Effect of Deep Brain Stimulation on Parkinson's Nonmotor Symptoms following Unilateral DBS: A Pilot Study.

Abstract

Parkinson's disease (PD) management has traditionally focused largely on motor symptoms. Deep brain stimulation (DBS) of the subthalamic nucleus (STN) and globus pallidus internus (GPi) are effective treatments for motor symptoms. Nonmotor symptoms (NMSs) may also profoundly affect the quality of life. The purpose of this pilot study was to evaluate NMS changes pre- and post-DBS utilizing two recently developed questionnaires. Methods. NMS-Q (questionnaire) and NMS-S (scale) were administered to PD patients before/after unilateral DBS (STN/GPi targets). Results. Ten PD patients (9 STN implants, 1 GPi implant) were included. The three most frequent NMS symptoms identified utilizing NMS-Q in pre-surgical patients were gastrointestinal (100%), sleep (100%), and urinary (90%). NMS sleep subscore significantly decreased (-1.6 points ± 1.8, P = 0.03). The three most frequent NMS symptoms identified in pre-surgical patients using NMS-S were gastrointestinal (90%), mood (80%), and cardiovascular (80%). The largest mean decrease of NMS scores was seen in miscellaneous symptoms (pain, anosmia, weight change, and sweating) (-7 points ± 8.7), and cardiovascular/falls (-1.9, P = 0.02). Conclusion. Non-motor symptoms improved on two separate questionnaires following unilateral DBS for PD. Future studies are needed to confirm these findings and determine their clinical significance as well as to examine the strengths/weaknesses of each questionnaire/scale.

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SAGE-Hindawi Access to Research
Parkinson’s Disease
Volume 2011, Article ID 507416, 4 pages
doi:10.4061/2011/507416
Clinical Study
Effectof DeepBrain StimulationonParkinson’s Nonmotor
SymptomsfollowingUnilateralDBS: APilot Study
Nelson Hwynn,1,2IhtshamUl Haq,1,3IreneA. Malaty,1AndrewS.Resnick,1
Yunfeng Dai,4KellyD.Foote,1HubertH.Fernandez,1,5SamuelS.Wu,4Genko Oyama,1
Charles E.Jacobson IV,1SungK. Kim,1andMichael S.Okun1
1Center for Movement Disorders & Neurorestoration, College of Medicine, University of Florida, Gainesville, FL 32610, USA
2Division of Neurology, Scripps Clinic Torrey Pines, La Jolla, CA 92037, USA
3Department of Neurology, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA
4Department of Biostatistics, University of Florida, Gainesville, FL 32610, USA
5Center for Neurological Restoration, Cleveland Clinic, Cleveland, OH, USA
Correspondence should be addressed to Michael S. Okun, okun@neurology.ufl.edu
Received 23 June 2011; Accepted 30 September 2011
Academic Editor: Fabrizio Stocchi
Copyright © 2011 Nelson Hwynn et al.ThisisanopenaccessarticledistributedundertheCreativeCommonsAttributionLicense,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Parkinson’s disease (PD) management has traditionally focused largely on motor symptoms. Deep brain stimulation (DBS) of the
subthalamicnucleus(STN)andglobuspallidusinternus(GPi)areeffectivetreatmentsformotorsymptoms.Nonmotorsymptoms
(NMSs) may also profoundly affect the quality of life. The purpose of this pilot study was to evaluate NMS changes pre- and post-
DBS utilizing two recently developed questionnaires. Methods. NMS-Q (questionnaire) and NMS-S (scale) were administered
to PD patients before/after unilateral DBS (STN/GPi targets). Results. Ten PD patients (9 STN implants, 1 GPi implant) were
included. The three most frequent NMS symptoms identified utilizing NMS-Q in pre-surgical patients were gastrointestinal
(100%), sleep (100%), and urinary (90%). NMS sleep subscore significantly decreased (−1.6 points ± 1.8, P = 0.03). The three
most frequent NMS symptoms identified in pre-surgical patients using NMS-S were gastrointestinal (90%), mood (80%), and
cardiovascular (80%). The largest mean decrease of NMS scores was seen in miscellaneous symptoms (pain, anosmia, weight
change, and sweating) (−7 points ± 8.7), and cardiovascular/falls (−1.9, P = 0.02). Conclusion. Non-motor symptoms improved
ontwoseparatequestionnairesfollowingunilateralDBSforPD.Futurestudiesareneededtoconfirmthesefindingsanddetermine
their clinical significance as well as to examine the strengths/weaknesses of each questionnaire/scale.
