Practice Guideline: The Treatment of Tics in People with

Tourette Syndrome and Chronic Tic Disorders

Report by:

Guideline Development, Dissemination, and Implementation Subcommittee of

the American Academy of Neurology
© 2019 American Academy of Neurology Slide 1
 Practice Guideline Funding

This practice guideline was developed with financial support

from the American Academy of Neurology (AAN). Authors
who serve as AAN subcommittee members (Y.H-M., M.O.) or
as methodologists (T.P.), or who are AAN staff (S.M.), were
reimbursed by the AAN for expenses related to travel to
subcommittee meetings where drafts of manuscripts were
reviewed.

© 2019 American Academy of Neurology Slide 2

 Sharing This Information

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© 2019 American Academy of Neurology Slide 3

 Presentation Objectives

• To present evidence on the efficacy of treatments for tics and the risks
associated with their use
• To present practice recommendations for when clinicians and patients
should treat tics and how clinicians and patients should choose between
evidence-based treatment options

© 2019 American Academy of Neurology Slide 4

 Overview

▪ Introduction
▪ Clinical questions
▪ American Academy of Neurology guideline process
▪ Methods
▪ Conclusions
▪ Practice recommendations

© 2019 American Academy of Neurology Slide 5

 Introduction
• This practice guideline reviews evidence for the efficacy of medical and behavioral
treatments for tics, including neurostimulation, and the risks associated with their use.
• Antipsychotic medications have been commonly prescribed since the 1960s. The adverse
effects associated with antipsychotic medications, including movement disorders such as
acute and tardive dystonia, tardive dyskinesia, akathisia and drug-induced parkinsonism, and
metabolic adverse effects, such as weight gain, hyperlipidemia, and hyperglycemia, have led
clinicians to search for other effective treatments.
• In recent years, there has been a resurgence in the interest in behavioral treatments and
neuromodulation for tics, yielding expanding evidence in this area.
• Although individuals with Tourette syndrome and chronic tic disorders often have comorbid
psychiatric disorders, the focus of this practice guideline is on the management of tics, as
treatment of comorbid conditions mainly follows recommendations given for the treatment of
these disorders without tics.

© 2019 American Academy of Neurology Slide 6

 Clinical Questions

The systematic review for this practice guideline

addressed the following questions:
• In children and adults with Tourette syndrome or a chronic tic disorder,
which medical, behavioral, and neurostimulation interventions, compared
with placebo or other active interventions, improve tic severity and tic-
related impairment?
• In children and adults with Tourette syndrome or a chronic tic disorder,
what are the risks of harm, including weight gain, elevated prolactin
levels, sedation, drug-induced movement disorders, hypotension,
bradycardia, and electrocardiogram changes with medical treatments,
compared with placebo or other active interventions?

© 2019 American Academy of Neurology Slide 7

 AAN Guideline Process*
• Clinical Questions

• Evidence

• Conclusions

• Recommendations

*Guideline developed using the 2011 AAN Clinical Practice Guideline Process Manual, as amended.

© 2019 American Academy of Neurology Slide 8

 Literature Search/Review
Rigorous, Comprehensive, Transparent
2,407 Five databases (MEDLINE, Embase, PsychINFO, CENTRAL,
abstracts and ClinicalTrials.gov) were searched through August 2016.
An updated search was conducted to include studies
published to September 2017.

Inclusion criteria: Exclusion criteria:

• Randomized controlled trials on • Randomized controlled trials that
the treatment of tics in included fewer than 20 participants
individuals with Tourette (fewer than 10 for crossover trials)
syndrome (TS) or chronic tic
disorders
• Cohort studies or case series
that specifically evaluated
adverse drug effects in
individuals with TS
81 rated
articles
Slide 9
 Class I
A clinical RCT of the intervention of interest with masked or objective outcome assessment, in a representative population.
Relevant baseline characteristics are presented and substantially equivalent between treatment groups, or there is appropriate
statistical adjustment for differences.
The following are also required:
a. Concealed allocation
b. No more than two primary outcomes specified
c. Exclusion/inclusion criteria clearly defined
d. Adequate accounting for dropouts (with at least 80% of enrolled subjects completing the study) and crossovers with numbers
sufficiently low to have minimal potential for bias.
e. For noninferiority or equivalence trials claiming to prove efficacy for one or both drugs, the following characteristics are also
required*:
i. The authors explicitly state the clinically meaningful difference to be excluded by defining the threshold for
equivalence or noninferiority.
ii. The standard treatment used in the study is substantially similar to that used in previous studies establishing efficacy
of the standard treatment (e.g., for a drug, the mode of administration, dose, and dosage adjustments are similar to
those previously shown to be effective).
iii. The inclusion and exclusion criteria for patient selection and the outcomes of patients on the standard treatment are
comparable to those of previous studies establishing efficacy of the standard treatment.
iv. The interpretation of the study results is based upon a per-protocol analysis that accounts for dropouts or crossovers.
f. For crossover trials, both period and carryover effects examined and statistical adjustments performed, if appropriate.
* Note that numbers I to iii in Class Ie are required for Class II in equivalence trials. If any one of the three is missing, the class is automatically downgraded to Class III.
Slide 10
Class II
An RCT of the intervention of interest in a representative population with masked or
objective outcome assessment that lacks one criteria a–e (see Class I) or a prospective
matched cohort study with masked or objective outcome assessment in a
representative population that meets items b−e (see Class I).
(Alternatively, a randomized crossover trial missing one of the following two
characteristics: period and carryover effects described or baseline characteristics of
treatment order groups presented.)
All relevant baseline characteristics are presented and substantially equivalent among
treatment groups, or there is appropriate statistical adjustment for differences.

Slide 11
AAN Classification of Evidence (2011)
Therapeutic Scheme
Class III Class IV

• All other controlled trials (including • Studies that (1) did not include patients
studies with external controls such as with the disease, (2) did not include
well-defined natural history controls). patients receiving different
• (Alternatively, a crossover trial missing interventions, (3) had undefined or
both of the following two criteria: unaccepted interventions or outcomes
period and carryover effects described measures, or (4) had no measures of
or baseline characteristics of treatment effectiveness or statistical precision
order groups presented.) presented or calculable.
• A description of major confounding
differences between treatment groups
that could affect outcome.** Outcome
assessment is masked, objective, or
performed by someone who is not a
member of the treatment team.
**Objective outcome measurement: an outcome measure that is unlikely to be affected by an observer’s (patient, treating physician, investigator)
expectation or bias (e.g., blood tests, administrative outcome data). Slide 12
Clinical Question 1

In children and adults with Tourette syndrome or a

chronic tic disorder, which medical, behavioral, and
neurostimulation interventions, compared with
placebo or other active interventions, improve tic
severity and tic-related impairment?

