Tourette Syndrome and Tic Disorders

Abstract

Objective: This is a practical review of Tourette syndrome, including phenomenology, natural history, and state-of-the-art assessment and treatment. Method: Computerized literature searches were conducted under the keywords Tourette syndrome,tics, and children-adolescents. Results: Studies have documented the natural history of Tourette syndrome and its frequent co-occurrence with attention problems, obsessive-compulsive disorder (OCD), and a range of other mood and anxiety disorders, which are often of primary concern to patients and their families. Proper diagnosis and education are often very helpful for patients, parents, siblings, teachers, and peers. When necessary, available anti-tic treatments have proven efficacious. First-line options include the alpha adrenergic agents and the atypical neuroleptics, as well as behavioral interventions such as habit reversal. Conclusions: The study of tics and Tourette symdrome has led to the development of several pathophysiological models and helped in the development of management options. However, fully explanatory models are still needed that would allow for accurate prognostication in the course of illness and the development of improved treatments.

Introduction

For many, the experience of transient tics may only be a temporary problem of preadolescence, but for those with Tourette syndrome (TS), the motor and vocal tics may be part of a crippling constellation of mental health problems that constitute a serious burden of illness. Tics have been the subject of medical speculation for hundreds of years.¹ Putative explanations for the occurrence of tics and their tremendous variability have included inherited factors, influence of toxins, and emotional, psychological, and infectious processes. Although major gaps remain in our knowledge of the etiology of tics and the most effective treatments, significant advances in our understanding of the neurophysiologic mechanisms at work have been made. Although no ideal treatment for tics has been established, our treatment armamentarium offers many options. This review summarizes the clinical features, assessment, and treatments of tics.

Phenomenology

TS is a developmental neuropsychiatric disorder of childhood onset. There is no diagnostic test for TS. According to Diagnostic and Statistical Manual, Fourth Edition, Text Revision (DSM-IVTR),² it is characterized by brief, stereotypical but nonrhythmic “jerky” movements and vocalizations called tics. Common tics include eye blinking, grimacing, jaw, neck, shoulder, or limb movements, sniffing, grunting, chirping, or throat clearing. Tics typically follow a waxing and waning pattern of severity, intensity, and frequency.^3,4 This makes decisions regarding the need to treat, as well as the results of treatment interventions, difficult to assess. Other common characteristics of tics include (a) transient worsening of symptoms during periods of emotional upset; (b) reduction during periods of concentration that require fine motor skills; and (c) partial and variable voluntary suppression.

In the natural history of TS, motor tics often begin between the age of 3 and 8, several years before the appearance of vocal tics. Tic severity usually peaks during the second decade of life with many patients showing a marked reduction in severity by young adulthood.^3,5,6 A recent report on 50 youths with TS indicated that the majority experienced a persistence of tic severity over two years, although impairment due to tics decreased over this time.⁷ In contrast to childhood and youth-onset TS, adult-onset tic disorders are associated with more severe symptoms, greater social morbidity, poorer response to neuroleptic medication, and a potential trigger event.⁸

Another feature of tics is that they are frequently associated with antecedent sensory phenomena, so-called premonitory urges, such as an impulse to scratch an itchy patch of skin. Such urges are experienced as nearly irresistible and occasionally painful, and in some individuals with TS, they are a major source of mental impairment.⁹ There may also be sensory cues, which prompt tics of a particular sort (e.g., a cough or a word), suggesting that specific motor patterns or habits are activated by specific sensory pathways.¹⁰ A momentary sense of physical relief or a generalized abatement of inner tension often follows performance of a tic,^11–13 suggesting the involvement of reward neurocircuitry.

Tics often occur in discrete bouts over time scales of days to years,¹⁴ but these patterns have yet to be usefully modeled to predict either outcome or treatment response. The bouts are characterized by brief periods of stable inter-tic intervals of short duration, typically 0.5 to 1.0 second, and inter-bout intervals that may last from minutes to hours over the course of a day. Understanding the upstream processes that govern the timing of tic expression ultimately may clarify both neural events occurring in millisecond time scales as well as the natural history of tic disorders that occurs over the first two decades of life.