1.Introduction
The traditional approach to Parkinson’s disease (PD) pa-
tients has focused heavily on addressing motor symptoms
and on-off fluctuations. Deep brain stimulation (DBS) of
the subthalamic nucleus (STN) and globus pallidus interna
(GPi) are potentially effective treatments for these motor
types of symptoms. Nonmotor symptoms (NMSs), however,
are also common and debilitating and have been reported
in up to 28% of PD cases. NMS have also been reported
by some investigators as being more debilitating than motor
symptoms [1]. Two scales that have recently been used
to quantify nonmotor symptoms include the nonmotor
Symptoms Questionnaire (NMS-Q) and the Non-motor
Symptom Scale (NMS-S). Both scales were recently validated
by Chaudhuri and colleagues [2–4]. The purpose of this
pilot study was to evaluate NMS pre- and postoperatively
in unilateral PD cases utilizing these scales to determine
changes in overall NMS and to potentially guide a future
study.
2.Methods
Consecutive PD patients undergoing initial unilateral DBS
implantation at the University of Florida were screened. All
subjects were between the ages of 18 to 85, had the diagnosis
of idiopathic PD confirmed by a movement disorders
specialist (utilizing UK Brain Bank criteria), and had a docu-
mented 30% or better improvement in motor performance

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2 Parkinson’s Disease
following levodopa administration (as measured by the
Unified Parkinson’s Disease Rating Scale Part III). Subjects
were excluded from DBS implantation and consequently
from this study if they had significant and active psychiatric
disease as determined by a semistructured clinical interview
(SCID) or if neuropsychological testing revealed moderate
to severe cognitive impairment (DRS score of <130) or
dementia based on a neuropsychological profile indicating
declines in multiple cognitive domains). The NMS-Q and
NMS-S scales were used to follow nonmotor symptoms pre-
and post-DBS. The NMS-Q was based on patient response
with “yes” and “no” questions. The NMS-S was a clinician-
based assessment questionnaire that both documents the
presence of the non-motor symptoms as well as their
frequency and duration.
Utilizing the NMS-Q form, the subsets were divided (in
an attempt to derive comparisons to the NMS-S) as follows:
questions 1, 3, 4–7 were grouped under the gastrointestinal
symptoms subset, questions 8-9 were grouped under the
urinary symptoms subset, questions 2, 10-11 and 27-28
were grouped under the miscellaneous symptoms subset,
questions 12-13 and 15 were grouped under the cognition
symptoms subset, questions 16-17 were grouped under
the mood symptoms subset, questions 18-19 were grouped
under the sexual dysfunction symptoms subset, questions 20-
21 were grouped under the cardiovascular/falls symptoms
subset, questions 22–26 were grouped under the sleep
symptoms subset, and questions 14, 29-30 were grouped
under perceptual symptoms subset. A patient was counted as
having the symptom if (s)he has a positive answer in at least
one of the questions in the corresponding subset.
Utilizing the NMS-S form, the subsets were divided
as follows: questions 1-2 were grouped under the cardio-
vascular/falls symptom subset; questions 3–7 were grouped
under the sleep/fatigue symptoms subset; questions 8–14
were grouped under the mood symptoms subset; questions
15–17 were grouped under the perceptual symptoms subset;
questions18–20weregroupedunderthecognitionsymptoms
subset; questions 21–23 were grouped under the gastroin-
testinal symptoms subset; questions 24–26 were grouped
under the urinary symptoms subset; questions 27-28 were
grouped under the sexual dysfunction symptoms subset;
questions 29–32 were grouped under the miscellaneous
symptoms subset.
The primary analysis included the changes observed at
baseline versus 6 months on the total NMS-Q and NMS-
S scales. As secondary outcomes we examined subscores;
however, sample sizes limited the overall interpretation.
3.Results
Ten PD patients (9 STN implants, 1 GPi implant) were
included in this pilot study. All patients were screened and
consented for research participation in the Movement Disor-
dersCenterdatabase(INFORM-PD).Themeanagewas66.1
years ±7.8, and the mean disease duration was 9.9 years ±3.
The average time from preoperative to postoperative testing
was 12.1 months ±7.3 (range 1–25 months). The average
change of UPDRS motor score was −6.4 points ±13.1.
The primary analysis for the NMS-Q revealed that the
total score for NMS symptoms (total possible score 30
points) improved by an average of −3.7 points ±4.3 (P =
0.03) (Table 1). Secondary analyses of the sample were then
performed. The three most prevalent NMS symptoms iden-
tified in pre-surgical patients were gastrointestinal (100%),
sleep(100%),andurinarysymptoms(90%).Postoperatively,
the three most prevalent NMS symptoms were sleep (90%),
urinary (90%), and cognition (60%) subsets. The largest
mean decrease of NMS scores were sleep (−1.6 points ±1.8,
P = 0.03), gastrointestinal (−0.8 points ±1.1, P = 0.09),
and cardiovascular/falls (−0.5 ± 1.0, P = 0.23) subsets. Only
the sleep subscore in this small sample size reached statistical
significance. Some other NMS categories also improved
(but did not reach statistical significance) postoperatively
including sexual dysfunction (−0.22 points ±0.83), mood
(−0.2 points ±0.8), and miscellaneous (unexplained pain,
excessive sweating, leg swelling) items (−0.5 points ±1.8).
