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Tourette Syndrome

BASICS

DESCRIPTION

- Abnormality of basal ganglia development - Thought to result from a complex interaction between social, environmental, and multiple genetic abnormalities. - Mechanism is uncertain; may involve dysfunction of basal ganglia " “thalamocortical circuits, likely involving decreased inhibitory output from the basal ganglia, which results in an imbalance of inhibition and excitation in the motor cortex - Controversial pediatric autoimmune neuropsychiatric disorder association with Streptococcus (PANDAS) - TS/OCD cases linked to immunologic response to previous group A Ž ˛-hemolytic streptococcal infection (GABHS) - Thought to be linked to 10% of all TS cases - Five criteria - Presence of tic disorder and/or OCD - Prepubertal onset of neuropsychosis - History of sudden onset of symptoms and/or episodic course with abrupt symptom exacerbation, interspersed with periods of partial/complete remission - Evidence of a temporal association between onset/exacerbation of symptoms and a prior streptococcal infection - Adventitious movements during symptom exacerbation (e.g., motor hyperactivity)

- Treatment assessment - Yale Global Tic Severity Score - Tourette-Syndrome Severity Scale - Global Assessment of Functioning Scale - Gilles de la Tourette Syndrome-Quality of Life Scale

- Neuroleptics - Typical antipsychotics - High risk for extrapyramidal symptoms (EPS) - Haloperidol: initiate 0.5 mg/day and titrate 0.5 mg/week up to 1 to 4 mg at bedtime (3)[B] - FDA-approved for treating tics - Considered last option of typical antipsychotics due to lower efficacy and increased side effects compared to similar medications

- Quetiapine: initiate 100 to 150 mg/day; titrate to 100 to 600 mg/day - Well tolerated but limited data exists

- Ziprasidone: 5 to 40 mg/day - Aripiprazole: initiate 2 mg/day; titrate up to 20 or 30 mg/day - Few studies but favorable side-effect profile

- Alternative treatments - Topiramate: 25 to 200 mg/day (2)[A]; promising data but not sufficient efficacy so far to recommend as first or second line - Tetrabenazine - Baclofen

- Treatment of OCD in patients with tics (6)[B] - SSRIs - First-line treatment of OCD; can be used in TS as well - Side effects include nausea, insomnia, sexual dysfunction, headache, and agitation. - Comorbid tic disorder not a contraindication; exacerbation of tics neither clinically significant nor common. - Black box warning for suicidality with SSRIs - Fluoxetine: 10 to 80 mg/day - Fluvoxamine: 50 to 300 mg/day - Sertraline: 50 to 200 mg/day

- Tricyclic antidepressants - Clomipramine: 25 to 200 mg/day - Can be used in patients refractory to SSRIs or to augment SSRIs in partial responders - Side effects: weight gain, dry mouth, lowered seizure threshold, and constipation; ECG changes, including Q " “T prolongation and tachycardia

  • Tourette syndrome (TS) is a movement disorder most commonly seen in school-age children. A childhood-onset neurobehavioral disorder characterized by the presence of multiple motor and at least one phonic tic (see "Physical Exam " ť).Tics are sudden, brief, repetitive, stereotyped motor movements (motor tics) or sounds (phonic tics) produced by moving air through the nose, mouth, or throat.Tics tend to occur in bouts.Tics can be simple or complex.Motor tics precede vocal tics.Simple tics precede complex tics.Tics often are preceded by sensory symptoms, especially a compulsion to move.Patients are able to suppress their tics, but voluntary suppression is associated with an inner tension that results in more forceful tics when suppression ceases.System(s) affected: nervous

EPIDEMIOLOGY

Incidence

  • The onset occurs before 18 years of age.
  • Predominant ageAverage age of onset: 7 years (3 to 8 years)Tic severity is greatest at ages 7 to 12 years.96% present by age 11 yearsOf children with TS, 50% will experience complete resolution of symptoms by age 18 years (based on self-reporting).
  • Predominant sex: male > female (3:1)
  • Predominant race/ethnicity: clinically heterogeneous disorder, but non-Hispanic whites (2:1) compared with Hispanics and/or blacks

Prevalence

0.77% overall in children ‚

  • 1.06% in boys
  • 0.25% in girls

ETIOLOGY AND PATHOPHYSIOLOGY

Abnormalities of dopamine neurotransmission and receptor hypersensitivity, most likely in the ventral striatum, play a primary role in the pathophysiology. ‚