The description of tics as simply intermittent trains of completely involuntary motor discharge is incomplete. Indeed, many tics are often under partial voluntary control, evidenced by patients' capacity to suppress them for brief periods of time, subject to many factors including everyday stress, anxiety, and emotion.^15,16

Tics may be thought of as part of a spectrum of partially voluntary behaviors that include compulsions, substance abuse, pathological gambling, and perhaps even our daily personal and interpersonal habits. Interestingly, activities that require focused attention and fine motor control, such as reading aloud, playing a musical instrument, engaging in certain sports, and even performing surgery, are associated with transient improvements in tics. Finally, although much diminished, tics can sometimes occur during sleep, distinguishing them from many other movement disorders. Indeed, polysomnographic studies indicate that sleep disturbance is also part of the TS picture, with decreased quality and increased arousal phenomena.^17,18 Associated comorbidities are also likely to contribute to sleeping difficulties.¹⁹

Comorbidity

A plethora of associations exist between tics and other psychiatric symptomatology,²⁰ as well as social and academic interference. It is generally agreed that about 50 percent of patients with TS have substantial obsessive-compulsive (OC) symptoms. OC behaviors are also commonplace in children with TS. Typically, these symptoms may include a need for things to look or feel “just right,” as well as preoccupation with symmetry, order, counting, and ritualistic repetition.

Attention-deficit hyperactivity disorder (ADHD) is frequently diagnosed in children with TS, with a prevalence as high as 70 percent.^21–24 This comorbidity is associated with disruptive behaviors, such as aggression, inappropriate expression of anger, low frustration tolerance, and noncompliance.^25–27 Disruptive behavior in TS patients may occur with a wide frequency range of 26 to 75 percent, depending on the sample. These co-occurring ADHD and disruptive behavior problems deserve further study, in addition to the core movement symptoms, since they often add considerable burdens to affected patients, including academic problems, peer rejection, and family conflict.^28,29

It remains unclear whether these conditions constitute a risk factor for TS, occur in part due to TS, or share common neural mechanisms with TS. When present, these coexisting conditions can worsen the severity of TS, detracting seriously from the ability of patients to engage in a range of activities, which can lead to reduced quality of life and developmental delay.^30–32 Extreme forms of TS may involve violent episodes of self-injurious motor tics, including hitting or biting, and socially stigmatizing coprolalic utterances (e.g., shouting obscenities or racial slurs) and gestures. In these extreme cases, comorbidity with a range of other disorders is the rule rather than the exception. Depression and anxiety problems comorbid with TS may reflect the cumulative psychosocial burden of having tics or else some shared biological diatheses. The four-fold increase in migraine incidence in patients with TS³³ has suggested a possible shared mechanism between migraine and tics involving serotonin and the basal ganglia.^34,35 It has been suggested that shared biological and psychosocial stressors underlie migraines and psychiatric diagnoses, such as depression³⁶ and bipolar disorder.³⁷ Other biological theories to explain comorbidities include autonomic lability, abnormal basal ganglia function, motor cortex hyperexcitability, or decreased frontal lobe function.³⁸

Epidemiology

TS has been reported in virtually every part of the world in which it has been sought for study. Prevalence rates of TS and related conditions vary according to a wide range of measures, including age, sex, ethnicity, and method of assessment. Once considered a rare disorder, current best estimates of the prevalence of TS hover around 1 to 10 per 10,000 of school children between the ages of 6 and 17 years old, with a considerably higher percentage of children, in the range of 4 to 20 percent, experiencing transient simple tics.²⁰ Epidemiological studies involving direct observation indicate the highest prevalence of tics at 3 to 5 years of age and worst-ever symptoms at 9 to 12 years of age.³⁹

Differential Diagnosis

A number of conditions produce symptoms resembling the tics of TS, such as myoclonus, tremors, chorea, athetosis, dystonias, akathisic movements, paroxysmal dyskinisias, and ballistic movements.^40–42 The differential diagnosis of TS includes genetic conditions (e.g., Huntington's chorea), metabolic diseases (e.g., Wilson's disease), structural diseases (e.g., hemiballismus associated with insult to the subthalamic nucleus), post-infectious autoimmune processes (e.g., Sydenham's chorea), and side effects of neurotropic medications (e.g., dystonias and akathisia).

