Update on Tourette Disorder

7/26/2019

REBECCA K. LEHMAN, MD, FAAN ASSOCIATE PROFESSOR OF CLINICAL PEDIATRICS (CHILD NEUROLOGY) PALMETTO HEALTH-UNIVERSITY OF SOUTH CAROLINA MEDICAL GROUP PRISMA HEALTH CHILDREN’S HOSPITAL-MIDLANDS AUGUST 9, 2019

Disclosures

 Financial disclosures:  Reimbursement from TAA for travel to MAB meeting and lectures.  Participating (Sub-I/PI/Rater) in clinical trials for Neurocrine, Teva, and Emalex. Reimbursed for travel to investigator meetings. No other financial conflicts.  All of the treatments for Tourette Disorder are off- label, with the following exceptions:  Haloperidol (3 years and older)  Pimozide (12 years and older)  Aripiprazole (6-18 years)  Tetrabenazine (orphan drug designation for children 5- 16 years)

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Objectives

By the end of the lecture, attendees should be able to:  Describe the clinical characteristics of tics  Define Tourette Disorder (Syndrome)  Review the symptom criteria for the diagnosis of PANDAS (Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcal Infections)  Examine the controversies surrounding the diagnosis and treatment of PANDAS  List the neuropsychiatric conditions that commonly co-occur with TD  Outline the range of management strategies for TD  Identify resources that are available for patient education and support

What are tics?

 Movements or vocalizations that are:

 Sudden

 Abrupt

 Transient

 Repetitive

 Coordinated (stereotyped)

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Premonitory Urge

Leckman JF, Walker DE, Cohen DJ, 1993.

Other Characteristics of Tics

• Variable in appearance and frequency over time

• Briefly suppressible

• Worsened by stress and excitement

• Often reduced by focused concentration

• May persist in sleep but often abate

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Classification of Tics

Tic Symptom Dimensions Examples Simple motor tics: Sudden, brief, Eye blinking, nose twitching, grimacing, grinning, pouting, meaningless movements mouth opening, head jerking, shoulder shrugging, abdominal or buttock tensing, kicking, finger movements, rapid jerking of any part of the body Complex motor tics: Slower, longer, more Sustained “looks,” facial gestures, biting, touching “purposeful” movements objects/self, thrusting arms, throwing, banging, gestures with hands, gyrating and bending, dystonic postures, copropraxia (obscene gestures) Simple phonic tics: Sudden, meaningless Throat clearing, coughing, sniffing, spitting, screeching, sounds or noises barking, grunting, gurgling, clacking, hissing, sucking, animal noises, and innumerable other sounds

Complex phonic tics: Sudden, more Syllables, words or phrases (e.g., “Shut up!,” “Oh, okay.”); “meaningful” utterances speech atypicalities (variations in pitch, volume, etc.); palilalia (repetition of one’s own words) or echolalia (repetition of another’s words or phrases); coprolalia (obscene or inappropriate words or phrases)

I Have Tourette’s But Tourette’s Doesn’t Have Me

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Tourette Disorder (Syndrome)

 A. Both multiple motor and >/= 1 vocal tics have been present at some time during the illness, although not necessarily concurrently.  B. The tics occur many times a day (usually in bouts), nearly every day or intermittently throughout a period of >1 year; and during this period, there was never a tic-free period of >3 consecutive months.  C. Onset before age 18 years.  D. The disturbance is not due to the direct physiological effects of a substance (e.g. stimulants) or a general medical condition (e.g. HD or post-viral encephalitis)

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Other Tic Disorders

• Persistent (Chronic) Motor Tic Disorder

• Multiple motor tics

• Duration >1 year • Persistent (Chronic) Vocal Tic Disorder

• Multiple vocal tics

• Duration >1 year

Other Tic Disorders

 Provisional Tic Disorder

 Single or multiple motor and/or vocal tics

 Duration >4 weeks but <12 consecutive months

 Other Specified Tic Disorder, Unspecified Tic Disorder

 Any tic disorder that does not meet criteria for a specific tic disorder (e.g. tics lasting <4 weeks, onset after age 18)

