Tourette syndrome (TS) is a common genetic neurological disorder characterized by chronic motor and vocal tics beginning before adulthood.[1, 2, 3, 4] Affected individuals typically have repetitive, stereotyped movements or vocalizations, such as blinking, sniffing, facial movements, or tensing of the abdominal musculature. See the image below.
View Image
Tourette syndrome and other tic disorders. Graphic shows the relative likelihood of lifetime sensory tics in a given region, as based on self-report o....
Signs and symptoms
Tics are abnormal movements or vocalizations that are diverse in presentation. They can be categorized as either motor or vocal/phonic and simple or complex.
Simple motor tics involve a single muscle or group of muscles. Examples of simple motor tics include eye blinking, nose sniffing, coughing, neck twitching or jerking, eye rolling, and jerking or postured movements of the extremities.
Complex motor tics involve movements that often involve multiple muscle groups and may appear as semipurposeful movements or behaviors. Examples of complex motor tics include touching oneself or others, hitting, jumping, shaking, or performing a simulated motor task.
Simple phonic tics are simple vocalizations or sounds. Examples include grunting, coughing, throat clearing, swallowing, blowing, or sucking sounds.
Complex phonic tics are vocalizations of words and/or complex phrases. These verbalizations can be complex and sometimes socially inappropriate.
Behavioral symptoms are common in Tourette syndrome. The 2 most common disorders are OCD and ADHD.
See Clinical Presentation for more detail.
Diagnosis
The specific DSM-5 criteria for Tourette’s disorder are as follows[5] :
Both multiple motor and 1 or more vocal tics have been present at some time during the illness, though not necessarily concurrently. (A tic is a sudden, rapid, recurrent, nonrhythmic, stereotyped motor movement or vocalization)
The tics may wax and wane in frequency but have persisted for more than 1 year since first tic onset
The onset is before age 18 years
The disturbance is not due to the direct physiologic effects of a substance (eg, cocaine) or a general medical condition (eg, Huntington disease or postviral encephalitis)
The specific DSM-5 criteria for persistent (chronic) motor or vocal tic disorder are as follows[5] :
Single or multiple motor or vocal tics (eg, sudden, rapid, recurrent, nonrhythmic, stereotyped motor movement or vocalizations), but not both, have been present at some time during the illness
The tics may wax and wane in frequency but have persisted for more than 1 year since first tic onset
The onset is before age 18 years
The disturbance is not due to the direct physiologic effects of a substance (eg, cocaine) or a general medical condition (eg, Huntington disease or postviral encephalitis)
Criteria have never been met for Tourette’s Disorder
The specific DSM-5 criteria for provisional tic disorder are as follows[5] :
Single or multiple motor and/or vocal tics (eg, sudden, rapid, recurrent, nonrhythmic, stereotyped motor movement or vocalizations) are present
The tics have been present for less than 1 year since the first tic onset
The onset is before age 18 years
The disturbance is not due to the direct physiologic effects of a substance (eg, stimulants) or a general medical condition (eg, Huntington disease or postviral encephalitis)
Criteria have never been met for Tourette’s disorder or persistent (chronic) motor or vocal tic disorder
See Workup for more detail.
Management
Treatments for tics that have demonstrated efficacy in replicated controlled trials include the following:
Dopamine D2 receptor antagonist therapy
Dopamine agonist therapy
Habit reversal therapy
Patient education is very important for individuals with Tourette syndrome. Counseling and support including cognitive-behavioral therapy and social skills training should also be considered.
Tourette syndrome (TS) is a common genetic neurological disorder characterized by chronic motor and vocal tics beginning before adulthood.[1, 2, 3, 4] Affected individuals typically have repetitive, stereotyped movements or vocalizations, such as blinking, sniffing, facial movements, or tensing of the abdominal musculature.
Other neurobehavioral manifestations include attention-deficit-hyperactivity disorder, obsessive-compulsive disorder, poor impulse control, and other behavioral problems. Symptoms wax and wane and vary significantly from one patient to another. Although diagnosis requires the presence of chronic multiple independent motor tics and at least one phonic tic, these are not always the patient's most disabling symptom.
Historical background
A historical example of TS was provided by Samuel Johnson (1709-1784), the author of the first good English dictionary and the subject of Boswell's biography.[6, 7] Many of those who met him were surprised by his repetitive "nervous movements," and he often repeated word fragments or other sounds. His movements and sounds were suppressible, yet they were clearly not voluntary, as they were present even in situations that embarrassed him.
On one occasion, Johnson called his movement "involuntary," yet on another occasion, he called them a "bad habit." He touched objects in a stereotyped fashion, went through a complex ritual on passing through a doorway, and had excessive worries about his religious status and health. Additionally, he suffered from episodes of depression and ate, even in polite company, "like a wild animal." However, he was one of the great minds of his day, and he demonstrated remarkable persistence and clever wit in the face of his adversity.
Some of Johnson's contemporaries believed his odd behavior was a psychological disturbance, while others believed it was a variant of rheumatic chorea. Now, we would consider his symptoms typical of TS.
Go to Pediatric Tourette Syndrome for complete information on this topic.
Current understanding
TS was originally considered a rare psychogenic condition but is now thought to be a relatively common genetic disorder. It remains misunderstood by the lay public, and many people are still unaware that cursing tics (coprolalia) affect only a minority of patients (8%).
One of the first descriptions of tics appeared in 1825, when the French physician Jean Itard described 10 people with repetitive tics, including complex movements and inappropriate words.[8] Subsequently Charcot assigned his resident, George Gilles de la Tourette, to report on several patients treated at the Salpêtrière Hospital for repetitive behaviors. The goal was to define an illness distinct from hysteria and chorea.
In Tourette's 1885 paper, Study of a Nervous Affliction, he concluded that these patients suffered from a new clinical condition: "convulsive tic disorder."[9, 8] Tourette and Charcot thought it was untreatable, chronic, progressive, and hereditary. Although Charcot persisted in his efforts to distinguish "Gilles de la Tourette's tic disease" from other illnesses, his contemporaries generally did not agree.
Over the next century, little progress was made with respect to pathogenesis. A popular theory was that tics resulted from a brain lesion or lesions similar to those seen with rheumatic chorea or encephalitis lethargica. Another commonly proposed idea was that repetitive tics were caused by emotional and psychiatric factors and therefore would be best treated by Freud's psychoanalytic method.
In the United States, the view that TS was a rare, bizarre psychological disorder prevailed for much of the 20th century. In the 1970s, Drs Arthur and Elaine Shapiro, with Bill and Eleanor Pearl of the fledgling Tourette Syndrome Association (TSA), used the efficacy of haloperidol and other clinical data to support the conclusion that TS was a relatively common neurological disorder and not a mental or emotional problem.
The pathophysiology underlying TS remains unknown. Biochemical, imaging, neurophysiologic and genetic studies support the hypothesis that TS is an inherited, developmental disorder of neurotransmission.
The basal ganglia and inferior frontal cortex have been implicated in the pathogenesis of TS, as well as obsessive-compulsive disorder (OCD) and attention deficit–hyperactivity disorder (ADHD). Neuropathological studies, however, have failed to reveal any consistent structural abnormalities in these areas.
Volumetric MRI studies have suggested that the normal asymmetry of the basal ganglia is lost in affected individuals. Healthy right-handed males normally demonstrate a predominance of the left putamen but this appears to be absent in TS, supporting the possibility of a developmental abnormality.
Little is known about the role of the thalamus in the pathogenesis of TS. A recent study using conventional measures of volumes and surface morphology demonstrated enlargement of the thalamus of more than 5% in affected patients of all ages. These findings raise the possibility of activity-dependent hypertrophy and therefore suggest that TS may involve previously unsuspected motor pathways.[10]
Biochemical studies
Abnormalities of central neurotransmitters have been implicated as a cause of TS. Limited post mortem studies have shown low brainstem serotonin, low levels of glutamate in the globus pallidus, and low levels of cyclic adenosine monophosphate (AMP) in the cortex.
Affected individuals have also been shown to have an increased rate of binding of 3H-mazindol to the presynaptic dopamine-uptake-carrier sites. This observation has led some investigators to conclude that TS results from dopaminergic hyperinnervation of the ventral striatum and associated limbic system. Several studies using single-photon emission computed tomography (SPECT) have found an increase in the density of the presynaptic dopamine transporter and the postsynaptic D2 dopamine receptor.
Some neuropathological studies have supported these findings. TS may therefore result from abnormal regulation of dopamine uptake and release.
Noradrenergic pathways have also been studied, in part because tics may improve with the centrally acting alpha2-noradrenergic agonist clonidine.[11] However, studies have failed to demonstrate abnormal concentrations of norepinephrine or its metabolites in serum, cerebrospinal fluid (CSF), or urine in patients with TS.
Serotonin's role in TS remains controversial. Patients have been found to have lower plasma tryptophan levels than normal[12] and some postmortem studies have shown reduced brain tryptophan concentrations.
Unconfirmed results suggest a possible genetic link between TS and a serotonin metabolic enzyme.[13] A [123 I]b-CIT SPECT study suggested lower serotonin transporter binding in patients with TS that seemed to have an inverse correlation with clinical severity.[14] However, the relevance of these findings is unknown. Serotonin-3 receptor genes showed no clear abnormalities in TS.[15]
Most treatments that modify serotonin function (eg, fluoxetine therapy, tryptophan depletion therapy) have not produced consistent responses. However, a double-blind randomized controlled trial of the serotonin-3 receptor antagonist drug ondansetron did suggest efficacy.[16]
Other transmitter systems that may provide insights into tic production include cannabinoid/anandamide receptors, which are located densely in internal globus pallidus (among other areas). Evidence supports the efficacy of cannabinoids in reducing tic severity in some patients.[17]
Gamma-aminobutyric acid (GABA) is the most common inhibitory transmitter in the brain. Several studies have shown no abnormalities in patients with TS relative to control subjects.
The role of glutamate, the brain's predominant excitatory transmitter, needs further study. One postmortem report showed markedly different glutamate levels in the internal segment of globus pallidus (GPi), but this finding awaits confirmation. A transgenic mouse model has shown increased stereotypic activity at rest, which was worsened by administration of the noncompetitive glutamate N -methyl-D-aspartate (NMDA) receptor antagonist MK-801, which is similar to phencyclidine.[18]
The GABA-ergic striatal medium spiny neurons use enkephalin and dynorphin as cotransmitters. Although occasional patients seem to benefit from opioid agonists or antagonists, the data remain sparse. CSF dynorphin concentrations are normal in individuals with TS.[19] One small positron emission tomographic (PET) study demonstrated changes in opioid receptor binding in TS; this remains an interesting area for research.[20]
Dopamine - clinical observations
Substantial evidence indicates that neuroleptic and atypical antipsychotic agents reduce tic severity. Presynaptic dopamine-depleting agents also improve tics, and in some patients, tics may be worsened by neuroleptic withdrawal or, possibly, stimulant use. However, other data do not support a simple hypothesis that dopamine function is hyperactive in individuals with TS.
Tics are not abated with the subsequent development of Parkinson disease.[21] However, in Parkinson disease, dopamine loss is most evident in posterior putamen,[22] whereas caudate and ventral striatum are more implicated in TS.
Furthermore, dopamine receptor agonists have also been used to successfully treat tics, and patients whose tics improved with an agonist had evidence of prolactin inhibition, consistent with a postsynaptic effect.[23, 24, 25] With adequate carbidopa pretreatment, a single dose of levodopa was followed by diminished, not worsened, tic severity.[23]
In summary, clinical evidence suggests that dopaminergic function is abnormal in TS. However, the site of dopamine involvement within the pathway remains unknown.
Dopamine-specific genes
Several studies have examined dopamine-related candidate genes for association with a diagnosis of TS. Studies suggest a possible association with the dopamine D2 or D4 receptors.[26, 27] ; however, specific TS genes remain to be identified.
