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Tic Disorders in Childhood

Joseph M. Dooley, MB, BCh, FRCPC


Despite our familiarity with tic disorders, their management remains challenging. The difculty seldom relates to the diagnosis, which is usually based on the history, but rather in dealing with the impact of the tics and multiple comorbidities. The child and family must be educated and must be taught how to facilitate a positive attitude among others who come in contact with the patient. Knowledge and acceptance of the tics by other family members, peers, teachers, and coaches often become central to the childs well-being. Although many children can be managed without pharmacotherapy, medications are often central to achieving success. The goals of therapy and the appropriate choice of medication must be individualized. We are frequently challenged not only by the wide array of medication choices available but also by the decision of which symptom to treat rst. The tics, despite being amboyant, are often viewed by the child and family as less disabling than co-occurring conditions, such as attention-decit hyperactivity disorder, obsessivecompulsiveness, or rage. Even when tics are the major issue, patients must dene their goals for therapy. It is unreasonable to expect a complete resolution of tics and safety usually rules in favor of better tolerated but potentially less efcacious therapies. Developing strategies to minimize the lifelong impact of the multiple components of Tourette syndrome is an essential aspect of the care of these patients. Semin Pediatr Neurol 13:231-242 2006 Elsevier Inc. All rights reserved. KEYWORDS tourette, TS, tics, ADHD, obsessive-compulsive, rage

HE management of tics is integral to the practice of most pediatric neurologists and pediatricians. Overall, about 5% of school-aged children have tics and approximately 1% have Tourette syndrome (TS), although estimated prevalence rates vary from 4% to 19% for tics and 0.5% to 3.8% for TS.1-6 Within the ofce setting, one must initially conrm the presence of tics, which are dened as sudden rapid repetitive nonrhythmic stereotyped movements or sounds. Tics are fragments of normal movements or sounds but are inappropriate for the situation or context. They are most easily differentiated from other movement disorders by the patients ability to voluntarily inhibit them. Tics therefore are suppressible but irresistible. After establishing the presence of tics either through observation or history, one must next categorize them as transient, chronic, or TS, as this allows a more accurate prediction of the future. Reliance on a family history of tics is unreliable for predicting the subsequent course because all 3

disorders may coexist within a family, suggesting that they constitute components of a tic disorder spectrum.

Clinical Features
Most children present with a simple motor tic involving a single muscle in the head, face, neck, or arms. When seen at this stage, it is impossible to predict whether the tic will be transient or not. Transient tics usually begin between 3 and 10 years of age and wax and wane over a period of 4 weeks to 1 year. The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition Text Revision (DSM-IV-TR) criteria state that they must persist for less than 6 months (Table 1).7 In practice, however, some patients will have tics for up to a year with subsequent permanent resolution. As with all tics, transient tics are more common in boys. Over the subsequent weeks or months, other tics may emerge. Phonic tics are uncommon as transient tics, but when they do occur, they consist of any sound produced through the nose, throat, or mouth and do not necessarily involve the larynx. Therefore, the term vocal tic may be misleading. The evolution of the tics is variable and may include complex motor or phonic tics (Table 2). Complex phonic tics comprise syllables, words, phrases, or musical sounds. Cop231

From the Pediatric Neurology Division, Dalhousie University and IWK Health Centre, Halifax, Nova Scotia, Canada. Address reprint requests to Joseph M. Dooley, Pediatric Neurology Division, Dalhousie University and IWK Health Centre, 5850/5980 University Avenue, Halifax, Nova Scotia B3K 6R8, Canada. E-mail: jdooley@dal.ca

1071-9091/06/$-see front matter 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.spen.2006.09.004

232
Table 1 Diagnostic Criteria

J.M. Dooley

Diagnostic and Statistical Manual or Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR)34
Tourette syndrome (307.23) A. Both multiple motor and one or more vocal tics have been present at some time during the illness, although not necessarily concurrently B. The tics occur many times a day (usually in bouts) nearly every day or intermittently throughout a period of more than a year; and during this period there was never a tic-free period of more than 3 consecutive months C. Onset before age 18 years D. The disturbance is not due to the direct physiological effects of a substance (eg, stimulants) or a general medical condition (eg, Huntingtons chorea or postviral encephalitis) Chronic motor or vocal tic disorder (307.22) A. Single or multiple motor or vocal tics, but not both, have present at some time during the illness B. The tics occur many times a day, nearly every day, or intermittently throughout a period of more than 1 year; during this period there was never a tic-free period of more than 3 consecutive months C. Onset before age 18 years D. The disturbance is not due to the direct physiological effects of a substance (eg, stimulants) or a general medical condition (eg, Huntingtons chorea or postviral encephalitis) E. Criteria have never been met for Tourette disorder Transient tic disorder (307.21) A. Single or multiple motor or vocal tics B. The tics occur many times a day, nearly every day for at least 4 weeks, but for no longer than 12 consecutive months C. Onset before age 18 years D. The disturbance is not due to the direct physiological effects of a substance (eg, stimulants) or a general medical condition (eg, Huntingtons chorea or postviral encephalitis) E. Criteria have never been met for Tourette disorder or chronic motor or vocal tic disorder

rolalia (uttering obscenities) is the most celebrated phonic tic and reportedly occurs in 10% of patients with TS,8 although my experience would suggest that this is a much less common phenomenon in the pediatric population. A diagnosis of chronic tic disorder is made for those with either motor or phonic tics, but not both, which have persisted continuously or intermittently for more than a year (Table 1). The distribution of chronic tics is similar to those in transient tics and again motor tics are more common. As

