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Thalamic Deep Brain Stimulation
Comparison Between Unilateral and Bilateral Placement
William Ondo, MD;
Michael Almaguer, RN;
Joseph Jankovic, MD;
Richard K. Simpson, MD, PhD
Arch Neurol. 2001;58:218-222.
ABSTRACT
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Background Unilateral thalamic deep brain stimulation (DBS) is accepted as an effective
treatment for essential tremor (ET) and the tremor of Parkinson disease (PD).
There are, however, relatively little data concerning bilateral thalamic DBS
and no thorough comparisons between the 2 methods.
Methods To assess the relative benefit of a staged second contralateral DBS
placement in patients with PD and ET, we compared preoperative baseline assessments
with those at 3 months after the initial implantation, and again at 3 months
after the second contralateral implantation. The assessments included the
Unified Parkinson's Disease Rating Scale for patients with PD (n = 8) and
a modified Unified Tremor Rating Assessment for patients with ET (n = 13).
The design included open and blinded (unknown activation status) assessments.
Results Overall, after the second implantation, all specific measures assessing
tremor contralateral to that side improved in patients with PD and ET, generally
without sacrificing those contralateral to the first side implantation. Midline
tremors (face and head) improved only after the second side implantation.
In patients with ET, functional and subjective scores tended to further improve
after the second placement; however, patients with PD had less subjective
improvement. Hand tremor scores in patients with ET randomized to "on" stimulation
improved from 6.7 ± 0.9 to 1.3 ± 1.2 (P<.005).
The scores of patients with PD randomized to on stimulation improved from
9.3 ± 1.0 to 1.0 ± 0.5. (Data are given as mean ± SD.)
Tremor scores did not change from baseline in those patients randomized to
"off" stimulation in either group. Adverse events related to stimulation increased
after the second implantation in both groups.
Conclusions Bilateral thalamic DBS is more effective than unilateral DBS at controlling
bilateral appendicular and midline tremors of ET and PD. Despite this, overall
functional disability only improved in patients with ET, possibly secondary
to more problematic adverse events in patients with PD, especially balance
problems. Bilateral DBS should be considered when unilateral DBS does not
offer satisfactory benefit, especially in patients with ET.
INTRODUCTION
ESSENTIAL TREMOR (ET) and Parkinson disease (PD) can produce high-amplitude,
disabling tremors that can clinically and pathophysiologically overlap.1, 2, 3, 4, 5, 6, 7
In most cases, the tremor is bilateral, although one side may predominate.
Through mechanisms that are not yet well understood, high-frequency
thalamic deep brain stimulation (DBS) improves tremor contralateral to the
site of implantation.8, 9, 10, 11, 12
Results from these studies have demonstrated remarkably uniform tremor improvement
of about 75% in those who undergo unilateral thalamic DBS. Although less frequently
reported, bilateral thalamic DBS appears to safely improve bilateral tremors.13, 14, 15, 16 There
are, however, little data directly comparing the relative effects of unilateral
with bilateral thalamic DBS. We report our results in 21 patients who underwent
staged bilateral DBS to compare the efficacy and adverse events (AEs) 3 months
after the first DBS placement with those 3 months after the second DBS placement.
PATIENTS AND METHODS
Thirteen patients with ET and 8 with tremor-dominant PD recruited from
the Baylor College of Medicine Parkinson's Disease Center and Movement Disorders
Clinic, Houston, Tex, completed the entire protocol. Two other patients with
ET underwent their second implantation without an adequate first side evaluation
and were not included. The diagnosis of ET was based on that proposed by the
Tremor Investigational Group.17 The diagnosis
of PD required the presence of 2 of 3 cardinal manifestations (tremor, rigidity,
and bradykinesia). All patients with PD reported at least transient improvement
with levodopa, and all were taking some PD medications at the time of surgery.
Exclusion criteria included significant dementia (Mini-Mental State Examination
score <24), a history of brain surgery, significant comorbid disease that
resulted in unacceptable surgical risk, and age older than 80 years. Tremor
medications for patients with ET were discontinued 1 month before the study.
Patients with PD continued to take medications, but no medication changes
were allowed from 1 month before enrollment or during the study.
