Journal of Neural Transmission (2020) 127:843–850

https://doi.org/10.1007/s00702-019-02105-w

NEUROLOGY AND PRECLINICAL NEUROLOGICAL STUDIES - REVIEW ARTICLE

Treatment of tics associated with Tourette syndrome

Joseph Jankovic1 

Received: 10 October 2019 / Accepted: 14 November 2019 / Published online: 18 January 2020
© Springer-Verlag GmbH Austria, part of Springer Nature 2020

Abstract
Motor and phonic tics associated with Tourette syndrome (TS) can range in severity from barely perceptible to disabling and
most patients have a variety of behavioral co-morbidities, particularly, attention deficit disorder and obsessive compulsive
disorder. Therefore, therapy must be tailored to the individual needs of the patients. In addition to behavioral therapy, oral
medications such as alpha agonists, dopamine depletors, anti-psychotics, and topiramate are used to control the involuntary
movements and noises. Botulinum toxin injections are particularly effective in patients with troublesome focal motor and
phonic tics, including coprolalia. Deep brain stimulation may be considered for patients with “malignant” TS, that is, refrac-
tory to medical therapy. When appropriate therapy is selected and implemented, most patients with TS can achieve their full
potential and lead essentially normal life.

Keywords  Tics · Tourette syndrome · Obsessive-compulsive disorder · Attention deficit disorder · Deutetrabenazine ·
Botulinum toxin

Introduction of tics in people with Tourette syndrome and chronic tic

Treatment of Tourette syndrome (TS) must be individual-
ized and may require a combination of behavioral, phar-
macologic, and botulinum toxin therapies, as well as surgi-
cal intervention such as deep brain stimulation in disabling
(“malignant”) medically refractory cases (Cheung et al.
2007; Black et al. 2014; Jankovic 2015; Thenganatt and
Jankovic 2016). Because behavioral and psychiatric co-
morbidities are common, a multidisciplinary approach is
often needed to achieve optimal outcomes. This review will
focus on pharmacologic treatment of tics as the other thera-
peutic approaches, including surgical treatments, are cov-
ered elsewhere (Thenganatt and Jankovic 2016; Coulombe
et al. 2018; Quezada and Coffman 2018; Krack et al. 2019;
Pandey and Dash 2019). The readers are also referred to the
recently published Report of the Guideline Development,
Dissemination, and Implementation Subcommittee of the
American Academy of Neurology (AAN) on “The treatment
disorders” (Pringsheim et al. 2019a, b). This report focuses
on double-blind, placebo-controlled clinical trials, which
provide evidence-based data that has been critically ana-
lyzed. Despite the comprehensive and systematic review, it
is important to acknowledge, however, that this approach has
some limitations and the findings may not be generalizable
to all patients with TS. For example, because of rigid inclu-
sion/exclusion criteria required for enrollment, the findings
from these therapeutic trials may not apply to patients who
would not qualify for the studies, because of their clinical
profile, potential interactions with concomitant drugs, the
presence of co-morbidities, and other reasons. Furthermore,
most of the controlled clinical trials are relatively short and,
therefore, do not allow for long-term observations on effi-
cacy and safety.
Behavioral therapy

* Joseph Jankovic
Numerous studies have provided evidence that behavioral
josephj@bcm.edu therapies are effective in patients with TS. In the abovemen-
https://www.jankovic.org tioned AAN guideline report (Pringsheim et al. 2019a, b)
1
there was high confidence that the Comprehensive Behav-
Department of Neurology, Parkinson’s Disease Center
and Movement Disorders Clinic, Baylor College
ioral Intervention for Tics (CBIT), including Habit Rever-
of Medicine, 7200 Cambridge, Suite 9A, Houston, sal Therapy (HRT), was more likely than psychoeducation
TX 77030‑4202, USA

