Tics and Tourette Syndrome

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6

Tics and Tourette Syndrome

Introduction

Tourette syndrome (TS) is named after the French physician Georges Gilles de la Tourette, who in 1885 reported nine patients with chronic disorders characterized by the presence of involuntary motor and phonic tics.1 This syndrome, however, represents only one entity in a spectrum of disorders that have tics as their cardinal feature, ranging from a mild transient form to Tourettism. In addition to tics, children with tic disorders often suffer from a variety of concomitant psychopathologies, including attention-deficit/hyperactivity disorder (ADHD), obsessive-compulsive disorder (OCD), anger outbursts, learning difficulties, sleep abnormalities, and other behaviors.

Tic Phenomenology Formal definitions of tics include involuntary, sudden, rapid, abrupt, repetitive, nonrhythmic, simple or complex movements or vocalizations (phonic productions). Nevertheless, observation either directly in the office or via homemade video is essential for the correct diagnosis. Tics are classified into two categories (motor and phonic) with each being subdivided into a simple and complex grouping. Brief rapid movements that involve only a single muscle or localized group are considered “simple” (eye blink, head jerk, shoulder shrug), whereas complex tics involve either a cluster of simple actions or a more coordinated sequence of movements. Complex motor tics can be nonpurposeful (facial or body contortions), appear purposeful but actually serve no purpose (touching, hitting, smelling, jumping, echopraxia, copropraxia), or have a dystonic character. Simple phonations include various sounds and noises (grunts, barks, sniffs, and throat clearing), whereas complex vocalizations involve the repetition of words, that is, syllables, phrases, echolalia (repeating other people’s words), palilalia (repeating one’s own words), or coprolalia (obscene words). Unique tics have included vomiting and retching,2 anterior-posterior displacement of the ­external ear,3 sign language tics,4 air swallowing,5 palatal 40

­ ovements,6 and an array of nonspeech motor behavm iors (eye blinking or deviation, head jerks, limb and trunk movements) in individuals who stutter.7 Some complex motor tics may be repetitive and appear stereotypic. Features of catatonia, including classic negative symptoms such as immobility, staring, and posturing, are referred to as “blocking” tics.8 Nontic movements that need to be distinguished include those that are drug-induced (akathisia, dystonia, stereotypy, parkinsonism), associated with common comorbidities such as OCD, ADHD, impulsive and antisocial behaviors, or are motor stereotypies.9,10 Tics have several characteristics that are useful in confirming their presence. A waxing and waning pattern, the intermixture of new and old tics, and a fluctuating frequency and intensity are expected. Brief exacerbations are often provoked by stress,11,12 anxiety, excitement, anger, fatigue, or infections, although the mechanism for prolonged tic exacerbations, whether environmental or biologic, remains to be determined. Although stress influences tics, the onset of TS is not related to stressful life events or to an interaction between stressful life events and personality.13 Tic reduction often occurs when the affected individual is concentrating, focused, emotionally pleased, or sleeping. The absence of tics during sleep is commonly reported by observers/parents. Polysomnograms of TS subjects, however, demonstrate tics in all phases of sleep.14 About 90% of adults15 and 37% of children16 report a premonitory urge/sensation just before a motor or phonic tic, vaguely defined as an urge, tension, pressure, itch, or feeling.17 Attempts to voluntarily suppress tics often trigger an exacerbation of premonitory sensations or a sense of increased internal tension. Both of these conditions resolve when the tic is permitted to occur. Misdiagnoses are common; for example, eye blinking tics may be thought to stem from ophthalmologic problems, ocular tics are confused with opsoclonus, throat-clearing tics are thought to be due to sinusitis or allergic conditions, involuntary sniffing frequently results in referral to an allergist, and a chronic ­persistent cough-like bark is called asthma.

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Chapter 6  Tics and Tourette Syndrome



Tic Disorders The diagnosis of a tic disorder is based on historical features and a clinical examination that confirms their presence and eliminates other conditions. There is no currently available blood test, brain scan, or genetic screen. Tourette syndrome represents only one entity in a spectrum of disorders that have tics as their cardinal feature, ranging from a mild transient form to TS.18 The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV), classifies tics into four major categories including Transient tic disorder (TTD), Chronic motor or vocal tic disorder (CMVTD), Tourette’s disorder (TD), and Tic disorders, not otherwise specified (Tic disorder-NOS). Recognizing that formal DSM modifications are currently under review, several diagnostic guidelines are suggested based on the following principles: a) a duration of tics for greater than 12 months is required for a chronic disorder (i.e., Tourette syndrome, TD, or CMVTD); b) a tic disorder of less than 12 months duration should be considered a Provisional tic disorder (or Tic disorder-diagnosis deferred); c) Tourette ­syndrome/TD requires the presence of both motor and vocal tics; d) tic disorders have appeared after 18-21 years (adult onset); and e) tic disorders may occur in association with other medical conditions (Tic ­disorder-NOS or Tourettism/Secondary).