Table 2 Common Motor and Vocal Tics Simple motor tics Eye blinking Eye rolling Eye opening Shoulder shrugging Head jerks/hair icking Mouth opening Arm extension Facial grimacing Licking lips Squinting Hopping Fist clenching Complex motor tics Touching Smelling Shaking Jumping Echopraxia Copropraxia Simple phonic tics Throat clearing Grunting Screaming Snifng Clicking Barking Snorting Coughing Spitting Squeaking Animal noises Complex phonic tics Humming Echolalia Whistling Singing Palilalia

with TS, chronic tics may be associated with comorbid attention-decit hyperactivity disorder (ADHD). If both motor and phonic tics have persisted for more than a year, a diagnosis of TS is appropriate. Characteristically, the tics uctuate in type, frequency, severity, and location over time (Table 1). Boys are affected up to 5 times more frequently and tend to have an earlier onset of tics than girls.9 The median age of onset of tics is usually between 5 and 6 years of age,10 with a peak in severity between 10 and 12 years of age and subsequent gradual improvement in the later teenage years. The initial tics usually involve the face and neck. The commonest tics are outlined in Table 2, but virtually any voluntary movement can occur as a tic. Within bouts of tics, there are usually clusters of increased severity that can last from seconds to minutes. There are innumerable stimuli that can act as tic precipitants or exacerbators. These vary from one patient to the next but are often constant within an individual. Patients may report a predictable tic response to specic sounds or voices or in response to seeing specic patterns.11 For example, some children will have a tic in response to a particular action or comment by their teacher. They are typically aggravated by stress, tiredness, or boredom and are often more prominent while watching television. They can be suppressed for a brief period, and some children manage to hide their tics throughout the school day. In my experience, such suppression is usually followed by the release of the tic buildup, although studies have failed to conrm this rebound phenomenon.12,13 Complex phonic tics almost never occur without coexisting motor and simple phonic tics. Complex motor tics may be difcult to distinguish from obsessive-compulsive behav-

Tic disorders
iors (OCBs) when they involve stereotyped actions such as brushing the hair or tapping something a specic number of times. OCB is usually performed to prevent anxiety. In contrast, tics are often done in response to sensory tics or premonitory urges, which reportedly occur in 90% of adults11,14 and 37% of children.15 Within the pediatric population, these sensory urges are more readily recognized by adolescents than by younger children10 and are seldom present within the rst 3 years after tic onset.10 Patients often nd it difcult to describe the urges, although they appear to represent an inner buildup of tension that becomes extremely distracting and uncomfortable until temporarily relieved by expressing the tic. Urges may be specically localized to the shoulders, throat, hands, anterior abdomen, or thighs. They may be perceived by the patients as more problematic than the tics, which might be considered as voluntary movements to appease the urges. Many patients describe a constant internal battle to control these urges, which may have a compulsive component because the tics may need to be repeated until they feel just right and the sensory urge is satised. More simple tics, such as blinking, are not associated with a premonitory urge.11 The impact on the childs life usually reects not only the number, frequency, intensity, and complexity of the tics but also their social impact. Thus, an infrequent tic that involves a socially unacceptable act, such as touching the groin, may be much more disabling than a frequent head twitch. Echo phenomena can also be troublesome. Echolalia (copying the words or sounds of others) and echopraxia (imitating the actions of others) occur in 11% to 44% of patients.9 Palilalia (repeating ones own last syllable, word, or phrase) occurs in 6% to 15%.9 Copropraxia (making obscene gestures) is said to occur in 1% to 2% of patients attending TS clinics but is rare in the general pediatric TS population.
Table 3 Common Obsessive-Compulsive Symptoms Arranging things Placing things in right place Rechecking things Touching things/touching with second hand Touching objects just right Touching exact number of times Dressing perfectly Pulling up socks Fiddling with objects or clothes Erasing mistakes Washing hands

233

Hoarding Sending Eating Talking Smelling things (eg, food) Washing food before eating Sexually touching Pulling hair out Cracking knuckles Nail biting Echolalia-echopraxia

second opinion for a patient with ADHD, comorbid TS or OCB have been previously overlooked.

