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1. TITLE PAGE
1.1. Title : DOUBLE BLIND ASSESSMENT OF PALLIDAL DEEP BRAIN
STIMULATION IN SELECTED PATIENTS WITH GILLES DE LA TOURETTE
SYNDROME
Short title: Pallidal Stimulation for Gilles de la Tourette Syndrome
1.2 Investigators
Dr Hugh Rickards
Dr Hardev Pall
Professor Marwan Hariz
Mrs. Rosalind Mitchell
Dr Patricia Limousin
Professor Marjan Jahanshahi
Professor Eileen Joyce
Professor Mary Robertson
Dr Ian Mitchell
Mr Ludvic Zrinzo
1.3 Protocol details
Version 9
February 2008
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2. CONTENTS PAGE
1.1. Title :
1.2 Investigators
1.3 Protocol details
2. CONTENTS PAGE
3. LIST OF ABBREVIATIONS AND DEFINITIONS
4. SUMMARY
5. BACKGROUND
6. TRIAL OBJECTIVE AND PURPOSE
7. STUDY DESIGN
8. SUBJECT SELECTION
9. SUBJECT RECRUITMENT
10. TRIAL INTERVENTIONS
10.1 General information
10.2 Use within the trial
11. RANDOMISATION
12. BLINDING & OTHER MEASURES TAKEN TO AVOID BIAS.
13. DATA
13.1 Data to be collected
13.2 Data handling and record keeping
14. STATISTICAL CONSIDERATION
15. COMPLIANCE AND WITHDRAWAL
15.1 Subject compliance
15.2 Withdrawal / drop our of subject
16. INTERIM ANALYSIS AND DATA MONITORING
17. ETHICAL CONSIDERATIONS
18. FINANCING AND INSURANCE
19. REPORTING AND DISSEMINATION
REFERENCES
APPENDIX
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3. LIST OF ABBREVIATIONS AND DEFINITIONS
DBS
GTS
MRI
YGTSS
GPi
YBOCS
TS-QoL
Deep brain stimulation
Gilles de la Tourette syndrome
Magnetic Resonance Imaging
Yale Global Tics Severity Scale
Globus pallidus internum
Yale Brown Obsessive Compulsive Scale
Tourette Syndrome Quality of Life Scale
LFP
EEG
NART
WASI
CVLT
RMF
Local field potential
Electro-encephalogram
National Adult Reading Test
Wechsler Adult Scale for Intelligence
California Verbal Learning Test
Recognition Memory for Faces
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4. SUMMARY
Aims and rationale
To investigate whether deep brain stimulation (DBS) of the globus pallidus internum
(GPi) can alleviate tics in Gilles de la Tourette syndrome (GTS) and whether this
treatment has any influence on social, psychological and behavioral disability and
quality of life.
The rationale is that GPi DBS is efficient in alleviating other movement disorders
such as dystonia and dyskinesias, and there are few well documented case reports in
Tourette syndrome showing promising results.
Interventions/measures
Up to 20 participants will be recruited into this study. They will be recruited from the
Tourette Clinic at The National Hospital for Neurology and Neurosurgery at Queen
Square, London and the Tourette syndrome clinic at the Queen Elizabeth Psychiatric
Hospital in Birmingham. The study will include a 6 months period with doubleblinded assessments with stimulation on vs. off in a cross-over design.
Primary and secondary objectives
The primary objective is to study the effect of DBS in the GPi on the frequency and
severity of Tics assessed with validated scales. Secondary objectives are to evaluate
the impact of DBS on neuropsychiatric and cognitive parameters and quality of life.
Brief description of methods
Patients will undergo tests using validated scales prior to surgery.
Surgery will be performed in a similar fashion to that for dystonia, a routine
indication in the 2 participating sites. Stereotactic implantation of DBS electrodes in
the GPi is performed under general anesthesia.
Programming of stimulation will be optimized by clinicians over the first 6 weeks.
Patients will be randomly assigned to either ON or OFF stimulation for the next 3
month period. Blinded assessment will be conducted at the end of this period
followed by a crossover in the stimulation condition in each patient for an additional 3
months. After final blinded assessment, patients will be offered the opportunity of
participating in an “open label" extension study.