All preoperative baseline evaluations were performed within 3 days of
surgery, and all second side (bilateral) evaluations were performed 3 months
after the second implantation. The first side "3-month" evaluations were performed
at 3 months after the first surgery (14 patients), at 2 to 2 months
after the first surgery (6 patients), and at 6 months after the first surgery
(1 patient). The 6 patients who underwent the first side evaluation before
3 months did so at their request to expedite second side placement. The single
patient with a 6-month evaluation missed the scheduled 3-month visit. The
actual duration between first and second side implantations ranged from 72
to 1059 days (median, 139 days).
Adjustments of the stimulator device settings for optimal tremor control,
with minimal AEs, were performed at both postoperative visits, and at other
times as necessary. Adjustable device settings included voltage (1-8 V), pulse
frequency (90-400 Hz), pulse width (100-450 µs), and the electrode montage
(4 electrodes, 1.5 mm apart from each other).
Patients were assessed according to the North America Multi-Center Deep
Brain Stimulation Trial protocol.8 All assessments
were performed by a single investigator (W.O.) who was familiar with the study
protocol. The ET evaluation included subjective questions based on the Unified
Tremor Rating Assessment,17 clinical assessments
of arm, leg, voice, head, face, and tongue tremors (0-4 scale based on amplitude
of tremor). For example, for arm tremor, 0 indicates no tremor; 1, slight
tremor, <1 cm; 2, moderate tremor, 1 to 2 cm; 3, marked tremor, 2 to 6
cm; and 4, severe tremor, >6 cm. Subjects also drew a series of spirograms,
straight lines, and cursive writing samples and performed a water pouring
test (0-4 scale) on both sides. Patients with PD were evaluated with the Unified
Parkinson's Disease Rating Scale (UPDRS), which included a 0 to 4 rating of
rest, posture, and kinetic tremors in the arms and legs. Overall subjective
assessments (much worse to much better) and the Mini-Mental State Examination
were scored in patients with ET and PD. Adverse events included all symptoms
that the patient believed occurred immediately after surgery or only occurred
while the device was activated.
At the 3-month second side evaluation, all patients also underwent a
"blinded" motor evaluation identical to that used in the North America Trial
except that both stimulators were randomized (random number generator) to
either "on" or "off" at the device settings from the previous visit, without
the rater being aware of the activation status. The blinded examination included
the UPDRS part 3, with posture and kinetic tremor ratings for both arms and
legs in patients with PD and tremor ratings of arms, legs, voice, head, face,
and tongue in patients with ET. After stimulator adjustments, patients underwent
the complete open-label assessments. We herein describe only the 3-month second
side blinded data, as the first side blinded data were previously reported.12 The surgical methods for device placement are also
identical to those previously reported.12
Statistical evaluation consisted of Wilcoxon signed rank tests to compare
preoperative with postoperative blinded and unblinded results, and postoperative
first side with postoperative second side results. Data are given as mean
± SD unless otherwise indicated.
RESULTS
Twenty-three patients completed the 3-month bilateral DBS evaluations;
however, 2 did not have adequate first side 3-month evaluations for comparison.
The mean age of the 13 patients with ET who completed all data points was
71.5 ± 4.9 years, and the mean age of the 8 patients with PD was 71.4
± 6.1 years. All patients with ET chose to initially implant the side
that would improve their dominant hand. Of the 8 patients with PD, 6 elected
to initially improve their dominant side.
PATIENTS WITH ET
After the initial implantation, visual assessments of tremor contralateral
to the implantation site improved significantly (Table 1). Contralateral pouring and writing scores also improved.
There were no significant (P = .22) changes in any
midline tremor assessments or measurements ipsilateral to the implantation
site. All subjective measures of functional improvement also significantly
improved in patients with ET after the first implantation. Patients rated
themselves as "markedly improved" (n = 10), "moderately improved" (n = 2),
and "mildly improved" (n = 1). No patient believed that there was any worsening.