OCBs
As symptoms are often insufciently severe to warrant a diagnosis of OCD, the designation of OCBs is frequently more appropriate. OCD affects approximately 2% of the general population, but among patients with TS about 50% have OCB (range, 13%-66%) and one third have obsessive-compulsive disorder (OCD).9,18 Similarly, approximately 30% of patients with OCD will have tics, and about 10% will meet criteria for TS.18 The presence of OCB and tics seems to be associated with increased tic severity,19 an earlier onset, and differences in characteristics of OCB.18 Those with tics are more likely to have violent, religious, and sexual content to their obsessive thoughts. Hoarding, checking, and counting are more common as are a need for symmetry and for things to be just right. Patients often report a need to touch, rub, or smell objects. When smelling is a compulsion, I nd that smelling food before it is eaten is most prominent. Common OCBs are presented in Table 3. OCB can result in danger to the patient, as in the compulsion to touch objects, such as a hot stove or iron. Most children with this compulsion do not feel a need to touch the stove or iron when they are cold. Other self-injurious behavior can result in signicant injury, such as bilateral retinal detachment.20 A genetic susceptibility is likely because the rst-degree relatives of those with tics are more likely to have OCD and rst-degree relatives of those with OCD are more likely to have tics. Patients with a parent who has OCD tend to have a later onset of tics, which also tend to be more complex.21 To date, molecular genetic studies have failed to reveal consistent associations, and environmental factors are also important in the expression of OCD. These include perinatal difculties, exposure to caffeine, nicotine or alcohol in utero, and stressful life events.18 When assessing children with TS, it is important to be aware that the parent may have OCB. Helping a mother whose obsessional anxiety is focused on her childs tics can be demanding and challenging.

Comorbid Conditions
The appropriate care of children with tics often requires the major focus to be directed to dealing with the multitude of cooccurring conditions, rather than on the tics. Among children and adolescents referred because of TS, 50% to 90% have comorbid ADHD, conduct disorder, or oppositional deant disorder.16

ADHD
ADHD occurs in approximately 50% of patients with TS, with a range of 21% to 90%.17 The presence of ADHD in patients with TS is associated with increased psychosocial problems, disruptive behavior, functional impairment and school-related problems.17 Children with TS alone do not tend to differ from control populations, whereas those with TS and ADHD are more likely to have aggression and delinquency.16 It is therefore mandatory to address the possibility of ADHD in all children seen because of tics. Similarly, those referred because of ADHD should be questioned about the presence of tics. I frequently nd that, when asked to offer a

Site Sensitization
Leckman22 has used the term site sensitization to describe the remarkable awareness and intolerance that many of these

234 patients have to particular sensory stimuli. In my experience, the most common of these phenomena is the distraction and distress that many patients experience from the tags and labels on clothing. Many parents report that they must remove the labels from underwear and T-shirts before their child can wear them.

J.M. Dooley
between TS and PDD can be difcult. A child who has social difculties, obsessive and compulsive behaviors, and learning difculties may well meet criteria for PDD. If tics are added, then a diagnosis of TS is made. Understanding the relationship between these 2 disorders will await further knowledge of their etiology and pathogenesis.

Oppositional Deant Disorder and Conduct Disorder


Both oppositional deant disorder and conduct disorder are more common in children with TS, although at least some of this association is related to the co-occurrence of ADHD, and both may be less prevalent in those with TS without ADHD.6 Patients with TS are more likely to engage in socially inappropriate behaviors, such as arguing or insulting others, thus aggravating their social isolation.6

Anxiety Disorders
Anxiety disorders are also more common in TS, including separation anxiety, panic, and agoraphobia.27 The association with anxiety may be multifactorial, reecting the presence of a socially debilitating chronic condition (TS) or even the effects of medication, such as haloperidol.

Sleep-Related Problems
Sleep-related problems are reported in 20% to 50% of children with TS.17 These include problems falling asleep, staying asleep, and parasomnias. These difculties may also be related to ADHD or obsessive thoughts.

Episodic Rage
Anger may be associated with both ADHD, oppositional deant disorder, and conduct disorder,5 but other patients have episodic rage unassociated with these phenomena, which can be extremely prominent and troublesome. The rage episodes tend to occur with minimal provocation and can lead to alarmingly aggressive and violent outbursts. Families often report that rage is considerably more disruptive than tics.23 Many families live as hostages to the possibility of a rage outburst, which prevents them from bringing their children to social events or restaurants.