Dopamine studies
Several groups have studied D2-like dopamine receptor binding in TS by using PET or SPECT. Four studies showed no meaningful differences between TS and control groups with the use of carbon-11 raclopride, [iodine-123]iodo-6-methoxybenzamide (IBZM), [123 I]iodo-2[beta]-carbomethoxy-3[beta]-(4-iodophenyl)tropane (beta-CIT), or11 C 3-N -methylspiperone.[28, 29, 30, 31] (However, a preliminary report from 1 of these studies did describe positive findings.)
Another study compared more severely affected monozygotic twins with TS to their less affected co-twins by using IBZM SPECT and found a correlation of severity with binding in the caudate but not the putamen.[32] This finding suggests that the caudate may play an important role in the pathogenesis of tics.[33]
Studies using a newer D2 ligand ([18 F] N -methylbenperidol) have concluded that D2-like receptor binding is probably normal in TS. However, a number of reports show that presynaptic markers of dopamine innervation may be abnormal in TS. Studies have shown consistently higher concentrations of presynaptic markers or activity in the ventral striatum.[34, 35, 28, 36, 37, 38, 39, 40, 41, 42]
These markers have been shown to appear to begin in childhood before treatment has been started.[43] Therefore, in TS, abnormal dopamine production (or abnormal regulation of dopamine production) may lead to abnormal movement and perhaps other altered behavior.
Singer et al demonstrated normal dopamine release at baseline in TS but altered dopamine release in response to a pharmacologic challenge with amphetamine.[40] This observation may explain the essentially normal neurologic function seen in TS when tics are not apparent.
Studies of dopamine breakdown products (homovanillic acid) in the CSF and/or tissue tyrosine hydroxylase levels have failed to consistently demonstrate abnormalities indicative of altered dopamine metabolism.
Dopamine-pharmacologic activation neuroimaging
The author and his colleagues have studied volunteers with chronic tic syndromes and control subjects by using a pharmacologic activation functional magnetic resonance imaging (pharmacologic fMRI, or phMRI) design.[44] This method attempts to map and quantify the brain's responsiveness to a dopamine challenge. Preliminary analyses were complicated by methodological difficulties inherent in the blood oxygenation level–dependent (BOLD) fMRI signal response over long periods (unpublished data). Additional analyses are under way.
A subset of these patients participated in a pharmacologic-cognitive interaction fMRI study. Subjects performed a working memory ("2-back") task or a response inhibition ("go/no-go") task before and again during infusion of levodopa (with carbidopa). Some but not all other studies of patients with TS have shown higher-than-normal commission errors on response inhibition tasks.[45, 46, 47] However, in this study, no differences between groups were observed with the response inhibition task.[48]
As task performance was similar in the 2 groups, the results are best explained by a true difference in brain response between the 2 groups: The TS group apparently requires more activation of several working memory–related regions to sustain normal task performance. These exciting results, if confirmed, suggest that TS patients may have a dopamine-responsive abnormality of brain function in nonmotor as well as motor brain circuits.
Functional imaging studies
In general, the resting metabolic activity of the brain in TS appears to be normal. Studies using blood oxygen level–dependent fMRI comparing activity during a tic with brain activity when tics were absent suggest that tics are associated with activation of broad areas of the neocortex, some limbic areas, the striatum, and the thalamus.
Resting cerebral blood flow or metabolism
Several groups compared patients with TS with control subjects in terms of regional resting brain function, as indexed by blood flow or metabolism.[38] The results suggested no alteration in average whole-brain activity, but some relatively consistent regional differences were found. Increased activity was observed in primary sensorimotor cortex, which may be a nonspecific reflection of excessive movement. All groups found decreased activity in the basal ganglia, perhaps best localized to ventral striatum.[49, 50, 51, 52, 53, 54, 55]
Some investigators found increased activity in the orbital frontal cortex.[56, 57] Others, however, found decreased orbital activity.[49]
Eidelberg et al examined the correlation of metabolism among specific brain regions and showed differences between TS and controls, some of which related specifically to tic severity.[58]
Correlations with tic severity or tic suppression
In an fMRI study, self-rated intensity of the current urge to tic was correlated with right caudate BOLD signal intensity.[59] Findings also implicated the cingulate cortex.
Similar results emerged from a PET study in which regional cerebral blood flow was correlated with tic frequency in individuals with TS.[60] In this study, atlas-normalized blood flow was searched voxel by voxel for within-subject correlations with the number of tics observed during each of several blood flow scans; tics were associated not only with the expected increased activity in primary motor cortex but also with altered activity in more sensory or volitional brain regions, such as anterior cingulate.
In a [18 F]fluorodeoxyglucose (FDG) PET study, caudate and thalamus metabolism was inversely correlated with clinical severity.[61]
A case report described fMRI correlates of coprolalia in 1 subject with TS. The results offered support to the hypothesis of a tic-generating circuit model.[62] In ongoing fMRI studies, Stuart Mostofsky at the Kennedy Krieger Institute uses the important control of intentional tic-like movements in people with TS.
Functional imaging with intentional motor activation
In an fMRI study, volunteers with TS performing a simple finger-tapping task had a larger activation of sensorimotor and supplementary motor area than that of control subjects.[63]
By contrast, an fMRI study of precision movement showed decreased activity of supplementary motor area in tic patients versus control subjects.[64]
Functional imaging with behavioral or cognitive activation
In 2001, Rauch and colleagues reported findings from a pilot study in which TS patients (like patients with OCD) showed deficient activation of striatum during implicit learning.[65]
In the same year, Swerdlow and colleagues developed a method for imaging brain function during prepulse inhibition of the startle reflex, a well-studied phenomenon that requires striatal activation.[66]
Neuroanatomic studies
Lesion studies
Several cases of tics beginning after a focal lesion to the prefrontal cortex, basal ganglia, and thalamus have been reported. One series described 6 patients who suddenly developed tics, obsessions, and/or compulsions after anaphylactic reaction to wasp stings produced bilateral globus pallidus lesions.[67, 68]
Evaluation of tics secondary to encephalitis or degenerative illnesses
Motor and vocal tics and compulsions frequently were reported in patients who survived the encephalitis lethargica epidemic in the 1910s and 1920s. Similar symptoms also occur in some patients with Huntington disease, Wilson disease, neuroacanthocytosis, or frontal lobe degeneration. Although none of these illnesses cause discrete, circumscribed lesions, these observations support the impression that the basal ganglia and frontal cortex are involved in tic production.
Autopsy studies
A limited number of autopsied cases have shown a reduction in tonically active parvalbumin-positive interneurons in the caudate and putamen. Postmortem studies have also shown a doubling of the parvalbumin-positive projections from the globus pallidus interna to the thalamus.
Although the importance of these findings is uncertain, parvalbumin is known to be a marker for fast-spiking interneurons that have widespread influence. These neurons are thought to be output neurons and their reduction could diminish output from the globus pallidus interna.
In vivo volumetry
Standard neuroimaging studies in TS are unremarkable. However, volumetric MRI has suggested that the normal asymmetry of the basal ganglia is absent.
The largest study of regional brain volumes to date, which involved more than 150 individuals with TS and a similar number of comparison children and adults, showed that subjects with TS had large dorsal prefrontal and parieto-occipital regions and smaller inferior occipital volumes.[69, 70] Symptom severity was best correlated with volume in the orbitofrontal, midtemporal, and parieto-occipital cortex.
TS patients were found to have significantly reduced caudate volumes.[70, 71] The importance of this finding is highlighted by the fact that, on prospective follow-up of patients who had MRI volumetry, smaller caudate volume in childhood correlated significantly with severity of tics, obsessions, and compulsions an average of 7.5 years later.[72]
Another study showed that patients with TS had small right frontal lobes, large left frontal lobes, and more frontal lobe white matter compared with healthy control subjects.[73] Other investigators also found increased frontal white matter.[74]
Two prior studies had selectively examined basal ganglia volumes and had found slightly smaller left putamen volume and a diminution of the normal asymmetry of basal ganglia volume.[69] These findings were not replicated when more- and less-affected twins with TS were compared.[75]
One MRI study revealed abnormal T2 relaxation time in the putamen and caudate nuclei.[76] One case report described a child with a sudden onset of stereotyped behaviors after a streptococcal infection; this child had basal ganglia volumes larger than those of age-matched controls during the acute illness and smaller volumes months later.[77]
Some consistencies arise from these studies. These include decreased caudate volume and, possibly, increased prefrontal white matter and dorsolateral prefrontal gray matter volumes. In one volumetric study, abnormal basal ganglia volumes in a group of patients with TS were entirely attributable to comorbid attention deficit hyperactivity disorder (ADHD).[78]
Similar results were reported from a study of regional brain volumes in relation to streptococcal antibody titers in TS.[79] In other studies, however, the effects of OCD or ADHD were examined and did not explain all of the imaging findings.
The implication is that at a minimum, careful clinical assessment, including information about OCD or ADHD symptoms, is required when the results of any new neuroimaging study are interpreted in individuals with TS. Hopefully, structural imaging will eventually identify a specific anatomic shape that will assist in the identification of responsible genes.
Electrophysiologic studies
Studies using back-averaging techniques have shown that the premovement potential in TS is often absent prior to the appearance of an involuntary movement. This observation supports that the tics are involuntary.[80] Event-related potentials that indicate motor preparation, inhibition of prepotent motor responses, or unexpected events have been variably abnormal in TS patients.[81, 82, 81, 83]
Several laboratories have used short-interval transcranial magnetic stimulation (TMS) to investigate cortical inhibition in TS. In 1997, Ziemann et al showed abnormal cortical inhibition in tic patients.[84] However, in 2001 Moll et al suggested that this was not specific to a TS diagnosis but was accounted for by a comorbid diagnosis of ADHD.[85] Findings from a follow-up study in 2003 suggested that an OCD diagnosis might also account for the original results.
In a 2004 study using transcranial magnetic stimulation, Gilbert et al found that current (recent) severity of tics and hyperactivity in a group of TS subjects was associated significantly and independently with short-interval cortical inhibition.[86] ADHD symptoms, specifically hyperactivity, showed the closest correlation. Repeat studies in the same children replicated these findings and demonstrated their temporal stability.[87] The results have been independently replicated.[88]
Other pathophysiologic studies
Neuropsychological studies have been conducted to study specific areas of cognitive function. Among other goals, this purpose may inform our understanding of the genesis of tics. (The interested reader can consult an excellent review by Como in 2001.[89] )
Independent studies found that patients with TS performed worse than controls on a weather-prediction task that involved habit learning. In this task, cues predict outcomes at probabilities between 0 and 100%; the subject gradually learns to predict outcomes correctly even though feedback to the subject appears to be inconsistent. Worse performance on this task correlates with more severe illness.[90, 91]
In animal and human studies, habit-learning tasks require a healthy striatum. Other forms of memory, including other kinds of procedural learning, are generally normal in TS.[92]
Intentional and reflexive eye movements were studied in TS; the results are summarized as being consistent with the hypothesis that the ability to inhibit or delay planned motor programs is significantly impaired in TS. Altered cortical-basal ganglia circuitry may lead to reduced cortical inhibition, making it harder for TS subjects to withhold the execution of planned motor programs.[93]
Startle reflexes can be studied in a repeatable way and are abnormal in TS, as in OCD. Advances that allow the study of such reflexes in the functional MRI environment and in preclinical models offer hope for rapid screening of potential treatments.[66]
Immune studies related to group A streptococcal infections are discussed below. In addition, a large longitudinal study suggests that 2 cytokines, interleukin-12 and tumor necrosis factor-alpha, are associated with recrudescences of symptoms in patients with TS.[94] Whether these are markers specifically for TS symptoms remains to be determined.
Although a pilot microarray study of gene expression in TS peripheral blood did not find a statistically different pattern of expression, the 6 genes with increased expression in TS were all related to immune function.[95] However, none of these same genes were detected in a microarray study of post mortem putamen tissue, suggesting that further study is required in this area.[96]
The high male-to-female ratio in TS (up to 10:1 in some prevalence studies) suggests a possible androgen-mediated effect, perhaps occurring during prenatal development. A study that examined gender identity and gender role behavior in males and females with tic disorders offered some support for this hypothesis: in this study, females demonstrated more gender dysphoria, increased masculine play preferences, and a more typically "masculine" pattern of performance, while males reported increased masculine play preference.[97]
Timing of tics
Peterson and Leckman have drawn attention to the timing of tics.[98] In the course of an office visit, tics tend to occur in bouts rather than being distributed evenly. Similarly, viewed over the course of several months, days with worse tics also tend to cluster together.