Transient Tic Disorder The mildest and most common tic disorder, requires that tics be present for at least 4 weeks, resolve before 1 year, typically after several months’ duration. Since transient tic disorder requires a duration of tics for less than 1 year, the diagnosis is strictly retrospective.

Provisional Tic Disorder (Tic DisorderDiagnosis Deferred) These terms are used to designate an individual with ongoing fluctuating tics that have been present for less than 1 year. A provisional diagnosis is required because it is impossible to predict whether an individual’s tics will persist for the requisite one-year time interval required for a “chronic” designation or fall into the transient category.

Chronic Motor or Phonic Tic Disorder (CMVTD) CMVTD requires that tics be present for more than 1 year and individuals have either entirely motor or, less commonly, solely vocal tics. Several studies have documented that chronic motor tic disorder represents a mild form of Tourette syndrome and both are transmitted as inherited traits in the same family.19,20

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Tourette Syndrome and Tourette’s Disorder Formal criteria for Tourette syndrome based on the definition provided by the Tourette Syndrome Classification Study Group18 are similar to, but have minor differences from, Tourette’s disorder, as ­outlined by the DSM-IV.21 The DSM-IV criteria for Tourette’s disorder reduce the age of onset to less than 18 years and require that no tic-free interval can be greater than 3 months’ duration. Coprolalia, one of the most socially distressing symptoms, is not a diagnostic criterion, and studies have suggested that possibly fewer than 10% of patients exhibit this symptom.22

Tic Disorder; Not Otherwise Specified This category as currently defined includes all individuals who do not meet the criteria for TD, CMVTD, or TTD. However, in recognition of the fact that this category could contain subjects with ongoing tics that have been present for less than one year, a new provisional category has been provided. Tic disorder-NOS also includes individuals with tics associated with other neurological conditions. An alternate terminology for this latter group would be Tourettism, Tourette-like, or Secondary disorder.

Tourettism, Tourette-like, or Secondary Tic Disorder These are terms are suggested for tic syndromes that do not meet the criteria for TS because they are associated with another medical condition,23 such as infection,24–27 drugs,28–30 toxins,31 stroke,32,33 head trauma,34–36 peripheral trauma,37 and surgery,38,39 or found in association with a variety of sporadic, genetic, and neurodegenerative disorders, such as neuroacanthocytosis, Huntington’s disease, and Creutzfeldt-Jakob disease.40–42 This category would also include the subset of children who have the abrupt onset and repeated exacerbation of tics associated with evidence of group A β-hemolytic streptococcal infections, designated pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS).43,44 Tardive Tourette is the term for individuals who develop tics following the use of neuroleptics.45

Epidemiology Tourette syndrome occurs worldwide with increasing evidence for common features in all cultures and races. The current prevalence figure (number of cases in population at a given time) for tics in childhood is about 6% to 12% (range 4% to 24%).46–48 The precise prevalence of chronic motor and vocal tics (TS) is unknown, but the estimate for moderately severe

42 Section 3  Paroxysmal Movement Disorders

cases is 1 to 10 per 1000 children and adolescents with an additional 10 to 30 per 1000 children and adolescents having mild unidentified “true” cases.46,49,50 TS is more common in males than in females (more than 3:1), the mean age of onset is typically between 5 and 7 years, and most patients develop tics before their teenage years.47,48,51 Tic phenomenology and severity appear to be similar between children and adults.52 Adult-onset tic disorders have been reported and are often associated with potential environmental triggers, severe symptoms, greater social morbidity, and a poorer response to medications.53 TS is common in children with autism, Asperger syndrome, fragile X syndrome,54 and other autistic spectrum disorders,55 but its presence appears to be unrelated to the severity of autistic symptoms.56 Tics and related behaviors have not been found to be overrepresented among adult inpatients with psychiatric illnesses.57 Neurologic examination and neuroradiographic studies are typically normal. “Soft” signs, including abnormalities of coordination and fine motor performance, synkinesis, and motor restlessness, are often observed in affected children— especially those with ADHD.

