Tourette's syndrome: from behaviour to biology

Review

Tourette’s syndrome: from behaviour to biology Harvey S Singer

Lancet Neurol 2005; 4: 149–59

Tourette’s syndrome (TS) is a chronic neuropsychiatric disorder characterised by motor and vocal tics. Diagnosis is based solely on clinical criteria. The prevalence of this syndrome is estimated to be between one and ten per 1000 children and adolescents and the outcome is generally favourable; most patients improve by their late teens or early adulthood. Affected individuals are at increased risk of various comorbid neurobehavioural problems, the negative effects of which commonly exceed those of tics. Despite evidence that TS is an inherited disorder, the exact genetic abnormality is unknown. Environmental factors might have an important role in the expression of tics, and a poststreptococcal autoimmune cause has been proposed but is unproven. Brain imaging, neurophysiological, and post-mortem studies support involvement of cortical–striatal–thalamocortical pathways, but the definitive pathophysiological mechanism or neurotransmitter abnormality is unknown. Recent evidence, however, suggests a prefrontal dopaminergic abnormality. Traditional neuroleptics are the standard treatment for TS, but there is increasing interest in non-neuroleptic drugs, behavioural therapies, and surgical approaches. In 1885, the French physician Georges Gilles de la Tourette reported nine patients with chronic tic disorders characterised by involuntary motor and phonic tics. One case in this report was the Marquise de Dampierre, a French noblewoman who had persistent body tics, barking sounds, and uncontrollable utterances of obscenities, which had been previously described by Itard. In retrospect, it has been speculated that several notable historic figures, including the Roman Emperor Claudius, Wolfgang Amadeus Mozart, and Dr Samuel Johnson (the prominent 18th century literary figure), were afflicted with this syndrome. Tourette reportedly became interested in patients expressing peculiar sounds and movements after learning about the “jumping Frenchmen of Maine”, a cohort of people with perceptible startle reactions and echolalia.1,2 Although some of the clinical characteristics described in early reports are valid, many diagnostic features have been redefined and coexisting problems clarified. Similarly, suggestions that this was a rare disorder of psychogenic origin have been replaced by evidence suggesting a common disorder of genetic cause with neurotransmitter abnormalities. In this review I aim to provide the reader with a comprehensive update on Tourette’s syndrome (TS).

Description and diagnostic features Tics, the hallmark of TS, are easily observed but broadly defined (involuntary, sudden, rapid, repetitive, nonrhythmic, stereotyped) movements or vocalisations (phonic productions). Tics have different degrees of severity and duration, and no two patients have the same course. Simple motor tics are brief rapid movements that typically involve only one muscle group—eg, eye blink, head jerk, shoulder shrug. Complex motor tics are abrupt movements that involve either a cluster of simple movements or a more coordinated sequence of movements; they serve no purpose (eg, facial or body contortions), even when they seem to be purposeful (eg, touching, hitting, smelling, jumping, or obscene gestures), and can have a dystonic character. Simple http://neurology.thelancet.com Vol 4 March 2005

Department of Neurology and Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA (H S Singer MD) Correspondence to: Dr Harvey S Singer, Division of Pediatric Neurology, Johns Hopkins Hospital, 124 Jefferson Building, Baltimore, MD 21287-1000, USA [email protected]

vocal tics include sounds and noises such as grunting, barking, yelping, sniffing, and throat clearing. Complex vocalisations include syllables, phrases, echolalia (repetition of other people’s words), palilalia (repetition of one’s own words), or coprolalia (uttering of obscene words). Coprolalia, one of the most distressing and recognisable symptoms, occurs in only about 10% of patients.3

Characteristics of tics Tics are commonly exacerbated during periods of anticipation, emotional upset (eg, anxiety, excitement, anger), or fatigue;4,5 they tend to subside when the person is absorbed in activities, concentrating, pleased, or asleep. Although a diminution or complete absence of tics is typical during sleep, polysomnograms of people with TS have shown an increased rate of tics during REM sleep.6 In many patients, active suppression of tics is associated with a build-up of inner tension that resolves when the tic happens. Tics can be exacerbated during inquiries about specific movements or after the observation of a movement or sound (echophenomena). A premonitory sensation can precede tics. Premonitory sensations are sensory events, commonly an urge, impulse, tension, pressure, itch, or tingles that take place before a motor or phonic tic. Many of these sensations are localised to discrete anatomical regions.7 In people with tics, premonitory sensations occur in more than 90% of adults7,8 and 37% of young children.9 The recognition that tics may be a voluntary response to an involuntary sensation, has led some investigators to classify tics as “unvoluntary” rather than involuntary. The course of TS fluctuates but the environmental or biological factor that causes tics to wax and wane is unknown. Psychosocial stress and adversities have been implicated, because both are prominent in children with TS,10 but additional studies are needed to assess their possible role in the exacerbation of the disorder. In most patients, changes in tics are not accounted for by small stressful life events11 or by newly acquired streptococcal infections.12 The recurrent (“burst-like”) bouts of motor 149

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TS*

Tourette disorder‡

Onset Motor tics Vocal tics Course Duration Tic-free intervals Drugs

By age 21 years Multiple At least one Gradual; wax and wane More than 1 year ·· Not due to use of tic-provoking substancessubstances (eg, stimulants) Medical disorders Not associated with other disorders (eg, Huntington’s chorea, postviral encephalitis) Witnessed Tics observed by a knowledgeable individual

By age 18 years Multiple At least one Gradual; wax and wane More than 1 year Not more than 3 consecutive months Not due to use of tic-provoking substances substances (eg, stimulants) Not associated with other disoders (eg, Huntington’s chorea, postviral encephalitis) ··

*Tourette Syndrome Classification Group;14 ‡DSM-IV-TR.15

Table: Diagnostic criteria

and vocal tics in a non-random pattern has led to suggestions of a “fractal, deterministic, and possibly chaotic process” underlying the waxing and waning of tic activity.13

disorder [OCD], anxiety). TS typically begins with motor tics at age 6–7 years, with vocal tics presenting later. Several factors may assist the clinician in differentiating between tics and other disorders, including the patients’ reported perceptions, suppressibility, factors that exacerbate, variability, presence during sleep, and associated disturbances (eg, hyperactivity or compulsions).30 Commonly misdiagnosed symptoms in TS include eye blinking, ocular tics, a chronic persistent cough, or tics mimicking asthma. Diagnoses are typically retrospective, because there is no accurate way to predict whether an individual’s tics will resolve within months, others will be added, or that persistent tics will become chronic. Severe tics can lead to physical injury (eg, myelopathy31 and bilateral retinal detachment32), and iatrogenic eye injury has occurred during ocular assessments.33 There can be various movements in patients with TS that are not tics, such as drug-induced movements (akathisia, dystonia, chorea, parkinsonism) or those associated with comorbid disorders (OCD, ADHD, or antisocial behaviour).30

Tic disorders TS is one disorder in a spectrum of disorders, ranging from a mild transient form to TS, that have tics as their main feature.14 Tic disorders can be divided into two main categories according to their duration: “transient”, present for less than 12 months, and “chronic”, present for more than 12 months. Transient tic disorder is the mildest and most common. In chronic (motor or phonic) tic disorder, the tics are either entirely motor or, less commonly, solely vocal tics. The formal criteria for TS, given by The Tourette Syndrome Classification Study Group, include: multiple motor and at least one vocal tic (not necessarily concurrently); a waxing and waning course with increasing severity over time; tic symptoms for at least 1 year; symptom onset before age 21 years; no precipitating illnesses (eg, encephalitis, stroke, or degenerative disease) or drugs; and the observation of tics by a medical professional (table).14,15 Adult onset tic disorders have been reported and are commonly associated with potential environmental triggers, severe symptoms, greater social morbidity, and a poorer response to drugs.16 For tic syndromes that do not meet the criteria for TS, such as those associated with another medical disorder, the terms tourettism, Tourette-like disorder, or secondary tic disorder are used. For example, tic-like features may be caused by infection,17,18 drugs,12,19,20 toxins,21 stroke,22 head trauma,23,24 and surgery,25,26 and are also found in various sporadic, genetic, and neurodegenerative disorders.27–29