A consistent temporal pattern when viewed at any of various time scales is a fractal pattern, a typical feature of a chaotic mathematical system. This suggests the possibility of searching for neuronal firing patterns or other physiologic processes that replicate on even smaller time scales the timing of tics as observed over minutes or months.
Several clinical syndromes are distinct from TS but have overlapping features. These include the repetitive, intrusive thoughts or suppressible but eventually irresistible rituals in OCD, and echophenomena or utilization behavior in patients with catatonia or frontal lobe injury. Conceivably, progress in any of these conditions may yield further insights into the pathophysiology of tic disorders.
Additional insights into tics may be gathered by reference to other illnesses with overlapping features. Tics may be classified as a stereotypic movement disorder, in that the movements are often complex and are repetitive rather than random.
Stereotypies are observed in a number of human and animal situations and may bear some relevance to the anatomy and pathophysiology of TS. Animal models include stallions with inherited repetitive movements, grooming rituals, and self-injury; tethered sows or other animals confined to small quarters; Labrador dogs who repeatedly lick their paws to the point of abrasions; rodents given apomorphine or stimulants; and more recently, rodents injected with plasma from patients with TS. The relevance of these animal models has been reviewed.
In people, a spectrum of stereotyped movement severity ranging from normal to problematic may occur.[99] Simple stereotypies are common in infancy and early childhood. Habits and mannerisms are nearly ubiquitous. However, stereotypies become clearly pathologic in autism or Rett syndrome. Determining why tics chronically persist in a few individuals but briefly appear and then wane in others is important.
A model of tic production
Knowledge about primate basal ganglia anatomy and physiology has been summarized (see the image below).[100, 101, 102] In this view, motor patterns are generated in the cerebral cortex and brain stem. Performance of a specific intended movement includes not only selection of the desired movement but also inhibition of antagonistic movements and of similar movements of neighboring body parts.
View Image
Tourette syndrome and other tic disorders. Schematic of the hypothetical reorganization of the basal ganglia output in tic disorders, with excitatory ....
The basal ganglia are organized so as to inhibit, or apply a "brake" to these undesired motor programs. Normally, the basal ganglia allow selective release of the brake from the desired action. Tics may result from a defect in this braking function. This may be caused by an episode of overactivity in a focal subset of striatal neurons, perhaps in the striatal matrisomes identified by Graybiel and colleagues.[103] The episodic focal overactivity may result from any of various mechanisms acting at any of various locations from cortex to thalamus.
Dopaminergic innervation of striatum has several characteristics that would allow generation of such abnormal epochs of striatal activity; these include dopamine's modulation of the resting membrane potential set point and the influence of dopamine on long-term potentiation or long-term depression (relatively long lasting changes in neuronal excitability based on the prior neuronal inputs).
Finally, this theory is largely derived from studies of the motor circuit involving motor cortex, striatum, internal pallidum, subthalamic nucleus, and ventral thalamus. However, parallel neuronal circuits influence other regions of frontal cortex, including orbitofrontal, medial prefrontal, and dorsolateral prefrontal cortex. These pathways are relatively separated in the cortex, yet they physically course closer together in the basal ganglia, thalamus, and midbrain.
Lesional and neuroimaging data in individuals with OCD or ADHD implicate abnormalities in nonmotor regions of frontal cortex. Possibly the frequent, but not uniform, occurrence of these symptom complexes in patients with tics represents processes of similar pathology but overlapping anatomy (see image below).
Causes of TS may be genetic or nongenetic. The latter category includes cases related to streptococcal infection and cases following other brain insult.
Genetic causes
TS is known to be familial; prevalence of TS in first-degree relatives is 5-15%, or at least 10 times the prevalence in the general population. Chronic motor tics (without vocal tics) are also common in relatives. This is not surprising, since vocal tics are essentially motor tics of the muscles used in speech. In the rest of this article, chronic motor or vocal tic disorder is not distinguished from TS.
Genetic factors are implicated in twin studies, which show that the ratio of concordance in monozygotic versus dizygotic twin pairs is approximately 5:1.[104] By the early 1990s, available data supported a single major autosomal dominant gene with pleiotropic expression (ie, chronic motor tics, TS, or OCD) and incomplete penetrance (about 70% in women, 99% in men).[105, 106] Family linkage methods excluded a single dominant gene in most of the genome, however.
More recent results suggest alternative models. These models include the involvement of several genes rather than one, intermediate penetrance in heterozygotes than in homozygotes, or mixed genetic-environmental causes.[107]
A sibling-pair approach, which may be more sensitive under these conditions, is currently being employed to search for TS genes. The TSA and the National Institutes of Health have supported an international collaborative genetic study using linkage and sibling methods to analyze 500 markers in over 2200 individuals from 269 families.[108] For example, this research has identified DLGAP3 as a promising candidate gene for TS.[109]
Other approaches to identifying specific genes related to TS include examination of families with visible chromosomal abnormalities or a high degree of consanguinity.[110] One such association has been reported, but it affects at most a small minority of people with tics.[111]
Nongenetic causes
Nongenetic causes also must exist, because discordant monozygotic twin pairs are known. Additional evidence for environmental or epigenetic causes includes differences in severity between affected monozygotic twins, with greater severity in the twin with perinatal complications than in the co-twin and cases of secondary (symptomatic) tics with vascular, degenerative, toxic, or autoimmune causes.[112]
The possibility that some, or perhaps many, cases of TS may be caused by an abnormal immune response to streptococcal infection has generated substantial interest.
Streptococcal infections
In the late 1800s and early 1900s, chorea was widely assumed to be usually due to rheumatic fever. The link of chorea to prior streptococcal illness first was proven in the 1950s. The delay occurred partly because in many cases chorea does not follow streptococcal recurrence until several months afterward, and it often occurs without coeval arthritis, carditis, or serologic abnormality.
In the 1970s, patients with Sydenham chorea were demonstrated to have high levels of antibodies that react to human brain. These antibodies have since been shown to cross-react to certain proteins on group A beta-hemolytic streptococci (GABHS).[113]
Although tics and chorea can be differentiated clinically, the definitions were less clear in the 19th century. For instance, Charcot and Gilles de la Tourette distinguished tics and chorea primarily on grounds of course and presumed cause rather than phenomenology.
In recent years, interest has been growing in the possibility that streptococcal illness may produce not only chorea but also tics, obsessions, or compulsions. In several cases tics began suddenly after a streptococcal infection, and investigators proposed a research case definition for poststreptococcal autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS).[114]
Although streptococcal infection may cause TS symptoms in a small subgroup of patients, the precise relationship between such infections, antineuronal antibodies, and TS remains unknown.
Some observations support a connection between GABHS infection and tics.[115] OCD occurs more frequently in children with Sydenham chorea than in healthy controls or those who have rheumatic fever without chorea.[116] In a large case-control study, children with OCD or a chronic tic disorder were more than twice as likely as controls to have had a documented GABHS infection in the 3 months prior to the neuropsychiatric diagnosis, and children with multiple GABHS infections in a 12-month period were 13.6 times more likely to later be diagnosed with TS.[117]
Several patients with either tics or OCD have been found to have high levels of antistreptococcal or anti-DNase antibodies.[114] This is not a nonspecific indicator of distress, since other patient populations do not have these findings. Patients with tics or OCD also have high levels of a B-cell marker (D8/17) that similarly is elevated in Sydenham chorea.[118] Finally, children with TS may have increased levels of circulating antineuronal antibodies (see the image below).[119, 120, 121, 122]
View Image
Tourette syndrome and other tic disorders. Immunologic response found in patients with Sydenham chorea is also found in patients with Tourette syndrom....
The results above must be tempered by several considerations.[123, 124] First, almost all humans have a GABHS infection at some time, whereas more than 95% never develop OCD or chronic tics, suggesting a substantial role for host factors.
Second, any stressor—including an acute infectious illness—can exacerbate tics. Even without a direct causal link, patients or their parents first may notice tics at a time of stress. The association of TS with immune response is not specific to GABHS (see Pathophysiology).[125]
Third, a positive laboratory result for streptococcal infection can occur without current illness. Additionally, most people with tics simply do not meet a case definition of sudden onset with infection and dramatic subsequent remission. For instance, a nationwide search for such cases for a treatment study sponsored by the National Institute of Mental Health resulted in only approximately 50 referrals.[126]
Fourth, some laboratory reports contradict the aforementioned results.[127, 128] A large study found no evidence for abnormal serum antineuronal antibodies in patients diagnosed either with PANDAS or with TS.[129]
Streptococcal involvement represents a promising lead that may result in breakthroughs in the understanding of tic pathogenesis. However, treatment based on this hypothesis is not standard care at present. A controlled study showed that, in highly selected patients, OCD can improve after intravenous immunoglobulin (IVIG) therapy.[126] However, achieving true blinding for IVIG administration is difficult, and a placebo effect cannot be excluded. Tics were not affected by treatment in the blinded condition.
Whether antibody-mediated poststreptococcal illness causes most, a few, or no cases of TS is still unknown. In the meantime, a reasonable approach in these cases is to treat acute GABHS infections or rheumatic fever with antibiotics to prevent cardiac sequelae but to avoid invasive immune therapies. A possible exception may be highly select cases of OCD that fit stringent criteria for PANDAS, which might be treated in a research protocol.
Other causes
Several cases of tics beginning after a focal lesion to the prefrontal cortex, basal ganglia, and thalamus have been reported. One series described 6 patients who suddenly developed tics, obsessions, and/or compulsions after anaphylactic reaction to wasp stings produced bilateral globus pallidus lesions.[67, 68]
Motor and vocal tics and compulsions frequently were reported in patients who survived the encephalitis lethargica epidemic in the 1910s and 1920s. Similar symptoms also occur in some patients with Huntington disease, Wilson disease, neuroacanthocytosis, or frontal lobe degeneration.
The exact prevalence of TS is not known. This is in part because of the lack of agreement on a precise definition of the disorder. Observational studies have suggested a prevalence of 0.7%, with up to 4.2% of all children having some type of tic disorder.
The Centers for Disease Control and Prevention (CDC) estimate that the prevalence of a lifetime diagnosis of TS is 3 cases per 1,000 population. This estimate is based on parent report of TS diagnosed by a physician or other healthcare provider from a nationally representative sample of US children and adolescents aged 6-17 years.[130]
International statistics
A recent epidemiological review suggests a 1% international prevalence of TS.[131] However, prevalence figures for TS have varied between 0.4% and 3.8%; in addition, different figures have been reported for some parts of the world and races, with a lower rate in sub-Saharan black Africans.
Several possible reasons for variations in reported rates have been suggested. These include the lack of a definitive diagnosis of TS; the variable manifestations of the syndrome; the methods employed in different epidemiological studies; different cultural propensities of people with tics to seek medical care; and possibly genetic and allelic differences in different races.[132]
Racial differences in incidence
TS has been described in people of many ethnic origins. In the US, the CDC found that a diagnosis of TS was twice as likely for non-Hispanic white persons than for Hispanic and non-Hispanic black persons. However, this observation may be influenced by differences in seeking of healthcare rather than in actual symptomatic prevalence.
Sexual differences in incidence
Boys are more likely than girls to have chronic tics. The male-to-female ratio in TS and in chronic motor tic disorder is approximately 5:1 (between 2:1 and 10:1 in different studies).
Age-related differences in incidence
By definition, TS has onset in childhood (usually age 5-10 y). The Diagnostic and Statistical Manual of Mental Disorders, 4th Edition Text Revision (DSM-IV-TR) requires onset before age 21. A multicenter study of German families showed that this definition is arbitrary but reasonable. In relatives of TS probands who also had tics, the tics usually started when the individual was younger than 18 years, but 5 relatives had otherwise typical histories for TS with onset after the age of 21 years.[133]
One study of a birth cohort with TS showed that the most common age for tic onset was 9-14 years.[134] The CDC found that diagnosed TS is approximately twice as common in persons 12-17 years old compared with those 6-11 years old.