Etiology
The etiology of TS and tics in general remains unclear. Genetic factors are clearly implicated, although the search for the gene has been unrewarding. In 2005, an individual with TS and a chromosome inversion at 13q31.1 to 31.3 was identied.28 Subsequent screening identied a frameshift mutation was due to a single-base deletion in SLITRK1. This nding indicates that a single gene defect may account for some patients with tics. For most, however, TS is probably polygenic. Penetrance is almost complete in males when only TS and chronic tic disorder are included compared with 56% for females. If obsessive-compulsiveness is included, penetrance rises to 70% for females. The likelihood of both parents having tics is 6% to 15%, but when other TS-related features (such as OCB, ADHD, panic attacks, and substance abuse) are included, the risk is increased to 26% to 41%.17 Genetic factors alone are insufcient to explain the etiology of TS, and environmental factors must also be important. A relationship with pre- and perinatal difculties9; head injury26; and infections with varicella, herpes simplex, HIV, mycoplasma pneumoniae, and Lyme disease26 have all been described. A connection with a streptococcal infection has been the subject of considerable debate. Obsessive-compulsiveness is noted in as many as 70% of patients with Sydenham chorea but is rare in patients with rheumatic fever who do not have chorea.29,30 This observation of obsessive-compulsiveness and a movement disorder in apparent association with streptococcal infection led to the hypothesis that some patients with tics might also have a streptococcal induced autoimmune phenomenon. The current criteria for diagnosing pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS) are (1) presence of OCD and/or tic disorder, (2) prepubertal age of onset, (3) sudden acute onset of symptoms and an episodic course with exacerbations and remissions, (4) a temporal association

Depression
Depression is also more prevalent6 and is associated with the duration of TS.9 Depression may be partly related to the presence of OCD, an association that is well recognized.24 It may also be caused by the difculty of living with TS and its chronic socially stigmatizing implications, genetically related causes, or as an adverse effect of medication.

Learning Difculties
Learning difculties occur in almost 25% of children with TS,25 and many children will require detailed neuropsychological testing. Learning difculties may be secondary to tics themselves or to co-occurring ADHD, OCB, or as a side effect of medications. Those with tics, such as a head ick, may nd themselves constantly struggling to refocus on where they were on a work page before the tic interrupted. Similarly, patients with a compulsion to read every page 3 times or to repeat certain words until they sound just right will quickly fall behind in their work. Patients may be distracted from their schoolwork by their constant struggle to suppress their tics. Some children have specic learning disabilities that may affect written expression, reading comprehension, and especially math.

Pervasive Developmental Disorders


Pervasive developmental disorders (PDDs) are reported in 12.5% of patients with tics.26 Many children in my practice with TS have siblings with typical PDD. The differentiation

Tic disorders
between onset and exacerbations and group A streptococcus with either a positive throat culture or a history of scarlet fever, and (5) evidence of concurrent motoric neurologic abnormalities such as chorea during exacerbations.29 These criteria are arbitrary and continue to be a source of debate. Diagnosing streptococcal infection can be difcult. Those who favor the existence of PANDAS point out that elevated antistreptolysin O titers have been described in 38% of 150 children with tics compared with only 2% of 150 controls.31 Similarly, exacerbations in tic severity have been occasionally associated with rises in streptococcal titers.29 These associations do not, however, prove causation, and a number of studies have failed to conrm the association.32-34 To date, there is no denitive evidence of an autoimmune process in patients with TS.35 Of particular importance, there is no evidence that these children should be investigated and treated any differently than other children with TS, with the exception of treating active streptococcal infection.36 Further studies will be needed to establish whether it is indeed an autoimmune phenomenon or whether PANDAS, rheumatic fever, OCD, and TS share a genetic susceptibility as risk factors for other conditions.18 Tics have also been associated with a number of drugs and toxins. Medications that have been implicated include antiseizure drugs (carbamazepine, phenytoin, lamotrigine, and phenobarbitol),37 stimulants (methylphenidate, dextroamphetamine, amphetamines, and pemoline), cocaine, heroin, dopamine-blocking agents, and levodopa. Implicated toxins include carbon monoxide, wasp venom, and mercury.26

235 and are associated with an increased rate during rapid eye movement sleep.40 Most parents have some information on tics and TS, although the accuracy is often dismal and is based on television depictions of TS and neighborhood lore. Families are often aware of some but not all tics. Thus, they may report blinking, grimacing, and throat clearing as tics but perceive sniffing as an allergic symptom. It is often helpful to share a list of common tics with the family because this helps them identify tics that they may have previously regarded as idiosyncratic irritants. During the consultation, remember that tics may be suggestible, and discussion of previous tics may result in their subsequent reemergence. Younger children may be unaware of their tics. In 1 family study, 21% of reportedly unaffected children had tics.41 It is important to arm even these children with an explanation for their peers who ask why they blink, grimace, and so on. I advise them to explain their movements or sounds as habits or because they have TS. Young peers are often less assured if told that the child has tics, which they misinterpret as ticks (cooties). Most youngsters are satised once they are given some reason for the apparently bizarre behaviors. A neurologic examination is important to rule out other abnormalities but is inevitably normal.42 Some physicians recommend measuring thyroid function, although I am unaware of evidence that patients with thyroid disease can present with tics without other symptoms and signs. Other tests are of little value. Magnetic resonance imaging, functional MRI, and magnetic resonance spectroscopy have all provided interesting research ndings but do not have a role at this time in the management of patients with tics. Similarly, EEG is not indicated. When tics begin beyond the typical pediatric age range, other conditions such as Huntington disease, neuroacanthocytosis, Hallervorden-Spatz disease, and strokes involving the basal ganglia must be considered.26 The differentiation between PDD, especially Asperger syndrome, and TS can be difcult. Both conditions are associated with attention problems, obsessive compulsiveness, and disinhibition. Asperger syndrome can be associated with stereotypies, which can be difcult to distinguish from tics. Numerous other conditions have been described to occur with tics. These include Down syndrome, Duchenne muscular dystrophy, tuberous sclerosis, and Beckwith-Wiedermann syndrome.26 Many of these associations are probably serendipitous, and it is unlikely that they shed light on the pathogenesis of TS. The diagnosis must also focus on comorbid conditions. Occasionally, tics appear to be of psychogenic origin. Distinguishing these movements from coexisting more typical TS will be essential to appropriate management.43

