STN-DBSinTS: Subthalamic Stimulation in Tourette's Syndrome
Study Details
Study Description
Brief Summary
The main objective of this project is to evaluate the efficacy of subthalamic nucleus deep brain stimulation (STN DBS) in treating motor and phonic tics in medically refractory Tourette's syndrome (TS).
Secondary objectives are to individuate and standardize the best electrical parameters for STN stimulation in TS, to evaluate the efficacy and safety on non-motor TS features, such as behavioral abnormalities and psychiatric disorders, during chronic STN stimulation, to correlate the improvement of TS motor and non-motor symptoms to the modification in brain activity recorded by PET study and to explore the pathophysiology of TS, and to evaluate the safety of STN DBS in TS patients.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
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Phase 2 |
Detailed Description
Background Tourette's syndrome (TS) is characterized by the occurrence, before 18 years of age, of multiple motor and vocal tics, which do not necessarily occur concomitantly. Tics constitute the clinical hallmark of TS; they are sudden, brief, intermittent involuntary (or semi-involuntary) movements (motor tics) or noises (sound tics). Tic severity is variable: some patients have mild or bearable tics, whereas in others tics are so severe to cause bone fractures or cervical myelopathy. Diagnostic criteria set by the Tourette Syndrome Classification Study Group and the American Psychiatric Association are commonly used. It is currently recognized that TS is far more common than previously thought, with a prevalence of 1 to 10 children of adolescents per 1000.
Tics are usually treated in cases where disability at school, in the social environment or at home is severe enough to warrant medical intervention. TS commonly presents with co-morbid features, mainly consisting in obsessive-compulsive traits, attention deficit with hyperactivity disorder and depression. Psychopathologic features are partly an aftermath of tics, particularly in those patients who display severe tics affecting their social and work activities. Therefore, amelioration of tics may substantially improve daily life and adaptation to social and work environments.
Medication is the first choice treatment, with the aim to reduce the intensity of tics and the associated clinical features. Different drugs, belonging to several pharmacologic classes, such as α-adrenergic drugs, typical and atypical neuroleptics, and tetrabenazine are used. In some cases drug treatment provides satisfactory symptomatic benefit. Overall, it is reckoned that a meaningful proportion of TS patients do not have adequate benefit with drug treatment and the majority of patients have side effects of variable severity.
Ablative psychosurgery has been historically used to treat more severe cases of TS, but the results have been disappointing and burdened by irreversible side effects. The recently developed technique of deep brain stimulation (DBS) allows to selectively modulate the activity of brain structures that control movements and behaviors in patients with different neurological disorders. This approach is warranted in those patients who respond poorly to available medical therapy.
Recently, therapeutic DBS trials have been performed in patients with severe TS, who were not satisfactorily controlled by medication. At first, the same thalamic nuclei targeted by ablative surgery, particularly the centromedian-parafascicular (CM-pf) nuclear complex, have been implanted with some success.
Another anatomical target has been the anterior capsule in proximity of the nucleus accumbens or the nucleus accumbens itself, aiming at interfering with tics and obsessive-compulsive features at the same time. More recently, the globus pallidus internum (GPi) has been implanted. This constitutes the main output station of the basal ganglia towards the thalamus and the cerebral cortex.
Hypothesis driven rationales
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There is preliminary evidence that the subthalamic nucleus can be another promising target in treating motor and non-motor feature of TS. A clinical observation has recently shown that STN DBS improved motor and vocal tics in a patient with consistence of Parkinson's disease and TS
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Literature evidences have showed that stereotyped behaviors in nonhuman primates, resembling tics and compulsive disorders, were related to dysfunction of the limbic parts of the globus pallidus externum, the STN, and the SN reticulata, rather than to dysfunction of the GPi
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From a physiologic perspective, STN occupies a privileged position influencing both output nuclei of the basal ganglia, GPi and substantia nigra (SN) reticulata. Several findings have highlighted the putative role of the STN in integrating emotional, cognitive and motor functions and this nucleus would thus be an effective target for the treatment of conditions that combine motor symptoms, behavioral disorders, obsessive-compulsive disorders
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Involvement of the SN in TS was also found in a functional MRI study. Furthermore, stimulation of the anterior STN was effective in reducing stereotypes in a primate model of behavioral disorder and STN DBS in PD can also result in behavioral changes. Indeed, the small size of this nucleus may allow modulation of abnormal neuronal activity of both limbic and sensorimotor territories, more easily than GPi or thalamic DBS
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The small and well-defined volume of the STN combined with well standardized implant techniques, would lead to a reduced inter-patient variability in targeting
The novelty of the project The STN may be a potential target for DBS in TS. The choice of STN as a target for this project is the current model of basal ganglia functioning: this anatomical location aims at modulating the sensory-motor, associative and limbic subdivisions of cortico-subcortical-cortical loops that are thought to be dysfunctional in TS. STN DBS may provide a quicker relief of symptoms than medial thalamic nuclei or GPi stimulation.