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Table 1. Thalamic DBS in 11 Patients With ET: Open Triala
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After implanting the second side, tremor measures contralateral to that
side significantly improved, mostly without significantly changing those referable
to the initial implantation. Writing scores contralateral to the initial side
(dominant hand in all cases), however, did worsen after the second side implantation,
but were still better than at baseline (Table 1). In 9 patients with ET, head tremor significantly improved
only after the second implantation. Functional scores and disability scores
tended to further improve after the second placement, but were not statistically
different from those after the first implantation. When compared with their
first implantation, patients rated themselves as markedly improved (n = 7),
moderately improved (n = 4), mildly improved (n = 1), and "no change" (n =
1) after the second implantation. Mini-Mental State Examination scores did
not change during the study: baseline, 27.8 ± 1.1; 3-month first side
implantation, 28.5 ± 1.0; and 3-month second side implantation, 28.7
± 1.4.
The blinded motor examination results closely resembled those of the
unblinded data (Table 2). At baseline,
the 2 groups were similar except that the off stimulation randomized group
showed less leg tremor. In patients with ET randomized to on stimulation,
the arm tremor (n = 12 arms) and leg tremor (n = 12 legs) ratings improved,
whereas patients randomized to off stimulation (n = 10 for arms and legs)
showed no improvement.
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Table 2. Three-Month Second Side Randomized, Blinded Assessments in
Patients With ET*
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PATIENTS WITH PD
After the first implantation, total visual assessments of contralateral
tremor significantly improved (Table 3).
Subjective disability scores and total UPDRS part 2 subjective scores also
improved. Patients rated themselves as markedly improved (n = 5), moderately
improved (n = 2), and no change (n = 1). None of the patients believed that
their tremor worsened.
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Table 3. Thalamic DBS in 8 Patients With PD: Open Triala
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After the second side implantation, total visual assessment of tremor
contralateral to that side significantly improved (P
= .01), without significantly affecting the first side tremor scores (Table 3). The 6 patients with PD who had
facial tremor also improved only after the second implantation. Functional
scores, however, were no longer significantly improved compared with the preoperative
baseline status, although there was no significant worsening of functional
scores between the 3-month first and the 3-month second side assessments.
Nevertheless, after the second procedure, patients rated themselves as markedly
improved (n = 3), moderately improved (n = 2), mildly improved (n = 1), no
change (n = 1), and "mildly worse" (n = 1). Mini-Mental State Examination
scores did not change during the study: baseline, 27.0 ± 2.0; 3-month
first side implantation, 27.3 ± 1.9; and 3-month second side implantation,
27.5 ± 2.5.
The blinded PD scores closely resembled unblinded scores. Unfortunately,
only 2 patients were randomized to "on" status, so no meaningful analysis
could be performed (Table 4).
In patients with PD randomized to on stimulation (n = 4 arms), the blinded
arm tremor scores improved from 9.3 ± 0.9 to 1.0 ± 0.5, whereas
patient arms randomized to off stimulation (n = 12) showed no change from
their preoperative scores (Table 4).
Concurrent adjustment of bilateral devices was generally more arduous than
that of a single device. In almost all cases, the first side implantation
required readjustment. There was, however, no clear pattern, as settings were
increased in some and decreased in others, resulting in no overall difference
(Table 5). There were also no
differences between settings for PD and ET.
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Table 4. Three-Month Second Side Randomized, Blinded Assessments in
Patients With PD*
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Table 5. Adverse Events and Device Variables*
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Adverse events were usually mild to moderate, but tended to occur more
frequently in patients with ET (12 of 13 or 92%) than in patients with PD
(4 of 8 or 50%), and more frequently in those with bilateral compared with
(16 of 21 or 76%) unilateral placement (11 of 21 or 52%) (Table 5). The most problematic stimulation-related AEs were gait
disorders and dysarthria. There were no serious perioperative AEs.
COMMENT
Our results show that unilateral and bilateral ventral intermediate
nucleus DBS procedures are safe and effective treatments for ET and the tremor
of PD. The addition of a second side DBS significantly improved tremor measures
contralateral to that placement without meaningfully affecting tremor contralateral
to the first side DBS by most measures in patients with ET and PD. Midline
tremors, such as head and voice, also improved only after the second implantation.
Subjectively, patients with ET robustly improved after the second implantation,
whereas PD global impressions improved less and activity of daily living scores
actually tended to worsen.
