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  • 1. The n e w e ng l a n d j o u r na l of m e dic i n e clinical practice Tourette’s Syndrome Roger Kurlan, M.D. This Journal feature begins with a case vignette highlighting a common clinical problem. Evidence supporting various strategies is then presented, followed by a review of formal guidelines, when they exist. The article ends with the author’s clinical recommendations. A 9-year-old boy has a 3-year history of hyperactive behavior, distractibility, and inat- tention. He is starting to fall behind in school. During the past year, he has had fre- quent eye blinking and throat clearing. How should he be evaluated and treated? The Cl inic a l Probl emFrom the Movement Disorders Program, Tourette’s syndrome (sometimes called Tourette’s disorder) is a childhood-onsetAtlantic Neuroscience Institute, Overlook condition characterized by motor and vocal tics that are chronic (duration of >1 year).Hospital, Summit, NJ. The standard diagnostic criteria for Tourette’s syndrome are listed in Table 1.1 MotorThis article (10.1056/NEJMcp1007805) was tics include simple tics such as twitching, eye blinking, facial grimacing, or head jerk-updated on February 2, 2011, at NEJM ing; slow twisting movements (dystonic tics); isometric contractions (tonic tics) such.org. as tensing of the abdominal muscles; and more complicated, purposeful-lookingN Engl J Med 2010;363:2332-8. movements (complex motor tics) such as touching or tapping. Vocal tics (also calledCopyright © 2010 Massachusetts Medical Society. phonic tics) include inarticulate noises such as throat clearing, sniffing, or coughing (simple vocal tics) and words or partial words (complex vocal tics). Because of the nature of tics, children are often referred to ophthalmologists or allergists before they receive the proper diagnosis of tics. Virtually any movement or sound that the human body is capable of making can be a manifestation of a tic. The most notorious tic of Tourette’s syndrome, obscene or insulting utterances (coprolalia), occurs in less than 50% of cases in reported series.2 Tics are often preceded by premonitory urges or uncomfortable sensations that are usually localized at the site of the tic; patients frequently report that their tics An audio version relieve the sensations.3 Tics have been described as “unvoluntary,” meaning there is of this article some ability initially to voluntarily suppress their expression, but the urges and is available at sensations build until there is an irresistible impulse to release the tics. Children NEJM.org tend to suppress tics (sometimes subconsciously) in socially sensitive places such as school or church; this suppression often leads to a sense of mental fatigue. Most patients with Tourette’s syndrome have multiple types of tics that vary in type over time; these tics occur in waves and vary in frequency and intensity from week to week or month to month. Although tics tend to worsen during times of stress, the waxing and waning of tics is a characteristic of the natural history of Tourette’s syndrome, and exacerbations are not necessarily linked to any type of emotional problem. Tourette’s syndrome is now viewed as a neuropsychiatric spectrum disorder in which tics are commonly associated with obsessive−compulsive symptoms that do not always meet the full diagnostic criteria for obsessive−compulsive disorder (OCD) and with disturbances of attention that do not always meet the full criteria for attention deficit–hyperactivity disorder (ADHD).4 The combination of tics, OCD, and ADHD is often called “the Tourette’s syndrome triad.” Studies have suggested a familial aggregation and hereditary relationship among these three conditions.5,62332 n engl j med 363;24 nejm.org december 9, 2010 The New England Journal of Medicine Downloaded from nejm.org on March 1, 2011. For personal use only. No other uses without permission. Copyright © 2010 Massachusetts Medical Society. All rights reserved.
