JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL SCIENCES

Jiao Fuyong,Guo Xiangyang,Yan Xianpeng,Wei Li. Update situation of . J Pharm Biomed Sci 2014; 04(04): 327-337.

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ISSN NO- 2230 – 7885 CODEN JPBSCT NLM Title: J Pharm Biomed Sci.

Jiao Fuyong,Guo Xiangyang,Yan Xianpeng,Wei Li

Review article Update situation of Tourette Syndrome

Fuyong Jiao1,*, Xiangyang Guo2, Xianpeng Yan3, Li Wei4

Affiliation:- Executive councilor of International Society for 1Professor, Department of Pediatrics the Shaanxi Prevention of Child Abuse and Neglect ( ISPCAN ) Phone: ( 86) 029 -85368194, 85521331ext2361(O) Provincial People's Hospital of Xi,an Jiaotong Mail Add: No.256 youyi West Rd. Xi,an 710068 China Univeristy, Xi,an China [email protected] 2 Assistant Professor, Section of pediatric Neurology, Dept. of Pediatrics the Shaanxi Provincial People's Abstract: Hospital of Xi,an Jiaotong Univeristy, Xi,an China Tourette syndrome is an inherited neuropsychiatric 3Department of Pediatrics the Shaanxi Provincial disorder with onset in childhood, characterized by People's Hospital of Xi,an Jiaotong Univeristy, Xi,an multiple motor and at least one vocal . As the China diagnostic threshold and assessment methodology 4Department of Pediatrics the Shaanxi Provincial have moved towards recognition of milder cases, the People's Hospital of Xi,an Jiaotong Univeristy, Xi,an prevalence increase gradually. Males are more likely China than females to express tics. The exact cause of TS is

unknown, but environmental insults interact with

The name of the department(s) and institution(s) to genetic or other risk factors to engender the which the work should be attributed: specificity suggested by neuropathological findings. Section of pediatric Neurology, Department of The treatment of TS focuses on identifying and Pediatrics, 3rd affiliated hospital, Xi,an Jiaotong helping the individual manage the most troubling or University, Xi,an, China impairing symptoms. Knowledge, education and understanding are uppermost in management plans. *To whom it corresponds: New studies on large prospective cohorts of patients Fuyong Jiao. of different age and the identification of reliable Prof. and Head biomarkers or environmental insults are needed. Dept. of Pediatrics the Shaanxi Provincial People's Hospital of Xi,an Jiaotong Univeristy, Xi,an China Tourette syndrome; environmental President of China Society for Prevention of Child Keywords: Abuse and Neglect insults; ; supportive environment.

Article citation: Jiao Fuyong,Guo Xiangyang,Yan Xianpeng,Wei Li. Update situation of Tourette syndrome. J Pharm Biomed Sci 2014; 04(04): 327-337. Available at www.jpbms.info.

INTRODUCTION ourette syndrome (also called Tourette' Gilles de la Tourette, a French physician and disorder, Gilles de la Tourette syndrome, or neurologist, who published an account of nine T more commonly simply Tourette's or TS) is patients with TS in 1885. TS was once considered an inherited neuropsychiatric disorder with onset a rare and bizarre syndrome, most often in childhood, characterized by multiple physical associated with the exclamation of obscene words (motor) tics and at least one vocal (phonic) tic. or socially inappropriate and derogatory remarks, These tics characteristically wax and wane, can be but this symptom is present in only a small suppressed temporarily, and are preceded by a minority of people with TS1. TS is no longer . TS is defined as part of a considered a rare condition, but it is not always spectrum of tic disorders, which includes transient correctly identified because most cases are mild and chronic tics. TS was first reported by Georges and the severity of tics decreases for most children