The modal age of symptom onset increases roughly with complexity: Simple tics are reported earliest in life, while complex tics, compulsions, obsessions, and sensory tics, and/or premonitory sensations tend to develop somewhat later. Generally, simple motor tics (eg, blinking) are first noticed when the individual is approximately 5-10 years old, with vocal tics starting at 8-15 years.
Fortunately, by age 18 years, approximately 50% of patients are essentially free of tics. Tic severity tends to peak in early to mid adolescence and wanes thereafter. Tics may persist into adulthood but their severity is almost always diminished.
TS almost always persists throughout life. Fortunately, by age 18 years, approximately 50% of patients are essentially free of tics. Tic severity tends to peak in early to mid adolescence and wanes thereafter. Tics may persist into adulthood but their severity is almost always diminished.
Many people with tics lead a fairly normal life. However, even mild tics can be distressing.
For example, a patient of one of this article's authors is a man with mild TS who has a successful professional career and a good family life. He is used to his tics and does not prefer any treatment with noticeable adverse effects. However, he finds his symptoms annoying and would rather be free of them if given the choice. He states, "It is like I am on stage 16 hours a day. Every waking moment I am trying not to tic when people are watching." Other people with TS have more severe symptoms. Occasionally, the symptoms can be disabling.
The most common disability is social in nature.[135, 136] Patients with loud vocalizations or large movements either endure substantial criticism or they withdraw from many activities. Prejudice in work and school settings is common.
Tics also interrupt the individual's behavior and thought. Most patients find that they sometimes lose track of a conversation or that they are slow to complete a task because of incessant interruptions by their tics.
Self-injurious behavior is not uncommon. Occasionally, self-injury is intentional and due to a comorbid problem (eg, suicide during an episode of major depression). At times self-injury is pseudointentional; an example is repeatedly hitting one's face as a complex tic.
Perhaps more common than self-injuries are inadvertent injuries.[137, 138] Sometimes, these injuries are due to complex tics or compulsions, such as a need to touch high-voltage wires. Other times, they are due to inattentiveness or impulsivity. (In one of the author's cases, the father of a man with TS does not allow him to use power tools because he had had several near catastrophes.) Inadvertent injuries such as broken bones, cervical arthritis, or shin splints can also occur after simple yet repetitive and/or intense tics.
In clinical samples, most morbidity is due to inattention, impulsivity, obsessions, compulsions, or complex behavioral symptoms such as inappropriate social behavior, rage attacks, or insistence on sameness.
A minority of people with chronic tic syndromes receive disability compensation.
Tics tend to fluctuate in severity, distribution, and character over intervals that are usually of weeks to years. A typical example is as follows: A boy starts blinking excessively when aged 5 years and develops a repetitive nonrhythmic palatal click several months later. By age 7 years, the blinking persists, while forceful nasal exhalations and shoulder shrugging have replaced the click. As a teenager, he has all the old tics present together with violent head shaking. In college, subtle head shaking and hardly visible abdominal tensing may be the only remaining tics, with exacerbations during examination week.[139]
Two case definitions for TS are accepted widely: the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) definition from the American Psychiatric Association, 2013,[1] which is widely used in the United States for clinical purposes (see the DSM-5 criteria for tic disorders below); and the Tourette Syndrome Study Group (TSSG) definition, 1993[2] (see TSSG criteria for tic disorders below). Experts identify similar groups of patients by using either set of criteria.
American Psychiatric Association criteria for tic disorders
Diagnostic criteria for Tourette syndrome (DSM-5 307.23) are as follows:
Both multiple motor and 1 or more vocal tics have been present at some time during the illness, though not necessarily concurrently. (A tic is a sudden, rapid, recurrent, nonrhythmic, stereotyped motor movement or vocalization)
The tics occur many times a day (usually in bouts) nearly every day or intermittently throughout a period of more than 1 year, and during this period there was never a tic-free period of more than 3 consecutive months
The onset is before age 18 years
The disturbance is not due to the direct physiologic effects of a substance (eg, stimulants) or a general medical condition (eg, Huntington disease or postviral encephalitis)
Diagnostic criteria for chronic motor or vocal tic disorder (DSM-5 307.22) are as follows:
Single or multiple motor or vocal tics (eg, sudden, rapid, recurrent, nonrhythmic, stereotyped motor movement or vocalizations), but not both, have been present at some time during the illness
The tics occur many times a day nearly every day or intermittently throughout a period of more than 1 year; and during this period there was never a tic-free period of more than 3 consecutive months
The onset is before age 18 years
The disturbance is not due to the direct physiologic effects of a substance (eg, stimulants) or a general medical condition (eg, Huntington disease or postviral encephalitis).
Criteria have never been met for TS
Diagnostic criteria for transient tic disorder (DSM-5 307.21) are as follows:
Single or multiple motor and/or vocal tics (eg, sudden, rapid, recurrent, nonrhythmic, stereotyped motor movement or vocalizations) are present
The tics occur many times a day, nearly every day for at least 4 weeks, but for no longer than 12 consecutive months
The onset is before age 18 years
The disturbance is not due to the direct physiologic effects of a substance (eg, stimulants) or a general medical condition (eg, Huntington disease or postviral encephalitis)
Criteria have never been met for TS or chronic motor or vocal tic disorder
Specify if this is a single or recurrent episode
Tic disorder not otherwise specified (DSM-5 307.20): This category is for disorders characterized by tics that do not meet criteria for a specific tic disorder. Examples include tics lasting less than 4 weeks or tics with an onset after age 18 years.
Tourette Syndrome Study Group criteria for tic disorders
Diagnostic criteria for TS (coded as A-1 or A-2 depending on source of information) are as follows:
Both multiple motor and one or more vocal tics have been present at some time during the illness, though not necessarily concurrently
The tics occur many times a day, nearly every day, or intermittently throughout a period of more than 1 year
The anatomic location, number, frequency, complexity, type, or severity of tics changes over time
Tics have their onset before age 21 years
Involuntary movements and noises cannot be explained by other medical conditions
Motor and/or vocal tics must be witnessed by a reliable examiner directly at some point in the illness or be recorded by videotape or cinematography (for definite TS, A-1) or (for tics not witnessed by a reliable examiner) tics must be witnessed by a reliable family member or close friend, and description of tics as demonstrated must be accepted by reliable examiner (for TS by history, A-2)
Diagnostic criteria for chronic multiple motor tic or phonic tic disorder (B-1 and B-2) are as follows:
Either multiple motor or vocal tics, but not both, have been present at some time during the illness
The tics occur many times a day, nearly every day, or intermittently throughout a period of more than 1 year
The anatomic location, number, frequency, complexity, or severity of tics changes over time
Tics have their onset before age 21 years
Involuntary movements and noises cannot be explained by other medical conditions
Motor and/or vocal tics must be witnessed by a reliable examiner directly at some point in the illness or be recorded by videotape or cinematography (for definite chronic multiple motor tic or phonic tic disorder, B-1) or (for tics not witnessed by a reliable examiner) tics must be witnessed by a reliable family member or close friend, and description of tics as demonstrated must be accepted by a reliable examiner (for chronic multiple motor tic or phonic tic disorder by history, B-2)
Diagnostic criteria for chronic single tic disorder (C-1 and C-2): This disorder is the same as in the previous category (B-1 and B-2), but with a single motor or vocal tic.
Diagnostic criteria for transient tic disorder (D-1 and D-2) are as follows:
This disorder is characterized by single or multiple motor and/or vocal tics
The tics occur many times a day, nearly every day, for at least 2 weeks, but for no longer than 12 consecutive months, although the disorder began over 1 year ago
The anatomic location, number, frequency, complexity, or severity of tics changes over time
The patient has no history of TS or chronic motor or vocal tic disorders
Tics have their onset before age 21 years
Motor and/or vocal tics must be witnessed by a reliable examiner directly at some point in the illness or be recorded by videotape or cinematography (definite transient tic disorder, D-1) or (for tics not witnessed by a reliable examiner) tics must be witnessed by a reliable family member or close friend, and description of tics as demonstrated must be accepted by a reliable examiner (for transient tic disorder by history, D-2)
Diagnostic criteria for nonspecific tic disorder (E-1 and E-2) are as follows:
Tics that do not meet the criteria for a specific tic disorder fall into this category; an example would be a tic disorder with tics lasting less than 1 year and without any change over that period of time
Motor and/or vocal tics must be witnessed by a reliable examiner directly at some point in the illness or by videotape or cinematography (for definite nonspecific tic disorder, E-1) or (for tics not witnessed by a reliable examiner) tics must be witnessed by a reliable family member or close friend, and description of tics as demonstrated must be accepted by a reliable examiner (for nonspecific tic disorder by history, E-2)
Diagnostic criteria for definite tic disorder, diagnosis deferred F: This disorder meets all criteria for definite TS (first definition, A1), but duration of illness has not yet extended to 1 year.
Diagnostic criteria for probable TS type G are as follows:
Type 1 fulfills all criteria for definite TS (first definition, A1) except for the third and fourth criteria
Type 2 fulfills all criteria for definite TS (first definition, A1) except for the first criterion; this type can be either a single motor tic with vocal tics, or multiple motor tics with possible vocal tic(s)
Diagnostic criteria for probable multiple tic disorder, or motor and/or vocal tics type H: This disorder fulfills all criteria for definite chronic multiple tic disorder (second definition) completely, except for the third and/or fourth criteria.
An important caveat is that many patients with tics may not demonstrate them on their first office visit, especially when the examiner is looking directly at the patient. In such cases, important aids to diagnosis can include obtaining the patient's history from several sources; scheduling follow-up office visits; and, most importantly, assigning the patient (or his or her parents) to bring a home video to show their behavior. Learning to watch the patient out of the corner of one's eye while speaking with a family member or writing in the chart is also helpful.
The remainder of the physical examination is important primarily for differential diagnosis. Special attention should be paid to the patient's mental status, cornea (Kayser-Fleischer rings), eye movements, abnormal movements, muscle tone, gait, postural stability, and bradykinesia or tremor if any. General neurological and psychiatric examinations are also important.
A number of non-tic symptoms are relatively common in patients with TS and are described briefly in the Table below.
Table. Symptoms of TS
View Table
See Table
Described below are the classification of tics, their general features, and the signs and symptoms of specific tics (sensory tics, dystonic tics, and coprolalia) and of related conditions such as OCD and ADHD.
Classification of tics
Tics are traditionally (if arbitrarily) classified by their distribution and complexity. Tics most often occur in the face, neck, pharynx, shoulders, and midline torso but can affect nearly any body part (see the image below).
View Image
Tourette syndrome and other tic disorders. Graphic shows the relative likelihood of lifetime sensory tics in a given region, as based on self-report o....
Albin has pointed out that stimulation of the ventral basal ganglia can reproduce some socially meaningful complex gestures (eg, stereotyped fear or pleasure displays in rodents), and that socially meaningful gestures predominantly involve these same body regions.[141] However, some tics do not readily fit traditional classifications.
General features of tics
Most tics are simple, meaningless movements. Tics are not entirely random, however, often involving elements of experience, practice, and social convention.
Echolalia or echopraxia (ie, imitation of another's speech or movements) occurs in as many as one third of patients. Seeing another person with tics with excessive blinking may induce a bout of blinking in someone who has not had that tic for years. Similarly, hearing about tics increases their severity.
Tics sometimes appear to recapitulate a new, voluntary behavior. One example is "air typing" as a complex tic after learning to touch type (observed in 2 unrelated individuals by one of the authors).
A man whose self-history was published in 1902 described his tics as often involving an urge to do just what was forbidden, such as "clucking" when told to be quiet in school. He compared his motor and vocal tics to a "desire for forbidden fruit".[142] Complex tics can include inappropriate activities such as touching a hot iron or a stranger's breasts.
As with most movement disorders, tics are worse at times of emotional stress and are diminished dramatically during sleep.