  • 2. clinical pr acticeEvidence suggests that boys are more likely to Table 1. Diagnostic Criteria for Tourette’s Syndrome.*have tics and ADHD, whereas girls are more likelyto have OCD.7 Other psychiatric problems that are Both multiple motor tics and one or more vocal tics have been present atreported to occur more frequently in children some time during the illness, although not necessarily concurrently.with Tourette’s syndrome than in children with- The tics occur many times a day (usually in bouts) nearly every day or inter- mittently throughout a period of more than 3 consecutive months.out Tourette’s syndrome include rage attacks, de-pression, bipolar disorder, impulse-control prob- The onset is before 18 years of age.lems, and anxiety, although their prevalence and The disturbance is not due to the direct physiological effects of a substancethe exact nature of their relationship to Tourette’s (e.g., stimulants) or a general medical condition (e.g., Huntington’s dis- ease or postviral encephalitis).syndrome remain unclear. For example, some be-havioral problems may arise from difficulties in * Criteria are from the Diagnostic and Statistical Manual of Psychiatry, 4th edition.1living with Tourette’s syndrome. The prevalence of Tourette’s syndrome amongchildren is estimated to be approximately 1%.8 Tics should be distinguished from compul-Risk factors for this condition include male sex sions. Unlike tics, compulsions occur in responseand a family history of tics, OCD, and possi- to an obsession (e.g., hand washing due to fear ofbly ADHD. contamination), according to rules (e.g., a certain Most longitudinal and retrospective studies sug- number of times or in a certain order), or to wardgest that as children grow into adolescence and off harm to self or others. However, tics and com-adulthood, tics resolve in about one third of cases pulsions commonly coexist and have phenome-and become substantially less severe in another nologies that are so similar that sometimes it isthird.9,10 In the remainder of cases, Tourette’s difficult to distinguish between them.12syndrome is lifelong, with no substantial reduc- Tics commonly accompany developmentaltion of symptoms. There are no known reliable disorders such as mental retardation, autism, andpredictors of the ultimate outcome. For patients Asperger’s syndrome,13 and many experts do notwho do have improvement in symptoms, tics typi- diagnose Tourette’s syndrome when these othercally begin to lessen in severity at approximately disorders are present. In these cases, the tics are13 years of age, but they may not resolve until 30 considered to be secondary to the developmentalyears of age. Data from well-designed longitudinal disorder. Other neurologic disorders can also causestudies of Tourette’s syndrome are lacking, and tics, but these disorders are rare.information on the natural course of the condition In most children, the diagnosis of Tourette’sis thus limited. syndrome is made clinically; neuroimaging or other laboratory testing is not necessary to estab- S t r ategie s a nd E v idence lish the diagnosis.14 Tic suppression is common in physicians’ offices, and the best time to look forEvaluation tics is when the patient is walking into or out ofThe diagnosis of Tourette’s syndrome is made the examination room. Clinical rating scales thatwhen motor and vocal tics have been present for can be used to assess the child for coexistingat least 1 year.1 The temporal criterion is used to psychiatric conditions include the Yale−Browndistinguish the tics of Tourette’s syndrome from Obsessive−Compulsive Scale,15 the Conners Parentidentical-appearing tics that can occur transient- or Teacher ADHD Rating Scales,16 and the Childly during normal development.11 Traditional di- Depression Inventory.17agnostic distinctions between Tourette’s syndromeand conditions such as chronic motor tic disorder Managementand chronic vocal tic disorder in which there are In many children with Tourette’s syndrome, ticsmotor or vocal tics, but not both, are probably are mild and not disabling, and education aboutinvalid from a neurobiologic perspective, since the condition with some supportive counseling ischronic motor or vocal tic disorder and Tourette’s sufficient. A key focus is on maintaining andsyndrome are believed to result from similar mech- strengthening the child’s self-confidence and self-anisms. Thus, most clinicians now consider pa- esteem. Supportive counseling may be helpful fortients who have chronic motor or vocal tics or both these purposes, although it has not been rigor-types of tics to have Tourette’s syndrome. ously studied. Tics can be disabling by causing n engl j med 363;24 nejm.org december 9, 2010 2333 The New England Journal of Medicine Downloaded from nejm.org on March 1, 2011. For personal use only. No other uses without permission. Copyright © 2010 Massachusetts Medical Society. All rights reserved.