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Jiao Fuyong,Guo Xiangyang,Yan Xianpeng,Wei Li as they pass through adolescence. Between 0.4% common tics of eye blinking, coughing, throat and 3.8% of children ages 5 to 18 may have TS2, clearing, sniffing, and facial movements. Extreme the prevalence of transient and chronic tics in TS in adulthood is a rarity, and TS does not school-age children is higher, with the more adversely affect intelligence or . were fewer than 100 cases in the United States,11 EPIDEMIOLOGY and a 1973 registry reported only 485 cases The tics of TS begin in childhood and tend to remit worldwide12. However, multiple studies published or subside with maturity; thus, a diagnosis may no since 2000 have consistently demonstrated that longer be warranted for many adults, and the prevalence is much higher than previously observed prevalence rates are higher among thought13. Discrepancies across current and prior children than adults2. As children pass through prevalence estimates come from several factors: adolescence, about 25% become tic-free, almost ascertainment bias in earlier samples drawn from one-half see their tics diminish to a minimal or clinically referred cases, assessment methods that mild level, and less than one-quarter have may fail to detect milder cases, and differences in persistent tics. Only 5 to 14% of adults experience diagnostic criteria and thresholds12. There were worse tics in adulthood than in childhood1,4. few broad-based community studies published TS is found among all social, racial and ethnic before 2000 and until the 1980s, most groups and has been reported in all parts of the epidemiological studies of Tourette syndrome world1,5; it is three to four times more frequent were based on individuals referred to tertiary care among males than among females2. The reported or specialty clinics14. Children with milder prevalence of TS varies "according to the source, symptoms are unlikely to be referred to specialty age, and of the sample; the ascertainment clinics, so these studies have an inherent bias procedures; and diagnostic system"5 from a low of towards more severe cases15. Studies of TS are 0.05% in a 1993 study to a high of 2.9% in a 1998 vulnerable to error because tics vary in intensity study1. and expression, are often intermittent, and are not always recognized by clinicians, patients, family Up to 1% of the overall population experiences tic members, friends or teachers16,17; approximately disorders, including chronic tics and transient tics 20% of persons with TS do not recognize that they of childhood6. Chronic tics affect 5% of children, have tics16. Newer studies—recognizing that tics and transient tics affect up to 20%7. Robertson may often be undiagnosed and hard to detect—use suggests that the prevalence of TS alone in the direct classroom observation and multiple general population is also 1%, with a range informants (parent, teacher, and trained reported between 0.4% and 3.8% for children ages observers), and therefore record more cases than 5 to 182. Singer states the prevalence of TS in the older studies relying on referrals18.19. As the overall population at any time is 0.1% for diagnostic threshold and assessment methodology impairing cases and 0.6% for all cases1, while have moved towards recognition of milder cases, Bloch et al., states the overall prevalence as the result is an increase in estimated prevalence13. between 0.3% and 1% 8. According to Lombroso and Scahill the emerging consensus is that 0.1% to TS is associated with several comorbid conditions, 1% of children have TS9. Bloch and Leckman and or co-occurring diagnoses, which are often the Swain report a range of prevalence in children of major source of impairment for an affected child5,8. 0.4 to 0.6%5,7,while Du et al. report that 1 to 3% of Most individuals with tics do not seek medical Western school-age children have TS4. Prevalence attention, so epidemiological studies of TS reflect a rates in special education populations are higher2. strong ascertainment bias8, but among those who Using year 2000 census data, a prevalence range of do warrant medical attention, the majorities have 0.1 to 1% yields an estimate of 53,000–530,000 other conditions, and up to 50% have ADHD or school-age children with TS in the US6, and a OCD8. One author reports that a ten-year overview prevalence estimate of 0.1% means that in 2001 of patient records revealed about 40% of patients about 553,000 people in the UK age 5 or older with TS have "TS-only" or "pure TS", referring to would have TS. Most cases would be mild and Tourette syndrome in the absence of ADHD, OCD almost unrecognizable in older individuals10. TS and other disorders20,21. In children with tics, the was once thought to be rare in 1972, the US additional presence of ADHD is associated with National Institutes of Health (NIH) believed there functional impairment, disruptive behavior, and tic severity. Other comorbid conditions include

