Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT03156517 |
| Other study ID # |
2013/1013 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
April 20, 2014 |
| Est. completion date |
December 5, 2019 |
Study information
| Verified date |
October 2020 |
| Source |
Oslo University Hospital |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Action tremor of the arms can be an invalidizing symptom of diseases such as Essential
Tremor, Dystonic Tremor, Parkinson's disease and Multiple Sclerosis. In this study we compare
the efficacy and safety of two different brain targets for deep brain stimulation (DBS) that
both are known to reduce action tremor of the arms. These two targets are called the VIM
nucleus of the thalamus (VIM) and the posterior subthalamic area (PSA), which includes the
Zona Incerta. Both targets can be reached by one lead (wirh four electrode contact).
Patients that are found eligible for DBS because of severe action tremor of the arms are
invited to participate. After randomization, half of them are stimulated first in the VIM for
3 months and then in the PSA for 3 months, and the other half first in the PSA and then VIM
for 3 months each. Tremor severity is scored on a clinical quantitative scale at baseline and
at the end of each of these two 3-month periods, and eventual side-effects are registered.
The best target is then selected and after another 6 months scoring is repeated. We intend to
provide robust data about whether one of the two targets is superior to the other both
regarding ability to reduce tremor efficiently and to avoid or minimize side-effects, or if
there is no significant difference between the two targets. We also carefully check the exact
position of the active electrode contact in the brain and compare this with efficacy and
safety evaluations. Long-term follow-up is planned after 3, 5, 7 and 10 years.
Description:
Tremor is defined as rhythmic and oscillating involuntary movements of a body part. Action
tremor occurs when a body part is activated, and is clinically most frequently seen in
Essential (idiopathic) Tremor (ET), with an overall prevalence of 0.9 %, and of 4.6 % in
people over 65 years. But it can also be the most disabling symptom in many other
neurological diseases such as dystonia, multiple sclerosis (MS), advanced Parkinson's disease
(PD), and some spino-cerebellar ataxias/hereditary disorders with dysfunction of cerebellar
connections. The cerebello-thalamo-cortical pathway is probably involved in all tremors. The
exact mechanisms that disrupt these pathways and produce tremor remain, however, largely
unknown. The cerebello-thalamic tract originates from the cerebellar nuclei (dentate,
emboliform and globose), ascends and crosses in the pons and enters the red nucleus (RN) in
the mesencephalon. Most fibers project further to the ventral thalamic nuclei - oralis (VO)
and intermedius (VIM). The posterior subthalamic area (PSA) is the region inferior to VO and
VIM, dorsal and posterior to the subthalmic nucleus (STN) , and lateral to RN. Its principal
components are the nucleus called Zona Incerta (ZI) and the fiber bundle called the
prelemniscal radiation (RaPrl). Whereas STN and RN are visible on standard T2-weighted
MRI-scans, PSA is only indirectly defined by these surrounding structures. Classification and
differential diagnosis of action tremor disorders can be difficult, since with rare
exceptions there are no confirmative diagnostic tests or biomarkers for the primary tremor
forms. Differential diagnosis of primary action tremor forms such as ET, Dystonic tremor (DT)
and Cerebellar tremor (CbT), therefore relies mainly on clinical examination and the
exclusion of underlying diseases causing secondary action tremors (such as PD and MS). Action
tremor is divided into postural (when a position is maintained), or kinetic (when a movement
is made). Other neurological findings (dystonia, cerebellar, pyramidal, parkinsonian,
neuropathic signs), and systemic signs must be assessed. Supplementary diagnostic workup
includes MRI in all cases to show/exclude tremor-causing lesions such as infarcts, MS plaques
or other inflammatory diseases, cerebellar atrophy, or atrophy or pathological signal changes
along the cerebello-thalamo-cortical circuits, including the basal ganglia. DAT-scan
(131I-FP-CIT SPECT) of the DopAmine Transporter (DAT) shows reduced binding in the striatum
in PD and other degenerative parkinsonian disorders, but not in ET, DT or CbT. It is
performed in all patients who have rest tremor or other parkinsonian signs. Necessary
laboratory tests of blood (+/- CSF and urine) are also performed. Medical treatment available
for primary (and most secondary) action tremor disorders are only symptomatic. The two most
commonly used drugs for ET, the non-selective beta-blocker propranolol and the anticonvulsant
primidone both received a level A recommendation of efficacy by the American Academy of
Neurology in 2005. This was based on mostly small and short-term studies (3-6 weeks), showing
an average tremor reduction of about 50-60% in about 50% of patients. No controlled long-term
studies have been done, but open-label studies indicate development of tolerance and reduced
effect in 10-15%. Level B evidence of a probable effect has been given to other beta-blockers
(atenolol, sotalol) and the antiepileptics alprazolam, topiramate and gabapentin. There have
been no systematic studies for other tremors like dystonic or cerebellar tremors. Thus, for
these patients no medications with established efficacy exist, except intramuscular botulinum
toxin injections for dystonic head tremor.