Miscellaneous symptom scores increased (50% to 60%),
while urinary scores were unchanged (90%).
Using the NMS-S (total possible score 384 points), the
primary analysis revealed that the NMS scores improved
by an average of −38.5 points ±30.9 (P
secondary analysis then revealed that three most prevalent
NMS symptoms identified in pre-surgical patients were
gastrointestinal (90%), mood (80%), and cardiovascular
(80%) symptoms. Postoperatively, the most prevalent NMS
symptoms were urinary (80%), mood (70%), sexual (60%),
and gastrointestinal (60%) symptoms. The largest mean
decrease of NMS scores was in the categories of mood (−9.3
points ±13.8), sleep (−9 points ±13.3), and miscellaneous
(−7 points ±8.7). Only miscellaneous symptoms (pain,
anosmia, weight change, and sweating) (−7 points ±8.7),
and cardiovascular/falls (−1.9, P = 0.02) reached statistical
significance (Tables 1 and 2).
Reports of sexual symptoms increased slightly from
55.6% preoperatively to 60% postoperatively.
= 0.01). A
4.Discussion
Both scales we administered revealed an improvement in
non-motor symptoms following unilateral DBS, although
the sample size limited our understanding of specific symp-
toms that may change. Sleep was, however, one feature that
emerged as potentially important. Sleep impairment has
been reported recently by several prepost-DBS studies, and
this may be supported by our data [5]. Changes revealed in
cardiovascular status, autonomic features, or falling may also
be reported by some patients undergoing DBS; however, the
small sample size of this study make interpretation difficult.
Nonmotor symptoms are common in PD patients and
can be important in determining overall quality of life
[6]. The effects of DBS on NMS symptoms in advanced
PD cohorts have not been entirely clarified [7]. In a
study by Witjas and colleagues, 40 PD patients implanted
with bilateral STN DBS experienced significant benefits
with sensory/painful fluctuations, dysautonomia (excessive
sweating), and cognitive fluctuations [8]. In another study

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Parkinson’s Disease3
Table1:Changesinnonmotorsymptom(NMS)scorefromquestionnaire.Theleft-sidedgroupshowspercentofsubjectswhohadapositive
answer in at least one of the questions in the corresponding subset. The right-sided group shows changes in NMS score as represented by
the difference in total score. Improvements of NMS scores prepost-deep brain stimulation surgery were significant. Also, sleep improved
prepost-DBS (P = 0.03).
Frequency of NMS reported
(% present)
Pre-DBS Post-DBS
P Value∗
NMS-Q——
Gastrointestinal 100.0%50.0%
Urinary 90.0% 90.0%
Miscellaneous50.0%60.0%
Perceptual 30.0%30.0%
Attention/memory70.0% 60.0%
Mood60.0%50.0%
Sexual55.6%50.0%
Cardiovascular/falls80.0%50.0%
Sleep100.0%90.0%
∗: P-values based on McNemar’s test.
∗∗: P-values based on Wilcoxon signed rank sum test.
NMS
NMS Total point
difference
SD
4.27
1.14
0.67
1.84
0.63
0.62
0.79
0.83
0.97
1.84
Mean
−3.70
−0.80
0.00
−0.50
0.20
−0.10
−0.20
−0.22
−0.50
−1.60
P Value∗∗
0.03
0.09
1.00
0.45
0.63
0.81
0.75
0.75
0.23
0.03
—
NA
1.00
0.66
1.00
0.56
0.56
1.00
0.18
NA
Table 2: Changes in nonmotor symptoms (NMS) scale. The left-sided group shows prepost-DBS change in prevalence of NMS symptoms.
The right-sided group shows changes in NMS score as a difference in total score. Improvements of NMS scores pre-post deep brain
stimulationsurgeryweresignificant(P = 0.01).Meanscoresinmiscellaneoussymptoms(P = 0.03)aswellascardiovascular/falls(P = 0.02)
symptoms had significant improvement. Prevalence of CV/falls was also significantly different between pre- and post-DBS.