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Jiao Fuyong,Guo Xiangyang,Yan Xianpeng,Wei Li self-injurious behaviors (SIB), anxiety, depression, the precise etiology is unknown. Tics are believed personality disorders, oppositional defiant to result from dysfunction in cortical and disorder, and conduct disorders22. subcortical regions, the thalamus, basal ganglia and frontal cortex23. Neuroanatomic models AETIOLOGY implicate failures in circuits connecting the brain's The exact cause of TS is unknown, but it is well cortex and subcortex19, and imaging techniques established that both genetic and environmental implicate the basal ganglia and frontal cortex8. factors are involved23. Genetic epidemiology A series of parallel cortico-striatal-thalamocortical studies have shown that the overwhelming (CSTC) circuits has provided a clue for majority of cases of TS are inherited, although the understanding the interconnected neurobiological exact mode of inheritance is not yet known and no relationships that exist between TS and its gene has been identified4,8,24. In other cases, tics multiple comorbid problems33-35. In classical are associated with disorders other than TS, a models of movement disorders the basal ganglia phenomenon known as tourettism25. was believed to influence behavior by changing A person with TS has about a 50% chance of cortical excitability through the interplay of the passing the gene(s) to one of his or her children, “direct” [striatum to globus pallidus interna (GPi) but TS is a condition of variable expression and and the multisynaptic “indirect” striatum to globus incomplete penetrance26. Thus, not everyone who pallidus externa (GPe) to subthalamic nucleus inherits the genetic vulnerability will show (STN) to GPi pathway36. According to this model, symptoms; even close family members may show hyperkinetic disorders were the result of different severities of symptoms, or no symptoms increased cortical excitability, due to either a at all. The gene(s) may express as TS, as a milder reduction of direct pathway excitatory effect or an (transient or chronic tics), or as increase in the indirect inhibitory effect. Since this obsessive–compulsive symptoms without tics. direct/indirect pathway approach failed to Only a minority of the children who inherit the address the specificity of tics, other hypotheses gene(s) have symptoms severe enough to require have been developed that view the basal ganglia as medical attention27. Gender appears to have a role performing a process of action selection, i.e., in the expression of the genetic vulnerability: focused facilitation of selected movements and males are more likely than females to express inhibition of competing motor patterns37. Within tics28. this system, tics are viewed as a focal excitatory abnormality in the striatum that causes an Non-genetic, environmental, post-infectious, or erroneous inhibition of a group of neurons in the psychosocial factors—while not causing TS—can GPi and in turn a disinhibition of cortical influence its severity16. Autoimmune processes neurons38,39. may affect tic onset and exacerbation in some cases. In 1998, a team at the US National Institute Functional imaging has shown that activity in of Mental Health proposed a hypothesis based on striatum, as well as in prefrontal and premotor observation of 50 children that both obsessive– cortex, correlates with the frequency and intensity compulsive disorder (OCD) and tic disorders may of tics40. Voluntary tic suppression leads to arise in a subset of children as a result of a activation of the basal ganglia, as well as of poststreptococcal autoimmune process2. This afferent cortical areas. The magnitude of this contentious hypothesis is the focus of clinical and activation correlates inversely with tic severity41. laboratory research, but remains unproven1,2,29. Despite a long-standing interest in the Some forms of OCD may be genetically linked to contribution of the basal ganglia to TS, it is only TS5,30. A subset of OCD is thought to be relatively recently that reproducible cellular etiologically related to TS and may be a different abnormalities in these regions have been expression of the same factors that are important identified in post-mortem studies. Using unbiased for the expression of tics31. The genetic stereological counts in brains from adult TS relationship of ADHD to Tourette syndrome, patients and matched controls, Flora Vaccarino’s however, has not been fully established21. The laboratory at Yale42 found a reduction in exact mechanism affecting the inherited parvalbumin-expressing fast-spiking interneurons vulnerability to TS has not been established, and in the dorsal striatum of affected individuals. In contrast, the number and density of these neurons