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Epidemiology

• Boys: girls = 3-4: 1

• Affects all ethnic groups

• Prevalence among school-age children:

 Provisional (transient) tic disorders – 20-25%

 Chronic tic disorders – ~1%

 Tourette syndrome – 0.3-0.8%

Prevalence of TD

 Community studies* 0.6%

 Diagnosed + Not Diagnosed Suggests that ~50% of  Ages 0-19 years children with TS are undiagnosed  National survey data** 0.3%

 Diagnosed only

 Ages 6-17 years

*Knight et al (2012), Scharf et al., 2014. **Bitsko et al. (2014), CDC (2009)

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Leckman, J. F. et al. Pediatrics 1998;102:14-19

Take Home Point #1

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Differential Diagnosis

 Eye rolling -> Absence seizures  Blinking -> Allergy, poor vision, blepharospasm  Facial grimacing -> Dystonia  Sniffing -> Allergy  Scratching -> Scabies, lice, skin disorders  Tics during sleep -> Hypnic myoclonus, PLMS, epilepsy, parasomnias  Extremely exaggerated tics -> Functional movement disorder  Other movement disorders (myoclonus, tremor, chorea, dystonia)  Compulsions

PANDAS

 Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcal Infections (Swedo et al, 1998)

 OCD and/ or tics

 Prepubertal onset

 Episodic (saw-tooth) course

 Associated with Group A beta-hemolytic Strep infections

 Association with neurological signs

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PANS

 Pediatric Acute-Onset Neuropsychiatric Syndrome (Swedo et al, 2012)  Abrupt, dramatic onset  OCD or severely restricted food intake  Two or more of:

 Anxiety

 Emotional lability or depression

 Irritability, aggression, and/or severely oppositional behavior

 Behavioral regression

 Deterioration in school

 Sensory or motor abnormalities

 Somatic symptoms, including sleep disturbances, enuresis, and urinary frequency  Symptoms not better explained by another neurological or medical disorder

Cunningham Panel

Antibody Moleculara Upper Hesselmark Upper Limit of Normal Limit of Normal Calcium/ 130 197 Calmodulin Kinase II Anti-Dopamine 8,000 15,200 Receptor 1 Anti-Dopamine 16,000 18,400 Receptor 2 Lysoganglioside 640 1,280 GM01 Antibody Beta-Tubulin 1,000 8,000 Antibody

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Current State of Evidence

 Guidelines are based on expert consensus

 Insufficient, high-quality data to support the use of long-term antibiotics, immunomodulation, and/or tonsillectomy

 Treatment studies have small numbers of subjects

 Controlled studies have been negative

 No studies of more specific immunomodulators

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EMTICS: European Multicentre Tics in Children Studies

 Longitudinal, observational, prospective study involving 16 sites in Europe

 Goal:

 To investigate the association of environmental factors (GAS infection, psychosocial stress) with the onset and course of tics and/or OCD

 To characterize the immune response to microbial antigens and the hosts immune response regulation in association with onset and exacerbations of tics

 To increase knowledge of the human gene pathways influencing the pathogenesis of tic disorders

 To develop prediction models for the risk of onset and exacerbations of tic disorders

https://cordis.europa.eu/project/rcn/102102/reporting/en

EMTICS Design

 ONSET cohort

 At-risk individuals

 N = 260 children aged 3-10 years who are tic-free at study entry and have a first-degree relative with a chronic tic disorder

 COURSE cohort

 Affected individuals

 N = 715 youth aged 3-16 years with a tic disorder

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EMTICS Conclusions

 No indication for a role of new GAS exposures in relation to exacerbations of tic disorders

 GAS infections are frequent and exposure at some point in childhood is nearly universal

 Co-occurrence of tic exacerbations and recent new GAS exposures is most likely due to chance

 Anti-GAS responses in patients with tics did not increase after tic exacerbations