Outcome Although TS was originally proposed to be a lifelong disorder, its course can be highly variable, with most patients having a spontaneous remission or marked improvement over time. The maximum severity of tics tends to be between ages 8 and 12 years.58 Long term, most studies support a decline in symptoms during the teenage–early adulthood years.59,60 The “rule of thirds,” that is, one third disappear, one third are better, and one third continue, is a reasonable estimate of outcome.61 Although tic resolution is reported by many adults, whether they fully resolve has been questioned.62 Proposed predictors of severity and longevity remain controversial.63 Included in this list are factors such as tic severity, fine motor control, and the volumetric size of brain regions such as caudate and subgenual areas.64,65 The presence of coexisting ­neuropsychiatric issues has a significant effect on impairment; individuals solely with chronic tics are less impaired than those with OCD, ADHD, mood disorders, and other associated behaviors.66,67

Associated Behaviors and Psychopathologies in Tic Disorders Georges Gilles de la Tourette, in his early descriptions, noted the presence of a variety of comorbid neuro-behavioral problems, including obsessive compulsive symptoms, anxieties, and phobias.1 As the list of associated

problems has expanded, it has become clear that psychopathology is more pervasive than previously thought and its clinical impact may be more significant than the tics.68 For example, health-related quality of life (HR-QOL), as measured by HR-QOL scales, confirms that outcome is predicted by comorbidities such as ADHD and OCD rather than tic severity.69,70 Hence, it is essential that the physician caring for an individual with a tic disorder be aware of potential psychopathologies, be able to differentiate comorbidities from tics, and be part of a comprehensive treatment program.

Attention-Deficit Hyperactivity Disorder ADHD is characterized by impulsivity, hyperactivity, and a decreased ability to maintain attention. Symptoms usually precede the onset of tics by 2 to 3 years. ADHD is reported to affect about 50% (range 21% to 90%) of referred cases with TS.71 Attentional impairments in TS + ADHD subjects differ from those with ADHD only, the latter having greater impairment on tests that measure visual search and mental flexibility, slower reaction times, and fewer corrective responses on simple and choice reaction time tasks.72 In patients with tics, the addition of ADHD symptoms correlates with increased psychosocial difficulties, disruptive behavior, emotional problems, functional impairment, learning disabilities, and school problems.73–76 TS and ADHD are not alternate phenotypes of a single underlying genetic cause but there is likely an overlap in their underlying neurobiology.77

Obsessive-Compulsive Disorder Obsessions are recurrent ideas, thoughts, images, or impulsions that intrude on conscious thought, are persistent, and are unwelcome (egodystonic). Compulsions are repetitive, seemingly purposeful behaviors usually performed in response to an obsession, or in accord with certain rules, or in a stereotyped fashion. Obsessivecompulsive behaviors (OCBs) become obsessive-compulsive disorder (OCD) when activities are sufficiently severe to cause marked distress, take up more than 1 hour of the day, or have a significant impact on normal routine, function, social activities, or relationships. A genetic association has been identified between OCD and TS.78–80 OCBs generally emerge several years after the onset of tics, usually during early adolescence. Behaviors occur in 20% to 89% of patients with TS and typically become more severe at a later age.81–83 Two subtypes of OCD, based on differences in prevalence in age-groups and implied etiologic relationships, have been proposed: a juvenile subtype and one related to tics.84,85 In patients with TS, OCBs usually include a need for order or routine and a requirement for things



Chapter 6  Tics and Tourette Syndrome

to be symmetric or “just right,” for example, arranging, ordering, hoarding, touching, tapping, rubbing, counting, checking for errors, and performing activities until things are symmetric or feel/look just right (“evening-up” rituals). In contrast, OCD subjects without tics typically have fear of contamination and cleaning compulsions. Differentiating OCBs from tics may be difficult, with clues favoring OCB including the following: a cognitive-based drive and need to perform the action in a particular fashion, that is, a certain number of times, until it feels “just right,” or equally on both sides of the body.