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Jiao Fuyong,Guo Xiangyang,Yan Xianpeng,Wei Li in the globus pallidus, in which they constitute the medications can treat the dystonic effects of D2 principal cell type, was increased in patients. This antagonism; and ACh and dopamine are oppositely may indicate a developmental abnormality in cell regulated by reinforcement during certain migration, whereby an approximately normal learning tasks50. A reduction in TAN number in number of parvalbumin-expressing neurons are Tourette syndrome, therefore, may lead to generated but become abnormally distributed disinhibited and excessive dopamine tone, between striatum and globus pallidus. producing a hyperdopaminergic state in TS. A recent follow-up study from the same laboratory replicated this finding in a somewhat larger series GENETICS of patients43. In addition, a second population of The familial nature of Tourette syndrome has been striatal interneurons, the cholinergic tonically well appreciated from its initial description by active neurons (TANs), was reduced in the dorsal Gilles de la Tourette in 1885. studies, though striatum (both caudate and putamen). In contrast, relatively modest in size, have long supported a neither medium spiny neurons, the predominant high degree of heritability51. More recent studies52- cell type in the striatum, nor mediumsized 54 point to complex inheritance. In comparison to calretinin-positive interneurons were decreased. many other neuropsychiatric syndromes, the Understanding the development of these defined volume of data from genetic studies in TS remains populations of interneurons may lead to new quite limited. insights into the manner in which genetic, toxic, Many fundamental questions remain regarding the infectious, hypoxic, or other environmental insults overall genomic architecture of Tourette disrupt their division, migration, differentiation, or syndrome, including the potential contribution of integration into local circuits and thus lead to the common polymorphisms, the relevance of types of circuit-level abnormalities thought to transmitted and de novo submicroscopic copy underlie TS. The considerable evidence for a number variation (CNV). Sundaram and genetic contribution suggests that developmental colleagues55 reporting on 184 individuals (111 disruption plays a key role. The interaction of probands). The authors used state-of-the-art environmental factors and disrupted methods to control for potential confounds and, neurodevelopment is suggested by the finding that even in this small sample, identified an overlap of neonatal hypoxia is a predictor of tic severity in genetic risks among diagnostically distinct TS44,45, though this finding has not been uniformly syndromes, identifying rare CNVs previously observed across all studies46. In experimental implicated in disorders and animals, developmental hypoxia appears to schizophrenia, including the gene NRNX1 and a produce particular damage to interneurons, at specific region of 1q21. in 2003 a least in cortex47, though this phenomenon has not chromosomal insertion at 7q35–q36 was found to yet been documented in detail in the striatum. It disrupt the CNTNAP2 locus in three affected may be that environmental insults interact with individuals from a single family43. Similarly, a genetic or other risk factors to engender the involving coding segments of the gene specificity suggested by neuropathological NLGN4X (neuroligin 4X) was identified in a family findings43. with Tourette syndrome and autism57, These studies highlight the increasing likelihood that The observed interneuronal pathology is specific genetic variations disrupting key consistent with a long-standing conceptualization molecular pathways underlying of TS, at least in part, as involving excessive neurodevelopmental processes may manifest in a dopamine. This notion is supported by model wide range of behavioral and cognitive systems data, neuroimaging studies (though these phenotypes. They also point to the relevance of have not been entirely consistent in this regard) studying found in less than 1% of the and the observation that neuroleptic medications, general population. The value of the discovery of which block the D2 dopamine receptor, remain the rare variants carrying large effect sizes has also most effective pharmacotherapy for TS48. been demonstrated through a parametric linkage Acetylcholine (ACh), which in the striatum derives study of a densely affected family, in which a exclusively from the TANs, is thought to exist in an father and his eight children were affected by antagonistic balance with striatal dopamine: ACh Tourette syndrome and obsessive compulsive can reduce dopamine release in the striatum, at disorder58. Traditional linkage mapping revealed a least at lower firing frequencies49; anticholinergic