The most common AEs included dysarthria, gait or disequilibrium problems,
and paresthesias, and were more problematic after bilateral implantation in
both groups. The gait or disequilibrium problems were phenotypically varied
but most resembled unsteadiness. Only one patient (a patient with PD) actually
reported the onset of falls after implantation. Adverse events were more frequent
in patients with ET; however, when they occurred, dysarthria and gait problems
tended to be more significant in patients with PD. Overall, patients with
ET had fairly consistent but mild problems that usually responded well to
adjustments, whereas the AEs in patients with PD were inconsistent but more
frequently compromised the benefits of DBS. Compared with other reports of
thalamic stimulation, our patients tended to experience more gait difficulty
but less paresthesia and dystonia. This could reflect differences in patient
selection, differences in placement of the electrodes, or programming tendencies.
The lack of functional improvement seen after the second placement in
patients with PD, as determined by UPDRS part 2, despite clear improvement
in tremor, probably results from the fact that the dominant hand was already
improved from the first placement in most cases. Furthermore, part 2 of the
UPDRS is not weighted to assess disability directly resulting from tremor,
and many of the functional assessments only require one hand. The improved
global assessment after second implantation despite lack of part 2 UPDRS improvement
also highlights the fact that tremor is the major concern for most patients
with PD.18 This contrasts to the view of most
physicians who believe that bradykinesia causes the most disability.
Several other factors could also explain the relative lack of subjective
improvement in PD following the second implantation. First, although the results
showed robust second side improvement, we were not always able to maximize
bilateral tremor improvement without incurring intolerable AEs, usually balance
problems. Second, gait and bulbar AEs, seen mostly with bilateral implantations,
increased overall disability in patients with PD. Finally, disease progression
in tremor and other aspects of PD between surgical procedures could have negated
some observable functional improvement with second side placement. Although
we did not believe that there was meaningful disease progression between surgical
procedures in most cases, 2 patients with PD waited more than 12 months before
their second implantation, which may have lessened their apparent improvement.
Our results are generally similar to those of others who have assessed
bilateral thalamic DBS. Pahwa et al,15 in the
only other report comparing bilateral with unilateral placement in the same
patients, reported that 9 patients with ET had significant improvement in
tremor examination and activity of daily living scores after bilateral DBS.
Results tended to be better than those after the first procedure and were
maintained for 1 year. Taha et al16 reported
midline tremor improvement after bilateral placement but did not compare this
with unilateral placement. The increase in AEs after the second implantation,
especially balance and bulbar problems, also appears to be a consistent finding,
although less than that seen with bilateral thalamotomies.19, 20, 21
We included only those patients with PD in whom tremor was the main
cause of disability. These patients tended to have relatively little bradykinesia
and rigidity. We would not, therefore, advocate thalamic DBS in patients with
PD in whom tremor was a minor contributor to overall disability. In contrast
to ventral intermediate nucleus DBS, subthalamic DBS improves all the cardinal
manifestations of PD.22, 23 The
extent of tremor suppression has been less thoroughly evaluated; however,
if it improves tremor as much as ventral intermediate nucleus DBS, then subthalamic
DBS should be considered even for tremor-dominant PD. Disadvantages of subthalamic
DBS include its greater technical requirements, its more complex device programming,
and the lack of Food and Drug Administration approval for the procedure in
the United States.
Weaknesses of our study include the relatively small sample size, the
short period of evaluation, and the intrinsic inability to control for disease
progression. All patients were given the choice of whether to undertake the
second procedure; therefore, our group of patients who chose the second procedure
are biased toward more severe cases. Nevertheless, our results provide further
support for the use of unilateral and bilateral ventral intermediate nucleus
DBS in patients with ET and in selected patients with tremor-dominant PD who
are refractory to medications.
AUTHOR INFORMATION
Accepted for publication June 23, 2000.
This study was supported in part by grants from Medtronic Inc, Minneapolis,
Minn; by the Methodist Hospital, Houston, Tex; and by the National Parkinson
Foundation, Miami, Fla.
From the Departments of Neurology (Drs Ondo and Jankovic and Mr Almaguer)
and Neurosurgery (Dr Simpson), Baylor College of Medicine, Houston, Tex.
Corresponding author and reprints: William Ondo, MD, Department of
Neurology, Baylor College of Medicine, 6550 Fannin Dr, Suite 1801, Houston,
TX 77030 (e-mail: wondo{at}bcm.tmc.edu).
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