Differentiation of tics from other movement disorders
Tics are distinguished from other movement disorders by several typical characteristics. First, tics are most commonly brief movements, yet not so brief as the movements of myoclonus.
Myoclonus is not suppressible, whereas tics (and chorea) are suppressible. Often, after prolonged forced suppression, a rebound of tic severity occurs, though this is hard to demonstrate in controlled settings.[143] Similarly, tics tend to improve somewhat when the individual is absorbed in an enjoyable or demanding activity.
Individual tics may resemble the individual movements of chorea, yet tics are repeated stereotyped movements, while chorea consists of movements that are unpredictably distributed through the body. For example, a man with tics may be "the guy who shakes his head," while someone with chorea may be simply "the guy that twitches a lot." However, in distinction to tremor or most stereotypies, including typical tardive dyskinesia, tics are not rhythmic.
The volition of tics
Tics are nearly unique compared with other movement disorders in the perceived degree of volition. Although tics are clearly not voluntary in the usual sense (no one decides to have tics), the term involuntary is not strictly accurate.
Often in children and occasionally in adults, tics appear to be truly involuntary: The person tics without awareness or without a sense of voluntary movement. However, when pressed for details, adults describe most tics as a volitional response to an irresistible impulse, rather than an involuntary movement.[144] For example, patients often say, "I shake my head" rather than "my head shakes."
One of the authors' patients tried to describe his tics to people who have not experienced them: "Think of the last time you were at the symphony or at church and you had a tickle in your throat. Maybe you could hold it back until the end of the quiet movement or the end of the prayer, but then you just had to cough or clear your throat. This is something like what it feels like to have a tic, but with TS it is happening throughout the day, every day."
Tic syndromes can nearly always be differentiated from uncomplicated OCD. Simple tics or pure obsessions are easily identified, and essentially all patients with chronic tics have simple tics at some point. However, because the definitions overlap, individual complex actions cannot always be labeled clearly as a tic rather than a compulsion.
Complex tics are generally preceded by sensory phenomena or occur without warning, whereas compulsions generally involve obsessive worries and themes of contamination or guilt. However, both can be associated with symmetry concerns or a need to repeat something until an ineffable sense of "getting it just right" is achieved.[145, 146]
Sensory tics
Sensory tics refer to repeated, unwanted, uncomfortable sensations, often in the absence of a verifiable stimulus.[147, 148] Common examples are "something in the throat," or a hard-to-describe local discomfort in the shoulders.
Sensory tics often precede motor or vocal tics but can occur independent of externally apparent tics. In the former case, they also are called premonitory sensations, and often the actual movement or vocalization is perceived as relieving the uncomfortable sensation, akin to "scratching the itch." Blinking after an uncomfortable sensation in the eye is one example. At other times, patients report a more generalized discomfort or restlessness, sometimes reminiscent of the subjective component of akathisia.
Some published self-descriptions of tics identify these sensory phenomena as the core symptoms of TS.[149] However, developmentally, children have motor tics several years (on average) before they first report premonitory sensations.
Not surprisingly, the distribution of sensory tics mimics that of motor and vocal tics.
Dystonic tics
Dystonic tics refer to repeated movements that resemble fragments of childhood-onset generalized dystonia. An example is one of the authors' patients, a man with lifelong mild motor and vocal tics who when 45 years old developed typical blepharospasm (involuntary squeezing of the eyelids). After 2 years, the blepharospasm remitted while other tics predominated, only to recur after a year or so.
This name also has been used to describe simpler nonclonic tics that alternatively, perhaps more aptly, have been called tonic tics. These are common, and examples include 1- to 5-second isometric contractions at the shoulders or repeated tensing of the abdominal muscles.
Coprolalia
Coprolalia refers to unprovoked, unwanted outbursts of obscenities and occurs in 10-40% of patients with TS, depending on the method of ascertainment. Many observers find coprolalia to be uncommon, occurring in fewer than 10% of patients.
A well-known case history describes a woman with coprolalia, among other tics, who became deaf in childhood.[150] She learned sign language and could communicate without tics until becoming fluent, whereupon she developed signing tics, including socially unacceptable signs. Signing tics also occur in prelingually deaf individuals.[151]
Obsessive-compulsive symptoms
Obsessions are unwanted repetitive thoughts, fears, or mental images, eg, "I better do that over again until it looks right." Compulsions are actions, generally perceived as volitional but irresistible, performed repeatedly to reduce obsessive worries or according to rigid rules. Common compulsions are counting, checking, straightening, hoarding, or grooming. Phenomenologically, obsessions and compulsions share many features with tics, and historically, some authors have referred to them as mental tics or psychic tics.
Obsessions and compulsions occur in tic patients about 20 times more commonly than in the general population. In many cases, symptoms meet DSM-IV criteria for OCD. Relatives also have markedly elevated rates of obsessions and compulsions, with or without tics. Conversely, relatives of children with OCD have high rates of TS whether or not the proband has TS.[152, 153] These facts support the view that obsessive-compulsive symptoms, like tics, are part of the natural TS phenotype rather than a comorbid second illness.[154, 108]
Findings such as those just described may suggest useful avenues for research into the treatment of tics. On the other hand, the observation that purely symptomatic therapies may treat 1 symptom but not the other makes sense if one accepts that they may be generated by different, but similarly affected, areas of the brain.
Attention deficit–hyperactivity disorder symptoms
Attention deficit–hyperactivity disorder (ADHD refers to a clinically defined syndrome beginning in childhood and characterized by inattention and distractibility, behavioral hyperactivity, or marked impulsivity.
In recent years, several important findings have emerged from studies of (nontic) ADHD. The reliability of ADHD diagnosis by experts compares well with that of most other medical illnesses.
Findings suggest that, like essential hypertension, ADHD as currently defined represents a clinically convenient threshold imposed on a unimodal population distribution of symptom severity. The syndrome is highly heritable whether the phenotype is defined by clinician diagnoses or parents' reports of symptoms. Finally, safe treatments of proven efficacy are available.
Clearly, ADHD is common in patients with TS seen by physicians. A Centers for Disease Control and Prevention (CDC) survey, 64% of TS patients had also been diagnosed with ADHD. To some extent, the prevalence may represent primarily referral bias; patients with uncomplicated tics are less likely to seek medical attention. However, ADHD is common even in epidemiologic samples of TS and in TS-affected relatives of pure-TS probands.
The genetic relationship of TS with ADHD is less clear than its relationship with OCD.[108] The clinical picture is similar to that observed in populations without tics.
When an appropriately experienced physician finds typical indications of Tourette syndrome (TS) in the patient's history and examination, no further workup is generally necessary. Further workup may be needed if unusual features are present in the history or physical examination or if other abnormalities are found on neurological examination.
Unusual findings may include rigidity, bradykinesia, spasticity, myoclonus, chorea, dementia, or psychosis. Further workup may include corroboration of the patient's history with that of another source, with clinical follow-up, or with laboratory testing.
Go to Pediatric Tourette Syndrome for complete information on this topic.
Serum ceruloplasmin or slit lamp examination for Kayser-Fleischer rings might be considered. This examination is not always necessary. However, if unusual features are present, these tests may lead to lifesaving measures by confirming the presence of Wilson disease.
Neuropsychological testing may be useful: Patients with difficulties in the school or work setting may benefit from an evaluation for learning disorders so that adaptive strategies can be identified.
Structural imaging studies are not routinely needed in the evaluation of patients with a typical history and examination findings. These studies are indicated only to exclude specific illnesses suggested by abnormal history or examination findings.
At present, functional imaging studies have no proven clinical utility in the evaluation of tic disorders.
Data from unpublished reports suggest possible future clinical benefits of neuroimaging. For example, caudate volume in childhood is inversely associated with illness severity in adulthood.[155]
Some general principles must be kept in mind. First, present treatments of Tourette syndrome (TS) are purely symptomatic. No curative or preventive treatments are known. Second, tics often are not the worst problem. Third, this is a chronic disorder, and usually the goal is long-term benefit rather than quick improvement at any cost. Fourth, symptoms frequently improve or worsen over any period of time, even in untreated TS.
Corollaries of these principles include the following:
Treatment is not always needed
Treatment should be directed first at the most troublesome symptom
Apparent success or failure of any treatment may be coincidental
Beginning with reasonable trials of single agents is usually better than rushing to high doses or polypharmacy
TS has been described as either a neurological or a psychiatric disorder. These labels have nothing to do with the cause or treatment of TS but simply relate to the fact that neurologists and psychiatrists have been the main medical experts who have researched and treated TS.
These specialists have been well represented on the medical and scientific advisory boards to the Tourette Syndrome Association (TSA). A parent of a child with TS gave the author the following advice on choosing a physician: "We don't care if it's a psychiatrist or a neurologist, but we do care that it is someone who has experience treating Tourette's syndrome and who will treat all the symptoms."
Chronic motor (or vocal) tic disorder is managed similarly to TS and not discussed separately.
Discussed below are proven treatments for tics from replicated controlled studies, other treatments for tics, treatment for obsessive-compulsive symptoms in patients with tics, treatment for attention deficit–hyperactivity disorder (ADHD) in patients with tics, and treatment for other symptoms in patients with tics.
Treatments for tics that have demonstrated efficacy in replicated controlled trials (RCTs) include the following:
Dopamine D2 receptor antagonist therapy
Dopamine agonist therapy
Habit reversal therapy
Dopamine D2 receptor antagonist therapy
In 1959, soon after its introduction, chlorpromazine was reported to dramatically improve tic severity.[156] Since then, several allocation randomized controlled trials with various neuroleptics (eg, haloperidol, fluphenazine, pimozide) have confirmed these initial results.[157] On average, tic severity declines by approximately 50-80% with neuroleptic treatment.
Neuroleptic drugs are the current standard in terms of efficacy in the treatment of tics. They can be effective at doses far below the usual treatment dose for psychosis, and most adverse effects are manageable with pharmacologic manipulations. Unfortunately, many patients do not tolerate acute adverse effects (most commonly sedation, weight gain, depression, lethargy, and akathisia), and prolonged treatment poses a small risk of tardive dyskinesia. Therefore, other treatments have been investigated.
Risperidone, olanzapine,[158] and ziprasidone have been shown to produce at least as much clinical effect as a classic neuroleptic comparator, with fewer adverse effects.[159, 160, 161] A small study of clozapine suggested little effect.[162] Small studies of the dopamine D2R partial agonist aripiprazole show that it is effective for tic suppression.[163, 164] RCT data are not yet available, however.
Metoclopramide is a D2 receptor antagonist that is usually used for nausea. A case series[165] and an RCT[166] suggest it treats tics with good short-term tolerability. However, long-term use of metoclopramide has been associated with tardive dyskinesia.
Dopamine agonist therapy
Paradoxically, several mixed dopamine agonists have also been proven effective in reducing tic frequency.[23, 167, 25] To date, they have been tested exclusively in relatively low doses, partly because of a theory that, at these doses, they must antagonize dopamine function by selective action at presynaptic receptors.
Accumulating evidence suggests that this rationale is faulty, however, and trials with higher doses may be expected.
Habit reversal therapy
Five RCTs have demonstrated the efficacy of a specific form of behavior therapy for tics.[168, 169, 83, 170, 171, 172] The originally tested treatment consisted of a package of interventions called habit reversal therapy,[173] which comprises monitoring, relaxation, and other nonspecific elements of behavior therapy. The most important element is application of a competing response whenever the patient notices either a tic or the urge to tic.
Initially, heavy effort on the part of the patient may be needed. However, in all 4 reported studies, at long-term follow-up at least one half of treated patients had greater than 75% reduction in overall tic severity, whether based on self-report of home tic counts or on blind review of a videotape filmed in the clinic.
The effort expended by patients decreased dramatically as tic frequency declined, usually within the first few weeks of treatment. No substitution of other tics was noted, which commonly occurs when patients substitute a volitional action on a haphazard basis (see image below).
View Image
Tourette syndrome and other tic disorders. In a randomized controlled trial of habit reversal therapy (HRT), results differed significantly from those....
Anecdotally, others have not found such impressive results, which may relate to patient selection or therapeutic technique. Further replication studies are being supported by the TSA.