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Jiao Fuyong,Guo Xiangyang,Yan Xianpeng,Wei Li single region of the genome reaching the feeling of having something in one's throat, or a maximum theoretical LOD score (LOD=2.1) for the localized discomfort in the shoulders, leading to pedigree and sequencing of all known in the the need to clear one's throat or shrug the linkage interval revealed a single nonsense shoulders. The actual tic may be felt as relieving , in the gene for L-histidine decarboxylase this tension or sensation, similar to scratching an (HDC), the rate-limiting enzyme in histamine itch. Another example is blinking to relieve an biosynthesis. uncomfortable sensation in the eye. These urges and sensations, preceding the expression of the CLINICAL PRESENTATION AND movement or vocalization as a tic, are referred to DIAGNOSE as premonitory sensory phenomena or Tics are sudden, repetitive, nonrhythmic premonitory urges. Because of the urges that movements (motor tics) and utterances (phonic precede them, tics are described as semi-voluntary 61 tics) that involve discrete muscle groups59. Motor or "unvoluntary" , rather than specifically tics are movement-based tics, while phonic tics are involuntary; they may be experienced as a involuntary sounds produced by moving air voluntary, suppressible response to the unwanted through the nose, mouth, or throat. Although TS is premonitory urge1. Published descriptions of the the more severe expression of the spectrum of tic tics of TS identify sensory phenomena as the core disorders60, most cases are mild2. The severity of symptom of the syndrome, even though they are 67,69,70 symptoms varies widely among people with TS, not included in the diagnostic criteria . and mild cases may be undetected59. While individuals with tics are sometimes able to Tics are movements or sounds "that occur suppress their tics for limited periods of time, intermittently and unpredictably out of a doing so often results in tension or mental 1,4 background of normal motor activity",61 having exhaustion . People with TS may seek a secluded the appearance of normal behaviors gone wrong62. spot to release their symptoms, or there may be a The tics associated with TS change in number, marked increase in tics after a period of 62 frequency, severity and anatomical location. suppression at school or at work . Some people Waxing and waning—the ongoing increase and with TS may not be aware of the premonitory decrease in severity and frequency of tics—occurs urge. Children may be less aware of the differently in each individual. Tics also occur in premonitory urge associated with tics than are "bouts of bouts", which vary for each person59. adults, but their awareness tends to increase with maturity61. They may have tics for several years (the spontaneous utterance of socially before becoming aware of premonitory urges. objectionable or taboo words or phrases) is the Children may suppress tics while in the doctor's most publicized symptom of TS, but it is not office, so they may need to be observed while they required for a diagnosis of TS and only about 10% are not aware they are being watched28. The of TS patients exhibit it1. (repeating the ability to suppress tics varies among individuals, words of others) and (repeating one's and may be more developed in adults than own words) occur in a minority of cases59, while children. Although there is no such thing as a 16 the most common initial motor and vocal tics are, "typical" case of Tourette syndrome , the respectively, eye blinking and throat clearing63. condition follows a fairly reliable course in terms In contrast to the abnormal movements of other of the age of onset and the history of the severity movement disorders (for example, choreas, of symptoms. Tics may appear up to the age of dystonias, myoclonus, and dyskinesias), the tics of eighteen, but the most typical age of onset is from TS are temporarily suppressible, nonrhythmic, and five to seven59. A 1998 study of the Yale Child 20 often preceded by an unwanted premonitory Study Center showed that the ages of highest tic urge64. Immediately preceding tic onset, most severity are eight to twelve (average ten), with tics individuals with TS are aware of an urge65,66, steadily declining for most patients as they pass similar to the need to sneeze or scratch an itch. through adolescence5. The most common, first- Individuals describe the need to tic as a buildup of presenting tics are eye blinking, facial movements, tension, pressure, or energy66,67 which they sniffing and throat clearing. Initial tics present consciously choose to release, as if they had to do most frequently in midline body regions where it to relieve the sensation68 or until it feels just there are many muscles, usually the head, neck 16 right5,68. Examples of the premonitory urge are the and facial region . This can be contrasted with the stereotyped movements of other disorders (such