Diagnosis The diagnosis of a tic disorder is made from patients’ histories and clinical assessment. There is no diagnostic laboratory test and there is no requirement for the presence of any comorbid problems (eg, attention deficit hyperactivity disorder [ADHD], obsessive-compulsive 150

Course Tics typically wax and wane. Although the long-term course of TS can be variable, most studies suggest that tics improve in late adolescence or early adulthood.34–36 Leckman and colleagues35 used a mathematical model to assess the time course of tic severity over the first two decades and suggested that maximum tic severity occurs age 8–12 years, after which there is a steady decline in symptoms.35 A follow-up study of 58 teenagers and young adults, 15–25 years old, showed that tics disappeared in 26%, diminished substantially in 46%, were stable in 14%, and increased in 14%.34 Comparison of videotapes and assessments of people as children and as adults found that tic severity and disability diminish in adulthood, though 90% still have tics. Reported improvement was not related to the use of drugs.36 Physician reliance on strictly historical data, rather than direct observation, can lead to inaccurate reports. For example, 21% of reportedly unaffected children studied because of a positive family history met criteria for a tic disorder37 and 50% of adults who had tics in childhood and thought they were tic-free as adults had tics on direct observation.36 Early tic severity is not a good predictor of later tic severity35 and people with only chronic tic disorder are less impaired than those with coexisting disorders.38,39

Epidemiology TS affects people across the world and evidence of common features in all cultures and races is increasing. The prevalence of tic disorders varies widely in published reports. Discrepancies can be explained by selection and attribution biases (eg, the age and gender of the selected population), different sources of patients (eg, from regular or special-education classrooms, http://neurology.thelancet.com Vol 4 March 2005

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hospitals, or communities), differences in diagnostic criteria and inclusion thresholds, and varied study designs and methodologies. Age, season, gender, comorbidity, and classroom setting can affect the prevalence of this disorder. Tics are most prevalent age 9–11 years,40 have a higher incidence in winter than in spring,40 occur in more males than females (ratio three to one), are more common in children with ADHD,41 and are also more common in children attending special education programmes than in those attending regular classes.42 Despite these variations, the prevalence of tics is estimated to be 6–12% (range 4–24%).42,43 Although TS was once thought to be a rare disorder, the prevalence is now about one to ten in 1000 children and adolescents.42,44,45 TS is common in children with autism, Asperger syndrome, and other autistic-spectrum disorders, but its presence is unrelated to the severity of autistic symptoms.46 Tics and related behaviours are not over-represented among adult inpatients with psychiatric illnesses.47

Comorbidity Psychopathology Psychopathology in TS is more pervasive than was previously estimated and associated problems in TS are increasingly recognised.48 A child with TS, especially one with behavioural comorbidity, can have a substantial negative effect on the parents and life at home.49 Several common comorbid problems are described. Obsessive-compulsive behaviours occur in about 20–60% of patients with TS, but some studies report them in up to 89%.50 OCD is less common than behaviours; the disorder is characterised by prolonged recurrent thoughts or repetitive behaviour that causes distress and interferes with function. Obsessive behaviours generally emerge several years after the onset of tics, typically during early adolescence. Several researchers have proposed two subtypes of OCD from differences in prevalence in age groups and implied causal relations: a juvenile subtype and one related to tics.51 In a study comparing symptom profiles in children with OCD with and without tics, the absence of tics was associated with an increased frequency of contamination and washing rituals and repetitive requests for reassurance. Tics were associated with an increased frequency of repetitive behaviours that were unrelated to avoidance of harm.51 Obsessivecompulsive behaviours in adults with TS are associated with the presence of ADHD and self-injurious behaviours,52 whereas in children with TS they are associated with impulsive and aggressive behaviour, depression, and anxiety.53 ADHD is characterised by impulsivity, hyperactivity, and a decreased ability to maintain attention; it typically begins about age 4–5 years and precedes the onset of tics by 2–3 years. In patients with TS, ADHD is reported to affect about 50% (21–90%) of referred cases.54 Occurrence http://neurology.thelancet.com Vol 4 March 2005

of ADHD is not associated with the concurrent severity of tics, although ADHD is common in those with severe tic symptoms.55 In patients with tics, the addition of ADHD symptoms correlates with increased psychosocial problems, disruptive behaviour, functional impairment, and school-related problems.39,56–58 Several studies have found an increased incidence of depression and anxiety in patients with TS.39,59,60 In a report assessing 100 children and adolescents, 76% met the criteria for mood disorder and 67% the criteria for non-obsessive-compulsive anxiety disorder.60 Episodic outbursts of rage and self-injurious behaviour have been described in patients with TS.61,62 These behaviours might be caused by other disruptive psychopathology, such as obsessions, compulsions, ADHD-related impulsivity, risk-taking, rage, or affective disorders. Severe tics, psychosocial problems, ADHD, OCD, learning disabilities, and drugs can result in poor school performance in children with tics.63 Individuals with TS typically have normal intellectual functioning, although there may be executive dysfunction, discrepancies between performance and verbal IQ, impairments of visual perceptual achievement, or a decrease in visualmotor skills.38,64–67

Other problems The occurrence of migraine in patients with TS is several times higher than that in the general population. Migraine questionnaires have shown that 25% of patients with TS have migraine, which exceeds the general estimates of 10–13% in adults and 2–10% in children.68 Problems associated with sleep have been reported in about 20–50% of children and young adults with TS; the most common of these are difficulties in falling and staying asleep and parasomnias.6,69 Polysomnographic studies have shown disturbed sleep quality with increased sleep latency, reduced sleep efficiency, prolonged wakefulness after sleep onset, larger sleep stage changes, and altered slow-wave sleep. Sleep is accompanied by tics in all sleep stages, frequent arousals, periodic limb movements, parasomnias, and sleep apnoea.6,69,70 Associated comorbidities such as ADHD and anxiety (including separation anxiety, mood disorders, and OCD) can, however, contribute to the sleep deficits.71 Several clinical and pathological features overlap in patients with TS and restless-legs syndrome: a desire to move the limbs in association with a preceding urge or sensation; worsening at the end of the day; periodic limb movements in sleep; and shared pathological associations with dopamine and frontal-striatal cortical circuits.70,72,73 10% of TS patients within a FrenchCanadian population had restless-legs syndrome and its prevalence may be underestimated, in part because of confusion with ADHD, complex tics, and compulsions.73 151

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Genetics Although Gilles de la Tourette suggested that TS was an inherited disorder, the precise pattern of transmission and the identification of genes is elusive.74 Strong support for a genetic disorder is provided by studies of monozygotic twins, which show an 86% concordance rate for chronic tic disorder compared with 20% in dizygotic twins.75,76 A complex genetic cause is also supported by a study of at-risk children who were free of tics at baseline and subsequently developed a tic disorder.37 Earlier proposals suggesting a sex-influenced, autosomal-dominant inheritance with variable expressivity as TS, chronic tic disorder, or OCD77 have been questioned. Other researchers have proposed a single major locus in combination with a multifactorial background—ie, either additional genes with different effect sizes or environmental factors.78 An assessment of 108 extended families of patients with TS by use of a data-modelling computer program has suggested that transmission of TS is not consistent with mendelian inheritance.79 Many approaches are being used to search for a genetic site, including genetic linkage, cytogenetics, candidate gene studies, and molecular genetic studies.74 Linkage analyses have suggested several chromosomal locations, without a clear reproducible locus or convergence of findings: chromosomes 4q and 8p in a sibling-pair study; chromosomes 5 and 19 in eight large families; 2p, 8q, and 11q in a population study; chromosome 11 in one large Canadian family; loci on chromosomes 5, 10, and 13 in a single large pedigree; and 17q25 in two independent family samples.80 Several cytogenetic abnormalities have been reported in patients with tic disorders and molecular genetic abnormalities include findings of a balanced translocation between chromosomes 6 and 8 with a translocation breakpoint on chromosome 8q,81 an 18q21.1 to 18q22.2 inversion,82 a de-novo duplication of the long arm of chromosome 7,83 and a complex chromosomal insertion or translocation involving chromosomes 2 and 7 affecting the gene for contactin-associated-protein 2, a membrane protein at nodes of Ranvier.84 Linkages to candidate genes associated with specific synaptic neurochemical markers have been negative or equivocal. The possible effects of genomic imprinting, bilineal transmission, epigenetic factors, and gene–environment interactions further complicate our understanding of the genetics of TS. In TS, the role of genomic imprinting is controversial and conflicting reports need resolution.85,86 Bilineal transmission (ie, genetic contribution from both sides of the family), in general implies recessive or polygenic transmission patterns and a unilinealtransmission pattern implies dominant inheritance. Which behaviours should be considered when assessing for bilineal transmission is unclear. Studies have reported that the likelihood of both parents of a patient with TS having tics is about 6–15%, but when other 152

factors (OCB, ADHD, panic attacks, drug or alcohol abuse) are included, the incidence of bilineality rises to 26–41%.87,88 Potential epigenetic risk factors have been assessed, such as timing of perinatal care, severity of mother’s nausea and vomiting during the pregnancy, low birth weight, the Apgar score at 5 min, and nonspecific maternal emotional stress.89 Replication of these studies is needed.