Diagnosis
Many families present with a history of prior visits to an optometrist because of frequent blinking. This is often followed by an ear, nose, and throat consultation for repeated coughing and an assessment by an allergist for snifng. A few children arrive with buzz cuts after seeing an enthusiastic hair dresser because of a head twitch, which the parents thought would resolve if their sons hair was shorter. Finally, the patient sees you. If witnessed within the ofce setting, tics are seldom difcult to diagnose. More commonly, tics are suppressed throughout the consultation, and the diagnosis is therefore dependent on the history from the child and family. The diagnosis for each of the tic disorders is currently based on the criteria proposed by the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (Table 1).7 Somewhat different criteria are offered by the International Classication of Disease and Related Health Problems, 10th Revision38 and in the Classication of Tic Disorders by the Tourette Syndrome Classication Group.39 Distinguishing tics from other movement disorders is usually uncomplicated. Tics can both coexist with dystonia and at times can be difcult to differentiate from dystonia when the movement is maintained.26 Even these children usually have a history of more typical tics. Myoclonus can usually be differentiated because it cannot be suppressed and is not preceded by sensory symptoms. Tics also persist during sleep

Treatment
Historically, the focus of treatment in TS has centered on pharmacotherapy. As the full spectrum of tic disorders has been recognized, it is clear that patients with transient tics or those with mild chronic tics or TS merely require reassurance, counseling on the condition, and information on the prognosis.

236 Armed with such information, parents and patients can subsequently educate school personnel and others who come in contact with their child. Helpful websites include the Tourette Syndrome Association (www.tsa-usa.org) or the Tourette Syndrome Foundation of Canada (www.tourette.ca). It is always essential to establish if there are comorbidities, which may be of greater signicance to the patient and family than the tics.23 Details of the full spectrum of the disorder are often not revealed at the rst visit but become an evolving story as the patient builds trust with the physician. When addressing the impact of tics on the family, it is important to discover how the parents deal with the tics. Some parents punish their child for ticcing, whereas others are embarrassed by the tics and therefore avoid bringing their child to social functions. Parents often feel stressed by their childs tics. Although such family turmoil is important to identify and treat, it should never be a reason to medicate the child. Parents and school personnel should be encouraged to identify and focus on the childs strengths. Frequently, all emphasis is placed on the TS symptoms with resultant detrimental effects on the childs self-esteem. There is increasing interest in nonpharmacological approaches to the management of tics. Preliminary evidence supports techniques, such as habit reversal training, as effective interventions.44,45 Habit reversal training consists of 5 components: (1) awareness training, (2) competing response training, (3) contingency management, (4) relaxation training, and (5) generalization training. An example of a competing response for a vocal tic would be slow rhythmic nasal breathing. Other behavioral approaches have not been systematically evaluated, although there is some preliminary evidence to suggest that self-monitoring and relaxation training may be of benet for some children.46 The decision to introduce medication is dependent on the impact of symptoms on the childs quality of life. Before the introduction of medication, it is helpful for patients and their families to have the opportunity to talk to other patients. This can sometimes be done through the local TS association. TS is frequently associated with a sense of isolation and uniqueness, and nding others with almost identical issues can be cathartic.

J.M. Dooley
When medication is initiated, every attempt should be made to use low-dose monotherapy, although this is often impossible as one manages not only tics but comorbid ADHD, OCB, or rage. Families should identify the symptom that is most disruptive to the patient, and therapy should be directed toward alleviating this symptom rst. For many families, this results in therapy of the ADHD or rage symptoms rather than the tics.23 In choosing a medication, families need to be aware that almost all have potential serious side effects and none work quickly. Several classes of medication have been shown to be useful in treating tics (Fig. 1). The various currently used medications are outlined in Table 4, along with suggested initial and maintenance doses.