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Jiao Fuyong,Guo Xiangyang,Yan Xianpeng,Wei Li as stims and stereotypies of the autism spectrum majority of cases) or moderate, to severe (the rare, disorders), which typically have an earlier age of but more widely recognized and publicized cases) onset, are more symmetrical, rhythmical and 3. Coughing, eye blinking and tics that mimic bilateral, and involve the extremities (e.g., flapping asthma are commonly misdiagnosed1. the hands)72. Tics that appear early in the course The diagnosis is made based on observation of the of the condition are frequently confused with individual's symptoms and family history1, and other conditions, such as allergies, asthma, and after ruling out secondary causes of tic disorders27. vision problems: pediatricians, allergists and In patients with a typical onset and a family ophthalmologists are typically the first to see a history of tics or obsessive–compulsive disorder, a child with tics59. basic physical and neurological examination may be sufficient60. Among patients whose symptoms are severe enough to warrant referral to clinics, obsessive– There is no requirement that other comorbid compulsive disorder (OCD) and attention-deficit conditions (such as ADHD or OCD) be present1, but hyperactivity disorder (ADHD) are often if a physician believes that there may be another associated with TS5. Not all persons with TS have condition present that could explain tics, tests may ADHD or OCD or other comorbid conditions, be ordered as necessary to rule out that condition. although in clinical populations, a high percentage An example of this is when diagnostic confusion of patients presenting for care do have ADHD5,72. A between tics and seizure activity exists, which ten-year overview of patient records revealed would call for an EEG, or if there are symptoms about 40% of patients with TS have "TS-only" or that indicate an MRI to rule out brain "pure TS", referring to Tourette syndrome in the abnormalities5. TSH levels can be measured to rule absence of ADHD, OCD and other disorders20,21. out hypothyroidism, which can be a cause of tics. Another reports that 57% of 656 patients Brain imaging studies are not usually warranted74. presenting with tic disorders had uncomplicated In teenagers and adults presenting with a sudden tics, while 43% had tics plus comorbid onset of tics and other behavioral symptoms, a conditions62. urine drug screen for cocaine and stimulants might be necessary. If a family history of liver According to the revised fourth edition of the disease is present, serum copper and Diagnostic and Statistical Manual of Mental ceruloplasmin levels can rule out Wilson's Disorders (DSM-IV-TR), TS may be diagnosed disease60. Most cases are diagnosed by merely when a person exhibits both multiple motor and observing a history of tics16. Secondary causes of one or more vocal tics (although these do not need tics (not related to inherited Tourette syndrome) to be concurrent) over the period of a year, with are commonly referred to as tourettism25. no more than three consecutive tic-free months. Dystonias, choreas, other genetic conditions, and The previous DSM-IV included a requirement for secondary causes of tics should be ruled out in the "marked distress or significant impairment in differential diagnosis for TS60. Other conditions social, occupational or other important areas of that may manifest tics or stereotyped movements functioning", but this requirement was removed in include developmental disorders, autism spectrum the most recent update of the manual, in disorders75, and stereotypic movement recognition that clinicians see patients who meet disorder76,77; Sydenham's chorea; idiopathic all the other criteria for TS, but do not have dystonia; and genetic conditions such as distress or impairment73. The onset must have Huntington's disease, , occurred before the age of 18, and cannot be Hallervorden-Spatz syndrome, Duchenne attributed to the direct physiological effects of a muscular dystrophy, Wilson's disease, and substance or a general medical condition. Hence, tuberous sclerosis. Other possibilities include other medical conditions that include tics or tic- chromosomal disorders such as , like movements—such as autism or other causes Klinefelter's syndrome, XYY syndrome and fragile of —must be ruled out before X syndrome. Acquired causes of tics include drug- conferring a TS diagnosis. There are no specific induced tics, head trauma, encephalitis, stroke, medical or screening tests that can be used in and carbon monoxide poisoning25,60. The diagnosing TS5; it is frequently misdiagnosed or symptoms of Lesch-Nyhan syndrome may also be underdiagnosed, partly because of the wide confused with TS71. Most of these conditions are expression of severity, ranging from mild (the rarer than tic disorders, and a thorough history