Anxiety and Depression The incidence of generalized anxiety disorder in TS subjects ranges from 19% to 80%.86,87 TS patients are likely to be more depressed than controls, and depression has correlated positively with earlier onset and longer duration of tics.86,87 Genetic studies show that major depressive disorder (MDD) is genetic but that TS and MDD are unrelated.88

Episodic Outbursts (Rage) and Self-Injurious Behavior Rage attacks, difficulty with aggression, and self-injurious behaviors are common in patients with TS.89,90 Whether these behaviors are due to the presence of other disruptive psychopathology, such as obsessions, compulsions, ADHD-related impulsivity, risk-taking behaviors, or affective disorders, is unclear.

Other Psychopathologies Antisocial behaviors, oppositional behaviors, and personality disorders are more frequent in TS, but the cause of this increase may be attributed to childhood ADHD, OCD, family, or economic issues.91 Schizotypal traits are relatively common in TS.92 A variety of other behavioral/emotional problems have been identified in patients with TS. For example, in studies based on the Child Behavior Checklist (CBCL), up to two thirds of TS subjects had abnormal scores, with clinical ­problems including OCBs, aggressiveness, hyperactivity, immaturity, withdrawal, and somatic complaints.93–95 Antisocial personality, coupled with impulsivity, occasionally leads to actions that involve the legal system, although there is no evidence that TS patients are more likely to engage in criminal behavior than those without TS.96

Academic Difficulties Poor school performance in children with tics can be secondary to several factors, including severe tics, psychosocial problems, ADHD, OCD, learning

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­ isabilities, or medications.97 For example, poor arithd metic performance was found only in children with TS who had attentional deficits.75 Individuals with TS typically have normal intellectual functioning, although there may be concurrent executive dysfunction, discrepancies between performance and verbal IQ testing, impairment of visual-perceptual achievement, and decrease in visual-motor skills.66,98–101

Sleep Disorders Problems associated with sleep have been reported in about 20% to 50% of children and young adults with TS. Common symptoms include difficulties falling asleep, difficulties staying asleep, restless sleep, increased movement-related arousals, and parasomnias.14,102 Sleep deficits may be associated with the presence of other comorbidities such as ADHD, anxiety, mood disorders, or OCD.103,104

Etiology Genetic Basis Despite Georges Gilles de la Tourette’s suggestion of an inherited nature for TS, the precise pattern of transmission and the identification of the gene remain elusive. The strongest support for a genetic disorder are studies of monozygotic twins, which show an 86% concordance rate with chronic tic disorder compared with 20% in dizygotic twins.105,106 A complex genetic etiology is also supported by a study of at-risk children free of tics at baseline who subsequently developed a tic disorder.107 A multifactorial inheritance with at least one major locus seems likely.108,109 Although susceptibility loci have been identified in TS, it is possible that no causative gene has been identified because of phenotypic heterogeneity.110 Several approaches have been used to identify the genetic site, including linkage analysis, cytogenetics, candidate gene studies, and molecular genetic studies.111 Linkage analyses have suggested a number of chromosomal locations, but without a clear reproducible locus or convergence of findings. One analysis performed in 238 affected sibling pair families and 18 multigenerational families identified significant evidence for linkage to a marker on chromosome 2p23.2,112 but studies remain inconsistent. Suggestions of an association with SLITRK1113 have not been confirmed in additional TS populations.114 The possible effects of genomic imprinting (sex of the transmitting parent affects the clinical phenotype), bilineal transmission (genetic contribution from both sides of the family),115–117 genetic heterogeneity, epigenetic factors, and gene–environment interactions further complicate the understanding of TS genetics. Potential ­epigenetic risk factors

44 Section 3  Paroxysmal Movement Disorders

that have been suggested include timing of perinatal care, severity of mother’s nausea and vomiting during the pregnancy, low proband birth weight, the Apgar score at 5 minutes, thimerosal,118 nonspecific maternal emotional stress,119 and prenatal maternal smoking.120 Further replication of these latter studies is necessary before any significance can be truly claimed. It has also been suggested that TS is not genetic but rather represents a common disorder in the general population.121

