Tourette's Syndrome

Number: 0480

Policy

Aetna considers certain procedures and services medically necessary for assessment and treatment of Tourette's syndrome (TS) when all of the following selection criteria are met.

  • Both multiple motor and 1 or more vocal tics have been present at some time during the illness, although not necessarily simultaneously; and
  • The disturbance causes significant distress or marked impairment in social, occupational, or other important areas of functioning; and
  • The disturbance is not due to direct physiological effects of a substance (e.g., stimulants) or a general medical condition (e.g., Huntington's disease or post-viral encephalitis); and
  • The onset is before the age of 21 years; and
  • The tics occur many times a day (usually in bouts) almost every day or periodically throughout a duration of more than 1 year, and during this period there was never a tic-free period of more than 3 consecutive months.

The following procedures and services are considered medically necessary for the assessment and treatment of TS when the selection criteria outlined above are met:

  1. Assessment

    1. Electroencephalography (EEG) or neurological consult (only in the presence of focal signs or clinical suggestions of seizure disorder or degenerative condition)
    2. Medical evaluation (complete medical history and physical examination)
  2. Treatment

    1. PharmacotherapiesFootnotes for pharmacy benefit*:

      1. Clonazepam (Klonopin and generics)
      2. Clonidine (Catapres and generics)
      3. Fluphenazine (Prolixin and generics)
      4. Haloperidol (Haldol and generics)
      5. Pimozide (Orap)
      6. Risperidone (Risperdal)
      7. Tetrabenazine
      8. Tricyclic anti-depressants (for TS members who also exhibit attention deficit hyperactivity disorder)
         

      Footnotes*Note

      Self-administered prescription medications are covered under the pharmacy benefit.  Formulary restrictions may apply.  Please check plan benefit description for details.

    2. Psychotherapy (if member also exhibits anxiety and/or depression)

Note: Psychotherapeutic interventions are covered under the member's behavioral health benefits.  Please check benefit plan descriptions.

The following procedures and services are considered experimental and investigational for the assessment and treatment of TS because of insufficient evidence of their effectiveness for this indication:

  1. Assessment

    1. Computerized EEG (brain mapping or neurometrics, please see CPB 0221 - Quantitative EEG (Brain Mapping))
    2. Genetic studies
    3. Measurement of serum ferritin level
    4. Neuroimaging (e.g., CT, MRI, PET, and SPECT)
  2. Treatment

    1. Acupuncture (please see CPB 0135 - Acupuncture)
    2. Adaptive (responsive) deep brain stimulation
    3. Anti-glutamatergic drugs (e.g., gabapentin, lamotrigine, riluzole, and topiramate)
    4. Aripiprazole
    5. Bilateral stereotactic lesions of the anterior cingulate gyrus
    6. Bilateral thalamic stimulation/deep brain stimulation (please see CPB 0208 - Deep Brain Stimulation)
    7. Botox injections (please see CPB 0113 - Botulinum Toxin)
    8. Cannabinoids (e.g., delta-9-tetrahydrocannabidiol (THC) and nabiximols)
    9. Dietary interventions
    10. Ecopipam
    11. EEG biofeedback (please see CPB 0132 - Biofeedback)
    12. Electroconvulsive therapy
    13. Intravenous immunoglobulins (IVIG) (please seeCPB 0206 - Parenteral Immunoglobulins)
    14. N-acetylcysteine
    15. Metoclopramide
    16. Omega-3 fatty acids (also known as ω-3 fatty acids or n-3 fatty acids)
    17. Pramipexole
    18. Repetitive transcranial magnetic stimulation (please see CPB 0469 - Transcranial Magnetic Stimulation and Cranial Electrical Stimulation)
    19. Transcranial direct current stimulation
    20. Valproate
    21. Vesicular monoamine transporter type 2 inhibitors (e.g., amphetamine, methamphetamine, and tetrabenazine)
    22. VMAT-2 inhibitors (e.g., valbenazine)

Note: Most Aetna medical plans exclude coverage of educational interventions.  Under these plans, educational and achievement testing as well as educational interventions (including classroom environmental manipulation, academic skills training, and parental training) are not covered.  Please check benefit plan descriptions for details.

Background

Tourette's syndrome (TS) is a familial neurobehavioral disorder characterized by fluctuating motor and/or vocal tics.  Tics can also be classified as
  1. simple or
  2. complex. 
Simple motor tics include eye blinking, neck jerking, shoulder shrugging, and facial grimacing.  Complex motor tics include facial gestures, groaning behaviors, hitting or biting oneself, jumping, touching, stamping, and smelling.  Simple vocal tics entail coughing, throat clearing, grunting, sniffing, snoring, and barking.  Complex vocal tics entail repeating words or phrases out of context, coprolalia (use of obscenities), palilalia (increasingly rapid repetition of a phrase or word), and echolalia (repeating the words of other people).  The symptoms of TS generally appear before the patient is 21 years old.

There are no specific blood tests or other laboratory tests that definitively diagnose TS.  Diagnosis of this disorder is a clinical one, and is made by patient history, family history, family recounting of events and behaviors of the patient, as well as by direct observation of the patient.  A medical evaluation, including a complete history and physical is necessary for diagnosis.  According to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV), both motor and vocal tics must be present for at least 1 year to establish a diagnosis of TS.  Brain mapping (computerized electroencephalography [EEG]) as well as neuroimaging studies, such as computed tomography, magnetic resonance imaging, positron emission tomography, and single photon emission computed tomography, usually do not aid in the diagnosis of TS.  Adams et al (2004) stated that the cause or causes of TS remain unknown.  Functional imaging studies have evaluated several implicated neurotransmitter systems and focused predominantly on the frequency or severity of tics.  The results have been inconclusive and frequently contradictory with little light shed on pathogenetic mechanisms.  Electroencephalography or neurological consultation is indicated only in the presence of focal signs or clinical suggestions of seizure disorder or degenerative condition.

A working group of the European Society for the Study of Tourette Syndrome (ESSTS) has developed the first European assessment guidelines of TS (Cath et al, 2011).  The available literature including national guidelines was thoroughly screened and extensively discussed in the expert group of ESSTS members.  Detailed clinical assessment guidelines of tic disorders and their co-morbidities in both children and adults were presented.  Screening methods that might be helpful and necessary for specialists' differential diagnosis process were suggested in order to further analyze cognitive abilities, emotional functions and motor skills.  Besides clinical interviews and physical examination, additional specific tools (e.g., questionnaires, checklists and neuropsychological tests) are recommended.

Tourette syndrome is a heterogeneous disorder with complex inheritance patterns and phenotypic manifestations.  O'Rourke et al (2009) assessed recent advances in the genetics of TS.  These investigators focused on
  1. the genetic etiology of TS;
  2. common genetic components of TS, attention deficit hyperactivity disorder (ADHD), and obsessive compulsive disorder (OCD);
  3. recent linkage studies of TS;
  4. chromosomal translocations in TS; and
  5. candidate gene studies. 
Family, twin, and segregation studies provide strong evidence for the genetic nature of TS.  Family studies of TS and OCD indicate that an early-onset form of OCD is likely to share common genetic factors with TS.  While there apparently is an etiological relationship between TS and ADHD, it appears that the common form of ADHD does not share genetic factors with TS.  The largest genome wide linkage study to date observed evidence for linkage on chromosome 2p23.2 (P = 3.8x10(-5)).  No causative candidate genes have been identified, and recent studies suggest that the newly identified candidate gene SLITRK1 is not a significant risk gene for the majority of individuals with TS.  The authors concluded that the genetics of TS are complex and not well understood.  The Genome Wide Association Study (GWAS) design can hopefully overcome the limitations of linkage and candidate gene studies.  However, large-scale collaborations are needed to provide enough power to utilize the GWAS design for discovery of causative mutations.  Knowledge of susceptibility mutations and biological pathways involved should eventually lead to new treatment paradigms for TS.

Dehning et al (2010) stated that TS is a complex neuropsychiatric disorder probably originating from a disturbed interplay of several neurotransmitter systems in the prefrontal-limbic-basal ganglia loop.  Polygenetic multi-factorial inheritance has been postulated; nevertheless, no confirmed susceptible genes have been identified yet.  As neuroimaging studies allude to dopaminergic and serotonergic dysfunction in TS and serotonin as an important factor for dopamine release, genotyping of common polymorphisms in the serotonergic receptor (HTR1A: C-1019G; HTR2A: T102C, His452Tyr, A-1438G; HTR2C: C-759T, G-697C) and transporter genes (SLC6A4) was performed in 87 patients with TS, compared with 311 matched controls.  These investigators found a nominally significant association between both polymorphisms in the HTR2C and the GTS, which was more pronounced in male patients.  Analysis of the further serotonergic polymorphisms did not reveal any significant result.  A modified function of these promoter polymorphisms may contribute to the complex interplay of serotonin and dopamine and then to the manifestation of TS.

For most patients with TS, the clinical course is benign.  For patients whose symptoms interfere with daily functioning, pharmacotherapy may help in alleviating symptoms.  The most commonly used medications for the treatment of TS are haloperidol (Haldol), pimozide (Orap), fluphenazine (Prolixin), and clonidine (Catapres).  Clonazepam (Klonopin) and risperidone (Risperdal) have been shown to be beneficial in some patients.  Furthermore, tricyclic anti-depressants can be used for the treatment of TS patients who also exhibit attention deficit hyperactivity disorder.  Psychotherapy is appropriate for TS patients who experience anxiety or depression.

There is insufficient scientific evidence to support the use of Botox (botulinum toxin) injections, biofeedback, bilateral stereotactic lesions of the anterior cingulate gyrus, bilateral thalamic stimulation, intravenous immunoglobulins and repetitive transcranial magnetic stimulation for the treatment of TS.

Maciunas et al (2007) performed a prospective double-blind cross-over trial of bilateral thalamic deep brain stimulation (DBS) in 5 adults with TS.  An independent programmer established optimal stimulator settings in a single session.  Subjective and objective results were assessed in a double-blind randomized manner for 4 weeks, with each week spent in 1 of 4 states of unilateral or bilateral stimulation.  Results were similarly assessed 3 months after unblinded bilateral stimulator activation while repeated open programming sessions were permitted.  In the randomized phase of the trial, a statistically significant (p < 0.03) reduction in the modified Rush Video-Based Rating Scale score (primary outcome measure) was identified in the bilateral on state.  Improvement was noted in motor and sonic tic counts as well as on the Yale Global Tic Severity Scale and TS Symptom List scores (secondary outcome measures).  Benefit was persistent after 3 months of open stimulator programming.  Quality of life indices were also improved; 3 of 5 patients had marked improvement according to all primary and secondary outcome measures.  The authors concluded that bilateral thalamic DBS appears to reduce tic frequency and severity in some patients with TS who have exhausted other available means of treatment.  The findings of this study need to be validated by longer studies with larger sample sizes.

