I have often wondered about this.  My disease progression (except for 
difficulty speaking which could be attributed to DBS) seems to have stalled 
after DBSs in 2003.  However, I seem to have gotten worse after my fall on 
my tail bone in April.

Rayilyn Brown
Director AZNPF
Arizona Chapter National Parkinson Foundation
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----- Original Message ----- 
From: "schild.m" <[log in to unmask]>
To: <[log in to unmask]>
Sent: Wednesday, August 06, 2008 5:11 AM
Subject: Is deep brain stimulation neuroprotective if applied early in the 
course of PD?


s deep brain stimulation neuroprotective if applied early in the course of 
PD?
P David Charles*, Chandler E Gill, Thomas L Davis, Peter E Konrad and
Alim-Louis Benabid  About the authors
Correspondence *Department of Neurology, Vanderbilt University Medical 
Center,
A-0118 MCN, Nashville, TN 37232–2551, USA

Email [log in to unmask]
Parkinson's disease (PD) is a progressive and disabling disorder that 
affects
millions worldwide and is characterized by tremor, bradykinesia, rigidity 
and
balance difficulties. Nonmotor features, including cognitive decline,
autonomic disorders and sleep disruption, are present in a considerable
minority of individuals with PD and dramatically increase disability.
Although PD was first described 200 years ago, we have not yet identified 
the
cause or developed a cure or treatment to slow progression. Hundreds of
putative neuroprotective agents have been tested in clinical trials over the
past two decades, but none of these agents has been successful at preventing
the progression of PD. Deep brain stimulation (DBS) of the bilateral
subthalamic nucleus (B-STN) is a safe, effective and cost-effective 
treatment
for the motor symptoms of advanced PD,1, 2 and recent literature has
suggested that DBS may also provide a neuroprotective benefit.3, 4 We 
believe
that DBS will be the first therapy proven to slow PD progression, and that 
it
must be applied in the earliest stages of the disease to have such an 
effect.
Pioneered at the University of Grenoble in the 1980s, B-STN DBS provides
long-term symptomatic benefit and improves quality of life for many patients
with PD.2, 5 However, despite the technique's widespread use, we do not 
fully
understand its mechanism of action—neither the proven symptomatic benefit 
nor
the potential neuroprotective effect. Several theories have been proposed to
explain the neuroprotective properties of DBS. One such theory is based on
the idea that PD develops after initial injury to the substantia nigra,
mainly its pars compacta, causing the substantia nigra to become hypoactive.
Other areas of the basal ganglia, including the STN, become hyperactive as a
result of loss of inhibition. The STN is the main relay of the indirect
pathway of the basal ganglia; it influences motor output through the globus
pallidus internus and substantia nigra. The hyperactive STN may promote
glutamate excitotoxicity, further accelerating dopaminergic cell death in 
the
substantia nigra. It has been proposed that high-frequency B-STN DBS alters
STN activity, resulting in the removal of a source of toxic glutamate input
to the substantia nigra, which in turn leads to the preservation of
dopaminergic cells.
Two recent reports provide evidence in support of this theory. Temel  et al.
found that B-STN DBS protected nigral neurons in the 6-hydroxydopamine rat
model of PD—cell loss in the substantia nigra of DBS-treated animals was 28–
30% lower than that in controls.4 The animals received DBS during ongoing
neurodegeneration, which more accurately represents clinical practice than
previous animal experiments in which lesioning or stimulation was performed
before treatment with 6-hydroxydopamine. Kainic-acid-induced lesion of the
STN also reduces the loss of nigral dopaminergic cells in the
6-hydroxydopamine rat model,6 supporting the hypothesis that DBS at high
frequency has inhibitory effects. Wallace and colleagues made similarly
exciting observations when using the
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of PD in primates.
These authors found that STN stimulation both before and after MPTP injury
prevented further neuronal loss (MPTP-treated animals that received STN
stimulation had 20% more dopaminergic cells in the substantia nigra than
animals that did not receive stimulation).3 In this study,
kainic-acid-induced lesion of the STN also had neuroprotective effects that
were comparable to those of STN DBS.
Clinical results, on the other hand, are conflicting. During the initial
clinical trials that investigated the efficacy of DBS in PD, some patients
seemed to stabilize after implantation of the DBS electrodes (AL Benabid,
unpublished data). A more-recent trial of DBS in patients with advanced PD
confirmed this observation,7 although neuroprotection was not a stated end
point. The authors noted no significant clinical deterioration during 4 
years
of DBS therapy,7 which is clearly different from the expected natural
progression of PD. Many trials, however, have noted clinically and
statistically significant deterioration of motor symptoms after initiation 
of