Neuroimmunology In 1998, Swedo and colleagues90 proposed that a subset of children with tic disorders, OCD, or both had an abrupt exacerbation of symptoms at about the same time as a streptococcal infection. Labelled as paediatric autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS), the notion of this entity is controversial.91,92 Support for PANDAS is derived from the description of additional cohorts,93 familial studies showing that first-degree relatives of children with PANDAS have higher rates of tic disorders and OCD than do those in the general population,94 and expanded expression of a trait marker for susceptibility in rheumatic fever (the monoclonal antibody D8/17) in individuals with PANDAS.95 Despite these findings, debate about the existence of PANDAS continues.92,96,97 No prospective epidemiological study has confirmed that an antecedent Group A beta haemolytic streptococcal (GABHS) infection is specifically associated with either the onset or exacerbation of tic disorders or OCD. Diagnostic criteria for PANDAS are potentially confounded by the phenotypic variability commonly associated with tic disorders, such as a normal fluctuation in the frequency and severity of symptoms, exacerbation of tics by stress, fatigue, and illness, occurrence of “sudden, abrupt” onset and recurrence of tics in patients without PANDAS,98 and the absence of a precise definition for associated neurological disorders. Additionally, longitudinal laboratory data, rather than studies that use only a throat culture or only a single antistreptolysin O or antideoxyribonuclease B titre, are necessary to confirm the presence of a previous GABHS infection. Two prospective longitudinal studies showed no clear relation between new GABHS infections and the development or exacerbation of tic or OCD symptoms.12,99 According to a model proposed for Sydenham’s chorea, it is hypothesised that the underlying pathology in PANDAS involves an immune-mediated mechanism with molecular mimicry.90 Antibodies produced against GABHS are believed to cross-react with neuronal tissue in specific brain regions (ie, become antineuronal antibodies) and result in tic or behavioural symptoms or both. A single study that examined the response of patients with PANDAS to immunomodulatory therapy supports this hypothesis.100 In this partially double-blind protocol, the severity of obsessive-compulsive symptoms http://neurology.thelancet.com Vol 4 March 2005

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improved after either plasmapheresis or intravenous immunoglobulin treatment, and tics were reduced after plasmapheresis. Antineuronal antibodies have been assessed in patients with PANDAS with variable results. Pooled data from 40 children with movement disorders associated with streptococcal infections (20 with PANDAS, 16 with Sydenham’s chorea, and four with “idiopathic” movement disorders) suggest that this cohort can be differentiated from various disease controls by ELISA and western immunoblotting.101 In frozen tissue, by use of a colorimetric assay, only a few bands were detected in controls (limited reactivity against any basal ganglia antigens), but substantially more bands (at 60 kDa, 45 kDa, and 40 kDa) were found in patients after streptococcal infection. By contrast, other investigators who have used several different epitopes, including supernatant, pellet, and synaptosomal fractions from homogenised fresh human post-mortem caudate, putamen, and globus pallidus, were unable to distinguish 15 patients with PANDAS from controls.102 Additionally, comparison of serum antineuronal antibodies against supernatant fractions from fresh adult post-mortem caudate, putamen, and prefrontal cortex (Brodmann’s area 10) in 48 children with PANDAS to similar fractions in 46 children with TS did not find differences in ELISA optical density values or bands identified on immunoblotting in any brain region.103 Furthermore, the microinfusion of serum samples from children with PANDAS into rodent striatum does not reliably change the number of observed motor stereotypy behaviours.104,105

Neurobiology Direct and indirect evidence has found that cortico–striatal–thalamocortical pathways are involved in the expression of TS and its accompanying neuropsychiatric problems (figure).106–108 Although there is general consensus of a cortico–striatal–thalamocortical circuit abnormality, the pathophysiological locations are speculative. Many investigators have focused on the striatal component,109,110 perhaps influenced by knowledge of associations between basal ganglia dysfunction and movements in other disorders. However, evidence is accumulating to support a cortical dysfunction in TS: many children with TS have executive dysfunction;66,67,111 volumetric MRI studies have shown larger dorsolateral prefrontal regions in children with TS, but significantly smaller volumes in adults with the disorder;112 children with TS have increased cortical white matter in the right frontal lobe113 or decreases in the deep left frontal region;114 midsagittal measurements have shown variable changes in size of the corpus callosum;115–117 functional imaging suggests tic suppression involves activation of the prefrontal cortex;118 event-related PET has shown relations between http://neurology.thelancet.com Vol 4 March 2005

GABA GABA

Glu Glu Indirect

D2

Glu

Direct Matrix Striatum Matrix

D1

Thalamus

DA

DA DA VTA GABA

SNpc

NE LC

GABA ENK

GABA SUBP

Glu

MR

S

GPi SNpr

GPe Glu

GABA

STN

Figure: Pathophysiology of TS This figure shows the cortico–striatal–thalamocortical pathway and ascending cortical inputs. Hypothesised abnormalities have included disorders of excess excitation or diminished inhibition, disruptions in frontal cortex, striatum, or striosomes, and abnormalities of various synaptic neurotransmitters. DA=dopamine; ENK=enkephalins; Glu=glutamate; GPe=globus pallidus externa; GPi=globus pallidus interna; LC=locus coeruleus; MR=median raphe; NE=norepinephrine; S=serotonin; SNpc=substantia nigra pars compacta; SNpr=substantia nigra pars reticulata; SUBP=substance P; STN=subthalamic nucleus; VTA=ventral tegmental area.

tics and cortical brain activity in the dorsolateral–rostral prefrontal cortex;119 transcranial-magnetic-stimulation studies suggest that tics originate from impaired inhibition at the motor cortex;120 and semiquantitative immunoblotting investigations on post-mortem caudate, putamen, ventral striatum, and prefrontal cortex (Brodmann’s area 9) showed the prefrontal cortex had the greatest number of changes compared with that of controls.121 The presence of dopaminergic, glutamatergic, GABAergic, serotoninergic, cholinergic, noradrenergic, 153

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and opioid systems within cortico–striatal– thalamocortical circuits raises the possibility that various transmitters may be involved in the pathobiology of TS. Even though my bias is that the dopaminergic system has a substantial role, because many transmitter systems are interrelated in the production of complex actions, it is indeed possible, if not probable, that imbalances exist within several transmitter systems. A microarray analysis of gene expression pattern in post-mortem putamen of patients with TS has shown several genes to be upregulated or downregulated, including several that affect synaptic neurotransmission.122 The possibility of a dopaminergic abnormality in TS continues to receive attention because of therapeutic response to neuroleptics, results from various nuclear imaging protocols,123–127 CSF,128 and post-mortem studies.121,129,130 Studies to date have mostly focused on potential dopaminergic changes in the striatum. With some variability, striatal data suggest that there are increases in the number of dopamine receptors, high concentrations of dopamine transporters (not associated with dopamine hyperinnervation except possibly in the ventral striatum), and increased intrasynaptic dopamine release. My co-workers and I123 have speculated that the tonic-phasic model of dopamine release is a unifying hypothesis—ie, a reduction in tonic (basal) dopamine, thought to be due to an overactive dopamine transporter system, could result in a system with high concentrations of dopamine receptors and an increased phasic release of dopamine. If TS is associated with excess nigrostriatal dopaminergic activity, either via supersensitive dopamine receptors, dopamine hyperinnervation, or abnormal presynaptic terminal function, a substantial hyperkinetic effect is expected.106 We have also shown that Brodmann’s area 9 has increased concentrations of D2 dopamine receptors, dopamine transporter, vesicular monoamine transporter type 2, and  adrenergic receptors.121 Because dopaminergic fibres arise from the ventral tegmental area and form synapses on both pyramidal neurons (stimulate) and interneurons (inhibit) within the prefrontal cortex,131 we have hypothesised a prefrontal dopaminergic abnormality.