Complex motor tics may appear very much like other movements, such as stereotypies, and may be indistinguishable from some compulsive rituals. Vocal tics can be helpful in ruling out other diagnoses because they are extremely rare in other neurological conditions. An exception is Huntington's disease, where there may be brief sniffing and vocalizations. Please see Table 1 for differential diagnoses of TS.

Table 1.

Differential diagnoses of the tics of Tourette syndrome

Movement	Features	Associated Illness
Tics	Involuntary or semi-voluntary, multi-focal, rapid and brief, non-rhythmic but stereotypic movements and vocalizations, often with premonitory sensations, worse with stress, and temporarily suppressible	Tourette syndrome
Myoclonus, chorea, paroxysmal dyskinesia, ballismus, dystonia, muscle spasm	Involuntary, focal, sudden onset but may persist	Infection, medication reaction, Huntington's disease, and Sydenham's chorea
Tremor	Involuntary, rhythmic	Metabolic disturbances, drugs and medications, essential tremor, and Parkinson's disease
Athetosis	Involuntary, continuous, slower than tics, usually hands and feet	May be associated with dance-like chorea
Akathisia-related movements	Feeling of restlessness and voluntary, associated with nervousness	Antipsychotic toxicity

Etiology/Physiology

Theories of the causes of TS and its multifaceted phenotype have advanced over the last 10 years with the development of powerful techniques in the study of human genetics and the neurophysiology of motor control. Genetic vulnerability factors have been implicated in the vertical transmission of TS and related disorders.⁴³ The pattern of hereditary transmission in affected family members suggests major gene effects. Indeed, the results of segregation analyses are consistent with models of autosomal transmission set against a polygenic background.

An environmental stress diathesis model of pathogenesis is also frequently invoked to explain the variable expression of tic disorders. A strong anecdotal clinical association between TS symptoms and stressful life events has been noted since the initial description by Gilles de la Tourette. Such factors may find a common final pathway in the hypothalamic-pituitary-adrenal (HPA) axis, the associated stress-related neurotransmitters and hormones, and their targets. In support of this, data suggest that TS patients may have a heightened reactivity of the HPA and noradrenergic sympathetic systems as compared to healthy control subjects.¹⁵ In addition, the impact of genes, specific infectious and environmental factors including gestational and perinatal insults, sex hormones, heat, fatigue, and postinfectious autoimmune mechanisms on specific motor control brain circuits are topics of ongoing research (for a comprehensive review, please see Swain, et al.,⁴⁴ in press).

Assessment of TS

The last 10 years have seen a reinforcement of the position that clinical evaluation of the child or adolescent with tics should review the “whole person” possessing a rich personal and interpersonal life rather than just a collection of abnormal motor symptoms.^45,46 In the process of a comprehensive evaluation, the full range of difficulties and competencies should be charted. During the process of evaluation, the clinician, family, and child collaborate in the reconstruction of the child's history, tic symptomatology (onset, progression, waxing and waning, and factors that have worsened or ameliorated tic status), and current functioning. A critical question is the degree to which tics are interfering with the child's emotional, social, familial, and school experiences. To determine this, it is useful to monitor symptoms over a few months in order to assess their severity and fluctuation, impact on the family, and the child's and family's adaptation. This monitoring can often be accomplished with the family keeping records or using standard forms.⁴⁷

While the distressed family may focus on the annoying and socially stigmatizing tics, the clinician must recontextualize these symptoms with respect to the child and his overall development. By the time of evaluation, the child may be extremely upset by his experiences and by criticism from parents, teachers, and peers who have scolded and threatened in an effort to stop his strange behavior, which they may believe he can control. Central tasks of evaluation are to explicate, clarify, and address family issues, including parental guilt. Diagnostic evaluation is closely connected with the first steps of treatment. During the process of clinical inquiry, the physician can approach sensitive issues through clarification, education, and therapeutic discussions with the child and family.