Autoimmune Disorder Several investigators have proposed that, in a subset of children, tic symptoms are caused by a preceding group A β-hemolytic streptococcal infection (GABHS).44,122 Labeled as pediatric autoimmune neuropsychiatric disorder associated with streptococcal infection (PANDAS), proposed criteria include the following: the presence of OCD and/or tic disorder; prepubertal age at onset; sudden, “explosive” onset of symptoms and/or a course of sudden exacerbations and remissions; a temporal relationship between symptoms and GABHS; and the presence of neurologic abnormalities, including hyperactivity and choreiform movements. On the basis of a model proposed for Sydenham’s chorea, it has been hypothesized that the underlying pathology in PANDAS involves an immune-mediated mechanism with molecular mimicry.44 The PANDAS hypothesis remains controversial on both clinical grounds and failure to ­confirm an immune process.123–128 For example, in many individuals the diagnosis is based on incomplete criteria,129,130 studies do not consistently support an epidemiologic link to GABHS,131 family histories are similar to individuals with standard tic disorders,132 neuropsychological functioning is similar to subjects without an infectious background,133 and the presence of proposed putative pathologic antibodies134,135 does not convey either a distinct phenotypical difference136 or structural abnormality of gray or white matter.137 Further, a longitudinal study in children with PANDAS has shown little ­association between GABHS and symptom­ exacerbation138 and no correlation between exacerbation of symptoms and changes in antineuronal antibodies, antilysoganglioside GM1 antibodies, or cytokines.127 Last, it is emphasized that the required steps to confirm autoimmunity as the basis for tic disorder have not been fulfilled, that is, the consistent identification of autoantibodies, the presence of immunoglobulins at the pathologic site, a positive response to immunomodulatory therapy, the induction of symptoms with autoantigens, and the ability to passively transfer the disorder to animal models with the induction of behavioral symptoms.139

Pathophysiology of Tic Disorders Neuroanatomic Localization A series of parallel cortico-striatal-thalamocortical (CSTC) circuits provide a unifying framework for understanding the interconnected neurobiologic relationships that exist between movement disorders and associated behaviors.140–142 The motor circuit, proposed to be abnormal in the production of tic symptoms, originates primarily from the supplementary motor cortex and projects to the putamen in a somatotopic distribution. The oculomotor circuit, possibly influencing ocular tics, begins principally in the frontal eye fields and connects to the central region of the caudate. The dorsolateral prefrontal circuit links Brodmann’s areas 9 and 10 with the dorsolateral head of the caudate and appears to be involved with “executive functions” (flexibility, organization, constructional strategy, verbal and design fluency) and “motor planning” (sequential and alternating reciprocal motor tasks). The lateral orbitofrontal circuit originates in the inferior lateral prefrontal cortex (areas 11 and 12) and projects to the ventral medial caudate. This circuit is associated with obsessive-compulsive behaviors, personality changes, mania, disinhibition, and irritability. The anterior cingulate circuit arises in the cingulate gyrus and projects to the ventral striatum, which also receives input from the amygdala, hippocampus, medial orbitofrontal cortex, entorhinal, and perirhinal cortex. Hence, as described, a variety of behavioral problems may be linked to this circuit. Although direct and indirect evidence suggests that components of CSTC circuits are involved in the expression of tic disorders, identification of the ­primary abnormality remains an area of active research. Striatum

Associations between basal ganglia dysfunction and movements in other disorders, as well as numerous neuroimaging studies,64,143–150 have led some investigators to emphasize the striatal component. Diffusiontensor magnetic resonance imaging (DT-MRI), sensitive to the diffusion of water, has been used to monitor microstructural abnormalities in TS subjects. Reduced white matter integrity of subcortical structures has been ­suggested based on increased mean water diffusivity bilaterally in the putamen and decreased uneven diffusion (anisotropy) in the right thalamus.151 One hypothesis suggests a striatal compartment abnormality at the level of striosome-matrix organization based on anatomic, physiologic, and lesion studies,152,153 the clinical response to dopamine receptor agonists,154 and the association of stereotypies with variations in the inducibility of ­immediate-early



Chapter 6  Tics and Tourette Syndrome

genes for the Fos/Fra family of transcription factors within the striosomes and matrix.155 Recent ­post-mortem investigations have compared the density of ­parvalbumin-staining inhibitory interneurons in TS. A reduced number and density of parvalbumin ­positive neurons were observed in caudate and globus pallidus externa, and a higher number in globus pallidus interna, in TS brains suggesting inhibitory deficits in basal ganglia.257 Other investigators have focused on the ventral striatum, based on its role in sequential learning and habit formation156 and imaging studies indicating monoaminergic hyperinnervation. For example, positron emission tomography (PET) imaging studies have demonstrated a ventral-to-dorsal gradient of increased striatal dopaminergic innervation using a ligand for type-2 vesicular monoamine transporters (VMAT2).157 PET studies with 11C-raclopride and amphetamine have also shown robust increases in dopamine release in the ventral striatum of TS subjects as compared with controls.158 Cortical