Visser-Vandewalle (2007) noted that following the introduction of DBS of the thalamus as a new treatment for TS in 1999, several other brain loci (e.g., globus pallidus internus, anteromedial and ventroposterolateral part, and the nucleus accumbens) have been targeted in a small number of patients.  In published reports, a tic reduction rate of at least 66 % has been described.  The effects of DBS on associated behavioral disorders are more variable.  The number of treated patients is small and it is unclear if the effects of DBS are dependent on the target nucleus.  The author stated that a meticulous evaluation of the electrode position, and a blinded assessment of the clinical effects on tics and behavioral disorders, is absolutely mandatory in order to identify the best target of DBS for TS.

Habit reversal therapy (HRT), also known as cognitive behavior intervention for tics, is a behavioral ttreatment for TS.  It usually entails 4 main components:
  1. awareness training,
  2.  relaxation training,
  3. competing response training (contingent), and
  4.  contingency management.
Habit reversal therapy usually involves making the patient aware of the tic or the urge to tic building up and training the patient to engage in a response that would be muscularly competing or incompatible with the tic.  Different investigators and clinicians may use slightly different variations in their protocols, but the competing response is a core feature of the technique (Black 2003).

Carr and Chong (2005) reviewed studies that used HRT to treat tics in terms of their methodological characteristics and rigor.  Guidelines developed by the Task Force on Promotion and Dissemination of Psychological Procedures were used to evaluate the state of the literature.  From an initial database that included 29 studies, 12 were included in the final analysis.  Results indicated that although research has been conducted in this area for almost 30 years, the majority of studies contain considerable methodological shortcomings.  Based on the Task Force guidelines, the existing literature on the use of HRT to treat tics can be classified as probably efficacious.  Furthermore, Bloch (2008) examined the evidence base for current treatments for TS; and indicated that emerging treatments for this disorder include DBS, HRT, and repetitive transcranial magnetic stimulation.

In a Cochrane review, Curtis and colleagues (2009) evaluated the safety and effectiveness of cannabinoids as compared to placebo or other drugs in treating tics, premonitory urges and obsessive compulsive symptoms (OCS), in patients with TS.  These investigators searched the Cochrane Central Register of Controlled Trials (CENTRAL) (in The Cochrane Library Issue 4 2008) , MEDLINE (January 1996 to date), EMBASE (January 1974 to date), PsycINFO (January 1887 to date), CINAHL (January 1982 to date), AMED (January 1985 to date), British Nursing Index (January 1994 to date) and DH DATA (January 1994 to date).  They also searched the reference lists of located trials and review articles for further information.  These researchers included randomized controlled trials (RCTs) comparing any cannabinoid preparation with placebo or other drugs used in the treatment of tics and OCS in patients with TS.  Two authors abstracted data independently and settled any differences by discussion.  Only 2 trials were found that met the inclusion criteria.  Both studies compared a cannabinoid, delta-9-tetrahydrocannabinol (Delta(9)THC), either as monotherapy or as adjuvant therapy, with placebo.  One was a double-blind, single-dose cross-over trial and the other was a double-blind, parallel-group study.  A total of 28 different patients were studied.  Although both trials reported a positive effect from Delta(9)THC, the improvements in tic frequency and severity were small and were only detected by some of the outcome measures.  The authors concluded that there is insufficient evidence to support the use of cannabinoids in treating tics and obsessive compulsive behavior in people with TS.

In a retrospective study, Kuo and Jimenez-Shahed (2010) examined the safety and effectiveness of topiramate in the treatment of TS.  Charts of subjects whose conditions were diagnosed as tic disorders seen at the authors' clinic from 2003 to 2007 were reviewed.  Patients who met diagnostic criteria for TS and were started on topiramate with at least 1 follow-up visit after beginning topiramate were included.  The efficacy of topiramate on a subjective scale, the global impression of response (0 = no response/worse, 1 = mild improvement, 2 = moderate improvement, 3 = marked improvement), and adverse effects were recorded for analysis.  Of 453 subjects, 367 met diagnostic criteria for TS and 41 (11.1 %; 34 males) were treated with topiramate for tics for 9.43 +/- 7.03 months (range of 1 to 27 months).  Mean age at onset of tics was 6.93 +/- 2.78 years (range of 2 to 14 years) and at start of topiramate treatment was 14.83 +/- 5.63 years (range of 9 to 27 years).  The average efficacy on tics was 2.15 +/- 1.11, and 75.6 % (n = 31) of subjects had moderate-to-marked improvement and adverse effects included cognitive/language problems (24.4 %, n = 10) and aggression or mood swings (9.8 %, n = 4).  The authors concluded that this retrospective chart review suggested that topiramate can be used for tics in TS with at least moderate efficacy and typical adverse effects.  They stated that RCTs are needed.

In a a randomized, double-blind, placebo-controlled, parallel-group study, Jankovic et al (2010) examined the effects of topiramate on TS.  To be included in the study, subjects required a DSM-IV diagnosis of TS, were 7 to 65 years of age, had moderate-to-severe symptoms (Yale Global Tic Severity Scale (YGTSS) greater than or equal to 19), were markedly impaired as determined by the Clinical Global Impression (CGI) scale severity score of greater than or equal to 4 and were taking no more than 1 drug each for tics or TS co-morbidities.  There were 29 patients (26 males), mean age of 16.5 (SD 9.89) years, randomized, and 20 (69 %) completed the double-blind phase of the study.  The primary endpoint was Total Tic Score, which improved by 14.29 (10.47) points from baseline to visit 5 (day 70) with topiramate (mean dose of 118 mg) compared with a 5.00 (9.88) point change in the placebo group (p = 0.0259).  There were statistically significant improvements also in the other components of the YGTSS as well as improvements in various secondary measures, including the CGI and premonitory urge CGI.  No differences were observed in the frequency of adverse events between the 2 treatment groups.  The authors concluded that this study provides evidence that topiramate may have utility in the treatment of moderately severe TS.  The drawbacks of this study were its small sample size, the relatively high drop-out rate (31 %), and the apparent lack of follow-up data.  These findings need to be validated by further investigation.

Pourfar et al (2011) studied metabolic brain networks that are associated with TS and co-morbid OCD.  These investigators utilized [(18)F]-fluorodeoxyglucose and PET imaging to examine brain metabolism in 12 unmedicated patients with TS and 12 age-matched controls.  They utilized a spatial co-variance analysis to identify 2 disease-related metabolic brain networks, one associated with TS in general (distinguishing TS subjects from controls), and another correlating with OCD severity (within the TS group alone).  Analysis of the combined group of patients with TS and healthy subjects revealed an abnormal spatial co-variance pattern that completely separated patients from controls (p < 0.0001).  This TS-related pattern (TSRP) was characterized by reduced resting metabolic activity of the striatum and orbito-frontal cortex associated with relative increases in pre-motor cortex and cerebellum.  Analysis of the TS cohort alone revealed the presence of a second metabolic pattern that correlated with OCD in these patients.  This OCD-related pattern (OCDRP) was characterized by reduced activity of the anterior cingulate and dorso-lateral pre-frontal cortical regions associated with relative increases in primary motor cortex and precuneus.  Subject expression of OCDRP correlated with the severity of this symptom (r = 0.79, p < 0.005).  The authors concluded that these findings suggested that the different clinical manifestations of TS are associated with the expression of 2 distinct abnormal metabolic brain networks.  These, and potentially other disease-related spatial co-variance patterns, may prove useful as biomarkers for assessing responses to new therapies for TS and related co-morbidities.  Furthermore, they noted that more studies are needed to evaluate the expression of TSRP and OCDRP patterns in larger patient and control cohorts, ideally including non-TS-associated OCD.  It is important to ascertain if existing or novel therapeutic interventions can suppress the activity of these and related functional brain networks.  If validated in independent populations, and found to be reproducible, these patterns may be useful as adjunctive outcome measures in clinical trials.  One of the drawbacks of this study was that subjects were all adults (mostly men) and the symptoms were "mild" as they did not require treatment with medication.

Ackermans et al (2011) stated that DBS of the thalamus has been proposed as a therapeutic option in patients with TS who are refractory to pharmacological and psychotherapeutic treatment.  Patients with intractable TS were invited to take part in a  randomized, double-blind, cross-over study evaluating the safety and effectiveness of stimulation of the centromedian nucleus-substantia periventricularis-nucleus ventro-oralis internus cross-point in the thalamus.  After surgery, the patients were randomly assigned to 3 months stimulation followed by 3 months OFF stimulation (group A) or vice versa (group B).  The cross-over period was followed by 6 months ON stimulation.  Assessments were performed prior to surgery and at 3, 6 months and 1 year after surgery.  The primary outcome was a change in tic severity as measured by the Yale Global Tic Severity Scale and the secondary outcome was a change in associated behavioral disorders and mood.  Possible cognitive side effects were studied during stimulation ON at 1 year post-operatively.  Interim analysis was performed on a sample of 6 male patients with only 1 patient randomized to group B.  Tic severity during ON stimulation was significantly lower than during OFF stimulation, with substantial improvement (37 %) on the Yale Global Tic Severity Scale (mean 41.1 +/- 5.4 versus 25.6 +/- 12.8, p = 0.046).  The effect of stimulation 1 year after surgery was sustained with significant improvement (49 %) on the Yale Global Tic Severity Scale (mean 42.2 +/- 3.1 versus 21.5 +/- 11.1, p = 0.028) when compared with pre-operative assessments.  Secondary outcome measures did not show any effect at a group level, either between ON and OFF stimulation or between pre-operative assessment and that at 1 year post-operatively.  Cognitive re-assessment at 1 year after surgery showed that patients needed more time to complete the Stroop Colour Word Card test.  This test measures selective attention and response inhibition.  Serious adverse events included 1 small hemorrhage ventral to the tip of the electrode, 1 infection of the pulse generator, subjective gaze disturbances and reduction of energy levels in all patients.  The authors concluded that these preliminary findings suggest that stimulation of the centromedian nucleus-substantia periventricularis-nucleus ventro-oralis internus cross-point may reduce tic severity in refractory TS, but there is the risk of adverse effects related to oculo-motor function and energy levels.  They stated that further RCTs on other targets are urgently needed since the search for the optimal one is still ongoing.

The European clinical guideline for "Tourette syndrome and other tic disorders. Part IV: Deep brain stimulation" (Muller-Vahl et al, 2011) stated that "[a]t present time, DBS in TS is still in its infancy.  Due to both different legality and practical facilities in different European countries these guidelines, therefore, have to be understood as recommendations of experts.  However, among the ESSTS working group on DBS in TS there is general agreement that, at present time, DBS should only be used in adult, treatment resistant, and severely affected patients.  It is highly recommended to perform DBS in the context of controlled trials".