As with other children with school performance problems, the child with TS requires a careful assessment of cognitive functioning and school achievement. Children with TS tend to have difficulties with attention, perseverance, and the ability to keep themselves focused and their work organized. Many have poor penmanship. Schoolwork may also be impaired by a variety of compulsions, such as the need to scratch out words or return to the beginning of a sentence.

The neurological examination of a child with TS can be of considerable value. Tics are sudden, habit-like movements or utterances that typically mimic some fragment of normal behavior and that involve discrete muscle groups. As such, they can be confused with normal coordinated movements or vocalizations. Tics can also be mistaken for akathisia, tardive dyskinesia, or other hyperkinetic movement disorders. These may suggest disturbances in the body schema and in the integration of motor control, but their relevance is not really clear. Electroencephalography and structural magnetic resonance imaging are generally normal and are not clinically useful (except where there are other neurological suspicions). Similarly, laboratory studies may establish a child's general health profile and assist in the differential diagnosis of other movement disorders, but there are no laboratory tests for the positive diagnosis of TS or other tic disorders.

Diagnostic criteria currently in use include the International Classification of Disease and Related Health Problems, 10th Revision (ICD-10)⁴⁸ and the DSM-IVTR.² Although clear differences exist, they are broadly congruent with each other. Finally, to minimize error in case ascertainment and produce an instrument measuring the likelihood of having TS, an international team of experts has recently published a TS Diagnostic Confidence Index.⁴ Scores on this Diagnostic Confidence Index are highly correlated with current tic severity, as measured by a psychometrically sound, widely used, clinician-rating scale, the Yale Global Tic Severity Scale.⁴⁹

Indeed, eliciting a thorough tic inventory, including timing, severity, and exacerbating and ameliorating factors, is extremely important in order to make treatment decisions and follow the course of illness. The Yale Children's Global Stress Index (YCGSI) is a standard tool for such evaluations. In addition, obtaining a thorough perinatal, personal, and family history as well as screening for possible comorbidities including ADHD, OCD, and learning difficulties, are essential. Although childhood tic severity is only modestly predictive of adult tic severity, tic-related obsessive-compulsive symptoms, which are likely to develop about two years later than tics, are more likely to persist into adulthood.⁵ A complete review of stressors is also in order as stress is a key determinant of outcome.¹⁵ It is important to review the strengths and abilities of a patient, along with an exploration of how these may be fully explored. Children with TS are often observed to be particularly attuned to the concerns and well being of others, possibly because their own experience of illness. Assessment of community issues and possible support are also important. As with any psychiatric illness, adequate pediatric medical care, including physical examination and laboratory work-up to rule out any medical conditions (e.g., infections or neurological conditions), should be included in the plan of care. Psychological testing is often also useful to assess and manage possible learning difficulties.

Once the diagnosis has been established, a careful assessment will allow the clinician to learn about the fluctuation of symptoms. As the child becomes more comfortable, he will show his symptoms with less suppression or inhibition. Only with trust in the doctor is a child or adult likely to acknowledge the most frightening egodystonic symptoms (e.g., bathroom rituals or aggressive thoughts). Moreover, a patient or family members may only recognize a symptom as a tic after they have been educated about possible symptoms.