Treatment of tics The decision to treat each patient should be made from the findings of an initial comprehensive assessment that includes analysis of tics, documentation of comorbid disorders, assessment of severity, as well as the resulting impairment. The treatment of tics and any comorbidities should be prioritised according to the impairment caused by each problem. Physicians considering behavioural or pharmacological treatments should be aware of the natural waxing and waning of tics, large placebo response, and the effect of psychopathologies on outcome. 154

Non-pharmacological treatments Various behavioural treatments (conditioning techniques, massed negative practice, awareness training, habit reversal, relaxation training, biofeedback, and hypnosis) have been proposed as alternative therapeutic approaches, but the effectiveness of few has been adequately assessed. In a small study comparing relaxation therapy and minimal (control) therapy, there was a trend toward improvement in the relaxation treatment group, but the benefit was only short-term.132 Habit reversal training substantially improved tics as compared with a supportive therapy group, and the beneficial effect was present 10 months later at a followup assessment.133 In a small cohort, habit reversal therapy reduced the severity of vocal tics.134 Acupuncture might suppress tics135 but there is not much published data. There is little or no scientific evidence supporting the use of alternative dietary therapies (ie, vitamins, protein supplementation, elimination diets, and others).

Pharmacotherapy There is no cure for tics and all pharmacotherapy must be regarded as symptomatic therapy. If a tic-suppressing drug is indicated, a two-tiered approach is recommended: first, non-neuroleptic drugs for mild tics, and second, typical or atypical neuroleptics for more severe tics (panel). The goal of treatment is not complete suppression of all motor and phonic tics, but to reduce them such that they no longer cause substantial psychosocial disturbance. Tier one drugs include clonidine,136 guanfacine,137 baclofen,138 and clonazepam.139 Several anticonvulsant drugs, such as topiramate, levetiracetam, and gabapentin, are under study as tic-suppressing drugs. In tier two, classic neuroleptics, such as D2 dopamine receptor antagonists, are effective tic-suppressing drugs, but side-effects may restrict their use. Some researchers prefer pimozide or fluphenazine to haloperidol, because the observed occurrence of side-effects is reduced. Sulpiride and tiapride, both substituted benzamides, have been beneficial in Europe, but neither is available in the USA. Newer atypical neuroleptics (risperidone, olanzapine, ziprasidone, quetiapine) are characterised by a greater affinity for 5-HT2 receptors than for D2 receptors and the potential for fewer extrapyramidal side-effects than typical neuroleptics. Substantial variations in receptor affinity profiles for subtypes of dopamine receptors, serotonin receptors, and adrenergic receptors exist among these atypical neuroleptic drugs, suggesting that there may be important differences in clinical effects. In this group, risperidone has been studied most extensively. In two randomised, doubleblind, placebo-controlled trials, risperidone at a mean and median daily dose of 2·5 mg/day gave a substantial reduction of tics compared with placebo.140,141 When compared with other drugs, risperidone was equally as effective as clonidine136 and seemed superior to pimozide http://neurology.thelancet.com Vol 4 March 2005

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in the suppression of tics.142 Reported side-effects include weight gain,142 acute social phobia,140 major depressive disorder and dysphoria, sedation,136 and suspected drug interaction with HIV drugs ritonavir sulfate and indinavir.143 Several small studies have confirmed clinical effectiveness of olanzapine,144,145 ziprasidone,146,147 and quetiapine.148,149 Because results with the atypical neuroleptics clozepine have been inconsistent, the combination of 5-HT2 and D2 receptor antagonist is not always successful in suppressing tics.150 Several studies have confirmed that tetrabenazine, a benzoquinolizine derivative that depletes the presynaptic stores of catecholamines and blocks postsynaptic dopamine receptors, is effective.151 The dopamine agonists pergolide and ropinirole improve tics when given at much lower doses than those prescribed to treat Parkinson’s disease.152,153 The mechanism of action is speculated to involve presynaptic rather than postsynaptic striatal or cortical dopamine receptors. Not all dopamine agonists produce similar therapeutic effects, because treatment of adults with TS with talipexole did not improve tics.154 Multiple non-dopaminergic therapies have been proposed for the treatment of tic disorders. Several clinical trials have suggested a beneficial response of TS to delta-9-tetrahydrocannabinol, the main psychoactive ingredient of cannabis.155,156 Nicotine has various potential mechanisms of action in the CNS157 and there are reports indicating improved tic control when nicotine gum or a skin patch is used in conjunction with a neuroleptic drug.158 Donepezil, a non-competitive inhibitor of acetylcholinesterase, has improved tics in a few patients.159 Intravenous immunoglobulin (1 mg/kg on 2 consecutive days) was not substantially better than placebo in suppressing tics.160 Botulinum toxin has been used to treat both motor and vocal tics with success.161,162 In 30 patients who received 2·5 IU of botulinum toxin-A in both vocal cords, phonic tics were improved in 11 and stopped in 15.163 The mean time until a response was 5·8 days and the mean duration of the treatment effect was 102 days. Hypophonia was a common side-effect.

Surgical therapy Multiple neurosurgical approaches, with target sites including the frontal lobe (bimedial frontal leucotomy and prefrontal lobotomy), limbic system (anterior cingulotomy and limbic leucotomy), cerebellum, and thalamus have been tried in attempts to reduce severe tics.164 Deep brain stimulation, a stereotactic treatment developed for other movement disorders, has been suggested as a potential therapy for the control of tics.165 Target coordinates have been selected according to the results of lesion studies—ie, the centromedian nucleus (part of the intralaminar thalamic nuclei), the substantia periventricularis (part of the midline thalamic nuclei), and the ventro-oralis internus.166 Although this http://neurology.thelancet.com Vol 4 March 2005

Panel: Pharmacotherapy of tics Tier 1 Clonidine Guanfacine Baclofen Clonazepam Under investigation: gabapentin, topiramate, levetiracetam Tier 2 Neuroleptics Pimozide Fluphenazine Sulpiride Tiapride Haloperidol Trifluoperazine Arpiprazole Atypical neuroleptics Risperidone Olanzapine Ziprasidone Quetiapine Additional Tetrabenazine Pergolide Donepezil Other In selected situations Botulinum toxin Nicotine patch Delta-9-tetrahydrocannabinol Experimental Transcranial magnetic stimulation Deep brain stimulation

technique has several advantages over other neurosurgical approaches (lack of permanent complications typically associated with lesioning procedures, access to less-accessible surgical brain regions, and bilateral sites can be stimulated simultaneously), pending patient selection criteria and the outcome of carefully controlled clinical trials, a cautious approach is recommended.

Conclusion Despite a myriad of reports on TS, there are many unresolved facts. For the treating physician, many patients have complex intertwined problems and commonly provide a therapeutic challenge. For researchers interested in the genetics, neuroimmunology, and neurobiology of TS, much work is needed. With great anticipation, I look forward to future definitive reports on this fascinating disorder. 155

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Search strategy and selection criteria References for this review were identified by searches of PubMed up to 2004 with the terms “Tourette syndrome” and “tics”. Many papers were also identified from the files of the author and from references given in relevant articles. Abstracts and reports from meetings were included. Only papers published in English were reviewed. The final reference list was generated from the criteria of relevance to the review topics and originality.

