A d v a n c e s i n Tou re t t e S y n d ro m e Diagnoses and Treatment Fatema J. Serajee,



, A.H.M. Mahbubul Huq,




KEYWORDS  Tourette  Tics  ADHD  OCD KEY POINTS  Tourette syndrome (TS) is a childhood-onset neurodevelopmental disorder characterized by multiple motor tics and at least one vocal or phonic tic, and often one or more comorbid psychiatric disorders.  Premonitory sensory urges before tic execution and desire for “just-right” perception are central features.  The pathophysiology involves cortico-striato-thalamo-cortical circuits and possibly dopaminergic system.  TS is considered a genetic disorder but the genetics is complex and likely involves rare mutations, common variants, and environmental and epigenetic factors.  Treatment is multimodal and includes education and reassurance, behavioral interventions, pharmacologic, and rarely, surgical interventions.


The prevalence of Tourette syndrome (TS) is approximately 0.3% to 1% with a male to female ratio of 4:1.1,2 TS is considered a disorder of cortico-striato-thalamo-cortical circuits that is involved in motor, cognitive, and motivational aspects of behavior.3 Direct striatonigral (dopamine D1 receptor) and indirect striatopallidal (dopamine D2 receptor) pathways are parallel loops in this circuit that provide excitatory and inhibitory feedback.4 Tics

Disclosure: The authors have nothing to disclose. a Department of Pediatrics, Children’s Hospital of Michigan, Wayne State University, 3901 Beaubien Street, Detroit, MI 48201, USA; b Department of Neurology, Children’s Hospital of Michigan, Wayne State University, 3901 Beaubien Street, Detroit, MI 48201, USA * Corresponding author. Department of Pediatrics, Children’s Hospital of Michigan, Wayne State University, 3901 Beaubien Street, Detroit MI 48201. E-mail address: [email protected] Pediatr Clin N Am 62 (2015) 687–701 http://dx.doi.org/10.1016/j.pcl.2015.03.007 pediatric.theclinics.com 0031-3955/15/$ – see front matter Ó 2015 Elsevier Inc. All rights reserved.


Serajee & Mahbubul Huq

and unwanted behaviors can result from reduced activity of indirect striatopallidal (D2 receptor) pathway leading deficient inhibition of unwanted or off-target movements and behavior. Consistently reported neuroanatomical abnormalities in TS include reduced caudate volumes across the lifespan, thinning of sensorimotor cortices correlating with tic severity in children, hypertrophy of the limbic and prefrontal cortices, and a smaller corpus callosum correlating with fewer symptoms in children.5 Focal ischemic damage to the striatum can produce tics.6 Similarly, tics and TS-like behavior abnormalities are elicited by local striatal disinhibition in monkeys.7 Disruption of dopaminergic modulation in basal ganglia is implicated in TS, although other neurotransmitters are likely involved.7,8 The dopamine D2 receptor antagonists haloperidol and pimozide are among the most effective used to treat severe tics.9 Although the evidence for a genetic contribution in TS is strong, its exact nature is not known. Monozygotic twins are concordant for TS approximately 50% of the time compared with 10% for dizygotic twins. When all tic disorders are considered, the concordance rate for monozygotic twins is 77% compared with 23% for dizygotic twins; studies estimate a sibling relative risk of 6 to 8.10 Segregation analyses suggest that the transmission of TS and related phenotypes within families is complex, and likely involves many genetic loci.11 Up to 40% of pedigrees with multiple affected children have bilineal inheritance of tics and obsessivecompulsive disorder (OCD). Linkage analyses results have been inconsistent; however, a locus on chromosome 2p was detected that achieved genome-wide significance (p 5 9.8  10 8).12 The genetic risks for TS include both common and rare variants and may involve complex multigenic inheritance or, in rare cases, a single major gene.13–17 Cytogenetic abnormalities involving inner mitochondrial membrane protein 2L (IMMP2L), contactin-associated protein-like 2 (CNTNAP2), neuroligin 4, X-linked (NGLN4X), and Slit and Trk-like, Family Member 1 (SLITRK1) genes have been identified in rare patients with TS.18 Chromosome microarray studies have suggested common copy number variants (CNVs) in TS and other neurodevelopmental disorders (eg, CNVs involving neurexins, neuroligins, and genes from the histaminergic and glutamatergic pathways).14,18 Several studies implicated CNVs that are seen in autism such as neurexin 1 (NRXN1), catenin, alpha 3 (CTNNA3); and 16p13.11deletions.13,14,19,20 Enrichment of genes involved in histamine signaling within CNVs, an excess of large (>500 Kb) CNVs compared with controls, and a higher burden of large deletions within regions previously known to harbor recurrent pathogenic CNVs in subjects with other neurodevelopmental disorders, have been reported.13,20 A rare coding mutation in the gene L-histidine decarboxylase, which is the ratelimiting enzyme in histamine biosynthesis, has been described.21 A genome-wide association study (GWAS) with 1285 TS European ancestry cases and 4964 ancestry-matched controls22 with a parallel GWAS of OCD23 demonstrated that the most TS heritability could be explained by common polymorphisms rather than rare mutations. In addition, TS and OCD had an estimated genetic correlation of 0.41, confirming the presence of shared genetic variation between the disorders. Nongenetic factors, including perinatal complications, maternal smoking, and maternal stress during pregnancy, may play a role.24,25 Whether the generation of tics in some individuals involves a postinfectious autoimmune component remains controversial.26