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5. BACKGROUND
Gilles de la Tourette’s syndrome (GTS) is a chronic disabling disorder characterized
by multiple motor and vocal/phonic tics. Co-morbid symptoms and disorders are
common including Obsessive-compulsive disorder, attention deficit hyperactivity
disorder and depression. When severe, GTS may cause considerable social
impairment. A substantial proportion of patients with GTS improve markedly when
they reach adulthood, but the prevalence, and potentially disabling nature, of adult
GTS is probably under recognized. There is good evidence to indicate a significant
genetic component although the underlying gene(s) remain unknown.
Treatment is directed towards symptom relief and relies largely on the
pharmacological modification of the dopaminergic system. Standard treatments
include behaviour therapies and a variety of neurotransmitter modulators which, in
the majority of patients, are successful in bringing about an improvement of
symptoms. However, a number of patients fail to respond and continue to suffer.
Additionally, pharmacological treatment of tics may come at the price of marked side
effects and is not always helpful (Leckman, 2002; Robertson, 2000). Alternative
treatments for tics need to be explored, particularly in those who are severely affected,
resistant to conventional treatments and suffering a markedly reduced quality of life.
Deep brain stimulation has proven a valuable, and safe, additional treatment in
patients with other movement disorders such as Parkinson’s disease or dystonia.
Several case reports suggest that DBS may be helpful in severe GTS. Thus there is a
need for a systematic evaluation of this treatment in GTS.
In the past, neurosurgical procedures for GTS have been used including limbic
leucotomy, frontal lobotomy, anterior cingulotomy, thalamic and infrathalamic
lesions (for review see Temel and Visser-Vandewalle, 2004). However, the results
have often been unsatisfactory partly due to side effects caused by the lesioning
procedure. At the National Hospital for Neurology and Neurosurgery, limbic
leucotomy has been used in two patients with success but less for the movements and
more for the associated self-mutilative and obsessive compulsive behaviours
(Robertson et al., 1990). In their review Temel and Visser-Vandewalle (2004) point
out that thalamic lesions as performed by Hassler and Dieckmann (1970) showed the
best results with respect to reduction of tics in Tourette’s patients. Hassler and
Dieckmann (1970) reported the results of three TS patients where they carried out
numerous coagulations bilateral in the intralaminar, medial thalamic nuclei and the
nucleus ventro-oralis internus resulting in an improvement in tics of 70%-100%.
Targeting the basal ganglia and the thalamus in Tourette’s syndrome is matched by
results in animal studies on the role of these structures in the occurrence of stereotypy
and tics (for example Graybiel and Canales, 2001; Mink, 2001). Abnormalities of the
basal ganglia and related thalamo-cortical circuits in Tourette’s patients have been
described in various neuropathological and imaging studies (Moriarty et al., 1997;
Stern et al., 2000) suggesting their fundamental pathophysiological importance in
GTS. Correspondingly, defective dopamine transmission has been revealed in patients
with GTS (Heinz et al., 1998; Singer et al., 2002). It is hypothesised that an abnormal
spontaneous activation of discrete sets of striatal neurones (possible dopaminedependent effects) inhibit Gpi and substantia nigra reticulate (SNr) neurons that
would normally be active to suppress unwanted movements. This would result in a
defective suppression of competing motor pattern generation and behavioural
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programs at the level of the basal ganglia and disinhibition of thalamo-cortical circuits
leading to the stereotypic features in GTS (Graybiel et al., 1994; Mink, 2001).
Deep brain stimulation (DBS), a safe and reversible neurosurgical approach, has been
established recently in the treatment of other movement disorders such as Parkinson’s
disease and dystonia (Limousin et al., 1995; Coubes et al., 2001). Here, among other
motor symptoms, hyperkinesias have been successfully treated by high frequency
stimulation of the globus pallidus internum (Gpi) (Coubes et al., 2000; Follett, 2004).
Thalamic DBS (ventral intermediate thalamic nucleus) has been used successfully in
patients with myoclonus−dystonia (Trottenberg et al., 2001) and essential tremor
(Lyons and Pahwa, 2004) without occurrence of severe side effects. The
centromedian nucleus of the thalamus has been used as a target in functional
neurosurgery in epilepsy and pain with beneficial effects (Velasco et al., 1995; Hariz
and Bergenheim, 1995). Furthermore, 17 patients with cervical dystonia have been
treated by unilateral lesioning of the ventro-oralis internus (Voi) nucleus of the
thalamus (von Essen et al., 1980).
With this background, a number of patients have been reported in the literature as
having undergone DBS for GTS.
