Subthalamic Stimulation in Tourette’s Syndrome

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Brief Title

Subthalamic Stimulation in Tourette's Syndrome

Official Title

Subthalamic Nucleus Deep Brain Stimulation in Tourette's Syndrome

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.
    

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

        1. 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

        2. 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

        3. 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

        4. 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

        5. 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

        -  Tourette's motor and phonic tics checklist

        -  YTGSS

        -  Global assessment scale (GAS)

        -  Global Clinical Impression Scale (GCI-S)

        -  Sickness Impact Profile (SIP)

        -  Gilles de la Tourette syndrome-quality of life scale (GTS-QOL)

      Behavioral evaluations

        -  Y-BOCS

        -  Depression (MADRS, HAM-D)

        -  ADHD and Anxiety (ADHD-RS, HAM-A)

      Neuropsychological evaluations

        -  Global deterioration

        -  Executive functions

        -  Working memory

        -  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 Phase

Phase 2

Study Type

Interventional


Primary Outcome

Change in Yale Global Tic Severity Scale

Secondary Outcome

 Change in Milan Overall Dementia Assessment (MODA)

Condition

Tourette's Syndrome

Intervention

STN DBS

Study Arms / Comparison Groups

 STN DBS ON First
Description:  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.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Procedure

Estimated Enrollment

10

Start Date

December 2011

Completion Date

December 2015

Primary Completion Date

December 2015

Eligibility Criteria

        Inclusion Criteria:

          -  Age at least of 18 years (with potential exceptions)

          -  Diagnosis of TS based on the diagnostic criteria of the Tourette Syndrome
             Classification Study Group

          -  A Yale Tic Global Severity Scale (YTGSS) > 35/50 for at least 12 months, with tic
             severity documented by a standardized videotape assessment

          -  Inadequate response to standard drug treatment or botulinum toxin

        Exclusion Criteria:

          -  Diagnosis of secondary tic disorder, of heredodegenerative or neurometabolic diseases
             or history of toxic exposures or encephalitis

          -  Previous surgery for TS (with potential exceptions)
      

Gender

All

Ages

18 Years - 60 Years

Accepts Healthy Volunteers

No

Contacts

Luigi M Romito, MD, PhD, , 

Location Countries

Italy

Location Countries

Italy

Administrative Informations


NCT ID

NCT02619084

Organization ID

RF-131

Secondary IDs

GR-2009-1594645

Responsible Party

Principal Investigator

Study Sponsor

Fondazione I.R.C.C.S. Istituto Neurologico Carlo Besta

Collaborators

 Ministry of Health, Italy

Study Sponsor

Luigi M Romito, MD, PhD, Principal Investigator, IRCCS Istituto Neurologico Carlo Besta, Milano, Italy


Verification Date

February 2016