13
Vol.:(0123456789)
 J. Jankovic
844
and supportive therapy to reduce tics. Although highly
recommended CBIT is often difficult to access, because of
lack of trained and certified psychologists or occupational
therapists, poor insurance coverage, and high demands on
patients and their parents to fully comply with the instruc-
tions. In this regard, an interactive online treatment pro-
gram, called “TicHelper” (https​://www.tiche​lper.com) has
been launched. In a direct comparison of pharmacotherapy
with behavioral therapy in children and adolescents with TS,
both approaches were effective in reducing tics and improv-
ing quality of life, but only pharmacotherapy was effective
in reducing obsessive–compulsive symptoms (Rizzo et al.
2018).
Pharmacological therapy
Alpha‑2 agonists
Alpha agonists, such as clonidine and guanfacine, are often
prescribed especially by pediatricians and psychiatrists as
the “first-tier” medications in patients with newly diagnosed
TS. Several studies have demonstrated that these drugs may
be useful in the treatment of mild tics with co-coexisting
mild attention deficit hyperactivity disorder (ADHD) and
impulse control disorder. In a 16-week, multi-center, ran-
domized, double-blind clinical trial in which 136 children
with ADHD and a chronic tic disorder were randomly
administered clonidine alone, methylphenidate alone, com-
bination of the two drugs, or placebo the greatest benefit in
improving tics and attention occurred with the combination
of the two active drugs (Tourette’s Syndrome Study Group
2002). Although 28% of the patients reported moderate or
severe sedation with clonidine, the drugs were generally well
tolerated. Since there was no worsening of tics with methyl-
phenidate, the results of this study argue against prior rec-
ommendations to avoid CNS stimulants in patients with the
combination of TS and ADHD. Nevertheless, it is generally
considered a prudent practice to attempt to control tics first
(usually with anti-dopaminergic drugs) before introducing
CNS stimulants. Besides oral preparation, clonidine is also
available as a transdermal patch. In a 2008 double-blind,
placebo-controlled trial involving 437 TS patients, the clo-
nidine patch was significantly more effective than placebo
(Du et al. 2008).
A meta-analysis of published studies of alpha-2 agonists
for treatment of TS found a medium to large effects on tics
in subjects who had co-existing ADHD, but only a small,
non-significant benefit on tics in studies that excluded co-
existing ADHD (Weisman et al. 2013). Clonidine may be
more helpful for sleep initiation at night, but daytime seda-
tion, which may be reversed with CNS stimulants, limits
its use. Because guanfacine seems to be less sedating than
13
clonidine, it is often preferred, especially in the treatment
of co-morbid ADHD and impulse control. Both alpha-2
agonists, however, have limited efficacy in the treatment of
tics. In one study, involving 34 children with chronic tic
disorder, extended release of guanfacine did not exert a
clinically meaningful effect, as determined by reduction in
Global Tic Severity Scale Total Tic Score (YGTSS-TTS)
and other scales, compared to placebo (Murphy et al. 2017).
Besides sedation, other potential side effects of alpha-2
agonists include fatigue, dry mouth, headaches, irritability,
bradycardia, and orthostatic hypotension. Because of some,
albeit modest, efficacy of alpha-2 agonists, these drugs may
be helpful in patients with mild tics that are troublesome
enough to require pharmacologic therapy.
Dopamine receptor blocking drugs
Dopamine receptor blocking drugs (also known as neuro-
leptics or anti-psychotics) have been traditionally used in
the treatment of TS, but the drugs are often associated with
undesirable adverse effects, especially metabolic syndrome
and tardive dyskinesia. In a study of 7804 individuals (76.4%