 Assessing GAS exposure in children with tic disorders is not clinically meaningful

 Possible altered post-infectious immune response in patients with TD/ OCD

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Take Home Point #2

Co-morbid Conditions

• ADHD

• Anxiety/ OCD

• Learning difficulties

• Mood disorders

• Impulse control disorders

• Dysgraphia/ fine motor impairment

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Treatment of Tics

 Take Home Point #3: Not all patients require treatment  Current treatments do not “cure” tics  Think about treating patients whose tics are causing:

 Pain/injury

 Social distress

 Significant disturbance to others in classroom environment  No scientific evidence to support the use of dietary interventions  Take Home Point #4: Comorbid disorders are often more impairing than the tics themselves and are associated with poorer long-term outcomes. Assess for comorbid disorders and treat most impairing condition first.

Take Home Point #5

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Figure 2 . Mean change from Questionnaire-Teacher baseline on the Conners Abbreviated Symptom (ASQ- Teacher) at each evaluation visit for the four treatment groups. Error bars represent 1 SEM. CLON = clonidine; MPH = methylphenidate.

Figure 3 . Mean change from baseline on the Yale Global Tic Severity Scale (Y-GTSS) at each evaluation visit for the four treatment groups. Error bars represent 1 SEM. CLON = clonidine; MPH = methylphenidate.

(Tourette Syndrome Study Group, 2002)

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Take Home Point #6

 Patients with TD/ CTD are at increased risk of suicide

 Clinicians must inquire about suicidal thoughts and suicide attempts in people with TS and refer to appropriate resources if present

Fernandez del la Cruz L., Rydell M, Runeson B, et al. Suicide in Tourette’s and chronic tic disorders. Biol Psychiatry 2017;82:111-118.

Treatment Options

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Comprehensive Behavioral Intervention in Tics (CBIT)

Components of CBIT

 Habit Reversal Training  Tic-awareness

 Self-monitoring of current tics

 Focus on premonitory urge or other early sign that tic is going to occur  Competing response training

 Engagement in a voluntary behavior that is physically incompatible with the tic

 Goal is to disrupt the negative reinforcement cycle rather than to simply suppress the tic  Plus…Relaxation training and a functional intervention to address situations that sustain or worsen tics

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CBIT Study Design

Piacentini et al., JAMA. 2010;303(19):1929-1937.

Baseline, Week 5, and Week 10 Scores

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• Durable response at 3 and 6 months • Clinical Global Impressions Improvement Scale was significantly higher for the behavioral vs. control (52.5%; 32/61 vs. 18.5%; 12/65, p<0.001)  NNT=3  ARR=34%

Alpha-2 Agonists

 Act presynaptically to inhibit NE release  Examples:  Clonidine (Catapres)  Clonidine ER (Kapvay)  Guanfacine (Tenex)  Guanfacine XR (Intuniv)  Side effects  Sedation  Drowsiness  Hypotension  Bradycardia  QTc prolongation (guanfacine XR)

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Alpha-2 Agonist Safety Issues

1) Counsel about side effects

2) Monitor pulse and blood pressure

3) Monitor QTc interval if patient is taking guanfacine XR and has a history of cardiac conditions, are on other QTc prolonging agents, and/or have a family history of long QTc syndrome

4) Taper alpha-2 agonists gradually to avoid rebound hypertension

D2 Antagonists: Atypical and Typical Antipsychotics

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D2 Antagonists

Medication Initial dose Dose range Typical Haloperidol 0.25-0.5 mg/d 0.25-6 mg/d Pimozide 1 mg/d 1-10 mg/d Atypical Risperidone 0.25-0.5 mg/d 0.25-6 mg/d Ziprasidone 5-20 mg/d 5-100 mg/d Aripiprazole 2.5-5 mg/d 5-30 mg/d

General Principles of Prescribing D2 Antagonists

 Insufficient evidence to determine the relative efficacy of the antipsychotic drugs

