Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT03593512 |
| Other study ID # |
13340 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
September 9, 2018 |
| Est. completion date |
August 8, 2022 |
Study information
| Verified date |
May 2022 |
| Source |
University of Oxford |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Patients referred to neurosurgery routinely and safely undergo deep brain stimulation (DBS)
for treatment of symptoms related to neurodegenerative conditions, most commonly Parkinson's
disease.
In the investigators experience, and published evidence shows, that stimulation has effects
on the autonomic nervous system. In patients undergoing therapeutic DBS for a particular
subtype of Parkinsonism, Multiple System Atrophy, the further effects on autonomic parameters
such as blood pressure and bladder symptoms as well as the originally intended indications
(gait and movement disorder) will be investigated. The mechanisms of any effects will also be
studied by using a number of techniques such as magnetoencephalography (MEG) and Muscle
Sympathetic Nerve Activity (MSNA) recording.
Key goals are to:
1. Demonstrate that stimulation of the peduculopontine nucleus (PPN) improves autonomic
function and has an attendant improvement on patients' quality of life
2. Investigate the role of the PPN and how it interacts with other brain areas.
This translational strategy will lead to a larger efficacy study of DBS for MSA as well as
revolutionizing neural-based treatments in other autonomic disorders such as orthostatic
hypotension and pure autonomic failure.
Description:
AIMS OF THE PROJECT AND IMPORTANCE
Multiple system atrophy (MSA) is a form of Parkinsonism and is a neurodegenerative condition
that is characterized by gait and autonomic failure. MSA symptoms are generally poorly
responsive to medicines that treat Parkinson's disease (PD), and so symptom control is
difficult.
The aim is to assess the effects of deep brain stimulation (DBS) of the pedunculopontine
nucleus (PPN) on autonomic and gait symptoms to show that it improves quality of life in
patients with MSA.
Secondary aims are to assess the effects of stimulation on autonomic parameters
(cardiovascular and bladder function) as well as the routine parameters of the movement
disorder (gait, freezing and falls, etc).
In addition, there is a mechanistic component of the study looking at both peripheral
autonomic activity and brain networks associated with stimulation.
BACKGROUND AND WORK LEADING UP TO THE PROJECT
DBS is a routine treatment for movement disorders such as Parkinson's disease and dystonia.
MSA is a 'Parkinsonian' condition similar to PD and is a progressive, incurable,
neurodegenerative condition characterized by a combination of Parkinsonism, ataxia, and
autonomic failure. Autonomic dysfunction is the presenting feature in half of patients that
have Parkinsonism or ataxia predominant MSA.
Whilst DBS is sometimes performed for the treatment of MSA, the primary outcome measure is
usually the motor outcome, despite the fact that the autonomic symptoms may be the
predominant factor in causing a reduced quality of life. This is because DBS is traditionally
used to control motor symptoms and the exploration of its effects on autonomic function are
relatively new, and pioneered by our group. The most common complaints caused by autonomic
dysfunction in MSA are related to orthostatic hypotension and neurogenic bladder, both of
which have been studied by the investigators previously.
Part of the aim of this study is to look at orthostatic BP changes with and without
stimulation and see whether these are improved by DBS. Bladder dysfunction includes
incontinence and incomplete emptying. These will be investigated using urodynamic testing,
with a standard protocol. Other 'autonomic' problems include sleep disorders, exercise
intolerance and problems with thermoregulation and sweating. These will be captured using
questionnaires.
Regarding the target used for DBS, a well-established target to improve gait and postural
abnormalities in PD is the pedunculopontine nucleus (PPN). The investigators have previously
demonstrated that the PPN is also a brain area that, when stimulated, improves bladder
function in these patients. They have also shown (unpublished data) that PPN stimulation
reduces postural fall in BP in a group of PD patients treated primarily for gait and postural
problems. It has also been shown that stimulation of a related brain area can improve
orthostatic hypotension.
Mechanistic Studies
These are important in order to understand how PPN DBS alters autonomic function. Previously,
the investigators have studied the effects of central stimulation of the subthalamic nucleus
and periaqueductal grey area (amongst others) on peripheral sympathetic nerve activity. These
techniques (muscle sympathetic nerve activity (MSNA)) will be applied in the current study to
find out whether PPN DBS alters peripheral sympathetic nervous system activity.
