Tourette's Syndrome, The New England Journal of Medicine, Otro de Psicología. Universidad Nacional de Educación a Distancia  - UNED
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Tourette's Syndrome, The New England Journal of Medicine, Otro de Psicología. Universidad Nacional de Educación a Distancia - UNED

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Description, diagnosis, pathogenesis and treatment about Tourette's Syndrome
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101801 Tourette's Syndrome

Medical Progress

1184

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N Engl J Med, Vol. 345, No. 16

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October 18, 2001

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www.nejm.org

The New England Journal of Medicine

T

OURETTE

S

S

YNDROME

J

OSEPH

J

ANKOVIC

, M.D.

From the Parkinson’s Disease Center and Movement Disorders Clinic, Department of Neurology, Baylor College of Medicine, 6550 Fannin, Suite 1801, Houston, TX 77030, where reprint requests should be addressed to Dr. Jankovic.

OURETTE’S syndrome is a neurologic dis- order named after the French neurologist Georges Gilles de la Tourette, who, in 1885,

described nine patients with childhood-onset tics, ac- companied in some by uncontrollable noises and ut- terances, as well as features that are now associated with attention-deficit–hyperactivity disorder, obses- sive–compulsive disorder, poor impulse control, and other coexisting behavioral problems.

1-3

Although Tourette considered the disorder he described to be hereditary, it was ascribed to psychogenic causes for nearly a century after the original report. The percep- tion of Tourette’s syndrome as a rare, bizarre psycho- logical disorder began to change in the 1960s, when the beneficial effects of neuroleptic drugs on the symp- toms of the syndrome began to be recognized.

4

This observation helped to stimulate research into the neurobiologic mechanisms of Tourette’s syndrome, as a result of which it is now recognized as a relatively common, biologic, genetic disorder with a spectrum of neurobehavioral manifestations that wax and wane during its natural course. The marked fluctuations in the severity and frequency of symptoms, coupled with the striking variation in manifestations from one pa- tient to another, however, contribute to frequent mis- diagnosis.

5

Despite greater awareness of Tourette’s syndrome as a result of increased educational efforts directed at physicians and other health care providers, psychologists, educators, and the general public, many cases still remain undiagnosed, or patients’ symptoms are wrongly attributed to hyperactivity, nervousness, habits, allergies, asthma, dermatitis, and other con- ditions.

6,7

DIAGNOSIS

The diagnosis of Tourette’s syndrome (Fig. 1) is based on a history and observation of tics, often sup- ported by the presence of coexisting behavioral dis- orders, particularly attention-deficit–hyperactivity dis- order and obsessive–compulsive disorder, and a family history of similar symptoms. Tics, the clinical hall- mark of Tourette’s syndrome, are sudden, brief, in- termittent, involuntary or semivoluntary movements

T

(motor tics) or sounds (phonic or vocal tics). They typically consist of simple or coordinated, repetitive or sequential movements, gestures, and utterances that mimic fragments of normal behavior.

3,8

Simple motor tics involve only a single muscle or a group of muscles, and often cause a brief, jerking movement (clonic tics); they may also be slower, causing a briefly sustained abnormal posture (dystonic tics) or an iso- metric contraction (tonic tics).

8

Examples of simple clonic motor tics include blinking, nose twitching, and head and limb jerking.

Dystonic tics include sustained eye closure (bleph- arospasm), ocular deviations, bruxism, mouth open- ing, torticollis, and shoulder rotation. Tonic tics are typically manifested by tensing of abdominal or limb muscles. Examples of complex motor tics include head shaking, trunk bending or gyrating, brushing hair, touching, throwing, hitting, jumping, kicking, making rude gestures, grabbing one’s genitalia and making other lewd or obscene gestures (copropraxia), and imitating others’ gestures (echopraxia). Burping, vom- iting, and retching have also been described as part of the clinical picture of Tourette’s syndrome. Some complex, repetitive movements and sounds may be considered a compulsion when they are preceded by or associated with a feeling of anxiety or a fear that if

Figure 1.