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22 Acknowledgments Pamela Talalay is thanked for her review of the manuscript. Conflicts of interest I am the recipient of a grant from UCB Pharmaceuticals to study the effect of levetiracetam in the treatment of tics. Role of the funding source No funding source had a role in the preparation of this review or the decision to submit it for publication. References 1 Kushner HI. A cursing brain? The histories of Tourette syndrome. Cambridge, MA: Harvard University Press, 1999. 2 Singer HS, Walkup JT. Tourette syndrome and other tic disorders: diagnosis, pathophysiology, and treatment. Medicine (Baltimore) 1991; 70: 15–32. 3 Goldenberg JN, Brown SB, Weiner WJ. Coprolalia in younger patients with Gilles de la Tourette syndrome. Mov Disord 1994; 9: 622–25. 4 Wood BL, Klebba K, Gbadebo O, Lichter D, Kurlan R, Miller B. Pilot study of effect of emotional stimuli on tic severity in children with Tourette’s syndrome. Mov Disord 2003; 18: 1392–95. 5 O’Connor K, Briseboise H, Brault M, Robillard S, Loiselle J. Behavioral activity associated with onset in chronic tic and habit disorder. Behav Res Ther 2003; 41: 241–49. 6 Cohrs S, Rasch T, Altmeyer S, et al. Decreased sleep quality and increased sleep related movements in patients with Tourette’s syndrome. J Neurol Neurosurg Psychiatry 2001; 70: 192–97. 7 Leckman JF, Walker DE, Cohen DJ. Premonitory urges in Tourette’s syndrome. Am J Psychiatry 1993; 150: 98–102. 8 Kwak C, Dat Vuong K, Jankovic J. Premonitory sensory phenomenon in Tourette’s syndrome. Mov Disord 2003; 18: 1530–33. 9 Banaschewski T, Woerner W, Rothenberger A. Premonitory sensory phenomena and suppressibility of tics in Tourette syndrome: developmental aspects in children and adolescents. Dev Med Child Neurol 2003; 45: 700–3. 10 Findley DB, Leckman JF, Katsovich L, et al. Development of the Yale Children’s Global Stress Index (YCGSI) and its application in children and adolescents with Tourette’s syndrome and obsessivecompulsive disorder. J Am Acad Child Adolesc Psychiatry 2003; 42: 450–57. 11 Hoekstra P, Steenhuis M, Kallenberg C, Minderaa R. Association of small life events with self reports of tic severity in pediatric and adult tic disorder patients: a prospective longitudinal study. J Clin Psychiatry 2004; 65: 426–31. 12 Luo F, Leckman JF, Katsovich L, et al. Prospective longitudinal study of children with tic disorders and/or obsessive-compulsive disorder: relationship of symptom exacerbations to newly acquired streptococcal infections. Pediatrics 2004; 113: e578–85. 13 Peterson BS, Leckman JF. The temporal dynamics of tics in Gilles de la Tourette syndrome. Biol Psychiatry 1998; 44: 1337–48. 14 The Tourette Syndrome Classification Study Group. Definitions and classification of tic disorders. Arch Neurol 1993; 50: 1013–16. 15 American Psychiatric Association. Diagnostic and statistical manual of mental disorders (DSM-IV-TR). Washington, DC: American Psychiatric Press Inc, 2000. 16 Eapen V, Lees A, Lakke J, Trimble M, Robertson M. Adult-onset tic disorders. Mov Disord 2002; 17: 735–40.

156

23

24 25

26 27 28

29

30

31 32

33 34 35

36

37

38

39

40

41

42

43

Northam RS, Singer HS. Postencephalitic acquired Tourette-like syndrome in a child. Neurology 1991; 41: 592–93. Riedel M, Straube A, Schwarz MJ, Wilske B, Muller N. Lyme disease presenting as Tourette’s syndrome. Lancet 1998; 351: 418–19. Klawans HL, Falk DK, Nausieda PA, Weiner WJ. Gilles de la Tourette syndrome after long-term chlorpromazine therapy. Neurology 1978; 28: 1064–66. Singer WD. Transient Gilles de la Tourette syndrome after chronic neuroleptic withdrawal. Dev Med Child Neurol 1981; 23: 518–21. Ko S, Ahn T, Kim J, Kim Y, Jeon B. A case of adult onset tic disorder following carbon monoxide intoxication. Can J Neurol Sci 2004; 31: 268–70. Kwak CH, Jankovic J. Tourettism and dystonia after subcortical stroke. Mov Disord 2002; 17: 821–25. Majumdar A, Appleton RE. Delayed and severe but transient Tourette syndrome after head injury. Pediatr Neurol 2002; 27: 314–17. Krauss J, Jankovic J. Tics secondary to craniocerebral trauma. Mov Disord 1997; 12: 776–82. Singer HS, Dela Cruz PS, Abrams MT, Bean SC, Reiss AL. A Tourette-like syndrome following cardiopulmonary bypass and hypothermia: MRI volumetric measurements. Mov Disord 1997; 12: 588–92. Chemali Z, Bromfield E. Tourette’s syndrome following temporal lobectomy for seizure control. Epilepsy Behav 2003; 4: 564–66. Jankovic J, Ashizawa T. Tourettism associated with Huntington’s disease. Mov Disord 1995; 10: 103–5. Scarano V, Pellecchia M, Filla A, Barone P. Hallervorden-Spatz syndrome resembling a typical Tourette syndrome. Mov Disord 2002; 17: 618–20. Romstad A, Dupont E, Krag-Olsen B, Ostergaard K, Guldberg P, Guttler F. Dopa-responsive dystonia and Tourette syndrome in a large Danish family. Arch Neurol 2003; 60: 618–22. Kompoliti K, Goetz CG. Hyperkinetic movement disorders misdiagnosed as tics in Gilles de la Tourette syndrome. Mov Disord 1998; 13: 477–80. Dobbs M, Berger J. Cervical myelopathy secondary to violent tics of Tourette’s syndrome. Neurology 2003; 60: 1862–63. Lim S, Rezai KA, Abrams GW, Eliott D. Self-induced, bilateral retinal detachment in Tourette syndrome. Arch Ophthalmol 2004; 122: 930–31. Margo C. Tourette syndrome and iatrogenic eye injury. Am J Ophthalmol 2002; 134: 784–85. Erenberg G, Cruse RP, Rothner AD. The natural history of Tourette syndrome: a follow-up study. Ann Neurol 1987; 22: 383–85. Leckman JF, Zhang H, Vitale A, et al. Course of tic severity in Tourette syndrome: the first two decades. Pediatrics 1998; 102: 14–19. Pappert EJ, Goetz CG, Louis ED, Blasucci L, Leurgans S. Objective assessments of longitudinal outcome in Gilles de la Tourette’s syndrome. Neurology 2003; 61: 936–40. McMahon W, Carter AS, Fredine N, Pauls DL. Children at familial risk for Tourette’s disorder: child and parent diagnoses. Am J Med Genet 2003; 121B: 105–11. Channon S, Pratt P, Robertson MM. Executive function, memory, and learning in Tourette’s syndrome. Neuropsychology 2003; 17: 247–54. Sukhodolsky DG, Scahill L, Zhang H, et al. Disruptive behavior in children with Tourette’s syndrome: association with ADHD comorbidity, tic severity, and functional impairment. J Am Acad Child Adolesc Psychiatry 2003; 42: 98–105. Snider L, Seligman L, Ketchen B, et al. Tics and problem behaviors in schoolchildren: prevalence, characterization, and associations. Pediatrics 2002; 110: 331–36. Spencer T, Biederman M, Coffey B, Geller D, Wilens T, Faraone S. The 4-year course of tic disorders in boys with attentiondeficit/hyperactivity disorder. Arch Gen Psychiatry 1999; 56: 842–47. Kurlan R, McDermott MP, Deeley C, et al. Prevalence of tics in schoolchildren and association with placement in special education. Neurology 2001; 57: 1383–88. Gadow K, Nolan E, Sprafkin J, Schwartz J. Tics and psychiatric comorbidity in children and adolescents. Dev Med Child Neurol 2002; 44: 330–38.