The main objective of this project is to evaluate the efficacy of subthalamic nucleus deep brain stimulation (STN DBS) in treating motor and phonic tics in medically refractory Tourette's syndrome (TS).
Secondary objectives are to individuate and standardize the best electrical parameters for STN stimulation in TS, to evaluate the efficacy and safety on non-motor TS features, such as behavioral abnormalities and psychiatric disorders, during chronic STN stimulation, to correlate the improvement of TS motor and non-motor symptoms to the modification in brain activity recorded by PET study and to explore the pathophysiology of TS, and to evaluate the safety of STN DBS in TS patients.
Clinical evaluation will include a complete neurological examination (videotaped tic scales throughout), a structured psychological interview and a psychiatric evaluation. Quantitative evaluations will be performed using appropriate validated neurological (including the Yale Tic Global Severity Scale (YTGSS) and neuropsychological rating scales, including the Yale-Brown Obsessive Compulsive scale (Y-BOCS), as detailed hereafter.
Neurological evaluations
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Tourette's motor and phonic tics checklist
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YTGSS
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Global assessment scale (GAS)
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Global Clinical Impression Scale (GCI-S)
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Sickness Impact Profile (SIP)
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Gilles de la Tourette syndrome-quality of life scale (GTS-QOL)
Behavioral evaluations
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Y-BOCS
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Depression (MADRS, HAM-D)
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ADHD and Anxiety (ADHD-RS, HAM-A)
Neuropsychological evaluations
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Global deterioration
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Executive functions
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Working memory
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Fluency
Power calculation. A retrospective analysis of published data on DBS-treated TS patients reports an average YGTSS at inclusion of 50 ±15 points. This is in keeping with our inclusion criteria of YGTSS >35. Considering a 50% improvement as meaningful, a 25-point variation is expected from baseline to post-implant in the active stimulation group and a 10% 5-point variation in the sham stimulation group. The investigators assume a comparable standard deviation at baseline and at end of the observational periods and a good correlation of YGTSS measures (correlation coefficient: 0.8). An actual number of at least 5 patients per group should allow to demonstrate a 25-point YGTSS difference between the two active stimulation and the sham stimulation groups, with a statistical potency of 85% (bilateral Mann-Whitney-Wilcoxon test, alpha = 5 %).
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: STN DBS ON First The study will be performed according a randomized, double-blind, crossover design with two 3-month phases, during which the stimulation could be switched "on" or "off", separated by a 1-month washout period, At the end of the second double-blind phase, a further open period of 6 months with stimulation switched "on" will follow. |
Procedure: STN DBS
Bilateral STN DBS
Other Names:
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| Experimental: STN DBS OFF First The study will be performed according a randomized, double-blind, crossover design with two 3-month phases, during which the stimulation could be switched "on" or "off", separated by a 1-month washout period, At the end of the second double-blind phase, a further open period of 6 months with stimulation switched "on" will follow. |
Procedure: STN DBS
Bilateral STN DBS
Other Names:
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Outcome Measures
Primary Outcome Measures
- Change in Yale Global Tic Severity Scale [Three months after stimulation switched ON v pre-operative condition]
Primary outcome measure will evaluate the efficacy of subthalamic nucleus deep brain stimulation (STN DBS) in controlling motor and phonic tics (by evaluating the reduction on the Yale Global Tic Severity Scale - YGTSS) in patients with medically refractory Tourette syndrome (TS), in a study to be performed according a randomized, double-blind, crossover design with two 3-month phases, during which the stimulation could be switched "on" or "off", separated by a 1-month washout period. The assumption tested is that of a meaningful tic improvement by bilateral STN DBS (considered as ≥ 50% reduction in Yale Global Tic Severity Scale - YGTSS from baseline to post-implant in the active stimulation group). YGTSS is a semistructured clinician-rated instrument that assesses the severity and frequency of motor and phonic tics.