Treatment of Tics

Despite the advances of the last 10 years, ideal anti-tic treatments have not been forthcoming. The decision to begin treatment is based on symptom severity and clinical presentation of each case and often involves a multimodal approach.⁵⁰ Many cases of TS are more troubling to family members than to the affected individual and may be managed successfully without resorting to medications. In patients presenting with comorbid ADHD, OCD, depression, or bipolar disorder, it is usually better to treat the comorbid condition first, as treatment of such disorders will likely diminish tic severity. While a thorough review of these interventions is beyond the scope of this review, some of the most recent studies are mentioned in passing, and further detail may be found elsewhere.⁵¹

Medications for TS must be used with meticulous care as the natural, idiosyncratic, and sometimes dramatic variations in tic severity in TS will suggest an effective period of medication action that is purely coincidental or will temporarily mask a potentially useful treatment. For example, coincidental remittance of tic severity due to the natural history of the illness with initiation of a medication convinces clinician and family that a medication was effective. Later, natural worsening of the symptoms leads to reactive and sometimes dangerous increases in medication far beyond any effective anti-tic doses, which lead to crippling side effects and frustration. Often the most difficult but wise course of treatment consists of education, reassurance, and a period of watchful waiting while stressors are reduced and the family adjusts.

Lifestyle and diet. Acute and chronic stress can exacerbate tics, so an attempt to reduce the stress of patients with TS is reasonable. Psychotherapy sessions may be useful to improve self-esteem, social coping, family strain, and school adjustment, but it is unclear if they directly affect tic severity. Regular appointments with the same clinical team, who can help the patient deal with the changing manifestations of the disorder through the years, are highly recommended. Regular contact via telephone or e-mail may also be helpful. Participation in regular school and extracurricular activities is encouraged.

No specific diet is known to be of particular benefit, though a balanced, healthy diet might contribute to overall well being and stress reduction. Caffeine should be minimized as it may exacerbate tics in some children. The impact of physical exercise on tic symptoms has not been systematically studied, though a regular program of exercise can be beneficial by reducing stress, increasing the child's sense of mastery, and contributing to overall well being.^52,53

Educational interventions. With the support of advocacy groups, such as the Tourette Syndrome Association, TS awareness for families, educators, and peers may promote community understanding, tolerance, and support, which can have a positive influence on the overall course of illness. Active collaboration with the school is essential to ensure appropriate classroom management, curricular planning, strength building, and matter-of-fact teacher and community education about TS.

Behavioral therapy. Although not yet well established, a number of reports have appeared that support several forms of behavioral therapy for tic disorders. Habit reversal training and, to a lesser extent, awareness training and exposure therapy have been conducted, especially with adults.^54,55 Four randomized placebo-controlled studies suggested that Habit Reversal Training may be an effective treatment for tic reduction.^56–59 Cognitive-behavioral treatments, such as exposure and response prevention, continue to be a mainstay for the treatment of obsessive-compulsive disorder, especially when there is significant anxiety or phobic avoidance.⁶⁰ Parent training⁶¹ and anger management⁶² for disruptive behavior in children and adolescents with TS may also be helpful. There is one report supporting the utility of hypnotherapy for TS.⁶³ Though not rigorously supported by controlled research, other formal dynamic interpersonal or supportive psychotherapeutic interventions may facilitate normal developmental tasks of friendship development, school mastery, coherent personality formation, and day-to-day self-esteem and family functioning.

Pharmacological treatment of tics. Despite our advances, there is no ideal anti-tic pharmacotherapy. Results are highly variable and are unfortunately often associated with a heavy side-effect burden. However, novel psychotropics are continually appearing, each with a different array of cellular and subcellular targets. It is hoped that converging pharmacologic and neuropathological research will yield medications that are both highly effective and have minimal side effects. Medications with at least one positive double-blind controlled clinical trial include alpha-adrenergic agents as well as atypical and typical neuroleptics (Table 2). The descriptive measure of effect size for tic severity was estimated based on the difference between means divided by the standard deviation.

Table 2.

Medications with at least one double-blind, controlled trial

Medication	Estimated Effect Size	Starting Dose (mg)	Usual Dose Range (mg/day)
Guanfacine	0.67 after 8 weeks	0.25–0.5	1.0–3.0
Clonidine	0.57 after 12 weeks	0.25–0.5	0.15–0.3
Haloperidol	0.8 after 6 weeks	0.25–0.5	0.75–2.5
Pimozide	0.8 after 6 weeks	0.5–1.0	2.0–4.0
Risperidone	>0.8 after 12 weeks	0.5–1.0	1.0–3.0
Ziprasidone	>0.6 after 8 weeks	5.0	<40.0
Olanzapine	>1.0 after 10–12 weeks	2.5	5.0–20.0

Other promising drugs are also described below along with some agents that are ineffective against tics. Other reviews^44,50 provide more exhaustive drug-by-drug summaries of proven effects, side-effects, dosing, effect sizes, and costs. The choice of treatment should include consideration of these factors along with a full discussion with the family.