Slide 13
Clinical Question 1:Conclusions
High Confidence in the Evidence

People with tics receiving the Comprehensive Behavioral Intervention

for Tics are more likely than those receiving supportive psychotherapy
to have reduced tic severity (SMD 0.56; 95% confidence interval [CI], 0.31
to 0.82], high confidence, 2 Class I studies22, 23).

Slide 14
Note: Unless otherwise specified, trial participants included both children (individuals aged 18 years and younger)
and adults (individuals older than 18 years).
Clinical Question 1:Conclusions
Moderate Confidence in the Evidence

People with tics receiving the following interventions are probably

more likely than those receiving placebo to have reduced tic severity:
• Haloperidol, SMD 0.59 (95% CI, 0.11 to 1.06), 2 Class II studies24, 25
• Risperidone, SMD 0.79 (95% CI, 0.31 to 1.27), 2 Class II studies26, 27
• Aripiprazole, SMD 0.64 (95% CI, 0.31 to 0.97), 1 Class I study28 and 1 Class II study29
(children only)
• Tiapride, SMD 0.62 (95% CI, 0.36 to 0.88), 1 Class I study30 (children only)
• Clonidine, SMD 0.45 (95% CI, 0.13 to 0.77), 1 Class I study31 and 2 Class II studies32, 33
• Onabotulinum toxin A injections, SMD 1.27 (95% CI, 0.51to 2.03), 1 Class II study34;
confidence in evidence upgraded due to magnitude of effect
• Ningdong granule (as formulated by Zhao), SMD 0.97 (95% CI, 0.45 to 1.49), 1 Class II
study35; confidence in evidence upgraded due to magnitude of effect (children only)
• 5-Ling granule, SMD 0.55 (95% CI, 0.33 to 0.76), 1 Class I study30 (children only)

Slide 15
Note: Unless otherwise specified, trial participants included both children (individuals aged 18 years and younger) and
adults (individuals older than 18 years).
Clinical Question 1:Conclusions
Moderate Confidence in the Evidence (continued)

People with tics and a comorbid diagnosis of attention-

deficit/hyperactivity disorder receiving the following interventions
are probably more likely than those receiving placebo to have
reduced tic severity:
• Clonidine plus methylphenidate, SMD 0.72 (95% CI, 0.22 to 1.22), 1 Class I
study31 (children only)
• Methylphenidate, SMD 0.61 (95% CI, 0.13 to 1.10), 1 Class I study31 (children
only)
• Desipramine, SMD 1.13 (95% CI, 0.47 to 1.79), 1 Class II study36; confidence in
evidence upgraded due to magnitude of effect (children only). Desipramine is now
rarely used in children after several case reports of sudden death associated with
the use of this medication.37

Slide 16
Note: Unless otherwise specified, trial participants included both children (individuals aged 18 years and younger) and
adults (individuals older than 18 years).
Clinical Question 1:Conclusions
Moderate Confidence in the Evidence (continued)

People with tics receiving active deep brain stimulation (DBS) of the
globus pallidus are probably more likely than those receiving sham DBS to
have reduced tic severity (SMD 0.77 [95% CI, 0.14 to 1.40), 2 class II
studies38, 39 (adults only).

Slide 17
Note: Unless otherwise specified, trial participants included both children (individuals aged 18 years and younger) and
adults (individuals older than 18 years).
Clinical Question 1:Conclusions
Low Confidence in the Evidence

People with tics receiving the following interventions are possibly more likely than
those receiving placebo to have reduced tic severity:
• Pimozide, SMD 0.66 (95% CI, 0.06 to 1.25), 3 Class II studies,24, 40 confidence in evidence
downgraded due to imprecision
• Ziprasidone, SMD 1.14 (95% CI, 0.32 to 1.97), 1 Class II study41 (children only)
• Metoclopramide, SMD 1.14 (95% CI, 0.33 to 1.95), 1 Class II study42 (children only)
• Guanfacine, SMD 0.45 (95% CI, 0.03 to 0.87)1 Class I study43 and 2 Class II studies,44, 45
confidence in evidence downgraded due to imprecision (children only)
• Topiramate, SMD 0.91 (95% CI, 0.11 to 1.71), 1 Class II study46
• Tetrahydrocannabinol, SMD 0.62 (95% CI, 0.01 to 1.22), 1 Class II47 and 1 Class III study48
(adults only)

Slide 18
Note: Unless otherwise specified, trial participants included both children (individuals aged 18 years and younger) and
adults (individuals older than 18 years).
Clinical Question 1:Conclusions
Low Confidence in the Evidence (continued)

For people with tics and a comorbid diagnosis of attention-

deficit/hyperactivity disorder, atomoxetine does not worsen tics relative to
placebo (1 Class II study49) (children only).