Piedad et al (2012) noted that over the past decade, DBS has been increasingly advocated as a reversible and controllable procedure for selected cases of TS.  These researchers set out to answer 2 clinically relevant questions:
  1. what patients with TS should be treated with DBS, and
  2. what is the best target? 
They conducted a systematic literature review of the published studies of DBS in TS and critically evaluated the current evidence for both patient and target selection.  Since 1999, up to 99 cases of DBS in TS have been reported in the scientific literature, with varying selection criteria, stimulation targets, and assessment protocols.  The vast majority of studies published to date are case reports or case series reporting successful outcomes in terms of both tic severity improvement and tolerability.  The reviewed studies suggested that the best candidates are patients with significant functional impairment related to the tic symptoms, who did not respond to conventional pharmacological and behavioral interventions.  The globus pallidus internus and thalamus appear to be the safest and most effective targets, especially for patients with "pure" TS and patients with co-morbid obsessive-compulsive symptoms, anxiety, and depression.  The authors concluded that DBS is a promising treatment option for severe cases of GTS.  They stated that there is a need to reach consensus on the definition of "treatment-refractoriness" and to conduct larger double-blind RCTs on the most promising targets.
Gabbay et al (2012) noted that clinical observations have suggested therapeutic effects for omega-3 fatty acids (O3FA), also known as ω−3 fatty acids or n−3 fatty acids, in Tourette's disorder (TD), but no RCTs have been reported.  In a placebo-controlled trial, these researchers examined the effectiveness of O3FA in children and adolescents with TD.  A total of 33 children and adolescents (ages of 6 to 18 years) with TD were randomly assigned to O3FA or placebo for 20 weeks.  Omega-3 fatty acids consisted of combined eicosapentaenoic acid and docosahexaenoic acid.  Placebo was olive oil.  Groups were compared by using
    1. intent-to-treat design, with the last-observation-carried-forward controlling for baseline measures and ADHD via
      1. logistic regression, comparing percentage of responders on the primary Yale Global Tic Severity Scale (YGTSS)-Tic and secondary (YGTSS-Global and YGTSS-Impairment) outcome measures and
      2. analysis of covariance; and
    2. longitudinal mixed-effects models. 
    At end point, subjects treated with O3FA did not have significantly higher response rates or lower mean scores on the YGTSS-Tic (53 % versus 38 %; 15.6 +/- 1.6 versus 17.1 +/- 1.6, p > 0.1).  However, significantly more subjects on O3FA were considered responders on the YGTSS-Global measure (53 % versus 31 %, p = 0.05) and YGTSS-Impairment measure (59 % versus 25 %, p < 0.05), and mean YGTSS-Global scores were significantly lower in the O3FA-treated group than in the placebo group (31.7 +/- 2.9 versus 40.9 +/- 3.0, p = 0.04).  Obsessive-compulsive, anxiety, and depressive symptoms were not significantly affected by O3FA.  Longitudinal analysis did not yield group differences on any of the measures.  The authors concluded that O3FA did not reduce tic scores, but it may be beneficial in reduction of tic-related impairment for some children and adolescents with TD.  Drawbacks of this study included small sample size and the possible therapeutic effects of olive oil.

    Wenzel et al (2012) stated that aripiprazole is an atypical neuroleptic with agonistic and antagonistic dopaminergic and serotonergic effects.  Because preliminary data obtained from uncontrolled studies suggested that aripiprazole may be effective in the treatment of tics, these investigators performed a retrospective study with a large group of patients with TS.  A total of 100 patients (78 men and 22 women; mean +/- SD age, 27.1 years (+/- 11.5) years) who had been treated with daily doses of 5 to 45 mg (mean, 17.0 +/- 9.6 mg) aripiprazole at the authors’ specialized TS outpatient clinic were included; 95 patients with insufficient pre-treatment (1 or more neuroleptics) were switched to aripiprazole.  Eighty-two patients exhibited a considerable reduction in tic severity.  In 48 patients, effective treatment lasted for more than 12 months.  Five patients reported additional beneficial effects on behavioral co-morbidities such as depression, anxiety, and auto-aggression.  Altogether, 31 patients (31 %) dropped out of the treatment owing to inefficacy (n = 7), adverse effects (n = 15: drowsiness, agitation, weight gain, and sleep disturbances), both (n = 4) or other reasons (n = 5).  The authors concluded that this study was the largest case series on the treatment of tics with aripiprazole so far.  Overall, these findings corroborated previous data suggesting that aripiprazole is safe and effective in most patients.  In particular, these data confirmed effectiveness in adult patients and clarified that beneficial effects sustain.  However, in contrast to previous data, in 1 of 3 of the highly selected patients, aripiprazole was ineffective or not well-tolerated.  Optimal dose seems to be individually different and may range from 5 to 45 mg.

    Waldon et al (2013) the pharmacological treatment of TS focuses on the modulation of monoaminergic pathways within the cortico-striato-thalamo-cortical circuitry.  These investigators evaluated the safety and effectiveness of pharmacological agents used in the treatment of tics in patients with TS, in order to provide clinicians with an evidence-based rationale for the pharmacological treatment in TS.  In order to ascertain the best level of evidence, these researchers conducted a systematic literature review to identify double-blind RCTs of medications in TS populations.  They identified a large number of pharmacological agents as potentially effective in improving tic symptoms.  The alpha-2 agonist clonidine is among the agents with the most favorable efficacy-versus-adverse events ratio, especially in patients with co-morbid ADHD, although effect sizes vary evidence-based studies.  The authors concluded that these findings are in line with the findings of uncontrolled open-label studies.  However, most trials have low statistical power due to the small sample sizes, and newer agents, such as aripiprazole, have not been formally tested in double-blind RCTs.  They stated that further research should focus on better outcome measures, including Quality of Life instruments.

    An UpToDate review on “Tourette syndrome” (Jankovic, 2014) states that “A possible approach to improve symptoms is reduction of hyperexcitability in the motor and premotor cortex.  In a small single-blinded, placebo-controlled, crossover trial in patients with TS, repetitive transcranial magnetic stimulation to reduce activity in these areas did not improve symptoms.  Patients with disabling tics that are refractory to optimal medical management may be candidates for deep brain stimulation of globus pallidus, thalamus or other subcortical targets.  However, the available evidence is preliminary, and large clinical trials are needed to determine whether DBS is beneficial for controlling tics in patients with TS”.

    Chen et al (2012) examined the clinical efficacy and tolerability of tetrabenazine (TBZ) in the management of dystonia, Huntington chorea, tardive dyskinesia (TDk), and tic disorders.  A Cochrane Library, EMBASE, MedlinePlus, PubMed, and clinical trials database search (up to May 2012) was conducted to identify articles and studies using the subject terms tetrabenazine, Huntington disease, dystonia, tardive dyskinesia, Tourette, tics, and hyperkinetic movement.  Only English-language articles were reviewed.  Tetrabenazine variably undergoes extensive first-pass metabolism to active metabolites, some of which are metabolized by the cytochrome P450 2D6 isozyme.  Pharmacology studies demonstrate that TBZ reversibly inhibits the activity of vesicular monoamine transporter 2, resulting in depletion of central dopamine.  For management of dystonias, 1 of 3 small prospective blinded studies and 4 of 5 retrospective studies reported clinical benefit with TBZ use in pediatrics and adults.  For Huntington chorea, 2 randomized, double-blind, placebo-controlled studies along with open-label studies demonstrated the effectiveness of TBZ in adults.  For TDk, 9 of 11 studies (prospective controlled and retrospective) reported positive benefit.  For TS, 9 of 11 studies (prospective controlled and retrospective) reported positive benefit on motor and phonic tics in pediatric and adult patients.  Overall, adverse effects are dose- and age-related; and included depression, fatigue, parkinsonism, and somnolence.  The authors concluded that TBZ is an effective oral therapy for chorea of Huntington disease and may be considered as an alternative agent for the management of dystonia, TDk, and tic disorders (these latter 3 conditions are off-label uses in the United States).  The drug possesses an acceptable tolerability profile and has been used in pediatric and adult populations.

    In the Canadian guidelines for the evidence-based treatment of tic disorders: Pharmacotherapy, Pringsheim et al (2012) performed a systematic review of the literature on the treatment of tic disorders.  A multi-institutional group of 14 experts in psychiatry, child psychiatry, neurology, pediatrics, and psychology engaged in a consensus meeting.  The evidence was presented and discussed, and nominal group techniques were employed to arrive at consensus on recommendations.  A strong recommendation is made when the benefits of treatment clearly outweigh the risks and burdens, and can apply to most patients in most circumstances without reservation.  With a weak recommendation, the benefits, risks, and burdens are more closely balanced, and the best action may differ depending on the circumstances.  Based on these principles, weak recommendations were made for the use of pimozide, haloperidol, fluphenazine, metoclopramide (children only), risperidone, aripiprazole, olanzapine, quetiapine, ziprasidone, topiramate, baclofen (children only), botulinum toxin injections, TBZ, and cannabinoids (adults only).  Strong recommendations were made for the use of clonidine and guanfacine (children only).  While the evidence supported the efficacy of many of the anti-psychotics for the treatment of tics, the high rates of side effects associated with these medications resulted in only weak recommendations for these drugs.  In situations where tics are not severe or disabling, the use of a medication with only a weak recommendation is not warranted.  However, when tics are more distressing and interfering, the need for tic suppression to improve quality of life is stronger, and patients and clinicians may be more willing to accept the risks of pharmacotherapy.

    Also, an UpToDate review on “Tourette syndrome” (Jankovic, 2014) states that “We treat tics with drugs that block dopamine receptors, such as fluphenazine, pimozide, and tetrabenazine, which depletes neuronal dopamine.  These drugs appear to have a similar response rate, reducing the frequency and intensity of tics by approximately 60 to 80 percent.  In our experience, these drugs are more effective and better tolerated than haloperidol.  Tetrabenazine, which depletes dopamine by inhibiting vesicular monoamine transporter type 2 (VMAT2), is particularly useful because it is as effective as the typical neuroleptics, but it does not cause tardive dyskinesias …. For patients with TS and bothersome tics, we recommend drugs such as fluphenazine starting at 1 mg daily, pimozide starting at 2 mg daily, or tetrabenazine starting at 12.5 mg daily”.

    Termine et al (2013) noted that TS is a neurodevelopmental disorder characterized by multiple motor/phonic tics and a wide spectrum of behavioral problems (e.g., complex tic-like symptoms, attention deficit hyperactivity disorder, and obsessive-compulsive disorder).  It can be a challenging condition even for the specialists, because of the complexity of the clinical picture and the potential adverse effects of the most commonly prescribed medications.  Regarding non-pharmacological interventions for TS, some of the more recent treatments that have been studied include electro-convulsive therapy and repetitive transcranial magnetic stimulation (rTMS).  The authors focused primarily on the safety and effectiveness of these emerging treatment strategies in TS.

    The Tourette Syndrome Association International Deep Brain Stimulation (DBS) Database and Registry Study Group (Schrock et al, 2015) stated that “ Tourette syndrome patients represent a unique and complex population, and studies reveal a higher risk for post-DBS complications.  Successes and failures have been reported for multiple brain targets; however, the optimal surgical approach remains unknown.  Tourette syndrome DBS, though still evolving, is a promising approach for a subset of medication refractory and severely affected patients”.

    Anti-Glutamatergic Drugs and Vesicular Monoamine Transporter Type 2 Inhibitors:

    Kious et al (2016) reviewed strategies for the management of TS. These investigators considered emerging treatments for refractory cases, including DBS, electroconvulsive therapy (ECT), rTMS, and novel pharmacological approaches (e.g., anti-glutamatergic drugs, cannabinoids, and new vesicular monoamine transporter type 2 inhibitors).