Deep brain stimulation (DBS) of the Nucleus Ventralis Intermedius of the thalamus (VIM) is
still considered the target of choice for patients with disabling action tremor at most
centers. Open-label, mostly short-term studies of VIM-DBS in ET have reported up to 80-90%
reduction of action tremor, but long-term clinical experience and studies show that gradual
loss of tremor control over months and years occurs in many patients. Masked raters were not
used, except for one study. The problem termed "development of tolerance" to stimulation, is
emphasized in recent reviews and clearly limits the functional long-term benefit of VIM-DBS.
VIM-DBS also tends to be less effective on proximal tremor, which is often the most severe
symptom. Because VIM cannot be clearly outlined on MRI or mapped using microelectrode
recordings, targeting it employs the use of standard stereotaxic coordinates.The definition
of these varies between centers. They are defined in relation to the inter-commissural line
(ICL). Final placement of the electrode is decided after peroperative clinical testing of
effect on tremor and side effects in the awake patient. Bilateral VIM-stimulation is
associated with a relatively high rate of side effects. In a meta-analysis of 430 patients,
19 % had paresthesias, 9 % dysarthria, 7 % headache and 6 % unsteadiness or gait
difficulties. Therefore, many centers offer only unilateral stimulation to most patients even
if they have bilateral tremor. The limitations of VIM-stimulation have led to a renewed
interest in exploring the PSA as an alternative. Open label case series from several centers
indicate better results from PSA-DBS than VIM-DBS, particularly in reducing kinetic tremor,
including proximal arm tremor and intention tremor. The targeted area within the PSA varies
among centers. Plaha et al reported results from blinded 1-year follow-up of bilateral
stimulation of the caudal ZI in 5 patients with PD tremor, and 13 patients with action
tremors from a range of diseases (ET, MS, CbT, DT, Holmes tremor). Average improvement of
postural/action tremor was 88% and of rest tremor 95%. In the MS-patients, both severe
proximal arm tremor, truncal ataxia and severe head-and-neck tremor improved. There was no
significant decline of clinical efficacy or significant change in stimulation parameters
during serial follow-ups, but some side-effects were seen in a few patients due to misplaced
electrodes or edema. Blomstedt et al reported results of PSA-DBS in 21 patients with ET (most
unilateral), achieving on average 95% tremor reduction and 87% functional improvement in the
contralateral arm. Transient, mild expressive dysphasia was observed in eight patients. In
summary, the most frequent side-effects reported in PSA-DBS series are paresthesias,
dysarthria, dysequilibrium and blurred vision, and thus similar to those observed with
VIM-DBS, but are consistently reported to be mild and transient in almost all patients. So
far no controlled comparison of the efficacy and safety between stimulation of the two
targets has been reported.With respect to the ICL, the targets for PSA used in the above
studies were 10-14 mm lateral, 6-7.5 mm posterior to the midpoint of the ICL, and 2-4 mm
inferior. Few authors have studied different targets in the same patients. Herzog et al
compared stimulation with the upper electrode contacts the thalamic level, and with the lower
contacts 1.5mm below the ICL in 21 patients with ET or MS-tremor. The results favoured the
contacts below the ICL.
To overcome the limitations of today´s standard method of treating severe action tremors with
VIM-DBS, we are performing a double-blind, randomized, controlled and comparative study of
VIM-DBS versus PSA-DBS in patients with disabling action tremor. We will implant one
quadripolar electrode (each contact 1.5 mm, interspace 0.5 mm) so that it covers both targets
on one side, unilaterally or bilaterally as indicated clinically. The efficacy of stimulating
each target will be studied in individual patients and between patient groups in a cross-over
design, in two consecutive randomized 3-month periods, by the use of validated tremor scores.
Further continuous stimulation of the most effective target in each patient will be evaluated
after another 6 months. This will provide unbiased efficacy-data about the two targets, both
within each patient, and between patient groups. Stimulation efficacy will also be evaluated
in relation to the exact target localization, defined by merging post-op helical CT scan
(which shows the four electrode contacts), with pre-op MRI, including Diffusion Tensor
Imaging/fiber tracking. Such high-resolution correlation data has to date only been published
in a few action tremor patients world-wide, and will add important new data to aid DBS
targeting in the future. Since little is known about whether cognitive functions are altered
by the disease or the treatment, we will include neuropsychological testing before and after
effective DBS treatment.