Clinical Hallmarks of Tourette’s Syndrome. The diagnosis is based on the occurrence of tics along with be- havioral disorders, including attention-deficit–hyperactivity dis- order (ADHD) and obsessive–compulsive disorder (OCD). Other behavioral disorders include anxiety and mood disorders, learn- ing disorders, sleep disorders, conduct and oppositional behav- ior, and self-injurious behavior.

ADHD OCD

Tics

poor impulse control, and other behavioral

disorders

Tourette's syndrome

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they are not promptly or properly executed, “some- thing bad” will happen.

Simple phonic tics typically consist of sniffing, throat clearing, grunting, squeaking, screaming, coughing, barking, blowing, and making sucking sounds. Complex phonic tics include linguistically meaningful utterances and verbalizations, such as the shouting of obscenities, profanities, or otherwise so- cially inappropriate words or phrases (coprolalia), the repetition of someone else’s words or phrases (echola- lia), and the repetition of one’s own utterances, par- ticularly the last syllable, word, or phrase in a sentence (palilalia). Coprolalia, perhaps the most recognizable and certainly one of the most distressing symptoms of Tourette’s syndrome, is actually present in less than half of patients with Tourette’s syndrome. The true frequency of coprolalia, however, is unknown, because some patients are able to modify the utter- ances by using only fragments of the word, such as “sh” or “f,” and others have only “mental” coprola- lia and do not actually utter the word.

Motor and phonic tics are often preceded by pre- monitory sensations, which consist of localizable par- esthesia or discomfort; these sensations are temporari- ly relieved after the execution of the tic. Examples include a burning feeling in the eye before an eye blink, tension or a crick in the neck that is relieved by stretching the neck or jerking the head, a feeling of tightness or constriction that is relieved by exten- sion of the arm or leg, nasal stuffiness before a sniff, dry or sore throat before throat clearing or grunting, and itching before a rotatory movement of the scap- ula.

8

Besides such local or regional premonitory sen- sations, there may be nonlocalizable and less specific premonitory phenomena, such as urges, anxiety, an- ger, or other psychic symptoms. Many patients re- port that in order to relieve the uncomfortable urge they have to repeat a particular movement until “it feels good” or “it feels just right.”

9

The ability of patients to suppress their tics helps to differentiate tics from other hyperkinetic move- ment disorders such as chorea, dystonia, athetosis, myoclonus, and paroxysmal dyskinesias.

10

Many pa- tients with Tourette’s syndrome note a reduction in the frequency and severity of their tics when they are concentrating on mental or physical tasks or sensa- tions (such as playing a video game or having an or- gasm). In addition to their temporary suppressibility, tics are also characterized by suggestibility, and by ex- acerbation with stress, excitement, boredom, fatigue, and exposure to heat. The frequency of tics may also increase during relaxation after a period of stress — thus, children often “release” their tics when they come home from school. Although the tics have tra- ditionally been thought to disappear during sleep, a variety of sleep studies have demonstrated that mo- tor and phonic tics may persist during all stages of sleep.

11,12

Tics can be troublesome for patients with

Tourette’s syndrome, because they cause embarrass- ment, interfere with social interactions, and can, at times, be quite painful or uncomfortable. In rare in- stances, they can cause secondary neurologic deficits, such as compressive cervical myelopathy as a result of violent head and neck tics.