    Mindfulness-Based Stress Reduction:

    In a pilot study, Reese and associates (2015) developed and tested a modified form of mindfulness-based stress reduction (MBSR-tics) for the treatment of TS and chronic tic disorder (CTD). The specific aims were:
    1. to determine the feasibility and acceptability of an 8-week trial of MBSR-tics in individuals 16 and older with TS or CTD, and
    2. to determine the effectiveness of an 8-week trial of MBSR-tics in individuals 16 and older with TS or CTD. 
    A total of 18 individuals aged 16 to 67 years completed an uncontrolled open trial of MBSR-tics.  The intervention consisted of 8 weekly 2-hour classes and 1 4-hour re-treat in the 5th or 6th week of the program.  Symptomatic assessments were performed at baseline, post-treatment, and 1-month follow-up.  Mindfulness-based stress reduction proved to be a feasible and acceptable intervention.  It resulted in significant improvement in tic severity and tic-related impairment; 58.8 % of subjects were deemed treatment responders.  Therapeutic gains were maintained at 1-month follow-up.  Improvements in tic severity were correlated with increases in self-reported levels of mindfulness.  The authors concluded that the findings of this small open pilot study provided preliminary support for the feasibility, acceptability, and effectiveness of MBSR-tics for individuals 16 or older with TS or CTD.  Moreover, they stated that a larger RCT with blind assessment is needed to confirm these initial, promising findings.

    N-Acetylcysteine:

    In a randomized, double-blind, placebo-controlled clinical trial, Bloch et al (2016) examined the effectiveness of N-acetylcysteine (NAC) for the treatment of pediatric TS. A total of 31 children and adolescents 8 to 17 years of age with TS were randomly assigned to receive NAC or matching placebo for 12 weeks.  The primary outcome was change in severity of tics as measured by the YGTSS, and Total tic score.  Secondary measures assessed co-morbid OCD, depression, anxiety, and ADHD.  Linear mixed models in SAS were used to examine differences between NAC and placebo.  Of the 31 randomized subjects, 14 were assigned to placebo (2 females; 11.5 +/- 2.8 years) and 17 to active NAC (5 females; 12.4 +/- 1.4 years) treatment.  No significant difference between NAC and placebo was found in reducing tic severity or any secondary outcomes.  The authors concluded that they found no evidence for effectiveness of NAC in treating tic symptoms.  They stated that these findings stood in contrast to studies suggesting benefits of NAC in the treatment of other obsessive-compulsive spectrum disorders in adults, including OCD and trichotillomania, but were similar to a recent placebo-controlled trial of pediatric trichotillomania that found no benefit of NAC.

    Valproate:

    In a systematic review and meta-analysis, Yang and colleagues (2015) evaluated the safety and effectiveness of sodium valproate for children with TS. These investigators searched PubMed, EMBASE, the Cochrane library, Cochrane Central, CBM, CNKI, VIP, WANG FANG database and relevant reference lists.  A total of 5 RCTs (n = 247) and 5 case series (n = 163) studies were included.  Only 1 RCT (n = 93) evaluated total YGTSS scores and there was significant difference in the reduction of total YGTSS scores between sodium valproate and the control group (3.50 ± 4.59 versus 7.86 ± 7.03, p < 0.01).  One RCT (n = 30) evaluated motor and vocal tics, and there was significant difference in the reduction of motor and vocal tics scores between sodium valproate and haloperidol (10.45 ± 4.15 versus 14.92 ± 3.01, p < 0.01).  Meta-analysis of 3 RCTs (n = 124) showed there was no significant difference in the reduction of the number of tics between sodium valproate and the positive control group (relative risk (RR) = 1.09, 95 % confidence interval [CI]: 0.92 to 1.30, p = 0.30).  The pooled proportion in 5 case series studies which used tics symptom improvement self-defined by authors was 80.7 % (95 % CI: 73.7 to 86.2, I(2) = 0).  No fatal side effects were reported.  The authors concluded that based on the limited evidence, the routine use of sodium valproate for treatment of TS in children is not recommended; further well-conducted trials that examine long-term outcomes are needed.

    Tetrabenazine:

    Paleacu et al (2004) tetrabenazine (TBZ)  is a catecholamine depletor used for the treatment of a variety of movement disorders.  The purpose of this study was to assess the efficacy of TBZ in a retrospective chart review in 3 tertiary care movement disorders centers over long-term treatment.  Of 150 patients to whom TBZ was prescribed, 118 were followed-up and assessed using the Clinical Global Impression of Change (CGIC), (-3 to +3), a composite grade from a patient and caregiver scale over variable periods.  The patients had a variety of hyperkinetic movement disorders including dystonia (generalized and focal: axial, Meige syndrome, torticollis, blepharospasm, bruxism), Huntington disease (HD) or other choreas, tardive dyskinesia (TD) or akathisia, and Tourette syndrome.  Mean patient age was 48.8 +/- 18.7 years; 48 were men (40.7 %) with a mean disease duration of 93 months.  The mean follow-up time was 22 months and the mean TBZ dose was 76.2 +/- 22.5 mg/d (median of 75 mg, range of 25 to 175 mg/d).  The mean CGIC score was +1 (mild improvement).  The group of patients who scored +3 on the CGIC (very good improvement) represented 18.6 % (n = 22) of all patients.  They had HD or other types of chorea 7.6 % (n = 9), facial dystonia/dyskinesia (n = 7, 5.9 %), 1 with TD, 2 with trunk dystonia, 2 with Tourette syndrome, and 1 with tardive akathisia.  This group had the longest treatment duration and received a mean TBZ dose of 70.5 mg/d (median of 75 mg/d) for a mean of 25.4 +/- 21.3 months.  The authors concluded that TBZ is a moderately effective treatment of a large variety of hyperkinetic movement disorders, with excellent effects in a subgroup with chorea and facial dystonia/dyskinesias.

    Lopez Del Val et al (2009) noted that TBZ is a benzoquinolizine with a high anti-dopaminergic potential due to a monoamine depletion effect that acts equally on the three main neurotransmitters (dopamine, noradrenalin and serotonin).  This potentially explains why this group of pharmaceutical agents has been used for years to treat different types of hyperkinetic syndromes.  These researchers examined both the pharmacokinetic and the pharmacodynamic characteristics of TBZ.  A thorough review was performed of the literature on the main indications established over the years for the therapeutic utilization of TBZ, the most important hyperkinetic syndromes of which include: tardive dyskinesias, athetosis, ballism, dystonias (primary, tardive, etc.,), tics or Tourette syndrome, and finally the semiological group consisting of choreas (Huntington's disease, Sydenham's chorea and other pediatric choreas).  The authors concluded that TBZ appears to be an excellent pharmacological agent for use in a number of pathologies that are accompanied by hyperkinesias; it is well-tolerated and has few complications or side effects deriving from its administration.

    Chen et al (2012) examined the clinical efficacy and tolerability of TBZ in the management of dystonia, Huntington chorea, tardive dyskinesia (TDk), and tic disorders.  A Cochrane Library, EMBASE, MedlinePlus, PubMed, and clinical trials database search (up to May 2012) was conducted to identify articles and studies using the subject terms tetrabenazine, Huntington disease, dystonia, tardive dyskinesia, Tourette, tics, and hyperkinetic movement.  Only English-language articles were reviewed.  TBZ variably undergoes extensive first-pass metabolism to active metabolites, some of which are metabolized by the cytochrome P450 2D6 isozyme.  Pharmacology studies demonstrate that TBZ reversibly inhibits the activity of vesicular monoamine transporter 2, resulting in depletion of central dopamine.  For management of dystonias, 1 of 3 small prospective blinded studies and 4 of 5 retrospective studies reported clinical benefit with TBZ use in pediatrics and adults.  For Huntington chorea, 2 randomized, double-blind, placebo-controlled studies along with open-label studies demonstrate the effectiveness of TBZ in adults.  For TDk, 9 of 11 studies (prospective controlled and retrospective) reported positive benefit.  For Gilles de la Tourette syndrome, 9 of 11 studies (prospective controlled and retrospective) reported positive benefit on motor and phonic tics in pediatric and adult patients.  Overall, adverse effects are dose- and age-related; and included depression, fatigue, parkinsonism, and somnolence.  The authors concluded that TBZ is an effective oral therapy for chorea of Huntington disease and may be considered as an alternative agent for the management of dystonia, TDk, and tic disorders (these latter 3 conditions are off-label uses in the United States).  The drug possesses an acceptable tolerability profile and has been used in pediatric and adult populations.

    The Canadian guidelines for the evidence-based treatment of tic disorders: Pharmacotherapy (Pringsheim et al, 2012) performed a systematic review of the literature on the treatment of tic disorders.  A multi-institutional group of 14 experts in psychiatry, child psychiatry, neurology, pediatrics, and psychology engaged in a consensus meeting.  The evidence was presented and discussed, and nominal group techniques were employed to arrive at consensus on recommendations.  A strong recommendation is made when the benefits of treatment clearly outweigh the risks and burdens, and can apply to most patients in most circumstances without reservation.  With a weak recommendation, the benefits, risks, and burdens are more closely balanced, and the best action may differ depending on the circumstances.  Based on these principles, weak recommendations were made for the use of pimozide, haloperidol, fluphenazine, metoclopramide (children only), risperidone, aripiprazole, olanzapine, quetiapine, ziprasidone, topiramate, baclofen (children only), botulinum toxin injections, TBZ, and cannabinoids (adults only).  Strong recommendations were made for the use of clonidine and guanfacine (children only).  While the evidence supports the efficacy of many of the antipsychotics for the treatment of tics, the high rates of side effects associated with these medications resulted in only weak recommendations for these drugs.  In situations where tics are not severe or disabling, the use of a medication with only a weak recommendation is not warranted.  However, when tics are more distressing and interfering, the need for tic suppression to improve quality of life is stronger, and patients and clinicians may be more willing to accept the risks of pharmacotherapy.

    Also, an UpToDate review on “Tourette syndrome” (Jankovic, 2017) states that “For patients with TS who have tics that are mild and nondisabling, we suggest education and counseling without pharmacologic tic suppression therapy (Grade 2C).  For patients with TS and bothersome tics, we suggest medication treatment with tetrabenazine starting at 12.5 mg daily (Grade 2C).  For patients with TS who have only focal motor or vocal tics, we suggest treatment with botulinum toxin injections into the affected muscles (Grade 2C).  For patients with TS and bothersome tics who either prefer nonpharmacologic treatment or who have not tolerated or responded to pharmacologic interventions, we suggest behavioral therapy with habit reversal training, where available (Grade 2B)”.

    Acupuncture:

    Yu and colleagues (2016) searched for RCTs using acupuncture to treat TS written in English or Chinese without restrictions on publication status.  Study selection, data extraction, and assessment of study quality were conducted independently by 2 reviewers.  Meta-analyses were performed using Review Manager (RevMan) 5.3 software from the Cochrane Collaboration.  Data were combined with the fixed-effect model based on a heterogeneity test.  Results were presented as risk ratios for dichotomous data and mean differences (MDs) for continuous data.  This review included 7 RCTs with a total of 564 participants.  The combined results showed that acupuncture may have better short-term effect than Western medicine for TS and that acupuncture may be an effective adjuvant therapy in improving the effect of Western medicine on TS, but the evidence is limited because of existing biases.  The authors concluded that there is a need for large-scale and well-designed RCTs of acupuncture for TS with rigorous methods of randomization, blinding, and adequately concealed allocation, as well as validated outcome measures; and all information including adverse effects should be reported in detail.