Visser-Vandewalle (2003) reports on three patients where bilateral DBS electrodes
were implanted at a strategic point allowing stimulation of either the centromedian
nucleus, the substantia periventricularis and/or the ventro-oralis internus. The
selection of the thalamus as a target for DBS has been based on the lesion studies by
Hassler and Dieckmann (1970) and justified by the involvement of the ventral and
medial thalamic nuclei in the basal ganglia-cortical circuits and additional neuronal
projections from the midline and intralaminar nuclei to the striatum (overview in
Visser-Vandewalle et al., 2003). The inhibition of these targets during high frequency
stimulation is likely to influence activity levels in motor and limbic basal ganglia
circuits. In this study, all three male patients presented with intractable GTS without
co-morbidity except for associated behavioural problems. A significant reduction in
frequency and severity of tics was revealed after one week of continuous DBS (about
50%-80%) and long-term follow-up showed an improvement in tics of about 70%90% and a reduction in compulsive and self-injurious behaviour (Visser-Vandewalle
et al., 2003). None of the patients showed severe side effects of DBS but all patients
reported a feeling of “reduced energy”. Neuropsychological assessment has not been
reported in detail but at least one patient showed decreased reaction time and word
fluency during DBS (Visser-Vandewalle et al., 2003). Similarly, active DBS contacts
have not been related to the neuroanatomical target structures in this study.
Interestingly, different active contacts have been used across patients and stimulation
frequency is remarkably less in one patient when compared to parameter settings used
in PD or dystonia. Unfortunately, the results of surgery have not been uniformly or
comprehensively analyzed in all patients. The largest series of DBS targeting specific
thalamic nuclei reports an improvement in all 18 patients (Servello et al). However
these findings are not supported by a well designed randomized trial of 5 patients.
Another patient reported is a 36 year old woman with severe GTS who has been
operated simultaneously in the centromedian-parafascicular complex of the thalamus
and the anteromedial part of the Gpi (Houeto et al., 2005). Thalamic as well as
pallidal high frequency stimulation lead to significant improvement in severity and
frequency of tics by about 70% but no add-on effect has been described during
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simultaneous stimulation at both targets (Houeto et al., 2005). In this patient, thalamic
stimulation resulted in amelioration of depression and mood stabilization, not
observed during Gpi-DBS (Houeto et al., 2005). A small number of patients have
undergone GPi DBS with promising results. These preliminary results suggest that
DBS of the thalamus or the pallidum holds promise for the treatment of intractable
GTS using its advantage as a reversible and adjustable method. A number of factors
point towards the GPi as an attractive target for DBS in Tourette syndrome.
Information flow in neural circuits can be influenced at a number of sites. It is well
known from the movement disorder literature that bilateral surgery is better tolerated
on the pallidum than in the thalamus. Additionally, the pallidal target can be easily
visualized on MRI allowing uniformity of targeting across patients. Targeting of
thalamic sub nuclei does not enjoy this important practical advantage
Currently, systematic studies with an interdisciplinary team are needed to refine
patient selection and stimulation parameter settings as well as to gain further insights
into the beneficial effects of this new approach on the various aspects of GTS (motor
symptoms and associated behavioural disorders).
7. TRIAL OBJECTIVE AND PURPOSE
The trial is non-commercial, there is a clinical and research element.
The primary objective of this trial is to establish if deep brain stimulation of the
internal pallidum is effective to improve tics in GDS. For this purpose, GPi DBS will
be compared to off-DBS condition in double blind.
The secondary objectives are assessing the effect of GPi DBS on quality of life,
cognitive and behavioral functions.
8. STUDY DESIGN
The primary end point will be the clinical rating score for tics, at the end of 3 month
period on-DBS versus 3 months off-DBS in a randomised order, with double blind
assessment. The Yale Global Tic Severity Scale, clinician rated and patient rated
scales will both be used. Rush video assessment scale, a clinician rated video score
from a 12 minute video sequence will be obtained in a standardized way and assessed
by an independent rater. All the video sequences will be assessed blindly. We have
chosen a cross-over design since this will allow each patient to be his own control, in
a small group of patients it seems the most appropriate way to have a control group.
We anticipate that any carry over effect will be diluted in the 3 months period.
This is a phase II study.
This treatment, if effective is a life long treatment. In addition to the 6 months period
in double blind it is important to follow this improvement over time and make sure it
is maintained. For this reason, we intend to proceed to an open label extension study
after completion of the cross-over period.
