pallidus internus was superior to thalamic target; long-term benefits seemed greater with the latter target (158). Deep brain stimulation continues to be evaluated in patients with Tourette syndrome and future advances should lead to better selection of patients and better long-term outcomes (147).
The American Academy of Neurology issued practice guidelines based on a systematic review of the literature on the treatment of Tourette syndrome (186; 187). They concluded that there was high confidence that the Comprehensive Behavioral Intervention for Tics was more likely than psychoeducation and supportive therapy to reduce tics. There was moderate confidence that haloperidol, risperidone, aripiprazole, tiapride, clonidine, onabotulinum toxin A injections, 5-ling granule, and Ningdong granule were probably more likely than placebo to reduce tics. There was low confidence that pimozide, ziprasidone, metoclopramide, guanfacine, topiramate, tetrahydrocannabinol, and deep brain stimulation of the globus pallidus were possibly more likely than placebo to reduce tics.
Some worsening of tics during pregnancy has been observed, although not predictably (162). The use of haloperidol should be restricted to the second and third trimesters due to potential embryotoxicity. Other therapies such as pimozide and clonidine have not been evaluated in pregnancy.
Because of the risk of injury from sudden movements, Tourette patients may require general anesthesia for typically outpatient procedures such as routine dental interventions (248). No problems were encountered in 2 patients undergoing general anesthesia after sufficient preoperative reassurance of patients and families that the tics would not interfere with the surgery or anesthesia and that the anesthetic agents would not aggravate the tic disorder (154). A 21-year-old woman with Tourette syndrome successfully underwent general anesthesia for Caesarean section without perioperative complications (202).
Joseph Jankovic MD
Dr. Jankovic, Director of the Parkinson's Disease Center and Movement Disorders Clinic at Baylor College of Medicine, received research and training funding from Allergan, F Hoffmann-La Roche, Medtronic Neuromodulation, Merz, Neurocrine Biosciences, Nuvelution, Revance, and Teva and consulting/advisory board honorariums from Abide, Lundbeck, Retrophin, Parexel, Teva, and Allergan.See Profile