Slide 19
Note: Unless otherwise specified, trial participants included both children (individuals aged 18 years and younger) and
adults (individuals older than 18 years).
Clinical Question 1:Conclusions
Very Low Confidence in the Evidence
There is insufficient evidence to determine whether people with tics receiving the following interventions are
more or less likely than those receiving placebo to have reduced tic severity:
• Baclofen, SMD 0.55 (95% CI, -0.39 to 1.49) 1 Class II study50; confidence in evidence downgraded due to imprecision (children only)
• Levetiracetam, SMD 0.22 (95% CI, -0.38 to 0.82), 1 Class II study51; confidence in evidence downgraded due to imprecision (children
only)
• N-acetylcysteine, SMD 0.45 (95% CI, -0.27 to 1.17), 1 Class II study52; confidence in evidence downgraded due to imprecision (children
only)
• Omega-3 fatty acids, SMD 0.69 (95% CI, 0.00 to 1.39), 1 Class II study53; confidence in evidence downgraded due to imprecision
(children only)
• Ningdong granule (as formulated by Wang), 1 Class II study17 (children only)
• Nicotine, SMD 0.38 (95% CI, -0.14 to 0.90), 1 Class III study54 (children only)
• Nicotine patch added to haloperidol, SMD 0.71 (95% CI, 0.17 to 1.25), 1 Class III study55 (children only)
• Mecamylamine, 1 Class II study16 (children only)
• Flutamide, 1 Class I study14 (adults only)
• Riluzole, SMD 0.17 (95% CI, -0.91 to 1.25), 1 Class I study56; confidence in evidence downgraded due to imprecision (children only)
• D-serine, SMD -0.04 (95% CI, -1.13 to 1.05), 1 Class I study56; confidence in evidence downgraded due to imprecision (children only)
• Ondansetron, SMD 0.53 (95% CI, -0.20 to 1.25), 1 Class III study57
• Pramipexole, SMD 0.00 (95% CI, -0.53 to 0.53), 1 Class II study58; confidence in evidence downgraded due to imprecision (children only)
• Intravenous immunoglobulin, SMD 0.50 (95% CI, -0.24 to 1.24), 1 Class II study59; confidence in evidence downgraded due to
imprecision
• Deprenyl, SMD 0.47 (95% CI, -0.05 to 0.99), 1 Class II study60; confidence in evidence downgraded due to imprecision (children only)
Slide 20
Note: Unless otherwise specified, trial participants included both children (individuals aged 18 years and younger) and
adults (individuals older than 18 years).
Clinical Question 1:Conclusions
Very Low Confidence in the Evidence (continued)
There is insufficient evidence to determine whether people with tics receiving the following interventions are more or
less likely than those receiving an alternate intervention to have reduced tic severity:
• Haloperidol versus pimozide, SMD 0.11 (95% CI, -0.41 to 0.62), 2 Class II studies,24, 25 confidence in evidence downgraded due to imprecision
• Risperidone versus pimozide, SMD 0.24 (95% CI, -0.51 to 0.99), 2 Class II studies, confidence in evidence downgraded due to imprecision
• Risperidone versus clonidine, SMD -0.19 (95% CI, -1.06 to 0.68), 1 Class II study,e1 confidence in evidence downgraded due to imprecision (children only)
• Aripiprazole versus risperidone, SMD 0.17 (95% CI, -0.34 to 0.68), 1 Class II study,e2 confidence in evidence downgraded due to imprecision (children only)
• Clonidine versus levetiracetam, SMD 0.86 (95% CI, -0.03 to 1.75), 1 Class II studye3 (children only)
• Habit reversal therapy versus exposure and response prevention, SMD 0.25 (95% CI, -0.40 to 0.90), 1 class II study,e4 confidence in evidence downgraded due
to imprecision
• Habit reversal therapy versus educational group treatments, SMD 0.55 (95% CI, -0.17 to 1.27), 1 Class II study,e5 confidence in evidence downgraded due to
imprecision (children only)
• Face-to-face habit reversal therapy versus habit reversal therapy through video conferencing, SMD 0.24 (95% CI, -0.70 to 1.18), 1 Class II study,e6
confidence in evidence downgraded due to imprecision (children only)
• Habit reversal therapy by video conferencing versus wait list control, SMD 0.24 (95% CI, -0.65 to 1.14), 1 Class II study,e7 confidence in evidence downgraded
due to imprecision (children only)
• Relaxation therapy versus minimal therapy, 1 Class III study20 (children only)
• Biofeedback versus sham, 1 Class III study15 (adults only)
• Active DBS of the thalamus versus sham DBS of the thalamus, SMD 1.58 (95% CI, -0.12 to 3.28), 1 Class III studye8 (adults only)
• Active DBS of the centromedian-parafascicular complex versus sham DBS of the centromedian-parafascicular complex, SMD 0.99 (95% CI, -0.28 to
2.26), 1 Class III studye9 (adults only)
• Continuous theta burst transcranial magnetic stimulation of the supplementary motor area versus sham transcranial magnetic stimulation, SMD
-0.15 (95% CI, -1.29 to 0.99), 1 Class II studye10; confidence in evidence downgraded due to imprecision
• Repetitive transcranial magnetic stimulation (rTMS) of the supplementary motor area versus sham stimulation, SMD 0.19 (95% CI, -0.69 to 1.07), 1
Class II study,e11 confidence in evidence downgraded due to imprecision (adults only)
• rTMS of the left motor or prefrontal cortex versus sham stimulation, 1 Class III study13 Slide 21

Note: Unless otherwise specified, trial participants included both children (individuals aged 18 years and younger) and adults
(individuals older than 18 years).
Clinical Question 2
In children and adults with Tourette syndrome or a chronic tic
disorder, what are the risks of harm, including weight gain,
elevated prolactin levels, sedation, drug-induced movement
disorders, hypotension, bradycardia, and electrocardiogram
changes with medical treatments compared with placebo or
other active interventions?

Slide 22
Clinical Question 2:Conclusions
Weight Gain

• People with tics receiving risperidone are probably more likely to gain weight than
people receiving placebo (moderate confidence, 2 Class II studies27, e1).
• People with tics receiving aripiprazole are probably more likely to gain weight than
those receiving placebo (moderate confidence, 1 Class I study28 and I Class II
study29) (children only).
• People with tics receiving aripiprazole are possibly more likely to have an increase
in body mass index and waist circumference than people receiving placebo (low
confidence, I Class II study29) (children only).
• People with tics and a comorbid diagnosis of ADHD who are receiving
atomoxetine are possibly more likely to have a decrease in body weight than
people receiving placebo (low confidence, 1 Class II study49) (children only).

Slide 23
Note: Unless otherwise specified, trial participants included both children (individuals aged 18 years and younger) and
adults (individuals older than 18 years).
Clinical Question 2:Conclusions
Elevated Prolactin Levels

• People with tics receiving pimozide are possibly more likely to

have increased prolactin levels than people receiving placebo
(low confidence, 1 Class II study24).
• People with tics receiving haloperidol are possibly more likely to
have increased prolactin levels than people receiving placebo
(low confidence, 1 Class II study24).
• People with tics receiving metoclopramide are possibly more likely
to have greater increases in prolactin levels than people receiving
placebo (low confidence, 1 Class II study42) (children only).