Medications for Tics


Alpha-2-Adrenergic Agonists
Clonidine is frequently considered the medication of rst choice for the treatment of tics because of its low incidence of side effects and because it can also be of benet in ameliorating comorbid ADHD. Clonidine is effective in about 50% of patients47 and has been shown to be as effective as risperidone in treating tics.48 The only common side effect is sedation, which is usually well tolerated. Despite initial concerns, it does not appear to have an effect on the electrocardiogram.49 The use of a clonidine weekly patch has been complicated by hypersensitivity reactions. Guanfacine may be superior to clonidine because it has less sedating effects and has a longer duration of action.45 It may, however, cause syncope. Another -2 adrenergic agonist, lofexidine, may also have benet for both tics and ADHD.

Dopamine (D2) Receptor Antagonists


When the -2 adrenergic agonists are unsuccessful in managing tics, treatment with D2 antagonists should be considered. Haloperidol has been recognized as effective in the treatment of tics for the last 45 years.50,51 Controlled studies have shown many neuroleptics, including haloperidol, pimozide, risperidone, ziprasidone, and olanzepine, to be effective in treating tics.45 Side effects include weight gain, sedation, anxiety, and extrapyramidal movements. Tardive dyskinesia has been described as a side effect to neuroleptics in patients with TS,52-54 with an overall risk in the range of 1% to 5% for children and adolescents.55 Both haloperidol and pimozide are effective in about 70% of cases, but overall pimozide may have slightly fewer adverse effects, although it can cause cardiac arrhythmias.56 Suggested doses are outlined in Table 4. Haloperidol saturates 80% of D2 receptors at a dose of about 2 mg/d,47 and increasing the dose beyond those suggested in the table is unlikely to provide benet. Among the atypical neuroleptics, risperidone seems safe for short-term tic treatment. It is better tolerated than haloperidol and has been shown to be superior to pimozide for treatment of tics. Its major adverse effect is weight gain, which can be substantial.45 It may also cause sedation and elevated prolactin levels, but it appears to be associated with

Pharmacotherapy
Despite the prevalence of patients with tics in our practices, there are few guidelines on when to initiate treatment and which treatments to use. It is important for the patient, family, and physician to understand the childs tic pattern because the waxing and waning in some children can allow prediction of when the tics are likely to improve spontaneously. If therapy is started at these times, it can be difcult to differentiate the response to medication from the natural history of the disorder. For most children, the tics are most severe between the ages of 10 and 12, and it may be worth considering a trial of medication during this period.16 Families must be aware that the treatments are purely symptomatic and do not affect the long-term prognosis.

Tic disorders
Table 4 Medications for Tics Medication (Generic) Haloperidol Brand Name Haldol Starting Daily Dose 0.25 to 0.5 mg Usual Maintenance Dose 1 to 5 mg/d

237

Common Side Effects Fatigue, weight gain, rigidity, tardive dyskinesia, phobias, cognitive slowing, depression Same as for haloperidol, EKG prolonged QTc interval Weight gain, as for haloperidol Somnolence, as for haloperidol Same as for risperidone Irritability, fatigue, hypotension, sleep problems Sedation, dizziness, headache, hypotension, dry mouth, Same as for haloperidol Irritability, fatigue, disinhibition, dizziness Depression, parkinsonism, akathesia

Pimozide

Orap

0.5 to 1 mg

1 to 10 mg/d

Risperidone Ziprasidone Olanzepine Guanfacine

Risperdal Geodon Zyprexa Tenex

0.25 mg 5 mg 1.25 mg 0.25 to 0.5 mg

1 to 3 mg/d 5 to 40 mg/d 1.25 to 2.5 mg/d 0.5 to 3 mg/d

Clonidine

Catapres Dixarit

0.025 to 0.05 mg

0.1 to 0.5 mg/d

Fluphenazine Clonazepam Tetrabenazine

Prolixin Klonopin Rivotril Nitoman or Xenazine

0.25 to 1 mg 0.025 to 0.5 mg 12.5 mg

0.5 to 6 mg/d 0.5 to 3 mg/d 25 to 150 mg

tardive dyskinesia only at doses above 6 mg/d.45,57 All of the newer atypical neuroleptics are potentially associated with diabetes mellitus.45 Clozapine has not been shown to have benet in controlled trials and may aggravate OCB or increase tics and stuttering.45 Although it does not cause tardive dyskinesia, it may cause agranulocytosis. Metoclopramide has been shown to be effective and may be better tolerated than the other neuroleptics.58 Ziprasidone has also been shown to be effective in a small number of children and has the advantage of not inducing tardive dyskinesia. Further data are needed to establish its long-term safety and value in treating tics. It is known to potentially prolong the QTc interval.59 Olanzepine seems to be better than pimozide and appears well tolerated, but like risperidone, it may cause signicant weight gain.45 It has been shown to alter cholesterol and triglyceride levels.45 Quetiapine seems to have benet but has not been subjected to controlled trials.