There is persuasive evidence to support cortical ­dysfunction in TS. Children with TS have executive dysfunction,99,100 cognitive inhibitory deficits,159 larger dorsolateral prefrontal regions on volumetric MRI,160 larger hippocampal regions,161 controversial alterations of amygdala volume and morphology,161,162 increased cortical white matter in the right frontal lobe163 or decreases in the deep left frontal region,164 and alterations in size of the corpus callosum.165,166 DT-MRI studies of the corpus callosum in TS have shown lower fractional anisotrophy, suggesting reduced white matter connectivity in this interhemispheric pathway.167 Imaging has identified frontal and parietal cortical thinning, most prominent in ventral portions of the sensory and motor homunculi.168 Additional suggestions of possible fronto-parietal control network abnormalities have been based on measures of MRI resting-state functional connectivity.169 Functional MRI studies suggest that tic suppression involves the prefrontal cortex,170 event-related PET techniques reveal correlations between tics and cortical brain activity,149 and transcranial magnetic stimulation studies demonstrate several forms of reduced inhibition in motor cortex.171,172 Direct evidence also comes from semiquantitative immunoblot investigations on ­postmortem tissue that showed a greater number of changes in prefrontal centers (BA9) than in caudate, putamen, or ventral striatum.173,174 Last, some have suggested that the primary dysfunction lies not in these circuits but rather in the midbrain. For example, building on early work by Devinsky,26

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a single MRI study has shown increased left midbrain gray matter volume in TS patients as compared with controls.175

Neurotransmitter Abnormalities Neurochemical hypotheses tend to be based on clinical responses to specific classes of medications; from cerebrospinal fluid (CSF), blood, and urine studies in relatively small numbers of patients; from neurochemical assays on a few postmortem brain tissues; and from PET or single-photon emission computed tomography (SPECT) studies.176 Although the dopaminergic system may play a dominant role, the serotoninergic, glutamatergic, GABAergic, cholinergic, noradrenergic, and opioid neurotransmitter systems may have ­additional important effects. Dopamine

With some variations, studies of the striatum have shown a slight increase in the number of striatal177 or cortical173,174 dopamine receptors, greater binding to dopamine transporters (DAT),178–180 altered DATbinding ratio after methylphenidate,181 an increased release of dopamine following amphetamine stimulation,158,182 and altered D2 receptor availability in mesolimbocortical areas.183 These findings have led to a potentially unifying hypothesis involving the tonic-phasic release of dopamine,158,182 first proposed by Grace for schizophrenia.184,185 The phasic DA hypothesis is further supported by clinical findings, including (1) the exacerbation of tics by stimulant medications, likely secondary to enhanced dopamine release from the axon terminal; (2) tic exacerbation by environmental stimuli, such as stress, anxiety, and medications, events shown to increase phasic bursts of dopamine; and (3) tic suppression with very low doses of dopamine agonists, likely due to presynaptic reduction of phasic dopamine release. Although the dopaminergic tonic-phasic model hypothesis could exist in either the cortex or striatum, a frontal dopaminergic abnormality is favored based on the presence of dopaminergic abnormalities in this area.173,174 An association has been identified between a polymorphism of the dopamine transporter gene, DAT DdeI, and TS.186 Serotonin

Direct evidence for a serotoninergic role in TS comes from serum studies in TS patients that show decreased levels of serum serotonin and tryptophan.187 Although 5-HIAA (a serotonin metabolite) levels in TS subjects were normal in the cortex,188 levels in basal ganglia189 and CSF190 were found to be decreased. Investigators

46 Section 3  Paroxysmal Movement Disorders

have reported a negative correlation between vocal tics and [123I]βCIT binding to the serotonin transporter (SERT) in the midbrain thalamus,191 indicating that serotoninergic neurotransmission in the midbrain and serotoninergic or noradrenergic neurotransmission in the thalamus may be important factors in the expression of TS. [123I]βCIT and SPECT studies investigating serotonin transporter binding capacity in TS  patients also show reduced binding in TS, but findings appear to be associated with the presence of OCD.191 The finding of diminished serotonin transporter and ­elevated serotonin 2A receptor binding in some patients has suggested a possible serotonergic modulatory effect.158 Positron emission tomography of tryptophan metabolism has demonstrated abnormalities in cortical and subcortical regions.192 The finding of increased dopamine release, decreased SERT binding potential, and possible elevation of 5-HT2A receptor binding in individuals with TS + OCD has suggested a condition of increased phasic dopamine release modulated by low 5-HT in TS + OCD.158 Polymorphic variants of tryptophan hydroxylase 2 have been postulated to be associated with TS.193 Glutamate