http://neurology.thelancet.com Vol 4 March 2005

Review

44 45

46

47

48 49

50

51

52

53

54

55

56 57

58

59

60 61

62

63

64

65

66

67

Robertson MM. Diagnosing Tourette syndrome: is it a common disorder? J Psychosom Res 2003; 55: 3–6. Khalifa N, von Knorring AL. Prevalence of tic disorders and Tourette syndrome in a Swedish school population. Dev Med Child Neurol 2003; 45: 315–19. Baron-Cohen S, Mortimore C, Moriarty J, Izaguirre J, Robertson M. The prevalence of Gilles de la Tourette’s syndrome in children and adolescents with autism. J Child Psychol Psychiatry 1999; 40: 213–18. Eapen V, Laker M, Anfield A, Dobbs J, Robertson MM. Prevalence of tics and Tourette syndrome in an inpatient adult psychiatry setting. J Psychiatry Neurosci 2001; 26: 417–20. Kurlan R, Como PG, Miller B, et al. The behavioral spectrum of tic disorders: a community-based study. Neurology 2002; 59: 414–20. Cooper C, Robertson MM, Livingston G. Psychological morbidity and caregiver burden in parents of children with Tourette’s disorder and psychiatric comorbidity. J Am Acad Child Adolesc Psychiatry 2003; 42: 1370–75. Robertson MM, Trimble MR, Lees AJ. The psychopathology of the Gilles de la Tourette syndrome: a phenomenological analysis. Br J Psychiatry 1988; 152: 383–90. Scahill L, Kano Y, King RA, et al. Influence of age and tic disorders on obsessive-compulsive disorder in a pediatric sample. J Child Adolesc Psychopharmacol 2003; 13 (suppl 1): S7–17. Eapen V, Fox-Hiley P, Banerjee S, Robertson M. Clinical features and associated psychopathology in a Tourette syndrome cohort. Acta Neurol Scand 2004; 109: 255–60. Banaschewski T, Siniatchkin M, Uebel H, Rothenberger A. Compulsive phenomena in children with tic disorder and attention deficit-hyperactive disorder. Z Kinder Jugendpsychiatr Psychother 2003; 31: 203–11. Comings DE, Comings BG. A controlled study of Tourette syndrome I: attention-deficit disorder, learning disorders, and school problems. Am J Hum Genet 1987; 41: 701–41. Robertson MM, Stern JS. Tic disorders: new developments in Tourette syndrome and related disorders. Curr Opin Neurol 1998; 11: 373–80. Abwender DA, Como PG, Kurlan R, et al. School problems in Tourette’s syndrome. Arch Neurol 1996; 53: 509–11. Hoekstra PJ, Steenhuis MP, Troost PW, Korf J, Kallenberg CG, Minderaa RB. Relative contribution of attention-deficit hyperactivity disorder, obsessive-compulsive disorder, and tic severity to social and behavioral problems in tic disorders. J Dev Behav Pediatr 2004; 25: 272–79. Spencer TJ, Biederman J, Faraone S, et al. Impact of tic disorders on ADHD outcome across the life cycle: findings from a large group of adults with and without ADHD. Am J Psychiatry 2001; 158: 611–17. Rickards H, Robertson M. A controlled study of psychopathology and associated symptoms in Tourette syndrome. World J Biol Psychiatry 2003; 4: 64–68. Coffey BJ, Park KS. Behavioral and emotional aspects of Tourette syndrome. Neurol Clin 1997; 15: 277–89. Budman CL, Rockmore L, Stokes J, Sossin M. Clinical phenomenology of episodic rage in children with Tourette syndrome. J Psychosom Res 2003; 55: 59–65. Mathews CA, Waller J, Glidden D, et al. Self injurious behaviour in Tourette syndrome: correlates with impulsivity and impulse control. J Neurol Neurosurg Psychiatry 2004; 75: 1149–55. Singer HS, Schuerholz LJ, Denckla MB. Learning difficulties in children with Tourette syndrome. J Child Neurol 1995; 10 (suppl 1): S58–61. Brand N, Geenen R, Oudenhoven M, et al. Brief report: cognitive functioning in children with Tourette’s syndrome with and without comorbid ADHD. J Pediatr Psychol 2002; 27: 203–8. Schuerholz LJ, Singer HS, Denckla MB. Gender study of neuropsychological and neuromotor function in children with Tourette syndrome with and without attention-deficit hyperactivity disorder. J Child Neurol 1998; 13: 277–82. Harris EL, Schuerholz LJ, Singer HS, et al. Executive function in children with Tourette syndrome and/or attention deficit hyperactivity disorder. J Int Neuropsychol Soc 1995; 1: 511–16. Schuerholz LJ, Baumgardner TL, Singer HS, Reiss AL, Denckla MB. Neuropsychological status of children with Tourette’s syndrome

http://neurology.thelancet.com Vol 4 March 2005

68 69

70

71

72

73

74 75 76

77

78

79

80

81

82

83

84

85

86

87

88 89 90

with and without attention deficit hyperactivity disorder. Neurology 1996; 46: 958–65. Kwak C, Vuong KD, Jankovic J. Migraine headache in patients with Tourette syndrome. Arch Neurol 2003; 60: 1595–98. Kostanecka-Endress T, Banaschewski T, Kinkelbur J, et al. Disturbed sleep in children with Tourette syndrome: a polysomnographic study. J Psychosom Res 2003; 55: 23–29. Voderholzer U, Muller N, Haag C, Riemann D, Straube A. Periodic limb movements during sleep are a frequent finding in patients with Gilles de la Tourette’s syndrome. J Neurol 1997; 244: 521–26. Allen RP, Singer HS, Brown JE, Salam MM. Sleep disorders in Tourette syndrome: a primary or unrelated problem? Pediatr Neurol 1992; 8: 275–80. Muller N, Voderholzer U, Kurtz G, Straube A. Tourette’s syndrome associated with restless legs syndrome and akathisia in a family. Acta Neurol Scand 1994; 89: 429–32. Lesperance P, Djerroud N, Diaz Anzaldua A, Rouleau GA, Chouinard S, Richer F. Restless legs in Tourette syndrome. Mov Disord 2004; 19: 1084–87. Pauls DL. An update on the genetics of Gilles de la Tourette syndrome. J Psychosom Res 2003; 55: 7–12. Price RA, Kidd KK, Cohen DJ, Pauls DL, Leckman JF. A twin study of Tourette syndrome. Arch Gen Psychiatry 1985; 42: 815–20. Hyde TM, Aaronson BA, Randolph C, Rickler KC, Weinberger DR. Relationship of birth weight to the phenotypic expression of Gilles de la Tourette’s syndrome in monozygotic twins. Neurology 1992; 42: 652–58. Pauls DL, Leckman JF. The inheritance of Gilles de la Tourette’s syndrome and associated behaviors: evidence for autosomal dominant transmission. N Engl J Med 1986; 315: 993–97. Walkup JT, LaBuda MC, Singer HS, Brown J, Riddle MA, Hurko O. Family study and segregation analysis of Tourette syndrome: evidence for a mixed model of inheritance. Am J Hum Genet 1996; 59: 684–93. Seuchter SA, Hebebrand J, Klug B, et al. Complex segregation analysis of families ascertained through Gilles de la Tourette syndrome. Genet Epidemiol 2000; 18: 33–47. Paschou P, Feng Y, Pakstis AJ, et al. Indications of linkage and association of Gilles de la Tourette syndrome in two independent family samples: 17q25 is a putative susceptibility region. Am J Hum Genet 2004; 75: 545–60. Crawford FC, Ait-Ghezala G, Morris M, et al. Translocation breakpoint in two unrelated Tourette syndrome cases, within a region previously linked to the disorder. Hum Genet 2003; 113: 154–61. State MW, Greally JM, Cuker A, et al. Epigenetic abnormalities associated with a chromosome 18(q21-q22) inversion and a Gilles de la Tourette syndrome phenotype. Proc Natl Acad Sci USA 2003; 100: 4684–89. Kroisel PM, Petek E, Emberger W, Windpassinger C, Wladika W, Wagner K. Candidate region for Gilles de la Tourette syndrome at 7q31. Am J Med Genet 2001; 101: 259–61. Verkerk AJ, Mathews CA, Joosse M, Eussen BH, Heutink P, Oostra BA. CNTNAP2 is disrupted in a family with Gilles de la Tourette syndrome and obsessive compulsive disorder. Genomics 2003; 82: 1–9. Furtado S, Suchowersky O. Investigation of the potential role of genetic imprinting in Gilles de la Tourette syndrome. Am J Med Genet 1994; 51: 51–54. Eapen V, O’Neill J, Gurling HM, Robertson MM. Sex of parent transmission effect in Tourette’s syndrome: evidence for earlier age at onset in maternally transmitted cases suggests a genomic imprinting effect. Neurology 1997; 48: 934–37. Lichter DG, Dmochowski J, Jackson LA, Trinidad KS. Influence of family history on clinical expression of Tourette’s syndrome. Neurology 1999; 52: 308–16. Hanna PA, Janjua FN, Contant CF, Jankovic J. Bilineal transmission in Tourette syndrome. Neurology 1999; 53: 813–18. Burd L, Severud R, Klug MG, Kerbeshian J. Prenatal and perinatal risk factors for Tourette disorder. J Perinat Med 1999; 27: 295–302. Swedo SE, Leonard HL, Garvey M, et al. Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections: clinical description of the first 50 cases. Am J Psychiatry 1998; 155: 264–71.