males, median age at first diagnosis, 13.3 years) with TS or
chronic tic disorder, a higher risk (hazard ratio adjusted by
sex and birth year of 1.99; 95% CI 1.90–2.09) of any meta-
bolic or cardiovascular disorders was noted compared with
the general population and sibling controls (Brander et al.
2019). This included higher risk for obesity, type 2 diabetes,
and circulatory system diseases. The finding draws atten-
tion to the importance of carefully monitoring cardiac and
metabolic health in patients with TS treated with dopamine
receptor blocking drugs. Furthermore, all dopamine receptor
blocking drugs, with the possible exception of clozapine,
can cause tardive dyskinesia. Indeed, one systematic review
found evidence of motor and phonic tics occurring during
treatment (n = 44) or following discontinuation (n = 16) of
dopamine receptor blocking drugs, particularly first-gener-
ation antipsychotics (Kim et al. 2018).
Currently, three drugs, all dopamine receptor block-
ing agents, have been approved by the US Food and Drug
Administration (FDA) for the treatment of TS: haloperidol,
pimozide, and aripiprazole. The approval of aripiprazole
was partly based on results of a randomized, double-blind,
placebo-controlled trial of aripiprazole, which included 61
children and adolescents with TS (Yoo et al. 2013). After
10 weeks, there was a significantly greater improvement in
the YGTSS-TTS compared to baseline in the active treat-
ment arm compared to placebo (− 15.0 vs. 9.6, respectively,
p = 0.0196). Response rate, as determined by the Tourette’s
Syndrome Clinical Global Impression-Improvement, was
66% and 45% in the aripiprazole and placebo groups,
respectively. Mean decrease in the Tourette’s Syndrome
Clinical Global Impression-Severity of Illness score was also
Treatment of tics associated with Tourette syndrome 845
significantly different between the groups in favor of ari-
piprazole (p = 0.0321). Side effects of aripiprazole included
significant increase in mean body weight, body mass index,
and waist circumference. These findings were confirmed by
a phase 3, randomized, double-blind, placebo-controlled
trial, which enrolled 133 patients (Sallee et al. 2017). At
week 8, the treatment difference in YGTSS-TTS vs. pla-
cebo was − 6.3 (p = 0.0020) and − 9.9 (< 0.0001), respec-
tively. Furthermore, 69% (29/42) of patients in the low-dose
(5–10 mg/day) and 74% (26/35) of patients in the high-dose
aripiprazole (10–20 mg/day) groups indicated that they were
much or very much improved. Although aripiprazole is mar-
keted as an atypical antipsychotic with low risk of tardive
dyskinesia, there have been many reports of this iatrogenic
side effect in patients treated with the drug (Peña et al. 2011;
Carbon et al. 2018).
Besides these three neuroleptics, there have been many
other dopamine receptor blocking drugs used in the treat-
ment of TS such as risperidone and ziprasidone (Weisman
et al. 2013; Pandey and Dash 2019). Tiapride is one of the
most frequently prescribed drugs for tics in Europe although
double-blind, placebo-controlled trials are lacking (Roessner
et al. 2013). Fluphenazine, a typical antipsychotic found to
be effective for TS in small studies, has been also found
to be safe and effective in long-term observational stud-
ies. In a retrospective review of the use of fluphenazine for
the treatment of TS conducted at Baylor College of Medi-
cine, which included 268 patients treated for an average of
2.6 ± 3.2 years (range 0.01–16.8, 40 patients over 5 years and
13 patients over 10 years), the response to fluphenazine was
rated as “moderate to marked” in 80.5% of patients at first
follow-up visit and 76% at last follow-up (Wijemanne et al.
2014). The mean dose at last follow-up was 3.2 ± 2.3 mg
(range 0.5–12 mg) per day. The most common side effects
were drowsiness (26.1%), weight gain (11.6%), akathisia
