Aim and patient group:
Multiple System Atrophy is a form of Parkinsonism and is a neurodegenerative condition
that is characterized by gait and autonomic failure. The aim of this study is to assess
the effects of aDBS of the Pedunculopontine Nucleus (PPN) on autonomic and gait symptoms
in a group of 5 patients with MSA. Patients will enter our routine selection process but
patients in the study will be selected for predominantly autonomic symptoms as per the
inclusion criteria below. The aim is to test whether or not PPN aDBS improves quality of
life, and has an effect on a variety of measurable autonomic parameters in this subset of
patients. Secondary aims are to assess the safety of DBS in MSA, and to look at the
structural projections and effects on brain networks associated with stimulation.
Background:
Deep Brain Stimulation (DBS) is a routine treatment for movement disorders such as
Parkinson's disease (PD). In Oxford, around 80 DBS operations per year are performed, and
approximately two thirds of these are in patients with PD. Multiple System Atrophy (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. Any one of these three features may predominate, making diagnosis
difficult; however, virtually all patients have autonomic dysfunction. Indeed, autonomic
dysfunction is the presenting feature in half of patients that have Parkinsonism or
ataxia predominant MSA. The motor manifestations such as gait problems, ataxia, and
postural abnormalities are very similar to those encountered by patients with Parkinson's
disease, though unfortunately are usually less responsive to dopamine agonists and so can
be more disabling. Patients tend to progress more quickly, often confined to a wheelchair
within 3-5 years of diagnosis, and death is usually within a decade.
Whilst DBS has sometimes been performed for the treatment of MSA, including in Oxford ,
the primary outcome measure is usually the motor outcome, despite the fact that the
autonomic symptoms are probably 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 the
investigators.
The most common complaints caused by autonomic dysfunction in MSA are related to
orthostatic hypotension and neurogenic bladder. The former causes dizziness, fatigue and,
when a severe fall in BP occurs on standing, can lead to collapse. This may be, at least
in part, a cause for the numerous falls that these patients suffer. 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. This may correlate with a reduction in falls, although
this study is unlikely to be powered to answer this specific question. Other 'autonomic'
problems include bladder dysfunction, 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). It has been demonstrated that
the PPN is also a brain area that, when stimulated, improves bladder function in these
patients. It has also been shown that PPN stimulation reduces postural fall in BP in a
group of PD patients treated primarily for gait and postural problems. Whilst these
studies provide a rationale for looking at similar parameters in MSA patients, this study
aims to answer the question as to whether it will work for these symptoms in MSA, in
addition to the motor symptoms routinely treated.
The investigators have already shown in 5 patients with MSA that these symptoms are
improved with PPN DBS. The difference in this trial is the usage of a new DBS device.
This is a novel device where stimulation parameters can be changed in response to changes
in the patient's position, activity, or physiological parameters.
Usage of adaptive stimulation:
The investigators intend to study the usage of motion-based control of stimulation. In
the current trial, the main aim is to assess the effects of DBS on gait, sleep, and blood
pressure control.
In previous studies, the investigators have noted that while standing, blood pressure is
increased with stimulation, as is lying blood pressure. Supine hypertension may increase
the stroke risk for these patients. Furthermore, the best improvement in gait is seen
with a slightly different stimulation waveform.
In order to correct for this, the investigators propose to introduce motion-based
adaptive stimulation which would involve the use of an accelerometer in changing between
different stimulation parameters depending on the patient's position - so delivering a
different waveform for lying and standing.
Justification/importance:
A trial of DBS to assess the effect on autonomic symptomatology of MSA has never been
performed. We aim to combine a five patient clinical pilot study of DBS for MSA with an
investigation of the neural circuitry underpinning autonomic control.
This translational strategy is likely to 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.