13

Tourette’s syndrome, the most common cause of tics, is manifested in a broad spectrum of motor and behavioral disturbances and affects males approxi- mately three times as frequently as females. To aid in the diagnosis of Tourette’s syndrome, the Tourette Syndrome Classification Study Group

14

has formu- lated the following criteria for a definite diagnosis of Tourette’s syndrome: both multiple motor tics and one or more phonic tics must be present at some time during the illness, although not necessarily concur- rently; tics must occur many times a day, nearly every day, or intermittently throughout a period of more than one year; the anatomical location, number, fre- quency, type, complexity, or severity of tics must change over time; the onset must occur before the age of 21 years; involuntary movements and noises must not be explainable by other medical conditions; and motor tics, phonic tics, or both must be wit- nessed directly by a reliable examiner at some point during the illness or be recorded by videotape or cin- ematography. These and other diagnostic criteria

15,16

are designed to assist in accurate diagnosis, in genetic- linkage studies, and in differentiating Tourette’s syn- drome from other tic disorders (Table 1).

17,18

Although these diagnostic criteria require that the onset occur before the age of 21 years, in 96 percent of patients the disorder is manifested by 11 years of age, typically beginning between 3 and 8 years of age.

19

According to one study, the average age at the onset of tics is 5.6 years, and tics usually become most severe at 10 years of age; by 18 years of age, half of patients with Tourette’s syndrome are free of tics.

20

Tics may persist into adulthood, although their se- verity is usually gradually diminished (Fig. 2). In the majority of cases, tics in adults represent the persist- ence or recurrence of childhood-onset tics,

21

but in rare instances, patients may have their first occurrence of tics during adulthood.

22

In these adults with new- onset tics, it is important to search for secondary causes such as infection, trauma, use of illicit drugs, exposure to neuroleptic drugs, and neuroacanthocy- tosis (Table 1).

17,22

In addition to involuntary noises, some patients have speech dysfluencies that resemble developmen- tal stuttering, and as many as half of all patients with developmental stuttering may have undiagnosed Tou- rette’s syndrome.

23

Except for tics, increased rates of blinking,

24

subtle oculomotor disturbances related to saccadic eye movements,

25

and other evidence of mild impairment of motor control (e.g., poor pen- manship), the results of neurologic examination in patients with Tourette’s syndrome are normal.

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In addition to motor and phonic tics, patients with Tourette’s syndrome often have a variety of behav- ioral symptoms, particularly those associated with at- tention-deficit–hyperactivity disorder and obsessive– compulsive disorder. A thorough discussion of the pathogenesis of these coexisting disorders is beyond the scope of this review.

26,27

These coexisting behav- ioral conditions often interfere more than tics do with overall functioning and with academic and work per- formance; if these disorders are left untreated, they may lead to social and emotional maladjustment. Al- though only 3 to 6 percent of school-aged children have attention-deficit–hyperactivity disorder,

27

a ma- jority of patients with Tourette’s syndrome have symp- toms of attention-deficit–hyperactivity disorder, ob- sessive–compulsive disorder, or both at some time during the course of their illness (Fig. 1).

28

In many patients, the inability to pay attention is the result not only of coexisting attention-deficit–hyperactivi-

ty disorder but also of uncontrollable intrusions of thoughts or obsessive fixation of attention on irrele- vant objects or topics, of the mental concentration that is exerted in an effort to suppress tics and pre- monitory urges, and of the sedative effects of the medications used to treat Tourette’s syndrome.

That obsessive–compulsive disorder is a part of the spectrum of neurobehavioral manifestations of Tou- rette’s syndrome has been well accepted for a long time.

19

Obsessions — characterized by intense, in- trusive thoughts (such as worries about bodily waste and secretions); unfounded fears; a need for exact- ness, symmetry, evenness, and neatness; an excessive concern with matters of religion; perverse sexual thoughts; and intrusions of words, phrases, or music — can lead to the slowing of cognitive function.

29

Compulsions consist of subjective urges to perform meaningless and irrational rituals, such as checking, counting, cleaning, washing, touching, smelling, hoarding, and rearranging. Obsessive–compulsive disorder is now considered to be a multidimensional condition that can occur alone as a primary (idio- pathic or familial) disorder, as a coexisting disorder in patients with Tourette’s syndrome, or as a result of a variety of lesions in the frontal–limbic–subcor- tical circuits.