Slide 24
Note: Unless otherwise specified, trial participants included both children (individuals aged 18 years and younger) and
adults (individuals older than 18 years).
Clinical Question 2:Conclusions
Sedation

• People with tics receiving risperidone are possibly more likely to experience fatigue
and somnolence than people receiving placebo (low confidence, 1 Class II study26).
• People with tics receiving aripiprazole are possibly more likely to experience sedation
and somnolence than people receiving placebo (low confidence, 1 Class II study29)
(children only).
• People with tics receiving tiapride are probably more likely to experience higher rates
of physical tiredness and sleep disturbances compared with people receiving placebo
(moderate confidence, 1 Class I study30) (children only).
• People with tics receiving clonidine are probably more likely to experience sedation
than people receiving placebo (moderate confidence, 1 Class I31 and 1 Class II
studies33).
• People with tics receiving guanfacine are probably more likely than those receiving
placebo to have drowsiness (moderate confidence, 1 Class I study43) (children only).
Slide 25
Note: Unless otherwise specified, trial participants included both children (individuals aged 18 years and younger) and
adults (individuals older than 18 years).
Clinical Question 2:Conclusions
Drug Induced Movement Disorders

• People with tics receiving pimozide are probably more likely to have
extrapyramidal symptoms than people receiving placebo (moderate confidence, 2
Class II studies40).
• People with tics receiving haloperidol are possibly more likely to have
extrapyramidal symptoms than people receiving pimozide and placebo (low
confidence, 1 Class II study24, 25).
• People with tics receiving risperidone are possibly more likely to have higher
parkinsonism scores on the Extrapyramidal Symptom Rating Scale Score than
people receiving placebo (low confidence, 1 Class II study26).
• People with tics receiving risperidone are possibly more likely to require
antiparkinsonian medication than people receiving placebo (low confidence, 1
Class II study26).

Slide 26
Note: Unless otherwise specified, trial participants included both children (individuals aged 18 years and younger) and
adults (individuals older than 18 years).
Clinical Question 2:Conclusions
Blood Pressure

People with tics and a comorbid diagnosis of ADHD receiving

desipramine are possibly more likely to have an increase in
diastolic blood pressure than people receiving placebo (low
confidence, 1 Class II study36) (children only).

Slide 27
Note: Unless otherwise specified, trial participants included both children (individuals aged 18 years and younger) and
adults (individuals older than 18 years).
Clinical Question 2:Conclusions
Heart Rate

• People with tics and a comorbid diagnosis of attention-

deficit/hyperactivity disorder (ADHD) receiving atomoxetine
are possibly more likely to have an increase in heart rate
than people receiving placebo (low confidence, 1 Class II
study49) (children only).
• People with tics and a comorbid diagnosis of ADHD
receiving desipramine possibly more likely to have an
increased heart rate than people receiving placebo (low
confidence, 1 Class II study36) (children only).

Slide 28
Note: Unless otherwise specified, trial participants included both children (individuals aged 18 years and younger) and
adults (individuals older than 18 years).
Clinical Question 2:Conclusions
Electrocardiogram changes

People with tics receiving pimozide are possibly more likely to

have a prolonged QT interval than people receiving placebo
and haloperidol (low confidence, 1 Class II study25).

Slide 29
Note: Unless otherwise specified, trial participants included both children (individuals aged 18 years and younger) and
adults (individuals older than 18 years).
Practice Recommendations
Recommendation 1:
Natural History of Tourette syndrome
Rationale
Providing information to families about the natural history of a disorder can help
inform treatment decisions. Tics begin in childhood and demonstrate a waxing
and waning course. Peak tic severity usually occurs between the ages of 10
years and 12 years, with many children experiencing an improvement in tics in
adolescence.1 A longitudinal study demonstrated that tic severity declined yearly
during adolescence, with 18% of adolescents older than 16 years having no tics
and 60% having minimal or mild tics 6 years after initial examination.2 There is no
evidence that treatment is more effective the earlier it is started. As tics may
improve with time, watchful waiting is an acceptable approach in individuals who
do not experience any functional impairment from their tics. However, even in
such cases, the Comprehensive Behavioral Intervention for Tics (CBIT) could be
employed if the patient is motivated to attempt treatment. As a result of partial or
complete remission during the natural course of the disorder, medication
prescribed for tics in childhood may no longer be required over time.
Slide 30
Practice Recommendations

Recommendation Statements 1a−1e:

• Recommendation 1a: Clinicians must inform patients and their caregivers about
the natural history of tic disorders (Level A).
• Recommendation 1b: Clinicians must evaluate functional impairment related to
tics from the perspective of the patient and, if applicable, the caregiver (Level A).
• Recommendation 1c: Clinicians should inform patients and caregivers that
watchful waiting is an acceptable approach in people who do not experience
functional impairment from their tics (Level B).
• Recommendation 1d: Clinicians may prescribe Comprehensive Behavioral
Intervention for Tics (CBIT) as an initial treatment option relative to watchful
waiting, for people with tics who do not experience functional impairment if they
are motivated to attempt treatment (Level C).
• Recommendation 1e: Physicians prescribing medications for tics must
periodically re-evaluate the need for ongoing medical treatment (Level A).
Slide 31
Practice Recommendations
Recommendation 2:
Psychoeducation—Teacher and Classroom
Rationale

Tourette syndrome is common, affecting approximately 1%

of schoolchildren.3 Psychoeducation about TS with peers
can result in more positive attitudes toward a person with
TS, while psychoeducation about TS with teachers can
improve knowledge about the condition.4 Improving peers’
attitudes about and teachers’ knowledge of TS may
positively affect people with TS.

Slide 32
Practice Recommendations

Recommendation Statement 2:

• Clinicians should refer people with Tourette syndrome to

resources for psychoeducation for teachers and peers, such
as the Tourette Association of America (Level B).