  • Abnormality of basal ganglia development
  • Thought to result from a complex interaction between social, environmental, and multiple genetic abnormalities.
  • Mechanism is uncertain; may involve dysfunction of basal ganglia " “thalamocortical circuits, likely involving decreased inhibitory output from the basal ganglia, which results in an imbalance of inhibition and excitation in the motor cortex
  • Controversial pediatric autoimmune neuropsychiatric disorder association with Streptococcus (PANDAS)TS/OCD cases linked to immunologic response to previous group A Ž ˛-hemolytic streptococcal infection (GABHS)Thought to be linked to 10% of all TS casesFive criteriaPresence of tic disorder and/or OCDPrepubertal onset of neuropsychosisHistory of sudden onset of symptoms and/or episodic course with abrupt symptom exacerbation, interspersed with periods of partial/complete remissionEvidence of a temporal association between onset/exacerbation of symptoms and a prior streptococcal infectionAdventitious movements during symptom exacerbation (e.g., motor hyperactivity)

Genetics

  • Predisposition: frequent familial history of tic disorders and OCD
  • Precise pattern of transmission and genetic origin unknown. Recent studies suggest polygenic inheritance with evidence for a locus on chromosome 17q; sequence variants in SLITRK1 gene on chromosome 13q also are associated with TS.
  • Higher concordance in monozygotic compared with dizygotic twins; wide range of phenotypes

RISK FACTORS

  • Risk of TS among relatives: 9.8 " “15%
  • First-degree relatives of individuals with TS have a 10- to 100-fold increased risk of developing TS.
  • Low birth weight, maternal stress during pregnancy, severe nausea and vomiting in 1st trimester

COMMONLY ASSOCIATED CONDITIONS

  • OCD (28 " “67%)
  • ADHD (50 " “60%)
  • Conduct disorder
  • Depression/anxiety including phobias, panic attacks, and stuttering
  • Learning disabilities (23%)
  • Impairments of visual perception, sleep disorders, restless leg syndrome, and migraine headaches

DIAGNOSIS

HISTORY

Diagnosis of TS is based on history and clinical presentation (i.e., observation of tics with/without presence of coexisting disorders). Identify comorbid conditions. ‚

PHYSICAL EXAM

  • Typically, the physical exam is normal.
  • Motor and vocal tics are the clinical hallmarks.
  • Tics fluctuate in type, frequency, and anatomic distribution over time.
  • Multiple motor tics include facial grimacing, blinking, head/neck jerking, tongue protruding, sniffing, touching, and burping.
  • Vocal tics include grunts, snorts, throat clearing, barking, yelling, hiccupping, sucking, and coughing.
  • Tics are exacerbated by anticipation, emotional upset, anxiety, or fatigue.
  • Tics subside when patient is concentrating/absorbed in activities.
  • Motor and vocal tics may persist during all stages of sleep, especially light sleep.
  • Blink-reflex abnormalities may be observed.
  • No known clinical measures reliably predict children who will continue to express tics in adulthood; severity of tics in late childhood is associated with future tic severity.
  • Diagnostic and Statistical Manual of Mental Disorders (5th ed.; DSM-5) criteria (1)[C]:A. Both multiple motor and one or more vocal tics have been present at some time during the illness, although not necessarily concurrently.B. The tics may wax and wane in frequency but have persisted for more than 1 year since first tic onset.C. Onset is before age 18 years.D. The disturbance is not attributable to the physiologic effects of a substance (e.g., cocaine) or another medical condition (e.g., Huntington disease, postviral encephalitis).

DIFFERENTIAL DIAGNOSIS

  • Chorea/Huntington disease
  • Myoclonus
  • Seizure
  • Ischemic or hemorrhagic stroke
  • Essential tremor
  • Posttraumatic/head injury
  • Headache
  • Dementia
  • Wilson disease
  • Sydenham chorea
  • Multiple sclerosis
  • Postviral encephalitis
  • Toxin exposure (e.g., carbon monoxide, cocaine)
  • Drug effects (e.g., dopamine agonists, fluoroquinolones)

DIAGNOSTIC TESTS & INTERPRETATION

Initial Tests (lab, imaging)

  • No definitive lab tests diagnose TS. Based on clinical features, particularly the presence of multiple motor and vocal tics.
  • Thyroid-stimulating hormone (TSH) should be measured because of association of tics with hyperthyroidism.
  • No imaging studies diagnose TS
  • EEG shows nonspecific abnormalities; useful only to differentiate tics from epilepsy.

Test Interpretation

  • Smaller caudate volumes in patients with TS
  • Striatal dopaminergic terminals are increased, as is striatal dopamine transporter (DAT) density.