Benzodiazepines
Clonazepam, and possibly other benzodiazepines, may be of benet, although they seem to be less effective than the other medications discussed. The side effects may be less well tolerated in those with coexisting ADHD. I restrict their use to acute situations where emergency intervention is required.

Other Pharmacotherapies
Ondansetron, a selective 5-HT3 receptor antagonist, may be of benet.62 Nicotine patches were popular in the past but seldom offered benet and have fallen out of favor. Mecamylamine is a nicotine antagonist, which has not been proven to have benet. Among the calcium channel blockers, both verapamil and nifedipine appear effective although further trials are needed. -9 tetrahydrocannabinol, the most active component of cannabis, reportedly reduces tics and may improve aggression in patients with TS without signicant adverse effects or impairment on neuropsychological testing.63,64 Botulinum toxin may be helpful in patients in whom tics are limited to a few restricted muscles. Other medications that have been suggested to be of benet include leviteracetam,65 aripiprazole,66 amisulpride,67 and celecoxib.68

Dopamine Receptor Agonists


Early data suggest that both pergolide and ropirinol may be helpful in managing tics.45,60 Their effect is probably because of presynaptic inhibition at low doses. Side effects include dyskinesia, nausea, dizziness, and somnolence.

Presynaptic Dopamine Depletion


Tetrabenazine is effective for treating tics, and although it does not cause tardive dyskinesia, it may cause depression and parkinsonism.45,61

Medications for ADHD


The treatment of comorbid ADHD in children with TS has been a source of emotional debate. More recent evidence

238
Table 5 Medications for OCB Starting Dose Medication (Generic) Fluoxetine Brand Name Prozac Preadolescent 2.5 to 10 mg Adolescent 10 to 20 mg Daily Dose 5 to 80 mg

J.M. Dooley

Adverse Dffects Insomnia, GI upset, sexual dysfunction, restlessness As for uoxetine As for uoxetine As for uoxetine Somnolence or insomnia, GI upset, dry mouth, sexual dysfunction Fatigue, constipation, dry mouth, blurred vision, weight gain, EKG changes

Sertraline Paroxetine Fluvoxamine Citalopram

Zoloft Paxil Luvox Celexa

12.5 to 25 mg 2.5 to 10 mg 12.5 to 25 mg 2.5 to 10 mg

25 10 25 10

to 50 mg mg to 50 mg to 20 mg

50 10 50 10

to to to to

200 mg 50 mg 300 mg 60 mg

Clomipramine

Anafranil

12.5 mg

25 mg

50 to 200 mg

GI gastrointestinal.

suggests that although some children may experience an exacerbation of their tics, this is an uncommon phenomenon.69 Children who require intervention for ADHD should be treated as outlined by Wolraich in this issue of Seminars in Pediatric Neurology. There is evidence, however, that the combination of methylphenidate and clonidine is superior to either medication alone.70 Atomoxetine, a selective norepinephrine reuptake inhibitor, seems effective for both ADHD and possibly tics.71

atypical neuroleptics to an SSRI may enhance the effectiveness.18

Treatment for Other Co-occurring Conditions


Anxiety
The treatment of other anxiety disorders, such as separation anxiety, is probably also best achieved with an SSRI, with the concomitant use of clonazepam for acute situations. Behavior therapy, such as relaxation, should also be considered.

Medication for OCD/OCB


When obsessive compulsive symptoms require intervention, the rst choice is usually a selective serotonin reuptake inhibitor (SSRI). Medications that have shown efcacy in children include uoxetine, uvoxamine, sertraline, and paroxetine.27 Currently, only uvoxamine, sertraline, and uoxetine are approved by the Food and Drug Administration for the treatment of OCD in children.72 A trial of up to 3 months is needed before deciding that an SSRI is ineffective. Side effects include agitation, gastrointestinal upset, and akathesia. There is a slightly increased suicidal risk especially in those with depression. The risk appears to be about 4% compared with 2% on placebo and is highest during the rst 12 weeks of therapy. Older medications, such as clomipramine, are also effective but may be associated with more side effects, including mouth dryness, weight gain, constipation, and prolongation of the QTc interval. Suggested doses are outlined in Table 5. In a randomized control trial, the combination of sertraline and behavior therapy was more effective than either medication or behavior therapy alone.73 Approximately one third of patients will not respond to SSRI therapy, and there is some evidence that the addition of one of the

Rage
Aggression is common in patients with TS, and 25% to 70% reportedly have difculties with anger control and emotional lability.74 When rage occurs in the context of a child with both TS and ADHD, a trial of stimulants, with or without clonidine, is worthwhile as the initial intervention. If this is unsuccessful, a trial of other therapy is necessary. Most of the medications used have not been subjected to double-blind controlled trials, and therefore much of the available evidence is anecdotal. Medications that have been shown in open-label studies to be of help include citalopram, paroxetine, and trazadone. There is evidence from placebo-controlled trials in favor of mood-stabilizing drugs, such as valproate, carbamazepine, and lithium.74 Most physicians who treat children with TS have found that the atypical neuroleptics are most effective in this setting. The most commonly used in this group are risperidone, ziprasidone, olanzepine, and clozapine. As noted earlier, the use of atypical neuroleptics can be associated with weight gain, sedation, elevated prolactin levels, and extrapyramidal side effects. Risperidone has been shown to be more effective than placebo and has