(8.5%), and acute dystonic reactions (7.0%), but there were
no cases of tardive dyskinesia. The low risk of tardive dys-
kinesia in this study is probably due to relatively young age
of the studied population, the mean age at initiation was
15.8 ± 10.8 years (range 4.1–70.2).
While the benefits of dopamine receptor blocking drugs
in reducing tics have been demonstrated in multiple trials,
their use is limited by short-term and long-term side effects,
including sedation, school phobia, weight gain, metabolic
syndrome, hyperprolactinemia, acute dystonic reactions,
Parkinsonism, tardive dyskinesia, and neuroleptic malignant
syndrome (Mogwitz et al. 2013).
In addition to the above anti-psychotics which block pre-
dominantly D2 dopamine receptors, there are novel, experi-
mental, anti-dopaminergic drugs currently investigated in
the treatment of TS. Based on studies of animal models
exhibiting tic-like behaviors, including the D1CT-7 mouse,
blocking the direct, D1 receptor mediated, “net excitatory”,
pathway has been suggested to suppress tics (Godar et al.
2016; Santangelo et al. 2018). In this regard, ecopipam, a
selective D1 receptor antagonist, was evaluated in a 4-week
double-blind, placebo-controlled crossover study of 40 TS
patients, aged 7–17 years, randomized to either ecopipam
(50 mg/day for weight of < 34 kg, 100 mg/day for weight
of > 34 kg) or placebo for 30 days, followed by a 2-week
washout and then crossed to the alternative treatment for
30 days (Gilbert et al. 2018). The YGTSS-TTS decreased
more robustly in patients randomized to ecopipam rela-
tive to those exposed to placebo: from 32.8 to 27.2 (− 5.6)
with ecopipam vs. from 33.7 to 30.3 (− 3.4) with placebo
(p = 0.043). The study confirmed the findings from an ear-
lier, smaller trial (Gilbert et al. 2014), but further studies are
needed before the drug will be approved by the FDA for the
treatment of TS.
Dopamine‑depleting drugs
While dopamine receptor blocking drugs are generally quite
effective in reducing tics, they are associated with a variety
of potential serious and permanent complications such as
tardive dyskinesia. Dopamine-depleting drugs that act by
inhibiting vesicular monoamine transporter 2 (VMAT2)
have been used in the treatment of a variety of hyperkinetic
movement disorders, including tics, without causing tardive
dyskinesia (Jankovic 2016).
Tetrabenazine, approved by the FDA for the treatment of
chorea associated with Huntington disease, has been shown
to be effective in several open-label trials for the treatment
of tics associated with TS (Kenney et al. 2007; Chen et al.
2012). Although effective in the treatment of a variety of
hyperkinetic movement disorders, tetrabenazine has been
reported to be associated with various side effects, includ-
ing drowsiness, parkinsonism, depression, and akathisia. In
the United States, tetrabenazine (now available as a generic
drug) carries a black-box warning regarding the risk of
depression and suicidality. A recent study of patients with
Huntington disease, however, has suggested that patients
taking tetrabenazine may actually have a lower risk of
depression and suicidality than those not taking the drug
(Schultz et al. 2018).
Other dopamine depletors currently investigated in the
treatment of TS include deutetrabenazine (also known as
SD-809 or TV50717) and valbenazine (also known as NBI-
98854). In a pilot, open-label, study of deutetrabenazine, 23
adolescent patients (mean age 16 years; range: 12–18) with
moderate-to-severe tics associated with TS were titrated over
a 6-week period and maintained for 2 weeks at a mean dose
of 32.1 mg (range: 18–36 mg) of SD-809 (Jankovic et al.
2016). An independent blinded rater assessed tic severity
using the YGTSS and tic impact by the TS-Clinical Global
Impression (TS-CGI). The mean YGTSS Total Tic Score
13
 J. Jankovic
846