Pharmacological treatment is often started with low doses of alpha-adrenergic drugs, which have effect sizes over 0.5 and double-blind, placebo controlled studies to support them.^64–66 Clonidine primarily activates presynaptic autoreceptors in the locus ceruleus to reduce norepinephrine release and turnover in cortex. Reduced levels of norepinephrine in these structures may be responsible for the experience of sedation and reduced motoric activity with these medications. It is recommended that low divided doses starting at 0.05mg per day gradually aim for target doses of 0.2- to 0.3mg/day. Primary side effect considerations for adrenergic medications are mild initial sedation, blood pressure decrease, constipation, and mid-sleep waking. Transdermal patches of clonidine are now available. Another first-line alpha adrenergic blocker with less sedation is guanfacine, which is an alpha 2 adrenergic agonist and activates postsynaptic prefrontal alpha adrenergic cortical receptors thought to improve impulsivity, attention, and working memory.⁶⁷ The target dose for the longer-acting guanfacine is 1.5- to 4mg/day.

Guanfacine has also been shown to be effective in treating ADHD symptoms, which are comorbid with TS, in a double-blind and placebo-controlled study.⁶⁵ In this study of 34 subjects after eight weeks of treatment with up to 4mg per day in three divided doses, guanfacine was associated with substantial improvements in ADHD symptomatology, including the teacher-rated ADHD Rating Scale, the Clinical Global Improvement scale, and the mean score on the parent-rated hyperactivity index, as well as the continuous performance index. In addition, tic severity decreased by over 30 percent.

Neuroleptics have a long history of use against tics with effect sizes for treating tics of at least 0.6. They are thought to act primarily by blocking dopamine receptors and thereby decreasing dopaminergic input from substantia nigra and ventral tegmentum to the basal ganglia. Of the typical neuroleptics, haloperidol and pimozide have been the best studied with double-blind, controlled studies to support them.^68–70 These medications, however, are associated with significant side effects, including acute dystonic reactions, oculogyric crises, torticollis, drug-induced Parkinsonism, akathisia, social phobia, weight gain, sedation, loss of drive, energy, and personality, dry mouth, blurred vision, galactorrhea, gynecomastia, constipation, urinary retention, EKG changes, including tachycardia, and tardive dyskinesia. Thus, after adrenergic medications have been tried and found ineffective, the atypical neuroleptics are usually the next class of medications tried before typical neuroleptics. Atypical neuroleptics are antidopaminergic and anti-serotonergic medications that carry a lower risk of tardive dyskinesia, but have not been used as much for tics or with children than typical neuroleptics. There are double-blind, controlled trials indicating effectiveness against tics for the atypical neuroleptic risperidone^71–74 and ziprasidone.⁷⁵ The anti-tic use of olanzapine is less well supported by two open label trials^76,77 and two small controlled studies.^78,79 However, these drugs also carry with them risks of significant weight gain, glucose and lipid metabolism abnormalities, sedation, and sleep disturbance. Another promising agent is the atypical antipsychotic aripiprazole, which was effective in reducing tics for a group of two adult patients with TS.⁸⁰ EKG cardiac monitoring for possible QTc changes should be conducted with all the neuroleptics in children, as well as baseline and periodic glucose and lipid metabolic screens.