  • 3. The n e w e ng l a n d j o u r na l of m e dic i n e social embarrassment, isolation, and sometimes Pharmacotherapy conflict (e.g., because of vocal insults). Some tics The only medications for Tourette’s syndrome that (e.g., neck jerking) are painful, and some (e.g., have been approved by the Food and Drug Admin- scratching and poking) can be self-injurious. When istration (FDA) are the classic neuroleptic antipsy- tics are disabling, tic-suppressing therapy is indi- chotic agents haloperidol and pimozide, which cated. General approaches to treating Tourette’s block D2 dopamine receptors (Table 3). Data from syndrome and its common coexisting conditions controlled clinical trials provide support for their are summarized in Table 2. efficacy,19,20 although many of these early trials used outcome measures that were not standard- Behavioral Therapy ized. Long-term tic control often requires long- Clinical trials have shown that a form of cogni- term therapy. In a controlled trial involving patients tive behavioral therapy termed habit-reversal treat- whose tics were controlled after 1 to 3 months of ment is efficacious in suppressing tics. This form pimozide therapy, the mean time to relapse (as of therapy involves training patients to monitor defined by the need for an increase in drug dos- their tics and premonitory sensations and to re- age) was significantly shorter for patients in whom spond to them with a voluntary behavior that is therapy was withdrawn (the placebo group) than physically incompatible with the tics.18 In a clini- for those who continued to receive medication cal trial that compared habit-reversal treatment (37 vs. 231 days).21 with supportive therapy and education, habit re- Randomized, controlled trials have also pro- versal (carried out in eight weekly sessions) re- vided support for the efficacy of a newer atypical sulted in modestly greater improvement as mea- antipsychotic agent, risperidone, in suppressing sured by the score on the Yale Global Tic Severity tics, with a magnitude of benefit that is similar to Scale at 10 weeks (mean score reduction, 7.6 vs. that of the classic neuroleptics.22,23 One study, for 3.5 points). This two-part scale measures the se- example, showed a mean reduction of 32% in the verity of tics and overall impairment; scores for score for the tic portion of the Yale Global Tic each part range from 0 to 50, with higher scores Severity Scale after 8 weeks of treatment, as com- indicating greater disability, and a change in the pared with a 7% reduction among patients who total score of 2.5 to 5.0 points is considered a received placebo.23 Observational data suggest that minimal clinically significant difference. Potential some of the other members of this drug class may shortcomings of habit-reversal therapy are that it likewise lessen the severity of tics. The most fre- is not widely available, it is time-consuming, and its quent side effects of all antipsychotic agents are long-term benefits have not been examined. Its sedation, depression, increased appetite, and par- clinical value remains controversial, but some ex- kinsonism. Although the atypical antipsychotics perts advocate trying this therapy before initiating have fewer motor complications, such as parkin- medication in cases that are not severe. sonism, they commonly induce weight gain (which is often pronounced),24 and glucose intolerance (the metabolic syndrome), and these risks must be Table 2. Treatment Options for the Tourette’s Syndrome Triad.* taken into account in selecting therapy for chil- Tics OCD ADHD dren with Tourette’s syndrome. Habit reversal Cognitive behavioral Behavioral therapy Although studies have shown that antipsychot- therapy ics are efficacious in suppressing tics, because of Alpha-agonists Alpha-agonists Selective serotonin- their frequent side effects, other medications are Tetrabenazine reuptake inhibitors Atomoxetine often used first. Several trials have provided sup- Atypical antipsychotic agents Atypical antipsychotic Methylphenidate port for the efficacy of the α2-adrenergic drugs Classic neuroleptic agents agents clonidine and guanfacine.25-27 The magnitudes Deep-brain stimulation of benefit reported are generally lower than those Botulinum toxin associated with the antipsychotics, although no Deep-brain stimulation? head-to-head comparisons have been published. Since they also have efficacy for ADHD, the alpha-* ADHD denotes attention deficit–hyperactivity disorder, and OCD obsessive− compulsive disorder. agonists may be a good choice in patients with both tics and ADHD.27,28 Common side effects of2334 n engl j med 363;24 nejm.org december 9, 2010 The New England Journal of Medicine Downloaded from nejm.org on March 1, 2011. For personal use only. No other uses without permission. Copyright © 2010 Massachusetts Medical Society. All rights reserved.