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A randomised cross-over study of DBS in Severe Tourette
syndrome.
Surgery
Randomisation.
Stimulator
on.
Stimulator off.
O.L.E.
t-2 mo
t-1 mo
t + 6 wks
Stimulator
off.
Stimulator on.
t=0
t + 18 weeks
= Assessment
Visit Schedule for DBS in Tourette syndrome trial.
t=30 weeks
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Visit 1.
Screening
t-2 months
Visit 2.
Visit 3.
Consent Surgery
t-1 month t=0
Visit 4.
Baseline
t + 6 wks
Visit 5.
Visit 6.
Crossover End
t + 18 wks t + 30 wks
Screening
Psychiatric examination
Neurological Examination
Trial Consent
Surgical Consent
Surgery
YGTSS
Video rating
DCI
Y-BOCS
NPI
BDI
STAI
TS-QoL
MOVES
NART
WASI
CVLT
RMF
Fluency
Trail making test
Stroop test
Paced serial addition
letter cancellation
Corsi blocks
Adverse effects
Key.
DCI = Diagnostic confidence index
YGTSS = Yale Global Tic Severity Scale
Y-BOCS = Yale-Brown obsessive Compulsive Scale
NPI = Neuropsychiatric Inventory
BDI = Beck Depression inventory II
STAI = Spielberger State Trait Anxiety Inventory
TS-Qol = Tourette syndrome Quality of Life Scale
MOVES = Movement Disorder self-report scale
NART = National Adult Reading Test
WASI = Wechsler Adult Scale for Intelligence
CVLT = California Verbal Learning Test
RMF = Recognition Memory for Faces
Primary outcome measure.
The primary outcome measure will be the change in YGTSS between start and end of
“stimulator on” phase compared with change in YGTSS between the start and end of
“stimulator off” phase, when compared within patients.
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Secondary end point will include:
 Assessment of quality of life: TS-QoL, disease specific scale administered at
visits 2,4,5 and 6.
 Assessment of depression and anxiety: Beck Depression Inventory and
Spielberger State-trait Anxiety index administered at visits 2,4,5, and 6.
 Assessment of behaviour: Neuropsychiatric Inventory, a career rated
instrument administered at visits 2,4,5, and 6
 Obsessive Compulsive rating scale: YBOCS- clinician rating administered at
visits 2,4,5, and 6.
 Cognitive function
o Measures of intellectual ability (NART, WASI)
o Verbal and non-verbal memory (CVLT, RMF)
o Tests of executive function and attention: phonemic and semantic word
fluency, Trail Making Test, Stroop, paced serial addition test, letter
cancellation test, Corsi blocks
These tests will be administered by a neuropsychologist at visits 2,4,5 and 6
 Adverse effects from surgery.
9. SUBJECT SELECTION
Two centres will be involved. Patients will be selected from the specialist Tourette
clinics at the NHNN and in Birmingham. These clinics have assessed around 3000
patients between them. Patients will be selected by the clinician running the clinic.
The inclusion criteria are
- Adults with stable Tourette syndrome. In most cases this means being over 25
years of age but there may be rare exceptions to this
- Chronic and severe Tourette syndrome with a Yale Global Tourette Severity
Scale of at least 35/50for at least 12 months
- Resistant to adequate trials of conventional medical and psychological
treatment
- Stable medical treatment for a year
- Compliant with treatment plans
The exclusion criteria are
Tics attributable to another neurological diagnosis
Treatment with anticoagulants or antiaggregants that cannot be stopped for 2
weeks before and 2 weeks after surgery
- Coagulation problems
- Other disease compromising life expectancy
- Other medical or psychiatric conditions which increase the risk of a failed
procedure
- Patient likely to benefit significantly from psychological intervention
- Psychosocial risk factors which increase the risk of the procedure or may
compromise post-operative care
- Patient unwilling to co-operate with post-op assessment and care.
We intend to recruit 20 patients.
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10. SUBJECT RECRUITMENT
Patients will be recruited in the relevant clinics (see above). Clinicians responsible for
the clinics will identify patients that could potentially benefit from this operation.