Slide 33
Practice Recommendations
Recommendation 3:
Assessment and Treatment of attention-deficit/hyperactivity disorder (ADHD)
Rationale
Comorbid ADHD is common in people with Tourette syndrome (TS), with
prevalence ranging from 30% to 50%.5, 6 Several trials have specifically
addressed the medical treatment of both ADHD and tics in children with
both disorders. This includes trials of psychostimulants and atomoxetine, in
which the aim was to demonstrate efficacy of these treatments for ADHD
symptoms without concomitant worsening of tics. In children with tics and
ADHD, clonidine, clonidine plus methylphenidate, methylphenidate, and
guanfacine are probably more likely than placebo to reduce tic severity and
reduce ADHD symptoms. In children with tics and ADHD, atomoxetine
does not worsen tics relative to placebo and reduces ADHD symptoms.
Comorbid ADHD is strongly associated with functional impairment in
children with TS.7 While ADHD symptoms may improve in adolescence,2
adults with TS may require ongoing care for this comorbidity.
Slide 34
Practice Recommendations

Recommendation Statements 3a−3c:

• Recommendation 3a: Clinicians should ensure an assessment for

comorbid attention-deficit/hyperactivity disorder (ADHD) is
performed in people with tics (Level B).
• Recommendation 3b: Clinicians should evaluate the burden of
ADHD symptoms in people with tics (Level B).
• Recommendation 3c: In people with tics and functionally
impairing ADHD, clinicians should ensure appropriate ADHD
treatment is provided (Level B).

Slide 35
Practice Recommendations
Recommendation 4:
Assessment and Treatment of Obsessive-Compulsive (OCD) in Children with Tics
Rationale
Obsessive-compulsive behaviors are common in people
with Tourette syndrome, with a comorbid diagnosis of OCD
made in 10% to 50%.5, 6 Sub-analyses of trials of
interventions for OCD in children suggest that individuals
with tics may not respond as well as those without tics to
selective serotonin reuptake inhibitors but respond equally
well to cognitive behavioral therapy (CBT) for OCD
symptoms.8, 9 For this reason, CBT is considered first-line
treatment of OCD in individuals with tic disorders.
Slide 36
Practice Recommendations

Recommendation Statements 4a−4b:

• Recommendation 4a: Clinicians should ensure an assessment
for comorbid obsessive-compulsive disorder (OCD) is
performed in people with tics (Level B).
• Recommendation 4b: In people with tics and OCD, clinicians
should ensure appropriate OCD treatment is provided (Level B).

Slide 37
Practice Recommendations
Recommendation 5:
Other Psychiatric Comorbidities
Rationale
Population-based and clinic-based studies have shown that people
with Tourette syndrome (TS) are at high risk of other psychiatric
comorbidities, including anxiety disorders, oppositional defiant
disorder, and mood disorders.5, 6 Comorbid mood disorders appear
more prevalent in adolescents and adults than children and in those
with greater tic severity.6, 10 A matched case-cohort study using a
national registry has shown an increased risk of dying by suicide and
attempting suicide in people with TS compared with controls, which
persisted after adjusting for psychiatric comorbidity. Persistence of tics
beyond young adulthood, previous suicide attempts, and comorbid
personality disorders increased the risk of death by suicide.11
Slide 38
Practice Recommendations

Recommendation Statements 5a−5b:

• Recommendation 5a: Clinicians must ensure appropriate
screening for anxiety, mood, and disruptive behavior disorders
is performed in people with tics (Level A).
• Recommendation 5b: Clinicians must inquire about suicidal
thoughts and suicide attempts in people with TS and refer to
appropriate resources if present (Level A).

Slide 39
Practice Recommendations
Recommendation 6:
Assessment of Tic Severity and Treatment Expectations
Rationale
There are several rating scales available for measuring tic
severity, with the Yale Global Tic Severity Scale the most
extensively deployed and validated.12 Evaluation of the
effect of treatment on tic severity in trials is measured using
such scales. The use of validated scales to measure tic
severity can aid the evaluation of treatment response in the
clinical setting. While medications, behavioral therapy, and
neurostimulation can result in meaningful reduction in, these
interventions rarely result in complete cessation of tics.
Slide 40
Practice Recommendations

Recommendation Statements 6a−6b:

• Recommendation 6a: Clinicians may measure tic severity using

a valid scale to assess treatment effects (Level C).
• Recommendation 6b: Clinicians must counsel patients that
treatments for tics infrequently result in complete cessation of
tics (Level A).

Slide 41
Practice Recommendations
Recommendation 7:
Behavioral Treatments
Rationale
People with tics receiving Comprehensive Behavioral Intervention for Tics (CBIT) are more likely than those
receiving psychoeducation and supportive therapy to have reduced tic severity. CBIT is a manualized
treatment program consisting of habit reversal training (HRT), relaxation training, and a functional intervention
to address situations that sustain or worsen tics.13 The child and adult CBIT trials demonstrated the efficacy of
an 8-session protocol, though cases complicated by poor tic awareness, treatment motivation, more severe
tics, or substantial clinical comorbidity may benefit from a longer course of therapy. Most children (aged 9 years
or older) and adults showing an initial positive response to CBIT will maintain their treatment gains for at least 6
months. CBIT can be effective for children younger than 9 years, though there is little evidence to determine
efficacy in children of this age group.14 There is some evidence that the efficacy of CBIT for reducing tics is
greater for patients not concurrently taking anti-tic medication.15 There is insufficient evidence to determine the
relative efficacy of HRT compared with exposure and response prevention or educational group treatment in
reducing tic severity. There is insufficient evidence to determine the relative efficacy of HRT by video
conferencing compared with either face-to-face HRT or wait-list control for reducing tic severity. There is
insufficient evidence to determine the efficacy of relaxation training for reducing tic severity. The evidence
demonstrates no increased risk of adverse effects for people treated with CBIT compared with those treated
with psychoeducation plus supportive therapy. The effect size for CBIT appears similar to effect sizes for
medications. In light of clinician responsibility to optimally balance safety and effectiveness in treatment
decisions, CBIT should be considered as an initial treatment choice for tics. Given the effort required from
patients or their families, along with its benign safety profile, CBIT is an acceptable intervention for people with
tics that lead to psychosocial or physical impairment and who are motivated to participate in treatment.
Slide 42
Practice Recommendations

Recommendation Statements 7a−7c:

• Recommendation 7a: For people with tics who have access to
Comprehensive Behavioral Intervention for Tics (CBIT), clinicians should
prescribe CBIT as an initial treatment option relative to other
psychosocial/behavioral interventions (Level B).
• Recommendation 7b: For people with tics who have access to CBIT,
clinicians should offer CBIT as an initial treatment option relative to
medication (Level B).
• Recommendation 7c: Clinicians may prescribe CBIT delivered over
teleconference or secure voice-over-internet protocol delivery systems if
face-to-face options are unavailable in a patient care center. If CBIT is
unavailable, other behavioral interventions for tics may be acceptable,
such as exposure and response prevention (Level C).