Glutamate is the primary excitatory neurotransmitter in the mammalian brain, with approximately 60% of brain neurons using glutamate as their primary neurotransmitter.194 Several lines of evidence suggest that a dysfunction of the glutamatergic system may have a role in TS: reduced levels of this amino acid have been identified in the globus pallidus interna (GPi), globus pallidus externa (GPe), and substantia nigra pars reticulata (SNpr) regions of four TS brains195; glutamate has an essential role in pathways involved with cortico-striatal-thalamocortical circuits189 there is an extensive interaction between the glutamate and dopamine neurotransmitter systems254-258,; and glutamatealterng medications have a beneficial therapeutic effect on obsessive-compulsive symptoms.254–255

Treatment General Principles The initial step in establishing a therapeutic plan for individuals with tic disorders is the careful evaluation of all potential issues and the determination of their resulting impairment. In conjunction with the patient, family, and school personnel, it is essential to ­identify whether tics or associated problems, for example, ADHD, OCD, school problems, or behavioral disorders, represent the greatest handicap. The discussion of tics and comorbid symptoms as separate entities frequently enables families and health care

specialists to focus on the patient’s immediate needs more effectively. A health-related quality of life scale has been developed and validated in patients with TS.69 Therapy should be targeted and reserved for those problems that are functionally disabling and not remediable by nondrug interventions. Providing clear and accurate information and allowing adequate time for questions and answers enhances the ability of patients and family members to cope with issues surrounding this disorder. For many, education about the diagnosis, outcome, genetic predisposition, underlying pathophysiologic mechanisms, and availability of ticsuppressing pharmacotherapy often obviates or delays the need for medication. The treatment of a child with TS requires a chronic commitment and often a comprehensive ­multidisciplinary approach, especially in those individuals with academic or psychiatric difficulties.

Tic Suppression There is no cure for tics, and all pharmacotherapy is symptomatic. Physicians considering pharmacologic treatment should be aware of the natural waxing and waning course of tics and the influence of ­­psychopathologies on outcome. Specific criteria for initiating tic-suppressing medication include the presence of psychosocial (i.e., loss of self-esteem; peer problems; difficulty participating in academic, work, family, social, and afterschool activities; and disruption of classroom settings) and/or musculoskeletal/physical difficulties. The goal of treatment is not complete suppression of tics, but rather their reduction to a level where they no longer cause ­significant psychosocial or physical disturbances. Nonpharmacologic Treatments

A variety of behavioral treatments (conditioning techniques, massed negative practice, relaxation training, biofeedback, awareness training, habit reversal, and hypnosis) have been proposed as alternative therapeutic approaches for tics, but few have been adequately evaluated. Massed negative practice (deliberately repeating the tic alternating with periods of rest) was suggested to be somewhat effective, but additional studies showed that the long-term benefit was minimal.196,197 Exposure and response prevention, consisting of exposure to premonitory sensory experiences during prolonged tic suppression, has been reported to be beneficial.198,199 Self-monitoring (subject taught to ­recognize and record tics) reduced symptoms in a few isolated reports, possibly by increasing patient ­awareness of these behaviors.200,201 Awareness training is usually combined with other behavioral instructions, either competing response therapy (tensing muscles that are incompatible with the tic) or with a more comprehensive habit