30

Other behavioral problems associated with Tou- rette’s syndrome include poor impulse control and an inability to control anger, as a result of which some patients may have outbursts of temper, episodic at- tacks of rage, emotional storms, inappropriate sexual aggressiveness, antisocial or oppositional behavior, and symptoms of anxiety and depression. One of the most distressing symptoms of Tourette’s syndrome is self- injurious behavior.

2,6

Commonly, such behavior in- volves the compulsive, repetitive inflicting of damage to the skin by biting, scratching, cutting, engraving,

6

or hitting (particularly in the eye and throat), often accompanied by an irresistible urge (obsession). It has also been reported that Tourette’s syndrome is fre- quently associated with migraine headaches, which were present in 26.6 percent of patients in one study.

31

PATHOGENESIS

Various biochemical, imaging, neurophysiological, and genetic studies support the notion that Tou- rette’s syndrome is an inherited, developmental dis- order of synaptic neurotransmission resulting in the disinhibition of the cortico–striatal–thalamic–cortical circuitry.

1

Although postmortem neuropathological examinations of the brains of patients with Tourette’s syndrome have not revealed any specific pathologic changes,

32

the basal ganglia, particularly the caudate nucleus and the inferior prefrontal cortex, have been implicated in the pathogenesis of Tourette’s syn- drome, as well as in that of obsessive–compulsive disorder and attention-deficit–hyperactivity disorder.

33

There are no animal models of Tourette’s syndrome,

T

ABLE

1.

E

TIOLOGIC

C

LASSIFICATION

OF

T

ICS

.

Primary causes

Sporadic tics Transient motor or phonic tics (for <1 yr) Chronic motor or phonic tics (for >1 yr) Adult-onset (recurrent) tics Tourette’s syndrome Primary dystonia

Inherited tic disorders Tourette’s syndrome Huntington’s disease Primary dystonia Neuroacanthocytosis Hallervorden–Spatz disease or neurodegeneration with brain iron accu-

mulation type 1 Tuberous sclerosis Wilson’s disease

Secondary causes

Infections (e.g., encephalitis, Creutzfeldt–Jakob disease, neurosyphilis, Sydenham’s chorea)

Drugs causing tardive tics (e.g., amphetamines, methylphenidate, pemo- line, levodopa, cocaine, carbamazepine, phenytoin, phenobarbital, la- motrigine, antipsychotics, and other dopamine-receptor–blocking drugs)

Toxins (e.g., carbon monoxide) Developmental problems (e.g., static encephalopathy, mental-retardation

syndromes, chromosomal abnormalities, autistic-spectrum disorders [Asperger’s syndrome])

Chromosomal disorders (e.g., Down’s syndrome, Klinefelter’s syndrome, XYY karyotype, fragile X syndrome, triple X syndrome, 9p mosaicism, partial trisomy 16, monosomy 9p, citrullinemia, Beckwith–Wiede- mann syndrome)

Other (e.g., head trauma, stroke, neurocutaneous syndromes, schizophre- nia, neurodegenerative diseases)

Related manifestations and disorders

Stereotypes, habits, and mannerisms Self-injurious behavior Motor restlessness Akathisia Compulsions Excessive startle Jumping Frenchmen of Maine syndrome

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but several families of horses with equine self-mutila- tion syndrome have been described that have features resembling human Tourette’s syndrome.

34

Neuroimaging

Although standard anatomical neuroimaging stud- ies in patients with Tourette’s syndrome are unremark- able, volumetric magnetic resonance imaging (MRI) studies have suggested that the normal asymmetry of the basal ganglia, with the volume normally larger on the right than the left, is lost in Tourette’s syndrome, supporting the notion that there is a developmental abnormality.

33

Functional MRI studies in patients with Tourette’s syndrome have shown decreased neu- ronal activity during periods of suppression in the ventral globus pallidus, putamen, and thalamus and increased activity in the prefrontal, parietal, temporal, and cingulate cortical areas normally involved in the inhibition of unwanted impulses.