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Jiao Fuyong,Guo Xiangyang,Yan Xianpeng,Wei Li and examination may be enough to rule them out, people with tics have comorbid conditions31, but without medical r screening tests16. Although not when those conditions are present, they often take all people with TS have comorbid conditions, most treatment priority. There is no cure for TS and no TS patients presenting for clinical care at specialty medication that works universally for all referral centers may exhibit symptoms of other individuals without significant adverse effects. conditions along with their motor and phonic Knowledge, education and understanding are tics21.Associated conditions include attention- uppermost in management plans for tic disorders1. deficit hyperactivity disorder (ADD or ADHD), The management of the symptoms of TS may obsessive–compulsive disorder (OCD), learning include pharmacological, behavioral and disabilities and sleep disorders1.Disruptive psychological therapies. While pharmacological behaviors, impaired functioning, or cognitive intervention is reserved for more severe impairment in patients with comorbid TS and symptoms, other treatments (such as supportive ADHD may be accounted for by the comorbid psychotherapy or cognitive behavioral therapy) ADHD, highlighting the importance of identifying may help to avoid or ameliorate depression and and treating comorbid conditions1,4,5,72. Disruption social isolation, and to improve family support. from tics is commonly overshadowed by comorbid Educating a patient, family, and surrounding conditions that present greater interference to the community (such as friends, school, and church) is child16. Tic disorders in the absence of ADHD do a key treatment strategy, and may be all that is not appear to be associated with disruptive required in mild cases1,18. behavior or functional impairment6, while impairment in school, family, or peer relations is Medication is available to help when symptoms greater in patients who have more comorbid interfere with functioning27. The classes of conditions and often determines whether therapy medication with the most proven efficacy in is needed62. Because comorbid conditions such as treating tics—typical and atypical neuroleptics OCD and ADHD can be more impairing than tics, including risperidone (trade name Risperdal), these conditions are included in an evaluation of ziprasidone (Geodon), haloperidol (Haldol), patients presenting with tics. The initial pimozide (Orap) and fluphenazine (Prolixin)—can assessment of a patient referred for a tic disorder have long-term and short-term adverse effects74. should include a thorough evaluation, including a The antihypertensive agents clonidine (trade family history of tics, ADHD, obsessive–compulsive name Catapres) and guanfacine (Tenex) are also symptoms, and other chronic medical, psychiatric used to treat tics; studies show variable efficacy, and neurological conditions. Children and but a lower side effect profile than the adolescents with TS who have learning difficulties neuroleptics79,88-90. Stimulants and other are candidates for psychoeducational testing, medications may be useful in treating ADHD when particularly if the child also has ADHD74. it co-occurs with tic disorders. Drugs from several Undiagnosed comorbid conditions may result in other classes of medications can be used when functional impairment, and it is necessary to stimulant trials fail, including guanfacine (trade identify and treat these conditions to improve name Tenex), atomoxetine (Strattera) and tricyclic functioning. Complications may include antidepressants. Clomipramine (Anafranil), a depression, sleep problems, social discomfort and tricyclic, and SSRIs—a class of antidepressants self-injury60. including fluoxetine (Prozac), sertraline (Zoloft), and fluvoxamine (Luvox)—may be prescribed TREATMENT when a TS patient also has symptoms of The treatment of TS focuses on identifying and obsessive–compulsive disorder. Several other helping the individual manage the most troubling medications have been tried, but evidence to or impairing symptoms1. Most cases of TS are support their use is unconvincing74. The mild, and do not require pharmacological Commission approved the Spanish government of treatment27; instead, psychobehavioral therapy, Andalusia, Spain pediatrics and medical experts education, and reassurance may be sufficient78. according to DSM-IV criteria (307.23) and clinical Treatments, where warranted, can be divided into data and YGTSS (Yale scale) for 7-14 year-old those that target tics and comorbid conditions, children with Tourette using magnesium sulfate which, when present, are often a larger source of 0.5mg / (kg . d) and vitamin B6 2mg / (kg.d) (oral) impairment than the tics themselves74. Not all randomized double-blind placebo-controlled method for magnesium and vitamin B6 in efficacy