improved by 37.6% (p < 0.0001) and there were also sig-

nificant improvements in secondary outcome measures,
including TS-Clinical Global Impression, TS-Patient Global
Impression of Change, Tic-Related Impairment Score, Beck
Depression Inventory II, and the Children’s Yale–Brown
Obsessive Compulsive Scale. No serious or severe adverse
effects were reported. This drug, a deuterated form of tetra-
benazine, may have a more favorable pharmacokinetic
profile than tetrabenazine and may be administered twice
per day instead of 3 times per day. Furthermore, based on
studies in Huntington disease and tardive dyskinesia, deu-
tetrabenazine seems to be better tolerated than tetrabena-
zine, including having less sedation (Niemann and Jankovic
2018; Bashir and Jankovic 2018). There are currently three
ongoing trials designed to examine deutetrabenazine in TS:
1. ARTISTS1 (TV50717-CNS-30046; NCT03452943), a
12-week phase 2/3 randomized clinical trial; 2. ARTISTS2
(TV50717-CNS-30060; NCT03571256), an 8-week phase
3 randomized clinical trial with fixed low-dose and high-
dose cohorts and provision to reduce dosage in the setting Fig. 1  Therapeutic algorithm for the treatment of tics. BoNT botuli-
of CYPD26 impairment (NCT03571256), and 3. ARTSTS num neurotoxin, CBIT/HRT comprehensive behavioral intervention
(TV50717-CNS-30047; NCT03452943), an open-label, for Tics/habit reversal therapy, GPi globus pallidus internus
28-week, extension study.
Preliminary findings suggest that studies with valbena-
zine in TS failed to reach their primary endpoint. These (Yang et al., 2013). The most common adverse events were
include T-Force GREEN, a pediatric phase 2 study, T-Force drowsiness (3.3–16%), loss of appetite (4–16.7%), cognitive
GOLD, a pediatric phase 3 study, and T-Forward, an adult dysfunction (7.89–12.5%), and weight loss (6–10.5%). The
phase 2 study. The reasons for these failures are not well authors concluded that “The current evidence is promising
understood, but may be related to methodological problems but not yet sufficient to support the routine use of topiramate
such as inclusion of relatively mild cases and underdosing. for TS in children due to low quality of the study designs.”
Although no randomized, double-blind, placebo-con- Levetiracetam has been shown to be helpful in the treatment
trolled trials have been published with the VMAT2 inhibi- of tics in open-label studies, but randomized, controlled
tors in the treatment of tics, many experts used them as a studies failed to demonstrate its benefit (Hedderick et al.
first-line treatment in patients with TS who experience trou- 2009; Cavanna and Nani 2013).
blesome tics (Fig. 1).
Serotonergic drugs
Antiepileptic drugs
Numerous clinical drug trials, neurophysiological and imag-
A variety of antiepileptic drugs have been studied in TS for ing studies, and analyses of human samples (e.g., blood,
some time, but none of them have emerged as the main- urine, cerebrospinal fluid, brain tissue) have led to several
stay treatment. In a multi-center, placebo-controlled study hypotheses regarding the neurochemical abnormalities in TS
of topiramate involving 29 patients with TS (mean age (Robertson et al. 2017). Although dopaminergic dysfunc-
16.5 years), we showed a significantly greater improvement tion has been proposed as the predominant neurotransmit-
in the YGTS-TTS at day 70 compared to baseline in the ter abnormality, imbalances in serotonergic, noradrenergic,
topiramate group (mean dose 118 mg) compared to placebo glutamatergic, cholinergic, and GABAergic systems have
(− 14.29 vs. 5.00, p = 0.0259) (Jankovic et al. 2010). There also been implicated (Lerner et al. 2012; Draper et al. 2014).
was also a significant improvement in the clinical global Reduced cerebrospinal fluid levels of 5-hydroxyindoleacetic
impression and premonitory urge; there was no difference acid in patients with TS compared to healthy controls has
in adverse events between the groups. A meta-analysis been used to support the role of serotonin in TS (Paschou
of topiramate for TS, which identified 14 trials involving et al. 2013). Stimulation of upregulated 5-HT2A receptors
1003 TS patients found significant difference in the mean may contribute to the elevated phasic release of dopamine
change of YGTSS score during the treatment period (mean in TS. Indeed, serotonin transporter binding was found to be
difference = − 7.74) between topiramate and control groups increased, particularly in caudate and midbrain, in patients