33

In one study, pos- itron-emission tomography (PET) with

18

F-fluorode- oxyglucose showed two patterns: evidence of increased metabolic activity in the lateral premotor and supple- mentary motor cortexes and in the midbrain (pattern 1) and decreased metabolic activity in the caudate and thalamic areas (limbic basal-ganglia–thalamocorti- cal projection system) (pattern 2).

35

Using PET with [

15

O]water, Stern et al.

36

found increased activity in the areas responsible for sensorimotor, language, ex- ecutive, and paralimbic function and in the frontal sub- cortical area that was temporally related to the motor and phonic tics and the irresistible urge that precedes these behaviors.

Neurophysiology

Studies using back-averaging electroencephalo- graphic techniques have found that the premovement

potential (Bereitschaftspotential) is absent in some pa- tients before the execution of motor tics. This finding suggests that the movements are truly involuntary, but this potential may be present in other patients, provid- ing evidence of a voluntary component to some tics.

37

Furthermore, studies using transcranial magnetic stim- ulation have demonstrated that the cortical silent peri- od is shortened and intracortical inhibition is defective in patients with Tourette’s syndrome and in patients with obsessive–compulsive disorder and tics. This pro- vides a possible explanation for the decreased motor inhibition and intrusive phenomena in Tourette’s syn- drome and obsessive–compulsive disorder.

Neurochemistry

An alteration in the central neurotransmitters has been suggested as a cause of Tourette’s syndrome, chiefly because there have been relatively consistent responses to the modulation of the dopaminergic system. The few brains that have been studied post mortem have had low levels of serotonin in the brain stem, low levels of glutamate in the globus pallidus, and low levels of cyclic AMP in the cortex.

3,32

The ob- served increase in the rate of binding of 3H-mazin- dol to the presynaptic dopamine-uptake–carrier sites suggests that Tourette’s syndrome represents a devel- opmental disorder resulting in dopaminergic hyperin- nervation of the ventral striatum and the associated limbic system.

3

With the use of single-photon-emission computed tomography or PET, some studies,

39

but not all,

40

have demonstrated increased density of the presynaptic dopamine transporter and the postsynaptic D2 dopamine receptor and have suggested that there is abnormal regulation of dopamine release and uptake in Tourette’s syndrome.

41

Figure 2.

The Natural History of Tourette’s Syndrome.

1 2 3 4 5 6 7 8 9

Age (years)

Natural History of Tourette’s Syndrome

10 11 12 13 14 15 16 17 18 19 20

Exacerbation sible remissionPos

Attention-deficit–hyperactivity disorder

Motor tics (rostral caudal progression)

Vocal tics (simple complex)

Obsessive–compulsive behavior

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Genetics

Finding a genetic marker, and ultimately the gene that may be responsible for the disorder, has been the highest priority in research on Tourette’s syndrome during the past decade. Unfortunately, despite a con- certed effort by many investigators, Tourette’s syn- drome genes have thus far remained elusive. A system- atic genome scan involving 76 affected families with a total of 110 pairs of siblings showed two regions, 4q and 8p, with increased lod scores, suggesting that these loci may contain Tourette’s syndrome–related genes.

42

Other genetic studies have found possible associations with various candidate genes, but their relevance to the pathogenesis of Tourette’s syndrome has been questioned. Future genetic studies must con- sider the common observation that both parents of a child with Tourette’s syndrome often have Tourette’s syndrome or a forme fruste of it. Such bilineal trans- mission is present in 25 to 41 percent of families with Tourette’s syndrome.

43,44

Twin studies, which have found 89 to 94 percent concordance for Tourette’s syndrome, also provide strong evidence of a genetic cause.

45

In one study involving 16 pairs of monozy- gotic twins, low birth weight was a strong predictor of more severe tics.

45

Other factors that may influence the expression of a Tourette’s syndrome gene include maternal life stress and nausea and vomiting during the first trimester of pregnancy.