Interestingly, several elements of this treatment are reminiscent of treatments used by Brissaud in 1902 (though with a radically different theoretical background).[8] Some data now explain why his treatments may not have been as effective. If the competing response is not paired with tic urges or tics, no benefit is observed.[174] Similarly, other behavior therapies used in the last several decades (eg, massed practice) are relatively ineffective.
Since the realization of the failures of psychoanalysis in treating tic disorders in the 1970s, patients and physicians have looked askance at psychological treatment, including behavior therapy. The available data no longer justify this view.
In fact, the plausibility of behavior therapy makes some sense on an intuitive level. Since tics respond briefly even to random environmental influences, it is not surprising that a well-designed behavioral intervention may produce more satisfactory results. Note that this is very different from simply telling the patient not to tic, or from "trying harder," neither of which tends to be effective over the long run.
A parallel is present with obsessions and compulsions, which share many phenomenologic characteristics with tics. Obsessive-compulsive disorder (OCD) symptoms do not respond well to psychodynamic treatment but are effectively treated with behavior therapy. Such treatment has biologic effects, such as normalization of abnormally high baseline metabolism in the orbitofrontal cortex. Case series have shown a reduction in tics by using the same behavior therapy method proven to benefit patients with OCD.[175, 176]
Other treatments for tics
Treatments for tics that have not been proven in replicated RCTs include the following:
Guanfacine
Clonidine
Topiramate
Norepinephrine reuptake inhibitors
Botulinum toxin injections and oral baclofen
Tetrabenazine
Benzodiazepines
Levetiracetam
Selective serotonin reuptake inhibitors (SSRIs)
Ondansetron
Naltrexone/naloxone
Cannabinoids
Nicotine
Guanfacine was tested in an RCT in children with both ADHD and chronic tic disorders and was found to be clearly superior to placebo in the reduction of both ADHD and tic symptoms (31% on average), with few adverse effects.[177] This drug also has been shown to be efficacious in adults with nontic ADHD.
Clonidine has frequently been used to treat tics. A large RCT confirmed its efficacy for both ADHD symptoms and tics in patients with TS.[178] Clonidine or guanfacine may be appropriate as a first agent in many patients.
A double-blind, placebo-controlled study examined topiramate at a dosage of about 100 mg/day, and concluded that it may be safe and effective in decreasing Total Tic Score, but noted that a larger study with longer followup than their 10 weeks was needed.[179] However, a Chinese meta-analysis of 9 randomized controlled trials did not show significant difference in reducing tic occurrence between topiramate and haloperidol or tiapride.[180]
The norepinephrine reuptake inhibitors desipramine and atomoxetine have shown definite though modest benefit for tics in tic patients being treated for ADHD.[181, 182]
Botulinum toxin injections and oral baclofen were initially the subject of enthusiastic retrospective reports, but blinded trials of these 2 agents have revealed statistically significant but clinically modest benefit compared with placebo.[183] Botulinum toxin injections may improve urges or sensory tics, as well as observable tics, and it may be the treatment of choice for patients with a single, especially problematic, dystonic tic.
Tetrabenazine is a presynaptic dopamine-depleting agent with the advantage that it has not been reported to cause tardive movement disorders. A retrospective report noted marked clinical improvement in 57% of 47 patients with TS.[184] Its acute adverse effects are similar to those of neuroleptics. Tetrabenazine is approved by the US Food and Drug Administration (FDA) only for the treatment of chorea in Huntington's disease.[185]
Baclofen has little effect on average. However, it also has relatively few adverse effects and may be appropriate in select patients.[186]
Benzodiazepines, such as clonazepam, have reduced tic severity in some patients in retrospective reports. The effect is less than that of neuroleptics and probably nonspecific. Adverse effects are fairly common. However, clonazepam is tolerated better than haloperidol on average, and when no clinical pressure exists for urgent treatment, it is a reasonable option.
Levetiracetam was found to be well tolerated and possibly effective in an initial study.[187] However, two subsequent double-blind studies found no benefit.[188, 189]
SSRIs (eg, clomipramine, fluoxetine) improve tics in some patients, worsen them in others, and have no effect on tics in yet others.[190, 191, 192, 193] SSRIs may be reasonable first agents in patients with significant depression or OCD symptoms.
Ondansetron (8-24 mg/d) showed efficacy for a self-report but not an observer-rated measure of clinical improvement in a double-blind RCT in patients aged 12-46 years with TS.[16]
Naltrexone/naloxone have been reported helpful in a few patients, but other studies have shown transient worsening of tics with opioid antagonists.[194, 195] An RCT of naloxone showed some benefit at low doses, but worsening of tics at higher doses.[196] Case reports also have described benefit with opioid agonists.[197, 198]
Cannabinoids may reduce tic severity in some patients. Two RCTs support the efficacy of cannabinoids in this setting.[17]
Nicotine,[199] as well as a nicotine antagonist, mecamylamine, have been touted as treatments for tics. The antagonist has few adverse effects at the doses recommended, but 1 RCT found no statistically significant effect versus placebo.[200] A small blinded study did show some benefit.[88] However, given that nicotine is not a safe drug, its therapeutic use should await more compelling proof of efficacy.
Repetitive transcranial magnetic stimulation (rTMS) has not been effective in TS.[201] Surgical treatments are described in Surgical Care.
Treatment for Obsessive-Compulsive Symptoms in Patients With Tics
Initial treatment of OCD in patients with tics usually consists of an SSRI, generally at 3-4 times the antidepressant dose. More recently, risperidone monotherapy has been advocated as a first treatment, especially in patients with significant impairment from tics and from OCD symptoms.
Behavior therapy for OCD (eg, exposure and response prevention) is clearly proven to be effective.[202] A trial of behavior therapy is indicated for every patient with clinically significant OCD symptoms unless the symptoms are substantially remitted by another intervention.
In patients with tics (and perhaps in their relatives), obsessions respond better to fluoxetine plus haloperidol than to fluoxetine plus placebo.[203] Therefore, even if tics are well-controlled, addition of a D2 antagonist is indicated if bothersome OCD symptoms do not respond adequately to conventional initial treatment.
In a highly select group of patients who fit research criteria for sudden onset of tics or OCD associated with a proven recent streptococcal infection, OCD responded dramatically to intravenous immunoglobulin G (IVIG) or plasmapheresis.[126]
See the article Obsessive-Compulsive Disorder or the 2003 review by Miguel and colleagues[204] for further details of OCD treatment.
ADHD can be significant in patients referred for treatment of TS. Stimulants such as methylphenidate or dextroamphetamine represent the oldest class of psychotropic drugs still in common use, and have known safety profiles. They are the most effective treatments of ADHD. Methylphenidate may be better tolerated than dextroamphetamine in people with TS.[205]
Stimulant use in people with ADHD does not cause future drug abuse and may even prevent it.[206] A comorbid tic disorder should not be considered a serious contraindication to the use of stimulants for treatment of ADHD.[207] Several studies have shown that stimulants do not cause lasting worsening of tics. Their labeling includes warnings that they may cause tics,[205] but several recent prospective studies show that their effect on tics is at worst temporary, even with continued use.[208, 209, 210, 178]
Clonidine has also been proven useful for ADHD in people with TS. The benefits of clonidine and methylphenidate are additive.[178] Guanfacine most likely has similar effects.
RCTs have also shown that desipramine and atomoxetine help with ADHD symptoms in people with TS[181, 182] ; tics also improve slightly.
A double-blind RCT showed possible benefit for selegiline on ADHD symptoms and tics.[211]
Bupropion may benefit ADHD but may temporarily worsen tics.[212]
See the article Attention Deficit/Hyperactivity Disorder for further details on the conventional pharmacologic and behavioral treatment of ADHD.
Treatment for Other Symptoms in Patients With Tics
In carefully selected, tic-free adolescents with affect-laden episodes of aggression, replicated results from controlled trials show substantial efficacy of divalproex.[213] Whether these results can be confirmed for rage attacks in TS remains to be proven. A retrospective observational study found that explosive outbursts refractory to previous treatment improved with aripiprazole in 24 of 25 patients; however, 22% of subjects discontinued treatment due to inability to tolerate the drug.[214] SSRIs may also be useful.[190]
Research on the management of (other) conduct disorder symptoms in TS is sorely needed.
Stereotactic neurosurgery, either to place deep brain stimulators or to ablate tissue, is indicated only rarely for the treatment of obsessions, compulsions, and possibly tics. Case reports suggest deep brain stimulation (DBS) in various sites may be helpful.
A double-blind, randomized, cross-over trial by Ackermans et al determined that stimulation of the centromedian nucleus–substantia periventricularis–nucleus ventro-oralis internus crosspoint in the thalamus may reduce tic severity in refractory TS.[215] The study was limited by small size and unique indication.
This approach is limited to patients with exceptionally debilitating symptoms and those in whom prior, thorough trials of less dramatic interventions were ineffective. Such surgery should be carried out only in referral centers experienced with these procedures and after multispecialty evaluation of the patient.
Ordinary diet is not known to have an effect on tics. Some concentrated dietary supplements used as drugs (also called nutraceuticals) may affect tic severity. For example, one of the author's patients had a marked increase in tic severity while taking an herbal product marketed for weight loss that contained ephedrine, ginkgo, caffeine, guaraná, and other ingredients.
Some nutraceuticals may possibly improve tic symptoms, but no adequate evidence exists at present. Furthermore, because these products do not undergo the meticulous scrutiny required of other drugs by the FDA, their safety in general is not well established. This is important since a large majority of patients with TS have used these drugs. However, both the National Institutes of Health and the TSA have expressed interest in supporting properly designed research on such treatments, and adequately tested products may be hoped for in the future.
No reason exists to suspect that an individual has diminished capacity (eg, the ability to consent to treatment, participate in research, or make a will) because of a diagnosis of TS.
Parents of children with TS frequently ask whether TS causes diminished responsibility—for example, "When he hits his brother during a rage attack, is that him or is that the Tourette disease?" Occasionally the same question comes up in the legal arena, eg, "Should Mr A be exculpated for a crime he committed because he has TS?"
Group studies clearly show that TS can cause complex unwanted behavior. Sometimes, the answer is obvious, and sometimes, all that is needed is education about what is and is not typical of TS. The TSA and its local affiliates produce some excellent education materials addressed to family, friends, or teachers.
Convincingly answering what caused a specific complex act in an individual patient often is impossible. The author finds that discussions about whether the child is guilty tend to be fruitless. It is more helpful to focus on interventions and results: Are we likely to fix this problem by writing a prescription, by providing rewards and punishments, by instructing the patient to stop doing it, or by simply ignoring it?
The public does not necessarily credit the physician with indisputable authority regarding guilt, forgiveness, or legal culpability. However, physicians speak from a position of strength when they focus on available treatments and likely prognosis. Also, this approach focuses attention away from punishment and toward problem solving.
Some rights of people with TS are protected by US federal legislation. Examples include the right to public education in the least restrictive educational setting (Individuals with Disabilities Education Act) and the right to reasonable accommodations in public settings or the workplace (Americans with Disabilities Act). Legal advice and discussion with experienced support group members can be helpful in deciding when and how to pursue legal remedies under these laws.
Patients should be evaluated at least once by someone with experience treating patients with TS, and they should be informed about how to contact a local support group or the national Tourette Syndrome Association office.
Additional referrals may be needed for the following measures, depending on the needs of the patient and the skills of the primary physician evaluating the patient's TS:
Botulinum injections
Habit reversal therapy for tics; behavior therapy for OCD, ADHD, or conduct disorder; or psychiatric care of OCD, ADHD, or comorbid anxiety or depressive illness
Neuropsychological testing and educational interventions to address learning disabilities or to help formulate an individualized education program
Education of teachers, classmates, or work colleagues may be helpful[216]
Legal assistance (eg, to protect a child's educational rights under the federal Individuals with Disabilities Education Act or for protection under the Americans with Disabilities Act)
In 2019, the American Academy of Neurology (AAN) released guidelines for treating tics in people with Tourette syndrome. Recommendations address counseling, comorbid disorders, and treatment.[217]
Counseling
Inform patients and their caregivers about the natural history of tic disorders.