  • 4. clinical pr actice Table 3. Tic-Suppressing Medications.* Medication Daily Dose Common Side Effects Comments mg Alpha-agonists Clonidine 0.05–0.5 Sedation, dizziness, headache, irritability Oral and transdermal forms available Guanfacine 0.5–4.0 Sedation, dizziness, headache, irritability Less sedation than with clonidine, and fewer doses needed Antipsychotic agents Haloperidol† 0.5–20.0 Sedation, depression, increased appetite, parkinsonism Fluphenazine 0.5–20.0 Sedation, depression, increased appetite, parkinsonism Pimozide† 0.5–10.0 Sedation, depression, increased appetite, ECG monitoring of the QT interval parkinsonism needed Risperidone 0.5–16.0 Sedation, weight gain, glucose intolerance, parkinsonism Dopamine depleter Tetrabenazine 12.5–100.0 Sedation, insomnia, depression, restlessness Expensive, dose influenced by CYP2D6 genotype* This list is not comprehensive. ECG denotes electrocardiographic.† This drug is approved by the Food and Drug Administration for this indication.the alpha-agonists are sedation, dizziness, head- Botulinum Toxinache, and irritability. Hypotension is generally not Local intramuscular injection of botulinum toxina problem, although syncope is a rare side effect. is a therapeutic option for some types of particu-Guanfacine is usually preferred because it tends to larly bothersome tics, although data from con-cause less sedation and can be given once (at bed- trolled trials are lacking. Case series indicate thattime) or twice daily as compared with three or four this treatment can reduce tics as well as associ-daily doses of clonidine. A transdermal form of ated premonitory sensations and pain.33,34 Botu-clonidine is available and useful in children who linum toxin is used most frequently for eye blink-cannot swallow pills.29 ing and neck and shoulder tics. The benefits are Tetrabenazine is a drug that depletes presyn- temporary, lasting 3 to 6 months.aptic dopamine and, in case series, has been re-ported to reduce tics.30,31 Some clinicians recom- Deep-Brain Stimulationmend tetrabenazine as a first-line treatment for Surgical treatment with deep-brain stimulationtics, since tardive dyskinesia has not been reported has recently been used in patients with Tourette’swith its use. No comparison trials have been per- syndrome who have disabling tics that are refrac-formed to determine the best initial medication. tory to medication. The results of double-blindThe most common side effects of tetrabenazine are trials of thalamic stimulation with the use of asedation, insomnia, restlessness, and depression. crossover design (comparing stimulation on with A recent small clinical trial showed that topi- stimulation off) indicate that some patients haveramate is effective for tics.32 There is inadequate a substantial benefit.35,36 The largest publishedevidence to recommend other medications sug- trial showed a mean reduction of 29% in thegested to lessen tics, including clonazepam, leve- score on the Yale Global Tic Severity Scale duringtiracetam, and baclofen. stimulation. However, the criteria for identifying It is common practice to combine drug classes, patients with Tourette’s syndrome who will havesuch as an antipsychotic and an alpha-agonist. the greatest benefit from deep-brain stimulationHowever, in the treatment of tics, this approach have not been established, and the optimal loca-has not been studied systematically. tion for the electrodes in such patients is not clear; n engl j med 363;24 nejm.org december 9, 2010 2335 The New England Journal of Medicine Downloaded from nejm.org on March 1, 2011. For personal use only. No other uses without permission. Copyright © 2010 Massachusetts Medical Society. All rights reserved.
  • 5. The n e w e ng l a n d j o u r na l of m e dic i n e the globus pallidus, putamen, subthalamic nucle- sistent.40 Neuroimaging has not identified increas- us, and other areas have been used. Deep-brain es in striatal presynaptic monoaminergic vesicles41 stimulation can be complicated by stroke, infec- or striatal dopaminergic innervation42 in patients tion, and side effects during stimulation such as with Tourette’s syndrome as compared with con- paresthesias, visual symptoms, and dysarthria. trols. Family studies suggest a complex inheri- tance pattern in Tourette’s syndrome43 that often Management of Coexisting Conditions includes bilineal (maternal and paternal) trans- An important part of treating patients with Tou- mission.44 Associations have been reported be- rette’s syndrome is the appropriate treatment of tween Tourette’s syndrome and some genetic coexisting conditions. A detailed discussion of loci,45,46 but they appear to account for only a the management of ADHD, OCD, and other co- small portion of cases. Tourette’s syndrome has existing conditions is beyond the scope of this also been associated with recurrent exonic copy- article.37,38 In brief, cognitive behavioral therapy, number variants (DNA deletions and duplica- selective serotonin-reuptake inhibitors, and atyp- tions),47 which appear to be involved in a variety of ical antipsychotics are established therapies for neurodevelopmental disorders.48 OCD; deep-brain stimulation has been shown to