    Dietary Interventions:

    Whittington and associates (2016) conducted a systematic review of interventions for children and young people with TS.  Databases were searched from inception to 1 October 2014 for placebo-controlled trials of pharmacological, behavioral, physical or alternative interventions for tics in children and young people with TS or CTD.  Certainty in the evidence was assessed with the GRADE approach.  A total of 40 trials were included [pharmacological (32), behavioral (5), physical (2), dietary (1)].  For tics/global score there was evidence favoring the intervention from 4 trials of α2-adrenergic receptor agonists [clonidine and guanfacine, standardized MD (SMD) = -0.71; 95 % CI: -1.03 to -0.40; n = 164] and 2 trials of HRT/comprehensive behavioral intervention (CBIT) (SMD = -0.64; 95 % CI: -0.99 to -0.29; n = 133).  Certainty in the effect estimates was moderate.  A post-hoc analysis combining oral clonidine/guanfacine trials with a clonidine patch trial continued to demonstrate benefit (SMD = -0.54; 95 % CI: -0.92 to -0.16), but statistical heterogeneity was high.  Evidence from 4 trials suggested that anti-psychotic drugs improved tic scores (SMD = -0.74; 95 % CI: -1.08 to -0.40; n = 76), but certainty in the effect estimate was low.  The evidence for other interventions was categorized as low or very low quality, or showed no conclusive benefit.  The authors concluded that when medication is considered appropriate for the treatment of tics, the balance of clinical benefits to harm favors α2-adrenergic receptor agonists (clonidine and guanfacine) as first-line agents.  Anti-psychotics are likely to be useful but carry the risk of harm and so should be reserved for when α2-adrenergic receptor agonists are either ineffective or poorly tolerated.  They stated that there is evidence that HRT/CBIT is effective, but there is no evidence for HRT/CBIT alone relative to combining medication and HRT/CBIT.  Moreover, they noted that there is currently no evidence to suggest that the physical and dietary interventions reviewed are sufficiently effective and safe to be considered as treatments.

    Measurement of Serum Ferritin Level:

    Ghosh and Burkman (2017) stated that tics can be considered hyperkinetic movements akin to restless leg syndrome (RLS).  Drawing the analogy of iron deficiency as an etiology of RLS, it is conceivable that iron deficiency may underlie or worsen tics in TS.  These investigators evaluated the relationship between serum ferritin levels and tic severity, as well as consequent impact on life, in children with TS.  Children less than 18 years of age, diagnosed with TS during 2009 to 2015, were reviewed.  Only those with serum ferritin testing were included.  The following data were collected: tic severity, impact on life, medication, co-morbidities, blood count, and serum ferritin at diagnosis and follow-up.  In 57 patients, male to female ratio of 2:1, serum ferritin was 48.0 ± 33.28 ng/ml, tic severity score 2.3 ± 0.80, impact on life score 2.2 ± 0.93, and composite score 4.57 ± 1.6.  Serum ferritin was not influenced by co-morbid obsessive compulsive disorder (OCD), attention deficit hyperactive disorder (ADHD), or anxiety (p > 0.16); 38 % with low serum ferritin (less than or equal to 50 ng/ml) (n = 37) had severe tics (greater than 5 composite score), compared with 25 % in normal ferritin group (n = 20).  Over 6 to 12 months, tic severity score improved in both iron-treated groups, deficient (2.70 to 1.90) and sufficient (2.40 to 1.95), whereas tics worsened or remained the same when not treated with iron.  The authors concluded that these findings suggested that iron deficiency may be associated with more severe tics with higher impact on TS children, independent of the presence of OCD, ADHD, or anxiety.  Iron supplementation showed a trend towards improvement of tic severity upon follow-up.  These researchers suggested a double-blind, placebo-controlled, prospective study to reach a definite conclusion.

    Botulinum Toxin:

    In a Cochrane review, Pandey and colleagues (2018) determined the safety and effectiveness of botulinum toxin in treating motor and phonic tics in people with TS, and to analyzed the effect of botulinum toxin on premonitory urge and sensory tics.  These investigators searched the Cochrane Movement Disorders Group Trials Register, CENTRAL, Medline, and 2 trials registers to October 25, 2017.  They reviewed reference lists of relevant articles for additional trials.  These researchers considered all randomized, controlled, double-blind studies comparing botulinum toxin to placebo or other medications for the treatment of motor and phonic tics in TS for this review.  They sought both parallel group and cross-over studies of children or adults, at any dose, and for any duration.  These researchers followed standard Cochrane methods to select studies, assess risk of bias, extract and analyze data.  All authors independently abstracted data onto standardized forms; disagreements were resolved by mutual discussion.  Only 1 randomized, placebo-controlled, double-blind, cross-over study met the selection criteria.  In this study, a total of 20 participants with motor tics were enrolled over a 3-year recruitment period; 18 (14 of whom had a diagnosis of TS) completed the study; in total, 21 focal motor tics were treated.  Although these investigators considered most bias domains to be at low risk of bias, the study recruited a small number of participants with relatively mild tics and provided limited data for the key outcomes.  The effects of botulinum toxin injections on tic frequency, measured by videotape or rated subjectively, and on premonitory urge, were uncertain (very low-quality evidence).  The quality of evidence for adverse events following botulinum toxin was very low; 9 people had muscle weakness following the injection, which could have led to un-blinding of treatment group assignment.  No data were available to evaluate whether botulinum injections led to immuno-resistance to botulinum.  The authors concluded that they were uncertain about botulinum toxin effects in the treatment of focal motor and phonic tics in select cases since the quality of the evidence as very low.  Moreover, they stated that additional RCTs are needed to demonstrate the benefits and harms of botulinum toxin therapy for the treatment of motor and phonic tics in patients with TS.

    Deep Brain Stimulation:

    In a randomized, double-blind, controlled trial, Welter and colleagues (2017) evaluated the efficacy of anterior internal globus pallidus (aGPi) DBS for patients with  severe TS.  Patients aged 18 to 60 years with severe and medically refractory TS from 8 hospitals specialized in movement disorders in France were recruited for this study.  Enrolled patients received surgery to implant bilateral electrodes for aGPi DBS; 3 months later they were randomly assigned (1:1 ratio with a block size of 8; computer-generated pairwise randomization according to order of enrolment) to receive either active or sham stimulation for the subsequent 3 months in a double-blind fashion . All patients then received open-label active stimulation for the subsequent 6 months.  Patients and clinicians assessing outcomes were masked to treatment allocation; an unmasked clinician was responsible for stimulation parameter programming, with intensity set below the side-effect threshold.  The primary end-point was difference in YGTSS score between the beginning and end of the 3 month double-blind period, as assessed with a Mann-Whitney-Wilcoxon test in all randomly allocated patients who received active or sham stimulation during the double-blind period.  These researchers assessed safety in all patients who were enrolled and received surgery for aGPi DBS.  Between December 6, 2007 and December 13, 2012, a total of 19 patients were enrolled.  The authors randomly assigned 17 (89 %) patients, with 16 completing blinded assessments (7 [44 %] in the active stimulation group and 9 [56 %] in the sham stimulation group).  These researchers noted no significant difference in YGTSS score change between the beginning and the end of the 3 month double-blind period between groups (active group median YGTSS score 68.5 [inter-quartile range [IQR] 34.0 to 83.5] at the beginning and 62.5 [51.5 to 72.0] at the end, median change 1.1 % [IQR -23.9 to 38.1]; sham group 73.0 [69.0 to 79.0] and 79.0 [59.0 to 81.5], median change 0.0 % [-10.6 to 4.8]; p=0.39).  A total of 15 serious adverse events (SAEs; 3 in patients who withdrew before stimulation and 6 each in the active and sham stimulation groups) occurred in 13 patients (3 who withdrew before randomization, 4 in the active group, and 6 in the sham group), with infections in DBS hardware in 4 patients (2 who withdrew before randomization, 1 in the sham stimulation group, and 1 in the active stimulation group).  Other SAEs included 1 electrode misplacement (active stimulation group), 1 episode of depressive signs (active stimulation group), and 3 episodes of increased tic severity and anxiety (2 in the sham stimulation group and 1 in the active stimulation group).  The authors concluded that 3 months of aGPi DBS was insufficient to decrease tic severity for patients with TS.  Moreover, they stated that future research is needed to examine the efficacy of aGPi DBS for patients over longer periods with optimal stimulation parameters and to identify potential predictors of the therapeutic response.

    Jo and co-workers (2018) stated that DBS of the thalamus is a promising therapeutic alternative for treating medically refractory TS.  However, few human studies have examined its mechanism of action.  Therefore, the networks that mediate the therapeutic effects of thalamic DBS remain poorly understood.  In this study, a total of 5 participants diagnosed with severe medically refractory TS underwent bilateral thalamic DBS stereotactic surgery.  Intra-operative functional magnetic resonance imaging (fMRI) characterized the blood oxygen level-dependent (BOLD) response evoked by thalamic DBS and examined if the therapeutic effectiveness of thalamic DBS, as assessed using the Modified Rush Video Rating Scale test, would correlate with evoked BOLD responses in motor and limbic cortical and subcortical regions.  The results reveal that thalamic stimulation in TS participants had wide-ranging effects that impact the fronto-striatal, limbic, and motor networks.  Thalamic stimulation induced suppression of motor and insula networks correlated with motor tic reduction, while suppression of frontal and parietal networks correlated with vocal tic reduction.  These regions mapped closely to major regions of interest (ROI) identified in a non-human primate model of TS.  The authors concluded that these findings suggested that a critical factor in TS treatment should involve modulation of both fronto-striatal and motor networks, rather than be treated as a focal disorder of the brain.  Using the novel combination of DBS-evoked tic reduction and fMRI in human subjects, these researchers provided new insights into the basal ganglia-cerebellar-thalamo-cortical network-level mechanisms that influence the effects of thalamic DBS.  They stated that future translational research should identify whether these network changes are cause or effect of TS symptoms.

    Per the International Tourette Syndrome Deep Brain Stimulation Public Database and Registry, Martinez-Ramirez and colleagues (2018) stated that DBS is a promising therapy for TS.  Moreover, these investigators noted that DBS was associated with symptomatic improvement in patients with TS but also with important AEs.  Furthermore, Martino and Pringsheim (2018) stated that DBS is a potential option for medically refractory, severely disabled patients with tics, but age and target selection require further investigation.