Slide 43
Practice Recommendations
Recommendation 8:
Alpha Agonists for the Treatment of Tics
Rationale
People with tics receiving clonidine are probably more likely than those
receiving placebo to have reduced tic severity, and people with tics receiving
guanfacine are possibly more likely than those receivng placebo to have
reduced tic severity, with the majority of trials conducted in children. In children
with tics and comorbid attention-deficit/hyperactivity disorder (ADHD), clonidine
and guanfacine have demonstrated beneficial effects on both tics and ADHD
symptoms. The effect size of clonidine and guanfacine on tics appears larger in
children with tics and ADHD compared with individuals with tics without a
comorbid diagnosis of ADHD. Relative to placebo, clonidine is probably
associated with higher rates of sedation, and guanfacine is probably associated
with higher rates of drowsiness. A systematic review of alpha-2 adrenergic
agonists for ADHD in children and adolescents demonstrated hypotension,
bradycardia, and sedation with both agents, and QTc prolongation with
guanfacine extended release.16 Abrupt withdrawal of alpha-2 adrenergic
agonists may cause rebound hypertension.17
Slide 44
Practice Recommendations
Recommendation Statements 8a−8f:
• Recommendation 8a: Physicians should counsel individuals with tics and
comorbid ADHD that alpha-2 adrenergic agonists may provide benefit for both
conditions (Level B).
• Recommendation 8b: Physicians should prescribe alpha-2 adrenergic agonists for
the treatment of tics when the benefits of treatment outweigh the risks (Level B).
• Recommendation 8c: Physicians must counsel patients regarding common side
effects of alpha-2 adrenergic agonists, including sedation (Level A).
• Recommendation 8d: Physicians must monitor heart rate and blood pressure in
patients with tics treated with alpha-2 adrenergic agonists (Level A).
• Recommendation 8e: Physicians prescribing guanfacine extended release must
monitor the QTc interval in patients with a history of cardiac conditions, patients
taking other QT-prolonging agents, or patients with a family history of long QT
syndrome (Level A).
• Recommendation 8f: Physicians discontinuing alpha-2 adrenergic agonists must
gradually taper them to avoid rebound hypertension (Level A). Slide 45
Practice Recommendations
Recommendation 9:
Antipsychotic Treatment for Tics
Rationale
Haloperidol, risperidone, aripiprazole, and tiapride are probably more likely than placebo to
reduce tic severity, and pimozide, ziprasidone, and metoclopramide are possibly more likely
than placebo to reduce tic severity. There is insufficient evidence to determine the relative
efficacy of these drugs. Relative to placebo, the evidence demonstrates a higher risk of drug-
induced movement disorders with haloperidol, pimozide, and risperidone, a higher risk of weight
gain with risperidone and aripiprazole, a higher risk of somnolence with risperidone,
aripiprazole, and tiapride, a higher risk of QT prolongation with pimozide, and a higher risk of
elevated prolactin with haloperidol, pimozide, and metoclopramide. Systematic reviews of trials
and cohort studies demonstrate a higher risk of drug-induced movement disorders (including
tardive dyskinesia, drug-induced parkinsonism, akathisia, acute dystonia and tardive dystonia),
weight gain, adverse metabolic side effects, prolactin increase, and QT prolongation with both
first- and second-generation antipsychotics across psychiatric and neurologic conditions.18, 19
The long-term use of metoclopramide is associated with tardive dyskinesia, resulting in a black
box warning from the US Food and Drug Administration.20 The relative propensity for these
adverse effects varies by agent and are often dose dependent. Physicians have a duty to
monitor the effectiveness and safety of prescribed medications, and evidence-based monitoring
protocols are available.21 Abrupt discontinuation of antipsychotic medications can cause
withdrawal dyskinesias.22, 23
Slide 46
Practice Recommendations
Recommendation Statements 9a−9f:
• Recommendation 9a: Physicians may prescribe antipsychotics for the treatment of tics when
the benefits of treatment outweigh the risks (Level C).
• Recommendation 9b: Physicians must counsel patients on the relative propensity of
antipsychotics for extrapyramidal, hormonal, and metabolic adverse effects to inform
decision making on which antipsychotic should be prescribed (Level A).
• Recommendation 9c: Physicians prescribing antipsychotics for tics must prescribe the lowest
effective dose to decrease the risk of adverse effects (Level A).
• Recommendation 9d: Physicians prescribing antipsychotics for tics should monitor for drug-
induced movement disorders and for metabolic and hormonal adverse effects of
antipsychotics, using evidence-based monitoring protocols (Level B).
• Recommendation 9e: Physicians prescribing antipsychotics for tics must perform
electrocardiography and measure the QTc interval before and after starting pimozide or
ziprasidone, or if antipsychotics are coadministered with other drugs that can prolong the QT
interval (Level A).
• Recommendation 9f: When attempting to discontinue antipsychotics for tics, physicians
should gradually taper medications over weeks to months to avoid withdrawal dyskinesias
(Level B).
Slide 47
Practice Recommendations
Recommendation 10:
Botulinum Toxin Injections for Tics
Rationale
Botulinum toxin injections with onabotulinum toxin A are probably
more likely than placebo to reduce tic severity in adolescents and
adults. Premonitory urges may also be improved by botulinum
toxin injections.24 Relative to placebo, onabotulinum toxin A is
associated with higher rates of weakness. Hypophonia is a
common side effect of botulinum toxin injections in the laryngeal
muscles for vocal tics.25 The effect of botulinum toxin injections
last 12 to 16 weeks, after which treatment needs to be repeated.