The observation that Tourette’s syndrome re- be effective in severe cases. There has been con- solves or becomes less severe in a substantial cern that the use of psychostimulant drugs for number of patients as they grow into adulthood coexisting ADHD might exacerbate tics in pa- suggests that the underlying mechanisms involve tients with Tourette’s syndrome because of the processes that may correct themselves as the brain pharmacologic effects on catecholamine neuro- matures. On the basis of clinical similarities be- transmission. However, a 12-week randomized, tween Sydenham’s chorea and Tourette’s syndrome double-blind, placebo-controlled trial involving with OCD, the PANDAS syndrome (pediatric au- children with both Tourette’s syndrome and toimmune neuropsychiatric disorders associated ADHD showed that methylphenidate was effec- with streptococcal infections) was hypothesized as tive for ADHD and did not exacerbate tics.28 An- an autoimmune response to streptococcal infec- other multicenter, controlled trial showed that tion that might precipitate or exacerbate tics. A the selective norepinephrine-reuptake inhibitor recent intensive, prospective, blinded, clinical and atomoxetine likewise was associated with im- laboratory cohort study, however, did not identify provement of ADHD symptoms without worsen- any temporal link between streptococcal infection ing of tics in children with both conditions.39 and clinical exacerbations in patients who met the Other stimulants, such as dextroamphetamine criteria for PANDAS.49 sulfate and amphetamine salts, have not been studied in controlled trials involving patients Guidel ine s with Tourette’s syndrome. Given the fact that many patients with Tou- The Practice Parameter Group of the Tourette Syn- rette’s syndrome require treatment for both tics drome Association has published recommenda- and coexisting conditions, combination therapy tions for the evaluation, diagnosis, and treatment with tic-suppressing, anti-OCD, and anti-ADHD of Tourette’s syndrome and associated psychiatric medications is commonly used. No formal assess- conditions.14 The group emphasized the impor- ments of such combination therapy have been tance of accurate diagnosis, including identifica- reported. tion of coexisting conditions. For the treatment of Tourette’s syndrome, the recommendations are A r e a s of Uncer ta in t y that guanfacine or clonidine be considered as a first-line medication for moderate or more severe Although there is evidence of a state of excessive tics, that botulinum toxin may be considered in central dopamine neurotransmission in Tourette’s patients with a single interfering tic, and that more syndrome, the fundamental cause of the illness and potent medications such as risperidone, pimozide, its neurobiologic mechanisms remain poorly un- or fluphenazine may be considered for tics with derstood. Neuroimaging studies have shown vol- an inadequate response to the alpha-agonists. A umetric changes in the basal ganglia and other report by the Therapeutics and Technology Assess- brain regions, but the results have not been con- ment Subcommittee of the American Academy of2336 n engl j med 363;24 nejm.org december 9, 2010 The New England Journal of Medicine Downloaded from nejm.org on March 1, 2011. For personal use only. No other uses without permission. Copyright © 2010 Massachusetts Medical Society. All rights reserved.
  • 6. clinical pr acticeNeurology, which focused on neurologic uses of focusing can also be due to obsessive thinking,botulinum toxin therapy, concluded that it is an compulsions, anxiety, or low mood. The patientappropriate treatment for tics in patients with Tou- should be evaluated for these potential coexistingrette’s syndrome.34 conditions. For combined Tourette’s syndrome and ADHD, guanfacine would be a good first- choice medication, since it can improve both con- C onclusions a nd R ec om mendat ions ditions, although this agent is not approved by the FDA for Tourette’s syndrome. If control of ticsThe boy described in the case vignette has had is inadequate, adding an antipsychotic drug wouldmotor and vocal tics for more than 1 year, sug- be reasonable. Inadequate control of ADHD wouldgesting the diagnosis of Tourette’s syndrome. His warrant the addition of a methylphenidate prepa-problems with performance in school may be ex- ration.plained in part by his tics (e.g., eye-blinking tics Dr. Kurlan reports receiving consulting fees from Boehringeraffect reading, arm tics affect writing, and the Ingelheim and Biovail and grant support from the Michael J. Foxmental effort expended in suppressing tics affects Foundation, Kyowa, and Neurologix. No other potential conflict of interest relevant to this article was reported.attention and concentration). His history of inat- Disclosure forms provided by the author are available with thetention and hyperactivity suggests possible coex- full text of this article at NEJM.org.isting ADHD, but problems with attention andReferences1. Diagnostic and statistical manual of 11. Kurlan R. Hypothesis II: Tourette’s Short-term vs. longer term pimozide ther-psychiatry. 4th ed. rev. 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