TREATMENT

GENERAL MEASURES

  • Treatment assessmentYale Global Tic Severity ScoreTourette-Syndrome Severity ScaleGlobal Assessment of Functioning ScaleGilles de la Tourette Syndrome-Quality of Life Scale
  • A detailed history is crucial to management, because tics and comorbidities are interrelated. Goal of treatment should be to improve social functioning, self-esteem, and quality of life.
  • Educate that tics are neither voluntary nor psychiatric.
  • Many patients require no treatment; patient should play an active role in treatment decisions.
  • Educate patient, family, teachers, and friends to identify and address psychosocial stressors and environmental triggers.
  • No cure for tics: Treatment is purely symptomatic, and multimodal treatment usually is indicated.
  • Neurologic and psychiatric evaluation may be useful for other primary disorders and comorbid conditions (especially ADHD, OCD, and depression).
  • TS clusters with several comorbid conditions; each disorder must be evaluated for associated functional impairment because patients often are more disabled by their psychiatric conditions than by the tics; choice of initial treatment depends largely on worst symptoms (tics, obsessions, or impulsivity).
  • Nonpharmacologic therapy " ”reassurance and environmental modification, identification and treatment of trigger, and cognitive behavior therapy
  • When pharmacotherapy is employed, monotherapy is preferred to polytherapy.

MEDICATION

First Line

  • Atypical antipsychoticsRisperidone: now recommended for standard therapy (2)[A]Initiate 0.25 BID; titrate to 0.25 to 6 mg/dayAs effective as haloperidol and pimozide for tics with fewer side effectsEffective against comorbidities such as OCDSide effects may limit use: sedation, weight gain, and fatigue.
  • α2-Adrenergic receptor agonists (2)[B]Historically first-line agents due to favorable side-effect profile, but suboptimal efficacy in limited clinical trialsSide effects: sedation and hypotension commonInitiate therapy gradually and taper when discontinuing to avoid cardiac adverse events.Clonidine 0.1 to 0.3 mg/day given BID " “TIDMaximum dose: 0.5 mg/day25 " “50% of patients report at least some reduction in tics.Guanfacine 1 to 3 mg/day given daily or BIDLess sedating and longer duration of action compared with clonidineImproves motor/vocal tics by 30% in some studies; no better than placebo in others

Second Line

  • NeurolepticsTypical antipsychoticsHigh risk for extrapyramidal symptoms (EPS)Haloperidol: initiate 0.5 mg/day and titrate 0.5 mg/week up to 1 to 4 mg at bedtime (3)[B]FDA-approved for treating ticsConsidered last option of typical antipsychotics due to lower efficacy and increased side effects compared to similar medicationsPimozide: initiate 0.5 mg/day and titrate 0.5 mg/week up to 1 to 4 mg at bedtime (4)[A]FDA-approved for treating ticsRisk of cardiac toxicity (prolonged Q " “T interval and arrhythmias); must be given under ECG monitoring; long-term use may induce sedation, weight gain, depression, pseudoparkinsonism, and akathisia.Found to work better in long-term control of tics versus acute exacerbationsFluphenazine: 2.5 to 10 mg/dayEffective but less favored due to side effectsAtypical antipsychotics (3)[C]Olanzapine: initiate 2.5 to 5.0 mg/day; titrate up to 20 mg/dayEqually effective as haloperidol and pimozideMay cause metabolic disturbances and weight gainQuetiapine: initiate 100 to 150 mg/day; titrate to 100 to 600 mg/dayWell tolerated but limited data existsZiprasidone: 5 to 40 mg/dayAripiprazole: initiate 2 mg/day; titrate up to 20 or 30 mg/dayFew studies but favorable side-effect profile
  • Alternative treatmentsTopiramate: 25 to 200 mg/day (2)[A]; promising data but not sufficient efficacy so far to recommend as first or second lineTetrabenazineBaclofen
  • Treatment of ADHD in patients with tics (5)[A]StimulantsComorbid tic disorder is not a serious contraindication, as previously held; exacerbation of tics is neither clinically significant nor common.Methylphenidate: 2.5 to 30 mg/dayDextroamphetamine: 5 to 30 mg/dayα2-Adrenergic agonistsGuanfacineClonidineThe combination of methylphenidate and clonidine has shown superior efficacy in treating both ADHD and tic symptoms compared to monotherapy with either agent in one trial.Other medications
  • Treatment of OCD in patients with tics (6)[B]SSRIsFirst-line treatment of OCD; can be used in TS as wellSide effects include nausea, insomnia, sexual dysfunction, headache, and agitation.Comorbid tic disorder not a contraindication; exacerbation of tics neither clinically significant nor common.Black box warning for suicidality with SSRIsFluoxetine: 10 to 80 mg/dayFluvoxamine: 50 to 300 mg/daySertraline: 50 to 200 mg/dayTricyclic antidepressantsClomipramine: 25 to 200 mg/dayCan be used in patients refractory to SSRIs or to augment SSRIs in partial respondersSide effects: weight gain, dry mouth, lowered seizure threshold, and constipation; ECG changes, including Q " “T prolongation and tachycardia