Slide 48
Practice Recommendations
Recommendation Statements 10a−10c:
• Recommendation 10a: Physicians may prescribe botulinum
toxin injections for the treatment of adolescents and adults
with localized and bothersome simple motor tics when the
benefits of treatment outweigh the risks (Level C).
• Recommendation 10b: Physicians may prescribe botulinum
toxin injections for the treatment of older adolescents and
adults with severely disabling or aggressive vocal tics when the
benefits of treatment outweigh the risks (Level C).
• Recommendation 10c: Physicians must counsel individuals with
tics that botulinum toxin injections may cause weakness and
hypophonia, and that all effects are temporary (Level A).

Slide 49
Practice Recommendations
Recommendation 11:
Topiramate for the Treatment of Tics
Rationale
Topiramate is possibly more likely than placebo to reduce tic
severity. In patients with mild but troublesome tics who are not
obtaining a satisfactory response or experience adverse
effects from other treatments, topiramate may be a useful
alternative. While generally well tolerated at low doses (25 to
150 mg/d) it may cause adverse effects, including cognitive
and language problems, somnolence, and weight loss, and
may increase the risk of renal stones.26-28

Slide 50
Practice Recommendations
Recommendation Statements 11a−11b:
• Recommendation 11a: Physicians should prescribe topiramate
for the treatment of tics when the benefits of treatment
outweigh the risks (Level B).
• Recommendation 11b: Physicians must counsel patients
regarding common adverse effects of topiramate, including
cognitive and language problems, somnolence, weight loss, and
an increased risk of renal stones (Level A).

Slide 51
Practice Recommendations
Recommendation 12:
Cannabis-Based Medications for the Treatment of Patients with Tourette Syndrome (TS)
Rationale
Some patients with TS use cannabis as a self-medication for tics and comorbidities.29
There is limited evidence that delta-9-tetrahydrocannabinol (THC), dronabinol, is possibly
more likely than placebo to reduce tic severity in adults with TS. There is insufficient
evidence to determine whether the efficacy of nabiximols, nabilone, and cannabidiol
(CBD) as well as different strains of medicinal cannabis—standardized for different levels
of THC and CBD—is similar to THC. Compared with placebo, cannabis-based
medications are associated with increased risk of short-term adverse events, most
commonly dizziness, dry mouth, and fatigue.30 There is no evidence that controlled
treatment with cannabis-based medication may induce addiction to cannabinoids. Acute
withdrawal of cannabinoids is generally safe and well tolerated without significant adverse
events.30, 31 Cannabis-based medications should be avoided in children and adolescents,
not only due to a paucity of evidence but due to the association between cannabis
exposure in adolescence and potentially harmful cognitive and affective outcomes in
adulthood.32 Cannabis-based medication should not be used in women who are
pregnant or breastfeeding or in patients suffering from psychosis. Prescription of and
access to medical marijuana varies by region; practitioners must abide by regional
legislation on the use of medical marijuana.
Slide 52
Practice Recommendations
Recommendation Statements 12a−12f:
• Recommendation 12a: Due to the risks associated with cannabis use and widespread self-medication
with cannabis for tics, where regional legislation and resources allow, physicians must offer to direct
patients to appropriate medical supervision when cannabis is used as self-medication for tics (Level
A). Appropriate medical supervision would entail education and monitoring for efficacy and adverse
effects.
• Recommendation 12b: Where regional legislation allows, physicians may consider treatment with
cannabis-based medication in otherwise treatment-resistant adults suffering from clinically relevant
tics (Level C).
• Recommendation 12c: Where regional legislation allows, physicians may consider treatment with
cannabis-based medication in adults with TS who already use cannabis efficiently as a self-medication
in order to better control and improve quality of treatment (Level C).
• Recommendation 12d: Where regional legislation allows, physicians prescribing cannabis-based
medication must prescribe the lowest effective dose to decrease the risk of adverse effects (Level A).
• Recommendation 12e: Physicians prescribing cannabis-based medication must inform patients that
medication may impair driving ability (Level A).
• Recommendation 12f: Physicians prescribing cannabis-based medication to patients with TS must
periodically reevaluate the need for ongoing treatment (Level A).

Slide 53
Practice Recommendations
Recommendation 13:
Deep Brain Stimulation for Tics in the Setting of Tourette Syndrome (TS)
Rationale
Patients with severe TS, resistant to medical and behavioral therapy, may benefit from the application of deep brain
stimulation (DBS). An important challenge and limitation in the evaluation of the evidence around DBS in TS is that, even
in expert DBS centers, few operations per year are performed. Furthermore, there is limited information from randomized
clinical trials for analysis and interpretation. There is no consensus on the optimal brain target for the treatment of tics, but
the following regions have been stimulated in patients with TS: the centromedian thalamus, the globus pallidus internus
(ventral and dorsal), the globus pallidus externus, the subthalamic nucleus, and the ventral striatum/ventral capsular
nucleus accumbens region. DBS of the anteromedial globus pallidus is probably more likely than sham stimulation to
reduce tic severity. There is insufficient evidence to determine the efficacy of DBS of the thalamus or the centromedian-
parafascicular complex region of the thalamus in reducing tic severity. Complications of treatment, including infection and
removal of hardware, appear more common with TS than with other neurologic conditions.

Recommendations from the Movement Disorders Society suggest that, when DBS is used in TS, best practices used for
other DBS applications are followed, including confirmation of diagnosis, use of multidisciplinary screening, and
stabilization of psychiatric comorbidities inclusive of active suicidality.33 Appropriate patient selection is one of the most
important predictors of success of DBS treatment, making multidisciplinary evaluation essential.34 Because of the
complexity of the patient population, centers performing DBS have been encouraged to screen candidates preoperatively
and to follow them postoperatively. There has been concern about high risk of suicide and other negative psychiatric
sequelae in patients with TS not screened and monitored for depression, anxiety, and bipolar tendencies. The largest
available randomized trials of DBS have revealed benefits on motor and phonic tics for the ventral globus pallidus internus
and the centromedian thalamic region target; however, these studies have raised methodologic concerns that need to be
addressed in future trials.35 There is little information on the effects of DBS on psychiatric comorbidities and on the efficacy
of DBS in children with TS. Slide 54
Practice Recommendations
Recommendation Statements 13a−11b:
• Recommendation 13a: Physicians must use a multidisciplinary evaluation
(psychiatrist or neurologist, neurosurgeon, and neuropsychologist) to establish when
the benefits of treatment outweigh the risks for prescribing DBS for medication
resistant motor and phonic tics (Level A).
• Recommendation 13b: Physicians should confirm the DSM-5 diagnosis of TS and
exclude secondary and functional tic-like movements when considering DBS for
medication-resistant tics (Level B).
• Recommendation 13c: A mental health professional must screen patients
preoperatively and follow patients postoperatively for psychiatric disorders that may
impede the long-term success of the therapy (Level A).
• Recommendation 13d: Physicians must confirm that multiple classes of medication
(antipsychotics, dopamine depleters, alpha-1 agonists) and behavioral therapy have
been administered (or are contraindicated) before prescribing DBS for tics (Level A).
• Recommendation 13e: Physicians may consider DBS for severe, self-injurious tics,
such as severe cervical tics that result in spinal injury (Level C).