Tic disorders

239

Medication Choices

Tics

ADHD

OCB

Rage

Clonidine

Stimulants

SSSRI

Stimulant

Dopamine antagonists

Atomoxetine

Clomipramine

Atypical neuroleptic

Tetrabenazine

Clonidine

SSRI + Atypical neuroleptic

Dopamine agonist

Tricyclic antidepressants
Figure 1 Treatment approach for patients with TS.

fewer side effects than older dopamine antagonists.75 The treatment of other comorbid psychiatric conditions, such as bipolar disorder, are better cared for by a pediatric psychiatrist and should be referred to the appropriate clinic.

Neurosurgery
Neurosurgical intervention is possibly the most intriguing potential new therapy. Deep brain stimulation of the anterior limb of the internal capsule has been used to treat OCD.76 Bilateral stimulation of the midline and intralaminar thalamic nuclei and globus pallidus interna have shown promising early results,76,77 although the place of these interventions in the management of TS remains to be claried. Other surgical interventions with reported benet include unilateral pallidotomy78 and bilateral anterior capsulotomy.79

year.80 Unfortunately, there are no controlled trials on their efcacy in TS. Patients perceive their use of such therapies as contrary to mainstream medicine and therefore seldom conde in their doctor.80 A nonjudgmental approach is most likely to be successful while offering to advise if what they are using is safe. Although many of these therapies are safe, they are frequently ineffective and costly. It is important for families to be aware that in most jurisdictions herbal medicines do not have to provide safety data before going to market. Knowledge of alternate therapies can be very important. For example, medications that are metabolized by cytochrome P450 3A4 or the P-glycoprotein transmembrane pump may interact with St. Johns wort.81

Prognosis
Most parents want predictions of the future for their child. This, however, is one of the more challenging aspects of caring for the child with TS. Although tics may improve with time, the persistence of comorbid symptoms can have a detrimental effect on quality of life.

Alternative Therapies
There is a general acceptance among many patients that natural therapies are preferable to pharmacotherapy. A recent study in a general pediatric clinic found that 30% had used complementary and alternative medicine in the previous

240 Interpreting the literature on the persistence of tics in adults is complicated by the methods used to determine whether tics have indeed resolved. In 1 study, video assessment showed that 90% still had tics as adults, although many felt they were tic free.82 Increased tics during the initial stages of TS suggest increased tic severity later in the course,83 although other reports have failed to nd this association. Goetz and coworkers84 found that 75% had mild symptoms as adults despite moderate to severe symptoms in childhood. In a follow-up study of 58 patients aged 15 to 25 years, 26% had experienced a resolution of their tics, there was a substantial diminishment in 46%, 14% were stable, and only 14% had had an increase in tics.85 In a recent report, 85% reported a decrease in tics during adolescence.83 In general, one can offer the following prediction: one third will experience a resolution of their symptoms, one third will have an improvement in their tics, and the remaining one third will have ongoing symptoms.86 Tics alone, however, may not predict the childs wellbeing. Referral to a mental health specialist is much more likely for children with tics. Hornsey and coworkers5 reported that 26% of those with tics had been referred to a mental health specialist compared with 11% of those without tics. We found that children with mild to moderate tics can also be withdrawn, aggressive, and less popular.87 Quality of life measures have shown more difculties in patients with TS than in the general population. When assessed in the third decade of life, almost 20% of those diagnosed with TS in childhood were moderately impaired or worse.10 Outcome was associated, not only with the severity of tics both in adulthood and childhood but also with obsessive compulsiveness and ADHD in childhood.10 At present, there is no denitive way of predicting the future for an individual patient and the most severe tics may have their onset in adulthood.21 The management of children with tics has, however, seen signicant advances. Our understanding of the pathogenesis of TS, although still far from complete, has seen considerable advances. Similarly, the available therapeutic options have hugely expanded, although the ideal medication remains elusive. Possibly most importantly, societal attitudes have changed as a result of public education endeavors. This acceptance of TS as a neurologic condition has enhanced the lives of patients and has allowed them to become more readily accepted. For pediatric neurologists, recognizing that TS consists of more than tics and twitches has allowed us to focus on comorbid conditions and their management. Although polypharmacy is generally discouraged in medicine, it can have a valuable role in managing the multiple difculties experienced by these patients. It is our responsibility to acquire expertise in the use of the various medication choices. The future is brighter now than ever before for those with TS. We continue to have an important role to play in further enhancing the quality of life of these patients.

J.M. Dooley
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31. 32.

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41.

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49.

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