157

Review

91

92

93

94

95

96

97 98 99

100

101

102 103

104

105

106

107

108

109

110

111

112

158

Swedo SE, Leonard HL, Rapoport JL. The pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS) subgroup: separating fact from fiction. Pediatrics 2004; 113: 907–11. Kurlan R, Kaplan EL. The pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS) etiology for tics and obsessive-compulsive symptoms: hypothesis or entity? Practical considerations for the clinician. Pediatrics 2004; 113: 883–86. Murphy ML, Pichichero ME. Prospective identification and treatment of children with pediatric autoimmune neuropsychiatric disorder associated with group A streptococcal infection (PANDAS). Arch Pediatr Adolesc Med 2002; 156: 356–61. Lougee L, Perlmutter SJ, Nicolson R, Garvey MA, Swedo SE. Psychiatric disorders in first-degree relatives of children with pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS). J Am Acad Child Adolesc Psychiatry 2000; 39: 1120–26. Swedo SE, Leonard HL, Mittleman BB, et al. Identification of children with pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections by a marker associated with rheumatic fever. Am J Psychiatry 1997; 154: 110–12. Kurlan R. Tourette’s syndrome and ‘PANDAS’: will the relation bear out? Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection. Neurology 1998; 50: 1530–34. Singer HS, Loiselle C. PANDAS: a commentary. J Psychosom Res 2003; 55: 31–39. Singer HS, Giuliano JD, Zimmerman AM, Walkup JT. Infection: a stimulus for tic disorders. Pediatr Neurol 2000; 22: 380–83. Perrin EM, Murphy ML, Casey JR, et al. Does group A betahemolytic streptococcal infection increase risk for behavioral and neuropsychiatric symptoms in children? Arch Pediatr Adolesc Med 2004; 158: 848–56. Perlmutter SJ, Leitman SF, Garvey MA, et al. Therapeutic plasma exchange and intravenous immunoglobulin for obsessivecompulsive disorder and tic disorders in childhood. Lancet 1999; 354: 1153–58. Church AJ, Dale RC, Giovannoni G. Anti-basal ganglia antibodies: a possible diagnostic utility in idiopathic movement disorders? Arch Dis Child 2004; 89: 611–14. Singer HS, Loiselle CR, Lee O, Minzer K, Swedo S, Grus FH. Antibasal ganglia antibodies in PANDAS. Mov Disord 2004; 19: 406–15. Hong JJ, Rippel CA, Yoon DY, Pardo CA, Singer HS. Comparison of anti-basal ganglia antibodies in PANDAS and Tourette Syndrome. Ann Neurol 2004; 56: S129. Loiselle CR, Lee O, Moran TH, Singer HS. Striatal microinfusion of Tourette syndrome and PANDAS sera: failure to induce behavioral changes. Mov Disord 2004; 19: 390–96. Singer H, Mink J, Hallett J, Lombroso P. Is the microinfusion of antineuronal antibodies into rodent striatum a valid method to evalutate autoimmunity in pediatric movement disorders? Ann Neurol 2004; 56 (suppl 8): S89. Singer HS, Minzer K. Neurobiology of Tourette’s syndrome: concepts of neuroanatomic localization and neurochemical abnormalities. Brain Dev 2003; 25 (suppl 1): S70–84. Berardelli A, Curra A, Fabbrini G, Gilio F, Manfredi M. Pathophysiology of tics and Tourette syndrome. J Neurol 2003; 250: 781–87. Hoekstra PJ, Anderson GM, Limburg PC, Korf J, Kallenberg CG, Minderaa RB. Neurobiology and neuroimmunology of Tourette’s syndrome: an update. Cell Mol Life Sci 2004; 61: 886–98. Singer HS, Reiss AL, Brown JE, et al. Volumetric MRI changes in basal ganglia of children with Tourette’s syndrome. Neurology 1993; 43: 950–56. Peterson BS, Thomas P, Kane MJ, et al. Basal Ganglia volumes in patients with Gilles de la Tourette syndrome. Arch Gen Psychiatry 2003; 60: 415–24. Mahone EM, Koth CW, Cutting L, Singer HS, Denckla MB. Executive function in fluency and recall measures among children with Tourette syndrome or ADHD. J Int Neuropsychol Soc 2001; 7: 102–11. Peterson BS, Staib L, Scahill L, et al. Regional brain and ventricular volumes in Tourette syndrome. Arch Gen Psychiatry 2001; 58: 427–40.

113 Fredericksen KA, Cutting LE, Kates WR, et al. Disproportionate increases of white matter in right frontal lobe in Tourette syndrome. Neurology 2002; 58: 85–89. 114 Kates WR, Frederiksen M, Mostofsky SH, et al. MRI parcellation of the frontal lobe in boys with attention deficit hyperactivity disorder or Tourette syndrome. Psychiatry Res 2002; 116: 63–81. 115 Peterson BS, Leckman JF, Duncan JS, et al. Corpus callosum morphology from magnetic resonance images in Tourette’s syndrome. Psychiatry Res 1994; 55: 85–99. 116 Baumgardner TL, Singer HS, Denckla MB, et al. Corpus callosum morphology in children with Tourette syndrome and attention deficit hyperactivity disorder. Neurology 1996; 47: 477–82. 117 Plessen KJ, Wentzel-Larsen T, Hugdahl K, et al. Altered interhemispheric connectivity in individuals with Tourette’s disorder. Am J Psychiatry 2004; 161: 2028–37. 118 Peterson BS, Skudlarski P, Anderson AW, et al. A functional magnetic resonance imaging study of tic suppression in Tourette syndrome. Arch Gen Psychiatry 1998; 55: 326–33. 119 Stern E, Silbersweig DA, Chee KY, et al. A functional neuroanatomy of tics in Tourette syndrome. Arch Gen Psychiatry 2000; 57: 741–48. 120 Moll GH, Wischer S, Heinrich H, Tergau F, Paulus W, Rothenberger A. Deficient motor control in children with tic disorder: evidence from transcranial magnetic stimulation. Neurosci Lett 1999; 272: 37–40. 121 Minzer K, Lee O, Hong JJ, Singer HS. Increased prefrontal D2 protein in Tourette syndrome: a postmortem analysis of frontal cortex and striatum. J Neurol Sci 2004; 219: 55–61. 122 Hong JJ, Loiselle CR, Yoon DY, Lee O, Becker KG, Singer HS. Microarray analysis in Tourette syndrome postmortem putamen. J Neurol Sci 2004; 225: 57–64. 123 Singer HS, Szymanski S, Giuliano J, et al. Elevated intrasynaptic dopamine release in Tourette’s syndrome measured by PET. Am J Psychiatry 2002; 159: 1329–36. 124 Wong DF, Singer HS, Brandt J, et al. D2-like dopamine receptor density in Tourette syndrome measured by PET. J Nucl Med 1997; 38: 1243–47. 125 Serra-Mestres J, Ring HA, Costa DC, et al. Dopamine transporter binding in Gilles de la Tourette syndrome: a [123I]FP-CIT/SPECT study. Acta Psychiatr Scand 2004; 109: 140–46. 126 Wolf SS, Jones DW, Knable MB, et al. Tourette syndrome: prediction of phenotypic variation in monozygotic twins by caudate nucleus D2 receptor binding. Science 1996; 273: 1225–27. 127 Albin RL, Koeppe RA, Bohnen NI, et al. Increased ventral striatal monoaminergic innervation in Tourette syndrome. Neurology 2003; 61: 310–15. 128 Singer HS, Butler IJ, Tune LE, Seifert WE Jr., Coyle JT. Dopaminergic dsyfunction in Tourette syndrome. Ann Neurol 1982; 12: 361–66. 129 Singer HS, Hahn IH, Moran TH. Abnormal dopamine uptake sites in postmortem striatum from patients with Tourette’s syndrome. Ann Neurol 1991; 30: 558–62. 130 Singer HS, Dickson J, Martinie D, Levine M. Second messenger systems in Tourette’s syndrome. J Neurol Sci 1995; 128: 78–83. 131 Gonzalez-Burgos G, Kroner S, Krimer LS, et al. Dopamine modulation of neuronal function in the monkey prefrontal cortex. Physiol Behav 2002; 77: 537–43. 132 Bergin A, Waranch HR, Brown J, Carson K, Singer HS. Relaxation therapy in Tourette syndrome: a pilot study. Pediatr Neurol 1998; 18: 136–42. 133 Wilhelm S, Deckersbach T, Coffey BJ, Bohne A, Peterson AL, Baer L. Habit reversal versus supportive psychotherapy for Tourette’s disorder: a randomized controlled trial. Am J Psychiatry 2003; 160: 1175–77. 134 Woods DW, Twohig MP, Flessner CA, Roloff TJ. Treatment of vocal tics in children with Tourette syndrome: investigating the efficacy of habit reversal. J Appl Behav Anal 2003; 36: 109–12. 135 Wu L, Li H, Kang L. 156 cases of Gilles de la Tourette’s syndrome treated by acupuncture. J Tradit Chin Med 1996; 16: 211–13. 136 Gaffney GR, Perry PJ, Lund BC, Bever-Stille KA, Arndt S, Kuperman S. Risperidone versus clonidine in the treatment of children and adolescents with Tourette’s syndrome. J Am Acad Child Adolesc Psychiatry 2002; 41: 330–36.