Slide 55
Suggestions for Future Research
1. Future research on behavioral interventions for tics should include comparisons of the relative efficacy of
Comprehensive Behavioral Intervention for Tics (CBIT) versus pharmacotherapy. Additional research should
be conducted on treatment sequencing and decision making and for whom particular sequences of treatment
are most effective. Further research should continue to test the efficacy of other behavioral treatments,
including exposure and response prevention, mindfulness-based treatments, or more global tic-related
interventions.36 As the evidence is insufficient at present to conclude that CBIT delivered by teleconference is
as effective as face-to-face treatment, further well-designed studies with adequate sample sizes are needed to
establish noninferiority. Additional work to more accurately characterize the neurocognitive and behavioral
mechanism of action underlying CBIT will be necessary to enhance the overall effectiveness and inform
patient-treatment matching algorithms.37
2. Future research on medications for tics should include noninferiority trials of agents commonly used for the
treatment of tics for which limited evidence from randomized controlled trials is available. Agents for which
evidence is promising but limited include the first-generation antipsychotic fluphenazine.38-40 Trials are currently
underway with the selective D1 antagonist ecopipam and evidence on the efficacy of this drug is expected
soon.
3. The dopamine depleters, tetrabenazine, deutetrabenazine, and valbenazine, act by blocking vesicular
monoamine transporter type 2 (VMAT2). Although no randomized controlled trials have been published with
the VMAT2 inhibitors in the treatment of tics, these drugs are increasingly used off label. When appropriately
dosed, these drugs are generally well tolerated but may be associated with drowsiness, depression, and
parkinsonism. Although an initial phase II trial of valbenazine did not reach the primary endpoint in adults and
children with Tourette syndrome (TS), this was thought to be due to underdosing. Further and better-designed
trials are currently underway with valbenazine and deutetrabenazine for the treatment of tics.41-43
Slide 56
Suggestions for Future Research (continued)
4. Our systematic review included 3 different traditional Chinese medicine products, the 5-Ling
granule,44 the Ningdong granule formulated by Zhao,45 and the Ningdong granule formulated by
Wang.46 We did not make formal recommendations for or against the use of these compounds, all
of which reported superiority over placebo. Our panel had concerns about the inclusion criteria for
the 5-Ling granule study, as participants also had a condition fitting the “excessive subtype” in
traditional Chinese medicine-based diagnosis (see full and unabridged practice guideline for full
details), with no equivalent diagnosis in Western medicine or clear understanding of
pathophysiology. Furthermore, this study excluded children with the 2 most common comorbidities
seen with TS—attention-deficit/hyperactivity disorder and obsessive-compulsive disorder. There
are therefore concerns with respect to the generalizability of these findings. Finally, the availability
of these compounds outside of the trials is unknown and safety concerns remain regarding the
ingredients—the Ningdong granule formulated by Wang contains human dried placenta. Further
research and information on the safety and reliability of production of these agents is required
before formal recommendations can be made.
5. There is a need for more long-term studies of drug efficacy and adverse effects as well as the
efficacy and safety of medication combinations for severe tics resistant to monotherapy.

Slide 57
Suggestions for Future Research (continued)
6. Few studies have been performed investigating the efficacy and safety of cannabis-based medicine in
children with various diseases. Recently it was reported that cannabidiol may significantly reduce convulsive
seizure frequency in children with Dravet syndrome.47 There is preliminary evidence that delta-9-
tetrahydrocannabinol might also be effective in children for vomiting due to antineoplastic treatment48, 49 and
in treatment-resistant spasticity.50 There is increasing evidence that cannabis-based medicine might be
effective in adults with TS.51 A recent press release for a single-dose study of a first-in-class small molecule
inhibitor of monoacylglycerol lipase, ABX-1431, which regulates one of the key natural activators of the
central cannabinoid CB1 receptor, suggests efficacy for the treatment of tics.52
7. Case reports and case series have comprised the majority of the outcomes data on the efficacy of deep
brain stimulation (DBS) for TS. An international DBS registry53 has been developed to collect data on DBS
outcomes in patients with TS implanted in various centers. The registry also collects information about
response to nonstandardized selection criteria, various brain targets, differences in hardware, and variability
in the programming parameters used. The goal of future research on DBS in TS should be to improve
outcomes and quality of life by conducting well-designed multicenter studies, share data across centers,
uncover best practices, and provide critical information to regulatory agencies that will lead to approval of
DBS in TS. There are important limitations to the currently available trials using DBS in TS. The uncertainty in
optimal target and the individual variability in programming and management between participants make
trials challenging. Recent research on DBS in TS has revealed the intriguing possibility that it may not be
necessary to have the devices activated continuously as has been the standard for other movement
disorders. Moreover, adaptive closed-loop DBS is being explored in an ongoing clinical trial.
8. Future research on the effect of special diets, nutritional supplements and exercise on tic severity is
needed.
Slide 58
References

References cited here can be found in the

recommendations summary article and systematic review
summary article. To locate these materials, please visit
AAN.com/guidelines.

Slide 59
 Access Guideline and
Summary Tools
• To access the complete guideline and related summary
tools, visit AAN.com/guidelines.
• Summary recommendations and systematic review articles
• Full-length guideline article
• Summary for clinicians
• Summary for patients/families

Slide 60
 Thank You.

© 2019 American Academy of Neurology

 Questions?

© 2019 American Academy of Neurology