Secondary Outcome Measures
- Change in Milan Overall Dementia Assessment (MODA) [Three months after stimulation switched ON v pre-operative condition]
To evaluate the effects on TS neuropsychological features of STN stimulation. Assessments will be performed by administering the MODA (assessing specific neuropsychological tests, exploring the global deterioration, the executive functions, the working memory and fluency).
- Change in brain activity recorded by PET [Three months after stimulation switched ON v pre-operative condition]
To correlate the improvement of TS motor and non-motor symptoms to the modification in brain activity recorded by PET study and to explore the pathophysiology of TS
- STN DBS safety in treating medically-refractory Tourette syndrome [24 months]
An analysis of adverse and side effects of surgery and STN stimulation will be performed during the whole observation period (24 months)
- Change in Yale-Brown Obsessive Compulsive scale (Y-BOCS) [Three months after stimulation switched ON v pre-operative condition]
One of the secondary outcome will measure the effect of STN DBS in controlling obsessive-compulsive features (by evaluating the change on the Y-BOCS) in patients with medically refractory TS
- Change in Global assessment scale (GAS). [Three months after stimulation switched ON v pre-operative condition]
To evaluate the effects of STN stimulation on the overall functioning of a TS subjects during the specified time period on a continuum from psychological or psychiatric sickness to health. Assessments will be performed by administering the GAS.
- Change in Global Clinical Impression Scale (GCI-S) [Three months after stimulation switched ON v pre-operative condition]
To evaluate the effects of STN stimulation on the overall status of a TS subjects during the specified time period. Assessments will be performed by administering the GCI-S.
- Change in Gilles de la Tourette syndrome-quality of life scale (GTS-QOL) [Three months after stimulation switched ON v pre-operative condition]
To evaluate the effects of STN stimulation on the overall QoL of a TS subjects during the specified time period. Assessments will be performed by administering the GTS-QOL.
- Change in Montgomery-Åsberg Depression Rating Scale (MADRS) [Three months after stimulation switched ON v pre-operative condition]
To evaluate the effects of STN stimulation on the depressive features of a TS subjects during the specified time period. Assessments will be performed by administering the MADRS.
- Change in ADHD Rating Scale-IV (ADHD-RS) [Three months after stimulation switched ON v pre-operative condition]
To evaluate the effects of STN stimulation on the ADHD symptoms of a TS subjects during the specified time period. Assessments will be performed by administering the ADHD-RS.
- Change in Hamilton Anxiety Rating Scale (HAM-A) [Three months after stimulation switched ON v pre-operative condition]
To evaluate the effects of STN stimulation on the anxiety symptoms of a TS subjects during the specified time period. Assessments will be performed by administering the HAM-A.
Eligibility Criteria
Criteria
Inclusion Criteria:
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Age at least of 18 years (with potential exceptions)
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Diagnosis of TS based on the diagnostic criteria of the Tourette Syndrome Classification Study Group
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A Yale Tic Global Severity Scale (YTGSS) > 35/50 for at least 12 months, with tic severity documented by a standardized videotape assessment
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Inadequate response to standard drug treatment or botulinum toxin
Exclusion Criteria:
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Diagnosis of secondary tic disorder, of heredodegenerative or neurometabolic diseases or history of toxic exposures or encephalitis
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Previous surgery for TS (with potential exceptions)
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Fondazione IRCCS Istituto neurologico Carlo Besta | Milan | Italy | 20133 |
Sponsors and Collaborators
- Fondazione I.R.C.C.S. Istituto Neurologico Carlo Besta
- Ministry of Health, Italy
Investigators
- Principal Investigator: Luigi M Romito, MD, PhD, IRCCS Istituto Neurologico Carlo Besta, Milano, Italy
Study Documents (Full-Text)
None provided.More Information
Publications
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- RF-131
- GR-2009-1594645