NMS
Frequency of NMS reported
(% present)
Post-DBS
—
60.0%
80.0%
40.0%
20.0%
60.0%
70.0%
60.0%
30.0%
100.0%
NMS total point
difference
SD
30.94
7.33
6.11
8.69
1.25
8.20
13.78
7.29
2.08
13.28
Pre-DBS
—
90.0%
70.0%
70.0%
20.0%
70.0%
80.0%
55.6%
80.0%
100.0%
P value∗
—
0.18
0.56
0.08
1.00
0.56
0.56
1.00
0.03
NA
Mean
−38.50
−0.30
−3.30
−7.00
0.00
−3.50
−9.30
−4.78
−1.90
−8.95
P value∗∗
0.01
0.93
0.14
0.03
1.00
0.30
0.09
0.13
0.02
0.13
NMS-S
Gastrointestinal
Urinary
Miscellaneous
Perceptual
Attention/memory
Mood/cognition
Sexual
Cardiovascular/falls
Sleep/fatigue
∗: P-values based on McNemar’s test.
∗∗: P-values based on Wilcoxon signed rank sum test.
by Zibetti and colleagues, sleep and constipation were the
only symptoms that improved following bilateral STN DBS
surgery in 36PD patients [9]. Our pilot data, although
derived from a small number of patients, utilized two
recently validated NMS questionnaires and did point to
improvements in NMS and particularly improvements in
sleep.
Within our cohort, sleep, gastrointestinal, and cardio-
vascular/falls improved the most when using the NMS-Q
while mood, sleep, and miscellaneous symptoms improved
when employing the NMS-S. A possible explanation for the
differences in the two scales may have been the number
of symptoms attributed to each subscore. In the NMS-Q
there were 2 questions that comprised the mood subset,
while in the NMS-S, there were 7. In another example, the
NMS-Qgastrointestinalsubsetwascomposedof9questions,
while, in the NMS-S scale, it was only 3. Finally, mood
symptomsweremorecommonlyreportedintheNMS-S,but
not in the NMS-Q. Devoting more questions to a particular
symptom could increase the sensitivity of any scale for a
particular area, and this may have biased our dataset. While
the changes in overall score were close between the two scales
(∼10% improvement), one might hypothesize for future
investigations that greater information may be derived from
the NMS-S (when compared to the NMS-Q) as it queries
both frequency and severity of symptoms.
The major limitation of this pilot study was the sample
size. Our analysis yielded results which reached significance

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4 Parkinson’s Disease
when employing the total scores of the scales (NMS-Q, P =
0.03; NMS-S, P = 0.01) but yielded less significant and
impressive results when parceling subitems. Further, it is not
clearwhatdegreeofchangeintheseNMSquestionnaireswill
prove clinically significant. We emphasize that there was a
small sample size used in this pilot study, therefore, results
should be considered preliminary and speculative. Future
studies should focus on both STN and GPi (our sample
was small for GPi) and should include both unilateral and
bilateral cases preferably with a larger sample size and longer
clinical followup. Based on the preliminary data, there is
reason to believe that NMS have the potential to change pre-
and post-unilateral DBS, and better understanding NMS
will help us to achieve greater benefits and more realistic
expectations from our DBS patients.
Conflict of Interests
Dr. Hwynn has received honoraria from Medtronic for
educational activities. Dr. Haq reports nothing to disclose.
Dr. Malaty has received grant support from the National
Parkinson Foundation. Mr. Resnick reports nothing to
disclose. Mr. Dai reports nothing to disclose. Dr. Foote’s
institution has received Medtronic fellowship training and
research grants and has participated in CME activities
on movement disorders sponsored by the University of
South Florida CME office. Dr. Fernandez received personal
compensation for being a Medical Editor of the Movement
Disorders Society Website and financial support for research
activities from the National Institute of Neurological Dis-
orders and Stroke, Michael J Fox Foundation, the National
Parkinson Foundation, the Movement Disorders Society,
the Huntington Study Group, Acadia, AstraZeneca, Solvay
Pharmaceuticals, and Teva Pharmaceuticals. Dr. Wu received
personal compensation from Bioness Inc. for consulting
services from Journal of Physical Therapy for serving as
a statistical reviewer. Dr. Oyama reports nothing to dis-
close. Mr. Jacobson reports nothing to disclose. Mr. Kim
reports nothing to disclose. Dr. Okun serves as a consultant
for the National Parkinson Foundation and has received
research grants from National Insitute of Health, National
Parkinson Foundation, the Michael J. Fox Foundation, the
Parkinson Alliance, the Medtronic fellowship training grants
(to the institution), and the UF Foundation. Dr. Okun has
not received industry sponsored honoraria in the past 24
months. Dr. Okun has received royalties for publications
with Demos, Manson, and Cambridge (movement disorders
books). Dr. Okun has participated in CME activities on
movement disorders sponsored by the University of South
Florida CME office purview, and Vanderbilt University.
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