Evaluate functional impairment related to tics from the perspective of the patient and, if applicable, the caregiver.
If prescribing medications for tics, periodically re-evaluate the need for ongoing medical treatment.
Assessing comorbid disorders
Assess for comorbid ADHD in people with tics, evaluate the burden of ADHD symptoms, and ensure appropriate ADHD treatment is provided.
Assess for comorbid OCD in people with tics and ensure appropriate OCD treatment is provided.
Ensure appropriate screening for anxiety, mood, and disruptive behavior disorders is performed in people with tics.
Ask the patient about suicidal thoughts and attempts and refer to appropriate resources.
Alpha-agonist treatment
If treating patients with tics with α2 adrenergic agonists, you must monitor heart rate and blood pressure.
If prescribing guanfacine extended release, you must monitor the QTc interval in patients with a history of cardiac conditions, patients taking other QT-prolonging agents, or patients with a family history of long QT syndrome.
Gradually taper α2 adrenergic agonists to avoid rebound hypertension.
Antipsychotic treatment
Counsel patients on the relative propensity of antipsychotics for extrapyramidal, hormonal, and metabolic adverse effects.
When prescribing antipsychotics for tics prescribe the lowest effective dose to decrease the risk of adverse effects.
If prescribing antipsychotics, you must perform electrocardiography and measure the QTc interval before and after starting pimozide or ziprasidone, or if antipsychotics are coadministered with other drugs that can prolong the QT interval.
Deep brain stimulation
Confirm the DSM-5 diagnosis of Tourette syndrome and exclude secondary and functional tic-like movements when considering DBS for medication-resistant tics.
A mental health professional must screen patients preoperatively and follow patients postoperatively for psychiatric disorders that may impede the long-term success of the therapy.
Confirm that multiple classes of medication (antipsychotics, dopamine depleters, α2 agonists) and behavioral therapy have been administered (or are contraindicated) before prescribing DBS for tics.
The choice of initial treatment depends largely on the following factors:
Which symptoms (eg, tics, obsessions, impulsivity) are most problematic
The severity of symptoms
The patient's sense of urgency for treatment
The patient's aversion to risk of likely or unlikely adverse effects
For many patients the most reasonable option is to forgo treatment altogether. Education of patient and family (and teacher or employer) may suffice. If a single dystonic tic predominates, especially in the face, neck, or larynx, botulinum toxin injection is a reasonable first treatment.
If ADHD symptoms predominate, they can be addressed first. Guanfacine or clonidine has the best evidence for also improving tics; stimulants have the best efficacy for ADHD symptoms. Other options are noted in the treatment section above.
If OCD symptoms predominate, they can be addressed first, most likely with a serotonin reuptake inhibitor and/or risperidone.
If severe tics are the presenting symptom, a newer antipsychotic agent may be the best initial treatment. The dose used is substantially lower than the dose used to treat psychosis.
If tics are mild to moderate in severity or if they occur in risk-averse patients, any of the non-antipsychotic treatments described in Treatment can be tried sequentially. Clonidine may be the most widely used, while habit reversal therapy likely has the lowest risk of serious adverse effect. The combination of dopamine antagonists with stimulants is used sometimes, yet it makes little enough sense pharmacologically that other options should be explored thoroughly.
Dopamine agonists suppress tics with few adverse effects and modest but proven efficacy. Pergolide was withdrawn from the US market March 29, 2007, because of heart valve damage resulting in cardiac valve regurgitation. It is important not to abruptly stop pergolide. Health care professionals should assess patients' need for dopamine agonist (DA) therapy and consider alternative treatment. If continued treatment with a DA is needed, another DA should be substituted for pergolide.
Clinical Context:
Risperidone is a mixed dopamine-serotonin antagonist that may produce less sedation than other antipsychotics. Theoretically, risperidone has a lower risk of tardive dyskinesia than haloperidol; it clearly produces fewer acute adverse effects.
Clinical Context:
Olanzapine is an atypical antipsychotic that produces fewer acute parkinsonian, akathisic, or dystonic adverse effects than haloperidol. In schizophrenia, it has approximately 33%-50% the risk of tardive dyskinesia compared with haloperidol.
Clinical Context:
Ziprasidone is an atypical antipsychotic. In a head-to-head study, this agent caused less weight gain than olanzapine in schizophrenia.
Clinical Context:
The anti-tic efficacy of haloperidol has been known for 40 years. It blocks postsynaptic mesolimbic dopaminergic D1 and D2 receptors in the brain. It also decreases hypothalamic and hypophyseal hormones.
Clinical Context:
Fluphenazine is a high-potency typical antipsychotic with pharmacology similar to that of haloperidol. It is proven to diminish tic severity.
Clinical Context:
Pimozide is an atypical neuroleptic approved by the US Food and Drug Administration (FDA) for treatment of tics. It is rarely indicated in current practice, as it offers no substantial advantage over other high-potency neuroleptics (risperidone and olanzapine are better tolerated), has significant drug interactions, and poses a slight but serious risk of cardiac arrhythmia.
Clinical Context:
This agent depletes neurotransmitter stores of dopamine, serotonin, and noradrenaline within nerve cells in the brain, thereby altering the transmission of electric signals from the brain that control movement by reversibly inhibiting vesicular monoamine transporter 2 (VMAT2).
These agents suppress tics. They are presynaptic depleting agents that have acute adverse effects similar to neuroleptics but theoretically may avoid the risk of tardive dyskinesia.
Clinical Context:
Clonidine is less effective than neuroleptics in suppressing tics and less effective than stimulants at treating ADHD symptoms. However, it has modest adverse effects and benefits some patients.
Clinical Context:
Although slightly effective in children with TS, baclofen's primary effect may not be on tics but on other symptoms; adverse effects are modest.
Clinical Context:
Clonazepam reduces tics in some patients, although blinded controlled studies are lacking. Its half-life is longer than 30 hours, but its clinical effect wanes more rapidly.
By binding to specific receptor sites, these agents appear to potentiate the effects of gamma amino-butyric acid (GABA) and facilitate inhibitory GABA neurotransmission and other inhibitory transmitters.
Clinical Context:
This agent inhibits release of acetylcholine at neuromuscular junction; it is injected directly into muscle. It is most useful for dystonic tics (eg, sustained eye closure) or only 1 or 2 especially problematic tics (eg, repeatedly flinging head to 1 side causing neck pain and broken glasses). Tics and tic urges may improve; effect can be seen in absence of gross weakness. Successful outcomes require substantial specialized experience in the treating physician.
How is Tourette syndrome (TS) characterized?What are the DSM-5 diagnostic criteria for Tourette disorder?What are the signs and symptoms of Tourette syndrome (TS)?What are the DSM-5 diagnostic criteria for persistent (chronic) motor or vocal tic disorder?What are the DSM-5 diagnostic criteria for provisional tic disorder?What are effective treatments for tic disorders?What is Tourette syndrome (TS)?What is an historical example of Tourette syndrome (TS)?What is the historical evolution of the understanding of Tourette syndrome (TS) and other tic disorders?What is the pathophysiology of Tourette syndrome (TS)?What is the role of biochemistry in the pathophysiology of Tourette syndrome (TS)?What is the role of dopaminergic function in the pathophysiology of Tourette syndrome (TS) and other tic disorders?What is the role of genetics in the pathophysiology of Tourette syndrome (TS)?What is the role of D2-like dopamine-receptors in the pathophysiology of Tourette syndrome (TS)?What is the role of amphetamines in the pathophysiology of Tourette syndrome (TS)?What is the role of dopamine breakdown products in the pathophysiology of Tourette syndrome (TS)?Which pharmacologic fMRI (phMRI) results have increased the understanding of Tourette syndrome (TS) and other tic disorders?Which findings on functional imaging studies are characteristic of Tourette syndrome (TS) and other tic disorders?What is the role of metabolism in the pathophysiology of Tourette syndrome (TS) and other tic disorders?Which findings on functional imaging studies correlate with tic severity or tic suppression in Tourette syndrome (TS) and other tic disorders?Which findings on functional imaging are related to motor activation in the pathophysiology of Tourette syndrome (TS) and other tic disorders?Which findings on functional imaging suggest deficient striatal activation in the pathophysiology of Tourette syndrome (TS) and other tic disorders?What is the role of focal lesions in the pathophysiology of Tourette syndrome (TS) and other tic disorders?Which neuroanatomic studies support the theory of basal ganglia and frontal cortex involvement in the pathophysiology of Tourette syndrome (TS) and other tic disorders?Which autopsy findings have increased the understanding of the pathophysiology of Tourette syndrome (TS) and other tic disorders?What is the role of brain volume in the pathogenesis of Tourette syndrome (TS) and other tic disorders?What causes involuntary tics in Tourette syndrome (TS)?What have neuropsychological studies contributed to the understanding of the pathogenesis of Tourette syndrome (TS) and other tic disorders?What is the role of the timing of tics in the pathophysiology of Tourette syndrome (TS) and other tic disorders?What is a possible model of tic production in the pathophysiology of Tourette syndrome (TS) and other tic disorders?What causes Tourette syndrome (TS) and other tic disorders?What are the genetic causes of Tourette syndrome (TS) and other tic disorders?What are the nongenetic causes of Tourette syndrome (TS) and other tic disorders?What is the role of streptococcal infections in the etiology of Tourette syndrome (TS) and other tic disorders?What is the role of focal lesions in the etiology of Tourette syndrome (TS) and other tic disorders?What is the role of encephalitis lethargica in the etiology of Tourette syndrome (TS) and other tic disorders?What is the prevalence of Tourette syndrome (TS) and other tic disorders in the US?What is the global prevalence of Tourette syndrome (TS) and other tic disorders?What are the racial predilections of Tourette syndrome (TS) and other tic disorders?What are the sexual predilections of Tourette syndrome (TS) and other tic disorders?When is the typical onset of Tourette syndrome (TS) and other tic disorders?What is the prognosis of Tourette syndrome (TS) and other tic disorders?Where can patient education materials about Tourette syndrome (TS) and other tic disorders be found?Which clinical history findings are characteristic of Tourette syndrome (TS) and other tic disorders?What are the diagnostic criteria for Tourette syndrome (TS) (DSM-5 307.23)?What are the diagnostic criteria for chronic motor or vocal tic disorder (DSM-5 307.22)?What are the diagnostic criteria for transient tic disorder (DSM-5 307.21)?What are the Tourette syndrome (TS) Study Group diagnostic criteria for Tourette syndrome (TS) (A-1 or A-2)?What are the Tourette syndrome (TS) Study Group diagnostic criteria for chronic multiple motor tic or phonic tic disorder (B-1 and B-2)?What are the Tourette syndrome (TS) Study Group diagnostic criteria for transient tic disorder (D-1 and D-2)?What are the Tourette syndrome (TS) Study Group diagnostic criteria for nonspecific tic disorder (E-1 and E-2)?What are the Tourette syndrome (TS) Study Group diagnostic criteria for probable Tourette syndrome (TS) type G?What are the signs and symptoms of attention deficit–hyperactivity disorder in Tourette syndrome (TS) and other tic disorders?What is included in the physical exam to evaluate Tourette syndrome (TS) and other tic disorders?What are the non-tic signs and symptoms of Tourette syndrome (TS) and other tic disorders?How are tics classified in Tourette syndrome (TS) and other tic disorders?What are the general features of tics in Tourette syndrome (TS) and other tic disorders?How are Tourette syndrome (TS) and other tic disorders differentiated from movement disorders?How is the volition of tics characterized in Tourette syndrome (TS) and other tic disorders?How are Tourette syndrome (TS) and other tic disorders differentiated from OCD?Which physical findings are characteristic of sensory tics in Tourette syndrome (TS) and other tic disorders?Which physical findings are characteristic