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Jiao Fuyong,Guo Xiangyang,Yan Xianpeng,Wei Li and safety were studied, the results suggest that TS, although there may be learning disabilities1. new treatments can improve and control attack Severity of tics early in life does not predict tic and help reduce side effects. severity in later life1, and prognosis is generally Because children with tics often present to favorable84, although there is no reliable means of physicians when their tics are most severe, and predicting the outcome for a particular individual. because of the waxing and waning nature of tics, it The gene or genes associated with TS have not is recommended that medication not be started been identified, and there is no potential cure84. A immediately or changed often16. Frequently, the higher rate of migraines than the general tics subside with explanation, reassurance, population and sleep disturbances are reported84. understanding of the condition and a supportive environment16. When medication is used, the goal Several studies have demonstrated that the is not to eliminate symptoms: it should be used at condition in most children improves with the lowest possible dose that manages symptoms maturity. Tics may be at their highest severity at without adverse effects, given that these may be the time that they are diagnosed, and often more disturbing than the symptoms for which improve with understanding of the condition by they were prescribed16. individuals and their families and friends. The statistical age of highest tic severity is typically Cognitive behavioral therapy (CBT) is a useful between eight and twelve, with most individuals treatment when OCD is present80, and there is experiencing steadily declining tic severity as they increasing evidence supporting the use of habit pass through adolescence. One study showed no reversal in the treatment of tics81. Relaxation correlation with tic severity and the onset of techniques, such as exercise, yoga or meditation, , in contrast with the popular belief that may be useful in relieving the stress that may tics increase at puberty. In many cases, a complete aggravate tics, but the majority of behavioral remission of tic symptoms occurs after interventions (such as relaxation training and adolescence3,85. However, a study using videotape biofeedback, with the exception of habit reversal) to record tics in adults found that, although tics has not been systematically evaluated and is not diminished in comparison with childhood and all empirically supported therapies for TS82. measures of tic severity improved by adulthood, 90% of adults still had tics. Half of the adults who TS is a spectrum disorder—its severity ranges considered themselves tic-free still displayed over a spectrum from mild to severe. The evidence of tics83. majorities of cases are mild and require no treatment27. In these cases, the impact of It is not uncommon for the parents of affected symptoms on the individual may be mild, to the children to be unaware that they, too, may have extent that casual observers might not know of had tics as children. Because TS tends to subside their condition. The overall prognosis is positive, with maturity, and because milder cases of TS are but a minority of children with Tourette syndrome now more likely to be recognized, the first has severe symptoms that persist into adulthood23. realization that a parent had tics as a child may not A study of 46 subjects at 19 years of age found that come until their offspring is diagnosed. It is not the symptoms of 80% had minimum to mild uncommon for several members of a family to be impact on their overall functioning, and that the diagnosed together, as parents bringing children other 20% experienced at least a moderate impact to a physician for an evaluation of tics become on their overall functioning59. The rare minority of aware that they, too, had tics as a child. severe cases can inhibit or prevent individuals from holding a job or having a fulfilling social life. Children with TS may suffer socially if their tics In a follow-up study of thirty-one adults with TS, are viewed as "bizarre". If a child has disabling all patients completed high school, 52% finished at tics, or tics that interfere with social or academic least two years of college, and 71% were full-time functioning, supportive psychotherapy or school employed or were pursuing higher education83. accommodations can be helpful27.Because Regardless of symptom severity, individuals with comorbid conditions (such as ADHD or OCD) can TS have a normal life span. Although the cause greater impact on overall functioning than symptoms may be lifelong and chronic for some, tics, a thorough evaluation for comorbidity is the condition is not degenerative or life- called for when symptoms and impairment threatening. Intelligence is normal in those with warrant60.

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Competing interest / Conflict of interest The author(s) have no competing interests for financial support, publication of this research, patents and royalties through this collaborative research. All authors were equally involved in discussed research work. There is no financial conflict with the subject matter discussed in the manuscript.

Copyright © 2014 Jiao Fuyong,Guo Xiangyang,Yan Xianpeng,Wei Li. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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