46

Immunology

The potential role of antecedent infection with group A beta-hemolytic streptococcus and the con- sequent presence of antineuronal antibodies have been explored in patients with a variety of neurologic dis- orders, including Sydenham’s chorea and Tourette’s syndrome.

47-49

Evidence cited in support of the im- munologic theory of Tourette’s syndrome includes el- evated titers of antistreptococcal antibodies in some patients,

50

the frequent presence of B lymphocyte antigen D8/17,

51

and increased levels of antineuronal antibodies against putamen in patients with Tou- rette’s syndrome.

52

There is, however, no relation be- tween the presence of the antineuronal antibodies and the age at onset, the severity of tics, or the pres- ence of coexisting disorders.

52

Although streptococ- cal infection may trigger the onset of symptoms in a small subgroup of patients with Tourette’s syndrome, the relation among group A beta-hemolytic strepto- coccus, antineuronal antibodies, and Tourette’s syn- drome has yet to be resolved, and further studies are needed.

53

Because of uncertainties about the possi- ble causal relation between streptococcal infection and Tourette’s syndrome and because of potential risks, immunologic therapies — such as plasmaphe- resis, the use of intravenous immune globulin,

54

and the administration of antibiotics for acute exacerba- tions of the symptoms of Tourette’s syndrome — are currently considered to be unwarranted.

55

Epidemiology

The epidemiology of Tourette’s syndrome is not precisely defined.

43,56

Observational studies in public schools have suggested that the prevalence of Tou- rette’s syndrome is about 0.7 percent,

43,57

but estimates of its prevalence have varied markedly, with some es- timates as high as 4.2 percent when all types of tic disorders are included.

58,59

There are many reasons for this wide variation, the most important of which are different methods of ascertainment of cases, differ- ent study populations, and different clinical criteria.

TREATMENT

The first step in the treatment of a patient with Tourette’s syndrome is the proper education of the patient, family members, teachers, and other persons who interact with the patient. Parents, educators, and physicians must work as partners in advocating the best possible school environment for children with Tourette’s syndrome. National and local support groups, such as the Tourette Syndrome Association (http://www.tsa-usa.org), can provide additional in- formation and can serve as a valuable resource for patients and their families. Given the time and effort that various behavioral therapies require on the part of the patient, the family members, and the thera- pist, it is not surprising that even if they are effective, the benefits of such therapies are usually only tem- porary. These therapies, however, may be useful an- cillary techniques for patients in whom the response to other therapies, including pharmacotherapy, is not entirely satisfactory.

60

Medications are usually consid- ered when symptoms begin to interfere with peer relationships, social interactions, academic or job performance, or activities of daily living. Because of the broad range of neurologic and behavioral mani- festations and their varying severity, therapy for Tou- rette’s syndrome must be individualized and tailored specifically to the needs of the patient, and the most troublesome symptoms should be targeted first (Ta- ble 2).

61

To avoid unnecessary changes that might be made in response to normal variations in symptoms during the natural course of the disease, each med- ication and each dosage regimen should be given an adequate trial.

Treatment of Tics

In treating tics, the goal should not be to elimi- nate all the tics completely but to relieve tic-related discomfort or embarrassment and to achieve a de- gree of control of tics that allows the patient to func- tion as normally as possible. A number of rating scales for tics have been used in various studies of treatments for tics.

62

Although there have been only a limited number of double-blind, placebo-controlled trials, the dopamine-receptor–blocking drugs (neu- roleptics) are considered the most effective anti-tic agents (Table 2). Haloperidol and pimozide are the

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only neuroleptic drugs currently approved by the Food and Drug Administration for the treatment of Tourette’s syndrome. In one randomized, double- blind, controlled study, pimozide was found to be superior to haloperidol with respect to efficacy and side effects.