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Patients will be given verbal information and an information sheet. Patients interested
in taking these further will be screened for exclusion criteria. The consent for the
study will be obtained by two senior clinicians at both sites. Surgical consent will be
obtained separately by the neurosurgeon (Prof.Hariz, Mr. Zrinzo or Mrs. Mitchell)
11. TRIAL INTERVENTIONS
11.1 General information
Deep brain stimulation (DBS) is regularly used for the treatment of Parkinson’s
disease. Over recent years new applications such as dystonia have been developed. A
few papers have reported in a small number of patients improvement of tics in
patients with Tourette syndrome. The use of DBS is recommended by NICE for
dystonia and tremor.
Risk and benefits
DBS implies a surgical procedure to implant electrodes in the brain. It has been used
for more than 15 years to treat tremor and Parkinson’s and for more than 10 years to
treat Dystonia. It is approved by NICE and is considered a very safe surgical
treatment in terms of severe morbidity, with a very low risk of hemorrhage, stroke,
paralysis etc. (less than 1%).
11.2 Use within the trial
The DBS procedure will be done the same way it is routinely done for dystonia and
for Parkinson’s disease (pallidal procedures). It will be done in general anesthesia,
electrode will be implanted in the posteroventral internal pallidum under MRI
guidance, using the Leksell stereotactic system. Postoperative MRI will be to verify
good placement of the electrodes. Thus, the surgery itself is identical to the one used
routinely to treat dystonia and parkinsonian dyskinesias.
12. RANDOMISATION
The protocol includes a 6 months randomized blinded period. Patients will be
randomized to either “stimulation on first” or “stimulator off first” The clinician
responsible for the programming of the stimulator will be informed of this via a
sealed envelope and program the patient accordingly. The patients, the clinicians and
psychologists involved in rating will not be aware of the condition.
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13. BLINDING & OTHER MEASURES TAKEN TO AVOID BIAS.
- All the clinical scores done after 3 month on-stimulation and 3 month offstimulation will be double-blind, the patient and the clinician directly involved in the
scoring will not be aware of the condition of stimulation.
- The video assessments of tics done at all time points will be assessed by 2
investigators who will be blinded of the timing of the recording and the stimulation
condition.
- The clinician doing the programming will spend the same time adjusting the
stimulator of the patient at the start of the on or off-stimulation period. The electrical
parameters will be selected in a way that does not induce any side-effect perceived by
the patient.
14. DATA
14.1 Data to be collected
Data will be collected before surgery, at baseline and at the end of each block
Data include validated scales of the patients’ symptoms and quality of life to measure
changes within patients comparing “stimulator on” to “stimulator off” settings
Measures of cognitive functions will also be recorded to evaluate any eventual side
effect from the operation on those functions.
14.2 Data handling and record keeping
Data will be collected on paper; they will be stored in a locked cabinet. Later on data
will be coded and entered on computers protected by password. Records will be kept
securely for 10 years after the end of the study.
The rule of Data Protection Act 1998 will be followed.
15. STATISTICAL CONSIDERATION
To assess clinical outcome repeated measure ANOVA will be used to compare the
conditions “before surgery”, “stimulation on” and “stimulation off” for each patient.
This is a pilot study since until now only case reports have been published in this area.
The decision on the sample size has been based on practical considerations and not
formal calculation. The results of this study could be used for the sample size of a
multicenter trial if the results are favorable to design such a trial.
16. COMPLIANCE AND WITHDRAWAL
16.1 Subject compliance
The stimulator works automatically and the patients will not be able to alter the
setting programmed by the physicians.
16.2 Withdrawal / drop our of subject
If a patient withdraws from the study before surgery he will be replaced.
17. INTERIM ANALYSIS AND DATA MONITORING
A data monitoring committee will be convened to perform interim analysis if
required.
A separate safety committee will be convened to provide independent advice about
safety and adverse events during the trial.
18. ETHICAL CONSIDERATIONS
Information sheet and informed consent forms are included in the appendix.
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Only patients over 20 and able to give informed consent will be included. Patients
will be able to withdraw from the study.
19. FINANCING AND INSURANCE
Standard NHS Indemnity arrangements apply for providing indemnity and/or
compensation in the event of a claim by, or on behalf of participants for negligent
harm. No compensation arrangements for non-negligent harm are available under
NHS indemnity for providing indemnity and/or compensation in the event of a claim
by, or on behalf of participants
20. REPORTING AND DISSEMINATION
Results will be reported in meeting and submitted to journals after agreements of all
investigators.
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DYT1−generalised dystonia by stimulation of the
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2. Follett KA. Comparison of pallidal and subthalamic deep brain stimulation for the
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APPENDIX
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Patient information sheet
Patient consent form
Ethics form