http://neurology.thelancet.com Vol 4 March 2005

Review

137 Scahill L, Chappell PB, Kim YS, et al. A placebo-controlled study of guanfacine hydrochloride in the treatment of children with tic disorders and attention deficit hyperactivity disorder. Am J Psychiatry 2001; 158: 1067–74. 138 Singer HS, Wendlandt J, Krieger M, Giuliano J. Baclofen treatment in Tourette syndrome: a double-blind, placebo-controlled, crossover trial. Neurology 2001; 56: 599–604. 139 Gonce M, Barbeau A. Seven cases of Gilles de la Tourette’s syndrome: partial relief with clonazepam: a pilot study. Can J Neurol Sci 1977; 4: 279–83. 140 Scahill L, Leckman JF, Schultz RT, Katsovich L, Peterson BS. A placebo-controlled trial of risperidone in Tourette syndrome. Neurology 2003; 60: 1130–35. 141 Dion Y, Annable L, Sandor P, Chouinard G. Risperidone in the treatment of tourette syndrome: a double-blind, placebo-controlled trial. J Clin Psychopharmacol 2002; 22: 31–39. 142 Gilbert DL, Batterson JR, Sethuraman G, Sallee FR. Tic reduction with risperidone versus pimozide in a randomized, double-blind, crossover trial. J Am Acad Child Adolesc Psychiatry 2004; 43: 206–14. 143 Kelly DV, Beique LC, Bowmer MI. Extrapyramidal symptoms with ritonavir/indinavir plus risperidone. Ann Pharmacother 2002; 36: 827–30. 144 Stephens RJ, Bassel C, Sandor P. Olanzapine in the treatment of aggression and tics in children with Tourette’s syndrome: a pilot study. J Child Adolesc Psychopharmacol 2004; 14: 255–66. 145 Budman CL, Gayer A, Lesser M, Shi Q, Bruun RD. An open-label study of the treatment efficacy of olanzapine for Tourette’s disorder. J Clin Psychiatry 2001; 62: 290–94. 146 Sallee FR, Kurlan R, Goetz CG, et al. Ziprasidone treatment of children and adolescents with Tourette’s syndrome: a pilot study. J Am Acad Child Adolesc Psychiatry 2000; 39: 292–99. 147 Sallee FR, Gilbert DL, Vinks AA, Miceli JJ, Robarge L, Wilner K. Pharmacodynamics of ziprasidone in children and adolescents: impact on dopamine transmission. J Am Acad Child Adolesc Psychiatry 2003; 42: 902–07. 148 Mukaddes NM, Abali O. Quetiapine treatment of children and adolescents with Tourette’s disorder. J Child Adolesc Psychopharmacol 2003; 13: 295–99. 149 Schaller JL, Behar D. Quetiapine treatment of adolescent and child tic disorders: two case reports. Eur Child Adolesc Psychiatry 2002; 11: 196–97. 150 Schmider J, Hoff P. Clozapine in Tourette’s syndrome. J Clin Psychopharmacol 1998; 18: 88–89. 151 Jankovic J, Orman J. Tetrabenazine therapy of dystonia, chorea, tics, and other dyskinesias. Neurology 1988; 38: 391–94.

http://neurology.thelancet.com Vol 4 March 2005

152 Gilbert DL, Dure L, Sethuraman G, Raab D, Lane J, Sallee FR. Tic reduction with pergolide in a randomized controlled trial in children. Neurology 2003; 60: 606–11. 153 Anca MH, Giladi N, Korczyn AD. Ropinirole in Gilles de la Tourette syndrome. Neurology 2004; 62: 1626–27. 154 Goetz CG, Stebbins GT, Thelen JA. Talipexole and adult Gilles de la Tourette’s syndrome: double-blind, placebo-controlled clinical trial. Mov Disord 1994; 9: 315–17. 155 Muller-Vahl KR, Schneider U, Prevedel H, et al. Delta 9tetrahydrocannabinol (THC) is effective in the treatment of tics in Tourette syndrome: a 6-week randomized trial. J Clin Psychiatry 2003; 64: 459–65. 156 Muller-Vahl KR, Schneider U, Koblenz A, et al. Treatment of Tourette’s syndrome with delta 9-tetrahydrocannabinol (THC): a randomized crossover trial. Pharmacopsychiatry 2002; 35: 57–61. 157 Dursun SM, Kutcher S. Smoking, nicotine and psychiatric disorders: evidence for therapeutic role, controversies and implications for future research. Med Hypotheses 1999; 52: 101–9. 158 Sanberg PR, Silver AA, Shytle RD, et al. Nicotine for the treatment of Tourette’s syndrome. Pharmacol Ther 1997; 74: 21–25. 159 Hoopes SP. Donepezil for Tourette’s disorder and ADHD. J Clin Psychopharmacol 1999; 19: 381–82. 160 Hoekstra PJ, Minderaa RB, Kallenberg CG. Lack of effect of intravenous immunoglobulins on tics: a double-blind placebocontrolled study. J Clin Psychiatry 2004; 65: 537–42. 161 Awaad Y. Tics in Tourette syndrome: new treatment options. J Child Neurol 1999; 14: 316–19. 162 Trimble MR, Whurr R, Brookes G, Robertson MM. Vocal tics in Gilles de la Tourette syndrome treated with botulinum toxin injections. Mov Disord 1998; 13: 617–19. 163 Porta M, Maggioni G, Ottaviani F, Schindler A. Treatment of phonic tics in patients with Tourette’s syndrome using botulinum toxin type A. Neurol Sci 2004; 24: 420–23. 164 Temel Y, Visser-Vandewalle V. Surgery in Tourette syndrome. Mov Disord 2004; 19: 3–14. 165 Vandewalle V, van der Linden C, Groenewegen HJ, Caemaert J. Stereotactic treatment of Gilles de la Tourette syndrome by high frequency stimulation of thalamus. Lancet 1999; 353: 724. 166 Hassler R, Dieckmann G. Stereotaxic treatment of tics and inarticulate cries or coprolalia considered as motor obsessional phenomena in Gilles de la Tourette’s disease. Rev Neurol (Paris) 1970; 123: 89–100.

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