To look at central mechanisms, two techniques will be used. Firstly, diffusion tensor imaging
is routinely obtained as part of surgical planning. The hypothesis is that connections from
PPN to areas that are part of the central autonomic network are important for influencing
autonomic control. By looking at tracts to and from the target area, it will be investigated
whether connections to the rostroventrolateral medulla (RVLM) are important for changes in
MSNA. The RVLM is an important area that receives feedback from the periphery and is in turn
influenced by higher centres.
A second part of the central mechanism study will utilize MEG scanning. The investigators
have previously applied this technique to patients who have undergone DBS. The investigator
are interested in whether PPN DBS alters cortical activity, both in the insula and anterior
cingulate cortices (these are important in autonomic control) and also the motor cortex
(important for motor control).
KEY METHODOLOGIES AND TECHNIQUES
Recruitment
Patients will be identified in a movement disorder clinic by a consultant neurologist. If
they decide to take part, they will attend to proceed with the consent process and baseline
measurements. The pathway for each participant through the study will follow a standardized
pattern that is essentially identical to the pathway that current DBS patients for all
movement disorder indications go through.
Baseline Assessments
1. Questionnaires
1. EQ-5D - quality of life questionnaire
2. UMSARS - Unified MSA rating scale
3. Freezing of Gait (FOG) Questionnaire
4. Autonomic questionnaire
5. Falls diary
2. Neuropsychology assessment. Includes HAD, FLP and MOCA questionnaires and interview.
3. MRI scan with DTI. This is routine for surgical planning.
4. Gait analysis. Patients will be asked to walk along a special gait flooring which will
allow us to obtain specific parameters concerning their gait.
5. Urodynamics and Cardiovascular tests
1. Urodynamics
The 'gold standard' is video urodynamics. This involves urethral catheterisation
and insertion of a rectal probe and measurements of detrusor pressures, bladder
capacity, reflux, sensory urgency and voiding differences such as rate of urinary
flow. Patients who are unwilling to undergo these tests will still fill in voiding
diaries and urinary symptom questionnaires that are part of the questionnaires
listed above.
2. Tilt table tests
Patients will undergo continuous ECG monitoring whilst standing upright and then
whilst tilted into a lying down position using the tilt table. Changes in heart
rate, heart rate variability and blood pressure will be recorded and integrated
using our analysis program.
3. Ambulatory BP
This involves wearing a blood pressure cuff for 24 hours, which will be timed with the other
baseline assessments or, if the participant prefers, this can be done at home.
Subsequent Visits
1. Surgery
This will follow routine clinical practice. Electrodes will be implanted under general
anaesthetic using a standard stereotactic frame. Electrodes will be externalized for a
week of clinical testing. During the week of testing, the priority will be to titrate
the stimulator for clinical effects. Further gait analysis, tilt table tests and
ambulatory BP may be used to inform parameter settings. In addition, we may perform
local field potential recordings (recording electrical activity from the electrodes)
during these tests. This will give information as to how the PPN is responding to
movement and tilt etc. At the end of one week, a second procedure will be performed to
insert the implantable pulse generator (the battery). They will return at 6 weeks for
stimulator titration only (this is part of routine care).
2. 3 month primary outcome follow up
1. Questionnaires (section 1 and 2 in baseline assessments above) will be performed as
at baseline except the full neuropsychology assessment will not be performed (just
the HADS, FLP and MOCA).
2. The following tests will be repeated on and off stimulation; i) Urodynamics ii)
Tilt table tests iii) Gait analysis
3. The participants will attend for a second day and will undergo two further tests ON
and OFF stimulation
i. Magnetoencephalography (MEG) scan. This records cortical signals ON and OFF
stimulation with the aim of demonstrating how PPN suppression or excitation alters
cortical activity, especially in the areas important for autonomic and motor control ii.
MSNA (microneurography). This technique entails insertion of two very fine needles
(30-40microns in diameter) below the knee. The first will record directly from the
common peroneal nerve whilst the second will lie subcutaneously as a reference. This is
an established technique for measuring peripheral sympathetic activity. Neurograms will
be recorded with stimulation ON and then OFF during the same sitting. The aim is to
establish whether any changes in autonomic symptomatology are correlated with changes in
sympathetic nerve activity, thereby providing a mechanism of action.
iii. Sleep EEG studies with varying stimulation ON and OFF in order to investigate the
role of the PPN in sleep stages and EEG waveforms.