63

Some clinicians, however, prefer risperi- done,

64

fluphenazine, thioridazine, trifluoperazine, molindone, thiothixene, or tiapride. It is not clear whether the atypical neuroleptics, such as clozapine, olanzapine, or quetiapine, will be effective in the treatment of tics and other manifestations of Tou- rette’s syndrome, but ziprasidone was found in one study to diminish the severity of tics by 35 percent.

65

Tetrabenazine, a drug that depletes monoamine and blocks the dopamine receptors (but is not yet avail- able in the United States), is a powerful anti-tic drug, and it has an advantage over the conventional neuro- leptics in that it does not cause tardive dyskinesia.

66

Other side effects that may be associated with neu- roleptics include sedation, depression, weight gain, school phobia, and hepatotoxicity. In addition, pi- mozide may prolong the QT interval, and it is there- fore recommended that electrocardiography be per- formed before a patient starts taking pimozide, three months after it is begun, and at least once a year thereafter.

Other drugs found to be useful in the treatment of tics include clonazepam, pergolide, cannabinoids, nic- otine gum, and transdermal nicotine patches, but none of these drugs have been studied in well-designed, placebo-controlled trials.

67

Focal motor and vocal tics have also been treated successfully with injections of botulinum toxin in the affected muscles.68-70 Such lo- cal chemical denervation not only ameliorates invol- untary movements but may also eliminate the premon- itory sensory component. The benefits last three to four months, on average, and no serious complications have been reported. Although stereotactic surgery has not generally been found to be useful in the treatment of tics, a preliminary report of the case of a 42-year- old man whose severe motor and phonic tics have been controlled by high-frequency deep-brain stim- ulation of the thalamus is encouraging.71

Treatment of Coexisting Behavioral Symptoms

Behavioral modification and adjustments in the school and classroom environments play an impor- tant part in the treatment of patients with Tourette’s syndrome and are helpful in raising self-esteem and improving motivation.72 It is beyond the scope of this review to provide a comprehensive description of drug treatment for behavioral disturbances.26,73,74

Attention-Deficit–Hyperactivity Disorder

Central nervous system stimulants, such as methyl- phenidate, controlled-release methylphenidate, dextro- amphetamine, a mixture of amphetamine salts (Ad- derall), and pemoline, are clearly the most effective

agents in the treatment of attention-deficit–hyperac- tivity disorder.75 These agents have also been found useful as a short-term therapy for conduct disorders.76 In addition to the possible development of tolerance, there are other potential adverse effects of these stim- ulant drugs, such as nervousness, irritability, insomnia, anorexia, abdominal pain, and headaches.77 Pemoline can produce hepatotoxic effects in rare instances. Al- though central nervous system stimulants may ini- tially increase the frequency and intensity of tics, with continued use these drugs can be well tolerated with- out sustained exacerbation of tics.78,79 The antidopa- minergic drugs can be combined with the central nervous system stimulants if the latter produce an un- acceptable exacerbation of tics.

Although attention-deficit–hyperactivity disorder was initially considered to be a noradrenergic disor- der,80 recent studies have provided evidence that the beneficial effects of methylphenidate on the disorder are mediated by the serotonin system.81 The a2-adre- nergic agonists are also useful in the treatment of at- tention-deficit–hyperactivity disorder, particularly if

*CNS denotes central nervous system, ADHD attention-deficit–hyperactivity disorder, and OCD obsessive–compulsive disorder.

†Adult dosages are given; they must be adjusted for children.