Chapter 6  Tics and Tourette Syndrome



reversal protocol.202–204 Habit reversal training significantly improved tics as compared with a supportive therapy group, and the beneficial effect persisted to the time of a 10-month follow-up evaluation.201,205–207 Relaxation training (biofeedback, progressive muscle relaxation, deep breathing, visual imagery, autogenic training, and producing postures and activities characteristic of a relaxed state) reduced tic severity in a formally trained group after 6 weeks of individual instruction, but values failed to reach statistical significance and improvement was short-lived.208 Preliminary studies using repetitive transcranial magnetic stimulation (rTMS) have been beneficial when the supplemental motor area is targeted,209 but of little success stimulating motor or premotor regions.210,211 In two patients, transcranial direct current stimulation was beneficial.212 Reports have suggested a worsening of symptoms associated with caffeinated beverages213 and a beneficial tic response to the use of alternative dietary therapies (i.e., vitamin B6, magnesium),214 but, to date, there is no scientific evidence to support the use of diets, food restrictions, or general use of minerals or vitamin preparations. Acupuncture was beneficial in a single study,215 but has not received much attention in the scientific literature. Pharmacotherapy

A two-tiered approach is recommended: for milder tics, nonneuroleptic medications (tier 1), and for more severe tics, typical and atypical neuroleptics (tier 2) (Figure 6-1). Therapeutic agents should be prescribed at the lowest effective dosage and the patient carefully followed with periodic determinations made about the need for continued therapy. Generally, after several months of successful treatment, consider a gradual taper of the medication during a nonstressful time, typically during vacation time. If significant symptoms reemerge, treatment is reinstituted. TREATMENT OF TICS Education Behavioral approaches Pharmacotherapy 1st tier Clonidine Guanfacine Baclofen Topiramate Levetiracetam Clonazepam

2nd tier Pimozide Fluphenazine Risperidone Aripiprazole Olanzapine Haloperidol Ziprasidone Quetiapine Sulpiride Tiapride

Other Dopamine agonists Tetrabenazine Botulinum toxin

Deep brain stimulation Figure 6-1 Approaches to the Treatment of Tics.

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Only two medications, pimozide and haloperidol, are approved by the Food and Drug Administration (FDA) for tic suppression. The extent of supporting evidence for many of the medications has been documented.216,217 Tier One Medications

In general, there is fair evidence for the use of alphaadrenergics for tic suppression as initial medications for tic suppression. Medications in this category include clonidine,218 guanfacine.219 Anticonvulsants, such as topiramate222,260 and levetiracetam,223 have been tried, although data are either limited or controversial.216,224,225 A recent placebo controlled study, although small, provided more support for tic suppressing benefit from topiramate.259 There is minimal evidence for use of baclofen 220 and long term clonazepam 221 for use for tic suppression. Tier Two Medications

Medications in this category include those that act as dopamine receptor antagonists (antipsychotics). Although often effective tic-suppressing agents, side effects from the use of typical and atypical neuroleptics frequently limit their usefulness. The sequence of drug usage varies among physicians, and the order listed in Figure 6-1 represents that of the authors. Pimozide and fluphenazine are preferred to haloperidol, because of reduced side effects. Atypical neuroleptics (risperidone, olanzapine, ziprasidone, quetiapine) are characterized by a relatively greater affinity for 5HT2 receptors than for D2 receptors and a reduced potential for extrapyramidal side effects. In this group, risperidone has been studied most extensively.226,227 Several small studies have confirmed the clinical effectiveness of olanzapine,228–230 ziprasidone,231,232 quetiapine,233,234 and aripiprazole.235,236 Tetrabenazine, a benzoquinolizine derivative that depletes the presynaptic stores of catecholamines and blocks postsynaptic dopamine receptors, may also be effective.237,238 Sulpiride and tiapride, substituted benzamides, have been beneficial in European trials, but neither is available in the United States. Other Medications and Botulinum Toxin

The dopamine agonists pergolide and ropinirole, prescribed at lower doses than used in treating Parkinson’s disease, have been beneficial, but ergot-containing medications should be avoided because of side effects.154,239 Delta-9-tetrahydrocannabinol, the major psychoactive ingredient of marijuana, has been effective,240,241 but it is unlikely that this compound, illegal in multiple countries, will have widespread use. Botulinum toxin (Botox), which reduces muscle activity by inhibiting acetylcholine release at neuromuscular junctions, has had a beneficial effect on both dystonic motor and vocal tics.242–247

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Surgical Approaches

Deep brain stimulation (DBS), a stereotactic treatment, has had preliminary success in treating tics.248–250 Target sites for high-frequency stimulation have included the centromedian-parafascicular complex of the thalamus, the globus pallidus interna, and the anterior limb of the internal capsule.251 Although this technique has several advantages over other neurosurgical approaches, pending determination of patient selection criteria and the outcome of carefully controlled clinical trials, a cautious approach is recommended.252 Other 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.253

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