Clinical Trial Details
— Status: Recruiting
Administrative data
NCT number |
NCT05362448 |
Other study ID # |
274481 |
Secondary ID |
|
Status |
Recruiting |
Phase |
N/A
|
First received |
|
Last updated |
|
Start date |
May 23, 2022 |
Est. completion date |
November 1, 2022 |
Study information
Verified date |
May 2022 |
Source |
University College London Hospitals |
Contact |
Patricia Limousin, MD PhD |
Phone |
02034567890 |
Email |
p.limousin[@]ucl.ac.uk |
Is FDA regulated |
No |
Health authority |
|
Study type |
Interventional
|
Clinical Trial Summary
Essential tremor is a chronic and progressive neurological disease characterized by upper
limb tremor. This is one of the most frequent movement disorders. Most of the time the
disease worsens over the time, affecting patients' work abilities and in the most severe
cases activities of daily living such as eating or dressing. For the most disabled patients,
Deep brain stimulation (DBS) of the thalamic ventral intermediate median nucleus (Vim), a
procedure consisting in an electrode implantation in a structure of the brain involved in
tremor genesis, is the gold standard treatment. While this therapy is most of the time highly
effective in alleviating the tremor, some subjects may exhibit gait impairment or upper limb
coordination troubles years after the surgery, which are thought to be due to the involuntary
stimulation of efferent cerebellar fiber tract. Unfortunately, this DBS induced side effect
cannot be systematically avoided and may limit the possibilities of settings adaptation
required to control the tremor. Surprisingly, while it could be a valuable therapeutic option
for these patients suffering from DBS induced balance troubles, little is known about the
effect of varying the rate of stimulation on the gait disorders associated with essential
tremor and Vim DBS. The aim of or study is consequently to assess the effect of different
frequency of stimulation on tremor, gait and balance disorders as well as on eye movements in
patients uni or bilaterally stimulated in the Vim for a severe and medically intractable
essential tremor. Patients followed at the National Hospital for Neurology and Neurosurgery
(University College London Hospital) will be included. To better characterize the different
symptoms, the investigators will use ataxia and tremor rating scale together with 3D gait
motion analysis, oculography and computerized spiral test analysis. Our findings might lead
to a better understanding of Vim-DBS associated gait disorders in essential tremor.
Description:
Essential tremor (ET) is a chronic, progressive neurological disease characterized by a
symmetrical 4-12 Hz kinetic tremor constantly affecting hands and arms. The tremor can also
involve the neck, the lower limb, the voice, the mouth, the tongue or other body regions. ET
is among the most frequent movement disorders, with an estimated prevalence of 0,9% of the
global population. While the tremor can be mildly disabling at the beginning of the disease,
most patients experience a worsening of their tremor over the time. Eventually, disease
progression can lead to severe disability, impacting patients' working abilities and in the
most severe cases, activity of daily living. Though ET being a frequent debilitating
condition, there are still few therapeutic options for the most disabled patients. Several
surgical procedures have been evaluated in ET including Deep brain Stimulation (DBS) of
Thalamic Ventral intermediate nucleus (Vim) or within the posterior subthalamic area,
surgical thalamotomy, Gamma knife or, more recently, MRI guided focused ultrasound
thalamotomy. While Gamma knife and focused ultrasound thalamotomy may be safer due to the
absence of craniotomy, Vim-DBS remains currently the reference treatment and the most used
procedure for medically refractory ET.
Besides the early side effects of Vim-DBS such as haemorrhagic, ischemic and infectious
complications occurring immediately after the electrodes implantation procedure, late
side-effects such as cerebellar symptoms including gait or upper limb cerebellar ataxia,
paraesthesia, dysarthria, dysphagia, and cognitive difficulties are quite frequent. These
long-term consequences of the stimulation may dramatically impact the quality of life of
patients suffering from ET years after the surgery and mitigate the benefits of this
intervention. Considering gait ataxia, it has been reported that this complication may affect
up to 37% of ET patients following Vim-DBS surgery and seem to occur more frequently in
patient who had pre-operative gait impairment, greater disease severity, older age and when
DBS was performed bilaterally. Upper limb ataxia is also common and characterized by the
occurrence or the paradoxical worsening of an intention tremor together with asynergy,
dyschronometria and dysdiadochokinesia. It has been shown that this latter can be induced by
suprathreshold stimulation.