    Adaptive (Responsive) Deep Brain Stimulation:

    Marceglia and colleagues (2017) noted that DBS has emerged as a novel therapy for the treatment of several movement and neuropsychiatric disorders, and may also be suitable for the treatment of TS.  The main DBS targets used to date in patients with TS are located within the basal ganglia-thalamo-cortical circuit involved in the pathophysiology of this syndrome.  They include the ventralis oralis/centromedian-parafascicular (Vo/CM-Pf) nucleus of the thalamus and the nucleus accumbens.  Current DBS treatments deliver continuous electrical stimulation and are not designed to adapt to the patient's symptoms, thereby contributing to unwanted side effects.  Moreover, continuous DBS can lead to rapid battery depletion, which necessitates frequent battery replacement surgeries.  Adaptive DBS (aDBS), which is based on neurophysiological biomarkers, is considered one of the most promising approaches to optimize clinical benefits and to limit the side effects of DBS.  Adaptive DBS consists of a closed-loop system designed to measure and analyze a control variable reflecting the patient's clinical condition and to modify on-line stimulation settings to improve treatment efficacy.  Local field potentials (LFPs), which are sums of pre- and post-synaptic activity arising from large neuronal populations, directly recorded from electrodes implanted for DBS can theoretically represent a reliable correlate of clinical status in patients with TS.  The well-established LFP-clinical correlations in patients with Parkinson's disease reported in the last few years provide the rationale for developing and implementing new aDBS devices whose efficacies are under evaluation in humans.  Only a few studies have investigated LFP activity recorded from DBS target structures and the relationship of this activity to clinical symptoms in TS.  These investigators reviewed the available literature supporting the feasibility of an LFP-based aDBS approach in patients with TS.  In addition, to increase such knowledge, these researchers reported explorative findings regarding LFP data recently acquired and analyzed in patients with TS after DBS electrode implantation at rest, during voluntary and involuntary movements (tics), and during ongoing DBS.  Data available up to now suggested that patients with TS have oscillatory patterns specifically associated with the part of the brain they are recorded from, and thereby with clinical manifestations.  The Vo/CM-Pf nucleus of the thalamus is involved in movement execution and the pathophysiology of TS.  Moreover, the oscillatory patterns in TS are specifically modulated by DBS treatment, as reflected by improvements in TS symptoms.  The authors concluded that these findings suggested that LFPs recorded from DBS targets may be used to control new aDBS devices capable of adaptive stimulation responsive to the symptoms of TS.  Moreover, they stated that further studies are needed to better understand the LFP signatures of psychiatric co-morbidities and non-tic disease manifestations.  These studies should include other DBS targets that are now considered very promising for the treatment of TS, such as the anterior globus pallidus internus.

    Molina and associates (2017) stated that DBS has emerged as a promising intervention for the treatment of select movement and neuropsychiatric disorders.  Current DBS therapies deliver electrical stimulation continuously and are not designed to adapt to a patient's symptoms.  Continuous DBS can lead to rapid battery depletion, which necessitates frequent surgery for battery replacement.  Next-generation neuro-stimulation devices can monitor neural signals from implanted DBS leads, where stimulation can be delivered responsively, moving the field of neuromodulation away from continuous paradigms.  To this end, these researchers designed and chronically implemented a responsive stimulation paradigm in a patient with medically refractory TS.  The patient underwent implantation of a responsive neuro-stimulator, which was capable of responsive DBS, with bilateral leads in the centromedian-parafascicular (Cm-Pf) region of the thalamus.  A spectral feature in the 5- to 15-Hz band was identified as the control signal.  Clinical data collected prior to and after 12 months of responsive therapy revealed improvements from baseline scores in both Modified Rush Tic Rating Scale and Yale Global Tic Severity Scale scores (64 % and 48 % improvement, respectively).  The effectiveness of responsive stimulation (p = 0.16) was statistically identical to that of scheduled duty cycle stimulation (p = 0.33; 2-sided Wilcoxon unpaired rank-sum t-test).  The authors concluded that responsive DBS resulted in a 63.3 % improvement in the neuro-stimulator's projected mean battery life.  These researchers presented the first proof-of-concept for responsive DBS in a patient with TS.

    Investigational Pharmacological Agents:

    Kanaan and colleagues (2017) noted that early anecdotal reports and preliminary studies suggested that cannabinoid-based medicines such as delta-9-tetrahydrocannabinol (THC) are effective in the treatment of Gilles de la TS.  These investigators reported a single case study of a patient with otherwise treatment-resistant TS successfully treated with nabiximols.  The patient was a 22-year old man suffering from severe and complex TS.  Treatment with nabiximols was commenced at a dose of 1 puff/day (= 100 μL containing 2.7 mg THC and 2.5 mg cannabidiol (CBD)) and slowly increased up to a dosage of 3 × 3 puffs/day (= 24.3 mg THC and 22.5 mg CBD).  Several clinical measures for tics, premonitory urges, and global impairment were acquired before and after 2 weeks of treatment.  Treatment with nabiximols resulted in major improvements of both tics and premonitory urges, but also global impairment and health-related quality of life (QOL) according to all used measurements without causing relevant adverse effects.  These findings provided further evidence that treatment with nabiximols may be effective in the treatment of patients with TS.  The authors concluded that given the positive response exhibited by the patient highlighted in this report, further investigation of the effects of nabiximols is proposed on a larger group of patients in a clinical trial setting.

    Quezada and Coffman (2018) noted that TS is a neurodevelopmental disorder of unknown etiology characterized by spontaneous, involuntary movements and vocalizations called tics.  Once thought to be rare, TS affects 0.3 to 1 % of the population.  Tics can cause physical discomfort, emotional distress, social difficulties, and can interfere with education and desired activities.  The pharmacologic treatment of TS is particularly challenging, as currently the genetics, neurophysiology, and neuropathology of this disorder are still largely unknown.  However, clinical experience gained from treating TS has helped to better understand its pathogenesis and, as a result, derive therapeutic options.  The strongest data exist for the anti-psychotic agents, both typical and atypical, although their use is often limited in children and adolescents due to their side-effect profiles.  There are agents in a variety of other pharmacologic categories that have evidence for the treatment of TS and whose side-effect profiles are more tolerable than the anti-psychotics; these include clonidine, guanfacine, baclofen, topiramate, botulinum toxin A, tetrabenazine, and deutetrabenazine.  A number of new agents are being developed and tested as potential treatments for TS.  These include valbenazine, delta-9-tetrahydrocannabidiol (THC), and ecopipam.  Additionally, there are agents with insufficient data for efficacy, as well as agents that have been shown to be ineffective.  Those without sufficient data for efficacy include clonazepam, ningdong granule, 5-ling granule, omega-3 fatty acids, and n-acetylcysteine.  The agents that have been shown to be ineffective include pramipexole and metoclopramide.

    Martino and Pringsheim (2018) stated that anti-psychotics (e.g., fluphenazine, haloperidol and pimozide) and alpha adrenergic agonists (e.g., clonidine and guanfacine) remain 1st-line pharmacological interventions for tics, although VMAT-2 inhibitors appear promising.

    Transcranial Direct Current Stimulation:

    Eapen and colleagues (2017) stated that transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation technique that is being investigated for a variety of neurological and psychiatric conditions.  Preliminary evidence suggested that tDCS may be useful in the treatment of TS.  These investigators reviewed the literature on the use of tDCS in commonly occurring co-morbid conditions that are relevant to its proposed use in TS.  They described the protocol for a double-blind, cross-over, sham-controlled trial of tDCS (Trial ID: ACTRN12615000592549, registered at www.anzctr.org.au) investigating the efficacy, feasibility, safety, and tolerability of tDCS in patients with TS aged 12 years and over.  The intervention consists of cathodal tDCS positioned over the supplementary motor area.  Patients receive either sham tDCS for 3 weeks followed by 6 weeks of active tDCS (1.4 mA, 18 sessions over 6 weeks), or 6 weeks of active sessions followed by 3 weeks of sham sessions, with follow-up at 3 and 6 months.  Pilot findings from 2 participants were presented.  There was a reduction in the frequency and intensity of patients' tics and premonitory urges, as well as evidence of improvements in inhibitory function, over the course of treatment.  The authors concluded that larger scale studies are needed to determine the maintenance of symptom improvement over time, as well as the long-term consequences of the repetitions of sessions.

    Table: CPT Codes / HCPCS Codes / ICD-10 Codes
    Code Code Description

    Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+":

    CPT codes covered if selection criteria are met:

    +90785 Interactive complexity (List separately in addition to the code for primary procedure)
    90832 Psychotherapy, 30 minutes with patient and/or family member
    90838 Psychotherapy, 60 minutes with patient and/or family member when performed with an evaluation and management service (List separately in addition to the code for primary procedure)
    90839 Psychotherapy for crisis; first 60 minutes
    90840 Psychotherapy for crisis; each additional 30 minutes (List separately in addition to code for primary service)
    95812 - 95830 Routine electroencephalography
    99201 - 99215 Evaluation and management, office or other outpatient services

    CPT codes not covered for indications listed in the CPB:

    Transcranial direct current stimulation - no specific code:

    0042T Cerebral perfusion analysis using computed tomography with contrast administration, including post-processing of parametric maps with determination of cerebral blood flow, cerebral blood volume, and mean transit time
    61735 Creation of lesion by stereotactic method, including burr hole(s) and localizing and recording techniques, single or multiple stages; subcortical structure(s) other than globus pallidus or thalamus
    61863 Twist drill, burr hole, craniotomy, or craniectomy with stereotactic implantation of neurostimulator electrode array in subcortical site (e.g., thalamus, globus pallidus, subthalamic nucleus, periventricular, periaqueductal gray), without use of intraoperative microelectrode recording; first array
    + 61864     each additional array (List separately in addition to primary procedure)
    61867 Twist drill, burr hole, craniotomy, or craniectomy with stereotactic implantation of neurostimulator electrode array in subcortical site (e.g., thalamus, globus pallidus, subthalamic nucleus, periventricular, periaqueductal gray), with use of intraoperative microelectrode recording; first array
    + 61868     each additional array (List separately in addition to primary procedure)
    61880 Revision or removal of intracranial neurostimulator electrodes
    61885 Insertion or replacement of cranial neurostimulator pulse generator or receiver, direct or inductive coupling; with connection to a single electrode array
    61886 Insertion or replacement of cranial neurostimulator pulse generator or receiver, direct or inductive coupling; with connection to 2 or more electrode arrays
    61888 Revision or removal of cranial neurostimulator pulse generator or receiver
    64612 Chemodenervation of muscle(s); muscle(s) innervated by facial nerve, unilateral (eg, for blepharospasm, hemifacial spasm)
    64616 Chemodenervation of muscle(s); neck muscle(s), excluding muscles of the larynx, unilateral (eg, for cervical dystonia, spasmodic torticollis)
    64617     larynx, unilateral, percutaneous (eg, for spasmodic dysphonia), includes guidance by needle electromyography, when performed
    70450 Computed tomography head or brain; without contrast material
    70460     with contrast material(s)
    70470     without contrast material, followed by contrast material(s) and further sections
    70496 Computed tomographic angiography, head, without contrast material(s), including noncontrast materials, if performed, and image processing
    70544 Magnetic resonance angiography, head; without contrast material(s)
    70545     with contrast material(s)
    70546     without contrast material(s), followed by contrast material(s) and further sequences
    70551 Magnetic resonance (e.g., proton) imaging, brain (including brain stem); without contrast material
    70552     with contrast material(s)
    70553     without contrast material, followed by contrast material(s) and further sequences
    70554 Magnetic resonance imaging, brain, functional MRI; including test selection and administration of repetitive body part movement and/or visual stimulation, not requiring physician or psychologist administration
    70555     requiring physician or psychologist administration of entire neurofunctional testing
    78600 Brain imaging, less than 4 static views
    78601     with vascular flow
    78605 Brain imaging; minimum 4 static views
    78606     with vascular flow
    78607      Brain imaging, tomographic (SPECT)
    78608 Brain imaging, positron emission tomography (PET); metabolic evaluation
    78609     perfusion evaluation
    78610 Brain imaging, vascular flow only
    82728 Ferritin
    88245 - 88269, 88280 - 88289 Chromosome analysis
    88271 - 88275 Molecular cytogenetics
    88291 Cytogenetics and molecular cytogenetics, interpretation and report
    90281 Immune globulin (Ig), human, for intramuscular use
    90283 Immune globulin (IgIV), human, for intravenous use
    90867 Therapeutic repetitive transcranial magnetic stimulation treatment; planning
    90868      subsequent delivery and management, per session
    90869      subsequent motor threshold re-determination with delivery and management
    90875 Individual psychophysiological therapy incorporating biofeedback training by any modality (face-to-face with the patient), with psychotherapy (eg, insight oriented, behavior modifying or supportive psychotherapy); 30 minutes
    90876     approximately 45 minutes
    90901 Biofeedback training by any modality
    95836 Electrocorticogram from an implanted brain neurostimulator pulse generator/transmitter, including recording, with interpretation and written report, up to 30 days
    95961 Functional cortical and subcortical mapping by stimulation and/or recording of electrodes on brain surface, or of depth electrodes, to provoke seizures or identify vital brain structures; initial hour of attendance by a physician or other qualified health care professional
    + 95962     each additional hour of attendance by a physician or other qualified health care professional (List separately in addition to code for primary procedure)
    95970 Electronic analysis of implanted neurostimulator pulse generator system (eg, rate, pulse amplitude, pulse duration, configuration of wave form, battery status, electrode selectability, output modulation, cycling, impedance and patient compliance measurements); simple or complex brain, spinal cord, or peripheral (ie, cranial nerve, peripheral nerve, sacral nerve, neuromuscular) neurostimulator pulse generator/transmitter, without reprogramming
    95971 Electronic analysis of implanted neurostimulator pulse generator system (eg, rate, pulse amplitude, pulse duration, configuration of wave form, battery status, electrode selectability, output modulation, cycling, impedance and patient compliance measurements); simple spinal cord, or peripheral (ie, peripheral nerve, sacral nerve, neuromuscular) neurostimulator pulse generator/transmitter, with intraoperative or subsequent programming
    95977 Electronic analysis of implanted neurostimulator pulse generator/transmitter (eg, contact group[s], interleaving, amplitude, pulse width, frequency [Hz], on/off cycling, burst, magnet mode, dose lockout, patient selectable parameters, responsive neurostimulation, detection algorithms, closed loop parameters, and passive parameters) by physician or other qualified health care professional; with complex cranial nerve neurostimulator pulse generator/transmitter programming by physician or other qualified health care professional
    95983 Electronic analysis of implanted neurostimulator pulse generator/transmitter (eg, contact group[s], interleaving, amplitude, pulse width, frequency [Hz], on/off cycling, burst, magnet mode, dose lockout, patient selectable parameters, responsive neurostimulation, detection algorithms, closed loop parameters, and passive parameters) by physician or other qualified health care professional; with brain neurostimulator pulse generator/ transmitter programming, first 15 minutes face-to- face time with physician or other qualified health care professional
    95984 Electronic analysis of implanted neurostimulator pulse generator/transmitter (eg, contact group[s], interleaving, amplitude, pulse width, frequency [Hz], on/off cycling, burst, magnet mode, dose lockout, patient selectable parameters, responsive neurostimulation, detection algorithms, closed loop parameters, and passive parameters) by physician or other qualified health care professional; with brain neurostimulator pulse generator/transmitter programming, each additional 15 minutes face-to-face time with physician or other qualified health care professional (List separately in addition to code for primary procedure)
    97802 - 97804 Medical nutrition therapy
    97810 - 97814 Acupuncture

    Other CPT codes related to the CPB:

    96372 Therapeutic, prophylactic, or diagnostic injection (specify substance or drug); subcutaneous or intramuscular

    HCPCS codes covered if selection criteria are met:

    Tetrabenazine – No specific code:

    C9037 Injection, risperidone (perseris), 0.5 mg
    J0735 Injection, clonidine hydrochloride (HCL), 1 mg
    J1630 Injection, haloperidol, up to 5 mg
    J1631 Injection, haloperidol decanoate, per 50 mg
    J2680 Injection, fluphenazine decanoate, [Prolixin Decanoate], up to 25 mg
    J2794 Injection, risperidone, long-acting, 0.5 mg

    HCPCS codes not covered for indications listed in the CPB:

    Ecopipam, pramipexole, VMAT-2 inhibitors (e.g., valbenazine) - nNo specific code:

    A9583 Injection, Gadofosveset Trisodium, 1 ml [Ablavar, Vasovist]
    A9585 Injection, gadobutrol, 0.1 ml
    C1767 Generator, neurostimulator (implantable), non-rechargeable
    C1787 Patient programmer, neurostimulator
    C1820 Generator, neurostimulator (implantable), non high-frequency with rechargeable battery and charging system
    C1883 Adaptor/extension, pacing lead or neurostimulator lead (implantable)
    E0746 Electromyography (EMG), biofeedback device
    J0132 Injection, acetylcysteine, 100 mg
    J0400 Injection, aripiprazole, intramuscular, 0.25 mg
    J0401 Injection, aripiprazole, extended release, 1 mg
    J0585 Botulinum toxin type A, per unit
    J0587 Botulinum toxin type B, per 100 units
    J1561 Injection, immune globulin, (Gamunex/Gamunex-C/Gammaked), nonlyophilized (e.g., liquid), 500 mg
    J1566 Injection, immune globulin, intravenous, lyophilized (e.g., powder), not otherwise specified, 500 mg
    J1568 Injection, immune globulin, (Octagam), intravenous, nonlyophilized (e.g., liquid), 500 mg
    J1569 Injection, immune globulin, (Gammagard liquid), nonlyophilized, (e.g., liquid), 500 mg
    J1942 Injection, aripiprazole lauroxil, 1 mg
    J2765 Injection, metoclopramide hcl, up to 10 mg.
    J7608 Acetylcysteine, inhalation solution, FDA-approved final product, non-compounded, administered through DME, unit does form, per gram
    L8679 Implantable neurostimulator, pulse generator, any type
    L8681 Patient programmer (external) for use with implantable programmable neurostimulator pulse generator, replacement only
    L8686 Implantable neurostimulator pulse generator, single array, non-rechargeable, includes extension
    L8687 Implantable neurostimulator pulse generator, dual array, rechargeable, includes extension
    L8688 Implantable neurostimulator pulse generator, dual array, non-rechargeable, includes extension
    L8689 External recharging system for battery (internal) for use with implantable neurostimulator, replacement only
    S8040 Topographic brain mapping
    S9452 Nutrition classes, non-physician provider, per session
    S9470 Nutritional counseling, dietitian visit

    ICD-10 codes covered if selection criteria are met:

    F95.2 Tourette's disorder

    The above policy is based on the following references:

    1. Bagheri M, Kerbeshian J, Burd L. Recognition and management of Tourette's syndrome and tic disorders. Am Fam Phys. 1999;59(8):2263-2272, 2274.
    2. Awaad Y. Tics in Tourette syndrome: New treatment options. J Child Neurol. 1999;14(5):316-319.
    3. Robertson MM, Stern JS. The Gilles de la Tourette syndrome. Crit Rev Neurobiol. 1997;11(1):1-19.
    4. Kurlan R. Tourette syndrome. Treatment of tics. Neurol Clin. 1997;15(2):403-409.
    5. Hyde TM, Weinberger DR. Tourette's syndrome. A model neuropsychiatric disorder. JAMA. 1995;273(6):498-501.
    6. Diagnostic criteria for Tourette's disorder. In: Diagnostic And Statistical Manual Of Mental Disorders, DSM-IV. 4th ed. Washington, DC: American Psychiatric Association; 1994:103.
    7. U.S. Department of Health and Human Services, National Institutes of Health (NIH). Tourette syndrome. NIH Publication No. 95-2163. Bethesda MD: NIH; February 1995.
    8. Tremor, myoclonus, focal dystonia, and tics. In: Principles of Neurology. 6th ed. RD Adams, et al., eds. New York, NY: McGraw-Hill; 1997; Ch. 6:94-113.
    9. No authors listed. Definitions and classifications of tic disorders. The Tourette Syndrome Classification Study Group. Arch Neurol. 1993;50(10):1013-1016.
    10. Jimenez-Jimenez FJ, Garcia-Ruiz PJ. Pharmacological options for the treatment of Tourette's disorder. Drugs. 2001;61(15):2207-2220.
    11. Jankovic J. Tourette's syndrome. N Engl J Med. 2001;345(16):1184-1192.
    12. George MS, Sallee FR, Nahas Z, et al. Transcranial magnetic stimulation (TMS) as a research tool in Tourette syndrome and related disorders. Adv Neurol. 2001;85:225-235.
    13. Kossoff EH, Singer HS. Tourette syndrome: Clinical characteristics and current management strategies. Paediatr Drugs. 2001;3(5):355-363.
    14. Leckman JF. Tourette's syndrome. Lancet. 2002;360(9345):1577-1586.
    15. Visser-Vandewalle V, Temel Y, Boon P, et al. Chronic bilateral thalamic stimulation: A new therapeutic approach in intractable Tourette syndrome. Report of three cases. J Neurosurg. 2003;99(6):1094-1100.
    16. Temel Y, Visser-Vandewalle V. Surgery in Tourette syndrome. Mov Disord. 2004;19(1):3-14.
    17. Adams JR, Troiano AR, Calne DB. Functional imaging in Tourette's syndrome. J Neural Transm. 2004;111(10-11):1495-1506.
    18. Chae JH, Nahas Z, Wassermann E, et al. A pilot safety study of repetitive transcranial magnetic stimulation (rTMS) in Tourette's syndrome. Cogn Behav Neurol. 2004;17(2):109-117.
    19. Hoekstra PJ, Minderaa RB, Kallenberg CG. Lack of effect of intravenous immunoglobulins on tics: A double-blind placebo-controlled study. J Clin Psychiatry. 2004;65(4):537-542.
    20. Visser-Vandewalle V, Temel Y, van der Linden Ch, et al. Deep brain stimulation in movement disorders. The applications reconsidered. Acta Neurol Belg. 2004;104(1):33-36.
    21. Houeto JL, Karachi C, Mallet L, et al. Tourette's syndrome and deep brain stimulation. J Neurol Neurosurg Psychiatry. 2005;76(7):992-995.
    22. Orth M, Kirby R, Richardson MP, et al. Subthreshold rTMS over pre-motor cortex has no effect on tics in patients with Gilles de la Tourette syndrome. Clin Neurophysiol. 2005;116(4):764-768.
    23. Shekelle P, Maglione M, Bagley S, et al. Comparative effectiveness of off-label use of atypical antipsychotics. Comparative Effectiveness Review No. 6. Rockville, MD: Agency for Healthcare Research and Quality (AHRQ); 2007.
    24. Mantovani A, Lisanby SH, Pieraccini F, et al. Repetitive transcranial magnetic stimulation (rTMS) in the treatment of obsessive-compulsive disorder (OCD) and Tourette's syndrome (TS). Int J Neuropsychopharmacol. 2006;9(1):95-100.
    25. Frey KA, Albin RL. Neuroimaging of Tourette syndrome. J Child Neurol. 2006;21(8):672-677.
    26. Maciunas RJ, Maddux BN, Riley DE, et al. Prospective randomized double-blind trial of bilateral thalamic deep brain stimulation in adults with Tourette syndrome. J Neurosurg. 2007;107(5):1004-1014.
    27. Visser-Vandewalle V. DBS in tourette syndrome: Rationale, current status and future prospects. Acta Neurochir Suppl. 2007;97(Pt 2):215-222.
    28. Larson PS. Deep brain stimulation for psychiatric disorders. Neurotherapeutics. 2008;5(1):50-58.
    29. Black KJ. Habit reversal therapy (HRT) for Tourette syndrome. St. Louis, MO: Washington University in St. Louis School of Medicine, Mallinckrodt Institute of Radiology, Neuroimaging Laboratory; August 2003. Available at: http://www.nil.wustl.edu/labs/kevin/move/HRT.htm. Accessed May 15, 2009.
    30. Carr JE, Chong IM. Habit reversal treatment of tic disorders: A methodological critique of the literature. Behav Modif. 2005;29(6):858-875.
    31. Bloch MH. Emerging treatments for Tourette's disorder. Curr Psychiatry Rep. 2008;10(4):323-330.
    32. Welter ML, Mallet L, Houeto JL, et al. Internal pallidal and thalamic stimulation in patients with Tourette syndrome. Arch Neurol. 2008;65(7):952-957.
    33. Pringsheim T, Marras C. Pimozide for tics in Tourette's syndrome. Cochrane Database Syst Rev. 2009;(2):CD006996.
    34. O'Rourke JA, Scharf JM, Yu D, Pauls DL. The genetics of Tourette syndrome: A review. J Psychosom Res. 2009;67(6):533-545.
    35. Curtis A, Clarke CE, Rickards HE. Cannabinoids for Tourette's syndrome. Cochrane Database Syst Rev. 2009;(4):CD006565.
    36. Dehning S, Müller N, Matz J, et al. A genetic variant of HTR2C may play a role in the manifestation of Tourette syndrome. Psychiatr Genet. 2010;20(1):35-38.
    37. Jankovic J, Jimenez-Shahed J, Brown LW. A randomised, double-blind, placebo-controlled study of topiramate in the treatment of Tourette syndrome. J Neurol Neurosurg Psychiatry. 2010;81(1):70-73.
    38. Pourfar M, Feigin A, Tang CC, et al. Abnormal metabolic brain networks in Tourette syndrome. Neurology. 2011;76(11):944-952.
    39. Ackermans L, Duits A, van der Linden C, et al. Double-blind clinical trial of thalamic stimulation in patients with Tourette syndrome. Brain. 2011;134(Pt 3):832-844.
    40. Cath DC, Hedderly T, Ludolph AG, et al; ESSTS Guidelines Group. European clinical guidelines for Tourette syndrome and other tic disorders. Part I: Assessment. Eur Child Adolesc Psychiatry. 2011;20(4):155-171.
    41. Roessner V, Plessen KJ, Rothenberger A, et al; ESSTS Guidelines Group. European clinical guidelines for Tourette syndrome and other tic disorders. Part II: Pharmacological treatment. Eur Child Adolesc Psychiatry. 2011;20(4):173-196.
    42. Verdellen C, van de Griendt J, Hartmann A, Murphy T; ESSTS Guidelines Group. European clinical guidelines for Tourette syndrome and other tic disorders. Part III: Behavioural and psychosocial interventions. Eur Child Adolesc Psychiatry. 2011;20(4):197-207.
    43. Muller-Vahl KR, Cath DC, Cavanna AE, et al; ESSTS Guidelines Group. European clinical guidelines for Tourette syndrome and other tic disorders. Part IV: Deep brain stimulation. Eur Child Adolesc Psychiatry. 2011;20(4):209-217.
    44. Piedad JC, Rickards HE, Cavanna AE. What patients with gilles de la tourette syndrome should be treated with deep brain stimulation and what is the best target? Neurosurgery. 2012;71(1):173-192.
    45. Gabbay V, Babb JS, Klein RG, et al. A double-blind, placebo-controlled trial of ω-3 fatty acids in Tourette's disorder. Pediatrics. 2012;129(6):e1493-e1500.
    46. Wenzel C, Kleimann A, Bokemeyer S, Müller-Vahl KR. Aripiprazole for the treatment of Tourette syndrome: A case series of 100 patients. J Clin Psychopharmacol. 2012;32(4):548-550.
    47. Waldon K, Hill J, Termine C, et al. Trials of pharmacological interventions for Tourette Syndrome: A systematic review. Behav Neurol. 2013;26(4):265-273.
    48. Chen JJ, Ondo WG, Dashtipour K, Swope DM. Tetrabenazine for the treatment of hyperkinetic movement disorders: A review of the literature. Clin Ther. 2012;34(7):1487-1504.
    49. Pringsheim T, Doja A, Gorman D, et al. Canadian guidelines for the evidence-based treatment of tic disorders: Pharmacotherapy. Can J Psychiatry. 2012;57(3):133-143.
    50. Jankovic J. Tourette syndrome. UpTodate Inc., Waltham, MA. Last reviewed March 2014.
    51. Termine C, Selvini C, Rossi G, Balottin U. Emerging treatment strategies in Tourette syndrome: What's in the pipeline? Int Rev Neurobiol. 2013;112:445-480.
    52. Saleh C, Fontaine D. Deep brain stimulation for psychiatric diseases: What are the risks? Curr Psychiatry Rep. 2015;17(5):565.
    53. Farkas A, Bluschke A, Roessner V, Beste C. Neurofeedback and its possible relevance for the treatment of Tourette syndrome. Neurosci Biobehav Rev. 2015;51:87-99.
    54. Schrock LE, Mink JW, Woods DW, et al; Tourette Syndrome Association International Deep Brain Stimulation (DBS) Database and Registry Study Group. Tourette syndrome deep brain stimulation: A review and updated recommendations. Mov Disord. 2015;30(4):448-471.
    55. Reese HE, Vallejo Z, Rasmussen J, et al. Mindfulness-based stress reduction for Tourette syndrome and chronic tic disorder: A pilot study. . J Psychosom Res. 2015;78(3):293-298.
    56. Yang CS, Zhang LL, Lin YZ, Guo Q. Sodium valproate for the treatment of Tourette׳s syndrome in children: A systematic review and meta-analysis. Psychiatry Res. 2015;226(2-3):411-417.
    57. Servello D, Zekaj E, Saleh C, Zanaboni Dina C, Porta M. 16 years of deep brain stimulation in Tourette's syndrome: A critical review. J Neurosurg Sci.2016;60(2):218-229.
    58. Kious BM, Jimenez-Shahed J, Shprecher DR. Treatment-refractory Tourette Syndrome. Prog Neuropsychopharmacol Biol Psychiatry. 2016;70:227-236.
    59. Bloch MH, Panza KE, Yaffa A, et al. N-acetylcysteine in the treatment of pediatric Tourette syndrome: Randomized, double-blind, placebo-controlled add-on trial. J Child Adolesc Psychopharmacol. 2016;26(4):327-334.
    60. Paleacu D, Giladi N, Moore O, et al. Tetrabenazine treatment in movement disorders. Clin Neuropharmacol. 2004;27(5):230-233.
    61. Lopez Del Val LJ, Lopez-Garcia E, Martinez-Martinez L, Santos-Lasaosa S. Therapeutic use of tetrabenazine. Rev Neurol. 2009;48(10):523-533.
    62. Chen JJ, Ondo WG, Dashtipour K, Swope DM. Tetrabenazine for the treatment of hyperkinetic movement disorders: A review of the literature. Clin Ther. 2012;34(7):1487-1504.
    63. Pringsheim T, Doja A, Gorman D, et al. Canadian guidelines for the evidence-based treatment of tic disorders: Pharmacotherapy. Can J Psychiatry. 2012;57(3):133-143.
    64. Yu J, Ye Y, Liu J, et al. Acupuncture for Tourette syndrome: A systematic review. Evid Based Complement Alternat Med. 2016;2016:1834646.
    65. Whittington C, Pennant M, Kendall T, et al. Practitioner review: Treatments for Tourette syndrome in children and young people - a systematic review. J Child Psychol Psychiatry. 2016;57(9):988-1004.
    66. Jankovic J. Tourette syndrome. UpToDate Inc., Waltham, MA. Last reviewed February 2017.
    67. Ghosh D, Burkman E. Relationship of serum ferritin level and tic severity in children with Tourette syndrome. Childs Nerv Syst. 2017;33(8):1373-1378.
    68. Welter ML, Houeto JL, Thobois S, et al; STIC study group. Anterior pallidal deep brain stimulation for Tourette's syndrome: A randomised, double-blind, controlled trial. Lancet Neurol. 2017;16(8):610-619.
    69. Marceglia S, Rosa M, Servello D, et al. Adaptive deep brain stimulation (aDBS) for Tourette syndrome. Brain Sci. 2017;8(1).
    70. Kanaan AS, Jakubovski E, Müller-Vahl K. Significant Tic reduction in an otherwise treatment-resistant patient with Gilles de la Tourette syndrome following treatment with nabiximols. Brain Sci. 2017;7(5).
    71. Eapen V, Baker R, Walter A, et al. The role of transcranial direct current stimulation (tDCS) in Tourette syndrome: A review and preliminary findings. Brain Sci. 2017;7(12).
    72. Molina R, Okun MS, Shute JB, et al. Report of a patient undergoing chronic responsive deep brain stimulation for Tourette syndrome: Proof of concept. J Neurosurg. 2017 Sep 29:1-7 [Epub ahead of print].
    73. Pandey S, Srivanitchapoom P, Kirubakaran R, Berman BD. Botulinum toxin for motor and phonic tics in Tourette's syndrome. Cochrane Database Syst Rev. 2018;1:CD012285.
    74. Jo HJ, McCairn KW, Gibson WS, et al. Global network modulation during thalamic stimulation for Tourette syndrome. Neuroimage Clin. 2018;18:502-509.
    75. Martinez-Ramirez D, Jimenez-Shahed J, Leckman JF, et al. Efficacy and safety of deep brain stimulation in Tourette syndrome: The international Tourette syndrome deep brain stimulation public database and registry. JAMA Neurol. 2018;75(3):353-359.
    76. Martino D, Pringsheim TM. Tourette syndrome and other chronic tic disorders: An update on clinical management. Expert Rev Neurother. 2018;18(2):125-137.
    77. Quezada J, Coffman KA. Current approaches and new developments in the pharmacological management of Tourette syndrome. CNS Drugs. 2018;32(1):33-45.