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Clinical history is of utmost importance in establishing the diagnosis. Cardinal features of TS are vocal and phonic tics. Tics are unwanted, brief, repetitive, nonrhythmic motor movements and vocalizations. Tics that involve a single muscle or a small group of muscles are considered simple; those that include a coordinated pattern of movement or sound and resemble purposeful action or speech are considered complex (Table 1). Involuntary expression of socially unacceptable words (coprolalia) or gestures (copropraxia) and nonobscene socially inappropriate behaviors are present in a small minority of individuals.27 Coprolalia and copropraxia appear when tics are most severe, and are positively associated with psychiatric comorbidity and more severe form of disease. The typical age of onset for TS is between 3 and 8 years (mean age w7 years) with motor tics most often preceding vocal tics. Tics have a waxing and waning course, suppressibility followed by rebound, and suggestibility.28 Tics tend to be aggravated by anxiety and stress and alleviated by physical and mental tasks requiring concentration. In adults and older children, tics are often preceded by premonitory sensations, a sense of inner tension that is reduced or relieved by the performance of the tic, and they may occur in orchestrated sequences.28 Comorbid psychiatric disorders are present in 90% of individuals with TS both in clinical and community cohorts. The most common comorbidities are attentiondeficit hyperactivity disorder (ADHD), OCD, autistic spectrum disorders, depression, anxiety, and behavioral disorders such as oppositional defiant and conduct disorder (Table 2).29,30 The onset of ADHD typically precedes the onset of tics and may be associated with academic, social, and family difficulties.31 ADHD symptoms often persist into adulthood despite the tendency for tics to diminish. OCD is also commonly observed in individuals with TS32 and in family members.33 Tic-related OCD may represent a subtype of OCD comprising concerns about symmetry, evening-up behaviors, obsessional counting, and “just-right” perceptions; whereas patients with pure OCD have higher rate of cleaning rituals, compulsive washing, and fears of contamination.33 Tic-related OCD also has an earlier age of Table 1 Common motor and phonic tics Motor



Eye blinking Shoulder shrugging Eye rolling Nose twitching Mouth pouting Head jerking Muscle tensing Finger flexing

Throat clearing Cough Gulping Snorting Sniffing Grunting Barking Belching Hiccough