Methods: i) Clinical evaluation and scoring. Before the patients are invited to participate,
they have been thoroughly evaluated for correct diagnosis, including a complete clinical
neurological examination, MRI of the head/brain (+/- spine/spinal cord), laboratory tests,
etc. The inclusion examination ensures that inclusion criteria are fulfilled and that none of
the exclusion criteria are met. The study examinations include clinical examination and
scoring performed at baseline -end of 1. Random.per./3 mo. - end of 2. Random.per./6 mo.- 1
year
Performed at all study visits:
- The Fahn-Tolosa-Marin tremor scale contains 21 items scored 0-4, with 0 indicating no
tremor/disability and 4 severe tremor (constant, high amplitude)/inability to perform a
task due to tremor. Item 1-9 score tremor for face, tongue, voice, head, trunk and the
four extremeties. For face only rest tremor is scored, for tongue, head and trunk rest
and postural tremor, and for the extremities action/intention tremor is also scored.
Items 10-13 test handwriting, and spiral drawing with right and left hand, and line
drawing between defined points. Item 14 tests pouring of water from one plastic cup to
the other, and Item 15-21 describe functional disability of speaking, feeding (not
liquids), bringing liquids to mouth, hygiene, dressing, writing, working.
- Quality of life in Essential Tremor- scale (QUEST). A 30 item questionnaire developed
specifically for tremor patients, evaluating quality of life, cognitive, and emotional
aspects of the tremor.
- VAS of Global Disease Burden (patient evaluated). Visual analogue 0-10 centimeter
continuous scale, on which the patient scores at which severity they assess the global
tremor disease burden.
- The Hospital Anxiety and Depression Scale. A well-established and validated self-report
questionnaire which contains 14 items expressing emotions, alternating between 7
emotions of anxiety and 7 of depression. Scores for each item ranging from 0-3. Cut-off
sum-scores exist for clinically significant symptoms of anxiety and depression,
respectively.
In addition,complete neurological exam. and neuropsychological testing is performed at
baseline and at 1 year of DBS.
ii) Operation. Preoperative axial MRI sequences (T2-weighted fast-spin-echo,
diffusion-weighted spin-echo echo-planar imaging, and 3D inversion prepared T1-weighted
gradient-echo) will be obtained on a 3 Tesla MRI-scanner the day before the operation. In
local anaesthesia a CRW™ stereotactic frame, (Radionics, MA, USA) is mounted, placed
parallell to the AC-PC line, before performing a stereotactic 3D CT scan. The MRI and CT
scans are merged using the iPlan™ (version 3.0 or later) computer-aided neuronavigation
system (BrainLAB, München, Germany), which is also used to plan the targets based on
predefined stereotactic coordinates for VIM and PSA, refined according to relationship to the
MRI-visible STN and RN. Trajectory angle will be chosen to cover VIM and to enter PSA
slightly posterior and medial to STN, at the level of maximal diameter of RN. To ensure
safety, trajectories are always planned to avoid vessels, sulci and ventricles.
Microelectrode recordings (MER) will not be performed.
Clinical test stimulation will be performed in the awake patient, at four 2 mm steps, from 8
mm above the most caudal target in the PSA (Caudal Zona Incerta) using the permanent
quadripolar electrode, and the placement accepted if good tremor suppression is confirmed and
no unacceptable side effects observed. Electrode position is checked using perioperative
radiography, and the electrodes fixed to the scull. After removal of the stereotactic frame,
the electrodes are connected to a pulse generator implanted in the subclavicular or abdominal
region.
iii) Randomization periods/stimulation treatment. Half the patients are randomized to receive
VIM-stimulation from 0-3 months after surgery and then switched to receive PSA-stimulation
for the next 3 months, and the other half to receive PSA-stimulation the first three months
and VIM-stimulation the next 3 months. During these two randomization periods the pulse width
will be held constant at 60 microseconds and frequency 130 Hz, monopolar mode (bipolar mode
only if monopolar leads to intolerable side effects). Current should not exceed 3 mA during
the randomization periods. After scoring at the end of the last 3-month randomization period,
the electrode contact yielding the best tremor reduction with no or only minor/possible side
effects is chosen for further treatment. During follow-up to 1-yr post-op there may be 2
additional visits for optimal adjustment of stimulation parameters. Randomization is
performed through a web-based program provided by Faculty of Medicine, unit for Applied
Clinical Research at the Norwegian University of Science and Technology, Trondheim.
iv) Neuropsychological examinations. A standard set of well-known and validated
neuropsychological tests will be performed pre-op and 1-yr post-op.