Several important lines of medications have been shown to be ineffective for the treatment of tic disorders. There is currently no evidence that selective serotonin reuptake inhibitors (SSRIs) are effective in suppressing tics. SSRI treatment for mood or anxiety disorders is well tolerated by children without TS, so presumably would be useful for children with TS who have these conditions comorbidly.⁸¹ Clinicians should be mindful, however, of possible behavioral activation or agitation with SSRIs.⁸² The GABAergic muscle relaxant baclofen has been shown to improve tics in one large open trial although it lacked baseline or follow-up scores.⁸³ In the one small, double-blind, placebo-controlled, crossover study, no significant difference was found in tic severity in children treated with baclofen, though there was some improvement in impairment after four weeks.⁸⁴ Attempts have been made with nicotinic drugs, including nicotine chewing gum and patch, to treat tics. It has been thought that nicotinic receptor binding might affect tics by prolonging inactivation of acetylcholine receptor subtypes and possibly potentiate neuroleptic action. In open trials, encouraging effects of nicotine on tics were reported.^85–87 However, in the only placebo controlled trial there was little evidence of beneficial effects on tics.⁸⁸ In that study, the nicotine patch was added as an adjunctive medication with haloperidol. The study only showed a modest benefit in overall impairment, not an actual effect on tic severity. This could reflect a placebo-like psychophysiological effect, rather than a psychopharmacological effect of nicotine. Also, the nicotine antagonist, mecamylamine, has been tested against tics. Promising initial retrospective case studies⁸⁹ were again countered by a double-blind, placebo-controlled study, which failed to find significant effects.⁹⁰ Finally, the major side effects of nausea and vomiting limit the usefulness of nicotinic drugs in routine clinical practice.

An invasive procedure worthy of consideration for severe tics involves injections of botulinum toxin into discrete muscle groups.^91,92 Botulinum toxin blocks acetylcholine release at the neuromuscular junction and produces a reversible and temporary reduction in muscle activity, which may last weeks to months for dystonic tics. Main side effects include soreness, transient weakness, ptosis if injected for eye blinking, and mild transient dysphagia if injected into the larynx.

Other emerging/experimental therapies. In accord with the theory that a subtype of TS, characterized by abrupt onset and co-occurring group A beta hemolytic streptococcus infection, may be the result of an autoimmune process,⁵⁵ immune therapies have been examined with inconsistent results. For example, Perlmutter and colleagues⁹³ found that intravenous gamma globulin was effective in reducing tic and OCD symptoms, although Hoesktra and colleagues⁹⁴ reached opposite conclusions after evaluating their data. At present, the clinician is simply encouraged to be vigilant in assessing children with pharyngitis or those exposed to streptococcus, and vigorously treat with antibiotics if there is a positive throat culture. Plasmaphoresis, intravenous immunoglobulin, or corticosteroids are experimental treatments under study, but are of uncertain benefit at this point. They should only be undertaken with experts in the context of a formal research study. With certain unambiguous and sudden tic onset associated with streptococcal infection, antibiotic treatment has been occasionally remarkably effective; but again, antibody treatment is only warranted when there is clear evidence of streptococcal infection.

Transcranial magnetic stimulation is a new technology in which a brief, powerful magnetic field is generated by a small coil positioned over the skull and which induces an electrical current in the brain. Such noninvasive brain stimulation may effect long-term changes in cortical excitability, which may be abnormal in TS.⁹⁵ This is still an experimental therapy, of which the therapeutic stimulation parameters are unknown. However, a recent pilot study suggests that the treatment is safe and warrants further study.⁹⁶

The results of neurosurgical procedures reinforce the functional importance of thalamic regions that are part of the cortical-subcortical loops.^97,98 A single case study found that high frequency stimulation of the median and rostral intralaminar thalamic nuclei produced a significant reduction of tics. This effect is believed to be due to the influence of these midline thalamic nuclei on specific cells of the striatum and/or broadly distributed cortical systems and their corticostriatal projections. As in other movement disorders, a deeper understanding of the circuitry involved in TS may lead to specific circuit-based therapies using deep-brain stimulation to treat refractory cases.⁹⁹ However, since TS often spontaneously resolves by adolescence, surgical intervention would be extraordinary and only considered in the most severe and refractory cases that interfere with function and persist into adulthood.