13
Treatment of tics associated with Tourette syndrome 847
with TS and obsessive compulsive disorder (Müller-Vahl
et al. 2019). Treatment with escitalopram, a serotonin re-
uptake inhibitor of the patients, resulted in a significant
reduction in serotonin transporter binding. Other serotonin
re-uptake inhibitors and drugs that modulate serotonergic
activity have been found to be effective in treating tics, as
well as the co-morbid obsessive compulsive behavior. Small,
open-label studies have shown some benefit in patients with
TS treated with serotonin antagonists such as ketanserin and
ondansetron (Toren et al. 2005). Clonazepam, a benzodiaz-
epine which presumably acts predominantly on the seroto-
nin system has been found effective in many patients with
TS, but its usefulness is limited by sedation and depression.
Therefore, newer serotonergic agents are currently being
explored in the management of TS.
Pimavanserin is a non-dopaminergic, potent, and selec-
tive serotonin inverse agonist. It acts like an agonist in that
it binds to the same receptor as serotonin, however, it pro-
duces the opposite effect. While traditional antagonists block
the effects of binding agonists, inverse agonists inhibit the
basal activity of the receptor. Pimavanserin has high affin-
ity at the 5-HT2A receptor, but also has lower affinity at the
5-HT2C serotonin receptor (Sahli and Tarazi 2018). Cur-
rently approved by the FDA for treatment of psychosis in
Parkinson’s disease, pimavanserin is currently studied in a
pilot, open-label trial in adult patients with TS.
Cannabinoids
There is a growing public interest in marijuana and can-
nabinoids for treatment of movement disorders, including TS
(Kluger et al. 2015; Lim et al. 2017). Patients often report
an improvement in tics with cannabis, but the response is
usually quite non-specific and difficult to substantiate. In
two small controlled trials, an improvement in tics was dem-
onstrated with delta-9-tetrahydrocannabinol without major
side effects (Müller-Vahl 2013). According to a Cochrane
review on the efficacy of cannabinoids in TS, definite con-
clusions about the safety and efficacy of cannabinoids in
the treatment of TS cannot be drawn (Curtis et al. 2009).
Well-designed controlled studies with a large number of
patients are needed to determine the efficacy and safety of
cannabinoids for treatment of TS. A systematic review and
meta-analysis found “little evidence for the effectiveness of
pharmaceutical CBD or medicinal cannabis” for the treat-
ment of various disorders, including TS (Black et al. 2019).
A preliminary report of finding of a phase IIa study at
Yale University showed that THX-110, a combination drug
of dronabinol and palmitoylethanolamide, met its primary
endpoint and significantly improved symptoms in adult sub-
jects with TS (https​://clini​caltr ​ials.gov/ct2/show/NCT03​
65172​6). Further studies in TS using a combination of
tetrahydrocannabinol and palmitoylethanolamide are cur-
rently ongoing.
ABX-1431 is a monoacylglycerol lipase, an enzyme that
regulates 2-arachidonoylglycerol, which is an endogenous
agonist of cannabinoid CB1 and CB2 receptors. Inhibi-
tion of this enzyme has shown anti-nociceptive, anxiolytic,
and anti-inflammatory effects, and exerted neuroprotective
effects in animal models of Parkinson’s disease and Alzhei-
mer’s disease (Jiang and van der Stelt 2018). A double-blind
crossover single-dose randomized clinical trials involving
19 adult TS patients showed a modest (10%) but significant
reduction in YGTSS-TTS at 8 h after dosing (Bellows and
Jankovic 2020). A phase 2 randomized clinical trial testing
two dose levels is currently underway in adult TS patients
(NCT03625453).
The AAN guideline report (Pringsheim et al. 2019a, b)
found moderate confidence that haloperidol, risperidone,
aripiprazole, tiapride, clonidine, onabotulinumtoxinA injec-
tions probably more likely reduce tics than placebo. There
was low confidence that pimozide, ziprasidone, metoclo-
pramide, guanfacine, topiramate, and tetrahydrocannabinol
were possibly more likely than placebo to reduce tics. Other
drugs occasionally prescribed for TS such as baclofen, lev-
etiracetam, riluzole, pramipexole, flutamide, mecamylamine,
and selegiline received “very low-level confidence” that they
reduced tic severity more likely than placebo.
Botulinum toxin injections
Botulinum toxin injections have been used in the treatment
of focal motor tics and in some simple and complex phonic
tics (including coprolalia) for long time, but rigorous stud-
ies are lacking (Scott et al. 1996; Lotia and Jankovic 2016;
Jankovic 2018; Pandey et al. 2018; Pandey and Dash 2019).
Open-label studies and cases series have demonstrated the
