December 20, 2017 - Deep-brain
stimulation of a novel brain region can be safely performed in
patients with Parkinson's disease dementia, and although it may not
improve cognition, it does appear to have benefits on other
Parkinson's symptoms, a new study suggests.
"This was a
proof-of-concept study. We have demonstrated that it is possible to
use deep-brain stimulation safely in patients with Parkinson's
disease dementia by targeting different areas of the brain,"
senior author, Thomas Foltynie, MD, the National Hospital for
Neurology and Neurosurgery, London, United Kingdom, told Medscape
Medical News.
"We didn't see
an improvement in cognition as hoped for, but we did show benefits on
movement symptoms and on hallucinations. These results open up the
possibility of using deep-brain stimulation in this population for
whom it has so far not been recommended."
The study was
published in JAMA Neurology on December 18.
Dr Foltynie
explained that deep-brain stimulation treatment in Parkinson's is
known to help with the movement issues characteristic of the disease,
but stimulation of the usual target — the subthalamic nucleus —
also carries a risk of upsetting other brain functions, including
cognition, so it is not performed in patients with Parkinson's
dementia.
For the current
study, the researchers targeted a different part of the brain: the
nucleus basalis of Meynert. "Animal studies have suggested that
stimulation of this area leads to an increase in acetylcholine
throughout critical regions of the brain and improves memory, and
there has been a case report in which brain stimulation of the
nucleus basalis of Meynert showed a striking increase in cognitive
performance in a dementia patient," Dr Foltynie said. "This
part of the brain represents a novel target, and we wanted to pursue
this further."
The nucleus basalis
of Meynert is just below another region of the brain, the globus
pallidus, which has also been used as a target for deep-brain
stimulation. "Stimulation of the globus pallidus is also
associated with benefits on movement in Parkinson's and is more
forgiving in terms of cognitive issues, so in our study we placed the
stimulation electrodes so that they went through both the globus
pallidus and the nucleus basalis of Meynert, with contacts in both
sites. These were activated separately so we could discern which
region was associated with any effects seen," Dr Foltynie noted.
"Our hypothesis
was that by selecting new regions as targets for deep-brain
stimulation we may be able help patients with Parkinson dementia with
both movement and cognition symptoms."
The randomized,
double-blind, crossover clinical trial involved six patients (average
age, 65 years) with Parkinson's disease dementia who underwent
surgery for electrode implantation and were assigned to receive
either low-frequency (20-Hz) active stimulation to the nucleus
basalis of Meynert or sham stimulation for 6 weeks, followed by the
opposite treatment for 6 weeks.
Results showed that
surgery and stimulation were well tolerated by all six patients, with
no serious adverse events during the trial. No consistent
improvements were observed in the primary cognitive outcomes or in
results of resting state functional MRI.
However, scores on
the Neuropsychiatric Inventory improved by 5 points with the
stimulation. This improvement was driven primarily by a reduction in
hallucinations subscale scores in two patients.
In the paper, the
researchers report that the two patients with hallucinations both
experienced "near-complete cessation of visual hallucinations
after surgery when nucleus basalis of Meynert stimulation was turned
on, followed by a resurgence of hallucinations when stimulation was
subsequently turned off."
Dr Foltynie
elaborated: "Two patients with quite troublesome hallucinations
showed a dramatic improvement. This was an unexpected benefit.
However, this was a secondary outcome, and we have to be cautious
about overinterpreting these observations. But I would say it is
something to be investigated in future studies."
Three patients
showed improvement in levodopa-induced dyskinesias during
on-stimulation.
The researchers
suggest this may be explained by spread of current from the nucleus
basalis of Meynert to the overlying globus pallidus. They add that
conventional deep-brain stimulation of the globus pallidus for
dyskinesia control in Parkinson disease is delivered at high
frequency, "so the finding that low-frequency stimulation
directed toward the nucleus basalis of Meynert also attenuated
dyskinesias warrants further study."
Dr Foltynie noted
that two patients went on to receive long-term stimulation of the
globus pallidus and showed clear movement benefits.
He explained that
deep-brain stimulation works best for the Parkinson's symptoms of
slowness, stiffness, and tremor but does not have much impact on
balance and freezing. It is appropriate for only a small percentage
of patients with Parkinson's disease — probably less than 10%.
"There is a
window of opportunity — we don't use it in early disease as
symptoms can be well controlled with medication and we wouldn't want
to expose these patients to the risk of surgery. But when patients
start to become refractory to dopamine therapies, deep-brain
stimulation can still show a benefit. Although when patients
deteriorate further then it too will become ineffective."
He noted that it is
easier to place the electrodes correctly in the younger brain, where
there hasn't been too much shrinkage. "The best candidates are
patients with early-onset Parkinson's disease — those in their 50s
or 60s — who could have benefit for up to 10 years. While not many
of these younger patients will have Parkinson's dementia, there will
be some who do and our study opens up this therapy to them. "
He cautioned,
however, that such treatment should still be viewed as experimental
and should be performed only at one of the specialist centers with
particular expertise in deep-brain stimulation.
What Now for
Deep-Brain Stimulation in Dementia?
Dr Foltynie said the
future for deep-brain stimulation in dementia is uncertain. "A
Canadian group is looking at targeting stimulation to the fornix area
of the brain in Alzheimer's, but their results have not been
encouraging either. Other research has suggested that while
high-frequency stimulation in the subthalamic nucleus makes dementia
worse, using low-frequency stimulation may show some benefit, and
further research on this approach is ongoing," he reported.
In an accompanying
editorial, Wissam Deeb, MD, Michael S. Okun, MD, and Leonardo
Almeida, MD, Center for Movement Disorders and Neurorestoration,
University of Florida, Gainesville, state: "Although the primary
outcome of this study was not met, these results challenge the
consensus in the field that DBS [deep-brain stimulation] is
contraindicated in PDD [Parkinson's disease dementia]."
They add: "The
authors provide evidence for the safety and the tolerability of
nucleus basalis of NBM [Meynert] DBS, albeit in a small number of
patients. There will need to be more work to refine the target and
trajectory, as well as programming strategies (duty cycle, frequency,
and pulse shapes). The findings from the current study will require
replication in larger cohorts. Finally, this and future DBS studies
in Parkinson's disease dementia could provide insights into the
cholinergic network underpinning cognitive dysfunction."
This study was
funded by a grant from the Brain Research Trust and was sponsored by
University College London. Dr Foltynie reports receiving honoraria
from Medtronic, St Jude Medical, Profile Pharma, Bial, AbbVie
Pharmaceuticals, UCB Pharmaceuticals, and Oxford Biomedica.
JAMA Neurol.
Published December 18, 2017. Full text, Editorial. Fonte: MedScape.