TABLE 2. DRUG TREATMENT OF TOURETTE’S SYNDROME.*

DRUG INITIAL DOSE†

mg/day

Dopamine-receptor blockers for tics Fluphenazine 1.0 Pimozide 2.0 Haloperidol 0.5 Risperidone 0.5 Ziprasidone 20.0 Thiothixene 1.0 Trifluoperazine 1.0 Molindone 5.0

Dopamine deplete for tics Tetrabenazine 25.0

CNS stimulants for ADHD Methylphenidate 5.0 Pemoline 18.7 Dextroamphetamine 5.0

Noradrenergic drugs for impulse control and ADHD

Clonidine 0.1 Guanfacine 1.0

Serotonergic drugs for OCD Fluoxetine 20.0 Clomipramine 25.0 Sertraline 50.0 Paroxetine 20.0 Fluvoxamine 50.0 Venlafaxine 25.0

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central nervous system stimulants are not well toler- ated or are contraindicated. Clonidine, a presynaptic a2-adrenergic agonist that is used as an antihyper- tensive drug because it decreases plasma norepineph- rine levels, reduces the symptoms of attention-deficit– hyperactivity disorder and impulse-control problems, and may also ameliorate tics. The drug is also avail- able in the form of a transdermal patch. Guanfacine is pharmacologically similar to clonidine and may be effective in patients in whom clonidine fails to con- trol behavioral symptoms.82 Guanfacine may have some advantages over clonidine in that it has a long- er half-life, appears to be less sedating, and produces less hypotension. Although less effective than meth- ylphenidate in controlling attention-deficit–hyperac- tivity disorder, the drugs have an advantage over meth- ylphenidate in that they do not increase the frequency or severity of tics.83 The most frequently encountered side effects of clonidine and guanfacine include se- dation, dry mouth, itchy eyes, dizziness, headaches, fatigability, and postural hypotension. Selegiline, a monoamine oxidase B inhibitor used primarily in the treatment of Parkinson’s disease, has also been found to be effective in controlling the symptoms of atten- tion-deficit–hyperactivity disorder without exacerbat- ing tics.84 Other drugs occasionally used in the treat- ment of mild cases of attention-deficit–hyperactivity disorder include tricyclic antidepressants, such as im- ipramine, nortriptyline, and desipramine. Because of potential cardiotoxicity, an electrocardiographic or car- diologic evaluation is recommended before the initi- ation of desipramine therapy, and follow-up electro- cardiography should be performed every three to six months.

Obsessive–Compulsive Disorder

The selective serotonin-reuptake inhibitors are clear- ly the most effective drugs in the treatment of obses- sive–compulsive disorder.85,86 These include fluoxetine, fluvoxamine, clomipramine, paroxetine, sertraline, ven- lafaxine, and citalopram. Although there have been no comparative trials, long-term clinical trials indicate that fluoxetine, sertraline, and fluvoxamine are among the best tolerated of the selective serotonin-reuptake inhibitors.85,87 In some cases that are refractory to treatment, selective serotonin-reuptake inhibitors may need to be combined with buspirone, clonazepam, lithium, and even neuroleptics.88 When a combina- tion of drugs is used, it is prudent practice to discuss with the patients potential adverse reactions, includ- ing the so-called serotonin syndrome (characterized by confusion, hypomania, agitation, myoclonus, hy- perreflexia, sweating, tremor, diarrhea, and fever), withdrawal phenomena, and possible extrapyramidal side effects.89 The selective serotonin-reuptake inhib- itors are effective not only in the treatment of obses- sive–compulsive disorder associated with Tourette’s syndrome but also in the management of associated

anxiety and social phobias.90 In patients with extreme- ly severe and disabling obsessive–compulsive disorder in whom optimal pharmacologic therapy has failed, psychosurgery — either limbic leucotomy or cingu- lotomy — may be considered as a last resort.91,92

CONCLUSIONS

The progress in research on Tourette’s syndrome has been extraordinary.93 Coupled with a growing recognition of the richness of the clinical phenome- nology of Tourette’s syndrome and related disorders and fueled by remarkable advances in the neurosci- ences, research promises to provide new insights into this complex neurobehavioral disorder. Since Tou- rette’s syndrome is considered a model disorder for the study of the interaction among the developmen- tal, neurobiologic, and behavioral systems, it is likely that these findings will enhance our understanding not only of Tourette’s syndrome but of many other neurologic and behavioral disorders as well.

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