of dystonic tics Tourette syndrome (TS) and other tic disorders?Which physical findings are characteristic of coprolalia, in Tourette syndrome (TS) and other tic disorders?What are the obsessive-compulsive symptoms of Tourette syndrome (TS) and other tic disorders?Which conditions are included in the differential diagnoses of Tourette syndrome (TS)?What are the differential diagnoses for Tourette Syndrome and Other Tic Disorders?What is the role of lab testing in the workup of Tourette syndrome (TS) and other tic disorders?What is the role of serum ceruloplasmin or slit-lamp exam in the workup of Tourette syndrome (TS) and other tic disorders?What is the role of neuropsychological testing in the workup of Tourette syndrome (TS) and other tic disorders?What is the role of imaging studies in the workup of Tourette syndrome (TS) and other tic disorders?How are Tourette syndrome (TS) and other tic disorders treated?Which treatments for tics are effective?What is the role of dopamine D2 receptor antagonist therapy in the treatment of Tourette syndrome (TS) and other tic disorders?What is the role of dopamine agonist therapy in the treatment of Tourette syndrome (TS) and other tic disorders?What is the role of habit reversal therapy in the treatment of Tourette syndrome (TS) and other tic disorders?Which medications have been used in the treatment of tics?What is the role of guanfacine and clonidine in the treatment of Tourette syndrome (TS) and other tic disorders?What is the role of topiramate in the treatment of Tourette syndrome (TS) and other tic disorders?What is the role of norepinephrine reuptake inhibitors in the treatment of Tourette syndrome (TS) and other tic disorders?What is the role of botulinum toxin injections in the treatment of Tourette syndrome (TS) and other tic disorders?What is the role of tetrabenazine in the treatment of Tourette syndrome (TS) and other tic disorders?What is the role of baclofen in the treatment of Tourette syndrome (TS) and other tic disorders?What is the role of clonazepam in the treatment of Tourette syndrome (TS) and other tic disorders?What is the role of levetiracetam in the treatment of Tourette syndrome (TS) and other tic disorders?What is the role of SSRIs in the treatment of Tourette syndrome (TS) and other tic disorders?What is the role of ondansetron in the treatment of Tourette syndrome (TS) and other tic disorders?What is the role of naltrexone/naloxone in the treatment of Tourette syndrome (TS) and other tic disorders?What is the role of cannabinoids and nicotine in the treatment of Tourette syndrome (TS) and other tic disorders?What is the role of repetitive transcranial magnetic stimulation (rTMS) in the treatment of Tourette syndrome (TS) and other tic disorders?How are obsessive-compulsive symptoms treated in Tourette syndrome (TS) and other tic disorders?How is attention deficit–hyperactivity disorder (ADHD) treated in Tourette syndrome (TS) and other tic disorders?What is the role of divalproex in the treatment of Tourette syndrome (TS) and other tic disorders?What is the role of stereotactic neurosurgery in the treatment of Tourette syndrome (TS) and other tic disorders?Which dietary modifications are used in the treatment of Tourette syndrome (TS) and other tic disorders?What are legal issues that may arise concerning Tourette syndrome (TS) and other tic disorders?Which specialist consultations are beneficial to patients with Tourette syndrome (TS) and other tic disorders?Which factors should be considered in treatment selection decisions for Tourette syndrome (TS) and other tic disorders?Which medications in the drug class Neuromuscular Blockers are used in the treatment of Tourette Syndrome and Other Tic Disorders?Which medications in the drug class Benzodiazepines are used in the treatment of Tourette Syndrome and Other Tic Disorders?Which medications in the drug class Skeletal Muscle Relaxants are used in the treatment of Tourette Syndrome and Other Tic Disorders?Which medications in the drug class Alpha2-Adrenergic Agonists are used in the treatment of Tourette Syndrome and Other Tic Disorders?Which medications in the drug class Presynaptic Dopamine-Depleting Agents are used in the treatment of Tourette Syndrome and Other Tic Disorders?Which medications in the drug class Antipsychotic Agents are used in the treatment of Tourette Syndrome and Other Tic Disorders?
William C Robertson, Jr, MD, Professor, Departments of Neurology, Pediatrics, and Family Practice, Clinical Title Series, University of Kentucky College of Medicine
Disclosure: Nothing to disclose.
Specialty Editors
Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Received salary from Medscape for employment. for: Medscape.
Chief Editor
Stephen L Nelson, Jr, MD, PhD, FAACPDM, FAAN, FAAP, Chief, Pediatric Neurology, Professor of Pediatrics, Neurology, Neurosurgery, and Psychiatry, Epileptologist, Medical Director, Tulane Center for Autism and Related Disorders, Co-Director, Developmental Neurogenetics Center, Tulane University School of Medicine
Disclosure: Serve(d) as a speaker or a member of a speakers bureau for: Biomarin; Supernus<br/>Received income in an amount equal to or greater than $250 from: Biomarin; Supernus; American Board of Pediatrics.
Additional Contributors
Raj D Sheth, MD, Chief, Division of Pediatric Neurology, Nemours Children's Clinic; Professor of Neurology, Mayo Clinic Alix School of Medicine; Professor of Pediatrics, University of Florida College of Medicine
Disclosure: AAN reviewer, ACNS Ed board, Infantile spasms consultant for: AAN; ACNS; Mackilrodt.
References
American Psychiatric Association. American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 5th ed. Washington, DC: American Psychiatric Association; 2013.
American Psychiatric Association. Obsessive-Compulsive and Related Disorders. In: Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. 5th ed. Arlington, Va: American Psychiatric Association; 2013.
Kushner HI. A Cursing Brain--The Histories of Tourette Syndrome. Cambridge, MA: Harvard University Press;. 1999.
Gilles de la Tourette G. Etude sur une Affection Nerveuse Caracterisee par de l'Incoordination Motrice Accompagnee d'Echolalie et de Coprolalie. Archives de Neurologie. 1885. 9:19-42, 158-200.
Gilbert DL, Sallee FR, Sine L. Behavioral and hormonal effects of low-dose pergolide in children and adolescents with Gilles de la Tourette's syndrome. Curr Ther Res Clin Exp. 2000. 61:378.
Wong D, Singer H, Marenco S. Dopamine transporter reuptake sites measured by [11C]WIN 35,428 PET imaging are elevated in Tourette syndrome. J Nucl Med. 1994. 35:130.
Black KJ, Hershey T, Akbudak E, et al. Levodopa activation pharmacologic fMRI in Tourette syndrome. Abstract presented at: 34th Annual Meeting of the Society for Neuroscience. October 23-27, 2004;. San Diego, CA.
Hall M, Costa DC, Shields J, et al. Brain perfusion patterns with Tc-99m-HMPAO/SPET in patients with Gilles de la Tourette syndrome. Eur J Nucl Med. 1990. 16:WP18.
Pauls D. Genome scans in sibpairs and trios: new data. Presented at: 4th International Scientific Symposium on Tourette Syndrome; June 25-27, 2004; Cleveland, OH.
Albin R. Neurobiology of basal ganglia and TS: neurotransmitters and neurochemistry overview. Presented at: 4th International Scientific Symposium on Tourette Syndrome;. June 25-27, 2004; Cleveland, Ohio.
Jenkins BG, Chen YI, Sanchez Pernaute R, et al. Mapping dopaminergic function in normal and MPTP treated monkeys with pharmacologic MRI and PET. Presented at: Annual Meeting of the Society of Neuroscience; November 10-15, 2001; San Diego, CA.
Jankovic J, Jimenez-Shahed J, Brown LW. A randomised, double-blind, placebo-controlled study of topiramate in the treatment of Tourette syndrome. J Neurol Neurosurg Psych. 2010 Jan. 81(1):70-3.
Yang CS, Zhang LL, Zeng LN et al. Topiramate for Tourette's syndrome in children: a meta-analysis. Ped Neurol. 2013 Nov. 49(5):344-50.
U.S. Food and Drug Administration. FDA Approves First Drug for Treatment of Chorea in Huntington's Disease. FDA. Available at http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2008/ucm116936.htm. Accessed: August 31, 2009.
Brauser D. Potential New Risk Factors for Tourette's, Tics Identified. Available at http://www.medscape.com/viewarticle/819287. Accessed: January 19, 2014.
Tourette syndrome and other tic disorders. Graphic shows the relative likelihood of lifetime sensory tics in a given region, as based on self-report of patients with Tourette syndrome. Overt tics are distributed similarly.
Tourette syndrome and other tic disorders. Schematic of the hypothetical reorganization of the basal ganglia output in tic disorders, with excitatory projections (open arrows) and inhibitory projections (solid arrows). Line thickness represents the relative magnitude of activity. When a discrete set of striatal neurons becomes active inappropriately (right), aberrant inhibition of a discrete set of internal segment of globus pallidus (GPi) neurons occurs. The abnormally inhibited GPi neurons disinhibit thalamocortical mechanisms involved in a specific unwanted competing motor pattern, resulting in a stereotyped involuntary movement.
Tourette syndrome and other tic disorders. Immunologic response found in patients with Sydenham chorea is also found in patients with Tourette syndrome and obsessive-compulsive disorder. Points on the graph represent percent expression of D8/17 antigen on circulating B lymphocytes.
Tourette syndrome and other tic disorders. Graphic shows the relative likelihood of lifetime sensory tics in a given region, as based on self-report of patients with Tourette syndrome. Overt tics are distributed similarly.
Tourette syndrome and other tic disorders. In a randomized controlled trial of habit reversal therapy (HRT), results differed significantly from those of a control therapy (massed practice; P < .001, analysis of variance). The HRT group had a 97% reduction in tics at 18-month follow-up, with 80% of patients tic-free.
Tourette syndrome and other tic disorders. Schematic of the hypothetical reorganization of the basal ganglia output in tic disorders, with excitatory projections (open arrows) and inhibitory projections (solid arrows). Line thickness represents the relative magnitude of activity. When a discrete set of striatal neurons becomes active inappropriately (right), aberrant inhibition of a discrete set of internal segment of globus pallidus (GPi) neurons occurs. The abnormally inhibited GPi neurons disinhibit thalamocortical mechanisms involved in a specific unwanted competing motor pattern, resulting in a stereotyped involuntary movement.
Tourette syndrome and other tic disorders. Segregated anatomy of the frontal-subcortical circuits: dorsolateral (blue), lateral orbitofrontal (green), and anterior cingulate (red) circuits in the striatum (top), pallidum (center), and mediodorsal thalamus (bottom).
Tourette syndrome and other tic disorders. Graphic shows the relative likelihood of lifetime sensory tics in a given region, as based on self-report of patients with Tourette syndrome. Overt tics are distributed similarly.
Tourette syndrome and other tic disorders. Immunologic response found in patients with Sydenham chorea is also found in patients with Tourette syndrome and obsessive-compulsive disorder. Points on the graph represent percent expression of D8/17 antigen on circulating B lymphocytes.
Tourette syndrome and other tic disorders. In a randomized controlled trial of habit reversal therapy (HRT), results differed significantly from those of a control therapy (massed practice; P < .001, analysis of variance). The HRT group had a 97% reduction in tics at 18-month follow-up, with 80% of patients tic-free.
Symptom
Description/Comment
Sensory hypersensitivity
Cannot stand to have wrinkly socks, cuts the tags off his or her shirts, refuses all but bland food, or becomes agitated in a visually complex environment
Learning disability
Approximately 20% in clinical samples, more closely associated with comorbid ADHD than with tics; also associated with male sex, earlier onset, severity, perinatal problems, and lower rates in family members[140]
School phobia
Can be an adverse effect of neuroleptic treatment
Complex socially inappropriate behavior
Insults, racial slurs, and paraphilias (or, more commonly, suppressed urges) are present in a large minority of patients with TS, associated with comorbid ADHD
Rage attacks
Sudden outbursts lasting approximately 5-30 min, usually in children or teenagers; inconsolable, unremitting violent frustration, commonly after being denied an unreasonable request; often followed by apparently sincere contrition and remorse
Insistence on sameness
Refusal to take a different route home or omit a step in a routine, even when hurried; often without a clear obsession or other obsessive-compulsive symptoms
Anxiety and depression
Common in patient samples but not clearly more common in the general TS population
TS with both OCD and episodes of mania
Surprisingly high rates of mania in patients with TS and OCD shown in at least 2 studies, management frequently difficult
){kind=link}
){kind=link}
){kind=link}
){kind=link}