ADDITIONAL THERAPIES

  • Botulinum toxin injections in severe cases or where chronic medication therapy is not preferred.
  • Habit-reversal training provides a viable tic suppression treatment: Works equally for motor and vocal tics.

SURGERY/OTHER PROCEDURES

Thalamic ablation and deep brain stimulation have been used experimentally (7)[C]. ‚

COMPLEMENTARY & ALTERNATIVE MEDICINE

Nonpharmacologic therapy ‚

  • Reassurance and environmental modification
  • Identification and treatment of triggers
  • Behavioral therapy: awareness/assertiveness training, relaxation therapy, habit-reversal therapy, and self-monitoring has shown to significantly decrease tic severity.
  • Hypnotherapy
  • Biofeedback
  • Acupuncture
  • Cannabinoids: insufficient evidence to recommend; small trials show small positive effects in some parameters (8)[A].

ONGOING CARE

FOLLOW-UP RECOMMENDATIONS

Patient Monitoring

Observe for associated psychiatric disorders. ‚

PATIENT EDUCATION

  • Reassurance that many patients with tics do not need medication; often education and/or therapy is all that is required.
  • National Tourette Syndrome Association: http://www.tsa-usa.org

PROGNOSIS

  • Symptoms will fluctuate throughout illness.
  • Tic severity typically stabilizes by age 25 years.
  • 60 " “75% of young adults show some improvement in symptoms.
  • 10 " “40% of patients will exhibit full remission.

REFERENCES

11 Kenney ‚ C, Kuo ‚ SH, Jimenez-Shahed ‚ J. Tourette 's syndrome. Am Fam Physician. 2008;77(5):651 " “658.22 Huys ‚ D, Hardenacke ‚ K, Poppe ‚ P, et al. Update on the role of antipsychotics in the treatment of Tourette syndrome. Neuropsychiatr Dis Treat. 2012;8:95 " “104.33 American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Arlington, VA: American Psychiatric Association; 2013.44 Roessner ‚ V, Plessen ‚ KJ, Rothenberger ‚ A, et al. European clinical guidelines for Tourette syndrome and other tic disorders. Part II: pharmacological treatment. Eur Child Adolesc Psychiatry. 2011;20(4):173 " “196.55 Pringsheim ‚ T, Marras ‚ C. Pimozide for tics in Tourette 's syndrome. Cochrane Database Syst Rev. 2009;(2):CD006996.66 Pringsheim ‚ T, Steeves ‚ T. Pharmacological treatment for attention deficit hyperactivity disorder (ADHD) in children with comorbid tic disorders. Cochrane Database Syst Rev. 2011;(4):CD007990.77 Lombroso ‚ PJ, Scahill ‚ L. Tourette syndrome and obsessive-compulsive disorder. Brain Dev. 2008;30(4):231 " “237.88 Savica ‚ R, Stead ‚ M, Mack ‚ KJ, et al. Deep brain stimulation in Tourette syndrome: a description of 3 patients with excellent outcome. Mayo Clin Proc. 2012;87(1):59 " “62.

ADDITIONAL READING

Curtis ‚ A, Clarke ‚ CE, Rickards ‚ HE. Cannabinoids for Tourette 's syndrome. Cochrane Database Syst Rev. 2009;(4):CD006565. ‚

CODES

ICD10

F95.2 Tourette 's disorder ‚

ICD9

307.23 Tourette 's disorder ‚

SNOMED

  • 5158005 Gilles de la Tourette 's syndrome (disorder)
  • 23772009 Dysphonia of Gilles de la Tourette 's syndrome (disorder)

CLINICAL PEARLS

  • TS is diagnosed by history and witnessing tics; have parent video patient 's tics if not present on exam in your office.
  • Nearly 50% of children with tics also have ADHD. Stimulants may be used as first-line treatment for ADHD (tics are not a contraindication, as previously believed).