DBS therapy. For example, off-medication Unified Parkinson Disease Rating
Scale motor scores of the first 49 patients who were treated with DBS 
therapy
in Grenoble deteriorated by 7 points from year 1 to year 5 of the follow-up
period.2 In 2005, Hilker  et al. used serial 18F-fluorodopa PET as a
surrogate marker for disease progression and found that dopaminergic 
function
had continued to decline in patients with advanced PD after 16 months of
clinically effective B-STN DBS therapy.8
Several factors limit the capacity of the clinical results to date to rule 
out
DBS as a neuroprotective therapy. First, continued functional decline does
not eliminate the possibility of positive disease modification—it only
eliminates the possibility that DBS might result in a complete halt in
progression. Furthermore, none of the studies so far has included a control
group that was treated with standard drug therapy, and, thus, progression
rates between the two groups have not been compared.
An additional limitation is that all studies to date have been in patients
with features of advanced PD, including motor complications of therapy. A
majority of nigral neurons have died by the time patients with PD first
present to a neurologist. Currently, patients do not receive DBS therapy
until they have developed intractable symptoms and motor complications of
therapy; electrode implantation both in clinical trials and in standard of
care takes place at an average of 11 years after diagnosis, at which point
considerable cell death has occurred, and potentially neuroprotective
strategies are unlikely to demonstrate a clear benefit. Animal data seem to
be in agreement with this view; in general, studies that report a lack of
neuroprotection with the use of DBS have employed extensive neurological
injuries to model PD (resulting in the death of 75–90% of all nigral cells),
whereas other authors who have induced lesser injuries have found positive
results.3, 9 A nigral cell death rate of 85% is representative of a patient
with advanced disease who receives DBS through current standard of care,
whereas a nigral cell death rate of 50% is representative of a patient in 
the
earliest symptomatic stages. The fact that studies to date have tested the
therapy in patients with advanced disease may partially explain why many of
these trials have failed to document neuroprotection.2, 8
We believe that DBS slows the progression of PD, and we are currently
conducting a pilot clinical trial of B-STN DBS in early-stage PD
(ClinicalTrials.gov identifier NCT00282152), collecting preliminary data
necessary to launch a multicenter phase III trial to definitively test this
hypothesis. When designing our pilot study, we took into account several
lessons from previous DBS and neuroprotection trials. Only patients with
early-stage disease, who hold the greatest potential for disease
modification, will enroll. They must be in Hoehn and Yahr stage II, have 
been
on anti-PD medications for less than 4 years, and cannot have developed 
motor
fluctuations. The trial is designed as a single-blind, randomized,
parallel-group study, with 30 patients randomized to either optimal drug
therapy alone or optimal drug therapy plus B-STN DBS. Patients undergo 8-day
inpatient evaluations at baseline and at 6-month intervals for 2 years.
During each evaluation, medications and stimulation are withdrawn and motor
scales are administered daily. The purpose of this design is to fully
characterize the washout of stimulation plus medication versus the washout 
of
medication alone, and to determine the minimum time necessary for patients 
to
remain off drugs or stimulation to assess underlying disease. The data from
this trial will provide essential information for the design of any phase 
III
trial that will test neuroprotection. If our data support the safety of DBS
in early PD, the current study will be extended into a delayed-start design,
with surgery offered to patients in the drug therapy only arm 3 years after
original randomization.
While our trial addresses many criticisms of recent neuroprotection and DBS
trials, there are considerable hurdles to overcome before any therapy can be
definitively proven to modify human disease progression. Most notable are 
the
lack of an accepted biomarker of PD progression,10 and the difficulty in
separating symptomatic benefit from actual prevention of cell death and from
the maintenance or facilitation of mechanisms that compensate for the loss 
of
dopaminergic neurons. These barriers may take years to overcome. Being able
to prove that a therapy halts or slows progression of clinical symptoms,
however, is a worthwhile and achievable goal.
Our hypothesis is bold and ambitious and, if correct, would enable 
achievement
of a goal held by both physicians and patients. Any treatment for PD that
proves to be neuroprotective will be applied as soon as the diagnosis is
reasonably confirmed. These clinical trials represent the essential steps
toward finally developing a treatment that slows this relentlessly
progressive and disabling illness.

http://www.nature.com/ncpneuro/journal/v4/n8/full/ncpneuro0848.html

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