benefits of botulinum toxin not only in reducing the inten-
sity and frequency of the tics, but also in ameliorating the
regional premonitory urge (Kwak et al. 2003). The effects
of botulinum toxin was also studied in an open-label, lon-
gitudinal study of 35 patients (30 male) treated with botuli-
num toxin for problematic tics present for a mean duration
15.3 years (range 1–62 years) (Kwak et al. 2000). During a
mean follow-up of 21.2 months (range 5–84 months) and
115 treatment sessions (mean number of visits 3.3), the mean
peak effect response was 2.8 (0 = no response; 4 = marked
improvement in both severity and function); the mean dura-
tion of benefit was 14.4 weeks (maximum, 45 weeks). Fur-
thermore, 21 (84%) of 25 patients with premonitory sensa-
tions derived marked relief of these symptoms (mean benefit
70.6%). Total mean dose of onabotulinumtoxinA per visit
was 119.9 U (range 15–273 U). Sites of injections were as
follows: cervical or upper thoracic area (17), upper face (14),
13
 J. Jankovic
848
lower face (7), vocal cords (4), upper back and/or shoulder
(3), scalp (1), forearm (1), leg (1), and rectus abdominis
(1). Complications included neck weakness (4), dysphagia
(2), ptosis (2), nausea (1), hypophonia (1), fatigue (1), and
generalized weakness (1), which were all mild and transient.
In another study, involving 30 TS patients treated with botu-
linum toxin, improvement in phonic tics was reported by
93% of patients and 50% were reportedly free of phonic tics
after the botulinum toxin injection; premonitory sensation
and quality of life also improved. (Porta et al. 2004). The
most common side effect was hypophonia, noted in 80%
of patients. A randomized, double-blind placebo-controlled
study of botulinum toxin for motor tics demonstrated a sig-
nificant improvement in urge and tic frequency (Marras et al.
2001). There was 39% reduction in tics/min with botulinum
toxin vs. 6% increase with placebo (p = 0.004). Furthermore,
the urge score decreased by 0.46 with botulinum toxin and
increased by 0.49 with placebo (p = 0.02). There was no sig-
nificant change in other measures such as severity score, tic
suppression, pain, and patient global impression, possibly
because of its small sample size, relatively mild symptoms,
and a fixed treatment protocol.
Botulinum toxin is clearly an effective treatment particu-
larly in patients with bothersome tics that are refractory to
oral medications such as repetitive cervical extension (so
called “whiplash tics”) seen in some cases with “malignant”
TS (Cheung et al. 2007). Botulinum toxin injections into the
extensor muscles of the neck have been reported to reverse
compressive cervical myelopathy as a complication of the
“whiplash” tics (Krauss and Jankovic, 1996). Although focal
weakness can occur after botulinum toxin injection, this is
rarely troublesome of disabling and it is always transient.
Surgical therapy
Deep brain stimulation targeting various subcortical struc-
tures has been proposed as a treatment option for severe
TS, but only a few trials have provided data based on “con-
trolled” design (Viswanathan et al. 2012). In a randomized,
double-blind, crossover trial of deep brain stimulation of
globus pallidus internus in 15 patients with medically intrac-
table TS, there was 40.1% improvement in tics (Kefalopou-
lou et al. 2015). In an international deep brain stimulation
registry involving 185 patients treated with deep brain
stimulation targeting centromedian thalamic region (57%),
anterior globus pallidus (25%), and other areas the YGTSS
mean total score improved 45% (from 75.0 at baseline to
41.2) (Martinez-Ramirez et al. 2018).
The AAN guideline report (Pringsheim et al. 2019a, b)
found low confidence that deep brain stimulation of the
globus pallidus was possibly more likely than placebo to
reduce tics. The conclusions from this report, which focused
13
on controlled trials and evidence-based data, should be bal-
anced against and coupled with a more pragmatic approach,
based on long-term experience and expert opinion. While
the AAN guidelines did not specifically differentiate which
therapeutic approaches may be more appropriate for children
versus adults, most cited studies were performed in adult
populations. Because the risk of tardive dyskinesia is much
higher in adults than in children, we are less likely to use
dopamine receptor blocking drugs in adults with TS. On the
other hand, we tend to consider surgical intervention, such
as deep brain stimulation, more commonly in adults than in
children. This again highlights the importance of individual-
ized approach to the treatment of TS.
References
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