One of the major assets of Vim-DBS over surgical thalamotomy remain its ability to steadily
adapt the current delivered by the electrodes by changing the stimulation parameters. Using
traditional Implantable Pulse Generator (IPG), it is possible to modify the stimulation mode
(monopolar or bipolar stimulation), amplitude, frequency and pulse width as well as to modify
the contacts of the electrodes delivering the current. However, despite DBS being a treatment
largely available worldwide as well as being part of the routine care for medically
refractory tremor, only few studies have assessed the effects of varying DBS settings on
cerebellar symptoms presented by patients suffering from ET and stimulated within the Vim. It
has been reported that tremor responds best to amplitude, which is usually increased until a
complete resolution of the tremor is obtained. Increasing the stimulation pulse width
produces a similar clinical effect and may help to alleviate tremor. Interestingly, it has
recently been shown that decreasing the pulse width may improve the gait disorders, widen the
therapeutic window and diminishes DBS induced side effects. This clinical finding is
supported by the recent dissection of the neuronal network underlying Vim DBS clinical
response which suggest that tremor suppression could be due to dentato-rubro-thalamic tract
stimulation while gait and limb ataxia could be promoted by the stimulation of the
cerebello-rubro-spinal and the rubro-olivo-cerebellar tract meaning the possibility of
correcting these side effects by accurately optimizing the DBS parameters.
Among the clinical effect of the different types of parameters, the stimulation frequency has
certainly been the less extensively studied in ET. This is at first sight quite surprising
given that decreasing the frequency of stimulation of the Subthalamic nucleus (STN) is a
valuable therapeutic option in Parkinson's disease especially for patient presenting with
dopa-refractory symptoms such as freezing of gait or speech impairment. Lower frequency
stimulation has also shown to be beneficial for some patients suffering from dystonia, and it
has been suggested that this sustained clinical improvement was obtained by avoiding the
stimulation of the structure responsible of side effects.
In comparison, a very low number of studies has focused on the consequences of lower
frequency stimulation on tremor. Noteworthy is the fact that most of them have pointed that
the tremor suppression was better achieved for a frequency around 100 Hz, with little
evidence for a small additional therapeutic effect for frequencies above 130 Hz. Conversely,
frequency of 50 Hz or lower seems to not suppress tremor and could even worsen it or induce
myoclonic jerks. Based on these clinical findings, it is currently admitted initiating the
stimulation with a frequency of 130 Hz and increasing it up to 180 Hz if the therapeutic
effect on tremor remains unsatisfying despite concomitant high amplitude and large pulse
width. A recent small case series has interestingly shown that some patients presenting with
balance disorder years after Vim DBS surgery were having their trouble improved when the
stimulation frequency was decreased to 130 Hz. Additionally, there are some evidence that,
similarly to short pulse width stimulation, decreasing the frequency up to 100 Hz may help to
optimize postural or intention tremor and DBS side effects control by widening the
therapeutic window. Taken together, these findings suggest that, similarly to shorter pulse
width, a lower frequency of stimulation could be an interesting therapeutic approach for ET
patients suffering from balance disorders or upper limb ataxia promoted by Vim-DBS. However,
since all the above-mentioned studies were unblinded and non-randomized, the level of
evidence supporting such a strategy remain weak. Additionally, none of these works has aimed
at evaluating the effect of decreasing DBS frequency on gait and balance, neither by using
clinical testing, nor by using quantitative measurement such as 3D motion analysis or
computerized posture assessment.
For these reasons, the aim of the present study will be to study the effect of varying
Vim-DBS frequency on cerebellar features including gait and upper limb ataxia in ET by using
non-invasive quantitative physiological tools, namely computerized spiral test analysis, 3D
infrared gait motion analysis, balance measure against force perturbation analysis and
oculography.
Patients presenting an ET treated by Vim-DBS stimulation for more than 3 months, followed at
the National Hospital of Neurology and Neurosurgery, University College London Hospital,
London, United Kingdom will be included.
Regarding the procedure, the investigators will first assess the therapeutic window by
estimating the therapeutic and side effect thresholds for three different frequencies (80
Hz-130 Hz-180 Hz). Additionally, the investigators will subsequently analyse balance and gait
using a 3D motion analysis system, the tremor using a tablet coupled to a computerized spiral
analysis software and eye movements using oculography for the three different settings and
with the DBS turned off.
Eventually, the investigators will localize the position of the electrodes and model Volume
of Tissue Activated using the DBS planning software Guide-XT® and the pre and postoperative
brain MRI.