 Atypical antipsychotics are not inherently safer than typical antipsychotics

 Use the lowest effective dose

 Reevaluate need for treatment on an ongoing basis

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D2 Antagonist Safety Issues

 Side Effects:  Drug-induced movement disorders  Weight gain  Somnolence  Adverse metabolic side effects  Increased prolactin  QTc prolongation  Monitor for side effects using evidenced-based protocols (www.camesaguideline.org)  Obtain an EKG before and after starting pimozide and ziprasidone or if antipsychotics are being co-administered with medications that prolong the QTc interval  Taper antipsychotics gradually to avoid withdrawal dyskinesias

Pringsheim T, Panagiotopoulos C, Davidson J, Ho J; Canadian Alliance for Monitoring Effectiveness and Safety of Antipsychotics in Children (CAMESA) guideline group. Evidence-based recommendations for monitoring safety of second-generation antipsychotics in children and youth. Paediatr Child Health. 2011;16(9):581–589.

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The Other Players…

 Benzodiazepines

 Clonazepam

 Substituted benzamides

 Sulpiride

 Tiapride

 Metoclopromide

 Monoamine-depleting

 Tetrabenazine

 Botulinum toxin

Limited Evidence

 Baclofen  Anticonvulsants  Topiramate (Topamax)  Levetiracetam (Keppra)  Dopamine agonists  Pergolide (Permax) (Cianchetti et al., 2005; Gilbert et al., 2005)

 Ropinirole (Requip) (Anca et al., 2004)  Levodopa

 Apomorphine (Feinberg and Carroll, 1979)  Cannabinoids  Nicotine

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Experimental Therapies

Ineffective/ Discontinued Under Investigation

 N-Acetylcysteine  D1 dopamine receptor antagonist  Fatty acid amide  Ecopipam (D1amond, hydrolase Emalex)  Pramipexole  VMAT inhibitors

 Valbenazine (T-Force  Deutetrabenazine Gold/ Platinum, (Artists2, Teva) Neurocrine)  Cannabis-related/ cannabinoid compounds  D-cycloserine (Abide)  Oral appliance  Deep brain stimulation

Augustine F, Singer HS. Merging the Pathophysiology and Pharmacotherapy of Tics. Tremor Other Hyperkinet Mov (N Y). 2019;8:595. Published 2019 Jan 9. doi:10.7916/D89C8F3C

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Oral Orthotic

Proof of Concept Study of an Oral Orthotic to Reduce Tic Severity in Chronic Tic Disorder and Tourette Syndrome

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Schrock, LE et al. and Tourette Syndrome Association International Deep Brain Stimulation (DBS) Database and Registry Study Group (2015), Tourette syndrome deep brain stimulation: A review and updated recommendations. Mov. Disord., 30: 448–471. doi: 10.1002/mds.26094 53

DBS Targets for TS

(Hariz, MI and Robertson MM, EJNR, 2010) 54

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Additional Resources EDUCATIONAL MATERIALS & PATIENT/ FAMILY SUPPORT

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Tourette Association of America (www.tourette.org)

Family Guide Care Providers Guide

Tourette Association YouTube

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Helpful Books & Resources

Family Information for Tourette OCD

 A Families Guide to TS  Anxiety Workbook for Teens

 10 Secrets to a Happier Life with TS  Up and Down the Worry Hill

 TS- What Families Should Know  Freeing Your Child from OCD

 The Keeper (Tim Howard’s Book for  Talking Back to OCD Adults and Children)  Taming the Tiger  Natural Remedies for Tics and Tourette’s Syndrome Executive Functioning Tourette Education for Children  See It, Say It, Do It

 Quit It  Smart but Scattered

 A Test of Will  Smart but Scattered Planner

 Matthew, Sally and Simon Story Series

 Twitch and Shout

 Front of The Class (Movie)

 I Have Tourette’s, but It Doesn’t Have Me

CPRI Brake Shop

Brake Shop Clinic Leaky Brake Toolkit http://www.cpri.ca/content/page.aspx?section=26

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Tic Helper