Touching Flexing of abdomen Kissing Squatting Jumping Copropraxia Echopraxia

Coprolalia Echolalia Palilalia



Serajee & Mahbubul Huq

Table 2 Prevalence of comorbid disorders Condition

Prevalence in TS

Any neurobehavioral problem29,30



Clinical setting32: 50%–90% Community-ascertained30,34: 20%–50%



Behavior, conduct problems35


Mood disorders36

Depressive symptoms: 76% Major depression: 13% Bipolar disorder: 7%–28%



Personality disorder37


Learning disability34


Speech and language disorder35


Intellectual disability35






Pathologic nail biting39


Sleep disorders40


onset, is more common in males, and is associated with higher rate of ADHD and disruptive behaviors. Difficulties with learning are common in children and adolescents with TS.34 Specific cognitive deficits in TS consist of visuomotor integration problems, impaired fine motor skill, and executive dysfunction.41 The presence of comorbid conditions, notably ADHD and OCD, seems to significantly increase the likelihood that an individual with TS will also have learning problems or some demonstrable cognitive impairment. Parents of children with TS and ADHD also have an elevated rate of language-based learning problems. Mood disorders are common in individuals with TS.36 Dysthymia, major depressive disorder, and depressive illness occur in 13% to 76% of persons with TD who attend specialty clinics.36 Bipolar disorder has been reported in 7% to 28% of the TS population.42 Individuals with TS have significantly elevated rates of anxiety disorders, including separation anxiety, simple phobia, social phobia, and agoraphobia, compared with those who do not have TS in both community-based studies and clinically ascertained samples.38,43 Impulse control disorders, including intermittent, explosive disorder, self-injurious behavior, trichotillomania, and impulsive-compulsive sexual behavior, are more common in clinic populations with TS than in the general population.44 PHYSICAL EXAMINATION

Physical examination is usually not very helpful; however, a careful neurologic examination should be performed to exclude secondary causes. DIAGNOSIS

The diagnosis of TD is made clinically based on the history, pattern, and intensity of the symptoms. The standard diagnostic criteria for Tourette disorder in the United

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States are defined by the American Psychiatric Association Manual of Psychiatric Diseases, 5th edition (DSM V) (Table 3).45 Other movement disorders, including Huntington disease, Wilson disease, chorea, dystonia, myoclonus, dyskinesia, or stereotypies and dissociative disorders, may mimic TS. Complex motor tics may be difficult to distinguish from compulsive rituals. The early onset and waxing, waning, and fluctuating symptoms of tics, co-occurrence of simple and complex tics, normal neurologic examination, suppressibility, the premonitory sensation, and “just-right” perception are all highly suggestive of TS. Late onset of tics or the presence of complex tics in the absence of a history of simple tics should warrant further investigation. IMAGING AND ADDITIONAL TESTING

Imaging, electrophysiology, biochemical, and molecular genetic testing are of little clinical relevance currently and cannot confirm the presence of TS; however, rarely, they may be needed to establish alternative diagnoses. A neuropsychological evaluation is helpful for assessing comorbid cognitive deficits and emotional problems. Several standardized instruments may be useful for research, establishing severity, and assessing the response to medication. These include the Yale Global Tic Severity Scale,46 the Yale-Brown Obsessive Compulsive Scale,47 or the Children’s Yale-Brown Obsessive Compulsive Scale.48 PHARMACOLOGIC TREATMENT OPTIONS

 Only few large double-blind clinical trials are available for TS patients. Treatment decisions are often guided by individual needs and the personal experience of treating clinicians.  The treatment of TS should address both tics and psychiatric comorbidities, including ADHD, OCD, depression, and anxiety, which are often of greater clinical concern than the tics. Table 3 Diagnostic criteria Diagnosis

DSM V Criteria

Tourette syndrome  2 or more motor tics and at least 1 vocal tic, not necessarily concurrent  Tics present for at least 1 y  Onset before age 18 y  Tics not due to direct physiologic effects of a substance (eg, cocaine) or a general medical condition Persistent (chronic)  Single or multiple motor or vocal tics, not both motor or vocal tic  Tics present for at least 1 y  Onset before age 18 y  Tics not due to direct physiologic effects of a substance (eg, cocaine) or a general medical condition Provisional tic disorder


Single or multiple motor and/or vocal tics Tics present for

Advances in Tourette syndrome: diagnoses and treatment.

Tourette syndrome (TS) is a childhood-onset neurodevelopmental disorder characterized by multiple motor tics and at least one vocal or phonic tic, and...
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